582 Journal of Chemical Education • Vol. 74 No. 5 May 1997In the Laboratoryendo- and exo-Stereochemistry in the Diels–Alder Reaction:Kinetic versus Thermodynamic Control1James H. Cooley and Richard Vaughan WilliamsDepartment of Chemistry, University of Idaho, Moscow, ID 83844-2343In these experiments, which were used in the problem-solving mode (1), the stereoselectivity of the Diels–Alder cy-cloaddition of N-phenylmaleimide to furan is deduced by thecharacteristic splitting patterns in the proton-NMR spec-tra. The relationship of coupling constants to dihedral angle,as described by the Karplus equation, is illustrated. Thedata can also be used to demonstrate the concept of kineticversus thermodynamic control.Two recent papers in this Journal reported laboratoryexperiments illustrating the stereochemistry of the Diels–Alder reaction (2, 3). Pickering (2) described the reaction ofmaleic anhydride with cyclohexadiene, α-phellandrene, andfuran. Cyclohexadiene and α-phellandrene gave the endostereoisomer, whereas furan gave the exo stereoisomer.These experiments were used in the problem-solving modeand students were asked to decide, by comparing their datawith that in the literature, which stereoisomer was formed.In another experiment, Harrison (3) used NMR to study theDiels–Alder reaction between norbornadiene andphencyclone (reaction 1). The stereochemistry of this reac-tion was established from the fact that the methylene pro-tons lie in the shielding cone of the aromatic system. (1)The majority of general organic chemistry texts presentthe Diels–Alder reaction as yielding endo products. In mostcases the exo product is the thermodynamically more stable,but the endo adduct forms much more rapidly, and kineticcontrol is observed (4). The exceptional exo stereochemistryof the furan–maleic anhydride adduct was first demon-strated by Woodward and Baer (5) using classical methodsand later confirmed by X-ray crystallography (6). More re-cently Lee and Herndon (7) demonstrated that the endo iso-mer forms more rapidly in a reversible reaction, resultingin the ultimate dominance of the thermodynamic (exo) prod-uct.In the norbornene (bicyclo[2.2.1]heptene) system, 1(which results from Diels–Alder additions to cyclopenta-diene), endo and exo stereochem-istry can be deduced experimen-tally from differences in the cou-pling constants of the bridge-head protons on C-1 and C-4(Hb) to the exo (Hx) or endo (Hn)protons on C-5 and C-6 (see be-low) (8).The geometry of the 7-oxabicyclo[2.2.1]heptene systemis very similar to that of thenorbornenes; consequently, thecorresponding coupling con-stants are very similar.We felt that an ideal experiment would be one in whichboth endo and exo products are formed, with each productgiving an NMR spectrum that students could use to assignstereochemistry. N-Phenylmaleimide (9) reacts with furanto produce a mixture containing the endo and exo isomers.These isomers may be separated by column chromatogra-phy as described below. As expected, the proton NMR of theendo isomer shows a coupled2 signal for the C-5/C-6 pro-tons (δ 3.8 ppm for the C-5/C-6 protons), while that for theexo isomer shows a singlet for the C-5/C-6 protons (δ 3.0ppm). These spectra are shown in Figures 1 and 2. Thesplittings of the bridgehead protons are more complex (ow-ing to additional coupling with the vinylic protons) andtherefore less diagnostic. Thus reaction ofN-phenylmaleimide with furan is an ideal system for teach-ing about the stereochemistry of the Diels–Alder cycloaddi-tion.The 7-oxabicyclo[2.2.1]heptene ring system is confor-mationally rigid. The difference in splitting patterns ob-served between the exo and endo adducts (2 and 3) resultsfrom the very different dihedral angles between the exo andendo protons (on C-5/C-6) and the bridgehead protons (onC-1/C-4). Examination of models of 2 and 3 indicates a di-hedral angle (H–C5–C4–H) of almost 90° for the exo isomer2 and a small dihedral angle for the endo isomer 3. Thesedihedral angles are calculated to be 83° and 33.8° respec-tively using AM1 (10) as implemented in the HyperChem(11) software package. Using the Karplus equation (12), J= 8.5 cos2θ – 0.28 where θ = the dihedral angle, the cou-pling constants for the exo isomer (2) and the endo isomer(3) are calculated to be 0.05 and 5.2 Hz, respectively.At room temperature, the reaction of N-phenyl-maleimide with furan may be run neat, in ether solution (amixture of the two isomers precipitate), or in benzene solu-tion (almost pure exo isomer 2 precipitates). Alternatively,in CDCl3 solution the reaction may be followed by NMRwith the following results (ratios obtained from integration[δ 6.8 for N-phenylmaleimide, 3.7 for endo, and 3.0 for exo]):1J (Hb,Hx) = 3.66 HzJ (Hb,Hn) = 0.55 Hz23emiTpmeToxe(2))%(odne(3))%(N-lynehp-edimielam)%(syad70°C639441syad7tneibma841411syad02tneibma86a32a9asyad7h5neht0°C06°C341263aEquilibrium ratio.Vol. 74 No. 5 May 1997 • Journal of Chemical Education 583In the LaboratoryFigure 1. Proton-NMR spectrum of endo isomer in CDCl3. For a student experiment, the first task is the prepa-ration of N-phenylmaleimide, which is then reacted with fu-ran (neat) for one week at room temperature. The productsare analyzed by thin-layer chromatography and NMR andseparated by column chromatography. Students are askedto determine the structures of all products (including thestereochemistry of the Diels–Alder adducts) and to providea theoretical explanation for the changes in endo to exo ra-tio observed in the NMR experiment.To do this students must understand the Karplus equa-tion well enough to decide which of the isomeric productswill show the observed splitting pattern in the NMR. In ad-dition, NMR data similar to those described above are ei-ther collected by students or provided to them for interpre-tation and explanation of the changes.Because the first product in the reaction series,maleanic acid, is not soluble in CDCl3, the NMR spectrumin d-6 DMSO was provided for student interpretation. Us-ing this and other IR and NMR spectral data, our studentshave had little trouble deciding onthe correct structures for themaleanic acid and N-phenyl-maleimide. Moreover, most ofthem concluded that two productswere produced in the Diels–Alderreaction, and that these are ad-ducts of the two reactants.To give students a betterchance to obtain the correct stere-ochemistry of the final products,we used a prelaboratory
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