1. via a low energy barrier, the dominant product will be determined by the activation barrier to form each product. 1 The benzene oxide/oxepin system plays a critical role in benzene metabolism. The interconversion of benzene oxide to oxepin is calculated to be exothermic by less than 1 kcal/mol, and has an activation barrier of only 6 kcal/mol. 2 As the barrier is so small, the dominant products of the reactions of either benzene oxide (1A) or the oxepin (2A) in any concerted process, such as a Diels-Alder reaction or an epoxidation, is thought to be determined based on the Curtin-Hammett principle. Computational studies, performed at the B3LYP/6-31G(d) level of theory, of the benzene oxide system and two dimethyl derivatives, 1,2-dimethylbenzene oxide/2,7- dimethyl oxepin (1B/2B) and 3,4- dimethylbenzene oxide/4,5-dimethyl oxepin (1C/2C), followe the reaction pathways for Diels Alder reaction with both maleic anhydride and E or Z- azodicarboxylates and for epoxidation with dioxirane. Curtin-Hammett Principle: Application to Benzene Oxide-Oxepin Tautomers Jessica P. Morgan and Arthur Greenberg Department of Chemistry, University of New Hampshire The top three depictions to the right show the reaction diagram for the reaction of the benzene oxide/oxepin system (1A/2A) with maleic anhydride (MA), dimethyl-E(or Z)-azodicarboxylate (E-AZDI or Z-AZDI), and dioxirane (DIOX) respectively. Images of the transition state geometry appear below each of the diagrams. In the case of MA, the benzene oxide is the intermediate that reacts with the MA, 3 however, both E-AZDI and Z-AZDI react with the oxepin and not the benzene oxide. It is important to note that whether E-AZDI or Z-AZDI reacts with the benzene oxide/oxepin system, the product formed is trans due to the low inversion barrier of amines. In the case of epoxidation of the parent system, the epoxidation of oxepin is favored slightly over a second epoxidation of benzene oxide. In the Diels-Alder reaction with MA, all three benzene oxide/oxepin systems, 1A/2A, 1B/2B, and 1C/2C (respectively from top to bottom), the product distribution would favor the adduct from the benzene oxide. However, in the case of the 1B/2B system, the product is favored only slightly when the difference in energy of the benzene oxide/oxepin is taken into account. While in equilibrium, the majority of valence tautomer resides as 2,7-dimethyloxepin rather than 1,2-dimethylbenzene oxide since the oxepin is 5 kcal/mol lower in energy than the benzene oxide. Z-AZDI endo attack was predicted to have a lower energy barrier than E-AZDI with each benzene oxide and oxepin. 3,4-Dimethyl derivative of benzene oxide is predicted to form the adduct, whereas, both the parent oxepin and the 2,7-dimethyl oxepin form the adduct. This is confirmed experimentally by Rastetter and Richard. 4,5 The Z-AZDI and E-AZDI were originally thought to interconvert as well causing a “double Curtin-Hammett” effect, however, the barrier to inversion from Z to E is 32.6 kcal/mol, 2,6 greater than most of the activation barriers of the Diels Alder reactions. Epoxidation by dioxirane, is more likely to occur with oxepin than with the benzene oxide. However, it is noteworthy that formation of 2,3-epoxyoxepin is calculated to be more exothermic than 4,5- epoxyoxepin, but 4,5-epoxyoxepin is predicted to form more rapidly. Experimental results have shown that while the 2,7-dimethyloxepin forms only the 2,3- product, 8 the reaction of dimethyl dioxirane with the parent system produces only the 4,5-product. 7 The equilibrium of benzene oxide/oxepin tautomers is of interest in studies of benzene metabolism. While 2,7-dimethyloxepin is the only detectable species of the equilibrium, it is the benzene oxide which undergoes Diels-Alder reaction with maleic anhydride. Calculations of the azodicarboxylate seem to follow experimental results, but only for the Z-dimethyl not for the E-dimethyl. The E is commercially available, but the transition barrier between E and Z is comparable to or greater than the barriers for the addition to the benzene oxide/oxepin. Epoxidation occurs preferentially the oxepins, but whether the 2,3- or the 4,5- is formed is difficult to predict. The Curtin- Hammett Principal states that if two intermediates (I1 and I2) are rapidly interconverted INTRODUCTION 1.Hammett L. P., Physical Organic Chemistry, Second Edition, McGraw-Hill Book Co., New York, 1970, pp 119-120. 2.Morgan, J., Greenberg, A. Struct. Chem., published online May 2013 doi: 10.1007/s11224-013-0274-5 3.Vogel, E., Günther, H., Angew. Chem. Int. Ed. Engl., 1967, 6(5), 385-401 4.Rastetter, W. H., Richard, T. J., Tetrahedron Lett., 1978, 2995-2998. 5.Rastetter, W. H., Richard, T. J., Tetrahedron Lett., 1978, 2999-3002. 6.Vrábel, I., Biskupič, S., Staško, A., J. Phys. Chem. A, 1997, 101(32), 5805- 5812. 7.Bleasdale, C., Cameron, R., Edwards, C., Golding, B. T., Chem. Res. Tox., 1997, 10(12), 1314-1318. 8.Greenberg, A., Ozari, A., Carlin, C.M., Struct. Chem., 1998, 9(3), 223-236 CONCLUSIONS RESULTS AND DISCUSSION REFERENCES Ground state molecules calculated in this study. A series: (R 1 = R 2 = H); B series: (R 1 = CH 3 ; R 2 = H); C series: (R 1 = H, R 2 = CH 3 ) MAE-AZDI/Z-AZDIDIOX