Sequential electron-transfer and proton-transfer pathways in hydride-transfer reactions from dihydronicotinamide adenine dinucleotide analogues to non-heme oxoiron(IV) complexes and p-chloranil. Detection of radical cations of NADH analogues in acid-promoted hydride-transfer reactions

Article abstract of DOI:10.1021/ja804969k

Hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogues, such as 10-methyl-9,10-dihydroacridine (AcrH₂) and its derivatives, 1-benzyl-1,4-dihydronicotinamide (BNAH), and their deuterated compounds, to non-heme oxoiron(IV) complexes such as [(L)Fe^IV(O)] ²⁺ (L = N4Py, Bn-TPEN, and TMC) occurs to yield the corresponding NAD⁺ analogues and non-heme iron(II) complexes in acetonitrile. Hydride transfer from the NADH analogues to p-chloranil (Cl₄Q) also occurs to produce the corresponding NAD⁺ analogues and the hydroquinone anion (Cl₄QH^-). The logarithms of the observed second-order rate constants (log k_H) of hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes are linearly correlated with those of hydride transfer from the same series of NADH analogues to Cl ₄Q, including similar kinetic deuterium isotope effects. The log k_H values of hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes are also linearly correlated with those of deprotonation of the radical cations of NADH analogues. Such linear correlations indicate that overall hydride-transfer reactions of NADH analogues to both non-heme oxoiron(IV) complexes and Cl₄Q occur via electron transfer from NADH analogues to the oxoiron(IV) complexes, followed by rate-limiting deprotonation from the radical cations of NADH analogues and subsequent rapid electron transfer from the deprotonated radicals to the Fe(III) complexes to yield the corresponding NAD⁺ analogues and the Fe(II) complexes. The electron-transfer pathway was accelerated by the presence of perchloric acid, and the resulting radical cations of NADH analogues were detected by electron spin resonance spectroscopy and UV-vis spectrophotometry in the acid-promoted hydride-transfer reactions from NADH analogues to non-heme oxoiron(IV) complexes. This result provides the first direct evidence that a hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes proceeds via an electron-transfer pathway.

Full text of DOI:10.1021/ja804969k

Published on Web 10/21/2008
Sequential Electron-Transfer and Proton-Transfer Pathways in
Hydride-Transfer Reactions from Dihydronicotinamide Adenine
Dinucleotide Analogues to Non-heme Oxoiron(IV) Complexes
and p-Chloranil. Detection of Radical Cations of NADH
Analogues in Acid-Promoted Hydride-Transfer Reactions
Shunichi Fukuzumi,*,† Hiroaki Kotani,† Yong-Min Lee,‡ and Wonwoo Nam*,‡
Department of Material and Life Science, Graduate School of Engineering, Osaka UniVersity,
SORST, Japan Science and Technology Agency (JST), Suita, Osaka 565-0871, Japan, and
Department of Chemistry and Nano Science, Center for Biomimetic Systems, Ewha Womans
UniVersity, Seoul 120-750, Korea
Received June 28, 2008; E-mail: fukuzumi@chem.eng.osaka-u.ac.jp; wwnam@ewha.ac.kr
Abstract: Hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogues, such as 10-
methyl-9,10-dihydroacridine (AcrH2) and its derivatives, 1-benzyl-1,4-dihydronicotinamide (BNAH), and their
deuterated compounds, to non-heme oxoiron(IV) complexes such as [(L)FeIV(O)]2+ (L ) N4Py, Bn-TPEN,
and TMC) occurs to yield the corresponding NAD+ analogues and non-heme iron(II) complexes in
acetonitrile. Hydride transfer from the NADH analogues to p-chloranil (Cl4Q) also occurs to produce the
corresponding NAD+ analogues and the hydroquinone anion (Cl4QH-). The logarithms of the observed
second-order rate constants (log kH) of hydride transfer from NADH analogues to non-heme oxoiron(IV)
complexes are linearly correlated with those of hydride transfer from the same series of NADH analogues
to Cl4Q, including similar kinetic deuterium isotope effects. The log kH values of hydride transfer from NADH
analogues to non-heme oxoiron(IV) complexes are also linearly correlated with those of deprotonation of
the radical cations of NADH analogues. Such linear correlations indicate that overall hydride-transfer
reactions of NADH analogues to both non-heme oxoiron(IV) complexes and Cl4Q occur via electron transfer
from NADH analogues to the oxoiron(IV) complexes, followed by rate-limiting deprotonation from the radical
cations of NADH analogues and subsequent rapid electron transfer from the deprotonated radicals to the
Fe(III) complexes to yield the corresponding NAD+ analogues and the Fe(II) complexes. The electron-
transfer pathway was accelerated by the presence of perchloric acid, and the resulting radical cations of
NADH analogues were detected by electron spin resonance spectroscopy and UV-vis spectrophotometry
in the acid-promoted hydride-transfer reactions from NADH analogues to non-heme oxoiron(IV) complexes.
This result provides the first direct evidence that a hydride transfer from NADH analogues to non-heme
oxoiron(IV) complexes proceeds via an electron-transfer pathway.
Introduction
characterized spectroscopically by Wieghardt and co-workers
for the first time.3 Subsequently, the first crystal structure of an
Non-heme iron enzymes are involved in metabolically
important oxidative transformations, in which high-valent oxo-
iron(IV) species are frequently invoked as the key intermediates
responsible for the oxidation of organic substrates.1 Within the
past five years, non-heme oxoiron(IV) intermediates have been
characterized in the catalytic cycles of Escherichia coli taurine:
R-ketogultarate dioxygenase (TauD), prolyl-4-hydroxylase, and
halogenase CytC3.2 These results demonstrate unambiguously
that non-heme oxoiron(IV) intermediates are capable of ab-
stracting C-H bonds of substrates in biological reactions. In
biomimetic studies, a non-heme oxoiron(IV) intermediate was
oxoiron(IV) complex, [(TMC)FeIV(O)]2+ (TMC ) 1,4,8,11-
tetramethyl-1,4,8,11-tetraazacyclotetradecane), was obtained in
the reaction of [FeII(TMC)]2+ and artificial oxidants.4 Since then,
extensive efforts have been devoted to examining the reactivities
of mononuclear non-heme oxoiron(IV) complexes bearing
tetradentate N4 and pentadentate N5 and N4S ligands in the
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Tirupati, B.; Bollinger, J. M., Jr.; Krebs, C. Biochemistry 2003, 42,
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† Osaka University.
‡ Ewha Womans University.
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N. Chem. ReV. 2005, 105, 2227–2252. (c) Borovik, A. S. Acc. Chem.
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15134 J. AM. CHEM. SOC. 2008, 130, 15134–15142
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2008 American Chemical Society

Acid-Promoted Hydride Transfer from NADH Analogues
A R T I C L E S
oxidation of various substrates, including alkane hydroxylation,
olefin epoxidation, alcohol oxidation, N-dealkylation, and the
oxidation of sulfides and PPh3.5-8 More recently, we have
reported the electron-transfer properties (i.e., the reorganization
energies and the one-electron reduction potentials) of non-heme
oxoiron(IV) complexes.9 However, hydride-transfer reactions
of non-heme oxoiron(IV) complexes have never been explored
previously.10
Among hydride donors, dihydronicotinamide adenine di-
nucleotide (NADH) and analogues have attracted particular
interest, because NADH is the most important source of hydride
ion (two electrons and a proton) in biological redox reactions.11-13
There has been extensive discussion on the mechanism of
hydride-transfer reactions of NADH and analogues, such as
concerted hydride transfer vs sequential electron-proton-electron
(equivalent to a hydride ion) transfer.14-24 In contrast to the
one-step hydride-transfer pathway that proceeds without an
intermediate, the electron-transfer pathway would produce
radical cations of NADH and its analogues as reaction
intermediates.25,26 Such an electron-transfer pathway can be
accelerated by an acid due to the protonation of the one-electron-
reduced species.27-31 Indeed, we have recently reported the
successful detection of a radical cation of an NADH analogue,
9,10-dihydro-10-methylacridine (AcrH2), in the acid-promoted
hydride transfer from AcrH2 to 1-(p-tolylsulfinyl)-2,5-benzo-
quinone.32 However, the hydride-transfer mechanism has yet
to be clarified in the case of non-heme oxoiron(IV) complexes.
Also, neither the effect of acid on hydride-transfer reactions
from NADH analogues to non-heme oxoiron(IV) complexes nor
the detection of radical cations of NADH analogues in the
hydride-transfer reactions has so far been reported.
We report herein the first example of hydride transfer from
a series of NADH analogues, 10-methyl-9,10-dihydroacridine
(AcrH2) and its 9-subsituted derivatives (AcrHR: R ) H, Ph,
Me, and Et), 1-benzyl-1,4-dihydronicotinamide (BNAH), and
their deuterated compounds, to mononuclear non-heme oxo-
iron(IV) complexes, [(L)FeIV(O)]2+ (L ) N4Py, N,N-bis(2-
pyridylmethyl)-N-bis(2-pyridyl)methylamine; Bn-TPEN, N-benzyl-
N,N′,N′-tris(2-pyridylmethyl)ethane-1,2-diamine; TMC, 1,4,8,11-
tetramethyl-1,4,8,11-tetraazacyclotetradecane) (see Chart 1). The
mechanism of hydride transfer from NADH analogues to non-
heme oxoiron(IV) complexes is clarified in relation to hydride
transfer from the same series of NADH analogues to a
p-benzoquinone derivative.22 The promoting effect of perchloric
acid on hydride-transfer reactions from NADH analogues to
[(L)FeIV(O)]2+ is extensively compared with the hydride-transfer
reactions without acids. In addition, we have succeeded in
detecting radical cations of NADH analogues in acid-promoted
hydride-transfer reactions from NADH analogues to [(L)FeIV-
(O)]2+. This result provides direct evidence that hydride transfer
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A R T I C L E S
Fukuzumi et al.
Chart 1
Reaction Procedure. Typically, AcrH2 (1.0 × 10-3 M) was
added to a CD3CN solution (0.6 mL) containing [(N4Py)FeIV(O)]2+
(1.0 × 10-3 M) in an NMR tube. The reaction was complete in 10
min under these conditions. The products were identified as AcrH+
and [(N4Py)FeII]2+ by comparing their 1H NMR spectra with those
in the literature.36 1H NMR measurements were performed with a
from NADH analogues to non-heme oxoiron(IV) complexes
proceeds via an electron-transfer pathway.
Experimental Section
Materials. Commercially available reagents, 1-benzyl-1,4-di-
hydronicotinamide (BNAH), 9-phenyl-10-methylacridinium ion
(Acr+-Ph), 10-methylacridone, acridine, methyl iodide (MeI),
NaBH4, p-chloranil (Cl4Q), and ferrocene from Tokyo Chemical
Industry Co., Ltd., and LiAlD4 and NaBD4 from CIL, Inc., were
of the best available purity and used without further purification
unless otherwise noted. Acetonitrile (MeCN) and ether were dried
according to the literature procedures and distilled under Ar prior
to use.33 Iodosylbenzene (PhIO) was prepared by a literature
method.4,6e Non-heme iron(II) complexes, Fe(TMC)(CF3SO3)2,
Fe(N4Py)(CF3SO3)2, and Fe(Bn-TPEN)(CF3SO3)2, and their oxo-
iron(IV) complexes, [(TMC)FeIV(O)]2+, [(N4Py)FeIV(O)]2+, and
[(Bn-TPEN)FeIV(O)]2+,werepreparedbytheliteraturemethods.4,6aFor
example, [(TMC)FeIV(O)]2+ was prepared by reacting
Fe(TMC)(CF3SO3)2 (0.5 mM) with 1.2 equiv of PhIO (0.6 mM) in
CH3CN at ambient temperature. 10-Methyl-9,10-dihydroacridine
(AcrH2) was prepared from 10-methylacridinium iodide (AcrH+I-)
by reduction with NaBH4 in methanol and purified by recrystallization
1
JMN-AL-300 (300 MHz) NMR spectrometer at 298 K. H NMR
(CD3CN): AcrH+, δ 4.75 (s, 3H), 7.98 (t, 2H), 8.41 (t, 2H), 8.50
(d, 2H), 8.54 (d, 2H), 9.86 (s, 1H); [(N4Py)FeII]2+, δ 4.25-4.45
(m, 4H), 6.32 (s, 1H), 7.04 (d, 2H), 7.35 (m, 4H), 7.69 (m, 2H),
7.80-7.90 (m, 4H), 8.92 (d, 2H), 9.01 (d, 2H).
Spectral Measurements. Hydride transfer from AcrH2 to
[(N4Py)FeIV(O)]2+ (5.0 × 10-5 M) was examined by monitoring
spectral changes in the presence of appropriate amounts of AcrH2
(1.0 × 10-3-5.0 × 10-3 M) at 298 K with a Hewlett-Packard
8453 photodiode-array spectrophotometer and a quartz cuvette (path
length ) 10 mm). Typically, a deaerated MeCN solution of
[(N4Py)FeIV(O)]2+ (5.0 × 10-5 M) was added with a microsyringe
to a deaerated MeCN solution containing AcrH2.
Kinetic Measurements. Kinetic measurements were performed
on a UNISOKU RSP-601 stopped-flow spectrometer equipped with
a MOS-type highly sensitive photodiode-array or a Hewlett-Packard
8453 photodiode-array spectrophotometer at 298 K. Rates of hydride
transfer from AcrHR derivatives to [(L)FeIV(O)]2+ (L ) N4Py, Bn-
TPEN, and TMC) were monitored by the increase and decrease of
absorption bands due to Acr+-R (λmax ) 358 nm, ꢀmax ) 1.80 × 104
from ethanol.25 AcrH+I- was prepared by the reaction of acridine
-
with MeI in acetone, converted to the perchlorate salt (AcrH+ClO4
)
by the addition of magnesium perchlorate to AcrH+I-, and purified
by recrystallization from methanol.25 The dideuterated compound,
[9,9′-2H2]-10-methylacridine (AcrD2), was prepared from 10-methy-
lacridone by reduction with LiAlD4 in ether.25 9-Substituted (9-alkyl
or 9-phenyl) 10-methyl-9,10-dihydroacridine (AcrHR; R ) Me, Et,
and Ph) was prepared by the reduction of AcrH+I- with the
corresponding Grignard reagents (RMgX).25 AcrDPh was prepared
by reducing Acr+-Ph with NaBD4 and purified by recrystallization
from ethanol. 9-Substituted 10-methylacridinium perchlorate
(AcrR+ClO4-; R ) Me, Et, and Ph) was prepared by the reaction of
10-methylacridone in dichloromethane with the corresponding Grignard
reagents (RMgX) and purified by recrystallization from ethanol-diethyl
ether.22 The dideuterated compound, 1-benzyl-1,4-dihydro[4,4′-
2H2]nicotinamide (BNAH-4,4′-d2), was prepared from monodeuterated
compound (BNAH-4-d1)34 by three cycles of oxidation with p-chloranil
in dimethylformamide and reduction with dithionite in deuterium
oxide.35
M-1 cm-1 22 and [(L)FeIV(O)]2+ (L ) N4Py, λmax ) 695 nm; Bn-
)
TPEN, λmax ) 739 nm; and TMC, λmax ) 820 nm). Rates of hydride
transfer from AcrHR to Cl4Q were determined from the appearance
of the absorbance due to AcrR+ or the radical anion (Cl4Q•-: λmax
)
585 nm, ꢀmax ) 5.6 × 103 M-1 cm-1).22 The concentration of AcrHR
or BNAH was maintained at more than 10-fold excess of the other
reactant to attain pseudo-first-order conditions. Pseudo-first-order rate
constants were determined by a least-squares curve fit. The first-order
plots were linear for three or more half-lives, with the correlation
coefficient F > 0.999. In each case, it was confirmed that the rate
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Caution: Perchlorate salts are potentially explosiVe and should
be handled with care!
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Acid-Promoted Hydride Transfer from NADH Analogues
A R T I C L E S
Figure 1. (a) Spectral changes observed in the reaction of [(N4Py)FeIV(O)]2+ (5.0 × 10-5 M) and AcrD2 (2.0 × 10-3 M) in deaerated MeCN at 298 K.
Inset: Time profiles of absorption changes at λ ) 357 and 695 nm for the formation of AcrH+ and decay of [(N4Py)FeIV(O)]2+, respectively. (b) UV-vis
spectra of AcrH+ (6.0 × 10-5 M) and [(N4Py)FeII]2+ (6.0 × 10-5 M) in MeCN. (c) Plots of the pseudo-first-order rate constants (kobs) of [(N4Py)FeIV(O)]2+
vs AcrH2 (O) or AcrD2 (b).
The formation rate of AcrH+, which was determined from
constants derived from at least five independent measurements agreed
within an experimental error of (5%.
an increase in absorbance at 357 nm, coincides with the decay
rate of [(N4Py)FeIV(O)]2+ determined from a decrease in
absorbance at 695 nm (Figure 1a, inset). The rates obey
pseudo-first-order kinetics in the presence of a large excess
Electron Spin Resonance (ESR) Measurement. ESR detection
of AcrDPh•+ was performed as follows. Typically, a MeCN solution
of [(N4Py)FeIV(O)]2+ (1.0 × 10-4 M) in the presence of HClO4
(1.0 × 10-3 M) in an ESR cell (3.0 mm i.d.) was purged with
nitrogen for 5 min. AcrDPh (1.0 × 10-2 M) was then added to the
solution, which was already cooled near the melting point of MeCN.
The mixed solution was immediately cooled to 77 K in a liquid N2
dewar for ESR measurements. The ESR spectrum of AcrDPh•+
was recorded on a JEOL JES-RE1XE spectrometer at 77 K in frozen
MeCN. The magnitude of modulation was chosen to optimize the
resolution and signal-to-noise (S/N) ratio of the observed spectra
under nonsaturating microwave power conditions. The g value was
calibrated using an Mn2+ marker (g ) 2.034, 1.981). Computer
simulation of the ESR spectra was carried out by using Calleo ESR
version 1.2 (Calleo Scientific Publisher) on a personal computer.
of AcrH2, and the pseudo-first-order rate constants (kobs
)
increase linearly with the increase of the AcrH2 concentration
(Figure 1c, O). The second-order rate constant (kH) for the
reaction of [(N4Py)FeIV(O)]2+ and AcrH2 was determined
to be 1.1 × 102 M-1 s-1 from the linear plot of kobs vs
concentration of AcrH2. When AcrH2 was replaced by the
dideuterated compound (AcrD2), a large deuterium kinetic
isotope effect (KIE) value of 13.5 was observed (Figure 1c,
b).
The rate of hydride transfer from 1-benzyl-1,4-dihydroni-
cotinamide (BNAH) to [(N4Py)FeIV(O)]2+, which was much
faster than the reaction rate of AcrH2, was determined using
a stopped-flow technique. The formation of [(N4Py)FeII]2+
is seen as a recovery of bleaching absorption at 450 nm in
the difference transient absorption spectrum, and this is
accompanied by the decay of the absorbance at 695 nm due
to [(N4Py)FeIV(O)]2+, as shown in Figure 2a. Both the
formation and decay rates obey pseudo-first-order kinetics
with the same slopes (Figure 2a, inset). The kH values of
BNAH and the dideuterated compound (BNAH-4,4′-d2) were
Results and Discussion
Hydride Transfer from NADH Analogues to Non-heme
Oxoiron(IV) Complexes. The visible spectral changes in hydride
transfer from an NADH analogue (AcrH2) to [(N4Py)FeIV(O)]2+
are shown in Figure 1a, where the absorption band at 695 nm
due to [(N4Py)FeIV(O)]2+ decreases, accompanied by an
increase in the absorption band at 357 nm due to 10-
methylacridinium ion (AcrH+) and the absorption bands at 380
and 450 nm due to [(N4Py)FeII]2+. The spectrum after the
reaction, as shown in Figure 1a, agrees well with the superposi-
tion of the AcrH+ and [(N4Py)FeII]2+ spectra (Figure 1b). Thus,
the stoichiometry of the reaction is given by eq 1.37
determined to be 7.8 × 102 and 1.7 × 102 M-1 s-1
,
respectively, giving a KIE value of 4.6 (Figure 2b). Hydride-
transfer reactions were also investigated with other NADH
analogues and non-heme oxoiron(IV) complexes, and the kH
values for other NADH analogues are listed in Table 1 (see
the columns kH ([(L)FeIV(O)]2+)).
Hydride Transfer from NADH Analogues to p-Chloranil. It
has been reported previously that hydride-transfer reactions
from AcrH2 and BNAH to hydride acceptors such as
(37) [(L)FeIII(OH)]2+ was not detected in the course of the reaction owing
to the rapid electron transfer from the resulting AcrH• to [(L)FeIII
-
(OH)]2+. [(L)FeII]2+ was produced from [(L)FeII(OH)]+ by protonation
and dehydration due to residual water contained in MeCN. The
formation of AcrH+ and [(N4Py)FeII]2+ was also confirmed by 1H
NMR (see Experimental Section).
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A R T I C L E S
Fukuzumi et al.
Figure 2. (a) UV-vis spectral changes observed in hydride transfer from BNAH-4,4′-d2 (5.0 × 10-3 M) to [(N4Py)FeIV(O)]2+ (3.0 × 10-5 M) in MeCN
at 298 K. Inset: First-order plots at λ ) 450 and 695 nm. (b) Plots for the determination of second-order rate constants (kH) in the reactions of [(N4Py)FeIV(O)]2+
with [BNAH (O) or BNAH-4,4′-d2 (b)].
Table 1. Oxidation Potentials (Eox) of NADH Analogues, Rate Constants (kd) of Deprotonation of Radical Cations of NADH Analogues, and
Rate Constants (kH) for the Reactions of Hydride Transfer from NADH Analogues to Cl4Q and Oxoiron(IV) Complexes ([(L)FeIV(O)]2+) in
Deaerated MeCN at 298 K
kH ([(L)FeIV(O)]2+), M-1 s-1
a
Eox (V vs SCE)
NADH analogue
kd,b s-1
kH (Cl4Q), M-1 s-1
L ) N4Py
L ) Bn-TPEN
L) TMC
1
2
3
4
5
6
7
8
BNAH
BNAH-4,4′-d2
AcrH2
0.57
0.57
0.81
0.81
0.84
0.88
0.84
0.88
2.4 × 10
1.8 × 10
6.4
1.0 × 103
1.9 × 102
1.5 × 10
1.7
7.8 × 102
1.7 × 102
1.1 × 102
8.4
1.8 × 104
2.2 × 103
1.3 × 103
7.4 × 10
6.2 × 10
7.0 × 10
2.0 × 10
4.0
4.0 × 102
7.0 × 10
AcrD2
7.1 × 10-1
AcrHMe
AcrHPh
AcrHEt
AcrDPh
1.1
4.1
9.4 × 10-1
6.6 × 10-1
4.6 × 10-1
1.3 × 10-1
1.0 × 10
1.1 × 10
4.0
4.9 × 10-1
n.d.
8.0 × 10-1
a Taken from ref 22. b Taken from ref 25.
p-chloranil (eq 2)15 and tetracyanoethylene (TCNE)38 occur
efficiently, followed by a subsequent fast electron transfer
complexes and a p-benzoquinone derivative, we determined
the rate constants of hydride-transfer reactions from the same
series of NADH analogues to p-chloranil (Cl4Q) as employed
in the reactions of non-heme oxoiron(IV) complexes. The
kH values determined are listed in Table 1 (see the column
kH (Cl4Q)).
Comparison of the Hydride-Transfer Reactivity of
Non-heme Oxoiron(IV) Complexes vs p-Chloranil. It should be
noted that the kH value for hydride transfer from BNAH to Cl4Q
(1.0 × 103 M-1 s-1) is similar to the kH value for hydride
transfer from BNAH to [(N4Py)FeIV(O)]2+ (7.8 × 102 M-1 s-1).
This result indicates that the reactivity of [(N4Py)FeIV(O)]2+ is
similar to that of Cl4Q in hydride-transfer reactions. Similar
reactivity between non-heme oxoiron(IV) complexes and Cl4Q
is further exemplified in Figure 3, which shows a comparison
of the kH values between [(L)FeIV(O)]2+ and Cl4Q for hydride-
transfer reactions of NADH analogues. The kH values deter-
mined in the reactions of [(L)FeIV(O)]2+ and Cl4Q vary
significantly depending on NADH analogues, in particular on
the substituent R in AcrHR. The significant decrease in the
reactivity upon the introduction of a substituent R at the C-9
position can hardly be reconciled by a one-step hydride-transfer
mechanism. The alkyl or phenyl group at the C-9 position is
known to be in a boat axial conformation, and thereby the
hydrogen at the C-9 position is located at the equatorial position,
where steric hindrance due to the axial substituent is minimized
in the hydride-transfer reactions.25 The introduction of an
electron-donating substituent R would activate the release of a
from the reduced product (Cl4QH-) to the hydride acceptors
and disproportionation of the resulting radical. We have also
reported previously that hydride transfer from a series of
AcrHR to hydride acceptors such as 2,3-dichloro-5,6-dicyano-
p-benzoquinone (DDQ) proceeds via sequential electron and
proton transfer, followed by rapid electron transfer, rather
than one-step hydride transfer.22 In order to compare the
hydride-transfer reactivity between non-heme oxoiron(IV)
(38) Fukuzumi, S.; Kondo, Y.; Tanaka, T. J. Chem. Soc., Perkin Trans. 2
1984, 673–679.
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Acid-Promoted Hydride Transfer from NADH Analogues
A R T I C L E S
acridine ring, as indicated by the decrease in the hyperfine
coupling constant of the C-9 equatorial proton in AcrHR•+
,
resulting in an increase in the deprotonation barrier to form the
planar AcrR•.25,39,40 Since the Eox values of AcrHR are rather
invariant irrespective of the difference in R,25 the variation in
the reactivity of AcrHR in the hydride-transfer reactions by
[(L)FeIV(O)]2+ in Figure 3 may result from the difference in
the reactivity of the proton-transfer step from AcrHR•+ to
[(L)FeIII(O)]+ following the initial electron transfer. Thus, the
kH values of hydride transfer from NADH analogues to
[(L)FeIV(O)]2+ obtained in the present study are linearly
correlated well with the rate constants of deprotonation of
NADH radical cations (kd), as shown in Figure 4.25,26
The initial electron-transfer step from NADH analogues (e.g.,
AcrHR) to [(L)FeIV(O)]2+ (ket) is endergonic (∆Get > 0),
judging from the Eox values of AcrHR (e.g., 0.81 V vs SCE for
AcrH2)15 and Ered values of [(L)FeIV(O)]2+ (e.g., 0.51 V vs SCE
for [(N4Py)FeIV(O)]2+).9 The subsequent proton-transfer step
from AcrHR•+ to [(L)FeIII(O)]+ (kp) competes with the back-
electron-transfer step (k-et). The final electron-transfer step from
AcrR• to [(L)FeIII(OH)]2+ must occur rapidly because this step
is highly exergonic (∆Get, 0) based on the negative Eox values
of AcrR• (e.g., -0.46 V vs SCE for AcrH•)25 and positive Ered
values of [(L)FeIII(OH)]2+ (vide supra).9 In such a case, the
observed rate constant (kH) is given by eq 3.
Figure 3. Plots of kH for hydride transfer from NADH analogues to [(Bn-
TPEN)FeIV(O)]2+ (b), [(TMC)FeIV(O)]2+ (0), and [(N4Py)FeIV(O)]2+ (O)
vs kH for hydride transfer from the same series of NADH analogues to
Cl4Q in MeCN at 298 K.
negatively charged hydride ion if the concerted hydride transfer
should take place. The remarkable decrease in the reactivity with
the increasing electron-donor ability of R rather indicates that the
reactivity is determined by the process in which a positive charge
is released. Further, there is an excellent linear correlation between
the kH values of hydride-transfer reactions of NADH analogues
with [(L)FeIV(O)]2+ and the corresponding values with Cl4Q.
Mechanism of Hydride Transfer from NADH Analogues
to Non-heme Oxoiron(IV) Complexes. Linear correlations be-
tween hydride-transfer reactions of NADH analogues with [(L)FeIV-
(O)]2+ and Cl4Q in Figure 3 imply that the hydride-transfer
mechanism of [(L)FeIV(O)]2+ is virtually the same as that of Cl4Q.
Although there is still debate on the mechanism(s) of hydride
transfer from NADH analogues to hydride acceptors in terms of
an electron-transfer pathway vs a one-step hydride-transfer pathway,
the electron-transfer pathway is now well accepted for hydride
transfer from NADH analogues to hydride acceptors that are strong
electron acceptors.13-24 It should be noted that the Ered values of
non-heme oxoiron(IV) complexes ([(L)FeIV(O)]2+: 0.39-0.51 V
vs SCE)9 are more positive than that of Cl4Q (0.01 V vs SCE).15
This means that the [(L)FeIV(O)]2+ complexes are much stronger
electron acceptors than Cl4Q. Thus, the electron transfer from
NADH analogues (AcrHR) to [(L)FeIV(O)]2+ is highly likely to
occur, and this is followed by rapid proton transfer from AcrHR•+
to [(L)FeIII(O)]+ and electron transfer from the resulting AcrR• to
[(L)FeIII(OH)]2+, affording the final products, AcrH+ and [(L)FeII-
(OH)]+, as shown in Scheme 1.
We have previously succeeded in detecting transient absorp-
tion and ESR spectra of AcrHR•+ and BNAH•+ produced by
the electron-transfer oxidation of AcrHR and BNAH by
[Fe(phen)3]3+ (phen ) 1,10-phenanthroline), respectively.25,26
The transient absorption spectra of AcrHR•+ exhibit diagnostic
long-wavelength absorption maxima at λmax ) 640-710 nm,
depending on the substituent R.25 The decay of AcrHR•+ obeyed
first-order kinetics, and the decay rate constant of AcrHR•+ (kd)
corresponds to the rate constant of deprotonation from AcrHR•+
to produce AcrR•.25 The kd value becomes smaller by changing
R from H to Ph, Me, and Et (see the column kd in Table 1).25
The introduction of a substituent R at the C-9 position in AcrH2
causes an increase in the magnitude of nonplanarity of the
kH ) kpket ⁄ (k-et + kp)
(3)
When kp . k-et, kH corresponds to ket, and the rate-determining
step is the initial electron-transfer step, which would exhibit
no deuterium KIE. The observation of significant deuterium
KIEs (Figures 1c and 2b) indicates that kp , k-et when kH
corresponds to kp(ket/k-et). Thus, the observed deuterium KIEs
are ascribed to the proton-transfer step from the radical cations
of NADH analogues to [(L)FeIII(O)]+. The kH/kD value of 4.6
for hydride transfer from BNAH to [(N4Py)FeIV(O)]2+ is similar
to the kH/kD value of 5.3 for the hydride transfer from BNAH
to Cl4Q. In the case of AcrH2, however, the kH/kD value of 13.5
for [(N4Py)FeIV(O)]2+ is larger than the value of 8.8 for Cl4Q.
The latter big discrepancy is ascribed to the fact that kH/kD values
vary depending on the pKa values of radical cations of NADH
analogues, Cl4QH• and [(L)FeIII(OH)]2+
.
Detection of Radical Cations of NADH Analogues in
Acid-Promoted Hydride Transfer from NADH Analogues to
Non-heme Oxoiron(IV) Complexes. The electron-transfer path-
way of hydride transfer from AcrHR to [(L)FeIV(O)]2+ was
confirmed by the direct detection of the radical cation (AcrHR•+)
that is produced in the acid-promoted hydride transfer from
AcrHR to [(L)FeIV(O)]2+ (vide infra). We have previously
reported that hydride transfer from AcrH2 to a p-benzoquinone
derivative, 1-(p-tolylsulfinyl)-2,5-benzoquinone (TolSQ), is
made possible by the presence of perchloric acid (HClO4) (eq
4).32 The promoting effect of HClO4 on hydride transfer from
9
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A R T I C L E S
Fukuzumi et al.
Scheme 1. Proposed Mechanism of the Hydride Transfer from AcrHR to [(L)FeIV(O)]2+
AcrH2 to TolSQ results from the protonation of TolSQ (TolSQ
+ H+ f TolSQH+), which is confirmed by UV-vis spectral
changes of TolSQ in the presence of various amounts of
HClO4.32 Addition of AcrH2 to a deaerated MeCN solution of
TolSQ containing HClO4 resulted in the instant appearance of
a transient absorption band at λmax ) 640 nm, which is ascribed
G), which is reduced by the magnetogyric ratio of proton to
deuteron (0.153) and the maximum slope line width (∆Hmsl
6.0 G).25 The g-value of the observed spectrum (g ) 2.003)
also agrees with the reported value for AcrHPh•+ 25
)
.
The electron-transfer rate was determined by the appearance
of absorbance at λmax ) 670 nm due to AcrHEt•+ using a
stopped-flow technique. The results are shown in Figure 7a,
where the appearance of absorbance at λmax ) 670 nm due to
AcrHEt•+ is followed by the decay, which coincides with the
appearance of absorbance at 380 nm due to [(N4Py)FeII(OH)]+.
This is shown as the recovery of bleaching because the transient
absorption spectra were measured as the difference spectra from
the final spectrum. These results indicate that an acid-promoted
electron transfer from AcrHR to [(N4Py)FeIV(O)]2+ occurs first
to produce AcrHR•+ and [(N4Py)FeIII(O)]+, followed by the
generation of AcrR• resulting from the deprotonation of
AcrHR•+. Subsequently, electron transfer from AcrR• to
[(N4Py)FeIII(OH)]2+ affords the final products, AcrR+ and
[(N4Py)FeII(OH)]+, as shown in Scheme 2.
•+
to the formation of AcrH2 that was fully characterized
spectroscopically, including ESR.25 Thus, the occurrence of
electron transfer from AcrH2 to TolSQH+ was confirmed by
•+
the formation of AcrH2 detected by ESR and absorption
spectra.32
In the present case, addition of AcrDPh to a deaerated MeCN
solution of [(N4Py)FeIV(O)]2+ containing HClO4 also results
in instant appearance of a transient absorption band at λmax
)
680 nm, which is ascribed to the formation of AcrDPh•+, as
shown in Figure 5a.25 The disappearance of the absorbance at
λmax ) 680 nm coincides with the appearance of absorbance at
380 nm due to [(N4Py)FeII]2+ and at 360 nm due to Acr+-Ph
(see Figure 5a, inset). Similarly, formation of AcrHEt•+ was
observed in the acid-promoted hydride transfer from AcrHEt
to [(N4Py)FeIV(O)]2+, as shown in Figure 5b, where the
disappearance of the absorbance at λmax ) 685 nm due to
AcrHEt•+ coincides with the appearance of absorbance at 360
nm due to Acr+-Et (see Figure 5b, inset).
The rate of the AcrHEt•+ formation obeys first-order kinetics,
and the first-order rate constant increases linearly with increasing
concentration of HClO4 without exhibiting a saturation behavior
(Figure 7b). This indicates that electron transfer from AcrHEt
to [(N4Py)FeIV(O)]2+ is promoted by protonation of the one-
electron-reduced species ([(N4Py)FeIII(O)]+), which produces
[(N4Py)FeIII(OH)]2+. It was confirmed that no protonation of
[(N4Py)FeIV(O)]2+ was observed in the presence of HClO4.41
In contrast to the initial electron-transfer step, the rate constant
for the decay of AcrHEt•+ remains constant with the increase
of the HClO4 concentration. This result indicates that the
deprotonation of AcrHEt•+ is not affected by the presence of
HClO4.
The formation of AcrDPh•+ in the acid-promoted hydride
transfer from AcrDPh to [(N4Py)FeIV(O)]2+ was also confirmed
by ESR detection, as shown in Figure 6, where the observed
ESR spectrum agrees with the computer-simulated spectrum
obtained by using the reported hyperfine coupling constants of
AcrHPh•+, except for that of deuterium (I ) 1; aD(C-9) ) 3.4
In conclusion, we have examined hydride-transfer reactions
with a series of NADH analogues and non-heme oxoiron(IV)
complexes. The reactivity of non-heme oxoiron(IV) complexes
is similar to that of Cl4Q in hydride-transfer reactions, and there
is a linear correlation between the reactivities of non-heme
oxoiron(IV) complexes and Cl4Q. The variation of the reactivity
of AcrHR depending on the type of the R group is well
correlated with the difference in the deprotonation reactivity of
(39) Anne, A.; Fraoua, S.; Hapiot, P.; Moiroux, J.; Save´ant, J.-M. J. Am.
Chem. Soc. 1995, 117, 7412–7421.
(40) Anne, A.; Fraoua, S.; Grass, V.; Moiroux, J.; Save´ant, J.-M. J. Am.
Chem. Soc. 1998, 120, 2951–2958.
(41) Virtually no protonation of [(N4Py)FeIV(O)]2+ (1.0 × 10-5 M) occurs
in the presence of HClO4 (1.0 × 10-3 M) containing 30% water in
MeCN, which is confirmed by the UV-vis spectral titration.
Figure 4. Plot of log kH for the reactions of AcrH2 with [(Bn-
TPEN)FeIV(O)]2+ (b), [(TMC)FeIV(O)]2+ (0), and [(N4Py)FeIV(O)]2+ (O)
vs log kd for deprotonation of AcrHR•+ in MeCN at 298 K.
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Acid-Promoted Hydride Transfer from NADH Analogues
A R T I C L E S
Figure 5. Absorption spectral changes observed upon addition of (a) AcrDPh (2.5 × 10-3 M) and (b) AcrHEt (2.5 × 10-3 M) to a solution of
[(N4Py)FeIV(O)]2+ (5.0 × 10-5 M) in MeCN in the presence of HClO4 (2.2 × 10-3 M) at 298 K. Inset: Time profiles of the absorption change at (a) λ )
380 and 680 nm and (b) λ ) 380 and 685 nm.
Figure 6. (a) ESR spectrum of AcrDPh•+ in frozen MeCN at 77 K after the addition of AcrDPh (1.0 × 10-2 M) to a deaerated solution of [(N4Py)FeIV(O)]2+
(1.0 × 10-4 M) in the presence of HClO4 (1.0 × 10-3 M). Asterisk denotes an Mn2+ marker. (b) Computer-simulated spectrum obtained using the hyperfine
coupling constants shown above ∆Hmsl ) 6.0 G.
Figure 7. (a) Absorption spectral changes observed upon addition of AcrHEt (1.3 × 10-3 M) to a deaerated solution of [(N4Py)FeIV(O)]2+ (2.5 × 10-5
M) in MeCN in the presence of HClO4 (2.1 × 10-3 M) at 298 K. Inset: Time profiles of the absorption change at λ ) 380 and 670 nm. (b) Dependence
of kobs on [HClO4] in acid-promoted electron transfer from AcrHEt (b) and AcrDPh (O) to [(N4Py)FeIV(O)]2+
.
AcrHR•+, produced by electron transfer from AcrHR to the
hydride acceptors. Thus, hydride transfer from NADH analogues
to non-heme oxoiron(IV) complexes may occur via electron
transfer from NADH analogues to the oxoiron(IV) complexes,
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Scheme 2. Electron-Transfer Pathway in Acid-Promoted Hydride Transfer from AcrHR to [(L)FeIV(O)]2+
Acknowledgment. This work was supported by a Grant-in-Aid
(No. 19205019 to S.F.) and a Global COE program, “the Global
Education and Research Center for Bio-Environmental Chemistry”,
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan (to S.F.), and the Korea Science and Engineering
Foundation through the CRI Program (to W.N.).
followed by the rate-limiting proton transfer from the radical
cations of NADH analogues. Rapid electron transfer from the
deprotonated radicals to the Fe(III) complexes then occurs to
yield the final products, such as the corresponding NAD+
analogues and the Fe(II) complexes. The occurrence of electron
transfer has been confirmed by the detection of AcrHR•+ in the
acid-promoted hydride-transfer reactions from AcrDPh and
AcrHEt to [(N4Py)FeIV(O)]2+. The present results provide
important clues to understand the mechanism(s) of hydride-
transfer reactions mediated by high-valent metal-oxo species.19,42
JA804969K
(42) Matsuo, T.; Mayer, J. M. Inorg. Chem. 2005, 44, 2150–2158.
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15142 J. AM. CHEM. SOC. VOL. 130, NO. 45, 2008