Conformational Properties of 5-Alkoxy and 5-Alkyl Substituted Trimethylene Phosphates in Solution

John Alan Gerlt, Neal I. Gutterson, Reed E. Drews, Jay A. Sokolow

Research output: Contribution to journalArticlepeer-review


The results of thermochemical experiments and ab initio and molecular mechanics calculations on the enthalpies of hydrolysis of structural analogues of cyclic AMP suggested that 5 kcal/mol of the 8 kcal/mol more exothermic enthalpy of hydrolysis of cyclic AMP relative to trimethylene phosphate can be explained by geometric strain resulting from the trans fusion of the trimethylene phosphate and ribofuranoside rings. The remaining 3 kcal/mol of excess enthalpy of hydrolysis could not be accounted for by strain. In this paper we present the results of NMR studies on the solution conformations of trimethylene phosphate (2-hydroxy-2-oxo-1,3,2-dioxaphosphorinane) substituted at the 5 position with alkyl and alkoxy groups. The conformational energies of the alkyl groups are essentially independent of solvent, with values ranging from 0.5 to 0.8 kcal/mol being found for the equatorial preferences of methyl, ethyl, isopropyl, and tert-butyl. However, with alkoxy groups, the conformational energies were found to be solvent dependent, with the values for 5-methoxy ranging from 1.0 kcal/mol favoring the axial position in D2O to 0.2 kcal/mol favoring the equatorial position in acetone-d6. These results can be explained by assuming that polar solvents preferentially solvate the most polar conformation of a conformationally flexible solute. Since the 5-alkoxy substituent of the trimethylene phosphate ring in cyclic AMP is constrained to be in an equatorial position by the trans fusion of the trimethylene phosphate-ribofuranoside ring system, solvation effects appear to be important in the observed thermodynamic instability of cyclic AMP in water. A biochemical role for this solvation effect is proposed.

Original languageEnglish (US)
Pages (from-to)1665-1670
Number of pages6
JournalJournal of the American Chemical Society
Issue number5
StatePublished - Feb 1980
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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