Copper catalyst efficiency for the CuAAC synthesis of a poly(N-isopropylacrylamide) conjugated hyaluronan.

Abstract

Poly(N-isopropylacrylamide) conjugated hyaluronan (HA-pN), a brush-like copolymer system which serves as a polymer vehicle for cellular and drug delivery, has been previously synthesized via the copper catalyzed azide-alkyne reaction (CuAAC) using a combination of copper sulfate and ascorbic acid (CuAsc) as the catalytic system of choice. Bromotris(triphenylphosphine) copper(I) (CuBr(PPh3)3) is an alternative catalytic compound containing a phosphorous ligand which stabilizes copper in the +1 oxidative state in aqueous solvents and can be employed at true catalyst concentrations. CuAsc and CuBr(PPh3)3 were compared for their efficiency; 1) in the synthesis of HA-pN via CuAAC; 2) in producing thermoresponsive compositions and 3) in being extracted from the polymeric compositions. The synthesis of the brush copolymer was carried out under strict Schlenk conditions, then characterized by ATR-FTIR, 1H NMR, ICP-SFMS, and rheological measurements. CuBr(PPh3)3 catalyzed CuAAC leads to better grafting in water, at a true catalyst concentration, compared to CuAsc. Polymeric solutions exhibited similar traits of increasing mechanical stiffness with rising temperature. Despite purification via chelation and/or dialysis, residual copper was present in similar concentrations in the final polymers. In the CuAAC driven copolymer synthesis of the HA-pN, CuBr(PPh3)3 is a better catalyst than CuAsc.