Construction of persistent phenoxyl radical with intramolecular hydrogen bonding [3]

Full text of DOI:10.1021/ja002453+

J. Am. Chem. Soc. 2001, 123, 3371-3372
3371
Construction of Persistent Phenoxyl Radical with
Intramolecular Hydrogen Bonding
Toshihide Maki, Yoko Araki, Yukihiro Ishida,
Osamu Onomura, and Yoshihiro Matsumura*
Faculty of Pharmaceutical Sciences, Nagasaki UniVersity
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
ReceiVed July 6, 2000
Figure 1. Phenol derivatives 1-4 having the R-alkylamino group at
the ortho or para position.
ReVised Manuscript ReceiVed January 22, 2001
The oxidation of phenols has attracted much attention of
chemists because of its involvement in biologically important
processes.1 One of its particularly interesting points lies in a
formation of persistent phenoxyl radical such as tyrosine phenoxyl
radical (tyrosyl radical) which is elucidated to play significant
roles in a variety of biological systems involving proteins and
enzymes.2-9 Recent extensive research with X-ray crystallography,
high-frequency EPR, and ENDOR spectroscopy provided some
structural information about local protein environments surround-
ing the tyrosyl radical.10a-f The intriguing results imply that
hydrogen bonding between phenol hydrogen and a properly
oriented basic group such as histidine residue regulates the redox
behavior of the tyrosine/tyrosyl radical (Scheme 1).11a-h
Development of proper model compounds may be helpful to
precisely understand such regulation in the biological processes.
However, there have been no precedent model compounds to
show clearly the effect of hydrogen bonding on the redox behavior
of phenols, though some models other than phenols do define
the proton-coupled electron transfer.12 The generation of phenoxyl
radicals by oxidation of phenols commonly accompanies O-H
bond dissociation, leading to an irreversible process as exemplified
Scheme 1. Postulated Proton-Coupled Electron Transfer To
Form Hydrogen-Bonded Tyrosyl Radical with Histidine
Residue
by the oxidation of phenol assisted with intermolecular phenol-
hydrogen-coupled bases.13
On the other hand, a recently reported B3LYP calculation
suggests an involvement of a coupled spontaneous proton transfer
in the oxidation of a phenol-imidazole hydrogen-bonded com-
plex.14 We present herein the first model compound that allows
the reversible electron transfer between phenol and phenoxyl
radical with an assistance of hydrogen bonding.
Our strategy to design the model compound was based on the
following assumption. That is, in a biological system, (a) phenol
moiety may be present in a sterically shielded field to avoid
undesired side reactions such as phenolic coupling15,16 and (b)
phenol hydrogen may be associated with some basic functionality
such as the imidazolyl group. Thus, we planned to synthesize
sterically hindered 2,4,6-trisubstituted phenols having two tert-
butyl groups at the 2 and 4 positions17 and an R-alkylamino group
at the 6 (ortho) position which was aimed for associating phenolic
hydrogen intramolecularly. The reasons why the R-alkylamino
group was selected as a basic functionality are as follows. First,
the group at the ortho position could efficiently associate with
phenolic hydrogen to form a six-membered intermediate. Second,
the intervention of the alkyl group between aromatic ring and
amino group would prevent a conjugation of the amino group
with the aromatic ring, which might largely change the electronic
character of phenols. On the basis of these consideration, the
phenols 1-4 were synthesized (Figure 1).
Cyclic voltammograms (CV’s) of phenols 1-3 in acetonitrile
are shown in Figure 2a-c. Among them, phenol 3 showed a
reversible redox couple on CV (Figure 2c), while phenols 1 and
2 did have partially reversible CV’s (Figure 2a,b) and para-
derivative 4 exhibited an irreversible CV (Figure 2S).
Controlled potential electrolysis of a solution of 3 in 20 mM
acetonitrile or dichloromethane with a divided cell at the anodic
peak potential of 3 afforded a blue species 3•+ that was persistent
enough for spectroscopic characterization even at room temper-
ature, though it gradually decayed over 30 min to give a yellow
solution. The oxidized species was EPR active, though its hfc
was not observed under a variety of conditions (Figure 3).18 The
oxidized species also exhibited typical UV-visible absorption
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122, 1974-1978. (e) Ito, N.; Philips, S. E. V.; Stevens, C.; Ogel, Z. B.;
McPherson, M. J.; Keen, J. F.; Yadav, K. D. S.; Knowles, P. F. Nature, 1991,
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(11) (a) Uhlin, U.; Eklund, H. Nature 1994, 370, 533-539. (b) Nordlund,
P.; Ekhund, H. J. Mol. Biol. 1993, 232, 123-164. (c) Sjoberg, B.-M. Structure
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H. Theor. Chem. Acc. 1997, 97, 289-300. (e) Rova, U.; Goodtzova, K.;
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(17) It is well-known that sterically hindered phenolate ions afford persistent
phenoxyl radicals by one-electron oxidation; see ref 16.
(18) All EPR measurements of 3 gave a similar spectrum to that in Figure
S4: 0.1 to 1.0 mM in frozen CH3CN, C6H6, or CH2Cl2.
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10.1021/ja002453+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/15/2001

3372 J. Am. Chem. Soc., Vol. 123, No. 14, 2001
Communications to the Editor
Figure 6. Zwitterionic phenolate 5.
Scheme 2. Proposed Redox Process of 3/3•+ through
Minimum Proton Migration
Figure 2. Cyclic voltammograms of 1 ((a) 5.0 mM), 2 ((b) 4.2 mM), 3
((c) 5.9 mM), and 5 ((d) 20mM) in CH3CN solution containing Et4NBF4
(0.1 M): Pt disk electrode (φ ) 1.6 mm); scan rate 0.1 V/s; Ag/AgCl
reference electrode.
we observed a reversible CV for compound 3. Thus, the processes
from 3 to 3•+ and from 3•+ to 3 are considered to occur with an
outer sphere electron transfer (Scheme 2).20
The redox potentials of 1 (Epa ) 847 mV, Epc ) 674 mV)
and 2 (Epa ) 816 mV, Epc ) 691 mV) were similar to that of 3
(Epa ) 826 mV, Epc ) 687 mV). This observation suggests that
the redox process of 1 and 2 is initiated by electron transfer from
phenols associated with intramolecular hydrogen bonding in a
similar way to that of 3. On the other hand, the reversibility was
reduced in order of 3 > 2 > 1,21 referring to the persistency of
phenoxyl radical cations which may depend on the extent of
hydrogen bonding.22 The spin distribution of phenoxyl radical
changed by hydrogen bonding14 may be responsible for the
persistency of phenoxyl radical cations.
Figure 3. EPR spectrum of phenoxyl radical 3•+ generated by electro-
chemical oxidation of 3 in CH2Cl2 at room temperature; g ) 2.0046,
frequency ) 9.238 GHz, field center ) 332.00 mT, power ) 1.0 mW,
amplitude ) 5.0 × 100.
The reversible redox potential of 3 (E1/2 ) 757 mV) was more
positive than that of 2,4,6-tri-tert-butylphenolate ion (E1/2 ) -186
mV) and more negative than that of 2,4,6-tri-tert-butylphenol
(Ep ) 1487 mV).19 The large potential shift observed in the CV
of 3 is presumably due to an intramolecular hydrogen bonding
and an electrostatic effect of a proton. To estimate the effect of
the hydrogen bonding on the potential shift, we prepared a
zwitterion 5 (Figure 6), which exhibited a reversible redox couple
of 5/5•+ at E1/2 ) 333 mV on CV (Figure 2d). The observed
potential difference (424 mV) between 3/3•+ and 5/5•+ may be
responsible for an intramolecular hydrogen bonding.
Figure 4. UV visible spectrum of phenoxyl radical 3•+ ganerated by
electrochemical oxidation of 3 in CH3CN.
In conclusion, we characterized phenoxyl radical cation 3•+ as
a proper model for hydrogen-bonded phenoxyl radicals in
biological systems. In this model, an intramolecular proton
migration occurs at its redox process with the minimum nuclear
motion requirement. This result suggests that some basic func-
tional group located near the tyrosine residue in an active site of
enzyme may control the redox potential of the tyrosyl radical
with hydrogen bonding.23 Further study on phenols having a
variety of basic functionality and an effort for full characterization
of 3•+ are currently under investigation.
Acknowledgment. This study was supported by a Grant-in-Aid (No.
11771414) from the Ministry of Education, Science, and Culture, Japan.
We thank Prof. Y. Naruta and Dr. F. Tani at Kyushu University for the
measurement of EPR spectra.
Figure 5. EPR spectrum of phenoxyl radical 3•+ oxidized by Cu(ClO4)2
(0.8 mM) of 3 (1.0 mM) in frozen CH3CN: g ) 2.0048, frequency )
9.248 GHz, field center ) 300.00 mT, modulation ) 100 kHz, power )
1.12 mW, amplitude ) 1.25 × 10.
Supporting Information Available: Full experimental data for
compounds 1-5 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA002453+
characteristic of phenoxyl radicals at around 600 nm (broad) and
at 386 and 404 nm (strong bands) (Figure 4).16 A similar spectrum
was observed in a one-electron oxidation of 3 with Cu(II) (Figure
S3). The species generated by Cu(II) oxidation seems to be an
interesting example such as the Cu(I)-coordinated phenoxyl
radical, which presented a strong EPR signal (Figure 5).
As noted in the introductory part, the oxidation of 2,4,6-tri-
tert-butylphenol exhibits an irreversible CV since the process
accompanies O-H bond dissociation.19 In contrast with this fact,
(19) Bordwell, F. G.; Cheng, J.-P. J. Am. Chem. Soc. 1991, 113, 1736-
1743. E1/2, 193 mV vs Ag/AgI for 2,4,6-tri-tert-butylphenolate ion and Ep,
1850 mV vs Ag/AgI for 2,4,6-tri-tert-butylphenol.
(20) Marcus, R. A.; Sutin, N. Biochim Biophys. Acta 1985, 811, 265-
322.
(21) The reversibility was not significantly changed as the scan rate of
CV was increased.
(22) The different reversibility observed on CV’s between 1 and 2 cannot
be explained in terms of the bulkiness of the benzylic position.
(23) Vass, I.; Styring, S. Biochemistry 1991, 30, 830-839.