Hydration of nitriles: an examination in terms of No Barrier Theory

Nitriles pose an interesting problem to the explanatory powers of organic chemistry because, despite the favorable overall thermodynamics of hydrolysis to the corresponding amides, the reactions are inherently slow. The rate determining step is hydration of the nitrile to give the imidic acid, which quickly tautomerizes to the amide. In terms of Marcus Theory, the intrinsic barriers for acid and base‐catalyzed hydration are higher for nitriles than for amides, which are themselves slow reactions. It is remarkable that hydration of a nitrile, for which the free energy change is close to zero except for polyhaloacetonitriles, is much slower than hydration of an amide, which is energetically unfavorable. This can be explained by No Barrier Theory in terms of the high energetic cost of the geometrical distortions in “one thing at a time” corner species. There are no experimental equilibrium constants for this initial hydration step, so we have determined them computationally. The free energy change for the initial hydration is small; it is the fast and energetically downhill second step, tautomerization to the amide, which makes the overall hydrolysis of nitrile to amide thermodynamically favorable. Very few of the pKa values needed in the acid and base‐catalyzed mechanisms are known, so we used linear free energy relations and treat the parent pKa values as adjustable parameters. This procedure leads to pKa values in accord with expectation based on such data as are available and permits calculation of rate constants in satisfactory agreement with experiment. Copyright © 2013 John Wiley & Sons, Ltd. Nitrile hydrolysis is surprisingly slow despite the favorable thermodynamics of hydrolysis. In terms of Marcus Theory, the intrinsic barriers for acid and base‐catalyzed hydration are higher for nitriles than for amides. No Barrier Theory provides both a qualitative explanation of this slow reaction and a method for quantitative prediction of rates. Although agreement with experiment was achieved with pKa values estimated using such experimental data as there are, and physical organic reasoning, agreement was improved by adjusting the pKa values.