Reaction optimization, combinatorial

Relative purity measurement and the relative purity-based reaction optimization have long been used in combinatorial synthesis. In order to make high-through-put purification a success, the yield-based optimization is essential. Chemiluminescent nitrogen detection (CLND) [4] with HPLC determines the quantitative yield after each reaction step during the library feasibility and rehearsal stages. The yield of each synthetic step provides guidance for the final library synthesis. 

Q. Liu, L. A Comparison of Various FTIR and FT Raman Methods Applications in the Reaction Optimization Stage of Combinatorial Chemistry, J. Comb. Chem. 1999, 7, 46. 

LeProust, E., Pellois, J. P., Yu, P., et al. (2000) Digital light-directed synthesis. A microarray platform that permits rapid reaction optimization on a combinatorial basis. J. Comb. Chem. 2, 349-354. 

Y Zhang, X Gong, H Zhang, RC Larock, ES Yeung. Combinatorial screening of homogeneous catalysis and reaction optimization based on multiplexed capillary electrophoresis. J Comb Chem 2 450-452, 2000. 

Common goals of optimization of combinatorial reactions include maximizing reaction yield, reduction of reaction by-products, and improvement of reaction reproducibility. The varied and optimized parameters depend on the nature of the process and can include reaction conditions (temperature, pressure, solvent or carrier gas), processing conditions (addition sequence and timing), and reaction interferences (concentration of various species) The set of parameters that describes how a reaction is carried out defines a reaction space, and reaction optimization explores as wide a variety of reaction spaces as possible to achieve the desired goal. 

SCHEME 10.15 Combinatorial reaction optimization for a synthesis of polymer-snpported tetrapeptides including two Af-methylamino acids. 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

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