The author replies to Ault.

In his response to my article regarding general acid catalysis (GAC) (1), Ault (2), makes some good points. One issue that deserves some clarification is the mechanistic ambiguity of GAC. Suppose a reaction is performed in a solution that is buffered by a monoprotic acid HA and a salt of its conjugate acid A−, and one suspects that HA contributes to the observed rate of reaction via GAC. If the reaction is faster when repeated at a higher buffer concentration Ca = [HA] + [A−], then the increase in rate could be attributed to increased GAC arising from the increase in [HA] or to increased general base catalysis (GBC) arising from the increase in [A−]. For simplicity, assume the pH is unchanged at higher buffer concentrations, such that increased specific acid catalysis by hydronium ion cannot be responsible for the increase in overall rate of reaction. The simplest resolution to this dilemma is to repeat the experiment using a structurally dissimilar buffer, since the effectiveness of general catalysis is linked to the structure of the catalyst; for example, it seems unlikely that phosphate, a moderately effective nucleophile, would be just as effective as perchlorate, a poor nucleophile. However, the mere observation that a different buffer causes a different increase in rate does not rule out either mechanism. A more definitive resolution might be obtained by Hammett-type studies, since GAC involves a formally neutral rate-determining transition state, while GBC involves an anionic one.

Ault also raises an interesting question: what factors control the rate of proton transfer? A commonly held opinion is that proton transfer to oxygen is fast while transfer to carbon is slow. In fact, studies by Kresge and others (3) have demonstrated that transfer is rapid when the basic lone pair is localized on one atom and does not change hybridization upon transfer (the Principle of Least Motion; ref 4). For example, the phenylacetylide (PhCC−) and trichloromethyl (Cl3C−) anions deprotonate water rapidly at a rate (∼1010 M-1 s-1) consistent with diffusion control (5–7). Thermodynamic considerations also play a role; for example, although ethyl vinyl ether is more delocalized than isobutylene, the former is protonated 5000 times faster (8, 9). However, when the data are corrected for the fact that proton transfer to isobutylene is less favorable by 50 kJ/mol, the result is that the “intrinsic activation barriers” for ethyl vinyl ether and isobutylene are 50 and 25 kJ/mol, respectively, as expected. Inexplicably, the N-protonation of amides is diffusion controlled (10) despite the high resonance energy of approximately 90 kJ/mol (11).

Proton transfer to any atom may also be slowed by intramolecular hydrogen bonding; for example, proton transfer from mono-protonated 1,8-bis(dimethylamino)­-naphthalene (Proton Sponge) is known to be slow (∼105 M-1 s-1) (12, 13). More detailed studies indicate that the energy needed to bring the reactants together is about 40 kJ/mol, while the barrier to proton transfer itself varies with substrate (3). Protonation of an aromatic ring requires ∼40 kJ/mol, while protonation of typical oxygen and nitrogen bases by acetic acid or phenol requires only 8 kJ/mol, a value consistent with the barrier to diffusion.

The action of general catalysis should be inferred if the rate of reaction is increased when the buffer concentration is increased at constant pH. This is likely when the pH is near the pKa of the buffer, the degree of protonation in the transition state is partial (Brønsted α is approximately 0.5), and when proton transfer is slow, yet compensated by the increased reactivity of the conjugate acid of the reactant. Proton transfer is slow when the basic lone pair is delocalized or when a hybridization change must accompany transfer.

Literature Cited

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