The quest for function in systems with two dynamic covalent bonds
Marić, Ivana
DOI:
10.33612/diss.167788912
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Publication date: 2021
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Marić, I. (2021). The quest for function in systems with two dynamic covalent bonds: supramolecular self-assembly, self-replication and hydrogels for biomedical applications. University of Groningen.
https://doi.org/10.33612/diss.167788912
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Functional Systems
That Use One or More
Dynamic Covalent Bonds
1.
1.1 Systems Chemistry
For many years now, chemistry has had a central role among the sciences.1 Used as a tool to understand the fundamental principles of nature, develop drugs or materials, chemistry facilitated an era of transformative discoveries and technologies. However, the focus has been mainly on the synthesis and isolation of single molecules, rather than embracing complex mixtures and their emergent behaviors. In sharp contrast, nature has mastered interconnected systems for achieving complex operations, such as the paradigmatic example of life. A striking feature of emergent properties and behaviors of complex systems is that they arise from a collection of elements defined by individual characteristics but go well beyond the simple sum of parts.2
Chemists have started to embrace the systems approach3 in the past two decades, with the advent of technologies and tools to aid the study of interconnected mixtures of molecules. The field of systems chemistry aims to develop complex networks of inter-acting molecules and explore their emergent properties. Similar to complex systems present in nature, emergent behaviors of complex synthetic systems are a result of in-teractions between molecules that make a particular system, rather than components themselves.4 The dynamic nature of these networks and their self-organization are fundamental characteristics, making them widely applicable in areas ranging from materials science to functional, biomimetic systems. The field of systems chemistry also aims to understand an essential fundamental topic - emergent behavior in early evolution.5 The questions addressed by systems chemistry are often highly original and demanding, reflecting the versatile and interdisciplinary nature of the field. This thesis aims to study systems that use two orthogonal covalent chemistries, as well as non-covalent interactions, towards achieving different behaviors and functions (self-assembly, self-replication, hydrogelation, etc.). This work encompasses principles of both dynamic combinatorial and supramolecular chemistry, as tools for the con-struction of reversible reaction (covalent and non-covalent, respectively) networks, giving rise to the emergence of self-assemblies, susceptible to further modification for a specific outcome. In this introductory chapter, we aim to provide an overview of types of dynamic combinatorial chemistries, with an emphasis on functional systems that use more than one dynamic covalent bond. Also, the post-modification of supra-molecular assemblies for late-stage derivatization in terms of structure and function will be briefly discussed.
1.2 Dynamic Combinatorial Chemistry
Dynamic combinatorial chemistry (DCC)4,6-9 is a useful tool to generate complex networks of interconverting molecules, in which constituents undergo exchange to-wards an equilibrium point. DCC encompasses dynamicity on both molecular and supramolecular levels due to the lability of interactions that hold molecular entities together.
Dynamic covalent bonds are specific because of their dual behaviour. Depending on reaction conditions, they can be permanent and stable as covalent bonds, or labile and reversible as non-covalent bonds. Up until now, a plethora of reversible covalent bonds has been explored. The most frequently used dynamic covalent chemistries are disul-fide (S-S), acetal (C-O), imine (C=N), (acyl-)hydrazone (C=N), and boronic ester (B-O) exchange (Scheme 1.1a).6 Other promising alternatives are emerging (Scheme
1.1b), among which somewhat exotic in terms of reversibility, such as organometallic C-C bond formations,10 pericyclic,11 and radical reactions.12
R1SSR2 + R3 SSR4 R1 R2 + OR RO R1SSR4 + R3SSR2 R3 R4 OR’ R’O R3 R4 + OR RO R1 R2 OR’ R’O R1 NR2 + R3 NR4 R1 NR4 + R3 NR2 R1 N H NR + 2 R3 N H NR 4 R1 N H NR + 4 R3 N H NR 2 R1 N H N R2 + O R3 N H N R4 O R1 N H N R4 + O R3 N H N R2 O R1BOH OH R2 OH R2 OH R1BO O R2 R2 H2O + + disulfide acetal imine hydrazone acyl-hydrazone boronic ester a) b) thioesters hemiacetals hemiaminals nitrones alkenes ...
Scheme 1.1 a) The most common dynamic covalent bonds used in DCC; b) other promising alternative reversible chemistries.
Non-covalent interactions (hydrogen bonding, cation-π, and π-π interactions, metal-ligand exchange, hydrophobic interactions, etc.) due to their reversibility, comple-ment the toolkit of dynamic covalent bonds, rendering a vast repertoire of reactions for building dynamic chemical systems.
The work presented in this thesis is based on the two reversible chemistries: disulfide13 and acyl-hydrazone14 (Scheme 1.2).
Disulfides are generated by air oxidation of thiols or using other oxidizing agents. Disulfide exchange occurs through the nucleophilic attack of a deprotonated thiol on the S-S bond, which results in the formation of a new disulfide and regeneration of another thiolate anion. The exchange is highly pH dependant as it requires the pres-ence of a deprotonated thiol. Typically, pH 7-9 is considered a suitable range for the process to occur in the absence of any catalyst. When the system is depleted of thiols or thiolate anions by complete oxidation or protonation, respectively, the exchange is stopped. “Reactivation” of DCL can be achieved by the addition of a catalytic amount of reducing agent, allowing the system to re-equilibrate.6,7
While disulfide exchange is favoured at basic pH, under acidic conditions, aldehydes or ketones react with primary amines to form reversible imine bonds, and the equi-librium often lies towards the starting materials. However, the substitution pattern of the imine, both the carbonyl-derived and α-substituted amine components, can significantly influence the thermodynamic stability of C=N adducts. Concretely, N- or O- substituted amines have a higher nucleophilic character due to the presence of free electron pair on the adjacent atom to the reactive nitrogen, which consequentially increases the stability of the newly formed C=N bond by reducing the electrophilic-ity of the imine.15 Those products can undergo hydrolysis and exchange only under acidic conditions (pH 4 and below)16 or at higher temperatures.17 Electron withdraw-ing group (EWG), such as an acyl group, moderates this stabilizwithdraw-ing effect to the level where the equilibrium favours the product, which is still susceptible to the reactions of hydrolysis and transamination, even under acidic to neutral conditions.18 Therefore, acyl-hydrazones are considered to be adequate candidates for the use in DCC.
a) b) R1 S SR2 + R3 S R1 S S R3 + R2 S + R 2 SH R1 S S R2 R1 SH O2 H2O R1 NHNH2 + R2 R1 NH N + O H O H2O O R2
Scheme 1.2 a) Disulfide bond formation upon oxidation of thiols (top) and disulfide exchange in the presence of deprotonated thiol (bottom); b) acyl-hydrazone condensation and exchange.
Figure 1.1 a) Schematic representation (the font size corresponds to the concentrations of library mem-bers) and b) illustrative representation of the selection/adaptation process in dynamic combinatorial chemistry. The free energy landscape of an exemplary DCL shows that starting building blocks can form different products through the formation and breakage of reversible bonds. Upon the addition of an external template, one of the species is selectively bound and amplified. Reprinted with permission from ref. 20. Copyright©, 2002, AAAS.
In DCL, molecules exist in a dynamic equilibrium and can undergo reorganization based on their interactions with the target compound or copies of themselves. Such reorganization essentially represents a shift of the thermodynamic equilibrium, which can result in the formation of an amplified amount of molecule that: a) is the best host/receptor for the added guest/ligand (Figure 1.2a); b) is the best guest/ligand for the introduced host/receptor (Figure 1.2b), c) stabilizes itself through intermolecular non-covalent interactions to yield assemblies or aggregates (Figure 1.2c) and d) stabi-lizes itself through intramolecular non-covalent interactions due to particular confor-mational properties to yield for example foldamers (Figure 1.2d).7 Amplification or selection of one specific compound occurs at the expense of other library members by virtue of the Le Chatelier principle (Figure 1.1a).
1.3 Dynamic Combinatorial Library
Dynamic combinatorial libraries (DCLs)7,19 are products of DCC, and their compo-sition is determined by the thermodynamic stability of each library member, under given experimental conditions. The dynamicity of the molecular network allows for the adaptation of the system as a response to changes in physical conditions or chemi-cal environment (Figure 1.1). This intrinsic feature makes DCLs powerful platforms for exploring emergent behaviours, structures, and properties, as well as screening for new drugs, inhibitors, self-synthesizing materials, etc.
b) template
A
B CD
TB
T a)Figure 1.2 Selection and amplification of a specific library member in dynamic combinatorial libraries via non-covalent interactions - external templating for the discovery of a) host molecules; b) guest mol-ecules; and internal templating for the development of c) self-assemblies; d) foldamers. Reprinted and adapted with permission from ref. 7. Copyright©, 2006, American Chemical Society.
1.4 Systems with Multiple Dynamic Covalent Bonds
Natural functional systems very often utilize multiple non-covalent interactions. For example, the formation of DNA duplexes or folding of proteins into secondary and tertiary structures involves a combination of hydrogen bonding, π-π stacking, electro-static interactions, and hydrophobicity. Analogously, synthetic chemists make use of non-covalent and dynamic covalent interactions simultaneously, and in recent years even two and more dynamic covalent bonds in tandem have been employed, for the discovery of new properties and functions.21 The essential characteristic of non-cova-lent interactions that nature combines into one system is their orthogonality. That is, no cross-reactivity or 100% selectivity between the chemistries.22 Therefore, dynamic covalent bonds that are employed in the construction of orthogonal DCLs bear func-tional groups that are noncomplementary and can be independently activated under different experimental conditions. Various combinations involve imines and disul-fides, imines and boronate esters, hydrazones and disuldisul-fides, disulfide and thioesters, imines and alkanes, as well as multiple reversible exchange reactions and different non-covalent interactions.23 On the other side, examples of the one-pot combination of multiple dynamic covalent chemistries that can intercommunicate are also being explored.24,25 Such approach allows the preparation of complex multilayer reaction networks, as exchange pools share one building block type and consequently can af-fect each other due to competition over the particular building block.26 Overall, the incorporation of multiple reversible reactions (orthogonal or not) is a promising tool for the fabrication of a remarkably diverse collection of functions, which will be dis-cussed below in detail.a)
b)
c)
Early reports of dynamic combinatorial libraries encompassing multiple reversible co-valent bonds were focused on identifying appropriate experimental conditions under which orthogonal control over chemistries in use can be achieved. One such example combines disulfide and hydrazone chemistry in an aqueous solution (Figure 1.3).27 The model compound 1, disulfide-containing bishydrazine, can undergo two different exchange reactions independently or simultaneously, only by adjusting the pH. The S-S bond was found to be reactive at pH 8.5 and in the presence of thiol 2, giving rise to the product of oxidation of 2, molecule 5, as well as compounds formed via disulfide exchange 6 and 7. Inversely, at pH 2.5, products of hydrazone formation (11) and exchange (12 and 13) were observed. Moreover, mixing of 1, 2, and 3 at the intermediate pH (4.5) resulted in the formation of products where both chemistries have taken place. Under these conditions and in the presence of 4, the rate of hydra-zone exchange significantly decreased, but was much faster in the presence of aniline as the nucleophilic catalyst.28
N H O H2N SS HN O NH2 O H OH O SH O H HO OH 1 3 2 4 5 6 7 8 9 10 11 12 13 (pH 8.5) (pH 2.5) (pH 2.5)
Building block pool
Product pool
Oxidation and disulfide exchange
Hydrazone formation
Hydrazone exchange
Figure 1.3 Building blocks and schematic representation of possible products formed through oxidation of thiols and disulfide exchange; and condensation between aldehyde and hydrazide and hydrazone exchange. Reprinted and adapted with permission from ref. 27. Copyright©, 2008, The Royal Society of
Chemistry.
In a conceptually similar study,29 the susceptibility of a building block containing a disulfide bond and protected aldehyde group to undergo an exchange of thiols and
Figure 1.4 Dynamic system in chlorinated solvent that combines hydrazones and disulfides. By exposing the molecule bearing two different reactive groups (14), hydrazone or disulfide exchange could be turned on and off by merely changing the TEA/TFA ratio. Reprinted and adapted with permission from ref. 29. Copyright©, 2008, The Royal Society of Chemistry.
1.4.1 Self-Replication
Defining what life is, is a long-standing challenge, tackled by the experts in the variety of scientific fields such as astrobiology, synthetic biology, (bio)chemistry, the origins of life, etc.30 Self-replication,31-33 alongside metabolism34-36 and compartmentaliza-tion37-39 is considered to be an essential trait of life as we know it. Self-replication is the ability of a molecule to make copies of itself, through which information content is transferred from one generation to another. The process can be error-prone to a cer-tain extent. It allows mutation and selection40 of variations beneficial for the stability of replicator, towards Darwinian evolution in an open-ended sense.41 Additionally, a system encompassing the three vital characteristics should also be out-of-equilibri-um42,43 to resemble life.44 Understanding of how life came into existence, in other words, how life emerged from inanimate matter, but also how this transition can be achieved in laboratory settings are questions that scientists studying synthetic systems based on the above-mentioned core criteria, are trying to address.45
hydrazides at different ratios of trifluoroacetic acid (TFA) and triethylamine (TEA) was investigated. The results indicate that two chemistries can be addressed selectively and repeated in a bidirectional fashion, by appropriate adjustment of reaction condi-tions (high content of TFA – hydrazone exchange; high content of TEA – disulfide exchange) (Figure 1.4). N H O O O SS N N H N H NH2 HS TEA N H O O O SS N N H N H NH2 HS TFA N H O O O SS N N H N H NH2 HS N H O O O SS N N H N H NH2 HS TEA TFA Hydrazone exchange Hydrazone exchange Disulfide exchange Disulfide exchange 14 15 16 17
Self-replication, i.e., the ability of a molecule to catalyse its own formation, can be de-scribed by a minimal model of the autocatalytic cycle46-48 depicted in Figure 1.5a. First, building blocks A and B react to yield a replicating template T, through an uncatalyzed, bimolecular reaction (Pathway 1). When enough of replicator T is formed, the auto-catalytic cycle (Pathway 2) becomes dominant. As molecules A and B are equipped with complementary functionalities, they can associate with the template T through the non-covalent interactions, resulting in the complex [A·B·T]. Bringing the two components in close proximity and right orientation increases the rate of formation of T, compared to the uncatalyzed reaction. To complete the autocatalytic cycle, complex [T·T] dissoci-ates to return two free catalysts T to the reaction mixture. Exponential growth in the concentration of T then ideally arises, since two templates make four, four makes eight, etc. The characteristic sigmoidal curve (Figure 1.5b) of such process portrays steps of the autocatalytic cycle: lag phase – an insufficient amount of T to catalyse its own for-mation; exponential phase or maximum autocatalytic rate – the rate of reaction accelerates if [T·T] dissociation is efficient and at the end of n cycles, 2n of templates will be pro-duced; and reactant limiting stage – when the starting material is depleted, the reaction rate decreases and replicator concentration reaches a steady state. On the other hand, if [T·T] dissociation is slow, the concentration as a function of the time profile shows parabolic growth (Figure 1.5b). Another possible pathway (Pathway 3) that can de-crease catalytic activity involves the reversible formation of the complex [A·B] through the interaction of complementary sites. Due to an increase in effective molarity, such complex subsequently can undergo an intramolecular covalent reaction to yield Tincative. When it comes to designing self-replicating systems, considerations regarding side reac-tions, and stability of [T·T] should be taken into account.
Pathway 3 a) Pathway 1 Pathway 2 Autocatalytic cycle [A∙B] [A∙B∙T] [T∙T] Tinactive A B T [P rodu ct ] (µM ) Time (min) 0 50 100 150 200 250 0 20 40 60 80 100 b)
Figure 1.5 a) Minimal model for the self-replicating system. Building blocks, A and B react to form an inactive complex (Tincative) or catalytically active molecule T. T accelerates the reaction between A and B
through the template-directed synthesis to yield complex [T·T], which can dissociate into two distinct molecules T. Reprinted and adapted with permission from ref. 32. Copyright©, 2017, The Royal Society
of Chemistry. b) Kinetic profiles of autocatalytic processes: exponential curve – fast, and parabolic curve – slow dissociation of the complex [T·T]. Reprinted with permission from ref. 47. Copyright©, 2008,
Figure 1.6 The first minimal self-replicating system featuring natural building blocks (nucleotides), but no enzymes. Trinucleotides 18 and 19 react to form molecule 20. 20 is capable of template-directed self-replication. Due to the palindromic base sequence of the template molecule, the reaction between 18 and 19 yields a product that has precisely the same sequence as a template. Reprinted and adapted with permission from ref. 49. Copyright©, 1986, Wiley-VCH.
Von Kiedrowski has reported the first example of a minimal non-enzymatic self-rep-licating system.49 In this study, he used two trideoxyribonucleotides, 18 of sequence 5’-CCG-3’, with the 5’ hydroxyl group being protected as methyl ether and a phos-phate at the 3’ end, and 19 of sequence 5’-CGG-3’, with the free hydroxy group at the 5’ terminus and an o-chlorophenyl protected phosphate at the 3’ end (Figure 1.6). Upon chemical activation of 18 (with EDC), the two molecules ligate to form a hexa-nucleotide 20 with a palindromic base sequence. Hexamer 20 catalyses its formation through directed templating – ternary complex [18·19·20] is formed via complemen-tary base pairing, which brings the activated 3’ end of 18 near the 5’ terminus of 19. Although exponential growth in the concentration of 20 was not observed, possibly due to the high thermodynamic stability of the [20·20] dimer, the autocatalytic na-ture of the process was proved by adding small amounts of the preformed template to the reaction mixture.
O O O N N NH2 O P O O O O O N N NH2 O P O O O O O N P O OR O N N NH NH2 O O O HO N N NH2 O P O O O O O N P O O O O O N P O O O N N NH NH2 O Cl O O O N N NH2 O P O O O O O N N NH2 O P O O O O O N P O O O N N NH NH2 O O O N N NH2 O P O O O O O N P O O O O O N P O O O N N NH NH2 O Cl N N H N EDC N N NH O NH2 N N NH O NH2 H 5’ 3’ 5’ 3’ 18 19 20 18: 18*: [20∙20] 5’-MeCCGCGGp -3’3’- pGGCGCCMe-5’ (inactivated) (activated)
Figure 1.7 Replication mechanism of the peptide-based system developed by the Otto research group. Upon oxidation of dithiol building block 21, a DCL is formed. One of the library members, a hexamer, can stabilize itself through self-assembly, which shifts the equilibrium towards the formation of that par-ticular building block. Mechanical agitation breaks fibers into shorter fragments, providing more fiber ends from which fibers can grow, allowing exponential growth of self-replicating species. Reprinted and adapted with permission from ref. 57. Copyright©, 2010, AAAS.
Building up on the pioneering work of von Kiedrowski50 the research groups of Ghad-iri,51 Chmielewski,52 Ashkenasy,53 Fletcher,54 Philp,55 and others,56 have developed self-replicating systems which make use of very different chemistries and molecular structures that necessarily do not resemble those found in nature.
Our group has developed57 and extensively studied58 mechanosensitive self-assembly driven self-replicators under dynamic conditions. A self-replicator spontaneously emerges from a dynamic mixture of differently sized macrocycles, formed through oxidation and disulfide exchange of dithiol aromatic core bearing a short oligopeptide (Figure 1.7). The carefully designed peptide sequence of alternating hydrophobic and hydrophilic amino-acid residues facilitates the assembly of a specific macrocycle into fibers employing β-sheet formation. Further work encompassing this self-replicating model focused on multicomponent systems59, auto- and cross-catalytic60 behaviours and integration of other traits of life e.g., metabolism.61 Aside from studying funda-mental aspects of self-replication in the context of the origin of life and the synthesis of de novo life, this system has found its application in devising supramolecular block copolymers 62 and self-synthesizing soft materials.63
exchange oxidation elongation fragmentation elongation nucleation S S SH HS N H O H N O O N H NH3 O H N ON H NH3 O O 21
Figure 1.8 A pool of compounds (22-29) can be irreversibly transferred to a pool of products (31-32)
through the reaction of nitrones (28 and 29) with maleimide 30. In this product mixture, trans-32 acts as a catalyst for its own formation, resulting in this species being the dominant one in the product pool. Reprinted and adapted with permission from ref. 64. Copyright©, 2008, Wiley-VCH, and ref. 32.
Copyright©, 2017, The Royal Society of Chemistry.
The coupling of dynamic systems with self-replication will be further discussed and investigated throughout the thesis. In this work, two dynamic covalent chemistries, In contrast to the self-replicating system designed by the Otto group, which employs disulfide exchange, examples of dynamic combinatorial libraries that use multiple reversible bonds to find the best autocatalyst are extremely rare. To the best of our knowledge, only one such system, making use of nitrone and imine exchange, has been reported thus far by Sadownik and Philp (Figure 1.8).64 The DCL constructed from two unreactive imines (26 and 27), two reactive nitrones (28 and 29), and their precursors (22-25) is allowed to react with maleimide 30, to yield a variety of diastereomeric cycloadducts (cis- and trans-31; cis- and trans-32). However, only one of the products, trans-32, can catalyse its own formation, accelerating the cycloaddi-tion between 29 and 30 by a factor more than 100, via a template-mediated reaccycloaddi-tion involving complex [29·30·trans-32]. This results in amplification of trans-32, at the expense of other library members until the self-replicator dominates the product pool.
N NH O N F O N N H O O N F N F O HOHN F F H2N N NH O N F O N O O CO2H O N N H H O O HO2C F O N N H H O O HO2C F O N N H H O O HO2C F O N H N O N N H H O O HO2C F O N H N 26 28 27 29 22 24 23 25 30
cis-31 trans-31 cis-32 trans-32
Non-recognition
bimolecular reaction Autocatalyticamplification
Catalytically inactive products
Exchange pool
namely disulfide and acyl-hydrazone, are employed to form potential self-replicators and expand the scope of their functions.
1.4.2 Complex Molecular Architectures
The use of multiple orthogonal dynamic reactions rapidly proved to be a straight-forward strategy to construct complex molecular architectures, as they allow error-correction, similar to non-covalent interactions.
In one of the first demonstrations, authors reported the formation of triple helix 33, by means of three different chemistries: disulfide, imine, and metal coordination.65 Soon after, the utility of only covalent bonds was shown by the construction of metal-free, iminoboronate-based assembly 34.66 In contrast to the previous two examples, which were prepared by classical solution-based reactions, multicomponent cage 35, based on boronic esters and imines, was generated through ball milling, showcasing the potential of this dry-state method, as well as the robustness of orthogonal covalent bonds (Figure 1.9).67 B N N B OO OO O O B N N O O B N N B B B OO OOB N O O OBO N O O O O B N N N S S N N S N S N N N S N S N N N Fe Fe 4+ 33 34 35
Figure 1.9 Complex molecular architectures with orthogonal dynamic covalent bonds: double helix 33, macrocycle 34, and cage 35. Reprinted with permission from refs. 65 (Copyright©, 2007, Wiley-VCH),
66 (Copyright©, 2008, Wiley-VCH), and 67 (Copyright©, 2009, American Chemical Society).
The combination of imine condensation and metal coordination has been extensively used by the group of Nitschke to construct dynamic metal-organic cages. Roberts et
al. recently reported that inverse electron-demand Diels-Alder reaction (orthogonal to
other functional groups and chemistries present) triggers a structural transformation, starting from FeII
4L6 tetrahedral precursor 36, to dinuclear triple helicate structure
38a (Figure 1.10). Susceptibility of the imine bond to undergo reversible chemical exchange was employed to substitute electron-poor 4-fluoroanline residues within helicate 38a, with electron-rich 4-methoxyaniline, to obtain 38b. Subcomponent
exchange (SE) increases the strength of the metal-ligand bond, thus influencing the supramolecular product distribution to favour the helicate structure. Alternatively, covalent post-assembly modification (PAM) and SE can be performed in a concerted manner to achieve the formation of an identical product, 38b. In the last step, the third assembly, FeII
8L12 twisted square prism (39), is formed via anion templation.68 Although this example uses essentially only one dynamic covalent bond, it depicts the benefits of combining reversible covalent bonds with (orthogonal) permanent covalent bonds and non-covalent interactions. It also emphasizes the emerging ap-plicability of the PAM strategy to introduce covalent derivatization into the system to alter electronic, steric, and functional parameters of self-assemblies. These new PAM protocols will be discussed in Section 1.5.
36
36
37a 37b
38a 38b
39
Figure 1.10 Stimulus-response scheme showing the major multicomponent assemblies that can undergo covalent post-assembly modification (PAM), subcomponent exchange (SE), and anion templation (AT). Reprinted and adapted with permission from 68 (Copyright©, 2018, American Chemical Society).
1.4.3 Dynamic Materials
Dynamic covalent bonds have been extensively used for the fabrication of functional materials that address some challenging topics which cannot be tackled utilizing per-manent covalent interactions. For example, self-healing, shape memory, and stimuli-induced stiffness changes are properties that can be achieved by the implementation of reversible bonds into dynamic hydrogels.69 However, the combination of multiple dy-namic orthogonal chemistries has made its way into functional materials only recently, and exciting examples have started to emerge.70,71
Chen and co-workers developed one of the first self-healable hydrogels containing both disulfide and acyl-hydrazone bonds (Figure 1.11).72 Due to the reversibility of interac-tions, the system is equipped with an intrinsic repair mechanism that does not require the addition of a healing agent. Compound 1, fitted with a central disulfide bond and two hydrazide termini, can cross-link trialdehyde-functionalized poly(ethylene glycol) (PEG) polymer (40), yielding a hydrogel 41 that can select a particular self-healing route depending on the environmental conditions. Under acidic conditions, the repair of damage occurs via the acyl-hydrazone exchange, while the presence of a base catalyses the disulfide exchange to result in intact gels. In accordance with both chemistries, heal-ing was not achieved at pH 7, while the addition of aniline catalysed acyl-hydrazone exchange even under neutral conditions. Moreover, the material exhibits responsiveness to change in pH and redox external stimuli by undergoing a sol-gel transition.
OHC O O OO O O CHO CHO n n n H2N H N O SS ON H NH2 NHN O SS ON H N H2N H N O SS ON H NH2 O H O H N H N O SH HS O N H N + 40 1 in water hydrogel 41 acyl-hydrazone (pH responsive)
self-healing under acidic or neutral conditions
disulfide
(redox responsive)
self-healing under basic conditions
Figure 1.11 a) The system based on acyl-hydrazone and disulfide chemistry used to construct dynamic hydrogels able to undergo adaptive self-healing; b) Hydrogel, after being cut (middle symbol), can repair itself under basic conditions (disulfide exchange, red symbol) or under acidic conditions (acyl-hydrazone exchange, blue symbol). Reprinted and adapted with permission from ref. 72 Copyright©, 2012,
Ameri-can Chemical Society, and ref. 21 Copyright©, 2014, The Royal Society of Chemistry, respectively.
In another approach, the authors made use of thiol-ene Michael polyaddition and borax-diol chemistry to produce gels based on PEG (45) (Figure 1.12), which show healable properties without an external stimulus.73 It was found that borax catalyses the reaction between PEG diacrylate and thiols, and induces the formation of transient boronate ester linkages, promoting rapid hydrogelation and imparting self-repairing character to the material. Although the Michael addition of thiols to enones can be viewed as a reversible covalent reaction,74 in this work it had a role of static chemistry, while the dynamicity of the network was strictly attributed to boronate ester bonds.
self-healing pH 5 self-healingpH 9 cut pH 7 pH 7cut b) O O O O HS SH OH OH BOH HO HO OH n + + S O S O B OO O O O O S O S O B O O O O O O n n One Pot Thiol-ene Michael addition Borax diol complexation 42 43 44 45
Figure 1.12 Schematic representation of a “one-pot” preparation of thiol-ene PEG-based hydrogels, which shows self-healing properties due to the reversibility of used chemistries. Reprinted and adapted with permission from ref. 73. Copyright©, 2015, American Chemical Society.
Covalent organic frameworks (COFs) are a class of highly ordered, porous organic ma-terials whose structure is predetermined via the topological design of building blocks, and either irreversible or reversible chemical reactions drive the organization of the extended network. Crystallinity, structural integrity, and ability to manage desired functions make this group of molecules suitable for a variety of applications, ranging from semiconductors and systems for energy storage, to materials for adsorption and
separation, and even drug delivery platforms.75 Orthogonal linkage strategies have also been explored in designing COFs, increasing their structural and functional diversity.76 In this procedure, one of the building blocks has to be equipped with at least two functional groups to be able to form two types of covalent bonds (Figure 1.13). For example, 4-formylphenylboronic acid (FPBA) (46) can react with 47, yielding
COF-48, through the formation of imine bonds and boroxine rings. In a three-component system, COF-50 is constructed, where molecules 46 and 47 are held by imine bonds, and 46 and 49 by C2O2B boronate rings. The system consisting of multiple compo-nents, COF-50, exhibited high surface area and high H2 adsorption capacity.77
NH2 NH2 H2N O B HO OH HO OH OH OH HO HO N N B OB O B O N N B O B OB O N N B O B O B O N N B B N N B N N B B O O O O O O O O O O O B O B O O O B O OB O 46 47 49 1 3 1 COF-48 COF-50
Figure 1.13 Syntheses of COF-48 and COF-50 involving the formation of two types of orthogonal covalent bonds. Reprinted and adapted with permission from ref. 77. Copyright©, 2015, American
Chemical Society.
Orthogonal dynamic bonds have also been recognized as attractive tools for building functional multicomponent architectures directly on solid surfaces with the focus on self-organizing surface-initiated polymerization (SOSIP)78 and templated stack ex-change (TSE).79 For more information about these methods and their applications, the reader is directed elsewhere.80
Figure 1.14 In starting molecule 51, the “walker” is on the left side of the track. Light-induced isomerisa-tion of a double bond brings the second part of the track in a suitable posiisomerisa-tion to form 52. The addiisomerisa-tion of base induces disulfide exchange to move the “walker” one step forward, making compound 53. The second isomerisation of a double bond adds strain to the central macrocycle of 54. This strain can be released by hydrazone exchange upon acidification, which moves the walker to the end of the track (55). Reprinted and adapted with permission from ref. 81. Copyright©, 2011, Wiley-VCH.
Other unique applications involve the employment of dynamic covalent interactions in molecular sensing,82 cellular uptake,83 and release,84 and formation of quaternary structures with antimicrobial properties.85 Undoubtedly, the incorporation and com-bination of multiple orthogonal bonding pairs have already resulted in advances in a variety of disciplines. Thus, we can rightfully expect that this approach is going to bring answers to many unusual questions and impact in diverse, challenging topics.
1.4.4 Versatile Examples
The versatility of functions that can be built by the implementation of multiple revers-ible bonds is clear from the above-discussed applications. Self-replicators, dynamic materials, and molecular architectures are just the tip of the diversity of the field. Some of the examples that are of less importance for this thesis, but of outstanding elegance, will be briefly mentioned below.
The “molecular walkers” are one of the most remarkable examples of systems involv-ing orthogonal covalent bonds.81 Here, a molecular component (in red, structure 51,
Figure 1.14) moves along the track by detaching/attaching one “foothold” at a time. Control over which “foothold” is detached/attached is achieved by adjustment of reac-tion condireac-tions to switch on and off the desired chemistry on-demand.
S S NH O N O SS O O O O S S NH O N O O O S S O O S O O O S S S O O N HN O S O O O S S S O O N HN O N NH S S O O S O O S O O light base light base 51 52 53 54 55
1.5 Covalent Post-Assembly Modification
The post-assembly modification (PAM) is a synthetic tool for late-stage derivatiza-tion of self-assembled complexes and materials, to graft new funcderivatiza-tionalities, induce structural transformation or stabilize metastable structures (Figure 1.15). The use of it has grown in recent years, as it allows the introduction of functionalities that may be incompatible with the synthetic route of the non-assembled building block or interfere with the formation of the target assembly. Conceptually, PAM resembles post-translation modification of proteins, where the modification strategy is employed to mediate the folding into a proper conformation, alter biological activity, etc. The essential difference between derivatization at the later stage of proteins and supramo-lecular assemblies, and also between COFs, MOFs, and self-assemblies, is that the latter are held by weak and dynamic interactions that are easily disrupted, resulting in decomposition. Therefore, one of the crucial characteristics of reactions used for PAM is to be compatible (even orthogonal) with the dynamic nature of the self-assembled complex, which often excludes strong nucleophiles and electrophiles, oxidizing/re-ducing agents, highly coordinating species, etc.86,87 The representative examples that fall into categories that are of relevance for this thesis and which served as a source of inspiration for the work reported in the following chapters, will be discussed briefly.
link functionalize lock transform a) c) b) d)
Figure 1.15 The four main applications of post-assembly modification reactions: a) synthesis of covalent molecules through supramolecular templating; b) post-functionalization of self-assembled structure; c) covalent “locking”, i.e., stabilization of labile supramolecular complex and d) supramolecular structural transformations triggered by introducing new molecular entity via covalent reaction. Reprinted and adapted with permission from ref. 87. Copyright©, 2020, Wiley-VCH.
Post-assembly modification in the context of modular derivatization for change in a particular physical property (e.g., polarity) or the emergence of behavior or function is attracting a lot of attention, as it allows the creation of diverse product libraries without extensive pre-assembly ligand synthesis. One of the examples that depict this application was designed by the group of Nitschke. They report on a combination of
Figure 1.16 a) Schematic representation of reaction cascade. The cube FeII
8L12 (56) and tetrahedron
FeII
4L6 (58) are self-assembled from building block pairs A/B and C/D, respectively. The addition of
the trigger molecule (NBD) induces the cascade that begins with the IEDDA of NBD and the tetrazine moiety of the cube. The by-product of this reaction, cyclopentadiene, participates in a normal-demand DA reaction of the tetrahedron (58) to produce lipophilic compound 59. b) The change in polarity upon completion of the cascade sequence drives complex 59 into the non-polar phase (cyclopentane). Reprinted and adapted with permission from ref. 88. Copyright©, 2017, Springer Nature.
self-assembled metal-organic architectures that can undergo a reaction cascade com-prised of sequentially coupled PAM reactions to increase the lipophilicity of one of the complexes.88 The two self-assembled complexes, tetrazine-edged cube 56 and ma-leimide-functionalized tetrahedron 58 feature reactive sites suitable for carrying out an inverse demand Diels-Alder (IEDDA) reaction and a normal electron-demand DA reaction, respectively (Figure 1.16a). The addition of a norbornadiene-based (NBD) molecule triggers the cascade by participating in the IEDDA reaction with the assembly 56, resulting in a reactive by-product that itself undergoes a second-ary PAM reaction with the maleimide functionality of tetrahedron 58. Functionaliza-tion of 58 with alkyl-substituted cyclopentadiene furnishes metal-organic complex 59 sufficiently lipophilic to cross a phase boundary from the polar acetonitrile reaction phase to a non-polar cyclopentane extraction phase (Figure 1.16b).
Cyclopentane CD3CN/CDCl3 17 C18 trigger 12 Cyclopentane CD3CN/CDCl3 8+ 8 NTf2– N N N NN N N N tBu tBu O O N 16+ 16 NTf2– O O N N N O O N N N NN N O O NH2 tBu 16+ 16 NTf2– 8+ 8 NTf2– R R N N N N N N N N Trigger Fe2+ 24 N N N N N N tBu tBu IEDDA stage 12 R Relay 12 DA stage R NBD: R = H C6-NBD: R = C6H13 C10-NBD: R = C10H21 C18-NBD: R = C18H37 CPD: R = H C6-CPD: R = C6H13 C10-CPD: R = C10H21 C18-CPD: R = C18H37 8 Fe(NTf2)2 CD3CN 333 K, 16 h R 12 6 H2N O O N 4 Fe(NTf2)2 CD3CN 333 K, 16 h 12 D A B C 56 57 58 59a: R = H 59b: R = C6H13 59c: R = C10H21 59d: R = C18H37 a) b)
Polymerization-induced self-assembly (PISA) is a powerful and versatile method for the synthesis of a variety of organic diblock copolymer nanostructures of controllable size, morphology, and surface functionality. A water-soluble polymer (An) is extended using a water-miscible monomer (B) to form initially a water-soluble diblock polymer (AnBm). At some critical degree of polymerization, the growing diblock polymer be-comes water-insoluble, which causes self-assembly of AnBm into a nano-object, so that the insoluble block is shielded from solvent.89
The covalent post-assembly modification was employed to achieve structural transfor-mations of polymerization-induced self-assemblies between a range of versatile nano-structures (Figure 1.17).90 The polymerization of compounds 60 and 61 readily yields diblock copolymer (62) that assembles into micelles (65) or vesicles (66) depending on the ratio of building blocks. Further polymerization of “seed” micelles (65) or vesicles (66) with a third building block (63), in different ratios resulted in a series of structural transformations, highlighting the utility of PAM in applications that are at the interface of polymer and supramolecular chemistry.
Figure 1.17 a) Stepwise polymerization to the triblock copolymer. b) Schematic illustrations of structural transformation of “seeds” micelles and vesicles upon the incorporation of the
third building block. Reprinted and adapted with permission from ref. 90. Copyright©, 2017,
American Chemical Society.
HOOC CN S S O O N m HOOC CN O O N m O O S S O O n HOOC CN O O N m O O C8F18 O O n S S O O C8F18 l 60 PDMA PDMA-b-PBzMA-b-PFMA Dispersion
polymerization dispersionSeeded polymerization 62 PDMA-b-PBzMA PDMA-b-PBzMA-b-PFMA64 61 63 66 65 DP of FMA DP of BzMA PDMA-b-PBzMA seeds a) b)
1.6 Conclusion
In the past two and a half decades, dynamic combinatorial chemistry has become a widespread tool for the generation of molecules with a plethora of functions and behav-iours. Numerous reversible chemistries are utilized to fabricate DCLs, while research is still ongoing on establishing additional ones. In particular, the focus is on those performed under the physiological conditions and in the presence of other functional groups. Construction of DCLs has led to the development of molecules with recogni-tion properties, to explore synthetic receptors, ligands for biomolecules, foldamers, etc. Furthermore, DCLs are of interest on themselves, as they may exhibit unique proper-ties or behaviours that emerge from the system, rather than being simple characteristics of components of the molecular network.
The orthogonal combination of different covalent reversible bonds allows for a broader diversity of interconnectivity among the constituents of the system, thus providing a structural basis for the discovery of new functions and features. A remarkably wide variety of highly demanding topics has already been covered by using this approach. In this introductory chapter, we tried to summarize the research that has been done in the areas of synthetic self-replicators, complex molecular architectures, and dynamic materials, as the work presented in the following chapters aims to contribute to these applications. The field of self-replicating molecules, to a certain extent, is still less fa-miliar to a broader scientific audience. Therefore, principles and some milestone ex-amples were presented, although they don’t necessarily use dynamic covalent bonds or the combination thereof.
The post-translational modification (PTM) of proteins is a nature’s way to extend the chemical repertoire of the 20 standard amino acids by modification or introduction of a new functional group, to increase the functional diversity of the proteome while keeping the information content limited. This “ingenuity” of nature served as an in-spiration for chemists, who have devised the synthetic parallel to the PTM - the post-assembly modification. The strategy was rapidly recognized as a versatile tool to modu-late and expand the functionality of synthetic systems. Here, we discussed the concepts of PAM, as well as two examples that make use of covalent PAM to achieve functional behaviour and influence the self-assembly process. Realizing the utility of PAM, in this thesis we aimed to investigate whether different (dynamic covalent) modifications of self-assembly can induce the emergence of new characteristics and functions, therefore diversify the parent system in a straightforward fashion.
1.7 Acknowledgments
Ankush Sood is gratefully acknowledged for proof-reading of this chapter and giving valuable feedback.
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