Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole

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Origin of Substituent Effect on Tautomeric Behavior of 1,2,4Triazole Derivatives. Combined Spectroscopic and Theoretical Study Tetiana Sergeieva, Maria Bilichenko, Sergiy Holodnyak, Yulia V. Monaykina, Sergiy I. Okovytyy, Sergiy Ivanovich Kovalenko, Eugene Voronkov, and Jerzy Leszczynski J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b08317 • Publication Date (Web): 05 Dec 2016 Downloaded from http://pubs.acs.org on December 5, 2016

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The Journal of Physical Chemistry

Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-triazole Derivatives. Combined Spectroscopic and Theoretical Study Tetiana Sergeieva, †, II Maria Bilichenko, † Sergiy Holodnyak, II Yulia V. Monaykina, II Sergiy I. Okovytyy *, †, ‡ Sergiy I. Kovalenko, II Eugene Voronkov┴, Jerzy Leszczynski ‡ †

Department of Chemistry, Oles Honchar Dnipropetrovsk National University, 72 Gagarina Ave., Dnipro, 49050, Ukraine *e-mail: [email protected], tel.:+380505919276

‡

Interdisciplinary Nanotoxicity Center, Jackson State University, 1400 J. R. Lynch Str., Jackson, Mississippi, 39217, USA II

Department of Pharmacy, Zaporihzhya State Medical University, 26 Mayakovsky Ave., Zaporihzhya, 69035, Ukraine

┴

Department of Physics, V. Lazaryana Dnipropetrovsk National University of Railway Transport, 2 Lazaryana Str., Dnipro, 49010, Ukraine

ACS Paragon Plus Environment

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Abstract

The reaction of 2-aryl-[1,2,4]triazolo[1,5-c]quinazolines with nucleophilic reagents (hydrazine hydrate, sodium hydroxide, sodium methoxide, hydrochloric acid) under acidic conditions leads to formation of compounds which tend to tautomerism. The products of the transformation are distinguished by the position (ortho-, meta-, para-) of the OCH3 group in the aryl moiety. To assign their structures we used the combined approach: experiment and theoretical modeling. The procedure included calculation of the relative stability for possible tautomers, simulation of UV/Vis spectra for the most stable forms and comparison of the resulting curves with the experimental spectral data taking into account the Boltzmann weighting. Through computations, we showed that the orientation of OCH3 substituent remarkably impacts on the tautomeric behavior of triazoles. In the case of ortho-OCH3 it is controlled by formation of the intramolecular hydrogen bond while for meta- and para- derivatives the degree of conjugation plays the decisive role. In order to balance the accuracy and cost of calculations we evaluated the performance of selected DFT methods and 6-31G*, 6-311++G**, STO##-3Gel basis sets. The last one is physically justified basis set previously constructed in our group and its combination with PBE1PBE approach shown to be the best choice for UV/Vis simulations in the frame of the current research.

1 Introduction Computer modeling is a valuable tool in the age of target-based drug discovery. The essential factor that determines the success of the computer-aided drug design is the structural presentation of compounds in the chemical databases, which is used for virtual screening.


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Regarding this issue special attention should be paid to the tautomerism, since wrong tautomeric form can be a reason of incorrect predictions. Tautomeric equilibrium of C-substituted 1,2,4-triazoles, which are popular scaffolds in drug design,1,2 has been extensively studied experimentally and computationally in many contexts.3-9 A few types of systems were considered therein (Figure 1) to elucidate the influence of the substituents: direct attachment of groups to the triazole ring (compounds of type 1) or by introducing groups into the phenyl ring that is attached to the triazole (type 2 molecules). Type1 Substituent

Ref.

R=CH3

3

R=SCH3 R=OH R=NH2

5

4 4 4 6 7

R=OCH3 Type2 R1=NH2; R2=para-MeOC6H4 R1=NH2; R2=para-MeC6H4 R1=SCH3; R2=para-NH2C6H4 R1=SCH3; R2=para-MeOC6H4

7 8 9 9 5 5

Predominant form 1H, 2H 2H 2H 1H 1H 2H 1H 1H 2H 1H 1H 1H 1H

Figure 1. The systems which were subjected for studying of tautomeric behavior. Concerning the first case, the information about tautomeric preferences in the series of 1,2,4triazoles is rather controversial,3-8 while for aryl-1,2,4-triazoles is fragmentary, since the effect of only para-oriented electron donating groups (EDG) was studied.5, 9 To draw the full picture of substituent position impact upon the tautomeric preference of triazole derivatives we explored recently synthesized in our group methoxy 2-(3-aryl-1,2,4-


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triazole-5-yl)anilines (Scheme 1).10 In order to obtain reliable results, we have applied complex approach combining UV/Vis spectroscopy and theoretical calculations.

Scheme 1. Hydrolytic cleavage of 2-aryl-[1,2,4]triazolo[1,5-c]-quinazolines (1A-1C).

2 Theoretical methods Quantum mechanical calculations were carried out using the Gaussian 09 suite of programs.11 The geometries optimization were performed at PBE1PBE level12 in conjunction with Pople’s type 6-311++G** basis set. Calculation of harmonic vibrational frequencies was done using the same level of theory and allowed introducing the thermochemical corrections to ∆G at 298.15 K. The geometries of the most stable structures selected on the basis of the Gibbs free energies calculations served as inputs for UV/Vis spectra simulation. During this step we have tested the performance of DFT functionals (PBE1PBE, cam-B3LYP, M06, M11, WB97XD) that were shown to be suitable for prediction of UV/Vis spectra.13-16 Standard 6-31G*, 6-311++G** and physically adapted STO##-3Gel17 basis sets were utilized therein (See basis set for selected atoms in SI). The last one was developed in our group by augmentation of standard STO-3G basis set by additional functions obtained from solution of nonhomogeneous Schrödinger equation for the model problem “one-electron atom in an external uniform field”. As have been shown in


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previous studies17-19 the basis sets constructed in such a way demonstrate high efficiency for electric and magnetic properties calculation. The intensities of the calculated spectra were scaled and resulted curves shifted (see shifting values in the last columns of Table 2, 3) using Gabedit program20 to fit the most intensive band obtained experimentally. To account for solvent effect the SMD model21 with methanol (ε=32.613) as a solvent was applied. The assignments of calculated absorption bands for tautomeric forms were based on analysis of Molecular Orbitals (MO).

3 Results and discussion 3.1 Conformational analysis and population of tautomers Tautomeric forms of 2A-2C are depicted in Figure 2.

Figure 2. Tautomers of 2A-2C. The ability of aryl rings to free rotation results in the existence of each tautomer of 2A, 2B in one of four possible conformations specified by torsion angles ψ1 and ψ2 (Figure 3). In contrast, changing of ψ2 on 180° gives the same comformation of 2C due to symmetry of the paraMeOC6H4 fragment. Thus the only two conformers differ in ψ1 (c1, c2) could be defined.

Figure 3. Conformers of 2A, 2B.


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Therefore, we consider 12 structures for 2A and 2B and 6 for compound 2C. The summary of tautomer’s relative Gibbs free energies and population along with values of ψ1 and ψ2 are listed in Table 1. Table 1. Selected structural parameters, relative Gibbs free energies* and population of triazoles 2A-2C. SMD/PBE1PBE/6-311++G**. P,% ΣP,% Structure ψ1, deg. ψ2, deg. ∆Grel, kcal⋅mol-1 2A-T-1c1 -26.1 -23.5 5.8 0.00 2A-T-1c2 -172.2 -24.0 3.2 0.32 0.76 2A-T-1c3 -167.4 141.8 3.0 0.43 2A-T-1c4 -25.3 -137.8 5.2 0.01 2A-T-2c1 -0.15 -0.64 0.0 67.92 2A-T-2c2 -171.2 -0.1 0.5 26.51 95.66 2A-T-2c3 -176.1 -141.6 3.1 0.34 2A-T-2c4 -0.7 -140.3 2.6 0.89 2A-T-3c1 -9.7 37.5 5.6 0.00 2A-T-3c2 -151.5 38.1 8.8 0.00 3.55 2A-T-3c3 -153.8 178.1 5.2 0.00 2A-T-3c4 -6.3 -178.0 1.7 3.55 2B-T-1c1 -25.9 4.8 2.8 0.34 2B-T-1c2 -170.2 -1.0 0.0 36.78 69.57 2B-T-1c3 -170.1 176.8 0.1 31.77 2B-T-1c4 -26.1 -177.0 2.4 0.68 2B-T-2c1 0.3 17.3 0.4 18.98 2B-T-2c2 173.0 12.9 1.4 3.58 29.87 2B-T-2c3 -170.4 -167.0 1.4 3.26 2B-T-2c4 1.4 -163.8 1.3 4.05 2B-T-3c1 4.0 12.3 4.3 0.03 2B-T-3c2 152.8 7.3 6.2 0.00 0.55 2B-T-3c3 -151.0 168.7 6.1 0.00 2B-T-3c4 -4.4 -179.1 2.5 0.52 2C-T-1c1 26.1 – 1.9 1.97 51.95 2C-T-1c2 -168.7 – 0.0 49.98 2C-T-2c1 -2.6 – 0.2 34.49 47.42 2C-T-2c2 172.9 – 0.8 12.93 2C-T-3c1 2.5 – 2.6 0.62 0.62 2C-T-3c2 150.5 – 6.0 0.00 *relative to the most stable tautomer in each group (2A-T-2c1, 2B-T-1c2, 2C-T-1c2)


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The computed values of population gathered in Table 1 showed that the most abundant form for 2A is T-2 (96%), while for 2B and 2C the existence of T-1:T-2 mixture is observed. Such tautomeric distribution might depend on the degree of conjugation, which illustrated in Figure 4 by resonance structures.


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Figure 4. Resonance structures of 2A. In contrast to calculations, the examination of the resonance structures for system 2A showed that T-1 and T-2 forms should co-exist. This conclusion was made through separate consideration of the influence of NH2 and OCH3 groups (Figure 4, blue and green rectangles) upon the tautomeric behavior of the triazole. In the first case, when ortho-OCH3C6H4 group is omitted, the most favorable electronic density distribution corresponds to tautomer T-1. However, if the same is done with ortho-NH2C6H4 (green rectangle), T-2 is preferable. Thus, combination of effects for two quite strong electron donors in ortho-positions gave us the reason to anticipate the tautomeric mixture. However, the results of computed Gibbs free energies (Table 1) show that the most stable form for 2A is T-2, while the others are populated in less than 4%. We concluded that advantage of T-2 over T-1 results from formation of two intramolecular hydrogen bonds N2H···O and N1···H/N4···H (Figure 5). One notices that the only two structures, (T-2c1, T-2c2) among of entries 2A-T-1c1–2A-T-3c4, are highly planar which promotes aromaticity and thus raising their population.

Figure 5. The most stable structures of 2A.


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In contrast to compound 2A where formation of hydrogen bonds plays a key role in establishing of the tautomeric equilibrium, 2B and 2C deal with involvement of pure electronic effects. Competition of methoxy group in para-position and amino in ortho- leads to existing of triazole 2C as a mixture of T-1 and T-2 (52%:47%). Bearing OCH3 substituent meta-oriented (2B) the stabilization strength toward T-2 is reduced giving T-1:T-2 ratio equals to 70%:30%. The origin of such observation originated from violation of conjugation as shown in Figure 6.

Figure 6. Resonance structures of 2B. 3.2 Performance of selected functionals and basis sets for UV/Vis spectra simulation We tested the most popular density functionals PBE1PBE, M06, CAM-B3LYP, WB97XD, M11 paired with three basis sets: 6-31G*, 6-311++G**and STO##-3Gel for prediction of UV/Vis spectra for 2A. The results of calculations are presented in Figure 7 and Table 2.


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Figure 7. Experimental UV/Vis spectrum of 2A in methanol and computed Boltzmann weighted sum spectra (2A-T-2c1; 2A-T-2c2) using 6-31G* (a), 6-311++G** (b), STO##-3Gel (c) basis sets.


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Comparison of simulated spectra has shown the significant differences in performance among all considered theory levels (Table 2).

Table 2. Computed absorption maxima (nm) for Boltzmann weighted sum spectra (2A-T-2c1; 2A-T-2c2) and their comparison with experimental data. Experimental bands 214 250 Method Calculated bands PBE1PBE/6-31G* 214 259 M06/6-31G* 214 260 CAM-B3LYP/6-31G* 214 265 WB97XD/6-31G* 214 260 M11/6-31G* 214 PBE1PBE/6-311++G** 214 256 M06/6-311++G** 214 250 CAM-B3LYP/6-311++G** 214 265 WB97XD/6-311++G** 214 M11/6-311++G** 214 PBE1PBE/STO##-3Gel 214 250 ## M06/STO -3Gel 214 255 CAM-B3LYP/STO##-3Gel 214 265 ## WB97XD/STO -3Gel 214 ## M11/STO -3Gel 214 *Values used for shifting of the calculated spectra

305 308 305 300 295 287 305 296 300 300 282 305 303 300 295 282

Shift* 25 19 28 28 31 15 3 20 23 23 16 8 20 21 23

It is clear that PBE1PBE and M06 approaches are much more accurate than the other functionals. They well reproduce (within 10 nm), the major absorption peaks detected experimentally. In contrast, CAM-B3LYP tend to red-shift (15 nm) the band λ250 and blue-shift (5 nm) the maximum at λ305, while WB97XD and M11 totally failed. It also turns out that the oscillator strengths (f) computed by CAM-B3LYP, WB97XD, M11 functionals do not


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significantly depend on the basis set being used. The opposite trend is observed in the case of PBE1PBE and M06. The best balance between cost and accuracy was achieved using STO##3Gel, which is about the same size as minimal 6-31G* and twice smaller than 6-311++G** basis set. It is noteworthy, that STO##-3Gel combined with PBE1PBE yields perfectly converged λmax and f, values so we selected this approach for further computations. 3.3 Calculation of UV/Vis spectra and bands assignment for selected conformers of 2A-2C Having established the most populated conformer in each group of tautomers for 2A–2C, we next calculated their UV/Vis spectra at PBE1PBE/STO##-3Gel level and depicted them in Figure 8. If the tautomer is represented by several conformations populated more than 10% as well as the existing of the tautomeric mixture the Boltzmann weighted sum spectrum was generated. All calculated curves were compared with the experimental data (Figure 8).


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Figure 8. Experimental UV/Vis spectra of 2A (a), 2B (b), 2C (c) in methanol along with calculated ones for selected forms. PBE1PBE/STO##-3Gel. Since the Boltzmann weighted sum spectra included data of several forms the assignments of absorption bands would be too complicated. For this reason we further will discuss those cases where the only one conformer is populated to the significant extent within the certain tautomer. The first calculated band at λ326 in the spectrum of 2A-T-1c3 (Figure 8a, Table 3) appears due to HOMO–LUMO transition (Figure 9). Corresponding excitation (λ356) of 2A-T-3c4, compared to the 2A-T-1c3, is bathochromically shifted. This correlates with lowering of a HOMO–LUMO


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gap (Figure 9). An experimental spectrum of 2A in contrast to theoretical predictions does not have a well-defined peak in this region (Figure 8a).

Figure 9. The diagram of molecular orbitals involved in the main electronic transitions for tautomeric forms of 2A: 2A-T-1c3 (a), 2A-T-3c4 (b). PBE1PBE/STO##-3Gel. Table 3. Computed absorption maxima (nm) for selected conformers and their comparison with experimental data. SMD/PBE1PBE/STO##-3Gel. Experimental bands 2A 2A-T-1c3 2A-T-3c4

I 214

2B-T-2c1 2B-T-3c4

IV Shift*

214 238 285 326 214 236 299 356 Boltzmann weighted sum spectra (2A-T-2c1; 2A-T-2c2) 214

2B

II III 250 305 Calculated bands

250 305 Experimental bands

356

II III IV 255 320 Calculated bands 219 243 304 219 292 353 Boltzmann weighted sum spectra (2B-T-1c2; 2B-T-1c3) 219 282 320

16 23 16

I 219


9 18 9

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Boltzmann weighted sum spectra (2B-T-1c2; 2B-T-1c3; 2B-T-2c1) 219

-

282

317

9

Experimental bands 2C

I 213

II 232

2C-T-1c2 2C-T-3c1

213 213

-

III IV 256 Calculated bands 258 250

303

V 322 333 353

18 22

Boltzmann weighted sum spectra (2C-T-2c1; 2C-T-2c2) 213 265 310

12

Boltzmann weighted sum spectra (2C-T-1c2; 2C-T-2c1; 2C-T-2c2) 213

-

265

-

322

14

*Values used for shifting of the calculated spectra The absorption peak of 2A-T-1c3 at λ285 originates from the HOMO to LUMO+1 excitation. The intensity of this band relative to the experimental (λ305) is much lower. On the contrary, the absorption band at λ299 in the spectrum of 2A-T-3c4 possesses quite high intensity and arises from transition between HOMO-1 and LUMO. The characteristic shoulder is present in experimentally obtained spectra (2A) at λ250. The HOMO-3–LUMO crossing results in barely detectable shoulder at λ238 in 2A-T-1c3 spectrum The signal broadening in the spectrum of 2A-T-3c4 (approximately at λ236) is scarcely recognizable and corresponds to excitation from HOMO-1 to LUMO+4. The most intense peak for 2A-T-1c3 and 2A-T-3c4 consists of several excitations with the involvement of lower lying orbitals. Orbitals associated with calculated bands for tautomers of 2B and 2C (Figure 8b, 8c; Table 3) are represented in Figure 10.


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E, eV


Figure 10. The diagram of molecular orbitals involved in the main electronic transitions for 2BT-2c1 (a); 2B-T-3c4 (b); 2C-T-1c2 (c); 2C-T-3c1 (d). PBE1PBE/ STO##-3Gel. The excitation at λ353 (2B-T-3c4) corresponds to the HOMO-LUMO transition. The absorption band λ304 (2B-T-2c1) arises from the excitation out of the HOMO to the LUMO+1. Calculations show that the peak at λ292 in the spectrum of 2B-T-3c4 appears not only due to HOMO-1–LUMO crossing, but also involves НОМО, НОМО-2 and LUMO+1 orbitals. The shoulder at λ243 is present in the spectra of 2B-T-2c1. It originates from HOMO-3–LUMO transition. Finally, the bands with the highest intensity are composed of transitions that involve participation of deeper orbitals: HOMO-2, HOMO-4, LUMO+2, LUMO+4. Considering tautomers of 2C, the bands at the region of 280-355 nm are attributed to HOMO– LUMO and HOMO-1–LUMO crossing, whereas excitations which required more energy lie in the range of 200-265 nm (Table 3). In general, we can suppose that if the population of any tautomer is close to 100% its calculated spectrum might perfectly match the shape of experimental one. This is true for 2A, but very unlikely for cases 2B and 2C (Figure 8b, 8c), which confirms our conclusions about 2B existing as a mixture of T-1c2; T-1c3; T-2c1 and 2C in forms of T-1c2; T-2c1; T-2c2. The last


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statement is confirmed by comparison of experimental spectra of 2B and 2C with the corresponding Boltzmann weighted sum spectra, which shows satisfactory results (Figure 8b, 8c; Table 3).

4 Conclusions The tautomerism of methoxy 2-(3-aryl-1,2,4-triazole-5-yl)anilines (2A-2C) was examined by using both experimental and theoretical techniques. The obtained data suggests that in all cases tautomer T3 is the least abundant form. The preference of T1 or T2 strongly depends on the orientation of methoxy group. Ortho- location of the substituent led to predominance of T2, meta- resulted in high population of T1. The system with para- position of the methoxy group group gave the ratio T1:T2 as 52%:47%. In order to support our findings UV/Vis spectra of the most stable tautomeric forms of 2A-2C were simulated and compared with experiment. At this point we have assessed the efficiency of selected DFT functionals and basis sets for reproducing the experimental wavelengths and oscillator strengths. The investigation showed that CAM-B3LYP, WB97XD, M11 poorly estimate the absorption peaks, while PBE1PBE and M06 provide more consistent results for the molecules studied here. On the other hand, the last two functionals are sensitive to the basis sets. Based on the observations we presume that PBE1PBE in combination with STO##-3Gel basis set will be suitable for prediction of UV/Vis spectra of similar compounds. Among 2A tautomers, the UV/Vis Boltzmann weighted sum spectrum (T-2c1; T-2c2) perfectly agrees with experimental one, which is also consistent with its population. In case of 2B and 2C the molecules exist as a mixture of T1 and T2 which made the study more complex. The resulting simulated Boltzmann weighted sum spectra (2B-T-1c2; 2B-T-1c3; 2B-T-2c1) and (2CT-1c2; 2C-T-2c1; 2C-T-2c2) are in good agreement with the experimental ones.


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Acknowledgments The authors gratefully acknowledge the funding of this research by the Ministry of Education and Science of Ukraine (Project #0116U001520) and National Science Foundation (NSF/CREST HRD-1547754). This work also used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation (Grant #ACI1053575). Supporting information Supporting information includes XYZ coordinates of all studied molecules. Fig. S1-S3 represents the molecular orbitals involved in the main electronic transition of the selected tautomeric forms of 2A-2C. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) Eswaran, S.; Adhikari, A. V.; Shetty, N. S. Synthesis and Antimicrobial Activities of Novel Quinoline Derivatives Carrying 1,2,4-triazole Moiety. Eur. J. Med. Chem. 2009, 44, 4637–4647. (2) Romagnoli, R.; Giovanni Baraldi, P.; Cruz-Lopez, O.; Lopez Cara, C.; Dora Carrion, M.; Brancale, A.; Hamel, E.; Chen, L.; Bortolozzi, R.; Basso, G., et al. Synthesis and Antitumor Activity of 1,5-Disubstituted 1,2,4-Triazoles as Cis-Restricted Combretastatin Analogues. J. Med. Chem. 2010, 53, 4248–4258. (3) Nagy, P. I.; Tejada, F. R.; Messer, W. S. Jr. Theoretical Studies of the Tautomeric Equilibria for Five-member N-heterocycles in the Gas Phase and in Solution. J. Phys. Chem. B 2005, 109, 22588–22602. (4) Ozimiński, W. P.; Dobrowolski, J. Cz.; Mazurek, A. P. DFT Studies on Tautomerism of C5substituted 1,2,4-triazoles. THEOCHEM. 2004, 680, 107–115. (5) Kubota, S.; Uda, M. 1,2,4-Triazoles. IV. Tautomerism of 3,5-Disubstituted 1,2,4-Triazoles. Chem. Pharm. Bull. 1975, 23, 955–966.


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Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole

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