Density functional theory study of tautomerization of 2-aminothiazole in the gas phase and in...

Density Functional Theory Study ofTautomerization of 2-Aminothiazole inthe Gas Phase and in Solution

YI ZENG, YI RENCollege of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China

Received 15 February 2006; accepted 20 March 2006Published online 2 August 2006 in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/qua.21059

ABSTRACT: The amino/imino tautomeric equilibrium in the isolated, mono-, di-, andtrihydrate forms and dimer of 2-aminothiazole, and the effects of hydration or self-assistance on the transition state structures corresponding to proton transfer from the aminoto imino form, have been investigated by the B3LYP method in conjunction with 6-31�G(d,p) and 6-311�G(3df,2p) basis sets in the gas phase and in solution. The amino formhas been found to be the predominant tautomer. The tautomeric barrier heights for water-and self-assisted tautomerization reactions are significantly lower than that from the aminoto imino form by the intramolecular proton transfer, showing the catalytic effect of watermolecule(s) and the important role of 2-aminothiazole itself for intermolecular protontransfer. Comparison between the tautomeric barriers demonstrates that the self-associationtautomerization through the dimerization is the most favorable pathway. Bulk solventeffects have been taken into account using the polarizable continuum model (PCM) ofwater and CCl4. The polar medium is favorable for the population of the imino form. Theamino/imino equilibrium is also analyzed using the aromaticity index nucleus-independentchemical shift (NICS); the NICS values for the amino form (about �10 ppm) are morenegative than the imino species (about �8 ppm), showing that the amino form is morestable. The time-dependent density functional theory (TDDFT) calculations of electronicabsorption spectra suggest that the �max of dimer is 255 nm. The oscillator strength of theimino forms is less than the amino form, and increases with the polarity of the solvents. Allcalculations for the tautomerization of 2-aminothiazole are in reasonable line with theavailable experiments. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem 107: 247–258, 2007

Key words: 2-aminothiazole; tautomerization; density functional theory; solvent effect

Correspondence to: Y. Ren; e-mail: [email protected] grant sponsor: Scientific Research Foundation for

the Returned Chinese Scholars of Sichuan University.

International Journal of Quantum Chemistry, Vol 107, 247–258 (2007)© 2006 Wiley Periodicals, Inc.

Introduction

2 -Aminothiazole and its derivatives continueto attract the attention of biologists because of

their wide use in the treatment of biological sys-tems, such as in many anti-inflammatory, analgesic,and antipyretic medicines [1–5]. It is well knownthat, in principle, 2-aminothiazole can exist in twotautomeric forms: amino (A) and imino (B), illus-trated in Scheme 1. Previous experiments have re-vealed that the tautomerism of amino heterocyclesdirectly affects the orientation of substitution andthe product assignments when they act with theother compounds [6–9]. Therefore, greater efforthas been placed on the tautomeric equilibrium of2-aminothiazole and its derivatives. Numerous ex-perimental studies, including infrared (IR) [10, 11],ultraviolet (UV) [12], and H-nuclear magnetic res-onance (H-NMR) [13–15] spectra, indicate thatsome 2-aminothiazole derivatives exist in solution,preferentially in the amino form, based on the anal-ysis of the reactivity data. Additionally, using anexperimental pKa value 5.32 in water at 25°C, For-lani et al. [16] reported the tautomeric equilibriumconstant of 2-aminothiazole, KT � 4.76 � 10�5, KT �Kimino/Kamino [16], which quantitatively describesthe distribution of two tautomeric forms (seeScheme 1).

In contrast to numerous reports on experimentalresults, to the best of our knowledge, very fewtheoretical studies are available for the tautomer-ization of 2-aminothiazole, except for an early re-port on the relative stability of these tautomers withthe Huckel molecular orbit (HMO) calculations[17]. However, several theoretical studies werefound for the tautomerism of 2-aminothiazoline,similar to 2-aminothiazole, and no CAC doublebond in the five-membered ring. In 2001 Remko etal. [18] reported the tautomeric geometries andequilibrium of 2-aminothiazoline in the gas phaseat the B3LYP/6-311�G(d,p), MP2/6-311�G(d,p),and CBS-Q levels, and concluded that the aminoform was more stable than the imino form. Similar

results have been obtained for the tautomerism ofN-methyl- and N-phenyl-substituted cyclic thiazo-lines, using the B3LYP and ONIOM theories [19].However, fewer studies are directed toward theprocess of proton transfer (PT) and other relateddetails because the PT process from the amino tothe imino nitrogen is rapid and the prototropicprocess in compounds containing the amidinegroup is exceptionally difficult to study using cur-rent experimental physicochemical methods [20–22]. More recently, Xue et al. [23] studied the tau-tomeric PT reaction of 2-amino-2-thiazoline withthe density functional theory (DFT) technique, con-sidering the direct intramolecular and water-as-sisted PT process by up to two water molecules.However, the question is whether there are, at leastin principle, other possible PT paths for the tautom-erism besides the familiar direct and solvent-as-sisted PT pathways discussed in the literature. Theexisting studies do not appear to be conclusive, andwe will concentrate our attention on this topic.

In 2001 Forlani et al. [24] proposed that thedimeric forms of 2-aminothiazole and its deriva-tives are probably intermediate in the tautomerismbased on the fact that the dimers of some amin-othiazoles, such as 4-methyl-2-aminothiazole, canbe detected at increased concentrations in their ex-periment, but there have been no theoretical worksto ascertain this until now. In 2002 Moran et al. [25]examined the dimers in the tautomeric equilibriumof 2-pyridinethiol/2-pyridinethione at the level ofB3LYP/6-311�G(3df,2p) and drew the extraordi-nary conclusion that the tautomerism was pro-moted by dimerization. These previous studies ledus to make a systematical theoretical investigationto shed greater light on the tautomeric mechanismof 2-aminothiazole.

Accordingly, we examined three possible typesof PT pathways by adopting DFT (B3LYP) [26, 27].One type is the intramolecular PT process, illus-trated in Figure 1, in which one of the protons onthe NH2 group in amino form A migrates directlyto the heterocyclic ring nitrogen, forming iminoform B. The second type of PT pathway is associ-ated with the assistance of water molecules, inwhich the water molecules mediate the tautomericprocess by establishing a bridge from intermolecu-lar hydrogen bonds, and that can significantlylower the tautomeric barrier, as noted in manystudies on the tautomerization of keto/enol [28, 29]and thione/thiol [30]. To learn more about the in-fluence of different numbers of water moleculesparticipating in the PT process on the tautomeric

SCHEME 1. Tautomeric equilibrium of 2-aminothia-zole.

ZENG AND REN

248 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY DOI 10.1002/qua VOL. 107, NO. 1

barrier, we will also take into account up to threewater-assisted PT processes (Fig. 1). The third typeof tautomerization worth noting is the dimerizationof 2-aminothiazole, called self-association, in whichone 2-aminothiazole acts on the catalysis to facili-tate the PT instead of the water molecules. Threetypes of PT process are summarized: (i) direct in-tramolecular PT, A 3 B, path 1; (ii) water-assistedPT, A � nH2O 3 B � nH2O, n � 1, 2, and 3, corre-sponding to path 2, path 3, and path 4, respectively;and (iii) intermolecular PT through dimerization,A2 3 B2, path 5.

It is known that solvation will play an importantrole in affecting tautomeric equilibrium. Recent ex-periments on UV/Vis and NMR spectroscopy indifferent organic solvents indicate that the in-creased polarity of the medium causes a shift in thetautomeric equilibrium toward the imino form [25].Also, considerable efforts have been made in thisfield using the self-consistent reaction field (SCRF)model [18], as well as classical molecular dynamics(MD) [19] and Monte Carlo (MC) simulations [23],and have obtained some satisfactory results regard-ing 2-aminothiazoline, indicating that an aqueoussolution is favorable for the imino form. In an at-tempt to investigate how the solvent with differentpolarity affects the tautomerism of 2-aminothiazole,in the present study, we choose two solvents, theprotic polar (water, � � 78.39) and nonpolar (CCl4,� � 2.228), by performing SCRF calculation com-bined with the polarizable continuum model(PCM).

Meanwhile, calculations on the electronic ab-sorption spectra of 2-aminoazole were carried outthrough the time-dependent density functional the-ory (TDDFT) [31–34], which has emerged as a reli-able and cost-effective tool for studying the elec-tronic spectra of large molecules. These theoreticalresults were compared with reported experimentalUV spectral data. All calculations are helpful forbetter understanding the prototropic tautomeriza-tion of 2-aminoazole in the gas phase and in me-dium.

Computational Details

All species in the five pathways were fully opti-mized at the B3LYP/6-31�G(d,p) level. The natureof the stationary points was further confirmed byharmonic frequency analysis at the same level;scaled zero-point vibrational energies (ZPVE) by afactor of 0.98 were used in the calculations of rela-

tive energies. Considering the effect of basis set,single-point calculations with an extended basis setup to B3LYP/6-311�G(3df,2p) level of theory werecarried out on B3LYP/6-31�G(d,p) geometries.

DFT single-point calculations in water and CCl4solution were performed on the gas-phase opti-mized geometries employing the SCRF–PCM [35].Within this PCM, the solvent is represented by adielectric continuum characterized by its relativestatic dielectric permittivity, �. The molecule is in-serted in a cavity of realistic shape formed by in-terlocking spheres centered on solute atoms or anatomic group. Solute–solvent interactions are re-produced by means of point charges disseminatedon the cavity surface, which can obtain accuratesolvation energies, �Gsol, for a large variety of com-pounds. The Gibbs free energy in solution can becalculated with the following equation:

Gsol � Gg � �Gsol.

The B3LYP/6-31�G(d,p) geometries were alsoused in the calculations of electronic vertical singletexcitation energies by the TDDFT method at thelevel of B3LYP/6-31�G(d,p) level. To estimate thesolvent effects on the excitation energies of the tau-tomers, the SCRF–PCM was used in conjunctionwith the TDDFT method.

Throughout the present study, all atomic dis-tances are in Ångstroms (Å), and all angles are indegrees (°). Relative energies correspond to freeenergy changes (�G kcal/mol�1) at the level ofB3LYP/6-311�G(3df,2p)//B3LYP/6-31�G(d,p).The Gaussian 98 package of program [36] is appliedto all calculations.

Results and Discussion

GEOMETRIES

The selected geometries of species in paths 1–4are listed in Table I. Only Z-isomers of imino formwere considered in this study because the Z-isomerwith the intramolecular hydrogen bond is morestable than the E-isomer [18]. The optimized resultsshow that the amino group of 2-aminothiazolespossesses a distinctly nonplanar pyramidal struc-ture, similar to some nucleic acid bases (NABs) [37,38]. Interestingly, we find that the diffuse functionsare necessary to predict the pyramidal structure ofthe amino form for this system, because an attemptto locate the pyramidal structure of A is not suc-

DFT STUDY OF TAUTOMERIZATION OF 2-AMINOTHIAZOLE IN GAS PHASE AND SOLUTION

VOL. 107, NO. 1 DOI 10.1002/qua INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 249

FIGURE 1. Optimized structures for all species in the five possible PT pathways (bond length in regular and anglein italics) and NICS values at the center of the five-membered rings in A and B forms (ppm) at the B3LYP/6-31�G(d,p) level.

ZENG AND REN


cessful without the diffuse functions. For the non-planarity, as addressed in a previous work [37],there are two structural characteristics: (i) a partialsp3 hybridization of the amino group, which can beevaluated as the deviation of the sum of the anglesaround the nitrogen atom from 360° (see � in TableI); and (ii) the interaction of the amino group hy-drogen atoms with the nitrogen and sulfur atomsattached to the thiazole ring. The formation of hy-dration complexes reduces the nonplanarity of theamino group, and the � values in amino formsfollow the order 14.8 (A) � 10.0 (A � H2O) � 6.5 (A �3H2O) � 3.1°(A � 2H2O), which probably implies asimilar trend for the corresponding PT barrier.Compared with the amino forms, there is a narrowrange of � values (0.0–6.7°) in the transition states,showing less nonplanarity due to the transitionstructure with more product-like geometry. More-over, the pyramidal structures disappear in the im-ino forms as a result of the completion of protonshift, and the H7 exits in the same plane with N6,C2, and N3, leading to tautomer B with Cs symme-try.

In addition to the nonplanarity of amino group,the geometries in Figure 1 also exhibit other impor-tant structural changes as the tautomerism pro-ceeds. When going from the amino to the iminoform, the C2ON6 bond length is reduced from1.378 in tautomer A to 1.277 Å in B, while theC2ON3 distance increases from 1.304 in A to 1.386Å in B. These are consistent with the gradual for-mation of the C2AN6 double bond and corre-sponding breaking of the C2AN3 double bond.

RELATIVE STABILITY IN THE GAS PHASE

The relative energies (see Table II) between theamino and imino forms show that the amino forms

are more stable, lower by �5–8 kcal/mol�1 in en-ergy than the imino forms. The free energy differ-ence in the isolated state is 7.52 kcal/mol�1 in favorof A, and reduces to 6.22 (n � 1), 5.51 (n � 2), and5.19 kcal/mol�1 (n � 3) in the hydrated complexesA � nH2O and B � nH2O, respectively. Therefore, theincreased addition of water molecules will enhancethe stabilization of the imino forms, whereas it doesnot change the preference of the amino forms.

PROTON TRANSFER IN THE GAS PHASE

The calculated PT barriers in the five pathwaysare presented in Table II, clearly indicating that thebarrier (�50 kcal/mol�1) in path 1 is higher thanthe others. As expected, the inclusion of water mol-ecule(s) for paths 2–4 lowers the barrier heightsdrastically by �30 kcal/mol�1, showing the catal-ysis of water molecule in the tautomerism of 2-ami-nothiazole. It is worth noting in Table II that thetautomeric barrier in path 5 is lower than those inthe water-assisted PT processes, implying that thetautomerism of 2-aminothiazole through self-asso-ciation (path 5) is the most favorable. The followingwill make a detailed discussion for the five possibletautomeric pathways.

Path 1: Direct Intramolecular PT A 3 B

The N3OH8 distance clearly plays an importantrole in the intramolecular PT reaction. Without wa-ter molecule(s) participating in the PT process, it isdifficult for the A form to transfer the proton di-rectly from the N6 to N3, because of a long N3OH8distance (2.525 Å). The bare A tautomer is unfavor-able for the formation of an intramolecular hydro-gen bond. The direct PT would take place through

FIGURE 1. Continued.



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ZENG AND REN


a rather tense four-membered ring TS with a smallangle �C2ON6OH8 of 74.4°. The N6OH8 bond(1.410 Å) is almost broken, and the N3OH8 bond(1.320 Å) is unformed in TS. This highly distortedstructure should demand a large amount of defor-mation energy, resulting in a high-energy barrier of50.20 kcal/mol�1, indicating that the direct protontransfer of bare A is unlikely to occur in the gasphase.

Paths 2–4: Water-Assisted PT

Formation of complexes with water moleculeswill slightly affect the structures of the amino andimino units. As expected, the influences of the in-teractions with water molecules on the geometriesof amino tautomers are manifested mainly in theregion of intermolecular hydrogen bonds. Figure 1shows that the C2ON6 bond length decreases from1.378 Å in A to 1.365–1.353 Å in A � nH2O, whereasthe N6OH8 bond length increases from 1.012 Å to1.020–1.027 Å, as well as the C2ON3 bond lengthfrom 1.304 Å to 1.313–1.317 Å in the hydration ofamino complexes, A � nH2O (n � 1–3). These geo-

metric changes will favor the following PT reac-tions with lower barrier heights.

Additionally, two intermolecular hydrogenbonds, NOH. . .O and N. . .HOO, are formed in A �nH2O. The PT processes will proceed more easilythan in the bare amino form because the H2O mol-ecules act as a bridge between the NH2 group andthe nitrogen atom (N3) and PT paths are signifi-cantly shorter in A � nH2O (1.781–2.053 Å) than thatin the bare form A (2.525 Å).

We are interested in comparing the tautomericbarriers for A � nH2O (n � 1–3) in paths 2–4, re-spectively. This difference appears to stem fromgeometrical consideration.

One-Water Assisted PT: A � H2O 3 B � H2O (Path2). We can refer to the process as an almost syn-chronous double PT based on the analysis of TS �H2O, which has a less tense six-membered structurethan the TS in path 1. Less geometrical deformationwas found in forming TS � H2O, N6OH8 bondincreasing only from 1.020 Å to 1.216 Å and�C2ON6OH8 angle deducing from 114.9° to107.3°, respectively. Thus, the PT barrier is de-creased to 18.34 kcal/mol�1, much less than that in

TABLE II _____________________________________________________________________________________________Relative Gibbs free energies, �G (kcal/mol�1), of amino and imino forms and transition structures in thetautomerization of isolated, mono-, di-, trihydrated, and dimeric species of 2-aminothiazole.

Path

B3LYP/6-31�G(d,p) B3LYP/6-311�G(3df,2p)

Gas Water CCl4 Gas Water CCl4

1 A 0 0 0 0 0 0TS 50.08 53.75 51.09 50.20 54.50 51.29B 7.79 6.02 7.40 7.52 7.26 7.27

2 A � H2O 0 0 — 0 0 —TS � H2O 17.09 17.54 — 18.34 19.08 —B � H2O 6.19 5.58 — 6.22 5.69 —

3 A � 2H2O 0 0 — 0 0 —TS � 2H2O 13.21 13.28 — 15.03 15.02 —B � 2H2O 5.37 5.08 — 5.51 4.38 —

4 A � 3H2O 0 0 — 0 0 —TS � 3H2O 15.48 15.83 — 17.93 19.18 —B � 3H2O 4.99 4.84 — 5.19 5.27 —

5 A2 0 0 0 0 0 0(TS)2 11.57 11.70 11.08 12.57 13.34 12.11B2 10.21 9.40 9.89 10.23 8.34 9.86



the direct intramolecular PT pathway by �32 kcal/mol�1. Thus, the introduction of one water mole-cule boosts the stability of the transition state sothat the PT process can be easily carried out.

Two-Water Assisted PT: A � 2H2O 3 B � 2H2O(Path 3). The binding of two water molecules in theA � 2H2O still lower the barrier to 15.03 kcal/mol�1,catalyzing tautomerization by the concerted triplePT mechanism through an eight-membered ringTS � 2H2O. This can be rationalized by a smallergeometrical deformation from A � 2H2O to TS �2H2O, the �C2ON6OH8 angle slightly expandingby 1.8° and the N6OH8 bond increasing by 0.147 Å,less than those in path 2. We conclude that theeight-membered ring TS � 2H2O structure is morefavorable than the six-membered ring in TS � 2H2O.

This lowering of the tautomeric barrier frompath 2 to path 3 could be analyzed further from thecomparison of intermolecular hydrogen bonds inTS � H2O and TS � 2H2O. Although it is difficult todetect the geometry of the hydrogen bond, a statis-tical analysis of X-ray crystallographic data hasshown that most hydrogen bonds in crystals arenonlinear by �10° to 15°. The angles of hydrogenbonds in TS � 2H2O are 167–173°, obviously betterthan those in the TS � H2O (�150°) because of thelarger repulsion between two heavy atoms withhigher electronegativity in TS � H2O, leading to lessstabilization of transition state and higher tauto-meric barrier for path 2 than path 3 by �3.3 kcal/mol�1.

Three-Water Assisted PT: A � 3H2O 3 B � 3H2O(Path 4). For the case of A � 3H2O, three watermolecules take part in the PT process, leading to a10-membered ring H-bond structure. When pro-ceeding from A � 3H2O to TS � 3H2O, the N6OH8bond is lengthened only from 1.027 to 1.134 Å, lessthan that in path 3, and the tautomeric barrier is17.93 kcal/mol�1, higher than that in path 3 by �3kcal/mol�1, indicating that path 4 is less kineticallyfavorable than path 3. To answer the question re-garding the unfavorable transition structure inwhich more than two water molecules participatein the PT process in 2-aminothiazole, we focus inthe following discussion on the comparison of tran-sition structures TS � nH2O (n � 1–3).

In forming TS � 3H2O, four hydrogen atoms areinvolved in the PT process, and quite a large num-ber of hydrogen atoms have to be moved from theirmore stable position to a somewhat distorted ge-ometry accompanying the elongation of the BOH

bond(s), in which the letter B represents an O or Natom in TS � 3H2O. Taking its cost in terms of moredeformation energy, that will lead to higher barrier.Even though there are only two hydrogen bonds inthe A � H2O complex, these hydrogen bonds are lesseffective (�N6OH8OO11 � 143.3°, �N3OH13OO11 � 148.8°), which implies that some strain re-mains in the ring and increases the difficulty for thePT. The three hydrogen bonds exist in A � 2H2Owith angles of 162.0–177.3°, and the more relaxedgeometry in TS � 2H2O clearly favors the tripleproton transfer compared with the strained TS �H2O. The increment from the eight-membered ringstructure, A � 2H2O, to the 10-membered ring struc-ture, A � 3H2O, does not relax the strain in thegeometry of the hydrogen bonds. Another reasonfor the higher tautomeric barrier for path 4 than forpath 3 may be from the obvious deviation of thethree-water bridge from the plane of 2-aminothia-zole in A � 3H2O, making it difficult for subsequentPT to form TS � 3H2O. For the A � 2H2O, there iscoplanarity for the eight-membered ring structure,which will facilitate the PT process. We concludethat path 3 with the eight-membered ring transitionstructure, TS � 2H2O, should be the most favorablein the water-assisted PT process for 2-aminothia-zole.

Path 5: Intermolecular PT ThroughDimerization: A2 3 B2

To verify the proposition reported by Forlani et al.[23] regarding the dimeric form probably being inter-mediate in the tautomerism of 2-aminothiazoles, wemade a comprehensive theoretical study for the tau-tomerization of 2-aminothiazoles through self-associ-ation.

As shown in Figure 2, because of the pyramidalstructure of the amino group, the dimer-A2 canexist in either C2 or Ci conformations with imposing

FIGURE 2. Side views of dimer A2 (Ci) and A2 (C2)optimized at the B3LYP/6-31�G(d,p) level.

ZENG AND REN


symmetry. As expected, the Ci minima is preferredby just 0.44 kcal/mol�1 to the C2 isomer at B3LYP/6-31�G(d,p) level. So, the dimer with Ci symmetrywill be the model for the following study.

Thermodynamic parameters at the level ofB3LYP/6-31�G(d,p) for the monomer/dimer equi-librium are illustrated in Scheme 2, revealing thestronger hydrogen bonding ability of nitrogen forthe dimeric adduct formation of 2-aminothiazole,and paving a reasonable way for the further study.

The activation free energy through dimerizationis presented in Table II, indicating that the tauto-meric barrier for path 5 is even lower than that forpath 3 (two-water assisted) by 2.46 kcal/mol�1,called self-catalysis or self-assisted, showing thatthe PT process of 2-aminothiazole by self-associa-tion is the most kinetically preferable. The follow-ing will only make some comparisons between path5 and path 3.

In the two pathways, although the PT processesare completed through eight-membered ring tran-sition structures resulting from intermolecular hy-drogen bonds, the number of the protons involvedis different, two for path 5 and three for path 3,respectively. Based on the above discussion, thefewer protons migrating in path 5 probably contrib-ute to a lower tautomeric barrier. Another factorgoverning the lower barrier for path 5 is that twonitrogen atoms act as a proton acceptor in (TS)2, incontrast to only one nitrogen atom in TS � 2H2O.The nitrogen atom is a better proton acceptor andwill facilitate the PT process.

SOLVENT EFFECT

The optimized geometries of the isolated 2-ami-nothiazole, A, in solvents are listed in Table I, indi-cating that few geometrical changes are induced bythe dielectric surrounding. Therefore, it is a reason-able approximation to assume that all species are

not affected by the presence of the bulk solvent.Only single-point calculations with the PCM areperformed on the optimized B3LYP/6-31�G(d,p)geometries in the gas phase, called the direct sol-vent effect.

The solvation free energies, �Gsol, at the level ofB3LYP/6-31�G(d,p) presented in Table III showclearly that the imino form is more solvated thanthe amino form by 0.15–1.77 kcal/mol�1 in H2Oand 0.3–0.4 kcal/mol�1 in CCl4 probably because ofthe slightly larger dipole moments of the iminoforms, which will increase the population of theimino form in solution. In addition, the imino formis found to be more favorable in the polar watersolvent than in the nonpolar solvent CCl4, in agree-ment with the experiments of Forlani et al.

Combining the reaction free energies in the gasphase with those in solutions at the level of B3LYP/6-31�G(d,p) (see Table II), it can be easily illumi-nated in the following way:

Path 1: 6.02 [�G1 (H2O)] 7.40[�G1 (CCl4)] 7.79kcal/mol�1 [�G1(gas)]

Path 2: 5.58 [�G2 (H2O)] 6.19 kcal/mol�1

[�G2(gas)]Path 3: 5.08 [�G3 (H2O)] 5.37 kcal/mol�1

[�G3(gas)]Path 4: 4.84 [�G4 (H2O)] 4.99 kcal/mol�1

[�G4(gas)]

TABLE III ____________________________________Solvation free energies �Gsol (kcal/mol�1) and gas-phase dipole moments, � (Debye) of amino andimino forms, and TSs in the five tautomeric paths.

Path Species

B3LYP/6-31�G(d,p)

Water CCl4 �

1 A �9.00 �2.29 1.73TS �5.34 �1.29 1.12B �10.77 �2.68 2.78

2 A � H2O �7.68 — 1.16TS � H2O �7.23 — 2.70B � H2O �8.29 — 2.02

3 A � 2H2O �8.39 — 1.24TS � 2H2O �8.32 — 3.40B � 2H2O �8.68 — 1.61

4 A � 3H2O �9.16 — 1.19TS � 3H2O �8.81 — 4.93B � 3H2O �9.31 — 1.55

5 A2 �7.58 �0.50 0(TS)2 �7.45 �0.99 1.51B2 �8.39 �0.82 0

SCHEME 2. Thermodynamic parameters, �H (kcal/mol�1) and �S (kcal/mol�1 ��1) for the dimerization of2-aminothiazole at the B3LYP/6-31�G(d,p) level.



Path 5: 9.40 [�G5 (H2O)] 9.89 [�G5(CCl4)] 10.21 kcal/mol�1 [�G5(gas)]

Accordingly, the medium causes a shift of the tau-tomeric equilibrium toward the imino species inpolar H2O solution more than in CCl4.

Because of more solvated amino species than thecorresponding transition states, the tautomeric bar-rier in the bulk solvent surrounding is increased by0.7–4.3 kcal/mol�1. Comparison of the tautomericbarriers among five pathways in solution showsthat the water catalysis makes the tautomeric bar-rier of 2-aminothiazole �13–18 kcal/mol�1, muchlower than �54 kcal/mol�1 in the direct intramo-lecular PT; the tautomerization by self-association(path 5) is still more favorable than water-assistedtautomeric processes. Hence, we suggest that thetautomerism of 2-mainothiazole by dimerization isthe most favorable in solution, while the two-water-assisted path 3 is a mainly competitive process ifthe tautomerization occurs in aqueous solution.

According to the earlier reported experimentalequilibrium constant [16] KT � 4.76 � 10�5 in waterat 25°C, we can determine the free energy change,�Gexp

0 � 5.89 kcal/mol�1. Our theoretical results(see Table II) at the B3LYP/6-31�G(d,p) level arereasonably consistent with the experiments. Thereis little influence on the relative free energy usinglarger basis set 6-311�G(3df,2p).

In contrast, the nonpolar solvent CCl4 (� �2.228), due to its much lower polarity, has littleinfluence on the energies of amino, imino formsand transition states. As can be seen in Table III, the�Gsol in CCl4 is smaller than those in H2O by �4–8kcal/mol�1, leading to the slight changes of theactivation free energies with respect to those in thegas phase. As for the possible PT processes in CCl4,we only consider the direct solvent effect by PCMwithout explicit water molecules involved, includ-ing intramolecular PT (path 1) in isolated form andself-association (path 5) of 2-aminothiazole. Thetautomeric barrier by self-association is calculatedto be 12.11 kcal/mol�1, much less than 51.29 kcal/mol�1 by intramolecular PT. It is clear that thetautomerization of 2-aminothiazole by dimeriza-tion facilitates the PT process both in the gas phaseand in solution.

NICS ANALYSIS

In 1996, Schleyer et al. [39] proposed a new def-inition, using nucleus-independent chemical shifts(NICS) as an effective aromaticity criterion. This

approach can be used in evaluating the stability ofcyclic system, especially conjugated system, by cal-culating the NICS values at the center of the ring,negative and positive NICS values correspondingto aromaticity and anti-aromaticity, respectively. Inthis study, the presence of aromaticity for theamino and imino forms can be probed by comput-ing NICS values at the center of five-memberedheterocycle using B3LYP/6-31�G(d,p) (see Fig. 1),following the order �10.3 ppm (A) �7.7 ppm (B);�10.2 ppm (A � H2O) �8.3 ppm (B � H2O); �10.0ppm (A � 2H2O) �8.4 ppm (B � 2H2O); �10.0 ppm(A � 3H2O) �8.3 ppm (B � 3H2O). Remarkably, theNICS values of the amino species (� �10 ppm) areless than those in the imino species (� �8 ppm).This confirms the stronger aromaticity of aminothan imino forms due to a more electron delocal-ization at the ring center of the amino forms, pro-viding further evidence of the different stabilities ofthe two tautomers and serving as reasonable sup-port for the preference of amino forms in two tau-tomers of 2-aminothiazoles.

UV/VIS ABSORPTION SPECTRUM

To check the electron absorption spectrum of2-aminothiazole in solution, vertical excitation en-ergies for the singlet transition energies of all spe-cies in the tautomerization of 2-aminothiazole wereevaluated using a TD-B3LYP/6-31�G(d,p)//B3LYP/6-31�G(d,p) approach, explicitly taking bulk sol-vent effects into account by means of the PCM. Thecalculated maximum adsorption wavelength �max(nm), the corresponding vertical excitation energiesE (eV), and the oscillator strengths f are presentedin Table IV. Only one strong spectrum band isexhibited at 255 nm in the available experimentalresult [40]. Our calculated results show that thevalues of the �max lie in the 238–259 nm region,reasonably in line with the experiments. Further-more, the �max (255 nm) of dimer A2 (Ci) is inexcellent coincidence with the experimental value,implying the existence of the dimer of 2-aminothi-azole. We can also analyze the calculated oscillatorstrength, f, to understand why the amino form isdominant in the tautomeric equilibrium. The datapresented in Table IV show that the f values ofamino species are larger than those of the corre-sponding imino species. The differences in the fvalues between two kinds of tautomers becomesmaller, especially in polar water solution, if thesolvent effects are taken into account. The f valuesincrease with the polarity of solvents, in which the

ZENG AND REN


imino forms exhibit a stronger increasing trend.These results may indicate the higher population ofthe imino form in the polar solvent due to the shiftof the tautomeric equilibrium toward it.

Conclusions

We have systematically investigated the amino/imino PT process and the tautomerism equilibriumof 2-aminothiazole in the gas phase, polar solvent(H2O), and nonpolar solvent (CCl4), employing theDFT–B3LYP method, with the following conclu-sions:

1. The B3LYP method assesses certain accuracyon the energy calculations for this system. Inconjunction with the basis sets 6-31�G(d,p),one can obtain reasonable results. Larger basissets 6-311�G(3df,2p) have little effect on therelative energies.

2. The amino form is always predominant in thegas phase and in medium. With the increasingpolarity of the solvent, the stability of theimino form is notably enhanced.

3. Our theoretical results show that tautomeriza-tion of 2-aminothiazole by water-assisted(paths 2–4) and self-association (path 5) isenergetically preferred over the direct in-tramolecular tautomeric process (path 1) inthe gas phase and in solution, and signifi-cantly reduces the barrier by �30 kcal/mol�1.In the tautomeric process involving watermolecule(s) as the catalyst, two-water-assisted

PTs (path 3) are more favorable than one-water-assisted (path 2) and three-water-as-sisted (path 4).

4. Comparison between all possible tautomericpathways shows that tautomerization of 2-ami-nothiazole by self-association is the most favor-able both in gas-phase and in solution.

5. The polar solvent will make the tautomericequilibrium toward the imino form, but can-not change the preference of amino form.

6. The NICS values for the amino forms are ��10 ppm, smaller than those of imino forms(� �8 ppm), showing the stronger aromatic-ity of amino forms.

7. Theoretical results of the UV/Vis spectra ofthe tautomers using the TDDFT method are inreasonable accord with the experiments, inwhich the �max of dimer A2 (Ci) is equal to 255nm, excellently consisting with the experi-mental value 255 nm and confirming the ex-istence of the dimer. The oscillator strength fof the amino forms is larger than the iminoform, and increases with the polarity of thesolvents. The difference in oscillator strengthbetween the two kinds of tautomers becomessmaller in polar solution probably because ofthe tautomeric shift toward imino forms in thepolar solvents.

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TABLE IV ____________________________________________________________________________________________Calculated the maximal adsorption wavelength �max (nm), the corresponding vertical excitation energies E(eV), and the oscillator strengths f at the B3LYP/6-31�G(d,p) level.

Gas Water CCl4E �max f E �max f E �max f

A 5.14 241 0.1186 5.07 244 0.1536 5.09 243 0.1143B(Cs) 5.20 238 0.002 4.98 249 0.1327 5.29 234 0.0020A � H2O 5.07 245 0.1568 5.05 245 0.1551 — — —B � H2O 4.95 250 0.1276 4.98 249 0.1512 — — —A � 2H2O 5.02 247 0.157 5.02 247 0.1636 — — —B � 2H2O 4.94 251 0.1444 4.96 250 0.1551 — — —A � 3H2O 5.03 247 0.1597 5.03 247 0.1638 — — —B � 3H2O 4.96 250 0.1255 4.96 250 0.1575 — — —A2(Ci) 4.85 255 0.0315 4.86 255 0.0468 4.86 255 0.0355B2(C2h) 4.79 259 0.0039 4.81 258 0.0466 4.81 258 0.0180



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