Confined space catalysis

Chemists have synthesised many molecular cages in order to mimic the pocket of enzymes. Those confined catalysts can be of many different chemical natures and present a broad palette of features. A quick survey including self-assembled cages, U-shaped catalysts, cucurbiturils, calixarenes, cyclodextrins, and hemicryptophanes will be presented.

A. Self-Assembled Cages Self-assembled molecular cages are based on the combination of transition metals with appropriate ligands to induce the formation of discrete containers that are able to host substrates and/or catalysts. The choice of the metal and the ligand is crucial to avoid the formation of polymers and to get the desired shape for the assembly. [9], [10] Early examples of molecular assemblies were reported by Makoto Fujita and his team. They reported in 1995 the formation of a polycationic, octahedron-shaped, molecular cage 1 composed of palladium(II) and 2,4,6-tri(pyridin-4-yl)-1,3,5-triazine units (Scheme I-1 A)). [11] This cage was used to form selective inclusion complexes with two olefins, quinone 2 and acenaphtylene 3 to induce the cross-photodimerization of the olefins. [12] Here, the keyfeature of the cage relied on its specificity to host two different guests (Scheme I-1 B)). The specific formation of this inclusion complex, induced, after photo-irradiation, the selective formation of the cross-coupling product 4-OEt that was not formed in the absence of the cage.

By changing the 5-ethoxy group on the quinone for a methoxy or a simple proton, photoirradiation of the inclusion complexes gave rise to the formation of homo-dimerization products. This result showed that the exclusive formation of 4-OEt was controlled by steric restrictions within the cavity and the ability of the cage to selectively host two different guests.

Scheme I-8. Simplified mechanism of CB[6] catalysed azide-alkyne cycloaddition. CB[n] have also been employed as mimics of Diels-Alderase enzymes. [38] The authors used CB [7] to catalyse the cyclization of N-allyl-2-furfuryl-amines (Scheme I-9).

First of all, I would like to thank Pr. Olivia Reinaud and Pr. Gerhard Erker for taking the time to review this manuscript. I also would like to thank Dr. Emmanuelle Schultz, Pr.

Louis Fensterbank and Dr. Thibault Cantat for taking part of this PhD defense jury.

Evidemment, je tiens à remercier Matthieu pour m'avoir donné l'opportunité d'effectuer cette thèse dans un cadre remarquable et pour la confiance que tu m'as apportée en me confiant ce sujet plein de défis.

Je tiens également à remercier Thibault Cantat, Lucile Anthore-Dalion et Emmanuel Nicolas pour leur aide lors de mes venues au lointain CEA.

Il va sans dire que je remercie tous les membres de l'équipe GOBS. Tout d'abord les membres permanents, Mickaël, Sylvain, Berni, Guillaume et Yongmin. Merci pour les questions « pièges » en group meeting et pour nos discussions autour de la sacro-sainte machine à café qui ont mené à plus de réflexions sur le sujet.

Viennent ensuite les doctorantes et doctorants que j'ai eu la chance d'avoir pu côtoyer durant ma thèse. Tout d'abord ceux qui sont partis vers de nouvelles aventures. Jorge, merci pour ton aide lors de mon arrivée dans l'équipe que ce soit pour la chimie ou bien pour mon intégration. Hugo, navré de t'avoir battu lors des pronos de la CDM 2018, à charge de revanche cette année ! Léonid, спасибо большое. Je tiens également à remercier Zhonghang, Zhihao et Changping.

Je remercie également celles et ceux qui sont encore présents. Enxu, courage pour les rotaxanes, tu vas y arriver (au pire, on pourra toujours mettre de la β-CD dans des boissons anisées) ! I also would like to thank Haipeng, thank you for always being in a good mood and for the Chinese lessons, 谢谢 ! I also would like to thank Jinge, Fang, Thanaphon, Yupeng and Jiaxu, good luck for the next few years. Je tiens aussi à remercier Laora, j'espère que ton sel légendaire pourra un peu se diluer pendant ces trois ans. Hugo, je te laisse avec plaisir la charge de 99% de l'humour du labo, j'espère que le carnet se remplira bien vite.

Clara, bon courage pour la reprise du sujet de Flo. Pablo à qui j'en veux un tout petit peu d'avoir rendu la playlist du labo un peu plus potable. N'oublions pas les personnes « de passage » mais qui m'ont apporté beaucoup, Nihal, Louise et Maxime tout d'abord, Geoffrey ensuite, j'espère que le traumatisme musical va passer, je suis (à peine) désolé d'être en partie la cause de ton aversion pour Wejdene.

Je tiens tout particulièrement à remercier celles et ceux que j'ai côtoyé chaque jour.

Le labo 511, merci Jiang, merci Sawsen, de m'avoir accueilli lors de mon arrivée et pour tous les bons moments passés ensemble. Je remercie tout particulièrement Flo, ma grandesoeur de thèse. Il me faudrait un quatrième chapitre pour te remercier correctement, je n'aurais pas pu rêver mieux comme acolyte de thèse. Et dire que tout ça a débuté à cause d'un bouchon en verre grippé (et de Johnny, Céline, Benoit, Félicien…). Evidemment vient ensuite le sang de la veine, Rebecca. Merci pour tout pour cette dernière année, ce fut un immense plaisir de partager ce beau labo 509 avec toi. J'ai hâte de revenir maniper histoire de redonner ses lettres de noblesses à pera de non qualité.

Je tiens aussi à remercier le Bijouard sub-group autrement dit les stagiaires que j'ai eu la chance d'encadrer, Kouceila, merci énormément pour ton travail, Till, merci pour ta motivation sans faille et Carlota, merci pour ton débordement d'énergie.

Une thèse ne se faisant pas cloitré dans son équipe, je me dois de remercier toutes celles et ceux qui m'ont aidé, de près ou de loin, à la réaliser, Virginie, Claire, Aurélie, Régina (on l'aura ce signal 11 B !), Omar, Sylvie, Lise-Marie, Christel et bien entendu les thésardes et thésards avec lesquels j'ai eu la chance de réaliser ma thèse, Dylan, Mehdi (malgré le fait que tu sois cachanais), Laura, Thomas, Cassandre, Quentin, Dorian, Océane, Ahmad, Richard, Gredy, Ruben, Aurélie et de manière générale tous les membres de l'IPCM. Je tiens aussi à remercier les personnes que j'ai pu croiser au CEA, pour leur aide avec les BAG et autres simples ou doubles rampes que j'ai découvert derrière ces grilles si bien gardées, Clément tout d'abord, Gabriel, Martin, Marie, Kieu, Marie-Hélène, Marianne et Etienne.

Je souhaite également remercier mes proches depuis tant d'années, sans votre soutien je n'aurais pas pu arriver où j'en suis aujourd'hui. Les cochons (ça fait déjà plus de 10 ans !), Alexandre, Quentin, Louis, Johan, Salman, Tom, Maxence et Sophie. Les potes de la résidence et associés, Lotti, Sonja, Sabi, Yacine, Marika, Emilienne, Ashraf, Bettina, Franck, Camille, Jazia, Nolwenn, Julien et Julia. Une petite phrase à part pour remercier Mélissa, notamment pour sa relecture de l'anglais et ses idées de mots de liaisons de qualité. Les potes de P7, Fabien, Jean-Paul, Aymeric et Martin. Finalement je tiens à remercier Solène, Amaury et Gabrielle.

Je souhaite terminer cette partie plus « libre » par l'illustration que j'ai utilisée pour le concours Ma thèse en 180 secondes (que je ne peux que conseiller à toutes et à tous !).

Merci encore Louis pour cette superbe illustration. Chapter I. Introduction

The Concept of Catalysis

Lowering the carbon footprint of the chemical industry and imagining new atomeconomical reactions are major challenges chemists are facing today. Catalysts, species that increase reactions rates by lowering their activation barrier without being consumed or produced, have been used extensively for many years for this purpose.

Historically, the first reported use of catalysis by mankind was in 6,000 B.C. by the Sumerians in Mesopotamia for the alcoholic fermentation of sugars by enzymes. [1] During the ages, many renown chemists (Antoine-Augustin Parmentier, Calm Wilhelm Scheel, Joseph Priestley, Constantin Kirchhoff…) encountered catalysed reactions without theorising the concept. [2] In the late 18 th century, Elizabeth Fulhame, a Scottish chemist working on heavy-metal dyeing of clothes demonstrated that water is required for many oxidation reactions and that water is regenerated at the end of the reactions. [3], [4] Elizabeth Fulhame was the first chemist to extensively study the catalysis of one class of reactions and even proposed mechanisms that were way ahead of her time. However, it is Jöns Jacob Berzelius who theorised the concept and employed the term catalysis (from ancient Greek κατάλυσις, kata-down and luein-loosen, to untie) for the first time in 1835 to describe reactions that are accelerated by substances that remain unchanged at the end of the reaction. [5] From this day, catalytic reactions have been broadly studied and many of them remain iconic and were awarded the Nobel Prize: the Haber-Bosch process, the Sharpless epoxidation, the Schrock's and Grubb's metathesis, the Heck, Negishi and Suzuki-Miyaura palladium-catalysed couplings and this year's Nobel Prize has been awarded for the development of asymmetric organocatalysis to Benjamin List and David MacMillan.

Despite chemists' efforts in obtaining more efficient, more selective and "greener" catalysts, it is undeniable that Nature has got a head-start of a few billion years. Life's chemical factories are catalysts called enzymes. 1 They are believed to have appeared billion years ago concurrently with DNA. Enzymes catalyse more than 5,000 reactions from oxydations to izomerizations, [6] are highly substrate-selective, efficient and perform regioand/or enantioselective reactions in water. The reactions take place in the active site of the protein which represents only 10 to 20% of the volume of the enzyme. Those pockets, formed by the folding of the protein, induce the phenomal selectivities seen in enzymatic catalysis.

The confinement of the active site induces a preferential orientation of the reactant due to interactions with the pocket, leading to those great regio-and/or enantioselectivities.

Chemists have been trying to use or mimic these powerful catalysts by using two main strategies.

Frances Arnold, recipient of the 2018 Nobel Prize, used directed evolution of enzymes to form new catalysts. Inducing mutagenesis and screening the newly formed enzymes, she, for example, managed with her team to make enzymes catalyse cyclopropanation reactions via carbene transfer and nitrene transfers that do not occur naturally. [7], [8] The other strategy relies on the synthesis and/or the functionalisation of molecules in which catalysis occurs inside a cavity or a molecular assembly. The following part of this introduction will present such systems.

Introduction of catalysts inside self-assembled cages can be done by covalent attachment of the catalyst [13] or by encapsulating catalysts by hydrophobic effect. [14], [15] Covalent attachment usually involves long synthetic routes to get the right ligand whereas encapsulation requires the need to find the right capsule for the right catalyst while letting enough space for substrate co-encapsulation.

Another way involves the functionalisation of the ligand with binding motifs for both the catalyst and the substrate. This strategy has been used by Joost Reek and his team for the formation of self-assembled nanospheres presenting guanidinium units pointing inside the capsule 5 (Scheme I-2 A) & B)). [16] The presence of those guanidinium units allowed the binding of a gold complex (TPPMSAu + ) bearing a sulfonate moiety 8 for the catalysis of the cyclization of acetylenic acid 6. Whilst the gold catalyst was strongly binded inside the sphere, the deprotonation of acetylenic acid 6 triggered the encapsulation of its conjugated base 7 which also interacted with a guanidinium unit (Scheme I-2 C)). The pre-organization of the gold catalyst and the acetylenate substrate induced a kinetic template effect for the cyclization reaction that led to a conversion of 6 above 95% with a TOF (Turnover frequency) of 5.75 h -1 .

This template effect has been proven by a series of control experiments. Using only the gold catalyst 8 led to a 44% conversion (TOF = 0.45 h -1 ) whereas the use of the gold catalyst 8

with Et3N led to a conversion of 19% (TOF = 0.19 h -1 ).

Finally, after completion of the cyclization, the uncharged produced enol lactone 9 had no longer any affinity for the binding sites and thereby escaped the nanosphere, avoiding product-inhibition of the catalyst. Chemists are also working on mimicking a key feature of enzymes: the allosteric effect. For an allosteric protein, the fixation of a guest induces a conformational change of the protein and increases or decreases its affinity for another guest. [17] Quing-Fu Sun and his team have synthesised a guest-adaptative self-assembled cage. [18] Without any guest, the cage took the form of a capsule (10). The presence of a guest induced a change in conformation to resemble a bowl (11) with the guest sitting in the bowl (Scheme I-3 A)). This system was shown to be effective for the binding of sulfides and for mimicking photooxidases. Here, sulfides were oxidized to sulfoxides by reactive oxygen species (O2 •-) under light irradiation (450 nm). The authors believe that the transformation of capsule 10 into bowl 11 (from the binding of the guest) gave rise to new π-π stacking interactions between the bowl and the sulphide 12. Those interactions enhanced visible-light absorption and promoted the photooxidation of the sulfide through the formation of the superoxide ion.

Finally, the formed sulfoxide 13 (in 85 to 98% conversion) was easily replaced in the capsule/bowl system due to its enhanced hydrophilicity and its reduced shape complementarity for the capsule (Scheme I-3 B)). Additional studies performed by the authors showed that poor conversions (6 to 37%) were obtained when a rigid capsule, that did not undergo conformational change, was used.

This example shows an ingenious way of using molecular capsules to mimic nature. Taking inspiration from allosteric proteins, the authors clearly showed that their molecular assembly's ability to change shapes allows the catalytic activity for the sulfide oxidation. In summary, self-assembled cages have imposed themselves as elegant structures for performing confined space catalysis. They can be synthesised in a few steps, present many different shapes and catalyse a variety of reactions. Many examples were brought by many renown groups such as Dean Toste's or Julius Rebek's. However, the versatility of one cage to catalyse different reactions is rather limited. On the opposite of massive self-assembled cages, confined space catalysis has also been performed using small flexible molecules.

B. U-Shaped catalysts

Among the broad palette of molecules used for confined space catalysis comes, the family of U-shaped molecules shows particularly interesting properties. Those molecules are not made from assemblies nor do they present a rigid macrocycle. U-shaped catalysts are relatively small molecules composed of a rigid platform, composing the bottom of the "U", linked to bulky and often planar moieties composing the sides providing the hindrance required to create the confined space (Figure I-1). [19] Figure I-1. Highlighted U-shape of (DHQ)2-PHAL ligand used in olefin dihydroxylation.

One of the earliest examples of small molecules presenting a molecular cavity was reported by Barry Sharpless in 1980 and 1992 for the enantioselective osmium-catalysed dihydroxylation of olefins. [20], [21] The U-shaped catalysts called "AD-mix" are composed of a hydroquinidine 1,4-phtalazinediyl diether ((DHQD)2PHAL) ligand (14 & 15) mixed with potassium osmate ([K2OsO2(OH)4]), can be prepared on a kilogram scale and are commercially available (costing about 4 €/g).

The chiral quinine ligand being available in its two enantiomeric forms, two enantiomeric catalysts were synthesised. The ligand bearing the hydroquinidine moiety is called (DHQD)2-PHAL 14 and composes the AD-mix-β catalyst whereas the one bearing the hydroquinine moiety is called (DHQ)2-PHAL 15 and composes the AD-mix-α.

Those catalysts presented excellent enantioselectivities for the dihydroxylation of mono-, diand tri-substituted olefins and each catalyst gave one of the two possible enantiomers (Scheme I-4 A)). The catalytic loading could be lowered to 0.01 mol% and still gave a 96% enantiomeric excess (ee) for the dihydroxylation of stilbene.

The authors studied the conformation of the catalysts involved in this highly selective reaction by modulating all the parts of the catalyst (ring system, phtalazine platform…) and studying the new kinetics involved in the reaction. [22] Completed with NMR (Nuclear Magnetic Resonance) studies and molecular mechanics calculations, they concluded that the quinoline and the phtalazine moieties "set up a binding pocket" in which aromatic olefins can interact by π-stacking and edge-to-face interactions, stabilising transition states thus explaining the obtained high rates and enantioselectivities (Scheme I-4 B)). Concerning aliphatic olefins, the authors believe the compounds are forced in the pocket by van der Waals and solvophobic effects.

Scheme I-4. A) Osmium catalysed enantioselective dihydroxylation of olefins developed by Barry Sharpless B)

Representation of the U-shape catalyst with styrene in its core.

More recently, Kazuaki Ishihara and his team have developed chiral supramolecular U-shaped Lewis acids for the catalysis of Diels-Alder reactions. [23] Those catalysts were formed from a BINOL unit bearing amide functions, an arylboronic acid and tris(pentafluorophenyl)borane (BCF) (Figure I-2). The Lewis adduct formed between the amide and BCF played a significant role in the design of those catalysts. The two BCF units acted as bulky groups forming a chiral cavity around the central Lewis acidic boron. Moreover, the use of electron-accepting BCF enhanced the Lewis acidity of the catalyst. The authors used catalyst 16 to catalyse Diels-Alder reactions of propargyl aldehydes (Scheme I-5 A)). [24] After optimization by tuning the amide and arylboronic moieties, the Diels-Alder reaction between cyclopentadiene 17 and propiolaldehyde 18 gave the exoproduct 19 in 95% yield with an excellent ee of 90% and only 4% of products coming from a second Diels-Alder reaction. This selectivity is believed to come from the specific U-shape of the catalyst. First, the propiolaldehyde 18 coordinates to the central boron atom then, cyclopendatiene 17 can approach in two different ways. The endo-approach is disfavoured by steric hindrance coming from the BCF units whereas the exo-approach doesn't suffer such constraints. Once the Diels-Alder reaction occurs, another diene cannot enter the chiral cavity and react due, once again, to steric hindrance, giving almost exclusively the endoproduct 19 without over-reaction (Scheme I-5 B)). This method was extended to reactions with 5-alkyl-substituted cyclopentadiene, cyclohexadienes and cyclohexadiene-derived triene and tetraene still with great endo-and enantioselectivities.

Scheme I-5. A) Diels-Alder catalysed by the U-shaped catalyst developed by Kazuaki Ishihara B) Proposed explanation for the selectivity through the confined space.

Amidst small molecules forming cavities, Benjamin List and his team developed imidodiphosphorimidates (IDPi) Brønsted-Lowry catalysts. [25] Those catalysts arose from the combination of disulfonimides, presenting high activities but low stereoselectivities in and giving high stereoselectivities thanks to the presence of the BINOL units. The properties of those catalysts can be modulated by changing the groups on the BINOL units and the ones on the sulfones. This gave rise to a range of new catalysts with pKa values as low as ≤ 2 in MeCN managing to catalyse many reactions such as the asymmetric synthesis of unprotected β 2 -amino acids, [26] deprotosilylation of ketones, [27] asymmetric Diels-Alder reactions of cyclohexadienones [28] and asymmetric Mukaiyama aldolizations. [29] The BINOL derivative units combined with the bulky aromatic groups allow the formation of an artificial cavity, narrower than a U-shaped catalyst, presenting the reactive centre in the middle (Figure I-3 B)).

Figure I-3. A) Structure of disulfonimide, imidodiphosphate and imidodiphosphorimidate catalysts B) Highlighted cavity

formed by an IDPi (crystallographic structure). [30] In the following example, IDPi 20 bearing perfluorinated naphthalene units on the sulfone and biaryl units decorated with alkyl groups on the BINOL moiety allowed the asymmetric intramolecular hydroarylations of unactivated olefins with indoles (Scheme I-6 A)). [31] After screening different catalysts, IDPi 20 allowed the formations of different tetrahydrocarbazoles bearing alkyls chains, aromatic moieties and even allowed the presence of iodine on the alkyl chain. Concerning the electronic tuning of the aromatic moiety, the reactions tolerated the presence of electron-donating groups (methoxy and benzoxy) and electron-withdrawing groups (bromo, chloro and fluoro). The reactions all gave excellent yields (up to 97%) and enantioselectivities (up to 98:2).

In this reaction, the Brønsted-Lowry acidic IDPi 20 first protonates the olefin kept in the cavity by hydrogen-binding. The indole then performs a nucleophilic addition on the carbocation and the asymmetric counter-anion directs this attack leading to the enantioselectivity. Finally, a rapid stereoretentive migration of the alkyl moiety liberates the tetrahydrocarbazole and restores the catalyst (Scheme I-6 B)).

The authors speculate that the high tolerance in functional groups comes from confinement effects in which the transition state is encapsulated within the IDPi's cavity but in which the olefin substituent is outside the cavity thus not interfering with the reaction. The authors conclude that their catalyst is on the edge of small molecule catalysis, considering the size of the IDPi, and macromolecular catalysis since IDPi present a cavity acting like an active site.

Scheme I-6. A) IDPi catalysed intramolecular hydroarylations of unactivated olefins B) Partial proposed mechanism for the reaction within the confined space.

In conclusion, U-Shape catalysts present an interesting way of forming confined spaces while using small molecules by taking profit of sterically hindering groups. The formation of IDPi allowed the enantioselective catalysis of many reactions thanks to their high Brønsted-Lowry and Lewis acidities and sterically hindering BINOL groups. Among the most studied confined space catalysts comes the family of rigid, covalent cages presenting many different members.

C. Cucurbituril Cucurbit[n]urils (CB[n]

) are pumpkin-shaped macromolecules formed of n glucoluril units (n ∈ [5,11]) synthesised from the condensation reaction of glycoluril and formaldehyde. [32] Cucurbit [6]uril was first synthesised in 1905 by Robert Behrend (Scheme I-7). [33] However, its structure has only been elucidated in 1981 by William Mock. [34] CB [n] present hydrophobic cavities, allowing the binding of non-polar guests, whereas the polar urea-units composing the rims, called portals, allow to bind ions. [32] Concerning their uses on a supramolecular level, CB[n] have been, for example, immobilized on silica for HPLC alkaloid separation. [35] Scheme I-7. Synthesis of CB [6] developed by Robert Behrend in 1905.

Concerning catalysis, CB [n] have been extensively used to catalyse azide-alkyne cycloaddition (AAC) reactions (Scheme I-8). The portals, allowing the binding of the alkylammonium ions, preorganized the reactants thus accelerated the AAC reactions. CB [6] catalysed AAC reactions have been used for the synthesis of pseudo-/poly-/rotaxanes and allowed protein-peptide and protein-DNA conjugations. [36], [37] Here again, the preoganization of the reactant by the hydrophobic cavity and electrostatic interaction between the ammonium, formed thanks to a phosphate buffer saline solution (PBS), and the urea units catalysed the reaction. 50% conversion was achieved in 1.2 h with one equivalent of CB [7] whereas without any catalyst, the same conversion was achieved in 600 h.

Scheme I-9. Simplified mechanism of CB [7] catalysed Diels-Alder cyclization.

To sum up, CB [n] have been employed in a few catalysed reactions. Their functionalization is pretty limited and their poor solubility in usual solvents make them rarely used in confined space catalysis.

D. Calixarenes

Calix [n]arenes are a class of macromolecules formed by the condensation of n parasubstituted phenols with formaldehyde (n ∈ [4,8] for the most common ones). Their name comes from their shape resembling ancient Greek mixing bowls called Calyx Krater (Figure

I-4 B)
). [9] Each phenol unit being able to flip, several conformations are possible for calix[n]arenes. However, in a cone conformation, calix [n]arenes are composed of an upper, larger, rim generally composed of alkyl groups, a central hydrophobic annular system composed of aromatic rings and a lower, smaller, rim composed of alcohol functions (Figure

I-4 A)
). [39] Calix [n]arenes are able to coordinate cations [40], [41] with their lower rim and form coordination complexes with molecules of biological interest such as anti-cancer agents. [42], [39] Functionalisation of calix[n]arenes has been well studied and many molecules bearing a variety of chemical moieties arose (carboxylates, [43] phosphates, [44] squaramides, [45] bridged by a salen [46] ). Olivia Reinaud and her team showed that calix [6]arenes can be modified to present three nitrogen ligands on the lower rim to mimick the tris-histidine pocket of a metalloenzyme. Those functionalised calix [6]arenes can coordinate metal ions such as Zn II , [47] Cu II [48] and Cu I . [49] Those "funnel complexes" are able to encapsulate neutral guests within their cavities in the manner of enzymes. The calix [6]arene 21 presenting alternatively a methyl and a picolyl moiety on the lower rim can be used as a ligand for Cu II . [48] This complex has been shown to be active in the oxidation of ethanol and benzene in presence of H2O2 (Scheme I-10). Here, the copper ion is surrounded by the pyridine groups and a water molecule. Hence, the hydroperoxo adduct speculated to be responsible for the oxidation reactions can only be formed inside the cavity of the calix [6]arene. Thus, the reaction can only take place within the confined space. In this reaction, ethanol is oxidised to formaldehyde and formic acid in a 57:43 ratio. Benzene is oxidized to phenol and pbenzoquinone in a 24:76 ratio. However, only traces of hydroquinone were observed and no catechol or o-benzoquinone were obtained implying a certain chemo-and regioselectivity for the reaction.

Scheme I-10. Oxidation of ethanol and benzene catalysed by a Cu II -calix [6]arene.

Xiao-Quiang Sun and collaborators synthesised the calixarene 22 bearing a L-proline moiety on the lower rim of a calix [4]arene. [50] This molecule is water-soluble and has been shown to be active in the aldol reaction between functionalised benzaldehydes and cyclic ketones (Scheme I-11 A)). Here, the functionalised calix [4]arene 22 allowed the obtention of aldols with great anti/syn selectivities (up to 97:3) and excellent ees up to >99% with pentanone and hexanone. The authors believe that the presence of the carboxylic acid of the proline forming hydrogen bonds with water allows the formation of a hydrophobic region from the proline unit to the bottom of the calix [4]arene, thus creating a microreactor for the reaction (Scheme I- 11 B)). This in situ formed hydrophobic region is believed to explain the activity and the selectivities obtained with the catalyst. According to the proline-catalysed aldol reaction mechanism, the reaction goes through the formation of an enamine between the proline and the ketone. [51] The authors believe that the enamine is encapsulated within the calix [4]arene explaining the obtained high dia-and enantioselectivities (Scheme I-8 C)).

This supposition is supported by the low yields (28%) and selectivies (anti/syn: 45:55, syn:

17% ee) obtained using cycloheptanone for which the corresponding enamine is believed to be too big to enter the cavity.

Scheme I-11. A) Asymmetric aldol reaction catalysed by a proline-functionalised calix[4]arene B) Postulated formed hydrophobic region C) Postulated enamine intermediate.

In conclusion for this part, calixarenes were broadly used for studying the effect of metal confinement in a cavity and these complexes were even shown to be active in catalysis.

The possibility of functionalising calixarenes enabled their use in numerous catalysis

examples and among them many organocatalysed reactions.

E. Cyclodextrins

Cyclodextrins (CDs) are cyclic oligosaccharides composed of glucopyranose units.

The most common CDs are composed of 6, 7 and 8 glucopyranose units and are called α-, β-and γ-CD respectively. [9] In their native state they are hydrosoluble and present a hydrophobic cavity. CDs, thanks to their cavity, are being used in medicinal chemistry for drug delivery, [52] in chiral HPLC [53] or in food industry. [54] α-CD have also been used in one of the first examples of supramolecular catalysis.

In 1969, Ronald Breslow and Peter Campbell used α-CD to selectively chlorinate anisole (Scheme I-12 A)). [55] The reaction took place in water, in the presence of hypochlorous acid.

As anisole was encapsulated in the hydrophobic cavity of the CD, only its para-position was not hindered by the CD and therefore was chlorinated (Scheme I-12 B)). The authors showed that adding 0.09 equivalents of CD to the reaction enhanced the ortho/para selectivity from a 60:40 ratio to 77:23. This selectivity was even better when 0.9 equivalents of α-CD were used and reached a ratio of 96:4 in favour of the para-substituted chloroanisole.

Scheme I-12. Selective chlorination of anisole catalysed by an α-cyclodextrin.

Being easily functionalised, CDs have extensively been used as platforms for catalysis. Phosphine ligands were grafted to perform asymmetric Truji-Trost couplings [56] and they enabled selective rhodium-catalysed hydroformylations of olefins. [57], [58] Lavina Marinescu and Mikael Bols showed that bridging α-and β-CDs with a ketone (similar to 1,3-diacetoxyacetone) allowed their uses as oxidase mimics. [59] Those CDs, in presence of hydrogen peroxide in water catalysed the oxidation of benzylic alcohols to aldehydes following Michaelis-Menten kinetics. After addition of hydrogen peroxide to the ketone, benzylic alcohol gets encapsulated inside the cavity of the CD, in the fashion of enzyme active sites, and gets oxidized, reforming the ketone-CD-catalyst (Scheme I-13).

The α-CD-catalysed reaction occurred 1,690 times faster than the uncatalysed reaction whereas 1,3-diacetoxyacetone only improved the kinetics by 9.8-fold. form metal complexes with coinage metals (Cu, Ag, Au). [60] Those complexes present the particularity of having the reactive centre confined within the cavity of the CD. Those complexes are active toward catalysis and the (β-ICyD)Au I complex can catalyse the alkoxycyclization reaction of enynes while being substrate-and enantio-selective (Scheme I-14 A)). [61] In this example, the (β-ICyD)AuCl complex 23 first reacted with silver hexafluoroantimonate to form the active (β-ICyD)Au I specie. Following classical gold reactivity, the enyne formed an intermediate (26) with the complex that could react following two pathways. If a nucleophile is present in the media, the intermediate undergoes the alkoxycyclization reaction. However, in the absence of a nucleophile, the intermediate undergoes a rearrangement to form a diene. Here, the cavity of the CD selected the nucleophile according to its size (Scheme I-14 B)). The authors showed that isopropanol, because of its size, reacted slowly with the intermediate 26 thus letting it enough time to rearrange, giving a 77% yield for the rearrangement product 24. On the contraty, methanol, which is much smaller, entered the cavity without any trouble and performed the alkoxycyclization reaction to give 25 in 57% yield. The authors didn't observe the formation of the rearrangement product when methanol was used as nucleophile.

The other feature of CDs for this reaction came from the deformation of the cavity induced by the bridging by the NHC. [60], [62] The cavity being deformed, a chiral environment was created and the alkoxycyclization reaction became enantioselective showing great enantiomeric ratios up to 97:3. To sum up, being easily obtained from starch, CDs have been broadly studied for confined space catalysis. Native CDs were shown to induce regioselectivities and their simple functionalisation allowed the obtention of new ligands. ICyD ligands allowed the obtention of complexes presenting deeply buried metal ions. These complexes allowed the obtention of several regio-and enantioselective reactions thanks to the cavity of CDs.

As CDs are in the core of this PhD thesis, they will be presented more thoroughly later in this chapter.

F. Hemicryptophanes

Hemicryptophanes are molecular cages derived from cryptophanes first synthesised by Jacqueline Gabard and André Collet in the 1980s. [63] Both molecules present a cyclotribenzylene (CTB) unit which is then linked to another CTB unit for cryptophanes or another moiety for hemicryptophanes (Figure I-5). Those molecules are hemicarcerands meaning that guests can enter and exit the cage freely. Before the 2000s, the chemistry of hemicryptophanes was reduced to a few examples reported by Jean-Marie Lehn and André

Collet, [64] François Diederich and Luis Echegoyen [65] and Jean-Pierre Dutasta. [66] Today, hemicryptophanes are well studied and many, containing moieties such as a tren [67] or a benzenic platform, [68] and even chimeras with cyclodextrins [69] or calixarenes cores, [70] were synthesised. Hemicryptophanes can be used for recognition of ammoniums, zwitterions or sugar guests. [71] Figure I-5. Stuctures of cyclotriveratribenzylene, cryptophane A and an hemicryptophane bearing a tren platform.

Concerning catalysis, few catalysts derive from hemicryptophanes. Metalhemicryptophanes bearing metal active sites can be used to catalyse sulfoxide reductions (with V II ), [72] carbonate hydrolysis (with Zn II ), [73] alcohol oxidations (with Ru II ), [74] and cycloalkanes oxidation to alcohol (with Cu II ). [75] Alexandre Martinez and his team developed the synthesis of an encapsulated proazaphosphatrane. [76] Those bases, also called Verkade's bases, present high pKa in acetonitrile (pKa = 32.9) when they are not encapsulated. [77] The authors showed that the confinement of the base could enhance the basicity by a 30-fold. [78] Encapsulated proazaphosphatranes were used to catalyse Diels-Alder reactions and more recently the Morita-Baylis-Hillman (MBH) reaction. [79] The MBH reaction corresponds to the coupling of an aldehyde with an activated alkene and is catalysed by a Lewis base. The reaction's rate can be enhanced by the use of a Lewis acid to activate the electrophilic aldehyde. [80] Alexandre Martinez and his team used the encapsulated proazaphosphatrane 27 in presence of TiCl4 to catalyse the MBH reaction between substituted benzaldehydes and cyclopentenone (Scheme I-15).

The authors showed that the reaction gave poor yields without TiCl4. Moreover, the addition of the non-encapsulated base did not (or poorly) improve the reaction rate probably due to the formation of a Lewis adduct. However, the use of encapsulated proazaphosphatrane 27 in addition to TiCl4 improved the reaction rate up to 450% showing the necessity of the confinement.

After showing that the reaction did not occur with a bulky enone, the authors inhibited the The key feature of the reaction is the cavity impeding the formation of the Lewis adduct, between 27 and TiCl4, thus allowing a rate improvement for the catalysed MBH reaction.

By preventing this Lewis adduct formation, the authors showed that encapsulated catalysts can be used in a concept developed during the past 15 years called Frustrated Lewis Pairs (FLPs).

In conclusion for this part, many ways exist to perform confined-space catalysis.

Assembled molecular cages presenting large volumes can bring reactants together and encapsulate catalysts. However, encapsulating catalysts, through long synthetic pathways or fine tuning of the ligands, can be harsh.

Covalent cages can offer smaller volumes for catalysis and a variety of catalysts, may they be organometallic or organic. However, it is often difficult to truly encapsulate the catalyst within the confined space. One example for organometallic catalysis, by Matthieu Sollogoub and two for organocatalysts, by Kazuaki Ishihara and Benjamin List were here mentioned.

As shown with CDs, cavities can also serve to discriminate substrates by their size or prevent catalyst poisoning in the case described with hemicryptophanes. Those examples can serve as a proof-of-concept for new kinds of FLPs in which the usually used bulky groups can be replaced by cavities thus creating new Cavity Separated Lewis Pairs.

Frustrated Lewis Pairs

In 1923, Gilbert Lewis defined "a basic substance [as] one which has a lone pair of electrons which may be used to complete the stable group of another atom, and […] an acid substance [as] one which can employ a lone pair from another molecule". [81] In other terms, what we call today a Lewis base is a chemical specie that has a lone electron pair able to form a dative bond with a Lewis acid which is a chemical specie containing an empty orbital that can accept this electron pair. Usually, when a Lewis base is in presence of a Lewis acid, they interact with each other forming a Lewis adduct.

A. "Exceptions" to the Lewis rule and Frustrated Lewis Pairs

Soon after the definition given by Gilbert Lewis, chemists found "exceptions" to the Lewis rule. In 1942, Herbert Brown and Samuel Cardon described that trimethylborane and lutidine did not form a Lewis adduct as expected. They explained this exception through steric hindrance between the two Lewis partners (Scheme I-16 B)). [82] In 1950, Georg Wittig and Alfred Rückert reported that a tetrahydrofuran-triphenylborane complex did not form a

Lewis adduct with trityl anion but instead, the Lewis partners opened the THF ligand (Scheme I-16 C)). [83] In the same fashion, in 1959, Georg Wittig this time with Eberhard Benz showed that instead of forming a Lewis adduct, triphenylborane and triphenylphosphine formed a zwitterionic specie with benzyne (Scheme I-16 D)). [84] Scheme I-16. A) Formation of a Lewis adduct B) Lewis rule "exception" C) Lewis pair addition to THF D) Lewis pair addition to benzyne E) General scheme for FLPs

Those "exceptions to the Lewis rule" remained unexploited until 2006 when Douglas

Stephan with his team showed that the perfluorinated phosphine-borane 28 allowed a reversible heterolytic dihydrogen splitting, the Lewis base bearing the hydride and the Lewis acid bearing the proton (Scheme I-17). [85] This compound represents the first example of metal-free dihydrogen activation. This activation is possible because compound The chemistry of FLPs quickly grew and many systems arose for H2 activation, led by the work of Douglas Stephan's and Gerhard Erker's groups. FLPs may be intramolecular or intermolecular (Scheme I-18 A)) [86] and the definition may be extended, as lutidine and BCF are able to activate H2 while forming an equilibrated Lewis adduct (Scheme I-18 B)). [87] Scheme I-18. A) Intermolecular FLP B) Lewis-adduct equilibrated FLP.

Usually, FLPs for H2 activation present strong Lewis acids and weak/moderately strong Lewis bases (vide supra). In 2016, Clemens Krempner and his team showed that "inverse" FLPs, in which a strong Lewis base and a weak Lewis acid are employed, can activate H2.

Phosphazene 37 (pKa = 28.4 in MeCN) (Scheme I-19 A)) and Verkade's base 40 (pKa = 33.6 in MeCN) [88] (Scheme I-19 B)) were shown to activate H2 in presence of the weak Lewis acid triphenylborane 38. This work revealed that fine-tuning of the Lewis partners strengths can be made to find a FLP that activates H2.

Scheme I-19. A) H2 activation using a phosphazene and BPh3 B) H2 activation using Verkade's base and BPh3.

B. FLP-mediated hydrogenations

FLP-mediated activation of H2 allowed the FLP-mediated reduction of imines

(Scheme I-20 A) & B)
), [89], [90] silyl enol ethers (Scheme I-20 C)) [91] or enamines (Scheme I-20 D)). [90] For imine reduction, the Lewis base employed for H2 activation can be the imine itself. [92] For those reduction reactions, the difficulty comes from the possibility to form a strong Lewis adduct between the Lewis acid and the substrate that would quench the FLP.

To bypass this issue, the reduced molecules present most of the time bulky groups on their heteroatom.

Scheme I-20. FLP-mediated imine reduction B) FLP-mediated imine reduction with the imine as the Lewis base C) FLPmediated enol reduction D) FLP-mediated enamine reduction.

The logical continuation when working on reduction reactions is the obtention of enantioselectivity. Diajun Chen and Jürgen Klankermayer brought the first examples of enantioselective reductions by synthesising strong Lewis acids with chiral moieties from the combination of BCF with (+)-α-pinene 48 (Scheme I-21 A)) [93] or (1R)-(+)-camphor 49 (Scheme I-21 B)). [94] Those chiral Lewis acids allowed the enantioselective reduction of imine 50 with ees of 13% and 79% and other examples led to ees up to 83%. Timo Repo and co-workers synthesised several chiral ammonium-borates FLPs by reacting enantiopure amines with 1-bromo-2-(bromomethyl)benzene then grafting a borane (ClB(C6F5)2) directly on the benzene moiety. Finally, activating H2 with these FLPs led notably to the obtention of the chiral ammonium-borate 53 (Scheme I-22 A)). [95] This synthesis allowed the presence of both the Lewis acid and the Lewis base on a chiral scaffold.

The chiral ammonium-borate 53 allowed enantioselective imine reductions under lower H2 pressure (2.0 bar) (Scheme I-22 B)). However, the presence of both the Lewis partners on the chiral FLP did not improve the obtained ees. The reduction of imine 54 gave an ee of 35% and the best excess obtained was of 37%. Another strategy in obtaining asymmetric hydrogenations was brought by Haifeng Du and his team. [96] They used sterically hindered binaphtyl-dienes to form, in situ, chiral Lewis acids by alkene hydroboration with Piers' borane (HB(C6F5)2) (Scheme I-23 A)).

After screening several chiral binaphtyl-BCF acids, the authors found out that compound 57 allowed asymmetric hydrogenation of imine 50 giving an ee of 78% and with ees up to 89%

with other examples (Scheme I- 23 B)). The originality of this strategy comes from the facile in situ formation of the chiral Lewis acid. In 2015, Timo Repo et al. took the concept of binaphtyl-based FLP forward by synthesising chiral molecular tweezers bearing both the Lewis partners (58). [97] The presence of an ammonium and a boronate allowed imine and enamine reduction under low pressure of H2 (2.0 bar) here with great ees as imine 54 was reduced giving 83% ee (and up to >99%

for enamines) (Scheme I-24).

Scheme I-24. Enantioselective imine reduction using chiral FLP 58.

Gerhard Erker and this team developed a ferrocene-based phosphane-borane FLP that was shown to activate H2 (Scheme I-25). [98] When made chiral, the corresponding phosphonium-hydridoborate 60 was able to reduce imines under high pressures (60 bar) with ees up to 69% and of 52% for imine 50. [99] This example is atypical due to its unusual ferrocene scaffold that avoids the use of sensitive alkylboranes.

Scheme I-25. Imine reduction using chiral ferrocene-based FLP 60.

FLP-mediated asymmetric reductions also allowed the chiral hydrogenations of carbonyl-based compounds such as ketones and enones, [100] 1,2-diketones and α-keto esters, [101] and silyl enol ethers. [102] C. FLP in CO2 reduction and other gases activation Soon after the development of FLPs for H2 activation, Gehard Erker and his team showed that phosphine-borane FLPs 62 and 64 manage to reversibly activate CO2 under low pressure (1-2 bar), forming an adduct in which the Lewis base is linked to the carbon atom and an oxygen atom to the Lewis acid (Scheme I-26 A) & B)). [103] Scheme I-26. A) CO2 activation by an intermolecular FLP B) CO2 activation by in an intramolecular FLP.

Andrew Ashley and Dermot O'Hare later showed that BCF alongside with tetramethylpiperidine (TMP) managed to concomitantly activate CO2 and H2 for CO2 reduction (Scheme I-28 A)). [104] The corresponding hydroboration of CO2 was quantitative and distillation of the mixture afforded methanol in a 17-25% yield. Warren Piers later showed that the presence of triethylsilane and boratocarbamate-TMPH ion pair 66 induced a deoxygenative hydrosilylation of CO2 leading to the formation of methane (Scheme I-28 B)). [105] Those powerful methods opened the door to FLP-mediated CO2 reduction although not being viable yet.

Scheme I-27. A) FLP-mediated CO2 reduction B) Triethylsilane-medited deoxygenative hydrosilylation of 66.

In 2016, Thibault Cantat and his team used a nitrogen/silylium FLP 67 to activate CO2 that could then be hydroborated by 9-BBN to afford reduced CO2 in quantitative yield (Scheme I-28). [106] This method presented the advantage of reducing CO2 at ambient pressure and temperature.

Scheme I-28. FLP-mediated CO2 reduction.

Many other gases can be activated by FLP systems. The groups of Gerhard Erker and Douglas Stephan showed that carbon monoxide (Scheme I-29 A)), [107] nitric oxide (Scheme I-29 B)), [108] nitrous oxide (Scheme I-29 C)) [109] and sulfur dioxide (Scheme I-29 D)) [110] can be activated by phosphine-borane or nitrogen-borane FLPs.

Scheme I-29. A) FLP-mediated CO activation B) FLP-mediated NO activation C) FLP-mediated N2O activation D) FLPmediated SO2 activation.

In conclusion, FLPs emerged as powerful tools for small molecules activation.

Dihydrogen activation allowed the reduction of many unsaturated compounds, and enantioselective hydrogenations with high selectivities have been achieved. The activation of other greenhouse effect gases represents a milestone for research against global warming.

To our knowledge, only one example of FLP containing macrocycles for gas activation was published. Douglas Stephan and Stephen Loeb used a rotaxane (68) to activate H2 thanks to a nitrogen-BCF system (Scheme I-30). [111] The frustration here came from the crown-etherlike macrocycle shielding the Lewis base. The starting point of this thesis was the hypothesis that frustration coming from a more hindering cavity might lead to "more frustrated" Lewis pairs while taking advantage of the features brought by the cavity (substrate selectivity, enantioselectivity…). Therefore, the axis of this thesis is the design of CD-based Lewis bases and acids.

Scheme I-30. [2]rotaxane-based FLP for H2 activation.

Cyclodextrins

CDs have been already evoked earlier on as molecular containers for confined space catalysis. CDs will be presented more thoroughly.

A. Structure of cyclodextrins and their uses in molecular assemblies CDs are cyclic oligosaccharides composed of glucopyranose units linked together by an α-1,4 glyosidic bond. CDs were discovered by Antoine Villiers-Moriamé in 1891 and are the product of degradation of starch by the bacteria clostridium butyricum (or bacillus amylobacter). [112] CDs have for molecular formula (C6H10O)n in their native state. The most common ones are composed of n ∈ [6,8] glucopyranose units and are called α-, β-and γcyclodextrin respectively. [9] In their native state, CDs present a narrower primary rim composed of primary alcohols, on position 6 of the sugar units, and a larger secondary rim composed of secondary alcohols, on positions 2 and 3 (Figure

I-6 B) & C)).
Those sugar units behave the same way as glucose. Thereby, the primary alcohol on position 6 is the more nucleophilic, the alcohol on position 2 is the more acidic and the one on position 3 is the more sterically hindered and the less reactive.

Concerning their nomenclature, the IUPAC advocates the naming of the glucopyranose units with Roman numerals. However, by convenience, and using the laboratory's convention, the units will be identified by capital letters, following the alphabetical order, and go through This property, alongside with their low cell-toxicity, makes CDs compounds of choice for drug delivery [52] or as a flavour enhancer in food industry (E459 for β-CD). [113] Figure I-7. Higlighted H 5 and H 3 point towards the inside of the cavity.

Those host-guest complexes also allow the formation of molecular assemblies [114] such as rotaxanes as MRI contrast agents (Figure I-8 A)) [115] or such as the formation of fiber-shaped hierarchical molecular assemblies with siRNA presenting lengths up to several micrometres

(Figure I-8 B)
). [116], [START_REF] Evenou | Assemblages supramoléculaires hiérarchiques de cyclodextrines fonctionnalisées et de siRNA, application à la thérapie antisens[END_REF] Figure I-8. A) [3]rotaxane used as MRI contrast agent B) Molecular assemblies with functionalised β-CD and siRNA, cryo-EM spectroscopy image. [START_REF] Evenou | Assemblages supramoléculaires hiérarchiques de cyclodextrines fonctionnalisées et de siRNA, application à la thérapie antisens[END_REF]

B. Cyclodextrins in catalysis

As mentioned in part 1-D), CDs have been used in one of the first examples of supramolecular catalysis by Ronald Breslow and Peter Campbell. [55] Their hydrophobic cavity explains the trend in using CDs for catalysis. Soon, chemists got interested in functionalising CDs in order to get new catalysts. In 1978, Ronald Breslow and his team.

described the synthesis of the bis-imidazol β-CD 70 as a model for ribonuclease. [START_REF] Breslow | [END_REF], [119] This functionalised β-CD has been used as a catalyst for the trans-selective aldol cyclization of keto aldehyde 71 (Scheme I-31). [120] In this study, the authors showed that at neutral pH, the presence of β-CD 70 increased the reaction rate by a factor of 20 compared to the reaction in presence of the native β-CD. By modulating the pH of the reaction to 6.2 (close to the pKa of 70), the authors observed a decrease in reaction rate and concluded that the reaction was catalysed by a bifunctional catalyst, bearing an imidazole and an imidazolium moiety.

Interestingly, thanks to the cavity, the cyclic aldolization occured with a trans-selectivity and no cis-keto alcohol was obtained. However, the enantioinduction remained low with an ee below 10%. Many other functionalised CDs were synthesised for catalysis such as CDs bearing thiazolium units for benzoin condensation, [121] CDs bearing enamine units for aldol condensations, [122] CDs bearing peptides for ester hydrolysis [123] … However, none of those catalysts bear a reactive centre within the cavity of the cyclodextrin.

Chemists also focused their interest on the complexation of metals with CDs. The main strategy implies the functionalisation of the CD with one or several ligands thus coordinating the metal above the primary rim of the CD.

Concerning CDs bearing one ligand, Dominique Matt and Dominique Armspach monofunctionalised α-and β-CDs with a phosphine, creating a new class of ligands called HUGPHOS ligands. [58] Those ligands could form complexes with rhodium (73 and 74) and be active for the hydroformylation of styrene (Scheme I-32). The screening of reaction conditions revealed that high temperatures and low pressures of the CO/H2 mixture induced good conversions but low selectivities. However, with the right conditions (40 bar, 4 or 20 °C), the linear hydroformylated product could be exclusively obtained with α-HUGPHOS ICyDs can form metal complexes with coinage metals and are active in catalysis. [62] Figure or 77 (Scheme I-34). The deprotonation of the alcohols by sodium hydride followed by a nucleophilic substitution on benzyl chloride in DMSO afforded the perbenzylated CDs with good yields and an easy purification on silica gel chromatography. The second step consisted in the regioselective deprotection of two alcohols present on the primary rim. This methodology was described by the team in 2000 [125] and afforded a diol presenting the two deprotected alcohols in opposite positions to each other. Once again, good yields were obtained (α-CD 80: 93%, β-CD 81: 80%).

Scheme I-34. Synthesis of diametrically opposed diols of α-and β-CDs.

Mechanistic studies (Scheme I-35) [126] of the debenzylation reaction revealed that After the obtention of the diol, the alcohols were mesylated using methanesulfonyl complexes. [60], [62] The silver complexes could undergo a transmetallation reaction with gold(I) chloride to afford the corresponding gold(I) complexes 90 and 23 (Scheme I-37).

Those compounds were obtained with good yields and were stable on silica. The synthesis of the copper complexes has been scaled-up up to 10 g, affording air and moisture stable complexes.

Scheme I-37. Synthesis of (α/β-ICyD)MCl metal complexes.

The possibility of selectively debenzylate two alcohols on the primary rim of CDs led to the bridging of CDs with imidazole units. These new ligands, ICyDs, were reactive and allowed the obtention of encapsulated metal complexes within the cavity of CDs.

b. Characterisation of ICyD-Complexes Benzylated complexes being difficult to crystallize, the characterization of these compounds has been done by NMR spectroscopy. The main issue was to prove that the metal is, indeed, inside the cavity.

First evidences were brought by NOESY (Nuclear Overhauser Effect SpectroscopY) experiments. The nuclear Overhauser effect corresponds to the transfer of nuclear spin polarization via cross-relaxation through space and can show correlations up to 5-6 Å.

The NOESY experiment performed on (α-ICyD)CuCl 86 showed cross-correlations between the protons carried by the imidazole moiety (H N-CH=CH-N) and the H 6 protons of the sugar units A (H 6 A) and B (H 6 B) (Figure I-11). [START_REF] Suárez | Confinement of Metal Complexes in NHC-Cyclodextrins[END_REF] The correlation between H 6 B and H N-CH=CH-N was less intense due to the greater distance between the two protons.

Here, the NOESY clearly proved that the NHC is pointing towards the cavity and that the metal is encapsulated inside the cavity. As mentioned in this part of the introduction, the cavity is paved with C-H bonds (H 3 and H 5 ). These protons can act as probes of the interior of the cavity. In order to better understand these new complexes, a comparison of the chemical shifts H 3 and H 5 with different complexes has been conducted. [60] The formation of ICyD-metallic complexes induced a deshielding of the H 3 and H 5 protons indicating an interaction of the metal with the cavity of the CDs. By comparing the NMR spectra of (α-ICyD)AuCl 90, (α-ICyD)AgCl 88 and (α-ICyD)CuCl 86, the authors noted strong shielding (0.75 ppm) of the H 5 A protons when going from the gold complex to the silver complex while the other H 5 protons chemical shifts remained relatively unchanged (Figure I-12). The chemical shift of the H 5 A got deshielded of 0.14 ppm when going from the silver to the copper complex. However, the H 3 C were barely influenced by those metal changes as the maximal amplitude between two chemical shifts was only of 0.13 ppm. The authors concluded that the metal is placed at the level of the H 5 in the cavity and that H 5 A are the closest to the metal centre.

A similar experiment was conducted by changing the counter-ions of (α-ICyD)AgCl 88.

Here, the authors noted that for chloride, acetate and benzoate counter-ions, the chemical shifts of H 5 A hardly changed whereas the chemical shifts of H 3 C were strongly shielded following that order. The authors concluded that the counter-ion was at the level of the H 3 in the cavity and that H 3 C was the closest to the counter-ion. These analysis were later confirmed by the obtention of crystals made possible by the synthesis of ICyDs bearing methyl protecting groups instead of benzyls (the presence of methyl protecting groups is indicated by "Me" in superscript). [START_REF] Dos Passos | [END_REF] The X-ray analysis of (α-ICyD Me )CuCl confirmed the presence of the copper inside the cavity (Figure I-13). H 5 A is indeed the closest to the metal centre (2.451 Å vs 3.338 Å for H 5 B and 3.807 Å for H 5 C) and therefore is the most impacted by the change of the metal. In the same way, H 3 C is the closest to the counter-ion (3.192 Å vs 3.973 Å for H 5 B and 4.707 for H 5 A). To conclude, NMR experiments helped to better understand the interior of ICyDsmetal complexes. The metal ions were shown to be deeply buried inside the cavity as they are present at the level of the H 5 protons. These analyses were later confirmed by crystallographic analysis. γ-CDs were also studied but smaller interactions between the metal and the CD were found due to the size of the CD, meaning the metal was less encapsulated within the CD. γ-CD ICyDs were therefore rarely used in catalysis.

c. ICyD-metal complexes reactivity

As mentioned earlier, ICyD-metal complexes are active in catalysis. Early examples of this activity involved the use of the copper complexes.

In 2017, the laboratory used the (ICyD)CuCl complexes to catalyse the hydroboration reaction of terminal alkynes which appeared to be regioselective in function of the nature of the CD (α or β). [129] This work was based on Amir Hoveyda's work who demonstrated that electronic-tuning of the ligand on NHC-CuCl complexes can lead to different selectivities. [130] The use of N-mesityl substituted NHC-CuCl led to the formation of the linear hydroborated product whereas the use of N-adamantyl NHC-CuCl led to the formation of the branched hydroborated product. This regioselectivity was explained by electronic factors coming from the N-substituents.

Performed with the (α-ICyD)CuCl 86 complex, the copper-catalysed hydroboration of phenylacetylene revealed the formation of the linear product 91 with a 91:9 selectivity. In contrast, the use of (β-ICyD)CuCl 87 complex induced the formation of the branched product 92 with a 90:10 selectivity (Scheme I-38). Here, the NHC was bearing cyclodextrins in both cases thus electronic factors could not be invoked to explain this difference in selectivity.

Scheme I-38. Regioselective hydroboration of phenylacetylene catalysed by (α-) and (β-ICyD)CuCl.

DFT calculations revealed that when (β-ICyD)CuCl 87 was used, phenylacetylene enters the cavity following a parallel approach with the formed ICyD-Cu-BPin reactive specie (Figure -14). In this approach, the phenyl moiety is oriented towards the outside of the cavity due to steric hindrance. This orientation implies that the BPin reacts with the closest carbon to the phenyl moiety, leading to the obtention of the branched product 92. On the contrary, when the smaller (α-ICyD)CuCl 86 was used, phenylacetylene could not enter the cavity, therefore, a parallel approach was not conceivable. DFT calculations showed that for this reaction, phenylacetylene undergoes a perpendicular approach in which the phenyl moiety can stay out of the cavity ( This example showed the importance of the size of the cavity. The cavity could act as a mechanistic switch in which the presence or lack of space induced opposite regioselectivities due to different substrate approaches. In the same fashion, (α-ICyD)CuCl 86 was later shown to selectively form the linear product in methylboration of terminal alkynes. [131] As mentioned in part I-D), (β-ICyD)AuCl 23 was used as a substrate-selector in the enantioselective alkoxycyclization reaction of enynes thus revealing the capacity of CDs to act as molecular bouncers, discriminating molecules by their size (Scheme I-38). [61] Scheme I-39. Substrate-and enantioselective alkoxycyclization of enynes catalysed by (β-ICyD Me )AuCl.

I
Synthesising the water-soluble methyl-protected (α-ICyD Me )AuCl 93 and (β-ICyD Me )AuCl 94 complexes revealed the capacity of ICyDs to also perform catalysis in water. The complexes allowed to catalyse the hydration reaction of alkynes, the lactonization of γ-alkynoic acids, hydroarylation reactions, enantioselective enyne cycloisomerization and enantioselective hydroxylation-cyclisation of enynes (Scheme I-40 A)). [132] Scheme I-40. A) Enantioselective hydroxylation-cyclisation of enynes catalysed by (α/β-ICyD Me )AuCl in water B) Structure of (α-ICyD Me )AuCl and (β-ICyD Me )AuCl.

In conclusion, ICyDs, considering their easy 4-step synthesis, have imposed themselves as ligands of choice for organometallic catalysis using CDs. The environment of the metal is well-controlled and the cavity allows the obtention of selectivities in catalysis.

PhD Project

This PhD project aims at synthesising unprecedented organocatalysts confined inside the cavity of CDs. The backbones of those catalyst will be the imidazolium salts 84 and 85 as they were shown to form metal complexes pointing towards the inside of the cavity and therefore encapsulating the reactive sites in a well-controlled environment.

The imidazolium backbones will be used to synthesise new Lewis acids and bases confined within the cavity and to study their properties coming from their encapsulation.

N-Heterocyclic Imines

Lewis bases are chemical entities presenting one or several lone electron pairs. Typical Lewis bases present atoms from group 15 with an oxidation degree of III (nitrogen and phosphorus) and from group 16 with an oxidation degree of II (oxygen and sulfur).

These atoms were incorporated in NHC-adducts forming respectively imidazolin-2-imine and imidazolin-2-iminato ligands, [1] carbene-phosphinidene ligands, [2] imidazolin-2-one ligands [3] and imidazolin-2-thione ligands (Figure II-1). [4], [5] Figure II-1. Structures of NHC-adducts with nitrogen, phosphorus, oxygen and sulphur.

These ligands were used in complex with numerous metals including zirconium, [6] titanium, [7] tungsten, [8], [9] gold, [10], [11] copper [10], [12], [13] and molybdenum [9] complexes.

Among these NHC-main group elements adducts, imidazoline-2-imine and imidazoline-2iminate ligands are the most studied.

A. Synthesis and reactivity of N-Heterocyclic Imines

Imidazolin-2-imines, also called N-Heterocyclic Imines (NHIs) were first synthesised by Norbert Kuhn and co-workers in 1995 by methylating the readily available 2-amino-1-methylimidazole 95 (Scheme II-1 A)). [1] NHIs can be obtained via multi-step synthesis [14] or, more usually, directly from the corresponding carbenes using trimethylsilyl azide (TMSN3) (Scheme II-1 B)) [15] or tert-butyl azide (tBuN3) (Scheme II-1 C)). [16] Scheme II- As mentioned earlier, these ligands could form metal complexes. The addition of a titanium complex (104) to the silylated NHI 99 led to the formation of the NHI-titanium complex 105

which was used as a catalyst for ethylene polymerization (Scheme II-2). [17] Scheme II-2. NHI-Titanium complex 105 synthesis.

NHIs could also be combined with another imidazolium to form highly stable and alkali base-resistant bis(N,N'-dialkylimidazolium)amide salts, such as 107, for phase-transfer catalysis (Scheme II-3). [16] Scheme II-3. Bis(N,N'-dialkylimidazolium)amide salt 107 synthesis.

Amidine and guanidine bases are known to form adducts with CO2. NHIs, that can be seen as a combination of an NHC and a guanidine, are no exception to the rule. Fabian Dielmann and co-workers synthesised several NHIs and tested their ability to form CO2 adducts. [18] NHIs bearing an imidazole (Scheme II-4 A)) and a 4,5-dimethyl-imidazole (Scheme II-4 B)) moiety were shown to activate CO2 under two bars of pressure in CD3CN.

The zwitterionic adducts were isolated with quantitative yields when the reaction was performed in pentane. However, the use of benzimidazole-(Scheme II-4 C)) and imidazolidine-based NHI (Scheme II-4 D)) did not lead to any adduct formation.

Scheme II-4. A) CO2-adduct formation using imidazolin-2-imines B) CO2-adduct formation using 4,5-dimethylimidazolin-2-imines C) Absence of CO2-adduct formation using benzimidazolin-2-imines D) Absence of CO2-adduct formation using imidazolidin-2-imines

The authors then showed that their adducts presented high thermal stabilities directly related to the size of the alkyl substituent present on the exo-cyclic nitrogen. When bearing a methyl group, the CO2 adducts 108 and 109 were stable over 120 °C but the presence of a tert-butyl (110) or a n-alkyl group (111 & 112) lowered the decomposition temperature to 100 °C and 75 °C respectively (Scheme II-5).

Scheme II-5. Thermal stability of NHI-CO2 adducts

The hydrolysis stability of the adducts was also tested. The adducts bearing proton groups on the exo-cyclic nitrogen, 113 and 114, were the less stable resulting in full conversion to bicarbonate salts in the fashion of classical triazabicyclodecene-CO2 adducts (Scheme II-6 A)). [19] Bearing tert-butyl or n-alkyl groups, the adducts underwent hydrolysis without complete conversion (Scheme II-6 B)). Surprisingly, the presence of methyl groups on the exo-cyclic nitrogen (108 and 109) totally prevented the adduct of being hydrolysed even with large excesses of water and at high temperature (70 °C) (Scheme II-6 C)).

Scheme II-6. A) Total hydrolysis of NHI-CO2 adducts B) Partial hydrolysis of NHI-CO2 adducts C) Absence of hydrolysis of NHI-CO2 adducts.

This work showed the ability of NHIs to capture CO2, forming surprisingly stable adducts thus opening the way in their uses as organocatalysts or in direct air CO2 capture for CO2 conversion. Very recently, this work was extended to photoswitchable NHIs for reversible CO2 capture. [20] In conclusion, NHIs are extensively used as ligands and where also shown to be powerful in CO2 activation because of their great basicities.

B. NHI's pKBH+

NHIs can be seen as belonging to the family of superbases, defined by Paul Caubert as bases resulting from a mixing of two (or more) bases leading to new basic species possessing inherent new properties. [21] Among nitrogen-based organic superbases, the most renown are 1,1,3,3-tetramethylguanidine (TMG, pKa = 23.3 in acetonitrile), [22] 1,8diazabicyclo[5.4.0]undec-7ene (DBU, pKa = 23.9 in acetonitrile) [22] and 1,5,7-triazabicyclo-[4.4.0]dec-5-ene (TBD, pKa = 26.0 in acetonitrile) [22] presenting high pKa values thanks to the many existing resonance structures when the molecules are protonated (Scheme II-7 A), B) & C)). NHIs, thanks to the endo-cyclic nitrogen atoms, also present many resonance structures stabilising the protonated N-Heterocyclic iminiums (Scheme II-7 D)). Roman Kunetskiy, Ilya Lyapkalo and coworkers synthesised many NHIs and measured, along with other known bases, their pKa (pKBH+) values in acetonitrile using photometrical titrations. [14] Most of the bases were shown to be stronger than DBU.

Increasing the bulkiness of the substituent present on the exo-cyclic nitrogen increased the pKBH+ value with a maximum value (30.2) obtained with a tert-butyl substituent. Increasing even more the bulkiness (tert-heptyl and tert-octyl) led to a decrease in basicity. These bulky bases were shown to be even more basic than phosphazene P1-t-Bu-tris(tetramethylene) (P1(pyrr)) but their pKBH+ remained lower than phosphazene P2-t-Bu-tris(dimethylamine) [14] The high pKBH+ values of NHIs, their ability to activate CO2, their potential in organocatalysis and especially their synthesis being directly possible via a NHC make NHIs compounds of choice for synthesising the first encapsulated organosuperbases inside the cavity of a CD.

(P2(dma)) (Figure II-2).

Encapsulated NHI synthesis

As mentioned in Chapter I-4-C-b, the bridging of a CD by an imidazole moiety led to the formation of an imidazolium salt with the pro-carbene carbon pointing towards the inside of the cavity. Those (ICyD)HCl salts could then lead to the formation of ICyD-metal complexes with the metal encapsulated within the cavity of the CD. Logically, the starting point for the formation of encapsulated-NHIs was the use of the readily available imidazolium salts (84 and 85). The reactions were first conducted using (β-ICyD)HCl 85, presenting a bigger cavity than the α-CD salt 84, in order to prevent any potential steric conflicts. A. Development of the synthesis using sodium amide

The first trials for the synthesis of encapsulated NHIs were conducted following a method described by Gouriprasanna Roy and his team. [23] This method presented the advantage of not using small azides but sodium amide. The authors showed that their method opened the way to obtain numerous NHIs presenting imidazole or benzimidazole moieties with various substituents (alkyl, aromatic) and with excellent yields up to 91% (Scheme II-8 A)). Replacing sodium amide with substituted amines allowed the formation of the corresponding N-functionalised NHIs.

Concerning the mechanism, the authors believe that potassium carbonate leads to the formation of the NHC that reacts with iodine, forming the charged NHC-Iodine adduct 117

(Scheme II-8 B)). This electrophilic adduct is then attacked by sodium amide that, after rearrangement, forms the corresponding NHI 118.

Therefore, the method was applied using one equivalent of the imidazolium salt 85 and the reaction was followed by thin layer chromatography (TLC) and ESI-MS. The first trial was conducted following the described method (Table II-1, entry 1).

Reacting two equivalents of potassium carbonate, one equivalent of iodine and 1.2 equivalents of sodium amide with one equivalent of 85 in methanol led to the formation of a complex mixture. No formation of NHI 116 or 119 was detected by ESI-MS before and after silica-gel chromatography. However, the corresponding urea 121 was isolated and a mixture containing starting material and the intermediate 120 was also obtained.

A quick comparison of the pKa values of sodium amide (37.8) [24] and methanol (15.3) [25] clearly suggested that in the reaction medium, methanol gets deprotonated by sodium amide forming ammonia and sodium methanolate. Thus, the reaction was conducted in an aprotic and polar solvent: THF.

The reaction was carried in THF using more equivalents of K2CO3 (3.0 eq) and iodine (2.0 eq) to ensure the formation of the NHC-I + intermediate 120 and 40.0 equivalents of sodium amide to force the formation of the NHI (Table II-1, entry 2). Unfortunately, the reaction did not undergo full conversion after 6 hours of reaction and a peak corresponding to the urea 121 was found by ESI-MS in the crude product. After silica gel chromatography, a fraction containing an approximately 1:1 inseparable mixture, determined by 1 H NMR, of the imidazolium 85 and the protonated NHI 119, was obtained. Considering an iodine counterion, the yield for this reaction is approximately of 16%. This result showed that it is necessary to obtain a total conversion of the imidazolium salt in order to isolate the NHI.

Finally, to ensure the formation of the carbene, for the formation of the NHC-I + 120 adduct, a solution of KHMDS (0.5 M in toluene) was used and the equivalents of iodine were increased (Table II-1, entry 3). However, once again the reaction led to the formation of the inseparable imidazolium 85 and protonated NHI 119 mixture.

Considering the protonation of sodium amide in methanol, the source of nitrogen could not come from the amide. Thus, other sources of nitrogen were tried without much more success.

Entry Eq. K2CO3 X2 (eq) Nitrogen Regarding the lack of reactivity of the NHC-I + 120 adduct, the reaction was tried by replacing iodine by molecular bromine (Scheme II-9). Unfortunately, the conversion was, once again, incomplete but the NHI 119 product was detected by ESI-MS.

Scheme II-9. NHI formation trial with Br2.

The obtention of the NHC-I + adduct 120 in almost all cases without further reaction clearly indicates a lack of reactivity of this key intermediate. This inertness might come from the lack of space imposed by the cavity, preventing the amine to perform the nucleophilic addition. Another strategy was therefore needed for the formation of the encapsulated NHIs.

B. Development of the synthesis using azidotrimethylsilane

To bypass this nucleophilic addition issue, the synthesis using TMSN3 was then investigated. In this reaction, TMSN3 reacts with a carbene forming an intermediate (122) believed to undergo a Staudinger-type reaction forming the NHC=N-SiMe3 adduct 123 while releasing N2 (Scheme II-10 B)). [26], [27] The silicon-adduct can then be reacted with methanol to form the corresponding NHI (Scheme II-10 A)). [15] Scheme II-10. A) NHI synthesis using TMSN3 B) Proposed mechanism of NHI formation using TMSN3.

The development of this reaction was carried out using one equivalent of imidazolium salt 85 in screwed caps tubes that were sealed after addition of the azide. Finally, the reaction was carried out with 10.0 equivalents of TMSN3 (Table II-3, entry 3) but did not lead to the obtention of a clean product.

Despite its poor yield, this method afforded, for the first time, the NHI 119 as the sole product, without any imidazolium 85 in the mixture. Increasing the number of equivalents did not improve the yield but on the contrary prevented the obtention of a clean product. The based on crystalline data of (β-ICyD Me )CuCl [28] and highlighted steric hindrance. View from the secondary rim of the CD B) Topological representation of the represented intermediate.

C. Development of the synthesis using tert-butyl azide

The method using tert-butyl azide as nitrogen source was first described by Roman Kunetskiy, Ilya Lyapkalo and collaborators (Scheme II-11 A)). [16] The carbene is reacted involves the deprotonation of the tBu moiety by the triazene unit itself, leading to the charged product 128 that, after liberation of N2, forms the protonated NHI.

Scheme II-11. A) NHI synthesis developed using tBuN3 B) Proposed mechanism of NHI formation using tBuN3 and NH4BF4.

The described procedure was slightly modified and applied to the β-CD. Hence, the imidazolium salt 85 was first reacted with KHMDS (1.1 eq, 0.5 M in toluene) in order to form the carbene in situ (Scheme II-12). A 1:1 tBuN3/toluene mixture 2 (1.1 eq) was then added and the reaction mixture heated to 60 °C. The reaction was followed by NMR, monitoring the disappearance of the 1 H-imidazolium peak and the appearance of a tert-butyl singlet. To our delight, this first step went smoothly, bringing full conversion after 24 hours and leading to the formation of the recognizable NHC-N3tBu adduct 129 (Figure II-6).

Unfortunately, this intermediate could not be isolated. The solvents were then removed in vacuo, the mixture solubilized in a 1:1 methanol/toluene mixture and ammonium hexafluorophosphate was added leading to an effervescence of the mixture. Toluene was used to ensure the solubility of the CD whereas methanol was used to ensure the solubility of the ammonium salt. A salt containing a phosphorus atom (NH4PF6) was selected because of the sensitivity of 31 P NMR. This will allow to attribute without doubt the counter-ion of our product. The extraction of the mixture using chloroform and the washing of the organic layer with water led to the obtention of a crude product presenting broad peaks in 1 H NMR (Figure II-6). Fortunately, silica gel flash chromatography afforded the encapsulated NHI 130 with the hexafluorophosphate counter-ion in 38% yield. However, other fractions were obtained containing an NHI but with other counter-ions. Supposing a chloride counter-ion for these fractions, the obtained yield was of 25% bringing the overall yield for the NHI to 63%.

Scheme II-12. Synthesis of encapsulated NHI 130 using tBuN3 and quenching with NH4PF6. The different counter-ions led to similar NMR spectra in the sugar region (≈ 3-5 ppm).

However, the imidazole peaks (green on It is noteworthy to mention, once again, the impossibility to separate mixtures containing encapsulated NHI 130 or 119 and the (β-ICyD)HCl 85. Thus, it is necessary to obtain full conversion of the starting material and not to get the ICyD back after quenching, in order to get a clean product.

The reaction was then quenched using one molar hydrochlorous acid in diethyl ether to avoid the potential presence of other anions (Scheme II-13). The reaction was carried using 1.2 equivalents of KHMDS and 2.5 equivalents of tBuN3. Under these conditions, the carbene underwent full conversion after only 12 hours. After quenching, the mixture was then evaporated and directly purified using silica gel chromatography to avoid the possibility of obtaining another counter-ion. Excepting apolar impurities, only one product was detected by TLC and isolated. This product was identified as the encapsulated NHI, (β-ICyD)NH2Cl Modulating the electronic properties of the imidazole-moiety should bring different properties for the corresponding NHI. Thus, two other NHIs, bearing a benzimidazole and a 4,5-dimethyl-imidazole moiety, were synthesised in order to get a complete set of encapsulated NHIs.

Bridging the CD with benzimidazole led to the obtention of the corresponding benzimidazolium salt 132 in 33% yield (Scheme II-14 A)). The salt then underwent the amination reaction. Here, more equivalents of tBuN3 were needed to obtain full conversion.

Nonetheless, the corresponding NHI 133, (β-BiCyD)NH2Cl, 3 was obtained in 33% yield.

4,5-dimethyl-imidazole 134 was synthesised following a procedure described in the literature [30] and bridged on the CD affording the corresponding salt 135 in 54% yield (Scheme II-14 B)). This new ligand reacted in the same conditions as imidazolium 85 and afforded the corresponding NHI 136, (β-MiCyD)NH2Cl,4 in 64% yield. In conclusion for this part, the presence of the CD cavity prevented the possibility of performing nucleophilic additions on the carbene carbon with an amide or an amine. To circumvent this issue, azides were used. The Staudinger-type rearrangement required with the use of TMSN3 was probably the reason of the poor yields obtained using this azide. On the contrary, using tBuN3 always led to full conversion of the imidazolium salt before the quench of the reaction. Finally, quenching the reaction with a solution of hydrochlorous acid in ether, thus avoiding the presence of water and thereby of other anions, led to the obtention of the encapsulated NHI 131 as the sole product with an excellent yield of 87%. The use on a strong acid clearly indicated that the quench followed the pathway for which the triazene unit deprotonates the tBu moiety. This synthesis was even scaled up to the gram scale. This strategy was also successful for the obtention of the (β-BiCyD)NH2Cl 133 and the (β-MiCyD)NH2Cl 136 in 33% and 64% yields respectively. This strategy was then applied to α-CDs. (α-ICyD)HCl 84 was first reacted under the reaction conditions used for (β-ICyD)HCl (Table II-4, entry 1). Unfortunately, the sole product obtained was the imidazolium salt 84. The strong acidic quench caused the reaction to go backwards.

Thus, the first conditions tried with β-CD were tried (Table II-4, entry 2). After obtaining full conversion into the triazene intermediate 137, the reaction was quenched with NH4PF6.

After silica gel flash chromatography, a fraction containing a mixture of imidazolium salt 84

and NHI 138 bearing a PF4 -counter-ion was obtained. The NHI could not be separated from the imidazolium salt thus leading to a very low yield, 1%, of an impure product. In the same fashion as for β-CD, the impossibility to separate (α-ICyD)HCl 84 and the NHI led to the necessity of obtaining full conversion of the starting material and the need to prevent its formation during the quench of the reaction. However, here, the use of a weak acid, presenting a basic conjugate base, seemed to be the key for obtaining the α-CD NHIs.

The reaction was then carried using 10.0 equivalents of tBuN3 to ensure the presence of the triazene unit and quenched with NH4Cl (Table II- The obtention of the NHI, even impure, using an ammonium salt seemed to indicate a different quenching pattern using α-CD. In this case, it seemed that a base was needed to deprotonate the tBu moiety and to trigger the rearrangement. This seemed to indicate that pattern (b) (Scheme II-11, B)) was followed using α-CD. Another peculiarity was the observed requirement to quickly induce the rearrangement as the imidazolium salt 84 was found in all the reactions after the quench despite its absence before the quench. Thus, another ammonium salt, Et3NHCl, was tried as it presents a higher pKa value than NH4PF6 and NH4Cl. [31] Hence, the reaction was carried out using only 2.5 equivalents of tBuN3 and quenched with 5.0 equivalents of Et3NHCl (Table II-4, entry 4). Here, the NHI 139 was present but, once again, mixed with the imidazolium salt.

Increasing the number of equivalents of Et3NHCl to 10.0 led to the first obtention of the NHI 139 without imidazolium (Table II-4, entry 5) in 55% yield. The product was first believed to contain several ions as the 1 H NMR was not neat at all. Washing the product with HCl and NaCl aqueous solutions did not lead to any improvement of the NMR spectrum. Using a chloride ion exchange resin did not lead either to an improvement. However, using tBuOK to deprotonate the charged NHI 139 led to the obtention of a well-defined NMR spectrum corresponding to the neutral NHI 140 (Figure II-9 B)). This indicated that after silica gel chromatography, the obtained product was, in fact, a mixture of the protonated and neutral NHI 139 and 140.

Finally, aiming to accelerate the rearrangement, the quenched mixture was heated to 60 °C

for one hour (Table II-4, entry 6). This method afforded the protonated/neutral mixture of 139 and 140 in 61% yield. The obtention of this inverted NHI can be explained by the lack of space inside α-CD for the formation of the NHC-N3tBu intermediate 137. The intermediate, obtained before the quench, was analysed but the NOESY spectrum did not help to indicate whether the adduct was pointing towards the inside or the outside of the cavity. However, the most plausible explanation for this inversion lies in the possibility for the carbene to "flip" in order to form adducts with bulky metal complexes as demonstrated recently with (α-ICyD)PdCl2(pyr). [32] In this case, the bulkiness of tBuN3 must have induced the inversion of the imidazole bridge and formed the corresponding adduct 141 with the triazene outside the cavity. The charged NHI 142 will be called (α-out-ICyD)NH2Cl and the neutral NHI 143 (α-out-ICyD)NH, in order to specify this inversion (Scheme II-15). Once again, the 1 H NMR spectrum of the protonated NHI 145 was not well-defined but the addition of tBuOK led to the obtention of a clean NMR spectrum for NHI 146 (Figure II-11). The NOESY spectrum did not lead to the obtention of correlations with the hydrogen present on the methyl groups and the rest of the molecule. The hydrogen carried by the exocyclic nitrogen was not found thus, the confinement of the NHI cannot be formally proved.

However, the deshielding of the H 5 A at 4.47 ppm compared to H 5 B (4.14 ppm) and H 5 C (3.84 ppm) was similar to the ones obtained with the encapsulation of metals inside CDs. Thus, the nitrogen atom is very likely encapsulated within the cavity. Imidazolium salt 147 was first reacted using few equivalents of KHMDS and tBuN3 (1.3 eq and 2.0 respectively) (Table II-5, entry 1). After the quench, the reaction did not lead to the formation of the desired product but led to the obtention of the starting material.

The reaction was thus carried out using more equivalents of base (2.0 eq) and tBuN3 (10.0 eq) and quenched once again with Et3NHCl (Table II-5, entry 2). This reaction led to the obtention of the product, that was only seen by ESI-MS, and of the starting material. Silica gel chromatography did not afford the clean product. Surprisingly, the triazene intermediate 148 was also detected by ESI-MS even after the quench. This indicates a difficulty for the triazene rearrangement in the presence of an acid (Et3NHCl), that was shown to induce the obtention of the NHIs with other ligands.

The reaction was then carried out under the same conditions but quenched using NH4Cl (Table II-5, entry 3). However, the same result was obtained, the mixture contained (α-BiCyD)HCl 147, the NHI 149 and the triazene 148, all detected by ESI-MS.

Quenching the reaction using MeNH3Cl led to full conversion of the triazene intermediate and the obtention of a complex mixture containing (α-BiCyD)HCl 147 and NHI 149 (Table II-5, entry 4).

Finally, quenching the reaction with an HCl solution (1 M in Et2O) led to the formation of the starting material 147 (Table II-5, entry 5).

The obtention of the triazene intermediate even after the quench of the reaction was puzzling.

Following Le Chatelier's principle, [33] once the protonation of the triazene intermediate occurs, the rearrangement should be fast since it releases gases, isobutylene and nitrogen.

Here, the key might have relied on the triazene protonation step. The use of strong acids (HCl and not shown PTSA) for the formation of (α-BiCyD)NH2Cl led to the obtention of the starting (α-BiCyD)HCl 147. However, even by modulating the strength of weak acids (Et3NHCl, MeNH3Cl, NH4Cl), full conversion of the triazene intermediate was not always achieved. Quenching with MeNH3Cl did lead to full conversion of the triazene but the presence of the starting imidazolium salt 147 prevented the obtention of a clean product.

To sum up, the method used for the synthesis of encapsulated NHIs with β-CDs revealed it-self to be ineffective for α-CDs. The use of HCl to induce the triazene rearrangement led to the obtention of the starting (α-ICyD)HCl 84 salt. Screening of several reaction conditions and of weak acids allowed the obtention of the (α-ICyD)NH2Cl salt 142 using a Et3NHCl quench. Contrarily to the (β-ICyD)NH2Cl NHI 131, the exo-cyclic nitrogen was not inside the cavity. This inversion, probably resulted from a "flip" of the NHC during the formation of the triazene intermediate, due to a lack of space inside the smallest CD. The use of (α-MiCyD)HCl 144 allowed the obtention of the NHI 145 for which no NOESY correlations indicated an inversion of the 4,5-dimethylimidazole moiety. However, the observed H 5 A deshielding was consistent with an atom encapsulation. This probably resulted from the presence of the methyl groups impeding the inversion. For both of these NHIs, the protonated forms 142 and 145 led to poorly defined 1 H NMR spectra. Thus, the characterizations of these molecules were performed with the neutral NHI, the deprotonation reactions being done using tBuOK. The formation of the (α-BiCyD)NH2Cl product was not achieved. Surprisingly, the triazene intermediate 148 was often found by ESI-MS after quenching the reaction. This might come from the strongest π-accepting property of the benzimidazole [2] leading to a weaker basicity of the triazene intermediate. This weaker

B. Preliminary results

Before actually measuring the pKBH+ values of the new encapsulated NHIs, it was required to find a base for which an equilibrium was created in the presence of the protonated 131/(β-ICyD)NH 116 couple was around the value of triethylamine (pKa = 18.83). [35]

Figure II-13. Cropped 1 H NMR spectra of A) (β-ICyD)NH2Cl B) (β-ICyD)NH2Cl and DBU (1.0 eq) mixture C) (β-ICyD)NH2Cl and Et3N (1.0 eq) mixture D) (β-ICyD)NH and Et3NHCl (1.0 eq) mixture E) (β-ICyD)NH (CD3CN, 400

MHz, 300 K).

The presence of the two species, 131 and 116, indicated a slow exchange in the time scale of the NMR. Thus, the possibility of getting back to the concentrations of the species inside the mixture relied on the possibility of integrating the spectra.

Unfortunately, due to the overlapping of the peaks belonging to (β-ICyD)NH2 + and (β-ICyD)NH, and the broad peaks of (β-ICyD)NH2 + , integrating the signals was not possible and getting the concentrations of the species in the mixture was not possible either.

Therefore, the use of 1 H NMR to measure a pKBH+ value has been discarded.

The use of quantitative 15 N NMR for getting the relative concentrations of the four species was discussed. Preliminary results afforded a signal in 15 N NMR for the exo-cyclic nitrogen of (β-ICyD)NH2Cl 131 with a chemical shift of δ = 59.8 ppm (Annex II-1). However, this signal was obtained using a HSQC sequence often used in protein NMR. This sequence involves a polarization transfer from the proton, linked to the nitrogen, to the studied nitrogen nucleus via an Insensitive Nuclei Enhanced by Polarization Transfer (INEPT) step.

Therefore, the obtained results were not quantitative. Obtaining this correlation via INEPT resulted in an NMR analysis lasting more than 17 hours. The obtention of a signal, without

INEPT, with a signal to noise ratio good enough to allow integration must last a time that is not reasonable. Therefore, the use of 15 N NMR for measuring pKBH+ values has been also discarded. 19 Fluorine is a sensitive nucleus presenting a spin value of ½ and being 100% abundant making its NMR peaks integrable. NMR sequences involving 19 F are well known and easy to set up. Therefore, the use of an acid or a base bearing a fluorine atom was studied.

C. Use of p-fluorophenol for pKBH+ measurements Among the variety of fluorinated molecules, p-fluorophenol 156, was selected. As shown in chapter I-4-B with Ronald Breslow and Peter Campbell's work, anisole is able to enter the cavity of α-CD. [36] Moreover, phenylacetylene was shown to react with (α-ICyD)CuCl for the hydroboration reaction of alkynes. [37] Therefore, p-fluorophenol, by its similar shape and size, should be able to enter the cavity of both α-CD and β-CD NHI to interact with the base.

To our surprise, the pKa of p-fluorophenol has not been tabulated before. This result was in accordance with other values found in literature as phenol presents a pKa value of 29.2 and 4-CF3-phenol a pKa value of 26.5 in acetonitrile. [35] p-fluoroanisole 158 was used as a reference for this chemical shifts measurements. The obtained values for β-CD NHIs did not much vary, considering the employed ligand (Δ = 0.4). This difference is not significant due to possible errors in manipulations. Thus, the obtained pKBH+ values may be seen as constant for β-CD NHIs. However, the employed ligand for the model NHIs gave important differences (Δ = 1.6) and logically led to the 4,5dimethyl-NHI 165 being the more basic thanks to its donating methyl groups.

Considering the high pKa value obtained for p-fluorophenol 156, the obtained values should not be seen as precise values but used only for comparison of the different synthesised NHIs.

The use of another base with a pKa value closer to Et3N's one should be considered in order to obtain precise values. The use of phosphorus bases might be considered as 31 P NMR is known to be sensitive and has already been used for pKBH+ measurements of organic bases. [38] Figure Alexandre Martinez and his team showed that the encapsulation of a proazaphosphatrane base led to an increase of basicity up to a 30-fold. [39], [40] This increase was attributed to stabilising cation-π interactions between the acidic proton and the aromatic linkers present on the hemicryptophane (see Scheme I-15).

Enzyme actives sites are known to perturb the pKa values of the bases present within the hydrophobic pockets. Acidic species tend to be more acidic within the pocket whereas bases see their basicity decrease. These perturbations are explained by the possibility of having interactions between the studied base or acid, and the environment. These interactions can be of different nature such as charge-charge interactions, charge-dipole interactions or from desolvation effect. [41] The case of encapsulated proazaphosphatranes falls in charge-dipole interactions as the aromatic linkers create microscopic dipoles able to stabilize the positive charge present on the phosphorus atom (Figure II-17 A)). However, the case of encapsulated NHIs could not be explained by charge-charge or charge-dipole interactions as the interior of the CDs are paved with C-H bonds.

Acetoacetate decarboxylase (AAD) is an enzyme known to catalyse the decarboxylation reaction of acetoacetate through the formation of a Shiff base intermediate with a nucleophilic lysine. This lysine was shown to present a pKa value decreased of 4.4 unit when buried inside the enzyme compared to the non-buried one. [42] This decrease was explained by the hydrophobic environment of the active site that destabilised the protonated amine

(Figure II-17 B)
). [43] This comes from desolvation effects that correspond to the unfavourable transfer of a single charged group from an aqueous solvent of high polarity to the hydrophobic interior of a protein presenting a much lower dielectric constant.

The case of CD-encapsulated NHIs might fall in this case as they present a hydrophobic

Comparison of Lewis basicities

This unexpected cavity effect for Brønsted-Lowry basicities led to questioning this effect on Lewis basicity.

Several scales exist for measuring Lewis basicity and affinity. [44] The usual techniques in condensed phase involve the addition of SbCl5 or BF3 and the calorimetric measurement of the reaction's enthalpy. Despite the usefulness of these methods and the numerous tabulated Lewis bases affinities, these methods require specific setups and expertise as, for example, the BF3 affinity scale requires the use of pure gaseous borate.

Due to the difficulty of performing such measurements, a simple Lewis basicity comparison of the synthesised NHIs was chosen. Inspired by the BF3 affinity scale, the neutral NHIs were mixed with borane dimethylsulfide complex (2 M in THF) and the 11 ). [2] The benzimidazole carbene is the strongest π-acceptor, followed by the imidazole one and finally the 4,5-dimethyl one. This result was in accordance with what might be expected considering the modification of the electronic nature of the ligand.

In the same way as for pKBH+ measurements, β-CD NHIs borane adducts presented similar chemical shifts with a maximal variation of 0. To sum up, the addition of Me2S•BH3 on NHIs revealed a diminution of the Lewis basicity for encapsulated NHIs. Whereas the model compounds presented 11 B chemical shifts in accordance to their π-donation properties, encapsulated NHIs all led to the obtention of the same 11 B chemical shift. The different ligands did not lead to any significant differences and the inverted NHI (α-out-ICyD)NH 143 led to the formation of an adduct presenting a similar 11 B chemical shift close to the model compound. Therefore, the sole role of the cavity is to consider in the decrease of the Lewis basicity. The pavement of the CDs cavity with C-H bonds is probably the reason of this decrease and has yet to be explained.

Freeze-pump-thawing solutions of β-CD NHIs with CO2 did not lead to the formation of an adduct. However, these trials should be performed again using higher pressures in order to draw conclusions about encapsulated NHIs abilities to form adducts with CO2.

Conclusion

In conclusion, the synthesis of encapsulated NHIs was achieved through the use of )

As the pKa value of a base with its conjugated acid is commonly called a pKBH+ value:

(B) 𝑝𝐾 𝐵𝐻+(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) = 𝑝𝐾 𝑎(𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) + log (

𝑥 𝑒𝑞 ² (𝐶 0 -𝑥 𝑒𝑞 )(𝐶 ′ 0 -𝑥 𝑒𝑞 )
)

Combining equations (A) and (B) affords the possibility of measuring pKBH+ values using 19 F NMR.

Annex II-2. Demonstrations of the equations used for pKa and pKBH+ determinations.

Lewis acidic boron compounds

Lewis acids are chemical entities presenting an empty orbital. Amidst Lewis acids are compounds containing a boron atom. Boron is a metalloid and the first element of group 15. When trivalent, its electronic configuration, [He] 2s 2 2p 4 , indicates the presence of an empty orbital that is usually filled by a Lewis base, forming a Lewis adduct. Boroncontaining compounds are often used for hydroboration reactions (with boranes), as electrophilic activators for substitution reactions (with BF3) and in Suzuki-Miyaura couplings (with boronic acids). Boranes are also the archetypical Lewis acids used in FLPs (Scheme III-1). [1]- [3] Scheme III-1. Examples of boron-containing FLPs for gas activation.

The strong Lewis acidity of these fluorinated aryl boranes is the reason for their popularity in FLP chemistry. However, cationic two-, three-and four-coordinated boron compounds exist and present usually stronger Lewis acidities.

Cationic boron compounds, borocations

Cationic boron compounds, also called borocations, gained attention with the structural elucidation of "diammoniate of diborane", [H2B(NH3)2 + ][Cl -], complex in 1955 by Sheldon Shore and Robert Parry. [4] These sextet boron salts can be described in function of their valences. Borinium ions are two-coordinated cations presenting two σ bounds.

Borenium ions are three-coordinated cations presenting two σ bounds and a dative bond stabilising the cation. [5] Boronium ions are four-coordinated cations presenting two σ bounds and two dative bonds increasing the stabilisation, and are the most common (Figure III-1). Borocations can be formed following several strategies summarized in Scheme III-2. [5], [6] B-X bond hydrolysis by a metal Lewis acid can afford borinium and borenium ions

(Scheme III-2 A) & B)
). The protonation of an amine ligand of borane amine complexes can afford borenium ions (Scheme III-2 C)). The presence of an electrophile inducing its addition at a B-N bond can afford a borinium ion (Scheme III-2 D)). The nucleophilic displacement of a leaving group with a ligand can afford a borenium ion (Scheme III-2 E)). The metathesis of an electrophile with a metal salt can also lead to the formation of a borenium ion (Scheme III-2 F)).

Scheme III-2. Usual strategies for borocations formation.

These strategies were used for the formation of the different borocations and will now be presented.

A. Borinium ions

Because of their extremely low-valence, borinium ions are highly reactive and their obtention in condensed-phase is harsh to achieve. They were first described in 1948 by Vernon Dibeler and Fred Mohler with the formation of the BH2 + ion 165 by electron ionization of diborane 164 (Scheme III-3 A)). [7] In 1982, John Higashi, Alan Eastman and Robert Parry reported the first obtention of a borinium ion in condensed phase. [8] Reacting boramine 166 with one equivalent of AlCl3 led to the obtention of the bis(amido)borinium ion 167 (Scheme III-3 B)). This formation was made possible by the presence of the two amido substituents stabilizing the ion by π-donation.

Scheme III-3. A) Formation of the first borinium ion B) Formation of the first condensed-phase borinium ion.

During the 20 th century, only few borinium ions bearing alkyl-and aryl-substituents (168 and 169, Scheme III-4) were described. [4] These borinium ions were also formed through a B-X bond heterolysis. They were shown to be unstable at room temperature and required the presence of the bulky tetramethylpiperidino group for their formation.

Scheme III-4. Borinium ions bearing alkyl-and aryl-substituents.

The chemistry of condensed-phase borinium ions recently gained attention with the synthesis of several stable borinium ions. The borinium ion bearing phosphinimides groups 170 was isolated in 2002, [9] the borinium ion 171 bearing two mesityl groups in 2014 [10] and the borinium ion stabilised by an NHI, 172, in 2019 (Figure III-2). [11] Finally, the borinium ion 173 was isolated in 2021 and was said to catalyse cyanosilylation and hydrosilylation reactions. [12] All condensed-phase borinium ions presented groups performing π-donations in order to stabilise the cation. Hence, borinium ions, due to their high reactivity are difficult to form and to isolate.

Their use in catalysis is harsh because of these high reactivities.

B. Borenium ions

The first notation of a borenium ion appeared in the literature in 1933 in a publication by Egon Wiberg and Karl Schuster. [13] The reaction of dichloro(dimethylamino)borane 174 and hydrochloric acid was said to induce the formation of "BCl2N(CH3)2•HCl" which in today's terms would correspond to the borenium ion 175 (Scheme III-5). However, no charge was drawn nor the compound was described as a low-valance boron compound.

Scheme III-5. First notation of a borenium ion by Egon Wiberg and Karl Schuster

Until 1970, borenium ions were only assumed to exist. In a work named "A Trigonal Boron Cation", George Ryschkewitsch and Wendell Wiggins described the formation of borenium 177 by the B-Cl bond metathesis of borate 176 using Al2Cl6 (Scheme III-6 B)). [14] This borenium ion was characterized by NMR and presented the exceptionally high chemical shift of 47.3 ppm in 11 B NMR. Unfortunately, 177 was not isolated. However, its close analogue, bearing a lutidine ligand (178) instead of the picoline, was recently isolated and presented a similar 11 B NMR chemical shift of 46.9 ppm confirming the formation of 177 in the first place. [15] Scheme III-6. B) First described borenium ion B) Analogue 178.

Since these pioneering works, different strategies were used for the formation of borenium ions. The protonation of the B-N bond of oxazaborolidine 179 with triflic acid afforded the borenium salt 180 that was not directly observed but used as a Lewis acid catalyst for Diels-Alder reactions (Scheme III-7 A)). [16] The borenium salt 182 was formed through the B-Cl bond heterolysis of borane 181 with the use of SbCl5 and presented a 11 B NMR signal at 58.2 ppm (Scheme III-7 B)). [17] This strategy was applied to the formation of the borenium salt 184 (Scheme III-7 C)). [18] The use of [Et3Si + ][B(C6F5)4 -] allowed a B-F bond heterolysis and afforded the borenium ion with the convenient weakly interacting tetrakis(pentafluorophenyl)borate anion. This borenium ion presented a 11 allowed the hydride abstraction reaction on borate 185, leading to the formation of the corresponding borenium ion 186 presenting a broad 11 B NMR signal at 59 ppm (Scheme III-7 D)). [19] Scheme III-7. A) Borenium ion formation using the protonation of a B-N bond strategy B) Borenium ion formation using B-X heterolysis with SbCl5 C) Borenium ion formation using B-X heterolysis using triethylsilylium ion D) Borenium ion formation using hydride abstraction.

These borenium salts all presented a nitrogen atom directly linked to the boron centre. The nitrogen atom could stabilise the charge by π-donation. The presence of an oxygen atom or an aromatic group also acted for charge-stabilisation by π-donation. The high 11 B chemical shifts of these compounds are characteristic of cationic trivalent boron species.

Concerning their reactivity, chemists took advantage of the high Lewis acidity of borenium ions.

Chiral borenium ion 180 was shown to catalyse asymmetric Diels-Alder reactions (Scheme III-8). [16] The reaction allowed the obtention of a high exo/endo selectivity of 81:17.

Scheme III-8. Borenium ion catalysed asymmetric Diels-Alder reaction.

Borenium ions were also shown to perform C-H borylation reactions of arenes. [20] This reactivity was used for the formation of picanol boronates building blocks (Scheme III-9). [21] First, chloroborane 187 was reacted with AlCl3 forming the borenium salt 188 by B-Cl bond heterolysis. The salt was reacted with N,N-dimethylaniline and the borenium performed an electrophilic borylation reaction, selectively on the para position, forming borane 189.

Finally, picanol and Et3N were added leading to the formation of the arylated pinacolborane 190 with 85% yield. This method was extended to numerous aryl groups.

Scheme III-9. Pinacole boronate synthesis through arene borylation with a borenium ion.

Tricoordinate boron compounds were shown to insert in C-H bonds upon heating. [22] Borenium ions are no exception to the rule and, because of their high Lewis acidity, can react at lower temperature. Aleksandrs Prokofjevs and Edwin Vedejs took advantage of this reactivity to perform aliphatic C-H borylations (Scheme III-10). [23] In this reaction, sterically Scheme III-10. C-H borylation of alkyl with a borenium ion.

In summary, borenium ions were synthesised using three main strategies and afforded many compounds. All presented strongly deshielded 11 B NMR signals that were often broad. These compounds were shown to be very reactive towards C-H insertion reactions offering new strategies to synthesise valuable building blocks as shown with the formation of aryl pinacolboranes. So far, all compounds presented amino groups that stabilised the formed borenium ions. NHCs can also be used as ligands to stabilise these ions and will be presented in a separated part.

C. Boronium ions

Among tricoordinate borocations, boronium ions were the most studied because of their relative stability. The presence of two ligands concomitantly to the two covalent bonds help to stabilise the cationic specie. H. Nöth, H. Beyer and H.-J. Vetter [24] on one hand and V. Sheludyakov, T. Shchegoleva and B. Mikhailov [25] on the other hand formed the first boronium salts almost at the same time. Both teams used the nucleophilic displacement strategy, with a chloride for the German team (Scheme III-11 A)) and a thiolate for the Soviet Union team (Scheme III-11 B)). (Scheme III-12). [26] The 11 The addition of bisamino-naphtalene ligand 200 to the triflimide-BBN borate 199 led to the formation of borenium ion 201 by nucleophilic displacement (Scheme III-13). [27] The intermediate reacted immediately with the other amine present on the naphthalene moiety, leading to the formation of the extremely sterically hindered boronium salt 202. This boronium ion presented a surprisingly high 11 The addition of triflic acid to a boronic acid presenting an alcoholate ligand led to the formation of the corresponding boronium ion 203 with a THF ligand (Scheme III-14). [28] This boronium salt showed a 11 B NMR signal at 3.91 ppm indicating a tetracoordinated borocation and was shown to catalyse the polymerisation reaction of propylene oxide by its Lewis acidity.

Scheme III-14. Formation of boronium 203 through protonation inducing a nucleophilic displacement.

To sum up, boronium ions were broadly studied thanks to their relative stability brought by the additional ligand compared to borenium ions. Their 11 B NMR signals were upfielded compared to borenium ions, due to their lower acidity. Nonetheless, boronium salts were shown to be reactive in stoichiometric C-H borylation reactions and also as catalysts for polymerisation reactions.

In summary for this part, the family of borocations contains three members. Dicoordinated borinium ions present two covalent bonds and are very reactive. Due to this high reactivity, only few were obtained in condensed phase. Three-coordinated borenium ions present two covalent bonds and a ligand. Numerous borenium ions were obtained thanks to their higher stability. However, all stable borenium ions presented amine groups stabilizing the cation and most of them were sterically hindered. Due to their high reactivity, aminestabilised dihydrido borenium ions were not isolated. Still, considering their relatively easy obtention and their reactivity, borenium ions stand as compounds of choice for performing reactions using borocations. Their strong Lewis acidity was evaluated and was shown to depend on the steric and the electronic availability of the vacant p-orbital on the boron centre. [29] Finally, Four-coordinated boronium ions present two covalent bonds and two ligands stabilizing even more the ion. They were the most studied thanks to their relative stability. Nonetheless, boronium ions were used in catalysis and strongly Lewis acidic boronium ions were able to perform C-H borylation reactions. In this presentation of borocations, borenium ions presenting a carbene as a ligand were omitted and will now be presented. The charge of the ions will now no longer be presented in brackets but simply on the top right corner of the cation, for clarity.

NHC-borenium ions

NHCs were shown to be very useful for the formation of stable metal complexes and to use in catalysis. Their strong π-donation was used for the formation of NHC-borane complexes and their transformation to the corresponding borenium ions.

A. NHC-boranes NHC-boranes were synthesised at the end of the 20 th century, first using two methods. The use of BuLi on imidazole-borane complex 204 led to the formation of the corresponding carbene inducing the ligand exchange forming the carbone-borane adduct 205

(Scheme III-15 A)). [30] The addition of MeI led to the formation of the NHC-borane adduct 206 with a 69% yield and presenting a 11 B chemical shift of -12.6 ppm indicating the formation of a tetracoordinated boron atom. An easier protocol was described by Norbert Kuhn, Andreas Maulitz and their collaborators (Scheme III-15 B)). [31] The simple addition of borane dimethylsulfide complex to a NHC led to the formation of the corresponding NHC-borane adducts presenting methyl (207), ethyl (208) or iso-propyl (209) groups on 1,3 positions. These new borane complexes presented 11 B chemical shifts of -34.9, -35.1 and -34.1 ppm respectively indicating once again the presence of a tetracoordinated boron atom.

Many other NHC-borane adducts were synthesised including ones presenting dipp groups on 1,3 positions (210) [32] and BF3 [33] or B(C6F5)3 [34] groups (Scheme III-15 C)). Usually, NHC-boranes bearing BH3 groups and monoalkyl-and arylborane complexes are stable and can even be purified on silica gel chromatography. [35], [36] dimerization was caused by the lack of steric hindrance at the boron atom and by the weak stabilisation brought by the NHC ligand. The addition of (E)-3-hexene after the formation of bistriflimide borane 212 induced, after workup, the formation of 3-hexanol indicating the alkene underwent a hydroboration reaction (Scheme III-18). The reaction was also performed using catalytic amounts of HNTf2

indicating the presence of a reactive boron specie towards the hydroboration reaction.

Scheme III-18. Catalysed hydroboration of (E)-3-hexene followed by an oxidation. The dihydrido borenium ion 214 is believed to be a possible active specie in the catalytic hydroboration reaction of alkenes. However, it could not be isolated. Other methods were tried in order to isolate a dihydrido borenium ion.

Isolation of a stable dihydrido borenium ion

The use of hydride-abstracting Lewis acids with non-coordinating counter-anion also led to the obtention of the bridged compounds.

The use of 0.5 equivalents of trityl salt with borane 191 afforded the dimeric compound 192 (Scheme III-19 A)). [23], [38] Concerning NHC-boranes, the use of 1.0 equivalent of BCF led to the consumption of only 0.5 equivalents of the Lewis acid and the formation of the bridged compound 217 (Scheme III-19 B)). [39] Scheme III-19. A) Formation of bridged compound 192 through hydride abstraction using a trityl salt B) Formation of bridged compound 217 through hydride abstraction using BCF.

The presence of only one stabilising group on the desired borenium ions, coupled with the lack of steric hindrance around the boron centre are believed to be responsible for the spontaneous formation of the bridged compounds 192 and 217 and the impossibility to observe the monomeric dihydrido borenium ions.

Manuel Alcarazo and his team managed to overcome this issue by using hexaphenylcarbodiphosphorane 218 as the ligand. [39] The corresponding borane 219 was formed using Me2S•BH3. BCF was then used to perform the hydride abstraction which afforded the dihydrido borenium salt 220 in 97% yield (Scheme III-20 A)). This ion was characterised by X-ray crystallography and presented a broad 11 B NMR signal at 57.0 ppm.

The isolation of this borenium salt was made possible by the use of a carbodiphosphorane ligand. This ligand presents strong π-and σ-donation effects thanks to the four valence electrons present on the central carbon (Scheme III-20 B)). It is the presence of those four electrons that stabilised the dihydrido borenium ion.

Scheme III-20. A) Formation of a dihydrido borenium ion stabilised by a carbodiphosphorane ligand B) Highlighted stabilisation mechanisms brought by the ligand.

Hence, NHC-boranes were mainly synthesised using the ligand exchange strategy with another borane complexes. These boranes showed poor reactivity towards acid/base reactions with acids presenting pKa values above 2, showing their stability. The presence of stronger acids allowed the formation of boranes with a counterion covalently linked to the boron centre. Bistriflimide borane 212 allowed to catalyse a hydroboration reaction that do not occur in presence of NHC-BH3 boranes. A possible active specie was believed to be the NHC-dihydrido borenium ion. It was not isolated due to the lack of stabilising groups and of the poor steric hindrance at the boron atom. Manuel Alcarazo and his team managed to form a dihydrido borenium ion using a carbodiphosphorane ligand that managed to stabilise this reactive specie thanks to the presence of four electrons. Nonetheless, many other NHCborenium salts were synthesised while bearing alkyl or aryl groups. These borenium ions display interesting properties towards gas activation and catalysis, and will now be presented.

B. NHC-borenium ions

Despite the apparent impossibility to obtain an NHC-dihydrido borenium ion, the presence of other sterically hindering groups on the boron centre allows the formation of stable NHC-borenium ions.

These NHC-borenium were formed in apolar solvents (toluene, benzene derivatives or CD2Cl2) to avoid the formation of the corresponding boronium salts. The use of the Almost all these NHC-borenium ions were characterised by X-ray diffraction thanks to the obtention of crystals. Nevertheless, the NMR of these compounds revealed interesting information.

NMR characterization of borenium ions

Boron nucleus presents two isotopes, 11 Boron being a quadripolar nucleus, the electric charge distributed inside the nucleus is not spherical. Because of this anisotropy, the electric charge can interact with any field gradient present around the nucleus. This implies a very efficient relaxation mechanism, dominated by the quadrupolar relaxation mechanism. This leads to very short relaxation times. [48] The line width at half height (ν1/2, Hz) of the 11 B NMR signal depends on the transverse relaxation time (T2) following ν1/2 ≈ 1/T2. This implies that the shorter the relaxation time, the broader the signal.

This effect can also be observed on the NMR spectra of other nuclei linked to the boron atom. The spin-spin couplings between an atom and the boron nucleus can be clearly visible, partially or completely collapsed or reduced to a single sharp line depending on the quadrupolar effect.

Usually, the 11 . Almost all these signals were described as "broad" singlets, up to ν1/2 = 1500 Hz for 234. This indicated a very fast relaxation mechanism inducing a short relaxation time. [6] The charge on the borenium ions interacts with the field gradient around the boron nucleus and heightens the quadrupolar effect of the boron. The quadrupolar effect being more important, the relaxation times get smaller and the line widths bigger. In order to increase the sensitivity of the NMR experiments, the 11 B NMR spectra of borenium 224 have been recorded in a quartz NMR tube presenting about 0.01 ppm of boron atoms. [41] Figure III-5. 11 B NMR data of several NHC-borenium ions.

The line width of an NMR signal is dependant of the correlation time (τC) of the molecule. The correlation time corresponds to the time needed for a molecule to spin of one radian. Therefore, an increase of the temperature leads to smaller τC values and sharpens the NMR signal. This property was used by Gerhard Erker and his team to prove the obtention of a 11 B NMR signal for borenium ion 233. [45] At room temperature, the 11 Performing a variation of temperature induced the disappearance of the 11 B NMR signal at low temperatures allowing the attribution of the signal to the borenium centre without a doubt. 1 H NMR was also impacted by the formation of the borenium ions as the signals did not present any spin-spin couplings as in the corresponding boranes.

Reactivity of NHC-borenium ions

NHC-borenium ions were shown to perform hydroboration reactions. They also operate C-H borylation reactions of alkyl and aryl compounds. [45] These reactivities were used by Frank Würthner and his team for the formation of a boron-doped perylene. [49] Reacting borane 235 with HNTf2 formed the elusive dihydrido borenium ion which then performed a hydroboration and a C-H borylation reaction on anthracene 236 forming compound 237. Treatment of this compound with TEMPO afforded perylene 238 in an elegant use of borenium ions (Scheme III-22).

Scheme III-22. Synthesis of a boron-dopped perylene by NHC-borenium mediated hydroboration and C-H borylation

NHC-borenium ions were also shown to open THF when a nucleophile was present in the media (Scheme III-23). [50] Many Lewis acids are known to open THF.

Scheme III-23. THF opening by an NHC-borenium ion in presence of a nucleophile.

Borenium ion 226 was used by Douglas Stephan and his team to activate H2 in an FLP system with PtBu3, affording borane 225 (Scheme III-24 A)). [42] This borenium was used to catalyse imine and enamine reductions under high pressures of H2 (102 bars). In this example, the imine or enamine present in the reaction plays the role of the base in the FLP for H2 activation, before it is reduced by the formed borane 225 (Scheme III-24 B)).

Scheme III-24. A) NHC-borenium ion, FLP-mediated, H2 activation B) Proposed mechanism for imine reduction and reduced imines and enamines.

Borenium ion 228 formed by Huadong Wang and his team managed to activate H2 without the help of an exogenous Lewis base, forming the boronium salt 239 (Scheme III-25). [43] Scheme III-25. H2 activation by borenium ion 228.

The borenium salt 230 was recently shown to activate methane, under 60 bars of pressure, to afford the alkylated borenium ion 240 (Scheme III-26). [51] The addition of two equivalents of HBcat induced a double hydride transfer reaction leading to the methylation of Bcat and the formation of the starting borane 229. This alkyl activation was also performed using ethane (30 bar), n-octane (300 eq) and toluene (350 eq).

Scheme III-26. Synthetic cycle of methane activation and HBcat methylation by borenium ion 230.

Borenium ion 233, formed by Gerhard Erker and his team, managed to perform a classical hydroboration reaction of an alkene, leading to the formation of borenium ion 241 bearing a phosphine group (Scheme III-27 A). [45] This intramolecular FLP managed to activate H2 under one bar of pressure. Borenium ion 233 also formed adducts with carbon monoxide leading to the formation of boronium salt 243 (Scheme III-27 B)). This boronium salt reacted with several nucleophiles that got attached to carbon monoxide's carbon atom.

Boronium 243 also reacted with Schwartz's reagent (Cp2Zr(H)Cl) which reduced the carbonyl ligand that, after addition of pyridine, afforded the boronium salt 244.

Scheme III-27. A) Formation of intramolecular FLP 241 and H2 activation B) Formation of boronium 243 containing CO and its reduction.

The same borenium ion was also reacted with elemental sulfur, leading to the formation of the protonated thioxoborane 245 (Scheme III-28). [52] This protonated thioxoborane 245 managed, after deprotonation, to perform CO2 activation via a formal

[2+2] cycloaddition reaction.

Scheme III-28. Formation of thioxoborane 245 and its use in CO2 activation.

Hence, NHC-borenium ions were shown to perform a variety of reactions. The use of their ability to perform hydroboration and C-H borylation reactions allowed their use in the formation of a boron-doped perylene. They were also used in FLP systems and used for imine reductions. The carborane-based NHC-borenium ion 230 even managed to activate methane and to perform the methylation reaction of HBPin. NHC-borenium ions also allowed the formation of adducts with carbon monoxide that were then reduced thanks to this activation. NHC-borenium also allowed the obtention of a NHC-stabilised thioxoborane that showed reactivity towards CO2 activation.

In conclusion for this part, it has been shown that among Lewis acids, boroncontaining compounds are very popular. The formation of cationic di-, tri-and tetracoordinate boron compounds opened the way for the obtention of new reactivities.

Borinium ions, due to their lack of electrons, were shown to be very reactive and hard to get in condensed phase. Borenium ions, on the contrary, were shown to be isolable and presented interesting reactivities towards C-H borylation reactions. Boronium ions were the most studied thanks to their relative stability. NHC-stabilised borenium ions were discovered at the end of the 20 th century, and attention for these ions has grown during the past decade.

Many alkylated and arylated NHC-borenium ions arose, and the NHC-dihydrido borenium, believed to be present in several reactions, is yet to be isolated. These NHC-borenium ions presented similar, downfield and broad 11 B NMR signals. However, the use of quartz NMR tubes or variable temperature allowed the characterisation of the 11 B NMR signal of these borenium ions. NHC-borenium ions managed to perform hydroboration reactions and C-H borylation reactions, as the ones stabilised with other ligands. However, these ions were shown to be particularly interesting for small molecule activation. They were shown to activate H2 and methane and to form adducts with CO and elemental sulfur.

As the objective of this thesis was the synthesis of Lewis acids and bases confined within the cavity of CDs, the formation of a NHC-borenium ion inside the cavity seemed to be the perfect choice to obtain new catalysts. The cavity might bring the steric hindrance needed for the obtention of new borenium ions while still presenting its benefits in catalysis.

Encapsulated NHC-boranes

The synthesis of a borane encapsulated inside the cavity of a CD was first tried using 9-BBN. This compound was chosen because it is a precursor of a borenium ion that was shown to perform imine reduction reactions with H2. [42] The reaction between (β-ICyD)HCl 85, KHMDS and 9-BBN did not lead to the formation of the encapsulated borane 247 (Scheme III-29).

Scheme III-29. Trial of (β-ICyD)BBN 247 synthesis.

The impossibility to obtain an NHC-9BBN inside the cavity of a β-CD was probably due to the size of 9-BBN that could not get inside the CD. Therefore, the formation of an encapsulated borane was carried out using the smallest, commercially available, borane, Me2S•BH3. As mentioned in this part introduction, the NHC-dihydrido borenium ion was not isolated due to a lack of stabilisation brought by the NHC ligand. Bringing a cavity into the equation could not help towards electronic stability. However, its presence might bring enough steric hindrance to prevent the dimerization of the borenium ion, thus allowing its formation.

A. Synthesis of NHC-boranes encapsulated inside CDs.

Reacting the (ICyD)HCl salts 84 -85, 132, 135, 144 and 147, with KHMDS (2.0 eq) and Me2S•BH3 (2.0 eq) in THF led to the easy obtention of the corresponding encapsulated boranes with good yields (Scheme III-30). The (α-ICyD)BH3 adduct 248 was obtained in 81% yield, the (α-BiCyD)BH3 adduct 249 in 47% yield, the (α-MiCyD)BH3 250 adduct in 70% yield, the (β-ICyD)BH3 adduct 251 in 74% yield, the (β-BiCyD)BH3 adduct 252 in 22% yield and finally, the (β-MiCyD)BH3 adduct 253 in 78% yield. These compounds were stable on silica and gram-scale synthesis were performed. However, lowering the equivalents of KHMDS and Me2S•BH3 led to lower yields.

B. NMR spectra of encapsulated NHC-boranes

The 1 H NMR spectra of encapsulated NHC-boranes revealed a strong deshielding of the H 5 A/D of α-CDs and of H 5 A and H 5 D for β-CDs (Table III-2). These deshieldings were similar to the ones obtained with the encapsulation of metals within the cavity of CDs.

Among the two series of CDs, the BiCyD ones presented the highest deshieldings (6.34 ppm for (α-BiCyD)BH3 249 and 5.10 & 5.11 ppm for (β-BiCyD)BH3 252).

H 5 A/D (ppm) H 5 A & H The reason for the deshielding of the H 5 A/D protons of (α-ICyD Me )Au,Ag,Cu complexes was recently studied. [53] NMR analysis coupled to DFT calculations revealed the presence of "contra-electrostatic H bonds" between the encapsulated metal and the H 5 protons. In these special H bonds, the metal donates electrons through its d orbital to the σ * orbital of the C-H 5 bond (Figure III-8). This component is stabilising. Because of that donation, the metal and the H 5 present positive partial charges (Figure III-8). This leads to a repulsive electrostatic component. Partially because of that electrostatic interaction, the closest the H 5 is to the metal, the most it gets partially charged. Therefore, it is logical that H 5 A, the closest proton to the metal centre, presents the more deshielded signal in 1 H NMR. Boron does not present a filled d orbital. Therefore, "contra-electrostatic H bonds" may not be considered to explain the deshieldings. Computational studies of the boranetrimethylamine dimer revealed the presence of dihydrogen bonding between B-H and methylic C-H hydrogens for a distance of 2.4 Å between the two atoms. [54] This interaction implied the formation of a partial positive charge on the C-H proton (Figure III-9).

Extrapolating this result to encapsulated boranes, the H 5 may also form dihydrogen bonding with the borane leading to the presence of a partial positive charge (Figure III-9). This partial positive charge could lead to the observed strong deshieldings of the H 5 A/D protons. DFT studies of encapsulated boranes could be very interesting for the understanding of this unusual interaction. In order to understand the effect of encapsulation on the boron nucleus, a model compound bearing iso-propyl groups 235 was synthesised (Scheme III-31).

Scheme III-31. Synthesis of model IiPrNHC-borane 235.

For encapsulated boranes, the obtained 11 B{ 1 H} NMR shifts, between -32.3 and -35.9 ppm, were characteristic of NHC-boranes (Table III-3). [36], [55] However, 11 δ 11 As expected for quadripolar nuclei, the peak broadness was also found on 1 H NMR spectra. In order to prove the efficiency of the decoupling method, the NMR sequence was also performed on model compound 235. sequence with an inverse gate on a 600 MHz NMR spectrometer. An inverse gate is a mode of decoupling that prevents the NOE effect to be transferred to the decoupled nucleus. This transfer would result in a loss of intensity of the signal. Unfortunately, the T2 * value of (α-ICyD)BH3 248 could not, yet, be obtained due to an NMR probe issue. Measurements were made on a 400 MHz spectrometer but led to unexploitable results due to bad signal-to-noise ratios. The model compound 235 afforded a 11 Quadripular nuclei present an anisotropic distribution of the electric charge around the nuclei which is sensitive to any field gradient. The electrical symmetry of the molecule is known to impact the field gradient. For a symmetric field gradient, the quadripolar effect is moderated. Whereas, for an asymmetric field gradient, the quadripolar effect is exacerbated.

Model compound 235 is a small molecule and the environment around the boron nucleus rather "free". Therefore, the electric field gradient around the boron nucleus is not very asymmetric and even may be averaged by the solvent.

The presence of the cavity around the boron nucleus will induce a strong asymmetry in the environment of the nucleus. (β-ICyD)BH3 251 presents a C1 symmetry. Therefore, the boron nucleus is subject to seven different electric environments and each should interact with the field gradient. The field gradient around the boron nucleus is likely strongly asymmetric and probably leads to an exacerbated quadripolar effect. This asymmetry in the electric field gradient around the boron nucleus probably explains the 50-fold difference on T2 * between model compound 235 and (β-ICyD)BH3 251.

If the NMR signal is in a Lorentzian lineshape, it is possible to get an approximation of the transversal relaxation time by applying the following relation:

𝑇 2 * = 1 𝜋 𝜈 1/2
Applying this relation to encapsulated boranes led to the obtention of approximative but coherent transversal relaxation times that should be confirmed by thorough measurements (Table III The model compound presented a chemical shift at -37.0 ppm (Table III- δ 11 The 11 B chemical shifts of β-CD encapsulated boranes did not vary much with nature of the ligand. However, (α-BiCyD)BH3 249 led to the most upfield 11 B chemical shift of -32.3 ppm consistent with the poor σ-donation of the benzimidazole carbene. (α-BiCyD)BH3 also led to the most deshielded hydrides at 1.92ppm.

The study of the 13 C shifts of the carbon atom linked to the borane was consistent with the poor π-donation of the benzimidazole units ( Hence, the encapsulation of boranes led to important deshieldings of the H 5 A and H 5 D (for β-CDs) pointing towards the inside of the cavities. These deshieldings were consistent with metal encapsulation that were studied in the laboratory and might indicate dihydrogen bonding between the hydrides and the H 5 of the CDs. Interestingly, the 11

C. Obtention of crystals for X-ray diffraction measurements

The obtention of crystals with benzylated CDs is not possible. However, the synthesis of CDs bearing methyl protecting groups leads to compounds that can form crystals suitable for X-ray diffraction measurements.

The synthesis of methylated CD-encapsulated boranes required additional steps (Scheme III-32). The previously formed diols 80 and 81 were first protected with THP groups forming 254 and 255. The CDs were then catalytically debenzylated using H2 with palladium on carbon to afford 256 and 257. The products were then methylated using NaH and MeI and finally the THP protecting groups were removed under acidic conditions to afford diols 260 (16% yield over four steps) and 261 (47% yield over four steps). The diols were then mesylated and the mesylates exchanged with iodine to afford the di-iodo products 262 and The very small distance between the boron atom and H 5 A/D (2.522 Å) may serve the hypothesis of dihydrogen bonding between the hydrides and H 5 A/D. This would explain the strong deshielding observed for H 5 A/D. The distance between the boron atom and the NHC carbon atom (1.609 Å) was in accordance with the distances usually found for other NHC-BH3 adducts. [31] Figure III-14. A) Crystallographic structure of (α-ICyD Me )BH3 268 B) Highlighted H 5

protons inside (α-ICyD Me )BH3

268, half sugar units omitted for clarity.

To sum-up, the synthesis of methylated CDs allowed the obtention of (α-ICyD Me )BH3

268 crystals suitable for X-ray diffraction analysis. The boron atom was found at the level of the H 5 . Despite not having obtained crystals for the other encapsulated boranes, the deshieldings of the H 5 A and H 5 D (for β-CDs) of these adducts were coherent with the boron atom being encapsulated within the cavity.

Finally (β-ICyD)BH3 251 was reacted with the triethyloxonium [OEt3][BF4] in order to try the hydride abstraction reaction with a small electrophile (Scheme III-35 A)). The expected boronium ion 271 was not obtained. In fact, the obtained product was characterised as the trifluoroborane 270 probably formed through a fluorine exchange followed by a borane exchange (Scheme III-35 B)).

Scheme III-35. A) Reaction of (β-ICyD)BH3 251 with [OEt3][BF4] B) Possible mechanism for (β-ICyD)BF3 270

formation.

Hence, encapsulated boranes reacted as their non-encapsulated analogues. Acetic acid did not react on (α-ICyD)BH3 248. The use of stronger triflic acid led to the formation of unknown products with the disappearance of the NHC-borane 11

Encapsulated borenium ions

As encapsulated boranes were found to react with the hydride abstracting oxonium The usual protocols for the isolation of borenium ions involve a recrystallisation process. [42], [45] As the obtention of crystals is not possible with benzylated CDs, the formed compound was studied in situ by NMR.

The cavity of CDs was shown to prevent the dimerization of copper hydride that usually happens even with very bulky ligands (Figure III-16 A) & B)

). [56], [57] Therefore, the presence of the cavity around the boron atom should also prevent the formation of the bridged compound of the dihydrido borenium ion (α-ICyD)BH2 + 272 with the borane. For unencapsulated NHC-boranes, only 0.5 equivalents of the hydride-abstracting reagent reacted and led to the formation of the dimeric-bridged compound 217 (Scheme III-37 A)). [39] Therefore, having a full conversion of the trityl salt was a good indication for the absence of formation of the bridged compound.

Scheme III-37. A) Formation of bridged compound with an NHC-borane B) Possible prevention of the formation of the bridged compound by the cavity of the CD.

The 11 B{ 1 H} NMR spectrum of the reaction only afforded a signal for the counterion B(C6F5)4 -. The 11 B signal of the formed specie was not found. An important parameter was the stability of the formed specie. Borenium ions are known to be very reactive and, among other things, they perform slow hydride-chloride exchange reactions in CD2Cl2 (Scheme III-38). [45] Scheme III-38. Chloride-hydride reaction between borenium ion 233 and CD2Cl2.

The hydride abstraction reaction of (α-ICyD)BH3 248 was performed under several different conditions and the reactions were monitored over time by 1 H NMR. For instance, the addition of an excess of the trityl salt led to a degradation of the CD. 1 H NMR spectra showed the disappearance of the remaining CPh3 + signals and the broadening of the CD signal (blue on Figure III-18). This was concomitant with the appearance, and the Next, the reaction was performed with 0.8 equivalents of trityl which led to the obtention of a mixture containing (α-ICyD)BH3 248 (H 5 A in geen on Figure III-19) and possibly (α-ICyD)BH2 + 272. This proved that no dimerization occurred in the reaction. The reaction was also monitored over time by 1 H NMR which showed that the newly formed compound was not stable at R.T. in CD2Cl2 as new peaks appeared very quickly (blue on Figure III-19). No signal that might correspond to CD2HCl, the product of halide-hydride exchange, was found on the spectrum but it might have been lost in the signal of the CD.

Nonetheless, the use of CD2Cl2 led to a degradation of the formed specie.

Figure III-19. Time resolved 1 H NMR spectra of the reaction between (α-ICyD)BH3 248 and 0.8 eq. of [CPh3][B(C6F5)4],

highlighted H 5 A peak of (α-ICyD)BH3 248 (green) and appearing peaks in blue (CD2Cl2, 400 MHz, 300 K).

C6D5Br is often used as the solvent in FLP chemistry and for the formation of borenium ions. This solvent allows the solubility of many organic species, does not present any exchangeable halides and is not coordinating. The reaction between (α-ICyD)BH3 248 and [CPh3][B(C6F5)4)] (0.8 eq) was therefore carried out in C6D5Br and once again led to the formation of a colourless solution (Scheme III-39).

As mentioned above, the 11 B NMR signals of the described borenium ions are affected by the presence of a charge. This charge interacts with the field gradient around the boron nucleus, exacerbates the quadrupolar effect of the nucleus and leads to a shortening of the relaxation times. The shortening of the relaxation times induces the broadening of the 11 B NMR signals of borenium ions.

The addition of the trityl salt on (α-ICyD)BH3 248 probably led to the formation of a borenium ion. Therefore, the relaxation time of the boron nucleus will be influenced by the presence of a charge and be shortened.

The transverse relaxation times of encapsulated boranes were shown to be very short and should even be shorter for the potential borenium ion 272. Simple 11 B{ 1 H} NMR acquisitions did not lead to the obtention of a signal implying very short relaxation times for the boron nucleus of 272. This means that the boron nucleus could relax so quickly that its signal might be lost before the recording of the signal occurs. Therefore, NMR acquisitions were performed using a very short relaxation delay (D1 = 0.05 s) and a very short acquisition time (Acq = 0.08 s). Simple 11 B NMR sequences with a 90-degree excitation pulse were chosen in order to avoid any useless steps (such as decoupling) that may induce a loss of the borenium ion signal. These parameters were chosen in order to try to accumulate as much weak signal as possible, hopefully leading to an observable peak.

Considering the broadness of the 11 B{ 1 H} NMR signal obtained for encapsulated boranes, the potential borenium 272 11 B signal should be even broader and difficult to obtain. Thus, the reaction and measurements were carried out in a natural quartz J-Young NMR tube, containing less than 0.1 ppm of boron, in order to avoid, as much as possible, the signal of borosilicates.

As shown by Gerhard Erker and his team, the temperature of the sample can influence the 11 B NMR signal of a borenium ion due to a difference in correlation time (τC). [45] Therefore, a temperature variation was performed. The absence of any signal might be explained by the short T2 * relaxation times already obtained for the encapsulated boranes (≈ 1 ms). As the formation of a borenium ion should even shorten this time, the boron nucleus could relax so quickly that it would not be possible to record any signal due to physical and electronical limitations.

The use of the 1 H/ 11 B HMBC sequence did not lead to the obtention of a correlation.

In order to present a correlation, this sequence requires the input of the 11 B chemical shift for the offset of the transmitter (O2P). Some downfield values were tried without success.

As the 1 H NMR shifts of the protons present on the boron nucleus are known to be deshielded (4.14 for 230, 5.02 for 233, 6.64 for 234), [44], [45] 1 H{ 11 B} sequences were performed. The spectra did not show the appearance of any peak that may correspond to the (α-ICyD)BH2 + protons. The signal may be lost in the CD signal.

A few solutions can be considered in order to get a signal. As τC depends on the temperature, increasing the temperature could lead to a narrowing of the signal.

Bromobenzene presents a boiling point at 156 °C however, due to the possibility of performing C-H borylation reactions, the temperature was not increased too much. The solvent may be replaced by C6F6 as C-F borylation reactions were only achieved using metallic catalysts or via a radical mechanism from a NHC-borane. [59]- [61] Therefore, lowering the possibility of reactions with the solvent, the temperature could be increased without performing side reactions.

An NMR spectrometer presenting a stronger magnetic field and the use of a recent console pulse may also decrease the signal-to-noise ratio and allow the obtention of a signal. 2D NMR sequences of the potential (α-ICyD)BH2 + 272 borenium ion were also recorded in order to study the influence of the hydride abstraction on the CD. However, the obtained spectra were unexploitable due to bad resolution even at 283 K, the acquisitions should be tried again soon at a lower temperature.

B. The potential [β-ICyD)BH2][B(C6F5)4] borenium ion

The hydride abstraction reaction was also carried out on The 2D NMR sequences recorded for this specie did not allow the interpretation of all the peaks due to bad resolution. However, the HSQCed (Hetero Single Quantum Coherence Edited) sequence recorded was well resolved and gave interesting information.

The HSQC experiment shows the correlation between a proton and the carbon nucleus directly linked to it through 1 JC,H couplings. The HSQCed sequence allows a distinction between the primary and tertiary protons (correlation coloured in red on This also made them recognisable among the other correlations. This indicated that the trityl cation abstracted a hydride from the encapsulated boranes and that, unlike for unencapsulated boranes, the species did not undergo dimerization. The 11 B{ 1 H} NMR analysis of the reaction did not lead to the obtention of a signal other than the one for the B(C6F5)4 -anion. As the probably formed [(α-ICyD)BH2][B(C6F5)4] 272 would be charged, the quadripolar effect of the boron nucleus would be exacerbated. Performing the 11 B NMR analysis in a quartz J-Young NMR tube, with short a relaxation delay, a short acquisition time and cooling the sample did not lead to the appearance or the disappearance of any signal. Here, the issue may come from the NMR itself as the boron nucleus might relax so quickly that the limits of NMR spectroscopy might be reached. As borenium ions present strong Lewis acidities, one way to characterise them comes from the measurement of their Lewis acidity. These measurements have been performed using the Gutmann-Becket Lewis acidity scale in the first instance

C. Lewis acidity studies

The IUPAC defines the Lewis acidity as the thermodynamic tendency of a substrate to act as a Lewis acid. [62] In other terms, the "strength" of a Lewis acidity may be seen as the favourable thermodynamics (enthalpy and entropy) of a Lewis acid to form a Lewis adduct in presence of a base. [63] Experimentally, the Lewis acidity of a compound can be obtained by forming a Lewis adduct and measuring the effect of the adduct formation on the Lewis base. Methods involving IR/UV/fluorescence spectroscopy can be used. [64]- [66] However, the most popular methods involve NMR spectroscopy and are called the Gutmann-Becket (GB) and the Childs methods.

The GB method involves the use of Et3PO (TEPO) as a probe. [67]- [69] The addition of TEPO to a Lewis acid induces the formation of a Lewis adduct and a deshielding of the 31 P chemical shift of the coordinated TEPO (Scheme III-41). The stronger the deshielding, the stronger the acid. Usually, the studied value is the difference in chemical shifts between the coordinated TEPO and the "free" TEPO (Δδ). As TEPO is a hard Lewis acid, the GB method is preferred for hard Lewis acids. [63] Scheme III-41. General scheme for the GB method's Lewis adduct formation.

The Childs method involves the use of trans-crotonaldehyde as a probe. [70], [71] The addition of trans-crotonaldehyde to a Lewis acid induces the formation of a Lewis adduct and a deshielding of the 1 H NMR shift of H3 (red on Scheme III-42). Once again, the stronger the deshielding, the stronger the acid. As trans-crotonaldehyde is a soft Lewis base, the Childs method is preferred for soft Lewis acids. [63] Scheme III-42. General scheme for the Childs method's Lewis adduct formation.

The two methods rely on the comparison of NMR chemical shifts. Therefore, the obtained scales are not absolute but relative. Moreover, Andrew Ashley, Dermot O'Hare and their collaborators have shown that the GB and the Childs method were sensitive to steric effects. [72] Among the series of boranes B(C6F5)n(C6Cl5)3-n, B(C6F5)3 (n = 0) was found to be the strongest Lewis acid by both GB and Childs methods (Figure III-26). However, computational and electrochemical studies have shown that B(C6Cl5)3 actually was the strongest Lewis acid. The C6Cl5 group is, as a matter of fact, the more electron-withdrawing group but also the more sterically hindering. Therefore, the results obtained by using the GB and the Childs methods were underestimated because of steric hindrance. The GB method is the most used for the study of boranes and borenium ions Lewis acidity.

The Lewis acidity of a compound can also be studied by DFT calculations. The most popular method, called Fluoride Ion Affinity (FIA) implies the study of the binding enthalpy of the fluoride ion with a Lewis acid in the gas phrase. [73]- [75] Usually, the obtained values are positive and calculated via the study an isodesmic reaction with Me3SiF (Scheme III-43).

Scheme III-43. General scheme for FIA calculations.

The FIA method for determining a Lewis acidity has the advantage of being influenced by steric hindrance only in extreme cases. [76] Therefore, this method, can give complementary indications for Lewis acidity. Another method, called Hydride Ion Affinity (HIA) can also be used.

The GB method was applied to the product of hydride abstraction on encapsulated boranes.

GB method applied to the potential encapsulated borenium ions

In order to apply the GB method to CDs, the encapsulated borenium ions were formed as previously in J-Young NMR tubes and a solution of TEPO in CD2Cl2 was added (1.0 eq) (Scheme III-44). In some occasions, the solution remained yellow after the addition of the trityl salt but it lost its colour after the addition of TEPO. Interestingly, the boranes capped with the benzimidazole bridge (249 and 252) did not react immediately with Comparison in the α-CD series showed highest 31 P deshieldings for the benzmidazole- One convenient way to compare the results given by the GB method consists in the calculation of the acceptor number (A.N.). [67] This scale is defined by two reference points consisting of the 31 . All encapsulated Lewis acids were stronger than BCF 284, [77] Piers' borane 287 [45] and Guillaume Berionni's planar triaryl boranes 285 [78] and 286 [79] known for their strong Lewis acidities. Most of the encapsulated ions were weaker than Gerhard Erker's borenium ions 233 and 234. [45] However, the potential (β-BiCyD)BH2OPEt3 + adduct 282 led to an A.N. of 106.7 which made it stronger that SbCl5, the borenium ions 233 and 234 and the strong Lewis acid BCl3. [69] The encapsulated Lewis acids remained less Lewis acidic than BBr3 and BI3. [69] Figure Therefore, it has been shown that the Lewis acidities of the products of hydride abstraction of encapsulated boranes were consistent with the formation of strong Lewis acids. However, 11 B NMR analysis of the adducts did not lead to the obtention of a signal that could have confirmed the formation of a boronium ion. Nonetheless, the obtention of high Lewis acidities may serve as a first proof for the obtention of the dihydrido borenium ions.

In fact, the obtained acidities were close, or higher, to the ones obtained with borenium ions bearing a C6F5 group, without presenting electron-withdrawing groups.

Therefore, the encapsulated NHC-BH2(C6F5) 288 borane was synthesised in order to understand a potential effect of the cavity on Lewis acidity (Scheme III-45). Lancaster's borane 287 was synthesised following literature [80] and reacted with imidazolium salt 85 The use of the GB method showed that products 272 -277 presented high Lewis acidities. All the adducts were stronger than BCF and Pier's borane and Lewis acidities close to the ones obtained with borenium ions 233 and 234. Therefore, the produced Lewis acids were more than likely the dihydrido borenium ions.

after

Fluoride Ion Affinity

In view to understand the possible effect of the cavity on the Lewis acidity of the formed borenium ions, the FIAs of the encapsulated borenium ions were studied. 7 The FIA The study was performed using a model compound 290, (α-MiCyD)BH2 + 275 and (β-MiCyD)BH2 + 277 (Figure III-32). The tabulated enthalpy of the fluorine dissociation reaction of Me3SiF: ΔrH2 0 = 958.44 kJ.mol -1 was used. [63] The calculations were performed using the B3LYP/def2-SV(P) level of theory.

In summary, the use of the GB acidity measurements allowed to show that the products from the hydride abstraction reaction of encapsulated boranes were strongly Lewis acidic. These products presented acidities comparable to known borenium ions. Therefore, the formed products were very likely to be the corresponding dihydro borenium ions. The β-CD encapsulated borenium ions were shown to be stronger than the ones in α-CDs. This Borenium ions are reactive towards hydroboration reactions and gas activation, the ability of encapsulated borenium ions to perform these reactions was therefore tested.

E. Reactivity of borenium ions

Borenium ions are reactive towards hydroboration reactions. Therefore, right after the formation of the encapsulated borenium 273, phenylacetylene was added in order to test the ability of the dihydrido borenium ion to perform hydroborations (Scheme III-48).

Scheme III-48. Potential hydroboration reaction between borenium ion 273 and phenylacetylene.

The reaction was followed by 1 The reaction should be tried again with simpler alkynes or alkenes in order to try to characterise the hydroboration product.

The activation of H2 was also tried with the encapsulated borenium ion 273 (Scheme III-49). The reaction was carried with only 0.5 equivalents of the trityl salt in order to ensure the stability of the formed borenium ion and also to see the peaks of the borane (β-ICyD)BH3

251 grow by 1 H NMR. After addition of the trityl salt, TMP was added, the mixture freezepumped-thawed with H2 and the reaction let under 2.5 bars of H2. In 1996, Warren Piers, and his team, have shown that BCF could be used as a catalyst for the hydrosilylation reaction of carbonyls in the presence of triphenylsilane (Scheme III-50 A)). [83] The reaction gave good yields and is believed to go through the formation of a silylium adduct (299) that is reduced by H-B(C6F5)3 -(Scheme III-50 B)). [84] As the encapsulated borenium ions are strong Lewis acids encapsulated in a chiral environment, the obtention of an enantioselective hydrosilylation reaction was tempting.

triplet corresponding to the methyl group of 302 appeared, indicating that the deoxygenation reaction also happened in presence of α-CD 272. ), the reactions afford the deoxygenated product 302. [84] Therefore, it was not surprising to get this product in the presence of highly Lewis acidic borenium ions. However, the obtention of the hydrosilylated product with α-CD 272 compared to the use of β-CD 273 was interesting.

This difference in reactivity probably resulted from the smaller cavity of α-CD that prevents the silylated alcohol 301 from entering the cavity and being reduced once more.

The silylated alcohol 301 obtained from the reaction catalysed by α-CD 272 was isolated and its optical rotation was measured. To our surprise, the sample did not afford any rotation.

Another mechanism for the hydrosilylation reaction is conceivable. For this mechanism, the reduction step is not performed by the borane but by another molecule of HSiPh3 (Figure III-37). [84] This mechanism would be consistent with a higher affinity of the borenium ion for the hydride, impeding the hydride transfer to the silylium intermediate 303. As the borane does enter the reduction step, the absence of enantioselectivity is not surprising. To sum up, the β-CD encapsulated borenium ion showed reactivity towards the hydroboration reaction of phenylacetylene. The structure of the product could not be obtained thus, the reaction should be performed again with simpler alkynes and alkenes in order to understand the reaction. Unfortunately, the borenium ion did not perform H2 activation through a FLP-type reactivity. This lack of reactivity might be due to the steric hindrance brought by the cavity but also from a poor choice of the Lewis base. A screening of several Lewis bases will be performed in order to understand this possible lack of activation. Moreover, other gases, such as carbon monoxide, should be added in the presence of encapsulated borenium ions in order to test their reactivity.

The use of the encapsulated borenium ions 272 and 273 as catalysts for the hydrosilylation reaction of acetophenone led to the obtention of the reduced product with α-CD 272 and to the obtention of the deoxygenated product with β-CD 273. This difference in reactivity should probably be explained by the smaller cavity of the α-CD slowing down the deoxygenation process. The α-CD-catalysed reaction did not show any enantioselectivity probably due to the hydride transfer being performed by the silane and not by the borane.

Conclusion

In conclusion for this part, the synthesis of encapsulated boranes revealed the effect of the cavity on a quadripolar nucleus. The relaxation time of the 11 B nuclei was shortened by a 50-fold by the presence of the cavity. This probably resulted from a stronger field gradient brought by the presence of the sugar units around the nucleus. These short relaxation times resulted in the impossibility to find the 11 B signals of the probable encapsulated borenium ions formed after hydride abstraction reaction of the corresponding boranes.

Despite the current absence of characterisation of these products, the GB method allowed to show that the products were strongly Lewis acidic. Presenting A.N. around 100, comparable to described borenium ions, the products of the hydride abstraction reactions are very likely to be borenium ions. The NMR characterisations have yet to be done. However, this would probably represent the first synthesis of NHC-dihydrido borenium ions that are believed to be too unstable to be isolated. The presence of the cavity of CDs prevents the dimerization of the borenium with the borane and thus probably affords the monomeric dihydrido borenium ions.

The borenium ions reacted with phenylacetylene but the right FLP system has yet to be found The Lewis basicity of the encapsulated NHIs was also influenced by the encapsulation. The encapsulated NHI-BH3 adducts presented much lower 11 B chemical shifts than the unencapsulated model molecules. The influence of the cavity on these basicities is currently being studied by DFT calculations.

In future work, the exo-cyclic nitrogen atoms of the encapsulated NHIs should be methylated in order to study the influence of steric hindrance directly on the basic site. These

NHIs may be used for CO2 activation, under pressures above 1 bar, and for Lewis basecatalysed reactions.

Encapsulated boranes were synthesised with a whole set of α-and β-CDs. The encapsulation of the boron atom led to the obtention of poorly-defined 11 B NMR spectra.

The cavity probably increased the field gradient around the boron nucleus, exacerbating its quadripolar effect. This strong quadripolar effect led to short relaxation times and broad In addition to the study of the reactivity of these new encapsulated organocatalysts, the synthesis of an encapsulated organophosphorus catalyst could be of interest as phosphorous plays a major role in catalysis and in FLP systems. The synthesis of CDs bearing both Lewis partners, in order to get intramolecular FLPs with a geometrical frustration, could also be interesting.

General information

All synthesis involving air-and moisture sensitive compounds were carried out in flame-dried glassware and under argon. The formation of borenium ions was carried out in a MBraun ® glovebox or in a PLAS-LABS, INC. ® glovebox under a nitrogen flux. Unless stated otherwise, all chemicals were purchased from commercially available sources and used as received. Except for the synthesis of methylated CDs, THF was freshly distilled from sodium/benzophenone. Dichloromethane was freshly distilled from CaH2, acetonitrile from CaH2 and toluene from sodium/benzophenone. ESI-MS analysis were recorded on a Bruker micrOTOF spectrometer. NMR spectra were recorded on a:

- 13 C NMR). The coupling constants J are indicated in Hertz (Hz). Assignments were aided by COSY, HSQCed, HMBC, NOESY and TOCSY experiments. The following abbreviations are employed for describing the multiplicity of the signals: s: singlet, d: doublet, t: triplet: q: quartet, p: pentet, s: sextet, sept.: septet, br: broad. CO2 (ultrapure grade) and H2 (premier plus grade) were supplied by Airproducts. Silica gel flash chromatographic separations were carried out over Merck silica gel 60 (0.040 -0.063 mm). Analytical thin layer chromatography (TLC) were performed on Merck silicagel TLC plates F-254.

Methodology for NMR characterisation of CDs

Because of the complexity of differentiated CDs, the methodology for the attribution of all the NMR signals requires several NMR experiments. An example using the results obtained for (α-MiCyD)BH3 250 will now be presented. The first step is to identify the H 1 protons (also called anomeric protons). The 13 After reporting the chemical shifts for each sugar units, the use of a COSY experiment allows to find the sequence of protons for each sugar unit. The COSY experiment allows to see 1 H/ 1 H coupling up to 3 bonds. Therefore, H 1 correlates with H 2 which correlates with H 3 …

C signals of the anomeric carbon atoms have the peculiarity of presenting NMR signals around

The following example shows the determination of the chemical shifts from the sugar unit II. Finally, after finding the "A" (and "D") sugar units and attributing all the 13 C signals, a NOESY experiment allows to find the sequence of each sugar unit in the CD. The Overhauser effect allows to see couplings though space up to 5 Å. Therefore, the H 1 proton of a given unit couple with the H 4 of the neighbouring sugar unit. The NOESY spectra usually present scalar coupling with neighbouring protons (H 2 for a H 1 ) and should not be confused with spatial couplings. Here, the NOESY experiment afforded the following sequence: The HMBC experiment can also be used for the determination of the sugar sequence. The H 1 signal usually shows correlations with the C 4 carbon of the neighbouring unit.

H 1 I -> H 4 A, H 1 A -> H 4

A-G ,3 A-G ,6 A-G -Octadeca-O-Benzyl-β-Cyclodextrin (79)

To a mixture of native β-cyclodextrin (10.00 g, 8.81 mmol) and DMSO (380 mL), sodium hydroxide (60% in oil, 14.8 g, 370 mmol) was added portion wise. Benzyl chloride (42.6 mL, 370 mmol) was added dropwise after 15 minutes of stirring. The reaction was quenched after 9 hours by careful addition of distilled water (160 mL). Diethyl ether (170 mL) was added to the mixture and the aqueous phase was extracted with diethyl ether (5 x 100 mL). The combined organic phases were washed with water (5 x 200 mL), dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (cyclohexane up to 80:20 cyclohexane/ethyl acetate) afforded cyclodextrin 79 (19.1 g, 71%) as a white foam. The spectral data are in accordance with the data described in the literature. [1] 2 A-F ,3 To a mixture of α-cyclodextrin 78 (3.57 g, 1,38 mmol) in dry toluene (6.3 mL) under a weak nitrogen flow was added a solution of DIBAL-H (1,5 M in toluene, 18.4 mL, 27.6 mmol). The reaction was carefully monitored by TLC (cyclohexane/ethyl acetate 75:25). After stirring for 2 hours at 50 °C, the flow was increased and the temperature raised to 60 °C. After stirring for 3 hours, the reaction was cooled to room temperature and poured over a mixture of ice (200 g), aqueous solution of HCl (1 M, 200 mL) and ethyl acetate (200 mL). After stirring for 9 hours, the aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (95:5 up to 70:30 cyclohexane/ethyl acetate) afforded the diol 80 (2.29 g, 93%) as a white foam. The spectral data are in accordance with the data described in the literature. [1] To a mixture of β-cyclodextrin 79 (10.0 g, 3.51 mmol) in dry toluene (20.0 mL) under a weak nitrogen flow was added a solution of DIBAL-H (1,5 M in toluene, 58.5 mL, 87.8 mmol). The reaction was carefully monitored by TLC (cyclohexane/ethyl acetate 75:25). After stirring for 2 hours at 80 °C, the reaction was cooled to room temperature and poured over a mixture of ice (200 g), aqueous solution of HCl (1 M, 200 mL) and ethyl acetate (200 mL). After stirring for 9 hours, the aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (95:5 up to 70:30 cyclohexane/ethyl acetate) afforded the diol 81 (7.51 g, 80%) as a white foam. The spectral data are in accordance with the data described in the literature. [1] 6 A ,6 D -di-O-methanesulfonyl-2 A-F ,3 The spectral data are in accordance with the data described in the literature. [2] 6 A ,6 D -di-O-methanesulfonyl-2 A-G ,3 The spectral data are in accordance with the data described in the literature. [3] The spectral data are in accordance with the data described in the literature. [3] The spectral data are in accordance with the data described in the literature. [3] A mixture of α-cyclodextrin 82 (2.14 g, 0.83 mmol) and benzimidazole (3.9 g, 33.3 mmol) dissolved in DMF (55.0 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (60 mL) and washed with an aqueous solution of HCl (1M, 1 x 20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 95:5 DCM/Methanol) afforded the benzimidazolium salt 147 (1.77 g, 84 %) as a white foam.

1 H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 9.84 (s, 1H), δ

The spectral data are in accordance with the data described in the literature. [4] The spectral data are in accordance with the data described in the literature. [4] 6 ), δ 3.51 (dd, 3 J = 9.8 Hz, 3 J = 3.1 Hz, 2H, 2 x H 2 A), δ 3.40 (dd, 3 J = 9.9 Hz, 3 J = 3.3 Hz, 2H, 2 x H 2 B), δ 3.25 (d, 2 J = 10.9 Hz, 2H, 2 x H 6 B), δ 3.12 (dd, 2 J = 10,9 Hz, 3 J = 5,0 Hz, 2H, 2 x H 6 B), δ 1.90 (d, 6H, 6 x H H3C-C=C ). A mixture of β-cyclodextrin 85 (2.02 g, 0.67 mmol) and 4,5-dimethyl-imidazole (2.59 g, 27.0 mmol) dissolved in DMF (16.6 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (40 mL) and washed with an aqueous solution of HCl (1M, 1 x 20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 95:5 DCM/Methanol) afforded the 4,5dimethyl-imidazolium salt 135 (1.14 g, 54%) as a white foam.

MS (ESI): calculated for C153H161N2O28 [M]

Experimental part for Chapter II A. N-Heterocyclic Imines synthesis tert-butyl azide

This synthesis should be performed with care as aliphatic azides and HN3 are explosive.

Concentrated H2SO4 (37.3 mL, 0.70 mmol) was added dropwise to a stirring solution of H2O cooled down to 5 °C over a time period of 20 minutes. The mixture was cooled to 3 °C and NaN3 (9.0 g, 138 mmol) was added. The temperature has to be kept around 20 °C to avoid volatilization of explosive HN3. After dissolution of HN3, tBuOH (0.12 mmol) was added to the mixture. The mixture was stirred for 5 minutes then allowed to stand at R.T. for 24 hours, stirred for 5 minutes and allowed to stand at R.T. for 12 hours. The mixture was poured in a separatory funnel and tBuN3 (top layer) separated from the aqueous phase. tBuN3 was then washed with an aqueous solution of NaOH (2M, 2 x 20 mL, to remove all traces of HN3), and poured in a bottle with Na2SO4 in the bottom for long-term storage. The yield was 81% of clear liquid. The density of tBuN3 was measured in order to simplify its further use and afforded ρ = 0.83.

1 H NMR (CDCl3, 300 MHz, 300 K, ppm) δ 1.28 (s).

The spectral data are in accordance with the data described in the literature. [5] (β-ICyD)NH2Cl ( 131)

Imidazolium salt 85 (1.09 g, 0.37 mmol) was dissolved in dry THF (10.0 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 890 μL, 0.45 mmol) was added. The reaction was stirred for one hour and tBuN3 (110 μL, 0.93 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 1.0 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (98:2 up to 95:5 DCM/MeOH) afforded 131 (953 mg, 87%) as a white foam. (β-BiCyD)NH2Cl (133)

Benzimidazolium salt 132 (660 mg, 0.22 mmol) was dissolved in dry THF (7.0 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 890 μL, 0.45 mmol) was added. The reaction was stirred for one hour and tBuN3 (266 μL, 2.22 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 4.0 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (98:2 up to 95:5 DCM/MeOH) afforded 133 (319 mg, 33%) as a white foam.

Because of the poor resolution of the 13 C NMR spectrum of this product, the complete characterisation could not have been performed. New experiments will be performed soon.

The unit IV seems to be bridged as it presents a C 6 at 44.49 ppm. The 13 C chemical shifts were obtained by the use of the HMQCed spectrum. However, the ESI-MS of the product did afford the right mass for (β-BiCyD)NH2 + .

1 H NMR (600 MHz, CD3CN, 300 K, ppm) δ 7.35 -6.86 (m, 95H, 95 x H Ar ), δ 6.70 (d, 3 J = 7.6 Hz, 1H, H Benzimidazol) , 6.64 (d, 3 J = 7.6 Hz, 1H, 1 x H Benzimidazol ), δ 5.83 (d, 3 J = 3.7 Hz, 1H, 1 x H 1 VII), δ 5.82 (d, 3 J = 3.6, 1H, 1 x H 1 VI), δ 5.36 (d,2 J = 11.1 Hz, 1H, 1 x H CHPh ), δ 5.30 (d, 2 J = 11.0 Hz, 1H, 1 x H CHPh ), δ 5.24 (d, 2 J = 11.1 Hz, 1H, 1 x H CHPh ), δ 5.18 (d, 2 J = 10.5 Hz, 1H, 1 x H CHPh ), δ 5.13 (d, 2 J = 10.8 Hz, 1H, 1 x H CHPh ), δ 4.99 (d, 3 J = 3.7 Hz, 1H, 1 x H (β-MiCyD)NH2Cl (136)

4,5-dimethyl-imidazolium salt 135 (171 mg, 0.06 mmol) was dissolved in dry THF (1.7 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 140 μL, 0.07 mmol) was added. The reaction was stirred for one hour and tBuN3 (17.4 μL, 0.15 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 1.0 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (98:2 up to 95:5 DCM/MeOH) afforded 136 (110 mg, 64%) as a white foam.

1 x H 3 G, 1 x H 3 B/C, 1 x H 4 F, 1 x H 4 A, 1 x H 4 B/C, 1 x H 4 B/C, 1 x H 4 E, 1 x H 5 G, 1 x H 5 A, 1 x H 5 E, 2 x H 6 F, 1 x H 6 A, 1 x H 6 B/C, 1 x H 6 E, 1 x H 6 B/C), 3.62 (dd, 3 J = 10.4 Hz, 3 J = 8.8 Hz, 1H, 1 x H 4 D), δ 3.58 -3.54 (m, 5H, 1 x H 2 A, 1 x H 2 E, 1 x H 5 D, 1 x H 6 D, 1 x H 6 B/C), δ 3.51 -3.48 (m, 2H, 1 x H 2 F, 1 x H 2 G
), δ 3.38 (dd, 3 J = 9.9 Hz, 3 J = 3.2 Hz, 1H, 1 x H 2 D), δ 3.35 (dd, 3 J = 9.9 Hz, 3 J = 3.3 Hz, 1H, 1 x H 2 B/C), δ 3.30 (dd, 3 J = 9.4 Hz, 3.3 Hz, 1H, 1 x H 2 B/C), δ 3.22 (d, 2 J = 9.6 Hz, 1H, 1 x H 6 B/C), 3.16 (d, 2 J = 10.6 Hz, 1H, 1 x H 6 G), δ 3.03 (dd, 2 J = 10.7 Hz, 3 J = 2.7 Hz, 1H, 1 x H 6 G), δ 1.77 (s, 3H, 3 x H N-C(CH3)=C ), δ 1.62 (s, 3H, 3 x H N-C(CH3)=C ). (α-out-ICyD)NH2Cl (142)

Imidazolium salt 84 (500 mg, 0.20 mmol) was dissolved in dry THF (5.0 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 835 μL, 0.41 mmol) was added. The reaction was stirred for one hour and tBuN3 (122 μL, 1.0 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture quenched by Et3NCl (141 mg, 1.0 mmol).

After one hour at 60 °C, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (98:2 up to 95:5 DCM/MeOH) afforded 142 (310 mg, 61%) as a white foam. The product was analysed as its neutral counterpart 143. Rf = 0.13 (95:5 DCM/MeOH). (α-out-ICyD)NH (143)

MS (ESI

A spatula tip of tBuOK was added a mixture of NHI 142 (30 mg) in THF (3.0 mL). After 30 minutes, the solvents were evaporated under reduced pressure. The mixture was dissolved in dry toluene (10.0 mL), filtered over cotton and evaporated. Finally, the mixture was dissolved in CD3CN and the NMR experiments were run. (α-MiCyD)NH2Cl (145)

(α-MiCyD)NH (146)

A spatula tip of tBuOK was added a mixture of NHI 145 (30 mg) in THF (3.0 mL). After 30 minutes, the solvents were evaporated under reduced pressure. The mixture was dissolved in dry toluene (10.0 mL), filtered over cotton and evaporated. Finally, the mixture was dissolved in CD3CN and the NMR experiments were run. Figure EP-28. 13 C UDEFT NMR spectrum of (α-MiCyD)NH (CD3CN, 151 MHz, 300 K).

4,5-dimethyl-imidazole (134)

In a round-bottom flash, (NH4)2(SO4) (52.8 g, 400 mmol) was dissolved in water (100 mL). Formaldehyde (37% in H2O, 14.9 mL, 200 mmol) and butane-2,3-dione (17.5 mL, 200 mmol) were added. The reaction was refluxed for 2 hours. The reaction was then cooled to 0 °C and NaOH (16.0 g, 400 mmol) was added. The mixture was then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure. Washing the product with chilled ether afforded 134 (8.75 g, 46%) as a red powder. The product is described as a white powder. However, only shades of red products were obtained by the washing with ether.

1 H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 8.12 (br s, 1H), δ 7.42 (s, 2H), δ 2.17 (s, 12H).

The spectral data are in accordance with data described in the literature. [6] 1,3-di-iso-propyl-imidazolium iodide (150)

Imidazole (1.36 g, 20 mmol) was added to a solution of flame dried K2CO3 (3.05 g, 22 mmol) and dry acetonitrile (12 mL). After stirring for an hour, 3-iodo-pronane (6.0 mL, 60 mmol) was added. After refluxing the reaction for 1 hour, DCM (20 mL) and H2O (20 mL) were added. The aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phases were dried over MgSO3 and evaporated under reduced pressure. Washing the product with chilled ethyl acetate afforded 150 (5.1 g, 91%) as a white solid.

1,3-di-iso-propyl-benzimidazolium iodide (152)

Benzimidazole (2.36 g, 20 mmol) was added to a solution of flame dried K2CO3 (3.05 g, 22 mmol) and dry acetonitrile (12 mL). After stirring for an hour, 3-iodo-pronane (6.0 mL, 60 mmol) was added. After refluxing the reaction for 1 hour, DCM (20 mL) and H2O (20 mL) were added. The aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phases were dried over MgSO3 and evaporated under reduced pressure. Washing the product with chilled ethyl acetate afforded 151 (6.6 g, quantitative) as a white solid.

1 H NMR (CDCl3, 300 MHz, 300 K, ppm) δ 10.88 (s, 1H), δ 7.82 (dd, 3 J = 6.3 Hz, 3 J = 3.2 Hz, 2H), δ 7.65 (dd, 3 J = 6.3 Hz, 3 J = 3.2 Hz, 2H), δ 5.22 (sept, 3 J = 6.8 Hz, 2H), δ 1.87 (d, 3 J = 6.8 Hz, 12H).

The spectral data are in accordance with data described in the literature. [8] 1,3-di-iso-propyl-4,5-dimethyl-imidazolium iodide (154)

4,5-dimethylimidazole 134 (1.95 g, 20 mmol) was added to a solution of flame dried K2CO3 (3.05 g, 22 mmol) and dry acetonitrile (12 mL). After stirring for an hour, 3-iodo-pronane (6.0 mL, 60 mmol) was added. After refluxing the reaction for 1 hour, DCM (20 mL) and H2O (20 mL) were added. The aqueous phase was extracted with DCM (3 x 20 mL). The combined organic phases were dried over MgSO3 and evaporated under reduced pressure.

Washing the product with chilled ethyl acetate afforded 151 (4.45 g, 75%) as a white solid.

2-amino-1,3-di-iso-propyl-imidazolium chloride (151)

Imidazolium salt 150 (536 mg, 1.91 mmol) was dissolved in degassed dry THF (3.0 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 4.2 mL, 2.1 mmol) was added. The reaction was stirred for one hour and tBuN3 (250 μL, 2.1 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 3.0 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (95:5 DCM/MeOH) afforded 151 (230 mg, 59%) as a white solid.

2-amino-1,3-di-iso-propyl-benzimidazolium chloride (153)

Benzimidazolium salt 152 (503 mg, 1.67 mmol) was dissolved in degassed dry THF (1.7 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 3.65 mL, 1.82 mmol) was added. The reaction was stirred for one hour and tBuN3 (218 μL, 1.82 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 2.0 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (96:4 DCM/MeOH) afforded 153 (133 mg, 34%) as a white solid.

2-amino-1,3-di-iso-propyl-4,5-dimethyl-imidazolium chloride (155)

4,5-dimethyl-imidazolium salt 154 (542 mg, 1.76 mmol) was dissolved in degassed dry THF (1.8 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 3.9 mL, 1.93 mmol) was added. The reaction was stirred for one hour and tBuN3 (231 μL, 1.93 mmol) was added. The reaction was brought to R.T. and the tube was sealed.

The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture was cooled to 0 °C and HCl (1M in Et2O, 2.3 mL) was added dropwise. After one hour, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 96:4 DCM/MeOH) afforded 155 (115 mg, 28%) as a white solid.

B. pKBH+ measurements

Potassium p-fluorophenolate

In a PLAS-LABS, INC. ® glovebox, p-fluorophenol (14.2 mg, 0.13 mmol) was dissolved in a J-Young NMR tube in CD3CN (500 μL). p-fluoroanisol (5.0 μL, 0.04 mol) was added to the solution and 1 H and 19 F NMR spectra were acquired. The NMR tube was inserted the glovebox and KHMDS (0.5 M in toluene, 253 μL, 0.127 mmol) was added. 1 H and 19 F NMR spectra were acquired.

pKa determination of p-fluorophenol

In a PLAS-LABS, INC. ® glovebox, p-fluorophenol (14.7 mg, 0.13 mmol) was dissolved in a J-Young NMR tube in CD3CN (500 μL). p-fluoroanisol (15.0 μL, 0.13 mol) was added to the solution and 1 H and 19 F NMR spectra were acquired. The NMR tube was inserted the glovebox and Et3N (18.0 μL, 0.13 mmol) was added. 1 H and 19 F NMR spectra were acquired and the pKa of p-fluorophenol calculated. As 19 F NMR indicated a chemical shift at -127.83 ppm, the calculated value was: pKa = 26.5 (in acetonitrile). pKBH+ determination of (β-ICyD)NH ( 116)

In a round-bottom flask, a spatula tip of tBuOK was added to a mixture of NHI 131 (23.0 mg, 7.84 μmol) dissolved in dry THF (1 mL). After one hour at R.T., the solvents were evaporated under reduced pressure. The vacuum was broken with argon and the residue placed in a PLAS-LABS, INC. ® glovebox. The residue was dissolved in dry toluene and filtered through cotton. The obtained mixture was evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of (β-ICyD)NH (22.7 mg, quantitative) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and pfluoroanisol (5 μL, 44.2 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed the glovebox and a solution of p-fluorophenol (15 μL of a solution containing 5.8 mg dissolved in 100 μL of CD3CN, 7.71 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -127.88 ppm, the calculated value was: pKBH+ = 16.5. Figure EP-37. 19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

pKBH+ determination of (β-BiCyD)NH (159)

In a round-bottom flask, a spatula tip of tBuOK was added to a mixture of NHI 133 (23.0 mg, 7.82 μmol) dissolved in dry THF (1 mL). After one hour at R.T., the solvents were evaporated under reduced pressure. The vacuum was broken with argon and the residue placed in a PLAS-LABS, INC. ® glovebox. The residue was dissolved in dry toluene and filtered through cotton. The obtained mixture was evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of (β-BiCyD)NH (19.5 mg, 86%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and pfluoroanisol (4 μL, 35.3 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of p-fluorophenol (8 μL of a solution containing 9.1 mg dissolved in 100 μL of CD3CN, 6.50 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -128.08 ppm, the calculated value was: pKBH+ = 16.6.

pKBH+ determination of (β-MiCyD)NH (160)

In a round-bottom flask, a spatula tip of tBuOK was added to a mixture of NHI 136 (28.4 mg, 9.60 μmol) dissolved in dry THF (1 mL). After one hour at R.T., the solvents were evaporated under reduced pressure. The vacuum was broken with argon and the residue placed in a PLAS-LABS, INC. ® glovebox. The residue was dissolved in dry toluene and filtered through cotton. The obtained mixture was evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of (β-MiCyD)NH (27.1 mg, 97%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and pfluoroanisol (5 μL, 44.2 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of p-fluorophenol (11.5 μL of a solution containing 9.1 mg dissolved in 100 μL of CD3CN, 9.34 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -128.08 ppm, the calculated value was: pKBH+ = 16.9. pKBH+ determination of (α-out-ICyD)NH (143)

In a round-bottom flask, a spatula tip of tBuOK was added to a mixture of NHI 142 (33.1 mg, 13.2 μmol) dissolved in dry THF (1 mL). After one hour at R.T., the solvents were evaporated under reduced pressure. The vacuum was broken with argon and the residue placed in a PLAS-LABS, INC. ® glovebox. The residue was dissolved in dry toluene and filtered through cotton. The obtained mixture was evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of (α-out-ICyD)NH (29.9 mg, 92%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and pfluoroanisol (11 μL, 60.8 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of p-fluorophenol (11.5 μL of a solution containing 12.4 mg dissolved in 100 μL of CD3CN, 9.34 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -127.56 ppm, the calculated value was: pKBH+ = 16.3.

pKBH+ determination of (α-MiCyD)NH (146)

In a round-bottom flask, a spatula tip of tBuOK was added to a mixture of NHI 145 (22.4 mg, 8.87 μmol) dissolved in dry THF (1 mL). After one hour at R.T., the solvents were evaporated under reduced pressure. The vacuum was broken with argon and the residue placed in a PLAS-LABS, INC. ® glovebox. The residue was dissolved in dry toluene and filtered through cotton. The obtained mixture was evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of (α-MiCyD)NH (13.8 mg, 63%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and pfluoroanisol (3.2 μL, 22.3 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of p-fluorophenol (11.0 μL of a solution containing 5.7 mg dissolved in 100 μL of CD3CN, 5.59 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -129.69 ppm, the calculated value was: pKBH+ = 17.4. pKBH+ determination of 2-amino-1,3-di-iso-propyl-imidazolium chloride (161) Hexane (5.0 mL) and an aqueous solution of KOH (50%, 1.0 mL) were added to a mixture of NHI 151 (10.3 mg, 50.6 μmol) dissolved in dry MeOH (1 mL). After one hour at R.T., the hexane layer was poured in a flame-dried round-bottom flash and the MeOH layer was extracted with hexane (2 x 5 mL). The combined hexane layers were dried over Na2SO4 and placed a PLAS-LABS, INC. ® glovebox. The mixture was filtered through cotton and evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of neutral NHI (2.6 mg, 32%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and p-fluoroanisol (9.0 μL, 79.5 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of pfluorophenol (11.4 μL of a solution containing 12.1 mg dissolved in 100 μL of CD3CN, 15.0 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -129.03 ppm, the calculated value was: pKBH+ = 18.0. After one hour at R.T., the hexane layer was poured in a flame-dried round-bottom flash and the MeOH layer was extracted with hexane (2 x 5 mL). The combined hexane layers were dried over Na2SO4 and placed in a PLAS-LABS, INC. ® glovebox. The mixture was filtered through cotton and evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of neutral NHI (14.1 mg, 77%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and p-fluoroanisol (40 μL, 353 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of pfluorophenol (40.0 μL of a solution containing 15.6 mg dissolved in 100 μL of CD3CN, 70.7 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -127.83 ppm, the calculated value was: pKBH+ = 18.2. After one hour at R.T., the hexane layer was poured in a flame-dried round-bottom flash and the MeOH layer was extracted with hexane (2 x 5 mL). The combined hexane layers were dried over Na2SO4 and placed in a PLAS-LABS, INC. ® glovebox. The mixture was filtered through cotton and evaporated under reduced pressure. The vacuum was broken with argon and the residue immediately dried in vacuo. After one hour, the residue was placed in the glovebox. The residue was dissolved in dry toluene and transferred in a J-Young NMR tube. The solvents were evaporated in vacuo. After 12 hours in vacuo, the J-Young NMR tube was weighted and the mass of neutral NHI (10.2 mg, 63%) obtained. The J-Young NMR tune was placed in the glovebox and the residue dissolved in CD3CN. A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and p-fluoroanisol (30 μL, 265 μmol) was added). 1 H and a 19 F NMR were acquired. The J-Young NMR tube was placed in the glovebox and a solution of pfluorophenol (66.0 μL of a solution containing 5.86 mg dissolved in 100 μL of CD3CN, 53.0 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 19 F NMR spectra were recorded. As 19 F NMR indicated a chemical shift at -130.87 ppm, the calculated value was: pKBH+ = 19.6. Figure EP-51. 19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Lewis basicity determination of (β-ICyD)NH (116)

The deprotonation of (β-ICyD)NH2Cl

Lewis basicity determination of (β-BiCyD)NH (159)

The deprotonation of (β-BiCyD)NH2Cl 133 (16.5 The deprotonation of (α-MiCyD)NH2Cl 145 (14.5 mg, 5.73 μmol) underwent the same process as for pKBH+ determination and afforded (α-MiCyD)NH 146 (8.3 mg, 58%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 2.5 μL, 5.0 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -29.01 ppm.

Lewis basicity determination of 2-amino-1,3-di-iso-propyl-imidazol (161)

The deprotonation of NHI 151 (35.1 mg, 172 μmol) underwent the same process as for pKBH+ determination and afforded neutral NHI 161 (3.8 mg, 13%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL).

A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 11.5 μL, 23.0 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -37.62 ppm. The deprotonation of NHI 153 (8.8 mg, 34.7 μmol) underwent the same process as for pKBH+ determination and afforded neutral NHI 162 (7.5 mg, quantitative). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S

CO2 activation trial using (β-MiCyD)NH (160)

In an MBraun ® glovebox, (β-MiCyD)NH2Cl 136 (36.0 mg, 12.6 μmol) was weighed in a 2 mL vial and dissolved in THF. A spatula-tip of tBuOK was added to the mixture and the mixture stirred for 2 hours. The mixture was then filtered through glass wool in a 25 mL vial. Pentane (20 mL) was added, leading to a precipitation of the CD and the mixture stored in a -20 °C freezer. After 12 hours, the supernatant was removed and the precipitate dissolved in THF, poured in a J-Young NMR tube and dried in vacuo. The residue was dissolved with THF-d8 (500 μL) and a 1 H NMR was recorded to ensure the full deprotonation. The mixture was then freeze-pumped two times and freeze-pumped-thawed once with CO2 (1.0 bar). After 24 hours, the 1 H NMR did not show any CO2 adduct formation.

Experimental part for Chapter III

(α-BiCyD)BH3 (249)

In a round-bottom flask, α-cyclodextrin benzimidazolium chloride 147 (500 mg, 0.20 mmol) was dissolved in freshly distilled THF (5.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0. (α-MiCyD)BH3 (250)

In a round-bottom flask, α-cyclodextrin 4,5-dimethyl-imidazolium chloride 144 (420 mg, 0.17 mmol) was dissolved in freshly distilled THF (4.2 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 700 μL, 0.34 mmol) was added dropwise inducing a quick orange-colouring of the medium. After one hour at 0 °C, Me2S

(β-ICyD)BH3 (251)

In a round-bottom flask, β-cyclodextrin imidazolium chloride 85 (1.0 g, 0.34 mmol) was dissolved in freshly distilled THF (10.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.

(β-BiCyD)BH3 (252)

In a round-bottom flask, β-cyclodextrin benzimidazolium chloride 132 (406 mg, 0.14 mmol) was dissolved in freshly distilled THF (4.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 550 μL, 0.

(β-MiCyD)BH3 (253)

In a round-bottom flask, β-cyclodextrin 4,5-dimethyl-imidazolium chloride 135 (505 mg, 0.17 mmol) was dissolved in freshly distilled THF (5.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 700 μL, 0.34 mmol) was added dropwise inducing a quick orange-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 170 μL, 0.34 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 253 (398 mg, 78%) as a white foam.

I i Pr-BH3 (235)

In a round-bottom flask, 1,3-di-iso-propylimidazolium chloride (170 mg, 0.9 mmol) was dissolved in freshly distilled THF (13.5 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 1.8 mL, 0.9 mmol) was added dropwise inducing a quick redcolouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 0.5 mL, 0.9 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (DCM) afforded the encapsulated borane 235 (108 mg, 72%) as a white solid.

Me2S•BH2(C6F5) (287)

In an MBraun ® glovebox, B(C6F5)3 (105 mg, 203 μmol) was dissolved with Et2O (200 μL).

After one hour at -20 °C, the product precipitated. The supernatant was removed and the rest of the solvents evaporated in vacue affording Et2O•B(C6F5)3. The residue was placed in the glovebox and dissolved in toluene (1.7 mL). Me2S•BH3 (66 μL, 696 μmol) was added to the mixture. After 24 hours at 80 °C, 1 H, 19 F and 11 B NMR spectra revealed that the experiment was not complete. The mixture was heated at 100 °C for 3 hours and NMR experiment revealed the completion of the reaction. The solvents were evaporated in vacuo.

The residue was placed in the glovebox and solubilised with DCM (200 μL). Pentane (20 mL) was added and the mixture placed in the freezer at -20 °C. After two weeks, crystals grew. The supernatant was removed and the crystals dried affording 287 (35.6 mg, 72%) as white crystals.

11 B{ 1 H} NMR (CD2Cl2, 128 MHz, 300 K, ppm) δ -17.2 (bs s).

19 F NMR (CD2Cl2, 377 MHz, 300 K, ppm) δ -130.4 (dd, 1 J = 25.5 Hz, 3 J = 10.2 Hz), δ -157.4 (t, 3 J = 20.5 Hz), δ -163.8 (m).

The spectral data are in accordance with the data described in the literature. [11] (β-ICyD)BH2(C6F5) (288)

In a round-bottom flask, β-cyclodextrin imidazolium chloride 85 (95.5 mg, 32.4 μmol) was dissolved in freshly distilled THF (1.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0. were added to a solution of α-CD 80 (9.4 g, 3.9 mmol) dissolved in DCM (55 mL). After stirring the mixture at R.T. during 12 hours, the reaction was quenched by a saturated aqueous solution of NaHCO3 (25 mL). The aqueous phase was extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was dissolved in a 3:1 THF/H2O mixture (375 mL:125 mL) and degassed three times with argon. Pd/C (5.0 g, 50% mw) was added to the mixture and the reaction media degassed three times with H2. The reaction was carefully monitored by ESI-MS. After stirring for 8 hours under one bar of H2, the mixture was filtered through celite ® (washed with MeOH/H2O 1:1) and evaporated under reduced pressure. The crude product was dissolved in DMF (125 mL). NaH (60% in oil, 5.0 g, 0.125 mol) was added portion wise to the mixture. After stirring for one hour at R.T., methyl iodide (6.15 mL, 0.125 mol) was added to the mixture. The reaction was monitored by ESI-MS. After 12 hours at R.T., the mixture was quenched with MeOH (50 mL) at 0 °C and evaporated under reduced pressure. The obtained residue was dissolved in water (100 mL) and extracted with ether (5 x 100 mL). The combined organic layers were dried over Na2SO2 and evaporated under reduced pressure. The crude product was dissolved in MeOH (200 mL) and PTSA (1.52 g, 39.0 mmol) was added to the mixture. After stirring for 12 hours, the reaction was quenched by a saturated aqueous solution of NaHCO3 (200 mL). The aqueous phase was extracted with ether (5 x 200 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 98:2 DCM/MeOH) afforded diol 260 (753 mg, 16% over 4 steps) as a white foam.

A ,D -dihydroxyl-β-CD Me (261)

Pyridinium p-toluenesulfonate (0.1 g, 0.4 mmol) and dihydropyran (1.1 mL, 11.8 mmol) were added to a solution of β-CD 81 (5.6 g, 1.9 mmol) dissolved in DCM (30 mL). After stirring the mixture at R.T. during 12 hours, the reaction was quenched by a saturated aqueous solution of NaHCO3 (15 mL). The aqueous phase was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was dissolved in a 3:1 THF/H2O mixture (192 mL:64 mL) and degassed three times with argon. Pd/C (2.9 g, 50% mw) was added to the mixture and the reaction media degassed three times with H2. The reaction was carefully monitored by ESI-MS. After stirring for 8 hours under one bar of H2, the mixture was filtered through celite ® (washed with MeOH/H2O 1:1) and evaporated under reduced pressure. The crude product was dissolved in DMF (63 mL). NaH (60% in oil, 3.0 g, 0.076 mol) was added portion wise to the mixture. After stirring for one hour at R.T., methyl iodide (3.75 mL, 0.076 mol) was added to the mixture. The reaction was monitored by ESI-MS. After 12 hours at R.T., the mixture was quenched with MeOH (20 mL) at 0 °C and evaporated under reduced pressure. The obtained residue was dissolved in water (50 mL) and extracted with ether (5 x 50 mL). The combined organic layers were dried over Na2SO2 and evaporated under reduced pressure. The crude product was dissolved in MeOH (100 mL) and PTSA (3.8 g, 20.0 mmol) was added to the mixture. After stirring for 12 hours, the reaction was quenched by a saturated aqueous solution of NaHCO3 (100 mL). The aqueous phase was extracted with ether (5 x 100 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 98:2 DCM/MeOH) afforded diol 261 (1.24 g, 47% over 4 steps) as a white foam. The spectral data are in accordance with the data described in the literature. [13] 6 A ,6 The spectral data are in accordance with the data described in the literature. [14] 6 A ,6 Sodium iodide (1.17 g, 7.8 mmol) was added to a solution of α-CD 263 (1.22 g, 0.78 mmol) dissolved in acetone (32 mL). After 12 hours at 60 °C, the reaction was quenched by water (15 mL). The aqueous phase was extracted with ether (5 x 50 mL). The combined aqueous layers were dried over Na2SO4 and evaporated under reduced pressure affording crude 265 (1.33 g) as a white foam. The crude mixture was directly engaged for the imidazolium salt 267 synthesis.

(α-ICyD Me )HI (266)

Imidazole (850 mg, 12.4 mmol) was added to a solution of α-CD 264 (1.76 g, 1.24 mmol) dissolved in dry acetonitrile (80 mL). The mixture was degassed with argon three times and heated at 120 °C. After 12 hours, the mixture was evaporated. Silica gel flash chromatography (DCM up to 98:2 DCM/MeOH) afforded 266 (1.9 g, 65%) as a white foam.

(β-ICyD Me )HI (267)

Imidazole (376 mg, 5.52 mmol) was added to a solution of α-CD 265 (895 g, 0.55 mmol) dissolved in dry acetonitrile (35 mL). The mixture was degassed with argon three times and heated at 120 °C. After 12 hours, the mixture was evaporated. Silica gel flash chromatography (DCM up to 98:2 DCM/MeOH) afforded 267 (390 g, 47%) as a white foam. The spectral data are in accordance with the data described in the literature. [14] (α-ICyD Me )BH3 (268)

In a round-bottom flask, methylated α-cyclodextrin imidazolium chloride 266 (102 mg, 72.0 μmol) was dissolved in freshly distilled THF (2.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 288 μL, 0.14 mmol) was added dropwise inducing a quick red-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 72 μL, 0.14 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (95:5 DCM/methanol) afforded the encapsulated borane 268 (31 mg, 34%) as a white foam. (β-ICyD Me )BH3 (269)

MS (ESI

In a round-bottom flask, methylated β-cyclodextrin imidazolium chloride 267 (192 mg, 13.0 μmol) was dissolved in freshly distilled THF (4.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 522 μL, 0.26 mmol) was added dropwise inducing a quick red-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 130 μL, 0.26 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (95:5 DCM/methanol) afforded the encapsulated borane 269 (140 mg, 74%) as a white foam. The NMR tube was vigorously shaken. A first 1 H NMR spectrum of the mixture showed an incomplete conversion of (α-BiCyD)BH3. Therefore, the NMR tube was vigorously shaken and 1 H NMR showed, this time, full conversion of the borane. The J-Young NMR tube was placed in the glovebox and a solution of Et3PO (8.3 μL of a solution containing 10.3 mg of Et3PO dissolved in 100 μL of CD2Cl2, 6.4 μmol) was added to the mixture. The J-Young NMR tube was vigorously shaken and 1 H and 31 P{ 1 H} NMR spectra were recorded affording δ 31 P{ 1 H} = 86.09 ppm and A.N. = 99.6.

Figure 0 - 1 .

 01 Figure 0-1. Illustration de FLP et de CASPAIR pour la réduction du CO2 -Louis Vigreux.

Scheme I- 2 .

 2 Scheme I-2. A) Molecular structure of nanosphere 5 B) PM3-Spartan model of nanosphere 5 with the guanidinium groups shown in space-filling mode. Adapted by permission from Springer Nature Customer Service Centre GmbH: Nature, J. Reek et al., Nature Chemistry, 2016, 8, 225-230 C) Schematic representation of the catalysed cyclization of 6 inside the nanosphere.

Scheme I- 3 .

 3 Scheme I-3. A) Synthesis of the self-assembled capsule 10 and of the bowl 11, right images adapted with permission from Q.-F. Sun, J. Am. Chem. Soc. 2021, 143, 16087-16094. Copyright 2021 American Chemical Society B) Proposed catalytic cycle for the photooxidation of sulphides.

Figure I- 2 .

 2 Figure I-2. Structure and highlighted U-shape of Lewis acidic catalyst developed by Kazuaki Ishihara.

Brønsted-

  Lowry and Lewis acid catalysis and imidodiphosphates (IDP) which are moderately acidic but give high stereoselectivities (Figure I-3 A)). Replacing the oxygen atoms in the IDP by NTf (N-triflate) groups allowed the formation of the first IDPi catalyst presenting low pKa values (4.5 in MeCN for R = Ph), being active in Lewis acidic catalysis

Figure I- 4 .

 4 Figure I-4. A) Structure of p-t-butyl-calix[4]arene B) Calyx Krater: Return of Hephaistos to Olympus, circa 500 B.C., reproduced with permission from Harvard Art Museums.

  Scheme I-13. Functionalised-cyclodextrin catalysed oxidation of phenol. Functionalisation of CDs also enabled their bridging by an N-Heterocyclic Carbene (NHC) ligand, creating a new class of ligands called ICyD ligands (for Imidazolium-capped CycloDextrin). Those ICyD ligands, developed by Matthieu Sollogoub and his team, can

Scheme I- 14

 14 Scheme I-14. A) Substrate and enantioselective alkoxycyclization of enynes catalysed by (β-ICyD)AuCl 23 B) Substrateselectivity by the (β-ICyD)Au I .

Scheme I- 22

 22 Scheme I-22. A) Synthesis of FLP 53 B) Enantioselective imine reduction using chiral FLP 53.

the α- 1 , 4

 14 glycosidic bond (anticlockwise) (Figure I-6 A))Their height is invariable in function of the number of glucopyranose units but their circumference varies. Thereby the α-CD presents a smaller cavity-volume than the β-CD that is smaller than the γ-CD (Figure I-6 D)). Throughout this manuscript, α-CDs will be represented in yellow, β-CDs in blue (vide infra) and non-specified CDs in grey.

Figure I- 6 .

 6 Figure I-6. A) Topological representation of CDs and capital letter-nomenclature B) Glucopyranose unit of a CD C) Representation of CDs in this manuscript D) Comparison of CDs dimensions (crystallographic data). Native CDs are water soluble and their cavities paved with C-H bonds (H 3 and H 5 ) (Figure I-7) are hydrophobic thus allowing the formation of host-guest complexes in water.

Scheme I- 31

 31 Scheme I-31. A) Trans-selective aldol cyclisation described by Ronald Breslow B) Inclusion complex of β-CD 70 and the keto aldehyde.

73

  and with excellent selectivity with β-HUGPHOS 74. Both reactions also gave great ees in favour of the (R) product. Of course, those selectivities were explained by the presence of the chiral CD. C. NHC-Capped Cyclodextrins (ICyDs) The team of Matthieu Sollogoub managed to bridge the cavity of CDs with an NHC ligand pointing towards the inside of the cavity (Figure I-8). Those new NHC ligands called

I- 9 .

 9 Figure I-9. Structure of ICyD-Metal complexes.

  Scheme I-35. Proposed mechanism for the selective DIBAL-H mediated debenzylation of the primary rim of cyclodextrins. It should be noted that the debenzylation of α-CD 78 leads to the formation of diol 80 presenting a C2 symmetry. Therefore, only three sugars are distinguishable. However, β-CD diol A,D 81 presents a C1 symmetry (Figure I-10).

Figure I- 10 .

 10 Figure I-10. Structures of the obtained diols.

  chloride and triethylamine, leading to bismesylated CDs 82 and 83 in quantitative yields. The last step before the obtention of metal complexes involved the bridging of the CDs with imidazole. This reaction took place in DMF at 120 °C and afforded the imidazolium salts (α-ICyD)HCl 84 and (β-ICyD)HCl 85 in good yields (51% and 61% respectively). The imidazolium salts, precursors to the carbene formation, were obtained in good overall yields of 35% for the α-CD and 30% for the β-CD (Scheme I-36). The difference in obtaining the imidazolium-bridged cyclodextrins or the bis-imidazole CD 75 lies in the use of a base (NaH) to deprotonate the imidazole to form the unbridged compound.

Scheme I- 36 .

 36 Scheme I-36. Synthesis of the (α-ICyD)HCl 84 and (β-ICyD)HCl 85 imidazolium salts. The obtained imidazolium salts 84 and 85 were reacted with copper or silver oxide to afford the corresponding (α/β-ICyD)CuCl (86 & 87) and (α/β-ICyD)AgCl (88 & 89) metallic

Figure I- 11 .

 11 Figure I-11. Key NOESY cross correlations of (α-ICyD)CuCl (CDCl3, 600 MHz, 300 K).

Figure I- 12 .

 12 Figure I-12. Stacked NMR spectra of (α-ICyD)AuCl, (α-ICyD)AgCl and (α-ICyD)CuCl and comparision of their H 5 A and H 3 C (CDCl3, 600 MHz, 300 K).

Figure I- 13

 13 Figure I-13. A) Crystallographic structure of (α-ICyD Me )CuCl B) Highlighted proximity of the H 5 to the copper ion and of the H 3 to the chloride ligand, half the units omitted for clarity.

Figure I- 14 .

 14 Figure I-14. Schematic representation of the parallel approach of phenylacetylene in (β-ICyD)CuBPin and transition step leading to the formation of the branched product.

  Figure I-15). Here, the BPin reacts with the terminal position of the alkyne, providing the linear product 91.

Figure I- 15 .

 15 Figure I-15. Schematic representation of the perpendicular approach of phenylacetylene in (α-ICyD)CuBPin and transition step leading to the formation of the linear product.

  These new organocatalysts should allow their future use in FLP systems, for small molecule activation, where the frustration will come from the steric hindrance brought by the cavity while drawing the benefits obtained with ICyD ligands (regio/enantioselectivity, substrate selectivity…) (Figure I-16).

Figure I- 16 .

 16 Figure I-16. Project involving the synthesis of new encapsulated organocatalysts for their forward use in cavity separated Lewis pairs.

Scheme II- 7 .

 7 Scheme II-7. A) Resonance structure of protonated TMG B) Resonance structure of protonated DBU C) Resonance structure of protonated TBD D) Resonance structure of protonated NHI.

Figure II- 2 .

 2 FigureII-2. Photometrical titration-mesured pKBH+ values in acetonitrile of several NHIs and known strong bases.[14]

Figure II- 3 .

 3 Figure II-3. Summary of the strategy for the synthesis of the first CD-encapsulated Lewis base.

Figure II- 4 .

 4 Figure II-4. Retrosynthetic route for obtaining (β-ICyD)NH, the first encapsulated NHI inside a β-CD.

121 a

 121 Presence of NHI determined by NMR or ESI-MS b Products detected by ESI-MS.

  poor yield (25%) might be explained by the required formation of the very bulky 4membered ring intermediate (Scheme II-10 B)). Its formation might be toughened by the presence of the cavity (Figure II-5). Nevertheless, the use of azides seemed to be key to obtain encapsulated NHI.

Figure II- 5

 5 Figure II-5. A) Universal Force Field geometry optimization of the Staudinger-type rearrangement intermediate in β-CD based on crystalline data of (β-ICyDMe )CuCl[28] and highlighted steric hindrance. View from the secondary rim of the CD B) Topological representation of the represented intermediate.

  with tBuN3, forming a triazene intermediate 125 that undergoes a rearrangement when quenched with ammonium tetrafluoroborate, forming the protonated NHI and liberating molecular nitrogen and isobutylene. The rearrangement of the triazene intermediate 125 is believed to be feasible following two pathways (Scheme II-11 B)). In the first one (a), after protonation of the triazene unit, the conjugated base (B -) deprotonates the tBu moiety leading to the liberation of isobutylene and formation of 127. One more protonation leads to the liberation of N2 and the formation of the protonated NHI. The second pathway (b)

Figure II- 6 .

 6 Figure II-6. Cropped 1 H NMR spectra of imidazolium salt 85 and the follow-up of the reaction described in Scheme II-12 (CD3CN, 400 MHz, 300 K).

Figure II- 7 )

 7 and more importantly, the guanidinium peaks (blue on FigureII-7) were strongly influenced by the different counter ions. The effect of counter-ions led to differences in chemical shifts up to 0.24 ppm for the guanidinium protons.

Figure II- 7 .

 7 Figure II-7. Selected region of 1 H NMR spectra of the NHI obtained with the reaction described in Scheme II-12 (CD3CN, 400 MHz, 300K). Guanidinium signal coloured in blue and imidazole signals coloured in greed.Scaling up the reaction led to the obtention of four products bearing different counterions. These ions might come from different sources, the imidazolium salt 85 bears a chloride ion and the washing of the organic layer with water might also have brought different ions.

131 ,

 131 Scheme II-13. Synthesis of encapsulated NHI 131 using tBuN3 and quenching with HCl (1.0 M in Et2O).

Figure II- 8 . 1 H

 81 Figure II-8. 1 H NMR spectra of the follow-up of the reaction described in Scheme II-13 (CD3CN, 400 MHz, 300 K). Guanidinium signal coloured in blue and imidazole signals coloured in greed.

  Scheme II-14. A) Synthesis of the benzimidazolium salt 132 and of the encapsulated NHI 133 B) Synthesis of the 4,5dimethylimidazolium salt 135 and of the encapsulated NHI 136.

D.a

  Development of the synthesis with α-CD Having managed to synthesise encapsulated NHIs with β-CD, the next part involved the synthesis of NHIs encapsulated in α-CDs. 5 For the following reactions, one equivalent of (α-ICyD)HCl imidazolium salt 84 was reacted in a screwed cap tube and the reaction monitored by NMR. Before the quench, all the reactions presented a full conversion to the triazene intermediate 137. Presence of products determined by NMR b Isolated yield.

  4, entry 3). Silica gel chromatography afforded a mixture containing the imidazolium salt 84 and what was later shown to be the charged NHI 139 and the neutral NHI 140. The yield for this reaction was about 44%. Once again, the imidazolium salt 84 was inseparable from the NHI.

Figure II- 9 . 1 H

 91 Figure II-9. 1 H NMR spectra of A) Obtained mixture of protonated 139 and neutral α-CD NHI 140 after purification B) After addition of tBuOK C) After addition of HCl (1M in Et2O) (CD3CN, 400 MHz, 300 K).

Figure II- 10 .

 10 Figure II-10. Key NOESY cross correlation of H N-CH=CH-N and H 5 C proving the inversion of the imidazole moiety (CD3CN, 600 MHz, 300 K).

Scheme II- 15 .

 15 Scheme II-15. Synthesis of the inverted NHI 142 and formation of 143. The use of other bridges, 4,5-dimethylimidazole and benzimidazole, should prevent such inversions thanks to the presence of bigger groups on the 4 and 5 positions of the imidazole unit.

Figure II- 11

 11 Figure II-11. 1 H NMR spectra of A) (α-MiCyD)NH2Cl 145 obtained after purification B) (α-MiCyD)NH 146 obtained after addition of tBuOK (CD3CN, 400 MHz, 300 K).

F.a

  Scheme II-17. Synthesis of (α-BiCyD)HCl 147.

  basicity might have led to a difficulty in the triazene protonation thus preventing the rearrangement. The use of strong acids (HCl and PTSA) led to the obtention of the starting (α-BiCyD)HCl 147. In conclusion, the use of KHMDS and tBuN3 on the different NHC-capped CDs led to the obtention of the first encapsulated NHIs and the first encapsulated bases inside the cavity of CDs. The developed method afforded three new β-CD-based NHI bearing three different imidazole moieties, namely imidazole (131), benzimidazole (133) and 4,5dimethylimidazole (136). The formation of α-CD NHIs revealed to be harsher. The use of (α-ICyD)HCl led to the obtention of an inverted NHI 142 with the exo-cyclic nitrogen pointing outside the cavity. The presence of the methyl groups on (α-MiCyD)HCl allowed the formation of the encapsulated α-CD NHI (α-MiCyD)NH2Cl 145. However, the obtention of (α-BiCyD)NH2Cl 149 was not achieved probably due to the nature of the benzimidazole ligand and of the CD.Having synthesised new encapsulated bases, the next step was the study of their properties.

Figure II- 12 .

 12 Figure II-12. Obtained CD-encapsulated NHIs, inverted (α-out-ICyD)NH2Cl and their overall yields.

(β-ICyD)NH2Cl 131 .

 131 The trials were performed in CD3CN as it solubilises CDs and is used in pKa determination for organic bases. Adding one equivalent of DBU to a solution of protonated NHI 131 (Figure II-13 B)) led to full conversion in favour of the neutral NHI 116 meaning DBU is a much stronger base than (β-ICyD)NH 116. On the contrary, adding one equivalent of triethylamine (Figure II-13 C)) led to the obtention of a mixture containing both species. This was seen by the presence of broad H N-CH=CH-N and H C=NH2 signals in 1 H NMR spectrum. Doing the same equilibrium with the basic (β-ICyD)NH 116 and Et3NHCl (Figure II-13 D)) led to the obtention of a similar 1 H NMR spectrum. Interestingly, the obtained spectrum was not the opposite of the one obtained for C) as expected. However, once again, an equilibrium was obtained indicating that the pKBH+ of the (β-ICyD)NH2Cl

  Adding one equivalent of Et3N to a solution of p-fluorophenol led to a shielding of the 19 F signal indicating a weak interaction or a fast-exchanged acid-base reaction. Taking the side of the fast-exchanged acid-base reaction and knowing the 19 F chemical shifts of the 156/Et3N mixture (Figure II-14 C)), of 156 (Figure II-14 A)) and of p-fluorophenolate 157 (Figure II-14 B)) allowed the obtention of the concentrations of all four species engaged in the equilibrium following equations described in Annex II-2. Knowing these concentrations and the pKa of Et3N (18.83) afforded a pKa value of 28.77 for p-fluorophenol 156 in acetonitrile.

Figure II- 14 . 19 F

 1419 Figure II-14. 19 F NMR spectra of A) p-fluorophenol B) p-fluorophenolate C) 1:1 mixture of p-fluorophenol and Et3N (CD3CN, 376 MHz, 300K).

Figure II- 15 .

 15 Figure II-15. Obtained pKBH+ values for synthesised NHIs using p-fluorophenol. Surprisingly, the obtained basicities with CDs were much lower, about 2 units, than the one obtained using the model NHIs (see Figure II-16 for a pKBH+ plot). The important difference in pKBH+ values between model NHIs and CD-encapsulated-NHIs seemed to indicate that isopropyl-groups present on the model NHIs hindered more the NHIs than the CDs did. The other explanation might come from iPr groups being more electro-donating than the CDs. The encapsulated NHI inside an α-CD, (α-MiCyD)NH 146, gave the highest pKBH+ for CDs, 17.4, and the inverted NHI, (α-ICyD)NH 143 gave the lowest, 16.3. The lowest value might be explained by the lack of steric hindrance from the absence of the cavity. As shown by Roman Kunietsky and Ilya Lyapkalo (Figure II-2), increasing the steric hindrance of NHIs led to higher basicities. Following this logic, it is not surprising that (α-MiCyD)NH 146 brought the highest value for CDs.

  Figure II-16. Plot of NHIs pKBH+ values in function of the ligand. The lack of, or minor, ligand influence for β-CD NHIs and the important difference in pKBH+ values between the CDs and the model NHIs are puzzling and therefore interesting.

  interior and a base comparable to the AAD's one (Figure II-17 C)). The cavity might impede the formation of the usually found solvation cage around the "free" NHIs and therefore destabilize the protonated state of the NHI thus leading to a decrease in the pKa value. The impact of the cavity on the basicity of NHIs is currently being studied by DFT calculations.

Figure II- 17

 17 Figure II-17. A) Azaphosphatrane and schematic representation of charge-dipole interactions B) AAD's active site view, hydrophobic residues in yellow, polar residues in grey and lysine with decreased pKa. Adapted by permission from Springer Nature Customer Service Centre GmbH: M.-C. Ho et al., Nature, 2009, 459, 393-397 C) Universal Force Field geometry optimization of (β-ICyD H )NH2 + based on crystalline data of native β-CD. View from the secondary rim.

  B chemical shift of the adduct acquired (Figure II-18 A)).Here, the stronger the Lewis base is, the stronger the shielding of the signal will be, due to a stronger electron-donation from the ligand. In CD2Cl2, borane dimethysulfide showed a chemical shift of -19.33 ppm. Adding NHIs led, as expected, to a shielding of the signal up to -39.13 ppm (Figure II-18 B)). The11 B NMR spectra presented the signal of the sulfide complex as well as the NHI-BH3 complex probably due to the difficulty of adding precisely one equivalent of sulfide.

Figure II- 18

 18 Figure II-18. A) Proposed experiment for Lewis basicity comparison B) Obtained chemical shifts for NHI-BH3 adducts.Model NHIs borane adducts led to the obtention of different chemical shifts following the π-acceptance properties of the corresponding carbenes (FigureII-19).[2] The

  21 ppm. Surprisingly, α-CD encapsulated NHI (α-MiCyD)NH-BH3 adduct presented a chemical shift similar to the one obtained using β-CDs. This base presented the highest pKBH+ value among encapsulated NHI. Inverted (α-out-ICyD)NH-BH3 adduct presented a chemical shift close to the one obtained with the model NHI (-36.88 ppm vs -37.62 ppm).

Figure II- 19 .

 19 Figure II-19. Plot of NHI-borane adducts 11 B chemical shift in function of the ligand. Considering these results, the impact of the encapsulation of NHIs was undeniable. All encapsulated NHIs presented Lewis basicities comparable to the one obtained with the weak benzimidazole-based model NHI. The cavity seemed to lower the basicities of the NHIs without any influence of the electronic property of the ligand. Steric effects seemed to be excluded due to the obtention of the same result using α-CD and β-CD. This supposition was supported by the obtention of similar chemical shifts using the inverted (α-out-ICyD)NH-BH3 adduct and the imidazole-based model NHI. The only difference between these two molecules relied in different groups on the endo-cyclic nitrogen atoms. The absence of cavity around the exo-cyclic nitrogen leading to the obtention of similar chemical shifts showed the sole impact of the cavity on the basicity of the encapsulated NHIs.

Scheme II- 20 .

 20 Scheme II-20. Trials of CO2 adducts formations with β-CD encapsulated NHIs.

  KHMDS and tBuN3. α-CD and β-CD encapsulated NHIs reacted differently through the quench of the reaction. β-CD NHI were quenched using a solution of HCl (1 M in Et2O) and afforded three encapsulated NHIs namely (β-ICyD)NH2Cl 131, (β-BiCyD)NH2Cl 133 and (β-MiCyD)NH2Cl 136 with overall yields from 6% to 26%. α-CD NHIs were quenched using Et3NHCl and afforded two new NHIs, (α-out-ICyD)NH2Cl 142 and (α-MiCyD)NH2Cl 145. The product with α-ICyD was found to be inverted, the exo-cyclic nitrogen pointing towards the outside of the cavity. This result probably came from the lack of space inside of the α-CD for the formation of the triazene intermediate and the ability of the ICyD to invert. The use of the MiCyD ligand prevented this inversion and led to the formation of the encapsulated NHI. These compounds reacted with tBuOK forming the corresponding deprotonated NHIs. The use of p-fluorophenol afforded pKBH+ values that were compared with model compounds bearing isopropyl groups on the 1 and 3 positions. These measurements revealed a difference of 2 pKBH+ units between the β-CD NHIs and the model compounds. These results might be explained by the similarity of the cavity with AAD's hydrophobic active site and are currently under investigation. (α-MiCyD)NH 146 gave the highest pKBH+ value among CD bases NHIs and might be explained by the biggest steric hindrance brought by the cavity. Considering the high pKa value obtained for p-fluorophenol156, the use of this base for obtaining an acid-base equilibrium with NHIs might not have been judicious. The use of another base, presenting a phosphorus atom for example, should be considered for obtaining precise pKBH+ values. However, as the obtention of precise pKBH+ values might be discussed, the effect of the cavity on the basicity is undeniable. The formation of NHI-borane adducts revealed similar behaviours for encapsulated NHIs with α-and β-CDs. These adducts presented similar11 B chemical shifts, close to the one obtained with the weakest model NHI 162, affirming a cavity effect for the Lewis basicity of encapsulated NHIs. However, while model NHIs followed the π-acceptance order of the ligands, the (α-out-ICyD)NH-BH3 gave a11 B chemical shift close to the one obtained with the model NHI, reinforcing the hypothesis of a cavity effect on the basicity. Trials for β-CD NHI-CO2 adducts were non-conclusive under one bar and trials using higher pressures will be performed.The synthesis of encapsulated NHIs led to the obtention of weakly basic bases probably due to the hydrophobic environment present inside the cavity. This result might be helpful in the Taking the side of a fast equilibrium between F(C6H4)OH and F(C6H4)O -, the19 F chemical shift of the mixture leads to an average between the 19 F chemical shifts of F(C6H4)OH and F(C6H4)O -. p-fluoroanisole is used as an internal reference. Knowing the chemical shifts of the phenol and the phenolate, the

Figure III- 1 .

 1 Figure III-1. Structure of borinium, borenium and boronium ions.

Figure III- 2 .

 2 Figure III-2. Structures of borinium ions 170, 171, 172, and 173.

  B NMR chemical shift at 24 ppm with a broad signal (ν1/2 ≈ 330 Hz). The other generally used strategy for borenium ion formation relied on hydride abstraction. The use of [CPh3 + ][B(C6F5)4 -]

  hindered amino borate 191 reacted with 0.5 equivalents of [CPh3 + ][B(C6F5)4 -] to form dimer 192 in which a hydride is shared in the well-known 3 atoms, 2 electrons, bond. Adding 0.5 equivalents of the trityl salt resulted in the disappearance of the singlet corresponding to the tBu moiety and to the appearance of a 11 B signal at 69.3 ppm indicating the formation of 194 concurrently with H2 liberation. Finally, the mixture was quenched using [nBu4N + ][BH4 -] affording borylated compound 195. The elusive dihydridoborenium ion 193 was not detected.

  Scheme III-11. A) Formation of a boronium ion by H. Nöth, H. Beyer and H.-J. Vetter B) Formation of a boronium ion by V. Sheludyakov, T. Shchegoleva and B. Mikhailov. Other strategies were used for the formation of boronium ions. The protic attack of the B-N bond of diamino borate 196 with HCl or HBr led to the protonation of the amine

Figure III- 3 .

 3 Figure III-3. Structures of borinium, borenium and boronium ions and their relative stability.

  Scheme III-17. A) Formation of bistriflimide NHC-borane 212 B) Formation of bridged compound 213.

  The hydroboration step is believed to be performed by the unobserved dihydrido borenium ion 214 or by the more stable, and observed, dimer 213 (FigureIII-4). Because of their cationic forms, 213 and 214 would be able to perform hydroboration reactions. The double hydroboration reaction on 213 and 214 affords the dialkyl borenium 215 that performs a hydride abstraction on borane 211 reforming the catalyst and affording the dialkyl NHCborane 216. After an oxidative workup, the alcohols are afforded. This reaction was run with HNTf2 loadings as low as 5 mol% supporting the idea that a hydride transfer was reforming the active, cationic, catalytic specie.

Figure III- 4 .

 4 FigureIII-4. Proposed mechanism for the HNTf2 catalysed hydroboration of alkenes through the formation of a NHCdihydrido-borenium ion.

[

  CPh3][B(C6F5)4] salt for borenium ion formation allowed the presence of the weakly coordinating B(C6F5)4 -counter-ion. Concerning mono-hydrido NHC-borenium ions, 230, 233 and 234, the groups present on the boron centre were all sterically hindering in order to avoid the formation of bridged compounds.

  B NMR signals of NHC-boranes are in negative values in accordance with a tetracoordinated boron atom, and present well-resolved signals when coupled to a 1 H nucleus. The 11 B NMR signals obtained for borenium ions where shown to be strongly deshielded, above 50 ppm in CD2Cl2, and to depend on the solvent: 50.6 ppm in CD2Cl2 and 27.1 ppm in C6D5Br for 233 (Figure III-5)

  B{ 1 H} NMR spectrum of 233 presented a large signal at 27.1 ppm in C6D5Br overlapping the signal of the borosilicate glass composing the NMR tube (Figure III-6 A)). Cooling the sample to 0 °C led to the disappearance of this signal allowing its clear attribution to borenium ion 233. Forming the borenium ion in situ allowed the obtention of a clearer signal. The signal of the 1 H atom linked to the boron centre was also impacted and presented a very large singlet (Figure III-6 B)). In comparison, the hydrogen atoms present on the corresponding borane presented a quartet signal due to 1 J couplings with the boron nucleus (Figure III-6 C)). For the borenium ion 233, the spin-spin coupling completely collapsed.

Figure III- 6

 6 Figure III-6. A) 11 B{ 1 H} temperature dependant NMR of borenium ion 233 (C6D5Br, 192 MHz) B) Selected B-H(C6F5) 1 H NMR signal of borenium ion 233 (C6D5Br, 600 MHz, 299 K) C) Selected B-H2(C6F5) 1 H NMR signal of borane 231 (CD2Cl2, 600 MHz, 299 K). Reproduced by permission from Wiley. In conclusion, the study of the NMR spectrum of NHC-borenium ions led to the obtention of valuable information. The 11 B NMR signals are downfielded up to 83.8 ppm and present broad signals. The broadness of the signals indicates very short transverse relaxation times for the studied compounds resulting from a strong field gradient present at the boron nucleus. The use of quartz NMR tubes could help to obtain neater signals.

Figure III- 7 .

 7 Figure III-7. Summary of the strategy the synthesis of the first CD-confined organic Lewis acid.

Figure III- 8 .

 8 Figure III-8. Representations of stabilising orbital component and repulsive electrostatic component in "contraelectrostatic H bonds".

Figure III- 9 .

 9 Figure III-9. Representation of the computed dihydrogen bonding in borane-trimethylamine dimer and extrapolation to CD-encapsulated boranes.

  B NMR spectra did not show any correlation with the hydrogen atoms present on the borane. 11 B{ 1 H} NMR spectra showed not intense broad singlets up to ν1/2 = 313 Hz (Figure III-10). This broadness indicates short relaxation times for the encapsulated boron nucleus. On the opposite, the model compound 235 led to the obtention of a neat quartet for 11 B NMR (Figure III-10).

Figure III- 10

 10 Figure III-10. A-F) 11 B{ 1 H} NMR spectra of encapsulated boranes (CD2Cl2, 192 or 128 MHz, 300 K), G) 11 B NMR spectrum of model compound 235 (CD2Cl2, 192 MHz, 300 K).

  (α-ICyD)BH3 248 presented a very broad peak (ν1/2 ≈ 174 Hz) at 1.68 ppm (Figure III-11 A)). This signal was proved to belong to the BH3 by performing a 1 H NMR decoupled from 11 B ( 1 H{ 11 B}) experiment that narrowed the signal (Figure III-11 B)). For this sequence, finding the right decoupling power was important in order to get the decoupling without broadening the rest of the spectrum (Annex III-1).

Figure III- 11

 11 Figure III-11. A) 1 H NMR spectrum of (α-ICyD)BH3 248 (CD2Cl2, 600 MHz, 300 K) B) 1 H{ 11 B} NMR spectrum of (α-ICyD)BH3 248 (CD2Cl2, 600 MHz, 300 K).

The 1 H

 1 NMR spectrum showed, as expected for a NHC-BH3 adduct, a quartet signal presenting four peaks of same intensity (red on Figure III-12 A)). Irradiating the sample at the frequency of 11 B (192 MHz for 14.1 T) led to the formation of a singlet from the disappearance of the spin-spin couplings between the 1 H and the 11 B nuclei (red on Figure III-12 B)). Around the singlet, the 10 B component of the borane, which was not decoupled, could be seen (green on Figure III-12 A) & B)).Because of the broad signal obtained for 1 H{ 11 B} NMR in the case of (α-ICyD)BH3 248, the10 B component was not obtained. Still, this method afforded a narrowing of the hydrides signal.

Figure III- 12

 12 Figure III-12. A) 1 H NMR spectrum of model compound 235 (CD2Cl2, 600 MHz, 300 K) B) 1 H{ 11 B} NMR spectrum of model compound 235 (CD2Cl2, 600 MHz, 300 K).

A 1 H

 1 /11 B HMQC sequence was also performed to prove the correlation between the boron signal and the BH3 group. This heteronuclear coherence sequence led to the obtention of a single cross-correlation between the11 B signal and the broad peak shown before as the signal of the NHC-BH3 (FigureIII-13). These experiments were also performed on the other encapsulated boranes.

Figure III- 13

 13 Figure III-13. 1 H/ 11 B HMQC spectrum of (α-ICyD)BH3 248 and highlighted correlation (CD2Cl2, 600 MHz, 300 K). The obtention of these broad signals was clearly correlated to short relaxation times for the boron nucleus. The only difference between the encapsulated boranes and the model compound relied on the presence of CDs. In order to confirm the cavity influence, transverse relaxation time (T2 * ) of the boron nuclei of model compound 235 and of (β-ICyD)BH3 251 were measured. T2 * corresponds to the transverse relaxation time accounting the field inhomogeneities. The obtained value when a transverse relaxation time is measured is always accounting these field inhomogeneities. The transverse relaxation time plays an important role in the obtention of neat NMR signals. When recording an NMR spectrum, it is possible to adjust the relaxation delay (D1) in function of the longitudinal relaxation time (T1). However, no parameter exists to affect T2 for an experiment. Therefore, the T2 * values of the model compound 235 and of (β-ICyD)BH3 251 were measured thanks to an echo spin

  (β-ICyD)BH3 251 afforded a T2 * value that is 50 times smaller than the one obtained for model compound 235. The presence of the cavity around the boron nucleus clearly leads to an important decrease of the relaxation time.

  6). The presence of β-CDs brought the chemical shifts between -35.9 and -35.8 ppm indicating an effect of the cavity on the borane. The α-CDs influenced even more the 11 B NMR as the obtained chemical shifts were between -34.0 and -32.3 ppm. β-CDs had less influence on the 11 B chemical shifts than α-CDs probably due to their bigger cavity. The signals of the hydrides were also influenced by the cavity. The model compound 235 presented the hydrides at 0.97 ppm whereas β-CDs presented signals at 1.38 and 1.41 ppm. Here again, the α-CDs had the biggest influence with signals between 1.66 and 1.92 ppm.

13 C

 13 B signals of the encapsulated boranes were very broad, indicating fast quadripolar relaxation mechanisms. This effect was also seen on the 1 H NMR of the hydrides. The measurement of the transverse relaxation times of the model compound 235 (64.3 ms) and (β-ICyD)BH3 251 (1.3 ms) confirmed the effect of the cavity on the quadripolar relaxation of the boron nuclei. This effect might be explained by the important electric field gradient brought by the encapsulation of the borane in the CD. The relationship between T2 * and ν1/2 was exploited to get an approximation of the relaxation times of the other boranes and all gave very small values. Compared to the model compound 235, β-CD encapsulated boranes gave deshielded but similar 11 B chemical shifts. The α-CD series gave even more deshielded signals and (α-BiCyD)BH3 249 gave an even more downfield signal at -32.3 ppm. The comparison of the signals of the carbon atoms linked to the borane gave more evidence of the special nature of benzimidazole-based encapsulated boranes. Their shifts were the more deshielded in accordance with their poorest π-donation properties.

263.

  Scheme III-32. Synthesis of (α-ICyD Me )BH3 268 and (β-ICyD Me )BH3 269.The methylated CDs were then dissolved in DCM and various vapour diffusion crystallisations were set with different solvent systems. (α-ICyD Me )BH3 268 afforded crystals with two solvent systems (Et2O and Et2O/pentane) that were suitable for X-ray diffraction analysis. However, despite numerous trials, (β-ICyD Me )BH3 269 never afforded crystals that were suitable for analysis.

  B NMR signal. Adding PTSA or CSA on encapsulated boranes led to the formation of the corresponding imidazolium salts. Finally, reacting (β-ICyD)BH3 251 with triethyloxonium led to an exchange of ligand forming (β-ICyD)BF3 270. These results showed the possibility to perform hydride abstraction reactions needed for the formation of borenium ions. However, this formation required other conditions involving the use of non-coordinating and nonreactive counter-anions.

[

  Scheme III-36. Reaction of (α-ICyD)BH3 248 and [CPh3][B(C6F5)4] in CD2Cl2.

Figure III- 16

 16 Figure III-16. A) Dimerization equilibrium for Bertrand's copper hydride B) Structure of the CD-encapsulated stable monomeric copper hydride complexes.

Figure III- 17

 17 Figure III-17. 11 B{ 1 H} NMR spectrum of the reaction between (α-ICyD)BH3 248 and [CPh3][B(C6F5)4] (CD2Cl2, 128 MHz, 300 K).

The 11 B

 11 Figure III-21. Variable temperature 11 B NMR spectra of the reaction between (α-ICyD)BH3 248 and 0.8 eq. of [CPh3][B(C6F5)4] (C6D5Br, 192 MHz).

  Solid state NMR is less sensitive than liquid state NMR. Therefore, numerous techniques were developed for the obtention of signals and, among others, techniques for the obtention of quadrupolar nuclei signals. The 11 B NMR signals of (α-ICyD)BH3 248 and (β-ICyD)BH3 251 were recorded and showed well-defined signals (Figure III-22). These spectra were recorded using a Hanh spin echo sequence that allows the obtention of more resolved signals. The solution in obtaining the boron signal of (α-ICyD)BH2 + 272 may lay in the use of solid state NMR. The obtention of a powder after the addition of the trityl cation will be tried soon.

Figure III- 22 .

 22 Figure III-22. Solid state 11 B MAS NMR of (α-ICyD)BH3 248 and (β-ICyD)BH3 251 (224 MHz, rotation speed: 14 kHz 300 K).

  Scheme III-40. Reaction between (β-ICyD)BH3 251 and [CPh3][B(C6F5)4] in CD2Cl2.

Figure III- 23 . 1 H

 231 Figure III-23. 1 H NMR spectrum of the reaction between (β-ICyD)BH3 251 and [CPh3][B(C6F5)4] (CD2Cl2, 400 MHz, 300 K).

Figure III- 24 &Figure III- 25 )

 2425 Figure III-25) and the secondary protons (correlation coloured in blue on correlation coloured in red on Figure III-24 & Figure III-25). This distinction becomes very useful when it comes to CDs. For glucopyranose units, the C 1 present chemical shifts around 100 ppm. They are usually alone in this region which makes them easy to recognise (green square on Figure III-24). For (β-ICyD)BH3 251 (and for the other encapsulated boranes), the C 5 A and C 5 D signals were shielded due to the close presence of the nitrogen atom (orange square on Figure III-24).

Figure III- 24 .

 24 Figure III-24. Selected part of the HSQCed spectrum of (β-ICyD)BH3 251, highlighted H 1 /C 1 correlations in green square, highlighted H 5 A/C 5 A and H 5 D/C 5 D correlations in orange square (CD2Cl2, 600 MHz, 300 K). The HSQCed experiment of the potential (β-ICyD)BH2 + ion 273, in C6D5Br, presented 7 correlations on the C 1 region, indicating the presence of only one specie as β-CD is composed of 7 glucopyranose units (green on Figure III-25). Moreover, the C 5 A and C 5 D signals were not found deshielded from the rest of the signals as for (β-ICyD)BH3 251. This indicated a lower electronic density around these carbon atoms consistent with the presence of a charge. Unfortunately, the other 2D sequences did not allow a full characterisation of

Figure III- 25 .

 25 Figure III-25. Selected part of the HSQCed spectrum of the potential (β-ICyD)BH2 + ion 272, highlighted H 1 /C 1 correlations in green square, highlighted H 6 A/C 6 A and H 6 D/C 6 D correlations in purple square (C6D5Br, 600 MHz, 300 K).

  (β-ICyD)BH3 251 also underwent a full hydride abstraction reaction with the trityl salt. The HSQCed experiment indicated the presence of only one specie in the medium and allowed to show a shielding of the C5 A and C 5 D chemical shifts consistent with the presence of a charge on the imidazole moiety. These clues are not enough to characterise the formed molecule as [(β-ICyD)BH2][B(C6F5)4] 273 but the NMR experiments should be performed again in order to get more certainty.

Figure III- 26 .

 26 Figure III-26. Comparison of steric hindrance, GB and Childs relative scales and obtained computational and electrochemical acidities of B(C6F5)n(C6Cl5)3-n boranes.

[

  Scheme III-44. General scheme for GB Lewis acidity measurements.The addition of TEPO led to strong deshieldings of the31 P NMR signals, up to 89.3 ppm, which was consistent with its addition to strong Lewis acids (Figure III-27 & Annex III-2).

Figure III- 27 .

 27 Figure III-27. Obtained 31 P NMR chemical shifts for GB Lewis acidity measurements. The experiments performed on [(β-MiCyD)BH2][B(C6F5)4] 277 and [(β-BiCyD)BH2][B(C6F5)4] 276 led to the presence of two 31 P signals (at 86.7 & 84.9 ppm and 89.3 & 88.4 ppm respectively). This could be attributed to the presence of two isomers for the formation of these adducts. The HSQCed spectrum of [(β-MiCyD)BH2OPEt3][B(C6F5)4] 283 showed the presence of 14 H 1 /C 1 cross-couplings consistent with the presence of two different CDs in the medium (Figure III-28).

Figure III- 28 .

 28 Figure III-28. Selected part of HSQCed spectrum of the potential adduct 283, highlighted H 1 /C 1 correlations in green square (CD2Cl2, 600 MHz, 300 K).

bridged ion 279

 279 followed by the imidazole-bridged 278, and finally by the 4,5dimethylimidazole-bridged one 280 (Figure III-29). Surprisingly, the value obtained for the (β-ICyD)BH2OPEt3 + adduct 281 was the almost identical to the one obtained for the (α-ICyD)BH2OPEt3 + adduct 271. On the contrary, the values obtained for the other β-CDs 282 and 283 were much higher than for the α-CDs. The highest value was obtained for the benzimidazole-bridged ion 282 which led to a deshielding at 89.3 ppm. As mentionned, the GB method is sensitive to steric effects. The observed difference might be explained by the smaller cavity of the α-CD although the imidazol-bridged adducts 278 and 281 gave almost the same result. Moreover, because of the steric-dependance of the GB method, the obtained results may have been underestimated because of the steric hindrance brought by the cavity.

Figure III- 29 .

 29 Figure III-29. Plot of the obtained 31 P NMR chemical shifts for GB Lewis acidity measurements applied to encapsulated potential borenium ion.

  P NMR shifts of TEPO with hexane (δ = 41.0 ppm, A.N. = 0) and SbCl5 (δ = 86.1 ppm, A.N. = 100). A higher A.N. value indicates a greater Lewis acidity. The A.N. of a molecule can be calculated with: 𝐴. 𝑁. = 2.21 (𝛿 𝑃 31 𝑠𝑎𝑚𝑝𝑙𝑒 -41) The A.N. of the obtained adducts were calculated and compared with known boron-based Lewis acids (Figure III-30)

  Figure III-30. Comparison of A.N. of several boron-based Lewis acids.

  Scheme III-45. (β-ICyD)BH2(C6F5) borane synthesis and borenium ion formation trial.

  is calculated from the difference in binding enthalpy of the fluoride ion with a Lewis acid in the gas phase. The calculation is made via the study of an isodesmic reaction with Me3SiF (Figure III-31).

Figure III- 31 .

 31 Figure III-31. General scheme for FIA calculations.

  Scheme III-46. Cristallisations trials for α-CD borenium and boronium ions.

  H NMR and allowed to see the disappearance of the phenylacetylene signal after 12 hours (blue square on Figure III-34). This disappearance was concomitant with the appearance of a new product (red square on Figure III-34). This new product couldn't be characterised by NMR or ESI-MS. However, phenylacetylene did react with the formed borenium ion as the remaining (β-ICyD)BH3 251 signals (coloured in green on Figure III-34) did not change over time. On the contrary, the peak corresponding to the borenium ion 273, coloured in orange, lost in intensity. The conversion of the borenium ion was not total maybe due to the presence of less equivalents of phenylacetylene than intended.

Figure III- 34 . 1 H

 341 Figure III-34. 1 H NMR spectra of the reaction between borenium ion 273 and phenylacetylene (CD2Cl2, 400 MHz, 300 K).

Figure III- 35 . 1 H

 351 Figure III-35. 1 H NMR spectra of the H2 activation trial by borenium ion 273 and TMP (CD2Cl2, 400 MHz, 300 K).H2 activation was also tried with lutidine under 5.0 bars of H2 but, once again the reaction did not afford the borane. A screening of phosphorus and nitrogen-based Lewis bases for H2 activation will be performed in order to understand this potential lack of reactivity. The activation might be toughened by the steric hindrance brought by the CD.

Figure III- 36 .

 36 Figure III-36. Selected parts of the 1 H NMR spectra of the αand β-CD borenium ion catalysed hydrosilylation reaction of acetophenone (CD2Cl2, 400 MHz, 300 K). The study of the mechanism of the BCF-catalysed hydrosilyation reaction showed that in the presence of strong Lewis acids ([CPh3][B(C6F5)4] and [Et3Si][B(C6F5)4]), the reactions

Figure III- 37 .

 37 FigureIII-37. Alternative mechanism for the Lewis acid-catalysed hydrosilylation reaction of acetophenone.

  for H2 activation. The Lewis acidity of the encapsulated borenium ions was used to catalyse the hydrosilylation of acetophenone. α-CD 272 led to the obtention of the hydrosilylated product whereas β-CD 273 afforded the deoxygenated product. This resulted from the different cavity-sizes that could be used in the future for tuning the frustration of a FLP. During the course of this PhD work, the first CD-encapsulated Lewis bases and acids were synthesised. Encapsulated N-Heterocyclic Imines were obtained through the use of tert-butyl azide and the corresponding carbenes. This method afforded three β-CD encapsulated NHIs, namely (β-ICyD)NH2Cl 131, (β-BiCyD)NH2Cl 133 and (β-MiCyD)NH2Cl 136. Performed on the α-CD, the reaction afforded the reversed NHI (α-out-ICyD)NH2Cl 142. The bridging of the α-CD with 4,5-dimethylimidazole allowed the obtention of an NHI, (α-MiCyD)NH2Cl 145, with the nitrogen atom encapsulated within the cavity of the α-CD. The study of these CD-based NHIs revealed the influence of the cavity on Brønsted-Lowry basicity. The cavity lowered the Brønsted-Lowry basicity up to 2 pKBH+ units independently of the electronic-tuning of the bridge. This important difference might be explained by the C-H bonds paving the inside of the cavity. Because of these C-H bonds, the surroundings of the exo-cyclic nitrogen probably present a different dielectric constant than in the absence of the cavity. This may destabilise the charged nitrogen, as for the AAD enzyme, and induce lower basicities.

Figure IV- 1 .

 1 Figure IV-1. Synthesised CD-based NHIs and comparison of their pKBH+ valued with model compounds.

  signals for the boron nucleus. Because of this enhanced quadripolar effect, the characterisation of the hydride abstraction products from the encapsulated boranes was toughened. The addition of the[CPh3][B(C6F5)4] salt to encapsulated boranes led to the full consumption of the trityl salt. The use of less than one equivalent of the trityl salt did not lead to the dimerization of the encapsulated borane with the product which was a first in the formation of NHC-dihydrido borenium ions. The Lewis acidity of the products was measured using the Gutmann-Becket method. The obtained values were close, or higher, than the ones described for borenium ions. Therefore, the products of the hydride abstraction reactions on encapsulated boranes are probably the corresponding NHC-dihydrido borenium ions. NMR characterisations, or the obtention of crystals, should confirm the obtention of the first stable NHC-dihydrido borenium ions.

Figure IV- 2 .

 2 Figure IV-2. Synthesised probably CD-encapsulated NHC-dihydrido borenium ions, their A.N. values and comparisonwith two borenium ions.The [(β-ICyD)BH2][B(C6F5)4)] borenium ion 273 was reactive, as expected, with phenylacetylene. However, the product could not be characterised. Therefore, in order to ensure the reactivity of the ions towards hydroboration reactions, a simpler alkyne or alkene should be used in order to confirm the hydroboration reaction. The same ion did not activate H2 in presence of TMP and lutidine. This may be explained by the steric hindrance around the Lewis acidic boron atom. However, a screening with several Lewis bases has to be done in order to ensure this possible lack of reactivity. The activation of other gases should also be tried. The difference of reactivity of the α-and the β-CD towards the hydrosilylation of acetophenone enlightened the possibility of tuning the reactivity of Lewis acids encapsulated within the cavity of CDs.

Figure IV- 3 .

 3 Figure IV-3. Possible structures of a phosphorous organocatalysts encapsulated within the cavity of CDs and of intramolecular CD-base FLPs.

Figure EP- 1 .

 1 Figure EP-1. Topological structure of (α-MiCyD)BH3 250.

Figure EP- 3 .

 3 Figure EP-3. Selected part of the TOCSY 260 ms spectrum of (α-MiCyD)BH3 250, highlighted correlations between the anomeric protons (C 1 ) and the other protons present on the sugars (CD2Cl2, 600 MHz, 300 K).

Figure EP- 4 .

 4 Figure EP-4. Selected part of the COSY spectrum of (α-MiCyD)BH3 250, highlighted pathway for finding the sequence of protons of unit II (CD2Cl2, 600 MHz, 300 K).After obtaining the sequence of the protons of each sugar units, the HSQCed experiment allows to find the carbon chemical shifts for each proton. Usually, the C 2 , C 3 and C 4 signals are found around 80 ppm and the C 5 and C 6 around 70 ppm. In the, usual, case where only one H6 was found with the TOCSY or the COSY experiment, the HSQCed allows to find the other H6 since both are on the same carbon atom. Moreover, because of the nitrogen atom, the bridged units present deshielded C 5 and C 6 signals. Therefore, they are, usually, usually found and the sugar unit can be labelled "A". The "A" ( and"D" for β-CD) sugar units are always the ones bearing the imidazole bridge. Here, H 5 II was found to be the more deshielded and therefore corresponds to H5 A.

Figure EP- 5 .

 5 Figure EP-5. Selected part of the HSQCed spectrum of (α-MiCyD)BH3 250, highlighted C 6 A/H 6 A and C 5 A/H 5 A couplings (CD2Cl2, 600 MHz, 300 K).

Figure EP- 6 .

 6 Figure EP-6. Selected part of the NOESY spectrum of (α-MiCyD)BH3 250, highlighted H 1 /H 4 correlations (CD2Cl2, 600 MHz, 300 K).

  combination of the NMR experiments leads to the attribution of all the NMR signals and the resolution of the sugar sequence of the CD.

Figure EP- 7 .

 7 Figure EP-7. Determined sugar sequence for (α-MiCyD)BH3 250.

1 H

 1 NMR (400 MHz, CDCl3, 300 K, ppm) δ 7.30 -7.15 (m, 105H), δ 5.22 (d, 3 J = 3.3 Hz, 7H), δ 5.11, 4.81 (d, 2 J = 11.0 Hz, 14 H), δ 4.54, 4.50 (d, 2 J = 12.8 Hz, 14H), δ 4.43, 4.39 (d, 2 J = 12.2 Hz, 14Hz), δ 4.10 -3.98 (m, 28H), δ 3.58 (d, 2 J = 10.6 Hz, 7H), δ 3.52 (dd, 3 J = 9.2 Hz, 3 J = 3.3 Hz, 7H).

1 H

 1 NMR (400 MHz, CDCl3, 300 K, ppm) δ 7.31 -7.11 (m, 80H), δ 5.77 (d, 3 J = 3.9 Hz, 2H), 5.49 (d, 2 J = 10.4 Hz, 2H), δ 5.23 (d, 2 J = 10.7 Hz, 2H), δ 4.94 (d, 2 J = 10.4 Hz, 2H), δ 4.93 (d, 2 J = 11.8 Hz, 2H), δ 4.83 (d, 2 J = 11.8 Hz, 2H), δ 4.81 (d, 2 J = 11.0 Hz, 4H), δ 4.76 (d, 3 J = 3.3 Hz, 2H), δ 4.75 (d, 3 J = 3.4 Hz, 2H), δ 4.60 (d, 2 J = 12.1 Hz, 2H), δ 4.59 (d, 2 J = 12.4 Hz, 2H), δ 4.58 (d, 2 J = 12.6 Hz, 2H), δ 4.54 (d, 2 J = 12.6 Hz, 2H), δ 4.53 -4.51 (m, 6H), 4.41 (d, 2 J = 12.6 Hz, 2H), ), δ 4.36 (d, 2 J = 12.6 Hz, 2H), δ 4.25 (br dd, 3 J = 9.7 Hz, 3 J = 7.3 Hz, 2H), δ 4.14 (br t, 3 J = 9.1Hz, 2H), δ 4.06 (dd, 3 J = 9.6 Hz, 3 J = 8.5 Hz, 2H), δ 4.04 -3.73 (m, 20H), δ 3.70 -3.66 (m, 2H), δ 3.61 (dd, 3 J = 9.6 Hz, 3 J = 3.9 Hz, 2H), δ 3.47 -3.44 (m, 4H), δ 3.35 (br t, 3 J = 5.3 Hz, 2H).

1 H

 1 NMR (400 MHz, CDCl3, 300 K, ppm) δ 7.33 -7.12 (m, 95H), δ 5.67 (d, 3 J = 3.7 Hz, 2H), δ 5.56 (d, 3 J = 3.8 Hz, 2H), δ 5.30 (d, 2 J = 10.7 Hz, 1H) δ 5.25 -5.21 (m, 3H), δ 5.06 (d, 2 J = 12.3 Hz, 1H), δ 5.04 (d, 3 J = 3.5 Hz, 1H), δ 5.02 (d, 3 J = 3.4 Hz, 1H), δ 5.00 (d, 3 J = 4.0 Hz, 2H), δ 4.98 (d, 3 J = 3.7 Hz, 1H), δ 4.89 (d, 3 J = 3.3 Hz, 1H), δ 4.88 -4.44 (m, 33H), δ 4.15 -3.60 (m, 37H), δ 3.54 -3.44 (m, 5H), 2.78 (bs s, 1H), 2.69 (br s, 1H).

(d, 2 J

 2 = 10.8 Hz, 2H), δ 5.11 (d, 3 J = 3.6 Hz, 2H), δ 5.02 (d, 1 J = 11.4 Hz, 2H), δ 4.95 -4.81 (m, 12H), δ 4.57 -4.29 (m, 20H), δ 4.26 -3.90 (m, 22H), δ 3.72 (d, 2 J = 10.5 Hz, 2H), δ 3.60 (t, 3 J = 9.0 Hz, 2H), δ 3.52 -3.47 (m, 4H), δ 3.41 (dd, 3 J = 9.8 Hz, 3 J = 3.2 Hz, 2H), δ 3.35 (dd, 3 J = 9.8 Hz, 3 J = 3.2 Hz, 2H), δ 2.60 (s, 6H).

1 H

 1 NMR (CDCl3, 400 MHz, 300 K, ppm) δ 7.26 -6.87 (m, 95H), δ 5.46 (d, 3 J = 3.6 Hz, 1H), δ 5.20 (d, 2 J = 9.6 Hz, 1H), δ 5.18 (d, 2 J = 10.2 Hz, 1H), δ 5.13 (d, 3 J = 3.8 Hz, 1H), δ 5.12 (d, 3 J = 3.6 Hz, 1H), δ 5.07 (d, 2 J = 10.8 Hz, 1H), δ 5.01 (d, 2 J = 10.7 Hz, 1H), δ 4.95 (d, 3 J = 3.4 Hz, 1H), δ 4.94 (d, 2 J = 11.0 Hz, 1H), δ 4.91 (d, 3 J = 3.2 Hz, 1H), δ 4.87 (d, 3 J = 3.4 Hz, 1H), δ 4.85 (d, 3 J = 3.4 Hz, 1H), δ 4.77 (d, 2 J = 10.9 Hz, 1H), δ 4.73 -4.62 (m, 9H), δ 4.60 (d, 2 J = 10.7 Hz, 1H), δ 4.59 (d, 2 J = 1.4 Hz, 1H), δ 4.49 (d, 2 J = 12.1 Hz, 1H), δ 4.47 -4.26 (m, 24H), δ 4.27 (d, 2 J = 12.6 Hz, 1H), δ 4.21 -3.99 (m, 3H), δ 3.99 -3.72 (m, 21H), δ 3.70 H (br d, 2 J = 10.7 Hz, 1H), δ 3.65 (dd, 3 J = 8.6 Hz, 3 J = 9.7 Hz, 1H), δ 3.56 (br t, 3 J = 9.2 Hz, 1H), δ 3.51 (br d, 3 J = 10.4 Hz, 1H), δ 3.49 -3.33 (m, 7H), δ 3.31 -3.25 (m, 2H), δ 2.63 (s, 3H), δ 2.61 (s, 3H).

  α-cyclodextrin 82 (524 mg, 204 µmol) and imidazole (278 mg, 4,08 mmol) dissolved in DMF (9.0 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (20 mL) and washed with an aqueous solution of HCl (1M, 1 x 20 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 95:5 DCM/Methanol) afforded the imidazolium salt 82 (254 mg, 51 %) as a white foam. 1 H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 9,09 (s, 1H), δ 7,43 -7,07 (m, 70H), δ 6,97 -6,95 (m, 4H), δ 6,88 -6,83 (m, 8H), δ 5,66 (d, 3 J = 3,7 Hz, 2H), δ 5,39 (d, 3 J = 10,8 Hz, 2H), δ 5,08 (d, 3 J = 10,4 Hz, 2H), δ (4,85, 3 J = 11,5 Hz, 2H), δ 4,82 (d, 3 J = 3,4 Hz, 2H), δ 4,79 (d, 3 J = 3,2 Hz, 2H), δ 4,76 (d, 3 J = 10,8 Hz, 2H), δ 4,71 -4,36 (m, 24H), δ 4,29 (d, 3 J = 12,2 Hz, 2H), δ 4,16 -4,09 (m, 4H), δ 3,85 -4,02 (m, 12H), δ 3,75 -3,67 (m, 6H), δ 3,57 (dd, 3 J = 10,3 Hz, 3 J = 3,7 Hz, 2H), δ 3,52 (br dd, 3 J = 9,7 Hz, 3 J = 9,7 Hz, 3 J = 5,0 Hz, 2H), δ 4,47 (dd, 3 J = 9,8 Hz, 3 J = 3,1 Hz, 2H), δ 3,38 (dd, 3 J = 9,8 Hz, 3 J = 3,3 Hz, 2H), δ 3,25 (d, 3 J = 10,6 Hz, 2H), δ 3,11 (dd, 3 J = 10,8 Hz, 3 J = 5,2 Hz, 2H).

  β-cyclodextrin 83 (3.76 g, 1.25 mmol) and imidazole (1.7 g, 25.0 mmol) dissolved in DMF (60.0 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (20 mL) and washed with an aqueous solution of HCl (1M, 1 x 20 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 95:5 DCM/Methanol) afforded the imidazolium salt 85 (2.2 g, 61 %) as a white foam. 1 H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 9.12 (br s, 1H), δ 7.41 -6.82 (m, 97H), δ 5.79 (br d,3 J = 3.9 Hz, 2H), δ 5.38 (d, 2 J = 11.3 Hz, 1H), δ 5.27 (d, 2 J = 11.2 Hz, 1H), δ 5.19 (d, 2 J = 10.5 Hz, 1H), δ 5.06 (d, 2 J = 10.6 Hz, 1H), δ 4.98 (d, 3 J = 3.3 Hz, 1H), δ 4.89 (d, 3 J = 3.9 Hz, 1H), δ 4.82 -4.80 (m, 3H), δ 4.76 -4.70 (m, 5H), δ 4.66 (d, 2 J = 3.9 Hz, 1H), δ 4.61 -4.30 (m, 31H), δ 4.12 -4.06 (2H), δ 4.00 -3.48 (m, 28H), δ 3.43 -3.38 (m, 2H), δ 3.31 (t, 3 J = 2.7 Hz, 1H), δ 3.29 (t, 3 J = 2.8 Hz, 1H), δ 3.20 (d, 2 J = 11.3 Hz, 1H), δ 3.10 (d, 2 J = 10.7 Hz, 1H), δ 2.84 (dd, 2 J = 10.7 Hz, 3 J = 4.8 Hz, 1H).

  β-cyclodextrin 83 (5.76 g, 1.92 mmol) and benzimidazole (4.5 g, 38.5 mmol) dissolved in DMF (280 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (100 mL) and washed with an aqueous solution of HCl (1M, 1 x 40 mL). The aqueous layer was extracted with DCM (3 x 40 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 95:5 DCM/Methanol) afforded the benzimidazolium salt 132 (1.88 g, 33 %) as a white foam. 1 H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 7.65 (s, 1H), δ 7.50 (d, 3 J = 8.4 Hz), δ 7.38 -6.81 (m, 97H), δ 5.86 (m, 2H), δ 5.43 (d, 2 J = 11.6 Hz, 1H), δ 5.34 (br d, 2 J = 11.5 Hz, 1H) δ 5.22 -5.17 (m, 2H), δ 5.09 (br d, 2 J = 11.5 Hz, 1H), δ 5.00 (s, 1H), δ 4.94 -4.90 (m, 3H), δ 4.85 -4.26 (m, 40H), δ 4.15 -3.42 (m, 29H), δ 3.36 (dd, 3 J = 9.9 Hz, 3 J = 3.6 Hz, 1H), δ 3.28 (dd, 3 J =9.6 Hz, 3 J = 3.0Hz, 1H), δ 3.24 (dd, 3 J = 8.5 Hz, 3 J = 2.5 Hz, 1H), δ 2.79 -2.72 (m, 2H), δ 2.41 -2.34 (m, 2H).

  α-cyclodextrin 82 (1.70 g, 0.66 mmol) and 4,5-dimethyl-imidazole (1.05 g, 10.7 mmol) dissolved in DMF (55.0 mL) was heated at 120 °C during 12 hours. The mixture was cooled to ambient temperature and the solvents evaporated under reduced pressure. The obtained residue was dissolved in DCM (60 mL) and washed with an aqueous solution of HCl (1M, 1 x 20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (DCM up to 90:10 DCM/Methanol) afforded the 4,5dimethyl-imidazolium salt 144 (1.16 g, 68 %) as a white foam. 1 H NMR (600 MHz, CD3CN, 300 K, ppm) δ 9.05 (s, 1H, 1 x H NCHN ), δ 7.37 -6.85 (m, 80H, 80 x H Ar ), δ 5.70 (d, 3 J = 3.7 Hz, 2H, 2 x H 1 C), δ 5.40 (d, 2 J = 10.7 Hz, 2H, 2 x H CHPh ), δ 5.10 (d, 2 J = 10.4 Hz, 2H, 2 x H CHPh ), δ 4.87 -4.85 (m, 4H, 2 x H 1 A, 2 x H CHPh ), δ 4.83 (d, 3 J = 3.4 Hz, 2H, 2 x H 1 B), δ 4.79 (d, 2 J = 10.7 Hz, 2H, 2 x H CHPh ), δ 4.71 (d, 2 J = 11.1 Hz, 2H, 2 x H CHPh ), δ 4.66 -4.63 (m, 4H, 4 x H CHPh ), δ 4.59 (d, 2 J = 12.3 Hz, 2H, 2 x H CHPh ), δ 4.55 -4.52 (m, 4H, 4 x H CHPh ), δ 4.49 -4.38 (m, 15H, 2 x H

13 C

 13 NMR (151 MHz, CD3CN, 300 K, ppm) δ 140,15 (2 x C (IV)Ar ), δ 139,96 (2 x C (IV)Ar ), δ 139,83 (2 x C (IV)Ar ), δ 139,61 (2 x C (IV)Ar ), δ 139,47 (2 x C (IV)Ar ), δ 139,16 (4 x C (IV)Ar ), δ 138,88 (2 x C (IV)Ar ), δ 133,64 (C N-C-N ), δ 130,45 (2 x C Ar ), δ 129,72 (2 x C N-C=C-N ), δ 129,44 -127,67 (C Ar ), δ 98,90 (2 δ 77,25 (2 x C CHPh ), δ 77,11 (2 x C 4 A), δ 76,51 (2 x C CHPh ), δ 74,84 (2 x C CHPh ), δ 74,65 (2 x C CHPh ), δ 74,54 (2 x C 5 C), δ 74,12 (2 x C CHPh ), δ 73,93 (2 x C CHPh ), δ 73,83 (2 x C CHPh ), δ 73,18 (2 x C CHPh ), δ 73,14 (2 x C 5 B), δ 71,33 (2 x C 6 C), δ 71,30 (2 x C 5 A), 69,01 (2 x C 6 B), δ 50,49 (2 x C 6 A), δ 8,69 (2 x C H3C-C=C ). Rf = 0.11 (95:5 DCM/MeOH).

Figure EP- 8 . 1 H

 81 Figure EP-8. 1 H NMR spectrum of (α-MiCyD)HCl (600 MHz, CD3CN, 300K).

Figure EP- 9 .

 9 FigureEP-9. JMod NMR spectrum of (α-MiCyD)HCl (CD3CN, 151 MHz, 300 K).

1 H

 1 NMR (CD3CN, 400 MHz, 300 K, ppm) δ 9.14 (s, 1H), δ 7.37 -7.11 (m, 91H), 9.97 (t,3 J = 7.3 Hz, 1H), δ 6.88 -6.81 (m, 4H), δ 5.83 -5.82 (m, 2H), δ 5.44 (d, 2 J = 9.6 Hz, 1H), δ 5.28 (d, 2 J = 11.3 Hz, 1H), δ 5.24 (d, 2 J = 10.6 Hz, 1H), δ 5.19 (d, 2 J = 10.9 Hz, 1H), δ 5.05 (d, 2 J = 10.3 Hz, 1H), δ 5.00 (d, 3 J = 3.3 Hz, 1H), δ 4.95 (d, 3 J = 3.5 Hz, 1H), δ 4.85 -4.69 (m, 10H), δ 4.63 -4.30 (m, 29H), δ 4.17 -3.48 (m, 28H), δ 3.41 (dd, 3 J = 9.7 Hz, 3 J = 3.5 Hz, 1H), δ 3.33 (dd, 3 J = 9.4 Hz, 3 J = 3.4 Hz, 1H), δ 3.29 (dd, 2 J = 10.0 Hz, 3 J = 3.1 Hz, 1H), δ 3.80 (dd, 2 J = 11.6 Hz, 3 J = 2.7 Hz, 1H), δ 3.10 (d, 2 J = 11.4 Hz, 1H), δ 3.00 (d, 2 J = 10.6 Hz, 1H), δ 2.67 (dd, 3 J = 10.7 Hz, 3 J = 3.6 Hz, 1H), δ 1.96 (s, 3H), δ 1.84 (s, 3H).13 C NMR: analysis in progress. Rf = 0.19 (95:5 DCM/MeOH). MS (ESI): calculated for C180H189N2O33 [M] + : 2906.3167, found: 2906.9526.

Figure EP- 10 . 1 H

 101 Figure EP-10. 1 H NMR of (β-MiCyD)HCl (CD3CN, 400 MHz, ppm).

Figure EP- 11 . 1 H

 111 Figure H NMR spectrum of (β-ICyD)NH2Cl (CD3CN, 600 MHz, 300 K).

Figure EP- 12

 12 Figure EP-12.13 C UDEFT spectrum of (β-ICyD)NH2Cl (CD3CN, 600 MHzn 300 K).

Figure EP- 13 .

 13 Figure EP-13. Selected part of the NOESY spectrum of (β-ICyD)NH2Cl, highlighted correlation between H C=NH2 and H 3 C (CD3CN, 600 MHz, 300 K).

Figure EP- 14 . 1 H

 141 Figure EP-14. 1 H NMR spectrum of (β-BiCyD)NH2Cl (CD3CN, 600 MHz, 300K).

Figure EP- 15

 15 Figure EP-15.13 C UDEFT NMR spectrum of (β-BiCyD)NH2Cl (CD3CN, 151 MHz, 300 K).

Figure EP- 16 .

 16 Figure EP-16. Selected part of the HSQCed spectrum of (β-BiCyD)NH2Cl, highlighted H 6 IV cross-correlations (CD3CN, 600 MHz, 300 K).

1 H

 1 NMR (600 MHz, CD3CN, 300 K, ppm) δ 7.45 -7.01 (m, 95H, 95 x H Ar ), δ 6.29 (br s, 2H, 2 x H NH2 ), δ 5.81 (d, 3 J = 3.8 Hz, 1H, 1 x H 1 E), δ 5.41 (d, 2 J = 11.3 Hz, 1 x H CHPh ), δ 5.32 (d, 3 J = 2.7 Hz, 1X, 1 x H 1 A), δ 5.29 (d, 2 J = 10.7 Hz, 1H, 1 x H CHPh ), δ 5.22 (d, 2 J = 11.2 Hz, 1H, 1 x H CHPh ), δ 5.19 (d, 2 J = 10.9 Hz, 1H, 1 x H CHPh ), δ 4.99 (d, 3 J = 3.9 Hz, 1H, 1 x H 1 G), δ 4.89 (d, 3 J = 3.4 Hz, 1H, 1 x H 1 F), δ 4.86 (d, 3 J = 3.2 Hz, 1H, 1 x H

13 C

 13 NMR (151 MHz, CD2Cl2, 300 K ppm) δ 144.35 (C C=NH2 ), δ 140.98 (C (IV)Ar ), δ 140.88 (C (IV)Ar ), δ 140.63 (C (IV)Ar ), δ 140.61 (C (IV)Ar ), δ 139.97 (C (IV)Ar ), δ 139.82 (C (IV)Ar ), δ 139.68 (C (IV)Ar ), δ 139.66 (C (IV)Ar ), δ 139.56 (C (IV)Ar ), δ 139.54 (C (IV)Ar ), δ 139.51 (C (IV)Ar ), δ 139.41 (C (IV)Ar ), δ 139.29 (C (IV)Ar ), δ 139.26 (C (IV)Ar ), δ 139.21 (C (IV)Ar ), δ 139.03 (C (IV)Ar ), δ 138.84 (C (IV)Ar ), δ 138.73 (C (IV)Ar ), δ 128.78 -127.83 (C Ar ), δ 127.76 (C N-C(CH3)=C ), δ 119.49 (C N- C(CH3)=C ), δ 101.35 (C 1 B/C), δ 100.53 (C 1 D), δ 100.34 (C

Figure EP- 17 . 1 H

 171 Figure EP-17. 1 H NMR spectrum of (β-MiCyD)NH2Cl (CD3CN, 600 MHz, 300 K).

Figure EP- 18

 18 Figure EP-18.13 C UDEFT NMR spectrum of (β-MiCyD)NH2Cl (CD3CN, 151 MHz, 300 K).

Figure EP- 19 .

 19 FigureEP-19. Selected part of HMBC NMR spectrum of (β-MiCyD)NH2Cl, highlighted cross-correlation between H6 A and C C=NH2 (CD3CN, 600 MHz, 300 K).

Figure EP- 20 .

 20 FigureEP-20. Selected part of the NOESY spectrum of (β-MiCyD)NH2Cl, highlighted correlation between H C=NH2 and H 5 F (CD3CN, 600 MHz, 300 K).

  ): calculated for C151H158N3O28 [M] + : 2461.1026, found: 2962.5262.

Figure EP- 21 . 1 H

 211 Figure H NMR spectrum of (α-out-ICyD)NH2Cl after silica gel flash chromatography (CD3CN, 400 MHz, 300 K).

  δ 3.40 (dd, 3 J = 10.0 Hz, 3 J = 3,5 Hz, 2H, 2 x H 2 A), δ 3.36 (dd, 3 J = 9.7 Hz, 3 J = 3.0 Hz, 2H, 2 x H 2 C), δ 3.27 (bt, 3 J = 12.0 Hz, 2H, 2 x H 5 C), 3.21 (d, 2 J = 11.2 Hz, 2H, 2 x H 6 A). 13 C NMR (151 MHz, CD3CN, 300 K, ppm) δ 154.78 (C C=NH ), δ 140.72 (2 x C (IV)Ar ), δ 140.55 (2 x C (IV)Ar ), δ 140.38 (2 x C (IV)Ar ), δ 139.92 (2 x C (IV)Ar ), δ 139.84 (2 x C (IV)Ar ), δ 139.66 (2 x C (IV)Ar ), δ 139.34 (2 x C (IV)Ar ), δ 138.93 (2 x C (IV)Ar ), δ 129.94 (2 x C Ar ), δ 129.38 -127.64 (m, C Ar ), δ 126.28 (2 x C Ar ), δ 114.16 (2 x C H-C=C ), δ 98.96 (2 x C

Figure EP- 22 . 1 H

 221 Figure EP-22. 1 H NMR spectrum of (α-out-ICyD)NH (CD3CN, 600 MHz, 300 K).

Figure EP- 23

 23 Figure EP-23.13 C UDEFT NMR spectrum of (α-out-ICyD)NH (CD3CN, 151 MHz, 300 K).

Figure EP- 24 .

 24 Figure EP-24. Selected part of 1 H/ 1 3C HMBC spectrum of (α-out-ICyD)NH, highlighted H N-CH=CH /C C=NH correlation (CD3CN, 600 MHz, 300 K).

Figure EP- 25 .

 25 Figure EP-25. Selected part of NOESY spectrum of (α-out-ICyD)NH, highlighted H5C/HN-CH=CH correlation (CD3CN,600 MHz, 300 K).

Figure EP- 27 . 1 H

 271 Figure EP-27. 1 H NMR spectrum of (α-MiCyD)NH (CD3CN, 600 MHz, 300 K).

Figure EP- 32 . 1 H

 321 Figure EP-32. 1 H NMR spectrum after addition of KHMDS (CD3CN, 300 MHz, 300 K).

Figure EP- 34 . 1 H

 341 Figure EP-34. 1 H NMR spectrum obtained after addition of Et3N (CD3CN, 300 MHz, 300 K).

Figure EP- 35 . 19 F

 3519 FigureEP-35. 19 F NMR spectrum obtained after addition of Et3N (CD3CN, 282 MHz, 300 K).

Figure EP- 36 . 1 H

 361 Figure EP-36. 1 H NMR of (β-ICyD)NH after 12 h in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 38 . 1 H

 381 Figure H NMR spectrum of (β-BiCyD)NH after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 39 . 19 F

 3919 Figure EP-39.19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 40 . 1 H

 401 Figure EP-40. 1 H NMR spectrum of (β-MiCyD)NH after 12 h in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 41 . 19 F

 4119 Figure EP-41.19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 42 . 1 H

 421 Figure EP-42. 1 H NMR spectrum of (α-out-ICyD)NH after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 43 . 19 F

 4319 FigureEP-43. 19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 44 . 1 H

 441 Figure EP-44. 1 H NMR spectrum of (α-MiCyD)NH after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 45 . 19 F

 4519 FigureEP-45. 19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 46 . 1 H

 461 Figure EP-46. 1 H NMR of NHI after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 47 . 19 F

 4719 Figure EP-47.19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 48 . 1 H

 481 Figure EP-48. 1 H NMR of NHI after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 49 . 19 F

 4919 Figure EP-49.19 F NMR spectrum obtained after addition of p-fluorophenol (CD3CN, 282 MHz, 300 K).

Figure EP- 50 . 1 H

 501 Figure EP-50. 1 H NMR of NHI after 12 hours in vacuo (CD3CN, 300 MHz, 300 K).

Figure EP- 56

 56 Figure EP-56. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K).

Figure EP- 57

 57 Figure EP-57. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K).

Figure EP- 60 . 1 H

 601 Figure EP-60. 1 H NMR spectrum of (α-ICyD)BH3 (CD2Cl2, 600 MHz, 300K).

Figure EP- 61 .

 61 FigureEP-61. JMod NMR spectrum of (α-ICyD)BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 62 .

 62 FigureEP-62. Selected part of 1 H/13 C HMBC spectrum of (α-ICyD)BH3, highlighted H N-CH=CH-N /C C- BH3 correlation (CD2Cl2, 600 MHz, 300 K).

Figure EP- 63

 63 Figure EP-63. 11 B{ 1 H} NMR spectrum of (α-ICyD)BH3 (CD2Cl2, 193 MHz, 300 K).

Figure EP- 64

 64 Figure EP-64.1 H/11 B HMQC spectrum of (α-ICyD)BH3 and highlighted NHC-BH3 correlation (CD2Cl2, 600 MHz, 300 K).

Figure EP- 65 . 1 H

 651 Figure EP-65. 1 H NMR spectrum of (α-BiCyD)BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 66 .

 66 FigureEP-66. JMod NMR spectrum of (α-BiCyD)BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 67 .

 67 Figure EP-67. Selected part of 1 H/ 13 C HMBC spectrum of (α-BiCyD)BH3, highlighted H 6 A/C C-BH3

Figure EP- 68

 68 Figure EP-68. 11 B{ 1 H} NMR spectrum of (α-BiCyD)BH3 (CD2Cl2, 193 MHz, 300 K).

Figure EP- 69

 69 Figure EP-69. 1 H{ 11 B} NMR spectrum (top) of (α-BiCyD)BH3, 1 H NMR spectrum of (α-BiCyD)BH3 (bottom) (CD2Cl2, 400 MHz, 300 K).

13 C

 13 NMR (151 MHz, CD2Cl2, ppm) δ 171.57 (C CBH3 ), δ 140.38 (2 x C (IV)Ar ), δ 140.28 (2 x C (IV)Ar ), δ 140.05 (2 x C (IV)Ar ), δ 139.35 (2 x C (IV)Ar ), δ 139.14 (2 x C (IV)Ar ), δ 138.92 (2 x C (IV)Ar ), δ 138.90 (2 x C (IV)Ar ), δ 138.80 (2 x C (IV)Ar ), δ 128.76 -127.12 (C Ar ), δ 123.92 (2 x C N-C=C-N ), δ 99.00 (2 x C

Figure EP- 70 . 1 H

 701 Figure EP-70. 1 H NMR spectrum of (α-MiCyD)BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 71 .

 71 FigureEP-71. JMod NMR spectrum of (α-MiCyD)BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 72 .

 72 Figure EP-72. Selected part of 1 H/ 11 C HMBC spectrum of (α-MiCyD)BH3, highlighted H 6 A/C C-BH3

Figure EP- 73

 73 Figure EP-73. 11 B{ 1 H} NMR spectrum of (α-MiCyD)BH3 (CD2Cl2, 193 MHz, 300 K).

Figure EP- 74

 74 Figure EP-74. 1 H{ 11 B} NMR spectrum (top) of (α-MiCyD)BH3, 1 H NMR spectrum of (α-MiCyD)BH3(bottom) (CD2Cl2, 400 MHz, 300 K).

Figure EP- 75 . 1 H

 751 Figure EP-75. 1 H NMR spectrum of (β-ICyD)BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 76 .

 76 FigureEP-76. JMod NMR spectrum of (β-ICyD)BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 77

 77 Figure EP-77. 11 B{ 1 H} NMR spectrum of (β-ICyD)BH3 (CD2Cl2, 128 MHz, 300 K).

Figure EP- 78

 78 Figure EP-78. 1 H/ 11 B HMQC NMR spectrum of (β-ICyD)BH3, highlighted NHC-BH3 correlation (CD2Cl2, 400 MHz, 300 K).

Figure EP- 79 . 1 H

 791 Figure EP-79.1 H NMR of (β-BiCyD)BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 80 .

 80 FigureEP-80. JMod NMR of (β-BiCyD))BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 81 .

 81 Figure EP-81. Selected part of 1 H/ 13 C HMBC of (β-BiCyD)BH3, highlighted H 6 A/C C-BH3 correlation (CD2Cl2, 600 MHz, 300 K).

Figure EP- 82

 82 Figure EP-82. 11 B{ 1 H} NMR of (β-BiCyD)BH3 (CD2Cl2, 192 MHz, 300 K).

Figure EP- 83 . 1 H

 831 Figure EP-83. 1 H NMR spectrum of (β-MiCyD)BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 84 .

 84 FigureEP-84. JMod NMR spectrum of (β-MiCyD)BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 85

 85 Figure EP-85. 13 C UDEFT NMR spectrum of (β-MiCyD)BH3 centered on C C-BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 86 .

 86 FigureEP-86. Selected part of 1 H/13 C HMBC of (β-MiCyD)BH3, highlighted H6 A/C C-BH3 correlation (CD2Cl2, 600 MHz, 300 K).

Figure EP- 87

 87 Figure EP-87. 11 B{ 1 H} NMR spectrum of (β-MiCyD)BH3 (CD2Cl2, 192 MHz, 300 K).

Figure

  Figure EP-88. 1 H{ 11 B} NMR spectrum (top) of (β-MiCyD)BH3, 1 H NMR spectrum of (α-MiCyD)BH3 (bottom) (CD2Cl2, 400 MHz, 300 K).

1 H

 1 NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.30 (d, 3 J = 4.0 Hz, 1H), δ 5.27 (d, 3 J = 3.9 Hz, 1H), δ 5.15 (d, 3 J = 3.5 Hz, 1H), δ 5.10 (d, 3 J = 3.0 Hz, 1H), δ 5.09 (d, 3 J = 3.6 Hz, 1H), δ 5.02 (d, 3 J = 3.5 Hz, 1H), δ 4.05 -3.39 (m, 92H), δ 3.27 -3.20 (m, 7H), δ 3.10 -3.01 (m, 2H).

1 H

 1 NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.05 (d, 3 J = 3.4 Hz, 2H), δ 5.02 (m, 2H), δ 5.00 (m, 2H), δ 4.64 (dd, 2 J = 11.3 Hz, 3 J = 1.4 Hz, 2H), δ 4.33 (dd, 2 J = 11.7 Hz, 3 J = 6.0 Hz, 2H), δ 4.07 (m, 2H), δ 4.04 (m, 2H), δ 3.87 (dd, 3 J = 8.9 Hz, 3 J = 3.6 Hz, 2H), δ 3.82 (m, 2H), δ 3.70 (m, 2H), δ 3.66 (s, 6H), δ 3.64 (s, 6H), δ 3.60 (s, 6H), δ 3.64 (m, 4H), δ 3.53 (m, 4H), δ 3.48 (m, 12H), δ 3.40 (s, 6H), δ 3.38 (s, 6H), δ 3.29 (t, 3 J = 9.4 Hz, 2H), δ 3.17 (m, 2H), δ 3.15 (m, 2H), δ 3.12 (m, 2H), δ 3.07 (s, 6H).

6 A , 6 D

 6 -di-iodo-β-CD Me (265)

1 H

 1 NMR (CD3CN, 400 MHz, 300 K, ppm) δ 9.08 (br s, 1H), δ 7.48 (m, 1H), δ 7.41 (m, 1H), δ 5.66 (d, 3 J = 3.5 Hz, 1H), δ 5.61 (d, 3 J = 3.3 Hz, 1H), δ 5.08 (d, 3 J = 3.3 Hz, 1H), δ 4.99 (d, 3 J = 3.3 Hz, 1H), δ 4.96 (d, 3 J = 3.7 Hz, 1H), δ 4.93 (d, 3 J = 3.5 Hz, 1H), δ 4.85 (d, 3 J = 3.3 Hz, 1H), δ 4.63 (m, 1H), δ 4.59 (m, 1H), δ 4.45 (m, 1H), δ 4.14 (m, 1H), δ 4.11 (m, 1H), δ 3.96 (m, 1H), δ 3.88 (m, 2H), δ 3.80 (m, 1H), δ 3.79 (m, 1H), δ 3.78 (m, 1H), δ 3.70 (s, 3H), δ 3.69 (m, 1H), δ 3.68 (m, 1H), δ 3.64 (m, 1H), δ 3.62 (m, 1H), δ 3.61 (s, 3H), δ 3.59 (m, 1H), δ 3.58 (m, 2H), δ 3.57 (m, 4H), δ 3.55 (m, 8H), δ 3.54 (m, 6H), δ 3.53 (m, 1H), δ 3.52 (s, 3H), δ 3.50 (s, 3H), δ 3.49 (s, 3H), δ 3.47 (m, 1H), δ 3.44 (s, 3H), δ 3.43 (m, 4H), δ 3.42 (s, 6H), δ 3.41 (m, 1H), δ 3.40 (s, 3H), δ 3.35 (m, 1H), δ 3.34 (m, 1H), δ 3.32 (s, 3H), δ 3.31 (s, 3H), δ 3.29 (m, 1H), δ 3.28 (s, 3H), δ 3.27 (s, 3H), δ 3.25 (m, 1H), δ 3.22 (m, 1H), δ 3.16 (m, 1H), δ 3.14 (m, 1H), δ 3.11 (m, 3H), δ 3.08 (m, 1H), δ 3.05 (m, 4H), δ 2.80 (dd, 2 J = 10.6 Hz, 3 J = 6.6 Hz, 1H).

4 A)

 4 , δ 3.21 (s, 6H, 6 x H OCH3 ), δ 3.19 (dd, 3 J = 9.5 Hz, 3 J = 3.5 Hz, 2H, 2 x H 2 A), δ 3.15 (s, 6H, 6 x H OCH3 ), 3.08 (dd, 3 J = 5.6 Hz, 3 J = 4.0 Hz, 2H, 2 x H 2 C), δ 3.07 (dd, 3 J = 9.5 Hz, 3 J = 3.5 Hz, 2H, 2 x H 2 B), δ 2.82 (d, 1 J = 10.8 Hz, 2H, 2 x H 6 B), δ 1.75 (br s, 3H, 3 x H BH3 ).

13 C

 13 NMR (151 MHz, CD2Cl2, 300 K, ppm) δ 174.04 (C C-BH3 ), δ 120.93 (C H-C=C ), δ 99.δ 62.1 (2 x C OCH3 ), δ 62.0 (2 x C OCH3 ), δ 61.0 (2 x C OCH3 ), δ 60.2 (2 x C OCH3 ), δ 59.2 (2 x C OCH3 ), δ 59.1 (2 x C OCH3 ), δ 58.0 (2 x C OCH3 ), δ 57.6 (2 x C OCH3 ), δ 52.9 (2 x C 6 A). 11 B{ 1 H} NMR (192 MHz, CD2Cl2, 300 K, ppm) δ -35.0 (br s). Rf = 0.15 (95:5 DCM/MeOH).

Figure EP- 93 . 1 H

 931 Figure EP-93. 1 H NMR spectrum of (α-ICyD Me )BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 94 .

 94 FigureEP-94. JMod NMR of (α-ICyD Me )BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 95 .

 95 Figure EP-95. Selected part of 1 H/ 13 C HMBC of (α-ICyD Me )BH3, highlighted H N-CH=CH-N /C C-BH3correlation (CD2Cl2, 600 MHz, 300 K).

Figure EP- 96

 96 Figure B{ 1 H} NMR spectrum of (α-ICyD Me )BH3 (CD2Cl2, 192 MHz, 300 K).

  δ 62.31 (C OCH3 ), δ 62.20 (C OCH3 ), δ 62.19 (C OCH3 ), δ 62.14 (C OCH3 ), δ 62.07 (C OCH3 ), δ 60.71 (C OCH3 ), δ 60.67 (C OCH3 ), δ 60.05 (C OCH3 ), δ 59.40 (C OCH3 ), δ 59.30 (C OCH3 ), δ 59.12 (C OCH3 ), δ 59.11 (C OCH3 ), δ 59.08 (C OCH3 ), δ 58.62 (C OCH3 ), δ 58.40 (C OCH3 ), δ 58.29 (C OCH3 ), δ 58.20 (C OCH3 ), δ 52.93 (C 6 D), δ 52.15 (C 6 A).

Figure EP- 97 . 1 H

 971 Figure EP-97.1 H NMR spectrum of (β-ICyD Me )BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 98 .

 98 FigureEP-98. JMod NMR spectrum of (β-ICyD Me )BH3 (CD2Cl2, 151 MHz, 300 K).

Figure EP- 99 .

 99 Figure EP-99. Selected part of 1 H/ 13 C HMBC spectrum of (β-ICyD Me )BH3, highlighted correlation between H N-CH=CH-N /C C-BH3 (CD2Cl2, 600 MHz, 300 K).

Figure EP- 100

 100 Figure EP-100. 11 B{ 1 H} NMR spectrum of (β-ICyD Me )BH3 (CD2Cl2, 192 MHz, 300 K).

Figure EP- 102

 102 Figure EP-102. 31 P{ 1 H} NMR spectrum after addition of OPEt3 (CD2Cl2, 162 MHz, 300 K).

Figure EP- 103

 103 Figure EP-103. 31 P{ 1 H} NMR spectrum after addition of OPEt3 (CD2Cl2, 162 MHz, 300 K).

Figure EP- 104

 104 Figure EP-104. 31 P{ 1 H} NMR spectrum after addition of OPEt3 (CD2Cl2, 162 MHz, 300 K).

Figure EP- 107 . 1 H

 1071 Figure EP-107. 1 H NMR spectra of the reaction between phenylacetylene and the formed borenium ion (CD2Cl2, 400 MHz, 300 K).

Figure EP- 111

 111 Figure EP-111. 1 H NMR spectra of the borenium ion-catalysed hydrosilylation reaction of acetophenone (CD2Cl2, 400 MHz, 300 K).

  28 does not polymerize through Lewis adducts formation due to the bulky moieties present on the phosphine and the borane. This pioneering work created a new branch in small molecule

	activation with compounds called Frustrated Lewis Pairs (FLPs) defined as sterically
	hindered Lewis bases and/or acids not able to form classical Lewis adducts (Scheme I-16
	E)).

Scheme I-17. First FLP used for H2 activation.

Table II -

 II 1. Development of encapsulated NHI synthesis using sodium amide.

Table II -

 II 2. Development of encapsulated NHI synthesis using other sources of nitrogen. use of methylammonium chloride led to the formation of the urea 121 and the NHC-I + 120 adduct (Table II-2, entry 3). No NHI 116 or 119 was detected for both reactions.

	Freeze-pump-thawing the mixture with ammonia and letting the reaction under one bar of
	ammonia led to the formation of the urea 120 but no NHI 116 or 119 was detected. (Table
	II-2, entry 1).
	The use of ammonium chloride in presence of an excess of potassium carbonate (15.0 eq,
	5.0 for carbene formation, 10.0 for amine formation) led to the detection of the NHC-I +
	adduct 120 by ESI-MS without further reaction (Table II-2, entry 2). In the same reaction
	conditions, the

Table II

 II

	Reacting one equivalent of 85 with 1.1 equivalents of KHMDS (0.5 M in toluene) at
	0 °C resulted in a change of colour (orange/red) of the reaction mixture indicating the
	formation of the carbene. TMSN3 (1.1 eq) was then added to the reaction mixture (Table II-
	3, entry 1). After 72 hours at 120 °C, the reaction mixture was evaporated. Silica gel flash
	chromatography of the crude product afforded the silylated NHI 124 in 24% yield and the
	NHI 119 with a yield of 10% considering a chloride counter-ion. The NMR spectra of the
	compounds were not conclusive and the obtention of the products was only confirmed by
	ESI-MS.
	The reaction was then carried out with 5.0 equivalents of TMSN3 to ensure the formation of
	the silylated NHI 124 (Table II-3, entry 2). After three days, the reaction was quenched with
	methanol during 12 hours at 80 °C to perform the desilylation of the NHI. Silica gel flash
	chromatography afforded this time the NHI 119 in 25% yield considering a chloride counter-
	ion.
	-3. Development of encapsulated NHI synthesis using TMSN3.

Table II -

 II

4. Development of α-CD encapsulated NHI synthesis.

Table II -

 II

5. Trials for (α-BiCyD)NH2Cl 149 synthesis.

  19 F chemical shift of the mixture can be written as:

	The reaction constant can be written as:
	𝐾 =	[𝑁𝐻𝐼(𝐻 2 ) + ][𝐹(𝐶 6 𝐻 4 )𝑂 -] [𝑁𝐻𝐼(𝐻)][𝐹(𝐶 6 𝐻 4 )𝑂𝐻]	=	𝐾 𝑎((𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) 𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻))
	With:
	𝐾 𝑎((𝐹(𝐶 6 𝐻 5 )𝑂𝐻/𝐹(𝐶 6 𝐻 5 )𝑂 -) =	[𝐹(𝐶 6 𝐻 4 )𝑂 -][𝐻 3 𝑂 + ] [𝐹(𝐶 6 𝐻 4 )𝑂𝐻][𝐻 2 𝑂]
	And:
		𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) =	[𝑁𝐻𝐼(𝐻)][𝐻 3 𝑂 + ] [𝑁𝐻𝐼(𝐻 2 + )][𝐻 2 𝑂]
	Thus, by replacing the right terms:
	𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) =	𝐾 𝑎((𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) 𝐾
	𝑝𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) = -log (	𝐾 𝑎((𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) 𝐾	)
	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 = 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 𝑝𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 )	[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶′ 0	+ 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -	[𝐹(𝐶 6 𝐻 4 )𝑂 -] 𝐶′ 0
	Replacing the right terms affords:
	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 = 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻	[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶′ 0	+ 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -	𝐶′ 0 -[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶′ 0
	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 = 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻	[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶′ 0	+ 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -(1 -	[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶′ 0 )
	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 =	[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶 ′ 0	(𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -) + 𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -
		[𝐹(𝐶 6 𝐻 4 )𝑂𝐻] 𝐶 ′ 0	=	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -(𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -)
			𝐶′ 0 -𝑥 𝐶 ′ 0	=	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -(𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -)
			1 -	𝑥 𝐶 ′ 0	=	𝛿 𝐹 19 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -(𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -)
	At equilibrium, the reaction progress can be written as:
			(A) 𝑥 𝑒𝑞 = 𝐶 ′	0 (1 -	𝛿 𝐹 19 (𝛿 𝐹(𝐶 6 𝐻 4 )𝑂𝐻 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -) 𝑚𝑖𝑥𝑡𝑢𝑟𝑒 𝑒𝑞 -𝛿 𝐹(𝐶 6 𝐻 4 )𝑂 -	)

+

/𝑁𝐻𝐼(𝐻)) = 𝑝𝐾 𝑎(𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) -log ( 1 𝐾 ) 𝑝𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) = 𝑝𝐾 𝑎(𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) + log(𝐾) With the reagents' concentrations, the equation becomes: 𝑝𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) = 𝑝𝐾 𝑎(𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) + log ( [𝑁𝐻𝐼(𝐻 2 ) + ][𝐹(𝐶 6 𝐻 4 )𝑂 -] [𝑁𝐻𝐼(𝐻)][𝐹(𝐶 6 𝐻 4 )𝑂𝐻] ) Finally, replacing the concentrations with the reaction progress: 𝑝𝐾 𝑎(𝑁𝐻𝐼(𝐻 2 ) + /𝑁𝐻𝐼(𝐻)) = 𝑝𝐾 𝑎(𝐹(𝐶 6 𝐻 4 )𝑂𝐻/𝐹(𝐶 6 𝐻 4 )𝑂 -) + log ( 𝑥 𝑒𝑞 ² (𝐶 0 -𝑥 𝑒𝑞 )(𝐶 ′ 0 -𝑥 𝑒𝑞 )

  B chemical shift of 197 of 1.5 ppm was in accordance with a tetracoordinate cationic boron atom.

Scheme III-12. Formation of boronium salt 197 and 198 through protic attack of the B-N bond.

  B and10 B. Both these isotopes are quadripolar nuclei, presenting respectively a nuclear spin I of 3/2 and 3. Quadripolar nuclei frequently lead to a broadening of the resonance signals. The11 B isotope is the most frequently studied due to its higher natural abundance, better sensitivity, and smaller quadrupolar moment (TableIII-1).[46],[47]

		11 B	10 B
	Natural abundance (%)	81.17	18.83
	Nuclear spin I	3/2	3
	Gyromagnetic ratio (radians s -1 T -1 )	8.852•10 7	2.875•10 7
	Relative sensitivity a	0.165	1.88•10 -2
	Electric quadrupole moment Q (10 -28 m 2 )	0.0355	0.111

a Relative sensitivity at constant field or equal number of nuclei Table III-1. Nuclear properties of

11

B and

10 B isotopes.

Table III -

 III 2. Chemical shifts of H5 A and H 5 D for CD-encapsulated boranes (CD2Cl2, 600 MHz, 300 K).

Table III -

 III 4. Values of measured T2 * values for model compound 235 and (β-ICyD)BH3 251 (CD2Cl2, 192 MHz, 300 K).

Table III -

 III 6. Measured11 B and 1 H chemical shifts of synthesised boranes (CD2Cl2, 192 & 600 or 128 & 400 MHz, 300 K).

  Table III-7). (β-BiCyD)BH3 252 gave a13 C shift of 183.4 ppm and (α-BiCyD)BH3 249 a shift at 182.12 ppm. These shifts were deshielded about 10 ppm compared to the other encapsulated boranes.

		13 C-BH3 (ppm)		13 C-BH3 (ppm)
	IiPrNHC-BH3 235	169.7
	(β-ICyD)BH3 251	-	(α-ICyD)BH3 248	173.3
	(β-BiCyD)BH3 252	183.4	(α-BiCyD)BH3 249	182.1
	(β-MiCyD)BH3 253	172.8	(α-MiCyD)BH3 250	173.6
	Table III-7. 13 C chemical shifts of C-BH3 of synthesised boranes (CD2Cl2, 151 MHz, 300 K)..

  Bruker AVANCE II 600 MHz spectrometer equipped with a Bruker Console AVANCE III, BBFO probe 5 mm 1 H/ 19 F/ 31 P-15 N/ 2 D z gradient or a TBI probe 5 mm 1 H/ 31 P/ 109 Ag-7 Li/ 2 D z gradient. -Bruker AVANCE I 400 MHz spectrometer equipped with a Bruker console AVANCE I, BBFO probe 5 mm 1 H/ 19 F/ 31 P-15 N/ 2 D z gradient. The chemical shifts are indicated in ppm compared to the solvent used as internal reference (CDCl2: 7.26 ppm, CD3CN: 1.94 ppm, CD2Cl2: 5.32 ppm, THF-d8: 1.72 ppm C6D5Br: 7.16 ppm for 1 H NMR, CD3CN: 1.32 ppm, CD2Cl2: 53.84 ppm for

A-F ,6 B ,6 C ,6 E ,6 F -Hexadeca-O-Benzyl-α-Cyclodextrin (80)

A-F ,6 B ,6 C ,6 E ,6 F -Hexadeca-O-Benzyl-α-cyclodextrin (82)

  Triethylamine (930 µL, 6.64 mmol) was added to a solution of α-cyclodextrin 80 (4.01 g, 1.66 mmol) dissolved in DCM (110 mL) at 0 °C. After stirring for one hour, methanesulfonyl chloride (510 µL, 6.64 mmol) was added. After stirring for 12 hours at ambient temperature the reaction was quenched with distilled water (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the bis-mesyl α-CD 82 (4.3 g, quantitative) as a white foam.

1

H NMR (CDCl3, 300 MHz, 300 K, ppm) δ 7.29 -7.09 (m, 80H), δ 5.34 (d, 2 J = 11.1 Hz, 2H), δ 5.17

  Triethylamine (3.0 mL, 19.3 mmol) was added to a solution of β-cyclodextrin 81 (5.5 g, 1.93 mmol) dissolved in DCM (140 mL) at 0 °C. After stirring for one hour, methanesulfonyl chloride (1.5 mL, 19.3 mmol) was added. After stirring for 12 hours at ambient temperature the reaction was quenched with distilled water (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. Silica gel flash chromatography(80:20

	A-G ,6 B ,6 C ,6 E ,6 F -Nonadeca-O-Benzyl-β-cyclodextrin
	(83)

cyclohexane/ethyl acetate) afforded the bis-mesyl β-CD 83 (5.8 g, quantitative) as a white foam.

  NMR (151 MHz, CD2Cl2, 300 K, ppm) δ 144.66 (C C=NH2 ), δ 140.84 (C (IV)Ar ), δ 140.58 (C (IV)Ar ), δ 140.54 (C (IV)Ar ), δ 139.97 (C (IV)Ar ), δ 139.79 (C (IV)Ar ), δ 139.75 (C (IV)Ar ), δ 139.60 (C (IV)Ar ), δ 139.55 (C (IV)Ar ), δ 139.51 (C (IV)Ar ), δ 139.44 (C (IV)Ar ), δ 139.34 (C (IV)Ar ), δ 139.32 (C (IV)Ar ), δ 139.26 (C (IV)Ar ), δ 139.22 (C (IV)Ar ), δ 139.07 (C (IV)Ar ), δ 139.78 (C (IV)Ar ), δ 138.74 (C (IV)Ar ), δ 129.78 -127.86 (C Ar ), δ 118.97 (C N-CH=C D), δ 117.06 (C N-CH=C A), δ 101.27 (C 1 CHPh ), δ 74.04 (C CHPh ), δ 74.00 (C 5 B), δ 73.90 (C CHPh ), δ 73.68 (C CHPh ), δ 73.55 (C CHPh ), δ 73.45 (C CHPh ), δ 73.20 (C CHPh ), δ 73.17 (C CHPh ), δ 73.14 (C CHPh ), δ 73.12 (C

	Unit A 1 2 13 C C), 1 H (ppm) 13 C (ppm) Unit B 1 H (ppm) 13 C (ppm) 4.83 100.44 1 5.76 96.90 3.34 80.43 2 3.76 81.43 3 3.86 81.83 3 4.07 80.13
	δ 100.44 (C 1 4	A), δ 99.99 (C 1 3.52	D), δ 99.48 (C 1 77.67	F), δ 98.52 (C 1 4	E), δ 96.90 (C 1 3.84	B), δ 95.82 (C 1 82.06	G), δ
	83.31 (C 4 C 3 D), δ 81.07 (C 4 C), δ 82.68 (C 3 E), δ 82.06 (C 4 G), δ 80.82 (C 3 C), δ 80.68 (C 2 B), δ 81.78 (C 2 D), δ 80.43 (C 2 E), δ 81.52 (C 4 A), δ 80.17 (C 2 F), δ 81.43 (C 2 5 3.82 72.07 5 3.77 74.00 B, C 3 F), δ 80.13 (C 3 F, C 3 B), A, δ 79.63 (C 2 C, δ 78.53 (C 2 G), δ 77.67 (C 4 A), δ 76.93 (C CHPh ), δ 76.79 (C CHPh ), δ 76.30 (C 5 C), δ 76.05 (C CHPh ), δ 75.83 (C 5 E), δ 75.44 (C CHPh ), δ 75.01 (C 4 E, C 5 D, C 3 G), δ 74.73 (C 5 6 4.81 49.10 6 3.75 69.64 6' 3.47 6' 3.31 G), δ Unit C 1 H (ppm) 13 C (ppm) Unit D 1 H (ppm) 13 C (ppm) 74.11 (C CHPh ), 1 4.79 101.27 1 4.86 99.99
	δ 72.56 (C CHPh ), δ 72.34 (C 4 69.64 (C 6 B), δ 68.99 (C 6 F), δ 68.58 (C 6 D), δ 72.07 (C 5 C), δ 50.77 (C 6 A), δ 71.82 (C 5 2 3.31 79.63 2 D), δ 49.10 (C 6 F), δ 70.98 (C 6 3.36 A). 3 3.83 80.82 3 3.88	E), δ 70.25 (C 6 80.68 81.43	G), δ
	Rf = 0.21 (95:5 DCM/MeOH). 4 367	83.31		4	3.64	74.34
	MS (ESI): calculated for C178H186N3O33 [M] + : 2893.2963, found: 2896.9783. 5 3.74 76.30 5 3.69	75.01
		6 6'		3.89 3.70		68.58		6 6'	4.41 3.58	50.77
	Unit E	1 H (ppm)	13 C (ppm)	Unit F	1 H (ppm)	13 C (ppm)
		1		4.84		98.52		1	4.96	99.48
	44 (s, 1H, 80.17 D), δ 5.76 (d, 3 J = A), δ 6.18 (br s, 2H, 2 x H C=NH2 ), δ 6.01 (d, 1H, 1 x H N-CH=CH 1 x H N-CH=CH 2 3.49 81.78 2 3.48 3.8 Hz, 1H, 1 x H 1 B), δ 5.32 (br d, 2 J = 11.1 Hz, 1H, 1 x H CHPh ), δ 5.25 -5.19 (m, 3H, 1 x 3 3.92 82.68 3 3.79 81.43
	H 1	G, 2 x H CHPh ), δ 5.06 (br d, 2 J = 10.8 Hz, 1H, 1 x H CHPh ), δ 4.96 (d, 3 J = 3.9 Hz, 1H, 1 x 4 3.70 75.01 4 3.74 81.52
	H 1	F), δ 4.86 (d, 3 J = 3.5 Hz, 1H, 1 x H 1 5 4.03 75.83	D), δ 4.84 -4.80 (m, 5H, 1 x H 1 5 3.90	A, 1 x H 1 71.82 E, 1 x H 6	A, 2
	x H CHPh ), δ 4.79 (d, 3 J = 3.4 Hz, 1H, 1 x H 1 -4.34 (m, 30H, 1 x H 6 D, 29 x H CHPh ), δ 4.33 (d, 2 J = 12.2 Hz, 1H, 1 x H CHPh ), δ 4.17 (d, 2 J C), δ 4.76 (d, 2 J = 10.7 Hz, 1H, 1 x H CHPh ), δ 4.73 6 3.92 70.98 6 3.22 68.99 6' 4.04 6' 3.13 = 12.0 Hz, 1H, 1 x H CHPh ), δ 4.07 (dd, 3 J = 9.1 Hz, 3 J = 7.2 Hz, 1H, 1 x H 3 B), δ 4.04 -4.00 (m, 2H, 1 x H 5 E, 1 x H 6 E), δ 3.94 -3.62 (m, 26H, 1 x H 2 B,1 x H 3 A, 1 x H 3 C, 1 x H 3 Unit G 1 H (ppm) 13 C (ppm) D, 1 x H 3 E, 1 5.23 95.82
		2		3.58		78.53
		3		4.01		75.03
		4		3.74		81.07
		5		3.72		74.73
		6 6'		3.69 3.64		70.25

1 H NMR (600 MHz, CD3CN, 300 K, ppm) δ 7.42 -7.04 (m, 95H, 95 x H Ar ), δ 6.

  CHPh ), δ 4.33 (d, 2 J = 12.8 Hz, 1H, 1 x H CHPh ), δ 4.30 (d, 2 J = 12.1 Hz, 1H, 1 x H CHPh ), δ 4.25 (m, 1H, 1 x H 6 IV), δ 4.22 (d, 2 J = 12.1 Hz, 1H, 1 x H CHPh ), δ 4.17 (d, 2 J = 12.0 Hz, 1H, 13 C NMR (151 MHz, CD2Cl2, 300 Kn ppm) δ 154.49 (C C=NH2 ), δ 141.12 (C (IV)Ar ), δ 140.91 (C (IV)Ar ), δ 139.85 (C (IV)Ar ), δ 139.70 (C (IV)Ar ), δ 139.46 (C (IV)Ar ), δ 139.32 (C (IV)Ar ), δ 139.12 (C (IV)Ar ), δ 129.58 -127.88 (C Ar ), δ 108.07 (C Benzimidazol ), δ 107.72 (C Benzimidazol ), δ 97.77

	1 4.80 (d, 2 J = 11.2 Hz, 1H, 1 x H CHPh ), δ 4.77 (d, 2 J = 10.7 Hz, 1H, 1 x H CHPh ), δ 4.75 -4.72 V), δ 4.88 -4.86 (m, 2H, 1 x H 1 III, 1 x H CHPh ), δ 4.83 (d, 3 J = 3.4 Hz, 1H, 1 x H 1 II), δ (m, 3H, 1 x H 1 I, 2 x H CHPh ), δ 4.70 (d, 3 J = 2.6 Hz, 1H, 1 x H 1 IV), δ 4.62 -4.38 (m, 25H, 25 II), δ 99.64 (C 1 III), δ 97.78 (C 1 IV), δ 96.92 (C 1 V), δ 96.61 (C 1 VI), δ 96.47 (C 1 VII). Rf = 0.33 (95:5 DCM/MeOH). MS (ESI): calculated for C182H188N3O33 [M] + : 2943.3120, found: 2946.7974. Unit I 1 H (ppm) 13 C (ppm) Unit II 1 H (ppm) 13 C (ppm) 1 4.73 100.70 1 4.83 99.77 2 3.24 79.9 2 2.31 80.48 3 3.90 81.19 3 3.93 81.38 4 3.74 82.08 4 4.62 83.00 5 3.43 3.43 5 3.74 72.96 6 2.59 68.74 6 3.56 70.06 6' 3.61 6' 3.59 Unit III 1 H (ppm) 13 C (ppm) Unit IV 1 H (ppm) 13 C (ppm) 1 4.87 99.64 1 4.70 97.78 2 3.50 81.71 2 3.36 81.76 3 4.04 80.90 3 3.93 83.13 4 3.77 80.80 4 3.80 81.56 5 ? 5 3.82 74.49 6 ? 6 4.26 44.49 6' ? 6' 3.90 Unit V 1 H (ppm) 13 C (ppm) Unit VI 1 H (ppm) 13 C (ppm) 1 4.99 96.92 1 5.82 96.61 2 3.39 80.67 2 3.47 78.62 3 3.82 81.96 3 4.11 80.63 4 ? 4 4.05 80.43 5 3.78 73.69 5 x H (C 1 6 2.97 69.69 6 3.83 71.12 6' 2.83 6' 3.92
	Unit VII 1 H (ppm)	13 C (ppm)
	1	5.83	96.47
	2	81.67	81.67
	3	4.04	81.01
	4	3.93	81.30
	5
	6
	6'

  CHPh ), δ 73.90 (C CHPh ), δ 73.79 (C CHPh ), δ 73.67 (C CHPh ), δ 73.57 (C CHPh ), δ 74.43 (C CHPh ), δ 73.28 (C CHPh ), δ 73.16 (C CHPh ), δ 72.85 (C CHPh ), δ 72.60

	Unit A		1 H (ppm)	13 C (ppm)		Unit B	1 H (ppm)	13 C (ppm)
	1		5.32		95.61		1	4.82 or 4.82	100.34 or 101.35
	2		3.58		79.07		2	3.35 or 3.30	80.62 or 79.94
	3 96.67 (C 1 4	4.03 E), 95.61 (C 1 3.79	76.03 A), δ 83.55 (2 x C 4 76.60	1 B/C), δ 99.18 (C 1 4.03 or 3.85 B/C), δ 83.22 (C 4 3 E), δ 82.85 (C 3 F), δ 82.58 (C 3 G), δ 98.38 (C 1 81.17 or 82.58 F), δ B/C), δ 4 3.68 or 3.70 83.55 or 83.53
	81.75 (C 2 5	F), δ 81.43 (?), δ 81.29 (C 3 3.88 71.92 G), δ 81.17 (C 3 5	B/C), δ 80.98 (C 3 3.96 or 4.53 D), δ 80.66 (?), δ 80.62 76.60 or ?
	(C 2 δ 76.92 (C CHPh ), δ 76.82 (C CHPh ), δ 76.60 (C 4 B/C), δ 80.57 (C 2 D, C 3 E), δ 80.22 (C 2 G), 79.94 (C 2 A), δ 76.56 (C 4 B/C), δ 79.07 (C 2 D), δ 76.38 (C CHPh ), δ 76.31 E, C 2 A), δ 77.09 (C CHPh ), (C CHPh ), δ 76.03 (C 3 A), δ 75.75 (C 5 B/C), δ 75.32 (C 4 F), δ 74.74 (C 5 6 4.52 46.73 6 3.58 or 3.88 69.97 or 69.06 6' 3.73 6' 3.71 or 3.22 F), δ 74.21 (C CHPh ), δ 74.14 (C CHPh ), δ 74.08 (C 5 Unit C 1 H (ppm) 13 C (ppm) Unit D 1 H (ppm) 13 C (ppm) E), δ 73.93 (C (C 5 B/C), δ 72.08 (C 5 G), δ 71.92 (C 5 A), 71.21 (C 6 E), δ 69.97 (C 6 B/C), δ 69.06 (C 6 F, C 6 1 4.82 or 4.82 100.34 or 1 4.86 100.53 101.35 B/C), δ 68.89 (C 6 G), δ 64.33 (C 5 D), δ 46.73 (C 6 A), δ 45.30 (C 6 D), δ 8.94 (C N-C(CH3)=C ), δ 8.76 (C N-2 3.35 or 3.30 80.62 or 79.94 2 3.38 80.57
	C(CH3)=C ). 3		4.03 or 3.85 81.17 or 82.58	3	3.91	80.98
	Rf = 0.15 (95:5 DCM/MeOH). 4 3.68 or 3.70 83.55 or 83.53	4	3.62	76.56
	MS (ESI): calculated for C180H190N3O33 [M] + : 2920.7356, found: 2920.7568. 5 3.96 or 4.53 76.60 or ? 5 3.56	74.74
	6 6'		3.58 or 3.88 3.71 or 3.22	69.97 or 69.06	6 6'	4.61 3.57	45.30
	Unit E		1 H (ppm)	13 C (ppm)		Unit F	1 H (ppm)	13 C (ppm)
	1		5.81		96.97		1	4.89	98.38
	2		3.55		79.07		2	3.49	81.75
	3		4.21		80.57		3	3.97	82.85
	4		3.69		83.22		4	3.77	75.32
	5		3.78		74.08		5	4.52	64.33
	6 6'		4.11 3.83		71.21		6 6'	3.74 3.06	69.06
	Unit G		1 H (ppm)	13 C (ppm)
	1		4.99		99.18
	2		60.66		80.2
	3		3.82		81.29
	4		?		?
	5		3.83		72.08
	6 6'		3.03 3.16		68.89

  J = 10.5 Hz, 2H, 2 x H CHPh ), δ 5.23 (d, 2 J = 10.9 Hz, 2H, 2 x H CHPh ), δ 4.88 (d, 2 J = 11.8 Hz, 2H, 2 x H CHPh ), δ 4.87 -4.84 (m, 4H, 2 x H 1 A, 2 x H CHPh ), δ 4.78 (d, 3 J = 3.1 Hz, 2H, 2 x H 1 C), δ 4.70 -4.67 (m, 4H, 4 x H CHPh ), δ 4.62 -4.59 (m, 4H, 4 x H CHPh ), δ 4.55 (d, 2 J = 11.8 Hz, 2H, 2 x H CHPh ), δ 4.61 -4.46 (m, 4H, 4 x H CHPh ), δ 4.43 (d, 2 J = 11.8 Hz, 2H, 2 x H CHPh ), δ 4.37 -4.32 (m, 6H, 6 x H CHPh ), δ 4.29 (d, 2 J = 11.9 Hz, 2H, 2 x H CHPh ), δ 4.23 -4.21 (m, 4H, 2 x H 5

	1 H NMR (600 MHz, CD3CN, 300 K, ppm) δ 7.37 -6.81 (m, 80H, 80 x H Ar ), δ 5.85 (s, 2H,
	2 x H H-C=C ), δ 5.65 (s, 2H, 2 x H 1 B), δ 5.45 (d, 2 A, 2 x H CHPh ), δ 4.18 -
	4.10 (m, 4H, 2 x H 3	B, 2 x H 5	B), δ 4.04 -3.91 (m, 10H, 2 x H 3	A, 2 x H 4	B, 2 x H 6	B, 2 x H 3	C, 2
	x H 6	C), δ 3.83 (d, 2 J = 10.8 Hz, 2H, 2 x H 6 B), δ 3.80 -3.77 (m, 4H, 2 x H 4	A, 2 x H 6	A), δ 3.52
	-3.47 (m, 4H, 2 x H 2	B, 2 x H 4	C),

  4,5-dimethyl-imidazolium salt 144 (505 mg, 0.20 mmol) was dissolved in dry THF (5.0 mL) in a screwed cap tube. The mixture was cooled at 0 °C and KHMDS (0.5 M in toluene, 815 μL, 0.41 mmol) was added. The reaction was stirred for one hour and tBuN3 (244 μL, 2.0 mmol) was added. The reaction was brought to R.T. and the tube was sealed. The reaction was followed by 1 H NMR, monitoring the disappearance of the imidazolium peaks and the appearance of a tBu peak. After 12 hours at 60 °C, the mixture quenched by Et3NCl (281 mg, 2.0 mmol). After one hour at 60 °C, the solvents were evaporated under reduced pressure. Silica gel flash chromatography (98:2 up to 95:5 DCM/MeOH) afforded 145 (160 mg, 31%) as a white foam. The product was analysed as its neutral counterpart 146.

	Rf = 0.23 (95:5 DCM/MeOH).
	MS (ESI): calculated for C153H162N3O28 [M] + : 2489.1339, found: 2490.0217.
	Figure EP-26. 1 H NMR spectrum of (α-MiCyD)NH2Cl after silica gel flash chromatography (CD3CN,
	400 MHz, 300 K).

  131(31.6 mg, 10.8 μmol) underwent the same process as for pKBH+ determination and afforded (β-ICyD)NH 116 (27.8 mg, 90%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 4.8 μL, 9.6 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -28.94 ppm.

	Figure EP-52. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K).

  mg, 5.54 μmol) underwent the same process as for pKBH+ determination and afforded (β-BiCyD)NH 159 (10.8 mg, 66%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 2.8 μL, 5.6 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -29.15 ppm.The deprotonation of (β-MiCyD)NH2Cl 136 (20.0 mg, 6.76 μmol) underwent the same process as for pKBH+ determination and afforded (β-ICyD)NH 160 (17.8 mg, 90%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 4.2 μL, 9.2 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -29.13 ppm.

	Figure EP-53. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K). Figure EP-54. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K).

  •BH3 (2.0 M in THF, 17.3 μL, 34.6 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -29.03 ppm.The deprotonation of NHI 155 (16.6 mg, 71.6 μmol) underwent the same process as for pKBH+ determination and afforded neutral NHI 163 (6.8 mg, 49%). The J-Young NMR tube was transferred in a PLAS-LABS, INC. ® glovebox and the residue dissolved in CD2Cl2 (500 μL). A 1 H NMR spectrum of the mixture was recorded to ensure the full deprotonation of the product. The J-Young NMR tube was placed in the glovebox and Me2S•BH3 (2.0 M in THF, 17.4 μL, 34.8 μmol) was added. The J-Young NMR tube was vigorously shaken and 1 H and 11 B{ 1 H} NMR spectra were recorded affording δ 11 B{ 1 H} = -39.13 ppm.

	Figure EP-58. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K). Figure EP-59. 11 B{ 1 H} NMR spectrum of NHI-borane adduct (CD2Cl2, 128 MHz, 300 K).

  In a round-bottom flask, α-cyclodextrin imidazolium chloride 84 (300 mg, 0.12 mmol) was dissolved in freshly distilled THF (3.0 mL). After cooling the reaction medium at 0 °C, KHMDS (0.5 M in toluene, 480 μL, 0.24 mmol) was added dropwise inducing a quick redcolouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 120 μL, 0.24 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 248 (250 mg, 81%) as a white foam.

	Rf = 0.49 (75:25 cyclohexane/ethyl acetate).
	A. Synthesis of CD-encapsulated boranes MS (ESI): calculated for C151H159BN2NaO18 [M+Na] + : 2482.1065, found: 2482.9834.
		Unit A/D			1 H (ppm)	13 C (ppm)
			1			4.75	98.38
			2			3.37	81.36
			3			4.15	82.49
			4			3.53	78.43
			5			6.19	67.07
			6 6'			3.48 4.73	53.58
		Unit B/E			(α-ICyD)BH3 (248) 1 H	13 C
			1			4.71	98.46
			2			3.40	79.95
			3			4.12	81.33
			4			3.79	81.92
			5			4.12	71.52
			6 6'			2.77 3.23	68.82
	1 H NMR (600 MHz, CD2Cl2, 300 K ppm) δ 7.38 -6.89 (m, 80H, 80 x H Ar ), δ 6.28 (s, 2H, Unit C/F 1 H 13 C
	2 x H H-C=C ), δ 6.19 (t, 3 J = 10.2 Hz, 2H, 2 x H 5 1 5.57	A), δ 5.57 (s, 2H, 2 x H 1	C), δ 5.56 (d, 2 J = 10.8 99.21
	Hz, 2H, 2 x H 6 C), δ 5,29 (d, 2 J = 10.9 Hz, 2H, 2 x H CHPh ), δ 4.94 (d, 2 J = 10.8 Hz, 2H, 2 x 2 3.53 78.26
	H 6	C), δ 4.88 (d, 2 J = 10.8 Hz, 2H, 2 x H CHPh ), δ 4.83 (d, 2 J = 10.9 Hz, 2H, 2 x H CHPh ), δ 4.76 3 4.51 80.27
	-4.70 (m, 10H, 2 x H 1 4	A, 2 x H 6	A, 2 x H 1 3.92	B, 4 x H CHPh ), δ 4.57 -4.45 (m, 14H, 2 x H 3 83.14	C, 12 x
	H CHPh ), δ 4.38 (2, 2 J = 12.5 Hz, 2H, 2 x H CHPh ), δ 4.31 (d, 2 J = 12.5 Hz, 2H, 2 x H CHPh ), δ 5 4.11 74.79
	4.26 (d, 2 J = 12.0 Hz, 2H, 2 x H CHPh ), δ 4.17 -4.11 (m, 10H, 2 x H 3 H 5 C, 2 x H CHPh ), δ 3.92 (t, 3 J = 8.5 Hz, 2H, 2 X H 4 C), δ 3.88 -3.84 (m, 2H, 2 x H CHPh ), δ 3.79 A, 2 x H 3 B, 2 x H 5 B, 2 x (d, 3 J = 9.8 Hz, 2H, 2 x H 4 B), δ 3.57 -3.45 (m, 6H, 2 x H 4 A, 2 x H 6 C), δ 3.41 -3.36 A ,2 x H 2 6 4.94 76.62 6' 5.56
	(m, 4H, 2 x H 2	A, 2 x H 2 B), δ 3.24 (dd, 2 J = 11.1 Hz, 3 J = 3.0 Hz, 2H, 2 x H 6	B), δ 2.77 (d, 2 J
	= 11.1 Hz, 2H, 2 x H 6 B), 1.68 (bs, 3H, 3 x H BH3 ).
	13 C NMR (151 MHz, CD2Cl2, 300 K, ppm) δ 173.26 (C C-BH3 ), δ 140.48 (2 x C (IV)Ar ), δ
	140.42 (2 x C (IV)Ar ), δ 140.21 (2 x C (IV)Ar ), δ 139.52 (2 x C (IV)Ar ), δ 139.38 (2 x C (IV)Ar ), δ
	139.07 (2 x C (IV)Ar ), δ 138.87 (2 x C (IV)Ar ), δ 128.87 -127.18 (m, C Ar ), δ 124.41 (2 x C H-C=C ),
	δ 99.21 (2 x C 1 C), δ 98.46 (2 x C 1 B), δ 98.38 (2 x C 1	A), δ 83.14 (2 x C 4 C), δ 82.49 (2 x C 3	A),
	δ 81.92 (2 x C 4	B), δ 81.36 (2 x C 2	A), δ 81.33 (2 x C 3	B), δ 80.27 (2 x C 3 C), δ 79.95 (2 x C 2	B),
	δ 78.43 (2 x C 4	A), δ 78.26 (2 x C 2 C), δ 77.19 (2 x C CHPh ), δ 76.62 (2 x C 6 C), δ 74.79 (2 x C 5 C),
	δ 74.70 (2 x C CHPh ), δ 74.12 (2 x C CHPh ), 73.73 (2 x C CHPh ), δ 73.62 (2 x C CHPh ), δ 73.53 (2 x
	C CHPh ), δ 72.63 (2 x C CHPh ), δ 71.52 (2 x C 5	B), δ 71.37 (2 x C CHPh ), δ 68.82 (2 x C 6	B), δ 67.07
	(2 x C 5	A), δ 53.58 (2 x C 6 A).

11 B{ 1 H} NMR (192 MHz, CD2Cl2, 300 K ppm) δ -34.0 (br s).

  5 M in toluene, 790 μL, 0.40 mmol) was added dropwise inducing a quick orange-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 200 μL, 0.40 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 249 (231 mg, 47%) as a white foam. J = 11,8 Hz, 2H, 2 x H CHPh ), δ 5.00 -4.94 (m, 6H, 6 x H CHPh ), δ 4.90 (d, 2 J = 11.8 Hz, 2H, 2 x H CHPh ), δ 4.86 (d, 2 J = 10.8 Hz, 2H, 2 x H CHPh ), δ 4.85 -4.80 (m, 6H, 4 x H CHPh , 2 x MS (ESI): calculated for C155H161BN2NaO28 [M+Na] + : 2532.1121, found: 2533.7817.

			Unit A/D	1 H (ppm)	13 C (ppm)
						4.69	98.49
						3.45	91.21
						4.24	82.44
						3.78	78.05
						6.34	67.04
				6'		4.14 4.95	48.87
			Unit B/E	1 H (ppm)	13 C (ppm)
						5.66	99.12
						3.59	78.38
						4.59	80.05
						3.94	83.16
						4.22	74.76
	1 H NMR (600 MHz, CD2Cl2, 300 K ppm) δ 7.42 -6.88 (m, 84H, 84 x H Ar ), δ 6.34 (t, 3 J = 10.3 Hz, 2H, 2 x H 5 A), δ 5.66 (s, 2H, 2 x H 1 B), δ 5.61 (d, 2 J = 10.4 Hz, 2H, 2 x H CHPh ), δ 5.33 3.82 71.36 6' ? Unit C/F 1 H (ppm) 13 C (ppm) (d, 2 H 6 A), δ 4.71 -4.67 (m, 4H, 2 x H 1 C, 2 x H 1 A), δ 4.60 -4.53 (m, 6H, 2 x H 3 B, 4 x H CHPh ), δ 4.69 99.23
	4.44 -4.41 (m, 4H, 4 x H CHPh ), δ 4.38 (d, 1 J = 12.1 Hz, 2H, 2 x H CHPh ), δ 4.23 (d, 2 J = 12.5 3.40 79.79
	Hz, 2H, 2 x H CHPh ), δ 4.26 -4.21 (m, 4H, 2 x H 5 4.14	B, 2 x H 3	A), δ 4.16 -4.12 (m, 6H, 2 x H 3 81.21	C,
	2 x H 5	C, 2 x H 6	A), δ 3.94 (t, 3 J = 8.4 Hz, 2H, 2 x H 4 3.74	B), δ 3.84 -3.72 (m, 6H, 2 x H 4 81.93	C, 2 x
	H 4	A, 2 x H 6	B), δ 3.59 (dd, 3 J = 10.1 Hz, 3 J = 2.3 Hz, 2H, 2 x H 2 4.16	B), δ 3.49 (d, 2 J = 12.0 Hz, 71.28
	2H, 2 x H CHPh ), δ 3.45 -3.43 (m, 4H, 2 x H 2 Hz, 2H, 2 x H 2 C), δ 2.89 (d, 2 J = 10.5 Hz, 2H, 2 x H 6 A, 2 x H CHPh ), δ 3.40 (dd, 3 J = 10.0 Hz, 3 J = 2.6 C), δ 2.36 (d, 2 J = 10.5 Hz, 2H, 2 x H 6 C), 2.89 68.38 6' 2.36
	δ 1.95 (br s, 3H, 3 x H BH3 ).
	13 C NMR (151 MHz, CD2Cl2, 300 K, ppm) δ 182.12 (C CBH3 ), δ 140.32 (2 x C (IV)Ar ), δ 140.25
	(2 x C (IV)Ar ), δ 140.03 (2 x C (IV)Ar ), δ 139.30 (2 x C (IV)Ar ), δ 139.18 (2 x C (IV)Ar ), δ 138.89 (2
	x C (IV)Ar ), δ 138.70 (2 x C IV(Ar) ), δ 138.64 (2 x C (IV)Ar ), δ 134.11 (2 x C (IV)Ar ), δ 128.78 -
	127.10 (m, C Ar ), δ 124.45 (2 x C * ), δ 111.08 (2 x C # ), δ 99.12 (2 x C 1	B), δ 98.49 (2 x C 1	A), δ
	98.23 (2 x C 1 C), δ 83.16 (2 x C 4 B), δ 82.44 (2 x C 3	A), δ 81.93 (2 x C 4	C), δ 81.21 (2 x C 2	A, 2
	x C 3 C), δ 80.05 (2 x C 3	B), δ 79.79 (2 x C 2 C), δ 78.38 (2 x C 4	A), δ 78.05 (2 x C 2	B), δ 77.06 (2
	x C CHPh ), δ 76.51 (2 x C CHPh ), δ 74.76 (2 x C 5 B), δ 74.71 2 x (C CHPh ), δ 73.98 (2 x C CHPh ), δ
	73.56 (2 x C CHPh ), δ 73.41 (2 x C CHPh ), δ 72.58 (2 x C CHPh ), δ 72.44 (2 x C CHPh ), δ 71.36 (2 x
	C 6	B), δ 71.28 (2 x C 5	C), δ 68.38 (2 x C 6	C), δ 67.04 (2 x C 5	A), δ 48.87 (2 x C 6 A).

11 B{ 1 H} NMR (192 MHz, CD2Cl2, 300 K, ppm) δ -32.3 (br s). Rf = 0.30 (75:25 cyclohexane/ethyl acetate).

  •BH3 (2.0 M in THF, 170 μL, 0.34 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 250 (293 mg, 70%) as a white foam.

						4 Hz,
	2H, 2 x H 5	A), δ 5.59 -5.57 (m, 4H, 2 X H 1	C, 2 x H CHPh ), δ 5.34 -5.31 (m, 2H, 2 x H CHPh ), δ
	4.95 (d, 1 J = 10.5 Hz, 2H, 2 x H CHPh ), δ 4.88 -4.84 (m, 4H, 4 x H CHPh ), δ 4.82 -4.77 (m,
	6H, 2 x H 1	A, 4 x H CHPh ), δ 4.72 (s, 2H, 2 x H 1	B), δ 4.63 (d, 3 J = 13.9 Hz, 2H, 2 x H 6	A), δ 4.60
	-4.55 (m, 8H, 2 x H 3	C, 6 x H OBn ), δ 4.50 (s, 4H, 4 x H CHPh ), δ 4.40 (d, 1 J = 12.5 Hz, 2H, 2 x
	H CHPh ), δ 3.33 (d, 1 J = 12.5 Hz, 2H, 2 x H CHPh ), δ 4.21 -4.12 (m, 12H, 2 x H 3	A, 2 x H 3	B, 2 x
	H 5	B, 2 x H 5	C, 4 x H CHPh ), δ 3.96 (t, 3 J = 8.3 Hz, 2H, 2 x H 4	C), δ 3.84 (t, 3 J = 9.3 Hz, 2H, 2 x
	H 4	B), δ 3.81 (s, 4H, 4 x H 6	C), δ 3.63 -3.58 (m, 4H, 2 x H 4	A, 2 x H 6	A), δ 3.55 (dd, 3 J = 10.3
	Hz, 3 J = 2.8 Hz, 2H, 2 x H 2	C), δ 3.43 -3.42 (m, 4H, 2 x H 2	A, 2 x H 2	B), δ 3.13 (d, 1 J = 10.9
	Hz, 2H, 2 x H 6	B), δ 2.69 (d, 1 J = 10.9 Hz, 2H, 2 x H 6	B), δ 1.73 (s, 6H, 6 x H H3C-C=C ), δ 1.66
	(s, 3H, 3 x H BH3 ).

1 H NMR (600 MHz, CD2Cl2, ppm) δ 7.39 -6.93 (m, 80H, 80 x H Ar ), δ 6,16 (t, 3 J = 10.

  5 M in toluene, 1.38 mL, 0.69 mmol) was added dropwise inducing a quick orange-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 345 μL, 0.69 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 251 (733 mg, 74%) as a white foam.

	C=C Hz, 1H, 1 x H 1 D), δ 6.20 (s, 1H, 1 x H H-C=C C), δ 5.44 (d, 2 J = 10.0 Hz, 1H, 1 x H CHPh ), δ 5.40 (d, 2 J = 11.0 Hz, 1H, 1 x A), δ 5.81 (d, 3 J = 3.4 Hz, 1H, 1 x H 1 G), δ 5.81 (d, 3 J = 3.7 H CHPh ), δ 5.34 -5.31 (m, 5H, 5 x C CHPh ), δ 5.22 (d, 2 J = 10.9 Hz, 1H, 1 x C CHPh ), δ 5.03 -4.97 (m, 2H, 1 x H 5 D, 1 x H 6 D), δ 4.93 -4.84 (m, 7H, 1 x H 1 A, 1 x H 1 B, 1 x H 6 A, 4 x H CHPh ), δ 4.82 -4.64 (m, 15H, 1 x H 1 D, 1 x H 1 E, 1 x H 1 F, 1 x H 5 A, 11 x C CHPh ), δ 4.59 -4.30 (m, 13H, 1 x H 3 G, 12 x H CHPh ), δ 4.26 (d, 1 J = 12.9 Hz, 1H, 1 x C CHPh ), δ 4.20 -4.14 (m, 5H, 1 x H 3 1 H (ppm) 13 C (ppm) Unit B 1 H (ppm) 13 C (ppm) 1 4.89 98.73 1 4.87 96.75 2 3.44 80.64 2 3.41 79.94 3 4.20 82.16 3 4.05 80.94 4 3.63 74.13 4 3.83 81.27 5 4.82 69.74 5 3.82 or 3.85 71.34/73.44 6 4.87 52.25 6 3.77 70.12 6' 3.40 6' 4.15 Unit C 1 H (ppm) 13 C (ppm) Unit D 1 H (ppm) 13 C (ppm) 1 5.81 96.85 1 4.70 97.22 2 3.47 78.27 2 3.37 81.20 3 4.16 80.68 3 4.06 82.43 4 3.77 80.32 4 3.61 72.77 5 3.75 73.49 5 4.99 68.11 6 3.99 70.51 6 5.03 53.03 6' 3.72 6' 3.32 Unit E 1 H (ppm) 13 C (ppm) Unit F 1 H (ppm) 13 C (ppm) 1 4.74 100.41 1 4.73 100.13 2 3.34 79.23 2 3.34 79.30 3 3.99 80.81 3 3.99 80.68 4 3.84 82.67 4 3.60 83.10 5 3.37 71.85 5 3.68 72.65 6 3.63 69.23 6 3.78 70.27 6' 2.99 6' 3.72 A, 1 x H 3 Unit A Unit G 1 H (ppm) 13 C (ppm)
	1	5.81	96.80
	2	3.50	78.42
	3	4.50	79.92
	4	4.16	80.64
	5	3.82 or 3.85	71.34/73.44
	6 6'	2.81 ?	69.02

1 H NMR (600 MHz, CD2Cl2, ppm) δ 7.47 -6.87 (m, 95H, 95 x H Ar ), δ 6.37 (s, 1H, 1 x H H-

  28 mmol) was added dropwise inducing a quick orange-colouring of the medium. After one hour at 0 °C, Me2S•BH3 (2.0 M in THF, 136 μL, 0.28 mmol) was added and the ice bath removed. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (80:20 cyclohexane/ethyl acetate) afforded the encapsulated borane 252 (90 mg, 22%) as a white foam.

	Unit A	1 H (ppm)	13 C (ppm)		Unit B	1 H (ppm)	13 C (ppm)
		1		4.90	98.77		1	4.71	100.16
		2		3.55	80.66		2	3.29	79.28
		3		4.30	82.28		3	3.98	80.64
		4		3.84	73.39		4	3.81	81.18
		5		5.10	69.05		5	3.27	71.81
		6 6'		3.90 5.27	50.26		6 6'	2.20 3.16	68.14
	Unit C	1 H (ppm)	13 C (ppm)		Unit D	1 H (ppm)	13 C (ppm)
		1		4.74	100.24		1	4.59	97.06
		2		3.33	79.24		2	3.34	80.96
		3		4.00	80.94		3	4.10	82.33
		4		3.61	82.83		4	3.82	72.93
		5		3.69	72.49		5	5.11	69.85
		6 6'		3.56 3.56	69.72		6 6'	5.11 4.07	47.90
	Unit E	1 H (ppm)	13 C (ppm)		Unit F	1 H (ppm)	13 C (ppm)
	1 = 7.2 Hz, 2H, 2 x H Ar ), δ 7.38 -6.88 (m, 95H, 95 x H Ar ), δ 5.89 (s, 2H, 1 x H 1 4.87 96.84 1 5.88 2 3.40 78.81 2 3.51 5.47 (d, 2 J = 10.0 Hz, 1H, 1 x H CHPh ), δ 5.45 (d, 2 J = 11.2 Hz, 1H, 1 x H CHPh ), δ 5.37 (d, 2 J = 96.82 45 (d, 3 J F, 1 x H 1 78.23 G), δ 3 4.03 80.88 3 4.47 80.18
	10.9 Hz, 1H, 1 x H CHPh ), δ 5.34 -5.32 (m, 1H, 1 x H CHPh ), δ 5.27 (d, 2 J = 13.0 Hz, 1H, 1 x 4 3.77 80.09 4 4.14 80.74
	H 6	A), δ 5.20 (d, 2 J = 10.9 Hz, 1H, 1 x H CHPh ), δ 5.15 -5.09 (m, 3H, 1 x H 5 5 3.71 71.17 5 3.95	A, 1 x H 5 73.73	D, 1 x
	H 6 H CHPh ), δ 4.82 (d, 2 J = 10.9 Hz, 1H, 1 x H CHPh ), δ 4.78 -4.68 (m, 9H, 1 x H 1 D), δ 4.99 (d, 2 J = 11.1 Hz, 1H, 1 x H CHPh ), δ 4.93 -4.86 (m, 3H, 1 x H 1 A, 1 x H 1 B, 1 x H 1 E, 1 x C, 7 x 6 2.06 68.77 6 ? ? 6' 2.39 6' ?
	H CHPh ), δ 4.62 -4.32 (m, 16H, 1 x H 1 Unit G 1 H (ppm) 13 C (ppm) D, 1 x H 3	F, 9 x H CHPh , 2 x H 6	F, 2 x H 6 G), δ 4.31 -4.08
	(m, 10H, 1 x H 3 1	A, 1 x H 3 D, 1 x H 6 5.89 96.77 D, 1 x H 4	F, 1 x H 3	G, 5 x H CHPh ), δ 4.06 -3.80 (m, 15H, 1 x
	H 4 H CHPh ), δ 3.77 (t, 3 J = 9.2 Hz, 1H, 1 x H 4 A, 1 x H 6 A, 1 x H 3 B, 1 x H 4 B, 1 x H 3 C, 1 x H 4 E), δ 3.72 -3.68 (m, 3H, 1 x H 5 D, 1 x H 3 E, 1 x H 5 F, 1 x H 4 2 3.53 78.47 C, 2 x H CHPh ), δ 3.61 G, 1 x H 5 G, 5 x (t, 3 J = 9.4 Hz, 1H, 1 x H 4 C), δ 3.56 -3.52 (m, 6H, 1 x H 2 A, 2 x H 6 C, 1 x H 2 F, 1 x H 2 3 4.23 80.41 G, 1 x H CHPh ), δ 3.40 (dd, 3 J = 9.9 Hz, 3 J = 2.9 Hz, 1H, 1 x H 2 E), δ 3.36 -3.26 (m, 4H, 1 x H 2 4 3.86 82.92 B, 1 x H 5 B, 1 x H 2 C, 1 x H 2 5 3.80 74.72 D), δ 3.24 (d, 2 J = 12,1 Hz, 1H, 1 x H CHPh ), δ 3.16 (d, 2 J = 11.1 Hz, 1H, 1 x H 6 B), δ 2.39 (d, 2 J = 10.9 Hz, 1H, 1 x H 6 E), δ 2.20 (d, 2 J = 11,1 Hz, 1H, 1 x H 6 B), δ 2.07 (d, 2 J = 10.9 Hz, 1H, 1 x H 6 E), δ 1.69 (br s, 3H, 3 x H BH3 ). 6 ? ? 6' ?

1 H NMR (600 MHz, CD2Cl2, 300 K, ppm) δ 7.49 (d, 3 J = 7.3 Hz, 2H, 2 x H Ar ), δ 7.

  J = 11.0 Hz, 1H, 1x H CHPh ), δ 5,39 (d, 2 J = 10.9 Hz, 1H, 1 x H CHPh ), δ 5.35 (d, 2 J = 10.8

	Unit A	1 H (ppm)	13 C (ppm)	Unit B	1 H (ppm)	13 C (ppm)
	1		4.83				97.16	1	4.90	96.80
	2		3.43				81.26	2	3.46	79.90
	3		4.09				82.44	3	4.07	80.93
	4		3.70				74.51	4	3.92	80.08
	5		4.99				68.55	5	3.81	73.52
	6 6'		4.82 3.56				47.67	6 6'	4.18 4.66	73.36
	Unit C	1 H (ppm)	13 C (ppm)	Unit D	1 H (ppm)	13 C (ppm)
	1		5.84				96.80	1	4.94	98.99
	2		3.47				78.22	2	3.49	78.48
	3		4.48				79.97	3	4.24	82.19
	4		4.14				80.81	4	3.67	72.55
	5		3.91				73.52	5	4.95	69.95
	6 6'		3.57 2.94				68.50	6 6'	3.39 4.94	49.43
	Unit E	1 H (ppm)	13 C (ppm)	Unit F	1 H (ppm)	13 C (ppm)
	1 1 H NMR (600 MHz, CD2Cl2, 300 K, ppm) δ 7.49 -7.48 (m, 2H, 2 x H Ar ), δ 7.42 -6.88 (m, 4.82 100.02 1 4.74 100.48 93H, 93 x H Ar ), δ 5.84 (s, 2H, 1 x H 1 G, 1 x H 1 2 3.37 79.41 2 3.33 79.14 C), δ 5.47 (d, 2 J = 10.1 Hz, 1H, 1 x H CHPh ), 5.42 3 4.03 80.73 3 4.01 80.73 (d, 2 Hz, 1H, 1 x H CHPh ), δ 5.24 (d, 2 J = 10.9 Hz ,1H, 1 x H CHPh ), δ 5.01 -4.90 (m, 7H, 1 x H 5 A, 4 3.86 81.44 4 3.70 82.66
	1 x H 1 B, 1 x H 1 5	D, 1 x H 5 3.45	D, 1 x H 6	D, 2 x H CHPh ), δ 4.89 (d, 2 J = 10.1 Hz, 1H, 1 x H CHPh ), δ 4.83 72.72 5 8.81 71.38
	-4.72 (m, 11H, 1 x H 1 6 3.90 6' 4.05	A, 1 x H 6	A, 1 x H 1 72.23	E, 1 x H 1	F, 7 x H CHPh ), δ 4.70 -4.66 (m, 4H, 1 x H 6 B, 6 2.94 68.46 6' 2.82
	Unit G	1 H (ppm)	13 C (ppm)
	1		5.85				96.80
	2		3.50				78.48
	3		4.19				80.33
	4		3.79				83.07
	5		3.67				73.09
	6 6'		4.25 4.39				73.05

  5 M in toluene, 71 μL, 35.5 μmol) was added dropwise inducing a quick orangecolouring of the medium. After one hour at 0 °C, Me2S•BH2(C6F5) (165 μL of a solution containing 35.6 mg of Me2S•BH2(C6F5) dissolved in 500 μL of toluene, 49 μmol) was added to the mixture. After 12 hours at R.T., the solvents were evaporated under reduced pressure. Silica gel flash chromatography (7:1 up to 5:1 cyclohexane/ethyl acetate) afforded the encapsulated borane 288 (10.9 mg, 11%) as a white foam.

	Unit A	1 H (ppm)	13 C (ppm)	Unit B	1 H (ppm)	13 C (ppm)
	1	4.80	97.38		1	4.77	97.73
	2	3.44	84.41		2	4.41	81.57
	3	3.99	82.95		3	4.16	81.07
	4	3.64	73.24		4	3.78	80.96
	5	5.26	67.54		5	3.98	71.33
	6 6'	3.55 3.64	52.58		6 6'	2.78 2.87	68.88
	Unit C	1 H (ppm)	13 C (ppm)	Unit D	1 H (ppm)	13 C (ppm)
	1	5.67	97.79		1	4.88	98.13
	2	3.45	78.17		2	3.41	80.59
	3	4.63	79.64		3	3.69	82.62
	4	4.10	80.40		4	3.54	73.09
	5	3.91	74.20		5	4.08	71.07
	6 6'	3.92 3.74	70.65		6 6'	5.24 3.33	52.42
	1 H NMR (600 MHz, CD2Cl2, 300 K, ppm) δ 7.37 -6.98 (m, 95H, 95 x H Ar ), δ 6.37 (d, 3 J = 1.8 Hz, 1H, 1 x H N-CH=CH D), δ 5.99 (d, 3 J = 1.8 Hz, 1H, 1 x N-CH=CH A), δ 5.75 (d, 3 J = 3.7 Hz, Unit E 1 H (ppm) 13 C (ppm) Unit F 1 H (ppm) 13 C (ppm)
	1H, 1 x H 1 1	G), δ 5.70 (d, 3 J = 3.7 Hz, 1H, 1 x H 1 4.71 102.32	C), δ 5.48 (d, 2 J = 10.7 Hz, 1H, 1 x H CHPh ), δ 1 4.75 98.67
	5.41 (d, 2 J = 11.6 Hz, 1H, 1 x H CHPh ), δ 5.40 -5.33 (m, 4H, 1 x H 5 2 3.25 78.45 2 3.38 A, 1 x H 6	D, 5 x H CHPh ), δ 80.19
	5.09 (d, 2 J = 10.9 Hz, 1H, 1 x H CHPh ), δ 4.89 -4.78 (m, 6H,1 x H 1 4.77 (d, 3 J = 3.8 Hz, 1H, 1 x H 1 B), δ 4.75 -4.65 (m, 7H, 1 x H 1 E, 1 x H 1 A, 1 x H 1 3 3.90 79.97 3 4.08 F, 5 x H CHPh ), δ 4.64 D, 4 x H CHPh ), δ 81.70 -4.56 (m, 6H, 1 x H 3 C, 7 x H CHPh ), δ 4.54 -4.46 (m, 7H, 1 x H 6 4 3.78 80.96 4 3.88 81.73 A, 6 x H CHPh ), δ 4.44 -4.36 (m, 6H, 6 x H CHPh ), δ 4.34 -4.31 (m, 4H, 4 x H CHPh ), δ 4.24 -4.14 (m, 5H, 1 x H 3 B, 1 x H 6 5 3.23 71.30 5 3.76 72.36 G, 6 3.14 69.13 6 3.88 70.97 6' 3.78 6' 3.48
	Unit G	1 H (ppm)	13 C (ppm)
	1	5.75	96.20
	2	3.44	79.72
	3	3.58	80.76
	4	3.87	81.73
	5	3.58	72.51
	6 6'	4.21 3.86	70.10

Figure EP-89. 1 H NMR spectrum of (β-ICyD)BH2(C6F5) (CD2Cl2, 600 MHz, 300 K).

Figure EP-90. JMod NMR spectrum of (β-ICyD)BH2(C6F5) (CD2Cl2, 151 MHz, 300 K).

Figure EP-91. 11 B{ 1 H} NMR spectrum of (β-ICyD)BH2(C6F5) (CD2Cl2, 192 MHz, 300 K).

Figure EP-92.

19

F NMR spectrum of (β-ICyD)BH2(C6F5) (CD2Cl2, 565 MHz, 300 K).

CD Me (262)

  Triethylamine (1.18 mL, 10.8 mmol) was added to a solution of α-CD 260 (1.62 g, 1.4 mmol) in dry DCM (64 mL) at 0 °C. After stirring for one hour, methanesulfonyl chloride (840 μL, 10.8 mmol) was added. After stirring for 12 hours at R.T., the mixture was quenched by water (50 mL). The aqueous phase as extracted with DCM (5 x 50 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure. Silica gel chromatography (98:2 DCM/MeOH up to 95:5 DCM/MeOH) afforded 262 (1.68 g, 92%) as a white foam.

D -di-O-mehanesulfonyl-α-

CD Me (263)

  Triethylamine (770 μL, 7.1 mmol) was added to a solution of α-CD 261 (1.24g, 0.88 mmol) in dry DCM (51 mL) at 0 °C. After stirring for one hour, methanesulfonyl chloride (550 μL, 7.1 mmol) was added. After stirring for 12 hours at R.T., the mixture was quenched by water (40 mL). The aqueous phase as extracted with DCM (5 x 40 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure. Silica gel chromatography (98:2 DCM/MeOH up to 95:5 DCM/MeOH) afforded 263 (1.22 g, 89%) as a white solid.Sodium iodide (1.86 g, 12.4 mmol) was added to a solution of α-CD 262 (1.68 g, 1.24 mmol) dissolved in acetone (50 mL). After 12 hours at 60 °C, the reaction was quenched by water (20 mL). The aqueous phase was extracted with ether (5 x 100 mL). The combined aqueous layers were dried over Na2SO4 and evaporated under reduced pressure affording crude 264 (1.76 g) as a white foam. The crude mixture was directly engaged for the imidazolium salt 266 synthesis.

	6 A ,6 D -di-iodo-α-CD Me (264)

D -di-O-methanesulfonyl-β-

  NMR (600 MHz, CD2Cl2, 300 K, ppm) δ 6.93 (s, 2H, 2 x H H-C=C ), δ 5.73 (bt, 2H, 2 x H 5 A), δ 5.26 (d, 3 J = 4.0 Hz, 2H, 2 x H 1 C), δ 4.92 (d, 3 J = 3.5 Hz, 2H, 2 x H 1 A), δ 4.85 (d, 3 J = 3.8 Hz, 2H, 2 x H 1 B), δ 4.48 (d, 2 J = 15.7 Hz, 2H, 2 x H 6 A), δ 3.84 (dd, 2 J = 14.4 Hz, 3 J = 7.8 Hz, 2H, 2 x H 6 A), δ 3.71 (s, 6H, 6 x H OCH3 ), δ 3.70 -3.63 (m, 10H, 2 x H 3

				A, 2 x H 5	B, 2 x
	H 5	C, 2 x H 6 C, 2 x H 3	C), δ 3.63 (s, 6H, 6 x H OCH3 ), δ 3.62 -3.59 (m, 4H, 2 x H 4	B, 2 x H 6 C), δ
	3.59 (s, 6H, 6 x H OCH3 ), δ 3.55 (m, 2H, 2 x H 4	C), δ 3.55 (s, 6H, 6 x H OCH3 ), δ 3.48 (m, 2H, 2
	x H 3 B), δ 3.43 (s, 6H, 6 x H OCH3 ), δ 3.42 (s, 6H, 6 x H OCH3 ), δ 3.37 -3.30 (m, 4H, 2 x H 6	B, 2
	x H

1 H

  ): calculated for C55H95BN2NaO28 [M+Na] + : 1265.6057, found: 1265.9814.

	Unit A/D	1 H (ppm)	13 C (ppm)
		4.93	97.91
		3.19	83.43
		3.70	83.93
		3.37	79.26
		5.73	63.30
	6'	3.84 4.48	52.94
	Unit B/E	1 H (ppm)	13 C (ppm)
		4.85	97.88
		3.07	81.58
		3.48	82.20
		3.59	81.61
		3.69	70.95
	6'	3.33 2.82	70.98
	Unit C/F	1 H (ppm)	13 C (ppm)
		5.26	99.01
		3.08	81.12
		3.64	81.67
		3.55	82.99
		3.68	73.48
	6'	3.67 3.59	72.50

  C NMR (151 MHz, CD2Cl2, ppm) δ 174.30 (C C-BH3 ), δ 121,28 (C H-C=C A), δ 121.00 (C H-

									A),
	δ 5.68 (s, 1H, 1 x H 1	G), δ 5.64 (s, 1H, 1 x H 1 D), δ 4.94 (s, 1H, 1 x B, 1 x H 3 C), δ 4.97 (s, 1H, 1 x H 1 E, 6 x H OCH3 ), δ 3.31 (s, 3H, 3 x H OCH3 ), δ 3.26
	-3.25 (m, 4H, 1 x H 5	E, 3 x H OCH3 ), δ 3.21 (d, 3 J = 9.7 Hz, 1H, 1 x H 2	D), δ 3.16 (s, 3H, 3 x
	H OCH3 ), δ 3.15 -3.05 (m, 5H, 1 x H 2	A, 1 x H 2	B, 1 x H 2	C, 1 x H 2	F, 1 x H 2	G), δ 3.02 (t, 2 J = 9.8
	Hz, 1H, 1 x H 2	E), δ 2.89 (d, 2 J = 11.0 Hz, 1H 1 x H 6	E), δ 2.71 (s, 2H, 2 x H 6	C or F), 1.02 (br s,
	3H, 3 x H BH3 ).
	C=C	D), δ 99.30 (C 1	B), δ 98.95 (C 1	E), δ 98.69 (C 1	D), δ 97.48 (C 1	A), δ 96.58 (C 1 C), δ 96.12 (C 1	G),
	δ 96.11 (C 1	F), δ 84.18 (C 3	A), δ 83.96 (C 3	D, C 4	C), δ 83.62 (C 2	A), δ 83.44 (C 2	D), δ 82.83 (C 3	C),
	δ 82.15 (C 3	F), δ 82.05 (C 4	F), δ 81.95 (C 2	B, C 2	E), δ 81.81 (C 3	B), δ 81.72 (C 3	E), δ 81.62 (C 2	C or
	G), δ 81.59 (C 2	F), δ 81.23 (C 4	E, C 3	G), δ 80.60 (C 4	B), δ 80.45 (C 4	G), δ 80.36 (C 2	C or G), δ 74.67
	(C 4	A), δ 7319 (C 5	F), δ 72.82 (C 5	C), δ 72.78 (C 4	D), δ 72.72 (C 6	B), δ 72.14 (C 6	G), δ 71.92 (C 6

1 H NMR (600 MHz, CD2Cl2, ppm) δ 6.86 (s, 1H, 1 x H H-C=C D), δ 6.80 (s, 1H, 1 x H H-C=C 13

  Rf = 0.19 (95:5 DCM/MeOH).MS (ESI): calculated for C64H111BN2NaO33[M+Na] + : 1469.7054, found: 1469.6036.

	Unit A	1 H (ppm)	13 C (ppm) Unit B	1 H (ppm)	13 C (ppm)
	1	4.76	97.48	1	4.94	99.30
	2	3.14	83.62	2	3.08	81.95
	3	3.68	84.18	3	3.41	81.81
	4	3.48	74.67	4	3.53	80.60
	5	4.87	68.15	5	3.72	71.79
	6 6'	4.78 3.56	52.15	6 6'	3.83 3.59	72.72
	Unit C	1 H (ppm)	13 C (ppm) Unit D	1 H (ppm)	13 C (ppm)
	1	5.64	96.58	1	4.97	98.69
	2	3.11	81.62/80.36	2	3.21	83.44
	3	3.52	82.83	3	3.74	83.96
	4	3.71	83.96	4	3.46	72.78
	5	3.63	72.82	5	4.73	69.44
	6 6'	3.83 or 3.72 2.71	71.92 or 71.05	6 6'	4.86 3.56	52.93
	Unit E	1 H (ppm)	13 C (ppm) Unit F	1 H (ppm)	13 C (ppm)
	1	4.88	98.95	1	4.88	96.11
	2	3.02	81.95	2	3.07	81.59
	3	3.37	81.72	3	3.47	82.15
	4	3.57	81.23	4	3.53	82.05
	5	3.25	71.41	5	3.69	73.19
	6 6'	2.88 3.48	70.85	6 6'	3.83 or 3.72 2.71	71.92 or 71.05
	Unit G	1 H (ppm)	13 C (ppm)
	1	5.68	96.12
	2	3.10	81.62 or 80.36
	3	3.91	81.32
	4	3.83	80.45
	5	3.64	72.86
	6 6'	3.71 3.5430	72.14

11 B{ 1 H} NMR (192 MHz, CD2Cl2, ppm) δ -36.3 (br s).

Tabke 1. Crystal data and structure refinement for kbb498_0m_pl.

	Identification code	kb498_0m_pl
	Empirical formula	C62.5H113BN2O28
	Formula weight	1351.35
	Temperature/K	200.
	Crystal system	trigonal
	Space group	P3221
	a/Å	21.4240(6)
	b/Å	21.4240(6)
	c/Å	13.7674(6)
	α/°	90
	β/°	90
	γ/°	120
	Volume/Å 3	5472.5(4)
	Z	3
	ρcalcg/cm 3	1.230
	μ/mm -1	0.800
	F(000)	2193.0
	Crystal size/mm 3	0.12 × 0.1 × 0.09
	Radiation	CuKα (λ = 1.54178)
	2Θ range for data collection/° 7.996 to 135.15
	Index ranges	-25 ≤ h ≤ 25, -25 ≤ k ≤ 25, -16 ≤ l ≤ 16
	Reflections collected	103334
	Independent reflections	6588 [Rint = 0.0330, Rsigma = 0.0136]
	Data/restraints/parameters	6588/23/455
	Goodness-of-fit on F 2	1.037
	Final R indexes [I>=2σ (I)] R1 = 0.0528, wR2 = 0.1501
	Final R indexes [all data]	R1 = 0.0545, wR2 = 0.1531
	Largest diff. peak/hole / e Å -3 0.98/-0.27
	Flack parameter	-0.01(2)

Table 2 Fractional Atomic Coordinates (×10 4 ) and Equivalent Isotropic Displacement Parameters (Å 2 ×10 3 ) for kb498_0m_pl. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor.

 2

	Atom	x	y	z	U(eq)
	O2B2	1047(11)	-2415(12)	-1229(17)	94(6)
	O1A	2424.4(12)	-2328.2(11)	1470.7(14)	47.3(5)
	O1B	2485.6(13)	-1303.3(12)	-1206.2(15)	53.7(6)
	O1C	2752.4(11)	-1039.0(10)	4043.8(13)	41.4(4)
	O2A	1494.1(14)	-3411.3(12)	2731.9(19)	60.7(6)
	O2C	1645.5(15)	-937.3(17)	4927(2)	69.1(7)
	O2B	1188(3)	-2639(3)	-1456(4)	74.0(15)
	O3A	1682.8(15)	-2519.8(13)	4349.4(19)	64.4(7)
	O3B	1187.2(18)	-3233.1(16)	330(2)	85.0(11)
	O3C	2343(2)	578.1(18)	5261(3)	80.2(8)
	O5A	3391.8(12)	-2014.4(11)	2528.0(14)	45.1(5)
	O5B	3077.6(16)	-1966.7(12)	-1054.1(15)	57.7(6)
	O5C	3491.1(13)	-471.2(11)	5387.8(14)	48.3(5)
	O6B	3827(3)	-2478(2)	181(3)	108.0(13)
	O6C	5061.6(18)	405.0(19)	4832(3)	82.1(9)
	N1	4509.8(12)	-373.8(12)	2260.2(18)	38.8(5)
	C1	4307.9(19)	0	1666.67	41.9(8)
	C2AA	5196.2(16)	-230.9(16)	2044(3)	45.3(6)
	C1A	2723.6(18)	-2573.4(15)	2171(2)	46.0(7)
	C1B	2495(2)	-1932.8(17)	-1459(2)	60.5(10)
	C1C	2776.4(18)	-900.5(16)	5042.6(19)	45.1(6)
	C2A	2188.2(19)	-2874.0(15)	3023(2)	49.7(7)
	C2B	1802(2)	-2585(2)	-1097(3)	72.7(12)
	C2C	2351.1(19)	-525.9(19)	5278(2)	52.9(7)
	C8B2	900(30)	-2560(30)	-2270(30)	110(13)
	C3A	2112.8(18)	-2270.3(15)	3495(2)	47.4(7)
	C3B	1778(2)	-2574.3(19)	10(3)	61.4(9)
	C3C	2718(2)	241(2)	4875(2)	54.5(8)
	C4A	2850.3(17)	-1631.1(14)	3773.0(19)	40.9(6)
	C4B	2465(2)	-2483.7(17)	461(2)	50.5(8)
	C4C	2832.4(19)	-674.4(16)	-1818(2)	48.9(7)
	C5A	3343.5(16)	-1406.6(15)	2881.3(19)	39.5(6)
	C5B	3135.4(18)	-1870.3(16)	-15(2)	47.2(7)
	C5C	3887.7(18)	246.1(15)	4976.1(19)	44.0(6)
	C6A	4104.6(16)	-815.3(15)	3109(2)	43.0(6)
	C6B	3835(2)	-1817(2)	278(3)	60.5(8)
	C6C	4627(2)	574.9(18)	5417(2)	53.1(8)
	C7A	1460(3)	-4044.4(19)	2368(3)	70.6(11)
	C7C	5781(3)	739(4)	5167(5)	108(2)
	C7E	4125(8)	-2591(7)	-638(9)	141(4)
	C8A	987(3)	-2594(2)	4232(4)	86.7(15)

Table 3 Anisotropic Displacement Parameters (Å 2 ×10 3 ) for kb498_0m_pl. The

 3 -Y+X,-Y,1/3-Z; 2 -Y+X,-Y,4/3-Z; 3 -X,-X+Y,5/3-Z

	Anisotropic	displacement	factor	exponent	takes	the	form:	-
	2π 2 [h 2 a* 2 U11+2hka*b*U12+…].
	Atom	U11		U22	U33		U23		U13	U12
	O2B2	58(8)	77(13)	103(12)		-8(9)	-21(8)	1(7)
	O1A	57.3(12)	37.3(10)	36.8(10)	0.8(8)	1.7(9)	15.7(9)
	O1B	58.2(13)	42.4(11)	39.5(10)	1.7(8)	-4.5(9)	9.4(10)
	O1C	53.0(11)	36.0(9)	31.4(9)	0.4(7)	0.2(8)	19.4(9)
	O2A	62.8(15)	33.5(10)	60.7(13)	0.6(9)	5.7(11)	5.4(10)
	O2C	56.7(14)	77.3(17)	62.6(14)	-11.9(13)	3.9(11)	25.6(13)
	O2B	69(3)	54(3)	66(3)		-4(2)	-29(2)	6(2)
	O3A	71.1(16)	45.6(12)	57.4(14)	9.6(10)	25.3(12)	14.8(11)
	O3B	67.9(18)	59.7(16)	70.0(17)	7.5(13)	-1.3(14)	-11.2(14)
	O3C	93(2)	80.2(19)	88.3(19)	-6.0(16)	16.6(17)	58.6(18)
	O5A	52.4(12)	36.2(10)	43.6(10)	-2.4(8)	1.4(9)	20.0(9)
	O5B	84.7(17)	42.0(11)	35.1(10)	-0.7(8)	1.3(10)	23.3(11)
	O5C	60.1(13)	36.4(10)	37.5(10)	5.1(8)	-5.7(9)	15.9(9)
	O6B	139(4)	87(2)	121(3)	28(2)	39(3)	74(3)
	O6C	76.4(19)	86(2)	96(2)	-39.3(17)	-39.0(17)	50.2(17)
	N1	35.5(11)	31.7(10)	47.8(12)	0.4(9)	-0.5(9)	15.7(9)
	C1	37.8(14)	36.0(18)	51(2)	4.9(16)	2.4(8)	18.0(9)
	C2AA	37.8(14)	34.4(13)	64.7(18)	2.1(12)	-1.5(13)	18.8(11)
	C1A	58.6(17)	30.9(13)	40.1(14)	1.1(11)	2.4(13)	16.0(13)
	C1B	82(2)	35.0(14)	37.4(14)	-5.5(11)	-11.1(16)	8.8(15)
	C1C	56.1(17)	38.9(13)	30.7(12)	1.6(10)	0.1(12)	16.5(13)
	C2A	61.8(19)	29.9(13)	43.1(14)	4.3(11)	6.1(14)	12.2(13)
	C2B	78(3)	42.5(17)	54.1(19)	-3.0(14)	-22.7(18)	-2.4(17)
	C2C	59.9(19)	57.5(18)	36.6(14)	-3.7(13)	5.2(13)	25.6(16)

1

Table 5 Bond Angles for kb498_0m_pl.

 5 -Y+X,-Y,1/3-Z; 2 -Y+X,-Y,4/3-Z; 3 -X,-X+Y,5/3-Z

	Atom Atom Atom	Angle/˚	Atom Atom Atom	Angle/˚
	C8B2 O2B2 C2B	100(2) O2C C2C C1C	109.7(3)
	C1A O1A C4B	119.1(3) O2C C2C C3C	111.4(3)
	C1B O1B C4C	120.4(3) C1C C2C C3C	111.6(3)
	C1C O1C C4A	115.8(2) O3A C3A C2A	110.9(2)
	C2A O2A C7A	114.4(3) O3A C3A C4A	108.3(2)
	C2C O2C C8C	114.6(3) C2A C3A C4A	111.4(3)
	C2B O2B C8B	114.8(8) O3B C3B C2B	108.4(3)
	C3A O3A C8A	113.1(3) O3B C3B C4B	109.1(3)
	C9B O3B C3B	114.2(4) C4B C3B C2B	111.9(4)
	C9C O3C C3C	114.1(4) O3C C3C C2C	107.0(3)
	C1A O5A C5A	112.4(2) O3C C3C C4C 1	109.6(3)
	C1B O5B C5B	113.7(3) C4C 1 C3C C2C	112.6(3)
	C1C O5C C5C	115.3(2) O1C C4A C3A	108.2(3)
	C7E O6B C6B	118.6(6) O1C C4A C5A	108.3(2)
	C7E2 O6B C6B	123.0(12) C5A C4A C3A	108.7(2)
	C6C O6C C7C	112.1(4) O1A C4B C3B	104.9(3)
	C1	N1	C2AA	111.0(2) O1A C4B C5B	110.7(2)
	C1	N1	C6A	126.4(3) C3B C4B C5B	111.7(3)
	C2AA N1	C6A	122.2(2) O1B C4C C3C 1	104.2(3)
	N1	C1	N1 1	104.3(3) O1B C4C C5C 1	111.8(2)
	N1	C1	B1	127.86(17) C3C 1 C4C C5C 1	111.2(2)
	N1 1	C1	B1	127.85(17) O5A C5A C4A	109.7(2)
	C2AA 1 C2AA N1	106.81(17) O5A C5A C6A	107.0(2)
	O1A C1A O5A	112.4(2) C6A C5A C4A	112.4(2)
	O1A C1A C2A	107.3(3) O5B C5B C4B	109.0(2)

1

Table 8 Atomic Occupancy for kb498_0m_pl.

 8

	Atom	Occupancy	Atom	Occupancy	Atom	Occupancy
	O2B2	0.25 O2B	0.75 H2BA	0.5
	H2BB	0.5 C8B2	0.25 H8BA	0.25
	H8BB	0.25 H8BC	0.25 C7E		0.75
	H7EA	0.75 H7EB	0.75 H7EC	0.75
	C8B	0.75 H8BD	0.75 H8BE	0.75
	H8BF	0.75 C10	0.5 C12		0.5
	C11	0.5 C7E2	0.25 H7ED	0.25
	H7EE	0.25 H7EF	0.25 C21		0.5
	C23	0.25 C22	0.5 C2		0.5
	C5	0.5

Ribozymes, discovered in 1982, are RNA molecules that can also act as catalysts while bearing, unlike enzymes, genetic information.

Scheme I-1. A) Makoto Fujita's self-assembled coordination cage B) Cavity induced selective cross-photodimerization.

tert-butyl azide was synthesised following literature.[29] The azide was first stored as a 1:1 solution of tBuN3/toluene to improve safety. However, even pure tBuN3 is considered as a quite stable reagent, and no incident was observed during the few years of regular use and handling.

Here, BiCyD stands for Benzimidazolium-Capped CycloDextrin.

Here, MiCyD stands for 4,5-diMethylimidazolium-Capped CycloDextrin.

Parts of this work has been done by Kouceila Abdelli, master chemistry student.

The studies on11 B NMR were performed in collaboration with Régina Maruchenko, NMR engineer.

This work has been done in collaboration with Till Neumann, master chemistry student and Etienne Derat, researcher at Institut Parisien de Chimie Moléculaire, Paris, France.

Annex III-2.31 P NMR spectra of the GB method measurements (CD2Cl2, 162 MHz, 300 K).

A-G ,3 A-G ,6 B ,6 C ,6 E ,6 F ,6 G -Nonadeca-O-Benzyl-β-Cyclodextrin (81)

x H 3 F, 1 x H 3 G, 1 x H 4 B, 1 x H 4 C, 1 x H 4 D, 1 x H 4 E, 1 x H 4 F, 1 x H 4 G, 1 x H 5 A, 1 x H 5 B, 1 x H 5 C, 1 x H 5 D, 1 x H 5 F, 1 x H 5 G, 1 x H 6 B,

x H 6 C, 1 x H 6 D, 1 x H 6 E, 2 x H 6 G) δ

3.58 (dd, 3 J = 9.1 Hz, 3 J = 3.7 Hz, 1H, 1 x H 2 G), δ 3.55 -3.44 (m, 5H, 1 x H 2 A, 1 x H 2 E, 1 x H 2 F, 1 x H 4 A, 1 x H 6 A), δ 3.36 (dd, 3 J = 9.9 Hz, 3 J = 3.3 Hz, 1H, 1 x H 2 D), δ 3.33 -3.29 (m, 2H, 1 x H 2 C, 1 x H 6 B), δ 3.22 (d, 2 J = 10.7 Hz, 1H, 1 x H 6 F), δ 3.12 (br d, 1H, 1 x H 6 F).

x H CHPh ), δ 4.12 -4.03 (m, 6H, 1 x H 3 III, 1 x H 1 VI, 1 x H 1 VII, 1 x H 6 , 1 x H 4 VI, 1 x H ? ), δ 3.95 -3.72 (m, 16H, 1 x H 3 I, 1 x H 3 II, 1 x H 3 IV, 1 x H 3 V, 1 x H 4 I, 1 x H 4 III, 1 x H 4 IV, 1 x H 5 II, 1 x H 5 IV, 1 x H 5 V,

x H 6 VI, 1 x H6 IV, 1 x H 6 , 2 x H ? ), δ

3.65 -3.43 (m, 9H, 1 x H 2 III, 1 x H 2 VI, 1 x H 2 VII, 1 x H 4 II, 1 x H 5 I, 2 x H 6 III, 2 x H 6 ), δ 3.39 (dd, 3 J = 9.7 Hz, 3 J = 3.6 Hz, 1H, 1 x H 2 V), δ 3.37 -3.34 (m, 2H, 1 x H 2 IV, 1 x H 6 ), δ 3.31 (dd, 3 J = 9.9 Hz, 3 J = 3.4 Hz, 1H, 1 x H 2 II), δ 3.23 (dd, 3 J = 9.9 Hz, 3 J = 3.4 Hz, 1H, 1 x H 2 I), δ 2.96 (br d, 1H, 1 x H 6 V), δ 2.82 (d, 2 J = 11.1 Hz, 1H, 1 x H 6 V), δ 2.59 (d, 2 J = 11.3 Hz, 1H, 1 x H 6 V).

H NMR (CDCl3, 300 MHz, 300 K, ppm) δ 10.17 (s, 1H), δ 7.55 (s,

2H), δ 4.93 (sept, 3 J = 6.7 Hz, 2H), δ 1.61 (d, 3 J = 6.7 Hz, 12H).The spectral data are in accordance with data described in the literature.[7]

H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 9.84 (s, 1H), δ 4.60 (sept, 3 J = 6.8 Hz,

2H), δ 2.30 (s, 6H), δ 1.72 (d, 3 J = 6.8 Hz, 12H).The spectral data are in accordance with data described in the literature.[9]

H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 7.66 (dd, 3 J = 6.1 Hz, 3 J = 3.2 Hz,

2H, 2 x H Ar ), δ 7.34 (dd, 3 J = 6.1 Hz, 3 J = 3.2 Hz, 2H, 2 x H Ar ), δ 6.77 (br s, 2H, 2 x H N=H2 ), 4.68 (m, 2H, 2 x H CH(CH3)2 ), δ 1.62 (d, 3 J = 6.9 Hz, 12H, 12 x H CH(CH3)2 ).Rf= 0.13 (98:2 DCM/MeOH). MS (ESI): calculated for C13H20N3 [M] + : 218.1652, found: 219.1017.Figure EP-30. 1 H NMR of 153 (CD3CN, 400 MHz, 300 K).

H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 5.82 (br s,

2H, 2 x H N=H2 ), δ 4.52 (m, 2H, 2 x H CH(CH3)2 ), δ 2.14 (s, 6H, 6 x H N-C(CH3)=C(CH3) ), δ 1.46 (d, 3 J = 7.0 Hz, 2H, 2 x H CH(CH3)2 ). Rf = 0.15 (96:4 DCM/MeOH). MS (ESI): calculated for C11H22N3 [M] + : 196.1808, found: 197.1250.Figure EP-31. 1 H NMR of 155 (CD3CN, 300 MHz, 300 K).

B{ 1 H} NMR (128 MHz, CD2Cl2, ppm) δ -33.7 (br s). Rf = 0.16 (80:20 cyclohexane/ethyl acetate). MS (ESI): calculated for C153H163BN2NaO28 [M+Na] + : 2510.1378, found: 2511.0020.

x H CHPh ), δ

4.60 -4.55 (m, 4H, 4 x H CHPh ), δ 4.50 -4.47 (m, 5H, 1 x H 3 C, 4 x H CHPh ), δ 4.44 -4.32 (m, 9H, 1 x H 6 G, 8 x H CHPh ), δ 4.31 (d, 2 J = 12.3 Hz, 1 x H CHPh ), δ 4.25 -4.23 (m, 2H, 1 x H 3 D, 1 x H 6 G), δ 4.20 -4.17 (m, 2H, 1 x H 6 B, 1 x H 3 G), δ 4.14 (t, 3 J = 8.7 Hz, 1H, 1 x H 4 C), δ 4.11 -4.01 (m, 5H, 1 x H 3 A, 1 x H 3 B, 1 x H 3 E, 1 x H 6 E, 1 x H CHPh ), δ 3297 -3289 (m, 4H, 1 x H 4 B, 1 x H 5 C, 1 x H 3 F, 1 x H 6 E), δ 3.86 (t, 3 J = 9.3 Hz, 1H, 1 x H 4 E), δ 3.83 -3.78 (m, 5H, 1 x H 5 B, 1 x H 5 F, 1 x H 4 G, 2 x H CHPh ), δ 3.72 -3.65 (m, 5H, 1 x H 4 A, 1 x H 4 F, 1 x H 5 G, 1 x H 4 D, 1 x H CHPh ), δ 3.58 -3.54 (m, 2H, 1 x H 6 C, 1 x H 6 A), δ 3.50 -3.35 (m, 8H, 1 x H 2 A, 1 x H 2 B, 1 x H 2 C, 1 x H 2 D, 1 x H 6 D, 1 x H 2 E, 1 x H 5 E, 1 x H 2 G), δ 3.33 (dd, 3 J = 10.0 Hz, 3 J = 3.1 Hz, 1H, 1 x H 2 F), δ 2.94 (d, 2 J = 11,3 Hz, 1H, 1 x H 6 C), δ 2.86 (d, 2 J = 11.2 Hz, 1H, 1 x H 6 F), δ 2.82 (d, 2 J = 11.2 Hz, 1H, 1 x H 6 F), δ 1.83 (s, 3H, 3 x H H3C-C=C D), δ 1.69 (s, 3H, 3 x H H3C-C=C A), 1.38 (br s, 3H, 3 x H BH3 ).

C NMR (151 MHz, CD2Cl2, 300 K, ppm) δ 172.77 (C CBH3 ), δ

140.48 (C (IV)Ar ), δ 140.45 (2 x C (IV)Ar ), δ 140.22 (C (IV)Ar ), δ 140.02 (C (IV)Ar ), δ 139.56 (C (IV)Ar ), δ 139.37 (C (IV)Ar ), δ 139.34

H NMR (CD2Cl2, 600 MHz, 300 K, ppm) δ 6.95 (s,

2H), δ 5.07 (p, 3 J = 6.8 Hz, 2H), δ 1.37 (d, 3 J = 6.8 Hz, 12H), 0.97 (q, 1 J = 86.5 Hz, 3H).11 B NMR (CD2Cl2, 192 MHz, 300 K, ppm) δ -36.0 (q, 1 J = 86.5 Hz).The spectral data are in accordance with the data described in the literature.[10]

x H CHPh ), δ

4.11 -4.05 (m, 3H, 1 x H 4 C, 1 x H 5 D, 1 x H 3 F), δ 4.00 -3.94 (m, 2H, 1 x H 3 A, 1 x H 5 B), δ 3.94 -3.85 (m, 7H, 1 x H 5 C, 1 x H 6 C, 1 x H 3 E, 1 x H 4 F, 1 x H 6 F, 1 x H 4 G, 1 x H 6 G), δ 3.80 -3.73 (m, 5H, 1 x H 4

H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.30 (s, 3H), δ 5.13 (d, 3 J = 3.5 Hz,

2H), δ 5.04 -5.01 (m, 2H), δ 3.92 -3.75 (m, 16H), δ 3.69 -3.59 (m, 26H), δ 3.59 -3.49 (m, 21H), δ 3.39 (m, 16H), δ 3.19 -3.15 (m, 6H).The spectral analysis are in accordance with the data described in the literature.[12]

H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.14 (d, 3 J = 4.0 Hz, 1H), δ 5.13 -5.08 (m, 5H), δ 5.07 (d, 3 J = 3.6 Hz, 1H), δ 4.60 -4.49 (m, 3H), δ 4.45 (dd,

J = 10.9 Hz,

J = 3.7 Hz, 1H), δ

4.00 (m, 2H), δ 3.93 (m, 2H), δ 3.87 (dd, 2 J = 10.6 Hz,3 J 3.7 Hz, 1H), δ 3.83 -3.74 (m, 5H), δ 3.79 -3.60 (m, 29H), δ 3.57 -6.40 (m, 34H), δ 3.37 -3.36 (m, 15H), δ 3.20 -3.13 (m, 7H), δ 3.40 (m, 6H).The spectral analysis are in accordance with the data described in the literature.[14]

H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.09 (d, 3 J = 3.4 Hz,

2H), δ 5.06 -5.04 (m, 4H), δ 4.14 (dd, 2 J = 10.8 Hz, 3 J = 3.2 Hz, 2H), δ 3.86 -3.46 (m, 62H), δ 3.43 (m, 6H), δ 3.43 (m, 6H), δ 3.27 (t, 3 J = 8.9 Hz, 2H), δ 3.20 -3.13 (m, 6H). Rf = 0.52 (95:5 DCM/MeOH).

H NMR (CDCl3, 400 MHz, 300 K, ppm) δ 5.17 -5.11 (m, 4H), δ 4.11 (td, 3 J = 8.8 Hz, 3 J 4.6 Hz,

2H), δ 3.87 -3.97 (m, 94H), δ 3.33 -3.28 (m, 2H), δ 3.22 -3.16 (m, 4H).

H NMR (CD3CN, 400 MHz, 300 K, ppm) δ 8.91 (s, 1H), δ 7.54 (d, 3 J = 6.7 Hz,

2H), δ 5.38 (d, 3 J = 3.6 Hz, 2H), δ 4.50 (d, 2 J = 13.5 Hz, 2H), δ 4.29 (m, 4H), δ 3.77 (m, 2H), δ 3.69 (m, 8H), δ 3.63 (m, 2H), δ 3.57 (s, 6H), δ 3.59 (m, 2H), δ 3.55 (s, 6H), δ 3.54 (m, 2H), δ 3.53 (s, 6H), δ 3.49 (m, 4H), δ 3.48 (m, 2H), δ 3.43 (m, 2H), δ 3.42 (s, 12H), δ 3.35 (m, 2H), δ 3.32 (m, 2H), δ 3.30 (s, 6H), δ 3.24 (m, 2H), δ 3.09 (m, 2H), δ 3.06 (m, 2H), δ 3.04 (s, 6H).The spectral data are in accordance with the data described in the literature.[14]

x H OCH3 ), δ 3.60 -3.50 (m, 31H, 1 x H6 A, 1 x H

B, 1 x H6 B, 1 x H 3 C, 1 x H 4 E, 1 x H 4 F, 1 x H 6 G, 24 x H OCH3 ), δ 3.49 -3.42 (m, 17H, 1 x H 4 A, 1 x H 4 D, 1 x H 6 D, 1 x H 6 E, 1 x H 3 F, 12 x H OCH3 ), δ 3.41 -3.34 (m, 8H, 1 x H 3

Remerciements

Experimental part

Table of contents

Scheme I-32. HUGPHOS-catalyzed hydroformylation of styrene.

Cyclodextrins can also be selectively functionalised with several ligands. Matthieu Sollogoub and his team synthesised the palladium(II) complex 75 bearing two diametrically opposed NHC ligands. This complex was shown to be active in catalysis and managed to perform the Suzuki-Miyaura coupling between phenylboronic acid and p-bromoacetophenone affording an 83% yield and with a very low catalyst loading of only 0.1 mol% (Scheme I-33). [124] Scheme I-33. Suzuki-Miyaura coupling catalysed by a CD-based bis-NHC palladium (II) complex.

Once again, chemists showed ingenuity in using CDs for catalysis, managing to complex metals close to the primary rim leading to chirality transfers and regioselectivity in the case of the HUGPHOS ligands. The versatility of CDs allowed the formation of the firsts fully encapsulated metal-complexes inside a small cavity that will now be described.

Scheme II-8. A) NHI synthesis using sodium amide B) Mechanism of NHI formation using sodium amide.

pK BH+ measurements for encapsulated NHIs

NHIs are Lewis bases as well as Brønsted-Lowry bases. Thus, measuring their pKBH+ values should allow a better comprehension of the cavity influence on encapsulated NHIs.

In order to better understand the systems, NHIs not encapsulated by CDs were also synthesised.

A. Synthesis of unencapsulated NHIs

Following the encapsulated NHIs obtained with three different imidazole bases, three model NHIs bearing isopropyl groups were synthesised (Scheme II-18). The first step was the alkylation of the endo-cyclic nitrogen atoms using K2CO3 (1.1 eq) and 2-iodopropane (3.0 eq). [34] This step afforded the 1,3-diisopropylimidazolium salts 150, 152 and 154 with yields from 75% to 100%. The salts were then reacted in the same fashion as the CDs for the formation of the corresponding NHIs affording three 1,3-diisopropyl, "free", NHIs bearing an imidazole group 151 (59%), a benzimidazole group 153 (34%) and a 4,5dimethylimidazole group 155 (28%).

Scheme II-18. Synthesis of unencapsulated model NHIs.

These bases were then used for comparison with encapsulated NHIs.

D. pKBH+ measurements

The synthesised protonated encapsulated NHIs were reacted with tBuOK in THF.

The mixtures were evaporated, the CDs were then solubilised in toluene and filtered to remove the salts to afford the corresponding neutral NHIs with good yields (Scheme II-19 A)). For unencapsulated NHIs, the reaction took place, following described procedure, in presence of KOH (50% in water) in a hexane/MeOH mixture. The hexane phase was separated, dried over Na2SO4 and evaporated (Scheme II-19 B)). [14] Scheme II-19. A) Deprotonation reaction of CD-based NHI B) Deprotonation reaction of model NHIs.

After one night under vacuum in a J-young NMR tube, the deprotonated NHIs were placed in a PLAS-LABS, INC. ® glovebox and solubilized in CD3CN. p-fluoroaniline 158 (5.0 eq) and p-fluorophenol (1.0 eq) were added. 19 F NMR spectra of the mixtures were acquired and the pKBH+ were calculated according to the obtained chemical shifts. The obtained values are summarised in Figure II-15. understanding of CD's properties and might serve as a model for enzymes. In order to confirm these results, pKBH+ values measured with another base should be acquired. The synthesis of water-soluble encapsulated NHIs should be considered, as pKBH+ values could then be measured in water for a direct comparison with enzymes such as AAD. Concerning the reactivity, NHC-borane 210 was shown not to react with acetic acid even at 100 °C. In general, NHC-borane adducts do not undergo any acid/base reaction with other weak acids such as water, alcohols and phenols. [36] However, the use of stronger acids, presenting pKa values lower than 2, led to acid-base reactions with NHC-borane 210 forming the corresponding halide NHC-boranes (Scheme III-16). [37] Scheme III-16. Acid-base reactions between NHC-borane 210 and strong Brønsted-Lowry acids.

Chapter III. Encapsulated NHC-borane adducts precursors to borenium ions

Concerning their use in catalysis, NHC-boranes were used for hydroboration reactions thanks to the use of bistriflimidic acid.

1. Use of a NHC-BH3 for hydroboration reactions NHC-BH3 boranes are known to be unreactive towards hydroboration reactions.

However, the use of a strong Brønsted-Lowry acid can unlock this reactivity. [35] The use of bistriflimidic acid with NHC-borane 211 induced the formation of the corresponding borane bearing a bistriflimide group 212 (Scheme III-17 A)). [35] The corresponding borenium ion could not be isolated. However, the addition of 0.5 eq of HNTf2 led to the formation of the cationic bridged compound 213 (Scheme III- 17 B). The These new encapsulated NHC-boranes were characterised by NMR.

D. Reactivity of encapsulated boranes

The reactivity of the synthesised encapsulated boranes was then tested. First, (α-ICyD)BH3 248 was mixed with acetic acid (Scheme III-33). As expected, the borane did not react with the acid. On the contrary, reacting the NHC-borane with triflic acid led to the obtention of unknown products in CD2Cl2 and CD3CN. The disappearance, of a singlet at 4.62 ppm which might correspond to the signal of H2 which is tabulated at 4.59 ppm in CD2Cl2. [58] Figure The highest value was obtained for the unencapsulated model compound 290 with a FIA of 768.95 kJ.mol -1 . The higher FIA obtained for (β-MiCyD)BH2 + 277 (719.16 kJ.mol -1 ) compared to (α-MiCyD)BH2 + 275 (700.20 kJ.mol -1 ) was consistent with the observations obtained with the GB method. Therefore, it is rather unlikely that the steric hindrance brought by the α-CD led to a strong underestimation of the GB value (although the FIA may be influenced by steric hindrance in extreme cases [76] ). The important difference in FIA values between the three compounds clearly implies a cavity effect on the borenium ion. The smaller values obtained for the CD-encapsulated borenium ions indicate that the boron atom is less acidic when it is inside the cavity. Further work is ongoing to better understand this effect and also to get the FIA values for the other encapsulated borenium ions.

A comparison of the obtained FIA values with the ones in the literature indicated than the encapsulated borenium ions 277 and 275 were stronger than BCl3, BBr3, BI3, BCF and the borenium ion 291 (Figure III-33). [78], [81], [82] However, the FIAs indicated that 275 and 277 were weaker than Berionni's planar triarylboranes 285 and 286. [78], [79] Figure III-33. Comparison of FIA of several boron-based Lewis acids.

It is worth noting that the FIA acidities are inverted compared to the GB method acidities. The anomeric protons are reported and given a roman numeral corresponding to the sugar unit it belongs.

The use of a 2D 1 H/ 1 H TOCSY sequence allows to find the protons on one sugar unit.

The TOCSY experiment shows scalar coupling between protons. The presence of a heteroatom disrupts TOCSY transfer. Therefore, from an anomeric proton signal, all the correlations will be for protons present on the same sugar unit. The mixing time parameter of the TOCSY experiment allows to modulate the time during which the magnetization is transferred thorough the bonds. Usually, from the signal of an anomeric proton, a mixing time of 60 ms allows to show correlations up to the H 3 and sometimes H 4 . A mixing time of 260 ms can allow to show correlations up to the H 6 . The spectral data are in accordance with the data described in the literature. [1] Figure EP-33. 19 F NMR spectrum after addition of KHMDS (CD3CN, 282 MHz, 300 K).

Imidazolium-brigded cyclodextrins synthesis

Lewis basicity determination of (α-out-ICyD)NH (143)

The deprotonation of (α-out-ICyD)NH2Cl 142 ( added to the mixture and the reaction was followed by 1 H NMR. The NMR spectra indicated a disappearance of the phenylacetylene peaks but the formed compound could not be characterised.

F. Crystallographic data for (α-ICyD)BH3

A single crystal of the compound was selected, mounted onto a cryoloop, and transferred in the cold nitrogen gas stream of an Oxford Cryostream. Intensity data were collected with a BRUKER Kappa-APEXII diffractometer with micro-focused Cu-Kα radiation (λ=1.54178 A) at 200K. APEX 3 suite and SAINT program (BRUKER) were used to carry out data collection, unitcell parameters refinement, integration and data reduction. SADABS (BRUKER) was used for scaling and multi-scan absorption corrections. In the Olex2 suite, [15] the structure was solved with SHELXT-14 [16] program and refined by full-matrix least-squares methods using SHELXL-14. [17] All non-hydrogen atoms of the CD molecule were refined anisotropically. Hydrogen atoms were observed on Forier difference maps but were placed at calculated positions and refined with a riding model. Several restrains and constraints were introduced for highly disordered pentane solvent molecules. 1 -Y+X,-Y,1/3-Z; 2 -Y+X,-Y,4/3-Z; 3 -X,-X+Y,5/3-Z