CONSTITUESTS O F WEST A F R I C W hIEDICINA1, PLANTS. XXV11.l ALKALOIDS O F RHIGIOCARY.4 RACEMIFERA AN D STEP H A -YIA D I S K LA GE I D. DTT.UM.+BADL-, J. S. K. Ain>f, S . F. W I T H E Rand S S . 0 . AGTEXISG D e p a r t m e n t of Pharmaceutical C h e m i s t r y , Faculty of P h a r m a c y , Gniversity of Science and Technology, K z i m a s i , Ghana, TT7estA f r i c a and A. AI. ATEYA,AI. 31.E L - h Z I , J. E. KSAPP,D. J . SLATKIK and P. L. SCHIFF, JR.* D e p a r t m e n t of Pharmacognosy, School of P h a r m a c y , Cnir'ersity of P i t t s b u r g h , P i t t s b u r g h , Pennsylcania 15861 .iBsTRAcT.-Rhigiocarya racemqera and Stephania Dinklagei are menispermaceous climbing shrubs of the forests of Ghana and other parts of West Africa which have been used natively as medicinal agents. Chromatography of an extract of the roots of R . racemifera afforded the alkaloids 0-methylflavinantine (l),liriodenine (2), palmatine 13), menisperine (.l=methylisocorydine) (4) and magnoflorine ( 5 ) . -4similar treatment of an estract of the stems of S. Dinklagei afforded the alkaloids S-methylglaucine (7) and .V-methylcorydine ( 9 ) .
Rhigiocarya racemifera lliers (Menispermaceae) is a climbing shrub indigenous to the forests of Ghana and other parts of West -Africa (1). The roots have been added to palm n-ine while extracts of the plant have been used medicinally as nasal drops and a < an aphrodisiac (1). The only reference to this genus in the literature cited the isolation of the niorphinandienone alkaloid 0-methylflavinantine (1) from an extract of the roots ( 2 ) . The analgeaic activity of O-methylflavinantine ha. been established (3), and further pharmacological investigation of this alkaloid continues (4). It was decided t o undertake a phytochemical investigation of thii species in order to isolate additional compounds with potential biological activity and to further our knowledge of the constituents of this genus. This paper is to report the re-isolation of 0-methylflavinantine (1) and the isolation of the oxoaporphine alkaloid liriodenine (2), the protoberberine alkaloid palmatine (3), and the aporphine alkaloids meniiperine (S-niethylisocorydine) (4) and niagnoflorine ( 5 ) from extracts of the roots of R. racemifera. The dried, powdered roots ivere extracted with dilute acetic acid, and the aqueous acidic extract \vas alkalinized with ammonium hydroxide and extracted with chloroform. The chloroform extract was chromatographed over alumina in ether to afford 0-methylflavinantine (1) and liriodenine (2). Both alkaloids n-ere identified by direct comparison (uv, ir, nmr, ms, mp, mmp) n ith authentic reference samples. The alkaline solution remaining after extraction of the nonquaternary alkaloids was re-acidified n-ith hydrochloric acid, and the quaternary bases n-ere precipitated with Mayer's Reagent. The crude quaternary alkaloid complex was filtered, washed with water, di.solved in methanol. and treated n itli an anion exchange resin (iodide). After eschange, the yuaternar- alkaloid iodide mixture x a i chromatographed over silica gel in chloroform. Elution n itli 2cc methanol in chloroform afforded planiatine iodide (3), and elution with 4qc methanol in chloroform gave meniiperine (S-methylibo'Previous Paper: Dnunia-Badu, D., .J. S. K. A>-im,0. Rexford, -1.11.-1teya, D . J . Slatkin, J . E. Knapp and P. L. Schiff, J r . 1979. Constituents n i West .ifrican Medicinal Plants. S I T - I . dlkaloids of h~olobopetcllnnio ~ i r i r i i l ~ ~ uPh?.iocheiiiis!r?., ~n. -1ccepted for publication. *To Thorn inquiries should he directed.
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1
2
N
h/
R
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3
N
R,-CH,, R,=OH, R,-H
5 R,-R3-H, R,ZOH
N
7
N
R1=CH,,R,-H, R3:OCH3
9 Rl- H I RZ-OCH, R3- H N
CH30
R3 6 R,-CH,, R,=OH, R,-H
ILr
8 R,~CH~,R,'H,R,=OCH~ 10 R1- H , R,'OCH3, R3-H
U
N
corydine) iodide (4). These alkaloids were identified by direct comparison (uv, ir, nmr, ms, mp, mmp) with authentic reference samples. (Menisperine iodide was prepared by the addition of methyl iodide to an acetone solution of ibocorydine (6)). Elution with 47, methanol in chloroform gave magnoflorine iodide (3), identified by direct comparison (uv, ir, ms, mp, mmp) with an authentic reference sample. Elution with 8% methanol in chloroform afforded trace amounts of
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another base RRQB-3B; its identity is unknonn pending the isolation of additional quantities. Liiiodenine (2), the first oxoaporphine alkaloid to be icolated from a natural -ource, was initially obtained from the lieartn ood of the J ellon poplar tree. Liriodeitdroiz tiilzpzjera L. (Xagnoliaceae) in 1960 ( 5 ) It. structure n a5 subsequently correctlj- a-igned shortly thereafter ( 6 ) . Liriodenirie has demonstrated a cytotoxic activity again-t the 9-BB cell culture (7) and has been isolated from different genera in the families Annonaceae. Araceae. Eupomaticaceae. Lauraceae, llagnoliaceae, Jleni-permaceae. Monimiaceae. SJmphaceae. Papaveiaceae. Rhanniaceae and Rutaceae ( 8 , 9). Palniatine (3) is a rather c o m m o n l ~ occurring protoberberine alkaloid from selected genera in the fnmilie- Lliinonaceae, Berberidaceae. Convolvulaceae, Fumariaceae, Lauraceae, Neni-permaceae. Papaveraceae. Ranunculaceae and Riitacene (10. 11). Palniatiiie 11-a- found to po'-e+ antiarrhj thniic, poqitire inotropic. adrenocorticotropic, anticlioline-terase. analgesic and bactericidal propertie; (12). Nenisperme (S-meth:, lisocorydine) (4) is a quaternary aporphine alkaloid n hich ha- been isolated from certain genera of the families Annonaceae. -4riitolochiaceae. Berberidaceae, Lauraceae. Menispermaceae, Papaveraceae and Rutaceae (9. 13). Administration of menisperine chloride (-\--metliyli~ocor\dine chloride) t o animals produced apnea arid cardiac failure. -In increa-e in excitability n a s observed in rabbits nliile a decrease n a s -een in rats (14). JIenisperine iodide (-\--nieth!-lisocorydiiie iodide) hac been fourid to exert a hj-poten+-e effect on anesthetized clog-. block neural transmission through feline cuperior cervical ganglia and. in large doses, block neuromuscular transmission in dogs and rabbits (1.5). llagnofloriiie (5) is perhaps the most n-idely distributed naturally occurring quatern:iry aporphine alkaloid. I t hac been found in numerouq genera of the families hnnonaceae, dristolochiaceae, Berberidaceae, Euphorbiaceae, Magnoliaceae. llenicpermaceae. Ranunculaceae and Rutaceae (16, 17). Nagnoflorine has been -1ionn to exert a Iijpotensire effect and a curare-like activity in animals (15). This i. the first reported isolation of liriodenine, palmatine and menisperine from the genus Rhigzocarya and, accordingly, the first reported isolation of oxoaporphine. protoberberine and aporphine alkaloids within this genuStephaiua Diiiklagei (Engl.) Diels (lleni-permaceae) ic a climbing shrub of the deciduouq foreqts of both East and Kest Africa (18). The roots and .terns h a r e been used medicinally in Ghana in the treatment of menorrhagia and as a vermifuge, an analgedc, an aphrodisiac and a sedatire (18). The leaves of the plant are used in folkloric medicine in the treatment of infertilit? in the female and impotence in the male (19). The stemq have also been used as a fish poison (16). Sumerous phenylalanine-tyrosine derived alkaloids of the benzylisoquinoline, bicbenzj lisoquiiioline, proaporphine, aporphine. osoaporphine, protoberberine, and hasubanail type have been isolated from var) ing Stephariia specie3 (20-25). early examination of extracts of 5'. Dinklagei reeulted in the isolation of an unknon n alkaloid de-ignated dinklageine (26). Later. a mixture of the aporphine alkaloid- isocor? dine and dicentrine were isolated from the Same species ( 2 i ) . Allboutten J ear- ago, cor! dine, isocorydine, and roemerine TT-ere icolated and five other alkaloid- detected in extracts of S.Dinklaget (2s). Finally, in 1974. Slatkin et a l . reported the ipolation of corydine, norcorydine, steporphine, Gtepharine, and the nen alkaloid -tephalagine from extracts of the stems (29). It was decided t o
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undertake an investigation of the quaternary alkaloids of this plant in order to complement our study of the nonquaternary bases (29) and to seek a source of compounds of potential biological or phytochemical importance. The extraction, fractionation, and preparation of a crude llayer’s quaternary complex from the stems of the plant was the same as that described earlier in this paper for R. racemijera. The JIayer’s quaternary complex was converted to a quaternary chloride mixture via an anion exchange resin. This mixture was chromatographed over alumina in chloroform. Elution with 25y0 methanol in chloroform afforded S-methylglaucine chloride ( 7 ) , which was converted to the iodide via anion exchange resin, and identified by direct comparison (uv, ir, ms, mp, mmp) w-ith an authentic reference sample (prepared by treating an acetone solution of glaucine (8) with methyl iodide). Continued elution n-ith the same solvent gave S-niethylcorydine chloride (9), which was identified in a like manner by conversion t o the iodide via anion exchange resin and direct comparison (uv, ir, nmr, ms, mp, mmp) with an authentic reference sample (prepared by treating an acetone solution of corydine (10) with methyl iodide). Finally, continued elution with the same solvent afforded a small quantity of a yet unidentified alkaloid, designated SDQ-3. To our knom-ledge, this is the first reported occurrence of the quaternary aporphine S-methplglaucine ( 7 ) as a naturally occurring alkaloid. Glaucine (8), the tertiary analogue of S-methylglaucine, has been isolated from selected genera of the families Annonaceae, Lauraceae, llagnoliaceae, Papaveraceae and Ranunculaceae (30). T o our knowledge, no reports of the pharmacological properties of S-methylglaucine have appeared in the literature, but glaucine has been shov-n to induce hypotension and inhibit respiration in cats (15). I n addition, glaucine has adrenolytic, antitussive, and hypotensive effects in cats and rats (15). S-l\Iethylcorydine (9) has been previously isolated from Fagara itigresceizs (Rutaceae) (31, 32), Polyathia oliceri (Annonaceae) (33), and Kolobopetalum auriculatum (llenispermaceae) (34). S-Nethylcorydine iodide has been shown to decrease the blood pressure of anesthetized dogs, block transmission of nerve impulses through the superior cervical ganglia of cats and, in large doses, block neuromuscular transmission in frogs and rabbits (15). To our knowledge, this is the first reported iqolation of .l--methylcorydine from the genus Stephania. PLAXTM A T E R I A L . - Tplant ~ ~ material used in this study was collected in Ghana in 1977. Voucher specimens are on deposit at the Faculty of Pharmacy, University of Science and Technology, Kumasi, Ghana.‘ The leaves, stems, and roots were separated, dried, and ground to a coarse powder. Welting points were taken on a Thomas-Hoover apparatus or a Fisher-Johns Apparatus and are uncorrected. The uv spectra were obtained on a Perkin-Elmer model 202 recording spectrophotometer in methanol and the ir spectra --ere determined on a Perkin-Elmer model 257 recording spectrophotometer in KBr pellets. The nmr spectra were recorded in deuterated chloroform (unless otherwise designated) on a Hitachi Perkin-Elmer model R-24 high resolution spectrometer x-ith tetramethylsilane as internal standard and chemical shifts recorded in 6 (ppm) units. The mass spectra n-ere taken with a LKB-9000 mass spectrometer. The optical rotations were with a LKB-9000 mass spectrometer. The optical rotations were measured on a Perkin-Elmer model 241 polarimeter. Silicic acid (100 mesh) (RIallinckrodt), silica gel ,G (Camag or BDH) and alumina (neutral) (Spence) n-ere used for column chromatography while silica gel G (Camag) was used for thin-layer chromatography. All solvents were evaporated under reduced pressure at 40”. *The plant material was collected and identified by Mr. K . Obeng-Darko (F.L.S.) of the Faculty of Agriculture, University of Science and Technology, Kumasi, Ghana, West Africa.
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P.-IRT 1-Rhigiocarya
EXTRACTIOS, FR.ACTIOSATIOS
12;
racemqera
dried rOOtS (2 kgi O f R h i g i o c a r j a racemifera Miers (Rlenispermaceae) %-ere percolated with aqueous acetic acid ( 8 5 ) (4 liters) for 24 hours and filtered. The process --as repeated three more times and the filtrates combined, alkalinized with conc SHdOH t o p H 9, and extracted with chloroform (10 liters) (3s). The chloroform extracts were combined, dried (anhydrous Ka?S04),filtered, and evaporated t o afford a dark residue (11 g). This residue was dissolved in chloroform, adsorbed onto alumina (25 g), and chromatographed over a column of alumina (150 g) in diethyl ether. . i S D CHRo~fAToGRAPHl-.-Po~-dered
ISOL-ATIOS OF 0-METHYLFLAYI -TISE (1).-Elution of the column with diethyl ether (2 liters) afforded a residue (1.6 g) ich upon treatment with diethyl ether or methanol, gave 0-meth:-lflavinantine (1) (1.05 g) as white feathery needles, mp 1'24-26", [c~]*~D-10'(c=0.29 in MeOHj, identical by direct comparison (uv, ir, nmr, ms, mp, mmp) with an authentic sample (21, I~OL.ATIOS OF LIRIODESISE (2).-Continued elution with diethyl ether (2 liters) gave a residue (110 mg) which, on treatment with methanol, afforded dark yellon- needles of liriodenine (2) (85 mgj, mp 263-65", identical by direct comparison (uv, ir, ms, mp, mmp) with an authentic sample (35). PREP.iR.ATIOS OF THE QCATERKARY COMPLEX A S D CHROU.ATOGR.APHi..-The alkaline SOlUtiOn remaining after extraction of the non-quaternary alkaloids R-ith chloroform was acidified t o pH 2 wirh conc. HCl and treated with an excess of hIayer's Reagent (36) until precipitation ceased. The crude quaternary alkaloid complex was filtered by suction, x-ashed with H?O, dissolved in methanol-water (3:2) (1 liter) and passed over an anion exchange resin column (IR-i-401S [Iodide])j (150 9). The column was rinsed with additional methanol-m-ater 13:2) (600 ml), and the eluate and rinsings were combined and evaporated t o leave a dark residue (40 g) of crude quaternary alkaloid iodide salts. The residue was dissolved in methanol (ZOO ml), adsorbed onto silica gel (80 g) in chloroform, and chromatographed over silica gel (250 g) in chloroform.
ISOL.ATIOS OF PALMATISE IODIDE (3) .-Elution of the column with chloform-methanol (98:2) (200 mlj afforded a residue. Treatment of this residue with methanol gave yellow needles of palmatine iodide (3) (60 mg), mp 227-29', identical to an authentic sample (37) bg a direct comparison I'UV, ir, nip, mmp). ISOLATIOS OF MESISPERISE IODIDE (4) .-Elution of the column with chloroform-methanol (96:4) (400 ml) afforded a pale b r o m residue, which on treatment with methanol gave white needles (82 mg) of menipserine iodide (4), mp 222-24" (after darkening a t 215") (lit. 219" (38)j ; [a]:oD+134" (c=0.67 in MeOH) (lit. +139" (hleOH) (38)); ir, vmax (KBr) 3210, 3010, 2970, 2930, 2830, 1595, 1470, 1425, 1230, 1117, 1045, 1003 and 810 cm-l: uv Xmas (MeOH) 223 nm (log t 4.70), 272(4.26) and 304(3.91): nmr, dmso-ds . 2.90(s, 3H, 'SCH,): 3.66(s, 3H, OCH,), 3.78(s, 3H, OCH,), 3.85(s, 3H, OCH,), 6.95(s, ZH, ArH) and 7.03(s, l H , ArH); ms, hl- m,le 356 (ls), 355(2), 342(9), 341133), 328(10), 284(10), 283(11), 270(67), 255(24), 212Cl8),. 142(100), 127138), 59(27) and 58(96) identical t o an authentic sample prepared from isocorydine b y direct comparison (uv, ir, ms, mp, mmp). PREPARATIOS O F MESISPERISE IODIDE (12'-METH5-LSIOCORYDISE
IODIDE)
(4)
FROM I S O C O R T D I S E
(6).-To a solution of iosocorydine (6) (8 mg) (39) in acetone (3 ml) x a s added methyl iodide (0.2 ml). rifter standing overnight a t room temperature, the resulting granular precipitate was filtered by suction and washed n-ith acetone t o yield I~~-methylisocorydine iodide imenisperine iodide) ((4) (7 mg), mp 216'.
ISOL-~TIOS OF %i.iGsOFLoRIsEIODIDE ( 5 ) .-Continued elution n-ith chloroform-methanol (96:4) (400 ml) afforded a crystalline residue. Treatment of this residue with methanol gave magnoflcirine iodide ( 5 ) as x-hite rods (%rng), mp 249-50' (after darkening a t 230"), ja]**~+198" (c=O.A5 in MeOH) identical to an authentic sample (40) b5- direct comparison (uv, ir, nmr, ms, mp, mnipj. I S O L ~ T or I ORRQB-3B.-ElutiOn S with chloroform-methanol (92:8) (200 ml) afforded a small amount ( 2 mg) of an uncharacterized alkaloid, designated RRQB-3B, mp. 185-95' islow decomp. 1 . P-IRT 2-Steplrniiia Dinklagei EXTIUCTIOS, FRICTIOS.ATIOS AID CHRo~.r.AToGR.~PHl-.-Pox-dered, dried stems (1.5 kgj of Stepha?ric; Dinklagei (Engl.j Diels (lknispermaceae) w r e percolated with aqueous acetic acid iGr,) (3 liters) for 24 hours and filtered. The process was repeated three more times, and the 5.imberlite ion-eschange resin, Jlallinckrodt, St. Louis, RIO.
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filtrates were combined, alkalinized with conc. ",OH t o pH 9, and extracted with chloroform (9 liters) (3x). The chloroform extracts were combined, dried (anhydrous N a 2 S 0 4 ) ,filtered, and evaporated t o leave a dark residue (83 g ) . This residue, containing the nonquaternary alkaloids, &-asplaced aside due t o our earlier investigation of this species (29). PREP.lR.%TIOK OF .i QC.\TERS.IRT COJIPLEX .ISD CHROMATOGR.lPH17.-The alkaline sOlUtiOIl remaining after extraction of the nonquaternaq- alkaloids with chloroform was acidified t o pH 2 n-ith conc. HCI and treated with an excess of Mayer's Reagent (36) until precipitation ceased. The crude quaternary alkaloid complex was filtered bj- suction, washed with n-ater, dissolved in acetone-nater (1:9) (500 ml), and passed over an anion exchange resin column (IRA-4OlS [Cl]): (100 9 ) . The column was rinsed with additional acetone-m-ater (1:9) (400 nil); the eluate and rinsings were ccnibined and evaporated t o leave a dark residue (24 g) of crude quaternary chloride salts. The residue v-as dissolved in methanol (100 ml), adsorbed onto neutral alumina (40 g ) , and chromatographed over neutral alumina (240 g) in chloroform. I S O L I T I O K O F ,\i-hfETHYLGLAUCI~E IODIDE ( 7 ).-Elution O f the column with chloroformmethanol (3:l) (300 ml) afforded a residue (423 mg). This residue was dissolved in methanol (50 ml) and passed over an anion eschange resin column (IRA4-301S [Iodide])j (20 g ) . The column -'as rinsed ivith methanol (50 nil), and the eluate and rinsings were evaporated t o leave a brownish-m-hite residue. Treatment of this residue n-ith methanol afforded (+)-S-methylglaucine iodide ( 7 ) as n-hite needles (108 mg), mp 217-220" after softening a t 213" (ref 216-19" 30)): [ a ] ~ + 8 1 "(c=0.53 in MeOH) (ref [a!"D-72" (30)); ir vmas (KBr) 3000 cm-l, 1518, 1480, 1463, 1432, 1421, 1398, 1390, 1358, 1342, 1325, 1272, 1250, 1235, 1225, 1122, 1105, 1033, 1007, 973, 955. 923. 877 and 7 i O : uv. Xmas 1MeOH) 223 nni iloe e 4.61). 28314.12) and 30414.14): nmr (MeOH-dr), 6 3 09(s,3H, -SCH3), 3 47(s, 3H, -SCH,)P3 68(s,'3H, OCHa), 3.83(s, 3H, OCH3), 3.89(s, GH, 2 0 C H 3 ) , 6.88(s, l H , ;irH), 7.04(s, l R , ArH) and i . 9 5 ( s , lH, A r H ) . ms, AI- m / e 370(1), 369(3), 355(1), 142(1), 128(6), 127(4), 59(3) and 58(1000). The alkaloid n-as identical (uv, ir, ms, mp, mmp).to an authentic reference sample of -V-methylglaucine iodide ( 7 ) prepared by the treatment of a solution of (+) glaucine (8) in acetone with methyl iodide.
PREPAR.ATIOX OF AV-lmTHTLGL.\urIxEIODIDE ( 7 ).-To a solution of (+)-glaucine (8) (6 mg) in acetone (5 ml) &-as added methyl iodide (0.2 ml). After standing overnight, the resulting crystalline mass was filtered, rinsed with acetone, and dried t o afford white rods of S-methylglaucine iodide ( 7 ) (5 nig), mp 216-18". ISOLATIOX OF ~\--I\IETHYLCORYDISE IODIDE (9) .-Elution Of the column n-ith additional chloroform-methanol (3:l) (200 ml) afforded a tan residue (810 mg). This residue was dissolved in methanol (100 ml) and passed over an anion exchange resin column (IRA-401s [Iodide])j (40 g). The column was rinsed with methanol, and the eluate and rinsings n-ere evaporated t o leave a pale brown residue. Treatment of this residue with methanol afforded A methylcorydine iodide (9) as white needles (206 mg), mp. 2 0 2 4 4 " after darkening a t 195"; :a]20~+154'(c=1.09 in LIeOH), identical t o an authentic sample by direct comparison (34).
ISOLATIOS OF s~~-3.-Continued elution with the same solvent (300 ml) afforded a small amount ( 5 mg) of an uncharacterized alkaloid, designated SDQ-3, mp. 240" dec. ACKSOWLEDGRIESTS The authors are grateful t o Mr. John Saworal: Graduate School of Public Health, Cniversity of Pittsburgh, for determining the mass spectra: to Professor Jack L. Beal, College of Pharmacy, The Ohio State University, for a sample of liriodenine and t o D r . D . S.,Bhak!ini, Central Drug Research Institute, Lucknow, India, for a sample of isocorydine. The investigation was supported in part by grants from the International Foundation of Science, Stockholm, Sweden; the Health Research Service Foundation (R-15) and by the National Institutes of Health, Education and Welfare, Bethesda, AIaryland 20014, (5SOlRRO455-10). The mass spectrometry facility n a s supported by Research Grant R R 4 0 2 7 3 t o the University of Pittsburth from the Sational Institutes of Health.
Receiiled 9 Jiily 1979. LITERAATURE C I T E D 1. F. R . Irvine, "Woody Plants of Ghana", Oxford University Press, London, 1961, p. 33. Tackie, i. D . Dwuma-Badu, J. E . Knapp, D . .J. Slatkin and P. L. Schiff, Jr., Phyto2 . A. ? chemistry, 13, 2884 (1974). 3. E . 8.Gyang, D . Dwuma-Badu, J. S. K. .4yim, B. K . Noamesi and R . Ansa-Asamoah, Glinne Pharmeceiiticiil Joxriinl, 3, 130 (1975). 4. D . Dnuma-Badu, 1979. Personal Communication. 5. AI, A. Buchanan and E. E. Dickey, J . O r g . C h e m . , 25, 1389 (1960). 6. W.I . Taylor, T e t m h e d r o n , 11, 42 (1961). 7 . D . Warthen, E . L. Gooden and 31.Jacobson, J . Pliarni. Sci., 58, 637 (1969). 8. H. Guinaudeau, 11.Leboeuf and A . CavC, Lloydiii, 38, 304 (1975).
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