(359c) Computer-Aided Solvent Design for Optimal Selectivity of a Williamson Ether-Synthesis Reaction

Williamson ether-synthesis (WES) is an important reaction of an organohalide and an alkoxide widely used in organic synthesis of ethers in industry. However, due to the strong-base nature of the alkoxide, side reaction(s) can occur when multiple electrophilic sites are present, complicating the process of purification. In this context, it is crucial to improve the reaction selectivity while maintaining the production rate of the main reaction. It has been found that the choice of solvent can dramatically influence the selectivity of WES; for example, the ratios of O-alkylated to C-alkylated product of the WES reaction of benzyl bromide and sodium β-naphthoxide at 298 K can be improved from 72:28 to 97:3 when changing the solvent from methanol to acetonitrile [1], thus opening the path of tuning reaction selectivity by a judicious choice of solvent. In the current work, we implement a computer-aided molecular design (CAMD) approach [2] that integrates quantum-mechanical (QM) calculations, model-based design of experiments (DoE) and mathematical optimization via a multivariate linear regression (MLR) model (as a surrogate for the QM model). We apply our DoE-QM-CAMD method to the WES reaction of benzyl bromide and sodium β-naphthoxide. In this case study, several protocols for training the MLR model are evaluated based on a set of statistical criteria and model performance indicators in order to improve the reliability of the MLR model. Selected MLR models for each of O-alkylation and C-alkylation are incorporated into a multi-objective optimization problem that is solved in order to identify a series of pareto optimal solutions: those corresponding to optimal solvents that efficiently balance the selectivity and reaction rate. Thus, experimental efforts can be focused on the identified promising solvents generated by DoE-QM-CAMD. Our work demonstrates the potential of DoE-QM-CAMD in guiding experiments and reducing experimental cost for reaction solvent selection. The method can be applied to a wide range of organic reactions.

Reference

[1] A. Diamanti, Z. Ganase, E. Grant, A. Armstrong, P.M. Piccione, A.M. Rea, J. Richardson, A. Galindo, C.S. Adjiman, Mechanism, kinetics and selectivity of a Williamson ether synthesis: Elucidation under different reaction conditions, Reaction Chemistry and Engineering. 6 (2021) 1195–1211.

[2] H. Struebing, Z. Ganase, P.G. Karamertzanis, E. Siougkrou, P. Haycock, P.M. Piccione, A. Armstrong, A. Galindo, C.S. Adjiman, Computer-aided molecular design of solvents for accelerated reaction kinetics, Nature Chemistry. 5 (2013) 952–957.