The Mystery of the Benzene-Oxide/Oxepin Equilibrium—Heavy-Atom Tunneling Reversed by Solvent Interactions

Article abstract of DOI:10.1002/anie.202010452

The equilibrium between benzene oxide (1) and oxepin (2) is of large importance for understanding the degradation of benzene in biological systems and in the troposphere. Our studies reveal that at cryogenic temperatures, this equilibration is governed by rare heavy-atom tunneling. In solid argon at 3 K, 1 rearranges to 2 via tunneling with a rate constant of approximately 5.3×10^?5 s^?1. Thus, in a nonpolar environment, 2 is slightly more stable than 1, in agreement with calculations at the CCSD(T) level of theory. However, if the argon is doped with 1 % of H₂O or CF₃I as typical hydrogen or halogen bond donors, respectively, weak complexes of 1 and 2 are formed, and now 2 is tunneling back to form 1. Thus, by forming non-covalent complexes, 1 becomes slightly more stable than 2 and the direction of the heavy-atom tunneling is reversed.

Full text of DOI:10.1002/anie.202010452

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: The Mystery of the Benzene Oxide – Oxepin Equilibrium – Heavy
Atom Tunneling Reversed by Solvent Interactions
Authors: Wolfram Sander, Tim Schleif, and Melania Prado Merini
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010452
Link to VoR: https://doi.org/10.1002/anie.202010452

10.1002/anie.202010452
Angewandte Chemie International Edition
COMMUNICATION
The Mystery of the Benzene Oxide – Oxepin Equilibrium – Heavy
Atom Tunneling Reversed by Solvent Interactions
Tim Schleif,[a] Melania Prado Merini,[a] and Wolfram Sander*[a]
Dedicated to Prof. Wolfgang Kirmse on the occasion of his 90th birthday
[a]
Dr. T. Schleif, M. Prado Merini, Prof. Dr. W. Sander
Lehrstuhl für Organische Chemie II
Ruhr-Universität Bochum
Universitätsstraße 150, 44801 Bochum (Germany)
E-mail: wolfram.sander@rub.de

These authors contributed equally.
Supporting information for this article is given via a link at the end of the document.
and oxepin 2 was now the major constituent with 70%. The
Abstract: The equilibrium between benzene oxide 1 and oxepin 2 is
of large importance for understanding the degradation of benzene in
biological systems and in the troposphere. Our studies reveal that at
cryogenic temperatures this equilibration is governed by rare heavy
atom tunneling. In solid argon at 3 K, 1 rearranges to 2 via tunneling
with a rate constant of approximately 5.3 x 10-5 s-1. Thus, in a nonpolar
environment, 2 is slightly more stable than 1, in agreement with
calculations at the CCSD(T) level of theory. However, if the argon is
doped with 1% of H2O or CF3I, respectively, as typical hydrogen or
halogen bond donors, weak complexes of 1 and 2 are formed, and
now 2 is tunneling back to form 1. Thus, by forming non-covalent
complexes, benzene oxide 1 becomes slightly more stable than
oxepin 2, and the direction of the heavy atom tunneling is reversed.
equilibrium was also studied by low-temperature NMR
7]
spectroscopy in CF3Br/pentane mixtures.[5,
These studies
revealed that in this solvent 1 is energetically more stable than 2
by 1.7 kcal mol-1. However, the entropy favors 2, and at room
temperature G is approximately -1.3 kcal mol-1, thus shifting the
equilibrium towards 2 (Scheme 1). The rearrangement is very
rapid at room temperature, and temperatures below -120 °C were
necessary to sufficiently slow down the rearrangement to resolve
individual spectra of 1 and 2 by NMR.
Calculations at the CCSD(T)/def2-TZVP level of theory suggest
that the energies of 1 and 2 are nearly degenerate with 2 being
only 0.89 kcal mol-1 more stable than 1. This small energy
difference is below the accuracy of these calculations, and
therefore it is not clear which of the two valence tautomers is more
stable in the gas phase. Moreover, since the experimental
equilibrium constant is strongly solvent-dependent, it does not
reflect the intrinsic stabilities of 1 and 2. The same is true for the
kinetics of the 1 ⇌ 2 rearrangement, where the activation barrier
of 7.2 kcal mol-1 measured in CF3Br/pentane might be solvent-
dependent and not reflect the gas phase barrier.
Benzene oxide 1 is the primary product of the cytochrome P450
oxidation of benzene in eukaryotic cells.[1] Its high reactivity leads
to a number of secondary metabolites which are linked to the
toxicity of benzene.[2] Benzene oxide 1 has also been suggested
as an intermediate in the tropospheric benzene oxidation.[3] The
fundamental importance of 1 for the biological and environmental
benzene degradation has triggered a large number of studies on
this molecule. Most important for the understanding of the
chemistry of 1 is the rapid equilibration with its valence tautomer
oxepin 2 via a disrotatory electrocyclic rearrangement (Scheme
1).[4]
The opening of the C(1)–C(6) bond in 1 to form 2 requires only
small displacements of the C(1) and C(6) atoms. The largest
geometrical change is the increase of the C(1)–C(6) bond
distance from 1.50 Å in 1 to 2.29 Å in 2 (CCSD(T)/def2-TZVP),
while the displacement of the other atoms, including the H atoms,
is very small. Since both the activation barrier and the barrier
width are small, the 1 ⇌ 2 rearrangement is a viable candidate for
a rare heavy atom tunneling process. Prerequisite for efficient
heavy atom tunneling is a low activation barrier, but even more
important is a small barrier width.[8]
Scheme 1. Equilibrium between 1 and 2, thermochemical data from ref. [5].
The first synthesis of 1 and 2 as an equilibrium mixture was
reported in 1965 by Vogel, Böll, and Günther.[6] From the analysis
of the UV spectra at room temperature, these authors concluded
that the equilibrium is strongly solvent-dependent. In water –
methanol mixture 90% of 1 and only 10% of 2 was observed,
whereas in the nonpolar isooctane the equilibrium was shifted,
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202010452
Angewandte Chemie International Edition
COMMUNICATION
To shed light on the benzene oxide 1 – oxepin 2 rearrangement
and to provide evidence for heavy atom tunneling, the kinetics of
the rearrangement were measured at temperatures below 30 K in
rare gas matrices. At these temperatures, the available thermal
energy is far too low to overcome an activation barrier of 7.2 kcal
mol-1, and thus any observable rearrangement could be attributed
to tunneling. In addition, rare gases are weakly interacting cryo-
solvents, and therefore are not expected to introduce large
changes in the thermodynamics and kinetics compared to the gas
phase. The equilibrium mixture of 1 and 2 was sublimed at - 40 °C
through a tube at room temperature and deposited together with
a large excess of argon on a CsI window at 3 K. Under these
conditions, the room temperature equilibrium is rapidly quenched,
and thus the initial ratio measured in the matrix at 3 K resembles
the room temperature equilibrium. From the matrix IR spectra, the
ratio between 1 and 2 was determined to be 1:13 which
corresponds to ΔG298 = -1.51 kcal mol-1, in reasonable agreement
with our calculations at the CCSD(T)/def2-TZVP level of theory
which predict ΔG298 = -1.20 kcal mol-1 (Table 1).
Keeping the argon matrix in the dark at 3 K leads to the
disappearance of the peaks assigned to 1 and the concomitant
rise of signals assigned to 2 with a first order rate constant of
approximately 5.3 x 10-5 s-1 (Figure 1). Raising the matrix
temperature from 3 K to 25 K did not change the kinetics within
the error limit. Thus, the kinetics of the rearrangement is
temperature-independent even after increasing the absolute
temperature by a factor of 8 which suggests that the Arrhenius
activation barrier is zero. This is in contradiction to an activation
barrier of 7.2 kcal mol-1 measured in solution,[5] which strongly
indicates that the rearrangement is dominated by tunneling at
cryogenic temperatures.
Scheme 2. Examples of rearrangements of cyclopropane derivatives involving
heavy atom tunneling. The bonds in red are opening or closing.
Oxepin 2 is calculated to be 0.89 kcal mol-1 more stable than
benzene oxide 1 (CCSD(T)/def2-TZVP, Table 1), and therefore,
at 3 K the equilibrium should be completely shifted towards 2.
However, even after more than 10 half-lives, the ratio between 1
and 2 drops only from 1:13 to 1:20, much less than expected from
the calculated energy difference. A similar behavior was also
observed for the tunneling rearrangement of the deuterated
semibullvalene 11, where the tunneling was observed, but the
expected ratio of the isotopomers never reached.[13] An
explanation for this could be that trapping of 1 and 2 in an argon
matrix leads to a distribution of matrix sites with slightly different
geometries and interaction patterns resulting in a distribution of
energy differences between 1 and 2. Thus, the relative stability of
1 and 2 might depend on the matrix environment and even be
reversed for a small fraction of molecules.
Heavy atom tunneling has been experimentally observed in a
small number of examples,[8] many of those involving the opening
or the closing of a bond in three-membered rings (Scheme 2).
Thus, bicyclopentanes 3 are formed from cyclopentanediyls 4 and
bicyclobutanes 5 from cyclobutanediyls 6 via heavy atom
tunneling.[9] The highly strained cyclopropenes 7 and 9 undergo a
tunneling reaction to give the corresponding carbene 8 and
nitrene 10, respectively.[10] [11] All these reactions involve heavy
atom tunneling in the direction determined by the
thermodynamics of the rearrangement. The Cope rearrangement
in semibullvalene 11 is a degenerate tunneling rearrangement, so
there is no driving force. To become observable a small
thermodynamic driving force had to be introduced by asymmetric
deuterium substitution.[12, 13]
Table 1. Thermodynamic parameters (given in kcal mol-1 and cal mol-1 K-1) for
the ring expansion 1 → 2 as determined by experimental and computational
studies.
Ratio 1/2
ΔE0 K
ΔG298 K
ΔH298 K
ΔS298 K
298 K
3 K
calc.
- 0.17
- 0.89
- 0.02[e]
/
- 0.47
- 1.20
+ 0.14
- 0.59
/
2.03
2.05
/
1 : 2
1 : 1012
(DFT)[a]
calc.
1 : 8
1 : 13[f]
1 : 8
1 : 1064
1 : 20[e]
/
(CC)[b]
exp.
- 1.51[f]
(IR)[c]
exp.
+ 1.7
10
- 1.28
(lit.)[d]
Figure 1. Heavy atom tunneling in the interconversion of 1 and 2. a)
CCSD(T)/def2-TZVP computed IR spectra of 1 (pointing downwards) and 2
(pointing upwards). b) IR difference spectrum obtained after keeping an argon
matrix containing 1 and 2 in the dark at 3 K for 18 h.
[a] M06-2X-D3/def2-TZVP. [b] CCSD(T)/def2-TZVP. [c] IR in solid argon. [d]
NMR in CF3Br/pentane, refs. [5, 7]. [e] Determined at the “end” of the reaction,
i. e. after > 10 half-lives (s. SI). [f] Determined immediately after deposition under
the assumption that this ratio reflects the ratio in the gas phase at 298 K (s. SI).
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202010452
Angewandte Chemie International Edition
COMMUNICATION
the 1/2 ratio can be only roughly estimated. The IR spectra clearly
reveal that the direction of the heavy atom tunneling is reversed
by the formation of weakly bound complexes (Figure 3), thus
confirming the predictions from our calculations.
Since the early reports on the 1 ⇌ 2 rearrangement already
reported strong solvent effects,[5] we studied the influence of
hydrogen and halogen bonding on the rearrangement. H2O and
CF3I are typical hydrogen bond and halogen bond donors,
respectively, that could interact with the lone pairs at the oxygen
atoms of 1 and 2. According to DFT calculations (M06-2X-
D3/def2-TZVP), benzene oxide 1 is slightly more stabilized by
hydrogen or halogen bonding than oxepin 2. For the most stable
molecular complexes, the relative stabilization of 1 compared to 2
is 0.6 kcal mol-1 for the interaction with H2O, and 0.9 kcal mol-1 for
the interaction with CF3I (Figure 2). An explanation for the slightly
larger stabilization of 1 might be its larger dipole moment of 1.9 D
compared to 1.3 D of 2 (M06-2X-D3/def2-TZVP). Since the
complexes of 1 with the Lewis acids (LA) H2O and CF3I (1··LA)
are slightly more stabilized than 2··LA, the equilibrium should be
shifted towards 1··LA after complex formation.
Scheme 3. Reversible tunneling rearrangement between 1 and 2. After
deposition of the matrix at 3 K, 1 rearranges slowly (hours) to 2 via tunneling.
Subsequent annealing at 25 K results in the fast (minutes) formation of
complexes of 1 and 2 with H2O or CF3I, respectively. After cooling back to 3 K,
the complexes of 2 slowly (hours) rearrange to 1.
Figure 2. Most stable structures of H2O and CF3I complexes of 1
and 2 and corresponding complexation energies calculated at the
M06-2X-D3/def2-TZVP level of theory. For other complexes
potentially being formed see SI.
This hypothesis was tested by depositing matrices at 3 K
containing the room temperature equilibrium of 1 and 2 with a
large excess of argon doped with 1% H2O or CF3I, respectively.
Under these conditions, most molecules of 1 and 2 are isolated in
argon without interacting with the Lewis acids, since, statistically,
interactions with the additional dopant are rare, and at 3 K
diffusion even of small molecules is inhibited in the rigid low
temperature matrix. Benzene oxide 1 reacts partially to 2 via a
tunneling rearrangement as described above in pure argon. If the
matrix is subsequently annealed at temperatures between 20 and
25 K, H2O and CF3I can diffuse in the solid argon and form
aggregates with themselves (e. g. water oligomers) but also form
the Lewis acid – Lewis base complexes 1··LA and 2··LA (Scheme
3). For these complexes, the equilibrium between 1··LA and 2··LA
is shifted slightly towards 1··LA, and thus excess 2··LA
rearranges via tunneling to 1··LA. Thus, the 1/2 ratio in the doped
matrices changes from 1 : 13 directly after deposition of the
matrices (before complexes are formed) to > 9 : 1 after formation
of the LA complexes via annealing for several minutes and
subsequent cooling to 3 K for several hours to allow for the
tunneling rearrangement. The 1/2 ratios after tunneling are similar
for both H2O and CF3I. However, since the IR spectra of 1 and 2
are very similar to those of their corresponding complexes 1··LA
and 2··LA, the integration of IR signals is prone to large errors and
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202010452
Angewandte Chemie International Edition
COMMUNICATION
Figure 3. Inversion of the direction of the tunneling equilibrium between 1 and
2 upon complexation with Lewis acids. a) IR difference spectrum obtained after
keeping an argon matrix containing 1 and 2 in the dark at 3 K for 18 h. b) IR
difference spectrum obtained after keeping an argon matrix containing
complexes 1··ICF3 and 2··ICF3 in the dark at 3 K for 66 h. c) IR difference
spectrum obtained after keeping an argon matrix containing complexes 1··H2O
and 2··H2O in the dark at 3 K for 40 h.
Rothman, S. M. Rappaport, Carcinogenesis 2018, 39, 661-
668.
B. Klotz, I. Barnes, K. H. Becker, Chem. Phys. 1998, 231,
289-301; G. Ghigo, G. Tonachini, J. Am. Chem. Soc. 1998,
120, 6753-6757.
J. Morgan, A. Greenberg, Struct. Chem. 2013, 24, 1945-
1956.
E. Vogel, H. Günther, Angew. Chem. Int. Ed. 1967, 6, 385-
401.
E. Vogel, W. A. Böll, H. Günther, Tetrahedron Lett. 1965, 6,
[3]
[4]
[5]
[6]
Both the experiments in weakly interacting argon matrices and
the CCSD(T) calculations reveal that oxepin 2 is energetically
slightly more stable than benzene oxide 1. Since the entropy also
favors 2, the equilibrium should be shifted towards 2 at all
temperatures. The 1 ⇌ 2 rearrangement proceeds via heavy atom
tunneling with a half-life of several hours if the available thermal
energy does not allow to surmount the thermal activation barrier.
Thus, the equilibration between 1 and 2 cannot be prevented even
by cooling to cryogenic temperatures. Since this rearrangement
is energetically nearly degenerate, the direction of the tunneling
rearrangement is controlled by small changes in the relative
stability of 1 and 2 induced by solvent interactions.
609-615.
[7]
[8]
H. Günther, Tetrahedron Lett. 1965, 4085-4090.
W. T. Borden, Wiley. Interdiscip. Rev. Comput. Mol. Sci.
2016, 6, 20-46; C. Castro, W. L. Karney, Angew. Chem. Int.
Ed. 2020, 59, 8355-8366.
S. L. Buchwalter, G. L. Closs, J. Am. Chem. Soc. 1975, 97,
3857-3858; S. L. Buchwalter, G. L. Closs, J. Am. Chem.
Soc. 1979, 101, 4688-4694; M. B. Sponsler, R. Jain, F. D.
Coms, D. A. Dougherty, J. Am. Chem. Soc. 1989, 111,
2240-2252.
W. Sander, G. Bucher, F. Reichel, D. Cremer, J. Am. Chem.
Soc. 1991, 113, 5311-5322; M. Ertelt, D. A. Hrovat, W. T.
Borden, W. Sander, Chem. Eur. J. 2014, 20, 4713 - 4720.
C. M. Nunes, A. K. Eckhardt, I. Reva, R. Fausto, P. R.
Schreiner, J. Am. Chem. Soc. 2019, 141, 14340-14348.
X. Zhang, D. A. Hrovat, W. T. Borden, Org. Lett. 2010, 12,
2798-2801.
T. Schleif, J. Mieres-Perez, S. Henkel, M. Ertelt, W. T.
Borden, W. Sander, Angew. Chem. Int. Ed. 2017, 56,
10746-10749; T. Schleif, J. Tatchen, J. F. Rowen, F. Beyer,
E. Sanchez-Garcia, W. Sander, Chemistry – A European
Journal 2020, 26, 10452-10458.
[9]
[10]
[11]
[12]
[13]
The previous findings that 1 is the more stable isomer have to
be attributed to solvent effects. Both hydrogen and halogen
bonding stabilize 1 slightly more than 2 and shift the equilibrium
towards 1. This agrees with the earlier findings that in water –
methanol mixtures 1 is the prevalent species, whereas in
isooctane 2 is dominant.[5] It also explains the findings from NMR
studies in CF3Br/pentane mixtures.[7] This solvent mixture was
selected since it has a very low melting point which allowed to
record NMR spectra at -120 °C. However, CF3Br is a strong
halogen bond donor, comparable to CF3I that we used in our
matrix studies (see SI). Therefore, in the presence of CF3Br,
halogen bonding shifts the equilibrium towards 1, as was
observed in the NMR studies (Table 1).
In summary, in non-interacting environments, oxepin 2 is
slightly more stable than its isomer, benzene oxide 1. However,
the relative stability can be reversed by solvent effects. At
cryogenic temperatures, the equilibration is dominated by heavy
atom tunneling.
Acknowledgements
This
Forschungsgemeinschaft (DFG, German Research Foundation)
under Germany’s Excellence Strategy EXC-2033
research
was
funded
by
the
Deutsche
-
-
Projektnummer 390677874. The authors would like to thank
Philipp Neigenfind for his contribution to the synthesis of
oxepin/benzene oxide.
Conflict of interest
The authors declare no conflict of interest.
Keywords: tunneling • rearrangement • matrix isolation • halogen
bonding • noncovalent interactions
[1]
[2]
T. J. Monks, M. Butterworth, S. S. Lau, Chem.-Biol. Interact.
2010, 184, 201-206.
H. Grigoryan, W. M. B. Edmands, Q. Lan, H. Carlsson, R.
Vermeulen, L. Zhang, S.-N. Yin, G.-L. Li, M. T. Smith, N.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202010452
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Matrix isolation studies reveal a long-standing misconception about the benzene oxide – oxepin equilibrium by proving the intrisic
greater stability of oxepin. They also find that this equilibration proceeds via a rare heavy-atom tunneling process at cryogenic
temperatures. Finally, the solvent control of heavy-atom tunneling is demonstrated for the first time as the direction of the reaction is
inverted in the presence of the Lewis acids.
5
This article is protected by copyright. All rights reserved.