A CuI/CuIII prototypical organometallic mechanism for the deactivation of an active pincer-like CuI catalyst in Ullmann-type couplings

Article abstract of DOI:10.1039/c7cc04491g

Unraveling the mechanistic details of copper-catalyzed arylation of nucleophiles (Ullmann-type couplings) is a very challenging task. It is a matter of intense debate whether it is a radical-based process or an organometallic redox-based process. The ancillary ligand choice in Ullmann-type couplings plays a key role in such transformations and can strongly influence the catalytic efficiency as well as the mechanism. Here, we show how a predesigned tridentate pincer-like catalyst undergoes a deactivation pathway through a Cu^I/Cu^III prototypical mechanism as demonstrated by helium-tagging infrared photodissociation (IRPD) spectroscopy and DFT studies, lending a strong support to the existence of an aryl-Cu^III species in the Ullmann couplings using this tridentate ligand.

Full text of DOI:10.1039/c7cc04491g

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Ribas, Chem. Commun., 2017, DOI: 10.1039/C7CC04491G.
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CuI/CuIII prototypical organometallic mechanism for the
deactivation of an active pincer-like CuI catalyst in Ullmann-
type couplings
Received 00th January 20xx,
Accepted 00th January 20xx
Mireia Rovira,a Lucie Jašíková,b Erik Andris,b Ferran AcuñaꢀParés,a Marta Soler,a Imma Güell,a
DOI: 10.1039/x0xx00000x
MingꢀZheng Wang,a Laura Gómez,a,c Josep M. Luis,a Jana Roithováb,* and Xavi Ribasa,*
www.rsc.org/
Unraveling the mechanistic details of copper-catalyzed arylation discussion in the literature concerning the mechanistic pathway
of nucleophiles (Ullmann-type couplings) is a very challenging for Ullmann condensation reactions. The most invoked
task. It is a matter of intense debate whether it is a radical-based mechanisms for Ullmann couplings are based on either oneꢀ
or an organometallic redox-based process. The ancillary ligand electron redox processes through radical intermediates that may
choice in Ullmann-type couplings plays a key role in such operate via a CuI/CuII catalytic cycle, or twoꢀelectron redox
transformations and can strongly influence the catalytic processes via
efficiency as well as the mechanism. Here, we show how a Recently, Peters, Fu and coꢀworkers reported
predesigned tridentate pincer-like catalyst undergoes photoluminescent Cu–carbazolide complex bearing
deactivation pathway through
CuI/CuIII prototypical monophosphine ligands for promoting the photoinduced C–N
a
CuI/CuIII catalytic cycle (Scheme 1b).5
a
a
a
mechanism as demonstrated by helium-tagging infrared bond forming reaction.13ꢀ15 Upon photoexcitation of the Cu–
photodissociation (IRPD) spectroscopy and DFT studies, lending carbazolide complex, a Cuꢀcontaining radical is formed, as
a strong support for the existence of an aryl-CuIII species in the detected by EPR spectroscopy. This radical intermediate reacts
Ullmann couplings using this tridentate ligand.
with aryl halides via Single Electron Transfer (SET) to afford
the corresponding C–N coupling product. Therefore, it is likely
that several mechanisms might be possible simultaneously and
the experimental conditions used are crucial to determine the
operative one.
Modern Cuꢀcatalyzed crossꢀcoupling reactions have recently
evolved into reliable and efficient methods for the formation of
CꢀC and Cꢀheteroatom bonds which are present in a large
number of natural and pharmaceutical products.1ꢀ3 Unravelling
the mechanistic details of copperꢀcatalyzed arylation of
nucleophiles (Ullmannꢀtype couplings, Scheme 1a) is a very
challenging task and a matter of intense debate in order to
clarify which of the two main mechanistic proposals is taking
place: a radicalꢀbased or an organometallicꢀbased process.4, 5
Since late 1990s, much effort has been devoted to the use of
chelating ligands, such as diamines, triamines, amino acids,
Cu (cat.)
a)
X
Nu
Auxiliary ligand
T: 25 -150 ˚C
R
+
NuH
R
NuH: Amides, Amines, Alcohols, Thiols
X: I, Br, Cl
b)
Non-Radical intermediates
Nu
Oxidative addition
L
CuIII
X
Reductive elimination
2e- redox process
CuI/CuIII
H-Nu
Base
Ph-X
LCuI-Nu
LCuI-X
Ph-Nu
Radical intermediates
phenanthroline derivatives and
βꢀdiketones, to perform
Single Electron
Transfer
coupling reactions under milder conditions while achieving
enhanced yields.3, 6, 7 The detection of intermediate species after
the activation of the aryl halide, which is usually rateꢀlimiting,
is very limited and most mechanistic proposals are derived
from kinetic and computational studies.8ꢀ12 There is an ongoing
X
(SET)
LCuII-Nu
1e- redox process
CuI/CuII
Scheme 1. a) Copperꢀcatalyzed Ullmannꢀtype CꢀHeteroatom
couplings and b) the two main mechanistic proposals.
Focusing our attention on the design of proper auxiliary ligands
for Ullmann couplings under standard thermal conditions, we
have previously demonstrated that a CuI/CuIII catalytic cycle is
operative in model macrocyclic aryl halide substrates, where
active arylꢀCuIIIꢀX species have been completely characterized
16, 17
within these systems.5,
Finding inspiration in the
macrocyclic model systems, in this work we specifically design
auxiliary ligand L3 (Figure 1) to reproduce the equivalent
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geometry of the Cu center, so that the stabilization of arylꢀCuIII was further confirmed by measuring the IRPD spectrum of an
might become possible (Figure 1).
authentic sample of [(L3ꢀC6H5)ꢀCuI]+ (complexation of the
independently synthesized ligand L3ꢀC6H5 and CuI). This
spectrum is identical with the IRPD spectrum of the ions found
in the reaction mixture for the Ullmann coupling of
iodobenzene with pꢀmethoxyphenol using the copper catalyst
with L3 (Figure 3).
+
N
N
X
H N
HN H
X
H N
III N H
Cu
via CuIII
intermediate
species
Model Substrate
CuI (10 mol%), L3 (10 mol%)
O
+
I
HO
K3PO4 (2 equiv.)
+
50 ˚C, N2, 0.5 h, DMSO
O
?
N
CuIII
O
X
N
H N
N H
NH
HN
L3
Tridentate Auxiliary Ligand
Figure 1. Design of the auxiliary ligand L3 used in this work.
In order to gain insight into the plausible operative
mechanisms, we initially undertook a ColdꢀSpray18 MS study
using L3 as auxiliary ligand for the CꢀO Ullmannꢀtype coupling
of iodobenzene and pꢀmethoxyphenol (2) as a model reaction
(standard 24h reaction afforded a 45% yield of the diarylether
product).19 Notably, an intense peak at m/z = 304.0877 was
detected in positive ESI mode after 0.5 hour (see Supporting
Information for the details of the procedure). At first sight, this
peak could correspond to a putative CuIII intermediate species
involved in the reaction ([L3’ꢀCuIIIꢀ(C6H5)]+), L3’ being the
monodeprotonated version of L3 (Figure S1). We found the
same analogous peak when using either bromobenzene (m/z =
304.0877), 1ꢀiodoꢀ4ꢀmethylbenzene (m/z = 318.1008) and 1ꢀ
iodoꢀ3,5ꢀdimethylbenzene (332.1167) (Figures S2ꢀS4).
Additionally, when submitting geometrically similar tridentate
ligands (L4 (2,6ꢀpyridinediyldimethanamine) and L5 (N,N’ꢀ
diethylꢀ2,6ꢀbis(aminomethylpyridine)), the peaks analogous to
304.0877 were also observed at m/z = 276.0540 and 332.1144,
respectively (Figure S5ꢀS6).
Figure 2. Experimental HeꢀIRPD spectrum of ions with m/z
332 isolated from the crude reaction mixture after 0.5 h (a),
compared to the theoretical IR spectra (B3LYPꢀD3/6ꢀ
31G**(Cu:6ꢀ311G*), scaling factor: 0.98) of other plausible
species involved in the reaction (b, c, d).
In an effort to validate whether this peak was a possible interꢀ
mediate in the reaction mechanism, we extensively investigated
the crude reaction mixture after 0.5 hour by characterizing the
massꢀselected ions at m/z = 332.1167 formed when using L3
and 1ꢀiodoꢀ3,5ꢀdimethylbenzene (Figure S4 in the SI) by
When [(L3ꢀC6H5)ꢀCuI]+ was identified in the reaction mixture,
we immediately considered the possibility that it could be the
actual catalyst of the CꢀO coupling. However, this was
discarded based on our experimental findings. The use of the
independently synthesized [(L3ꢀC6H5)ꢀCuI]+ complex as catalyst
heliumꢀtagging
infrared
photodissociation
(IRPD)
spectroscopy.20ꢀ22 IRPD spectroscopy provides well resolved
infrared spectra of massꢀselected ions.23 The experimental
IRPD spectrum of the ions with m/z 332 and the theoretical
spectra of possible complexes corresponding to the same mass
are shown in Figure 2. We assumed that the detected ions could
correspond to the proposed ([L3’ꢀCuIIIꢀ(C6H2Me2)]+)
intermediate. The theoretical spectrum of this copper(III)
complex, however, does not contain any band that could be
attributed to the experimental peak at 1070 cmꢀ1 (highlighted by
the red line in Figure 2). The search for alternative structures
resulted in finding a more stable isomer, in which the phenyl
group migrated to the nitrogen atom forming a complex of
copper(I) with Nꢀphenylated ligand [(L3ꢀC6H3Me2)ꢀCuI]+
(Figure 2c). The peculiar band at 1070 cmꢀ1 can be assigned to
the NꢀC(aromatic) stretching band of this complex. This result
(10 mol%) for the arylation of
2 afforded 16% yield of the
biaryl ether product, compared to 45% yield when using [L3
ꢀ
CuI]+ under the same catalytic conditions (Figure S20). Similar
drop in yield was found for the arylation of benzamide (from
75% down to 29%) and cyclohexylamine (from 21% down to
0%).
In light of these results, we propose that CuI/CuIII cycle may be
the main operative mechanism of this coupling reaction, the
detected species being the intramolecular reductive elimination
product ([(L3ꢀC6H5)ꢀCuI]+) of the putative [L3’ꢀCuIIIꢀ(C6H5)]+
species, i.e. a decomposition product of the active catalyst. This
nonꢀradical mechanism may involve the formation of the [L3
ꢀ
2 | J. Name., 2012, 00, 1-3
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CuI]+ active species followed by a lowꢀbarrier aryl iodide competing arylꢀN coupling leading to the catalyst
oxidative addition and deprotonation of one of the secondary decomposition proceeds via a higher energy barrier (11.7
amines to produce [L3’ꢀCuIIIꢀ(aryl)]I. At this reaction crossroad, kcal·molꢀ1; Figure 4b). The presence of phenolate makes the
axial ligand exchange by the nucleophile may trigger reductive arylꢀN coupling less favourable, because it turns the nitrogen
elimination to afford the diaryl ether coupling product, or deprotonation, i.e. the step preceding the CꢀN coupling, from an
destabilization of the CuIII complex can induce intramolecular exergonic to an endergonic process (ꢀ2.3 kcal·molꢀ1 for the
D
reductive elimination, yielding the CuI amineꢀarylation byꢀ
product detected by MS.
→
E
transformation in the absence of phenolate vs. 5.0
kcal·molꢀ1 for the
transformation when phenolate is
present; compare Figure 4a and 4b). After the amine
deprotonation, first undergoes the required conformational
change of the aryl ligand that has a free energy cost of 6.7
kcal·molꢀ1
M). Finally, the very reactive intermediate
proceeds to the detected species through barrierless reductive
elimination transition state ( ). Mechanistic insights on the
H
→ K
CuI (10 mol %), L3 (10 mol %)
O
I
HO
K
K3PO4 (2 equiv.)
+
50 ˚C, N2, 0.5 h, DMSO
O
O
(
M
O
N
selectivity between CꢀO and CꢀN couplings in Ullmann
catalysis have been documented.24ꢀ26
a)
+ I-
N
+ I-
CuI/III N
N
H
H
N
I
N
N
CuI
N
H
H
I
H
N
N
CuIII/I
7.4
C
+ I-
I
5.8
I
N
B
3.5
N
N
CuIII
DMSO
H
H
F
0.0
PhI
A
+ I-
Figure 3. Experimental HeꢀIRPD spectrum of a) the isolated peak
m/z 304 from the crude reaction mixture after 0.5 h, compared to the
experimental IRPD spectrum of b) an authentic sample of [(L3ꢀ
C6H5)ꢀCuI].
D
-4.7
K3PO4
K2HPO4 + KI
N
N
H
N
N
N
CuI
N
CuI
-7.0
E
H
H
O
S
I
I
N
-37.7
N
N
CuIII
DFT calculations were performed to unravel the mechanism of
the formation of [(L3ꢀC6H5)ꢀCuI]+ complex (Figure 4a). The
H
G
b)
grouping of the aryl iodide adduct (
η2 fashion to the copper center (d(CuꢀCipso) = 1.999 Å and
d(CuꢀCortho) = 2.045 Å, is endergonic (
G = 5.8 kcal·molꢀ1).
However, the adduct easily undergoes oxidative addition to
species [L3ꢀCuIIIꢀ(C6H5)]+
D) through the transition state
which is only 1.6 kcal·molꢀ1 higher in energy than G# =
(i.e.
7.4 kcal·molꢀ1). Removal of
iodine anion and NH
deprotonation of
affords [L3’ꢀCuIIIꢀ(C6H5)]+ intermediate (E)
Finally,
proceeds to the detected species [(L3ꢀC6H5)ꢀCuI]+
) through reductive elimination transition state with a
barrier of 10.5 kcal·molꢀ1. Transition state
involves a
B), which is coordinated in
H3CO
Ph
O
N
N
+ I-
N
H
N
CuIII
H
N
ꢀ
N
CuIII/I
N
CuI/III
N
N
O
B
H
Ph
H
OCH3
Ph
H3CO
O
OCH3
(
C,
O
Ph
N
11.7
M
11.1
L
10.4
N
N
CuIII
H
N
B
ꢀ
8.6
I
a
5.0
KI + K2HPO4
K
D
.
+ I-
0.0
E
C-O bond
C-N bond
K3PO4
+ I-
H
N
(
G
F
N
H
N
CuI
OCH3
Ph
H
O
F
Ph
O
N
OCH3
N
conformational change of the aryl ligand to achieve a proper
geometrical orientation that favours the arylꢀN coupling.
Precedents of arylation of amines are known using wellꢀdefined
macrocyclic arylꢀCuIII model systems5 and standard Ullmann
systems.19 DFT calculations predict that the geometry adopted
by the copper centre significantly varies depending on the
oxidation state of the metal (Figures S18 and S19). Further
experimental substantiation of this structural variability is
H
N
N
CuIII
N
CuI
N
H
-23.6
J
H
O
-31.7
O
H3CO
Ph
Figure 4. a) DFT (B3LYP/ccꢀpVTZ,I:SDD+d+f) free energy
profile (
in kcal·molꢀ1) for the reaction of [L3ꢀCuI(DMSO)]I
(species A) with PhI in the presence of K3PO4 as external base
in DMSO solvent (SMD model). The K3PO4, K2HPO4, KI, PhI
and DMSO molecules are included in the calculation to ensure
ꢀ
G
provided by the crystal structures of the tetrahedral the correct energetic balance in all the reaction steps. b) Free
[(L3)CuI(Br)]n and squareꢀpyramidal (tetragonally distorted)
energy profile for the competing arylꢀO coupling towards
product formation and the arylꢀN coupling towards catalyst
deactivation. Hydrogen atoms in the inserted figures are
omitted for clarity, except the NH moieties (N atoms in blue, I
atoms in violet; see SI for full description of the computational
details).
[(L3)CuII(OTf)2](OTf) complexes shown in Figures S18ꢀS19.
In the presence of
pꢀmethoxyphenolate, theoretical
calculations predict a favourable arylꢀO coupling to form the
biaryl ether product (free energy barrier of 8.6 kcal·molꢀ1). The
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Therefore, a CuI/CuIII mechanism underlying the coupling
reaction of iodobenzene and phenols derivatives stems from the
above experimental and theoretical data; further proof was
achieved by conducting the coupling experiment using the
radical clock 1ꢀallyloxyꢀ2ꢀiodobenzene (rc) as substrate and
Notes and references
‡ CCDC 1054559 (
CCDC 1054556 ([
L
L
3·2HCl), CCDC 1054555 ([(
L
3)CuI(Br)]n) and
3-CuII(OTf)2]) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
p
MeOꢀphenol (
2
), benzamide (
3
) and cyclohexamine (
4
) as
27, 28
nucleophiles (see Scheme 3).13,
The formation of the
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ꢀ
4
H
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O
O
H
CuI (10 mol %), L3 (10 mol %)
I
HO
K3PO4 (2 equiv.)
O
O
O
O
2
+
+
+
O
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rc-H
2
rc-cyc-2
32% (46%)
14% (46%)
0% (46%)
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HN
H
O
H2N
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I
K3PO4 (2 equiv.)
O
O
O
NH
+
+
2
+
O
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rc-3
rc-H
rc-cyc-3
rc
3
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60% (71%)
0% (71%)
0% (71%)
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O
H
O
CuI (10 mol %), L3 (10 mol %)
NH2
I
CsF (2 equiv.)
HN
O
+
+
O
2
+
90 ˚C, N2, 24 h, DMSO
rc-4
rc-H
rc-cyc-4
4
rc
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25% (42%)
0% (42%)
14% (42%)
Scheme 3. Selected coupling reactions using radical clock rc as
substrate (conversion in parenthesis).
In conclusion, the efficient auxiliary ligand L3 in CꢀO Ullmannꢀ
type couplings undergoes a decomposition pathway following a
CuI/CuIII mechanism via intramolecular arylation of one of the
secondary amines of the complex. The helium tagging IRPD
studies and DFT mechanistic studies, along with the absence of
cyclized products using rc radical clock and the observation of
protodecupration products, strongly support the existence of
arylꢀCuIII species in the Ullmann couplings using this specially
designed tridentate L3 ligand. Decomposition insight gained
from this model system has turned out to be valuable in catalyst
and process design work, shedding light into the complex
chemistry of Ullmann couplings.
This work was financially supported by grants from the
European Research Council (Starting Grant Project ERCꢀ2011ꢀ
StGꢀ277801 and CoG IsoMS), the Spanish MICINN
(CTQ2016ꢀ77989ꢀP, CTQ2014ꢀ52525ꢀP), the Catalan DIUE of
the Generalitat de Catalunya (2014SGR862). We thank Prof. J.
LloretꢀFillol (ICIQꢀTarragona) for fruitful discussions. X.R.
thanks an ICREA Acadèmia award and F. A. thanks Universitat
de Girona for a PhD grant. We thank COST Action CHAOS
(CA15106) and STR from UdG for technical support.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC04491G
Journal Name
COMMUNICATION
Graphical and textual abstract for the contents pages
Coupling Product
+
via
N
I
l
o
H
N
N
CuI
m
/
l
a
+
c
k
CuI (10 mol %)
7
.
RO
8
RO
N
+
H
N
N H
CuIII
HO
+
N
O
NH
HN
N
H
N
N
CuI
L3
(10 mol %)
putative intermediate
Catalyst Deactivation
Copper-catalyst decomposition pathways in the Ullmann-type
couplings studied have been clarified by means of helium
tagging IRPD and DFT mechanistic studies, and strong support
for the existence of aryl-CuIII species have been obtained.
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