Anomeric effect in "high energy" phosphate bonds. Selective destabilization of the scissile bond and modulation of the exothermicity of hydrolysis

Eliza A. Ruben, Joshua A. Plumley, Michael S. Chapman, Jeffrey D. Evanseck

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


A natural bonding orbital (NBO) analysis of phosphate bonding and connection to experimental phosphotransfer potential is presented. Density functional calculations with the 6-311++G(d,p) basis set carried out on 10 model phosphoryl compounds verify that the wide variability of experimental standard free energies of hydrolysis (a phosphotransfer potential benchmark) is correlated with the instability of the scissile O-P bond through computed bond lengths. NBO analysis is used to analyze all derealization interactions contributing to O-P bond weakening. Phosphoryl bond lengths are found to correlate strongest (R = 0.90) with the magnitude of the ground-state n(O) → σ*(O-P) anomeric effect. Electron-withdrawing interactions of the substituent upon the σ(O-P) bonding orbital also correlate strongly with O-P bond lengths (R = 0.88). However, an analysis of σ*(O-P) and σ(O-P) populations show that the increase in σ*(O-P) density is up to 6.5 times greater than the decrease in σ(O-P) density. Consequently, the anomeric effect is more important than other derealization interactions in impacting O-P bond lengths. Factors reducing anomeric power by diminishing either lone pair donor ability (solvent) or antibonding acceptor ability (substituent) are shown to result in shorter O-P bond lengths. The trends shown in this work suggest that the generalized anomeric effect provides a simple explanation for relating the sensitivity of the O-P bond to diverse environmental and substituent factors. The anomeric n(O) → σ*(O-P) interaction is also shown to correlate strongly with experimentally determined standard free energies of hydrolysis (R = -0.93). A causal mechanism cannot be inferred from correlation. Equally, a P-value of 1.2 × 10-4 from an F-test indicates that it is unlikely that the ground-state anomeric effect and standard free energies of hydrolysis are coincidentally related. It is found that as the exothermicity of hydroylsis increases, the energy stabilization of the ground-state anomeric effect increases with selective destabilization of the high-energy O-P bond to be broken in hydrolysis. The anomeric effect therefore partially counteracts a larger resonance stabilization of products that makes hydrolysis exothermic and needs to be considered in achieving improved agreement between calculated and empirical energies of hydrolysis. The avenues relating the thermodynamic behavior of phosphates to underlying structural factors via the anomeric effect are discussed.

Original languageEnglish (US)
Pages (from-to)3349-3358
Number of pages10
JournalJournal of the American Chemical Society
Issue number11
StatePublished - Mar 19 2008
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


Dive into the research topics of 'Anomeric effect in "high energy" phosphate bonds. Selective destabilization of the scissile bond and modulation of the exothermicity of hydrolysis'. Together they form a unique fingerprint.

Cite this