Palladium(II) pyrazolyl–pyridyl complexes containing a sterically hindered N-heterocyclic carbene moiety for the Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.ica.2017.03.026

Cationic palladium complexes stabilized by a tridentate neutral {N,N,C} ligand containing a sterically hindered N-heterocyclic carbene (NHC) moiety have been prepared and characterized. The nature of the anionic counterion in the palladium complex has been varied to get crystals suitable for X-ray diffraction. The square planar structure of one of these complexes along with the axial contribution of the sterically hindered NHC fragment has been confirmed by X-ray analysis. In addition, all the isolated [{κ³-N,N,C}Pd^IICl]⁺X^? [X^? = Cl, PF₆, BF₄, B(C₆H₃Cl₂)₄] ion pairs have been scrutinized as catalysts in the cross-coupling Suzuki-Miyaura reaction between phenylboronic acid and variably substituted halo-aryl acceptors. Selected issues from this series have shown improved catalyst turn-over frequencies (TOFs) with respect to structurally related catalytic systems of the state-of-the-art.

Full text of DOI:10.1016/j.ica.2017.03.026

Accepted Manuscript
Research paper
Palladium(II) Pyrazolyl–Pyridyl Complexes Containing a Sterically Hindered
N-Heterocyclic Carbene Moiety for the Suzuki-Miyaura Cross-Coupling Reac-
tion
Lapo Luconi, Zufar Gafurov, Andrea Rossin, Giulia Tuci, Oleg Sinyashin,
Dmitry Yakhvarov, Giuliano Giambastiani
PII:
S0020-1693(17)30152-4
http://dx.doi.org/10.1016/j.ica.2017.03.026
ICA 17486
DOI:
Reference:
Inorganica Chimica Acta
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Received Date:
Revised Date:
Accepted Date:
31 January 2017
10 March 2017
13 March 2017
Please cite this article as: L. Luconi, Z. Gafurov, A. Rossin, G. Tuci, O. Sinyashin, D. Yakhvarov, G. Giambastiani,
Palladium(II) Pyrazolyl–Pyridyl Complexes Containing a Sterically Hindered N-Heterocyclic Carbene Moiety for
the Suzuki-Miyaura Cross-Coupling Reaction, Inorganica Chimica Acta (2017), doi: http://dx.doi.org/10.1016/j.ica.
2017.03.026
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Palladium(II) Pyrazolyl–Pyridyl Complexes Containing
a Sterically Hindered N-Heterocyclic Carbene Moiety
for the Suzuki-Miyaura Cross-Coupling Reaction
Lapo Luconi,[a],ϕ Zufar Gafurov,[b],ϕ Andrea Rossin,*,[a] Giulia Tuci,[a] Oleg Sinyashin,[b]
Dmitry Yakhvarov*,[b,c] and Giuliano Giambastiani*,[a,c]
[a] Institute of Chemistry of OrganoMetallic Compounds, ICCOM-CNR, Via Madonna del Piano,
10, 50019 Sesto Fiorentino, (Florence), Italy. Fax: +39 055 5225203.
Email: giuliano.giambastiani@iccom.cnr.it, a.rossin@iccom.cnr.it
[b] A.E.Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences,
Arbuzov str. 8, 420088 Kazan, Russian Federation. Email: yakhvar@iopc.ru
[c] Kazan Federal University, 420008 Kazan, Russian Federation.
ϕ These co-authors contributed equally to this work
Abstract
Cationic palladium complexes stabilized by a tridentate neutral {N,N,C} ligand containing a
sterically hindered N-heterocyclic carbene (NHC) moiety have been prepared and characterized.
The nature of the anionic counterion in the palladium complex has been varied to get crystals
suitable for X-ray diffraction. The square planar structure of one of these complexes along with the
axial contribution of the sterically hindered NHC fragment has been confirmed by X-ray analysis.
In addition, all the isolated [{κ3-N,N,C}PdIICl]+X- [X- = Cl, PF6, BF4, B(C6H3Cl2)4] ion pairs have
been scrutinized as catalysts in the cross-coupling Suzuki–Miyaura reaction between phenylboronic
acid and variably substituted halo-aryl acceptors. Selected issues from this series have shown
improved catalyst turn-over frequencies (TOFs) with respect to structurally related catalytic systems
of the state-of-the-art.
1

Keywords: NHC-containing ligand; Palladium complexes; Suzuki-Miyaura coupling
1. Introduction
The design and synthesis of new ligands featured by a mixed-donor atom set and including one or
more N-heterocyclic carbene (NHC) frameworks have received a great deal of attention in the last
decade because of their high versatility in the fields of coordination chemistry and homogeneous
catalysis.[1] The strong σ-donor and relatively weak π-acceptor properties of NHCs make them
valuable mimics of phosphines in transition-metal coordination chemistry.[2] In addition, NHC
frameworks generally present higher donor capability and basicity than phosphines and offer more
versatility to the easy tuning of their stereo-electronic properties compared to their P-based
counterparts whose manipulation is often not trivial.[3] In this paper, a highly sterically hindered
NHC group has been selected as the third donor site for the construction of a tridentate pyrazolyl-
pyridyl ligand [L(N,N,C)] containing a hemilabile coordinative arm (N-pyrazole) (Scheme 1).[4-8]
Scheme 1. General sketch of ligand and complexes described in this paper.
From a homogeneous catalysis viewpoint, the ligand hemilability provides access to a vacant
coordination site at the metal center and facilitates an effective coordination, activation and
transformation of the substrate. The neutral [L(N,N,C)] ligand has been used to synthesize a series of
Pd(II) complexes to be used in turn as pre-catalysts for the cross-coupling reaction between an
organoboron reagent and an organic halide (Suzuki-Miyaura cross coupling).[9] The strong σ-donor
character of NHC trans to the N-pyrazole is thought to speed up the N-dissociation (trans effect),
thus making this coordinative position more reactive in the interaction with the substrate throughout
the catalytic process. Structurally related ligands featuring with the same donor atom set but
2

containing less sterically demanding substituents at the NHC fragment have been discussed in the
literature and scrutinized in combination with a Pd(II) precursor for the Suzuki-Miyaura cross-
coupling.[10] This reaction consists of three consecutive steps in the catalytic cycle: the substrate
oxidative addition, an aryl transmetallation from boron to palladium and the final product reductive
elimination.[11] Overall, the process benefits from the use of electron-donating and sterically
demanding ligands for promoting the first and last steps, respectively.[9, 12] Herein, we describe
the methodology applied for the synthesis of a sterically hindered imidazolium salt as precursor of
the neutral [L(N,N,C)] ligand and the isolation and characterization of cationic Pd(II) complexes with
different counterions. The effect of bulky substituents on NHC-based palladium complexes has
important precedents in the literature, particularly regarding the development of protocols devised
for the cross-coupling of sterically challenging substrates. Seminal issues about the (NHC)Pd-
catalyzed Suzuki-Miyaura reaction [9, 13, 14] have demonstrated that the higher the steric
hindrance of NHC substituents, the lower the catalyst loading required for the process to occur.[15]
The effects of ligand and ion pair and NHC steric hindrance have been discussed in the Suzuki-
Miyaura reaction for the cross-coupling of phenylboronic acid (PBA) with a variety of aryl halides.
2. Experimental
2.1 General considerations and characterization methods.
All reactions dealing with ligand and complexes syntheses were performed under an inert
atmosphere in flame-dried flasks using standard Schlenk-type techniques or in a glovebox filled
with nitrogen. Acetonitrile (CH3CN) and diethyl ether (C4H10O) were obtained by means of a
MBraun solvent purification system. Pentane and CH2Cl2 were also used after a preliminary
treatment through columns of activated alumina and molecular sieves. CD2Cl2 and DMSO-d6 were
dried over activated 4 Å molecular sieves or calcium hydride. Na[B(3,5-C6H3Cl2)4] [16, 17] and cis-
PdCl2(PhCN)2 [18] were prepared according to the published procedures. All other reagents and
3

1
solvents were used as purchased from commercial suppliers and used as received. H, 13C{1H},
31P{1H} NMR and 11B{1H} NMR spectra were obtained on a Bruker Avance 400 or Bruker Avance
300 MHz instrument. Chemical shifts are reported in ppm (δ) relative to TMS, referenced to the
chemical shifts of residual solvent resonances (1H and 13C), and coupling constants are given in Hz.
11
31P{1H} NMR spectra are referenced to an external 85% H3PO4 sample (0 ppm). B{1H} NMR
spectra are referenced to boron trifluoride diethyl etherate (BF3 · Et2O). The N, C, H elemental
analyses were carried out at ICCOM by means of a Carlo Erba Model 1106 elemental analyzer. The
GC-MS analyses were performed on a Shimadzu QP2010S apparatus equipped with with a flame
ionization detector and a Supelco SPB1 fused silica capillary column (30 m length, 0.25 mm i.d.,
0.25 µm film thickness).
2.2 Synthesis of the imidazolium salt 3. A mixture of 1 (0.600 g, 2.67
mmol) and imidazole 2 (0.611 g, 2.67 mmol) was sealed in a glass
ampoule under nitrogen and heated to 190 °C for seven days. After
cooling to room temperature, the crude product was dissolved in the
minimum amount of CH2Cl2 and added dropwise in a large excess of diethyl ether under stirring to
give a precipitate that was filtered on Buchner funnel and washed with diethyl ether to give the final
1
product as light brown powder (1.090 g, 90 % yield). H NMR (400 MHz, CD2Cl2, 293K): δ 1.19
3
3
(d, JHH = 6.8 Hz, 6H, CH(CH3)), 1.27 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 2.42 (sept, 3JHH = 6.8 Hz,
3
2H, CH(CH3)), 6.52 (m, 1H, CH Ar, Pyrazolyl), 7.38 (d, JHH = 7.8 Hz, 2H, CH Ar), 7.53 (m, 1H,
imidazole), 7.61 (t, 3JHH = 7.8 Hz, 1H, CH Ar), 7.77 (m, 1H, CH Ar, Pyrazolyl), 8.12-8.21 (2H, CH
3
Ar, Py), 8.75 (m, 1H, CH Ar, Pyrazolyl), 8.81 (d, JHH = 7.8 Hz, 1H, CH Ar, Py), 9.11 (m, 1H,
imidazole), 11.3 (m, 1H, imidazole). 13C{1H}m NMR (100 MHz, CD2Cl2, 293 K): δ 24.2
(CH(CH3)2,), 24.3 (CH(CH3)2,), 29.1 (CH(CH3)2), 109.1 (CH Ar), 112.9 (CH Ar), 114.1 (CH Ar),
120.9 (CH Ar), 125.0 (CH Ar), 125.9 (CH Ar), 128.1 (CH Ar), 130.3 (Cq), 132.3 (CH Ar), 136.7
4

(CH Ar), 143.4 (CH Ar), 143.7 (CH Ar), 144.7 (Cq), 145.5 (Cq), 151.0 (Cq). Anal. Calcd (%) for
C23H26BrN5 (452.39): C 61.06, H 5.79, N 15.48; found C 61.11, H 5.70, N 15.53.
2.3 General procedure for the synthesis of complexes [(κ3-NNC)PdCl]+X-
(X = Cl, 4a; X = PF6, 4b; X = BF4, 4c; X = B(C6H3Cl2)4, 4d). A suspension
of 3 (0.200 g, 0.44 mmol), Ag2O (5 eq., 0.512 g, 2.21 mmol), and activated
molecular sieves 4 Å (200% w/w) in CH2Cl2 (10 mL) was stirred at reflux
for 18 h in the dark. After cooling to room temperature, the suspension was filtered by cannula and
the solution was dried under vacuum to give a pale brown foam. The residue was re-dissolved in
dry and degassed CH3CN (10 mL) and PdCl2(PhCN)2 (0.160 g, 0.42 mmol) was added to the
solution. The resulting mixture was stirred at reflux for 16 h. After cooling to room temperature, a
fine suspension of AgCl was filtered off and the clear solution underwent different treatments
depending on the nature of the desired complex counterion. For 4a, the solution was concentrated to
1/3 of its initial volume and the addition of an excess of Et2O caused the formation of a light brown
precipitate. The precipitate was collected and washed with Et2O to give the pure product with fairly
good yield (0.200 g, 88 % yield). For complexes 4b-d, a crude mixture of 4a was treated at room
temperature with an equimolar amount of a silver or sodium salt containing the desired counterion
[AgX (X = PF6, BF4) or NaX (X = B(C6H3Cl2)4) (0.42 mmol)] and stirred for further 5 h under
these conditions. Afterwards, the resulting suspensions were filtered off and solutions concentrated
to 1/3 of their initial volume. Addition of Et2O afforded the desired complexes 4b-d in the form of
pale yellow microcrystals. Each precipitate was collected and washed with Et2O to give the final
product with isolated yields ranging from 53 to 79%. Crystals of 4d suitable for X-ray diffraction
analysis were grown by layer diffusion of Et2O to a concentrated CH3CN solution of the complex at
1
room temperature. 4a (88 % yield of the isolated product): H NMR (400 MHz, DMSO-d6, 293K):
3
3
δ 1.13 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 1.25 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 2.53 (m, 2H,
3
3
CH(CH3)), 6.99 (m, 1H, CH Ar, Pyrazolyl), 7.34 (d, JHH = 7.8 Hz, 2H, CH Ar), 7.53 (t, JHH = 7.8
Hz, 1H, CH Ar), 7.99 (m, 1H, NCHCHN, imidazole), 8.07 (m, 1H, CH Ar, Pyrazolyl), 8.23-8.26
5

(2H, CH Ar, Py), 8.72 (m, 1H, CH Ar, Py), 8.83 (m, 1H, NCHCHN, imidazole), 9.26 (m, 1H, CH
Ar, Pyrazolyl). 13C{1H} NMR (100 MHz, DMSO-d6, 293 K): δ 23.2 (CH(CH3)2,), 24.1
(CH(CH3)2,), 28.0 (CH(CH3)2), 109.3 (CH Ar), 109.7 (CH Ar), 110.9 (CH Ar), 119.2 (CH Ar),
123.6 (CH Ar), 126.4 (CH Ar), 130.5 (CH Ar), 133.1 (Cq), 133.2 (CH Ar), 144.3 (Cq), 144.7 (CH
Ar), 146.2 (CH Ar), 147.5 (Cq), 148.6 (Cq), 154.4 (Pd-C). Anal. Calcd (%) for C23H25Cl2N5Pd
(548.80): C 50.34, H 4.59, N 12.76; found C 50.30, H 4.57, N 12.80. 4b (68 % yield of the isolated
1
3
product): H NMR (400 MHz, CD2Cl2, 293K): δ 1.13 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 1.25 (d,
3JHH = 6.8 Hz, 6H, CH(CH3)), 2.53 (m, 2H, CH(CH3)), 6.99 (m, 1H, CH Ar, Pyrazolyl), 7.34 (m,
2H, CH Ar), 7.53 (m, 1H, CH Ar), 7.98 (m, 1H, NCHCHN, imidazole), 8.07 (m, 1H, CH Ar,
Pyrazolyl), 8.22-8.25 (2H, CH Ar, Py), 8.71 (m, 1H, CH Ar, Py), 8.82 (m, 1H, NCHCHN,
imidazole), 9.25 (m, 1H, CH Ar, Pyrazolyl). 13C{1H} NMR (100 MHz, DMSO-d6, 293 K): δ 23.2
(CH(CH3)2,), 24.1 (CH(CH3)2,), 28.1 (CH(CH3)2), 109.3 (CH Ar), 109.7 (CH Ar), 110.9 (CH Ar),
119.2 (CH Ar), 123.7 (CH Ar), 126.4 (CH Ar), 130.5 (CH Ar), 133.2 (CH Ar and Cq), 144.3 (CH
31
Ar), 144.7 (Cq), 146.2 (CH Ar), 147.6 (Cq), 148.6 (Cq), 154.4 (Pd-C). P{1H} NMR (161 MHz,
DMSO-d6, 293 K): δ -144.1 (sept). Anal. Calcd (%) for C23H25ClF6N5PPd (658.32): C 41.96, H
1
3.83, N 10.64; found C 42.00, H 3.87, N 10.61. 4c (79 % yield of the isolated product): H NMR
3
3
(400 MHz, CD2Cl2, 293K): δ 1.10 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 1.22 (d, JHH = 6.8 Hz, 6H,
CH(CH3)), 6.97 (m, 1H, CH Ar, Pyrazolyl), 7.32 (m, 2H, CH Ar), 7.51 (m, 1H, CH Ar), 7.97 (m,
1H, NCHCHN, imidazole), 8.06 (m, 1H, CH Ar, Pyrazolyl), 8.18-8.22 (2H, CH Ar, Py), 8.68 (m,
1H, CH Ar, Py), 8.79 (m, 1H, NCHCHN, imidazole), 9.22 (m, 1H, CH Ar, Pyrazolyl). 13C{1H}
NMR (100 MHz, DMSO-d6, 293 K): δ 23.3 (CH(CH3)2,), 24.1 (CH(CH3)2,), 28.1 (CH(CH3)2),
109.3 (CH Ar), 109.7 (CH Ar), 110.9 (CH Ar), 119.2 (CH Ar), 123.7 (CH Ar), 126.4 (CH Ar),
130.5 (CH Ar), 133.2 (CH Ar and Cq), 144.3 (CH Ar), 144.7 (Cq), 146.3 (CH Ar), 147.6 (Cq),
148.6 (Cq), 154.4 (Pd-C). 11B{1H} NMR (128 MHz, DMSO-d6, 293 K): δ -1.2 (s). Anal. Calcd (%)
for C23H25BClF4N5Pd (600.16): C 46.03, H 4.20, N 11.67; found C 46.01, H 4.17, N 11.64. 4d (53
6

3
% yield of the isolated product): 1H NMR (400 MHz, CD2Cl2, 293K): δ 1.12 (d, JHH = 6.8 Hz, 6H,
3
CH(CH3)), 1.25 (d, JHH = 6.8 Hz, 6H, CH(CH3)), 2.52 (m, 2H, CH(CH3)), 6.89 (m, 8 H, o-CH Ar,
B(C6H3Cl2)4), 6.99 (m, 1H, CH Ar, Pyrazolyl), 7.16 (m, 4 H, p-CH Ar, B(C6H3Cl2)4), 7.34 (m, 2H,
CH Ar), 7.53 (m, 1H, CH Ar), 7.99 (m, 1H, NCHCHN, imidazole), 8.08 (m, 1H, CH Ar, Pyrazolyl),
8.23-8.26 (2H, CH Ar, Py), 8.71 (m, 1H, CH Ar, Py), 8.83 (m, 1H, NCHCHN, imidazole), 9.25 (m,
1H, CH Ar, Pyrazolyl). 13C{1H} NMR (100 MHz, DMSO-d6, 293 K): δ 23.2 (CH(CH3)2,), 24.1
(CH(CH3)2,), 28.1 (CH(CH3)2), 109.3 (CH Ar), 109.7 (CH Ar), 110.9 (CH Ar), 119.2 (CH Ar),
123.1 (CH Ar), 123.7 (CH Ar), 126.4 (CH Ar), 130.5 (CH Ar), 132.5 (CH Ar and Cq (B(ArCl2)4)),
133.1 (Cq), 133.2 (CH Ar), 144.3 (CH Ar), 144.7 (Cq), 146.3 (CH Ar), 147.6 (Cq), 148.6 (Cq),
154.4 (Pd-C), 165.2 (Cq, 1JBC = 49 Hz, B(ArCl2)4) . 11B{1H} NMR (128 MHz, DMSO-d6, 293 K): δ
-7.2 (s). Anal. Calcd (%) for C47H39BCl9N5Pd (1110.16): C 50.85, H 3.54, N 6.31; found C 50.87,
H 3.57, N 6.29.
2.4 General procedure for the Suzuki-Miyura Reactions. In a typical run, the selected catalyst (4a-
d) was added to a solution of aryl halide (1.0 mmol), phenylboronic acid (PBA, 1.5 mmol) and
Cs2CO3 (2.0 mmol) in 5 mL of solvent (DMF/H2O v/v = 10:1). The resulting mixture was
maintained under stirring and heated at the desired temperature (Table 1) using a pre-heated oil
bath. The reaction course was monitored by sampling the mixture at fixed times and analyzing it via
GC-MS technique. The reaction was stopped by cooling the mixture down rapidly to room
temperature through addition of 15 mL of cold water. For a quantitative estimation of the diphenyl
derivative obtained in the process, the crude mixture was treated with a fixed amount of Fluorene
(C13H10) as internal standard for GC analysis. Afterwards, the crude mixture was extracted with
diethyl ether (3 x 15 mL) and the collected organic phases were dried over Na2SO4. Solvent
removal under reduced pressure gave the crude material that was purified by flash chromatography
on silica gel to afford the pure diphenyl derivative. Isolated yields are given as average values of
two separate runs at least.
7

2.5 X-ray Diffraction Data. Single crystal X-Ray data of 4d were collected at low temperature (100
K) on an Oxford Diffraction XcaliburPX diffractometer equipped with a CCD area detector using
Cu Kα radiation (λ = 1.5418 Å). The program used for the data collection was CrysAlis CCD
1.171.[19] Data reduction was carried out with the program CrysAlis RED 1.171 [19] and the
absorption correction was applied with the program ABSPACK 1.17. Direct methods implemented
in Sir97 [20] were used to solve the structures and the refinements were performed by full-matrix
least-squares against F2 implemented in SHELX97.[21] All the non-hydrogen atoms were refined
anisotropically, while the hydrogen atoms were fixed in calculated positions and refined
isotropically with the thermal factor depending on the one of the atom to which they are bound
(riding model). Molecular plots were produced by the program ORTEP3.[22] CCDC-1528509
contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
ccdc.cam.ac.uk/community/requestastructure.
3. Results and Discussion
3.1 Synthesis of the {N,N,CH}+Br- ligand precursor (3) and related palladium complexes [{κ3-
N,N,C}PdIICl]+X- [X- = Cl, PF6, BF4, B(C6H3Cl2)4] (4a-d)
Scheme 2 illustrates the stepwise procedure adopted to synthesize the desired ligand precursor 3 and
palladium complexes in good yields. Two synthetic steps have been used for preparing the key
organic building blocks 1 and 2 in gram scale from commercially available precursors, following
literature procedures.[23, 24] Both reactions proceed smoothly to give 1 and 2 as white crystalline
solids after chromatographic purification with fairly good yield (1: 93%; 2: 56%). Quaternarization
of the N-substituted imidazole 2 is obtained by melting it with the bromo-pyridine 1 at 190°C in a
sealed ampule under rigorous N2 atmosphere [25] and keeping the system without stirring under this
8

conditions for days (see Experimental Section). The reaction mixture is then dissolved in CH2Cl2
and the imidazolium salt (3) is precipitated in nearly quantitative yield (93 %) from the solution
using an excess of diethyl-ether. The recovered light-brown microcrystals are then washed several
times with Et2O, dried under vacuum at room temperature till constant weight and stored under N2
atmosphere.
t
Scheme 2. Synthesis of ligand 3 and complexes 4a-d. Reaction conditions: i) BuOK, dioxane, reflux, 48h; ii) H2CO
35% in H2O, NH3 25% in H2O, MeOH, 70 °C; iii) 190 °C, neat, 7 days; iv) Ag2O, CH2Cl2, 40 °C, 18h; v)
PdCl2(PhCN)2, CH3CN, 16 h, reflux; vi) AgPF6 (4b) or AgBF4 (4c) or NaB(C6H3Cl2)4 (4d), CH3CN, 5 h, r.t.
The treatment of 3 with a silver base (Ag2O) is used to activate the imidazolium salt thus providing
the corresponding AgI-NHC compound. [26, 27] Transmetallation with PdCl2(PhCN)2 gives 4a as
analytically pure light-brown microcrystals in 88 % yield.[10] The nature of the counterion (Cl-) in
4a has been assigned based on a low resolution mass analysis [LRMS (ESI-)]. The experimental MS
spectrum regarding mass values and isotopic profile perfectly matches with the simulated one thus
confirming Cl- as counterion (Fig. S1). A counterion exchange is accomplished upon treating a
freshly prepared CH3CN solution of 4a with a silver or sodium salt of the desired anion. The
treatment with AgX (X = PF6, BF4) provides complexes 4b and 4c in 68 and 79 % isolated yield,
respectively. 4a-c are isolated from the mother liquors as highly twinned snowflakes crystals not
suitable for X-ray analysis and their characterization is given in solution by means of multinuclear
NMR spectroscopy (1H and 13C{1H} NMR for 4a-c; 31P{1H} NMR for 4b and 11B{1H} NMR for
4c) (Figs. S4-S11). Elemental analysis has confirmed the occurrence of a complete anion exchange
9

as well as the analytical purity of the isolated complexes. Complex 4d containing the bulkier and
-
weakly coordinating B(C6H3Cl2)4 anion is obtained in 53 % isolated yield from the reaction of 4a
with NaB(C6H3Cl2)4. 4d is isolated as off-white single needles suitable for X-ray diffraction
analysis. All the solid systems prepared (4a-d along with their ligand precursor 3) are air- and
moisture-stable compounds. All complexes are highly soluble in common polar organic solvents
(i.e. CH3CN, DMSO, DMF), moderately soluble in chlorinated hydrocarbons (CH3Cl and CH2Cl2)
and scarcely soluble or insoluble in Et2O including the more common aliphatic or aromatic
1
hydrocarbons. The H and 13C{1H} NMR spectra of complexes 4a-c show almost superimposable
patterns with the only exception of 4d because of the presence of typical low-field signals attributed
to the tetra-aryl counterion (Figs. S12-S13). Evidences for the generation of carbene complexes
(Pd-NHC) are given by the disappearance of the typical imidazolium resonance (δΗ over 11 ppm) in
1
the H NMR spectrum of 3 (Fig. S2) together with the appearance of diagnostic peak (δC around
154 ppm) in the 13C{1H} NMR spectra of all isolated organometallics and ascribed to the ipso C-
site (Figs. S5, S7, S10, S13). Each iPr fragment in ligand 3 and complexes 4a-d shows an evident
proton shielding of one of the methyl groups. Such an effect is indicative of an appreciable extent of
conformational rigidity of the N-carbene substituent already present in the sterically hindered ligand
precursor. In 4a-d such a rigidity is additionally emphasized by the appearance of two well-resolved
high-field resonances in the 13C{1H} NMR spectra ascribed to couples of diastereotopic methyl
groups.
The X-ray structure of 4d has contributed to elucidate the metal coordination sphere of the
isolated compound. A perspective view is given in Fig. 1 along with a selection of the most
significant bond lengths and angles in the figure caption.
10

-
Fig. 1. Crystal structure of [{κ
3-N,N,C}PdIICl]+ B(C6H3Cl2)4 (4d). Thermal ellipsoids
are drawn at the 40% probability level. Hydrogen atoms are omitted for clarity. Selected
bond lengths (Å) and angles (o): Pd(1)-Cl(1) 2.2775(12), Pd(1)-N(1) 2.097(4), Pd(1)-
N(3) 1.968(4), Pd(1)-C(8) 1.963(5), N(3)-C(5)-N(4)-C(8) 1.65(6), N(3)-C(1)-N(2)-N(1)
-6.33(6), C(8)-N(5)-C(9)-C(10) 97.3(6).
Complex 4d crystallizes in the monoclinic P21/c space group with 4 molecules per unit cell. The
PdII center adopts a distorted-square-planar coordination geometry (τ4 = 0.17) [28] with the N-
carbene substituent lying in an almost orthogonal position with respect to the {N,N,C}coordination
plane. Bond lengths and angles measured within the [{κ
3-N,N,C}PdIICl]+ fragment of 4d fall in the
typical range observed for related cationic Pd-fragments in square-planar environments.[10]
Extensive C−H···Cl hydrogen bonding is present between the aromatic C−H bonds on the anion
rings and on the pyrazole substituent and chlorine atoms from adjacent molecules in the lattice
[mean d(C···Cl) = 3.59 Å]. Tables S1-S5 list all the main crystal and structural refinement data for
4d.
3.2 The Suzuki-Miyaura cross-coupling reaction of phenylboronic acid (PBA) with various aryl-
halides catalyzed by complexes 4a-d.
The Palladium-catalyzed Suzuki-Miyaura reaction (SMr) certainly ranks among the most utilized
tools for the construction of a C-C bond between and organoboron reagent and an organic halide in
the presence of a base. Its practical use along with very high turn-over numbers (TONs) in
combination with specific catalytic systems,[29, 30] have made this process highly popular in the
11

pharmaceutical and chemical industries.[31] The recent literature in the field has demonstrated how
the use of palladium complexes [32] stabilized by sterically bulky mono- or bis-NHC ligands leads
to outstanding catalytic performances already under moderate reaction temperatures and in the
presence of low catalyst loadings.[13, 14, 33-36] In addition, the renowned ability of related
pyrazolyl–pyridyl complexes containing less sterically demanding NHC moieties at performing the
SMr efficiently[10] prompted us to test complexes 4a-d in the process. Table 1 lists the coupling
reactions of selected aryl halides with phenylboronic acid (PBA) promoted by complexes 4a-d. All
reactions were carried out in a solvent mixture of DMF and H2O (10:1 v/v) using Cs2CO3 as the
base in the 80-120 °C temperature range depending of the mixture or reagents used. For all issues,
the catalyst loading ranged between 0.5 and 5.0 mol% and the reaction course was monitored
through thin layer chromatography (TLC) by sampling the reaction mixtures at different times.
Selection of reagents was accomplished with the final aim of comparing the catalytic performance
of complexes 4a-d in the model cross-coupling process with those of related but less sterically
hindered NHC-Pd complexes from the literature.[10] Under optimized experimental conditions
(catalyst loading and reaction temperature), all catalysts 4a-d showed from good to excellent
performance in the Suzuki-Miyaura reaction with PBA. All conversions were firstly estimated via
GC-MS analysis before being confirmed on the basis of the isolated products as obtained from
chromatographic purification of crude mixtures. As table 1 shows, a rational trend between
chemical yield (or catalyst turn-over frequency TOF) and nature of the anionic counterion seems
-
rather hard to be unambiguously traced out. Under the adopted conditions, chlorine (Cl-), PF6 and
-
BF4 as palladium counterions showed only minor effects on TOFs and little differences reasonably
fall in the statistical experimental data error.
Table 1. Suzuki-Miyaura Reactions Catalyzed by 4a-d.
12

Catalyst Time
(mol%) (h)
Yieldb (%)
(isol. yield)
Entry
ArX
Product
TOFd
1
2
4a (0.5)
4b (0.5)
4c (0.5)
4d (0.5)
4a (0.5)
4b (0.5)
4c (0.5)
Cat. (3)
4d (0.5)
4a (3)
0.2
0.2
0.2
0.2
2
>99 (99)
96 (94)
97 (94)
52 (48)
98 (94)
>99 (>99)
98 (96)
(95)
-
964
969
518
98.0
-
3
4
5
6
2
7
8c
2
98.2
15.8
93.2
-
2
9
2
93 (90)
>99 (>99)
98 (95)
93 (90)
81 (80)
89 (86)
92 (88)
89 (87)
73 (72)
84 (84)
89 (88)
82 (80)
65 (64)
23 (20)
19 (n.d.)
21 (20)
18 (n.d.)
10
11
12
13
14
15
16
17
18e
19e
20e
21e
22e
23e
24e
25e
5
4b (3)
4c (3)
5
6.58
6.23
5.41
5.93
6.14
5.95
4.89
3.38
3.55
3.28
2.61
0.91
0.75
0.85
0.71
5
4d (3)
4a (3)
5
5
4b (3)
4c (3)
5
5
4d (3)
4a (5)
5
5
4b (5)
4c (5)
5
5
4d (5)
4a (5)
5
5
4b (5)
4c (5)
5
5
4d (5)
5
aReaction Conditions: ArX, 1.0 mmol; phenylboronic acid, 1.5 mmol, Cs2CO3, 2.0 mmol; solvent,
DMF/H2O (v/v = 10:1), 5mL; temperature: 80 °C. b Conversion measured by GC-MS using fluorene as
internal standard. c 3 mol% of Cat.:[{κ3-N,N,CNHC(nBu)}PdIICl]+BF4- from ref. [10] d expressed as mmol of
aryl-halide converted per (mmol of catalyst)-1 (h)-1; mmol of aryl halide converted as measured by GC-
MS on the crude mixture. e temperature: 120 °C.
On the contrary, a more appreciable deviation was measured for almost all catalytic issues with
-
complex 4d. The bulkier and weakly coordinating B(C6H3Cl2)4 anion was found to have a
detrimental effect on the catalyst TOF if compared with the performance of the 4a-c congeners
under identical conditions (i.e. Table 1, entry 4 vs. 1-3). Although any explanation for this
observable lies on a mere speculative ground, the different behavior of 4d can be tentatively
ascribed to a decrease of the catalytically active species concentration [Pd(0)] in solution. Such a
decrease may be due to an inherent inertness of 4d (or one of its adducts) to undergo reduction.
Indeed, the loose ion pair formed in 4d combined with an easy pyrazole detachment may induce the
13

formation of Pd(µ-Cl)2Pd dimeric forms (4d-dim) [37, 38] potentially reluctant to reduction to
Pd(0) under the adopted experimental conditions (Scheme 3).[11]
Scheme 3. Supposed dimerization of 4d to give 4d-dim as a Pd(II) species less
easy to be reduced under the Suzuki-Miyaura conditions.[11]
An increased catalyst concentration appears to be crucial also in the case of less reactive aryl
bromides like those containing amino (Table 1, entries 10-13) or hydroxyl (Table 1, entries 14-17)
functional groups. 3 mol% of each pre-catalyst and prolonged reaction time (5 h) are needed to get
quantitative conversion of the aryl bromides into the corresponding diphenyl derivatives 13 and 14.
A special comment is needed to rationalize TOF values recorded for each catalyst from this series
(compared to TOFs measured with related catalytic systems on the state-of-the-art) in the cross-
coupling of PBA with the deactivated 4-methoxybromoaryl (Table 1, entries 5-7, 9). With 0.5 mol%
of each catalyst (4a-c) an almost complete substrate conversion is obtained after keeping the system
for two hours under stirring at 80 °C (Table 1, entries 5-7 and 9). Zeng and co-workers have
reported this challenging issue (Table 1, entry 8) with 95% of the isolated 12 using 3 mol% of the
n
less sterically hindered palladium analogue of 4c (containing a Bu chain as N-substituent at the
NHC moiety).[10] In 4c, the steric hindrance generated by the 2,6-iPr(C6H3) fragment eventually
increases the catalyst performance thus ensuring a complete substrate conversion to 12 already at
reduced palladium loading (Table 1, entry 8 vs. 7). Finally, the cross-coupling reaction with the
activated 4-acetylchlorobenzene (Table 1, entries 18-21) gave fairly good substrate conversions
only with 5 mol% of each catalyst and at a higher reaction temperature (120 °C) (Table 1, entries
18-21). Chloride derivatives classically exhibit lower reactivity than their iodide and bromide
14

analogues. This was confirmed by the moderate conversions obtained in the cross-coupling reaction
of the relatively unreactive phenylchloride (10) (Table 1, entries 22-25 vs. 1-4).
Conclusions
In summary, the synthesis and characterization of a series of cationic pyrazolyl-pyridyl Pd(II)
complexes containing a highly sterically demanding N-heterocyclic carbene unit and featuring with
different counterions have been described. At odds with related NHC-containing ligands of the
state-of-the-art, the synthetic methodology applied to the synthesis of the sterically hindered
imidazolium salt as ligand precursor has provided it in the form of light-brown microcrystals with
an overall 48% yield over three steps. Its activation with a silver base (Ag2O) followed by
transmetallation with a Pd(II) precursor and counterion exchange led to the isolation of four
-
-
-
{[N,N,C]Pd+Cl}X- (X- = Cl-, PF6 , BF4 , B(C6H3Cl2)4 ) complexes whose full spectroscopic
characterization is provided along with the X-ray structure of the system containing the bulkier and
weakly coordinating B(C6H3Cl2)4 anion. All isolated compounds have been scrutinized as catalyst
precursors in the cross-coupling Suzuki-Miyaura reaction with phenylboronic acid and variably
substituted halo-aryl acceptors. Selected issues from this series have shown improved catalyst turn-
over frequencies (TOFs) compared with related (but less sterically demanding) catalytic systems of
the state-of-the-art. In addition, the nature of the counterion has been evaluated under the adopted
experimental conditions showing an appreciable deviation from TOFs in the case of the looser ion
pair (4d) only.
Acknowledgments
The Italian team would like to thank the Bilateral CNR-RFBR Project (Italy-Russian Federation)
for the financial support to this work. the common program of the Russian Foundation for Basic
Research and the Government of the Republic of Tatarstan (project 15-43-02667). GG also thank
Prof. G. Poli for fruitful suggestions.
15

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Table of Contents
Four cationinc pyrazolyl-pyridyl Pd(II) complexes containing a sterically demanding N-
heterocyclic carbene unit have been synthesized and spectroscopically characterized. The sterically
demanding nature of the ligand and the effect of the palladium counterion were evaluated in the
cross-coupling Suzuki-Miyaura reaction between phenylboronic acid and variably substituted halo-
aryl acceptors.
17

Highlights
•
•
A novel synthetic protocol for the synthesis of sterically hindered N,N,C ligand.
A tridentate pyrazolyl-pyridyl ligand containing a a highly sterically hindered NHC
group.
•
•
Synthesis of a series of Pd(II) complexes as pre-catalysts for the Suzuki-Miyaura
cross-coupling reaction.
The higher the steric hindrance of NHC substituents, the lower the catalyst loading
required for the cross-coupling process to occur.
18