DYNAMIC COVALENT CHEMISTRY OF C=N, C=C AND QUATERNARY AMMONIUM CONSTITUENTS

Keywords: dynamic covalent library, organocatalysis, imine, Knoevenagel compound, nucleophilic substitution, ammonium salt, reversible reaction, iodide catalysis

Chapter 1 General Introduction……………………………………………………… 1.1 The concept of Dynamic Chemistry………………………………......... 1.2 Dynamic combinatorial chemistry using exchange reactions………….. 1.2.1 Reversible exchange reactions based on covalent bonding………. 1.2.2 Reversible exchange reactions based on noncovalent bonding…………………………………………………………… 1.3 The general characteristics of imine compounds………………………. 1.4 General aspects of Knoevenagel compound chemistry………………… 1.5 General aspects of Oganocatalysis……………………………………... 1.6 References……………………………………………………………… Chapter 2 Organocatalysis of Exchange Processes between Knoevenagel-and Imine-derivatives in Dynamic Covalent Chemistry………………..………………… 2.1 Introduction …………………………………………………………….. 2.2 Results and Discussion ………………………………………………… 2.2.1 Organocatalysis of imine/imine, C=N/C=N, exchange Processes………………………………………………………….. 2.2.2 The C=N/C=N exchange using aniline as a nucleophilic Catalyst…………………………………………………………… 2.2.3 Organocatalysis of benzylidene/imine, C=C/C=N, exchange Processes…………………………………………………………. 2.2.4 Organocatalysis of Benzylidene/Benzylidene, C=C/C=C, Cross-exchange Processes………………………………………... 2.3 Conclusions …………………………………………………………….. 2.4 References………………………………………………………………. I am very grateful to Jacline for all her

Chapter 3 Uncatalyzed C=C/C=N exchange Processes between Knoevenagel-and Imine-derivatives in

First and foremost I would like to thank my supervisor, Prof. Jean-Marie Lehn, for giving me the great opportunity to pursue my PhD at the University of Strasbourg and for his close and excellent guidance throughout the past four years of my research. His enthusiastic and understanding approach gave me enormous inspiration and he taught me so many things not only concerning chemistry but also about French culture.

I would also like to thank Prof. Jack Harrowfield, for many valuable discussions and for carefully checking my manuscripts, making sure both the English and the chemistry were up to scratch. I thank Dr. Jean-Louis Schmitt for his help in the laboratory, particularly with NMR spectroscopy, and also for checking the experimental sections of my manuscripts. I would particularly like to thank Dr. James Hutchison who supported me in many ways, including cheering me up during the difficult days of thesis writing.

I would like to express my gratitude to my parents (Mr. Wiriya Kulchat and Mrs.

Nantawan Kulchat), my lovely brother (Mr. Siripong Kulchat), and my extended family for their encouragement, love, and support, without which I could never have begun my French adventure. I would like to thank all my current and former colleagues in Prof. Lehn's group, particularly Dr. Nadine Wilhelms who taught me how to conduct lab work when I first arrived in Strasbourg in late September 2011, Dr. Petr Kovaříček who helped me with kinetics and NMR experimental analysis amongst many other discussions, and Dr. Lars Ratjen and Dr. Lutz Greb for their valuable assistance in completing projects. I must not forget to thank Qing-Yuan, Rafel, the warm grandfather, Anne, with her nice smile, Katerina and her nice teas, Annie for her kindness, Gaël for being a wonderful colleague and brother, and most of all, Ghislaine who stayed with me in lab 515 for three years, invited me to many social events, and translated endless French documents for me.

There are many more recent colleagues who I very much appreciate, Jan, who always makes me laugh, Karolina, a very kind colleague, Sebastien, Michel, Martin, Men, Mihail, Li-Yuan, Antonio for his Gaussian calculation experience, Annia for her help, and Sawsen for her kindness. I must specially thank the people who proof-read my thesis, Dr. Ghislaine Vantomme for the French Résumé, Prof. Jack Harrowfield, Dr. James Hutchison, Dr. Nema Hafezi, and Dr. Kanchit Rongchai.

Résumé

La Chimie Dynamique Constitutionnelle (CDC) implique la recombinaison dynamique de composants moléculaires liés par des interactions non covalentes ou des liaisons covalentes réversibles. Ces dernières années, la Chimie Covalente Dynamique (CCD) a émergé comme une approche puissante pour créer des bibliothèques dynamiques de composants afin d'analyser leur diversité structurelle. L'analyse de ces Bibliothèques Covalentes Dynamiques (BCDs) fournit de nouvelles perspectives dans l'élaboration de récepteurs, la découverte de médicaments, la résolution dynamique, l'auto-triage, la catalyse, la détection et pour des aspects variés de la science des matériaux. Des exemples représentatifs de réactions réversibles compatibles avec le concept de CCD comprennent les condensations amine/carbonyle, les transestérifications, les échanges de disulfures, les Le mécanisme proposé de la réaction d'échange catalysée par la proline implique une attaque nucléophile de la L-proline sur l'imine pour former un aminal, lequel peut ensuite réaliser une élimination pour donner un intermédiaire zwittérionique hautement réactif (Figure 3). Cette espèce, bien plus réactive que le simple composé carbonyle qui peut être formé par hydrolyse, réalise une attaque rapide avec une amine libre pour donner un nouvel aminal qui ensuite élimine la L-proline pour former une nouvelle imine, complétant ainsi l'échange et la libération du catalyseur. seul, ainsi qu'en présence de 10 mol% de L-proline. Les moments où la moitié des réactifs de départ est consommé (le premier temps de demi-vie, t 1/2 ) et les pourcentages des compositions des solutions obtenues sont listés dans la Table 3. Les paramètres d'équilibre n'ont pas été calculés, à cause de la quantité variable d'hydrolyse. Les résultats démontrent que la réaction d'échange entre les benzylidènes dépend du profil électronique des deux substrats. Des réactions secondaires, où l'adduit de type Michael se forme (voir Figure 5), ont été observées par spectroscopie de masse haute résolution. Dans cette étude, la L-proline utilisée comme organocatalyseur accélère efficacement l'échange, jusqu'à 89 fois (Table 3, Entrée 4). Le mécanisme de la réaction d'échange proposé entre les composants C=C/C=C en présence de L-proline se déroule par un mécanisme similaire à celui proposé pour l'échange C=N/C=C (Figure 5). Ici, les composants benzylidène servent d'accepteur de Michael et réalisent une addition conjuguée par la L-proline pour remplacer les centres benzylidène, formant le même iminium réactif mentionné précédemment, qui facilite l'échange de composés. Ainsi les réactifs de départ ou les produits d'échanges dérivés de fonctions aldéhyde portant des groupes électro-attracteurs peuvent réagir avec le malononitrile anionique libéré pour donner des intermédiaires adduits de type Michael. réduit grandement l'hydrolyse (moins de 10 %) et l'échange C=C/C=N se déroule, exhibant une accélération marquée par la L-proline. (5) Les composants portant des substituants électro-donneurs donnent le moins d'hydrolyse dans les échanges. De plus, la L-proline est capable d'accélérer la vitesse de l'échange Knoevenagel C=C/C=C, et des adduits de type Michael sont formés durant le procédé d'échange. (6) La %-composition des produits à l'équilibre dépend de l'affinité électronique des substrats de départ.

Le chapitre trois décrit les échanges benzylidène/imine, C=C/C=N, impliquant l'acide N,N'-diméthylbarbiturique en CCD. Ici, des études précédentes ont été étendues pour l'échange C=C/C=N entre les composants de Knoevenagel dérivés de l'acide 1,3diméthylbarbiturique (4a-4e) et des mêmes composés imines (1v, 1u, 1f, 1t, et 1b) utilisés précédemment. La solubilité des composants de Knoevenagel a été analysée dans différents solvants et s'est avérée très élevée dans CDCl 3 . Les réactions d'échange ont donc été réalisées dans CDCl 3 (filtré précédemment dans une colonne d'alumine basique pour retirer les traces fortuites de HCl qui peuvent causer de la catalyse acide) avec des quantités équimolaires de dérivés de diméthylbarbiturates de benzylidène et de composants imines (20 mM chacun). A la fois les réactions aller et retour ont été suivies par spectroscopie 1 H-RMN. Au vue des vitesses rapides des réactions d'échange, les constantes de vitesse n'ont pas été obtenues, mais, les constantes d'équilibre ont été déterminées, et sont présentées dans la Table 4.

Les échanges C=C/C=N entre les imines et les dérivées Knoevenagel du N,N'diméthylbarbiturique sont rapides et réversibles dans une solution de CDCl 3 à température ambiante en absence de catalyseur, comme illustré en Table 4. Ce fait permet la formation efficace de diversité par échange C=C/C=N. Cela peut aussi signifier un changement dans le mécanisme pour un procédé plus proche de la métathèse, peut-être via un intermédiaire azétidine. De plus, la formation de gels par ce type de composants Knoevenagel (4f-4i) a été initialement étudiée en utilisant différents systèmes de solvants (Figure 6). Les résultats montrent que 4f-4i forment un gel dans l'éthanol, le méthanol, et l'acétonitrile, alors que 4i et 4g ne sont pas capables de former de gel dans l'acétonitrile et le méthanol, respectivement (en utilisant 1% w/v de gélateur dans un solvant approprié).

Table 4 La sélection de réactions d'échange Knoevenagel/imine. Les proportions [%] des différents composés dans les réactions d'échange C=C/C=N entre les diméthylbarbiturates de benzylidène et les imines dans

Organogel a) Représentation des composés barbiturates de benzylidène (4f

La capacité de 4g à former des gels ou non dans les solvants acétonitrile (2), décanol (3), méthanol (4) et cyclohexane (5).

L'étude de la sélection de gel par l'échange C=C/C=N a été réalisée et il a été que la réaction d'échange entre 4b et 1w dans CD 3 CN/EtOH 9/1 donne des produits d'échange dont 4f pour former le gel qui ne forme pas de gel. Les résultats décrits ici montrent la création de BCDs de grande diversité chimique, permettant ainsi la génération par CCD de récepteurs, de de matériaux fonctionnels et de biomatériaux de plus en plus Le chapitre quatre décrit l'échange de composants de sels d'ammonium quaternaires par substitution nucléophile bimoléculaire dans une CCD. Les constantes d'équilibre des substitutions nucléophiles d'échange des sels de pyridinium ont été calculées (Table 5). 6). Certains de ces sels de pyridinium qui constituent ces bibliothèques dynamiques sont connus comme des liquides ioniques, ainsi, nous avons voulu générer des bibliothèques dynamiques de liquides ioniques avec ou en absence de solvant. Cette approche a remarquablement étendue la CCD, facilitant la formation de plus de bibliothèques dynamiques et permettant la génération de nouvelle diversité.

) Distribution de composés [%] b ) k [x10 -3 M -1 s -1 ] t 1/2 [h] K b c ) K c d ) 1a 4b 1b 4a a b c d 1 1a + 4b f b 13

La chapitre cinq

Chapter 1

General Introduction 1.1 The concept of Dynamic Chemistry

Supramolecular chemistry has seen enormous development over the past halfcentury as chemistry moved beyond the molecule [1,2] to investigate the use and control of non-covalent interactions such as van der Waals forces, π-π stacking, cation-π interactions, different types of dipole interactions, hydrogen bonding, ion-pairing, and coordinative metal complexation. It is a multidisciplinary field which has influenced diverse disciplines, for instance, the traditional areas of organic chemistry, inorganic chemistry and materials chemistry. Supramolecular chemistry is aimed at creating highly complex, self-organized systems by careful design of molecular precursors, thus paving the way towards chemistry as an information science. Information can be stored by appropriate manipulation at the molecular level and then transferred and processed at the supramolecular level through molecular recognition processes.

Supramolecular chemistry is intrinsically highly dynamic [2] due to the lability of most non-covalent interactions. This allows self-organisation by design to evolve towards self-organisation by selection. For instance, in the presence of several different molecular precursors, the lowest energy self-organized system can emerge and come to dominate over the large number of other possible supramolecular systems by rapid exchange of molecular precursors. [2] This is an example of constitutional dynamics, the reversible change in the constitution of a supramolecular entity by component exchange.

Chemistry involving the latter dynamics, so-called Constitutional Dynamic Chemistry (CDC) is the central focus of this thesis. CDC naturally occurs at the supramolecular level as described above. CDC at the molecular level is, however, less studied in organic system as non-labile bonding is normally employed in the quest for molecular stability (in particular, in the sense of kinetic inertness). Nevertheless CDC can indeed be implemented at the molecular level if reversible covalent bonding is employed (or a catalyst for the facile breaking and making of bonds is available, as happens in Nature, where enzymes can convert inherently very inert species into labile ones), allowing a continuous change in molecular constitution by reorganization and exchange (Figure Dynamic Combinatorial Chemistry (DCC) [3][4][5] is a branch of CDC that focuses on the generation of diversity by constitutional exchange. The aim is to employ a small set of molecular or supramolecular components that can, by rapid and reversible reactions under thermodynamic control, form a much larger array of more complex species. This route to the generation of dynamic diversity, resulting in so-called dynamic combinatorial libraries (DCLs), [6] is at the heart of DCC. A DCL can be characterized by three main features:

Conversion, representing the total amount of constituents created with respect to free components;

Composition, representing the distribution of relative amounts of the different constituents;

Expression of a given constituent, which might be defined as the product of conversion and selectivity.

The conversion and composition of a DCL are determined by the relative thermodynamic stability of each component (relative Gibbs free energy of formation).

Once a DCL has been established, one can employ external stimuli to alter the potential energy landscape, thus altering the DCL composition/conversion. That is to say, a DCL is not a fixed entity. For instance, non-covalent binding to an introduced template might amplify a particular component, an example of expression (Figure 1.2) and a demonstration of the adaptive capability of CDC. biological 'lock'. The traditional approach [1] to finding the right key would be to synthesize a particular key and test its activity for binding to the lock, and though laborious this could be done for many keys using high throughput screening. DCC provides an alternative and likely more efficient approach, in which the components for all possible keys are mixed together and allowed to exchange. The full range of possible keys from combinations of the keys' fragments constitutes the 'virtual' DCL while the actual composition will depend on thermodynamic factors. Since many keys form by rapid exchange of fragments, finding a key, or key fragment, that fits the lock may be faster than in the traditional approach. The key or key fragment may enter the lock either under thermodynamic control (the best fit to the lock) or by kinetic selection (the fastest to bind). A decade ago, DCC was conceptualized and implemented in various chemical systems. [8,9] Initial explorations focused on the principles and procedures required to generate dynamic libraries through reversible chemical transformations. These will be discussed in detail in the following section.

Dynamic combinatorial chemistry using exchange reactions

The main drivers of dynamic combinatorial chemistry (DCC) are the reversible reactions that exchange building blocks between the different components of the system.

These reversible exchange reactions [3] should have the following characteristics:

The timescale of the exchange reaction should be short so that equilibration and selection occur essentially simultaneously.

They need to operate under mild experimental conditions (e.g. temperature, pressure, concentration, solvent, pH, catalyst).

The solubility of all building blocks and library components is required because if any insoluble material is present, it can act as a thermodynamic sink or slow the reaction rate (kinetic trap).

The reversible reactions are divided into three main types, depending on whether covalent, non-covalent, or coordinate bonds are involved. The non-covalent interactions typically reach equilibrium rapidly whereas the covalent reactions proceed more slowly and can require the presence of a catalyst to fulfill the requirement for lability listed above.

Some examples of DCC using covalent exchange reactions are discussed next.

Reversible exchange reactions based on covalent bonding

Recently, numerous covalent reversible exchange reactions have been used for DCC [5,[10][11][12][13][14][15][16][17][18][19][20] even though it is often difficult to establish true equilibrium. Some examples of the generation of dynamic covalent libraries (DCLs) involving labile covalent bonding are illustrated below.

Imine (C=N) formation and exchange -

The condensation product obtained by the reaction of a carbonyl compound and a primary amine is called an imine or, commonly, a Schiff base. [21] Imine formation is reversible and the equilibrium can be forced towards the imine product by removing water. [22,23] An imine can react with amine to undergo the reversible exchange process called transimination. [10][11][12][13][14][15]17,[24][25][26][27] Furthermore, an imine can exchange its amine component (and simultaneously its carbonyl compound component) for that of another imine, the so-called imine/imine exchange reaction (Scheme 1.1), via either nucleophilic catalysis, [26] hydrolysis/re-combination being an obvious example of such a pathway, [28] or by a direct metathesis involving a single, cyclic intermediate/transition state. [29][30][31][32][33][34][35][36][37][38][39][40] Scheme 1.1 Imine formation and exchange reactions.

Boronic ester formation and exchange -Boronic esters are formed by the condensation between a boronic acid and alcohols and it usually requires a dehydration procedure to drive the reaction to completion. Recently, iminoborane compounds were used to perform self-assembly by reversible B-O and imine bond formation giving an iminoboronate ester. [41,42] This suggests that the versatile exchange motif between imine and diol bonds could be useful in dynamic covalent systems (Scheme 1.2).

B OH OH R 1 R 2 R 3 OH OH B O OH OH R 1 NH B N R 1 O O R 2
OH Scheme 1.2 Boronic ester and iminoboronate ester formation.

Diels-Alder Reaction

to form a substituted cyclohexene product. This reaction is reversible under certain conditions, where the reverse or retro Diels-Alder reactions have been shown to undergo reversible component exchange to form DCLs under mild conditions.

generate dynamic polymers, "dynamer temperature. [44] The use of such a system with a low equilibrium constant allowed the formation of materials with self diene Scheme 1.3 a) The general equation for Diels (reverse) reactions b) An example of a Diels conditions. [45] a)

b)

B O O R 1 R 3 R 2 2H 2 O
Boronic ester f orm

H 2 B N R 1 O O OH OH Iminoboronate est 2 NH 2 B N R 2 O O X B N R 1 O O X H OH

Substitution reactio iminoborane with am T ransf ormation of i with diols

Boronic ester and iminoboronate ester formation.

Reaction is the cyclization reaction between a diene and dienophile substituted cyclohexene product. This reaction is reversible under certain conditions, where the reverse or retro-Diels-Alder reaction is efficient. These Dynamic Alder reactions have been shown to undergo reversible component exchange to form under mild conditions. [43,44] Reversible Diels-Alder reactions have been used to generate dynamic polymers, "dynamers", which undergo rapid exchange at room

The use of such a system with a low equilibrium constant allowed the formation of materials with self-healing properties. The use of such a system with a low equilibrium constant allowed the

Alder (forward) and retro-Diels-Alder Alder reaction which is dynamic under mild

Olefin metathesis is a versatile tool for organic [46][47][48] and organometallic synthesis. [49] This reaction occurs through an essentially reversible process via a series of [2+2] cycloaddition/cycloreversion steps using metallocatalysts, [50] of which the family of Grubbs' catalysts [51,52] is the most effective.

Scheme 1.4

The fundamental catalytic cycle for an olefin/alkene metathesis reaction. [3] (Scheme reproduced from reference [3] and slightly modified) Disulfide exchange is an important reaction in biology, being, for instance, involved in the folding of proteins. [53] It is one of the few reversible covalent reactions that are compatible with biomolecules. [54][55][56] The mechanism of the exchange [57] is the nucleophilic displacement of a thiolate anion from the disulfide through attack by another thiolate anion, thus, basic conditions are required.

Scheme 1.5 The general equation for a) disulfide formation (involves oxidation, with H 2 as the other formal product) and b) disulfide exchange (also involves oxidation state changes at sulfur).

Michael reaction is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound or conjugate with an electron withdrawing group. It is one of the most useful methods to make C-C bonds. Cases, where the reverse (retro-Michael) reaction occurs readily, are known and studies of the thermodynamics and kinetics of Michael/retro-Michael reactions have been reported involving both sulfur and [58] oxygen-derived nucleophiles. [59] Thiol-based Michael donors can be used to generate DCLs based on the reversibility of this reaction. [60] Scheme 1.6 Equation for a) the Michael reaction in general and b) an example of a reversible Michael/retro-Michael reaction. EWG = electron-withdrawing group.

Reversible exchange reactions based on noncovalent bonding.

The kinetic lability of hydrogen bonds and many coordination bonds has been used to self-assemble diverse supramolecular architectures. [61][62][63][64][65][66] Investigation of the generation of DCLs by reversible non-covalent assembly has been undertaken by several research groups.

Hydrogen Bonding is an attractive interaction between a hydrogen-bond donor (HBD) XH and a hydrogen-bond acceptor (HBA). [67] In general, the hydrogen bond reflects the ability of bound H to form additional weak interactions, usually to rather electronegative atoms with lone pairs. Many researchers have been inspired to investigate DCLs based on reversibly hydrogen-bonded assemblies. [68][69][70][71] Often they have used a combination of H-donors and acceptors which build highly complex architectures with large numbers of hydrogen bonds (e.g. as many as 36). [72] Hydrogen bonding has some limitations for the generation of DCLs as H-donors/acceptors can self-aggregate, or competitive binding by polar solvents or by the presence of traces of water can disrupt the assembly.

Metal-Ligand Coordination -the use of metal-ligand coordination in DCLs

requires at least some ligand substitution reactions within the coordination sphere to be fast. The rates of these reactions, however, depend on many factors relating to the nature of the ligand and metal and their complex but by careful control of these factors, complexes between metals (e.g. Co 2+ , Cu + , Cu 2+ , Fe 2+ , Zn 2+ ) [73][74][75][76][77][78] and various ligands have been used to build-up DCLs via metal-ligand exchange. This type of DCL is compatible with biomolecules as either templates or building blocks (Figure 1.4). [79,80] Figure 1. 4 The composition of a DCL based on metal-ligand interactions using Zn 2+ for self-selection through alkene metathesis. [78] (Note: The ligand shown around the Zn 2+ is porphyrin; this is a species where four sites (donor atoms from porphyrin) are inert and only the two axial sites are labile) The Fe in the ferrocene units is of course completely inert and the phosphine ligands on the Grubbs catalyst are also inert to substitution. (Figure reproduced from reference [3])

Example of selection in a DCL

The expression of a particular component of a DCL through its dynamic response to internal stimuli was shown by Lehn's group [81] (Figure 1.5) working with DCLs of guanine quartet-based hydrogels. The guanosine hydrazide (1) was found to be a very powerful hydrogelator when linked by a metal ion into its quartet form. It is able to react with several aldehydes to form acylhydrazones which provide gels of different stability when a metal ion is added. Thus, by adding a metal ion to the DCL formed from 1, acetylserinehydrazide, 3, and the aldehydes pyridoxal phosphate, 2, and 2-formylbenzene sulfonate 4, the reversibility of the hydrazine formation leads to the selective formation of the gel B containing the pyridoxal-derived hydrazone. This is an expression of triple constitutional dynamics, two at supramolecular levels (the metal complexation and the hydrogel formation of the guanosine hydrazide quartet) and a third (the acylhydrazone formation) at a dynamic covalent level. [81] The red sphere indicates a metal ion. (Figure reproduced from reference [1])

Figure 1.5 The constitutional dynamic selection driven by self-organisation in the formation of a G-quartet based gel (B).

Nitschke and Lehn also reported self-organization by selection with the generation of a tetranuclear [2x2] grid-type metallosupramolecular architecture (Figure 1.6). [15] The grid formation involves two dynamic processes, which are reversible covalent bond connection (imine reversible bond) and reversible metal ion coordination. In the system, studied, aminophenols were mixed with carbonyl compounds in a solution to form a dynamic covalent library of imine. Then, Zn(II) was added to drive the system to that containing the most effective complexing agent (Figure 1.6). Again the expression of a single component of a virtual DCL was induced by the addition of a metal ion. The dominant DCL component was generated through both reversible covalent (imine) grid complex from metal cations and organic building blocks using both reversible imine exchange and reversible metal-ligand interactions. [1] (Figure reproduced from reference [1])

DCLs involving different types of dynamics

While constitutional dynamics only has been discussed so far, Lehn's group also reported other types of dynamics which can affect the composition/conversion of a DCL, for instance, motional dynamics, or configurational exchange, being the external and internal reorientations of a molecule. [82][83][84] Particularly interesting again are the imines since they can be doubly dynamic, with both motional and constitutional functionality.

They have been shown to have intrinsic properties of a molecular motor type, as they are able to undergo cis-trans isomerism and ring inversions which can be used to drive unidirectional rotation in the case of a chiral imine. [82] Motional and constitutional exchange in imines typically occurs on very different timescales however. This fact has been used to control information storage for either the short or long term in doubly dynamic imine systems. [83] In that work a hydrazone was shown to undergo photoinduced isomerization (with thermal back reaction), constitutional exchange with amines, and finally metal ion binding, giving respectively short term, long term, and permanent (locked) information storage (Figure 1.7a). [85] In other work, oligoamine chains were shown to undergo constitutional exchange with an aldehyde to form imine compounds (Figure 1.7b), which then underwent motional dynamics whereby the alkylidene residues were able to shift to a neighboring site. [27] This work showed that oligoamines have the potential to provide a molecular "walking" track under the correct circumstances. Clearly imines behave as very simple but highly versatile systems for combining in beneficial ways both constitutional and motional dynamic processes. [84,86] (3) lock-in by metalion (locked). [84] b) The reversible formation of imines from a carbonyl entity (red sphere) and a terminal diamine (blue connected spheres), the exchange of diamines through transimination (blue frame), and the back and forth motion of the alkylidene moiety between the terminal amine sites (red frames) are indicated. (Figure reproduced from reference [84])

DCLs and multiple external stimuli

Recently, Lehn's group reported a DCL of pyridylhydrazones and pyridylacylhydrazones which undergoes double adaptation in response to two orthogonal agents involving chemical effectors (metal cation) and a physical stimulus (light irradiation).

These DCLs show a selection and adaptation in respond to multiple external stimuli thus allowing component exchange and leading to adaptation of two orthogonal selection processes (Figure 1.8). [71] a) b)

Figure 1.8 A DCL of four pyridylacylhydrazones (top) is influenced by external stimuli

such as addition of a metal ion or light irradiation. [87] (Figure reproduced from reference [84])

General direction of this thesis

Taking all the works mentioned above collectively, it is clear that CDC and the resulting DCLs give rapid access to a high level of self-organization and diversity. At the highest level of complexity, one may even begin to speak of constitutional dynamic networks (CDNs). [1] Recently, CDC has been implemented to produce a diverse range of targets useful in, for instance, receptor design, [88][89][90][91][92][93][START_REF] Furlan | Proc. Natl. Acad. Sci[END_REF][START_REF] Schmuck | [END_REF][96][97][98][99][100][101][102][103][104][105] biological studies, [106][107][108][109][110][111] materials sciences, [30,88,89,[112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130] dynamic resolution, [131] self-sorting, [132] DNA-templated synthesis, [133][134][135] catalysis, [88,[136][137][138] sensing, [102,[139][140][START_REF] Vendrell | Chemosensors: Principles, Strategies, and Applications[END_REF] and the controlled release of bioactive compounds. [117,140,[START_REF] Herrmann | [END_REF] Among the DCLs studied to date, the formation of imines by the reversible reaction of carbonyl compounds with amine derivatives is one of the most extensively investigated. This thesis expands on these studies and also investigates the dynamic covalent chemistry of Knoevenagel compounds, which have a variety of useful applications. Both imine and Knoevenagel CDC have been studied in the presence of organocatalysts. Thus, in the following, the chemistry of imines, Knoevenagel compounds, and organocatalysis, will be discussed in depth.

The general characteristics of imine compounds 1.3.1 Imine formation -

As noted earlier, imines (C=N) are compounds formed by the condensation between either an aldehyde or a ketone with a primary amine. They are called Schiff bases if just the C=N bond or the azomethine linkage is present (Scheme 1.7), the reaction being discovered in 1864 by Schiff. [143] When the reaction is performed with an amino compound (H 2 N-X) where X is an oxygen or a nitrogen atom, the resulting imine is called an oxime (-HC=NOR, i.e. X = OR), or a hydrazone (-HC=NNHR, X = NHR), respectively (Scheme 1.7). In addition, the condensation of an aldehyde or a ketone with a secondary amine results in an iminium ion which can convert to an enamine product.

Scheme 1. 7 The reversible formation of imines, hydrazones, and oximes. [START_REF] Herrmann | [END_REF] The reaction typically requires an acid catalyst and careful temperature control. [17] The mechanism of imine formation (Scheme 1.8) is considered to be a nucleophilic addition-elimination reaction. In the first step of the formation of imines (VIII), [144] the primary amine (II) attacks at the carbonyl carbon (I). Then, the alkoxide ion (III) abstracts a proton from an acid to form an ammonium species (IV). The loss of a proton from the ammonium ion (giving, overall, what is equivalent to an intramolecular proton transfer in III) then forms a neutral tetrahedral intermediate (V), called a carbinolamine or hemiaminal. The next step is protonation of the hydroxyl group and the elimination of water to generate a protonated imine (VII) and finally the loss of a proton to afford the imine (VIII). While the reaction proceeds, the removal of water is necessary in order to drive the equilibrium to the product side. The multiple proton transfers involved in this mechanism explain why the pH dependence of imine formation can be very complicated. [145][146][147] Thus, the pH at which imine formation is carried out must be carefully controlled.

There must be sufficient acid present to protonate the tetrahedral intermediate, however if the medium is too acidic it will protonate the reactant amines. The resultant ammonium ion is not a nucleophile and will not react with the other reactant's carbonyl group. The intermediate (V), commonly termed a carbinolamine, is a labile species and generally cannot be isolated or detected. The stability of carbinolamines does depend on the nature of substituents, however, and this is not always the case. [148][149][150][151] Scheme 1.8 A proposed mechanism of imine formation (nucleophilic addition-elimination reaction) involving a primary amine (On the other hand, III can also undergo a direct intramolecular proton transfer to give V). [144] One of the most important characteristics of imine (C=N) compound formation is its reversibility. Imines occur naturally and are widely studied in biology, [START_REF] Jencks | Catalysis in Chemistry and Enzymology[END_REF][START_REF] Stryer | [END_REF][START_REF] Hochgurtel | Fragment-based Approaches in Drug Discovery[END_REF] they are also of interest to organic chemists [22,23,25,101,116,143,[START_REF] Patai | The Chemistry of the Carbon-Nitrogen Double Bond[END_REF][START_REF] Carey | Advanced Organic Chemistry[END_REF][START_REF] Belowich | [END_REF][158][159][160] where their reversibility is exploited for applications. With regards to CDC and the generation of DCLs, the imine linkage has several practical advantages. The large variety of imines derived from the many substituents (R 1-3 ) possible, allows the formation of DCLs with a broad range of structural diversity. As just discussed, the rate of the imine formation is very sensitive to medium pH thus this can be one of the stimuli that control the composition/conversion of an equilibrated mixture of imines. Importantly, exchange reactions between imines and reactant amines, transimination, and exchange reactions between different product imines, imine metathesis, allow the system to attain even more diversity via a second generation of dynamic covalent chemistry. The mechanistic details of these exchanges will be described next.

Transimination

-One mechanism of transimination is similar to imine formation, proceeding via reversible formation of an aminal which then releases fragments to afford a new imine and an amine (Scheme 1.1b and 1.9). The overall exchange process involves a proton transfer from the amine nitrogen atom to the imine nitrogen atom. The rates and equilibrium parameters depend on the relative basicity of amines. In fact, imines react with the nucleophiles N of amines more rapidly than the carbonyl compounds [161,162] so that the alternative mechanism of hydrolysis followed by recondensation is not favored.

During the transimination process, the rate-determining step is the addition step if the nucleophilicity of the amine is less than the basicity of the amine which is condensed as the imine. When the reaction is occurring in the opposite direction, the rate-determining step is the formation-decomposition of the aminal. [163] Scheme 1.9 The general mechanism of the transimination via aminal formation. [164] The influence of acids (Brønsted and Lewis acid) on the transimination reaction has been investigated [17] and Sc(III) triflate, for example, has been shown to catalyze the rate of exchange between sterically hindered imines (derived from 9-anthracenecarboxaldehyde)

and several amines by up to five-fold in CDCl 3 . A mechanism was proposed in which the metal ion polarises the imine, aiding the nucleophilic attachment of the free amine. In other work, the transition state of the transimination leading to the formation of aminal was proposed to be polar in the case of aliphatic amines and almost apolar in the case of aromatic amines. [25] 1.3.3 Imine exchange -The imine exchange reaction, or imine metathesis, is the reaction between two imines to form two new imines (Scheme 1.1c). Nearly a century ago Ingold et al. [165,166] suggested that the exchange proceeded by a concerted mechanism involving the formation and decomposition of a dimeric intermediate with a 1,3-diazetidine structure. However, the energy of the transition state for this symmetry forbidden [2π + 2π] cycloaddition reaction has been calculated to be too high (Scheme 1.10a). [29] About half a century ago, Messmer et al. [167] suggested the imine exchange reaction could occur via a stepwise mechanism involving the formation of ionic intermediates (Scheme 1.10b). They showed that the rate constants of the exchange reaction in polar solvents were higher than in less polar solvents, consistent with formation of an ionic intermediate rather than the neutral intermediate of the concerted process. The exchange reaction did not occur in the absence of protons or in a high concentration of protons, consistent with an acid catalyzed nucleophilic attack. Attack of a neutral imine on a protonated imine could result in passage through three transient intermediates (Scheme 1.10b). The reaction does not take place in the absence of protons as one of the imines needs to be activated in the first step, while in excessively acidic conditions both imines would be also protonated preventing reaction.

Scheme 1.10 Possible mechanisms of the imine exchange reaction a) via concerted [2+2] mechanism b

) for an aromatic Schiff base via the acid-catalyzed ionic intermediate pathway. [167] Olefin metathesis has generated great interest in organometallic chemistry leading to similar interest in analogous metal-catalyzed imine exchange metathesis. [168][169][170][171][172] In the late 20 th century, the imine cross-metathesis was investigated [35,[37][38][39][40][173][174][175] using CpM(=NR)Cl 2 as the catalyst (Cp = cyclopentadiene, M = Zr, Mo, Nb, Ti, Ta). The proposed mechanism for the metal-imido catalysis does not involve the direct reaction between imines. The reaction occurs via the imine reacting with a metal-imido compound to form a diazametallacycle intermediate, its subsequent breakdown resulting in the imine exchange product and a new metal-imide (Scheme 1.11) following a Chauvin-type mechanism. [176] Similarly, a second imine also reacts with metal-imido catalyst then gives a second imine exchange product. The metal complex can be thought to act as a Lewis acid activator of one imine toward nucleophilic attack of another imine reactant. [36] The role of the trace amount of amines in the imine exchange via metal-imido (CpTa(dNBu t )Cl 2 ) catalysis has also been investigated demonstrating that amines play a primary role in the reaction mechanism in the presence of excess imines. [33] Scheme 1.11 A possible mechanism of imine metathesis following a Chauvin-type catalytic cycle using a metal as the catalytic center. [164] (Figure reproduced from reference [164] and slightly modified)

In other investigations, imine exchange via an amine-mediated mechanism has been suggested to occur via the coupled transiminations between imine reactants and trace amounts of amine. Recently, Di Stefano et al. [25,26] have shown that transimination reactions are accelerated in organic solvents in the presence of trace amounts of amine (either aromatic or aliphatic). The amine initially undergoes transimination with one of the imines, the product amine then undergoing transimination with the other imine, and so on (see Scheme 1.12b for details).

Scheme 1.12

The Imine metathesis catalyzed by the trace amount of primary amine. R 1 , R 2 = aliphatic or aromatic [164] (Figure reproduced from reference [164] and slightly modified).

In summary the reversible formation, transimination and exchange reactions of imines under mild conditions, or in the presence of organocatalysts, have great potential for the generation of DCLs of imines which will be illustrated in Chapters 2 and 5.

General aspects of Knoevenagel compound chemistry

The Knoevenagel reaction is a facile and versatile method for the formation of carbon-carbon bonds named after Emil Knoevenagel, a German chemist (18 June 1865 -11 August 1921). [177,178] It is a nucleophilic addition between aldehydes or ketones and an active methylene compound, using ammonia or other weakly basic amines as catalysts in organic solvents, followed by elimination of water to afford a α,β-unsaturated compound (Scheme 1.13a). The methylene activity is induced by either R 3 This reaction is considered to be a modification of the aldol reaction; what distinguishes the Knoevenagel reaction is the more active methylene hydrogen when compared to an α-carbonyl hydrogen. [START_REF] Menegatti | Green Chem. -Environ. Benign Approaches[END_REF] The Henry reaction is a variant of the Knoevenagel condensation that uses compounds with an α-nitro active methylene. [START_REF] Menegatti | Green Chem. -Environ. Benign Approaches[END_REF] Knoevenagel compounds have been used to synthesize coumarins and their derivatives which are important intermediates in the cosmetic and pharmaceutical industries. [START_REF] Tietze | Compr. Org. Synth[END_REF] A variety of Knoevenagel reaction products has also been used as efficient enzyme inhibitors, and anti-bacterial, anti-tumor, and anti-inflammatory agents. [START_REF] Lubisch | [END_REF][182][183][184][185][186] Next, some properties of Knoevenagel compounds are described.

Recent work using Knoevenagel compounds

In the group of Mayr, the electrophilicity of Knoevenagel compounds such as 5-benzylidene-1,3-dimethylbarbituric acid and thiobarbituric acid were studied (1a-1e, Figure 1.9). [159] They were allowed to react with either neutral nucleophiles (e.g. enamines, amines, water, and hydroxide) in DMSO at 20 o C. The electrophilicity parameter (E) of each compound was determined from kinetic studies and particularly the second-order rate constants for the reaction (using the Mayr-Patz equation [189] (log(k) = s(N + E); where k is the second order reaction rate constant at 20 o C, N is a nucleophilicity parameter, E is an a) b) electrophilicity parameter, s is a nucleophile-dependent slope parameter. The constant s is defined as 1 with respect to 2-methyl-1-pentene as the nucleophile). They reported that the E parameters of the thiobarbituric acids were in the range of 10.4 -13.9. These values are comparable with those of substituted benzylidene-malononitriles. [188] These Knoevenagel compounds can also act as Michael acceptors and electronically neutral organic Lewis acids. [190] Figure 1.9 The reaction used in the investigation of the electrophilicity of Knoevenagel compounds 1a-e. [187] The group of Wang reported that the Knoevenagel compounds derived from 5-benzylidene barbituric acid (Figure 1.10, IH and IM) could be used as anion detectors by their colour changes in the visible spectrum. [191] Both receptors showed a high sensitivity and a low detection limit for fluoride ion. The sensing mechanism for both IH and IM occurs via the anion-induced retro-Knoevenagel reaction (anion-induced deprotonation at the methylene carbon) to liberate aldehyde and the corresponding barbituric acid, which then leads to a double addition product. The sensing behavior of IH can also be driven by hydrogen bonding of, for instance, a fluoride ion with the receptor N-H proton, which shifts the charge transfer absorption band of IH. This approach suggests new perspectives for anion sensing by barbituric acid derivatives. changes observed after adding anions to solutions of IH and IM. [191] (Figure reproduced from reference [191])

Spange et al. have shown that supramolecular self-assembly via hydrogen bonding interaction between a highly dipolar pyridinium-barbiturate-betaine (3) with 2,6diacetamidopyridine (DAC) or 9-ethyladenine (EtAd), or 2,6-bis(trifluoroacetamino) pyridine (BTF) has a marked effect on the reactivity of the barbiturate with several nucleophiles (Figure 1.11a). [192] They also demonstrated that barbituric-merocyanines (Figure 1.11b) could form a supramolecular complex via hydrogen bonding with DAC and have an electrophilic behavior enabling them to react with some nucleophiles. [193] In summary, with such a broad range of interesting properties and applications, the 3) with artificial receptors DAC, EtAd, or BTF, [192] b) barbituric-merocyanines (1a, 1b). [193] (Figure reproduced from reference [192,193])

General aspects of Organocatalysis

Organocatalysis is the acceleration of chemical reactions with small amounts of an organic compound which does not contain a metal ion at the actual catalytic centre. [194] In recent decades, the field of organocatalysis has expanded enormously as it has been shown that reaction pathways catalyzed by organocatalysts can have much lower transition state energies than the corresponding metal-catalyzed reactions, i.e. they can be more efficient, and also more environmentally/bio-friendly. Long known, transition-metal-mediated coupling reactions, such as Suzuki, [195][196][197] Sonogashira, [198] and Heck type reactions, [199] can now be performed under metal-free conditions. The most common organocatalysts are bifunctional with both Bronsted acid and Lewis base centers which can activate the reagent and accelerate the reaction. [200,201] Of course, organic molecules have been used since the beginnings of chemistry as catalysts, but new applications such as enantioselective catalysis continue to emerge or re-emerge. [200,[202][203][204][205][206] The majority of all organocatalytic reactions are amine-based reactions, so-called asymmetric aminocatalysed. [207] Most of these processes pass through the formation of either iminium or through both iminium and enamine intermediates. As noted earlier, the condensation reaction between aldehydes or ketones and a secondary amine can give an enamine product via an iminium ion intermediate (Scheme 14). Iminium salts are more electrophilic than aldehydes or ketones. Therefore, the reversible iminium salt/enamine formation can activate carbonyl compounds toward nucleophilic attack. These reactions include cycloadditions, nucleophilic additions (providing the formation and deprotonation of enamine components can occur), and also retro-aldol type reactions such as decarboxylation. An example of iminium activation is depicted in Scheme 1.14. [208] Scheme 1. 14 The formation of imine or enamine via iminium ion. [208] The first established case of iminium catalysis was the Knoevenagel condensation catalyzed by primary or secondary amines. [209] Knoevenagel himself suggested the possibility of an aldehyde-derived imine or aminal intermediate in this reaction. [177] In 1952, Crowell and Peck [210] obtained kinetic evidence for an imine/iminium intermediate in the Knoevenagel condensation between piperonal and nitromethane. Moreover, in 1962, Jencks and co-workers [211] described an aniline catalyzed semicarbazone formation which occurred via transimination of the iminium ion. They confirmed the existence of the iminium intermediate by kinetic experiments.

1.
Recently, secondary amines such as L-proline have found to be the most successful catalysts for the enamine-iminium catalytic pathway. Figure 1.12 shows how L-proline can react with a ketone then transform to a nucleophilic iminium/enamine intermediate which is easy to trap with an introduced active electrophilic species (such as aldehyde ketone or an azocarboxylate), this leading to regeneration of an iminium ion which subsequently releases the product and L-proline to continue the cycle.

The N-atom of L-proline has a higher basicity and a greater nucleophilicity than those of other amino acids. [194] It can react with carbonyl groups or Michael acceptors to form the iminium ion and/or enamine. The carboxylic group of L-proline can also act as a Bronsted acid, thus, it can be used as a bifunctional catalyst (Figure 1.12). Proline is not the only organic molecule which can activate iminium/enamine reactions, and not all iminium/enamine reactions can be catalyzed by L-proline. Nevertheless, L-proline and its derivatives (Figure 1.13) play a major role as organocatalysts.

Figure 1.12

The enamine-iminium catalytic cycle in the presence of L-proline. [194] (Figure reproduced from reference [194] with minor modification) Figure 1. 13 Examples of proline derivatives used as organocatalysts. [194] There are several amine-catalyzed reactions that cannot easily be classified into either enamine or iminium mechanism types, or it is possible that both mechanisms cooperate at the same time. Mostly the reactions proceed through enamines, but the possibility of iminium ions as active intermediates cannot be excluded. [208] List et al. in 2004, reported the intramolecular Michael reaction (Figure 1. 14), where a C-C bond is formed between the α-carbon of saturated aldehyde group and the carbon at the β-position of an enal or enone. [212] They suggested that the reactions might proceed via either enamine catalysis or a dual enamine-iminium pathway.

Figure 1.14 Intramolecular enantioselective Michael addition. [208,212] In 2000, MacMillan et al. [213] described the first enantioselective organocatalyst for Diels-Alder cycloaddition reactions. Chiral amino derivative 7 was a suitable catalyst for the reaction between α,β-unsaturated aldehydes and various dienes through an iminium ion intermediate mechanism (Figure 1.15). The efficiency of the organocatalyst 7 depended on the diene structure.

Figure 1.15

The first enantioselective organocatalyst for a Diels-Alder reaction via the formation of an iminium ion intermediate. [213] (Figure reproduced from reference [213])

Dawson et al. [214] examined the use of aniline as a nucleophilic catalyst in hydrazone formation between two unprotected peptides as well as the transimination reactions of these peptides with amines (Scheme 1. 16). The reaction rates were compared in the presence and absence of aniline and showed a marked increase in the presence of the catalyst. They proposed that the formation and transimination reaction proceeded via an iminium intermediate as Jencks had suggested previously. [211] Scheme 1. 16 Aniline-catalyzed hydrazone formation. [208,214] Lam et al. [215] investigated the piperidinium-catalyzed condensation between 2-hydroxybenzaldehyde and Meldrum's acid in the synthesis of derivatives of coumarins (Scheme 1.17). The reactions proceeded in very high yields. Similarly, L-proline-catalyzed

Knoevenagel condensation has been used [216] in the synthesis of alkylidene and arylidene malonates.

Scheme 1.17 The condensation between aldehydes and Meldrum's acid via an iminiumcatalyzed pathway. [215] Furthermore, proline has been used extensively in a nucleophilic catalytic cycle of aldol reactions based on cinchona alkaloids and oligopeptides. It has been used to catalyze an asymmetric intramolecular aldol reaction to obtain a bicyclic β-lactone cyclization product using O-acylated cinchona alkaloids. [217] The synthesis of an analogue of a cinchona alkaloid has been achieved using a similar enantioselective reaction. Finally, oligopeptides with an N-terminal proline [218] have been used instead of L-proline in asymmetric aldol reactions. The catalyst could be optimized for the substrate and reaction conditions.

In conclusion, an increasing number of organocatalysts is being developed especially for organic reactions involving iminium/enamine intermediates. These catalysts can allow otherwise slow reversible reactions to occur quickly under mild conditions, thus satisfying the criterion for fast exchange in the generation of DCLs. Therefore, the implementation of organocatalysis offers much potential for expanding the range of exchange processes that can be used in CDC as well as improving their reactional features.

The organocatalytic pathway for the generation of a DCL is treated in detail in Chapter 2.

Organocatalysis of Exchange Processes between

Knoevenagel and Imine Compounds in Dynamic

CHAPTER 2

Organocatalysis of Exchange Processes between

Knoevenagel and Imine Compounds in Dynamic Covalent Chemistry

Chapter 1

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Organocatalysis of Exchange Processes between

Knoevenagel and Imine Compounds in Dynamic 2.1 Introduction

Dynamic Covalent Chemistry (DCC), [1][2][3] the covalent wing of Constitutional Dynamic Chemistry (CDC), [4,5] rests on the implementation of reversible chemical reactions to generate dynamic covalent libraries (DCLs) based on interconverting molecular constituents. A major feature of DCLs is the production of high molecularstructural diversity for application in both biological [1][2][3][4][5][6][7][8][9][10][11][12][13] and material sciences. [1][2][3][4][5][14][15][16][17][18][19] Reversible reactions such as amine/carbonyl condensations, disulfide exchange, boronic ester formation, Diels-Alder condensations etc, have been implemented in numerous studies in DCC. [1,2,[4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The C=N bond is of particular interest in the view of its range of structural variations, such as in imines, hydrazones and oximes, its reversibility, its easy synthesis, and its broad range of implementation. [1][2][3][4][5]20,21,[27][28][29][30] The rapidity of formation and breakdown (amine+carbonyl)/imine formation and breakdown reactions is highly suitable for DCC applications, and a major goal is to optimize fast component exchange. In recent years, organocatalysis has been developed as an efficient methodology for the acceleration of various chemical reactions. [31][32][33][34][35] Among the different types of catalytic processes involving unsaturated reactants, that involving the enamine/iminium pathway is well established. In particular, L-proline, a naturally occurring chiral secondary amine, and its derivatives have been extensively used and studied as catalysts for numerous reactions, including asymmetric synthesis. [36][37][38][39] The implementation of organocatalysis in dynamic covalent chemistry offers much potential for extending the range of exchange processes and improving their reactional features.

The work presented in this chapter was performed in collaboration with Dr. Nadine Wilhelms and Assist. Prof. Kamel Meguellati. It concerned DCC processes involving reversible exchange of components between imine constituents (imine/imine, C=N/C=N exchange) as well as between benzylidene and imine constituents (C=C/C=N exchange), and involved the investigation of the use of L-proline, its derivatives, and other organocatalysts such as aniline, to catalyze these reactions. The dynamic exchange between Knoevenagel-type C=C bonds and imines is of special interest for generating increased diversity. In the last part of this chapter, catalysis of the exchange of substituents around C=C bonds [40][41][42] using secondary amine catalysis including L-proline is described.

Such exchange has already been described for Michael reactions of benzylidene compounds. [43]

Results and Discussion

Organocatalysis of imine/imine, C=N/C=N, exchange processes.

The C=N/C=N exchange of residues within pairs of imines, chosen among the imines 1a-1s (Figure 2 in the literature. [44,45] For the present study of organocatalysis, DMSO-d 6 was chosen as solvent, in view of its ability to dissolve most organic substances. 1% D T R I S i n t h e p r e s e n c e o f O 9 9 / 1 + 1 0 e q u i v . B I S-T R I S ,

T o i n v e s t i g a t e t h e p o t e n t i a l o f o r g a n o c a t a l y s i s i n im i n e / im i n e e x c h a n g e , t h e p r o l i n e a n d o f i t s T a b l e 2 . 2 . A p o s s i b l e , f o l l ow i n g t h a t p r o p o s e d i n t h e p r o l i n e , L -p r o l i n e t e r tr e a c t i o n . O n l y i n t h e d i d a m a r k e d i n c r e a s e i n C =N / C =N e x c h a n g e r a t e o c c u r a n d t h e e q u i l i b r i um s t a t e o f t h e m i x t u r e w a s r e a c h e d w i t h i n a c om p a r a t i v e l y s h o r t t im e . T h e s e

results indicate the likely participation of L-proline carboxylic acid in the catalytic mechanism (The benzoic acid and L-proline tert-butyl ester are ineffective indicating that L-proline may act as a bifunctional catalyst). [31] Additionally, Dr. Nadine Wilhelms investigated the transimination between 1g and heptylamine in the presence of the different organocatalysts (20 mol% each) L-proline, L-proline-tert-butyl ester, N-Cbz-L-proline, morpholine, piperidine, sarcosine-tertbutylester, decanoic acid, thiourea, and BINOL (2,2'-binaphthol) in pure DMSO-d 6 at room temperature (Figure 2.3). All of these catalysts were able to catalyze the transimination reactions. L-proline, N-Cbz-L-proline and decanoic acid were far more effective than other catalysts, indicating that the dominant catalytic pathway must involve substrate protonation due to the carboxylic groups. Since acid catalysis of transimination reactions has been previously characterized (see above), studies in pure (neutral) DMSO were discontinued.

Figure 2.3 Transimination between N conducted in the presence of the different catalysts N-Cbz-L-proline, morpholine, piperidine, sarcosine Scheiner catalyst (thiourea), and BINOL in DMSO

Screening for organocatalytic activity of L-proline, of its derivatives exchange process shown above

Exchange Processes of C=N/C=N, C=C/C=N, C=C/C=C in DCC Chapter 2

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) and n-heptylamine proline-tert-butyl ester, butylester, decanoic acid, at room temperature.

N of its derivatives and

These preliminary results established that crucial factors for fast imine/imine exchange were the structure of the studied imines, the solvent, and the catalyst. Initially, imines with only aromatic substituents were used in DMSO-d 6 /D 2 O 99/1 as a solvent system. In these reactions, the exchange could not be achieved either with or without a catalyst. The only reaction observed was that of hydrolysis, indicating that the aromatic amines were insufficiently nucleophilic to maintain imine formation under the given conditions. Next, an attempt to conduct the exchange reaction with imines derived from aliphatic amines and aliphatic aldehydes failed as well because again of the fast hydrolysis of both imines.

The influence of the solvent was investigated using the reaction of 1a and 1b to give 1c and 1d as the exchange products in the presence of the catalysts 10 mol% L-proline and 10 mol% decanoic acid. The five different solvent systems used are given in Table 2.1.

The exchange reaction occurred without appreciable interference from hydrolysis in DMSO-d 6 /D 2 O mixtures, as well as in pure DMSO-d 6 , and was most rapid when BIS-TRIS was added to the mixture. No reaction was apparent in either CD 3 CN or CDCl 3 , although it was only possible to examine decanoic acid as a catalyst in these solvents because the solubility of L-proline in both is very low. That decanoic acid in DMSO-d 6 showed its greatest efficiency in the presence of BIS-TRIS is interesting and may mean that protonated BIS-TRIS is a more effective acid catalyst than decanoic acid. The catalysis is nonetheless far less effective, by nearly two orders of magnitude, than that of L-proline under the same conditions, showing that a nucleophilic catalytic pathway must be dominant there.

Finally, nucleophilic aliphatic amines were condensed with electrophilic heteroaromatic aldehydes (2-pyridyl, 4-pyridyl, and 2-thiophenyl-carboxaldehydes) as well as with salicyl aldehyde to give the imines 1a-d,h-s. Using these substrates did lead to the desired C=N/C=N exchange, that could be followed conveniently by 1 H-NMR spectroscopy (Figure 2.5). No hydrolysis products could be detected up to the time that the exchange appeared to reach equilibrium. The exchanges were catalyzed by L-proline in basic (BIS-TRIS) solution and on the basis of literature precedents [see ref. 31-35], the proposed mechanism for these exchanges is one involving the action of L-proline as a nucleophile (Scheme 2.2) to react at both imines leading to iminium intermediates by addition-elimination, followed by the condensation of the released amines with the iminium intermediates to provide the exchange products. Scheme 2.2 Proposed mechanism for the organocatalysis of C=N/C=N exchange. [31][32][33][34][35] Hydrolysis has not been represented in this mechanistic scheme.

In order to evaluate the scope of the organocatalysis of imine/imine exchange, a number of [2 × 2] imine libraries were explored (Table 2.2). For each pair of imines, both the forward and reverse reactions were followed without (blank) or with added L-proline. The imine exchanges processes were found to obey the kinetics of a reversible first order reaction. It might be expected that such reactions would obey the kinetics for reversible second order processes but attempts to fit the obtained data to this behavior were unsuccessful (the Rorabacher equation [47] plot being far from linear). Actually, the data provided a good fit to a reversible first order reaction. This indicated that the imine exchange reaction obeyed a reversible first order behavior. (See more details in Experimental part of Chapter 7).

Thus, the corresponding rate constants, k c and k b, were calculated as indicated in the Experimental Part (Chapter 7) and are listed in Table 2.2. [48] The reaction in the absence of catalyst for reverse reactions in Table 2.2, Entry 3 (1n + 1o) and 4 (1a + 1b) were very slow and the rate constants were calculated from the first 10% of the reaction [49] using the irreversible first-order kinetic equation. Then, the rate constants for the reaction in the presence of catalyst for both reactions ((1n + 1o) and (1a + 1b)) were also calculated using the first 10% of the reaction in order to estimate the acceleration ratio. The equilibrium constants were calculated from the rate constants (see caption of Table 2.2). [48] An acceleration of the C=N/C=N exchange by 10 mol% L-proline up to about 22-fold was achieved (Table 2.2, Entry 4). The accelerations of the forward and reverse reactions were similar. The equilibrium constants K b and K c obtained for the blank and catalyzed reactions in both the forward and backward directions were similar within the experimental uncertainty, indicating that the reactions were under thermodynamic control. Error in 1 H-NMR signal integration, ∼4-5%.

Table 2.2 Organocatalysis by 10 mol% L-proline of a set of imine/imine exchange reactions for [2×2] imine libraries in DMSO-d 6 /D 2 O 99/1, 10 equiv. BIS-TRIS solution at room temperature.

Entry ER a ) A a ) B a ) C a ) D a ) b ) k b c ) k c d ) K b e ) K c f ) Acc g ) 1 1h+1i 1j+1k n- Propyl c
Continuing the investigation of imine exchanges, the reactions in the absence of catalyst were also monitored but the rates were very slow. In fact, any reaction seemed to be attributable to a hydrolysis mechanism involving catalysis by water. A plausible mechanism for such catalysis is shown in Scheme 2.3. While simple hydrolysis of both reactants would lead to a mixture of aldehydes and amines which could then combine in the alternate ways (as well as to regenerate the reactants), the fact that imines are known [50] to be much more rapidly attacked by amines than are their parent carbonyl compounds leads to the proposal that attack of free amine on residual imine species to give aminal intermediates would provide a more efficient catalytic pathway for exchange. Thus, if a

small amount of H 2 O is

Scheme 2.3 The imine exchange mechanism in the absence of organocatalyst via hydrolysis and aminal formation reactions (the water acts as a nucleophilic catalyst).

To explore the broader applicability of the present organocatalysis procedure to biology and materials science, two [3x3] dynamic libraries of imines were generated (Scheme 2.4) in the presence of 10 mol% L-proline and in the absence of catalyst in DMSO-d 6 /D 2 O 99/1 with addition of 10 equiv BIS-TRIS at room temperature. Library 1 consisted of the previously studied imines 1h, 1i and 1l (see Table 2.2, Entries 1-3). Thus, the three [2x2] libraries can be directly compared to the equivalent [3x3] library based on the same three aldehydes and three amines. Here, an acceleration of 7.9-fold was observed, which corresponds to the exchange of Entry 3. Thus, the larger library reaches equilibrium at approximately the same rate as the fastest of the three smaller libraries. The second DCL consisted of 1c, 1d and 1p and refers to the [2x2] libraries shown in Entries 4-6 of Table 2.2. Precise values of the equilibrium constants were not obtained for the [3x3] libraries.

While the reactions were followed until the spectra did reach a point where further changes were not detectable and thus it was assumed that equilibrium had been attained, this was not confirmed by studying the reverse process.

Scheme 2.4 Imine exchange in two [3 × 3] imine libraries -Applicability of organocatalysis to larger libraries for increasing diversity.

Entry 1

Entry 2

In addition, we studied the formation of the imines which were used in the exchange processes. Three different aldehydes (salicylaldehyde, 2-pyridyl aldehyde, and 2-thiophenol aldehyde) and three amines (benzylamine, isobutylamine, and heptylamine)

were employed in a single reaction. The reaction was run in DMSO-d 6 /D 2 O 99/1 using 10 equiv. BIS-TRIS in the absence of catalyst at room temperature (Scheme 2.5). All nine possible imines were detectable immediately after mixing, although the equilibration time for this reaction was about 60 minutes, indicating relatively facile imine formation under these conditions, leading to equilibrium %ratios of 1c (17%), 1l (13%), 1b (11%), 1q

(15%), 1p (8%), 1s (7%), 1a (15%), 1r (8%), 1d (7%), respectively.

Scheme 2.5 Study of the formation and equilibrium distribution of nine imines from three

different aldehydes and amines using 10 equiv. BIS-TRIS in DMSO-d 6 /D 2 O 99/1 at room temperature.

The C=N/C=N exchange using aniline as a nucleophilic catalyst.

Recently, nucleophilic catalysts have been shown to accelerate hydrazone and oxime formation as well as transimination and imine metathesis reactions. Aniline and its derivatives having been found to be effective, [29,50,51] we turned to aniline as a possible catalyst of the presently studied imine exchange. A preliminary investigation was based on 1h and 1o as representative substrates for imine exchange in DMSO-d 6 /D 2 O 99/1 at room temperature.

Table 2.3 Thermodynamic and kinetic parameters for the imine exchange between 1h and 1o using aniline as a nucleophilic catalyst.

OH N N N DMSO-d 6 /D 2 O 99/1 OH N N N 1h 1o 1j 1m
Aniline, r.t.

Entry Condition

K eq a ) k (10 -3 s -1 ) b ) 1 Blank 1.13 0.0173 2 0.1 equiv. Aniline 1.23 0.0346 3 10.0 equiv. Aniline 1.13 0.1082 a ) K eq = [C][D]/[A][B], b )
As in earlier work, the reaction was found experimentally to conform to first-order kinetics. Error in 1 H-NMR signal integration, ∼4-5%.

Although the imine exchange of 1h and 1o to give 1j and 1m occurs, it is very slow (Table 2.3) in the absence of aniline and is only accelerated by a factor of ∼2 in the presence of 0.1 equiv. aniline. Under this condition, a trace amount (∼0.7%) of an intermediate (aminal) was observed. In the presence of 10 equiv. aniline, the reaction is about 11 times faster than in the absence of catalyst and a trace amount of aniline imine could be detected along with the same aminal intermediate being observed (∼1.8%) as well. In comparison, the reaction in the presence of 0.1 equiv. aniline as the catalyst is ca. 3 times slower than the one in the presence of 0.1 equiv. of L-proline. L-proline can be considered a better catalyst than aniline both because it gives a faster reaction and because side products and intermediates do not attain appreciable levels. Moreover, L-proline is to be preferred for use as a catalyst because it has much lower toxicity.

Organocatalysis of benzylidene/imine, C=C/C=N, exchange processes.

After the successful implementation of organocatalysis in the generation of DCLs of imines, we explored its extension to other related reactions. In particular, the C=C/C=N exchange, involving two different types of double bonds, appears to have much potential for generating dynamic libraries of constituents of great diversity. Given the reversibility of imine formation, that of the condensations giving benzylidene barbiturate derivatives (and similar species) seemed to be a promising accompaniment for achieving such an exchange process. Firstly, possible substrates for the C=C/C=N exchange were investigated under different conditions in the presence and absence of a catalyst. 4-Dibutylaminobenzylidenebarbiturate was reacted with aromatic imines (Figure 2.7a) in the presence of the catalysts such as L-proline, L-proline t-butyl ester, N-Cbz-L-proline, and benzoic acid in pure DMSO-d 6 . No changes were apparent at room temperature in the 1 H-NMR spectra.

Heating at 80 o C still did not lead to exchange but instead to hydrolysis and some decomposition. Next, the same benzylidene-barbiturate was reacted with aliphatic imines (Figure 2.7b) using various catalysts. In the presence of 20 mol% L-proline, the new imine formed but the new benzylidene barbiturate was not present, with only the hydrate form of benzaldehyde being observable. In DMSO-d 6 /D 2 O 99/1 solvent (added 1% of D 2 O to ensure a known %water in the solvent system), the 4-nitrobenzylidene-barbiturate was used to exchange with an aliphatic imine (Figure 2.7c) and although the new imine appeared, the benzylidene-barbiturate underwent rapid hydrolysis, making this also an unsuitable system for study of the simple equilibrium.

Figure 2.7 Screening reactions for C=C/C=N exchange using different starting materials and different conditions.

The next cross exchange reaction investigated was that of the C=C substrate derived from benzylidene-barbiturate and the imine derived from 2-pyridyl aldehyde and benzylamine (Figure 2.8a). However, after 3 h, although the new imine could be detected, both benzaldehyde and its hydrate were present due to hydrolysis of the barbiturate.

Figure 2.8 Screening for C=C/C=N exchange with different starting materials and under different conditions.

The barbiturate was then substituted with benzylidene-malononitrile (Figure 2

.8b).

Here, in the reaction mixture with L-proline as catalyst, hydrolysis of benzylidenemalononitrile was observed and formation of the new imine was not detectable. The analogous reaction with a 2-thiophenol aldehyde imine (Figure 2.8c) did give a small amount of the new imine but again involved mostly hydrolysis of the benzylidene malononitrile. The reaction of 4-nitrobenzylidene-malononitrile with 1b gave similar results (Figure 2

.8d).

Overall, it was clear that benzylidene-barbiturates derived from salicylaldehyde and 2-pyridyl aldehyde were not suitable as cross-exchange substrates because of their fast hydrolysis. In fact even during the synthesis of these benzylidene-barbiturates, it was difficult to isolate the product.

These preliminary results showed that the C=C/C=N cross exchange reaction is very sensitive to the starting substrates and that the reaction conditions have to be compatible with the persistence of both Knoevenagel (C=C) and imine (C=N) compounds.

Therefore, the C=C substrates should contain a moderately reactive aldehyde and the imine compound should be derived from a reactive amine (for instance, an aliphatic amine) in order to assure the formation of a new imine in the cross exchange reaction.

Thus, the benzylidene barbiturates 2a, 2b, 2e, 2f and imines 1b, t-v were chosen to be the substrates for the exchange reaction with imines derived from aliphatic amines and aromatic aldehydes (Scheme 2.6). The reactions were carried out using equimolar amounts of benzylidene derivatives and imine compounds (19.35 mM each) in a mixture of DMSO- Both forward and reverse reactions were followed by 1 H-NMR spectroscopy.

Compared to C=N/C=N exchange, a higher temperature was required. The proportions of the different compounds were determined by integration of the imine CH=N as well as of the benzylidene CH=C proton 1 H-NMR signals. The hydrolysis accompanying the exchange rendered the reaction kinetics too complicated for a precise analysis. The results are illustrated in Figure 2.10 and listed in Table 2. 4. In all cases, the compositions of the mixtures are given for a reaction time at which no further change in compound percent was detectable.

B

These studies were extended to an evaluation of the influence of substitution within the vinylidene head-groups on the exchange reaction. Thus, the reaction between the benzylidene barbiturate 2a, bearing an electron-donating group (EDG), and the imine 1t, bearing an electron-withdrawing group (EWG), gave only the imine 1v, but the expected new benzylidene barbiturate 2e was lost, due to hydrolysis (Table 2.4,Entry 1). The 1 H-NMR spectrum of the equilibrated mixture (Figure 2.10) showed a signal at 5.9 ppm assigned to be the -CH(OH) 2 -methane proton of 4-chlorobenzaldehyde hydrate. The formation of 2e is apparently hindered by the tendency of 4-chlorobenzaldehyde to give a hydrate at equilibrium. Hence, it was surmised that decreasing the hydration tendency of the aldehyde of the imine by replacing the EWG by an EDG would favor its condensation with barbiturate to give the Knoevenagel product in this medium.

Figure 2.10 1 H-NMR spectrum of the products of the exchange reaction between 2a and 1t at equilibrium. The characteristic -CH=N peaks are indicated for 2a, 1t, 1v, 4-chlorobenzaldehyde (g), 4-dimethylamino benzaldehyde (i), 4-chlorobenzaldehyde hydrate (l) in 99/1 DMSO-d 6 /D 2 O.

The reverse reaction was performed by mixing compounds 2e and 1v in 1:1 ratio in the same solvent (Table 2.4, Entry 2). Here, both starting compounds hydrolyzed over a few hours (as followed by observation of the aldehydes formed) after mixing.

Simultaneously, the new exchanged compounds, the benzylidene-barbiturate 2a and the imine 1t, were progressively formed, but at the end of the reaction the hydrolyzed d ) a ) b, blank reactions, and c, catalyzed reactions with 10 mol% L-proline as a catalyst. b ) Reaction time indicates the time when no further change in composition could be observed. c ) Error on 1 H-NMR signal integration, ∼4-5%. d ) Compound not observed. e ) Only traces of product detected. compounds were predominant. The 4-cholorobenzaldehyde recombined partially with the benzylamine to form 1v, while the 4-dimethylaminobenzaldehyde gave only a small amount of the condensation product with barbiturate, 2a. The addition of 10% L-proline increased the speed of the reaction, leading to completion within 6 hours compared to 20 hours in the absence of L-proline.

.4 Proportions (%) of the different compounds in the cross-exchange reactions C=C/C=N between benzylidene barbiturates and imines in 99/1 DMSO-d 6 /D 2 O at 60° C (Scheme 2.6). g = 4-chlorobenzaldehyde, h

= 4-methyoxybenzaldehyde, i = 4-dimethylamino benzaldehyde, j = 2-thiophenecarboxaldehyde, l = 4-chlorobenzaldehyde hydrate, m = 4-methyoxybenzaldehyde hydrate, n = 4-dimethylamino benzaldehyde hydrate, o = 2-thiophenecarboxaldehyde hydrate Entry a ) Reaction Time [h] b ) Compound Distribution [%] c ) Starting compounds 2a + 1t 2a 1t 2e 1v g i l n 1b 0 48 52 -d ) -d ) -d ) -d ) -d ) -d )
Confirming the conclusion drawn above as to the influence of substituents on the reactant structures, the exchange between 2a and 1b, both bearing EDGs, was found to give rise to both products 2e and 1v (Table 2.4, Entry 3) although the hydrolysis products 4-dimethylaminobenzaldehyde and 2-thiophenecarboxaldehyde were still present in significant amounts. The reverse reaction with 2e and 1v (Table 2.4, Entry 4) gave the same final product distribution, showing that a true equilibrium was attained despite the concomitant hydrolysis.

In another case of both reactants having EDG substituents, the exchange reaction of 2b and 1v to give 2a and 1u (Table 2.4, Entry 5) was also successful but was associated with almost complete hydrolysis of 2b, so that very little was detectable at equilibrium. Thus, in DMSO-d 6 /D 2 O 99/1, it appeared very difficult to avoid interference from hydrolysis and thus to obtain accurate values of the exchange equilibrium constants.

In order to avoid, or at least to reduce the amount of hydrolysis, exchange reactions were performed in the presence of lower amounts of water. The reaction between 2b and 1v (Table 2.5, Entry 1) was run with 0.5 vol% D 2 O (DMSO-d 6 /D 2 O 99.5/0.5) as well as with only 0.2 vol% D 2 O (Table 2.5, Entry 2) (DMSO-d 6 /D 2 O 99.8/0.2) added water. The products 2a and 1u were obtained in these conditions (averaging 20% each), but also large amounts of hydrolysis products (>10%) in the presence of L-proline. In a further attempt to decrease amount of hydrolysis products, the benzylidene/imine exchange was run in pure DMSO-d 6 (given as containing less than 0.02% of water) at 60 o C. The reaction of benzylidene 2b with imine 1v (Table 2.6, Entry 1), both bearing an EDG, gave 2a and 1u. The equilibrium was reached after 2 hours in the presence of 10% L-proline as compared to 22 hours in its absence. Under these conditions, the hydrolysis products amounted now to less than 10%. The reverse process, starting with 2a and 1u formed 2b and 1v and gave the same final product distribution. Finally, the exchange reaction between 2f and 1v (Table 2.6, Entry 3) and its reverse reaction with 2a and 1b (Table 2.6, Entry 4) gave identical final distributions, consistent with a true equilibrium being attained. In these conditions, L-proline performed marked organocatalysis, as it accelerated the reaction from 6-fold (Table 2.6, Entry 4) up to 22-fold (Table 2.6, Entry 3) when one compares the blank reaction at the same reaction time to that of the completed catalyzed reaction. ) b, blank reactions, and c, catalyzed reactions with 10 mol% L-proline as a catalyst. b ) Reaction time indicates the time when no further change in composition could be observed. c ) Error on 1 H-NMR signal integration, ∼4-5%. d ) Compound not observed. e ) Only traces of product detected.

Table 2.5 Proportions (%) of products of the cross exchange reaction between 2b and 1v in

a) Time [h] b) Compound distribution [%] c) Starting compound 2b + 1v e ) 2b 1v 2a 1u h i m n 1b 0 50 50 -d ) -d ) -d ) -d ) -d ) -d )
+ 1v f ) 2b 1v 2a 1u h i m n 2b 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 3 1 18 19 28 7 16 11 -d ) 2a 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 3 40 42

Table 2.6 Proportions (%) of the different compounds in the cross exchange reactions C=C/C=N between benzylidene barbiturates and imines in DMSO-d 6 at 60 o C. h = 4-methyoxybenzaldehyde,

i = 4-dimethylaminobenzaldehyde, j = 2-thiophenecarboxaldehyde, m = 4-methyoxybenzaldehyde hydrate, n = 4-dimethylaminobenzaldehyde hydrate, o = 2-thiophenecarboxaldehyde hydrate. Entry a ) Reaction Time [h] b ) Compound Distribution [%] c ) Starting compounds 2b + 1v 2b 1v 2a 1u h i m n 1b 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 2 50 50 <1 e ) <1 e ) <1 e ) <1 e ) <1 e ) -d ) 22 7 12 34 33 7 3 4 -d ) 1c 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 2 5 9 32 33 8 7 6 -d ) Starting compounds 2a + 1u 2a 1u 2b 1v h i m n 2b 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 2 49 49 1 1 <1 e ) <1 e ) <1 e ) -d ) 24 39 39 7 10 3 <1 e ) 2 -d ) 2c 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 2 34 32 4 12 7 5 6 -d ) Starting compounds 2f + 1v 2f 1v 2a 1b i j n o 3b 0 50 50 -d ) -d ) -d ) -d ) -d ) -d ) 3 50 50 <1 e ) <1 e ) <1 e ) <1 e ) -d ) <1 e ) 66 28 27 20 20 3 <1 e ) -d ) 2 3c 0 50 50 -d ) -d ) -d ) -d ) -d ) -d )
A plausible mechanism for exchange between C=C and C=N in the presence of L-proline and water is shown in Scheme 2.7, following sequential hydrolysis/condensation steps (see also ref. [52]). It may be considered to involve addition of L-proline to the benzylidene and imine reactants leading to iminium intermediates by subsequent elimination, followed by condensation of the released anionic barbiturate and benzylamine with the aldehydes resulting from the cleavage. The formation of hydrates [53] of the aldehydes bearing electron-withdrawing substituents opposes the formation of the exchanged products.

Y N HN NH O O O X HN NH O O O X NH 2 X HO OH O Y O Y HO OH X N HN NH O O O Y H N CO 2 H HN HO 2 C Y N H HN NH O O O X N CO 2 H N HO 2 C X N CO 2 H Y N -O 2 C I II III IV V VI VII VIII IX X XI XII IX X Scheme 2.7
Possible mechanism of the cross exchange between a Knoevenagel-type substrate (C=C) and an imine (C=N) following sequential hydrolysis/condensation steps. [52]

Organocatalysis of Benzylidene/Benzylidene, C=C/C=C, Cross-exchange

Processes.

In published work, [54] we have already described some aspects of the generation of DCLs involving imine/imine (C=N/C=N) and benzylidene/imine (C=C/C=N) exchange processes and exploiting L-proline as an organocatalyst. To further extend the range of covalent dynamic libraries, we investigated the benzylidene/benzylidene (C=C/C=C) cross-exchange reaction between benzylidenebarbiturates (2a- . Neither adduct could be isolated. In the reaction mixture, the most reactive electrophiles [55] are 2d and 3d, so they may react with the better nucleophile, the manolonitrile anion formed from 3d (pK a of VI > V), affording adducts XI and XII. Thus, product 2c is formed, but it is trapped as its Michael-type adduct XII. On the other hand, the reaction of malononitrile with 3d precludes the formation of the product 3a. A possible mechanism of this cross exchange reaction is shown in Scheme 2.9. compounds following sequential hydrolysis/condensation Steps. [31,52] The reversibility of this reaction was studied by combining 2d and 3a (Table 2.7, Entry 2). Both starting compounds were fully hydrolyzed, and the anticipated products 2a and 3d did not form even after 20 days, at which time decomposition of the compounds had occurred. This result indicates that hydrolysis precludes the recondensation to form 2a and 3d and thus the exchange reaction. For the same reason, no Michael-type adduct XII was observed.

Next, 2c and 3d were selected as starting compounds, both bearing EWGs (Table 2.7, Entry 3). These substrates were more suitable for the cross-exchange than the molecules exhibiting a large difference in their electrophilicity (2a and 3d), and both products 2d and 3c were formed. The hydrolysis products were observed to be less than 10% at equilibrium. In addition, the Michael-type adducts XI and XII were also detected in the 1 H-NMR spectrum of the mixture which showed characteristic doublets peaks at 4.94, 5.32 ppm belonging to adduct XI (1%) and 4.72, 6.20 ppm belonging to adduct XII (9%), in agreement with reported values [56] and with mass spectral data (see below). The reverse reaction was performed by mixing compound 2d and 3c (Table 2.7, Entry 4), and components 2c and 3d were obtained in comparable amounts as in the forward case, indicating that the reaction was reversible and that the equilibrium had more or less been reached. In the reverse case, only Michael-type adduct XII was detected, its Interestingly, the reaction in the absence of L-proline did not result in the formation of any Michael-type adducts, instead only the hydrolysis products formed, although the hydrolysis products in both the presence and absence of L-proline were less than 2%.

Finally, the exchange reaction between 2g and 3e (Table 2.7, Entry 9) both bearing electron donating groups, in the presence of 10 mol% L-proline was studied, giving the product distribution as following 2g (30%), 3e (22%), 2f (23%), and 3i (23%) after 23 h with half-life (t 1/2 ) of 5 h. The reaction in the absence of L-proline was very slow, giving the exchange products 2f (10%) and 3i (3%) after 168 h. Interestingly, the Michael-type adducts were not present in both conditions and the hydrolysis products were observed in less than 7% yield. Next, the reversibility of this reaction was examined by mixing 2f and 3i (Table 2.7, Entry 10) both in the presence and absence of the catalyst. The reverse reactions in both conditions were extremely slow, giving the exchange products 2g (3%) and 3e (7%) after 220 h. The addition of 10 mol% L-proline did not affect the rate of the reverse process. Under these conditions, L-proline demonstrated marked organocatalysis, as it accelerated the reaction from two-fold (Table 2.7, Entry 3) up to about 89-fold (Table 2.7, Entry 8), when one compares the blank reaction at the same reaction time as that of the completed catalyzed reaction. In principle, the electrophilic behavior of the benzylidene derivative is strongly dependent on the nature of the probe head (barbituric acid or malononitrile). The most reactive are the benzylidene derivatives whose probe-head is the strongest EWG and has the lowest pK a . Therefore, diethylbenzylidenemalonate (pK a (diethyl malonate) = 16.4) proved to be less reactive than the benzylidene-malononitrile (pK a (malononitrile) = 11.1), and much less reactive than the barbituric acid (pK a (barbituric) = 4.0). [43] To further explore this hypothesis, we prepared the ethylbenzylidene malonates (3f, 3g, and 3h), and studied their exchange reactions with benzylidene barbituric acid (2a-b, 2d) as depicted in Scheme 2.10.

) -b ) <1 c ) 12 <1 c ) 1 2 1 -b ) -b ) 2c n.a. 142 32 52 -b ) -b ) <1 c ) 9 <1 c ) 3 2 1 -b ) -b ) Starting compound 2c + 3d 2c 3d 2d 3c b c h i B M
-b ) -b ) -b ) -b ) -b ) -b ) -b ) -b ) n.a. 488 f ) 35 37 12 12 2 1 -b ) -b ) <1 c ) <1 c ) -b ) -b ) 5c 9 29 24 24 19 24 1 3 <1 c ) 1 2 <1 c ) 1 -b ) Starting compound 2b + 3a 2b 3a 2a 3b a d g j B M XI XII 6b n.a. 95 d ) 48 49 1 <1 c ) 1 <1 c ) -b ) -b ) -b ) -b ) -b ) -b ) n.a. 533 f ) 43 48 1 2 1 5 -b ) -b ) 1 -b ) -b ) -b ) 6c 30 98 23 30 19 19 <1 c ) 4 <1 c ) 1 3 <1 c ) <1 c ) -b ) Starting compound 2f + 3b 2f 3b 2b 3e d e j k B M XI XII 7b 40 128 46 43 6 6 1 -b ) <1 c ) -b ) -b ) <1 c ) -b ) -b ) 7c 2 6 43 40 6 7 2 -b ) <1 c ) -b ) 1 1 1 -b ) Starting compound 2b + 3e 2b 3e 2f 3b d e j k B M XI XII 8b 180 532 8 8 42 40 2 -b ) -b ) -b ) 1 <1 c ) -b ) -b ) 8c 2 6 6 8 42 39 3 -b ) -b ) -b ) 1 1 1 -b ) Starting compound 2g + 3e 2g 3e 2f 3i e f k l B M XI XII 9b n.a. 168 f ) 45 38 10 3 2 -b ) -b ) 1 -b ) <1 c ) -b ) -b ) 9c 5 23 30 22 23 23 1 -b ) -b ) 1 -b ) -b ) -b ) -b ) Starting compound 2f + 3i 2f 3i 2g 3e e f k l B M XI XII 10b n.a. 220 f ) 43 41 3 7 1 -b ) -b ) 6 -b ) -b ) -b ) -b ) 10c n.a. 220 f ) 47 45 2 6 1 -b ) -b ) 3 -b ) -b ) -b ) -b ) a )

Scheme 2.10 Representative of the metathesis C=C/C=C reaction between barbituratebenzylidenes (2a,b,d) and differently substituted cyanoacetate-benzylidenes (3f,g,h) in DMSO-d 6 at 60 o C.

Firstly, the exchange process between 2a and 3h (Table 2.8, Entry 1) was studied in pure DMSO-d 6 at 60 o C with and without 10 mol% L-proline. After 7 h, trace amounts of exchange products, 2d and 3f, started appearing in the 1 H-NMR spectrum indicating that this reaction occurred very slowly. The %-composition of reaction was unchanged after 94 h, giving 2d (3%) and 3f (5%). In addition, the hydrolysis products, for instance, 4nitrobenzaldehyde (5%), 4-dimethylaminobenzaldehyde (5%), and ethyl cyanoacetate (4%) were also detected. In the absence of L-proline, the exchange was detectable after 94 h, giving 2d (2%) and a trace amount of 3f (1%). New 1 H-NMR multiplet peaks near 6.05, 7.27, and 7.78 -7.51 ppm were detected here as well and assigned to Michael-adducts. In the reverse process, compound 2d and 3f (Table 2.8, Entry 2) were mixed. The anticipated products 2a and 3h did not form; only hydrolysis products were detected indicating that equilibrium could not be achieved in this system.

Next, 2a was combined with 3g (Table 2.8, Entry 3) in pure DMSO-d 6 at 60 o C in the presence of 10 mol% L-proline. As expected, products 2b and 3f, formed to the extent of 13% and 20% after 121 h. The reaction in the absence of L-proline occurred very slowly and the %-composition was unchanged after 178 h. For the reverse process, 2b and 3f (Table 2.8, Entry 4) were also mixed, and 2a and 3g started forming after 33 h indicating that this reaction was reversible. In the absence of L-proline, the reverse reaction was not detectable. These results show that ethylbenzylidenemalonate compounds are significantly less reactive than benzylidene-malononitrile derivatives. The electronic absorption spectra of benzylidene barbiturates (2a-2f, 2g) and benzylidene malononitrile (3a-3e) were measured in DMSO at room temperature, Table 2.9 being a compilation of the absorption maxima wavelengths and molar absorptivities. This indicated that the benzylidene-barbiturates or benzylidene malononitriles which contained the probe-head with an EDG showed a red-shift of the principal absorption band compared to those with an EWG. This is potentially a measure of the effectiveness of the substituents in influencing the exchange equilibrium position.

Conclusions

The results described above lead to the following conclusions:

1) Significant organocatalysis can be achieved in Dynamic Covalent Chemistry processes.

2) The secondary amine L-proline is an efficient organocatalyst for C=N/C=N imine exchange reactions at a catalyst loading of 10 mol%, providing accelerations up to 22-fold at ambient temperature. Imines derived from aliphatic/nucleophilic amines and highly electrophilic aldehydes were found to be the most suitable starting components, giving only the exchange and no hydrolysis products after completion of the reaction.

Uncatalyzed C=C/C=N exchange Processes between in Dynamic

Introduction

Dynamic Covalent Chemistry (DCC) [1] is the branch of Constitutional Dynamic Chemistry (CDC), [2] resting on the implementation of reversible covalent reactions for the generation of dynamic covalent/combinatorial libraries (DCLs) of constituents from the reversibly connecting components. The implementation of DCLs requires fast conversion of components into equilibrated systems under mild conditions under which the equilibrium can be perturbed later by external stimuli (chemical or physical) to reorganize the system. In this way, the system is able to undergo adaptation to build up more complicated system. [1,3,4] Recently, among the reversible covalent reactions, the condensation between a carbonyl and an amine to form the imine bond (C=N) has been of much interest for DCC and materials science. [5][6][7][8][9][10][11] Imines are formed readily and reversibly and they can also react with an introduced amine via a transimination process to give an amine-exchange product, [12][13][14] as well as with another imine to undergo exchange of both amine and carbonyl compound pairs, the imine-exchange reaction. [15][16][17] Furthermore, the condensation between an aldehyde or ketone and an active methylene compound to form a Knoevenagel compound (C=C) has also received considerable attention, especially concerning the derivatives of benzylidene barbituric acid. [18] The benzylidene barbituric acids are defined by their strongly polarized exocyclic double bond with a positive partial charge on the arylidene carbon. [19,20] They have been classified as electrically neutral organic Lewis acids [21] because they are able to react with Lewis bases, for instance, alkoxides, [22] amines, [22][23][24] thiols, [25] water, [26,27] hydrogen sulfide ion, [28,29] and carbon nucleophiles. [30][31][32][33] They can be used as building blocks for the synthesis of pyrimidine derivatives [34] and have also been used to trap radicals and as the stabilizers in PVC. [35] The electrophilicity of 5-benzylidene-1,3-dimethylbarbituric acid and thiobarbituric acids has been recently quantified by Mayr et al. [36] To further extend the scope of DCC, reactions based on dimethylbenzylidene-barbituric acid and imine compounds were exploited in the work described in this chapter.

Thus, investigation have been made of the generation of DCC processes based on the interconversion of constituents between C=C/C=N species in the absence of a catalyst.

In addition, a theoretical study of the mechanism has been undertaken to try to understand the metathesis-like mechanism of C=C/C=N exchange and to draw comparisons with imine/imine (C=N/C=N) exchange [16] . Finally, the production of organogels produced by the exchange process between C=C/C=N substrates is also reported. All of the processes investigated here were followed by 1 H-NMR spectroscopy and the fractions of the different compounds in the DCLs were determined by signal integration.

Results and Discussion

Benzylidene-(dm)barbiturates/imine, C=C/C=N, exchange processes.

In Chapter 2, the C=C/C=N interconversion implementing Knoevenagel compounds formed from barbituric acid (2a-b, e-f) to achieve the cross exchange in pure DMSO-d 6 using 10 mol% L-proline as an organocatalyst was described. Herein, these studies are extended to the manipulation of the C=C/C=N cross-exchange between Knoevenagel compounds derived from 1,3-dimethylbarbituric acid ((dm)barbituric acid) (4a-4e) and the same imines as in Chapter 2. The solubility of the Knoevenagel compounds was screened in different solvents and found in particular to be high in CDCl 3 .

The cross-exchange reactions could therefore be carried out in CDCl 3 (filtered prior to use through a column of basic alumina to remove HCl and avoid acid-catalysis) with equimolar amounts of benzylidene-(dm)barbiturate derivatives and imine compounds (20 mM each). Both the forward and reverse reactions were followed by 1 H-NMR spectroscopy. In view of the fast rates of the exchange reactions, the rate constants could not be obtained by NMR but the equilibrium constants were determined instead, using the equation below, and are given in Table 3.1.

K eq = [4x][1y]/[4y][1x] (3.1)
In one of the initial C=C/C=N cross exchange experiments, 4a and 1b (Table 3.1, Entry 1), both bearing electron donating groups, were combined in CDCl 3 . After 68 min, no further change in the percentage of the exchange products 4e and 1v could be detected, indicating that equilibrium had been reached. When 4e and 1v were mixed under the same conditions, 4a and 1b were formed to give a mixture containing, after the same time, the same relative percentage of all four compounds, thus confirming that an effective thermodynamic equilibrium has been attained. The first set of experiments (Entry 1, Table 3.1) demonstrated that the interconversion of the Knoevenagel compound and an imine was facile and under thermodynamic control when the substrates both bore EDGs. We continued exploring the interconversion efficiency as a function of substrate electron affinity, choosing next compounds 4b, bearing EDGs, and 1f, bearing EWGs (Table 3.1, Entry 2). The interconversion products in CDCl 3 , 4c and 1u, were formed immediately after mixing in a ratio that did not change after 2 min. In addition, the reverse reaction, determined by combining 4c and 1u under the same conditions, also furnished the products 4b and 1f.

N N O O O X Y N Ph N N O O O Y X N Ph 4a X = 4-Me 2 N-C 6 H 4 4b X = 4-MeO-C 6 H 4 4c X = C 6 H 5 4d X = 4-Cl-C 6 H 4 4e X = S 1v Y = 4-Me 2 N-C 6 H 4 1u Y = 4-MeO-C 6 H 4 1f Y = C 6 H 5 1t Y = 4-Cl-C 6 H 4 1b Y = S
For this exchange, 4c and 1u were the more thermodynamically stable pair in these conditions. In this reaction, hydrolysis products were observed in trace amounts.

Next, we selected the substrates 4b and 1b for the forward reaction and combined 4e and 1u for the reverse one (Table 3.1, Entry 3). The electronic donating properties of the substituent on 4b are expected to be weaker than those on 4a (Table 3.1, Entry 1). The favored compounds at equilibrium were 4e and 1u as expected from the predicted electronic effects of the substituents. In this case, for both forward and reverse reactions, hydrolysis products formed in trace amounts.

The substrates for the next experiment were 4b and 1v for the forward and 4a and 1u for the reverse reaction (Figure 3.1 and Table 3.1, Entry 4). The forward and reverse reactions reached equilibrium after 11 min and 3 min, respectively. As compared to the reaction in Entry 2, 1v has higher electron donating ability than 1f; therefore the forward reaction in Entry 4 was slightly slower than the one in Entry 2. Clearly the efficiency of Knoevenagel/imine exchange depends on the electronic affinity of both substrates.

In order to explore the exchange reaction between substrates of markedly different electron withdrawing ability, a mixture of 4d and 1v, bearing EWGs and EDGs respectively, was studied. Following mixing, the reaction again occurred immediately and reached equilibrium after 11 min, with only small amounts of the starting materials unreacted (about 3%). Conversely, the backward reaction was performed by combining 4a and 1t, giving 4d and 1v as the exchange products (3% each at equilibrium). Thus, the favored products at equilibrium were 4a and 1t for both the forward and backward reactions under these conditions. Finally, the reaction of substrates 4d and 1u (Table 3.1, Entry 6) was examined, where 1u has less electron donating ability than 1v (Table 3. Another experiment was performed by using CD 2 Cl 2 because this solvent contained less hydrochloric acid than CDCl 3 . The reaction between 4a and 1b was evaluated, giving 4e and 1v and reaching equilibrium after 30 minutes. In the reverse process, starting with 4e and 1v, compounds 4a and 1b were obtained, with equilibrium attained after 3 hours.

To investigate the influence of the solvent, 1,2-dichlorobenzene-d 4 was selected for the same reaction as described above. The behavior of the 4a and 1b exchange reaction was similar to the one performed in CD 2 Cl 2 .

Figure 3.2 a)

The exchange reaction between 4a and 1b giving the exchange product 4e and 1v in CD 2 Cl 2 . Experiments were performed at room temperature.

Another benzylidene derivative was investigated by using benzylidene-ethyl cyanoacetate (3g) to exchange with 1v in filtered CDCl 3 (Scheme 3.2a). The anticipated exchange products (3f and 1u) were not formed. Next, the reaction between 4a and 3c was studied under the same conditions (Scheme 3.2b). The reaction did not afford the exchange products, even with piperidine added as a catalyst. However, when using a nucleophilic catalyst such as 10% n-propylamine, a trace amount (∼2-3%) of exchange products was formed. Lastly, the exchange reaction between 3a and 1b was attempted (Scheme 3.2c), but again the exchange products could not be detected. All of the results mentioned above strongly suggest that 5-benzylidene-1,3-dimethylbarbituric acid (4a-4e) has a special characteristic (neutral Lewis acid) allowing it to undergo exchange reactions with some imine derivatives.

Scheme 3.2

The exchange reaction between a) 3g and 1v b) 4a and 3b c) 4a and 3b in CDCl 3 at room temperature. All of these reactions did not give the exchange products.

The cross-exchange reactions observed here may proceed in principle following two different mechanisms. A dissociation/recondensation process may well take place due to the presence of (unobservable) traces of water, similarly to the reaction scheme of the L-proline catalyzed reactions conducted in DMSO (Scheme 2.9). On the other hand, the very fast exchange observed in chloroform, where no aldehyde could be detected, would reactions of aldehydes to nitro olefins, [37,38] and also in the interconversion of carbonyl compounds and iminium ion through 1,3-oxazetidinium ions. [39]

Scheme 3.3 Possible metathesis-like mechanism of the cross-exchange between a knoevenagel-type substrate (C=C) and an imine (C=N).

In summary, the interconversion between benzylidene-(dm)barbiturate and imine, depends on the attached aldehyde of both the benzylidene-(dm)barbiturate and the imine.

The dimethyl barbituric acid acts as an electron withdrawing group, causing the benzylidene-(dm)barbiturate to be a push-pull molecule. The more favoured reactant compounds for the exchange reactions of C=C/C=N type are the benzylidene-(dm)barbiturates with an aldehyde containing an EDG moiety at the para-position and the imines with an aldehyde contained an EWG. Interestingly, this exchange reaction of C=C/C=N type between Knoevenagel-type compounds and imines in the absence of catalyst is not general and fails for other types of Knoevenagel compounds such as 3g and 3a with imines and also for C=C/C=C exchange with 4a and 3c. These results suggest that benzylidene-(dm)barbiturates have special characteristics in the presence of imines derived from benzylamine which leads to their efficient interconversion.

Theoretical Study of the Metathesis-like Mechanism of the Cross-Exchange between a Knoevenagel-Type Substrate (C=C) and an Imine (C=N).

In the previous section, the exchange reaction between benzylidene-(dm)barbiturates and imines involving fast exchange rate in the absence of catalyst was described. The proposed mechanism is shown in Scheme 3.3 indicating that the exchange reaction between these two different substrates might occur via the metathesis-like mechanism to form an azetidine intermediate (IV), with the subsequent release of the exchange products is shown in Scheme 3.3. Herein, a computational study using the density-functional theory (DFT) method was carried out in order to assess the plausibility of the results obtained. The B3LYP functional in combination with the 6-31G* basis set were used throughout the calculations. In this investigation, starting materials (4a and 1b)

and the exchange products (4e + 1v) were selected as an example model for the calculation. The result obtained from the calculation represents gas phase conditions.

In the work of Baik, the investigation of the acid catalysis of imine metathesis employing the DFT calculation method was carried out in analogy to that of olefin metathesis. [16] The models for their calculation were imine metathesis of PhHC=NPr + The energy of adduct IV relative to the sum of the energies of the starting material is 12.0 kcal/mol, similar to the relative intermediate energy in the imine metathesis studied by Baik (∼13 kcal/mol). [16] Thus, the metathesis-like exchange mechanism between C=C/C=N is reasonable from an energetic perspective. Of course, that does not state anything about the kinetic feasibility. From this initial exploration, it is worth investigating the possible transition states (TS1 and TS2 in Figure 3.3a) of this metathesis-like exchange reaction in order to explain the mechanistic behavior.

Organogel selection based on the exchange reaction of C=C/C=N

Gels are soft materials and defined as substantially dilute cross-linked systems, which exhibit no flow in the steady state. This internal network structure may result from physical bonds (physical gel) or chemical bonds (chemical gel). A supramolecular gel is often composed of a low-molecular weight gelator (LMWGs) that can self-assemble in suitable conditions to form micro-or nano-scale networks, for instance, fibers, ribbons, sheets, or spheres. That structure then forms higher order three-dimensional networks. [40] The self-assembly of LMWGs to form supramolecular gels is an important phenomenon that demonstrates the power of supramolecular chemistry in materials science, [41][42][43] and also in drug delivery. [44] However, gels have their own dynamic and reversible character due to the non-covalent interactions that define their structures, thus, they can respond sensitively to external stimuli (temperature, pH, solvent, light and redox reactions). [40,[45][46][47][48] Recently, organogels based on bismelamine-cyanurate/barbiturates were investigated using hydrogen-bonding interactions to form the gel in binary systems. [49][50][51] Figure 3.5 Representation of the formation of a supramolecular gel from a 3D network of self-assembled structures such as fibers, ribbons, sheets, and spheres. [40] (Figure reproduced from reference [40])

Importantly, gel selection in a DCC system has been demonstrated using a hydrogel based on guanine-quartet formation to drive the selection of the components that form the constituent leading to the most stable gel in the system. [52] Following DCC-based, gel selection, Knoevenagel/imine (C=C/C=N) exchange was examined in order to find appropriate components to select the most stable gel in the system.

Firstly, the benzylidene condensations between barbituric acid and aldehydes ( formation ability of these compounds was evaluated in different solvents systems such as ethanol, methanol, cyclohexane, acetonitrile, and decanol.

of 4g (Table 3.3, Entry 2) is shown in followed by acetonitrile (using 1% w/v of gelator in the solvent).

was also observed under an optical microscope ( between gelator structures (fib ) is shown in Figure 3.6a, the gel of 4g formed best in ethanol followed by acetonitrile (using 1% w/v of gelator in the solvent). In addition, the gel of was also observed under an optical microscope (Figure 3.6b) showing the cross fibers) in the system. Thus, gel formation from carbon chain on the benzaldehyde moiety ( a longer carbon chain, gel formation formed fastest in ethanol. For all the derivatives investigated, no gel was formed in cyclohexane.

N N O O O R 1 R 1 4f: R 1 = CH 3 , 4g: R 1 = C 7
1 OR 2 R 2 = C 16 H 33 5 , R 2 = C 16 H 33 5 , R 2 = C 4 H 8 5 , R 2 = C 2 H 5 solvent N N O O O R 1 R 1 O

Organog

Representation of the benzylidene barbiturate compounds (

Table 3.3 Gelation properties of

Entry Compounds a ) EtOH 1 4f G 2 4g G 3 4h G 4 4i G a ) [Gelator] = 1 %w/v. b )
G, gel; S, solution; P, precipitate; F, fiber.

Uncatalyzed Exchange Processed of C=C/C=N in DCC

Next, a gel formation study of 4h was performed in the same range of solvents as Table 3.3, Entry 3). The results showed that gel formation of occurs in ethanol and methanol but only partially in acetonitrile. A gel of in decanol and cyclohexane. Finally, the gel formation ability of studied in the same range of solvents (Table 3

.3, Entry 4). A gel of 4i

MeOH followed by EtOH. In decanol, the gel also formed but at a very slow rate and in CN, a small amount of fiber formation was observed only. A gel of cyclohexane. Finally, a gel of 4f was formed in EtOH, MeOH, and acetonitrile ( he gel formation ability of 4h in different solvents in 1) EtOH, 2) CH Decanol, MeOH, and Cyclohexane.

Thus, gel formation from Knoevenagel compounds such as 4h and carbon chain on the benzaldehyde moiety (-OR) occur quickly in MeOH. In contrast, with a longer carbon chain, gel formation formed fastest in ethanol. For all the derivatives investigated, no gel was formed in cyclohexane.

ion properties of organogelators (4f-4i) at room temperature

Solvents b ) EtOH CH 3 CN Decanol MeOH G G S G G G S P G G S G G F G (slow) G ) G
, gel; S, solution; P, precipitate; F, fiber. Next, the exchange reaction in a benzylidene-barbiturate/imine (C=C/C=N) system CN/EtOH 9/1. The chosen starting substrates were could not form a gel in this solvent system although 1w can form a crystalline precipitate.

The reaction was left for 21 h at room temperature to ensure that the system reached

). 1 H-NMR spectroscopy was used to characterize selection from the exchange study (Figure 3.9). In the reaction mixture, the exchange reaction gave the compound distribution as 4b (20%), 1w (14%), 4f (33%), and of the exchange reaction mixture was measured, and a value Based on these preliminary results, more complex DCLs will be developed for gel selection from non-gel starting material. The discovery of new gels is important for materials science and drug delivery.

Conclusions

The results described above for the exchange reaction between C=C/C=N species lead to a number of conclusions:

1) The C=C/C=N exchange between imines and Knoevenagel derivatives of N,N-dimethylbarbiturate is fast and reversible in CDCl 3 solution at room temperature in the absence of catalyst. This feature provides access to efficient diversity generation via C=C/C=N exchange. It may also signify a change in mechanism to a metathesis-like process, via an azetidine intermediate.

2) The computational study suggested the metathesis-like mechanism of the exchange reaction between C=C/C=N component is reasonable at least on energetic grounds.

3) The gel formation investigation showed that the Knoevenagel compounds (4f-4i)

were able to form a gel in an appropriate solvent. Moreover, the C=C/C=N exchange reaction could be applied to select for a gel.

The results described herein enable the creation of DCLs of higher chemical diversity, thus allowing for the generation by DCC of receptors, dynamic polymers or biomaterials of increased complexity.

1 Introduction

Constitutional dynamic chemistry (CDC) and in particular on the molecular level, dynamic covalent chemistry (DCC) play an increasingly important role in diverse research fields. [1][2][3][4][5] DCC is based on the implementation of rapid reversible covalent bond formation and breakage reactions to generate dynamic covalent libraries (DCLs) of molecular constituents interconverting through component exchange and that are in thermodynamic equilibrium. [6,7] These libraries may contain the full set of constituents resulting from all possible combinations of the available components although they can remain virtual, [6] depending on the reaction and the conditions. Representative examples of reversible reactions implemented in DCC by different research groups over the last decade comprise:

amine/carbonyl condensation, [8][9][10][11] disulfide exchange, [12][13][14] olefin metathesis, [15,16] imine exchange, [17][18][19] Knoevenagel/imine exchange, [17,20] Knoevenagel/Knoevenagel exchange, [20] boronic ester formation, [21,22] peptide exchange, [23] and Diels-Alder condensation. [24][25][26][27] CDC, both molecular and supramolecular, also provides new perspectives in areas such as materials science [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] and drug design. [43][44][45][46][47][48][49][50] To further extend the realm of DCC, there is a constant requirement for new reversible reactions to generate DCLs of increasing structural and chemical diversity and complexity.

More than a century ago, the first preparation and study of the chiral ammonium salt [Me(Et)N + (All)Ph]I . CHCl 3 (All = allyl, CH 2 CH=CH 2 ) in 1903 [51] revealed the occurrence of racemisation by reversible dissociation into the amine and allyl halide. The rate of racemisation depended on the anion, decreasing in the sequence I > Br > Cl. [51] Half a century later, in 1954 the spontaneous resolution of this salt was described and its chiroptical active properties were confirmed. [52] Again about half a century later, solid state molecular structure of this salt was determined [53] and its conglomerate formation features were investigated. [54] Racemisation was proposed to occur via attack of the halide at the γ-position of the allyl group of the quaternary cation following what has been termed an S N 2' mechanism (Scheme 4.1). [53] Scheme 4.1 Racemisation of the Wedekind-Fock-Havinga's salt (S-(+)-a) via an S N 2ʹ mechanism, as proposed by Kostyanovsky, where iodide attacks at the γ-carbon of the allyl group of the ammonium salt to give the inverting amine and allyliodide. [53] In recent times, chiral ammonium salts have been frequently used as catalysts in asymmetric synthesis, [55][56][57] as ionic liquids, [58][59][60] and in crystal engineering. [61] Furthermore, the reaction of an ammonium cation such as N-benzyl-N,Ndimethylanilinium salt with nucleophilic carbanions [62] and the reversibility of the nucleophilic reaction between benzyl bromide and N,N-dimethylaniline have been investigated. [63] The long known reaction between tertiary amines or aza-aromatics (e.g. pyridine) and alkyl halides to give quaternary ammonium/pyridinium cations, the Menschutkin reaction, [64][65][66] has been studied in detail in the case of reactions of pyridine with benzylic halides in a variety of molecular solvents and ionic liquids. [67][68][69] In general, pyridinium salts are easily accessed and are versatile precursors to expanded nitrogencontaining heterocycles. They have been exploited for the total synthesis of natural products as well as in asymmetric or regioselective addition reactions. [70][71][72][73][74] In this chapter, the generation of dynamic covalent libraries based on nucleophilic substitution reactions is reported. More specifically, a study of new DCC processes involving the exchange of the tertiary amine component of quaternary ammonium salts based on S N 2' and S N 2 types of nucleophilic substitution reactions are presented (see Scheme 4.3). The ability of iodide to act as a nucleophile to catalyze the exchange between components is described. Iodide catalysis of such reactions has also been reported, for example, in the self-assembly of donor-acceptor [3]catenanes. [75] Microwave heating irradiation was used to assist the exchange between pyridinium salts and pyridine derivatives. In addition, as some ammonium salts used in this study are ionic liquids, [76] the generation of dynamic libraries in these ionic liquids as well as in their solutions in molecular solvents has been explored. All the processes investigated were followed by 1 H-NMR spectroscopy and the fractions of the different compounds in the DCLs were determined by signal integration.

Results and Discussion

Study of exchange processes between quaternary allyl-ammonium salts and tertiary amines via S N 2' type nucleophilic substitution.

Quaternary allyl ammonium salts are obtained by reaction of an allyl halide with a tertiary amine. Based on the work, mentioned above, on racemisation of optically active quaternary allyl-ammonium salts, the reversibility of the process is presumed to involve the dissociation into tertiary amine and allyl halide via attack of the anion on the allyl double bond within the salt following an S N 2' mechanism (Scheme 4.1). [53] On the basis of this reversible reaction, we have generated dynamic covalent libraries based on quaternary allyl ammonium salts and tertiary amines. The capacity of various ammonium salts 1a-1e or 3a-3e ( The exchange reaction between 1a-Br and 2a was used first to identify the best solvent out of CDCl through donor H-bonding, thus reducing their nucleophilicity. [77] In the very weakly polar and poor H-bond donor solvent CDCl 3 , the reaction rate was the slowest observed.

In all reaction mixtures, a trace amount (∼3%) of the amino-claisen product 2-allyl-N,N-dimethylaniline (VIII) [78,79] was detected in the 1 H-NMR spectrum, which showed a characteristic peak at 3.93 ppm (-CH 2 CH=CH 2 ), and was also apparent in the electrospray high resolution mass spectrum (peak at m/z 162.128 [M+H] + ).

The potential reverse reaction, that of 3a-Br and 4a, was investigated under various conditions (Table 4.2) but was not detectable even after 14 days. Thus, the reaction between 1a-Br and 2a appeared to be essentially irreversible. Another exchange was performed by mixing 1a-Br and 2c in CD 3 CN at 60 o C, yielding largely 3c (43%) and 4a

(40%) (Table 4.3). The reaction between 1a-Br and 2d gave the exchange products 3d-Br and 4a after a few hours but this reaction also was irreversible. In order to evaluate the scope of the exchange reactions of 1a-Br and 1e-Br, those with the aliphatic tertiary amines (2a-2e) were monitored by 1 H-NMR spectroscopy (Table 4.4). For each pair of the exchange reactions, only the reaction starting from 1a-Br and 2a-2e were followed, both without (in the absence of catalyst) or with added iodide (1 equiv.).

Second-order rate constants for the forward reaction were estimated by treating the process as an irreversible second order reaction for the first 10% of conversion (see the experimental part, Chapter 7). The half-lives (t 1/2 ) of the reactions were determined by integration of the decreasing 1 H-NMR signals of the starting material as a function of time and analyzing by estimating the time at which starting material was reduced to 50%.

In all six cases, 1a-Br and 1e-Br underwent exchange with the aliphatic tertiary amines 2a-e giving the products 3a-3e, but the reverse reactions were not detectable, indicating that the reaction was completely in favour of the products, with the equilibrium being strongly shifted towards the formation of the aliphatic allyl ammonium product. The addition of iodide (1 equiv. TEAI) resulted in an acceleration of up to ca. 2-fold (Figure 4.3). Attempts to observe an exchange reaction between 3c-Br and 2a or its formal reverse as the reaction between 3a-Br and 2c were unsuccessful in that no reaction in either sense was detectable over 3 days in CD 3 CN at 60 o C. This indicated that any reaction between a quaternary aliphatic ammonium salt and a tertiary amine must be extremely slow. ) f b , forward reaction in the absence of catalyst; f c , forward reaction in the presence of TEAI (1 equiv.) as catalyst. b ) Error on 1 H-NMR signal integration: ±4%. c ) n.a., not applicable. d ) Compound not observed.

Table 4.4 Kinetic and thermodynamic parameters for the exchange reaction between the N-allyl-N,N-dimethyl-anilinium salt 1a-Br and 1e-Br and the aliphatic tertiary amines 2a-2e 1/1 each at 20 mM concentration in CD 3 CN at 60 o C. Half-life t 1/2 . Proportion (%) of the different compounds. a = allyl bromide, b = allyl iodide, c = amino-Claisen rearrangement product. In this table only the organic cation is indicated, all anions are bromide.

Entry Starting compound a ) Compound distribution [%] b ) k [x10 -3 M -1 s -1 ] t 1/2 [
As seen above, N-allyl-N,N-dimethylanilinium bromide (1a-Br) did exchange with aliphatic tertiary amines but these reactions were irreversible. Consequently, it appeared that in order to achieve reversibility, it would be necessary to perform the exchange reactions between aromatic partners. To this end, the reactions of N-allyl-N,Ndimethylanilinium bromide (1a-Br) with N,N-dimethylaniline-type aromatic tertiary amines (4a-e) were investigated in CD 3 CN at 60 o C at 1/1 ratio and 60 mM final concentration with TBAI (60 mM) as catalyst (in the earlier study the final concentration for exchange between 1a-Br and aliphatic tertiary amines was 20 mM, but the exchange reactions of 1a-Br with aromatic tertiary amines were performed at 60 mM to attain a more convenient rate of reaction). It was found that the exchange between 1a-Br and the aromatic tertiary amines was now indeed reversible.

For all of the exchange processes of allyl-N,N-anilinium salts (1a-1f) and the N,Ndimethylaniline-type aromatic tertiary amines (4a-4e), the second-order rate constants for both forward and reverse reactions were estimated by treating the process as an irreversible second order reaction for the first 10% of conversion (see experimental part, Chapter 7).

The half-lives (t 1/2 ) of the reactions were determined by integration of the decreasing 1 H-NMR signals of the starting material as a function of time and taken to be the time at which the starting material was reduced to 50% with respect to the equilibrium value. No special significance is given to the half-lives measured in this way; they are simply a convenient way to compare the rates of several reactions. In addition, the equilibrium constants for the exchange processes were calculated from the product distributions in the cases where equilibrium had been reached (see experimental part).

The results, compound distributions, rate constants of the exchange reactions, and equilibrium constants are listed in Table 4.5. The distributions were the same for both forward and reverse reactions, indicating that thermodynamic equilibrium had been reached. Furthermore, the reactions were accelerated by a factor of about 1.5-2 on addition of an equimolar amount of iodide (TBAI) as nucleophilic catalyst.

Figure 4.4 1 H-NMR study of the nucleophilic substitution exchange of N-allyl-N,Ndimethylanilinium bromide (1a-Br) and 4-N,N-trimethylaniline (4b) by observation of the signals of the aromatic H d and H b proton (4a and 4b) and the α-CH 2 -proton signal of the allyl group (1a-Br and 1b-Br), before (bottom, t = 0 h) and after (top, t = 30 h) exchange at equilibrium. t

= 0 h t = 30 h 1a (H a ) 1b (H c ) 1a (H a ) 4b (H b ) 4b (H b ) 4a (H d )

Table 4.5 Kinetic and thermodynamic parameters for the exchange reaction between the N-allyl-N,N-anilinium salts 1a-1e and the N,N-dimethylaniline-type aromatic tertiary amines 4a-4e in 1/1 ratio at 60 mM concentration in CD 3 CN at 60 o C. Half-life t 1/2 . Proportion (%) of the different compounds. a = allyl bromide, b = allyl iodide, c and d = amino-Claisen rearrangement products. In this table only the organic cation is indicated, all anions are bromide except entries 5

and 6 where the anions are iodides. No Reaction No Reaction a ) f b , forward reaction in the absence of catalyst; f c , forward reaction in the presence of TBAI (60 mM.) as catalyst; r b , Reverse reaction in the absence of catalyst; r c , Reverse reaction in the presence of TBAI (60 mM) as catalyst. b ) Error in 1 H-NMR signal integration: ±4%. c ) K b , Equilibrium constant of the uncatalyzed. d ) K c , Equilibrium constant of the catalyzed reaction. e ) n.a., not applicable. f ) Compound not observed.

Entry Starting compound a ) Compound distribution [%] b ) k [x10 -3 M -1 s -1 ] t 1/2 [h] K b c ) K c d ) 1a
When N-allyl-4-bromo-N,N-dimethylanilinium bromide (1d-Br) was combined with N,N-dimethylaniline (4a) or, in reverse, N-allyl-N-N-dimethylanilinium bromide (1a-Br) combined with 4-bromo-N,N-dimethylaniline (4d), no reaction was observed in either case other than a very slow decomposition to unidentifiable materials. Thus, neither bromide ion catalysis nor direct attack of the aromatic amines seemed to be effective in these cases.

Exchange was observed in the cases of 1e-Br+4a and 1e-Br+4b, and marked line broadening was observed for the aromatic 1 H-NMR signals of liberated diethyl aniline both in the presence and absence of iodide ion (Figures 4. 5 and 4.6). It may be due to the formation of the radical cation of free diethyl aniline by oxidation in the conditions of the experiments. When the corresponding iodide 1e-I was used in the exchange reaction with 4b (Table 2,Entry 5), no such line broadening of liberated diethyl aniline was observed (Figure 4.7). This suggested that in addition to the faster reaction of iodide ion at the γ-position of the allyl group of 1e-I, compared to bromide in 1e-Br, if the radical species of diethyl aniline was generated, it might be reduced by iodide ion (the yellow colour of the solution was observed). In addition, the dissociation of 1a-Br was studied by dissolving 1a-Br in CD 3 CN at 60 o C (Figure 4.8). Again the broadening of the aromatic proton signals of liberated dimethyl aniline was observed and assumed to be due to the formation of its radical. The electronic absorption spectrum of this reaction mixture (Figure 4.9) also provided evidence that the radical of dimethyl aniline [80] was generated under these conditions. Next, the dissociation of 1a-Br was examined in the presence of iodide ion (Figure 4.10). The line broadening of the free dimethylaniline signals appeared after 2 h and disappeared after 43 h. Taken together, these results support the conclusion that the radical cation of dimethyl aniline was generated in these experiments and that it was reduced by iodide. The electronic absorption spectrum of the mixture produced by deallylation of 1a-Br (λ max 505 nm) in CH 3 CN (5 mM), showing evidence of absorption due to the radical cation of dimethyl aniline (r-4a) in the visible region. [80,81] (The electronic spectrum was measured after reacting 1a-Br (20 mM) in CD 3 CN at 60 o C overnight. The solution for this spectrum was prepared from this reaction mixture after the purple color was observed by dilution from 20 mM to 5mM)

H c H a H b

To evaluate the influence of the counter-anion nucleophilicity on the exchange kinetics and the possibility of "direct" exchange by attack of the amine on the allyl group of the quaternary reactant, the ammonium salt 1a-PF 6 with the very weakly nucleophilic hexafluoro-phosphate (PF 6 -) anion was prepared and tested for its reaction with the aromatic amine 4b (Scheme 4.2). The reaction was very slow, giving only 5% 1b-PF 6 after 162 h, about 40 times slower than for the bromide salt. This result confirmed that the reaction in the presence of halide ions (e.g. bromide or iodide) must proceed predominantly through the intermediacy of the allyl halides. Nonetheless, the formation of the small amount of 1b-PF 6 indicates that the direct reaction pathway can make a small contribution.

Scheme 4.2 Exchange reaction of 1a-PF 6 and 4b. % (±4%) of compounds after 162h reaction time. c = Amino-Claisen rearrangement products.

In the reactions of 1a-Br with the aliphatic amines 2a or 2b, small amounts of allyl bromide were detected. In contrast, for the exchange between 1a and 2c or 2d no allyl bromide was observed. This could mean that the substrates 2c and 2d compete more effectively than 2a and 2b with bromide for an attack on the terminal allyl carbon atom of 1a-Br (Scheme 4.3b). We have tested this hypothesis by reacting 2c or 2d with the salt 1a-PF 6 containing hexafluorophosphate anion, which is far less nucleophilic than any of the halides (Figures 7.65 and 7.67, Chapter 7). The results show that 3c-PF 6 and 3d-PF 6 do form under these conditions at similar rates to those with the bromide salts (0.172 x 10 -3 M -1 s -1 for 1a-PF 6 -and 2c; 0.325 x 10 -3 M -1 s -1 for 1a-PF 6 -and 2d) in the absence of iodide as catalyst. In contrast, the reaction of 1a-PF 6 -with 2a was about 20 times slower than that of 1a-Br with 2a. This difference in reactivity might be due to steric bulk which would hinder the reaction of the more bulky amine 2a at the γ-carbon of the allyl group of 1a-Br, compared to the amines 2c and 2d (see also chapter 7).

From the results mentioned above, lead to a proposed plausible mechanism of the tertiary amine exchange processes between quaternary allyl-ammonium salts and tertiary amines as will be described here. The exchange of the amine moiety between quaternary N-allyl-N,N-dimethylanilinium salts and a tertiary amine may be considered to take place following two mechanistic pathways both of S N 2' type as outlined in Scheme 4. ii) a direct pathway (Scheme 4.3b) whereby the tertiary amine introduced reacts directly at the γ-carbon of the allyl group to provide the exchange product V or VII.

In addition, trace amounts of the amino-Claisen rearrangement product of the N-allyl-N,N-dimethylanilinium cation were also observed as a side reaction during the exchange process. The Claisen rearrangement reaction is an indication of the electrophilicity of the allyl group (presumably enhanced by the fact that the reaction is intramolecular)

Taken together, the results obtained indicate that the exchange reactions studied here may occur by the indirect pathway, via the intermediate formation of allyl bromide/halide as well as by the direct pathway, by attack on the free amine at the γ carbon of the allyl group. The presence of catalytic iodide anions may be expected to favour the indirect pathway via the formation of allyl iodide. Some comments can be made on the basis of the results obtained: 1) much faster exchange rates for bromide than for PF 6 -salts are observed for the aromatic aniline compounds together with the formation of allyl bromide, favouring an indirect S N 2' mechanism (Entries 1 and 3 in Table 4.5); 2) with the more nucleophilic aliphatic benzylamines there is a comparatively small rate difference between bromide and PF 6 -salts and no allyl bromide is observed, indicating that the direct mechanism is favored (Entries 3, and 4, Table 4.4); 3) steric bulk also affects the exchange process, slowing down the rate and shifting it towards the indirect mechanism, as is particularly notable in the case of N(diethyl) on both partners (Entry 6, Table 4.4). Of course, the different mechanisms probably coexist and may be favored depending on these various factors (nucleophilicity of the amine, steric bulk, nature of the counteranion….).

N N Br - N Br - N Br R 2 R 3 R 1 R 1 R 2 R 3 N Y N Y Br - N Y N X X X
S N 2' S N 2 N N Y I X VI Br - or N R 2 R 3 R 1

IV

Or

Scheme 4.3 Possible pathways for exchange of the amine moiety between N-allyl-N,Ndimethylanilinium bromide and an aliphatic or aromatic tertiary amine via an S N 2' mechanism

Study of exchange processes between quaternary benzyl-ammonium salts and tertiary amines via S N 2 type nucleophilic substitution.

DCC involving exchange of the tertiary amine may also take place with quaternary benzyl ammonium salts. Thus, we extended the generation of DCLs of quaternary ammonium cations by exploring amine exchange reactions between the N-benzyl-N,Ndimethylanilinium salts (5a-c-Br) and the tertiary amines (4a-c). An evaluation of the effect of iodide anion as a catalyst by addition tetrabutylammonium iodide (TBAI) on the exchange reaction of 5a-Br and 4b (Figure 4.11) indicated similar reaction rates using 1 or 2 equiv. Therefore, the addition of 1 equiv. of iodide was chosen for the exchange study. The exchange reactions between the salts 5a-c-Br and the tertiary dimethyl-aniline amines 4a-c were studied in CD 3 CN at 60 o C (Table 4.6). The rate constants and half-lives were calculated using the same method as for the exchange reaction of allyl ammonium salt with tertiary amines (Chapter 7). The reactions in the forward and reverse directions gave identical product distributions within experimental error, showing that the reactions reached a true equilibrium. The rates were about 2-fold faster in both directions on addition of 1 equiv. of iodide. To investigate the role of the bromide ion in assisting the exchange reaction, the salt 5a-OTf was prepared by substitution of the bromide ion of 5a with trifluoromethanesulfonate (OTf -) as counterion. The exchange of 5a-OTf and 4b (Figure 7.68) was slower than 5a-Br and 4b by a factor of about 76, confirming that the presence of the nucleophile bromide strongly increased the rate of reaction. Similarly, the reaction of 5a-PF 6 (PF 6 -as a counter anion) with 4b (Figure 7.69, Chapter 7), gave the exchange products 5b-PF 6 (13%) and 4a (13%) after 137 h being slower than the reaction of 5a-Br and 4b by a factor of 215. In comparison, the exchange reaction of quaternary benzyl ammonium salts with aromatic tertiary amine (5a-Br + 4b, Table 4.6, Entry 1; rate constant 6.66 x 10 -3 M -1 s -1 ) was faster than the exchange of quaternary allyl ammonium salt (1a-Br + 4b; rate constant 0.663 x 10 -3 M -1 s -1 ,with a final solution 20 mM) by about 10-fold. ) f b , forward reaction in the absence of catalyst; f c , forward reaction in the presence of TBAI (20 mM) as catalyst; r b , Reverse reaction in the absence of catalyst; r c , Reverse reaction in the presence of TBAI (20 mM) as catalyst. b ) Error in 1 H-NMR signal integration: ±4%. c ) K b , Equilibrium constant of the uncatalyzed reaction. d ) K c , Equilibrium constant of the catalyzed reaction. e ) n.a., not applicable.

) k [x10 -3 M -1 s -1 ] t 1/2 [h] K b c ) K c d ) 5a
As in the case of quaternary allyl ammonium salts discussed above and the results mentioned in this part, the mechanism of the exchange of the tertiary amine moiety between quaternary N-benzyl-N,N-dimethylanilinium salts and a tertiary amine can be described as following two mechanistic pathways both of S N 2 type as outlined in Scheme 4.4:

i) an indirect pathway (Scheme 4.4a) involving a) the nucleophilic attack of bromide anion at CH 2 carbon of the benzyl group of the N-benzyl-N,N-dimethylanilinium salt (IX) to liberate the N,N-dimethylaniline (II) and benzyl bromide (X), b) subsequent reaction of X with the introduced tertiary amine VI giving the exchange product XI in a reversible process.

ii) a direct pathway (Scheme 4.4b) whereby the tertiary amine VI introduced reacts directly at the CH 2 carbon of the benzyl group of IX to provide the exchange product XI.

As in the previous case, for the allyl anilinium quaternary cations above, the much slower reaction observed above when PF 6 -or OTf -were used as counteranions as compared to bromide indicates that the exchange processes studied here occur mainly through the indirect pathway 4.4a) via the intermediate formation of benzyl bromide/halide, with negligible if any participation of the direct pathway 4.4b). Thus, the exchange rate is much slower for (benzyl) 5a-PF 6 + 4b than for 5a-Br + 4b, and the change from bromide to PF 6 slows down the rate much more for the benzylic cations than for the comparable allyl cations (compare (benzyl) 5a-PF 6 + 4b 215 times slower than 5a-Br + 4b; (allyl) 1a-PF 6 + 4b 40 times slower than 1a-Br + 4b).

Scheme 4.4 Pathways for exchange of the tertiary amine moiety between N-benzyl-N,Ndimethylanilinium bromide and an aromatic tertiary amine via an S N 2 mechanism

Study of exchange processes between N-allyl-and N-benzyl-pyridinium salts and pyridine components via S N 2 and S N 2' nucleophilic substitution processes.

To further extend the range of DCLs generated via nucleophilic substitution processes of S N 2 and S N 2' types, we investigated the exchange reactions between the N-benzyland N-allyl-pyridinium salts 6a-6f and the pyridine derivatives 7a-7d (Table 4 In terms of exchange mechanisms and on the basis of the discussions above concerning both the quaternary allyl-and benzyl-anilinium compounds, the reactions of Table 4.8 involving the N-benzyl-pyridinium bromides may be considered to occur via an S N 2 pathway with direct attack of bromide anion on the benzylic CH 2 center and formation of benzyl bromide, which then reacts further with the added pyridine, in analogy with the discussion above (Scheme 4.4a). On the other hand, the processes involving the N-allylpyridinium salts appear to follow an S N 2' pathway via the intermediate generation of allyl bromide, which then reacts further (see also Scheme 4.3a).

The ability of pyridinium salts and pyridine derivatives to undergo interconversion was studied by considering the effect of ortho and para-substitution on pyridine derivatives. The component exchange between 6a and 2-methylpyridine resulted in the starting compounds 6a (26%), 2-methylpyridine (38%) and exchange products 1-benzyl-2methylpyridinium bromide (12%), pyridine (17%), and benzyl bromide (7%). Due to steric hindrance at the ortho-position in 2-methylpyridine, only a small amount of the exchange product was obtained, together with a significant amount of liberated benzyl bromide. Therefore, for the following investigations, only para-substituted pyridine derivatives (7a-d) were used, giving the results shown in Table 4.8. The interconversion between 6a and 7b (Figure 4.12 and Table 4.8, Entry 1) and the reverse reaction under the conditions mentioned above, gave the exchange products as 6b (35%) and 7a (33%) with a trace amount of benzyl bromide (2%).

Next, the reaction of the pyridinium salt 6a and pyridine 7c (bearing the electron donating dimethylamino group in para-position) under the same conditions, was found to afford 6c (50%) and 7a (50%) (Table 4.8, Entry 2). The full conversion indicated that this reaction would not be reversible. Indeed, similar treatment of (6c + 7a) did not provide the exchange products, confirming that this process was irreversible. On the other hand, exchange between 6a and 7d afforded 6d and 7a and was reversible (Table 4.8, Entry 3), reaching thermodynamic equilibrium.

Figure 4.12 1 H-NMR spectrum of the distribution of constituents obtained by component exchange between 6a (14%) and 7b (16%) to give the product 6b (35%) and 7a (33%) at equilibrium. The characteristic -CH 2 -Ph signals are indicated for 6a, 6b and benzyl bromide (A), 4-methylpyridine (7b), pyridine (7a).

The exchange of the pyridine component of allylpyridinium salts was investigated by combining the N-allylpyridinium bromide 6e and pyridine 7b. The reaction yielded 6f and 7a in 30% and 29% proportions together with 3% free allyl bromide (Table 4.8, Entry 4). The reversibility was studied by starting with 6f and 7a to give products 6e and 7b in similar amounts to those obtained in the forward process, thus indicating thermodynamic equilibrium was attained. In line with the discussion above, the mechanism of this exchange is expected to follow a S N 2' nucleophilic substitution pathway (Scheme 4.3a) starting with attack of bromide ion at the γ-carbon of the allyl group of the pyridinium cation. Finally, cross-exchange between N-benzyl and N-allyl-pyridinium salts involving nucleophilic substitution interconversion by both S N 2' and S N 2 pathways, was investigated by combining 6b and 6e. The desired products 6f (16%) and 6a (9%) were observed together with significant amounts of other released components as shown in Table 4.9.

This reaction was shown to be reversible by mixing 6f and 6a which gave the products 6e (6%) and 6b (14%). The forward reaction was also conducted for 90 min and afforded a similar distribution as for 30 min, indicating that equilibrium was reached after 30 min.

The reverse reaction was slower and equilibrium was not reached after 90 min. In addition, the nucleophilic substitution exchange of an ionic liquid compound derived from imidazole derivatives was investigated in a molecular solvent under the same conditions as used for the pyridinium salt. 3-Benzyl-1-methyl-1H-imidazol-3-ium bromide (8a) was synthesized then used to exchange with pyridine (7a) under the same conditions as the exchange of pyridinium salts were performed. The result showed that this exchange reaction did not occur because of the stability of 8a. In contrast, the inverse of this reaction was studied by combining 9a and 6a, giving the desired exchange products 8a (38% after 30 min) and 7a (34% after 30 min) as shown in Table 4.10. Next, the exchange reactions between 8a and either 9b or allyl bromide (B) were examined (Schemes 4.5a and 4.5b, respectively). In addition, another derivative of imidazolium salt 8d was used to exchange with 4-nitrobenzyl bromide (C) as shown in Scheme 4.5c. None of these reactions was detectable and we can conclude that all of the imidazolium salts were highly stable and resistant to exchange with other compounds.

Generation of libraries of Dynamic Ionic Liquids (DILs)

Ionic liquids have attracted great interest and acquired much importance in many areas of chemistry. [82][83][84][85][86][87] They usually involve organic quaternary cations, in particular, imidazolium and pyridinium derivatives. [76] We thus were interested in the possibility of generating dynamic libraries of ionic liquids, which might present specific properties not presented by the usual ones based on "static" constituents. Considering the results obtained for the pyridinium salts, in particular, 6e and 6f, we performed some experiments aimed at the generation of dynamic libraries of ionic liquids.

To this end, we have investigated the exchange reaction of pyridinium salts with derivative of pyridines in the absence of added molecular solvent taking into account that 6e and 6f are known to be ionic liquids. [76] Combining 6e and in a ratio of 1:2 afforded 6f (11%) and 7a (19%) as the exchange products (Scheme 4.6a) together with some free allyl bromide (8%). However, the reaction medium became coloured, indicating that some decomposition had taken place. Of special interest is the generation of a dynamic ionic liquid library by component exchange in the solid state, i.e. from solid constituents. Thus, starting from a mixture of the two solid precursors 6e and 6b, in the absence of solvent, and heating by microwave irradiation, an ionic liquid mixture was obtained having the composition 6e (18%), 6b (35%), 6f (17%), and 6a (30%) (Scheme 4.6b). These results, although limited at this stage, demonstrate that dynamic ionic liquid libraries may in principle be generated from solid materials. One may point out that such a passage from solid to liquid phase also raises the question whether it may be accompanied by a component selection, i.e. whether component exchange and selection would lead to those constituents that provide the ionic liquid presenting the lowest solidification temperature. As it seems that no ionic liquids based on anilinium salts have been reported, the exchange reaction between 5b-Br and 1c-Br was tried in the absence of solvent. Only decomposition of the components was observed after heating.

Conclusions

The results described here extend dynamic covalent chemistry to both a new class of constituents, quaternary ammonium salts, and a new class of dynamic reactions, nucleophilic substitutions. They are thus of interest whenever processes implementing such compounds and transformations are pursued. They also suggest further exploration, for instance towards exchanges and DCLs based on other nucleophilic substitution reactions (e.g. R-X / R'-Y) or towards other classes of compounds such as quaternary phosphonium salts, [88] or also towards other types of applications such as the generation of dynamic ionic liquid phases, thus pushing further the realm of dynamic structural diversity and functional complexity.

Kinetic and Thermodynamic selectivity of Imine in Dynamic Covalent Chemistry

Introduction

One of the fundamental aspects for the generation of dynamic combinatorial chemistry (DCC) is the operation of one or several reversible inter-or intramolecular exchanges involving covalent or non-covalent interactions. Of these reversible reactions, imine formation by condensation of carbonyl groups with amines is of considerable interest, in view of its role in both chemical synthesis and in biology. Imines have been used recently in dynamic covalent chemistry, adaptive chemistry, and also in supramolecular chemistry because they allow facile formation/breaking of covalent bonds to exchange with other molecules. Thus, many DCC processes are based on imine formation, selection, exchange, and/or hydrolysis. [1][2][3][4][5] The nature of amine condensation with aldehydes has been evaluated widely.

Primary amines, hydroxylamine, and hydrazine derivatives have all been investigated to develop useful strategies in imine formation as conjugates in chemistry and biology. [6][7][8][9][10][11][12][13][14][15][16][17] Nucleophiles such as hydrazine and hydroxylamine where the amino group has an alphasubstituent bearing a lone pair have long been known to act as stronger nucleophiles than normal primary amines [18] and their low basicity allows the formation of more stable imine products. [19] In recent times, imine formation from these alpha nucleophiles has received much attention in chemical biology, [6][7][8] polymer chemistry, [9][10][11] dynamic combinatorial chemistry, [12][13][14][15][16] and reaction development [20] . This chapter describes studies of the efficiency of imine formation from different aldehydes and various amino derivatives (including primary amine, hydrazine, hydrazide and aminooxy compounds) in aqueous solution (under pD control) and in organic solvents (CD 3 OD or CD 3 CN). Moreover, competitive reactions (to generate Dynamic Covalent Libraries, DCLs) between different amino derivatives to form different imines in a single system have been studied in order to understand the relative reactivity and stability of these imines in aqueous solutions and organic solvents. These experiments were designed to provide a basis for predicting the stability of imines and their formation efficiency in various systems. They were also directed to the exploration of the regioselective transformation of one molecule possessing different functional groups in order to select different products based on kinetic or thermodynamic selectivity as shown in

Results and Discussion

In this investigation, the selected aldehydes first group is that of the water ), benzhydrazide (G), used in this study.

Scheme 5.2 Structures of the different amino derivatives (A-H) used in this study

Two criteria defining the reactivity and stability are the rate of conversion (kinetic products: kinetic selectivity) and the degree of conversion (thermodynamic products: thermodynamic selectivity). Both the rates and equilibrium positions of processes investigated were monitored by 1 H-NMR spectroscopy, with the fractions of different compounds being determined by signal integration with respect to the peak of 1,4-dioxane as an internal standard. Over the initial stages of the reaction (i.e. when reverse reaction of the products could be ignored), the time dependence of the concentrations provided a good fit to simple second-order kinetics (for details, Chapter 7), thus providing the rate constants given herein.

Study of imine formation in aqueous solution from reaction of sodium 5-formyl-2methoxybenzene sulfonate ("sulfonate aldehyde") (1) and pyridoxal phosphate (2) with different amino derivatives (A, B, C, D, and E)

Imine formation reactions are generally well understood, but studies of imine formation in water are limited and insufficient to establish the stability of imines with low equilibrium constants. [21][22][23][24][25] This is because the hydration of the aldehyde or the imine will always compete with imine formation to a greater or lesser extent depending on the electronic properties of the amine or aldehyde. [26] Thus, imine formation reactions were performed in organic solvents not only to avoid hydration of aldehyde but also to shift the equilibrium toward the condensation products by favoring elimination of water from carbinolamine intermediates. DCC of imine compounds has been investigated in organic solvents, [27] aqueous-organic mixtures, [28] and aqueous solutions. [13,[29][30][31][32][33] The objective here was to extend these works to assess the reactivity of several different amino derivatives towards a single aldehyde in a competition reaction to generate a DCL.

The study of imine formation from sulfonate aldehyde (1)

In preliminary studies, imine formation was assessed under different conditions using sulfonate aldehyde 1 with several amino derivatives separately (propylamine (A), pentylamine (B), O-methoxyamine (C), acethydrazide (D), and methylhydrazine (E)).

DMSO-d 6 and D 2 O were employed as solvents (Table 5 In the next screening experiment (without any pH control, this experiment could only be expected to give very rough indications of rates and equilibria), a DCL was generated by combining all the amino derivatives A, C, D, E, together with sulfonate aldehyde 1 in D 2 O (Scheme 5.3) in a mixture of 20 mM of each compound at 25 o C. The 1 H-NMR spectra were recorded immediately after mixing, and the reaction was followed until sulfonate aldehyde 1 could no longer be detected. This took 5 h (Figure 5.2). After mixing, all imines (1A, 1C, 1D, 1E) were formed initially but 1A rapidly disappeared as the reaction continued. The thermodynamically most preferred (high conversion) products in this system were 1C and 1E. At equilibrium, the %-formation of imines was in the order 1C > 1E > 1D indicating that 1C was the most stable compound. The pD value measured after equilibration was 6.0. The second screening experiment was performed in the same conditions as the previous one but pentylamine B was employed instead of propylamine A.

Entry Product Time [h] c ) Product [%] d ) 1 a ) 1A 120 18 1 b ) 0.03 f ) 11 2 a ) 1B 119 31 2 b ) 0.05 f ) 32 3 a ) 1C 15
The results shown in Figure 5.2 indicate that only the oxime (1C) and hydrazone (1E) were formed while compounds 1B and 1D did not form in appreciable concentrations at anytime during the reaction. The pD value of this reaction mixture was 8.4 as measured after equilibration. That changing the primary amine from propylamine (pK a 10.71) to pentylamine (pK a 10.63) led to very different pD of the final solution was a surprising result given that both amines appeared to be free in the final solutions, which thus would have been expected to have a pD close to 11 in both cases. Assuming that both the lower pD values and the fact that 1D was formed in quite different amounts in the two tests might have been consequences of acid-bases reactions between the amines and the weakly acidic acethydrazide, further experiments were conducted using buffered solutions.

Scheme 5.3 DCL of the 5 components 1, A, C, D, E and the four possible imine products 1A, 1C, 1D, 1E. The study was performed at 25 o C using a solution where each component was initially present at a concentration of 20 mM.

Figure 5.2 a) Kinetics of imine formation (1A, 1C, 1D, 1E) in D 2 O (pD = 6.0 after equilibration). b) Kinetic trace of the imine formation (1B, 1C, 1D, 1E) in D 2 O (pD = 8.4 after equilibration). Each data point was obtained by integration of the 1 H-NMR signal corresponding to the -CH=N-proton with respect to an internal standard, 1,4-dioxane.

Error in 1 H-NMR integration: ∼4-5%.

In addition, it is of course well known for imine formation in general that both the rates and equilibria are pH-dependent. [34][35][36][37][38] Thus, further experiments were performed under controlled pD conditions (pD = 5.0, 8.5, and 11.4; the pD value was calculated employing pD = pH + 0.4 where "pH" is the apparent pH value indicated by the conventional glass electrode [26,39] ) using phosphate buffers (160 mM NaH 2 PO 4 /Na 2 HPO 4 ) mixtures.

Firstly, the formation of 1B, 1C, 1D and 1E was studied in order to determine the kinetic and thermodynamic parameters of each individual reaction using initial reactant concentrations of 20 mM in all three buffers at 25 o C (Table 5.2). The results showed that 1B did not form at pD 5.0. At pD 8.5 and 11.4, 1B formed rapidly after mixing but the %-product at equilibrium was very low. The oxime 1C formed faster at pD 5.0 than at higher pD values, showing that acidic media are preferable for oxime formation, although it is presumed that if the solution were acidic enough to protonate completely the amine C, nucleophilic addition to the aldehyde would be inhibited. The pK a of O-methoxyamine is 1D also formed faster at pD 5.0 than at pD 11.4 but did not form at all at pD 8.5.

The pD values of all three buffers exceed the pK a of acethydrazide (pK a = 3.25) meaning that acethydrazide would have been at least predominantly in its neutral form in all three buffers. Finally, the hydrazone 1E formation was nearly insensitive to solution pD but formed slightly slower at pD 11.4, despite the fact that, given the pK a of the conjugate acid of E (methylhydrazine) is 7.87, the reactant would have been present very largely in its protonated form at pD 5.0 but largely in its neutral from at pD 8.5 and 11.4. These results provide a good illustration of the possible complexity of the pH dependence of imine formation. [26] expected from its pK a , that pentylamine was protonated and could not react with sulfonate aldehyde 1). 1C was both a kinetically and thermodynamically stable product.

Entry pD Product Product [%] a ) Time [h] b ) k c ) [x10 -3 M -1 s -1 ] 1 5.0 1B -d ) -d ) n.d. e ) 1C 89
agreement with the first set of results of the individual rates of formation of imines 1D, and 1E (Table 5.2, Entry 1 5.

3
giving the compound distribution 1C (86%), 1D (9%), 1E (5%) with no , that pentylamine was protonated and could not react with sulfonate was both a kinetically and thermodynamically stable product.

agreement with the first set of results of the individual rates of formation of imines

4). The study was performed using an initial concentration of 20 mM

Time [h] a ) Compound Distribution [%] b ) 1B 1C 1D -c ) 86 9 -c ) 37 -c ) -c ) 15 -c
) indicate when no further change (<2%) was detectable in the concentrations.

) Compound not formed. The results show that the 5.3, Entry 2), and that only two imine compounds 1C (37%) and 1E (63%) were formed while 1B and 1D were not detected. At equilibrium, 1E

was more abundant than 1C. Finally, the DCL of the same mixture was established at pD 11.4 (Figure 5.3c and Table 5.3, Entry 3). The rate of the reaction was similar to that at pD 5.0, with equilibrium reached after 1.2 h. The equilibrium compound distribution was 1C (15%) and 1E (85%), with again no evidence that 1B and 1D were present.

In summary, DCLs of the mixture of 1, B, C, D, and E in acidic conditions were dominated by the oxime 1C whereas, in basic solution, the hydrazone 1E was more stable.

The times to reach equilibrium for both acidic and basic media were about 1 h. Meanwhile, in slightly basic solutions (pD 8.5), the reaction progressed relatively slowly. At all pD values, imine 1B was not detectable, meaning that it was less stable than oxime 1C or hydrazone 1E. These results show that the acidity of the medium is an effective tool for controlling the relative concentration of imines in a DCL in aqueous solution.

The study of imine formation from pyridoxal phosphate (2)

Pyridoxal phosphate (2) was chosen as an aldehyde reactant because it is known to exist in nature as the coenzyme for a wide range of different reactions, [40][41][42][43] and to play a significant role in the metabolism of amino acids and other biological processes, [44,45] as well as in dynamic covalent systems. [46] Firstly, imine formation between pyridoxal phosphate 2 and the different amino derivatives (B, C, D, E) was monitored separately at different pD values (pD = 5.0, 8.5, and 11.4) under the same conditions as used with the sulfonated aldehyde 1 (Table 5.4).

Imine formation from pyridoxal phosphate 2 and pentylamine B did not occur at any pD because of the dominance of the hydrated form of pyridoxal phosphate (as detected by 1 H-NMR). The formation of 2C occurred quickly at all pD values, reaching equilibrium after 5 min without any residual hydrated form of 2 being detectable. In contrast, very little of imine 2D was formed at any of the three pD values (3% yield). The hydrazone 2E was formed in 100% yield at both pD 5.0 and 8.5 while at pD 11.4 the reaction was faster (reaching equilibrium after 5 min) but with only 70% conversion at equilibrium.

Kinetic and Thermodynamic Selectivit

These results show that C, D, and E at different pD values, the oxime species. At low pD, 2C had the highest %

Imine formation from 2-pyridyl aldehyde (3) and salicylaldehyde (4) and various amino derivatives (B, F, G, and H) in organic solvents

Imine formation from 2-pyridyl aldehyde (3)

2-pyridyl aldehyde ( 3) is known to react efficiently with amino compounds. It contains a sp 2 nitrogen atom that can be used as a binding site for metal-ion, thus offering other means of modifying its properties. [47] Furthermore, the pyridine-N can serve as a site for intramolecular H-bonding of inappropriately functionalized imines, thus serving, for example, to stabilize the Z isomer of hydrazones susceptible to photochemical interconversion between E and Z forms. [47,48] In 2013, Stadler studied competitive imine formation in the reactions of a mixture of a primary amine and hydrazine with 2-pyridyl aldehyde and its derivatives in CD 3 CN, showing that the kinetic product was the imine derived from the primary amine while the thermodynamic product was the hydrazone. [49] DCC of the imines derived from aldehyde 3 has been widely investigated. [47,48,50,51] Here we extend these studies to determine the kinetic and thermodynamic selectivity for imine formation resulting from the reaction of aldehyde 3 with different amino compounds both separately and within DCLs.

Firstly, imine formation between 3 and four different amino derivatives (pentylamine (B), O-benzylhydroxylamine (F), benzhydrazide (G), and phenyl hydrazine (H)) was evaluated in pure CD 3 OD. The results shown in Table 5.6 indicate that imine 3B

was formed very quickly with the reactions reaching equilibrium after 2 h with 86% conversion. 3F, 3G, and 3H were formed more slowly than 3B and reached equilibrium after ca. 18 h, with about 92% conversion each. In the process of imine formation, the hemiaminal intermediate was observed in all the reactions. [52] The measurements of imine formation here were just meant to provide a rough guide as to the differences given that, because there was no pH control and various intermediates were detectable, a proper kinetic analysis would be impossibly complicated.

Competitive reactions of two amino compounds with 2-pyridyl aldehyde (3)

The reaction between aldehyde 3 and equimolar amounts of pentylamine B and O-benzylhydroxylamine F was followed in pure CD 3 OD at 25 o C (Figure 5.6a, Table 5.7, Entry 1). In this case, only imine 3B (34%) was detected immediately after mixing, being present along with the hemiaminal intermediate. Subsequently, the concentrations of 3B and 3F increased with time but at different rates such that after about 50 min, the concentration of 3B began to decrease and 3F became the predominant species. The reaction was followed up to 27 h, at which point the product conversions were 3B (15%) and 3F (85%).

Next, an equimolar mixture of the two amino derivatives B and G with aldehyde 3 was studied at 25 o C (Figure 5.6b and Table 5.7, Entry 2). Initially, aldehyde 3 reacted rapidly with both amino compounds, giving imine 3B (23%) and acylhydrazone 3G (6%), with the presence of the hemi-aminals again being detectable. Later, 3B was lost, to be replaced by more 3G, that was then the major final product at 3.5 h, when the amounts were 3B (13%) and 3G (87%). Then, an equimolar mixture of the two amino compounds, B and H, with aldehyde 3 was analyzed under the same conditions as in the preceding cases (Figure 5.6c and Table 5.7, Entry 3). For this mixture, only 3B (28%) was observed immediately after mixing all the components together. Subsequently, the concentration of 3B increased rapidly until about 18 min, reaching 57% composition, before slowly beginning to decrease. 3H started to appear after 5 min and slowly increased in concentration with time. The reaction was followed up to 5 h, giving 3H (73%) as a major product and 3B (27%) as a minor product. These results show that oxime 3F, acylhydrazone 3G, and hydrazone 3H are more stable than imine 3B. Pentylamine B has a higher basicity than the other amino compounds (for comparison, the pK a of pentylamine is 10.63, [53] while the pK a of benzhydrazide is 3.0, [54] O-benzyl hydroxylamine is 4.23, [55] and phenylhydrazine is 5.21). [56] Imine 3B formed faster than 3F, 3G and 3H at the beginning of the reaction and was, therefore, the kinetic product, whereas 3F, 3G, and 3H were the thermodynamic products. The thermodynamic preference is due to the oxime, acylhydrazone, and hydrazone having electron pairs on a heteroatom near the nitrogen of the imine bond (-CH=N-X; X = O or N) which can delocalize over the molecule thus stabilizing it. [19,57] a) b) c) The reaction of 3, F, and G (Figure 5.7a and Table 5.7, Entry 4) showed 3F and 3G to be formed very rapidly upon mixing, with %-compositions of 67% and 9%, respectively. At equilibrium, attained in about 0.18 h, the composition was 87% 3F and 13% 3G. The reaction of 3, F, and H was studied (Figure 5.7b and Table 5.7, Entry 5) under the same conditions, giving 3F (2%) and 3H (15%) after mixing and reaching equilibrium in about 4 h, with 3F (30%) and 3H (68%), respectively. These results show that the stability of the condensation products lies in the order 3H > 3F > 3G.

Reactions of three and four amino compounds with 2-pyridyl aldehyde (3)

For the reaction of an equimolar mixture of 3, B, G and H in pure CD 3 OD and at 25 o C (Figure 5.8a and Table 5.8, Entry 1), only imine 3B (23%) and acylhydrazone 3G (7%) were detectable immediately after mixing. After about 15 min, 3B started to decrease in concentration and completely disappeared after 2 h as 3G (79%) and 3H (21%) rose in concentration. Interestingly, for this system, 3G was formed more efficiently than 3H

suggesting that intramolecular hydrogen bonding in 3G made it more stable than 3H. Next, the equimolar mixture of 3, F, G, and H was run, with only 3F (1%) and 3H (11%) being detectable immediately after mixing (Figure 5.8b and Table 5.8, Entry 2). The reaction reached equilibrium after 1.6 h, giving 3F (20%), 3G (3%), 3H (71%). In the reactions without pentylamine B, 3G is strongly diminished compared to when pentylamine is present, meaning that pentylamine could well be a catalyst for the formation of 3G. [58] Finally, the DCL of the mixture of aldehyde 3 and four different amino derivatives (B,F,G,H) was studied under the same conditions (Scheme 5.6, Figure 5.9, and Table 5.8, Entry 3). Only 3B (15%) and 3G (3%) were detectable immediately after mixing while the hemiaminal species were also observed. At about 0.5 h, the compound distribution changed to 3B (28%), 3F (5%), 3G (54%), and 3H (13%). After this, 3B started decreasing in concentration and completely disappeared after 2.6 h while the concentrations of the other imines increased with time, giving 3F (10%), 3G (64%), and 3H (26%).

Interestingly, the concentration of 3G decreased slightly after 2.6 h whereas those of 3F and 3H slightly increased, indicating that the components in the mixture were still able to exchange with each other, giving 3F (16%), 3G (53%), and 3H (32%) at 22 h. After about 238 h, the concentration of 3G had decreased to 29% while those of 3F and 3H had increased to 32% and 39%. Scheme 5. 6 The DCL formed from the 5 components 3, B, F, G, H and its transformations with time. In summary, for the study of imine formation for 2-pyridyl aldehyde 3 and different amino derivatives (B, F, G, and H) in pure CD 3 OD at 25 o C, the most reactive amino compound was pentylamine B, and 3B was the kinetic product (kinetic selectivity). In contrast, the imines ultimately present in the DCL were 3F, 3G, and 3H, so all three could be classified as thermodynamic products (thermodynamic selectivity). 3G, in particular, was formed in higher %-composition than 3F and 3H at the beginning of the reaction (after 2 or 3 h) showing some kinetic selectivity to apply to its formation also. However, equilibrium had not been attained even after 10 days of reaction and further work is required to define the true equilibrium for this DCL.

Study of imine formation from salicylaldehyde (4)

Salicylaldehyde 4 has displayed remarkable imine formation and exchange properties in DCC studies. [5,[59][60][61][62][63] It can provide internal hydrogen bonding between the amine nitrogen and the hydroxyl group of the aldehyde that gives the resulting imine the ability to display dynamic covalent motion in DCC. [5] In the following the kinetic and thermodynamic selectivity of aldehyde 4 toward different amino derivatives (pentylamine B, O-benzylhydroxylamine F, benzhydrazide G, and phenylhydrazine H) is examined.

Initially, the individual reactions forming imines 4B, 4F, 4G, and 4H were monitored in pure CD 3 OD at 25 o C (Table 5.9). The rate constants for imine formation were estimated from the initial changes in the system and were in the order 4B > 4H > 4F > 4G, indicating that pentylamine B was more reactive than the alpha-substituted nucleophiles towards 4. Amongst the alpha nucleophiles, phenylhydrazine H, was the most reactive.

Table 5.9 The reaction time, %-composition and second order reaction rate constant for imine formation between salicylaldehyde 4 and several amino derivatives in CD 3 OD at 25 o C. The initial solution was equimolar (20 mM) in all the reactants. 1 H-NMR integration: ±5%. b ) Reaction time indicates the time when reactions were terminated. c ) Rate constants were calculated from a fit to a unidirectional second-order reaction.

Entry Product Product [%] a ) Time [h] b ) k [x 10 -3 M -1 s -1 ] c ) 1 4B 90
The competitive reaction between aldehyde 4 and the amines, B, G, H was followed at 25 o C in a mixture where the initial concentration of each reactant was 20 mM (Figure 5.10a and Table 5.10, Entry 1). Three imines were detected immediately after mixing, being 3B (44%), 3G (6%), and 3H (32%). The concentration of 3B then decreased as a function of time to reach 2% at equilibrium. In contrast, the concentrations of both 3G and 3H increased, being 3G (18%), 3H (81 (%) at equilibrium after 3 h. Thus, 3B was a kinetic product and 3G and 3H the thermodynamic products. The reaction of aldehyde 4 with amines F, G, H was followed similarly (Figure 5.10b and Table 5.10, Entry 2). 4F and 4H were detectable immediately after mixing at concentrations of 2% and 14%, respectively. Their concentrations at equilibrium (after 4 h) were 4F (18%) and 4H (81%).

In contrast, 4G barely formed, representing only 1% of the reaction mixture. Thus, the hydrazone 4H was clearly the dominant component of this DCL. B, F, G, andH) was also examined under the same conditions (Figure 5.11a and Scheme 5.7). All of the imine compounds were found to be present immediately after mixing with relative %compositions of 4B (42%), 4F (6%), 4G (4%), and 4H (23%). As the reaction progressed, 4B was gradually lost and replaced by the other imines in the mixture, being undetectable after 0.6 h. Compounds 4F, 4G, and 4H rose in concentration over time, attaining 4F (27%), 4G (16%), and 4H (58%), at 1.4 h respectively. After 3.5 h, 4G started to be lost, the concentrations then being 4F (29%), 4G (9%), and 4H (63%), and after 21h only 4H (65%) and 4F (35%) were detectable as products. Thus, the most favored compound for a) b)

kinetic selection is the imine 4B whereas for thermodynamic selection it is the hydrazone 4H. The same DCL was then monitored in pure CD 3 CN rather than CD 3 OD (Figure 5.11b), again at 25 o C. Only the imine 4B was detectable immediately upon mixing and after 1 h, it began to be slowly consumed at the expense of growth of the other three imines 4F, 4G, and 4H. Thus, similar DCL characteristics are observed in CD 3 CN as in CD 3 OD except that overall the reactions are slowed down dramatically. that this imine is the kinetic product. The most stable imines were 4F and 4H (the thermodynamic products). In contrast to the case of aldehyde 3, compound 4G did not form competitively in the presence of the four amino compounds (B, F, G, and H). This may mean that the intramolecular hydrogen bonding in 3G is stronger than in 4G.

The kinetic/thermodynamic selectivity of imine formation on aminoglycoside

An aminoglycoside is a molecule containing amino-modified sugars. These compounds are composed of an inositol moiety substituted with two amino or guanidino groups as well as with either sugars or amino sugars on the molecule, for instance, amikacin, arbekacin, gentamicin, kanamycin, neomycin, and streptomycin. They are used to treat infections caused by gram-negative bacteria and are also classified as bactericidal because of their interference with bacterial replication. All of the aminoglycoside antibiotics are highly toxic, requiring monitoring of blood serum levels at frequent

H O O NH 2 N H O NH 2 H N NH 2 NH 2 4 F G H B OH CD 3 OD, RT N H N N O N H N 4G (9%) 4B (29%) 4H (63%) 3.5 h O OH OH OH CD 3 OD, RT N H N N O N H N 4G (4%) 4F (6%) 4H (23%) after mixing O OH OH OH N 4B (42%) OH N O N H N 4F (35%) 4H (65%) OH OH CD 3 OD, RT
intervals and careful observation of the patient for signs of toxicity, particularly ototoxicity and nephrotoxicity.

Imine formation of the amino group of aminoglycosides has been reported in aqueous alcoholic media. [64] In 2012, Dikiy et al. reported imine formation from kanamycin A and pyridoxal 5'-phosphate as well as with other aldehydes in aqueous solution. [65] They found that imines were formed with an equimolar ratio of aldehydes with close to 100% yield at pH 7. They also defined the specific amino group at which imine formation occurred using 1 H-NMR spectroscopy. The DFT-GIAO B3LYP/6-31G (d) level was used to calculate the possible structure. They concluded that kanamycin A had the ability to form imine derivatives in high percent yields in an equimolar mixture with aldehydes.

In this investigation, the aminoglycoside neomycin was chosen as the substrate to study imine formation including its kinetic and thermodynamic selectivity. According to the structure of neomycin shown in Figure 5.12, there are six amino groups in one molecule indicating that there are six possible sites for imine formation. The aim of this work is to examine the possibility of forming imine bonds in aqueous solution with positional selectivity for neomycin in the presence of an aldehyde.

Conclusions

The results described constitute a wide-ranging investigation of the kinetic and thermodynamic selectivity of imine formation arising from the reaction of an aldehyde with an amine.

1) Formation in aqueous phosphate buffer solutions having pD values of 5.0, 8.5 and 11.4 of imines derived from sulfonate aldehyde 1 and amino derivatives B, C, D and E occurs such that the conversion efficiency is in the order 1C>1D>1E (1B was not formed) at pD 5.0, 1B>1E>1C (1D was not formed) at pD 8.5, and 1B>1E>1C>1D at pD 11.4.

Imine formation from pyridoxal phosphate 2 and the same amino derivatives separately was not sensitive to pD and the conversion efficiency was in the order 2C>2E>2D, 2B not being a significant component of any equilibrium mixture.

2) The DCLs formed by sulfonate aldehyde 1 and the four amino derivatives B, C, D, and E in buffers at three different pD values reflected the fact that the kinetic and thermodynamic products under all conditions were 1C and 1E, respectively. The DCLs for pyridoxal phosphate 2 and the same amino derivatives under the same conditions showed similar trends, with 2C and 2E the kinetic and thermodynamic products. The preferred compounds in an acidic medium were oximes 1C and 2C whereas in a basic solution they were hydrazones 1E and 2E.

3) Imine formation from 2-pyridyl aldehyde 3 and salicylaldehyde 4 with each of the amino derivatives B, F, G, and H in organic solvents showed that the product stability was in the order B > H > F > G.

4) The DCL for equimolar mixtures of 2-pyridyl aldehyde 3 or salicylaldehyde 4

with different amino derivatives (B, F, G, and H), showed that the kinetic product was always imine 3B or 4B while the thermodynamic products were 3Fand 3H or 4F, and 4H.

The knowledge gained here could be applied in future synthetic work, for instance, regioselective synthesis. It could also be applied to more complicated DCC systems involving amino derivatives, aldehydes, and imines.

Conclusions and Perspectives

Chapter 6

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Conclusions and Perspectives

This thesis has treated in detail dynamic covalent/combinatorial chemistry (DCC)

focusing on the generation of dynamic covalent libraries (DCLs) via reversible exchange reactions of several types of compounds such as imines, Knoevenagel compounds, and ammonium salts. It began in the first chapter with a general introduction of the concept of dynamic chemistry as well as the important features of imine and Knoevenagel chemistry.

The main focus of the second chapter was the using of organocatalysts in the Finally in the fifth chapter, the kinetic and thermodynamic selectivity of imine formation in DCC was described. In this investigation, two systems were chosen, sulfonate aldehyde and pyridoxal phosphate in aqueous solution at different pD (5.0, 8.5, 11.4), and 2-pyridy aldehyde and salicylaldehyde in organic solvents. The results showed that oxime and hydrazone were the kinetic and thermodynamic products in aqueous solution.

However, in organic solvent, the kinetic product was an imine derived from an aliphatic amine and the thermodynamic products were oxime and hydrazone.

Taken together the results of this thesis extend the fundamental knowledge of dynamic covalent chemistry, but they also clearly show its power to quickly generate molecular diversity. Furthermore, turning external parameters such as pH and catalyst completely modified the final composition of the molecular libraries, pointing the way to future adaptive and evolutive chemistry with great potential application in materials and biological sciences.

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CHAPTER 7

Experimental Part Deuterated solvents were purchased from Euriso-TOP and used without further purification except CDCl 3 , which was passed through a column of activated alumina (aluminium oxide 90 active basic). Anhydrous CH 2 Cl 2 was obtained by passage through columns of activated molecular sieves. Deionized water was obtained from a Millipore Elix 10 water purifier.

Instruments

Nuclear Magnetic Resonance (NMR)

1 H-NMR spectra were recorded with a Bruker Avance 400 MHz spectrometer and were referenced to the solvent. Chemical shifts are given in ppm. Residual solvent peaks were taken as reference (CHCl 3 : 7.24 ppm, DMSO: 2.50 ppm, CH 3 CN 1.94 ppm and CH 3 OH: 4.78 ppm). The coupling constants J are given in hertz. Peaks are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), doublet of doublet (dd), and multiplet (m). The assigned proton is written in italics. Unless otherwise noted, spectra were recorded at 25 o C.

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Mass Spectrometry

High-resolution Electrospray Ionization Mass spectrometry (HR-ESI-MS) was carried out using a Bruker Micro TOF mass spectrometer at the Service de Spectrometrie de Massse, Université de Strasbourg. The observed pattern was always confirmed to match the theoretical pattern. LC/MS was performed using reverse phase on a MSQ Plus mass spectrometer with Accela LC system from Thermo Fisher Scientific with a hypersil gold C8, 2 µm column.

Elemental Analysis

Elemental analysis was performed at the Service de Microanalyse, Universite de Strasbourg on a Flash 2000 from Thermo Fisher Scientific. Data are given in percentage and were measured with a "Vario EL III' from Elementar to analyze simultaneously the elementals C, H and N.

pH Measurement

All pH and pD measurements were recorded directly after calibration of the pHmeter in aqueous pH 4, pH 7, and pH 10 buffer (Fluka) on a Metler-Toledo Multi-Seven pHmeter using a Hamilton Spintrodemini-probe.

Melting points Measurement

Melting points were measured on a Büchi B-540 apparatus.

Microwave oven

The reactions were performed on a CEM Discovery microwave, with power up to 300 W, in a pressure vessel.

UV/Vis spectra

UV-Vis spectra were recorded on a JASCO dual beam spectrophotometer.

Column Chromatography

Column chromatography (CC) was performed using silica gel (Gedurun silica gel 60 (230 -400 mesh, 40-63 µm, Merck) on a classic glass column.

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Chapter 2, Organocatalysis of Exchange Processes between Knoevenagel and Imine

Compounds in Dynamic Covalent Chemistry

Synthesis Procedure and Characterization

Standard Procedure for the synthesis of imines and Knoevenagel compounds

General procedure for the synthesis of imines. Equimolar amounts of amine and aldehyde were dissolved in dry CH 2 Cl 2 and MgSO 4 was added. The mixture was stirred at r.t. for 24 h -5 days and the solid was filtered off. After drying or distillation in vacuum the products were isolated as colored oils or needles.

General procedure for the synthesis of Knoevenagel condensation products. To 30 mL anhydrous ethanol was added barbituric acid (3.0 mmol), the corresponding substituted benzaldehyde (3.0 mmol), and L-proline in a catalytic amount (10%). The solution was then refluxed for 3-4 hr. The Knoevenagel condensation products that precipitated out of the cooled solution were filtered and washed with diethyl ether.

Characterization Part

Imines compounds

1. (E)-2-((heptylimino)methyl)phenol (1a) [1] Yield: 2.08 g, 99%; yellow oil. [2] Yield: 1.93 g, 90%; yellow oil. (E)-1-phenyl-N-(pyridin-4-ylmethylene)methanamine (1n) [12] Yield: 1.87 g, 90%; yellow oil. 13. (E)-N-(pyridin-2-ylmethylene)cyclohexanamine (1o) [7] Yield: 1.80 g, 91%; orange oil. 1

(E)-1-phenyl-N-(thiophen-2-ylmethylene)methanamine (1b)

(E)-3-methyl-N-(pyridin-2-ylmethylene)butan-1-amine (1p)

Yield: 0.492 g, 93%; orange oil. 1 H-NMR (400 MHz, DMSOd 6 , 25 o C; δ/ppm): 0.97 (d, J = 6.5 Hz, 6 H), 1.63 (q, J = 7.2 Hz, 2 H), 1.71 (m, J = 6.7 Hz, 1 H), 3.71 (t, J = 7.3 Hz, 2 H), 7.32 (m, 1H), 7.75 (dt, J = 1.5, 7.7 Hz, 1 H), 8.00 (d, J = 7.9 Hz, 1 H), 8.40 (s, 1 H), 8.66 (d, J = 4.6 Hz, 1 H). 13 [13] Yield: 0.489 g, 85%; orange oil. 1 H-NMR (400 MHz, DMSOd 6 , 25 o C; δ/ppm): 0.99 (d, J = 6.6 Hz, 6 H), 1.62 (q, J = 7.1 Hz, 2 H), 1.76 (m, 1 H), 3.64 (t, J = 7.1 Hz, 2 H), 6.90 (t, J = 7.5 Hz, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 8.37 (s, 1 H), 13.73 (br s, 1 H). ESI-MS: m/z: 192.1 (100%). HRMS (ESI, m/z): calcd. for C 12 H 18 NO 192.138; found 192.139. 5-(4-chlorobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (2e) [19] Yield: 0.505 g, 67%; yellow solids. M.p.: 282°C, lit m.p. 280°C. [19] Yield: 0.580 g, 87%; brown yellow solids. M.p.: 275°C, lit m.p. 273°C.

(E)-2-((isopentylimino)methyl)phenol (1q)

2-(4-(dimethylamino)benzylidene

)malononitrile (3a) [21] Yield: 0.410 g, 70%. Orange solids. M.p. 177 -181°C, lit m.p. Ethyl 2-cyano-3-(4-methoxyphenyl)acrylate (3g) [27] Yield: 0.464 g, 67%. Yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 1.30 (t, J = 7.1 Hz, 3H); 3.87 (s, 3H); 4.30 (q, J = 7.0 Hz, 2H); 7.16 (d, J = 9.0 Hz, 2H); 8.09 (d, J = 9.0 Hz, 2H); 8.32 (s, 1H). 13 C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 13.9, 55.7, 62.0, 98.5, 114.9, 116.2, 123.9, 133.5, 154.4, 162.3, 163.5.

15.

Ethyl-2-cyano-3-(4-nitrophenyl)acrylate (3h) [27] Yield: 0.633 g, 85%. Yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 1.32 (t, J = 7.2 Hz, 3H); 4.35 (q, J = 7.0 Hz, 2H); 8.23 (d, J = 8.9 Hz, 2H), 8.41 (d, J = 8.9 Hz, 2H), 8.57 (s, 1H). 13 (1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)methylene)malononitrile (3i) [28] Yield: 0.49 g, 86%. Organge solid. 1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 1.71 (q, J = 5.6 Hz, 4H); 2.35 (m, 4H); 3.21 (t, J = 5.5 Hz, 4H), 7.26 (s, 2H), 7.61 (s, 1H). 13 C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 20.3, 26.9, 49.6, 65.7, 116.1, 116.9, 117.8, 120.7, 130.8, 148.6, 157.6.

Study of Imine/Imine (C=N/C=N) exchange

General procedure for C=N/C=N exchange. All reactions with 2 imines were carried out at r.t. with a final concentration of 19.35 mM and a total volume of 620 µL with 10 equiv. of BIS-TRIS to maintain a constant pH. For mixtures of 3 imines the final concentration was about 14.63 mM and the total volume 615 µL. All stock solutions of reactants and catalyst were 60 mM and had a total volume of 1 mL. The BIS-TRIS stock solution was 600 mM. as following (Eq. (7.1)) could, in principle, occur as a single, concerted process passing through a four-membered-ring transition state [29] and thus be considered as a reversible, second-order reaction.

A-B + C-D A-D + C-B (7.1)
This would be a thermally forbidden process by Woodward-Hoffmann rules and in fact there is no evidence that the reaction will occur at a significant rate in the absence of an acid or a nucleophilic catalyst (including water). Attempts to fit the present data to the equation for a reversible second-order reaction were unsuccessful (the Rorabacher equation [30] plot being far from linear) and, as seen in a study of a simpler catalyzed imine exchange reaction, [31] the data actually provided a good fit to a reversible first-order reaction. Given that the imine exchange reaction is at least formally bimolecular, the reason for the observation of reversible first-order behavior deserves a closer explanation.

For a true reversible first-order reaction:

[A] [B] (7.2)
The equilibrium constant for the reaction (K eq ) is:

K eq = [B] eq /[A] eq = k f /k r (7.3)
And rate law can be written as

R = -d[A]/dt = k f [A] t -k b [B] t (7.4)
Where

, B t = [A] 0 -[A] t , then R = d[A]/dt = k b ([A] 0 -[A] t ) -k f [A] t = k b [A] 0 -(k f + k b )[A] t (7.5) k f k b
224 | P a g e Thus, this equation connects two variables ([A] t and t) and their measurement followed by fitting to this equation enables determination of the rate constants. The direct relationship between [A] t and t is obtained by integration of the rate equation, which takes the form after separation of the variables of

[ ]/( [ ] - + [ ] ) = , (7.6)
which becomes

ln{(k f + k b )[A] t -k b [A] 0 )/k f [A] 0 } = -(k f + k b )t, or (7.7)
{(k f + k b )[A] t -k b [A] 0 )/k f [A] 0 } = when t = ∞, [A] t = [A]
eq and e -∞ = 0, thus, this equation give

(k f + k b )[A] eq = k b [A] 0 (7.8)
This is also clear directly from the equilibrium condition that the rates of the forward and backward reactions are equal, i.e.

k f [A] eq = k b [B] eq = k b ([A] 0 -[A] eq ), leading
to:

(k f + k b )[A] t -k b [A] 0 = {(k f + k b )[A] t -(k f + k b )[A] eq = ([A] t -[A] eq )(k f + k b ) (7.9)
And that

k f [A] 0 = ([A] 0 -[A] eq )(k f + k b ) so that, finally, ([A] t -[A] eq )/([A] 0 -[A] eq ) = (7.10)
Or equivalently

([ ] [ ] ) ([ ] [ ] ) = -( + ) (7.11)
Thus the quantity ln([A] t -[A] eq ) should be linear as a function of time and indeed that for any parameter X (such as the integral of an NMR peak) proportional to the concentration of A, that ln([X] t -[X] e ) should be a linear function of time (since the proportionality constant just adds another constant to the equation).

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In earlier studies of the imine exchange, [32,33] it was shown that the reaction is subject to catalysis by water, although not simply through hydrolysis of both reactant imines followed by reformation in the mixture of both reactant and product imines.

Instead, it has been shown that amine attack on imines is much faster than that on carbonyl compounds, so that exchange occurs principally through the attack of some initially released amine upon residual imine(s), as shown in Scheme 7.1. The rate determining step in these reactions was proposed to be proton transfer within the aminal intermediates.

According to the imine exchange reaction in 227 | P a g e This is simplified in that proton transfers involved in the addition and elimination steps are not separated from the actual addition and elimination processes (following Mandolini, [31] it would be assumed that the values of the overall rate constants would in fact be determined by the proton transfer rate constants) and also in that the direct reactions as following below are not included.

A N B C N D A N D C N B A N B +H 2 O -H 2 O H 2 N B A O C N D C N D NH 2 B -NH 2 -D(D) +NH 2 -D(D) C N B A-B C-D A-D C-B A-B 1 C-D 2 C-B A N D C-B C N B A-D (b) (c) (a)
A-B + D A-D + B (7.16)

C-D + B C-B + D (7.17)
This doesn't affect greatly the conclusions that can be drawn from analysis of the above scheme. A standard treatment of complex reaction schemes such as that of equation ( 1) -( 4) involves the use of the steady state approximation (SSA). This is based on the assumption that where reactive intermediates are involved, after a short initial period where their concentration rises, their concentration then stays effectively constant over the major period of the reaction. If the concentration of X as a function of time is constant, then of course dX/dt = 0. Note that this does not mean that the concentration must be very small, even though this appears to be true for all species other than A-B, C-D, A-D, and C-B in the imine exchange reaction.

Thus, applying the SSA to the reactive intermediate of equation (7.12) - (7.15) leads to constants. However, it isn't essential to go this far to understand the behavior of the present system. Taking the species A-B, for example, the rate of reaction with respect to it is given by

d[A-B-N]/dt = k 1 [A-B][N] + k 4 [A-N][B] -(k 2 + k 3 )[A-B-N] = 0 (7.18) d[C-D-N]/dt = k 5 [C-B][N] + k 8 [C-N][D] -(k 6 + k 7 )[C-DN] = 0 (7.19) d[A-D-N]/dt = k 9 [A-D][N] + k 12 [A-N][D] -(k 10 + k 11 )[A-D-N] = 0 (7.20) d[C-B-N]/dt = k 13 [C-B][N] + k 16 [C-N][B] -(k 14 + k 15 )[C-B-N] = 0 (7.21) d[B]/dt = k 3 [A-B-N] + k 15 [C-B-N] -(k 4 [A-N][B] + k 16 [C-N][B]) = 0 (7.22) d[D]/dt = k 7 [C-D-N] + k 11 [A-D-N] -(k 8 [C-N][D] + k 12 [A-N][D]) = 0 (7.23) d[A-N]/dt = k 3 [A-B-N] + k 11 [A-D-N] -(k 4 [A-N][B] + k 12 [A-N][D]) = 0 (7.24) d[C-N]/dt = k 7 [C-D-N] + k 15 [C-B-N] -(k 8 [C-N][D] + k 16 [C-N][B]) = 0 (7.25) d[N]/dt = k 2 [A-B-N] + k 6 [C-D-N] + k 10 [A-D-N] + k 14 [C-B-N] - (k 1 [A-B] + k 5 [C-D] + k 9 [A-D] + k 13 [C-B])[N] = 0 (7.
R A-B = d[A-B]/dt = k 2 [A-B-N] -k 1 [A-B][N] (7.27)
From application of the SSA to the rate of reaction of A-B-N (equation (7.18)) i.e. the differential equation for a reversible first-order reaction. Note, however, that the k obs obtained by fitting the time dependence of [A-B] is not then the sum of the forward and back rate constants for a single step.

[A-B-N] = (k 1 [A-B][N] + k 4 [A-N][B])/(k 2 + k 3 ) (7.28) So that R A-B = [A-N][B]k 2 k 4 /(k 2 + k 3 ) -[A-B][N]k 1 k 3 /(k 2 + k 3 ) (7.

Results of kinetic study of imine/imine derivatives exchange

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) (E)-N-(pyridin-4-ylmethylene)cyclohexanamine (1i).

In an NMR tube, compound 1h and 1i were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.53 ppm for 1h and 8.39 ppm for 1i) and the exchange products (8.56 ppm for 1j and 8.37 ppm for 1k) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) (E)-N-(pyridin-4-ylmethylene)cyclohexanamine (1i).

In an NMR tube, compound 1h and 1i were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.53 ppm for 1h and 8.39 ppm for 1i) and the exchange products (8.56 ppm for 1j and 8.37 ppm for 1k) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.2.

The imine/imine exchange reaction between (E)-2-(cyclohexylimino)methyl)phenol (1j) (E)-N-(pyridin-4-ylmethylene)propan-1-amine (1k).

In an NMR tube, compound 1j and 1k were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.56 ppm for 1j and 8.37 ppm for 1k) and the exchange products (8.53 ppm for 1h and 8.39 ppm for 1i) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in In an NMR tube, compound 1j and 1k were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.56 ppm for 1j and 8.37 ppm for 1k) and the exchange products (8.53 ppm for 1h and 8.39 ppm for 1i) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) ((E)-1-phenyl-N-(pyridin-2-ylmethylene)methanamine (1l).

In an NMR tube, compound 1h and 1l were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.53 ppm for 1h and 8.48 ppm for 1l) and the exchange products (8.70 ppm for 1c and 8.33 ppm for 1m) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) ((E)-1-phenyl-N-(pyridin-2-ylmethylene)methanamine (1l).

In an NMR tube, compound 1h and 1l were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.53 ppm for 1h and 8.48 ppm for 1l) and the exchange products (8.70 ppm for 1c and 8.33 ppm for 1m) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in In an NMR tube, compound 1c and 1m were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.70 ppm for 1c and 8.33 ppm for 1m) and the exchange products (8.53 ppm for 1h and 8.48 ppm for 1l) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) (E)-N-(pyridin-2-ylmethylene)propan-1-amine (1m).

In an NMR tube, compound 1c and 1m were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=N-protons of the starting materials (8.70 ppm for 1c and 8.33 ppm for 1m) and the exchange products (8.53 ppm for 1h and 8.48 ppm for 1l) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-4-((cyclohexylimino) methyl) pyridin-3ol (1i) (E)-1-phenyl-N-(pyridin-2-ylmethylene)methanamine (1l).

In an NMR tube, compound 1i and 1l were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.39 ppm for 1i and 8.50 ppm for 1l) and the exchange products (8.34 ppm for 1n and 8.54 ppm for 1o) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.9. In an NMR tube, compound 1i and 1l were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.39 ppm for 1i and 8.50 ppm for 1l) and the exchange products (8.34 ppm for 1n and 8.54 ppm for 1o) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-1-phenyl-N-(pyridin-4-ylmethy lene)methanamine (1n) (E)-N-(pyridin-2-ylmethylene)cyclohexanamine (1o).

In an NMR tube, compound 1n and 1o were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.34 ppm for 1n and 8.54 ppm for 1o) and the exchange products (8.39 ppm for 1i and 8.50 ppm for 1l) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-1-phenyl-N-(pyridin-4-ylmethy lene)methanamine (1n) (E)-N-(pyridin-2-ylmethylene)cyclohexanamine (1o).

In an NMR tube, compound 1n and 1o were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.34 ppm for 1n and 8.54 ppm for 1o) and the exchange products (8.39 ppm for 1i and 8.50 ppm for 1l) were followed. This reaction was not reached equilibrium; thus, the kinetic data were fit assuming an irreversible first-order reaction as shown in Figure 7.12. In an NMR tube, compound 1c and 1d were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10 mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.70 ppm for 1c and 8.42 ppm for 1d) and the exchange products (8.60 ppm for 1a and 8.53 ppm for 1b) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.13. Figure 7. 13 The plot of the kinetic study of the imine exchange between 1c and 1d in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) (E)-N-(thiophen-2-ylmethylene)octan-1-amine (1d).

In an NMR tube, compound 1c and 1d were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.70 ppm for 1c and 8.42 ppm for 1d) and the exchange products (8.60 ppm for 1a and 8.53 ppm for 1b) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1a) (E)-N-(thiophen-2-ylmethylene)octan-1-amine (1b).

In an NMR tube, compound 1a and 1b were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.60 ppm for 1a and 8.53 ppm for 1b) and the exchange products (8.70 ppm for 1c and 8.42 ppm for 1d) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in In an NMR tube, compound 1a and 1b were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10% of BIS-TRIS as a buffer solution. The 1 H-NMR of -CH=N-protons of the starting materials (8.60 ppm for 1a and 8.53 ppm for 1b) and the exchange products (8.70 ppm for 1c and 8.42 ppm for 1d) were followed and the reaction did not reach equilibrium. The kinetic data were fit assuming an irreversible firstorder reaction as shown in

The imine/imine exchange reaction between (E)-3-methyl-N-(pyridin-2-ylmethylene)butan-1-amine (1p) and (E)-2-((benzylimino)methyl)phenol (1c).

In an NMR tube, compound 1p and 1c were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.34 ppm for 1p and 8.70 ppm for 1c) and the exchange products (8.48 ppm for 1l and 8.55 ppm for 1q) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.17.

The imine/imine exchange reaction between (E)-3-methyl-N-(pyridin-2-ylmethylene)butan-1-amine (1p) and (E)-2-((benzylimino)methyl)phenol (1c).

In an NMR tube, compound 1p and 1c were mixed with a final concentration 19.35 mM and a total volumn of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.34 ppm for 1p and 8.70 ppm for 1c) and the exchange products (8.48 ppm for 1l and 8.55 ppm for 1q) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-3-methyl-N-(pyridin-2-yl methylene)butan-1-amine (1l) and (E)-2-((benzylimino)methyl)phenol (1q).

In an NMR tube, compound 1l and 1q were mixed with a final concentration 19.35 mM and a total volumn of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.48 ppm for 1l and 8.55 ppm for 1c) and the exchange products (8.34 ppm for 1p and 8.70 ppm for 1c) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.20

The imine/imine exchange reaction between (E)-3-methyl-N-(pyridin-2-yl methylene)butan-1-amine (1p) and (E)-N-(thiophen-2-ylmethylene)heptan-1-amine (1d).

In an NMR tube, compound 1p and 1d were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.34 ppm for 1p and 8.43 ppm for 1d) and the exchange products (8.32 ppm for 1r and 8.45 ppm for 1s) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in In an NMR tube, compound 1p and 1d were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.34 ppm for 1p and 8.43 ppm for 1d) and the exchange products (8.32 ppm for 1r and 8.45 ppm for 1s) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-N-(pyridin-2-ylmethylene)heptan-1amine (1r) and (E)-3-methyl-N-(thiophen-2-ylmethylene)butan-1-amine (1s).

In an NMR tube, compound 1r and 1s were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.32 ppm for 1r and 8.45 ppm for 1s) and the exchange products (8.34 ppm for 1r and 8.43 ppm for 1s) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-N-(pyridin-2-yl methylene)heptan-1amine (1r) and (E)-3-methyl-N-(thiophen-2-ylmethylene)butan-1-amine (1s).

In an NMR tube, compound 1r and 1s were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.32 ppm for 1r and 8.45 ppm for 1s) and the exchange products (8.34 ppm for 1r and 8.43 ppm for 1s) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) and (E)-1-phenyl-N-(pyridin-4-ylmethylene)methanamine (1n).

In an NMR tube, compound 1h and 1n were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.53 ppm for 1h and 8.51 ppm for 1n) and the exchange products (8.70 ppm for 1c and 8.37 ppm for 1k) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) and (E)-N-(pyridin-4-ylmethylene)propan-1-amine (1k).

In an NMR tube, compound 1c and 1k were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.70 ppm for 1c and 8.37 ppm for 1k) and the exchange products (8.53 ppm for 1h and 8.51 ppm for 1n) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) and (E)-N-(pyridin-4-ylmethylene)propan-1-amine (1k).

In an NMR tube, compound 1c and 1k were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.70 ppm for 1c and 8.37 ppm for 1k) and the exchange products (8.53 ppm for 1h and 8.51 ppm for 1n) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) and (E)-N-(pyridin-2-ylmethylene)cyclohexanamine (1o).

In an NMR tube, compound 1h and 1o were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.53 ppm for 1h and 8.35 ppm for 1o) and the exchange products (8.55 ppm for 1j and 8.33 ppm for 1m) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) and (E)-N-(pyridin-2-ylmethylene)cyclohexanamine (1o).

In an NMR tube, compound 1h and 1o were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of starting materials (8.53 ppm for 1h and 8.35 ppm for 1o) and exchange products (8.55 ppm for 1j and 8.33 ppm for 1m) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in

The imine/imine exchange reaction between 2-((cyclohexylimino)methyl)phenol (1j) and (E)-N-(pyridin-2-ylmethylene)propan-1-amine (1m).

In an NMR tube, compound 1j and 1m were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS. The 1 H-NMR of -CH=Nprotons of the starting materials (8.55 ppm for 1j and 8.33 ppm for 1m) and the exchange products (8.53 ppm for 1h and 8.35 ppm for 1o) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure 7.32.

Studying of Knoevenagel/Imine (C=C/C=N) derivatives exchange

General procedure for C=C/C=N exchange. Stock solutions (0.50 mL) of

Results of the study of Knoevenagel/Knoevenagel (C=C/C=N) derivatives exchange

The cross-exchange C=C/C=C reaction between 5-(4-(dimethylamino)benzylidene) pyrimidine-2,4,6(1H,3H,5H)-trione (2a) and 2-(4-nitrobenzylidene)malononitrile (3d)

Synthesis and Characterization

Synthesis of Knoevenagel compounds

General procedure for the synthesis of Knoevenagel condensation products. To 30 mL anhydrous ethanol was added barbituric acid (3.0 mmol), the corresponding substituted benzaldehyde (3.0 mmol), and L-proline in a catalytic amount (10%). The solution was then refluxed for 3-4 hr. The Knoevenagel condensation products that precipitated out of the cooled solution were filtered and washed with diethyl ether and dried under vacuum for 2-3 h.

Characterization of Knoevenagel compounds

1.5-(4-(dimethylamino)benzylidene)-1,3-dimethylpyrimidine-,4,6(1H,3H,5H)-trione (4a) [34,35] Yield: 0.78 g, 90%. Orange solids.

5-(4-methoxybenzylidene

)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4b) [35] Yield: 0.73 g, 88%. Yellow solids. 3. 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4c) [35] Yield: 0.398 g, 54%. Yellow solids. )-trione (4d) [36] Yield: 0.373 g, 45%. Yellow solid. [37] Yield: 0.65 g, 87%. Brown yellow solid. [37] Yield: 0.722 g, 74%. Yellow solid. 7. 1,3-diheptyl barbituric acid (VI) [38] N The solution was evaporated under pressure to obtain a yellow liquid (3.00 g, 79% yield). N-allyl-4-bromo-N,N-dimethylbenzenaminium bromide (1d-Br) [42] Prepared in 25% yield as a white solid analogous to the route described for 1c. M.p. 5. N-allyl-N,N-dimethylbenzenaminium iodide (1a-I) [42] To a stirred solution of dimethylaniline (0.38 mL, 3.0 mmol) was added allyl iodide (0.82 mL, 9.0 mmol), then the solution was stirred at 30 o C overnight. The color of the solution became yellow as the reaction went on. The solvent was evaporated and dried under vacuum for 3 hours to give a dark-brown solid (0.860 g, 99% yield). M.p. 87

N-allyl-N,N,4-trimethylbenzenaminium iodide (1b-I)

Prepared in 90% yield as an orange liquid by a route analogous to that described for 1e. M.p. not determined, liquid at room temperature. 7. N-allyl-N,N-diethylbenzenaminium bromide (1e-Br) [43] Diethylaniline (0.48 mL, 3.0 mmol) and allyl bromide (0.78 mL, 9.0 mmol) were combined and kept stirring at 50 o C for 48 hours. The white solid was precipitated then washed with diethyl ether. The product was dried under vacuum to obtain a white solid (0.702, 87% yield). M.p. 144 -146 o C.

N-allyl-N,N-dimethylbenzenaminium hexafluorophosphate (1a-PF 6 )

N-allyl-N,N-dimethylbenzenaminium bromide (1a) (0.072 g, 0.3 mmol) was dissolved in water (1 mL) and combined with a saturated solution of potassium hexafluorophophate in water. A white solid immediately precipitated. The compound was extracted with dichloromethane and dried with magnesium sulfate. The solvent was evaporated to afford a pink solid then recrystallized by dichloromethane/diethyl ether to afford 1i (0.08 g, 87 % yield). m.p. 88 -90 o . The compound was tested with silver nitrate (AgNO 3 ) demonstrating the absence of bromide ion. Prepared in 80% yield as a white solid by a route analogous to that described for 1i. 1 11. N,N,N-triethylprop-2-en-1-aminium bromide (3a-Br) [44,45] Prepared in 92% yield as a white hygroscopic solid by a route analogous to that described for 1a. Prepared in 73% yield as a yellow solid by a route analogous to that described for 1a. 1 H-NMR (CD 3 CN) δ ppm: 5.97 (m, 1H), 5.69 (d, J = 11.6 Hz, 1H), 5.66 (d, J = 4.6 Hz, 1H), 3.85 (d, J = 7.5 Hz, 2H), 3.27 (q, J = 7.24 Hz, 4H), 2.89 (s, 3H), 1.28 (tt, J = 1.5 Hz, 6H). 13 13. N-benzyl-N,N-dimethylprop-2-en-1-aminium bromide (3c-Br) [43] Prepared in 30% yield as a white hygroscopic solid by a route analogous to that described for 1a.

N,N-diethyl-N-(2-hydroxyethyl)

prop-2-en-1-aminium bromide (3d-Br) [46] Prepared in 72% yield as a white solid by a route analogous to that described for 1a. 15. 4-methoxy-N,N-dimethylaniline (4c) [47] A 50 mL round bottom flask equipped with a reflux condenser was charged with 4-methoxyaniline (1.51 g, 12.26 mmol), tetra-Nbutylammonium iodide (0.316 g, 0.856 mmol), potassium hydroxide (1.644 g, 29.2 mmol), benzene 14 mL, and water 2 mL. After 10 min, iodomethane (0.78 mL, 12.58 mmol) was added dropwise over 2 min and stirred at room temperature for 7 hours. Then, additional tetra-n-butylammonium iodide (0.156 g, 0.42 mmol), potassium hydroxide (0.726 g, 12.92 mmol) and iodomethane (0.14 mL) were added and stirred at room temperature for 11 hours. The organic layer was separated and washed with a 10 mL portion of water, saturated sodium carbonate and brine, and dried over anhydrous sodium sulfate. Filtration and solvent removal under vacuum gave a dark yellow oil. The crude product was purified by chromatography (silica gel) using 5% ethylacetate/pentane as an eluent to afford a yellow solid (0.953 g, 51% yield). 1 H-NMR (CDCl 3 )δ ppm: 6.92 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 3.82 (s, 3H), 2.92 (s, 6H). N-benzyl-N,N-dimethylbenzenaminium bromide (5a-Br) [48] Dimethylaniline (0.70 mL, 5.5 mmol) and benzylbromide (0.59 mL, 5.0 mmol) were combined in dry benzene and stirred at room temperature for 24 hr. A white solid precipitated in the solution. The compound was washed with diethylether and dried under vacuum for 4 hr to afford white solids (0.288 g, 20%). M.p. 17. N-benzyl-N,N,4-trimethylbenzenaminium bromide (5b-Br) [48] Prepared in 40% yield as a white solid by a route analogous to that described for 5a. M.p. 183 -184 o . 1 18. N-benzyl-4-methoxy-N,N-dimethylbenzenaminium bromide (5c-Br) [48] Prepared in 25% yield as a white solid by a route analogous to that described for 5a. M.p. 148 -149 o 1 H-NMR (CD 3 CN) δ ppm: 7.44 -7.56 (m, 3H), 7.34 (t, J = 8.4 Hz, 2H), 7.05 -7.08 (m, 4H), 4.87 (s, 2H), 3.85 (s, 3H), 3.50 (s, 6H).

19. 1-benzylpyridin-1-ium bromide (6a) [49] A solution of pyridine (0.4 mL, 5 mmol) and benzylbromide (0.59 mL, 5 mmol) in dry toluene (20 mL) was stirred at room temperature for 24 hr. After filtration, the solid was washed with diethyl ether to give 6a as a white solid (1.052, 84% yield). M.p. 66 -70 o 1 H-NMR (CD 3 CN) δ ppm: 8.91 (t, J = 5.5 Hz, 2H), 8.51 (t, J = 8.0 Hz, 1H), 8.03 (t, J = 6.8 Hz, 2H), 7.46 -7.51 (m, 5H), 5.82 (d, J = 3.0 Hz, 2H). [50] A solution of 4-picoline (0.68 mL, 7 mmol) and benzylbromide (0.83, 7 mmol) in acetonitrile (1 mL) was stirred at 45 o C for 3 hr. The precipitate formed was washed with diethyl ether and dried under vacuum to give 6b as a white crystal (1.665 g, 80%). M.p. 1-benzyl-4-(dimethylamino)pyridin-1-ium bromide (6c) [51] Prepared in 92% yield as a white solid by a route analogous to that described in the literature. M.p. 216 -217 o 1 H-NMR (CD 3 CN) δ ppm: 8.06 (d, J = 7.9 Hz, 2H), 7.40 -7.46 (m, 3H), 7.34 -7.37 (m, 2H), 6.85 (d, J = 8.0 Hz, 2H), 5.30 (s, 2H), 3.16 (s, 6H).

1-benzyl-4-methylpyridin-1-ium bromide (6b)

22. 1-benzyl-4-(tert-butyl)pyridin-1-ium bromide (6d) [51] Prepared in 73% yield as a white solid by a route analogous to that described for 6c. M.p. 163 o 1 H-NMR (CD 3 CN) δ ppm: 8.87 (d, J = 6.5 Hz, 2H), 8.01 (d, J = 6.7 Hz, 2H), 7.43 -7.53 (m, 5H), 5.78 (s, 2H), 1.37 (s, 9H).

23. 1-allylpyridin-1-ium bromide (6e) [52] A solution of pyridine (0.81, 10 mmol) and allylbromide (1.1 mL, 10 mmol) in acetonitrile (10 mL) was stirred at 50 o C overnight. The crude product was concentrated and dried under vacuum to obtain a light brown solid (1.8902 g, 95% yield). M.p. 92 -94 o 1 H-NMR (CD 3 CN) δ ppm: 8.89 (d, J = 6.3 Hz, 2H), 8.54 (t, J = 8.1 Hz, 1H), 8.06 (t, J = 6.8 Hz, 2H), 6.09 -6.20 (m, 1H), 5.52 (d, J = 14 Hz, 2H), 5.28 (d, J = 6.6 Hz, 2H).

24. 1-allyl-4-methylpyridin-1-ium bromide (6f) [53] Prepared in 96% yield as a brown solid by a route analogous to that described for 6e. M.p. 76 -78 o 1 H-NMR (CD 3 CN) δ ppm: 8.78 (d, J = 6.5 Hz, 2H), 7.86 (d, J = 6.2 Hz, 2H), 6.08 -6.18 (m, 1H), 5.48 (d, J = 13.8 Hz, 2H), 5.24 (d, J = 6.5 Hz, 2H), 2.63 (s, 3H).

Kinetic Study for Ammonium salt exchange with tertiary amines

General Procedure for ammonium salt and tertiary amine exchange. Stock solutions (0.5 ml) of ammonium salt (60 mM or 180 mM), tertiary amine (60 mM or 180 mM), tetraethylammonium iodide (TEAI) 60 mM, and tetrabutylammonium iodide (TBAI) stock solution (180 mM) were prepared in the desired solvent. For the uncatalyzed reaction, 200 µL of each solution was added to a NMR tube followed by 200 µL of solvent to adjust to a final volume of 600 µL. For the catalyzed reaction, 200 µL of iodide stock solution was added to a NMR tube, followed by the addition of 200 µL of each solution. The stock solution of 60 mM was used to make the final solution of 20 mM. The stock solution of 180 mM was used to make the final solution of 60 mM.

General Procedure for N-benzyl-N,N-dimethylanilinium salts and tertiary amine exchange. Stock solutions (0.5 ml) of N-benzyl-N,N-dimethylanilinium salts (60 mM), tertiary amine (60 mM) and tetrabutylammonium iodide (60 mM) in CD 3 CN were prepared. Then, 200 µL of each stock solution was added to a NMR tube to a final volumn 600 µL. The final solution was 20 mM in each component.

General procedure for pyridinium salt and derivative of pyridine exchange using microwave irradiation. Stock solutions (500 µL) of pyridinium salt (40 mM) and tertiary amine or the derivative of pyridine (40 mM) in CD 3 CN were prepared. Then, 400 µL of each stock solution was added to a microwave tube to a final volume of 800 µL.

General Procedure for kinetic measurement of exchange reaction between ammonium salts and tertiary amine.

The concentrations of each component were determined by integration of the Nallyl-N,N-dimethylanilinium salts CH 2 =CH 2 -Ph, N-benzyl-N,N-dimethylanilinium salts -CH 2 -Ph, tertiary amine -N(CH 3 ) 2 , allyl bromide CH 2 =CH 2 -Br, and benzyl bromide Br-CH 2 -Ph 1 H-NMR signals respectively as a function of time. The reaction rate constants were calculated from plots of reactant concentration versus time during the first 10% of the reaction, where [A] 0 = [B] 0 . [54] It was found that [A] and [B] reacted with 1:1 stoichiometry over this time scale. The plot of 1/[A] (or 1/[B]) vs t was linear. This is consistent with an overall second order reaction at early time, first order in [A] and [B], respectively. The half-lives (t 1/2 ) of the reactions were determined by integration of the decreasing 1 H-NMR signals of the starting material as a function of time and taken to be the time at which the starting material was reduced to 50% with respect to the equilibrium value. The equilibrium constants are obtained from the amounts of reactants and products according to equation (7.20).

K = [C][D]/[A][B]

(7.20) Next, the reaction of 1a-PF 6 and 2a (Scheme 7.2) was examined in the presence of 10mol% TBAF, giving 1a-PF 6 (48%), 2a (45%), 3a-PF 6 (2%), 4a (3%), c 1 (2%) at 21 hr.

The reaction between 1a-PF 6 and 2c was also performed in presence of 10mol% TBAF (Figure 7.66), the same results were obtained, indicating that no allyl fluoride was formed.

Scheme 7.2

The exchange reaction between 1a-PF 6 and 2a in CD 3 CN at 60 o C in the presence of 10mol% TBAF.

The reaction of 1a-PF 6 + 2c + 2a (Scheme 7.3) was performed, giving 1a-PF 6 (25%), 2c (30%), 2a (27%), 3c-PF 6 (7%), 3a-PF 6 (2%), 4a (7%), c (3%) at 23 hr.

Scheme 7.3

The exchange reaction between 1a-PF 6 , 2a, and 2c in CD 3 CN at 60 o C.

The reaction of 1a-PF 6 + 2c + 2a (Scheme 7.4) was performed in the presence of 10mol% TBAF, giving 1a-PF 6 (26%), 2c (32%), 2a (25%), 3c-PF 6 (5%), 3a-PF 6 (1%), 4a (9%), c 1 (2%) at 21 hr. A sodium 5-formyl-2-methoxybenzenesulfonate (0.280 g, 1.18 mmol) was dissolved in methanol (20 mL) and followed by adding pentylamine (0.15 mL, 1.30 mmol). The solution was stirred at 50 o C for 48 hr. Then, the solvent was removed by evaporator and the product washed with diethyl ether to afford 1A as a white solid (0.30 g, 81% yield). 1 H-NMR (D 2 O) δ ppm: 8.20 (s, 1H), 8.14 (d, J = 2.6 Hz, 1H), 7.78 (dd, J = 2.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.50 (t, J = 7.3 Hz, 2H), 1.61 (q, J = 7.3 Hz, 2H), 1.29 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H).

Sodium (E)-2-methoxy-5-((methoxyimino)methyl)benzenesulfonate (1C)

A sodium 5-formyl-2-methoxybenzenesulfonate (0.217 g, 1.00 mmol) and O-methoxylamine (0.092, 1.10 mmol) were dissolved in methanol (20 mL) then phosphate buffer pH 11 (2 mL) was added. The solution was stirred at 50 o C for 24 hr. Then, the solvent was removed by evaporator. The product was extracted with ethanol and the solvent removed again. The compound was washed with diethyl ether to obtain 1C as a white solid (0.23 g, 86% yield).

Sodium (E)-2-methoxy-5-((2-methylhydrazono)methyl)benzenesulfonate (1E)

A sodium 5-formyl-2-methoxybenzenesulfonate (1.191 g, 5.00 mmol) was dissolved in phosphate buffer pH 8.0 (20 mL). Then, methylhydrazine (0.29 mL, 5.50 mmol) was slowly dropped into the solution followed by stirring at 50 o C overnight. The solvent was removed by evaporator and the product extracted with methanol. The methanol was removed then the compound was washed with diethyl ether to give a white solid (0.9182, 69% yield). 306 | P a g e 4. Pentyl-pyridin-2-ylmethylene-amine (3B) [55] Prepared in 95% yield as a pale yellow liquid by a route analogous to that described for imine synthesis in Chapter 2. C-NMR (100 MHz, CD 3 OD; δ/ppm): 14.5, 23.6, 30.7, 31.5, 62.4, 122.8, 126.7, 138.8, 150.4, 155.3, 163.2. [56] Pyridine (0.89 mL, 11.00 mmol, 1.1 equiv.) was added dropwise to a stirred solution of O-benzylhydroxylamine hydrochloride (1.996 g, 13.00 mmol, 1.3 equiv.) and 2-pyridine carboxaldehyde (1.07, 10.00 mmol, 1.0 equiv.) in methanol 40 mL and the mixture was heated at reflux for 4 h. The solvent was removed under reduced pressure, and the remaining solid residue was dissolved in dichloromethane (200 mL) and washed with water (200 mL). The aqueous layer was extracted with dichloromethane (200 mL x 3) and the combined organic layers were dried over MgSO 4 . The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to obtain a yellow liquid (1.50 g, 71% yield). 1 H-NMR (CD 3 OD) δ ppm: 8.48 (d, J = 5 Hz, 1H), 8.11 (s, 1H), 7.79 (t, J = 6.8 Hz, 2H), 7.21 -7.37 (m, 6H), 5.18 (s, 2H). [57] Benzhydrazide (0.408 g, 3 mmol) was dissolved in methanol (10 mL) then a solution of 2-pyridine carboxaldehyde (0.29 mL, 3.00) in methanol (10 mL) was added drop wise to the solution. The mixture was refluxed for 2 h. Then, the solution was evaporated on a steam bath and cooled to room temperature to obtain a white solid (0.33 g, 49% yield). (E)-2-((2-phenylhydrazono)methyl)pyridine (3H) [58] Phenylhydrazine (1.08 mL, 11.00 mmol) was dissolved in methanol (10 mL) and then a solution of 2-pyridyl aldehyde (0.95 mL, 10.00 mmol) in methanol (10 mL) was added dropwise. The product precipitated after a short time and was left standing for 2 h. Then, the product was washed with methanol and dried under vacuum to afford a white solid (0.753, 37% yield). [59] Prepared in 90% yield as a yellow liquid by a route analogous to that described for imine synthesis in Chapter 2. 1 H-NMR (CD 3 OD) δ ppm: 0.85 (t, J = 7.4 Hz, 1H), 1.29 -1.34 (m, 4H), 1.63 (quint, J = 7.2 Hz, 2H), 3.53 (t, J = 6.98, 2H), 6.68 -6.74 (m, 2.17), 7.18 -7.23 (m, 2H), 8.33 (s, 1H). 13 C-NMR (100 MHz, CD 3 OD; δ/ppm): 14.5, 23.6, 30.5, 31.7, 58.8, 118.8, 118.9, 119.7, 133.1, 134.3, 165.7, 166.9. [60] O-benzylhydroxylamine hydrochloride (0.479 g, 3.00 mmol) was dissolved in methanol then salicylaldehyde (0.32 mL, 3.00 mmol) was added dropwise to the solution. The mixture was refluxed overnight and then the solvent was removed to obtain a white solid (0.45 g, 66% yield). 1 H-NMR (CD 3 OD) δ ppm: 8.27 (s, 1H), 7.23 -7.35 (m, 6H), 7.17 (t, J = 8.1 Hz, 1H), 6.79 (t, J = 6.5 Hz, 2H), 5.09 (s, 2H). C-NMR (100 MHz, CD 3 OD; δ/ppm): 77.7, 117.4, 118.3, 120.8, 129.3, 129.6, 129.7, 131.3, 132.4, 138.7, 152.2, 158.5. [61] Benzhydrazide (0.408 g, 3.00 mmol) was dissolved in methanol then salicylaldehyde (0.32 mL, 3.00 mmol) was added dropwise to the solution. The mixture was refluxed overnight and then the solvent was removed and the product washed with hexane to obtain a white solid (0.67 g, 73% yield). 1 H-NMR (CD 3 OD) δ ppm: 8.44 (s, 1H), 7.86 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.85 (t, J = 8.4 Hz, 2H). 13 C-NMR (100 MHz, CD 3 OD; δ/ppm): 117.8, 119.6, 120.7, 128.9, 129.9, 131.9, 133.0, 133.6, 134.1, 152.0, 159.6, 166.5. [62] Phenylhydrazine (0.295, 3.00 mmol) was dissolved in methanol then salicylaldehyde (0.32 mL, 3.00 mmol) was added dropwise to the solution. The mixture was refluxed for 4 h then solvent was evaporated to an oily residue that crystallized upon cooling. The residue was dissolved in hot hexane to get a white solid (0.563 g, 88% yield). 1 H-NMR (DMSO-d 6 ) δ ppm: 10.52 (s, 1H), 10.39 (s, 1H), 8.14 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.7 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.5 Hz, 2H), 6.87 (t, J = 9.0 Hz, 2H), 6.77 (t, J = 7.5 Hz, 1H). 13

(E)-picolinaldehyde O-benzyl oxime (3F)

(E)-N'-(pyridin-2-ylmethylene)benzohydrazide (3G)

(E)-N-(pyridin-2-ylmethylene)pentan-1-amine (4B)

(E)-picolinaldehyde O-benzyl oxime (4F)

(E)-N'-(pyridin-2-ylmethylene)benzohydrazide (4G)

General procedures for the study of kinetic and thermodynamic experiments

A typical protocol was realized by the preparation in a NMR tube of a fresh solution of the compounds in D 2 O, DMSO-d 6 , CD 3 OD, CD 3 CN, and sodium phosphate buffer solution. All reactions with aldehyde and amine were carried out at room temperature with a final concentration of 20 mM and a total volume of 600 µL.

The buffer concentration was 160 mM in all cases and buffer solution at different pDs were made to pD 5.0 (NaH 2 PO 4 /Na 2 HPO 4 + NaOD), pD 8.5 (NaH 2 PO 4 / Na 2 HPO 4 + NaOD), and pD 11.4 (NaH 2 PO 4 /Na 2 HPO 4 + NaOD). The pD was calculated using pD = pH + 0.4. [63] 1) For the imine formation study: A NMR tube was first charged with solvent.

Then, the prepared solutions 200 µL of aldehyde and amine (60 mM in both) were added to the NMR tube to obtain a final volume of 600 µL. The NMR tubes were topped with Teflon caps to keep a constant volume (concentration). 1 H-NMR spectra were measured immediately after mixing.

2) For the competition reactions: The stock solutions (120 mM) were prepared using the desired solvents. A NMR tube was first charged with 1,4-dioxane (100 µL) followed by the addition of 100 µL of each solution. Finally, aldehyde was added and 1 H-NMR spectra were measured immediately after mixing and at least 8 acquisitions of the 1 H-NMR spectra were obtained for each time point.

The course of imine formation was followed by the appearance of a signal due to the -CH=N-of the imine products in the 1 H-NMR spectra. The %-formation of imine was determined by integration of the imine products signal referenced to the signal of an internal standard (1,4-dioxane). The time required for equilibration depended on the starting compound and varied with different conditions. The error in 1 H-NMR integration is about 4-5%.

Sodium (E)-5-((2-acetylhydrazono)methyl)-2-methoxybenzenesulfonate formation

(E)-2-hydroxybenzaldehyde O-benzyl oxime formation

(E)-2-((2-phenylhydrazono)methyl)phenol formation

1 Chapter 6

 16 Dynamic Covalent Chemistry………………...……………… 3.1 Introduction……………………………………………………………... 3.2 Results and Discussion……………………………………………….... 3.2.1 Benzylidene-(dm)barbiturates/imine, C=C/C=N, exchange Processes………………………………………………………….. 3.2.2 Theoretical Study of the Metathesis-like Mechanism of the Cross Exchange between a Knoevenagel-Type Substrate (C=C) and an Imine (C=N)……………………………………………………… 3.2.3 Organogel selection based on the exchange reaction of C=C/C=N……………………………………………………….… 3.3 Conclusions ………………………………………….............................. 3.4 References…………………………………………………………….… Chapter 4 Dynamic Covalent Chemistry of Nucleophilic Substitution Component Exchange of Quaternary Ammonium Salts ………………………………….………. 4.1 Introduction ………………………………………................................. 4.2 Results and Discussion……………………………………………......... 4.2.1 Study of exchange processes between quaternary allylammonium salts and tertiary amines via S N 2 or S N 2' type nucleophilic substitution………………………………………….. 4.2.2 Study of exchange processes between quaternary benzyl-ammonium salts and tertiary amines via S N 2 type nucleophilic substitution………………………………………….. 4.2.3 Study of exchange processes between N-allyland N-benzyl-pyridinium salts and pyridine components via S N 2 and S N 2' nucleophilic substitution processes…………………….. 4.2.4 Generation of libraries of Dynamic Ionic Liquids (DILs)………... The study of imines formation in aqueous solution of sodium 5-formyl-2-methoxybenzene sulfonate (1) and pyridoxal phosphate (2) toward different amino derivatives (A, B, C, D, and E)………………………………………………... 5.2.1.1 The study of imine formation from sulfonate aldehyde (1) 5.2.1.2 The study of imines formation from Pyridoxal phosphate (2)………………………………… 5.2.2 Imine formation from 2-pyridyl aldehyde (3) and salicylaldehyde (4) and various amino derivatives (B, F, G, and H) in organic solvents…………………………………………………………... 5.2.2.1 Imine formation from 2-pyridyl aldehyde (3)…………… 5.2.2.2 Imine formation from salicylaldehyde (4)……………… 5.2.3 The kinetic/thermodynamic selectivity of imine formation on aminoglycoside…………………………………………………Conclusions and Perspective……………………………………………............... Chapter 7 Experimental Part………………………………………………………………… 7.1 General Methods and Materials………………………………………………..7.1.1 Reagents…………………………………………………………………..

7. 1 .2 Instruments………………………………………………………………. 7 . 2 2 ,

 1722 Chapter Organocatalysis of exchange processes between knoevenagel and imine compounds in dynamic covalent chemistry……………………………………………………………………….. 7.2.1 Synthesis procedure and characterization……………………..………… 7.2.2 Study of Imine/Imine (C=N/C=N) derivatives exchange…………..…… 7.2.3 Study of Knoevenagel/Imine (C=C/C=N) derivatives exchange……….. 7.2.4 Study of Knoevenagel/Knoevenagel (C=C/C=C) derivatives exchange………………………………………………..…….

Figure 1

 1 Figure 1 Structures des différentes imines utilisées dans les échanges imine/imine (C=N/C=N) et les échanges imine/Knoevenagel (C=N/C=C) Dans cette étude, les réactions en présence de L-proline protégée en N-Boc, de L-proline t-butyle ester, de L-proline et d'acide benzoïque ont été comparées dans les mêmes conditions en présence et en absence de catalyseurs. Seule la L-proline a prouvé être un catalyseur largement utilisé permettant d'atteindre des équilibres. Les facteurs cruciaux pour l'échange rapide imine/imine ont été déterminés comme étant la structure des imines, le solvant et le catalyseur. Les imines qui s'échangent sont celles dérivées des amines aliphatiques nucléophiles et des aldéhydes héteroaromatiques électrophiles (les 2-pyridyle, 4-pyridyle, et 2-thiophényle-carboxaldéhyde) ainsi que le salicylaldéhyde (Figure 1, 1a-d, h-s). Les quantités optimales de catalyseur, de solvant et de température sont 10mol% de L-proline, dans le DMSO-d 6 /D 2 O 99/1 et à température ambiante. De plus, 10 equiv. de BIS-TRIS ont été ajoutés pour éviter les contributions des catalyseurs acides.Un certain nombre de bibliothèques d'imines [2x2] a été exploré (Table1). Pour

  = réaction d'échange, A-D: substituants des imines étudiées. b ) f = réaction aller; r = réaction retour. c ) k b = constante de vitesse de la réaction de contrôle [10 -3 s -1 ]. d ) k c = constante de vitesse de la réaction catalysée [10 -3 s -1 ]. e ) K b = constante d'équilibre de la réaction de contrôle = k b (aller)/k b (retour). f ) K c = constante d'équilibre de la réaction catalysée= k c (aller)/k c (retour). g ) Acc. = Accélération = k c /k b ; h ) La réaction n'a pas atteint l'équilibre. i ) La constante de vitesse est calculée a partir des premiers 10% de la réaction. j ) n.d. = non déterminé. Erreur sur l'intégration du signal 1 H-RMN, ∼4-5%. Les études sur les échanges imine/imine ont été étendues à des bibliothèques dynamiques [3x3] (Figure 2), catalysées par 10 mol% de L-proline dans DMSO-d 6 /D 2 O 99/1 et à température ambiante. Les résultats ont été comparés avec la bibliothèque de constituants [2x2]. Cette plus grande bibliothèque atteint l'équilibre à approximativement la même vitesse que la plus rapide des trois petites bibliothèques.

Figure 2

 2 Figure 2 Echange d'imines sélectionnées dans une bibliothèque d'imines [3x3] -Application de l'organocatalyse à de plus grande bibliothèque pour augmenter la diversité.

Figure 3

 3 Figure 3 Le mécanisme proposé pour l'organocatalyse de l'échange C=N/C=N.

Figure 4

 4 Figure 4 Le mécanisme possible de l'échange entre un substrat de type Knoevenagel (C=C) et une imine (C=N) suivant des étapes séquentielles d'addition/élimination.

  de demi-vie (t 1/2 ), (-) = réaction trop lente pour déterminer le paramètre, n.a. = non applicable. Proportions [%] des différents composés dans la réaction d'échange C=C/C=C entre barbiturate de benzylidène et benzylidène malononitrile dans le DMSO-d 6 à 60 o C. a = 4-diméthylaminobenzaldéhyde, d = 4-méthoxybenzaldéhyde, e = 2thiophène-carboxaldéhyde, f = 4-(diméthylamino)benzaldéhyde hydraté, i = 4-méthoxybenzal déhyde hydraté, j = thiophène-2-carboxaldéhyde hydraté, B = barbiturique, M = malononitrile, et XI, XII = adduits de type Michael.

  , réaction de contrôle, et c, réaction catalysée avec 10 mol% de L-proline comme catalyseur. b ) Composé non observé. c ) Seulement traces de produits détectés. d ) La réaction au départ. e ) Le temps de réaction indique le temps quand aucun changement supplémentaire n'est observé. f ) La réaction n'a pas atteint l'équilibre. Toutes les mesures ont été répétées trois fois. La reproductibilité des valeurs obtenues est de ±2%

Figure 5

 5 Figure 5 Mécanisme possible de la réaction d'échange entre les composés Knoevenagel suivant des étapes séquentielles d'hydrolyse/condensation.

  CDCl 3 à température ambiante. a = 4-diméthylamino benzaldéhyde, b = benzaldéhyde, c = 4-nitrobenzaldéhyde, d = 4-méthoxybenzaldéhyde, et e = 2thiophène-carboxaldéhyde. a ) f, Réaction aller. b ) r, Réaction retour. c ) Seulement traces de produits détectés. d ) Composé non observé. e ) Le temps de réaction indique le temps quand aucun changement supplémentaire n'est observé (<1-2%). Toutes les mesures ont été répétées 4-5 fois et moyennées. (Déviation standard <2%).

5 solvantFigure 6

 56 Figure 6 a) Représentation des composés l'étude de gel. b) La capacité de acétonitrile (2), décanol (3), méthanol (4) et c

4 5

 4 siècle, la première préparation d'un sel d'ammonium chiral Me(Et)N + (All)PhI réalisée par Wedekind, montrant une racémisation spontanée par une dissociation réversible en une amine rapidement inversée et un halogénure d'allyle racémisation dépend du type d'anion: I > Br > Cl. De plus, Havinga décrit en 1954 une procédure pour réaliser la résolution de ce sel et pour confirmer ses propriétés chiroptiques. stal est connue. Récemment, les sels d'ammonium chiraux ont été fréquemment utilisés comme catalyseurs dans la synthèse asymétrique, comme liquides ioniques, et dans l'ingénierie des cristaux. De plus, la réaction du sel de avec un carbanion nucléophile, et la réversibilité de la réaction nucléophile entre le bromure de benzyle et la N,N-diméthylaniline ont été étudiées substitution nucléophile entre la pyridine et les dérivés du bromure de benzy pyridinium (réaction de Menschutkin) a été examinée en solution et . Les sels de pyridinium peuvent être obtenus facilement, sont utilisés comme précurseurs versatiles dans la synthèse d'hétérocycles contenant de l'azote, utilisés dans à former des gels ou non dans les solvants éthanol (1), L'étude de la sélection de gel par l'échange C=C/C=N a été réalisée et il a été CN/EtOH 9/1 à une pour former le gel, et pas de Les résultats décrits ici montrent la création de BCDs de insi la génération par CCD de récepteurs, de de matériaux fonctionnels et de biomatériaux de plus en plus s de sels d'ammonium quaternaires par substitution nucléophile bimoléculaire dans une CCD. Il y a plus d'un (All)PhI -. CHCl 3 a été par une dissociation réversible en une amine rapidement inversée et un halogénure d'allyle. La vitesse de : I > Br > Cl. De plus, Havinga décrit en 1954 une r ses propriétés chiroptiques. stal est connue. Récemment, les sels d'ammonium chiraux ont été dans la synthèse asymétrique, comme liquides éaction du sel de N-benzyl-N,Net la réversibilité de la réaction ont été étudiées. La benzyle pour former a été examinée en solution et être obtenus facilement, sont ocycles contenant de l'azote, 3 sont exploités de multiples façons dans la synthèse totale de produits naturels et sont utilisés dans l'addition asymétrique et régiosélective. Dans ce chapitre, les principes de la CCD sont utilisés dans les échanges réversibles de composants de sels d'ammonium bimoléculaires pour générer des BCDs. Plus précisément, les réactions d'échange sont basées sur des sels d'allyle d'ammonium quaternaires permettant des réactions de substitutions nucléophiles avec les anions composant la paire d'ion pour donner une amine tertiaire et un halogénure d'allyle. Le mécanisme peut être décrit comme un passage direct S N 2/S N 2' ou indirect S N 2/S N 2'(Figure7).

Figure 7

 7 Figure 7 Les chemins possibles pour l'échange de groupe amine entre le bromure de Nallyl-N,N-diméthylanilinium et une amine tertiaire aliphatique ou aromatique via un mécanisme S N 2'.

Figure 8

 8 Figure 8 Représentation des réactions d'échange entre a) les sels d'allyle d'ammonium quaternaires et des dérivées d'amines tertiaires dans CD 3 CN à 60 o C. b) les sels de pyridinium et les dérivées de pyridine dans CD 3 CN en utilisant l'irradiation du four à micro-ondes (MW) à 300 W à 150 o C.

  ) f b , Réaction aller en absence de catalyseur; f c , Réaction retour en présence de TBAI (60 mM.) comme catalyseur; r b , Réaction retour en absence de catalyseur; r c , Réaction retour en présence de TBAI (60 mM) comme catalyseur. b ) Erreur sur l'intégration des signaux 1 H-RMN: ±4%. C ) K b , Constantes d'équilibre de la réaction non catalysée. d ) K c , Constantes d'équilibre de la réaction catalysée. e ) n.a., non applicable. f ) Composé non observé. Pour développer davantage les BCDs de substitutions nucléophiles (de types S N 2 et S N 2'), les réactions d'échange entre les sels de pyridinium et les dérivées de pyridine ont été étudiées par irradiation dans le four à micro-ondes à 150 o C (300 W) dans CD 3 CN, comme expliqué dans la Figure 8b. Toutes les réactions sont réversibles et sous contrôle thermodynamique. Les constantes d'équilibre des substitutions nucléophiles des sels de pyridinium ont été calculées (Table

  décrit la sélectivité cinétique et thermodynamique de la formation d'imines dans la CCD. Un pré-requis critique pour la génération de la CCD est l'opération d'un ou plusieurs procédés réversibles. En plus de ces transformations, la formation d'imines par condensation de groupes carbonyles avec des amines est d'intérêt considérable pour des applications chimiques et biologiques. En outre, la réactivité des amines utilisées (tels que les amines primaires, les composants oxyamine et les dérivées d'hydrazine) dans leur condensation avec un aldéhyde a été évaluée. Il est déjà connu que les composés possédant soit des groupes hydrazine soit des groupes oxyamine sont de meilleurs nucléophiles que les amines à cause de l'effet alpha et de leur faible basicité permettant de former des produits imines plus stables. Ainsi, le degré de formation d'imines entre différents aldéhydes et amines (composants amine primaire, hydrazine, hydrazide et oxyamine) dans deux systèmes, en solution (Figure 8, aldéhydes 1-2, amines B-E) ou en solvant organique (Figure 8, aldéhydes 3-4, amines B, F-H) a été étudié. En outre, les réactions de compétition (pour générer une BCD) pour former différentes imines à partir de différentes amines dans un unique système ont été explorées dans le but de définir la réactivité des amines et la stabilité des constituants imine dans les solutions aqueuses et dans les solvants organiques.

Figure 9

 9 Figure 9 Représentation des structures des aldéhydes (1-4) et des différentes amines (A-H) utilisés dans la formation d'imines dans cette étude.

Figure 10 Figure 11

 1011 Figure 10 La distribution des différentes imines mélange du sulfonate d'aldéhyde 160 mM NaH 2 PO 4 /Na 2 HPO 4 soit atteint. Les quantités de composés ont été ca signaux 1 H-RMN des protons

  Une étude indépendante sur la formation d'imines entre la 2-pyridylaldéhyde 3, le salicylaldéhyde 4 et les différentes amines (B, F, G, et H) a indiqué que l'amine la plus réactive est la pentylamine B suivie par la phénylhydrazine H, la O-benzylhydroxylamine F et la benzhydrazide G. La formation du mélange de la BCD entre la 2-pyridylaldéhyde 3 et les différentes amines (B, F, G, et H) a montré que le produit cinétique est 3B alors que les produits thermodynamiques sont 3F, 3G et 3H (Figure 12 et Table 7, Entrée 1). Finalement, dans la BCD dérivée du salicylaldéhyde 4 et des différentes amines (B, F, G, et H), le produit cinétique est l'imine 4B et les produits thermodynamiques sont 4F et 4H.

Figure 12

 12 Figure 12 Les tracés de la cinétique de formation des imines dans CD 3 OD dans le mélange réactionnel de a) 3 + B + F + G + H, b) 4 + B + F + G + H. La concentration finale est 20 mM. Chaque point a été obtenu par intégration des signaux des protons -CH=N-contre une référence interne (1,4-dioxane). Les erreurs sur l'intégration 1 H-RMN sont de ±5%.

1. 1 ).

 1 Whether at the molecular or supramolecular level, CDC can allow a system to react to external stimuli by component exchange, thus opening a path towards adaptive and evolutive chemistry.

Figure 1 . 1

 11 Figure 1.1 Constitutional dynamic chemistry (CDC) covers both dynamic molecular chemistry and supramolecular chemistry involving dynamic covalent and non-covalent bonds (Figure reproduced from reference [1])

Figure 1 . 2 A

 12 Figure 1.2 A DCL is generated from the reversible exchange of and between various components. The addition of a template to the library will change the component distribution, amplifying the component which forms the most stable complex with the template (Figure reproduced from reference[7]).

Figure 1 . 3

 13 Figure 1.3 shows how DCC can be used to effectively search for a bioactive substance, where DCL components are represented as molecular 'keys' for a specific

Figure 1 . 3

 13 Figure 1.3 The representation scheme of the fundamental concept of dynamic combinatorial/covalent chemistry (DCC, Figure reproduced from reference [1]).

  general equation for Diels-Alder (forward) and retro (reverse) reactions b) An example of a Diels-Alder reaction which is dynamic under mild Chapter 1 46 | P a g e mation ter f or mation on of mine iminoborane reaction between a diene and dienophile substituted cyclohexene product. This reaction is reversible under certain Alder reaction is efficient. These Dynamic Alder reactions have been shown to undergo reversible component exchange to form Alder reactions have been used to s", which undergo rapid exchange at room

  metal ion coordination. The two-level self-organization finally imposed selection or 'self-design' on otherwise dynamic diversity generated by the DCL building blocks.

Figure 1 . 6

 16 Figure 1.6 DCL formation with selection to generate a [2x2] grid complex from metal cations and organic building blocks using both reversible imine exchange and reversible metal-ligand interactions.[1] (Figure reproduced from reference[1])

Figure 1 .

 1 Figure 1.7 a) A bispyridyl-hydrazone molecule demonstrating three types of multiple dynamics: (1) configuration, photochemical, and thermal isomerization (short-term); (2) constitutional interconversion by component exchange (long-term); (3) lock-in by metalion (locked).[84] b) The reversible formation of imines from a carbonyl entity (red sphere) and a terminal diamine (blue connected spheres), the exchange of diamines through transimination (blue frame), and the back and forth motion of the alkylidene moiety between the terminal amine sites (red frames) are indicated. (Figure reproduced from reference[84])

Figure 1 .

 1 Figure 1.10 a) The Knoevenagel compounds IH and IM as anion receptors. b) Color changes observed after adding anions to solutions of IH and IM.[191] (Figure reproduced from reference[191])

Figure 1 .

 1 Figure 1.11 a)The supramolecular self-assembly via hydrogen-bonding of barbituric dye(3) with artificial receptors DAC, EtAd, or BTF,[192] b) barbituric-merocyanines (1a, 1b).[193] (Figure reproduced from reference[192,193])

FT o i n v e s t i g a t e t h e p o t e n t i a l o f o r g a n o c a t a l y s i s i n im i n e / im i n e e x c h a n g e e x c h a n g e r e a c t i o n s w e r e s t u d i e d d e r i v a t i v e s . T h e r e s u l t s a r e p r e s e n t e d i n m e c h a n i sm o f t h e p r o c e s s l i t

  i g u r e 2 . 2 I n f l u e n c e o f t h e a d d i t i o n o f 1% D 1 0 m o l% L -p r o l i n e i n DM SO = DM SO -d 6 /D 2 O 9 9 / 1 , ∆ = DM SO e r a t u r e . [ 3 1 -3 5 ] T h e r e a c t i o n s i n b u t y l e s t e r , L -p r o l i n e a n d b e n z o i c a c i d c a s e o f L -p r o l i n e d i d a m a r k e d i n c r e a s e i n C =N / C =N e x c h a n g e r a t e o c c u r a n d t h e e q u i l i b r i um s t a t e o f t h e m i x t u r e w a s r e a c h e d w i t h i n a c om p a r a t i v e l y s h o r t t im e .

E x c h

  a n g e P r o c e s s e s o f C = N / C = N , C = C / C = N , C = C / C = C i n D C F u r t h e rm o r e , i n o r d e r t o a v o i d a c i d -d e p e n d e n t r e a c t i o n p a t hw a y s , t h e r e a c t i o n w e r e m a d e b a s i c b y t h e a d d i t i o n o f a l a r g e e x c e s s o f t h e h i n d e r e d t e r t i a r y am i n e t r i s ( h y d r o x ym e t h y l )m e t h a n e ( B I S -T R I S ) . I t i s i n a d d i t i o n t o b e i n g a p o o r n u c l e o p h i l i c c a n n o t u n d e r g o e l im i n a t i o n , s o t h a t a t m o s t i t c a n u n d e r g o a d d i t i o n o n l y t o a c a r b o n y l c e n t e r . I n f a c t , n o e v i d e n c e w a s o b t a i n e d t h a t e v e n j u s t t h i s o c c u r r e d t o a n a p p r e c i a b l e e x t e n t . Al l im i n e s w e r e p r e p a r e d b y a u r e 2 . 2 s h ow s a c o n t r o l e x p e r im e n t , i n d i c a t i n g t h a t c h o s e n t h e im i n e / im i n e e x c h a n g e w a s n o t g r e a t l y i n f l u e n c e d r o l i n e I n f l u e n c e o f t h e a d d i t i o n o f 1% D 2 O a n d 1 0 e q u i v . B I S -T R I S i n t h e p r e s e n c e o f DM SO-d 6 s o l u t i o n . ο = DM SO -d 6 / D 2 O 9 9 / 1 + 1 0 e q u i v . B I S = DM SO -d 6 . T o i n v e s t i g a t e t h e p o t e n t i a l o f o r g a n o c a t a l y s i s i n im i n e / im i n e e x c h a n g e w e r e s t u d i e d i n t h e a b s e n c e a n d p r e s e n c e o f L -p r o l i n e d e r i v a t i v e s . T h e r e s u l t s a r e p r e s e n t e d i n F i g u r e 2 . 4 a n d 2 . 5 , a n d i n T a b l e m e c h a n i sm o f t h e p r o c e s s i s d e p i c t e d i n S c h em e 2 . 2 , f o l l ow i n g t h a t p r o p o s e d i n t h e T h e r e a c t i o n s i n t h e p r e s e n c e o f N -B o c p r o t e c t e d L -p r o l i n e a n d b e n z o i c a c i d w e r e c om p a r e d w i t h t h e b l a n k r e a c t i o n d i d a m a r k e d i n c r e a s e i n C =N / C =N e x c h a n g e r a t e o c c u r a n d t h e e q u i l i b r i um s t a t e o f t h e m i x t u r e w a s r e a c h e d w i t h i n a c om p a r a t i v e l y s h o r t t im e .

E x c h

  a n g e P r o c e s s e s o f C = N / C = N , C = C / C = N , C = C / C = C i n D C C C h a p t e r 2 8 3 | P ag e d e p e n d e n t r e a c t i o n p a t hw a y s , t h e r e a c t i o n w e r e m a d e b a s i c b y t h e a d d i t i o n o f a l a r g e e x c e s s o f t h e h i n d e r e d t e r t i a r y am i n e I t i s h i g h l y s o l u b l e i n i n a d d i t i o n t o b e i n g a p o o r n u c l e o p h i l i c c a n n o t u n d e r g o e l im i n a t i o n , s o t h a t a t m o s t i t c a n u n d e r g o a d d i t i o n o n l y t o a c a r b o n y l c e n t e r . I n f a c t , n o e v i d e n c e w a s o b t a i n e d l l im i n e s w e r e p r e p a r e d b y a s h ow s a c o n t r o l e x p e r im e n t , i n d i c a t i n g t h a t f o r t h e w a s n o t g r e a t l y i n f l u e n c e d b y t h e a d d

Figure 2 . 4

 24 Figure 2.4 Screening for organocatalytic activity of benzoic acid on the imine exchange process shown above

  a ) ER = exchange reaction, A-D: substituents of the studied imines. b ) f = forward reaction; r = reverse reaction. c ) k b = rate constant of the blank reaction [10 -3 s -1 ]. d ) k c = rate constant of the catalyzed reaction [10 -3 s -1 ]. e ) K b = equilibrium constant of the blank reaction = k b (forward)/k b (reverse). f ) K c = equilibrium constant of the catalyzed reaction = k c (forward)/k c (reverse). g ) Acc. = Acceleration = k c /k b ; h ) The reaction did not reach equilibrium. i ) Rate constant is calculated from the first 10% of the reaction. j ) n.d. = not determined.

  present in a mixture of A-B and C-D, some A-B can be hydrolyzed to liberate amine (B) which can then react with imine C-D through an aminal-intermediate to provide the imine C-B as an exchange product. Similarly, if C-D is partly hydrolyzed to liberate amine D, it will then react with A-B to give A-D as the exchange product. The net result is that A-D and C-B gradually increase in the reaction mixture at the expense of A-B and C-D, respectively, until the two equilibria ((b) and (c)) are simultaneously established.

Figure 2 . 6

 26 Figure 2.6 Structure of the benzylidene barbiturates (2a-2g) used in the present study.

Figure 2 . 5

 25 Figure 2.5 Influence of aniline as a nucleophilic catalyst in the imine exchange reaction between 1h and 1o in DMSO-d 6 /D 2 O 99/1.

d 6 /

 6 D 2 O 99/1 at 60 o C with 10 mol% L-proline as organocatalyst. As for the C=N/C=N exchange studies described in the previous section, BIS-TRIS did not have much influence on the reaction rate. In contrast, in DMSO-d 6 /D 2 O 99/1 solvent and in the presence of 10 equiv. BIS-TRIS, the hydrolysis of benzylidene-barbiturate (2c) occurred immediately (Figure2.9). Therefore, for the cross exchange of C=C/C=N, BIS-TRIS could not be used in the medium.

Figure 2 . 2 . 6

 226 Figure 2.9 1 H-NMR spectra of a) 2c in DMSO-d 6 /D 2 O 99/1 b) 2c plus 10 equiv. BIS-TRIS in DMSO-d 6 /D 2 O 99/1 showing the hydrolysis of 2c after adding BIS-TRIS to a solution. b = benzaldehyde formyl proton, g = benzaldehyde hydrate methane proton, and B = barbituric acid methylene protons

  DMSO-d 6 /D 2 O 99.5/0.5 and DMSO-d 6 /D 2 O 99.8/0.2 at 60 o C. h = 4-methoxybenzaldehyde, i = 4-dimethylaminobenzaldehyde, m = 4-methoxybenzaldehyde hydrate, and n = 4-dimethyl aminobenzaldehyde hydrate.

Entry

  a ) b, Blank reactions, and c, catalyzed with 10 mol% L-proline as a catalyst. b ) Reaction time indicates the time when no further change in composition could be observed. c ) Error on 1 H-NMR signal integration, ∼4-5%. d ) -, compound not observed. e ) in DMSO-d 6 /D 2 O 99.5/0.5. f ) DMSO-d 6 /D 2 O 99.5/0.2.

Scheme 2 . 9

 29 Scheme 2.9 Possible mechanism of the Cross-Exchange reaction between Knoevenagel

  b, blank reactions, and c, catalyzed reaction with 10 mol% L-proline as a catalyst. b ) Compound not observed. c ) Only traces of product detected. d ) The reaction started. e ) Reaction time indicates the time when no further change in composition could be observed. f ) The reaction did not reach equilibrium. All measurements were repeated three times and averaged. The reproducibility of the values obtained was ±2%

Figure 2 .

 2 Figure 2.12 1 H-NMR spectrum of the exchange reaction between compound 2g and 3e in DMSO-d 6 in the presence of 10mol% piperidine as a function of time.

Figure 2 . 13

 213 Figure 2.13 The exchange reaction profile between compound 2g and 3e in DMSO-d 6 in the presence of 10 mol% piperidine as a function of time.

3 )

 3 In contrast, the C=C/C=N interconversion of Knoevenagel substrates and imines cannot be performed under similar conditions, as extensive hydrolysis occurs. Conducting the reactions in pure DMSO-d 6 at 60 o C greatly reduced hydrolysis (less than 10 %) and C=C/C=N exchange took place, displaying marked acceleration in the presence of 10 mol% L-proline of up to 22-fold. Compounds bearing electron-donating substituents gave the least hydrolysis in the cross-exchange. 4) Furthermore, 10 mol% L-proline is able to accelerate the rate of cross-Knoevenagel C=C/C=C exchange up to about 89-fold at 60 o C, although Michael-type adducts are also formed during the cross exchange process. The %-composition of products at equilibrium depends on the electron affinity of the starting substrates. 5) The results described herein stress the potential of organocatalysis for DCC, facilitating the formation of dynamic libraries and allowing for increased diversity generation.

  ) f, Forward reaction. b ) r, Reverse reaction. c ) Only traces of product detected. d ) Compound not observed. e ) Reaction time indicates the time when no further change (<1-2%) in composition could be observed. %-Compound distribution values measured 4-5 times and averaged (Standard deviation <2%).

Figure 3 . 1

 31 Figure 3.1 The 1 H-NMR spectrum of the exchange reaction at equilibrium between a) 4b and 1v, b) 4a and 1t CDCl 3 at room temperature.

1 ,

 1 Entry 5). The formation of the products 4b and 1t was instantaneous. The reverse reaction was performed by mixing 4b and 1t which gave immediately 4d and 1u. Both the forward and reverse reactions gave the same mixture of the four constituents, indicating that thermodynamic equilibrium was reached immediately after mixing.

  suggest a mechanism of metathesis type, whereby the benzylidene-(dm)barbiturate would function as a neutral organic Lewis acid while the imine would be able to act as neutral organic nucleophile. Such a metathesis-like mechanism of C=C/C=N interchange would involve the nucleophilic addition of the imine nitrogen at the CH end of (ring)C=CHdouble bond of the benzylidene-(dm)barbiturate to form the benzylidene-(dm)barbiturateiminium adduct III, followed by internal cyclization to a four-membered azetidine ring intermediate IV, which then could break up giving either the starting compounds back or the products VII and VI, resulting from the cross-exchange of the components as represented in Scheme 3.3. In a related fashion, the formation of a four-membered carbocyclic intermediate has been found to occur in organocatalysis of Michael addition

  PrN=CHPh (Pr = propyl) and the analogous reaction of N-aryl imine PhHC=NTol + TolHC=NPh (Tol = 4-methylphenyl). Their calculations revealed, in solution phase and in the absence of proton as a catalyst, activation free energies of 78.8 and 68.5 kcal/mol for the N-alkyl and N-aryl cases, respectively. This result indicated that replacing the =CR 2 functionality by =NR is not compatible with a [2+2] cyclization reaction in the solution phase due to the high activation energy. Importantly, protonation of one imine nitrogen lowered the transition state energy from ∼70 kcal/mol to about ∼25 kcal/mol. The relative energies of the four-membered ring intermediate of the [2+2] cyclization reaction, for both N-alkyl and N-aryl cases, were about 13 kcal/mol higher.Accordingly, a similar approach to Baik's work was followed in terms of the C=C (Knoevenagel type compound) and CH=NR (imine compounds) functionality. Herein, the activation energy (transition state) of the reaction was not calculated. The geometry of the starting materials (4a and 1b) and exchange products (4e and 1v) were optimized by using DFT method with B3LYP/6-31G* (d, p) type wave functions. Also, the energy of the azetidine intermediate (IV from Scheme 3.3) was calculated by using the same method as for starting materials and products. The results are shown in Table3.2 and Figure 3.3 and 3.4.

  07016573 a ) S.M.; Starting Material, I; Intermediate, P; Product. b ) 1a.u. = 627.5095388 kcal/mol The optimized structures show a C=C bond length of 1.38 Å in 4a, a C=N bond length of 1b 1.28 Å in 1b, a C=C bond length in 4e of 1.38 Å, and a C=N bond length in 1v of 1.28 Å. The structure for the four-membered intermediate, IV, shows an unsymmetrical four-membered ring with a C 1 -C 2 bond length of 1.60 Å, a C 2 -C 3 bond length of 1.61 Å, a C 3 -N bond length of 1.48 Å and a N-C 1 bond length of 1.46 Å (Figure 3.3). Once the four-membered ring is formed, the C-C bond length elongates to 1.61 Å from 1.38 Å and one of the C-N bonds elongates to 1.48 Å from 1.38 Å. Furthermore, the four-membered ring shows an angle inside the ring between C 1 -C 2 -C 3 of 84.5 o , C 2 -C 3 -N of 89.4 o , C 3 -N-C 1 of 94.6 o , and N-C 1 -C 2 of 88.3 o , respectively.

Figure 3 .Figure 3 . 4

 334 Figure 3.3 a) Representative of a possible intermediate in the exchange reaction of Knovenagel-Type (C=C) and Imine (C=N) compounds, b) Relative energy of the starting materials (4a + 1b), products (4e + 1v) involved intermediate (4a + 1b)-I, obtained with the DFT (B3LYP/6-31G* (d,p)) method. The small numbers in blue next to bond are distances in Angstrom.

15 Scheme 3 . 4

 1534 Scheme 3.4 Representation of the used in gel investigations.

Figure 3 .

 3 Figure 3.6 a) the gel formation ability of Decanol, 4) MeOH, and 5) EtOH by Optical Microscope.

  a) the gel formation ability of 4g in different solvents, 1) EtOH, 2) CH 5) Cyclohexane. b) Observation of the gel formation of EtOH by Optical Microscope.

  seeChapter 7). Then, the gel formation ability of these compounds was evaluated in different solvents systems such as of the gel formation formed best in ethanol In addition, the gel of 4g) showing the cross-linking OR 2 gel compounds (4f-4i) which were 1) EtOH, 2) CH 3 CN, 3) ) Observation of the gel formation of 4g in Next, a gel formation study of used for 4g (Figure 3.7, Table 3.3 occurs in ethanol and methanol but only partially i obtained in decanol and cyclohexane. Finally, the gel formation ability of studied in the same range of solvents MeOH followed by EtOH. In decanol, the CH 3 CN, a small amount of fiber formation was observed only. A gel of cyclohexane. Finally, a gel of Entry 1).

Figure 3 . 7

 37 Figure 3.7 The gel formation ability of Decanol, MeOH, and Cyclohexane.

Figure 3 .

 3 Figure 3.8 a) The exchange reactio product 4f and 1u in CD 3 CN/EtOH. between 4b and 1w after 21 h.

Figure 3 .

 3 Figure 3.9 1 H-NMR spectra of the exchange reaction a) measured at 25 broad peaks of 4f and 1w, b) measured at 60

  C=C/C=N between 4b and 1w to give the exchange CN/EtOH. b) The NMR tube of the mixture of exchange reaction after 21 h. ctra of the exchange reaction a) measured at 25 , b) measured at 60 o C showing the sharp peaks of a g e barbiturate/imine (C=C/C=N) system CN/EtOH 9/1. The chosen starting substrates were 4b and 1w which can form a crystalline precipitate. The reaction was left for 21 h at room temperature to ensure that the system reached NMR spectroscopy was used to characterize the gel In the reaction mixture, the exchange (33%), and 1u (33%) , and a value of 57 o C was to give the exchange The NMR tube of the mixture of exchange reaction ctra of the exchange reaction a) measured at 25 o C showing the C showing the sharp peaks of 4f and 1w. b)

Figure 4 . 1 )

 41 to undergo exchange with several aliphatic (2a-e) and N,N-dimethylaniline-type aromatic (4a-e) tertiary amines (Figure4.2) was evaluated at 1/1 ratio in the absence or in the presence of iodide as nucleophilic catalyst in the form of tetraethyl-or tetrabutyl-ammonium iodide (TEAI or TBAI, respectively).

Figure 4 . 1

 41 Figure 4.1 Structures of the quaternary allyl ammonium salts of aromatic N,N-dialkylanilinium-derived (1a-e) and aliphatic (3a-e) types used in the present study.

Figure 4 . 2

 42 Figure 4.2 Structure of aliphatic (2a-e) and N,N-dimethylaniline-type aromatic (4a-e) tertiary amines used in the present study.

Figure 4 . 3 .

 43 Figure 4.3. Effect of the addition of iodide anion on the nucleophilic substitution exchange reaction between 1a and 2c in CD 3 CN at 60 o C. Tetraethylammonium iodide (TEAI) was used as iodide source (1 equiv.)

Figure 4 . 5 .

 45 Figure 4.5. 1 H-NMR spectra for the exchange reaction between 1e-Br and 4b in CD 3 CN at 60 o C a) after mixing. b) at 41 h demonstrating the line broadening peak of liberated diethylaniline.

Figure 4 . 6 .Figure 4 .

 464 Figure 4.6. 1 H-NMR spectra for the exchange reaction between 1e-Br and 4a in CD 3 CN at 60 o C a) after mixing b) at 50 h demonstrating the line broadened peaks of liberated diethylaniline.

Figure 4 . 8 .Figure 4 . 9

 4849 Figure 4.8. a) The dissociation of 1a-Br and %-compound at equilibrium. b) Kinetic trace of the dissociation of 1a-Br. c) 1 H-NMR spectrum of the dissociation of 1a-Br as a function of time showing the line broadening of the peaks of liberated dimethyl aniline due to the exchange with the paramagnetic radical of dimetyl aniline.

Figure 4 .

 4 Figure 4.10 a) The product distribution at equilibrium, attained after 43 h, in the dissociation of 1a-Br in the presence of iodide ion. b) 1 H-NMR spectra showing the progress of the deallylation of 1a-Br in the presence of iodide ion in CD 3 CN at 60 o C as a function of time.

3 :

 3 The exchange of the amine moiety between quaternary N-allyl-N,N-dimethylanilinium salts and a tertiary amine may occur via S N 2 or S N 2' mechanisms. The latter S N 2' may itself follow either a direct or an indirect pathway, as outlined in Scheme 4.3. i) an indirect pathway (Scheme 4.3a) involving a) the nucleophilic attack of bromide anion at the γ-carbon of the allyl group of the N-allyl-N,N-dimethylanilinium salt (I) to liberate N,N-dimethylaniline (II) and allyl bromide (III), b) subsequent reaction of III with the introduced tertiary amine IV or VI to furnish the exchange product V or VII in an irreversible or a reversible process respectively with an aliphatic IV or an aromatic VI tertiary amine.

Figure 4 . 11

 411 Figure 4.11 Effect of the addition of iodide anion on the nucleophilic substitution exchange reaction between 5a-Br and 4b in CD 3 CN at 60 o C. Tetrabutylammonium iodide (TBAI) was used as iodide source (1 and 2 equiv.)

  ; X= H, Z = Br 5a-OTf; X= H, Z = OTf 5a-PF 6 ; X= H, Z = OMe 5b-Br; X= Me, Z = Br 5b-OTf; X= Me, Z = OTf 5b-PF 6 ; X= Me Z = OMe 5c-Br ; X = OMe, distribution [%] b

  in 1 H-NMR signal integration: ±4%. b ) Compound not observed.

Scheme 4 . 5

 45 Scheme 4.5 The nucleophilic reaction of a) 8a and 9b, b) 8a and allyl bromide (B), c) 8d and 4-nitrobenzyl bromide (C) in CD 3 CN under microwave irradiation 150 o C (300 W) for 30 min.

Scheme 4 . 6

 46 Scheme 4.6 Exchange reaction between a) 6e and 7b and b) 6e and 6b in the absence of molecular solvent under microwave irradiation at 150 o C for 20 minutes.

  Figure 5.1.

Figure 5 . 1

 51 Figure 5.1 Model for the regioselective groups in order to select different products based on kinetic or thermodynamic selectivity

sulfonate ( 1 )

 1 and pyridoxal phosphate composed of 2-pyridyl aldehyde ( organic solvents. The different amino comprise aliphatic amines (propylamin acethydrazide (D), methylhydrazine ( and phenylhydrazine (H).

1 Scheme 5 . 1 O

 151 Scheme 5.1 Structures of aldehydes

  -d 6 was employed as a solvent. b ) D 2 O was employed as a solvent. c ) Reaction time indicates the time when further changes in the reactant concentrations were below the limit of detection. d ) Error in 1 H-NMR signal integration: ±5%. e ) Compound not formed. f ) Reaction reached equilibrium.

4. 6 ,

 6 and thus at pD 5.0 (pH = 4.6), approximately half of the reactant should still be present as neutral methoxylamine to attach the aldehyde. a) b)

Scheme 5 . 4

 54 Scheme 5.4 DCL of the 5 components 1, B, C, D, E and the four possible imines 1B, 1C, 1D, 1E to be analyzed in different buffers (pD = 5.0, 8.5, and 11.4). The study was performed at 25 o C using an initial solution concentration of 20 mM for each reactant.

Figure 5 . 3

 53 Figure 5.3 Kinetic trace for imine formation from the 5 components 1, B, C, D, E in D 2 O in phosphate buffers a) pD = 5.0 b) pD = 8.5 c) pD 11.4. The concentrations of reactants were 20 mM in all cases. Error in 1 H-NMR integration: ∼4-5%.

Figure 5 . 4 5 sulfonate aldehyde 1 ,

 5451 Figure 5.4 Equilibrium distribution of mixture of the sulfonate aldehyde of 5.0, 8.5 and 11.4.

  istribution of different imines 1B-1E in the DCL generated from a mixture of the sulfonate aldehyde 1 and various amino derivatives B, C, D

5 11. 4 pD

 54 further change (<2%) was detectable in the concentrations. b ) Error in in the DCL generated from a D, E at pD values The DCL of an equimolar mixture of 1, B, C, D, and E was next examined at pD 8.5, the results showing that the reaction was slower than at pD 5.0, reaching equilibrium after 11 h (Figure 5.3b and Table

Scheme 5 . 5

 55 Scheme 5.5 Potential DCL of the 5 components 2, B, C, D, E and the four possible imine products 2B, 2C, 2D, 2E studied in phosphate buffers at different pD values (5.0, 8.5, and 11.4) at 25 o C.

Figure 5 . 5

 55 Figure 5.5 Equilibrium distributions of different a mixture of pyridoxal phosphate of 5.0, 8.5 and 11.4.

Figure 5 . 6

 56 Figure 5.6 Kinetic traces for imine formation from the reactions between a) 3 + B + F, b) 3 + B + G, and c) 3 + B + H in CD 3 OD in at 25 o C. Initial reactant concentration were all 20 mM. Error in 1 H-NMR integration: ∼5%.

Figure 5 . 7

 57 Figure 5.7 Kinetic traces for imine formation in CD 3 OD in the reaction mixtures of a) 3 + F + G, b) 3 + F + H. Error in 1 H-NMR integration: ∼5%.

Figure 5 . 8

 58 Figure 5.8 Kinetic traces for imine formation in CD 3 OD in the reaction mixtures of a) 3 + B + G + H, and b) 3 + G + F + H. Error in 1 H-NMR integration: ∼5%.

Figure 5 . 9

 59 Figure 5.9 Kinetic traces of imines formation in CD 3 OD in the mixture 3 + B + F + G + H. Error in 1 H-NMR integration: ∼5%.

Figure 5 . 10

 510 Figure 5.10 Kinetic traces of imine formation in CD 3 OD in the reaction mixture of a) 4 + B + G + H, b) 4 + F + G + H. Error in 1 H-NMR integration: ∼5%. The reaction of aldehyde 4 with four different amino derivatives (B, F, G, and H)

  ) Reaction times indicate the certain time of the reaction. b ) Error on 1 H-NMR integration: ±5%. c ) n.d.; not determined. d ) Compound not formed.

Figure 5 . 11 Scheme 5 . 7

 51157 Figure 5.11 Kinetic traces for imine formation in a) CD 3 OD, b) CD 3 CN in a mixture of 4 + B + F + G + H at 25 o C. Error in 1 H-NMR integration: ∼5%.

Figure 5 . 12

 512 Figure 5.12 The molecular structure of neomycin

  generation of DCLs via imine/imine (C=N/C=N), Knoevenagel/imine (C=C/C=N), and Knoevenagel/Knoevenagel (C=C/C=C) exchange reactions. The results showed that 10% mol L-proline as an organocatalyst facilitated DCL generation and most of the reactions reached a true equilibrium. The best conditions for imine exchange were 10 mol% L-proline in DMSO-d 6 /D 2 O 99/1 with 10 equiv. BIS-TRIS at room temperature, for which the imine exchange reaction was enhanced up to 22-fold compared to in the absence of catalyst. Imines derived from aliphatic/nucleophilic amines and highly electrophilic aldehydes were found to be the most suitable starting components, giving only the exchange products with no hydrolysis observed. For C=C/C=N exchange, the best conditions were 10 mol% L-proline in pure DMSO-d 6 at 60 o C. L-proline accelerated the C=C/C=N exchange up to 22-fold and starting materials bearing electron-donating groups gave the least hydrolysis products during the cross-exchange. Finally, the C=C/C=C exchange benefitted from the same conditions as optimized for the C=C/C=N exchange, giving a 89-fold catalytic enhancement. In the latter case however, Michael-type adducts were formed during the exchange process. Once again, the efficiency of C=C/C=C exchange depended on the electron affinity of the starting materials.In the third chapter, the DCC of Knoevenagel/imine (C=C/C=N) exchange involving N,N'-dimethyl barbituric acid was evaluated. The exchange reactions were fast at room temperature in the absence of catalyst. The exchange mechanism is possibly a metathesis-like process via an azetidine intermediate. Furthermore, some of the Knoevenagel compounds formed gels in EtOH or MeOH and a preliminary gel selection study was undertaken based on C=C/C=N exchange.Conclusions and PerspectivesChapter 6208 | P a g eIn Chapter 4, novel DCC generation was reported based on nucleophilic substitution (S N 2/S N 2') component exchange of quaternary ammonium cations with tertiary amines. The exchange reactions between either N-allyl-N,N-anilinium salt or N-benzyl-N,N-anilinium salt and tertiary amines were conducted at 60 o C to generate DCLs under thermodynamic and kinetic control and were accelerated using iodide as a nucleophilic catalyst. Moreover, microwave irradiation was used to assist the exchange reaction between pyridinium salts and pyridine derivatives. The generation of dynamic ionic liquids was also initiated.

13 C-

 13 NMR spectra were recorded with a Bruker Avance 400 MHz spectrometer at 100 MHz. Chemical shifts are given in ppm. Residual solvent peaks were taken as reference (CHCl 3 : 77.0 ppm, DMSO: 39.43 ppm, CH 3 CN 1.24 ppm and CH 3 OH: 49.05) 2D NMR (COSY, NOESY) were recorded with a Bruker Avance 400 MHz spectrometer.

  13 C-NMR (100 MHz, CDCl 3, 25 o C; δ/ppm): 14.0, 22.6, 27.1, 29.0, 30.9, 31.7, 59.5, 117.0, 118.3, 118.8, 131.0, 132.0, 161.4, 164.4. ESI-MS: m/z: 220.2 (100%). HRMS (ESI, m/z): calcd. for C 14 H 22 NO 220.170; found 220.170.

  1 H-NMR (400 MHz, CDCl 3 , 25 o C; δ/ppm): 4.80 (s, 2 H), 7.15-6.96 (m, 1 H), 7.39-7.23 (m, 6 H), 7.41 (d, J = 5.0 Hz, 1 H), 8.46 (s, 1 H). 13 C-NMR (100 MHz, CDCl 3 , 25 o C; δ/ppm): 64.4, 127.0, 127.3, 128.0, 128.5, 129.0, 130.6, 139.0, 142.4, 155.2. ESI-MS: m/z: 202.1 (100%). HRMS (ESI, m/z): calcd. for C 12 H 12 NS 202.068; found 202.070.

  General procedure for C=N/C=N exchange of 2 imines. A NMR tube was first charged with 200 µL of BIS-TRIS stock solution (600 mM in DMSO-d 6 /D 2 O, 99/1). For the catalyzed reaction, 20 µL of a L-proline stock solution (60 mM in DMSO-d 6 /D 2 O, 99/1) was added. For the uncatalyzed reaction, 20 µL DMSO-d 6 /D 2 O, 99/1 was mixed with 200 µL of BIS-TRIS stock solution (600 mM in DMSO-d 6 /D 2 O, 99/1) in another NMR tube. To these prepared solutions, 200 µL of each imine solution (60 mM in DMSOd 6 /D 2 O, 99/1) were added and the NMR spectra were measured immediately after mixing. Kinetics of imine exchange (C=N/C=N) exchange. The imine exchange reaction

  [A] eq and [B] eq are the concentration of [A] and [B] respectively at equilibrium, and [A] t and [B] t are the concentration of [A] and [B], respectively, at any given time t. If the initial conditions are [A] = [A] 0 and [B] = [B] 0 = 0, so that, by stoichiometry

  Scheme 7.1, a common feature of the two reversible reactions ((b) and (c)) is that the imine reactant in (b) is also a reactant in (c), and vice versa. Therefore, if a small amount of H 2 O is present in a mixture of A-B and C-D, A-B will be hydrolyzed to liberate amine (B), then, it will react with imine C-D through the aminal-intermediate mechanism to provide an imine C-B as an exchange product. Similarly, C-D will be hydrolyzed to liberate amine (D), and D will then react with A-B to give A-D as the exchange product. The net result is that A-D and C-B gradually increase in the reaction mixture at the expense of A-B and C-D, respectively, until the two equilibria ((b) and (c)) are simultaneously established.

Scheme 7 . 1 Scheme 7 . 2

 7172 Scheme 7.1 The imine exchange mechanism in the absence of organocatalyst via hydrolysis and recondensation reaction (the water acts as a nucleophilic catalyst).

  26) 228 | P a g e These equations are based upon the rate law for a single reaction step being proportional to the product of the concentration of each of the reactants raised to the power that it appears in the given reaction equation, being one in all the present cases.In principle, the simultaneous equation (7.18) -(7.26) can be solved so as to allow the rates of interest, i.e., d[A-B]/dt, d[C-D]/dt, d[A-D]/dt and d[C-B]/dt to be expressed in terms of just the measurable concentrations [A-B], [C-D], [A-D], and [C-B] and the 16 rate

29 )

 29 Since the application of the SSA is based upon the condition that [A-N], [B] and[N] are constant so that this equation is mathematically equivalent toR A-B = -d[A-B]/dt = (constant)[A-B] -another constant(7.30)

Figure 7

 7

Figure 7 . 1

 71 Figure 7.1 The plot of the kinetic study of the imine exchange between 1h and 1i in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 2

 72 Figure 7.2 The plot of the kinetic study of the imine exchange between 1h and 1i in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.3.

Figure 7 . 3

 73 Figure 7.3 The plot of the kinetic study of the imine exchange between 1j and 1k in DMSOd 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 4 .

 4 The imine/imine exchange reaction between (E)-2-(cyclohexylimino)methyl)phenol (1j) (E)-N-(pyridin-4-ylmethylene)propan-1-amine (1k).

Figure 7

 7

Figure 7 . 4

 74 Figure 7.4 The plot of the kinetic study of the imine exchange between 1j and 1k in DMSOd 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 Figure 7 . 5

 775 Figure 7.5 The plot of the kinetic study of the imine exchange between 1h and 1l in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7

 7

Figure 7 . 6

 76 Figure 7.6 The plot of the kinetic study of the imine exchange between 1h and 1l in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 7 .

 7 The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) (E)-N-(pyridin-2-ylmethylene)propan-1-amine (1m).

Figure 7

 7

Figure 7 . 7

 77 Figure 7.7 The plot of the kinetic study of the imine exchange between 1c and 1m in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.8.

Figure 7 . 8

 78 Figure 7.8 The plot of the kinetic study of the imine exchange between 1c and 1m in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 9

 79 Figure 7.9 The plot of the kinetic study of the imine exchange between 1i and 1l in DMSOd 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 10 .

 10 The imine/imine exchange reaction between (E)-4-((cyclohexylimino) methyl) pyridin-3-ol (1i) (E)-1-phenyl-N-(pyridin-2-ylmethylene)methanamine (1l).

Figure 7

 7

Figure 7 . 10

 710 Figure 7.10 The plot of the kinetic study of the imine exchange between 1i and 1l in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 Figure 7 . 11

 7711 Figure 7.11 The plot of the kinetic study of the imine exchange between 1n and 1o in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 12

 712 Figure 7.12 The plot of the kinetic study of the imine exchange between 1n and 1o in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming an irreversible first-order reaction.

a g e 13 .

 13 The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1c) (E)-N-(thiophen-2-ylmethylene)octan-1-amine (1d).

Figure 7

 7 .14.

Figure 7 . 14

 714 Figure 7.14 The plot of the kinetic study of the imine exchange between 1c and 1d in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.15.

Figure 7 . 15

 715 Figure 7.15 The plot of the kinetic study of the imine exchange between 1a and 1b in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 16 .

 16 The imine/imine exchange reaction between (E)-2-((benzylimino)methyl)phenol (1a) (E)-N-(thiophen-2-ylmethylene)octan-1-amine (1b).

  Figure 7.16.

Figure 7 . 16

 716 Figure7.16 The plot of the kinetic study of the imine exchange between 1a and 1b in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 17

 717 Figure 7.17 The plot of the kinetic study of the imine exchange between 1p and 1c in DMSO-d 6 /D 2 O 99/1 in the presence of 10% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7

 7

Figure 7 . 18

 718 Figure7.18 The plot of the kinetic study of the imine exchange between 1p and 1c in DMSO-6 /D 2 O 99/1 and 10 equiv. of BIS-TRIS as buffer solution at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 19

 719 Figure7.19 The plot of the kinetic study of the imine exchange between 1l and 1q in DMSO-d 6 /D 2 O 99/1 in the presence of 10% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 20

 720 Figure 7.20 The plot of the kinetic study of the imine exchange between 1l and 1q in DMSO-d 6 /D 2 O 99/1 in 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.21.

Figure 7 . 21

 721 Figure 7.21 The plot of the kinetic study of the imine exchange between 1p and 1d in DMSO-d 6 /D 2 O 99/1 in the presence of 10% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 22 .

 22 The imine/imine exchange reaction between (E)-3-methyl-N-(pyridin-2-yl methylene)butan-1-amine (1p) and (E)-N-(thiophen-2-ylmethylene)heptan-1-amine (1d).

Figure 7

 7

Figure 7 . 22

 722 Figure 7.22 The plot of the kinetic study of the imine exchange between 1p and 1d in DMSO-d 6 /D 2 O 99/1 and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.23.

Figure 7 . 23

 723 Figure 7.23 The plot of the kinetic study of the imine exchange between 1r and 1r in DMSO-d 6 /D 2 O 99/1 in the presence of 10% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7

 7

Figure 7 . 24

 724 Figure 7.24 The plot of the kinetic study of the imine exchange between 1r and 1r in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

a g e 25 .

 25 The imine/imine exchange reaction between (E)-2-((propylimino)methyl)phenol (1h) and (E)-1-phenyl-N-(pyridin-4-ylmethylene)methanamine (1n).In an NMR tube, compound 1h and 1n were mixed with a final concentration 19.35 mM and a total volume of 0.62 mL with 10 equiv. of BIS-TRIS in the presence of 10mol% L-proline as catalyst. The 1 H-NMR of -CH=N-protons of the starting materials (8.53 ppm for 1h and 8.51 ppm for 1n) and the exchange products (8.70 ppm for 1c and 8.37 ppm for 1k) were followed until the reaction reached equilibrium. The kinetic data were fit assuming a reversible first-order reaction as shown in Figure7.25.

Figure 7 . 25

 725 Figure 7.25 The plot of the kinetic study of the imine exchange between 1h and 1h in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7

 7 .26.

Figure 7 . 26

 726 Figure 7.26 The plot of the kinetic study of the imine exchange between 1h and 1n in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.27.

Figure 7 . 27

 727 Figure 7.27 The plot of the kinetic study of the imine exchange between 1c and 1k in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS. Data were fit assuming a reversible first-order reaction.

Figure 7

 7

Figure 7 . 28

 728 Figure 7.28 The plot of the kinetic study of the imine exchange between 1c and 1k in DMSO-d 6 /D 2 O 99/1 and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

  Figure 7.29.

Figure 7 . 29

 729 Figure 7.29 The plot of the kinetic study of the imine exchange between 1h and 1o in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7

 7

Figure 7 . 30

 730 Figure 7.30 The plot of the kinetic study of the imine exchange between 1h and 1o in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 31

 731 Figure 7.31 The plot of the kinetic study of the imine exchange between 1j and 1m in DMSO-d 6 /D 2 O 99/1 in the presence of 10 mol% L-proline and 10 equiv. of BIS-TRIS at room temperature. Data were fit assuming a reversible first-order reaction.

Figure 7 . 32

 732 Figure 7.32 The plot of the kinetic study of the imine exchange between 1j and 1m in DMSO-d 6 /D 2 O 99/1 and 10 equiv. BIS-TRIS as buffer solution at room temperature. Data were fit assuming a reversible first-order reaction.

Knoevenagel 1 .Figure 7 . 33 7 252 | P a g e 2 .Figure 7 . 34 7 253 | P a g e 3 .Figure 7 . 35 a g e 4 .Figure 7 . 36 7 255 | P a g e 5 .Figure 7 . 37 6 .Figure 7 . 38 7 .Figure 7 . 39 8 .Figure 7 . 40 9 .Figure 7 . 41 10 .Figure 7 . 42 11 .Figure 7 . 43 12 .Figure 7 . 44 4

 1733727347373547367573767387739874097411074211743127444 Figure 7.33 The exchange reaction between 2a and 1t as a function of time a) in the presence of 10 mol% L-proline and b) in the absence of catalyst. g = 4chlorobenzaldehyde, i = 4-(dimethylamino)benzaldehyde, l = 4-chlorobenzaldehyde hydrate. Error in 1 H-NMR integration: ∼4-5%.

Figure 7 . 45 a g e 2 .Figure 7 . 46 3 .Figure 7 . 47 a g e 4 .Figure 7 . 48 5 .Figure 7 . 49 a g e 6 .Figure 7 . 50 7 .Figure 7 . 51 Figure 7 . 52

 745274637474748574967507751752 Figure 7.45 The exchange reaction between 2a and 3d as a function of time a) in the presence of 10 mol% L-proline and b) in the absence of catalyst.

Figure 7 . 53 Figure 7 . 54 Figure 7 . 55 Figure 7 . 56 7 272 | P a g e 7 . 3 Chapter 3 ,

 7537547557567733 Figure 7.53 An example of a 2D 1 H-COSY spectrum of the exchange reaction between 2a and 3d in DMSO-d 6 in the presence of 10 mol% L-proline. The signal from 4.73 -6.21 ppm showed the formation of the Michael-type adducts XI and XII.

5 -

 5 (4-chlorobenzylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H

  a g e Heptyl isocyanate (I)(3.22 mL, 20.00 mmol) was dissolved in hexane (100 mL) and then the mixture was cooled to 0 o C. A solution of n-heptylamine (II) (3.26 mL, 22.00 mmol) in hexane (20 mL) was carefully added. A white solid precipitated from the solution after which the solution was kept stirring for another 2 h. The product was collected by filtration and washed with cooled n-hexane to obtain a white solid (III) (3.93 g, 77%).Next, diheptylurea (III) (3.0 g, 11.7 mmol) and malonic acid (IV) (1.118 g, 10.74 mmol) were dissolved in acetic acid (20 mL). The mixture was stirred at 65 -70 o C then acetic acid (30 mL) was added dropwise. Then, the mixture was kept stirring at 90 o C for 2 hr.

Figure 7 . 57 a g e 7 . 3 . 3 . 2 3 RTFigure 7 . 58 a g e 7 . 3 . 3 . 3

 757733237587333 Figure 7.57 The 1 H-NMR spectrum of the exchange reaction at equilibrium between a) 4a and 1b, b) 4e and 1v in CDCl 3 at room temperature.

Figure 7 . 59 a g e 7 . 3 . 3 . 4

 7597334 Figure 7.59 The 1 H-NMR spectrum of the exchange reaction at equilibrium between a) 4b and 1b, b) 4e and 1u in CDCl 3 at room temperature.

Figure 7 . 60 a g e 7 . 3 . 3 . 4

 7607334 Figure 7.60 The 1 H-NMR spectrum of the exchange reaction at equilibrium between a) 4d and 1v, b) 4a and 1t in CDCl 3 at room temperature.

Figure 7 . 61

 761 Figure 7.61 The 1 H-NMR spectrum of the exchange reaction at equilibrium between a) 4d and 1u, b) 4b and 1t in CDCl 3 at room temperature.

  148 o C, lit m.p. 151-152 o C. 1 H-NMR (CD 3 CN) δ ppm: 7.79 (d, J = 9.4 Hz, 2H), 7.68 (d, J = 9.2 Hz, 2H), 5.61 (m, 3H), 4.42 (d, J = 6.3 Hz, 2H), 3.52 (s, 6H).

  1 H-NMR (CDCl 3 ) δ ppm: 7.76 (d, J = 7.4, 2H), 7.42 (d, J = 8.8 Hz, 2H), 5.87 (d, J = 16 Hz, 1H), 5.58 (d, J = 10 Hz, 1H), 5.49 (m, 1H), 5.07 (d, J = 7.4 Hz, 2H), 3.93 (s, 6H), 2.44 (s, 3H).

  1 H-NMR (CD 3 CN) δ ppm: 7.72 (br, 2H), 7.63 (m, 3H), 5.69 (m, 3H), 4.38 (d, J = 7.1 Hz, 2H), 3.81 (m, 4H), 1.10 (t, J = 7.1 Hz, 6H). a g e 8. N-allyl-N,N-diethylbenzenaminium iodide (1e-I) Prepared in 98% yield as a white solid by a route analogous to that described for 1g. M.p. 105 -106 o C 1 H-NMR (CDCl 3 ) δ ppm: 7.96 (d, J = 8.5, 2H), 7.65 (t, J = 7.8 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 5.62 -5.79 (m, 3H), 4.65 (d, J = 5.9 Hz, 2H), 4.20 (dt, J = 7.3, 2H), 4.07 (dt, J = 7.2 Hz, 2H), 1.22 (t, J = 7.0 Hz, 6H).

  1 H-NMR (CD 3 CN) δ ppm: 7.57 -7.70 (m, 5H), 5.49 -5.65 (m, 3H), 4.32 (d, J = 6.1, 2H), 3.48 (s, 6H). 10. N-allyl-N,N,4-trimethylbenzenaminium (1b-PF 6 )

  H-NMR (CD 3 CN) δ ppm: 7.55 (d, J = 8.6 Hz , 2H), 7.43 (d, J = 8.4 Hz , 2H), 5.49 -5.65 (m, 3H), 4.29 (d, J = 6.5 Hz , 2H), 3.45 (s, 6H), 2.40 (s, 3H).

  1 H-NMR (CD 3 CN) δ ppm: 5.93 (m, 1H), 5.68 (d, J = 12.1 Hz, 1H), 5.65 (d, J = 5.4 Hz, 1H), 3.76 (d, J = 7.0 Hz, 2H), 3.19 (q, J = 7.2 Hz, 6H), 1.25 (tt, J = 1.2 Hz, 9H).

  a g e 12. N,N-diethyl-N-methylprop-2-en-1-aminium bromide (3b-Br)

  1 H-NMR (CD 3 CN) δ ppm: 6.04 (m, 1H), 5.7 (d, J = 6.2 Hz, 1H), 5.67 (br, 1H), 4.03 (d, J = 7.7 Hz, 2H), 3.97 (m, 2H), 3.41 (t, J = 4.9 Hz, 2H), 3.08 (s, 6H).

  148 -149 o ([18]: 149-151 o ]). 1 H-NMR (CD 3 CN) δ ppm: 7.57 -7.67 (m, 5H), 7.46 (t, J = 8 Hz, 1H), 7.32 (t, J = 8 Hz, 2H), 7.07 (d, J = 7.7 Hz, 2H), 4.93 (s, 2H), 3.55 (s, 6H).

  159 -160 o 1 H-NMR (CD 3 CN) δ ppm: 8.70 (br, 2H), 7.82 (d, J = 6.3 Hz, 2H), 7.46 (s, 5H), 5.72 (s, 2H), 2.61 (s, 3H).

Figure 7 . 62 - 4 Figure 7 . 62 - 5 Figure 7 . 62 - 6 Figure 7 . 63 .

 762476257626763 Figure 7.62-4 The exchange reaction between 1a-Br and 2b (in the presence of iodide as catalyst)

Figure 7 . 63 - 1 Figure 7 . 63 - 2 Figure 7 . 63 - 3 Figure 7 . 63 - 4 Figure 7 . 63 - 5 Figure 7 . 63 - 6 Figure 7 . 63 - 7 Figure 7 . 63 - 8 Figure 7 . 63 - 9 Figure 7 . 63 - 10 Figure 7 . 63 - 11 Figure 7 . 63 - 12 Figure 7 . 63 - 13 Figure 7 . 63 - 14 Figure 7 . 63 - 15 Figure 7 . 63 - 16 Figure 7 . 63 - 17 Figure 7 . 63 - 18 Figure 7 . 63 - 19 Figure 7 . 63 - 20 Figure 7 . 64

 7631763276337634763576367637763876397631076311763127631376314763157631676317763187631976320764 Figure 7.63-1 The exchange reaction between 1a-Br and 4b (in the absence of catalyst)

Figure 7 . 64 - 1 Figure 7 . 64 - 2 Figure 7 . 64 - 3 Figure 7 . 64 - 4 Figure 7 . 64 - 5 Figure 7 . 64 - 6 Figure 7 . 64 - 7 Figure 7 . 64 - 8 Figure 7 .Figure 7 .

 7641764276437644764576467647764877 Figure 7.64-1 The exchange reaction between 5a-Br and 4b (in the absence of catalyst)

Figure 7 .Figure 7 .

 77 Figure 7.67 1 H-NMR spectra of the exchange reaction between 1i and 2d in CD 3 CN at 60 o C to afford the exchange products 3d-PF 6 and 4a. a) after mixing b) at 16 hr.

Figure 7 .Scheme 7 . 1

 771 Figure 7.69 1 H-NMR spectra of the exchange reaction between 5a-PF 6 and 4b in CD 3 CN at 60 o C to afford exchange products 5b-PF 6 and 4a. a) after mixing b) at 137 hr.

Scheme 7 . 4 7 305 | P a g e 7 . 5 Chapter 5 , 7 . 5 . 1

 747755751 Scheme 7.4 The exchange reaction between 1i, 2a, and 2c in CD 3 CN at 60 o C in the presence of 10mol% TBAF.

  1 H-NMR (D 2 O) δ ppm: 8.63 (s, 1H), 8.48 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H).

  1 H-NMR (D 2 O) δ ppm: 7.97 (d, J = 2.2 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J = 9.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 2.87 (s, 3H). 13 C-NMR (100 MHz, D 2 O; δ/ppm): 34.4, 55.9, 112.9, 126.4, 126.9, 130.1, 130.9, 141.8, 156.8.

  1 H-NMR (CD 3 OD) δ ppm: 0.87 (t, J = 7.31 Hz, 1H), 1.29 -1.36 (m, 4H), 1.67 (quint, J = 7.2 Hz, 2H), 3.62 (t, J = 7.15 Hz, 2H), 7.39 -7.43 (m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.55 (d, J = 4.29 Hz, 1H).

13

 13

  1 H-NMR (CD 3 OD) δ ppm: 8.53 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.86 (t, J = 8.4 Hz, 1H), 7.57 (t, J = 6.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 5.4 Hz, 1H), 4.5 (s, 1H).

  1 H-NMR (CD 3 OD) δ ppm: 8.37 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 5.5 Hz, 2H), 7.08 -7.21 (m, 5H), 6.76 (t, J = 7.4 Hz, 1H).

13 C

 13 -NMR (100 MHz, CD 3 OD; δ/ppm): 113.9, 120.9, 121.3, 123.8, 130.3, 136.6, 138.5, 146.4, 149.6 156.6.

13

 13

  a g e 11. (E)-2-((2-phenylhydrazono)methyl)pyridine (4H)

3

 3 Results of kinetic experiments for the imine formation study7.5.3.1 Sodium (E)-2-methoxy-5-(2-methoxyvinyl)benzenesulfonate formation

Figure 7 . 70

 770 Figure 7.70 Representative linear least-squares fit (" [ ] -" [ ] vs. t) of the imine formation between sulfonate aldehyde 1 and methyoxylamine C in phosphate buffer (160 mM NaH 2 PO 4 / Na 2 HPO 4 + NaOD) pH 4.6 at 25 o C. The final solution is 20 mM. The slope of the fit corresponds to the second order rate constant; R 2 vaues shown.

Figure 7 . 71

 771 Figure 7.71 Representative linear least-squares fit ( " [ ] -" [ ] vs. t) of the imine formation between sulfonate aldehyde 1 and acethydrazide D in phosphate buffer (160 mM NaH 2 PO 4 / Na 2 HPO 4 + NaOD) pH 4.6 at 25 o C. The final solution is 20 mM. The slope of the fit corresponds to the second order rate constant; R 2 vaues shown.

Figure 7 . 79

 779 Figure 7.79 Representative linear least-squares fit ( " [ ] -" [ ] vs. t) of the imine formation between Salicylaldehyde 4 and pentylamine B in CD 3 OD at 25 o C. The final solution is 20 mM. Slope correspond to the second order rate constant; R 2 vaues shown.

Figure 7 . 80

 780 Figure 7.80 Representative linear least-squares fit ( " [ ] -" [ ] vs. t) of the imine formation between Salicylaldehyde 4 and O-benzylhydroxylamine F in CD 3 OD at 25 o C. The final solution is 20 mM. The slope of the fit corresponds to the second order rate constant; R 2 vaues shown.

Figure 7 . 81

 781 Figure 7.81 Representative linear least-squares fit ( " [ ] -" [ ] vs. t) of the imine formation between Salicylaldehyde 4 and Benzhydrazide G in CD 3 OD at 25 o C. The final solution is 20 mM. The slope of the fit corresponds to the second order rate constant; R 2 vaues shown.

Figure 7 . 82 Figure 7 .

 7827 Figure 7.82 Representative linear least-squares fit ( " [ ] -" [ ] vs. t) of the imine formation between Salicylaldehyde 4 and Phenylhydrazine H in CD 3 OD at 25 o C. The final solution is 20 mM. The slope of the fit corresponds to the second order rate constant; R 2 vaues shown.

Figure 7 .Figure 7 .

 77 Figure 7.84 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of 1 + B + C + D + E at pD 8.5 as a function of time.

Figure 7 .

 7 Figure 7.86 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of + B + C + D + E at pD 5.0 at equilibrium.

Figure 7 .

 7 Figure 7.87 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of + B + C + D + E at pD 8.5 at equilibrium.

Figure 7 .

 7 Figure 7.88 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of 2 + B + C + D + E at pD 11.4 at equilibrium.

Figure 7 .

 7 Figure 7.89 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of 3 + B + G + H as a function of time.

Figure 7 .

 7 Figure 7.90 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of 3 + B + F + G + H as a function of time.

Figure 7 .

 7 Figure 7.91 1 H-NMR spectra of imine formation in CD 3 OD in the mixture of 4 + F + G + H as a function of time.

Table 1 )

 1 . Pour chaque paire d'imines, à la fois les réactions aller et retour ont été suivies avec et sans addition de L-proline comme catalyseur. Les procédés d'échange d'imines suivent une cinétique de réaction réversible de premier ordre et, dans la plupart des cas, atteignent un

équilibre. Les études cinétiques conduisent à une vitesse calculée et aux constantes d'équilibre listées dans la Table 1. Avec un chargement en catalyseur de 10mol%, l'échange C=N/C=N a été accéléré environ 22 fois (Table 1, Entrée 4).

Table 1 Réactions

 1

d'échange imine/imine dans des bibliothèques d'imines [2×2] avec l'organocatalyseur 10 mol% L-proline dans une solution de DMSO-d 6 /D 2 O 99/1, 10 equiv. BIS-TRIS à température ambiante (t.a.).

Table 2 .

 2 Forts de l'utilisation réussie de l'organocatalyse pour la génération de BCDs d'imines, son extension à d'autres réactions apparentées a été étudiée. En particulier, l'échange C=C/C=N, impliquant deux types différents de liaisons doubles, est considérablement prometteur pour former des bibliothèques dynamiques de grande diversité. La condensation donnant des dérivés de barbiturates de benzylidène a donc été étudiée dans le but de réaliser des procédés d'échanges réversibles. Les barbiturates de benzylidène 2a-2d et les imines 1b, t-v, comme montré dans la Table 2, ont été choisis comme substrats. Les réactions ont été réalisées en utilisant des quantités équimolaires de dérivées de benzylidène et de composants imines (19.35 mM chacun) dans un mélange de DMSO-d 6 /D 2 O 99/1 à 60 o C avec 10 mol% de L-proline comme organocatalyseur. Comme Pour chaque cas, les compositions des mélanges sont données à un temps de réaction pour lequel aucun changement dans la distribution des composants a été détecté par intégration des signaux des spectres RMN pour des temps plus longs.

pour l'étude sur les échanges C=N/C=N mentionnés précédemment, les réactions ont été conduites avec l'addition de 1% de D 2 O, mais sans tampon de BIS-TRIS à cause de l'hydrolyse rapide des benzylidènes dans ces conditions. A la fois les réactions aller et retour ont été suivies par spectroscopie

1

H-RMN. En comparaison avec l'échange C=N/C=N, une plus grande température fut nécessaire pour obtenir des vitesses de réaction comparables. Tout d'abord, pour la réaction dans DMSO-d 6 /D 2 O 99/1 à 60 o C, une grande quantité de produits d'hydrolyse (∼20%) a été observée. Dans le but d'éviter, ou du moins de réduire la quantité d'hydrolyse, les réactions d'échange ont été ensuite réalisées en présence de moins d'eau. La réaction entre 2b et 1v a été réalisée avec 0.5% (DMSOd 6 /D 2 O 99.5/0.5) ainsi qu'avec 0.2% (DMSO-d 6 /D 2 O 99.8/0.2) d'eau ajoutée. Les produits 2c et 1u ont été obtenus dans ces conditions (en moyenne 20% chacun), mais une hydrolyse significative était toujours observée. Dans le but de réduire davantage la quantité de produits d'hydrolyse, toutes les réactions d'échange furent réalisées dans le DMSO-d 6 pur à 60 o C, avec les produits d'échange observés en présence de moins de 10% de produits d'hydrolyse. Les résultats sélectionnés sont décrits dans la

Table 2

 2 Les réactions d'échange sélectionnées catalysées par la L-proline entre un ensemble de produits Knoevenagel/imine. Les proportions (%) des différents composés dans les réactions d'échange C=C/C=N entre les barbiturates de benzylidène et les imines dans le DMSO-d 6 à 60 o C.

h = 4-méthoxybenzaldéhyde, i = 4-(diméthylamino)benzaldéhyde, m = 4-méthoxybenzaldéhyde hydraté, n = 4-(diméthylamino)benzaldéhyde hydraté.

Table 3

 3 La sélection des transformations organocatalysées par la L-proline sur un ensemble de constituants Knoevenagel/Knoevenagel. Les paramètres cinétiques et thermodynamiques des réactions d'échange deKnoevenagel. Temps

Table 5

 5 Les

	Entrée	Composé de départ	a

paramètres cinétiques et thermodynamiques pour les réactions d'échange choisies entre les sels d'ammonium N-allyl-N,N-anilinium ou N-benzyl-N,N-diméthylanilinium 1a-1f et les amines tertiaires aromatiques de type N,N-diméthylaniline 4a-4e dans un ratio 1/1 à une concentration de 60 mM dans CD 3 CN à 60 o C. Temps de demi-vie t 1/2 . Proportion (%) des différents

composés. a = bromure d'allyle, b = iodure d'allyle, c et d = produits de réarrangement amino-Claisen, e = bromure de benzyle, f = iodure de benzyle. Dans cette table seul le cation organique est indiqué.

Table 6

 6 Echanges de composés entre les sels de N-benzylpyridinium (6a-f) et les pyridines (7a-d) dans CD 3 CN par irradiation dans le four à micro-ondes à 300 W à 150 o C pour 60 min. Les proportions (%) des différents composés. a = bromure de benzyle et b = bromure d'allyle.

	Entrée Réaction	a )	Distribution de composés e )			K eq
				6a	7b	6b	7a	a
	1	6a + 7b 6b + 7a	f r	14 14	16 16	35 35	33 33	2 2	5.16
				6e	7b	6f	7a	b
	2	6e + 7b 6f + 7a	f r	16 11	22 16	30 34	29 35	3 4	3.99

a ) f, Réaction aller; r, Réaction retour. b ) Erreur sur l'intégration des signaux 1 H-RMN: ±4%. c ) Composé non observé. d ) n.d., non déterminé.

Table 7

 7 La

	Entrée 1	Réaction 3 + B + F + G + H	Temps [h] 0.05	Distribution de composés [%] a ) 3B 3F 3G 15 -b ) 3	3H -b )
			0.48	28	5	54	13
			2.63 21.8	<1 -b )	10 16	64 53	26 32
	2	4 + B + F + G + H	0.03 1.4 3.5 21	42 -b ) -b ) -b )	6 27 29 35	4 16 9 -b )	23 58 63 65

distribution des composés des BCDs des réactions de compétition de différents systèmes. La concentration finale est de 20 mM. Les quantités relatives ont été obtenues par intégration des signaux

1

H-RMN des protons -CH=N contre une référence interne

(1,4-

dioxane). a ) Erreur sur l'intégration 1 H-RMN: ±5%. b ) Composé non formé. c ) n.d.; non déterminé. a) b) La conception et l'étude de ces expériences pourraient être appliquées à d'autres systèmes CCD et pourraient fournir une base pour la recherche d'imines structurellement stables sous différentes conditions. Cela pourrait aussi être appliqué pour la transformation régiosélective de molécules possédant différents groupes fonctionnels dans le but de sélectionner différents produits sous sélection cinétique ou thermodynamique. Le chapitre six décrit les conclusions générales présentées dans chaque chapitre. Le chapitre sept fournit les données expérimentales où sont décrites les synthèses et les caractérisations des composants utilisés dans la thèse. De plus, une analyse des données sur la cinétique des réactions d'échange imine/imine et ammonium quaternaire/amine tertiaire est fournie.

  Here again, the efficiency of benzylidene exchange depended on the nature of the head group substituent in these Michael acceptors. Considering first the pair of compounds 2a, bearing an electron-donating group (EDG), and 3d, bearing an electron-withdrawing group (EWG), the cross-exchange reaction is expected to yield the products 2d and 3a (Table2.7, Entry 1). The 1 H-NMR spectrum of the mixture after the exchange reaction started showed new signals at 4.73, 4.94, 5.32, 6.21, 7.26, 7.63, 7.76, 7.91, 9.50, and 12.2 ppm, which were assigned to the Michael-type adducts XI and XII shown in Scheme 2.9.

	NC	CN	NC	CN	NC	CN	NC	CN	NC	CN
										S
			NMe 2		OMe				NO 2
		3a		3b		3c		3d		3e
		O		O		O		NC	CN
	NC	O	NC	O	NC	O
									N
			NMe 2		OMe		NO 2
	3f In addition, the electrospray high resolution mass spectrum also supported the formation of 3g 3h 3i
	Figure 2.11 Structure of the benzylidene malononitrile derivatives (3a-3i) used in the adducts XI and XII, showing respectively peaks at m/z 338.343 ([M -+H + +Na + ]+
	present study CH 3 OH+H 2 O) and 360.324 ([M+H + ] + CH 3 OH)
	Benzylidenebarbiturates (2a-d, 2f-g) and benzylidenemalononitriles (3a-3e, 3i)
									d, 2f-g) and differently
	substituted benzylidenemalononitriles (3a-3e, 3i) as depicted in Scheme 2.8. The
	barbiturate-benzylidene compounds are easily hydrolyzed in DMSO-d 6 /D 2 O 99/1 solution
	so that pure DMSO-d 6 (given as containing less than 0.02% of H 2 O) was chosen as a
	solvent. Even then, some contribution of hydrolysis could not be avoided.

were selected as substrates for this exchange study. The reactions were carried out with equimolar amounts of the benzylidene derivatives (12.8 mM each) in pure DMSO-d 6 as well as in the presence of 10 mol% L-proline. The corresponding kinetic parameter (halflives t 1/2 ) (the half-lives of the reactions were determined by integration of the decreasing 1 H-NMR signals of the starting material as a function of time and analyzing the curve obtained) and %composition of the final solutions are listed in Table

2

.7. Equilibrium constants were not calculated, due to the occurrence of variable amounts of hydrolysis and because some reactions did not reach equilibrium in a reasonable time.

Scheme 2.8 Representation of the C=C/C=C cross-exchange reaction between barbiturate-benzylidene (2a

-d, 2f-g

) and differently substituted malononitrile-benzylidenes (3a-e, 3i) in DMSO-d 6 at 60 o C.

  The reverse reaction, starting with 2b and 3a (Table2.7, Entry 6), gave 2a and 3b in similar amounts to those of the forward reaction and approached equilibrium after 98 h in the presence of 10 mol% L-proline. Again, in the absence of L-proline, the exchange The exchange reaction between 2f and 3b (Table2.7,Entry 7) and its reverse reaction between 2b and 3e (Table2.7, Entry 8), yielding essentially identical mixtures in the presence of 10 mol% L-proline and were faster than other L-proline catalyzed

	reaction was significantly slower with exchange products formed only in trace amounts
	(about 1% each) after 4 days, with little change after 22 days where only 2a (1%) and 3b
	(2%) were observed. For both forward and back reactions (in the presence of L-proline),
	hydrolysis products were formed in yields of less than 4%.
	Knoevenagel
	formation was confirmed by HR-MS data with a peak at m/z 287.21 ([M -+2H 3 O + ]). The
	hydrolysis products in the presence of L-proline were less than 4%. Equilibrium was
	reached after 29 h in the presence of 10 mol% L-proline but in its absence the reaction was
	extremely slow, barely showing exchange after 23 h (1% each of the products 2b and 3a).

1

H-NMR spectrum showing an OH signal at 12.18 ppm and doublet peaks at 4.74 and 6.20 ppm of about 5% intensity under these conditions both in the presence and absence of L-proline.

Formation of XII was also confirmed by the electrospray high resolution mass spectrum showing a peak at m/z 346.34 ([M+H 3 O + ]).

Next, compounds 2a and 3b, both bearing EDGs, were reacted (Table

2

.7, Entry 5), giving 2b (19%) and 3a (24%) as products at equilibrium after about 29 h. The 1 H-NMR doublet signals at 4.48 and 6.09 ppm, observed during the exchange process in the presence of L-proline, are characteristic of the Michael-type adduct XI (1%), whose After 20 days, 2b and 3a formed in 12% yield each, showing that the reaction in the absence of catalyst was extremely slow. The uncatalyzed reaction did not show any Michael-adduct formation and involved the formation of trace amounts (1%) of hydrolysis products. cross-exchanges, approaching equilibrium after 6 h. The Michael-type adduct XI was observed in trace amounts (1%) for both forward and reverse reactions, showing the characteristic doublets peaks at 4.46 and 6.07 ppm. Electrospray high resolution mass spectroscopy was used to confirm the formation of the addition product showing a peak at m/z 287.2 ([M -+2H 3 O + ]). In the absence of L-proline, exchange products could only be observed after 23 h for both forward and reverse reactions. The equilibrium was approached after 128 h and 532 h for forward and backward directions, respectively.

Table 2 . 7

 27 Kinetic and equilibrium parameters for Knoevenagel cross-exchange reactions (Scheme 2.8). Half-life (t 1/2 ), (-) = reaction too slow to determine the parameter, n.a. = not applicable. Proportions [%] of the different compounds in the cross-exchange reaction C=C/C=C between benzylidenebarbiturates and benzylidene-malononitriles in DMSO-d 6 at 60

	Entry a ) 1b 1c 2b	t 1/2 [h] 50 45 n.a. 142 Reaction Time[h] e ) 164 144	Compound Distribution [%] Starting compound 2a + 3d 2a 3d 2d 3a a 35 30 5 11 1 33 26 5 13 2 Starting compound 2d + 3a 2d 3a 2a 3d a 33 50 -b	c 6 4 c	g -b ) -b )	g	i -b ) -b )	i	B 3 4 B	M 3 3 M	XI -b ) 2 XI	XII 6 7 XII

o C. a = 4-dimethylaminobenzaldehyde, b = benzaldehyde, c = 4-nitrobenzaldehyde, d = 4-methoxybenzaldehyde, e = 2-thiophene carboxaldehyde, f = 9-julolidenecarboxaldehyde, g = 4-(dimethylamino)benzaldehyde hydrate, h = benzaldehyde hydrate, i = 4-nitrobenzaldehyde hydrate, j = 4-methoxybenzaldehyde hydrate, k = 2thiophene carboxaldehyde hydrate, l = 9-julolidene carboxaldehyde hydrate, B = barbiturate, M = malononitrile, and XI, XII = Michael-type adducts.

Table 2 . 8

 28 Proportions (%) of the different compounds in the metathesis reaction C=C/C=C between benzylidene-barbiturates and benzylidene-ethylcyanoacetate in DMSO-d 6 at 60 o C. f = 4dimethyl aminobenzaldehyde, h = 4-nitrobenzaldehyde, i = 4-methoxybenzaldehyde, j = 4nitrobenzaldehyde hydrate, B = barbiturate, E = ethylcyanoacetate.

	Entry a ) 1b 1c 2b 2c 3b 3c 4b 4c a ) b, blank reactions, and c, catalyzed reaction with 10 mol% L-proline as a catalyst. b ) Error on 1 H-NMR Reaction Compound Distribution [%] b ) Time [h] Starting Compound 2a + 3h 2a 3h 2d 3f f h B E 94 c ) 48 47 2 1 1 1 <1 d ) 1 94 41 38 3 5 5 5 <1 d ) 4 Starting Compound 2d + 3f 2d 3f 2a 3h f h j E 74 34 51 -e ) -e ) 2 8 4 <1 d ) 74 25 62 -e ) -e ) 2 4 7 <1 d ) Starting Compound 2a + 3g 2a 3g 2b 3f f i B E 178 37 37 7 16 1 <1 d ) 1 <1 d ) 121 29 29 13 20 1 2 4 1 Starting Compound 2b + 3f 2b 3f 2a 3g f i B E 151 46 46 -e ) -e ) <1 d ) 8 <1 d ) <1 d ) 121 15 53 7 6 <1 d ) 4 14 1 signal integration, ∼4-5%.

c ) The reaction started. d ) Only traces of product detected. e ) Compound not observed.

Table 2 . 9

 29 The absorption maxima and molar absorptivity values for 2a -2f and 3a -3f (1x10

	Entry 1 2 3 4 5 6 7 8 9 10 11	Compound 2a 2b 2c 2d 2f 2g 3a 3b 3c 3d 3e		λ max (nm) 465 373 325 318 371 490 440 354 311 310 353		ε (cm -1 mol -1 L) 66496 30118 18981 13601 24566 81132 64687 28850 23429 18402 21891
	In a search for other organocatalysts, piperidine, as a secondary amine like
	O					O
	HN O	NH O	NC	CN S	DMSO-d 6 10 mol% Piperidine	HN O	NH O S	NC	CN	N
		N
		2g		3e			2f			3i
	and 3i were formed in significant yield (Figure 2.13), with 2g (19%), 3e (15%), 2f (31%),
	and 3i (31%) present after 25 h (equilibration time). The half-life (t 1/2 ) of this reaction was
	6 h. The hydrolysis products and Michael-adduct were observed but were less than 3%

L-proline, was investigated for its effects on these C=C/C=C exchanges. Benzylidenebarbituric acid 2g and benzylidene-malononitrile 3e, both bearing electron-donating group were selected for examination using this catalyst as shown in Scheme 2.11.

Scheme 2.11 Representative metathesis C=C/C=C reaction between 2g and 3e in 100% DMSO-d 6 at 60 o C using piperidine as catalyst.

The 1 H-NMR spectrum of the exchange reaction mixture in the presence of piperidine showed a broad peak at 10.8 ppm belonging to the barbituric protons of 2g (Figure

2

.12) indicating that they could possibly exchange with the -NH proton of piperidine. A control experiment was conducted by adding piperidine to 2g alone in DMSO-d 6 and a broad peak at 10.8 ppm was again observed. The exchange products 2f each. In addition, this reaction was conducted in the presence of 10 mol% L-proline, giving the compound distribution 2g (30%), 3e (22%), 2f (23%), and 3i (23%) after 23 h with half-life (t 1/2 ) of 5 h.

Table 3 .

 3

	Entry 1 2 3 4 5 6 a	Starting compounds 4a + 1b 4e + 1v 4b + 1f 4c + 1u 4b + 1b 4e + 1u 4b + 1v 4a + 1u 4d + 1v 4a + 1t 4d + 1u 4b + 1t	Reaction time e ) [min] f a ) 68 r b ) 69 f a ) 2 r b ) 2 f a ) 60 r b ) 13 f a ) 11 r b ) 3 f a ) 11 r b ) 3 f a ) 3 r b ) 2	Compound distribution [%] 4a 1b 4e 1v 22 21 28 29 18 17 33 32 4b 1f 4c 1u 13 14 37 36 13 14 37 36 4b 1b 4e 1u 6 4 44 45 5 4 46 45 4b 1v 4a 1u 9 7 43 42 7 8 45 41 4d 1v 4a 1t 5 4 46 45 3 3 47 47 4d 1u 4b 1t 14 14 37 35 12 14 38 36	a <1 c ) <1 c ) b <1 c ) <1 c ) b -d ) <1 c ) a <1 c ) <1 c ) a <1 c ) -d ) b <1 c ) -d )	e -d ) -d ) c <1 c ) <1 c ) e -d ) -d ) b -d ) -d ) d <1 c ) -d ) d <1 c ) -d )	f -d ) -d ) f -d ) -d ) f -d ) -d ) f -d ) -d ) f -d ) -d ) f -d ) -d )	K eq 2.5 7.3 92.1 30.4 152.8 7.3

1 Proportions (%) of the different compounds in the C=C/C=N cross-exchange reactions between benzylidene-(dm)barbiturates and imines in CDCl 3 at room temperature. a = 4dimethylaminobenzaldehyde, b = benzaldehyde, c = 4-nitrobenzaldehyde, d = 4methoxybenzaldehyde, e = 2-thiophene carboxaldehyde.

Table 3 . 2

 32 Optimization energy for the starting materials (4a, 1b), exchange products (4e, 1v), and intermediate 4a + 1b using the DFT (B3LYP/6-31G* (d, p)) method.

	Entry	Compounds	Energy (a.u.)	Sum energy (a.u.) a )	Relative Energy (kcal/mol) a,b )
	1 2 3 4 5	4a 1b 4a + 1b (I) 4e 1v	-971.86202778 -916.84376413 -1888.68656230 -1158.63374140 -730.	-1888.70579 (S.M.) -1888.68656230 (I) -1888.70391 (P)	∆E I-S.M. = +12.0 ∆E P-I = -10.8 ∆E P-S.M. = -1.1

  3 , DMSO-d 6 , CD 3 OD, CD 3 CN, and CD 3 CN/D 2 O 9/1 for reaction at 20 mM concentration. It was found to occur in all these solvents, as shown in Table4.1.However, the best conditions were in CD 3 CN at 60 o C, for which the fastest rate of exchange to give 3a-Br and 4a was observed (Table4.1, Entries 5 and 6).This exchange is consistent with the reaction following either an S N 2 or an S N 2' mechanism. The reaction also occurred in DMSO-d 6 but was slower than in CD 3 CN, consistent with the fact that charge dispersal must occur in the transition state and thus is favoured in a solvent which is a poorer ion solvator. Also, the reactions which were performed in CD 3 CN/D 2 O 9/1 containing 10% of polar protic solvent (D 2 O; the heavy water contains deuterons and not protons, but it would still be classified as a protic solvent), showed a slower rate of exchange than in CD 3 CN. The reaction in a pure polar protic solvent (CD 3 OD) was slow also. In addition to any influence it may have on transition state properties (see above), a protic solvent can strongly solvate nucleophiles

Table 4 . 1

 41 Optimization of conditions in the exchange reaction between 1a and 2a. In this table only the organic cation is indicated, all anions are bromide. Error on 1 H-NMR signal integration: ±4%. b ) Only trace amount of compound was detected.

	Entry	Cat./equiv	Solvent	T/ o C	Time [days]	Compound Distribution [%] a ) 1a 2a 3a 4a
	1 2 3 4 5 6 7 8 9	-TEAI/1 -TEAI/1 -TEAI/1 -TEAI/1 -	CDCl 3 CDCl 3 DMSO-d 6 DMSO-d 6 CD 3 CN CD 3 CN CD 3 CN/D 2 O (9/1) CD 3 CN/D 2 O (9/1) MeOD	rt rt 60 60 60 60 60 60 60	6 6 2 2 2 2 11 11 2	40 34 39 32 8 1 41 17 48	40 31 39 32 <1 b ) <1 b ) 37 17 48	10 18 8 14 43 46 11 34 <1 b )	10 17 13 21 49 53 11 33 <1 b )
	10	TEAI/1	MeOD	60	2	45	45	4	3
	a )

Table 4 . 2

 42 Optimization of conditions in the exchange reaction between 3a and 4a. In this table only the organic cation is indicated, all anions are bromide.

	Entry 1 2 3 4 5 6 7 8 9 10	Cat./equiv -TEAI/1 -TEAI/1 -TEAI/1 TEAI/2 TEAI/4 -TEAI/4	Solvent CDCl 3 CDCl 3 CD 3 CN CD 3 CN MeOD MeOD MeOD MeOD DMSO-d 6 DMSO-d 6	T/ o C rt rt 60 60 rt rt rt rt 60 60	Time [days] 8 8 16 16 6 6 5 5 10 10	Compound Distribution [%] a ) 3a 4a 1a 2a 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b ) 50 50 -b ) -b )

a ) Error on 1 H-NMR signal integration: ±4%. b ) Compound not observed.

Table 4 . 3

 43 Screening results of the S N 2' exchange reaction for various pairs under different conditions. In this table only the organic cation is indicated, all anions are bromide.

	Entry	Reaction	Cat./ equiv	Solvent	T/ o C	Time [h]	Compound Distribution [%] a ) 1a 2c 3c 4a
	1 2	1a + 2c 1a + 2c	-TEAI/1	CD 3 CN CD 3 CN	60 60	64 64	4 1	13 16	43 43	40 41
	3 4	3c + 4a 3c + 4a	-TEAI/1	CD 3 CN CD 3 CN	60 60	72 72	3c 50 50	4a 50 50	1a -b ) -b )	2c -b ) -b )
							1a	2d	3d	4a
	5 6	1a + 2d 1a + 2d	-TEAI/1	CD 3 CN CD 3 CN	60 60	41 41	8 6	21 12	37 42	34 40
	7 8	3d + 4a 3d + 4a	-TEAI/1	CD 3 CN CD 3 CN	60 60	41 41	3d 50 50	4a 50 50	1a -b ) -b )	2d -b ) -b )

a ) Error on 1 H-NMR signal integration: ±4%. b ) Compound not observed.

Table 4 .

 4

6 Kinetic and Thermodynamic Parameters for the exchange reaction between the Nbenzyl-N,N-anilinium salts 5a-c-Br and the N,N-dimethylaniline derivatives 4a-4c in 1/1 ratio at 20 mM concentration in CD 3 CN at 60 o C. Half-life t 1/2 . Proportion (%) of the different compounds. a = benzyl bromide, b = benzyl iodide. In this table only the organic cation is indicated, all anions are bromide.

Table 4 . 7

 47 .8). Initial exploration of solvents and temperatures (Table4.7) led to the use of microwave irradiation at 150 o C (300 W) for 60 minutes in acetonitrile-d 3 which provided the best reaction conditions. The composition of the final solutions and the corresponding equilibrium constants (K eq ) are listed in Table4.8. Optimization of solvent in the S N 2 exchange reaction of 6a and 7b.a

	Entry 1 2 3 4 5 6 7 8 9 10 a ) Reaction condition: The final solution is 20 mM. Solvent T/ o C MW b CD 3 CN 60 no rt no CDCl 3 90 no DMSO-d 6 130 yes CD 3 CN 150 yes CD 3 CN 150 yes CD 3 CN 150 yes CD 3 CN 150 yes CD 3 CN 150 yes CD 3 CN CD 3 CN 150 yes	Time (min) 1440 1440 1440 10 15 30 45 60 90 120	%-product 6b -c ) -c ) 4 6 27 31 34 35 35 35

b ) MW, microwave irradiation at 300 W. c ) Product did not form.

Table 4 . 8

 48 Component exchange between the N-benzylpyridinium salts (6a-f) and the pyridines (7ad) in CD 3 CN under microwave irradiation 300 W at 150 o C for 60 min. Proportion (%) of the different compounds. a = benzyl bromide and b = allyl bromide.

	Entry	Reaction	a )	Compound distribution [%] b )			K eq
				6a	7b	6b	7a	a
	1	6a + 7b 6b + 7a	f r	14 14	16 16	35 35	33 33	2 2	5.16
	2	6a + 7c 6c + 7a	f r	6a -c ) -c )	7c -c ) -c )	6c 50 50	7a 50 50	a -c ) -c )	n.d. d )
				6a	7d	6d	7a	a
	3	6a + 7d 6d + 7a	f r	13 12	15 16	36 35	33 35	3 2	6.23
				6e	7b	6f	7a	b
	4	6e + 7b 6f + 7a	f r	16 11	22 16	30 34	29 35	3 4	3.99
	a ) f, Forward reaction; r, reverse reaction.

b ) Error in 1 H-NMR signal integration: ±4%. c ) Compound not observed.

d

) n.d., not determined.

Table 4 . 9

 49 Reversible component cross-exchange between N-benzyl-(6a, 6b) and N-allyl-(6e, 6f)pyridinium bromides in CD 3 CN using microwave irradiation 300 W at 150 o C. Proportion (%) of the different compounds. 7a = pyridine, 7b = 4-methylpyridine, a = benzyl bromide and b = allyl bromide.

	Reaction	Time [min]	a )	Compound distribution [%] b ) 6e 6b 6f	6a	7a/7b/a/b
	6b + 6e	30	f	16	27	12	9	13/5/6/11
	6f + 6a	90 30	f r	16 6	25 14	15 25	12 17	13/4/5/10 16/3/10/9
		90	r	9	17	25	18	14/3/7/8
	a ) f, Forward reaction; r, Reverse reaction. b ) Error in 1 H-NMR signal integration: ±4%.

Table 4 .

 4 10 The S N 2 exchange reaction between 8a and 7a in CD 3 CN and its converse.

  .1) for equimolar (20 mM) mixtures of the aldehyde and a single amino compound at 25 o C. In most cases, imine formation was much slower in DMSO-d 6 than in D 2 O (the formation of hydrazone 1E, was the only exception). Imines 1A and 1B derived from aliphatic amines formed about 4000-fold slower in DMSO-d 6 than in D 2 O. That imines derived from these aliphatic amines form faster in D 2 O may in part be due to the different solvation in DMSO-d 6 and D 2 O. The oxime 1C also formed faster in D 2 O than DMSO-d 6

but gave a lower %-product at equilibrium. Compound 1D derived from acethydrazide did not form in DMSO-d 6 and was obtained only in a very low %-yield in D 2 O (6% after 120 h). Lastly, 1E was formed slower in D 2 O but was more stable than in DMSO-d 6 , attaining a higher %-product (92% yield after 140 h). Given these preliminary results indicating that imine formation from sulfonate aldehyde 1 and various amino compounds is mostly faster and proceeds further in D 2 O than in DMSO-d 6 , D 2 O was chosen as a solvent for all other studies.

Table 5 .

 5

1 Reaction time and %-product of imines formed in separate reactions between sulfonate aldehyde 1 and each of several amino derivatives in DMSO-d 6 and D 2 O. Equimolar, 20 mM solutions of reactants were employed at 25 o C.

Table 5 .

 5

2 Reaction time, %product formation, and second order rate constants for imine formation from sulfonate aldehyde (1) and several amino derivatives (B, C, D, E) separately. Reactions were performed in D 2 O in phosphate buffer at pD 5.0, 8.5, and 11.4. Solutions were equimolar (20 mM) in each reactant.

  Error in1 H-NMR determination: ±5%. b ) Reaction time indicates the time when the reactions were terminated. c ) Rate constant is calculated from a fit to a second-order reaction over the first 10% of the reaction. d ) Compound not formed. e ) n.d., not determined. f ) Reaction reached equilibrium within the time of mixing.

	2 3 a )	8.5 11.4	1D 1 E 1B 1C 1D 1 E 1B 1C 1D 1 E	37 31 4 36 -d ) 44 41 39 28 44	1.0 0.5 1.2 0.03 f ) 3.7 -d ) 3.4 0.03 f ) 17 142 24	203.5 20.32 4.25 n.d. e ) 3.05 n.d. e ) 5.12 n.d. e ) 0.537 0.172 2.575

Table 5 .

 5

	3 Equilibrium distribution of imines from a mixture of the sulfonate aldehyde buffers of pD 5.0, 8.5 and 11.4). for all reactants at 25 o C.
	Entry	pD	Time [h]
	1 2 3	5.0 8.5 11.4	1.0 11.2 1.2

a ) Reaction times indicate when no further change (<2%) was detectable in the concentrations.

1

H-NMR determination: ±5%. c ) Compound not formed.

Table 5 .

 5 2, Entry 1) which showed that 1C was formed fastest and

	Equilibrium distribution of imines 1B, 1C, 1D, and 1E in dynamic mixtures generated from a mixture of the sulfonate aldehyde 1 and different amino derivatives B, C, buffers of pD 5.0, 8.5 and 11.

Table 5 .

 5

	3, Entry 1),

Table 5 . 4

 54 Separate studies of imine formation between pyridoxal phosphate (2) and several amino derivatives (B, C, D, E) inD 2 O/phosphate buffers at pD values of 5.0, 8.5, and 11.4 at 25 o C. The initial concentration of each reactant was 20 mM.

	Entry 1 2 3 4 5 6 7 8 9 10 11 12 a	pD 5.0 8.5 11.4	Product 2B 2C 2D 2E 2B 2C 2D 2E 2B 2C 2D 2E	Time [min] a ) 120 5 120 120 120 5 120 120 120 5 5 5	Compound [%] b ) -c ) 99 2 99 -c ) 99 3 99 -c ) 99 4 70

Table 5 .

 5

	5 Equilibrium distribution of imines mixture of pyridoxal phosphate 8.5 and 11.4 at 25 o C. All reactions
	Entry	pD
	1 2 3 a ) Error in 1 H-NMR integration: ∼ 5.0 8.5 11.4

Table 5 . 6

 56 Equilibrated times and final imine percentages for the reaction between 2-pyridyl aldehyde 3 and amino derivatives B, F, G, and H separately in CD 3 OD. The study was performed at 25 o C using reactant concentrations of 20 mM.

	Entry	Product	Product [%] a )	Time [h] b )
	1 2 3 4 a ) Error in 1 H-NMR integration: ±5%. b ) Reaction time indicates the time when no further change (<2%) 3B 86 2 3F 92 18 3G 93 18 3H 92 18 could be detected.

Table 5 . 7

 57 Time-dependence of component distributions for competitive reactions of pairs of amino derivatives with a 2-pyridyl aldehyde (3).Reaction times indicate the certain time of the reaction. b ) Error in 1 H-NMR integration: ±4-5%. c ) Compound not formed. d ) n.d.; not determined.

	Entry 1 2 3 4 5 a )	Reaction 3 + B + F 3 + B + G 3 + B + H 3 + F + G 3 + F + H	Time [h] a ) 0.03 4.5 27.2 0.03 3.5 0.03 0.3 4.9 0.03 0.18 0.03 3.9	Compound distribution [%] b ) 3B 3F 34 -c ) 45 55 15 85 23 n.d. d ) 13 n.d. d ) 28 n.d. d ) 57 n.d. d ) 27 n.d. d ) n.d. d ) 67 n.d. d ) 87 n.d. d ) 2 n.d. d ) 30	3G n.d. d ) n.d. d ) n.d. d ) 6 87 n.d. d ) n.d. d ) n.d. d ) 9 13 n.d. d ) n.d. d )	3H n.d. d ) n.d. d ) n.d. d ) n.d. d ) n.d. d ) -c ) 18 73 n.d. d ) n.d. d ) 15 68

Table 5 . 8

 58 Time-dependence of a DCL distribution in the competitive reactions between mixed amino derivatives and 2-pyridyl aldehyde (3) in CD 3 OD. The study was performed at 25 o C using initial reactant concentration of 20 mM each.Reaction times indicate the certain time of the reaction. b ) Error in 1 H-NMR integration: ±5%.

	Entry 1 2 3 a )	Reaction 3 + B + G + H 3 + F + G + H 3 + B + F + G + H	Time [h] a ) 0.03 0.99 2.00 0.03 0.42 1.6 0.05 0.48 2.63 21.8	Compound distribution [%] b ) 3B 3F 23 n.d. d ) 9 n.d. d ) -c ) n.d. d ) n.d. d ) 1 n.d. d ) 10 n.d. d ) 20 15 -c ) 28 5 <1 10 -c ) 16	3G 7 74 79 -b ) 2 3 3 54 64 53	3H -c ) 18 21 11 56 71 -c ) 13 26 32

c ) Compound not formed. d ) n.d.; not determined.

Table 5 .

 5 10 Time-dependence of the distribution of DCL components in the competitive reaction of mixed amino derivatives with salicylaldehyde 4.

	Entry 1 2 3	Reaction 4 + B + G + H 4 + F + G + H 4 + B + F + G + H	Time [h] a ) 0.05 0.74 2.54 0.05 0.8 4.0 0.03	Compound distribution [%] b ) 3B 3F 44 n.d. c ) 2 n.d. c ) 2 n.d. c ) n.d. c ) 2 n.d. c ) 12 n.d. c ) 18 42 6	3G 6 24 18 -d ) 1 1 4	3H 32 74 81 14 66 81 23

  1 H-NMR (400 MHz, CDCl 3 , 25 o C; δ/ppm): 4.87 (s, 2 H), 7.39-7.24 (m, 5 H), 7.63 (d, J = 4.8 Hz, 2 H), 8.36 (s, 1 H), 8.69 (d, J = 4.9 Hz, 2 H). 13 C-NMR (100 MHz, CDCl 3 , 25 o C; δ/ppm): 65.0, 122.0, 127.2, 128.0, 138.4, 142.8, 150.4, 159.8. ESI-MS: m/z: 197.1 (100%). HRMS (ESI, m/z): calcd. for C 13 H 13 N 2 197.107; found 197.107.

  H-NMR (400 MHz, CDCl 3 , 25 o C; δ/ppm): 1.31-1.17 (m, 1 H), 1.37 (dd, J = 25.0, 12.3 Hz, 2 H), 1.64-1.52 (m, 2 H), 1.68 (d, J = 12.5 Hz, 1 H), 1.79 (dd, J = 28.1, 12.2 Hz, 4 H), 3.38-3.19 (m, 1 H), 7.29 (d, J = 6.0 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 8.39 (s, 1 H), 8.63 (d, J = 4.3 Hz, 1 H). 13 C-NMR (100 MHz, CDCl 3 , 25 o C; δ/ppm): 24.7, 25.6, 34.1, 68.6, 121.3, 124.5, 136.5, 149.3, 154.9, 159.5. ESI-MS: m/z: 189.1 (100%). HRMS (ESI, m/z): calcd. for C 12 H 17 N 2 189.139; found 189.141.

  C-NMR (100 MHz, CDCl 3 , 25 o C; δ/ppm): 22.4, 25.4, 39.3, 58.5, 120.3, 125.0, 136.8, 149.3, 154.2, 161.5. Anal. calc. for C 11 H 16 N 2 (176.258): C 74.96, H 9.15, N 15.89 ; found: C 74.87, H 9.16, N 15.69 ESI-MS: m/z: 177.1 (100%). HRMS (ESI, m/z): calcd. for C 11 H 17 N 2 177.139; found 177.138.

  1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 7.54 (d, J = 8.8 Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 8.25 (s, 1 H), 11.27 (s, 1 H), 11.41 (s, 1 H). 13 C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 119.7, 131.6, 134.6, 136.7, 150.1, 152.9, 161.5, 163.2.

	6. 5-(thiophen-2-ylmethylene)pyrimidine-2,4,6(1H,3H,5H)-trione (2f)

  1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 7.36 (dd, J = 5.0 Hz, 1 H), 8.18 (d, J = 3.9 Hz, 1 H), 8.28 (d, J = 4.6 Hz, 1 H), 8.57 (s, 1 H), 11.26 (s, 1 H), 11.30 (s, 1 H). 13 C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 111.6, 128.3, 136.3, 142.1, 145.7, 145.8, 150.2, 162.9, 163.5.

	7. 5-((1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)methylene)pyrimidine-2,4,6(1H,
	3H,5H)-trione (2g)
	Yield: 0.82 g, 88%. red solids. 1 H-NMR (400 MHz, DMSO-d 6 , 25 o C; δ/ppm): 1.89 (t, J = 5.5, 4 H); 2.68 (t, J = 5.7, 4H); 3.38 (t, J = 6.2, 4H); 7.99 (s, 1H); 8.06 (s, 2H); 10.77 (s, 1H); 10.92 (s, 1H). 13 C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 20.5, 26.9, 49.7, 107.3, 119.2, 120.0, 136.6, 148.8, 150.4, 154.9, 162.7, 164.9.

  C-NMR (100 MHz, DMSO-d 6 , 25 o C; δ/ppm): 13.9, 62.7, 106.7, 114.9, 124.1, 131.6, 137.2, 149.2, 152.6, 161.1.

	16. 2-(

.2 Study of Knoevenagel/Imine (C=C/C=N) derivatives exchange

  General Procedure for C=C/C=N Exchange. Stock solns. (40 mM, 0.4 ml) of Knoevenagel compounds were prepared in CDCl 3 . For each reaction, 350 µl of each soln.

	11. (E)-N-(4-(hexadecyloxy)benzylidene)-1-phenylmethanamine (1w)
							Yield: 0.52 g, 60%. White solid. 1 H-NMR (400 MHz, CDCl 3 ): 0.85 (t, J = 6.1, 3H), 1.21 -1.48 (m, 26H), 1.77 (t, J = 8.1, 2H), 3.97 (t, J = 6.8, 2H), 4.77 (s, 2H), 6.89 (d,
	J = 8.7, 2H), 7.30-7.33 (m, 5H), 7.69 (d, J = 8.4, 2H), 8.29 (s, 1H)
	1 H-NMR (400 MHz, CDCl 3 ): 0.85 (t, J = 6.8, 6H), 1.21 -1.34 (m, 19H), 1.51 -1.61 7.3
	(m, 4H), 3.62 (s, 2H), 3.83 (t, J = 7.8, 4H).
	8. 1,3-diheptyl-5-(4-(hexadecyloxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (4g)
	O C 7 H 15	N	O	N	O C 7 H 15		Yield: 0.32 g, 33%. Yellow solid. 1 H-NMR (400 MHz, CDCl 3 ): 0.86 (br, 9H), 1.21 -1.34 (m, 40), 1.44 (br, 2H), 1.62 6.8, 2H), 6.93 (d, J = 8.8, 2H), 8.27 (d, J = 9.2, 2H), 8.5 (s, (br, 4H), 1.79 (quint, J = 6.9, 2H), 3.94 (br, 4H), 4.04 (t, J =
							1H)
					O	C 16 H 33
	9. 5-(4-butoxybenzylidene)-1,3-diheptylpyrimidine-2,4,6(1H,3H,5H)-trione (4h)
	O C 7 H 15	N	O	N	O C 7 H 15 O	C 4 H 9	Yield: 0.332 g, 34%. Yellow solid. 1 H-NMR (400 MHz, CDCl 3 ): 0.86 (t, J = 6.5, 6H), 0.97 (t, J = 7.4, 3H), 1.20 -1.35 8.27 (d, J = 9.0, 2H), 8.47 (s, 1H). 2H), 3.93 (br, 4H), 4.05 (t, J = 6.6, 2H), 6.9 (d, J = 9.0, 2H), (m, 16), 1.48 (t, J = 7.2, 2H), 1.62 (br, 4H), 1.78 (quint, J = 6.9,
	10. 5-(4-ethoxybenzylidene)-1,3-diheptylpyrimidine-2,4,6(1H,3H,5H)-trione (4i)
	O C 7 H 15	N	O	N	O C 7 H 15		Yield: 0.465 g, 51%. Yellow solid. 1 H-NMR (400 MHz, CDCl 3 ): 0.86 (t, J = 6.1, 6H), 1.21 -1.36 (m, 16H), 1.44 (t, J = 6.9, 2H), 6.93 (d, J = 9.3, 2H), 8.28 (d, J = 9.3, 2H), 8.47 (s, 1H) 7.4, 3H), 1.57 -1.68 (m, 4H), 3.89 -3.98 (m, 4H), 4.11 (q, J =
					O	C 2 H 5
							275 | P a g e

  -88 o C, lit m.p. 87-88 o C. 1 H-NMR (CD 3 CN) δ ppm: 7.75 (d, J = 8.2 Hz, 2H), 7.61 (m, 3H), 5.59 (m, 3H), 4.44 (d, J = 5.6, 2H), 3.53 (s, 6H).

  13 C-NMR(100 MHz, CDCl 3 ): 21.0, 54.6, 71.1, 120.8, 124.8, 129.9, 131.4, 141.3. ESI-MS: 176.142 (100) (C 12 H 18 N + ; calc. 176.143). HR-ESI-MS: 302.0369 (100) (C 12 H 17 IN + ; calc. 302.0400).

  13 C-NMR(100 MHz, CDCl 3 ): 8.8, 58.0, 63.3, 122.7, 124.2, 129.4, 130.8, 131.3, 141.4. ESI-MS: 190.158 (100) (C 13 H 20 N + ; calc. 190.159). HR-ESI-MS: 316.0529 (100) (C 13 H 19 IN + ; calc. 316.064).

  H-NMR (CD 3 CN) δ ppm: 7.52 (d, J = 8.9 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.32 (t, J = 8.3 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 4.92 (s, 2H), 3.52 (s, 6H), 2.40 (s, 3H).

  C-NMR (100 MHz, CD 3 OD; δ/ppm): 113.2, 117.2, 120.6, 120.9, 120.94, 130.2, 130.5, 141.6, 146.1 158.2.

pD

5.0, 8.5 et 11.4) en fonction du pD après que l'équilibre soit atteint. Les quantités de composés ont été calculées à partir de l'intégration des des protons -CH=N-face à une référence interne(1,4-dioxane).

Acknowledgements

Abbreviations

Å

Uncatalyzed C=C/C=N exchange Processes between Knoevenagel and Imine Compound

Exchange Processes of C=N/C=N, C=C/C=N, C=C/C=C in DC CHAPTER 3 Scheme 5. 8 The reaction of neomycin and sulfonate aldehyde (1). The final concentration of neomycin was 20 mM and aldehyde, 20 mM. Next, the mole ratios of neomycin to sulfonate aldehyde (1) in the reaction solution were varied from 1:0.25, 1:0.5, 1:0.75, 1:2, 1:3, 1:6, and 1:10. All of these experiments showed similar results as the previous experiment (1:1 ratio). This further confirms that imine formation occurs at only one amine site on the neomycin. The fact that imine formation between neomycin and sulfonate aldehyde (1) was selective for only one position suggests that it is an example of kinetic and thermodynamic selectivity of imine formation for the biological compound. Further exploration is required to confirm the exact position of imine formation of neomycin in this case.

Uncatalyzed C=C/C=N exchange Processes between Knoevenagel and Imine Compounds in Dynamic

Synthesis and Characterization

1. N-allyl-N,N-dimethylbenzenaminium bromide (1a-Br) [39] The oil bath was preheated to 100 o C. Then dimethylaniline (0.38 mL, 3.0 mmol) was mixed with allylbromide (1.56 mL, 18.0 mmol) and refluxed for 2 hours. The white precipitate appeared as the reaction progressed changing to be a pink colored solid later. The reaction mixture was allowed to cool to room temperature. Then, the mixture was washed by diethyl ether and dried under vacuum for 4 hr to afford 1a as a white solid, 0.55 g, 76% yield). m.p. not determined, hygroscopic white solid. 1 H-NMR (CD 3 CN) δ ppm: 7.82 (d, J = 8.1 Hz, 2H), 7.60 (m, 3H), 5.59 (m, 2H), 5.52 (m, 1H), 4.55 (dd, J = 1.8 Hz, 2H), 3.58 (s, 6H). [40] 4,N,N-trimethylaniline (0.87 mL, 6.0 mmol) and allyl bromide (1.0 mL, 12.0 mmol) were combined in acetone. The solution was refluxed for 4 hours and then the solvent was evaporated. The product was dried under vacuum to afford 1b as a yellow liquid (1.235 g, 81% yield). M.p. not determined, liquid at room temperature. [41] 4-methoxy-N,N-dimethylaniline (4c) (0.4533 g, 3.0 mmol) was combined with allylbromide (0.78 mL, 9.0 mmol). The reaction was stirred at 40 o C for 10 minutes and a white solid precipitated as the reaction went on. The product was washed with diethyl ether and dried under vacuum for 4 hours to afford 1c as a white solid (0.6052, 74% yield). M.p.

N-allyl-N,N,4-trimethylbenzenaminium (1b-Br)

N-allyl-4-methoxy-N,N-dimethylbenzenaminium bromide (1c-Br)

. Representative linear least-squares fit (1/[A] vs. t) during the first 10% of the exchange reaction between N-allyl-N,N-anilinium salt (1a-Br) and different aliphatic tertiary amines (2a-e) in CD

Sodium (E)-2-methoxy-5-(2-methoxyvinyl)benzenesulfonate formation

Sodium (E)-2-methoxy-5-(2-methoxyvinyl)benzenesulfonate formation

Sodium (E)-2-methoxy-5-((2-methylhydrazono)methyl)benzenesulfonate formation

Résumé en anglais

This thesis describes the dynamic covalent chemistry (DCC) of imine/imine, Knoevenagel/imine, and Knoevenagel/Knoevenagel exchange. L-proline is shown to be an excellent organocatalyst to accelerate the formation of dynamic covalent libraries (DCLs). The interconversion between Knoevenagel derivatives of dimethylbarbituric acid and imines is found to occur rapidly in the absence of catalyst. A new class of DCC based on nucleophilic substitution (S N 2/S N 2') component exchange between quaternary ammonium salts and tertiary amines is developed, by the use of iodide as a catalyst. The exchange reactions between pyridinium salts and a pyridine derivative generate dynamic ionic liquids. Finally, kinetic and thermodynamic selection of imine formation in a DCC is perfomed in aqueous solution and organic solvent.