The first computational study for the oxidative aromatization of pyrazolines and 1,4-dihydropyridines using 1,2,4-triazolinediones: an anomeric-based oxidation

Abstract

In this study, the oxidative aromatization process of 1,3,5-trisubstituted pyrazolines and 1,4 dihydropyridines, as pharmaceutically important structural motifs, using 1,2,4-triazolinediones as efficient oxidative agents were investigated. The achieved data from this computational study confirmed that the newly expanded term of “anomeric-based oxidation” for the aromatization of 1,3,5-trisubstituted pyrazolines and 1,4 dihydropyridine derivatives occurs by the common concerted oxidation via hydrogen abstraction–addition mechanism.

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Introduction

Azole-based heterocyclic structural scaffolds like pyrazoles and pyrazolines derivatives are present in a broad scope of pharmaceuticals viz., antifungal, antidepressant, analgesic, anticancer, anticonvulsant, antimicrobial, antidiabetic, anti-inflammatory and antimalarial agents.^1,2 In addition, in the case of condensed pyrazoles, due to the existence of the pyrazole moiety and other therapeutically significant heterocyclic scaffolds within the structure, the biological importance of pyrazoles can multiply, as demonstrated in the literature.^3,4 Also, pyrazole derivatives, because of their high thermal and hydrolytic stability, have been applied as ligands in coordination chemistry.^5,6 The chemistry and pharmaceutical applications of pyrazole and pyrazoline derivatives have been well recorded in recent times (Scheme 1).^7–10

Scheme 1 Some bioactive pyrazole-based organic molecules.

On the other hand, as in the case of pyrazole and pyrazoline derivatives, the synthesis and applicability of the dihydropyridine structural motif attracts sizable consideration in both the fields of organic transformation and medical chemistry. Due to the extent of dihydropyridine derivative applications as drugs in medicinal chemistry for treatments of diseases, construction and investigation of the pharmaceutical activity of these versatile target compounds has been the subject of huge academic and industrial chemistry exploration.^11–13 One of the most important features of dihydropyridines is the application of a Hantzsch ester as an NAD(P)H analogue for the catalytic hydrogenation of unactivated aldehydes, and also as a reducing agent (Scheme 2).^14,15

Scheme 2 NADH and some typical synthesized NAD(P)H analogues 7–9.

In the past decade, triazolinediones have appeared as highly potential and reliable synthetic tools. They have found interesting possibilities in different research fields such as synthesis, oxidation, polymer science and click chemistry with high reactivity. Due to the sufficient stability and excellent reactivity of triazolinedione derivatives, many attempts have focused on the production and investigation on the applications of these versatile and enabling reagents.¹⁶

The “anomeric effect” is defined as a chemical stabilizing effect that cause favorable placement of electronegative substituents in the axial, rather than equatorial, position in a pyranoid ring system at C1. After the first investigation on the topic of the anomeric effect, a great deal of attention has focused on expanding and generalizing this stereoelectronic phenomenon.¹⁷ The investigations have demonstrated that the anomeric effect is not confined to carbohydrate chemistry, and this effect can be used as an explanation for varied chemical phenomena such as precedence of gauche positions over anti orientation in Newman projections,¹⁷ stereochemical selectivities in radical reactions and other conformational preferences.^18–22 The anomeric effect, as a basic concept in chemistry, has been extensively reviewed.²³ Moreover, recent investigations have disclosed that the anomeric effect can play a key role in the activation and fixation of small molecules at the carbene site of N-heterocyclic carbenes (Scheme 3).²⁴

Scheme 3 Activation and fixation of small compounds at the N-heterocyclic carbene via the anomeric effect.

In addition, in some cases such as tricyclic orthoamides,²⁵ as well as in the Cannizzaro reaction,^26–29 the anomeric effect can affect the mechanism of the reaction and lead to exceptional hydride transfer in the course of reaction, as depicted in Scheme 4 and 5.^25–29

Scheme 4 Anomeric effect leads to hydrogen releasing from the reaction of tricyclic orthoamides with HBF₄.²⁵

Scheme 5 Anomeric effect leads to hydride transfer in the Cannizzaro reaction mechanism.^26–29

Very recently, in light of the abovementioned facts about the significant role of the anomeric effect in the field of organic transformations, we have offered a new mechanistic vision for the oxidative aromatization of some heterocyclic molecules and introduced a new term entitled “anomeric-based oxidation (ABO)” for the final step of the aromatization mechanism. As experimental and computational studies confirmed, lone pair electrons of the heteroatom, through resonance, can interact with the anti-bonding orbital of C–H bonds and facilitate hydride transfer leading to H₂ releasing from the intermediate to yield the desired products (Schemes 6–9).^26–29

Scheme 6 ABO mechanism for the synthesis of 1,4-dihydropyrano-[2,3-c]-pyrazoles.²⁶

Scheme 7 ABO mechanism for the synthesis of 2,4,6-triarylpyridines.²⁷

Scheme 8 ABO mechanism for the synthesis of 2-amino-3-cyanopyridines.²⁸

Scheme 9 ABO mechanism for the synthesis of 2-substituted benz-(imida, oxa and oxathia)-zoles.²⁹

Since the development of the above mentioned ABO term is our main research proposal, we decided to develop the concept of anomeric based oxidation and/or aromatization for various molecules because the systematic study of the anomeric effect in target molecules allows for the design of synthetic strategies based on anomerically driven stereoselective reactions, or highly biased equilibria among isomeric products. To the best of our knowledge, many biological processes involve the oxidation–reduction of substrates by NAD⁺/NADH, respectively. The key feature of the oxidation mechanism is hydride transfer from carbon via an anomeric-based oxidation. Thus, development of an anomeric-based oxidation and/or aromatization mechanism leads to knowledge-based designing of biomimetic reactions in the future. We think that the obtained results from this research will support the idea of rational design and synthesis of molecules for the development of the anomeric-based oxidation and/or aromatization mechanism.

In continuation of our successive attempts for the synthesis of fascinating heterocyclic target molecules, such as 1,3,5-trisubstituted pyrazolines^30–32 and 1,4 dihydropyridines,^33–44 report the application of 1,2,4-triazolinediones as an efficient recyclable oxidant (Scheme 10)⁴⁵ and also in order to expand our lately established term of “anomeric-based oxidation (ABO)” as a new explanation for the aromatization of some heterocyclic compounds, we wish to investigate the computational study for utilizing of 1,2,4-triazolinediones as an efficient oxidizing agent for the oxidative aromatization of 1,3,5-trisubstituted pyrazolines and 1,4 dihydropyridines in two different plausible mechanisms: concerted ABO (Schemes 11 and 13) and concerted oxidation via hydrogen abstraction–addition mechanism (Schemes 12 and 14). In the case of both 1,3,5-trisubstituted pyrazolines and 1,4 dihydropyridines, in a plausible ABO mechanism as depicted in Scheme 11 and 13, interaction of the lone pair electrons of nitrogen atoms within the structure with the anti-bonding orbitals of C–H bonds leads to weakening of the bond and facilitates the hydride transfer to the 1,2,4-triazolinedione oxidizing agent.

Scheme 10 Recyclability potential of the presented oxidative systems.

Scheme 11 Stepwise ABO mechanism for the synthesis of 1,3,5-trisubstituted pyrazolines.

Scheme 12 Concerted oxidation via hydrogen abstraction–addition mechanism for the synthesis of 1,3,5-trisubstituted pyrazolines.

Scheme 13 Stepwise ABO mechanism for the aromatization of dihydropyridines.

Scheme 14 Concerted oxidation via hydrogen abstraction–addition mechanism for the aromatization of dihydropyridines.

Computational methods and modeling details

In this study, some of the appropriate quantum mechanical (QM) methods were applied for optimization of the structures and the reaction pathways. The best methods were chosen to report the results of the calculations. The interpretation of the results is based on the best results of the optimization and minimization of the reactants, intermediates and the transition states. The transition states were obtained by reaction coordinate methods. The HF/6-31G* method was applied for initial optimization of the precise transition states and then DFT-B3LYP/6-31G* was performed for final optimization of the transition states as well as the reactants and the intermediates. The vibration frequencies were checked (IRC) for optimized TS structures. The DFT-B3LYP method was performed by the Spartan'10 package.⁴⁶ In this molecular modeling study, the structures were minimized and optimized by B3LYP with the 6-31G* basis sets.^47,48 The results were scaled to compute G_products, G_TS, G_reactants, ΔG^# and Δ_rG at 298 K by equations:

ΔG^# = G_TS − G_reactants (1)

Δ_rG = ΣG_products − ΣG_reactants (2)

The calculations of the ground state molecular geometry and different forms of the suggested molecules (precursors (I) and (II), oxidative agents (a and b), transition states, intermediates and product (I) and (II)) in vacuum were performed by the DFT-B3LYP/6-31G* method by means of the standard polarized basis set, 6-31G*,^18,30–36 implemented in the Spartan'10 package.⁴⁶ The Hartree energies have been changed to kcal mol⁻¹. The relative energies have also been calculated. The results are demonstrated in the graphs and the related tables.

The oxidation reactions on the basis of the anomeric effect of precursor (I) and (II) by 4-(4-chlorophenyl)-4H-pyrazole-3,5-dione (a) and 4-propyl-4H-pyrazole-3,5-dione (b) as the oxidative agents, respectively, and the predicted reaction pathways (concerted and stepwise) were modeled with respect to the different aspects. Calculations on the Mulliken bond order (MBO) pathways, reaction pathways (concerted and stepwise), structures of precursor (I) and (II), the oxidative agents (a and b), the different positions of the transition states (TS), the intermediates and products (I) and (II) were undertaken by the DFT-B3LYP/6-31G* method.⁴⁶ The oxidation reactions on the basis of anomeric effect of the precursor (I)and (II) by 4-(4-chlorophenyl)-4H-pyrazole-3,5-dione (a) and 4-propyl-4H-pyrazole-3,5-dione (b) as the oxidative agents, respectively, and the predicted reaction pathways (concerted and stepwise) have modeled with respect to the different aspects.

Theoretical discussion on precursor (I) and the ABO reactions

The calculations on the two MBO pathways (1 and 2), reaction pathways (concerted and stepwise), structures of precursors (I) and (II), oxidative agents (a) and (b), the different positions of the transition states (TS), the intermediates and products (I) and (II) were undertaken by the DFT-B3LYP/6-31G* method.⁴⁶ The different conjugated pathways (1 and 2) for the anomeric effect on C1–H1 and C2–H2 bonds in the precursor (I) molecule related to the MBO method are displayed in Table 1. In Table 1, the MBO results of the two conjugation processes in precursor (I) for the anomeric effect on C1–H1 and C2–H2 bonds are demonstrated. The two pathways (1 and 2) of the conjugations are: N5N4C3C2H2 (long pathway) and N5C1H1 (short pathway), respectively. The long pathway (pathway-1: N5N4C3C2H2) of electron transfer includes: and . The other electron conjugation, i.e. pathway-2 (N5C1H1) includes: the electron conjugation. The MBO values of C1–H1 and C2–H2 bonds are: 0.92 and 0.90, respectively. The results of MBO analysis on the basis of DFT studies show that the C2–H2 (with MBO 0.90) had better priority to achieve [TS]₁ in the two steps pathway. Table 1 and its figures have demonstrated the anomeric structures for (I) under the conjugation pathways. Table 2 shows the selected structural data (bond length (Å), bond angle (°) and torsional angle (°)) of precursor (I), the transition states in the two predicted mechanism pathways (concerted and stepwise) with oxidative agent (a) with respect to precursor (I), intermediate and product (I). The optimized structure of (a) is demonstrated in Fig. 1.

Table 1 The different conjugated pathways (1 and 2) for the anomeric effect on C1–H1 and C2–H2 bonds in the precursor molecule (I) related to the MBO method, and the MBO data of the conjugation process in precursor (I) for the anomeric effect on C1–H1 and C2–H2 bonds in the two pathways. The hybrid form of the two conjugated pathways is shown in the right side of the figure

Structures and pathways	Bond orders (MBO)
	N4–N5	C1–N5	C2–C3	C3–H3	C1–H1	C2–H2	C1–C5	C2–C6
Pathway1	1.07	0.89	0.96	0.92	0.92	0.90	0.96	0.98
Pathway2	1.06	0.87	0.96	0.92	0.91	0.92	0.97	0.98
Concerted	1.06	0.87	0.96	0.92	0.91	0.92	0.97	0.98

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Table 2 The selected structural data (bond length (Å), bond angle (°) and torsional angle (°)) of the oxidative agent, precursor (I), transition state, intermediate and product (I) of the predicted concerted pathway (see Fig. 1 for the atom numbers)

Selected structural data	Stage of the pathways
	Oxidative reagent			Precursor	TS-concerted	Intermediate	Product
	a	B	C
Bond length (Å)
N1–C7	1.397	1.490	1.406	—	1.376	—	—
C7–O1	1.200	1.244	1.210	—	1.222	—	—
C7–N3	1.494	1.332	1.402	—	1.412	—	—
N3–H1	—	—	1.017	—	1.022	—	—
N2–H2	—	1.1005	1.017	—	1.840	—	—
N2–C8	1.494	1.350	1.402	—	1.361	—	—
C8–O2	1.200	1.242	1.210	—	1.223	—	—
N1–C8	1.397	1.409	1.406	—	1.479	—	—
N2–N3	1.241	1.406	1.423	—	1.403	—	—
C1–C5	—	—	—	1.517	1.473	1.528	1.477
C1–N5	—	—	—	1.481	1.353	1.322	1.379
N5–N4	—	—	—	1.382	1.410	1.435	1.360
N5–C4	—	—	—	1.409	1.437	1.439	1.426
N4–C3	—	—	—	1.280	1.287	1.281	1.325
C3–C2	—	—	—	1.513	1.498	1.501	1.417
C2–H2	—	—	—	1.096	—	1.102	—
Bond angle (°)
N1C7O1	130.61	122.70	128.46	—	134.54	—	—
O1C7N3	122.68	129.00	125.83	—	124.19	—	—
C7N3H1	—	—	112.86	—	114.86	—	—
O2C8N2	122.68	127.46	125.83	—	127.10	—	—
C8N2H2	—	123.44	112.86	—	113.99	—	—
C7N1C8	107.19	107.85	110.51	—	107.03	—	—
N3N2H2	—	120.26	112.96	—	117.01	—	—
N2N3H1	—	—	112.96	—	94.23	—	—
C1N5C4	—	—	—	123.47	128.78	130.99	129.71
H2C2C3	—	—	—	110.57	—	108.74	—
N5N4C3	—	—	—	109.53	106.28	105.60	104.81
N4C3H3	—	—	—	120.15	119.73	120.35	119.72
Dihedral angle (°)
N1C7N3H1	—	—	−138.87	—	−158.18	—	—
O1C7N3N2	180.00	180.00	166.44	—	162.80	—	—
N1C8N2N3	0.00	0.00	−13.42	—	−23.07	—	—
O2C8N2H2	—	0.00	41.07	—	21.18	—	—
H1C1N5N4	—	—	—	100.40	—	—	—
H2C2C3N4	—	—	—	−122.56	—	−113.64	—
H3C3N4N5	—	—	—	176.57	173.35	−179.22	−178.79
H2C2C1H1	—	—	—	13.31	—	—	—
C5C1N5C4	—	—	—	−122.69	−33.15	10.50	175.65

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Fig. 1 The species (precursor (I), oxidative agent (a), transition states, intermediate and product (I)) of the concerted and stepwise (2 steps) pathways of the ABO effect of (I).

Fig. 2 shows two predicted pathways (concerted and stepwise) of the oxidation reactions of precursor (I) by (a) as the oxidative agent. The calculated energy levels and structures of the transition states ([TS]_Concerted, [TS]₁ and [TS]₂) for the oxidation reactions on the basis of anomeric effects in precursor (I) with (a) are presented in Fig. 2, 3 and Tables 2, 3.

Fig. 2 The pathways (concerted and stepwise) of the reactions.

Fig. 3 The energy (in kcal mol⁻¹) and reaction diagram of the precursor (I) oxidation reaction on the basis of the anomeric effect by the oxidative agent for the two predicted pathways (concerted and two-step reactions) by the B3LYP/6-31G* method.

Table 3 The conjugated pathway for the anomeric effect on the C1–H1 bond in the precursor molecule (II-C_s) related to the MBO method and the MBO data of the conjugation process in (II) for the anomeric effect on the C1–H1 bond in one pathway (note the C_s point group of (II)). The hybrid form of the conjugated pathway is shown in the right side of the figure

Structure	Bond orders (MBO)
	C1–C2	C2–C3	C3–N4	N4–H2	N4–C4	C4–C5	C5–C1	C1–H1
Stepwise	0.94	1.66	0.99	0.83	0.95	1.71	0.94	0.90
Concerted	0.98	1.66	0.98	0.82	0.98	1.69	0.95	0.73

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In the concerted reaction of precursor (I) with (a), the bond lengths of [C1⋯H1 and H1⋯N2] and [C2⋯H2 and H2⋯N3] in the transition state ([TS]_Concerted) were obtained as: [1.550 and 1.612] and [1.614 and 1.610] Å, respectively. The DFT results show that this concerted reaction needs (ΔG^#) 76.93 kcal mol⁻¹. In the stepwise reaction of (I) with (a) in the transition state ([TS]₁), the bond lengths of C2⋯H2 and H2⋯N2 were obtained as: 1.781 and 1.684 Å, respectively. The calculated MBO values of C1–H1 and C2–H2 bonds (0.92 and 0.90, respectively) confirms that the first step in the stepwise reaction should pass from the transition state with [TS]₁ characteristics. In the second transition state (second step; [TS]₂), the bond lengths of C1⋯H1 and H1⋯O (the enolic form of the a-1H) were obtained as: 1.712 and 1.735 Å, respectively. The DFT results show that the enolic form is 0.10 kcal mol⁻¹ more stable than the keto form of the oxidative agent (see Fig. 3). The DFT results show that the first step of the stepwise reaction needs (ΔG^#) 45.51 kcal mol⁻¹. The intermediate of this reaction (between [TS]₁ and [TS]₂) was located 9.97 kcal mol⁻¹ lower than [TS]₁ (45.51 kcal mol⁻¹ higher than the precursor energy level). The transition state of the second step ([TS]₂) was 72.35 kcal mol⁻¹ higher than the precursor energy level. The (ΔG^#) for passing from intermediate to [TS]₂ was obtained to be 26.72 kcal mol⁻¹. The obtained product (I) of this reaction was 60.07 kcal mol⁻¹ more stable than the precursor (I) energy level (see Fig. 2 and 3). At the end of the reaction, oxidative agent (a) has attracted 2H from precursor (I). The DFT calculation presents that the trans form of (a-2H) is about 0.69 kcal mol⁻¹ more stable than its cis form. Overall, because of the lower (ΔG^#) in the stepwise reaction than the concerted pathway, this oxidation reaction prefers the stepwise mechanism.

Theoretical discussion on precursor (II) and the ABO reactions

Precursor (II) has a C_s point group and there is just one pathway for conjugation. The single conjugated pathway for the anomeric effect on the C1–H1 bond in precursor (II) related to the MBO method is displayed in Table 3. Table 3 demonstrates the MBO results of the conjugation process in precursor (II) for the anomeric effect on the C1–H1 bond. This conjugation pathway is N4C3C2C1H1. This pathway of electron transfer includes: , and . The obtained MBO value of the C1–H1 bond is 0.90. Table 3 and its figures have demonstrated the anomeric structures for precursor (II) under the conjugation pathway. Tables 4 and 5 show the selected structural data (bond length (Å), bond angle (°) and torsional angle (°)) of precursor (II), the transition states in the two predicted mechanism pathways (concerted and stepwise) with the oxidative agent 4-propyl-4H-pyrazole-3,5-dione (b). The optimized structures of (b) is demonstrated in Fig. 4.

Table 4 The selected structural data (bond length (Å), bond angle (°) and torsional angle (°)) of the oxidative agent species

Selected structural data	Oxidative agent
	b	D	E	F
Bond length (Å)
N1–C7	1.380	1.378	1.391	1.414
C7–O1	1.200	1.242	1.212	1.220
C7–N3	1.504	1.376	1.408	1.373
N3–H1	—	1.010	1.017	1.007
N2–H2	—	—	1.017	—
N2–C8	1.504	1.338	1.408	1.297
C8–O2	1.200	1.250	1.213	1.343
N1–C8	1.380	1.450	1.391	1.367
N2–N3	1.243	1.431	1.428	1.396
Bond angle (°)
N1C7O1	129.39	128.52	127.82	127.36
O1C7N3	124.64	128.60	126.52	130.64
C7N3H1	—	118.95	112.90	125.76
O2C8N2	124.64	130.83	126.54	125.71
C8N2H2	—	—	112.80	—
C7N1C8	109.06	110.07	111.52	107.07
Dihedral angle (°)
N1C7N3H1	—	151.79	−137.33	177.60
O1C7N3N2	−179.90	−172.33	42.30	−179.12
N1C8N2N3	−0.44	3.42	−13.41	0.09
O2C8N2H2	—	—	42.34	—
H1N3N2H2	—	—	−94.10	—

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Table 5 The selected structural data (bond length (Å), bond angle (°) and torsional angle (°)) of precursor (II), transition states, intermediate and the product (II) for the two-step pathway (see Fig. 4 for the atom numbers)

Selected structural data	Precursor	Intermediate	TS				Product
			[TS]1	[TS]′1	[TS]Concerted	[TS]2	C s	C 2
Bond length (Å)
C1–C2	1.529	1.413	1.476	1.476	1.406	1.476	1.406	1.406
C2–C3	1.362	1.394	1.381	1.381	1.414	1.381	1.409	1.408
C3–N4	1.387	1.358	1.403	1.403	1.418	1.403	1.339	1.340
N4–H2	1.009	1.017	1.014	1.014	1.729	1.014	—	—
N4–C4	1.387	1.358	1.386	1.386	1.402	1.386	1.339	1.340
C4–C5	1.362	1.394	1.354	1.354	1.353	1.354	1.409	1.480
C5–C1	1.529	1.413	1.547	1.547	1.508	1.547	1.406	1.406
C1–H1	1.092	—	1.645	1.865	1.664	1.865	—	—
N2–N3	—	—	1.243	1.251	1.349	1.251	—	—
N3–H1	—	—	—	—	—	—	—	—
N1–C7	—	—	1.380	1.377	1.370	1.377	—	—
C7–N3	—	—	1.504	1.412	1.340	1.412	—	—
C7–O1	—	—	1.223	1.223	1.253	1.223	—	—
C8–O2	—	—	1.200	1.210	1.217	1.210	—	—
Bond angle (°)
C1C2C3	121.11	120.29	121.99	121.99	118.79	121.99	119.35	119.45
C2C3N4	118.91	117.31	120.03	120.03	121.31	120.03	121.78	121.80
C3N4C4	123.96	125.93	121.69	121.69	118.07	121.69	119.99	119.88
N4C4C5	118.91	117.31	120.09	120.09	121.82	120.09	121.78	121.80
C4C5C1	121.11	120.29	121.78	121.78	119.10	121.78	119.35	119.45
H1C1C5	108.04	—	107.29	107.29	97.18	107.29	—	—
H1C1C2	108.04	—	110.30	110.30	101.82	110.30	—	—
H2N4C3	117.18	117.03	119.71	119.71	120.44	119.71	—	—
H2N4C4	117.18	117.03	116.21	116.21	119.46	116.21	—	—
O1C7N3	—	—	124.64	125.46	124.66	125.46	—	—
O2C8N2	—	—	124.64	123.31	118.18	123.31	—	—
Dihedral Angle (°)
C1C2C3N4	−6.68	−1.09	3.03	3.03	−2.63	3.03	−0.62	2.59
H1C1C2C3	140.38	—	103.63	103.63	92.94	103.63	—	—
H1C1C5C4	−140.38	—	−104.44	−104.44	−94.40	−104.44	—	—
H2N4C3C2	−177.07	−179.76	172.84	172.84	−147.23	172.84	—	—
H2N4C4C5	177.07	179.76	−172.46	−172.46	148.55	−172.46	—	—
C1C5C4N4	6.68	−1.09	−4.48	−4.48	0.80	−4.48	0.62	2.59
C7N3N2C8	—	—	−0.00	−0.00	−0.25	−0.00	—	—

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Fig. 4 The species (precursor (II), oxidative agent (b), transition states, intermediate and product (II)) of the concerted and stepwise (2 steps) pathways of the ABO effect of (II).

Fig. 5 shows two predicted pathways (concerted and stepwise) for the oxidation reactions of precursor (II) by (b). The calculated of the energy levels and structures of the transition states ([TS]_Concerted, [TS]₁, [TS]′₁ and [TS]₂) for the oxidation reactions on the basis of anomeric effects in precursor (II) with (b) are presented in Fig. 5 and 6 and Tables 4 and 5.

Fig. 5 The pathways (concerted and stepwise) of the reactions.

Fig. 6 The energy (in kcal mol⁻¹) and reaction diagram of the precursor (II) oxidation reaction on the basis of the anomeric effect by the catalyst agent for the two predicted pathways (concerted and two-step reactions) by the B3LYP/6-31G* method.

In the concerted reaction of precursor (II) with (b), the bond lengths of [C1⋯H1 and H1⋯N1] and [N4⋯H4 and H4⋯N2] in the transition state ([TS]_Concerted) were obtained as: [1.664 and 1.681] and [1.629 and 1.573] Å, respectively. The DFT results show that this concerted reaction needs a high energy (ΔG^#) equal to 109.66 kcal mol⁻¹. So, the concerted reaction could not be a candidate mechanism for this oxidation reaction. In the stepwise reaction of precursor (II) with (b) in the transition state ([TS]₁), the bond lengths of C1⋯H1 and H1⋯N1 were obtained as: 1.645 and 1.671 Å, respectively. This transition state was structurally named as the non-eclipsed form. The (ΔG^#) of [TS]₁ was obtained equal to 51.10 kcal mol⁻¹. Another possible form of the transition state ([TS]′₁) was structurally named as the eclipsed form and its (ΔG^#) was obtained equal to 53.00 kcal mol⁻¹ by the DFT-B3LYP/6-31G* method. So, the more plausible pathway in first step is passing from ([TS]₁) with a lower free activation energy. In the second transition state (second step, [TS]₂) the bond lengths of N4⋯H4 and H4⋯O (the enolic form of the b-1H) were obtained as: 1.612 and 1.750 Å, respectively. The DFT results present no differences between the energy levels of the enolic and keto forms of the oxidative agent (b) (see Fig. 6). The intermediate of this reaction (between [TS]₁ and [TS]₂) was located 76.97 kcal mol⁻¹ lower than [TS]₁ (25.87 kcal mol⁻¹ lower than the precursor (II) energy level). The transition state of the second step ([TS]₂) was 36.05 kcal mol⁻¹ higher than the precursor (II) energy level. The (ΔG^#) for passing from intermediate to [TS]₂ was obtained to be 61.92 kcal mol⁻¹. The obtained product (I) of this reaction was 56.87 kcal mol⁻¹ more stable than the precursor (II) energy level (see Fig. 5 and 6). At the end of the reaction, oxidative agent (b) has attracted 2H from precursor (II). The DFT calculation presents that the trans form of (b-2H) is about 6.09 kcal mol⁻¹ more stable than its cis form. Product (II) has two rotamers (by rotation around the C_sp²–COOMe bond) and its C₂ isomer is 19.93 kcal mol⁻¹ more stable than the C_s isomer of (II). Because of the lower (ΔG^#) in the stepwise reaction than the concerted pathway, this oxidation reaction prefers the stepwise mechanism.

The DFT modeling of the ABO effect of the precursors (I) and (II) show that in both cases, because of the lower ΔG^# in the stepwise reaction than the concerted pathway, both oxidation reactions prefer the stepwise mechanism with the oxidative agents (a) and (b). In the stepwise oxidation reaction of precursor (I) by (a), the second step needs more free activation energy than the first step. But, in the stepwise oxidation reaction of precursor (II) by (b), the second step needs lower free activation energy than its first step. This may be related to the point that the intermediate of the oxidation reaction of precursor (II) by (b) has aromatic cationic structure, but the intermediate of the oxidation reaction of the precursor (I) by (a) is not an aromatic species.

Conclusion

In conclusion, we investigated two plausible mechanisms for the aromatization of 1,3,5-trisubstituted pyrazolines and 1,4 dihydropyridines using 1,2,4-triazolinediones as oxidizing agent. In both oxidation reactions, as the DFT modeling of the ABO effect of the precursors (I) and (II) show, due to the lower (ΔG^#) in the stepwise reaction than the concerted pathway, the ABO mechanism passes through the common concerted oxidation via the hydrogen abstraction–addition mechanism. Many biological processes involve oxidation–reduction of substrates by NAD⁺/NADH, respectively. Thus, we think that the described results will support the idea of rational design and synthesis of target molecules for the development of biomimetic reactions, anomeric-based oxidations and aromatization mechanisms.

Acknowledgements

We thank Bu-Ali Sina University and Iran National Science Foundation (INSF) for financial support (Grant No: 95831207) to our research groups.

References

1. J. V. Mehta, S. B. Gajera, P. Thakor, V. R. Thakkar and M. N. Patel, RSC Adv., 2015, 5, 85350.
2. N. Harikrishna, A. M. Isloor, K. Ananda, A. Obaid and H. K. Fun, New J. Chem., 2016, 40, 73.
3. M. Li and B. X. Zhao, Eur. J. Med. Chem., 2014, 85, 311.
4. F. E. Boyer, J. Vara Prasad, A. L. Choy, L. Chupak, M. R. Dermyer, Q. Ding, M. D. Huband, W. Jiao, T. Kaneko, V. Khlebnikov, J. Y. Kim, M. S. Lall, S. N. Maiti, K. Romero and X. J. Wu, Bioorg. Med. Chem. Lett., 2007, 17, 4694.
5. M. A. Halcrow, Dalton Trans., 2009, 2059.
6. S. Trofimenko, Chem. Rev., 1972, 72, 497.
7. D. Raffa, B. Maggio, M. V. Raimondi, S. Cascioferro, F. Plescia, G. Cancemi and G. Daidone, Eur. J. Med. Chem., 2014, 72, 1.
8. R. S. Keri, K. Chand, T. Ramakrishnappa and B. M. Nagaraja, Arch. Pharm. Chem. Life Sci., 2015, 348, 1.
9. K. Manna, U. Banik, P. S. Ghosh and M. D. Nirma, Dhaka Univ. J. Pharm. Sci., 2014, 1, 37.
10. N. A. A. Elkanzi, Int. J. Res. Pharm. Biomed. Sci., 2013, 4, 17.
11. D. L. Comins, K. Higuchi and D. W. Young, Adv. Heterocycl. Chem., 2013, 110, 175.
12. V. G. Santos, M. N. Godoi, T. Regiani, F. H. S. Gama, M. B. Coelho, R. O. M. A. de Souza, M. N. Eberlin and S. J. Garden, Chem.–Eur. J., 2014, 20, 12808.
13. J. P. Wan and Y. Liu, RSC Adv., 2012, 2, 9763.
14. G. Hamasaka, H. Tsuji and Y. Uozumi, Synlett, 2015, 26, 2037.
15. T. He, R. Shi, Y. Gong, G. Jiang, M. Liu, S. Qian and Z. Wang, Synlett, 2016, 27, 1864.
16. K. D. Bruycker, S. Billiet, H. A. Houck, S. Chattopadhyay, J. M. Winne and F. E. Du Prez, Chem. Rev., 2016, 116, 3919.
17. (a) E. Juaristi and G. Cuevas, Tetrahedron, 1992, 48, 5019; (b) S. A. Glover, A. A. Rosser, A. Taherpour and B. W. Greatrex, Aust. J. Chem., 2014, 67, 507.
18. D. P. Curran, N. A. Porter and B. Giese, Stereochemistry of Radical Reaction, VCH, New York, 1995, p. 69.
19. V. F. Rudchenko, Chem. Rev., 1993, 93, 725.
20. V. F. Rudchenko, V. I. Shevchenko and R. G. Kostyanovskii, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1986, 543.
21. S. A. Glover, Tetrahedron, 1998, 54, 7229.
22. S. A. Glover and A. A. Rosser, J. Phys. Org. Chem., 2015, 28, 215.
23. (a) E. Juaristi and Y. Bandala, Adv. Heterocycl. Chem., 2015, 105, 189; (b) C. M. Filloux, Angew. Chem., Int. Ed., 2015, 54, 8880.
24. (a) H. Song, Y. Kim, J. Park, K. Kim and E. Lee, Synlett, 2016, 27, 477; (b) P. L. Arnold and I. J. Casely, Chem. Rev., 2009, 109, 3599; (c) S. T. Liddle, I. S. Edworthy and P. L. Arnold, Chem. Soc. Rev., 2007, 36, 1732.
25. (a) J. M. Erhardt and J. D. Wuest, J. Am. Chem. Soc., 1980, 102, 6363; (b) T. J. Atkins, J. Am. Chem. Soc., 1980, 102, 6364; (c) J. M. Erhardt, E. R. Grover and J. D. Wuest, J. Am. Chem. Soc., 1980, 102, 6365.
26. M. A. Zolfigol, F. Afsharnadery, S. Baghery, S. Salehzadeh and F. Maleki, RSC Adv., 2015, 5, 75555.
27. (a) M. A. Zolfigol, M. Safaiee, F. Afsharnadery, N. Bahrami-Nejad, S. Baghery, S. Salehzadeh and F. Maleki, RSC Adv., 2015, 5, 100546; (b) A. R. Moosavi-Zare, M. A. Zolfigol and Z. Rezanejad, Can. J. Chem., 2016, 94, 1.
28. M. A. Zolfigol, M. Kiafar, M. Yarie, A. A. Taherpour and M. Saeidi-Rad, RSC Adv., 2016, 6, 50100.
29. M. A. Zolfigol, A. Khazaei, S. Alaie, S. Baghery, F. Maleki, Y. Bayat and A. Asgari, RSC Adv., 2016, 6, 58667.
30. D. Azarifar, M. A. Zolfigol and B. Maleki, Synthesis, 2004, 11, 1744.
31. M. A. Zolfigol, D. Azarifar and B. Maleki, Tetrahedron Lett., 2004, 45, 2181.
32. M. A. Zolfigol, D. Azarifar, S. Mallakpour, I. Mohammadpoor-Baltork, A. Forghaniha, B. Maleki and M. Abdollahi-Alibeik, Tetrahedron Lett., 2006, 47, 833.
33. M. A. Zolfigol, M. H. Zebarjadian, M. M. Sadegh, I. Mohammadpoor-Baltork, H. R. Memarian and M. Shamsipur, Synth. Commun., 2001, 31, 929.
34. M. A. Zolfigol, F. Shirini, A. Ghorbani Choghamarani and I. Mohammadpoor-Baltork, Green Chem., 2002, 4, 562.
35. M. A. Zolfigol, A. Ghorbani Choghamarani, S. Dialameh, M. M. Sadeghi, I. Mohammadpoor-Baltork and H. R. Memarian, J. Chem. Res., Synop., 2003, 18.
36. M. A. Zolfigol, F. Shirini, A. Ghorbani Choghamarani and I. Mohammadpoor-Baltork, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178, 1709.
37. M. A. Zolfigol, A. Ghorbani Choghamarani, M. Shahamirian, M. Safaiee, I. Mohammadpoor-Baltork, S. Mallakpour and M. Abdollahi-Alibeik, Tetrahedron Lett., 2005, 46, 5581.
38. N. Koukabi, A. E. Kolvari, A. Khazaei, M. A. Zolfigol, B. Shirmardi-Shaghasemi and H. R. Khavasi, Chem. Commun., 2011, 47, 9230.
39. D. Habibi, M. A. Zolfigol and M. Safaee, J. Chem., 2013, 495982,  DOI:10.1155/2013/495982.
40. M. A. Zolfigol and M. Mokhlesi, J. Iran. Chem. Soc., 2008, 5, 91.
41. M. A. Zolfigol, P. Salehi and M. Safaiee, Lett. Org. Chem., 2006, 3, 153.
42. M. A. Zolfigol, P. Salehi, A. Khorramabadi-Zad and M. Shayegh, J. Mol. Catal. A: Chem., 2007, 261, 88.
43. M. A. Zolfigol and M. Safaiee, Synlett, 2004, 827.
44. M. A. Zolfigol, E. Kolvari, A. Abdoli and M. Shiri, Mol. Diversity, 2010, 14, 809.
45. (a) M. A. Zolfigol, A. Khazaei, T. Faal-Rastegar, S. Mallakpour, H. R. Khavasi, P. Salehi and M. Fakharian, Synthesis, 2016, 48, 1518; (b) M. A. Zolfigol, G. Chehardoli, F. Shirini, S. Mallakpour and H. Nasr-Isfahani, Synth. Commun., 2001, 31, 1965; (c) M. A. Zolfigol, M. Bagherzadeh, G. Chehardoli and S. Mallakpour, Synth. Commun., 2001, 31, 1149; (d) M. A. Zolfigol, M. H. Zebarjadian, G. Chehardoli, S. Mallakpour and M. Shamsipur, Tetrahedron, 2001, 57, 162; (e) M. A. Zolfigol, E. Madrakian, E. Ghaemi and S. Mallakpour, Synlett, 2002, 1633; (f) M. A. Zolfigol, G. Chehardoli and S. Mallakpour, Synth. Commun., 2003, 33, 833; (g) M. A. Zolfigol, R. Ghorbani-Vaghei, S. Mallakpour, G. Chehardoli, A. Ghorbani-Choghamarani and A. Yazdi, Synthesis, 2006, 10, 1631; (h) M. A. Zolfigol, M. Bagherzadeh, S. Mallakpour, G. Chehardoli, A. Ghorbani-Choghamarani, N. Koukabi, M. Dehghanian and M. Doroudgar, J. Mol. Catal. A: Chem., 2007, 270, 219; (i) A. Khoramabadi-zad, A. Shiri, M. A. Zolfigol and S. Mallakpour, Synthesis, 2009, 2729.
46. All of the calculations were performed by: Spatran'10-Quantum Mechanics Program: (PC/x86) 1.1.0v4. 2011, Wavefunction Inc., USA.
47. K. I. Ramachandran, G. Deepa and K. Namboori, Computational Chemistry and Molecular Modelling: Principles and Applications, Springer-Verlag, Berlin Heidelberg, 2008.
48. M. F. Budyka, T. S. Zyubina and A. K. Zarkadis, J. Mol. Struct.: THEOCHEM, 2002, 594, 113.

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