Dual Role of Acetate in Copper(II) Acetate Catalyzed Dehydrogenation of Chelating Aromatic Secondary Amines: A Kinetic Case Study of Copper-Catalyzed Oxidation Reactions

Article abstract of DOI:10.1002/ejic.201600540

Copper(II) acetate is a frequent empirical choice of the copper source in copper(II)-mediated redox reactions. The effect of the acetate counterion appears crucial but has not been adequately investigated. Herein, we report that copper(II) acetate catalyz

Full text of DOI:10.1002/ejic.201600540

DOI: 10.1002/ejic.201600540
Full Paper
Copper-Catalyzed Oxidation
Dual Role of Acetate in Copper(II) Acetate Catalyzed
Dehydrogenation of Chelating Aromatic Secondary Amines:
A Kinetic Case Study of Copper-Catalyzed Oxidation Reactions
Kesavapillai Sreenath,[a] Zhao Yuan,[a] Miguel Macias-Contreras,[a] Vasanth Ramachandran,[a]
Ronald J. Clark,[a] and Lei Zhu*[a]
Abstract: Copper(II) acetate is a frequent empirical choice of netic isotope and substituent effect experiments, suggests that
the copper source in copper(II)-mediated redox reactions. The acetate acts both as a bridging ligand of a dinuclear catalytic
effect of the acetate counterion appears crucial but has not center for mediating two-electron transfer steps and as a base
been adequately investigated. Herein, we report that copper(II) in the turnover-limiting C–H bond-cleavage step. Upon includ-
acetate catalyzes the aerobic dehydrogenation of chelating aro- ing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a surrogate
matic secondary amines. The chemoselectivity of acetate and base, DBU and acetate act in a complementary manner to ena-
chelating amines in this reaction provides a unique opportunity ble a rapid, catalytic dehydrogenation reaction of a chelating
for a mechanistic study. The progression of this homogeneous secondary amine substrate. Finally, the contrasting reactivities
reaction is monitored by using electron paramagnetic reso- between copper(II) acetate (promoting two-electron transfer)
nance spectroscopy, UV/Vis absorption spectroscopy, and ma- and copper(II) perchlorate (promoting single-electron transfer)
nometry. The kinetic dependence on the amine substrate, cop- underscores how a counterion could completely alter the
per(II), and acetate counterion, together with the results of ki- mechanistic pathway of a copper-mediated oxidation reaction.
Introduction
tween the +1 and +2 oxidation states. A dicopper center may
lower the activation barrier of two-electron transfer steps, simi-
lar to the cases demonstrated in dipalladium[10] and digold
chemistry,[11] which would circumvent the relatively unstable
mononuclear copper(III) intermediates. The utility of di- or mul-
tinuclear copper clusters in catalytic aerobic oxidation has been
recognized by the inorganic and bioinorganic communities.[12]
As a result, elaborated ligand-supported multinuclear com-
plexes have been created to mimic the functions of copper-
dependent oxidases and oxygenases.[13] However, the potential
of dinuclear (or multinuclear) copper redox catalysis has not
yet been fully materialized in synthetic chemistry development.
Furthermore, copper-catalyzed oxidation methods have been
developed at a rapid rate;[1b,1c,14] yet, the mechanistic clarifica-
tions of these reactions are disproportionally lagging behind.
The prevalence of +1 and +2 oxidation states of copper ensures
that copper salts are effective single-electron transfer mediators
in radical-involved organic transformations.[1] The majority of
organic redox elementary reactions, on the other hand, entail
two-electron transfer processes, of which palladium, an excel-
lent two-electron transfer mediator but a much less-abundant
element than copper, has been a major source of catalyst devel-
opment.[2] The two-electron shuttling between the +1 and +3
oxidation states of a mononuclear copper center is implicated
in a growing number of copper-involved reactions,[3] notably in
Gilman chemistry,[3b,4] Ullmann cross-coupling,[5] and C–H func-
tionalization reactions.[6] The ability of mononuclear copper to
engage in both single- and two-electron transfer reactions was
recently described by Stahl, Ribas, and co-workers.[5b,7] How-
ever, mononuclear copper(III) species have only been observed
in a handful cases in which a stabilizing macrocyclic li-
gand[6a,6b,8] was often present,[3c,9] which casts doubt on its
generality in the rapidly growing number of reported copper-
mediated redox reactions.
In our investigation on the mechanism of copper(II) acetate
mediated azide–alkyne cycloaddition (CuAAC) reactions,[15] we
offered evidence and arguments that the copper(II) acetate
dimer [Cu2(OAc)4(H2O)2] mediates the inducting alkyne oxida-
tive homocoupling (OHC)[16] stoichiometrically and the subse-
quent CuAAC reaction catalytically. The currently accepted
mechanistic models of both OHC[16,17] and CuAAC[15,18] include
copper-catalyzed two-electron transfer steps. Copper(II) acetate
equilibrates in solution between monomeric and dimeric forms,
depending on the solvent and additional ligand structures.[19]
Given the frequent empirical choice of copper(II) acetate in cop-
per-mediated oxidation reactions,[1c,7a,14,16,20] it is likely that the
acetate-bridged dinuclear copper(II) core acts as a two-electron
Dinuclear copper centers are capable of mediating two-elec-
tron transfer processes through collective redox switching be-
[a] Department of Chemistry and Biochemistry, Florida State University,
95 Chieftan Way, Tallahassee, FL 32306-4390, USA
E-mail: lzhu@chem.fsu.edu
http://chem.fsu.edu/zhu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejic.201600540.
Eur. J. Inorg. Chem. 2016, 3728–3743
3728
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
transfer mediator in many cases.[21] Herein, we report our first
case study, which is the copper-dependent dehydrogenation of
chelating secondary amines, in testing this hypothesis.[22–24]
Table 1. Reactivity profile of copper(II) acetate mediated dehydrogenation.[a]
Results and Discussion
Reactivity Profile
Secondary amine 1 (Scheme 1) was dehydrogenated rapidly to
1-im upon treatment with 1 mol-equiv. of Cu(OAc)2·H2O in
CH3CN (Table 1, Entry 1) under aerobic conditions (i.e., open to
air). A minor product of a deep-red color was also observed
(absorption centering at 505 nm, see Figure 1a), which upon
demetalation was characterized as the regiospecifically hydrox-
ylated derivative of 1-im (i.e., 1-im-OH) (see Figures S1–S4 in
the Supporting Information for characterization data). Titration
of Cu(OAc)2·H2O into a CH3CN solution of 1-im-OH reconsti-
tuted the absorption band of the reddish species (Figure 1b),
to which the formula [Cu(1-im-O)(OAc)] was tentatively as-
signed. The reaction shown in Scheme 1 may represent a simple
model of both copper-dependent oxidase (1 to 1-im) and oxy-
genase (1-im to 1-im-OH) activities,[7a,25] which entail benzylic-
like C(sp3)–H and aromatic C(sp2)–H functionalizations, respec-
tively. In this article, the investigation of the mechanism of the
transformation from 1 into 1-im is described, whereas that on
the formation of 1-im-OH is deferred to a later study.
Nonchelating compounds 2 and 3 (Table 1, Entries 2 and 3)
did not undergo dehydrogenation under the same conditions.
Replacing Cu(OAc)2·H2O with Cu(ClO4)2·6H2O (Table 1, Entry 4),
which is a stronger single-electron oxidant,[26] resulted in a
much lower conversion of 1 to a mixture of undefined products
[other tested copper(II) salts were also not as effective as
Cu(OAc)2·H2O; see Table S1]. If the reaction mixture was main-
tained under anaerobic conditions (Table 1, Entry 5), the reac-
tion proceeded at a reduced rate.[27] Aliphatic secondary
amines (Table 1, Entries 6 and 7) and a tertiary amine (1-Me
in Table 1, Entry 8) did not react. Upon installing an electron-
withdrawing group at the para position of the anilinyl moiety,
the reaction slowed down (Table 1, Entries 9–13). Finally, gem-
dimethyl substrate 11 did not undergo dehydrogenation, which
was expected, or hydroxylation (Table 1, Entry 14). These obser-
vations are summarized as follows: (1) the substrate needs to
be a chelating aromatic secondary amine; (2) molecular oxygen
is not required, but it accelerates the reaction; (3) Cu(OAc)2·H2O
is by far the most effective copper(II) salt; (4) oxidation of the
anilinyl moiety appears to be a kinetically significant step; (5) a
substrate that is unable to dehydrogenate (e.g., gem-dimethyl-
containing 11) cannot be hydroxylated.
[a] Procedure: An amine (0.08 mmol) substrate was dissolved in CH3CN
(4.0 mL) in a round-bottom flask equipped with a magnetic stir bar.
Cu(OAc)2·H2O (0.08 mmol) was added, and the mixture was stirred at r.t. for
the listed time. An ethylenediaminetetraacetic acid (EDTA) solution (5 mL,
0.1 M, pH > 10) was added, and the mixture was extracted with CH2Cl2 (2 ×
5.0 mL). The organic layer was separated and dried with anhydrous Na2SO4
or K2CO3. The solvent was removed under reduced pressure to obtain the
crude product, which was analyzed by 1H NMR spectroscopy (500 MHz,
CDCl3). [b] A complicated mixture of several compounds was observed. The
consumption of compound 1 was at best 11 %. [c] If the amount of
Cu(OAc)2·H2O was doubled to 0.16 mmol so that Cu(OAc)2·H2O was pre-
sumed to be the stoichiometric oxidant, the conversion went up to 26 % in
5 min.
Electron Paramagnetic Resonance Spectroscopy
Different techniques were applied to monitor the changes in
the key components over the course of this homogeneous reac-
Scheme 1. Cu(OAc)2-mediated oxidation of secondary amine 1.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3729
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 1. (a) Progression of the aerobic oxidation of 1 (0.06 m
complex [Cu(1-im-O)(OAc)] is indicated by a red arrow. (b) Absorption spectral change of 1-im-OH (0.1 m
0.1 m ).
M
) in the presence of Cu(OAc)2·H2O (0.05 m
M
) in CH3CN. The absorption of the reddish copper(II)
M) in CH3CN upon addition of Cu(OAc)2·H2O (0–
M
tion. The change in the copper oxidation state and/or nuclearity spectra involving reactive substrates decreased over time (e.g.,
was monitored by electron paramagnetic resonance (EPR) spec- compound 1 in Figure 2c), whereas that of nonreacting sub-
troscopy. The EPR signal of the copper(II) acetate dimer strates underwent little change (e.g., compound 4 in Figure S8
[Cu2(OAc)4(H2O)2] in CH3CN was undetectable at room tempera- and 1-Me in Figure 2d). Secondary chelating amines with elec-
ture (Figure S6). The addition of pyridine led to a small en- tron-poor anilinyl groups, such as cyano-substituted 10, hardly
hancement in the intensity of the EPR signals (Figure 2a). The amplified the EPR signal of Cu(OAc)2·H2O (Figure 2b). Therefore,
addition of nonchelating (e.g., compound 2, Figure S7) or their lack of reactivity of 10 was attributed to poor binding with
weakly chelating (e.g., compound 10, Figure 2b) amines also copper(II).
barely affected the spectrum of copper(II) acetate. However,
The process depicted in Scheme 2 accounts for the EPR data
mixing of copper(II) acetate with chelating amines, either sec- of copper(II) acetate upon binding with various substrates or
ondary (e.g., compounds 1, 4, and 8) or tertiary (e.g., compound ligands. The lack of EPR signals for copper(II) acetate and its
1-Me, Figure 2d), aromatic or otherwise, led to the immediate pyridine complex is attributed to antiferromagnetic coupling
appearance of a four-line signal characteristic of mononuclear between the two copper(II) centers in the acetate-bridged di-
isotropic hyperfine splitting (gisotropic = 2.1298; Aisotropic
=
mers,[29] which appears to dominate in CH3CN. Upon interact-
67 Gauss).[28] Under aerobic conditions, the intensity of the EPR ing with a pyridyl-containing secondary or tertiary amine, the
Figure 2. The EPR (X-band) spectra of Cu(OAc)2·H2O (10 m
M in CH3CN) in the presence of (a) 10 mM pyridine, (b) 10 mM of 10, (c) 10 mM of 1, and (d) 10 mM
of 1-Me over the allotted time. The y axes show the EPR intensity in arbitrary units of the same scale.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3730
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 2. Amine substrate binding with copper(II) acetate in acetonitrile. Acetate–copper(II) bonding is simplified as shown in the box, that is, a Cu–O bond
in the scheme counts for a half bond.
Figure 3. ORTEP views (50 % probability ellipsoids) of (a) the asymmetric unit of [Cu2(6-Me)2(OAc)4]; selected distances [Å]: Cu1–N1 2.219(5), Cu1–Cu2 2.644(1),
Cu1–O1 1.954(5), Cu1–O2 1.948(5), Cu1–O3 1.974(5), Cu1–O4 1.975(5); and (b) [Cu(11)(OAc)2]; selected distances [Å]: Cu1–N1 1.985(2), Cu1–N2 2.035(2), Cu1–
O1 1.958(2), Cu1–O2 2.597(2), Cu1–O3 1.957(2), Cu1–O4 2.572(2).
axial water ligands are replaced by the pyridyl portion of the
amine, as suggested by the dimeric structure of [Cu2(6-
Me)2(OAc)4] (Figure 3a). The dimer equilibrates with the EPR-
positive monomers, in which the chelating amine ligand is bi-
dentate as suggested by the structure of [Cu(11)(OAc)2] (Fig-
ure 3b).
Following the binding of a secondary chelating amine sub-
strate with copper(II) acetate, which increased the abundance
of the monomeric copper(II) complex and consequently pro-
duced a strong EPR signal, the decrease in the EPR intensity
accompanied the progress of the dehydrogenation reaction
(such as 1 in Figure 2c). A couple of scenarios may account for
the drop in EPR intensity as the reaction proceeds: (1) the cop-
per oxidation state changes from the paramagnetic +2 to the
EPR silent +1 state; (2) an antiferromagnetically coupled cop-
per(II) dimer is reconstituted owing to the fact that the binding
of the imine product to copper(II) is weaker than that of the
amine reactant. The EPR signal of secondary amine 8 (Figure 4a)
prepared under anaerobic conditions also decreased as the re-
action progressed, which supported the former scenario that
copper(II) was reduced to copper(I). The reddish color appeared
at the top of the EPR tube as a result of the slow entry of air
Figure 4. (a) Conversion of amine 8 into imine 8-im; (b) photographs of the
through the sealing grease and diffused down overtime, which
EPR tube containing 8 (10 mM) and Cu(OAc)2·H2O (10 mM) in CH3CN, which
was sealed with grease, overtime undisturbed; (c) the corresponding EPR
spectra at the time intervals shown in panel b.
suggested that the formation of the reddish copper(II)/8-im-OH
complex was O2-dependent.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3731
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Manometry
O2 accelerates the dehydrogenation reaction, as concluded by
comparing the data from Entries 1 and 5 of Table 1. The O2
consumptions with a few amine substrates were monitored by
manometry.[6c,30] The pressure change from 1 atm of air in a
closed reaction vessel was recorded for various secondary and
tertiary amines (Figure 5). Only chelating aromatic secondary
amines with adequate electron density on the anilinyl moiety
afforded a substantial reduction in pressure (e.g., compounds 1
and 8 in Figure 5). Neither tertiary amine 1-Me, which binds
copper(II) strongly as shown by EPR spectroscopy (Figure 2d),
nor p-cyano-substituted secondary amine 10, which at best
weakly associates with copper(II) (Figure 2b), enabled O2 up-
take. Therefore, the consumption of O2 was concurrent with
the progress of the dehydrogenation reaction under aerobic
conditions. The molar ratio between O2 and the amine reactant
was ca. 1:2 (Figure S9, Table S2), which suggested that O2 was
reduced to H2O.
Scheme 3. Reaction for the linear free-energy relationship (LFER) and kinetic
isotope effect (KIE) experiments. Substrates of the KIE study (kH/kD = 2.5): R =
H/D, X = OCH3; substrates of the LFER experiment (ρ = –1.0): R = H, X = H,
OCH3, iPr, CH3, Ph, I, and F.[31]
strate/copper complex. The fact that tertiary amine 1-Me is una-
ble to react (Table 1, Entry 8) suggests that N–H deprotonation
needs to occur before the turnover-limiting step. The primary
KIE suggests that C–H bond cleavage is turnover-limiting. Oxy-
genation of the substrate before dehydrogenation was not ob-
served. Consistent with the early-dehydrogenation model, an
oxygenated secondary aromatic amine was unable to dehydro-
genate if subjected under the reported reaction conditions
(data not shown). Furthermore, gem-dimethylated compound
11 under the reaction conditions failed to afford any anilinyl
hydroxylation product (Table 1, Entry 14), which further con-
firms that oxygenation occurs after, or simultaneously with, C–
H bond cleavage.
On the basis of the analysis at this stage, the validities of the
possible dehydrogenation/copper-oxygenation sequences
(Scheme 4) were assessed. The chelating amine substrate acts
as a bidentate ligand for copper(II). The acetate counterion acts
as an internal base to deprotonate the secondary amine to af-
ford copper(II) amido complex I. The internal base function of
the acetate (or other carboxylate or carbonate) counterions has
been proposed in Pd(OAc)2-catalyzed[36] and, more recently, in
Cu(OAc)2-catalyzed C–H functionalization reactions.[37]
From intermediate I, four possible pathways are illustrated in
Scheme 4. In the mononuclear two-electron transfer pathway
(Scheme 4a), I undergoes base-promoted C–H cleavage concur-
rent with the two-electron reduction of the copper(II) center
to produce dead-end copper(0) species III. The dinuclear two-
electron transfer pathway (Scheme 4b) is facilitated by the
bridging ability of acetate to afford dicopper(II) intermediate IV.
Deprotonation of the C–H bond would release two electrons
Figure 5. Pressure of the reaction vessel (total volume = 35 mL) over time of
mixtures of amines (1, 1-Me, 4, 8, 10, and 2-picoline, 0.25
Cu(OAc)2·H2O (0.25 ).
M in CH3CN) and
M
Linear Free-Energy Relationship and Kinetic Isotope Effect
The imine production was monitored by using UV/Vis absorp- that are collectively taken in by the two copper(II) centers to
tion spectroscopy (e.g., Figure 1a).[32] The linear free-energy re- afford dicopper(I) intermediate V. Transition from IV to V could
lationship (LFER) and deuterium kinetic isotope effect (KIE) were be either a concerted two-electron transfer that flips the oxid-
determined by using this method. If the substituent X ation state of both copper centers from +2 to +1 or a stepwise
+
(Scheme 3) was varied, an LFER against σpara was observed sequence led by the disproportionation of copper(II) to cop-
(Figure 6a).[33] A ρ value of –1.0 suggested that electron density per(III) and copper(I), which is followed by 2e reduction at the
of the anilinyl group was decreasing en route to the transition- copper(III) center.[6a,6c,30] O2 quickly traps the nascent dicop-
state structure of the turnover-limiting step, or a step of kinetic per(I) center in V to form μ-η1:η1-peroxo dicopper(II) intermedi-
relevance. This observation discounted the possibility that ate VI, which could be the precursor of the oxygenation agent
amine deprotonation was turnover-limiting, of which the oppo- to afford the hydroxylated minor product. On the basis of the
site LFER was expected. Rather, a step involving anilinyl oxid- observations of the LFER and KIE experiments, the conversion
ation was kinetically significant. The primary KIE (kH/kD = 2.5, from IV into V should be turnover-limiting (TOL).
Figure 6b), determined by comparing the rates independently
acquired by using protio and deuterio substrates,[34] indicated
that the C–H bond-cleavage step was turnover-limiting.[35]
On the basis of the suggestion of a reviewer, a ꢀ-hydride
elimination pathway is included as Scheme 4c. The mononu-
clear intermediate after ꢀ-hydride elimination (VII) would un-
On the basis of the reactivity profile data in Table 1 in con- dergo either reductive elimination or deprotonation to III, the
junction with the LFER and KIE observations, it is possible to unlikely dead-end Cu0 species. Intermediate VII could poten-
determine the relative timing of the three key steps: deprotona- tially be transformed through the assistance of another cop-
tion of the N–H and C–H bonds and oxygenation of the sub- per(II) to intermediate V in Scheme 4b. We did not consider
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3732
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 6. (a) Hammett plot for the reactions of various amines with Cu(OAc)2·H2O in CH3CN. (b) Absorption changes at 350 nm versus time for amines (50 μM);
1 (squares) and 1-d2 (circles) upon reaction with Cu(OAc)2·H2O (50 μM) in CH3CN.
Scheme 4. Possible deprotonation/copper-oxygenation sequences. Dative bonds illustrate the lone-pair contributions from the ligands. 0, +1, and +2 oxidation
states of copper are color-coded as gray, orange, and blue, respectively. TOL: turnover-limiting. S: a monodentate coordinating solvent, e.g., CH3CN; X: a singly-
charged counterion.
the ꢀ-hydride elimination pathway further owing to its lack of on macrocyclic amine oxidation by a mononuclear copper(II)
precedence in copper(II)-mediated oxidation reactions and its complex.[38]
lack of base dependence, which was observed in the dehydro-
genation reaction in the current work.
The pathways shown in Scheme 4b,d were considered fur-
ther, because they do not end with a Cu0 species. They differ
Lastly, single-electron transfer from the amido ligand to the in (1) the kinetic order of copper(II), (2) the dependence on O2,
copper(II) center could occur after the formation of intermedi- (3) the dependence on a base, and (4) the function of the acet-
ate I to afford VIII (Scheme 4d). Turnover-limiting hydrogen ate ion. A second-order dependence on copper(II) is expected
atom abstraction, on the basis of the KIE data, from VIII by for Scheme 4b, whereas Scheme 4d requires first-order kinetics
O2 results in intermediate IX and a hydroperoxy radical, which in copper. Contrary to the mononuclear pathway in Scheme 4d,
subsequently oxidizes the copper(I) center to form copper(II)– which requires O2 (or another hydrogen atom abstracting free
hydroperoxy complex X. The pathway shown in Scheme 4d, radical agent), the dinuclear pathway in Scheme 4b could pro-
which involves proton transfer followed by hydrogen-atom ceed anaerobically if copper(II) is provided stoichiometrically.
transfer, is similar to the proposal of Maseras and co-workers Finally, acetate acts as both a base and a bridging ligand in
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3733
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4b, whereas the route in Scheme 4d only requires a of the p-methoxyanilinyl group by Cu(ClO4)2·6H2O.[41] A control
base to reach early copper(II) amido intermediate I, following experiment to test the radical cation interpretation will be de-
which the acetate appears to be a spectator ion. The fact that scribed after the discussion on the data in Figure 8.
the dehydrogenation of 1 does proceed under the anaerobic
conditions (point #2), albeit at a slower rate than the open-to-
air reaction, favors Scheme 4b. The experiments described in
the following subsections were performed to distinguish the
pathways illustrated in Scheme 4b,d by looking at the differen-
ces raised in points #1, #3, and #4.
In the presence of 0.75 equiv. Bu4NOAc relative to the
amount of copper(II), the presumed radical cation band at
490 nm was diminished, yet no reaction occurred over the same
time period (Figure 8b). This observation suggested that the
addition of the acetate ion reduced the ability of copper(II) as
a single-electron oxidant. This possibility contradicts the mech-
anistic proposal illustrated in Scheme 4d, in which the addition
of acetate would have aided the formation of radical species
VIII.
Kinetic Orders of Reaction Components
Upon increasing the Bu4NOAc concentration up to
1.75 equiv. [relative to that of copper(II)], the reaction pro-
ceeded to afford both 1-im (centering at 350 nm) as the major
product and 1-im-OH [centering at 505 nm as its copper(II)
complex] as the minor component (Figure 8c). The rate was
enhanced in the presence of 2.5 equiv. of Bu4NOAc relative to
the amount of copper(II) (Figure 8d).
The kinetic orders of amine 1 and Cu(OAc)2·H2O were deter-
mined by using the initial-rate method under the open-to-air
conditions. Amine exhibited saturation kinetic behavior (Fig-
ure 7a,b), which suggests a fast binding equilibrium between 1
and the copper catalyst prior to the turnover-limiting step. The
kinetic order of Cu(OAc)2·H2O was 1.9 (Figure 7c), consistent
with a dinuclear transition-state structure for the turnover-limit-
ing step, and a mononuclear resting state of the copper cata-
lyst.[39] Similar scenarios have been reported in palladium(II)-
catalyzed C–H functionalization reactions.[40]
The absorption band centering on 490 nm in Figure 8a is
postulated as the radical cation of the anilinyl group from the
single-electron transfer to Cu(ClO4)2·6H2O. On the basis of the
To decouple the functions of copper(II) and the acetate ion, work of Stahl and co-workers,[42] an aryl radical cation resulting
Cu(ClO4)2·6H2O was used as the copper(II) source, and the reac- from single-electron oxidation from a copper(II) center can be
tion progress was monitored by using UV/Vis absorption spec- halogenated by a halide ion. The hypothesis of anilinyl radical
troscopy in the presence of increasing amounts of Bu4NOAc cation formation was then tested by including LiCl in the reac-
(Figure 8). Without Bu4NOAc, very little absorption change was tion mixture to trap the purported radical cation. As shown in
observed over 40 min (Figure 8a). The broad peak centered at Scheme 5a, in addition to being dehydrogenated, compound 1
490 nm could be the absorption of the radical cation (or a was also chlorinated to 1-Cl[43] upon treatment with a combina-
derivative thereof) resulting from the single-electron oxidation tion of Cu(ClO4)2·6H2O and LiCl. Tertiary amine 1-Me, under the
Figure 7. Log plots of the initial rate dependence on the concentrations of (a) amine 1 (600–700 μ
(32–82 μ ) in the presence of Cu(OAc)2·H2O (65 μ ), (c) Cu(OAc)2·H2O (20–60 μ ) in the presence of compound 1 (0.56 m
35 μ ) in the presence of 1 (100 μ ), DBU (80 μ ), and Bu4NOAc (30 μ ).
M
) in the presence of Cu(OAc)2·H2O (50 μ
M), (b) amine 1
M
M
M
M), and (d) Cu(ClO4)2·6H2O (5–
M
M
M
M
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3734
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 8. Absorption spectra over 40 min (2 min interval) of amine 1 (100 μ
M
in CH3CN) in the presence of Cu(ClO4)2·6H2O (50 μ
M) and an increasing amount
of Bu4NOAc (0 μ , a; 37.5 μ , b; 87.5 μ , c; 125 μM, d). The first and last spectra of each experiment are coded blue and red, respectively.
M
M
M
same conditions, was also chlorinated to 1-Me-Cl (Scheme 5c). ated the hypothesis that Cu(ClO4)2·6H2O oxidized the anilinyl
On the contrary, replacing Cu(ClO4)2·6H2O with Cu(OAc)2·H2O moiety in compound 1 by single-electron transfer and that
only led to the dehydrogenation of 1 (Scheme 5b), whereas no acetate attenuated the ability of copper(II) as a single-electron
reaction occurred with 1-Me (Scheme 5d). These data substanti- oxidant.
Scheme 5. Cu(ClO4)2 versus Cu(OAc)2 in the oxidation of chelating amines 1 and 1-Me. The copper salt (2.0 mol-equiv.), LiCl (2.0 mol-equiv.), CH3CN (4 mL),
and the amine (0.08 mmol) were added to a flask in this order. The resulting mixture was stirred at r.t. for 6 h. The reaction was then quenched by adding
an EDTA solution (0.1 M, 5 mL, pH > 10), and the mixture was extracted with CH2Cl2 (2 × 5.0 mL). The combined organic layers were dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was analyzed by 1H NMR spectroscopy (CDCl3, 500 MHz). The molar percentages
of identified compounds are included in parentheses.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3735
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Mechanistic Model
bidentate manner, as supported by the chemospecificity of che-
On the basis of these data, a catalytic cycle is sketched lating amines. Complex A also equilibrates with its off-cycle
(Scheme 6). Chelating aromatic secondary amine # first replaces monomeric form A′, which is the resting state of the catalyst.[44]
water in [Cu2(OAc)4(H2O)2] to afford A. Acetate counterions in Base-promoted C–H bond cleavage in in-cycle complex B redu-
complex A act as an internal base to deprotonate the amino ces the dicopper(II) core to dicopper(I) intermediate C, which
group to afford copper(II) amido complex B (i.e., “concerted may or may not traverse disproportionated intermediate B′.[45]
metalation deprotonation”[36d]), in which the amine binds in a The close contact between two copper(II) ions in B, which
Scheme 6. Dinuclear catalytic cycle. Evidence supporting the individual steps is noted in parentheses. All steps are balanced. Copper is color-coded for its
oxidation states: orange: +1; blue: +2; purple: +3. L is a monodentate ligand, such as CH3CN or monodentate acetate. B = acetate or DBU. Cu–O (acetate)
bond counts for a half bond (see footnote of Scheme 2).
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3736
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
should be similar to that in the copper(II) acetate dimers {e.g., crease and [AcOH] would increase [Equation (8)]. The participa-
dCu–Cu in [Cu2(6-Me)2(OAc)4] (Figure 3a) is 2.644(1) Å}, shall facili- tion of O2 leads to the regeneration of copper(II) in intermedi-
tate the two-electron transfer step. A recent computational ate D and the consumption of AcOH in the H2O2 disproportion-
study on the mechanism of a Cu(OAc)2-mediated C–H function- ation step to maintain constant values of [CuII]t and [AcOH] and,
alization reaction supports the beneficial ligand effect of acet- therefore, maximizes the rate. (2) The reaction is second order
ate in lowering the transition-state energy for the dispropor- in [CuII]t. (3) If one (x = 1) bidentate acetate is required for the
tionation step within an acetate-supported dicopper(II) core.[46] formation of dinuclear intermediates, the kinetic dependence
The “redox cooperation” between two interacting metal centers on acetate is between first and second order, depending on the
separated by a short distance[47] is also cited in dipalladium relative magnitude of the [AcOH] term in the denominator of
catalysis.[10,48] This situation is different from another case of Equation (8).
amine oxidation by a copper(II) complex, in which the shortest
d[P]
k1k2[A][L]2[base]
k–1[AcOH]2 + k2[base]
Cu–Cu distance is >7 Å and, hence, is less likely to have produc-
tive copper/copper interactions in aiding two-electron trans-
fer.[38]
=
(3)
dt
In the absence of O2, Cu(OAc)2·H2O becomes the stoichio-
metric oxidant [Equation (1)]. The rate of the reaction is lowered
as Cu(OAc)2·H2O is consumed. Under aerobic conditions, O2
shall trap C (Scheme 6) to regenerate copper(II) in the form of
μ-peroxo dicopper(II) species D and with subsequent steps
turns the process catalytic in Cu(OAc)2·H2O. Complex D may
undergo stepwise protonation possibly through E[49] to afford
complex F with the release of H2O2.[50] H2O2 rapidly dispropor-
tionates to O2 and H2O under copper-catalyzed conditions,[51]
which accounts for the observed 2:1 (amine/O2) stoichiometry.
Substrate turnover converts complex F back into A. The turn-
over-limiting step is C–H bond cleavage of the substrate, which
in effect is the oxidation of the amine at the expense of the
reduction of the dicopper(II) core. This conclusion is supported
by both the primary KIE (kH/kD = 2.5) and LFER (ρ = –1.0) data.
The steps after C are kinetically invisible and, therefore, are pro-
posed on the basis of precedented chemistry. Cu(OAc)2·H2O is
the catalyst, whereas O2 is the stoichiometric oxidant for cata-
lyst regeneration [Equation (2)]. This scenario is consistent with
the “oxidase” model summarized by Stahl and co-workers.[3d,7a]
Unlike Equation (1), there is no net production of AcOH if O2
drives the cycle.
[A] = K[A′]2
(4)
(5)
(6)
(7)
[A′] ≈ [CuII]t
K = K′[AcO–]x; x ≥ 1
[base] = [AcO–]
d[P] k1k2K′[CuII]t2[L]2[AcO–]x+1
=
; x ≥ 1
(8)
k–1[AcOH]2 + k2[AcO–]
dt
P = product imine; L = monodentate ligand (e.g., CH3CN or
monodentate acetate); k1, k2, and k–1 are marked on Scheme 6.
H2im + 2 Cu(OAc)2 → im + 2 Cu(OAc) + 2 AcOH
(1)
Cu(OAc)2
→
H2im + 1/2 O2
im + H2O
(2) The Dual Role of Acetate as a Base and a Bridging Ligand
The rate law of the conversion from A into C (bolded steps
in Scheme 6) was derived [Equation (3)] by assuming that a
steady state was reached at intermediate B. Further derivation
to relate the rate to the concentrations of copper(II) and the
acetate ions required the following approximations: (1) The
equilibrium between A and A′ [Equation (4)] favors mononu-
clear A′, as suggested by the EPR data, on the basis of which
we approximated [A′] to the total copper(II) concentration [CuII]t
[Equation (5)]. (2) The equilibrium constant K (see Scheme 6)
shall depend on the concentration of a bidentate ligand [acet-
ate in this case, Equation (6)], which would facilitate the forma-
tion of dimer A. (3) The base to deprotonate complex B is the
acetate counterion [Equation (7)]. Acceptance of these approxi-
mations resulted in the rate law [Equation (8)] on which the
following conclusions were drawn:
Acetate acts as the base in the reaction and the bridging biden-
tate ligand for facilitating the formation of dicopper intermedi-
ates. Both functions are factored into the rate law [Equation (8)].
To separate the functions of acetate as a base or a bridging
ligand, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the conjugate
acid of which has a pKa of 24.1 in CH3CN,[52] slightly larger than
that of acetate (23.5),[53] was examined as a surrogate base for
acetate. At a 40 mol-% loading of Cu(ClO4)2·6H2O (relative to
the amount of amine 1), which is a mononuclear copper(II)
source with little copper(II)/counterion interaction, in the pres-
ence of increasing amounts of DBU, the reaction proceeded at
a slow rate and stalled once DBU reached 2 mol-equiv. relative
to the amount of Cu(ClO4)2·6H2O (Figure 9, filled blue squares).
Acetate achieved a much higher rate at a high molar ratio (filled
red squares), for example, 3:1 relative to the amount of cop-
(1) Under anaerobic conditions, the rate of the reaction per(II). Furthermore, the rate was fitted as a quadratic function
would drop as the reaction proceeds, because [CuII]t would de- of [AcO–], which suggests second-order dependence.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3737
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
resting state and a mononuclear active state of the copper cata-
lyst.[55] Different from the rate dependence on acetate of the
reaction described in this paper (Figure 9), at high concentra-
tions of acetate, the aminooxygenation reaction was inhib-
ited.[54] The authors concluded that the function of added acet-
ate (in the form of Bu4NOAc) was to activate the dinuclear cop-
per(II) carboxylate to the active monomeric species. The carb-
oxylate counterion and/or the added acetate also acted as a
base for the formation of a copper(II) amido intermediate.
In the copper(II) acetate catalyzed Chan–Evans–Lam oxida-
tive coupling reaction studied by Stahl and co-workers
(Scheme 7b),[30] the reaction was either half or first order in
copper(II), depending on the conditions.[56] Acetate appeared
to facilitate the transmetalation step by interacting with the
boron center and to deprotonate the nucleophile methanol,
which also doubled as the solvent.[56] The addition of acetate
beyond an optimal ratio of copper and acetate inhibited the
reaction. The contrasting observations regarding acetate in the
two reactions in Scheme 7 and our current case underscore the
versatility of copper(II) acetate in mediating oxidation reactions
and caution us from drawing overreaching conclusions on the
mechanistic issues of copper catalysis and counterion ef-
fects.[57,40a,40b,44c,44d,58]
The extra benefit of including DBU is the elimination of the
formation of 1-im-OH. Because the inclusion of DBU did not
alter the stoichiometry of O2 consumption (Figure S9b), it is
likely that (1) DBU accelerates the disproportionation of H2O2
or the copper(II)-bound hydroperoxo moiety,[59] which thus pre-
vents the copper(II) catalyst from poisoning by the formation
of 1-im-OH, or (2) DBU disrupts the formation of electrophilic
dicopper/O2 complexes. In the presence of DBU, full conversion
of 1 into 1-im was achieved in the presence of 10 mol-%
Cu(ClO4)2·6H2O and 30 mol-% Bu4NOAc (Figure 10), which ren-
ders this reaction a true catalytic process.
Figure 9. Rate of dehydrogenation of 1 (100 μ
M) in CH3CN in the presence of
Cu(ClO4)2·6H2O (40 μ ) and increasing amounts of DBU (blue filled squares),
M
Bu4NOAc alone (red filled squares), and Bu4NOAc in the presence of 80 μ
of DBU (red open squares).
M
What was most intriguing was the mutually beneficial effect
of acetate and DBU, the combination of which enabled a much
faster reaction than either could manage alone. At 80 mol-%
loading of DBU (relative to the amount of amine 1), the rate of
the reaction increased linearly with growing concentrations of
AcO– (Figure 9, open red squares). Therefore, the reaction order
of acetate was reduced to first order with 80 mol-% DBU
present. It appears that DBU relieves acetate of the duty as a
base, the remaining function of which is to facilitate the forma-
tion of dinuclear intermediates as a bridging ligand. Under the
same conditions, for which both acetate and DBU were in-
cluded, the kinetic order of Cu(ClO4)2·6H2O was determined
once again to be second order (1.9, Figure 7d), which further
supports a dinuclear, rather than a mononuclear, pathway.
The function of acetate in copper(II) acetate mediated reac-
tions has been scrutinized in two recent cases. Chemler and
co-workers investigated the function of added acetate in the
copper(II) carboxylate catalyzed aminooxygenation of olefins
(Scheme 7a).[54] 2,2,6,6-Tetramethylpiperidin-1-oxyl (TEMPO)
was found to promote the reaction, which suggested a radical-
involved mechanism. The reaction exhibited half-order depend-
ence on copper(II) carboxylate, which supported a dinuclear
Figure 10. Absorption spectra of 1 (100 μ
M) in the presence of DBU (80 μ
M),
Cu(ClO4)2·6H2O (10 μ ), and Bu4NOAc (30 μ
M
M). Spectra were recorded at ev-
Scheme 7. Two other kinetically characterized Cu(OAc)2-mediated reactions.
eh = 2-ethylhexanoate, a soluble acetate surrogate.
ery 5 min. Inset shows variation in the absorbance at 350 nm versus time.
The reaction mixture was stirred at a constant speed in the cuvette.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3738
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2: Synthesized by a procedure similar to that described for 1-Me.
4-(Chloromethyl)pyridine hydrochloride (500 mg, 3.04 mmol) and
p-anisidine (450 mg, 3.65 mmol) were used. The crude product was
subjected to column chromatography (silica gel, 0–50 % EtOAc/
Conclusions
Copper(II) acetate catalyzes the aerobic dehydrogenation of
chelating aromatic secondary amines. In addition to acting as
a base, acetate aids the two-electron transfer elementary steps CH2Cl2). The product was isolated as an off-white solid. The yield
was 384 mg (59 %). 1H NMR (300 MHz, CDCl3): δ = 8.54 (d, J =
5.4 Hz, 2 H), 7.29 (d, J = 5.4 Hz, 2 H), 6.75 (d, J = 9.0 Hz, 2 H), 6.54
by facilitating the formation of dicopper species containing a
short Cu–Cu distance (ca. 2.6 Å). Copper(II) acetate, therefore,
is a simple dinuclear copper catalyst for two-electron transfer
reactions of suitably selected substrates. Copper(II) acetate cata-
(d, J = 9.0 Hz, 2 H), 4.43 (s, 2 H), 3.96 (br. s, 1 H), 3.73 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 152.5, 149.9, 149.5, 141.7, 122.3,
115.1, 114.2, 55.8, 48.0 ppm. HRMS (EI+): calcd. for C13H14N2O
lyzed dehydrogenation reactions with O2 as the stoichiometric
214.1106 [M]+; found 214.1119.
oxidant appeared in the literature more than half a century
6: A mixture of 2-pyridinecarbaldehyde (100 mg, 0.93 mmol) and
ago.[60] The importance of the dicopper(II) core of copper(II)
4-aminobiphenyl (157 mg, 0.93 mmol) was heated at reflux in dry
acetate in dehydrogenation reactions was postulated at the be-
toluene for 1 h. The solvent was removed under reduced pressure
ginning of this century.[61] The current work has provided cre-
dence to the hypothesis that copper(II) acetate is capable of
mediating two-electron transfer steps in dehydrogenation and
to afford the crude product, which was dissolved in CH3OH/CH2Cl2
[2:8 (v/v), 10 mL] and cooled in an ice bath. NaBH4 (52 mg,
1.39 mmol) was added in two batches between an interval of
perhaps in oxidative coupling and C–H functionalization reac- 30 min. After the complete addition of NaBH4, the mixture was
stirred for an additional 2 h. It was then diluted with water (100 mL)
and extracted with CH2Cl2 (3 × 20 mL). The organic layer was sepa-
rated and dried with anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the crude product was subjected to
column chromatography (silica gel, 0–10 % EtOAc/CH2Cl2). The
product was isolated as a pale-yellow solid. The yield was 169 mg
tions, in which the acetate counterion may function as a base,
a bridging ligand of a dinuclear catalyst, or both. This proposi-
tion shall be challenged experimentally and computationally
under the contexts of other reactions.[62] The copper(II) acetate
catalyzed dehydrogenation of a chelating aromatic secondary
amine and the following arene hydroxylation may represent a
simple functional model for both copper-dependent oxidases
and oxygenases, which in its own right merits further investiga-
tions.[63]
1
(70 %). H NMR (300 MHz, CDCl3): δ = 8.60 (d, J = 4.2 Hz, 1 H), 7.66
(dt, J = 7.8, 1.8 Hz,1 H), 7.16–7.48 (m, 9 H), 6.74 (d, J = 9.0 Hz, 2 H),
4.92 (br. s, 1 H), 4.51 (s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
158.4, 149.3, 147.4, 141.2, 136.7, 130.4, 127.9, 126.3, 126.2, 122.2,
121.6, 113.4, 49.3 ppm. HRMS (EI+): calcd. for C18H16N2 260.1313
[M]+; found 260.1304.
Experimental Section
6-Me: Compound 6 (100 mg, 0.38 mmol) was dissolved in dry THF
(10 mL) and cooled in an ice bath. tBuOK (64 mg, 0.57 mmol) was
added, and the mixture was stirred for 10 min. Iodomethane
(0.1 mL) was added, and the mixture was stirred for 12 h. Then, the
mixture was diluted with water (100 mL) and extracted with CH2Cl2
(3 × 20 mL). The organic layer was dried with anhydrous Na2SO4,
and the solvent was subsequently removed under reduced pres-
sure. The crude product was subjected to column chromatography
(silica gel, 0–20 % EtOAc/CH2Cl2). The product was isolated as an
off-white solid. The yield was 86 mg (82 %). 1H NMR (500 MHz,
CDCl3): δ = 8.61 (d, J = 4.2 Hz, 1 H), 7.61 (dt, J = 7.8, 1.8 Hz, 1 H),
7.55 (dd, J = 8.4, 1.2 Hz, 2 H), 7.48 (dd, J = 9.0. 2.4 Hz, 2 H), 7.39 (t,
J = 7.2 Hz, 2 H), 7.15–7.28 (m, 3 H), 6.78 (d, J = 9.0 Hz, 2 H), 4.71 (s,
2 H), 3.18 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.2, 149.6,
148.6, 141.1, 136.9, 129.4, 128.7, 127.9, 126.3, 126.1, 122.0, 120.8,
112.5, 58.8, 39.2 ppm. HRMS (EI+): calcd. for C19H18N2 274.1470 [M]+;
found 274.1473.
Materials and General Methods: Reagents and solvents were pur-
chased from various commercial sources and were used without
further purification unless otherwise stated. The purity of
Cu(OAc)2·H2O was >99 %. Analytical thin-layer chromatography
(TLC) was performed by using TLC plates precoated with silica gel
60 F254. Flash column chromatography was performed by using
40–63 μm (230–400 mesh) silica gel as the stationary phase. Silica
gel was carefully flame-dried under vacuum to remove adsorbed
moisture before use. 1H and 13C NMR spectra were recorded at 300
and 75 MHz or 500 and 125 MHz, respectively. All chemical shifts
are reported in δ units relative to tetramethylsilane. High-resolution
mass spectra were obtained by using a time-of-flight analyzer. Com-
pounds 1,[64] 3,[65] 4,[66] 5,[67] 7,[64a,68] and 9[66,69] are known.
Synthesis and Characterization of New Compounds
1-Me: 4-Methoxy-N-methylaniline (200 mg, 1.46 mmol), 2-(chloro-
methyl)pyridine hydrochloride (240 mg, 1.46 mmol), and hexadecyl- 8: Synthesized according to a procedure similar to that described
trimethylammonium chloride (HDTAC) (50 mg) were added to an
for 1-Me. 2-(Chloromethyl)pyridine hydrochloride (554 mg,
aqueous NaOH solution (7 mL, 5 ), and the mixture was stirred at
M
3.37 mmol) and 4-fluoroaniline (500 mg, 4.49 mmol) were used. The
r.t. for 12 h. The mixture was diluted with water (100 mL) and ex- mixture was diluted by the addition of water (100 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The organic layer was dried with
anhydrous Na2SO4, and subsequently, the solvent was removed un-
der reduced pressure. The crude product was subjected to column
chromatography (silica gel, 0–10 % EtOAc/CH2Cl2). The product was
isolated as a pale-brown solid. The yield was 210 mg (63 %). 1H
NMR (300 MHz, CDCl3): δ = 8.57 (d, J = 4.2 Hz, 1 H), 7.62 (dt, J =
7.2, 1.2 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.18 (t, J = 7.2 Hz, 1 H),
6.81 (d, J = 9.0 Hz, 2 H), 6.72 (d, J = 9.0 Hz, 2 H), 4.58 (s, 2 H), 3.74
(s, 3 H), 3.04 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.7,
151.9, 149.5, 144.3, 136.8, 121.9, 121.2, 114.9, 114.2, 60.0, 55.8,
39.8 ppm. HRMS (EI+): calcd. for C14H16N2O 228.1263 [M]+; found
228.1275.
tracted with CH2Cl2 (3 × 20 mL). The organic layer was dried with
anhydrous Na2SO4, and the solvent was removed under reduced
pressure. The crude product was subjected to column chromatogra-
phy (silica gel, 0–50 % EtOAc/CH2Cl2). The product was isolated as
a white solid. The yield was 381 mg (42 %). 1H NMR (300 MHz,
CDCl3): δ = 8.58 (d, J = 4.2 Hz, 1 H), 7.65 (dt, J = 7.8, 1.8 Hz, 1 H),
7.32 (d, J = 7.8 Hz, 1 H), 7.19 (t, J = 5.4 Hz, 1 H), 6.85–6.91 (m, 2 H),
6.57–6.63 (m, 2 H), 4.67 (br. s, 1 H), 4.41 (d, J = 5.4 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 158.4, 155.9 [d, J(13C,19F) = 233 Hz],
149.3, 144.4, 136.8, 122.3, 121.8, 115.7 [d, J(13C,19F) = 22 Hz], 113.9
[d, J(13C,19F) = 7.0 Hz], 49.9 ppm. HRMS (EI+): calcd. for C12H11FN2
202.0906 [M]+; found 202.0921.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3739
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
10: Synthesized according to a procedure similar to that described
for 6. 4-Aminobenzonitrile (110 mg, 0.93 mmol) was used instead
of 4-aminobiphenyl. The product was isolated as a white solid. The
yield was 132 mg (68 %). 1H NMR (300 MHz, CDCl3): δ = 8.59 (d, J =
4.2 Hz, 1 H), 7.68 (dt, J = 7.8, 1.8 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 2 H),
7.23–7.42 (m, 2 H), 6.64 (d, J = 8.4 Hz, 2 H), 5.56 (br. s, 1 H), 4.47 (d,
J = 4.8 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 156.5, 151.1,
149.4, 137.1, 133.9, 122.8, 121.9, 120.6, 112.8, 99.2, 48.2 ppm. HRMS
(EI+): calcd. for C13H11N3 209.0953 [M]+; found 209.0958.
33.8, 24.1 ppm. HRMS (ESI+): calcd. for C15H17N2 225.1392 [M + H]+;
found 225.1394. This compound is the imine precursor for the
amine (next compound) used for LFER studies.
(2-Pyridylmethyl)(4-isopropylphenyl)amine (14): N-(4-Isopropyl-
phenyl)-1-(pyridin-2-yl)methanimine (100 mg, 0.44 mmol) was dis-
solved in CH2Cl2/CH3OH (8:2) and cooled in an ice bath. NaBH4
(25 mg, 0.67 mmol) was added, and the mixture was stirred for an
additional 2 h. It was then diluted with water (100 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The organic layer was separated
and dried with anhydrous Na2SO4. The solvent was removed under
12: 2-Pyridinecarbonitrile (250 mg, 2.40 mmol) was dissolved in dry
toluene (10 mL) in a round-bottom flask under argon. Methylmag- reduced pressure, and the crude product was subjected to column
nesium iodide (3.0 mL) was added, and the mixture was heated at chromatography (silica gel, 0–10 % EtOAc/CH2Cl2). The yield was
1
reflux for 12 h. The mixture was cooled in an ice bath, and water 72 mg (71 %). H NMR (300 MHz, CDCl3): δ = 8.58 (d, J = 4.8 Hz, 1
(1 mL) was carefully added; the mixture was stirred for 10 min. The H), 7.64 (dt, J = 7.8, 1.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.18 (t, J =
mixture was diluted with water (50 mL) and extracted with CH2Cl2
(3 × 20 mL). The organic layer was collected and dried with anhy-
4.8 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 2 H), 6.62 (d, J = 9.0 Hz, 2 H), 4.45
(s, 2 H), 4.11 (br. s, 1 H), 2.80 (sept, J = 6.6 Hz, 1 H), 1.21 (s, 3 H),
drous Na2SO4. The solvent was removed under reduced pressure. 1.19 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.9, 149.2, 146.1,
The product was isolated as a pale-brown solid (185 mg, 57 %) 138.1, 136.6, 127.2, 122.1, 121.6, 113.1, 49.7, 33.2, 24.3 ppm. HRMS
(Scheme 8). 1H NMR (300 MHz, CDCl3): δ = 8.55 (d, J = 4.2 Hz, 1
H),7.63 (dt, J = 7.8, 1.8 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.12 (dt,
J = 4.8, 1.2 Hz, 1 H), 2.3 (br. s, 2 H), 1.52 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 168.2, 148.8, 136.6, 121.4, 118.5, 54.2,
31.3 ppm. HRMS (ESI+): calcd. for C8H13N2137.1079 [M + H]+; found
137.1090.
(ESI+): calcd. for C15H19N2 227.1548 [M + H]+; found 227.1538.
N-(4-Methoxyphenyl)-2-picolinamide (15): 2-Picolinic acid
(500 mg, 4.06 mmol) was dissolved in dry CH2Cl2 (10 mL). Oxalyl
chloride (1.0 mL) was added, and the mixture was stirred at r.t. for
30 min. The solvent was removed under reduced pressure. The
crude acyl chloride was then dissolved in dry CH2Cl2 (10 mL). Anhy-
11: Compound 12 (30 mg, 0.22 mmol), (4-methylphenyl)boronic drous Na2CO3 (860 mg, 8.12 mmol) and p-anisidine (500 mg,
acid (45 mg, 0.33 mmol), pyridine (52 mg, 0.66 mmol), and 4.06 mmol) were added sequentially, and mixture was stirred at r.t.
Cu(OAc)2·H2O (44 mg, 0.22 mg) were dissolved in CH3CN (8 mL),
and the mixture was stirred at r.t. for 12 h. A basic EDTA solution
After 12 h, the mixture was diluted with CH2Cl2 (50 mL) and washed
with dilute HCl (2 % v/v, 20 mL). The organic layer was neutralized
with a dilute NaHCO3 solution. The organic layer was collected and
dried with anhydrous Na2SO4, and the solvent was subsequently
removed under reduced pressure. The crude product was subjected
(5 mL, 0.1
M, pH 10) was added, and the mixture was stirred for
10 min. The mixture was then extracted with CH2Cl2 (2 × 10 mL).
The organic layer was collected and dried with anhydrous Na2SO4.
The solvent was removed under reduced pressure. The crude prod- to column chromatography (silica gel, CH2Cl2) to afford the pure
uct was subjected to column chromatography (silica gel, 0–30 %
EtOAc/CH2Cl2). The product was isolated as a pale-brown solid. The
yield was 31 mg (62 %) (Scheme 8). H NMR (500 MHz, CDCl3): δ =
8.60 (d, J = 4.8 Hz, 1 H),7.59 (d, J = 4.2 Hz, 1 H), 7.13 (q, J = 4.4 Hz,
1 H), 6.85 (d, J = 8.2 Hz, 2 H), 6.25 (d, J = 8.2 Hz, 2 H), 4.13 (br. s, 1
H), 2.2 (s, 3 H), 1.67 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
166.4, 148.9, 143.6, 136.9, 129.5, 126.8, 121.6, 120.9, 115.9, 57.9, 29.3,
20.5 ppm. HRMS (ESI+): calcd. for C15H18N2Na 249.1368 [M + Na]+;
found 249.1377.
product. The product was isolated as a dull-white solid. The yield
was 47 % (433 mg) (Scheme 9). H NMR (300 MHz, CDCl3): δ = 9.93
(br. s, 1 H), 8.61 (d, J = 4.8 Hz, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 7.90
(dt, J = 7.2, 1.2 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 2 H), 7.47 (t, J = 7.8 Hz,
1 H), 6.93 (d, J = 9.0 Hz, 2 H), 3.82 (s, 3 H) ppm.[70]
1
1
1-d2: Lithium aluminum deuteride (LiAlD4) (36 mg, 0.86 mmol) was
suspended in dry THF (10 mL) in a round-bottom flask (50 mL)
under argon and cooled in an ice bath. N-(4-Methoxyphenyl)-2-pic-
olinamide (100 mg, 0.44 mmol) in dry THF (2.0 mL) was added
N-(4-Isopropylphenyl)-1-(pyridin-2-yl)methanimine (13): A mix- slowly, and the mixture was heated at reflux for 12 h. The mixture
ture of 2-pyridinecarbaldehyde (500 mg, 4.66 mmol) and 4-isopro- was then cooled in an ice bath, and the reaction was quenched by
pylaniline (631 mg, 4.66 mmol) was heated at reflux in toluene the addition of water (1.0 mL), which was followed by the addition
(10 mL) for 1 h. The solvent was removed under reduced pressure, of an NaOH solution (5 % v/v, 20 mL). It was extracted with CH2Cl2
and the obtained residue was purified by precipitation from CH2Cl2/
hexanes. The product was isolated as an off-white solid. The yield
(2 × 50 mL). The organic layer was collected and dried with anhy-
drous Na2SO4. The solvent was removed under reduced pressure,
was 857 mg (82 %). 1H NMR (300 MHz, CDCl3): δ = 8.69 (d, J = and the crude product was subjected to column chromatography
4.8 Hz, 1 H), 8.62 (s, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.78 (t, J = 7.8 Hz,
(silica gel, 0–50 % EtOAc/CH2Cl2) to isolate the product. The product
1 H), 7.32–7.35 (m, 1 H), 7.22–7.29 (m, 4 H), 2.93 (sept, J = 6.6 Hz, 1 was isolated as pale-brown solid. The yield was 45 % (42 mg)
H), 1.27 (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = (Scheme 9). H NMR (300 MHz, CDCl3): δ = 8.59 (d, J = 4.8 Hz, 1 H),
1
159.7, 154.8, 149.7, 148.6, 147.8, 136.6, 127.3, 125.0, 121.8, 121.3, 7.62 (t, J = 9.0 Hz, 1 H), 7.35 (dd, J = 6.6, 1.2 Hz, 1 H), 7.17–7.19 (m,
Scheme 8. Synthesis of 11.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3740
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 9. Synthesis of 1-d2.
Scheme 10. Synthesis of 1-Cl.
1 H), 6.78 (d, J = 9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 3.73 (s, 3 H),
3.2 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 158.8, 152.2,
Electron Paramagnetic Resonance Measurements: Solution EPR
spectra were measured at the X-band microwave frequency
149.3, 142.3, 136.7, 122.1, 121.7, 114.9, 114.3, 55.8, 49.6 [quint, (9.4 GHz) by using a Bruker Elexsys-500 Spectrometer at r.t. The
J(13C,2H) = 21.5 Hz] ppm. HRMS (ESI+): calcd. for C13H13D2N2O
magnetic field was calibrated by using DPPH (2,2-diphenyl-1-picryl-
hydrazyl) standard (g = 2.0037), and the microwave frequency was
measured by using a built-in digital counter. The modulation ampli-
tude and microwave power were optimized for high signal/noise
ratio. Glass capillary tubes were used as sample holders. In a typical
measurement, a freshly prepared mixture was taken in a glass capil-
lary (borosilicate melting point tube, i.d. ca. 1.4 mm) and then
placed inside a standard quartz X-band sample tube. The back-
ground from the empty capillary tube was measured prior to each
sample measurement and was subsequently subtracted. Sufficient
care was taken to maintain similar experimental conditions during
both the background and sample measurements.
217.1309 [M + H]+; found 217.1297.
1-Cl: A mixture of 2-pyridinecarbaldehyde (200 mg, 1.87 mmol) and
4-amino-3-chlorophenol hydrochloride (336 mg, 1.87 mmol) was
heated at reflux in dry toluene (5 mL) for 1 h. The solvent was
removed under reduced pressure to afford the crude product,
which was dissolved in CH3OH (8 mL). The solution was heated at
50 °C, and then NaBH4 (120 mg, 3.17 mmol) was added. After the
complete addition of NaBH4, the mixture was heated at reflux for
30 min. To quench the reaction, water was added. Most of the
CH3OH was removed under reduced pressure, and then the aque-
ous solution was extracted with CH2Cl2. The organic layer was dried
with anhydrous Na2SO4, filtered, and concentrated in vacuo. The
resulting residue was dissolved in acetone (5 mL), and then K2CO3
(198 mg, 1.43 mmol) was added, followed by the addition of CH3I
(89 μL, 1.43 mmol). The mixture was heated at reflux for 3 h and
then stirred at r.t. overnight. The crude mixture was concentrated
in vacuo and then subjected to column chromatography (silica gel,
15 % EtOAc/hexanes) to afford the desired product as a yellow oil
(Scheme 10). 1H NMR (500 MHz, CDCl3): δ = 8.60–8.57 (m, 1 H), 7.64
(dt, J = 12.0, 6.0 Hz, 1 H), 7.34–7.30 (m, 1 H), 7.20–7.16 (m, 1 H),
6.92 (d, J = 2.4 Hz, 1 H), 6.69 (dd, J = 9.0, 3.0 Hz, 1 H), 6.54 (d, J =
9.0 Hz, 1 H), 4.79 (s, 2 H), 3.72 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 158.6, 151.7, 149.4, 138.3, 137.0, 122.3, 121.5, 120.0,
115.6, 113.8, 112.6, 56.1, 49.8 ppm. HRMS (ESI+): calcd. for
C13H14ClN2O 249.0795 [M + H]+; found 249.0785.
Manometry: A round-bottom flask equipped with a magnetic stir-
ring bar was connected to a computer-interfaced digital manome-
ter (VWR Traceable manometer) through a T-bore stopcock and Tef-
lon tubing. The amine solution in CH3CN was added to the reaction
vessel through the T-bore stopcock by using a syringe and allowed
to equilibrate at r.t. Then, a CH3CN solution of Cu(OAc)2·H2O was
added through the syringe, and immediately the T-bore stopcock
was turned to close the reaction vessel. The change in pressure with
respect to time was monitored by using Data Acquisition Software
(DASTM, Control Company).
Kinetic Measurements: CH3CN stock solutions of amine (0.2 m
M,
400 μL) and Cu(OAc)2·H2O (0.1 m , 400 μL) were successively added
M
by syringes into a semimicro quartz cuvette (1.5 mL). The combined
solutions were mixed for ca. 10 s before absorption spectra were
acquired. The spectroscopic data were collected at 22 °C every
2 min. The rate of the reaction was obtained from the slope of the
linear portion immediately after mixing up to the 14 min mark. The
absorption spectra of compounds 1 and 1-im in their metal-free
forms in CH3CN are shown in Figure S10.
Reaction under Anaerobic Conditions: A solution of amine 1
(0.08 mmol) in CH3CN (4.0 mL) was placed in a two-neck, round-
bottom flask. This flask was fitted with a solid addition adapter and
an argon-supplying adapter. Cu(OAc)2·H2O (0.08 mmol) was trans-
ferred to the solid addition adaptor. Through three freeze–pump–
thaw cycles, the system was put under argon. Once the system was
under argon, Cu(OAc)2·H2O (0.08 mmol) was added to the flask by
rotating the adapter, and the reaction was allowed to run under
constant stirring for 5 min. Afterwards, the reaction was quenched
X-ray Crystallography: A suitable single crystal was mounted on a
goniometer head of an APEX II diffractometer by using a nylon loop
with a small amount of Paratone oil. All three samples were run at
–170 °C with the first two at 60 s of frame time and the third at
40 s. For the first two, 0.5° Ω were employed, whereas the third was
0.3°. Data integration was performed by using the program SAINT,
by addition of an EDTA solution (0.1 M, pH > 10, 5 mL). The resulting
mixture was transferred into a separatory funnel and extracted with
CH2Cl2 (2 × 5.0 mL). The combined organic layers were dried with
anhydrous Na2SO4, filtered, and concentrated under reduced pres- which is part of the Bruker suite of programs. Empirical absorption
sure. The crude mixture was analyzed by 1H NMR spectroscopy
(CDCl3, 500 MHz) to determine the conversion value of the reaction
(Table 1, Entry 5).
correction was performed by using SADABS. XPREP was used to
obtain an indication of the space group, and the structure was
solved by direct methods and refined by SHELXTL. With the excep-
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3741
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[8]
a) H. Furuta, H. Maeda, A. Osuka, J. Am. Chem. Soc. 2000, 122, 803–807;
b) B. Adinarayana, A. P. Thomas, C. H. Suresh, A. Srinivasan, Angew. Chem.
Int. Ed. 2015, 54, 10478–10482; Angew. Chem. 2015, 127, 10624–10628.
M. Melník, M. Kabešová, J. Coord. Chem. 2000, 50, 323–338.
D. C. Powers, T. Ritter, Acc. Chem. Res. 2012, 45, 840–850.
tion noted below, all non-hydrogen atoms were refined anisotropi-
cally, whereas hydrogen atoms were typically placed in calculated
positions and constrained to a riding model. [Cu2(OAc)4(6-Me)2]
(Figure 3a) was needle-like and 8-im-OH (Figure S4) was a thin
sheet. Reflections were not found to adequately high angles in spite
of the longer frame times nor was the data collection complete.
Not surprisingly, the data/parameter ratio was generally not 10:1.
Notwithstanding these problems, both structures make chemical
sense, and only the fine details are in question. The dicopper(II)
tetraacetate structure of [Cu2(OAc)4(6-Me)2] is quite normal if com-
pared to the literature structures containing other axial ligands. In
the structure of 8-im-OH, electron density was found in the area
between molecules and it was assigned as oxygen from a water
molecule. It proved to be disordered and was refined as 1/2 of an
oxygen atom at each site. CCDC 1455876 {for [Cu2(6-Me)2(OAc)4]},
1455877 {for [Cu(11)(OAc)2]}, and 1455878 (for 8-im-OH) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre.
[9]
[10]
[11]
E. Tkatchouk, N. P. Mankad, D. Benitez, I. William, A. Goddard, F. D. Toste,
J. Am. Chem. Soc. 2011, 133, 14293–14300.
[12]
a) N. Kitajima, Y. Moro-oka, Chem. Rev. 1994, 94, 737–757; b) E. I. Solo-
mon, U. M. Sundaram, T. E. Machonkin, Chem. Rev. 1996, 96, 2563–2605;
c) E. I. Solomon, P. Chen, M. Metz, S.-K. Lee, A. E. Palmer, Angew. Chem.
Int. Ed. 2001, 40, 4570–4590; Angew. Chem. 2001, 113, 4702–4724; d)
K. D. Karlin, S. Itoh, Reactive Intermediates in Chemistry and Biology, vol.
4 (Ed.: S. E. Rokita), Wiley, Hoboken, NJ, 2011; e) M. Rolff, J. Schotten-
heim, H. Decker, F. Tuczek, Chem. Soc. Rev. 2011, 40, 4077–4098.
a) P. L. Holland, W. B. Tolman, Coord. Chem. Rev. 1999, 190–192, 855–869;
b) E. A. Lewis, W. B. Tolman, Chem. Rev. 2004, 104, 1047–1076; c) E. Kim,
E. E. Chufan, K. Kamaraj, K. D. Karlin, Chem. Rev. 2004, 104, 1077–1133;
d) L. M. Mirica, X. Ottenwaelder, T. D. P. Stack, Chem. Rev. 2004, 104,
1013–1045; e) L. Q. Hatcher, K. D. Karlin, J. Biol. Inorg. Chem. 2004, 9,
669–683.
X.-X. Guo, D.-W. Gu, Z. Wu, W. Zhang, Chem. Rev. 2015, 115, 1622–1651.
G.-C. Kuang, P. M. Guha, W. S. Brotherton, J. T. Simmons, L. A. Stankee,
B. T. Nguyen, R. J. Clark, L. Zhu, J. Am. Chem. Soc. 2011, 133, 13984–
14001.
P. Siemsen, R. C. Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39,
2632–2657; Angew. Chem. 2000, 112, 2740–2767.
[13]
[14]
[15]
Acknowledgments
[16]
[17]
This work was supported by the National Science Foundation
(CHE1213574) and the Florida State University Council on Re-
search and Creativity.
a) G. Zhang, H. Yi, G. Zhang, Y. Deng, R. Bai, H. Zhang, J. T. Miller, A. J.
Kropf, E. E. Bunel, A. Lei, J. Am. Chem. Soc. 2014, 136, 924–926; b) R. Bai,
G. Zhang, H. Yi, Z. Huang, X. Qi, C. Liu, J. T. Miller, A. J. Kropf, E. E. Bunel,
Y. Lan, A. Lei, J. Am. Chem. Soc. 2014, 136, 16760–16763.
[18]
[19]
a) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302–1315; b) B. T.
Worrell, J. A. Malik, V. V. Fokin, Science 2013, 340, 457–460; c) L. Jin, D. R.
Tolentino, M. Melaimi, G. Bertrand, Sci. Adv. 2015, 1, e1500304.
a) J. K. Kochi, R. V. Subramanian, Inorg. Chem. 1965, 4, 1527–1533; b)
A. T. A. Cheng, R. A. Howald, Inorg. Chem. 1968, 7, 2100–2105; c) P. Shar-
rock, M. Melník, Can. J. Chem. 1985, 63, 52–56; d) Y. Fujii, N. Nakasuka,
M. Tanaka, H. Yamada, M. Mizuta, Inorg. Chem. 1989, 28, 3600–3602.
S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400–5449;
Angew. Chem. 2003, 115, 5558–5607.
Copper(II) acetate may carry different roles, as exemplified by the two
recently reported reactions shown in Scheme 7 and discussed in the
accompanying section.
Various synthetic methods have been reported for copper-mediated
amine-to-imine or alcohol-to-imine oxidations (see ref.[23a–23g]); ref.[24] is
an example of the copper(II) acetate catalyzed dehydrogenation of ami-
nals.
a) R. D. Patil, S. Adimurthy, Adv. Synth. Catal. 2011, 353, 1695–1700; b) T.
Sonobe, K. Oisaki, M. Kanai, Chem. Sci. 2012, 3, 3249–3255; c) M. Larg-
eron, M.-B. Fleury, Angew. Chem. Int. Ed. 2012, 51, 5409–5412; Angew.
Chem. 2012, 124, 5505–5508; d) J. Kim, S. S. Stahl, ACS Catal. 2013, 3,
1652–1656; e) M. Largeron, M.-B. Fleury, Chem. Eur. J. 2015, 21, 3815–
3820; f) W. Yin, C. Wang, Y. Huang, Org. Lett. 2013, 15, 1850–1853; g) H.
Chen, Q. Wang, Y. Huang, Tetrahedron 2015, 71, 3632–3636.
M. T. Richers, C. Zhao, D. Seidel, Beilstein J. Org. Chem. 2013, 9, 1194–
1201.
There is another mechanistically characterized case in which a copper
catalyst mediates both dehydrogenation (dehydrogenative coupling) as
the major reaction and oxygenation as a minor path; distinguished from
the current work, the oxygenated minor product in the referenced study
was postulated to be a cofactor in the major dehydrogenative coupling
pathway with a different kinetic profile: J. B. Hewgley, S. S. Stahl, M. C.
Kozlowski, J. Am. Chem. Soc. 2008, 130, 12232–12233.
a) M. Kirchgessner, K. Sreenath, K. R. Gopidas, J. Org. Chem. 2006, 71,
9849–9852; b) K. Sreenath, C. V. Suneesh, V. K. R. Kumar, K. R. Gopidas,
J. Org. Chem. 2008, 73, 3245–3251.
The comparison of the reaction progress in a UV/Vis assay is shown in
Figure S5. Whereas the ratio of initial rates (up to 10 min point) of 1-im
production under aerobic and anaerobic conditions was ca. 5-fold, the
ratio of the 1-im-OH production rate was ca. 13-fold. These data suggest
that O2 participates in the oxygenation reaction, rather than the acetate
Keywords: Amines · Bridging ligands · Copper ·
Dehydrogenation · Dinuclear catalysis · Oxidation
[1] a) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–3131;
b) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464–3484; c)
S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem. Rev.
2013, 113, 6234–6458.
[2] a) J. Hartwig, Organotransition Metal Chemistry – From Bonding to Cataly-
sis, University Science Books, Sausalito, CA, 2010; b) S. S. Stahl, Angew.
Chem. Int. Ed. 2004, 43, 3400–3420; Angew. Chem. 2004, 116, 3480–3501;
c) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169; d) C. C. C.
Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew.
Chem. Int. Ed. 2012, 51, 5062–5085; Angew. Chem. 2012, 124, 5150–5174;
e) K. M. Engle, J.-Q. Yu, J. Org. Chem. 2013, 78, 8927–8955.
[3] a) T. Cohen, J. Wood, A. G. J. Dietz, Tetrahedron Lett. 1974, 15, 3555–
3558; b) N. Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339–2372; c)
A. Casitas, X. Ribas, Chem. Sci. 2013, 4, 2301–2318; d) S. D. McCann, S. S.
Stahl, Acc. Chem. Res. 2015, 48, 1756–1766.
[4] a) E. Nakamura, S. Mori, Angew. Chem. Int. Ed. 2000, 39, 3750–3771;
Angew. Chem. 2000, 112, 3902–3924; b) S. H. Bertz, R. A. Hardin, T. J.
Heavey, C. A. Ogle, Angew. Chem. Int. Ed. 2013, 52, 10250–10252; Angew.
Chem. 2013, 125, 10440–10442.
[5] a) A. Casitas, A. E. King, T. Parella, M. Costas, S. S. Stahl, X. Ribas, Chem.
Sci. 2010, 1, 326–330; b) L. M. Huffman, A. Casitas, M. Font, M. Canta, M.
Costas, X. Ribas, S. S. Stahl, Chem. Eur. J. 2011, 17, 10643–10650; c) M.
Font, T. Parella, M. Costas, X. Ribas, Organometallics 2012, 31, 7976–7982;
d) C. Sambiagio, S. P. Marsden, A. J. Blacker, P. C. McGowan, Chem. Soc.
Rev. 2014, 43, 3525–3550.
[6] a) X. Ribas, D. A. Jackson, B. Donnadieu, J. Mahía, T. Parella, R. Xifra, B.
Hedman, K. O. Hodgson, A. Llobet, T. D. P. Stack, Angew. Chem. Int. Ed.
2002, 41, 2991–2994; Angew. Chem. 2002, 114, 3117–3120; b) B. Yao, D.-
X. Wang, Z.-T. Huang, M.-X. Wang, Chem. Commun. 2009, 2899–2901; c)
A. E. King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas, S. S. Stahl, J. Am.
Chem. Soc. 2010, 132, 12068–12073.
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[7] a) A. E. Wendlandt, A. M. Suess, S. S. Stahl, Angew. Chem. Int. Ed. 2011,
50, 11062–11087; Angew. Chem. 2011, 123, 11256–11283; b) A. M. Suess,
M. Z. Ertem, C. J. Cramer, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 9797–
9804.
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3742
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ions, as in an oxidative acetoxylation reaction. For examples of copper-
catalyzed oxidative acetoxylation, see: a) Y. Takizawa, A. Tateishi, J. Sugi-
yama, H. Yoshida, N. Yoshihara, J. Chem. Soc., Chem. Commun. 1991, 104–
105; b) X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc.
2006, 128, 6790–6791; c) Z. Wang, Y. Kuninobu, M. Kanai, Org. Lett. 2014,
16, 4790–4793.
longer a local minimum) on the reaction potential energy surface. In its
place, two copper(II) centers may undergo a collective two-electron
transfer “reductive elimination” to afford the oxidized product and two
copper(I) centers. The difference between the “concerted” [i.e., no cop-
per(III)] and “stepwise” [i.e., copper(III) is an intermediate] is energetically
subtle but consequential in guiding catalyst development in copper-
mediated reactions. This argument clearly needs to be tested further in
future studies.
[28] a) H. R. Gersmann, J. D. Swalen, J. Chem. Phys. 1962, 36, 3221–3233; b)
J. A. Weil, J. R. Bolton, J. E. Wertz, Electron Paramagnetic Resonance –
Elementary Theory and Practical Applications, Wiley, New York, 1994; c)
R. Kannappan, R. Mahalakshmy, T. M. Rajendiran, R. Venkatesan, P. S. Rao,
J. Chem. Sci. 2003, 115, 1–14.
[29] B. Bleaney, K. D. Bowers, Proc. R. Soc. London, Ser. A 1952, 214, 451–465.
[30] A. E. King, T. C. Brunold, S. S. Stahl, J. Am. Chem. Soc. 2009, 131, 5044–
5045.
[46] L. Ling, J. Chen, J. Song, Y. Zhang, X. Li, L. Song, F. Shi, Y. Li, C. Wu, Org.
Biomol. Chem. 2013, 11, 3894–3902.
[47] The M–M distance is ca. 2.6 Å for acetate-supported dicopper(II) and ca.
2.8 Å for acetate-supported dipalladium(II).
[48] D. C. Powers, D. Benitez, E. Tkatchouk, W. A. Goddard, T. Ritter, J. Am.
Chem. Soc. 2010, 132, 14092–14103.
[31] M. Montalti, A. Credi, L. Prodi, M. T. Gandolfi, Handbooks of Photochemis-
try, 3rd ed., CRC Taylor & Francis, Boca Raton, FL, 2006, pp. 624–628.
[32] The absorption spectra of independently prepared 1 and 1-im are in-
cluded in Figure S10.
[33] See more data in Table S3 and Figure S11.
[34] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066–3072;
Angew. Chem. 2012, 124, 3120–3126.
[49] a) K. D. Karlin, R. W. Cruse, Y. Gultneh, J. Chem. Soc., Chem. Commun.
1987, 599–600; b) P. Ghosh, Z. Tyeklar, K. D. Karlin, R. R. Jacobson, J.
Zubieta, J. Am. Chem. Soc. 1987, 109, 6889–6891.
[50] D and E might be the sources of the oxygenation reaction to afford the
hydroxylated imine. However, at this point we do not have an experi-
mentally tested model to describe this side reaction.
[51] H. Sigel, C. Flierl, R. Griesser, J. Am. Chem. Soc. 1969, 91, 1061–1064.
[52] I. Kaljurand, A. Kütt, L. Sooväli, T. Rodima, V. Mäemets, I. Leito, I. A. Kop-
pel, J. Org. Chem. 2005, 70, 1019–1028.
[53] A. Kütt, I. Leito, I. Kaljurand, L. Sooväli, V. M. Vlasov, L. M. Yagupolskii,
I. A. Koppel, J. Org. Chem. 2006, 71, 2829–2838.
[54] M. C. Paderes, L. Belding, B. Fanovic, T. Dudding, J. B. Keister, S. R. Chem-
ler, Chem. Eur. J. 2012, 18, 1711–1726.
[55] Similar to the current work, the resting state was structurally character-
ized, whereas the structure of the in-cycle active catalyst engaging in
turnover was inferred.
[56] A. E. King, B. L. Ryland, T. C. Brunold, S. S. Stahl, Organometallics 2012,
31, 7948–7957.
[57] A similar situation was found in palladium catalysis, for which both half
order and second order in palladium were reported; see ref.[40,44b,44c,58]
[58] G.-J. t. Brink, I. W. C. E. Arends, G. Papadogianakis, R. A. Sheldon, Appl.
Catal. A 2000, 194–195, 435–442.
[35] See time-dependent spectra in Figure S12.
[36] a) B. Biswas, M. Sugimoto, S. Sakaki, Organometallics 2000, 19, 3895–
3908; b) D. L. Davies, S. M. A. Donald, S. A. Macgregor, J. Am. Chem. Soc.
2005, 127, 13754–13755; c) D. García-Cuadrado, A. A. C. Braga, F. Ma-
seras, A. M. Echavarren, J. Am. Chem. Soc. 2006, 128, 1066–1067; d) H.-Y.
Sun, S. I. Gorelsky, D. R. Stuart, L.-C. Campeau, K. Fagnou, J. Org. Chem.
2010, 75, 8180–8189.
[37] a) M. Nishino, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2012,
51, 6993–6997; Angew. Chem. 2012, 124, 7099–7103; b) M. Nishino, K.
Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2013, 52, 4457–4461;
Angew. Chem. 2013, 125, 4553–4557; c) J. Dong, F. Wang, J. You, Org.
Lett. 2014, 16, 2884–2887; d) X. Li, Y.-H. Liu, W.-J. Gu, B. Li, F.-J. Chen, B.-
F. Shi, Org. Lett. 2014, 16, 3904–3907; e) P. Subramanian, K. P. Kaliappan,
Eur. J. Org. Chem. 2014, 5986–5997; f) M. Shang, S.-Z. Sun, H.-L. Wang,
B. N. Laforteza, H.-X. Dai, J.-Q. Yu, Angew. Chem. Int. Ed. 2014, 53, 10439–
10442; Angew. Chem. 2014, 126, 10607–10610.
[38] G. J. Christian, A. Llobet, F. Maseras, Inorg. Chem. 2010, 49, 5977–5985.
[39] D. B. Collum, A. J. McNeil, A. Ramirez, Angew. Chem. Int. Ed. 2007, 46,
3002–3017; Angew. Chem. 2007, 119, 3060–3077.
[40] a) D. C. Powers, T. Ritter, Nat. Chem. 2009, 1, 302–309; b) N. R. Deprez,
M. S. Sanford, J. Am. Chem. Soc. 2009, 131, 11234–11241; c) K. J. Stowers,
M. S. Sanford, Org. Lett. 2009, 11, 4584–4587.
[41] M. Oyama, M. Goto, Indian J. Chem. A 2003, 42A, 733–738.
[42] L. Yang, Z. Lu, S. S. Stahl, Chem. Commun. 2009, 6460–6462.
[43] The structure was confirmed by comparison with independently pre-
pared 1-Cl, shown in Scheme S10.
[59] M. He, G. Chen, X. Huang, R. Xu, Z. Zeng, J. Yang, Polym. Chem. 2014, 5,
2951–2960.
[60] a) M. Weiss, M. Appel, J. Am. Chem. Soc. 1948, 70, 3666–3667; b) M. L.
Lewbart, V. R. Mattox, J. Org. Chem. 1963, 28, 2001–2006.
[61] S. Kambourakis, J. W. Frost, J. Org. Chem. 2000, 65, 6904–6909.
[62] We did not model the postulated mechanism computationally, because
we do not have the expertise to do so or to interpret such data with
confidence at this point.
[63] L. Que Jr., W. B. Tolman, Nature 2008, 455, 333–340.
[64] a) V. Diez, J. V. Cuevas, G. García-Herbosa, G. Aullón, J. P. H. Charmant, A.
Carbayo, A. Muñoz, Inorg. Chem. 2007, 46, 568–577; b) C.-H. Chien, S.
Fujita, S. Yamoto, T. Hara, T. Yamagata, M. Watanabe, K. Mashima, Dalton
Trans. 2008, 916–923.
[65] F. M. Garibotto, M. A. Sortino, V. V. Kouznetsov, R. D. Enriz, S. A. Zacchino,
ARKIVOC (Gainesville, FL, U.S.) 2011, 149–161.
[66] H. A. Michaels, C. S. Murphy, R. J. Clark, M. W. Davidson, L. Zhu, Inorg.
Chem. 2010, 49, 4278–4287.
[67] P. Bandyopadhyay, S. Jha, S. K. I. Ali, J. Agric. Food Chem. 2009, 57, 9780–
9786.
[44] The resting state of a catalyst sometimes is found outside of the catalytic
cycle and might be the only catalytic species observed; see: a) F. Paul, J.
Patt, J. F. Hartwig, J. Am. Chem. Soc. 1994, 116, 5969–5970; b) G. P. F.
van Strijdonck, M. D. K. Boele, P. C. J. Kamer, J. G. de Vries, P. W. N. M.
van Leeuwen, Eur. J. Inorg. Chem. 1999, 1073–1076; c) T. Rosner, J. L.
Bars, A. Pfaltz, D. G. Blackmond, J. Am. Chem. Soc. 2001, 123, 1848–1855;
d) G.-J. t. Brink, I. W. C. E. Arends, R. A. Sheldon, Adv. Synth. Catal. 2002,
344, 355–369; e) E. Alvaro, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131,
7858–7868; f) Z. Shen, P. K. Dornan, H. A. Khan, T. K. Woo, V. M. Dong, J.
Am. Chem. Soc. 2009, 131, 1077–1091.
[68] V. V. Kouznetsov, L. Y. V. Méndez, M. Sortino, Y. Vásquez, M. P. Gupta, M.
Freile, R. D. Enriz, S. A. Zacchino, Bioorg. Med. Chem. 2008, 16, 794–809.
[69] Z. Zheng, G. Zhao, R. Fablet, M. Bouyahyi, C. M. Thomas, T. Roisnel,
O. C. Jr., J.-F. Carpentier, New J. Chem. 2008, 32, 2279–2291.
[70] A. Begouin, M.-J. R. P. Queiroz, Eur. J. Org. Chem. 2009, 2820–2827.
[45] A growing number of CuIII species resulting from disproportionation of
two copper(II) centers have been observed and characterized (e.g., see
ref.[3c]) They have been shown as competent intermediates to undergo
reductive elimination. However, the majority of the reported copper(III)
species are stabilized by macrocyclic arene ligands. Without the stabiliz-
ing ligands, the copper(III) intermediate may have been skipped (i.e., no
Received: May 9, 2016
Published Online: July 19, 2016
Eur. J. Inorg. Chem. 2016, 3728–3743
www.eurjic.org
3743
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim