One-electron oxidation of a hydrogen-bonded phenol occurs by concerted proton-coupled electron transfer

Article abstract of DOI:10.1021/ja031583q

The hydrogen-bonded phenol 2-(aminodiphenylmethyl)-4,6-di-tert-butylphenol (HOAr-NH₂) was prepared and oxidized in MeCN by a series of one-electron oxidants. The product is the phenoxyl radical in which the phenolic proton hastransferred to the

Full text of DOI:10.1021/ja031583q

Published on Web 09/21/2004
One-Electron Oxidation of a Hydrogen-Bonded Phenol Occurs by Concerted
Proton-Coupled Electron Transfer
Ian J. Rhile and James M. Mayer*
UniVersity of Washington, Department of Chemistry, Box 351700, Seattle, Washington 98195
Received December 8, 2003; E-mail: mayer@chem.washington.edu
Table 1. Rate and Equilibrium Constants for Oxidations of
HOAr-NH2
Proton-coupled electron transfer (PCET) is of much current
experimental and theoretical interest.1 When an e- and a H+ transfer
together from one reactant to another (AH + B f A + HB), the
reaction is hydrogen-atom transfer.1b,c There are also processes in
which e- and H+ both transfer but are separated, such as AH + B
+ C f A + HB+ + C-. An important example of this second
class of PCET reactions is the formation of tyrosyl radicals in pro-
teins from tyrosine residues, by long-range electron transfer coupled
to deprotonation by a nearby base.2 In photosystem II, oxidation
of tyrosine Z (YZ) by P680•+ likely occurs with transfer of the
tyrosyl proton to a hydrogen-bonded histidine.3 In a number of sys-
tems, the mechanisms of such processes are controversial, especially
whether e- and H+ transfer occurs in two steps (ET and PT) or in
a single concerted PCET process.1-3 Described here are outer-sphere
oxidations of a phenol with a pendent base (abbreviated HOAr-
NH2, eq 1), both as a model both for the oxidation of YZ and as a
prototype for this class of PCET reactions. Mechanistic studies in-
dicate that the e- and H+ transfer in one kinetic step, with no in-
termediate along the reaction coordinate. Analysis of these unusual
reactions with Marcus theory gives large apparent intrinsic barriers
(λ > 30 kcal mol-1).
k
a
1
b
oxidant
E1
/
(M-1 s-
)
Keq
2
[Fe(bpy)3]3+
0.70
0.67
(4 ( 1) × 106
>102
>102
[N(p-C6H4Br)3]•+
(4 ( 2) × 107
[Fe(5,5′-Me2bpy)3]3+
0.58 (1.5 ( 0.2) × 105 >102
[N(p-C6H4OMe)(p-C6H4Br)2]•+ 0.48
(8 ( 1) × 105
c
[N(tol)3]•+
0.38 (1.1 ( 0.2) × 105 2.0 ( 0.5
[N(p-C6H4OMe)2(p-C6H4Br)]•+ 0.32 (2.7 ( 0.3) × 104 0.21 ( 0.06
[N(p-C6H4OMe)3]•+
0.16 (1.1 ( 0.1) × 103 (2.9( 0.3) × 10-4
+/0
b
a Potentials (V) vs FeCp2
((0.02 V) in MeCN.4 Keq ) [•OAr-
NH3+][Red]/[HOAr-NH2][Ox]. c Not determined.
Scheme 1. Mechanisms for Electron Transfer from HOAr-NH2 to
X+
Reaction of HOAr-NH2 with [N(p-C6H4Me)3]•+ ([N(tol)3]•+, E1/2
) 0.38 V), forms an equilibrium mixture (eq 2). Addition of N(tol)3
HOAr-NH2 + [N(tol)3]•+ a •OAr-NH3+ + N(tol)3
(2)
KNtol3
shifts the equilibrium to the left, as does the addition of triflic acid
(by protonating and thereby removing HOAr-NH2). These inde-
pendent experiments give KNtol3 ) 2.0 ( 0.5.8 This and equilibrium
constants derived from similar reactions with [N(p-C6H4OMe)3]•+
and [N(p-C6H4OMe)2(p-C6H4Br)]•+ confirm the +0.36 V redox
potential of HOAr-NH2 (Table 1). These equilibration experiments
indicate the stability of the phenoxyl radical •OAr-NH3+, as
expected for a phenoxyl radical with tertiary substituents at the 2,
HOAr-NH2 was prepared by addition of benzophenone to
dilithiated 2,4-di-tert-butylphenol and then by treatment with HCl
and finally ammonia.4 An X-ray crystal structure (Figure S3)4
confirms the structure and shows an OH‚‚‚N hydrogen bond, as is
typical for such Mannich bases.5a The O-H and N‚‚‚H distances
are 0.90(3) and 1.75(3) Å (averages of two independent molecules).
Cyclic voltammetry of HOAr-NH2 using a glassy carbon working
electrode reveals a quasi-reversible wave at 0.36 ( 0.02 V (0.1 M
TBAPF6, MeCN, vs Cp2Fe+/0, ∆Ep ) 163 mV). Related R-alkyl-
amino phenols undergo similar oxidations to the corresponding
phenoxyl radical/protonated base.6 The potentials for these oxida-
tions are much lower than those for phenol oxidations without pro-
ton movement (e.g., E ) 1.09 V for 2,4,6-tri-tert-butylphenol (tBu3-
ArOH)7). Monitoring the chemical oxidation of HOAr-NH2 by
[N(p-C6H4Br)3]•+ (E ) +0.67 V) in CD3CN shows the disappear-
t
4, and 6 positions (e.g., Bu3ArO•).9
The kinetics of outer-sphere oxidations of HOAr-NH2 have been
measured in anaerobic MeCN using stopped-flow spectrophotom-
etry. Under pseudo-first-order conditions, the disappearance of
[N(tol)3]•+ follows first-order kinetics, and the kobs varies linearly
with the phenol concentration, indicating a second-order rate law
with kNtol3 ) (1.1 ( 0.2) × 105 M-1 s-1. Rate constants for different
oxidants are shown in Table 1. With [N(p-C6H4Br)3]•+, electron
transfer is complete within 20 ms even with near stoichiometric
amounts of HOAr-NH2, giving kN(ArBr)3 ) (4 ( 2) × 107 M-1 s-1
.
The three most likely mechanisms for the oxidation of HOAr-
•
+
NH2 to OAr-NH3 are shown in Scheme 1. Initial outer-sphere
electron transfer (top path, ET1-PT1) would form the radical cation
1
•
+
•+HOAr-NH2, which would rapidly rearrange to OAr-NH3 by
proton transfer. Alternatively, in the bottom PT2-ET2 path, initial
preequilibrium proton transfer (too rapid to be rate limiting) would
ance of the H NMR signals for HOAr-NH2 and the appearance
of N(p-C6H4Br)3; UV-vis spectra show bleaching of the blue
aminium ion. An EPR spectrum of a reaction mixture in CH2Cl2
•
+ 4
+
shows a new complex multiplet presumably due to OAr-NH3
.
give the zwitterion -OAr-NH3 as the species that undergoes
9
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10.1021/ja031583q CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
exchange (that should have a comparable donor/acceptor distance).15b
Hammarstro¨m et al. have reached a similar conclusion, reporting
λ ) 55 kcal mol-1 for the related aqueous PCET oxidation of
3+ 13a,14c
tyrosine to tyrosyl radical + H3O+ by a tethered Ru(bpy)3
.
These analyses assume adiabatic ET; nonadiabatic behavior would
give lower values of λ. In either case, the concerted PCET is
intrinsically more difficult than related ET reactions, either because
of a larger λ or due to increased nonadiabaticity.
In sum, the mechanism of one-electron oxidation of the phenol-
amine HOAr-NH2 involves intramolecular proton transfer concerted
with transfer of the electron in a single kinetic step. Stepwise
mechanisms involving initial ET or PT are disfavored because they
involve high-energy intermediates, which overshadows the larger
intrinsic barrier for the proton-coupled electron transfer. The
oxidation of HOAr-NH2 is a prototype of PCET reactions in which
the e- and H+ are separated. It is also a good model for biologically
important oxidations of tyrosine residues to tyrosyl radicals. Further
studies to define the characteristics of this class of PCET reaction
are in progress.
•+
Figure 1. log(k) vs E1/2(oxidant) for oxidation of HOAr-NH2 by NAr3
(b) and [Fe(R2bpy)3]3+ (O). The curves are fits to k ) 1011 exp(-[1/4λ(1
+ ∆G°/λ)2]/kT) with λ ) 34 and 40 kcal mol-1, respectively.
electron transfer. Finally, the transfer of both the electron and proton
could occur by concerted PCET, in a single kinetic step.
Three lines of evidence indicate that oxidation proceeds by the
concerted PCET pathway, without involving an intermediate. First,
a primary kinetic isotope effect kH/kD ) 2.4 ( 0.2 is found upon
oxidation of DOAr-ND2 by [N(tol)3]•+. Neither rate-limiting
electron transfer (ET1-PT1) nor preequilibrium proton transfer
(PT2-ET2) are consistent with this result.
Acknowledgment. We thank Antonio G. DiPasquale for the
X-ray crystal determination and Mark A. Lockwood for previous
work on a related system. We gratefully acknowledge support from
the NIH (Grant 2 R01 GM50422-05).
Second, the rates are too fast to be consistent with high-energy
Supporting Information Available: Synthetic details for HOAr-
NH2, experimental details for equilibration and kinetics studies, and
electrochemistry. Crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
intermediates along the pathway. The ∆G°ET1 for the first step in
the ET1-PT1 mechanism, HOAr-NH2 + [N(tol)3]•+
f
•+HOAr-
NH2 + [N(tol)3], is +16.4 kcal mol-1, Keq,ET1 ) 10-12, estimated
using E(tBu3ArOH•+/0)7 as a model for E(HOAr-NH2/•+HOAr-
NH2).4 The ∆G°ET1 is larger than ∆Gq ) 11 kcal mol-1 from the
Eyring equation.10 From another perspective, Keq,ET1 ) 10-12 means
that the forward rate constant kET1 cannot be 105 M-1 s-1 because
back ET would have occur with an unreasonable kET-1 ) 1017 M-1
s-1. A very short-lived successor complex [•+HOAr-NH2|NAr3]
is conceivable but unlikely for similar reasons.11 In the PT2-ET2
pathway, an upper limit of KPT2 < 10-4 for the initial preequilibrium
PT can be estimated following studies of other Mannich bases.5
Optical spectra of saturated solutions of HOAr-NH2 in MeCN show
no evidence for the zwitterion -OAr-NH3+ (using the spectrum of
the phenoxide -OAr-NH2 as a model for this species4,5). With KPT2
< 10-4, the observed k > 107 M-1 s-1 for [N(p-C6H4Br)3]•+ would
References
(1) (a) Cukier, R. I.; Nocera, D G. Annu. ReV. Phys. Chem. 1998, 49, 337-
369. (b) Mayer, J. M. Annu. ReV. Phys. Chem. 2004, 55, 363-390. (c)
Mayer, J. M.; Rhile, I. J. Biochim. Biophys. Acta 2004, 1655, 51-58. (d)
Hammes-Schiffer, S. ChemPhysChem 2002, 3, 33-42. (e) Stubbe, J.;
Nocera, D. G.; Yee, C. S.; Chang, M. C. Y. Chem. ReV. 2003, 103, 2167-
2201.
(2) (a) Stubbe, J.; van der Donk, W. A. Chem. ReV. 1998, 98, 705-762. (b)
Pesavento, R. P.; van der Donk, W. A. AdV. Protein Chem. 2001, 58,
317-385.
(3) (a) Tommos, C.; Babcock, G. T. Biochim. Biophys. Acta 2000, 1458, 199-
219. (b) Rappaport, F.; Lavergne, J. Biochim. Biophys. Acta 2001, 1503,
246-259. (c) Nugent, J. H. A.; Rich, A. M.; Evans, M. C. W. Biochim.
Biophys. Acta 2001, 1503, 138-146. (d) Haumann, M.; Mulkidjanian,
A.; Junge, W. Biochemistry 1999, 38, 1258-1267. (e) Kuhne, H.; Brudvig,
G. W. J. Phys. Chem. B 2002, 106, 8189-8196. (f) Faller, P.; Goussias,
C.; Rutherford, A. W.; Un, S. Proc. Natl. Acad. Sci. U.S.A. 2003, 100,
8732-8735. (g) See ref 2.
+
require kET2 from -OAr-NH3 to occur at >1011 M-1 s-1, faster
than the diffusion limit.
(4) Full experimental details are given in the Supporting Information.
(5) (a) Koll, A.; Wolschann, P. Monatsch. Chem. 1996, 127, 475-486. (b)
Koll, A.; Wolschann, P. Monatsch. Chem. 1999, 130, 983-1001.
(6) (a) Maki, T.; Araki, Y.; Ishida, Y. Onomura, O.; Matsumura, Y. J. Am.
Chem. Soc. 2001, 123, 3371-3372. (b) Benisvy, L.; Blake, A. J.; Collison,
D.; Davies, E. S.; Garner, C. D.; McInnes, E. J. L.; McMaster, J.;
Whittaker, G.; Wilson, C. J. Chem. Soc., Dalton Trans. 2003, 1975-
1985 (c) Thomas, F.; Jarjayes, O.; Jamet, H.; Hamman, S.; Saint-Aman,
E.; Duboc, C.; Pierre, J.-L. Angew. Chem., Int. Ed. 2004, 43, 594-597.
(7) Bordwell, F. G.; Cheng, J.-P. J. Am. Chem. Soc. 1991, 113, 1736-1743.
(8) The added TfOH experiments also rule out the possibility that HOAr-
Third, concerted PCET is indicated by the dependence of the
rate constants on driving force, ∆∆Gq/∆∆G° ) 0.53.4 This indicates
that the reactions are in the regime |∆G°| , λ expected for the
PCET path. In the stepwise paths, kET-1 and kET2 would need to be
close to (if not faster than) the diffusion limit (see above), a regime
1
where |∆G°| = λ and ∆∆Gq/∆∆G° is far from /2.12
The oxidations of HOAr-NH2 therefore occur by concerted
proton and electron transfer (note that concerted does not imply
synchronous). Concerted PCET is advantageous because it avoids
the higher free energy intermediates •+HOAr-NH2 and -OAr-
NH3+. This contradicts the frequent intuition that stepwise mech-
anisms are in general preferred to concerted PCET.
•
+
NH2 could be deprotonating OAr-NH3 (see Supporting Information).
(9) Altwicker, E. R. Chem. ReV. 1967, 67, 475-531.
(10) Using an alternative preexponential factor (e.g., Z ) 1011 M-1 s-1
)
or
12
including nonadiabaticity would give a lower calculated barrier and
strengthen this argument.
(11) A reviewer has simulated the kinetics with a stepwise mechanism involving
precursor and successor complexes; we argue against this model.4
(12) (a) Marcus, R. A.; Sutin, N. Biochim. Biophys. Acta 1985, 811, 265-
322. (b) Sutin, N. Prog. Inorg. Chem. 1983, 30, 441-499.
(13) Compare: (a) Sjodin, M.; Styring, S.; Åkermark, B.; Sun, L.; Hammar-
stro¨m, L. J. Am. Chem. Soc. 2000, 122, 3932-3936. (b) Roth, J. P.; Yoder,
J. C.; Won, T.-J.; Mayer, J. M. Science 2001, 294, 2524-2526.
(14) (a) Hammes-Schiffer, S. Acc. Chem. Res. 2001, 34, 273-281. (b) Cukier,
R. I. J. Phys. Chem. B 2002, 106, 1746-1757. (c) Carra, C.; Iordanova,
N.; Hammes-Schiffer, S. J. Am. Chem. Soc. 2003, 125, 10429-10436.
(15) (a) Wherland, S. Coord. Chem. ReV. 1993, 123, 169-199. (b) Eberson,
L. Electron-Transfer Reactions in Organic Chemistry; Springer-Verlag:
New York, 1987; pp 55-56.
HOAr-NH2 is an unusual electron-transfer reagent because of
its intramolecular proton transfer. Using Marcus theory to analyze
PCET reactions is of experimental13 and theoretical interest.14
k(HOAr-NH2+[NAr3]•+) are well fit by the adiabatic Marcus
equation (Figure 1), with an intrinsic barrier λ ) 34 kcal mol-1
The limited data for [Fe(R2bpy)3]3+ give λ ≈ 40 kcal mol-1
.
,
consistent with the higher intrinsic barrier for iron complexes.15
These intrinsic barriers are significantly larger than those for most
organic molecules, such as λ ) 12 kcal mol-1 for [N(tol)3]•+/0 self-
JA031583Q
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