lsomerization of Dimethyl Maleate to Dimethyl Fumarate An Undergraduate Experiment Illustrating Amine-Catalyzed Alkene Isomerization, Stereochemical Principles, Sublimation, and Product ldentification by Spectroscopic ~ e t h o d s Craig B. ~ r ~ h l eCarol ', M. ~ybak,'and Kenneth E. ~ulley' Pacific Lutheran University, Tacoma, WA 98447
The amine:catalyzed isomerization of dimethyl maleate to dimethvl fumarate (ea 1) orovides a simple oreanic laboratory experunent with a number of pedagogical rirtucs. Students are challenlred to identlfv an unknowncompound when the instruct& withholds "the identity of the maleatelamine reaction product. Once the product is identified, students can then be asked to propose a rational mechanism for its formation, an exercise requiring that subtle stereochemical issues be considered. The importance of these stereochemical aspects can be underscored by discussion of their significanckin the analogous biochemical reactions of argini,succ~nasennd adenylosuccinase ( 1 1 . Both of these enzymes produce fumara& by way of an elimination reaction that parallels the one described here. Furthermore, sublimation of the product a t atmospheric pressure produces spectacular spars of sublimate, demonstrating sublimation as a useful technique applicable to volatile solids. Finally, practice in spectroscopic methods is orovided since the product is readilv identified bv NMR &/or gas chromat&aphy with mais selective ditection (GCIMSI),. IfFouriertrnnsform NMR data isobtained," the product identification process affords an excellent opportunity to introduce simple 13C, APT (attached proton test), and C-H HETCOR (heteroscalar 2-D correlation) NMR spectra.
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The Reaction When dimethyl maleate is dissolved in diethylamine a mildly exothe&c reaction commences and a white precipitate of dimethyl fumarate begins to separate within five to ten minutes. The isomerization presumably occurs by the conjugate addition and subsequent elimination of diethvlamine from dimethvl maleate (Fie. 1).Althoueh we have conducted the isomerization using several amines, diethylamine seems to work best4
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Identification of the Product The student's initial hypotheses about the reaction mechanism and product usually include either simple conjugate
addition of diethylamine to dimethyl maleate (without subsequent elimination) or formation of the mono or bis diethylamide. The 'H NMR spectrum of the product, however, markedly resembles the spectrum of dimethyl maleate and clearly indicates the absence of the one or more diethylamino moieties that would be present in the addition product or monolbisamide. This information together with GCMSD and mp data unambiguously identify the product as dimethyl fumarate. The two isomers are easily C on a n HP-1 capillary column using a resolved a t 50 O Hewlett Packard (HP) 5970 GC with detection by an HP 5890 Mass Selective Detector (Fig. 2). 13C,APT,and C-H HETCOR data (Fig. 3) can also be provided3for additional assistance in product identification. Experimental procedure5
Tare a 15-mLround bottom flask containing a magnetic stir bar. Charge the flask with diethylamine (0.50 g, 6.8 mmol) and dimethyl maleate (0.25 g, 1.7 mmol), and begin magnetic stirring of the mixture. Although crystal formation usually occurs within 5-10 min, continue stirring for an additional 10 min once crystallization seems compicte. Remove as much of the liquid as poasible by I'asteur pipet and then free the crystais of remaining liquid by r&ry evaporation in vacuo for 15-20 min, making sure that the bath temperature is less than 30 "C to avoid premature sublimation of the product. Determine the weight of crude product in the tared flask. Save a small sample for mp analysis, reweigh the flask to determine the weight of sample to be purified, and transfer.the remaining crystals to a 125-mL filter flask for sublimation a t atmospheric pressure. Fit the neck of the filter flaskwith a #3 neoprene conical filter adapter and attach a drying tube to the vacuum nipple (Fig. 4). Insert a cold finger consisting of a 16- x 150-mm test tube filled with ice water into the flask. The cold finger should be suspended about 15 mm above the crystals by the snug fit ofthe filter cone around the test tube. Clamp the sublimation apparatus in a Thermowell heater or sand bath and heat gradually to 100 C . During this time large spars of sublimate should grow from the cold finger. Maximumcrystulgrowthoccum hetween80and 100 "C. If the cold finger inside the flask appears wet early in 'A~tnorto whom corresponoence snoL d oe adaressed. 2CMRana AEP (Paclc Lulneran Lnlversiry undergraduates)were supported by summer research stipends from the Robert C. Olsen Fund and M. J. Murdock Charitable Trust, respectively. APT, and C-H 3Copies of 300 MHz NMR spectra ('H, HETCORI and GCIMSD data can be obtained from CBF. bv the 4Theisomerization of dirnethvl rnaleate to dimethvlfumarate ~, . . ~, actionof severa pr rnary and ;econoary am nes was oescrbea by C emo an0 Graham In J. Cnem. Sac.. 1930.213 5An eq~iprnenrreagent I st and a StJdenl hanoo-t wllh expermental information for the isomerization reaction can be obtained from CBF. ~
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Figure 1. Mechanism for the amine-catalyzed isomerization of dimethyl maleate to dimethyl fumarate. Hydrogens ofstereochemical interest are labeled 'H and b ~ .
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Journal of Chemical Education
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160
I80
200
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Figure 2. (a,left, above)GCIMSD data (aftersublimation)for product of the reaction of dimethyl maleate with diethylamine. (b,left , below) GCIMSD data for dimethyl maleate. Retentiontime: 10.7 min, m/z: 144, 113, 99, 85, 69, 59. (c, above) GCIMSD data for admixture of dimethyl maleate and dimethyl fumarate stock reagents. Dimethyl fumarate retention time: 11.4 min, m/z: 144, 113. 100, 85. 69, 59.
bulk of the amine as well as anv residual dimethvl maleate. The duration of rotary evaporation is kept to minimum in order to reduce the loss of dimethyl fumarate by premature sublimation. The sublimation apparatus used is similar to those wmmonly described in organic laboratory texts (3). Student yields after sublimation average 65%, with melting ranges centered about 95 "C. The melting point is slightly depressed due to the small amount of amine-addition product that sublimes with the fumarate. ~ecrystallizatio~ produces higher melting points, but sacrifices the o ~ ~ o r t u n ito t ydemonstrate sublimation. ~ l t h o u &blimat$n ~h of the crude product produces very gratifymg visual results, it is important that students gain an appreciation for factors that may influence the limited abilitv. in this case. of sublimation to purify the isomerization Goduct. Such considerations shoild either be included in the instructor's remarks accompanying the experiment or in questions posed to the students. If purity of the product is the overarching goal, recrystallization can be employed, as noted earlier.
a
the sublimation, remove the cold finger with the filter cone, wipe it dry, and replace it quickly. After the sublimation is complete, allow the flask to cool. Remove the water from the cold finger by Pasteur pipet. Gently, and in one operation (to minimize the falling of sublimate onto the residue on the bottom of the flask), tilt the apparatus to pour out the icelwater and then, while it is still tilted, carefully remove the cold finger and collect the sublimate from it and the upper walls of the flask. Determine the yield and melting point of the sublimed crystals (lit. mp 102 OC (2)). Rewrd the 'H NMR spectrum (as well as %,APT, andC-H HETCOR, if available) and obtain GCIMSD data for your reaction product. Identify the unknown compound by interpretation of the NMR spectra, melting point, and GCIMSD data, and propose a detailed mechanism for its formation. Answer any other questions that may have been specified by the instructor. Notes on the Procedure
Withdrawing the liquid portion of the reaction mixture by Pasteur pipet before rotary evaporation removes the
Acquisition of Spectral Data
Depending on the NMR spectrometer used, a 25-mg sample of the product dissolved in 0.5 mL of CDCla allows collection and plotting in about 10 min of 'H, 13C,APT, and C-H HETCOR FT-NMR ~ p e c t r aFor . ~ GCIMSD analysis, a 0.5-pL injection of a l-mglmL sample prepared in anhy6A General Electric QE-Plus 300-MHz spectrometer was used to acquire the FT-NMR data presented in Figure 3, where a macro provided with theQE-Plussoftwareproduced thisdatain under 9 min.
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APT
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't 80
60
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20
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Figure 3. FT-NMR data for the sublimation product. drous diethyl ether works well. The oven temperature parameters (HP-1column) are as follows: 50°C isothermal for 12 min, followed by ramping a t 15 ' C h i n to a final temperature of 240°C to clear the column. Even though the maleate and fumarate esters are resolved a t 50 'C under the given conditions, ramping to 240 "C elutes the minor contaminent of conjugate addition product present in the sublimate. (Consideration by the students of the mass spectrum from this minor GC peak can be a hint regarding the mechanism.) Solubility tests on the product may also be run to provide additional information for its identification.
Discussion Princiules of stereochemistrv and conformational analysis relevant to conjugate addition and alkene-forming elimination reactions are ex~loredin this ex~erimentwhen the students postulate mechanisms for themaleatetfumarate isomerization. The concept of diastereotopic relationships is used when they consider the possibility for formation of either maleate or fumarate. To wit, elimination of bH (Fig. 1) from the diethylamine-maleate addition product to form dimethyl fumarate versus elimination of 'H to reform dimethyl maleate highlights the diastereotopic nature of these two hydrogen atoms. This experiment provides a n excellent opportunity to discuss the biochemical importance offundamental organic reaction mechanisms and stereochemical principles. For 1052
Journal of Chemical Education
example, the biological significance of diastereotopic hydrogens and elimination reactions is made clear by the mechanisms of arginosuccinase and adenylosuccinase ( I ) . Both of these enzymes catalyze the formation of fumarate by elimination of an -NHR moiety during the respective elimination reaction catalyzed by each.7 Additional consideration of conjugate addition reactions could be incorporated through questions assigned to the students about these enzymatic reactions or other examples. For instance, students could be asked to predict the result from reaction of di-tert-butyl malonate with benzalacetone (4). All of these topics could be raised either by supplementary lecture material or in the form of exercises for the students. References to background material on pertinent reaction mechanisms should be provided with the exercises in either case (1,5). Reactions such a s this one that yield products whose identity is not obvious are excellent vehicles for providing organic unknowns to students. We have used this diethylamine-catalyzed isomerization of dimethyl maleate in this capacity, along with other reactions that give unknownproducts, in our Organic Special Projects laboratory Rather than simply give each student a n organic unknown '~igures depicting the mechanisms of arginosuccinase and adenylosuccinase are provided in Waish, Mechanisms of Enzymatic Reactions (1).
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16mm x 150mm testtube, to be
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Figure 4. Apparatus for sublimation at atmospheric pressure. as a pure compound or hinary mixture, a s is traditionally done, a more realistic experience in chemistw is provided bv characterization. and identification of ~" the ~ - ourification. - ~ a n unknown compound generated b i a chemical reaction (which typically give crude products that are challenging mixtures). During the identification of the unknown product the student can use her or his develo~ineknowledee of organic reactivity and reaction mechanisms and a t the same time a ~ o"l vinstrumental and traditional methods available for product analysis.8 &
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Conclusion Some isomerization reactions that have ~reviouslvbeen described a s undergraduate laboratory ex'perirnents have included carbon skeleton rearrangements, such a s the alu~~
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'Furlher educational value can be gained from the dimethyi maieatenumarate isomerization reaction by incorporating the HPLC anaiysis and thermodynamic considerations discussed in Lediie, D. 0.; Wenzel, T. J.; Hendrickson, S. M. J. Chem Educ. 1989, 66(9), 781.
minum ehloride-catalyzed formation of adamantane from endo-tetrahydrodicyclopentadiene(61, and geometric isomerizations of alkenes, such a s the photochemical trans to cis isomerization of 1,2-dibenzoylethane (7) and the halogen and light catalyzed isomerizations of (Z,E)-l,4-diphenyl-1,3-butadiene (8)and dimethyl maleate (9, 10).Anumher of these reactions utilize noxious reagents, including aluminum chloride and bromine. Some also require nontrivial workup prcxedures, and one proceeds in very low yield. I n contrast, the isomerization described here is brief, utilizes relatively imocuous reagents, and simply involves removal of the amine solvent/eatalvst bv e tevaDo" " ~. .i ~and ration followed by sublimation of the ~somcrizedd~ester. In short. the diethvlamine-catalvzed isomerization of dimethyl kaleate is a"simple and rL1iable reaction that is eminentlv suitable for studv in the undereraduate laboratory he isomerization reiction affords opportunities to consider stereochemical principles that have far-reaching importance to organic chemistry and biochemical pathways. Furthermore, this experiment incorporates application ofimportant moderninstrumental methods for organic structure analysis. Acknowledament " Pacific i.utheran ilniversity gratefully acknowledgesNationai Science Foundation grants CSI 8650770 and USE895065 1, rripectively, for assistance in the purchase of the GC MSD and FT-NMR instrumentation used. Additional fundine from the M. .I. Murdock Charitable Trust for the F T - N ~ Rspectrometer and summer stipends for CBF and KEP is also appreciated. Martha A. Riggers and Michael Thielman helped with the development of some aspects of this experiment. Llterature Cited 1. Walsh, C.EniymaficRmtlonM&nisms:W.H.
Freeman: San Prandsco, 1919; pp 567-569 andreferences cited therein. 2. DiFt~naryofOrganianiCompaunds,5thd.;Bu~ham,J.,Ed.;ChapmanandHall: New York, 1982,Vol.3. 3. For examples see: (a1Williamson, K L. Moemmie and Micmsmle OrgonicExpee"tents; Heath: Leuogan, MA, 1969; pp 111 snd 114. 1bl Mayo, D.: Pike, R. M.: Butcher, S. S. MlcrmcobOrgonicLabomfory. 2nd ed.: Wiley: New York,1989: pp
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4. Coutlangus, M. L.:FiUa,S.A.:Rawhd,A.T. J ChemEduc 1989,66(61,520. 5. Is) March. J.,A d u a d Ogonic Chemistry, 3rd ed.; Wiley: New York,1985; pp 664-666.sndrefereneeeeitedthereii.ineluding5bbelow.1b)PataiandRappopart. inPatai. TheCh~mlstryofAlkenes;Wlley-1nterscience:NervYork. 1964:Vol. 1,pp. 461C564. 6. (a1 Ault, A. T=hnGpes ondEzperiment8 far Organic Chrmistry, 5th ed.; AUyn and Becon: Boston, 1987: pp 346348. (bl The above is baaed on Ault, A,; Kopet, R. J Chem. Educ 1969.46.612, 7. la)Seeref~,pp3~-351.(b)Mayo,D.;Plke,R.M.;Butcher.S.S.MicmsmkOrgonic Lobomfory.2ndod; Wiley:NewYmk, 1989:pp 10&116. 1elTheaboveareadapted from: Paste, D. J.;Oucan, J. A.; Silversmith, E. F. J Chrm. Educ 1974,51,277 and Silversmith. E. F.; Dunsun, F. C. J. Chem. Educ 1973.50.568. 8. Pavia, D. L.; Lampman, G. M.; f i z , 0.S. Intmdudlon fo Organic Laboratory Techniques, 3rd ed.; Ssunders:New York, 1988: pp 39W04. 9. Iadlie,D. B.; Wenzel, T. J.;Hendtickaon. S.M. J ChrmEdue. 1989,66191,781. lo. Lehman, J.W. Opemiload Orgonic Chemistry, h d ed.; AUyn and Bamn. Ine.: Boston, 1985;pp. 114-122.
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