Vol.:(0123456789) 1 3 Theoretical Chemistry Accounts (2020) 139:27 https://doi.org/10.1007/s00214-019-2530-2 REGULAR ARTICLE Reactivity and stability of ion pairs, dimers and tetramers versus solvent polarity: S N Ar fuorination of 2‑bromobenzonitrile with tetramethylammonium fuoride Ellen V. Dalessandro 1  · Josefredo R. Pliego Jr. 1 Received: 3 August 2019 / Accepted: 15 December 2019 / Published online: 18 January 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Anion–molecule reactions have a substantial solvent efect, which decreases with the solvent polarity. However, less solvation leads to the formation of ion pairs and higher aggregates that are usually less reactive. Consequently, theoretical determination of the best solvent for the reaction needs to consider all the species in equilibrium. In this report, we have investigated the wide range of solvent polarity in the S N Ar reaction of the tetramethylammonium fuoride (TMAF) with 2-bromobenzonitrile, as well as the formation of ion pairs, dimers and tetramers using molecular dynamics and density functional calculations with continuum solvation. Five solvents were considered: methanol, dimethylformamide, pyridine, tetrahydrofuran and benzene. The TMAF exists predominantly as free ions in methanol, as ion pairs in dimethylformamide and pyridine, and as tetramers in tetrahydrofuran and benzene. The reaction takes place through free ions in methanol, ion pairs in dimethylformamide, pyridine and tetrahydrofuran, and via dimer in benzene. The calculations suggest that dimethylformamide and pyridine are the best solvents for this reaction. Keywords Ion pairing · Solvent efect · Nucleophilic fuorination · Aggregation · Counter-ion efect · Nucleophilic aromatic substitution · SNAr 1 Introduction Reactions of ions with molecules, such as S N 2, E2 and S N Ar, can take place via the solvated ion in polar solvents. Increasing the solvation power (usually related to polarity) of the medium leads to increase in the activation free energy barrier. This is a classical view on this kind of reaction [1, 2]. Nevertheless, the counter-ion is also present in solu- tion and formation of ion pairs takes place even in aqueous solution [3, 4]. With the decrease in the solvent polarity, dimers, trimers, tetramers and even higher aggregates can be formed [5]. Ionic reactions can also occur via these aggre- gates, although it is usually thought that single ions are more reactive [6]. Based on this view, aggregates can work like a bufer on the reactivity [7]. Indeed, reaction kinetics of the solvated ion becomes higher with the decrease in the solvent polarity and reaches the maximum value in the gas phase. Nevertheless, less polar solvents lead to formation of ion pairs and higher aggregates, which are usually less reactive. Consequently, there is an ideal solvation that produces the highest reactivity and it is worth to know how the reaction kinetics changes with the solvent polarity. Figure 1 shows a possible profle of the activation free energy versus solva- tion of the medium. In this profle, there is an ideal solvation window that leads to the highest kinetics. In some situations, the solubility can be an additional factor that decides the best solvent. An example is the S N 2 reaction of cesium fluoride with alkyl halides or alkyl mesylates. Experimental data point out that while the reaction takes place in tert-butanol solvent, it is much less efective in methanol and acetonitrile solvents [8, 9]. Quantum chemistry and molecular dynamics calculations “Festschrift in honor of Prof. Fernando R. Ornellas” Guest Edited by Adélia Justino Aguiar Aquino, Antonio Gustavo Sampaio de Oliveira Filho & Francisco Bolivar Correto Machado. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00214-019-2530-2) contains supplementary material, which is available to authorized users. * Josefredo R. Pliego Jr. pliego@ufsj.edu.br 1 Departamento de Ciências Naturais, Universidade Federal de São João del-Rei, São João del-Rei, MG 36301-160, Brazil