Principal Properties and Designs for Discrete Variations¹

Abstract

A problem that is often encountered when a new synthetic reaction is developed is to determine suitable combinations of reagents, co-reagents, catalysts, solvents, etc. This contribution presents general strategies for designing experiments when the objective is to explore the discrete variations defined by different reagents, different catalysts, different solvents, etc. The concept of principal properties is introduced, and it is shown how the principal properties of the constituents of the reaction system can be used for the selection of suitable test systems. Chemical examples are provided by the following: the selection of test solvents in the reduction of an enamine; the selection of combinations of Lewis acids and amines in the synthesis of benzamides; the selection of ketone substrates, amines, and solvents in the Willgerodt−Kindler reaction; and the selection of ketone substrates, Lewis acid catalysts, and solvents for analysing the regioselectivity in the Fischer indole synthesis with dissymmetric ketones.

Design and Application of a Screening Set for Monophosphine Lig-ands in Metal Catalysis

“…The specific workflow for the selection of a diverse molecule set adopted herein (Figure 2) represents just an example of a more general procedure where different choices can be made at every step, depending on the application. Indeed, others have used similar procedures to generate diverse sets of molecules in unique contexts, 7,9,[11][12][13][14][15][16] including phosphorus ligand sets. 8,[17][18][19] First, selecting a set of ligands that covers the entire range of ligand properties requires a means to quantify this range in advance, thus defining the search space.…”

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

“…The combination of PCA with DoE allows for a very efficient investigation of the whole chemical space for a given reaction [16]. When PCA and DoE are combined during reaction screening it directs the future experimental effort into the regions of chemical space where the specific chosen reaction occurs most successfully.…”

Ligand and solvent selection in challenging catalytic reactions

“…PCA can be combined with DoE as has been well described by Carlson . In essence, this enables the discrete parameters to be treated as continuous parameters through experimental design.…”

“…Our approach to catalysis more closely follows Carlson, in that we generally use three PCs to describe the ligands, and three PCs to describe the solvents (since this is expected to explain >75% variation in the results most of the time). Typically, up to nine continuous parameters (e.g.…”

“…PCA can be combined with DoE as has been well described by Carlson. 25 In essence, this enables the discrete parameters to be treated as continuous parameters through experimental design. In this way they can be related to one another, and the number of experiments required can be reduced to a practicable number while still providing a wealth of information.…”