A Quantitative Organic Analysis Using Carbon Magnetic Resonance A Study in Enarnine Isomer Distribution and Relative Stabilities A. Gilbert Cook Valparaiso University, Valparaiso, IN 46383
The FT-NMR spectrometer is one of the most important tools for the modern organic chemist. There are few undergraduate experiments published that utilize the I3C capabilities of this instrument.' The following experiment involving the synthesis of enamines demonstrates the use of CMR in quantitative analysis. It also shows the usefulness of molecular modeling. Proton magnetic resonance is commonly used in introductory organic chemistry laboratories to determine quantitatively the relative amounts of products obtained in an organic reaction. Carbon magnetic resonance is more difficult to use in quantitative analysis because of the nuclear Overhauser effect(NOE)that tends to increase the line intensities for carbons with protons bonded to them as contrasted to quaternary carbons which remain unaffected, and the long relaxation times of many 13C nuclei that lead to lower intensities in varying degrees for the carbon atoms. The most common method for synthesizing enamines is the acid-catalyzed reaction between a ketone or aldehyde and a secondary amine ( I ) . In the case of ketones, this reaction can lead to two or more possible isomers. For example the reaction between 2-methylcyclohexanone (1) and pyrrolidine (2) leads to a mixture of two structural isomers (241, and the l-pyrrolidino-6-methylcyclohexeneisomer (3)exists in unequal amounts of two conformers with the axial conformer being the predominant conformer (2, 5). The reaction is thermodynamically controlled, so that the relative amounts of each of the product compounds is determined by their relative stability. The pyrrolidine enamines shown above are formed readily. However, they are rather unstable and colorize in the presence of atmospheric oxygen. In addition only a small portion of the product mixture is tetrasubstituted isomer 4 (10%) (2). So this is not the best reaction to be performed and analyzed by students. A better reaction (even though it reacts a t a slower rate) is t h e reaction of morpholine (5) with 2methylcyclohexanone (1). This enamine remains stable and colorless over a reasonable period of time. The methyl proton signals for 6 and 7 appear a t 0.98 (d) and 1.61 (s) ppm, respectively. However, the latter signal is overlapped by other methylene signals, and the former signal is overlapped by the residual starting ketone's methyl signal (0.97 ppm (dl. So CMR is a better oution for ouantitative analvsis since the I3C signals do ndt overlap. some of the chemical shifts for each of the rnorpholine and pyrrolidinc cnamlnes shown in the 'The instrument used by the author is a Bruker AC 200 FT-NMR. Partial funding for this instrument was provided by the National Sci-
equations above along with those of starting ketone 1are listed in the following table. Comparing methyl group signals is the best method for determining the relative amounts of the isomers because this triprotonated carbon should have the shortest spin-lattice relaxation time (TI,. Wc also will bc comoarine identical tvDrs of carbons. Furthermore, the presence of starting ketone 1does not interfere with the enamine methyl signals. The TI for enamine 6's methyl is 2.52 s, and that for enamine 7's methyl is 4.96 s. The rule ofthumb is a relaxation delay time of 5T1which would mean a delay of about 25 s between pulses. The T;s for C1and C2in these enamines are much longer.
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Experimental In a 100-mLround-bottomed flask equipped with a magnetic stirrer and stirring bar, a Dean-Stark trap, a reflux condenser and an electric heat source is placed 5.6 g (0.05 mole) of 2-methylcyclohexanone, 9.2 g (0.08 mole) of morpholine, 0.05 g of p-toluenesulfonic acid, and 50 mL of toluene. The stirred reaction mixture is refluxed until about 0.9 mL of water is collected in the DeanStark trap (about 1to 2 h). The toluene solvent and excess reactants are removed using a rotating evaporator under aspirator vacuum and steam bath heat. The mass of the residual oil is measured. The residual oil can be used directly without further purification to obtain an infrared spectrum and a CMR spectrum. The crude yield can be calculated by measurina the relative area of the startine ketone's methvl " sienal (14.5 ppm, Tl 5.12 s) as compared to that of the enamines. This assumes that the starting ketone is the only contaminant and that none of the ketone is lost during evaporation.
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Volume 70 Number 10 October 1993
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Some 13cChemical Shifts (ppm) Good CMR data is obtained either by usinginverse gated decoupling with a 30-s relaxation delay time between pulses, or by using a relaxation agent such a s ferric acetylacetonate (ACAC) with a 5-s delay time. The literature values for percentaces of 6 and 7 of 52% and 48%. correspond closely to those obtained b i respectively (3,4), this method. The pvrrolidine enamine isomeric mixture is reported to havepercentngesof9Ori for3 and 10': for4 t.?, 4). The uyrrolidine reaction can hc used Instead ufthe morpholincreaction with the advantage of its being a faster reaction. The disadvantages of this reaction were mentioned above. DEPT (Distortionless Enhancement by Polarization Transfer) spectra or some similar APT (Attached Proton Test) spectra should be obtained by the students for their samples in order to introduce them to the use of this technique. This technique will indicate the number of hydmgen atoms attached to each of the carbon atoms. These spectra will help them to make assignments to the various CMR signals in their samples rather than having the instructor give the students this information. All of these techniques generate subspectra that differ according to the pulse widths or angles used to produce them. The DEPT technique carries out two functions. The first function is spectrum editing that occurs by obtaining spectra at the following pulse angles: 45' (pmtonated carbon signals only, CH, CH2, and CHd; 90" (tertiary carbons, CHI; and 135' (primary and tertiary carbons, CH and CH3, are phased up and secondary carbons, CH2, are phased down). The second function is enhancing the 13Csignal intensity by a factor of four using polarization transfer. A 2-D heteronuclear COSY (COrrelated SpectroscopY) spectrum of UC and 'H should then be given to the students to help them complete the assignments. This correlated spectrum shows coupling between hydrogen and carbon atoms on the contour diagram by points that connect the hydrogen and carbon signals. The infrared spectrum of the morpholine reaction mixt u r e shows bands a t 1713 (ketone G O ) , 1682 (tetrasubstituted enamine C=C), and 1642 cm" (trisubstituted enamine C=C).
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Journal of Chemical Education
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Compound 1
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-CH3
C1
C2
C6
14.5
213
45
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Relative Isomeric Energies from Molecular Modeling Trisubstituted enamines 3 and 6 can each exist as two possible conformers, one with the methyl in a pseudo-axial position and the other in a pseudo-equatorial position. The students can determine which conformer is more stable by using a molecular modeling program such as PCMODEL, LabVision, or Spartan.' The more stable conformer has been shown to have the methyl group in a pseudo-axial position (4). This is due to A". strain (1, 6). The relative stabilities of the tetrasubstituted isomers~. (4 or 71 compared to the t~isubstitutedisomers (3ur 6) can be determined in a similar manner. Thc neater stabil~tvofthe trisubstituted isomer is due to theiarge A".3' strain (I, 6)in the tetrasubstituted isomer. This strain is greatest for the pyrrolidine enamine where pi-overlap is the greatest. The students should discuss these sources for differing stabilities in their reports. This exercise also gives the students experience in using a molecular modeling program in which they obtain graphical as well as numeric output.
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Literature Cited
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4. Gurowitz, W.D.; Jaaeph, M.A. J Drg C h m 1981.32.3289.
6.Toume,O.;VanBinst,O.:deGrssf,S.A.G.:Pandit,U. K.Or& MognRosononcelWS. 7,433. 6. Johnson. F Chem. RPu.1868.68.315.
2 ~ C ~ o d Serena el, Sofhvare, Blooinington, IN; LabVision, T r i p s Associates, St. Louis, MO;Spartan, Wavefunction, Inc., Irvine, CA.
