Synthesis and Simple Immobilization of Palladium(II) Acyclic Diaminocarbene Complexes on Polystyrene Support as Efficient Catalysts for Sonogashira and Suzuki-Miyaura Cross-Coupling

Article abstract of DOI:10.1021/acs.organomet.6b00144

Immobilization of palladium(II) acyclic diaminocarbene (Pd(II)-ADC) complexes on a resin support surface has been easily performed by metal-mediated addition of amino groups of benzhydrylamine-polystyrene to the coordinated isocyanide ligand of cis-PdCl₂(CNR)₂ (R = t-Bu, Cy). The investigation of the benzhydrylamine reaction with palladium-coordinated isocyanides in solution has revealed that, depending on the reaction conditions, two carbene-type complexes can be obtained as a result of the addition to the CN triple bond, as well as a third complex which is formed via substitution of the isocyanide ligand by benzhydrylamine. Nucleophilic addition of an amino group to the isocyanide ligand has led to a cis-acyclic diaminocarbene complex or a cationic diaminocarbene complex with trans configuration and an intramolecular hydrogen-bonded chloride anion (the nature of this noncovalent interaction was analyzed by DFT calculations, including AIM analysis). The unsupported and resin-supported palladium catalysts have demonstrated high catalytic activity in both Sonogashira and Suzuki-Miyaura cross-coupling. The supported catalyst can be recovered and repeatedly reused without a significant loss in efficiency. The degree of the palladium binding with polystyrene, the oxidation state, and the palladium leaching level were investigated by XPS and XRF analyses.

Full text of DOI:10.1021/acs.organomet.6b00144

Article
pubs.acs.org/Organometallics
Synthesis and Simple Immobilization of Palladium(II) Acyclic
Diaminocarbene Complexes on Polystyrene Support as Efficient
Catalysts for Sonogashira and Suzuki−Miyaura Cross-Coupling
Vladimir N. Mikhaylov,† Viktor N. Sorokoumov,† Kirill A. Korvinson,†,‡ Alexander S. Novikov,†
and Irina A. Balova*,†
†St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg 199034, Russia
‡Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, New York 10016, United States
S
* Supporting Information
ABSTRACT: Immobilization of palladium(II) acyclic diami-
nocarbene (Pd(II)-ADC) complexes on a resin support surface
has been easily performed by metal-mediated addition of
amino groups of benzhydrylamine-polystyrene to the coordi-
nated isocyanide ligand of cis-PdCl2(CNR)2 (R = t-Bu, Cy).
The investigation of the benzhydrylamine reaction with
palladium-coordinated isocyanides in solution has revealed
that, depending on the reaction conditions, two carbene-type
complexes can be obtained as a result of the addition to the
CN triple bond, as well as a third complex which is formed via
substitution of the isocyanide ligand by benzhydrylamine.
Nucleophilic addition of an amino group to the isocyanide
ligand has led to a cis-acyclic diaminocarbene complex or a
cationic diaminocarbene complex with trans configuration and an intramolecular hydrogen-bonded chloride anion (the nature of
this noncovalent interaction was analyzed by DFT calculations, including AIM analysis). The unsupported and resin-supported
palladium catalysts have demonstrated high catalytic activity in both Sonogashira and Suzuki−Miyaura cross-coupling. The
supported catalyst can be recovered and repeatedly reused without a significant loss in efficiency. The degree of the palladium
binding with polystyrene, the oxidation state, and the palladium leaching level were investigated by XPS and XRF analyses.
efficient phosphane-free catalysts,51−54 among which palladium
INTRODUCTION
■
complexes with N-heterocyclic carbenes (NHCs)55−62 and
Nowadays it is hard to imagine the development of synthetic
acyclic diaminocarbene (ADC) ligands are very promis-
organic chemistry without Pd-catalyzed reactions. A large
number of reports and reviews published in the last decades
ing.54,63−66
Homogeneous conditions, however, do not allow catalyst
recovery; consequently they cannot be applied to technological
have proved the efficiency of Pd catalysts in various significant
reactions:1−7 for example, the hydrogenation of C−C
bonds,8−14 C−heteroatom bond formation,15−25 including the
processes. By comparison, heterogeneous catalysis offers a
asymmetric reaction,8,11,12,26,27 the synthesis and functionaliza-
number of advantages such as the ease of handling, stability, the
tion of heterocycles,28−35 etc.
Among palladium-catalyzed reactions, great attention has
been paid to C−C bond formation, which is regarded as a
convenient methodology that simplifies the synthesis of
possibility of catalyst recycling, continuous processing, and ease
of separation. Because of these, there is an ongoing interest in
the development of stable heterogeneous systems containing
palladium species, which exhibit long-lasting catalytic activity
and could be rapidly reused without a significant loss in
complex organic molecules, natural product precursors,
activity.67−71
pharmaceuticals and advanced materials.36−42 The importance,
scope, and potential of cross-coupling chemistry for both
academia and industry were marked by the Nobel Prize for
Chemistry in 2010, which was awarded to Richard F. Heck, Ei-
ichi Negishi, and Akira Suzuki “for palladium-catalyzed cross
couplings in organic synthesis”.7,43−48
Given the significance of palladium-mediated catalysis in
organic synthesis, numerous reports have been published
focusing on the excellent properties of phosphanes72 or
NHCs73−101 containing Pd catalysts attached to polymeric
materials, including their recyclability. However, recently
reported procedures of palladium complex immobilization are
A broad spectrum of new available palladium complexes have
been proposed as precatalysts in homogeneous organic
catalysis, most of which contain phosphane ligands.49,50 Recent
advances in this area relate to the creation and application of
Received: February 21, 2016
© XXXX American Chemical Society
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Table 1. Influence of Reaction Conditions on the Outcome of 2aBHA
a
ratio of products
entry
solvent
time, h
T, °C
2aBHA
3aBHA
4aBHA
1
2
3
4
5
6
THF
12
12
12
5
20
20
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
0
0
0
CHCl3
THF
−15 to 20
CHCl3
CH2Cl2
C6H6
50
20
20
20
20
50
12
16
6
b
7
CHCl3
CHCl3
c
8
c
24
1
9
CHCl3
a
b
c
1
According to H NMR. t-BuNC (1 equiv) was introduced into the reaction mixture. NEt3*HCl (1 equiv) was introduced into the reaction
mixture.
Figure 1. Molecular structures of Pd complexes 2aBHA, 3aBHA, and 4aBHA.
generally complicated, involve multiple steps, and are non-
selective (Pd black formation during Pd(II) immobilization
processes),97,102 which are regarded as additional challenges to
finding simpler and more convenient methods.
In the past few years, the catalytic properties of Pd(II)-ADC
complexes in homogeneous catalysis and their application in
organic synthesis have been investigated and assessed.64,103
Their great potential as strong donors and flexible ligands in
palladium-mediated catalysis due to the absence of a rigid
backbone has been revealed. As an additional advantage, the
desired Pd(II)-ADC complexes can be synthesized by a simple
We have found that, in contrast to the previously reported66
direction of the homogeneous metal-mediated reaction, which
involved a direct attack of an amine moiety on the coordinated
isocyanide to give a Pd(II)-ADC complex, the reaction of
benzhydrylamine occurs with a simultaneous formation of two
different types of complexes: cationic and neutral.
We have successfully extended this reaction to heterogeneous
conditions and also report herein the synthesis of the first
example of a Pd(II)-ADC catalytic system on a polystyrene
support.
RESULTS AND DISCUSSION
■
pathway of nucleophilic addition of readily available N-
Synthesis of Unsupported Palladium(II) Acyclic Dia-
minocarbene Complexes. The efficient method for the
preparation of unsymmetrically substituted palladium(II)
acyclic diaminocarbene complexes from amines and Pd-
activated isocyanides previously reported66 by Hashmi et al.
prompted us to choose commercially available benzhydryl-
amine-polystyrene with primary amino groups (BHA-polystyr-
ene) as a support for the immobilization of the Pd(II)-ADC
complex.
nucleophiles to palladium-activated isocyanides in good to
quantitative yields.104−107
However, despite the keen interest in Pd(II)-ADC
complexes and active research in this field, there have been
no reports to date concerning the immobilization of palladium-
(II) acyclic diaminocarbene complexes on supports.
Herein we report the results of our investigation of the metal-
mediated reactions of isocyanide palladium(II) complexes with
benzhydrylamine in homogeneous and heterogeneous con-
ditions.
Since primary amines, in particular benzhydrylamine, have
not been previously investigated as nucleophiles, we decided to
B
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Scheme 1. Possible Mechanism of the Formation of 3aBHA and 4aBHA
Scheme 2. Synthesis of Palladium(II) Acyclic Diaminocarbene Complexes 2aBHA, 2bBHA, and 3aBHA
verify their reactivity in the nucleophilic addition to Pd-
coordinated tert-butyl isocyanide and catalytic activity of the
expected product of the reaction: Pd(II)-ADC complex 2aBHA
(Table 1).
For the initial studies of this reaction we chose the conditions
described in the aforementioned work (THF as a solvent at 20
°C). To our surprise, after a full conversion of the starting
materials an equimolar mixture of the complexes 3aBHA and
4aBHA was obtained instead of the desired Pd(II)-ADC
complex 2aBHA. A change in solvent or temperature did not
significantly affect the outcome of the reaction (see Table 1,
entries 1−6).
The structures of the complexes 3aBHA and 4aBHA were
determined by 1H and 13C NMR, ESI-MS, and IR spectral data
and were unambiguously proven by X-ray structure analysis
(Figure 1). It was found that the cationic complex 3aBHA has a
trans configuration with the intramolecularly hydrogen bonded
chloride in the outer coordination sphere. The IR spectra of
complexes 3aBHA and 4aBHA both have a strong stretching
vibration band at 2227 and 2240 cm−1, respectively.
The fact that 3aBHA and 4aBHA always exist in the reaction
mixture in equimolar amounts led us to assume that the
conversion of 2aBHA, which is obviously an intermediate for
3aBHA formation, proceeds more quickly than the formation
of 2aBHA from the starting materials (Scheme 1). In order to
prove the existence of an equilibrium between 1a and 4aBHA,
an additional amount of tert-butyl isocyanide was introduced
into the reaction mixture (Table 1, entry 7) and the complex
3aBHA was obtained as the only product in the 95% isolated
yield. Since we aimed at the synthesis of easily obtained
polymer-supported Pd(II)-ADC complexes, the use of an extra
amount of t-BuNC made the procedure complex and more
expensive. Therefore, we decided to identify reaction
conditions under which the conversion of 2aBHA to 3aBHA
could be suppressed.
The analysis of the proposed transformation scheme
(Scheme 1) led us to assume that the presence of extra
chlorine anions can shift the equilibrium toward 2aBHA
formation. To prove our hypothesis, a source of chlorine anions
(Et3N·HCl) was introduced into the reaction mixture (Table 1,
1
entry 8). H NMR was used to follow the reaction process.
1
According to H NMR at room temperature, directly after the
addition (approximately 5 min) of the complex 1a into a
mixture of benzhydrylamine (1 equiv) with Et3N·HCl (2 equiv)
in CDCl3, the formation of 2aBHA along with 3aBHA and
4aBHA in the ratio 1.7:1:1 was detected at 53% conversion of
the starting material. During the next 30 min, the amount of
3aBHA and 4aBHA remained constant and the reaction
proceeded toward 2aBHA formation. Within 30 min, the
conversion of the starting material was estimated as 92% and
the ratio of the products was 4:1:1. After 3.5 h, almost a full
conversion (96%) of the starting material was achieved and the
1
ratio of products was 10:1:1. The last H NMR spectrum was
recorded after 12 h, when 2aBHA was found to be the only
product. The presence of Et3N·HCl did not make the
purification procedure complex. After the evaporation of
CHCl3, the precipitate was washed with an Et2O/EtOH
mixture to remove Et3N·HCl. Then the crude product was
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recrystallized by a slow diffusion of pentane into the CH2Cl2
solution to give the compound 2aBHA in a good isolated yield.
The complex 2bBHA was also obtained under the same
conditions in a good yield (Scheme 2). The IR spectra of
complexes 2aBHA and 2bBHA both have a strong stretching
vibration band at 2223 and 2225 cm−1, respectively. As a result,
we found the conditions for the selective formation of
complexes 2aBHA, 2bBHA, and 3aBHA.
Theoretical DFT Calculations for Bifurcated Hydrogen
Bonding and Anagostic Interactions in 3aBHA. A study of
the crystallographic data showed the presence of three-centered
(bifurcated) hydrogen bonding (N−H···Cl···H−N) and
anagostic interactions (C(Ph)2H···Pd and CH3···Pd) in
3aBHA. In order to confirm the existence of these noncovalent
interactions in the solid state and CHCl3 solution and to
quantify their energies, we carried out theoretical DFT
calculations and performed a topological analysis of the
electron density distribution within the formalism of Bader’s
theory (AIM method).112 The results of this theoretical study
are summarized in Tables 2 and 3; a contour line diagram of
the Laplacian distribution ∇2ρ(r), the bond paths, and selected
zero-flux surfaces for 3aBHA are shown in Figure 2.
The structures of Pd(II)-ADC complexes 2aBHA, 3aBHA,
and 4aBHA were confirmed by X-ray single-crystal analysis
(Figure 1 and Supporting Information).108
According to the X-ray data, complexes 2aBHA and 3aBHA
both have a diaminocarbene nature with equivalent N−C−N
bonds: 1.328, 1.329 Å and 1.325, 1.326 Å, respectively.
Furthermore, N−C−N bond angles of the palladium-bonded
diaminocarbene are 115.7° for 2aBHA and 116.1° for 3aBHA,
significantly larger than the typical angles of 104−107° known
for N-heterocyclic carbenes.109 The substituents at the nitrogen
atoms in 2aBHA and 3aBHA are arranged in a syn,syn
configuration, where both tert-butyl and benzhydryl groups are
pointing toward the same side of the palladium atom. The X-
ray diffraction studies of 2aBHA and 3aBHA revealed an
interaction of the methanetriyl group CH(Ph)2 hydrogen with
palladium with relatively short M···H distances (Pd···H-
[CH(Ph)2] = 2.56 Å for 2aBHA and Pd···H[CH(Ph)2] =
2.62 Å for 3aBHA) and relatively small M···H−C bond angles
(117° for 2aBHA and 121° for 3aBHA).
It is well-known that ADCs and related acyclic carbene
ligands can adopt different conformations, denoted as syn or
anti, relative to the Pd−Ccarbene-NHR bond, depending on the
nature and bulkiness of these groups.66,110 However, in the
NMR spectra of both 2aBHA and 2bBHA, only one rotamer is
observed. In order to determine the conformation of the
diaminocarbene fragment in solution (CDCl3), NOE experi-
ments were performed. The NOESY spectrum of 2bBHA
obtained in CDCl3 at room temperature revealed an interaction
between the NH atoms of the diaminocarbene fragment, which
is only possible in the syn,syn conformation (see the
Supporting Information). Moreover, the signals of the
methanetriyl group hydrogens in 1H NMR of the major
syn,syn conformer for both 2aBHA and 2bBHA complexes are
shifted downfield (7.26 and 7.09 ppm, respectively) in
comparison with the uncoordinated methanetriyl group
hydrogen atoms in the minor syn,anti conformations of
complexes 2aBHA and 2bBHA (5.67 and 5.80 ppm,
respectively) (eq 1). The bulkier substituents on the N atom
The geometry optimization of 3aBHA in the CHCl3 solution
indicates that the H···Cl, C(Ph)2H···Pd, and CH3···Pd distances
in the isolated cluster are even shorter than those in the crystal
(2.26−2.23 Å vs 2.45−2.32 Å, 2.48 Å vs 2.62 Å, and 2.54 Å vs
2.55 Å, respectively). The AIM analysis demonstrates the
presence of two bond critical points (BCPs) (3, −1) for the
three-centered hydrogen bonds N−H···Cl···H−N and two
BCPs for the anagostic interactions C(Ph)2H···Pd and CH3···
Pd in 3aBHA in both the solid state and CHCl3 solution
(Tables 2 and 3). The low magnitude of the electron density,
the positive values of the Laplacian, and the zero or very close
to zero energy density in these BCPs are typical of noncovalent
interactions.115,116 We defined the energies for three-centered
hydrogen bonds N−H···Cl···H−N according to the procedures
proposed by Espinosa et al.113 and Vener et al.,114 and one can
maintain that these interactions can be formally classified as
hydrogen bonds from weak to moderate strength (4−5 kcal/
mol for solid state and 5−6 kcal/mol for CHCl3 solution)
mainly due to electrostatics following the classification of
Jeffrey117 (“strong” H bonds, 40−15 kcal/mol; “moderate” H
bonds, 15−4 kcal/mol; “weak” H bonds, <4 kcal/mol). The
balance between the Lagrangian kinetic energy G(r) and
potential energy density V(r) at the bond critical points (3, −1)
reveals the nature of these interactions: if the ratio − G(r)/V(r)
> 1 is satisfied, then the nature of the appropriate interaction is
purely noncovalent; in the case of −G(r)/V(r) < 1 some
covalent component is observed.118 On the basis of this
criterion, we can argue that the covalent component for the
bifurcated hydrogen bond N−H···Cl···H−N in 3aBHA is
absent for the solid state and negligible for the CHCl3 solution
and the anagostic interactions C(Ph)2H···Pd and CH3···Pd in
3aBHA are clearly noncovalent for both the solid state and the
CHCl3 solution. The negligible nonzero values of the Wiberg
bond indices for N−H···Cl···H−N, C(Ph)2H···Pd, and CH3···
Pd contacts in the optimized structure of 3aBHA (0.08, 0.02,
and 0.02, respectively) computed by using the natural bond
orbital (NBO) partitioning scheme119 additionally confirm the
electrostatic nature of these noncovalent interactions.
In addition, according to the NMR data (1H and 13C) in the
presence of triethylamine hydrochloride, only syn,syn con-
formers of 2aBHA and 2bBHA exist in solution (the minor
isomer is not detected) due to an intermolecular three-centered
hydrogen bond (NH···Cl−···HN) formation, which demon-
strates the stabilizing effect of the chloride ion. It is remarkable
that 2aBHA is insoluble in neat CHCl3 and soluble in CHCl3
with the Et3N·HCl additive or DMSO because of the
destruction of intermolecular hydrogen bond interactions in
the solid state of the complex. The intermolecular bifurcated
hydrogen bond interaction NH···O(DMSO)···HN between
(t-Bu vs Cy) led to an increase in the syn,syn/syn,anti isomeric
ratio. This observation is in accordance with the hydrogen-
bonded description of the interaction and could be described as
an anagostic interaction.111 These results are consistent with
the solid-state structure.
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Table 2. Values of the Density of All Electrons (ρ(r)), Laplacian of Electron Density (∇2ρ(r)), Energy Density (Hb), Potential
Energy Density (V(r)), and Lagrangian Kinetic Energy (G(r)) (hartree) at the Bond Critical Points (3, −1), Corresponding to
the Bifurcated Hydrogen Bonding N−H···Cl···H−N in 3aBHA for the Solid State and CHCl3 Solution, Appropriate Bond
Lengths d(H···Cl) (Å), and Energies of These Interactions (Eint) (kcal/mol), Defined by Two Approaches
a
b
ρ(r)
∇2ρ(r)
Hb
V(r)
G(r)
Eint
Eint
d(H···Cl)
Solid State
0.017
0.021
0.058
0.068
0.001
0.000
−0.012
−0.016
0.013
0.017
3.77
5.02
3.50
4.58
2.45
2.32
CHCl3 Solution
−0.018
−0.019
0.024
0.026
0.065
0.068
−0.001
−0.001
0.017
0.018
5.65
5.96
4.58
4.85
2.26
2.23
Eint = −V(r)/2.113 Eint = 0.429[G(r)].114
a
b
Table 3. Values of the Density of All Electrons (ρ(r)), Laplacian of Electron Density (∇2ρ(r)), Energy Density (Hb), Potential
Energy Density (V(r)), and Lagrangian Kinetic Energy (G(r)) (hartree) at the Bond Critical Points (3, −1), Corresponding to
Anagostic Interactions C(Ph)2H···Pd and CH3···Pd in 3aBHA for the Solid State (Normal Text) and CHCl3 Solution (in
Parentheses), Appropriate Bond Lengths d(H···Pd) (Å), Bond Angles C−H−Pd (deg), and Energies of These Interactions (Eint)
(kcal/mol), Defined by Two Approaches
a
b
ρ(r)
∇2ρ(r)
Hb
V(r)
G(r)
Eint
Eint
d(H···Pd)
C−H−Pd
C1 H···Pd
CH3···Pd
0.015 (0.019)
0.052 (0.058)
0.053 (0.051)
0.001 (0.000)
0.001 (0.000)
−0.011 (−0.015)
−0.012 (−0.012)
0.012 (0.015)
0.013 (0.012)
3.45 (4.71)
3.77 (3.77)
3.23 (4.04)
3.50 (3.23)
2.62 (2.48)
2.55 (2.54)
121 (121)
129 (123)
2
0.016 (0.016)
Eint = −V(r)/2.113 Eint = 0.429[G(r)].114
a
b
phane and N-heterocyclic palladium(II) diaminocarbene
complexes in catalytic applications in transition-metal-catalyzed
organic transformations.103,106,120 Thus, we turned to the
evaluation of catalytic activity of the Pd(II)-ADC complexes
2aBHA, 2bBHA, and 3aBHA in cross-couplings. In our recent
studies we found that the addition of PPh3 promoted a higher
rate of Sonogashira coupling when Pd(II)-ADC species were
used as precatalysts.121 Therefore, the PPh3 additive was used
for the Sonogashira coupling of 2-methyl-3-butyn-2-ol (5a)
with iodo- and bromoarenes 7 and 8 (Table 4, entries 1−9).
Our first studies of the catalytic activity in Sonogashira
coupling were carried out with a fixed time (3 h) and revealed a
high efficiency of all of the complexes 2aBHA, 2bBHA, and
3aBHA as precatalysts. With the use of 0.5 mol % catalyst
loading, the coupling proceeded smoothly, with iodoarene 7a
having an electron-donating MeO group and aryl bromides
8b,c, and led to cross-coupling products 9a−c (Table 4, entries
3−6). We did not find any significant difference in the catalytic
activities of the complexes 2aBHA and 3aBHA (Table 4,
entries 3 and 4). In order to estimate the TONs, the catalysts
2aBHA and 3aBHA were used in extremely low concentrations
(0.002 and 0.01 mol %) (Table 4, entries 8 and 9). It was found
that TONs of up to 17000 for aryl iodides and up to 1200 for
aryl bromides could be achieved with the use of the Pd(II)-
ADC complexes 2aBHA and 3aBHA as precatalysts at 70 °C.
We also tested the initial complex 1a in Sonogashira coupling
using the conditions of entry 1 (Table 4) and found a
comparable but somewhat lower catalytic activity (the yield of
9a was 21% with 0.1 mol % catalyst 1a loading).
Figure 2. Contour line diagram of the Laplacian distribution ∇2ρ(r),
bond paths, and selected zero-flux surfaces for 3aBHA (optimized
structure in CHCl3 solution). Bond critical points (3, −1) are shown
in blue, ring critical point (3, +1) in orange, and nuclear critical points
(3, −3) in pale brown. Lengths are given in Å.
DMSO and 2aBHA molecules was also revealed in the solid
state of 2aBHA (crystallization from DMSO/CHCl3) by X-ray
crystallography.
Thus, the formation of the three-centered hydrogen bond
determines the formation of 3aBHA in the reaction of
benzhydrylamine with 1a (Scheme 1), as well as the shift of
equilibrium from 3aBHA toward 2aBHA by the addition of an
external chloride ion (Et3N·HCl).
Catalytic Activity of Unsupported Pd(II)-ADC Com-
plexes 2aBHA, 2bBHA, and 3aBHA in Sonogashira and
Suzuki Coupling Reactions. It is well-known that ADC
ligands have the following unique properties: strong σ-donor
ability, conformational flexibility (adjustment to the specific
catalytic cycle stage), and a large NCN angle that can favor the
stability of the active catalytic Pd species. Pd(II)-ADC
complexes demonstrate competitive advantages over phos-
An analysis of recently published papers showed that the
complexes obtained are among the best catalysts for the
Sonogashira reaction. Thus, Valishina and co-workers122
reported TONs of up to 3.7 × 104 for the selected acyclic
diaminocarbene palladium(II) catalyst (the average value
among the series of catalysts tested in this paper is 1× 104).
In another paper,123 the authors reported TONs for the
palladium complexes of 2-formylpyridine thiosemicarbazone of
around 1 × 104 for both Sonogashira and Suzuki couplings. The
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Table 4. Sonogashira and Suzuki−Miyaura Cross-Couplings Catalyzed by 2aBHA, 2bBHA, and 3aBHA
a
b
entry
halide
Pd(II)-ADC
base
catalyst, mol %
temp, °C
time, h
product
yield,
%
TON
TOF
1
7a
7a
7a
7a
8b
8c
7b
7a
8c
8c
8b
8c
2bBHA
3aBHA
2aBHA
3aBHA
2aBHA
2aBHA
2aBHA
2aBHA
3aBHA
2aBHA
2aBHA
2aBHA
Et3N
0.1
50
50
50
50
70
70
70
70
70
70
70
70
3
3
9a
30
35
98
97
75
27
58
34
12
75
99
52
300
350
100
117
65
2
Et3N
0.1
9a
3
Et3N
0.5
3
9a
196
4
Et3N
0.5
3
9a
194
65
5
Et3N
Et3N
0.5
3
9b
9c
150
50
6
0.5
3
54
18
7
Et3N
0.01
0.002
0.01
0.5
3
9b
9a
5800
17000
1200
150
1933
177
13
8
Et3N
96
96
4
9
Et3N
9c
10
11
K2CO3
K2CO3
K2CO3
10c
10b
10c
32
0.5
4
198
42
c
12
0.5
4
104
22
a
Conditions unless specified otherwise: entries 1−9, aryl halide 1 equiv, alkyne 1.5 equiv, CuI 5 mol %, PPh3 8 mol %, Et3N 4 equiv, DMF; entries
b
c
10−12, aryl halide 1 equiv, phenylboronic acid 1.2 equiv, base 4 equiv, DMF/H2O (10/1). GCMS yield with dodecane as internal standard. PPh3 8
mol % was added.
Scheme 3. Preparation of Polystyrene-Supported Pd(II)-ADC Complexes 2aBHA@PS and 2bBHA@PS
Pd-NHC catalysts reported by Dahm124 and John125 also
exhibited similar catalytic activity in the Sonogashira coupling
reaction, but the amount of catalyst used was noticeably larger,
in the range of 1−4%.
The Pd(II)-ADC complex 2aBHA was also tested in the
Suzuki−Miyaura coupling of aryl bromides 8b,c with phenyl-
boronic acid (6) (Table 4, entries 10−12). After 4 h,
substituted biphenyls 10b,c were obtained in high to
quantitative yields. These results led us to assume that the
BHA-polystyrene-supported Pd(II)-ADC complex could ex-
hibit relatively high and quite stable catalytic activity for both
cross-coupling reactions.
Preparation of Polystyrene-Supported Pd(II)-ADC
Complexes 2aBHA@PS and 2bBHA@PS. At the next step
we investigated the scope of metal-mediated addition of the
amine moiety of benzhydrylamine-polystyrene (BHA@PS) to
palladium-coordinated isocyanides. Commercially available
polystyrene resin modified with benzhydrylamine hydro-
chloride (0.6−0.9 mmol/g loading) was first sustained in
CHCl3 for 30 min and then treated with an equimolar amount
of Et3N to unlock the amino groups on the support. The
resulting suspension containing triethylamine hydrochloride
was used for further modification.
F
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a
Table 5. Evaluation of the Catalytic Properties of 2aBHA@PS, 2bBHA@PS in Sonogashira Cross-Coupling
b
c
entry
substrate
Pd catalyst/amt mol %
temp, °C
time, min
product
yield,
%
cycles
1
2
7a
7a
7a
7b
8c
8c
7h
7d
7b
7b
7g
7g
7c
7c
8f
2aBHA@PS/10
2bBHA@PS/10
2aBHA@PS/10
2aBHA@PS/10
2aBHA@PS/10
2bBHA@PS/10
2aBHA@PS/10
2aBHA@PS/10
2aBHA@PS/10
2bBHA@PS/10
2bBHA@PS/10
2bBHA@PS/10
2bBHA@PS/5
2bBHA@PS/5
2aBHA@PS/10
2aBHA@PS/10
2bBHA@PS/10
2aBHA@PS/10
2bBHA@PS/10
2aBHA@PS/1
2aBHA@PS/1
2aBHA@PS/1
2aBHA@PS/1
2aBHA@PS/1
2aBHA@PS/0.5
40
40
40
40
70
70
40
40
16
20
20
20
40
40
70
70
70
40
40
40
40
40
40
70
40
55
55
40
5
9a
99
98
98
99
97
98
94
95
99
99
99
99
97
96
92
95
96
93
95
98
99
99
99
99
99
3
2
2
6
3
1
2
1
8
3
2
5
1
1
2
2
2
2
2
1
1
1
1
1
2
9a
d
3
9a
4
9b
9c
5
70
80
45
60
20
20
45
50
55
45
90
55
50
50
55
180
120
80
90
150
60
6
9c
7
11h
11f
9b
9b
9g
8
9
10
11
12
13
9g
9c
d
14
9c
15
16
17
18
19
9f
8g
8g
7h
7h
7a
7b
7c
7e
8e
7b
12g
12g
12h
12h
9a
d
20
d
21
9b
9c
d
22
d
23
9e
d
24
9e
25
9b
a
b
Reaction conditions unless specified otherwise: arylhalide 1 equiv, alkyne 1.5 equiv, CuI 10 mol %, Et3N 4 equiv. 1H NMR yield, average per cycle.
c
d
A number of reactions carried out continuously with the appropriate substrate with the same sample of catalyst. With PPh3 (5 mol %).
The suspension was mixed with cis-PdCl2(CN-R)2 (1a, R = t-
Bu; 1b, R = Cy) in chloroform (Scheme 3). The reactant ratio
was chosen in such a way as to provide a 10-fold excess of
surface amino groups in relation to cis-PdCl2(CN-R)2. The
degree of palladium bonded to polystyrene was quantitative and
was determined by X-ray fluorescence analysis (XRF) of the
PS and 2bBHA@PS, respectively, which proves the presence of
only one isocyanide ligand in the surface complexes. The CN
stretching frequencies in IR spectra of the supported and
unsupported Pd(II)-ADC complexes are similar.
Moreover, the data obtained are consistent with the spectral
characteristics of nonsupported species 2aBHA and 2bBHA
(see the Supporting Information).
1
filtrate cross-checked with H NMR after the immobilization.
The yield of surface complexes was estimated as 0.075 mmol of
Catalytic Activity of Polystyrene-Supported Pd(II)-
ADC Complexes Pd(II)-ADC@PS in Sonogashira and
Suzuki−Miyaura Cross-Coupling Reactions. To elucidate
the scope of applications of Pd(II)-ADC@PS (2aBHA@PS,
2bBHA@PS) for catalysis, their activity was tested in
Sonogashira and Suzuki−Miyaura cross-coupling in DMF in
air. The outcome of the experiments of Sonogashira coupling is
given in Table 5. Taking into account that nonsupported
analogues 2aBHA and 2bBHA have relatively low TOF values
but outstanding TON values and that the overall reaction rate
in heterogeneous processes is generally limited by the diffusion
rate to catalytically active centers, we decided to use 10 mol %
of the catalyst (according to the weight concentration of Pd(II)
complexes) as the initial conditions.
Pd/g.
Curiously, in contrast to the homogeneous conditions, the
reaction of benzhydrylamine bonded to resin with cis-
PdCl2(CN-t-Bu)2 both in the presence and in the absence of
triethylamine hydrochloride occurred with the formation of
2aBHA immobilized on the polystyrene support. The
formation of Pd(II)-ADC complexes on the surface of BHA-
polystyrene (2aBHA@PS, 2bBHA@PS) was confirmed by IR
studies of the samples obtained. While the starting cis-
PdCl2(CNR)2 complexes display two overlapping stretches
(2257 and 2243 cm−1 for 1a, 2252 and 2233 cm−1 for 1b), after
the modification of the isocyanide ligand via the nucleophilic
addition of amine moiety of the resin, strong new stretching
vibration bands appeared at 2224 and 2225 cm−1 for 2aBHA@
G
DOI: 10.1021/acs.organomet.6b00144
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a
Table 6. Dependence of Palladium Leaching on PPh3 Concentration in Sonogashira Coupling
b
entry
substrate
Pd catalyst
PPh3, mol %
temp, °C
time, min
product
yield, %
Pd leached, %
1
7g
7g
8c
8c
7g
7g
8c
8c
8c
8c
7g
7g
8c
8c
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
2aBHA@PS
2bBHA@PS
0
0
40
40
70
70
40
40
70
70
80
80
40
40
70
70
25
25
70
70
15
15
70
70
70
70
15
15
65
65
9g
9g
9c
9c
9g
9g
9c
9c
9c
9c
9g
9g
9c
9c
97
96
98
96
97
94
95
97
12
9
0.34
0.41
1.02
1.19
0.26
0.24
1.13
1.08
15.60
14.90
0.12
0.08
0.91
2
3
0
4
0
5
5
6
5
7
5
8
5
9
5
10
11
12
13
14
5
10
10
10
10
95
98
94
96
1.00
a
b
Reaction conditions: aryl halide 1 equiv, alkyne 1.5 equiv, CuI 10 mol %, Et3N 4 equiv, catalyst 10 mol %, PPh3 0−10 mol %, DMF 5.5 mL. The
relative uncertainty of the XPS method was estimated as 10%.
For the synthesis of aryl-substituted alkynes, we tested a wide
range of aryl halides containing both electron-donating and
electron-withdrawing groups. To determine the time of full
conversion of the starting aryl halides, the reactions were
monitored by TLC. We found that the common conditions for
Sonogashira coupling (DMF, 4 equiv of Et3N, 10 mol % CuI)
were effective in this case for the preparation of arylacetylenes.
It is also worth noting that a fairly high solubility of all the
starting materials, products, and byproducts in DMF provided
us with a very simple procedure for catalyst regeneration. Thus,
the sequentially applied sample of the catalyst (which was
recovered and reused six times in a row) yielded a sufficient
amount of the coupling product in a very short time, 5 min
(Table 5, entry 4).
As expected, the coupling of the bromo-substituted
substrates proceeded at a higher temperature in comparison
with that for iodo-substituted substrates (Table 5, entries 5, 6,
and 15−17), which is usually attributed to the strength of the
C−X bond.126 As a consequence, the resistance of aryl
bromides to oxidative addition to active Pd centers at the
critical first step of the catalytic cycle results in a reduction in
the reaction rate. Hence, heating the reaction mixtures to 70 °C
for 50−90 min with 10 mol % catalyst loading was sufficient to
obtain cross-coupling products in high yields (up to 98%) even
in the case of the electron donor substituted bromide 8f (Table
5, entry 15). In order to reduce the conversion time of
bromoarenes, we attempted to increase the temperature.
However, it was found that at 80 °C 2aBHA@PS turned
black in the same way as for 2bBHA@PS, which was
apparently caused by the decomposition of the palladium
complexes on the surface. Further experiments demonstrated
that the Pd(II)-ADC@PS catalytic system remained effective
for synthetic purposes with lower catalyst loadings (Table 5,
entries 13, 14, and 20−25). Thus, the aryl halide 7b smoothly
reacted with 2-methyl-3-butyn-2-ol (5a) even at 0.5 mol %
catalyst loading of 2aBHA@PS to give the product 9b in a 99%
yield (Table 5, entry 25). We did not find significant differences
in the catalytic activities of 2aBHA@PS and 2bBHA@PS: the
conversion time as well as yields remained almost the same
with identical catalyst loadings.
Next we decided to examine the stability of the supported
catalysts 2aBHA@PS and 2bBHA@PS by measuring the
palladium concentration in the solution using X-ray photo-
electron spectroscopy (XPS) upon completion of the reactions
for the samples of 2aBHA@PS. In all experiments, the
percentage of palladium leached is given with respect to the
amount of catalyst introduced. Blank experiments with the
catalyst 2aBHA@PS were accomplished without addition of
substrates (Et3N, DMF, 1 h) and demonstrated that palladium
leaching caused by thermal decomposition is very low at 40 °C
(0.03%) and tended to be more notable upon heating to 70 °C
(0.82%). The analysis of the product mixture obtained after the
separation and washing of Pd-containing resin indicated that
palladium leaching from the support remained constant after
each cycle, 0.46−0.53% (2bBHA@PS) and 0.71−0.98%
(2aBHA@PS) in the 20−40 °C range, and increased up to
1.20% and 1.38% for 2bBHA@PS and 2aBHA@PS,
respectively, at 70 °C. Such a low palladium leaching level
showed that our initial conditions of 10 mol % of the catalyst
(according to the weight concentration of Pd(II) complexes) is
not a disadvantage for synthetic purposes.
In our recent study we found that the addition of PPh3
caused a higher rate of the Sonogashira cross-coupling when
Pd(II)-ADC species were used as precatalysts.121,127 In the case
of polystyrene-supported catalytic systems containing Pd(II)-
ADC complexes, we also found that presence of PPh3
accelerated the reaction rate. Thus, PPh3 supplement resulted
in an ∼20% decrease of the reaction time for aryl iodides
(Table 6, entries 1, 3, 13, and 14).
H
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a
Table 7. Evaluation of the Catalytic Properties of 2aBHA@PS and 2bBHA@PS in Suzuki−Miyaura Cross-Coupling
b
c
entry
substrate
Pd catalyst/ mol %
DMF/H2O, v/v
temp, °C
time, min
product
yield,
%
catalytic cycles
Pd leached, %
e
1
7a
7b
7b
8c
8c
8c
8c
8c
8i
2aBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
2bBHA@PS/5
2aBHA@PS/5
2bBHA@PS/5
2aBHA@PS/5
2bBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
2aBHA@PS/5
100/0
100/0
100/0
100/0
95/5
65
65
65
75
70
70
70
70
70
70
70
70
70
70
120
120
90
10a
10b
10b
10c
10c
10c
10c
10c
10i
10i
10c
10i
10i
10i
96
95
98
97
98
97
93
95
98
96
65
71
98
96
2
1
1
2
3
2
3
3
2
2
2
3
3
3
n/d
e
2
n/d
e
3
n/d
e
4
150
50
n/d
5
0.57
0.64
0.63
0.38
0.80
0.50
0.13
0.16
0.05
0.03
6
95/5
55
7
90/10
90/10
95/5
60
8
60
9
50
10
11
12
8i
95/5
50
8c
8i
80/20
80/20
95/5
50
55
d
13
8i
50
d
14
8i
95/5
50
a
Reaction conditions unless specified otherwise: aryl halide 1 equiv, phenylboronic acid 1.2 equiv, base (Et3N for entries 1, 2 and 4; K2CO3 for
b
c
entries 3 and 5−14) 4 equiv, catalyst 0.5−5 mol %. 1H NMR yield, average per cycle. The number of consequent reactions carried out with the
same substrate. With PPh3 (5 mol %). Not detected. The relative uncertainty of the XRF method was estimated as 10%.
d
e
f
An analysis of the triphenylphosphine additive effect on the
palladium leaching level indicated a sufficient drop of palladium
concentration in stock solutions in the case of aryl iodides
accompanied by a noticeable cut in the conversion times.
Encouraged by these results, we turned our attention to the
exploration of this intriguing effect. The dependence of
palladium leaching on the PPh3 concentration in solution was
examined by X-ray fluorescence analysis (Table 6). For this
purpose, we employed the reactions of bromide 8c and iodide
7g with 2-methyl-3-butyn-2-ol (5a) as a coupling partner.
Unexpectedly, the addition of PPh3 significantly decreased (up
to 8 times) palladium leaching in the cross-coupling with
iodides. The best results were obtained when 10 mol % of PPh3
was used (Table 6, entries 11 and 12). In contrast to the
reactions with iodoarenes and PPh3, the additive did not affect
palladium leaching when Sonogashira coupling was performed
with aryl bromides at 70 °C.
It is noteworthy that recent experiments have demonstrated
that, in the presence of an excess of a soft ligand (PPh3, AsPh3
etc.), the bimetallic (Pd,Cu-containing) complex formed during
the transmetalation step rapidly undergoes decomposition to
give the actual transmetalation complex [Pd(η3-allyl)(alkynyl)-
L].128 In addition, the aforementioned effect cannot be
obtained by amines, which are commonly used as bases in
Sonogashira cross-coupling. The data are in full agreement with
the rate acceleration observed, as demonstrated on the donor-
substituted aryl iodide 7a, which was fully converted to 9a in 40
min in the presence of 10 mol % of the catalyst 2aBHA@PS
and 5 mol % of PPh3 (Table 5, entry 3) in comparison with the
PPh3-free experiment (Table 5, entry 1: 10 mol % of 2aBHA@
PS, 55 min).
However, using K2CO3 as a base instead of Et3N caused a
decrease in the coupling time (Table 7, entries 2 and 3). Thus,
a full conversion of the starting 1-iodo-4-nitrobenzene (7b) at
65 °C was observed within 120 min in the case of Et3N and
within 90 min when K2CO3 was employed. For a further
optimization, we attempted to use a DMF/H2O mixture as the
solvent due to the higher solubility of K2CO3 in aqueous media.
The results obtained indicated that the coupling of phenyl-
boronic acid and aryl halides proceeded much more quickly
(50−60 min) in the presence of 5−10% (vol) of water as a
cosolvent and 4 equiv of K2CO3 as a base, giving cross-coupling
products in quantitative yields (Table 7, entries 5−14). Under
these conditions, a variety of differently substituted aryl
bromides smoothly underwent cross-coupling with a 1.2
equiv excess of phenylboronic acid to afford biphenyls 10a−
c,i in excellent yields.
Using X-ray fluorescence analysis, we found that palladium
leaching is noticeably less in the Suzuki−Miyaura coupling in
comparison with the Sonogashira coupling even at 75 °C. The
addition of PPh3 also decreased palladium leaching in this case
(Table 7, entries 13 and 14).
Thus, these results suggest that the catalytic system
developed appears to be relatively stable in the 20−70 °C
range and can be successfully applied to Sonogashira and
Suzuki−Miyaura cross-coupling with a wide range of iodo- as
well as bromoarenes.
XPS Studies. Previously, some heterogeneous NHC-based
catalysts were characterized by the X-ray photoelectron
spectroscopy (XPS) method.75,76,80,82,89,91,97,102,129−132 How-
ever, Pd-NHC-containing polystyrene has only been inves-
tigated once by XPS prior to our work.82
The ability of the polymer-bonded Pd(II)-ADC species
2aBHA@PS and 2bBHA@PS to catalyze Suzuki−Miyaura
coupling was also examined (Table 7). The initial experiments
demonstrated that commonly used conditions (Et3N/DMF)
are not favorable even in the case of the activated iodide 7b.
To evaluate the applicability of the XPS analysis method, we
used a freshly prepared sample of 2aBHA@PS, containing 30%
of modified amino groups. This degree of modification was
found to provide a good signal intensity, suitable even for
quantitative analysis.
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The presence in the XPS spectrum of two signals at 342.4
and 337.2 eV with good resolution and intensity corresponding
to the binding energies of Pd 3d5/2 and Pd 3d3/2 electrons,
respectively, proved that the freshly prepared 2aBHA@PS
precatalyst contains only Pd(II) species. The results obtained
have demonstrated the possibility of the successful use of XPS
analysis for the study of the surface composition of the catalyst
developed. The samples of the polystyrene-supported catalysts
2aBHA@PS were also analyzed by XPS before and after the
Sonogashira and Suzuki−Miyaura coupling reactions (Figures 3
and 4). Some interesting differences were obtained.
It was found that palladium leaching is noticeably lower in
the case of Suzuki−Miyaura coupling in comparison with the
Sonogashira reaction (compare Tables 6 and 7). We attribute
this tolerance of the Suzuki−Miyaura coupling to the fact that
the starting Pd(II) complex on the surface of 2aBHA@PS most
likely did not convert to the less stable Pd(0) complex at the
end of the reaction. In addition, the XPS analysis of the
2aBHA@PS catalyst recovered after the Suzuki−Miyaura
coupling (4-iodoanisole, 1.2 equiv of phenylboronic acid, 4
equiv of K2CO3, and 1 mol % of 2aBHA@PS) confirmed that
the oxidation state of Pd is +2 (Figure 4), which is in agreement
with the data reported earlier.133
CONCLUSION
■
Depending on the reaction conditions, the nucleophilic
addition of the primary amino group of benzhydrylamine to
the isocyanide ligand of cis-PdCl2(CN-t-Bu)2 complexes has led
to a cis-acyclic diaminocarbene complex or a trans-acyclic
diaminocarbene cationic complex. It has been found that the
formation of a three-centered hydrogen bond (NH···Cl···HN)
is crucial for the formation and stabilization of the cationic
complex. Both of the complexes exhibited high catalytic activity
in Sonogashira and Suzuki−Miyaura coupling.
A very simple and convenient method of one-pot preparation
and bonding of palladium(II) acyclic diaminocarbene com-
plexes with polymer support via nucleophilic addition of the
amine moiety to Pd-activated isocyanides has been developed.
Using this approach, new catalytic systems for palladium-
catalyzed organic transformations have been prepared. The
heterogeneous catalytic system developed has displayed high
and stable activity in Sonogashira and Suzuki−Miyaura cross-
couplings with aryl iodides and aryl bromides containing both
electron-donating and electron-withdrawing groups. The
addition of triphenylphosphine has been found to accelerate
the Sonogashira coupling reaction rate, decrease palladium
leaching, and reduce the amount of catalyst loading.
Figure 3. XPS spectra of the Pd-containing support 2aBHA@PS
before and after the Sonogashira reaction.
EXPERIMENTAL SECTION
■
General Remarks. Solvents and all reagents for catalytic studies
were obtained from commercial sources and used as received, unless
stated otherwise. Benzhydrylamine resin·HCl (2% cross-linked, 200−
400 mesh, ca. 0.6−0.9 mmol/g, Bachem) was used as received.
Chloroform was dried and purified by washing with concentrated
sulfuric acid and distilled. DMF was purified via azeotropic distillation
with benzene and water, distilled under reduced pressure, and stored
under molecular sieves 4 Å. Infrared spectra (4000−200 cm−1) were
recorded on a Bruker Tensor 27 instrument as KBr pellets. NMR
spectra were recorded at ambient temperature with a Bruker 400
Avance spectrometer at 400.13 (1H) and 100.61 (13C) MHz. Chemical
shifts (δ) are given in ppm relative to the resonances of solvents (1H, δ
7.26 for CDCl3; 13C, δ 77.16 for CDCl3). Coupling constants (J) are
given in Hz. Multiplicities of signals are described as follows: s =
singlet, d = doublet, t = triplet, m = multiplet. The XPS spectrum of
2aBHA@PS was analyzed by X-ray photoelectron spectroscopy (XPS)
using a Thermo Fisher Scientific Escalab 250Xi spectrometer equipped
with a monochromatic Al X-ray source. XPS analysis of the resin was
performed in the Pd 3d region with a 20 eV pass energy, a 0.05 eV
step, and a 0.5 s dwell time. Charge compensation was used, as each
sample was nonconductive. All of the binding energy values are
calibrated by using C(1s) = 284.6 eV as a reference. A graphical
representation of XPS analysis data was performed with Thermo
Avantage 5.52 (Avantage software). Mass spectra were recorded with a
BrukerMicroTOF instrument (ESI). The instrument was operated in
positive ion mode using an m/z range of 50−3000. The capillary
voltage of the ion source was set at −4500 V (ESI+-MS) and the
Figure 4. XPS spectra of the Pd-containing support 2aBHA@PS
before and after the Suzuki−Miyaura reaction.
To determine the surface composition and oxidation state of
the catalyst after the Sonogashira coupling, we performed the
reaction of 4-iodoanisole (7a) with 1.5 equiv of 2-methylbut-3-
yn-2-ol (5a) in the presence of 2aBHA@PS (1 mol %
according to weight concentration of Pd(II) complexes), 5 mol
% of PPh3, 10 mol % of CuI and 4 equiv of Et3N in DMF under
air conditions at 40 °C. After the Sonogashira coupling the XPS
spectrum of 2aBHA@PS displayed two peaks of the binding
energies of Pd 3d5/2 and Pd 3d3/2 electrons at 340.7 and 335.5
eV, respectively (Figure 3), which indicated the presence of
Pd(0) and the absence of any Pd in the 2+ oxidation state in
the recovered catalyst.
To determine the structural changes that occurred, 2aBHA@
PS was characterized by IR after Sonogashira coupling (Table
5, entry 23). In the IR spectrum of the recovered sample of the
heterogeneous catalyst, the band of the isocyanide ligand was
observed with a slight long-wavelength shift (see Figure S17 in
the Supporting Information). This indicates that Pd species
remain connected to the support with a change in their ligand
environment under the reaction conditions.
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capillary exit at 50−100 V. The nebulizer gas flow was 0.4 bar and
drying gas flow was 4.0 L/min. For ESI, species were dissolved in
MeOH. In the isotopic pattern, the most intense peaks are reported.
Mass calibration for data system acquisition was achieved using CsI.
Elemental analyses were performed on EURO EA3000 vectro model
instrument. Thin-layer chromatography (TLC) was performed using
Polygram precoated plastic sheets SIL G/UV254 (SiO2, 0.20 mm
thickness) from Macherey-Nagel. Column chromatography was
performed using silica gel (40.0−63.0 nm particle size) from
Macherey-Nagel. The complexes PdCl2(CNCy)2 and PdCl2(CN-t-
Bu)2 were synthesized according to the literature procedure.134
Computational Details. The full geometry optimization of
3aBHA and single-point calculations have been carried out at the
DFT level of theory using the M06 functional (this functional
reasonably describes weak dispersion forces and noncovalent
interactions)135 with the help of Gaussian-09 program package.136
The experimental X-ray geometry was used as the starting point. The
calculations were performed using the quasi-relativistic Stuttgart
pseudopotential that described 28 core electrons and the appropriate
contracted basis sets137 for the palladium atoms and the 6-31+G* basis
set for other atoms. No symmetry restrictions have been applied
during the geometry optimization. The solvent effects were taken into
account using the SMD continuum solvation model by Truhlar et
al.138 with CHCl3 as solvent. The Hessian matrix was calculated
analytically in order to prove the location of correct minima (no
imaginary frequencies). The topological analysis of the electron
density distribution with the help of the atoms in molecules (AIM)
method developed by Bader has been performed by using the
Multiwfn program (version 3.3.4).139 The Cartesian atomic
coordinates of the calculated equilibrium structure of 3aBHA are
presented in Table 21S in the Supporting Information.
H), 7.22−7.05 (m, 4H, Ar-H and CH), 4.44 (m, 1H, CH(Cy)-NH),
3.26 (m, 1H, CH(Cy)-NC), 2.14 (d, J = 9.2 Hz) and 1.88−1.05(m,
20H, Cy-H); 13C NMR (101 MHz, DMSO-d6) δ 180.99 (Ccarbene),
142.07 (C(Ar)), 141.02 (C(Ar)), 128.62 (CH(Ar)), 128.57 (CH(Ar)),
128.36 (CH(Ar)), 128.30 (CH(Ar)), 127.40 (CH(Ar)), 127.07
(CH(Ar)), 66.90 (CH), 59.17 (CH(Cy)-NH), 54.92 (CH(Cy)-N
C), 33.40 (CH2), 33.13 (CH2), 31.72 (CH2), 31.67 (CH2), 25.22
(CH2), 24.93 (CH2), 24.87 (CH2), 24.58 (CH2), 22.94 (CH2)
(isocyanide carbon atom were not detected); IR (KBr, selected bands,
cm−1) ν 3246, 3054, 2929, 2855, 2225 (CN), 1588, 1573, 1451,
744, 700; HRMS (ESI+,70 V, MeCN) found 542.1618 [M − Cl],
calcd for C27H35ClN3Pd 542.1554.
Synthesis of C28H40Cl2N4Pd (3aBHA) and C18H22Cl2N2Pd
(4aBHA). PdCl2(CN-t-Bu)2 (0.069 g, 0.2 mmol) and CHCl3 (2
mL) were placed in a screw-cap vial. After homogenization and cooling
to 0 °C of the resultant reaction mixture a solution of benzhydryl-
amine (0.038 g, 0.2 mmol) in 1 mL of CHCl3 was added. The vial
equipped with a magnetic stir bar was placed in a steel bath, and the
mixture was stirred at room temperature (20 °C) for 12 h. The organic
solvent was removed under reduced pressure. Then THF (5 mL) was
added to the obtained residue and the resulting suspension filtered.
The precipitate was washed with diethyl ether (2 × 3 mL) and dried at
room temperature to give the corresponding cationic complex 3aBHA
in 47% (0.057 g) yield. The filtrate was then concentrated to 1 mL,
and hexane was added to afford a yellow solid. Recrystallization of the
obtained residue from a dichloromethane/pentane mixture gave
complex 4aBHA in 45% (0.040 g) yield.
3aBHA: colorless solid; 1H NMR (400 MHz, CDCl3) δ 10.90 (d, J
= 10.3 Hz, 1H, NH), 10.33 (s, 1H, NH), 7.50 (d, J = 7.5 Hz, 4H, Ar-
ortho-H), 7.29 (t, J = 7.6 Hz, 4H, Ar-meta-H), 7.19 (t, J = 7.4 Hz, 2H,
Ar-para-H), 6.65 (d, J = 10.3 Hz, 1H, CH), 1.57 (s, 9H, NH-C
(CH3)3), 1.24 (s, 18H, CN- C (CH3)3); 13C NMR (101 MHz,
CDCl3) δ 177.32 (Ccarbene), 141.48 (C(Ar)), 129.04 (C-meta-H(Ar)),
127.71 (C-para-H(Ar)), 127.16 (C-ortho-H(Ar)), 69.92 (CH),
59.78(NH-C(CH3)3), 54.12(CN-C(CH3)3), 31.37 (NH-C(CH3)3),
29.52 (CN−C (CH3)3) (isocyanide carbon atom was not detected);
IR (KBr, selected bands, cm−1) ν 3191, 2979, 2228 (CN), 1589,
1568, 1453, 1186, 765, 702; HRMS (ESI+,70 V, MeCN) found
573.1990 [M − Cl], calcd for C28H40ClN4Pd 573.1976. Anal. Calcd for
C28H40Cl2N4Pd (609.98): C, 55.13; H, 6.61; N, 9.19. Found: C, 55.18;
H, 6.75; N, 9.20. X-ray-quality crystals of 3aBHA were obtained by
slow evaporation of a saturated solution (pentane/CH2Cl2 mixture).
4aBHA: light yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.38 (d,
J = 4.3 Hz, 8H, Ar-H), 7.32 (m, 2H, Ar-H), 5.66 (t, J = 7.5 Hz, 1H,
CH), 3.47 (d, J = 7.0 Hz, 2H, NH2), 1.48 (s, 9H, CN-C(CH3)3);
13C NMR (126 MHz, CDCl3) δ 140.65 (C(Ar)), 129.12 (C-meta-
H(Ar)), 128.28 (C-para-H(Ar)), 127.51 (C-ortho-H(Ar)), 60.78(C
N-C(CH3)3), 30.08 (CN−C(CH3)3) (isocyanide carbon atom was
not detected); IR (KBr, selected bands, cm−1) ν 3311, 3246, 2984,
2240 (CN), 1585, 1573, 707, 337; HRMS (ESI+,70 V, MeCN)
found 407.0491 [M − Cl], calcd for C18H22ClN2Pd 407.0506. Anal.
Calcd for C18H22Cl2N2Pd (443.71): C, 48.73; H, 5.00; N, 6.31. Found:
C, 48.65; H, 5.09; N, 6.24. X-ray-quality crystals of 4aBHA were
obtained by slow evaporation of a saturated solution (pentane/CH2Cl2
mixture).
Synthesis of C23H31Cl2N3Pd (2aBHA). PdCl2(CN-t-Bu)2 (0.069
g, 0.2 mmol), Et3N·HCl (0.069 g, 0.5 mmol), and CHCl3 (2 mL) were
placed together in a screw-cap vial. After homogenization of the
resultant reaction mixture a solution of benzhydrylamine (BHA; 0.038
g, 0.2 mmol) in 1 mL of CHCl3 was then added. The vial equipped
with a magnetic stir bar was then placed in a steel bath, and the
mixture was stirred at room temperature for 12 h. Then the organic
solvent was evaporated under reduced pressure. A solvent mix
(C2H5OH/Et2O 2 mL/2 mL) was then added to the obtained residue
and the resulting suspension filtered. The precipitate was washed with
diethyl ether (2 × 3 mL) and dried at room temperature to give the
corresponding Pd(II)-ADC complex 2aBHA (colorless solid). Yield:
0.087 g (83%). Anal. Calcd for C23H31Cl2N3Pd (526.84): C, 52.44; H,
5.93; N, 7.98. Found: C, 52.48; H, 5.83; N, 7.87. According to NMR
data, the product was obtained as a mixture of two isomers (isomer
1
ratio is 19:1), Major syn,syn isomer: H NMR (400 MHz, CDCl3/
DMSO-d6 10/1) δ 8.37 (d, J = 8.8 Hz, 1H, NH), 7.78 (s, 1H, NH),
7.34−7.10 (m, 11H, Ar-H and CH), 1.55 (s, 9H, NH-C(CH3)3), 1.04
(s, 9H, CN- C(CH3)3); 13C NMR (101 MHz, CDCl3:DMSO-d6
10:1) δ 184.36 (Ccarbene), 141.79 (C(Ar)), 141.28 (C(Ar)), 128.65
(CH(Ar)), 128.59 (CH(Ar)), 128.29 (CH(Ar)), 127.61 (CH(Ar)),
127.52 (CH(Ar)), 127.21 (CH(Ar)), 66.36 (CH), 58.29(NH-
C(CH3)3) 54.17(CN-C(CH3)3), 31.61(NH-C (CH3)3),
29.45(CN−C(CH3)3) (isocyanide carbon atom were not detected);
IR (KBr, selected bands, cm−1): ν 3241, 3064, 3030, 2980, 2223(C
N), 1559, 1454, 1371, 1199, 702; HRMS (ESI+,70 V, MeCN) found
490.1216 [M − Cl], calcd for C23H31ClN3Pd 490.1241. X-ray-quality
crystals of 2aBHA were obtained by slow evaporation of a saturated
solution (DMSO/CHCl3 mixture).
Synthesis of C27H35Cl2N3Pd (2bBHA). The compound was
prepared by a procedure similar to that for 2aBHA. A mixture of
PdCl2(CN-Cy)2 (0.079 g, 0.2 mmol), Et3N·HCl (0.069 g, 0.5 mmol),
and BHA (0.038 g, 0.2 mmol) was used. A colorless solid was
obtained. Yield: 0.093 g (80%). Anal. Calcd for C27H35Cl2N3Pd
(578.92): C, 56.02; H, 6.09; N, 7.26. Found: C, 56.01; H, 6.04; N,
7.19. According to NMR data, the product was obtained as a mixture
of two isomers (isomer ratio is 13:1), Major syn,syn isomer: 1H NMR
(400 MHz, CDCl3) δ 8.45 (d, J = 8.9 Hz, 1H, NH), 7.98 (d, J = 8.9
Hz, 1H, NH), 7.54 (d, J = 7.3 Hz, 2H, Ar-H), 7.35−7.29 (m, 5H, Ar-
Synthesis of Complexes C28H40Cl2N4Pd (3aBHA) and
C34H46Cl2N4Pd (3bBHA). PdCl2(CN-R)2 (R = t-Bu, Cy; 0.2 mmol)
and CHCl3 (2 mL) were placed in a screw-cap vial. After
homogenization of the resultant reaction mixture a solution of
benzhydrylamine (0.038 g, 0.2 mmol) and tert-butyl isocyanide (0.017
g, 0.2 mmol) in 1 mL of CHCl3 was added. The vial equipped with a
magnetic stir bar was placed in a steel bath, and the mixture was stirred
at the appropriate temperature for 6 h. The organic solvent was
removed under reduced pressure. Recrystallization of the obtained
residue from a dichloromethane/hexane mixture gave complexes
3aBHA and 3bBHA in 95% (0.116 g) and 96% (0.132 g) yields,
respectively.
3bBHA: colorless solid; 1H NMR (400 MHz, CDCl3) δ 10.83 (d, J
= 8.7 Hz, 1H, NH), 10.23 (d, J = 9.2 Hz, 1H, NH), 7.48 (d, J = 7.6 Hz,
4H, Ar-ortho-H), 7.31 (t, J = 7.5 Hz, 4H, Ar-meta-H), 7.20 (t, J = 7.3
K
DOI: 10.1021/acs.organomet.6b00144
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Hz, 2H, Ar-para-H), 6.45 (bs, 1H, CH), 3.98 (m, 1H, CH(Cy)-NH),
3.69−3.44 (m, 2H, CH(Cy)-NC), 1.90−1.13 (m, 30H, Cy-H). 13C
NMR (101 MHz, CDCl3) δ 176.46 (Ccarbene), 141.35 (C(Ar)), 129.04
(C-meta-H(Ar)), 127.71 (C-para-H(Ar)), 127.23 (C-ortho-H(Ar)),
68.61 (CH), 58.9417 (CH(Cy)-NH), 55.67 (CH(Cy)-NC), 33.59
(CH2), 31.60 (CH2), 31.56 (CH2), 25.01 (CH2), 24.41 (CH2), 24.33
(CH2), 22.65 (CH2) (isocyanide carbon atom was not detected); IR
(KBr, selected bands, cm−1) ν 3168, 2933, 2856, 2232(CN), 1591,
1578, 1450, 1352, 753, 700; HRMS (ESI+,100 V, MeOH) found
651.2423 [M − Cl], calcd for C18H22ClN2Pd 651.2446. Anal. Calcd for
C34H46Cl2N4Pd (688.09): C, 59.35; H, 6.74; N, 8.14. Found: C, 59.47;
H, 6.65; N, 8.20.
X-ray Fluorescence Analysis. XRF analysis was performed with a
Rigaku NANOHUNTER benchtop total reflection X-ray fluorescence
(TXRF) spectrometer. A Cu anode X-ray tube was used for excitation
at 50 kV and 0.6 mA. X-ray fluorescence was detected using an Si/Li
dispersive detector in a coplanar, right angle geometry to the X-ray
source. Spectra were acquired over a 300 s acquisition period. Each
solution of palladium was sampled (100 μL) three times on sodium
glass plates as specified by the manufacturer and dried at 70 °C and
each sample was measured twice; an average of six runs is reported.
For quantitative analysis the palladium fluorescence was measured
against an internal standard of known concentration (KI, 56 μg K/
probe for Sonogashira coupling; p-TsOH, 101 μg S/probe for Suzuki−
Miyaura coupling). The exact amount of Pd in solution was
determined using the linear area of the calibration curve IPd/Istandard
= f([Pd]). Standard solutions of known concentrations of palladium
were prepared as follows: bis(acetonitrile)palladium(II) dichloride (2
mg) was dissolved in absolute acetone (10 mL), and the desired
amounts of the resulting solution were transferred to glass vials using a
microsyringe. Vials were dried at 50 °C for 10 min, cooled to room
temperature, and filled with 5 mL of an internal standard solution in
DMF (47.6 mg/L of KI corresponding to 56 μg of potassium/probe or
108.5 mg/L of TsOH corresponding to 101 μg of sulfur/probe).
Preparation and Characterization of Supported Pd(II)-ADC
Complexes. Benzhydrylamine hydrochloride resin (1 g, 200−400
mesh; BHA resin·HCl), Et3N (55 mg, 0.55 mmol), and CHCl3 (20
mL) were placed in a screw-cap vial equipped with a magnetic stir bar.
The resulting suspension was vigorously stirred for 10 min. After this,
cis-PdCl2(CNR)2 (R = t-Bu, 20.6 mg, 0.06 mmol; R = Cy, 23.7 mg,
0.06 mmol) was added and stirring was continued for 24 h. The
obtained 2aBHA@PS (R = t-Bu) or 2bBHA@PS (R = Cy) was
filtered off, washed with 10 mL of CHCl3, and dried under reduced
pressure. The filtrate was then concentrated and analyzed by NMR
and XRF, which showed the starting complex completely bonded to
the surface: white solid, estimated concentration of Pd 0.075 mmol/g.
2aBHA@PS: IR (KBr, cm‑1) 3082, 3060, 3024, 3002, 2919, 2851,
2224 (CN), 1944, 1874, 1807, 1745, 1720, 1671, 1600, 1583, 1562,
1493, 1449, 1371, 1330, 1314, 1279, 1217, 1199, 1182, 1155, 1067,
1028, 906, 843, 744, 697, 667, 621, 541.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00144.
2bBHA@PS: IR (KBr, cm‑1) 3082, 3059, 3025, 2920, 2849, 2225
(CN), 1943, 1872, 1803, 1663, 1600, 1492, 1451, 1365, 1181, 1154,
1068, 1027, 906, 842, 754, 695, 536.
Crystallographic data and bond lengths and angles for
complexes 2aBHA, 3aBHA, and 4aBHA, NMR and IR
spectra of all complexes, details of XRF analysis, and
theoretical studies (PDF)
Crystallographic data for complexes 2aBHA, 3aBHA,
and 4aBHA (CIF)
General Procedure for Sonogashira Cross-Coupling. The
polymer-supported palladium catalyst (2aBHA@PS or 2bBHA@PS;
100 mg, 0.0075 mmol, 10 mol % according to weight concentration of
surface complexes) in a 10 mL round-bottom flask was first sustained
in 2 mL of DMF for 10 min, followed by 2 mL of a DMF solution of
aryl halide (0.075 mmol), alkyne (0.113 mmol), Et3N (30 mg, 0.3
mmol), and PPh3 (5−10 mol %, if required). The flask then was
placed in a preheated oil bath and CuI (1.4 mg, 0.0075 mmol, 10 mol
%) was added at once. The resulting heterogeneous system was stirred
for the required time, cooled to room temperature, and filtered. The
supported catalyst was washed with an additional portion of DMF
(10−15 mL). A 5 mL portion of the combined filtrate (20 mL in total)
was sampled and analyzed by XRF, and the residual DMF solution was
poured into 30 mL of water, followed by extraction with ethyl acetate.
The extract was evaporated under reduced presser, dissolved in
Cartesian coordinates for the calculated structures (XYZ)
AUTHOR INFORMATION
Corresponding Author
*E-mail for I.A.B.: i.balova@spbu.ru.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
CDCl3, and analyzed by H NMR.
■
General Procedure for Suzuki−Miyaura Cross-Coupling. The
polymer-supported palladium catalyst (2aBHA@PS or 2bBHA@PS;
50 mg, 0.0036 mmol, 5 mol % according to weight concentration of
surface complexes) in a 10 mL round-bottom flask was first sustained
in 2 mL of DMF for 10 min, followed by 2 mL of a DMF solution of
aryl halide (0.075 mmol), phenylboronic acid (11 mg, 0.09 mmol),
aqueous K2CO3 or Et3N (0.3 mmol), and PPh3 (5−10 mol %, if
required). The flask then was placed in a preheated oil bath and the
resulting heterogeneous system was stirred for the required time,
cooled to room temperature, and filtered. The supported catalyst was
washed with an additional portion of DMF (10−15 mL). A 5 mL
portion of the combined filtrate (20 mL in total) was sampled and
analyzed by XRF, and the residual DMF solution was poured into 30
mL of water, followed by extraction with ethyl acetate. The extract was
evaporated under reduced pressure, dissolved in CDCl3, and analyzed
This study was supported by Saint Petersburg State University
(research project 12.38.195.2014). V.N.S. acknowledges the
President of the Russian Federation for a research grant for
young scientists (MK-3322.2014.3). V.N.M. is grateful to the
Russian Foundation for Basic Research for support; the
reported study was funded according to the research project
no. 16-33-00659 mol_a. A.S.N. is grateful to the Russian
Foundation for Basic Research for support; the reported study
was funded according to the research project no. 16-33-60063
mol_a_dk. Scientific research was performed at the resource
centers of Saint Petersburg State University: Centre of
Magnetic Resonance, Centre for Chemical Analysis and
Materials Research, Centre for X-ray Diffraction Studies,
Center of Physical methods of surface investigation, and
Chemistry Educational Centre.
1
by H NMR.
General Procedure for Supported Catalyst Recycling. After
separation of the product mixture and washing with an additional
portion of DMF, the supported catalyst was washed with 10 mL of
CH2Cl2 and dried at room temperature under reduced pressure. In
some cases, when K2CO3 as a base was used, the catalyst was first
washed with 10 mL of water followed by 5 mL of DMF and the
required amount of CH2Cl2.
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