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

Paola R Campodónico,Ricardo A Tapia,Cristian Suárez-Rozas

doi:10.3389/fchem.2021.740161

Abstract

The reactions between 2-chloro-5-nitro pyrimidine with a serie of α-nucleophile derivatives were kinetically evaluated. The kinetic study was carried out in aqueous media and the data shown an unusual split on the Brønsted type-plot, opening a controversial discussion based on reactivities and possible reaction pathways. These split Brønsted type-plots are discussed over the hypothetical transition state (TS) structures associated to concerted or stepwise mechanisms with emphasis on hydrogen bond interactions between electrophile/nucleophile pair able to determine the reactivities and the plausible reaction routes.

Highlights

The alpha effect accounts for the increased nucleophilic strength due to the presence of an adjacent atom to the nucleophilic center with a lone pair of electrons (Jencks and Carriuolo, 1960a, 1960b; Edwards and Pearson, 1962; Dixon and Bruice, 1972; Buncel and Um, 2004; Kirby et al, 2005; Ren and Yamataka, 2007; 2009; Ormazábal-Toledo et al, 2013b; Kool et al, 2014; Kölmel and Kool, 2017) The nucleophilic strength has been frequently related with the basicity of the nucleophile
Sometimes the nucleophilicity is greater than the basicity (Anderson and Jencks, 1960) The nucleophilicity concept is associated to electron-rich species, at the same way, the electrophilicity to electron-deficient species (Ingold, 1929, 1933, 1934) Both concepts are based on electron theory of Lewis (Lewis, 1923) and the general acid-base theory of Brönsted and Lowry (Brönsted, 1923; Lowry, 1923) nucleophilicity/electrophilicity have been used as quantitative scales in order to rationalize the chemical reactivity (Contreras et al, 2003)
The experimental results shown an unusual broken on the Brönsted type-plot for the alpha nucleophiles studied, suggesting transition state (TS) structures structurally different given by the reactivities associated to the chemical structure of them: First, an HB interaction is suggested between the α-hydrogen atom of the nucleophile which is oriented toward the nitrogen atom of the pyrimidine moiety

Summary

Introduction

The alpha effect accounts for the increased nucleophilic strength due to the presence of an adjacent atom to the nucleophilic center with a lone pair of electrons (Jencks and Carriuolo, 1960a, 1960b; Edwards and Pearson, 1962; Dixon and Bruice, 1972; Buncel and Um, 2004; Kirby et al, 2005; Ren and Yamataka, 2007; 2009; Ormazábal-Toledo et al, 2013b; Kool et al, 2014; Kölmel and Kool, 2017) The nucleophilic strength has been frequently related with the basicity of the nucleophile. For better understanding the α-effect, in the present work we studied the magnitude of the α-effect of the reacting pair (electrophile/ nucleophile) evaluating the nucleophilic rate coefficients of a nucleophilic aromatic substitution (SNAr) reaction in aqueous media (Cho et al, 2014) The postulated mechanism for a SNAr reaction involves a nucleophilic addition followed by elimination of a leaving group (LG) and it requires the presence of at least one strong electron-withdrawing (Bunnett and Morath, 1955; Liebman et al, 1996) substituent in the ring of the electrophile to stabilize the intermediate, called Meisenheimer Complex (MC) and good LG (Bunnett and Zahler, 1951; Banjoko and Babatunde, 2004; Crampton et al, 2004, 2007; Um et al, 2007; Terrier, 2013; Ormazábal-Toledo et al, 2013b; Gallardo-Fuentes et al, 2014; Gazitúa et al, 2014; Contreras et al, 2015; Calfumán et al, 2017; 2018; Sánchez et al, 2018b) The first step of the reaction mechanism corresponds to the formation of a MC. The nucleophilic attack on the ipso carbon at the aromatic ring occurs concertedly with the LG departure within a single stepwise pathway without a MC formation (Terrier, 2013; Neumann et al, 2016; Calfumán et al, 2017; Neumann and Ritter, 2017; Stenlid and Brinck, 2017; Kwan et al, 2018; Campodónico et al, 2020) The literature summarizes the mechanistic trends based on the chemical nature of substrates and nucleophiles(OrmazábalToledo et al, 2013b; Gazitúa et al, 2014; Alarcón-Espósito et al, 2015, 2016, 2017; 2018; Sánchez et al, 2018a; Campodónico et al., α-nucleophiles Formula

Methods

Results

Conclusion