Ring Opening Metathesis Polymerization of 1-Substituted Cyclobutene Derivatives and Its Application to Antimicrobials: From Homopolymers to Alternating Copolymers

Abstract

Ring opening metathesis polymerization (ROMP) is a chain-growth polymerization based on the ring opening of strained cyclic olefins providing a range of polymeric materials. Living ROMP of highly strained norbornene derivatives generates linear polymers with accurate molecular weight control and low polydispersities (PDIs). However, internally heterogeneous mixtures are obtained because the polymerization reactions lack complete stereochemical and regiochemical control. 1-Substituted cyclobutene amides undergo ruthenium-catalyzed ROMP to provide polymers with translationally invariant backbones (E-configuration) and excellent PDIs. To better understand the structural factors that control the regio- and stereochemistry of the ROMP reactions of 1-substituted cyclobutenes, several 1-subsituted cyclobutenes with varied electron densities or steric interactions in the olefin bonds were prepared. 1-Cyclobutene esters, 1-cyclobutene secondary amides, 1-cyclobutene tertiary amides or 1-cyclobutenylmethyl acetates, were subjected to ROMP. The stereo- and regiochemistry of the ROMP polymers were studied by 1D and 2D-NMR spectroscopy. NBO charge and energy difference calculations for intermediates and products were undertaken to explain the experimental results. Electrostatic interactions during formation of the initial π-complexes and steric interactions during metallocyclobutane formation determine the regio- and stereoisomers formedROM of 1-substituted cyclobutene ester by ruthenium catalysts generates kinetically trapped enoic ruthenium carbene that cannot undergo additional metathesis with 1-cyclobutene esters. However, the enoic ruthenium carbene can ring-open cyclohexene to generate a ruthenium alkylidene that will in turn react with a highly strained 1-cyclobutene ester to regenerate the enoic ruthenium carbene. As a result, alternating cyclobutene and cyclohexene units are incorporated into the propagating polymer chain. The precisely alternating pattern was confirmed by 1H-NMR spectroscopy and stable isotope-labeling experiments. The alternating ring opening metathesis polymerization (AROMP) is tolerant to 4-substitution on the cyclohexene and various types of esters on the cyclobutene.The amphipathic nature of antimicrobial peptides (AMPs) facilitates their disruption of bacterial membranes and bacterial death. A series of alternating amphiphilic copolymers (AMP mimics) containing different cationic groups and varying hydrophobicity were synthesized through AROMP of 1-cyclobutene ester and cyclohexene derivatives. Their antimicrobial activities were assayed and their selectivities were compared with random copolymers or homopolymers of similar charge. Their mechanisms of action were studied by cross-section transmission electron microscopy (TEM), dye leakage vesicle assays, membrane depolarization assays, and potassium release assays. It is concluded that mimics with a 8-10 spacing between cationic residues and ~ 4 repeating units exhibited the best antimicrobial activities and selectivities.The amphiphilic polymers form vesicles in aqueous solution as demonstrated by TEM and dynamic light scattering (DLS). The pH and ionic strength dependence of vesicle formation was characterized by DLS. Polymer vesicles containing quarternary ammonium groups are insensitive to changes in pH, whereas, for polymers containing primary ammonium groups, size change upon increasing pH change is a result of protonation and deprotonation of primary amine groups.