The slow rearrangement of a sterically hindered nitro-cyclohexadienone and the absence of phenol oxidation by nitrogen monoxide

Article abstract of DOI:10.1002/ejoc.200901074

The exposure of 2,4,6-tri-tert-butylphenol (1) in solution to NO ₂ results in the rapid formation of 2,4,6-tri-tert-butyl-4nitro-2,5- cyclohexadienone (2), which then undergoes a slow (ca. 3 d) rearrangement in the absence of air. The mechanism, that describes this rearrangement is understood for the first time and involves the initial isomerization of 2 to form a (-ONO)-substituted cyclohexadieneone (6). The nitrite moiety undergoes bond homolysis releasing NO. while forming an oxyl radical intermediate. An lntermolecular, concerted hydrogen abstraction, which proceeds between 6 and this oxyl radical, results in the simultaneous formation of all stable products, some of which have not been previously observed, Furthermore, when 1 is exposed, to NO. under anaerobic conditions, no reaction is observed. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200901074

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901074
The Slow Rearrangement of a Sterically Hindered Nitro-Cyclohexadienone and
the Absence of Phenol Oxidation by Nitrogen Monoxide
Steven J. Peters,*[a] Trisha M. Blood,[a] and Mark E. Kassabaum[a]
Keywords: Bond homolysis / Nitrogen oxides / Radical reactions / Rearrangement
The exposure of 2,4,6-tri-tert-butylphenol (1) in solution to
NO2 results in the rapid formation of 2,4,6-tri-tert-butyl-4-
an oxyl radical intermediate. An intermolecular, concerted
hydrogen abstraction, which proceeds between 6 and this
·
nitro-2,5-cyclohexadienone (2), which then undergoes a slow oxyl radical, results in the simultaneous formation of all
(ca. 3 d) rearrangement in the absence of air. The mechanism
that describes this rearrangement is understood for the first
time and involves the initial isomerization of 2 to form a
(–ONO)-substituted cyclohexadieneone (6). The nitrite moi-
ety undergoes bond homolysis releasing NO· while forming
stable products, some of which have not been previously ob-
served. Furthermore, when 1 is exposed to NO· under anaer-
obic conditions, no reaction is observed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
perimental results have been obtained confirming any of
the postulated intermediates.[3d,3e] We have found that the
rearrangement of 2 is remarkably slow under the conditions
used allowing for the identification of intermediates and
new products not seen in these previous studies.[3] A signifi-
cant finding, not observed until now, is the release of NO·
via bond homolysis.
Introduction
The importance of phenoxyl radicals and the free radical
nitrogen monoxide (NO·) in many environmental and bio-
logical processes has made these species the subject of many
studies. Phenoxyl radicals are commonly used to protect or-
ganic materials from oxidative stress and are important in
the combustion of aromatic compounds.[1] In biological sys-
tems they act as catalysts and are involved in protein redox
reactions.[2a–2c] Furthermore, its been shown that these
phenoxyl radical species can function as NO· carriers.[2d,2e]
With NO· linked to many physiological processes, the reac-
tivity and stability of these coupled species are the subject
of continued interest.[2c,2f] For well over a century, the oxi-
dation of sterically hindered phenols by nitrogen oxide free
radicals has been explored.[3] Although the literature results
for NO· are conflicting,[2d,3f] it is clear that nitrogen dioxide
Scheme 1. Nitrogen dioxide reaction with 2,4,6-tri-tert-butylphenol
(1).
·
Finally, when the reaction between 1 and NO· was car-
ried out under vacuum conditions, we observed a very dif-
ferent result from those previously published.[2d,3g]
(NO2 ) quickly oxidizes phenols.[3c–3f]
In the case of 2,4,6-tri-tert-butylphenol (1), and other
sterically hindered phenols, previous kinetic studies indicate
·
that NO2 initially extracts a phenolic hydrogen atom, gen-
erating a phenoxyl radical which then couples with a second
NO2 to form 2,4,6-tri-tert-butyl-4-nitro-2,5-cyclohexadien-
·
Results and Discussion
one (2), see Scheme 1.[3c] Further studies have revealed that
2 is not the thermodynamically stable product, but it un-
dergoes significant rearrangement to final products that no
longer contain the nitro group (or nitrogen atom) originat-
ing from the bound NO2·.[3d,3e] Surprisingly, the mechanism
for this reaction is not completely understood, and no ex-
When a cyclohexane solution of 1 was allowed to react
·
with a molar excess of NO2 in a closed evacuated apparatus
with an attached NMR tube, a completely anaerobic reac-
tion ensued. After a few minutes, the excess NO2 and the
·
solvent were removed leaving behind a solid, yellow residue.
Deuteriated cyclohexane (C6D12), needed for the NMR
lock, was placed into the apparatus. The resulting yellow
solution was poured into the NMR tube which was sub-
sequently sealed from the apparatus. The solution was then
monitored, under anarobic conditions, over an extended
period of time using NMR techniques.
[a] Department of Chemistry, Illinois State University,
Normal, Illinois 61790-4160, USA
Fax: +1-309-438-5538
E-mail: sjpeter@ilstu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901074.
6104
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6104–6108

Rearrangement of a Sterically Hindered Nitro-Cyclohexadienone
1
The first H NMR spectrum, collected after the NMR field resonance is that of the nitro group on 2,[6] and the
1
sample was removed from the apparatus (0.17 h), shows a 15N coupling is also apparent in the H NMR spectrum
strong down-field resonance at δ = 7.15 ppm from two where the resonance at δ = 7.15 ppm is now split into a
equivalent Hs on the cyclohexadienone ring of 2, Figure 1. doublet (3J1H–15N = 1.08 Hz). The down-field resonance is
commonly found in systems that contain an O-bound ni-
trite (ONO-) substituent;[6] the structure of this compound
must be 1,3,5-tri-tert-butyl-4-oxocyclohexa-2,5-dienyl ni-
1
trite (4). The peak at δ = 6.71 ppm in the H NMR spec-
4
trum remains a singlet; no J1H-15N coupling is observed.
Although 4 has been postulated as a reactive intermediate
by others, it has never been detected until now.[3d,3e] How-
ever, in the absence of air (i.e., under vacuum conditions),
it appears that 4 is quite stable becoming the dominant spe-
cies in solution.
Figure 1. Down-field expansion of the 400-MHz 1H-NMR spectra
recorded at various time intervals as the rearrangement of 2 pro-
gressed at 298 K. The different arrows (pointing down) mark the
1H resonances for all species found in solution. The expanded re-
gions have been magnified vertically (8ϫ).
There are also two strong proton resonances in the up-
field region at δ = 1.26 ppm and δ = 1.04 ppm with a peak
integrated ratio of 2:1, respectively, which are from the two
different sets of tert-butyl groups on 2 (see Supporting In-
formation). The spectrum recorded at 0.17 h shows that 2
is the dominant species in solution, and no NMR peaks
Figure 2. 50.70-MHz 15N-NMR spectra recorded at various time
intervals as the rearrangement of 2 progressed at 298 K. The spec-
trum collected at 23.5 h was collected for a longer time period
(10ϫ). 15N-Nitrobenzene (Ph-15NO2) was used to calibrate the 15N-
chemical shifts. (Inset) Expansion of the downfield region of the
top spectrum that shows the resonance for 6.
due to 1 were observed, Figure 1.[4] A closer look at this
spectrum reveals that a small amount of 2,4,6-tri-tert-butyl-
4-hydroxycyclohexa-2,5-dienone (3) (ca. 2%) was also
· [5]
formed in the initial minutes of exposure to NO2 . As the
reaction progressed, the yellow solution turned emerald
green, and the most notable changes in the NMR spectrum
were the decrease in intensity of the peak at δ = 7.15 ppm
A closer look the 1H NMR spectra (expanded regions in
and the appearance and growth of a new resonance at δ = Figure 1) reveals that there are three other cyclohexadien-
6.71 ppm (Figure 1). The growth of this singlet peak also one derivatives in solution that vary in concentration over
correlates with the growth of two other peaks at δ = time.
1.24 ppm and δ = 0.988 ppm in the up-field tert-butyl signal
They are structurally different from 2, 3 or 4, because
region that also integrate as 2:1, respectively. This new spe- the ring protons are no longer magnetically equivalent. Af-
cies must have a structure that is quite similar to that of 2. ter careful analysis of the 1H NMR spectroscopic data,
If it contains a nitrogen atom from the rearrangement of along with 13C{1H} NMR and 2D heteronuclear (1H-13C
the nitro group on 2 then 15N isotopic labeling coupled with HSQC and HMBC) and homonuclear (1H-COSY) spec-
15N-NMR would be definitive.
troscopy, the structures of these three species have been de-
The experiment was repeated with 15N-nitrogen dioxide, termined, Scheme 2.[7] One of these is 4,6-di-tert-butyl-o-
and the resulting C6D12 solution was analyzed using 15N- benzoquinone (5) which has been isolated by others,[3d,3e]
NMR spectroscopy (Figure 2). The resonance at δ = while the other two have not been previously observed.[8]
12 ppm diminishes in intensity while the one at δ = 204 ppm The presence of 1,3,5-tri-tert-butyl-6-oxocyclohexa-2,4-di-
increases in intensity, just as shown in Figure 1. The up- enyl nitrite (6), the asymmetric isomer of 4, was also con-
Eur. J. Org. Chem. 2009, 6104–6108
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6105

S. J. Peters, T. M. Blood, M. E. Kassabaum
SHORT COMMUNICATION
firmed in the 15N-NMR spectroscopic data (see inset in
Figure 2) having a weak resonance at δ = 208 ppm. The
formation of 2,4,6-tri-tert-butyl-6-hydroxy-cyclohexa-2,4-
dienone (7) was quite unexpected, because no other study
has detected it in solution or proposed it as a viable product
or intermediate.[3d,3e] Lastly, the presence of isobutylene (8)
1
was also detected in the H NMR spectroscopic data at δ
= 4.62 ppm (2 H atoms) and at δ = 1.68 ppm (6 H atoms),
see Supporting Information
Figure 3. Concentration vs. time plots for all species observed in
1
solution at 298 K in the H NMR spectroscopic data. The concen-
Scheme 2. The three other derivatives formed from 2 with 1H-
trations were determined from the 1H peak integrations and the
initial concentration of 2. Symbols representing each species are: 2
(᭹), 3 (᭺), 4 (᭛), 5 (ᮀ), 6 (᭢), 7 (∆), 8 (؋).
4
chemical shifts (in ppm). JHH are below the curved arrows.
To our surprise, when the evacuated NMR tube was
·
opened to air, a brown gas (believed to be NO2 ) appeared
·
instantly. Because NO2 forms when nitrogen monoxide (a simultaneous production of 5 and 8. A mechanism that ac-
colorless gas) and oxygen are mixed, it would seem that counts for all of these aspects is presented in Scheme 3.
NO· is produced during the rearrangement of 2. In a sepa-
The equilibrium formation of 4 and 6 are the first steps
rate experiment, the gas generated from the rearrangement in the rearrangement of 2, and it takes many hours for them
was condensed into an evacuated IR cell via the vacuum to accumulate in solution, Figure 3. No further rearrange-
manifold and the FT-IR spectrum obtained. A strong ab- ment of 4 is expected, because it shows little sign of abating
sorption band centered at 1876 cm–1 was observed confirm- and therefore is not very reactive under these conditions.
ing the presence of NO·.[9]
The path by which 2 rearranges to form 4 and 6 could not
With all species in solution now identified, we tracked be determined from these studies. However it has been pro-
·
their change in concentration over the course of the reac- posed that 2 dissociates back to NO2 and a phenoxyl radi-
1
tion using the H NMR peak integrations and the initial cal (see Scheme 1) before forming the nitrite species.[3b,3d,3e]
concentration of 2, Figure 3. We see from the plots that 2 The buildup of 6 is necessary to drive the reaction forward
decreases rapidly while that for 4 increases rapidly early on during which this unstable species undergoes homolysis to
in the rearrangement. After some time, the rate of change form NO· and a 6-oxylcyclohexadienone radical intermedi-
for both slows significantly where the former continues to ate, Scheme 3. Two reactions then ensue with this radical.
exhibit a steady loss in concentration while the latter re- The presence of 3 in solution (formed from the initial expo-
·
mains essentially constant. There is also a rapid production sure of 1 to NO2 ) provides a hydrogen donor to the oxyl
of 6 followed by a steady decay suggesting that this species radical generating 7, as well as more 4,[10] which would ex-
is a true intermediate. The expanded spectra in Figure 1 plain the observed loss of 3. Finally, as the concentration
clearly show this loss of 6 as seen from the peaks at δ = of 6 increases, an intermolecular, concerted hydrogen ab-
5.855 ppm and at δ = 6.853 ppm. Moreover, 7 is also pro- straction between 6 and the oxyl radical proceeds. This re-
duced quickly at first, but its rate of growth then slows and sults in the simultaneous formation of 5 and 8, and the
remains linear. With 5 and 8 we find that they are generated production of more NO·. These two reaction paths also ac-
much more slowly, but their rates of growth and concentra- count for the greater production of 7 relative to that of 5.
tion are identical throughout the course of the reaction. We considered a possible intramolecular 1,4-hydrogen ab-
·
Furthermore, we find that 3, produced during the NO2 ex- straction between the -O· moiety and one of the hydrogen
posure, actually decreases in concentration initially, after on the geminal tert-butyl group. However, this would lead
which a slow and steady production occurs. Finally, we see to very different products than those observed in the NMR
that decreasing the initial concentration of 2 reduces the spectroscopic data.
rate of production of all species as expected.
Interestingly, when the solution was analyzed via EPR
A proposed mechanism that accounts for all of these ob- spectroscopy, no radical was detected. This is explained by
servations requires at least three important factors. First, a the slow progress of this reaction, which suggests that the
homolytic bond cleavage of the nitrite moiety is necessary equilibrium formation of the oxyl radical intermediate must
for the formation of NO·. Second, hydrogen extraction from lie far to the left and have a high energy of activation. How-
a tert-butyl group must occur during the formation of 8, ever, once formed the oxyl radical reacts quickly to generate
and finally, this hydrogen extraction must coincide with the the observed products. Nitrogen monoxide was also not ob-
6106
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6104–6108

Rearrangement of a Sterically Hindered Nitro-Cyclohexadienone
Scheme 3. Proposed mechanism for the rearrangement of 2.
served via EPR, but this is not surprising because EPR spin the potential complications from exposure to air, which was
traps are needed for its detection.[11]
critically important when characterizing all products and
A nearly identical mechanism involving a 4-oxylcyclo- intermediates formed. Because radical intermediates and
hexadienone radical intermediate (from the homolysis of 4) NO· are clearly involved in this mechanism, the exposure of
and 6 would explain the formation of 3 observed later in the this system to the atmosphere (particularly O2) will com-
course of the reaction. However with such a small amount pletely alter its chemistry and kinetics. Therefore, our
produced, this homolytic cleavage must be less favorable method is quite advantageous, because it removes this com-
than that for 6, because the loss of 4 is quite slow.
plication, and can be applied to a host of nitrogen oxide/
With the generation of NO· during the course of re- phenoxyl radical reactions using NMR spectroscopy for
arrangement, we anticipated that a possible side reaction analysis. We are currently exploring the role of O2 in the
would take place between NO· and the phenoxyl radical rearrangement of 2 and how its presence may account for
intermediate that is expected to form during the equilibrium the discrepancy between our results and those of others.[2d,3]
isomerization between 2, 4 and 6 (see Scheme 3). Based on These studies are quite valuable for gaining more insight in
Janzen’s observations,[2d] we would expect to see nitroso- this important area of phenoxyl and nitrogen oxide radical
substituted species (R–N=O, where R is the hindered cyclo- chemistry, which has considerable biological interest. In
hexadieneone) in the NMR spectroscopic data. However, particular, NO· does not react with tri-tert-butylphenol un-
we found no evidence for these compounds. These results der anaerobic conditions!
motivated us to investigate further the reaction between
NO· and 1 using nearly the same procedures described
above. After the C6D12 solution containing 1 was generated
Experimental Section
in the evacuated apparatus, a molar excess of NO· was then
To a glass apparatus was added 1.0 mL of a cyclohexane solution
added. The apparatus was sealed, and the resulting solution
(27.5 m) containing 1. A glass-break tube containing 2.0 µL tet-
ramethylsilane (TMS) was also added. The TMS served as a peak
was mixed for 30 min under this NO· atmosphere. After this
time, an NMR sample was collected while maintaining this
integration reference. The apparatus was attached to a vacuum line
1
NO· atmosphere. Remarkably, the H NMR spectrum ob-
·
and evacuated. Next, approximately 0.3 mmol of NO2 gas (a ten-
fold excess) was released into the manifold and condensed into the
apparatus using liquid nitrogen. The apparatus was isolated, using
tained looked identical to that of 1! No reaction between
the hindered phenol and NO· was apparent (see Supporting
Information for NMR spectra). We are currently investiga-
ting the exposure of NO· to other hindered phenols to see
if similar results are obtained.
an attached stopcock, warmed to ambient temperature, and the
solution was mixed for 3 min. The apparatus was re-attached to
the vacuum manifold and the excess NO2 and solvent were
pumped away. One milliliter of C6D12 was vacuum distilled into
the apparatus which was then isolated via a stopcock on the appa-
ratus. The TMS break tube was broken and the contents well
mixed. A portion of the C6D12 solution was transferred to an
·
Conclusions
The pristine experimental conditions used in this work
have allowed us to observe the rearrangement of 2 without NMR tube (attached to the apparatus) which was subsequently
Eur. J. Org. Chem. 2009, 6104–6108
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6107

S. J. Peters, T. M. Blood, M. E. Kassabaum
SHORT COMMUNICATION
Sortino, J. Am. Chem. Soc. 2007, 129, 480–481; f) B. Halliwell,
J. M. Gutteridge, in: Free Radicals in Biology and Medicine,
Oxford University Press, New York, 1998, and references
within.
sealed, while maintaining vacuum conditions, using a glass torch.
For the 15N experiments with 15NO2 , 15N-nitrobenzene (Ph-15NO2)
·
was placed in the break tube instead of TMS. The sealed NMR
sample was then analyzed over a period of 80 h at 298 K using
either a 400 MHz (for 1H NMR experiments) or 500 MHz (for 15N,
13C and 2D experiments) Bruker Avance III NMR spectrometer
with a variable temperature, pulsed field gradient probe. The sam-
ple was left in the NMR probe and continuously spun at 20 Hz for
the duration of the experiment; NMR spectra were obtained at
fixed time intervals using an automation routine within the Bruker
NMR software.
[3] a) P. F. Frankland, R. C. Farmer, Proc. Chem. Soc. London
1901, 17, 201; b) C. D. Cook, R. C. Woodworth, J. Am. Chem.
Soc. 1953, 75, 6242–6244; c) R. G. Coombes, A. W. Diggle, S. P.
Kempsell, Tetrahedron Lett. 1994, 34, 6373–6376; d) M. P.
Hartshorn, J. A. Kennedy, R. W. Simpson, J. Vaughan, G. J.
Wright, Aust. J. Chem. 1985, 38, 735–743; e) P. Astolfi, M.
Panagiotaki, L. Greci, Eur. J. Org. Chem. 2005, 3052–3059; f)
E. Giorgini, R. Petrucci, P. Astolfi, R. P. Mason, L. Greci, Eur.
J. Org. Chem. 2002, 4011–4017; g) For thorough review of NO
chemistry see: J. Hartung, Chem. Rev. 2009, 109, 4500–4517.
[4] The 1H NMR assignments for 1 in C6D12 are: δ = 7.13 ppm (2
H), δ = 4.78 ppm (1 H), δ = 1.414 ppm (18 H) and δ =
1.268 ppm (9 H) and was not observed in these experiments.
[5] The 1H NMR assignments for 3 are close to those measured
by other groups, see reference 3d. The signals of the two equiv-
alent ring hydrogen atoms appear at δ = 6.56 ppm.
Supporting Information (see also the footnote on the first page of
this article): Experimental details and all 1D and 2D NMR spec-
troscopic data.
Acknowledgments
[6] M. Witanowski, G. A. Webb, in: Nitrogen NMR, Plenum Pub-
lishing Company Ltd. London, 1973, pp. 233–245.
We thank Research Corporation for the Advancement of Science
for support. This material was also supported by the National Sci-
ence Foundation (NSF) under CHE-0722385.
[7] HSQC Heteronuclear Single Quantum Coherence detects H,C
1
correlations via JHC, HMBC-Heteronuclear Multiple Bond
2
3
Coherence detects H,C correlations via JHC and JHC. See
Supporting Information for complete 13C assignments and 2D
spectra.
[1] a) D. S. Haynes, in: Fossil Fuel Combustion, Wiley-Interscience,
New York, 1991, pp. 261; b) L. R. Mahoney, Angew. Chem.
Int. Ed. Engl. 1969, 8, 547–555; c) G. W. Burton, K. U. Ingold,
Acc. Chem. Res. 1986, 19, 194–201.
[2] a) Y. Shimazaki, S. Huth, A. Odani, O. Yamauchi, Angew.
Chem. Int. Ed. 2000, 39, 1666–1669; b) J. A. Irwin, H. Ostdal,
M. J. Davies, Arch. Biochem. Biophys. 1999, 362, 94–104; c)
M. P. Schopfer, B. Mondal, D. Lee, A. A. Sarjeant, K. D. Kar-
[8] The broadening of the 1H resonance at δ = 5.855 ppm (6) is
likely due to rotational motion of the nitrite moiety.
[9] S. Pinchas, I. Laulicht, in: Infrared Spectra of Labelled Com-
pounds, Academic Press, London, 1971, p. 217.
[10] For example of hydrogen extraction see: E. R. Altwicker,
Chem. Rev. 1967, 67, 475–531.
lin, J. Am. Chem. Soc. 2009, 131, 11304–11305; d) E. G. Janzen, [11] V. Misik, P. Riesz, J. Phys. Chem. 1996, 100, 17986–17994.
A. L. Wilcox, V. Manoharan, J. Org. Chem. 1993, 58, 3597–
3599; e) E. B. Caruso, S. Petralia, S. Conoci, S. Giuffrida, S.
Received: September 21, 2009
Published Online: October 29, 2009
6108
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6104–6108