WANG Zhi-Ling WANG Zhi-Na LU Xiu-Hui

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Theoretical Study on the Mechanism of a New Synthesis Reaction of 1,3,5-Substituted-1,2,4-triazoles by Carboxylic Acids, Amidines, and Hydrazines①

WANG Zhi-Ling②WANG Zhi-Na LU Xiu-Hui②

(250022)

The synthesis of 1,3,5-substituted-1,2,4-triazoles from-imino-3-pyridine formic acid, acetamidine and anisole hydrazineas a model reaction in this paper and the synthesis mechanism of 1,3,5-substituted-1,2,4-triazole compounds from carboxylic acids, amidines and hydrazines have been first investigated with the B3LYP/6-311++G** method. According to the potential energy profile, it can be predicted that the course of the reaction consists of five reactions containing six elementary reactions. The-imino-3-pyridine formic acid and acetamidine form first an intermediate product througha dehydration reaction; the intermediate product further combines with hydrogen ion to form a positive ion; the positive ion reacts with anisole hydrazine by a dehydration reaction to form another positive ion; then, followed bytwo isomerization reactions, the final reaction with the acetate ion (Ac-) produces the final product. The research results reveal the laws of synthesis reaction of 1,3,5-substituted-1,2,4-triazoles bythe carboxylic acids, amidines, hydrazines and their derivatives on theoretical level. It provides the systemic theoretical basis for the synthesis, development and application of 1,3,5-substituted-1,2,4- triazole compounds.

1,3,5-substituted-1,2,4-triazole, synthetic reaction, potential energy profile, molar gibbs free energy of reaction (Drm)-;

1 INTRODUCTION

1,2,4-Triazole is a five-membered ring heteroaro- matic compound, containingthree nitrogen atoms. It has a 6electronic conjugated system, and shows strong abilities of coordination and hydrogen bond formation. It could form hydrogen bonds with enzymes and receptors in organisms, and it could coordinate with metal ions and experience hydrophobic interaction,-stacking, electrostatic effect and so on. These unique structural features make 1,2,4-triazole compounds exhibit a wide range of biological activities and some special properties. It has been widely studied and applied in the field of medicine and pesticide. At the same time, it presents the potential values of research and deve- lopment in the field of chemistry, supramolecule, physics, material science and life science. These make the 1,2,4-triazole compoundsextremely po- pular[1-3]. In medicalfield, the compounds contain- ing 1,2,4-triazole a biological activity of spectrum, such as anti-fungal, anti-bacterial, anti-tuberculous, anti-viral, anti-tumor, anti-eclamptic, anti-parasite, anti-inflammatory and so on. It is an important direction of research and development for new drugs[4, 5]. At the same time, as agricultural fun- gicides, herbicides, pesticides and plant growth regulators, it shows a great potential for develop- ment[6]. Considering the immense development value and the potential wide variety of applications of the 1,2,4-triazole compounds, their effective syntheses have received much interest of the chemists and great progress has been made[7-10]. According to the results of chemists’ study, we first studied the reaction mechanism of 1,3,5-sub- stituted-1,2,4-triazole with-imino-3-pyridine formic acid, acetamidine and anisole hydrazine,with the synthetic reaction equations as follows:

The results show that the course of the reaction consists of five reactions containing six elementary reactions:

The research findings have theoretically revealed the mechanism of the reaction generating 1,3,5- substituted-1,2,4-triazole compound by the carboxy- lic acids, amidines, hydrazine and their derivatives, which provides systemic theoretical basis for the synthesis, development and application of 1,3,5-substituted-1,2,4-triazole compounds.

2 CALCULATION METHODS

B3LYP/6-311++G**[11]implemented in the Gaussian 09 package[12]is employed to locate all the stationary points along the reaction pathways. Full optimization and vibrational analysis are done for the stationary points on the reaction profile. Finally, the intrinsic reaction coordinate (IRC)[13, 14]is also calculated for all the transition states to determine the reaction paths and directions.

3 RESULTS AND DISCUSSION

3. 1 Reaction mechanism

The theoretical calculations indicate that the ground state of-imino-3-pyridine formic acid (R1), acetamidine (R2) and anisole hydrazine (R3) are the singlet states. The geometrical parameters of the reactants (R1, R2, R3), transition states (TS1, TS2, TS3, TS4) and products (P1+H2O, P2, P3+H2O, P4, P5, P6+NH3·HAc) which appear in the synthesis reaction of 1,3,5-substituted-1,2,4-triazoles by-imino-3- pyridine formic acid, acetamidine and anisole hydrazine are given in Fig. 1. The energies are listed in Table 1, and the potential energy profile of the reaction is shown in Fig. 2. The entropy, enthalpy and Gibbs free energy are listed in Table 2.

Fig. 1. Optimized B3LYP/6-311++G** geometrical parameters and the atomic numbering for the species inthe synthesis. Bond lengths in angstroms and bond angles in degree

Table 1. Total Energies (ET, in a.u) and Relative Energies (ER, in kJ/mol) for the Species from B3LYP/6-311++G** Methods at 298 K and 101325 Pa

aR=T－(R1 + R2),bRT(P1 + H+),cRT(P2 + R3),dRT(P3),eRT(P5 + Ac–)

Table 2. Entropy (S, in a.u), Enthalpy (H, in a.u) and Gibbs Free Energy (G, in a.u) for the Species from B3LYP/6-311++G** Methods at 298 and 101325 Pa

Fig. 2. Potential energy profile for the synthesis of 1,3,5-substituted-1,2,4-triazoles from α-imino-3-pyridine formic acid, acetamidine and anisole hydrazinewith B3LYP/6-311++G**

3. 2 Analysis and explanation of the reaction mechanism

According to Fig. 1, when R1 starts to react with R2, as the length of C(1)–N(3) bond (R1 + R2: ∞; TS1: 1.485 ?; P1 + H2O:1.391 ?) decreases, the C(1)–O(2) and N(3)–H(7)bonds (R1 + R2: 1.366 ?, 1.016 ?; TS1: 2.147 ?, 1.059 ?; P1 + H2O: 3.911 ?,1.932 ?) elongate gradually. Before the transition state (TS1), the C(1)–O(2) bond is broken, and C(1) and N(3) formacovalentbond. After the transition state (TS1), the N(3)–H(7) bond is broken, and the H(7)+ion and [O(2)H(1)]-hydroxyl combine to form a stable water molecule. Thus, the first step has completed (R1 + R2 → P1 + H2O). In the second step, under acidic condition provided by acetic acid (HAc), the O(1) atom in P1 combines with H(13)+ion to form a P2 positive ion. In the third step, as the C(1)–N(5) bond (P2 + R3: ∞; TS2: 1.583 ?; P3 + H2O: 1.368 ?) decreases, the O(1)–C(1) and H(14)–N(5) bonds (P2 + R3: 1.348 ?; 1.014 ?; TS2: 2.100 ?, 1.082 ?; P3 + H2O: 6.151 ?, 6.765 ?) elongate gradually.Before the transition state (TS2), the O(1)–C(1) and H(14)–N(5) bonds are broken. After the transition state (TS2), C(1) and N(5) formacovalentbond, and the H(14)+ion and [O(1)H(13)]-hydroxyl combine to form a stable water molecule. Thus, the third step reaction has completed (P2 + R3 → P3 + H2O). In the fourth step, as the C(7)–N(6) bond (P3:2.825 ?; TS3: 1.558 ?; P4: 1.445 ?) gradually decreases, the H(15)–N(6) and C(7)–N(4) bonds (P3: 1.017 ?, 1.337 ?; TS3: 1.329 ?, 1.527 ?; P4: 2.448 ?, 1.568 ?) elongate gradually. Before the transition state (TS3), H(15)–N(6) bond is broken, and C(7) andN(6) formacovalentbond. After the transition state (TS3), H(15)+andN(4) formacovalentbond. Thus, P3 isomerizes to P4 via transition state (TS3). In the fifth step, the C(7)–N(4) bond (P4: 1.568 ?; TS4: 1.620 ?; P5: 3.831 ?) elongates gradually.Before the transition state (TS4), the C(7)–N(4) bond is broken. After the transition state (TS4), it forms hydrogen bonds between N(4) and H(16). Thus, P4 isomerizes to P5 via transition state (TS4). In the sixth step, owing to the interaction between [N(4)H(11)H(12)H(15)] in P5 and Ac-, the N(6)– H(16) bond fracture occurs. [N(4)H(11)H(12)H(15)H(16)]+in P5 and Ac-combine to form NH3·HAc, which results in the formation of P6 + NH3·HAc.

4 CONCLUSION

On the basis of the potential energy profile obtained with the B3LYP/6-311++G** method for the synthesis of 1,3,5-substituted-1,2,4-triazoles bythe singlet-imino-3-pyridine formic acid, acetami- dine and anisole hydrazine, it can be predicted that the course of the reaction consists of five reactions containing six elementary reactions. (1)-imino- 3-pyridine formic acid (R1) and acetamidine (R2) form an intermediate product (P1) through a dehydration reaction with an energy barrier of 140.4 kJ/mol. (2) Under acidic condition provided by acetic acid (HAc), P1 further combines with hydrogen ion to form a positive ion (P2). This is a barrier-free exothermic reaction. (3) P2 and R3 form a positive ion (P3) through a dehydration reaction with an energy barrier of 129.8 kJ/mol. (4) P3 isomerizes to a positive ion (P4) via a transition state (TS3) with an energy barrier of 166.8 kJ/mol. (5) P4 further isomerizes to a positive ion (P5) via a transition state (TS4) with an energy barrier of 30.3 kJ/mol. (6) P5 further reacts with Ac-to form 1,3,5-substituted-1,2,4-triazole compound and ammonium acetate, and this is a barrier-free exo- thermic reaction. The synthesis of 1,3,5-substituted- 1,2,4-triazoles bythe singlet-imino-3-pyridine formic acid, acetamidine and anisole hydrazineis a spontaneous exothermic reaction at ordinary pressure and room temperature (101325 Pa, 298 K).

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12 July 2017;

22 November 2017

①The work was supported by the National Natural Science Foundation of China (No. 51102114)

. Wang Zhi-Ling, born in 1960, professor, majoring in organic chemistry. E-mail: chm_wangzl@ujn.edu.cn; Lu Xiu-Hui, born in 1956, professor, majoring in physical chemistry. E-mail:lxh@ujn.edu.cn

10.14102/j.cnki.0254-5861.2011-1783