RINGSIZEIN OPTICALROTATORY DISPERSION
Jan. 5, 1959
Experimental Umbellulone (I).-Umbellulone was isolated from the oil of the California Bay Tree by the bisulfite addition method of Wienhaus and Todenhofer.8~9 T h e product had b.p. 99.099.8' a t 15 mm., showed a single peak on the gas chromatogram obtained from a 12' X 8 mm. silicone oil on Celite gas chromatography column, and had a n infrared absorption which was identical with that of a highly purified sample prepared by Eastman and Oken? Photolysis.-Small (1-6 ml.) samples of umbellulone were photolyzed in soft-glass or quartz test tubes filled with nitrogen. Irradiation of a 5-ml. sample of umbellulone for 48 hours with radiation from a H400 General Electric mercury arc lamp gave a quantitative yield of thymol, while illumination for only 20 hours of a similar sample but in a quartz test tube gave identical results. Irradiation for 50 hours in the quartz test tube using a 2537 A. source (Mineralite) gave a mixture of 90% starting material and 10% thymol. Illumination for 50 hours in quartz with a 75 watt tungsten incandescent lamp produced only traces of thymol. In all cases the extent of reaction and the identity of products were established by liquid-vapor partition chromatography and infrared absorption spectroscopy. Pyrolysis.-Umbellulone was pyrolyzed in a tube furnace a t 280 z!= 2' in small, sealed Pyrex tubes (ca. 10 cm. X 8 mm.). Sample sizes were ca. 0.5 ml. and the duration of the heating was 18 hr. The crude reaction mixture was seeded with a crystal of thymol (m.p. 50.5-51.0') (Eastman Kodak Co.). After centrifugal filtration to remove the thymol which crystallized, the mother liquors were analyzed on a 12' X 8 mm. silicone oil on Celite gas chromatography column and were found t o be approximately one-third symthymol and two-thirds thymol. The sym-thymol collected A sample five a t the exit of the column melted a t 37-38'. (81 H. Wienhaus and K. T . Todenhofer, Schimmel's Be7 , 285 (1929). (9) K. H. Eastman and A. Oken, THIS JOURNAL, 7 6 , 1029 (1952).
[CONTRIBUTION FROM THE
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times recrystallized from pentane melted at 49.5-50.0'. A mixture of thymol and sym-thymol was liquid a t 25 . sym-Thymol (VI).-3-Methyl-5-isopropylcyclohex-2-en-1one was prepared from isobutyraldehyde and acetoacetic ester according to the method of Knoevenagel.6" Our product boiled a t 120-122" a t 15 mm. (reportedsa 124' a t 15 mm.) and had an infrared spectrum very similar to that of piperitone. The ketone was aromatized using S-bromosuccinimide and dehydrohalogenation. I n a typical run the ketone (5 cc., 4.7 g., 0.03 mole) was dissolvedincarbon tetrachloride (30 cc.). N-Bromosuccinimide (6.2 g., 0.035 mole) was added and a reflux condenser attached. The flask was illuminated with a 250 watt flood lamp which produced a reddish color in the solution which persisted until the reaction was complete. The reaction mixture was filtered to remove the succinimide and the carbon tetrachloride was distilled off under reduced pressure after the solution had been dried with sodium sulfate. The residual oil was separated on the silicon gas chromatography column. The major product (0.2 8.) was sym-thymol. The sym-thymol collected a t the exit of the column melted a t 39.5-41.0'. I t was recrystallized five times from pentane to produce a white solid (0.13 g.) melting a t 49.5-50.0'. Knoevenage16" reported a melting point of 54". Hovxver, Carpenter and EasterlO found that sym-thymol prepared by the Knoevenagel synthesis melted a t 50.0-50.5". B mixed melting point of the synthetic sym-thymol and sym-thymol from umbellulone showed no depression. The infrared spectra of the two samples were identical, and markedly different from that of thymol. Anal.'l Calcd. for CloHlaO: C, i9.95; H, 9.39. Found: C, 79.81; H, 9.60. ~
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(10) hI. S Carpenter and W. hl. Easter, J . Org. C h e w . , 20, -101 (1955). (11) Analyses by Microchemical Specialties Co., Berkeley, Calif.
STANFORD, CALIF.
DEPARTMENT OF CHEMISTRY O F
Optical Rotatory Dispersion Studies. XX1.I
WAYNE STATE L N I V E R S I T Y ]
Effect of Ring Size2
B Y CARL DJERASSI AND G. w. KRAKOWER3 RECEIVED JULY 14, 1958 The rotatory dispersion curves of a series of 3-methylcycloalkanones were determined, all of them possessing the same absolute configuration ( R ) a t the single asymmetric center. The sign of the Cotton effect was found to be identical in the five- and six-membered rings and was then inverted in the case of the seven-membered ketone. No further change was encountered up t o and including 3-methylcyclopentadecanone ( I V ) . The synthetic work in the nine-membered series (XYXVIII) involved acyloin condensation of ( )-p-methylazelaic acid dimethyl ester, produced by anodic coupling, while 3methylcycloheptanone was formed by diazomethane ring expansion of 3-methylcyclohexanone. This ring expansion produced both 3-methyl- and 4-methylcycloheptanone, rotatory dispersion being used t o differentiate between the two structures since the 4-methyl isomer VI exhibited a plain dispersion curve in contrast t o the anomalous one of 3-methylcycloheptanone (V).
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Our investigations of the application of rotatory dispersion to organic chemical problems4 have encompassed many areas including the determination of absolute configuration, the detection of conformational distortion and the location of carbonyl groups. One field which has as yet not been examined systematically is the effect of ring size upon the shape of the optical rotatory dispersion curve and the present paper is concerned with experimental work along those lines. (1) Paper XX, N. J. Leonard, J. A. Adamcik, C. Djerassi and 0. Halpern, TEIS JOURNAL, 80, 4858 (1958). (2) Supported by grant No. CY-2919 from the National Cancer Institute, National Institutes of Health, U. S. Public Health Service. (3) Taken from P a r t I1 of t h e Ph.D. dissertation of G. W. K. (4) For pertinent review of the first ten papers in this series see C. Djerassi, Bull. SOL. chim. France, 741 (1957). For additional references to later papers see ref. 1.
The reference compound for the entire investigation was (+)-3-methylcyclohexanone (11) which is available in one step by acid-catalyzed retroaldolization6 of (+) -pulegone (I), whose absolute configuration is The rotatory dispersion of (+)-3-methylcyclohexanone (11) has already been recorded in the literature* and we have confirmed (see Fig. 1) that i t is characterized by a single positive Cotton effect curve.g The next lower (5) See J. L. Simonsen and L. N. Owen, "The Terpenes," Cambridge University Press, Cambridge, 1953, 2nd ed., Vol. I, p. 371. (6) See E. J. Eisenbraun and S. M. McElvain, THIS J O U R N A L 77 ,, 3383 (1955). (7) See A. J. Birch, A n n . Repls., Chem. Soc., 47, 192 (1950), and J. A. Mills and W. Klyne in W. Klyne's "Progress in Stereochemis try," Academic Press, Inc , New York, N. Y , 19.54, Vol. I, Chapter 5 . ( 8 ) H. S. French and M . Naps, THIS JOURNAL, 58, 2303 (1936). (9) For nomenclature see C. Djerassi and W.Klyne, Proc. C h e w . SOC.,55 (1957).
CARLDJERASSIAND G. U'. KRAKOWEIZ
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The results summarized in Fig. 1 denioiistrate the striking fact that the rotatory dispersion curve of the large membered ring ketone I\r possesses a Cotton effect curve of opposite sign as compared to the corresponding five- (111)and sis-membered (11) ketones in spite of the fact that all of them contain only a single asymmetric carbon atom of identical absolute configuration (R) and which is separated from the carbonyl group in each instance by one carbon atom. Therefore for potential assignments of absolute configurations of cycloalkanones by rotatory dispersion means, i t was clearly desirable t o determine a t what ring size-between six (11) and fifteen (1V)-this inversion of the Cotton effect occurred and since no such ketones wt're known, a synthetic program had to be undertaken. In view of the above observation that inversion of the Cotton effect can occur in a homologous series of cyclic ketones with identical absolute coli-13 L A figuration but differing in the size of thc ring, it was indispensable that the synthetic ketones had to be of known absolute configuration. This essentially eliminated syntheses involving resolution of the -426 final ketone and required synthetic routes starting with precursors of established absolute configuration. For the cycloheptanone series, i t was felt that the diazomethane ring expansion procedure'j could be employed, especially since i t has been WAVE LENGTH (my). claimed'6 that treatment of optically active 3Fig. 1 .-Optical rotatory dispersion curves (methanol inethylcyclohexanone with diazomethane yielded (I1 j , ( +)-3- only 3-methylcycloheptanone (V) rather than the solution) of ( $)-3-methylcyclohexanone nietliylcyclopentanone (111) and ( - )-muscone (I\'). expected mixtureI5.17 of 3- (V) ;rnd -k-niethyl-(Vl)cycloheptanone. honiolog, (+)-3-methylcyclopentanone (111), has Since the diazomethane ring exparlsion fulfillctl been synthesized,8Sl0from (+) -pulegone (I) without the requirement of not affecting the asyrnmetric disturbing the asymmetric center and the rotatory center, i t was applied t o (+)-3-~nethylcyclohexadispersion curve (Fig. 1) of this ketone exhibits a none (11) and yielded a mixture of cycloheptanones positive Cotton effect curve of rather high ampli- and cyclooctanones. The cycloheptanone fraction t ~ d e .Since ~ both (+)-3-methylcyclohexanone (11) was separated readily and was fractionated careand (+)-3-methylcyclopentanone (111) are de- fully. While the boiling point and refractive index rived from (+)-pulegone (I), the absolute con- of the various fractions did not differ significantly figuration of the asymmetric center in all three and only one peak was observed upon vapor phasc ketones is (R)." chromatography, differences in the optical rotation A third readily available 3-methylcycloalkanone is were noted. As demonstrated in Fig. 2 , the rotathe naturally occurring (-)-muscone (3-methyl- tory dispersion curves of two cycloheptanone fracpentadecanone) (IV) l 2 whose absolute configura- tions of identical boiling point were found to bc tion (R) was established by its synthesisla from 0- completely different, one of them exhibiting a negamethylglutaric acid monomethyl ester of established tive Cotton effect curve while the other one p s stereochemistry. The optical rotation of (-)sessed only a plain curve. Both fractions were muscone (IV) has already been m e a ~ u r e d 'a~t four shown to be methylcycloheptanones by elciiientary different wave lengths down t o 404.6 mp and the analysis, irifrarcd exaniiiiation and foriliation of values were found to be progrcssively more mga- sernicarbxzones (melting points not coiilpletcly tive. This indicated that the compound most likely identical but undeprcssetl upon aclriiixture). b 7 c : possessed a negative Cotton effect curve and when conclude, therefore, that contrary to the earlier its rotatory dispersion was determined more pre- report, l6 both 3-~nethylcycloheptanone (17) and 4cisely in our laboratory14 throughout the relevant inethylcycloheptanone (VI) were produced. The ultraviolet region, (-)-muscone was found (Fig. product with the negative Cotton effect curve is 1) to have a negative Cotton effect curve of rather assigned the 3-methyl structure V while the matesinall amplitude. rial with the plain curve is believed t o be the 4methyl isomer V I , since model experiments with (10) For leading references see G . H. Stempel, W. 0. Forshey and G . S. SchafTel, T H I S JOURNAL, 6 7 , 344 (1045). aliphatic ketones and aldehydes18s1gshowed that
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(11) Accordinfi t o the new convention of K. S. Cahn, C. K. Ingold and V. Prelog, Ezperientia, l a , 81 (1956). ( 1 2 ) L. Ruzicka, H e h . Chim. Acta, 9 , 1008 (1926). (13) S. Stallberg-Stenhagen, Avkis K e m i , 3, 517 ('951). (14) T l i e measurements were carried 011t on a sample of natural (-)-muscone kindly provided by Dr. A I . Stull, Firmenich a n d Cie., Geneva, Switzerland.
(15) C. D. Gutsrhe, Ovg. Rencliozs, 8 , 364 (1954). (16) hf. hlousseron and G. Manon, Bull. SOC. chin&. Prance, 302
(i949). (17) Sce 13. U '. Adamson nod J . Kenner, J . Chein. Soc., 181 (1939). (18) C . njerassi and L . I.:. Geller. to he published. (19) See P. A. Levene and A. Rothen, J . Chem. P h y s . , 4, 48 (1936)
KINGSIZEIN OPTICAL ROTATORY DISPERSIOK
Jan. 3, 1959
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Fig. 2.-Optical rotatory dispersion curves (methanol solution) of ( -)-3-methylcycloheptanone ( V ) and ( -)-4 methylcycloheptanone (VI).
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Fig. 3.-Optical rotatory dispersion curves (methanol solution) of ( ) @-methylazeloin(XV), ( - )-@-methylazelit (XVII) and ( - )-3(or 4)-niethylcyclononanone (XVIII).
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@-methyladipate (X) where the asymmetric center possesses the (R) configuration. This half-ester was selected as one component for the synthesis of separation of the asymmetric center from the car- the requisite azelaic acid for the acyloin condensabonyl function by two carbon atoms resulted in a tion. It was planned to prepare the acid by anodic tendency toward a plaing dispersion curve. This couplingzaand for that purpose, benzylz4hydrogen structure assignment to the methylcycloheptanone glutarate (XI) was selected as the other partner in mixture arising Erom diazomethane ring expansion order to facilitate the separation of the three posof 3-methylcyclohexanone (11) by means of rotatory sible products formed during anodic coupling of two dispersion affords still another illustration of the different esters. The primary products (XIIa, utility of this physico-chemical tool. XI11 and XIVa) were debenzylated catalytically While it appears from the above observation and the neutral product, @,@‘-dimethylsebacicacid (Fig. 2) that inversion of the Cotton effect curve dimethyl ester (XIII), removed by ether extraction occurs already a t the stage of the seven-membered from alkaline solution. The acidic fraction, conketonez0it was, nevertheless, important to examine sisting of suberic acid (XIIb) and the monomethyl a t least one example of a medium-sized ring ketone ester of P-methylazelaic acid (XIVb), was separated in order to see whether this trend continued or was by fractional distillation followed by further puriperhaps reversed due to the well-knownz1 trans- fication via the dimethyl ester, thus affording the annular effects operating in such rings. desired (+)-@-methylazelaic acid dimethyl ester One of the best syntheses for medium-sized ringsz1 (XIVc) . Acyloin condensationzz produced ( -)-/3is the acyloin condensationzzand it was decided to methylazeloin, which may possess either structure utilize this procedure for the preparation of an XVa or XVb, and which was characterized by conoptically active cycloiionanotie. In order to fulfill version to ( -)-p-methylazelil (4-methylcyclothe above-mentioned criterion of known absolute nonane-1,3-dione) (XVII). As shown in Fig. 3, configuration, we employed (+)-citronellal (VII) both compounds are characterized by negative Cotwhich was oxidized to (+)-citronellic acid (VIII) ton effect curvesz5and this also applied to the corand then transformed into its methyl ester IX. responding methylcyclononanone (XVIII) . Ozonization now produced (+)-methyl hydrogen (23) See W. S. Greaves, R . P. Linstead, B. R. Shephard, S. L. S . ( 2 0 ) If the ”octant rule” (C. Djerassi. W. Klyne, W. Moffitt, A. Moscovitz, and R. B. Woodward, in preparation) can be applied to cycloheptanoaes, then it would be predicted that the boat form of V would exhibit a negative, and the chair form of V a positive Cotton effect. (21) See V . Prelog in A. Todd’s “Perspectives in Organic Chemistry.” Interscience Publishers, Inc., New York, N. Y.,1956. pp. 96133 (22) (a) V. L. Hansley, U. S. Patent 2,228,268, (b) V. Prelog, L. Frenkiel. M. Kobelt and P. Barman, Hclo. C him. Acta, 30, 1741 (1947); (c) hf. Stoll and 1. Hulstkamp, i b i d . , 30, 1815, 1822, 1837 (1947).
Thomas and B. C. L. Weedon, J. Chem. SOL.,3326 (1950), and succeeding papers by R . P.Linstead, et ai. (24) The use of a benzyl half-ester, which aids in the separa tion of the products fiom a mixed anoding coupling reaction, has been introduced by L. Dolejs and L. Novotny, Coll. Czech. C h e m . Comm., 19, 716 (1954). and by R. P. Linstead, B. C . L. Weedon and B. Wladislaw, J . Chem. SOC.,1097 (1955). See also F. S a m , ht Streibl, V . Jarolim, L.Novotny,L. DolejsandV. Herout,Chemistry&Indirsfry,25? (1954). ( 2 5 ) The rotatory dispeision of (steroidal) ketols is discussed in detail by C. Djerassi, 0. I%alpern, V Halpern, 0. Schindler and C. Tamm, Helu. Chim. A d a , 41, 250 (1958).
CARLDJERASSI AND G. W. KRAKOWER
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Vol. 81
suggest strongly that the negative Cotton effect observed in the seven- (V) and fifteen- (IV) m e n bered ketones applies also to the intermediate ring sizes. In Fig. 4 are collected the rotatory dispersion curves of three ketones, X I X , 2 gXX30aand XXI,30b which are related to caryophyllene. They represent further examples of anomalous dispersion curves exhibited by 7 - and 9-membered ketones in which an asymmetric center is not more than one carbon atom removed from the carbonyl group.
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far as the conversion of the keto XV to the corresponding ketone XVIII is concerned, the first experiments were conducted using the zincacetic acid procedure.22bjc The results were not too satisfactory and recourse was taken t o the recently developed calcium-ammonia reduction, 26 which has been used with such success for the deacetoxylation of steroidal ketol acetate^.^^^^^ Indeed, when (-)P-methylazeloin (XVa and/or XVb) was transformed into its acetate (XVIa and/or XVIb) and then treated with calcium in liquid ammonia, a ketone (XVIII) was obtained uncontaminated by acyloin, alcohol or acetate. Using the argument employed above in the structure assignment of 3-methylcycloheptanone (V) , the fact that an anomalous rotatory dispersion curve was produced indicates that the ketone should be largely 3-methylcyclononanone (XVIIIa) rather than the 4-methyl isomer XVIIIb. Unfortunately, this cannot be done with the same degree of certainty because i t is quite possible that the “distance factor”I8 is rendered meaningless by operation of a trans-annular effect. 1,28 Nevertheless, the rotatory dispersion curves collected in Fig. 3 (218) J. H. Chapman, J. Elks, G. H. Phillipps and L. J. Wyman, J . I’hem. Soc., 4341 (1950). (27) J. S. Mills, I
