A Centenary Synthesis of Carone and Dicarvelone D. E. F. Armstead Reading College of Technology, Reading, England Carone (1)is a colorless liquid having a pleasant peppermint odor. I t was first synthesized 100 years ago by von Baeyer ( 1 )following the scheme illustrated by eq 1.'
tassium hydroxide and converted to carone (1). The pedagogical value of this synthesis goes beyond providing novel examples of reduction, addition, and elimination reactions; there is a n additional element of serendipity. The formation of an unexpected crystalline prodwt (a-dicarvelone) can provide the student with a problem-solving exercise similar to that faced by industrial chemists who investigate impurities and side reactions, for example, in drug synthesis. For the advanced student, there is ample opportunity to establish or confirm the stereochemistry of the reaction products and investigate the reactions of the byproduct, a-dicarvelone (81,for example,
The bicyclic structure of carone was first suggested by Wagner ( 2 )and established jointly by Baeyer (3) and Wallach (4).Since then the synthesis has been repeated many times to provide materials for further study ( 5 ) .Carone has not been detected in nature but, given the wide distribution of the related carenes. i t mav be resent i n essential oils. (-1-Carvone (2) is the major component of spearmint oil. I t is used commerciallv in the nroduction of chewing gum, sanp. .111ddental prcparatmns The lirsr stnee ofthe ssnrhesis involves reducinac-.-carvone with zinc dust in aqueous-alcoholic potassium hydroxide. The maior reduction product is the dihvdrocarvone (31,which hBs opposite optical rotation to th& of the orieinal cawone (6).A bv-~roductof this reduction is a-di-
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Furthermore, a detailed investigation of the reduction procedure, i n terms of sequence of contacting the reactants, reaction time, and solvent could further optimize the formation of the required reaction product and shed light on the reaction mechanisms that possibly involve free radicals. Dicarvelone was first investigated by Wallach (7a, b ) . The stereochemistry of a-dicarvelone has been established more recently by Verghese et al. (8).a-Dicarvelone is produced as a minor product (4-5%) by following the reduction procedure described i n the experimental section of this article. It m a s be isolated from the crude dihydrocarvone by cooling, when it crystallizes as a white solid. The ~ r o c e d u r eis desimed to maximize the vield of dicarvelone. here is evidence to indicate that the production of dicarvelone is minimized by carrying out the reaction more quickly and pouring the alkali into the hot, vigorously stirred mixture of carvone, alcohol, and powdered zinc (5g).Isolation, purification, and identification of a-dicarvelone provides a useful student investigation. In stage 2, dihydrocarvone is reacted with hydrogen bromide, in acetic acid, to provide the hydrobromide (4). In the final stage the hydrobromide is treated with alcoholic po'The reactions~,oroduce mixtures of stereoisomers The formulas shown are tnose of me preoommanl somers Informallon regarnmg somerc composl on of reacl on prooxls is g ven in !he exper menla sea on an0 n me leraldrecleo ~
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Journal of Chemical Education
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Experimental The experimental details given below are based on the original work of Baeyer and Wallach but have been developed to provide more convenient procedures for student investigation. The conditions for hydrobromination and elimination are derived from related work bv the author (9).The simple methods for isolating and puXfying the dicarvelone have not, as far as is known. been described meviously. (+)-Dihydrocarvone and (+)-a-Dicawelone (lR,4R)-p-menth-8-en-2-0ne and (1 R,I'R,4R,4'R,6R,6'R)-6.6- bis(p-menth-8-en-2-one) Introduce powdered zinc (50 g), distilled water (100 cm3), potassium hydroxide solution (50 cm3, aq 9.3 M) and R-(kcarvone (Aldrich), 25 g i n 200 cm3 ethanol, into a 500-em3 round-bottomed flask fitted with a reflux condenser. Using an electric beating mantle, reflux the mixture for 2.5-3 h. Allow to cool, and filter to remove solids. Retain the filtrate. Ti-ansfer the solids to a beaker, and quench with water before discarding.
Reduce the volume of the filtrate by about a half on a rotary evaporator. Add distilled water (150 an3), and extract with dichloromethane (3 x 70 an?). Dry the extract with anhydrous sodium sulfate and evaporate to provide crude product (about 45 g). Store in a freezer for 2 4 4 8 h. During this period crystals of a-dicarvelone will form in the bott&of the storage vial, Separate the solid and liquid by decantation and fit&ion. his provides approxima&ly 211 g of a-dimelone. TLC (silica gel, 8:2 petroleum spirits (40-60):ethoxyethane, spray:dodecaphosphomolybdic acid (5% in ethanol). H e a t plate a t 120 'C) shows that the filtrate consists of dihydrocarvone (Rf= 0.61,0.49) and a t least two other substances (Rf= 0.14 to 0.35). The dihydrocarvone spots correspond to a n approximate 7 5 2 5 ratio of the C-1 epimers of (+I-dihydrocarvone and (+I-isodihydrocarvone (6).These geometrical isomers may be separated by flash chromatography on silica gel ( 8 2 petroleum spirit (40-60):ethoxyethane). However, for the next stage, this separation i s not essential, and simple distillation (107-118 "C a t 20 mm Hg or 200-225 "C a t atmosoheric oressure) orovides adeauate purification. Distilled material eives a semicarbazone. mu 179-181 "c, once recrysta~~ized from 1:1 waterlethaiol, kt. 189 "C (4); [ao]P= +17.3" in CH2C12,lit. [ao]$ = +18.3" (5i).IR and PMR confirm that the product has the required structure.
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Summary of PMR: (60 MHz, TMS, CDCl3) 6 1.03, d, CH,; 6 1.10, d, CH3 (due t o minor constituent of epimeric mixture); 6 1.77, dhroadi, CH3; 6 2.41, m, CHiCH; 6 4.83,
dbroad), >C=CH1. Purification and Characterizationof u-Dicarvelone The solid a-dicarvelone is purified by washing with petroleum spirit (40-60) and recrystallizing from ethanol, mp 149-151 "C, lit. 148-149 "C (7a); [alf = +74", i n CH2C12,lit. [a];' = +73.2" (7~). The semicarbazone melts with decomposition at 262 ' C . IK, l'.\lR, and U S ronfirm thar the product has the structure shown (5). Summary of PMR: (60 MHz, TMS, CDCI3) 6 1.05, d, CH3; 6 1.82, dhroad), CH?; 6 2.44, m, CHdCH; S 4.92, dbroadi,
>C=CH2 Summary ofMS: (EIi mlr 302 (Mt, C20H3002); mlz 151 (base)
Dihydrocarvone Hydrobromide (1R,4R)-8-bromo-p-menthan-2-one
Dissolve dih drocarvone (10 g, 65.8 mmol) in glacial acetic acid (15 cm{) .m a 150-cm3conical flask. Stir (magnetic) and cool the solution i n ice-water. Continue stirring and add, from a dropping funnel arranged above the conical flask, hydrogen bromide solution (20 cm3, 45% wlv i n glacial acetic acid); add this slowly over a 15-min period. Remove the cooline. and stir for another 15 min a t room temperature. Add d k i l l e d water (150 cm3), and stir for 2 or 3 min. Pour the contents of the reaction vessel into a seDarating funnel, and add dichloromethane (50 cm3). Mix the contents (allow for expansion), and run off the bottom dichloromethane layer into a clean beaker. Extract the aqueous phase with a further portion of dichloromethane (50 em3). Combine the dichloromethane extracts. Discard the remaining aqueous phase, and wash the dichloromethane extract with 10% sodium carbonate solution (100 cm3) and distilled water (100 cm3). Dry the dichloromethane extract with anhydrous sodium sulfate. Evaporate, on the rotary evaporator, to provide
crude hydrobromide (14.0 g). This material may be used i n the final stage without further purification; [a'lil = +8.0° i n CH2C12. IR and PMR confirm that the majority of the crude product comprises material of the required structure. Summary of PMR: (60 MHz, CDC13, TMS) 6 1.05, d(5 Hz),
CH3; 6 1.83, two singlets, (CH3i2CBr;S 2.32, dhroad), CHiCH. Carone 7-trimethylbicyclo[4,l.O]heptan-2-one (1Sf13R,6R)-3,7,
Introduce dihydrocarvone hydrobromide (10 g, 43 mmol) into a 250-em3 round-bottomed flask, and add methanolic potassium hydroxide (100 em3, 2M KOH i n methanol). Swirl the contents. fit the flask with a reflux condenser. and heat a t 50 "C f i r 15 min. Reflux for 30 min on a wate; bath. Pour the contents of the flask into brine (100 an3. 10% aq sodium chloride) contained in a separating funnel: Extract this mixture with 3 x 30 cm3 dichloromethane. Wash the combined dichloromethane extract with distilled water (50 cm3). Drv the extract with anhvdrous sodium sulfate. Evaporate on a rotary evaporator to provide crude ~ r o d u c(6.5 t a). TLC (silica gel, 2:l petroleum spirit (40-60)lethoxyethane) shows one major component (RI= 0.70) and a number of minor components t h a t a r e all well separated. Carone i s isolated from the crude mixture by flash chromatography (same conditions a s for the TLC). Two grams of the crude product provides 1.7 g of purified carone. GLC (DEGS, 180 "C) indicates that the purified material is a three-comoonent mixture (20:3:1). PMR s~ectroscoov indicates that the majority of this is trans- and cis-carone (20:3): this aerees with the findings of other workers who also identified ?,-carvenone as a fulrther minor constituent of the reaction oroduct (5h).. a% l.' ."= -166.0" in CHCl?. " ", lit. [a"]!' = -169.5 " (10). Summary of ZR: (em-') 2950(strong), 1685(strang), 1470(medium), 1020(medium),930(rnediurni,800(mediumi SummaryofPMR: 6 1.08,pair ofdauhlets(5Hz), a-CH3(Eand Z); 6 1.22, pair of singlets, gem-dimethyl: S 1.40-2.30, m(hroad1, CH2/CH Semicarbazone twice recrystallized, 166-172 "C, lit. value 170.5-172.5 OC (5h). Repeated recrystallization gradually removes the cis isomer and gives a higher and sharoer meltine semicarbazone. W absorption, 209 nm, E = 4510, indicating hyperconjugation between the cyclopropane ring and the carbonyl
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Literature Cited 1. Baeyer. A. B w 1894.27, 1915. 2. Wagner, G. Be?. 1894,27.1652,2270. 3. Baeyer, A ; Ipatleff, W. Be,. 1896.29.2796, 4. Wallaeh, 0. Lkbigs Ann. 1994,279,377. 5 . la1 Wallach, OAnnalen. 1894,279,389.ibl Wallaeh. 0,Annmbn. 1895,286,127. icl Johnston, R. G.: Resd. J. J. Chem. Soc. 1934,233.Id1 Klotz,I. M. il A m r Cham. Sor. 1944,66,88.lei Joshida, M. Chsm. ond P h a m . Bull. (Japan, 1955.3,215. itl Halaall,T.G.;Thcobald, 0. W.:Walshaw, K B. J Chem. Soc. 1964 1029. IglHumber, D. C.; Pinder,A.R. J Or& Chrm. ISM, 32,4188. lhl Dauben, W. G.; Shaffifif, G.W.; Deviny E. J. J . Amer Chem. Soc. 1910.92.6273. lil Fsirlie, J. C.;Hdgson, G. L.; Money, T. J . Chem. Soe (Perkin Ill1 1913,2109.(11 Carman, R. M.; Venzke, 6. N.Aust J. Chsm. 1973,26,1977. 6. Verghese,J. Perfumer andFlauorisl 1980.5.23. 7. (a1 Wallach, 0. Lkbigs Ann. 1889,305,223.1bl Wallach, 0. &bigs Ann. 1914,403, 07
8. Carman, R. M.: Samswaihi,G. N.; Verghese, J A u s t . J. Chem. IW73.26.883. 9. Armstead. D. E. F Edumlian in Chemistry 1990.27161. 168. 10. Heilbron. I.; Bunbury. H. M. DClionary of Organic Compounds,Eyre and Spottiswoode: Landon, 1953;Vol. 1. p 434.
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