ORIGINAL PAPER

DFT studies of the conversion of four mesylate estersduring reaction with ammonia

Andrzej Nowacki amp Karol Sikora amp

Barbara Dmochowska amp Andrzej Wiśniewski

Received 1 January 2013 Accepted 20 March 2013 Published online 10 April 2013 The Author(s) 2013 This article is published with open access at Springerlinkcom

Abstract The energetics of the Menshutkin-like reactionbetween four mesylate derivatives and ammonia have beencomputed using B3LYP functional with the 6-31+G basisset Additionally MPW1K6-31+G level calculationswere carried out to estimate activation barrier heights inthe gas phase Solvent effect corrections were computedusing PCMB3LYP6-31+G level The conversion of thereactant complexes into ion pairs is accompanied by a strongenergy decrease in the gas phase and in all solvents The ionpairs are stabilized with two strong hydrogen bonds in the gasphase The bifurcation at C2 causes a significant activationbarrier increase Also bifurcation at C5 leads to noticeablebarrier height differentiation Both B3LYP6-31+G andMPW1K6-31+G activation barriers suggest the reaction 2(2a+NH3) to be the fastest in the gas phase The reaction 4 isthe slowest one in all environments

Keywords Ammonium salts DFTcalculations

Menshutkin-like reaction Nucleophilic substitution THFconformation

Introduction

Menshutkin was the first scientist to describe the reactionleading to the formation of quaternary ammonium salts(QASs) [1] In Menshutkinrsquos classical method (theMenshutkin reaction MR) an alkyl halide (an electrophile)is treated with a tertiary heterocyclic amine (acting as anucleophile) The MR has been used to obtain QASs fromdifferent classes of organic compounds Twenty years after

Menshutkinrsquos original work Fisher and Raske proved itsusefulness for the synthesis of N-glycopyranosyl quaternarysalts [2]

Detailed studies of the MR have answered the questionsregarding both the mechanistic aspects of this reaction andthe experimental conditions required for it to occur Now wehave a profound understanding of the factors influencingthis reaction the solvent the nucleophile and the leavinggroup It has been established that polar solvents stabilizeboth the transition state and the ionic products therebyspeeding up the reaction In contrast to polar solvents theMR is dramatically retarded in less polar media

The alkyl halide can be replaced by a sulfonate esterwhich leads to a reaction analogous to the classical MRThis kind of reaction has been used to synthesize N-glycoammonium and N-glycopyridinium tosylates [3ndash7]

The classical MR has been the subject of extensive the-oretical study [8ndash20] at first the reaction between ammoniaand methyl halide was mostly explored in this way Such asimple model enables calculations to be performed in boththe gas phase and in solution Recently however thanks tothe increase in computational efficiency a significantly ex-tended model has been used for the calculations [19]

Our group has long been interested in the synthesisof quaternary aminium salts [3ndash6] via the halide andsulfonate ester derivatives of monosugars and alditolsIn recent years we have been concentrating on thetheoretical aspects of the reaction between sulfonateesters and tertiary amines both aliphatic and heterocy-clic [21ndash23] In continuation of our theoretical studieswe now present the results concerning the ammonia-assisted conversion of four mesylate derivatives Sur-prisingly no theoretical studies of the reaction betweenammonia and sulfonate esters have yet been carriedout in contrast to the classical MR The structuresstudied and the IUPAC names of the three mesylates

A Nowacki () K Sikora B Dmochowska A WiśniewskiFaculty of Chemistry University of Gdańsk Sobieskiego 1880-952 Gdańsk Polande-mail anowackichemunivgdapl

J Mol Model (2013) 193015ndash3026DOI 101007s00894-013-1835-7

are shown in Fig 1 The salts under discussion areanalogues of (+)-muscarine the principal alkaloid insome poisonous fungi There has been a resurgence ofinterest in muscarine in recent years following thediscovery of a relationship between a cholinergic deficitand the pathology of Alzheimerrsquos disease [24] We alsodid the calculations for the conversion of methylmesylate Our aim was to produce a kinetic and ther-modynamic description of this type of modified MRAs before we also wanted to assess the influence ofthe branching three bonds distant from the reactioncenter (the methyl or methoxy group bound to C5 ofthe THF ring is cis-oriented in relation to C1) Withthis work we have completed the review of differentnucleophilic agents typically used in the classic variantof the MR

Computational details

All the calculated structures were prepared in theMOLDEN program [25] The geometries were thenoptimized using density functional theory (DFT) basedon Beckersquos three-parameter hybrid exchange functional[26] involving the gradient-corrected correlation func-tional of Lee Yang and Parr [27] with the split-valence basis set including polarized and diffuse func-tions [28 29] mdash (B3LYP6-31+G method) Optimi-zations for reactant complexes and transition states wereadditionally done using the MPW1K6-31+G method[30] This functional (Pedrew-Wang 1-parameter modelfor kinetics MPW1K) gives remarkably accurate activa-tion barrier heights The optimization was consideredsatisfactory if the energy difference between optimiza-tion cycles was less than 1times10minus6 Hartree and a gradientof lt1times10minus4 au was achieved The convergence of allthe systems studied was checked by harmonic vibration-al analysis No imaginary frequencies were observed forthe ground state and there was only one for the transi-tion state

Solvent effects were included in the calculationsemploying the self-consistent reaction field SCRF-PCM solvation model [31] for the reactions studied inchloroform (isin=49) and water (isin=7839) at theB3LYP6-31+G level Implicit solvent calculationsimply the generation of a vacuum cavity inside acontinuous and homogeneous dielectric field In PCMmodel the cavity is built up by a series of interlockingatomic spheres We used UA0 with scale factor alpha=12for water and 14 for chloroform [18] Individual spheres werecentered on acidic hydrogen atoms

All DFT calculations were done with the aid of theGaussian 03 program [32]

Results and discussion

General characteristic of the reaction pathway

The studied reactions together with atom numbering orderare shown in Scheme 1 The atom numbering orderpresented in Scheme 1 is not compatible with the namesshown in Fig 1 and IUPAC recommendations but we use itin order to make the presentation of our results clearer

Reaction 1 is closely related to the classical MR differingonly in the leaving group We carried out calculations forthis reaction to compare the influence of leaving groupexchange on the reaction

The next two reactions (2 and 3) involve anhydroalditolswhereas the last one (4) relates to the glycoside The spatialarrangement of the aglycone (here the OCH3 group) inrelation to the THF ring in glycosides is governed by thesteric factor and by the so-called exo-anomeric effect Thiseffect forces the aglycone to be located in a position wherean acute torsion angle is formed in relation to the endocyclicoxygen atom This requirement is satisfied in two orien-tations minussc and +sc (Fig 2) but the steric hindrancepresent in the +sc conformation disqualifies it so thepreferred one is minussc

The H3CndashO5ndashC5ndashO2 torsion angle ranges from minus65deg tominus82deg all along the reaction pathway (Table 1) However this isnot a golden rule since we showed previously that in thereaction of mesylate derivative 4a with a bulky trimethylaminethe minussc orientation of the methoxyl group appeared to beunfavorable because of steric hindrance and thus changed toap [21]

The steps of the reactions under discussion are analogousto those reported previously [21ndash23] The energy (E0) andpseudochemical potential (U0) [33] profiles for the conver-sion of the mesylates into the corresponding ammoniumsalts (Fig 3) in the gas phase and in solvents consists ofan asymmetric double-well potential with five stationarypoints corresponding to the separated reactants (R)reactant complex (RC) transition state (TS) productcomplex (PC) and separated ionic products (P) Tworeactants (electrophile mdash mesylate derivative and nu-cleophile mdash ammonia) approach one another forming avan der Waals reactant complex This complex convertsinto an ionic pair which requires an activation barrier tobe overcome Finally the constituents of the ionic pairare separated to an infinitely great distance The maindifference between the energy diagrams shown in Fig3and those presented elsewhere [21ndash23] is on the productside Previously the last stage of the reaction was endergonicin the gas phase and in chloroform whereas it was exergonicin polar solvents In the reactions being studied here separa-tion of the ion pair constituents requires the application energyin the gas phase and in all solvents

3016 J Mol Model (2013) 193015ndash3026

Gas-phase calculations

Table 1 lists the activation and reaction energies forboth the gas state and solutions together with importantgeometrical parameters of all the stationary points onPES A scaling factor of 09877 was used for the zero-point vibrational energy (ZPVE) correction of the cal-culated total energies [34]

To discuss the conformational details of the THF ring theAltonandashSundaralingam (AS) pseudorotational phase angle(P) and the AS puckering amplitude (ϕm) were considered[35 36] The THF ring conformations P and ϕm values aregiven in Table 2 together with the set of the endocyclictorsion angles ϕ0ndashϕ4 whereas the definition of these anglesis shown in Fig 4 The conformational descriptors that weadopted differ from the classical ones because of the

different atom numbering scheme Table 2 also lists twotorsion angles (χ) describing the spatial disposition of theexocyclic groups

The calculated geometries together with selected bonddistances valence angles and relative energies correspond-ing to all the stationary points along the reaction pathwayare presented in Figs 5 and 6 The relative energies refer tothe sum of the separate reactant energies

The first point on the energy curves (Fig 3) correspondsto the separate reactants ie mesylate derivative and am-monia In the case of reaction 2 (Table 2) the THF ring takesthe E4 conformation (P=349deg ϕm=36deg) in which C1 atomis in the pseudo-equatorial position (χ1=minus1445deg) Thesame ring conformation is found for the individualmesylate in reaction 4 (P=336deg ϕm=36deg) whereasthe 4E conformation is observed for the separate

Scheme 1 Reactions ofammonium salt formation

Fig 1 Structures of mesylatederivatives converted intoammonium salts

J Mol Model (2013) 193015ndash3026 3017

mesylate in reaction 3 (P=155deg ϕm=minus36deg) The E4 con-formation is free of 13-diaxial-like steric interactions and theeclipsed orientation of the substituents as we described pre-viously [23] The mesylate C1 atom in reaction 4 is in thepseudo-equatorial orientation (χ1=minus1385deg) whereas theOCH3 group is in the pseudo-axial position (χ2=846deg) Thusthe THF ring avoids the unfavorable 13-diaxial-like stericinteractions between these two groups The THF ring inreaction 3 bears two bulky substituents on the same side ofthe ring hence two reverse conformations should be consid-ered namely those in which the C1 or C6 atom is in thepseudo-equatorial orientation (the 3E or 4E conformation re-spectively) Both conformations have features thought to sta-bilize five-membered rings because they hold two bulkygroups moved away from one another avoiding steric repul-sion and there are no eclipse orientations of any substituentsin the THF ring According to the B3LYP functional 4Econformation that with the pseudo-equatorially located CH3

group (χ2=1567deg) and pseudo-axially oriented CH2OMsgroup (χ1=minus1007deg) is more stable by about 1 kcal molminus1

The next point on the energy diagrams represents thereactant complex In all the cases studied the approach ofthe individual reactants is accompanied by a slight energydecrease (Table 1 Figs 5 and 6) in the gas phase Gibbs freeenergies however predict that reactant complex formationwill be unfavorable (ΔG=50ndash62 kcal molminus1)

The small value of the complexation energy(minus29 kcal molminus1 minus22 kcal molminus1 minus21 kcal molminus1

and minus24 kcal molminus1 for 1a 2a 3a and 4a respective-ly) indicates that the interaction (hydrogen bond) be-tween these two molecules in this complex isrelatively weak The intermolecular interaction be-tween mesylate and ammonia in reactant complexesis slightly stronger than the one for trimethylamine[21] and comparable with that for pyridine [22 23]This may be related to the type of intermolecularinteraction A typical SndashOHndashN hydrogen bond stabilizesthe reactant complex in these reactions whereas an atypicalSndashOHndashC hydrogen bond interaction was observed for thereactions with trimethylamine [21] After decades of the con-troversy on whether OHndashC hydrogen bonds really exist it isaccepted now that they do exist although OHndashC hydrogenbonds are mostly weak in comparison with classical ones [37] T

able

1Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

oftherelevant

stationary

pointson

thePESin

thegasph

aseat

B3L

YP6-31+

G

calculated

forreactio

ns1ndash4

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

R(CO)

1450

1461

2060

3619a

infin1458

1470

2059

3430a

infin1458

1470

2069

3451a

infin1458

1470

2057

3466

ainfin

R(CN)

infin3488

1932

1483

1516

infin3482

2077

1490

1519

infin3480

2078

1489

1519

infin3489

2068

1489

1521

ΔR

ndashinfin

minus2027

0128

2136

infinminusinfin

minus2012

minus0011

1940

infinminusinfin

minus2010

minus0009

1962

infin-infin

minus2019

minus0011

1977

infin

angOCN

1000

1788

381

a

967

1573

453a

945

1642

447

a

964

1628

439

a

A

minus669

minus637

minus130

1732

1610

minus733

minus710

04

1723

1587

minus673

minus649

minus159

1730

1632

B

1633

1784

1795

1762

C

minus663

minus653

minus643

minus693

minus818

ΔE

00

minus29

293

minus125

1052

00

minus22

288

minus152

940

00

minus21

292

minus149

934

00

minus24

308

minus147

944

ΔG

00

50

382

minus41

1043

00

58

386

minus57

936

00

62

388

minus56

930

00

58

413

minus50

938

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ionpairand(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

Fig 2 Rotamers exhibiting possible spatial arrangements of the OCH3

group in relation to the heterocyclic oxygen atom The preferredorientation is in the box

3018 J Mol Model (2013) 193015ndash3026

The shape of the THF ring does not change whilereactants are approaching one another The E4 confor-mation is observed for THF ring in reactant complexes2a and 4a whereas the 4E conformation is noted in 3a(Table 2) A noteworthy fact is that in reaction 4 twodifferent conformations (E4 for the separate mesylateand 2E for the reactant complex) were preferred forthe THF ring when the conversion with pyridine wasbeing studied and described [23]

The next stationary point on the energy curve shown inFig 3 corresponds to the transition state The relativeenergy values matching the transition states with respect tothe separated reactants are given in Table 1 and in Figs 5and 6 whereas the activation barriers relating to the reactantcomplexes are listed in Table 3

The geometry of the relevant transition state can becharacterized by the CO and CN distances OCN

valence angles and two torsion angles (A B Table 1)Whereas the CO and CN distances are roughly the samein all TSs (about 206 Aring and 208 Aring respectively) the CNdistance in reaction 1 is much shorter (193 Aring)

Table 1 and Fig 5 indicate that the transition state forreaction 1 is linear the valence angle OCN being1788deg The other three TSs are slightly bent the citedvalence angle ranging from sim156deg to sim164deg which is theresult of the steric hindrance

The approach of the ammonia molecule to C1 induces achange in the OndashC1ndashC2ndashC3 torsion angle (Table 1) In thereactant complex this angle is about minus65deg whereas in thetransition state it takes values of minus130deg 04deg and minus159deg forreactions 2 3 and 4 respectively The observed differencesin values of the torsion angle come from the variation of theTHF ring conformation The preferred conformation of theTHF ring in the transition state corresponding to conversions 2

Fig 3 Energy (E0) and pseudochemical potential (U0) profiles for reactions 1ndash4 calculated at B3LYP6-31+G level in the gas phase chloroform and water

J Mol Model (2013) 193015ndash3026 3019

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

are shown in Fig 1 The salts under discussion areanalogues of (+)-muscarine the principal alkaloid insome poisonous fungi There has been a resurgence ofinterest in muscarine in recent years following thediscovery of a relationship between a cholinergic deficitand the pathology of Alzheimerrsquos disease [24] We alsodid the calculations for the conversion of methylmesylate Our aim was to produce a kinetic and ther-modynamic description of this type of modified MRAs before we also wanted to assess the influence ofthe branching three bonds distant from the reactioncenter (the methyl or methoxy group bound to C5 ofthe THF ring is cis-oriented in relation to C1) Withthis work we have completed the review of differentnucleophilic agents typically used in the classic variantof the MR

Computational details

All the calculated structures were prepared in theMOLDEN program [25] The geometries were thenoptimized using density functional theory (DFT) basedon Beckersquos three-parameter hybrid exchange functional[26] involving the gradient-corrected correlation func-tional of Lee Yang and Parr [27] with the split-valence basis set including polarized and diffuse func-tions [28 29] mdash (B3LYP6-31+G method) Optimi-zations for reactant complexes and transition states wereadditionally done using the MPW1K6-31+G method[30] This functional (Pedrew-Wang 1-parameter modelfor kinetics MPW1K) gives remarkably accurate activa-tion barrier heights The optimization was consideredsatisfactory if the energy difference between optimiza-tion cycles was less than 1times10minus6 Hartree and a gradientof lt1times10minus4 au was achieved The convergence of allthe systems studied was checked by harmonic vibration-al analysis No imaginary frequencies were observed forthe ground state and there was only one for the transi-tion state

Solvent effects were included in the calculationsemploying the self-consistent reaction field SCRF-PCM solvation model [31] for the reactions studied inchloroform (isin=49) and water (isin=7839) at theB3LYP6-31+G level Implicit solvent calculationsimply the generation of a vacuum cavity inside acontinuous and homogeneous dielectric field In PCMmodel the cavity is built up by a series of interlockingatomic spheres We used UA0 with scale factor alpha=12for water and 14 for chloroform [18] Individual spheres werecentered on acidic hydrogen atoms

All DFT calculations were done with the aid of theGaussian 03 program [32]

Results and discussion

General characteristic of the reaction pathway

The studied reactions together with atom numbering orderare shown in Scheme 1 The atom numbering orderpresented in Scheme 1 is not compatible with the namesshown in Fig 1 and IUPAC recommendations but we use itin order to make the presentation of our results clearer

Reaction 1 is closely related to the classical MR differingonly in the leaving group We carried out calculations forthis reaction to compare the influence of leaving groupexchange on the reaction

The next two reactions (2 and 3) involve anhydroalditolswhereas the last one (4) relates to the glycoside The spatialarrangement of the aglycone (here the OCH3 group) inrelation to the THF ring in glycosides is governed by thesteric factor and by the so-called exo-anomeric effect Thiseffect forces the aglycone to be located in a position wherean acute torsion angle is formed in relation to the endocyclicoxygen atom This requirement is satisfied in two orien-tations minussc and +sc (Fig 2) but the steric hindrancepresent in the +sc conformation disqualifies it so thepreferred one is minussc

The H3CndashO5ndashC5ndashO2 torsion angle ranges from minus65deg tominus82deg all along the reaction pathway (Table 1) However this isnot a golden rule since we showed previously that in thereaction of mesylate derivative 4a with a bulky trimethylaminethe minussc orientation of the methoxyl group appeared to beunfavorable because of steric hindrance and thus changed toap [21]

The steps of the reactions under discussion are analogousto those reported previously [21ndash23] The energy (E0) andpseudochemical potential (U0) [33] profiles for the conver-sion of the mesylates into the corresponding ammoniumsalts (Fig 3) in the gas phase and in solvents consists ofan asymmetric double-well potential with five stationarypoints corresponding to the separated reactants (R)reactant complex (RC) transition state (TS) productcomplex (PC) and separated ionic products (P) Tworeactants (electrophile mdash mesylate derivative and nu-cleophile mdash ammonia) approach one another forming avan der Waals reactant complex This complex convertsinto an ionic pair which requires an activation barrier tobe overcome Finally the constituents of the ionic pairare separated to an infinitely great distance The maindifference between the energy diagrams shown in Fig3and those presented elsewhere [21ndash23] is on the productside Previously the last stage of the reaction was endergonicin the gas phase and in chloroform whereas it was exergonicin polar solvents In the reactions being studied here separa-tion of the ion pair constituents requires the application energyin the gas phase and in all solvents

3016 J Mol Model (2013) 193015ndash3026

Gas-phase calculations

Table 1 lists the activation and reaction energies forboth the gas state and solutions together with importantgeometrical parameters of all the stationary points onPES A scaling factor of 09877 was used for the zero-point vibrational energy (ZPVE) correction of the cal-culated total energies [34]

To discuss the conformational details of the THF ring theAltonandashSundaralingam (AS) pseudorotational phase angle(P) and the AS puckering amplitude (ϕm) were considered[35 36] The THF ring conformations P and ϕm values aregiven in Table 2 together with the set of the endocyclictorsion angles ϕ0ndashϕ4 whereas the definition of these anglesis shown in Fig 4 The conformational descriptors that weadopted differ from the classical ones because of the

different atom numbering scheme Table 2 also lists twotorsion angles (χ) describing the spatial disposition of theexocyclic groups

The calculated geometries together with selected bonddistances valence angles and relative energies correspond-ing to all the stationary points along the reaction pathwayare presented in Figs 5 and 6 The relative energies refer tothe sum of the separate reactant energies

The first point on the energy curves (Fig 3) correspondsto the separate reactants ie mesylate derivative and am-monia In the case of reaction 2 (Table 2) the THF ring takesthe E4 conformation (P=349deg ϕm=36deg) in which C1 atomis in the pseudo-equatorial position (χ1=minus1445deg) Thesame ring conformation is found for the individualmesylate in reaction 4 (P=336deg ϕm=36deg) whereasthe 4E conformation is observed for the separate

Scheme 1 Reactions ofammonium salt formation

Fig 1 Structures of mesylatederivatives converted intoammonium salts

J Mol Model (2013) 193015ndash3026 3017

mesylate in reaction 3 (P=155deg ϕm=minus36deg) The E4 con-formation is free of 13-diaxial-like steric interactions and theeclipsed orientation of the substituents as we described pre-viously [23] The mesylate C1 atom in reaction 4 is in thepseudo-equatorial orientation (χ1=minus1385deg) whereas theOCH3 group is in the pseudo-axial position (χ2=846deg) Thusthe THF ring avoids the unfavorable 13-diaxial-like stericinteractions between these two groups The THF ring inreaction 3 bears two bulky substituents on the same side ofthe ring hence two reverse conformations should be consid-ered namely those in which the C1 or C6 atom is in thepseudo-equatorial orientation (the 3E or 4E conformation re-spectively) Both conformations have features thought to sta-bilize five-membered rings because they hold two bulkygroups moved away from one another avoiding steric repul-sion and there are no eclipse orientations of any substituentsin the THF ring According to the B3LYP functional 4Econformation that with the pseudo-equatorially located CH3

group (χ2=1567deg) and pseudo-axially oriented CH2OMsgroup (χ1=minus1007deg) is more stable by about 1 kcal molminus1

The next point on the energy diagrams represents thereactant complex In all the cases studied the approach ofthe individual reactants is accompanied by a slight energydecrease (Table 1 Figs 5 and 6) in the gas phase Gibbs freeenergies however predict that reactant complex formationwill be unfavorable (ΔG=50ndash62 kcal molminus1)

The small value of the complexation energy(minus29 kcal molminus1 minus22 kcal molminus1 minus21 kcal molminus1

and minus24 kcal molminus1 for 1a 2a 3a and 4a respective-ly) indicates that the interaction (hydrogen bond) be-tween these two molecules in this complex isrelatively weak The intermolecular interaction be-tween mesylate and ammonia in reactant complexesis slightly stronger than the one for trimethylamine[21] and comparable with that for pyridine [22 23]This may be related to the type of intermolecularinteraction A typical SndashOHndashN hydrogen bond stabilizesthe reactant complex in these reactions whereas an atypicalSndashOHndashC hydrogen bond interaction was observed for thereactions with trimethylamine [21] After decades of the con-troversy on whether OHndashC hydrogen bonds really exist it isaccepted now that they do exist although OHndashC hydrogenbonds are mostly weak in comparison with classical ones [37] T

able

1Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

oftherelevant

stationary

pointson

thePESin

thegasph

aseat

B3L

YP6-31+

G

calculated

forreactio

ns1ndash4

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

R(CO)

1450

1461

2060

3619a

infin1458

1470

2059

3430a

infin1458

1470

2069

3451a

infin1458

1470

2057

3466

ainfin

R(CN)

infin3488

1932

1483

1516

infin3482

2077

1490

1519

infin3480

2078

1489

1519

infin3489

2068

1489

1521

ΔR

ndashinfin

minus2027

0128

2136

infinminusinfin

minus2012

minus0011

1940

infinminusinfin

minus2010

minus0009

1962

infin-infin

minus2019

minus0011

1977

infin

angOCN

1000

1788

381

a

967

1573

453a

945

1642

447

a

964

1628

439

a

A

minus669

minus637

minus130

1732

1610

minus733

minus710

04

1723

1587

minus673

minus649

minus159

1730

1632

B

1633

1784

1795

1762

C

minus663

minus653

minus643

minus693

minus818

ΔE

00

minus29

293

minus125

1052

00

minus22

288

minus152

940

00

minus21

292

minus149

934

00

minus24

308

minus147

944

ΔG

00

50

382

minus41

1043

00

58

386

minus57

936

00

62

388

minus56

930

00

58

413

minus50

938

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ionpairand(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

Fig 2 Rotamers exhibiting possible spatial arrangements of the OCH3

group in relation to the heterocyclic oxygen atom The preferredorientation is in the box

3018 J Mol Model (2013) 193015ndash3026

The shape of the THF ring does not change whilereactants are approaching one another The E4 confor-mation is observed for THF ring in reactant complexes2a and 4a whereas the 4E conformation is noted in 3a(Table 2) A noteworthy fact is that in reaction 4 twodifferent conformations (E4 for the separate mesylateand 2E for the reactant complex) were preferred forthe THF ring when the conversion with pyridine wasbeing studied and described [23]

The next stationary point on the energy curve shown inFig 3 corresponds to the transition state The relativeenergy values matching the transition states with respect tothe separated reactants are given in Table 1 and in Figs 5and 6 whereas the activation barriers relating to the reactantcomplexes are listed in Table 3

The geometry of the relevant transition state can becharacterized by the CO and CN distances OCN

valence angles and two torsion angles (A B Table 1)Whereas the CO and CN distances are roughly the samein all TSs (about 206 Aring and 208 Aring respectively) the CNdistance in reaction 1 is much shorter (193 Aring)

Table 1 and Fig 5 indicate that the transition state forreaction 1 is linear the valence angle OCN being1788deg The other three TSs are slightly bent the citedvalence angle ranging from sim156deg to sim164deg which is theresult of the steric hindrance

The approach of the ammonia molecule to C1 induces achange in the OndashC1ndashC2ndashC3 torsion angle (Table 1) In thereactant complex this angle is about minus65deg whereas in thetransition state it takes values of minus130deg 04deg and minus159deg forreactions 2 3 and 4 respectively The observed differencesin values of the torsion angle come from the variation of theTHF ring conformation The preferred conformation of theTHF ring in the transition state corresponding to conversions 2

Fig 3 Energy (E0) and pseudochemical potential (U0) profiles for reactions 1ndash4 calculated at B3LYP6-31+G level in the gas phase chloroform and water

J Mol Model (2013) 193015ndash3026 3019

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

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WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

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15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

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26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

Gas-phase calculations

Table 1 lists the activation and reaction energies forboth the gas state and solutions together with importantgeometrical parameters of all the stationary points onPES A scaling factor of 09877 was used for the zero-point vibrational energy (ZPVE) correction of the cal-culated total energies [34]

To discuss the conformational details of the THF ring theAltonandashSundaralingam (AS) pseudorotational phase angle(P) and the AS puckering amplitude (ϕm) were considered[35 36] The THF ring conformations P and ϕm values aregiven in Table 2 together with the set of the endocyclictorsion angles ϕ0ndashϕ4 whereas the definition of these anglesis shown in Fig 4 The conformational descriptors that weadopted differ from the classical ones because of the

different atom numbering scheme Table 2 also lists twotorsion angles (χ) describing the spatial disposition of theexocyclic groups

The calculated geometries together with selected bonddistances valence angles and relative energies correspond-ing to all the stationary points along the reaction pathwayare presented in Figs 5 and 6 The relative energies refer tothe sum of the separate reactant energies

The first point on the energy curves (Fig 3) correspondsto the separate reactants ie mesylate derivative and am-monia In the case of reaction 2 (Table 2) the THF ring takesthe E4 conformation (P=349deg ϕm=36deg) in which C1 atomis in the pseudo-equatorial position (χ1=minus1445deg) Thesame ring conformation is found for the individualmesylate in reaction 4 (P=336deg ϕm=36deg) whereasthe 4E conformation is observed for the separate

Scheme 1 Reactions ofammonium salt formation

Fig 1 Structures of mesylatederivatives converted intoammonium salts

J Mol Model (2013) 193015ndash3026 3017

mesylate in reaction 3 (P=155deg ϕm=minus36deg) The E4 con-formation is free of 13-diaxial-like steric interactions and theeclipsed orientation of the substituents as we described pre-viously [23] The mesylate C1 atom in reaction 4 is in thepseudo-equatorial orientation (χ1=minus1385deg) whereas theOCH3 group is in the pseudo-axial position (χ2=846deg) Thusthe THF ring avoids the unfavorable 13-diaxial-like stericinteractions between these two groups The THF ring inreaction 3 bears two bulky substituents on the same side ofthe ring hence two reverse conformations should be consid-ered namely those in which the C1 or C6 atom is in thepseudo-equatorial orientation (the 3E or 4E conformation re-spectively) Both conformations have features thought to sta-bilize five-membered rings because they hold two bulkygroups moved away from one another avoiding steric repul-sion and there are no eclipse orientations of any substituentsin the THF ring According to the B3LYP functional 4Econformation that with the pseudo-equatorially located CH3

group (χ2=1567deg) and pseudo-axially oriented CH2OMsgroup (χ1=minus1007deg) is more stable by about 1 kcal molminus1

The next point on the energy diagrams represents thereactant complex In all the cases studied the approach ofthe individual reactants is accompanied by a slight energydecrease (Table 1 Figs 5 and 6) in the gas phase Gibbs freeenergies however predict that reactant complex formationwill be unfavorable (ΔG=50ndash62 kcal molminus1)

The small value of the complexation energy(minus29 kcal molminus1 minus22 kcal molminus1 minus21 kcal molminus1

and minus24 kcal molminus1 for 1a 2a 3a and 4a respective-ly) indicates that the interaction (hydrogen bond) be-tween these two molecules in this complex isrelatively weak The intermolecular interaction be-tween mesylate and ammonia in reactant complexesis slightly stronger than the one for trimethylamine[21] and comparable with that for pyridine [22 23]This may be related to the type of intermolecularinteraction A typical SndashOHndashN hydrogen bond stabilizesthe reactant complex in these reactions whereas an atypicalSndashOHndashC hydrogen bond interaction was observed for thereactions with trimethylamine [21] After decades of the con-troversy on whether OHndashC hydrogen bonds really exist it isaccepted now that they do exist although OHndashC hydrogenbonds are mostly weak in comparison with classical ones [37] T

able

1Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

oftherelevant

stationary

pointson

thePESin

thegasph

aseat

B3L

YP6-31+

G

calculated

forreactio

ns1ndash4

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

R(CO)

1450

1461

2060

3619a

infin1458

1470

2059

3430a

infin1458

1470

2069

3451a

infin1458

1470

2057

3466

ainfin

R(CN)

infin3488

1932

1483

1516

infin3482

2077

1490

1519

infin3480

2078

1489

1519

infin3489

2068

1489

1521

ΔR

ndashinfin

minus2027

0128

2136

infinminusinfin

minus2012

minus0011

1940

infinminusinfin

minus2010

minus0009

1962

infin-infin

minus2019

minus0011

1977

infin

angOCN

1000

1788

381

a

967

1573

453a

945

1642

447

a

964

1628

439

a

A

minus669

minus637

minus130

1732

1610

minus733

minus710

04

1723

1587

minus673

minus649

minus159

1730

1632

B

1633

1784

1795

1762

C

minus663

minus653

minus643

minus693

minus818

ΔE

00

minus29

293

minus125

1052

00

minus22

288

minus152

940

00

minus21

292

minus149

934

00

minus24

308

minus147

944

ΔG

00

50

382

minus41

1043

00

58

386

minus57

936

00

62

388

minus56

930

00

58

413

minus50

938

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ionpairand(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

Fig 2 Rotamers exhibiting possible spatial arrangements of the OCH3

group in relation to the heterocyclic oxygen atom The preferredorientation is in the box

3018 J Mol Model (2013) 193015ndash3026

The shape of the THF ring does not change whilereactants are approaching one another The E4 confor-mation is observed for THF ring in reactant complexes2a and 4a whereas the 4E conformation is noted in 3a(Table 2) A noteworthy fact is that in reaction 4 twodifferent conformations (E4 for the separate mesylateand 2E for the reactant complex) were preferred forthe THF ring when the conversion with pyridine wasbeing studied and described [23]

The next stationary point on the energy curve shown inFig 3 corresponds to the transition state The relativeenergy values matching the transition states with respect tothe separated reactants are given in Table 1 and in Figs 5and 6 whereas the activation barriers relating to the reactantcomplexes are listed in Table 3

The geometry of the relevant transition state can becharacterized by the CO and CN distances OCN

valence angles and two torsion angles (A B Table 1)Whereas the CO and CN distances are roughly the samein all TSs (about 206 Aring and 208 Aring respectively) the CNdistance in reaction 1 is much shorter (193 Aring)

Table 1 and Fig 5 indicate that the transition state forreaction 1 is linear the valence angle OCN being1788deg The other three TSs are slightly bent the citedvalence angle ranging from sim156deg to sim164deg which is theresult of the steric hindrance

The approach of the ammonia molecule to C1 induces achange in the OndashC1ndashC2ndashC3 torsion angle (Table 1) In thereactant complex this angle is about minus65deg whereas in thetransition state it takes values of minus130deg 04deg and minus159deg forreactions 2 3 and 4 respectively The observed differencesin values of the torsion angle come from the variation of theTHF ring conformation The preferred conformation of theTHF ring in the transition state corresponding to conversions 2

Fig 3 Energy (E0) and pseudochemical potential (U0) profiles for reactions 1ndash4 calculated at B3LYP6-31+G level in the gas phase chloroform and water

J Mol Model (2013) 193015ndash3026 3019

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

mesylate in reaction 3 (P=155deg ϕm=minus36deg) The E4 con-formation is free of 13-diaxial-like steric interactions and theeclipsed orientation of the substituents as we described pre-viously [23] The mesylate C1 atom in reaction 4 is in thepseudo-equatorial orientation (χ1=minus1385deg) whereas theOCH3 group is in the pseudo-axial position (χ2=846deg) Thusthe THF ring avoids the unfavorable 13-diaxial-like stericinteractions between these two groups The THF ring inreaction 3 bears two bulky substituents on the same side ofthe ring hence two reverse conformations should be consid-ered namely those in which the C1 or C6 atom is in thepseudo-equatorial orientation (the 3E or 4E conformation re-spectively) Both conformations have features thought to sta-bilize five-membered rings because they hold two bulkygroups moved away from one another avoiding steric repul-sion and there are no eclipse orientations of any substituentsin the THF ring According to the B3LYP functional 4Econformation that with the pseudo-equatorially located CH3

group (χ2=1567deg) and pseudo-axially oriented CH2OMsgroup (χ1=minus1007deg) is more stable by about 1 kcal molminus1

The next point on the energy diagrams represents thereactant complex In all the cases studied the approach ofthe individual reactants is accompanied by a slight energydecrease (Table 1 Figs 5 and 6) in the gas phase Gibbs freeenergies however predict that reactant complex formationwill be unfavorable (ΔG=50ndash62 kcal molminus1)

The small value of the complexation energy(minus29 kcal molminus1 minus22 kcal molminus1 minus21 kcal molminus1

and minus24 kcal molminus1 for 1a 2a 3a and 4a respective-ly) indicates that the interaction (hydrogen bond) be-tween these two molecules in this complex isrelatively weak The intermolecular interaction be-tween mesylate and ammonia in reactant complexesis slightly stronger than the one for trimethylamine[21] and comparable with that for pyridine [22 23]This may be related to the type of intermolecularinteraction A typical SndashOHndashN hydrogen bond stabilizesthe reactant complex in these reactions whereas an atypicalSndashOHndashC hydrogen bond interaction was observed for thereactions with trimethylamine [21] After decades of the con-troversy on whether OHndashC hydrogen bonds really exist it isaccepted now that they do exist although OHndashC hydrogenbonds are mostly weak in comparison with classical ones [37] T

able

1Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

oftherelevant

stationary

pointson

thePESin

thegasph

aseat

B3L

YP6-31+

G

calculated

forreactio

ns1ndash4

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

R(CO)

1450

1461

2060

3619a

infin1458

1470

2059

3430a

infin1458

1470

2069

3451a

infin1458

1470

2057

3466

ainfin

R(CN)

infin3488

1932

1483

1516

infin3482

2077

1490

1519

infin3480

2078

1489

1519

infin3489

2068

1489

1521

ΔR

ndashinfin

minus2027

0128

2136

infinminusinfin

minus2012

minus0011

1940

infinminusinfin

minus2010

minus0009

1962

infin-infin

minus2019

minus0011

1977

infin

angOCN

1000

1788

381

a

967

1573

453a

945

1642

447

a

964

1628

439

a

A

minus669

minus637

minus130

1732

1610

minus733

minus710

04

1723

1587

minus673

minus649

minus159

1730

1632

B

1633

1784

1795

1762

C

minus663

minus653

minus643

minus693

minus818

ΔE

00

minus29

293

minus125

1052

00

minus22

288

minus152

940

00

minus21

292

minus149

934

00

minus24

308

minus147

944

ΔG

00

50

382

minus41

1043

00

58

386

minus57

936

00

62

388

minus56

930

00

58

413

minus50

938

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ionpairand(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

Fig 2 Rotamers exhibiting possible spatial arrangements of the OCH3

group in relation to the heterocyclic oxygen atom The preferredorientation is in the box

3018 J Mol Model (2013) 193015ndash3026

The shape of the THF ring does not change whilereactants are approaching one another The E4 confor-mation is observed for THF ring in reactant complexes2a and 4a whereas the 4E conformation is noted in 3a(Table 2) A noteworthy fact is that in reaction 4 twodifferent conformations (E4 for the separate mesylateand 2E for the reactant complex) were preferred forthe THF ring when the conversion with pyridine wasbeing studied and described [23]

The next stationary point on the energy curve shown inFig 3 corresponds to the transition state The relativeenergy values matching the transition states with respect tothe separated reactants are given in Table 1 and in Figs 5and 6 whereas the activation barriers relating to the reactantcomplexes are listed in Table 3

The geometry of the relevant transition state can becharacterized by the CO and CN distances OCN

valence angles and two torsion angles (A B Table 1)Whereas the CO and CN distances are roughly the samein all TSs (about 206 Aring and 208 Aring respectively) the CNdistance in reaction 1 is much shorter (193 Aring)

Table 1 and Fig 5 indicate that the transition state forreaction 1 is linear the valence angle OCN being1788deg The other three TSs are slightly bent the citedvalence angle ranging from sim156deg to sim164deg which is theresult of the steric hindrance

The approach of the ammonia molecule to C1 induces achange in the OndashC1ndashC2ndashC3 torsion angle (Table 1) In thereactant complex this angle is about minus65deg whereas in thetransition state it takes values of minus130deg 04deg and minus159deg forreactions 2 3 and 4 respectively The observed differencesin values of the torsion angle come from the variation of theTHF ring conformation The preferred conformation of theTHF ring in the transition state corresponding to conversions 2

Fig 3 Energy (E0) and pseudochemical potential (U0) profiles for reactions 1ndash4 calculated at B3LYP6-31+G level in the gas phase chloroform and water

J Mol Model (2013) 193015ndash3026 3019

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

The shape of the THF ring does not change whilereactants are approaching one another The E4 confor-mation is observed for THF ring in reactant complexes2a and 4a whereas the 4E conformation is noted in 3a(Table 2) A noteworthy fact is that in reaction 4 twodifferent conformations (E4 for the separate mesylateand 2E for the reactant complex) were preferred forthe THF ring when the conversion with pyridine wasbeing studied and described [23]

The next stationary point on the energy curve shown inFig 3 corresponds to the transition state The relativeenergy values matching the transition states with respect tothe separated reactants are given in Table 1 and in Figs 5and 6 whereas the activation barriers relating to the reactantcomplexes are listed in Table 3

The geometry of the relevant transition state can becharacterized by the CO and CN distances OCN

valence angles and two torsion angles (A B Table 1)Whereas the CO and CN distances are roughly the samein all TSs (about 206 Aring and 208 Aring respectively) the CNdistance in reaction 1 is much shorter (193 Aring)

Table 1 and Fig 5 indicate that the transition state forreaction 1 is linear the valence angle OCN being1788deg The other three TSs are slightly bent the citedvalence angle ranging from sim156deg to sim164deg which is theresult of the steric hindrance

The approach of the ammonia molecule to C1 induces achange in the OndashC1ndashC2ndashC3 torsion angle (Table 1) In thereactant complex this angle is about minus65deg whereas in thetransition state it takes values of minus130deg 04deg and minus159deg forreactions 2 3 and 4 respectively The observed differencesin values of the torsion angle come from the variation of theTHF ring conformation The preferred conformation of theTHF ring in the transition state corresponding to conversions 2

Fig 3 Energy (E0) and pseudochemical potential (U0) profiles for reactions 1ndash4 calculated at B3LYP6-31+G level in the gas phase chloroform and water

J Mol Model (2013) 193015ndash3026 3019

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

and 4 is 3T4 (P=2deg ϕm=39deg and P=358deg ϕm=40deg for 2 and 4respectively Table 2) This conformation is free of theeclipsed orientation of the substituents and 13-diaxial-likesteric interactions (in reaction 4) as C1 is moved away fromthe THF ring (χ1=minus154deg Table 2) In consequence the MsOleaving group is also located beside the THF ring In reac-tion 3 the THF ring adopts the 4T3 conformation (P=174degϕm=minus37deg) in which the C6 atom is moved away from thering (χ2=153deg Table 2) In this conformation the MsOleaving group is located above the THF ring

The C2ndashC1ndashH1andashH1b deformation torsion angle (B Table 1)reflects the planar placing of substituents at the C1 atom in thetransition state This indicates that the transition state geometry isexactly halfway between the reactant and product complex forreactions 2 3 and 4 whereas the late transition state is observedfor reaction 1

The calculated barriers are higher than those for the re-actions with trimethylamine [21] and pyridine [22 23]which corresponds to the lower basicity of ammonia in avacuum (Fig 7) The proton affinity of ammonia is2040 kcal molminus1 but is 2251 kcal molminus1 and2208 kcal molminus1 for trimethylamine and pyridine respec-tively [38] The energy barrier is the lowest for reaction 2but the highest for reaction 4 Interestingly the energybarrier for reaction 1 is higher than for reactions 2 and 3according to both B3LYP and MPW1K methods Thisstands in contrast to the reactions of the same mesylatederivatives with other nucleophiles studied earlier [21ndash23]where the barrier was the lowest for the reaction of methylmesylate with the corresponding nucleophile (Fig 7) Pre-sumably hydrogen bond formation between the endocyclic

oxygen atom and the hydrogen atom attached to the nitrogenatom stabilizes the transition state geometry Such an inter-action cannot occur in reaction 1

The second minimum on the reaction pathway corre-sponds to ion pairs Both ΔE and ΔG predict that theconversion of the reactant complexes to the respective ionpairs is accompanied by an energy decrease in the gas phaseThis effect is smallest in reaction 1 and the energy of the ionpair 1b is ca 10 kcal molminus1 lower than that of the reactantcomplex Interestingly ΔE and ΔG at this stage wereexpected to be unfavorable for the reaction of methylmesylate and pyridine [22] On the other hand ion pairformation was slightly favorable (ΔE=minus15 kcal molminus1)when trimethylamine was the nucleophile [21] The conver-sion of complexes into ion pairs is rather more favorable forthe remaining three reactions (about 12 kcal molminus1) than forreaction 1 The constituents of ion pair 1b are oriented insuch a way that the whole geometry has the Cs symmetry(Fig 8) with two carbons oxygen sulfur and nitrogenbeing planar The anion and the cation are held togetherdue to two strong hydrogen bonds which may be

Table 2 Selected torsion anglesand calculated values of thepseudorotational phase angle (P)and of the puckering amplitude(ϕm) of the THF ring for all sta-tionary points for conversions 2ndash4

aDefinition of the torsion anglesϕ0 ndash C5ndashC4ndashC3ndashC2 ϕ1 ndash C4ndashC3ndashC2ndashO2 ϕ2 ndash C3ndashC2ndashO2ndashC5 ϕ3 ndash C2ndashO2ndashC5ndashC4 ϕ4 ndashO2ndashC5ndashC4ndashC3 χ1 ndash C1ndashC2ndashC3ndashC4 χ2 ndash RndashC5ndashC4ndashC3where R represents the substitu-ent attached to C5

P ϕm ϕ0 ϕ1 ϕ2 ϕ3 ϕ4 χ1 χ2

Reaction 2

R E4 349 36 356 minus260 52 182 minus336 minus1445 RC E4 345 36 352 minus241 23 208 minus349 minus1426 TS 3T4 2 39 391 minus334 143 110 minus316 minus1545 IP 3T4 4 36 362 minus319 146 91 minus287 minus1506 P 3T4 2 36 365 minus311 134 104 minus295 minus1481 Reaction 3

R 4E 155 minus36 minus330 186 44 minus258 363 minus985 1562

RC 4E 151 minus37 minus320 165 70 minus278 368 minus1007 1567

TS 4T3 174 minus37 minus371 285 minus84 minus154 327 minus923 1530

IP E5 117 minus39 minus177 minus50 279 minus394 345 minus1232 1540

P 4E 149 minus37 minus313 148 85 minus285 365 minus1015 1561

Reaction 4

R E4 336 36 328 minus193 minus31 247 minus357 minus1383 846

RC E4 337 36 330 minus198 minus25 242 minus355 minus1389 848

TS 3T4 358 40 397 minus318 113 143 minus339 minus1540 860

IP E4 342 36 345 minus223 05 220 minus352 minus1421 849

P E4 334 37 334 minus183 minus47 261 minus368 minus1364 820

Fig 4 Definition of the endocyclic torsion angles ϕ0ndashϕ4

3020 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

responsible for the stronger stability of the ion pairSuch interactions are also found in the ion pairs formedin the other reactions studied

In ion pair 2b the THF ring has the 3T4 conforma-tion (P=4deg ϕm=36deg) as in the corresponding transitionstate whereas in ion pair 3b the almost ideal E5 conformationof the THF ring (P=117deg ϕm=minus39deg) is preferred (Table 2)This means that a conformational change occurs on goingdownhill from the energy maximum to the valley In the caseof reaction 4 the THF ring adopts the same conformation as inthe reactant complex ie E4 (P=342deg ϕm =36deg)

The last stage of the reactions studied consists in theseparation of the ion pair constituents Again this pro-cess is extremely unfavorable in the gas phase Morethan 90 kcal molminus1 in relation to the sum of the ener-gies of the individual reactants must be supplied tomove the ions to an infinite distance from one another(Table 1) Ion pair dissociation is more endoenergetichere than it was in the reactions with trimethylamineand pyridine [21ndash23]

Calculations in solution (SCRF-PCM)

Tomasirsquos polarizable continuum model (PCM) was used toinvestigate the influence of the liquid phase on the course ofthe reactions under scrutiny [31] The PCM model permits

the self-consistent computation of free energies of solvationincluding polarized solutesolvent interactions and non-electrostatic terms in the Hamiltonian On the other hand itshould be emphasized that reaction field models are incapa-ble of modeling specific (short range) solutesolvent inter-actions that is those occurring in the first solvation sphereThus the conclusions drawn based on the calculationswhere such interactions occur should be interpreted withcare Although PCM operates better in aprotic solvents ithas also been used to predict the solvation effect in proticsolvents [15 39]

Keeping in mind the limitations of the implicit sol-vent models PCM approach was applied to both mini-mum energy structures and saddle point configurationsIn our previous papers [23] we showed that almost theentire solvent effect is achieved after single point PCMcalculations and no significant energy changes wereobserved during the optimization in water Moreoverwe showed that the TS geometry changes were not soprofound as those experienced with the classicalMenshutkin reaction [17 40] Although previously westudied the solvent effect in three solvents this time wedecided to carry out full optimization only in two sol-vents that is chloroform and water We resigned fromdoing the calculation in ethanol because energy changesin ethanol and water were roughly the same

Fig 5 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 1 and 2 in the gas phaseSelected distances in Aring and valence angles in degrees

J Mol Model (2013) 193015ndash3026 3021

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

The results of calculations in chloroform and in water arelisted in Table 4 whereas Fig 9 illustrates the geometries ofthe transition states optimized in water

Significant changes in the energy diagrams are observedalong the reaction path in both solvents as compared withthe gas phase (Fig 3) especially on the product side Inchloroform a solvent of low polarity the energy sum of theseparated ions decreases dramatically but the overall pro-cess is still endothermic relative energy ranges from23 kcal molminus1 (reactions 2 and 3) to almost 29 kcal molminus1

(reaction 1) with respect to individual reactants (Table 4)The Gibbs free energy also predicts the process to be slight-ly unfavorable (ΔGasymp4 kcal molminus1) In very polar solvent inturn the reactions are exothermic and favorable The ener-gies of the separated ions are less than those of the individ-ual reactants by about minus2 kcal molminus1 (reaction 1) and about5 kcal molminus1 for other reactions

According to the ΔU0 values complexation is slightlyexothermic in chloroform (Table 4) On the other hand ΔGsindicate that this step of the reaction is strongly unfavorableabout 6 kcal molminus1 on average must be supplied to form thereactant complex Also in water medium the reactant complexformation is unfavorable It means that interactions betweenthe constituents of the reactant complex are rather weak Thesame conclusions were drawn previously [21ndash23]

Castejon et al [17] studied the relationship between thestability of the reactant complexes (and ion pairs as well)and solvent polarity for the Menshutkin reaction Theynoticed that neither the reactant complex nor the ion pairwere energy minima in very polar solvents like dimethylsulfoxide However in our case they appeared to be realenergy minima in water although certain geometry differ-ences were observed The geometries of reactant complexesand ion pairs are roughly the same within the mesylatederivatives in the gas phase and in water However thereactant complexes differ in the relative positions of theirconstituents The CN distance is 3488 Aring on average inthe gas phase whereas in water it is much longer about37 Aring The reactant complexes and ion pairs formed in thereactions under discussion owe their stability to the hydro-gen bonds formed between H and O atoms from the nucle-ophile and mesylate moiety respectively

BothΔU0 and ΔG showed that ion pair formation was anexoenergetic process in solvents with respect to the reactantcomplex as in a vacuum In reaction 1 taking place in chlo-roform the decrease in energy is minus129 kcal molminus1 (ΔG)whereas in water the conversion of the reactant complex intothe ion pair is more exoenergetic (minus168 kcal molminus1) than inchloroform The free energy changes accompanying ion pairformation in the other three reactions are roughly the same

Fig 6 Geometries of the stationary points and ΔE (kcal molminus1) computed at the B3LYP6-31+G level for reactions 3 and 4 in the gas phaseSelected distances in Aring and valence angles in degrees

3022 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

(about minus14 kcal molminus1 and 17 kcal molminus1 in chloroform andwater respectively) as for the reaction 1

Optimization of transition states in chloroform leads torather insignificant geometry changes These changes arethe greatest for the reaction 1 where the CO distancedecreases from 2060 Aring in the gas phase to 1967 Aring inchloroform and the CN distance increases from 1932 Aringto 2040 Aring (Table 4) This means that the transition state isshifted toward an earlier stage of the reaction For the otherthree reactions the transition state geometry changes areeven less

In turn more significant changes in transition state ge-ometry in relation to the gas phase take place duringoptimization in water especially for reactions 1 and 4 Inreaction 1 the CO distance decreases to 1909 Aring whereasthe CN distance increases to 2113 Aring with respect to thevalues found in the gas phase Analogous geometry changesin transition state geometries occur for reactions 2 and 3however here the CO distance decreases by about 005 Aringwhereas the CN distance increases by about 01 Aring Thedescribed geometrical changes are not as profound as in theclassical Menshutkin reaction [17 40] Like in chloroformthese geometrical changes shifts transition states back to anearlier stage of the reaction

Apart from the geometry changes at the reactioncenter there is an additional variation of the transitionstates in reactions 2ndash4 particularly in water In reaction2 the OndashC1ndashC2ndashC3 torsion angle (A Table 4) increasesfrom minus130deg in the gas phase to 538deg in water Thevalue is similar for reaction 3 (432deg) whereas forconversion 4 it is 60deg This indicates that in two TSs(reactions 2 and 3) the leaving group is shifted abovethe THF ring Rotation about the C1ndashC2 bond inducesthe ring conformation switch (4T3 rarr E5) in reaction 3In reactions 2 and 4 the THF ring conformation changesare not significant (3T4 rarr E4)

It is well recognize that the transfer from the gas phase tosolvent leads to a significant energy barrier drop Indeed theB3LYP level barriers calculated in both solvents are muchlower than those calculated for the gas phase In the case ofthe reaction 1 occurring in chloroform calculated barrier islower by about 8 kcal molminus1 whereas in water it is ca13 kcal molminus1 less For the other three reactions the differ-ences between barriers in the gas phase and in solvents aresignificantly lower For the reaction 4 barriers are lower byabout 5 kcal molminus1 and 8 kcal molminus1 in chloroform andwater respectively

A different barriers height order is found in the gas phaseand in solvents In the gas phase the lowest barrier wasfound for the reaction 2 In turn for the reaction 1 takingplace in chloroform the barrier is by about 3 kcal molminus1

lower than for the reaction 2 The difference between barrierheight are even greater in water This may suggest thathydrogen bond stabilizing TS in the gas phase is weakerin solvents

Like in the gas phase also in solvents the barrier heightdepends on the type of the substituent at C5 The presenceof a spatial group attached to this carbon atom slightlyincreases the barrier although the differences are rathersmall in chloroform It is difficult to judge which reaction2 or 3 should be faster based on the free energy barrierscalculated in water

The transfer from the gas phase to the solvent leadsto a significant energy drop in the final step of thesereactions While separating the ion pair constituents re-quires about 100 kcal molminus1 (ΔG) in a vacuum inchloroform over 30 kcal molminus1 need to be supplied toaccomplish this step of the reaction In water in turnonly about 5 kcal molminus1 are required

Table 3 Activation energies calculated for the conversion of reactantcomplexes 1a 2a 3a and 4a in the gas phase All energy values inkcal molminus1

B3LYP6-31+G MPW1K6-31+G

ΔEDagger ΔGDagger ΔEDagger ΔGDagger

Reaction 1 3222 3313 3478 3562

Reaction 2 3098 3279 3388 3561

Reaction 3 3126 3266 3410 3603

Reaction 4 3318 3550 3617 3873

Fig 7 Comparison of activation barriers for reactions 1 and 2 withdifferent nucleophiles in the gas phase

Fig 8 Geometry of the ion pair in reaction 1

J Mol Model (2013) 193015ndash3026 3023

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

Tab

le4

Geometry

parametersrelativ

eenergies

andrelativ

eGibbs

free

energies

ofrelevant

stationary

pointson

theFESatB3L

YP6-31+

G

calculated

forreactio

ns1ndash

4in

chloroform

andwater

Reaction1

Reaction2

Reaction3

Reaction4

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

(R)

(RC)

(TS)

(IP)

(P)

Chloroform

R(CO)

145

1146

1196

7364

6ainfin

145

9146

9200

3343

1ainfin

145

9147

0202

5358

6ainfin

145

9146

92011

358

5ainfin

R(CN)

infin350

6204

0148

8150

0infin

353

1215

6149

0151

6infin

353

4214

4149

2151

4infin

351

5213

9149

2151

6

ΔR

minusinfin

minus204

5minus007

3215

8infin

minusinfin

minus206

2minus015

3194

1infin

minusinfin

minus206

4minus0119

209

4infin

minusinfin

minus204

6minus012

8209

3infin

angOCN

10

01

1771

395a

971

1656

453

a

93

616

45

421

a

96

216

40

417

a

A

minus66

7minus63

9minus54

1732

1643

8minus73

3minus70

993

1690

1624

minus67

0minus64

5minus10

217

34

1681

B

17

55

1745

1755

1766

C

minus67

0minus66

1minus64

9minus70

4minus76

5

ΔU0

00

minus15

227

minus15

628

700

minus11

259

minus17

023

100

minus09

268

minus17

323

200

minus11

278

minus16

924

5

ΔG

00

69

320

minus60

285

00

69

363

minus73

232

00

82

379

minus71

239

00

73

379

minus69

243

ΔU0Dagger

243

270

277

289

ΔGDagger

251

294

296

307

Water

R(CO)

145

4146

2190

9346

0ainfin

146

1146

7200

8369

1ainfin

146

1146

9201

3364

9ainfin

146

1146

7198

0365

4ainfin

R(CN)

infin359

82113

149

5150

6infin

376

1216

4149

5151

0infin

369

1217

8149

5150

9infin

368

6220

5149

6151

0

ΔR

minusinfin

minus213

6minus020

4196

5infin

minusinfin

minus229

4minus015

6219

6infin

minusinfin

minus222

2minus016

5215

4infin

minusinfin

minus221

9minus022

5215

8infin

angOCN

10

09

1767

456a

992

1635

411

a

90

116

28

420

a

95

016

52

416

a

A

minus66

0minus66

753

817

13

1677

minus72

2minus73

143

216

72

1640

minus67

0minus64

960

1741

1709

B

17

49

1783

1773

1697

C

minus66

9minus67

1minus65

0minus67

8minus71

8

ΔU0

00

minus02

184

minus18

7minus25

00

minus01

238

minus20

4minus53

00

minus01

238

minus20

4minus54

00

minus01

247

minus19

9minus45

ΔG

00

76

285

minus92

minus27

00

76

349

minus114

minus52

00

72

344

minus91

minus55

00

71

348

minus10

3minus49

ΔU0Dagger

186

239

239

248

ΔGDagger

209

272

272

277

Allenergy

values

inkcal

mol

minus1Rin

Aringandangles

indeg

ReactioncoordinateΔR=R(CO)-R(CN)The

smallestvalueof

thedistance

betweenCandO

was

takento

define

thereactio

ncoordinate(R)separate

reactants(RC)reactant

complex(TS)

transitio

nstate(IP)ndashionpair(P)separate

ions

Atorsionangle

(OndashC

1ndashC2ndash

C3)

forRRCandTS

(NndashC

1ndashC2ndash

C3)

forIP

andP

InRthistorsionanglecorrespo

ndsto

mesylatewhereas

inPthisanglecorrespo

ndsto

thecatio

n

Bdeform

ationangleC2ndash

C1ndash

H1 andashH

1 b(for

thereactio

n1

HndashC

ndashHandashHb)describing

theplanarity

ofthetransitio

nstategeom

etry

Ctorsionangledefining

thepo

sitio

nof

theaglycone

inrelatio

nto

THFring

(H3CndashO

ndashC5ndash

O2)

atheO

atom

closestto

thereactio

ncenter

carbon

atom

was

used

toob

tain

thisvalue

3024 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

Conclusions

In this work we continued our DFT study into ammoniumsalt formation in a Menshutkin-like reaction between am-monia and four mesylate derivatives methyl mesylate (1a)(S)-14-andydro-23-dideoxy-5-O-mesylpentitol (2a)(2S5S)-25-andydro-134-trideoxy-6-O-mesylhexitol (3a)and methyl 23-dideoxy-5-O-mesyl-β-D-pentofuranoside(4a) The reactions were investigated using the B3LYPfunctional with the 6-31+G basis set in the gas phaseand in solvents Additionally MPW1K6-31+G level cal-culations were carried out to estimate activation barrierheights Apart from that the reactions were studied in twosolvents (chloroform and water) using the PCM model

The energy diagrams presented in Fig 3 exhibit twominima corresponding to the reactant complex and the ionpair in the gas phase Clearly ion pairs are more stable thanthe respective reactant complexes but this is not a goldenrule For example in the reaction between methyl mesylateand pyridine the reactant complex is more stable The twostrong hydrogen bonds formed between the mesylate anionand the ammonium cation are responsible for the extraordi-nary stability of the ion pair with respect to the individualreactants The ion pair stability is even greater in solventsThis unusual stabilization of ion pairs causes the final stepof the reaction to be endergonic in solvents

Energy and Gibbs free energy values indicate that theoverall process is highly unfavorable in the gas phase Inchloroform it is still unfavorable but in more polar solventsthe sum of the energies of the individual ions is less than thatof the separate reactants

According to B3LYP and MPW1K functionals the ener-gy barrier is the lowest for reaction 2 and not reaction 1 incontrast to the reactions with trimethylamine or pyridineHowever reaction 1 should be the fastest one in solventsused in the calculations In turn reaction 4 seems to be theslowest both in the gas phase and in chloroform In waterhowever the difference between calculated barriers are in-significantly small thus do not indicate univocally the reac-tion 4 to be the slowest one It should be emphasized onceagain at this place that reaction field models do notdescribe hydrogen bonding interaction which could af-fect the energetics of reactions studied thus results ofthe calculations in water should be taken with carePossibly the solution for this problem would beachieved based on the calculation of the model withdiscrete water molecule

We have also discussed the conformational behaviorof the THF ring along the reaction pathway noting thatin reactions 2 and 4 the THF ring adopts a conforma-tion from the narrow region of the northern half of thepseudorotational circle In turn the THF ring is solelyin conformations located in the southern half in reaction3 The THF ring conformation switch (4T3 rarr E5) wasobserved for the reaction 3 transition state geometryduring the optimization in water which is the result ofrotation about the C1ndashC2 bond

Acknowledgments This workwas supported byDS530-8451-D193-13All DFT calculations were carried out using the resources of the

Informatics Centre of the Metropolitan Academic Network in Gdańsk(CI TASK)

Fig 9 Geometries of thetransition states optimized at theB3LYP6-31+G level inwater Selected distances in Aringand valence angles in degrees

J Mol Model (2013) 193015ndash3026 3025

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use distribution andreproduction in any medium provided the original author(s) and thesource are credited

References

1 Menschutkin N (1890) Z Physik Chem 5589ndash6012 Fischer E Raske K (1910) Chem Ber 431750ndash17533 Pellowska-Januszek L Dmochowska B Skorupa E Chojnacki J

WojnowskiWWiśniewski A (2004) Carbohydr Res 3391537ndash15444 Skorupa E Dmochowska B Pellowska-Januszek L Wojnowski W

Chojnacki J Wiśniewski A (2004) Carbohydr Res 3392355ndash23625 Dmochowska B Skorupa E Pellowska-Januszek L Czarkowska M

Sikorski A Wiśniewski A (2006) Carbohydr Res 3411916ndash19216 Dmochowska B Skorupa E Świtecka P Sikorski A Łącka I

Milewski S Wiśniewski AJ (2009) Carbohydr Chem 28222ndash2337 Mantell SJ Ford PS Watkin DJ Fleet GWJ Brown D (1993)

Tetrahedron 493343ndash33588 Viers JW Schug JC Stovall MD Seeman JI (1984) J Comput

Chem 5598ndash6059 Solagrave M Lledoacutes A Duran M Bertraacuten J Abboud J-LM (1991) J Am

Chem Soc 1132873ndash287910 Gao J Xia X (1993) J Am Chem Soc 1159667ndash967511 Maran U Pakkanen TA Karelson M (1994) J Chem Soc Perkin

Trans 22445ndash245212 Shaik S Ioffe A Reddy AC Pross A (1994) J Am Chem Soc

116262ndash27313 Fradera X Amat L Torrent AM Mestres J Constans P Besaluacute E

Martiacute J Simon S Lobato M Oliva JM Luis JM Andreacutes M Solagrave MCarboacute R DuranM (1996) J Mol Struct (THEOCHEM) 371171ndash183

14 Truong TN Truong T-TT Stefanovich EV (1997) J Chem Phys1071881ndash1889

15 Amovilli C Mennucci B Floris FM (1998) J Phys Chem B1023023ndash3028

16 Webb SP Gordon MS (1999) J Phys Chem A 1031265ndash127317 Castejon H Wiberg KB (1999) J Am Chem Soc 1212139ndash214618 Poater J Solagrave M Duran M Fradera X (2001) J Phys Chem A

1056249ndash625719 Faacutebiaacuten A Ruff F Farkas Ouml (2008) J Phys Org Chem 21988ndash99620 Acevedo O Jorgensen WL (2010) J Phys Chem B 1148425ndash843021 Nowacki A Dmochowska B Jączkowska E Sikora K

Wiśniewski A (2011) Comput Theor Chem 97353ndash6122 Nowacki A Dmochowska B Sikora K Madaj J Wiśniewski A

(2012) Comput Theor Chem 98685ndash92

23 Nowacki A Sikora K Dmochowska B Wiśniewski A (2012)Comput Theor Chem 100033ndash41

24 Wu ESC Griffith RC Loch JT III Kover A Murray RJ MullenGB Blosser JC Machulskis AC McCreedy SA (1995) J MedChem 381558ndash1570

25 Schaftenaar G Noordik JH (2000) J Comput Aided Mol Des14123ndash134

26 Becke AD (1993) J Chem Phys 985648ndash565227 Lee C Yang W Parr RG (1988) Phys Rev B 37785ndash78928 Hehre WJ Ditchfield R Pople JA (1972) J Chem Phys 562257ndash

226129 Clark T Chandrasekhar J Spitznagel GW von Ragueacute Schleyer P

(1983) J Comp Chem 4294ndash30130 Lynch BJ Fast PL Harris M Truhlar DG (2000) J Phys Chem A

1044811ndash481531 Tomasi J Persico M (1994) Chem Rev 942027ndash209432 Frisch MJ Trucks GW Schlegel HB Scuseria GE Robb MA

Cheeseman JR Montgomery JA Jr Vreven T Kudin KNBurant JC Millam JM Iyengar SS Tomasi J Barone VMennucci B Cossi M Scalmani G Rega N Petersson GANakatsuji H Hada M Ehara M Toyota K Fukuda RHasegawa J Ishida M Nakajima T Honda Y Kitao O NakaiH Klene M Li X Knox JE Hratchian HP Cross JB BakkenV Adamo C Jaramillo J Gomperts R Stratmann RE YazyevO Austin AJ Cammi R Pomelli C Ochterski JW Ayala PYMorokuma K Voth GA Salvador P Dannenberg JJZakrzewski VG Dapprich S Daniels AD Strain MC FarkasO Malick DK Rabuck AD Raghavachari K Foresman JBOrtiz JV Cui Q Baboul AG Clifford S Cioslowski JStefanov BB Liu G Liashenko A Piskorz P Komaromi IMartin RL Fox DJ Keith T Al-Laham MA Peng CYNanayakkara A Challacombe M Gill PMW Johnson B ChenW Wong MW Gonzalez C Pople JA (2004) Gaussian 03revision E01 Gaussian Inc Wallingford

33 Kim Y Mohring JR Truhlar DG (2010) J Am Chem Soc13211071ndash11082

34 Andersson MP Uvdal P (2005) J Phys Chem A 1092937ndash294135 Altona C Sundaralingam M (1972) J Am Chem Soc 948205ndash

821236 Houseknecht JB Altona C Hadad CM Lowary TL (2002) J Org

Chem 674647ndash465137 Koch U Popelier PLA (1995) J Phys Chem 999747ndash975438 Lias SG Lieberman JF Levin RD (1984) J Phys Chem Ref Data

13695ndash80839 Martiacutenez AG Vilar ET Barcina JO de la Moya Cerero S (2005) J

Org Chem 7010238ndash1024640 Acevedo O Jorgensen WL (2010) Acc Chem Res 43142ndash151

3026 J Mol Model (2013) 193015ndash3026