- Email: [email protected]
Synthesis of 2,2′-oxirane fatty esters and a study of some of their physical properties
ChemistryandPhysicsofLipids, 46 ( 1988) 193-- 198 Elsevier Scientific Publishers Ireland Ltd.
193
Synthesis of 2,2'-oxirane fatty esters and a study of some of their physical properties
Marcel S.F. Lie Ken Jie and Y.F. Zheng Department of Chemistry, University of Hong Kong, Pokfulam Road (Hong Kong) Received August 3rd, 1987; revised and accepted September 9th, 1987) Two-phase methylene transfer reaction involving methyl 12-oxo-octadecanoate and trimethylsulfonium methysulfate gave methyl 12-(2,2'-oxiran-2-yl)-octadecanoate,while methyl 9,10- and 9,12-dioxooctadecanoate furnished the corresponding methyl 2,2'-bioxiran-2-yl-octadecanoatederivatives. The methylene protons of the 2,2'-oxirane system were characterized by a singlet signal at 2.57d (IH-NMR), and by signals at 52.50 and 59.54 ppm corresponding to the methylene and quaternary carbon atoms, respectively (13C-NMR). Acid-catalysed ring opening reaction facilitated bond rupture between the quaternary carbon and the oxygen of the 2,2'-oxirane system, furnishing the corresponding methoxy-carbinol derivative in the case of methyl 12-(2,2'oxiran-2-yl)-octadecanoate.
Keywords: 2,2'-oxirane; epoxy; fatty acid; synthesis; physical properties. Introduction
Results and discussion
Fatty acids containing epoxy groups o f the 2,3-oxirane type have been extensively studied, as such compounds occur in m a n y seed oils and are readily prepared f r o m ethylenic fatty esters by peracid epoxidation [1--4]. The usefulness o f epoxides in organic synthesis has been recently reviewed [5] and reactions involving epoxy fatty acids have led to m a n y interesting derivatives o f fatty acid [6,7]. However, no natural long chain fatty acid containing a 2,2'-oxirane structure has yet been described. In view of the important role played by epoxy groups, especially in the cyclisation reaction of diepoxy fatty esters to oxygen heterocyclic and furanoid fatty derivatives [8,9], this paper describes the synthesis o f 2,2'-oxirane fatty esters f r o m readily available keto fatty esters by means of the two-phase methylene transfer reaction described by Mosset and Gree [ 10].
Synthesis o f 2,2"-oxirane fatty esters (Scheme 1)
Correspondence to: Dr. M.S.F. Lie Ken Jie.
Reaction of methyl 12-oxo-octadecanoate with trimethylsulfonium methylsulfate and aqueous sodium hydroxide in methylene chloride gave compound 1 (580/o yield). This methylene transfer reaction was extended to methyl 9,10- and 9,12-dioxo-octadecanoate, which furnished the corresponding 2,2'-bioxirane derivatives (2,3) in 2107o and 80% yield, respectively (Scheme 1). During the extraction of the organic product with diethyl ether, no mineral acid was added to the reaction mixture in order to prevent hydrolysis of the acid-sensitive 2,2'-oxirane system. The ethereal extract was washed several times with water until neutral and the isolated 2,2'oxirane ester derivative purified by flash column chromatography [11]. The reaction also resulted in the production of about 20°7o of the sodium salt of the oxirane derivative. However, treatment of the aqueous layer with mineral acid caused ring opening of the oxirane system.
0009-3084/88/$03.50 © 1988 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
194 0 ^.-~) II (i) 58% H=4. [ R,--C--R 2 ~ .~C_
q-
O~ I -,~CH, .~C~
ilia) 95% (iib) 57% )
C,H20H R~-"-~--R=/
1
R3--C--C--R 4
•~
R3
4
--
R.
2
o RI_ Id_CH2CH2_~_R4
(i) 80%
,,<_Lc.,c.,_c%.
R~ = CH3{CH2)5; R2 = (CH2)~oCOOCH3; R3 = CH3{CH2)7; R4 = (CH2) 7 COOCH 3 + (i) (CHa)3SCH a SO~. NaOH/H20, CH=Cl2; (iia) BF3--CH3OH; (iib) H2SOJH20, CH3OH; (iic) HCI/H20, CH3OH, THF Scheme 1. Synthesis of 2,2'-(bi) oxirane derivatives from methyl oxo and dioxostearate (1,2,3) and hydrolysis product of methyl 12(2,2'-oxiran-2-yl)-octadeeanoate (4)
Physical properties of 2,2'-oxirane fatty esters (TableD. The TLC behavior of the 2,2'-oxirane fatty esters was similar to that of the more common 2,3-oxirane fatty esters, when chromatographed on silicic acid using a mixture of petroleum ether/diethyl ether (6:4, by vol.) as developer. The RI values of compounds 1, 2 and 3 were 0.6, 0.45 and 0.45, respectively. On a 2-m OV101 packed column, the GLC analysis of compound 1 gave a single peak with an equivalent chain length (ECL) value of 20.5, but compounds 2 and 3 furnished a broad hump indicative of a mixture of closely related isomers. When the analysis was conducted on a 30-m OV-101 capillary column, compound 2 separated into two partially overlapping peaks with ECL values of 21.75 and 22.0, while compound 3 gave four partially overlapping peaks with ECL values of 22.4, 22.6, 22.7 and 22.9. The GC/MS analysis of these overlapping peaks (taken at the
apex of each component for each set) gave almost identical fragmentation patterns with variations in fragment intensities only. From these data it appeared that compounds 2 and 3 consisted of a mixture of configurational isomers, which resulted from the attack of the carbonyl groups by the methylide ion from different directions during the methylene transfer reaction. The 2,2'-oxirane system was readily recognized by the appearance of a signal (singlet) at 2.576 in the proton NMR spectrum for the protons of the methylene of an isolated oxirane system, O--/CH2as in compounds 1 and 3. In the x / --C--
case of compound 2, where the two oxirane rings were situated alpha to each other, two signals (singlets) at 2.58 and 2.626 were observed. The cause of these different chemical shifts for the methylene protons of the oxirane rings was most likely attributed to the different
0.45
0.45
0.30
2
3
4
2.57
1.62 1 . 6 2
1.2--1.6
3.18
0.9 1.2--1.7 | 1.2--1.7 OCH 3
/
2.30
2.30
3.67
I CH3(CH2)5 --C--(CH2)9(CH2)gCH2~H3
CH2OH
3.47 2.12
1.2--1.6
3.66
0.9
3.62
(broad)
? cH2
2.57
2.30
CH3(CH2)s--C-- CH2--CH2--C--(CH 2 )6CH2COOCH3
2.57
1.2--1.5
C--(CH2)sCH 2 COOCHj
22.0~23.2
1.2--1.5
CH~(CH2)s--C 0.89
21.5--22.4
2.58 2.62
CH3ICH2)5 - C--(CH2)gCH 2 COOCH3 0.88 1.2--1.6 1.2--1.6 2.30 3.66
JH-NMR (d)
(broad
20. 5
GLC (OV-101) ECL
•PE40 = petroleum ether/diethyl ether (60:40, by vol.) as developer.
0.60
R!
PE40'
TLC
1
Compound
20
~ 21
22.64 14.09 J 50.71 C-19/-2O~t 49.62 49.51
C-17 C-18
174.00 34.02 24.92 29.42 29.42
C-6 C-7 C-8 C-9 C-10
2o
29.42 24.81 34.29 58.89 29.52
29.52 58.89 34.45 24.81 30.77
CH~OH I
C-11 C-12 C-13 C-14 C-15
12
9
C-16 31.80 C-17 22.59 C-18 14.03 C-19 51.30 C-2O/-21 J 52.28 1 52.11
I
C-1 C-2 C-3 C-4 C-5
174.17 34.02 24.92 29.09 29.09
C-6 C-7 C-8 C-9 C-10
29.36 29.47 29.47 29.90 23.08
C-II C-12 C.13 C-14 C-15
32.12 78.88 32.12 23.08 30.23
C-16 C-17 C-18 C-19 C-20 C-21
31.75 22.59 13.98 51.25 63.87 48.59
CH3CH2CH2CH2CH2CH2--C--CH2CH2CH 2 CH2CH2CH2CH2CH2CH2CH2COOCH3 18 [ 12 1 19 OCH 3 21
C-I C-2 C-3 C-4 C-5
18
19
CHjCH2CH2CH2CH2CH2--C--CH2--CH2--C-- CH2CH2CH2CH2CH2CI'~CH2COOCH3
20
C-12 C-13 C-14 C-15
24.92 29.47 29.47 29.25
24.54 32.61 [ 59.81 C-9/-101' 59.64 | 57.80
C-7 C-8
C-2 C-3 C-4 C-5
34.08 24.32 29.25 29.25
C--CH 2 CH2CH2CH2 CH2CH2'C-'CNX~H~ 9 1 19 32.23 C-16 31.70
121
CH3CH2CH2CH 2CH2CH2CH 2CH2--C 18 10 C-I 174.11 C-6 29.42 C-II
20
CHjCH2CH2CH zCH2CH2--C-- CI-I2--CH2CH2CH 2CH2CH2CH 2CH2CH2CH2COOCH; 18 12 I 19 C-I 174.28 C-6 629.42 C-11 34.29 C-16 31.64 C-2 34.13 C-7 29.42 C-12 59.54 C-17 22.59 C-3 24.97 C-8 29.42 C-13 34.29 C-18 14.03 C-4 29.25 C-9 29.42 C-14 24.86 C-19 51.36 C-5 29.42 C-10 24.86 C-15 29.80 C-2O 52.50
13C-NMR (ppm)
Physical properties of 2,2'-(bi) oxirane derivatives of C,, fatty esters (1, 2, 3) and a hydrolysed product (4).
TABLE I
196
chemical environments experienced by these nuclei, resulting from the presence of different configurational isomers. The ~3C-NMR spectrum of the 2,2'-oxirane fatty esters gave typical signals for the carbon nuclei of the oxirane system between 40 and 70 ppm. In the mono oxirane fatty ester (compound 1) signals appearing at 52.50 and 59.54 ppm corresponded to the methylene carbon and the quaternary carbon atom of the oxirane, respectively. Both shifts were confirmed by the off-resonance technique [12], whereby the signal due to the methylene carbon was split into a distinct triplet, and the signal due to the quaternary carbon remained as a singlet. Within this range was also found the shift for the methoxy carbon of the ester (--COO_CH3) group at 51.36 ppm. The ~3C-NMR spectrum of compound 2 gave a total of 8 signals between 40 and 70 ppm. Discounting the signal at 51.36 ppm for the methoxy carbon of the ester group, the remaining signals appeared at (intensity given in bracket relative to methoxy carbon signal of the ester group at 51.36): 49.51(0.5); 49.62(0.55); 50.71(0.75); 57.80(0.8); 59.64(0.53); and 59.81(0.25) ppm. The first three signals formed triplets, while the remaining three signals remained singlets by the off-resonance technique. The complexity of the spectrum was apparently due to the presence of the various configurational isomers in compound 2, whereby the contribution of the alpha neighbouring effects of the two oxirane rings towards each other resuited in the different chemical shifts. For compound 3, where the oxirane systems were two methylene groups apart, the 13C-NMR spectra showed four signals between 40 and 70 ppm range. The ester methoxy carbon appeared at 51.30 (1.0 intensity). The signals at 52.11(0.8) and 52.28(0.75) ppm gave triplets, while the signal at 58.89(1.05) ppm remained as a singlet by off-resonance technique. The cause of the different chemical shifts of the methylene carbon nuclei in compound 3 giving rise to two signals (52.11 and 52.28 ppm), was probably due to a long-range effect of the oxygen in one oxirane on the methylene carbon of the other oxirane ring via a possible six-membered cyclic system,
as illustrated below: CH2--O ....... CH~--O
\/ c /\
R~
\/ c /\
CH2--CH
R 1 = CH3(CH2)5;
2
R2
R 2 = (CHa);,COOCH 3
Difficulties remained in the interpretation of the various chemicals shifts, unless pure isomers were produced and studied in isolation for both compounds (2) and (3). The mass spectral analysis of compound 1 provided three significant fragments, allowing the position of the oxirane system to be determined from its fragmentation pattern:
O•CH2 CH3(CH 2 ~ - t - C ~ C H 2 - - C H 2 T I I I I re~z= 8 5 ( 4 9 . 6 % ) - - . - J I I 127 (22.9%) . . . . J
155 (22.9%)
CH3(CH2),-C.x
CH2)eCOOCH 3 I I I 4 3 (CH3C-= O ÷, 1 0 0 % ) I f
/CH 2 CH 2
However, the mass spectra of compounds 2 and 3, although giving a base peak (100°70) for the M-31 fragment, left the rest of the fragments in the low mass unit region, due to extensive rearrangements involving the oxirane systems in the excited molecular species. The mass spectral analysis therefore could provide no clear indication as to the locations of the oxirane rings in a bi-oxirane fatty ester.
Effect o f acids on methyl 12-(2,2'-oxiran-2-yl)octadecanote (1) Treatment of compound 1 with boron trifluoride--methanol complex or mineral acids in methanol gave exclusively the corresponding methoxy-carbinol derivatives (4) (Scheme 1). The infrared analysis of compound 4 confirmed the presence of a hydroxy group (3400 cm-]). The
197
tH-NMR spectrum provided evidence for the methoxy group (3.186), the methylene group of the carbinol system (3.476), while the shift for the methoxy protons of the ester group appeared at 3.66d. The ~3C-NMR results showed four significant signals between 40 and 80 ppm. The methoxy carbon of the ester group appeared as expected at 51.25 ppm, while the carbon of the methoxy group attached at C-12 position gave a signal at 48.59 ppm (quartet by off-resonance technique). The carbon shift of the methylene carbon of the carbinol group appeared at 63.87 ppm, while the quarternary carbon (C-12) was shifted to 78,88 ppm. Both signals were confirmed by offresonance techique, showing a triplet for the signal at 63.87 ppm and a singlet for that appearing at 78.88 ppm. The mass spectral analysis of derivative 4 provided a significant fragment at m / z = 327 (M-31, 100070, base peak), and a range of insignificant small mass unit fragments. The ring opening reaction was performed by using boron trifluoride--methanol complex, dilute sulfuric acid or hydrochloric acid in methanol. In all instances the major product isolated was identified as compound 4. These results indicated that the reaction favored ring opening of the protonated oxirane system between the quaternary carbon and the oxygen of the oxirane, forming a tertiary carbonium ion intermediate, which was attacked by methanol. In the reactions where either dilute sulfuric acid or hydrochloric acid was used, water in the reaction mixture did not attack the tertiary carbonium intermediate as no corresponding dihydroxy derivative could be isolated at the end of the reaction period. A plausible mechanism for this reaction is given below: +
I HOCH CFI2OH R~--~ --R 2 R~ = CHa(CH2)s; R2 = {CH2)~oCOOHa
OCH 3 4
Experimental Methyl 9,12-epoxy-9,11-octadecadienoate and 9,12-dioxo-octadecanoate were prepared as described earlier [13,14]. Methyl 9,10-dioxo-octadecanoate was obtained from oleic acid by the procedure described by Jensen and Sharpless [15]. Trimethylsulfonium methylsulfate was prepared from dimethylsulfide and methylsulfate in acetone [10]. All solvents were purified by distillation and dried. Flash column chromatographic separation was carried out using silicic acid (Merck, no. 8764) and mixtures of petroleum ether/diethyl ether were used as eluant according to the method described by Still et al. [11]. GC/ MS analyses were conducted on a Hewlett Packard HP5970 gas chromatograph fitted with a Mass Selective DetectorT M and a 30-m OV-101 capillary column. ~H- and ~3C-NMR spectra were obtained on a JEOL FX90 (90 MHz) instrument. Methyl 12-oxo-octadecanoate
A mixture of methyl ricinoleate (3.89 g, 12.4 mmol), methanol (15 ml) and palladium on charcoal (5070, 70 mg) was shaken in an atmosphere of hydrogen for 1 h at 5 atm pressure. The mixture was filtered and the solvent removed under reduced pressure to give methyl 12hydroxy-octadecanoate (3.70 g, 95070). The latter compound was dissolved in diethyl ether (100 ml) and chromic acid (10 ml, prepared from 20 g Na2Cr207, 28 g H2SO4 and 65 ml water) was added over 15 min. The ethereal layer was isolated and washed with water (30 ml). The oxidation process was repeated with a further 10 ml of chromic acid. The ethereal layer was then washed with water (2 x 30 ml), dilute sodium bicarbonate (1007o aq., 30 ml) and water (30 ml). Purification by flash column chromatography furnished methyl 12-oxo-octadecanoate (3.17 g, 84070). GLC, ECL = 19.7 (OV-101); infrared (cm-l), 1720 (s), 1745 (s); IH-NMR (6), 0.88 (3H), 1.2--1.6 (24H), 2.0 (4H), 2.30 (2H), 3.66 (3H).
198
General procedure for the preparation o f oxirane derivatives ( 1, 2, 3) A mixture of the mono or dioxo fatty ester (0.39 mmol), trimethylsulfonium methylsulfate (0.95 mmol), aqueous sodium hydroxide (50o70, by wt., 4 ml) and dichloromethane (20 ml) was refluxed for 48 h. Water (30 ml) was added to the cooled reaction mixture. The organic phase was isolated and the aqueous layer extracted with diethyl ether (3 × 50 ml). The ethereal extract was washed with water (3 x 20 ml) and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the product purified by flash column chromatography (20 g of silicic acid, petroleum ether/diethyl ether, 3:2, by vol., 30 × 15 ml fractions). The physical properties of the oxirane derivatives are summarized in Table I.
Ring opening reactions involving methyl 12(2,2'-oxiran-2-yO- octadecanoate (1) Reaction with boron trifluoride--methanol complex A mixture of compound 1 (0.3 g, 0.91 mmol) and boron trifluoride--methanol complex (3°70, I0 ml) was refluxed for 15 min. Water (30 ml) was added to the reaction mixture and the product extracted with diethyl ether (2 x 20 ml). The ethereal extract was washed with water (30 ml) and dried over anhydrous sodium sulfate. Purification by flash column chromatography gave methyl 12-methoxy-12-carbinol-octadecanoate (4, 0.31 g, 95°7o).
Reaction with dilute hydrochloric acid in methanol A mixture of compound 1 (0.3 g, 0.91 mmol), dilute hydrochloric acid (2 M, 2 ml), methanol 10 ml and tetrahydrofuran (12 ml) was stirred at room temperature for 4 h. Water (20 ml) was added and the product isolated. Chromatographic purification gave compound 4 (0.26 g, 57O70).
Acknowledgements We thank Mr. Nelson Pang, Hong Kong Baptist College, for conducting the GC/MS analyses, the Lipid Research Fund and the Research Grant Committee of the Hong Kong University for financial support.
References 1 2 3 4 5 6 7 8 9 10 11
Reaction with dilute sulfuric acid in methanol A mixture of compound 1 (0.45 g, 1.26 mmol), dilute sulfuric acid (2 M, 4 ml) and methanol (20 mi) was refluxed for 2 h. The reaction product was isolated in the usual way and chromatographic purification gave compound 4 (0.26 g, 57o70).
12 13 14 15
F.D. Gunstone and F.R. Jacobsberg, Chem. Phys. Lipids, 9 (1972) 26--34. C.Y. Hopkins and M.J. Chisholm, J. Amer. Oil Chem. Soc., 37 (1960) 682--684. C.R. Smith Jr., Prog. Chem. Fats Other Lipids, 11 (1971) 137--177. M.S.F. Lie Ken Jie and C.H. Lam, Chem. Phys. Lipids, 20 (1977) 1--12. J. Gorzynski Smith, Synthesis, (1984) 629--656. F.D. Gunstone and G.G. Abbot, Chem. Phys. Lipids, 7 (1971) 290--302. F.D. Gunstone and H.R. Schuler, Chem. Phys. Lipids, 15 (1975) 174---188. M.S.F. Lie Ken Jie and F. Ahmad, J. Am. Oil Chem. Soc,, 60 (1983) 1783--1785. F.D. Gunstone and R.C. Wijesundera, Chem. Phys. Lipids, 24 (1979) 193--208. P. Mosset and R. Gree, Synth. Commun., 15 (1985) 749--757. W.C. Still, M. Khan and A. Mitra, J. Org. Chem., 43 (1978) 2923--2925. J.B. Stothers, Carbon-13 NMR Spectroscopy, Academic Press, New York, 1972, p. 38. M.S.F. Lie Ken Jie, H.W.M. Chan, J.S.M. Wai and S. Sinha, J. Am. Oil Chem. Soc., 58 (1981) 705--706. M.S.F. Lie Ken Jie and S. Sinha, Chem. Phys. Lipids, 28 (1981) 99--109. H.P. Jensen and K.B. Sharpless, J. Org. Chem., 39 0974) 2314.
193
Synthesis of 2,2'-oxirane fatty esters and a study of some of their physical properties
Marcel S.F. Lie Ken Jie and Y.F. Zheng Department of Chemistry, University of Hong Kong, Pokfulam Road (Hong Kong) Received August 3rd, 1987; revised and accepted September 9th, 1987) Two-phase methylene transfer reaction involving methyl 12-oxo-octadecanoate and trimethylsulfonium methysulfate gave methyl 12-(2,2'-oxiran-2-yl)-octadecanoate,while methyl 9,10- and 9,12-dioxooctadecanoate furnished the corresponding methyl 2,2'-bioxiran-2-yl-octadecanoatederivatives. The methylene protons of the 2,2'-oxirane system were characterized by a singlet signal at 2.57d (IH-NMR), and by signals at 52.50 and 59.54 ppm corresponding to the methylene and quaternary carbon atoms, respectively (13C-NMR). Acid-catalysed ring opening reaction facilitated bond rupture between the quaternary carbon and the oxygen of the 2,2'-oxirane system, furnishing the corresponding methoxy-carbinol derivative in the case of methyl 12-(2,2'oxiran-2-yl)-octadecanoate.
Keywords: 2,2'-oxirane; epoxy; fatty acid; synthesis; physical properties. Introduction
Results and discussion
Fatty acids containing epoxy groups o f the 2,3-oxirane type have been extensively studied, as such compounds occur in m a n y seed oils and are readily prepared f r o m ethylenic fatty esters by peracid epoxidation [1--4]. The usefulness o f epoxides in organic synthesis has been recently reviewed [5] and reactions involving epoxy fatty acids have led to m a n y interesting derivatives o f fatty acid [6,7]. However, no natural long chain fatty acid containing a 2,2'-oxirane structure has yet been described. In view of the important role played by epoxy groups, especially in the cyclisation reaction of diepoxy fatty esters to oxygen heterocyclic and furanoid fatty derivatives [8,9], this paper describes the synthesis o f 2,2'-oxirane fatty esters f r o m readily available keto fatty esters by means of the two-phase methylene transfer reaction described by Mosset and Gree [ 10].
Synthesis o f 2,2"-oxirane fatty esters (Scheme 1)
Correspondence to: Dr. M.S.F. Lie Ken Jie.
Reaction of methyl 12-oxo-octadecanoate with trimethylsulfonium methylsulfate and aqueous sodium hydroxide in methylene chloride gave compound 1 (580/o yield). This methylene transfer reaction was extended to methyl 9,10- and 9,12-dioxo-octadecanoate, which furnished the corresponding 2,2'-bioxirane derivatives (2,3) in 2107o and 80% yield, respectively (Scheme 1). During the extraction of the organic product with diethyl ether, no mineral acid was added to the reaction mixture in order to prevent hydrolysis of the acid-sensitive 2,2'-oxirane system. The ethereal extract was washed several times with water until neutral and the isolated 2,2'oxirane ester derivative purified by flash column chromatography [11]. The reaction also resulted in the production of about 20°7o of the sodium salt of the oxirane derivative. However, treatment of the aqueous layer with mineral acid caused ring opening of the oxirane system.
0009-3084/88/$03.50 © 1988 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
194 0 ^.-~) II (i) 58% H=4. [ R,--C--R 2 ~ .~C_
q-
O~ I -,~CH, .~C~
ilia) 95% (iib) 57% )
C,H20H R~-"-~--R=/
1
R3--C--C--R 4
•~
R3
4
--
R.
2
o RI_ Id_CH2CH2_~_R4
(i) 80%
,,<_Lc.,c.,_c%.
R~ = CH3{CH2)5; R2 = (CH2)~oCOOCH3; R3 = CH3{CH2)7; R4 = (CH2) 7 COOCH 3 + (i) (CHa)3SCH a SO~. NaOH/H20, CH=Cl2; (iia) BF3--CH3OH; (iib) H2SOJH20, CH3OH; (iic) HCI/H20, CH3OH, THF Scheme 1. Synthesis of 2,2'-(bi) oxirane derivatives from methyl oxo and dioxostearate (1,2,3) and hydrolysis product of methyl 12(2,2'-oxiran-2-yl)-octadeeanoate (4)
Physical properties of 2,2'-oxirane fatty esters (TableD. The TLC behavior of the 2,2'-oxirane fatty esters was similar to that of the more common 2,3-oxirane fatty esters, when chromatographed on silicic acid using a mixture of petroleum ether/diethyl ether (6:4, by vol.) as developer. The RI values of compounds 1, 2 and 3 were 0.6, 0.45 and 0.45, respectively. On a 2-m OV101 packed column, the GLC analysis of compound 1 gave a single peak with an equivalent chain length (ECL) value of 20.5, but compounds 2 and 3 furnished a broad hump indicative of a mixture of closely related isomers. When the analysis was conducted on a 30-m OV-101 capillary column, compound 2 separated into two partially overlapping peaks with ECL values of 21.75 and 22.0, while compound 3 gave four partially overlapping peaks with ECL values of 22.4, 22.6, 22.7 and 22.9. The GC/MS analysis of these overlapping peaks (taken at the
apex of each component for each set) gave almost identical fragmentation patterns with variations in fragment intensities only. From these data it appeared that compounds 2 and 3 consisted of a mixture of configurational isomers, which resulted from the attack of the carbonyl groups by the methylide ion from different directions during the methylene transfer reaction. The 2,2'-oxirane system was readily recognized by the appearance of a signal (singlet) at 2.576 in the proton NMR spectrum for the protons of the methylene of an isolated oxirane system, O--/CH2as in compounds 1 and 3. In the x / --C--
case of compound 2, where the two oxirane rings were situated alpha to each other, two signals (singlets) at 2.58 and 2.626 were observed. The cause of these different chemical shifts for the methylene protons of the oxirane rings was most likely attributed to the different
0.45
0.45
0.30
2
3
4
2.57
1.62 1 . 6 2
1.2--1.6
3.18
0.9 1.2--1.7 | 1.2--1.7 OCH 3
/
2.30
2.30
3.67
I CH3(CH2)5 --C--(CH2)9(CH2)gCH2~H3
CH2OH
3.47 2.12
1.2--1.6
3.66
0.9
3.62
(broad)
? cH2
2.57
2.30
CH3(CH2)s--C-- CH2--CH2--C--(CH 2 )6CH2COOCH3
2.57
1.2--1.5
C--(CH2)sCH 2 COOCHj
22.0~23.2
1.2--1.5
CH~(CH2)s--C 0.89
21.5--22.4
2.58 2.62
CH3ICH2)5 - C--(CH2)gCH 2 COOCH3 0.88 1.2--1.6 1.2--1.6 2.30 3.66
JH-NMR (d)
(broad
20. 5
GLC (OV-101) ECL
•PE40 = petroleum ether/diethyl ether (60:40, by vol.) as developer.
0.60
R!
PE40'
TLC
1
Compound
20
~ 21
22.64 14.09 J 50.71 C-19/-2O~t 49.62 49.51
C-17 C-18
174.00 34.02 24.92 29.42 29.42
C-6 C-7 C-8 C-9 C-10
2o
29.42 24.81 34.29 58.89 29.52
29.52 58.89 34.45 24.81 30.77
CH~OH I
C-11 C-12 C-13 C-14 C-15
12
9
C-16 31.80 C-17 22.59 C-18 14.03 C-19 51.30 C-2O/-21 J 52.28 1 52.11
I
C-1 C-2 C-3 C-4 C-5
174.17 34.02 24.92 29.09 29.09
C-6 C-7 C-8 C-9 C-10
29.36 29.47 29.47 29.90 23.08
C-II C-12 C.13 C-14 C-15
32.12 78.88 32.12 23.08 30.23
C-16 C-17 C-18 C-19 C-20 C-21
31.75 22.59 13.98 51.25 63.87 48.59
CH3CH2CH2CH2CH2CH2--C--CH2CH2CH 2 CH2CH2CH2CH2CH2CH2CH2COOCH3 18 [ 12 1 19 OCH 3 21
C-I C-2 C-3 C-4 C-5
18
19
CHjCH2CH2CH2CH2CH2--C--CH2--CH2--C-- CH2CH2CH2CH2CH2CI'~CH2COOCH3
20
C-12 C-13 C-14 C-15
24.92 29.47 29.47 29.25
24.54 32.61 [ 59.81 C-9/-101' 59.64 | 57.80
C-7 C-8
C-2 C-3 C-4 C-5
34.08 24.32 29.25 29.25
C--CH 2 CH2CH2CH2 CH2CH2'C-'CNX~H~ 9 1 19 32.23 C-16 31.70
121
CH3CH2CH2CH 2CH2CH2CH 2CH2--C 18 10 C-I 174.11 C-6 29.42 C-II
20
CHjCH2CH2CH zCH2CH2--C-- CI-I2--CH2CH2CH 2CH2CH2CH 2CH2CH2CH2COOCH; 18 12 I 19 C-I 174.28 C-6 629.42 C-11 34.29 C-16 31.64 C-2 34.13 C-7 29.42 C-12 59.54 C-17 22.59 C-3 24.97 C-8 29.42 C-13 34.29 C-18 14.03 C-4 29.25 C-9 29.42 C-14 24.86 C-19 51.36 C-5 29.42 C-10 24.86 C-15 29.80 C-2O 52.50
13C-NMR (ppm)
Physical properties of 2,2'-(bi) oxirane derivatives of C,, fatty esters (1, 2, 3) and a hydrolysed product (4).
TABLE I
196
chemical environments experienced by these nuclei, resulting from the presence of different configurational isomers. The ~3C-NMR spectrum of the 2,2'-oxirane fatty esters gave typical signals for the carbon nuclei of the oxirane system between 40 and 70 ppm. In the mono oxirane fatty ester (compound 1) signals appearing at 52.50 and 59.54 ppm corresponded to the methylene carbon and the quaternary carbon atom of the oxirane, respectively. Both shifts were confirmed by the off-resonance technique [12], whereby the signal due to the methylene carbon was split into a distinct triplet, and the signal due to the quaternary carbon remained as a singlet. Within this range was also found the shift for the methoxy carbon of the ester (--COO_CH3) group at 51.36 ppm. The ~3C-NMR spectrum of compound 2 gave a total of 8 signals between 40 and 70 ppm. Discounting the signal at 51.36 ppm for the methoxy carbon of the ester group, the remaining signals appeared at (intensity given in bracket relative to methoxy carbon signal of the ester group at 51.36): 49.51(0.5); 49.62(0.55); 50.71(0.75); 57.80(0.8); 59.64(0.53); and 59.81(0.25) ppm. The first three signals formed triplets, while the remaining three signals remained singlets by the off-resonance technique. The complexity of the spectrum was apparently due to the presence of the various configurational isomers in compound 2, whereby the contribution of the alpha neighbouring effects of the two oxirane rings towards each other resuited in the different chemical shifts. For compound 3, where the oxirane systems were two methylene groups apart, the 13C-NMR spectra showed four signals between 40 and 70 ppm range. The ester methoxy carbon appeared at 51.30 (1.0 intensity). The signals at 52.11(0.8) and 52.28(0.75) ppm gave triplets, while the signal at 58.89(1.05) ppm remained as a singlet by off-resonance technique. The cause of the different chemical shifts of the methylene carbon nuclei in compound 3 giving rise to two signals (52.11 and 52.28 ppm), was probably due to a long-range effect of the oxygen in one oxirane on the methylene carbon of the other oxirane ring via a possible six-membered cyclic system,
as illustrated below: CH2--O ....... CH~--O
\/ c /\
R~
\/ c /\
CH2--CH
R 1 = CH3(CH2)5;
2
R2
R 2 = (CHa);,COOCH 3
Difficulties remained in the interpretation of the various chemicals shifts, unless pure isomers were produced and studied in isolation for both compounds (2) and (3). The mass spectral analysis of compound 1 provided three significant fragments, allowing the position of the oxirane system to be determined from its fragmentation pattern:
O•CH2 CH3(CH 2 ~ - t - C ~ C H 2 - - C H 2 T I I I I re~z= 8 5 ( 4 9 . 6 % ) - - . - J I I 127 (22.9%) . . . . J
155 (22.9%)
CH3(CH2),-C.x
CH2)eCOOCH 3 I I I 4 3 (CH3C-= O ÷, 1 0 0 % ) I f
/CH 2 CH 2
However, the mass spectra of compounds 2 and 3, although giving a base peak (100°70) for the M-31 fragment, left the rest of the fragments in the low mass unit region, due to extensive rearrangements involving the oxirane systems in the excited molecular species. The mass spectral analysis therefore could provide no clear indication as to the locations of the oxirane rings in a bi-oxirane fatty ester.
Effect o f acids on methyl 12-(2,2'-oxiran-2-yl)octadecanote (1) Treatment of compound 1 with boron trifluoride--methanol complex or mineral acids in methanol gave exclusively the corresponding methoxy-carbinol derivatives (4) (Scheme 1). The infrared analysis of compound 4 confirmed the presence of a hydroxy group (3400 cm-]). The
197
tH-NMR spectrum provided evidence for the methoxy group (3.186), the methylene group of the carbinol system (3.476), while the shift for the methoxy protons of the ester group appeared at 3.66d. The ~3C-NMR results showed four significant signals between 40 and 80 ppm. The methoxy carbon of the ester group appeared as expected at 51.25 ppm, while the carbon of the methoxy group attached at C-12 position gave a signal at 48.59 ppm (quartet by off-resonance technique). The carbon shift of the methylene carbon of the carbinol group appeared at 63.87 ppm, while the quarternary carbon (C-12) was shifted to 78,88 ppm. Both signals were confirmed by offresonance techique, showing a triplet for the signal at 63.87 ppm and a singlet for that appearing at 78.88 ppm. The mass spectral analysis of derivative 4 provided a significant fragment at m / z = 327 (M-31, 100070, base peak), and a range of insignificant small mass unit fragments. The ring opening reaction was performed by using boron trifluoride--methanol complex, dilute sulfuric acid or hydrochloric acid in methanol. In all instances the major product isolated was identified as compound 4. These results indicated that the reaction favored ring opening of the protonated oxirane system between the quaternary carbon and the oxygen of the oxirane, forming a tertiary carbonium ion intermediate, which was attacked by methanol. In the reactions where either dilute sulfuric acid or hydrochloric acid was used, water in the reaction mixture did not attack the tertiary carbonium intermediate as no corresponding dihydroxy derivative could be isolated at the end of the reaction period. A plausible mechanism for this reaction is given below: +
I HOCH CFI2OH R~--~ --R 2 R~ = CHa(CH2)s; R2 = {CH2)~oCOOHa
OCH 3 4
Experimental Methyl 9,12-epoxy-9,11-octadecadienoate and 9,12-dioxo-octadecanoate were prepared as described earlier [13,14]. Methyl 9,10-dioxo-octadecanoate was obtained from oleic acid by the procedure described by Jensen and Sharpless [15]. Trimethylsulfonium methylsulfate was prepared from dimethylsulfide and methylsulfate in acetone [10]. All solvents were purified by distillation and dried. Flash column chromatographic separation was carried out using silicic acid (Merck, no. 8764) and mixtures of petroleum ether/diethyl ether were used as eluant according to the method described by Still et al. [11]. GC/ MS analyses were conducted on a Hewlett Packard HP5970 gas chromatograph fitted with a Mass Selective DetectorT M and a 30-m OV-101 capillary column. ~H- and ~3C-NMR spectra were obtained on a JEOL FX90 (90 MHz) instrument. Methyl 12-oxo-octadecanoate
A mixture of methyl ricinoleate (3.89 g, 12.4 mmol), methanol (15 ml) and palladium on charcoal (5070, 70 mg) was shaken in an atmosphere of hydrogen for 1 h at 5 atm pressure. The mixture was filtered and the solvent removed under reduced pressure to give methyl 12hydroxy-octadecanoate (3.70 g, 95070). The latter compound was dissolved in diethyl ether (100 ml) and chromic acid (10 ml, prepared from 20 g Na2Cr207, 28 g H2SO4 and 65 ml water) was added over 15 min. The ethereal layer was isolated and washed with water (30 ml). The oxidation process was repeated with a further 10 ml of chromic acid. The ethereal layer was then washed with water (2 x 30 ml), dilute sodium bicarbonate (1007o aq., 30 ml) and water (30 ml). Purification by flash column chromatography furnished methyl 12-oxo-octadecanoate (3.17 g, 84070). GLC, ECL = 19.7 (OV-101); infrared (cm-l), 1720 (s), 1745 (s); IH-NMR (6), 0.88 (3H), 1.2--1.6 (24H), 2.0 (4H), 2.30 (2H), 3.66 (3H).
198
General procedure for the preparation o f oxirane derivatives ( 1, 2, 3) A mixture of the mono or dioxo fatty ester (0.39 mmol), trimethylsulfonium methylsulfate (0.95 mmol), aqueous sodium hydroxide (50o70, by wt., 4 ml) and dichloromethane (20 ml) was refluxed for 48 h. Water (30 ml) was added to the cooled reaction mixture. The organic phase was isolated and the aqueous layer extracted with diethyl ether (3 × 50 ml). The ethereal extract was washed with water (3 x 20 ml) and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the product purified by flash column chromatography (20 g of silicic acid, petroleum ether/diethyl ether, 3:2, by vol., 30 × 15 ml fractions). The physical properties of the oxirane derivatives are summarized in Table I.
Ring opening reactions involving methyl 12(2,2'-oxiran-2-yO- octadecanoate (1) Reaction with boron trifluoride--methanol complex A mixture of compound 1 (0.3 g, 0.91 mmol) and boron trifluoride--methanol complex (3°70, I0 ml) was refluxed for 15 min. Water (30 ml) was added to the reaction mixture and the product extracted with diethyl ether (2 x 20 ml). The ethereal extract was washed with water (30 ml) and dried over anhydrous sodium sulfate. Purification by flash column chromatography gave methyl 12-methoxy-12-carbinol-octadecanoate (4, 0.31 g, 95°7o).
Reaction with dilute hydrochloric acid in methanol A mixture of compound 1 (0.3 g, 0.91 mmol), dilute hydrochloric acid (2 M, 2 ml), methanol 10 ml and tetrahydrofuran (12 ml) was stirred at room temperature for 4 h. Water (20 ml) was added and the product isolated. Chromatographic purification gave compound 4 (0.26 g, 57O70).
Acknowledgements We thank Mr. Nelson Pang, Hong Kong Baptist College, for conducting the GC/MS analyses, the Lipid Research Fund and the Research Grant Committee of the Hong Kong University for financial support.
References 1 2 3 4 5 6 7 8 9 10 11
Reaction with dilute sulfuric acid in methanol A mixture of compound 1 (0.45 g, 1.26 mmol), dilute sulfuric acid (2 M, 4 ml) and methanol (20 mi) was refluxed for 2 h. The reaction product was isolated in the usual way and chromatographic purification gave compound 4 (0.26 g, 57o70).
12 13 14 15
F.D. Gunstone and F.R. Jacobsberg, Chem. Phys. Lipids, 9 (1972) 26--34. C.Y. Hopkins and M.J. Chisholm, J. Amer. Oil Chem. Soc., 37 (1960) 682--684. C.R. Smith Jr., Prog. Chem. Fats Other Lipids, 11 (1971) 137--177. M.S.F. Lie Ken Jie and C.H. Lam, Chem. Phys. Lipids, 20 (1977) 1--12. J. Gorzynski Smith, Synthesis, (1984) 629--656. F.D. Gunstone and G.G. Abbot, Chem. Phys. Lipids, 7 (1971) 290--302. F.D. Gunstone and H.R. Schuler, Chem. Phys. Lipids, 15 (1975) 174---188. M.S.F. Lie Ken Jie and F. Ahmad, J. Am. Oil Chem. Soc,, 60 (1983) 1783--1785. F.D. Gunstone and R.C. Wijesundera, Chem. Phys. Lipids, 24 (1979) 193--208. P. Mosset and R. Gree, Synth. Commun., 15 (1985) 749--757. W.C. Still, M. Khan and A. Mitra, J. Org. Chem., 43 (1978) 2923--2925. J.B. Stothers, Carbon-13 NMR Spectroscopy, Academic Press, New York, 1972, p. 38. M.S.F. Lie Ken Jie, H.W.M. Chan, J.S.M. Wai and S. Sinha, J. Am. Oil Chem. Soc., 58 (1981) 705--706. M.S.F. Lie Ken Jie and S. Sinha, Chem. Phys. Lipids, 28 (1981) 99--109. H.P. Jensen and K.B. Sharpless, J. Org. Chem., 39 0974) 2314.