A Chromium(III)-Superoxo Complex as a Three-Electron Oxidant with a Large Tunneling Effect in Multi-Electron Oxidation of NADH Analogues

Article abstract of DOI:10.1002/anie.201611709

Metal-superoxo species are involved in a variety of enzymatic oxidation reactions, and multi-electron oxidation of substrates is frequently observed in those enzymatic reactions. A Cr^III-superoxo complex, [Cr^III(O₂)(TMC)(Cl)]⁺ (1; TMC=1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), is described that acts as a novel three-electron oxidant in the oxidation of dihydronicotinamide adenine dinucleotide (NADH) analogues. In the reactions of 1 with NADH analogues, a Cr^IV-oxo complex, [Cr^IV(O)(TMC)(Cl)]⁺ (2), is formed by a heterolytic O?O bond cleavage of a putative Cr^II-hydroperoxo complex, [Cr^II(OOH)(TMC)(Cl)], which is generated by hydride transfer from NADH analogues to 1. The comparison of the reactivity of NADH analogues with 1 and p-chloranil (Cl₄Q) indicates that oxidation of NADH analogues by 1 proceeds by proton-coupled electron transfer with a very large tunneling effect (for example, with a kinetic isotope effect of 470 at 233 K), followed by rapid electron transfer.

Full text of DOI:10.1002/anie.201611709

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611709
German Edition: DOI: 10.1002/ange.201611709
Proton-Coupled Electron Transfer
A Chromium(III)-Superoxo Complex as a Three-Electron Oxidant
with a Large Tunneling Effect in Multi-Electron Oxidation of NADH
Analogues
Tarali Devi, Yong-Min Lee, Jieun Jung, Muniyandi Sankaralingam, Wonwoo Nam,* and
Shunichi Fukuzumi*
Abstract: Metal-superoxo species are involved in a variety of
enzymatic oxidation reactions, and multi-electron oxidation of
substrates is frequently observed in those enzymatic reactions.
A CrIII-superoxo complex, [CrIII(O2)(TMC)(Cl)]+ (1; TMC =
1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), is de-
scribed that acts as a novel three-electron oxidant in the
oxidation of dihydronicotinamide adenine dinucleotide
(NADH) analogues. In the reactions of 1 with NADH
and biological chemistry, since the intermediates have been
ꢀ
invoked as reactive species in the C H bond activation and
oxygen atom transfer reactions by nonheme iron and copper
enzymes.[11,12] In biomimetic studies, a number of metal-
superoxo complexes have been successfully synthesized and
characterized structurally and spectroscopically, and their
reactivities have been investigated in both electrophilic and
nucleophilic oxidative reactions.[13–19] However, the chemical
properties of metal-superoxo species are less clearly under-
stood and remain elusive in many respects. For example,
although mechanisms of hydride transfer from dihydronico-
tinamide adenine dinucleotide (NADH) analogues to high-
valent metal-oxo complexes have been discussed recently,[20]
hydride-transfer reactions by metal-superoxo complexes have
never been explored previously. Additionally, although it has
been shown that metal-superoxo complexes (M-O2Cꢀ) are
capable of abstracting a hydrogen atom (H-atom) from
substrates (that is, a one-electron oxidant),[21–23] there has
been no example showing that metal-superoxo complexes
(M-O2Cꢀ) can be a three-electron oxidant without a change in
the oxidation state of metal ions.
analogues, a CrIV-oxo complex, [CrIV(O)(TMC)(Cl)]+ (2), is
II
ꢀ
formed by a heterolytic O O bond cleavage of a putative Cr -
hydroperoxo complex, [CrII(OOH)(TMC)(Cl)], which is
generated by hydride transfer from NADH analogues to 1.
The comparison of the reactivity of NADH analogues with
1 and p-chloranil (Cl4Q) indicates that oxidation of NADH
analogues by 1 proceeds by proton-coupled electron transfer
with a very large tunneling effect (for example, with a kinetic
isotope effect of 470 at 233 K), followed by rapid electron
transfer.
M
etal–oxygen intermediates, such as high-valent metal-
oxo, metal-superoxo, and metal-(hydro)peroxo species, are
involved in the activation of dioxygen and the oxygenation of
organic substrates by metalloenzymes and their model
compounds.[1–3] Among them, high-valent metal-oxo species
have been extensively investigated in a variety of oxidation
reactions over several decades, and especially in heme and
nonheme iron systems and water oxidation in photo-
system II.[4–10] Recently, metal-superoxo species have
attracted much attention in the communities of bioinorganic
We report herein the first example of hydride transfer
from NADH analogues to
a
nonheme CrIII-superoxo
complex, [CrIII(O2)(TMC)(Cl)]+ (1, see the structure in
Scheme 1A; TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraaza-
cyclotetradecane).[21,22] Compound 1 acts as a novel three-
electron oxidant in the oxidation of NADH analogues[23,24] to
produce a CrIII-hydroxo complex and two- or four-electron
oxidized products of NADH analogues (Scheme 1B). Mech-
anisms of the multi-electron oxidation of NADH analogues
by 1 are proposed based on the kinetics and mechanistic
studies, including the characterization of intermediates and
their involvement in the NADH oxidation reactions. The rate
constants of hydride transfer from NADH analogues to 1 are
also compared with those of hydride transfer from the same
NADH analogues to an iron(IV)-oxo complex, [FeIV(O)-
(TMC)]2+, and p-chloranil;[20a] leading us to propose that the
hydride-transfer reaction by 1 occurs by a rate-determining
concerted proton-coupled electron transfer (PCET) from
NADH analogues to 1, followed by a rapid electron transfer.
Interestingly, a very large deuterium kinetic isotope effect
(KIE) is observed in the reactions of 1 with 10-methyl-9,10-
[*] T. Devi, Dr. Y.-M. Lee, Dr. J. Jung, Dr. M. Sankaralingam,
Prof. Dr. W. Nam, Prof. Dr. S. Fukuzumi
Department of Chemistry and Nano Science
Ewha Womans University
Seoul 03760 (Korea)
E-mail: wwnam@ewha.ac.kr
Prof. Dr. S. Fukuzumi
Faculty of Science and Engineering, SENTAN Japan Science and
Technology Agency (JST), Meijo University
Nagoya, Aichi 468-8502 (Japan)
E-mail: fukuzumi@chem.eng.osaka-u.ac.jp
Prof. Dr. W. Nam
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences
Lanzhou 730000 (China)
dihydroacridine (AcrH2) and
a deuterated compound
(AcrD2; for example, KIE = 470 at 233 K).
The CrIII-superoxo complex, [CrIII(O2)(TMC)(Cl)]+ (1),
was synthesized and characterized according to the published
methods.[21,22] When 1 was reacted with 1 equiv of 1-benzyl-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611709.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Scheme 1). The formation of 2 along with BNA+ was
confirmed with electrospray ionization mass spectrometry
(ESI-MS) of the reaction solution (Supporting Information,
Figure S1). The stoichiometry of the reaction of BNAH with
1 was determined to be 1:1 from the spectral titration
experiments (Figure 1b). Thus, an overall reaction is sum-
marized in [Eq. (1)].
BNAHþ½CrIIIðO2ÞðTMCÞðClÞꢁþ ð1Þ
!
ð1Þ
BNAþ þ ½CrIVðOÞðTMCÞðClÞꢁþ ð2Þ þ OHꢀ
A mechanism is proposed as follows: in the 1:1 reaction of
1 and BNAH, the first step is a hydride transfer from BNAH
to 1, resulting in the formation of BNA+ and [CrII(OOH)-
(TMC)(Cl)] (Scheme 2A, reaction a). Subsequently, the
Scheme 1. A) Schematic structures of CrIII-superoxo (1), CrIV-oxo (2),
and CrIII-hydroxo (3) complexes. B) Reactions showing the oxidation of
NADH analogues by a CrIII-superoxo complex (1).
1,4-dihydronicotinamide (BNAH; frequently used as an
NADH analogue)[23,24] in deaerated acetonitrile (MeCN) at
253 K, the absorption bands at 470, 550, 645, and 675 nm
arising from 1 disappeared within 4 min and bands at 605 and
960 nm corresponding to [CrIV(O)(TMC)(Cl)]+ (2)[21,22]
appeared simultaneously (Figure 1; see the structure of 2 in
Scheme 2. Proposed mechanisms for the oxidation of BNAH by 1 (A)
and 2 (B).
II
ꢀ
hydroperoxo O O bond of the putative [Cr (OOH)(TMC)-
(Cl)] intermediate is cleaved heterolytically to form 2 and
OHꢀ (Scheme 2A, reaction b). Recently, we have shown that
a nonheme FeII-OOH species, [FeII(OOH)(TMC)]+, cleaves
ꢀ
its hydroperoxo O O bond heterolytically, resulting in the
formation of iron(IV)-oxo complex [FeIV(O)(TMC)]2+ and
OHꢀ.[25] It was also confirmed that no reaction occurred
between BNA+ and OHꢀ in deaerated MeCN (Supporting
Information, Figure S2b) when BNA+ was produced in the
oxidation of BNAH by H2O2 in the presence of Fe(ClO4)3
(Supporting Information, Figure S2a). This is explained by
the resonance structures of the amide group in BNA+
(Supporting Information, Figure S3), in which the negative
charge on the amide oxygen prohibits the addition of OHꢀ at
the 4-position of BNA+.
Figure 1. a) UV/Vis spectral changes observed in the oxidation of
BNAH (1.0 mm) by 1 (1.0 mm) in deaerated MeCN at 253 K. Inset
shows the time profile monitored at 550 nm arising from the decay of
1. b) Titration experiments performed with 1 and BNAH in deaerated
MeCN at 253 K.
In the reaction of 1 with an excess amount of BNAH,
[CrIV(O)(TMC)(Cl)]+ (2), which was formed in the reaction
2
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
of 1 and BNAH (Scheme 2A), reacted further with a second
reductant) are oxidized by four molecules of 1 (3-electron
molecule of BNAH to produce BNAC and [CrIII(OH)(TMC)-
(Cl)]+ (3; Scheme 1) by hydrogen atom (H-atom) transfer
(Scheme 2B, reaction a). Subsequently, a fast electron trans-
fer occurred from BNAC (Eox = ꢀ1.1 V vs. SCE)[24] to another
molecule of 2 to give BNA+ and [CrIII(O)(TMC)(Cl)]
(Scheme 2B, reaction b). The latter species, [CrIII(O)(TMC)-
(Cl)], was unstable and thus hydrolyzed to give [CrIII(OH)-
(TMC)(Cl)]+ and OHꢀ (Scheme 2B, reaction c). The forma-
tion of the BNA+ and [CrIII(OH)(TMC)(Cl)]+ products in the
oxidation of BNAH with 2/3 equiv of 1 [Eq. (2)] was analyzed
oxidant; Scheme 1B).
A mechanism for the reaction of 1 and AcrH2 is proposed
as follows. Hydride transfer from AcrH2 to
1 forms
10-methylacridinium ion (AcrH+) and [CrII(OOH)(TMC)-
II
ꢀ
(Cl)], followed by heterolytic O O bond cleavage of [Cr -
(OOH)(TMC)(Cl)] to give 2 and OHꢀ; as described by
[Eq. (3)] and Scheme 2A. Subsequently, OHꢀ is added to
AcrH+ to produce AcrH(OH) [Eq. (4)];[27,28] the observation
of the reaction of OHꢀ with AcrH+ is in sharp contrast to the
case of BNA+ (see earlier), in which no reaction occurs
between OHꢀ and BNA+ (Supporting Information, Fig-
ure S2b). Indeed, the reaction of AcrH+ and OHꢀ was
confirmed independently by adding tetramethylammonium
hydroxide (Me4NOH) to a deaerated MeCN solution of
AcrH+, in which addition of OHꢀ at the 9-position of AcrH+
afforded the formation of AcrH(OH) (Supporting Informa-
tion, Figure S10).[27,28] Subsequently, a second hydride transfer
3 BNAHþ2 ½CrIIIðO2ÞðTMCÞðClÞꢁþ ð1Þ þ H O
!
2
ð2Þ
3 BNAþ þ 2 ½CrIIIðOHÞðTMCÞðClÞꢁþ ð3Þ þ 3 OHꢀ
by ESI-MS and electron paramagnetic resonance (Supporting
Information, Figure S4 for UV/Vis and ESI-MS, Figure S5 for
EPR). The amount of the [CrIII(OH)(TMC)(Cl)]+ (3) product
was determined to be 93(5)% by comparing the double
integration of the EPR signal of 3—which was produced in
the oxidation of BNAH by 1—with that of an authentic 3
reference complex prepared independently (Supporting
Information, Figure S5 and Table S1). Thus, in the reaction
of 1 and an excess amount of BNAH, 1 acts as a three-electron
oxidant that oxidizes BNAH to BNA+ [Eq. (2)].
In a separate study, we synthesized 2 according to the
published method[21] and reacted it with BNAH under pseudo
first-order reaction conditions (Supporting Information,
Figure S6); a second-order rate constant of 16mꢀ1 sꢀ1 at
253 K was determined in the reactions of 2 with different
amounts of BNAH (Supporting Information, Figure S7b).
Similarly, a second-order rate constant of 27mꢀ1 sꢀ1 at 253 K
was obtained in the reaction of 1 with different amounts of
BNAH (Supporting Information, Figure S7a), indicating that
the reactivity of 1 is slightly greater than that of 2 in this
hydride-transfer reaction. We have shown recently that 1 is
much more reactive than 2 in oxygen atom transfer reactions
(for example, oxidation of thioanisole derivatives by 1 and
2).[26]
=
from AcrH(OH) to 1 yields Acr O, 2, and H2O [Eq. (5)].
Furthermore, H-atom transfer from AcrH(OH) to 2 produces
AcrOHC and 3 [Eq. (6)],[29] and a subsequent H-atom transfer
=
from AcrOHC to 2 produces Acr O and 3 [Eq. (7)]. The
=
formation of Acr O in the hydride transfer from AcrH(OH)
to 1 [Eq. (5)] and the H-atom transfer from AcrH(OH) to 2
[Eq. (6) and (7)] were confirmed by carrying out independent
reactions of AcrH(OH) with 1 and 2 (Supporting Informa-
tion, Figure S11a and S11b, respectively). Notably, 2 predom-
inantly reacts with AcrH(OH), rather than AcrH2, because
the oxidation of AcrH2 by 2 produces AcrH+ (Supporting
Information, Figure S12), which was not produced in the
oxidation of AcrH2 by 1. The yield of 3 was also determined to
be 91(4)% by comparing the EPR signal of 3 produced with
that of an authentic reference (Supporting Information,
Table S1 and Figure S13). Thus, the overall stoichiometry is
shown in [Eq. (8)], which agrees well with the stoichiometry
When BNAH was replaced by AcrH2, four-electron
oxidation of AcrH2 by 1 occurred to produce 10-methyl-
[27]
=
acridone (Acr O)
and 3 (Supporting Information, Fig-
ure S8 for cold-spray ionization mass spectrometry (CSI-
MS)). The 18O-labeling experiments were performed to
=
confirm that the oxygen atoms in Acr O were derived from
1. [CrIII(O2)(TMC)(Cl)]+ (1-18O) was synthesized by reacting
[CrII(TMC)(Cl)]+ with 18O2 (98% 18O-enriched), as reported
previously.[21,22] In the hydride-transfer reaction from AcrH2
18
to 1- O, Acr 18O was obtained quantitatively together with
=
[CrIII(18OH)(TMC)(Cl)]+ (3-18O), as shown in Figure S8c
(Supporting Information), clearly demonstrating that the
=
oxygen atoms in the Acr O product were derived from 1. The
stoichiometry of the reaction of AcrH2 and 1 was determined
to be 3:4 (Supporting Information, Figure S9), where the
=
concentration of Acr O was 75% of the initial concentration
of 1 (Supporting Information, Figure S9c). Such a unique
stoichiometry also indicates that 1 acts as a three-electron
=
oxidant in the four-electron oxidation of AcrH2 to Acr O. In
the 3:4 stoichiometry, three molecules of AcrH2 (4-electron
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
determined spectroscopically (Supporting Information,
Figure S9).
the pre-exponential factor (AH/AD) < 0.6.[30,31] To study the
involvement of H-tunneling, we examined the temperature
dependence of the second-order rate constants (k2) in the
hydride-transfer reactions from both AcrH2 and AcrD2 to
1 over the temperature range from 253 K to 233 K (Support-
ing Information, Table S3); the Arrhenius plots are shown in
Figure 2b. The activation energies (EH and ED) and the pre-
exponential factors (AH and AD) were determined from the
Arrhenius plots (Supporting Information, Table S4). The
large difference between ED and EH (EDꢀEH = 45 kJmolꢀ1)
and the extremely small ratio of AH/AD = 4.1 ꢀ 10ꢀ8 demon-
strate a large tunneling effect in the hydride-transfer reactions
from AcrH2 and AcrD2 to 1. To the best of our knowledge, the
KIE value of 470 ꢂ 30 at 233 K is the largest ever reported in
the oxidation reactions by metal–oxygen intermediates. The
AcrHðOHÞþ½CrIVðOÞðTMCÞðClÞꢁþ ð2Þ
!
ð6Þ
ð7Þ
III
AcrOH þ ½Cr ðOHÞðTMCÞðClÞꢁþ ð3Þ
C
IV
AcrOH þ ½Cr ðOÞðTMCÞðClÞꢁþ ð2Þ
C
!
Acr¼O þ ½CrIIIðOHÞðTMCÞðClÞꢁþ ð3Þ
Yielding the overall reaction [Eq. (8)]: 3 ꢀ [Eq. (3)] + 3 ꢀ
[Eq. (4)] + [Eq. (5)] + 2 ꢀ [Eq. (6)] + 2 ꢀ [Eq. (7)].
3 AcrH2 þ 4 ½CrIIIðO2ÞðTMCÞðClÞꢁþ ð1Þ
!
ð8Þ
3 Acr¼O þ 4 ½CrIIIðOHÞðTMCÞðClÞꢁþ ð3Þ þ H2O
ꢀ
second largest KIE value was reported in the C H bond
The hydride transfer from AcrH2 to 1 obeyed pseudo first-
order kinetics in the presence of an excess amount of AcrH2,
and the second-order rate constant (k2) of 2.0 at 253 K was
determined from the slope of the plot of pseudo first-order
rate constants (k1) versus concentration of AcrH2 (Figure 2a).
The k2 values of other dihydroacridine derivatives (AcrHR,
R = Me and Et) were determined as well (Supporting
Information, Table S2 and Figure S14). Interestingly, a large
KIE value of 74 ꢂ 5 was determined at 253 K in the reaction
of AcrH2 and a deuterated compound (AcrD2; Figure 2a).
The large KIE can be ascribed to the involvement of H-atom
tunneling in the hydride-transfer reaction.[30,31] Since it is the
curvature of the Arrhenius plot that demonstrates incidence
of tunneling experimentally, there are two criteria for the
recognition of the tunneling effect: 1) the difference in
activation energy (EDꢀEH) > 6 kJmolꢀ1 and 2) the ratio of
activation of benzyl alcohol by an iron(IV)-oxo porphyrin
ꢀ
p-radical cation, [(TMP)+CFeIV(O)][ClO4 ] (TMP2ꢀ
=
5,10,15,20-tetramesitylporphyrin dianion), with a KIE of
360 ꢂ 20 in MeCN at 243 K.[32] The large tunneling effect in
the hydroxylation of xanthene and 1,2,3,4-tetrahydronaph-
thalene by [(TMP)C FeIV(O)]+ has also been confirmed by the
+
non-linear Arrhenius plots in dichloromethane in a wide
range of temperatures.[33]
When AcrH2 was replaced by 9-methyl-10-methyl-9,10-
dihydroacridine (AcrHMe), the stoichiometry of the reaction
=
of 1 and AcrHMe was also 3:4 and the yield of Acr O was
75(5)% based on the amount of 1 used (Supporting Informa-
tion, Figure S15). The 3:4 stoichiometry entails removal of 12
electrons from three molecules of AcrHMe (4-electron
reductant) by four molecules of 1 (3-electron oxidant).
When AcrHMe was replaced by AcrHEt, the same stoichi-
ometry was obtained (Supporting Information, Figure S16).
The yields of 3 produced in the oxidation of AcrHMe and
AcrHEt by 1 were also determined to be 92(4)% and 90(4)%
by EPR, respectively (Supporting Information, Table S1).
As reported previously, hydride transfer from NADH
analogues to hydride acceptors, such as p-chloranil (Cl4Q)
and 2,3-dichloro-5,6-dicyano-p-benzoquinone, occurs by
a concerted PCET mechanism followed by a rapid electron
transfer.[17] Since a reactivity comparison between high-valent
metal–oxo complexes and Cl4Q was used as evidence
supporting the concerted PCET mechanism in hydride-trans-
fer reactions,[20] the rate constants of hydride transfer from
NADH analogues to 1 were also compared with those of
hydride transfer from the same NADH analogues to Cl4Q
(Supporting Information, Table S2), as shown in Figure 3.
There is a good linear correlation between the k2 values of
1 and the corresponding values of Cl4Q, implying that hydride
transfer from NADH analogues to 1 occurs by a concerted
PCET, followed by a rapid electron transfer.
In conclusion, we have reported the first example of
a hydride-transfer reaction by a synthetic metal-superoxo
complex (that is, CrIII-superoxo complex, [CrIII(O2)(TMC)-
(Cl)]+). We have shown that the CrIII-superoxo complex acts
as a three-electron oxidant in multi-electron oxidation of
NADH analogues (up to four electrons). We have also shown
that a very large KIE is obtained in the hydride transfer from
NADH analogues to a metal-superoxo complex. The present
Figure 2. a) Plots of pseudo first-order rate constants against concen-
*
trations of AcrH2 and AcrD2 for hydride transfer from AcrH2 ( ) and
*
AcrD2 ( ) to 1 (0.50 mm) in MeCN at 253 K. b) Arrhenius plots of the
*
second-order rate constants for hydride transfer from AcrH2 ( ) and
*
AcrD2 ( ) to 1 in deaerated MeCN (Supporting Information, Table S3).
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
[6] M. Suga, F. Akita, K. Hirata, G. Ueno, H. Murakami, Y.
Nakajima, T. Shimizu, K. Yamashita, M. Yamamoto, H. Ago, J.-
R. Shen, Nature 2015, 517, 99.
[7] a) J. Yano, V. Yachandra, Chem. Rev. 2014, 114, 4175; b) H.
Ogata, W. Lubitz, Angew. Chem. Int. Ed. 2014, 53, 13007; Angew.
Chem. 2014, 126, 13221.
[8] N. Cox, D. A. Pantazis, F. Neese, W. Lubitz, Acc. Chem. Res.
2013, 46, 1588.
[9] a) K. J. Young, B. J. Brennan, R. Tagore, G. W. Brudvig, Acc.
Chem. Res. 2015, 48, 567; b) J. J. Concepcion, J. W. Jurss, M. K.
Brennaman, P. G. Hoertz, A. O. T. Patrocinio, N. Y. M. Iha, J. L.
Templeton, T. J. Meyer, Acc. Chem. Res. 2009, 42, 1954.
[10] a) H. Li, F. Li, B. Zhang, X. Zhou, F. Yu, L. Sun, J. Am. Chem.
Soc. 2015, 137, 4332; b) P. Du, R. Eisenberg, Energy Environ.
Sci. 2012, 5, 6012; c) K. S. Joya, Y. F. Joya, K. Ocakoglu, R.
van de Krol, Angew. Chem. Int. Ed. 2013, 52, 10426; Angew.
Chem. 2013, 125, 10618; d) M. D. Kꢂrkꢂs, O. Verho, E. V.
Johnston, B. ꢃkermark, Chem. Rev. 2014, 114, 11863.
[11] E. G. Kovaleva, J. D. Lipscomb, Science 2007, 316, 453.
[12] a) J. M. Bollinger, Jr., C. Krebs, Curr. Opin. Chem. Biol. 2007,
11, 151; b) J. P. Klinman, J. Biol. Chem. 2006, 281, 3013.
[13] a) C.-W. Chiang, S. T. Kleespies, H. D. Stout, K. K. Meier, P.-Y.
Li, E. L. Bominaar, L. Que, Jr., E. Mꢄnck, W.-Z. Lee, J. Am.
Chem. Soc. 2014, 136, 10846; b) S. Hong, K. D. Sutherlin, J. Park,
E. Kwon, M. A. Siegler, E. I. Solomon, W. Nam, Nat. Commun.
2014, 5, 5440; c) F. Oddon, Y. Chiba, J. Nakazawa, T. Ohta, T.
Ogura, S. Hikichi, Angew. Chem. Int. Ed. 2015, 54, 7336; Angew.
Chem. 2015, 127, 7444.
Figure 3. Plot of logk2(1) for hydride transfer from NADH analogues to
[CrIII(O2)(TMC)(Cl)]+ (1) in MeCN at 253 K vs. logk2(Cl4Q) for hydride
transfer from the same series of NADH analogues to Cl4Q in
deaerated MeCN at 253 K.
study paves a new way to utilize metal-superoxo complexes as
novel three-electron oxidants.
Acknowledgements
This work was supported by a SENTAN project from Japan
Science and Technology Agency (JST) and JSPS KAKENHI
(No. 16H02268) from MEXT, Japan to S.F. and NRF of Korea
through the CRI (NRF-2012R1A3A2048842) and GRL
(NRF-2010-00353) programs to W.N.
[14] a) L. M. Mirica, X. Ottenwaelder, T. D. P. Stack, Chem. Rev.
2004, 104, 1013; b) E. A. Lewis, W. B. Tolman, Chem. Rev. 2004,
104, 1047; c) R. A. Himes, K. D. Karlin, Curr. Opin. Chem. Biol.
2009, 13, 119; d) E. I. Solomon, D. E. Heppner, E. M. Johnston,
J. W. Ginsbach, J. Cirera, M. Qayyum, M. T. Kieber-Emmons,
C. H. Kjaergaard, R. G. Hadt, L. Tian, Chem. Rev. 2014, 114,
3659.
Conflict of interest
[15] a) P. Pirovano, A. M. Magherusan, C. McGlynn, A. Ure, A.
Lynes, A. R. McDonald, Angew. Chem. Int. Ed. 2014, 53, 5946;
Angew. Chem. 2014, 126, 6056; Corrigendum: P. Pirovano, A. M.
Magherusan, C. McGlynn, A. Ure, A. Lynes, A. R. McDonald,
Angew. Chem. Int. Ed. 2014, 53, 12004; Angew. Chem. 2014, 126,
12199; b) B. N. Sꢅnchez-Eguꢆa, M. Flores-Alamo, M. Orio, I.
Castillo, Chem. Commun. 2015, 51, 11134.
The authors declare no conflict of interest.
Keywords: chromium(III)-superoxo complexes ·
hydride transfer · hydrogen atom transfer · NADH analogues ·
three-electron oxidant
[16] a) R. L. Peterson, R. A. Himes, H. Kotani, T. Suenobu, L. Tian,
M. A. Siegler, E. I. Solomon, S. Fukuzumi, K. D. Karlin, J. Am.
Chem. Soc. 2011, 133, 1702; b) R. L. Peterson, J. W. Ginsbach,
R. E. Cowley, M. F. Qayyum, R. A. Himes, M. A. Siegler, C. D.
Moore, B. Hedman, K. O. Hodgson, S. Fukuzumi, E. I. Solomon,
K. D. Karlin, J. Am. Chem. Soc. 2013, 135, 16454; c) R. Cao, C.
Saracini, J. W. Ginsbach, M. T. Kieber-Emmons, M. A. Siegler,
E. I. Solomon, S. Fukuzumi, K. D. Karlin, J. Am. Chem. Soc.
2016, 138, 7055.
[17] a) A. Kunishita, M. Kubo, H. Sugimoto, T. Ogura, K. Sato, T.
Takui, S. Itoh, J. Am. Chem. Soc. 2009, 131, 2788; b) T. Tano, Y.
Okubo, A. Kunishita, M. Kubo, H. Sugimoto, N. Fujieda, T.
Ogura, S. Itoh, Inorg. Chem. 2013, 52, 10431.
[1] a) G. Yin, Acc. Chem. Res. 2013, 46, 483; b) J. A. Kovacs, Acc.
Chem. Res. 2015, 48, 2744; c) Z. Chen, G. Yin, Chem. Soc. Rev.
2015, 44, 1083.
[2] a) F. Nastri, M. Chino, O. Maglio, A. Bhagi-Damodaran, Y. Lu,
A. Lombardi, Chem. Soc. Rev. 2016, 45, 5020; b) W. Wang, A. D.
Liang, S. J. Lippard, Acc. Chem. Res. 2015, 48, 2632.
[3] a) W. Nam, Acc. Chem. Res. 2015, 48, 2415; b) K. Ray, F. F. Pfaff,
B. Wang, W. Nam, J. Am. Chem. Soc. 2014, 136, 13942; c) J. Cho,
R. Sarangi, W. Nam, Acc. Chem. Res. 2012, 45, 1321.
[4] a) W. Nam, Acc. Chem. Res. 2007, 40, 465; b) W. Nam, Y.-M.
Lee, S. Fukuzumi, Acc. Chem. Res. 2014, 47, 1146; c) S.
Fukuzumi, K. Ohkubo, Y.-M. Lee, W. Nam, Chem. Eur. J.
2015, 21, 17548.
[18] A. R. Corcos, O. Villanueva, R. C. Walroth, S. K. Sharma, J.
Bacsa, K. M. Lancaster, C. E. MacBeth, J. F. Berry, J. Am. Chem.
Soc. 2016, 138, 1796.
[19] J. Cho, H. Y. Kang, L. V. Liu, R. Sarangi, E. I. Solomon, W. Nam,
Chem. Sci. 2013, 4, 1502.
[20] a) S. Fukuzumi, H. Kotani, Y.-M. Lee, W. Nam, J. Am. Chem.
Soc. 2008, 130, 15134; b) S. Fukuzumi, N. Fujioka, H. Kotani, K.
Ohkubo, Y.-M. Lee, W. Nam, J. Am. Chem. Soc. 2009, 131,
17127; c) Y. Han, Y.-M. Lee, M. Mariappan, S. Fukuzumi, W.
Nam, Chem. Commun. 2010, 46, 8160; d) H. Yoon, Y.-M. Lee, W.
Nam, S. Fukuzumi, Chem. Commun. 2014, 50, 12944; e) J. Jung,
[5] a) X. Engelmann, I. Monte-Pꢁrez, K. Ray, Angew. Chem. Int.
Ed. 2016, 55, 7632; Angew. Chem. 2016, 128, 7760; b) S. Hong,
Y.-M. Lee, K. Ray, W. Nam, Coord. Chem. Rev. 2017, 334, 25;
c) H. M. Neu, R. A. Baglia, D. P. Goldberg, Acc. Chem. Res.
2015, 48, 2754; d) M. Puri, L. Que, Jr., Acc. Chem. Res. 2015, 48,
2443.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
S. Kim, Y.-M. Lee, W. Nam, S. Fukuzumi, Angew. Chem. Int. Ed.
2016, 55, 7450; Angew. Chem. 2016, 128, 7576.
[28] S. Shinkai, T. Tsuno, O. Manabe, J. Chem. Soc. Perkin Trans. 2
1984, 661.
[21] a) J. Cho, J. Woo, W. Nam, J. Am. Chem. Soc. 2010, 132, 5958;
b) J. Cho, J. Woo, J. E. Han, M. Kubo, T. Ogura, W. Nam, Chem.
Sci. 2011, 2, 2057.
[22] J. Cho, J. Woo, W. Nam, J. Am. Chem. Soc. 2012, 134, 11112.
[23] S. Fukuzumi, Y. Tokuda, T. Kitano, T. Okamoto, J. Otera, J. Am.
Chem. Soc. 1993, 115, 8960.
[29] For H-atom transfer of 2, see: A. Yokoyama, K.-B. Cho, K. D.
Karlin, W. Nam, J. Am. Chem. Soc. 2013, 135, 14900.
[30] H. Kwart, Acc. Chem. Res. 1982, 15, 401.
[31] S. Fukuzumi, T. Kobayashi, T. Suenobu, J. Am. Chem. Soc. 2010,
132, 1496.
[32] Z. Pan, J. H. Horner, M. Newcomb, J. Am. Chem. Soc. 2008, 130,
7776.
[33] Z. Cong, H. Kinemuchi, T. Kurahashi, H. Fujii, Inorg. Chem.
2014, 53, 10632.
[24] S. Fukuzumi, S. Koumitsu, K. Hironaka, T. Tanaka, J. Am. Chem.
Soc. 1987, 109, 305.
[25] S. Bang, S. Park, Y.-M. Lee, S. Hong, K.-B. Cho, W. Nam, Angew.
Chem. Int. Ed. 2014, 53, 7843; Angew. Chem. 2014, 126, 7977.
[26] Y. R. Goo, A. C. Maity, K.-B. Cho, Y.-M. Lee, M.-S. Seo, Y. J.
Park, J. Cho, W. Nam, Inorg. Chem. 2015, 54, 10513.
[27] a) S. Fukuzumi, M. Ishikawa, T. Tanaka, J. Chem. Soc. Perkin
Trans. 2 1989, 1037; b) J. Jung, K. Ohkubo, D. P. Goldberg, S.
Fukuzumi, J. Phys. Chem. A 2014, 118, 6223.
Manuscript received: December 1, 2016
Revised: January 15, 2017
Final Article published: && &&, &&&&
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Proton-Coupled Electron Transfer
A CrIII-superoxo complex involved in the
oxidation of dihydronicotinamide ade-
nine dinucleotide analogues functions as
a novel three-electron oxidant with a very
large tunneling effect. The hydride-trans-
fer reaction occurs by a concerted proton-
coupled electron transfer mechanism.
T. Devi, Y.-M. Lee, J. Jung,
M. Sankaralingam, W. Nam,*
S. Fukuzumi*
&&&& — &&&&
A Chromium(III)-Superoxo Complex as
a Three-Electron Oxidant with a Large
Tunneling Effect in Multi-Electron
Oxidation of NADH Analogues
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!