molecules Article How Do Aromatic Nitro Compounds React with Nucleophiles? Theoretical Description Using Aromaticity, Nucleophilicity and Electrophilicity Indices Kacper Błaziak 1,2,* , Witold Danikiewicz 3 and Mieczysław M ˛akosza 3 1 Faculty of Chemistry, University of Warsaw, 01-224 Warsaw, Poland 2 Biological and Chemical Research Center, University of Warsaw, 01-224 Warsaw, Poland 3 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; [email protected] (W.D.); [email protected] (M.M.) * Correspondence: [email protected] Received: 16 September 2020; Accepted: 16 October 2020; Published: 20 October 2020 Abstract: In this study, we present a complete description of the addition of a model nucleophile to the nitroaromatic ring in positions occupied either by hydrogen (the first step of the SNAr-H reaction) or a leaving group (SNAr-X reaction) using theoretical parameters including aromaticity (HOMA), electrophilicity and nucleophilicity indices. It was shown both experimentally and by our calculations, including kinetic isotope effect modeling, that the addition of a nucleophile to the electron-deficient aromatic ring is the rate limiting step of both SNAr-X and SNAr-H reactions when the fast transformation of σH-adduct into the products is possible due to the specific reaction conditions, so this is the most important step of the entire reaction. The results described in this paper are helpful for better understanding of the subtle factors controlling the reaction direction and rate. Keywords: nucleophilic aromatic substitution; reaction mechanism; DFT 1. Introduction Nucleophilic aromatic substitution of halogens in halonitroarenes is one of the fundamental processes of organic chemistry widely used for industrial and laboratory organic synthesis [1–3]. The reaction proceeds via the addition of nucleophiles to the aromatic rings at positions occupied X by halogen X to form σ -adducts followed by spontaneous departure of X− anions to give the substitution products. The addition is connected with dearomatization of the rings, whereas formation of the product by departure of X− results in rearomatization, thus, as a rule, the addition is the slow, rate limiting step of the reaction. This mechanism, formulated by J.F. Bunnett [4,5], was confirmed in numerous mechanistic studies and presently is generally accepted [6]. It has been also confirmed by numerous quantum chemical calculations of the reaction pathways between halonitrobenzenes and nucleophiles [7–18]. These calculations showed that depending on the structure of the reactants—nitroarenes and nucleophiles—the σX-adduct can either be an intermediate, i.e., is located in a local energy minimum on the potential energy surface (PES) of the reaction, or a transition state [19]. The nitro group in halonitrobenzenes activates three positions of the ring (two ortho and one para position) towards nucleophilic addition, thus the nucleophiles can add also at positions occupied by hydrogen. Indeed, there are a few old reports of reactions that proceed via addition of nucleophiles to p- and o-chloronitrobenzenes at positions occupied by hydrogen and further conversions of the produced σH-adducts, such as von Richter reaction [20] or formation of benzisoxazoles [21]. Molecules 2020, 25, 4819; doi:10.3390/molecules25204819 www.mdpi.com/journal/molecules Molecules 2020, 25, 4819 2 of 11 Molecules 2020, 25, x FOR PEER REVIEW 2 of 11 yearsSome ago, years it ago, was itshown was shown that the that addition the addition of nucleo of nucleophilesphiles to halonitroarenes to halonitroarenes at positions at positions occupied occupied by hydrogenby hydrogen proceeds proceeds faster faster than than at those at those occupied occupied by halogens by halogens and that and there that thereare a few are ageneral few general ways H ofways conversion of conversion of the of theinitially initially formed formed σH-adductsσ -adducts into into products products of of nucleophilic nucleophilic substitution substitution of of hydrogen S NAr-H,Ar-H, such such as as oxidation oxidation [22,23], [22,23], vicarious vicarious nucleophilic nucleophilic substitution substitution (VNS) (VNS) [24,25], [24,25], etc. etc. (Scheme 11).). InIn fact,fact, oxidativeoxidative nucleophilicnucleophilic substitutionsubstitution ofof hydrogen,hydrogen, ONSH,ONSH, vicariousvicarious nucleophilicnucleophilic substitution of hydrogen, VNS, and some other variants of S NAr-HAr-H are are presently presently well well recognized recognized and widely used processes in organic sy synthesisnthesis [3,26–32]. [3,26–32]. On On the basis of these results, it was concluded thatthat classical classical S NAr-XAr-X of of halogens halogens is is a a secondary secondary process process preceded preceded by by fast fast and and reversible reversible formation of H thethe σH-adducts-adducts [33]. [33]. Scheme 1.1. NucleophilicNucleophilic substitution substitution of halogenof halogen SNAr-X SNAr-X (a) and (a hydrogen) and hydrogen SNAr-H (SbN)Ar-H in para (substitutedb) in para substitutednitrobenzenes nitrobenzenes (X = halogen). (X = halogen). However, even in recent publications on the mechanism of SNArAr reactions reactions this situation situation was not takentaken into into account account [3,34]. [3,34]. Moreover, Moreover, in in all all quantum quantum ch chemicalemical calculations calculations of the the energy energy profiles profiles of the addition of nucleophiles to halonitrobenzenes only the addition at positions occupied by halogens has been considered [7–18,34]. [7–18,34]. It It is is really surpri surprising,sing, because calculations of of a a reaction between two reactants shouldshould look look for for the the pathways pathways that that proceed proceed via transition via transition states states (TS) of (TS) the lowestof the freelowest energies, free energies,thus they thus have they ignored have faster ignored addition faster ataddition positions at positions occupied occupied by hydrogen. by hydrogen. Previously we have presented results of DFT calculations of the reactions between a model nucleophile: carbanion of chloromethyl phenylphenyl sulfonesulfone1 1and and three three model model nitroarenes: nitroarenes: nitrobenzene nitrobenzene2, 2p,-fluoro- p-fluoro- and andp-chloronitrobenzenes p-chloronitrobenzenes3 and 34 andfor the 4 gasfor phasethe gas and phase DMF solutions.and DMF Thesesolutions. calculations These calculationshave shown have that theshown addition that the at positionsaddition at occupied positions by occupied hydrogen by proceeds hydrogen via proceeds TS of lower via TS free of energy lower freethan energy at those than occupied at those by occupied halogens by (Figure halogens1); thus, (Figure they 1); are thus, in agreement they are within agreement the experimental with the experimentalresults. On this results. basis, On a this real, basis, corrected a real, mechanism corrected mechanism of nucleophilic of nucleophilic aromatic substitutionaromatic substitution has been hasformulated been formulated [35–37]. The[35–37]. model The nucleophile model nucleophile (chloromethyl (chloromethyl phenyl sulfone phenyl anion) sulfone has anion) been chosenhas been as chosenan example, as an which,example, due which, to its nature,due to isitsmuch nature, less is amuchffected less by affected the solvent’s by the eff solvent’sects contrary effects to thecontrary other tomost the commonother most protic common or polar protic nucleophiles or polar nucl [35].eophiles [35]. The aim of this paper is to present a full mechanistic picture of nucleophilic aromatic substitution in halonitroarenes and nitrobenzene embracing such subtle features as changing aromaticity of the nitroarenes as well as electrophilicity of nitroarenes and nucleophilicity of the carbanion in the addition process, kinetic isotope effects and effects of substituents on the rates of the addition on the basis of DFT calculation and experimental results. Molecules 2020, 25, x FOR PEER REVIEW 2 of 11 years ago, it was shown that the addition of nucleophiles to halonitroarenes at positions occupied by hydrogen proceeds faster than at those occupied by halogens and that there are a few general ways of conversion of the initially formed σH-adducts into products of nucleophilic substitution of hydrogen SNAr-H, such as oxidation [22,23], vicarious nucleophilic substitution (VNS) [24,25], etc. (Scheme 1). In fact, oxidative nucleophilic substitution of hydrogen, ONSH, vicarious nucleophilic substitution of hydrogen, VNS, and some other variants of SNAr-H are presently well recognized and widely used processes in organic synthesis [3,26–32]. On the basis of these results, it was concluded that classical SNAr-X of halogens is a secondary process preceded by fast and reversible formation of the σH-adducts [33]. Scheme 1. Nucleophilic substitution of halogen SNAr-X (a) and hydrogen SNAr-H (b) in para substituted nitrobenzenes (X = halogen). However, even in recent publications on the mechanism of SNAr reactions this situation was not taken into account [3,34]. Moreover, in all quantum chemical calculations of the energy profiles of the addition of nucleophiles to halonitrobenzenes only the addition at positions occupied by halogens has been considered [7–18,34]. It is really surprising, because calculations of a reaction between two reactants should look for the pathways that proceed via transition states (TS) of the lowest free energies, thus they have ignored faster addition at positions