AmidoImidol Tautomerization by Acid-Catalyzed Addition of Nitriles to

β-butoxypropionitrile, β-amyloxypropionitrile, β-isoamyloxypropionitrile, ethylcyanoacetate, o-carboxyphenylacetonitrile, benzonitrile, and benzyl ...
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Ind. Eng. Chem. Res. 2005, 44, 254-260

Amido-Imidol Tautomerization by Acid-Catalyzed Addition of Nitriles to 16-Hydroxyhexadec-cis-9-enoic Acid: A Novel Route for 9-[Substituted Amido]-16-ol-hexadecanoic Acids, and Their Biological Importance and Possible Industrial Utilization Kallappa M. Hosamani* and Raghavendra M. Sattigeri P.G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad-580 003, India

Considering the extensive applications of oleochemicals as industrial products, a series of novel 9-[substituted amido]-16-ol-hexadecanoic acids have been synthesized by the reaction of different nitriles with 16-hydroxyhexadec-cis-9-enoic acid. The specific nitriles, including acetonitrile, propionitrile, β-methoxypropionitrile, β-ethoxypropionitrile, β-(2-ethoxy)ethoxypropionitrile, β-butoxypropionitrile, β-amyloxypropionitrile, β-isoamyloxypropionitrile, ethylcyanoacetate, o-carboxyphenylacetonitrile, benzonitrile, and benzyl cyanide, were added to the double bond of 16-hydroxyhexadec-cis-9-enoic acid in the presence of concentrated sulfuric acid followed by hydrolysis. The mechanism of acid-catalyzed addition of nitriles to 16-hydroxyhexadec-cis-9enoic acid has been confirmed by its amido-imidol tautomerization. Thus, the addition of nitriles at carbon-9, instead of carbon-10, of 16-hydroxyhexadec-cis-9-enoic acid has been confirmed by mass spectral fragmentation of McLafferty rearrangement due to the secondary amide group, which showed molecular ion peaks at m/z 144 in all of the compounds. Further, these newly synthesized oleochemicals have been studied and characterized by FTIR, 1H NMR, and 13C NMR spectroscopies; MS; and elemental analyses. Introduction New and interesting novel oleochemicals are being exploited for industrial utilization. During the past decade, the production and utilization of oleochemicals have grown in size and diversity. Oleochemicals are essential to a variety of industrial products such as surfactants, plasticizers, lubricant additives, cosmetics, pharmaceuticals, soaps, detergents, textiles, plastics, protective coatings, dispersants, intermediate chemicals, urethane derivatives, organic pesticides, and a variety of synthetic intermediates. In the industrial field, there has been competition between oleochemicals and petrochemicals. The ever-increasing cost of petrochemicals has diverted the attention of chemists to the synthesis of new oleochemicals derived from natural oils and fats.6 The amides and hydrazides have been known to be associated with antibacterial,3 antifungal,2 anthelmintic,1 and anticonvulsant7 activities. Thus, interest in the biological and industrial potential of oleochemicals has resulted in the development of various synthetic procedures for the introduction of heterocyclic moieties into the hydrocarbon chain. Therefore, today, oleochemicals have gained considerable momentum next only to that of petrochemicals in various industries. An exhaustive survey of the literature reveals that no work has been reported on the reactions of different nitriles with 16-hydroxyhexadec-cis-9-enoic acid in strong sulfuric acid medium. Considering the extensive applications of oleochemicals as biological and industrial products, an attempt has been made to synthesize novel 9-[substituted amido]-16-ol-hexadecanoic acids by the reactions of specific nitriles including acetonitrile, propionitrile, β-methoxypropionitrile, β-ethoxypropionitrile, β-(2-ethoxy)ethoxypropionitrile, β-butoxypropionitrile, * To whom correspondence should be addressed. Fax: 0836747884. E mail: [email protected].

β-amyloxypropionitrile, β-isoamyloxypropionitrile, ethylcyanoacetate, o-carboxyphenylacetonitrile, benzonitrile, and benzyl cyanide with the double bond of 16-hydroxyhexadec-cis-9-enoic acid. However, the reactions of nitriles with alkenes in strong acid medium yielding the corresponding substituted amides have been described.8 Results and Discussion All of the compounds (Ia-Il) showed IR absorption bands at 3500-3400 cm-1 for the -OH group that were merged with -NH stretching bands. -NH stretching bands at 3370-3289 cm-1 and -NH bending bands at 1597-1542 cm-1 were observed for the presence of secondary amide functional groups. The carbonyl stretching bands at 1739-1702 and 1678-1641 cm-1 were observed for the saturated aliphatic carboxylic acids and secondary amide carbonyl functional groups, respectively. The 1H NMR spectra of all of the compounds (Ia-Il) exhibited structures revealing proton signals at δ 11.7-12.3 (broad singlet, 1H, -COOH, disappeared upon addition of D2O), 4.3-5.1 (broad doublet, 1H, -NH, disappeared upon addition of D2O), 3.8-3.9 (singlet, 1H, -CH2-OH, disappeared upon addition of D2O), 3.2-3.5 (multiplet, 8H, -CH2-OH + -CH2-CHCH2- + -CH2-COOH), 2.2-2.7 (broad multiplet, 1H, -CH-CH3), 1.3-1.6 (broad multiplet, shielded methylene protons, -CH2), and 0.7-0.8 (triplet, 3H, -CH3). The other important signals were also observed. The 13C NMR spectra of all of the compounds (Ia-Il) showed sharp singlet signals at δ 174-177 for carbonyl carbon, δ 173-175 for amide carbonyl carbon atoms, δ 74-145 aromatic carbon atoms, and δ 13-75 saturated carbon atoms and tertiary carbon atoms. The solvent DMSO-d6 exhibited the signals at δ 40-45. The molecular ion peaks of a straight-chain monocarboxylic acid are weak but usually discernible. However, the molecular ion peaks of all of the 9-[substituted

10.1021/ie0207865 CCC: $30.25 © 2005 American Chemical Society Published on Web 12/03/2004

Ind. Eng. Chem. Res., Vol. 44, No. 2, 2005 255 Scheme 1

Scheme 2

amido]-16-ol-hexadecanoic acids (Ia-Il) were quite distinguishable. The most characteristic peaks at m/z 60 and 144, due to McLafferty rearrangements, were observed in all of the compounds for monocarboxylic acid and secondary amides functional groups. Moreover, the addition of nitriles at carbon-9 instead of carbon-10 is confirmed by the McLafferty rearrangement due to secondary amide group, which gave rise to molecular ion peaks at m/z 144 in all of the compounds. Otherwise, molecular ion peaks would have been observed at m/z 130 in all of the compounds, if the addition of nitriles at carbon-10 instead of carbon-9. The McLafferty rearrangement due to the carboxylic acid groups (Scheme 1) showed molecular ion peaks at m/z 60 in all of the compounds. The McLafferty rearrangement due to the secondary amide groups Scheme 2) showed molecular ion peaks at m/z 144 in all the compounds. Besides the McLafferty rearrangement molecular ion peaks, the mass spectra of each compound resembles series of hydrocarbon clusters at intervals of 14 mass units (Figure 1).

Figure 1.

FTIR, 1H NMR, 13C NMR, and MS data for all of the compounds (Ia-Il) are summarized in Table 1. Spectral Results 9-Acetamido-16-ol-hexadecanoic Acid (Ia): IR (neat) 3302 cm-1 (sNH stretching), 1597 cm-1 (sNH bending), 1709 cm-1 (sCdO stretching of sCOOH group), 1665 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 1.3 (bm, 20H, chain

sCH2s), 2.1 (m, 1H, sCHs), 2.25 (s, 3H, sCOCH3), 3.3 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2s COOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.8 (bs, 1H, sNH, disappeared upon D2O addition), 12.0 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 74-15 (saturated carbon atoms with DMSO carbon atoms); MS m/z 329 [M+] 312, 284, 270, 256, 242, 228, 214, 200, 186. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-Propionamido-16-ol-hexadecanoic Acid (Ib): IR (neat) 3396 cm-1 (sNH stretching), 1554 cm-1 (sNH bending), 1739 cm-1 (sCdO stretching of sCOOH group), 1641 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.8 (t, 3H, s CH2sCH3), 1.3 (bm, 20H, chain sCH2s), 2.2 (m, 1H, sCHs), 2.6 (q, 2H, sCH2sCH3), 3.2 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, s OH, disappeared upon D2O addition), 4.8 (d, 1H, sNH, disappeared upon D2O addition), 12.1 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 175 (carbonyl carbon), 174 (amide carbonyl carbon), 74-14 (saturated carbon atoms with DMSO carbon atoms); MS m/z 343 [M+] 326, 298, 284, 270, 256, 242, 228, 214, 200. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Methoxypropionamido)-16-ol-hexadecanoic Acid (Ic): IR (neat) 3289 cm-1 (sNH stretching), 1597 cm-1 (sNH bending), 1709 cm-1 (sCdO stretching of sCOOH group), 1665 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 1.4 (bm, 20H, chain sCH2s), 2.1 (t, 4H, sCH2sCH2sOs CH3), 2.6 (m, 1H, sCHs), 3.0 (s, 1H, sOH, disappeared upon D2O addition), 3.2 (m, 8H, HOsCH2 + sCH2s CHsCH2s + sCH2sCOOH), 3.8 (s, 3H, sOsCH3), 4.5 (d, 1H, sNH, disappeared upon D2O addition), 11.7 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR

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Table 1. Spectral Analysis

Ind. Eng. Chem. Res., Vol. 44, No. 2, 2005 257 Table 1 (Continued)

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(DMSO-d6) at δ 175 (carbonyl carbon), 173 (amide carbonyl carbon), 75-15 (saturated carbon atoms with DMSO carbon atoms); MS m/z 373 [M+] 356, 328, 314, 300, 286, 272, 258, 244, 230. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Ethoxypropionamido)-16-ol-hexadecanoic Acid (Id): IR (neat) 3289 cm-1 (sNH stretching), 1597 cm-1 (sNH bending), 1709 cm-1 (sCdO stretching of sCOOH group), 1659 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.7 (t, 3H, sCH2sCH3), 1.4 (bm, 20H, chain sCH2s), 2.3 (t, 4H, sCOCH2sCH2sOs), 2.7 (q, 3H, sCHs + sOsCH2sCH3), 3.2 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.7 (d, 1H, sNH, disappeared upon D2O addition), 12.1 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 175 (carbonyl carbon), 174 (amide carbonyl carbon), 74-16 (saturated carbon atoms with DMSO carbon atoms); MS m/z 387 [M+] 370, 342, 328, 314, 300, 286, 272, 258, 244. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-[3-(2-Diethoxy)propionamido]-16-ol-hexadecanoic Acid (Ie): IR (neat) 3296 cm-1 (sNH stretching), 1595 cm-1 (sNH bending), 1715 cm-1 (sCdO stretching of sCOOH group), 1665 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.7 (t, 3H, sCH3), 1.3 (bm, 20H, chain sCH2s), 2.2 (m, 4H, sCOCH2sCH2sOs), 2.7 (t, 7H, sCHs + sOsCH2sCH2sCH2s), 3.3 (m, 8H, HOsCH2s + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.7 (d, 1H, sNH, disappeared upon D2O addition), 11.7 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 74-16 (saturated carbon atoms with DMSO carbon atoms); MS m/z 431 [M+] 414, 386, 372, 358, 344, 330, 316, 302, 288. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Butoxypropionamido)-16-ol-hexadecanoic Acid (If): IR (neat) 3370 cm-1 (sNH stretching), 1554 cm-1 (sNH bending), 1733 cm-1 (sCdO stretching of sCOOH group), 1647 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.8 (t, 3H, sCH2sCH3), 1.3 (bm, 20H, chain sCH2-), 2.3 (m, 3H, sCHs + sCH2sCH3), 2.7 (t, 8H, sCOsCH2sCH2s + sOsCH2sCH2s), 3.3 (m, 8H, HOsCH2s + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 5.1 (d, 1H, sNH, disappeared upon D2O addition), 12.3 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 73-15 (saturated carbon atoms with DMSO carbon atoms); MS m/z 415 [M+] 398, 370, 356, 342, 328, 314, 300, 286, 272. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Amyloxypropionamido)-16-ol-hexadecanoic Acid (Ig): IR (neat) 3370 cm-1 (sNH stretching), 1542 cm-1 (sNH bending), 1733 cm-1 (sCdO stretching of sCOOH group), 1678 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.8 (t, 3H, sCH2sCH3), 1.4 (bm, 20H, chain sCH2s), 2.2 (m, 5H, sCHs + sCH2sCH2sCH3), 2.7 (t, 8H,

sCOsCH2sCH2s + sOsCH2sCH2s), 3.2 (m, 8H, HOsCH2s + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.4 (d, 1H, sNH, disappeared upon D2O addition), 12.1 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 73-13 (saturated carbon atoms with DMSO carbon atoms); MS m/z 429 [M+] 412, 384, 370, 356, 342, 328, 314, 300, 286. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Isoamyloxypropionamido)-16-ol-hexadecanoic Acid (Ih): IR (neat) 3289 cm-1 (sNH stretching), 1554 cm-1 (sNH bending), 1739 cm-1 (sCdO stretching of sCOOH group), 1641 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.7 [d, 6H, sCHs(CH3)2], 1.3 (bm, 20H, chain sCH2s), 2.2 [m, 2H, sCHs + sCHs(CH3)2], 2.7 [t, 8H, sCOsCH2sCH2s + sOsCH2sCH2sCHs(CH3)2], 3.3 (m, 8H, HOsCH2s + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.8 (d, 1H, sNH, disappeared upon D2O addition), 11.7 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 75-14 (saturated carbon atoms with DMSO carbon atoms); MS m/z 429 [M+] 412, 384, 370, 356, 342, 328, 314, 300, 286. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(3-Ethylacetamido)-16-ol-hexadecanoic Acid (Ii): IR (neat) 3289 cm-1 (sNH stretching), 1560 cm-1 (sNH bending), 1733 cm-1 (sCdO stretching of sCOOH group), 1647 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 0.7 (t, 3H,-CH2sCH3), 1.3 (bm, 20H, chain sCH2s), 2.1 (s, 2H, sCOCH2sCOO), 2.6 (m, 1H, sCHs), 3.2 (d, 10H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH + sCH2sCOOCH2sCH3), 3.9 (s, 1H, sOH, disappeared upon D2O addition), 4.7 (d, 1H, sNH, disappeared upon D2O addition), 12.1 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 174 (carbonyl carbon), 173 (amide carbonyl carbon), 73-14 (saturated carbon atoms with DMSO carbon atoms); MS m/z 401 [M+] 384, 356, 342, 328, 314, 300, 286, 272, 258. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-[2-(2-Carboxyphenyl)acetamido]-16-ol-hexadecanoic Acid (Ij): IR (neat) 3296 cm-1 (sNH stretching), 1597 cm-1 (sNH bending), 1709 cm-1 (sCdO stretching of sCOOH group), 1659 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 1.4 (bm, 20H, chain sCH2-), 2.3 (s, 2H, sCOCH2C6H4), 2.5 (m, 1H, sCHs), 3.3 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.3 (d, 1H, sNH, disappeared upon D2O addition), 7.8 (m, 4H, aromatic protons), 11.9 (bs, 2H, sCH2COOH + sC6H4COOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 177 (carbonyl carbon), 175 (amide carbonyl carbon), 140-80 (aromatic carbons), 75-25 (saturated carbon atoms with DMSO carbon atoms); MS m/z 449 [M+] 432, 404, 390, 376, 362, 348, 334, 320, 306. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively.

Ind. Eng. Chem. Res., Vol. 44, No. 2, 2005 259

9-(1-Benzamido)-16-ol-hexadecanoic Acid (Ik): IR (neat) 3296 cm-1 (sNH stretching), 1557 cm-1 (sNH bending), 1702 cm-1 (sCdO stretching of sCOOH group), 1665 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 1.4 (bm, 20H, chain sCH2s), 2.5 (m, 1H, sCHs), 3.3 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.7 (d, 1H, sNH, disappeared upon D2O addition), 7.5 (m, 5H, aromatic protons), 11.7 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 176 (carbonyl carbon), 174 (amide carbonyl carbon), 145-74 (aromatic carbons), 67-26 (saturated carbon atoms with DMSO carbon atoms); MS m/z 391 [M+] 374, 346, 332, 318, 304, 290, 276, 262, 248. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. 9-(2-Phenylacetamido)-16-ol-hexadecanoic Acid (Il): IR (neat) 3296 cm-1 (sNH stretching), 1554 cm-1 (sNH bending), 1721 cm-1 (sCdO stretching of sCOOH group), 1641 cm-1 (sCdO stretching of secondary amide group); 1H NMR (DMSO-d6) at δ 1.6 (bm, 20H, chain sCH2s), 2.4 (s, 2H, sCH2sC6H5), 2.7 (m, 1H, sCHs), 3.4 (m, 8H, HOsCH2 + sCH2sCHsCH2s + sCH2sCOOH), 3.8 (s, 1H, sOH, disappeared upon D2O addition), 4.5 (d, 1H, sNH, disappeared upon D2O addition), 7.5 (m, 5H, aromatic protons), 11.7 (bs, 1H, sCOOH, disappeared upon D2O addition); 13C NMR (DMSO-d6) at δ 176 (carbonyl carbon), 174 (amide carbonyl carbon), 145-74 (aromatic carbons), 72-25 (saturated carbon atoms with DMSO carbon atoms); MS m/z 405 [M+] 388, 360, 346, 332, 318, 304, 290, 262. McLafferty rearrangement molecular ion peaks at m/z 144 and 60 due to secondary amide and carboxylic acid functional groups, respectively. Experimental Section Aleuritic acid (95%, lot no. A013141301, Acros Organics), nitriles (Fluka AG), and sulfuric acid AR (98%, Glaxo Laboratories India Ltd.) were used. Instrumentation. Infrared spectra were recorded on an Impact 410 model instrument, using KBr pellets. 1H NMR spectra were recorded on Bruker (300- and 400MHz) model instruments using DMSO-d6 as the solvent. The chemical shifts were measured in parts per million (ppm) downfield from internal TMSi at δ ) 0. The mass spectra were recorded on a Finnigan Mat with PDP Micro Computer 810 at 70 eV with a source temperature of 150 °C. Preparation of 9-(Acetamido)-16-ol-hexadecanoic Acid. A homogeneous mixture of 8.1 g (1 mol) of 16hydroxyhexadec-cis-9-enoic acid (obtained from aleuritic

Scheme 3 a

a Where R ) (a) -CH , (b) -CH -CH , (c) -(CH ) -O-CH , 3 2 3 2 2 3 (d) -(CH2)2-O-C2H5, (e) -(CH2)2-O-(CH2)2-O-C2H5, (f) -(CH2)2-O-(CH2)3-CH3, (g) -(CH2)2-O-(CH2)4-CH3, (h) -(CH2)2-O-(CH2)2-CH-(CH3)2, (i) -CH2-COOC2H5, (j) -CH2-C6H4-COOH, (k) -C6H5, (l) -CH2-C6H5.

acid4,5) and 3.7 g (3 mol) of acetonitrile was prepared and was added by dropping funnel in 30 min to 17.7 g (6 mol) of 95% sulfuric acid in a 1-L three-necked flask fitted with a thermometer and an efficient stirrer. The reaction temperature was maintained below 20 °C by external cooling. After complete addition, the mixture was poured into crushed ice and water. The reaction mixture was allowed to stand overnight in dilute acid. Then, it is washed with distilled water. Similarly, different 9-substituted amides including propionamido-, 3-methoxypropionamido-, 3-ethoxypropionamido-, 3-(2-diethoxy)propionamido-, 3-butoxypropionamido-, 3-amyloxypropionamido-, 3-isoamyloxypropionamido-, 3-ethylacetamido-, 2-(2-carboxyphenyl)acetamido-, 1-benzamido-, and 2-phenylacetamido-16ol-hexadecanoic acids were prepared using corresponding nitriles and 16-hydroxyhexadec-cis-9-enoic acid (Scheme 3). For analytical purposes, crude compound Ia was recrystalized from aqueous alcohol. The other componds (Ib-Il) were purified by column chromatography. Elemental analyses, yields, and melting points of all compounds are reported in Table 2. The melting points were determined by open capillary method and are uncorrected. In the proposed mechanism (Scheme 4), it is found that sulfuric acid first adds to the double bond of 16hydroxyhexadec-cis-9-enoic acid to form sulfate ester (1), followed by the reaction of this intermediate with the different nitriles. It might be significant that, when the reaction mixture is poured into ice-cold water to isolate the product, an oily material is obtained. The viscous, oily mass (2) undergoes amido-imidol tautomerization, after which the product (3) is obtained.

Table 2. Elemental Analyses of Compounds Ia-Il compd

molecular formula

yield (%)

mp (°C)

Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik Il

C18H35NO4 C19H37NO4 C20H39NO5 C21H41NO5 C23H45NO6 C23H45NO5 C24H47NO5 C24H47NO5 C21H39NO6 C25H39NO6 C23H37NO4 C24H39NO4

64.5 92.0 62.5 72.0 73.5 69.0 70.0 76.0 79.5 80.0 70.0 76.0

54-56 low low low low low low low low low low low

carbon (%) calcd found

hydrogen (%) calcd found

nitrogen (%) calcd found

65.62 66.47 65.08 64.31 66.81 62.84 70.55 71.11 64.03 66.50 67.13 67.13

10.70 10.78 10.66 10.52 8.68 9.72 9.46 9.62 10.44 10.84 10.95 10.95

4.25 4.08 3.61 3.74 3.11 3.49 3.58 3.45 3.24 3.37 3.26 3.26

65.40 66.32 65.00 64.20 66.70 62.68 70.38 71.01 63.93 66.38 67.01 66.99

10.58 10.67 10.48 10.40 8.57 9.59 9.34 9.51 10.23 10.69 10.83 10.81

4.14 3.99 3.49 3.62 3.01 3.38 3.47 3.33 3.13 3.26 3.15 3.14

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Scheme 4

Table 5. Notation Used in Tables 3 and 4 response (mm)

symbol

activity

transmission (%)

0 11-15 16-20 21-25 26-30

+ ++ +++ ++++

no activity positive activity positive activity positive activity positive activity

0 25 50 75 100

solution (i.e., 100 µg of the test compound); diameter of the cup, 10 mm; control, tetracycline. The results and observations of antimicrobial activity by the cup-plate method are summarized in Tables 3 and 4. The notation used in these tables is decribed in Table 5. Conclusion

a

Where R′ ) -(CH2)6-OH and R′′ ) -(CH2)7-COOH.

Table 3. Antibacterial Activities of Compounds Ia-Il zone of inhibition (activity) Escherichia Bacillus Pseudomonas Staphlococcus compd coli cirroflagellosus putida aureus Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik Il

+ + + + ++ + ++ ++ + ++ + + +

++ ++ ++ ++ + ++ + + ++ ++ ++ ++

+ + + + ++ + ++ ++ ++ + + +

++ ++ + ++ ++ + ++ + + ++ ++ ++

Table 4. Antifungal Activities of Compounds Ia-Il

We found a remarkable effect of sulfuric acid as a catalyst in the addition of nitriles to 16-hydroxyhexadeccis-9-enoic acid, especially in the amido-imidol tautomerization of 9-[substituted amido]-16-ol-hexadecanoic acids via the stable carbocation intermediates. In contrast, other mineral acids such as concentrated HCl and HNO3 did not work well. This approach has opened new directions for the synthesis of new oleochemicals for potential medical and industrial utilization. Furthermore, we succeeded in introducing heteroatoms into the fatty acid chain. Thus, we have synthesized different nitrogen derivatives of the form 9-[substituted amido]16-ol-hexadecanoic acids in a single step with good yield. Acknowledgment This research work was financially supported by the Council of Scientific & Industrial Research (CSIR), New Delhi, India (Ref. No. 01(1677)/00/EMR-II dated 07-122000).

zone of inhibition (activity) compd

Candida albicans

Aspergillus niger

Penicilluium notatum

Sclerotium rolfsil

Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik Il

+ + + + ++ + + + + + + +

++ ++ ++ + + + + + + + ++ +

++ ++ + ++ ++ + + + ++ ++ ++ ++

+ + + + ++ ++ ++ ++ ++ + + ++

Biological Evaluation. The newly synthesized 9-[substituted amido]-16-ol-hexadecanoic acids were screened for their antibacterial and antifungal activities at concentration of 1000 µg/mL, according to the cup-plate method.9 The compounds were tested against Escherichia coli, Bacillus cirroflagellosus, Pseudomonas putida, and Staphylococcus aureus for antibacterial activity. The antifungal activity tests were carried out with Candida albicans, Aspergillus niger, Penicilluium notatum, and Screlotium rolfsii. The antimicrobial activities of the compounds were compared with that of tetracycline at the same concentration. The conditions for the tests were as follows: concentration of the test compound in dimethyl formamide (DMF), 1000 µg/mL (i.e., 1 mg/mL); test solution, 0.1 mL of the above

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Received for review October 3, 2002 Revised manuscript received October 18, 2004 Accepted October 20, 2004 IE0207865