Experimental and Theoretical Studies on the Functionalization Reactions of 4-Benzoyl-1,5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid and Acid Chloride with 2,3-Diaminopyridine

The 1H-pyrazole-3-carboxylic acid 2 was converted in good yield (69%) into the corresponding 1H-pyrazole-3-carboxamide 5 via reaction of the acid chloride 3 with 2,3-diaminopyridine (4). A different product, the 3H-imidazo[4,5-b] pyridine derivative 6, was formed from the reaction of 3 with 4 and base in benzene for 5 hours. The structures of the synthesized compounds were determined spectroscopically. The mechanism of the reaction between 3 and 4 was examined theoretically.


Results and Discussion
Compound 3 reacts with 2,3-diaminopyridine (4) in two ways, thus yielding the 1H-pyrazole-3carboxamide derivative 5 or the 3H-imidazo [4,5-b] pyridine derivative 6. The substituted 2,3furandione 1 and 1H-pyrazole-3-carboxylic acid 2, as well as 1H-pyrazole-3-carboxylic acid chloride 3, which are important starting materials in the synthesis of the target heterocycles, were prepared using the literature procedures [1, 16,17]. Compound 5 was synthesized in good yield by refluxing 2,3diaminopyridine (4) and a two-fold molar excess of the pyrazole-3-carboxylic acid 2 or the pyrazole-3carboxylic acid chloride 3 in benzene, without opening of the pyrazole ring (see Scheme 1). The reactions were performed together with catalytic amounts of an acid (in the case of 2) or a base (in the case of 3), for 5-10 hours, by the usual chemical method (for details, see the Experimental section). Addition of binucleophile 4 to the acid 2 or acid chloride 3 usually starts with nucleophilic attack at the acid or acid chloride moieties in these compounds. Therefore, the newly obtained product 5 arises from the sequential attacks of the diamine 4 at the acid chloride moieties of two respective molecules of 3, followed by elimination of hydrogen chloride (in the case of 2, by elimination of water). The first step corresponds to the nucleophilic addition of one of 2,3-diaminopyridine's amino groups (N 9 ) to the electrophilic sp 2 -hybridized carbon atom (C 6 ) of the 1H-pyrazole-3-carboxylic acid chloride (See Figure 1).

Figure 1.
The total self-consistent field energy of reacting molecules (3+4), which are far from each other (C 6 -N 9 = 3.65 Å), is -1931.018 a.u. for RHF/STO-3G method. TS1 is the result of the C 6 -N 9 bond formation for the account of proton transfer to chlorine atom. The C 6 -N 9 , C 6 -Cl 8    The resulting SCF energy value is -1930.967 a.u. for an intermediate product IN(1). In theoretical chemistry, the reaction intermediates and transition states can be strictly distinguished by the use of vibrational analysis. For TS1 one imaginary frequency was found at -281 cm -1 . Molecule 4 approaches the molecular plane of 3 at an angle of 107.1 o . Torsion angle of H 9 -N 8 -C 6 -C 4 being equal to -111 o is not coplanar. When the bond length of C 6 -N 9 becomes 1.38 Å, IN(1) is formed. Torsion angle of H 9 -N 8 -C 6 -C 4 becomes 168 o and approximates to the coplanar one. When the bond C 6 -N 9 is formed, new charge redistribution is seen. The negative charge on the N 9 (RHF/STO-3G) decreases from -0.41 to -0.38 ē, positive charge on the C 6 atom and negative charges on the O 7 and Cl 8 atoms increase. In this way, a substantial polarization of bonds formed by the atom C 6 can be observed.
The calculations were done by using semi-empirical AM1 and ab initio methods. Ab initio calculations were carried out by using two different basis sets that differ in the polarization functions, namely, STO-3G and 3-21G. When the ab initio method is used instead of AM1, this causes electron redistribution and changes in bond lengths. The latter are also changed, when the same method but a different basis set is used. For example, the C 6 -O 7 bond length at 3-4 is 1.23 Å for AM1, 1.21 Å for RHF/ STO-3G, and 1.19 Å for RHF/3-21G.  In the second step of the reaction, nucleophilic addition of the other amino group (N 15 ) of IN1 to the sp 2 -hybridized carbon atom (C 19 ) of the second electrophilic 1H-pyrazole-3-carboxylic acid chloride happens. In this way the compound 5 was obtained. For the transitional state TS2, its interatomic distances are determined as R N15-C19 = 1.54 Å, R N15-H16 = 1.10 Å, R C21-Cl18 = 2.40 Å, R C18-H19 = 1.90 Å (see Table 2).  The structure of compound 5 was confirmed, besides elemental analysis, by IR and NMR spectroscopic techniques. These results are in full agreement with similar findings for substituted 1Hpyrazole-3-carboxamides [16][17][18]. The formation of 5 was supported by the results of both analytical and spectroscopic measurements, particularly by the presence of four characteristic absorption bands (FT IR: 1686.93 cm -1 , 1670.68 cm -1 ) for carbonyl (amidic and benzoyl) groups. The broad absorption band of NH⇌OH groups was at 3433.64 cm -1 [16][17][18]37], and the skeleton bands of benzene or pyrazole rings, together with N-H bending vibrations, were observed at 1596.77, 1581. 34, 1518.19, 1499.38, 1448.28 cm -1 (C ... C, C ... N). Important structural information about 5 can be obtained from its 13 C-NMR spectrum. The 13 C-NMR peaks were found to be at 197.68 (t, 3  Final confirmation of structure 5 was derived from its 1 H-NMR spectrum: δ is equal to 10.40 ppm (s, OH, tautomeric proton), 9.58 ppm (s, NH) and 8.21-7.18 ppm for a set of signals for aromatic protons [37].
In order to make the reaction selective, we had to determine the parameters, or, in other words, the reaction pathways, that could lead to such results. At this point, the reaction of 3 with 4 in boiling benzene for 5 hours with no catalytic amounts of pyridine or triethylamine gave another product, 2-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-1,4-diiumdichloride (6), which was also obtained in 49% yield by stirring at room temperature for 3-4 days (see Scheme 1). Thus, compound 3 reacts with 2,3-diaminopyridine (4) in two ways and yields either the 1H-pyrazole-3-carboxamide derivative 5 or the 3H-imidazo[4,5-b] pyridine derivative 6. These results were confirmed by TLC using authentic specimens of 5 or 6 and identified by elemental and spectral data. A Beilstein test gave a green colour for compound 6. The moderate to excellent yield of the reaction can be explained by the chemical behavior of acid chlorides, similar to the behavior of the compound 3 towards N-nucleophiles [16][17][18]. The formation of 6 can easily be explained by a nucleophilic attack on the carbonyl group of the acid chloride 3. It appears, that this process can be followed by elimination of a molecule of hydrogen chloride, formation of IN(1) as mentioned above, and elimination of a molecule of water, to give tautomers of 6, whose formation is rationalized in Scheme 2.
The elimination of water molecule may occur in two states. First, a new bond C 6 -N 15 is formed, being accompanied by the proton H 17 Table 3). Imaginary frequency for TS2 is -1854 cm -1 that indicates a substantial change in its structure. In the second stage of the reaction, final product 6 is obtained. In the transition state TS3, bond lengths are 1.60 Å for C 6 -O 7 , 1.47 Å for N 15 -C 6 1.26 Å for N 10 -H 11 . When the N 15 -C 6 bond is formed, C 6 -O 7 bond is broken simultaneously.

Conclusions
In this study, dicarboxamide derivative 5 was prepared in good yield (69%) without opening the pyrazole ring by the nucleophilic substitution reaction of a two-fold molar excess of compounds 2 or 3 and 2,3-diaminopyridine. The reaction of 3 with 4 in benzene with no catalytic amounts of triethylamine led to the formation of another product 6, besides 5. The structures of compounds 5 and 6 were confirmed by elemental analyses and spectroscopic data. The changes that occurred in some of the bond lengths during the IN(1) and product 6 formation (the lengths were determined by AM1 method) are shown in Figure 4. While IN(1) is being formed, C 6 -Cl 8 and N 9 -H 10 bonds are broken and C 6 -N 9 and Cl 8 -H 10 bonds are formed. In the same way, during the formation of product 6, C 6 -O 7 and N 15 -H 17 bonds are broken and N 15 -C 6 and O 7 -H 17 bonds are formed. As is seen from Figure 4, some important changes in the charges of atoms occur both under the formation and breakage of the bonds, at the time when IN(1) and product 6 are being formed. As an example, the charge density on chlorine atom is -0.06ē in 3+4 reactants, -0.56ē in TS1, -0.23ē in product. During the formation of product 6, charge density on carbon atom is 0. 39ē in IN(1), 0.35ē in TS2, 0.30ē in IN(2), 0.2 ē in TS3, and 0.09ē in product 6. Thus, in this paper we have presented a theoretical and experimental study of the preparation of either product 5 or 6.

Acknowledgements
Financial support from the Research Center of Erciyes University, is gratefully acknowledged.

General
Melting points were determined on an Electrothermal 9200 apparatus and are uncorrected. Microanalyses were performed on a Carlo Erba Elemental Analyser Model 1108. The IR spectra were recorded on a Jasco FT-IR spectrometer model 460, using KBr pellets. The 1 H-and 13 C-NMR spectra were obtained on Varian Gemini 200 instrument with CDCl 3 as solvent and TMS as internal standard. Mass spectra were measured on a Shimadzu GC/MS-QP 5050A spectrometer, using DI method with EI. After completion of the reactions, solvents were evaporated with rotary evaporator (Buchi RE model 111). All experiments were followed with TLC using DC Alufolien Kieselgel 60 F 254 (Merck) and a Camag TLC lamp (254/366 nm). Solvents were dried by refluxing with the appropriate drying agent and distilled before use. All other reagents were purchased from Merck, Fluka, Aldrich, Sigma and Acros Chemical Co. and used without further purification. All computations were done by the Gaussian 03W program. Quantum chemical calculations were done by means of semi-empirical AM1 and ab initio methods. The STO-3G and 3-21G basis sets were used throughout. Geometries were fully optimized with STO-3G and 3-21G basis sets in the frameworks of the methods used. All stationary points were characterized as minima or transition states by vibrational frequency calculations at the same level of theory as geometry optimization. In addition, intrinsic reaction coordinate (IRC) calculations for transition states were also performed.