Complex surface architectures: the discovery of the third orthogonal dynamic covalent bond

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Thesis

Reference

LASCANO, Santiago

Abstract

The SOSIP-TSE methodology was until recently based on only two orthogonal dynamic covalent bonds : Disulfides and hydrazones. The introduction of boronate esters to these architectures was possible, but they lacked orthogonality. We here show the first known example of three completely orthogonal dynamic covalent bonds, namely disulfides, hydrazones and boronate esters. After chosing the appropriate substrates, with adapted reactivity and stability, the conditions for the orthogonal exchange reactions were determined by experiments in solution. The compatibility of this system with surface architectures was then determined by 1H-NMR and mass spectrometry. The system was further enhanced by using more stable boronate esters, that showed impressive stability in acidic and aqueous conditions, while keeping their dynamic character when needed. These new more stable boronate esters were also shown to have impressive characteristics in surface architectures, showing their potential.

LASCANO, Santiago. Complex surface architectures: the discovery of the third

orthogonal dynamic covalent bond. Thèse de doctorat : Univ. Genève, 2016, no. Sc. 5044

URN : urn:nbn:ch:unige-919979

DOI : 10.13097/archive-ouverte/unige:91997

Available at:

http://archive-ouverte.unige.ch/unige:91997

Disclaimer: layout of this document may differ from the published version.

1 / 1

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UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES Section de chimie et biochimie

Département de chimie organique Professeur Stefan Matile

Complex Surface Architectures:

The Discovery of the Third

Orthogonal Dynamic Covalent Bond

THÈSE

pour obtenir le grade de Docteur ès sciences, mention chimie par

Santiago LASCANO de

Bassecourt (JU)

Thèse N° 5044 GENEVE

Atelier Repromail Uni Mail 2016

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A mis padres, mis abuelos y mis hermanos.

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Remerciements

accueilli au sein de son groupe et permis de me développer en tant que scientifique et en tant que personne. Je remercie aussi profondément le Dr.

années.

Je suis très reconnaissant au Prof. Davide Bonifazi et au Dr. Fabien thèse et les en remercie. Merci aussi à mes chers collègues et amis Paola Morelli, Dr. Yoann Cotelle et Dr. Éline Bartolami pour leurs contributions à la relecture et correction de celle-ci. Merci beaucoup bénéficié de son expérience et de son aide.

Merci à tous les professeurs et enseignants qui ont formé mon esprit tout au long de ma carrière scolaire et académique. Leur passion contagieuse a toujours

Je remercie du

la chance de partager tant de moments de joie ou de frustration, tant de rires mais aussi de bières et qui sont devenus de véritables amis. Je ne peux pas tous les citer, mais je remercie particulièrement le Dr. Jadwiga Gajewy pour sa générosité et sa bonne humeur.

Merci à mes amis pour leur soutien et ces bons moments de rires !

Merci de tout

inconditionnellement dans tout ce que je faisais. Merci à mes parents José et

-même. Ils nous ont appris à être curieux et à avoir soif de connaissance, je ne peux que

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son soutien et son oreille attentive lorsque le besoin est fait sentir. Merci à mon frère Clemente pour sa joie de vivre et sa vivacité intellectuelle qui se traduit en un flot de blagues de qualité certes inégale, mais qui ne manque jamais de me soutirer un sourire ! Merci à ma grand-mère Josefina qui était toujours aussi fière de ses petits-enfants et nous poussait toujours à

le savoir vers la Sc

bien plus difficile et bien moins belle. Son amour, son soutien et sa joie de

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List of Publications

1. Bolag, A.; López-Andarias, J.; Lascano, S.; Soleimanpour, S.; Atienza, C.;

Access Toward Oriented Charge-Transfer Cascades in Triple-Channel Angew. Chem. Int. Ed. 2014, 53, 4890-4895.

2. Charbonnaz, P.; Zhao, Y.; Turdean, R.; Lascano, S.; Sakai, N.; Matile, S.

Chem. Eur.

J. 2014, 20, 17143-17151.

3. Cotelle, Y.; Chuard, N.; Lascano, S.; Lebrun, V.; Wehlauch, R.; Bohni, N.;

Lörcher, S.; Postupalenko, V.; Reddy, S. T.; Meier, W.; Palivan, C. G.;

Chimia 2016, 70, 418-423.

4. Lascano, S.; Zhang, K.-D.; Wehlauch, R.; Gademann, K.; Sakai, N.;

Chem. Sci.

2016, 7, 4720-4724.

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I

Summary

The SOSIP-TSE methodology, introduced by the Matile group in 2011, is based on two orthogonal dynamic covalent bonds: disulfides and hydrazones.

The orthogonality of these bonds allows to sequentially build surface-bound molecular architectures of increasing complexity. This approach allowed to produce a large variety of systems, with a large library of chromophores, with two or three channels, to build oriented multicolored antiparallel redox gradients, etc.

The strength of orthogonal dynamic covalent bonds, however, resides in the use of several of them in a same system. Until recently, there was not any example of three fully orthogonal organic dynamic covalent bonds. The Matile group made a first advancement towards this goal by installing orthogonally boronate esters on a SOSIP-TSE architecture. However, their sensibility to acid and water made them too fragile to attempt hydrazone exchange.

Convinced that the discovery of the third orthogonal dynamic covalent bond was not only exciting but also possible, and based on previous work done in the group, we started studying ways of making the three reactions fully orthogonal.

Using partners with particularly high binding constants, we could achieve boronate esters stable enough to avoid exchange almost completely in the presence of another diol. While this boronate ester was relatively strong, the use of normal or even milder conditions for hydrazone exchange proved fatal for it. To solve this problem, the use of a novel catalyst for hydrazone exchange allowed us to use extremely mild conditions, mild enough to keep the boronate ester intact (Figure S1).

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II

Figure S1. Exchange reactions used to identify orthogonality under conditions A (DMSO-d6, 10% D2O, 2% DIPEA), B (2.0 mM benzylthiol, 2.0 mM TEA in DMSO-d6) and C (1.0 mM catalyst, 1.5 mM TFA in DMSO-d6).

With these results, we synthesized a surface architecture containing the three bonds and applied the conditions we had developed for hydrazone exchange. Analysis of the reaction mixture showed that we could recover the product of the hydrazone exchange, with the boronate ester still intact.

The result was an important step for us, but a step nevertheless, towards sturdier systems. Because it is not always possible to use mild conditions for hydrazone exchange and the possibility of working with harsher conditions without degradation is desirable, we intended to design and obtain stronger

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III boronate esters. The objective was to make them strong enough to withstand aqueous or harsh acidic conditions without cleavage, while still retaining their dynamic character.

After measuring the dissociations constants of a large library of boronic acids with a smaller library of diols by UV-Visible spectroscopy, a smaller sample of representative examples was chosen and subjected to more experiments. These chosen boronate esters were tested for acid sensitivity, hydrolytical stability and directed exchange by ¹H NMR spectroscopy. The experiments showed that the boronate esters of pinanediol with the majority of the tested boronic acids exhibited a remarkable stability towards both acid and water, while maintaining a dynamic character.

With these excellent results, we wanted to test the compatibility of the best boronic acid-diol pair on a surface architecture. After installation of the boronic acid with a weaker diol, the best binder could be installed by exchange. A subsequent boronate ester exchange showed that the system is sufficiently dynamic to allow addition and removal of the best binding diol in the right conditions (Figure S2).

Additionally, after installing the pinanediol, hydrazone exchange was made in two of the standard conditions used with SOSIP-TSE architectures. The reaction mixture was analyzed by LC-MS and showed the unambiguous presence of the desired compounds, proving its stability in both standard hydrazone exchange conditions and in chromatography.

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IV

Figure S2. Successive boronate ester exchange on SOSIP-TSE architecture of S15 and S16 successively, in conditions A and recovery of S17 by hydrazone exchange, in acidic conditions.

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V Architectures built using the SOSIP-TSE methodology were also used as photosystems and the influence of different parameters on the performance of the photosystems were studied. The first project was based on the synthesis and characterization of the surface-bound analogs of molecular dyads and triads.

After synthesis of quaterthiophene-EDOT SOSIP, TSE with a fullerene derivative or a quaterthiophene-fullerene dyad was made. The components were selected for their electronic levels, in order to create a lateral redox gradient (Figure S3). However, the photocurrent generation proved to be lower in the case of the triad-analog. Nevertheless, the charge recombination efficiency was also lower for the triad, hinting at a possible effect of the organization in the architecture of the electrode.

Figure S3. Electronic levels of the components of surface architectures S18 and S19. The arrows show the movement of the electrons (e^-) and holes (h⁺) upon photoexcitation.

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VI

Finally, the effect of the incorporation of two chromophores with hydrophobic or hydrophilic side-chains was studied. By introducing different ratios of two chromophores with either the same or different side-chains, we wanted to learn if any structurizing effect would arise from the mixtures and how they would translate in terms of photophysical properties of the resulting electrodes.

In the case of the mixture of chromophores with identical side-chains, the measurements seemed to show that the best results were obtained at higher or lower ratios of components, while equimolar mixtures seemed to give poorer performances. In the case of mixtures of chromophores with different side- chains, the results seem to point towards a linear dependence on the ratio of chromophores and a lack of interaction between the different components.

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VII

Résumé

La méthodologie SOSIP-TSE, introduite par le groupe Matile en 2011, se base sur deux liaisons dynamiques covalentes orthogonales : les disulfures et

séquentielle

surfaces. Cette approche a permis de produire une grande variété de systèmes, avec un grand nombre de différents chromophores, avec un ou deux canaux conducteurs de charges, de construire des gradients redox antiparallèles, orientés et multicolores, etc.

Le véritable potentiel des liaisons dynamiques covalentes orthogonales,

dynamiques covalentes pleinement orthogonales. Le groupe Matile fit le premier pas vers ce but en installant des esters de boronate orthogonalement sur une architecture basée sur la méthodologie SOSIP-TSE. Cependant, la fragilité desdits esters de boronate les rendait incompatibles avec un échange

Convaincus que la découverte de la troisième liaison dynamique covalente orthogonale était une quête non seulement passionnante mais aussi possible,

commencer à étudier différentes approches pour rendre ces trois types de liaisons dynamiques covalentes orthogonales.

particulièrement élevées, nous avons pu obtenir des esters de boronate suffisamment stables pour avec un autre diol présent en solution. Bien que cet ester de boronate fût relativement fort, les conditions standards, ou légèrement plus douces, pour un échange

menèrent à sa dégradation

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VIII

pour accélérer récemment décrit dans

la littérature, suffisamment douces pour

Figure S1. utilisées pour étudier dans les conditions suivantes : conditions A (DMSO-d6, 10% D2O, 2% DIPEA), B (2.0 mM benzylmercaptan, 2.0 mM TEA dans DMSO-d6) and C (1.0 mM catalyseur, 1.5 mM TFA dans DMSO-d6).

En nous basant sur ces résultats, nous avons ensuite synthétisé une architecture moléculaire sur une surface contenant les trois types de liaisons et

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IX réactionnel nous a montré la présence du produit de

ntact.

Ce résultat fut particulièrement intéressant et important, mais ne fut

cependant systèmes plus stables et robustes.

contrôlées et aussi

sans observer de dégradation, nous souhaitions résoudre ce problème. Le but isamment forts pour supporter des conditions aqueuses ou fortement acides sans rupture de la liaison, tout en conservant leur nature dynamique.

ectroscopie UV-Visible, un échantillon

supplémentaires. Ces esters de boronate furent soumis à des tests sur leur hydrolytique et sur leur capacité à échanger en réponse à un stimulus chimique. Ces expériences furent menées et suivies par spectroscopie RMN ¹H et ont montré que les esters de boronate de pinanediol avec la plupart des acides boroniques étaient remarquablement stables en conditions aqueuses et acides, tout en gardant leur nature dynamique.

Avec ces excellents résultats en main, nous voulions tester la compatibilité de la meilleure paire acide boronique-diol dans une architecture de surface.

Après avoir placé voir couplé avec un diol plus faible, le meilleur diol fut installé dans le système par échange. Un autre échange montra

s conditions étaient utilisées (Figure S2).

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X

Figure S2.

type SOSIP-TSE, premièrement avec S15, puis avec S16, en conditions A.

n conditions acides permit la récupération de S17.

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XI En plus de cela, après avoir incorporé le pinanediol, un échange s les plus couramment utilisées avec la méthodologie SOSIP-TSE. Le milieu réactionnel fut analysé par LC-MS et montra sans équivoque la présence du produit désiré,

conditions standards s et en chromatographie.

La méthodologie SOSIP-TSE fut aussi utilisée pour produire des

desdits photosystèmes fut étudiée. Le premier projet se basait sur la synthèse et

la caractérisation iées à des

électrodes.

Figure S3. Niveaux électroniques des composantes des architectures de surface S18 et S19. Les flèches montrent les mouvements des électrons (e^-) et des trous (h⁺) après photoexcitation.

- EDOT, nous avons incorporé soit un dérivé de fullerène, soit une dyade

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XII

quaterthiophene-fullerène. Les différentes composantes furent choisies en fonction de leurs niveaux électroniques afin de créer un gradient redox latéral (Figure S3). À notre surprise, la génération de photocourant est moins bonne recombinaison de charges pourrait indiquer

photophysiques.

latérales hydrophobes ou hydrophiles fut étudié. En introduisant différents ratios des deux chromophores, soit avec les mêmes chaînes latérales, ou avec des chaînes différentes, nous voulions découvrir si nous pouvions observer un effet structurant émerger des différents mélanges et comment cet hypothétique effet se traduirait pratiquement, en termes de propriétés photophysiques des électrodes.

Dans le cas des mélanges de chromophores avec des chaînes latérales identiques, les résultats semblaient montrer que les meilleures performances étaient obtenues lorsque le ratio était haut ou bas, alors que les mélanges équimolaires donnaient de moins bons résultats, suggérant une possible interaction négative entre les chromophores.

Dans le cas des mélanges de chromophores avec des chaînes latérales différentes, les résultats semblaient montrer une dépendance linéaire avec le ratio de chromophores. Ce résultat pourrait indiquer une contribution linéaire

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XIII

Chapter 1

INTRODUCTION

1.1. Boron and Organoboron Compounds

In 1979, the Nobel Prize in Chemistry was jointly awarded to Herbert C.

- and phosphorous-containing compounds, respectively, into important reagents in

[1] The story of how Brown got interested in the chemistry of boron is an interesting one.

Hydrides of Boron and Brown became interested in the hydrides of boron, which, at the time, were very rare substances. They were only made in two laboratories, one of

Schlesinger in the University of Chicago, where Brown ended up working on

particular book was because, at the time, they lived in great poverty and this

cents of sales tax.^[2]

a metaphor for the chemistry of boron itself. For the average organic chemist, boron and organoboron compounds are often seen merely as reagents or reactants, mostly reducing agents, Lewis acids or as transmetallation agents, for example in Suzuki-Miyaura couplings. However, when introduced to the domain, the richness and variety of the chemistry based on boron and organoboron compounds and its potential in a wide range of fields becomes evident. The following sections will try to give a brief but general overview of

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the field, with a particular focus on boronic acids and esters and their applications.

1.1.1. General Considerations on Boron

The fifth element in the periodic table, found at a concentration of 0.001%

[3] is a relatively rarely occurring element. As a pure substance, boron is very rare and exists either as an amorphous brown powder or as black crystals.^[4] With the rare exception of a few boron fluoride minerals, boron is only found in nature as oxygen-bound compounds, mostly in the form of borate minerals or boric acid, as sassolite. They are distributed widely in the environment and are found at measurable levels in rocks and soils as well as in nearly all natural waters.^[3]

Boron has been found to be an essential element for plants since the 1920s^[5], where it is thought to play a role in plant cell wall functions by ester crosslinking with carbohydrates as a boron diester.^[6] Boron is introduced in the food chain by herbivorous animals and is found in human blood and tissue in the range of 0.05 ppm to 10 ppm.^[7] Considerable evidence exists pointing that boron might also be essential to animals and humans.^[8] Additionally, natural bioactive molecules containing boron have been discovered such as Boromycin 1,^[9] Tartrolon 2,^[10] and Borophycin 3,^[11] (Figure 1) sparking interest in boron- containing drugs^[12] and resulting in the approval of Bortezomib 4 by the FDA,^[13] the first boronic acid-containing drug to be commercialized.

Anecdotally, a family of boron-containing pigments was also found and fully characterized from a more than 150-million-years old sample of the Jurassic putative red alga Solenopora jurassica.^[14] The simplest borolithochrome G (5) is shown in Figure 1.

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3 Figure 1. Structures of boron-containing bioactive and natural compounds.

Because of its electronic structure (1s² 2s² 2p¹), boron typically exists as a trigonal planar BR3 species 6 (Figure 2 a), where all three valence electrons engage in the formation of bonds, resulting in an sp² hybridization.^[3] The remaining empty pz orbital is the cause for much of the characteristic behavior of boron species and more particularly for their Lewis acidity, as this empty orbital will have a tendency to react with an electron donor to form a tetrahedral complex 7, thus complying with the octet rule (Figure 2 b). Because of this, boron is often described as electron deficient. Boron can also achieve the same result by -overlap with a suitable substituent X (8, Figure 2 c).^[15]

Figure 2. a) Trigonal planar form of a BR3 species; b) tetrahedral complex of a

BR3 -overlap with a substituent X on a

BR2X species. Adapted from reference.^[15]

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4

The electron-deficient nature of boron-containing compounds is reflected in the general high electrophilic reactivity of these molecules and can be seen in reactions such as oxidations, hydrolysis, alcoholysis and solvolysis with solvent containing donor atoms as well as in the formation of coordination compounds, particularly with nitrogen bases.^[16]

In these cases, boron forms strong covalent bonds with electronegative elements, particularly with oxygen; only fluorine forms stronger bonds with boron.^[3] This can be clearly seen in the reaction of borane with water to give boric acid, with methanol to give trimethyl borate and in general with the use of borane and borohydrides as reducing agents.

Organoboron compounds, where boron is linked to at least one carbon atom, can be obtained synthetically and are now widely found in organic chemistry, although arguably not to the extent of their full potential. The nomenclature of organoboron compounds depends on the nature and number of covalent bonds from boron to carbon (Figure 3).^[4]

Figure 3. Nomenclature of boron derivatives. Adapted from reference.^[4]

The B-C bond length, at around 1.55 1.59 Å, is not much greater than the typical C-C length (around 1.5 Å), and neither is the bond energy much smaller (323 kJ·mol^-1 versus 358 kJ·mol^-1).^[17] However, a dominant feature of organoborane chemistry is the ease with which it undergoes oxidative cleavage.

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5 The reason for this can be found in the difference in bond energy between C-O bonds and B-O bonds, respectively 384 kJ·mol^-1 and 519 kJ·mol^-1 in ethers and trigonal boronic acids.^[18] This remarkable strength of this bond is thought to result from the conjugation of the lone pairs of the oxygens with the empty pz

orbital of the boron, giving a partial double bond character to the B-O bond.^[18]

1.1.2. Boronic Acids and Derivatives

Boronic acids, in contrast to carboxylic acids, are not found in nature and are the product of a twofold oxidation of boranes. Their stability to atmospheric oxidation is understandably superior to the stability of borinic acids, as the latter result from the first oxidation of boranes. Their relative stability to oxidation, ease of handling and their unique properties and reactivity as mild organic Lewis acid have made boronic acids a particularly interesting class of synthetic intermediates of modern organic chemistry.

The stability of boronic acids, however, depends on their structure, and alkyl-substituted as well as some heteroaromatic boronic acids have been shown to have a limited shelf stability under atmospheric conditions,^[19] while aryl- and alkenylboronic acids are generally considered stable. It is worth mentioning that boronic acids might, upon dehydration, form linear or cyclic oligomeric anhydrides, such as boroxines (Figure 3). However, for synthetic purposes this behavior is inconsequential, as most reactions happen regardless of their acid or anhydride state.^[18] Anhydrides might, however, be a problem for analysis and quantification purposes.

Because of the wide availability of substituted arylboronic acids and their stability, they are probably amongst the most used of boronic acids. The difference in electronegativity between boron and carbon (B = 2.05 and C = 2.55) causes boron to behave as a weak electron donor on an aromatic ring, even though boron is electron deficient and could be expected to be an electron acceptor. However, this deficiency is compensated by the two electron-

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6

donating oxygens in the case of boronic acids. This can be seen by the very small ¹³C NMR alpha effect of a boronate group.^[20] It is also worth noting that in ¹³C NMR spectroscopy, carbons next to ¹¹B atoms tend to broaden, often making them disappear beyond noise limits, due to the quadrupolar relaxation of ¹¹B.^[18]

Although boron acts as a weak electron donor, some evidence suggest that B- -bonding exists to a certain extent. In arylboronic acids, the B-C bond distance is generally smaller than for alkylboronic acids and in the case of boronic acid 19, the B-C bond length (1.588 Å) is longer than in the case of phenylboronic acid 20 (1.568 Å). Crystal structure of compound 19 shows that, contrarily to 20,^[21] the boronic acid is not coplanar to the aromatic ring, for steric reasons, and the empty pz orbital can thus not conjugate with the aromatic ring.^[22] Further evidence can be seen when comparing the B-C bond distance in phenylboronic acid 20 and its adduct with diethanolamine, 21. For the latter, this distance increases by 0.045 Å,^[23] which can be interpreted as the effect of the coordination of the nitrogen to the vacant orbital of the boron, preventing

-bonding with the aromatic ring.

Figure 4. Selected arylboronic acids.

The acidic character of boronic acids in water has been known for decades, but it was only in 1959 that the structure of the boronate ion was determined.^[24]

Boronic acids do not act as Brønsted acids, releasing a proton from a hydroxyl group, as shown in Figure 5 a. Instead, the boron atom will accept an additional hydroxyl group and release a proton, as illustrated in Figure 5 b, resulting in a tetrahedral boronate.

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7 Figure 5.

Reaction of a boronic acid with water.

where boronic acids are thought to display Brønsted acidity. This is observed only when a tetrahedral conformation would be very disfavorable. This is the case for compound 24, as the tetrahedral form 25 would break the partial aromaticity of the central ring. In fact, evidence suggests that 26 is the conjugated base of compound 24.^[25]

Figure 6. Possible ionization equilibria of compound 24. Adapted from reference.

As exposed earlier,

proton transfer, via the coordination of a hydroxyl group and subsequent release of a proton. It is thus expected that more electrophilic boron atoms will better stabilize the resulting boronate anion and be, in general, more acidic.

This trend has been measured and quantified^[26] and, as a first approximation, the pKa of a boronic acid decreases with electron-withdrawing substituents and increases with electron-donating ones.

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8

Steric factors can also influence the pKa of boronic acids, boronic acid 27, for example, exhibits a higher pKa than the simple phenylboronic acid 20 (9.7 and 8.9 respectively). This is thought to be due to the steric inhibition of the formation of the tetrahedral boronate, as seen in Figure 7. When the methyl is at the 3- or 4-position, the steric effect disappears and the pKa values are much closer to that of phenylboronic acid 20.

Figure 7. Ionization equilibrium of o-tolylboronic acid 27. Adapted from reference.^[18]

Apart from electronic and steric factors, another main factor affecting the pKa of boronic acids is the anchimeric assistance of different groups to the electrophilicity of the boron atom. Anchimeric assistance is defined as the direct interaction of the reaction center with a lone pair of electrons of an atom - -bond contained within the parent molecule but not conjugated with the reaction center ^[27] Examples of this kind of interactions include 2-nitrophenylboronic acid 29, where it is believed that an oxygen of the nitro group interacts with the vacant orbital of the boron,^[22,28]

thus lowering its electrophilicity (Figure 8) and raising its pKa (9.2), both compared to phenylboronic acid 20 (8.9) and even more to its analog 4- nitrophenylboronic acid 30 (7.1). In this case, the anchimeric assistance of the nitro group is able to more than compensate the strong electron-withdrawing effect of this moiety.

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9 Figure 8. Examples of anchimeric assistance in boronic acids.

Other typical examples of anchimeric assistance include the so-called Wulff-type boronic acids, such as 31 (Figure 8), where the presence of an ortho-dialkylaminomethyl group lowers the pKa significantly, to around 5.2.

The precise behavior and structures involved in the acidification of the boronic acid was subject to much debate^{[29 32]} and only in 2006 was the currently accepted theory proposed.^[33] In this work, the authors use ¹¹B NMR evidence to show that, in aqueous 75% methanolic solution with HEPES, the first pKa

corresponds to the hydroxylation of the boron, while the second (after pH 9) should correspond to the deprotonation of the amine. The rationale for such an important decrease in pKa, by more than 3 units, is that the ammonium cation stabilizes the anionic tetrahedral boronate,^[33] however, a possible stabilization by hydrogen-bonding should not be excluded, as seen for 32 in Figure 8.

The behavior of compound 31 depends greatly on the nature of the solvent.

In aprotic solvents, such as CDCl3, 31 is found as a mixture of its open form, 31 33, where there is a N-B dative bond. In protic solvents, such as CD3OD, only the solvated form (32, where R = CD3) is observed.^[33] It is worth noting that even in aprotic solvents, there is always a small amount of the solvated form 32, which, according to the authors, is due to the minute amounts of impurities contained in the solvent, either water or other protic solvents. This shows the high propensity of this compound to adopt the solvated form 32.^[33]

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Another central example of anchimeric assistance are benzoboroxoles, or benzoxaboroles, currently the two most commonly used names for compounds derived from compound 34 (Figure 9).^[34] The oxaborole ring has been found to be extremely stable and to make benzoboroxoles less prone to hydrolysis to the corresponding phenol than the corresponding boronic acids.^[35] The great stability of the oxaborole ring translates in an extremely easy dehydration of ortho-boronobenzyl alcohols to the corresponding benzoboroxole.^[34] The pKa

of benzoboroxole 34 is around 1.5 units smaller than phenylboronic acid 20, at 7.3. This lower value has been rationalized by the release of the ring strain, upon formation of the tetrahedral boronate (35), from the planar trigonal boron (34).^[36]

Figure 9. Ionization equilibrium of o-tolylboronic acid benzoboroxole 34.

Compound 36 is an oddity among boronic acids, as ¹¹B NMR titration in water shows only the presence of tetrahedral boron in the whole tested pH range.^[37] It is thought that at pH < 5, the dominant form is the zwitterionic 37 (Figure 10), while an increase in pH will first deprotonate the nitrogen (38) and finally yield the tetrahedral trihydroxyboronate 39. In an aprotic solvent such as DMSO, 36 can only be observed in small amounts when increasing the temperature sufficiently to break the intramolecular B-O bond observed in 40, the main form in these conditions.^[37]

The analog 41 only shows the classical equilibrium observed with most boronic acids, with a calculated pKa of 8.87, only very slightly smaller than the simplest 20, confirming that the anchimeric assistance is essential for the particular behavior of 36.

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11 Figure 10. Structure and ionization equilibria of compounds 36 and 41.

Adapted from reference.^[37]

1.1.3. Boronate Esters

1.1.3.1. General Considerations

In an impressive series of publications over a period of 29 years, from 1911 to 1940, the absolute structural configuration of a library of saccharides and other compounds containing hydroxyls was determined by Böeseken et al., based on the knowledge that boric acid formed complexes with diols.^[38] A rise in acidity and conductivity was observed upon the formation of complexes with 1,2- and sometimes 1,3-diols. By keeping track of these changes upon the addition of saccharides, the relative configurations could be determined.

Surprisingly, it was not until 1954 that the same properties were observed with boronic acids. In their work, Kuivila et al.^[39] observed the formation of a new compound upon addition of phenylboronic acid 20 to a solution of mannitol, which was postulated to be a boronate ester, by analogy to the reaction with boric acid. This realization sparked a vivid interest in boronate esters and ever since, the interaction between boronic acids and sugars has been central in the field.

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12

However, boronate esters can happen with a large variety of substrates such as dicarboxylic acids,^[40] -hydroxy carboxylic acids,^{[33,41 44]} previously mentioned sugars,^{[45 48]} aliphatic diols,^{[49 51]} catechols,^{[52 55]} etc. One of the key properties of the formation of boronate esters is their rapidity and reversibility.^[56]

The formation of a boronate ester from the corresponding boronic acid and diol, here phenylboronic acid 20 and ethylene glycol 44, as well as their ionization, is depicted in Figure 11.

Figure 11. Equilibria for ionization 20 and 45 and for the formation of esters 45 and 46. Adapted from reference.^[57]

One very important characteristic of boronate esters is their higher acidity compared to their corresponding acids and differences in the order of several units of pKa are commonplace. For example, phenylboronic acid 20 has a pKa

of 9.0 in 0.1 M NaCl 1:2 (v/v) MeOH/water, while upon binding of this same boronic acid to fructose, the pKa [58] This change in pKa is commonly used for analyte recognition.^[30]

The explanation for such an increase in acidity is mostly based in the O-B-O bond angles. In an unbound phenylboronic acid, in a trigonal planar form, the O-B-O bond angles are expected to be of ~120°. In the case of cyclic boronate esters, it is expected that this angle will be reduced and the ring

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13 tension increased, of course depending heavily on the substrate. A good example where this can be seen is the crystal of a complex of two phenylboronic acid 20 with one fructose.^[59] In this case, the boron is in a planar trigonal form and the O-B-O bond angle is around 113° for both boronic esters.^[57]

It is expected that in the case of boronate esters, the tetrahedral sp³ hybridization provides a closer topographic match to the complex than the sp² hybridization to the trigonal planar form of a boronic ester. Indeed, it appears in crystal structures of boronate esters, that the O-B-O angles (102°, 106° and 110°)^[60] are closer to the ideal bond angle of tetrahedral sp³ orbitals, 109.5°.^[61]

1.1.3.2. Factors Influencing the Stability of Boronate Esters

From Figure 11, it can be seen that the formation of boronic esters can come either from the boronic acid, with an equilibrium constant named Ktrig, or from the boronate conjugate base, with an equilibrium constant Ktet.^[57] When no specific mention is made of the trigonal or tetrahedral state of the boron, it is assumed that the equilibrium constant is between free boronic acid, irrelevant of its hybridization, and the corresponding boronic ester (again, independently of its hybridization). In that case, the apparent equilibrium constant is named Kapp.^[62]

The precise mechanism of the formation of boronate esters is, at the very least, not well known. However, it is generally accepted that the boronate anion form has stronger binding strength towards diols than the corresponding trigonal boronic acid, thus that Ktet > Ktrig. This is one of the reasons given to explain the better binding of diols at higher pH.^[63] However, there is a controversy on the validity of this affirmation and the Ishihara group has shown this to be false in a variety of cases (mostly with acidic diols),^{[64 70]} although not all.^[71] It is worth noting that more acidic poly-hydroxyl species are known to exhibit considerable binding to the trigonal form.^[57] However, it is very

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14

probable that the answer heavily depends on a multitude of factors such as the boronic acid, the diol, the pH, the solvent, etc. The discussion on the topic is far from being closed.

lack of information about the state of the boron atom, the term boronate ester and boronic ester will be used interchangeably for both boronic esters (neutral trigonal form) and boronate esters (tetrahedral anionic form), without implying the state of the boron atom.

Independently from the actual mechanism, the binding with diols tends to be favored by a range of factors. In a first approximation, the binding constant increases with the introduction of electron withdrawing substituents on the phenylboronic acid aromatic ring. More generally, the binding constant increases with lower boronic acid pKa, as well as with a lower diol pKa. In a very interesting publication, Martínez-Aguirre et al. derived a set of equations describing the binding of diols with boronic acids as a function of their pKa.^[72]

The good correlation between predicted and experimental values showed the quality of this approach while also proving that the binding between two species is in great part determined by electronic factors. With their theoretical framework, the authors further predicted the logarithm of the Kobsmax values for combinations of boronic acid and diols of different pKa at the predicted optimum pH (Figure 12).

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15 Figure 12. Predicted logarithm of Kobsmax values corresponding to the optimum pH for boronic acid and diols of different pKa. Adapted from reference.^[72]

Even though the stability of a boronate acid/diol couple can be estimated by the pKa of the components in a first approximation, other factors are also extremely important and can sometimes dominate over the electronics.

Among these factors, steric effects have been shown to have dramatic effects on stability, as shown in a series of publications by Roy et al.,^[49,50,73] in which a series of diols were tested for their relative stability by quantifying the transesterification in chloroform of 45 with a library of diols (Figure 13).

Figure 13. Transesterification equilibrium used by Roy et al. to determine the relative stability of boronate esters. Adapted from reference.^[50]

Their results unequivocally showed the importance of the stabilizing effect of steric bulk, as well as other effects discussed further. This beneficial effect of

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16

steric hindrance on boronate esters stability is well known^[51] and commonly used to protect boronic acids in synthetic methods.

Indeed, the widespread use of pinacol 49 (Figure 14) as a protecting group for boronic acids is due to its high stability and pinacol boronates are routinely purified by chromatography and common substrates in Suzuki-Miyaura couplings. A variety of other protecting groups also rely on steric bulk to prevent the cleavage of the boronate esters and have been used as chirality inducers, such as 50-54.^{[74 81]} These highly stable boronate esters have the drawback of being rather difficult to cleave, which is usually done by destroying the diol unit with BCl3[80] or transforming the boronic ester into the corresponding borane^[82] or the difluoroborane,^[83] recovering the boronic acid after hydrolysis. Additionally, 55 has been shown to be even more stable towards hydrolysis than 50 or even pinanediol 54.^[51] It is important to point out that while steric hindrance can be greatly beneficial to overall stability, it can also be detrimental when excessive, lowering stability or formation rates.^[50]

Figure 14. Selection of sterically hindered diols used for stable boronate esters.

Another factor thought to increase the stability significantly is a small O-C- C-O dihedral angle in the diol and restricted rotations around the C-C bond, or rigidity.^[50,84] It is thought that a small dihedral angle, by having a smaller distance between oxygens, favors a smaller O-B-O angle, more similar to the

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17 angles found in sp³ hybridization than sp².^[84] Additionally, restricted, or lack of, rotation around the C-C bond favors preorganization, accelerating the formation of the boronate ester,^[50] which might explain the generally large binding constants of catechols. For similar geometric considerations, cis diols are strongly favored over trans diols, with 56 and 57 being much more stable than their trans counterparts 58 and 59 (Figure 15).

Figure 15. Cis diols and their trans analogs used by Roy et al.^[50]

Geometrical constraints also seem to result in higher stability for diols forming six-membered rings over those resulting in five-membered rings, while seven-membered rings are rather unstable (Table 1).^[50,85] However, this trend is generally inversed in carbohydrates where cis 1,2-diols generally form more stable boronates than the cis 1,3-diols, which are significantly more stable than trans 1,2-diols.

Anchimeric assistance has been shown to decrease the pKa of boronic acids and thus enhance the stability of the boronate esters. The effect of anchimeric assistance coming from the boronic acid was shown previously, but it can also originate from the diol itself. This can take the form of a dative bond from an amine^[50], such as the diethanolamine in 21, and ethynyl N-methyliminodiacetic acid (MIDA), of which the boronate ester 60 is a very useful building block for small molecule synthesis (Figure 16).^[86] From the boronic acid side, 61, an analog of 36, displays very good hydrolytical stability.^[87] The formation of tridentate boronate esters also increases the stability of boronate esters, as testified by the anomalously high binding constant of pentaerythritol (shown as the boronate ester 62), when compared to analogous 1,3-propanediol (Table 1).^[24] For the same reason, in 1:1 mixtures of p-tolylboronic acid and fructose, the major complex is tridentate 63.^[88,89]

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18

Figure 16. Examples of anchimeric assistance in boronate ester stabilization.

In a similar manner to multivalent binding to a boronate ester, multivalent binding to a polyol can also significantly increase the stability of the resulting boronate esters, and even inverse the selectivity for one substrate over another.

This was what the Shinkai group observed when synthesizing sensors 65^[30] and 66 (Figure 17).^[90] While the former had a standard selectivity,^[24] which appears to be inherent to most monoboric acids,^[91] with D-fructose > D-galactose >

D-glucose (Table 1), 66 showed an impressive reversal of selectivity, strongly binding glucose (Kobs = 1972 M^-1) over other monosaccharides, with the strongest being fructose (Kobs = 132 M^-1), in an aqueous methanolic phosphate buffer solution at pH 8.2.^[92] The authors postulated that the shape and size of the receptor closely matched those of glucose, causing the impressive increase in binding, and hypothesized that the complex adopted the pyranose conformation 67. Bielecki and coworkers, however, showed that this was true only in completely anhydrous conditions, and that in presence of water, it adopted the furanose conformation of 68, with the formation of a tridentate boronate ester.^[93]

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19 Figure 17. Examples of divalent boronic acid receptors and hypothesized structures of their complexes with glucose. Adapted from reference.^[94]

The similar sensor 69, designed by the Wang group,^[95] also showed impressive performances compared to the monoboronic acid 65, with the same inversion of selectivity and a very strong binding with glucose, as can be seen in Table 1.

Other subtler effects can also be used to indirectly increase the stability of boronate esters. For example, Lanni and coworkers have used hydrophobic moieties of increasing size to reduce the size and increase the hydrophobicity of the cavity of their covalent organic frameworks (COF).^[96] When comparing to the reference COF 70 (Figure 18), the more hydrophobic 71 showed an important increase in hydrolytical stability, which the authors assign to a water shielding of the boron atom by the hydrophobic chains, thus enhancing the stability.

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20

Figure 18. Covalent organic frameworks prepared by Lanni and coworkers.

Adapted from reference.^[96]

Solvent is also known to have an extremely important effect on the stability of boronate esters as shown, for example, by the more than twofold increase in binding constant for 64 with fructose, passing from 33% to 80%

CD3OD/D2O.^[97] Additionally, while it has been suggested in the literature that the nature and concentration of the buffer did not affect the binding constant of boronate esters, this has been shown to be wrong,^[98] and comparing values measured in different conditions should thus be made with extreme care.

Finally, high pH is commonly thought to increase binding,^[98] however this is not always true,^[99] and optimal pH depends on the pKa of both diols and boronic acids, among others.^[72]

As might appear evident from this chapter, boronic acid and esters have an extremely rich and complex chemistry, and their dynamicity, although it renders the precise description and understanding of the underlying processes

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21 more difficult, also makes them extremely interesting and contains a very large potential for all kind of dynamic systems.

Table 1. Binding constants of boronate esters.^a

Compound Ka (M^-1)

29 2.76^b

20 - propylene glycol 3.80^b

20 - catechol 17500^b

62 650^b

20 - 1,3-propanediol 0.88^b

65 - glucose 50^c

69 - glucose 1472^c

65 - fructose 940^c

69 - fructose 34^c

20 - fructose 4370

20 - galactose 276

20 - glucose 110

64 - fructose 115^d

64 - fructose 308^e

aThe presented values should only be compared when measured in the same conditions; ^bMeasured in water;^[24] ^cMeasured in phosphate buffer in MeOH/H2O 1:1, pH = 7.4;^[95] ^dMeasured in phosphate buffer in 33%

CD3OD/D2O, pH = 7.4;^[97] ^eMeasured in phosphate buffer in 60%

CD3OD/D2O, pH = 7.4;^[97]

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22

1.2. Dynamic Covalent Chemistry

Chemistry is often called the central science. Indeed, chemistry is at the interface between physics, biology, physiology, medicine, engineering, materials science, etc. and as such offers us the possibility to understand the underlying phenomena ruling Nature. Chemistry, and most particularly organic chemistry, also allows us to design and build molecules, assemble them in complex structures, make them react to stimuli, recognize other molecules, and, in general, accompl

imagination and by the current shared knowledge.

Building with organic chemistry is no different than building an object in the macroscopic world and we dispose of different sets of tools in both cases. In the same way that a nail creates a strong and permanent bond between two entities, a covalent bond will link two atoms in a strong and permanent way. If we want to create a weak and rapidly exchanging bond between two atoms, non-covalent bonds fill thi

shut. In between lies the screw, that can be strong in certain conditions or be removed easily with the right tool, and its chemical equivalent, the dynamic covalent bond (DCB). Dynamic covalent bonds can be defined as bonds that are strong, stable and permanent under certain conditions, while rapidly forming, breaking and exchanging in others.

In other words, the reactions involving traditional covalent bonds are generally performed under kinetic control, as the selectivity of a reaction is, in these cases, determined by the relative energies of the transition states of the different possible pathways. On the other hand, synthesis under thermodynamic control has been widely employed using the previously cited non-covalent bonds or interactions. The concept of the assembly of two or more molecules using these non-

by Jean-Marie Lehn, in 1978 already, his work in the field earning

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23 him the Nobel Prize in Chemistry in 1987. One of the main problems of these non-covalent assemblies, however, lies in their typically low kinetic stability, which complicates their isolation, characterization and application. Dynamic covalent chemistry is at the crossing of these two approaches, combining the best of both worlds with thermodynamic products and the robustness of covalent bonds.^[100] The reversibility of a reaction under thermodynamic control implies that the obtained products are determined by their relative

- -

[100] Unlike non-covalent thermodynamic products, however, with dynamic covalent bonds the exchanges are generally quite slower, reaching the equilibrium in a significantly longer time.^[101]

Dynamic covalent chemistry (sometimes abbreviated DCvC) can be defined as being adaptable chemistry.^[102] This means, practically, using dynamic processes (e.g. dynamic covalent bonds) allowing the exchange of different components or modules to create systems at different thermodynamic minima in response to different conditions or stimuli, such as solvent, temperature, pH, light, catalysts, etc. As it is easy to imagine from such a wide definition, the potential for such kind of chemistry is very large, and will be discussed in the following sections.

Closely related to the field of DCvC, the concept of dynamic combinatorial chemistry (DCC), was conceived independently by Jean-Marie Lehn at Strasbourg and Jeremy Sanders at Cambridge. DCC can be defined as chemistry where the system dynamically adapts not only to conditions or stimuli but also to a target, either a guest or a host, self-selects the best candidate or candidates and spontaneously amplifies the concentration of that or those selected systems. The limit between DCC and DCvC is not always clear and the precise definitions vary greatly. For example, DCC is sometimes considered as a general term covering both DCvC and dynamic non-covalent chemistry, which is also assimilated to supramolecular chemistry.^[102] For

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24

others, the term of DCvC, for example, does not necessarily imply the selection of a thermodynamic product by a separate host or guest, but rather the use of dynamic covalent bonds to create dynamic systems.^[101] In this work, DCvC will be used with the latter acception.

In the case of DCC, historically, in 1992 already, the notion was advanced that in order to develop synthetic receptors efficiently, a new approach had to be designed, mimicking the mammalian immune system and its combinatorial, selection and amplification elements.^[103] The idea at the time was that the equilibrium mixture of a library of macrocyclic hosts should be shifted by guests by selecting the best binder.^[103] The first work towards this idea was made by the group of Sanders with the transesterification of oligocholates,^[104]

achieving the first modest templating results in 1997.^[105]

Parallelly, in the mid-1990s, Lehn designed a system of metal helicates and observed that the major product in dynamic mixture was determined by the counterion that binds in the center of these helicates,^[106] thus starting the implication of Lehn in the field.

In the next sections, we will focus particularly on DCvC, the different available tools to work with, while focusing on particularly important ones.

1.2.1. Dynamic Covalent Bonds

1.2.1.1. Hydrazones

Hydrazones are made by condensation of a hydrazine with a carbonyl (Figure 19). This condensation can be made at neutral pH, however at a slow rate,^[107] while decreasing the pH generally increases the rate, by activating the carbonyl at the addition step and accelerating the dehydration by protonation.^[108]

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25 Figure 19. Condensation of a hydrazine with a carbonyl to give a hydrazone.

Hydrazones can be made from alkyl-, aryl-, or acyl-hydrazines, the latter being also called hydrazides, as well as aryl- or alkyl-aldehydes or ketones.

Kool and coworkers have screened a rather large library of reactants for the formation of hydrazones at physiological pH in water and measured the relative rate of formation.^[107,109] They discovered that substrates with acid/base-active moieties always accelerated the reaction, but also some more general trends.

For hydrazones,^[109] they discovered that lowering the nucleophilicity of the reacting amino group, either with electron-poor aromatics or electron- withdrawing substituents, such as carbonyls, slowed down the reaction, although not greatly. The rather small dependence of the rate of formation on the nature of the hydrazine was also confirmed by the group of Lehn.^[108]

On the carbonyl side,^[107,109] ketones are overall slower reactants than aldehydes, and among aldehydes, the aliphatic ones are the fastest by a large margin. The presence of electron-withdrawing moieties on aryl-aldehydes enhances the rate of formation, but the effects are moderate. The lower reactivity of aryl-aldehydes is attributed to the conjugation of the carbonyl with the aromatic ring, which is interrupted upon the formation of the tetrahedral intermediate.

Another way to accelerate the formation of a hydrazone is by using a catalyst. Probably the best known and oldest catalyst for this reaction is aniline. Adapted from a publication by Cordes on semi-carbazones^[110] and first developed for the catalysis of oxime ligation,^[111] it was then expanded to hydrazones by the Dawson group.^[112,113] However, aniline catalysis often requires excessively high concentrations and is problematic in biological applications because of its toxicity.^[114] A few attempts were made in order to

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26

improve on aniline,^{[115 117]} but probably the most successful was achieved in the Kool group, which proposed a large library of catalysts in a series of publications.[114,118,119] The authors aimed to produce better catalysts by increasing the nucleophilicity of the amino group while introducing an intramolecular proton donor. The mechanistic rationale is shown in Figure 20.

Figure 20. Proposed mechanism for the catalysis of hydrazone condensation with catalyst 77. Adapted from references.^[119,120]

Hydrazone condensation has been studied for a long time,[110,121,122] and is one of the earliest reactions used for bioconjugations due to its biomolecular orthogonality and because the two halves, the hydrazine and the carbonyl functional groups, can be easily installed into small molecules.^[107]

Bioconjugation represents a large part of hydrazone chemistry,^[123] but will not be further discussed here, as it falls outside of the field of DCvC.

Hydrazone exchange (Figure 21 a) can be seen as analogous to imine exchange, however hydrazones are in general considerably more stable than imines and as such are better suited for DCvC, as they are easier to keep inert when needed. The greater stability of hydrazones over imines has been attributed to the resonance forms of hydrazones that increase the negative- charge density on the carbon bound to the amine, thus lowering its

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27 electrophilicity and consequently slowing any hydrolysis (Figure 21 b).^[124]

Acylhydrazones, or hydrazones with electron-withdrawing substituents, are generally used over alkyl hydrazones, as the latter tend to be too stable (see above) to be used in DCvC.^[125]

Figure 21. a) Hydrazone exchange; b) Major resonance forms of hydrazone conjugates. Adapted from reference.^[124]

The mechanism for hydrazone exchange can be thought as analogous to the mechanism for hydrazone condensation shown in Figure 20, with an hydrazone replacing the starting aldehyde, and as such, the mechanism for the catalysis of this reaction should proceed in a similar way.

The large variety of examples of dynamic systems relying on hydrazones is a good indication of their versatility and usefulness. One interesting example is the work of the Sanders group with the divalent building block 92 (Figure 22).

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28

Figure 22. Structure of the major product 93 formed upon assembly of building block 92 in the presence of acetylcholine 94. Adapted from reference.^[126]

Building on previous work with similar building blocks,^[127,128] the authors showed that when 92 was left to react and exchange in an acidic solution, the mixture reached equilibrium after 3 days, with a series of cyclic oligomers, from the dimer to the hexamer with traces of higher oligomers. However, addition of a template, in this case acetylcholine 94, shifted the equilibrium first towards the cyclic dimer, but later to a new product, not observed without templation, the [2]-catenane 93, with a measured affinity of around 100 nM.

Experimental evidence seems to show that the Me3N⁺ group is essential for the binding.

Another very elegant example of amplification of a library member, is the work of the Lehn group^[129] in which the diketone 95 reacted with the pyridylhydrazine 96 to form a complex mixture of mono- and dihydrazones, with E or Z configuration (Figure 23). Upon addition of dibutylbarbiturate 97, the mixture was significantly simplified, as evidenced by ¹H NMR, by amplifying the formation of the hydrogen bonded complex 98.

Complex surface architectures: the discovery of the third orthogonal dynamic covalent bond

Thesis

Reference

Complex Surface Architectures:

The Discovery of the Third

Orthogonal Dynamic Covalent Bond

Remerciements

List of Publications

Summary

Résumé

Table of Contents

Chapter 1

INTRODUCTION

1.1. Boron and Organoboron Compounds

1.2. Dynamic Covalent Chemistry