Large yet flexible N-heterocyclic carbene ligands for palladium catalysis

Article abstract of DOI:10.1002/chem.201302471

A straightforward and scalable eight-step synthesis of new N-heterocyclic carbenes (NHCs) has been developed from inexpensive and readily available 2-nitro-m-xylene. This process allows for the preparation of a novel class of NHCs coined ITent ("Tent" for "tentacular") of which the well-known IMes (N,N′-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), IPr (N,N′-bis(2,6-di(2-propyl)phenyl)imidazol-2-ylidene) and IPent (N,N′-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) NHCs are the simplest and already known congeners. The synthetic route was successfully used for the preparation of three members of the ITent family: IPent (N,N′-bis(2,6- di(3-pentyl)phenyl)imidazol-2-ylidene), IHept (N,N′-bis(2,6-di(4-heptyl) phenyl)imidazol-2-ylidene) and INon (N,N′-bis(2,6-di(5-nonyl)phenyl) imidazol-2-ylidene). The electronic and steric properties of each NHC were studied through the preparation of both nickel and palladium complexes. Finally the effect of these new ITent ligands in Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-couplings was investigated. Tentacular NHCs: A straightforward, scalable eight-step synthesis of N-heterocyclic carbenes (NHCs) has been developed using inexpensive and readily available 2-nitro-m-xylene, allowing the preparation of a class of NHCs designated ITent ("Tent" for "tentacular"). The electronic and steric properties of each NHC were studied through the preparation of both nickel and palladium complexes, and the effect of these new ITent ligands in Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-couplings was investigated.

Full text of DOI:10.1002/chem.201302471

DOI: 10.1002/chem.201302471
Large yet Flexible N-Heterocyclic Carbene Ligands for Palladium Catalysis
Sebastien Meiries, Gaꢀtan Le Duc, Anthony Chartoire, Alba Collado, Klaus Speck,
Kasun S. Athukorala Arachchige, Alexandra M. Z. Slawin, and Steven P. Nolan*[a]
Dedicated to Professor Carl D. Hoff on the occasion of his 65th birthday.
Abstract: A straightforward and scala-
ble eight-step synthesis of new N-het-
di
(3-pentyl)phenyl)imidazol-2-ylidene)
(N,N’-bis
zol-2-ylidene) and INon (N,N’-bis
di(5-nonyl)phenyl)imidazol-2-ylidene).
The electronic and steric properties of
each NHC were studied through the
preparation of both nickel and palladi-
um complexes. Finally the effect of
these new ITent ligands in Pd-catalyzed
Suzuki–Miyaura and Buchwald–Hart-
wig cross-couplings was investigated.
ACHUTGTNRNEUG(N 2,6-diACHTGNUTRENNUNG
NHCs are the simplest and already
known congeners. The synthetic route
was successfully used for the prepara-
tion of three members of the ITent
family: IPent (N,N’-bisACTHNUTRGNEN(GU 2,6-diACHTUNTGREN(NUGN 3-pen-
tyl)phenyl)imidazol-2-ylidene), IHept
ACHTUNGTRENNUNG
A
N
ACHTUNGTRENNUNG
developed from inexpensive and readi-
ly available 2-nitro-m-xylene. This pro-
cess allows for the preparation of
a novel class of NHCs coined ITent
(“Tent” for “tentacular”) of which the
well-known IMes (N,N’-bis(2,4,6-tri-
Keywords: bulky · catalysis · flexi-
ble · N-heterocyclic carbene · palla-
dium · tentacular
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Introduction
struct may be considered a limitation of this specific NHC
ligand and the design of new NHC ligands possessing more
flexible bulk remains an area of interest in NHC synthesis.
In this context, we have explored new synthetic strategies
for the design and multigram-scale preparation of new NHC
ligands possessing bulky yet highly flexible motifs.
N-Heterocyclic carbenes (NHCs) are an important class of
compounds that has found application in various fields of
chemistry such as organic synthesis, catalysis and macromo-
lecular chemistry.[1] In the field of palladium catalysis, NHC
ligands are often compared with phosphine ligands.[2] How-
ever, metal-NHC complexes are now recognized for their
unique properties as well as their higher stability towards air
and moisture, in contrast to their phosphine analogues.[2]
The importance of NHC ligands in catalysis is related to
their s-donating properties as well as their variable steric
bulk, both of which have strong effects on oxidative addition
and reductive elimination processes in metal-mediated
cross-coupling reactions.[2] Spectacular reactivity has been
attributed to “flexible steric bulk”[3] in which the ligands
adjust towards incoming substrates, while enabling the stabi-
lization of reactive low-valent intermediates.[3–4] As an exam-
Results and Discussion
Preparation of the ITent·HCl salts: Several methods have
been reported for the synthesis of NHCs since their discov-
ery in the early 1990s.[1a,d–g,i,j,l,m] Although great structural di-
versity has been achieved already, on the whole, the classical
NHCs depicted in Figure 1 still remain the most employed,
particularly in homogeneous catalysis. The main reason for
their widespread use, beyond their unique properties, is
their straightforward preparation in multigram quantities
from inexpensive or commercially available amine or aniline
ple, the very bulky IPr* (IPr*=N,N’-bisACTHNUTRGNEUNG(2,6-bis(diphenyl-
methyl)-4-methylphenyl)imidazol-2-ylidene) ligand reported
by Markꢀ and co-workers[5] and further investigated by
Nolan and co-workers[6] exhibited excellent properties in
catalysis. However the limited flexibility of the IPr* con-
[a] Dr. S. Meiries, Dr. G. Le Duc, Dr. A. Chartoire, Dr. A. Collado,
K. Speck, K. S. A. Arachchige, Prof. Dr. A. M. Z. Slawin,
Prof. Dr. S. P. Nolan
EaStCHEM, School of Chemistry
University of St. Andrews, Purdie Bulding, North Haugh
St. Andrews, Fife, KT16, 9ST (UK)
E-mail: snolan@st-andrews.ac.uk
Figure 1. Most common imidazolium and imidazolinium chlorides used
for homogeneous catalysis. (S)IPr (R=diisopropylphenyl), (S)IMes (R=
mesityl), ICy (R=cyclohexyl), IAd (R=adamantyl), ItBu (R=tert-
butyl), IiPr (R=iso-propyl), IMe (R=Me). (S) denotes the saturated
character of imidazolinium NHC backbone.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302471.
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Chem. Eur. J. 2013, 19, 17358 – 17368

FULL PAPER
precursors. However, fewer examples of new NHCs bearing
bulky N-substituents stemming from non-commercial
amines/anilines have been reported in the field of transition
metal catalysis for reasons of synthetic accessibility.[3,4b–d,j,5,7]
Markꢀ[5] has reported a convenient multigram-scale prep-
aration of IPr* (R=2,6-bis(diphenylmethyl)-4-methylphen-
yl) which has proven to be fairly substrate-specific and
largely intolerant to chemical variations of the bulk.[8] In the
metal-mediated reduction methods (iron or zinc) were also
screened but the Pd/C hydrogenation appeared clearly as
the most convenient and efficient procedure. Freshly pre-
pared alkyl magnesium bromides (RCH2MgBr) were then
added to diester 4 to obtain diols 5–7 in excellent yield and
purity. Dehydration under harsh acidic conditions followed
by the hydrogenation of the intermediate crude bis-alkenes
finally provided 2,6-dialkylanilines IPent 8, IHept 9 and
INon 10 (Scheme 1). A one-pot version of the dehydration-
hydrogenation sequence also gave similar results although in
lower purity. This new 6-step synthetic route allowed for the
preparation of multigram quantities of commercially un-
available, unprecedented anilines with minimal or without
purification. Importantly, the rather expensive Pd/C used for
the nitro-reduction and the alkene-hydrogenation steps was
recovered with great ease by filtration and successfully
reused several times in subsequent reactions. Far beyond the
efficacy and the scalability of our new synthetic route, the
flexibility of our process by the economical and near-quanti-
tative Grignard addition is notable. Indeed, a very wide
range of Grignard reagents are readily available from chem-
ical suppliers and can be prepared safely in the laboratory
on a large scale. As a result of this remarkable versatility,
our process will find applications into the design of new ani-
lines and their ultimate conversion into a countless number
of tailor-made NHCs.
meantime, Organ[4a–c,9] has described the IPent (R=2,6-di
ACTHNUTRGNE(UNG 3-
pentyl)phenyl) ligand as a particularly efficient NHC ligand
for palladium-catalysis. The latter appeared to us as a good
starting point in our quest towards the design of “larger yet
flexible NHC ligands”. But surprisingly no information de-
tailing the synthesis of this non-commercially available
NHC or its possible precursors could be found in the litera-
ture. To the best of our knowledge, the one-step process re-
ported by Steele[10] for the preparation of the IPent aniline
(2,6-diACHTUNGTRENNUNG(3-pentyl)aniline, R=2,6-diACHTUGNTREN(NUGN 3-pentyl)phenyl) was the
only literature precedent available. Although this process
successfully afforded the IPent aniline in multigram quanti-
ties in a single step, this synthetic route suffered from signif-
icant drawbacks. The lack of flexibility of the approach, the
use of a mixture of non-commercial superbases as part of
the fairly complex procedure together with the purification
of the final reaction mixture by fractional distillation forced
us to envisage an alternate strategy that might lead to this
specific compound and possibly to an entire family of com-
pounds.
A novel approach was explored to access unprecedented
anilines as precursors for the preparation of tailor-made
NHC ligands. Our straightforward and highly scalable route
started with Etardꢂs double-oxidation of inexpensive and
readily available 2-nitro-m-xylene 1 to 2-nitroisophthalic
acid 2 which, in turn, was converted to its corresponding di-
methyl ester 3 (Scheme 1). All attempts towards the intro-
duction of alkyl chains at this stage by a Grignard reaction
were unsuccessful. To overcome this issue, the dimethyl 2-ni-
troisophthalate 3 was reduced to dimethyl 2-aminoisophtha-
late 4 by hydrogenation with palladium on charcoal. Other
Anilines 8–10 were then reacted with glyoxal under acidic
conditions to form the corresponding diimines 11–13 that
were in turn cyclized to form the corresponding imidazolium
chlorides 14–16 (Scheme 2). The entire synthetic sequence
Scheme 2. Synthesis of imidazolium chlorides 14, 15 and 16. Conditions:
i) glyoxal (40% in H2O), HCOOH, MeOH, RT, 3–5 h; ii) (CHO)n,
ZnCl2, HCl (4m in dioxane), 708C, 3 h.
required minimal purification by recrystallization and pro-
vided multigram quantities of IPent·HCl 14, IHept·HCl 15,
and INon·HCl 16 as white crystalline powders in high purity
as confirmed by elemental analysis. Interestingly, as opposed
to the rest of the synthetic sequence, the cyclisation yield
greatly depended on the size of the R alkyl chains with a sig-
nificantly lower yield observed for INon·HCl 16 and
IHept·HCl 15. Due to the size of their N-substituents, which
partially hinder the cyclization, the competing diimine
bridge cleavage was observed under acidic conditions, re-
generating the free anilines 8–10. It is important to note that
the alternative mild TMSCl protocol described by Hinter-
Scheme 1. Synthesis of anilines 8,
9 and 10. Conditions: i) KMnO4,
NaOH, H2O, reflux, 12 h; ii) H2SO4, MeOH, reflux, overnight; iii) 10%
Pd/C, H2, AcOEt, RT, 20 h; iv) alkylbromide RCH2Br (R=Me, Et, nPr),
Mg, THF, 08C to RT, 1–2 h; v) H2SO4, THF, 1008C, 1–2 h; vi) 10% Pd/C,
H2, EtOH, reflux, 6–48 h.
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17359

S. P. Nolan et al.
mann for less hindered NHCs failed to give the cyclisation
products 14–16 efficiently.[11]
Preparation of [NiACHTNUTRGNE(NUG ITent)(CO)3] complexes for the deter-
mination of ITent electronic properties: An established
method for the determination of the electron-donor ability
of two electron ligands is the measurement of the IR car-
bonyl stretching frequencies of the related [Ni(L)(CO)3]
complexes.[12,13] The A1 stretching frequency of the CO li-
gands is referred to as the Tolman Electronic Parameter
(TEP) and is directly correlated with its electron richness:
lower TEP values correspond to increased s-donating prop-
erties of Ni-bound ligands.[12] Very recently, our research
Scheme 4. Synthesis of [NiACHTNUGRTENUNG(ITent)(CO)3] (20–22).
group reported the synthesis of [NiACTHUNTRGNEU(GN IPent)(CO)3] (20) and
evaluated the electron donor properties of the IPent
Table 1. TEP values of [Ni
NHC
ACHTUNGTRNE(NUGN NHC)(CO)3] complexes.
ligand.[14] To extend this study to the new members of the
TEPDCM [cmÀ1
]
TEPhex [cmÀ1
]
ITent family, the corresponding [NiACTHUNGTRNEUNG(ITent)(CO)3] complexes
IMes[a]
2050.7
2051.5
2052.7
2049.3
2048.6
2048.5
2054.0
2055.1
were synthesized. Their preparation first required the gener-
ation of the free carbene species 17–19 by treatment of THF
solutions of ITent·HCl salts 14–16 with NaH and KOtBu at
room temperature for 16 h (Scheme 3). As already noted
IPr[a]
IPr*[b]
–
[c]
IPent (20)[d]
IHept (21)
INon (22)
2053.1
2052.5
2052.1
[a] Reference [13a]. [b] Reference [20]. [c] [Ni
be insoluble in hexane. [d] Reference [14].
ACHTUNGTRENN(NUG IPr*)(CO)3] was found to
in dichloromethane and hexane were obtained by recording
the A1 IR frequency of the CO ligand in these nickel com-
plexes. These data were compared with those of other [Ni-
AHCTUNGTREG(NNUN NHC)(CO)3] complexes (Table 1), demonstrating that the
ITent ligands are more s-donating than the most common
NHCs.[17] Interestingly, the longer the R alkyl chains, the
stronger the s-donation ability of the ligand, as observed
theoretically by Gusev for other NHCs.[18] Importantly, it
must be noted that the TEP difference between IPr,[19]
IPent, IHept and INon becomes smaller as chain length be-
comes longer. Thus, the following s-donating trend was ob-
served: IPr !IPent <IHept ~INon.
Scheme 3. Preparation of free carbenes (17–19).
with IPent·HCl salt 17,[14] 18 and 19 also exhibited higher
solubility in THF than other related NHC·HCl salts. Conse-
quently, the usual conversion to their corresponding
NHC·HBF4 salts was not necessary to access the free car-
benes. This counterion exchange prior to deprotonation usu-
ally leads to higher isolated yields of the most common
NHCs.
Synthesis of [Pd
nation of the ITent steric properties: With the development
of [Pd(IPent)
(PEPPSI)],[4a–c,9] Organ and coworkers suggest-
ACHTUNGTRENN(UNG ITent)(LX)Cl] complexes and determi-
Compounds 17–19 were characterized by H and 13C{1H}
A
ACHTUNGTRENNUNG
1
NMR spectroscopy and elemental analysis. The 13C{1H}
NMR spectrum of each derivative showed the characteristic
singlet in the low-field region corresponding to the carbenic
carbon atom, at 220.9 (17), 220.5 (18), and 220.7 ppm (19),
confirming the deprotonation of the imidazolium salts. Com-
pounds 17–19 were next reacted with a slight excess of
[Ni(CO)4][15] to easily afford the desired complexes 20–22 in
excellent yields and high purities (Scheme 4).
ed that “flexible steric bulk”, a concept initially proposed by
Glorius et al.,[3,4j] is essential for high catalytic activity. As
the newest members of the ITent ligand family feature both
excellent electron donors and large steric bulk, we suspected
the preparation of their palladium complexes would result
in promising new pre-catalysts for cross-coupling catalysis.
[PdACTHNUTRGENNG(U ITent)ACHTUTGNREN(NUGN cin)Cl] (cin=cinnamyl or phenylallyl) pre-cata-
lysts 23–25 were first prepared in a straightforward manner
as described in the literature (Scheme 5).[6d] The free car-
benes obtained from the ITent·HCl salts 14–16 were initially
generated in situ with KOtBu in THF in reaction conducted
for 3 h at room temperature. Their coordination to the palla-
1
Complexes 20–22 were characterized by H and 13C{1H}
NMR spectroscopy, IR and elemental analysis.[16] The coor-
dination of the NHC ligands to the metal center was con-
firmed by the presence of singlets at 196.8 (20), 196.6 (21),
and 196.9 ppm (22) in the 13C{1H} NMR spectra. The pres-
ence of three CO ligands in these complexes was confirmed
by the position and number of CO bands in their solution
IR spectra[13b] (Table 1) and unambiguously by elemental
analysis. As previously noted, the TEP of each NHC ligand
dium center was next achieved by adding [PdACHTNURGTENNUG(cin)CAHTUNGTRNEN(UGN m-Cl)]2 to
the reaction mixture affording the expected complexes 23–
25 in excellent yields. Compounds 23–25 were isolated in
high purity as indicated by elemental analysis and were
found to be air and moisture stable.
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Chem. Eur. J. 2013, 19, 17358 – 17368

Large, Flexible N-Heterocyclic Carbenes
FULL PAPER
alyst in solution. In addition, this spectroscopic handle
should be of great help in the design of future NHC ligands.
Suitable X-ray diffraction quality crystals of complexes
23–26 were grown by slow evaporation of saturated pentane
solutions.[22] In the case of 27 and 28, crystals were grown by
placing saturated methanol solutions in the freezer after ad-
dition of a drop of water to these solutions (Figure 2 and
Figure 3).[23]
Scheme 5. Preparation of [PdACTHNUTRGNENG(U ITent)ACHTUNTGREN(NUGN cin)Cl] complexes (23–25).
An additional family of palladium pre-catalysts can be
easily prepared by a synthetic route not requiring the isola-
tion of the free NHC, namely the [PdACTHNUTRGNENG(U ITent)ACHUTTGNREN(NUNG acac)Cl]
(acac=acetylacetonate) family. These complexes can be syn-
thesized by reacting the ITent·HCl salts 14–16 with [Pd-
ACHTUNGTRENNUNG
(acac)2], as described in the literature (Scheme 6).[21] The
newly prepared [Pd
N
N
ACHTUNGTRENN(UNG IHept)-
A
R
ACHTUNGTRENNUNG
as air- and moisture-stable yellow microcrystalline solids in
good yields and in high purity.
Figure 2. ORTEP diagrams of molecular structures of 23 (two conformers
I and II), 24 and 25 showing 50% probability ellipsoids. Hydrogen atoms
have been omitted for clarity. Selected bond lengths (ꢃ) and angles (8):
À
À
À
À
23-I Pd1 C1 2.019(8), Pd1 C41 2.123(9), Pd1 C42 2.150(9), Pd1 C43
2.214(9), Cl1-Pd1-C1 93.6(3), Cl1-Pd1-C43 96.5(3), C1-Pd1-C41 101.2(3),
À
À
C41-Pd1-C43 67.6(4). 23-II Pd51 C51 2.024(8), Pd51 C91 2.105(12),
Scheme 6. Preparation of [PdACHTNUTRGENN(UG ITent)AHCTUNGTRENN(UGN acac)Cl] (26–28).
À
À
Pd51 C92 2.098(15), Pd51 C93 2.225(13), Cl51-Pd51-C51 96.8(3), Cl51-
Pd51-C93 95.1(4), C51-Pd51-C91 100.8(4), C91-Pd51-C93 67.2(5). 24
À
À
À
À
Pd1 C1 2.031(5), Pd1 C4 2.105(7), Pd1 C5 2.152(8), Pd1 C6 2.251(6),
Cl1-Pd1-C1 92.16(17), Cl1-Pd1-C6 98.64(18), C1-Pd1-C4 100.2(3), C4-
The new [PdACHTUNGTRENNUNG(ITent)ACHTUNTGREN(NUGN acac)Cl] complexes 26–28 were fully
À
À
À
Pd1-C6 67.9(3). 25 Pd1 C1 2.037(4), Pd1 C54 2.129(4), Pd1 C55
characterized and interestingly, the 1H NMR spectroscopy
revealed that the differences in the chemical shifts of both
singlets of the “acac” methyl groups increases dramatically
À
2.140(4), Pd1 C56 2.230(4), Cl1-Pd1-C1 96.23(10), Cl1-Pd1-C56
92.98(11), C1-Pd1-C54 101.82(15), C54-Pd1-C56 68.31(16).
with the length of the R alkyl groups in the NHC ligand.
1
The H spectrum of [Pd
G
(acac)Cl] exhibited two close
Very interestingly, in both the acac- and cinnamyl-palladi-
um systems, the IPent ligand adopts two different configura-
tions (I and II) in the solid state. This situation was not ob-
served in the IHept and INon cases. This flexibility can pre-
sumably account for the dramatic gain in catalytic activity
observed with the IPent ligand compared to IPr in certain
applications. This observation is in agreement with the ex-
pected increase in flexibility of the alkyl chains. However,
we cannot provide an explanation as to why this phenomen-
on was not observed with IHept and INon ligands. Solid-
state structures represent minimum energy conformations
and these obtained for the ITent family members in the two
series provide useful insights into structural orientation of
singlets at 1.82 ppm and 1.84 ppm for the methyl groups of
the acac ligand.[21] The 1H NMR spectrum of 26 revealed
that these singlets were shifted upfield, the first one slightly
(1.73 ppm) and the second one more significantly
(1.53 ppm). This chemical shift difference is more marked in
27 (1.77 ppm and 1.40 ppm), and decreases slightly in 28
(1.75 ppm and 1.40 ppm), as the bulk increases but is located
further away from the metal center. This suggests that in so-
lution, the magnetic, and consequently, the chemical envi-
ronment around the metal is directly affected by the length
of the R alkyl groups. This information is critically impor-
tant for understanding of the effect of NHC bulk on the cat-
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17361

S. P. Nolan et al.
facilitate both oxidative addi-
tion and reductive elimination
steps resulting in better overall
catalytic activity. The buried
volume of the IHept ligand
seemed to vary depending on
the system it is associated with,
here again the flexibility of this
ligand motif is apparent. In
cinnamyl-Pd, the size of IHept
was found to be similar to that
of IPent (average of 23-I and
23-II). However, in the acac-
Pd system, IHept appeared to
be significantly larger than
IPent (average of 26-I and 26-
II). Finally, INon was shown to
be smaller than IHept in both
cases. This can presumably be
rationalized by the fact that
longer chains remain distant
from the first coordination
sphere and therefore do not in-
teract with the metal center.
Figure 3. ORTEP diagrams of molecular structures of 26 (two conformers I and II), 27 and 28 showing 50%
probability ellipsoids. Hydrogen atoms have been omitted for clarity. Selected bond lengths (ꢃ) and angles (8):
To obtain further insight
into the steric properties of
our new precatalysts 23–28,
a three-dimensional steric map
was generated by calculating
the %VBur in four different
regions around the metal
center.[26] Looking along the
À
À
À
26-I Pd1 C1 2.274(1), Pd1 O1 2.052(3), Pd1 O2 2.031(3), C1-Pd1-O1 174.8(1), O1-Pd1-O2 92.1(1), C1-Pd1-
À
À
À
Cl1 88.8(1), O1-Pd1-Cl1 87.4(4). 26-II Pd2 C2 2.278(1), Pd2 O3 2.050(3), Pd2 O4 2.024(3), C2-Pd2-O3
À
À
179.2(1), O3-Pd2-O4 92.1(1), C2-Pd2-Cl2 88.8(1), O3-Pd2-Cl2 88.3(2). 27 Pd1 C1 2.272(1), Pd1 O1 2.038(2),
Pd1 O2 2.025(3), C1-Pd1-O1 175.5(7), O1-Pd1-O2 92.1(3), C1-Pd1-Cl1 90.1(7), O1-Pd1-Cl1 85.8(1). 28 Pd1
À
À
À
À
C1 2.274(2), Pd1 O1 2.036(3), Pd1 O2 2.030(4), C1-Pd1-O1 174.6(2), O1-Pd1-O2 92.3(1), C1-Pd1-Cl1 88.8(1),
O1-Pd1-Cl1 85.8(1).
the alkyl moiety and spatial occupation about the metal
center. The percent buried volume for each structure 23–28
was then calculated with the SambVca application,[24,13b,25]
and results are summarized in Table 2. In both the acac and
cinnamyl systems, the IPr ligand was found to feature the
smallest buried volume (36.7% and 37.4%). Surprisingly,
a dramatic difference was observed between the configura-
tions I and II of the Pd-IPent complexes 23 and 26. This dif-
ference suggests that IPent-based palladium catalysts may
accommodate incoming substrates differently by adapting to
z axis, the calculation provides more information on how
the ligand adapts its shape to the metal environment (see
the Supporting Information). In general, two quadrants are
sterically crowded whereas the two remaining areas are
largely unhindered. The less hindered faces can be thought
of as the preferential approach for substrate leading to the
formation of the intermediate involved in oxidative addi-
tion.[6d,26] On the other hand, the reductive elimination and
the release of cross-products may presumably be facilitated
by the presence of highly bulky quadrants around palladi-
um. If this is the case then high reactivity under mild condi-
tions should ensue and be associated with bulky yet flexible
nature.[6d]
In Pd-cinnamyl systems, the previous remark was ob-
served with two pairs of quadrants having very similar
buried volumes, especially for 24 and 25. However, it has to
be noted that Pd-IHept 24 (%VBur =26.5) has more empty
space compared to Pd-INon 25 (%VBur =29.0). Moreover,
as described earlier, INon was again found to have smaller
buried volumes to IHept. More interestingly, the steric map
confirmed the very different nature of the two conformers,
with 23-II being much more crowded than 23-I (Figure 4).
In the Pd-acac system, more significant differences were
observed. Importantly, the sterics of 26-I and 26-II were dra-
matically different, with conformer 26-II having amazingly
Table 2. Bond distances and steric parameters of [PdCAHTUNGTRENNUNG
À
Complex
Pd CNHC [ꢃ]
[Pd
[Pd
N
G
2.041(9)
2.019(8)
2.024(8)
2.031(5)
2.037(4)
1.969
1.960
1.974
1.977
1.965
36.7
R
40.6 (I)
44.1(II)
41.5
39.0
37.4
34.3 (I)
46.6 (II)
45.7
[Pd
[Pd
[Pd
[Pd
ACHTUNGTRENNUNG(cin)Cl] 24
G
R
[Pd
[Pd
(acac)Cl] 27
R
43.7
[a] Calculation parameters: sphere radius, 3.50 ꢃ; distances for the
metal–ligand bond, 2.00 ꢃ; hydrogen atoms were omitted; scaled Bondi
radii were used as recommended by Cavallo.[24]
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Large, Flexible N-Heterocyclic Carbenes
FULL PAPER
whereas
the efficacy of [Pd
(PEPPSI)]. Consequently, the
Organ[4b]
showed
ACHTUNGTRENNUNG(IPent)-
AHCTUNGTRENNUNG
combination of the ITent and
cinnamyl ligands in well-de-
fined Pd-NHC pre-catalysts ap-
peared promising for this chal-
lenging cross-coupling.
Reaction optimization was
initially performed at room
temperature
common
with
base/solvent
various
sys-
tems.[29] The coupling of 2-
chloromesitylene and 2,6-dime-
thylbenzene boronic acid was
used as the benchmark reac-
tion for our optimization. In
our case, and as described by
Dorta,[26a] the use of KOtBu in
toluene was found to be the
best combination to promote
the coupling, with complete
conversion of the starting ma-
terials after 20 h with 1 mol%
of 23–25 (Table 3, entry 1). The
use of KOtBu in iPrOH, which
was previously found to be the
optimal system in the case
(cin)Cl],[27d] did not
of [PdACTHNURGTENN(UG IPr)ACHUTNGTRENNGUN
lead to any conversion in that
case.[29] Compared to some
other systems reported in the
literature, [PdACTHNUTRGENN(UG ITent)ACHTUNGTRENNUNG(cin)Cl]
complexes exhibited higher
catalytic activity at lower cata-
lyst loadings. Indeed, for a simi-
lar example, catalyst loading is
Figure 4. Top view (along z axis) mapping of the sterics for 23 (two conformers I and II), 24 and 25 with
%VBur values per quadrant.
large buried volumes (%VBur =65.3) and rather empty oppo-
site quadrants (%VBur =29.8 and 27.6). Conversely, 26-I ap-
peared almost free of steric hindrance, featuring four similar
quadrants. In the case of IHept, the unique conformer fea-
tured smaller buried volumes (%VBur =60.1 and 61.8) but as
divided by two (1 mol% vs 2 mol%) and reactivity occurs
at lower temperature (RT vs 658C).[4b,26a] Interestingly, as
previously observed by Organ,[4b] our preliminary optimiza-
tion confirmed that the increase of the NHC alkyl chain
length from IPr to IPent resulted in a significant improve-
ment of the catalytic activity (Table 3, entry 1). However, at
room temperature, the formation of a gel at the beginning
of the reaction was sometimes found to have a detrimental
effect on the reproducibility of the reaction, especially at
lower catalyst loadings.[29] The increase of the reaction tem-
perature to 658C and the dilution of the reaction medium
allowed us to circumvent this issue. Although the gel was
still formed, the reproducibility of the reaction was uneffect-
ed. Increasing the temperature also permitted us to reduce
the catalyst loading of 23–25 to 0.5 mol%, and full conver-
sion was still reached (Table 3, entry 2). To better identify
the marked differences in reactivity between the three new
complexes 23–25, the catalyst loading was further decreased
to 0.2 mol%, and the reaction was stopped after 4 h
(Table 3, entry 3). Interestingly, the catalytic activity was
seen before in 24, a marked void in one quadrant (%VBur
=
26.8), whereas 28 presented very asymmetric quadrants (Fig-
ures 4 and 5).
Preparation of tetra-ortho-substituted biaryls by Suzuki–
Miyaura cross-coupling with [PdACTHUNRTGENNUG(ITent)ACHTUNTGREN(NUGN cin)Cl] (23–25):
[PdACHTUNGTRENNUNG(NHC)ACHTUNGTRENNUNG(cin)Cl] pre-catalysts have found widespread ap-
plication in multiple cross-coupling reactions[6a,d,27] and have
À
proven highly active in C C cross-coupling of hindered sub-
strates. One of the remaining challenges in Suzuki–Miyaura
cross-coupling is the preparation of tetra-ortho-substituted
biaryls under mild conditions.[4j,28] Examples reported in the
literature highlight the use of bulky yet flexible ligands to
achieve this transformation. Notably, Nolan[6d] and Dorta[26a]
independently demonstrated the efficiency of [Pd
ACHTUNGTRNE(NUNG NHC)-
ACHTUNGTRENNUNG
Chem. Eur. J. 2013, 19, 17358 – 17368
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17363

S. P. Nolan et al.
lent yields (Scheme 6, 80–
97%). Both aryl chlorides and
bromides were used without
any loss of activity. In the case
of 2,3,5,6-tetramethylbenzene
and 2-methylnaphtalene bor-
onic acids, an increase of the
catalyst loading from 0.5 to
1 mol% was necessary to
reach completion (Scheme 7).
On the whole, 23 exhibited ex-
cellent catalytic activity, plac-
ing this new complex amongst
the most active pre-catalysts to
achieve the preparation of
tetra-ortho-substituted biaryls
by Suzuki–Miyaura cross-cou-
pling.[4b,26a] More specifically,
the catalyst loading reported
here (0.5–1 mol%) is very
competitive with the previous
investigations of Dorta[26a]
(0.5–2 mol%) and ourselves[6d]
(1 mol%). Finally, compared
to its [PdACTHNUGTRENNUG(IPent)ACHTUNGTRNE(NUGN PEPPSI)]
congener,[4b] our system proved
to be more active, globally
yielding the biaryls in better
yields, at lowest Pd loadings.
Buchwald–Hartwig Arylami-
nation
with
[PdACHTUNGTRENNUNG(ITent)-
AHCTUNGTRENNUNG
arylamination has become an
important method for the for-
Figure 5. Top view (along z axis) mapping of the sterics for 26 (two conformers I and II), 27 and 28 with
%VBur values per quadrant.
[27c,30]
À
mation of C N bonds.
As
with tertiary phosphine li-
gands,[31] literature precedents
slightly decreased by increasing the length of the R alkyl
chain in the ITent NHC ligands from IPent to IHept and fi-
nally to INon. These preliminary observations suggest that
the nature of the ligand has a noticeable impact on the over-
all catalytic activity. With 23 slightly better results were ob-
tained than with 24 (Table 3, entry 3, 66% vs 58%). Howev-
er, the additional length in INon by with 25 was not found
to be beneficial (Table 3, entry 3, 49% vs 58% and 66%).
This observation is consistent with the steric and electronic
information discussed above.
As a consequence, the scope of the reaction was explored
with 23 not only because it furnished the best result, but
also because its preparation as a well-defined precatalyst ap-
peared to be slightly more convenient compared to the
other congener 24. The reaction was studied under opti-
mized conditions, with 0.5 to 1 mol% of 23 and KOtBu in
toluene at 658C (results are summarized in Scheme 7). The
system displayed excellent catalytic activity for the coupling
of various unactivated and deactivated aryl, naphthyl or het-
eroaryl halides with aryl or naphthylboronic acids in excel-
have shown Pd–NHC complexes to be efficient precatalysts
for the catalytic Buchwald–Hartwig arylamination reac-
tion.[9f,27d,e,32] Nolan recently demonstrated the role of [Pd-
ACHUTNGREN(NUG NHC)HCATUNGTRENN(UGN acac)Cl] in this transformation, reaching remarkable
activities with the bulky but less flexible IPr* and IPr*OMe li-
gands.[6b,8] In this context, the effect of the R-alkyl chains
length on Pd complexes 26–28 was investigated in Buch-
wald–Hartwig arylamination of aryl chlorides with aniline
derivatives. Recent reports identified electron-rich aryl hal-
ides and electron-deficient anilines as highly disfavored cou-
pling partners for arylamination.[6b,8,9c] For these reasons,
these challenging substrates were examined with our new
acac-bearing catalysts.
4-Chloroanisole was coupled with 4-fluoroaniline or 3-tri-
fluoromethylaniline as benchmark reactions for our initial
optimization. After an initial base/solvent screening, the use
of KOtBu in toluene at 808C or at reflux (in the case of 3-
trifluoromethylaniline) was found to provide the best condi-
tions, leading to complete conversion of the starting materi-
als with 0.4 mol% of 26–28. To compare the catalytic prop-
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Chem. Eur. J. 2013, 19, 17358 – 17368

Large, Flexible N-Heterocyclic Carbenes
FULL PAPER
Table 3. [PdACHTUNGTRENNUNG(ITent)ACHTUNGTRENNUNG
(cin)Cl] pre-catalysts comparison.[a]
Entry T/[Pd]/time
Conversion [%][b]
RT[c]/1.0 mol%/
20 h
1
658C/0.5 mol%/
20 h
2[d]
3[d]
658C/0.2 mol%/4 h
Scheme 7. Scope of the Suzuki–Miyaura cross-coupling catalyzed with
[Pd
ACHUTGTNRNEUG(N IPent)ACHTGNUTRENNUNG
Ar’B(OH)2 (1.0 mmol), KOtBu (1.5 mmol), [Pd
N
ACHTUNGTRENNUNG
(x mol%), toluene (2.0 mL), 658C, 22 h. Reaction times have not been
optimized. Isolated yields after chromatography on silica gel, average of
two runs. [a] Reaction was performed with technical grade 1-bromo-2-
methylnaphtalene (90%).
[a] Reagents and conditions: 2-chloromesitylene (0.5 mmol), 2,6-dime-
thylbenzene boronic acid (1.0 mmol), KOtBu (1.5 mmol), [Pd(ITent)-
(cin)Cl] (23–25) (1 mol%), toluene (1 mL), T [8C), 20 h. [b] Conversion
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
to coupling product based on 2-chloromesitylene determined by GC,
average of at least 2 runs. [c] RT=25–288C. [d] Toluene (2 mL).
The overall positive effect attributed to the length of the R-
alkyl chains appeared to be maximal with the IHept ligand.
It appears that in the case of INon, the additional bulk is
too far from the coordination sphere of the metal center
and does not influence the catalytic properties of the com-
plex. This explanation is supported by our observed steric
and electronic trends and is of critical importance for fur-
ther ligand design efforts because the limit of flexible bulk
in NHC ligands has been reached.
erties of 26–28, the reaction was performed at lower catalyst
loadings. By employing 0.05 mol% of precatalyst, N-fluoro-
phenyl-p-anisidine was obtained in 58% conversion with 26,
83% with 27 and 76% with 28 (Table 4, entry 1). Similarly,
at higher temperature, the coupling of p-chloroanisole and
3-trifluoromethylaniline provided the desired products in
41%, 68% and 64% GC yields with 26, 27 and 28 respec-
tively (Table 4, entry 2). The
same reactivity order was ob-
Table 4. [PdACTHNUTRGENN(UG ITent)ACHTUNTGERN(NUGN acac)Cl] pre-catalysts comparison.
served for the third model reac-
tion between 3-chloropyridine
and 4-fluoroaniline, affording
the cross-product in 22%, 70%
and 61% GC yields with 26, 27
and 28 respectively (Table 4,
entry 3). Interestingly, the three
benchmark reactions followed
the same trend and no cross
coupling was observed with the
IPr ligand in any of these cases
as reported by Organ.[9c,33]
These results are in agreement
with the initial hypothesis in
which an increased flexible
bulk is essential for the optimal
catalytic activity of Pd–NHC
complexes. However, although
27 was more efficient than 26,
no gain in activity was observed
for 28, which was more active
Entry
1
Product
Conditions[a]
GC conversions [%][b]
A
2
3
B
A
[a] Reagents and conditions: ArX (0.5 mmol), Ar’NH2 (0.55 mmol), KOtBu (0.5 mmol), [Pd
(26–28), toluene (1.0 mL). Condition A: 0.05 mol% [Pd(ITent)(acac)Cl], 808C, 20 h; Condition B: 0.1 mol%
[Pd(ITent)(acac)Cl], 1108C, 20 h. [b] Conversion to coupling product based on starting aryl chloride by GC,
than 26 in every case (Table 4). by using dodecane as internal reference, average of three runs.
ACHUTGTNREN(UNG ITent)ACHTUNGTRENNUNG(acac)Cl]
A
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
Chem. Eur. J. 2013, 19, 17358 – 17368
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17365

S. P. Nolan et al.
Based on our preliminary results, 27 was selected as the
best precatalyst to explore the scope of the arylamination
reaction. The scope of the reaction was explored under the
previously optimized conditions, with 0.1–0.2 mol% of 27
and KOtBu in toluene at 808C or at reflux for 2–4 h
(Scheme 8). The system displayed excellent catalytic activity
cellent catalytic activity of 27 in Buchwald–Hartwig aryl-
AHCTUNGTREGaNNNU mination reaction and confirm that the “flexible steric
bulk” concept is essential in securing high catalytic activity
with Pd–NHC complexes.
Conclusion
The synthesis of a novel class of NHCs of which two ana-
logues (IHept and INon) are unprecedented are now report-
ed in the open literature. Our new synthetic strategy en-
AHCTUNGTREGaNNNU bled the preparation of multigram quantities of the final
NHCs in good overall yields after minimal purification.
These new NHCs expand the so-called “ITent” NHC family
in which the bulk around the metal center and the s-dona-
tion increase in the following order: IPr !IPent <IHept ~
INon. Beyond the novelty of these new compounds, their
preparation has rendered possible the study of a significant
number of compounds falling within the “ITent” series and
will help to understand which characteristics are crucial to
the design of “optimum” N-heterocyclic carbenes for palla-
dium catalysis. The steric and electronic parameters mea-
sured help explain the catalytic results and fully support our
initial hypothesis. The INon NHC was shown to feature flex-
ible bulk, yet experimentally it represents a limit beyond
which extra flexible bulk does not translate into gain in cata-
lytic activity. However, work is ongoing to fully capitalize on
the properties of these new ligands, such as their exceptional
solubility in non-polar media that might offer new horizons
in cross-coupling and related catalysis.[34] The initial catalytic
results with the ITent ligand family have permitted the iden-
tification of more active Pd-NHC precatalysts for Suzuki–
Miyaura and Buchwald–Hartwig cross-couplings and have
given precious information for improved understanding of
Pd-NHC catalysis.[35] The remarkable steric suppleness of
the large yet flexible ligand set is currently being further ex-
plored in late transition metal catalysis.
Acknowledgements
Scheme 8. Scope of the Buchwald–Hartwig arylamination catalyzed with
[Pd
ACHTUNGTRENNUNG(IHept)ACHTUNGTRENNUNG
We gratefully acknowledge the EC for funding through the seventh
framework project SYNFLOW. Frꢄdꢄric Izquierdo, Julie Mayen and
Enrico Marelli are thanked for their experimental contributions to the
project. Professor Luigi Cavallo and Laura Falivene are thanked for their
help regarding the use of the SambVca application. We would like to
thank the EPSRC National Mass Spectrometry Service Center in Swan-
sea for mass spectroscopic analyses and Umicore and Rockwood Lithium
for their generous gifts of materials. SPN is a Royal Society Wolfson Re-
search Merit Award holder.
RNH2 (0.55 mmol), KOtBu (0.5 mmol), [Pd
G
ACHTUNGTRENNUNG
(x mol%), toluene (1.0 mL). [a] 0.1 mol% 27, 808C, 2 h. [b] 0.2 mol%
27, 1108C, 4 h. Isolated yields after chromatography on silica gel, average
of two runs. [c] 20 h reaction time.
for the coupling of various deactivated aryl chlorides with
anilines, particularly with electron-poor anilines, which are
reported to be highly disfavored coupling partners. More-
over, very good yields were obtained with sterically hin-
dered substrates. Interestingly, the unprecedented coupling
of 2,6-dimethoxychlorobenzene was successfully achieved
with various anilines at low catalyst loading. Finally, the cat-
alytic system was also effective in the coupling of several
primary and secondary aliphatic amines, including the highly
challenging dibutylamine. Our results demonstrate the ex-
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Chem. Eur. J. 2013, 19, 17358 – 17368

Large, Flexible N-Heterocyclic Carbenes
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[35] The use of the [Pd
ACHUTGTNRNEUG(N ITent)ACHTUGNTREN(NNGU cin)Cl] system in Buchwald–Hartwig and
of the [Pd(ITent)(acac)Cl] complexes in Suzuki–Miyaura reactions
A
ACHTUNGTRENNUNG
lead to similar reactivity trends. These results will be reported sepa-
rately.
Received: June 26, 2013
Published online: November 14, 2013
17368
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Chem. Eur. J. 2013, 19, 17358 – 17368