Intramolecular Hydrogen Bonding Enhances Stability and Reactivity of Mononuclear Cupric Superoxide Complexes

Article abstract of DOI:10.1021/jacs.8b04671

[(L)Cu^II(O₂^?-)]⁺ (i.e., cupric-superoxo) complexes, as the first and/or key reactive intermediates in (bio)chemical Cu-oxidative processes, including in the monooxygenases PHM and DβM, have been systematically stabilized by intramolecular hydrogen bonding within a TMPA ligand-based framework. Also, gradual strengthening of ligand-derived H-bonding dramatically enhances the [(L)Cu^II(O₂^?-)]⁺ reactivity toward hydrogen-atom abstraction (HAA) of phenolic O-H bonds. Spectroscopic properties of the superoxo complexes and their azido analogues, [(L)Cu^II(N₃^-)]⁺, also systematically change as a function of ligand H-bonding capability.

Full text of DOI:10.1021/jacs.8b04671

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Communication
Intramolecular Hydrogen Bonding Enhances Stability and
Reactivity of Mononuclear Cupric Superoxide Complexes
MAYUKH BHADRA, Jung Yoon C. Lee, Ryan E. Cowley, Sunghee
Kim, Maxime A. Siegler, Edward I. Solomon, and Kenneth D. Karlin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04671 • Publication Date (Web): 29 Jun 2018
Downloaded from http://pubs.acs.org on June 30, 2018
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Intramolecular Hydrogen Bonding Enhances Stability and Reactivity of
Mononuclear Cupric Superoxide Complexes
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†
†
‡
†
†
Mayukh Bhadra, Jung Yoon C. Lee, Ryan E. Cowley, Sunghee Kim, Maxime A. Siegler, Ed-
‡
†
ward I. Solomon, * Kenneth D. Karlin *
†
Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
‡
Department of Chemistry, Stanford University, Stanford, California 94305, USA.
Supporting Information Placeholder
II
•–
2
+
II
•–
2
+
reactivity of these metastable [LCu (O )] spe-
ABSTRACT: [(L)Cu (O )] (i.e., cupric-superoxo) com-
2b,c,5
plexes, as the first and/or key reactive intermediates in
bio)chemical Cu-oxidative processes, including in the
monooxygenases PHM and DβM, have been systemati-
cally stabilized by intramolecular hydrogen bonding
within a TMPA ligand-based framework. Also, gradual
strengthening of ligand-derived H-bonding dramatical-
cies.
For example, increasing electron donation
to Cu, providing steric interactions, controlling co-
ordination geometry, and employing cryogenic con-
have each been
shown to stabilize the superoxide species and pre-
vent its subsequent reaction with a second equiv of
5
6
(
7
5
-8
ditions and suitable solvents
II
•–
+
I
ly enhances the [(L)Cu (O )] reactivity toward hydro-
2
the Cu precursor to yield thermodynamically fa-
gen-atom abstraction (HAA) of phenolic O–H bonds.
Spectroscopic properties of the superoxo complexes and
vored binuclear peroxo bridged dicopper(II) com-
plexes (Eqs. 1 & 2).
9
II
–
+
their azido analogues, [(L)Cu (N )] , also systematically
3
change as a function of ligand H-bonding capability
.
No H-Bonding Weak H-Bonding
The activation of molecular oxygen with copper is of
considerable interest in nature, as well as in oxidative
synthetic procedures and in addressing energy con-
1
cerns (e.g., fuel-cell O reduction catalysts). Reduc-
2
I
A. TMPA
B. BA
tion of O with Cu leads to complexes with singly or
2
H-Bonding
doubly reduced dioxygen (superoxo or (hy-
dro)peroxo, respectively); further important down-
II
•
stream intermediates (viz. Cu -O ) form following
2
I
reductive O−O cleavage. Various Cu -O2 derived
species are suggested to initiate substrate attack
leading to O-atom incorporation i.e., net hydroxyla-
tion in copper monooxygenases such as peptidylgly-
cine-α-hydroxylating monooxygenase (PHM) and
C. F
5
BA
D. MPPA
II
•–
+
Figure 1. [(L)Cu (O )] complexes without (A, L =
2
TMPA; tris-(2-pyridyl-methyl)amine) and with internal
H-bonding substituents (B-D, L = BA, F BA and MPPA),
3
dopamine-β-monooxygenase (DβM). For these cas-
5
corresponding resonance Raman spectra (λ = 413.1 nm)
es, along with the dehydrogenation of RCH OH in
ex
2
of complexes A-D in frozen 2-methyltetrahydrofuran
galactose oxidase (GO), copper amine oxidase imino-
semiquinone H-atom abstraction (HAA) and in GO
1
6
18
(
MeTHF) solutions prepared with O (blue) and O2
2
3
f
(red). Labels indicate the center of the Fermi doublets.
cofactor biogenesis (HAA from cysteine S−H),
a
II
•–
See Supporting Information for tabulation of
values.
ν(Cu–O)
mononuclear cupric superoxide (Cu -O ) interme-
2
10
diate is implicated in effecting key H-atom abstrac-
3
b,3c,4
tion (HAA) chemistry.
H-bonding in the secondary coordination sphere is
Thus there have been considerable efforts in the
design of appropriate synthetic ligands to probe the
factors affecting the formation, stabilization, and
II
2– 2+
known to stabilize binuclear [{(L)Cu } (O )] and
2
2
II
+
mononuclear [(L)Cu (OOH)] complexes with N O
3
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1
and N ligand architecture. Considering extensive
Figure 2. UV-Vis spectra of oxygenated mixtures of ~
4
I
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
4
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5
5
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5
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5
5
5
5
6
recent efforts in studying H-bonding influences on
model complexes and in biological systems (for ex-
ample, this plays a crucial role in stabilizing and acti-
vating O -intermediates, effecting nitrite reduction
and facilitating neural NOS activity ), the im-
portance of H-bonding on [(L)Cu (O )] chemis-
tries still remains a fundamental and critical area for
study.
In this report, we demonstrate that the imposition
of progressively enhancing H-bonding moieties in a
series of TMPA-based L-Cu complexes {Figure 1;
pKa’s of related relevant organic groups: pen-
0.4 mM of [(L)Cu ]B(C F ) (L = TMPA, BA, F BA and
6 5 4 5
1
2
MPPA) at –135 °C in MeTHF after 30 minutes. H-
bonding stabilizes superoxide species and prevents
1
0
13
14
trans-peroxide formation (see Figures S1-S4).
2
15
II
•–
+
This systematic H-bonding enhancement of
2
II
•–
+
[(L)Cu (O )] stabilization is further supported by
2
I +
corresponding UV-Vis data obtained at [(L)Cu ] ini-
tial concentrations of 0.1 Mm (see Figures S5-S8).
Analogous to synthetic and protein derived oxy-
1
0
0
1
2
3
4
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1
2
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0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
III
•–
2
heme adducts (formally Fe -O species), the prima-
ry effect of the H-bonding (e.g., for the distal His
residue in hemo- or myoglobins) is to dramatically
16
tafluorobenzylamine (~7) < benzylamine (9.3)} and
note that pivalamide and other amides are more
acidic than 2° amines} (i) inhibits the formation of
20
decrease the rate of O dissociation, hence lowering
2
k–1 thereby increasing K (Eq.1). With stronger H-
1
II
•–
+
bonding, [(L)Cu (O )] species becomes systemati-
2
corresponding
binuclear
trans-ꢀ-1,2-peroxo
II
2– 2+
cally more stable across B-D. Without the H-bond in
[
[
{(L)Cu } (O )] complex, in favor of monocopper
(L)Cu (O )] species, while (ii) also significantly
enhancing the HAA reactivity of the superoxo spe-
cies toward phenolic substrates.
When a 0.4 mM solution of [(TMPA)Cu (MeCN)]
2
2
II
•–
+
II
•–
2
+
[(TMPA)Cu (O )] (A), k is significant, more Cu(I)
2 –1
II
•–
+
becomes available, and [(L)Cu (O )] readily reacts
2
II
2– 2+
to yield the thermodynamic
product (Eq. 2).
[{(L)Cu } (O )]
2 2
I
Resonance Raman (rR) spectroscopy was used to
characterize the effect of H-bonding in the series of
superoxide complexes A-D in frozen MeTHF solu-
B(C F ) in MeTHF was subjected to dioxygen bub-
6
5 4
bling at –135 °C and allowed to equilibrate for 30 min,
9
the resulting mixture consisted of the known end-
II
•–
tion. Laser excitation (413.1 nm) of each superoxide
on superoxide (i.e., Cu −O−O ) complex
A
16/18
II
•–
+
complex (~1 mM) revealed two sets of
O isotope-
{
[(TMPA)Cu (O )] } (63% based on Cu (see Section
2
−
1
-1
sensitive enhanced modes at around 460 and 1120
4
.3(a) in the SI); λ
= 423 nm, ε = 5600 Μ cm ; 752
max
-1
1
0
cm (Figure 1), which are characteristic of ν(Cu−O)
nm) and the known trans-peroxide dicopper(II)
II
2– 2+
and ν(O−O), respectively (the latter appears as a
complex [{(TMPA)Cu } (O )] (37%; λmax = 525, 610
2
2
1
0
Fermi doublet (Figure 1), consistent with previous
nm) (Figure 2). With its ligand derived weak H-
bonding (vide infra), O -bubbling of [(BA)Cu )]
21
1
7
I
+
observations ), of end-on cupric superoxides (see
2
22
Section 5 in the SI for details). Interestingly, a sys-
significantly increased relative amounts of
B
II
•–
+
tematic trend is observed for the A-D complexes
{[(BA)Cu (O )] } (83% (see Section 4.3(b) in the SI);
2
1
8
−
1
-1
where the ν(O−O) values increased with enhancing
H-bonding ability of the systematically stronger N-H
dipoles present across B-D. Analogous to previously
λmax = 418 nm, ε = 4100 Μ cm ; 750 nm), compared
II
2– 2+
2
11
to [{(BA)Cu } (O )] (17%; λmax = 500, 605 nm).
2
However, dramatic stabilization is observed with
1
8,21c
reported cases,
we presume the observed incre-
utilization of F BA, a new ligand capable of stronger
5
mental trend in ν(O−O) across B-D is caused by en-
hanced structural vibrational coupling and align-
ment of increased O−O dipole opposite to the sys-
H-bonding
than
in
[(F BA)Cu (O )] (414 nm, ε = 4000 Μ cm ; 748
11c,18
BA
;
cupric-superoxide
II
•–
+
−1
-1
5
2
1
0
nm) is generated exclusively. Employing MPPA,
possessing the strongest H-bonding moiety, complex
D {[(MPPA)Cu (O )] } is formed. These superoxo
II
•–
tematically increasing N−H dipole. [(TMPA)Cu (O
)] (A), without any H-bonding moiety, exhibited the
2
+
II
•–
+
2
lowest (weakest) O−O stretch as expected.
In parallel, the doubly occupied superoxide
species, C and D, are very stable in solution (–135 °C);
they are fully formed and there appears to be no hint
1
0,19
of any peroxide analog present.
π ∗ (LMCT donor MO) undergoes more electrostatic
σ
525
II
2
2.0
Strong H-Bonding :
MPPA
stabilization compared to the Cu -dz (LMCT accep-
F BA
5
410
Weak H-Bonding :
No H-Bonding :
BA
TMPA
tor MO) with increasing H-bonding across the A-D
1.6
414
II
•–
+
[
(L)Cu (O )] series which increases the energy of
2
610
II
2
10
1.2
0.8
0.4
418
the LMCT (π * → Cu -d ) transition; hence, a sys-
σ z
tematic blue shift is observed in the higher energy
LMCT absorption, ranging from 423 nm to 410 nm
across A-D (Figure 2 & Table 1).
500
423
0.0
400
500
600
700
800
Wavelength(nm)
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Table 1. Summary of spectroscopic features (UV-
Bond
Length (Å)
II
•–
+
1
2
3
4
5
6
7
8
9
Vis, IR and rRaman) for [(L)Cu (O )] and
Cu1-N1
Cu1-N2
2.0118(13)
2.0410(13)
2.0207(14)
2.1968(13)
1.9512(13)
2.965
2
II
–
+
[
(L)Cu (N )] complexes.
3
Cu1-N3
N(amino)-H-N(azido) Cu1-N4
Hydrogen bond
TMPA
BA
F5BA
MPPA
Cu1-N6
N5
N5-H-N6
N7 N8
N6
Bond
Angles (%)
N4
rR O-O stretch 1119 {- 1123 {- 1126 {- 1130 {-
1
8
-1
N6-N7-N8
N5-H5-N6
175.34(18)
163(2)
{ꢁ O } (cm )
61}
64}
64}
63}
N3
N1
2
N2
II
•–
λmax Cu -O2
(nm)
423
413
418
414
410
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Displacement ellipsoid plot (50% probability
II
–
+
λmax
nm)
Cu -N3−
II
402
399
395
level) of the cationic [(BA)Cu (N )] at 110(2) K. A list of
3
relevant bond distances and angles is also provided.
The H-bonding between the benzylamine and the prox-
imal azide nitrogen is highlighted.
(
IR N≡N stretch
(
2046
2052
2063
-
1
cm )
2049
–
the antisymmetric N IR stretch (see the SI Section
3
10
II
–
+
7)
for the full series of complexes [(L)Cu (N )] .
3
The characteristic νN−N values (Table 1) increased
progressively with H-bonding strength across A-D
presumably due to increase in the triple-bond char-
acter of the azido ligand, resulting from removal of
electron density from the copper-bound Nazido-atom,
mirroring the increase in rRaman O−O stretches in
To obtain better insight into the H-bonding in
II
•–
+
these [(L)Cu (O )] complexes, we examined the
2
II
structures of the azido analogs, [(BA)Cu (N )]ClO ,
(F BA)-Cu (N )]ClO
4
3
4
II
[
[
and
5
3
II
F BA)Cu (OClO )(acetone)]ClO (for syntheses, see
5
3
4
1
0
II
the SI). Azide ion bound to Cu -complexes have
been previously used to model both electronic and
connectivity structural aspects for coordination of a
II
A-D. Additionally, the azido → Cu LMCT band
shifts progressively to higher energy with increased
ligand H-bonding (Table 1, also see Section 7 in the
2
3
peroxide dianion.
With respect to a cupric-
1
0
•–
2
II
SI) , consistent with the increasing trend in O
→
superoxide complex, a Cu -N moiety would be ex-
pected to have a very similar Cu -N-N-N binding
3
II
II
Cu LMCT energy across A-D.
II
Elucidation of the oxidative capability and scope of
mode (e.g., bond distances and the ∠Cu –N-N an-
gle). The crystal structure of [(BA)Cu (N )] (Figure
II
•–
+
II
–
+
reactivity for [(L)Cu (O )] complexes is a major
2
3
objective. We expected that systematic increased H-
3) experimentally determined via single crystal X-ray
crystallography revealed a weak but clearly observa-
ble H-bond found between the benzyl amino–N–H
hydrogen-atom and the azido N-atom (2.17(2) Å)
proximal to the Cu(II) ion. The Namino-H...Nazido dis-
tance is 2.965(2) Å with ∠Namino-H...Nazido = 163(2)°.
•
–
bonding to the O2 should stabilize its π* orbital and
also increase its electrophilicity. Indeed, we have
found a striking difference in the reactivity toward
phenols (electrophilic HAA) with varying O−H bond
strengths, across the A-D series.
Reactions with 2,6-di-tert-butyl-4-methoxyphenol
(DTBP) with a weak O–H bond (BDE = 82.0 kcal/mol
Similar H-bonding is observed in the F BA analog
5
1
0
mentioned above. This interaction, also observed in
other Cu -(X) (X = N , OOH or peroxo-Cu) instanc-
2
5
II
•–
2
II
– –
in DMSO ) were first investigated. [(TMPA)Cu (O
3
+
)] (A) reacts with a second-order rate constant of 3.11
es with TMPA based ligands possessing internal H-
–1
–1 –1
1
1,24
× 10 M s (–135 °C, MeTHF; Figure 4) as determined
by monitoring absorbance decrease at 752 nm due to
bonding groups,
supports the notion that the H-
bonding in complexes B-D occurs to the proximal O-
atom, as depicted in Figure 1.
II
+
A. [(TMPA)Cu OOH] (~80% yield, see Figure S42)
and the corresponding phenoxyl radical were ob-
served, demonstrating a net H-atom transfer from
To further support our suppositions concerning
II
•–
+
the H- bonding in these [(L)Cu (O )] complexes,
2
5
b,10
phenol to superoxo.
Importantly the correspond-
we examined
II
2–
ing peroxodicopper(II) complex [{(TMPA)Cu } (O
is observed to be completely unreactive toward
phenols (see Figure S27).
2
2
2+
)
]
1
0
The cupric superoxo complexes possessing intra-
molecular H-bonds (B-D) react more efficiently with
DTBP under the same conditions (Figure 4b), with k
2
–1
–1 -1
–1
–1 –1
=
×
5.73 × 10 M s (B), 11.47 × 10 M s (C), and 9.88
10 M s (D). In each case, the phenoxy radical was
-1
-1 –1
directly observed by both EPR (g ~ 2.0) and UV-Vis
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1
0
(
407 nm) spectroscopies (see Section 9.2 in the SI).
cleaner, and followed clear second-order decay (k =
2
–2
–1 –1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Formation of the hydroperoxo product (86% yield)
by C via net HAA from DTBP is also verified by spec-
trophotometric quatitative analysis of the amount of
H O released upon acidificaiton; see Section 9.3 in
2.33 × 10 M s ). The corresponding hydroperoxo-
Cu(II) product was also observed in UV-Vis spectros-
copy (Figure 4d). This is the first example of a much
stronger phenol being oxidized by a mononuclear
cupric superoxide compared to the previously re-
ported cases.
2
2
the SI). Although the spectroscopic data imply that
D is the most activated in the series, it is less reactive
towards DTBP than C. We presume that this appar-
ent anomaly is due to the larger steric interaction of
the tert-butyl group in D, inhibiting bulky substrate
approach and decreasing the advantage D should
have, with its strongest H-bonding pivalamido
group. Notably, C could also exert π-π stacking inter-
actions with DTBP, facilitating a much favorable sub-
strate approach compared to D, hence resulting in its
slightly enhanced reaction rate.
In conclusion, we report for the first time how H-
bonding strength in the ligand secondary coordina-
tion sphere can be tuned to systematically stabilize
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
II
•–
+
cupric superoxide ([LCu -(O )] ) species, control
2
the superoxide-peroxide equilibrium, and concur-
rently activate the superoxide toward enhanced ex-
ogenous O−H substrate oxidation. This was achieved
by systematically increasing the electrophilicity of
II
•–
+
[LCu -(O )] via implementation of differing H-
2
bonding moieties. The structures of the
II
−
+
[
(L)Cu (N )] analogs suggest that H-bonding occurs
3
II •– +
to the proximal O-atom in ([LCu (O )] ) complexes.
2
a)
4
23
BDE = 82 kcal/mol b)
Further use of H-bonding or other ligand modifica-
tions in order to generate cupric-superoxide com-
plexes with greater oxidative capabilities is being
explored.
0.4
0.3
0.2
0.1
0.0
Rates of Phenolic Oxidation
F5BA
0
.8
0.7
.6
0
Hydroperoxo (381 nm)
0.5
0.4
5
85
MPPA
0.3
0.2
0.1
0
752
BA
TMPA
0
2
4
6
8
10
12
ASSOCIATED CONTENT
Supporting Information
concentration of phenol (mM)
400
600
800
1000
Wavelength(nm)
Synthetic and analytical details (methodologies and
UV-Vis, EPR, NMR and FT-IR spectra); X-ray diffrac-
tion data. This material is available free of charge via
the Internet at http://pubs.acs.org.
BDE = 87.6 kcal/mol
c)
d) 1.6
410
0.45
0.40
0.35
0
.6
.4
423
0
0
.30
.25
Time trace of decay of 741 nm
Pseudo-first order Fit
1.2
0.8
0.4
0
0.20
0
.15
Hydroperoxo
0.10
(386 nm)
0
10
20
30
40
7
52
Time(min)
AUTHOR INFORMATION
0.2
7
41
Corresponding Author
*karlin@jhu.edu
300
400
500
600
700
800
900
1000
11
0.0
400
600
800
1000
Wavelength (nm)
Wavelength (nm)
Figure 4. a) UV-Vis monitoring of the reaction of A and
2,6-di-tert-butyl-4-methoxyphenol; b) contrasting rates
ORCID
Edward I. Solomon: 0000-0003-0291-3199
Kenneth D. Karlin: 0000-0002-5675-7040
of oxidation by A-D; k values are given in the text; c)
2
UV-Vis spectra of reaction of A with 4-methoxyphenol,
showing no reaction; d) reaction of D with 4-
methoxyphenol and (inset) kinetic trace of the decay of
741 nm band of D. See Section 6 in the SI for details.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
II
•–
+
Further, we tested our [(L)Cu (O )] complexes
2
The research support of the NIH (DK031450 to E.I.S.;
GM28962 to K.D.K.) is gratefully acknowledged.
A-D toward 4-methoxyphenol (MP), a substrate with
a stronger O–H bond (BDE = 87.6 kcal/mol in
2
5
II
•–
2
+
DMSO ). [(TMPA)Cu (O )] was completely unre-
REFERENCES
active toward 250 equiv of MP at –135 °C (Figure 4c).
II
•–
+
(1) McCann, S. D.; Stahl, S, S. Acc. Chem. Res., 2015, 48,
[(BA)Cu (O )] (B) exhibited exceedingly slow reac-
2
1756.
II
•–
2
+
tivity (completion took > 6 h) and [(F BA)Cu (O )]
5
(
2) (a) Lee, J. Y.; Karlin, K. D. Curr. Opin. Chem. Biol.
1
0
(C) reacted considerably faster. However the kinetic
behavior was complicated in these cases, and the
final copper complex product could not be identified,
similar to the observation by Tolman and cowork-
2015, 25, 184. (b) Elwell, C. E.; Gagnon, N. L.; Neisen, B. D.;
Dhar, D.; Spaeth, A. D.; Yee, G. M.; Tolman, W. B. Chem.
Rev. 2017, 117, 2059. (c) Itoh, S. Acc. Chem. Res. 2015, 48,
2066.
(3) (a) Klinman, J. P. Chem. Rev. 1996, 96, 2541. (b)
Klinman, J. P. J. Biol. Chem. 2006, 281, 3013. (c) Solomon, E.
2
6
III
ers in MP HAA by a Cu -hydroxide complex. The
II
•–
+
MP reaction with [(MPPA)Cu (O )] (D) was much
2
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Page 5 of 6
Journal of the American Chemical Society
I.; Heppner, D. E.; Johnston, E. M.; Ginsbach, J. W.;
Chem. Rev. 2014, 114, 3854. (e) Huang, X.; Groves, J. T.
1
2
3
4
5
6
7
8
9
Cirera, J.;
Kjaergaard, C.
Qayyum, M.;
Kieber-Emmons,
G.; Tian, L.
M.
T.;
Chem.
Chem. Rev. 2018, 118, 2491.
H.; Hadt, R.
(14) Merkle, A. C.; Lehnert, N. Dalt. Trans. 2012, 41, 3355.
(15) Poulos, T. L.; Li, H. Acc. Chem. Res. 2013, 46, 390.
(16) (a) Advanced Chemistry Development (ACD/Labs)
Software V11.02 (© 1994-2018 ACD/Labs) (b) Hall, H.K. J.
Am. Chem. Soc., 1957, 79, 5441. (c) Mareque Rivas, J. C.;
Hinchley, S. L.; Metteau, L; Parsons. S Dalton Trans. 2006,
2316.
(17) Kim, S.; Saracini, C.; Siegler, M. A.; Drichko, N.;
Karlin, K. D., Inorg. Chem. 2012, 51, 12603.
(18) Peterson, R. L.; Himes, R. A.; Kotani, H.; Suenobu,
T.; Tian, L.; Siegler, M. A.; Solomon, E. I.; Fukuzumi, S.;
Karlin, K. D., J. Am. Chem. Soc. 2011, 133, 1702.
Rev. 2014, 114, 3659. (d) Whittaker, J. W. Chem. Rev. 2003,
03, 2347. (e) Cowley, R. E.; Tian, L.; Solomon, E. I. Proc.
1
Natl. Acad. Sci. U.S.A. 2016, 113, 12035. (f) Cowley, R. E.;
Cirera, J.; Qayyum, M. F.; Rokhsana, D.; Dooley, D. M.;
Hedman, B.; Hodgson, K. O.; Solomon, E. I. J. Am. Chem.
Soc. 2016, 138, 13219.
(
4) Prigge, S. T.; Eipper, B. A.; Mains, R. E.; Amzel, L. M.
Science, 2004, 304, 864.
5) (a) Maiti, D.; Fry, H. C.; Woertink, J. S.; Vance, M. A.;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Solomon, E. I.; Karlin, K. D., J. Am. Chem. Soc. 2006, 129,
264. (b) Lee, J. Y.; Peterson, R. L.; Ohkubo, K.; Garcia-
Bosch, I.; Himes, R. A.; Woertink, J.; Moore, C. D.;
Solomon, E. I.; Fukuzumi, S.; Karlin, K. D., J. Am. Chem.
Soc. 2014, 136, 9925. (c) Kim, S.; Lee, J. Y.; Cowley, R. E.;
Ginsbach, J. W.; Siegler, M. A.; Solomon, E. I.; Karlin, K. D.,
J. Am. Chem. Soc. 2015, 137, 2796.
(19) A similar correlation between the H-bonding
sterngth of the ligand and the stability of the superoxo
complex is also observed at temperatures above -135 C,
o
where cupric superoxide adducts with weak or no H-
bonding readily transform into the corresponding trans-
peroxide species when compared with strongly H-bonded
systems.
(20) (a) Momenteau, M.; Reed, C.A. Chem. Rev. 1994, 94,
659. (b) Birukou, I.; Schweers, R.L.; Olson, J.S. J. Biol.
Chem. 2010, 12, 8840. (c) Momenteau, M.; Lavalette, D. J.
Chem. Soc.,Chem. Commun. 1982, 341.
(
6) (a) Würtele, C.; Gaoutchenova, E.; Harms, K.;
Holthausen, M. C.; Sundermeyer, J.; Schindler, S., Angew.
Chem. Int. Ed. 2006, 45, 3867. (b) Fujisawa, K.; Tanaka, M.;
Morro-oka,
Y.;
Kitajima,
N.
J.
Am.
Chem.Soc. 1994, 116 ,12079.
(7) Kunishita, A.; Kubo, M.; Sugimoto, H.; Ogura, T.;
Sato, K.; Takui, T.; Itoh, S., J. Am. Chem. Soc. 2009, 131,
2788.
(21) The O−O stretch was observed as a Fermi resonance
in at least one isotopologue of each complex, where ν(O−
O) is split by an unenhanced mode with the same
symmetry at similar energy. This assignment is supported
by the different relative intensities of the doublet between
(
8) Zhang, C. X.; Kaderli, S.; Costas, M.; Kim, E.;
Neuhold, Y. M.; Karlin, K. D.; Zuberbuhler, A. D. Inorg.
Chem. 2003, 42,1807.
1
6
18
(
9) (a) Karlin, K. D.; Kaderli, S.; Zuberbühler, A. D. Acc.
O and O isotopologues, which is expected for Fermi
Chem. Res. 1997, 30, 139. (b) Karlin, K. D.; Wei, N.; Jung, B.;
Kaderli, S.; Zuberbuhler, A.D. J. Am. Chem. Soc. 1991, 113,
resonance between isotope-sensitive and isotope-
insensitive modes. The presence of multiple species is less
likely since the ratio in a mixture should be independent of
isotopologue. Fermi resonances have been observed in
other cupric superoxides; see (a) Ref 18, (b) Woertink, J. S.;
Tian, L.; Maiti, D.; Lucas, H. R.; Himes, R. A.; Karlin, K. D.;
Neese, F.; Würtele, C.; Holthausen, M. C.; Bill, E.; Sunder-
meyer, J.; Schindler, S.; Solomon, E. I. Inorg. Chem. 2010,
49, 9450. (c) Peterson, R. L.; Ginsbach, J. W.; Cowley, R. E.;
Qayyum, M. F.; Himes, R. A.; Siegler, M. A.; Moore, C. D.;
Hedman, B.; Hodgson, K. O.; Fukuzumi, S.; Solomon, E. I.;
Karlin, K. D. J. Am. Chem. Soc. 2013, 135, 16454. (d) Cao, R.;
Saracini, C.; Ginsbach, J.W.; Kieber-Emmons, M.T.; Siegler,
M.A.; Solomon, E.I.; Fukuzumi, S.; Karlin, K.D. J. Am.
Chem. Soc, 2016, 138, 7055. The pre-interaction values of
ν(O−O) for A-D given in Figure 1 were determined from
the intensity-weighted average of the two observed
vibrations.
(22) (a) Ref 18. (b) Ref 21. (c) Kunishita, A.; Kubo, M.;
Sugimoto, H.; Ogura, T.; Sato, K.; Takui, T.; Itoh, S. J. Am.
Chem. Soc. 2009, 131, 2788. (d) Würtele, C.; Gaoutchenova,
E.; Harms, K.; Holthausen, M. C.; Sundermeyer, J.;
Schindler, S. Angew. Chem. Int. Ed. 2006, 45, 3867. (e) Kim,
S.; Lee, J. Y.; Cowley, R. E.; Ginsbach, J. W.; Siegler, M. A.;
Solomon, E. I.; Karlin, K. D. J. Am. Chem. Soc. 2015, 137,
2796. (f) Maiti, D.; Fry, H. C.; Woertink, J. S.; Vance, M. A.;
Solomon, E. I.; Karlin, K. D. J. Am. Chem. Soc. 2007, 129,
264.
5
868.
(
(
10) See Supporting Information.
11) (a) Wada, A.; Harata, M.; Hasegawa, K.; Jitsukawa,
K.; Masuda, H.; Mukai, M.; Kitagawa, T.; Einaga, H.,
Angew. Chem. Int. Ed. 1998, 37, 798. (b) Yamaguchi, S.;
Masuda, H., Sci. Technol. Adv. Mater. 2005, 6, 34. (c)
Yamaguchi, S.; Wada, A.; Funahashi, Y.; Nagatomo, S.;
Kitagawa, T.; Jitsukawa, K.; Masuda, H. Eur. J. Inorg. Chem.
2003, 42, 4378. (d) Yamaguchi, S.; Kumagai, A.; Nagatomo,
S.; Kitagawa, T.; Funahashi, Y.; Ozawa, T.; Jitsukawa, K.;
Masuda, H. Bull. Chem. Soc. Jpn. 2005, 78, 116. (e) Mann, S.
I.; Heinisch, T.; Ward, T.R.; Borovik, A.S. J. Am. Chem.
Soc., 2017, 139, 17289. (f) Dahl, E. W.; Dong, H. T.;
Szymczak, N. K. Chem. Commun. 2018, 54, 892.
(
12) (a) Nagaraju, P.; Ohta, T.; Liu, J.-G.; Ogura, T.;
Naruta, Y. Chem. Commun 2016, 52, 7213. (b) Matson, E.
M.; Park, Y. J.; Fout, A. R. J. Am. Chem. Soc. 2014, 136 ,
17398. (c) Macbeth, C. E.; Gupta, R.; Mitchell-Koch, K. R.;
Young Jr, V. G.; Lushington, G, H.; Thompson, W. H.;
Hendrich, M. P.; Borovik, A. S. J. Am. Chem. Soc. 2004, 126,
2556. (c) Borovik, A. S. Acc. Chem. Res. 2005, 38, 54.
(
13) (a) Yang, J.; Kloek, A. P.; Goldberg, D. E.; Mathews,
F. S. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 4224. (d) Lukin,
J. A.; Simplacean, V.; Zou, M.; Ho, N. T.; Ho, C. Proc. Natl.
Acad.Sci. USA 2000, 97, 10354. (c) Arroyo Mañez, P.; Lu, C.;
Boechi, L.; Martí, M. A.; Shepherd, M.; Wilson, J. L.; Poole,
R. K.; Luque, F. J.; Yeh, S. R.; Estrin, D. A. Biochemistry
2011, 50, 3946. (d) Sheng, Y.; Abreu, I. A.; Cabelli, D. E.;
Maroney, M. J.; Miller, A. F.; Teixeira, M.; Valentine, J. S.
(23) Pate, J. E.; Ross, P. K.; Thamann, T J.; Reed, C. A.;
Karlin, K. D.; Sorrell, T. N.; Solomon, E. I. J. Am. Chem. Soc.
1989, 111, 5198.
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24) Wada, A.; Honda, Y.; Yamaguchi, S.; Nagatomo, S.;
(26) Dhar, D.; Yee, G.M.; Markle, T.F.; Mayer, J.M.;
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4
4
5
5
5
5
5
5
5
5
5
5
6
Kitagawa, T.; Jitsukawa, K.; Masuda, H. Inorg. Chem. 2004,
43, 5725.
(25) Warren, J. J.; Tronic, T.A.; Mayer, J. M. Chem. Rev.
Tolman, W.B. Chem. Sci., 2017, 8, 1075.
2010, 110, 6961.
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