Synthesis, characterization and evaluation of bulky bis(pyrazolyl)palladium complexes in Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1039/c8ra01430b

Pyrazole-containing compounds have been used in recent times as ligands to stabilize metal complexes used as pre-catalysts in cross-coupling reactions. With various substituents at various positions in the pyrazole ring, the overall electrophilic and steric properties of the metal complexes can be fine-tuned. Herein, we report the synthesis of bulky pyrazole-based ligands by condensation of methyl 4-(bromomethyl)benzoate or benzyl bromide with various substituted pyrazole compounds. These ligands were utilised in the synthesis of bis(pyrazolyl)palladium(ii) complexes. The complexes' catalytic activity in Suzuki-Miyaura cross-coupling reactions was evaluated. Phenyl bearing pre-catalyst 7, at a catalyst loading of 0.33 mol%, successfully converted 98% of bromobenzene and phenylboronic acid to biphenyl in 4 h at 140 °C, while the tertiary butyl bearing pre-catalyst 8 converted up to 81% of the same substrates to biphenyl. An increase in conversion was seen for all pre-catalysts when an electron-withdrawing substituent was present on the aryl halide substrate, and the opposite was observed when the electron-withdrawing group was present on the phenyl boronic acid.

Full text of DOI:10.1039/c8ra01430b

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PAPER
Synthesis, characterization and evaluation of bulky
bis(pyrazolyl)palladium complexes in Suzuki–
Miyaura cross-coupling reactions†
Cite this: RSC Adv., 2018, 8, 13826
*
James Darkwa and Banothile C. E. Makhubela
*
Edward Ocansey,
Pyrazole-containing compounds have been used in recent times as ligands to stabilize metal complexes
used as pre-catalysts in cross-coupling reactions. With various substituents at various positions in the
pyrazole ring, the overall electrophilic and steric properties of the metal complexes can be fine-tuned.
Herein, we report the synthesis of bulky pyrazole-based ligands by condensation of methyl 4-
(bromomethyl)benzoate or benzyl bromide with various substituted pyrazole compounds. These ligands
were utilised in the synthesis of bis(pyrazolyl)palladium(II) complexes. The complexes' catalytic activity in
Suzuki–Miyaura cross-coupling reactions was evaluated. Phenyl bearing pre-catalyst 7, at a catalyst
loading of 0.33 mol%, successfully converted 98% of bromobenzene and phenylboronic acid to biphenyl
in 4 h at 140 ꢀC, while the tertiary butyl bearing pre-catalyst 8 converted up to 81% of the same
substrates to biphenyl. An increase in conversion was seen for all pre-catalysts when an electron-
withdrawing substituent was present on the aryl halide substrate, and the opposite was observed when
the electron-withdrawing group was present on the phenyl boronic acid.
Received 14th February 2018
Accepted 26th March 2018
DOI: 10.1039/c8ra01430b
rsc.li/rsc-advances
crystallography. Although these palladium complexes contain
bulky ligands, they do not in any way affect the formation of the
Introduction
active Pd(0) species that are used in the Suzuki–Miyaura cross-
coupling reactions. Bulky ligands, might, in fact, contribute to
stabilization of the active Pd(0) species, and in spite of their
steric bulk is able to isomerize to the cis conformation during
the catalysis.12
Synthesis of biaryl compounds, which are the building blocks
for the preparation of the Merck and Novartis hypertensive
drugs losartan and valsartan, involves the use of transition
metal catalysts such as palladium and copper.1–5 Most notably,
palladium complexes have gained widespread use as catalysts
in both industry and academia for performing cross-coupling
reactions mainly due to their thermal, oxidative and moisture
stability, facile synthesis and the ability to modulate the steric
and electronic properties of these palladium complexes.6 Bis-
ligated palladium complexes, especially those with bulky
monodentate ligands are well known for their anticancer
properties7,8 and as effective cross-coupling catalysts.9,10
The most popular ligand system in cross-coupling reactions
are ligands that have phosphorus donor atoms. Phosphorus-
containing ligands facilitate the formation of bulky and elec-
tron rich complexes which allow for the effective cross-coupling
of aryl halides and boronic acids.11 These ligands with phos-
phorus donor atoms have the ability to impart improved cata-
lytic activity when used to form transition metal complexes.
However, the drawback of phosphorus-containing ligands is
their extreme sensitivity to air and moisture. Nitrogen donor
ligands are providing alternatives to phosphorus donor ligands
in that they can be tuned to obtain desired electronic and steric
properties, in order to enhance the stability of the active Pd(0)
species.13 An interesting class of nitrogen donor ligands are
ligands that have pyrazolyl units. Pyrazolyl palladium
complexes are ideal for cross-coupling reaction because the
pyrazole nitrogen is a weaker s-donor compared to imine and
pyridines, and hence provides highly electrophilic metal
centres. Additionally, the ability to vary substituents on the
pyrazolyl ring allows the overall electrophilic and steric prop-
erties of resultant metal complexes to be adjusted.14–16 This is
because the type of substituent affects the nucleophilicity of the
nitrogen atoms in the ring and the bond strength of the
Palladium catalysts coordinated in a trans fashion have been
reported to demonstrate increased activity for cross-coupling
between a wide array of aryl chlorides and amines at low cata-
lyst loading, with a varied substrate scope.11 Similar observa-
tions have been made with the phosphine-ferrocenyl ligands
reported by Stepnicka et al.12 Despite the extreme bulk of these
ligands, they have insignicant distortion of the geometry
around the metal from square planar as conrmed by X-ray
ˇ
ˇ
ˇ
Department of Chemistry, University of Johannesburg, PO Box 524, Auckland Park,
2006, South Africa. E-mail: bmakhubela@uj.ac.za
† Electronic supplementary information (ESI) available: CCDC number 1555880
contains the supplementary crystallographic data for complex 7. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra01430b
13826 | RSC Adv., 2018, 8, 13826–13834
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subsequent ligated metal. Indeed several pyrazolyl palladium 7.86 (d, JHH ¼ 8 Hz, 2H, Harom), 7.42–7.31 (m, 8H, Harom), 7.15
complexes have been used in recent times as pre-catalysts in (d, 2H, JHH ¼ 8 Hz, Harom), 6.67 (s, 1H, Hpz), 5.42 (s, 2H, HCH ),
2
cross-coupling reactions.10,17,18 Also with an increase in electro- 3.87 (s, 3H, HCH ). 13C{1H} NMR (400 MHz, CDCl3, 30 ꢀC) (ppm)
3
philicity at the metal centre, the catalytic activity is ¼ 166.8; 151.3; 145.6; 142.8; 133.3; 130.5; 130.4; 130.2; 129.9;
enhanced.14,19,20 Mukherjee and Sarkar21 have demonstrated 129.3; 128.8; 128.7; 127.8; 126.7; 125.7; 103.9; 53.0; 52.1; ESI-MS
that pyrazolylimine palladium complexes have catalytic activi- [M + H]+ ¼ 369.16. Elemental analysis; anal. calcd for
ties for Suzuki–Miyaura cross-coupling reaction that is depen-
C24H20N2O2: C, 78.24; 5.47; N, 7.60%, found C, 78.42; H, 5.94; N,
dent on the donor atoms and their steric environment.21 These 7.31%.
pyrazolylimine ligands with low steric bulk and hard donor
Synthesis of methyl 4-((3,5-di-tert-butyl-1H-pyrazol-1-yl)
group such as NMe2 failed to catalyze the Suzuki–Miyaura cross- methyl)benzoate (2). Into a round bottom ask containing
coupling reactions. This indicates that the ligands could not 5 mL DMSO, 750.00 mg (4.16 mmol) of 3,5-di-tert-butyl-1H-
stabilize the Pd(0) species that is expected to catalyze the cross- pyrazole was added and stirred for 5 min. 363.00 mg (9.08
coupling reaction. However, larger aryl groups on the imine mmol) of 60% NaH was added and the mixture stirred at room
nitrogen in the pyrazolylimine ligands were efficient catalysts temperature for 1 h. Thereaer, 700.00 mg (3.79 mmol) of
for the Suzuki–Miyaura cross-coupling reaction.21
methyl-4-(chloromethyl)benzoate was added and the resulting
We herein report bis(pyrazolyl)palladium complexes with mixture stirred at room temperature for 3 h. The contents of the
bulky substituents on the ligands and their applications as round bottom ask were then transferred into 10 mL of distilled
catalysts in the Suzuki–Miyaura cross-coupling reaction that water. The mixture was then extracted with 4 ꢁ 20 mL portions
clearly support how steric bulk of ligands enhance catalytic of diethyl ether. The organic layer was washed with 2 ꢁ 5 mL
activities in cross-coupling reactions.
distilled deionized water. The crude product was then puried
by passing through a silica packed column and eluted with 1 : 3
diethylether : hexane mixture. The rst band was collected and
identied as of methyl-4-(chloromethyl)benzoate aer TLC
comparison. The desired product eluted as the second band.
Experimental
Materials
All reactions were carried out in air unless otherwise stated. All The solvent was then removed by rotary evaporation followed by
solvents used were reagent grade, purchased from Sigma drying in vacuo for 6 h to obtain the product. (Yield ¼ 501.22 mg,
Aldrich and dried under nitrogen before use. 4-(Chloromethyl) 40%). Solubility: soluble in chloroform, methanol, DCM,
benzoic acid, thionyl chloride, 1,3-diphenyl-1,3-propanedione, hexane and diethyl ether, insoluble in water. Melting point
1
hydrazine monohydrate, sodium hydride, 2,2,6,6-tetramethyl- range 138–139 C. FT-IR (nmax/cmꢂ1): 1713.12 (C]O). H NMR
ꢀ
3,5-heptanedione, potassium hydroxide, benzyl bromide, (400 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 7.90 (d, 2H, JHH ¼ 8 Hz,
benzyl chloride, sodium hydroxide, sodium bicarbonate,
H
arom), 6.90 (d, JHH ¼ 8 Hz, 2H, Harom), 5.92 (s, 1H, Hpz), 5.49 (s,
t t
potassium tert-butoxide, ethyl acetate and glacial acetic acid 1H, HCH ), 3.86 (s, 3H, HCH ), 1.29 (s, 9H, H Bu), 1.22 (s, 9H, H Bu).
2
3
were purchased from Sigma Aldrich and used without further 13C{1H} NMR (100 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 166.8; 160.6;
purication. PdCl2 was purchased from Heraeus South Africa 151.9; 144.6; 129.7; 129.6; 128.8; 125.8; 125.7; 100.3; 54.0; 51.9;
and used as received. [PdCl2(MeCN)2],22 3,5-di-tert-butylpyr- 31.2; 30.1: ESI-MS [M + H]+ ¼ 329.22; elemental analysis; anal.
azole,23 3,5-diphenylpyrazole24 and methyl-4-(chloromethyl) calcd for C20H28N2O2: C, 73.14; H, 8.59; N, 8.53%, found C,
benzoate25 were synthesized according to literature procedures. 73.22; H, 9.16; N, 7.85%.
Synthesis of methyl 4-((3,5-diphenyl-1H-pyrazol-1-yl)methyl)
Synthesis of 1-benzyl-3,5-diphenyl-1H-pyrazole (3). Into
benzoate (1). Into a round bottom ask containing 5 mL a round bottom ask containing 20 mL acetonitrile, 51.170 mg
DMSO, 916.31 mg (4.16 mmol) of 3,5-diphenyl-1H-pyrazole was (0.9120 mmol) of KOH was added and the mixture was stirred
added and stirred for 5 min. 363.00 mg (9.08 mmol) of 60% NaH for 10 min. 100.00 mg (0.45 mmol) of 3,5-diphenyl-1H-pyrazole
was then added and the mixture stirred at room temperature for was added and the reaction mixture was stirred for an addi-
1
h. Thereaer, 700.00 mg (3.79 mmol) of methyl-4- tional 20 minutes. Benzyl bromide 93.60 mg (0.55 mmol) was
(chloromethyl)benzoate was added and the resulting mixture then added slowly over an hour aer which the reaction mixture
ꢀ
stirred at room temperature for 3 h. The contents of the round was reuxed at 85 C for 24 h. A precipitate formed over time
bottom ask were then transferred into 10 mL of distilled water. which was ltered off. The residue was collected and the solvent
The mixture was then extracted with 4 ꢁ 20 mL portions of was removed by evaporation to give the crude product. The
diethyl ether. The organic layer was washed with 2 ꢁ 5 mL product was puried by passing through a silica packed column
distilled deionized water. The crude product was then puried and eluted with 3 : 7 hexane : diethyl ether mixture. The second
by passing through a silica packed column and eluted with 1 : 3 band was collected and identied as the product aer TLC
diethylether : hexane mixture. The solvent was then removed by comparison with the starting materials. The solvent was then
rotary evaporation followed by drying in vacuo for 6 hours to removed by rotary evaporation to obtain the product. Appear-
obtain the product. Appearance white solid (yield ¼ 603.00 mg, ance; white crystals (yield 96.000 mg, 68%). Solubility: soluble
43%). Solubility: soluble in chloroform, methanol, DCM, in chloroform, DCM, and diethylether, insoluble in hexane,
hexane and diethylether, insoluble in water. Melting point methanol and water. Melting point range 94–96 ꢀC. FT-IR (nmax
/
range 122–123 ꢀC. FT-IR (nmax/cmꢂ1): 1712 (C]O). 1H NMR (100 cmꢂ1): 1460 (C]N). 1H NMR (400 MHz, CDCl3, 30 ꢀC) (ppm) ¼
3
ꢀ
MHz, CDCl3, 30 C) (ppm) ¼ 7.95 (d, 2H, JHH ¼ 8 Hz, Harom), 7.71 (d, JHH ¼ 7.2 Hz, 2H, Harom), 7.35–7.23 (m, 11H, Harom),
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7.03 (d, 3JHH ¼ 6.8 Hz, 2H, Harom), 6.58 (s, 1H, Hpz), 5.31 (s, 2H, analysis; anal. calcd for C48H40Cl2N4O4Pd: C, 63.06; H, 4.41; N,
H
CH ). 13C{1H} NMR (100 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 150.9; 6.13% found C, 63.18; H 4.71 N, 5.83%.
2
145.4; 137.7; 133.4; 130.6; 128.8; 128.7; 128.4; 128.3; 127.5;
Synthesis of [{bis(methyl 4-((3,5-di-tert-butyl-1H-pyrazol-1-
127.4; 126.9; 126.8; 126.7; 103.7; 53.2: ESI-MS [M + H]+ ¼ 311.15 yl)methyl)benzoate)}-palladium(II) chloride] (6). Into a Schlenk
(100%). Elemental analysis; anal. calcd for C22H18N2: C, 85.13; tube, 200.00 mg of methyl 4-((3,5-di-tert-butyl-1H-pyrazol-1-yl)
H, 5.85; N, 9.03%, found C, 85.40; H, 5.65; N, 9.41%.
methyl)benzoate (0.61 mmol) was added to 78.990 mg (0.30
Synthesis of 1-benzyl-3,5-di-tert-butyl-1H-pyrazole (4). Into mmol) of [PdCl2(MeCN)2] using 5 mL of DCM as solvent. The
a round bottom ask containing 20 mL acetonitrile, 62.500 mg reaction mixture was then stirred for 24 h under argon at room
(1.11 mmol) of KOH was added and the mixture was stirred for temperature. The solvent was reduced in vacuo until the crude
10 minutes. 100.00 mg (0.55 mmol) of 3,5-di-tert-butyl-1H-pyr- product began to precipitate. Hexane 5 mL was then added drop
azole was added and the reaction mixture was stirred for an wise until the product completely precipitated from solution.
additional 20 minutes. Benzyl bromide 114.32 mg (0.67 mmol) The precipitate was ltered off and washed with 2 ꢁ 5 mL
was added slowly over an hour, aer which the reaction mixture hexane and dried under vacuum for 6 h in order to obtain the
ꢀ
was reuxed at 85 C for 24 h. A precipitate formed over time product. Appearance yellow powder, (184.24 mg, 73%). Solu-
which was ltered off. The residue was collected and the solvent bility: soluble in chloroform, DCM, partially soluble in xylene
evaporated to give the crude product. The product was puried and toluene, insoluble in hexane, diethylether, water and
by passing through a silica packed column and eluted with 3 : 7 methanol. Melting point range 241 ꢀC (decomposed without
1
hexane : diethylether mixture. The second band was collected melting). FT-IR (nmax/cmꢂ1): 1716 (C]O). H NMR (400 MHz,
and identied as the product aer TLC comparison with the CDCl3, 30 ꢀC) (ppm) ¼ 8.10 (d, JHH ¼ 8 Hz, 2H, Harom), 8.05 (d,
starting materials. The solvent was then removed by rotary JHH ¼ 7.6 Hz, 2H, Harom), 7.21 (d, JHH ¼ 8 Hz, 2H, Harom), 7.06 (d,
evaporation to obtain the product. Appearance; white crystals JHH ¼ 8 Hz, 2H, Harom), 6.02 (m, 6H, HCH , Hpz), 3.93 (s, 3H,
2
t
t
(yield ¼ 110.10 mg, 73%). Solubility: soluble in chloroform,
HCH ), 3.88 (s, 3H, HCH ), 1.93 (s, H Bu, 6H), 1.89 (s, H Bu, 1H),
3
3
t
t
t
insoluble in water at room temperature. Solubility: soluble in 1.81 (s, H Bu, 6H), 1.61 (s, H Bu, 2H), 1.54 (s, H Bu, 3H), 1.29 (s,
t
t
t
t
chloroform, methanol, DCM, hexane and diethyl ether, insol-
H Bu, 1H), 1.24 (s, H Bu, 7H), 1.22 (s, H Bu, 7H), 1.17 (s, H Bu, 3H),
uble in water. Melting point range 60–62 ꢀC. FT-IR (nmax/cmꢂ1): 13C{1H} NMR (100 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 167.3; 167.2;
1
ꢀ
1456 (C]N). H NMR (400 MHz, CDCl3, 30 C) (ppm) ¼ 7.25 167.1; 167.0; 165.5; 160.9; 157.2; 153.4; 144.2; 141.9; 141.7;
3
3
3
(t, JHH ¼ 5.6 Hz, JHH ¼ 9.2 Hz, 3H, Harom), 6.85 (d, JHH
¼
130.7; 130.6; 130.5; 130.3; 130.2; 130.1; 130.0; 129.9; 129.7;
7.2 Hz 2H, Harom), 5.89 (s, 1H, Hpz), 5.45 (s, 2H, HCH ), 1.29 127.2; 126.9; 125.8; 105.4; 105.1; 56.6; 51.9; 33.0; 32.8; 32.3; 31.8;
2
(s, 9H, H Bu), 1.23 (s, 9H, H Bu). 13C{1H} NMR (100 MHz, CDCl3, 31.7; 31.6; 31.5; 31.4; 31.3; 31.2; 30.5; 30.3; 29.9; ESI-MS [M]+ ¼
t
t
ꢀ
30 C) (ppm) ¼ 160.3; 151.2; 139.2; 128.3; 128.1; 126.7; 126.5; 835.28 (40%). Elemental analysis; anal. calcd for C40H56Cl2N4-
125.8; 100.1; 54.1; 31.9; 30.3; ESI-MS [M + H]+ ¼ 271.21; O4Pd: C, 57.59; H, 6.77, N, 6.72% found C, 57.06; H, 6.77; N,
elemental analysis; anal. calcd for C18H26N2: C, 79.95; H, 6.69%.
9.69; N, 10.36%, found C, 80.08; H, 9.34; N 10.14%.
Synthesis of [{bis(1-benzyl-3,5-diphenyl-1H-pyrazole)}-palla-
Synthesis of [{bis(methyl 4-((3,5-diphenyl-1H-pyrazol-1-yl) dium(II) chloride] (7). Into a Schlenk tube, 100.00 mg of 1-
methyl)benzoate)}-palladium(II) chloride] (5). Into a Schlenk benzyl-3,5-diphenyl-1H-pyrazole (0.32 mmol) was added to
tube, 200.00 mg of methyl 4-((3,5-diphenyl-1H-pyrazol-1-yl) 41.760 mg (0.1609 mmol) of [PdCl2(MeCN)2] using 5 mL of DCM
methyl)benzoate (0.54 mmol) was added to 70.417 mg (0.27 as solvent. The reaction mixture was then stirred for 24 h under
mmol) of [PdCl2(MeCN)2] using 5 mL of DCM as solvent. The argon at room temperature. The solvent was reduced in vacuo
reaction mixture was then stirred for 24 h under argon at room until the crude product began to precipitate. Diethylether 5 mL
temperature. The solvent was reduced in vacuo until the crude was then added drop wise until the product completely
product began to precipitate. Hexane 5 mL was then added precipitated from solution. The precipitate was ltered off and
drop-wise until the product completely precipitated from solu- washed with 2 ꢁ 5 mL diethyl ether and dried under vacuum for
tion. The precipitate was ltered off and washed with 2 ꢁ 5 mL 6 h in order to obtain the product. Appearance yellow powder,
hexane and dried under vacuum for 6 h in order to obtain the (71.211 mg, 55%). Solubility: soluble in chloroform and DCM,
product. Appearance yellow powder, (189.11 mg, 76%). Solu- partially soluble in xylene and toluene, insoluble in water,
bility: partially soluble in chloroform, DCM, xylene and toluene, diethyl ether, methanol and hexane. Melting point range 250–
insoluble in methanol, water, hexane and diethyl ether. Melting 251 ꢀC. FT-IR (nmax/cmꢂ1): 1639 (C]N). 1H NMR (400 MHz,
ꢀ
ꢀ
point range 275 C (decompose without melting). FT-IR (nmax
/
CDCl3, 30 C) (ppm) ¼ 8.20 (d, JHH ¼ 7.2 Hz, 2H, Harom), 7.29–
cmꢂ1): 1713 (C]O). 1H NMR (400 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 7.13 (m, 9H, Harom), 6.99 (d, JHH ¼ 7.2 Hz, 2H, Harom), 6.94 (t, JHH
1
8.15 (d, JHH ¼ 6.8 Hz, 2H, Harom), 7.92(d, JHH ¼ 8 Hz, 2H, Harom), ¼ 8 Hz, JHH ¼ 7.6 Hz, 2H, Harom), 6.30 (s, Hpz, 1H), 6.10 (s, HCH
,
2
7.33–7.28 (m, 6H, Harom), 6.99 (d, JHH ¼ 5.6 Hz, 4H, Harom), 6.37 2H); 13C{1H} NMR (100 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 155.3;
(s, Hpz, 1H), 6.16 (s, HCH , 2H), 3.90 (s, HCH , 3H); 13C{1H} NMR 149.1; 137.3; 131.0; 129.1; 129.0; 128.9; 128.8; 128.7; 128.6;
2
3
(100 MHz, CDCl3, 30 ꢀC) (ppm) ¼ 167.4, 156.2; 149.9; 138.3; 128.5; 128.4; 128.3; 128.2; 110.1; 56.4; ESI-MS [M + Na]+ ¼ 823.12
131.8; 129.4; 129.2; 128.9; 128.8; 128.7; 128.5; 128.4; 128.3; (50%); [M ꢂ Cl]+ ¼ 765.17 (50%); [M ꢂ 2Cl]+ ¼ 725.18 (5%)
128.0; 127.9; 105.1; 57.1; 52.1; ESI-MS [M]+ ¼ 913.15 (10%); [M ꢂ elemental analysis; anal. calcd for C44H36Cl2N4Pd: C, 66.22; H,
Cl]+ ¼ 878.18 (5%); [M ꢂ 2Cl]+ ¼ 840.21 (5%); elemental 4.55, N, 7.02% found C, 66.46; H, 4.51; N, 6.78%.
13828 | RSC Adv., 2018, 8, 13826–13834
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Synthesis of [{bis(1-benzyl-3,5-di-tert-butyl-1H-pyrazole)}-
RSC Advances
catalyst amount (catalyst loading in mol%) was then added and
the reaction le to proceed with a stir rate of 600 rpm. Aer
reaction time had elapsed, aryl halide conversion to biphenyl
was calculated by analyzing retention peak areas of aryl halide
with reference to internal standard n-decane. GC analyses were
performed using a Scion 456 GC with 30 m ꢁ 0.25 mm cyano-
propylphenylmethylpolysiloxane phase column set to an initial
palladium(II) chloride] (8). Into a Schlenk tube, 100.00 mg of 1-
benzyl-3,5-di-tert-butyl-1H-pyrazole (0.3700 mmol) was added to
48.00 mg (0.1850 mmol) of [PdCl2(MeCN)2] using 5 mL of DCM
as solvent. The reaction mixture was then stirred for 24 h under
argon at room temperature. The solvent was reduced in vacuo
until the crude product began to precipitate. Hexane 5 mL was
then added drop-wise until the product completely precipitated
from solution. The precipitate was ltered off and washed with
2 ꢁ 5 mL hexane and dried under vacuum for 6 hours in order
to obtain the product. Appearance yellow powder, (76.441 mg,
58%). Solubility: soluble in DCM, partially soluble in dieth-
ylether, xylene and toluene, insoluble in hexane, water and
methanol. Melting point range 222 ꢀC (decomposed without
temperatuꢂre1 of 80 ꢀC and then increased to 300 ꢀC at
ꢀ
10 C min
.
Results and discussion
Synthesis and characterization of pyrazolyl ligands (1–4)
Compounds 1–4 were synthesized in a substitution reaction
involving substituted pyrazoles with the respective benzylic
halides in the presence of excess base (Scheme 1). These
1
melting). FT-IR (nmax/cmꢂ1): 1536 (C]N). H NMR (100 MHz,
ꢀ
CDCl3, 30 C) (ppm) ¼ 7.4–7.2 (m, 6H, Harom), 7.04 (d, JHH
¼
t
4.8 Hz, 4H, Harom), 6.00 (m, 6H, Hpz, HCH ), 1.94 (s, H Bu, 7H), compounds were obtained in moderate to good yields. The
2
t
t
t
1.91 (s, H Bu, 2H), 1.83 (s, H Bu, 9H), 1.69 (s, H Bu, 2H), 1.26 (d, substitution reactions could readily occur at room temperature
t
t
JHH ¼ 14.4 Hz, H Bu, 7H), 1.19 (d, JHH ¼ 6 Hz, H Bu, 7H), 1.18 (s, using DMSO, DMF or acetonitrile as solvents. The compounds
t
t
H
Bu, 2H), 0.86 (s, H Bu, 2H). 13C{1H} NMR (100 MHz, CDCl3, 30 display excellent solubility in organic solvents such as chloro-
ꢀC) (ppm) ¼ 164.1; 164.0; 157.0; 156.9; 135.8; 135.6; 129.0; 128.8; form and DCM. They were extracted from either DMSO or DMF
128.6; 128.2; 128.1; 127.9; 127.0; 126.8; 125.8; 105.2; 105.1;
105.0; 55.9; 55.7; 33.0; 32.9; 30.5; 30.3; ESI-MS [M]+ ¼ 719.27
(100%); elemental analysis; anal. calcd for C36H52Cl2N4Pd: C,
60.21; H, 7.30, N, 7.80% found C, 60.35; H, 7.60; N, 7.70%.
aqueous mixtures using diethyl ether. The substituted pyrazolyl
ligands were characterized by 1H NMR spectroscopy, mass
spectrometry, elemental analysis and infrared spectroscopy.
Downeld shis in the 1H NMR signals of the benzylic CH2
linker protons from around 4.50 ppm to around 5.50 ppm was
observed indicating successful formation of the ligands.
Further evidence for the synthesis of these ligands was
conrmed via mass spectrometry and elemental analysis.
Characterization of compounds
NMR spectra was obtained using Bruker-400 MHz NMR spec-
trometer (1H at 400 MHz and 13C{1H} at 100 MHz). Spectrometer
chemical shis were reported relative to the internal standard
tetramethylsilane (d 0.00 ppm) and referenced to the residual
proton and carbon signals at 7.24 and 77.0 ppm respectively of
Synthesis and characterization of bis(pyrazolyl)palladium(II)
complexes (5–8)
CDCl3. Infrared spectra were obtained neat using a Perkin Complexes 5–8 were obtained by reacting the appropriate
Elmer Spectrum BX II tted with an ATR probe. Melting points ligands in a 2 : 1 ratio with [PdCl2(MeCN)2] in DCM at room
were obtained using a Gallenkamp Digital Melting-point temperature for 24 h. Over the course of the reaction, the
Apparatus 5A 6797. Elemental analysis was performed on resulting complexes 6, 7 and 8 remained soluble in DCM while 5
a Thermos Scientic FLASH 2000 CHNS-O Analyzer. Mass formed a yellow colloidal suspension. For all the complexes, the
spectrometry was performed using Waters Synapt G2 mass reaction mixtures were concentrated in vacuo and n-hexane or
spectrometer with both ESI positive and cone voltage 15 V. XRD diethyl ether was added to the concentrated solution to
spectra were obtained from a Bruker APEX-II CCD Diffractom- encourage precipitation. The precipitates were obtained as
eter. Analytical thin layer chromatography (TLC) was performed varying shades of yellow solids in moderate to good yields. The
on silica gel coated aluminium plates (0.2 mm). Developed complexes were also soluble in organic solvents such as DCM
plates were visualized with UV light or under iodine staining. and chloroform. Characterization of these complexes by 1H
Silica gel column chromatography was performed using silica NMR spectroscopy showed a shi in the benzylic (CH2) protons
gel 60 (70–230 mesh).
from around 5.40–5.50 ppm in the ligands to around 6.00–
6.10 ppm in the complexes. This was as a result of coordination
of the pyrazolyl nitrogen atoms to the palladium, resulting in
a reduced electron density around the CH2 protons. Mass
spectra for all the complexes also conrmed their synthesis by
showing the m/z of the molecular ion peak or fragmentation
patterns corresponding to the loss of chloride ions or gain of
sodium ions.
General experimental description of Suzuki cross-coupling
reaction
The Suzuki–Miyaura cross-coupling reaction was performed
using a Radleys Carousel 12 Plus Reaction Station™ using 24 ꢁ
150 mm quick-thread glass reaction tubes. The general proce-
dure involved charging the reaction vessel with required
amounts of aryl halide, boronic acid, base, internal standard (n-
decane) and solvent. A sample of the reaction mixture in the
Molecular structure of compound 7
reaction vessel was taken at time zero and analyzed by GC to The solid state structure of complex 7 was obtained using
determine the ratios of various components. The required single-crystal X-ray diffraction. Crystals for complex 7 were
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Scheme 1 Synthesis of pyrazolyl ligands and complexes.
grown by slow evaporation of a DCM solution of 7 at room
temperature and were obtained as yellow crystals. Complex 7
crystallized in a P1 space group with a distorted square planar
geometry at the palladium centre. The pyrazolyl ligands coor-
dinated to the palladium in a trans fashion (Fig. 1). The bond
angles around the Pd are between 89.61(4)ꢀ and 90.39(4)ꢀ which
is in agreement of a square planar geometry. The crystal data
and structure renement parameters for 7 are presented in
Table 1. With only a slight distortion at the palladium centre, 1H
NMR spectrum for 7 showed that all phenyl protons on the
pyrazole ring resided in the same chemical environments. Pd–
Catalytic studies
Evaluation of complexes 5–8 as pre-catalysts in Suzuki–
Miyaura cross-coupling reactions. Complexes 5, 6, 7 and 8 were
screened as pre-catalysts for the Suzuki–Miyaura cross-coupling
reactions. The cross-coupling reactions was performed using
phenyl boronic acid (8 mmol), and bromobenzene (5 mmol) as
model substrates. At 0.066 mol% catalyst loading, preliminary
studies indicated the cross-coupling reaction was complete
aer 4 h (Table SI-1†). Increasing the reaction temperature
resulted in a gradual increase in conversion. Beyond 140 ꢀC,
there was a decrease in conversion for all four pre-catalysts. This
was possibly as a result of the decomposition of the catalysts at
high temperatures (Table SI-2†). Using strong inorganic bases
like KOH, K2CO3 and Na2CO3 resulted in high conversions for
all 4 pre-catalysts. This may be as a result of the faster rate at
which the phenyl borate species is formed. Using the weak
organic base, triethylamine, resulted in poor conversions for all
four pre-catalysts (Table SI-3†). Increasing the catalyst loading
also resulted in increased conversions as expected (Table SI-4†).
At 0.33 mol% catalyst loading, using KOH as a base, 140 ꢀC and
4 h reaction time, 98% conversion was achieved by 5, 86%
conversion for 6, 98% conversion for 7 and 81% conversion for
8. Reducing the reaction time to 3 h or reducing the tempera-
ture to 130 ꢀC under these conditions resulted in reduced
conversions (Table SI-0†). In order to conrm the stereo-
electronic effects of the substitutents on the pyrazolyl ring,
dichlorido bis-(1H-pyrazole)palladium(II) was synthesized
according to literature procedures26 and evaluated as a catalyst
precursor in the Suzuki–Miyaura cross-coupling using phenyl-
boronic acid and bromobenzene as coupling partners. Evalua-
tion of dichlorido bis-(1H-pyrazole)palladium(II) in Suzuki–
Miyaura cross-coupling under the optimum reaction conditions
established for catalysts 5, 6, 7 and 8 resulted in conversion to
N
pz and Pd–Cl bond lengths as well as bond angles around the
palladium centre for 7 were within reported ranges for similar
bis(pyrazolyl)palladium complexes in literature.10
ꢀ
Fig. 1 Molecular structure of 7. Selected bond distance (A) and bond
angles (ꢀ); Pd(1)–Cl(1) 2.2924(4), Pd(1)–N(1) 2.0135(15), N(2)–N(1)
1.363(2); N(1)–Pd(1)–Cl(1) 90.39(4), N(1)–Pd(1)–Cl(1i) 89.61(4).
13830 | RSC Adv., 2018, 8, 13826–13834
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Table 1 Crystal data for 7
reactions. The presence of ester groups in 5 and 6 did not
contribute any steric effect but lowered the electron-donation
towards the palladium centre. This resulted in slightly low-
ered aryl halide conversions.
Identication code
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
Complex 7
44H36Cl2N4Pd
798.06
100(2)
Triclinic
C
Suzuki–Miyaura cross-coupling reactions between various
substrates using 5–8. Different boronic acids were coupled with
various aryl halides using pre-catalysts 5–8 to evaluate the
ability of the pre-catalysts to tolerate the presence of functional
groups during the Suzuki–Miyaura cross-coupling reactions
(Tables 2 and 3, Fig. 2). Using 4-bromotoluene and phenyl-
boronic acid as coupling partners, resulted in high conversions
to the respective biphenyls for pre-catalysts 5 and 7 (87% and
100% respectively) (Table 2, entries 5 and 7). Pre-catalysts 6 and
8 gave moderate conversions of 68% and 47% for the same
substrates (Table 2, entries 6 and 8). This excellent conversion
demonstrated by 5 and 7 could be as a result of increased
electron-donation of the phenyl groups (by forming a conju-
gated system) with the pyrazole ring as compared to the tertiary
butyl groups. Poor conversion for 6 (39%) (Table 2, entry 10) and
moderate conversion for 8 (70%) (Table 2, entry 12) could also
be a result of the steric bulk of the tertiary butyl substituents.
These bulky tertiary butyl groups may reduce interactions
between the palladium centre and the substrates resulting in
poor conversions. When the aryl halide (4-bromotoluene) was
changed to the more sterically hindered 2-bromotoluene
excellent conversion was obtained using 7 (98%). The other pre-
catalysts gave conversions from ca. 40% to 70%. This demon-
strated the effect of the electron-withdrawing ester substituents
on the phenyl rings of pre-catalysts 5 and 6. Reducing the
electron density from the palladium centre due to the presence
of ester groups, resulted in suppressed conversions (Table 2).
P-1
ꢀ
a/A
6.7767(6)
10.2586(9)
13.5319(13)
102.123(2)
98.442(2)
94.970(2)
903.05(14)
2
1.467
0.700
408.0
0.364 ꢁ 0.125 ꢁ 0.12
Mo Ka (l ¼ 0.71073)
4.092 to 56.714
ꢀ
b/A
ꢀ
c/A
a/ꢀ
b/ꢀ
g/ꢀ
ꢀ3
Volume/A
Z
rcalc. g cmꢂ3
m/mmꢂ1
F(000)
Crystal size/mm3
Radiation
2q range for data
collection/ꢀ
Index ranges
ꢂ8 # h # 9, ꢂ13 # k # 13,
ꢂ18 # l # 18
12 765
4497 [Rint ¼ 0.0346,
Rsigma ¼ 0.0391]
4497/0/304
Reections collected
Independent reections
Data/restraints/parameters
Goodness-of-t on F2
Final R indexes [I $ 2s (I)]
1.079
R1 ¼ 0.0287,
wR2 ¼ 0.0675
Final R indexes [all data]
Largest diff. peak/hole/e A
R1 ¼ 0.0316, wR2 ¼ 0.0688
0.46/ꢂ0.31
ꢀꢂ3
biphenyl of only 62%. This reduction in conversion demon-
strates the stereoelectronic effect, caused by substituents on the
pyrazole ring, on catalytic activity.
Table 2 Effect of the presence of electron-donating groups on aryl
halidesa
Carrying out the Suzuki–Miyaura cross–coupling reaction at
140 ꢀC resulted in the formation of Pd-black when using 5, 6, 7
and 8 irrespective of the solvent used. Similar observations have
been reported in literature for pyrazolyl palladium
complexes,21,27 which were used in cross-coupling reactions
carried out at temperatures higher than 65 ꢀC. However,
carrying out the Suzuki–Miyaura cross-coupling reaction using
7, at the established optimum reaction conditions, in toluene
(using bromobenzene and phenylboronic acid as cross-coupling
partners) with a large excess of mercury (300 : 1, Hg : Pd)
resulted in a drop in conversion from 98% to 84%. This
appreciably high conversion obtained using 7, in the presence
of mercury indicates in situ generated multi-species catalysts
responsible for the catalysis.28–30
Similar observations were made when 8 was used as a pre-
catalysts in the presence of metallic mercury, where conver- 10
sion dropped from 81% to 77%.
This is in contrast to other palladium catalyzed Suzuki–
Miyaura cross-coupling for which there was no aryl halide
conversion aer introducing mercury to the reaction mixture.
Generally phenyl bearing pre-catalysts 5 and 7 outperformed
their tertiary butyl counterparts 6 and 8 over the course of these
Selectivity
(%)
Entry
Cat.
X
Conv. (%)
TON
TOF (hꢂ1
)
1
2
3
4
5
6
7
8
9
5
6
7
8
5
6
7
8
5
6
7
8
H
H
H
H
4-CH3
4-CH3
4-CH3
4-CH3
2-CH3
2-CH3
2-CH3
2-CH3
98
87
98
81
87
68
100
47
64
39
98
70
100
100
100
100
100
99
99
97
100
99
99
298
263
298
245
262
206
303
141
195
117
298
212
74
66
74
61
66
51
76
35
49
29
75
53
11
12
97
a
Reactions carried out in toluene (4.27 mL) with 5 mmol of aryl halide,
8 mmol of phenyl boronic acid, 10 mmol of KOH and 0.3 mol% Pd
catalyst loading using n-decane as internal standard at 140 ꢀC for 4 h.
conversion. Average error estimates; 5
(ꢃ0.6210), 6 (ꢃ0.5919), 7 (ꢃ0.4987), 8 (ꢃ0.4331).
Cat.
¼
catalyst, Conv.
¼
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Table 3 Effect of the presence of electron-withdrawing groups on phenyl boronic acidsa
Selectivity
(%)
Entry
Cat.
X
Y
Conv. (%)
TON
TOF (hꢂ1
)
1
2
3
4
5
6
7
8
5
6
7
8
5
6
7
8
5
6
7
8
5
6
7
8
4-CHO
4-CHO
4-CHO
4-CHO
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
H
H
H
H
2-CN
2-CN
2-CN
2-CN
53
22
63
21
73
73
76
78
97
77
97
93
89
97
75
94
99
99
99
99
100
79
100
72
162
66
190
63
40
17
47
16
55
55
58
59
48
60
57
47
76
69
76
76
222
222
231
237
190
238
227
189
303
276
303
303
9
63a
79a
75a
62a
100a
91a
100a
100a
10
11
12
13
14
15
16
a
Reactions carried out in DMF (1.5 mL) with 1 mmol of aryl halide, 1.6 mmol of phenyl boronic acid, 2 mmol of KOH and varying 0.3 mol% Pd using
n-decane as internal standard at 140 ꢀC for 4 h. Reactions carried out in toluene (1.5 mL). Cat. ¼ catalyst, Conv. ¼ conversion. Average error
estimates; 5 (ꢃ0.5661), 6 (ꢃ0.4941), 7 (ꢃ0.5374), 8 (ꢃ0.4821).
The inuence of electron-withdrawing groups on the aryl obtained when 4-formylphenyl boronic acid and 4-bromo
halides was also investigated. When chlorobenzene was used as toluene were used. The presence of the lesser electron-
a coupling partner with phenylboronic acid, there were no withdrawing chloride resulted in increased aryl halide conver-
conversions with any of the pre-catalysts. However, in the sions as compared to the more electron-withdrawing formyl
presence of an electron-withdrawing cyano group in 2-chlor- substituent (entries 1–8, Table 3). The low conversions with the
obenzonitrile, we observed moderate conversions (46% for 5 phenyl boronic acid bearing electron-withdrawing group could
and 6, 44% for 7 and 30% for 8) with all the pre-catalysts despite be due to the decrease in the rate of the transmetallation step of
the steric limitations that might have been imposed by the the catalytic cycle as has been reported in literature.31
nitrile group. This was probably as a result of the decrease in the
bond dissociation energy of the C–Cl bond caused by the when
presence of the cyano group. Due to the electron-withdrawing
nature of the cyano group from the C–Cl bond, the 2-chlor-
obenzonitrile is activated, thus the energy required in the
formation of the oxidative addition intermediate is lowered.
A series of phenyl boronic acids with electron-withdrawing
substituents were investigated in order to evaluate their effect
on the Suzuki–Miyaura cross-coupling reactions. A typical
example of such phenyl boronic acid that was investigated was
4-chlorophenyl boronic acid. With the presence of an electron-
withdrawing group on the phenyl boronic acid, the results ob-
tained were contrary to having the electron-withdrawing group
on the aryl halide. For example, when phenyl boronic acid and
bromobenzene were used as substrates (entry 3, Table 2) 98%
conversion was obtained for 7. When 4-chlorophenyl boronic
acid and bromobenzene were used as substrates using 7, we
observed 75% conversion (entry 11, Table 3). Similar observa-
High conversions were observed for all four pre-catalysts
2-bromobenzonitrile was coupled with 4-
tions were also made for the other pre-catalysts. When 4-
chlorophenyl boronic acid and 4-bromo toluene were used as
substrates, conversion obtained for 7 was 76% whereas 63% was
Fig. 2 Effect of steric bulk on phenyl boronic acids and aryl halides.
Reactions carried out in DMF (1.5 mL) with 1 mmol of aryl halide,
1.6 mmol of phenyl boronic acid, 2 mmol of KOH and varying 0.3 mol%
Pd using n-decane as internal standard at 140 ꢀC for 4 h.
13832 | RSC Adv., 2018, 8, 13826–13834
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chlorophenylboronic acid. These high conversions were resulting in increased electron-donation to the palladium. This
t
observed despite the presence of an electron-withdrawing could also be as a result of steric bulk by the Bu substituents
chloro group on the phenyl boronic acid which would have that inhibits interaction between the palladium centre and the
been expected to reduce conversions (Table 3, entries 13–16). substrates. The presence of ester groups on two of the pre-
This was probably because the oxidative addition intermediate catalysts (5 and 6) resulted in slightly lowered conversions.
is expected to be formed relatively easily. Therefore, even if Generally, all the pre-catalysts were selective towards the
there is a decrease in the rate of transmetallation (with the formation of the biaryl and no homo coupling products were
presence of an electron-withdrawing group on the phenyl observed. The presence of electron-withdrawing groups on the
boronic acid), the reaction still gives excellent conversions.
aryl halide served to increase conversions while an electron-
We have observed that steric bulk around the carbon–boron withdrawing group on the phenyl boronic acid reduced
bond or carbon–halide bond resulted in poor conversions. An conversion. Steric bulk around either the carbon–halide bond
example is the reaction between 2-nitroboronic acid or 3- or the carbon–boron bond also lead to reduced conversions.
nitroboronic and bromobenzene. This reaction resulted in the
loss of the boronic acid during coupling to form nitrobenzene
which was conrmed by mass spectrometry. Using 4-for-
Conflicts of interest
mylboronic acid and 2-bromobenzene as substrates resulted in There are no conicts to declare.
no conversion for all four pre-catalysts. These poor conversions
could be as a result of steric hindrance or due to the electron-
withdrawing effect of the formyl group on the phenyl boronic
Acknowledgements
acids. When 4-bromotoluene was used instead of 2-bromo- We acknowledge the National Research Foundation of South
benzene as coupling partner with 4-formylboronic acid, there Africa (NRF) (Grant Numbers: 95517 and 99269), Sasol and the
was an increase in conversion possibly due to reduced steric University of Johannesburg Centre for Synthesis and Catalysis
hindrance (Table 3, entries 1–4). Similar observations were for nancial support. We would also like to acknowledge Mr
made when 4-chlorophenyl boronic acid was coupled with Gershon Amenuvor for his help in the solving of the crystal
either 4-bromotoluene or 2-bromotoluene. Surprisingly, structure.
conversions for 6 and 8 were not signicantly affected when an
electron-withdrawing halide was present on the boronic acid as
well as bulky group around the carbon bromide bonds (Fig. 2).
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13834 | RSC Adv., 2018, 8, 13826–13834
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