Intermediacy of Copper(I) under Oxidative Conditions in the Aerobic Copper-Catalyzed Decarboxylative Thiolation of Benzoic Acids

Article abstract of DOI:10.1021/acscatal.9b04110

An experimental mechanistic study of the aerobic copper-catalyzed decarboxylative thiolation of benzoic acids with arenethiols is reported. For the model reaction, the findings support the corresponding disulfide (PhSSPh) of the arenethiol (PhSH) as the active thiolating source under reaction conditions. Synthesis and reactivity studies along with kinetic measurements support the chemical and kinetic competence of catalytically active well-defined Cu complexes: (phen)Cu^I(O₂CC₆H₄-o-NO₂) (2), [(phen)Cu^I(μ-SC₆H₅)]₂ (3), (phen)Cu^I(C₆H₄-o-NO₂) (4), and (phen)Cu^II(O₂CC₆H₄-o-NO₂)₂ (5) (phen = 1,10-phenanthroline). The presence of an induction period in the stoichiometric reaction of the copper(II) complex (phen)Cu^II(O₂CC₆H₄-o-NO₂)₂ (5) with PhSSPh and the absence of an induction period in the analogous stoichiometric reaction of the copper(I) complex (phen)Cu^I(O₂CC₆H₄-o-NO₂) (2) suggest that a copper(I) carboxylate is a more likely intermediate than a copper(II) carboxylate. The observation of in situ reduction of Cu^II to Cu^I further supports Cu^I as the primary active catalytic species, and spectroscopic studies also indicate the catalyst resting state to be a Cu^I species. The catalytic reaction exhibits a first-order dependence on [Cu^I] and [2-nitrobenzoic acid] and a zero-order dependence on [PhSSPh] and p(O₂), suggestive of turnover-limiting decarboxylation of a copper(I) carboxylate. Oxygen was found to promote the essential oxidative cleavage of the copper(I) thiolate intermediate [(phen)Cu^I(μ-SC₆H₅)]₂ (3) to regenerate a catalytically active [(phen)Cu^II] (Cu_ox) species with concomitant formation of PhSSPh. On the basis of these findings, a reaction pathway is proposed for the C-S coupling reaction that includes the key Cu^I-based intermediates (phen)Cu^I(O₂CC₆H₄-o-NO₂) (2) and (phen)Cu^I(C₆H₄-o-NO₂) (4). The pathway accounts for the role of O₂ in generating the active thiolating source, PhSSPh, as well as enabling catalytic turnover of in situ generated [(phen)Cu^I(μ-SC₆H₅)]₂ (3).

Full text of DOI:10.1021/acscatal.9b04110

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Article
Intermediacy of Copper(I) under Oxidative Conditions in the Aerobic
Copper-Catalyzed Decarboxylative Thiolation of Benzoic Acids
Kerry Ann Green, and Jessica M Hoover
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04110 • Publication Date (Web): 30 Dec 2019
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Page 1 of 17
ACS Catalysis
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Intermediacy of Copper(I) under Oxidative Conditions in the
Aerobic Copper-Catalyzed Decarboxylative Thiolation of Ben-
zoic Acids
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Kerry-Ann Green and Jessica M. Hoover*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United
States
ABSTRACT: An experimental mechanistic study of the aerobic copper-catalyzed decarboxylative thiolation of
benzoic acids with aryl thiols is reported. For the model reaction, the findings support the corresponding disulfide
(PhSSPh) of the aryl thiol (PhSH) as the active thiolating source under reaction conditions. Synthesis and reactivity
studies along with kinetic measurements support the chemical and kinetic competence of catalytically active well-
I
I
I
defined Cu-complexes; (phen)Cu (O
2
CC
6
H
4
-o-NO
2
) (2), (phen)Cu (C
6
H
4
-o-NO
2
) (4), [(phen)Cu (µ-SC
6
H
5
)]
2
(3) and
II
(
phen)Cu (O
2
CC
6
H
4
-o-NO
2
)
2
(5), (phen = 1,10-phenanthroline). The presence of an induction period in the
II
stoichiometric reaction of copper(II) complex (phen)Cu (O
induction period in the analogous stoichiometric reaction of copper(I) complex (phen)Cu (O
suggests a copper(I) carboxylate is a more likely intermediate than a copper(II) carboxylate. The observation of in
situ reduction of Cu to Cu further supports Cu as the primary active catalytic species and spectroscopic studies
also indicate the catalyst resting state to be a Cu species. The catalytic reaction exhibits a first order dependence on
2 6 4 2 2
CC H -o-NO ) (5) with PhSSPh, and the absence of an
I
2
6 4 2
CC H -o-NO ) (2),
II
I
I
I
I
[
Cu ] and [2-nitrobenzoic acid] and a zero order dependence on [PhSSPh] and pO
2
, suggestive of turn-over-limiting
decarboxylation of a copper(I) carboxylate. Oxygen was found to promote the essential oxidative cleavage of the
II
copper(I)-thiolate intermediate [(phen)Cu(µ-SC
6 5 2
H )] (3) to regenerate a catalytically active [(phen)Cu ] (Cuox)
species with concomitant formation of PhSSPh. On the basis of these findings, a reaction pathway is proposed for
I
the C-S coupling reaction that includes the key Cu -based intermediates, (phen)Cu(O
2 6 4 2
CC H -o-NO ) (2), and
(
phen)Cu(C -o-NO ) (4). The pathway accounts for the role of O in generating the active thiolating source,
6
H
4
2
2
6 5 2
PhSSPh, as well as enabling catalytic turnover of in situ generated [(phen)Cu(µ-SC H )] (3). KEYWORDS: Aerobic,
Copper-Catalyzed, Decarboxylative, Thiolation, Mechanistic
11
INTRODUCTION
reactions, but it is also one of only a handful of
oxidative decarboxylative cross-coupling (ODC)
Copper-catalyzed
powerful tools for the construction of new C-C and C-
heteroatom bonds.
cross-coupling
reactions
are
reactions capable of employing O
2
as the terminal
3a,4b-d,6,12
oxidant.
Cu-mediated aerobic coupling
1
Transition metal-catalyzed
transformations are particularly attractive because of
the ubiquitous, cheap and environmentally benign
decarboxylative cross-coupling reactions offer the
advantage of providing high levels of regioselectivity
using stable, readily available, simple carboxylic acid
1
3-17
nature of oxygen as oxidant,
yet the majority of
ODC reactions are plagued by the need for
superstoichiometric silver-based oxidants which are
known to facilitate the decarboxylation step in many
2
,3
substrates.
These strategies have been applied
4
,5
6,7
extensively to C-C and C-N bond forming reac-
tions. The corresponding C-S coupling reactions,
however, are less developed and not well understood
2
a,18-20
cases.
An improved understanding of this copper-
catalyzed decarboxylative thiolation and related
reaction mechanisms could enable the development of
more efficient aerobic catalytic copper systems.
8
mechanistically, despite the importance of the aryl
sulfide motif in pharmaceutically and biologically
relevant compounds and as intermediates in organic
Copper-promoted
redox-neutral
decarboxylative
9
synthesis.
coupling reactions have been studied mechanistically,
and the generally accepted pathway for these reactions
We recently reported the aerobic copper-catalyzed
decarboxylative thiolation of benzoic acids with aryl
I
involves initial decarboxylation of a Cu -carboxylate to
1
0
I
thiols. Not only is this system one of the few copper
catalysts developed for decarboxylative thiolation
form a Cu -aryl species, followed by activation of the
5
c,21-24
aryl halide or proton-containing coupling partner.
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In contrast, the oxidative variants are less well
Page 2 of 17
intermediates, identify the active thiolating source and
establish the role(s) played by O . Our findings
demonstrate the importance of the disulfide as oxidant
and thiolating source; a reactivity pattern that has
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understood, in part due to the various oxidation states
accessible to copper. Typical mechanisms proposed for
these reactions include decarboxylation from in situ
2
I
II
generated Cu - or Cu -carboxylates to form the
been acknowledged or observed in related Cu-
I
II
32,33
corresponding Cu - or Cu -aryl species and subsequent
reaction with the nucleophilic coupling partner.
mediated thiolations.
Synthesis and reactivity
studies, along with kinetic measurements and
I
Although mechanistic proposals are posited in the
spectroscopic studies, support well-defined (phen)Cu
4d,6a,11a
literature,
I
experimental studies to probe these
species as key intermediates and indicate a Cu resting
pathways are limited.
state. A significant role of molecular oxygen is the
oxidative dissociation of the in situ generated cop-
per(I)-thiolate dimer to provide disulfide and regener-
ate a catalytically active Cu species. These findings of
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In the case of decarboxylative thiolation reactions,
mechanistic proposals are further complicated by the
multitude of reaction pathways available to thiols and
disulfides under copper-mediated conditions.
example, the redox-neutral thiolation of aryl halides
has been shown by Hartwig and coworkers to
proceed through activation of the aryl halide by
copper(I)-thiolate species, while Ribas and others
I
1
1a,25-28
the catalytic relevance of well-defined Cu species
For
under oxidative conditions may have implications for
related systems as researchers seek to expand the
scope and utility of aerobic Cu-mediated coupling
transformations.
2
9
3
0
have shown an aryl copper(III) pathway to be plausible
for the same reaction type (Scheme 1a). Similarly, the
RESULTS AND DISCUSSION
2
C(sp )-H thiolation reactions could proceed through
either initial C-H activation followed by reaction with
thiol or disulfide, or initial formation of a copper(I)-
thiolate which then cleaves the C-H bond to form the
coupled product (Scheme 1b). Thus, for the oxidative
decarboxylative thiolation reactions (Scheme 1c), a
number of pathways are possible and many
mechanistic questions remain.
Overview of the Catalytic System. For this
mechanistic study, we chose the model reaction of 2-
nitrobenzoic acid and thiophenol (PhSH), which
generates (2-nitrophenyl)(phenyl)sulfane (1) in 84%
yield (Scheme 2). Under the standard catalytic
conditions 2-nitrobenzoic acid (60 mM), PhSH (120
mM) and potassium carbonate are treated with 10
mol% of CuI and 12 mol% of 1,10-phenanthroline
3
1
(a) Redox-Neutral Thiolation of Aryl Halides
X
(
phen) in DMSO at 140 °C, under an aerobic
PhSH
III
10
LnCu Ar
2
atmosphere maintained with an O balloon. Decar-
Ar
X
I
X
L Cu X
n
boxylative coupling reactions are prone to competing
protodecarboxylation and molecular sieves are includ-
+
Ar SPh
PhSH
Ar
X
CuI SPh
ed in the standard conditions to prevent the formation
5e-f
of nitrobenzene.
The reaction time course can be
(b) Oxidative C-H Thiolation
1
LnCuI Ar
PhSSPh
monitored using an aliquot method with H NMR
spectroscopic analysis, which shows sharp signals for
the sulfide product (1). Monitoring the standard
catalytic reaction in this fashion reveals a time course
with an approximate 12 min induction period, followed
by exponential formation of the product. A linear fit to
the early time points following the induction period
Ar
H
I
L Cu X
n
+
Ar SPh
PhSH
Ar
H
CuI SPh
oxidant
(c) Oxidative Decarboxylative Thiolation
O
LnCuI Ar PhSSPh
-CO2
-1
provides an initial rate of 12.7 ± 0.6 mM h (Figure S6).
Ar
OH
L Cu X
I
n
+
Ar SPh
O
CuI (10 mol%)
Phen (12 mol%)
K CO (1 equiv)
2 3
O
SH
PhSH
Ar OH
oxidant
S
CuI SPh
+
HO
DMSO, 140 °C
Å MS, 24 h
O2 balloon
-
CO2
O N
2
O N
2
4
120 mM
60 mM
1, 84%
Scheme 1. Simplified Mechanistic Pathways for Cop-
per-Catalyzed Thiolation Reactions.
Scheme 2. Model Reaction for Mechanistic Study.
Herein, we report an experimental mechanistic study
of the aerobic copper-catalyzed decarboxylative
coupling reaction of benzoic acids and aryl thiols to
elucidate the nature of the key reactive Cu-based
PhSSPh in Catalytic Reactions. The copper-
mediated oxidation of thiols (RSH) to the
corresponding disulfides (RSSR) under aerobic
32,34
conditions is well established.
Furthermore, the
intermediacy of RSSR in related oxidative Cu-catalyzed
2
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ACS Catalysis
are an average of four runs and error bars shown are one
thiolation reactions has been supported by the
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standard deviation of the mean.
observed formation and demonstrated reactivity of
RSSR under typical reaction conditions.
32,35
Identification of a Copper(I) Resting State. The
standard catalytic reaction of 2-nitrobenzoic acid with
PhSSPh undergoes characteristic color changes as the
reaction progresses. Prior to heating, the reaction
mixture is a deep brown color. Upon heating, the
mixture turns green initially, followed by a gradual
change to yellow-green, and finally a persistent
orange-brown color. Because of the observed color
changes during the catalytic reactions and the
characteristic spectral features in the absorption
Under the standard catalytic decarboxylative thiolation
conditions, we observed the consumption of PhSH to
form PhSSPh. Similarly, the CuI/phen-catalyzed
aerobic oxidation of PhSH proceeds rapidly in the
absence of 2-nitrobenzoic acid, with
a
nearly
quantitative consumption of PhSH to form PhSSPh as
the only reaction product (84% yield) within the first 4
0
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2 3
min of the reaction, both with and without K CO .
1
Monitoring this catalytic PhSH oxidation by H NMR
spectroscopy provides an estimate of the rate of
I
II
spectra for Cu and Cu
species, UV-visible
formation of PhSSPh in the absence of K
2
CO
3
as 516 ±
spectroscopic studies were performed to gain insight
into the catalyst resting state.
-
1
49 mM h at [PhSH]
0
= 97 mM (Figure S7).
Furthermore, when PhSSPh was employed in place of
PhSH under otherwise standard catalytic decarboxyla-
The
UV-visible
spectroscopic
features
of
phenanthroline-ligated copper complexes are well
tive
thiolation
conditions,
(2-
I
I
established. The low valent (phen)Cu and (phen)
2
Cu
nitrophenyl)(phenyl)sulfane (1) was successfully
36
species exist in equilibrium and give rise to metal-to-
ligand charge transfer absorptions at 364 and 445 nm,
1
0
generated in 82% yield. The time course for this reac-
tion in which [PhSSPh] = 60 mM and [2-nitrobenzoic
1acid] = 60 mM shows an initial rate of 13.7 ± 3.7 mM h
(Figures 1 and S9). This reaction rate is within error of
3
7
0
respectively.
In contrast, the corresponding
-
II
0
(
phen) Cu displays a broad d-d transition band of
2
38
weak intensity around 700 nm. Because the ~364 nm
absorption range is obscured by the sulfane product 1
(lmax = 375 nm) under our reaction conditions, and
-
1
0
that involving PhSH (12.7 ± 0.6 mM h , at [PhSH] =
120 mM, vide supra), supporting the chemical and
kinetic competence of PhSSPh as the active thiolating
source under standard conditions.
given the rapid ligand-exchange equilibria common
with phenanthroline-ligated copper(I) species, we will
I
CuI (10 mol%)
O
use “(phen)Cu ” to refer to both the mono- and bis-
Phen (12 mol%)
S
S
+
HO
O
K
2
CO
3
(1 equiv)
phenanthroline ligated copper(I) species throughout
this study.
S
DMSO, 140 °C
4Å MS, 24 h
2
N
2
O N
O
2
balloon
1
2 3
The reaction mixture of CuI, phen, K CO , 2-
nitrobenzoic acid and PhSSPh was prepared in a
septum-sealed cuvette equipped with a stir bar and an
60 mM
60 mM
5
0
2
O balloon, then heated in a pre-heated aluminum
4
0
block. The reaction mixture has an initial brown color
and a strong absorption at 440 nm characteristic of a
20
15
I
37
(
phen)Cu species (Figure 2, black trace) and a broad
30
band of weak intensity around 699 nm attributed to
II 38
Cu . The presence of copper(II) in the initial reaction
2
0
0
0
1
0
5
0
mixture results from background oxidation of cop-
per(I) under these aerobic conditions. The band at 440
nm is suggestive of the formation of (phen)Cu . Upon
heating at 140 °C, the spectral band at 440 nm is
quenched (Figure 2, blue trace) followed by the
gradual appearance of a new band at 443 nm (Figure 2,
red trace). The appearance of this band was
I
1
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Time (h)
0
5
10
15
20
25
II
Time (h)
accompanied by the loss of the Cu feature at 699 nm.
The behavior observed in the visible region of the
spectrum supports a phenanthroline-ligated copper(I),
I
Figure 1. Formation of [(2-nitrophenyl)(phenyl)sulfane] (1)
over time for the standard catalytic reaction of 2-
nitrobenzoic acid with PhSSPh under O . The trace of the full
2
time course is not a fit and is included to guide the eye. The
inset shows the linear fit to early reaction times; data points
(phen)Cu , species as the catalyst resting state, and
suggests the initial formation and consumption of a
copper(II) species.
3
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Page 4 of 17
that appears to correlate with steps that generate an
active Cu -benzoate species. Although there is no
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significant induction period under standard catalytic
conditions (Figure 1), an induction period of ~12 min is
observed at low [CuI/phen], consistent with the
formation of an active copper(I) species during the
induction period. The events occurring during this
time include copper oxidation and reduction events
(vide infra), as well as formation of the copper-
benzoate species from copper, the benzoic acid, and
base. Thus, to gain further insight into the product
forming steps from copper carboxylate species, we
sought to explore the reactivity of well-defined copper
complexes as described below.
0
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9
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3
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0
70
(a)
6
5
4
0
0
0
Figure 2. Selected UV-visible spectra measured for the
standard catalytic reaction over 1 h. Reaction conditions: 2-
nitrobenzoic acid (9.3 mM), PhSSPh (9.7 mM), CuI (1.1 mM),
phen (1.0 mM), K CO (1.2 equiv), DMSO (2.5 mL), O bal-
2 3 2
loon, 140 °C. Final spectrum: from a 3-fold dilution of the
mixture after 1 h.
30
20
10
0
0
10
20
30
40
50
60
70
[Cu] (mM)
Determination of Kinetic Reaction Orders. The
kinetic dependence of reaction components were
measured using an aliquot method. Initial rate
measurements reveal a first order dependence on both
(b) 30
25
2
1
0
5
[
CuI/phen] ([Cu]
nitrobenzoic acid] ([2-nitrobenzoic acid]
mM, Figure 3b), and a zero order dependence on
PhSSPh] ([PhSSPh] = 10-120 mM, Figure 3c). The
0
= 3-60 mM, Figure 3a) and [2-
0
= 30-120
10
5
[
0
observed dependence are suggestive of a turn-over-
limiting step that involves a copper carboxylate spe-
cies. Given the high temperatures and forcing reaction
conditions often required for the decarboxylation of
0
0
20
40
60
80
100
120
140
[2-Nitrobenzoic Acid] (mM)
(c) 30
2
b,23,39-41
copper carboxylates,
it is plausible that decar-
boxylation from such a species could be turn-over-
limiting, however formation of a copper(I)-carboxylate,
or oxidation of such a species may also be turn-over-
limiting.
25
20
15
10
5
0
The possibility of turn-over-limiting oxidation by O
was explored by measuring the rate of the standard
catalytic reaction conducted under air (~21% O ) used
(14.9 ± 1.8 mM h , Figure S13). The data
show no dependence on pO and instead, indicate a
2
2
-
1
in place of O
2
2
0
20
40
60
80
100
120
140
[
PhSSPh] (mM)
turn-over-limiting-step that is either formation of or
decarboxylation from a copper(I)-carboxylate.
-1
I
Figure 3. Plot of initial rate (mM h ) versus (a) [Cu ] (mM),
b) [2-nitrobenzoic acid] (mM), and (c) [PhSSPh] (mM) for
the standard catalytic reaction of 2-nitrobenzoic acid with
PhSSPh under O . Data points are an average of two runs and
error bars shown are one standard deviation of the mean.
Given the observed kinetic dependence, the rate
constant for the standard catalytic reaction is
(
-1
-1
determined to be k = 0.038 ± 0.010 mM h . An
2
induction period is observed under some conditions,
4
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Intermediacy of Copper(I) Benzoate. Copper(I)
benzoate species have been proposed by us and others
brown to red-brown color throughout, indicative of
(phen)Cu . These data combined suggest that 2 is
kinetically competent under reaction conditions and is
likely a key reaction intermediate.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
I
as key intermediates in decarboxylative coupling
4a,11a,21,40,42
reactions
and
we
envisioned
(
phen)Cu(O
2
CC
6
H
4
-o-NO ) (2), as a likely species to be
2
generated under our reaction conditions. Therefore,
we sought to probe the formation of such a species
under typical reaction conditions. The stoichiometric
reaction of CuI, phen, 2-nitrobenzoic acid and K
2 3
CO
in DMSO-d under N at 80 °C was monitored by in situ
6
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
1
H NMR analysis (Figure S2). Under these conditions,
we observed the formation of 2 in approximately 57%
yield after 6 h. The reaction was conducted at 80 °C,
because complex 2 is reactive at the typical 140 °C reac-
tion temperature (vide infra). The identity of 2 was
verified by comparison with an authentic sample
4
a
synthesized according to a literature procedure. This
result provides support for the likely generation of 2
under the standard reaction conditions. Furthermore,
the relatively slow formation of 2 under these
conditions is consistent with the generation of this
species contributing to the induction period under
catalytic conditions (vide supra).
Complex 2 is also catalytically competent. The reaction
of 2-nitrobenzoic acid and PhSH with 10 mol% of
complex 2 provided (2-nitrophenyl)(phenyl)sulfane (1)
in 89% yield. Similarly, the stoichiometric reaction of 2
and PhSSPh in DMSO performed under oxygen
furnished 1 in 72% yield, while the analogous reaction
performed under nitrogen provided 1 in 75% yield
(Scheme 3).
O
S
N
DMSO, 140 °C
1
Cu
O
O
+
PhSSPh
1 equiv
4
Å MS, 24 h
or O
Figure 4. (a) Final H NMR spectrum of the reaction of
N
O N
N
2
2
2
2
N
(phen)Cu(O
2
CC
6
H
4
-o-NO
2
) (2) (12.7 µmol, 25.4 mM) and
after heating at 140
2
O2 atmosphere: 1, 72%
atmosphere: 1, 75%
N
2
PhSSPh (12.4 µmol, 24.8 mM) under N
2
o
C for 55 min in DMSO-d6. Residual PhSSPh is indicated by *.
(b) Plot of [(2-nitrophenyl)(phenyl)sulfane] (1) (mM) versus
time for the reaction of complex 2 (60 mM) and PhSSPh (60
Scheme 3. Stoichiometric Reactions of Complex 2
2 2
with PhSSPh under O and N Atmospheres.
2
mM) in DMSO under N . Inset: Early reaction times indicat-
1
ing the linear fit used to calculate the initial rate. Data points
are an average of four runs and error bars shown are one
standard deviation of the mean.
H NMR analysis of the stoichiometric reaction of 2
under N shows the
copper(I)-thiolate dimer [(phen)Cu(µ-SC )] (3) to
be the sole copper-containing product in 84% yield
Figure 4a). The identity of 3 was verified following the
with PhSSPh in DMSO-d
6
2
6
H
5
2
Intermediacy of Copper(I) Aryl. The efficient
generation of 1 from 2 and PhSSPh described above
likely involves a decarboxylation step paired with
(
independent synthesis of this complex from
a
I
11a
2
9
oxidative addition of Cu to the disulfide. SIIuI lfide
ligands are known to stabilize high-valent Cu and
literature protocol.
The initial rate of this
stoichiometric reaction under N
2
was determined to be
I
-
1
there are instances wherein disulfides oxidize Cu to
3
50.0 ± 30 mM h (at [2]
0
= 60 mM and [PhSSPh] = 60
0
III 43,44
Cu .
Consequently, discrete organocopper(III)
mM, Figures 4b and S17), slightly faster but of the same
order of magnitude as the rate predicted based on the
thiolate species have also been proposed as
intermediates in oxidative Cu-catalyzed thiolation
-
1
catalytic reaction rate (13.7 mM h at 6 mM Cu) and
the measured first order dependence on [CuI/phen]. In
addition, no induction period was observed for this
reaction, and the mixture maintained an intense
1
1a,45
reactions.
Thus we imagined a product-forming
pathway involving initial decarboxylation of 2 to
generate
a
copper(I)-aryl species capable of
5
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ACS Catalysis
agents
Page 6 of 17
9,10-
undergoing oxidative addition with PhSSPh (Scheme
).
(1,1-diphenylethylene
and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
dihydroanthracene). No radical trapped products were
observed in either reaction, and in both cases 1 and
complex 3 were formed in quantitative yields. Taken
together, these data support the formation of a reactive
organocopper(III) dithiolate complex via oxidative
addition of PhSSPh to 4 (Scheme 4).
O
SPh
CuIII SPh
Ar
Ar
-CO2
CuI Ar
PhSSPh
CuI
O
Ar SPh
Cu -SPh
2
I
-
Scheme 4. Plausible Pathway for Product For-
mation from Complex 2.
We therefore synthesized and explored the reactivity
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
I
4a
of the Cu -(aryl) complex (phen)Cu(C
as a possible reaction intermediate. When a mixture of
-nitrobenzoic acid and PhSH was treated with 10
6 4 2
H -o-NO ) (4)
2
mol% of 4 under standard catalytic conditions, the (2-
nitrophenyl)(phenyl)sulfane product (1) was obtained
in 75% yield. On treatment of 4 with a stoichiometric
amount of PhSSPh (1 equiv) under O 39% yield of 1
2
was obtained along with the 2,2’-dinitrobiphenyl
byproduct in 12% (Scheme 5). Both an improved yield
2
O N
N
S
2
PhSSPh
Cu
+
DMSO, 140 °C
4 Å MS, 24 h
N2 or O2
N
O N
O
2
N
NO
2
4
O
N
2
atmosphere: 1, 39%
atmosphere: 1, 52%
2
12%
6%
1
Scheme 5. Stoichiometric Reactions of Complex 4
with PhSSPh.
Figure 5. H NMR spectra of (a) 4 in DMSO-d
6
at rt, and (b) a
mixture of 4 (12.6 µmol, 25.2 mM) and PhSSPh (12.8 µmol,
5.6 mM) in DMSO-d (0.5 mL) under N after 7 min at rt.
Products: (2-nitrophenyl)(phenyl)sulfane (1) and 3. Residual
2
6
2
of 1 (52%) and a reduction in byproduct formation
(6%) resulted when the same reaction was conducted
PhSSPh is indicated by *.
under nitrogen. The moderate yields of 1 formed from
these stoichiometric reactions of 4 at 140 °C are
attributed to the competitive decomposition of 4 at
elevated temperatures. In a control experiment at 140
Synthesis and Reactivity of Copper(II) Benzoate.
The observed formation of Cu species at early
reaction times by UV-visible spectroscopy (vide supra)
suggests that divalent copper species could also be
II
6 2
°C in DMSO-d under N , 4 was observed to decompose
relevant
intermediates
in
these
oxidative
to a mixture containing nitrobenzene and 2,2’-
dinitrobiphenyl (see SI for details). Therefore, we also
explored the stoichiometric reaction of 4 with PhSSPh
under milder room temperature conditions.
decarboxylative thiolation reactions. The oxidation of a
Cu (aryl) species by a sulfenyl radical (•SR) to generate
the corresponding Cu (aryl)(SR) species has been
proposed in related systems and is a possible pathway
under our reaction conditions. Additionally, we and
others have shown Cu benzoate species to be likely
II
III
4
6
The reaction of 4 with PhSSPh was conducted under
1
II
N
2
at room temperature in a J. Young NMR tube. H
4
a
NMR analysis reveals the rapid formation of 1 in 82%
and [(phen)Cu(µ-SC )] (3) in 90% within
intermediates in decarboxylative arylation
and
selenation reactions. Consequently, the copper(II)
complex (phen)Cu(O CC H -o-NO ) (5) was pre-
4
7
6
H
5
2
approximately 7 min of mixing (Figure 5). No other
reaction products were observed. Because the reaction
is nearly complete within 7 min at room temperature,
we were unable to measure the initial rate for this
reaction. Nevertheless, these observations confirm the
facile formation of 1 from 4. These data are consistent
with an oxidative addition step to generate a cop-
per(III) intermediate as shown in Scheme 4, however a
pathway involving the formation of a copper(II) inter-
2
6
4
2 2
4
a
pared, and its reactivity probed. Complex 5 was
catalytically competent for the model reaction of 2-
nitrobenzoic acid with PhSH and generated (2-
nitrophenyl)(phenyl)sulfane (1) in 98% yield. We also
probed the stoichiometric reaction of 5 with PhSSPh
and observed the successful generation of 1 in 74%
yield under oxygen, and 76% under nitrogen (based on
carboxylate, Scheme 6).
2
8,46
mediate via ArS• addition to 4 is also a possibility.
Thus, this stoichiometric reaction of 4 with PhSSPh
was conducted in the presence of radical trapping
6
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Page 7 of 17
ACS Catalysis
and PhSSPh in DMSO at 140 °C under N
2
O N
2
the absorb-
1
2
3
4
5
6
O
ances at ~438 nm and 535 nm grow in over time,
PhSSPh (2 equiv)
DMSO, 140 °C
S
N
N
N
I
O
diagnostic of (phen)Cu (Figure 7). Concurrently, there
Cu
4Å MS, 24 h
N2 or O2
O
O
2
is a loss of the broad band at ~695 nm, typical of 5.
These observations indicate the generation of Cu
during this reaction and support its relevance under
reaction conditions.
I
O
O
2
atmosphere: 1, 74%
5
2
O N
N
2
atmosphere: 1, 76%
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Stoichiometric Reactions of Complex 5
with PhSSPh
Finally, monitoring the stoichiometric reaction under
1
N
2
by H NMR spectroscopy of reaction aliquots allows
When this stoichiometric reaction was conducted
us to probe the kinetic behavior of the reaction. For
the reaction in which [5] = 30 mM and [PhSSPh] = 60
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
under an air atmosphere in DMSO-d
6
no copper-
0
0
1
containing species could be observed by H NMR
spectroscopy at the end of the reaction. In contrast,
when the same stoichiometric reaction was conducted
mM the formation of product 1 produces an apparent
sigmoidal curve with an approximate 3 min induction
period (Figure 8, red points). Qualitative observations
of the reaction of 5 with PhSSPh also support the
reduction of copper(II) to copper(I) during the initial
lag phase. Visual observation reveals that upon
heating, the blue color characteristic of 5 dissipates
and the mixture becomes green. After the approximate
3 minute induction period, the mixture becomes
yellow-green, followed by a rapid change to a final
under
N
2
,
[(phen)Cu(µ-SC
6
H
5
)]
2
(3) was formed
quantitatively as the only copper-containing product
(Figure
6).
In
addition,
the
(2-
nitrophenyl)(phenyl)sulfane
(1)
is
formed
quantitatively and as the only organic reaction
product. Two equivalents of 1 are formed for each
equivalent of 5 indicating that both carboxylates of 5
are consumed to generate product with the reduction
I
persistent orange-brown color indicative of Cu .
II
I
of Cu to Cu .
Figure 7. UV–visible spectra for the stoichiometric reaction
of 5 and PhSSPh under N
ditions: (phen)Cu(O CC
1.6 mM), DMSO (2.5 mL), N
2
at 140 °C in DMSO. Reaction con-
-o-NO (5) (0.83 mM), PhSSPh
balloon, 140 °C.
2
6
H
4
2 2
)
1
(
2
Figure 6.
phen)Cu(O
PhSSPh (12.4 µmol, 20.7 mM) in DMSO-d (0.6 mL) under
6
. (a) mixture of 5 and PhSSPh in DMSO-d at rt (b) mixture
H
NMR spectra of the reaction of
(
2
CC
6
H
4
-o-NO (5) (6.1 µmol, 10.2 mM) and
2 2
)
The presence of an induction period and sigmoidal
time course for the reaction of complex 5 with PhSSPh
is in contrast to the observations for the copper(I)
complex 2, for which no induction period was observed
6
N
2
heated at 140 °C for 9 min (c) mixture heated at 140 °C for 40
min (d) mixture heated at 140 °C for 3 h 40 min. Residual
PhSSPh is indicated by *.
(vide supra). A comparison of the reaction time courses
for the stoichiometric reactions of complexes 2 and 5
II
I
The reduction of Cu to Cu in the stoichiometric
reaction of 5 with PhSSPh is supported by UV-visible
spectroscopic experiments. Upon heating complex 5
1
2
with PhSSPh under N at 140 °C, obtained by H NMR
analysis of reaction aliquots is represented in Figure 8.
Despite the difference in appearance of the two time
7
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ACS Catalysis
courses, both reactions form 1 and complex 3 in high
Page 8 of 17
I
5 to a final orange-brown color indicative of Cu
formation.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
yields and as the sole reaction products.
2
O N
The empirical observations combined with the lack of
an induction period in the case of 2 and the presence
of a ~3 min induction period in the case of 5 serve to
O
2
O N
O
N
N
N
N
O
DMSO
Cu
+
Cu
O
I
O
140 °C, N
2
corroborate the intermediacy of the Cu species and
NO2
O N
2
II
I
O
suggest reduction of Cu to Cu during the initial slow
phase. Additionally, the observed similarity in reaction
products for the reactions of 2 and 5 with PhSSPh is
consistent with Cu and Cu complexes generating
product via a common pathway. Thus, these data indi-
cate that direct decarboxylation from a copper(II) ben-
zoate intermediate is unlikely, and instead reduction
to copper(I) and subsequent decarboxylative coupling
from a copper(I) carboxylate is more plausible.
5
2
2
O N
Scheme 7. Proposed pathway for the reduction of 5
under N in the absence of PhSSPh.
I
II
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
Probing the same decarboxylation of 5 by UV-visible
spectroscopy, reveals the loss of the initial band at 695
nm characteristic of 5 with the formation of a new
band at about 444 nm and an additional increase in
absorption at ~543 nm. This final spectrum is identical
to the spectrum of 2 (Figure S31). The spectroscopic
data suggest that a decarboxylation pathway could be
II
I
responsible for the initial reduction of Cu to Cu .
II
I
Reduction of Cu to Cu prior to decarboxylation is
39
I
consistent with work by Cohen et al. who showed Cu
to be the active catalyst in the decarboxylation of
cupric aromatic carboxylates in quinoline solvent.
Evidence for the reduction of Cu to Cu in this prior
work was provided by the loss of the ESR signal within
a few minutes, prior to decarboxylation. In addition,
the observed Cu -(2-nitrobenzoate) was found to
decarboxylate 100 times slower than its Cu
counterpart. In these cases, the reduction of Cu to
Cu was attributed to the capability of the quinoline to
II
I
II
I
2
2
II
I
facilitate the conversion, via the possible formation of
-oxygenated quinolines.
3
9
2
II
I
The reduction of Cu to Cu in the absence of an
explicit reductant has been observed throughout the
realm of copper-mediated transformations.
example, in the related Ullmann-type coupling to form
C-O and C-N bonds,
observed that in the presence of coordinating nucleo-
philes, Cu reduces to active Cu species prior to
catalysis, with the concomitant oxidation of the
phenoxide and amine nucleophiles. More recently,
Jutand and coworkers reported on the reduction of
phenanthroline-ligated Cu precursors by alcohols or
amines to generate the active Cu catalyst in the
2 3
presence of Cs CO . Peñéñory and coworkers later
made a similar observation with a sulfur-based
nucleophile. Yi and coworkers, further reported on
the role of the tert-butoxide anion as base and as single
electron donor in promoting the reduction of Cu
precursors via the homolytic cleavage of an O-Cu
4
8,49
For
5
0,51
48a
Paine
51
and Weingarten
Figure 8. Comparison of reaction profiles for the reaction of
II
I
(
phen)Cu(O
2
CC
6
H
4
-o-NO
2
)
)
(2) (60 mM) , and
(5) (30 mM) ˜, with PhSSPh (60
(phen)Cu(O
2
CC
6
H
4
-o-NO
2
2
1
b
mM) under N
termined by quantitative H NMR analysis.
2
at 140 °C. Product concentrations were de-
1
37a
II
Decarboxylation of Copper(II) Benzoate. In the
I
II
absence of PhSSPh, the reduction of Cu complex 5
37b
occurs via a distinct, decarboxylation-based pathway to
generate 2 and 2,2’-dinitrobiphenyl as the oxidation
48b
1
product (Scheme 7). The H NMR spectrum of complex
5
in DMSO-d
6
at rt under N
2
is broad and almost
II
featureless. Upon heating at 140 °C, a gradual
sharpening of the signals occurs along with the
formation of nitrobenzene and 2,2’-dinitrobiphenyl.
II
bond. Thus, many pathways have been established for
II
I
1
the in situ reduction of Cu to Cu , however a unique
decarboxylation step appears to be responsible for the
reduction of these copper(II)-carboxylate species.
These changes in the H NMR spectra are accompanied
by a change in the color of the initially blue solution of
8
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ACS Catalysis
Based on the data above, we expected the reaction
shown in Scheme 7 to be responsible for the initial
uncatalyzed formation of from in the
In this model, Step 2 corresponds to the stoichiometric
reaction of complex 2 with PhSSPh, discussed above
(k = 0.097 ± 0.008 mM h ). The time course data for
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1 -1
2
5
stoichiometric reaction of 5 with PhSSPh. Alternative-
ly, 2 could also result from an initial step involving the
reaction of 5 with PhSSPh (Scheme 8, step 1). Thus, we
monitored the stoichiometric reaction of 5 with
the reaction of 5 with PhSSPh (30 mM) was fit to this
model using the reaction fitting and data simulation
54
software COPASI. The time course data are shown in
Figure 9 and the black trace shown is obtained from
fitting the experimental data to the model described
1
PhSSPh by H NMR spectroscopy at two different
initial concentrations of PhSSPh to help distinguish
between these two possible pathways (Figure 9).
Under these conditions, there is a clear dependence of
the initial lag phase on [PhSSPh] indicating a key role
0
for disulfide in the initial reaction of complex 5.
above. This fit provides rate constants of k
1
=0.0010 ±ꢀ
0.00045, k = 6.20 ± 0.63. This same model and rate
3
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
constants were then used to predict the time course for
the reaction of 5 with PhSSPh (60 mM, blue trace).
Both data sets are well described by the same model. It
is worth noting that this and all stoichiometric reac-
tions of 5 feature increased scatter in the data at later
reactions times, likely due to competing side reactions
and decomposition pathways, for example biaryl for-
mation (Figures S18 and S19).
O
2
N
O
O
N
N
N
N
O
Step 1
Cu
O
Cu
+ 1/2 PhSSPh
+
1
k
1
O
O
O N
2
2
5
O
2
N
Ph
O
N
N
N
N
N
S
Step 2
Cu
O
+
PhSSPh
1/2
Cu
Cu
+ 1
k
2
S
N
2
O N
Ph
2
3
O
2
N
O
O
N
N
N
O
O
Step 3
Cu
O
O
Cu
+ 1/2 PhSSPh
+
1
catalytic 3
N
k
3
2
N
Figure 9. Comparison of reaction profiles for the reaction of
O
5
2
O
2
N
(
phen)Cu(O
2
CC
6
H
4
-o-NO
2
)
2
(5) (30 mM) with PhSSPh at 30
at 140 °C. Product concen-
mM (˜) and 60 mM () under N
trations were determined by quantitative H NMR analysis.
2
Scheme 8. Proposed Pathway for the Reaction of 5
with PhSSPh under N2.
1
Loss of Induction Period with Complex 3. The time
course profiles for the stoichiometric reactions of
complex 5 all feature a distinctive sigmoidal shape.
Sigmoidal time course traces characterized by this type
of three-phase kinetic profile, i.e. a lag, exponential
and saturation phase, are common under conditions of
autocatalysis, in which a reaction product catalyzes its
To directly probe the possible catalysis by 3, the
inclusion of a small amount of 3 (0.05 or 0.1 equiv) at
the beginning of the reaction of 5 with PhSSPh led to
the disappearance of the induction period (Figure 10).
Variable time normalization analysis (VTNA) of these
time course data with the graphical evaluation method
55
developed by Burés and coworkers (Figure S20b) in-
5
2,53
own formation.
Because the stoichiometric reaction
dicates a 0.5 order dependence on [3], indicative of
dissociation of this dimeric complex to access the reac-
tive monomeric form, (phen)Cu(SPh).
of complex 5 with PhSSPh generates the copper(I)-
thiolate complex 3, we suspected that complex 3 may
catalyze the conversion of 5 to product 1 with the
concomitant formation of complex 2 (Scheme 9). The
resulting copper(I)-carboxylate
2
also generates
product 1 upon reaction with PhSSPh as shown in
Scheme 3 above, leading to the three step sequence
shown in Scheme 8. In this sequence, Steps 1 and 3 are
identical, with the exception that Step 3 is catalyzed by
complex 3.
9
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ACS Catalysis
complex (phen)Cu (O
Page 10 of 17
6 4 2
CC H -o-NO )(SPh) (Scheme 9,
II
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Step 1). This intermediate could react productively
with PhSSPh to form product 1 and regenerate
complex 3 (Scheme 9, Step 2). Thus, the overall
reaction would be the formation of product 1 and
complex 2 from 5 and PhSSPh, catalyzed by complex 3
as shown in Scheme 8 (Step 3).
2
O N
O
O
SPh
O
O
Step 1
CuII
n
+
1/2
L
n
CuI SPh
L
n
CuII
+
LnCuI
O
O
L
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
2
O
O
5
3
2
2
N
O
O
S
2
N
2
O N
SPh
O
CuII
L
n
Step 2
+
1/2 PhSSPh
+
1/2
L
n
CuI SPh
2
O
2
N
O
1
3
2
O N
a
n
L = 1,10-phenanthroline
Figure 10. Comparison of the reaction profiles for the reac-
tion of (phen)Cu(O CC -o-NO (5) (30 mM) with PhSSPh
60 mM) under N at 140 °C with ( ) and without (˜) com-
Scheme 9. Proposed Pathway for the Reaction of 5
2
6
H
4
2 2
)
a
(
2

with PhSSPh catalyzed by 3.
plex 3 (3 mM). Product concentrations were determined by
1
To explore the possible ligand exchange between
complexes 3 and 5, we conducted the stoichiometric
reaction of these two species under N at 140 °C. Under
2
these conditions, both product 1 and the 2,2'-
dinitrobiphenyl byproduct were formed in 35% and
26% yields respectively. When the same reaction was
quantitative H NMR analysis.
These time course data can also be fit using the same
three-step model shown in Scheme 8, with the
inclusion of a fourth step to describe the dissociation
of 3 (Scheme S3). This fit is shown in Figure 10 and
provides a rate constant for dissociation of k
4
= 2.64 ±
2
performed under an O atmosphere, 1 was formed in
0.48.
75% with no 2,2'-dinitrobiphenyl detected. The for-
mation of 1 from complexes 3 and 5 indicate facile lig-
and exchange under these conditions and support a
ligand exchange step en route to product formation in
the stoichiometric reactions of 5.
There are several examples of copper-catalyzed
reactions that exhibit autocatalytic behavior such as
5
6
57,58
52,59
polymerization, coupling
and cycloaddition
5
7
II
I
reactions. Lei et al. elegantly described Cu -Cu
cooperativity in the homocoupling of terminal alkynes
From the data described above, it is apparent that
copper(II)-carboxylates can generate product
through a pathway that involves initial reduction to
copper(I). More broadly, under our reaction conditions
decarboxylation occurs from a Cu species, and product
formation occurs from subsequent reaction of the
resulting Cu -(aryl) with PhSSPh as shown above. Cu -
carboxylate) species are not the catalytically relevant
species but can access the same pathway either via
decarboxylation (Scheme 7) or by ligand exchange in
the presence of 3 (Scheme 9).
II
with Cu . Biphenylacetylene, generated in situ, medi-
1
ates the reduction of CuCl (TMEDA) with an
2
accompanying induction period and autoacceleration
I
I
curve. Cu was confirmed as an autocatalyst, serving to
reduce the induction period and enhance the reaction
rate. Hartwig and coworkers have described the auto-
I
II
I
catalytic behavior of in situ generated Cu in the reac-
(
I
tion of well-defined Cu -amido complexes with io-
5
8
52
doarenes. Finally, Whitesides et al. have reported on
the autocatalytic behavior of the triazolyl product in
the copper-catalyzed azide-alkyne cycloaddition
Aerobic Oxidation of Copper(I)-Thiolate. Owing to
the formation of [(phen)Cu(µ-SC H )] (3) in the
6 5 2
(CuAAC) reaction between tripropargylamine and 2-
azidoethanol. In this example, the initial reduction of
II
I
stoichiometric reactions of complexes 2, 4, and 5 with
PhSSPh under nitrogen, we decided to explore the
reactivity of independently prepared 3 under catalytic
conditions. For the reaction of 2-nitrobenzoic acid and
PhSH with 3 as catalyst, in a sealed Schlenk tube
Cu to catalytically active Cu is attributed to the
terminal alkyne serving as a reducing agent, another
well-accepted reactivity pattern throughout the
5
2,60
literature.
We imagined that under our conditions, the catalysis
by 3 (Scheme 8, Step 3) could occur by ligand exchange
between complexes 3 and 5 to form the heteroleptic
equipped with an O
2
balloon, 1 was obtained in 88%
yield, demonstrating the catalytic competence of 3.
1
0
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1
ACS Catalysis
We considered two likely pathways for the turnover headspace at room temperature, by
1
H
NMR
of complex 3. First, we considered ligand exchange of
with benzoic acid or potassium 2-nitrobenzoate to
generate complex 2 directly (Scheme 10, Pathway A).
Alternatively, we considered a pathway in which O is
spectroscopy. Complex 3 was observed to gradually
generate PhSSPh in 71% conversion at room
temperature after 2 h (Scheme 12 and Figure S5). No
diamagnetic copper species were observed, indicating
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
2
I
required to facilitate the turnover of 3 (Scheme 10,
Pathway B).
the oxidation of Cu . Similarly, the color change from a
deep-brown to a final green color accompanies this
oxidation, consistent with the formation of a new
Pathway A
oxidized copper(II) species, Cuox
.
O
N
N
O
N
N
Ph
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
Cu SPh + HO
O N
Cu O
O N
N
N
N
N
+
+
PhSH
S
DMSO-d
6
PhSSPh + Cuox
2
Cu
Cu
2
rt, O2
1
/2 3
2
S
Pathway B
Ph
3
O
O
N
N
HO
O2
Scheme 12. Aerobic oxidation of [(phen)Cu(µ-
SC )] (3) in DMSO-d
Cu SPh +
Cu O
1/2 PhSSPh
N
N
O N
2
O N
6
H
5
2
6
2
1
/2 3
2
6 5 2
This aerobic oxidation of [(phen)Cu(µ-SC H )] (3) at
140 °C was also monitored by UV-visible spectroscopy.
Scheme 10. Possible pathways for the turnover of 3
In pathway A, complex 3 would be expected to form
product upon treatment with 2-nitrobenzoic acid un-
Complex 3 has characteristic bands at approximately
I
441 nm attributed to a (phen)Cu species and a
der N2. In addition, the sole role of O
2
in this manifold
shoulder at ~538 nm. A solution of 3 in DMSO was
prepared in a septum-sealed cuvette equipped with a
would be to generate PhSSPh from PhSH, and catalytic
turnover with PhSSPh would be expected to be effi-
cient under anaerobic conditions. Such a pathway was
ruled out based on a series of control experiments. The
stoichiometric reaction of 3 and 2-nitrobenzoic acid
stir bar, in a N
glovebox, an initial spectrum was taken after which an
balloon was inserted via the septum. The solution
2
filled glovebox. On removal from the
O
2
was heated with stirring at 140 °C in an aluminum
I
was conducted under both N
the presence of O , the sulfane product 1 is formed in
2% yield, while under N only 15% is obtained
Scheme 11). In addition, when the standard catalytic
reaction of 2-nitrobenzoic acid and PhSSPh was con-
ducted under only 15% yield of (2-
nitrophenyl)(phenyl)sulfane (1) was obtained, indicat-
ing an additional role for O in catalysis. These results
2
and O
2
atmospheres. In
block and the oxidation of Cu was followed by
monitoring the loss of the intense band shifted to ~429
nm upon heating. The appearance of a new band of
2
9
2
(
weak intensity between 711-722 nm attributed to
II
(phen)
2
Cu was also observed (Figure 11). An estimate
N
2
,
a
of the rate of oxidation for an initial concentration of
-
1
6 5 2
[(phen)Cu(µ-SC H )] = 0.17 mM was 0.23 mM h .
2
Thus, we envisioned that under catalytic conditions,
the aerobic oxidation of in situ generated 3 to liberate
PhSSPh and catalytically relevant oxidized copper
species, Cuox, is a key step in the process. The resulting
Cuox regenerates 2 in the presence of carboxylate, as a
path for re-entry into the cycle. We therefore explored
the reactivity of in situ generated Cuox in a series of
NMR tube experiments. When a solution of 3 in
are consistent with the quantitative formation of 3 in
all stoichiometric reactions conducted under nitrogen,
but it’s absence under aerobic conditions (vide supra).
We suspected that this species may be inert to turno-
ver in the absence of O
2
2
and thus requires O for catal-
ysis. These data indicate a clear role for O
2
in the acti-
vation of the copper(I)-thiolate dimer 3 as an entryway
into catalysis, and are consistent with pathway B.
DMSO-d
with O for several minutes and the resulting solution
subsequently treated with 2-nitrobenzoic acid (3
6
in a septum-sealed NMR tube was bubbled
2
Ph
O
N
N
S
N
N
S
N
°
DMSO, K
140 °C, 24 h
or O
2
CO
3
equiv) in the presence of K
2 3
CO with heating at 140 C,
Cu
Cu
+ HO
O
S
(2-nitrophenyl)(phenyl)sulfane (1) was observed in
2
N
Ph
3
N
2
2
O
2
6
1,62
98% yield, after 4 h.
These results are indicative of
O
2
atmosphere: 1, 92%
atmosphere: 1, 15%
N
2
the chemical competence of the Cuox species resulting
from the aerobic oxidation of 3.
Scheme 11. Stoichiometric Reaction of Complex 3
with 2-Nitrobenzoic Acid
2
The importance of O for product formation has been
observed in related aerobic Cu-catalyzed thiolation
reactions. Some of the more commonly proposed roles
We therefore investigated the interaction of 3 with O
by monitoring a solution of 3 in DMSO-d under an O
2
2
of O in these reactions include facilitating the
6
2
1
1
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conversion of thiol to disulfide, promoting the
Page 12 of 17
catalysts for the reaction of 2-nitrobenzoic acid with
PhSH, and the observed generation of
(phen)Cu(O CC -o-NO ) (2) under N from reaction
components strongly supports the intermediacy of this
species under reaction conditions. Additionally, the
spectroscopic data indicate a copper(I) resting state
and the measured reaction orders exclude a turn-over-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
formation of organocopper thiolates, mediating H-
atom abstraction in C-H substrates, oxidation of Cu(I)-
thiolates, suppressing undesired side reactions and
2
6
H
4
2
2
facilitating the regeneration of catalytically active
23,31,35
species.
Based on our findings, however, in
addition to facilitating the generation of RSSR from
RSH, a key role of O in this system is to enable
2
2
limiting step that is oxidation by O or reaction with
catalytic turnover via oxidative dissociation of an
otherwise tightly bound thiolate ligand in
PhSSPh. Instead, decarboxylation of a copper(I)-
carboxylate is the most likely turn-over-limiting step of
this reaction.
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
[
(phen)Cu(µ-SC
6
H
5
)]
2
(3). This observation is
consistent with findings of related aerobic copper-
catalyzed thiolation reactions wherein dramatically
Mechanistic studies of copper-mediated redox-neutral
decarboxylation reactions have shown these reactions
reduced yields are observed in the absence of O
thereby validating the importance of O in generating
relevant competent species including catalytically
2
to
proceed
through
a
pathway
involving
2
decarboxylation of a copper(I)-carboxylate. Under
oxidative conditions, however, we expected that
1
1a,25-27
active Cu species.
decarboxylation
from
a
copper(II)-carboxylate
intermediate may be plausible. Instead, our data
indicate two pathways for the possible reduction of a
copper(II)-carboxylate species to copper(I). In the
absence of disulfide,
a decarboxylative pathway
enables reduction of copper with concomitant
formation of the biaryl, while in the presence of
disulfide, decarboxylative coupling forms
1 and
copper(I). This pathway is evidenced by the dramatic
difference in reaction profiles of the stoichiometric
reactions of well-defined copper(I) and copper(II) car-
boxylate complexes. In particular, the reaction of cop-
per(II) features an induction period and sigmoidal
kinetics. This reaction behavior arises from the slow
initial reaction of
5
with PhSSPh, suggesting
decarboxylation from a copper(I)-carboxylate to be
operative under catalytic conditions.
2
O is essential for efficient product formation owing to
the poor yields of the diarylsulfide (1) obtained in its
absence. Although the oxidation of copper(I) species
has been observed to be turn-over-limiting in a
63-
number of other copper-catalyzed aerobic reactions,
65
we believe that under our conditions the oxidation
step is required in order to release a tightly bound
thiolate ligand from 3, regenerating the active catalyst
2
in the presence of 2-nitrobenzoic acid and base. This
was evidenced by the generation of PhSSPh upon the
exposure of a solution of [(phen)Cu(µ-SC )] (3) in
DMSO to O . The resultant in situ generated Cuox
species was also chemically competent in producing
2-nitrophenyl)(phenyl)sulfane (1).
Figure 11. UV–visible spectra for the aerobic oxidation of
o
[
(phen)Cu(µ-SC
tions: [(phen)Cu(µ-SC
balloon, 140 °C.
6
H
5
)]
2
(3) in DMSO at 140 C. Reaction condi-
6
H
5
2
6
H
5
)] (3) (0.2 mM), DMSO (2.5 mL),
2
2
O
2
(
Mechanistic Model. The above results reveal some
key features of the mechanism of this aerobic copper
catalyzed decarboxylative thiolation of benzoic acids.
First, the rapid conversion of PhSH to PhSSPh under
reaction conditions and the demonstrated chemical
and kinetic competence of PhSSPh suggest PhSSPh is
the active thiolating source. Secondly, all of the copper
complexes synthesized in this study are competent
Inhibition of copper catalysis by a sulfur-based ligand
has been observed in other systems, via the formation
of the thermodynamically stable Cu-SR bond.
1
2
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ACS Catalysis
CuI + phen
1
2
3
4
5
6
7
8
9
O
HO
O
+
2 3
K CO
2
N
O
N
N
O
Cu
O
HO
O
2
O N
2
N
2
CO
2
+
K
2
CO
3
Cuox
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
/2 PhSSPh
N
Cu
N
O
2
2
O N
4
Ph
Cu/O
2
PhSSPh
2 PhSH
N
N
N
N
N
S
Cu Cu
S
1
/2
Cu SPh
N
Ph
N
3
NO2
Cu SPh
S
N
N
SPh
O
2
1
Scheme 13. Proposed mechanism of the aerobic Cu-catalyzed oxidative decarboxylative thiolation of benzoic
acids.
66,67
Liebeskind and coworkers
have introduced a
was found to be the active thiolating source under
reaction conditions. Spectroscopic and kinetic studies
suggest catalytically-relevant discrete (phen)Cu
complexes are chemically and kinetically competent in
mediating product formation supporting their
intermediacy. UV-visible studies strongly support a Cu
resting state. These findings provide valuable insight
into key mechanistic steps for a phenanthroline-ligated
Cu catalyst system involved in the aerobic copper
catalyzed C-S coupling reactions. The findings may
have implications for related aerobic Cu-mediated C-
heteroatom bond formation reactions.
chelation-based dissociation strategy to re-activate the
Cu catalyst in their C-C coupling reactions. The gener-
ation of an active Cu-oxygenate species from Cu-SR
under aerobic conditions was believed be a significant
step in providing catalytic Cu for turnover. We believe
that related oxidative dissociation pathways may be
I
I
operative in
a variety of Cu-catalyzed aerobic
2
5
I
thiolation reactions.
Based on our findings we propose a reaction pathway
(Scheme 13), that involves the generation and
subsequent decarboxylation of 2 to form 4. This
decarboxylation precedes oxidative addition of the
PhSSPh to the Cu -(aryl) 4, to generate a highly
reactive organocopper(III)-dithiolate species that is
well-poised for rapid reductive elimination to generate
6
a,6c
I
AUTHOR INFORMATION
Corresponding Author
*
E-mail: Jessica.Hoover@mail.wvu.edu
the diaryl sulfide product 1 and [(phen)Cu(µ-SC
(3). This latter step is supported by literature
6 5 2
H )]
ASSOCIATED CONTENT
Supporting Information.
precedent
involving
well-defined
and
macrocyclic
sulfur-based
organocopper(III)
species
3
0
nucleophiles. The oxidative dissociation of 3 with O
liberates PhSSPh and Cuox which regenerates 2 in the
presence of 2-nitrobenzoic acid and K CO .
2 3
2
The Supporting Information is available free of charge
Experimental procedures, kinetic data, spectral
data (PDF)
CONCLUSIONS
In summary, this work describes an experimental
mechanistic study of the aerobic copper-catalyzed
decarboxylative thiolation of benzoic acids. PhSSPh
ACKNOWLEDEGMENTS
We are grateful to the NSF (CHE-1454879) and West
Virginia University for financial support of this work.
1
3
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Page 14 of 17
Lichte, D.; Gooßen, L. J. Decarboxylative Ipso Amination of Acti-
vated Benzoic Acids. Angew. Chem. Int. Ed. 2019, 58, 892-896.
NMR spectroscopy facilities were partially supported
by the NSF (CHE-1228336). We thank Donna Black-
mond for helpful discussions of reaction kinetics.
1
2
3
4
5
6
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9
1
1
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1
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6
(7) (a) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Decarboxyla-
3
tive sp C–N Coupling via Dual Copper and Photoredox Cataly-
sis. Nature. 2018, 559, 83-88. (b) Liu, Z.-J.; Lu, X.; Wang, G.; Li,
L.; Jiang, W.-T.; Wang, Y.-D.; Xiao, B.; Fu, Y. Directing Group in
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SYNOPSIS TOC
ACS Catalysis
1
2
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
I
, O
2
S
N
N
N
O
SH
+
(phen)Cu
-CO
CuI
O
HO
O
2
O
2
O2N
2
N
active
intermediate
O
N
N
N
N
O2N
Cu
I
O
Cu
I
SPh
O
PhSSPh
N
N
O
O
2
N
CuII
O
N
O
active copper(I)
inert without O
2
Cu
I
O2N
N
activated by
reduction to copper(I)
O
2
N
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
1
7
ACS Paragon Plus Environment