Density Functional Theory Study on Ring-Chain Isomerism of Semicarbazones ^†

Abstract

The conversion of semicarbazones to 1,2,4-triazolidin-3-ones and vice versa (ring-chain isomerism) was studied using the DFT B3LYP/6-311++G(d,p) method. The thermodynamic and kinetic characteristics of this reaction were calculated and discussed.

1. Introduction

Ring-chain isomerism is a phenomenon in which a molecule can exist in either cyclic or acyclic isomeric forms [1,2]. This type of isomerism is of great importance for understanding the structural features of various organic compounds and their chemical transformations. One of two principal pathways of chain-to-ring conversion involves the intramolecular addition of a functional group to a polar multiple bond. The reverse reaction of elimination leads to the conversion of a cyclic compound into its acyclic isomer. Ring-to-chain transformation of functionalized hydrazones (and vice versa) (for review, see ref. [3]), and in particular, the interconversion of aldehyde semicarbazones/1,2,4-triazolidin-3-ones, is an important example of ring-chain isomerism from both practical and theoretical points of view. Indeed, aldehyde semicarbazones are readily available compounds and their closed-ring isomerization followed by oxidative aromatization of the formed 1,2,4-triazolidin-3-ones could give access to 2,4-dihydro-3H-1,2,4-triazol-3-ones possessing various useful properties [4,5,6,7,8]. However, the cyclization of aldehyde semicarbazones to 1,2,4-triazolidin-3-ones still remains practically unexplored. There is only one report on the study of the ring-chain isomerism of semicarbazones of aromatic aldehydes using ¹H NMR spectroscopy [9]. The authors demonstrated that all the 36 tested compounds in DMSO-d₆ solution exist only in acyclic semicarbazone form. This form is also the only one in CF₃COOD solution, except for four compounds of the series of 2,4-dimethyl-substituted semicarbazones, which result in mixtures of the starting material with the corresponding 1,2,4-triazolidin-3-ones. It should be noted that all the experiments were performed in NMR tubes without isolating products. To the best of our knowledge, no preparative works on the chain-to-ring isomerization of any aldehyde semicarbazones into 1,2,4-triazolidin-3-ones have been described. There are a few reports on the one-pot syntheses of 1,2,4-triazolidin-3-ones via the reaction of some aromatic aldehydes with semicarbazide in the presence of complex catalysts [10,11,12], where the intermediate formation of semicarbazones followed by their cyclization is hypothesized. However, analysis of the reported spectroscopic data for the products obtained showed that, in at least in two studies [11,12], these products were the corresponding semicarbazones and not 1,2,4-triazolidin-3-ones. It should be noted that one of these articles [12] was retracted by the authors. Thus, the study of semicarbazones/1,2,4-triazolidin-3-ones interconversion remains a challenge for synthetic and theoretical chemistry. As a continuation of our interest in ring-chain isomerism [13] and the synthesis of polyaza compounds based on semicarbazones [14,15], we initiated a research program aiming to study the isomerization of semicarbazones into 1,2,4-triazolidin-3-ones.

Our preliminary experimental data showed that the cyclization of 2-alkylsubstituted semicarbazones of benzaldehyde 1 (R = Ph) does not proceed under various acidic conditions. In contrast, 2-alkylsubstituted semicarbazones of aliphatic aldehydes 1 (R = alkyl) completely cyclized under the action of very strong Brønsted acids (TfOH, HCl) in aprotic solvents at room temperature to obtain the corresponding salts of the N1-protonated 1,2,4-triazolidin-3-ones 2 (Scheme 1).

Herein, we report on the DFT B3LYP/6-311++G(d,p) study of the ring-chain isomerism of 2-alkylsubstituted semicarbazones. A plausible mechanism of this reaction is discussed. A comparison of chain-to-ring isomerization for 2-alkylsemicarbazones of aliphatic and aromatic aldehydes is presented.

2. Results and Discussion

Cyclization of 2-alkylsubstituted semicarbazones of aliphatic aldehydes was studied using the DFT B3LYP/6-311++G(d,p) method using ethanal 2-methylsemicarbazone (4) as a model compound and triflic acid as a promoter. Thermodynamic and kinetic parameters for the TfOH-promoted transformation of semicarbazone 4 into triazolidine salt 5 (Scheme 2) in CHCl₃ and MeCN solutions were calculated by employing the polarizable continuum model.

Table 1. Relative electronic (ΔE, kcal/mol) and Gibbs free energies (ΔG, kcal/mol) of the transition state (TS^#), the most stable stereoisomers of the intermediates 6–8, and the final product 5 ^a.

Compound or Transition State	CHCl3 Solution		MeCN Solution
	ΔE	ΔG	ΔE	ΔG
Pre-reaction complex of semicarbazone 4 with TfOH (intermediate 6)	0.00	0.00	0.00	0.00
Triflate of protonated semicarbazone 4 (intermediate 7)	−13.38	−9.63	−15.45	−11.88
Transition state (TS#)	1.56	6.31	−0.15	4.25
Triflate of N4-protonated triazolidinone (intermediate 8)	−10.72	−4.23	−12.61	−5.77
Triflate of N1-protonated triazolidinone (product 5)	−15.38	−9.31	−17.95	−12.98

^a Calculations were performed at the B3LYP/6-311++G(d,p) level. Free energies at 298 K and 1 atm.

and Figure 1 show the obtained results.

The calculations showed that the first step of the reaction involves the formation of the pre-reaction complex of semicarbazone 4 with TfOH (intermediate 6) followed by the proton transfer to obtain triflate 7. Noteworthy, the protonation leads to a significant change in the conformation via rotation around the N-N bond. Indeed, in CHCl₃ solution, the C=N-N-C dihedral angle in the most stable conformation of semicarbazone 4 is −179.46°, and in the intermediate 7 this angle is −94.58°. In MeCN solution, these angles are −179.49° and −99.42°, respectively (Figure 2a). This change is explained by a strong repulsion between the C=NH proton and one of the protons of the NH₂ group in the planar conformation of salt 7.

Interestingly, two oxygen atoms of the triflate anion in the formed non-planar conformation of salt 7 form two hydrogen bonds with the C=NH proton and one of the NH₂ protons. It should be noted that the described conformation of the intermediate 7 significantly facilitates its subsequent cyclization. The cyclization proceeds via the transition state TS^# (Figure 2c) to result in the N4-protonated triazolidinone triflate (intermediate 8) where two oxygen atoms of the triflate anion form two hydrogen bonds with the N₍₁₎-H and N₍₄₎-H protons (Figure 2b). The IRC analysis demonstrated that the found transition state connects the desired minima. The calculated activation barrier for the 7 → 8 transformation is rather low (ΔG^# = 15.95 kcal/mol in CHCl₃, ΔG^# = 16.13 kcal/mol in MeCN). The final step of the reaction involves the proton transfer from the N₍₄₎ nitrogen to the N₍₁₎ nitrogen to result in a more stable compound, the target product 5.

The transformation of semicarbazone 7 to triazolidinone 5 is thermodynamically favorable (ΔG = −1.10 kcal/mol) in MeCN and unfavorable (ΔG = 0.30 kcal/mol) in CHCl₃ solution. However, precipitation of the cyclization products in CHCl₃ (our experimental data) undoubtedly changes the thermodynamic characteristics of the reaction, resulting in its completion.

The DFT calculations also showed that Brønsted acid is required for the cyclization of aliphatic aldehyde semicarbazones to the corresponding triazolidin-3-ones. For example, the cyclization of semicarbazone 4 to 2,5-dimethyl-1,2,4-triazolidin-3-one without an acidic promoter is thermodynamically very unfavorable (ΔG = 7.17 kcal/mol in CHCl₃, ΔG = 6.77 kcal/mol in MeCN).

In contrast to aliphatic aldehyde semicarbazones, no cyclization products formed from benzaldehyde semicarbazones in the presence of very strong Brønsted acid (vide supra). To explain this difference, we performed the DFT B3LYP/6-311++G(d,p) calculations using benzaldehyde 2-methylsemicarbazone (9) as a model compound. Thermodynamic and kinetic parameters for the TfOH-promoted transformation of semicarbazone 9 into triazolidine salt 10 (Scheme 3) in MeCN solution were estimated by employing the polarizable continuum model.

The calculations showed that the cyclization of the intermediate salt 11 proceeds via the transition state TS^# to result in the N4-protonated triazolidinone triflate 12 followed by proton transfer, affording the final product 10. The IRC analysis demonstrated that the found transition state connects the desired minima. The activation barrier ΔG^# for the 11 → 12 transformation is low (19.67 kcal/mol in MeCN) (Figure 3).

However, the transformation of semicarbazone hydrotriflate 11 to triazolidinone salt 10 is thermodynamically unfavorable in MeCN (ΔG = 4.55 kcal/mol). This can be explained by the collapse of the π-π conjugation between the benzene ring and the C=N bond during the reaction.

3. Conclusions

In summary, aldehyde semicarbazones/1,2,4-triazolidin-3-ones chain-ring isomerism was first studied using the DFT B3LYP/6-311++G(d,p) method. Aliphatic aldehyde semicarbazones in the presence of very strong Brønsted acids (TfOH, HCl) in aprotic solvents (CHCl₃, MeCN) undergo protonation at the N₍₁₎ nitrogen, and the salts formed are completely cyclized at room temperature to give the corresponding salts of the N1-protonated 1,2,4-triazolidin-3-ones. The DFT calculations performed for the reaction of ethanal 2-methylsemicarbazone as a model compound with TfOH showed that the activation barrier of the cyclization is rather low (15.95 kcal/mol in CHCl₃, 16.13 kcal/mol in MeCN). From a thermodynamic viewpoint, the reaction in MeCN solution is favorable (ΔG = −1.10 kcal/mol) and in CHCl₃ solution it is unfavorable (ΔG = 0.30 kcal/mol); however, precipitation of the product in CHCl₃ shifts the equilibrium towards the N1-protonated 1,2,4-triazolidin-3-one triflates. In contrast to aliphatic aldehyde semicarbazones, the cyclization of benzaldehyde semicarbazones does not proceed in the presence of very strong Brønsted acids, which is explained by the unfavorable thermodynamics of this reaction. The DFT calculations performed for the reaction of benzaldehyde 2-methylsemicarbazone with TfOH in MeCN showed a positive change in the Gibbs free energy (ΔG = 4.55 kcal/mol) with a low activation barrier (ΔG^# = 19.67 kcal/mol).