Not‐So‐Innocent Anions Determine the Mechanism of Cationic Alkylators

Abstract Alkylating reagents based on thioimidazolium ionic liquids were synthesized and the influence of the anion on the alkylation reaction mechanism explored in detail using both experimental and computational methods. Thioimidazolium cations transfer alkyl substituents to nucleophiles, however the reaction rate was highly dependent on anion identity, demonstrating that the anion is not innocent in the mechanism. Detailed analysis of the computationally‐derived potential energy surfaces associated with possible mechanisms indicated that this dependence arises from a combination of anion induced electronic, steric and coordinating effects, with highly nucleophilic anions catalyzing a 2‐step process while highly non‐nucleophilic, delocalized anions favor a 1‐step reaction. This work also confirms the presence of ion‐pairs and aggregates in solution thus supporting anion‐induced control over the reaction rate and mechanism. These findings provide new insight into an old reaction allowing for better design of cationic alkylators in synthesis, gene expression, polymer science, and protein chemistry applications.


Introduction
In nucleophilic substitution, an electron-rich nucleophile attacks an electron-poore lectrophile, replacing al eaving group. Despite being an elementaryr eaction, challenges remain in predictings eemingly simple reactiono utcomes whether in biochemical pathways, [1] the design of cancert herapeutics, [2,3] the preparation of challengingn atural products and pharmaceuticals, [4,5] the development of next-generation alkylation technologies, [6,7] or in understandingt he mechanism of endogenous alkylators. For example, S-Adenosyl methionine (SAM) [8][9][10] is ac ofactor that regulates as eries of biochemical transformations via transfer of the methyl group located on a positivelyc harged sulfur atom (Scheme S1). Numerous studies have focused on understanding SAM's alkylation cycle and interaction with enzymes containinganegatively charged pocket; [11][12][13] however,n oi n-depth studies have sought to understand the eventual role of counteranions on the function of SAM. This begs the question whether free anionso ra nionic residues in the active site have an active role on the alkylation reaction by lowering activation energies or changing reaction pathways.
Answering these questions is particularly important to drive progressi na lkylation technology and the synthesis and understandingo fc ustom reagents for niche applications.F or example, solid-supported alkylators are finding applications in flowchemistry since they eliminate the need for side product removal, simplify purification, and reimagine the role of alkylation reaction in complex reactor setups. [14,15] Other "smart"a lkylation technologiesr ely on the use of triggerss uch as light, [16,17] certaine nzymes, [18,19] and electrophiles, [20] which provides both temporal and spatial control over the alkylation process. Semi-stable cations capable of controlled transalkylation have led to the discoveryo fa ne ntirely new class of polymer vitrimers pioneered by Drockenmuller et al. [21] and demonstrates an on-conventional use for cationic alkylators beyond synthesis. [22][23][24] We have been developing an ew class of highly tunable and non-volatile cationic alkylating agentsb ased on thioimidazolium ionic liquids. [25,26] In contrastw ith oxonium,a mmonium,o r sulfonium analogues, thioimidazoliums are more easily deriva-tizable and often milder alkylating reagents. For example, alkyl groups attached to the sulfur atom are exclusively transferred to an ucleophile under mild reaction conditions leaving all other positions unaffected, thus allowing for their derivatization without compromisingp roduct formation.O ur preliminary investigations showedt hat electron deficient thioimidazolium cations have weaker S-R bonds and correspondingly faster alkylation reactions [25] and that exchanging the iodide counteranion with the much less nucleophilic bis(trifluoro-methane)sulfonimide (TFSI) decreased the rate constant by 100-fold for reactions with pyridine. The addition of KI (0.1-1.0 equiv) to this reactionm ixture increased the reaction rate, [25] thus demonstrating anion-dependentr eactivity.W ep ostulated that iodide catalyzes alkylation via at ransient alkyl iodide intermediate (Scheme 1b), confirmed by the formation of MeI in solutionu pon heating, [25] while the non-nucleophilic TFSI anion likely forced ao ne-step process( Scheme 1c)t hat for an unknown reason,p roceeded slower. Despite theseo bservations, the existence of at wo-step mechanism for iodide does not preclude ac oncurrent one-step mechanism mediated by an iodide-cation complex, which mayi nf act be the lower energy pathway.T hese initial findings suggested mechanistic complexity for as eemingly simple reaction with implications for alkylation in material science, synthesis, and living systems. An understanding of the role of ion-pairing dynamics, aggregation, and structure-activity relationshipsi sr equired for effective synthetic reagents to be developed. This is av ery understudied field,w ith only af ew examples explicitly exploring the mechanistic role of counterions in complex reactions, [27] especially when changing the ion changes the product outcome; but nonef ocusing on the comparably subtle effects observed here. The former are highly exciting, but the latter class, where changing the counterion simply accelerateso rr etards ar eaction are far more common,and very industrially andbiological-ly relevant.W en eed ab etter understandingo ft hese more routine, but far more common phenomena.
In this context,w eh ere explore the role of the anioni nc ationic alkylationst hrough ac ombination of experimentala nd computational analysis. Twos eries of thioimidazolium salts, based on benzimidazolium and caffeine scaffolds with sixd ifferent anionsw ere prepared as models to examinea nion-influenced reactivity.B yc oupling kinetic analysis, molar conductivity,a nd ion-diffusivity data with molecular mechanics (MM), conformational analysis, and advanced quantum mechanical (QM) DFT-studies, we obtained ac omprehensive pictureo f how and why anions influence the reaction kinetics and mechanismso ft hese cationic alkylators. This combined-arms investigation demonstrates how "spectator" anions determine reactivity and brings new life to seemingly simple S N 2r eactions.

Results and Discussion
Thioimidazolium synthesisa nd kinetic evaluation Thioimidazolium salts were synthesized according to am odified version of our published procedure (See Supporting Informationa nd schemes S2 and S3). [25] To assess the anion's effect on alkylation kinetics, all salts were treated with 1.0 equiv of pyridine in DMSO at 90 8Ca nd conversion to 1-methylpyridinium was monitored by 1 H-NMR spectroscopy over1 5h. Second-order rate constants were obtained by plotting1 /[Pyr] as af unction of time and determining the slope (Table 1). Caffeine-based salts were more reactive than their benzimidazole analogues,c onsistent with previousf indings. [25] The relative reaction rates of the salts as af unction of anion was the same in both series:I À @ PF 6 À > CF 3 SO 3 À > PhSO 3 À > TFSI > CH 3 SO 3 À ,i ndicatingt hat the effect of the anion on the reaction rate is not cation-dependent for the series of tested cations. It was unclear what differentiates the other anionsW hile we suspected that at ransient MeI intermediate is responsible for the exceptionally high reactivity of the iodides, their reactiono rder is not consistentw ith the expected nucleophilicities of these anions based on their nucleofugality:I @ PhSO 3 À % CH 3 SO 3 À > TFSI > CF 3 SO 3 À @ PF 6 À (experimental Mayrvalues have not been computed for these anions). [28] PF 6 À cannot form another covalent bond, rendering it incapableof"shuttling" the methylsubstituent,y et it is the second most reactive salt, trailed closely by triflate,avery weak nucleophile.
Scheme1.Chemical structures of the thiouronium salts prepared and the proposed mechanismsfor their counteranion mediated alkylation reaction with pyridine. Mesylatea nd TFSI salts are the least reactive despite being intermediate in nucleophilicity between the others. These results illustrate that there are likely multiple factors contributing to reactivity through possibly two or more different mechanisms. To better understand the anion effect, we have computationally modeled multiple alternative transition states and precomplexes within the potential energy surface using density functional theory (DFT, Figure 1).

Structure determines conformation,determining mechanism
Selected lowest-energy transition states (TS1 a-f-py)a re provided in Figure 2( see Supporting Information for all other possible transition states). Each TS geometry differs substantially from the others relative to the positioning of the counterion; however,t hey fall into one of two broad classes. In the first, the counterion acts as the nucleophile (labelled as TS2Step); in the second, the pyridine is directly alkylatedb yt he thioimi-  dazolium cation (labelled as TS1Step). We found transition states for both mechanisms for all complexes, and identified that iodine alone works through the two-step pathway (with the formation of methyl iodide being rate determining), while the others follow the one-step route ( Figure 3A). Similar results for iodide-mediated N-alkylations has been previously found by using ac ombination of XPS and rheometry. [29] We then computationally probedt he minimume nergy mechanistic pathways for both mechanisms for three different benzimidazolium salts ( Figure 3B;s ee Supporting Information for the other pathways).
In all cases, alkylation commencesw itht he complexation of the benzimidazolium ion pair and pyridine (Pre-complex 1, Figure 3B). For the two-step pathways, alkyl transfer proceeds by an initial interaction of the methyl group with the coordinated counter anion via ar ate-determining TS1(First-Step) to form counterion alkylated intermediate (INT2). The second step proceeds via reorientation of pyridine and its nucleophilic attack on transient INT2 via TS2(Second-Step),t hereby releasing the benzimidazole. The rate of this two-step mechanism depends on the nucleophilicityo ft he counteranion since its attack on the methyl group is rate determining.
The second mechanistic scenario, where the counterion mediates the direct nucleophilic attack of the methyl group by pyridine via TS3(1Step),p roceedst hrough charge-separated intermediate (INT3),f ollowed by benzimidazole dissociation to provide the alkylatedp roduct (Figure 3a nd S15).
These mechanismss uggest that strongn ucleophilic anions like iodide would favor atwo-step mechanism while highly dissociativea nions (like PF 6 À ), lessc apable of delocalizing the positive charge on the benzimidazolium (thereby making it more reactive), would favor the one-step direct alkylation mechanism ( Figure 3A;see Supporting Information). To explain this counterion dependentm echanisticb ehaviour,w ec om- pared the activation barrier differences (DG°)b etween the rate determining TS3(1Step) and TS1(2Step) for each system. The lowest energy transitions tates for each salt support the mechanistic hypothesis. For example, in the case of iodide,t he precomplexed pyridine even assists in better orienting the iodide to capture the methyl group (TS1 a(2Step) = 23.9 kcal mol À1 ); this route lies 6.6kcal mol À1 lower than the direct attack pathway (TS3 a(1Step),3 0.5 kcal mol À1 ,F igure3). Iodide consequently has by far the lowest energy barrier of any process examined in this study (TableS4), consistent with experiment. This trend was maintained regardless of level of theory or size of basis set. Thise specially lowe nergy barrieri saresult of the pyridine being positioned through attractive interactions with the benzimidazolium.T his better orientst he iodide to capture the methyl group (TS1 a(2 step) = 23.9 kcal mol À1 )i nageometry that sets up the subsequentp yridine alkylation (TS2 a(2 step) = 22.5 kcal mol À1 ,F igure S15). Direct alkylation for iodide salts is disfavored (DG(1step)°= 30.5, Ta bles S4 and S15). Iodide is uniquea so ther counterions (CF 3 SO 3 À ,C H 3 SO 3 À ,T FSI, and PF 6 À )donot act as nucleophiles (Table S4). The least nucleophilic anion PF 6 À greatly favors the one-step process with TS3 b lying 15.5 kcal mol À1 below two-step TS1b. This is consistent with the non-nucleophilic nature of PF 6 À . The other salts are intermediate:n one are as nucleophilic as iodide, and none are as dissociateda sP F 6 À ;t he computational model appearst ob ea ccurate as the calculated activation energies match the experimental trend ( Figure 3A).
To elucidate the role of the counterion in the one step nucleophilic addition pathway,w efocusedo nt he most reactive (PF 6 À )a nd least reactive( CH 3 SO 3 À )s ystems (TS1 f(1 step) and TS1 b(1 step)). To this end, the electronic changes along the Npy···CH 3 bond forming and H 3 C···S bond breaking processes were evaluated using natural bond orbital( NBO) analysis. During nucleophilic attack, significantly better orbitalo verlap between the donor orbitalo fn ucleophile and the acceptor NBO orbital of the methyl group was observed for the PF 6 À mediated TS1 b(1 step) (D ENBO (total) = 308.1 kcal mol À1 )t han for CF 3 SO 3 À TS1 f(1 step) (D ENBO (total) = 130.5 kcal mol À1 ), helping to explain their differential reactivity.
Strong nucleophilic character is essential for af avorable two-stepm echanism. Mesylate is ap oor nucleophile and so it would not obviously favor the two-step process like that of iodide, however,i ti sc ertainly more competent than even less nucleophilic PF 6 À .I nc ontrast, the one-step direct alkylation is facilitated by as trongly delocalized counterion that increases the local positive charge on the methyl group, best exemplified by PF 6 À .M esylate again, although charged elocalized, does form as tronger direct interaction with the transferrable methyl group, making this pathway more inaccessible too. Sluggishu nder both mechanisms, mesylate results in the lowest reactionrate.

Orientation and anion nature define interaction energyand in turn ion-pair physical behavior
To betterc orrelate the energies of the one-step mechanisms with the structural parameters, we performed ac onformational energy search (see Supporting Information) anda ni n-depth DFT (wB97X-D/6-311G(d,p) study of the counter-ionc oordinated pre-complexes of PF 6 À (strongly reactive), CF 3 SO 3 À (medium reactive) andT FSI (weakly reactive) mediated transition state structures (TS3 b(1Step), TS3 c(1Step),a nd TS3 e(1Step)). While it is likely that the active speciesi sn ot as ingle ion-pair precomplex but rather an aggregate due to the high reaction concentrations (462 mm), this is likely not ac ritical parameter that needs to be consideredf or these energy calculations. Others have extensivelyi nvestigated the effect of ionic liquid aggregation/self-assembly on bulk physicala nd chemical properties, [30][31][32][33] and in most cases found that varying the number of molecules in the cluster had little effect on the interactions between thec omponents of as ingle ion pair or the coordination capability of the anion. Consequently,w ef ocused our efforts on the solvated optimized (IEFPCM model;D MSO) single pre-complexes of 1b (PF 6 À ), 1c (triflate), and 1e (TFSI) using QTAIM based analysisa tt he wB97X-D/6-311G(d,p)/SDD for iodine. These calculations indicatet hat in the optimal binding mode, the anions interact with the benzimidazolium cation's S-Me moiety through arich network of attractive noncovalent interactions including hydrogen bonds and attractive X-X (X = O, N, or F) contacts ( Figure 4). In 1c and 1e,t he assembliesb enefit from the specific orientation of the anion since the sulfonic functionalities form as eries of interactions via the Oa nd N atoms with the benzimidazole ring, whilet he Fa toms in both the triflate and TFSI associate with the aromatic protons and the alkyl moieties of the cation. In contrast, PF 6 À is an on-coordinating anion and can only establish weak electrostatic interactions,t hus limiting the strength attractive forces between the cation and anion.
The interaction strength of the non-covalenti nteractionsb etween thiobenzimidazolium and TFSI, triflate and PF 6 À can be described by the ion pair binding energy (Eb) and its components:e lectron correlation effects (EMP2)a nd electron density strength (Ex, Figure S16). Analysis of the density parameters at the bond criticalp oints (BCP) of the key interactions in the binary precomplexes also highlights the same order affinity: triflate forms stronger interactions( total electron density at BCPs, triflate 0.13 e/au3) than the TFSI (0.071 e/au3) or PF 6 À systems( 0.049 e/au3). This indicates that PF 6 À has the weakest ion-pairing binding energy of the three, with triflate being the strongest.
These interactions explain the higherc alculated binding energies of 1c and 1e (À85.0 and8 0.5 kcal mol À1 ,r espectively) than in the weaker bound PF 6 À 1b (À78.5 kcal mol À1 ). QTAIM analysisa llows us to more closely evaluate the density characteristics of the interactions in these three systems, confirming that the intermoleculari nteractions are non-covalent (see Supporting Information for ad etailed discussion). In addition, several keyX -X contacts (N-N, N-O, N-F,F -S, O-S andF -Car,F igure S17) clearly play an important role in properly orienting all three anionsw ithin the cavity.I np articular, the N-N contacts in 1e ( Figure S17) show the same topological behaviour as the weak H-bonds.T he components of the Laplacian fort he three systemsi ndicate that the electrostatic component of the dipole-dipole and polarization interactions are more important than the charge transfer between cation and anion,f or TFSI, as ar esulto fi ts increased delocalization, and triflate to al esser extent.F or PF 6 À ,c harge transfer and electrostatic attraction both contribute more equally (and weakly);t his is completely consistentw ith the energetic analysis described above (Figure 4; Table S6).
The interaction energy comprises severalorthogonal components: [34] the electrostatic energy representing the affinity between the charge distributions of undistorted monomers Ees; Eex the Pauli exchange-repulsion energy,E pl the polarization term representing the Coulombic interaction between the distorted ions, and the Morokuma delocalization, or charget ransfer term, Ect. To evaluatet he nature and strength of the binding interactions in 1b, 1c,and 1e complexesu sing av irial theorem approach, the energy density contributions were further analyzed using QTAIM. The total electronic energy density at the interaction BCP (H(rb)) can be deconstructed into the Laplacian, local electron energy at the BCP. 1 = 4 r21(rb) (correlated with Ect and Eex), and the kinetic energy density at the BCP ÀGb (correlated with Ees and Epl). Variationso f 1 = 4 r( r21(r) + (ÀG(r))and the H(b) energy densities were evaluated as afunction of the electronic charge density (1(r)) at the BCP (Figure S16 and accompanying text). Plotting (ÀG(rb)), 1 = 4 r21(rb) and H(rb)) as af unction of the 1(rb) values (ranging from 0.0019 to 0.0113) for the three precomplexes (Figure4)s hows that the Laplacian (ranging from 0.0092 to 0.0473, Ta ble S5, Figure S17) increases proportionally to an increasei nt he strength of the individual cation anion interaction electron density,w hile the kinetic energy density,( ÀG(rb)) decreases. The overall local electronic energy density,H (rb), increases slightly as the electron density increases. The energy densities and the interaction energy components correlate better (R2) with the 1(rb) in 1c and 1e than with the 1b precomplex althought he agreement is good in all cases.I na ddition, (ÀG(rb)) and 1(rb) correlateb etter than the Laplacian for 1c and 1e indicating that the electrostatic component of the dipole-dipole and polarization interactions are more important than the charget ransfer between cation and anion, especially in the case of the TFSI because of its increased delocalization. However,t his trend is not significant for PF 6 À as an early ideal linear correlationw as found between both (ÀG(rb)) and 1 = 4 r21(rb) and bondings trength suggesting am ore balanced contribution from both components.
These independenta nalyses all support as ingle conclusion: the PF 6 À coordinated precomplex is more looselya ssociated than either the TFSI or triflateo nes. This is because the interactions between the anions' individual atoms andthe benzimidazolium are tighter for the coordinating ions;e specially the O-Ni nteractions. PF 6 À on the other hand can both dissociate more easily andh as al ower tendency to formh ighero rder aggregates.
To gether these phenomena result in PF 6 À providing al oose ion pair,f acilitating the repositioningo ft he pyridine, and consequently accelerating alkylation. Our calculations show that the anion has ac rucial influence on the alkylation mechanism and reactivity of benzimidazolium cations.H owever,t his entire mechanistic discussion assumes that ion-pairso ra ggregates are present in solution.T he model would be inaccurate should the ions be fully solvated. In such as cenario, the identityo f the anion would not matter.H owever, this complication can be readily addressed:i on-pairb inding energies not only describe the stability of the complex, butt hey also can be used to predict experimental viscositya nd conductivity.T he shortrange dispersion component of the ion-pair binding energy correlates better with conductivity and viscosity properties of ion pairs while the long-range electrostatic and polarization components correlate with the melting point of ILs. [35] This motion must also be considered for ab etter understanding of the reactivityo ft hese systems. Strongly paired cation-anion complexes with few inter-cluster interactions will show lower conductivities and viscosities with motion largely determined by electron dispersion;h owever,t he existence of ion-pairs or higher order aggregates has not yet been experimentally demonstrated with these compounds. Experimentsw ere conducted in DMSO,w hich unlike water generally favors the formation of ionic liquid-rich clusters even at concentrationsb elow 10 wt %. [36,37] The formation of aggregates would be consistent with this explanation of the observed reactivity.

Diffusion and aggregation state of benzimidazolium salts in DMSO
To better understand the aggregation state of these salts and explore their anion-dependency,w eused ac ombination of conductivity measurements and DOSY NMR spectroscopy. [38] To gether this allows us to determine aggregation state as a functiono fc oncentration and an accurate determination of ion diffusivity and solvodynamic radius. Absolute conductivity increases as the concentration of salts 1a, 1b, 1c,a nd 1e in DMSO increases;h owever,r eplotting molar conductivity reveals an initial drop in conductivity with greater salt concentrations before rising again ( Figure 5; See Supporting Information for full data). This is ar esult of the transition from freely solvated/ionized species to neutral-contact pairs being formed, thus lowering the molar conductivity of the solution. [39] While there is an equilibrium between ion-pairs and solvent-separated ions at low concentrations, the balance of the equilibrium depends on the concentration and identity of the counterions. [40] Minimum molar conductivity is observed at:1 0mm (PF 6 À ; 1b), 20 mm (TFSI; 1e), 25 mm (I À ; 1a), and 30 mm (CF 3 SO 3 À ; 1c), which is considerably lower than the concentrations used in this study for reacting with pyridine (462 mm). At such high concentrations an equilibrium [40] between large charged aggregates, hydrogen bondeda ssemblies, charged triple ions and ion pairs is established. [41,42] These results provide evidencef or the presence of ion-aggregates at reaction concentrations indicating that cation-anion interactions likely affect reactivity while the comparatively narrow range for ion-pair formation for 1b is consistentw ith weaker ion-pair interactions that favors higher order aggregates as opposed to tightly bound pairs. These resultsa lso confirmt hat calculations treating these systems as ion pairs (as models of highero rder aggregates) is the appropriate method. Unlike fully solvated ions, ion-pairsa nd aggregates move sloweri ns olutiona nd therefore possess lower diffusion rates different and radii. To determine these parameters and providec omplementary evidence for their formation, we performed 1 Ha nd 19 F{ 1 H} DOSY experiments on compounds 1c, 1e and 1b at both their minimum molar conductivities, and at our normal reaction concentration (462 mm)i n[ D 6 ]DMSO (Tables S1-S2). [43] The diffusion coefficients fort he anions in all measured salts are smaller than those reported in literature for the single anionsa te ither concentration. [44][45][46] This suggests the presence of biggera nd thus slower moving objectsi ns olution,s uch as strongly coordinated ion pairs or higher-order aggregates instead of smaller,s eparated ions. As shown in Tables S1 and S2, the values for the cations are largert han those expected for isolated TFSI, PF 6 À , and CF 3 SO 3 À anions. [46][47][48] The PF 6 À anion has the highest diffusion coefficients under both conditions (4.28 10 À10 m 2 s À2 at the conc. of 462 mm), while triflate shows the lowest diffusion of the test anions (3.23 10 À10 m 2 s À2 ). These resultsa re consistent with our computational model that PF 6 À forms loose ionpairs with benzimidazolium duet oi ts propensity to form weak electrostatic interactions, while triflate promotes several attractive non-covalent interactions via the Oa nd Na toms, resulting in tighter ion-pairs. At low concentrations, all salts exhibit higher diffusion coefficients and smaller ionic radii than at 462 mm (e.g. 9.7 10 À10 m 2 s À2 against 4.3 10 À10 m 2 s À2 for PF 6 À anion), consistentw ith the formation close contact ionic pairs and low solvation and with the low molar conductivityd ue to the formationo ft he overall neutral ion pairs. At higher concentrationsw eo bserved ad ecreasei nt he diffusion coefficients for both cationsa nd anionsc ompared to the same salts at al ow concentration,a nd an increasei nt he ionic radii. While the increase in the radiii ndicatesg reater solvation of the ions Slower diffusion reflects the formation of biggera nd charged aggregate of ions typical of ILs in DMSO, consistent with the well documented tendency of DMSO to promote the formation of solvent-surrounded ion pairs over isolated free ions. [36] As aggregation is concentration-dependent, we can infer that the alkylatorr eactivity is also concentration-dependenta st he reaction proceeds through am inimum three-component system.I nt his regard we measured the rate constants for the reaction of 1c with pyridinea tt he concentration where its molar conductivity is at its lowest( 30 mm), and at 250 mm and 600 mm.W ef ound that there is ac oncentration dependency on the rate constant with values rangingf rom 6.3 10 À4 m À1 min À1 at 30 mm to 1.3 10 À2 m À1 min À1 at 600 mm ( Figure S13). This provides strong evidence that different aggregation states influence the activationenergy of the reaction as described in the previous sections;h owever more investiga- At very low concentrations, ions exist mainly as ionized species resulting in high molar conductivity.Asthe concentrationf urther increases,neutral ionpairs form resulting in ad rop in molar conductivity before increasing again as charged aggregates predominate. Alkylation reactionsperformed in this study is at ac oncentration where aggregates are present (462 mm). tions will provide furtherd etailst oe xplain these observations, as ion pair-dependent reactions represent an interesting tool in organic transformations and catalysis. [49] Conclusions Often when reactivity differs based on the nature of the counterion the discussion focusesa round pK a values or ac rude estimate of the relative coordinatinga bility of the anion. Here we reveal that this model is too simplistic and insteadi ntroduce a description of cation-anion interactions based on experimental and computational analysist hat explains trends in reactivity derived from am ultivariant approach. Even for an apparently trivial transformation: two distinct mechanismsc ompete the methylation of pyridine with ac ationic thiobenzimidazolium molecule, either ao ne-step or two-step process, and that reactivity in general is governed by cation-anion pairing effects.
In the case of this system, greater reactivity can be obtained with highly nucleophilic counterions since they form ar eactive alkylating intermediate, thus following at wo-stepm echanism. Meanwhiler easonable activity can be obtained using al oosely-associated counterion such as PF 6 À since it can facilitate the interaction of pyridine with the benzimidazolium cation and promote ao ne-step mechanism. Thus favoring neither reaction mechanism Anions such as mesylate are neither good nucleophiles nor assist pyridine, mesylate was the slowest of all tested anions. The reactionr ate is furtheri nfluenced by Hbonds, electrostatic,p olarization,a nd dispersive interactions aroundt he reactive site caused by the specific interplay between N, O, and Fa toms on the anion and the cation. By coupling molarc onductivity and DOSY experimentsw ith QMbased computational models, we showt hat ion pairs and/or aggregates are formed and that these ion-aggregates are likely responsible for the alkylation reaction in DMSO.U nlike free, cations present within an aggregate are strongly influenced by nearby. This model has been examined for benzimidazoliumbased alkylators fully solvated cations in solution,h owever our approachc an be appliedt oo ther commonly used salts. The effect of different halides was not examined here and would be of great interestg iven the uniqueb ehaviour of the iodide. The spectator anion,e specially in organic solvents, is not so innocent andc an be involved as an important component of the overall reaction.