Modeling the nucleophilic reactivity of small organochlorine electrophiles: A mechanistically based quantitative structure‐activity relationship

Abstract

Environmental pollutants can be divided into four broad categories, narcosis‐type chemicals, less inert (“polar narcosis”) chemicals, reactive chemicals, and specifically acting chemicals. For narcosis‐type, or baseline, chemicals and for less inert chemicals, adequate quantitative structure‐activity relationships (QSARs) are available for estimation of toxicity to aquatic species. This is not the case for reactive chemicals and specifically acting chemicals. A possible approach to develop aquatic toxicity QSARs for reactive chemicals based on simple considerations regarding their reactivity is given. It is shown that quantum chemical calculations on reaction transition states can be used to quantitatively predict the reactivity of sets of reactive chemicals. These predictions can then be used to develop aquatic toxicity QSARs.

Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas)

“…Although a number of QSARs for predicting the toxicity of electrophilic/proelectrophilic compounds have been reported, these relationships are typically based on small sets of congeneric chemicals [45–47], and there remains significant uncertainty concerning the proper selection of these models as a function of specific molecular mechanisms and associated two‐dimensional [25,48] versus stereoelectronic (i.e., three‐dimensional) structure [49–53]. Consequently, these QSARs were not employed in the evaluation of observed and predicted 96‐h LC50 values because their use would likely have confounded the resulting interpretation.…”

Multiple Computer‐Automated structure evaluation program study of aquatic toxicity 1: Guppy

“…For more active compounds, it has been postulated that electrophiles exert their toxicity by interacting with glutathione [11] and either remove or deactivate this key component of the biochemical chain in aquatic organisms. Here, the activity is believed to be produced when an electrophile conjugates with the thiol group of glutathione.…”

“…In the late 1980s, it became clear that the practice of sorting aquatic pollutants into groups of similar structures or classes might be more than just convenience and possibly reflected different mechanism of action. Several mechanisms of toxicity of chemicals for fish were subsequently reported [7,11]. Overall, they can be fundamentally divided into two major mechanisms: the narcosis effect and the specific interactions effects.…”

Quantitative structure‐property relationships for the chemical reactivity of acrylates and methacrylates

“…Chemical reactivity has been modeled successfully for a number of chemical classes using quantum chemical parameters [7]. Quantitative structure–property relationships (QSPRs) for organic electrophiles have been proposed among others for small chlorinated alkenes by Verhaar et al [8], for organophosphorus esters by Hermens et al [9] and Schüürmann [10], and for epoxides by Eriksson et al [11] and Purdy [12]. For the reactivity of chlorinated alkenes, activation energies were calculated.…”