Concerted Nucleophilic Aromatic Substitution Reactions

Abstract Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSNAr) rather than classical, two‐step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways.


Aromatic Substitution Reactions
Substitution reactions on aromatic rings are central to organic chemistry.B esides the commonly encountered electrophilic aromatic substitution, [1] other mechanisms include S N Ar nucleophilic aromatic substitutions [2,3] and the distinct but related S N ArH and vicarious nucleophilic substitutions, [4] substitutions brought about through benzyne intermediates, [5,6] radical mechanisms including electron transferbased S RN 1r eactions [7] and base-promoted homolytic aromatic substitution (BHAS) couplings, [8] sigmatropic rearrangements, [9] substitutions arising from deprotonation of arenes (directed metalations), [10] the vast array of organometallic mechanisms [11,12] and S N 1reactions. [13] All of these areas of chemistry are too vast to reference comprehensively,and so are simply represented here by one or two key reviews or recent references.A mong these various reaction types,S N Ar reactions have attracted al ot of recent attention, because of ar ecognition that many such reactions may proceed by concerted (cS N Ar), [14,15] rather than classical two-step mechanisms.

Classical Nucleophilic Aromatic Substitution
Nucleophilic aromatic substitutions have been studied at least since the 1870s. [16][17][18] Thel ong-accepted mechanism, [4,5] exemplified in Scheme 1f or dinitroarene 1,i nvolved at wostage process that featured aMeisenheimer intermediate 2.In these substitutions,t he arene is significantly activated for substitution by the presence of one or more electron-withdrawing substituents in the positions that are ortho or para to the site of substitution to provide resonance stabilisation, and with nitro as af avoured substituent. In Te rrierse xcellent book on S N Ar reactions in 2013, [3] he wrote that "concerted reactions are the exception rather than the rule"a nd "there is little doubt that most of the activated S N Ar substitutions must proceed through the early-recognised addition-elimination mechanism". Recent developments in experimental and computational chemistry have identified arapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cS N Ar) rather than classical, two-step,S N Ar mechanisms.W hereas traditional S N Ar reactions require substantial activation of the aromatic ring by electron-withdrawing substituents,such activating groups are not mandatory in the concerted pathways. Evidence in favour of at wo-stage substitution was cited when intermediates were isolated. Thus,a sr eviewed by Bunnett and Zahler [2] in 1951, anumber of reactions gave rise to isolated intermediate adducts (Scheme 2). Key studies were performed by Meisenheimer, [19] who isolated acommon intermediate 5 from reaction of methyl ether 4 with NaOEt, and from reaction of NaOMe with the ethyl ether 6.T his intermediate was then decomposed into am ixture of the parent ethers on acidification. Adduct intermediates of this sort, for example, 7-11,w hich are routinely called Meisenheimer intermediates,a re widespread in organic chemistry, and are well reviewed. [20] Nucleophilic aromatic substitutions are often carried out on pyridines,p yrimidines and related heterocycles,a nd indeed these substitutions are commonplace and important in medicinal chemistry and agrochemistry.A lthough intermediates from these substitutions have not been isolated where good leaving groups are present, we are familiar with isolation of intermediates where poor leaving groups are in play.E xamples of intermediates at the extreme of this scale that can be isolated are the salts resulting from addition of organolithium compounds to pyridines,s uch as 12,t hat is, compound 13 which, on heating, gives the substituted pyridine 14 with elimination of LiH (Scheme 3). [21][22][23] Generation and isolation of such intermediates will be affected by the power of the ring substituents in stabilising negative charge,a swell as by the pK a values of the conjugate acids of the incoming and departing groups.
Supportive evidence in favour of the nucleophilic nature of the substitution mechanisms arises from Hammett studies, where significant positive 1 values are associated with the rate-determining step.Itmust be remembered, when comparing 1 values,t hat they vary with the temperature of the experiments.
Examples reported by Miller [24,25] (Scheme 4) indicate that there is extensive negative charge build-up in the ratedetermining step.Although the cases below in Scheme 4have particularly high 1 values,i ti sr ecognised that many S N Ar reactions have values between + 3a nd + 5. Looking at the substrates chosen by Miller  NO 2 ,A c, CF 3 and Cl. Whereas NO 2 and Ac are substituents that can delocalise an egative charge by resonance,c learly CF 3 and Cl cannot, although they can contribute inductive stabilisation to different extents.M illersH ammett analysis showed [25] that the four substrates had an excellent correlation with s*f or these substituents, [26] suggesting ac ommon mechanism for them.

Concerted Nucleophilic Aromatic Substitution (cSNAr)-Early Developments
Although the literature adopted two-stage S N Ar reactions as the norm, despite the reactivity of substrates like 17 d studied by Miller, noted above,f urther anomalies began to appear. These studies have culminated in the recent paper by Jacobsen et al., [14] which transforms our perception of the prevalence of cS N Ar reactions.T his will be discussed later in Section 13 of this review.P apers referenced below are cited for their relevance to cS N Ar reactions.
Avery early example was the work of Pierre et al. [27] who, in just as ingle paper that was published in 1980, studied the reaction of KH with aryl halides.T his report simply involved hydrodehalogenation of substrates 19 in tetrahydrofuran (THF) as solvent (Scheme 5). Thereactions were not pursued with detailed mechanistic investigations,but the observations made were illuminating.
By conducting the experiments with KH in [D 8 ]THF, Pierre et al. were able to show that the substituting hydrogen indeed came from KH. They were able to dismiss any idea of abenzyne mechanism, since no H 2 was evolved. Theorder of reactivity was:A rI > ArBr > ArCl > ArF,w hich is the reverse of the order often found in classical S N Ar reactions. Since the reactions proceeded in the absence of activating substituents like nitro groups on the ring undergoing substitution, they proposed aconcerted reaction mechanism with af our-centred transition state but, at that time,n oc omputational methods were available to support these ideas.Perhaps because this reaction seemed so anomalous,b ut most likely because it was both asingle paper in this area by the authors and also was not written in English, the paper received very little attention. Nevertheless,i th eralded al ot of subsequent developments.W ew ill return to this example later in this review.
An early study pointing to concerted nucleophilic substitution was conducted by Frya nd Pienta who,i n1 985, [28] provided mechanistic evidence through Hammett correlations.When studying rate constants for nucleophilic aromatic substitution of arenesulfonate groups in 22 by halide anions in dodecyltributylphosphonium salts 23 (Scheme 6), using ar ange of different R 1 substituents,H ammett plots gave reasonable fits to straight lines,w ith 1 values of + 1.5 and + 1.1 for s and s À respectively (Scheme 6A). Theeffect of the R 1 -group on the rate of the reactions was therefore substantially lower than for many literature S N Ar reactions.I ndeed, the substrates that were trialled included 22 d (R 1 = OMe), which can clearly not provide credible stabilisation for ad eveloping negative charge on the ring in aM eisenheimer intermediate.I mportantly,t he reaction series also showed some sensitivity of the transition state to the R 2 -substituent on the leaving group (Scheme 6B, 1 =+0.22). Thes imilarity of rates regardless of the halide identity (Scheme 6C)ruled out an S RN 1m echanism, as the differences in halide redox properties would require am uch more substantial rate difference between the different halides.H owever,i nt heir conclusion, the authors postponed speculation on the precise mechanism of their reactions.
On the other hand, Williams et al. reported an umber of nucleophilic aromatic substitution reactions with concerted mechanisms on substituted 1,3,5-triazines 26-29. [29][30][31][32] They found that the reaction of various phenolate ions with 26 (Scheme 7), [29,30] followed alinear relationship on aBrønsted plot over ar ange of pK ArOH values above and below that of the conjugate acid of the leaving group (4-nitrophenol). The lack of curvature in the free energy relationship suggested that there was no change in mechanism when moving from strongly electron-withdrawing groups to weakly electrondonating groups,w hich is consistent with ac oncerted mechanism.
Thes ame 1,3,5-triazine core,w ith aryloxy and pyridine leaving groups,w as also studied in aminolysis reactions with various amines. [29,30] Hammett plots for the reaction of morpholine (1 =+1.65) and N,N-dimethylaminopyridine (1 =+0.82) were recorded. Detailed arguments allowed the authors to conclude that ac oncerted substitution was occurring. These rigorous papers were important in raising awareness of concerted nucleophilic aromatic displacements.

Some Contributions by Computational Studies
Related to these studies,c omputational methods were employed [33] to examine the hydrolysis of protonated chlorotriazines for example, 46,(Scheme 8) which are of interest in agrochemistry.Inboth gas phase and in water, Meisenheimer intermediates could not be located, suggesting that these reactions instead proceed in ac oncerted manner,a lbeit with high kinetic barriers,a tl east when an eutral water molecule was the nucleophile.
In fact, computational studies played asignificant part in providing credibility for the concerted nature of cS N Ar reactions over the past 30 years.I na ll the computational studies cited here,the geometries were optimised with density functional theory (DFT) methods unless otherwise stated. We now cluster some of the computational results that suggested the cS N Ar mechanism, although further cases will also be referenced at appropriate places later in this review.
Nucleophilic aromatic halogen identity-substitution reactions were investigated computationally in the gas phase (Scheme 9) by Glukhovtsev et al. [34] Thee xchange reactions of 49 with the corresponding halide anion X À (for Cl, Br, I) all proceed via aMeisenheimer-like transition state structure 50.

Reviews
Meisenheimer intermediates for the fluoride addition to fluorobenzene and for the chloride addition to 2,4-dinitrochlorobenzene and picryl chloride (2,4,6-trinitrochlorobenzene). This study was expanded by Uggerud et al. [35] with second-row (NH 2 À ,OH À ,F À ), third-row (PH 2 À ,SH À Cl À )and fourth-row (AsH 2 À ,S eH À ,B r À )n ucleophiles.A dditionally, am ore diverse array of substituents,R ,w as considered. A Meisenheimer intermediate was observed for all three second-row nucleophiles with substituents as different as -NH 2 and -NO 2 (for both NH 2 À and F À as the nucleophile) and for substituents -H and -NO 2 with OH À as the nucleophile. Fort he third-and fourth-row nucleophiles,c oncerted mechanisms were calculated in several instances.I ng eneral, ac oncerted mechanism was predicted for more electronrich aromatic systems.Astepwise mechanism with aMeisenheimer intermediate would become more favourable as electron-withdrawing groups are attached to the aromatic ring.
Building on the halogen-exchange reactions mentioned above,f luorodechlorination reactions and fluorodenitration reactions of aryl chlorides and nitroaryls in dimethyl sulfoxide (DMSO), were reported by Sun and DiMagno. [36] Computational studies were performed for the fluorodenitration reactions. para-Substituted nitroaryls were analysed and grouped according to the Hammett parameter of the substituents.Itwas observed that for substituents with aHammett constant s À 0(Hand more electron-donating substituents), the reaction proceeds via ac oncerted mechanism with aM eisenheimer-like transition state.
Nucleophilic displacement of nitro groups,i n5 ,7-dinitroquinazoline-4-one 51,b ym ethylamine as nucleophile,w as reported by Goel et al. [37] Their computational study built upon aprevious experimental study [38] that had shown that the nitro group in the peri-position to the carbonyl was regioselectively displaced over the nitro group in the para-position, affording 52 in 85 %yield (Scheme 10). In that experimental paper,the authors had proposed the reaction to occur via a sintermediate,b ut evidence for this complex was not presented. Goel et al. studied the formation of the s-complex, but no stable complex could be found by DFT calculations. [37] Theactivation energy for aconcerted nitro group substitution was found to be 33.8 and 18.1 kcal mol À1 for para-a nd perisubstitution via transition states 53 and 54,r espectively.T he reason for the regioselectivity is given by the hydrogenbonding stabilisation between the amine and the carbonyl in the transition state for peri-substitution, which is strong enough to divert the methylamine away from the less sterically hindered para-position.
Thee ffect of the medium on substitution reactions has also been investigated widely for S N Ar reactions.T he displacement reaction (Scheme 11) of the nitro group from nitrobenzene 55 with fluoride in the gas phase has been studied experimentally and computationally in the gas-phase by Riveros et al. [39] TheDFT model predicts that the reaction follows ac oncerted pathway with av ery low activation energy.
Theeffect of explicit solvation and counter-cations on the displacement of an itro group in nitrobenzene by af luoride anion has been reported by Park and Lee [40] through ac omputational approach. Including explicit solvation (two molecules of water) and different counter-cations led to the same concerted mechanism as predicted by Riveros et al. [39] for the gas phase,asdiscussed above.
Ther egiochemistry of displacement of halide leaving groups from poly-halogenated substrates has been widely studied by computational methods.I n1 999, Tanaka et al. reported their studies [41] on the regiochemistry of substitution of pentafluoronitrobenzene with ammonia as nucleophile,a s the solvent changed from hexane to nitromethane.T hese studies predicted (and provided am echanistic proposal to explain) concerted substitution in the para-position, but twostep substitution in the ortho-position.
In subsequent years,computation-based studies on regioselectivity have been widely undertaken. Perfluoroarenes, and perhaloarenes more generally,h ave been the subject of an umber of studies of selective substitution reactions, representing their importance in materials chemistry and in ligand generation as well as in detoxification programmes. Experimental and computational approaches have been combined by Paleta et al. in their study of pentafluorobiphenyl. [42] With ar ange of N-, O-and S-nucleophiles,t he regioselectivity of substitution of 2,3,4,5,6-pentafluorobiphenyl was explored and showed significant regioselectivity for substitution of the fluorine that was para-t ot he phenyl group.The computational studies which used the nucleophiles i) ammonia, ii)solvated lithium fluoride [as LiF.(Me 2 O) 2 ]and iii)solvated lithium hydroxide [as LiOH.(Me 2 O) 2 ], mirrored the experimentally observed regioselectivity but showed that, in all cases,ac oncerted one-step displacement reaction was occurring.
In acombined computational and experimental study,the substitution reactions of pentafluoropyridine by phenolates evidenced predominant displacement of the 4-substituent on the pyridine. [43,44] Fort he resulting phenoxypyridines,e xten-sive experimental analysis led the authors to understand that the displacement of 4-pentafluorophenoxide (as opposed to other leaving groups) by fluoride anion from 58 (Scheme 12) was anomalous,a nd semi-empirical computational studies (PM3) supported ac oncerted mechanism.
Following an earlier model for determining the site of substitution in aromatic perfluorocarbons, [45] predictions of the regioselectivity of S N Ar reactions were made by Brinck and an AstraZeneca team including Svensson, Liljenberg et al. [46,47] based on the relative stability of Meisenheimer intermediates.A ss uch, their model addressed the classical two-stage mechanism. However,t heir computational studies could not locate these intermediates in cases where the leaving group was chloride or bromide (such as in 61, Scheme 13), suggesting concerted reaction mechanisms in those cases.
Ad escriptor-based model to predict relative reactivity and regioselectivity in S N Ar reactions was introduced by Stenlid and Brinck. [48] In contrast to the selectivity models presented above,t his descriptor solely relies on the groundstate electronic structure of the aromatic substrate.C onsequently,i tc an also be applied to S N Ar reactions that do not proceed by as tepwise mechanism via aM eisenheimer intermediate,such as the reaction between 64 and piperidine (65)( Scheme 14). Thes eries spanned examples from R = NH 2 to R = NO 2 .T he rate constants for all these examples had been reported previously.Asatisfactory correlation between these constants and the newly introduced descriptor was found. Theobservation [48] that, according to the computational model, reactions of 68 with secondary amines do proceed via ac oncerted S N Ar reaction was related to an extensive experimental study of 1-X-2,4-dinitrobenzene with aseries of secondary amines. [49] Pliego and Piló-Veloso [50] investigated the effect of ionpairing,e xplicit hydration and solvent polarity on the fluorodechlorination reaction of 4-chlorobenzonitrile (70) (Scheme 15). This computational model predicts the reaction to follow ac oncerted mechanism. By varying the solvent polarity,itwas found that for agiven fluoride salt MF,there is as olvent with ideal polarity which just allows for the dissociation of the ion pair but does not solvate the fluoride ion too strongly.
In am ore recent contribution, Silva and Pliego investigated [51] S N Ar reactions on bromobenzene and (ortho-, meta-, or para-) methoxybromobenzenes with different nucleophiles in the gas phase and in solution phase by computational methods (Scheme 16). Ac oncerted mechanism was observed with hydroxide,c yanide,a nd methoxide nucleophiles attacking bromobenzene in the gas phase (albeit the transition state energy for the reaction with cyanide was high (DG* = 27.2 kcal mol À1 ). Including solvent effects in their computations made all three reactions kinetically less favourable (e.g.hydroxide in DMSO: DG* = 29.3 kcal mol À1 ; in MeOH: DG* = 37.8 kcal mol À1 .T hese barriers are markedly higher than in the gas phase DG* = 1.6 kcal mol À1 ).
No change in mechanism is mentioned when going from gas-phase to solution-phase models.I nterestingly,w hen the authors investigated meta-methoxybromobenzene with hydroxide,m ethoxide and cyanide as the nucleophile,t hey obtained lower activation barriers (e.g. DG* = 25.8 kcal mol À1 for m-methoxybromobenzene with methoxide in DMSO vs. DG* = 27.1 kcal mol À1 for bromobenzene with the same nucleophile in the same solvent).
Thee ffects of solvation on S N Ar reactions in liquid ammonia and in the gas phase by ac ombination of Scheme 12. Concerted mechanism proposed in displacements of 4pentafluorophenoxides.
Scheme 13. No Meisenheimer intermediates were found in computational studies on displacements on pentachloropyridine.
Scheme 14. Concerteds ubstitution reactions studied by Stenlid and Brinck. [48] Scheme 15. Studies on the effect of ion-pairing, explicit hydration and solvent polarity on the fluorodechlorination reaction.

Angewandte Chemie
Reviews metadynamics and committor analysis methods have been studied by Moors et al. [52] They found that for 4-nitrofluorobenzene (74)
When DFT studies were carried out, as ingle transition state, 88,was observed, which is characteristic of aconcerted mechanism. Al arge primary 16 O/ 18 Ok inetic isotope effect (KIE) (KIE = 1.08 AE 0.02) was observed, showing that the cleavage of the C À Obond is involved in the rate-determining step.AHammett plot also shows that there is no change in mechanism when moving from electron-deficient phenols to electron-rich phenols (1 =+1.8) indicating that there is not abuild-up of full negative charge in the ring at the transition state. [56] Thef ormation of the urea by-product is also highly exergonic,w hich contributes to the driving force for this reaction. These reactions feature spiro transition states, further examples of which will appear later in this review (Sections 7a nd 8).
On ar elated theme,S anford et al. reported am ild deoxyfluorination of phenols 97 via aryl fluorosulfonate intermediates 98. [57] This transformation was found to be compatible with ortho-, meta-, or para-electron-withdrawing groups,a nd could also be applied to electron-neutral and moderately electron-rich substrates to provide fluorinated products 100-111 (Scheme 20).
Computational data suggest that the binding of fluoride in 112 to sulfur to form pentacoordinate sulfonate 113 is enthalpically favourable and the activation enthalpy to the transition state (DH*) was found to be feasible at room temperature (Table 1). Thetransition state 114 was shown to involve concerted formation of the C À Fbond and cleavage of the C À Ob ond without the formation of aM eisenheimer intermediate ( Figure 1). Scheme 17. Gas-phase reactivity with ammonia as nucleophile.
Scheme 18. Reactivity in solution with ammonia as nucleophile.
AH ammett plot with p-substituted methoxyarenes 129 showed that the 1-value was low (1 =+1.99). Theproposal of ac oncerted mechanism was backed up by computational analysis,w here as ingle transition state was observed for the conversion of 140!141 with formation of ap artial negative charge,c onsistent with ac S N Ar process (DG* = 14.7 kcal mol À1 ,F igure 2). Chibasd emethoxylation studies feature deprotonated amines as nucleophiles.D emethoxylation by ah ydroxycyclopentadienyl iridium hydride nucleophile has been proposed as ac oncerted nucleophilic aromatic substitution by Kusumoto and Nozaki, [59] although no mechanistic evidence has yet been revealed to support this.
Chiba and co-workers extended their chemistry with NaH and additive salts to perform further intermolecular displacements. [60] Forexample,substitution of the methoxy group in 3methoxypyridine (145), (Scheme 23) by piperidine 146 was achieved in high yield using sodium hydride with LiI as additive.W ith NaI as alternative additive,t he reaction proceeded in much poorer yields and with NaH alone,n o reaction was seen.
This reaction is quite flexible.Inthe dimethoxy case 148, substitution at the 2-position occurs first to give 149,b ut the

Angewandte Chemie
Reviews product can undergo as econd substitution by ad ifferent amine to give 150.I n3 ,5-dimethoxy case 151,i terative diamination can again be achieved. In these cases,n o Hammett correlations have been published, but the displacement from the unactivated 3-position of apyridine identifies these reactions as prime candidates for cS N Ar pathways.

Hydrides as Nucleophiles
Recent discoveries relating to concerted aromatic substitutions have seen several that feature hydride as nucleophile or base.C hiba et al. recently reported the hydrodehalogenation of haloarenes 154,( Scheme 24) by their sodium hydride-iodide composite. [61] Without the addition of the iodide salt, sodium hydride cannot carry out this special function.
Va rious aryl bromides were reduced under these conditions,with both electron-rich and electron-deficient substituents being equally tolerated. Computational studies show ahighly exothermic reaction with asingle transition state 167 for concerted nucleophilic aromatic substitution, with an energy barrier of 20.9 kcal mol À1 (Figure 3). TheH ammett plot using NaH with NaI, converting iodoarenes to arenes in THF at 85 8 8Cshows alinear correlation with 1 =+0.47, which is supportive of ac S N Ar process.
As the cS N Ar pathway is initiated by an interaction between the hydride donor and the p*orbital of the aromatic ring, it was reasoned that this methodology could also be applicable to the reduction of haloalkenes,u pon treatment with the sodium hydride-iodide composite.
This was indeed the case,w ith retention of configuration being observed as the major product for both (Z)-and (E)alkenes 169 and 173 (Scheme 25). [61,62] Murphy,T uttle et al. recently reported on the solventdependent role of potassium hydride in haloarene reduction. [63] Pierre et al. had proposed ac S N Ar mechanism for dehalogenation of haloarenes in 1980, as mentioned earlier. [27] They had verified that the hydrogen atom delivered to the aryl halide had come from KH. They had ruled out abenzyne intermediate in their reactions,a nd presented their proposal based on the observed order of reactivity (ArI > ArBr > ArCl) which was in contrast to the normal order of reactivity   in astandard S N Ar reaction on iodobenzene 174 (Scheme 26). Pierresp roposal was therefore revolutionary,b eing made before computational methods became widely available. Murphy and Tu ttlesi nvestigation confirmed Pierresp roposed mechanism computationally,w ith aG ibbs free energy barrier of 22.4 kcal mol À1 .Studies carried out in [D 8 ]THF also reveal that the H-atom in 178 comes from the KH rather than from the solvent, in line with Pierresc laim. Surprisingly,i n benzene as solvent, Murphy and Tu ttle showed that aq uite different electron transfer mechanism played an important role in reduction of haloarenes with KH.
Computational studies on hydrodehalogenation of haloarenes by cS N Ar have been reported by Cramer et al. [64,65] In all cases,t he transition state for the addition of hydride to asubstituted site led to concerted displacement of the halide anion via transition state 180 (Scheme 27).
This hydrodefluorination process tolerated many other functional groups,i ncluding esters,n itriles and nitro groups.  key substitution steps are 19.0 kcal mol À1 and 10.8 kcal mol À1 , respectively.M eisenheimer intermediates were not detected for either pathway,i ndicative of cS N Ar reactivity.

P, N, Si, CNucleophiles
Ther ange of nucleophiles was further widened when Würthwein et al. reported the reaction of di-and trifluorobenzenes 204-206 with Me 2 EM (E = P, N; M= SiMe 3 ,SnMe 3 Li)( Scheme 30). [67,68] To illustrate the utility of the transformation, phosphane products were later used as ligands in polyfluorophosphane palladium dichloride complexes.C omputational chemistry was again shown to be au seful tool in predicting the mechanism of this reaction, indicating asingle transition state with no Meisenheimer adduct formation, that is,acS N Ar mechanism.
Thes ingle transition state corresponds to the simultaneous C À Eb ond formation, and in the case of Me 2 PSiMe 3 with fluorobenzene,p rovided ab arrier of DE* = 30.3 kcal mol À1 for the formation of the CÀPb ond and the Si-assisted loss of fluoride ( Figure 4). Di-and trifluorobenzenes were also examined experimentally and by computation, and provided faster reactions and lower calculated barriers. Compounds 210 and 211 form av an der Waals complex (vWc) 212,followed by acS N Ar reaction through 213,forming van der Waals complex 214.D issociation of this complex affords products 215 and 216 (Figure 4).
Aryl fluorides have recently been subjected to quite adifferent cS N Ar reaction by Würthwein, Studer et al.,using silyllithium reagents as nucleophiles. [69] This was an interesting development, as previous reactions of aryl halides (notably iodides) with similar reagents had led to substitution directly on the halogen atom to give as ilyl halide and an aryllithium as areactive intermediate that then conducted an S N 2r eaction on the silyl halide.I nt his case,h owever,a ryl fluorides underwent cS N Ar. Hammett studies gave a 1 value of + 3.2, and computational investigation afforded Gibbs free energies of activation of 19-21 kcal mol À1 (Scheme 31). Very recently,t wo related studies have appeared from other groups. 70,71 Af lexible route to phenanthridinium cations 224 was published by Hartley et al. using an imine nucleophile to displace ah alide (Scheme 32). [72] Thei mine 223 which is formed in situ is not isolated, but directly converted to product 224 by heating. Them echanism of the ring-forming S N Ar reaction from 223 to 224 was investigated computationally with model compounds.T he models were chosen to closely represent the synthesised molecules.Itwas found that for all examined model compounds,the reaction proceeds via ac oncerted S N Ar pathway.I np articular,aconcerted mechanism was not only observed for examples with electrondonating substituents (e.g. p-MeO) but also for examples with electron-withdrawing substituents (e.g. p-NO 2 ). All transition states were accessible (DG* = between 17 kcal mol À1 and 28 kcal mol À1 )w ith lower energy barriers for examples with more electron-withdrawing substituents,asexpected. Carbon nucleophiles were used by MØdebielle, Rossi et al. in the synthesis of tetracyclic indoles,f or example, 227 (Scheme 33 A) and azaindoles. [73] Computational studies were used to probe the mechanism of the reaction. Electron transfer was considered, but gave very high energy barriers. Them ost reasonable proposal was that the reactions proceeded by nucleophilic aromatic substitution. Thec alculated reaction profile showed no intermediates,t hat is,i tw as ac S N Ar reaction.
An unusual nucleophile 228 was employed by Tretyakov et al. [74] (Scheme 33 B) to afford anew nitronyl nitroxide 229. DFT calculations supported the observed regioselectivity and indicated that the reaction follows ac oncerted pathway.T he zwitterionic product was treated with sodium nitrite in acetic acid to yield the nitroxyl 230.

Organic Rearrangements via Spiro Species:I ntermediates or Transition States?
Spiro transition states appeared in the fluorodeoxygenation section of this review,but spiro species occur much more widely,asseen in this and the following section of this review. Te ll-tale signs of concerted nucleophilic substitutions arise when the arene at which substitution is occurring has no substituents to significantly stabilise aM eisenheimer intermediate.T his is the case in Claydenss tereocontrolled arylation of amino acids. [75,76] Here,i nfrared spectroscopy was used to follow the conversion of alanine derivatives 231-235,v ia their enolates 236 into products 238 as shown in Scheme 34. Conformational control of anilides plays an important role here.I nt ertiary anilides (e.g. 231), the aryl group is aligned strictly anti to the carbonyl group. [77] Formation of enolate 236 ensues,a nd transfer of the aryl group then occurs with control of stereochemistry to afford the anion 237,f rom which the amino acid product 238 was isolated. Plainly,w ithout appropriate stabilising substituents on the arene,noMeisenheimer intermediate can be detected or envisaged, and yet the transformation occurs smoothly in high yield. AH ammett plot for substrates 231-234 revealed 1 =+4.5 in this case against s À ,i ndicating significant charge build-up on the arene and showing that the arene-transfer step is the rate-determining step.T he leaving groups in these cases are amide anions.T he fact that they are not good leaving groups,i sc onsistent with the need for significant charge build-up on the ring in the transition state,before the departure of the leaving group is triggered.
On the other hand, for substituents on the arene where s À > + 0.2, the arene transfer is facilitated and is apparently no longer rate-determining;inthose cases,the enolate formation step takes over this role.
Prior to this most recent work, Clayden et al. had studied extensive alternative applications of these aryl transfer reactions,notably in ring-expansion reactions, [78][79][80][81][82][83] for example,with substrates 240, 241. [78] Although Hammett plots are not reported for these series,t he analogy to the amino acid cases just discussed make it highly likely that they follow Thesubstitution steps in Claydenswork are examples of Tr uce-Smiles rearrangements, [84] intramolecular substitution reactions that go through a spiro transition state or intermediate,w ith carbon nucleophiles and nitrogen leaving groups.Aquite different example of cS N Ar chemistry was reported by Coquerel [85] in 2013 that also involved aS milestype rearrangement, this time with an oxygen nucleophile and an itrogen leaving group.I nastudy of the reactions of benzyne with pyridine,t hey isolated an unusual product of rearrangement, 253.T his was rationalised through the pathway shown (Scheme 35) where generation of the zwitterion 257 leads to internal deprotonation to give pyridine carbene 258.T his nucleophilic carbene then reacted with the reactive ketone carbonyl group of N-protected isatin 259,a nd the resulting alkoxide then secured ap henyl transfer reaction to liberate aneutral pyridine nitrogen in 253. [85] Computational studies revealed that the conversion of 260 to 253 was occurring by ac oncerted process.I nt he transition state 261, the carbon atom undergoing substitution adopts sp 3 -like geometry as characterised by the computed bond angles and bond lengths.T he phenyl group bearing the pyridinium substituent in 261 did not feature any activating substituent [other than the leaving group] and the activation barrier (DE*) was very accessible at 10.9 kcal mol À1 .
TheJulia-Kocień ski reaction [86] (Scheme 36) also involves aS miles-type rearrangement step and has been studied in detail with computational methods.The effect of coordinating counter cations and different solvents on the Z/E selectivity of the product alkenes is rationalised. It was found that the rearrangement step through spiro species 265 (Scheme 36) follows aconcerted mechanism in all examined cases (different solvents and counter-ions). Thea uthors note that at no point during this rearrangement is as ignificant amount of negative charge transferred onto the tetrazole ring. Instead the negative charge is directly transferred from the attacking alkoxide nucleophile to the sulfur atom of the leaving group. Thet ransition state is asynchronous and early.T he new carbon-oxygen bond is formed to as ignificant extent while the carbon-sulfur bond still is mainly intact.
As mentioned above,t he Smiles rearrangement is an intramolecular substitution reaction featuring a spiro species on the reaction path. Concerted pathways had been considered for other examples of the Smiles rearrangement early on. [87] In contrast to the cases just cited, computational studies showed that several examples of the reaction proceed by astepwise mechanism via aM eisenheimer intermediate.
TheS miles rearrangement of 269 was investigated computationally with ar ange of different functionals (Scheme 37). [88] It was found that, depending on the functional, structure 270 can either be optimised as al ocal minimum or as at ransition state.B enchmark models at Møller-Plesset MP2/6-31 + G(d,p) and MP4(SDQ)/6-31 + G-(d,p) level of theory showed that 270 is an intermediate.I n general, functionals with < 10 %H artree-Fock (HF) exchange were unable to correctly identify 270 as al ocal minimum and predicted ac oncerted mechanism instead. Notably,t he popular B3LYP functional was found to fail to predict the correct stepwise mechanism despite having 20 % HF exchange.M 06, M06-2X and wB97X were found to give results satisfactorily close to the Møller-Plesset results,that is, they all predicted as tepwise mechanism with reasonably accurate barrier heights.

Newman-Kwart and Related Rearrangements
Closely related to the above reactions that featured fivemembered ring spiro species,f our-centred transient spiro rings are proposed for an umber of other rearrangement reactions,namely the Chapman, Schçnberg [93] and Newman-Kwart rearrangements.O ft hese,t he Schçnberg rearrangement of diarylthionocarbonates 281 to diarylthiolcarbonates 282 (Scheme 39) was studied intensively first.
Tarbell et al. [94] proposed afour-centred transition state to be at the heart of this rearrangement. Ther eactions are accelerated by electron-withdrawing substituents in the aryloxy ring. TheN ewman-Kwart rearrangement, for example, 283!284,w as excellently reviewed in 2008 by Lloyd-Jones et al. [95] Relles et al. found [96] similarities between the Chapman and Newman-Kwart rearrangements on studying their properties separately through Hammett correlations 1 = + 1.62 for the Newman-Kwart rearrangement and + 1.63 for the Chapman rearrangement. As imilar assessment by Miyazaki [97] versus s À gave 1 =+1.83 for the Newman-Kwart rearrangement and 1 =+1.06 for the Chapman rearrangement. Woodward, Lygo et al. [98] (2003) conducted computational studies on the Newman-Kwart rearrangement of two analogous series of atropisomerically pure thionocar-bamates,o ne derived from binol (288)a nd one from octahydrobinol (289)( Scheme 39). They observed experimentally that the octahydrobinol cases rearranged essentially without racemisation, while the binol case showed significant racemisation. Their computational studies at different levels of theory showed that the barrier for the rearrangement of the octahydrobinol case was notably lower than for the binol case, while the barrier for thermal racemisation of the substrates had the reverse order.J acobsen and Donahue [99] used DFT calculations to back the proposal for afour-centred transition state.
More recently,aradical cation version of the Newman-Kwart rearrangement has been discovered [100] that proceeds under mild conditions and that has quite adifferent response to substituents than in the thermal rearrangement. Cramer has reported recent studies that provide further computational characterisation of the thermal Newman-Kwart rearrangement as well as its radical cation counterpart;the radical cation variant is also viewed as being aconcerted substitution reaction. [101][102][103]
Here,the reaction commences with demethylation of the ArS-Me bond to afford an arenethiolate 291,w hich then

Angewandte Chemie
Reviews attacks the adjacent arene,d isplacing methanethiolate anion to complete ac ycle by forming 292.C omputational studies were unable to identify any intermediate in the latter step, which therefore appears to be concerted.
Hedrick, Alabugin et al. recently reported [105] that the synthesis of fluorinated poly(arylthioethers) 295 proceeds via aconcerted mechanism (Scheme 41). Through computational studies,i tw as shown that firstly triazabicyclodecene (TBD), 296,n ucleophilically attacks the trimethylsilyl (TMS) group of MeSSiMe 3 ,d isplacing am ethanethiolate anion which hydrogen bonds to the TBD-TMS cation forming 297.T his then forms ac omplex 298 with hexafluorobenzene (293), before the methanethiolate anion displaces fluoride in aconcerted manner in transition state 299,a ided by hydrogen bonding between the fluorine and the amine catalyst.
Dissociation of Me 3 SiF occurs from 301,regenerating 296, followed by complexation of another MeSSiMe 3 and the monothiolated arene 300,f orming 302.Asecond concerted displacement occurs para to the first displacement, due to stabilisation from the first methanethiolate group acting as a s-acceptor (via transition state 303). Dissociation of fluorotrimethylsilane regenerates the catalyst 301 and affords dithiolated product 304.
Calfumµnetal. carried out an experimental and computational study into the reaction of atrazine 305 with various biothiols 307-310,and propose that these reactions occur on the borderline between concerted and stepwise mechanisms (Scheme 42). [106] AB rønsted plot shows b =+0.5, which corresponds to as tepwise mechanism via aM eisenheimer intermediate,however,computational analysis of the intrinsic reaction coordinate reveals that no Meisenheimer intermediate can be found. Thea uthors suggest that this may be because the loss of the chloride is extremely fast.
Investigations [107] of the nucleophilic aromatic displacement of chloride from a4 -chlorobenzoyl CoA model compound 311 (Scheme 43) with the acetate ion suggest that this reaction proceeds via aconcerted mechanism. In the same study the nucleophilic aromatic substitution of chloride from tetrachlorohydroquinone 313 with thiomethanolate was found to proceed via aconcerted mechanism (with the semiempirical method, PM3). Thea uthors point out that in solution phase (or on the enzyme) the accumulating negative charge in the transition state may be stabilized. Consequently, the reaction that proceeds via aconcerted pathway in the gas phase could proceed via as tepwise pathway with aM eisenheimer intermediate in solution phase.

Hypervalent Iodine Substrates
Olofsson et al. investigated [108] O-arylations with diaryliodonium salts through experimental and computational methods,u sing hydroxide ion, alcohols and phenols as nucleophiles.T he iodonium salts are represented as covalent diaryliodine(III) triflates,f or example, 315 (Scheme 44) that undergo displacement of the triflate (-OTf)l eaving group in the Ar 2 I-OTf molecule by anucleophile,before other chemistry transpires.The overall mechanistic picture is complex in that different mechanistic possibilities arose depending on the nucleophile and the iodine(III) substrate.However,inelectron-poor iodine(III) substrates such as (p-NO 2 C 6 H 4 )I-(Ph)OTf, 315,t hey propose ad irect ipso displacement by hydroxide ion at the CÀIbond of the nitroarene ring to lead to p-nitrophenol. They similarly represent an attack of alkoxides on Ph 2 IOTf (318), as involving an initial conversion of the triflate complex to the dialkoxy "ate" complex that then undergoes concerted substitution at the ipso centre as shown. Additionally,t hey show oxidation of alcohols by the iodine(III) substrates as involving concerted delivery of hydride to the ipso carbon with loss of iodoarene.
Similar reactions were more recently carried out [109] on cyclic secondary amines by Stuart et al.,aswell as primary amines, [110] by Olofsson et al. Stuart describes the final step of his proposed reaction mechanism as ar eductive elimination whereby Ar À Nb onds were created in the same step as the Ar À Ib ond was being cleaved. No computational or Hammett or other analyses of these reactions are available at the time of writing this review, but the analogy to the reactions of Olofsson et al. with alcohols is clear.
Uchiyama et al. [111] provided ar oute to ortho-iodo diaryl ethers.T hey found that upon studying aryl-exchange reactions of diaryl-l 3 -iodanes with aryl iodides,the aryl exchange occurred via what they termed ac S N Ar process (Scheme 45 A), but different from those encountered so far in this review.S N 1r eactivity,b enzyne pathways,a nd single electron transfer were all ruled out. S N 1was ruled out by the absence of any fluoroarene that would be expected to form if the reaction proceeded via an aryl cation, such as seen in the formation of fluorobenzene 327 from benzenediazonium 326 (Scheme 45 B). Ab enzyne pathway was ruled out by deuterating one aryl group on 331 and no D/H scrambling was observed (Scheme 45 C). Aryl radical intermediates were ruled out by the addition of ar adical scavenger,9 ,10dihydroanthracene,( Scheme 45 D) and by preparation of aradical clock substrate 335,which did not afford any cyclised products (Scheme 45 E).
Kinetic data suggest that both reagents are involved in the transition state.D ensity Functional Theory (DFT) calcula-tions suggest that the reactants 336 and 337 weakly coordinate through the BF 4 ion before aconcerted aryl group migration occurs via two I(II) species with some positive charge development at the ipso-carbon (339,S cheme 46). Dissociation of the aryl iodide from the tetrafluoroborate affords the products 336 and 337.The reaction is reversible,and proceeds with thermodynamic control.
Bakalbassis et al. used computational methods to study the reaction of aryl migration in aryliodonium ylides 341 and 344,and found this to be aconcerted process with abarrier of 17.7 kcal mol À1 and 6.4 kcal mol À1 for substrates 341 and 344, through transition states 342 and 345 respectively (Scheme 47). [112]

Reactions of Arenediazonium Salts
Computational studies into the reaction of the benzenediazonium ion 347 with water have been reported by Glaser et al. [113] They considered three mechanisms (Scheme 48 A); i) au nimolecular S N 1Ar mechanism with generation of an intermediate phenyl cation;i i) ab imolecular S N Ar that proceeds without the pre-and post-coordination of the water and the diazonium salt;a nd iii)a bimolecular S N Ar that proceeds with pre-and post-coordination of the water and diazonium salt. [114] Scheme 44. cS N Ar substitutions on arenes with ahypervalent iodine substituent. Thea uthors propose that the transition state for the reaction features aphenyl cation which interacts loosely with both water and dinitrogen (350)v ia pathway (ii)i nS cheme 48 A, despite the fact that pathway (i)h as al ower DG * . This is explained by the fact that ap henyl cation 348 would not really exist in aqueous solutions,a nd the CÀNb ond cleavage could never evolve to completion without water binding to the developing phenyl cation. Thet ransition state was shown to involve the "out-ofplane" attack 352 a rather than the "in-plane" attack 352 b (Scheme 48 B). [113] Singleton and Ussing have also studied the hydrolysis of arenediazonium cations in water, and do not agree with the results of Glaser,d ue to there being no consideration of entropic values in Glaserswork, and the fact that it does not agree with kinetic data. [115] Kinetic isotope effects for 13 Ci ndicated that there is significant weakening not only of the C 1 À C 2 bond in the rate-determining step,but also of the C 2 ÀC 3 bonds (see 353,S cheme 48 C). This is consistent with astructure resembling adistorted aryl cation in the transition state,a sC 1 gains some sp character as ac ation. Thea uthors point out that in the transition state,b oth N 2 and water are distant from the forming cation, and that the mechanism lies somewhere between S N 1Ar and S N 2Ar.

Reactions of Metal Nucleophiles with Fluorinated Arenes
Thed isplacement of af luoride atom from polyfluoroarenes with amagnesium(I) complex was studied experimentally and computationally by Crimmin et al. [116] Them echanism was found to proceed via ac oncerted S N Ar pathway (Scheme 49). Thea ctivation energy found by the DFT method (25.7 kcal mol À1 )w as in good agreement with the experimentally determined activation energy (21.3 kcal mol À1 ). As imilar mechanism was found by DFT for the corresponding bimetallic Mg-Zn complex. In this complex the zinc centre acts as the nucleophile.Inanearlier study on the Mg-Mg complex, [117] experimental evidence speaking against single electron pathways was gathered. AS N Ar mechanism was proposed and predicted to be concerted by DFT.
In av ery recent study with an analogous fluoride-metal exchange reaction with ac orresponding bimetallic Mg-Fe complex, ac S N Ar pathway was identified by DFT. [118] However,a na lternative step-wise S N Ar mechanism was found to have al ower overall activation energy.W ith the Mg-Fe complex, the iron atom acts as the nucleophile. 13. An Updated Perspective Emerges on the Prevalence of cSNAr Reactions.
Building on computational and experimental observations,n otably from the Ritter group,J acobsen et al. recently surveyed [14] S N Ar reactions by acombination of experimental and computational methods (Scheme 50). In advance,t hey based their expectations on the fact that isolated Meisenheimer intermediates can arise when i) substituents on the arene undergoing substitution provide good stabilisation of an intermediate anion, and ii)where the leaving group is relatively poor, so that the intermediate has some kinetic stability.S pecifically they initially studied three reactions. Case As atisfies both of the above criteria, Case Bf eatures substituents that do not provide such good stabilisation of negative charge,a nd also boasts an excellent leaving group, bromide,while Case Cfeatures substituents that can provide excellent stabilisation while also bearing an excellent leaving group.A ss uch, Case Aw ould likely be ac lassical S N Ar reaction, Case Bwould likely be concerted and Case Ccould be borderline between the two mechanistic extremes.T heir experimental approach was based on studying kinetic isotope effects in substrates that involve fluoride as aleaving group or as anucleophile in S N Ar reactions.Ifakinetic isotope effect is involved in the formation or cleavage of the C À Fbond, then this will be reflected in a 13 C/ 12 Cisotope effect for that carbon. NMR methods for determining isotope effects were greatly developed by Singleton and Thomas [119] in 13 Cspectra, but the novel development of Jacobsen et al. is to make use of the NMR sensitivity of the 19 Fn ucleus.S tudying multiple quantum filtered (MQF) 19 F{ 1 H} spectra allowed clear observation and quantitation of the 13 C-19 Fs atellites to the 12 C- 19 Fp eak with very accessible acquisition times for reasonable quantities of substrate (the MQF technique suppresses the appearance of the latter peak).
With the isotope effects measured, the important point was to compare this figure with that calculated using benchmarked computational methods,w hich also indicate whether an intermediate or atransition state is present. Akey indicator of the concerted or stepwise nature of the reaction involving C À Fformation or rupture relates to acomparison of this KIE to the maximum computed KIE on the reaction energy surface.S trong bonds in the ground state can lead to loss of more vibrational energy in the TS and therefore to large KIEs.
Thel argest KIE values arise when the bonding to both nucleophile and leaving group are weak in the TS,t hat is,i n concerted reactions.F or example in Case A, as trong C À F bond is broken, leading to large maximum KIE (1.070). In contrast, in Case B, aweak CÀBr bond is broken as reflected in the lower maximum KIE (1.045). Them easured KIE in both cases was 1.035 but this represents 47 %ofthe maximum KIE for Case A, but 87 %o ft he maximum KIE for case B. This translates to astepwise nature for Case Aand aconcerted reaction for Case B. They then extended their studies to 120 S N Ar reactions with avariety of arene ring types,nucleophiles and leaving groups.T heir calculations showed that 99 of the selected substitution reactions (83 %) proceed with concerted mechanisms.

Summary and Outlook
In 2013, aromatic nucleophilic substitutions were reviewed, and the classical stepwise mechanism was deemed to be the usual mechanism, while concerted nucleophilic substitutions were very rare. [3] Thep ast six years have certainly built on the undercurrent that existed before 2013 and it is likely that at orrent of concerted examples will appear in the next few years.Investigations have been helped by computational techniques that shed light on the mechanisms.Whatisclear is that the concerted or stepwise nature of the reactions is strongly influenced by substrate nucleophile and leaving group,but also by the environment, and that some substitutions may present as concerted or stepwise depending on the conditions.W en eed to be careful about information from Hammett correlations for at least two reasons:i )Hammett 1-values depend on the temperature at which the experiments are performed and so comparisons need to bear this in mind;ii) if aparticular reaction undergoes atransition from stepwise to concerted for arange of substituents on the substrate,t his may present as ac lear change in 1-value,b ut the two pathways could have similar 1-values,and this could mask the transition. With computational methods,t he selection of the method and the basis set clearly influences the outcome of the calculations,a nd so continued study in this area will be crucial.
With these important changes in perception coming now for nucleophilic aromatic substitution and its implications for Meisenheimer intermediates,i ti si nteresting to see that the counterpart in electrophilic aromatic substitution, that is, concerted electrophilic aromatic substitution, featuring Wheland transition states rather than intermediates,i sa lso beginning to appear. [120][121][122] We are thus at at ime of exciting developments in mechanistic organic chemistry.