4.2 Aims and Objectives

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4.1 Introduction The reaction between the products of interaction of halogens and silver salts of carboxylic acids and olefns forms the basis of the Woodward and Prevost methods of cis- and trans-

1 4.1 Introduction The reaction between the products of interaction of halogens and silver salts of carboxylic acids and olefns forms the basis of the Woodward and Prevost methods of cis- and trans- hydroxylations respectively. In the Prevost method, the olefin is treated with iodine and silver benzoate in a 1:2 molar ratio 121,127,175. The initial addition is anti and results in β- halobenzoate. Under normal conditions, the iodine is replaced by a second PhCOO group to give 1, 2-dibenzoates which can be hydrolyzed to 1,2, diols. Thus the dihydroxylation by Prevost method is stereospecific and involves trans addition (section ). Woodward s method 122 is similar, but results in overall syn hydroxylation. The olefin is treated with iodine and silver acetate in a 1:1 molar ratio in aqueous acetic acid and the resulting mixture of mono and diacetates is subsequently hydrolsed to the dihydroxy compounds (section ).

2 The hydroxylation of olefins using the Prevost s or Woodward s method involves the use of silver carboxylate and halogen. The fact that silver carboxylates have the disadvantages of being expensive, frequently unstable and difficult to dry led to the search for modifications of Prevost and Woodward methods of hydroxylation. L. Mangoni and coworkers 132 have developed a convenient procedure that does not require the expensive silver carboxylates. They showed that olefinic compounds such as 5-α-cholest-2-ene, cyclohexene and oleic acid could be hydroxylated using iodine, potassium iodate and potassium acetate in acetic acid medium. R.C. Cambie and P.S.Rutledge 133 have suggested that Thallium acetate and iodine can be used to effect both cis- and trans- dihydroxylation of olefins. Thus when reacted with iodine and thallium acetate in dried acetic acid under reflux conditions for 10 hrs., cyclohexene gave trans-1,2- cyclo hexane diol. When the hydroxylation was carried out using the same reagent in presence of water, cyclohexene gave cis-1,2-cyclohexane diol. Hydroxylation of olefins using iodine and cobalt(ii) acetate in acetic acid have been reported by Yi Yi Mint and M.A. Pasha 135. Raman and Ashrof 136 have shown that lead acetate may be used in the place of silver acetate in the Woodward procedure for hydroxylation of oleic acid. 4.2 Aims and Objectives Investigations on modifications of Woodward- Prevost reactions by the use of less expensive and more readily available metal carboxylates in place of silver carboxylates is a topic of perpetual interest in the field of synthetic organic chemistry. In this context, the observation 136 that lead acetate may be used in the place of silver acetate in the Woodward s procedure for hydroxylation of oleic acid assumes significance. However, no attempt has hitherto been made on further investigations on the general applicability of this reagent for the hydroxylation of olefinic compounds. We considered the Analytical and Synthetic Investigations in Olefinic Compounds 84

3 general lack of research in this area a sufficient incentive to explore the use of lead acetate and iodine in the hydroxylation of olefinic compounds and the mechanistic aspects of such reactions. This chapter deals with the dihydroxylation of olefinic compounds of various types using lead acetate and iodine in aqueous acetic acid medium. The olefinic compounds selected for hydroxylation included some 1, 2- disubstituted olefinic compounds such as naturally occurring unsaturated fatty acids as well as some trisubstituted and cyclic olefinic hydrocarbons. 4.3 Results and Discussion Dihydroxylation of ethyl oleate (ethyl octadec-cis-9-enoate) using lead acetate and iodine Raman 126 has described a method for hydroxylation of erucic acid (docos-13-enoic acid) to 13, 14- dihydroxy docosanoic acid using silver acetate and iodine in acetic acid medium. A mixture of erucic acid, iodine and excess of silver acetate in wet acetic acid was heated on a water bath for 5 hours. Hydrolysis of the resulting product gave erythro-13, 14- dihydroxy behenic acid (erythro-13, 14- dihydroxy docosnaoic acid). A similar procedure was adopted in the present work for hydroxylating ethyl oleate using lead acetate and iodine. To a mixture of ethyl oleate (0.005 mole)and powdered lead acetate (0.005 mole) in acetic acid (10 ml) containing water (1 ml) was added powdered iodine (0.005 mole) in 4 lots and heated on a water bath for 2 hr. Hydrolysis of the resulting product gave crude dihydroxy acid (0.95g) which melted at C on crystallisation from ethanol and was proved to be erythro-9,10-dihydroxy stearic acid (52) by mixed melting point with an authentic specimen obtained by dilute alkaline Analytical and Synthetic Investigations in Olefinic Compounds 85

4 permanganate oxidation of oleic acid according to the method of Doree and Pepper 176. In the 1 H NMR spectrum of the product (52) the methyl group presented a signal at δ0.897 (t, J=6.8 Hz, 3H) and the α-methylene group resonated as triplet of 2 protons at (J=7.4Hz). The remaining methylene groups were visible as a multiplet of 26 protons between δ and the methine protons at C-9 and C-10 resonated as a multiplet of 2 protons centered at The 1 H NMR spectrum of compound (52) was found identical with that reported for erythro-9, 10-dihydroxy stearic acid. In the 13 C NMR spectrum, the methyl carbon was visible at δ15.0 and CH 2 CH 3 (C-17) appeared at δ The spectrum showed resonance at δ49.01 due to α-methylene carbon and at δ due to methine carbon atoms (C-9 and C-10). The 13 C NMR spectrum of compound 52 was found identical with that reported for erythro-9, 10-dihydroxy stearic acid. The IR spectrum showed a broad peak at 3339cm -1 due to OH group, a strong, sharp peak at 1699 cm -1 due to C=O group, and a strong peak at 1077 cm -1 due to C-O stretching. The IR spectrum of compound was found super imposable with that reported for erythro-9, 10-dihydroxy stearic acid. Formation of erythro-9, 10-dihydroxy stearic acid on oxidation of ethyl oleate (ethyl octadec-cis-9-enoate) reveals that lead acetate and iodine in acetic acid accomplishes syn-hydroxylation of olefins. COOC 2 H 5 1) (C H 3 COO) 2 Pb / I 2 / HO COO H Ethyl oleate CH 3 CH 3 COOH 2) Hydrolysis HO Erythro-9,10-dihydroxy stearic acid CH 3 52 Analytical and Synthetic Investigations in Olefinic Compounds 86

5 Hydroxylation of ethyl oleate using lead acetate and iodine was also attempted by employing the procedure analogous to that used in Prevost 121, Woodward 122 and silver succinate-iodine 129 methods. When lead acetate and iodine were heated in aqueous acetic acid the color of iodine was discharged only after heating for several hours. Hydroxylation could not be achieved by heating the reaction product with ethyl oleate indicating that unlike in Prevost, Woodward and silver succinate-iodine methods, no complex formation occurred by the interaction of lead acetate and iodine Presence of water has been reported to influence the products of dihydroxylation by Woodward s procedure 126. Hence it was thought worthwhile to investigate the effect of moisture in the dihydroxylation of olefins using lead acetate and iodine. Dihydroxylation of ethyl oleate was attempted using lead acetate and iodine in complete absence of water. The reaction was very slow and the color of iodine disappeared only after heating for 10 hrs. Hydrolysis of the resulting product, after filtering off the precipitated lead iodide, yielded the unreacted oleic acid. Thus it follows that, unlike in Woodward reaction, dihydroxylation using lead acetate and iodine can be accomplished only in presence of water Dihydroxylation of elaidic acid (octadec-trans-9-enoic acid) Elaidic acid (0.005 mole) was hydroxylated using lead acetate (0.005 mole) and iodine (0.005mole) in acetic acid (10 ml) containing distilled water (1 ml) as described under The resulting product on hydrolysis gave crude dihydroxy acid (1.08g). Recrystallisation from ethanol gave colorless crystals, melting at 98 0 C, undepressed on admixture with an authentic sample of threo-9, 10-dihydroxy stearic acid 176. The 1 H NMR spectrum of the product showed a triplet of 3 protons at δ0.897 (J= 7.0Hz) for methyl group; a triplet of two protons at δ2.277 (J= 7.2 Analytical and Synthetic Investigations in Olefinic Compounds 87

6 Hz) for the α-methylene group; a multiplet of 26 protons between δ for the remaining methylene groups; a multiplet of 2 protons centred at δ3.325 for the methine protons at C-9 and C-10. The 13 C NMR spectrum of the compound showed resonance at δ14.43 for methyl group, δ23.53 due to CH 2 CH 3 group(c-17), δ49.01 due to α- methylene carbon atom (CH 2 COOH), δ75.30 due to methine carbon atoms at C-9 and C-10, and δ due to the carboxyl group. The IR spectrum of the compound showed a broad peak at 3275cm -1 due to OH group, a strong, sharp peak at 1695cm -1 due to C=O group, and a strong peak at 1072cm -1 due to C-O stretching. The formation of threo-9, 10-dihydroxy stearic acid (53) on hydroxylation of elaidic acid (octadec-trans-9-enoic acid) also illustrates the syn-hydroxylating action of lead acetate and iodine in acetic acid medium. CH 3 1) COOH (CH 3 COO) 2 Pb / I 2 / CH 3 COOH HO COOH CH 3 Elaidic acid (Octadec-trans-9-enoic acid) 2) Hydolysis HO Threo-9,10-dihydroxy stearic acid Dihydroxylation of petroselenic acid (octadec-cis-6-enoic acid) Hydroxylation of petroselenic acid (0.005 mole) using powdered lead acetate and iodine in acetic acid containing water gave crude dihydroxy acid in 62% yield. Recrystallisation of the product from ethanol gave colorless crystals with m.p C, undepressed on admixture with an authentic specimen of erythro-6, 7-dihydroxy stearic acid Analytical and Synthetic Investigations in Olefinic Compounds 88

7 In the 1 H NMR spectrum of the product the methyl group presented a signal at δ0.895 (t, J=6.8 Hz) and the α-methylene group resonated as triplet at (J=6.6 Hz). The remaining methylene groups were visible as a multiplet of 26 protons between δ and the methine protons at C-9 and C-10 resonated as a multiplet of 2 protons centered at In the 13 C NMR spectrum, the methyl carbon was visible at δ14.32 and CH 2 CH 3 (C-17) appeared at δ The spectrum showed resonance at δ49.01 due to α-methylene carbon and at δ75.88 due to methine carbon atoms (C-9 and C-10). The IR spectrum showed a broad peak at 3237cm -1 due to OH group, a strong, sharp peak at 1690 cm -1 due to C=O group, and a strong peak at 1072 cm -1 due to C-O stretching Dihydroxylation of ethyl erucate (ethyl docos-cis-13-enoate) Hydroxylation of ethyl erucate was carried out using lead acetate and iodine exactly as described under Hydrolysis of the resulting product gave crude dihydroxy acid (58% yield) which on recrystallisation from ethanol gave colorless crystals with m.p C, undepressed on admixture with an authentic sample of erythro-13,14- dihydroxy behenic acid (erythro-13,14- dihydroxy docosanoic acid) Dihydroxylation of cyclohexene Cyclohexene (0.03 mole) was hydroxylated using lead acetate (0.033 mole) and iodine (0.03 mole) in acetic acid containing water (3 ml). Hydrolysis of the resulting product followed by extraction using chloroform gave crude cyclohexane diol (12% yield) which on recrystallisation from Analytical and Synthetic Investigations in Olefinic Compounds 89

8 petroleum ether ( ) gave colorless crystals, m.p.95 0 C (lit.m.p 96 0 C). The product gave a positive test for vicinal diol Dihydroxylation of diethyl fumarate A mixture of diethyl fumarate (0.02 mole), lead acetate (0.022 mole) in acetic acid ( 40 ml) containing distilled water (2 ml) and iodine(0.02 mole) was heated on a water bath. The decolorisation of iodine was slow and a portion of iodine remained unchanged even after heating for 10 hr. The resulting product was hydrolysed using alcoholic KOH and the hydrolysate was evaporated to dryness on a water bath. The residue was decomposed with concentrated hydrochloric acid and the liberated acid was converted to insoluble calcium salt by adding a concentrated solution of calcium chloride. The precipitated calcium salt was treated with calculated amount of 1N. Sulfuric acid. It was centrifuged and the centrifugate was evaporated to dryness on a water bath to give DL-tartaric acid (0.12g, 4%), melting at The m.p. of the product was not depressed on admixture with an authentic sample Attempted dihydroxylation of 2- methyl 2- butene Dihydroxylation of 2- methyl 2-butene (0.04 mole) was attempted by heating with lead acetate (0.044 mole), iodine (0.04 mole) and acetic acid (30 ml) containing water (4 ml). The resulting product on hydrolysis followed by extraction with ether gave a colorless, viscous liquid (0.33g) which gave a positive test for vicinal diol 177. The low yield of the product obtained in the dihydroxylation of 2- methyl 2-butene carried out at the temperature of boiling water bath may be attributed to the highly volatile nature of the olefinic hydrocarbon. Analytical and Synthetic Investigations in Olefinic Compounds 90

9 4.3.8 Summary The results of the dihydroxylation reactions of various olefinic compounds using lead acetate and iodine in acetic acid medium are summarized in table II. Table II. Olefinic Sl.. Product Yield m.p. of product stereochemstry of compound % Remarks No. used Found Reported hydroxyl ation Ethyl oleate Erythro-9,10-dihydroxy stearic acid Syn - 2 Elaidic acid Threo-9,10-dihydroxy stearic acid Syn - 3 Petroselenic acid Erythro-6,7-dihydroxy stearic acid Syn - 4 Ethyl erucate Erythro-13,14-dihydroxy behenic acid Syn - 5 Cyclohexene Cis-Cyclohexane-1,2-diol Syn - 6 Diethyl fumarate DL-Tartaric acid Syn Methyl 2-butene 2-methyl butane-2,3-diol Identity of the product was established by qualitative tests. 4.4 Conclusions Lead acetate and iodine in wet acetic acid medium is proved to be a simple and effective reagent for stereospecific hydroxylation of olefinic Analytical and Synthetic Investigations in Olefinic Compounds 91

10 compounds. Syn-hydroxlation of olefinic compounds can be accomplished using this reagent. It is particularly useful in the hydroxylation of non volatile olefinic compounds such as naturally occurring unsaturated fatty acids since the resulting diols are crystalline, water-insoluble solids which can be easily recovered and identified. Thus the reagent can hydroxylate cis-olefinic fatty acids to the corresponding erythro-dihydroxy acids and trans-acids to the corresponding threo-dihydroxy acids. 4.5 Experimental procedures All melting points are uncorrected and were determined on a Neolab melting point apparatus Dihydroxylation of ethyl oleate Dissolved ethyl oleate (1.55g,0.005 mole) in acetic acid (10 ml)and added distilled water (1ml)and powdered lead acetate(1.9g,0.005 mole). While heating the mixture on a water bath, powdered iodine (1.27g, mole) was added in four lots, vigorously shaking the mixture after each addition. After addition was over, continued heating until the color of iodine completely disappeared. After heating for another sixty minutes and cooling, the precipitated lead iodide was filtered off and washed with a little acetic acid. The combined filtrates and washings were diluted with 3-4 times its volume of water and extracted with ether. The ether solution was washed with water, and ether removed. The brownish yellow residue was saponified by refluxing with alcoholic potash (10%, 25 ml) for 45 minutes. Removed most of the alcohol, diluted with water and then acidified with concentrated hydrochloric acid. The dihydroxy acid (0.95g, 60% yield) was collected, dried in air for some time and triturated with cold petroleum ether (5 ml) to dissolve unreacted oleic acid. Filtered and crystallized from ethanol to give Analytical and Synthetic Investigations in Olefinic Compounds 92

11 erythro-9, 10- dihydroxy stearic acid, melting at C. There was no depression of the melting point when mixed with an authentic sample of erythro-9, 10-dihydroxy stearic acid obtained by dilute, alkaline potassium permanganate oxidation of oleic acid H NMR (400 MHz, MeOD) δ ppm (t, J= 6.8 Hz, 3H); (t, J= 7.4 Hz, 2H); (m, 26 H); 3.339(m, 2H) 13 C NMR (100 MHz, MeOD) δ 15.0,23.75,26.12, 26.98, 30.23, 30.45, 30.68, 30.88,33.07, 33.61, 34.99,49.01, IR (KBr) ν max. : 3339,2915, 2848,1699,1297, 1077, 923, 721cm Dihydroxylation of elaidic acid Elaidic acid (1.4g, mole)) was hydroxylated using lead acetate (1.9g, mole), iodine(1.27g, mole) and acetic acid (8 ml) containing distilled water (I ml) exactly as described under Hydrolysis of the resulting product gave crude dihydroxy acid (1.08g, 68%). It was dried in air and triturated with petroleum ether to dissolve the unreacted elaidic acid. Filtered and recrystallized from ethanol to give threo-9, 10- dihydroxy stearic acid, with m.p C, undepressed on admixture with an authentic specimen H NMR (400 MHz, MeOD): δ ppm (t, J=7.0 Hz, 3H) ; (t, J= 7.2 Hz, 2H) ; (m, 26 H); 3.25 (m, 2H) 13 C NMR (100 MHz, MeOD): δ 14.43, 23.74, 26.1, 27.08, 30.21, 30.44, 30.66, 30.86, 33.07, 33.9, 34.97, 49.01,75.70,77.72 Analytical and Synthetic Investigations in Olefinic Compounds 93

12 IR (KBr) ν max. : 3275, 2916, 2848, 1695, 1299, 1072, 934, 721cm Dihydroxylation of petroselenic acid Petroselenic acid (1.4g, mole) was hydroxylated using powdered lead acetate (1.9g, mole), powdered iodine(1.27g, mole) and acetic acid (10 ml) containing water (1ml) exactly as described under Hydrolysis of the reaction product yielded crude dihydroxy acid (0.98g, 62%). Treatment with petroleum ether and subsequent crystallization from ethanol gave a product with melting point C. There was no depression of melting point when mixed with an authentic sample of erythro-6, 7-dihydroxy stearic acid obtained by dilute, alkaline potassium permanganate oxidation of petroselenic acid H NMR (400 MHz, MeoD) δ 0.895ppm (t, J= 6.8 Hz, 3H); (t, J=6.6 Hz, 2H); (m, 26H); (m, 2H) 13 C NMR (100 MHz, MeOD) δ 14.32, 23.74, 26.22,27.04, 30.48, 30.77, 30.88, 33.08, 33.67, 35.02, 49.01,75.88 IR (KBr) ν max. 3237, 2914, 2848, 1690, 1274, 1072, 942, 719cm Dihydroxylation of ethyl erucate A mixture of ethyl erucat (1.83g, mole), lead acetate (1.9g, mole), acetic acid (10 ml), distilled water (1 ml) and iodine (1.27g, mole) was heated on a water bath for 2h. Hydrolysis of the resulting product gave crude dihydroxy acid (1.08g, 58%). Recrystallization of the product from ethanol, after treatment with petroleum ether gave erythro-13, 14- dihydroxy Analytical and Synthetic Investigations in Olefinic Compounds 94

13 docosanoic acid, which melted at C and showed no depression in melting point when mixed with the product obtained by dilute, alkaline permanganate oxidation of erucic acid Dihydroxylation of cyclohexene A mixture of cyclohexene (2.5g, 0.03 mole), lead acetate (12.6g, mole), acetic acid (25 ml) and water (3 ml) was heated on a water bath and added powdered iodine (7.62g, 0.03 mole) in 4 lots. Continued heating for one more hour after the color of iodine had completely disappeared. Filtered from precipitated lead iodide, extracted with ether and removed the solvent. The brownish residue was saponified with KOH (7g) in alcohol (40 ml). The hydrolysate derived from cyclohexene was evaporated to dryness on a water bath and the residue extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and solvent removed by distillation to get crude cis-cyclohexane-1,2-diol (0.42g, 12%) which on recrystallisation from petroleum ether ( C) gave colorless crystals, m.p C (lit.m.p C). The product gave positive test for vicinal diol Dihydroxylation of diethyl fumarate Dissolved diethyl fumarate (3.44g, 0.02 mole) in 40 ml acetic acid (40 ml) containing distilled water (2 ml). Added lead acetate (8.4g, mole), heated the mixture on a water bath and added powdered iodine (5.08g, 0.02 mole) in 4 lots. Continued the heating for 10 h. A portion of iodine remained unchanged even after heating for 10 h. Diluted the reaction mixture with water and extracted with ether. Washed the ether extract with sodium thiosulfate solution and then with water. Removed the solvent and refluxed with alcoholic potash (10%, 70 ml) for 3 hr. Cooled, filtered and evaporated the filtrate to dryness on a water bath. Analytical and Synthetic Investigations in Olefinic Compounds 95

14 Dissolved the residue in water (15 ml) and acidified with concentrate hydrochloric acid. Filtered the turbid solution and the filtrate was made faintly alkaline to phenolphthalein with sodium hydroxide solution. Added this solution to excess of clear, concentrated calcium chloride solution. The precipitated calcium salt was collected and acidified with calculated amount of 1N sulfuric acid. It was centrifuged and the centrifugate was evaporated to dryness on a water bath to give DL-tartaric acid (0.12g, 4%), melting at The m.p of the product was not depressed on admixture with an authentic specimen Attempted dihydroxylation of 2-methyl 2-butene 2-methyl 2-butene (2.88g, 0.04 mole) was heated with lead acetate (16.88g, mole), iodine (10.16g, 0.04 mole), acetic acid (30 ml) and water (4 ml)on a water bath for 3 hr. The resulting product was hydrolysed with KOH (9g) in alcohol (50 ml). The hydrolysate was evaporated to dryness on a water bath and the residue extracted with ether. Removal of the solvent by distillation gave a colorless, viscous liquid (0.33g, 8%) which gave positive test for vicinal diol 177. Analytical and Synthetic Investigations in Olefinic Compounds 96

3016 Oxidation of ricinoleic acid (from castor oil) with KMnO 4 to azelaic acid

3016 Oxidation of ricinoleic acid (from castor oil) with KMnO 4 to azelaic acid 6 Oxidation of ricinoleic acid (from castor oil) with KMnO 4 to azelaic acid CH -(CH ) OH (CH ) -COOH KMnO 4 /KOH HOOC-(CH ) -COOH C H 4 O (.) KMnO 4 KOH (.) (6.) C H 6 O 4 (.) Classification Reaction