Steric effect of NHC ligands in Pd(II)–NHC-catalyzed non-directed C–H acetoxylation of simple arenes

Article abstract of DOI:10.1016/j.jorganchem.2021.122047

Although there has been a lot of progress in oxidative arene C–H functionalization reactions catalyzed by Pd(II/IV) system, the non-directed, site-selective functionalization of arene molecules is still challenging. It has been established that ligands play a pivotal role in controlling rate- as well as selectivity-determining step in a catalytic cycle involving well-defined metal-ligand bonding. N-heterocyclic carbene (NHC) ligands have had a tremendous contribution in the recent extraordinary success of achieving high reactivity and excellent selectivity in many catalytic processes including cross-coupling and olefin-metathesis reactions. However, the immense potential of these NHC ligands in improving site-selectivity of non-directed catalytic C–H functionalization reactions of simple arenes is yet to be realized, where overriding the electronic bias on deciding selectivity is a burdensome task. The presented work demonstrated an initiative step in this regard. Herein, a series of well-defined discrete [Pd(NHCR′R)(py)I2] complexes with systematically varied degree of spatial congestion at the Pd centre, exerted through the R and R’ substituents on the NHC ligand, were explored in controlling the activity as well as the site-selectivity of non-directed acetoxylation of representative monosubstituted and disubstituted simple arenes (such as toluene, iodobenzene and bromobenzene, naphthalene and 1,2-dichlorobenzene). The resulting best yields were found to be 75% for toluene and 65% for bromobenzene with [Pd(NHCMePh)(py)I2], 75% for iodobenzene and 79% for naphthalene with [Pd(NHCMeMe)(py)I2], and 41% for 1,2-dichlorobenzene with [Pd(NHCCyCy)(py)I2]. Most importantly, with increasing the bulkiness of the NHC ligand in the complexes, the selectivity of the distal C-acetoxylated products in comparison to the proximal ones, was enhanced to a great extent in all cases. Considering the vast library of NHC ligands, this study underscores the future opportunity to develop more strategies to improve the activity and the crucial site-selectivity of C–H functionalization reactions in simple as well as complex organic molecules.

Full text of DOI:10.1016/j.jorganchem.2021.122047

Journal of Organometallic Chemistry 953 (2021) 122047
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Steric effect of NHC ligands in Pd(II)–NHC-catalyzed non-directed C–H
acetoxylation of simple arenes
Tanmoy Mandala, Sudha Yadav b, Joyanta Choudhurya,∗
a Organometallics & Smart Materials Laboratory, Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal
By-pass Road, Bhopal, 462 066, Madhya Pradesh, India
b Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Manauli, 140
306, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Although there has been a lot of progress in oxidative arene C–H functionalization reactions catalyzed by
Pd(II/IV) system, the non-directed, site-selective functionalization of arene molecules is still challenging. It
has been established that ligands play a pivotal role in controlling rate- as well as selectivity-determining
step in a catalytic cycle involving well-defined metal-ligand bonding. N-heterocyclic carbene (NHC) lig-
ands have had a tremendous contribution in the recent extraordinary success of achieving high reactiv-
ity and excellent selectivity in many catalytic processes including cross-coupling and olefin-metathesis
reactions. However, the immense potential of these NHC ligands in improving site-selectivity of non-
directed catalytic C–H functionalization reactions of simple arenes is yet to be realized, where overrid-
ing the electronic bias on deciding selectivity is a burdensome task. The presented work demonstrated
Received 20 July 2021
Revised 17 August 2021
Accepted 18 August 2021
Available online 24 August 2021
Keywords:
Palladium
N-heterocyclic carbene (NHC)
Non-directed C–H functionalization
Acetoxylation
an initiative step in this regard. Herein, a series of well-defined discrete [Pd(NHCRR )(py)I ] complexes
ꢀ
2
Arene
with systematically varied degree of spatial congestion at the Pd centre, exerted through the R and R’
substituents on the NHC ligand, were explored in controlling the activity as well as the site-selectivity
of non-directed acetoxylation of representative monosubstituted and disubstituted simple arenes (such
Site-selectivity
as toluene, iodobenzene and bromobenzene, naphthalene and 1,2-dichlorobenzene). The resulting best
Ph
yields were found to be 75% for toluene and 65% for bromobenzene with [Pd(NHC )(py)I2], 75% for
Me
Me
iodobenzene and 79% for naphthalene with [Pd(NHC )(py)I2], and 41% for 1,2-dichlorobenzene with
Cy
Me
[Pd(NHC )(py)I2]. Most importantly, with increasing the bulkiness of the NHC ligand in the complexes,
Cy
the selectivity of the distal C-acetoxylated products in comparison to the proximal ones, was enhanced
to a great extent in all cases. Considering the vast library of NHC ligands, this study underscores the fu-
ture opportunity to develop more strategies to improve the activity and the crucial site-selectivity of C–H
functionalization reactions in simple as well as complex organic molecules.
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
appropriate position of the molecule acts as a temporary ligand
and brings the catalytic metal center near to the target C–H bond
Activation and subsequent direct (oxidative) functionalization of
C–H bond(s) of aromatic molecules with a transition metal catalyst
has been recognized as a highly-desired step-economic synthetic
protocol, simply because it bypasses the additional one or more
pre-functionalization reaction steps in the C–H to C–FG (FG = the
target functional group) transformation sequence.[1,2] There are
two major routes of C–H activation-functionalization reactions –
(i) directing group (DG)-assisted route where an inherently present
or synthetically installed metal-coordinating directing group at an
for its intramolecular cleavage, and (ii) nondirected route which
involves unassisted intermolecular C–H bond cleavage via direct
substrate-catalyst interaction for molecules lacking such a DG to
engineer an easy disposition of the catalytic active site into the
proximity of the target C–H bond (Scheme 1, a-b). Obviously, in
comparison to the former, the latter route faces additional chal-
lenge in terms of reactivity due to a higher kinetic barrier, and in
terms of selectivity due to the presence of different types of un-
biased C–H bonds, thus making it a scarcely reported methodol-
ogy in literature.[3] It is noteworthy to mention that despite this
challenge, the advancement of the nondirected oxidative arene C–
H activation-functionalization chemistry during the past decade is
a result of some pioneering and innovative investigations, espe-
∗
Corresponding author.
E-mail address: joyanta@iiserb.ac.in (J. Choudhury).
https://doi.org/10.1016/j.jorganchem.2021.122047
0022-328X/© 2021 Elsevier B.V. All rights reserved.

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
tional (Scheme 1, c).[11-13] Keeping this fact in mind, Cárdenas,
[14] Choudhury, [15] and Wendt [16] independently developed
“Pd(II)-NHC”-based well-defined molecular complexes (NHC = N-
heterocyclic carbene) as robust yet active catalysts for oxidative
C–H acetoxylation and C–H halogenation of simple arenes. The key
hypothesis toward using NHC ligands was to exploit their strong
sigma-donor property in stabilizing the high-valent Pd(IV) inter-
mediates generated in the catalytic cycle which would enhance
the longevity of the catalytic system via preventing catalyst-
decomposition during the catalytic turnover (Scheme 1, c). In fact,
the above hypothesis was actually tested to be really functional,
as the heterogenized versions of the “Pd(II)-NHC” catalysts could
be recycled successfully for many times in catalytic heterogeneous
C–H acetoxylation/halogenation reactions without appreciable loss
of activity.[17]
In addition to the activity, the issue of controlling site-
selectivity of simple arenes has also been a primary focus of in-
vestigation through varying the steric profile of the employed lig-
ands in case of “Pd(OAc)2+ligand”-catalyzed non-directed acetoxy-
lation reactions of mono- and di-substituted arenes. In this context,
Sanford’s findings were significant as it was discovered that out of
many pyridine-based ligands, acridine was able to control site se-
lectivity efficiently in the C–H acetoxylation of substituted arenes
in combination with Pd(OAc)2/MesI(OAc)2 system, by providing
high distal C–H functionalized products over the proximal C–H
substituted ones (Scheme 1, d).[5b] Notably, however, this proto-
col necessitated the use of bulky oxidant MesI(OAc)2 to override
the electronic bias of the arenes for achieving the site-selectivity
which was desirably dictated by the steric environment within the
arene substrates. Later, Fernández-Ibáñez also demonstrated high
site selectivity in mono- and di-substituted arenes in favour of
distal C–H acetoxylated products employing 6-fluoro-pyridine car-
boxylic acid (FPCA) as the ligand partner of Pd(OAc)2/PhI(OAc)2
combination (Scheme 1, d).[11a] On the other hand, this impor-
tant aspect of controlling the distal versus proximal arene C–H
site-selectivity as a function of ligand’s steric factor, is yet to be
assessed for the well-defined “Pd(II)-NHC”-based catalytic systems
in case of nondirected acetoxylation reactions of simple arenes.
Of note, tuning of steric bulk of NHC ligands is achieved read-
ily just by attaching different N-wingtip groups (N-substituents in
the NHC ligands) through easy synthetic manipulation. Exploiting
this synthetic advantage, previously, Wendt explored the influence
of NHC ligand’s steric factor but in DG-assisted arene acetoxyla-
tion (DG = a pyridine unit here) reactions with “Pd(II)-NHC” com-
plexes using PhI(OAc)2 as oxidant; however it was found to have a
minor influence in dictating selectivity between mono- versus di-
acetoxylated products.[16] It is needless to mention here that, dis-
tal versus proximal arene C–H site-selectivity could not be investi-
gated in this case as the catalytic protocol involved DG-assisted C–
H activation wherein no such selectivity is expected for the reason
illustrated earlier. With this background in mind, we decided to
investigate whether the steric bulk of the NHC ligands could over-
ride the electronic bias of the arene substrates and tune the dis-
tal versus proximal C–H site-selectivity in “Pd(II)-NHC” complex-
catalyzed nondirected C–H acetoxylation of substituted arenes em-
ploying PhI(OAc)2 and not the sterically bulky MesI(OAc)2 as the
oxidant (Scheme 1, d).
Scheme 1. (a-b) Two common routes of catalytic C–H activation-functionalization
protocols. DG = directing-group; FG = functionalizing-group; M-X = a metal cat-
alyst. (c) Proposed and investigated Pd(II)/Pd(IV) catalytic cycle for non-directed
arene acetoxylation of simple arenes catalyzed by “Pd(II)-NHC” complexes, and
some salient features of the catalytic systems. (d) Previous work and key aspects
of the present work on controlling site-selectivity of arene acetoxylation in non-
directed protocol.
cially with Pd-based catalyst systems, by Crabtree, Sanford, Glo-
rius, Hartwig, Shi, Stahl, Strassner, and others.[4-10] This advance-
ment witnessed the transition from the historical Pd(OAc)2 as cat-
alyst to the present versions of combined “Pd(OAc)2+ligand” (lig-
and = pyridine, pyridine-derivatives, and other mono/bidentate
ligands) and well-defined Pd(II) complex-based catalysts in order
to improve both the activity and selectivity of a variety of such
(oxidative) transformations, viz., aromatic C–H hydroxylation (C–
H → C–OH), C–H acetoxylation (C–H → C–OAc), C–H halogenation
(C–H → C–X, X = Cl, Br, I), C–H cyanation (C–H → C–CN), C–H
arylation (C–H → C–Ar) etc.[11]
In parallel to the successful application of various
“Pd(OAc)2+ligand” mixtures as catalysts, recently well-
defined/structured molecular Pd(II) complexes consisting of
rationally selected ligands have been demonstrated for controlled
influence on reactivity and selectivity profile of nondirected ox-
idative C–H functionalization of simple arenes.[12] Due to the
oxidative nature of these transformations, sufficient amounts of
an oxidant with respect to the Pd(II) catalyst is maintained, and
Our working hypothesis for the above investigation is explained
below. The previous reports suggested that for “Pd(II)-NHC”-based
catalysts, a different reaction pathway is followed in arene C–
H acetoxylation reactions using PhI(OAc)2 as the oxidant. Herein,
the “Pd(II)-NHC” species gets oxidized to high-valent “Pd(IV)-NHC”
first by the oxidant due to the strong sigma-electron donation
from the NHC ligand to the metal, making the Pd(II) centre highly
electron-rich and susceptible toward easy oxidation, followed by
rate-determining arene C–H activation step to form “Ar-Pd(IV)-
therefore,
a catalytic cycle involving Pd(II)/Pd(IV) intermediate
species, instead of Pd(II)/Pd(0), has been accepted to be opera-
2

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
NHC” intermediate (Scheme 1, c).[15b] This is in contrast to most
of the previous Pd(II) systems with pyridine and similar weakly
sigma-donating ligands wherein the rate-determining arene C–H
activation takes place first at the Pd(II) centre followed by oxida-
tion of the “Ar-Pd(II)” intermediate to “Ar-Pd(IV)” by the oxidant.
[5c] Nevertheless, as the rate-determining step involves approach
of the arene (Ar-H) molecule to the “Pd(IV)-NHC” species, both
the catalytic activity and the arene C–H site-selectivity would be
expected to depend on the steric bulk of the Pd-bound NHC lig-
and. Based on this working hypothesis, in the present work, we
explored a series of structurally fine-tuned “Pd(II)-NHC” complexes
having variable steric property to investigate the activity-selectivity
profile in nondirected C–H acetoxylation of some mono- and di-
substituted arenes employing PhI(OAc)2 as the sterically-unbiasing
oxidant (Scheme 1, d).
similar type of Pd complexes.[14-16,20] In the ESI-MS spectra of
the complexes, peaks pertaining to pyridine and/or one/both iodide
ligand-dissociated fragments could be identified.
The molecular structures of C1-C6, as evident from SC-XRD
studies, confirmed the expected square-planar geometry around
the d8-Pd(II) centre (Fig. 1). The NHC and the pyridine ligands co-
ordinated the metal centre via the carbene carbon and the nitrogen
atoms respectively, and they occupied the trans positions to each
other, leaving the other two trans sites of the square plane for the
two iodide ligands. However, a careful analysis showed a slight dis-
tortion from the ideal situation. In all the complexes, the cis-angles
and trans-angles deviated to different extents from the ideal values
of 90° and 180° respectively (Table 1). The structural indexes, τ4
ꢀ
and τ4 , as shown in Table 1, were calculated to assess the extent
of distortion quantitatively. For four-coordinate compounds, the τ4
ꢀ
and τ4 values of 0 and 1 indicate ideal square-planar and tetrahe-
2. Results and discussion
dral geometries respectively. [21] The extent of deviation from the
ideal geometries thus can be gauged from the actual values calcu-
lated using the observed geometrical parameters. In case of C1-C6,
2.1. Synthesis of the “Pd(II)-NHC” complexes
ꢀ
the calculated τ4 and τ4 were in the range of 0.026-0.060, indi-
Our investigation initiated with the synthesis of a series of
“Pd(II)-NHC” complexes from the corresponding imidazolium io-
dides/chlorides as the desired NHC-ligand precursors.[18,19] A one-
step reaction between the imidazolium halides and Pd(OAc)2 in
the presence of an additional weak base, K2CO3 and a source of
iodide ligand, KI in pyridine (py) as the solvent afforded the de-
sired complexes C1-C6 with the general formula [Pd(NHCRRꢀ )(py)I2]
(R, R’ = Me, nBu, Cy, Mes, tBu, Ph) as air- and moisture-stable
yellowish-orange solids in good isolated yields (Scheme 2). To
avoid the formation of any kind of mixed halide/acetate ligated Pd
complexes, an excess of KI was used to ensure the presence of only
iodide as the required two anionic ligands around the Pd(II) cen-
tre. The fourth coordination site of the four-coordinate Pd(II) com-
plexes was occupied by the solvent-ligand, pyridine (py).
cating slight distortion from the ideal square-planar geometry, and
among all the complexes, C4 showed the highest distortion. More-
over, in the square-planar Pd(II)-NHC complexes, the plane of the
NHC ring lies almost perpendicular to the Pd-coordination plane
for steric reason. However, due to distorted geometry, the dihe-
dral angle between these two planes usually varies from the ex-
pected 90°. Interestingly, in case of the present Pd(II)-NHC com-
plexes, all had the NHC ring oriented nearly perpendicular to the
PdCNHCNpyI2 coordination plane (dihedral angle in the range 83.1°-
89.4°), except for C4 in which it was slightly more distorted with
a dihedral angle of 76.3° (Table 1).
The Pd-ligand bond lengths in all the complexes were pre-
sented in Table 2. The Pd–CNHC bond lengths were found in the
˚
range of 1.955-1.990 A, typical values for these types of com-
plexes as reported in literature. [14–16,20] The complexes C1 and
C6 showed similar Pd–CNHC bond length in the range of 1.950-
2.2. Characterization and structural features of the “Pd(II)-NHC”
complexes
˚
1.955 A, whereas C2, C3 and C5 exhibited a little larger Pd–CNHC
˚
bond length in the range of 1.963-1.968 A. Significantly, the com-
˚
All the complexes C1-C6 were characterized by NMR spec-
troscopy, electron-spray ionization mass spectrometry (ESI-MS)
and elemental analysis, and their molecular structures were fur-
ther confirmed by single-crystal X-ray diffraction (SC-XRD) studies.
In the 1H NMR spectra of the complexes, the characteristic down-
field resonance signals for the imidazolium C–H protons (NCHN)
of the free ligands (in the range of 9.0–10.5 ppm) were found to
be absent which suggested the Pd–NHC bond formation (see Sup-
porting Information for details). The Pd-bound pyridine ligand was
attested by the presence of resonances corresponding to five addi-
tional protons in three sets of 2:1:2 integral ratio, as expected. All
the aliphatic and aromatic N-substituents were also confirmed by
the appearance of the respective proton resonances in the expected
regions. The 13C{1H} NMR spectra of C1-C6 exhibited the charac-
teristic Pd-bound carbene carbon (Pd−CNHC) signals at 153.0–157.0
ppm, which matched with the values reported in literature for
plex C4 had the largest Pd–CNHC bond length of nearly 2.00 A. The
observed clear gradual trend of the Pd–CNHC bond length was pre-
sumably due to the different extents of steric hindrance caused by
the NHC ligands around the Pd centre, thus impacting the extent
of orbital overlap during covalent bond formation.
2.3. Spatial features of the Pd centre in the “Pd(II)-NHC” complexes
The various bond angles, bond lengths and other geometrical
parameters around the palladium centre in the complexes C1-C6,
as discussed earlier, provided an idea about the steric profile of the
NHC ligands in these Pd-complexes employed in the present in-
vestigation. With an aim to further understand the spatial feature
of the Pd centre in the complexes, the web application SambVca
[22] was used to calculate the percent buried volumes (%Vbur
)
of the NHC ligands from the crystal structures of the complexes.
Based on the variation in the N-substituents of the NHCs, a consid-
erably large range of buried volumes from 27.2% to 33.4% was ob-
served (Fig. 2). As expected, C1, in which the NHC contained both
the N-substituents as small methyl group, showed the least buried
volume of 27.2%. Complexes C2 and C3 containing symmetrical N-
substituents exhibited similar %Vburr values within the range of
28.1%-28.7%. Due to the presence of one bulky phenyl group and
one bulky tert-butyl group in the NHC ligands, the complex C6
and C5 displayed a considerably large buried volume of 30.8% and
32.3% respectively. The highest buried volume of 33.4% was ob-
served with complex C4 having very bulky mesityl substituents on
Scheme 2. Synthesis of the “Pd(II)-NHC” complexes with finely-tuned structural
features of the ligated NHC ligands. Synthesis of C1 and C6 were reported previ-
ously.[19,15b]
3

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
Fig. 1. Molecular structures of C1-C6 (thermal ellipsoids are shown at 50% probability level; all the H atoms were omitted for clarity). C1[19] and C6[15b] were reported
previously. Additional details of the other structures can be found through the CCDC numbers of the cif files: C2, 2097165; C3, 2097163; C4, 2097166; C5, 2097164.
Table 1
ꢀ
Bond angles (°) around Pd(II), structural indexes (τ4 and τ4 ), and dihedral angle (°) in complexes C1-
C6.a
Complex
∠C1-Pd-I1
∠I1-Pd-N3
∠C1-Pd-N3
∠I1-Pd-I2
τ4
τꢀ
Dihedral
4
C1
C2
C3
C4
C5
C6
87.78(16)
89.89(14)
88.42(14)
91.60(14)
87.76(18)
87.56(9)
91.29(12)
91.30(13)
91.21(11)
88.349(12)
90.55(15)
90.99(7)
177.99(19)
178.61(19)
179.41(2)
176.14(18)
176.3(2)
176.47(2)
176.88(2)
175.02(2)
175.23(2)
176.06(2)
177.41(11)
0.039
0.032
0.039
0.060
0.054
0.056
0.034
0.027
0.026
0.058
0.057
0.056
84.31
89.44
87.29
76.27
87.22
83.12
174.74(12)
360◦ −(α+β)
(β−α)
(180◦ −β)
a
ꢀ
The structural indexes are defined as shown: τ4 =
: τ4
=
+
(180◦ −θ)
, where β
360◦ −2θ
(360◦ −θ)
and α are the two greatest valence angles (β > α) of the coordination centre and
θ is the ideal
tetrahedral angle (109.5°). [21] The dihedral angle shown here refers to the angle between the NHC
ring plane and the PdCNI2 coordination plane.
Table 2
Bond distances (A) around Pd(II) in complexes C1-C6.
˚
Complex
Pd–C
Pd–N
Pd–I
C1
C2
C3
C4
C5
C6
1.9555(5)
1.967(5)
1.963(5)
1.990(5)
1.968(6)
1.953(3)
2.108(4)
2.101(4)
2.108(4)
2.119(4)
2.101(5)
2.094(3)
2.5961(6); 2.6041(6)
2.6054(6); 2.6104(6)
2.5978(6); 2.6065(6)
2.6122(8); 2.6153(7)
2.6109(7); 2.6168(6)
2.6009(3); 2.6005(3)
both sides of the NHC ligand, suggesting the most sterically en-
cumbered situation around the Pd centre in this case.
2.4. Acetoxylation of monosubstituted arenes
Fig. 2. Comparison of the percent buried volumes (%Vbur) of NHC ligands in the
˚
Pd(II)-NHC complexes C1-C6. Typical setting: Pd–CNHC (d) = 2.00 A; sphere radius
With the structural profile of all the Pd(II)-NHC complexes and
the spatial environment around the Pd centre in these complexes
in hand, we investigated the reactivity/selectivity performance of
the catalysts in C–H acetoxylation of some representative mono-
substituted arenes such as toluene, bromobenzene and iodoben-
zene, using PhI(OAc)2 as the sterically-unbiasing reagent. With
these arene substrates, the ortho- and para-sites (with respect to
˚
˚
(r) = 3.50 A; H atoms were included; mesh spacing = 0.10 A. [22,23]
the substituent) would be electronically-favored, while meta- and
para-sites would be sterically favored as the rate-determining step
involves arene C–H activation at the metal centre at which the
NHC ligand would exert the steric repulsion. Therefore, with in-
4

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
Fig. 3. Acetoxylation of monosubstituted arenes catalyzed by Pd(OAc)2 (labelled as Pd) and the “Pd(II)-NHC” complexes C1-C6. Reaction conditions: arene = 1.25 mmol,
PhI(OAc)2 = 0.125 mmol, catalyst = 2.5 mol% with respect to PhI(OAc)2, AcOH/Ac2O = 1 mL (9:1, v/v), 95 °C, 24 h. Yields of the combined isomeric products were shown
in bar plots, and the isomeric distributions were shown in pie plots. The yields and isomer ratio were calculated by GC-MS using chlorobenzene (0.125 mmol) as internal
standard added after the reaction was over.
creasing the ligand-induced steric hindrance around the Pd centre,
more hindered C–H bonds of the arene substrates (the ortho-ones)
are less favourable for activation in comparison to the other less
hindered C–H bonds (the meta- and para-ones). As a result, the
ortho-C–H bonds of the arene substrates are less prone to form C–
Pd intermediate relative to the meta/para-C–H bonds. In this way,
the distal (meta-/para-) versus proximal (ortho-) selectivity can be
finely controlled.
symmetrical N-substituents at the NHC ligand with one being the
small Me group, the activity was high but the selectivity was rel-
atively lower than that of C2 and C3 (and similar to that of C1
having both Me substituents) despite the larger overall value of
%Vburr of the former catalysts. This result suggested that, as far as
steric effect on the C–H activation step is concerned, bulky NHC
with large substituents at both the sides were preferred to ob-
tain higher distal selectivity. The non-bulky small substituent in
just one side of the NHC may be sufficient to provide the steri-
cally unbiasing C–H activation probabilities from that side, thereby
resulting in relatively lower distal selectivity. Notably, while the
yield of acetoxylated toluene with various Pd(II)–NHC catalysts re-
ported in literature was found to be in the range of 26-64%, a
substantial ortho product selectivity, in the range of 29-34%, was
also a major limitation with these catalysts. [14,15a-b,17c] In com-
parison, the “Pd(OAc)2/FPCA” combination catalyst developed by
Fernández-Ibáñez showed an yield of 62% with ortho product se-
lectivity of 29%. [11a] These comparative profiles underscored the
role of the steric modulation of the NHC ligands in both reactiv-
ity and selectivity of the resulting Pd catalysts. This type of steric
effect-guided fine-tuning of distal-to-proximal C–H functionaliza-
tion selectivity of mono-substituted arenes was further verified
with two more model substrates such as iodobenzene and bro-
mobenzene (Fig. 3b-c). A similar trend of the observed selectiv-
The acetoxylation reaction was carried out using 10:1 molar ra-
tio of arene and PhI(OAc)2, 2.5 mol% of Pd-catalyst at 95 °C in
AcOH/Ac2O (9:1) mixed-solvent for 24 h (Fig. 3). In case of toluene
as the substrate, the activity of all the catalysts was found to be
improved in comparison to that of the free Pd(OAc)2 catalyst, ex-
cept catalyst C4 (Fig. 3a). Most interestingly, with free Pd(OAc)2
catalyst, the ortho product was found to be major (40%), while
with increasing the bulkiness of the NHC ligand in the complexes,
the proximal C–H functionalization selectivity decreased and con-
sequently the distal selectivity increased, resulting the para prod-
uct as the major one (upto 47%)
(Fig. 3a). The catalyst C4 having the bulkiest NHC showed the
lowest amount of ortho product (16%) with a bit compromised
overall yield. However, both the yields and the selectivity for C2
and C3 were found to be very good, resulting only 19% and 18% of
ortho products respectively. Notably, for C5 and C6, containing un-
5

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
Fig. 4. Acetoxylation of disubstituted arenes catalyzed by Pd(OAc)2 (labelled as Pd) and the “Pd(II)-NHC” complexes C1-C6. Reaction conditions: arene = 1.25 mmol,
PhI(OAc)2 = 0.125 mmol, catalyst = 2.5 mol% with respect to PhI(OAc)2, AcOH/Ac2O = 1 mL (9:1, v/v), 95 °C, 24 h. Yields of the combined isomeric products were shown
in bar plots, and the isomeric distributions were shown in pie plots. The yields and isomer ratio were calculated by GC-MS using chlorobenzene (0.125 mmol) as internal
standard added after the reaction was over.
ity as a function of bulkiness of the NHC ligands, was observed as
shown in Fig. 3b-c. Based on a critical analysis, the catalysts C4, C2
and C3 were found to be the choice in terms of both reactivity and
selectivity were concerned.
additionally to use sterically biasing MesI(OAc)2 to achieve the dis-
tal:proximal selectivity of 4:1 in case of naphthalene. [5b]
For 1,2-dichlorobenzene as substrate, the yields were generally
low for all the catalysts (Fig. 4b). Nevertheless, the product se-
lectivity profile was maintained by the catalysts C1-C6. Thus the
distal:proximal selectivity was improved gradually on going from
free Pd(OAc)2 catalyst (≈ 2.57:1) to catalysts C1, C5, and C6 (≈
4:1) to catalysts C4, C3 (≈ 8:1) (Fig. 4b). In comparison, Sanford’s
“Pd(OAc)2+pyridine”/PhI(OAc)2, “Pd(OAc)2+pyridine”/MesI(OAc)2,
and “Pd(OAc)2+acridine”/MesI(OAc)2 systems provided the selec-
tivity of 2.45:1, 8:1, and 24:1 respectively. [5b] On the other hand,
the selectivity of Fernández-Ibáñez’s “Pd(OAc)2+FPCA”/PhI(OAc)2
system was found to be ≈ 8:1, a similar value as that of the
catalysts C4 and C3 in this study. [11a]
2.5. Acetoxylation of disubstituted arenes
The efficacy of the sterically-tuned Pd(II)-NHC complexes
in governing the site-selectivity of catalytic C–H acetoxyla-
tion reaction using PhI(OAc)2 was also scrutinized in case of
1,2-disubstituted arenes, by subjecting naphthalene and 1,2-
dichlorobenzene as model substrates (Fig. 4). There are two proba-
ble isomeric products for these 1,2-disubstituted arenes – the prox-
imal A and the distal B – as shown in Fig. 4. For naphthalene,
practically no preferential selectivity (distal:proximal ≈ 1:1) was
obtained for the free Pd(OAc)2 catalyzed reaction, although a good
product yield was obtained (Fig. 4a). Gratifyingly, the steric bulk
at the Pd-centre in the catalysts C1-C6 improved the selectivity
scenario dramatically, without compromising the activity as high
product yields were obtained in the range of 64-79%. Thus for C1,
C5 and C6, the distal:proximal selectivity enhanced to ≈ 2.33:1
(Fig. 4a). Most interestingly and desirably, the catalysts C4 and C3,
owing to their increased steric perturbation through both sides of
the NHC ligands, provided the highest distal:proximal selectivity of
≈ 3:1. In comparison to these observed enhanced selectivity, the
3. Conclusion
In conclusion, we demonstrated the power of steric factor
of NHC ligands in well-defined “Pd(II)-NHC” complexes to fine-
tune the reactivity and site-selectivity of catalytic non-directed
oxidative C–H acetoxylation of simple arenes, without imposing
the steric bias from the acetoxylating reagent. A series of well-
characterized discrete [Pd(NHCRRꢀ )(py)I2] complexes with system-
atically varied degree of steric congestion at the Pd centre, ex-
erted through the R and R’ substituents on the NHC ligand, were
explored in acetoxylation of representative three monosubstituted
arenes (toluene, iodobenzene and bromobenzene) and two dis-
ubstituted arenes (naphthalene and 1,2-dichlorobenzene). The se-
lectivity of distal versus proximal C–H activation-acetoxylation in
these arenes was found to be finely controlled by the steric
bulk of the NHC ligands employing these complexes as catalysts
t
Cárdenas “Pd(II)-NHC” catalyst having Bu and sulfinyl substituents
at the two N atoms of the NHC ligand, furnished only 1.17:1 ra-
tio of distal:proximal selectivity. [14] The “Pd(OAc)2+FPCA” sys-
tem developed by Fernández-Ibáñez, also gave less selectivity (dis-
tal:proximal ≈ 2.45:1) than the present catalysts C4 and C3. [11a]
On the other hand, Sanford’s “Pd(OAc)2+acridine” system required
6

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
and PhI(OAc)2 as acetoxylating reagent. Thus, with increasing the
bulkiness of the NHC ligand in the complexes, the ratio of dis-
tal:proximal C-acetoxylated products could be improved to a great
extent in all cases, viz., upto (37+47):16 for toluene, (44+42):18 for
iodobenzene, (42+57):7 for bromobenzene, 75:25 for naphthalene,
and 89:11 for 1,2-dichlorobenzene. Considering the easily achiev-
able wide variation of NHC ligands in the area of organometallic
chemistry, this study would be expected to open up more strate-
gies not only to improve the activity but also to control the site-
selectivity of C–H functionalization reactions in simple as well as
complex organic molecules.
slowly and the reaction mixture was stirred at 50 °C for overnight.
It was then allowed to cool to room temperature. Diethyl ether
(25 ml) followed by saturated sodium carbonate solution (25 ml)
were added to it. The organic layer was collected and the aqueous
layer was washed further with diethyl ether (3 × 25 ml). The com-
bined organic fractions were concentrated in vacuo. The residue
was taken up in dichloromethane (50 mL), dried with magnesium
sulfate, filtered and the solvent was removed in vacuum to afford
1,3-bis-(cyclohexyl) imidazolium chloride as an off-white solid. It
was immediately stored under N2. 1H NMR (500 MHz, CDCl3) δ
11.19 (s, 1H), 7.22 (d, J = 1.3 Hz, 2H), 4.58 (tt, J = 11.9, 3.8 Hz, 2H),
2.23 (d, J = 11.0 Hz, 4H), 1.92 (d, J = 13.9 Hz, 4H), 1.74 (dd, J = 12.1,
3.5 Hz, 6H), 1.58 – 1.44 (m, 4H), 1.26 (qt, J = 13.1, 3.7 Hz, 2H).
1,3-dimesityl-1H-imidazol-3-ium chloride: [27] Step-1: First,
2,4,6-trimethyllaniline (3.5 mL, 25.0 mmol) was dissolved in 20
4. Experimental section
4.1. General methods and materials
mL methanol in
a 50 mL round bottom flask. The resulting
Reactions were performed in oven-dried glassware. 1H and
13C{1H} NMR spectra were recorded in Bruker AVANCE III 400 MHz
and 500 MHz NMR spectrometers at 298 K. Chemical shifts (δ) are
expressed in ppm using the residual proton resonance of the sol-
vent as an internal standard (CHCl3: δ = 7.26 ppm for 1H spectra,
77.36 ppm for 13C{1H} spectra; DMSO: δ = 2.50 ppm for 1H spec-
tra, 39.52 ppm for 13C{1H} spectra. All coupling constants (J) are
expressed in hertz (Hz) and only given for 1H-1H couplings. The
following abbreviations were used to indicate multiplicity: s (sin-
glet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of
triplets), m (multiplet). ESI mass spectrometry was performed on
a Bruker micro TOF QII spectrometer. The GC-MS was performed
with Agilent 7890A GC (column: HP-5 having length = 30 m, in-
ner diameter = 0.32 mm, film thickness = 0.25 μm) coupled with
Agilent 5975C MS. Solvents and reagents were obtained from com-
mercial suppliers and used without further purification. Deuterated
solvents were purchased from Aldrich. Pd(OAc)2 was purchased
from Johnson Matthey and used as received without further pu-
rification.
solution was cooled to 0 °C. Then 40% aqueous glyoxal (1.42
mL, 12.5 mmol) and three drops of formic acid were added.
The solution was warmed to room temperature and stirred for
one day. The yellow suspension was filtrated, washed with min-
imum volume of methanol and ether to afford N,N’-bis(2,6-
diisopropylphenyl)ethane-1,2-diimine as a yellow powder. Step-2:
The yellow powder (1.50 g, 3.98 mmol) was taken in a 100 mL
round bottom flask. 30 mL of THF was added to it to make a yellow
solution. Then hydrochloric acid (4 M in dioxane) (1.40 mL, 5.57
mmol) and paraformaldehyde (119.5 mg, 3.98 mmol,) were stirred
in a test tube until complete dissolution of the white solid oc-
curred. This solution was then slowly added to the yellow solution.
The resulting solution was stirred at 40 °C for three days. Then the
suspension was cooled to room temperature and the white precip-
itate was collected by filtration, washed with THF and diethyl ether
to afford 1,3-dimesityl-1H-imidazol-3-ium chloride as white pow-
der. 1H NMR (500 MHz, CDCl3) δ 10.77 (s, 1H), 7.59 (d, J = 0.7 Hz,
2H), 7.02 (s, 4H), 2.33 (s, 6H), 2.18 (s, 12H).
1-(tert-butyl)-3-methyl-1H-imidazol-3-ium iodide: [28] 1-(tert-
butyl)-3-methyl-1H-imidazol-3-ium iodide was prepared in two-
step procedure. Step-1: First, glyoxal (2.3 mL) and tert-butyl amine
(2.1 mL) were taken in a 50 mL round bottom flask. Then, 4 mL of
water was added to this and the mixture was heated at 70 °C for
12 h. Then 40% aqueous solution of HCHO (1.7 mL) and 28% aque-
ous solution of NH3 were added to it. Further, 15 mL of methanol
was added and reaction was continued for more 6 h at 70 °C.
Then solvent extraction was performed using DCM/H2O. The or-
ganic layer was evaporated to obtain 1-(tert-butyl)-1H-imidazole.
Step-2: Methylation of 1-(tert-butyl)-1H-imidazole was performed
in DCM as solvent. 1-(tert-butyl)-1H-imidazole (0.5 mL) was taken
in a 50 mL round bottom flask. Next, 3.0 equivalent of methyl io-
dide was added to it and reaction was continued for 24 h at room
temperature. Then solvent was evaporated and the resulting solid
washed with THF to obtain the desired product. 1H NMR (500
MHz, CDCl3) δ 10.29 (s, 1H), 7.42 – 7.37 (m, 2H), 4.18 (s, 3H), 1.74
(s, 9H).
4.2. Synthesis of ligands
1,3-dimethyl-1H-imidazol-3-ium iodide: [24] 1-methyl imida-
zole (0.012 mol, 1.0 mL) was taken in a 50 mL round bottom flask
containing 20 mL of dry DCM and the mixture was stirred for 5
minutes. Then methyl iodide (0.021 mmol, 3.12 g) was added drop-
wise. The mixture was left for stirring at room temperature. Af-
ter 16 h, the solvent was evaporated to obtain a yellow-colored oil
which was washed with diethyl ether and THF to obtain the de-
sired product. 1H NMR (500 MHz, CDCl3): δ 9.06 (1H, s), 7.69 (2H,
d, J = 1.5 Hz), 3.85 (6H, s).
1,3-dibutyl-1H-imidazol-3-ium
iodide:
[25]
1-butyl-1H-
imidazole (0.945 g, 7.6 mmol) and 1-iodobutane (0.86 mL)
were taken in a Schlenk tube. The mixture was heated at 90 °C
for 15 h with stirring. Then it was transferred to a vial using DCM
as a solvent and then the volatiles were removed under vacuum
which afforded 1,3-dibutyl-1H-imidazol-3-ium bromide as brown
oil. 1H NMR (500 MHz, CDCl3) δ 10.13 (s, 1H), 7.50 (d, J = 1.5 Hz,
2H), 4.34 (t, J = 7.4 Hz, 4H), 1.94 – 1.86 (m, 4H), 1.42 – 1.31 (m,
4H), 0.94 (t, J = 7.4 Hz, 6H).
1-(phenyl)-3-methyl-1H-imidazol-3-ium iodide: [15b] Step-1: A
mixture of imidazole (10.0 mmol) and iodobenzene (10.0 mmol) in
the presence of 10 mol% copper(I) iodide and benzotriazole were
taken in a 100 mL round bottom flask. Next, 30 mL of DMF was
added to it and at last potassium tert-butoxide (15.0 mmol) was
added to the reaction. The reaction mixture was stirred at 100 °C
for 36 h. Next after cooling down the reaction mixture to room
temperature, solvent extraction was performed with ethyl acetate
and water. The organic solvent was evaporated and column chro-
matography was performed with the resulting crude mixture to
isolate pure phenyl imidazole. Step-2: Methylation of phenyl imi-
dazole was performed in THF. Thus, phenyl imidazole (2.0 mmol)
was taken in a 15 mL pressure tube and 3 equivalent of methyl
iodide (6.0 mmol) was added to it and the reaction was contin-
1,3-dicyclohexyl-1H-imidazol-3-ium chloride: [26] Cyclohexyl
amine (2.48 g, 25 mmol) was taken into a 250 mL round bot-
tom flask containing 25 mL of toluene under N2 atmosphere.
Paraformaldehyde (750 mg, 25 mmol) was added to it. This was
stirred vigorously for 30 min at room temperature and then cooled
to 0 °C. A further portion of cyclohexyl amine (2.48 g, 25 mmol)
was added and the solution was stirred at 0 °C for a further 10
min. Next, 3.3 M HCl (7.5 ml, 25 mmol) was added dropwise over
10 min and the solution was allowed to warm up to room tem-
perature. Then, 40% aqueous glyoxal (3.6 mL, 25 mmol) was added
7

T. Mandal, S. Yadav and J. Choudhury
Journal of Organometallic Chemistry 953 (2021) 122047
ued for 24 h at room temperature. Then solvent was evaporated
and the resulting residue was washed with THF to obtain the solid
product. 1H NMR (500 MHz, CDCl3) δ 10.29 (s, 1H), 7.75 – 7.69 (m,
4H), 7.56 – 7.50 (m, 3H), 4.24 (s, 3H).
mental analysis calculated (%) for (C13H19 N3I2Pd): C 27.04, H 3.32,
N 7.28; found (%): C 27.01, H 3.34, N 7.11.
C6: Yield = 85%. 1H NMR (400 MHz, CDCl3): δ = 8.82 (dd,
J = 6.3, 1.4Hz, 2H), 8.06-7.98 (m, 2H), 7.66 (tt, J = 7.7, 1.5Hz, 1H),
7.56 (dd, J = 10.4, 4.8Hz, 2H), 7.48 (t, J = 7.4Hz, 1H), 7.26-7.21(m,
2H), 7.18 (d, J = 2.0Hz, 1H), 7.10 (d, J = 2.0Hz, 1H), 4.09 (s, 3H). The
NMR spectral data were matched with the literature report. [15b]
4.3. Synthesis of the Pd complexes
General method: Pd(OAc)2 (28 mg, 0.125 mmol), the correspond-
ing ligand precursor (0.125 mmol), KI (83 mg, 0.5 mmol) and
K2CO3 (86.37 mg, 0.625 mmol) were taken in 2 mL of pyridine
and the mixture was refluxed for 24 h. After the reaction, the
solution was cooled to ambient temperature, and 8 mL of DCM
was added to it. Then, the reaction mixture was filtered through a
Celite bed to remove the solid residues. The filtrate was evaporated
completely under vacuum and the resulting solid was dissolved in
minimum amount of DCM and hexane was added to this which re-
sulted in the precipitation of the product as an orange-yellow solid.
The product was further purified by recrystallization (DCM/hexane)
or column chromatography on alumina using 10-50% DCM in hex-
ane as the eluent.
4.4. Single-crystal X-ray diffraction analysis
Single-crystal X-ray diffraction data were collected using
a
Bruker SMART APEX II CCD diffractometer with graphite mono-
˚
chromated Mo Kα (λ = 0.71073 A) radiation at different low
temperatures for each crystal. Structures were solved with di-
rect methods using SHELXS-97 and refined with full-matrix least-
squares on F2 using SHELXL-97 [29].
4.5. General procedure of acetoxylation of mono- and di-substituted
arenes
C1: Yield = 81%. 1H NMR (500 MHz, CDCl3): δ 9.04 (d, J = 4.9
Hz, 2H), 7.74 (t, J = 7.7 Hz, 1H), 7.35 – 7.31 (m, 2H), 6.92 (s, 2H),
3.97 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.9, 137.8, 124.6,
123.3, 39.1. The NMR spectral data were matched with the litera-
ture report. [19]
Diacetoxyiodobenzene (40.4 mg, 0.125 mmol), catalyst (2.5
mol% w.r.t. diacetoxyiodobenzene) and the arene substrate (1.25
mmol) were placed in a sealed tube which was equipped with a
magnetic bar. Next, 1 mL of freshly prepared acetic acid/acetic an-
hydride (9:1 v/v) mixed-solvent was added to the mixture. The
sealed tube was capped tightly and the reaction mixture was
stirred at 95 °C for 24 h. It was then cooled to room tempera-
ture and the yield was calculated by GCMS analysis using 0.125
mmol of PhCl (added after the completion of reaction) as an inter-
nal standard.
C2: Yield
=
85 %. 1H NMR (500 MHz, CDCl3) δ 9.03 (d,
J = 5.0 Hz, 2H), 7.73 (t, J = 8.1 Hz, 1H), 7.34 – 7.30 (m, 2H),
6.95 (s, 2H), 4.44 – 4.37 (m, 4H), 2.07 – 2.00 (m, 4H), 1.49 (dt,
J = 15.0, 7.4 Hz, 4H), 1.03 (t, J = 7.4 Hz, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 154.0, 144.1, 137.7, 124.6, 121.7, 51.7, 31.6, 20.1,
13.9. HRMS (ESI) m/z = 285.0577 [{(M)−2I−Py−H}]+ (calcd for
C11 H19 N2Pd+: m/z = 285.0582), m/z = 492.0116 [(M)−I]+ (calcd for
C16 H25N3IPd+: m/z = 492.0129). Elemental analysis calculated (%)
for [C16 H25N3I2Pd]: C 31.02, H 4.07, N 6.78; found (%): C 31.49, H
4.14, N 6.94.
5. Dedication
This paper is dedicated to Professor Pradeep Mathur on the oc-
casion of his 65th birthday.
C3: Yield = 70%. 1H NMR (500 MHz, CDCl3) δ 9.03 (d, J = 5.0
Hz, 2H), 7.73 (t, J = 8.1 Hz, 1H), 7.34 – 7.30 (m, 2H), 6.95
Declaration of Competing Interest
(s, 2H), 4.44
– 4.37 (m, 4H), 2.07 – 2.00 (m, 4H), 1.49 (dt,
J = 15.0, 7.4 Hz, 4H), 1.03 (t, J = 7.4 Hz, 6H). 13C{1H} NMR
(126 MHz, CDCl3) δ 154.0, 144.1, 137.7, 124.6, 121.7, 51.7, 31.6,
20.1, 13.9. HRMS (ESI) m/z = 416.1289 [{(M)−(2I)−H}]+ (calcd for
C20H28N3Pd+: m/z = 416.1321), m/z = 544.0408 [(M)−I]+ (calcd for
C20H29N3IPd+: m/z = 544.0443). Elemental analysis calculated (%)
for [C20H29N3I2Pd(CH2Cl2)0.25]: C 35.10, H 4.29, N 6.06; found (%):
C 35.08, H 4.30, N 6.08. Note: DCM was used as a solvent for crys-
tallization.
The authors declared that there is no conflict of interest.
Acknowledgements
Part
of
this
work
was
supported
by
DST-SERB
(CRG/2019/006038). This work was also supported by the in-
house grants from IISER Bhopal. The authors thank the NMR, Mass
(ESI-MS and GC-MS), and SC-XRD facilities of CIF, IISER Bhopal.
T.M. thanks CSIR for fellowship. S.Y. thanks DST for INSPIRE
fellowship during BS-MS studies at IISER Mohali.
C4: Yield
=
78 %. 1H NMR (500 MHz, CDCl3) δ 8.48 (2
H, d, J =5.0 Hz), 7.52 (1 H, t, J =7.6 Hz), 7.13 – 7.08 (2 H,
m), 7.05 (6 H, s), 2.46 (12 H, s), 2.39 (6 H, s). 13C{1H} NMR
(126 MHz, CDCl3) δ 155.5, 153.7, 139.2, 138.2, 137.1, 136.1,
129.6, 124.9, 124.1, 22.1, 21.3. HRMS (ESI) m/z
[{(M)−2I−Py−H}]+ (calcd for C21H23N2Pd+: m/z
=
409.0892
Supplementary materials
=
409.0899),
m/z
m/z
=
536.9998 [(M)−I−Py]+ (calcd for C21H24N2IPd+:
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2021.
122047.
=
544.0443), m/z
=
555.0112 [(M)−I−Py+H2O]+ (calcd
for C21H26N2IOPd+: m/z = 555.0127), m/z = 616.0414 [(M)−I]+
(calcd for C26H29N3IPd+: m/z
=
616.0446). Elemental analysis
calculated (%) for [C26H29N3I2Pd(CH2Cl2)0.5]: C 40.48, H 3.85, N
5.34; found (%): C 40.44, H 3.75, N 5.39. Note: DCM was used as a
solvent for crystallization.
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C5: Yield = 80 %. 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J = 4.9
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41.1, 32.5. HRMS (ESI) m/z = 261.0220 [{(M)−2I−Py−H+H2O}]+
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