On the Computational Determination of the pKa of Some Arylboronic Acids

An important property of arylboronic acids, particularly when considering their use in medicinal chemistry, is their pKa in aqueous solution. The results of computational determination of absolute pKas of arylboronic acids can be very disappointing in comparison to available experimental results, particularly in the case of large substituents. In this paper, the main origin of this problem is identified. It is shown that in order to obtain accurate pKa values for arylboronic acids from computational quantum chemistry, it is necessary to consider the effect of different possible conformations of the hydroxyl groups in the acid and its conjugate base together with the low-energy conformations of their substituents. An improved practical procedure for the computational determination of the pKas of arylboronic acids is proposed and applied to a set of recently synthesized arylboronic acids, yielding consistent results.