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Article How Do Aromatic Nitro Compounds React with ? Theoretical Description Using , Nucleophilicity and Electrophilicity Indices

Kacper Błaziak 1,2,* , Witold Danikiewicz 3 and Mieczysław M ˛akosza 3

1 Faculty of , University of Warsaw, 01-224 Warsaw, Poland 2 Biological and Chemical Research Center, University of Warsaw, 01-224 Warsaw, Poland 3 Institute of , 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 to the nitroaromatic ring in positions occupied either by (the first step of the SNAr-H reaction) or a (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; ; DFT

1. Introduction Nucleophilic aromatic substitution of 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 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 (PES) of the reaction, or a [19]. The nitro group in halonitrobenzenes activates three positions of the ring (two ortho and one para position) towards , 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: 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 .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 ’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 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 occupied by hydrogen. Previously we have presented results of DFT calculations of the reactions between a model nucleophile: carbanion of chloromethyl phenyl sulfone 1 and three model nitroarenes: nitrobenzene 2, p-fluoro- and p-chloronitrobenzenes 3 and 4 for the gas phase and DMF solutions. These calculations have shown that the addition at positions occupied by hydrogen proceeds via TS of lower free energy than at those occupied by halogens (Figure 1); thus, they are in agreement with the experimental results. On this basis, a real, corrected mechanism of nucleophilic aromatic substitution has been formulated [35–37]. The model nucleophile (chloromethyl phenyl sulfone anion) has been Moleculeschosen as2020 an, 25 example,, 4819 which, due to its nature, is much less affected by the solvent’s effects contrary3 of 11 to the other most common protic or polar nucleophiles [35].

Molecules 2020, 25, x FOR PEER REVIEW 3 of 11

Figure 1. Potential energy profiles for the limiting step of SNAr-H (left) and SNAr-X (right) reactions between model nuclephile 1 and para substituted halonitrobenzenes constructed based on our previous computation results published elsewhere [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 Figure 1. Potential energy profiles for the limiting step of S Ar-H (left) and S Ar-X (right) reactions addition process, kinetic isotope effects and effects of substituentsN on the ratesN of the addition on the between model nuclephile 1 and para substituted halonitrobenzenes constructed based on our previous basis of DFT calculation and experimental results. computation results published elsewhere [35].

2.2. ResultsResults and Discussion AsAs thethe model model nucleophile nucleophile in ourin our calculations, calculations, we havewe have used theused carbanion the carbanion of chloromethyl of chloromethyl phenyl sulfonephenyl 1sulfonethat was 1 that used was in experimental used in experimental mechanistic mechanistic studies of SstudiesNAr-H of reaction. SNAr-H It reaction. was also usedIt was in also the previousused in calculationsthe previous of calculatio the energyns profiles of the ofenergy the reaction profiles with of nitrobenzenethe reaction 2with, p-fluoronitrobenzene nitrobenzene 2, p3- andfluoronitrobenzenep-chloronitrobenzene 3 and 4p-chloronitrobenzene(Scheme2). 4 (Scheme 2).

Scheme 2. Nucleophilic substitution of halogen S Ar-X (upper) and hydrogen S Ar-H (lower) in para Scheme 2. Nucleophilic substitution of halogen SNNAr-X (upper) and hydrogen SNNAr-H (lower) in para substitutedsubstituted nitrobenzenes.nitrobenzenes. 2.1. Aromaticity 2.1. Aromaticity Nucleophilic addition to the nitroaromatic rings, regardless of positions of the addition, is connectedNucleophilic with addition dearomatization. to the nitroaromatic In fact, the rings, intermediate regardless adducts, of positions particularly of the σaddition,H-adducts, is H areconnected relatively with stable dearomatization. entities and have In the fact, structure the intermediate of cyclohexadienenitronate adducts, particularly anions [38 σ].-adducts, It is therefore are ofrelatively great interest stable toentities follow and the have change the of structure the aromaticity of cyclohexadienenitronate in the course of the reaction.anions [38]. It is therefore of greatThe interest results to of follow experimental the change studies, of the particularly aromaticity ratesin the of course the reactions, of the reaction. can clarify some key The results of experimental studies, particularly rates of the reactions, can clarify some key elements of the mechanism. In the case of SNAr-X and SNAr-H, they can be interpreted in terms of changeselements of of aromaticity the mechanism. in the In reaction the case course. of SNAr-X Nonaromatic and SNAr-H, structure they can of σ Hbe-adduct interpreted to p-substituted in terms of H nitrobenzeneschanges of aromaticity was directly in the determined reaction bycourse. observation Nonaromatic of its 1 structureH NMR spectra of σ -adduct [38]. to p-substituted 1 nitrobenzenesThese experimental was directly results determined provide by information observation about of its the H keyNMR steps spectra of the [38]. reaction. Changes of aromaticityThese experimental in the course ofresults nucleophilic provide additioninformation can beabout followed the key by steps quantum of the . calculations. Changes of Inaromaticity order to follow in the electroniccourse of reorganizationnucleophilic addition during can this be process, followed calculations by quantum based chemical upon the calculations. Harmonic OscillatorIn order to Model follow of Aromaticityelectronic re (HOMA)organization [39] wereduring performed. this proce Whenss, calculations the nucleophile based approaches upon the theHarmonic nitroarene Oscillator ring and Model the distance of Aromaticity between them(HOMA) decreases, [39] were the excessperformed. of negative When charge the nucleophile affects the shapeapproaches of the the ring. nitroarene Figure2 shows ring and the HOMAthe distance aromaticity between index them as decreases, a function the of the excess progress of negative of the reactioncharge affects between the our shape model of the nucleophile, ring. Figure the 2 anionshows of the chloromethyl HOMA aromaticity phenyl sulfone index 1asand a function2, 3 and of4. the In allprogress cases theof the to between the ring atour positions model nucleo occupiedphile, by the hydrogen: anion of orthochloromethyl- and para phenyl- of 2 and sulfoneortho 1- and 2, 3 and 4. In all cases the addition to the ring at positions occupied by hydrogen: ortho- and para- of 2 and ortho- of 3 and 4, size of the ring increases and it loses planarity. The circumference of the ring increases in all these cases by about 2% (see Supplementary Materials: S6, S7). It is therefore evident that the loss of aromaticity in the case of the σH-adducts is the largest, in agreement with experiments. It is a different situation in the case where the nucleophile adds to p-halonitrobenzenes at the position occupied by halogen. The addition at the position occupied by in 3 results in formation of the σF-adduct, located in a minimum of the free energy on the reaction profile. This Molecules 2020, 25, 4819 4 of 11 of 3 and 4, size of the ring increases and it loses planarity. The circumference of the ring increases in all these cases by about 2% (see Supplementary Materials: S6, S7). It is therefore evident that the loss of aromaticity in the case of the σH-adducts is the largest, in agreement with experiments. It is a different situation in the case where the nucleophile adds to p-halonitrobenzenes at the position Molecules 2020, 25, x FOR PEER REVIEW 4 of 11 occupied by halogen. The addition at the position occupied by fluorine in 3 results in formation of F H theadductσ -adduct, possesses located higher in aaromaticity minimum ofthan the σ freeH-adduct energy and on circumference the reaction profile. of the This ring adduct increases possesses by ca. H higher1.7%, perhaps aromaticity because than theσ electron-adduct withdrawing and circumference fluorine of the accepts ring increases a partially by ca.negative 1.7%, charge perhaps of becausethe ring. the electron withdrawing fluorine atom accepts a partially negative charge of the ring.

Figure 2. 2.The The Harmonic Harmonic Oscillator Oscillator Model Model ofof AromaticityAromaticity (HOMA)(HOMA) aromaticityaromaticity indexindex forfor the addition SNAr to thethe orthoortho ((leftleft)) andand parapara positionposition ((rightright),), calculated calculated at at PBE1PBE PBE1PBE/6-31/6-31 + +G(d) G(d)level levelof of theory theory (P (PSNArSNAr N stands for the product ofof thethe SSNArAr reaction).

The addition of 1 at position para of 4 occupied by results in the formation of the structure The addition of 1 at position para of 4 occupied by chlorine results in the formation of the Cl identical to the σ adduct,Cl however, it is not located at the local minimum of ∆G on the reaction structure identical to the σCl adduct, however, it is not located at the local minimum of ΔG on the pathreaction but path at the but saddle at the point, saddle thus point, it isthus the it transition is the transition state (Figure state (Figure3). This 3). phenomenon This phenomenon has been has discussedbeen discussed in recent in recent reports reports by Fern byández Fernández et al. [19 et.] and al. earlier[19] and in theearlier case in of electrophilicthe case of electrophilic reactions by Cl Gwaltney et al. [40]. Additionally, the observation that the σ -adduct is theCl transition state structure reactions by Gwaltney et al. [40]. Additionally, the observation that the σCl-adduct is the transition wasstate omitted structure in was a very omitted innovative in a very work innovative by Ormaz áworkbal-Toledo by Ormazábal-Toledo et al. [16] in which et. the al. authors[16] in which introduce the theauthors calculation introduce methodology the calculation used methodology by us in the next used parts by us of in the the present next parts work. of The the lowestpresent aromaticity work. The oflowest the system aromaticity is observed of the aftersystem the is transition observed state after when the thetransition rearomatization state when process the rearomatization starts with the departureprocess starts of the with the departure anion. The of the negative chloride charge anion. is removedThe negative from charge the ring is removed with theleaving from the group ring andwith thethe nitrobenzene leaving group ring and relaxes the nitrobenzene into the symmetric ring relaxes planar into shape. the Thesymmetric circumference planar shape. of the ringThe Cl increases by 1.9% when the σ -adduct is formed as theCl transition state. circumference of the ring increases by 1.9% when the σCl-adduct is formed as the transition state.

ClCl Figure 3.3. OptimizedOptimized structuresstructures ofof thethe σσCl-adduct as a transition state ( left) wherewhere thethe distancedistance FF between reaction centers is R C-C = 2.38 Å and the σF -adduct as an equilibrium structure (right) where between reaction centers is RC-CC-C = 2.38 Å and the σ -adduct as an equilibrium structure (right) where RC-C == 1.561.56 Å. Å. RC-C = 1.56 Å.

This part of the investigation shows clearly that the SNAr reactionN substitution of fluoride proceeds This part of the investigation shows clearly that the SNAr reaction substitution of fastest because during the reaction there is the smallest aromaticity loss, so the atomic system has the proceeds fastest because during the reaction there is the smallest aromaticity loss, so the atomic system has the best possibility to recover aromaticity. The replacement of chloride is slower because Cl the larger loss of aromaticity is observed during the reaction. The σCl-adduct is not a stable N intermediate product, which is why the SNAr reaction between p-chloronitrobenzene and the nucleophile is irreversible. These observations based on the aromaticity are in agreement with the kinetics. Finally, the addition at positions occupied by hydrogen smoothly leads to the highest Molecules 2020, 25, x FOR PEER REVIEW 5 of 11 aromaticityMolecules 2020 ,loss25, 4819 and the formation of stable intermediate σH-adducts, which can be transformed5 into of 11 the final SNAr-H product by several ways under the appropriate reaction conditions [24–28,41–45]. best possibility to recover aromaticity. The replacement of chloride is slower because the larger loss 2.2. Electrophilicity and Nucleophilicity of aromaticity is observed during the reaction. The σCl-adduct is not a stable intermediate product, whichThe is concepts why the SofN Arnucleophilicity reaction between and pelectroph-chloronitrobenzeneilicity are an and inseparable the nucleophile part of is nucleophilic irreversible. substitutionThese observations processes. based Over on the the ye aromaticityars, many areattempts in agreement to determine with thetheir kinetics. absolute Finally, and relative the addition values, at bothpositions experimentally occupied by [46–56] hydrogen and theoretically smoothly leads [16,18, to the57–60], highest have aromaticity been reported. loss In and the the particular formation case of H ofstable nucleophilic intermediate aromaticσ -adducts, substitution which of can halogens be transformed (SNAr-X) into and the hydrogen final SN Ar-H(SNAr-H), product in which by several the initialways understep is thenucleophilic appropriate addition reaction to the conditions electron-deficient [24–28,41– 45ring,]. electrophilicity is the factor deciding the rate of addition. 2.2. ElectrophilicityThus, the effect and of Nucleophilicity substituents on the rate of the addition can be considered as the effect on electrophilicityThe concepts of the of ring. nucleophilicity Although, as and a rule, electrophilicity the addition areis the an rate inseparable limiting step part of of SN nucleophilicAr reaction, thesubstitution effect of processes.substituents Over on thethe years, rate manyof substitution attempts toofdetermine halogen in their halonitrobenzenes absolute and relative containing values, variousboth experimentally substituents [cannot46–56] andbe considered theoretically as [ 16a ,measure18,57–60], of have electrophilicity been reported. of Inthe the ring, particular because case it depends on the kind of halogens and, particularly, because it is a secondary reaction preceded by fast of nucleophilic aromatic substitution of halogens (SNAr-X) and hydrogen (SNAr-H), in which the initial andstep reversible is nucleophilic addition addition at positions to the electron-deficient occupied by hydrogen. ring, electrophilicity Thus, real iselectrophilic the factor deciding activity theof substitutedrate of addition. nitroarenes was determined in relation to the rate of the addition reaction at positions occupiedThus, by the hydrogen. effect of For substituents technical reasons, on the rate relati ofve the rates addition of the canaddition be considered of the model as thenucleophile effect on 1 were determined in relation to the rate of addition at position ortho of nitrobenzene. These electrophilicity of the ring. Although, as a rule, the addition is the rate limiting step of SNAr reaction, experimentallythe effect of substituents determined on theelectrophilicities rate of substitution of p-substituted of halogen innitrobenzenes halonitrobenzenes are in containing good correlation various + withsubstituents the calculated cannot electrophilicity be considered asindices a measure ω of ofthese electrophilicity nitroarenes (Table of the ring,1, Figure because 4). These it depends data describeon the kind electrophilicity of halogens and,of the particularly, nitroarenes because before itthe is areaction. secondary Changes reaction of preceded electrophilicity by fast andof nitroarenesreversible addition and nucleophilicity at positions of occupied 1 along bythe hydrogen. reaction path Thus, can real be electrophilictracked only activityby computation of substituted [60]. Followingnitroarenes the was reaction determined coordinates, in relation calculations to the rate of thenucleophilicity addition reaction and atelectrophilicity positions occupied were performedby hydrogen. (for Formore technical details please reasons, consult relative Supplementary rates of the addition Information, of the SI) model for selected nucleophile parts 1ofwere the 16 atomicdetermined system in relation, according to the to ratemodels of addition shown in at Figure position 5. ortho of nitrobenzene. These experimentally determined electrophilicities of p-substituted nitrobenzenes are in good correlation with the calculated Table 1. Experimental relative activities [61] and calculated electrophilicity potential ω+ (eV) of para electrophilicity indices ω+ of these nitroarenes (Table1, Figure4). These data describe electrophilicity substituted nitro . of the nitroarenes before the reaction. Changes of electrophilicity of nitroarenes and nucleophilicity of

1 along the reaction pathX can be trackedt onlyBu by computationH F [60]. Cl Following Br theCF reaction3 CN coordinates, calculations ofRelative nucleophilicity activities and electrophilicity were performed (for more details please consult 0.36 1 50 130 16150 640 1050 Supplementaryexperimental Information, [61] SI) for selected parts of the atomic system , according to models shown in Figure5. ω+, calculated (eV) 3.18 3.40 3.45 3.57 3.59 3.93 4.50

FigureFigure 4. 4. TheThe correlation correlation between between the the calculated electrophilicity potential ω++ (eV)(eV) of of ppNBNB and and the the

experimentalexperimental relative relative activities activities of of the the orthoortho positionposition in in the case of the S NAr-HAr-H reaction. reaction. Molecules 2020, 25, 4819 6 of 11

Table 1. Experimental relative activities [61] and calculated electrophilicity potential ω+ (eV) of para substituted nitro benzenes.

X tBu H F Cl Br CF3 CN Relative activities 0.36 1 50 130 150 640 1050 experimental [61] + Molecules 2020ω ,, 25 calculated, x FOR PEER (eV) REVIEW 3.18 3.40 3.45 3.57 3.59 3.93 4.50 6 of 11

Molecules 2020, 25, x FOR PEER REVIEW 6 of 11

H X Figure 5. Models of σH - and σX -adducts as S Ar-H and S Ar-X reaction intermediates with breakdown FigureFigure 5. Models 5. Models of σ of- σ andH- and σ σ-adductsX-adducts as as S SNNAr-HAr-H and SSNNAr-XNAr-X reaction reaction intermediates intermediates with with breakdown breakdown into PG—permanentinto PG—permanent group, group, Nu—nucleophile,Nu—nucleophile, Nu—nucleophile, andandand LG—leavingLG—leaving group. group.group. Based on conceptual density functional theory [62,63], the electrophilicity and nucleophilicity BasedBased on conceptualon conceptual density density functional functional theorytheory [6[62,63],2,63], the the electrophilicity electrophilicity and and nucleophilicity nucleophilicity indices for the addition of the selected nucleophile in the ortho position of nitrobenzene derivatives indicesindices for the for additionthe addition of ofthe the selected selected nucleophile nucleophile inin thethe ortho ortho position position of ofnitrob nitrobenzeneenzene derivatives derivatives were calculated, Figure6. werewere calculated, calculated, Figure Figure 6. 6.

FigureFigure 6. Changes 6. Changes of of electrophilicity electrophilicity for for permanent permanent group group (upper (upper left), nucleophile left), nucleophile (lower left (lower) and left) and nucleophilicitynucleophilicity for for permanent permanent group group (upper (upper right right) and) and nucleophile nucleophile (lower (lower right right) during) during the the nucleophilicnucleophilic substitution substitution in thein theortho orthoposition. position. Figure 6. Changes of electrophilicity for permanent group (upper left), nucleophile (lower left) and Itnucleophilicity wasIt was proven proven for by by thepermanent the calculated calculated group activation activation (upper right barriersbarriers) and [35] [ 35nucleophile ](Figure (Figure 1)1 )that(lower that the the rightrate rate )of during ofσH-adductσH -adductthe formationnucleophilicformation is strictly is substitutionstrictly related related toin substituentthe to orthosubstituent position. effects effects in thein the aromatic aromatic ring. ring. The The electron-withdrawing electron-withdrawinge ffect of theeffect halogen of the in halogen the para inposition the para contributes position contributes to the activation to the activation of the ortho of positionthe ortho towardsposition towards nucleophilic attack.Itnucleophilic was In this proven case attack. theby resultstheIn thiscalculated obtainedcase the activation results for p-fluoro-, obtained barriersp -chloro-for [35] p-fluoro-, (Figure and unsubstitutedp -chloro-1) that andthe rateunsubstituted nitrobenzene of σH-adduct are veryformationnitrobenzene similar. is Thestrictly are upper veryrelated leftsimilar. diagramto substituentThe upper in Figure left effects diagra6 shows min in the Figure the aromatic calculated 6 shows ring. the electrophilicity calculated The electron-withdrawing electrophilicity of permanent of permanent group (PG). Each nitrobenzene derivative has different electrophilic character, thus the groupeffect of (PG). the Eachhalogen nitrobenzene in the paraderivative position contributes has different to electrophilicthe activation character, of the ortho thus position the potential towards to potential to react with the nucleophile decreases accordingly: p-chloro- > p-fluoro- > unsubstituted reactnucleophilic with the attack. nucleophile In this decreases case the accordingly: results obtainedp-chloro- for> pp-fluoro-,-fluoro- >p-chloro-unsubstituted and unsubstituted nitrobenzene. nitrobenzene. The electrophilicity of PG fell rapidly en route to the formation of σH-adducts and it nitrobenzene are very similar. The upper left diagram in Figure 6 showsH the calculated electrophilicity The electrophilicityslightly increased of in PG the fell nucleophile rapidly en atomic route system to the formation(lower left ofdiagram,σ -adducts Figure and 6). The it slightly upper right increased of permanentdiagram showsgroup that(PG). the Each calculated nitrobenzene nucleophilicity derivative of the has permanent different electrophilicgroup increases character, during thusthe the potentialaddition to react in the with ortho theposition. nucleophile Nucleophilicity decreases values accordingly: of the permanent p-chloro- group > pare-fluoro- mainly > affected unsubstituted by nitrobenzene.the type of The the electrophilicitynucleophile and ofits PGcharacter fell rapidly as a donor en route of extra to theelectron formation density. of This σH-adducts causes the and it slightlydifferences increased of nucleophilicity in the nucleophile between atomic nucleophile system acceptors (lower toleft be diagram, less pronounced. Figure 6). The upper right diagram shows that the calculated nucleophilicity of the permanent group increases during the addition in the ortho position. Nucleophilicity values of the permanent group are mainly affected by the type of the nucleophile and its character as a donor of extra electron density. This causes the differences of nucleophilicity between nucleophile acceptors to be less pronounced. Molecules 2020, 25, 4819 7 of 11 in the nucleophile atomic system (lower left diagram, Figure6). The upper right diagram shows that the calculated nucleophilicity of the permanent group increases during the addition in the ortho position. Nucleophilicity values of the permanent group are mainly affected by the type of the nucleophile and its character as a donor of extra electron density. This causes the differences of nucleophilicity between nucleophile acceptors to be less pronounced. Molecules 2020, 25, x FOR PEER REVIEW 7 of 11 On the other hand, the same factors in the form of electrophilicity and nucleophilicity indices for the SNArOn reaction the other were hand, calculated. the same The factors results in the suggest form thatof electrophilicity the electrophilicity and nucleophilicity of the permanent indices group in thefor case the of SNparaAr reactionsubstitution were calculated. is very similar The results to the suggest loss of aromaticitythat the electrophilicity and the nucleophilicity of the permanent trend of PG isgroup reversed, in the Figure case of7 para. substitution is very similar to the loss of aromaticity and the nucleophilicity trend of PG is reversed, Figure 7.

FigureFigure 7. Changes 7. Changes of of electrophilicity electrophilicity forfor permanentpermanent group group (PG) (PG) (upper (upper left left), leaving), leaving group group (LG) (LG) (middle(middle left) left nucleophile) nucleophile (Nu) (Nu) (lower (lower left )left and) and nucleophilicity nucleophilicity for for permanent permanent group group (PG) (PG) (upper (upper right ), leavingright group), leaving (LG) group (middle (LG) right (middle) and right nucleophile) and nucleophile (Nu) (lower (Nu) right (lower) during right) nucleophilic during nucleophilic substitution in thesubstitutionpara position. in the para position.

For pFor-chloronitrobenzene, p-chloronitrobenzene, the the electrophilicity electrophilicity decr decreaseseases until until the the transition transition state state structure structure is is formed;formed; after after the the chloride chloride anion anion detaches, detaches, thethe potentialpotential to to accept accept an an electron electron from from the theenvironment environment increases.increases. For pFor-fluoronitrobenzene p-fluoronitrobenzene and and nitrobenzene, nitrobenzene, the the trends trends of of the the factors factors are are very very similar similar toto those those obtained for the reaction in the ortho position. The reactions in the para position of p- obtained for the reaction in the ortho position. The reactions in the para position of p-fluoronitrobenzene fluoronitrobenzene and nitrobenzene lead to the formation of σF-adduct and σH-adduct, respectively. σF σH and nitrobenzeneThat observation lead is toalso the consistent formation with of the -adductaromaticity and changes-adduct, and the respectively. properties of That the formed observation σ- is also consistentadducts, where with the the σ aromaticityF-adduct and changesthe σH-adduct and the areproperties stable intermediates, of the formed and theσ-adducts, σCl-adduct where is a the F H Cl σ -adducttransition and state the structure.σ -adduct The substi are stabletution intermediates,of the chlorine atom and as the a firstσ order-adduct reaction is a is transitionalso visible state structure.in the Thecase of substitution nucleophilicity of the change chlorine trends atom of the as leaving a first group, order where reaction this is parameter also visible increases in the for case of nucleophilicitythe chloride change after trends its departure of the leaving from the group, nitrobenzene where thisring. parameterAll of the presented increases trends for the for chloride SNAr- ion X and SNAr-H reactions seem to reproduce reliably the nucleophilicity and electrophilicity changes after its departure from the nitrobenzene ring. All of the presented trends for SNAr-X and SNAr-H along the electron reorganization path during the bond formation-bond breaking processes between the nucleophile and the nitrobenzene derivatives.

2.3. Molecules 2020, 25, 4819 8 of 11 reactions seem to reproduce reliably the nucleophilicity and electrophilicity changes along the electron reorganization path during the bond formation-bond breaking processes between the nucleophile and the nitrobenzene derivatives.

2.3. Kinetic Isotope Effect Studies of kinetic isotope effects, KIEs, are an important tool for clarification of mechanisms of organic reactions. Since differences of rates of reactions in which isotopes are involved are functions of their mass differences, KIEs of hydrogen 1H vs. 2D are the most often studied. Nevertheless, on the 18 19 basis of the KIEs of fluorine F vs. F, it was shown that in SNAr of fluorine in 2,4-dinitrofluorobenzene in the reaction with piperidine, the addition or the elimination can be the rate limiting step depending on the solvent [63,64]. On the other hand, determination of KIEs of hydrogen H vs. D was of great importance for determination (elaboration) of the mechanism of SNAr-H reactions [65,66]. Thus, it was shown that the addition of the model carbanion 1 at positions occupied by hydrogen of 4-bromo-2-deuteronitrobenzene proceeds somewhat slower than at identically activated positions occupied by deuterium, KIE 0.8. Calculations of the energy profiles for this reaction in the gas phase ≈ by three DFT methods gave the results between 0.62 and 0.82, which are in a good agreement with the experimental data. These results show that calculation of KIE can be quite useful in studying reaction mechanisms, especially that it is much simpler compared to the experiment.

3. Conclusions

In conclusion, the detailed mechanistic picture of both variants: SNAr-X and SNAr-H of nucleophilic aromatic substitution pathways in halonitroarenes was fully described by the reactivity indices and kinetic isotope effect. The latter shows unequivocally that the addition of the nucleophile to the aromatic ring is the rate-determining step of all variants of SNAr-X mechanism and of SNAr-H, in specific conditions where the σH-adduct can be easily transformed to the products. Our results showed that there is a significant difference between reaction mechanisms of the substitution of chlorine and fluorine . The first reaction is a single step process, in which the σCl-adduct is a transition state. In contrast, in the case of the substitution of the fluorine atom, the σF-adduct is an intermediate product, which is always the case in the SNAr-H reactions. Our results show that the formation of H σ -adducts is preferred and, providing that they can undergo fast further transformations, the SNAr-H H reaction is dominating over the SNAr-X. Fluoronitrobenzene is a special case because both σ - and σF-adducts are intermediate products so the relative rate of the substitution of fluorine and hydrogen depends on the reaction conditions. Finally, we have shown that reactivity indices, when used correctly, are a very useful tool for describing mechanisms of the reactions between aromatic nitro compounds and nucleophiles.

Supplementary Materials: Description of computational procedures and method selection, geometries, and energies of the studied structures. Author Contributions: K.B. coordinated the study, conceived of the methodology plan, prepared graphics and led its design, performed the computations, analyzed data, and prepared a draft of the manuscript. M.M. conceived of the mechanistic study, M.M. and W.D. participated in the coordination of the project, contributed to the formulation of the final conclusions, and helped to draft the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research was founded by National Science Centre, Poland, Grant No. 2018/02/X/ST4/02643. Acknowledgments: This work has been financed by the National Science Centre, Poland, Grant No. 2018/02/X/ST4/02643. We express our thanks to the Wroclaw Center for Networking and Supercomputing (WCSS) and Interdisciplinary Centre for Mathematical and Computational Modeling (ICM) in Warsaw (Grant No. G50-2) for providing computer time and facilities. The authors wish to thank Artur Ulikowski for valuable discussion. Conflicts of Interest: The authors declare no conflict of interest. Molecules 2020, 25, 4819 9 of 11

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