Generalized anomeric interpretation of the "high-energy" N-P bond in N-methyl-N′-phosphorylguanidine: Importance of reinforcing stereoelectronic effects in "high-energy" phosphoester bonds

Eliza A. Ruben, Michael Chapman, Jeffrey D. Evanseck

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Electronic structure calculations have been performed on a model N-phosphorylguanidine, or phosphagen, to understand the stereoelectronic factors contributing to the lability of the "high-energy" N-P bond. The lability of the N-P bond is central to the physiological role of phosphagens involving phosphoryl transfer reactions important in cellular energy buffering and metabolism. Eight protonated forms of N-methyl-N′-phosphorylguanidine have been energy minimized at levels of theory ranging up to B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) to investigate the correlation between protonation state and N-P bond length. Selected forms have also been minimized using the CCSD/6-311++G(d,p) and QCISD/6-311++G(d,p) levels of theory. Bulk solvation energies using the polarized continuum model (PCM) with B3LYP/6-311++G(d,p) test the influence of the surroundings on computed structures and energies. The N-P bond length depends on the overall protonation state where increased protonation at the phosphoryl group or deprotonation at the unsubstituted N″ nitrogen results in shorter, stronger N-P bonds. Natural bond orbital analysis shows that the protonation state affects the N-P bond length by altering the magnitude of stabilizing n(O) → σ*(N-P) stereoelectronic interactions and to a lesser extent the σ(N-P) → σ*(C-N″) and σ(N-P) → σ*(C-N) interactions. The computations do not provide evidence of a competition between the phosphoryl and guanidinium groups for the same lone pair on the bridging nitrogen, as previously suggested by opposing resonance theory. The computed n(O) → σ*(N-P) anomeric effect provides a novel explanation of "high-energy" N-P bond lability. This offers new mechanistic insight into phosphoryl transfer reactions involving both phosphagens and other biochemically important "high-energy" phosphoester bonds.

Original languageEnglish (US)
Pages (from-to)17789-17798
Number of pages10
JournalJournal of the American Chemical Society
Issue number50
Publication statusPublished - Dec 21 2005
Externally publishedYes


ASJC Scopus subject areas

  • Chemistry(all)

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