Amino–imino tautomerism of mono- and diaminothiazoles: Quantum chemical study

Journal of Molecular Structure: THEOCHEM 817 (2007) 125–136 www.elsevier.com/locate/theochem

Amino–imino tautomerism of mono- and diaminothiazoles: Quantum chemical study Adel A. Mohamed *, Arwa W. El-Harby Umm Qurah University, Science Faculty, Chemistry Department, Makkah, Saudi Arabia Received 25 November 2006; received in revised form 22 April 2007; accepted 23 April 2007 Available online 29 April 2007

Abstract The amino–imino tautomerism of mono- and diaminothiazoles in the gas, water and CCl4 phases was investigated using the B3LYP and MP2(full) levels with the 6-311++G(d,p) basis set. The MP2 method predicted accurately the geometrical parameters of the compounds studied and showed that the amino forms predominate in solution as well as the gas phases. The tautomeric process is endothermic with a small entropy contribution to Gibbs free energy. Single point calculations at the MP4/6-311++G**, CISD/6-31+G**or QCISD/6-31+G**levels were also performed to improve the thermochemical values. 2-Aminothiazole-4(5H)-imino was found to be the most stable structure in gas and solution phases in good agreement with the experimental data. At the QCISD/6-31G*and CISD/ 6-31G*levels the diimino form was more stable than the corresponding diamino form 24ATH whereas the MP2 level resulted in stabilization of the diamino form 24ATH over the imino form 2A5ITH. For the 2,5-diamino isomer 25ATH the calculations at all levels showed that the diamino form is the stable configuration in the gas or solution phases.  2007 Elsevier B.V. All rights reserved. Keywords: Aminothiazoles; Diaminothiazoles; Ab initio calculations; Tautomerism

1. Introduction Tautomerism is involved in many chemical processes, including condensation reactions, proton transfer processes and hydrogen bonding. The synthesis of heterocyclic rings containing S and N atoms is attractive due to their applications in pharmacology [1,2]. Naturally occurring and synthetic thiazole derivatives find applications as antibiotic, anti-inflammatory and fungicidal [3–6]. The use of 2-aminothiazole derivatives as inhibitors of human cancer and Alzheimer’s disease was investigated [7–11]. Those derivatives are also used in the syntheses of various types of dyes [12–15]. Most theoretical and experimental studies have concentrated on the tautomerism of 2-hydroxypyridine, uracil, * Corresponding author. Permanent address: Helwan University, Faculty of Science, Chemistry Department, Helwan, Cairo, Egypt. Tel.: +96625542075; fax: +96625542673. E-mail address: [email protected] (A.A. Mohamed).

0166-1280/$ - see front matter  2007 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2007.04.024

thymine, cytosine and pyrazine [16–24]. Yet, thiazole derivatives were found to be more suitable as models in investigating the tautomerism of the amino group in heterocyclic series than pyridine derivatives [25]. In addition, solvent effects often play an important role in organic chemistry, since chemical equilibria are substantially modified by a change of molecular environment. The pKBH+ values of a number of 2-aminothiazoles and their derivatives showed that these generally exist in the amino aromatic form and are protonated at the aza-nitrogen [26]. The solution IR spectra shows NH2 stretching bands corresponding to the free and associated molecules. This indicates the predominant existence of the amino form in solutions [27,28]. The 1H NMR of several 2,4-diaminothiazoles and their hydrohalide salts shows that the imino form is prevalent [29]. The aim of the present work is to (i) check the validity of different theoretical methods to study the tautomerism of aminothiazoles (ii) obtain an accurate theoretical data of the geometrical structure, relative stability, dipole

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moment and other ground state properties of each tautomer in gas and in apolar and polar solvents (iii) study the mechanism of 1,3-sigmatropic rearrangement for the transformation between different tautomers (iv) evaluate the thermodynamic and activation parameters (v) explore the solvent effects on the thermodynamic properties of the tautomers and their prototropic equilibrium. 2. Computational methods The molecular orbital calculations were carried out using the GAMESS 6.4 program [30]. All molecules and conformers were fully optimized without any constrains at the two levels viz., the density functional theory (B3LYP) [31,32] and the Mu¨ller Plesset (MP2(full)) [33], with the basis set 6-311+G** [34]. The nature of each stationary point was characterized by calculating the corresponding vibrational frequencies. The transition state is that with an imaginary frequency. The use of B3LYP method is due to its properly prediction of the higher stability of imino tautomers and its well reproducibility concerning energy differences obtained by the conventional ab initio methods [35]. Single point calculations using fourth-order Moller–Plesset [36] including triple and quadruple excitations MP4(SDTQ)fc/6-311++G**, MP4(SDTQ)-fc/6-31+G** were performed at the B3LYP and MP2 geometries. In addition, the quadratic configuration interaction including single and double excitations QCISD [37] and CISD [38] methods at the 6-31+G** and 6-31G* basis sets was done for the same two geometries. The thermodynamic parameters of the tautomeric equilibrium in the gas phase, were calculated in the usual way. The solute–solvent effect was taken into account by using the polarized continuum model (PCM) [39]. Single point calculations were performed based on the assumption that the structures did not change from gas to the solution phases [40,41]. The gas phase molecular geometries obtained at the B3LYP/6-311++G** level were used for the PCM calculations. The solvation free energies DGsoln were calculated as the difference between the energies in solution DGs and gas phase DGg using the relation: DGsoln ¼ DGs þ DGg 3. Results and discussion 3.1. Geometry 3.1.1. Aminothiazoles IR [27,42], X-ray [43,44], 1HNMR [29,45,46] spectral data and pKa measurements [26] of 2-aminothiazole indicated that the amino form 2ATH is usually present in larger amounts than thiazole-2(3H)-imino 23ITH or thiazole-2(5H)-imino 25ITH forms. The structure and numbering system of the studied aminothiazoles are shown in Fig. 1. The geometries of the three tautomers obtained

by the B3LYP and MP2 methods as well as the experimental X-ray [43] and vibrational [42] together with the corresponding values for the transition states are also shown in Table 1. The calculations showed that 2ATH, 23ITH and 25ITH assume planar configurations with the exocyclic N-atom of 2ATH slightly out of the thiazole ring plane. The bond lengths of the thiazole ring are intermediate between single and double bonds indicating the aromatic character. Comparison to experimen´˚ tal results, double bonds are longer by only 0.006 A while the maximum error for single bond length is ´˚ 0.015 A whereas the calculated bond angles at the two levels show an error of about 1 (cf. Table 1). It must be emphasized that increasing the basis set size by additional higher momentum angular functions is sufficient for very accurate estimation of ground state properties. Similar accurate results using the MP2 and B3LYP methods were also found for the geometries of various heterocycles [47–49]. The geometrical parameters of 23ITH and 25ITH are totally different from the corresponding amino tautomer, due to disappearance of ring aromaticity. The C2S1 and C2N3 bonds became longer reaching single bonds while the C2N6 and C4N3 bonds ´˚ shorten by about 0.1 A reaching pure double bond length. There is a scarce information in literature concerning 5-amino isomer with respect to the other two position isomers, due to the difficulty of the preparation. Table 1 shows the optimized geometrical parameters of 4-aminothiazole 4ATH and its imino form 45ITH calculated at the same levels. Comparing the geometrical parameters of 4ATH and 2ATH shows that the two C2S1 and C5S1 bonds become shorter while the C–NH2 ´˚ and C4–C5 bonds elongate by 0.013 A . On the other hand, the geometrical parameters of 5-aminothiazole 5ATH show the elongation of the C–NH2 and C4–C5 bonds and shortening of C4–N3 bond. This is attributed to the difference in the extent of nitrogen lone pair conjugation in the three isomers. 3.1.2. Diaminothiazoles 2,4-Diaminothiazole can exist in five forms viz., 2,4-diaminothiazole 24ATH, 4-aminothiazole-2(3H)-imino 4A3ITH, 4-aminothiazole-2(5H)-imino 4A5ITH, 2-aminothiazole-4(5H)-imino 2A5ITH and thiazole-2(3H),4(5H)diimino 3I5ITH (Fig. 2). The five tautomres represent stationary point minima in the potential energy surface. The geometrical parameters of the most stable conformers of the above forms are collected in Table 2. The presence of the two amino groups remarkably affects the C–S and C5–C4 bond lengths. The C–S and N3C4 single bonds elongate and the C5–C4 and N3C2 double bonds shorten comparing to their values in 2ATH and 4ATH. This means that the contribution of the N3 lone pair of electrons in ring resonance in case of diamino 24ATH is lower than in case of 2ATH and 4ATH. The differences in bond lengths between the imino forms of mono and diaminothazoles are attributed to the contribution of N3 lone pair in ring resonance.

A.A. Mohamed, A.W. El-Harby / Journal of Molecular Structure: THEOCHEM 817 (2007) 125–136

H

9

H7

4

H

9

N

3

H 10

5

N

4

2

2

N6 H

S 1

H 10

5

S 1

8

H

6N

7

5

Thiazole-2(5H)-imino 25IT H

6

N3 S

H9

2

5

N

H9

2

1

Thiazole-4(5H)-imino 45ITH

3 7

H 4

H

N3

5

S

6

S

10

10 4

N3

4

5

N 8H

N

7 H H

4ATH

7H

N6 H

8

2-Aminothiazole 2ATH

4-Aminothiazole

H

S 1

H

1

10

3

H8

4

7

H

N

2 5

H 10

H8

10

4

H 7

8

T h iazole-2(3H)-imino 23ITH

H 6N

H

9

3

127

2

H9

N

1

8H

S

6

2

H9

1

5-Aminothiazole

Thiazole-5(4H)-imino

5AT H

54ITH

Fig. 1. Structure and numbering system of 2-aminothiazole (2ATH), 4-aminothiazole (4ATH), and 5-aminothiazole (5ATH) tautomers.

Table 1 Geometrical parameters of 2-, 4-, and 5-aminothiazole tautomers and their TSs calculated at the B3LYP and MP2/6-311++G**levels ˚ Bond length, A Bond angle, deg Expa Expb 2ATH 4ATH 5ATH 23ITH 25ITH 45ITH 54ITH c 2 ATH/23ITH TS c 2 ATH/25ITH TS c 4 ATH/45ITH TS c 5 ATH/54ITH TS

S1C2

S1C5

C2N3

N3C4

C4C5

CN6

1.746 1.724 1.767 1.739 1.735 1.713 1.761 1.729 1.809 1.780 1.805 1.779 1.766 1.746 1.792 1.770 1.745 1.728 1.814 1.786 1.754 1.731 1.841 1.795

1.750 1.731 1.749 1.722 1.736 1.709 1.750 1.726 1.768 1.747 1.823 1.804 1.833 1.810 1.814 1.785 1.780 1.747 1.825 1.774 1.809 1.776 1.744 1.730

1.306 1.304 1.298 1.310 1.299 1.317 1.291 1.313 1.385 1.383 1.425 1.429 1.277 1.289 1.086 1.087 1.345 1.347 1.379 1.401 1.302 1.314 1.270 1.292

1.392 1.372 1.379 1.376 1.378 1.368 1.376 1.370 1.385 1.381 1.271 1.282 1.416 1.420 1.450 1.452 1.372 1.375 1.313 1.311 1.372 1.375 1.412 1.410

1.310 1.367 1.356 1.370 1.372 1.382 1.369 1.380 1.341 1.352 1.506 1.504 1.533 1.527 1.529 1.523 1.356 1.367 1.445 1.457 1.456 1.449 1.448 1.441

1.300 1.387 1.377 1.389 1.390 1.398 1.393 1.402 1.272 1.285 1.262 1.273 1.266 1.276 1.260 1.274 1.321 1.335 1.326 1.346 1.314 1.324 1.313 1.327

Values in italic refer to MP2. a X-ray results obtained from Ref. [43]. b IR results obtained from Ref. [42]. c Transition state.

N6H7 0.900 1.011 1.013 1.009 1.011 1.011 1.013 1.571 1.562 4.540 4.525 1.781 1.767 1.778 1.726 1.410 1.431 1.383 1.350 1.352 1.350 1.373 1.321

CH7

1.094 1.094 1.089 1.091 1.094 1.093 — 1.406 1.370 1.483 1.470 1.502 1.477

N3C2S1

C4N3C2

C5C4N3

XCN6

CNH7

115.8 113.6 114.8 115.3 115.3 115.4 114.7 115.5 106.4 107.0 111.9 112.8 119.8 120.5 119.1 119.8 112.2 112.3 114.2 114.5 119.0 119.6 117.0 118.4

110.2 110.1 110.8 109.9 111.0 110.1 111.5 110.0 117.0 116.6 112.7 111.3 112.0 110.4 112.8 111.2 113.9 113.5 102.3 102.4 107.2 105.6 112.0 109.7

116.2 124.8 116.7 116.0 115.2 115.2 116.0 116.1 114.2 113.3 120.3 120.2 113.5 113.9 111.7 111.5 114.1 112.9 116.1 115.8 119.6 119.5 111.8 112.2

119.8 121.3 121.1 121.1 117.5 118.1 129.3 129.0 130.4 130.6 121.9 121.9 125.6 125.3 123.3 122.3 116.7 117.6 138.0 140.6 108.6 110.4 108.4 108.4

119.0 113.4 110.6 115.8 113.7 113.4 111.4 118.7 118.7 110.7 110.0 110.8 109.9 109.7 110.1 76.6 76.6 83.6 86.6 78.7 77.4 70.2 70.3

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H 12 9

H N 11

N3

4

11

H7 H

H 12

H 12

9

5

10

N6 H

2

S 1

H7 N3

H N 4

H 10

5

9

S 1

8

10

24ATH

4A3ITH 12

N3 S 1

H7 N3

4

H

N6 H8

2

5

S

10

N

2

1

6

H

8

Thiazole-2(3H),4(5H)-diimino

4A5ITH

3I5ITH

H

4

11 H

3

5

N

N

2

S

9

H

H

10

N

H7

11 H

H8

12

N 3

5

S

9

H

H

47

N

6

1

N

2

6

1

H

8

2,5-Diaminothiazole

5-Aminothiazole-2(3H)-imino

25ATH

3I5ATH

10

H 11 H

10

H7

4

N3

11

H H

5

N 12

N

4-Aminothiazole-2(5H)-imino

10

12

2-Aminothiazole-4(5H)-imino

11 H

7

5

1

H12 9

4

H H 10

H

9

4

N

3

5

S

2

1

N 6

H7 N6 H

2

2A5ITH

N

11 H

S

8

4-Aminothiazole-2(3H)-imino

H

5

8

2,4-Diaminothiazole

9

N

4

H H

N6 H

2

N 3

11

N H8

Thiazole-2(3H),5(4H)-diimino

12

H

9

2

S

N 6

1

H7 H8

2-Aminothiazole-5(4H)-imino

3I4ITH

2A4ITH

Fig. 2. Structure and numbering system of 2,4-diaminothiazole (24ATH), 2,5-diaminothiazole, (25ATH) and their tautomers.

2A5ITH, 4A3ITH and 4A5ITH exhibit more conjugation than in case of mono iminothiazoles as indicated by comparing the bond lengths values of thiazole rings in the two series of compounds. The bond length C2–N6 is 1.265, 1.272 and ˚ for 3I5ITH, 4A3ITH and 4A5ITH, respectively. 1.264 A Structure 4A3ITH has the highest extent of conjugation of N3 lone pair with the C2–N6 bond. On the other hand, the least conjugation is found in the 3I5ITH conformer because of the N3 lone pair participation in resonance with the two exocyclic amino groups. To elucidate the effect of –NH2 group position on structural properties and tautomeric process of diaminothiazole, the compound 2,5-diaminothiazole 25ATH was studied and the results are depicted in Table 2. The presence of the second –NH2 group in position five results in lengthening C2S1,C5S1, C4C5 and C2N6 bonds compared to 2ATH or 24ATH and shortening C2N3. This means that it decreases the extent of delocalization over the thiazole ring. The same trends were found in case of 5-aminothiazole2(3H)-imino 5A3ITH compared to 4A3ITH isomers.

3.2. Energies and relative stabilities 3.2.1. Aminothiazoles The tautomeric equilibrium for of 2-aminothiazole can be represented by the following sequence:

H N H N

S

H

N S

H

A

N S

H

B1

B2

2ATH

23ITH

N H H

H

+

N

H S C1

+

N

H H

25ITH

N S C2

N H

N

A.A. Mohamed, A.W. El-Harby / Journal of Molecular Structure: THEOCHEM 817 (2007) 125–136

129

Table 2 Geometrical parameters of 24ATH, 25ATH tautomers and their TSs calculated using the B3LYP and MP2 / 6-311++G** levels ˚ S1C5 C2N3 N3C4 C4 C5 C2N6 CN9 N6H7 Bond length, A S1C2 24ATH 25ATH 3I4ATH 2A5ITH 5I4ATH 3I5ITH 3I5ATH 2A4ITH 3I4ITH 24ATH/3I4ATH TS 24ATH/2A5ITH TS 24ATH/5I4ATH TS 25ATH/3I5ATH TS 25ATH/2A4ITH TS

1.758 1.733 1.771 1.744 1.802 1.777 1.791 1.771 1.820 1.791 1.803 1.781 1.812 1.783 1.812 1.788 1.801 1.779 1.740 1.723 1.785 1.760 1.817 1.786 1.740 1.730 1.851 1.809

1.756 1.727 1.771 1.741 1.775 1.755 1.830 1.809 1.821 1.803 1.837 1.817 1.786 1.763 1.811 1.786 1.791 1.771 1.783 1.752 1.825 1.792 1.841 1.775 1.816 1.768 1.752 1.737

1.299 1.309 1.293 1.307 1.388 1.389 1.289 1.294 1.397 1.407 1.383 1.387 1.378 1.382 1.268 1.280 1.380 1.391 1.346 1.347 1.316 1.319 1.362 1.389 1.346 1.346 1.271 1.289

1.381 1.377 1.383 1.378 1.390 1.389 1.395 1.404 1.288 1.291 1.378 1.382 1.396 1.395 1.444 1.449 1.454 1.456 1.376 1.377 1.356 1.364 1.329 1.314 1.373 1.379 1.420 1.417

1.365 1.372 1.359 1.373 1.346 1.352 1.537 1.525 1.518 1.512 1.525 1.517 1.343 1.353 1.532 1.522 1.520 1.512 1.365 1.370 1.466 1.457 1.459 1.461 1.359 1.371 1.438 1.434

1.376 1.389 1.383 1.393 1.272 1.283 1.351 1.361 1.264 1.275 1.265 1.276 1.273 1.284 1.371 1.378 1.267 1.277 1.321 1.335 1.345 1.359 1.329 1.349 1.323 1.338 1.379 1.385

1.392 1.400 1.401 1.405 1.398 1.402 1.270 1.278 1.354 1.363 1.271 1.279 1.400 1.404 1.260 1.273 1.263 1.275 1.389 1.396 1.314 1.320 1.358 1.377 1.398 1.404 1.317 1.330

1.011 1.013 1.012 1.014 2.573 2.561 1.008 1.011 4.532 4.506 2.561 2.547 2.572 2.542 1.011 1.013 2.687 2.661 1.414 1.433 1.008 1.010 1.343 1.321 1.414 1.435 1.012 1.014

N9H 1.009 1.012 1.012 1.013 1.011 1.013 2.763 2.885 1.005 1.008 2.865 2.791 1.012 1.013 2.744 2.666 2.674 2.621 1.009 1.012 1.328 1.314 1.006 1.010 1.010 1.012 1.361 1.362

Values in italic refer to MP2.

The calculated gas phase total energies and the relative stabilities of the different tautomers of 2ATH are given in Tables 3 and 4. According to the orientation of the H8 atom, the imino forms can exist in two conformers; B1 and B2 or C1 and C2, respectively. The form B1 was found to be more stable than B2 by 3.5 kcal/mol while C1 is less in energy than C2 by 1.23 kcal/mol at the B3LYP/6-311++G** level. Therefore, the amino conformer 2ATH together with the imino conformers B1 and C1 conformers will be used in this part of calculations. 2ATH form was found to be the most stable at both levels of calculations while the least one was 25ITH. The two imino 25ITH and 23ITH are, respectively, 11.72 and 7.76 kcal/mol higher than the amino form at the B3LYP/6-311++G** level. The values obtained at MP2 level are 14.38 and 12.23 kcal/mol. The addition of Zero point energy (ZPE) and thermal correction (TC) does not affect the order of relative stabilities. These results are in good agreement with the available experimental data [27,28,46] where the amino form was the only detected one. The tautomerization process 2ATH–23ITH passed through a barrier of 46.64 and 48.26 kcal/mol at the two levels. The Gibbs free energy change DG of the process was calculated at the two levels giving the values 7.18 and 10.59 kcal/mol. These values are close to

those obtained from enthalpy term DH alone. The entropy contribution is only 0.2 cal/mol indicating its negligible contribution to the Gibbs free energy. The corresponding equilibrium constant KT = [amino]/[imino] has the values: 1.82 · 105 and 5.74 · 107, respectively. The tautomeric constant (KT) was experimentally measured in water [26,50], the obtained values are 2.1 · 104 or 2.0 · 104. Other different theoretical levels were checked to find a more accurate reproduction of the experimental (KT) values. The results are summarized in Table 5. All methods over stabilize amino than imino forms with different extents. The smallest conversion energy DE value observed at the B3LYP/6-311++G** level was found to be 7.76 kcal/mol compared to 12.23 kcal/mol for the MP2/6-311++G** level. The single point calculations using MP4/6-311++G **, CISD/6-31+G** and QCISD/6-31+G** methods gave higher DE values than DFT one. However, the size of the basis set has a noticeable effect on DE value. Table 5 shows that the increase of the basis set size decreases the DE value. Consequently, using basis sets with more diffused and polarizated functions may approach the obtained experimental values. The effect of the amino group position on the energetics and thermodynamic properties of the studied tautomeric process was studied. The total energies of 4ATH and 5ATH are given in Table 3. The total energy of

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Table 3 Total energy Et in gas, water (w), and CCl4, net charges, zero point energy ZPE, thermal correction TC, ionization potential IP, energy gap DEg, dipole moment l in gas, water, and CCl4 of 2-, 4-, and 5-aminothiazoles tautomers calculated using B3LYP/6-311++G** and MP2/6-311++G** Parameter

2ATH

4ATH

5ATH

23ITH

25ITH

45ITH

54ITH

Et (gas) (a.u.)

624.51 623.46 45.02 45.37 48.42 48.77 74.30 74.44 624.51708 624.51124 6.074 8.536 8.52a 0.629 1.113 5.445 9.649

624.50 623.46 44.92 45.11 48.31 48.58 74.31 75.03 624.51167 624.50751 5.910 8.370

624.50 623.45 44.91 45.26 48.32 48.68 74.50 74.64 624.50641 624.49979 6.085 8.528

624.49 623.44 44.76 44.43 48.15 47.58 74.49 72.81 624.50592 624.49940 5.704 8.085

624.49 623.44 44.70 45.14 47.98 48.45 74.24 74.83 624.50060 624.49338 6.868 9.663

624.49 623.44 44.93 45.21 48.21 48.57 74.82 77.14 624.50170 624.49606 7.018 9.652

624.49 623.43 44.72 44.89 48.06 47.75 75.17 71.38 624.49505 624.48951 7.100 9.777

0.950 1.105 4.960 9.475

0.816 0.982 5.269 9.510

0.411 0.901 5.293 8.986

1.986 0.811 4.882 10.474

1.913 1.042 5.105 10.694

1.181 1.080 5.919 10.857

1.705 1.762 2.293 1.928

1.574 1.854 2.033 1.771

2.786 2.635 3.714 3.162

2.728 2.807 3.678 3.143

4.359 4.237 6.123 5.071

2.147 2.107 3.019 2.495

1.438 1.657 1.953 1.620

0.146 0.116 0.295 0.283 0.143 0.211 0.214 0.285 0.257 0.266

0.118 0.099 0.481 0.346 0.082 0.059 0.305 0.372 0.235 0.243

0.073 0.071 0.262 0.266 0.206 0.208 0.265 0.339 0.241 0.253

0.069 0.109 0.204 0.187 0.217 0.261 0.342 0.353 0.317 0.333

0.017 0.007 0.042 0.072 0.507 0.683 0.237 0.217 0.196 0.198

0.054 0.049 0.281 0.245 0.279 0.352 0.271 0.256 0.221 0.229

0.031 0.024 0.600 0.624 0.024 0.038 0.227 0.213 0.228 0.231

ZPE (kcal/mol) TC (kcal/mol) S (cal/mol/K) Et (W) (a.u.) Et (CCl4) (a.u.) IP (eV)

ELUMO (eV) DEg , (eV) l (D) (gas) (W) (CCL4) Charge N3 C4 C5 N6 H7

Values in italic correspond to MP2. a IP results (UV and visible spectra) obtained from Ref. [50].

4ATH is higher than that of 2ATH by 2.08 and 1.29 kcal/mol at the B3LYP and MP2 levels, respectively. The least stable isomer is 5ATH which is higher in energy than 2ATH by 7.44 and 6.54 kcal/mol at the two levels. This can be explained in terms of their number of resonance forms in each case. The tautomeric process of 4ATH given bellow was investigated. 45ITH (B) was found to be less stable than (C) tautomer by 3.68 kcal/mol at the B3LYP/6311++G** level, therefore (C) will be considered as the imino form. The reaction enthalpy DH between 4ATH and 45ITH is 7.33 and 11.10 kcal/mol at the B3LYP and

H

H

H N

N S

N

H N

N

H H

S

N

H H

S

4AT H

45ITH

45ITH

A

B

C

MP2/6-311++G** levels, respectively. The corresponding DG values are 7.17 and 10.47 kcal/mol and the KT values are 1.82 · 105 and 4.70 · 107 . Such high values of the thermodynamic parameters support the existence of only 4ATH form. The reaction enthalpy DH of 5ATH tautomerization was the lowest in the series at both levels (5.60 and 8.60 kcal/mol, respectively). The tautomeric constant KT in this case was 9.07 · 103 at the B3LYP method and 1.03 · 107 at the MP2 method, Table 4. On comparing the results of the tautomerization of the three aminothiazoles 2ATH, 4ATH and 5ATH, one can observes: (1) The amino form predominates as indicated from DG and KT parameters. (2) The activation energy of 2ATH–23ITH is lower than that of 4ATH and 5ATH where the differences are 17.35 and 20.05 kcal/mol, respectively, at the B3LYP level. (3) The DH and DG values of the two isomers 2ATH and 4ATH are similar.

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Table 4 Relative stabilities (conversion barrier) DEa(kcal/mol), activation energy Ea(kcal/mol), reaction energy DE (kcal/mol), reaction enthalpy DH (kcal/mol), the Gibbs free energy change DG (kcal/mol), and equilibrium constant KT for 2ATH, 4ATH, 5ATH, 24ATH and 25ATH calculated at the B3LYP, and MP2/6-311++G** levels DEa

Reaction

Ea

DE

DH

DG

2ATH–23ITH

54.34 55.18

46.64 48.26

7.76 12.23

7.23 10.10

7.18 10.59

2ATH–25ITH

106.24 103.10 71.69 74.49 74.39 76.44 55.30 56.08 63.35 66.26 97.31 95.43

98.47 95.31 64.14 67.55 65.96 68.30 48.17 49.45 55.62 59.30 89.94 88.22

53.68 54.34 71.94 73.21

45.38 47.44 63.70 65.10

11.72 14.38 7.42 11.01 6.05 9.90 9.90 13.25 0.66 1.68 0.04 2.65 1.88 4.89 7.88 12.30 0.43 3.63 6.46 10.33

10.96 13.83 7.33 11.10 5.60 8.60 9.81 13.02 0.84 2.12 0.17 2.90 2.23 5.49 7.32 11.64 6.7 · 103 3.28 6.04 10.10

10.98 13.71 7.17 10.47 5.40 9.57 9.83 13.16 1.28 2.30 0.35 2.90 2.08 5.79 7.19 11.66 5.89 · 102 3.35 5.94 10.32

4ATH–45ITH 5ATH–54ITH 24ATH–3I4ATH 24ATH–2A5ITH 24ATH–5I4ATH 24ATH–3I5ITH 25ATH–3I5ATH 25ATH–2A4ITH 25ATH–3I4ITH

Log K 5.259 7.759

8.048 10.05 5.259 7.672 3.957 7.013 7.207 9.648 0.936 1.688 2.54 · 101 2.124 1.525 4.244 5.272 8.546 4.32 · 102 2.452 4.351 7.561

KT 1.82 · 105 5.74 · 107 2.1 · 104a 2.0 · 104b 1.12 · 108 1.12 · 1010 1.82 · 105 4.70 · 107 9.07 · 103 1.03 · 107 1.61 · 107 4.44 · 109 0.12 48.77 0.56 1.33 · 102 33.49 1.75 · 104 1.87 · 105 3.52 · 108 9.05 · 101 2.83 · 102 2.24 · 104 3.64 · 107

Values in parenthesis refer to MP2. DH = DE + D(ZPE) + D(TC). a Results obtained from Ref. [26]. b Results obtained from Ref. [48].

3.2.2. Diaminothiazoles H

H H

N

N

H

N

H N

N

S

N

S H

H H

N

24ATH

3I5ITH

S

N H

2A5ITH H

N

H

H

H

H H

24ATH > 2A5ITH > 4A5ITH > 3I5ITH > 4A3ITH:

N

H H

In case of MP2 results, the stability of the diamino form 24ATH increased and thus the order of the stability becomes:

N S

H

H

N H H

N

N H S

N

H

3I4ATH

5I4ATH

The thermodynamic parameters of diaminothiazole tautomers are depicted in Tables 4 and 6. 24ATH was found to be more stable than its position isomer 25ATH by 6.31 kcal/mol. All the five structures of 24ATH represent stationary points minima in their potential energy surface on both levels. The results obtained using B3LYP/6311++G** method showed that the most stable one in gas phase was the imino 2A5ITH i.e. local minimum, while 4A3ITH was the highest one in energy. The order of stability of the five structures is; 2A5ITH > 24ATH  4A5ITH > 3I5ITH > 4A3ITH:

Angelova et al. [51] studied the tautomerism of 2,4-substituted azilidines using HF and MP2/6-31+G**. The two imino forms 4A5ITH and 2A5ITH were detected where the latter was more stable by only 0.18–0.28 kcal/mol. 24ATH has 0.78 and 1.79 kcal/mol more than the two imino 4A5ITH and 2A5ITH, respectively, at the MP2/6-31+G** level. Experimentally, NMR [29] studies showed that the imino form 2A5ITH is the detected species of 2,4-diaminothiazole. The other structures were unlikely in DMSO because the NMR spectra showed two protons bonded to C5 atom. Therefore, we conclude that the B3LYP method described the equilibrium better than MP2 method. Table 7 shows the results of the above tautomerism obtained using higher correlation levels. The MP4(SDTQ)/6-31+G** and MP4(SDQ)/6-31+G** levels gave the same trend obtained using B3LYP. The relative energy (DE) values became more negative i.e. 2A5ITH and 4A5ITH forms were more stabilized. At the same time, the QCISD/6-31G* and CISD/6-31G* methods stabilized 3I5ITH over 24ATH. This means that the B3LYP/ 6-311++G** is a very good choice for thermochemical

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Table 5 Relative energies (kcal/mol) for the tautomerism of monoaminothiazoles calculated at different levels Level

DEt 2ATH/23ITH

B3LYP/6-31+G* B3LYP/6-311++G** B3LYP/6-311++G**// MP2/6-311++G** B3LYP/6-311++G**//MP4(SDQ)/6-311++G** B3LYP/6-311++G**//MP4(SDTQ)/6-311++G** B3LYP/6-311++G**//CISD/6-31+G** B3LYP/6-311++G**// QCISD/6-31+G** MP2/6-31+G* MP2/6-311++G** MP2/6-311++G**//MP4(SDQ)/6-311++G** MP2/6-311++G**//MP4(SDTQ)/6-311++G** MP2/6-311++G**//CISD/6-31+G** MP2/6-311++G**// QCISD/6-31+G**

8.45 7.76 12.03 9.59 10.78 9.57 9.44 13.92 12.23 9.72 11.02 9.48 9.46

2ATH/25ITH

4ATH/45ITH

5ATH/54ITH

11.72 14.19 9.35 10.95 10.39 9.43

7.24 10.75 5.74 7.22 6.19 5.35

6.05 9.68 4.29 5.78 5.29 3.78

14.38 9.36 11 10.33 9.20

11.01 5.62 8.42 5.85 5.13

9.9 4.12 5.82 5.21 3.51

Table 6 Total energy Et (a.u.), zero point energy ZPE (kcal/mol), thermal correction TC (kcal/mol), entropy S (cal/mol/K), ionization potential IP (eV), energy gap DEg (eV), net charges and dipole moments l (D) in gas, water (w) and CCl4 of 24ATH, 25ATH and their tautomers calculated at the MP2 and B3LYP/6-311++G** levels

Et (gas) Et (w) Et (CCl4) ZPE TC S IP (eV) ELUMO (eV) DEg (eV) DM (gas) DM (W) DM (CCL4) Charge N3 C4 C5 N6 H7 N9 H11

24ATH

25ATH

3I4ATH

2A5ITH

4A5ITH

3I5ITH

3I5ATH

2A4ITH

3I4ITH

679.88601 -678.71328 679.89950 679.89172 55.46 55.98 59.79 60.35 81.03 81.52 5.320 7.878 0.495 1.129 4.825 9.007 0.566 0.601 0.792 0.649

679.87596 -678.70513 679.89031 679.88192 55.45 56.12 59.85 60.48 81.77 81.60 5.573 8.038 0.536 1.042 5.037 9.080 0.851 1.055 1.274 1.006

679.87023 -678.69217 679.88552 679.87679 55.45 55.92 59.71 60.18 80.96 81.03 5.377 7.861 0.743 0.833 4.634 8.694 3.751 3.661 4.946 4.276

679.88706 -678.71061 679.90251 679.89376 55.38 56.34 59.69 60.43 82.50 80.89 6.615 9.475 0.917 0.906 5.698 10.381 4.193 3.825 5.711 4.813

679.88607 -678.70905 679.90523 679.89415 55.43 56.22 59.69 60.36 81.63 81.54 6.512 9.407 1.045 0.626 5.467 10.033 6.633 6.074 9.182 7.683

679.88301 -678.70548 679.89765 679.88923 55.76 56.47 59.84 60.46 81.54 80.53 7.086 10.014 0.846 0.917 6.240 10.931 3.123 3.206 4.198 3.544

679.86341 -678.68553 679.87879 679.86993 55.16 55.81 59.58 60.13 82.18 81.53 5.331 7.837 0.629 0.819 4.702 8.656 3.907 3.831 5.205 4.467

679.87528 -678.69935 679.88884 679.88093 55.31 56.04 59.57 60.21 81.99 81.37 6.765 9.679 0.833 1.007 5.932 10.686 2.830 2.564 3.874 3.196

679.86567 -678.68867 679.88142 679.87217 55.34 56.16 59.54 60.21 82.11 80.87 7.021 9.940 0.950 0.838 6.071 0.778 3.007 2.730 4.092 3.444

0.197 0.153 0.480 0.362 0.103 0.027 0.229 0.301 0.253 0.263 0.328 0.397 0.237 0.266

0.141 0.110 0.256 0.272 0.210 0.215 0.223 0.296 0.254 0.264 0.317 0.373 0.242 0.255

0.134 0.135 0.434 0.296 0.167 0.041 0.353 0.350 0.299 0.304 0.343 0.422 0.258 0.267

0.152 0.132 0.200 0.139 0.340 0.422 0.249 0.290 0.275 0.278 0.317 0.291 0.221 0.228

0.131 0.098 0.052 0.028 0.380 0.454 0.286 0.284 0.214 0.228 0.317 0.353 0.267 0.264

0.045 0.054 0.090 0.024 0.433 0.542 0.317 0.304 0.219 0.331 0.346 0.320 0.219 0.190

0.107 0.090 0.083 0.166 0.357 0.271 0.339 0.340 0.315 0.305 0.295 0.359 0.238 0.252

0.124 0.094 0.565 0.602 0.054 0.055 0.222 0.295 0.258 0.270 0.233 0.213 0.214 0.216

0.104 0.102 0.440 0.465 0.109 0.136 0.285 0.266 0.262 0.261 0.234 0.210 0.212 0.219

calculations and gives better results than MP2/ 6-311++G** method. The DFT, MP2 and MP4 levels showed that the amino form 25ATH is lower in energy than the three imino tautom-

ers 5A3ITH, 3I4ITH and 2A4ITH with a stability order 25ATH > 2A4ITH > 3I4ITH > 5A3ITH. CI calculations using QCISD and CISD levels stabilized 2A4ITH over 25ATH, Table 7. The differences in energy between these

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133

Table 7 Relative energies (kcal/mol) for different tautomers of 2,4- and 2,5-diaminothiazoles calculated at different levels Level

DEt

B3LYP/6-311++G** B3LYP/6-311++G**// MP2/6-31+G** B3LYP/6-311++G**//MP4(SDQ)/6-31+G** B3LYP/6-311++G**//MP4(SDTQ)/6-31+G** B3LYP/6-311++G**//CISD/6-31G* B3LYP/6-311++G**// QCISD/6-31G* MP2/6-311++G** MP2/6-311++G**//MP4(SDQ)/6-31+G** MP2/6-311++G**//MP4(SDTQ)/6-31+G** MP2/6-311++G**//CISD/6-31G* MP2/6-311++G**// QCISD/6-31G*

24ATH / 2A5ITH

24ATH / 4A3ITH

24ATH/ 4A5ITH

24ATH / 3I5ITH

25ATH/ 2A4ITH

25ATH/ 3I4ITH

25ATH/ 3I5ATH

0.66 0.77 1.69 1.11 3.56 3.90 1.68 1.97 0.72 3.39 3.90

9.9 12.96 10.72 11.85 11.00 10.43 13.25 10.59 11.87 10.89 10.41

0.04 1.82 0.99 0.13 3.11 3.34 2.65 1.37 0.33 3.29 3.55

1.88 4.22 0.7 2.00 0.7 1.61 4.89 0.53 1.92 0.29 0.132

0.43 3.00 0.50 0.48 1.41 2.63 3.63 0.88 0.19 1.37 2.82

6.46 12.17 9.76 10.90 10.06 9.60 10.33 4.99 6.76 4.38 3.42

7.88 10.11 5.56 7.27 4.41 3.78 12.3 9.45 10.75 9.94 9.54

Table 8 The solvation free energy Gs ; relative solvation free energy DGs , the relative free energy in solution DGsoln , the relative free energy in gas phase DGg , and the equilibrium constants Ksoln in water (w) and CCl4 of mono (2ATH, 4ATH, 5ATH) and diaminothiazoles (24ATH, 25ATH) and their tautomers Tautomer

Gs (kcal/mol)

DGs (kcal/mol)

Monoamino 2ATH(w) (CCl4) 23ITH(w) (CCl4) 25ITH(w) (CCl4) 4ATH(w) (CCl4) 45ITH(w) (CCl4) 5ATH(w) (CCl4) 54ITH(w) (CCl4)

6.38 2.72 7.14 3.05 7.76 3.23 5.06 2.45 6.23 2.69 7.12 2.97 6.04 2.57

0.00 0.00 0.76 0.33 1.38 0.51 0.00 0.00 1.17 0.24 0.00 0.00 1.08 0.40

Diamino 24ATH(w) (CCl4) 3I4ATH(w) (CCl4) 2A5ITH(w) (CCl4) 5I4ATH(w) (CCl4) 3I5ITH(w) (CCl4) 25ATH(w) (CCl4) 3I5ATH(w) (CCl4) 2A4ITH(w) (CCl4) 3I4ITH(w) (CCl4)

8.46 3.58 9.59 4.12 9.69 4.20 12.02 5.07 9.19 3.90 9.00 3.74 9.65 4.09 8.51 3.55 9.88 4.08

0.00 0.00 1.13 0.54 1.23 0.62 3.56 1.49 0.73 0.32 0.00 0.00 0.65 0.35 0.49 0.19 0.88 0.34

tautomers are 0.43, 6.46 and 7.88 kcal/mol at the B3LYP level, respectively, Table 4. The Gibbs free energy change DG of the transformation 25ATH to 2A4ITH is only 0.06 kcal/mol indicating the existence of the two forms in equal amounts (KT = 0.905). On the other hand, the stability

DGg (kcal/mol)

DGsoln (kcal/mol)

Ksoln

6.42 6.85 9.60 10.47

5.08 · 104 1.05 · 105 1.09 · 107 4.72 · 107

7.17

6.00 6.93

2.50 · 104 1.2 · 105

5.40

6.48 5.80

5.62 · 104 1.78 · 104

9.83

8.70 9.29 2.51 1.90 3.91 1.84 1.35 1.76

7.18 10.98

1.28 0.35 2.08

7.19 5.89 · 102 5.94

6.54 6.84 0.43 0.13 5.06 5.60

2.38 · 106 6.44 · 106 1.54 · 102 4.05 · 102 1.36 · 103 4.48 · 102 9.76 19.50

6.22 · 104 1.03 · 105 2.07 1.25 5.11 · 103 1.27 · 104

of the other two imino forms 5A3ITH and 3I4ITH are lower than 25ATH, and hence their ratios are negligible compared to 25ATH or 2A4ITH tautomers (KT = 1.87 · 105 and 2.24 · 104), respectively. The MP2 level gives the same order of stability with equilibrium constant (KT = 2.83 · 102,

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3.64 · 107, 3.52 · 108) i.e. the stability of 2A4ITH decreases at MP2 level. The activation energy Ea of 24ATH is lower than for 25ATH (2.79 kcal/mol).

H N H

H N H

H

N

H H

S

H

H

H

25ATH

N

H

N

S

N H

N

N H

H

3I4ITH

N

H N

S

H H S

N H

3T5AH

N

H

The EHOMO, ELUMO and DEg values for the different diaminothiazoles isomers are given in Table 6. These results give the following: (1) Existence of second NH2 group destabilizes the HOMO and LUMO of diaminothiazoles, leading to lower IP values. (2) EHOMO of 25ATH (8.038 eV) is more stable than that of 24ATH (7.878 eV), while the reverse order is found for ELUMO (1.042 and 1.129 eV), respectively at the MP2 level. (3) The order of EHOMO for the two series at the MP2 level is

H

2A4ITH

4A3ITH  24ATH < 4A5ITH  2A5ITH < 3I5ITH 5A3ITH < 25ATH < 2A4ITH < 3I4ITH

Comparing the results of diamino derivatives with that for mono derivatives (2ATH, 4ATH and 5ATH), one notices that (Table 4): (1) The amino substitution in the 4-position in 2ATH destabilizes the imino form, i.e. the process 24ATH– 4A3ITH becomes more endothermic. Consequently, the free energy change DG increases. In the same time, the activation energy Ea has the same values in both processes. The equilibrium constant KT (1.61 · 107) is higher than that for 2ATH (1.82 · 105) i.e. the 23ITH is more favored than 4A3ITH. (2) For 4ATH tautomerization, the introduction of the NH2 group in position two facilitates the hydrogen transfer process 24ATH–2A5ITH with DH = 0.84 kcal/mol, and a decrease in Ea (55.62 kcal/mol). This is reflected in the increase of the amount of imino form since the equilibrium ratio 24ATH/2A5ITH is 0.12 compared to 1.82 · 105 for 4ATH/45ITH ratio. (3) The existence of NH2 group in position four increases the stability and the abundance of the imino 4A5ITH to reach (0.56) instead of (1.12 · 108) in case of 5ITH. (4) The diimino 3I5ITH is only 2.23 kcal/mol more in energy than the (24ATH).

3.3. Ionization potential It is interesting to compare the calculated IP and energy gap DEg of 2ATH, 4ATH and 5ATH and their imino isomers. Table 3 gives the IP, ELUMO and energy gap DEg for the studied aminothiazoles. The MP2 results compare well with the available experimental values [52], while those calculated at B3LYP level are underestimated. The IP for aminothiazoles follows the order: 23ITH < 4ATH < 5ATH  2ATH < 45ITH  25ITH < 54ITH. The energy gap (DEg) which is considered as a measure of the reactivity of the compound follows the sequence 23ITH < 4ATH < 5ATH < 2ATH < 25ITH < 45ITH < 54ITH which means that 2ATH is less reactive than both of 4ATH and 5ATH isomers.

(4) The order of mono- and diaminothiazoles energy gap DEg is; 5ATH  2ATH > 4ATH > 25ATH  24ATH (5) i.e. the reactivity of the diamino is more than that of the mono ones. (6) The reactivity of 24ATH is nearly equal to that of 25ATH as indicated by their DEg values (9.007 and 9.080 eV). (7) The order of energy gap DEg for each diamino series at the MP2 method is: 4A3ITH < 24ATH < 4A5ITH < 2A5ITH < 3I5ITH 5A3ITH < 25ATH < 2A4ITH  3I4ITH 3.4. Dipole moment and solvent effect The Mu¨lliken charge density at different centers of 2ATH is given in Table 3 with the values of the dipole moment. The negative charge on exocyclic nitrogen atom N6 is higher than that on endocyclic atom N3, while the atomic charge on C5 is lower than that on C4. This charge distribution proves the existence of an intermolecular association by hydrogen bonding between the amino group of one molecule and the basic thiazolinic nitrogen of another molecule especially in the solid state [42,43]. The computed gas phase dipole moment of 2ATH is 1.762 and 1.705 D at the MP2 and B3LYP levels, respectively, which seems to be dominated by the lone pairs of exo and endocyclic nitrogen atoms with little perturbing effect of the sulfur lone pair. The charge distribution on different centers changes on going from amino to imino forms. The charge on N6 and C5 in the case of the imino form increases leading to an increase in its dipole moment. Therefore, one expects a pronounced solvent effect on the equilibrium ratio of amino and imino forms in different solvents of different polarities. The calculated dipole moment of 4ATH is 1.574 D while it is 1.705 D for 2ATH isomer and 2.786 D for 5ATH, at the B3LYP level. This means that dipole vector of the exocyclic nitrogen atom governs the total

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dipole of aminothiazole system more than the lone pair of N or S atoms. The dipole moment of the corresponding imino forms of 2ATH and 4ATH are higher than those of their amino forms while for 5ATH, the reverse trend is observed. Therefore, their tautomerization processes will be affected by the solvent polarity in different directions. In case of 2,4-diamino, the Mu¨lliken atomic charge on the two exocyclic and endocyclic nitrogen atoms increases (more basic) compared to mono derivatives. This leads to a decrease in their dipole moment. Such is attributed as the opposite directions of dipole vectors of the ring and the two amino groups. The gas phase dipole moment values of the five tautomers of 2,4-diaminothiazole vary from 0.566 to 6.633 D at B3LYP level (Table 6) in the order: 24ATH < 3I5ITH < 4A3ITH < 2A5ITH < 4A5ITH. The charge distribution of 24ATH is totally changed upon change of –NH2 position to 25ATH. A negative charge is transferred and concentrated on C2 atom leading to an increase of its dipole moment by 0.29 D. On the other hand, the dipole moment trend is (3.907 D) 5A3ITH > (3.007 D) 3I4ITH > (2.830 D) 2A4ITH > (0.831)25ATH. Tables 3 and 6 show the dipole moment of mono- and diaminothiazoles tautomers in gas phase, carbon tetrachloride (nonpolar, e = 36.44) and water (polar, e = 76). The following points can be withdrawn from these results: (1) All of amino forms 2ATH, 4ATH, and 5ATH and their imino tautomers are polar compounds and the 5ATH forms are more polar than 2ATH or 4ATH tautomers. (2) The dipole moment of amino form is lower than the corresponding imino tautomers in the three phases, except in case of 5ATH. (3) The dipole moment of all species increases in both solvents and it has maximum value in water (Table 4) i.e. stabilized in more polar medium (water) than in less polar solvent (CCl4). The free energy of solvation ðDGs Þ of 2ATH, 4ATH, 5ATH and their imino tautomers are given in Table 8. The results show that all species are more stabilized with different extents in both media with the greater stabilization in water. The relative free energies in the two solvents, DGsoln , and the equilibrium constants are given in the same table. Comparing each compound with its tautomers, the relative free energies ðDGsoln Þ in the two solutions are less positive than in gas phase DGg , leading to an increase in the fraction of the imino form, the reverse is found in case of 5ATH. The solvation energy of 24ATH tautomers (Table 8) shows that all the species have been stabilized in the two solvents more than in gas phase as in case of mono thiazole due to their high values of dipole moment. 24ATH is the least stabilized one while 4A5ITH is the most stabilized form in both solutions. Therefore, the amount of 4A5ITH becomes more predominant than 2A5ITH in both

135

solvents. The order of stability of 24ATH tautomers changed in both solutions to be 4A5ITH > 2A5ITH > 24ATH > 3I5ITH > 4A3ITH. In case of 25ATH, the relative free energy changes in solution show that the order of amounts of 25ATH tautomers becomes 25ATH > 2A4ITH > 3I4ITH > 5A3ITH, i.e. the relative stability of 25ATH and 2A4ITH exchanged from gas phase to solutions. 4. Summary Molecular orbital calculations were performed on 2-, 4- and 5-amniothiazoles using different calculation levels in order to study the 1,3-hydrogen transfer between the amino group and the endocyclic nitrogen atom or carbon atom at position five. Comparing the results of the three aminothiazoles isomers 2ATH, 4ATH and 5ATH, one notices that: (1) The total energy of the isomer 4ATH is higher than that of 2ATH while the highest is 5ATH. (2) Gibbs free energy change DG of the process is similar to the corresponding enthalpy DH, due to small contribution of the entropy. (3) For the three isomers, the amino forms are the predominant as indicated by DG and KT parameters. (4) The activation energy of 2ATH–23ITH is lower than that of 4ATH and 5ATH. (5) In spite of the greater solvent stability of the imino form, the amino is the predominant species in solution and gas phase. (6) The B3LYP/6-311++G** calculations showed that the order of stability of the five tautomers of 2,4-diaminothiazole is; 2A5ITH > 24ATH  5I4ATH > 3I5ITH > 3I4ATH. In case of MP2, the order became 24ATH > 2A5ITH > 5I4ATH > 3I5ITH > 3I4ATH. (7) The amino group in the position four destabilizes the imino form of 2ATH, i.e. the process 24ATH– 3I4ATH becomes more endothermic. At the same time the stability and percent of 5I4ATH increase. (8) For 4ATH tautomerism, the introduction of the second NH2 group in position two facilitates the hydrogen transfer 24ATH–2A5ITH . (9) All levels showed that the amino form 25ATH is lower in energy than the imino tautomers 5A3ITH, 3I4ITH and 2A4ITH with a stability order 25ATH > 2A4ITH > 3I4ITH > 5A3ITH. References [1] M. Hudlic, A. Pavlath, Chemistry of Organic Fluorine compounds II. A critical review, American Chemical Society, Washington, DC, 1995. [2] J.T. Welch, Tetrahedron 43 (1987) 3123. [3] P. Crews, Y. Kakou, E. Quinoa, J. Am. Chem. Soc. 110 (1988) 4365. [4] J.V. Metzeger, in: K.T. Potts (Ed.), Part 4B, in: A.R. Katritzky, C.W. Rees (Eds.), Comprehensive Heterocyclic Chemistry, vol. 6, Pergamon Press, Oxford, 1984, p. 235.

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