The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis
2016 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 33, 10664-10673 p.Article in journal (Refereed) Published
Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group plc on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pK(a) increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pK(a)s studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears.
Place, publisher, year, edition, pages
2016. Vol. 138, no 33, 10664-10673 p.
Structural Biology Organic Chemistry
IdentifiersURN: urn:nbn:se:uu:diva-307885DOI: 10.1021/jacs.6b06277ISI: 000382181900044PubMedID: 27471914OAI: oai:DiVA.org:uu-307885DiVA: diva2:1048829
FunderEU, European Research Council, 306474The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), 2012-2097Swedish National Infrastructure for Computing (SNIC), SNIC 2015/16-12 2016/1-293