The Distal Effect of Electron-Withdrawing Groups and Hydrogen Bonding on the Stability of Peptide Enolates

Junming Ho, Christopher J. Easton, Michelle L. Coote

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17 Citations (Scopus)


Relative gas-phase carbon acidities have been computed for a series of acetamides, diketopiperazines, and linear dipeptides. The results show that N-electron-withdrawing substituents, protonation, and hydrogen bonding at amide nitrogen in these systems increase the acidity of both a C-H proton adjacent to the amide carbonyl and that of one proximal to the amide nitrogen. There is a good correlation between the magnitudes of the increases at the two positions, but the extent of the increase for the distal C-H adjacent to the carbonyl is greater than that for the proximal C-H, in most cases by a factor of about two. The effects on the stability of the distal enolate are shown to result from predominantly inductive affects. The size of these effects is such that protonation and hydrogen bonding at nitrogen increase the acidity of the distal C-H to almost the same extent as seen for the analogous interactions at the carbonyl oxygen. The effect is also seen in solution, where the computed aqueous pKa values are greater for the C-H adjacent to the amide carbonyl, by up to 13 units, and where preliminary experimental studies have shown that N-acetylation of an amide increases the rate of hydrogen-deuterium exchange via formation of the corresponding distal enolate by more than 3 orders of magnitude above the rates of exchange via the proximal enolate, of the nonacetylated amide and of diisopropylketone. The results also indicate that hydrogen bonding to amide nitrogen could be as important as bonding to oxygen in enzyme-catalyzed cleavage of α-C-H bonds.

Original languageEnglish
Pages (from-to)5515-5521
Number of pages7
JournalJournal of The American Chemical Society
Issue number15
Publication statusPublished - 21 Apr 2010
Externally publishedYes


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