Piperine Structure Determination and Synthesis

Oersted (1820) isolated piperine from the extract of pepper as a yellow crystalline substance having a melting point of 128-130°C. Piperine, C H O3 N, was shown to be a weak base which on hydrolysis with aqueous alkali or nitric acid yielded a volatile base, C5 H N, later identified as piperidine. The acidic product of hydrolysis, piperinic acid (C H O4, m.p. 216—217°C), was shown to be 5-(3,4-methylene dioxy phenyl)-2,4, pentadienoic acid by establishing two double bonds by the tetrabromo derivative as well as by oxidation to oxalic acid and piperonal.

The partial synthesis of piperine was achieved by Rugheimer in 1882 by condensing piperinic acid chloride with piperidine. Ladenberg and Scholtz (1894) established the structure of piperine by total synthesis of piperinic acid. By condensation of piperonal with acetaldehyde, followed by treatment with sodium acetate and acetic anhydride, piperinic acid was obtained. Thus the structure of piperine was established as piperinic acid piperidide.

Ott and Eichler (1922) postulated the presence of four geometric isomers from the formula of piperinic acid: 2 trans, 4 trans; 2 as, 4 trans; 2 trans, 4 cis and 2 cis, 4 cis. By the formation of oxalic acid and tartaric acid by careful oxidation of piperinic acid and its synthesis from 3,4 methylenedioxy-cinnamaldehyde, known to have a stable trans configuration, they assign trans-trans configuration to piperinic acid.

Due to controversey over the pungency of piperine and chavicine, a great amount of work was carried out to synthesise all the four isomers. Isopiperinic acid was synthesised by Ott and Eichler (1922) from piperonylidene malonic acid, the structure of which was known, by elimination of carbon dioxide and they assigned the cistrans configuration to this acid.

Grewe et al. (1970) carried out an unequivocal synthesis of all the three isomers of piperinic acid and recorded the physicochemical properties of the isomeric acids. They utilised triphenyl ethoxycarbonyl methylene phosphorane for preparing the isomers and it is shown in Scheme 1.

All the three isomers of piperinic acid were sensitive to light and convert almost completely to the trans-trans isomer in a short period of time. The corresponding piperidides of the isomers were prepared and they undergo conversion to trans-trans form by irradiation with U.V. light.

Upon alkaline hydrolysis, the trans-trans and cis-trans isomeric piperidides yielded only the trans-trans acid, while the trans-cis and cis-cis piperidides gave almost exclusively the trans-cis isomer. By simple taste tests, the three isomers of piperine were found to have very weak pungency. The structure of piperine along with the isomers are given in (6).

Yamamoto et al. (1974) investigated the photochemical changes of piperine. Irradiation of piperine in alcoholic solution under a high pressure mercury lamp gave a mixture of cis-trans (isopiperine) and trans-cis (isochavicine) as determined by U.V., I.R. and N.M.R. spectra. Isopiperine was synthesised following the method of Ott and Eichler (1922). The 1,2 trans 3,4 cis isomer, isochavicine was prepared by debromination of brominated piperic acid to yield trans 2-en-4 yn carboxylic acid.

Scheme 1 Synthesis of isomers of piperinic acid.

5 (3,4-methylena dloxyphenyl) penta 2,4-dlenoic acid piperidide

This was converted to the piperidide and partially hydrogenated to yield isochavicine. The trans-2-en-4-yn carboxylic acid piperidide was irradiated under high pressure mercury lamp for conversion to the cis form and then hydrogenated to yield the ciscis isomer chavicine. The piperine isomers were found to be considerably less pungent and could not be detected in black pepper.

The structure of piperine and its isomers have been confirmed by NMR by Del Clyn and Verzele (1975). Single crystal diffractometry study also proved the conjugated double bond system of piperine to be all trans. (Sumathikutty et al. 1981).

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