Proton Transfer at the Carboxylic Sitesof Amino Acids: A Single WaterMolecule Catalyzed Process

GANG YANG,1,2 XIAOMIN WU,1 YUANGANG ZU,1 CHENGBU LIU,2

YUJIE FU,1 LIJUN ZHOU1

1Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University,Harbin 150040, People’s Republic of China2Institute of Theoretical Chemistry, Shandong University, Jinan 250100, People’s Republic of China

Received 18 March 2008; accepted 22 April 2008Published online 15 August 2008 in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/qua.21797

ABSTRACT: Ab initio calculations at MP2 level of theory were used to study theproton transfer at the carboxylic sites of amino acids, in the isolated, mono- and di-hydrated forms. In the case of water dimer, two interaction modes with glycine neutralstructures (see Fig. 3) were explored, corresponding to the concerted and stepwisereaction pathways. Their transition states can be described as (H2OOHOOH2)� [Fig.4(a)] and (H2O---HOOH2)� [Fig. 4(b)], respectively. The energy analysis indicated thatthe concerted pathway is preferred. In the isolated, mono- and di-hydrated glycinecomplexes, the activation barriers of the proton transfer at the carboxylic sites werecalculated to be 34.49, 16.59, and 13.36 kcal mol�1, respectively. It was thus shown thatthe proton transfer is significantly assisted and catalyzed by water monomer so that itcan take place at room temperature. Instead, the further addition of water moleculesplays solvent effects rather than catalytic effects to this proton transfer process. Theabove results obtained with discrete water molecules were supported by the solventcontinuum calculated data. It was also observed that the heavy dependence of thesolvent continuum models on dipole moments may produce misleading results.© 2008 Wiley Periodicals, Inc. Int J Quantum Chem 109: 320–327, 2009

Key words: ab initio calculations; amino acids; water catalysis; proton transfer;solvent effects

Correspondence to: Y. Zu; e-mail: theobiochem@gmail.comContract grant sponsor: Major State Basic Research Develop-

ment Programs.Contract grant number: No. 2004CB719902.Contract grant sponsor: Talented Funds of Northeast For-

estry University.Contract grant number: 220–602042.

International Journal of Quantum Chemistry, Vol 109, 320–327 (2009)© 2008 Wiley Periodicals, Inc.

Introduction

T he carboxylic sites of proteins have been im-plicated in varieties of important chemical and

biological processes [1–5]. The active sites for cat-ions to link in biological pumps and cation channelsare usually the carboxylic O atoms [1]. In sarcoplas-mic reticulum Ca2� ATPase, the carboxylic groupsof Glu58 and Glu908 residues are protonated insolution at neutral pH, forming hydrogen-bondnetworks and thus providing extra stabilities forthe Ca2�-binding sites [4]. For the Zn2�-dependentfuculose aldolase, its catalytic effects are closelyrelated to the deprotonation and protonation dy-namics of the carboxylic site in the Glu73 residue[5]. The water molecules nearby are involved in theformation of hydrogen-bonded networks; in addi-tion, they can participate in the proton transferprocesses [6].

Glycine has been extensively used as the modelsto investigate peptides and proteins [7–35]. To date,the conformations of the (neutral) gas-phase gly-cine have been well understood at molecular level[7, 16, 30]. The protonated [8, 19], deprotonated [11,35], and radical [23, 35] forms of glycine are clear tous as well. However, the understanding of the pro-ton transfer processes is far lagged behind, espe-cially in the presence of solvents [6, 9, 13, 15, 21, 27,29]. Glycine zwitterion (abbreviated as ZW) is notstable in gas phase [21] and two water moleculesnearby can make it geometrically stable [13]. Com-bining the solvent continuum models and MP2/6–31�G(d,p) level of theory, it was found that the ZWconformer is more stable than the neutral conform-ers and that the energy barrier of the C07ZWtautomerization in Scheme 1(a) was calculated to be2.4 kcal mol�1 [15]. It indicated that this protontransfer proceeds very fast in solution. In addition,the reliabilities of the solvent continuum calcula-tions were analyzed by the comparisons of the rel-ative stabilities between different glycine neutralconformers and the theoretical and experimentalfrequencies of the ZW conformer [15]. However,the calculated activation barrier is in apparent dis-agreement with the experimental data [36]. Tor-tonda et al. [37] ascribed the discrepancy to thecoupling between the conformational and tauto-meric equilibria in solution. That is, the most stableneutral conformers are different in gas phase and insolution (A0 in gas phase and C0 in solution, re-spectively, see Scheme 1). Almost all the previousworks were dedicated to resolving the proton trans-

fer process ZW7C0, while the important A07C0tautomerization shown in Scheme 1(b) has beenignored. It was estimated by Tortonda et al. [37]that the energy barrier for the A07C0 tautomeriza-tion is very low; however, the direct evidence islacking. The A07C0 conversion can be divided intoseveral elementary steps, i.e., the proton transferprocess A07B0 [Scheme 1(c)] and the rotations ofthe carboxylic hydroxyl and amido groups. As elab-orated in the first paragraph, the proton transferA07B0 takes place at the carboxylic sites, which iscrucial to the biological systems. In this work, theproton transfer A07B0 [Scheme 1(c)] was investi-gated using ab initio methods. The previous studieson formamide and many other systems indicated thatthe water molecules around play an important roleand assist the proton transfer processes [6, 15, 37–42].Here, the solvent effects on the present A07B0 tau-tomerization processes were considered in two differ-ent ways: (a) Interactions with one and two discretewater molecules. In the case of water dimer, variousinteraction modes between water dimer and gly-cine molecule were explored; (b) The continuummodels, which were exerted on the glycine struc-tures with zero, one and two discrete water mole-cules around. On such basis, the catalytic or solventeffects of the water molecules on the proton transferA07B0 were attempted to be clarified.

SCHEME 1. The proton transfer and tautomerizationprocesses in amino acids.

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Computational Details

All the molecular geometries were optimized atMP2 level of theory, implemented within theGaussian 98 & 03 packages [43, 44]. The structuresof reactants, products, and transition states wererepresented as An, Bn, and Tsn, respectively,where n refers to the number of water molecules.That is, A0 [Fig. 1(a)] and B0 [Fig. 1(b)] are the twoneutral conformers of glycine in the absence ofwater molecules, with their transition state denotedas Ts1 [Fig. 1(c)]. The standard 6-31G(d,p) basis setwas used to describe all the elements. Frequencycalculations at the same level of theory were per-formed to confirm that all the structures are energyminima (no imaginary frequency) or transitionstates (one characteristic imaginary frequency). Toexamine the effect of basis sets, the larger6-311��G(d,p) basis set was employed to optimizeseveral structures. As the data in Figure 1 indicated,the A0, B0, and Ts1 geometries obtained with6-31G(d,p) and 6-311��G(d,p) basis sets quite re-semble each other. The validities of 6-31G(d,p) basisset were further confirmed by the energy computa-tions. Compared with A0, the relative energies ofB0 and Ts0 were calculated to be 1.66 and 34.49 kcalmol�1 by 6-31G(d,p) basis set and 1.59 and 35.78kcal mol�1 by 6-311��G(d,p) basis set, respec-tively. Accordingly, all the present theoretical re-sults will be based on MP2/6-31G(d,p) methods.

On basis of the previous work of other research-ers [15, 33, 45, 46] and our experience [47, 48], theself-consistent reaction field polarizable continuummodel (SCRF-PCM) [49, 50] are reliable to treat thesolvent effects. The SCRF-PCM method was alsofound widely used in glycine related systems [15,33, 45, 46, 48] and will continue to be used in thiswork, combining with MP2/6-31G(d,p) methods.The structures of the solvent continuum modelswere distinguished from those of gas phase by add-ing (s) behind. That is, A0(s) and B0(s) are thestructures of A0 and B0 treated with the solventcontinuum models.

Results and Discussion

PROTON TRANSFER BETWEEN A0 AND B0

As shown in Figure 1, the acidic H6 atom wasbonded to the O5 and O4 atoms in the equilibratedstructures of A0 and B0, respectively. The C3OO4

bond in A0 and C3OO5 bond in B0 are character-istic of double bonds. Except at the carboxylic sites,the geometries of A0 and B0 are close to each other.As described in computational details section, thegeometric results are in agreement with the previ-ous and present MP2/6-311��G(d,p) results [7,35]. The transition state structure Ts between A0and B0 was shown in Figure 1(c), where the acidicH6 atom is situated in the bisector of the �

O4OC3OO5 angle. Both of the O4OH6 and O5OH6distances are about 1.30 Å and of almost equivalentvalues. The � O4OC3OO5 angle in Ts is 12.50° lessthan those in A0 or B0. As a result of the protontransfer, the C2OC3 distance is slightly affected andthe fragments farther away from the carboxylicsites nearly uninfluenced. It indicates that the pro-ton transfer at the carboxylic sites is quite a local-ized process.

The activation barrier (Eac) of the A07B0 tau-tomerization was calculated to be 34.49 and afterzero point energy (ZPE) corrections to be 31.58 kcalmol�1 (Table I). As to the reaction heat (Erh), it wascalculated at 1.66 and with ZPE corrections at 1.25kcal mol�1, which is in good agreement with theprevious MP2/6-311��G(d,p) results [7, 35].

INTERACTION WITH ONE WATER MOLECULE

As shown in A1 in Figure 2(a), two hydrogenbonds of O4OH13 and O11OH6 were formed oninteracting with one water molecule on A0 [13, 51].The O4OH13 and O11OH6 distances are equal to1.992 and 1.768 Å, respectively, which are in goodagreement with the B3LYP/6-311��G(3d,3p) val-ues of 1.969 and 1.798 Å [51] whereas show somedeviations from the HF/DZP values of 2.20 and1.90 Å [13]. The disagreements may be caused bythe absence of correlation functional in the HF the-oretical results obtained by Jensen and Gordon [13].In comparison with A0, the C3OO5 bond in A1 wasshortened by 0.02 Å whereas the C3OO4 andO5OH6 bonds were elongated by 0.013 and 0.019 Å,respectively. The geometric influences by the addi-tion of the water molecule on A0 to form A1 arerestricted to the carboxylic sites. The water additionon B0 to form B1 [Fig. 2(b)] also brings about sim-ilar geometric changes [13]. The geometric influ-ences by the addition of water monomer are alsorestricted to the carboxylic sites, see the geometricdata in Figures 1(b) and 2(b). As to the transitionstate [Ts1 in Fig. 2(c)] of the A17B1 tautomeriza-tion, it contains a H3O� ion stabilized by two hy-

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drogen bonds formed with the carboxylic sites ofglycine.

The addition of water monomer on A0 is anexothermic process with the interaction energy (Eie)calculated at �13.92 and after ZPE corrections at�11.21 kcal mol�1. The reaction heat of A17B1tautomerization (Erh) is equal to 1.69 and with ZPEcorrections equals 1.28 kcal mol�1, which is close tothe value of A07B0 and indicated that the relativestabilities of A0 to B0 are almost uninfluenced bythe presence of water monomer. It is consistentwith the geometric results that the interactingmodes of water monomer with A0 and B0 are verysimilar. Albeit the numerous similarities, the acti-

vation barrier (Eac) of the A17B1 tautomerizationis remarkably reduced to 16.59 kcal mol�1 (13.53kcal mol�1 after being ZPE corrected), 48.1%(42.8%) of the A07B0 tautomerization. The effect ofwater monomer in this proton transfer process issimilar to that of the formamide-formaidic acid tau-tomerization process [38–40]. It may be caused bythe formation of the more stable H3O� species inTs1 instead of the H� species in Ts. In Ts1, thepositive charge is more dispersed and the relativestability of this transition state is therefore muchenhanced. This viewpoint was also supported bythe much larger interaction energy of water mono-mer with Ts0 to form Ts1 (�29.27 kcal mol�1 withZPE corrections) than that with A0 to form A1(�11.21 kcal mol�1 with ZPE corrections).

TABLE I ______________________________________Water interaction energies (Eie), reaction heats (Erh),and activation barriers (Eac) for the proton transferat the carboxylic sites of glycine structures.a,b

Reaction Eie Erh Eac

A0 3B0 1.25 (1.66) 31.58 (34.49)

A1 3B1 �11.21 (�13.92) 1.28 (1.69) 13.53 (16.59)

A2c 3B2c �11.58 (�14.08) 1.10 (1.07) 11.27 (13.36)

A2s 3B2s �6.58 (�8.34) 1.36 (1.34) 9.50 (11.13)

a Energy units in kcal mol�1.b The values in parentheses are uncorrected by zero pointenergy (ZPE).

FIGURE 1. Glycine structures A0 and B0 as well as their transition state Ts. The geometric parameters in parenthe-ses were obtained by 6-311��G(d,p) basis set. [Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

FIGURE 2. Monohydrated glycine structures A1 andB1 as well as their transition state Ts1. [Color figurecan be viewed in the online issue, which is available atwww.interscience.wiley.com.]

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INTERACTION WITH TWO WATERMOLECULES

As shown in Figure 3, two interaction modeswere observed in the case of water dimer. In thefirst interaction mode, the two water molecules aresimultaneously bound to the glycine fragmentsthrough hydrogen bonding [Figs. 3(a) and (c)],which was called a concerted process. In the otherinteraction mode, the first water molecule wasfound to interact directly with the glycine frag-ments through hydrogen bonding, while the sec-ond water molecule binds to the first through hy-drogen bonding but not interact directly with theglycine fragments [Figs. 3(b) and (d)]. It was calleda stepwise mode. The structures of the concertedand stepwise reaction pathways were distinguished

by adding s and c behind, respectively. For exam-ple, A2s shown in Figure 3(b) stands for the reac-tant of the stepwise pathway. The C3OO5, C3OO4bonds and the 208 O5OC3OO4 angle were opti-mized at 1.326, 1.233 Å, and 125.70° in A2c and1.337, 1.230 Å, and 124.61° in A2s, respectively. Itindicated that the geometric parameters of glycinein A2s are rather close to those in A0 or A1 whereasgeometric differences were observed between A2cand A0 (or A1). That is, the glycine geometries weredisturbed by the addition of the second water mol-ecule in the concerted processes whereas not in thestepwise processes. This conclusion was supportedby the structural analysis on B2c [Fig. 3(c)] and B2s[Fig. 3(d)]. The structure of A2c was previouslyobtained by Jensen et al. [13] at HF/DZP theoreticallevel, where the geometric parameters are in somedisagreements with the present work. It may becaused by the absence of correlation functional inthe HF methods as discussed earlier in the case ofwater monomer. Whether to the concerted or step-wise process, the addition of the second water mol-ecule is a localized behavior and causes negligiblegeometric differences on the glycine fragments ex-cept at the carboxylic sites, similar to the situationsof water monomer.

As given in Table I, the interaction energies ofthe second water molecule (Eie) on A1 to form A2cand A2s were calculated to be �14.08 (�11.58 withZPE corrections) and �8.34 kcal mol�1 (�6.58 kcalmol�1 with ZPE corrections), respectively. Accord-ingly, the addition of the second water moleculewill proceed in the concerted pathway. The data ofreaction heats (Erh) in Table I showed that the rel-ative stabilities of A0 and B0 remain the same onthe addition of the second water molecule, i.e.,structure An is slightly more stable than structureBn whether the number of water moleculesamounts to 0, 1, or 2.

For the proton transfer of A2c7B2c andA2s7B2s, the activation barriers were computed tobe 13.36 (11.27 with ZPE corrections) and 11.13 (9.50with ZPE corrections) kcal mol�1, respectively. Itindicates that the drops on the activation barriersby the second water molecule are not so pro-nounced than that of the first water molecule [38–40]. Their transition state structures Ts2c and Ts2swere computed and displayed in Figures 4 (a) and(b). Albeit the (H5O2)� species are formed in bothTs2c and Ts2s, the two transition states have no-ticeable divergences in the geometries. The twohydrogen bonds of O5OH6 and O4OH13 in Ts2cwere optimized at 1.352 and 1.343 Å, respectively,

FIGURE 3. Two interaction modes of water dimer onglycine structures A0 and B0, respectively. [Color figurecan be viewed in the online issue, which is available atwww.interscience.wiley.com.]

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which are stronger than the two hydrogen bonds ofO5OH6 and O4OH13 in Ts2s (1.423 and 1.411 Å,respectively). In Ts2c, the O14OH16 and O11OH16distances were optimized at 1.205 and 1.195 Å,respectively. The two distances are almost equiva-lent, implying that the H16 proton is evenly sharedby the two water molecules. Accordingly, the(H5O2)� species in Ts2c can be described in theform of (H2OOHOOH2)�. However, the O11OH12and O14OH12 distances in Ts2s are equal to 0.983and 1.878 Å, respectively. It indicated that the H12proton forms direct bond with the O11 atomwhereas forms hydrogen bond with the O14 atom.Accordingly, the (H5O2)� species in Ts2s can bedescribed in the form of (H2O---HOOH2)�. Owingto the more dispersed distribution of the positivecharge in Ts2c, this structure is more stable thanTs2s with the energy difference calculated to be�3.22 kcal mol�1 (with ZPE corrections).

ROLES OF THE FIRST AND SECOND WATERMOLECULES

As discussed in interaction with two water mol-ecules section, the second water molecule will in-teract in the concerted pathway due to its energypreference. As a result, the proton transfer A27B2will proceed in the concerted mechanism albeit theactivation barrier of the stepwise mechanism issomewhat lower. Figure 5 charted the activationbarriers in the presence of n � 0, 1, and 2 water

molecules. It can be clearly seen that the activationbarrier is remarkably decreased upon the introduc-tion of one water molecule. In the absence of watermolecules (n � 0), the activation barrier is very high(34.49 kcal mol�1) and will not proceed at roomtemperature, but the addition of a single watermolecule (n � 1) catalyzes this proton transfer byreducing the activation barrier to the value of 16.59kcal mol�1, small enough to take place at roomtemperature. The second water molecule (n � 2)results in a drop of 3.23 kcal mol�1 in the activationbarrier, which is so slight that the role of secondwater molecule can be regarded as solvent effectinstead of catalytic effect. Therefore, the An7Bntautomerization at the carboxylic site of amino ac-ids is a single-water catalyzed process.

THE SOLVENT CONTINUUM (SCRF-PCM)CALCULATIONS

The activation barriers (Eac) and reaction heats(Erh) of the proton transfer at the carboxylic sites ofglycine were plotted in Figure 5. It can be seen thatthe reaction heats change slightly within the rangeof 1.07�1.69 kcal mol�1 on the addition of watermolecules and even in solution calculated by sol-vent continuum models. That is, the relative stabil-ities of A0 and B0 are almost uninfluenced by in-teractions with water molecules at the carboxylicsites. However, the water addition exerts remark-

FIGURE 4. The transition states to the proton transferprocesses at the carboxylic sites of glycine structureswith the addition of water dimer. [Color figure can beviewed in the online issue, which is available at www.interscience.wiley.com.]

FIGURE 5. Energy profiles for the proton transfer atthe carboxylic sites of glycine structures. [Color figurecan be viewed in the online issue, which is available atwww.interscience.wiley.com.]

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able influences on the activation barriers. TheSCRF-PCM calculated activation barriers are equalto 35.51, 13.48, and 11.13 kcal mol�1 for theA0(s)7B0(s), A1(s)7B1(s), and A2c(s)7B2c(s) tau-tomerizations, respectively. In agreement with thediscrete water addition results, the SCRF-PCM cal-culations showed that the inclusion of more watermolecules than one has slight effects on the activa-tion barriers. The addition of the first water mole-cule greatly speeds up the proton transfer at thecarboxylic sites of glycine, i.e., the A07B0 tau-tomerization is catalyzed by a single water mole-cule. The surrounding water molecules at the car-boxylic sites except the first play solvent effects tothe proton transfer process.

The trend of the activation barriers in solutioncalculated by the SCRF-PCM calculations is depen-dent on the dipole moments of the related struc-tures [33, 46, 48], see the exact values in Table II. Inpolar solvents such as water, more polar moleculesor clusters are more strongly solvated by than theless polar ones. The dipole moment of Ts0 is lessthan that of A0, and therefore the activation barrierof the A07B0 tautomerization is increased with theinclusion of solvent effects as calculated by theSCRF-PCM models. However, the dipole momentsof the transition states of the A17B1 and A2c7B2ctautomerizations are larger than their correspond-ing reactants, and accordingly their activation bar-riers are decreased in a certain degree due to theinclusion of solvent effects as calculated by theSCRF-PCM models. The dependence of SCRF-PCMmodels on dipole moments is a severe disadvan-tage of SCRF-PCM models and sometimes may pro-duce misleading results.

Conclusions

The carboxylic site is one of the fundamentalgroups of biomolecules and the proton transfer is

one of the crucial biological processes. The presenttheoretical work concentrated on the proton trans-fer at the carboxylic sites of glycine, the widely usedmodels for biomolecules. The obtained results willhelp us to understand the important and yet com-plex proton transfer processes in larger biomol-ecules such as peptides and proteins, in the absenceand presence of the water solvent. Moreover, it wasfound that the proton transfer at the carboxylic siteof glycine is quite a localized process, and thereforethe calculated data can be referenced for largerbiomolecules. The main findings of the presentwork were given below.

The interaction structures of water monomer anddimer with glycine at the carboxylic sites were ob-tained, with their geometries discussed and com-pared with the previous data available to us. It wasfound that the water addition and proton transfer arequite localized and exert negligible influences on theOCH2NH2 parts in glycine structures. As to the watermonomer, it forms two hydrogen bonds with thecarboxylic sites of glycine. As to the water dimer, itwas observed that there exist two different interactionmodes, i.e., concerted and stepwise, respectively. Theconcerted mode is preferred due to the larger inter-action energy of the second water molecule and thusthe more stable product (A2c vs. A2s). The transitionstates of the concerted and stepwise pathways (Ts2cand Ts2s) are quite different in geometries and can bedescribed in the form of (H2OOHOOH2)� and(H2O---HOOH2)�, respectively.

In the absence of water, the proton transfer at thecarboxylic sites (i.e., the A07B0 tautomerization)was calculated to have a large activation barrier of34.49 kcal mol�1. On the addition of one watermolecule, the activation barrier was reduced to16.59 kcal mol�1 and therefore the proton transfercan take place at room temperature. The furtheraddition of water molecules exerts slight influenceon the activation barriers. Accordingly, this protontransfer is catalyzed by a single water molecule andthe further introduction of water molecules aroundthe carboxylic sites plays solvent effect rather thancatalytic effect to this process.

The calculated results of the solvent continuummodels (SCRF-PCM) are in general agreement withthe results of water addition structures. It was con-firmed that the proton transfer at the carboxylic sitesis catalyzed by a single water molecule. Meanwhile, itwas found that the solvent effect was improperlypredicted by the SCRF-PCM models in the case ofA07B0 tautomerization due to the heavy depen-dence of SCRF-PCM models on dipole moments.

TABLE II _____________________________________Dipole moments of An, Tsn, and Bn structures.a

An Tsn Bn

n � 0 1.29 0.59 1.83n � 1 1.94 3.02 1.92n � 2b 1.58 3.57 1.47

a Units in Debye.b The values of the concerted reaction pathway.

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References

1. Yu, X.; Hao, L.; Inesi, G. J Biol Chem 1994, 269, 16656.

2. Ban, F.; Kusalik, P.; Weaver, D. F. J Am Chem Soc 2004, 126,4711.

3. Toyoshima, C.; Nomura, H. Nature 2002, 418 605.

4. Sugita, Y.; Miyashita, N.; Ikeguch, M.; Kidera, A.; Toyo-shima, C. J Am Chem Soc 2005, 127, 6150.

5. Dreyer, M. K.; Schulz, G. E. J Mol Biol 1996, 259, 458.

6. Voth, G. A. Acc Chem Res 2006, 39, 143.

7. Csaszar, A. G. J Am Chem Soc 1992, 114, 9568.

8. Bouchonnet, S.; Hoppilliard, Y. Org Mass Spectrom 1992, 27,71.

9. Hu, C. H.; Shen, M.; Schaefer, H. F., III. J Am Chem Soc 1993,115, 2923.

10. Zhang, K.; Zimmerman, D. M.; Chung-Phillips, A.; Cassady,C. J. J Am Chem Soc 1993, 115, 10812.

11. Yu, D.; Rauk, A.; Armstrong, D. A. J Am Chem Soc 1995, 117,1789.

12. Godfrey, P. D.; Brown, R. D. J Am Chem Soc 1995, 117, 2019.

13. Jensen, J. H.; Gordon, M. S. J Am Chem Soc 1995, 117,8159.

14. Barone, V.; Adamo, C.; Lelj, F. J Chem Phys 1995, 102,364.

15. Tortonda, F. R.; Pascual-Ahuir, J. L.; Silla, E.; Tuoon, I. ChemPhys Lett 1996, 260, 21.

16. Neville, J. J.; Zheng, Y.; Brion, C. E. J Am Chem Soc 1996, 118,10533.

17. Hoyau, S.; Ohanessian, G. Chem Eur J 1998, 4, 1561.

18. Bonifacic, M.; Stefanic, I.; Hug, G. L.; Armstrong, D. A.;Asmus, K. D. J Am Chem Soc 1998, 120, 9930.

19. Zhang, K.; Chung-Phillips, A. J Comput Chem 1998, 19, 1862.

20. Wyttenbach, T.; Witt, M.; Bowers, M. T. J Am Chem Soc2000, 122, 3458.

21. Gutowski, M.; Skurski, P.; Simons, J. J Am Chem Soc 2000,122, 10159.

22. Remko, M.; Rode, B. M. Chem Phys Lett 2000, 316, 489.

23. Remko, M.; Rode, B. M. Phys Chem Chem Phys 2001, 3, 4667.

24. Croft, A. K.; Easton, C. J.; Radom, L. J Am Chem Soc 2003,125, 4119.

25. Rulisek, L.; Havlas, Z. J Phys Chem B 2003, 107, 2376.

26. Chaudhari, A.; Sahu, P. K.; Lee, S. L. J Chem Phys 2004, 120,170.

27. Remko, M.; Rode, B. M. Struct Chem 2004, 15, 223.

28. Constantino, E.; Rodriguez-Santiago, L.; Sodupe, M.; Torta-jada, J. J Phys Chem A 2005, 109, 224.

29. Leung, K.; Rempe, S. B. J Chem Phys 2005, 122, 184506.

30. Falzon, C. T.; Wang, F. J Chem Phys 2005, 123, 214307.

31. Hattori, T.; Toraishi, T.; Tsuneda, T.; Nagasaki, S.; Tanaka, S.J Phys Chem A 2005, 109, 10403.

32. Remko, M.; Rode, B. J Phys Chem A 2006, 110, 1960.

33. Marino, T.; Toscano, M.; Russo, N.; Grand, A. J Phys ChemB 2006, 110, 24666.

34. Corral, L.; Mo, O.; Yaoez, M.; Moran, D.; Radom, L.; Salpin,J. Y.; Tortajada, J. Chem Eur J 2006, 12, 6787.

35. Yang, G.; Zu, Y. G.; Zhou, L. J. J Phys Org Chem 2008, 21, 34.36. Slifkin, M. A.; Ali, S. M. J Mol Liq 1984, 28, 215.37. Tortonda, F. R.; Silla, E.; Tuoon, I.; Rinaldi, D.; Ruiz-Lopez,

M. F. Theor Chem Acc 2000, 104, 89.38. Wang, X. C.; Nichols, J.; Feyereisen, M.; Gutowski, M.; Boatz,

J.; Haymet, A. D. J.; Simons, J. J Phys Chem 1991, 95, 10419.39. Kallies, B.; Mitzner, R. J Mol Mod 1998, 4, 183.40. Fu, A. P.; Li, H. L.; Du, D. M.; Zhou, Z. Y. Chem Phys Lett

2003, 382, 332.41. Balta, B.; Aviyente, V. J Comput Chem 2004, 25, 690.42. Markova, N.; Enchev, V.; Timtcheva, I. J Phys Chem A 2005,

109, 1981.43. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;

Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgom-ery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.;Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski,J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.;Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts,R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill,P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.Gaussian 98, Revision A. 9 Gaussian, Inc.: Pittsburgh, PA,1998.

44. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven,T., Jr.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.;Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara,M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Naka-jima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jara-millo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford,S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-combe, M. P.; Gill, M. W.; Johnson, B.; Chen, W.; Wong,M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03 Revision C. 02,Gaussian Inc.: Wallingford, CT, 2004.

45. Hall, N. E.; Smith, B. J. J Phys ChemA 1998, 102, 3985.46. Selvarengan, P.; Kolandaivel, P. J Mol Struct Theochem 2002,

617, 99.47. Yang, G.; Han, X. W.; Liu, X. M.; Yang, P. Y.; Zhou, Y. G.;

Bao, X. H. J Phys Chem B 2005, 109, 18690.48. Yang, G.; Zu, Y. G.; Liu, C. B.; Fu, Y. J.; Zhou, L. J. J Phys

Chem B DOI: 10.1021/jp710394f.49. Mietus, S.; Scrocco, E.; Tomasi, J. J Chem Phys 1981, 55,

117.50. Cossi, M.; Barone, V.; Commi, R.; Tomasi, J. J Chem Phys

1996, 255, 327.51. Wang, W. Z.; Zheng, W. X.; Pu, X. M.; Wong, N. B.; Tian,

A. M. J Mol Struct Theochem 2002, 618, 235.

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