Johnathan N. Brantley

Unclicking the Click: Mechanically Facilitated 1,3-Dipolar Cycloreversions

Application of ultrasound can cleanly reverse a widely used chemical coupling reaction. The specific targeting of covalent bonds in a local, anisotropic fashion using mechanical methods offers useful opportunities to direct chemical reactivity down otherwise prohibitive pathways. Here, we report that embedding the highly inert 1,2,3-triazole moiety (which is often prepared using the canonical “click” coupling of azides and alkynes) within a poly(methyl acrylate) chain renders it susceptible to ultrasound-induced cycloreversion, as confirmed by comprehensive spectroscopic and chemical analyses. Such reactivity offers the opportunity to develop triazoles as mechanically labile protecting groups or for use in readily accessible materials that respond to mechanical force.

Methods for activating and characterizing mechanically responsive polymers

Mechanically responsive polymers harness mechanical energy to facilitate unique chemical transformations and bestow materials with force sensing (e.g., mechanochromism) or self-healing capabilities. A variety of solution- and solid-state techniques, covering a spectrum of forces and strain rates, can be used to activate mechanically responsive polymers. Moreover, many of these methods have been combined with optical spectroscopy or chemical labeling techniques to characterize the products formed via mechanical activation of appropriate precursors in situ. In this tutorial review, we discuss the methods and techniques that have been used to supply mechanical force to macromolecular systems, and highlight the advantages and challenges associated with each.

Molecular catch bonds and the anti-Hammond effect in polymer mechanochemistry.

While the field of polymer mechanochemistry has traditionally focused on the use of mechanical forces to accelerate chemical processes, theoretical considerations predict an underexplored alternative: the suppression of reactivity through mechanical perturbation. Here, we use electronic structure calculations to analyze the mechanical reactivity of six mechanophores, or chemical functionalities that respond to mechanical stress in a controlled manner. Our computational results indicate that appropriately directed tensile forces could attenuate (as opposed to facilitate) mechanochemical phenomena. Accompanying experimental studies supported the theoretical predictions and demonstrated that relatively simple computational models may be used to design new classes of mechanically responsive materials. In addition, our computational studies and theoretical considerations revealed the prevalence of the anti-Hammond (as opposed to Hammond) effect (i.e., the increased structural dissimilarity between the reactant and transition state upon lowering of the reaction barrier) in the mechanical activation of polyatomic molecules.

Chemical reactions modulated by mechanical stress: Extended Bell theory

A number of recent studies have shown that mechanical stress can significantly lower or raise the activation barrier of a chemical reaction. Within a common approximation due to Bell [Science 200, 618 (1978)], this barrier is linearly dependent on the applied force. A simple extension of Bells theory that includes higher order corrections in the force predicts that the force-induced change in the activation energy will be given by -FΔR - ΔχF(2)∕2. Here, ΔR is the change of the distance between the atoms, at which the force F is applied, from the reactant to the transition state, and Δχ is the corresponding change in the mechanical compliance of the molecule. Application of this formula to the electrocyclic ring-opening of cis and trans 1,2-dimethylbenzocyclobutene shows that this extension of Bells theory essentially recovers the force dependence of the barrier, while the original Bell formula exhibits significant errors. Because the extended Bell theory avoids explicit inclusion of the mechanical stress or strain in electronic structure calculations, it allows a computationally efficient characterization of the effect of mechanical forces on chemical processes. That is, the mechanical susceptibility of any reaction pathway is described in terms of two parameters, ΔR and Δχ, both readily computable at zero force.

Regiochemical Effects on Molecular Stability: A Mechanochemical Evaluation of 1,4- and 1,5-Disubstituted Triazoles

Poly(methyl acrylate) chains of varying molecular weight were grown from 1,4- as well as 1,5-disubstituted 1,2,3-triazoles. Irradiating acetonitrile solutions of these polymers with ultrasound resulted in the formal cycloreversion of the triazole units, as determined by a variety of spectroscopic and chemical labeling techniques. The aforementioned reactions were monitored over time, and the rate constant for the cycloreversion of the 1,5-disubstituted triazole was measured to be 1.2 times larger than that of the 1,4-disubstituted congener. The difference was attributed to the increased mechanical deformability of the 1,5-regioisomer as compared to the 1,4-isomer. This interpretation was further supported by computational studies, which employed extended Bell theory to predict the force dependence of the activation barriers for the cycloreversions of both isomers.

Mechanically Modulating the Photophysical Properties of Fluorescent Protein Biocomposites for Ratio‐ and Intensiometric Sensors

Mechanically sensitive biocomposites comprised of fluorescent proteins report stress through distinct pathways. Whereas a composite containing an enhanced yellow fluorescent protein (eYFP) exhibited hypsochromic shifts in its fluorescence emission maxima following compression, a composite containing a modified green fluorescent protein (GFPuv) exhibited fluorescence quenching under the action of mechanical force. These ratio- and intensiometric sensors demonstrate that insights garnered from disparate fields (that is, polymer mechanochemistry and biophysics) can be harnessed to guide the rational design of new classes of biomechanophore-containing materials.

Squeezing New Life Out of Polymers

The field of polymer mechanochemistry, 2] wherein macroscopic forces are translated into chemical transformations within polymeric matrices, is witnessing a rebirth. Unique or otherwise kinetically inaccessible chemical reactions are now possible when mechanically labile functionalities, termed mechanophores, are embedded within polymers and then subjected to exogenous mechanical forces. Paradigms in the field are shifting, however, and efforts are now focusing on using force as a method for driving the production of reactive chemical species. In particular, polymers that generate acids or redox reagents under the action of mechanical force are of interest, as such materials could find utility in applications that range from self-healing systems that undergo spontaneous repair through acid-catalyzed cross-linking reactions to mechanically driven syntheses. The production of valuable small molecules from mechanically activated polymers is still in its infancy, and reported methods for achieving this goal often require a thermal or chemical treatment step. 7] Designing materials that extrude well-defined chemical entities solely under mechanical force has proven considerably more challenging. In a seminal contribution, Moore and co-workers showed that dinitrogen could be expelled from a centrally positioned diazo unit in a poly(ethylene glycol) chain under ultrasonication. Although the chemical inertness of dinitrogen precluded its use in further reactions, this example laid the groundwork for two recent reports from the Moore and Grzybowski laboratories that beautifully demonstrated how reactive chemical reagents can be generated from mechanically responsive materials. The Moore group focused on generating Brønsted acids by compressing appropriately functionalized polymers. The design of the mechanically responsive materials was based on previous studies from Craig et al., who demonstrated that polymers containing multiple gem-dihalocyclopropane (gDHC) moieties could undergo mechanically facilitated electrocyclic rearrangements to afford dihaloalkenes. Subsequent thermal treatment (165 8C) of the olefinic products resulted in the extrusion of mineral acids (e.g., HCl). To reduce the temperature required for the elimination reaction, Moore et al. envisaged an indene-based analogue that could drive the rearrangement of the gDHC moieties and the elimination of HCl through aromatization (Scheme 1).

Investigating the reactivities of a polyketide synthase module through fluorescent click chemistry

A method for monitoring in vitro polyketide synthesis has been developed whereby nonchromophoric polyketide products are made brightly fluorescent in a simple, rapid, inexpensive, and bioorthogonal manner through CuAAC with a sulforhodamine B azide derivative.