Solvent Effects on Acid Catalysis

A variety of different solvent selection guides from GSK, Pfizer and Sanofi have been published, which suggest greener alternatives to the traditional solvents for chemical process development. A compilation of 

Acid catalysis in aqueous solution is well understood, however, it has been less studied in other polar protic solvents and aprotic solvents. Although solvent effects on acidity (p a) are documented independently in the literature, the first comprehensive, overarching book in this area was published recently in 2013 by Cox. Acidities in most common solvents are discussed, however, supercritical and higher temperature fluids are not considered. Some general considerations in this area are presented briefly below, however, for more detail we direct the reader to this excellent book. 

For weaker acids with acidities in the normal pH range there is an approximately linear relationship between the p Tg in aqueous versus 

The behaviour of acids in miscible aqueous organic mixtures is highly dependent upon the mole fraction of each solvent. In mixed-solvent systems, the solvent component with the greatest affinity for the solute will provide preferential solvation. Thus, when reducing the mole fraction of the preferred solvent, the properties of solutes display a significantly smaller than expected change until the preferred solvent drops below a certain mole fraction, typically below 20-40%, whereupon more dramatic changes in solute properties occur.  

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