Covalent mechanochemistry of four-membered carbocycles

The development of multi-mechanophore polymers (MMPs) has empowered new methodologies for observing and quantifying mechanochemical transformations. Previously developed techniques such as single-molecule force spectroscopy (SMFS) and pulsed ultrasound can be used to induce and observe up to hundreds of chemical reactions within a single polymer, enabling mechanistic insights into mechanochemical reactivity. The bulk of the work presented herein (Chapters 2-5) involves the use of these techniques to elucidate substituent effects on the covalent mechanochemistry of four-membered carbocycles, namely the force-triggered ring-opening reactions of fused-cyclobutane (CB) and cyclobutene (CBE) mechanophores.

MMPs that contain multiple CB and CBE repeats are typically synthesized via entropy-driven ring-opening metathesis polymerization (ED-ROMP, Chapters 3-5), a technique used widely in the field of polymer mechanochemistry. While useful for generating polymers for fundamental mechanistic investigations, there are several challenges inherent to the ED-ROMP approach that limit its impact and applicability (covered in Chapter 1). We therefore sought to overcome some of these challenges by introducing a new class of mechanophore monomers that are amenable to free-radical addition polymerization. In Chapter 2 we report that cyclobutene carboxylates that are fused to larger rings are amenable to controlled radical polymerization techniques, specifically reversible addition-fragmentation chain transfer (RAFT) copolymerization with butyl acrylate. The fused ring repeats act as stored-length mechanophores along the polymer backbone, and so these polymers are a rare example of high mechanophore content polymers formed by addition polymerization. Analysis of mechanophore activation as a function of polymer scission cycle reveals that these CB-based mechanophores operate in high force regimes. In addition, the kinetics and “controllability” of the RAFT polymerizations are investigated as a function of (co)monomer composition, providing a foundation for the design of bulk polymer networks that contain a tunable amount of these stored-length mechanophores.

In Chapter 3 we report the force-dependent kinetics of stored length release in a family of covalent domain polymers based on cis-1,2-substituted CB mechanophores, which have the potential to serve as covalent synthetic mimics of the mechanical unfolding of noncovalent “stored length” domains in structural proteins. The stored length is determined by the size (n) of a fused ring in an [n.2.0] bicyclic architecture, and it can be made sufficiently large (> 3 nm per event) that individual unravelling events are resolved in both constant-velocity and constant-force SMFS experiments. Replacing a methylene in the pulling attachment with a phenyl group drops the force necessary to achieve rate constants of 1 s-1 from ca. 1970 pN (dialkyl handles) to 630 pN (diaryl handles), and the substituent effect is attributed to a combination of electronic stabilization and mechanical leverage effects. In contrast, the kinetics are negligibly perturbed by changes in the amount of stored length. The independent control over unravelling force and extension holds promise as a probe of molecular behavior in polymer networks and for optimizing the behaviors of materials made from covalent domain polymers.

In Chapter 4 we use a combination of SMFS and computation to gain a fundamental understanding of substituent effects on a different class of force-triggered reactions: the forbidden disrotatory ring-opening reaction of CBE mechanophores. We synthesized a series of cis-ester-substituted CBE mechanophores that probed the effects of substituents attached to the breaking sigma bond and the nascent π bond. In general, we found that substituents connected to the breaking sigma bond had a larger influence on reaction kinetics. Computations reveal that the extent of mechanical coupling is similar between all derivatives studied, so we explain the observed differences (or lack thereof) in reactivity by examining the degree to which the substituents provide electronic stabilization to the TS, which has substantial diradical character. We find that an alkyne substituent connected to the breaking sigma bond provides the most stabilization. In addition, the alkyne is initially insulated from the nascent π bond of CBE, but extends the conjugation of the unveiled butadiene product enough to make it fluorescent, providing a foundation for CBEs to become a class of “turn-on” mechanofluorophores.

We combine our insights from Chapters 3-4 to better understand a new monomer presented in Chapter 5 that uses the photoswitching chemistry of a diarylethene (DAE) substituent to photochemically switch the mechanophore between cyclobutene-like and cyclobutane-like structures. Quantitative results derived from SMFS experiments reveal that the photochemical trigger can alter the reaction rate of the monomer by > 105 at a force of 810 pN (the CB-like monomer being easier to activate). We therefore have designed a polymer system whereby the mechanochemical reactivity of the polymer backbone can be regulated (sped up or slowed down) by a separate photochemical reaction. Interestingly, results from sonication studies reveal that despite their disparate reactivates, the two DAE isomers yield the same mechanochemical product. The mechanistic insights gleaned from these results will serve as a foundation for the future molecular-level design of similar, photoswitchable mechanophores.