Some factors which could induce the imine-enamine tautomerism of schiff’ bases adducts of gossypol

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Gossypol, a yellow pigment, isolated from cotton seeds, exhibits many interesting biological activities: antitumor, antimalarial, anti-HIV [1]. But gossypol is toxic and this toxicity may be related to the two-functional aldehyde groups [2]. Many authors prepared the Schiff’s’ base adducts of gossypol from 1985 to 2002, but these authors did not pay attention to the factor that these adducts may present under or the imine form or the enamine one.

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Nội dung Text: Some factors which could induce the imine-enamine tautomerism of schiff’ bases adducts of gossypol

Journal of Chemistry, Vol. 42 (3), P. 366 - 370, 2004 SOME FACTORS WHICH COULD INDUCE THE IMINE-ENAMINE TAUTOMERISM OF SCHIFF’ BASES ADDUCTS OF GOSSYPOL Received 14-4-2003 Nguyen Kim Phi Phung1, Ton That Quang1, Nguyen Thanh Binh1, Ginette Jaureguiberry2 1 University of Natural Sciences, National University of Ho Chi Minh City 2 Museum National d’Histoire Naturelle, 61 Buffon 75005 Paris Summary Gossypol, a yellow pigment, isolated from cotton seeds, exhibits many interesting biological activities: antitumor, antimalarial, anti-HIV [1]. But gossypol is toxic and this toxicity may be related to the two-functional aldehyde groups [2]. Many authors prepared the Schiff’s’ base adducts of gossypol from 1985 to 2002, but these authors did not pay attention to the factor that these adducts may present under or the imine form or the enamine one. In this study, the technique of 1H-NMR was used to determine the imine or the enamine form of Schiff’s’ base adducts of gossypol. This technique was also applied to study some factors which could induce the imine-enamine form of adducts. The factor was used aliphatic amine of from 3 to 8 carbons or aromatic amine that has different substituent at the position para that used to condense with gossypol. The factor used solid alumine. The reagents of gossypol and amine were separately impregnated on alumine, then these two reagents were mixed to react together at room temperature under visible light and without solvent. The factor VIS and UV254. I - INTRODUCTION imine form or the enamine one. This technique was also used to study some factors which could From 1985 to 2002, many authors had induce the imine-enamine tautomerism in the synthesized the Schiff’bases adducts of Schiff‘ bases adducts of gossypol. gossypol. These authors did not pay attention on the fact that the Shiff’ bases adduct of II - RESULTS AND DISCUSSION gossypol might tautomerizeto change from the imine form to the enamine one. 1. Examination the imine or the enamine form of Schiff’ base adducts of gossypol by It was showed that only the technique of 1 different methods H-NMR could be the useful tool to well determine whether the adducts were under the Our researching [3, 4] on the condensation of 366 (±)-gossypol-acetic acid with some aliphatic peak), 8.01 - 7.85 (none), 7.79 - 7.57 (H-4, a amines; with some aromatic amines; with pointed peak), 6.61 - 6.45 (OH at C-6, singlet, some amino acids showed that adducts were sometimes no peak) and 5.68 - 5.36 (OH at C-1, initially formed under the imine form. If singlet). adducts were immediatedly isolated out of the The enamine form: 13.60 - 13.33 (=CH-NH-, reaction solution and were dried, they always a round peak, disapeared on exchanging with stayed under the imine form. In case the D2O), 9.70 - 9.30 (=CH-NH-, doublet but adducts were still in the solution, after a sometims a round peak. On exchanging with D2O, certain time at room temperature in visible changed to a pointed peak), 8.01 - 7.85 (OH at C- light there happened the imine-enamine 6, a singlet but sometimes a round peak), 7.79 - tautomerism. 7.57 (H-4, a pointed peak), 6.61 - 6.45 (none); The adducts of gossypol were examined 5.68 - 5.36 (OH at C-1, singlet). by some different methods. So the 1H-NMR spectra was the best tool to distinguish the imine or the enamine form of the a) LC-MS, APCI spectra adducts of gossypol. The spectra of the adducts of (±)-gossypol- 2. Examination of the imine-enamine tauto- amine showed 2 close peaks ot in some cases these peaks were split into two as the tongue of merism when (±)-gossypol were coupled a snake. with different aliphatic amines; different aromatic amines in chloroform-methanol This method could not distinguish the imine at room temperature under visible light or the enamine form of the adducts. a) The condition of the reaction b) 13C-NMR spectra (±)-gossypol-acetic acid (0.069 mM) and The chemical shifts of the carbon of adducts amine (aliphatic or aromatic amine) (0.27 mM) under the imine form or the enamine form were were dissolved in chloroform-methanol (1 : 1); almost identical. For example: the Schiff’bases the medium was adjusted to pH = 4 - 5 by conc. of (±)-gossypol-propylamine and (±)-gossypol- sulfuric acid. The reaction solution was stirred at butyl-amine showed identical chemical shifts room temperature under visible light. After each for all carbons except little differences at C-7 hour (1, 2, 3 and 4 hours) the reaction solution and C-15. At C-17 the imine form =C- was dried by MgSO4 and then evaporated to yield OH...N=C- ( = 172.30 ppm) and the enamine dry yellow powder. This powder was studied by 1 form –C=O ( = 172.43 ppm). At C-15 the H-NMR. imine form –HC=N- ( = 162.98 ppm) and the b) The results enamine form =CH-NH- ( = 163.01). Adducts of (±)-gossypol-propylamine So, the 13C-NMR spectra were not useful to tautomerized to the enamine form after 10 hours distinguish the imine or the enamine form of the of reaction; (±)-gossypol-butylamine after 38 hours; adducts. (±)-gossypol-pentylamine after 10 hours; (±)- c) 1H-NMR spectra gossypol-hexylamine after 10 hours; (±)-gossypol- There are clear difference between imine octylamine after 8 hours; (±)-gossypol-aniline and the enamine form of the adducts of after 48 hours; (±)-gossypol-p-hydroxy-aniline gossypol. The 1H-NMR spectral information of after 48 hours; (±)-gossypol-p-chloro-aniline after 60 some protons of the Shiff’ bases adducts of hours; (±)-gossypol-p-nitroaniline after 10 hours. gossypol under the imine and the enamine c) Remarks form. (i) The Schiff’bases adducts of gossypol with The imine form (form low field to high aliphatic amine tautomerized to the enamine field; ppm) 9.70 - 9.30 (-CH=N-, a pointed 367 R R H 15 N H N OH CH=O OH C OH C15 H 2 OH R-NH2 ; VIS 2 OH 2 O 21 87 21 87 Time; VIS 21 8 7 4 56 CHCl - MeOH 4 56 CHCl - MeOH 4 56 OH 3 OH 3 OH 11 11 11 12 13 12 13 12 13 Schiff'bases adducts Schiff'bases adducts Gossypol of gossypol under of gossypol under the imine form the enamine form form after 8 - 10 hours of reaction. There was Dry powder of (±)-gossypol/Al2O3 and an exception: the adducts with butylamine alkylamine/Al2O3 were mixed together with the tautomerized after 48 hours. So, the length of ratio of 1 : 0.6 (w/w). The mixture was stirred at the carbon chain (from 3 to 8 carbons) of room temperature under visible light. After a aliphatic amine which was used to coupled to determined time (1 hours, 1 day, 4 days, 5 (±)-gossypol was not a factor that could induce days, 7 days, 15 days and 30 days) the powder the imine-enamine tautomerism. was extracted by ethyl acetate. The extracted (ii) Adducts from aromatic amine with the solution was evaporated to receive dry yellow substituents which had the donate electrons powder, this powder was studied by 1H-NMR. resonance effect such as -OH, -Cl... tautome- b) The results rized to the enamine form much more longer The reaction time of 1 hour, 1 day or 4 days (after 48 - 60 hours of reaction) than adducts was not sufficient, the compounds were not from aromatic amine with the substituents formed; the compound were just formed after 5 which had the withdraw electrons resonance days. Compounds that were formed after 5 days effect such as -NO2 (after 10 hours of reaction). or 7 days or 15 days or 30 days were Schiff’ So the aromatic amine with different substi- tuents at the para position which was used to base adducts of (±)-gossypol-amine under the imine form. couple to (±)-gossypol influenced on the imine- enamine tautomerism. c) Remark 3. Could the technique of separately impreg- With this technique, adducts could be kept always under the imine form. When we need to nating gossypol and amine on alumina use the adducts, they were extracted out of then reacting together in dry media, alumina and then be evaporated to dryness. In inhibit the imine-enamine tautomerism the solid state, adducts stayed always under the a) The condition of the reaction imine form. Aluminium oxide 90, activity II, 70 - 230 mesh Alumina is known to have the spinel ASTM was used to impregnate the reactants. In a structure of 2 2/3 Al21 1/3 O32 that means the flask of 100 ml, (±)-gossypol-acetic acid (1.6 g) spinel structure adopted a cubic cell with 32 were dissolved in methanol, then alumia (0.8 g) oxygen atoms, 21 Al atoms and 3 vacant was put in; the mixture was evaporated to dryness orbitals [5]. These vacant orbitals could capture to yield a bright yellow powder. That was (±)- the lone pair electrons of oxygen atom of gossypol impregnated on alumina with the hydroxy groups at C-7 and C-7’ of gossypol. concentration of 3.46 mM/1 g Al2O3. Similar work This capture inhibited the mentioned-lone pair was for propylamine and butylamine with the electrons moving into the naphthalene ring, concentration of 17.3 mM/1 g Al2O3. then up to the imino group. The consequence 368 was adducts stayed always under the imine under the imine form. form. b) Effect of UV254 on the imine-enamine tauto- R merism when Schiff’base adducts of H N Al 2O3 OH C gossypol under the enamine form were in O H the solvent 2 21 87 Al 2O 3 In normal NMR tubes, adducts under the 4 56 OH enamine form (obtained from preceeding reactions and were well determined their enamine form) were dissolved in deuterium The vacant orbital of alumina captured the alone chloroform CDCl3 and were irradiated at room pair electrons of –OH temperature in a certain time (1 hour, 2 hours, 4 4. Examination of the effect of lights (VIS hours, 6 hours, 1 day, 2 days, 3 days, 4 days, 5 and UV254) on the imine-enamine tauto- days, 6 days, 7 days...). After that time, the tube merism of Schiff’base adducts of gossypol were directly measured by 1H-NMR. a) Effect of VIS and UV254 on the imine- The results were (±)-gossypol-glycine benzyl ester tautomerized to the imine form after 4 hours enamine tautomerism when Schiff’base adducts of gossypol were in the solvent of irradiation; (±)-gossypol-propylamine after 7 days; (±)-gossypol-butylamine after 5 days; (±)- The condensation was realized in gossypol-octylamine after 4 days. chloroform-methanol (1 : 1) at room temperature between (±)-gossypol-acetic acid c) Effect of VIS and UV254 on the imine- and some aliphatic amines; and some aromatic enamine tautomerism when Schiff’base amines (p-hydroxyaniline; p-chloroaniline; p- adducts of gossypol were in dry powder nitroani-line); and some amino acids (±)-gossypol-propylamine under the imine (phenylalanine methyl ester; glycine benzyl ester; lysine(Z) methyl ester); the medium was form; (±)-gossypol-propylamine under the adjusted to pH = 4 - 5. After a determined time, enamine form; (±)-gossypol-butylamine under the reaction solution was dried and then the imine form and (±)-gossypol-butylamine evaporated under reduced pressure to give dry under the enamine form. powder. This powder was was assigned by 1H- (i) Adducts under the imine form were put NMR. in transparent glass tubes. The tubes were glued (i) The reaction solution was stirred under the on the glass window (the face in the room) and irradiation of VIS in 30 minutes or 1 hour or 4 presented under the irradiation of the sun days. The results shown that all adducts were within 35 days at room temperature. The formed after 30 minutes of the reaction and powder were well skaken each day. After that adducts were under the imine form. After 4 days time, the powder were measured by 1H-NMR. of reaction all adducts were under the enamine (ii) Adducts under the enamine form were form. put in transparent glass tubes. The tubes were (ii) Right after the two reactants dissolved in continously irradiated by UV254 within 7 days the solvent, the reaction solution was stirred and at room temperature. The powder were well continously irradiated by UV254 in 5 days. It could shaken each day. After that time, the powder be seen the adducts could not be formed; the were measured by 1H-NMR. The adducts obtained products were initial (±)-gossypol. products always kept their initial form. (iii) The reaction solution was stirred under Conclusions visible light within 30 minutes then was irradiated by UV254 in 4 days or in 10 days. The Photochemistry was a factor that could results shown that all obtained adducts were induce the imine-enamine tautomerism of the 369 Schiff’base adducts of gossypol. The affect of Schiff’base adducts of gossypol was resumed in the photochemistry on the tautomerism of the following schema. R R H N H N OH C OH C H 2 OH Chloroform-methanol; VIS Chloroform-methanol; VIS 2 O OH Chloroform-methanol; UVUV Chloroform-methanol; 254 OH 254 Shiff’ bases adducts of gosspypol under the Shiff’ bases adducts of gosspypol under the imine form enamine form • Schiff’ base adducts of gossypol under ester etc. degraded and destroyed gradually after the solid state (dry powder) could not be some days (2 - 4 days). affected by the lights (VIS and UV254). They stayed stable under their initial form. REFERENCES • Solvents of chloroform-methanol and the 1. D. F. Wu. Drugs, Vol. 38, No. 3, P. 333 - 341 visible light induced the tautomerims of adducts (1989). from the imine form to the enamine one. Solvent lonely was not sufficient, the presence of the 2. Robert E. Roger, Ray G. Mills, Stephen A. visible light was an obligatory need for the Young, David L. Vander Jagt. Pharma- tautomerims. cological Research, Vol. 31, No. 1, P. 49 - 52 (1995). • The solvent and the UV254 could induce the Shiff’ base adducts of gossypol tautomerize from 3. N. K. Phi Phung, Ton That Quang, N. Ngoc the enamine form to the imine one. Suong, P. Dinh Hung. J. of Chem., Vol. 40, No. 3, P. 94 - 97 (2002). • Adducts were very stable in the solution under the irradiation of UV254 in spite of 10 days 4. N. K. Phi Phung, Ton That Quang, N. Ngoc of irradiation. On the contrary, under the Suong, P. Dinh Hung. J. of Chem., Vol. 40, presence of visible light at room temperature, Specilal issue, P. 198 - 200 (2002). some adducts such as (±)-gossypol-glycine 5. Karl Sohlberg, Stephen J. Pennycook, benzyl ester; (±)-gossypol-lysine(Z) methyl Sokrate T. Pantelides. J. Am. Chem. Soc., ester; (±)-gossypol-phenylalanine-glycine methyl Vol. 121, P. 7493 - 7499 (1999). 370