Spectral characterization of some hydrazones derived from Isoeugenoxyacetic acid

Abstract. Eight hydrazones were synthesized from isoeugenoxyacetic acid via a three-step procedure (esterification, conversion to hydrazide, condensation with aromatic aldehydes and p-methylacetophenone). The IR, 1H NMR and 13C NMR spectra of the hydrazones were analyzed. 1H NMR and 13C NMR signals were assigned on the basis of spin-spin splitting patterns and cross peaks on HSQC, HMBC spectra. The NMR data show that examined hydrazones exist in two conformers at hydrazide sing bond CO-N, in which the propenyl group has E-configuration

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JOURNAL OF SCIENCE OF HNUE Natural Sci., 2008, Vol. 53, N ◦ . 5, pp. 66-72 SPECTRAL CHARACTERIZATION OF SOME HYDRAZONES DERIVED FROM ISOEUGENOXYACETIC ACID Hoang Thi Tuyet Lan, Le Thi Luyen and Nguyen Huu Dinh Hanoi National University of Education Abstract. Eight hydrazones were synthesized from isoeugenoxyacetic acid via a three-step procedure (esterification, conversion to hydrazide, condensa- tion with aromatic aldehydes and p-methylacetophenone). The IR, 1 H NMR and 13 C NMR spectra of the hydrazones were analyzed. 1 H NMR and 13 C NMR signals were assigned on the basis of spin-spin splitting patterns and cross peaks on HSQC, HMBC spectra. The NMR data show that examined hydrazones exist in two conformers at hydrazide sing bond CO-N, in which the propenyl group has E-configuration 1. Introduction There are many hydrazides, hydrazones, which possess high biological ac- tivities. Among them, isoniazide (pyridine-4-carboxylic acid hydrazide) and fti- vazide (N-(pyridine-4-carbonyl)-N'-(3-methoxy-4-hydroxybenzyliden)hydrazine) are used as antitubercular drug [1]. Eugenol is the main component of Ocimum Sane- tum L. essential oil, which is used in Vietnamese traditional medicine. Recently the anticarcinogenic effect of eugenol was detected by a simplified short-term technique based on the inhibition of microsomal degranulation of rat liver microsomes, in vitro [2]. Eugenoxyacetic and isoeugenoxyacetic acids are used as food additives [3]. Herein some hydrazones derived from isoeugenoxyacetic acid are described. 2. Results and discussion The reported compounds were prepared from isoeugenoxyacetic acid as follows: 66 Spectral characterization of some hydrazones derived from isoeugenoxyacetic acid In a previous paper [4] we proved that on refluxing methyl eugenoxyacetate and hydrazine for 10 hours, the allyl group was reduced to the corresponding saturated group, propyl. To avoid this reaction, hydrazine was slowly added to a solution of methyl isoeugenoxyacetate and the reaction time was reduced to 6 hours. The EI MS of isoeugenoxyacetylhydrazine, some hydrazones and the 1 H NMR of 1÷8 (see below) showed that in these compounds, the CH=CH group has not been reduced. Results of synthesis of hydrazones 1÷8 are given in Table 1. Table 1. Results of synthesis of hydrazones 1÷8 (*) Compd =CR-Ar Solvent for recrystn Form and colour Yield (%) M.p. ( 0 C) 1 Ethanol light yellow needle crystals 75 171 - 2 2 Ethanol/Water 1/1 light yellow needle crystals 73 185 - 6 3 Ethanol/Water 1/1 white crystals 63 155 - 6 4 Ethanol/Water 1/1 white solid 72 213 - 4 5 DMF/Water 2/1 yellow crystals 61 121 - 2 67 Hoang Thi Tuyet Lan, Le Thi Luyen and Nguyen Huu Dinh 6 Ethanol/Water 1/1 white solid 67 152 - 3 7 Ethanol/Water 1/1 yellow crystals 60 143 - 4 8 DMF/Water 2/1 light yellow needle crystals 57 144 - 5 (* The numeration is special for analyzing NMR) In IR spectra of the 1÷8 there are absorption bands characterized for N- H, C-H and C=O stretching vibrations. The stretching frequencies of hydrazone C=N, aromatic C=N, aromatic C=C may not be distinguished since they have no significant differences (Table 2). It is noted that, weak absorption band of ethylenic C=C is overlaid by stronger hydrazide C=O band, thus the band is not observed. Table 2. IR bands of studied compounds Compd νNH , νOH νCH νCH νC=O νC=C , νC=N νC−O aromatic aliphatic 1 3204 3024 2946, 2874 1668 1596, 1570, 1513 1234, 1134 2 3189 3096 2960, 2924 1680 1600, 1588, 1513 1264, 1141 3 3182 3039 2959, 2916 1653 1610, 1555, 1512 1224, 1137 4 3189 3082 2967, 2824 1680 1592, 1510, 1480 1260, 1140 5 3255, 3399 3069 2927, 2855 1665 1596, 1553, 1512 1258, 1140 6 3225 3075 2967, 2924 1697 1604, 1590, 1514 1262, 1160 7 3186 3032 2960, 2873 1666 1624, 1580, 1517 1271, 1147 8 3189 3104 2960, 2924 1682 1610, 1586, 1514 1272, 1141 In 1 H NMR and 13 C NMR spectra of compounds 1÷8 there are two sets of res- onance signals. The assignment of the 1 H NMR and 13 C NMR signals in many cases based on both their chemical shifts and their 2D spectra. For example, the HSQC spectrum of 7 (Figure 1) allows an unambiguous assignment of the correspondence 68 Spectral characterization of some hydrazones derived from isoeugenoxyacetic acid of the 1 H and 13 C signals, in HMBC spectrum reproduced in Figure 2, the signals of C1, C2, C3, C4, C5, C6, C8, C9, C12, C13, C14, and C15 were identified. The NMR data are presented in Table 3 and Table 4 (the numeration used for the analysis of NMR is given in Table 1). Figure 1. A part of HSQC of compound 7 Figure 2. A part of HMBC of compound Table 3. The 1 H NMR signals of 1÷8, δ(ppm), J (Hz) 1 2 3 4 5 6 7 8 H3 7.05; 7.02; d; J 1.5 7.04; 7.01; d; J 1.5 7.04; 7.01; d; J 1.5 7.04; 7.01; d; J 1.5 7.04; 7.01; d; J 1.5 7.05; 7.02; d; J 1.5 7.04; 7.01; d; J 1.5 7.05; 7.02; d; J 1.5 H5 6.86; 6.82; dd; J 8.5; 1.5 6.85; 6.82; dd; J 8.5; 1.5 6.85: 6.82; dd; J 8; 1.5 6.85; 6.82; dd; J 8.5; 1.5 6.85; 6.81; dd; J 8.5; 1.5 6.83; 6.82; dd; J 8.5; 1.5 6.84; 6.81; dd; J 8.5; 1.5 6.85; 6.81; dd; J 8.5; 1.5 H6 6.88; 6.80; d; J 8.5 6.87; 6.78; d; J 8.5 6.86; 6.78; d; J 8 6.87; 6.77; d; J 8.5 6.87; 6.75; d; J 8.5 6.88; 6.80; d; J 8.5 6.88; 6.74; d; J 8.5 6.88; 6.74; d; J 8.5 H7a 5.12; 4.63; s 5.10; 4.61; s 5.09; 4.61; s 5.08; 4.59; s 5.08; 4.58; s 5.13; 4.63; s 5.01; 4.59; s 5.12; 4.71; s H7b 3.82; 3.80; s 3.81; 3.79; s 3.82; 3.79; s 3.82; 3.80; s 3.82; 3.81; s 3.82; 3.80; s 3.81; 3.80; s 3.82; 3.80; s 69 Hoang Thi Tuyet Lan, Le Thi Luyen and Nguyen Huu Dinh H8 6.34; 6.32; d; J 16 6.33; 6.32; d; J 16 6.34; 6.33; d; J 16 6.33; 6.32; d; J 16 6.33; 6.32; d; J 16 6.34; 6.33; d; J 16 6.34; 6.33; d; J 16 6.34; 6.32 d; J 16 H9 6.19; 6.18; dq; J 16; 6.5 6.18; 6.17; dq; J 16; 6.5 6.16; 6.15; dq; J 16; 6.5 6.18; 6.17; dq; J 16; 6.5 6.18; 6.17; dq; J 16; 6.5 6.19; 6.18; dq; J 16; 6.5 6.18; 6.17; dq; J 16; 6.5 6.17; 6.16; dq; J 16; 6.5 H10 1.83; d; J 6.5 1.82; d; J 6.5 1.82; d; J 6.5 1.83; d; J 6.5 1.82; d; J 6.5 1.82; d; J 6.5 1.82; d; J 6.5 1.82; d; J 6.5 NH 11.83; 11.73; s 11.60; 11.58; s 11.61; 11.58; s 11.43; 11.40; s 11.38; 11.31; s 11.70; s 11.49; 11.47; s 10.75; 10.38; s H12 - 7.71; d; J 8.5 7.64; d; J 8 7.31; 7.26; s 7.27; 7.25 d; J 1.5 8.85; 8.83; s - 7.70; 7.68; d; J 8 H13 7.52; d; J 7.5 7.50; 7.48; d; J 8.5 7.62; d; J8 - - - 6.90; 6.86 m 7.23; 7.21; d; 8 H15 6.80; td; J 7.5; 2 7.50; 7.48; d; J 8.5 7.62; d; J8 6.98; 6.96; d; J 8.5 6.81; d; J 8 7.48; 7.45; m 7.83; 7.81; s 7.23; 7.21; d; 8 H16 7.98; 7.96; t; J 7.5 7.71; d; J 8.5 7.64; d; J 8 7.15; 7.11; d; J 8.5 7.08; 7.06; d; J 8 8.12; 8.10; s - 7.70; 7.68; d; J 8 H17 8.71; 8.39; s 8.29; 7.99; s 8.28; 7.97; s 8.20; 7.91; s 8.16; 7.88; s 8.36; 8.04; s 8.20; 7.89; s Others H14: 7.44; td; J 7.5; 2 - - H18: 6.08 6.07; s H18: 3.79; s; OH: 9.54; 9.49 8.60; 8.59; s H14: 6.62; m H18: 2.24; s; H19: 2.32; s Table 4. The 13 C NMR data of 1÷7, δ(ppm) 1 2 3 4 5 6 7 C1 146.74 146.35 146.81 146.44 146.81 146.41 146.87 146.45 146.91 146.46 146.77 146.40 146.89 146.42 C2 149.27 148.89 149.29 148.95 149.28 148.94 149.28 148.90 149.28 148.89 149.34 149.21 148.91 148.26 C3 109.35 109.29 109.39 109.34 109.33 109.38 109.32 109.58 109.38 109.39 109.34 109.30 C4 131.14 130.93 131.91 130.96 130.95 130.42 131.88 130.85 131.86 130.83 131.98 131.03 131.80 130.83 70 Spectral characterization of some hydrazones derived from isoeugenoxyacetic acid C5 118.27 118.32 118.32 118.33 118.33 118.32 118.30 C6 114.61 113.27 114.56 113.28 114.54 113.28 114.54 113.17 114.53 113.14 113.56 113.34 113.95 113.13 C7a 67.88 65.26 67.87 65.27 67.86 65.27 67.90 65.24 67.91 65.27 67.99 65.14 67.34 65.66 C7b 55.42 55.50 55.50 55.49 55.52 55.49 55.57 C8 130.48 130.36 130.53 130.43 130.53 130.16 130.55 130.43 130.54 130.42 130.53 130.43 130.54 130.45 C9 123.88 123.32 123.90 123.35 123.90 123.35 123.87 123.28 123.87 123.28 123.94 123.39 123.76 123.27 C10 18.04 18.09 18.10 18.09 18.08 18.10 18.07 C=O 169.12 164.62 169.06 164.48 169.07 164.48 168.85 164.15 168.69 163.94 168.79 164.37 169.71 164.23 C11 131.92 131.50 133.02 132.89 131.97 131.91 128.41 125.37 - 135.19 C12 133.14 132.83 128.86 128.81 138.78 131.73 105.13 115.47 115.38 148.98 148.96 128.89 C13 129.81 129.77 128.72 128.51 128.95 128.74 147.91 147.89 114.68 113.69 126.27 126.01 C14 131.25 134.56 134.31 133.37 133.23 149.12 148.87 149.02 148.73 112.14 112.09 130.45 C15 126.93 126.84 128.72 128.51 128.95 128.74 108.40 108.33 109.09 145.21 144.98 126.27 126.01 C16 127.49 128.86 128.81 131.78 131.73 123.35 123.04 122.09 121.21 - 128.89 C17 143.65 139.69 146.40 142.42 146.52 142.52 147.56 143.42 147.96 144.10 137.60 133.90 138.66 C18 - - - 101.51 101.45 55.52 - 13.61;13.39 C19:20.75 As expected, the chemical shifts for H3, H5, H7a, H7b, H8, H9, H10 and NH as well as for C1÷C10, and C=O of hydrazide moiety showed small change, in contrast the chemical shifts for protons and carbons of aldehyde moiety shows much change from one to another compound. As in Table 3, the H8-H9 coupling is 16 Hz. This shows that the propenyl group of 1-8 has E-configuration. It is known that some series of hydrazide-hydrazones can exist in two con- formers at hydrazide sing bond CO-N [5,6], we suggest that two sets of 1 H NMR and 13 C NMR signals of examined compounds are corresponding to two conformers A and B in Figure 3. The relative intensity of 1 H NMR signals indicates that the mole ratio of two conformers A and B for 1÷8 is 2:1. 71 Hoang Thi Tuyet Lan, Le Thi Luyen and Nguyen Huu Dinh Figure 3. Two conformers of examined compounds 3. Experimental • Isoeugenoxyacetic acid, methyl isoeugenoxyacetate, isoeugenoxyacetylhydrazine were prepared according to the method reported in reference [7]. • General procedure for preparation of hydrazones 1÷8: A mixture of isoeugenoxyacetylhydrazine (0.59 g, 2.5 mmole), an aromatic aldehyde (2.5 mmole) and piperidine (2 - 3 drops) in a minimum amount of ethanol was refluxed for 8 hours. The reaction mixture was cooled. The precipitate was filtered, washed with cool ethanol and recrystalized with suitable solvent . The results are given in Table 1. • The IR spectra were recorded in KBr discs at 400 - 4000 cm−1 on a FTS 60000 Bio-Rad. The EI MS were recorded by HP 5989 B mass-spectrometer. The NMR spectra were obtained at room temperature with a Bruker Avance 500 MHz spectrometer in d6-DMSO with TMS as the internal standard. REFERENCES [1] R.B. Silvermen, 1992. The Organic Chemistry of Drug Design and Drug Action. Academic Press, San Diego. [2] R. Selvi, R. Tamizh, Niranjali, 1998. Fitoterapia. Vol. 69, N ◦ . 2, pp. 115-117. [3] Onishi Takashi, Koiso Hiroaki, 1995. JPn Kokai Tokyo Koho JP 0779. 730. [4] Nguyen Huu Dinh, Duong Quoc Hoan, Nguyen Huu Canh, Nguyen Hien, Doan Thi Lan Huong, 2005. Journal of Chemistry. Vol. 43, pp. 437-441, (in Vietnamese). [5] Tran Quoc Son, Pham Quoc Toan, 2005. Journal of Chemistry. Vol. 43, pp. 27-31, (in Vietnamese). [6] Nguyen Huu Dinh, Hoang Thi Hue, Nguyen Thi Kim Phuong, 2003. Journal of Chemistry. Vol. 41, N ◦ . 4, pp. 50-54, (in Vietnamese). [7] Hoang Dinh Xuan, Hoang Thi Tuyet Lan, Nguyen Huu Dinh, 2007. Journal of Science. Hanoi National University of Education, Vol. 52, N ◦ . 1, pp. 25-29, (in Vietnamese). 72