Organic &Biomolecular Chemistry

PAPER

Cite this: Org. Biomol. Chem., 2013, 11,6170

Received 19th May 2013,Accepted 2nd August 2013

DOI: 10.1039/c3ob41038b

www.rsc.org/obc

Does the cation really matter? The effect of modifyingan ionic liquid cation on an SN2 process†

Eden E. L. Tanner,a Hon Man Yau,a Rebecca R. Hawker,a Anna K. Croft‡b andJason B. Harper*a

The rate of reaction of a Menschutkin process in a range of ionic liquids with different cations was investi-

gated, with temperature-dependent kinetic data giving access to activation parameters for the process in

each solvent. These data, along with molecular dynamics simulations, demonstrate the importance of

accessibility of the charged centre on the cation and that the key interactions are of a generalised electro-

static nature.

Introduction

Ionic liquids are salts which are liquid below 100 °C1 and aretypically made up of a bulky organic cation and a charge-diffuse anion.2–6 These solvents have potential advantages overmolecular solvents, including low vapour pressures2,7 and theability to manipulate solvent properties through modificationof the components.5–10 A current limitation to the widespreadapplication of these solvents is that organic reactivity in ionicliquids is often different to that observed in molecular sol-vents, and there is limited understanding of the underlyingprinciples controlling this reactivity.11§

We have previously examined a series of substitution,12–18

cycloaddition19,20 and catalytic processes21,22 in both mole-cular solvents and ionic liquids. For those cases where acti-vation parameter data could be determined,13–18,20 these dataindicate that interactions between the components of the ionicliquid and either the starting materials or the incipientcharges in the transition state result in significant changes toentropy and enthalpy of activation for the process. Given the

importance of the interactions of the components of the ionicliquid with species along the reaction coordinate, it is of inter-est to determine the nature of these interactions.

For the reaction outlined in Scheme 1, ordering of the ionicliquid solvent about the starting materials results in an entro-pic benefit on moving from a molecular solvent to an ionicliquid and, consequently, an increase in observed rate.14

Whilst it is likely that there is also increased stabilisation of,and ordering of the ionic solvent about, the transition state onmoving a molecular solvent to an ionic liquid, the activationparameter data shows the more significant effect is on thestarting materials. It is important to note that this is in con-trast to bimolecular substitution processes involving a chargednucleophile, where increased coordination of the nucleophileto the cation has been shown to slow the rate of reaction (see,for example, the work of Welton et al.23 and references citedtherein).

Further to the argument regards organisation of the com-ponents of the ionic liquid and the resulting effects on thereaction outlined in Scheme 1, it has been demonstrated that,through modification of the starting materials 1 and 2, theinteraction between the ionic liquid cation and the pyridinicnitrogen is the key interaction that leads to the changes inreactivity observed on going from a molecular solvent to anionic liquid.17 However, the site of interaction on the solventcation remains to be determined.

Scheme 1 The Menschutkin reaction between the bromide 1 and pyridine 2to give the corresponding salt 3.

†Electronic supplementary information (ESI) available: Preparation of the ionicliquids 5–9, rate data for the Eyring plot shown in Fig. 1, details of moleculardynamics simulations, figures showing cybotactic region around pyridine 2 insolvent 5 and radial distributions of cations of solvents 4 and 5 about thereagent 2, electrostatic potential mapping of the cations of ionic liquids 4 and 5.See DOI: 10.1039/c3ob41038b‡Previous address: School of Chemistry, University of Wales Bangor, Bangor,Gwynedd, LL57 2UW, UK.§In many cases, components of the ionic liquid participate directly in the reac-tion; this is exemplified by protic cations40,41 and basic anions.42,43 Such casesdo not rely on fundamental properties of the ionic liquid and are not discussedfurther here.

aSchool of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.

E-mail: j.harper@unsw.edu.au; Fax: +61 2 9385 6141; Tel: +61 2 9385 4692bDepartment of Chemical and Environmental Engineering, University of Nottingham,

University Park, Nottingham, NG7 2RD, UK

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In previous experiments examining ionic liquid effects onthe reaction outlined in Scheme 1,14,17 the ionic liquid usedwas 1-butyl-3-methylimidazolium ([Bmim]+) bis(trifluoro-methane-sulfonyl)imide ([N(CF3SO2)2]

−) 4 and hence it isunclear what structural features of the solvent cation areimportant. Directional polar interactions have been observedin the literature, using spectroscopic24 and computational25,26

approaches, between polar solutes and the C-2, C-4 and C-5positions, as well as with the delocalised π-system of the imi-dazolium cation in an ionic liquid. Is it either the presence ofthe C-2, C-4 and C-5 hydrogen atoms, the presence of a deloca-lised π-system or the accessibility of the charged nitrogencentre that afford the specific interactions that influence thereaction shown in Scheme 1?

The work described herein aims to answer the above ques-tion by systematically altering the cation and removing sites ofpotential specific interaction. The ionic liquids 5–9 allow foreach of these options to be considered, and the effect of thesesolvents on the activation parameters of the reaction of benzylbromide 1 with pyridine 2 were investigated.

Experimental

Benzyl bromide 1 was commercially available and was distilledprior to use. Pyridine 2 was purified using a literaturemethod27 and analytical grade deuterated acetonitrile wasused as received. The ionic liquids 5–8 were prepared from thecorresponding chloride,28,29 whilst ionic liquid 9 was preparedfrom the corresponding bromide (see ESI†);30 all were dried toconstant weight at 70 °C under vacuum (1 mbar). 1H NMRspectra were recorded either on a Bruker Avance 400 spectro-meter (400 MHz) or a Bruker Avance 600 spectrometer(600 MHz) using ca. 0.6 mL of reaction mixture (details below)in a 5 mm NMR tube.

Kinetic analyses were carried out in solutions containingthe bromide 1 (ca. 0.05 mol L−1) and pyridine 2 (ca. 10 equiv.)over a range of temperatures between 268 K and 333 K. In eachcase the reaction was followed using 1H NMR spectroscopyuntil more than 95% of the starting material was consumed.

Spectra were taken at regular intervals during the reaction andat least twenty spectra were obtained for each kinetic run. Theextent of reaction was deduced by integration of the signalcorresponding to the benzyl protons in the starting material 1(ca. δ 4.7). From this information, the pseudo-first order rateconstants for the reaction of the bromide 1 under these con-ditions were calculated and, subsequently, from the concen-tration dependence of these values, the second order rateconstants at each temperature were also calculated. The acti-vation parameters were then determined using the bimolecu-lar Eyring equation.31

Results and discussion

Initially the reaction was considered at an arbitrary tempera-ture (ca. 300 K) to determine whether there was a significantchange in the rate of the reaction on moving from a molecularsolvent to each of the ionic liquids 4–9 (see ESI† for completerate data). It is worth noting that the ionic liquids are allpresent at high mole fractions in the reaction mixture, withthe only remaining components of the solution being thereagents 1 and 2. This is important because the effects of ionicliquids on several reactions,32 including the reaction betweenbenzyl bromide 1 and pyridine 2,18 have been shown to varydramatically on changing the mole fraction of the ionic liquidpresent.

The ionic liquids could be initially grouped according totheir effects on the rate of reaction (see ESI†); the ionic liquids4, 5 and 8 gave an increase in the observed rate constants rela-tive to acetonitrile, the rate constants for the process in ionicliquids 6 and 7 were similar to those in acetonitrile, whilst thetetraoctylammonium salt 9 reduced the rate constant relativeto the molecular solvent.

In order to understand the origin of these changes in therate constants and to demonstrate whether or not they weregeneral, temperature-dependent kinetic analyses were carriedout. This allowed the construction of an Eyring plot31 (Fig. 1)

Fig. 1 Eyring plot for the second order rate constants for the reaction outlinedin Scheme 1 carried out in either acetonitrile (■) or one of the ionic liquids 4( ),14 5 ( ), 6 ( ), 7 ( ), 8 ( ) or 9 ( ). In all cases, the ionic liquid was onlydiluted by reagents 1 and 2 (mole fractions outlined in Table 1).

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from which the activation parameters for the process de-scribed in Scheme 1 in each of solvents, acetonitrile and theionic liquids 4–9 could be determined (Table 1).

As suggested previously,14 the increase in both the enthalpyand entropy of activation on moving from acetonitrile to theionic liquid 4 are consistent with an increase in the organis-ation of solvent around the starting materials relative to themolecular solvent case, particularly about the nitrogen of thenucleophile.17 The ionic liquid 5 has the C-2 hydrogen atom ofthe cation of parent ionic liquid 4 replaced by a methyl group.This position of imidazolium cations has been observed in theliterature to be the strongest site for interactions with electronrich species.24,26 As can be seen in Fig. 1, the rate constantsfor the reaction shown in Scheme 1 are very similar in boththe ionic liquids 4 and 5 across a range of temperatures andthe activation parameters for the process in each case arethe same. This indicates that specific interactions withthe C-2 hydrogen atom of the [Bmim]+ are not responsiblefor the cation-nucleophile association and the associatedrate enhancement of the Menschutkin reaction in the ionicliquid 4.

When the reaction was carried out in the pyrrolidinium-based ionic liquid 8, across the range of temperatures used therate constant for the process was the same as in the ionicliquids 4 and 5. This is consistent with previous studies on arelated substitution reaction between n-butylamine and methylp-nitrobenzenesulfonate.33 The activation parameters for thereaction between species 1 and 2 in solvent 8 underwent asmaller increase from those in the molecular solvent case,than for the cases when the imidazolium-based ionic liquids 4and 5 were used. This observation suggests less organisationof the cation of ionic liquid 8 about the starting material thanis seen with ionic liquids 4 and 5 and could be attributed to alack of a specific interaction between the nucleophile 2 andthe delocalised π system of the cation; this is the key differencebetween ionic liquid 8 and ionic liquids 4 and 5. However,both the magnitude of the changes in activation parameters,in this case relative to the reaction in ionic liquids 4 and 5,and the absolute rate data, suggest that this interaction is notthe key one that results in the rate enhancement of thisprocess. Rather, it suggests that the key interaction is present

in all the systems, suggesting that interaction with the chargedcentre of the cation is all that is required. The key interactionis unlikely to be hydrogen bonding due to the greatly differinghydrogen bond donating abilities of the ionic liquids 4,5 and 8.34

The ionic liquid 6 has both the C-4 and C-5 hydrogenatoms of the cation of parent ionic liquid 4 replaced by methylgroups. The rate constants for the Menschutkin reactionacross the temperature range studied were comparable in thissolvent to acetonitrile and slower than the cases in the pre-viously discussed ionic liquids 4, 5 and 8. Whilst this couldsuggest a directional interaction with the C-4 and C-5 positionsis responsible for the rate accelerations observed in the imida-zolium salts 4 and 5, this would be unexpected given the evi-dence for preferred interaction of polar solutes with the C-2position24,26 and the rate enhancement seen in the pyrrolidi-nium case. A potential explanation is that the cation methylgroups restrict access to the positively charged nitrogen centre,relative to the situation with the cations of the ionic liquids 4and 5. Activation parameter data is unenlightening here as,despite the absolute rate differences between the systems con-sidered, the data for the ionic liquids 4–6 and 8 are all verysimilar and show an enthalpic cost and an entropic benefit onmoving to the ionic liquid.

Methylation at the site of all the ring hydrogens on thecation of the ionic liquid 4 would remove all potential sites fordirectional interaction, and acts as a control for the results inionic liquids 5 and 6; hence, ionic liquid 7 was prepared.While this salt was reported as an oil,35 it was isolated in thiscase as a low melting point (31–32 °C) solid. While still anionic liquid, this did cause some difficulties in obtainingkinetic data as it placed a lower bound on the temperaturesthat could be used. Combined with the practical limitation ofthe maximum rate that could be readily followed, this methodled to greater uncertainties in the observed rate constants andhence in the activation parameter data. However, once morean enthalpic cost is offset by an entropic benefit and theresulting rates are comparable to the molecular solvent case.The limited change on moving from ionic liquid 6 to ionicliquid 7 is consistent with the negligible changes observed onmoving from the parent salt 4 to the methylated case 5.

The only ionic liquid that resulted in a significant ratedecrease relative to acetonitrile was the tetraalkylammoniumsalt 9. This ionic liquid differs from all of the others con-sidered in that the charged nitrogen centre of the cation iscomparably inaccessible; it is ‘buried’ by the four octyl chains.The markedly different rate constant and activation parameterdata between the tetraalkylammonium case 9 and the otherionic liquids 4–8 further suggest that the accessibility of thecationic centre is important in determining reaction outcome.

It is worthwhile considering the implications of the acti-vation parameters for the Menschutkin reaction in the ionicliquid 9 relative to acetonitrile. The rate decrease is the resultof an increase in the enthalpy of activation, with no change inthe entropy of activation. (This contrasts to the results in ionicliquids 4–8 where the enthalpic cost was either balanced or

Table 1 Activation parameters for the reaction described in Scheme 1 in thesolvent specified, with the mole fraction given for the ionic liquid cases

Solvent χIL ΔH‡ a/kJ mol−1 ΔS‡ a/J K−1 mol−1

Acetonitrile — 45.5 ± 0.7 −217 ± 24b 0.86 49.9 ± 0.8 −195 ± 35 0.88 53.5 ± 2.8 −183 ± 106 0.85 53.5 ± 1.1 −189 ± 47 0.85 52.7 ± 4.4 −195 ± 148 0.86 47.7 ± 1.3 −201 ± 49 0.74c 49.5 ± 2.3 −211 ± 7

aUncertainties quoted are standard deviations. bData reproducedfrom Yau et al.14 c The lower value in the tetraoctylammonium case 9 issimply due to the large size of the cation.

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overcome by an entropic benefit.) An increase in the enthalpyof activation of the reaction of the bromide 1 with pyridine 2in the ionic liquid 9 may either be the result of increasedstabilisation of the starting materials, decreased interactionswith the incipient charges in the transition state or a combi-nation of both, relative to the acetonitrile case. Given the hin-dered nature of the cationic component of ionic liquid 9,decreased stabilisation of the incipient charges in the tran-sition state seems most likely.

Up until this point, the anion of the ionic liquids 4–9 used([N(CF3SO2)2]

−) has not been discussed. While it might beargued that it is kept constant and hence any interactionsinvolving the anion do not change, such argument may be anoversimplification given that the cation is changing and thelargest interactions in an ionic liquid are those between thecation and the anion.36 However, given the previous evidenceof the principal interaction involving the cation,17 this is themost reasonable starting point. However, it is worth particu-larly considering the case of the ionic liquid 9, where theshielded nature of the cation may change the interactions insolution dramatically. In this case, the difference in activationparameters might be rationalised in terms of increased organi-sation of the anion around the starting materials 1 and 2 dueto decreased interactions with the hindered tetraoctylammo-nium cation. However, this is considered less likely than thepreviously presented argument, given the limited interactionsobserved previously between the anion and the startingmaterials 1 and 2.17

It is worth noting that the changes in rate constants seenspan less than an order of magnitude. Whilst this leads to asmall (ca. 5 kJ mol−1) change in activation energy and doeslimit the interpretation of activation parameters in somecases, the comparatively small uncertainties in the rate con-stant data (generally less than ca. 10%, see ESI†) give activationparameters with sufficiently small uncertainties that compari-sons can be reliably made between the values derived indifferent solvents. Further, the small uncertainties in the ratedata allow clear comparisons of solvent effects to be made;relative to acetonitrile, the rate constant for the reaction ofspecies 1 and 2 remains unchanged in ionic liquids 6 and 7,increases by a factor of ca. 2 in ionic liquids 4, 5 and 8 anddecreases by a factor of ca. 3 in the ionic liquid 9.

In combination, all of the results presented demonstrateone point clearly: the interactions between the cation of theionic liquid 4 and pyridine 2 responsible for the rate accelera-tion of the reaction between reagents 1 and 2 are not depen-dent on a particular specific interaction with a given structuralcomponent of the cation. Rather, any change in rate con-stants observed is dependent on the accessibility of thecharged centre and the ability for generalised electrostaticinteractions between the nucleophile 2 and the cation of theionic liquid. This is perhaps not surprising given the previousevidence that parallels ionic liquid effects with those of‘regular’ salts.15

The above arguments are supported by molecular dynamicssimulations involving the ionic liquids 4 and 5. Carried out as

described previously,16,17 these simulations show that thecybotactic region occupied by the cation of the ionic liquid 5about the nucleophile 2 (see Fig. S1, ESI†) is similar to thatobserved previously in the case of the dialkylimidazoliumionic liquid 4.17 That is, there exists a concave cybotacticregion of the cation about the electron rich nitrogen atom ofthe nucleophile 2. Further, the radial distribution functions ofthe centres of masses of each of the cations of each of theionic liquids 4 and 5 with respect to the pyridinic nitrogen arevery similar (see ESI, Fig. S2†).¶

Ideally, the equivalent organisational profiles of pyridine 2about the cations of the ionic liquids 4 and 5 would be avail-able. However, the requirement to model an infinitely dilutesolution (such that the reagents do not significantly changethe nature of the solvent) makes obtaining such profiles com-putationally prohibitive. Rather, the organisation of the anionabout the cation in each of the ionic liquids 4 and 5 (Fig. 2)was considered as indicative of the interaction of an electronrich species with the cation of the solvent in each case.

It is worth noting the changes in the cybotactic regionsabout the imidazolium cation on going from the dialkylimida-zolium ionic liquid 4 to the trialkylimidazolium ionic liquid 5.For the dialkylimidazolium cation, anionic cybotactic regionsare located near the hydrogen atoms at the 2-, 4- and 5-posi-tions as well as above and below the imidazolium ring, whichis consistent with what has previously been demonstrated inthe literature.37–39 The effect of introducing a methyl group atthe 2-position of the cation is clear in the organisation profileof the anion about the cation of ionic liquid 5 where the order-ing initially present at the 2-position is absent. Instead, newanionic cybotactic regions are found on either side of the2-methyl substituent, which indicates that there are still electro-static interactions present near the 2-position but they areoffset to either side of the 2-methyl substituent.

Fig. 2 Organisation of the [N(SO2CF2)2]− anion (based on the nitrogen centre)

about the cation of either ionic liquid 4 (left) or 5 (right). Configurations werepre-equilibrated and final trajectories were obtained at 400 K over 4 ns with 2 fstimesteps. The probability densities shown above have a probability cut-offof 0.007.

¶It may be of interest to also consider molecular dynamics simulations to deter-mine and organisation of the ionic liquid about the transition state. However,given the difficulty in reliably modelling such, as the transition state has beenshown by kinetic experiments to vary in nature between molecular solvents andthe fact that the interactions with the starting material dominate,14 this was notconsidered.

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Given these simulations, the negligible changes observed inthe activation parameters for the reaction outlined inScheme 1 suggest that the effect of replacing a hydrogen atomby a methyl substituent at the 2-position of the imidazoliumcation of an ionic liquid is to simply shift the surface availablefor electrostatic interactions with the electron-rich nucleophile2. Electrostatic potential surface mapping of the cations sup-ports this argument (see Fig. S3, ESI†), given that the electrondeficient region localised at the hydrogen atom at the 2-posi-tion of the dialkylimidazolium cation is simply displaced ontothe nearby regions upon substitution by a methyl group. Thatis, the charge remains accessible for interaction with thenucleophile 2 and the electrostatic interactions responsible forthe rate acceleration on moving to the ionic liquid 4 remain inthe ionic liquid 5.

These simulations also provide insight into the interactionsof the anions of the ionic liquids 4 and 5, and by inference thenucleophile 2, with the cations near the C-4 and C-5 positions.Importantly, these interactions are off-set from the C–H bondaxis at each position, towards the nucleophile.k This suggestsan interaction with the electron deficient nitrogen centresrather than the hydrogen atoms attached to the C4 and C-5positions. It is reasonable to suggest methylation at these posi-tions would block this interaction. Ideally, similar organi-sational profiles would be produced for the anions about thealkylated cations in ionic liquids 6 and 7 to confirm this.Unfortunately, force field parameters are not readily availablefor these cations.

A key outcome of the work presented is that altering thecation of the ionic liquid does not alter the outcome of thereaction between benzyl bromide 1 and pyridine 2, providedthat the positive charge remains accessible. This is significantas it means that the effects observed in ionic liquids based on[Bmim]+ can be extended to other ionic liquids, includingthose based on pyrrolidinium cations. As such, an ionic liquidthat might be appealing to use for other reasons (viscosity,cost, etc.) can be confidently substituted for one alreadystudied.

Conclusions

Modifying the cation of an ionic liquid has been shown to notaffect the outcome of the reaction between benzyl bromide 1and pyridine 2, providing that the charge remains available tointeract with the nucleophilic nitrogen of the reagent 2. Thisshows that the interactions responsible for the rate accelera-tions observed on moving from a molecular solvent to one ofthe ionic liquids 4, 5 and 8 cannot be localised to specific siteson the cation and are of a generalised electrostatic nature. Assuch, provided it is known whether the electron deficientcentres on the cation of an ionic liquid are accessible or not,

the effects of a given ionic liquid on the reaction discussedhere can be readily predicted.

Acknowledgements

HMY acknowledges the support of the Australian governmentthrough the receipt of an Australian Postgraduate Award. EELTacknowledges the support of Cochlear through the receipt ofan Undergraduate Award in Chemistry. AKC is grateful to theRoyal Society for the award of a Travel Grant. JBH acknowl-edges financial support from the University of New SouthWales Goldstar Grants Programme and the AustralianResearch Council Discovery Project Funding Scheme (ProjectDP130102331).

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Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 6170–6175 | 6175

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