The Utility of Chain-End Degradation for De Novo Sequencing of Sequence-Defined Oligourethanes

ConspectusPolymer chemistry has expanded considerably over the past century to include studies of sequence-controlled and sequence-defined polymers. What began as a discipline focused largely on bulk polymer properties, such as mechanical strength, thermal behavior, and processability, has increasingly shifted toward molecular-level precision. These developments were inspired and enabled in large part by earlier breakthroughs in biological polymers, most notably DNA sequencing and solid-phase peptide synthesis, which underscored the importance of monomer sequence and primary structure in dictating polymer function. These biological advances also provided methodological frameworks that could be adapted for synthetic systems. The iterative protection-deprotection cycles used in peptide synthesis inspired analogous strategies for abiotic sequence-defined polymers. In a similar vein, automated peptide synthesizers served as inspiration for recent successes in automating syntheses of sequence-defined peptoids and urethanes, among other examples. With numerous methods now available to access monodisperse, precisely designed abiotic polymers with diverse backbones and side chain functionalities, new applications for these compounds are being actively explored. Our group has been particularly interested in developing applications in information storage. As global data storage demands continue to increase, both biotic and abiotic sequence-defined polymers have emerged as promising alternatives to silicon-based technologies due to their high information density, minimal physical footprint, and long-term stability. Drawing on our group's expertise in chemical sensing, we recognized conceptual parallels between the self-sequencing behavior of self-immolative (or chain-end degrading) polymers and their potential utility in molecular information storage. Chain-end degrading polymers, which depolymerize in response to a single triggering event, inherently encode their structure in a directionally "readable" format, making them attractive scaffolds for encoding, protecting, and later retrieving information, provided that the depolymerization is traceable and the original polymer has a defined sequence. Leveraging these insights, we developed methods to synthesize and analyze sequence-defined oligourethanes. In doing so, we were able to demonstrate that a controlled O → N terminal chain-end degradation occurs via a 5<i>-exo-trig</i> cyclization mechanism in the presence of base and heat, which can be easily monitored by LC/MS. This strategy enables <i>de novo</i> sequencing without reliance on tandem MS, addressing key limitations in the field such as size and complexity of the monomer pool as well as solid-phase synthesis restrictions on polymer chain lengths. With this method we have gone on to encode a number of proof-of-concept pieces of information, including quotes in English and Mandarin, a complex password, and a 256-bit cipher key. We have also leveraged electrochemistry, automation, and high-throughput approaches to increase the accessibility and utility of the workflow. In this Account, we describe the development of these methods and highlight their emerging applications in molecular encoding.