Frank A. Leibfarth

Iterative exponential growth of stereo- and sequence-controlled polymers

Chemists have long sought sequence-controlled synthetic polymers that mimic natures biopolymers, but a practical synthetic route that enables absolute control over polymer sequence and structure remains a key challenge. Here, we report an iterative exponential growth plus side-chain functionalization (IEG+) strategy that begins with enantiopure epoxides and facilitates the efficient synthesis of a family of uniform >3 kDa macromolecules of varying sequence and stereoconfiguration that are coupled to produce unimolecular polymers (>6 kDa) with sequences and structures that cannot be obtained using traditional polymerization techniques. Selective side-chain deprotection of three hexadecamers is also demonstrated, which imbues each compound with the ability to dissolve in water. We anticipate that these new macromolecules and the general IEG+ strategy will find broad application as a versatile platform for the scalable synthesis of sequence-controlled polymers.

A facile route to ketene-functionalized polymers for general materials applications

Function matters in materials science, and methodologies that provide paths to multiple functionality in a single step are to be prized. Therefore, we introduce a robust and efficient strategy for exploiting the versatile reactivity of ketenes in polymer chemistry. New monomers for both radical and ring-opening metathesis polymerization have been developed, which take advantage of Meldrums acid as both a synthetic building block and a thermolytic precursor to dialkyl ketenes. The ketene-functionalized polymers are directly detected by their characteristic infrared absorption and are found to be stable under ambient conditions. The inherent ability of ketenes to provide crosslinking via dimerization and to act as reactive chemical handles via addition, provides simple methodology for application in complex materials challenges. Such versatile characteristics are illustrated by covalently attaching and patterning a dye through microcontact printing. The strategy highlights the significant opportunities afforded by the traditionally neglected ketene functional group in polymer chemistry.

Scalable synthesis of sequence-defined, unimolecular macromolecules by Flow-IEG

Significance Automated chemical processes, such as DNA sequencing and nucleic acid and peptide synthesis, have transformed the fields of genetics and biotechnology. There is no analogous automated or semiautomated process, however, to provide unimolecular, sequence-defined synthetic polymers to those interested in studying them. The combination of multistep continuous flow chemistry and polymer synthesis by iterative exponential growth (Flow-IEG) enables the semiautomated synthesis of perfect polymers reported herein. The user-friendly nature, scalability, and modularity of Flow-IEG provides a general strategy for the automated synthesis of sequence and architecturally defined, uniform macromolecules. We envision this polymer synthesis machine will serve as an enabling tool for both fundamental explorations and advanced applications in biotechnology, medicinal chemistry, and materials science. We report a semiautomated synthesis of sequence and architecturally defined, unimolecular macromolecules through a marriage of multistep flow synthesis and iterative exponential growth (Flow-IEG). The Flow-IEG system performs three reactions and an in-line purification in a total residence time of under 10 min, effectively doubling the molecular weight of an oligomeric species in an uninterrupted reaction sequence. Further iterations using the Flow-IEG system enable an exponential increase in molecular weight. Incorporating a variety of monomer structures and branching units provides control over polymer sequence and architecture. The synthesis of a uniform macromolecule with a molecular weight of 4,023 g/mol is demonstrated. The user-friendly nature, scalability, and modularity of Flow-IEG provide a general strategy for the automated synthesis of sequence-defined, unimolecular macromolecules. Flow-IEG is thus an enabling tool for theory validation, structure–property studies, and advanced applications in biotechnology and materials science.

Flow-IEG enables programmable thermodynamic properties in sequence-defined unimolecular macromolecules

Monodisperse oligomers are important intermediates for studying structure–property relationships in soft materials but are traditionally laborious to synthesize. A semi-automated synthetic system that combines the benefits of telescoped reactions in continuous flow with iterative exponential growth (IEG) greatly expedites this process and makes the rapid synthesis of structurally diverse oligomer libraries practical. Herein, the coupling chemistry in the Flow-IEG system has been upgraded and expanded to include both 1,4- and 1,5-triazole linkages between monomers through an improved copper-catalyzed azide–alkyne cycloaddition (CuAAC) and a newly-optimized ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC), respectively. Improvements to the Flow-IEG framework enabled the library synthesis of monodisperse oligomers with variations in triazole connectivity. These discrete oligomers allowed the systematic evaluation of the consequences of triazole sequence on material properties. The crystallization properties of these macromolecules were highly dependent on both their monomer sequence and triazole substitution pattern.

Regioselective C−H Xanthylation as a Platform for Polyolefin Functionalization

Polyolefins that contain polar functional groups are important materials for next-generation lightweight engineering thermoplastics. Post-polymerization modification is an ideal method for the incorporation of polar groups into branched polyolefins; however, it typically results in chain scission events, which have deleterious effects on polymer properties. Herein, we report a metal-free method for radical-mediated C-H xanthylation that results in the regioselective functionalization of branched polyolefins without coincident polymer-chain scission. This method enables a tunable degree of polymer functionalization and capitalizes on the versatility of the xanthate functional group to unlock a wide variety of C-H transformations previously inaccessible on branched polyolefins.

Continuous-flow chemistry for the determination of comonomer reactivity ratios

Presented herein is an operationally simple and reliable approach to the determination of comonomer reactivity ratios using continuous flow. The benefits of continuous-flow chemistry include the precise control of reaction time, heat transfer, and the ability to dynamically alter continuous variables within a single experiment. The flow system produces nine samples reacted to low conversions with systematically varied comonomer compositions in under one hour. The polymer compositions were fit to a model of terminal copolymerization resulting in point estimates for comonomer reactivity ratios. The continuous-flow system was validated by the determination of five comonomer reactivity ratios that provided good agreement with literature values. The method is demonstrated to streamline the determination of especially challenging comonomer systems, such as those with fast kinetics or disparate reactivity. Using sustainably-derived lignin-based methacrylates, our continuous-flow approach enabled the determination of reactivity ratios for three comonomer pairs that have not been previously reported. We envision the continuous-flow method will catalyze the further exploration of statistical copolymers in both batch and continuous flow.