The application of design of experiments (DoE) reaction optimisation and solvent selection in the development of new synthetic chemistry

Abstract

This article outlines the benefits of using 'Design of Experiments' (DoE) optimisation during the development of new synthetic methodology. A particularly important factor in the development of new chemical reactions is the choice of solvent which can often drastically alter the efficiency and selectivity of a process. Whilst solvent optimisation is usually done in a non-systematic way based upon a chemist's intuition and previous laboratory experience, we illustrate how optimisation of the solvent for a reaction can be carried out by using a 'map of solvent space' in a DoE optimisation. A new solvent map has been developed specifically for optimisation of new chemical reactions using principle component analysis (PCA) incorporating 136 solvents with a wide range of properties. The new solvent map has been used to identify safer alternatives to toxic/hazardous solvents, and also in the optimisation of an S(N)Ar reaction.

Tools and techniques for solvent selection: green solvent selection guides

“…The requirement of the solvent in chromatography as the mobile phase is so obvious in its importance that solvent guides for this application predate all other tools [90,91], and has now been revived as a research topic [92,93]. Technological requirements can be balanced against solvent greenness through general purpose solvent selection guides, and alternative methods of computational solvent optimisation [65,94]. This approach to separating technological and EHS considerations resolves a problem clearly evident in the CHEM21 solvent selection guide, where benign but high boiling solvents, including glycerol, are considered to have an undesirable environmental impact [56].…”

The Application of Advanced Design of Experiments for the Efficient Development of Chemical Processes

“…When the reaction mechanism is considered, it is not clear why the base is required (either catalytically or in stoichiometric quantities) [21][22][23]. There is evidence that added base is not required, and in fact, some substrates perform more efficiently with added acid 3 or the inclusion of molecular sieves [24]. A DoE was carried out to investigate the ligand and solvent effects on the reaction as well 3 Personal communication with Alan Pettman, Pfizer: the use of a catalytic acid such as TFA provided significant enhancements in the rate of some redox neutral couplings of alcohols and amines, presumably protonating the imine and increasing its rate of reduction.…”

“…The method uses statistics to determine the most important factors in a reaction and the interactions between these factors which may affect the outcome. In our experience, DoE is an underutilised technique throughout chemistry, although its benefits are being recognized and it is being adopted more readily in industrial settings [1][2][3]. One possibility for the slow update of experimental design is that it is a statistical method, however, the mathematics involved is simple and the focus should be on an improved understanding of chemical reactivity.…”

Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques

“…[64][65][66] In this section, we would like to present further justification of the benefits of DoE and its combination with flow chemistry.…”