Theoretical Study of the Importance of the Spectator Groups on the Hydrolysis of Phosphate Triesters

The spontaneous hydrolysis of a series of five triaryl and two dialkyl aryl phosphate triesters, previously studied experimentally, is examined theoretically using two different hybrid density functional methods, B3LYP and M06; two basic sets, 6-31+G­(d) and 6-311++G­(d,p); and the Gaussian 09 program. The B3LYP/6-31+G­(d) methodology combined excellent accuracy with minor computational cost. The calculations show excellent quantitative agreement with experiment, which is best in the presence of three discrete water molecules. The results support a two-step mechanism involving a pentacovalent addition intermediate, with a lifetime of tenths of a millisecond. The rate-determining formation of this intermediate involves general base catalysis, defined by concerted proton transfers in a six-membered cyclic activated complex (<b>TS1</b>), which involves two hydrogen-bonded water molecules supporting a well-developed H₂O···P bond (mean % evolution 77.83 ± 0.97). The third water molecule is hydrogen-bonded to PO and subsequently involved in product formation via <b>TS2</b>. The effects on reactivity of all the groups attached to phosphorus in <b>TS1</b> are examined in detail: the two non-leaving groups in particular are found to play an important role, accounting for the substantial difference in reactivity between triaryl and dialkyl aryl phosphate triesters

The Most Reactive Amide As a Transition-State Mimic For <i>cis</i>–<i>trans</i> Interconversion

1-Azatricyclo­[3.3.1.1^3,7]­decan-2-one (<b>3</b>), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed <i>cis</i>–<i>trans</i> rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making <b>3</b> by some way the most reactive known “amide”

The Most Reactive Amide As a Transition-State Mimic For <i>cis</i>–<i>trans</i> Interconversion

1-Azatricyclo­[3.3.1.1^3,7]­decan-2-one (<b>3</b>), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed <i>cis</i>–<i>trans</i> rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making <b>3</b> by some way the most reactive known “amide”

Dephosphorylation Reactions of Mono‑, Di‑, and Triesters of 2,4-Dinitrophenyl Phosphate with Deferoxamine and Benzohydroxamic Acid

This work presents a detailed kinetic and mechanistic study of biologically interesting dephosphorylation reactions involving the exceptionally reactive nucleophilic group, hydroxamate. We compare results for hydroxamate groups anchored on the simple molecular backbone of benzohydroxamate (BHA) and on the more complex structure of the widely used drug, deferoxamine (DFO). BHA shows extraordinary reactivity toward the triester diethyl 2,4-dinitrophenyl phosphate (DEDNPP) and the diester ethyl 2,4-dinitrophenyl phosphate (EDNPP) but reacts very slowly with the monoester 2,4-dinitrophenyl phosphate (DNPP). Nucleophilic attack on phosphorus is confirmed by the detection of the phosphorylated intermediates formed. These undergo Lossen-type rearrangements, resulting in the decomposition of the nucleophile. DFO, which is used therapeutically for the treatment of acute iron intoxication, carries three hydroxamate groups and shows correspondingly high nucleophilic activity toward both triester DEDNPP and diester EDNPP. This result suggests a potential use for DFO in cases of acute poisoning with phosphorus pesticides

Supramolecular Polymer/Surfactant Complexes as Catalysts for Phosphate Transfer Reactions

Designing artificial enzymes with tailored molecular interactions between the substrate and active site is of major intellectual and practical significance. We report the improved catalytic efficiency of a supramolecular polymer/surfactant complex comprised of PAIM^–, a poly­(acrylic acid) derivative with imidazole groups attached to the polymer by amide bonds, and the cationic surfactant cetyltrimethylammonium bromide (CTAB). Supramolecular complex formation, at concentrations below the respective CMC values, provides convenient hydrophobic pockets for the reactants close to the multiple catalytic centers, where imidazole and carboxylate groups act as nucleophiles for the degradation of a model phosphate triester, delivering the highly efficient performance of the supramolecular catalysts. Catalytic effects are on the order of thousands for nucleophilic catalysis and are higher by 2 orders of magnitude for the supramolecular polymer/surfactant complex at pH 9. The reported supramolecular catalytic complexes allow important changes in polarity and, given the presence of functional groups common to a variety of hydrolytic enzymes, could be of general applicability in such reactions