Copper-free and amine-free Sonogashira coupling in air in a mixed aqueous medium by palladium complexes of N/O-functionalized N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.jorganchem.2009.06.026

Highly convenient copper-free and amine-free Sonogashira coupling of aryl bromides and iodides with terminal acetylenes under amenable conditions in air and in a mixed aqueous medium are reported using several new, user friendly and robust palladium precatalysts (1-5) of N/O-functionalized N-heterocyclic carbenes (NHCs). In particular, the precatalysts, 1 and 2, were synthesized from the imidazolium chloride salts by the treatment with PdCl₂ in pyridine in presence of K₂CO₃ as a base while the precatalysts, 3-5, were synthesized from the respective silver complexes by the treatment with (COD)PdCl₂. The DFT studies carried out on the 1-5 complexes suggest the presence of strong NHC-Pd σ-interactions arising out of deeply buried NHC-Pd σ-bonding molecular orbitals (MOs) that account for the inert nature of the metal-carbene bonds and also provide insights into the exceptional stability of these precatalysts.

Full text of DOI:10.1016/j.jorganchem.2009.06.026

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Journal of Organometallic Chemistry 694 (2009) 3477–3486
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Copper-free and amine-free Sonogashira coupling in air in a mixed aqueous
medium by palladium complexes of N/O-functionalized N-heterocyclic carbenes
Manoja K. Samantaray a, Mobin M. Shaikh b, Prasenjit Ghosh a,
*
a Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
b National Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2009
Received in revised form 15 June 2009
Accepted 19 June 2009
Available online 25 June 2009
Highly convenient copper-free and amine-free Sonogashira coupling of aryl bromides and iodides with
terminal acetylenes under amenable conditions in air and in a mixed aqueous medium are reported using
several new, user friendly and robust palladium precatalysts (1–5) of N/O-functionalized N-heterocyclic
carbenes (NHCs). In particular, the precatalysts, 1 and 2, were synthesized from the imidazolium chloride
salts by the treatment with PdCl2 in pyridine in presence of K2CO3 as a base while the precatalysts, 3–5,
were synthesized from the respective silver complexes by the treatment with (COD)PdCl2. The DFT stud-
Keywords:
Carbenes
Functionalized NHC
Sonogashira coupling
Organometallic catalysis
Palladium–NHC complex
ies carried out on the 1–5 complexes suggest the presence of strong NHC–Pd
r-interactions arising out of
deeply buried NHC–Pd -bonding molecular orbitals (MOs) that account for the inert nature of the
r
metal–carbene bonds and also provide insights into the exceptional stability of these precatalysts.
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
potentially explosive Cu–acetylide species, thereby providing a
much needed answer for making the Sonogashira reaction more
The seemingly challenging C–C cross-coupling reaction, made
easy by palladium, has inundated the literature in last two decades
with several of its variants that mainly involve the coupling of aryl
or alkyl halides with organometallic nucleophiles depending upon
the requirement and the specificity of the cross-coupled products
[1–3]. One such emerging name is the Sonogashira coupling that
provide an easy pathway for the construction of all-important con-
jugate ‘‘enyne” and ‘‘arylalkyne” frameworks often encountered in
the natural products, pharmaceuticals, biologically important mol-
ecules, molecular electronics as well as in molecules with materials
related applications [4–7]. In particular, the Sonogashira reactions
involve the coupling of aryl and alkenyl halide with terminal acet-
ylenes and are catalyzed by palladium in a basic medium in pres-
ence of copper as a co-catalyst. The coupling of aryl and alkenyl
halide with terminal acetylenes proceeds with the in situ genera-
tion of an extremely sensitive organometallic species, the Cu–acet-
ylide, which renders the Sonogashira reactions air and moisture
sensitive and potentially explosive. Furthermore, the Cu–acetylide
species, under aerobic conditions yields the unwanted homo-cou-
pled product, instead of the desired cross-coupled product, and
thus restricts the Sonogashira reaction to stringent anaerobic con-
ditions [8]. Hence, an important objective in this area lies in devel-
oping Cu-free Sonogashira [9–13] reactions as these would
circumvent the formation of the air and moisture sensitive and also
tolerant towards aerobic conditions.
The other limitation of Sonogashira coupling arises from the
usage of not so environment friendly amines [14], which are fre-
quently used as bases in many of the coupling reactions [4–7].
Thus, significant efforts are underway toward developing amine-
free conditions for the Sonogashira couplings, in which traditional
bases are used in place of the amines. Worth noting that against
this backdrop, we decided to develop both Cu-free and amine-free
Sonogashira couplings [15–20] as the Cu-free feature would facili-
tate the reaction to proceed under normal aerobic conditions with-
out the requirement for the exclusion of air and moisture while the
amine-free feature would make the reaction more environment
friendly.
Our interest lies in developing the chemistry of N/O-functional-
ized N-heterocyclic carbenes [21–24] particularly with regard to
their utility in biomedical applications [25,26] and in chemical
catalysis [27–32], with special focus on the palladium mediated
C–C cross-coupling reactions namely the Suzuki–Miyaura coupling
[33,34], the Sonogashira and the Hiyama couplings [35,36]. In par-
ticular, we aim at designing efficient, robust and stable precatalysts
of N/O-functionalized N-heterocyclic carbenes that would carry out
the cross-coupling reactions under more amenable conditions. In
this regard, worth mentioning that the utility of N-heterocyclic
carbenes [37–44] in the Sonogashira coupling is relatively new
with most of the existing reports are of the phosphine based sys-
tems [45–51]. Furthermore, on many occasions these catalyses
were performed under ‘‘Ligand Assisted Catalysis” conditions
* Corresponding author. Tel.: +91 22 2576 7178; fax: +91 22 2572 3480.
E-mail address: pghosh@chem.iitb.ac.in (P. Ghosh).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.06.026

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M.K. Samantaray et al. / Journal of Organometallic Chemistry 694 (2009) 3477–3486
NH
O
Cl
Pd
Cl
Pd
N
N
N
N
N
N
N
Cl
Cl
1
4
N
N
N
Pd
NH
Cl
Cl
NH
3
O
O
Cl
Pd
Cl
Pd
N
N
N
N
N
N
N
Cl
Cl
O
HN
5
2
Fig. 1. Palladium complexes of N/O-functionalized and non-functionalized N-heterocyclic carbenes are shown.
(LAC), in which the catalytically active species were generated
in situ and as a result only a handful of examples exist of the
well-defined catalyst systems. Hence, in the light of these facts,
we set out to design well-characterized precatalysts for the Sono-
gashira couplings under both Cu-free and amine-free conditions.
Here in this contribution, we report several new palladium pre-
catalysts, 1–5 (Fig. 1), with improved attributes like high efficiency
and enhanced stability for the Sonogashira coupling under the
much desired Cu-free and amine-free conditions in air in a mixed
aqueous medium. Specifically, we report the utility of three types
of palladium precatalysts namely, the Pyridine Enhanced Precata-
lyst Preparation, Stabilization and Initiation (PEPPSI) [52–54]
themed trans-(NHC)PdCl2(pyridine) complexes, 1 and 2, a [N and
Ccarbene] chelating complex, 3, and the trans-(NHC)2PdCl2 type com-
plexes, 4 and 5, in the Sonogashira coupling reactions. Further in-
sights on the influence of the N/O-functionalized N-heterocyclic
carbene ligand (NHCs) in these 1–5 precatalysts were obtained
from the density functional theory (DFT) studies, which revealed
R2
R2
NH
NH
O
O
Cl
Pd
N
N
N
N
PdCl2
Cl-
N
K2CO3
Cl
N
R1
R1
1
2
(R1 = i-Pr, R2 = 2,6-i-Pr2C6H3)
(R1 = mesityl, R2 = C6H5)
Scheme 1.
N
that the NHCꢀPd
r-bonding molecular orbitals (MOs) were very
deep seated thereby indicating the inertness of the NHCꢀPd bond
in these 1–5 complexes.
N
N
Ag
N
(COD)PdCl2
N
Cl
Cl
Ag
N
Pd
Cl
Cl
N
N
3
N
2. Results and discussion
The PEPPSI themed trans-(NHC)PdCl2(pyridine) type complexes
1 and 2 were, respectively, synthesized from 1-(i-propyl)-3-(N-2,6-
di-i-propylphenylacetamido)imidazolium chloride and [1-(2,4,6-
trimethylphenyl)-3-(N-phenylacetamido)imidazolium chloride by
the reaction with PdCl2 in pyridine in presence of K2CO3 as a base
(Scheme 1). The [N and Ccarbene] chelating complex, 3, (Scheme 2)
Scheme 2.
complexes. It is interesting to note that both the 1H NMR and 13C
NMR spectrum of 3 showed two sets of resonances owing to E/Z-
isomerization observed earlier by us [21], Coleman et al. [55–57],
Bildstein et al. [58,59], and Tilset et al. [60–62] for the related li-
gand systems.
The molecular structures of the 1–5 complexes as determined
by X-ray diffraction established the monomeric nature of these
metal complexes with the palladium center being in expected
square-planar geometry (Figs. 2–4 and Supporting information
as well as the trans-(NHC)2PdCl2 type complexes,
4 and 5,
(Schemes 3 and 4) were prepared from the respective silver com-
plexes by treatment with (COD)PdCl2. Of foremost importance is
the 13C NMR spectrum which showed the appearances of the diag-
nostic Pd–Ccarbene resonance in the highly downfield shifted region
[1 (153.2 ppm), 2 (152.3 ppm), 3 (152.4 ppm), 4 (169.6 ppm) and 5
(166.5 ppm)], thus, confirming the formation of the palladium

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3479
Cl
Pd
N
N
N
N
N
N
(COD)PdCl2
Ag
Cl
Cl
4
Scheme 3.
Fig. 3. ORTEP of 3 with thermal ellipsoids drawn at 50% probability level. Selected
bond lengths (Å) and angles (°): N2–C1 1.354(7), N3–C1 1.346(7), Pd1–C1 1.952(5),
Pd1–N1 2.072(4), N2–C1–N3 105.5(5), and C1–Pd1–N1 86.27(19).
Scheme 4.
Fig. 4. ORTEP of 4 with thermal ellipsoids drawn at 50% probability level. Selected
bond lengths (Å) and angles (°): N1–C1 1.341(6), N2–C1 1.348(6), Pd1–C1 2.033(5),
Pd1–Cl1 2.3076(13), N1–C1–N2 105.0(4), and C1–Pd1–Cl1 88.05(14).
Of these, the PEPPSI themed 1 and 2 complexes, containing a
‘‘throwaway” pyridine moiety, exhibit an additional Pd–pyridine
distance of 2.1273(18) Å (1) and 2.091(3) Å (2) similar to that
observed in other related analogs like, the non-functionalized aryl
substituted trans-[1,3-bis(2,6-di-i-propylphenyl)-imidazol-2-yli-
dene]PdCl2(3-chloropyridine) [2.137(2) Å] [53], or the N/O-func-
tionalized ones like, the trans-[1-(benzyl)-3-(N-t-butylaceta-mido)
imidazol-2-ylidene]PdCl2(pyridine) [2.089(3) Å] [33], trans-[1-(2-
hydroxy-cyclohexyl)-3-(benzyl)imidazol-2-ylidene]PdCl2-(pyridine)
[2.096(3) Å] [33] and trans-[1-(o-methoxybenzyl)-3-(t-butyl)imi-
dazol-2-ylidene]PdBr2(pyridine) [2.100(8) Å] [33]. Furthermore,
in concurrence with the ‘‘throwaway” nature of the pyridine moi-
ety in 1 and 2, slightly elongated Pd–pyridine distance is observed
in 1 [2.1273(18) Å] and 2 [2.091(3) Å] as a consequence of strong
trans influence of the NHC ligand in these 1 and 2 complexes. For
example, fairly shorter Pd–pyridine distance is observed in the
Pd-bound pyridine complexes of non-NHC ligands like, in [2,6-
bis(20-indolyl)pyridine]Pd(pyridine) [2.040(3) Å], [68] [bis(bis(2-
Fig. 2. ORTEP of 1 with thermal ellipsoids drawn at 50% probability level. Selected
bond lengths (Å) and angles (°): N1–C1 1.348(3), N2–C1 1.348(3), Pd1–C1 1.959(2),
Pd1–N4 2.1273(18), N1–C1–N2 105.66(17), and C1–Pd1–N4 177.11(7).
Figs. S1 and S2). The Pd–Ccarbene bond distances in 1 [1.959(2) Å], 2
[1.961(4) Å], 3 [1.952(5) Å], 4 [2.033(5) Å] and 5 [2.0530(17) Å]
compare well with the other structurally characterized palladium
N-heterocyclic carbene complexes, i.e. [1-(mesityl)-3-(pyrimi-
dine)imidazole-2-ylidene]PdCl2 [1.964(3) Å] [63], [(1-benzyl-10-
methyl-3,30-ethylenediimidazolin-2,20-diylidene)]PdCl2 [1.967(5) Å
and 1.982(6) Å] [64], [(1,3-dibenzhydrylbenzimidazolin-2-yli-
dene)CH3CN]PdBr2 [1.938(4) Å] [65], [N,N0-bis-(2,2-diethoxyethyl)
imidazole-2-ylidene]2PdCl2 [2.013(7) Å] [66] and [1-(methyl)-3-
(N-2,6-di-methylphenylimino-2-phenylmethyl)imidazol-2-ylid-ene]
PdCl2 [1.9677(18) Å] [67].
pyridylmethyl)amine-N,N0,N00)]Pd(pyridine)](ClO4)2
[2.037(3) Å]

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M.K. Samantaray et al. / Journal of Organometallic Chemistry 694 (2009) 3477–3486
[69] and [(2,20:60,200-terpyridine)Pd(pyridine)](ClO4)2 [2.038(4) Å]
[70]. Lastly, consistent with the weakly bound pyridine moiety in
the PEPPSI themed 1 and 2 complexes, the formation of free
pyridine, as verified by GC and GCMS analysis, was indeed
observed for a representative complex 1 under the Sonogashira
catalysis conditions.
porting information Tables S14 and S15). Specifically, the Natural
Bond Orbital (NBO) analysis showed that the NHC–Pd bond is com-
posed of the interaction between a Ccarbene (sp2) orbital with a pal-
ladium based sd hybrid orbital (see Supporting information Table
S20).
The Charge Decomposition Analysis (CDA) was performed on
the 1–5 complexes to obtain a better understanding of the NHC–
Pd interaction by cleaving the NHC–Pd bond into its associated free
ligand and metal fragments and then looking into the extent of the
Quite interestingly, the complex 3 exhibits [N and Ccarbene
]
chelation similar to that observed in a related [1-(methyl)-3-
(N-2,6-di-i-propyl-phenylimino-2-propyl)imidazol-2-ylidene]PdCl2
complex [62] but differs from another close analog, [1-(methyl)-
3-(N-2,6-di-i-propyl-phenylimino-2-phenylethyl)imidazol-2-yli-
dene]2PdCl2 [61] which do not show such chelation.
Lastly, the complexes, 4 and 5, that display coplanar imidazole
rings, closely resemble other structurally characterized trans-(NHC)2
PdX2 (X = halide) type examples like, [1-benzyl-3-t-butylimidazol-
2-ylidene]2PdCl2 [26], [1-(o-methoxybenzyl)-3-(t-butyl)-imidazol-
2-ylidene]2PdCl2 [34] and trans-[1-(benzyl)-3-(3,3-dimethyl-2-
oxo-butyl)imidazol-2-ylidene]2PdBr2 [36].
r
p
NHC ! Pd forward donation, designated by d, and the NHC Pd
backward donation, designated by b, occurring in the NHC–Pd
interaction. Worth noting that a significantly high d/b ratio
(2.27–3.91) was estimated for the NHC–Pd interaction in all of
the 1–5 complexes and is in accordance with the strong
r-donat-
ing nature of the N-heterocyclic carbene ligand (see Supporting
information Tables S18 and S19).
The molecular orbital (MO) correlation diagram constructed
from the interaction of the associated metal and ligand fragment
Further insights on the nature of the NHC–Pd interaction in 1–5
were obtained from density functional theory (DFT) studies carried
out on these complexes. Specifically, geometry optimizations fol-
lowed by single-point calculations were performed at B3LYP/
SDD, 6-31G(d) level of theory using atomic coordinates obtained
from the X-ray analysis (Supporting information Tables S3–S5
and S7 & S8). The post wave function analysis using Natural Bond
Orbital (NBO) method was performed to gain additional under-
standing of the nature of the NHC–Pd interaction.
molecular orbitals (FMOs) depict the NHC–Pd r-interaction preva-
lent in these complexes, 1 (HOMO-18, HOMO-34), 2 (HOMO-18,
HOMO-29), 3 (HOMO-8, HOMO-31), 4 (HOMO-16, HOMO-31)
and 5 (HOMO-16, HOMO-45), (Figs. 5–7 and Supporting informa-
tion Figs. S3–S9). The stable and hence inert nature of the
NHC–Pd interaction is further evident from these deeply buried
NHC–Pd
r-bonding molecular orbitals [1 (HOMO-18, HOMO-34),
2 (HOMO-18, HOMO-29), 3 (HOMO-8, HOMO-31), 4 (HOMO-16,
HOMO-31) and 5 (HOMO-16, HOMO-45)] that make the NHC–Pd
interaction less vulnerable to electrophilic or nucleophilic attack.
In this regard, it is worth noting that the metal–carbene interac-
tions in N-heterocyclic carbene metal complexes are significantly
more stable than what is observed in the Fischer or Schrock car-
bene complexes, which are susceptible to both nucleophilic or
electrophilic attack [71–76]. Furthermore, a scrutiny of the molec-
ular orbitals, HOMO-18 (1), HOMO-18 (2), HOMO-8 (3), HOMO-31
The strong
r-donating ability of the N-heterocyclic carbene li-
gands was evident from both the Mulliken and Natural charge
analyses, which clearly showed significant increase in the electron
density on the palladium center upon binding of the NHC ligand
fragment (see Supporting information Tables S9–S13). A closer
scrutiny of the electronic configuration of the metal center in these
complexes further revealed that the electron donation from the
carbene lone pair occurred into the 5s orbital of palladium (Sup-
(4) and HOMO-45 (5), representing maximum
r-donation from
NH
NH
O
O
Cl
Pd
Cl
Pd
N
N
N
N
N
N
Cl
Cl
1
-2
-4
LUMO
HOMO
LUMO
8.3
18.9
-6
HOMO
HOMO-4
HOMO-8
HOMO-18
9.7
6.9
24.3
19.1
-8
HOMO-4
HOMO-8
-10
-12
HOMO-11
HOMO-12
HOMO-11
HOMO-12
Fig. 5. Simplified orbital interaction diagram showing the major contributions of NHC–palladium bond in 1.