Analysis of single polymer beads for solid phase combinatorial synthesis: the determination of reactive thiol and within batch polydispersity of bead loadings

Abstract

Polymer beads are the starting point of many synthetic protocols, and in a number of combinatorial syntheses such studies are based on single beads. It has therefore become important that individual beads carry the same functional group activity and quality control of populations of beads requires a knowledge of the distribution of activity between the individual beads. A procedure was developed for the measurement of the thiol loading of single copolymer beads which is based on the bleaching of Michler’s hydrol [4,4′-bis(dimethylamino)- diphenylcarbinol (BDC-OH)]. Flow injection colorimetry permits the small volumes of solution generated from single beads to be measured with rapid turnover and with a reproducibility of ca. 2%. The solution detection limit of 0.17 mM corresponds to a bead thiol concentration of 0.33 mmol g⁻¹. The procedure and the variability of a bead population were demonstrated using modified styrene–divinylbenzene copolymer beads. The apparatus allowed fast, simple and accurate determinations to be carried out on the individual polymer beads. Within a single batch of thiol-modified styrene–divinylbenzene beads thiol loadings ranged from <0.35 to 2.07 mmol g⁻¹ or 0.12 to 1.3 μmol per bead. Polydispersity may therefore significantly influence screening decisions based on single bead syntheses.