Ces travaux ont été réalisé à l'Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), au sein de l'équipe du Département des Matériaux Organiques (DMO). Ils concluent presque 4 ans de travail

Et puis les amis… vous êtes trop nombreux pour que je vous cite tous ici mais au cours de ces 8 ans de vie étudiante on a passé tellement de bons moments ensemble, vous m'avez doré ma vie à Strasbourg et vous m'avez permis de grandir et d'aller au-delà de ce que j'ai pu être avant. Lucas, Mayou, Guigui, Laura, Thibault, Élodie, Coco, Morgane, Nathan, Julie, Benji, Erika, Steuh, Alexandra, Ian, Émeu, Fred, Gilles, Keupon, Jonath et puis encore tant d'autres… Merci à vous tous ! Fritz, Til, Marcel, unsere gemeinsame Zeit fing vor dem Studieren an und wird auch noch lange danach währen. Auch das hätte ich mir früher nicht erträumt. Danke für alles, danke für den Halt den ihr mir gegeben habt über diese Jahre und ich freu mich auf den nächsten der mit dem PhD dran ist! Und auf die nächste Runde Hungry Hungry Felhound in meiner Bude, und auf ein nächstes Mal Hong Kong, und und und… Patrick, Anna, Christina, Philippe, Xixi euch möcht ich auch nicht missen, danke euch allen! Un grand merci à l'ASCS Athlétisme pour m'avoir procuré un environnement non seulement pour faire du sport, mais aussi des rencontres ! On n'oubliera pas le cadeau bonux et les compétitions sportives, qui m'ont été d'un grand soutien moral lors de mon stage de Master 2.

Pour finir, special thanks à Alcanes. Je ne peux pas m'imaginer ce que c'est d'être étudiant sans cette communauté, sans vous… ! Et finalement, very special thanks à Thomas Holstein. Frère Viking, nos domaines ne pourraient être plus loin l'un de l'autre, mais ta passion pour le tien m'a inspiré chaque fois qu'on s'est vu, que ce soit à Québec ou dans le sud, et toujours aux moments où j'en avais besoin. On a partagé une aventure et on en partagera encore d'autres, j'en suis certain. Fuego !!!

General Introduction

At university, most chemistry students will probably get in contact with chirality during their initial courses about atoms and molecules, or during their first organic chemistry course. Chirality is presented there as the result from four different substituents on a tetrahedral carbon atom or of blocked movements around a rotational axis. The example of thalidomide (sold in West Germany under the name Contergan), whose R-enantiomer is a sedative and whose S-enantiomer is teratogen, is often cited to illustrate the importance of chirality in organic molecules and the control of chirality in organic synthesis. However, the concept and the implications of chirality go far beyond symmetry planes and stereogenic centres.

Chirality is defined, in a very general sense, as a system or object which exists in two different, enantiomeric states which can be interconverted by space inversion but not by time reversal. [1] This definition accounts for chiral motions as well as for 3D structures. For chemists, it is the latter which matters most, as it confers objects a high spatial specificity. Only chiral molecules have a structure which affords three different spatial axes to define them. This is exemplified by Figure 1: the bear and its mirror image are identical, except that their z-axis is inverted. Therefore, an oriented z-axis is necessary to spatially describe the bear, in addition to oriented x-and y-axes. For an achiral object, z1 = z2 since it is superimposable with its mirror plane. In this case, the z-axis' orientation is unimportant and its spatial configuration less specific.

Figure 1: Illustration of the spatial specificity of chiral objects. Since the bear is chiral, its spatial configuration affords an oriented z-axis which is inverted in its mirror image.

The point where chirality comes into play for chemistry is that, the more molecules are well-defined in space, the more diverse are the interactions between them. Spatial specificity can lead to more specific interactions, which is important for chemical selectivity and information transfer. This is the reason why nature has chosen to encode biological information in chiral molecules and why proteins are particularly efficient (asymmetric) catalysts.

However, the spatial specificity of chiral molecules has not only an impact on molecular interactions, but also on light-matter interactions and physical properties. An example is the well-known difference of absorption of left-and right-handed polarised light in circular dichroism (CD), but it allows also to distinguish between "spin up" and "spin down" in electron transfer processes (chirality-induced spin selectivity, CISS) [2] and leads to the emergence of new phenomena in single molecule magnets (magneto-chiral effect). [3] This PhD thesis will attempt to account for the vast implications of chirality on science by addressing two different domains: non-linear effects (NLEs) in asymmetric catalysis and sum-frequency generation (SFG) in non-linear optics. The first is based on specific (diastereoisomeric) interactions between chiral catalysts, which gives rise to new phenomena like chiral amplification. We will first study a catalytic system showing a new type of NLE (i.e. Hyperpositive NLE, Chapter I) and then have a look at the effect of metallopolymers as catalysts on NLEs (Chapter II). Finally, we will use chiral metallopolymers to study chiral SFG, which is one of the few non-linear optical phenomena allowed in certain conditions (e. g. isotropic media), due to the spatial specificity of the chiral substrate, and which might be useful as a tool in chiral microscopy. We will give an introduction, present and discuss the results we have obtained and conclude on each of the three subjects.

Chapter I: Hyperpositive Non-Linear Effects Today, the synthetic chemist has various ways to obtain enantioenriched chiral products: racemic synthesis followed by separation of the enantiomers, "chiral pool" synthesis starting from natural, enantiopure molecules, enantioselective synthesis using chiral auxiliaries, biocatalysis or enantioselective catalysis. The latter is the most elegant method: the chiral catalyst transfers its chiral information to the prochiral substrate and allows an enantioselective reaction with the reactant, followed by release of the enantioenriched product. The catalyst can then engage in a new catalytic turnover (Figure 2). It requires a catalytic amount of chiral auxiliary, in contrast to the stoichiometric enantioselective synthesis, and may avoid the multiple (de-)protection and functionalisation steps often needed when starting from a chiral pool.

In order to obtain the product with an optimal enantiomeric excess (ee), it seems logical to use an enantiopure catalyst. Equation (1) gives the linear relation between the product's enantiomeric excess (eeP), the ligand's enantiomeric excess (eeL, as we will consider only metallic catalysts with a chiral, organic ligand) and the maximal product enantiomeric excess which can be achieved for a given catalytic system (eemax).

𝑒𝑒 𝑃 = 𝑒𝑒 𝑚𝑎𝑥 • 𝑒𝑒 𝐿 (1)
Indeed, eeP is maximised if eeL = 1. If eeL is diminished, eeP decreases in a proportional, linear way.

It is only in the middle of the 1980's that the group of Henri Kagan became interested in verifying equation 1, suspecting that the relationship between eeP and eeL might be more complex in some cases. [4] At that time it was known that the relationship between a product's ee and some of its physical properties, such as fusion/boiling points, NMR spectra or the specific optical rotation, is not linear for certain compounds. [5] An impressive example is the optical rotary power of (S)-2-ethyl-2methyl-succinic acid whose optical rotation sign changes from + to -upon dilution in chloroform (Figure 3). This was suspected to be due to diastereomeric interactions: aggregates of the chiral molecule may have different physical properties than the discrete compound. In non-enantiopure mixtures, the association of enantiomers of the same (homochiral) or opposite sign (heterochiral) even gives rise to different aggregates which may have distinct physical properties and free energies of formation. Already in 1976, Wynberg and Feringa had followed up on the question whether a compound's ee influences not only its physical properties but also its chemical reactivity. [6] Indeed, they had found in a coupling reaction between chiral phenols that a racemic starting material had given different homocoupled products than an enantiopure starting material.

This prompted Kagan to investigate whether catalytic reactions might be influenced by the catalyst's ee. [4] It turned out that the asymmetric oxygenation of a sulphide and a Robinson annulation, using non-enantiopure catalysts, yielded a lower product ee than expected from equation (1). On the other hand, the Sharpless epoxidation of geraniol gave rise to a product ee higher than expected. These phenomena were called "Non-Linear Effects" (NLE) since their principal characteristic is the deviation from the linear equation ( 1). Thus, a deviation leading to higher eeP is called a positive non-linear effect ((+)-NLE, often coined as "asymmetric amplification") and to lower eeP negative non-linear effect ((-)-NLE, "asymmetric depletion"), see Figure 4. Following this pioneering work, lots and lots of examples of NLEs have been reported. [7,8] This introduction will focus on NLEs in metal-catalysed synthetic reactions; NLEs in kinetic resolution [9][10][11][12] and stoichiometric asymmetric synthesis [13][14][15][16][17] have also been studied but will not be discussed here. It should be noted that Langenbeck and Triem [18,19] theorised already in 1936 (!) the possibility of asymmetric amplification in catalysis, after having observed an inherent increase of optical activity in the addition of scalemic (-)-menthol to oxalyl chloride -50 years before Kagan's first paper on the subject.

I.1.2 Kagan's mechanistic models: ML2 and reservoir effect

How do those NLEs arise? Kagan and co-workers reported an extensive theoretical study [20] in 1994 which is, up to now, a major reference in the field. They rationalised the existence of NLEs by the catalyst not being a discrete metal complex but forming aggregates, such as dimers. For a scalemic mixture of the catalyst, the dimers can be homo-or heterochiral and may then differ in their physical properties like thermodynamic stability, catalytic kinetics or solubility. [20]

Figure 2: Concentration-dependent specific optical rotation of (S)-2-ethyl-2-methylsuccinic acid. [5] The ML2 model (Figure 5) consists in the chiral ligand (R or S) and the metal M being in fast exchange with complexes bearing one metal and two ligands (the same model holds for two metals and two ligands) which are the actual catalytic species -monomeric MR or MS complexes are not considered as catalysts. From the three possible ML2 species, two are homochiral and opposite enantiomer to each other (MRR and MSS) and therefore catalyse the formation of products with opposite configuration (with an ee of eemax or -eemax, respectively) and with the same kinetic constant (kSS=kRR). The heterochiral complex MRS is a racemic meso compound, diastereoisomeric to MRR and MSS, and thus it yields a racemic product (eemax = 0) with a kinetic constant kRS. The relative stabilities of hetero-to homochiral dimers are represented through the equilibrium constant K. For K = 4 there is a statistical distribution of homo-and heterochiral dimers; for higher K values the balance is tipped towards the formation of the heterochiral dimer, lower K values favour homochiral dimers. From these relationships they derived equation (2), which corresponds to equation (1) with an additional correction factor:

𝑒𝑒 𝑃 = 𝑒𝑒 𝑚𝑎𝑥 • 𝑒𝑒 𝐿 1 + 𝛽 1 + 𝑔𝛽 (2)
With β being the ratio of hetero-to homochiral dimers and g being their relative activities:

𝑔 = 𝑘 𝑅𝑆 𝑘 𝑅𝑅 (3)
𝛽 = 𝑧 𝑥 + 𝑦 (4)
With x, y and z as the concentrations of MRR, MSS and MRS, respectively. β can be further expressed as a function of K and eeL:

Kagan used the more general expression "ee auxiliary" (eeaux) for the catalyst's ee since this model can also be applied to enantioselective synthesis. As our work treats only of catalytic reactions with one (or several) chiral, organic ligand(s) bound to a metal, we will stick to the term eeL to describe the catalyst's ee.

From a qualitative point of view, a (+)-NLE arises when homochiral dimers catalyse faster than their heterochiral counterparts, therefore g < 1. This leads indeed to a correction factor > 1 in equation ( 2) and thus to a higher eeP. The smaller the g value, the stronger the (+)-NLE. With g > 1, the reaction is dominated by the racemic catalysis of the heterochiral dimer and eeP depletes, leading to a (-)-NLE. Both (-)-and (+)-NLEs can arise as long as heterochiral dimers are formed (β > 0). If this is not the case, then β = 0 and equation ( 2) turns back to equation (1). The higher β, and therefore the higher K, the stronger the NLE (negative or positive). (-)-NLEs take profit of a higher proportion of racemic catalysts, which depletes eeP even more; in (+)-NLEs a bigger heterochiral pool changes the MRR/MSS ratio to the advantage of the major enantiomer, leading to a stronger asymmetric amplification. The ML2 model can concord nicely with experimental results when choosing the appropriate K and g values. Nevertheless, this should be handled with care since guessed parameters don't necessarily represent the truth, nor does a spindle-shaped curve (as NLEs often are) necessarily follow the ML2 model.

Kagan extended the ML2 model to cases with higher aggregates (i.e., ML3 and ML4), which do not differ in their fundamentals but can result in more complex NLEs such as bell-or S-shaped curves; the mathematical expressions also become more complicated. A particular case of the ML3 model leading to hyperpositive NLEs will be discussed in chapter I.2.1.3. Kagan developed also a different (and simpler) model which is called the reservoir effect. It considers a part of the catalyst being inactive, "trapped" in a reservoir. If the reservoir's ee (eeres) is different from the active species' ee (eeeff cat), then an NLE occurs. Such a reservoir could consist e. g. of polymeric or insoluble heterochiral aggregates, leaving only homochiral aggregates in solution and leading to an amplification of eeP (Figure 6). The reservoir model is described by equation (6). Combination with equation (1) (eeL = eeeff L) gives an expression for eeP, given by equation (7):

𝑒𝑒 𝑒𝑓𝑓 𝐿 = 𝑒𝑒 𝐿 -𝛼𝑒𝑒 𝑟𝑒𝑠 1 -𝛼 (6)
𝑒𝑒 𝑃 = 𝑒𝑒 𝑚𝑎𝑥 𝑒𝑒 𝐿 -𝛼𝑒𝑒 𝑟𝑒𝑠 1 -𝛼

With eeeff L being the ee of the active catalyst, eeres being the ee of the resting catalyst in the reservoir, eeL being the overall catalyst ee and α the fraction of total catalyst which can be taken up into the inactive reservoir. Equation ( 7) doesn't model a whole NLE curve as equation ( 2) does, it rather gives a rough estimation of the downward slope at low eeL in (+)-NLEs or at high eeL in (-)-NLEs. It is supplemented by a horizontal line with eeP = eemax in (+)-NLEs or eeP = 0 in (-)-NLEs; the rough fit is due to α and eeres not necessarily being constant. Overall, it is much easier to handle than the ML2 model: if eeres is known, then α is obtained by solving equation (7) for α and using a couple of eeP vs eeL values lying on the downward slope of the studied NLE. Overall, the reservoir model is most interesting for extreme cases with eeres = 0 or 100% and high (> 0.9) α values, which result in NLE curves featuring almost two straight lines joint by a sharp bend.

I.1.3 The Noyori Model

In 1986 the group of Ryoji Noyori investigated the enantioselective addition of dialkylzincs to aromatic aldehydes catalysed by diaminoisoborneol (DAIB), a camphor-based chiral aminoalcohol. [21] The ligand doesn't only achieve impressive yields and enantioselectivities (up to 98% ee), but exhibits also a very strong (+)-NLE. With benzaldehyde and ZnEt2, they obtained a 95% ee product with an only 15% ee ligand (Figure 7). [22] This was the starting point for an extensive study [21][22][23][24][25][26][27][28][29][30][31][32] in which they investigated the reaction mechanism and proposed a model to explain the strong (+)-NLE. Similar (+)-NLEs were achieved later on with the morpholine-variant MIB [33] and a thiolated norphedrine derivative [34] for the same catalytic reaction.

Figure 7: (+)-NLE observed for the (-)-DAIB-catalysed enantioselective addition of dialkylzinc to benzaldehyde. [22] The proposed reaction mechanism is shown in Figure 8. In a first step, (-)-DAIB reacts with one equivalent of dialkylzinc to form a 5-membered zinc chelate, which is the actual catalytic species. In the second step, the aldehyde coordinates to the zinc atom and another molecule of dialkylzinc binds to the complex' oxygen atom. An alkyl transfer from ZnR2 to the aldehyde generates a chiral zinc alcoholate (which is also the rate-limiting step), which upon decoordination releases the complex for a further catalytic turnover. The chiral zinc alkoxide product forms stable cubic tetramers, which usually do not interfere in the catalytic cycle (product inhibition is possible under certain reaction conditions), [29] until acidic work-up generates the chiral alcohol. The (-)-DAIB-zinc chelate acts here as a bifunctional catalyst: the electronically unsaturated sp 2 -hybridized Zn atom is a Lewis acidic and the electron-rich oxygen a Lewis basic site. They both activate and bring into spatial proximity the aldehyde and ZnR2. In addition, the chiral environment of (-)-DAIB's camphor scaffold privileges the orientation of the aldehyde's Si-face towards the ZnR2 moiety (for (+)-DAIB it is the Re-face), thus causing enantioselection in the addition reaction. Dialkylzinc and benzaldehyde react only very slowly without ligand since the sp-hybridised unligated ZnR2 is apolar. The complex' bifunctionality has also another consequence: it can associate with another complex to form stable, coordinatively saturated dimers (Figure 9). Those dimers are catalytically inactive and act as resting species. The heterochiral dimer (RS) is much more stable than the homochiral ones (RR and SS), therefore the latter dissociates more easily to form the active monomer. [25] Since the minor enantiomer is completely incorporated into the heterochiral aggregates, the homochiral ones consist of only one enantiomer and high eeP values are achieved, even with a scalemic catalyst. This is somewhat related to Kagan's reservoir effect with the heterochiral dimers as an inactive reservoir (Figure 6). Kagan also applied a modified ML2 model on the DAIB system considering an irreversible dissociation of ML2 to ML species. [20] However, the zinc chemistry is known for fast and reversible coordination processes: neither the reservoir effect nor the modified ML2 model depict accurately this behaviour. To overcome these shortcomings, Noyori developed a complex mathematical model based on the various equilibria shown in Figure 9, expressed by equations ( 8)- (10): 8) and ( 9) cannot be combined to form an equation of type eeP = f(eeL), values for α have to be chosen arbitrarily to give paired values of eeP and eeL.

𝑒𝑒 𝑃 = 𝑒𝑒 𝑚𝑎𝑥 √𝛼 2 -4𝛽/𝛼 (8)
𝑒𝑒 𝑐𝑎𝑡 = (2𝛼 𝐾 ℎ𝑜𝑚𝑜 ⁄ ) + 1 + 𝐾 𝑎𝑠𝑠𝑜𝑐 [𝑅𝑒𝑎][𝑆𝑢𝑏]√𝛼 2 -4𝛽 [𝐶 𝑡𝑜𝑡 ] (9)
The approach of the Noyori model differs a lot from the ML2 model and is much more complex, which is well illustrated by equations ( 8)- (10). The active species is monomeric, not dimeric; the actual catalytic species is the zinc chelate bound to one molecule of substrate and reactant, not the zinc chelate alone. This makes the NLE a function not only of the dimer's dissociation constants (Khomo, Khetero) and the catalyst's enantioselectivity (eemax) but also of the substrate, reactant and total catalyst concentrations ([Sub], [Rea], [Ctot]) and of the association constant of the catalyst-substratereactant complex (Kassoc). Concretely, it means that substrate and reactant are not innocent: their concentrations influence the monomer-dimer equilibrium. The higher they are, the more free R and S-catalysts are consumed, the more the dimers (homo-as well as heterochiral ones) dissociate.

Another difference to the ML2 model is the lack of kinetic constants: the NLE results from "enantiomorphic" catalytic cycles, where the only catalytic species are enantiomers of each other. These differ in their respective amounts, which the model aims to quantify, but not in their kinetic behaviours. This is in sharp contrast to the ML2 model where the relative reactivities of homo-and heterochiral aggregates, expressed through the term g, are mainly responsible for the sign and the amplitude of the NLE; the catalytic cycles there are "diastereomorphic". The values given for Kassoc, KHomo and KHetero are those for the (-)-DAIB-ZnMe complex at 40°C. [29] The question of the substrate's influence on the NLE can also be extended to its electronic properties. Chen, Costa and Walsh observed consistently strong (+)-NLEs with electron-rich aldehydes using the DAIB-derivative MIB. [35] This was unexpected as electron-rich substrates should bind more strongly to the complex, thus driving the dimer's dissociation and depleting the (+)-NLE. This behaviour was later addressed by Buono, Walsh and Blackmond [36] who proposed an extension of the Noyori model: in the case of a slow dissociation of heterochiral dimers compared to the catalysis timescale, called "strong binding limit", even electron-rich substrates will only be catalysed by the homochiral pool.

I.1.4 The Soai autocatalytic system

Another catalytic system which has to be considered when dealing with NLEs and asymmetric amplification is the so-called "Soai reaction", which was first described by Kenso Soai and co-workers in 1995. [37] It has attracted the attention of many researchers and there are still articles regularly being published on this subject, more than 20 years later. It deals also with dialkylzinc chemistry but differs from the Noyori model as the reaction is autocatalytic: the reaction product, a pyrimidyl zinc alkoxide, catalyses its own production from the respective aldehyde and Zn(iPr)2 -with a strong (+)-NLE (Figure 10). The system relies on a chiral, not necessarily enantiopure, initiator to produce the first zinc alkoxide molecules, which will have a higher ee than the initiator. Then, they catalyse the production of further alkoxide molecules with again an increase in ee, and so forth. This continuously changing system is denoted as an "unstable equilibrium" or "far-from-equilibrium process". [38] In their first publication Soai and co-workers used 20 mol% of the pyrimidyl alkanol with 5% ee in toluene as initiator to obtain an overall product (which includes the initiator) of 39% ee. Successive runs with an enantioenriched initiator from the previous run lead to 76% and finally to 85% ee of the pyrimidyl alkanol product in the 3 rd run. Although the absolute values of ee and the asymmetric amplification are not spectacular -Noyori's DAIB shows a much stronger chiral amplification with ZnEt2, cf. Figure 7 -Soai recognised the system's potential and studied various derivatives of the pyrimidyl aldehyde. A breakthrough was the introduction of a tert-butyl-alkynyl group in position 2 of the pyrimidine moiety, which gave enantiopure products (>99.5% ee) when used as precursor (alkanol) and as substrate (aldehyde) in cumene as solvent. [39] A ridiculously low ee of ca. 0.00005 % for the pyrimidyl alkanol initiator was then sufficient to obtain >99.5% ee products over 3 consecutive steps (99% ee after two steps) in less than 24h per step. [40] Soai's group made then an extensive survey of chiral initiators over nearly two decades. [41] The incredible sensitivity of the tert-butyl alkynyl-substituted pyrimidyl aldehyde makes seemingly any kind of chirality sufficient to trigger the enantioselective autocatalysis and to end up with near to enantiopure products. Some examples are circularly polarised light, [42,43] enantiomorphic quartz crystals [44] and other inorganic and organic crystals, cryptochiral hydrocarbons (i. e. which are chiral but optically inactive) [45] or chiral isotopomers -compounds with a chiral centre whose substituents differ, in part, only by their isotopic composition ( 12 C/ 13 C, 16 O/ 18 O, 14 N/ 15 N, cf. Figure 10). [46] The pyrimidyl aldehyde is even able to perform absolute asymmetric autocatalysis without initiator (Figure 11). [47] The slow direct addition of Zn(iPr)2 to the aldehyde produces some first chiral zinc alkoxide molecules with an aleatory absolute configuration; the small initial statistical imbalance of R and S isomers is sufficient to trigger chiral amplification and to yield enantioenriched compounds.

Over 37 experiments, Soai's group obtained an approximately equivalent number of R-and Senantioenriched samples. Although the term "non-linear effect" almost never appears in the literature about the Soai reaction -he did only one NLE probe in his 1995 publication (Figure 12) -it is at the heart of its fascinating chiral amplification: autocatalysis alone doesn't induce any chiral enrichment.

Frank [48] already published in 1953 a theoretical study about autocatalysis and asymmetric amplification in which he pointed out the necessity for a "specific mutual antagonism", which is nothing but the formation of inactive heterochiral aggregates outlined later by Kagan. Without this antagonism, the initiator's ee is preserved instead of amplified. The advantage of autocatalysis is that it accelerates the catalytic reaction, which would otherwise take phenomenal amounts of time and even be slower than the achiral background reaction. The kinetic aspects of NLEs have been pointed out by Donna Blackmond: the lower eeL in a (+)-NLE, the more the catalyst is taken in inactive heterochiral aggregates, the slower the catalytic reaction. [49,50] The mechanisms behind the Soai reaction are still a subject of debate but kinetic, [51,52] computational, [53][54][55] and X-ray diffraction studies [56] point towards catalysis by a dimeric or tetrameric homochiral aggregate, while its racemic counterpart is inert due to a fundamentally different spatial orientation. Aggregates including the substrate, through formation of hemiacetals, are also under investigation. [57] I.1.5 Application and implication of non-linear effects

Apart fascinating the scientific community, NLEs have also found practical applications in chemistry, mostly in the investigation of reaction mechanisms. For example, Evans et al. developed a ML2-type nickel catalyst bearing two diaminocyclohexane (DACH)-based ligands for the enantioselective addition of malonates to nitrostyrene. [58,59] They found a linear relationship between eeP and eeL, suggesting that not the ML2-complex catalyses the reaction but a monomeric species with only one ligand (Figure 13a). A (+)-NLE evidenced the aggregation of a Cu(II)/DiPPAM-catalyst in the Figure 4: Measured NLE of the autocatalytic system with R = H (see Figure 10). [37] enantioselective 1,4-and 1,6-addition of ZnEt2 to cyclic enones (Figure 13b) where other analytical methods such as mass spectrometry, NMR and X-ray diffraction had failed. [60] Pollice and Schnürch applied the principles of NLEs to analyse catalysis using different (co-)catalysts or substrates, going beyond enantioselective reactions. [61] Another potential utility of (+)-NLEs is their use in asymmetric synthesis. If the catalyst or chiral reagent doesn't need to be enantiopure to perform high enantioselectivity, then the costs of its synthesis may be greatly reduced. An example is α-pinene, whose cheap 85% ee-version has been used in the reduction of an aromatic ketone in 95% eeP by the Merck laboratories in the USA. [13] Figure 13: Examples for NLE probes which have been used as tools in mechanistic studies: a) linear effect of the nickelcatalysed addition of diethyl malonate to nitrostyrene, [59] b) (+)-NLE of the Cu(II)/DiPPAM-catalysed 1,6-conjugate addition of ZnEt2 to an enone. [60] Though the presence of NLEs attests the formation of catalyst aggregates, it doesn't tell if the catalysis is performed by dimers (Kagan ML2 model) or rather by monomers (Noyori model). Both mechanisms give, for simple cases involving dimers, the same spindle-shaped graphs. Noble-Terán et al. developed a system based on reaction kinetics to discriminate between dimer and monomer catalysis depending on the presence and the nature of the NLE, the reaction speed depending on eeL, the variation of eeP as a function of [Ctot], the catalyst and the substrate kinetic order. [62] From this they constructed a working decision table (Figure 14) which relates the results from a couple of simple experiments to one of the cases predicted by the authors, involving catalysis by dimers or monomers. Prior to this, the dependence of the nature of the NLE and of the reaction rate had been investigated by Blackmond. [49,50] She developed kinetic models derived from the ML2 model which serve as an additional verification for the validity of the ML2 model on a studied NLE.

a) b)

Figure 14: Working decision table for an easy discrimination between monomeric and dimeric catalysis. [62] It relates the presence of a NLE (asymmetric amplification, attenuation, no NLE), evolution of the reaction half-time (t1/2) when decreasing eeL, the catalyst kinetic order, evolution of eeP with the catalytic charge (r0) and the substrate kinetic order.

It is also important to note that NLEs may occur without catalyst aggregation, in a very particular case. Kalek and Fu [63] investigated kinetic resolutions where the catalyst first converts the racemic starting material into an achiral intermediate and then into an enantioenriched final product, without the starting material being subject to racemisation (Figure 15a). These reactions exhibit an intrinsic (-)-NLE which arises purely from the reaction kinetics and not from aggregation phenomena. The NLE's amplitude depends strongly on the conversion (in the initial stage of the reaction, almost no NLE is observed) and on the selectivity factor s, which is the kinetic ratio between the catalyst's association with one or the other starting material enantiomer (Figure 15b).

I.1.6 Biological homochirality

Although non-linear effects are of great utility in synthesis and mechanistic investigations, their most fascinating contribution lies in a much more fundamental subject: the origin of biological homochirality. It is well-known that building blocks of life such as sugars and amino acids are chiral.

a) b)

Of the two possible enantiomers for each molecule, only one (with few exceptions) is used in Nature: D-sugars in polysaccharides and nucleotides, L-amino acids in proteins (Figure 16). This is the reason why the enantiomers of chiral molecules bear different properties when subjected to living organisms: (-)-carvone smells like mint while the (+)-enantiomer has a smell of caraway; (+)thalidomide cures morning sickness while (-)-thalidomide causes birth defects. More than an curious outcome of evolution, the homochirality of biochemical systems is believed to be necessary for biomolecules to form higher-order aggregates [64] and oligomers [65,66] with a well-defined threedimensional structure [67] without they cannot perform their biochemical functions. If amino acids had not all the same spatial configuration, well-defined secondary structures like α-helixes and β-sheets could not be formed. The homochirality of sugars makes DNA strands always twisted in the same way, allowing the formation of stable double-strands. In a general sense, the spatial specificity of homochiral molecules allows a more efficient encoding of information [67] and is moreover responsible for the extremely efficient electron transfer in proteins. [2] Therefore, homochirality is at the origin of life itself. Although our world is mostly governed by symmetrical laws, there must have been a symmetrybreaking event that tipped the balance towards one of the two enantiomers of a given substance pool -let it be sugars or amino acids. [68] There are several theories how this could have happened (see below), however, in all cases the generated ee is very small and cannot account for the total disappearance of the minor enantiomer. This is where asymmetric amplification comes into play: a reaction including a strong (+)-NLE could have amplified this small ee and led to today's homochirality in the biosphere (Figure 17). This subject is often mentioned in the context of the Soai reaction due to its phenomenal amplification power, although the reaction itself cannot have happened in aqueous conditions.

Figure 17: Scheme for the rise of biological homochirality through a symmetry-breaking event followed by asymmetric amplification.

The way how the origins of homochirality and of life are connected is a fascinating and broad subject, which has been discussed in various reviews, [38,[68][69][70][71] which spans over a multitude of disciplines (catalysis, materials and surfaces chemistry, theoretical physics…) and which we can address here only briefly. The basics behind the symmetry breaking event have been under debate for decades: is today's homochirality predetermined by physical laws, since the electroweak interaction is inherently asymmetric and results e.g. in D-sugars and L-amino acids being slightly more stable than their enantiomers, [72][73][74] or is it the result of coincidence? The Soai reaction shows that, out of local statistical fluctuations, enantiomeric enrichment can be achieved without any source of asymmetry. Same goes for enantiomorphic NaClO3 crystals or racemisable organic molecules crystallising as conglomerates, which lead randomly to a single enantiomorph/enantiomer when subject to attrition ("Viedma ripening", Figure 18). [69] A random local symmetry break on earth or in space, coupled with asymmetric amplification, might then have led to today's homochirality, but it could have as well resulted in the opposite sugar and amino acid enantiomers being the bricks of life ("frozen accident" scenario). Circularly polarised light [75] (which is emitted by certain stars, but which applies also to sunlight reaching earth at dawn and dusk), [76] selective adsorption on chiral crystalline surfaces like on quartz or sodium perchlorate [77] or earth's rotary motion [78,79] might also have served as a local source of asymmetry, followed by asymmetric amplification. A big question is also the role of (pre-)biotic systems in the asymmetric amplification process: did the first biomolecules arise from an already enantiopure pool, or did enantioenrichment happen during the emergence of biomolecules and -systems? Homochiral oligomers (peptides, small nucleotide strands) are not only more stable than heterochiral ones, they also catalyse the formation of complementary strands having only the same chirality, therefore the emergence of homochirality may be the result of a sort of natural selection [70] -in other words, homochirality arose when it was needed.

Figure 18: Schematic representation of Viedma ripening. [69] Continuous attrition makes larger crystals grow at the expense of smaller crystals, leading randomly only to R-or S-crystals through statistical imbalances. The product has to crystallise as a conglomerate of R-and S-crystals to perform this, not as a racemate or an achiral crystal. However, the molecule in itself can be achiral (e. g. NaClO3) or a racemisable chiral compound (e. g. certain amino acid derivatives).

I. Ephedrine is an alkaloid (naturally occurring in plants of the ephedra type) which has been used a lot as medication against asthma, nasal congestion, narcolepsy, hypotension and other pathologies. Same goes for its diastereoisomer pseudoephedrine and their variants without N-methyl group, distinguished by the "nor" prefix in their names (Figure 19). Nowadays, these molecules are less used in medicine because of their various side effects, which include high blood pressure, stroke, heart attacks but also psychotropic effects. Ephedrine is easily converted into desoxyephedrine, better known as methamphetamine ("crystal meth"), an illegal drug. Thus, its commercialisation and that of the other ephedrine derivatives obey to strict regulation in most countries. Apart from their pharmaceutical applications, ephedrine-type molecules are also used as chiral scaffolds in organic synthesis [START_REF] Soai | Encyclopedia of Reagents for Organic Synthesis[END_REF] and coordination chemistry [START_REF] Contreras | [END_REF] and have been studied as a chiral auxiliary in asymmetric synthesis [82] and catalysis, [83] notably in the addition of dialkylzinc reagents to aromatic aldehydes (Figure 20). Their β-aminoalcohol scaffold promotes a similar catalytic action to Noyori's DAIB. Among the most active and selective ligands are di-nbutyl-and cyclic -(CH2)4substituted norephedrines, which catalyse the addition of ZnEt2 to aromatic and also aliphatic aldehydes in up to 95% product ee. [84][85][86] Increasing or decreasing the length of the N-alkyl chains results in a loss of selectivity and, in some cases, of catalytic activity. Another important effect is the substitution of the aminoalcohol's oxygen atom by sulfur: ees consistently higher than 90%, again with n-butyl or cyclic alkyl substituents on nitrogen, have been achieved in the addition of ZnEt2 to a large variety of aromatic or aliphatic aldehydes. [87,88] Even thioester derivatives give consistently high ees. [89] Figure 20: Some of the most selective ephedrine-type ligands in the asymmetric addition of ZnEt2 to aldehydes.

Figure 21: NLE curves of N-methyl ephedrine (NME) and its thiolated derivatives NMED and NMET.HCl in the enantioselective addition of ZnEt2 to benzaldehyde. [90] There have been only few mechanistic studies on ephedrine-mediated additions of dialkylzinc; most proposals simply follow Noyori's mechanism for DAIB. The thiol derivatives have received more attention due to their exceptionally high enantioselectivity and have also been checked for NLEs. Fitzpatrick and co-workers [90] found for N-methyl ephedrine (NME) an "essentially linear relationship" between eeL and eeP and a moderate (+)-NLE for some thiol derivatives (Figure 21). Cryoscopic weight measurements of NME and NMET.HCl gave molecular weight (MW) values beyond those of simple dimers, indicating that the zinc complexes form tri-or tetramers; extra ZnEt2 breaks those aggregates down into monomers. They claimed that the sulfur derivatives tend to higher-order and more stable aggregates due to the higher polarizability of the sulfur atom and to the sulfur-bound zinc's higher Lewis acidity. However, this assumption should be treated with care since it relies only on information about the homochiral species.

Figure 22: NLEs of N-piperidinonorephedrine ligand (dashed line) and its thiol derivative (full line). [34,91] Another study was made by Kang. [34,91] (1R,2S)-N-piperidinonorephedrine showed a moderate (+)-NLE while its thiolated version gives a very strong asymmetric amplification similar to DAIB (Figure 22). They determined the ΔGHomo and ΔGHetero values [which are related to KHomo and KHetero through ∆𝐺 = -𝑅𝑇𝑙𝑛(𝐾)] of the corresponding ethylzinc complexes, also through cryoscopic weight measurements. Although they found the heterochiral dimers to be more stable than their homochiral counterparts, the difference (1.12 kcal/mol) is not sufficiently high to explain the thiolated ligand's strong (+)-NLE -it is even smaller than for the oxygen-containing ligand (1.60 kcal/mol). This also doesn't concord with the high ΔGHetero/ΔGHomo difference of DAIB (4.78 kcal/mol).

The measured MW values didn't indicate the presence of aggregates higher than dimers, however they worked at lower concentration than Fitzpatrick. Investigation of the zinc complexes' coordination behaviour showed also that the zinc thiolates have a higher affinity for ZnEt2 than the zinc alkoxides; the latter coordinate preferentially to benzaldehyde, indicating that not the zinc thiolates but the zinc alkoxides are the better Lewis acids. In summary, both studies show that substitution of oxygen by sulfur is not only beneficial for the enantioselectivity but also for the emergence of (+)-NLEs, but the reason for this is unclear. Kang proposed the homochiral zinc thiolate dimers to catalyse the reaction, with a higher rate than all other zinc thiolate and alkoxide species, without showing any evidence for this.

I.2.1.2 NLEs of alkylated and unsubstituted ephedrine

Following the weak knowledge of NLEs with ephedrine-type ligands, we decided to make our own investigation and to check a variety of ephedrine derivatives for the presence of NLEs in the asymmetric addition of ZnEt2 to benzaldehyde. N-Methyl ephedrine (NME), N-nbutyl ephedrine (NnBE) and N-benzyl ephedrine (NBE) were easily obtained from (1R,2S)-(-)-ephedrine via Eschweiler-Clarke methylation [92] and nucleophilic substitution on bromobutane [93] or benzyl bromide, [94] respectively (Figure 23). We then fixed our experimental conditions: 0.93 M benzaldehyde in toluene as the solvent, 20 mol% catalyst, 1.2 equiv. ZnEt2. The standard in ephedrine-catalysed reactions is to use excess ZnEt2 (2-4 equivalents) since it has been reported to enhance the product ee (eeP), [95] but it also drives the dissociation of catalyst aggregates according to the Noyori model. Therefore, we chose to work with only 1.2 equivalents, from which 0.2 first react with the ligand to form the catalytically active complex. The reaction temperature was fixed at 0 °C to minimise the achiral background reaction [96] and the formation of the side-product benzyl alcohol. [23] The ligand ee was adjusted by mixing appropriate amounts of both enantiomers; each reaction was performed in triplicate, analysed via chiral stationary phase GC and the mean eeP value used to build the NLE curves. The standard deviation is mostly within ±0.5% ee and in most cases too small to be properly displayed with error bars.

The results for ephedrine, NME and NnBE are shown in Figure 24. The methyl-and nbutyl-substituted ligands show a linear relationship between eeP and eeL, whereas unsubstituted ephedrine exhibits a weak (-)-NLE (blue dots). The absence of NLE for NME is consistent with the previous report by Fitzpatrick and co-workers. [90] The (-)-NLE with ephedrine may indicate a greater stability of homochiral dimers compared to their heterochiral counterparts, which can be due to additional Hbonding by the NH-group on ephedrine. The lack of an acidic hydrogen on the zinc alkoxides of NME and NnBE prevents them from making H-bonds. The maximum eeP values are almost the same (NnBE: 66%, ephedrine: 67%, NME: 68% ee) for the three catalytic systems and are close to previous reports under similar conditions in the case of ephedrine (66% ee) and NME (64% ee, 5 mol% catalyst used). [97] Only NnBE has been reported to give a higher eeP of 73% using 3 equiv. ZnEt2 in a hexanetoluene mixture and 10 mol% ligand. [98] Figure 24: Observed NLEs using ephedrine, NME and NnBE as ligands in the enantioselective addition of ZnEt2 to benzaldehyde.

I.2.1.3 NBE ligand: Hyperpositive NLE

We then moved on to N-benzyl ephedrine (NBE), which shows a dramatically altered picture (Figure 25). Variation of eeL leads to a very strong (+)-NLE, eeP stays high down to an eeL of only 3%. There is, to the best of our knowledge, no precedent for a NLE with such a strong amplitude. Even more interesting is the shape of the curve: starting at 76% eeP with the enantiopure ligand, eeP increases to 81% when lowering eeL to 10-20%. The scalemic, enantioimpure catalyst leads to a more enantioselective reaction than the enantiopure one! As for the previously tested ephedrine ligands, the standard eeP deviation is negligible except for very low eeL values (cf. error bars in Figure 25), therefore the eeP increase (ΔeeP) of 5% is significative.

We switched then from ZnEt2 to ZnMe2 as the dialkylzinc reagent, using the same reaction conditions as before (only the benzaldehyde conc. was decreased slightly to 0.83 M). The reaction resulted into a spectacular increase of ΔeeP, the NLE curve resembles now an exponential function down to 5% eeL (Figure 26). The enantiopure ligand yields a very poor eeP of 16% but increases up to 53% at 5% eeL!

R = Me

Δee P = 37%

To the best of our knowledge, there is no experimental precedent for such a behaviour in asymmetric catalysis. However, there is a theoretical one: Henri Kagan discussed the possibility of an eeP increase while lowering eeL using the ML3 model and named it a hyperpositive non-linear effect. [20] As mentioned in the introduction (I.1.2, p. 14), the ML3 model is close to the ML2 model but bears also some differences (Figure 27). As in the ML2 model, monomers do not catalyse; the catalytic aggregates are trimers, which results in four different catalytic species: the homochiral trimers MRRR and MSSS and the heterochiral trimers MRRS and MSSR. In contrast to the ML2 model the two heterochiral aggregates are not achiral meso compounds but are enantiomeric to each other and catalyse the reaction with the enantioselectivity eemax(Hetero). In case where the heterochiral trimer is more selective (eemax(Hetero) > eemax(Homo)) and also faster (g > 1), eeP necessarily increases when lowering eeL as shown in Figure 28. When comparing the graphics in Figure 25, Figure 26 and Figure 28 it becomes clear that the hyperpositive NLEs with NBE as chiral auxiliary do not follow the ML3 model -the shape of the curves is totally different. Indeed, a system following the ML3 model can be hyperpositive only in the upper half of the eeL scale ("ee auxiliary" in Figure 28), whereas the maximum eeP is attained with only 5% eeL in Figure 26. Therefore, the mechanism behind NBE's hyperpositive NLE must be different.

The aim of the work presented in this chapter will be to identify and understand the causes of this hyperpositive NLE. In the following, we will make a mechanistic study and propose a model which explains NBE's behaviour in asymmetric catalysis. ). [20] I.2.2 Hyperpositive NLE: mechanistic study

MRRS MRRR

I.2.2.1 Catalyst loading

An additional observation we made when performing the experiments from Figure 25 and Figure 26 is the formation of a precipitate upon addition of ZnMe2 or ZnEt2 to scalemic NBE ligand (Figure 29). Solutions with enantiopure NBE stay clear, at 80% eeL a slight haze appears and at lower eeL the precipitate is thick and well-visible; it persists over the whole course of the reaction. The reaction becomes also much slower at low eeL: with ZnEt2, the yellow colour indicating the presence of free benzaldehyde vanishes after a couple of hours at high eeL but persists even after overnight stirring for eeL < 20%. Reactions with ZnMe2 and enantiopure ligand reach 70-80% conversion after 3 days, with 5% eeL and lower 40-50% conversion is observed after 4 weeks. It seems obvious that the precipitate is an insoluble heterochiral aggregate of the zinc aminoalkoxide, which does not exist in enantiopure samples. Filtration of a 50% eeL sample with ZnMe2 (same conditions as for catalytic runs, without addition of benzaldehyde) and subsequent hydrolysis in HCl/acetone yielded indeed the NBE ligand in its racemic form, as seen in polarimetry measurements. This is a classic example for Kagan's reservoir effect where only the major enantiomer catalyses because of an insoluble heterochiral aggregate (see Figure 6, p. 17); some examples of (+)-NLEs induced by racemic precipitates [99][100][101][102][103][104][105][106][107] and nonracemic insoluble aggregates [108] are known. It is also consistent with the observed reaction times: the lower eeL, the less active catalyst is in solution and the slower the reaction becomes. The precipitate could be a heterochiral dimer, a conglomerate of enantiopure R-and S-complexes or of heterochiral trimers: co-crystallising RRS and RSS trimers would also lead to an overall racemic precipitate. Zinc aminoalkoxides have been reported to form tri-and even tetramers. [90,[109][110][111] For convenience, we will treat the precipitate as a heterochiral dimer in the following discussion.

The reservoir effect explains the emergence of a (+)-NLE but not of a hyperpositive one. We soon came up with the idea that the hyperpositive eeP increase with decreasing eeL might be correlated with the decrease of catalyst concentration: the lower eeL, the lower the catalyst concentration, the higher eeP. Aggregation is a parameter affected by concentration; we also have to assume that NBE-ZnMe probably forms a homochiral dimer (or higher aggregate) in addition to the insoluble heterochiral one, similar to DAIB. If the homochiral aggregate is catalytically active, in addition to the monomer, and gives a different eeP, then the overall eeP should be strongly affected by the catalyst concentration. The reaction outcome would then be the result of two different catalytic cycles, one catalysed by the monomeric species, the other by the homochiral dimer. The latter being less enantioselective than the monomeric catalyst would explain the hyperpositive NLE: at high eeL the overall catalyst concentration is high, therefore the equilibrium shifts to the dimer and the overall eeP decreases (Figure 30). To check this hypothesis we performed the catalytic reaction with enantiopure (-)-NBE and varied the catalyst loading; the other reaction conditions were left unchanged. The results are shown in Figure 31. Indeed, we observe an eeP increase as the catalyst loading is decreased from 20 to 2.5 mol%: the eeP increases only slightly with ZnEt2 (76 to 84% ee) and in a much more pronounced way with ZnMe2 (16 to 49%). The increase is non-linear and fits best to a 2 nd order polynomial trendline in both cases, which we have drawn in Figure 31 (orange dotted line). We have added the trendlines here just for illustration purposes, however we will have a use for them in the application of Kagan's reservoir effect in chapter I.2.3.1. As the curvatures of the two plots look quite similar to those of the hyperpositive NLE curves in Figure 25 and Figure 26, we decided made a superimposition the catalyst loading screening and the hyperpositive NLE. This is possible since we can convert the "catalyst loading" axis in Figure 31 to an "eeL" axis if we consider that the heterochiral aggregate fully precipitates. For example, the eeP of a reaction with 20 mol% and 50% eeL (half of the catalyst has precipitated) must be equivalent to one with 10 mol% (half catalyst loading) of an enantiopure ligand. This way, the catalyst loading curve is changed into a simulated NLE curve. Figure 32 shows the superimposition of the hyperpositive NLE (blue dots) and the converted catalyst loading screening (orange squares). The match between both curves is excellent, as well with ZnEt2 as with ZnMe2. The catalyst loading screening models accurately the eeP evolution between eeL = 100% and the hyperpositive NLE's maximal eeP. The latter is probably the point where the major catalyst enantiomer's concentration is sufficiently low for the minor's concentration to become significant, so eeP decreases beyond that point when eeL is further lowered. The excellent fit of both curves supports our theory of the eeP increase being a function of the catalyst concentration, which is itself a function of eeL due to heterochiral aggregate precipitation. In addition, we made a series of experiments where the overall benzaldehyde/ZnR2-concentration is varied, while keeping the catalyst loading constant (Figure 33). As in the catalyst loading screening, eeP increases at lower overall concentration. However, the overall concentration affects the concentration of all the components at the same time, therefore it is difficult to conclude on these results.

I.2.2.2 Reaction temperature

Aggregation is a phenomenon sensitive not only to concentration but also to temperature: the dissociation of dimers is entropically favoured and thus driven by an increase in temperature. An example for this is the Soai autocatalytic reaction which becomes slower with increasing temperature, due to a dissociation of the catalytic aggregate. [52] Therefore, we performed a temperature screening of the catalytic reaction with 20 mol% of an enantiopure and of a 20% ee ligand, under otherwise unchanged conditions (Figure 34).

The system using ZnMe2 and enantiopure ligand (Figure 34b, blue dots) shows an impressive eeP increase from 16% at 0°C to 44% at 60 °C; with the scalemic ligand (orange dots) a slightly less pronounced eeP increase takes place. With ZnEt2 and enantiopure ligand (Figure 34a, blue dots) eeP stays constant around 76% ee; the scalemic ligand (orange dots) shows an eeP decrease above 0°C, falling below the blue line at 60 °C -the NLE is not hyperpositive anymore at this point.

Usually, eeP decreases with increasing temperature, since the difference between the kinetic barriers leading either to R-or S-product becomes smaller; this is the reason why asymmetric catalysis is often performed at low temperature. The results shown here are clearly the consequence of a change of the active catalyst. It is also coherent with our hypothesis developed in I.2.2.1: at high temperature the homochiral dimers would break up to the monomeric and more enantioselective catalyst, therefore the overall eeP would increase. The increase with 20% eeL in Figure 34b is lower than with 100% eeL probably because the homochiral dimers are already partly broken up; an increase of the heterochiral aggregate's solubility has also to be taken into consideration. With ZnEt2 and 100% eeL (Figure 34a), the eeP-gain might be smaller and therefore just enough to compensate the usual eeP decrease, leading to an almost constant eeP at 76%; with the scalemic catalyst the eeP decrease is not compensated anymore.

I.2.2.3 Mass spectrometry

Next, we sought to gather more information about the catalytic NBE-zinc complex and its homochiral aggregate, as we presume it also to be catalytically active. We didn't succeed in obtaining a crystal structure from enantiopure NBE-ZnMe so far (same goes for racemic NBE-ZnMe) but we could obtain some results from electrospray ionisation mass spectrometry (ESI-MS): two sets of peaks were identified to correspond to monomeric (Figure 35) and dimeric (Figure 36) NBE-ZnMe, both monoprotonated. The latter is a homochiral dimer since the sample was made from enantiopure (-)-NBE. The experimental spectra fit excellently to the simulated isotopic patterns. Since the sample is heated to 180 °C during the injection it is not self-evident to observe adducts originating from weak interactions like coordination bonds. This is a first proof for NBE-ZnMe forming a homochiral dimer, however it is not representative for the complexes' behaviour in solution. Therefore, we went on to analysis of NBE-ZnMe in solution by 1 H DOSY NMR.

I.2.2.4 1 H DOSY NMR

1 H DOSY NMR measures the diffusion coefficient (D) of the solubilised analyte which can be related to its volume or its molecular weight (MW). This allows us to work in conditions much closer to the catalytic reactions, namely in solution, at the same temperatures and in presence of reactant and/or substrate. We used Stalke's External Calibration Curves (ECC) to relate the measured diffusion coefficient to MW values. [112][113][114][115] A detailed explanation of the methodology and why it is our method of choice can be found in the supporting information, p. 161.

(a) 1 H NMR of NBE-ZnMe

For the analysis of the NBE zinc aminoalkoxide issued from ZnMe2 (NBE-ZnMe) we chose to work in the same conditions as in the catalytic runs for the temperature screening (0.83 M ZnMe2 and 20 mol% NBE-ZnMe) in toluene-d8, at temperatures from -20 to 60 °C. The 1 H NMR spectra (Figure 37) gave broad peaks at 25°C and higher (red spectrum), which can be easily attributed to the NBE-ZnMe complex. At lower temperature the peaks sharpen and new peaks appear, at -20°C the spectrum becomes extremely complex (blue spectrum). However, nearly all the peaks are correlated to a single D value: the exchange between the different species is too fast for the DOSY NMR timescale, therefore only mean D values were obtained. 1 H ROESY NMR confirmed the presence of several, interconverting species. The 1 H NMR spectrum's complexity at -20 °C is not surprising: the monomeric complex exists as a pair of diastereoisomers since the N atom becomes chiral upon coordination to zinc; the complexes may be coordinated to the excess ZnMe2 or not; and finally, NBE-ZnMe and its expected dimer probably have a different set of signals. In addition, we analysed also a sample in which one equivalent of benzaldehyde was added to be closer to the conditions of the catalytic reactions. We could analyse it only at low temperature (-20 to 40 The results from the DOSY experiments are summarised in Figure 38. At any temperature, the measured mean MW without benzaldehyde (orange dots) are clearly above the value of monomeric NBE-ZnMe; at 60°C, the measured value of 474 g/mol is close to the MW of the NBE-ZnMe-ZnMe2 complex but still above. In presence of benzaldehyde (grey dots) the overall MW is lower but still well above the values for NBE-ZnMe and also of the ZnMe2-benzaldehyde adduct (536 g/mol). In both cases, the mean MW decreases with increasing temperature, confirming the presence of homochiral aggregates which dissociate upon increase of the temperature. The absolute MW values of Figure 38 are all between the values for a monomeric and the heaviest possible dimeric NBE-ZnMe complex (bound to ZnMe2 or ZnMe2+benzaldehyde, respectively), except those at -20°C which are even higher (Table 2). This is interesting as it implies higher-order aggregates such as trimers, which have been excluded in the Noyori model for DAIB. On the other hand, this is consistent with the work of Fitzpatrick et al. where they claim to have found aggregates up to tetramers with the ZnEt complex of N-methyl ephedrine. [90] Complex (c) NBE-ZnMe-mimics: synthesis and 1

H DOSY NMR-analysis

To check the validity of Stalke's methodology we synthesised molecules 1 and 2 (Figure 39). They are designed to mimic NBE-ZnMe's shape (same five-membered ring, same substituents and spatial configuration on the carbon backbone) but without being able to aggregate via coordination bonds like zinc aminoalkoxides do. The compounds were analysed in 1 H DOSY NMR in the same conditions as NBE-ZnMe (0.17 M, toluene-d8, various temperatures). The DSE-ECC gave the best results and confirmed our choice for its use with NBE-ZnMe. Figure 40 shows the deviation of the measured MW from the calculated MW (MWdev). The results fit excellently at rt and higher (MWdev < 4%) but at lower temperatures the molecules' MW is overestimated, by 8% for 1 and by 18% for 2 at -20°C. Given the fact that 2 bears one aromatic ring more than 1, the deviation most probably results from π-interactions with the solvent (solvation sphere) or between analyte molecules (intramolecular aggregation). NBE-ZnMe and its aggregates also bear two aromatic rings per ephedrine unit, plus one if benzaldehyde is coordinated. Even though the data in Figure 38 is sufficient to conclude qualitatively that NBE-ZnMe indeed does form homochiral aggregates and that those dissociate at higher temperatures, the absolute measured MW values may not necessarily reflect the real monomer-dimer distribution; especially the conclusion on trimers at low temperature is questionable and should be verified by further experimental work. We also tried to synthesise boron complexes of NBE but without success; other complexes, based on zinc and bidentate and tetradentate ligands gave overestimated MW values in DOSY NMR, probably due to aggregation. We will not discuss these results here, but they can be found in the Supporting Information (V.2.1, p. 166).

I.2.2.5 Kinetics

To gain further insight into the NBE-catalysed addition of dialkylzincs to benzaldehyde, we decided to investigate the reaction's kinetic behaviour. Conversion vs time-and eeP vs time-plots can give valuable information about a reaction's underlying mechanics. The present study will first focus on the determination of the catalyst's partial order c and then examine the evolution of eeP over time.

(a) Partial catalyst order and aggregation

In general, the rate of catalysed reactions can be described by equation (11):

𝑑[𝑃𝑟𝑜𝑑] 𝑑𝑡 = -𝑑[𝑆𝑢𝑏] 𝑑𝑡 = 𝑘 𝑜𝑏𝑠 [𝐶𝑎𝑡] 𝑐 [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 (11)
With [Prod] being the product concentration, [Sub] the substrate concentration, [Rea] the reactant concentration, [Cat] the catalyst concentration, kobs the observed kinetic constant, x the partial substrate order, y the partial reactant order and c the partial catalyst order.

Equation ( 11) is true for simple catalytic reactions but can change for more complex ones. If e. g. the reaction product inhibits the reaction, then an additional "[Prod] P " term appears on the right side of equation (11), with the partial product order P < 0.

[Prod], [Sub] and [Rea] change over the course of the reaction; the other variables usually are constants but this may also not be true for all catalytic systems. Especially the partial orders are interesting: they reflect the number of molecules involved in the rate-determining step, e. g. a reaction where two catalyst molecules intervene simultaneously will have c = 2. However, the measured catalyst order can differ much if the catalyst is involved in other processes for which equation (11) does not account for. Those can be aggregation, deactivation by an impurity and others; there are even general methods to analyse changing catalyst or reactant orders ("elasticity coefficient"). [116] An example for a changing partial order in catalyst c is shown in Figure 41: Bures et al. investigated the effect of [Cat] on c in a Pd-catalysed cross-coupling reaction. [117] At low [Cat] c is close to 1, which reflects the mechanism of the Heck reaction where only one Pd moiety is involved. However, at higher [Cat] c drops to 0.55. This is due to the palladium complex aggregating to a catalytically inactive dimer: the higher [Cat], the higher the fraction of inactive catalyst. Since the effective [Cat] is lower than the initial [Cat], which is used in equation (11), c decreases to compensate for this discrepancy. -dependent change in catalyst order due to aggregation of the Pd-catalyst to an inactive dimer, in a Pd-catalysed Heck coupling. [117] Since our system with NBE does also deal with catalyst aggregation, we decided to investigate its catalyst order c by varying [Cat]. The kinetics of DAIB have been shown to follow equation ( 11) (except at high [Sub] and [Rea], where x = y = 0 because the catalyst is saturated in Rea and Sub; the reaction rate then depends only on the concentration of the catalytic Cat-Sub-Rea adduct) and should be applicable to NBE.

(b) Theoretical model

Prior to the experimental determination of kinetic profiles, we developed a simple theoretical model to describe the kinetics of a reaction which is catalysed by both a monomeric and a dimeric catalyst. We will consider the case of homochiral (-)-NBE where two different species catalyse: the monomeric complex NBE-ZnMe and its dimeric aggregate. The concentration of both is given by [R] and [RR], respectively. We can consider two extreme cases where only [R] or only [RR] catalyse:

-𝑑[𝑆𝑢𝑏] 𝑑𝑡 = 𝑘 1 [𝑅] 𝑐 1 [𝑆𝑢𝑏] 𝑥 1 [𝑅𝑒𝑎] 𝑦 1 (12) -𝑑[𝑆𝑢𝑏] 𝑑𝑡 = 𝑘 2 [𝑅𝑅] 𝑐 2 [𝑆𝑢𝑏] 𝑥 2 [𝑅𝑒𝑎] 𝑦 2 (13)
With x1, y1, c1 and k1 being the partial orders and the kinetic constant of the monomer-catalysed reaction and x2, y2, c2, and k2 those of the dimer-catalysed one. From a practical point of view, equation ( 12) could be valid only at very low catalyst concentration and/or high temperature (only Inactive monomers present) and equation (13) in the opposite conditions -very high catalyst concentration and/or low temperature. The conditions in which we worked so far are intermediate, [R] and [RR] are simultaneously present and catalyse both. The reaction's kinetics are then described by a combination of equations ( 12) and ( 13):

-

𝑑[𝑆𝑢𝑏] 𝑑𝑡 = 𝑘 1 [𝑅] 𝑐 1 [𝑆𝑢𝑏] 𝑥 1 [𝑅𝑒𝑎] 𝑦 1 + 𝑘 2 [𝑅𝑅] 𝑐 2 [𝑆𝑢𝑏] 𝑥 2 [𝑅𝑒𝑎] 𝑦 2 (14)
For the next step we will make an assumption: the inherent mechanism of both monomer-and dimer-catalysed reactions is similar and therefore also the nature of their rate-limiting step (similar to DAIB, see Figure 9). In this case, x1 = x2 = x, y1 = y2 = y and c1 = c2 = c. k1 and k2 can but don't need to be equal, therefore we will treat them separately. Equation ( 14) then becomes equation ( 15): (17), assuming that no higher aggregates than dimers exist in solution.

-𝑑[𝑆𝑢𝑏] 𝑑𝑡 = (𝑘 1 [𝑅] 𝑐 + 𝑘 2 [𝑅𝑅] 𝑐 )[𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 (15)

𝑎 = [𝑅] [𝐶𝑎𝑡 𝑡𝑜𝑡 ]

(16)

[𝐶𝑎𝑡 𝑡𝑜𝑡 ] = [𝑅] + 2[𝑅𝑅] (17)
Using equations ( 16) and (17) we can now eliminate [R] and [RR] from equation (15), giving equation ( 18):

-𝑑[𝑆𝑢𝑏] 𝑑𝑡 = (𝑘 1 (𝑎[𝐶𝑎𝑡 𝑡𝑜𝑡 ]) 𝑐 + 𝑘 2 ( (1 -𝑎) 2 [𝐶𝑎𝑡 𝑡𝑜𝑡 ]) 𝑐 ) [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 ⟺ -𝑑[𝑆𝑢𝑏] 𝑑𝑡 = (𝑘 1 𝑎 𝑐 + 𝑘 2 ( (1 -𝑎) 2 ) 𝑐 ) [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 𝑐 [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 (18)
= 𝑘 𝑜𝑏𝑠 Equation ( 18) now has the same form as equation (11), with a more complex expression for kobs. k1, k2 and c are constants while a depends on [Cattot]. If a = 1 only monomers are present and equation (18) simplifies to equation (12). Same for a = 0 where equation (18) simplifies to equation (13) because only dimers catalyse. For 0 < a < 1, kobs in equation (18) becomes an intermediate value between k1 and k2/2 which depends on [Cattot]. Therefore, a change of [Cattot] induces a change in kobs as long as 0 < a < 1. An exception to this rule is given if c = 1 and k1 = k2/2, meaning [RR] catalyses twice as fast as [R]. In this case the lowering of catalytic molecules due to aggregation is counterbalanced by the aggregates' higher catalytic activity: kobs stays constant whatever the value of a since kobs = k1 = k2/2.

(c) Catalyst order of the NBE-catalysed reaction

To study NBE's catalyst order we performed several kinetic runs in which the reaction progress was monitored via infrared spectroscopy (IR). Benzaldehyde has an intense C=O stretch around 1700 cm -1 which is perfectly suited for IR monitoring. The kinetic runs were performed with ZnMe2 in the same conditions as for the catalyst loading screening in Chapter I.2.2.1, with exception of the temperature which was elevated to 30°C to speed up the reaction. Figure 42 shows the results from kinetic runs with varying catalyst loadings from 2.5 to 20 mol%, in 2.5 mol%-steps. On a first glance it strikes that the reaction is significantly sped up when going from 2.5 to 5 mol%, however from 5 to 7.5 or 10 mol% the difference is much lower; at high catalyst loading the curves are almost identical. The reactions also don't reach full conversion but reach a plateau around 80% conversion, which is consistent with what we observed in former experiments; this may be the result from product inhibition.

To extract c from the kinetic rate profiles in Figure 42, we analysed the data using Visual Timenormalised Analysis (VTNA). It consists in a mathematical transformation of the time-axis which becomes "normalised" to the catalyst concentration. It results in the rate profiles being identical, i. e. overlaying, if they differ in their reaction parameters only in the catalyst concentration and if the right c has been chosen. Thus, c can be determined by a simple visual check. An example for VTNA is shown in Figure 43; a more detailed explanation of VTNA can be found in the supporting information, p. 163. Application of VTNA to the data from Figure 42 resulted in time-normalised rate profiles for which we could not find any c value which makes all of the curves overlay at the same time. This is indicative of a non-constant catalyst order. Therefore, we made a segmented analysis in which we overlaid only two neighbouring curves at a time to determine a c value valid for both curves: this allows us to monitor c over a range of catalyst loadings. The lower the difference in [Cat], the less the curves are visually affected by a change in c. Thus, we had to increase the difference in catalyst loading Δ[Cat] between two compared curves at higher catalyst loadings: curves with a Δ[Cat] of 2.5-5 mol% were compared from 2.5 to 10 mol%, between 10 and 20 mol% we had to increase Δ[Cat] to 5-7.5 mol%. Figure 44 shows the c vs catalyst loading plot, with Δ[Cat] represented by a horizontal bar for each determined c value. There is indeed a change of catalyst order when varying [Cat] but it is quite different from what is described in Figure 41, where c converges to a lower value when increasing [Cat]. To the best of our knowledge, there is no precedent for such a behaviour where c decreases and increases again in a Ushaped curve. However, it can be interpreted in a way which fits into our theory on a joint catalysis by monomers and dimers, and which concords with the theoretical kinetic model from chapter I.2.2.5(b).

We observe c = 1 at low catalyst loading, which is the expected value for the monomeric NBE-ZnMe (like its DAIB-based equivalent). If the dimeric catalyst works with a similar mechanism, we then expect its order also to be of one. Therefore, c should be equal to 1 in the far right and far left parts of the catalyst loading scale, where either only monomers or dimers are present, respectively (Figure 45). Figure 44 comes close to this with c = 1.0 on the left and c = 0.8 on the right.

Moreover, we know from equation ( 18) that kobs changes over varying [Cat] when both monomer and dimer exist in solution and catalyse. However, VTNA assumes kobs to be constant, according to equation (11). This leads the measured c to change over different [Cat] to compensate for the variation in kobs. This can be exemplified on Figure 43: it might be not because the wrong catalyst order is chosen that the curves do not overlay at c = 1, but because of their respective kobs are different. Therefore, the exemplified value of 0.4 in Figure 43b would be a purely mathematical construction to make equation (11) fit into equation (18). This applies to all the overlays used to construct Figure 44. (11). At very low and very high catalyst loading only one catalyst is present, either monomeric R or dimeric RR; both have an intrinsic catalyst order of 1, which corresponds also to the measured catalyst order. For intermediate reaction conditions, where both catalysts exist at the same time, the gradually changing kobs value leads to a non-linear rate increase upon increasing catalyst loading, therefore c ≠ 1.

However, this interpretation has to be taken with care as the theoretical model is built on certain assumptions and approximations which may turn out to be oversimplified or incorrect (this will be discussed in the next section). What seems to be quite certain is that the behaviour of c in Figure 44 shows that the nature of the catalytic species changes over variation of [Cat], not just its active fraction as in the example with Palladium in Figure 41. This supports our theory of homochiral aggregates also catalysing the reaction and being responsible for the hyperpositive NLE.

(d) eeP vs time

For now, we have considered only the reaction's conversion over time, without making the difference between R and S products. Noyori found eeP to be non-constant over time in the DAIBcatalysed enantioselective addition of ZnMe2 to benzaldehyde at 20% eeL. [29] It increases from 82% (5% conversion) to 89% (84% conversion). This could be rationalised from the decreasing benzaldehyde and ZnMe2-concentrations over time: less binding to substrate/reactant results also in less catalyst dimer dissociation; less dissociation of heterochiral DAIB-ZnMe dimer leads necessarily to higher eeP.

Under certain conditions he observed also product inhibition of the catalyst, as the product's desorption from the catalyst is, in fact, not irreversible but an equilibrium process (Figure 46). The zinc alkoxide product forms tetramers, which may be of homo-or heterochiral composition, the latter being less stable than the homochiral one. Therefore, if the reaction gives a low eeP at the beginning (e. g. with low DAIB-concentration and low eeL), the product is more likely to stay bound to the catalyst instead of forming tetramers, which drives further the dissociation of DAIB-ZnMe dimers and thus diminishes the (+)-NLE. Blackmond and co-workers did a kinetic study of the DAIB-variant Morpholinoisoborneol (MIB) in which they evidenced product inhibition. [118] A new model taking into account product desorption from the catalyst allowed an accurate prediction of the kinetic data.

Figure 46: Scheme for the equilibrium between the DAIB-ZnMe/zinc alkoxide adduct and uncomplexed DAIB-ZnMe + free zinc alkoxide, as a tetrameric aggregate. The Noyori model (see Figure 8 and Figure 9, p. 18) assumes that this is not an equilibrium but that the zinc alkoxide dissociates irreversibly from DAIB-ZnMe.

In the light of Noyori's work, we decided to investigate the evolution of eeP over time in the NBEcatalysed reaction. We performed another series of kinetic runs using similar conditions as for the runs in Figure 42, except for the temperature which was lowered to 0°C. Instead of in situ-monitoring by IR spectroscopy, aliquots were taken at the indicated reaction time and quenched rapidly, followed by GC analysis. In situ-monitoring of eeP is possible but affords special instrumentation which records IR and vibrational circular dichroism (VCD) spectra simultaneously. [119] Figure 47 shows the results from the kinetic runs (the results for 10, 12.5 and 17.5 mol% have been omitted for clarity; the full graph can be found in the experimental part, IV.1.2.5, p. 144). Indeed, in all runs eeP is not constant over time but it increases as the reaction proceeds. The lower the catalyst loading, the higher the eeP at which the reaction starts; the shape of the different curves seems to be quite similar. The reaction at 20 mol%, from which we know it gives 16 % eeP at the end of the reaction, starts with only 4% eeP after 10 minutes (1% conversion). The reaction with 2.5 mol% already is at 34% eeP after 20 min (0.4% conversion) but increases to 44% after 2h reaction time (2.2% conversion) and ends up at 49% eeP (see Figure 31b, p. 35).

The eeP increase over time in Noyori's system with scalemic DAIB was rationalised to come from an intrinsic increase of the (+)-NLE. Here, we use enantiopure (-)-NBE so the origin of the eeP increase must be different. Several scenarios could explain this behaviour:

-A participation of the reaction product in catalysis. An NBE-ZnMe/product-adduct could be imagined, catalysing the reaction in a more enantioselective way than NBE-ZnMe alone. However, Figure 47 shows that the catalyst-loading dependent eeP increase already takes place at the very beginning of the reaction, where a participation of the product is negligible. The zinc alkoxide alone is known to catalyse the reaction but yields racemic products and is very slow at 0°C. [29] -The reaction product influences the equilibrium between monomeric and dimeric NBE-ZnMe.

After the enantioselective alkyl-transfer to benzaldehyde, the product must decoordinate from the catalyst (monomer and dimer) to allow a new catalytic cycle. If the product decoordinates only slowly from the catalysts the amount of free, uncomplexed NBE-ZnMe diminishes the more the reaction goes on. This acts like a drop in catalyst concentration and should drive the dimer's dissociation. The higher monomer/dimer ratio results then in an eeP increase.

-Also, the decoordination doesn't need to happen at the same rate or to the same extend on both monomeric and dimeric catalyst. A higher affinity of the dimer for the product would selectively trap the dimers and increase the uncomplexed monomer/dimer ratio, at least at the beginning of the reaction. However, a too high affinity for the dimeric catalyst might also drive the monomer-dimer equilibrium to the formation of dimers. -If the reaction product has an influence on the monomer-dimer equilibrium, then the absence of starting material, which is consumed over the course of the reaction, could also have an impact, as it is in the case of the Noyori system. However, its influence is probably lower than that of the reaction product since the zinc alkoxide probably is a stronger coordinant than benzaldehyde and ZnMe2 are. So far, a dissociation of the dimers induced by product inhibition -due to a higher dimer's affinity for the product or not -is the most probable scenario. These results show also that the kinetic model presented in I.2.2.5(b) (where we assume the monomer/dimer ratio to be constant over time) is too simple to describe the NBE-catalysed reaction accurately, although it might be sufficient to discuss the catalyst order for now. The possibility for a high affinity of the dimer for the product can also be illustrated by an observation made by Noyori: he mixed 3 mM (S)-DAIB-ZnMe with the (S)-zinc alkoxide (both enantiopure) in a 1:5 ratio in toluene-d8. [29] 1 H NMR analysis gave rise to a spectrum which he interpreted as originating from an aggregate with a 6-membered Zn3O3 cycle, containing two DAIB-ZnMe and one product zinc alkoxide (Figure 48) -in other words, a homochiral dimeric complex bound to one product molecule.

I.2.2.6 Extended Noyori Model

The data gathered in this present chapter I.2.2 from the catalyst loading screenings, temperature screenings, DOSY analysis and kinetic studies allow us to make an extension of the Noyori model for the DAIB-catalysed addition of dialkylzincs to benzaldehyde. Noyori's model (cf. Figure 9, p. 20) is based on two different enantiomorphic cycles, where (-)-DAIB-ZnR as well as (+)-DAIB-ZnR catalyse in the same way but are not present in the same quantities; the enantiomer ratio of the catalysts depends on the catalyst concentration, but also on the substrate and reactant concentrations (which change over time); product inhibition is considered to be negligible as long one works in a certain range of concentration and catalyst/substrate ratio.

Figure 49 shows our proposed model. It includes the same enantiomorphic, monomer-catalysed cycles but adds also the respective dimer-catalysed cycles. Therefore it combines as well elements from the from Noyori and as from the Kagan model. We kept the Noyori nomenclature for Kassoc, k and eemax, which are denoted with 1 and 2 for the monomer and dimer-catalysed reactions, respectively. KHomo and KHetero are defined as the respective association constants (in the Noyori model those are dissociation constants) to form the respective dimeric species. We added also the term Kdissoc, which quantifies the product's dissociation from the catalyst, and KS to account for the heterochiral dimer's solubility. Each catalytic cycle starts with the coordination of benzaldehyde and ZnR2, ruled by the association constant Kassoc, to give the catalytic complex Cat-Rea-Sub. In an irreversible step Rea and Sub react to form the Cat-Prod complex, defined by the kinetic constant k and eemax for the R-catalyst, -eemax for the S-catalyst. Cat-Prod dissociates back to Cat and Prod, the latter gets incorporated into tetrameric aggregates. We introduce here the thermodynamic constant Kdissoc which quantifies the catalyst's affinity for the product. However, the dissociation probably is much more complex than shown here: it should be differentiated between the product's desorption from the catalyst and the subsequent aggregation into tetramers, which are two different steps. The first may be different if the catalyst and the product are of the same or opposite chirality; the latter depends heavily on the product ee, as it is known that the tetramer is more stable when made of enantiopure zinc alkoxides. [120] Thus, product inhibition depends not only on conversion, but also on eeP at a given time t. For simplicity we assume that the heterochiral dimer doesn't catalyse as we don't have any indication for or against its participation in the catalytic reaction.

I.2.3 Further studies on the NBE-catalysed reaction

The present section gathers studies we have performed on the NBE-catalysed reaction which do not aim at investigating the reaction mechanism, but to obtain more information about the ligand and the catalytic reaction. We will have a closer look at the role of the benzyl group in NBE, at the influence of different substrates on the hyperpositive NLE and the catalytic reaction in general, and we will also determine quantitatively some of the reaction parameters.

I.2.3.1 Reservoir effect & KS/KHetero

(a) Application of Kagan's reservoir effect model

Since the precipitation of a heterochiral aggregate is a classic example for Kagan's reservoir effect model (see chapter I.1.2, p. 16), we decided to apply it to both of our hyperpositive NLE curves. As the reservoir effect model is not intended to be used on a hyperpositive NLE, we made some modifications before we applied it to our data.

The parameter eemax is defined as the maximum ee the enantiopure ligand can yield, which is usually the eeP obtained from enantiopure catalyst. However, in our case the enantiopure ligand doesn't give highest eeP -it increases further at lower eeL. Therefore, we used the data from the catalyst loading screening which we had converted to a simulated NLE curve (chapter I.2.2.1, p. 33). The converted catalyst loading screening simulates the eeP obtained from enantiopure NBE as a function of eeL. Therefore, we define eemax to be equal to the trendline (2 nd order polynomial function) fitted to the catalyst loading screening, which we had shown in I.2.2.1 just for illustration purposes. The catalyst loadings, their trendlines, the trendline functions and the hyperpositive NLEs are shown in Figure 50. Now, we can determine the parameter α from equation (7), which stands for the fraction of catalyst trapped in the inactive reservoir. For eeP and eeL we used the datasets at eeL = 1 and 2% (also 3 % with ZnMe2; black circled datasets in Figure 50) from the hyperpositive NLE curves and calculated eemax independently for each eeL. The reservoir is a racemic meso-aggregate, therefore eeres = 0. The two (or three, respectively) α-values were averaged and used to draw equation ( 7) as a function of eeL (Figure 50, black dashed line).

We obtained nearly identical α-values for the ZnEt2-(97.3% ± 0.03) and the ZnMe2-system (96.6% ± 0.15). The NLEs' steep slope at eeL < 4% fits well to the graphical expression of equation ( 7), so that we can say that the hyperpositive NLEs are now fully and accurately modelled by the catalyst loading screening and the reservoir effect. In the reservoir effect model, α represents the fraction of catalyst which is trapped inside a reservoir, in our case a precipitate. The formation of the meso-aggregate is governed by a solubility constant, KS (see the extended Noyori model, p. 53). It seems logical that KS and α must be linked somehow, therefore we made a theoretical study to determine KS from α.

First, we have to consider the following equilibria, which are defined by the equilibrium constants in equations ( 19) and (20): To simplify the system, we will integrate Khetero into KS to obtain an apparent solubility constant, KS', which is related directly to [R] and [S] through equation ( 21). This goes along with the assumption made in chapter I.2.2.6 that both [RS] and [RS]p do not catalyse the reaction.

𝐾 ℎ𝑒𝑡𝑒𝑟𝑜 = [𝑅𝑆] [𝑅][𝑆] ( 19
)
𝐾 𝑠 = [𝑅𝑆] [𝑅𝑆] 𝑝 = [𝑅𝑆] (20)
𝐾 𝑆 ′ = 𝐾 𝑆 𝐾 ℎ𝑒𝑡𝑒𝑟𝑜 = [𝑅][𝑆] (21)
Now, we have to relate KS' to the known values α, [Cat]tot and eeL. For this, we will neglect the contribution of [RR] and [SS] to the catalytic process, the only catalytic species considered are [R] and [S]. We will also neglect the influence of the substrate and the catalysis product on the equilibria involving [R] and [S].

Figure 51: Scheme of the catalytic system considered as consisting of a heterochiral pool, which includes the inactive heterochiral dimers (precipitated as well as solubilised dimers) and an equal amount of active R-an d S-monomers, and of a homochiral pool consisting of the excess of major R enantiomer.

Let's consider the total catalyst [Cattot] consisting of an enantiopure R pool and a racemic heterochiral pool. The heterochiral pool consists of the inactive reservoir and from an equal quantity of free, catalytically active R-and S-monomers in equal parts (Figure 51). The concentrations of Rand S-catalysts in the pools and in the reservoir are defined by equations ( 22) and ( 23):

[𝑅] 𝐻𝑜𝑚𝑜 𝑝𝑜𝑜𝑙 = 𝑒𝑒 𝐿 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] (22)
[𝑅] 𝐻𝑒𝑡𝑒𝑟𝑜 𝑝𝑜𝑜𝑙 = [𝑆] 𝐻𝑒𝑡𝑒𝑟𝑜 𝑝𝑜𝑜𝑙 = (1 -𝑒𝑒 𝐿 )[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 (23)
In addition, we can describe, as a function of α, the catalytically inactive part (i. e. reservoir) of the heterochiral pool. It consists of R and S-monomers in equal parts and is therefore expressed by equation ( 24):

[𝑅] 𝑟𝑒𝑠 = [𝑆] 𝑟𝑒𝑠 = 𝛼[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 (24)
The total amount of active [R] has to be equal to the homochiral pool plus the amount of R-catalyst incorporated in the soluble part of the heterochiral pool [equation (25)]. On the other hand, the active S catalyst is issued only from the heterochiral pool's soluble part [equation (26)].

[𝑅] 𝑎𝑐𝑡𝑖𝑣𝑒 = [𝑅] 𝐻𝑜𝑚𝑜 𝑝𝑜𝑜𝑙 + [𝑅] 𝐻𝑒𝑡𝑒𝑟𝑜 𝑝𝑜𝑜𝑙 -[𝑅] 𝑟𝑒𝑠 ⇒ [𝑅] 𝑎𝑐𝑡𝑖𝑣𝑒 = 𝑒𝑒 𝐿 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] + (1 -𝑒𝑒 𝐿 )[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 - 𝛼[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 = (𝑒𝑒 𝐿 + 1 -𝑒𝑒 𝐿 -𝛼 2 ) [𝐶𝑎𝑡 𝑡𝑜𝑡 ] = 1 + 𝑒𝑒 𝐿 -𝛼 2 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] (25)
[𝑆] 𝑎𝑐𝑡𝑖𝑣𝑒 = [𝑆] 𝐻𝑒𝑡𝑒𝑟𝑜 𝑝𝑜𝑜𝑙 -[𝑆] 𝑟𝑒𝑠 ⇒ [𝑆] 𝑎𝑐𝑡𝑖𝑣𝑒 = (1 -𝑒𝑒 𝐿 )[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 - 𝛼[𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 = 1 -𝑒𝑒 𝐿 -𝛼 2 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] (26)
Now, equations ( 25) and ( 26) can be incorporated into equation ( 21):

⇒ 𝐾 𝑆 ′ = ( 1 + 𝑒𝑒 𝐿 -𝛼 2 ) ( 1 -𝑒𝑒 𝐿 -𝛼 2 ) [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 ⟺ 𝐾 𝑆 ′ = (1 -𝑒𝑒 𝐿 -𝛼 + 𝑒𝑒 𝐿 -𝑒𝑒 𝐿 2 -𝑒𝑒 𝐿 𝛼 -𝛼 + 𝑒𝑒 𝐿 𝛼 + 𝛼 2 ) [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 4 ⟺ 𝐾 𝑆 ′ = (1 -2𝛼 -𝑒𝑒 𝐿 2 + 𝛼 2 ) [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 4 ⟺ 𝐾 𝑆 ′ = [(1 -𝛼) 2 -𝑒𝑒 𝐿 2 ] [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 2 4 (27)
Since [Cattot] is a fix reaction parameter and α has been determined in chapter I.2.2.1, we can calculate KS' from equation (27). For eeL, we chose the same values used to determine α and calculated mean KS' and subsequently the solubility s' of [RS] (more detailed data can be found in the Supporting Information, V.2.2, p. 170). The results are shown in Table 3.

ZnR2 α KS' s' [mol/L] R = Et 0.966 4.

58

The calculated KS' and solubility values are close and indeed quite low, however we cannot conclude on them without a counter-check by an experimental determination of KS and KHetero, especially because of the approximations made at the beginning of the calculations. In a related system, Kagan calculated the eutectic composition (minimum eeL a solution can have without forming a racemic precipitate) of an insoluble meso catalyst from the fusion temperatures and fusion enthalpies of the enantiopure and racemic catalyst. [107] This might be also applicable to our system.

I.2.3.2 Eyring plots (a) Determination of eemax 1

We know that the homochiral catalyst dimer can be dissociated by decreasing the total catalyst concentration or increasing the reaction temperature (chapter I.2.2.1 and I.2.2.2). A combination of low [Cattot] and high temperature might enable us to reach conditions in which only the monomer catalyses. That would give us the opportunity to determine certain constants associated to the monomer mentioned in I.2.2.6: its enantioselectivity (eemax 1), its kinetic constant (k1), its association constant with the benzaldehyde and the dialkylzinc reagent (Kassoc 1) and the dissociation constant from the reaction product (Kdissoc 1). We will focus here on eemax 1 as it can be directly obtained from eeP using Eyring plots.

The enantioselectivity of a reaction is defined as the difference (ΔΔG ≠ ) between the free energies of the two transition states (ΔG ≠ R and ΔG ≠ S) of the rate-determining step leading either to R or S-product (PR and PS). The kinetic constants of those rate-determining steps are related through ΔΔG ≠ to the corresponding enthalpy and entropy terms:

ln ( 𝑘 𝑅 𝑘 𝑆 ) = -∆∆𝐺 ≠ 𝑅𝑇 = -∆∆𝐻 ≠ 𝑅𝑇 + ∆∆𝑆 ≠ 𝑅 (28)
With kR and kS as the kinetic constants of the rate-determining steps leading to PR and PS, respectively, ΔΔH ≠ as the difference in transition enthalpy, ΔΔS ≠ as the difference in transition entropy, R as the ideal gas constant and T as the reaction temperature.

The interesting point about equation ( 28) is that it can be represented as a linear function, if one plots ln(kR/kS) [which is equal to ln(PR/PS) for a single-catalyst reaction; the enantiomeric ratio PR/PS can be calculated directly from eeP] vs. T -1 . -ΔΔH ≠ /R then corresponds to the line's slope and ΔΔS ≠ /R to the y-intercept. Those so-called "Eyring plots" can give valuable information about the reaction, especially if they contain curvatures -that is usually an indication for a change of the reaction mechanism. [START_REF] Anslyn | Modern Physical Organic Chemistry[END_REF] The ΔΔS ≠ -term also explains why a catalyst's enantioselectivity is not a constant, but a temperature-dependent variable, which leads to lower eePs with increasing temperatures. The higher ΔΔS ≠ , the more eeP is sensitive to the reaction temperature. An Eyring plot of the NBEcatalysed reaction in conditions where either only the monomer or only the dimer catalyse would give us access to their respective ΔΔH ≠ and ΔΔS ≠ ; we would then also be able to predict their enantioselectivities eemax 1 and eemax 2 for any reaction temperature.

This prompted us to extend the temperature screening from chapter I.2.2.1 (Figure 34, p. 37) to a broader range of temperatures. Figure 52a shows the extended temperature screening using ZnEt2, with 2.5 and 20 mol% NBE. From -20 to 40 °C eeP either decreases slightly (2.5 mol%, orange dots) or forms a wave-like curve (20 mol%, blue dots). At 60 °C and higher, eeP starts to decrease strongly in both cases. With ZnMe2 (Figure 52b) eeP increases with temperature in a linear way, only the 2.5 mol%-plot shows a curvature above 60 °C. The linear downslope with ZnEt2 at high temperature is interesting as it might indicate that only the monomeric catalyst is active; at lower temperatures, the temperature-driven eeP decrease is probably compensated by dimer dissociation, so the slope is less inclined. Conversion of the datasets in Figure 52a from [eeP, T] to [ln(kR/kS), 10 -3 /T] allowed us to build the Eyring plot shown in Figure 53. Indeed, the 5 high-temperature datasets at 2.5 mol% NBE give an excellent linear fit (R² = 0.9988), which indicates most likely that only one species catalyses -the monomeric NBE-ZnEt catalyst. Therefore, the line is equal to the monomer's -ΔΔG ≠ /RT, from which we could obtain ΔΔH ≠ 1 and ΔΔS ≠ 1 (shown on the right, Figure 52b). This allows us now to predict the monomer's enantioselectivity eemax 1 for any temperature by converting the [ln(kR/kS), 10 -3 /T]-dataset back to [eeP, T]. At our standard catalysis temperature of 0 °C (corresponding to 3.6 1000/T, red dot in Figure 52a) we obtain an eeP of 88%: this is the eeP monomeric NBE-ZnEt would yield if it would be the only catalyst to be active at this temperature.

However, it should be noted that the four far-left datasets at 20 mol% also fit to a linear function, with an only slightly lower R² (0.9955, not shown). This is probably due to the 20 mol%-plot converging over a very broad T -1 -scale to the -ΔΔG ≠ 1/RT-line, thus being almost linear although there is some dimeric NBE left in these conditions. Therefore, the -ΔΔG ≠ 1/RT-line should be confirmed by temperature screenings at even lower catalyst loading than 2.5 mol%.

(b) Construction of an Eyring Plot Model

The dimeric catalyst's enantioselectivity eemax 2 might also be determined by the Eyring plot but affords additional datasets at lower temperature and/or higher catalyst loading, in order to reach the linear domain which corresponds to -ΔΔG ≠ 2/RT. The wave-like shape for the 20 mol%-data at low temperature (Figure 52a and Figure 53) raises also questions about how the plot might look like. Since we don't have more experimental data at hand, we opted for a modelling of the Eyring plot.

The Eyring plot is defined by ln(kR/kS), as discussed in the previous section. To account for the contribution of both monomer and dimer to the reaction, we defined the observed kinetic constants kR and kS as linear combinations of kR1 and kR2 or kS1 and kS2, respectively, as shown in equations ( 29) and ( 30):

𝑘 𝑅 = 𝑎𝑘 𝑅1 + ( 1 -𝑎 2 ) 𝑘 𝑅2 (29)
𝑘 𝑆 = 𝑎𝑘 𝑆1 + ( 1 -𝑎 2 ) 𝑘 𝑆2 (30)
With kR1 and kS1 as the kinetic constants of monomeric catalyst, kR2 and kS2 for the dimeric catalyst. a is the fraction of monomeric catalyst [R] of the total amount of catalyst [Cattot], as defined by equation ( 16) in the model of NBE's kinetics in chapter I.2.2.5(b), p. 45. a is considered to be constant over time. Integration of equations ( 29) and ( 30) into (28) gives equation ( 31):

ln(k R /k S ) 10 -3 /T [K -1 ] ee(max)1 at 0 °C 2.5 mol% 20 mol% R = Et a) -ΔΔH ≠ 1/R = 0.7987•10 3 K → ΔΔH ≠ 1 = -6.64 kJmol -1 ΔΔS ≠ 1/R = -0.1473 → ΔΔS ≠ 1 = -1.22 Jmol -1 K -1 ΔΔG ≠ 1 [J/mol] = -6640 + 1.22T b) -∆∆𝐺 ≠ 𝑅𝑇 = ln ( 𝑘 𝑅 𝑘 𝑆 ) = ln ( 𝑎𝑘 𝑅1 + ( 1 -𝑎 2 ) 𝑘 𝑅2 𝑎𝑘 𝑆1 + ( 1 -𝑎 2 ) 𝑘 𝑆2 ) 4
The term for -ΔΔG ≠ /RT now has become more complex and cannot be expressed as a linear function, unless a = 0 (only dimeric NBE catalyses) or a = 1 (only monomeric NBE catalyses). Those are the extreme cases were the Eyring plot is linear. Since we want to see what happens in between, we developed all terms in equation ( 31) which are a function of the temperature. First, we express the kinetic constants as the exponential containing their respective ΔH ≠ and ΔS ≠ :

ln ( 𝑘 𝑅 𝑘 𝑆 ) = ln ( 𝑎𝑒 -(∆𝐻 𝑅1 ≠ +𝑇∆𝑆 𝑅1 ≠ ) 𝑅𝑇 + ( 1 -𝑎 2 ) 𝑒 -(∆𝐻 𝑅2 ≠ +𝑇∆𝑆 𝑅2 ≠ ) 𝑅𝑇 𝑎𝑒 -(∆𝐻 𝑆1 ≠ +𝑇∆𝑆 𝑆1 ≠ ) 𝑅𝑇 + ( 1 -𝑎 2 ) 𝑒 -(∆𝐻 𝑆2 ≠ +𝑇∆𝑆 𝑆2 ≠ ) 𝑅𝑇 ) (32)
With R as the ideal gas constant (8.314 Jmol -1 K -1 ). Next, we developed a. The fraction of monomeric or dimeric catalyst must necessarily be a function of the total catalyst concentration [Cattot] and the dimerisation constant KHomo. Integration of equation ( 33) into (34) leads to a quadratic equation which can be solved for [R], giving equation (35):

𝐾 𝐻𝑜𝑚𝑜 = [𝑅𝑅] [𝑅] 2 ⟺ 𝐾 𝐻𝑜𝑚𝑜 [𝑅] 2 = [𝑅𝑅] (33)
[𝐶𝑎𝑡 𝑡𝑜𝑡 ] = [𝑅] + 2[𝑅𝑅] (34)
⟹ [𝐶𝑎𝑡 𝑡𝑜𝑡 ] = [𝑅] + 2𝐾 𝐻𝑜𝑚𝑜 [𝑅] 2 ⟺ 2𝐾 𝐻𝑜𝑚𝑜 [𝑅] 2 + [𝑅] -[𝐶𝑎𝑡 𝑡𝑜𝑡 ] = 0 ⟺ [𝑅] ± = -1 ± √1 + 8𝐾 𝐻𝑜𝑚𝑜 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 4𝐾 𝐻𝑜𝑚𝑜 (35)
The only solution giving positive values is [R]+, which gives equation (36) when integrated into the expression for a (cf. equation ( 16), p. 45):

⟹ 𝑎 = -1 + √1 + 8𝐾 𝐻𝑜𝑚𝑜 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] 4𝐾 𝐻𝑜𝑚𝑜 [𝐶𝑎𝑡 𝑡𝑜𝑡 ] (36)
[Cattot] is a fixed reaction parameter, while KHomo can be further developed as a function of the temperature:

𝐾 𝐻𝑜𝑚𝑜 = 𝑒 -(∆𝐻 𝐻𝑜𝑚𝑜 +𝑇∆𝑆 𝐻𝑜𝑚𝑜 ) 𝑅𝑇 (37)
Equation ( 32) can now be expressed, through equations ( 36) and ( 37), as a function of [Cattot], ΔHHomo, ΔSHomo and the ΔH ≠ and ΔS ≠ terms of each kinetic constant.

∆∆𝐻 2 ≠ = ∆𝐻 𝑅2 ≠ -∆𝐻 𝑆2 ≠ ∆∆𝑆 2 ≠ = ∆𝑆 𝑅2 ≠ -∆𝑆 𝑅2 ≠
Now, we must choose the parameters. For [Cattot] we chose the same concentration as used for our catalytic reactions with 20 mol% NBE; the ideal gas constant R is known; ΔH ≠ Homo and ΔS ≠ Homo were calculated from KHomo(T) at 25 and 60 °C, which was obtained from the mean MW values determined by DOSY NMR in chapter I.2.2.4(b). It should be noted that this was done only to have an idea of the order of magnitude of KHomo(T); the data from I.2.2.4(b) is not sufficient and not adapted (the excess ZnMe2 influences the complex' aggregation state) to perform an accurate determination of KHomo(T).

As we already know ΔΔH ≠ 1 and ΔΔS ≠ 1 (6.64 kJmol -1 and 1.22 Jmol -1 K -1 , respectively) from the experimental Eyring plots, we chose ΔH ≠ R1 and ΔH ≠ S1 as well as ΔS ≠ R1 and ΔS ≠ S1 in order to fulfil equations (38) and (39):

∆∆𝐻 𝑖 ≠ = ∆𝐻 𝑅𝑖 ≠ -∆𝐻 𝑆𝑖 ≠ ( 38
)
∆∆𝑆 𝑖 ≠ = ∆𝑆 𝑅𝑖 ≠ -∆𝑆 𝑆𝑖 ≠ (39)
All other parameters were chosen arbitrarily. Our basic set of parameters is shown in Table 4; we will use this set to model Eyring plots and vary some of these parameters to study their influence on the plot. We do not intend to make a full theoretical study of the model, but rather to illustrate how our experimental Eyring plots should behave.

ΔH ≠ R1 [kJmol -1 ] -16.6 ΔS ≠ R1 [Jmol -1 K -1 ] -100 ΔH ≠ S1 -10 ΔS ≠ S1 -98.8 ΔH ≠ R2 -16.6 ΔS ≠ R2 -100 ΔH ≠ S2 -16 ΔS ≠ S2 - 105
ΔH ≠ Homo -35 ΔS ≠ Homo -80 [Cattot] [mol/L] 0.166 R [Jmol -1 K -1 ]
8.314 Figure 54a shows the Eyring plot model with different values for ΔHHomo. There are two linear domains, which correspond to catalysis by the monomer (left, a ~ 1) and by the dimer only (right, a ~ 0). The domain in between, which we will call "intermediate region", is the one where both complexes catalyse and which bears, in this parameter configuration, a wave-like shape similar to what we see in the experimental Eyring plot (Figure 53).

The temperature range of this region depends on ΔHHomo: the more negative it is (a1 → a2 → a3), the more the wave is shifted to smaller 1000/T-values. Since the two lines converge around 1•10 -3 /T, the wave also becomes smaller. This is consistent with equation ( 37): the more negative ΔH ≠ Homo, the higher KHomo, the more the equilibrium is shifted to the dimeric catalyst. Therefore, it is necessary to increase the temperature to fully dissociate the dimer, therefore the left linear domain is reached only at lower 1000/T-values. Next, we varied the parameters associated with the dimeric catalyst only, in the linear domain on the right side. The line's slope depends on ΔΔH ≠ 2 according to equation ( 28), therefore we varied ΔH ≠ R2 and left ΔH ≠ S2 constant to obtain graphs with different ΔΔH ≠ 2 values. The results are shown in Figure 54b. As long as ΔΔH ≠ 2 is negative (b1 and b2) the right line has a positive slope; a positive ΔΔH ≠ 2 (b3, grey dots) gives a negative slope. In the latter case the intermediate domain has no wave-like shape anymore, it resembles a peak. Therefore, we may deduct that in the NBE-catalysed system, ΔΔH ≠ 2 must have a negative value. Since the dimeric catalyst is less enantioselective than the monomeric one, the slope for dimeric catalyst's line must be less steep than for the monomeric's, therefore ΔΔH ≠ 1 has to be more negative than ΔΔH ≠ 2. From that, we can conclude -6.64 < ΔΔH ≠ 2 < 0 kJmol -1 .

Finally, we will vary the dimer's ΔΔS ≠ 2, which defines the y-intercept of the right line. We have varied ΔS ≠ S2 to obtain graphs with different ΔΔS ≠ 2 shown in Figure 54c. The position of the right line has an influence on the shape of the intermediate domain: the lower it is, the more both linear domains diverge in the intermediate region, the more the wave-like shape is pronounced.

In principle, such model can be fitted to experimental data to determine unknown parameters. However, our model is probably not accurate enough to do this. We know from I.2.2.5(d) (p. 49) that eeP changes during the reaction, therefore the monomeric/dimeric catalyst-ratio changes over time. This means that the variable a cannot be constant over time and must be described by a much more complex expression than equation (36). However, our simplified model should be sufficient to get an idea of what the Eyring plot of our NBE-catalysed reaction should look like.

I.2.3.3 Influence of the ligand structure (a) NBE-derivatives

In order to get more information about effect of ligand structure on the hyperpositive NLE, we studied some derivatives of NBE. The absence of NLEs with ephedrine, NnBE and NME in chapter I.2.1.2 indicates that the benzyl substituent on NBE has a major influence on the catalytic system. It is very likely that it is responsible for the insolubility of the heterochiral NBE-ZnMe/Et aggregate, e. g. via extensive π-π stacking which stabilises the crystalline state. The question is also whether it has an influence on the catalytic activity of the homochiral aggregate. Therefore, we made variants of NBE with para-substituents on the benzylic ring, one electron-donating (X = Me) and one electronattracting (X = Br). Additionally, we made also a 2-naphtyl variant (N-2-naphtyl ephedrine, N2NE). The extended aromaticity might enhance π-π stacking in the crystalline state and further decrease the heterochiral aggregate's solubility in toluene.

The results are shown in Figure 55, Figure 56 and Figure 57. All ligands show a hyperpositive NLE quite similar to the one of NBE (see Figure 25, p. 31), all form a white precipitate at the beginning of the reaction if they are scalemic. In general, the substituents don't seem to affect a lot the catalytic system. Br-NBE shows a slightly lower enantioselectivity (75% eeP at 100% eeL, 79% at 20% eeL) than NBE (76 and 81% eeP, respectively). Me-NBE is also slightly less enantioselective than NBE (80% eeP at 10%-20% eeL). On the other hand, N2NE is slightly more enantioselective (77% eeP at 100% eeL, 83% at 20% eeL) but then shows an eeP drop at 10% eeL, where it isn't hyperpositive anymore; same goes for Br-NBE. The 2-naphtyl-group probably improves the ligand's eemax 1/2 or destabilises the homochiral aggregate, so that more of the more selective monomer catalyses, but decreases the heterochiral aggregate's solubility rather than increasing it. 30), probably due to the absence of a heterochiral precipitate. However, that doesn't rule out the possibility of catalysis by homochiral aggregates, so we checked for this by performing a catalyst loading screening on the NME-catalysed addition of ZnEt2, similar to the study on NBE in chapter I.2.2.1. Figure 58 shows a strong eeP increase upon reduction of the catalyst loading, from 68% eeP at 20 mol% to 80% eeP at 2.5 mol%. The eeP increase is even slightly stronger than with (-)-NBE (76% to 84% eeP at 1 mol%).

This is interesting as it shows that the benzyl substituent is responsible for the precipitation of the heterochiral aggregate, but not for the catalytic activity of the homochiral dimer. Theoretically, NME could also generate a hyperpositive NLE if the heterochiral aggregate would precipitate.

I.2.3.4 Effects of para-substituents on the substrate

So far, we have studied the catalysis by NBE mostly by varying the reaction conditions (temperature, concentration); apart from the dialkylzinc (ZnMe2 or ZnEt2) the compounds have been mostly the same in every experiment: benzaldehyde, NBE and toluene. We will now make a survey of substituted benzaldehydes in the NBE-catalysed addition of dialkylzincs and see if electrondonating/-attracting or bulky substituents have an impact on the catalysis, notably on the hyperpositive NLE. We will then make Hammett plots to see if the substituents' effects can be quantified.

(a) Screening of para-substituted benzaldehydes

We started to screen for different substrates with ZnEt2 as the dialkylzinc. The conditions are the same as for the hyperpositive NLE in Chapter I.2.1.2, datasets were obtained from enantiopure and from 20% ee ligand to probe for NLEs. We chose to work with para-substituted benzaldehydes to minimise any possible steric influence of the substituent on the aldehyde. The electron-donating orattracting effect of the substrate can be quantified by Hammett's σp-scale (see section V.1.3, p. 165 Catalyst loading [mol%] for further details);

R = Et

There are no clear trends to read from Figure 59, apart that the best substituents to obtain a hyperpositive NLE are those around σp = 0 if we consider OiPr to be an exception. The eeP-drop with scalemic ligand and OCF3, CN and SF5 indicates an increased activity of the minor NBE-enantiomer. This may come from a changed affinity of the substrate or the chiral zinc alkoxide product with the catalyst which drives the solubilisation of the heterochiral precipitate (although a precipitate was persistent in all reactions with 20% eeL).

Next, we screened para-substituted benzaldehyde using ZnMe2. We applied the same set of substrates as before, with exception of 2-naphtaldehyde, and added 4-Iodobenzaldehyde to the screening. The picture given by Figure 60 is somewhat clearer than the previous one: all substrates give hyperpositive NLEs [eeP(20% eeL) > eeP(100% eeL)], except OCF3 and SF5 which show again a strong eeP-drop with scalemic ligand. Apart those two substituents, all those with σp > 0.1 show constant eePs around 44% with scalemic ligand. On the other hand, as σp becomes lower than 0.1, eeP decreases continuously. The eePs with enantiopure NBE globally follow the trend of the scalemic ligand. OCF3 and SF5 are, again, exceptions: their eePs at 100% eeL are higher than the overall trend, which contributes to their NLE not being hyperpositive anymore. We also had a look at the conversion of the reactions in Figure 60 which we won't discuss here, but which can be found in the supporting information (V. In addition, we also made catalyst loading screenings on pCF3-and pCN-benzaldehyde to compare them with unsubstituted benzaldehyde. The catalyst loading screenings were performed as previously discussed in chapter I.2.2.1. The results are shown in Figure 61. eeP increases for CF3 and CN when lowering the catalyst loading, but the effect is less strong than with unsubstituted benzaldehyde. From the present data it is difficult to conclude why, it can be because of a lower eemax 1/eemax 2-difference or a less catalyst loading-sensitive monomer/dimer-ratio. It should also be noted that the overall eePs are lower with CN than with CF3 or H. We also made a full NLE curve with pCF3-benzaldehyde, ZnEt2 and NBE and compared it with the catalyst loading screening, as we have done before with unsubstituted benzaldehyde in chapter I.2.2.1. Figure 62 shows the superimposition of NLE (blue dots) and catalyst loading screening (orange squares). The NLE with pCF3-benzaldehyde is not hyperpositive as eeP stays constant at 76% from 100 to 20% eeL, it starts to drop only at lower eeLs. This concords with the catalyst loading screening: if the eeP increase at lower catalyst concentration is less pronounced than with unsubstituted benzaldehyde, then the NLE curve should also be less hyperpositive (lower ΔeeP), which is the case here. The graphs have been made from the reported tabular data. [30] Noyori made Hammett plots (see section V.1.3, p. 165 for more details about Hammett plots) for DAIB-catalysed addition of ZnMe2 to para-substituted benzaldehydes, with the intention to rule out the possibility of the heterochiral dimer catalysing the reaction. [30] For this, he made competitive reactions in which 0.5 equivalents of both substituted and unsubstituted benzaldehyde were reacted with ZnMe2, in presence of a catalytic amount of (-)-DAIB. He determined the initial rates (v0X and v0H, respectively) of both substrates and plotted log(v0X/v0H) vs σp of the respective substituted benzaldehyde. This resulted in a Hammett plot with ρ = 1.25 with an excellent fit (Figure 63a). In addition, we show here also a Hammett plot of the same data using the σp + -scale (Figure 63b).

In order to get more information about the NBE-catalysed reaction, we made Hammett plots for the NBE-catalysed addition of ZnMe2 using a strategy similar to Noyori's. We left our reaction conditions unchanged, except for the substrates which are both 0.5 equiv. instead of 1. The tabular data with the different conversion and eeP-values of the competitive runs can be found in the experimental section (IV.1.2.3, p. 142). Figure 64 shows the plot log(v0X/v0H) vs σp for NBE using the same set of substrates as Noyori did (Cl was replaced by Br, both have the same σp of 0.23). The resulting Hammett plot looks quite similar to DAIB's plot in Figure 63a: the fit is good (R² = 0.96) and only Me deviates significantly from the plot. However, ρ is with a value of 1.89 much higher than for DAIB (1.2). A higher ρ-value means that the NBE-catalysed reaction is more susceptible to substituent effects than DAIB, and that the transition state of the rate-determining step builds up more negative charge. A big difference between monomeric NBE-ZnMe's and DAIB-ZnMe's catalytic transition states would be rather surprising since their reactive centres are similar. However, it may be different for dimeric We then extended the competitive catalytic runs to other substrates, from strongly e --donating (OiPr) to strongly e --attracting substituents (CN). The resulting Hammett plot (Figure 65) shows a still linear but quite scattered relationship, especially at low σp, with a moderate R² of 0.83. The ρ-value of 1.24 is now close to Noyori's ρ for DAIB. Since scattering can originate from using the wrong σ-scale, we decided to check for other LFERscales. [START_REF] Anslyn | Modern Physical Organic Chemistry[END_REF] σp + gave a better linear correlation (R² = 0.94) and visibly less scattering, especially the strongly e --donating substituents now fit better to the linear trendline. The ρ-value is of 1.02; both ρ and R² are higher than for the Hammet plot of DAIB using the same σp + -scale (0.75 and 0.89, respectively, cf. Figure 63b). DAIB fits better to σp than to σp + and therefore shows a behaviour contrary to NBE. Hammett plots can also be constructed for stereo-or regioselective reactions, using the ratio of the two stereo-or regioisomers' kinetic constants for either H and X. In enantioselective reactions, log(kX/kH) becomes log(erX/erH) with the enantiomeric ratio er = kR/kS. The plots vs σp (Figure 67) and σp + (Figure 68) result in linear fits bearing low ρ values of 0.10 and 0.08, respectively. This is consistent with enantioselectivity usually being much more governed by steric than by electronic effects. As for the log(v0X/v0H)-plots, the σp + -scale gives a better overall correlation than σp, even though the R² remains moderate (0.83). The better fit to the σp + -scale for both log(v0X/v0H) and log(erX/erH) indicates that the catalysis may be sensitive to "through-conjugation". This is the delocalisation of electrons from the aromatic cycle and the para-substituent, if it is a mesomeric donor, into the aldehyde (cf. supporting information V.1.3, p. 165). This makes the aldehyde more electron-rich and a better coordinant, therefore these results may be indicative of the NBE catalyst being more electron-poor and a stronger Lewis acid than the DAIB catalyst. As mentioned before, monomeric NBE-ZnMe is not likely to be a fundamentally different catalyst than DAIB-ZnMe, this holds also for their Lewis acidity. However, dimeric NBE-ZnMe may be different from DAIB-ZnMe and be more Lewis acidic. Therefore, the better fit to the σp + -scale may be an indication for the joint catalysis by monomeric and dimeric NBE-ZnMe. A way to check this would be to repeat the competitive catalytic runs with a lower catalyst loading; the decreasing dimer/monomer ratio should then result in a Hammett plot which is closer to DAIB's and which fits less good to the σp + -scale.

(c) Size-optimised Hammett plots

However, the conclusion from the previous section should be treated with care. There can be other elements influencing the catalytic reaction, e. g. coordination of the substituents to other species. The alkoxy-substituents, CN and especially COOMe may coordinate to ZnMe2 or the catalyst and influence the various equilibria, their own catalytic reaction or induce side-reactions. The deviation of the electron-rich substituents in Figure 64 may also be due to their steric instead of their electronic properties. The alkoxy-(except OMe), 3,4-(CH2)4-and tBu-groups are much bigger than the halogens, CF3 or CN. Therefore, we made a size-optimised Hammett plot using the σp-scale (Figure 69) which excludes the mentioned bulky substituents (orange crosses), as well as COOMe. ρ takes an intermediate value of 1.64, still higher than for DAIB in Figure 63a but lower than for NBE in the equivalent plot with all substituents included (cf. Figure 64); the accuracy of the fit is with R² = 0.92 also intermediate. A similarly adapted Hammett plot for the reactions' enantioselectivities (Figure 70) gives an even better fit with R² = 0.97 and ρ = 0.15. At this point, it is difficult to say whether the standard σp-/σp + -plots or the size-optimised plots are more representative for the NBE-catalysed system. It would be useful to extend DAIB's Hammett plot to the substituents we have used in this study and see if the bulky substituents do also deviate.

I.2.3.6 Effects of ortho-substituents on the substrate

In addition, we tested also two substrates which are sterically crowded around the aldehyde, with one or two methyl substituents in the ortho position in addition to the para position. The results are shown in Table 6. The o,p-disubstituted benzaldehyde doesn't behave differently than its pmonosubstituted counterpart in Figure 59: the eeP difference between enantiopure and scalemic ligand is very small but still hyperpositive. However, the trisubstituted benzaldehyde yields an eeP at 100% eeL which is significantly higher than with the other substrates; it is the only one to be over 80% eeP. The eeP with scalemic ligand is with 79% on the level of the mono-and dimethyl substituted benzaldehydes. The high eeP at 100% eeL of the trisubstituted aldehyde can have different origins, but since eeP at 20% eeL is not different from the other aldehydes, one possibility stands out: the trisubstituted benzaldehyde might have a lower affinity for or a slower reaction with the dimeric NBE catalyst than the other substrates. Thus, it may be catalysed mainly by the monomeric catalyst which yields higher eePs. This is interesting as it would preclude that the dimeric catalyst is more sensitive to steric effects than the monomeric one. Another possibility would be that eemax 1 and/or eemax 2 are higher than with the other substrates, but then the trisubstituted's eeP with scalemic ligand should also be higher -which is not the case.

eeL [%] eeP [%] 100 76% 85% 20 78% 79%
The behaviour of the trimethyl-substituted benzaldehyde prompted us to make a catalyst loading screening with ZnEt2 as in chapter I.2.2.1 (Figure 31a, p. 35). The results are shown in Figure 71. eeP increases from 20 to 10 mol% but then decreases at lower catalyst loading. A decrease can be explained by the achiral background reaction becoming nonnegligible, since a lower catalyst loading implicates a slower catalytic conversion. Globally, we observed that the reaction with the trisubstituted benzaldehyde is slower than with unsubstituted one. The background reactions are negligible at 0°C using benzaldehyde [96] but there is, to the best of our knowledge, no data for the trisubstituted one. We made a full NLE curve of the reaction with the trisubstituted benzaldehyde and performed a superimposition of the concentration screening (Figure 72, orange squares) with the NLE curve (blue dots). The NLE follows the concentration screening, the maximal eeP being attained at ca. 50% eeL and decreasing at lower eeL. This is probably also at the origin of the downslope at low ligand ee (eeL < 30%) being larger and much more gradual than the sharp slope of the unsubstituted benzaldehyde's NLE (which is only at 10% eeL and lower) in Figure 25, p. 31.

These results concord with the hypothesis we have expressed earlier: the high eeP of 85% (enantiopure ligand) which increases only slightly to 87% eeP (60-40% eeP) might come from the trisubstituted benzaldehyde having a low affinity for the dimeric catalyst. Thus, it would be mainly catalysed by the monomer even at 100% eeL (= high catalyst concentration) and cannot be subject to a strong eeP increase at lower eeL or lower catalyst loading. This should be verified by determination of the monomer's enantioselectivity eemax 1 from an Eyring plots using the trisubstituted benzaldehyde as substrate. Indeed, the eemax 1 of the monomer-only catalysed addition on unsubstituted benzaldehyde (88%), calculated from an Eyring plot, is close to the trisubstituted's maximum eeP of 87% with 10 mol% (see Figure 53, p. 60).

I.3 Conclusion on Hyperpositive NLEs & Outlook

In summary, we have evidenced within the enantioselective NBE-catalysed addition of dialkylzincs to benzaldehyde an unprecedented catalytic system, in which both a monomeric and a dimeric complex catalyse simultaneously, giving products with different eePs. This has been evidenced by catalyst loading screenings, temperature screenings, 1 H DOSY NMR experiments and kinetic investigations. Moreover, along with a precipitation of a meso-aggregate of the catalyst, this system is at the origin of a hyperpositive non-linear effect, which has never been observed before but which has been theorised by Henri Kagan 30 years ago -albeit with a different catalytic model than in our case. We have proposed an extension of the Noyori model to explain this catalytic system and have been able to determine the monomer's enantioselectivity in the reaction with ZnEt2 and benzaldehyde, eemax 1.

We have also proposed a way to calculate the system's KS' from Kagan's reservoir model, studied the role of the benzylic substituent in the NBE ligand and investigated the effects of ortho-and para-and substituents on the substrate. The latter's effect on the catalytic reaction has been quantified by constructing Hammett plots.

Further work will aim at completing some of the studies here. It would also be interesting to apply an NBE-derivative whose alcohol has been replaced by a thiol -such aminothiols have proven to give high eePs and strong (+)-NLEs [34,90,91] -and to study its effects on the hyperpositive NLE.

The ultimate goal would be to make a full modelling of the monomer/dimer catalytic system and of the hyperpositive NLE, similar to what Noyori did with DAIB. However, the complexity of the reaction and the number of different parameters which have to be accounted for will probably make this a very difficult task.

The hyperpositive NLE in itself is a fascinating curiosity, as it shows that something totally counterintuitive -the obtention of higher eePs with scalemic ligand than with the enantiopure ligand -is possible. It probably won't have an impact on subjects usually associated to NLEs in asymmetric catalysis, like the discussion about the origin of biological homochirality. The way how the (+)-NLE arises -precipitation of a heterochiral aggregate -is not new (although its extent is exceptional). However, the joint catalysis by a monomeric and a dimeric complex deserves further discussions. It is in striking contrast to the Noyori model where catalysis by aggregates is excluded, a factor which has been rarely questioned in the literature of dialkylzinc chemistry.

In this context, the main question is whether our catalytic system is an exception in the aminoalcohol-catalysed addition of dialkylzincs to aromatic aldehydes or not. In this study, we have shown that the NME ligand probably also catalyses through both a monomeric and a dimeric complex. A look into literature reveals that some catalysts show a similar behaviour to NBE and NME: Chaloner noticed, when using N-isopropyl ephedrine as catalyst, an eeP increase when diluting the reaction and increasing the equivalents of ZnEt2 (the latter should drive the dissociation of dimers, as does the dilution). [95,97] They also observed a 40% eeP-drop when decreasing the temperature from 20 to -20°C with unsubstituted ephedrine as catalyst. An even more dramatic temperature effect has been reported by Zhang and Chan using a chiral ortho-(2-pyridyl)-phenol. [START_REF] Zhang | [END_REF] Those observations concord with our model in which both monomeric and dimeric complexes catalyse, the latter yielding a lower eeP than the first; diluted conditions and high temperatures favour the monomer over the dimer. Chaloner even stated: "If we assume that other alkylation reactions, occurring through different intermediates, are less optically efficient, this would account for the dependence of the optical yield on the Et2Zn:ArCHO ratio", [97] and Zhang and Chang wrote : "The possible temperaturedependent competing reactions between the monomeric and dimeric zinc species as the active catalyst might account for the inversion temperature" . [START_REF] Zhang | [END_REF] Another point which might be of importance is the astonishing absence of ZnMe2 in the literature of aminoalcohol-catalysed dialkylzinc additions; only Noyori makes in his studies of DAIB an extensive use of it. When looking at our results with ZnMe2 and NBE as the catalyst, the low eePs (16-54%) and the long reaction times are indeed disappointing if one seeks to develop a high-performing and efficient catalytic reaction. Might similar results with other aminoalcohols have led the scientific community to put ZnMe2 aside? Noyori obtained up to 95% eeP with ZnMe2 and DAIB, this proves that ZnMe2 is not a bad reactant in itself, and we know that in our case the low eePs come from the dimeric catalyst's contribution to the reaction. Therefore, low eePs with ZnMe2 and other aminoalcohols might be a hint that the joint monomer/dimer catalysis is a much more common case than one might think.

Finally, it should be noted that even Noyori didn't totally rule out the possibility of catalysis by dimeric DAIB-complexes. He could exclude it when working in a certain range of concentrations and of DAIB:benzaldehyde:ZnMe2-ratios, but also stated explicitly: "The dimer mechanism […] should be seriously considered under some special conditions, e.g. at very high concentrations of the catalyst and reactants". [30] Chapter II: Non-linear effects with metallopolymers

The dialkylzinc chemistry we have been dealing with so far, as well as most of the reported systems bearing NLEs, encompasses discrete complexes consisting of a ligand with a single coordination site (usually a bidentate one) and a metal. Those complexes may then form aggregates which are responsible for the emergence of NLEs. However, very little is known about NLEs with ligands bearing two coordination sites (i. e. ditopic ligand) or even more. Those ligands can, if bound to the appropriate amount of metal ions, form higher aggregates known as metallosupramolecular polymers (abbreviated here as metallopolymers) or coordination polymers. This chapter will treat of chiral metallopolymers applied to asymmetric catalysis and how their structure induces NLEs or influences existing ones.

II.1 Introduction to metallopolymers II.1.1 Covalent and non-covalent polymers

Classic polymers are chain-or network-like macromolecules consisting of repeating subunits (monomers) which are linked via covalent bonds. Most synthetic polymers in our everyday-life such as polyethylene (PE) or polystyrene (PS) are issued from radical chain reactions on ethylene-derived monomers (Figure 73a); cationic and anionic polymerisation do also exist, e. g. activation and ringopening of epoxides with a Lewis or Bronsted acid. Polycondensations, performed by the addition of a diamine or a dialcohol to a di-carboxylic acid derivative, lead to polyamides (e. g. Kevlar, Nylon) and polyesters (e. g. polyethylene terephthalate, PET, Figure 73b). Those linear, one-dimensional polymers can have different lengths and shapes according to the way how they fold and interact with other polymeric chains. This gives them properties like thermoplasticity; branched polymers can have additional properties like elasticity and superabsorbtion (gels). Metallopolymers differ from classical polymers as they are built not only of organic material and covalent bonds. They are formally copolymers consisting two different monomers: a ditopic, organic ligand and a metal capable of binding to two different ligands [123] -in other words, a bifunctional Lewis base and a bifunctional Lewis acid (Figure 73c). Trifunctional ligands and metals do also exist, but since we will work only on chain-like metallopolymers we won't discuss them further. The incorporation of metals into polymers may add features such as redox activity, magnetism and photophysical properties, which lead to application in optoelectronics, [124] light-emitting andresponsive devices, [125] electronic conduction, [126] energy production and conservation, [127] information storage [128] and more. The metal as part of the polymeric chain adds also another property: dynamics. The non-covalent nature of the metal-ligand bond opens the possibility of reversible association: in contrast to covalently bonded polymers (except, e. g. polymers issued from reversible polycondensation), metallopolymers may break as easily as they are formed as shown in Figure 73c, especially if they are constituted of 1 st -row d-block metals with a high ligand exchange rate (such as Ni, Cu and Zn) bound to L-type ligands. X-type ligands, which necessarily act as counterions, are bound too tightly to the metal to allow reversible bonding; certain L-type ligand/metal-bonds may also be irreversible because of an exceptional affinity, e. g. Fe or Ru with terpyridine ligands. Most ligands in dynamic metallopolymers will have nitrogen-based L-ligands but oxygen, sulphur and phosphorus are also possible. The reversible bonding confers the material a certain adaptability which is exploited for example in self-healing materials. [START_REF] Enke | Self-Healing Materials[END_REF] II.1.

Dynamic metallopolymers in asymmetric catalysis

The bonding reversibility allows to combine the properties of discrete metal complexes with those of polymeric chains, such as activity in homogeneous catalysis from the first and insolubility in certain solvents from the latter. Polymers tend (but do not need) to be less soluble than related small molecules because the interaction of the chain with the solvent is in competition with the interaction with itself; the system's gain in entropy may also be small or even unfavourable if a solvation sphere consisting of a multitude of small molecules is needed to solubilise a single, big molecule. Our group has been taking advantage of this to apply chiral metallopolymers in recyclable enantioselective catalysis, coined as dynamic self-supported catalysis. [START_REF] Bellemin-Laponnaz | [END_REF] A general scheme is shown in Figure 74. The catalyst, consisting of a chiral ditopic ligand and a metal ion, is a metallopolymer in its resting state. Upon dissolution in a coordinating solvent it dissociates into discrete complexes with free coordination sites on the metal, which are able to perform catalysis. The addition of a noncoordinating solvent at the end of the reaction regenerates metallopolymer and drives its precipitation; filtration allows the recovery of the complex for a further catalytic reaction. This method to recycle catalysts is particularly elegant since the catalysis is performed in a homogeneous way while the recovery is heterogeneous. The literature is full of examples of homogeneous catalysts attached on solid supports such a covalent polymers or silica, non-dynamic metallopolymers do also exist ("self-supported catalysis"). However, those adducts don't dissolve at all so the catalysis has to take place on the surface of the material, in a heterogeneous way. This often leads to a loss of product ee in enantioselective catalysis. Dynamic self-supported catalysis circumvents this problem by making the catalyst homogeneous only when needed, but it has also some drawbacks. The reaction (by-)product shouldn't prevent the metallopolymer's regeneration and should also not co-precipitate; the reaction further should not change the nature of the ligand or the metal. Reactions involving changes in the metal's oxidation state may be problematic as the oxidation state has to be controlled in order to properly regenerate the metallopolymer. Thus, the metal mostly plays only the role of a Lewis acid in dynamic self-supported catalysis.

Our group mostly has worked with di-, tri-and tetratopic bisoxazoline ligands and Cu(II) salts, such as ditopic ligand 3 and CuOTf2 (Figure 75a), to perform Michael additions of β-ketoesters to azodicarboxylates, [131] chiral resolutions of rac-or and desymmetrisations of meso-1,2-diols (also Arai and Sakagami) [132] and Henry reactions. [133] The group of Garcìa used azabisoxalines and Cu(I)/(II) salts in the allylic oxidation of cyclic alkenes, [134] Henry reactions [135,136] and in cyclopropanation reactions. [137][138][139] The procedure of the latter example is particularly elegant as the metallopolymer is not soluble in dichloromethane but solubilises as soon as the diazo starting material is added -not the solvent but the reactant is responsible for the dissociation of the metallopolymer. Once the reactant is consumed the metallopolymer regenerates and precipitates, without the need for adding a non-solvent. Non-copper examples for dynamic self-supported catalysis are a modified Ru/NHCcomplex for the (achiral) ring-closing metathesis of dienes [140,141] and the enantioselective Michael addition of malonates and β-ketoesters to nitrostyrenes, catalysed by a diaminocyclohexane (DACH) based ditopic ligand 4 and NiBr2 (Figure 75b). [142]

II.1.3 Metallopolymers and NLEs

Since NLEs are an excellent tool to study catalyst aggregation in asymmetric catalysis, our group checked for their presence in two reactions: the 3-Cu(OTf)2-catalysed α-hydrazination of β-ketoesters (Figure 76a) and the 4-NiBr2-catalysed addition of malonates to nitrostyrene (Figure 76b). Both exhibit (-)-NLEs with a bell-shaped curve, which is an indication for higher-order aggregates (ML3 and upwards according to the Kagan model). [20] The negative sign of the NLE is also expected since the ligands are pseudo-C2-symmetrical in both cases: this favours a homochiral configuration around the metal when in a square planar environment, like on Cu(II) in these complexes; [143] the nickel atom in 4-NiBr2 is octahedral but with the Br anions on the apical sites, the ligands therefore coordinate in a square-planar fashion. On the other hand, a tetrahedral coordination as on Zn(II) and Cu(I) favours a heterochiral arrangement. [144][145][146] This is accordance with a Ph-substituted bisoxazoline/Cu(I)-complex being reported to have a (+)-NLE, [147] other NLEs with Zn(II) and Cu(II) result from the insolubility of a meso complex which complements or prevails over favoured coordination modes. [100,103] One report depicts a square planar heterochiral Ph-substituted bisoxazoline/Cu(II) complex as the origin for a (+)-NLE but without providing any proof for, nor any discussion about the metal's coordination mode. [148] However, the origin of the NLE with 4-NiBr2 is less clear: Evans and co-workers' homoleptic complex 52-NiBr2 (cf. Figure 77), from which 4-NiBr2 is inspired, shows a linear relationship between eeL and eeP. [58,59] Either both homochiral and heterochiral 52-NiBr2 are equally stable, which is unlikely, or the lability of the 2 nd ligand is sufficiently high in both cases to be completely displaced by the substrate, so that there is no remaining 52-NiBr2 which could act as a resting species. Mechanistic investigations point to the latter option. This makes the emergence of 4-NiBr2's (-)-NLE even more interesting: the ditopic ligand 4 shouldn't be a significantly better or poorer coordinant compared to 5. At the moment we can only speculate on the origin of this NLE. A possible explanation could be the emergence of a reservoir effect through coil-like structures. We know that the coordination polymer can be broken at any time and at any monomer through dissociation of a Ni-N-bond, leaving a vacant coordination site on the metal to which the substrate can bind; an associative mechanism for substrate binding is not possible on the coordinatively saturated, octahedral Ni(II) atom. However, if such a break point is somewhere in the middle of the polymeric chain and thus possibly wrapped inside a coil where the substrate cannot diffuse into, the break is much more likely to close through re-coordination. Therefore, the potential catalytic sites are on the surface of the coil while the inside is kinetically blocked. This is true for both homochiral and heterochiral polymers; however, if the homochiral configuration around Ni(II) is more stable, then we can expect homochiral polymers to form longer chains since they are less prone to spontaneous rupture. The longer the polymer, the higher the chance to form coils in which a part of the chain is buried and acts as a homochiral reservoir.

We have also to consider that chiral polymers might not just form random coils but well-defined 2 ndorder structures, like helixes in proteins and DNA for example. Those structures are more stable when consisting of homochiral components, which is believed to be a reason why homochirality is a necessity for biomolecules. [66] Stable and well-defined secondary structures might favour inter-strand interactions and thus induce a reservoir effect, similarly to what we have described above. It should be noted that in contrast to 52-NiBr2 and also 3-Cu(OTf)2, 4-NiBr2 is only partially soluble in DCM or toluene during the reaction. The interactions between polymeric strands, favoured by 2 nd -order structures, may decrease the solubility of the homochiral polymers and contribute to the formation of a homochiral reservoir. These reflections show how a polymeric structure may add properties to the catalyst which don't exist in discrete complexes. This has led us to think about the possibilities it offers: if the polymeric structure can induce NLEs which don't exist in the discrete version of the complex, what happens if we make a polymer based on a discrete complex which is already known for generating NLEs (Figure 78)? Might the additional reservoir effect from 2 nd -order structures or precipitation further amplify a complex' inherent NLE by making a ditopic version the ligand?

The aim of this chapter will be to find an answer to those questions by designing new metallopolymers which we will probe for NLEs. DAIB is not only one of the most enantioselective ligands for the addition of dialkylzincs to benzaldehydes, it bears also one of the most powerful (+)-NLEs known to date (cf. Chapter I.1.3, p. 17). [22] Therefore, we will synthesise a ditopic version of DAIB capable of forming a metallopolymer and study its behaviour in NLEs. In addition, we will also investigate ephedrine as a building block for ditopic ligands and compare its NLEs with the results presented in Chapter I.

Figure 8: Scheme for the stipulated (+)-NLE [22] amplification by using a ditopic version of DAIB capable of forming heterochiral metallopolymers. The synthesis of (-)-DAIB is a well-documented 5 step-synthesis starting from cheap (+)-camphor, as shown in Figure 79. [149,150] tBuOK-mediated nucleophilic addition of (+)-camphor to iso-amylnitrite gives oxime 6 in a single step and has proven to be superior to the 2-step procedure involving oxidation of (+)-camphor with toxic SeO2, followed by condensation of hydroxylamine. [151] In the next step, reduction with LiAlH4 affords aminoalcohol 7 which is then methylated twice by conversion into carbamate 8 and addition of iodomethane, a second reduction with LiAlH4 affords the final DAIB ligand. To make DAIB a ditopic ligand, we introduced an aromatic motif on the nitrogen atom which links to ligand moieties, similar as in ligand 4. Therefore, we reacted carbamate 8 with p-α,α'-dibromoxylene instead of MeI and reduced it to the final ditopic ligand 9, which was recovered in 55% yield after recrystallisation from MeOH. The purity of the starting carbamate 8 proved to be crucial for the success of the synthesis: aminoalcohol 7 contains small amounts of unwanted endo-diastereoisomers which persist in 8 and which may react with the dibromide. Once attached to the linker and a moiety of 8, the impurity is difficult to remove. A recrystallisation of 8 in AcOEt/Hexane is reported in the literature but proved to be difficult, we didn't obtain more than 39% yield. [152] Thus, ditopic ligand 9 is obtained in 18% overall yield from (+)-camphor in 5 steps. An alternative to the synthetic path depicted in Figure 79 would have been a double reductive amination of 7 on terephtaldehyde, as in the synthesis of 4, followed by methylation; a parent reaction with benzaldehyde is described. [153] However, the reaction gave a complex mixture due to hemiaminal ether formation and incomplete conversion, therefore we didn't pursue this synthetic pathway.

II.2.1.2 NLE with ditopic DAIB

Next, we evaluated 9 in the enantioselective addition of ZnEt2 to benzaldehyde. The procedure differs from the one used in Chapter I with NBE: the overall concentration is ca. two times lower, most datasets were obtained with 8 mol% catalyst loading (16 mol% catalytic sites) but a few, notably at low catalyst ee, were also made with 4 and 16 mol% catalyst loading. The reactions were performed in a toluene/hexane 1:0.9 mixture, some additional runs also in toluene only. Each reaction was run only once; eePs were determined via HPLC on a Chiralcel OD-H column. The results are shown in Figure 80, along with the NLE of DAIB reported by Noyori (orange dashed line). [22] Figure 80: NLE curve of the addition of ZnEt2 to benzaldehyde catalysed by 8 (blue dots) and 16 mol% (turquoise dot) 9 in a toluene/hexane mixture. Some experiments were also run in toluene only with 8 (yellow triangle) and 4 mol% (grey triangle) 9. The orange dashed line represents Noyori's NLE from (-)-DAIB (same benzaldehyde concentration, 8 mol% ligand). [22] The enantiopure ligand in 8 mol% catalyst loading in toluene-hexane affords excellent 98% eeP products which is close to the 98% of DAIB; a benzylated derivative of DAIB has been reported to yield 95% eeP at 20°C. [96] However, the enantioselectivity starts to drop already at 20% eeL (89% eeP).

A higher catalyst loading (16 mol%) doesn't give a higher but a lower eeP with scalemic ligand. Switching to toluene as the only solvent (orange and grey triangles) lowered eeP even more. No precipitate was formed during the reaction.

Globally, the chiral amplification with 9 is weaker than with DAIB. A 2 nd -order chirality like described in the introduction, which favours homochiral polymers, may work against the ligand's inherent (+)-NLE. The more probable scenario is that the functionalisation on the N-atom perturbs the dimerisation constants, so that the KHomo/KHetero-difference becomes smaller. This is not surprising: to be so much more stable than the homochiral dimer, the heterochiral one must be a finely tuned and optimised system which is already altered by small modifications. The eeP decrease through higher catalyst loading is difficult to interpret: Noyori observed only an eeP increase with 20% eeL DAIB, until eeP reached saturation at ca. 8 mol% catalyst loading. A higher catalyst loading favours aggregation: in case of DAIB it benefits the heterochiral dimer while the homochiral stays sufficiently labile not to interfere in the NLE. In our case the heterochiral aggregation is maybe already at its maximum, a further increase of catalyst loading would lead only to more homochiral aggregation, which would work against the (+)-NLE -as a result, the amplification decreases. The catalyst loading increase may also have an impact on factors like the polymer chain length, whose impact on the NLE is difficult to predict. Concerning the eeP decrease using pure toluene as solvent: Noyori found enantiopure DAIB to catalyse as good in toluene as in mixtures with hexane and Et2O but he didn't check the solvent's effect on the NLE. [21] It is possible that with 9 the solvent influences the KHetero/KHomo ratio in a way that the heterochiral aggregate is disfavoured when switching to pure toluene. It is well-known that the solvent can have a strong impact on 2 nd -order structures. [154,155]

II.2.1.3 Outlook: alternative ligand design

The data presented in the last section are mere preliminary results but they are sufficient to conclude that we have to rethink the ligand design: it is highly doubtful that even an extensive optimisation of the reaction conditions might amplify the (+)-NLE to the level of DAIB or above. Moreover, we cannot be sure whether this is due to the ligand's polymeric structure or to the attachment of the linker to the nitrogen atom. To properly investigate the polymeric structure's effect on the NLE we have to rule out any influence of the linker on the coordination site. Therefore, the ditopic ligand must be redesigned with the linker being attached at some distance of the aminoalcohol.

A look into the literature reveals that there are indeed options to functionalise the back part of the bornane skeleton at carbons 5, 6 and 9, but they involve 2-4 synthetic steps starting from camphor (Figure 81). The first step is in common and consists of a bromination at the endo-3 position. A rearrangement (involving a chirality inversion) gives 10; [156] bromination at position 9 followed by debromination at position 3 gives 11; [157] a series of other transformations can also lead to 12. 10 can be further converted into alkene 13, which opens new options for functionalisation at C-5 and C-6 (hydroborations, Heck reactions). [156] A much more simple strategy is to iodinate cheap and available (+)-10-camphorsulfonic acid to give 14, however C-10 is closer to the future aminoalcohol -it is questionable whether a linker at this position will be without influence on the final ligand's active site. [158,159] Figure 81: Reaction scheme for the bromination of (+)-camphor at positions 5, 6 and 9, and for the iodination of (+)-10camphorsulfonic acid. (-)-6-endo-bromocamphor can be further converted into (-)-5,6-dehydrocamphor.

Once the camphor moiety has been halogenated we can proceed with the synthesis of the ditopic ligand, we propose the three different pathways shown in Figure 82. 11 can be dimerised via e. g. Pdor Ni-catalysed cross-couplings (path A), however this has to be done before we form the aminoalcohol using the methodology shown in Figure 79, otherwise the bromine might be removed during the steps involving LiAlH4. Given the purity problems we had for the synthesis of aminoalcohol 7, a double functionalisation on a ditopic camphor moiety might be even more problematic. Therefore, it might be better to substitute the halogen either by an alcohol which can be activated later, after having formed the methylated carbamate, by triflation or back-conversion into a halogen (path B). Cross-coupling followed by reduction of the ditopic carbamate would then yield the final ditopic DAIB. The alcohol may also be activated after reduction of the carbamate, but this affords a selective method leaving the aminoalcohol unmodified. The alcohol may also need an additional protection/deprotection step as it might interfer in other steps (carbamate formation, oxime addition).

In addition, we propose an alternative pathway (path C) where first an allyl group is attached to 11. This group is chemically inert to all transformations which will follow; the resulting aminoalcohol may then be dimerised via olefin metathesis with a Grubbs/Hoveyda-type catalyst. This is probably the shortest and less complicated pathway, but it also is the most limited concerning the choice of the linker. In path B we can choose to use longer or shorter linkers, aromatics, alkyl chains etc, which would be interesting since the nature of the linker (rigid, flexible, oriented…) is likely to have a great impact on the metallopolymer's properties. The three pathways are shown with 11 as starting material but applies as well to 14. The steps involving cross-couplings using 10 and 12 might be difficult because of the presence of β-hydrides, therefore the cross-coupling-method would have to be chosen carefully.

II.2.2 Ditopic Ephedrine

II.2.2.1 Ditopic Ephedrines 15 & 16: synthesis

Since the work on ditopic DAIB necessitates a lot of synthetic effort, we turned to ephedrine as a building block for ditopic ligands as it is cheap and readily available. The bridging group will also have to be attached to the nitrogen but this will be less of an issue in this project, as our goal here is not to obtain products with maximal eeP but to study the metallopolymer's behaviour in NLEs, to see if and how a polymeric catalyst influences catalysis and NLEs. For this purpose, we have synthesised two different ditopic ligands which differ in the nature of their linker: 15 has a flexible alkyl chain while 16 has a rigid, aromatic linker. The flexibility of the ditopic ligand has a big impact on the polymer's structure: a rigid one is more likely to form well-defined 2 nd -order structures while a flexible ligand should form more aleatory, coil-like structures. 93 15 and 16 have been obtained from a double nucleophilic substitution of ephedrine on 1,10diiododecane or p-α,α'-dibromoxylene, respectively (Figure 83). While the second is easily obtained with excellent yields, the first one needs purification via column chromatography to eliminate sideproducts, probably originating from elimination reactions on the alkyl iodide, resulting in a moderate yield of 56%. Both were applied in the enantioselective addition of ZnEt2 to benzaldehyde. The protocol follows the procedure for NBE in Chapter I, with the difference that we work with 10 mol% ligand since it represents 20 mol% in terms of active catalytic sites.

II.2.2.2 Ditopic ligand 15: catalysis & NLE

Figure 84 shows the eeL vs eeP plot of the 15-catalysed addition of ZnEt2 to benzaldehyde. The enantiopure ligand achieves a moderate eeP of 65%, which is very close to the alkyl-substituted monotopic ephedrine ligands NnBE and NME (cf. Chapter I.2.1.2, p. 29). What they also have in common is the absence of an NLE; the dots at 20 and 30% eeL are likely to be mere outliers. macrocycle. Although this is a homochiral interaction between both ends of the ditopic ligand, it is not an aggregation as it involves only one molecule. Therefore, it is concentration-independent and cannot generate NLEs. This phenomenon might be ruled out by using a ligand with a shorter linker which renders self-coordination impossible. Soai has worked with C2-and C3-linkers but without probing for NLEs. [160] Anyway, catalysis in conditions comparable to ours (except that he mostly deprotonates the ligands with butyllithium prior to ZnEt2 addition) yielded extremely low eeP with the C2-ligand (14%): the linker is probably so short that the neighbouring coordination site disturbs the catalytic reaction, and therefore also its aggregation. Slightly longer linkers such as C4-or C5chains are probably better suited for our studies.

II.2.2.3 Ditopic ligand 16: catalysis & NLE

(a) Temperature-dependent NLE Next, we evaluated 16 in enantioselective catalysis, which gives a dramatically altered picture. As shown in Figure 85, 16 generates a significant (+)-NLE. It is rather moderate at -20 °C but increasing the temperature enhances also the asymmetric amplification, resulting in a strong (+)-NLE at 40 °C.

Increasing the temperature to 60°C doesn't further enhance the (+)-NLE. The temperature profile in Figure 86 gives an overview of this evolution: while the 100% eeL-reaction stays almost perfectly constant at 75% eeP (similar value to NBE in Chapter I and higher than with 15) from -20 to 60°C, eeP at 20% eeL increases with temperature until it reaches a plateau of 67% eeP at 40°C. This kind of behaviour is, to the best of our knowledge, unpreceded and counter-intuitive: high temperatures should break aggregates and diminish the amplitude of NLEs, not enhance them. There are no temperature studies on classical NLEs in the literature, but the temperature screening on NBE in Chapter I.2.2.2 shows how the asymmetric amplification diminishes with increasing temperatures.

Interestingly, our observations with 15 and 16 parallel those with the monotopic ligands in Chapter I.2.1, where the ligand with an aromatic substituent also stands out with a distinct behaviour. However, there is a point where catalysis with 16 differs from NBE: no precipitate persists during the reaction. Only the enantiopure ligand forms a glassy, gel-like solid upon addition of ZnEt2, which disappears quickly after addition of benzaldehyde; the scalemic ones give clear solutions right from the start. Therefore, the chiral amplification with 16 is not precipitation-induced like with NBE and must have a different origin.

(b) Catalyst loading screening

This curious behaviour prompted us to make further investigations on 16. To see if there are more parallels to NBE we performed a screening of the catalyst loading as in Chapter I.2.2.1, the results are shown in Figure 87. The enantiopure ligand (blue dots) shows a behaviour similar to NBE: eeP increases as the catalyst loading is decreased, indicating catalysis by a less enantioselective homochiral aggregate (here, probably a polymer rather than a dimer). On the contrary, eeP goes up when the catalyst loading is increased using scalemic catalyst (20% eeL). The increase is significant between 1.25 and 5 mol%, at higher catalyst loading eeP reaches a plateau at 51% eeP. The eeP increase at high catalyst loading using scalemic ligand is a normal behaviour in NLEs of dialkylzinc chemistry: the higher the catalyst concentration, the more aggregates are formed which could act as an inactive reservoir; reaching a plateau means that all the minor enantiomer is trapped in inactive heterochiral aggregates. Noyori observed this behaviour with DAIB. [22] However, with 16 the eeP increase should be in competition with an eeP decrease due to a higher proportion of homochiral aggregate catalysis, as in the experiment with enantiopure ligand. It should be noted that we performed a similar catalyst loading screening using ZnMe2 as the dialkylzinc reagent. However, the results are again very different and not comparable with the presented work so far, therefore we won't discuss them here; they can be found in the supporting information (V.2.4, p.171).

(c) Temperature-driven equilibrium shifts? The point in which 16 clearly differs from NBE, and which is also the most peculiar one, is the amplification of the (+)-NLE at high temperatures with ZnEt2. This can be explained in two ways:

How
-the relative activity of heterochiral to homochiral/monomeric catalyst diminishes with increasing temperature. This would correspond to a decreasing g value in Kagan's ML2 model; -the distribution of hetero-and homochiral aggregates changes over temperature (Figure 88).

A higher proportion of heterochiral aggregate at higher temperature would lead to an increasing β-value, which leads also to a stronger (+)-NLE as long as g < 1 according to the ML2 model.

Without more data at hand, it is difficult to say which of the two (or if both) phenomena are taking place. However, the first hypothesis is viable only if there is a big difference in the ΔG # of the kinetic constants of both hetero-and homochiral/monomeric catalysts. Both kinetic constants increase with temperature, therefore the latter has to increase much more than the first at high temperatures.

Figure 88: Scheme for the temperature-dependent formation of heterochiral metallopolymers out of homochiral R and Smetallopolymers. The heterochiral polymers must be less active than the homochiral polymers in order to allow the emergence of a (+)-NLE.

A temperature-driven recombination of the aggregates, from homochiral-to more heterochiral polymers as in Figure 88, is interesting as it might be related to properties due to polymeric structures. If we consider the aggregates to consist of linear chains, then the heterochiral polymer may, for example, have a greater degree of freedom because of a less well defined 2 nd -order structure, which would be entropically favoured.

Another scenario is the formation of heterochiral macrocycles (Figure 89). Technically, an assembly of ditopic ligands and metals can also form a closed chain; it depends much on the constituents' structure and flexibility. A different relative stability of hetero-/homochiral macrocycles, compared to the corresponding linear polymers, might account for the temperature-dependent NLE. However, it is difficult to say which one would be entropically favoured: a single, polymeric chain may lead to several macrocycles and thus to an increased number of molecules in solution, however a linear chain should also have a greater degree of freedom than a closed cycle. An interesting precedent for such macrocycle formation is trianglimine 17 (Figure 90): it is formed quantitatively from enantiopure DACH and terephtaldehyde instead of the corresponding polymer. [161] Computational studies have led to the conclusion that 17 is not a thermodynamic but a kinetic product, resulting from conformational constraint of the reactive intermediates. [161,162] The use of racemic DACH yields a mixture of homo-and heterochiral isomers in a 1:1:3:3 ratio [(RRR):(SSS):(RRS):(RSS)], the heterochiral isomers being preferred. [163] Figure

II.3 Conclusion on NLEs with chiral metallopolymers

In summary, we have synthesised three new ditopic ligands: DAIB-derived ligand 9 and ephedrinebased ligands 15 and 16. All ligands have been applied in the enantioselective addition of ZnEt2 to benzaldehyde and probed for NLEs. 9 gave a less pronounced (+)-NLE than its monotopic counterpart; a redesign of the ligand in order to improve the NLE has been discussed. Ligands 15 and 16 have shown peculiar behaviours in NLEs: while the first has no NLE at all, the latter shows a strong (+)-NLE which increases with temperature; a catalyst loading screening showed that there are different catalytically active species even with enantiopure ligand, similar to NBE. The results with ligands 16 are promising as they might be an indication for the catalyst's polymeric structure having a significant impact on the NLE. However, more work is necessary to understand this behaviour, especially to find out which supramolecular structures complex 16-(ZnMe)2 adopts in solution and if those structures, or their distribution, change with temperature.

Chiral SFG was first described theoretically by Giordmaine in 1965, [165] but it is only in 2000 that Shen's group reported first experimental evidence using a concentrated solution of chiral limonene and IR-radiation. [166] A couple of years later, they published two studies using 1,1'-bi-2-naphtol (BINOL) where they expanded the application of SFG into the visible electromagnetic spectrum. [167,168] They used it also to perform 3D-imaging and to distinguish between layers of enantiopure and racemic BINOL, the latter being SFG-inactive. [169] Taupier and co-workers then applied SFG to solid samples by incorporating BINOL into a silica sol-gel. [164,170] Since the signal is generated only if the material is chiral, chiral SFG microscopy holds the promise of becoming an efficient tool to probe for molecular and supramolecular chirality, as quadratic optics allow much higher spatial resolution than linear optics. It responds to changes in concentration of media but may also reveal structural irregularities in solid samples. In addition, Taupier has been able to use SFG as an encryption tool: the BINOL-doped silica sol-gel becomes irreversibly damaged over prolonged irradiation. This is not detectable with a standard optical microscope but only with the SFG setup, as the deactivated zones do not generate any SFG signal (Figure 92).

Figure 92: Example of encryption using a SFG on a (2R,2'R)-BINOL-doped sol-gel film. [170] The letters "SFG" in c) have been etched into the sample by prolonged irradiation with the SFG setup, leading to an irreversible damage of the BINOL. These appear black because the SFG signal cannot be generated any more, while the surroundings (yellow) are still SFG-active. d) shows the same sample seen through an optical microscope, which cannot distinguish between etched and unetched material.

III.1.2 Fundamentals of chiral SFG

Chiral SFG is possible in any material which fulfils the following requirements:

-the material is isotropic, i. e. has no specific spatial orientation and extends uniformly in all directions, -it absorbs at the same λ as the generated ks radiation (300 nm in our setup), -it is not centrosymmetric, which is given if the material is chiral and enantiopure.

The requirements for SFG result from how the incident beams interact with the material. In this section, we will briefly discuss the physical fundamentals of SFG and non-linear optics in general, in order to understand the origin of these requirements.

III.1.2.1 Linear and non-linear optics

The interaction of a radiation's electric field E with a material leads to a polarisation of the latter, denoted as P, which is in turn a source of a new electromagnetic field. Usually, it is assumed that the polarisation increases in a linear way with E following equation (40) :

𝑃 ⃗ = 𝜖 0 𝜒𝑬 ⃗ ⃗ (40)
With ε0 being the vacuum permittivity and χ the electrical susceptibility. Equation ( 40) is an approximation valid for radiations at weak intensities; for high intensity radiation, e. g. resulting from a laser beam, additional higher-order terms must be considered, as described by the general equation ( 41):

𝑃 ⃗ (𝑛) = 𝜖 0 ∑ 𝜒 (𝑛) 𝑬 ⃗ ⃗ (𝒏) 𝑛 = 𝜖 0 [𝜒 (1) 𝑬 ⃗ ⃗ (𝟏) + 𝜒 (2) 𝑬 ⃗ ⃗ (𝟐) + 𝜒 (3) 𝑬 ⃗ ⃗ (𝟑) … ]

In contrast to (40), equation ( 41) is not a linear equation any more. Therefore, light-matter interactions following equation ( 41) are denoted as non-linear optics; in analogy to chapters I and II, we can speak also of a "non-linear effect" generated by the lasers' intensity. The interaction of the non-linear P with the electric field is at the origin of new optical phenomena, for instance SFG but also second-(SHG) and third-harmonic generation (THG), multi-photon-absorption and many others (Figure 93).

III.1.2.2 Polarisation and susceptibility in isotropic media

In chiral SFG, the generated radiation kS results from a 2 nd -order polarisation of the material, which is described by equation ( 42) in case of an isotropic material (we will discuss the non-isotropic case later in this section). It depends on the cross-product of the two incident electric fields (E(ω1) and E(ω2)) and on χchiral. This cross-product leads to the polarisation of kS being orthogonal to the plane defined by k1 and k2, which we will later refer to as "SPP mode".

𝑃 ⃗ 𝑆𝐹𝐺 (2) = 𝜖 0 𝜒 𝑐ℎ𝑖𝑟𝑎𝑙 (2) [𝑬 ⃗ ⃗ (𝜔 1 ) × 𝑬 ⃗ ⃗ (𝜔 2 )] (42)
χchiral is the non-linear susceptibility in chiral isotropic media. It accounts for the material's ability to generate the polarisation PSFG and thus to give rise to an SFG signal. According to equation (43), it depends on two factors: the density of molecules N and the orientationally averaged hyperpolarizability β. The higher these factors, the higher the probability to perform SFG: this is the reason why SFG has been mostly observed in the solid state or in highly concentrated solutions since diluted solutions lead to a low N.

𝜒 𝑐ℎ𝑖𝑟𝑎𝑙

= 𝑁〈𝛽〉

β is the most interesting factor as it accounts for two of the three prerequisites: chirality and absorption at the generated frequency ωs. It is expressed by equation ( 44):

〈𝛽〉 = 1 6ℏ𝜖 0 ∑ (𝝎 𝟏 -𝝎 𝟐 ) (𝝁 ⃗ ⃗ 𝒏𝒈 • (𝝁 ⃗ ⃗ 𝒈𝒎 × 𝝁 ⃗ ⃗ 𝒏𝒎 )) (𝝎 𝒔 -𝝎 𝒏𝒈 + 𝒊𝜸 𝒏𝒈 )(𝜔 1 -𝜔 𝑚𝑔 )(𝜔 2 -𝜔 𝑚𝑔 ) 𝑚𝑛 (44)
In equation ( 44) the material is considered in three different states: the ground state g, a first electronically excited state n and a second excited state m. This gives rise to three possible energetic transitions, as shown in Figure 94a. Each of these transitions is associated to a different transition dipole moment µ.

The three transition dipole moments are found in the blue part of equation ( 44) as a triple product. The vectors must not be coplanar but oriented along all three spatial dimensions (Figure 94b), otherwise the blue term turns zero and no polarisation is possible any more. This is possible only if the molecule itself has a well-defined spatial orientation along all three axes x, y and z, which requires the molecule to be chiral. Non-chiral molecules have a symmetry plane, therefore it is impossible to define an oriented z-axis for them (Figure 95). This leads their three µ to be in the same plane, the blue term would then turn 0. In the case of a chiral but racemic compound the blue term is ≠0 for each molecule, however it is of opposite sign for the two enantiomers. Therefore, the sum of the interactions is 0 and no SFG can take place. The red part of equation ( 44) is a resonance factor: the closer it gets to 0, the higher β becomes, which is achieved with ωs ≈ ωng; ωng is the frequency associated to the transition from the ground-to the 1 st excited state. This why this phenomenon is also referred to as "SFG near electronic resonance": if the material absorbs at a frequency ωng close or equal to the frequency of the emitted radiation ωs, β gets maximised and SFG is likely to be observed. iγng is an empirical correction factor which accounts for several attenuating effects, e. g. a variability in ωng, and is the reason why in practice the red term never gets equal to 0.

Figure 95: Scheme illustrating the spatial non-specificity of achiral molecules (with meso-tartaric acid as an example). Due to the symmetry plane (here the xy-plane

) the molecule's 3 rd spatial axis cannot be clearly defined, as both sides of the plane are identical. This leads the three transition dipole moments to be coplanar, which forbids SFG.

Technically, resonance of ωmg with ω1 or ω2 is also possible according to equation (44). However, the material would then directly absorb the laser beams (1-photon absorption), which would destroy the material given the lasers' intensity. Resonance at ωs also has another advantage: due to our experimental setup λs is necessarily at 300 nm, which is a wavelength easily attained in UV-visabsorption by substituting an aromatic ring with some donor and/or acceptor groups; 450 and 900 nm would afford a much more extensive e --delocalisation and/or metal-to-ligand transitions. We can also check a given molecule's λng to be close to 300 nm using UV-vis-spectroscopy, whereas λmg is difficult to verify -as well with experimental as with computational tools.

III.1.2.3 The advantage of isotropic media

As mentioned before, equation (42), and therefore also equations ( 43) and ( 44), are valid only for an isotropic material. Isotropicity is not a necessary requirement as SFG arises also from anisotropic materials but it simplifies the system considerably. In an anisotropic medium, with a crystalline structure for example, the interaction of k1 and k2 with the material and its response ks would not be independent from space anymore; it is not the same if the beams are e. g. parallel or perpendicular to one of the crystal's coordinates. Therefore, in an anisotropic material ωs, ω1 and ω2 would have to be expressed as vectors, which would lead to a multitude of different expressions for χchiral.

Moreover, an anisotropic material can give rise to SFG of non-chiral origin. The obtained signal thus would not be a reliable indicator for supramolecular chirality anymore, as it is difficult to distinguish between chiral and non-chiral SFG. Therefore, the isotropic medium does not only simplify the mathematical expressions but also the system's output. The only 300 nm-radiation emitted by an isotropic sample is SFG, and only if the material is chiral; SHG (Figure 93a) is forbidden in isotropic media because it would preclude that both incident lasers have the same frequency (ω1 = ω2) which would turn the green part of equation ( 44) to 0. The only problematic side-effect is frequency tripling (THG, Figure 93b) of the 900 nm-beam, leading also to a 300 nm signal. It arises in isotropic as well as anisotropic media, regardless of the material's chirality. However, our experimental setup allows us to cut the THG signal's contribution off, as we will explain in the following section.

III.1.3 SFG microscopy setup

Figure 96 shows the setup used for SFG experiments. A Ti:Sa-laser generates a 900 nm-beam which is split in two by a separator (S). One of the beams is converted to 450 nm in a BBO crystal (β-barium borate) and its intensity regulated with a filter; the other beam stays at 900 nm but is sent through a delay line to keep it in phase with the 450 nm-beam. Both then are polarised and sent through a 1 st objective, which focuses them to the same spot on the sample: this is where SFG takes place and where the 300 nm-signal is generated. A 2 nd objective turns the beams collinear again; the residual 450 and 900 nm-beams are filtered off and the 300 nm-signal is detected in a spectrograph.

As mentioned before, equation (42) precludes that the two incident polarised beams form a plane (P) which is perpendicular to the polarisation of the signal (S). This means that the polariser, placed at the right angle, can let the S-signal pass through and block orthogonally polarised signals; we refer then to the "SPP" mode (Figure 97a). Rotation of the polariser by 90° allows to selectively measure radiation which is not perpendicular, but parallel to the plane P ("PPP" mode, Figure 97b).

Figure 96: Scheme of the setup for the generation and detection of SFG. [START_REF] Taupier | Microscopie Par Génération de Somme de Fréquences Optiques : Application Aux Polymères de Coordination Chiraux[END_REF] M: mirror, S: separator, DM: dichroic mirror, BBO: β-barium borate.

Differentiating between SPP and PPP is useful to make sure that the recorded signal actually is of chiral origin. Achiral SFG, originating from possible anisotropic regions in the sample, may be polarised in several directions, not only along the S plane. A signal in PPP mode therefore indicates that the sample is not anisotropic and SPP signal possibly not or not entirely of chiral origin. In addition to achiral SFG there are also signals arising from single-beam-non-linear optics, like SHG and THG. SHG signals can arise only from anisotropic regions, interfaces or from impurities and are easy to differentiate from our chiral SFG signal, since λ1 and λ2 give SHG signals at 600 and 450 nm, respectively. However, THG from λ1 is at 300 nm and is allowed in isotropic as well as anisotropic material. Therefore, it is necessarily acquired along with the SFG signal. THG can be reduced by lowering the 900 nm-beam's intensity Iλ1 (ITHG ~ Iλ1 3 ) but at the expense of the SHG signal's intensity, see equation (42). Increasing the 450 nm beam-intensity to compensate is problematic as it may result in sample destruction due to two-photon absorption -the resulting 225 nm match the intense UV-bands of most aromatic molecules.

Figure 98: Scheme for the "in" and "out" modes in SFG microscopy experiments. In both modes single-beam phenomena like SHG and THG (dashed blue and red arrows) are generated, but only the "in" mode generates also sum-frequency (dashed green arrows). The "out" mode precludes SFG because λ1 and λ2 do not pass the sample at the same time.

To supress the THG's contribution from the measured signal, we record SPP and PPP spectra in an additional mode, "SSP out" and "PPP out" (Figure 98). The "out" modes (for out of coincidence) differ from the previous ones by putting a delay on one of the beams, so that both laser pulses do not pass the sample at the same time and SFG is not possible. This allows us to selectively acquire single-beam signals like THG which we then subtract from the "in"-mode spectra. This outcut has been realised on all SFG spectra shown in this work.

III.1.4 Metallopolymers in SFG

Our group started to work on this subject as it came out that one of our ditopic ligands has the properties needed to perform SFG microscopy. Ditopic bisoxazoline ligand 18 (Figure 99) is an unsaturated version of ligand 3 discussed in chapter II.1.2, the bisoxazolines being attached to the aromatic linker through a C-C double bond, and has been used before in a chirality-and coordination-mode-dependent copolymerization with metal ions. [144,145] The advantage of using a metallopolymer in SFG is that it has a lower tendency to crystallise, therefore it is isotropic and renders workarounds such as high-concentration solutions or incorporation into sol-gels unnecessary. The bisoxazolines are chiral and the doubly conjugated aromatic core acts not only as a linker but also as a chromophore absorbing close to 300 nm, so all requirements for SFG are fulfilled. Indeed, our group has been able to obtain an SFG signal from 18-Ni(BF4)2 by sandwiching a 0.05 M solution of 18 and Ni(BF4)2 in MeOH between two glass plates. [START_REF] Taupier | [END_REF] Slow evaporation of the solution yielded a film from which the SFG signal was obtained (Figure 100a). Cu(II) and Zn(II) gave also an SFG signal. [START_REF] Taupier | Microscopie Par Génération de Somme de Fréquences Optiques : Application Aux Polymères de Coordination Chiraux[END_REF] The absence of a PPP signal ensures that the SPP signal is of chiral origin. However, the ligand alone is SFG-inactive (Figure 100b); discrete Ni(II) and Cu(II)-dinuclear complexes with a 2:1 metal-to-ligand ratio gave an only a weak SFG signal (Figure 100c). Therefore, the SFG experiment acts as a probe for the complexes' polymeric organisation. Only the dinuclear complex from Zn(II) stands out with an SFG signal comparable to the metallopolymers. [START_REF] Taupier | Microscopie Par Génération de Somme de Fréquences Optiques : Application Aux Polymères de Coordination Chiraux[END_REF] a) b)

c)

The authors then checked for an SFG signal using a racemic ligand. Racemic limonene and BINOL have proven to be SFG-inactive. [164,[166][167][168] Metallopolymers constituted of racemic 18 form either homochiral metallopolymers of both enantiomers with Cu(II) or an alternated heterochiral copolymer with Zn(II). [144] Both yielded weak SFG signals (Figure 101). This may indicate SFG-active homochiral zones due to an inhomogeneous distribution of the enantiomers; a similar residual signal in racemic BINOL has been attributed to resonantly enhanced parametric light scattering. [169] The absence of an SFG signal with uncomplexed 18 is interesting as it gives rise to questions about the origin of the signal: the molecule just being chiral and absorbing at 300 nm is obviously not sufficient for SFG to take place. DFT calculations on free and complexed 18 have shown that the metal forces the two adjacent oxazolines to be in the same plane, leading to a distortion of the bisconjugated aromatic linker. [146] One of the possible conformations is a chiral helix-like twist which induces activity in circular dichroism (CD) spectroscopy; the uncomplexed ligand shows only negligible activity in CD. Therefore, the structure change-induced CD may be linked to the generation of sum-frequency. The lower conjugation of the double bonds with the aromatic core may also be the reason for the blue-shift of the linker's band in UV-vis spectroscopy upon addition of the metal.

b) a)

Figure 102: a) DFT-calculated "boat"-configuration of a dinuclear complex from 18 in which the ligand's chromophore is twisted in a chiral way, b) titration of 18 with Cu(BF4)2 monitored by CD, 2.5•10 -5 M in MeOH. While 18 bears only negligible CD features, the progressive addition of Cu(BF4)2 gives rise to an intense CD band. The inset shows the increase in CD intensity at 302 nm. [146] The aim of the work in this chapter will be to gather more information about chiral metallopolymerinduced SFG. For this purpose, we will design new ditopic ligands able to form metallopolymers and to apply them in SFG. Most of the ligands will be based on a structure similar to 18, namely with a bis-conjugated aromatic core, to obtain the required optical properties. The main component to have in mind when designing a ditopic ligand for application in SFG is, apart the chiral structure, the UV-vis-absorption: the molecule has to contain a chromophore absorbing at 300 nm. In 18, it is the bis-alkene-conjugated aromatic linker (Figure 103, red part of the left molecule). We wondered if a bis-imine-conjugated linker might have similar optical properties. The ligand could then be obtained from simple condensation of readily available chiral aminoalcohols and diamines on terephtaldehyde. (a) Aminoalcohol-based diimine ligands A series of diimines 19a-19g was synthesised from chiral aminoalcohols available in our lab and from terephtaldehyde in EtOH (Figure 104); only trans-2-aminoindanol 19d was reacted in DMF due to solubility issues. The final ditopic iminoalcohols were isolated mostly by evaporation giving quantitative yields; in some cases the product precipitates and was filtered, resulting in more variable yields.

Most of the ligands are in equilibrium with a closed form in which the alcohol has been added to the imine ("hemiaminal ether", Figure 105). This is possible on both coordination sites and gives rise to new stereocentres, resulting sometimes in complicated

(b) DACH-based diimine ligand

We made also a ligand derived from diaminocyclohexane (DACH). This originally started with ditopic ligand 4, which has been used before by our group in self-supported asymmetric catalysis (cf.

Chapter II.1.2, p. 83). [142] We attempted to oxidise the benzylic positions to obtain tetraimine ligand 20 using a method reported by Nicolaou (Figure 106). [173,174] However, the reaction of 4 with IBX in DMSO yielded a complex mixture of products with broad NMR peaks, some imine hydrolysis was also observed. Since the product cannot be purified by silica gel chromatography (all imines in this chapter hydrolyse on SiO2), we changed the synthetic strategy and attempted to condense two DACH units on terephtaldehyde. However, this resulted into the macrocycle 17 already discussed in Chapter II.2.2.3(c), p. 98. [161] 21 was formed quantitatively only when using a great excess of DACH (10 equiv), the purification being again difficult because of the hydrolysable imines. In order to circumvent trianglimine formation, we monofunctionalised DACH in three steps to obtain the dissymmetric amine 22, following a literature procedure (Figure 107). [175] 22 has only one primary amine and cannot form trianglimine 17, therefore condensation on terephtaldehyde gave ditopic iminoamine 23 in a similar fashion as the ditopic iminoalcohols. The whole synthesis is straightforward, high-yielding and doesn't require any further purification. before. [175] We then went on with the synthesis of metallopolymers (Figure 108). We chose Cu(II)-, Cu(I)-and Zn(II)-salts with weakly coordinating triflate or PF6 -anions to drive the coordination of two ligands on one metal; Ni(OTf)2 proved to be only sparingly soluble in common solvens. The complexes turned out to be all extremely sensitive to water, which precluded the use of hydrated BF4-salts. The Cu(OTf)2-complexes of ligands 19a-c are so sensitive that the solid compounds liquefy at air within a few seconds, even quick handling of the material didn't allow us to obtain a clean IR spectrum.

III.2.1.2 Complex synthesis & properties (a) Complex synthesis

Complexes from ligands 19f-g and 23 are stable enough to be handled at air for a short time, therefore our studies will focus on them. The Cu(I)-complexes are less sensitive to hydrolysis but oxidise rapidly at air, which is not surprising since there are no soft ligand atoms such as P or S to stabilise the +I oxidation state. Ligand 19d and its complexes proved to be problematic as they are insoluble in most solvent suited for complexation. The reaction works in DMF but remaining traces of the solvent, which we didn't achieve to eliminate, hindered the complexes' characterisation. Therefore, 19d and its complexes were not studied further.

(b) IR spectroscopy

Next, we characterised the complexes. IR spectroscopy proved to be a valuable tool as it gives us information about the materials in the solid state. Moreover, it can tell us if the complexes are metallopolymers or discrete molecules, like 1:1 metal/ligand complexes which do not polymerise because of e. g. steric hindrance.

The ligands' and complexes' most characteristic IR feature is the C=N-stretching. It usually doesn't overlay with other bands and is in the range of 1633-1644 cm -1 for the free ligands. Coordination on a metal leads either to a shift of the band to lower wavenumbers (+II salts: 8-11 cm -1 , CuPF6: 13-38 cm - 1

) or to the appearance of additional bands at higher wavenumbers. The number of imine bands for each ligand/metal combination is shown in Table 7. The presence of a single imine band in the complex precludes that all imine groups are equivalent, therefore the material is necessarily a metallopolymer. Two different imine bands are indicative of a discrete 1:1 metal/ligand complex in which one imine is coordinated to the metal and the other isn't; another possibility is a mixture of 2:1 complexes and of free ligand. We will consider only the complexes with a single imine band as metallopolymers, although we cannot exclude the possibility of non-equivalent imines inside of a metallopolymer.

Ligand CuPF6 Cu(OTf)2 Zn(OTf)2 19a - a - 19b - a - 19c - a - 19d b b b 19e 1 2 2 a 19f 1 1 2 a 19g 1 2 2 23 1 1 1
Globally, the iminoalcohols form metallopolymers only with CuPF6, with exception of 19d-CuOTf2.

Iminoamine 23 is the only ligand to give a single imine band with all metal salts tested and is therefore the best ligand to form metallopolymers. This may be due to the stronger donor properties of the amine: the alcohol in ligands 19e-g may be a too weak coordinant to displace the triflate ions, which occupy coordination sites and hinder the addition of a 2 nd ligand to the metal. Cu(I) is not as electron-poor as the +II-metals and doesn't require strong donor ligands to displace the PF6 -anion (which might also be a weaker coordinant than OTf -), therefore it facilitates the metallopolymer formation.

(c) UV-vis spectroscopy

Next, we verified the absorbance of the ligands and complexes by analysing them in UV-vis spectroscopy. Figure 109 shows the spectra of ligands 19e-g and 23 and their respective complexes. The cyclohexane-derived ligands 19g and 23 (black lines) have an intense absorption band at 277 nm and extending beyond 300 nm. Complexation on Cu(OTf)2 (blue lines) and Zn(OTf)2 (red line) shifts the band to 255 nm but doesn't affect much its intensity; a similar red-shift is observed with ditopic bisoxazoline 18. [144,146] This is due to the C-C double bonds not being fully conjugated any more with the central aromatic, thus increasing the energy required for the electronic transition. It is reasonable to think that a similar phenomenon takes place with our bis-imine ligands. The band of 19e-Cu(OTf)2 shifts less to the red than the other +II complexes (267 nm) and is less intense, however the spectrum was made in MeOH instead of THF -care should be taken when comparing this to the other complex spectra. It is also the only ligand whose chiral backbone is not fused with a cycle.

The CuPF6-complexes (orange lines) show a very distinct behaviour: the band shifts less to the blue (to 276 and 267 nm), loses approximately half of its intensity and becomes much broader. 23-CuPF6 even has a very large shoulder spanning from 350 to 600 nm: it could be the result of some additional phenomena, like metal-to-ligand charge transfer (MLCT) or exciton coupling between two nearby chromophores. This is consistent with the different imines bands in IR (from which one is similar to the free ligand's band) indicating the presence of different species; it could also be due to a low association constant, driving the complex' dissociation at the low concentration used to make the spectra.

Globally, the complexes all absorb at 300 nm with molar extinction coefficients mostly around 8000 Lcm -1 mol -1 , which makes them à priori suitable for SFG. Though, we should be careful with this conclusion as not the solution, but the solid-state properties of the complexes are of importance for the SFG experiments. The UV-spectra may be different in the solid state; Taupier observed an additional band at 350 nm on a solid sample of 18-Ni(BF4)2. [START_REF] Taupier | Microscopie Par Génération de Somme de Fréquences Optiques : Application Aux Polymères de Coordination Chiraux[END_REF] We also do not know if the complexes are present as metallopolymers, -oligomers or as mononuclear complexes in solution, at the concentration used in Figure 109. A UV-vis-monitored titration of the ligand with a metal salt solution can tell if a metallopolymer is formed (cf. chapter III.2.2.3(c), p. 128), however this is difficult to perform with air-sensitive compounds without specialised equipment.

(d) Circular Dichroism

The free ligands have a negative band around 277 nm with an intensity of -2•10 -4 to -8•10 -4 °cm 2 dmol - 1 which is of the same order of magnitude than bisoxazoline ligand 18; indanol-derived ligand 19f shows, as in UV, a very weak signal. However, the CD signal does not increase but decrease upon addition of a metal salt, which is in striking contrast By analogy with the UV-vis-spectra, the Cu(I)-complexes behave differently than their Cu(II)/Zn(II)counterparts. The intensity stays at -2 to -5•10 -4 °cm 2 dmol -1 , there is even a sign inversion with 19f-CuPF6. Moreover, the spectra are more complex: an additional, small band appears at 340-350 nm with 19e-, 19f-and 19g-CuPF6 which is of inversed polarity. 23-CuPF6 shows a sinusoidal curve between 350 and 600 nm: such spectra can arise from exciton coupling between two nearby chiral chromophores. The wave-like shape is also present in its Cu(II)-counterpart, albeit with a weaker amplitude. Here again, we must treat the data with care as the CD in solution might be different from the CD in solid state. Taupier observed a slight blue-shift of the 300 nm-band of 18-Ni(BF4)2 in the solid state, the dinuclear complex 18-[Ni(BF4)2]2, however, gives rise to a new band of opposite sign. We also cannot tell if the low CD intensity comes from the complexes being weakly CD-active or from a mutual cancelation of positive and negative signals at the same wavelength. This will be further discussed in chapter III.2.2.3(d), p. 131.

III.2.1.3 Application in SFG spectroscopy

After having studied the ligands and complexes by classical spectroscopic means, we went on to apply them in SFG microscopy. Due to limitations in our technical and human resources we could test only a few compounds, derived from ligands 23 and 19f.

(a) Ditopic iminoamine 23

First, we examined the complexes of ligand 23 as it is the most promising candidate, forming metallopolymers in the solid state with all three tested metal salts. The films for the SFG experiments were obtained by drop-casting a THF solution of the respective complex on a quartz plate and letting the solvent evaporate at air. The films were then irradiated for a given time in the "in" and "out" modes and each mode recorded in the PPP and SPP modes. Figure 112 shows the SFG spectra of 23-CuPF6 and 23-Cu(OTf)2, the SPP and PPP signals resulting from subtraction of the respective "out" from the "in" acquisitions, as explained in chapter III.1.3, p. 105. The results shown in Figure 112 are mere preliminary results, as the complexes were made from a batch of 23 containing significant amounts of terephtaldehyde (20 mol%) and a monocondensed terephtaldehyde-diamine adduct (40 mol%, see Figure 111). All three spectra exhibit also an extremely strong PPP signal; its broken shape comes from "PPP in" and "PPP out" acquisitions both saturating the detector, the subtraction thus resulting in a value of 0. An SFG spectrum of uncomplexed 23 (Figure 113) shows the same strong PPP signal, but no SPP. Despite the bad purity of ligand 23 used for these SFG experiments, the results are rather promising: an SPP signal, which is not existent in the ligand alone, appears in the copper complexes; in case of Cu(II) the signal even is of exceptional intensity. The strong PPP signal seems to originate from the ligand itself, probably from the mentioned byproducts. Figure 114

23-Cu(OTf

+ byproducts

23-Cu(OTf)2

Though, the nature of the PPP signal is not totally clear. The byproducts may cause crystalline regions in the sample which allow achiral SFG (see chapter III.1.2.3, p. 105), however it would mean that the crystals are oriented in a precise fashion which generates achiral SFG only in the P plane. Another possibility is THG (see chapter III.1.3, p. 105), whose contribution is meant to be cut off by subtraction of the "PPP out" acquisition. Fluctuations in the THG intensity may cause a non-zero PPP signal after subtraction. It is also questionable if the stabilisers present in the THF solvent (BHT, a phenol which absorbs at 300 nm) may have an influence. Finally, we cannot exclude the metallopolymer itself also to contribute to the PPP signal via achiral SFG.

(b) Ditopic Iminoalcohol 19f

We achieved also to obtain an SFG spectrum from 19f-CuPF6 (Figure 115). Similar to 23-Cu(OTf)2, the SPP signal with an intensity of ca. 3000 was acquired in only 18 seconds and attests the complex' high SFG activity. A curiosity here is the intense and negative PPP signal. This may be again an artefact caused by a fluctuating THG; having in mind the hydrolysis problematic discussed before with ligand 23 and the O2-sensitivity of 19f-CuPF6, it might be also due to ligand decomposition during the SFG experiment. The "in" modes are usually acquired before the "out" modes, so if hydrolysis takes place in between, the sample is enriched in hydrolysis products when making the "out" acquisition. A stronger "PPP out" than "PPP in" spectrum results then in a negative signal. In conclusion, we can say that the iminoalcohol and -amine complexes are very promising for applications in SFG, however their water-sensitivity complicates considerably the interpretation of the spectra. Therefore, they are unsuited for SFG microscopy. Nevertheless, those preliminary results encouraged us to continue to work with the bis-imine scaffold; in the following, we will focus on the development of water-stable alternatives to the ditopic iminoalcohol and -amine ligands.

19f-CuPF6

III.2.2 Ditopic iminoaniline ligands

In the following, we will present design, synthesis and metal complexation of a new iminoaniline ligand. Although we didn't have the occasion to apply it in SFG microscopy, we could make a more extensive study on the ligand's and its complexes' structure as it presents some peculiar spectroscopic characteristics.

III.2.2.1 Ligand design

It is known that imines become less water-sensitive with an increasing number of aromatic substituents: doubly aliphatic imines afford water-trapping techniques (addition of molecular sieves, Dean-Stark apparatus) during their synthesis to obtain them in high yields. Simple aromatic imines such as in our iminoalcohol/-amine ligands don't need special precautions during the synthesis; doubly aromatic imines are even more stable. Therefore, we decided to replace the aliphatic backbone of the ligand's chelating part by an aromatic ring (Figure 116). Since the aromatic is not chiral we introduced a chiral substituent on the X atom, which may be achieved by the addition of chiral amines or alcohols on the aromatic ring. In analogy the iminoalcohols and -amines, we will call this type of ligand a ditopic iminoaniline.

III.2.2.2 Ligand & complex synthesis

We chose to start with a chiral amine, as nitrogen-based ligands are the better coordinants (the superior coordination capacities of 23 over the iminoalcohols confirms this). (R)-1-Phenylethylamine is a cheap and readily available amine which was added to 2-fluoronitrobenzene via nucleophilic substitution, following a method described by Žurek. [176] We could confirm refluxing 1-butanol and DABCO as a base to be more performant than toluene/K2CO3. [177] A slight modification of the procedure allowed us to obtain pure 24 in quantitative yield without any purification by chromatography. We then reduced the nitro group with metallic zinc as it is cheaper and more convenient to handle as Pd/C-catalysed hydrogenation with H2 gas or toxic hydrazine. The reduction goes smoothly and yields dianiline 25 after 3 h under inert atmosphere, however the light green solution darkens within moments as it is exposed to air. Žurek and co-workers noticed their own dianilines to be very O2-sensitive. Some impurities are visible in 1 H NMR even after quick work-up; column chromatography on SiO2 didn't yield a purer product. We decided to go on and to condense 25 on terephtaldehyde. Ditopic iminoaniline 26 precipitates in MeOH, however filtration didn't allow 123 us to get fully rid of the impurities from the previous step. Therefore, we obtained 26 in an only moderate but sufficient purity for preliminary investigations. For future work, we consider ameliorating the synthetic procedure by forming 26 and condensing it on terephtaldehyde in a one-pot procedure, so that 25 doesn't need to be handled at air. However, we either must make sure that the zinc reductant does reduce the imine or aldehyde group or filter excess Zn dust prior to terephtaldehyde addition under argon using Schlenk techniques. Korich and Hughes have reported a procedure in which nitroarenes are reduced and added to benzaldehyde in a one-pot reaction using metallic iron and HCl. [178] In the next step, we made the corresponding metal complexes using the same metal salts as with the iminoalcohol/-amine ligands. We were delighted to observe no hydrolysis when performing the reaction in wet THF, the ligand indeed is resistant to hydrolysis. This allowed us to make also a Ni(II)complex from hydrated Ni(BF4)2. However, the CuPF6-complex remains as O2-sensitive as the previous ones. All complexes have single, broad imine bands which are slightly shifted to higher wavenumbers, indicating that all are metallopolymers in the solid state.

III.2.2.3 Spectroscopic and structural studies

Once we had obtained the iminoaniline complexes, we went on to spectroscopic studies by UV-vis and CD. As shown in the following, the ligand bears some peculiar properties in UV-vis which made us perform a broader study than before, including DFT calculations and a study of the metallopolymer formation in solution.

(a) UV-vis spectroscopy

As the previous diimine ligands and complexes, we analysed the iminoaniline ligand 26 and its complexes by UV-vis spectroscopy. The ligand has a UV-band at 306 nm which shifts to ca. 286 nm upon complexation (Figure 119,a). The band is less intense with the complexes than with the free ligand, except for 26-Cu(OTf)2 which shows even a slight intensity increase. At 300 nm, the complexes have rather high molar extinction coefficients in the range of 16 000 to 24 000 Lcm -1 mol -1 . 27 has a band centred close to 300 nm similar to all our diimine ligands, but like ditopic iminoaniline 26 it has also an additional band with a maximum at 344 nm. This shows that there is indeed additional conjugation of the pending phenyl groups with the diimine linker, giving rise to a new absorption band. In 26 the chiral amines provide additional conjugation, thus shifting the band to higher wavelengths. The breakdown of the 446 nm-band upon addition of a metal salt shows not only that the metal occupies the amine's lone e --pair, thus preventing conjugation with the aromatic system, but that the peripheric aromatics might also be not conjugated anymore with the diimine linker (Figure 121). data and details to the calculations are found in the experimental part (IV.2.2.2, p. 160). Linear regression gave values for 𝜈̅ 0 , s, a and b (in cm -1 ) with an excellent fit, summarised in equation ( 46): 𝜈̅ 𝑚𝑎𝑥 (𝑐𝑚 -1 ) = 22 026 + 783𝜋 * + 431𝛼 + 395𝛽 | 𝑅 2 > 0.99 (46) s, a and b have moderate positive values, which accounts for a slight blue-shift upon solvent polarity increase: the higher π*, α and β, the higher the overall 𝜈̅ 𝑚𝑎𝑥 , the lower the wavelength λmax. The highest λmax is with cyclohexane (454 nm), the lowest with MeOH (428 nm). The band of 26 in the visible region responds to solvent polarity but also to H-bond-donors and -acceptors, in a somewhat lower measure.

The negative solvatochromism of ligand 26 indicates that its ground state is more polar than the excited state. [START_REF] Valeur | Molecular Fluorescence[END_REF][START_REF] Nigam | [END_REF] The higher the solvent polarity (and/or, in our case, its H-bond donor/acceptor capability) the more ground state is low in energy, the higher the gap to the first exited state. DFT calculations of 26 in several conformations confirmed this when considering the molecule being a quadrupole, with both negative poles centred on the peripheral parts of the ligand and both positive poles being in the linker (Figure 123). This is consistent with the ligand structure containing electrondonating amines on the outer parts and electron-withdrawing imines in the central part. The transition into the excited state is accompanied by a partial charge transfer from the peripheral parts into the centre of the molecule, making it locally less polar and, therefore, less sensitive to the solvent's polarity; this leads to the observed negative solvatochromism in UV-vis spectroscopy. The molecule's dipolar moment changes only slightly upon excitation and is not sufficient to explain the observed blue-shift of the visible band.

(c) UV-vis titration

Since 26 and its complexes have distinct UV-features and are stable towards moisture, we performed a UV-vis titration. It is one of the few methods allowing us to study the metallopolymer formation in solution, as long as the free ligand and the complex have distinct UV-vis features. [183,184] It consists in monitoring by UV-vis spectroscopy the continuous addition of a metal salt-solution to a solution of the ligand. The spectra's evolution shows with how many metal equivalents the ligand reacts and thus if it forms a metallopolymer or rather a mononuclear species, followed by a dinuclear one (Figure 124). Intermediate species, like 1:2 metal-ligand-complexes, may also be revealed. ) the metal forms a metallopolymer, with a 1:2 metal/ligand-complex as a possible intermediate. The metallopolymer may also be broken up to form a dinuclear complex, but usually it takes an excess of metal salt to achieve this. The evolution from one complex to the other can be visualised by a titration of the ligand with a metal, monitored by UV-vis spectroscopy.

The results of the titration of 26 with Cu(OTf)2 in THF are shown in Figure 125: the 446 nm-band indeed decreases upon addition of metal solution, after addition of 1.2 equiv. the band has vanished (Figure 125a). The slight increase with more Cu(OTf)2 is probably due to the d->d transition of uncomplexed Cu(OTf)2. The plot of the absorption at 375 nm (where free copper doesn't absorb) vs metal equivalents (Figure 125b) shows an induction period until 0.2 equiv., then the absorption falls until it reaches a plateau at 1.2 equiv.; addition of more metal doesn't change the curve anymore.

The UV-band at 292 nm (Figure 125c) increases and shifts progressively to 298 nm until 1.2 equiv. Cu(OTf)2, the addition of more Cu(OTf)2 further increases the band slightly because of the UV-band of uncomplexed Cu(OTf)2. The simultaneous decrease of the visible and increase of the UV-band takes place around an isobestic point at 329 nm. The plateau at 1.2 equiv. and the evolution of the 292 nm-band prove that the ligand and the metal indeed form a metallopolymer and not a discrete 1:1 complex, otherwise we should see significant changes in the spectra at >1.2 equiv. (Figure 126). The impulsion at the beginning of the titration and the reaching of the plateau at 1.2 instead of 1.0 equiv. indicate that, at this concentration, the complex is in equilibrium with free 26 and Cu(OTf)2, so that a slight excess of metal is needed to drive the metallopolymer formation. From 0.2 to 1.2 equiv. the spectra evolve gradually, as seen by the presence of the isobestic point at 329 nm, and do not reveal any intermediate species. [184] a)

c) b)

Figure 126: Pathway for the Cu(OTf)2-complexation of 26. The ligand does not form a mononuclear complex but a metallopolymer, as seen by the absence of changes in the UV-vis spectra after addition of 1.2 equiv. of metal.

Titration of the 26 with Ni(BF4)2 (Figure 127) and Zn(OTf)2 (Figure 128) resulted only in minor changes of the UV-vis-spectrum, apparently the complex is not formed at this concentration. This is surprising since we obtained the UV-vis-spectra of 26-Zn(OTf)2 and 26-Ni(BF4)2 (see Figure 119), by dissolution of the isolated complexes, at the same concentration. There is probably a kinetic issue, either preventing the complex from formation during the titration or from dissociation when dissolving the isolated complex.

(d) Circular Dichroism

Next, we measured circular dichroism for 26 and its metal complexes; the spectra are shown in Figure 129. Similar to the iminoalcohols and -amine, the ligand exhibits a weak negative CD-band at 300 nm; there is also a broad band around 440 nm. Complexation with metals makes the 440 nmband disappear, as in UV, and the 300 nm-band's intensity decreases.

We know from the UV-vis studies in chapter III.2.2.3(a) that the aniline and bis-imine moieties in the complexed ligand are not conjugated anymore. Therefore, the complexed ligand probably is not planar, but the absence of strong CD features indicates that the complexes' conformation either is not chiral, or it doesn't have a significant preference for a chiral conformer over its mirror image in solution. We know that first-row d-block metals usually are quite flexible in their coordination mode. Therefore, it might be reasonable to presume that in solution the metals bind to two ligands in various distorted modes. Those different structures may give rise to both positive or negative CD signals, the CD spectrum in Figure 129 would then represent the sum of the contributions of those different conformations. This hypothesis is supported by an interesting tendency: while Cu(II) and Ni(II) give weaker but still negative bands, Cu(I) and Zn(II) switch to a positive sign. The latter are known to favour a tetrahedral coordination sphere while Cu(II) and Ni(II) tend to make planar structures. This might be an indication of the influence of the coordination sphere on the complexes' structure: the tetrahedral mode might cause a structure change in the chromophore leading to the opposite helicity, while a planar coordination mode rather preserves the initial chromophore structure. If the metals indeed have a certain degree of freedom in their coordination mode, it would not be surprising to have various different conformations causing CD signals of opposite signs in one sample. This may apply also to the complexes from the ditopic iminoamine-and alcohols.

Therefore, it might be interesting to study the effect of less flexible 2 nd or 3 rd -row d-block metals on the CD spectrum. Moreover, since the conformational flexibility is favoured by the high degree of freedom in solution, it might also be interesting to perform CD in the solid state. Finally, we also have to consider another factor possibly influencing the CD signal. The metal ion must be a chiral centre in these homoleptic complexes, except if it is in a perfect square planar coordination mode. As the metal is coordinated to the chromophore, it is not only proximate but also electronically connected to it. This can have an influence on the chromophore's CD activity, independently of any coordination-induced change of the chromophore's structure. [185]

III.3 Conclusion on chiral metallopolymers in SFG

In summary, we have developed a new type of ditopic, bis-imine ligands based on chiral aminoalcohols and diamines. The ligands and their complexes with Cu(I), Cu(II) and in parts also Zn(II) and Ni(II) have been characterised by IR, UV-vis and CD spectroscopy. While the aminoalcohol-based ligands form metallopolymers only with Cu(I) in the solid state, except complex 19f-Cu(OTf)2, the DACH-and dianiline-based ones form metallopolymers also with the +II-metals. In addition, we have shown through a UV-vis titration that 26-CuOTf2 also forms a metallopolymer in solution. All compounds have an intense absorption band close to 300 nm in UV-vis spectroscopy but bear only moderate features in CD. The complexes mostly have less intense CD-bands than the corresponding ligands alone, indicating that, if the coordination of the metal induces a chiral conformation of the ligand's chromophore, it doesn't favour one conformer over its mirror image when in solution.

Ligand 26 bears also some peculiar features in UV-vis which have given us information about the extent of the e --delocalisation in the free and in the complexed ligand.

Furthermore, we have been able to perform chiral SFG experiments on complexes of ligands 19f and 23. Despite the persistence of a PPP-signal, probably due to complex decomposition on moisture, the bis-imine scaffold proves to be a promising structure for the study of SFG on chiral metallopolymers.

In future work we will apply the water-stable complexes derived from ligand 26 in SFG microscopy, in order to circumvent the hydrolysis problems encountered with the ditopic iminoalcohols andamines. We will also extend the spectroscopic studies (UV-vis, CD) to solid films of the bis-imines to see if there are difference to the liquid phase. This is especially interesting concerning the features in CD, as the activity of complexes from bisoxazoline 18 in SFG has been correlated to their intense activity in CD so far. From this, we hope to gain more insights into the origin of the SFG signal in chiral metallopolymers.

IV : Experimental Part

All reactions were performed at air using technical grade solvents unless specified otherwise. Dry solvents for reactions were purchased from Acros or Aldrich and used without further purification. O2-free solvents were degassed using standard techniques. Substrates for catalysis (benzaldehyde and derivatives) and (R)-(+)-1-Phenylethylamine were distilled prior to use and stored at 4°C under inert atmosphere. All other reagents were used without further purification. Amino alcohols used in catalysis and metal complexes from ditopic iminoalcohols/-amine were stored in a N2-filled glovebox.

NMR spectra were recorded on a Bruker Avance III HD 500 MHz (equipped with a CPPBBO "Prodigy" cryo-probe) and a Bruker Avance I 300 MHz spectrometer, with the residual signal of the NMR solvent as reference. [186] 1 H DOSY NMR spectra were recorded on a Bruker Avance III 600 MHz spectrometer. Electrospray ionization mass spectra (ESI-MS) were recorded on a Bruker microTOF Q. Fourier-transformed Infrared spectra (FTIR) were recorded on a PerkinElmer Spectrum Two equipped with a UATR Two module. UV-vis-spectra were recorded on an Agilent Technologies Cary 100 UV-vis spectrometer. Circular dichroism spectra were recorded at 16 °C on a Jasco J-1700. THF was distilled prior to use in UV-vis/CD spectroscopy and stored under argon; water-sensitive compounds were analysed in dry THF obtained by distillation over Na/Benzophenone. Other dry solvents (MeOH, DCM) were purchased from Acros or Aldrich and used without further purification.

Details concerning GC analysis and IR-monitored kinetic runs are specified in the respective sections. (-)-NBE was prepared by a modified literature protocol. [94] (-)-Ephedrine (5 g, 30.3 mmol, 1 equiv) and BnBr (3.95 mL, 33.3 mmol, 1.1 equiv) were dissolved in MeCN (50 mL), then K2CO3 (12.6 g, 90.8 mmol, 3 equiv) was added and the mixture stirred at reflux for 3h. After letting the mixture cool down to rt, water (50 mL) was added, the phases separated and the aqueous phase washed with AcOEt (2x40 mL). The combined organic phases were dried over Na2SO4 and evaporated. The residue was taken in DCM, placed on a plug of SiO2 gel (ca. 300 mL, 4.5 cm height), washed with 300 mL DCM and then eluted with 800 mL DCM/MeOH 97.5/2.5. Evaporation yielded a white amorphous solid. 6.622 g, 86% yield. Spectral properties are identical with literature data. [94] (1R,2S)-N-methylephedrine (-)-NME (-)-NME was prepared from (-)-ephedrine, formaldehyde and formic acid in an Eschweiler-Clarke reduction following a reported procedure. [92] Spectral properties are identical with literature data.

(1R,2S)-N-n-butylephedrine (-)-NnBE (-)-NnBE was prepared from (-)-ephedrine (3.0 g, 18.2 mmol, 1 equiv), nbutyl bromide (2.9 mL, 27.2 mmol, 1.5 equiv), K2CO3 (7.53 g, 54.5 mmol, 3 equiv) in MeCN (30 mL) following the procedure for (-)-NBE (30h reflux). [93] The product was purified by direct elution with DCM/MeOH 95/5 on 40 mL SiO2 gel. Evaporation yielded a colourless oil. 3.95 g, 98% yield. Spectral properties are identical with literature data. [98] (1R,2S)-N-(2-naphtyl)ephedrine (-)-N2NE (-)-N2NE was prepared from (-)-ephedrine (2.24 g, 13.6 mmol, 1 equiv), 2-(bromomethyl)naphthalene (3 g, 13.6 mmol, 1 equiv), K2CO3 (5.63 g, 40.7 mmol, 3 equiv) in MeCN (30 mL) following the procedure for (-)-NBE. Purification over 40 mL SiO2 gel, direct elution of the product with DCM/MeOH 95/5. Evaporation yielded a white amorphous solid. 4.03 g, 97% yield. Spectral properties are identical with literature data. [187] (1R,2S)-N-(4-methylbenzyl)ephedrine (-)-Me-NBE (-)-Me-NBE was prepared from (-)-ephedrine (3 g, 18.2 mmol, 1 equiv), 4methylbenzyl bromide (3.36 g, 18.2 mmol, 1 equiv), K2CO3 (7.53 g, 54.5 mmol, 3 equiv) in MeCN (30 mL) following the procedure for (-)-NBE. After aqueous work-up, the product was recrystallised from AcOEt/Hexane at 0°C. White crystalline solid, 4.77 g, 98% yield.

136

[𝛼] 𝐷 20 (EtOH, c = 1.00 g/100 mL) = +11.0 cm³g -1 dm -1 .

(1R,2S)-N-(4-methylbenzyl)ephedrine (-)-Br-NBE (-)-Br-NBE was prepared from (-)-ephedrine (3 g, 18.2 mmol, 1 equiv), 4bromobenzyl bromide (4.54 g, 18.2 mmol, 1 equiv), K2CO3 (7.53 g, 54.5 mmol, 3 equiv) in MeCN (30 mL) following the procedure for (-)-NBE. After aqueous work-up, the product was recrystallised from DCM/Hexane at 0 °C. White crystalline solid, 4.418 g, 73%. Spectral properties are identical with literature data. [188] (1R,1'R,2S,2'S)-2,2'-(decane-1,10-diylbis(methylazanediyl))bis(1-phenylpropan-1-ol) 15:

(-) Ephedrine (2.05 g, 10.2 mmol, 2 equiv), 1,10-diiododecane (2.00 g, 5.10 mmol, 1 equiv) and K2CO3 (2.81 g, 20.3 mmol, 4 equiv) were taken in anhydrous DMF (25 mL) and stirred at rt for 48h under argon. The mixture was concentrated under reduced pressure, then water (50 mL) was added. The mixture was extracted with DCM (3x50 mL), the combined org. phases were dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (NEt3-treated SiO2, cyclohexane/AcOEt 60:40) to yield a colourless oil. 1.34g, 56% yield. [𝛼] 𝐷 20 (EtOH, c = 0.952 g/100 mL) = -3.68 cm³g -1 dm -1 .

(1R,1'R,2S,2'S)-2,2'-((1,4-phenylenebis(methylene))bis(methylazanediyl))bis(1-phenylpropan-1-ol) 16:

16 was prepared from (-)-ephedrine (4.10 g, 24.8 mmol, 2 equiv), α,α′-Dibromo-p-xylene (3.27 g, 12.4 mmol, 1 equiv) and K2CO3 (13.7 g, 99.2 mmol, 8 equiv) in MeCN (50 mL) following the procedure for (-)-NBE.

The resulting oily product was filtered over a plug of SiO2 and eluted with AcOEt, then evaporated under reduced pressure to yield a colourless liquid which solidifies over time to a white solid. 5.09 g, 95% yield. [𝛼] 𝐷 20 (EtOH, c = 1.09 g/100 mL) = +18.3 cm³g -1 dm -1 .

IV.1.1.2 Camphor-derived ligand 9

(1R,2S,6R,7S)-1,10,10-Trimethyl-4-oxo-5-aza-3-oxatricyclo[5.2.1.0]decane 8: 8 was synthesised in 3 steps from (+)-camphor following a reported procedure. [149,150] It was additionally purified by recrystallisation from AcOEt/Hexane. Spectral properties are identical with literature data.

(3aR,4S,7S,7aS)-7,8,8-trimethyl-3-(4-(((3aR,4S,7R,7aS)-7,8,8-trimethyl-2-oxohexahydro-4,7methanobenzo [d]oxazol-3(2H)-yl)methyl)benzyl)hexahydro-4,7-methanobenzo [d]oxazol-2(3H)-one 8a:

Potassium hydride 35% w/w in oil (892 mg, 7.78 mmol, 4 equiv) was placed in an oven-dried twonecked 100 mL flask under argon and washed twice with pentane, then anhydrous THF (40 mL) was added, followed by 8 (760 mg, 3.89 mmol, 2 equiv). The mixture stirred at rt for 10 min during which H2 bubbling occurred, then α,α'-dibromo-p-xylene (514 mg, 1.95 mmol, 1 equiv) was added. The mixture stirred overnight to give a white suspension, which was diluted with DCM (40 mL) and quenched carefully with H2O (40 mL). Brine (20 mL) was added after H2 evolution had ceased, the phases were separated and the aqueous phase extracted with DCM (2x40 mL). The combined organic phases were dried over anhydrous Na2SO4 and evaporated to give a white crystalline solid. 1.15 g, quantitative yield. [𝛼] 𝐷 20 (DCM, c = 0.13 g/100 mL) = -85.4 cm³g -1 dm -1 .

(1S,2S,3R,4S)-

heptan-2-ol 9:

9 (1.10 g, 2.23 mmol, 1 equiv) was added in one portion to a solution of LiAlH4 (847 mg, 22.3 mmol, 10 equiv) in anh. THF (30 mL), then the mixture was refluxed overnight. The mixture was let to cool to rt and then carefully quenched with AcOEt (5 mL). Saturated aqueous Na2SO4 (5 mL) was added and the mixture let to stir until a fine white, easy-to-stir precipitate had formed. The mixture was filtered over celite and filter cake washed with AcOEt (3x15 mL). The filtrate was dried over Na2SO4 and evaporated under reduced pressure. The product was recrystallised at -20 °C from boiling MeOH to give a white solid. 575 mg, 55% yield.

MS (ESI+): m/z = 469.3791 ([M + H + ], 100%).

[𝛼] 𝐷 20 (DCM, c = 1.28 g/100 mL) = -5.80 cm³g -1 dm -1 .

IV.1.1.3 NBE-mimics for 1 H DOSY NMR

(4S,5R)-3,4-dimethyl-5-phenyloxazolidine 1:

1 was prepared from (-)-ephedrine and formaldehyde following a literature procedure. [189] Spectral properties are identical with literature data.

(4S,5R)-

(1R,2S)-N-benzylnorephedrine [190] (413 mg, 1.71 mmol, 1 equiv) and TsOH•H2O (9.77 mg, 51.3 µmol, 0.03 equiv) were dissolved in 10 mL dry acetone, then activated 4 Å MS were added. The mixture stirred under argon at reflux for 7 days (ca. 50% conversion in 1 H NMR), then the mixture was let to cool down to rt and evaporated. The product was taken in a small amount of DCM, placed on a plug of SiO2 gel, and eluted with DCM. Evaporation yielded a slight yellow oil. 202 mg, 42% yield.

The 1 H and 13 C signals of MeA and MeB were attributed using NOESY NMR (cross-peaks between MeB and the Ph and Me groups on the asymmetric carbon atoms; no cross-peaks with MeA).

MS (ESI+): m/z = 282.1866 ([M + H + ], 100%).

[𝛼] 𝐷 20 (EtOH, c = 1.05 g/100 mL) = -3.98 cm³g -1 dm -1 .

IV.1.2 Catalysis

IV.1.2.1 General procedure -Aminoalcohol-catalysed addition of dialkylzincs to aromatic aldehydes

In an N2-filled glovebox, (-)-NBE (23.7 mg, 20 mol%, 92.6 µmol) and a magnetic stirring bar were placed in an oven-dried vial, which was then closed with a septum-containing screwcap. The vial was put out of the glovebox and a 15% ZnEt2 solution in toluene (0.5 mL, 1.2 equiv, 556 µmol) was added via syringe; gas evolution occurred. The mixture stirred for 10 min, then was cooled to 0 °C and the aromatic aldehyde (1 equiv, 463 µmol) was added via syringe. The yellow solution stirred overnight at 0 °C and turned colourless, then was quenched carefully with 3 M aqueous HCl in an ice-water bath under vigorous stirring. The isolated organic phase was diluted with toluene, dried over Na2SO4 and analysed by chiral stationary phase GC (cf. Table 14).

The ligand ee was adjusted by preparing appropriate mixtures of the (1R,2S)-and (1S,2R)enantiomers. The reaction temperature was adapted and controlled standard with heating plates or a Huber TC45E cryostat equipped with a Pt 100 temperature probe. ZnMe2 was used as a 1.2 M solution in toluene (0.5 mL, 1.2 equiv, 600 µmol), diluted to 1 M with dry toluene (0.1 mL), with adapted monotopic ligand (20 mol%, 100 µmol) and substrate quantities (1 equiv, 500 µmol). Reaction media with ZnMe2 stayed colourless and were let to stir for 4 days (100% ligand ee), 7 days (80-5% ligand ee) or 30 days (4-1% ligand ee). Ditopic ligands were used in half the molar quantity (10 mol%, 46.3 µmol). Solid substrates were added to the ligand inside the glovebox. The vial was then closed, put outside the glovebox and the ZnR2 solution was added via syringe at the appropriate temperature.

IV.1.2.2 Catalyst loading screening

The general procedure was applied with adapted ligand and aldehyde quantities, as shown in tables Table 8 to Table 12. "x" refers the catalyst loading in mol%. ZnR2 was kept at 0.5 mL unless the amount of ligand fell below 5 mg, in which case the reaction was upscaled to 1, 1.5 or 8.0 mL. To keep the benzaldehyde concentration at 0.93 mol/L (with ZnEt2) or 0.83 mol/L (with ZnMe2), anhydrous toluene was added prior to aldehyde addition as indicated in the tables below. The competitive reactions were performed following the general procedure, with a reversed addition order. The two aldehydes were first added to the ligand in half quantities each (0.5 equiv, 417 µmol), followed by dry toluene (0.1 mL). 1.2 M ZnMe2 (0.5 mL, 1.2 equiv, 600 µmol) was then added at 0°C. A 75 µL-aliquot was taken and quenched quickly after 120 min (or 20 min for some exceptions, see Table 13), diluted with 225 µL toluene, dried over Na2SO4 and injected directly in GC. Conversion and eeP were determined by GC from the integrated signals of the respective aldehyde and its R-and S-products. The response of the aldehyde and the chiral alcohols to the FID detector were approximated to be equal since their number of carbon atoms differ only slightly, which allowed us to calculate the conversion following equation ( 47):

𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 = 1 - 𝐴𝑟𝑒𝑎(𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒) 𝐴𝑟𝑒𝑎(𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒) + 𝐴𝑟𝑒𝑎(𝑅 𝑝𝑟𝑜𝑑𝑢𝑐𝑡) + 𝐴𝑟𝑒𝑎(𝑆 𝑝𝑟𝑜𝑑𝑢𝑐𝑡) (47)
The initial rates v0X and v0H were obtained from equation (48):

𝑣 0𝑋/𝐻 = 𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 • 0.417 𝑚𝑜𝑙/𝐿 𝑅𝑒𝑎𝑐𝑡𝑖𝑜𝑛 𝑡𝑖𝑚𝑒 [𝑚𝑖𝑛] (48)
The enantiomeric ratio (er) was obtained from eeP using equation ( 49):

𝑃 𝑅 𝑃 𝑆 = 1 + 𝑒𝑒 𝑃 1 -𝑒𝑒 𝑃 (49)
Table 13 shows the eeP and conversion data of the competitive runs. Conversions of benzaldehyde were mostly around 6% for the 120 min-lasting reactions while the substituted benzaldehydes showed quite variable conversions from 2 (e --donating) to 20% (e --attracting). The eeP(X) and eeP(H) follow the same trend: the more X is attracting, the higher eeP(X) and eeP(H), with some exceptions (OPh, 3,4-(CH2)4, COOMe). OiPr and OMe have barely detectable eeP(X)s under 1%. 2.0 1.9 4.9 6.5 0.66 0.66

The data was used to calculate log(v0X/v0H) and log (er0X/er0H), which were then plotted in Microsoft Excel 2016 against σ and fitted to a linear trendline to obtain the Hammett plots.

IV.1.2.4 IR-monitored kinetic runs

The kinetic runs were performed following the procedure for catalyst loading screenings on a 2 mL scale in a Schlenk tube at 30 °C as single runs. The benzaldehyde's concentration was monitored by a ReactIR 15 equipped with a DS AgX Comp probe. The acquisition was started 30 sec after the addition of benzaldehyde to the NBE/ZnMe2 solution, during which the IR probe was poured into the solution.

Acquisition parameters: 2000 to 650 cm -1 , 4 cm -1 resolution; one acquisition every 5 min; 128 scans per acquisition. The experiments were let to run over 2 days; two additional days were added for low catalyst loading-experiments (2.5 and 5 mol%) with one acquisition every 10 min.

The kinetic profiles were obtained by integrating the 1739 to 1675 cm -1 region of the IR spectra (benzaldehyde ν(C=O) at 1706 cm -1 ) from a single point baseline at 1739 cm -1 . The integral values were normalised to the integral of the first acquisition, which is considered being approximately equal to the benzaldehyde signal prior to the ZnMe2 addition. The data was then pasted into the appropriated excel spreadsheet provided by Bures and Nielsen to obtain the normalised kinetic profiles. [191] The catalyst order c between two curves was determined by adjusting c to make the curves overlay over the first 50% conversion.

IV.1.2.5 GC-monitored kinetic runs

The kinetic runs were performed with NBE (2.5-20 mol%) following the general procedure on a 1.5 mL scale. Aliquots were taken and quenched rapidly at the indicated reaction times, diluted with toluene if necessary, dried over Na2SO4 and injected directly into GC. The conversion was determined using equation (47), as in the competitive reactions. The complete set of data can be found in Figure 130.

IV.1.3 General conditions for GC analysis

The ee's of the catalytic runs' products were determined by analysis on a Varian 3900 GC with CP-8400 Autosampler, Chiraldex GT-A 25 m x 0,25 mm column, carrier gas: He, sample concentration:

~1.3x10

-2 M, sample volume: 1 µL, split: 1/20. The separation of the two considered enantiomers was verified by injecting racemic samples of the chiral alcohols, obtained by addition of 3 M EtMgBr or MeMgBr on the corresponding aldehyde in anh. THF under argon, followed by aqueous work-up with sat. aq. NH4Cl and DCM.

For the competitive catalytic reactions (Hammett plots) the conditions for X = H were applied in first time. Once the respective aldehyde and chiral alcohols were eluted, the pressure was adapted and the oven was heated (20 °C/min) to the conditions listed for the respective substituted aldehyde. The aminoalcohol or diamine (2 equiv) and terephtalaldehyde (1 equiv) were dissolved in EtOH (10 mL) and left to stir for 3h at rt, then the solvent was evaporated. Z/E-isomerism of the imine groups was not determined. Some iminoalcohols are, when in solution, in equilibrium with the hemiaminal ether resulting from nucleophilic addition of the alcohol to the imine group and gave rise to complex NMR spectra.

(2S,2'S)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(propan-1-ol) 19a:

From L-Alaninol (1 g, 13.3 mmol, 2 equiv) and terephtaldehyde (893 mg, 6.66 mmol). After 3h stirring a white precipitate had formed which was filtered off and washed with EtOH. The filtrate was evaporated under reduced pressure, redissolved in EtOH (10 mL), stored at -20 °C overnight and the newly formed precipitate filtered and washed with cold EtOH. White solid, combined mass: 1.03 g, 62% yield. No hemiaminal ether formation. [𝛼] 𝐷 20 (EtOH, c = 0.996 g/100mL) = +105 cm³g -1 dm -1 .

UV-vis (MeOH, 3. [𝛼] 𝐷 20 (EtOH, c =1.08 g/100 mL) = +127 cm³g -1 dm -1 .

UV-vis (MeOH, 3.34 [𝛼] 𝐷 20 (EtOH, c = 0.924 g/100 mL) = -49.6 cm³g -1 dm - [𝛼] 𝐷 20 : not sufficiently soluble in common solvents.

(1R,1'R,2S,2'S)-2,2'-(((1Z,1'Z)-1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(1phenylpropan-1-ol) 19e:

From (1R,2S)-(-)-Norephedrine (1 g, 6.61 mmol, 2 equiv) and terephtaldehyde (444 mg, 3.31 mmol). Yellow, amorphous solid, 1.32 g, quantitative yield. Some traces of hemiaminal ether in MeOH-d4. [𝛼] 𝐷 20 (EtOH, c = 0.822 g/mL) = -285 cm³g -1 dm -1 .

UV-vis (MeOH, 5,28•10 -5 M): εmax = 25 000 (277 nm) Lmol -1 cm -1 .

CD (MeOH, 5. From 22 (1.03 g, 7.26 mmol, 2 equiv; prepared from (1R,2R)-DACH following a literature procedure) [175] and terephtaldehyde (487 mg, 3.63 mmol). Off-white solid, 1.39 g, quantitative yield. [𝛼] 𝐷 20 (EtOH, c = 1.04 g/100 mL) = -230 cm³g -1 dm -1 .

UV-vis (MeOH, 3.05•10 -5 M): εmax = 39 300 (277 nm) Lmol -1 cm -1 .

CD (MeOH, 5.22•10 -5 M): [θ]max = -48 700 (279 nm) °cm 2 dmol -1 .

IV.2.1.2 Ditopic iminoaniline 26

(R)-2-nitro-N-(1-phenylethyl)aniline 24:

24 was prepared by adapting a published procedure. [176] DABCO (8.35 g, 3.5 equiv, 74.4 mmol) was dissolved in n-butanol (20 mL) under an argon atmosphere, then 1-Fluoro-2-nitrobenzene (2.24 mL, 1 equiv, 21.3 mmol) was added via syringe, followed by (R)-(+)-1-Phenylethylamine (3.25 mL, 1.2 equiv, 25.5 mmol). The solution refluxed under argon for 3 h and became deep red after a few minutes. The mixture was let to cool to rt, the solvent was evaporated and the residue taken in toluene (20 mL) and water (20 mL). 3 M HCl was added slowly until a pH of 1 was reached (approx. 35 mL), then the mixture was thoroughly shaken and extracted with toluene (3 x 30 mL). The combined organic phases were dried over Na2SO4 and evaporated to yield a bright red-orange oil. No further purification was necessary. Mass: 5.61 g, 99% yield. UV-vis (THF, 3.86 x 10 -5 M): εmax = 4146 (271 nm), 6641 (420 nm) Lmol -1 cm -1 .

[𝛼] 𝐷 20 (EtOH, c = 1.13•10 -2 g/100 mL) = -830 cm³g -1 dm -1 . (R)-N [𝛼] 𝐷 20 (EtOH, c = 9.96•10 -3 g/100mL) = -1054 cm³g -1 dm -1 .

CD (MeOH

IV.2.1.3 UV-vis reference compound 27

Terephtaldehyde (1 g, 7.46 mmol, 1 equiv) was suspended in EtOH (15 mL), then aniline (1.7 mL, 18.6 mmol, 2.5 equiv) was added. The suspension dissolved instantly, then a precipitate formed within a few minutes. After 1 h 1 H NMR indicated full conversion, the mixture was then filtered over reduced pressure and the filter cake washed three times with EtOH. The slightly yellow, thin plates were dried under vacuum. 1.87 g, 88% yield. Spectral properties are identical with reported data. [192] IV.

Complex synthesis

General procedure -Complex synthesis from diimines:

The diimine (1 equiv) and the corresponding metal salt (1 equiv) were dissolved in anh. MeOH or THF and stirred for 30 min athh rt under argon, then the solvent was evaporated. Reactions with ZnOTf2 were let to stir in a 1:1 THF-MeCN mixture overnight. The resulting product was recovered in quantitative yield and stored in a N2-filled glovebox. Complexes from aniline-derived ligand X were made at air, in technical grade THF and were stored at air. The complexes proved to be all too strongly coloured to obtain their [𝛼] 𝐷 20 .

19e-CuPF6:

From 19e (50 mg, 0.125 mmol) and Cu(MeCN)4PF6 (46.5 mg, 0.125 mmol) in MeOH, precipitates during the reaction. Bright yellow powder. With Dx,norm being the analyte's normalised diffusion coefficient, Dx the analyte's measured diffusion coefficient, Dref the reference's measured diffusion coefficient and Dref,fix a constant specific to the reference molecule.

Dividing Dx through Dref allows to cut off influences like temperature and viscosity since both molecules are subjected to the same conditions. However, it results also in a dimensionless factor which is meaningful only when comparing analytes to the same reference. Multiplying with Dref,fix, which is a constant value and empirically determined through linearization of Equation ( 52) (in fact, it is nothing but the reference's Dx,norm), turns Dx,norm back to a diffusion coefficient which is now "normalised", free of the beforementioned influences. The power of the ECC method lies in its general applicability: whatever the reference used, the same Dx,norm will be obtained; even the residual NMR solvent signal can be used as a reference. Stalke and co-workers have determined Dref,fix for a variety of reference molecules and plotted the obtained Dx,norm of a multitude of small molecules against their known molecular weight (MW) using the power law :

𝐷 𝑥,𝑛𝑜𝑟𝑚 = 𝐾 • 𝑀𝑊 𝛼 (53)
With 𝐷 𝑥,𝑛𝑜𝑟𝑚 being the normalised diffusion coefficient, K being a system-dependant prefactor, MW the analyte's molecular weight and α a factor accounting for the analyte's compactness. Linearisation by taking the logarithm of both sides allows isolation of MW.

From the various analytes (pentane, Si(SiMe3)4, BINAP, anthracene…) they obtained shape-optimised calibration curves which divide the analytes into three classes: compact spheres (CS, compact globular molecules), expanded disks (ED, flat polyaromatic molecules) and dissipated spheres & ellipsoids (DSE, less compact spheric or ellipsoidal molecules). The calibration curves (when used for a molecule with the appropriate shape) relate Dx,norm to MW with an astonishing precision: the standard deviation is of 4% and the maximum deviation of 9%. This is also true independently from concentration and temperature: the analysis of adamantane with the residual signal of toluene-d8 gave accurate MW from -75 to 100°C; various analytes at 120 mM gave identical or similar MW values compared to the standard concentration of 15 mM. It should only be ensured that reference and analyte cannot make unwanted intermolecular interactions: the MW of some molecules with large π-systems have been overestimated at high concentration, probably due to π-interactions; the residual signal of THF-d8 as a reference gave also overestimated MW values for Si(SiMe3)4 at temperatures below -50°C, presumably because of hydrogen bonding. Another factor is the molecular weight density: p-block and d-block elements from the 3 rd period on have a higher mass than C, H, O, or N but their volume does not increase in the same extend -their molecular weight density (MWD) is higher. If such elements contribute significantly to the analyte's MW they can lead to underestimated MW values from the present ECCs. For a whole molecule, MWD is defined by its molecular weight divided by the sum of the atom's volumes (approximated from their Van-der-Waals radii):

𝑀𝑊 𝐷 = 𝑀𝑊 𝑉 𝑊 = 𝑀𝑊 ∑ 3 4 𝜋𝑟 𝑤,𝑖 3 𝑛 𝑖=1 ⁄ (54)
With MWD being the molecular weight density, VW the analyte's total Van-der-Waals volume and rW the Van-der-Waals-radius of the atoms constituting the analyte.

Stalke and co-workers have defined their ECCs to work with molecules whose MWD are between 4.3 and 5.2•10 -29 gmol -1 m -3 . Thus, the sheer presence of heavy heteroatoms is not necessarily a problem as long as the analyte's total MW is within those limits. The ECCs have been successfully applied, e. g. in the determination of solution structures of Rb-and Cs-containing molecules. [113,[START_REF] Ojeda-Amador | [END_REF] However, analytes with MWD higher than 5.2•10 -29 gmol -1 m -3 are underestimated in their MW using the present ECCs. This deviation can be corrected with an empirical correction factor (Xcor); special calibration curves for bromine and iodine containing molecules have also been developed. Those workarounds work fine for organic molecules containing heavy halides but can be tricky for simple d-block metal complexes: Ferrocene and CpMn(CO)3 give reasonable MW values while PdCl2(PhCN)2 is heavily underestimated. [115] V.1.2 Kinetics: Visual Time-Normalised Analysis (VTNA)

VTNA is a technique which uses whole kinetic curves to determine the partial orders of the considered reaction and can even determine kobs. This is superior to the "v0-method" which consists in determining the initial rate v0 and then to plot log(v0) against log [Cat]. The data from several runs with different [Cat] gives a linear correlation which slope is equal to c, however this can be misleading if v0 is not representative for the whole catalytic reaction, e. g. because there is an induction period; it also affords considerable experimental effort and the correct determination of v0 can be difficult. On the other side, VTNA takes into account the whole reaction curve and is quite easy to set up. The techniques behind VTNA have already been used for more than a century by biologists but have been formalised and introduced to the chemistry community only recently by Jordi Burés. [117,191,196] The outcome of a kinetic runs consists of a plot [Sub] (or [P]) vs. time (t). It is mathematically described by the integrated form of equation ( 11):

-

𝑑[𝑆𝑢𝑏] = 𝑘 𝑜𝑏𝑠 [𝐶𝑎𝑡] 𝑐 [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 𝑑𝑡 ⇄ -𝑑[𝑆𝑢𝑏] [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 = 𝑘 𝑜𝑏𝑠 [𝐶𝑎𝑡] 𝑐 𝑑𝑡 ⇄ -∫ 𝑑[𝑆𝑢𝑏] [𝑆𝑢𝑏] 𝑥 [𝑅𝑒𝑎] 𝑦 [𝑆𝑢𝑏] 𝑡 [𝑆𝑢𝑏] 0 = 𝑘 𝑜𝑏𝑠 [𝐶𝑎𝑡] 𝑐 ∫ 𝑑𝑡 𝑡 0 ⇄ 𝐹([𝑆𝑢𝑏] 𝑡 , [𝑆𝑢𝑏] 0 , 𝜈 𝑆𝑢𝑏 , [𝑅𝑒𝑎] 0 , 𝜈 𝑅𝑒𝑎 ) = 𝑘 𝑜𝑏𝑠 [𝐶𝑎𝑡] 𝑐 𝑡 ⇄ [𝑺𝒖𝒃] 𝒕 = 𝐺(𝑘 𝑜𝑏𝑠 , [𝐶𝑎𝑡], [𝑆𝑢𝑏] 0 , 𝜈 𝑆𝑢𝑏 , [𝑅𝑒𝑎] 0 , 𝜈 𝑅𝑒𝑎 )𝒕 (55)
The x-axis is now a "t[cat] c "-axis as shown in Figure 131. The effect of the normalisation is that it cuts out [Cat]'s kinetic effect from the plot: if [Cat] is varied over different experiments while all other variables remain unchanged, then G will be identical for all chosen [Cat]. Graphically, it means that the curves all have the same shape; if put into the same graph those curves will overlay -as long as the right catalyst order is chosen. This is where the elegant simplicity of VTNA reveals itself: it is sufficient to plot the kinetic profiles into an Excel spreadsheet, to normalise their time axis and to adjust c until the curves visually overlay -this means that the right c has been chosen. In Figure 131 the two curves with 10 and 15 mol% catalyst do not overlay for c = 1 but they do for c = 0.4, so 0.4 is the partial catalyst order. The visual check is not an exact method but is sufficiently accurate to get reliable values; the human eye is also astonishingly good in identifying trends and outlying values. [117] The accuracy of the overlay may be additionally verified with mathematical tools such as linear regression. VTNA works even if there are only few points per curve or if there is a large error in the measured [Sub]t values. The time-scale normalisation is valid not only for [Cat] but also for the other reaction components [Sub] and [Rea], their partial orders x and y can also be determined this way. Moreover, the time scale can be normalised for [Cat], [Sub] and [Rea] simultaneously: this results in a single straight line whose slope is equal to kobs.

V.1.3 Linear Free Energy Relationships (LFER): Hammett plots

Louis Plack Hammett developed in the early 20 th century a methodology to compare different reactants in a reaction and to quantify the effect of their electron-donating or -withdrawing capabilities. For this, he developed the σ-scale which quantifies the electron-attracting (σ < 0) ordonating (σ > 0) effect of para-and meta-substituents on aromatic rings; it has been greatly extended since then. [197,198] Ortho-substituents have also significant steric influence on the reaction centre, therefore no σ-scale has been defined for them. The relationship between the substrate's reactivity (i.e. its reaction rate, expressed through the kinetic constant) and σ proved in many cases to be linear and became to be known as "Linear Free Energy Relationship" (LFER), following equation ( 57): [START_REF] Anslyn | Modern Physical Organic Chemistry[END_REF] log ( 𝑘 𝑋 𝑘 𝐻 ) = 𝜌𝜎

With kX being the kinetic constant of the reaction with substituted substrate, kH the kinetic constant of the reference substrate (X = H), σ the substrate's respective σ-value and ρ the "sensitivity constant".

Plots with log(kX/kH) vs σ are called "Hammett plots" and usually are linear, with ρ as their slope (Figure 132). ρ is an indicator for a charge buildup in the transition state associated to the ratelimiting step. If it builds up positive charge, it will be stabilised (and the reaction therefore accelerated) by electron-donating substituents and ρ is negative. A positive ρ-value stands for a negative charge-buildup which is stabilised by electron-attracting groups. In certain cases, ρ is not constant over a given range of σ; the plot then has the shape of a broken line or even a V-shape if ρ changes its sign. Such non-linear Hammett plots indicate a change in the rate-limiting step and/or a change of mechanism. One should keep in mind that the σ-scale is obtained from the pKas of the corresponding substituted benzoic acids (Figure 133a): the lower the pKa, the more the carboxylate anion is stabilised -i. e. by electron-attracting substituents -the higher the σ-value. The substituent's influence can be split into field, polarizability, inductive (the three are often summed up as "Field effects") and resonance effects. The latter depends a lot on the substituent's position (para-substituents can delocalise positive or negative charge onto the carbon ipso to the carboxylate, whereas meta-substituents

-0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8 1 1,2 -0,6 -0,1 0,4 0,9 1,4 log(k X /k H ) σ  ρ
don't) and its π-accepting (e. g. aldehydes, nitriles) or -donating properties (alcohols, amines). Specialised scales like σi/σr, the Swain-Lupton or Taft-Topsom-parameters separate field-from resonance effects. However, resonance is always defined as being confined inside of the aromatic ring as the benzoate cannot delocalise its negative charge into the ring, nor is the carboxylate a good π-acceptor. To account for molecules where there is significant "through-conjugation" into the reactive centre, special resonance scales have been developed (Figure 133b andc). The σ + -scale, obtained from the dissociation of phenyldimethyl chloromethanes, allows to quantify the effect of positive charge delocalisation; the σ --scale (from the deprotonation of phenols) does the same for the stabilisation of negative charges. As it is not always evident if through-conjugation is significant in a given reaction, or if there is a particular sensitivity to either field or resonance effects, it is best practice to plot the log(kX/kH) data against the different scales and to see which fits best.

V.2 Additional Results & Discussion

The present section gathers results which are not conclusive enough to add to the discussion in chapters I-III, but which are still of interest and which we wish to keep in this manuscript.

V.2.1 Additional complexes as references for 1 H DOSY NMR

V.2.1.1 Boron Complexes

The idea was to make metallacycles which cannot aggregate through coordination bonds, and therefore to be even closer to the structure of monomeric NBE-ZnMe (Figure 134). There are reports for BX2-aminoalkoxides similar to 28 in the literature. [190,199] The sole presence of two different stereoisomers due to the chiral tetracoordinate N atom cannot explain the complexity of the NMR spectra, there have to be more conformers and/or product degradation. We then changed the strategy and attempted first to synthesise the boric ester 29 and then to obtain 28 from a metathesis reaction; however, even after days at reflux in toluene with a Dean-Stark apparatus the condensation of NBE on boric acid didn't go past 2 equiv. of NBE for one boron. Reaction with BH3•SMe2 in THF at room temperature didn't give better results. NBE probably generates too much steric hindrance to allow the condensation of a 3 rd molecule on boron.

We turned then to another type of boracycle derived from catechol (Figure 135). The reaction of NME with catecholborane yielding 30-Me is described and has been successfully reproduced by us. [200] However, the same reaction using NBE instead of NME to give 30-Bn resulted again in complex 1 H NMR spectra. Substitution of catecholborane by pinacolborane gave clean 1 H NMR spectra for 31-Me and 31-Bn, but the products are most probably not suited for DOSY experiments. Both NMegroups in 31-Me appear as a single singlet, which indicates that the B-N-bond is labile at room temperature -the parent compound 30-Me shows two different NMe-singlets which are reported to merge together only at 55°C and higher. [200] The 1 H NMR spectrum of 31-Bn is even almost identical with that of the starting material NBE, only the CH-O-signal shifts significantly. This indicates that the boric ester has formed but that the boron is not coordinated to the nitrogen atom at all. The pinacol group seems to be too large to allow the coordination of boron to the nitrogen atom. Further evidence may be gained from 11 B NMR, where non-coordinated and N-coordinated boric esters bear signals with distinct chemical displacements (around 23 and 12 ppm, respectively). [200] Except 30-Me and maybe 31-Me, the present complexes are no suitable reference molecules to validate the DOSY methodology.

V.2.1.2 Zinc complexes

Next, we wanted to verify that the presence of zinc, a high MWD-metal, doesn't lead to underestimation of MW with Stalke's ECCs. To avoid complex aggregation as with NBE-ZnMe, the zinc atom needs to be coordinatively saturated; the whole molecule's MWD must also be below 5.2•10 -29 gmol -1 m -3 . We decided to make simple ZnX2-complexes with diamine ligand and carbonbased counter-ions (Figure 136); classical counter-ions like halides would increase the molecules' MWD. The complexes are all within the upper MWD-limit except 32-OAc, which is just on the limit of 5.2•10 -29 gmol -1 m -3 . decoordination of the ligand and therefore a MW underestimation. This wouldn't be surprising as ZnMe2 already is quite electron-rich, additional electron density from the ligand may be not very favourable. Indeed, the two NMe-signals in the 1 H NMR spectrum are separated at -20°C as expected for enantiotopic groups, but start to coalesce at 25°C to give a single NMe2 peak. This is accompanied by significative deshielding (Δδ = -0.19) of the ligand signals and shielding (Δδ = -0.19) of the ZnMesignal: both move towards the chemical displacement of the starting materials. However, the coalescence and the peak shift can also be due to topomerization as observed in enantiopure DAIB-ZnMe. [28] Figure 137: Temperature-dependent MW deviation of complexes 32-Me, 32-CN and 32-OAc.

On the other hand, Zn in complexes 32-CN and 32-OAc is less electron-rich and should be more tightly bound to the ligand. 32-CN is highly overestimated at -20°C but within the 9% limit at room temperature; 32-OAc is overestimated by 22% even at room temperature. An overestimation is contrary to the possible pitfall we await for Zn-containing analytes: here, we have to consider the possibility of aggregation induced by CN-or OAc-bridging between two Zn centres. In order to prevent anion-bridging, we designed L2X2-type ligand 33 and reacted it with ZnEt2 to form complex 33-Zn (Figure 138). Since the ligand acts as a counteranion it is tightly bound and the bulky tBu-groups should prevent the phenols from binding to other complexes. However, as shown in Figure 137, it is even more overestimated than the complexes from ligand 32. Recent, unpublished results from the group of Charles Romain (Imperial College London) revealed that the phenol's oxygen actually does bridge two Zn centres to form a dimeric complex, in the XRD-structure of an Al(III)-OR-complex of 33. Thus, it seems that none of the complexes of 32 and 33 are suitable, nonaggregating DOSY references. 3, R = Me). This comes from Kagan's definition of α being a constant, although the part of non-reacting catalyst necessarily changes when varying eeL. α is best defined as a maximal fraction of non-reacting catalyst which is attained only at eeL = 0. The NLE curve thus should converge to the dashed lines in Figure 32 for eeLs close to 0 and KS' being valid only at eeL = 0. However, we didn't determine α by drawing a tangent line on the NLE curve but by fitting the plot for equation (7) to low-eeL datasets, giving a slightly underestimated α. The resulting increase of the quadratic term in equation ( 27) can be compensated by taking eeLs slightly higher than 0. Therefore, it is best practice to use the same eeLs than those used to determine α to obtain representative values of KS'. A proper α determination by drawing the tangent line at eeL = 0 would probably give more accurate results but would require also a well-defined NLE curve for eeL < 1%.

V.2.2 KS' calculation

V.2.3 NBE-catalysed reaction of ZnMe2 to para-substituted substrates: conversion

This section is an appendix to chapter I.2.3.4(a), where we did a screening of different parasubstituted benzaldehydes in the NBE-catalysed addition of dialkylzincs. In addition to the reactions' eeP, we have had also a look at the conversion of the reactions with ZnMe2. ZnEt2 gives conversions over 90% after overnight stirring at 0°C, regardless of the aldehyde and eeL, ZnMe2 proves to be more sensitive to the substrate. Figure 139 shows the conversion of the reaction, with ZnMe2 and different aldehydes, after 3.5 days reaction time, at 20% (orange line) or 100% eeL (blue line). The conversion follows roughly the trend of eeP in Figure 60: the higher σp/eeP, the higher the conversion, the runs with scalemic ligand showing a throughout lower conversion than those with 100% eeL.

Here again, the substrates at σp > 0.1 don't necessarily follow the trend of the substrates at lower σp. CF3 is of particular interest since it shows a much higher conversion at 20% eeL than at 100%although there is 5 times less catalyst in solution in the first case than in the latter! This may be due to a low affinity or activity of the CF3-substrate for/with the dimeric catalyst -which is more present at 100% than at 20% eeL -or to a greater tendency of the chiral zinc alkoxide product to inhibit the catalyst at 100% eeL. It should be also noted that pCN-benzaldehyde shows a very low conversion with both scalemic and enantiopure ligand, however the next substrate in increasing σp-order, SF5, shows a normal behaviour: high conversions with both enantiopure and scalemic ligand, the latter being ca. 10% lower than the first.

V.2.4 16-catalysed addition of ZnMe2 to benzaldehyde

We performed catalysis with 16 and ZnMe2 as the dialkylzinc reagent. Figure 140 shows a temperature screening of the reaction with ZnMe2 with either enantiopure (blue dots) or 20% ee ligand (orange dots). The switch to ZnMe2 parallels our results with NBE: compared to ZnEt2 eeP dramatically decreases (12% at 0 °C) but it also increases at higher temperatures, much like in the temperature screenings of NBE and ZnMe2 (chapter I.2.2.2, p. 36). To our great surprise the scalemic ligand (20% eeL) gives a significantly higher ee than the enantiopure one: with ZnMe2 the 16catalysed reaction is hyperpositive! The eeP difference between scalemic and enantiopure ligand (ΔeeP) oscillates between 5 and 10%, the maximum being at 23 °C, there is no clear trend as with ZnEt2 in Figure 87. Another astonishing observation is the emergence of a white precipitate in the 20% eeL-runs over the course of the reaction, not right from the start like with scalemic NBE. The higher the reaction temperature, the faster the precipitation: it appears after a few hours in the 60 °C-samples, whereas in the 0 °C-samples it becomes visible only at the end of the reaction (3.5 days) as a fine haze. We couldn't observe any precipitate in the runs with enantiopure ligand. This drove us to conduct a 2 nd series of experiments with 20% eeL using a modified procedure (Figure 141): the ligand/ZnMe2-solution was let to stir at 60°C overnight to force the precipitate to appear in all samples, which were then let to cool down to the appropriate temperature; only then the benzaldehyde substrate was added and the catalysis started. Indeed, all samples contained a thick white precipitate after overnight stirring which persisted over the course of the catalytic reactions, regardless of the reaction's temperature. The eeP (Figure 140, reed triangles) are significantly higher than in the standard 20% eeL-runs, around +9-12% at 23 °C and higher; the 0°C-run stands out with +20%-difference. This precipitate is most probably a heterochiral aggregate whose production is increased or accelerated at high temperature. It is tempting to conclude that this illustrates an equilibrium shift towards a heterochiral aggregate, as discussed in chapter II.2.2.3(c). However, precipitation can also tip equilibria towards thermodynamically unfavoured species, therefore we cannot conclude on this result without having more data at hand. Une observation que nous avons faite lors de la catalyse avec NBE est qu'un précipité blanc apparait dès qu'on ajoute le dialkylzinc au ligand, mais uniquement si le ligand est scalémique -avec du NBE énantiopur la solution reste limpide. Ceci indique la présence d'un agrégat hétérochiral insoluble qui précipite ; en effet, filtration et hydrolyse du précipité résulte en l'obtention de NBE sous forme racémique (vérifié par polarimétrie). Ceci implique qu'à bas eeL, la concentration effective de catalyseur est faible puisque la majorité précipite sous forme racémique. Nous avons donc étudié l'évolution de eeP en variant la charge catalytique du ligand, cette fois uniquement énantiopur (Figure 145a). En effet, eeP augmente plus la charge en catalyseur est basse ; une conversion de l'axe « charge catalytique » en « eeL simulé » (on considère qu'un résultat à 10 mol% de ligand énantiopur est équivalent à 20 mol%, mais à 50% eeL où la moitié du catalyseur précipite) permet de superposer le screening de charge catalytique avec le NLE hyperpositif (Figure 145b). Les deux courbes concordent quasi parfaitement, l'hyperpositivité du NLE semble donc être lié à la concentration effective de catalyseur. Cette hypothèse a été vérifiée par plusieurs études : l'augmentation de la température de réaction, en utilisant ZnMe2 comme dialkylzinc, mène à une augmentation de eeP (Figure 146). Ceci est contraire à toute attente puisque l'énantiosélectivité d'une réaction diminue à température croissante, mais concorde avec notre hypothèse puisque les aggrégats se dissocient à haute température. Une plus grande proportion de monomères plus énantiosélectifs à haute température doit en effet mener à une augmentation de eeP. Le monomère et le dimère homochiral ont été observé en spectrométrie de masse ; des études en RMN 1 H DOSY ont mis en évidence l'agrégation du complexe NBE-ZnMe en solution à des températures de -20 à 60 °C, dans les mêmes conditions que pour les réactions catalytiques, en présence de ZnMe2 et en présence ou absence de benzaldéhyde (Figure 147a). La masse moléculaire moyenne (les échanges entre les différents complexes sont trop rapides pour pouvoir les distinguer à l'échelle de temps de la RMN) est plus haute que la masse du NBE-ZnMe seul à toute température, mais diminue plus la température est haute : ceci confirme la dissociation de dimères observé en catalyse plus tôt. En plus, des molécules ont été synthétisé qui miment la forme du NBE-ZnMe (notamment le squelette éphédrine et le cycle à 5 génération par la chélation du zinc) mais sans pouvoir s'agréger par coordination vu qu'elles sont purement organiques. Elles nous ont permis de valider la méthodologie que nous utilisons pour relier les résultats de la DOSY avec le poids moléculaire (Figure 147b). Finalement, nous avons fait des études cinétiques du système catalytique. L'ordre partiel en catalyseur est un bon indicateur pour l'agrégation de celui-ci : en général, cet ordre partiel est un paramètre constant mais qui peut varier avec la concentration en catalyseur si celui-ci s'agrège. Dans le cas d'un monomère actif et d'un dimère inactif, où une seule molécule du monomère participe à l'étape limitante de la catalyse, l'ordre est proche de 1 à basse concentration de catalyseur mais baisse et converge ver 0,5 à haute concentration ; ceci compense mathématiquement le fait que la concentration effective diminue à cause de la dimérisation. Nous avons donc fait des réactions catalytiques à diverses charges en catalyseur en suivant l'avancement de la réaction in situ par spectroscopie infrarouge. Les profils cinétiques obtenus ainsi ont été analysé par VTNA (Visual Time-Normalised Analysis) afin d'obtenir de manière l'ordre en catalyseur. La VTNA consiste à faire une transformation mathématique de l'axe du temps des profils cinétiques en une axe du temps normalisée au catalyseur. Ceci fait que, si le seul paramètre varié est la concentration en catalyseur, toutes les courbes se superposent à condition de choisir le bon ordre partiel. Ainsi, on peut obtenir l'ordre partiel de façon visuelle.

L'analyse par VTNA de tous les profils cinétiques n'a pas donné de résultats concluants : les courbes ne se superposent pas toutes à la fois, à aucun ordre en catalyseur. Ceci indique qu'en effet, l'ordre change avec la concentration en catalyseur. Nous avons donc procédé à une analyse segmentée ou uniquement deux profils adjacents ont été analysé à la fois. Le résultat (Figure 148) donne un graphe ordre partiel en catalyseur vs. charge en catalyseur atypique : l'ordre est de 1 à faible charge, diminue vers environ 0,4 à charge moyenne, puis augmente à nouveau à haute charge en catalyseur. Nous ne connaissons pas de précédent pour ce genre de comportement dans la littérature. Par contre, ce comportement atypique peut être expliqué par notre hypothèse : si nous considérons qu'à basse charge nous n'avons que du monomère et à haute charge que du dimère qui catalyse, et que les deux suivent un mécanisme réactionnel similaire (un seul complexe réagit avec un substrat et un réactif pour donner le produit final), alors nous nous attendons à un ordre partiel en catalyseur de 1 à haute et à basse charge, ce qui concorde avec nos observations. À charge catalytique intermédiaire, les deux catalyseurs sont présents : l'ajout de ligand n'augmente pas la vitesse de la réaction de façon proportionnelle puisqu'une partie du complexe résultant dimérise. Cette augmentation non linéaire de la vitesse résulte nécessairement en un ordre partiel en catalyseur différent de 1, ce qui correspond à ce que nous observons. Une étude théorique du système cinétique montre qu'en effet, la constante cinétique observée kobs (qui est constituée des constantes cinétiques respectives du dimère et du monomère et d'un facteur décrivant leur ratio par rapport à la quantité de ligand total) varie à charge catalytique intermédiaire. Une autre étude cinétique, dans laquelle nous avons étudié eeP en fonction du temps, montre en plus que le ratio monomère/dimère n'est pas constant durant la réaction (Figure 149). Plus la charge en catalyseur est basse, plus la réaction commence avec un eeP haut, mais dans tout les cas eeP augmente au fur et à mesure de l'avancement de la réaction. Ceci montre que le ratio monomère/dimère augmente au fur et à mesure du temps vu que le monomère est le catalyseur le plus énantiosélectif. La raison pour ce changement n'est pas totalement claire mais résulte probablement d'une interférence du produit de la réaction, qui influence l'équilibre monomèredimère et la concentration en complexes libres. Toutes ces études confirment l'hypothèse formulée initialement pour expliquer le NLE hyperpositif, nous pouvons donc conclure que nous avons bien un système catalytique où deux catalyseurs qui sont reliés par un équilibre monomère-dimère, catalysent l'addition de dialkylzincs au benzaldéhyde.

Ces deux catalyseurs donnent le même produit mais avec un eeP différent, ce qui cause avec la précipitation du dimère hétérochiral l'apparition d'un effet non-linéaire hyperpositif. En plus, nous avons fait des études additionnelles pour obtenir plus d'information sur le système catalytique. Nous avons varié le substrat en utilisant des benzaldéhydes para-substitués. Globalement, le NLE hyperpositif diminue et devient même un (+)-NLE simple en présence de substituants très donneurs ou très attracteurs. Nous avons utilisé ces substrats pour construire des plots de Hammett, où il s'est avéré que, pour quantifier le pouvoir donneur/attracteur des substituants en para, l'échelle σ + donne la meilleure corrélation entre les différents résultats de catalyse. Ceci diffère du DAIB qui marche mieux avec l'échelle σ et ceci pourrait donc être symptomatique du système à deux catalyseurs monomère et dimère ; par contre le système du NBE corrèle mieux avec l'échelle σ si on omet les substrats encombrants (tBu, OPh, OiPr), il pourrait donc y avoir aussi un biais par de la gène stérique. Cette étude nécessite plus de travaux, notamment des plots de Hammett faits à basse charge en catalyseur afin de pouvoir mieux discerner l'impact du système à deux catalyseurs sur ce genre de corrélation.

En revanche, l'étude de substrats substitués en ortho a montré que le catalyseur dimérique est probablement sensible aux effets stériques autour du centre réactionnel : le ortho,para,ortho'triméthylbenzaldéhyde donne un eeP anormalement haut avec le ligand énantiopur, qui n'augmente que très peu puis même baisse avec un eeL décroissant. Ceci indique que le catalyseur dimérique, qui est moins sélectif, ne joue qu'un rôle minoritaire dans la conversion du substrat et que le déplacement de l'équilibre du dimère vers le monomère n'a donc que peu d'influence sur le résultat de la réaction.

L'étude de variantes du NBE, où le groupement N-benzyle porte un méthyle ou bromure en para, ou bien est remplacé par un 2-naphtylméthylène, n'a pas donné de résultats significativement différents par rapport au NBE. Par contre, la N-méthyléphédrine (NME) montre une augmentation de eeP avec une charge en catalyseur décroissante similaire au NBE. Bien que le NME ne montre pas de NLE du tout (ce qui est probablement dû à l'absence de précipité hétérochiral), il semble être constitué du même système à deux catalyseurs monomère-dimère ; le NBE n'est donc pas un cas unique.

Finalement, nous avons fait aussi des études théoriques où nous avons appliqué le « modèle réservoir » de Henry Kagan au NLE hyperpositif du NBE. Ceci nous a permis d'obtenir le paramètre α, qui prend en compte la proportion de catalyseur inactif, et d'en déduire la constante KS' qui contient la constante de solubilité du dimère hétérochiral et sa constante d'association à partir de NBE-ZnMe monomérique. Nous avons également varié la charge catalytique et la température de réaction afin de trouver les conditions dans lesquelles uniquement le monomère est présent ; des plots de Eyring nous ont alors permis de trouver l'énantiosélectivité du monomère seul à 0 °C en utilisant ZnEt2. La forme des plots de Eyring, qui laisse deviner une double courbure en forme de vague, est corrélée au système à deux catalyseurs monomère-dimère ; ceci a pu être démontré par une prédiction mathématique des courbes de Eyring.

VI.2 Chapitre II

La deuxième partie de cette thèse de doctorat traite toujours sur les NLE en catalyse asymétrique, mais en utilisant un autre type de ligand : des ligands ditopiques qui, après coordination à un métal, sont capables de former des métallopolymères. Les métallopolymères ont des applications diverses en tant que matériaux, surtout par les propriétés qu'apporte le métal à la chaîne polymérique (magnétisme, luminescence, conductivité électrique, changement d'état redox…). Notre groupe a également utilisé des métallopolymères en catalyse asymétrique (avec un ligand ditopique chiral) en profitant des propriétés dynamiques du métallopolymère : la labilité de la liaison ligand-métal fait que le polymère peut être dissocié en espèces oligomériques ou discrètes, qui sont solubles et qui catalysent la réaction énantioselective, puis à nouveau réassocié par précipitation dans un contresolvent pour pouvoir être filtré et réutilisé. Une variation de la charge catalytique montre qu'avec un ligand 16 énantiopur, eeP augmente avec une charge catalytique décroissante de la même façon que NBE (Figure 152). Ceci indique qu'il y a apparemment le même phénomène de double catalyse qu'avec NBE, avec des bouts de chaînes qui catalysent avec un haut eeP et des milieux de chaîne (équivalent au catalyseur dimérique homochiral Le but de ces travaux est de synthétiser et d'appliquer en SFG de nouveau métallopolymères chiraux. Pour ceci, nous avons conçu des ligands ditopiques avec un lien aromatique doublement conjugué avec deux imines, de façon similaire que dans le ligand ditopique bisoxazoline. Une série de ligands a été obtenue par condensation de deux équivalents d'aminoalcools chiraux sur un équivalent de terephtaldéhyde ; une diamine dissymétrique à base de trans-diaminocyclohexane a également été utilisée (Figure 154). Les ligands ont été ensuite coordiné sur des sels de métaux à contre-ions peu coordinants (Cu(OTf)2, Zn(OTf)2, CuPF6) pour former des complexes. Ces résultats nous ont mené à poursuivre ce projet en développant de nouveaux complexes plus stables envers l'hydrolyse, afin de contrer les problèmes rencontrés jusqu'à présent. Le ligand ditopique 26 possède la même structure aromatique bis-conjuguée en guise de lien entre les deux sites chélatant, par contre les imines sont stabilisées par un 2 nd groupe aromatique qui sert support aux deux azotes chélatant. Les groupements chiraux sont maintenant attachés aux azotes périphériques (qui ne font pas partie du chromophore bis-imine). La synthèse a été effectuée en trois étapes simples, sans purifications et avec de bons rendements (Figure 156). Les complexes du ligand 26 forment tous des métallopolymère à l'état solide et absorbent vers 300 nm. Malheureusement nous n'avons pas pu les appliquer en SFG, en revanche nous avons pu faire des études spectroscopiques qui nous ont donné des informations structurales sur le ligand et les complexes. Le ligand 26 possède, en plus de sa bande UV, une bande centrée autour de 446 nm en spectroscopie UV-visible. Cette bande est inexistante dans les autres ligands et dans les complexes du ligand 26. Elle provient probablement d'une conjugaison englobant le lien bis-imine et en plus les aromatiques qui y sont attachés, le ligand libre doit donc être plan (Figure 157). Ceci a été confirmé par comparaison avec une molécule similaire comportant une bis-imine attaché à deux aromatiques et par des calculs DFT. La bande en question est sujette à un solvatochromisme négatif, que nous avons pu quantifier par une analyse de Kamlet-Taft, qui provient selon ces calculs DFT d'une réduction du moment quadrupolaire de la molécule. On peut lui associer deux pôles positifs sur le lien, correspondant aux imines pauvres en électrons, et un pôle négatif sur chaque aromatique périphérique, riches en électrons. Lors de l'excitation par absorption de lumière de la densité électronique est transférée des pôles -vers les pôles +, causant le solvatochromisme négatif et nécessitant la molécule d'être plane et conjuguée. Lors de la coordination avec le métal la conjugaison entre la bis-imine et les aromatiques périphériques est brisée, probablement parce que le ligand n'est plus plan. Catalyse énantiosélective, Chimie die coordination, éphédrine, effet non-linéaire hyperpositif, optique non-linéaire, génération de somme de fréquence.

Certains

VI.3 Chapitre III

A hyperpositive non-linear effect (NLE) was observed in the enantioselective addition of dialkylzincs to benzaldehyde catalyzed by chiral N-benzyl ephedrine. This is the first experimental evidence of such phenomenon were the maximum product ee is not achieved with an enantiopure, but a scalemic catalyst. The origin for this hyperpositive NLE was traced back to a joint catalysis by monomeric as well as homochiral aggregated catalysts which bear different enantioselectivities. With scalemic ligands, the precipitation of heterochiral aggregates decreases the amount of active homochiral catalyst in solution, thus shifting the equilibrium from the aggregated to the more enantioselective monomeric catalysts. The catalytic system was studied by varying catalyst concentration and reaction temperature, by analysis of the catalyst aggregation state via 1 H DOSY NMR, by kinetic studies and Hammett plots. A ditopic version of the ligand was also studied for NLEs, which in part turned out to be also hyperpositive.

New metallopolymers consisting of a ditopic, chiral ligand and a metal were developed for the application in sum-frequency generation (SFG). The ligands are prepared by the double addition of a chiral aminoalcohol or diamine on terephtaldehyde to obtain bis-imine-1,4-phenylenes absorbing at 300 nm. Some complexes exhibited a very strong activity in SFG but proved to be sensitive to moisture and thus were difficult to handle. A more stable variant based on a 2-aminoaniline was developed and its UV-vis-characteristics were studied.

Enantioselective catalysis, coordination chemistry, ephedrine, hyperpositive non-linear effect, nonlinear optics, sum-frequency generation.

I. 1

 1 Introduction to Non-Linear Effects in asymmetric catalysis I.1.1 Early studies: diastereomeric interactions

Figure 1 :

 1 Figure 1: General scheme for enantioselective catalysis

Figure 3 :

 3 Figure 3: Examples of NLE in asymmetric catalysis. Curve 1 shows a linear eeL vs eeP correlation, 2 shows a (+)-NLE and 3 a (-)-NLE.

Figure 5 :

 5 Figure 5: General scheme for enantioselective catalysis following the ML2 model. x, y and z represent the concentrations of MRR, MSS and MRS, respectively.

Figure 6 :

 6 Figure 6: Schematic example of a reservoir effect with heterochiral dimers as inactive reservoir (eeres = 0).

Figure 8 :

 8 Figure 8: Mechanism of the (-)-DAIB-catalysed addition of dialkylzinc to benzaldehyde.

10 )

 10 ℎ𝑒𝑡𝑒𝑟𝑜 (2𝛼 2 + 𝛼𝐾 ℎ𝑜𝑚𝑜 -([𝐶 𝑡𝑜𝑡 ] -𝐾 𝑎𝑠𝑠𝑜𝑐 [𝑅𝑒𝑎][𝑆𝑢𝑏]𝛼)𝐾 ℎ𝑜𝑚𝑜 ) 2(𝐾 ℎ𝑜𝑚𝑜 -2𝐾 ℎ𝑒𝑡𝑒𝑟𝑜 ) (With α = [R] + [S] and β = [R][S] (β ≥ 0). Since equations (

Figure 9 :

 9 Figure9: Mechanistic pathway for the (-)-DAIB-catalysed addition of dialkylzinc to benzaldehyde. The values given for Kassoc, KHomo and KHetero are those for the (-)-DAIB-ZnMe complex at 40°C.[29]

Figure 10 :

 10 Figure 10: Autocatalytic enantioselective addition of ZniPr2 to pyrimidyl-5-carboxaldehyde derivatives.

Figure 11 :

 11 Figure 11: Absolute asymmetric autocatalysis with statistical reaction outcome.

Figure 15 :

 15 Figure 15: a) General scheme for stereoconvergent kinetic resolutions, b) intrinsic (-)-NLE of stereoconvergent kinetic resolutions.[63]

Figure 16 :

 16 Figure 16: Scheme depicting the homochirality of biomolecules. a) DNA consists only of D-deoxyribose, b) polysaccharides, such as amylose, only of D-glucose, c) proteins only of L-amino acids.

Figure 19 :

 19 Figure 19: From left to right, (1R,2S)-(-)-Ephedrine, (1R,2S)-(-)-Norephedrine, their respective diastereoisomers (1R,2R)-(-)pseudoephedrine and (1R,2R)-(-)-norpseudoephedrine.

Figure 23 :

 23 Figure 23: Reaction Scheme for the synthesis of NnBE, NME and NBE from ephedrine.

Figure 25 :

 25 Figure 25: Observed hyperpositive NLE using (-)-NBE and ZnEt2.

Figure 26 :

 26 Figure 26: Observed hyperpositive NLE using (-)-NBE and ZnMe2.

Figure 27 :

 27 Figure 27: Scheme of Kagan's ML3 model. The two homochiral trimers are enantiomeric to each other and catalyse with the same rate but opposite enantioselectivity; same goes for the two heterochiral trimers.

Figure 5 :

 5 Figure 5: Graphical representation of computed hyperpositive NLE's using the ML3 model, with eemax(Homo) = 50%, eemax(Hetero) = 100% and a statistical distribution of homoand heterochiral complexes (minor enantiomer: S).[20]

Figure 29 :

 29 Figure 29: Presence or absence of a precipitate upon reaction of enantiopure or scalemic (-)-NBE with ZnR2 in toluene. The precipitate with a scalemic ligand corresponds to a racemic, heterochiral aggregate while the supernatant contains only enantiopure NBE-ZnR.

Figure 30 :

 30 Figure 30: Scheme of the proposed hypothetical monomer/homochiral dimer equilibrium of the NBE zinc aminoalkoxide. Aggregation is favoured at high catalyst concentration. Both catalyse the addition of ZnR2 to benzaldehyde with different enantioselectivities, leading to the observed hyperpositive NLE.

Figure 31 :

 31 Figure 31: Catalyst loading screening of the (-)-NBE catalysed addition of a) ZnEt2 or b) ZnMe2 to benzaldehyde. The trendlines (2 nd order polynomial) are intended for illustration purposes only.

Figure 32 :

 32 Figure 32: Superimposition of the hyperpositive NLE (blue), the catalyst loading screening (orange) with a) ZnEt2 or b) ZnMe2.

Figure 33 :

 33 Figure 33: Enantioselective NBE-catalysed addition of a) ZnEt2 and b) ZnMe2 to benzaldehyde at different concentrations.

Figure 34 :

 34 Figure 34: Temperature screening of the (-)-NBE (100% ee: blue dots, 20% ee: orange dots) catalysed addition of a) ZnEt2 and b) ZnMe2 to benzaldehyde. The trendlines (1 st and 2 nd order polynomial functions) are intended for illustration purposes only.

Figure 35

 35 Figure 35: a) Simulated and b) experimental ESI-MS spectra of monomeric NBE-ZnMe. The simulation was obtained from Prot Pi online Mass Spec simulator, www.protpi.ch.

Figure 36 :

 36 Figure 36: a) Simulated and b) experimental ESI-MS spectra of dimeric NBE-ZnMe. The simulation was obtained from Prot Pi online Mass Spec simulator, www.protpi.ch.

Figure 37 : 1 H

 371 Figure 37: 1 H NMR spectra of (-)-NBE-ZnMe in presence of 5 equiv. ZnMe2 at -20, 25 and 60°C.

Figure 38 : 1 H

 381 Figure 38: 1 H DOSY NMR analysis of (-)-NBE-ZnMe (0.1 M) in presence of ZnMe2 (0.83 M, orange dots) and of additional benzaldehyde (0.83 M, grey dots). Depicted are also the calculated MW of the monomeric NBE-ZnMe (black dashed line).

Figure 39 :

 39 Figure 39: Reaction scheme for the synthesis of the DOSY reference products 1 and 2.

Figure

  Figure 40: Deviation of the measured MW (toluene-d8, 0.17 M) from the calculated MW of 1 (blue dots) and 2 (orange dots). MWdev is calculated MW(measured)/MW(calculated), positive values mean that MW is overestimated (differs from Stalke's definition of MWdev).

Figure 41 :

 41 Figure 41: Example for a [Cat]-dependent change in catalyst order due to aggregation of the Pd-catalyst to an inactive dimer, in a Pd-catalysed Heck coupling.[117]

Figure 42 :

 42 Figure 42: Kinetic profiles of the (-)-NBE-catalysed addition of ZnMe2 to benzaldehyde with varying catalyst concentrations. The values of the benzaldehyde concentration were normalized to the initial concentration of 0.83 mol/L.

Figure 43 :

 43 Figure 43: Example of c adjusting using VTNA with a) c = 1.0 and b) c = 0.4. The two curves in each graph were obtained from different catalyst concentrations (blue curve: 0.15 M; orange curve: 0.10 M). The best overlay is obtained for c = 0.4 which is therefore the partial order in catalyst.

Figure 44 :

 44 Figure 44: Catalyst order c vs catalyst loading, with c being defined by equation (11). The error bars on each dot indicate which two kinetic curves have been used to determine c, which can be considered as a mean value over the respective Δ[Cat].

Figure 44

 44 Figure44gives a very interesting picture of c's evolution: it starts at c = 1 at low catalyst loading, decreases to 0.4 between 10 and 15 mol% but then increases back to 0.8 between 15 and 20 mol%. There is indeed a change of catalyst order when varying [Cat] but it is quite different from what is described in Figure41, where c converges to a lower value when increasing[Cat]. To the best of our knowledge, there is no precedent for such a behaviour where c decreases and increases again in a Ushaped curve. However, it can be interpreted in a way which fits into our theory on a joint catalysis by monomers and dimers, and which concords with the theoretical kinetic model from chapter I.2.2.5(b).

Figure 45 :

 45 Figure 45: Schematic hypothetical representation of the measured order c as a function of the catalyst composition, with c being defined by equation(11). At very low and very high catalyst loading only one catalyst is present, either monomeric R or dimeric RR; both have an intrinsic catalyst order of 1, which corresponds also to the measured catalyst order. For intermediate reaction conditions, where both catalysts exist at the same time, the gradually changing kobs value leads to a non-linear rate increase upon increasing catalyst loading, therefore c ≠ 1.

Figure 47 :

 47 Figure 47: Time-dependent eeP evolution of the (-)-NBE-catalysed addition of ZnMe2 to benzaldehyde at various catalyst loadings. The italic percentages indicate the approx. benzaldehyde conversion. The trendlines are for illustration purposes only.

Figure 6 :

 6 Figure 6: Presumed (DAIB-ZnMe)2-zinc alkoxide adduct.

Figure 49 :

 49 Figure 49: Proposed extension of the Noyori model for the enantioselective addition of dialkylzincs to benzaldehyde.

Figure 50 :

 50 Figure 50: Observed hyperpositive NLE curves (blue dots), catalyst loading screening (orange squares) and the reservoir effect (equation (7), dashed black line) obtained from the respective α-value with a) ZnEt2 and b) ZnMe2. α was calculated from datasets at low eeL (black circled blue dots). The trendline for the catalyst loading screening (orange dotted line; the respective function is shown in the orange rectangles) determines eemax for given eeL-values.

  With [R] and [S] being the concentrations of the respective monomeric catalyst enantiomers, [RS] the concentration of soluble heterochiral dimer and [RS]p the precipitated heterochiral dimer. Since the latter's activity is 1, KS = [RS].

Figure 52 :

 52 Figure 52: Extended temperature screenings at 2.5 and 20 mol% (-)-NBE with a) ZnEt2 and b) ZnMe2.

Figure 53

 53 Figure53: a) Eyring plot for the (-)-NBE-catalysed addition of ZnEt2 to benzaldehyde with 2.5 (blue dots) and 20 mol% ligand (orange dots). The dotted line was obtained from a fit to 5 points between 2.6 and 3.2 10 -3 /T (black circled blue dots) and represents the monomer's -ΔΔG ≠ /RT. The red dot corresponds to represents NBE's enantioselectivity (→ eemax 1 = 88%) if it was the only one to catalyse at 0°C. b) Calculation of monomeric NBE's thermodynamic data (ΔΔH ≠ 1, ΔΔS ≠ 1 and ΔΔG ≠ 1) from the linear -ΔΔG ≠ 1/RT-plot.

Figure 54 :

 54 Figure 54: Modelled Eyring plots. a) ΔHHomo equal to a1) -25, b1) -35, c1) -60 kJmol -1 ; b) ΔΔH ≠ 2 equal to b1) -1.6 (-17.6), b2) -0.6 (-16.6), b3) +0.4 (-15.6) kJmol -1 , the values in brackets are the ΔH ≠ R2-values used to make ΔΔH ≠ 2 vary; c) ΔΔS ≠ 2 equal to c1) 15 (-115), c2) 5 (-105), c3) -2 (-98) Jmol -1 , the values in brackets are the ΔS ≠ S2-values used to make ΔΔS ≠ 2 vary.

Figure 55 :

 55 Figure 55: Hyperpositive NLE of the Me-NBE catalysed addition of ZnEt2 to benzaldehyde.

Figure 56 :Figure 57 :

 5657 Figure 56: Hyperpositive NLE of the Br-NBE catalysed addition of ZnEt2 to benzaldehyde.

Figure 58 :

 58 Figure 58: Catalyst loading screening in the (-)-NME-catalysed addition of ZnEt2 to benzaldehyde.

Figure 59 :

 59 Figure59: Screening of para-substituted benzaldehydes in the (-)-NBE-catalysed addition of ZnEt2. Each substrate was used in a reaction with enantiopure (blue dots) and 20% ee ligand (orange dots).

Figure 60 :

 60 Figure 60: Screening of para-substituted benzaldehydes in the (-)-NBE-catalysed addition of ZnMe2. Each substrate was used in a reaction with enantiopure (blue dots) and 20% ee ligand (orange dots).

  Catalyst loading screening of pCF3-and pCN-benzaldehyde

Figure 61 :

 61 Figure 61: Catalyst loading screening of pCF3 (orange dots) and pCN-benzaldehyde (grey dots) in the NBE-catalysed addition of ZnEt2. The results for unsubstituted benzaldehyde (blue dots) are shown for comparison. The trendlines (2 nd order linear fits) are intended for illustration purposes only.

Figure 62 :Figure 63 :

 6263 Figure 62: NLE-curve for the (-)-NBE-catalysed addition of ZnEt2 to pCF3-benzaldehyde (blue dots). Catalyst loading screening of enantiopure (-)-NBE (2.5 to 20 mol%, orange squares) adapted to the eeL-scale as in chapter I.2.2.1. The orange trendline(2 nd order polynomial function) is intended for illustration purposes only.

Figure 64 :

 64 Figure 64: σp-Hammett plot of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes.

Figure 65 :

 65 Figure 65: Extended σp-Hammett plot of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes.

Figure 66 :

 66 Figure 66: σp + -Hammett plot of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes.

Figure 67 :Figure 68 :

 6768 Figure 67: σp-Hammett plot of the enantioselectivity of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes.

Figure 69 :

 69 Figure 69: σp-Hammett plots of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes. Bulky substituents (orange crosses) have been excluded from the linear fit to build the plot.

Figure 70 :

 70 Figure 70: size-optimised σp-Hammett plot of the enantioselectivity of the NBE-catalysed addition of ZnMe2 to substituted benzaldehydes. Bulky substituents (orange crosses) have been excluded from the linear fit to build the plot.

Figure 71 :

 71 Figure 71: Catalyst loading screenings of para-CN-and CF3-, ortho,para-ortho'-trimethyl substituted and unsubstituted benzaldehyde in the (-)-NBE-catalysed addition of ZnEt2.

Figure 72 :

 72 Figure 72: NLE-curve for the (-)-NBE-catalysed addition of ZnEt2 to ortho,para,ortho'-trimethylbenzaldehyde (blue dots). The catalyst loading screening of enantiopure (-)-NBE (2.5 to 20 mol%, orange squares) has been adapted to the eeL-scale as in chapter I.2.2.1. The trendline (orange dotted line, 2 nd order polynomial) is for illustration purposes only.

Figure 73 :

 73 Figure 73: Examples for a) ethylene-derived polymers, b) a polymer issued from polycondensation, polyethylene terephthalate (PET) and c) a metallopolymer consisting of a ditopic ligand (blue) and a metal (grey). The metallopolymer can be in equilibrium with smaller subunits, e. g. discrete ligand-metal complexes.

Figure 74 :

 74 Figure 74: General scheme for dynamic self-supported catalysis with metallopolymers.

Figure 75 :

 75 Figure 75: Structures of metallopolymer-forming a) 3 and CuOTf2, b) 4 and NiBr2.

Figure 76 :

 76 Figure 76: (-)-NLEs of enantioselective Michael additions catalysed by a) 3-Cu(OTf)2 and b) 4-NiBr2.

Figure 7 :

 7 Figure 7: Structure of complex 52-NiBr2.

?II. 2 . 1 . 1

 211 Ligand design and synthesis

Figure 79 :

 79 Figure 79: Synthetic pathway for (-)-DAIB and its ditopic version 9.

Figure 82 :

 82 Figure 82: Proposed synthetic pathways for a C-9-bridged ditopic DAIB ligand starting from 11; similar pathways can be envisioned using 10, 12 and 14.

Figure 83 :

 83 Figure 83: Synthesis of ditopic ligands 15 and 16.

Figure 84 :

 84 Figure 84: Linear effect of the 15-catalysed addition of ZnEt2 to benzaldehyde.

Figure 85 :

 85 Figure 85: Temperature-dependent NLE of 16 in the addition of ZnEt2 to benzaldehyde. The values for 60°C are essentially the same as for 40°C and thus not visible.

Figure 86 :

 86 Figure 86: Temperature profile of the 16-catalysed addition of ZnEt2 to benzaldehyde in Figure 85 with 100% eeL (blue dots) and 20% eeL (orange dots).

Figure 87 :

 87 Figure 87: Catalyst loading screening in the 16-catalysed addition of ZnEt2 to benzaldehyde with enantiopure (blue dots) or 20% ee ligand.

Figure 89 :

 89 Figure 89: Schematic equilibrium between homo-and heterochiral polymers and the corresponding macrocycles. The macrocycles have been chosen to consist of four ligands/metal ions for illustration purposes, smaller or larger macrocycles are also conceivable.

90 :

 90 Figure 90: Synthesis of trianglimines 17 from enantiopure and racemic DACH. The latter gives a mixture of diastero-and enantiomers in a 1:1:3:3 ratio [(RRR):(SSS):(RRS):(SSR)].

Figure 93 :

 93 Figure 93: Some examples for non-linear optic phenomena. a) Second-harmonic generation (SHG) or frequency doubling, b) third-harmonic generation (THG) or frequency tripling, c) multi-photon absorption (MPA), here exemplified by absorption of two photons of the same frequency bringing the material from its ground state g to an excited state n.

Figure 94 :

 94 Figure 94: a) Diagram of the material's electronic energy states g (ground state), n (1 st excited state) and m (2 nd excited state). The three possible transitions are each associated to a frequency (ω) and a transition dipole moment (µ). b) shows the required configuration of the three µ's to generate an SFG signal: they have to extend in all three spatial dimensions, i. e. form a volume.

Figure 97 :

 97 Figure 97: Scheme depicting the a) SPP and b) PPP acquisition modes.

Figure 99 :

 99 Figure 99: Scheme for ligand 18 and the metals salts used to form chiral metallopolymers.

Figure 100 :

 100 Figure 100: SFG spectra of a) 18-Ni(BF4)2 (18-Cu(BF4)2 and 18-Zn(BF4)2 gave similar spectra), b) 18 without metal and c) dinuclear complex 18-[Ni(BF4)2]2, 180s acquisition time.[START_REF] Taupier | Microscopie Par Génération de Somme de Fréquences Optiques : Application Aux Polymères de Coordination Chiraux[END_REF]

Figure 101 :

 101 Figure 101: SFG spectra of a) racemic 18-Cu(BF4)2 and b) racemic 18-Zn(BF4)2.

1

 1 Ditopic iminoalcohol and iminoamine ligands III.2.1.1 Ligand design & synthesis

Figure 103 :

 103 Figure 103: Scheme for the design of a novel ditopic ligands with a bis-imine-conjugated aromatic linker, inspired from ligand 18.

Figure 104 :

 104 Figure 104: Reaction scheme for the synthesis of bis-iminoalcohols 19a-g.

Figure 105 :

 105 Figure 105: Scheme for the equilibrium of ditopic iminoalcohol ligands with a simple and a double hemiaminal ether.

Figure 106 :

 106 Figure 106: Reaction schemes for the attempted synthesis of tetraimine ligand 20.

Figure 107 :

 107 Figure 107: Reaction scheme for the synthesis of 23 from (1R,2R)-DACH. The synthesis of intermediate 22 has been reportedbefore.[175]

Figure 108 :

 108 Figure 108: Reaction scheme for the synthesis of the Cu(I)-, Cu(II)-and Zn(II)-complexes of ligands 19a-g and 23.

Figure 109 :

 109 Figure 109: UV-vis spectra of ligands a) 23, b) 19g, c) 19f, d) 19e (black) and their respective Cu(OTf)2-(blue), Zn(OTf)2-(red) and CuPF6-complexes (orange). All spectra were made in THF, 3-6•10 -5 M, except 19f and 23-CuPF6 (DCM), 23, 19e and 19e-Cu(OTf)2 (MeOH).

to 18 .

 18 Cu(II)-complexes of 19e, 19g and 23 give only very weak CD signals; same goes for 23-Zn(OTf)2. 19g-Zn(OTf)2 and 19f-Cu(OTf)2 are the only +IIcomplexes with a relatively high molar ellipticity of -4•10 -4 to -6•10 -4 °cm 2 dmol -1 .

Figure 110 :

 110 Figure 110: CD spectra of ligands a) 23, b) 19g, c) 19f, d) 19e (black) and their respective Cu(OTf)2-(blue), Zn(OTf)2-(red) and CuPF6-complexes (orange). All spectra were made in THF, 3-6•10 -5 M, except 19f and 23-CuPF6 (DCM), 23, 19e and 19e-Cu(OTf)2 (MeOH).

Figure 9 :

 9 Figure 9: Decomposition products from hydrolysis of the metal complexes of ligand 23.

23 -

 23 CuPF6 exhibits an SPP signal with an intensity of ca. 3000 after 180 s irradiation, which is comparable to that of the bisoxazoline complexes (see Figure100, p. 108). However, 23-Cu(OTf)2 gives an SPP signal of 5500 in only a 10 th of the time, namely 18 s: the signal is much more intense than with the bisoxazoline polymers. On the other hand, 23-Zn(OTf)2 exhibits no SPP signal and thus no activity in SFG.

Figure 112 :

 112 Figure 112: SFG spectrum of complex a) 23-CuPF6 (180 s acquisition time), b) 23-Cu(OTf)2 (18 s) and c) 23-Zn(OTf)2 (180 s), containing byproducts shown in Figure 111, in SPP (red) and PPP-mode (blue).

Figure 113 :

 113 Figure 113: SFG spectrum of ligand 23, containing byproducts shown in Figure 111, in SPP (red) and PPP-mode (blue), 180 s acquisition time.

  shows the SFG spectrum of 23-CuOTf2 originating from a pure batch of 23: the strong PPP signal has given place to a weaker one, of approximately same intensity as the SPP signal whose intensity (ca. 4500) hasn't changed much. This indicates that the saturating PPP signals in Figure 112 and Figure 113 come from the byproducts. As 23-CuOTf2 is sensitive to moisture and the SFG experiment has been made at air, the remaining PPP in Figure 114 may origin from a small amount of hydrolysis byproducts (which are the same as in the bad 23 batch: terephtaldehyde and possibly a monohydrolysed ligand) formed during the sample preparation and the SFG experiment. The quick colour-change from violet to brown of the 23-CuOTf2-solution after drop-casting may be indicative of that.

Figure 114 :

 114 Figure 114: SFG spectrum of complex 23-Cu(OTf)2, from a pure batch of 23, in SPP (red) and PPP-mode (blue), 18s acquisition time.

Figure 115 :

 115 Figure 115: SFG spectrum of complex 19f-CuPF6 in SPP (red) and PPP-mode (blue), 18s acquisition time.

Figure 116 :

 116 Figure 116: Scheme for design of new and possibly more stable ditopic iminoaniline ligand.

Figure 117 :

 117 Figure 117: Scheme for the three-step synthesis of ditopic iminoaniline ligand 26.

Figure 118 :

 118 Figure 118: Synthesis of Cu(I)-, Cu(II), Zn(II)-and Ni(II)-complexes of ditopic iminoaniline ligand 26.

Figure 119 : 27 ,

 11927 Figure 119: UV-vis-spectra of 26 and 26-Cu(OTf)2/-Zn(OTf)2/-Ni(BF4)2 in THF, 3.3•10 -5 -5.7•10 -5 M.

Figure 120 :

 120 Figure 120: UV-vis spectrum of 27 in THF, 4.23•10 -5 M in THF.

Figure 121 :

 121 Figure 121: Scheme for the conjugation break in 26 upon coordination on a metal.

Figure 123 :

 123 Figure123: Scheme for the partial charge transfer from the outer parts into the centre of ligand 26 upon excitation with visible light. The positive (δ + ) and negative (δ -) partial charges are lower in the excited state, making it less sensitive to the solvent's polarity than the ground state.

Figure 124 :

 124 Figure124: scheme for the possible outcomes of the addition of metal to a ditopic ligand. a) the ligand forms first a mononuclear, then a dinuclear complex, b) the metal forms a metallopolymer, with a 1:2 metal/ligand-complex as a possible intermediate. The metallopolymer may also be broken up to form a dinuclear complex, but usually it takes an excess of metal salt to achieve this. The evolution from one complex to the other can be visualised by a titration of the ligand with a metal, monitored by UV-vis spectroscopy.

Figure 125 :

 125 Figure 125: a) UV-vis titration of ligand 26 (5,74•10 -5 M in THF) with CuOTf2-aliquots (0.1 equiv. each); evolution of the absorbance at b) 375 nm and c) 292 nm over the course of the titration. The spectra differ slightly from those in Figure 119 in the UV-region as the titration was done in BHT-stabilised THF.

Figure 127 :Figure 128

 127128 Figure 127: a) UV-vis titration of ligand 26 (5,74•10 -5 M in THF) with Ni(BF4)2-aliquots (0.1 equiv. each), b) evolution of the absorbance at 446 nm over the course of the titration.

Figure 129 :

 129 Figure 129: CD spectra of 26 and its CuPF6-, Ni(BF4)2-, Cu(OTf)2-and Zn(OTf)2-complexes in THF, 2.7-4•10 -5 M.

IV. 1

 1 Procedures for Chapters I & II IV.1.1 Synthesis IV.1.1.1 Ephedrine-derived ligands (1R,2S)-N-benzylephedrine (-)-NBE

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.36-7.30 (o-and mCHarom, m, 4H), 7.26-7.22 (pCHarom, m, 1H), 7.15 (CHarom-C-CH2, d, J = 8.2 Hz, 2H), 7.12 (CHarom-C-CH3, J = 8.4 Hz, 2H), 4.89 (O-CH, d, J = 4.7 Hz, 1H), 3.61 (N-CH2, d, J = 13.3 Hz, 1H), 3.56 (N-CH2, d, J = 13.3 Hz, 1H), 2.93 (N-CH, qd, J = 6.8, 4.7 Hz, 1H), 2.35 (CH3-Carom, 3H), 2.19 (N-CH3, s, 3H), 0.98 (N-CH-CH3, d, J = 6.8 Hz, 3H) ppm. NMR (125 MHz, CDCl3): δ = 142.6 (O-CH-Carom), 136.70 (Carom-CH3) 136.45 (Carom-CH2), 129.1 (CHarom-Carom-CH3), 128.8 (CHarom-Carom-CH2), 128.1 (mCHarom), 127.1 (pCHarom), 126.4 (oCHarom) 73.6 (O-CH), 63.4 (N-CH), 59.0 (N-CH2), 38.8 (N-CH3), 21.2 (CH3-Carom), 10.1 (N-CH-CH3) ppm.FTIR (ATR):𝜈̅ 𝑚𝑎𝑥 = 3200,3088, 3046, 3020, 2969, 2935, 2905, 2855, 2794, 1601, 1585, 1448, 1417, 1379, 1358, 1338, 1317, 1295, 1250, 1208, 1173, 1154, 1140, 1119, 1107, 1063, 1028, 1019, 989, 970, 950, 933, 915, 854, 815, 781, 764, 738, 700, 674, 644, 559, 506, 487, 440, 414 cm -1 . MS (ESI+): m/z = 270.1881 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.32 (o-and mCHarom, d, J = 4.4 Hz, 8H), 7.23 (pCHarom, m, J = 4.4 Hz, 2H), 4.85 (O-CH, d, J = 4.1 Hz, 2H), 2.82 (N-CH, qd, J = 6.8, 4.1 Hz, 2H), 2.50 (CH2-N, dt, J = 13.2, 7.1 Hz, 2H), 2.42 (CH2-N, dt, J = 13.2, 7.1 Hz, 2H), 2.27 (CH3-N, s, 6H), 1.27 ((CH2)6-CH2-CH2-N, s, 12H), 1.48 (CH2-CH2-N, tt, J = 7.1, 7.1 Hz, 4H), 0.86 (CH3-CH, d, J = 6.8 Hz, 6H) ppm. NMR (125 MHz, CDCl3): δ = 142.5 (Carom), 128.0 (mCHarom), 126.9 (pCHarom), 126.2 (oCHarom), 72.9 (O-CH), 63.6 (N-CH), 55.1 (CH2-N), 39.1 (N-CH3), 29.7 (CH2), 27.6 (CH2), 27.4 (CH2), 10.3 (CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3404, 3085, 3061, 3025, 2924, 2851, 2794, 1603, 1493, 1450, 1370, 1330, 1257, 1195, 1121, 1041, 1026, 996, 962, 914, 885, 834, 793, 742, 699, 677, 639, 553 cm -1 . MS (ESI+): m/z = 469.3804 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.33 (o-and mCHarom, d, J = 4.4 Hz, 8H), 7.29-7.23 (pCHarom, m, 2H), 7.17 (CHarom-C-CH2, s, 4H), 4.88 (O-CH, d, J = 4.7 Hz, 2H), 3.61 (N-CH2, d, J = 20.8 Hz, 2H), 3.59 (N-CH2, d, J = 137 20.8 Hz, 2H), 2.93 (N-CH, qd, J = 6.9, 4.7 Hz, 2H), 3.43 (OH, br s, 2H), 2.19 (N-CH3, s, 6H) 0.99 (CH-CH3, d, J = 6.9 Hz, 6H) ppm. NMR (125 MHz, CDCl3): δ = 142.6 (C-CH-O), 138.3 (C-CH2-N), 128.8 (CHarom-C-CH2), 128.1 (mCHarom), 127.1 (pCHarom), 126.3 (oCHarom), 73.8 (O-CH), 63.5 (N-CH), 59.1 (N-CH2), 38.8 (N-CH3), 10.1 (CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3086, 3054, 2979, 2939, 2875, 1602, 1512, 1492, 1449, 1425, 1385, 1369, 1344, 1249, 1215, 1163, 1119, 1065, 1032, 1007, 988, 964, 939, 861, 842, 822, 796, 747, 736, 701, 672, 653, 640, 600, 540, 476, 441, 412 cm -1 . MS (ESI+): m/z = 433.2850 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.28 (CHarom, s, 4H), 4.67 (N-CH2, d, J = 15.0 Hz, 2H), 4.22 (O-CH, d, J = 8.1 Hz, 2H), 4.12 (N-CH2, d, J = 15.0 Hz, 2H), 3.49 (N-CH, d, J = 8.1 Hz, 2H), 1.85 (N-CH-CH, d, J = 4.6 Hz, 2H), 1.69 (Ha, tt, J = 12.3, 4.4 Hz, 2H), 1.51 (Hc, ddd, J = 12.9, 12.2, 3.9 Hz, 2H), 1.03 (CH3h, s, 6H), 0.98 (CH3f + Hd, m, 8H), 0.86 (CH3g + Hb, m, 8 H) ppm. NMR (125 MHz, CDCl3): δ = 158.7 (C=O), 135.8 (Carom), 128.9 (CHarom), 85.3 (CH-O), 63.6 (CH-N), 48.5 (C-CH3g/f), 46.8 (CH2-N), 46.5 (C-CH3h), 45.6 (CH-CH-N), 31.9 (CH2 c/d), 24.9 (CH2 a/b), 23.3 (CH3g or f), 19.4 (CH3g or f), 10.8 (CH3h) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3007, 2963, 2930, 2880, 1729, 1515, 1485, 1444, 1416, 1327, 1288, 1236, 1114, 1089, 1040, 962, 931, 850, 757, 692, 653, 609, 550 cm -1 . MS (ESI+): m/z = 493.160 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.23 (CHarom, s, 4H), 4.50 (OH, br s, 2H), 4.20-2.96 (N-CH2, br, 4H) 3.54 (CH-O, d, J = 6.9 Hz, 2H), 2.53 (CH-N, d, J = 7.1 Hz, 2H), 2.13 (N-CH3, br s, 6 H), 2.10 (CH-CH-N, d, J = 3.9 Hz, 2H), 1.84-1.68 (Ha, m, 2H), 1.53-1.38 (Hc, m, 2H), 1.13 (CH3f, br s, 6H), 1.08-0.97 (Hb + Hd, m, 4H), 1.00 (CH3h, s, 6H), 0.79 (CH3g, s, 6H) ppm. NMR (125 MHz, CDCl3): δ = 137.6 (Carom), 129.2 (CHarom), 79.2 (CH-O), 73.6 (CH-N), 49.4 (C-CH3h), 47.0 (N-CH3), 46.8 (C-CH3g/f), 32.4 (CH2 c/d), 28.2 (CH2 a/b), 22.2 (CH3g), 21.1 (CH3f), 11.7 (CH3h) ppm. The N-CH2 signal is not visible at rt.FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3456, 2948, 2926, 2870, 2815, 2788, 1513, 1460, 1388, 1368, 1348, 1261, 1091, 1039, 1019, 930, 901, 814, 785, 587, 555, 513, 487, 433 cm -1 .

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 7.44-7.40 (N-CH2-C-CHarom, m, 2H), 7.40-7.35 (O-CH-C-CHarom, m, 2H), 7.34-7.27 (CHarom, m, 4H), 7.27-7.19 (CHarom, m, 2H), 5.09 (CH-O, d, J = 7.3 Hz, 1H), 3.85 (N-CH2-Ph, d, J = 14.7 Hz, 1H), 3.63 (N-CH2-Ph, d, J = 14.6 Hz, 1H), 3.42 (CH-N, qd, J = 6.9, 6.3 Hz, 1H), 1.45 (MeA, s, 3H), 1.37 (MeB, s, 3H), 0.45 (CH3-CH-N, d, J = 6.6 Hz, 3H) ppm. NMR (125 MHz, CDCl3): δ = 141.2 (N-CH2-C), 140.3 (O-CH-C), 128.23 (CHarom), 128.18 (CHarom), 127.9 (CHarom), 127.6 (CHarom), 127.4 (CHarom), 126.8 (CHarom), 95.1 (O-C-N), 80.7 (CH-O), 60.5 (CH-N), 51.7 (N-CH2-Ph), 27.7 (MeA), 21.3 (MeB), 16.0 (CH3-CH-N) ppm.

Figure 130 :

 130 Figure 130: Complete time-dependent eeP evolution of the (-)-NBE-catalysed addition of ZnMe2 to benzaldehyde at various catalyst loadings.

1 H 13 C

 113 NMR (500 MHz, MeOH-d 4 ): δ = 8.41 (CH=N, s, 2H), 7.85 (CHarom, s, 4H), 3.65 (CH2-O, dd, J = 10.8, 4.5 Hz, 2H), 3.60 (CH2-O, dd, J = 10.8, 8.1 Hz, 2H), 3.51 (CH-N, qdd, J = 6.4, 8.1, 4.5 Hz, 2H), 1.24 (CH-CH3, d, J = 6.4 Hz, 6H) ppm. NMR (125 MHz, MeOH-d 4 ): δ = 163.0 (CH=N), 139.4 (Cquat), 129.7 (CHarom), 69.4 (CH-N), 67.5 (CH2-OH), 18.6 (CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3187, 2977, 2963, 2930, 2899, 2871, 2832, 2771, 1635 (νC=N), 1569, 1445, 1434, 1397, 1373, 1355, 1343, 1309, 1250, 1218, 1144, 1119, 1090, 1052, 988, 919, 895, 853, 820, 808, 713, 635, 554, 530, 496, 441 cm -1 . MS (ESI+): m/z = 249.158 ([M + H + ], 100%).

1 H

 1 NMR (500 MHz, CDCl3): δ = 8.40 (N=CH, m, 1.7H), 7.90-7.58 (N=CH-C-CHarom, m, 4H), 7.48-7.27 (CHarom, m, 10H), 5.80-5.50 (hemiaminal ether O-CH-NH, m, 0.3H), 4.60-4.30 (N-CH, m, 2H), 4.10-3.70 (O-CH2, m, 4H), 2.19 (OH, br s, 2H) ppm. 13 C NMR (125 MHz, CDCl3): δ = 162.2 (N=CH), 140.6 (N-CH-Cquat), 138.2 (N=CH-Cquat), 126.0-130.0 (all CHarom), 93.1 (hemiaminal ether O-CH-N), 92.3 (hemiaminal ether O-CH-N), 77.6 (N-CH), 67.9 (O-CH2), 63.1 (N-CH), 60.9 (N-CH) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3313, 3059, 3028, 2924, 2854, 1601, 1583, 1635 (νC=N), 1567, 1491, 1451, 1416, 1381, 1338, 1298, 1216, 1053, 1026, 969, 900, 828, 801, 755, 698, 632, 578, 535, 508, 450 cm -1 . MS (ESI+): m/z = 373.191 ([M + H + ], 100%).

1 H 13 C

 113 •10 -5 M): εmax = 30 600 (277 nm) Lmol -1 cm -1 . (2R,2'R)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(3-methylbutan-1-ol) 19c: From D-Valinol (1 g, 8.70 mmol, 2 equiv) and terephtaldehyde (650 mg, 4.85 mmol). Yellow waxy solid, 1.48 g, quantitative yield. Complex NMR spectra due to hemiaminal ether formation. NMR (500 MHz, CDCl3): δ = 8.36-8.24 (N=CH, m, 1.2H), 7.95-7.44 (CHarom, m, 4H), 5.60-5.40 (hemiaminal ether O-CH-N, m, 0.8H), 4.03 (O-CH2, m, 1H), 3.82 (O-CH2, m, 2H), 3.48 (O-CH2, m, 1H), 3.15 (N-CH, m, 0.5H), 2.99 (N-CH, m, 1.5H), 1.96 (CH3-CH-CH3, m, 1H), 1.65 (CH3-CH-CH3, m, 1H), 0.85-1.10 (CH3-CH-CH3, m, 12H) ppm. NMR (125 MHz, CDCl3): 162.0-161.2 (N=CH), 142.3-136.3 (C), 128.9-128.3 (CHarom), 126.6-126.3 (CHarom), 93.3-91.8 (hemiaminal ether N-CH-O), 79.1-79.3 (N-CH), 69.7-70.2 (O-CH2), 66.4 (N-CH), 64.71 (O-CH2), 64.35 (N-CH), 30.1-32.1 (CH3-CH-CH3), 21.0-19.0 (CH3-CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3329, 2957, 2931, 2871, 1640 (νC=N), 1568, 1456, 1417, 1385, 1365, 1343, 1295, 1215, 1169, 1143, 1076, 1056, 1017, 962, 898, 829, 799, 735, 631, 498, 416 cm -1 . MS (ESI+): m/z = 305.219 ([M + H + ], 100%).

1 H

 1 NMR (500 MHz, DMSO-d6): δ = 8.60 (N=CH, s, 2H), 7.91 (N=CH-C-CHarom, s, 4H), 7.26 (CHarom-C-CH2, d, J = 7.0 Hz, 2H), 7.23 (CHarom-CH-C-CH2, t, J = 7.5 Hz, 2H), 7.17 (CHarom-CH-C-CH-N, t, J = 7.3 Hz, 2H), 6.99 (CHarom-C-CH-N, d, J = 7.4 Hz, 2H), 5.38 (OH, d, J = 5.5 Hz, 2H), 4.64 (CH-N, d, J = 5.9 Hz, 2H), 4.43 (CH-O, dddd, J = 7.7, 7.1, 5.9, 5.5 Hz, 2H), 3.25 (O-CH-CH2, dd, J = 15.5, 7.1 Hz, 2H), 2.83 (O-CH-CH2, dd, J = 15.5, 7.7 Hz, 2H) ppm. 13 C NMR (125 MHz, DMSO-d6): δ = 162.0 (C-CH-N), 140.4 (C-CH2), 138.5 (C-CH=N), 128.9 (CHarom-C-CH=N), 128.1 (CHarom-CH-C-CH2), 127.0 (CHarom-CH-C-CH-N), 125.2 (CHarom-C-CH2), 124.6 (CHarom-C-CH-N), 81.8 (C-N), 78.9 (C-O), 39.8 (CH2-C-O, overlaps with the residual signal of DMSO-d6, visible in DEPT and HSQC NMR) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3200, 3073, 3048, 3032, 2954, 2907, 2883, 2832, 1633 (νC=N), 1564, 1476, 1460, 1415, 1307, 1273, 1221, 1198, 1170, 1091, 1063, 1009, 988, 970, 902, 863, 839, 802, 742, 693, 642, 613, 581, 534, 511, 479, 465, 422 cm -1 . MS (ESI+): m/z = 397.188 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, MeOH-d4) : δ = 8.04 (N=CH, s, 1H), 7.61 (N=CH-C-CHarom, s, 2H), 7.31 (oCHarom, dd, J = 8.4, 1.4 Hz, 2H), 7.25 (mCHarom, dd, J = 8.4, 6.8 Hz, 2H), 7.17 (pCHarom, tt, J = 7.2, 1.4 Hz, 1H), 4.67 (O-CH, d, J = 6.8 Hz, 1H), 3.59 (N-CH, p, J = 6.4 Hz, 1H), 1.36 (CH3, d, J = 6.4 Hz, 3H) ppm. NMR (125 MHz, MeOH-d4): δ = 162.7 (N=CH), 143.8 (O-CH-C), 139.3 (N=CH-C), 129.4 (N=CH-C-CHarom), 128.9 (mCHarom), 128.3 (o-and pCHarom), 78.8 (O-CH), 73.5 (N-CH), 18.8 (CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3354, 3085, 3061, 3028, 2971, 2929, 2868, 1639 (νC=N), 1493, 1451, 1451, 1372, 1335, 1296, 1217, 1198, 1129, 1073, 1042, 1025, 997, 967, 830, 748, 699, 631, 518 cm -1 .

1 H 13 C 1 H

 1131 NMR (500MHz, CDCl3): δ = 8.64-8.50 (N=CH, m, 0.2H), 7.90-7.00 (all CHarom, m, 14H), 5.60-5.10 (hemiaminal ether O-CH-N, m, 1.7H), 5.10-4.60 (N-CH and O-CH, m, 4H), 3.40-3.10 (O-CH-CH2, m, 4H) ppm. NMR (125 MHz, CDCl3): δ = 165.0-138.0 (C), 131.0-123.0 (all CHarom), 94.0-68.0 (O-CH, N-CH, hemiaminal ether O-CH-N), 41.0-38.0 (O-CH-CH2) ppm.FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3286, 3058, 3023, 2931, 2848, 1642 (νC=N), 1606, 1585, 1518, 1479, 1460, 1434, 1361, 1326, 1298, 1255, 1214, 1192, 1169, 1095, 1075, 1034, 1019, 967, 902, 874, 859, 847, 822, 755, 710, 696, 654, 629, 590, 554, 509, 528, 509, 465, 423 cm -1 . MS (ESI+): m/z = 397.188 ([M + H + ], 100%).[𝛼] 𝐷20 (DCM, c = 1.09 g/100 mL) = -96,9 cm³g -1 dm -1 .UV-vis (DCM, 5.92•10 -5 M): εmax = 5950 (259 nm) Lmol -1 cm -1 .CD (DCM, 5.86•10 -5 M): [θ]max = -7070 (291 nm) °cm 2 dmol -1 . (1R,1'R,2R,2'R)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(cyclohexan-1-ol) 19d: From (1R,2R)-2-Aminocyclohexanol (1 g, 8.68 mmol, 2 equiv) and terephtaldehyde (582 mg, 4.34 mmol). Light brown solid, 1.43g, quantitative yield. No hemiaminal ether formation. NMR (500 MHz, CDCl3): δ = 8.32 (CH=N, s, 2H), 7.72 (CHarom, s, 4H), 3.74 (CH-O, ), 3.03 (CH-N, ), 2.39 (OH, br s, 2H), 2.08 (CH2 eq-CH-O, 2H), 1.86-1.74 (CH2 eq-CH2-CH- N + CH2 eq-CH-CH-O, m, 4H), 1.74-1.68 (CH2 eq-CH-N, m, 2H), 1.68-1.58 (CH2 ax-CH-N, m, 2H), 1.46-1.28 (CH2 ax-CH-N + CH2 ax-CH2-CH-N + CH2 ax-CH-CH-O, m, 6H) ppm.

151 13C

 151 NMR (125 MHz, CDCl3): δ = 161.4 (CH=N), 138.1 (Carom), 128.6 (CHarom), 73.9 (CH-N), 73.9 (CH-O), 32.7, 32.6 (CH2-CH-N + CH2-CH-O), 24.7, 24.5 (CH2-CH2-CH-N + CH2-CH2-CH-O) ppm.

[𝛼] 𝐷 20 (

 20 EtOH, c = 1.16 g/100 mL) = -101 cm³g -1 dm -1 . UV-vis (MeOH, 3.56•10 -5 M): εmax = 32 900 (277 nm) Lmol -1 cm -1 . CD (MeOH, 4.97•10 -5 M): [θ]max = -74 700 (281 nm) °cm 2 dmol -1 . (1R,1'R,2R,2'R)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(N,Ndimethylcyclohexan-1-amine) 23:

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 8.27 (N=CH, s, 2H), 7.76 (CHarom, s, 4H), 3.28 (CH-N=C, td, J = 9.5, 5.8 Hz, 2H), 2.73 (CH-NMe2, ddd, J = 11.2, 9.5, 3.7 Hz, 2H), 2.28 (NMe2, s, 12H), 1.90-1.83 (CH2 eq-CH-NMe2, m, 2H), 1.83-1.78 (CH2 eq-CH2- CH-NMe2, m, 2H), 1.77-1.70 (CH2 eq-CH2-CH-N=C, m, 2H), 1.69-1.61 (CH2-CH-N=C, m, 4H), 1.38-1.24 (CH2 ax-CH2-CH-NMe2 + CH2 ax-CH2-CH-N=C + CH2 ax-CH-NMe2, m, 6H) ppm. NMR (125 MHz CDCl3): δ = 159.1 (C=N), 138.4 (Carom), 128.5 (CHarom), 72.4 (CH-N=C), 66.7 (CH-NMe2), 41.0 (NMe2), 34.9 (CH2-CH-N=C), 25.6 (CH2-CH2-CH-NMe2), 25.4 (CH2-CH-NMe2), 24.8 (CH2-CH2-CH-N=C) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 2963, 2926, 2855, 2824, 2779, 2765, 1644 (νC=N), 1570, 1447, 1371, 1292, 1272, 1256, 1186, 1120, 1074, 1027, 944, 872, 841, 817, 754, 543, 507, 461 cm -1 . MS (ESI+): m/z = 383.3184 ([M + H + ], 100%).

1 H 13 C

 113 NMR (500 MHz, CDCl3): δ = 8.42 (NH, br d, J = 3.8 Hz, 1H), 8.17 (CHarom-C-NO2, dd, J = 8.6, 1.5 Hz, 1H), 7.36-7.31 (o-and pCHarom, m, 4H), 7.26 (pCHarom, tt, J = 8.7, 1.0 Hz, 1H), 7.25 (CHarom-CH-C-NH, ddd, J = 8.6, 7.1, 1.4 Hz, 1H), 6.63 (CHarom-C-NH, dd, J = 8.6, 1.2 Hz, 1H), 6.60 (CHarom-CH-C-NO2, ddd, J = 8.6, 7.1, 1.2 Hz, 1H), 4.69 (CH-NH, m, J = 6.5 Hz, 1H), 1.65 (CH3-CH-NH, d, J = 6.7 Hz, 1H) ppm. NMR (125 MHz, CDCl3): δ = 144.6 (C-NH), 143.6 (Cquat-CH-CH3), 136.0 (CHarom-CH-C-NH), 132.2 (Cquat-NO2), 129.0 (mCHarom), 127.5 (pCHarom), 126.8 (CH-C-NO2), 125.6 (oCHarom), 115.6 (CHarom-CH-C-NO2), 115.2 (CHarom-C-NH), 53.2 (CH-NH), 25.

  , 4.33•10 -5 M): [θ]max = -22 200 (281 nm) °cm 2 dmol -1 .

13 C

 13 NMR (125 MHz, CDCl3): 155.9 (CH=N), 145.5 (Carom-CH-CH3), 143.2 (Carom-NH), 138.9 (Carom linker), 136.0, (Carom-N=CH), 129.0 (CHarom linker), 128.7 (pCHarom), 128.4 (CHarom-CH-C-NH), 126.9 (oCHarom), 125.9 (mCHarom), 116.6 (CHarom-CH-C-N=CH), 116.4 (CHarom-C-N=CH), 111.7 (CHarom-C-NH), 53.5 (NH-CH-CH3), 53.5 (NH-CH-CH3) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3401, 3060, 3028, 2971, 2925, 2875, 1611 (νC=N), 1590, 1504, 1452, 1427, 1374, 1326, 1280, 1250, 1202, 1179, 1161, 1141, 1071, 1019, 963, 922, 877, 832, 743, 737, 697, 611, 568, 527, 492, 460 cm -1 . MS (ESI+): m/z = 519.2568 ([M -2 H2 + H + ], 100%); 521.2723 ([M -H2 + H + ], 100%); 523.2866 ([M + H + ], 100%). The first two peaks result probably from in situ-oxidation of one or two benzylic amines, respectively. UV-vis (THF, 3.58•10 -5 M): εmax = 21 419 (306 nm), 6256 (446 nm) Lmol -1 cm -1 . CD (THF, 5.68•10 -5 M): [θ]max = -27 800 (300 nm), -10 900 (441 nm) °cm 2 dmol -1 .

1 H

 1 NMR (500 MHz, MeOH-d4): δ = 8.74 (CH=N, s, 2H), 7.73 (CHarom, s, 4H), 7.66 (oCHarom, d, J = 7.3 Hz, 4H), 7.48 (mCHarom, t, J = 7.3 Hz, 4H), 7.36 (pCHarom, t, J = 7.3 Hz, 2H), 5.22 (CH-O, s, 2H), 4.11 (CH-N, m, 2H), 1.28 (CH3-CH-N, d, J = 6.4 Hz, 6H) ppm. 13 C NMR (125 MHz, MeOH-d4): δ = 166.9 (C=N), 142.1 (Carom), 139.5 (Carom linker), 129.6 (mCHarom), 128.9 + 128.8 (mCHarom + CHarom), 127.5 (oCHarom), 76.5 (CH-O), 73.5 (CH-N), 14.9 (CH3-CH-N) ppm.

Figure 131 :

 131 Figure 131: Example of c adjusting using VTNA with a) C = 1.0 and b) c = 0.4. The two curves in each graph were obtained from different catalyst concentrations (blue curve: 0.15 M; orange curve: 0.10 M). The best overlay is obtained for c = 0.4 which is therefore the partial order in catalyst.

Figure 132 :

 132 Figure 132: Example of a Hammett plot. The slope of the fitted line corresponds to ρ.

Figure 133 :

 133 Figure 133: Reactions of para-substituted a) benzoic acids, b) phenyldimethyl chloromethanes and c) phenols that define the σ, σ + and σ --scales, respectively.

  Therefore, we attempted to react NBE boron halogenides; the reaction schemes are shown in Figure134. Reaction of NBE with BF3•OEt2 in or NaH didn't show any reproducible conversion; reaction with DABCO yielded a product with a messy 1 H NMR spectrum. Same goes for the reaction with DABCO and BCl3 or BBr3.

Figure 134 :

 134 Figure 134: Scheme for the unsuccessful synthesis of NBE-based boracycle 28 and its boric ester precursor 29.

Figure 136 :

 136 Figure 136: Reaction scheme for the synthesis of 33-X and calculated MWD.

Figure 137 shows

 137 Figure137shows the deviation of the DOSY-determined MW from the calculated MW of the diamine complexes. 33-Me has a satisfying -3% deviation at -20°C but shows a stronger underestimation at higher temperatures. This can be interpreted as a systematic underestimation which is compensated by a solvation sphere or aggregation as in Figure40, although this is not very likely as the molecule lacks aromatic rings capable of π-stacking. The other possibility is that heat promotes the

Figure 138 :

 138 Figure 138: Complex 33-Zn

6 ➔

 6 𝑠′(𝑹 = 𝑴𝒆) = √𝐾 𝑆 ′ = 2.19 • 10 -3 𝑚𝑜𝑙 𝐿 It should be noted that the KS' values at different eePs are quite different, ranging from 1.78•10 -6 (eeL = 3%) to 7.33•10 -6 (eeL = 1%) (Table

Figure 139 :

 139 Figure 139: Conversions of the reactions from Figure 60 after 3.5 days.

Figure 140 :

 140 Figure 140: Temperature profile of the 16-catalysed addition of ZnMe2 to benzaldehyde, with enantiopure (blue dots) and 20% ee ligand (orange dots). The orange triangles represent catalytic runs where the precipitate has been formed by overnight stirring at 60 °C, prior to the addition of benzaldehyde.

Figure 141 :

 141 Figure 141: Scheme for the 16-catalysed addition of ZnMe2 to benzaldehyde after the precipitation of the presumably heterochiral aggregate.

V. 3

 3 Product characterisation: NMR-and FTIR-spectra V.3.1 Ephedrine-derived ligands (1R,2S)-N-(4-methylbenzyl)ephedrine (-)-Me-NBE V.3.3 Ditopic iminoalcohol ligands (2S,2'S)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(propan-1-ol) de la thèse en français VI.1 Chapitre ILes effets non-linéaires (NLE) en catalyse asymétrique sont des phénomènes où l'excès énantiomérique (ee) du produit final d'une réaction catalytique ne corrèle pas de façon linéaire avec le ee du catalyseur utilisé. Ainsi, il est possible d'obtenir des produits avec un ee supérieur au catalyseur même, comme p. ex. dans le l'éthylation énantiosélective du benzaldéhyde par le ZnEt2 catalysée par le ligand diaminoisobornéol (DAIB) de Noyori (Figure142). Ici, un produit avec 95% de ee est obtenu d'un ligand qui n'a qu'un ee de 15%.

Figure 142 :

 142 Figure 142: (+)-NLE observé pour l'addition énantiosélective de dialkylzincs au benzaldéhyde catalysée par le (-)-DAIB.

Figure

  Figure 143: Schéma général pour la catalyse énantiosélective suivant le modèle ML2. x, y et z représentent les concentrations respectives de MRR, MSS et MRS.

Figure 144 :

 144 Figure 144: Effet non-linéaire hyperpositif observé dans l'addition énantiosélective de a) ZnEt2, b) ZnMe2 au benzaldéhyde catalysée par (-)-NBE.

Figure 145 :

 145 Figure 145: a) eeP en fonction de la charge en catalyseur dans l'addition énantiosélective de ZnMe2 au benzaldéhyde catalysée par (-)-NBE, b) superposition de a) avec l'effet non-linéaire hyperpositif.

Figure 146 :

 146 Figure 146: Étude de l'effet de la température sur eeP dans l'addition énantiosélective de ZnMe2 au benzaldéhyde catalysée par (-)-NBE.

Figure 147 :

 147 Figure147: a) Masse moléculaire moyenne (MW) de (-)-NBE-ZnMe en fonction de la température obtenue de RMN1 H DOSY, en présence uniquement de 5 équivalents de ZnMe2 (triangles oranges) ou en plus avec 5 équivalents de benzaldéhyde

Figure 148 :

 148 Figure 148: Ordre partiel en catalyseur c en fonction de la charge en catalyseur. Les barres horizontales indiquent la charge en catalyseur deux profils cinétiques qui ont été utilisé pour obtenir c.

Figure 149 :

 149 Figure 149: Évolution de eeP en fonction du temps de réaction, à différentes charges en catalyseur.

Figure 150 :

 150 Figure 150: Effet non-linéaire dans l'addition énantiosélective de ZnEt2 au benzaldéhyde catalysée par le ligand ditopique 9 (points bleus), effet non-linéaire de la même réaction catalysée par le ligand monotopique DAIB (tirets oranges).

  Par la suite, nous nous sommes penchés sur des ligands ditopiques à base d'éphédrine, non plus dans l'idée d'amplifier des NLE déjà existants mais d'étudier l'effet de la structure polymérique sur l'émergence de NLE. Deux ligands ditopiques ont été obtenu par une simple addition de deux équivalents d'éphédrine sur un équivalent d'un double électrophile. Le ligand 15 avec une chaîne alkyle comme liaison entre les deux sites chélatant ne montre pas de NLE, tandis que le ligand 16 avec un lien aromatique possède un (+)-NLE (Figure151). Étonnamment, ce (+)-NLE est amplifié si on augmente la température de réaction de -20 à 40 °C, ce qui est contre-intuitif puisque les agrégats causant le NLE devraient plutôt se dissocier à haute température et diminuer l'amplitude du NLE. Une explication possible serait une grande différence de sensibilité à la température des constantes d'association homo-et hétérochirales (grande différence de leur ΔG respectifs). Si la constante d'association homochirale diminue plus que l'hétérochirale à température croissante, l'agrégation hétérochirale prend une ampleur de plus en plus grande et intensifie le (+)-NLE. Ceci peut provenir des agrégats hétérochiraux qui forment une superstructure (conformation de la chaîne polymérique, interactions entre chaînes) plus stable que leurs équivalents homochiraux. Le lien aromatique joue probablement un rôle par sa rigidité accrue comparée à la chaîne alkyle dans le ligand 15 : un lien trop flexible empêche la formation de superstructures bien définies, ce qui pourrait expliquer l'absence de NLE avec le ligand 15 ; il est également possible qu'il ne forme pas d'agrégats mais plutôt des macrocycles en interagissant avec lui-même, ce qui empêche la génération de NLE.

Figure 151 :

 151 Figure 151: Effet non-linéaire dans l'addition énantiosélective de ZnEt2 au benzaldéhyde catalysée par le ligand ditopique 16, à -20 (points bleus) et +40 °C (points rouges).

  qui catalysent avec un eeP plus bas. Plus la charge catalytique et basse, plus le polymère se dissocie et le nombre de bouts de chaîne augmente. Avec un ligand 16 scalémique, eeP diminue avec une charge catalytique décroissante, ce qui est un phénomène usuel en NLE : plus la concentration en catalyseur est faible, moins on forme les agrégats responsables du NLE.

Figure 152 :

 152 Figure 152: Variation de la charge en catalyseur dans l'addition énantiosélective de ZnEt2 au benzaldéhyde catalysée par 16 à 100% eeL (points bleus) et 20% eeL (points oranges).

Figure 153 :

 153 Figure 153: Schéma pour la génération de somme de fréquences (SFG) chirale dans un milieu isotrope.

λ1 = 450 nm ω1 =22 222 cm - 1 λ2Figure 154 :

 1154 Figure 154: Schéma réactionnel pour la synthèse de ligands ditopiques bis-imine et de leurs complexes respectifs.

Figure 155 :

 155 Figure 155: Spectres SFG des complexes 23-Cu(OTf)2 et 19f-CuPF6.

  L'intermédiaire 25 s'est avéré être très sensible au dioxygène et cause 26 à n'avoir qu'une pureté modérée, que nous n'avons pas pu améliorer à ce jour, mais qui suffit pour des études préliminaires. Les complexes métalliques de 26 se sont avérés être parfaitement stable à l'hydrolyse : la complexation a pu être faite dans du THF technique non séché et nous avons pu utiliser un précurseur de Ni(II) hydraté, ce qui était impossible avec les ligands précédents.

Figure 156 :

 156 Figure 156: Schéma réactionnel pour la synthèse du ligand ditopique 26 et de ses complexes respectifs.

Figure 157 :

 157 Figure 157: Schéma montrant la délocalisation du système π sur le ligand 26 libre et le ligand complexé.

  10 °C) to slow down the catalytic reaction. The formation of the chiral zinc alkoxide leads to changing peak intensities and chemical shifts and therefore complicates the DOSY measurements.

	(b) 1 H DOSY NMR and MW determination
	For the DOSY experiments, we used the residual signal of toluene-d8 as a reference to calculate
	Dx,norm; mean MW values were obtained from the Dissipated Spheres and Ellipsoids (DSE) ECC, as
	NBE-ZnMe's shape neither is a compact sphere nor an expanded disk. Stalke's ECC methodology is
	valid only if the analyte falls into a certain range of Molecular Weight Density (MWD, which is the
	analyte's MW divided by its volume, calculated from its sum of Van-der-Waals radii). Table 1 shows
	the calculated MWD values of NBE-ZnMe and of its adducts with ZnMe2 and/or benzaldehyde. All are
	within the limits in which the ECC is valable (4.3•10 -29 -5.2•10 29 gmol -1 m -3 ), except NBE-ZnMe + ZnMe2
	which is a borderline case due its high Zn/C ratio. The MW of possible ZnMe2 and/or benzaldehyde
	adducts of monomeric, dimeric and trimeric NBE-ZnMe complexes are compiled in
	Table 2.
	Complex	MWD [gmol -1 m -3 ]
	NBE-ZnMe only	4.96•10 29
	+ ZnMe2	5.22•10 29
	+ Benzaldehyde	4.92•10 29
	+ ZnMe2 + Benzaldehyde	5.15•10 29
	Table 1: Calculated MWD for NBE-ZnMe and its adducts with ZnMe2 and/or benzaldehyde. All are within the upper MWD
	limit of 5.20•10 29 gmol -1 m -3 , with exception of NBE-ZnMe + ZnMe2.

Table 2 : MW of ZnMe2 and/or benzaldehyde adducts of monomeric, dimeric or trimeric NBE-ZnMe complexes.

 2

		MW monomer	MW dimer	MW trimer
		[g/mol]	[g/mol]	[g/mol]
	NBE-ZnMe only	335	670	1004
	+ ZnMe2	430	765	1100
	+ Benzaldehyde	441	776	1110
	+ ZnMe2 + Benzaldehyde	536	871	1206

Table 3 :

 3

Calculated KS' and s' values of dimeric heterochiral NBE-ZnR for R = Et and R = Me.

Table 4 :

 4

Basic set of parameters used to model the Eyring plots

  Table 5 lists the para-substituents of the different benzaldehydes in increasing order of their respective σp value.

	X	OiPr	OMe	OPh	tBu	Me	H	2-napht
	σp	-0.45	-0.27	-0.32	-0.20	-0.17	0	0.04
	X	F	Cl	Br	OCF3	CF3	CN	SF5
	σp	0.06	0.23	0.23	0.35	0.54	0.66	0.68

Table 5 :

 5 List of para-substituents X and their σp used in this chapter. 2-napht refers to 2-naphtaldehyde.

Figure

59

shows the results of the substrate screening with ZnEt2. With enantiopure ligand (blue line), eeP remains constant between 75 and 78% for most substituents; only CN (73%), OMe (48%) and OiPr (69%) are out of this trend. The values for 20% eeL (orange line) show a much bigger variation: it is only for σps around 0 (H, F, 2-naphtaldehyde) and with OiPr that they are clearly above the eeP of enantiopure NBE (ΔeeP > 3%), thus rendering the NLE hyperpositive. For the other substituents both eePs are close or equal, only OCF3 and the strongly electron-withdrawing CN-and SF5-substituents have significantly lower eePs with 20% eeL than with enantiopure ligand, leading to a positive but not hyperpositive NLE at 20% eeL.

  ZnMe as we don't know its structure; the differing ρ might then be an indication for the monomer not being the only catalyst. The substituted benzaldehydes might have different relative affinities for monomeric/dimeric NBE-ZnMe (Kassoc 1/Kassoc 2, see chapter I.2.2.6) and react with different relative rates (k1/k2); the relative product inhibition of the substituted chiral zinc alkoxide (Kdissoc 1/Kdissoc 2) might also differ from the unsubstituted one.

	NBE-
	1,2
	/v 0H )
	log(v 0X
	-0,4	-0,2	0	0,2	0,4	0,6
			σ p

(b) Extension of the substrate scope: σp and σp +

Table 6 :

 6

eePs at 20 and 100% eeL with ortho,para-dimethyl-and ortho,para,ortho'-trimethylbenzaldehyde.

  , but contrary to NBE the heterochiral aggregate issued from 16 is not insoluble. Therefore, its (+)-NLE with ZnEt2 is issued from a soluble but less catalytically active heterochiral aggregate compared to monomer and the homochiral aggregate.

	catalyst loading screenings
	100
		80 90	82	81	79	77	75
	Product ee [%]	30 40 50 60 70	22	35	47	50	51
		20				100% eeL
		10				20% eeL
		0
		0	2		4 Cat loading [mol%] 6	8	10
							97

can we interpret this peculiar behaviour? It is tempting to say that both 15 and 16 have inherited from the properties of their monotopic counterparts. Alkyl-substituted ligands NnBE and NME have no NLE (cf. chapter I.2.1.2, p. 29), as does 15; Benzyl-substituted NBE gives a positive or even hyperpositive NLE, as does 16. While this relation is coherent for 15 (which has to be confirmed by experiments with shorter alkyl spacers, as discussed in II.2.2.2) the case of 16 is less clear. 12 and NBE catalyse both via monomeric and homochiral aggregated ligand-ZnR-complexes, as shown by the

  1 H NMR spectra. For example, 19f exists almost only as hemiaminal ether in CDCl3, whereas only the open form of 19a, 19d and 19g is visible in1 H NMR. The hemiaminal ether-part of 19e decreases from 40 to 10% when switching from CDCl3 to MeOH-d4. The closed form seems to be favoured by bulky substituents on the aminoalcoholbackbone; the effect is even stronger if both substituents form a closed cycle, as long as the stereochemistry allows it -the trans-configuration of alcohol and imine in 19d and 19g probably prevents hemiaminal ether formation.

Table 7 :

 7

Number of imine stretching bands in the IR spectra of the respective metal complexes of ligands 19a-g and 23. a)

compound is too water-sensitive to be properly analysed; b) the DMF solvent couldn't be completely evaporated and masks the imine bands in the IR spectrum.

  FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3086, 3063, 3027, 2975, 2929, 2883, 1604, 1586, 1494, 1454, 1373, 1315, 1294, 1259, 1218, 1186, 1143, 1094, 1079, 1061, 1042, 1027, 1006, 946, 909, 878, 858, 803, 750, 696, 667, 632, 586, 546, 523, 462 cm -1 .

Table 8 :

 8 Product quantities for catalyst loading screening of NBE/Benzaldehyde.

	X	(-)-NBE	ZnEt2, 15% in toluene (1,x equiv)	Benzaldehyde (1 equiv)	Toluene
	15	18.5 mg, 72.5 µmol	0.50 mL, 556 µmol	49 µL, 483 µmol	22 µL
	10	12.9 mg, 50.5 µmol	0.50 mL, 556 µmol	52 µL, 505 µmol	43 µL
	4	10.9 mg, 42.7 µmol	1.0 mL, 1.11 mmol	110 µL, 1.07 mmol	150 µL
	1	11.2 mg, 44.0 µmol	8.0 mL, 8.89 mmol	0.90 mL, 8.80 mmol	1.5 mL
	x [mol%]	(-)-NBE	ZnMe2, 1 M in toluene (1,x equiv)	Benzaldehyde (1 equiv)	Toluene
	15	16.7 mg, 65.2 µmol	0.50 mL, 500 µmol	44 µL, 435 µmol	22 µL
	10	11.6 mg, 45.5 µmol	0.50 mL, 500 µmol	46 µL, 455 µmol	46 µL
	5	12.2 mg, 47.6 µmol	1.0 mL, 1.00 mmol	97 µL, 952 µmol	140 µL
	2.5	6.2 mg, 24 µmol	1.0 mL, 1.00 mmol	99 µL, 976 µmol	175 µL

Table 9 :

 9 Product quantities for catalyst loading screening of NBE/pCF3-Benzaldehyde.

x

[

mol%] (-)-NBE ZnEt2, 15% in toluene (1,x equiv) pCF3-Benzaldehyde (1 equiv) Toluene

	15	18.5 mg, 72.5 µmol	0.50 mL, 556 µmol	66 µL, 483 µmol	22 µL
	10	12.9 mg, 50.5 µmol	0.50 mL, 556 µmol	69 µL, 505 µmol	43 µL
	5	13.5 mg, 52.3 µmol	1.0 mL, 1.11 mmol	145 µL, 1.06 mmol	145 µL
	2.5	10.4 mg, 40.7 µmol	1.5 mL, 1.67 mmol	223 µL, 1.63 mmol	260 µL

Table 10 :

 10 Product quantities for catalyst loading screening of NBE/o,o',p-TriMe-Benzaldehyde.

	x [mol%]	(-)-NBE	ZnEt2, 15% in toluene (1,x equiv)	o,o',p-TriMe-(1 equiv) Benzaldehyde	Toluene
	15	18.5 mg, 72.5 µmol	0.50 mL, 556 µmol	65 µL, 483 µmol	22 µL
	10	12.9 mg, 50.5 µmol	0.50 mL, 556 µmol	68 µL, 505 µmol	43 µL

Table 11 :

 11 Product quantities for catalyst loading screening of NBE/pCN-Benzaldehyde.

	x [mol%]	(-)-NBE	ZnEt2, 15% in toluene (1,x equiv)	pCN-Benzaldehyde (1 equiv)	Toluene
	15	18.5 mg, 72.5 µmol	0.50 mL, 556 µmol	63.4 mg, 483 µmol	22 µL
	10	12.9 mg, 50.5 µmol	0.50 mL, 556 µmol	66.2 µL, 505 µmol	43 µL
	5	13.5 mg, 52.3 µmol	1.0 mL, 1.11 mmol	139 mg, 1.06 mmol	145 µL
	2.5	10.4 mg, 40.7 µmol	1.5 mL, 1.67 mmol	213 µL, 1.63 mmol	260 µL

Table 12 :

 12 Product quantities for catalyst loading screening of ditopic Ephedrine 16/Benzaldehyde.

	x [mol%]	X	ZnEt2, 15% in toluene (1,x equiv)	Benzaldehyde (1 equiv)	Toluene
	7.5	15.7 mg, 36.2 µmol	0.50 mL, 556 µmol	49 µL, 483 µmol	22 µL
	5	10.9 mg, 25.3 µmol	0.50 mL, 556 µmol	66 µL, 505 µmol	43 µL
	2.5	11.5 mg, 26.5 µmol	1.0 mL, 1.11 mmol	108 µL, 1.06 mmol	145 µL
	1.25	8.8 mg, 20.3 µmol	1.5 mL, 1.67 mmol	165 µL, 1.63 mmol	260 µL
	x [mol%]	X	ZnMe2, 1.2 M

in toluene (1,x equiv) Benzaldehyde (1 equiv) Toluene

	7.5	16.9 mg, 39.1 µmol	0.50 mL, 600 µmol	53 µL, 522 µmol	162 µL
	5	11.8 mg, 27.3 µmol	0.50 mL, 600 µmol	55 µL, 545 µmol	154 µL
	2.5	12.4 mg, 28.6 µmol	1.0 mL, 1.20 mmol	116 µL, 1.14 mmol	368 µL
	1.25	9.5 mg, 22.0 µmol	1.5 mL, 1.80 mmol	178 µL, 1.76 mmol	611 µL
	IV.1.2.3 Competitive reactions for Hammett Plots

Table 13 :

 13 Conversion and ee data from the competitive catalytic runs after 120 min reaction time. The results are sorted by increasing σp. a): Some data for F and Cl was not e determined due to signal overlapping. b): After 20 min reaction time.

	X	Conversion (H) [%] Conversion (X) [%] eeP(H) [%] eeP(X) [%]	σp	σp +
	3,4-(CH2)4	6.2	1.6	6.8	0.5	-0.48	-0.41
	OiPr	6.7	7.4	7.2	4.8	-0.45	-0.83
	OPh	6.5	5.5	7.3	5.9	-0.32	-0.50
	OMe	5.5	-	7.8	-	-0.27	-0.78
	tBu	-	-	9.2	11	-0.20	-0.26
	Me	6.0	20	9.7	14	-0.17	-0.31
	H	6.6	19	11	15	0	0
	F a	-	-	-	14	0.06	-0.07
	I	1.3	16	9.0	18	0.18	0.14
	Br	1.2	9.7	11	22	0.23	0.15
	Cl a	6.2	1.7	6.5	0.7	0.23	0.11
	COOMe	6.3	3.9	6.7	7.8	0.45	0.49
	CF3 b	5.5	2.0	8.0	11	0.54	0.61
	CN b

Table 14 :

 14 GC conditions and retention times of chiral alcohols.

		50
		45
		40
		35
	[%] ee Product	20 25 30						2,5 mol% 5 mol% 7,5 mol% 10 mol%
		15						12,5 mol%
		10						15 mol%
		5						17,5 mol%
								20 mol%
		0
		0	50	100	150	200		250	300
				t [min]
		Substrate		Chiral alcohol (R)
					Temperature [°C]	P(He) [psi]	tmajor (min)	tminor (min)

  16•10 -5 M): εmax = 28 800 (274 nm) Lmol -1 cm -1 .

	(2R,2'R)-2,2'-((1,4-
	phenylenebis(methaneylylidene))bis(azaneylylidene))bis(2-
	phenylethan-1-ol) 19b:
	From (R)-(-)-2-Phenylglycinol (1 g, 7.29 mmol, 2 equiv) and
	terephtaldehyde (489 mg, 3.64 mmol). Yellow solid, 1.36 g,
	quantitative yield. Complex NMR spectra due to hemiaminal ether
	formation.

  14•10 -5 M): [θ]max = -24 100 (278 nm) °cm 2 dmol -1 . , the precipitate was filtered and washed with EtOH. The filtrate was stored at -20 °C overnight and the newly formed precipitate filtered and washed with cold EtOH. White solid, combined mass: 622 mg, 93% yield. Complex NMR spectra due to hemiaminal ether formation.

	(1S,1'S,2R,2'R)-1,1'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(2,3-dihydro-1H-
	inden-2-ol) 19f :
	From (1S,2R)-cis-1-Amino-2-indanol (500 mg, 3.35 mmol 2 equiv)
	and terephtaldehyde (225 mg, 1.68 mmol, 1 equiv). A white
	precipitate appears at the beginning of the reaction. After 3h
	stirring at rt

  FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3368, 3029, 2922, 2877, 2850, 1643 (νC=N), 1567, 1510, 1454, 1418, 1379, 1346, 1282, 1240, 1223, 1198, 1129, 1078, 1058, 1039, 972, 947, 932, 907, 855, 847, 829, 755, 567, 530, 494, 474, 450, 437, 415 cm -1 .

	MS (ESI+): m/z = 329.2234 ([M + H + ], 100%).

  1 (CH3-CH-NH) ppm. FTIR (ATR): 𝜈̅ 𝑚𝑎𝑥 = 3377, 3084, 3061, 3028, 2970, 2927, 2870, 1615, 1572, 1501, 1451, 1441, 1417, 1375, 1349, 1307, 1264, 1233, 1202, 1153, 1071, 1038, 1028, 1000, 947, 911, 859, 842, 823, 777, 762, 739, 699, 678, 629, 617, 608, 539, 520 cm -1 .

  CH-C-NH2, td, J = 7.3, 1.6 Hz, 1H), 6.42 (CHarom-C-NH, dd, J = 7.5, 1.7 Hz, 1H), 4.49 (NH-CH-CH3, q, J = 6.6 Hz, 1H), 3.49 (NH and NH2, br s, 3H), 1.55 (NH-CH-CH3, d, J = 6.7 Hz, 3H) ppm. CHarom linker, s, 4H), 7.42 (m'-and mCHarom, m, 4H), 7.34 (pCHarom, tt, J = 7.6, 1.6 Hz, 2H), 7.25 (oCHarom, dt, J = 6.7, 1.2 Hz, 2H), 7.23 (o'CHarom, dt, J = 6.7, 1.2 Hz, 2H), 7.11 (CHarom-C-N=CH, dd, J = 7.9, 1.4 Hz, 2H), 7.01 (CHarom-CH-C-NH, ddd, J = 8.2, 7.3, 1.4 Hz, 2H), 6.66 (CHarom-CH-C-N=CH, td, J = 7.6, 1.2 Hz, 2H), 6.45 (CHarom-C-NH, dd, J = 8.2, 0.9 Hz, 2H), 5.52 (NH, br s, 2H), 4.59 (NH-CH-CH3, q, J = 6.7 Hz, 2H), 1.63 (NH-CH-CH3, d, J = 6.7 Hz, 6H) ppm.

	(CHarom-2,2'-(((1Z,1'Z)-1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(N-((R)-1-
	phenylethyl)aniline) 26:
	25 (1.53 g, 2.4 equiv, 7.21 mmol) and terephtaldehyde (403 mg, 3.00 mmol, 1 equiv) were dissolved
	in MeOH (20 mL) and stirred overnight at rt, during which an orange precipitate formed. The
	precipitate was filtered off, washed with MeOH (4 x 5 mL) and dried under vacuum. Orange powder,
	1.27 g, 81% yield.
	1 H NMR (500 MHz, CDCl3): δ = 8.66 (CH=N, s, 2H), 8.07 (
	1 -(1-phenylethyl)benzene-1,2-diamine 25:
	24 (3 g, 12.4 mmol) and NH4Cl (13.3 g, 247 mmol, 20 equiv) were placed in a two-necked flask under
	argon, then freshly degassed MeOH (20 mL) and H2O (5 mL) were added via syringe. The mixture was
	cooled to 0 °C, then Zn powder (4.86 g, 74.3 mmol, 6 equiv) was added. The mixture became quickly
	dark and turned to a light forest green solution after 3 h stirring at rt. The mixture was filtered
	through a celite pad under reduced pressure, during which the solution turned black, and the filter
	cake thoroughly washed with DCM (3 x 30 mL). The filtrate was dried over Na2SO4 and evaporated to
	yield a black viscous product which was used without further purification. 2.62 g, 99% yield.
	1 H NMR (300 MHz, CDCl3) : δ = 7.42-7.27 (o-and pCHarom, m, 4H), 7.22 (pCHarom, ddt, J = 8.2, 6.1, 1.4
	Hz, 1H), 6.73 (CHarom-C-NH2, dd, J = 7.1, 1.9 Hz, 1H), 6.67 (CHarom-CH-C-NH, td, J = 7.3, 1.9 Hz, 1H), 6.61

  With [Sub]0 and [Rea]0 being the initial concentration and νSub and νRea the consumption rate of [Sub] and[Rea]. Equation(55) shows what we usually see on a kinetic curve: the substrate's concentration (y-axis) as a function of time (x-axis) and of a function G including kobs,[Cat] (which is considered to stay constant over the course of the reaction), [Sub]0, [Rea]0 and νSub and νRea.VTNA consists in taking out one of the factors, e. g. [Cat] c , from G to integrate it with t into the x-axis -the time scale is "normalised" for [Cat] c . This leads to equation (56) :[𝑺𝒖𝒃] 𝒕 = 𝐺(𝑘 𝑜𝑏𝑠 , [𝑆𝑢𝑏] 0 , 𝜈 𝑆𝑢𝑏 , [𝑅𝑒𝑎] 0 , 𝜈 𝑅𝑒𝑎 )𝒕[𝑪𝒂𝒕] 𝒄

  143: Schéma général pour la catalyse énantiosélective suivant le modèle ML2. x, y et z représentent les concentrations respectives de MRR, MSS et MRS.Ce sujet a reçu beaucoup d'attention puisque ce genre d' « amplification chirale » est présumée de jouer un rôle majeur dans l'émergence de l'homochiralité biologique et donc de la vie elle-même. Les NLE ont également été beaucoup utilisé comme outil mécanistique afin de vérifier l'agrégation de catalyseurs.Pour ce travail, nous nous sommes penchés sur l'addition de dialkylzincs au benzaldéhyde catalysée par des ligands dérivés de l'éphédrine. Ce dernier est un aminoalcool bon marché qui est censé agir de la même façon que le DAIB, nous nous sommes donc posé la question s'il génère également des

NLE en catalyse asymétrique. Des ligands éphédrine N-monoalkylées ont montré une relation strictement linéaire entre eeP et le ee du ligand (eeL), par contre la version benzylée, la Nbenzyléphédrine (NBE) montre non seulement un NLE très marqué mais particulier : c'est un NLE hyperpositif (Figure

144

). En partant d'un ligand énantiopur et diminuant son eeL, eeP ne diminue pas et ne reste pas constant, mais augmente -de 76 à 81% eeP avec ZnEt2, de 16 à 53% eeP avec ZnMe2. Le ligand scalémique est donc un meilleur catalyseur que le ligand énantiopur, dans le sens qu'il est plus énantiosélectif. Ce genre de comportement n'a, à ce jour, jamais été observé, mais étudié de façon théorique par Henri Kagan. En utilisant son système ML3 (qui diffère du ML2 par l'agrégation du complexe en trimères, non en dimères) il a pu prédire des courbes de NLE qui sont hyperpositives. Par contre, elles ne peuvent qu'être hyperpositives que de la moitié supérieure de l'axe eeL, ce qui diffère de nos propres courbes ; l'effet hyperpositif du NBE doit donc suivre un autre mécanisme que le ML3 de Kagan. Le but de ce travail va être de mettre en évidence ce mécanisme.

  Suite à ces observations, nous avons émis l'hypothèse d'un système catalytique où deux complexes de zinc issus du NBE catalysent : le complexe discret NBE-ZnMe et son dimère homochiral, tandis que le dimère hétérochiral précipite et ne participe pas à la réaction. Les monomère et le dimère homochiral donnent des eeP différents, le dimère étant moins énantiosélectif que le monomère, ce qui expliquerait la dépendance envers la charge catalytique : plus la concentration en catalyseur est grande (ce qui est équivalent à un haut eeL), plus l'équilibre monomère-dimère est déplacé vers le dimère, plus eeP est bas ; à basse concentration les dimères se dissocient en monomères qui sont plus énantiosélectifs et eeP augmente.

  de ces métallopolymères ce sont avérés avoir un NLE. Le cas d'un ligand ditopique à base de diaminocyclohexane chiral est particulièrement curieux car son homologue monotopique et donc non-polymérique ne présente pas de NLE, alors que la structure des sites chélatants est quasi identique dans les deux ligands. Ceci laisse penser que la structure polymérique en elle-même est responsable de l'émergence du NLE et nous a poussé à étudier ce phénomène plus en détail.Dans un premier temps, nous avons voulu faire une version ditopique d'un ligand possédant déjà un NLE marqué, dans l'idée que la structure polymérique de la version ditopique amplifie d'avantage le NLE déjà présent. Nous avons choisi le DAIB qui possède un (+)-NLE puissant et synthétisé le ligand ditopique 9 en 5 étapes à partir de camphre. Ce ligand 9 a ensuite été appliqué dans l'addition énantiosélective du ZnEt2 au benzaldéhyde (Figure150). Le ligand s'est avéré avoir un (+)-NLE marqué, mais moins intense que celui du DAIB monotopique ; une variation des conditions (solvant, charge catalytique) n'a pas amené d'amélioration des résultats. Il semble que la fonctionnalisation sur l'azote pour relier les deux entités DAIB est trop proche du site chélatant et diminue la stabilité des associations hétérochirales, ce qui mène a une diminution du (+)-NLE. Des ligands ditopiques alternatifs avec une fonctionnalisation sur le squelette carboné du DAIB ont été conçu et des possibles voies de synthèse ont été discutées.

  Ce chapitre traite à nouveau de métallopolymères chiraux mais dans un contexte très différent. Ils sont utilisés non comme catalyseurs mais comme matériaux, en génération de somme de fréquences (SFG) chirale. La SFG chirale est un phénomène d'optique non-linéaire, dans lequel un matériau (dans notre cas un métallopolymère chiral) est irradié par deux lasers à deux longueurs d'onde différentes (900 et 450 nm, Figure153). Les lasers interagissent avec le matériau et génèrent une nouvelle radiation (300 nm) qui a l'énergie additionné des deux lasers incidents. Ce phénomène n'est possible que si le matériau est chiral, s'il absorbe à la longueur d'onde sortante (300 nm dans notre cas) et s'il est isotrope. Cette dernière condition est la raison pour laquelle nous travaillons avec des métallopolymères : ils ne sont généralement pas cristallins mais amorphes et donc isotropes. Des molécules discrètes comme le BINOL doivent être encapsulées dans un sol-gel de silice pour empêcher leur cristallisation et pouvoir les appliquer en SFG.

(1R,1'R,2S,2'S)-2,2'-(decane-1,10-diylbis(methylazanediyl))bis(1-phenylpropan-1-ol) 15:

(1R,1'R,2S,2'S)-2,2'-((1,4-phenylenebis(methylene))bis(methylazanediyl))bis(1-phenylpropan-1-ol) 16:

(2R,2'R)-2,2'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(3-methylbutan-1-ol) 19c

(1R,1'R,2R,2'R)-1,1'-((1,4-phenylenebis(methaneylylidene))bis(azaneylylidene))bis(2,3-dihydro-1Hinden-2-ol) 19d

19e-Cu(OTf)2

26-Zn(OTf)2

Remerciements

Chapter III: Sum-frequency generation with chiral metallopolymers

This chapter will also deal with chiral metallopolymers, but in a different context than in chapter II: they are used as materials and not as catalysts, in the application of a physical phenomenon called sum-frequency generation (SFG).

This project was done in collaboration with Grégory Taupier, Alex Boeglin and Kokou Dodzi (Honorat) Dorkenoo from the Département d'Optique ultra-rapide et Nanophotonique (DON) at IPCMS. The SFG microscopy setup was designed and built by the aforementioned group and the SFG spectra recorded by Grégory Taupier (except Figure 114, which was made by the author); DFT calculations were performed by Alex Boeglin.

III.1 Introduction: sum-frequency generation III.1.1 Principles of chiral SFG in isotropic media

Sum-frequency-generation (SFG) consists in the irradiation of a chiral material, usually in form of a thin film (solid or high-concentration solution), with two linear polarised laser beams (k1 and k2, Figure 91). The laser beams interact with the material to generate a new radiation ks whose frequency ωs is the sum of the two incident frequencies ω1 and ω2. Outside of mathematical equations, the wavelength (λ; ω -1 = λ) will be used to describe the beams instead of the frequencies. Our setup uses incident beams with wavelengths λ1 = 900 nm and λ2 = 450 nm, therefore the generated signal has λs = 300 nm.

Figure 91: Scheme for chiral optical sum-frequency generation in isotropic media. [164] The incident beams k1 and k2 are polarised in the same plane P, to which the SFG signal ks is polarised orthogonally (S). Ligand 26's unusual band at 446 nm prompted us to make further studies, as it might reveal more information about the ligand's structure and how it changes upon addition of the metal. It turned out that the band shifts to the blue upon addition of more polar solvents like acetone ("negative solvatochromism", Figure 122). Such solvent-dependent shift can be quantified using the Kamlet-Taft-parameters. [START_REF] Valeur | Molecular Fluorescence[END_REF][START_REF] Nigam | [END_REF] Kamlet and Taft established empirical scales which account for a solvent's polarity (π*), its H-bond-donor (α) and its H-bond-acceptor capacity (β). [181,182] Equation (45) gives the studied band's 𝜈̅ 𝑚𝑎𝑥 (maximal frequency, expressed in wavenumbers) as a function of the maximal frequency in the reference solvent cyclohexane (𝜈̅ 0 ) and the parameters s, a and b which account for the influence of the individual solvent parameters π*, α and β on the band:

The analyte's 𝜈̅ 0 , s, a and b can be determined by measuring 𝜈̅ in a variety of solvents whose π*, α and β-parameters are known, followed by a linear regression. We performed such a Kamlet-Taftanalysis by measuring the 𝜈̅ 𝑚𝑎𝑥 of 26's band in the visible region in 13 different solvents; the tabular

IV.2.2 Spectral investigations

IV.2.2.1 UV-vis-titration experiments

A solution of 26 (2 ml, 5.74•10 -5 mol/L) in THF was placed in a quartz cuvette. A THF solution of a given metal salt (20 µl, 5.74 x 10 -4 mol/L, 0.1 equiv) was added successively; a UV-vis spectrum of the mixture was taken after each addition. To compensate for the solution's ongoing dilution, the absorption values of all spectra were corrected following equation (50):

With Abs(λ)n being the absorbance at wavelength λ after n additions of metal salt, Vn the total volume after n additions of metal salt, and V0 the initial volume (2 mL). The corrected absorption values now refer all to the initial ligand concentration of 5.74•10 -5 mol/L.

IV.2.2.2 Kamlet-Taft analysis

Solutions of ligand 26 in different solvents were analysed by UV-vis spectroscopy, the λmax of the band in the visible region determined and converted into wavenumbers (Table 15). The solvents' Kamlet-Taft parameters were all taken from Kamlet's collection, [181] except the ones for tBuOMe. [193] s, a and b were calculated from the data in Table 15 using the "Multiple Linear Regression" tool in Origin 16 software. V : Supporting Information

V.1 Methodologies

This section gives explanations to some of the methodologies used in this work which may be not familiar to all readers. Those are Stalke's ECCs for DOSY NMR, VTNA for the determination of the kinetic order in catalyst and the Hammett plots using different σ-scales.

V.1.1 1 H DOSY NMR: External Calibration Curves (ECCs)

The classical method to relate D to the analyte's volume is to use the Stokes-Einstein equation: [START_REF] Claridge | High-Resolution NMR Techniques in Organic Chemistry[END_REF] 𝐷 = 𝑘 𝐵 • 𝑇 6𝜋 • 𝜂 • 𝑟 (51) With kB being the Boltzmann constant, T the temperature, η the sample's viscosity and r the molecule's (hydrodynamic) radius. The molecule's volume can then be calculated from r.

The Stokes-Einstein equation is used a lot for the analysis of globular macromolecules like proteins. It assumes the analyte to be spherical but it can be modified to account for elliptic or flat molecular shapes. Nevertheless, it has a lot of disadvantages: it is adapted only to molecules much bigger than the solvent; the viscosity can be approximated to the solvent's viscosity at the chosen temperature only when working in dilute solutions; even though the Stokes-Einstein equation takes temperature into account, the analyte's diffusion behaviour can change over different temperatures, making D values representative only at room temperature; convection movements due to temperature gradients along the NMR tube can also falsify the measured D values. Those are inevitable especially at high temperature since the sample is heated with an airflow blowing from the bottom of the spectrometer, thus creating an inhomogeneous temperature distribution in and along the tube. However, convection can be reduced by using narrow NMR tubes (e. g. 3 instead of 5 mm diameter) and further compensated by the choice of an appropriate convection compensating pulse sequence.

To get representative diffusion values we will work in the same conditions as when performing catalysis, that is at high concentration (0.833 M with ZnMe2) and at different temperatures to follow the evolution of the aggregates' sizes or distribution. This disqualifies the use of the Stokes-Einstein equation and made us move to another method: Dietmar Stalke's External Calibration Curves (ECC). [112,114,115] It consists in measuring not only the analyte's diffusion coefficient but also the one of a reference molecule, which doesn't need to be inside the same NMR tube (this is why the calibration curves are coined as "external"), to obtain a normalised diffusion coefficient :