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
10.1021/ja073652x.s002
https://acs.figshare.com/articles/journal_contribution/Anomeric_Effect_in_High_Energy_Phosphate_Bonds_Selective_Destabilization_of_the_Scissile_Bond_and_Modulation_of_the_Exothermicity_of_Hydrolysis/2950606
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 delocalization
interactions contributing to O−P bond weakening. Phosphoryl bond lengths are found to correlate strongest
(<i>R</i> = 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 (<i>R</i> = 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 delocalization 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 (<i>R</i> = −0.93).
A causal mechanism cannot be inferred from correlation. Equally, a <i>P</i>-value of 1.2 × 10<sup>-4</sup> from an <i>F</i>-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.
2008-03-19 00:00:00
antibonding acceptor ability
delocalization interactions
pair donor ability
Phosphoryl bond lengths
NBO
anomeric effect
10 model phosphoryl compounds
hydrolysis