The reactivity of phosphate esters: reactions of monoesters with nucleophiles. Nucleophilicity independent of basicity in a bimolecular substitution reaction

Abstract

The reactions of amine nucleophiles at the phosphorus centre of monoand di-anions of phosphate monoesters involve concerted displacement processes. The reactivity of the dianions depends strongly on the leaving group, but only weakly on the basicity of the nucleophile, and for a sufficiently good leaving group the Bronsted coefficient is zero. Thus, substituted pyridines differing in basicity by more than eight powers of ten attack the dianion of 2.4-dinitrophenyl phosphate at the same rate. These reactions must lie close to the borderline between unimolecular and bimolecular processes. The reactions with the monoanions are sensitive to the basicity of the nucelophile, and also depend strongly on the leaving group. The reactivity of phosphate monoester monoanions is similar to that of the anions of the diesters, and both react readily with fluoride anion.CONTISCISG our study of the simple reactions of esters of phosphoric acid, we have examined in more detail the process of nucleophilic substitution at the phosphorus centre of phosphate monoesters. We showed previously that the reactivity of a series of amine nucleophiles towards p-nitrophenyl phosphate dianion can be described by a linear free-energy relationship between the logarithms of the second-order rate constants for the displacement reaction and the pK, values of the conjugate acids of the amines. Similar relationships between rate and the pK, of the leaving group are observed for the hydrolysis reactions of the mono-and dianions of phosphate monoesters.2 We now deal with the effect on reactivity of variation in both nucleophile and leaving group, and the markedly different behaviour of mono-and di-anions. ESPERIMEXTAL i~~ateviaZs.-Inorganic salts were of analytical grade, and were used without further purification, except that solutions were filtered before use. Distilled water was further twice glass-distilled. Solid compounds, and the hydrochlorides of volatile or thermally unstable amines, were recrystallised at least twice. Liquids were distilled twice under nitrogen and stored in the dark. Aniline was purified by way of the hydrochloride, by treatment with stannous chloride.3 Commercial 2,6-lutidine contained significant quantities of lower homologues, and was purified by treatment with boron t r i f l ~o r i d e . ~ NN-Dimethylglycine hydrochloride was prepared from glycine and f~rmaldehyde,~ and 4-methoxypyridine by treatment of the 4-cliloro-compound with sodium rnethoxide.'j 3-Nitropyridine was prepared from 2-chloro-3-nitropyridine by dechlorination with copper in molten benzoic acid,' using the conditions described by Brown.* 3-Aminopyridine was prepared inadvertently in an attempted 1

The effect of magnesium ions on triphosphate hydrolysis

“…These calculations demonstrated a clear preference for a solventassisted pathway for phosphate monoesters with good leaving groups, while hinting at a potential transition to a substrate-assisted pathway for compounds with poor leaving groups, although this would only happen for leaving groups with quite high pK a s (previous work suggested a crossover at a leaving group pK a of ~ 13). This predicted mechanistic preference is in good agreement with experimental considerations of kinetic isotope effects, entropic effects and linear free energy relationships for phosphate monoester dianion hydrolysis [21][22][23][24], all of which have been traditionally interpreted as pointing to a reaction proceeding through a concerted pathway with a loose, dissociative transition state.…”

Why nature really chose phosphate

“…while at the same time, being found to be practically independent of the pK a of the nucleophile (RkOH) (Kirby & Varvoglis, 1968b) :…”

“…From Eqs. (7)- (9), it should be possible (though somewhat difficult) to calculate the value of b i directly by observation of the rate constant and pK a of the reaction, and, in particular, the rate constant for the uncatalyzed reaction of phosphate ester dianions has been found to be highly sensitive to the dissociation constant of the leaving group (Kirby & Varvoglis, 1968b) :…”

“…Based on Brønsted coefficients of x1Á23 and 0Á13 for the nucleophile and leaving group, respectively, the reaction was assumed to proceed via a dissociative mechanism, with the involvement of a monomeric metaphosphate anion (Kirby & Varvoglis, 1968b). However, in contrast to the seemingly convincing picture that emerged from the above studies, a careful computational study of the experimental LFER for this system has demonstrated that, while the LFER for this reaction can indeed correspond to a dissociative mechanism, the predicted LFER for the associative mechanism is also consistent with the experimental LFER.…”

Reactions of alpha-nucleophiles with a model phosphate diester

“…The S N 2(P) reactions of monoester dianions (i), observed only for neutral nucleophiles, are typically most dependent on, and thus primarily driven by, the leaving group: when this is sufficiently good the dependence on basicity of the second order rate constant for the reaction with the nucleophile, as measured by the Brønsted parameter β nuc , may disappear. 1 Bond formation to both nucleophile and leaving group is thus weak, in what can be (loosely!) described as a "loose" transition state (TS in Scheme 1), with bonding to the nucleophile not significantly stronger than its hydrogen-bonding solvation.…”