Hammett Correlation in the Accelerated Formation of 2,3-Diphenylquinoxalines in Nebulizer Microdroplets

Abstract

The accelerated formation of 2,3-diphenylquinoxalines in microdroplets generated in a nebulizer has been investigated by competition experiments in which equimolar quantities of 1,2-phenylenediamine, C6H4(NH2)2, and a 4-substituted homologue, XC6H3(NH2)2 [X = F, Cl, Br, CH3, CH3O, CO2CH3, CF3, CN or NO2], or a 4,5-disubstituted homologue, X2C6H2(NH2)2 [X = F, Cl, Br, or CH3], compete to condense with benzil, (C6H5CO)2. Electron-donating substituents (X = CH3 and CH3O) accelerate the reaction; in contrast, electron-attracting substituents (X = F, Cl, Br and particularly CO2CH3, CN, CF3 and NO2) retard it. A structure–reactivity relationship in the form of a Hammett correlation has been found by analyzing the ratio of 2,3-diphenylquinoxaline and the corresponding substituted-2,3-diphenylquinoxaline, giving a ρ value of −0.96, thus confirming that the electron density in the aromatic ring of the phenylenediamine component is reduced in the rate-limiting step in this accelerated condensation. This correlation shows that the phenylenediamine acts as a nucleophile in the reaction.

Hammett correlation in competition experiments in dissociation of ionised substituted benzophenones and dibenzylideneacetones

“…This protocol was successfully extended to the complementary process in which phenylenediamine competes with either a mono- or di-substituted phenylenediamine to condense with benzil to form a mono- or di-substituted diphenylquinoxaline. 19 A negative ρ value of −0.96, which indicates that there is an appreciable reduction in the electron density on the amino group(s) during the rate-limiting step, established that the phenylenediamine acts as a nucleophile in the condensation. Moreover, analysis of the mixture of products formed by transmission through a nebuliser was found to be conveniently and reliably achieved by gas chromatography-mass spectrometry (GCMS).…”

A broadly applicable quantitative relative reactivity model for nucleophilic aromatic substitution (SNAr) using simple descriptors

“…To complement the existing S N Ar rate data from the literature, we measured relative reaction rates for 74 individual electrophilesincluding many nitrogen heterocycles relevant to pharmaceutical synthesisusing a competition experiment approach, which is commonly used to generate univariate Hammett plots. [76][77][78][79][80][81] Having control over the composition of our training set gives us the exibility to have a varied and balanced distribution of structural features, which is necessary to ensure both accuracy and applicability in making new predictions. To make the model easy to implement, and to reduce the computational cost required, we combined simple and easy-to-obtain ground state molecular descriptors with our own experimentally determined S N Ar rates.…”

Hammett Correlation in Competing Fragmentations of Ionized 2‐Substituted Benzanilides Generated by Electron Ionization Mass Spectrometry

“…The derived reaction constant, ρ, of 1.85 indicated that there is an increase in negative charge on the carbonyl carbon atom(s) of the benzil in the rate‐limiting step, thus revealing that this component behaves as an electrophile in the condensation. Furthermore, this novel methodology was successfully extended to the condensation of phenylenediamine and a substituted phenylenediamine with benzil [25] . The corresponding ρ value of −0.82 showed that the rate‐limiting step involves a reduction in the electron density in the phenylenediamine ring, which functions as a nucleophile.…”

“…Furthermore, this novel methodology was successfully extended to the condensation of phenylenediamine and a substituted phenylenediamine with benzil. [25] The corresponding 1 value of À 0.82 showed that the rate-limiting step involves a reduction in the electron density in the phenylenediamine ring, which functions as a nucleophile.…”