Mechanical activations of synthetic and biological systems
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Polymer mechanochemistry, wherein exogenous forces are harnessed to drive chemical processes within polymeric matrices, has afforded access to an astounding array of otherwise kinetically prohibitive reactivity. These multifarious mechanochemical transformations include formally symmetry forbidden electrocyclic processes, thermodynamically disfavored isomerizations, and thermally inaccessible cycloreversions of both carbocyclic and heterocyclic functionalities. The fundamental principles that govern mechanochemistry, however, remain elusive. To address this deficiency, we report a series of experimental and computational efforts that probe chemical reactivity under the action of mechanical force. Specifically, we have explored the formal 1,3-dipolar cycloreversion of 1,2,3-triazole moieties in an effort to understand the interplay between kinetic stability and mechanical perturbation. Briefly, 1,4-disubstituted 1,2,3-triazoles were embedded within high molecular weight poly(methyl acrylate) chains and reverted into their azide and terminal alkyne precursors sonochemically. The liberated azide and alkyne moieties were identified by orthogonal chemical ligation to chromophores, and the reactive azido- and alkynyl-polymer fragments could be recoupled through a copper-mediated cycloaddition. Inspired by this result, we developed a computational model to rapidly discover qualitative trends in mechanochemical reactivity. Application of this model to the cycloreversion of 1,2,3-triazoles revealed an intriguing result: the 1,5-disubstitued regioisomer was predicted to exhibit enhanced susceptibility to mechanical cycloreversion in comparison to the 1,4-disubstituted congener. This trend was experimentally verified upon embedding 1,5-disubstituted 1,2,3-triazoles into high molecular weight poly(methyl acrylate) chains and subjecting them to ultrasonication. Specifically, the observed rate constant for chain scission of a poly(methyl acrylate) material containing the 1,5-disubstituted isomer was 20% larger than that of an analogous material containing the 1,4-disubstituted congener. Having established confidence in the predictive capabilities of our model, we undertook an exhaustive evaluation of regiochemical effects on the activation of six previously reported mechanically labile scaffolds. Our theoretical work suggested that all of the evaluated scaffolds could exhibit suppressed reactivity under stress (an underexplored phenomenon), and this result was supported by experimental investigation. Moreover, our theoretical considerations predicted that anti-Hammond effects (i.e., increased structural dissimilarity between reactant and transition state geometries as the two approach energetically) could be predominant in mechanochemical processes. Finally, we endeavored to expand the scope of polymer mechanochemistry beyond traditional chemical systems to biologically relevant species. We found that the photophysical properties of fluorescent protein variants could be modulated by embedding the proteins within poly(methyl methacrylate) matrices and compressing the resulting composites.