Non-Covalent and Dynamic Covalent Strategies

Taking inspiration from the complex assemblies that can be found in Nature, the use of non-covalent bonds, such as the hydrogen bond, has now been implemented in a wide range of disciplines, such as polymer functionalization.^[64]

The use of supramolecular chemistry, that is the use of reversible and directional interactions, to build materials with growing degrees of complexity, can enable to overcome the synthetic difficulties which occur using traditional covalent bonds.^[63]

Supramolecular polymers are abundantly found in Nature, with DNA as a striking example, but also in synthetic polymers like nylons which are held together by cooperative hydrogen bonding.^[64] This field is growing

interactions, such as anion-π or chalcogen bonds.^[65] However, supramolecular stategies are not only used to synthesize new polymers, but also to modify polymers held together by covalent interactions. Indeed, the polymer backbone can be covalently linked together and contain molecular recognition motifs to achieve functionalization using a non-covalent strategy.^[66]

Sidechain functionalization can occur before or after polymerization, be single or multiple and involve the use of one or more non-covalent strategies.

The most common non-covalent force that is used for sidechain engineering is hydrogen bonding which can be weakened or strengthened according to the function of the resulting material. The first example was shown in 1989 by Kato and Fréchet who functionalized liquid crystalline polymer 33 by introducing benzoic acids in the sidechain that formed hydrogen bonds with pyridine 34 (Figure 20).^[67] More Nature-inspired recognition motifs have been developed by Rotello and coworkers by introducing triazines in the sidechain of poly(styrene) 35 which could then be post-functionalized through hydrogen bonding with gold nanoparticle 36 possessing thymine residues.^[68]

Figure 20. Examples of polymer sidechain functionalization using hydrogen bonding. Adapted from reference.^[66]

N O

Another common non-covalent interaction used for sidechain modification is metal coordination. The use of metal-ligand interactions can enable to screen a wide variety of polymers with catalytic or magnetic properties and the combination with hydrogen-bonding can solve solubility issues, as for the ruthenium aqueous micelles of Schubert and coworkers.^[69] However, there are certain disadvantages to using metals for sidechain engineering, such as incompatibility with most polymerization methods or lack of reversibility if not through ligand displacement.^[66]

Even though non-covalent interactions, and especially hydrogen bonding, are useful for self-assembly and the building of complex architectures with well-known recognition motifs, an excellent compromise between the reversibility of non-covalent interactions and the robustness of covalent ones is given by dynamic covalent bonds (DCB). Indeed, DCBs are strong, stable and permanent under certain conditions, while rapidly forming, breaking and exchanging in others. The disulfides described in the previous chapter, for example, are labile and can exchange in basic conditions, while being robust in acidic ones. These characteristics have also led to the use of dynamic covalent chemistry in polymer sidechain functionalization.

Montenegro and coworkers reported, indeed, in 2016 the use of DCBs for polymer functionalization.^[70] By introducing a hydrazide group in the scaffold, they screened different amphiphilic polymers for siRNA delivery through hydrazone formation. Starting from poly(acryloyl hydrazide) 37 (Figure 21), sidechain engineering was performed using different molar ratios of guanidinium-containing aldehyde 38 and more hydrophobic aldehydes, such as 39. At neutral pH, hydrazides are weakly protonated and can react with aldehydes to form hydrazones, like 40, that are stable at physiological conditions.

Thanks to the presence of the positive charge, 40 was used to form polyplexes with negatively charged siRNA for gene transfection.^[70]

Figure 21. Polymer sidechain functionalization using dynamic covalent bonds:

polymer 40 is obtained by hydrazone formation between hydrazide 37 and aldehydes 38-39. Figure adapted from reference.^[70]

Sidechain functionalization with hydrazones is also very attractive since it tolerates the presence of a second DCB, such as the disulfide bond. The orthogonality between the two different bonds enables the construction of fully dynamic covalent systems. In the SOSIP methodology developed by Matile and coworkers for example, hydrazones are introduced on the poly(disulfide)-containing backbone for post-modification in a strategy called templated stack exchange (TSE), shown in Figure 22. Indeed, they exploit the stability of hydrazones in basic conditions where the disulfide polymer is formed, and viceversa, can form new hydrazone bonds to introduce different functionalities in acidic conditions while keeping the poly(disulfide) scaffold intact.

In this example, a benzaldehyde hydrazone is introduced in the monomer which, after disulfide-exchange polymerization to give structure 41, is cleaved with excess hydroxylamine to give the free hydrazide 42. The hydrazides can then react with the desired aldehydes to form hydrazones 43. The SOSIP-TSE methodology was extensively used to introduce different properties to the photosystems starting from the same scaffold each time.^[71]

n

Figure 22. SOSIP-TSE methodology for post-functionalization using hydrazone formation in the presence of a poly(disulfide) backbone. Figure adapted from reference.^[71]

There is extensive use of disulfides and hydrazones in the literature to achieve orthogonal systems by simple adjustment of pH. The dynamic nature of these bonds is not only used to construct systems, but also to impart certain

have been introduced by Chen and coworkers in 2012 to construct dynamic hydrogels. As depicted in Figure 23, the aldehyde-containing polymer 44 reacts with a disulfide-containing hydrazide 45 to form hydrazone 46. This hydrogel can be cut and healed at pH 6 using hydrazone exchange and at pH 9 using disulfide exchange, but also at pH 7 when aniline is used as a catalyst for the hydrazone exchange.^[72]

Figure 23. Self-healing hydrogel 46 containing both hydrazones, from polymer 44, and disulfides, from 45. Figure adapted from reference.^[72]