Application of single bead FTIR in the optimization of solid-phase combinatorial and parallel syntheses

Abstract

Transfer of reaction conditions from solution to solid-phase is critical for combinatorial [1,2] and parallel solid-phase synthesis (SPS) [3]. This transfer and the further optimization of reaction conditions are not trivial undertakings. The lack of analytical methods for onsupport qualitative and quantitative analysis further accentuates the problem. To facilitate reaction optimization, the single bead FTIR method has been developed [4-6]. This method generates IR spectra with superior quality and provides an effective analytical tool. Reactions selected to synthesize a combinatorial library are usually well optimized in solution so that the corresponding SPS reactions would usually lead to expected products. Consequently, the analytical task is only to confirm the presence of the desired products. Single bead FTIR is particularly suited for this task because: (1) IR easily monitors functional group transformation; (2) building blocks used in synthesis can be selected to contain an IR detectable group; (3) direct monitoring of compounds on solidphase is generally quicker and more convenient than methods requiring cleavage and it is particularly advantageous when synthetic intermediates are unstable to the necessary cleavage conditions; (4) a single bead was shown representative of the whole population of beads [4]; and (5) IR spectra taken from different beads (different sizes or at different reaction times) can be compared using a polystyrene band as internal reference. Therefore, it is not necessary to examine the same bead for reaction kinetics study in the course of a synthesis.