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Ionisation influences so many of a compound’s properties: solubility, binding to ionic sub-sites, permeability and interactions with critical targets like the hERG ion channel.  This makes tuning the pKa of amines a frequent job for a medicinal chemistry team.  Ionisation is however notoriously hard to accurately predict from first principles, therefore chemists fall back on mental “milestones” of pKas in well studied sets of compounds and rules of thumb to adjust the pKa for different substituents.  One of the best collections of pairs and small sets of amines is in this joint publication led by Diederich at the ETH in Zurich collaborating with Roche in Basel, the University of Wein and the Johannes Gutenberg-Universität in Mainz.  A detailed exploration of the transmission of electronic effects through the sigma skeleton of organic bases in undertaken with a forensic analysis of the effect of conformation of substituents on basicity.

If you’re stuck trying to get the pKa of an amine just right – this is perfect background reading for you.

“Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities “

Diederich et al, ChemMedChem (2007), 2, 1100 – 1115

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