Curtin-Hammett Principle: Application to Benzene Oxide-Oxepin Tautomers
Jessica P. Morgan and Arthur Greenberg
Department of Chemistry, University of New Hampshire
INTRODUCTION
RESULTS AND DISCUSSION
The CurtinHammett
Principal states
that if two
intermediates
(I1 and I2) are
rapidly
interconverted
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.
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.
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/2,7dimethyl oxepin (1B/2B) and 3,4dimethylbenzene 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.
Ground state molecules calculated in this study. A series: (R1 = R2 =
H); B series: (R1 = CH3 ; R2 = H); C series: (R1 = H, R2 = CH3)
MA
E-AZDI/Z-AZDI
DIOX
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 4,5epoxyoxepin, but 4,5-epoxyoxepin is predicted to
form more rapidly. Experimental results have shown
that while the 2,7-dimethyloxepin forms only the 2,3product,8 the reaction of dimethyl dioxirane with the
parent system produces only the 4,5-product.7
CONCLUSIONS
• 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.
REFERENCES
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), 58055812.
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