UC Santa Barbara

The application of highly efficient “click” reactions to the synthesis and modification of soft materials has been a fruitful endeavor enabling chemists, material scientists, and engineers to efficiently prepare materials with optimized performance and utility. Diels–Alder (DA) cycloadditions are a particularly attractive class of click reaction for use in polymer and biomaterials as they are highly modular and can proceed rapidly in the absence of a catalyst given the appropriate diene–dienophile pairing. However, traditional diene choice for normal electron demand DA cycloadditions has been dominated by dienes that provide building block stability at the price of efficient reactivity (i.e., furan and anthracene). Cyclopentadiene (Cp) is an incredibly promising diene for rapid DA click chemistry; however, Cp is inherently unstable and readily dimerizes at room temperature. This instability prohibits the inclusion of Cp units in molecular and polymer building blocks, thus, limiting the utility of Cp-based DA cycloadditions in polymer materials.

Herein, several “tales” of taming the reactivity of this unruly diene are presented which enable the rapid synthesis, spatiotemporal functionalization, and property enhancement of polymer materials. In the first story, the use of norbornadiene (NBD) as a Cp precursor is described which enables the synthesis of complex polymer architectures. By incorporating NBD onto the chain end of macromolecular building blocks, a library of block copolymers was accessed from modular click reactions upon treatment of stable Cp precursors with a deprotecting agent, highlighting the utility of rapid DA cycloadditions in polymer click chemistry. Building upon the theme of on-demand Cp production, the second story presents the design and application of a novel Cp photocage. We demonstrate that access to photoprotected Cp affords spatiotemporal control over rapid DA click reactions, enabling the implementation of a DA-based photopatterning platform within polymer networks. To facilitate implementation in biological systems, an aqueous, photocaged Cp derivative was developed and implemented in a variety of PEG based hydrogels for subsequent patterning with dienophiles. Notably, because of the radical-free nature of this DA pattering platform, we demonstrate that this strategy can be used to pattern radical-sensitive, protein-based matrices for cell culture. Through patterned administration of biochemical cues within these bioactive hydrogels, we demonstrate spatial control over cellular growth and signaling. Finally, the last tale describes the use of a sterically tamed cyclopentadiene to access biocompatible materials with improved bulk properties. Through rational consideration of the mechanochemical activity of traditional furan–maleimide cycloadducts, we present a Cp derivative that increases the mechanical strength of the resulting cycloadduct and demonstrate the enhanced fracture resistance in corresponding hydrogel materials. With access to these three tamed Cp derivatives, practical uses of normal electron demand DA cycloadditions can be realized for the rapid synthesis and selective modification of polymer architectures to provide enhanced properties with novel biological and therapeutic applications.