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the microscale laboratory
ARDENP. ZIPP SUNY-Conland --ndsNy13045
The Microscale Synthesis and the Structure Determination of Ende%;yethoxycarbonyI3-oxatricyclo[4,2,1,0 1-2-nonanone Moses Lee Furman University Greenville, SC 2961 3 Modem spectroscopic instruments are important tools in contemporary organic chemistry. Examples are FT-NMR, multinuclei and two-dimensional methods FT-IR GC-mass spectrometry As art of our so~homorecourse in organic chemistry, we. wanted to introduce these important spectroscopic methods and several other commonly used techniqucs into the laboratory exercises: gas chromatography
thin-layer chromatography column chromatography We hoped that this would provide well-rounded training for students. Accordingly we have developed a laboratory exercise on the synthesis and structure determination of endo9-methoxycarbonyl-3-0xatricyelo[4,2,1,0~~1-2-nonanone (1) that will demonstrate the modem experimental techniques mentioned above. Synthesis of the Compounds The svnthesis of the titled com~ound(1) starts from the ~iels-/;lder rcaction of malcic anhydride with cyclopentadiene to give endo-hicyclo[2:2,1 Ihept-3-ene-23-dicarboxylic anhydride (2). The regm- and stnreospecificity, as well a s the hiah efficiencv of this reaction, have made it popular in organic chemistfi laboratory. Anhydride 2 is hydrolyzed with water to give endo-bicyclo[2,2,llhept-5-ene-2,3-dica1boxylic acid (3).Upon treatment with concentrated sulfuric acid, this provides lactone 4 in good yield (I)' Recently, procedures for performing these reactions on a microscale have been developed (2). The preparation and structure determination of compound 1, a s a n extension to the laboratory exercise on the synthesis of lactone 4, bas several advantages in the teaching of modem techniques in organic chemistry. Microscale esterification of compound 4 (about 200 mg) gives the titled compound 1in good yield. Then the crystalline product can be purified by either recrystallization or silica-column gel chromatography.
a s a brown spot by exposure to iodine vapor. This provides a quick method for analyzing the purity of the product. IR data and 'H- and 13C-NMR data are obtained. Since the signals in the ' H - N m spectrum (Fig. 1) a t 300 MHz are well-separated and well-resolved, the coupling constants of each proton signal can be readily obtained. Furthermore, the proton signals are assigned using 2D-NMR, such a s COSY (Fig. 21, which gives off-diagonal peaks or cross peaks that show the correlations among pairs of nuclei by their spin-spin coupling (3).The '%-NMR signals can be readily assigned using the attached proton test (4). ,,.
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Analyses Compound 1 separates well on a silicagel thin-layer chromatography plate, and the product can be visualized 'One of the exercises on the synthesis of lactone 4, given in ref id, includes the elucidation of its structure using a combination of IR data and. 'H- and. '3C-NMR data. Then a mechanism for its formationfrom . d~ac~d 3 1s proposed A172
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Figure 1. A 300-MHz 'H-NMR spectrum of compound 1, which was recorded on a Varian VXR 300s spectrometer. The assignment of the chemical shifts to sDecific Drotons of com~ound1 are given bv the . numbers on the spectrum.' (Continuedon page A174)
the microscale loborotory uated pipet. Cool the mixture in an ice bath. Remove from the bath, and add 0.1 mL of dry dimethylformamide over molecular sieves 3A. Swirl the contents. Loosely cork the test tube, and label it with your name. Allow it to stand in the hood for about 1h, or warm the test tube at 50 'C for 15 min. Connect the test tube to an aspirator and evaporate the excess thionyl chloride by keeping it under aspirator vacuum for about 5 min and warming to about 30 'C. (Be sure that the drain in the sink is tilled with ice during this process.) Cool the residue in an ice bath. Then add a solution of 1mL of methanol and 0.25 mL of pyridine, and swirl for 5 min. Warm the mixture in hot water at about 50 'C for 10 min, and pour the contents into 10 mL of ice water. Extract the aqueous layer with three 25-mL of portions ether using a separatory funnel. Combine the ether extracts, and wash them with 5 mL of 1M HC1. Dry the ether layer with anhydrous sodium sulfate. Then filter it, and concentrate it in a tared flask using a rotary evaporator. This will give compound 1as a white solid, which is essentially homogenous by TLC and 'H-NMR analysis. The solid residue is recrystallized from ether-hexane, and the vields obtained bv students were 40-70%. " Melting point: 77-78 'C. TLC (40% ethyl acetate-hexanel: Rf = 0.22. Spectral Data for Compound 1 IR Data
Proton NMR Data 'H-NMR (CDCI, 3 0 0 MHz) S 4.75 (dd, 5.1, 8.1, H4), 3.65 (s, OCH,), 3.23 (dt, 1.2, 5.1, Ha), 2.95 (ddd, 2.1, 2.4, 10.5, H9), 2.10 (dd.5.1.10.5.H1),2.58(sbr,H6),2.13(dd,2.1,14.4,H5a), 1.61(m,
Figure 2. COSY spectrum of compound 1. Experimental conditions: pw and pl = 90'; relaxation delay = I s ; np = f n = fnl = 512; and 16 FID's were collected for each of the 64 increments. Quaternary and methylene carbons give positive signals, while methyl and methine carbons give negative signals. Esters can be separated using gas chromatography. Thus, compound 1can also be analyzed by GGmass spectrometry to obtain data on the retention time, purity, and mass spectrum of the compound. The appearance of a molecular ion ~ e a at k n l z = 196 and the fragmentation pattern in the mass spectrum provide the student with additional informat~onin the determination of the structure of ester 1. This aids the determination of the structure of compound 4. The entire experiment for the synthesis of 1 from acid 4, plus the characterization of the former com.pound, takes an average of three hours.
Carbon NMR Data 13C-NMR (CDCI3, 75.4 MHz, - signals for CH and CH3; + signals far C and CH2) S 177.9 (C2, +), 171.2 (6C02-, +), 80.1 (C4, -1, 51.7 (-OCH3,-1, 48.4,48.1 (C1 and C9, both-), 41.6 (C8,-L39.4 (C6, -), 31.6 (C5, +), 32.9 (Cl, +). GC-MS Data GC-MS (HP5890A, 12 m x 0.2 mm Hp-1 cross-linked methyl silicone (film thickness:0.33 ~ m capillary ) GC column) retention time 12.6 min.
MS Data MS ( d z , re1 int.) 196 (Mi, 7), 165 (M+-OCH3,23),152(M%02, 29), 93(M%O-COzCH,, 14).
Literature Cited
Experimental Preparation of Compound I Place 200 mg (1.10 mmol) of compound 4 and 0.25 mL of thionyl chloride in a 13- x 100-mm test tube using a grad-
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1. islDiels,O.;Alder,K.h. 1928,348,9M22.(b1Staehnn,H.J Ov. Chem 1981, 26,2025-2029. (el Sheppard, W. J. J. Chem. Edue 1863,40,4%41. id1 Fie8er.L. F.: Williamson, K L. Orgonr Experiments, 7th ed.; D. C. Heath and Company: k i n g t o n 1992;pp 28S294. 2. Williamson.K. L. Micmseolp &gonlcEqerimonta: D. C. Heath: bidngtrm, 1987,pp
253-2M.
3. Williams, K R.;Kin& R. W J. Chem. Ed. 1890,67,A125-A137. 4. Pstt 5. L.:Sehoolq, J. N. J. Mogn. &son. 1982.46.535-539.
