Mechanism of Copper/Azodicarboxylate-Catalyzed Aerobic Alcohol Oxidation: Evidence for Uncooperative Catalysis

Article abstract of DOI:10.1021/jacs.5b09940

Cooperative catalysis between Cu^II and redox-active organic cocatalysts is a key feature of important chemical and enzymatic aerobic oxidation reactions, such as alcohol oxidation mediated by Cu/TEMPO and galactose oxidase. Nearly 20 years ago, Markó and co-workers reported that azodicarboxylates, such as di-tert-butyl azodicarboxylate (DBAD), are effective redox-active cocatalysts in Cu-catalyzed aerobic alcohol oxidation reactions [ Markó, I. E., et al. Science 1996, 274, 2044 ], but the nature of the cooperativity between Cu and azodicarboxylates is not well understood. Here, we report a mechanistic study of Cu/DBAD-catalyzed aerobic alcohol oxidation. In situ infrared spectroscopic studies reveal a burst of product formation prior to steady-state catalysis, and gas-uptake measurements show that no O₂ is consumed during the burst. Kinetic studies reveal that the anaerobic burst and steady-state turnover have different rate laws. The steady-state rate does not depend on [O₂] or [DBAD]. These results, together with other EPR and in situ IR spectroscopic and kinetic isotope effect studies, reveal that the steady-state mechanism consists of two interdependent catalytic cycles that operate in sequence: a fast Cu^II/DBAD pathway, in which DBAD serves as the oxidant, and a slow Cu^II-only pathway, in which Cu^II is the oxidant. This study provides significant insight into the redox cooperativity, or lack thereof, between Cu and redox-active organic cocatalysts in aerobic oxidation reactions.

Full text of DOI:10.1021/jacs.5b09940

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Article
Mechanism of Copper/Azodicarboxylate-Catalyzed Aerobic
Alcohol Oxidation: Evidence for Uncooperative Catalysis
Scott D. McCann, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09940 • Publication Date (Web): 22 Dec 2015
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Mechanism of Copper/Azodicarboxylate-Catalyzed
Aerobic Alcohol Oxidation: Evidence for
Uncooperative Catalysis
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Scott D. McCann and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin - Madison, 1101 University Avenue,
Madison, Wisconsin 53706
Abstract
II
Cooperative catalysis between Cu and redox-active organic cocatalysts is a key feature of
important chemical and enzymatic aerobic oxidation reactions, such as alcohol oxidation
mediated by Cu/TEMPO and galactose oxidase. Nearly twenty years ago, Markó and coworkers
reported that azodicarboxylates, such as di-tert-butyl azodicarboxylate (DBAD), are effective
redox-active cocatalysts in Cu-catalyzed aerobic alcohol oxidation reactions, but the nature of
the cooperativity between Cu and azodicarboxylates is not well understood. Here, we report a
mechanistic study of Cu/DBAD-catalyzed aerobic alcohol oxidation. In situ infrared
spectroscopic studies reveal a burst of product formation prior to steady-state catalysis, and gas-
uptake measurements show that no O
the anaerobic burst and steady-state turnover have different rate laws. The steady-state rate does
not depend on [O ] or [DBAD]. These results, together with other EPR and in situ IR
2
is consumed during the burst. Kinetic studies reveal that
2
spectroscopic and kinetic isotope effect studies, reveal that the steady-state mechanism consists
II
of two interdependent catalytic cycles that operate in sequence: a fast Cu /DBAD pathway, in
II
II
which DBAD serves as the oxidant, and a slow Cu -only pathway, in which Cu is the oxidant.
This study provides significant insight into the redox cooperativity, or lack thereof, between Cu
and redox-active organic cocatalysts in aerobic oxidation reactions.
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Introduction
Homogeneous catalysts for aerobic alcohol oxidation have been the focus of extensive
1
2
3
investigation. Noble-metal catalysts, such as those based on Ru and Pd, are comparatively well
characterized and often proceed via β-hydride elimination from a metal–alkoxide intermediate.
This pathway is facilitated by the closed-shell nature of the transition metal and the propensity of
second-row metals to undergo two-electron redox steps. Meanwhile, a number of recent studies
have demonstrated the synthetic utility of copper-based catalysts for aerobic alcohol
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b,e-f,4,5
oxidation.
A particularly effective class of catalysts features a bpy-ligated Cu species in
combination with TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) or a different
4
6
nitroxyl radical cocatalyst (Chart 1A). Mechanistic studies of these catalyst systems highlight
II
the role of redox cooperativity between the Cu center and the organic cocatalyst, both of which
undergo one-electron redox processes to achieve the net two-electron oxidation of alcohols. This
mechanistic feature is reminiscent of galactose oxidase, which features a mononuclear Cu center
7
with a coordinated redox-active phenoxyl radical (Figure 1), and a number of related
8
biomimetic catalyst systems.
Chart 1. Cu/TEMPO and Cu/DBAD Aerobic Alcohol Oxidation Catalyst Systems
A: Cu/TEMPO Catalyst System
I
[Cu (MeCN)4]OTf
N
N
bpy
Me
N
N
O
N
TEMPO
NMI
B: Cu/DBAD Catalyst System
I
Cu Cl
N
N
phen
O
Me
N
tBuO
K CO
2
3
N
t
(+/-)
N
O Bu
- or -
N
t
O
KO Bu
DBAD
NMI
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Tyr
Tyr
Cys
OH
S
O
HisN
CuII
H
R
HisN
O
H
Figure 1. Active site structure of galactose oxidase.
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In 1996, Markó and coworkers reported a Cu-based catalyst system for aerobic alcohol
oxidation that has a number of features in common with the Cu/nitroxyl catalyst systems, but
uses an azodicarboxylate, such as di-tert-butyl azodicarboxylate (DBAD), as a cocatalyst rather
5a
than a nitroxyl (Chart 1B). Subsequent studies showed that this catalyst system exhibits broad
synthetic scope, including utility with both activated and aliphatic 1° and 2° alcohols, as well as
alcohols containing nitrogen- and sulfur-containing functional groups. The optimal catalytic
Cu/DBAD reaction conditions are somewhat less favorable than the corresponding conditions for
Cu/nitroxyl reactions. For example, they are typically performed at higher reaction temperatures,
use a relatively expensive solvent (fluorobenzene), and employ pure O
2
rather than air as the
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5g
source of oxidant. Recent efforts have begun to address these issues, however, and the overall
effectiveness of the reactions surpasses the majority of other homogeneous metal catalyst
systems for aerobic alcohol oxidation. Moreover, the use of DBAD as a cocatalyst raises a
number of fundamental questions concerning the redox cooperativity between the Cu and
DBAD.
5
The mechanism of Cu/DBAD-catalyzed alcohol oxidation proposed by Markó, a simplified
version of which is shown in Scheme 1, exhibits a number of similarities to the mechanism
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b-f
elucidated for Cu/nitroxyl-catalyzed alcohol oxidation. For example, in both cases, the C–H
bond cleavage is proposed to proceed through hydride transfer from a Cu–alkoxide to the
coordinated organic cocatalyst via a six-membered-ring transition state. For the Cu/DBAD
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catalyst system, the reduced Cu /DBADH
2
complex is proposed to undergo aerobic oxidation to
I
a Cu (OH)/DBAD complex, which can undergo ligand exchange with an alcohol to begin
another round of turnover. An important distinction between these mechanisms is the
involvement of one- versus two-electron redox reactivity of the organic cocatalysts, TEMPO and
DBAD, respectively.
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Scheme 1. Simplified Mechanisms for Aerobic Alcohol Oxidation with Cu/TEMPO (A) and
Cu/DBAD (B) Catalyst Systems.
A: Mechanism of Cu/TEMPO-Catalyzed Aerobic Alcohol
Oxidation
O
R
CuI
L
n
1/2 O
2
+
TEMPOH
H
R
O
H
n
L Cu
n 2 2
1/2 [L Cu] (O )
O
N
TEMPOH
H
2
O
L
n
CuII OH
TEMPO•
HO
R
+
TEMPO•
B: Proposed Mechanism of Cu/DBAD-Catalyzed Aerobic
Alcohol Oxidation
L
n
CuI
O
R
1
/2 O
2
N
NH
Boc
Boc
H
R
O
N
O
N
2
L
n
CuI
H
1/2
L
CuI
n
N
NH
Boc
Boc
Boc
R
Boc
OH
N
2
H O
CuI
L
n
HO
N
Boc
Boc
Many aspects of the Cu/DBAD-catalyzed reaction mechanism have not yet been elucidated,
including the identity of the catalyst resting state and the turnover-limiting step of the reaction.
Herein, we report kinetic and in situ spectroscopic studies of Cu/DBAD-catalyzed alcohol
oxidation, which reveal that the mechanism is more complex that previously recognized. The
reaction proceeds via the alternating involvement of two interdependent catalytic cycles, one in
which DBAD mediates two-electron alcohol oxidation and the second of which involves alcohol
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oxidation by Cu without the involvement of DBAD. The results reveal a distinct lack of redox
cooperativity between Cu and DBAD, and they contrast the cooperativity evident in the
Cu/TEMPO catalyst system and Cu/organic-cofactors in enzymatic aerobic oxidation reactions.
The implications of these results for development of new synthetic aerobic oxidation catalysts
are discussed.
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Results
Cu/DBAD-Catalyzed Oxidation of 1-Phenylethanol: Observation and Analysis of a
Kinetic Burst. Kinetic studies of the oxidation of 1-phenylethanol were initiated by using
1
0
conditions similar to those reported by Markó and coworkers (eq 1). Product formation and
cocatalyst speciation (i.e., DBAD/DBADH ) were monitored in situ by IR spectroscopy, and
2
changes in oxygen pressure were measured within a sealed and temperature-controlled flask by
3c,d
using gas-uptake methods. The in situ IR data reveal a burst of product formation within the
first two minutes of the reaction, quantitatively correlating with the conversion of DBAD into
2
DBADH (Figure 2A). Control reactions indicate that negligible reactivity occurs in the absence
11
of Cu. The gas-uptake data show that O
2
is not consumed during the burst; O
2
consumption
only begins when all of the DBAD is reduced (Figure 2B). If DBADH
2
is used as the cocatalyst
precursor, a kinetic burst is not observed, and oxygen consumption begins immediately upon
exposure of the reaction mixture to substrate (Figure S2). Collectively, these data show that
DBAD acts as the stoichiometric oxidant during the burst (eq 2).
5
mol% (phen)CuCl
5 mol% DBAD
OH
O
(
1)
Ph
Me 2 equiv. K2CO3
Fluorobenzene
Ph
Me
6
50 torr O2, 27 °C
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Ph OH
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Boc
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DBAD (5 mol%)
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Me
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H
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.01
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N
Boc
Boc
N
0
5
10
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time (min)
2
2
1
1
50
00
50
00
B.
1
20
100
80
O
Ph
Me
6
4
2
0
0
0
0
O
2
5
0
0
0
5
10
15
20
time (min)
Figure 2. (A) Representative early time-course data for (phen)CuCl/DBAD-catalyzed aerobic
oxidation of 1-phenylethanol (eq 1). (B) Comparison of in situ IR and gas-uptake time course
showing the induction period for O
the presence of DBAD. Reaction conditions: 0.25 M 1-phenylethanol in 5 mL fluorobenzene,
(phen)CuCl] = 12.5 mM, [DBAD] = 12.5 mM, 2 equiv. K CO , 650 torr O , 27 °C.
2
consumption during the kinetic burst of product formation in
[
2
3
2
The kinetic dependence of the burst rate on each reaction component was determined by
analyzing initial rates of DBAD consumption in situ by IR spectroscopy under a nitrogen
atmosphere. The rate exhibits a nearly linear dependence on [(phen)CuCl]. The data are
influenced by the poor solubility of (phen)CuCl at ≥ 12 mM (solid (phen)CuCl is visible in the
reaction mixture), which causes the rate to plateau at high [(phen)CuCl]. A saturation
1
2
dependence on [DBAD] and first-order dependence on [alcohol] is also observed (Figure 3).
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These data show that the burst arises from anaerobic oxidation of alcohol with DBAD as the
oxidant, and the dependence of the rate on (phen)CuCl (and negligible rate in the absence of Cu)
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b
indicates that (phen)CuCl activates DBAD in the alcohol oxidation reaction.
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A.
B.
C.
Figure 3. Kinetic data from the anaerobic kinetic regime of 1-phenylethanol oxidation by
(
[
phen)CuCl/DBAD catalyst system assessing the kinetic dependence on (A) [(phen)CuCl] (B)
DBAD] and (C) [alcohol]. Rates were obtained by monitoring DBAD consumption using in situ
IR spectroscopy. Error bars correspond to ±σ for three trials under the standard reaction
conditions. Standard reaction conditions: 0.25 M 1-phenylethanol in 5 mL fluorobenzene,
[(phen)CuCl] = 12.5 mM, [DBAD] = 12.5 mM, 2 equiv. K CO , 1 atm N , 27 °C. Standard
2 3 2
conditions were employed, except for the concentration of the component being varied. Reaction
time course data is included in the Supporting Information (Figures S8, S10 and S12).
Cu/DBAD-Catalyzed Oxidation of 1-Phenylethanol: Analysis of Steady-State Catalytic
Turnover. Analysis of product formation and O
turnover revealed a 2:1 product-to-O stoichiometry (Figure 2B, Figure S3). In situ IR
spectroscopic data reveal that DBADH is the only form of the cocatalyst present during steady-
state turnover (i.e., no DBAD was detected). Rates of product formation during the aerobic phase
were monitored in situ by IR using DBADH as the cocatalyst precursor to avoid complications
2
consumption during steady-state catalytic
2
2
2
1
3
associated with the kinetic burst observed with DBAD as the cocatalyst precursor. The initial-
rate data reveal that the steady-state catalytic rate exhibits a saturation dependence on
2 2
[(phen)CuCl], a zero-order dependence on [DBADH ] and pO , and a first-order dependence on
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[
alcohol] (Figures 4 and S15). The curvature in Figure 4A again is undoubtedly influenced by
1
2
the poor solubility of (phen)CuCl at ≥ 12 mM.
A.
B.
C.
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Figure 4. Kinetic data from the aerobic kinetic regime of 1-phenylethanol oxidation by
2
catalyst system assessing the kinetic dependence on (A) [(phen)CuCl] (B)
DBADH ] (C) [alcohol]. Rates were obtained by monitoring product formation by in situ IR
spectroscopy. Error bars correspond to ±σ for four trials under the standard reaction conditions.
Standard reaction conditions: 0.25 M 1-phenylethanol in 5 mL fluorobenzene, [(phen)CuCl] =
2 2 3 2
12.5 mM, [DBADH ] = 12.5 mM, 2 equiv. K CO , 1 atm O , 27 °C. Standard conditions were
employed, except for the concentration of the component being varied. Reaction time course data
is included in the Supporting Information (Figures S9, S11 and S13).
(phen)CuCl/DBADH
[
2
(Phen)CuCl has been reported to mediate stoichiometric and catalytic oxidation of alcohols
5d,15
in the absence of DBAD.
In order to assess the relationship between this process and the
(
phen)CuCl/DBAD conditions, aerobic oxidation of 1-phenylethanol was monitored by in situ IR
spectroscopy in the absence of DBAD. Figure 5 compares the results obtained in the presence
and absence of DBADH (DBADH was used as the cocatalyst to avoid the burst phase, as noted
above). The catalytic rate with DBADH was two-fold faster than the rate in the absence of the
2
2
2
cocatalyst (Figure 5A). Furthermore, EPR spectra of the catalytic reaction mixtures with and
II
without DBADH
2
revealed the presence of Cu signals with superhyperfine coupling derived
from the phenanthroline ligand (Figure 5B). Simulation of the EPR spectra indicate that two
II
different (phen)Cu species are present, and the simulations are consistent with two nitrogen
ligands coordinated to the copper centers (see Figure S23 and Supporting Information for
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details). Double integration of the signal and calibration relative to an external standard
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showed that >80% of the copper in both reactions is present as EPR-active Cu species.
Moreover, the nearly identical spectra observed in the presence and absence of DBADH
that DBAD(H ) is not coordinated to the Cu center. This result aligns with the in situ IR data,
which show that all of the cocatalyst is present as free DBADH
2
suggest
2
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2
.
0
.03
A.
•
with DBADH
2
0.025 • without DBADH2
0
.02
.015
.01
0
0
0.005
0
0
5
10
time (min)
15
20
B.
–
–
with DBADH
2
without DBADH
2
2600
2800
3000
Field (G)
3200
3400
Figure 5. (A) Comparison of reaction time courses with and without DBADH
conditions: 0.25 M 1-phenylethanol in 5 mL fluorobenzene, [(phen)CuCl] = 12.5 mM,
DBADH ] = 12.5 mM, 2 equiv. K CO , 650 torr O , 27 °C. (B) EPR spectra of catalytic
reaction mixtures: during aerobic turnover with and without added DBAD. Reaction conditions:
.0 M 1-phenylethanol in 2 mL fluorobenzene, [(phen)CuCl] = 10 mM, [DBAD] = 10 mM, 2
equiv. K CO , 1 atm O , 27 °C. EPR spectra were collected at 115 K, with a microwave
frequency of 9.30 MHz.
2
. Reaction
[
2
2
3
2
1
2
3
2
Kinetic Isotope Effect (KIE) Studies. Kinetic isotope effects were measured in two
different ways, via comparison of the independent rates of oxidation of 1-phenylethanol and 1-
1
phenylethanol-1-d and via intramolecular competition with PhCHDOH as the substrate, and the
KIEs were obtained for both Cu/DBAD and Cu-only reaction conditions. The independent rate
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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measurements for aerobic oxidation of 1-phenylethanol and 1-phenylethanol-1-d
1
revealed that
/k = 2.1 ±
0.3 (Cu/DBAD) and 2.0 ± 0.2 (Cu-only) (Scheme 2A). These two catalyst systems exhibited
different intramolecular competition KIEs, however: k /k = 3.9 ± 0.1 (Cu/DBADH ) and 2.5 ±
.1 (Cu-only) (Scheme 2B). An intramolecular competition KIE was also measured for anaerobic
Cu/DBAD-mediated alcohol oxidation, reflecting the reactivity during the burst phase. In this
case an even larger KIE was observed: k /k = 5.4 ± 0.2 (Scheme 2B). Two mechanistically
significant outcomes from these studies include (1) the similarity between the independent-rate
KIE for Cu/DBADH conditions, the independent-rate KIE for Cu-only conditions, and the
reactions with the Cu/DBAD and Cu-only catalyst systems exhibited similar KIEs: k
H
D
H
D
2
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
0
H
D
2
intramolecular-competition KIE for the Cu-only conditions (KIEs = 2.1–2.5), and (2) that the
intramolecular-competition KIE for Cu/DBAD catalytic conditions (3.9) is halfway between the
KIEs observed for the anaerobic Cu/DBAD and Cu-only conditions (5.4 and 2.5, respectively).
The implications of these observations are elaborated below.
Scheme 2. KIE Experiments for Cu/DBAD Alcohol Oxidation Reactions.
A: Independent Rate KIE
OH
Me 5 mol% (phen)CuCl
Ph
H
(±) 5 mol% DBADH2
O
-or-
OH
Me
2
equiv. K2CO3
Ph
Me
Fluorobenzene
650 torr O2, 27 °C
Ph
D
KIE with DBADH2 = 2.1 ± 0.3
KIE without DBADH2 = 2.0 ± 0.2
B: Intramolecular Competition KIE
mol% (phen)CuCl
5
(±) 5 mol% DBAD(H2)
OH
(±) 1 atm O2
O
D
H
Ph
2 equiv. K2CO3 Ph
Fluorobenzene
H(D)
2
7 °C
Intramolecular
Competition KIEa
(
phen)CuCl DBAD(H ) O2
2
+
+
+
+
+
-
-
5.4 ± 0.2
3.9 ± 0.1
+
+
2.5 ± 0.1
a
1
KIE values determined using H NMR spectroscopy. Errors are the standard deviation of three independent reactions. Reaction conditions: 0.25
M substrate in 5 mL fluorobenzene, [(phen)CuCl] = 12.5 mM, [DBAD(H
experiment used DBAD, and the aerobic experiment used DBADH .)
2
2 3 2 2
)] = 12.5 mM, 2 equiv. K CO , 1 atm O or N , 27 °C. (The anaerobic
2
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Discussion
Proposed Mechanism and Its Relationship to Experimental Results. The original
mechanism proposed for Cu/DBAD-catalyzed aerobic alcohol oxidation (cf. Scheme 1B) is
chemically plausible and accounts for the overall stoichiometry of alcohol oxidation and
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cocatalyst regeneration by O
2
, but several features are not consistent with the experimental data
presented above. Briefly, (1) this mechanism does not provide a clear basis for the kinetic burst
at the start of the reaction, together with a lack of pO -dependence on the rate of the burst or
2
steady-state turnover, (2) it does not rationalize the different kinetic isotope effects obtained with
II
different substrate probes and/or under different conditions, (3) it does not predict that Cu and
2
DBADH should be predominant catalyst resting state or that these cocatalysts do not form a
resting-state complex under catalytic conditions, and (4) it does not explain the two-fold
difference in rate between (phen)Cu-catalyzed alcohol oxidation in the presence and absence of
DBAD (cf. Figure 5).
A revised mechanism consistent with each of these observations is shown in Scheme 3 and
II
features two interdependent catalytic cycles: (1) a fast Cu /DBAD pathway (bottom, blue cycle)
II
in which DBAD serves as a two-electron oxidant, and (2) a slow Cu -only pathway (top, red
II
I
cycle) in which two equivalents of Cu serve as the oxidant. The Cu species formed in the latter
I
pathway activate O
2
and contribute to four-electron oxidation of the cocatalyst system: 2 Cu →
II
2
Cu and DBADH
2
→ DBAD. The overall turnover-limiting step of the catalytic bicycle is
II
(
phen)Cu -mediated oxidation the alcohol (top left step in Scheme 3), as revealed by the steady-
II
II
state rate law (rate ∝ [(phen)Cu ]·[alcohol], cf. Figure 4) and the presence of (phen)Cu and
DBADH as the cocatalyst resting states. The kinetic burst exhibits a kinetic dependence on
(phen)CuCl], [DBAD] and [alcohol], and it arises from the use of DBAD as the source of
2
[
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2
cocatalyst. The combination of (phen)CuCl and DBAD promotes very rapid O -independent
5
b,11
alcohol oxidation by a pathway that resembles the blue pathway at the bottom of Scheme 3.
Scheme 3. Proposed Mechanism for Cu/DBAD-Catalyzed Aerobic Alcohol Oxidation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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3
4
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9
0
Me Ph
Turnover
Limiting
Step
LnCuII
O
+
H
2
H O
Me
Ph
LnCuII OH
Me Ph
O
+
II
Slow Cu -Mediated
Alcohol Oxidation
HO
H
2
H O
phen)CuII Resting
(
2 LnCuII OH State Identified by
2 LnCuI
EPR Spectroscopy
Fast
Aerobic O2
Oxidation
2
LnCuII OH
2
DBADH Resting
HN NH
Boc
Boc
N N
State Identified by IR
Spectroscopy
Boc
Boc
LnCuII OH +
Me Ph
HO
LnCuII OH +
Me Ph
O
Me
O
H
Ph
LnCuII
H
2
H O
2
H O
N
N
Boc
Boc
II
Fast Cu /DBAD-Mediated
Alcohol Oxidation
This revised mechanism also rationalizes all of the other experimental data. It correctly
2
predicts a zero-order pO -dependence on the reaction because neither alcohol oxidation by
II
(
phen)Cu during steady-state turnover nor Cu/DBAD-mediated alcohol oxidation in the burst
2
involves O . The KIE value observed during steady-state Cu/DBAD catalytic turnover (KIE =
3
.9) is the average of the KIEs observed for stoichiometric Cu/DBAD-mediated alcohol
oxidation in the burst (KIE = 5.4) and for steady-state turnover with the Cu-only catalyst system
(KIE = 2.5). This result is rationalized by the required sequence of the two cycles in Scheme 3:
I
the fast Cu/DBAD cycle can take place only after Cu is formed in the Cu-only cycle because
I
Cu /O
2
is needed to mediate the oxidation of DBADH
2
to DBAD. The two-fold difference in rate
between the Cu/DBAD vs. Cu-only catalyst systems has a similar rationale. Involvement of the
fast DBAD-mediated pathway means that the Cu/DBAD catalyst system oxidizes two
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equivalents of alcohol for each turnover of (phen)CuCl. The common turnover-limiting C–H
cleavage process in the Cu-only and Cu/DBAD-catalyzed reactions explains the very similar KIE
values observed with these two catalyst systems, which are also similar to the intramolecular-
competition KIE for the Cu-only conditions (Scheme 2).
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Analysis of Cu/DBAD Redox Cooperativity and Comparison to Cu/TEMPO Alcohol
Oxidation and Enzymes. As noted in the Introduction, the Cu/DBAD catalyst system closely
resembles the Cu/TEMPO system with respect to the catalyst components (Chart 1). The results
herein suggest that the catalytic mechanisms exhibit both similarities and differences.
Cu/DBAD-mediated alcohol oxidation is believed to involve a transition state that closely
6
b,c,f
resembles the transition state for alcohol oxidation by Cu/TEMPO (Figure 6).
The similar
KIEs observed for stoichiometric Cu/DBAD-mediated oxidation of PhCHDOH (KIE = 5.4) and
4b,6a
the same reaction with Cu/TEMPO (KIE = 5.4–6.1) may support this relationship.
+
+
H Ph
H Ph
O
O
O
N
N
N
N
N
~
Cu
H
N
Cu
H
N
Boc
Boc
Cu/DBAD
Cu/TEMPO
Figure 6. Comparison of the proposed transition-state structure for Cu/DBAD-mediated alcohol
oxidation and the transition-state structure for Cu/TEMPO-mediated alcohol oxidation.
The differences appear to arise from poor cooperativity between the Cu and DBAD
II
cocatalysts. In the Cu/TEMPO reactions, Cu and TEMPO are directly involved in the substrate
I
oxidation step and generate Cu and TEMPOH as byproducts of the reaction. These reduced
cocatalysts then undergo aerobic oxidation to complete the cycle. In the Cu/DBAD reactions, the
II
Cu species serves as a Lewis acidic template for the alkoxide and DBAD, and substrate
oxidation involves two-electron reduction of the DBAD cocatalyst to the hydrazine oxidation
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2
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2
2
2
2
2
2
2
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II
level. Cu is not reduced in this step. This reactivity is consistent with the ability of non-redox-
II
II
active Lewis acids, such as Zn and Mg , to promote stoichiometric azodicarboxylate-mediated
1
8
alcohol oxidation. Markó and coworkers similarly exploited this reactivity in (phen)CuCl-
5b
catalyzed oxidation of alcohols with stoichiometric DBAD. In order to achieve catalytic
0
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9
0
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0
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turnover, DBADH
2
must be oxidized back to DBAD, but Cu is not an effective oxidant for this
II
reaction under these conditions. Therefore, Cu and DBADH
2
accumulate as the catalyst resting
19
I
20
I
states. A more-reactive oxidant is accessible from the reaction of Cu and O
2
. Whereas Cu is
I
a natural byproduct of the alcohol oxidation step in Cu/TEMPO-catalyzed alcohol oxidation, Cu
forms via a comparatively slow Cu-only alcohol oxidation pathway in the Cu/DBAD-catalyzed
5
d,15,21
reaction.
The above analysis shows that the Cu and DBAD cocatalysts exhibit poor redox
cooperativity relative to other aerobic oxidation reactions involving transition-metal/organic
cocatalyst systems. Different forms of cooperativity have been observed in such reactions. In
II
alcohol oxidation reactions catalyzed by Cu/TEMPO and the enzyme galactose oxidase, Cu and
the oxyl radical serve as coupled one-electron oxidants that participate jointly in oxidation of the
2
alcohol and are subsequently regenerated together by reaction with O (cf. Scheme 1A and
Figure 1). An alternative form of cooperativity is evident in copper amine oxidases, which
feature an active-site Cu center together with a quinone cofactor, derived from post-translational
modification of a tyrosine residue (Scheme 4A). The quinone species mediate amine oxidation
without the involvement of Cu, but Cu plays an important role in aerobic oxidation of the
2
2
hydroquinone to quinone, following substrate oxidation (Scheme 4B). Similar concepts have
2
3
been implemented in bioinspired amine oxidation reactions involving quinone catalysts,
including examples in which Cu-based cocatalysts are used to facilitate aerobic oxidation of the
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4,25
hydroquinone species.
This form of cooperative catalysis is featured in a wide range of
2
6,27
aerobic oxidation reactions in chemistry and biology.
Scheme 4. (A) Copper Amine Oxidase Active Sites and (B) Coupled Catalytic Aerobic
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Oxidation Cycle.
A: Quinoenzyme Active Sites
Lys
Tyr
Tyr
O
O
HN
OH2
CuII
OH
OH2
O
OH2
NHis
OH2
NHis
NHis
NHis
NHis
NHis
CuII
O
Trihydroxyphenylalanine
Lysyl Tyrosylquinone
quinone (TPQ)
(LTQ)
B: Coupled Catalytic Aerobic Oxidation
R
1/
2 CuI
2 O2
2
R
NH2
O
O
R
H2O
2
CuII
R
N
R
OH
OH
The differences between the Cu/TEMPO and Cu/DBAD catalyst system arises, in part, from
the one-electron vs. two-electron redox chemistry of TEMPO and DBAD, respectively.
Nevertheless, role of quinones in copper amine oxidase examples in Scheme 4 illustrates that the
breakdown in cooperativity in Cu/DBAD-catalyzed alcohol oxidation is not a necessary
consequence of using a two-electron cocatalyst. Instead, the breakdown is linked to the inability
II
of Cu to oxidize DBADH
2
in a manner similar to the hydroquinone in Scheme 4B.
II
Regeneration of DBAD is possible only after Cu mediates the slower DBAD-free alcohol
oxidation. These insights have important implications for the development of cooperative
catalyst systems for aerobic oxidation. For example, it raises the possibility that modified
catalyst systems could be identified in which a more effective redox couple than
II
I
(
2
phen)Cu /(phen)Cu could enable oxidation of DBADH to exploit the faster rates associated
with the DBAD-based alcohol oxidation cycle. Another option would be the identification of a
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2
2
2
2
2
2
2
2
2
2
3
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less-oxidizing azo compound that could promote rapid alcohol oxidation while being compatible
II
with oxidation by Cu . Future progress toward these goals could provide the basis for the
development aerobic oxidation reactions that expand beyond alcohol oxidation.
Conclusions
0
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9
0
1
2
3
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8
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0
The mechanistic study of Cu/DBAD-catalyzed alcohol oxidation described above highlights
both similarities and differences relative to Cu/TEMPO- and Cu/quinone-catalyzed aerobic
oxidation reactions and related enzymatic oxidation reactions. An unusual catalytic bicycle was
identified that arises from a breakdown in the redox cooperativity between the Cu and DBAD
cocatalysts. Cu/DBAD neither functions in a directly coupled process like Cu/TEMPO and
galactose oxidase nor in a coupled multi-cycle mechanism similar to copper amine oxidases and
synthetic mimics. The former difference reflects the one-electron vs. two-electron redox activity
II
of TEMPO and DBAD, respectively, and the latter difference reflects the inability of Cu to
2
promote the oxidation of DBADH to DBAD. The concepts elucidated from this study provide
an important foundation for future studies directed toward the development of new catalyst
systems for selective aerobic oxidation of organic molecules.
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ASSOCIATED CONTENT
Supporting Information. Experimental details for data acquisition and additional kinetic data
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*
stahl@chem.wisc.edu
ACKNOWLEDGMENT
Financial support was provided by the DOE (DE-FG02-05ER15690). NMR spectroscopy
facilities were partially supported by the NSF (CHE-9208463) and NIH (S10 RR08389), and the
EPR facility was partially supported by the NSF (CHE-9629688).
References
1
. See reviews and references cited therein: (a) Zhan, B.-Z.; Thompson, A. Tetrahedron 2004,
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2
2
2
2
2
2
2
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3
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3
3
3
3
3
3
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3
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
. For representative studies of Ru-catalyzed aerobic alcohol oxidation see: (a) Bilgrien, C.;
Davis, S.; Drago, R. S. J. Am. Chem. Soc. 1987, 109, 3786-3787. (b) Bäckvall, J.-E.;
Chowdhury, R. L.; Karlsson, U. Chem. Commun. 1991, 473-475. (c) Lenz, R.; Ley, S. V. J.
Chem. Soc., Perkin Trans. 1 1997, 3291-3292. (d) Markó, I. E.; Giles, P. R.; Tsukazaki, M.;
Chellé-Regnaut, I.; Urch, C. J.; Brown, S. M. J. Am. Chem. Soc. 1997, 119, 12661-12662. (e)
Hanyu, A.; Takezawa, E.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39, 5557-5560. (f)
Dijksman, A.; Marino-González, A.; Mairata i Payeras, A.; Arends, I. W. C. E.; Sheldon, R.
A. J. Am. Chem. Soc. 2001, 123, 6826-6833. (g) Csjernyik, G.; Éll, A. H.; Fadini, L.; Pugin,
B.; Bäckvall, J.-E. J. Org. Chem. 2002, 67, 1657-1662.
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
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
II
3
. For representative mechanistic studies of Pd -catalyzed aerobic alcohol oxidation see: (a) ten
Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344, 355-369. (b),
ten Brink, G.-J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G; Sheldon, R. A. Adv. Synth.
Catal. 2003, 345, 497-505. (c) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc.
2
004, 126, 11268-11278. (d) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128,
348-4355. (e) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221-229. (f) Chung,
4
K.; Banik, S. M.; De Crisci, A. G.; Pearson, D. M.; Blake, T. R.; Olsson, J. V.; Ingram, A. J.;
Zare, R. N.; Waymouth, R. M. J. Am. Chem. Soc. 2013, 135, 7593-7602. (g) Ingram, A. J.;
Solis-Ibarra, D.; Zare, R. N.; Waymouth, R. M. Angew. Chem., Int. Ed. 2014, 53, 5648-5652.
4. For Cu/nitroxyl catalyst systems, see refs. 1e-j and the following primary references: (a)
Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A.; Chou, C. S. J. Am. Chem. Soc. 1984, 106,
3374-3376. (b) Gamez, P.; Arends, I. W. C. E.; Sheldon, R. A.; Reedijk, J. Adv. Synth. Catal.
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10901-10911. (e) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901-16910. (g)
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Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742-15745. (h) Sasano, Y.;
Nagasawa, S.; Yamazaki, M.; Shibuya, M.; Park, J.; Iwabuchi, Y. Angew. Chem., Int. Ed.
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. (a) Markó, I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science 1996, 274,
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Chem., Int. Ed. 1997, 36, 2208-2210. (c) Markó, I.; Gautier, A.; Chellé-Regnaut, I.; Giles, P.
R.; Tsukazaki, M.; Urch, C. J.; Brown, S. M. J. Org. Chem. 1998, 63, 7576-7577. (d) Markó,
I. E.; Giles, P. R.; Tsukazaki, M.; Chellé-Regnaut, I.; Gautier, A.; Brown, S. M.; Urch, C. J. J.
Org. Chem. 1999, 64, 2433-2439. (e) Markó, I. E.; Gautier, A.; Mutonkole, J.-L.; Dumeunier,
R.; Ates, A.; Urch, C. J.; Brown, S. M. J. Organomet. Chem. 2001, 624, 344-347. (f) Markó,
I. E.; Gautier, A.; Dumeunier, R.; Doda, K.; Philippart, F.; Brown, S. M.; Urch, C. J. Angew.
Chem., Int. Ed. 2004, 43, 1588-1591. (g) Nishii, T.; Ouchi, T.; Matsuda, A.; Matsubara, Y.;
Haraguchi, Y.; Kawano, T.; Kaku, H.; Horikawa, M.; Tsunoda, T. Tetrahedron Lett. 2012,
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3, 5880-5882.
6
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357-2367. (e) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. ACS Catal. 2013, 3, 2599-2605. (f)
2
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12166-12173. (g) Rabeah, J.; Bentrup, U.; Stösser, R.; Brückner, A. Angew. Chem. Int. Ed.
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. Whittaker, J. W. Chem. Rev. 2003, 103, 2347-2363.
. (a) Wang, Y.; DuBois, J. L.; Hedman, B.; Hodgson, K. O.; Stack, T. D. P. Science 1998, 279,
537-540. (b) Chaudhuri, P.; Hess, M.; Flörke, U.; Wieghardt, K. Angew. Chem., Int. Ed. 1998,
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Int. Ed. 1999, 38, 1095-1098. (d) Chaudhuri, P.; Hess, M.; Müller, J.; Hildenbrand, K.; Bill,
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T.; Stack, T. D. P. Coord. Chem. Rev. 2013, 257, 528-540.
9. Exceptions to these generalizations have been demonstrated. For example, Markó has shown
that bubbling air may be used to substitute for pure O (see ref. 5a), and Tsunoda and
2
coworkers recently developed modified conditions, including the replacement of phen with
4,7-diphenyl-1,10-phenanthroline, that permit Cu/DBAD-catalyzed aerobic alcohol oxidation
to proceed at room temperature in toluene (see ref. 5g).
1
1
0. Fluorobenzene was shown to be a superior solvent relative to toluene, see ref. 5c.
1. The anaerobic Cu/DBAD-mediated burst of product formation is significantly faster than
catalytic turnover, regardless of the initial oxidation state of the Cu source (i.e., CuCl vs.
2
CuCl ). See Supporting Information Figure S4.
1
2. The poor solubility of CuCl in fluorobenzene prevented the preparation of stock solutions,
which led to scatter in kinetic plots. Reaction solutions become homogeneous upon addition
of substrate below 12 mM (phen)CuCl. See Supporting Information for details.
1
3. Steady-state catalytic turnover proceeds at a similar rate regardless of the choice of cocatalyst
precursor. DBAD or DBADH
2
(see Figure S1).
] dependence under aerobic conditions was to assess the
14. Our intent in probing the [DBADH
2
role of DBAD under conditions relevant to the optimized catalytic conditions [Cu:DBAD(H
2
)
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=
1:1], and Cu:DBADH
2
ratios were analyzed from 1:0.5 – 1:2. As discussed below,
(phen)CuCl catalyzes alcohol oxidation in the absence of DBAD at a two-fold slower rate.
15. (a) Jallabert, C.; Riviere, H. Tetrahedron Lett. 1977, 14, 1215-1218. (b) Jallabert, C.;
Lapinte, C.; Riviere, H. J. Mol. Catal. 1982, 14, 75-86. (c) Franc, G.; Jutand, A. Dalton
Trans. 2010, 39, 7873-7875.
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60
1
6. The (super)hyperfine splitting pattern and simulated EPR parameters are most consistent
II
with an axial Cu species bearing two nitrogen and two (or more) oxygen ligands. See: (a)
Peisach, J.; Blumberg, W. E. Arch. Biochem. Biophys. 1974, 165, 691-708. (b) Subramanian,
P. S.; Suresh, E.; Dastidar, P.; Waghmode, S.; Srinivas, D. Inorg. Chem. 2001, 40, 4291-
4
301. (c) Lemoine, P.; Viossat, B.; Morgant, G.; Greenaway, F. T.; Tomas, A.; Dung, N.-H.;
Sorenson, J. R. J. J. Inorg. Biochem. 2002, 89, 18-28.
1
2
7. A thorough analysis of catalytic aliphatic alcohol oxidation by Cu/DBAD(H ) has not been
conducted, but oxidation of 1-octanol shows an approximately two-fold rate increase in the
presence of DBADH relative to Cu alone, suggesting the catalytic mechanism presented
here also describes the mechanism of aliphatic alcohol oxidation.
18. (a) Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1977, 50,
773-2776. (b) Cao, H. T.; Grée, R. Tetrahedron Lett. 2009, 50, 1493-1494.
2
2
1
9. To the best of our knowledge, aerobic oxidation of hydrazodicarboxylates by Cu has not
been reported. For, aerobic oxidation of similar molecules using Fe-based catalysts, see the
following: Hirose, D.; Taniguchi, T.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, 4613-
4
617.
2
0. For relevant discussion of reactive Cu/O
2
species, see the following reviews: (a) Mirica, L.
M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013-1045. (b) Lewis, E. A.;
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Tolman, W. B. Chem. Rev. 2004, 104, 1047-1076. (c) Hatcher, L. Q.; Karlin, K. D. Adv.
Inorg. Chem. 2006, 58, 131-184.
2
1. For precedents of Cu-catalyzed aerobic oxidation of alcohols without organic cocatalysts, see
the following references. Intramolecular competition kinetic isotope effect values reported in
refs. g and h are similar to the value obtained here. (a) Munakata, M.; Nishibayashi, S.;
Sakamoto, H. J. Chem. Soc., Chem. Comm. 1980, 219-220. (b) Jallabert, C.; Riviere, H.
Tetrahedron. 1980, 36, 1191-1194. (c) Jallabert, C.; Lapinte, C.; Riviere, H. J. Mol. Catal.
1980, 7, 127-136. (d) Capdevielle, P.; Audebert, P.; Maumy, M. Tetrahedron Lett. 1984, 25,
0
1
2
3
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0
1
2
3
4
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9
0
1
2
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0
1
2
3
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5
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7
8
9
0
4397-4400. (e) Sakharov, A. M.; Skibida, I. P. J. Mol. Catal. 1988, 48, 157-174. (f) Liu, X.;
Qiu, A.; Sawyer, D. T. J. Am. Chem. Soc. 1993, 115, 3239-3243. (g) Capdevielle, P.; Sparfel,
D.; Baranne-Lafont, J.; Cuong, N. K.; Maumy, M. J. Chem. Res., Synop. 1993, 10-11. (h)
Sakharov, A. M.; Skibida, I. P. Russ. Chem. Bull. 1995, 44, 1872-1878. (i) Korpi, H.; Polamo,
M.; Leskelä, M.; Repo, T. Inorg. Chem. Commun. 2005, 8, 1181-1184. (j) Korpi, H.; Figiel,
P. J.; Lankinen, E.; Ryan, P.; Leskelä, M.; Repo, T. Eur. J. Inorg. Chem. 2007, 2465-2471. (k)
Xu, B.; Lumb, J.-P.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2015, 54, 4208-4211
2
2. (a) Klinman, J. P.; Mu, D. Annu. Rev. Biochem. 1994, 63, 299-344. (b) Mure, M.; Mills, S.
A.; Klinman, J. P. Biochemistry 2002, 41, 9269-9278. (c) Mure, M. Acc. Chem. Res. 2004, 37,
1
31-139.
23. For reviews, see: (a) Largeron, M. Eur. J. Org. Chem. 2013, 2013, 5225-5235. (b)
Wendlandt, A. E.; Stahl, S. S. Angew. Chem., Int. Ed. 2015, 54, 14638-14658.
2
4. (a) Largeron, M.; Fleury, M.-B. Angew. Chem., Int. Ed. 2012, 51, 5409-5412. (b) Largeron,
M.; Fleury, M.-B. Chem.–Eur. J. 2015, 21, 3815-3820.
2
5. Cocatalysts other than Cu have been used similarly in these types of reactions. For leading
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references, see: (a) Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc.
2
012, 134, 13970-13973. (b) Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. Adv. Synth.
Catal. 2012, 354, 2899-2904. (c) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136,
06-512. (d) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 11910-11913. (e)
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Jawale, D. V.; Gravel, E.; Shah, N.; Dauvois, V.; Li, H.; Namboothiri, I. N. N.; Doris, E,
Chem. Eur. J. 2015, 21, 7039-7042.
2
2
6. (a) Piera, J.; Bäckvall, J.-E. Angew. Chem., Int. Ed. 2008, 47, 3506-3523. (b) Lee, J. M.; Na,
Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302-312.
7. Aerobic oxidation of hydrazine to diimide by flavin catalysts has been exploited in the
context of aerobic alkene hydrogenation, for example: (a) Imada, Y.; Iida, H.; Naota, T. J.
Am. Chem. Soc. 2005, 127, 14544-14545. (b) Marsh, B. J.; Heath, E. L.; Carbery, D. R.
Chem. Commun. 2011, 47, 280-282.
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TOC Graphic
O
OH
+ 2 CO32-
2
HCO3–
+
Ph Me
Ph Me
(phen)CuI
2 (phen)CuII
2
II
Cu -Only Pathway (slow)
BocNH NHBoc
+ O2 + 2 HCO3–
DBAD
2 CuI
1/2 O2
2 CuII
H2O
0
1
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0
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0
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1
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9
0
H2O + CO32-
DBADH2
2
OH
Ph Me
O
Ph Me
(
phen)CuII (x 2)
(phen)CuII (x 2)
+
DBAD-Mediated Pathway (fast)
+
BocN NBoc
DBAD
BocNH NHBoc
DBADH2
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