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.

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