Mechanism of Hydrolysis of Phosphorylethanolamine Triesters. Multiple Catalytic Effects of an Intramolecular Amino Group

Robert A. Lazarus, Stephen J. Benkovic

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Intramolecular displacement reactions at phosphorus have been examined in a series of n-alkyl-O-(arylphenylphos-phoryl)ethanolamines in 45% dioxane-water (v/v) at 35° C. The examination of the pH-rate profiles, the detection of external buffer catalysis, and the observation of deuterium solvent effects reveal the concurrent operation of three types of P-0 bond cleavage mechanisms: electrostatic catalysis by the protonated ammonium moiety of external nucleophilic attack by buffer bases at phosphorus, general-base-catalyzed intramolecular nucleophilic attack by the amino function to form the cyclic phosphoramidate, and intramolecular amine-assisted water displacement of the substituted phenol. The assignment of electrostatic rather than general acid catalysis as the role of the ammonium moiety derives from the identity in rate coefficients for nucleophilic attack by buffer species on the cationic trimethylammonium and protonated ammonium triesters. For nucleophilic fluoride attack in 85% dioxane-water this leads to a rate acceleration of ca. 103relative to a triester possessing no intramolecular ammonium moiety. Structure-reactivity correlations for the electrostatic process yield values of β1gdependent on the pKaof the nucleophile inferring a coupled transition state. A Bronsted plot for the general-base-catalyzed cyclization reaction yields a value of βgb=0.8 for a series of general base catalysts (pKa>7). Since proton removal from a putative pentacovalent intermediate would be thermodynamically favorable (βgb=0), the data collectively support either a concerted mechanism for the cyclization process apparently bypassing the formation of a pentacovalent intermediate with a discrete lifetime or a mechanism involving hydrogen-bonding stabilization of the rate-determining decomposition of the intermediate providing that this is faster than the diffusion away of the catalyst. In either case the lifetime of the pentacovalent intermediate is <10-12s.

Original languageEnglish (US)
Pages (from-to)4300-4312
Number of pages13
JournalJournal of the American Chemical Society
Issue number15
StatePublished - Jul 1 1979

All Science Journal Classification (ASJC) codes

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


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