Oxidation of (R)-(+)-Pulegone to (R)-(+)-3-Methyladipic Acid William J. ~cott: Gerald B. ~ a m m o n d ?Brian T. Becicka and David F. Wiemer The University of lowa, lowa City, IA 52242 Over the last decade there has been a growing effort to minimize the expense of operating organic chemistry laboratories by conducting "microscale" experiments (1).This tack both minimizes initial ex""" penditures on chemicals, and, as important, minimizes expenditures on waste disposal. There has been some concern, 1 though, that students taught exclusively using "microscale" techniques might experience some dikliculty in manipulation of reactions m on larger scale. We have developed a series of "normal scale" reactions that complement the techniques taught in our "microscale" experiments. We have chosen to make these experiments more cost effective by having the students synthesize compounds that are important intermediates in research projeds on-going in our d e p h e n t , 3 we have found that the abilib to link in the teachine.. laboratom to current research projects increases the interest ofthe student in the experiment beine taueht. imparts satisfaction a t contribucng to a r e s e a r s e f f h t , and vividly demonstrates that oceanic chemistrv is not a "dead science". Herein, we describe one such-experiment. During the course of a project directed toward the enantiospecific total synthesis of (+)-jatrophone, 1, and related diterpenoids, one of us had need for large quantities of (R)(+)-3-methyladipicacid, 2 (2).Though the chiral acid is available commercially, it is more economical to produce it through oxidation of (R)-(+)-pulegone, 3, using KMn04 (3).The synthesis of adipic acid by oxidation of cyclohexanone with KMn04 is a standard synthetic experiment (4). However, to our knowledge the oxidation of (R)-(+)-pulegone to (R)-(+)-3-methyladipicacid has not been adapted to the teaching laboratory. The complete oxidation of pulegone to methyladipic acid requires 2 moles of KMn04 per mole of pulegone. (This equation provides a good question on the balancing of redox reactions.) However, because of the difficulty in filtering the quantity of MnOz that is generated, we and others (3a) have found that yields are maximized on using slightly over 1 equiv of KMn04. The yield based on pulegone, therefore, is limited to 50%. Because insufficient oxidant is employed, it is
3
*--
,,....
,,,"' 0
2
3
not necessary to reduce remaining permanganate. Nevertheless, students are asked to run tests for unconsumed permangmate a number of times during the experiment. Because this oxidation involves a number of elementary techniques, such as vacuum fdtration with the aid of Celite and recrystallization, it is commonly taught early in our laboratory sequence. The purification of methyladipic acid by recrystallization from toluene provides a reliable example of this often difficult technique and, cvcn though typie callv 213 of the crude product is lost d u -~ recrvstalli;.ation, our students aiways have obtained crystalline product. Following the procedure described below a classof
'Author to whom correspondence should be addressed. Present address: DeDartment of Chemistrv. University of ~assachuseitsDartmouth, ~ o r t i ' ~ a ~ mouth. MA02747. 3The concept of preparing research chemicals in organic laboratory courses is not unprecedented. Similar approaches have been pioneered by Louis Fieser, Melvin Newman, and Henry Rapoport, among others. Figure I.'H NMR of diacid 2 recorded on a 300 MHz spectrometer. Volume 70 Number 11 November 1993
951
methyladipic acid (185 g; 23% based on pulegone, 46% based on KMn04) which compares favorably with that obtained in the research laboratory (approximately 40% based on pulegone). Experimental Procedure (R)-(+)-3-Methyladipic Acid, 2.
To a 250-mL Erlenmeyer flask containing 5 mL of (R)-(+)-pulegone4(30.8 mmol) and 40 mL of water is added 5 g of KMn04 (31.6 mmol, 1.03 equiv) with swirling. Swirling is continued for 10 min, then occasionally over 2 h. At the end of this time the mixture is heated over a boiling water bath for 10 min. CAUTION: The oxidation of pulegone is exothermic. An ice bath should be kept nearby in case of overheating. Figure 2. 13cNMR of diacid 2 recorded at 75 MHz. 160 students isolated a n average of 0.33 g (6.7% yield based on pulegone) of crystalline product with an average mp of 7%82 "C. Typically, approximately 10% of the class obtains yields of 0.66 g or more, while maintaining high melting points (280 OC), and 1.5-2.0 g of pure product are obtained bv the best few students. Only 14 of 160 students and only two reported 0:05 g or less of crystalline students reported no product. While the yield of diacid might appe& low, students were rt?a.;surcd to find that the average yield tor this class based on KMnO,, the limiting reage&bas 13%. The synthesis of (R)-(+I-3-methyladipicacid is an interesting example of the preparation of an optically active molecule in a teaching laboratory. The optical rotation of the product can be taken in most suitable polar solvents and corresponds well with literature values. Spectra of thc product are also instructive. The infrared soectrum disolavs classical acid absorbance%.Thc 'H NMR spectrum of diacid 2 provides a n excellent example of diastereotooic hvdroeens (Figs. 1and 2). Thus, in addition to the methyl d&blz a t 6 1.61 and the broad acid absorption centered at 6 10.3. separate single proton absorptions are observed a t 1.57 a i d 1 7 5 ppm &at &ay be assigned to the diastereotopic C-4 protons and a doublet of doublets a t 6 2.23 is observed for one of the C-2 protons. The C-3 methine proton appears a t 2.03 ppm as a n apparent octet, and the remaining 3 protons display overlapping absorptions a t 2.25-2.35 ppm. The 13CNMR is quite simple, showing a methyl resonance a t 6 19, three m&hylene resonances between 29 and 32 ppm, a methine resonance at 6 41, and carboxylic acid resonances at 179 and 180 ppm. The usefulness of this approach as a research aid is evident on realizing that the class of 160 students using 800 mL of pulegone produced 53 g of crystalline (R)-(+I-3methyladipic acid. Furthermore, a large additional portion of the diacid could be isolated from the combined waste streams. Indeed, recovery of the diacid by concentration of the combined toluene wastes afforded an additional 105 g of an oily diacid suitable for use in the next step of the reaction sequence (Fischer esterification) (2b). Similarly, concentration of the combined aqueous wastes afforded an additional 27 g of product, for a total yield of (R)-(+I-3-
..
?f
Co., in 80
952
Journal of Chemical Education
Prior to purification of the product, the reaction mixture is tested for remaining KMn04by withdrawing a drop of the mixture with a stirrine rod and touchine it to a oiece of filter ; will appear a s a purplekng about the paper. ~ ~ o s i t i test brown Mn02 solids. The Mn02 solids are removed by vacuum filtration through a bed of Celik, and the vacuum is maintained until the solids are reasonably dm. The resulting solids are washed with three conse&tive 10-mL portions of water, gently mixing the brown portion of the filtrate while wet to maximize washing. The solids are allowed to dry thoroughly between washings. (The Mn02 solids from the class are combined and saved for further treatment.) The combined aqueous solutions are concenallowcd to cool to room trated to 15 mL over a hot temperature, and acidified using 10 mL of concentrated HCI. If --- solids form at this ooint. .they" are removed hv filtration. The acidic aqueous solution is extracted with four consecutive 15-mL portions of CHzC12. (The aqueous layers from the class are combined and saved for further treatment.) The organic layers are combined, dried over anh. MgS04, and concentrated over a boiling water bath to afford an oily solid. CAUTION: CH2C12is toxic and should be removed in an adequate hood
.
Recrystallization of the oily solids from toluene (5 mL toluene per gram of solid) affords 0.2-0.6 g of white solid (The toluene filtrates from the class are combined and saved for further treatment): mp (avg. of 160 samples) 7882 OC [lit. mp 7 M 1 (3~1,84.5 (3d), 78-83 ( 3 ~"Cl; ) [WID% c6.5' (EtOH), +8.0" (H20)Pit. +8.3'(HzO) (3~1,+8.4 (HzO) (3c)l;IR (CHC13)3400-2500 (O-HI, 1700(C=0),1275(C-0) cm-'; 'H NMR (CDCl,, 300 MHz) 6 1.01 (d, J = 6.6 Hz, 3H), 1.50-1.62 (m, lH), 1.70-1.82 (m, lH), 2.03 (app oct, J = 6.8 Hz, lH), 2.23 (dd, J = 15.2, 7.4 Hz, 1H), 2.31-2.49 (m, 3H), 9.0-11.2 (br s, 2H); 13CNMR (CDC13,75 MHz) 6 19.3,29.5, 31.1,31.7,41.2, 179.2, 180.0. Literature Cited 1.lalMeyo.D. W.;Pike,R. M.;Butchu,S.S.Micmscole Organhhbomfow; John Wiley: Nervy&, 1986.(h)Pavis,D.L.;Lampman.G.M.;~z,G.S.;Engel,R.G.Infmdudion to organic Lo&rnt~ryTechniuus. A M i e m s d r A p p m h : Saunders College Publishing: Philadelphia, PA. 1992. fc) Nimitz, J. S.Experiments in Organic Chemistry; PrentirrHall: Englewood CtiRa. NJ, 1991.(d)Radig, 0. R.; BeU, C. E., Jr: Clark, A. K. Ormnic Chemistryhhmtory; Ssundem College Publishkg: Philadelphia. PA. 1990 2. (a) Han, Q.; Wiemer, D. F J.Am. Chm. Soe 1992, 114, 7692. (bl Bericks, B.T.; Koewitz, F L.:Dtfina, G. J.; Baenziger, N. C.; Wiemer, D. P J 0% Chem. 1990, cr ""AU. ce,, "", 3.(alJaekman,L.M.;Wehh,R.L.;Xck.H.C.J. OrgChrm.1982,47,1824.(h)SugaT.; von RudloR, E. Cm. J. C h m . 1968.47.3682. (c) Rupe, H. Chem. Ber. 1894.27, 582. fd)Semmler,F.W. Chem. Ber. 1892.25,3516. 4. (a) Fieser, L. F. Orgonh Experiments, 2nd ed.; Raytheon Education Co.: Leiraton, MA. 1968,p 108. (h) Fieser, L:I?; WiUismwn. K. L. Orgenie Erpprimnis, 7th 4.; D. C. Heath and Co.: Lexkgtoh. MA, 1992.
