Reactions of alpha-nucleophiles with a model phosphate diester

Abstract

We dedicate this paper to Prof. Harri Lönnberg on the occasion of his 60 th birthday, in recognition of his many lasting contributions to Bioorganic Chemistry. AbstractSubstantial rate enhancements are observed for the reactions of α-effect nucleophiles with 2,4-dinitrophenyl ethyl phosphate diester 4. The effect is largest (ca. 4500-fold) for the hydroperoxide anion. However, the most reactive α-effect nucleophile, and thus the most reactive nucleophile towards phosphate phosphorus at pHs near to or above its pK a of 13.74, is the hydroxylamine anion NH 2 O -. The kinetic reactivities of the α-effect nucleophiles follow aBrønsted correlation, with a slope β nuc = 0.41±0.03 greater than that (0.30) observed for non-α-effect nucleophiles, consistent with a thermodynamic origin for the effect.

Nucleophilic Neutralization of Organophosphates: Lack of Selectivity or Plenty of Versatility?

“…Although naphthyl phosphate esters are much less reactive than those of the 2,4dinitrophenyl phosphate esters and the magnitude of the effect depends on the type of electrophile under attack, these compounds show comparable reactivity towards these nucleophiles, in virtue of the general acid catalysis: the neighboring dimethylammonium group makes a strong intramolecular hydrogen bond to the leaving group oxygen in the reactant. [67] An interesting way to illustrate the alpha effect is by the Brønsted plot. Nome et al reported the degradation of DEDNPP promoted by the oxime 2-(hydroxyimino)-Nphenylacetamide (Ox 1) and included the data in the Brønsted plot in Figure 19 for some alpha-effect nucleophiles, which react with DEDNPP by a separate linear correlation than from the points for the H 2 O and HO À : the reactivity of the alpha-Table 1.…”

“…Alpha-effects compared for reactions of hydroxylamine with 2,4-dinitrophenyl and naphthyl phosphate esters. [67] Monoester dianion Diester anion Triester Data from literature. [52] nucleophiles is 3 × 10 3 fold higher than neutral and alkaline hydrolysis.…”

“…The effect for both phosphates with hydroxylamine follows the sequence triester>diester>monoester dianion. Although naphthyl phosphate esters are much less reactive than those of the 2,4‐dinitrophenyl phosphate esters and the magnitude of the effect depends on the type of electrophile under attack, these compounds show comparable reactivity towards these nucleophiles, in virtue of the general acid catalysis: the neighboring dimethylammonium group makes a strong intramolecular hydrogen bond to the leaving group oxygen in the reactant [67] …”

“…The reactions of phosphate diesters are slow enough that competition from nucleophilic aromatic substitution becomes significant. Considering only the attack at phosphorous, the reaction of hydroxylamine with EDNPP is over 2×10 5 times faster than the spontaneous hydrolysis [67] . On the other hand, the dephosphorylation reactions of DEDNPP and Paraoxon by hydroxylamine under mild conditions are selective (at P) and effective (fast): comparing with respective spontaneous hydrolysis, rate enhancements of 2×10 6 and 9×10 5 ‐fold are observed in the presence of NH 2 OH for DEDNPP [73] and Paraoxon, [75] respectively.…”

How the Nature of an Alpha-Nucleophile Determines a Brønsted Type-Plot and Its Reaction Pathways. An Experimental Study

“…The values of k N and pK a are summarized in Table 1 (kinetic details are in Experimental Section and SM). In order to have a reasonable set of nucleophiles of varying basicity (broad range of pK a values) and nucleophilicity, pK a data were taken from the literature (Kirby et al, 2008) The k N and pK a values from Table 1 were statistically corrected with p and q parameters, where q is the number of equivalent basic sites on the free nucleophile, and p is the number of equivalent dissociable protons on the conjugate acid of the nucleophile (Bell, 1973) The values accompanying k N in Table 1 correspond to the error associated to the slope to obtain these kinetic coefficient values.…”