Beruflich Dokumente
Kultur Dokumente
doi:10.1038/nature13384
The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the
most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we
provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and
uses and highlighting how these features are being exploited in a selection of pioneering recent studies.
1.49 A) , signifying that the C22nitrogen bonds possess partial doublebond character.
These general principles of carbene stabilization apply to all classes of
NHC although the relative importance of each effect varies from compound
An overview of
N-heterocyclic carbenes
Coordinated
to transition metals
Coordinated
to p-block elements
As organocatalysts
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, 48149 Munster, Germany.
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RESEARCH REVIEW
a
Backbone
- electronic stabilization from
aromaticity
- substituents affect carbene
electronics
N-substituent(s)
- kinetic stabilization from steric bulk
- electronic influence
- potential for asymmetric induction
IAd (1a)
c
N
Imidazolylidene (1)
R = Ad
R = Me
R = Mes
R = 2,6-(iPr)2C6H3
R = tBu
Ring size
- cyclic structure favours bent
singlet ground state
- ring geometry affects sterics
and electronics
IAd (1a)
IMe (1b)
IMes (1c)
IPr (1d)
ItBu (1e)
Imidazolinylidene (2)
R = Mes
SIMes (2a)
R = 2,6-(iPr)2C6H3 SIPr (2b)
N
N
Thiazolylidene (X = S, 3)
Oxazolylidene (X = O, 4)
Triazolylidene (5)
R = R' = Ph TPT (5a)
R
R
-electron-donating
R'
Nitrogen heteroatom(s)
- -electron-withdrawing
- -electron-donating
- inductive and mesomeric stabilization
- number and identity of heteroatoms
affects carbene electronics
Pyrrolidinylidene
(CAAC, 7)
Benzimidazolylidene (6)
R'
-electron-withdrawing
R'
N
R
Abnormal
imidazolylidene (8)
O
N
N,N'-Diamidocarbene
(DAC, 9)
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BOX 1
Coordination to
surfaces6870
Coordination
polymers36
Cross-coupling4851
NHCs coordinated
to transition metals29
Photoactive
materials37
Organometallic
materials33
Homogeneous
catalysis4144
Liquid
crystals35
Olefin metathesis52,53
Metalorganic
frameworks34
Asymmetric catalysis64
Metallopharmaceuticals38
RESEARCH REVIEW
BOX 2
R
X
M
X
R
X
Au
R
R
A
R = Bu, Bn
M = Pd, Pt
X = Cl, Br
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R
n
B
R = iPr, nPr, Et
X = Cl, Br
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a
N
Mes
Cl
Cl
Mes
Ru
Ph
PCy3
Alkene
complexation
k1
k2
Cl
Cl
+ PCy3
PCy3
Cl
Active
catalyst
PCy3
10a
Grubbs II
Cl
Phosphine
dissociation
Phosphine
association
Ph
PCy3
10b
Grubbs I
Cl
+R
Mes
Ru
N
Cl
11
11a (L = SIMes)
11b (L = PCy3)
k1
Ru
Ru
L
Cl
Cl
Mes
Ru
O
k2
iPr
Metathesis
products
Alkene
decomplexation
12
HoveydaGrubbs II
catalyst
k2 /k1 104 greater for 11a (L = SIMes) than for 11b (L = PCy3)
b
Me
Me
O
O
O
14
OAc
15 (7 equiv.)
13 (1 mol.%)
(single enantiomer)
THF, 1 h , 23 C
Ru
O
O
OAc
16
65%, 96:4 Z/E
95% e.e.
13
reactions was recognized with the award of the Nobel Prize for chemistry
in 2005.
As well as improving the efficiency, selectivity and practicality of transition-metal-mediated reactions, NHC-bearing catalysts can give access to
unprecedented reactivity pathways and selectivity paradigms that are not
observed using other ligands. Building on the foundations laid over the
last two decades, many research programmes are currently focused on the
development of the next generation of carbenemetal catalysts employing new NHCs. One such system has been recently developed in a series
of groundbreaking publications by the Grubbs group. As a result of the
dynamic nature of metathesis reactions, previously developed ruthenium
catalysts such as Grubbs first- and second-generation catalysts (10) and
the HoveydaGrubbs catalyst (12) favour formation of the thermodynamic E-alkene products. The selective generation of Z-configured alkenes,
which feature widely in natural products and biologically and industrially
relevant compounds, has been a major challenge limiting the usefulness of
ruthenium-catalysed olefin metathesis.
The major breakthrough in this field came in 2011 with the preparation
of ruthenium(II) complexes bearing an unsymmetrical N-adamantylsubstituted imidazolin-2-ylidene ligand that displayed high Z-selectivity
in cross-metathesis reactions55. Further optimization of the catalyst structure
led to the development of k2-nitrate-coordinated complex 13, which has
recently shown remarkable Z-selectivity in a range of transformations,
including ROMP and ring-closing metathesis56. The key feature in complex 13 and related catalysts is the presence of a second bond between the
metal and the NHC resulting from sp3-C2H activation at the N-adamantyl
substituent. As demonstrated by density functional theory (DFT) calculations, this chelation restricts rotation around the metalcarbene bond and
fixes the N-mesityl substituent over the catalytically relevant alkylidene
moiety. Steric clashing between these groups in the transition state then
explains the Z-selectivity. A further development of this methodology was
reported in 2013 in the asymmetric ring-opening/cross-metathesis of norbornene derivatives57. Chromatographic separation of two intermediate
carboxylate complexes followed by salt metathesis with sodium nitrate
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a
Electron-donating NHC
aids oxidative addition
[Pd0]
R1 R2
Reductive
elimination
Bulky NHC
aids reductive
elimination
R1 X
Oxidative
addition
N
R
R
Cl
Cross-coupling
N
Pd
Cl
N
R
R
Cl
[PdII] R 1
[PdII] R 1
R2
Transmetallation
MX
17
17a R = iPr
17b R = iPent
Pd-PEPPSI-IPr
Pd-PEPPSI-IPent
R2 M
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Figure 6 | NHC coordination to
nanoparticles and metal surfaces.
a, Preparation and catalytic reactivity
of NHC-stabilized Ru-nanoparticles
prepared by Chaudret and coworkers69. NHCs are capable of
binding to heterogeneous metallic
species in the same fashion as to
monomeric complexes leading to
nanoparticles that benefit from the
high degree of stabilization afforded
by the strength of the metal-NHC
coordination. b, Modification of
NHC ligands coordinated to a gold
surface reported by Johnson and
co-workers70. The strength of the
binding between the NHC ligands
and the metallic surface allowed for
cross-metathesis to be performed
directly on the surface-bound
ligands, leading to functionalized
materials. cod, 1,5-cyclooctadiene,
cot, 1,3,5,7-cyclooctatetraene ; RT,
room temperature; py, pyridine.
a
N
[Ru(cod)(cot)]
H2 (3 bar)
N
pentane, RT
Active hydrogenation
catalysts (18a,18b)
R
N
= Ru
18
18a (with 1e, 0.2 equiv.)
18b (with 1d, 0.2 equiv.)
18c (with 1d, 0.5 equiv.)
b
[Ru]
N
THF, RT THF, RT
2c
O
Mes
[Ru] =
F
Mes
Cl
py Ru
Cl py
= Au
Ph
19
F
F
NHCs in these adducts has been compared to that of ligands in lowoxidation-state transition-metal complexes with s-donation into vacant
orbitals leading to enhanced stability74. The steric and electronic properties
of NHCs have been found to have a great influence on the nature of adducts
formed upon activation of white phosphorus with species featuring P4, P8
and P12 clusters all having been obtained using different carbenes. By
contrast, reduction of an imidazol-2-ylidenePCl3 adduct by Robinson
and co-workers led to the diatomic P2 species 21, which features phosphorus in a form reminiscent of that of nitrogen in N2 (ref. 75). The same
group also reported the first complex featuring silicon in the zero oxidation state (22) upon reduction of a silicon(IV) precursor (Fig. 8b)76.
Similar adducts involving non-metals in the elemental oxidation state
have been prepared for other p-block elements such as arsenic and, notably,
carbon, with compound 23 being best described as a bent allene with an
Activation of small
molecules74,81
NHCboranes as
reagents and
radical sources72
Stabilization of
radicals84
NHCs coordinated to
p-block elements30
Adducts as reagents
in organic synthesis
Stabilization of
reactive species74
n
NHC-mediated
activation of
silicon reagents71
RESEARCH REVIEW
a
R1
Dipp
N
B
N
N
Dipp
R2
Si
Dipp
N
Dipp
21
Dipp
23
Dipp
Dipp
H
RT, 45 min
Dipp
CN
KHMDS
THF
Dipp
Dipp
O
N+
Cl
O
Ph
Hexane
RT, 30 min
CN
B
K+
B
K+
CN
25
24
7a
Dipp
22
CN
CN
Ph
131.8
Si
Dipp
20
R2 = H, alkyl, aryl
Dipp
Dipp
R2
R1
Dipp
R2
CN
26
95%
Me2N
Me2N
Dipp
NMe2
NMe2
R
O
Ph
Dipp
R
O
C2
C
Ph
27
81%
28
94%
N-C-C-O coplanar
40% spin density at C2
electronic structure featuring two lone pairs at the central carbon (Fig. 8c)77.
Adducts between NHCs and fullerenes have also been prepared78.
The stability and reactivity of NHCp-block element adducts is also
influenced by the p-properties of the NHC. In borane complexes 20, the
poor p-accepting ability of the carbene disfavours 1,2-migration of a boron
substituent onto the adjacent electrophilic carbon. In other cases, however,
the capacity to delocalize p-electron-density onto the NHC has helped
enable the generation of previously elusive reactive species. Notable
examples of this concept can also be found among NHCboron adducts,
where both borenium cations and boryl anions partially stabilized by pinteractions with imidazol-2-ylidene Lewis bases have been prepared72.
Current research efforts in this area have focused on more recently
developed classes of NHC, which offer improved characteristics for
stabilizing reactive intermediates. Significant advances have been made
by the Bertrand group using cyclic (alkyl)(amino)carbenes (CAACs, 7).
These NHCs, which feature only one nitrogen heteroatom in the ring,
are considerably more p-accepting than imidazol-2-ylidenes and have
enabled the preparation of unprecedented species such as the tri-coordinate neutral adduct 24, which possesses a lone pair at boron (Fig. 8d)79.
Moreover, CAAC 7a in complex 25 was recently found to be sufficiently
electron-withdrawing to invert the traditional polarity of boronhydrogen bonds80. Treatment of this complex with potassium hexamethyldisilazide resulted in deprotonation at boron and delivered the isolable
boryl anion 26 (Fig. 8e).
With filled s-frontier and vacant p-frontier orbitals, the electronic
structure of NHCs somewhat resembles that of transition metals and
NHCs may exhibit similar reactivity to metals in the activation of small
molecules81. p-Accepting classes of NHCs such as CAACs (7) and the
carbonyl-containing DACs (9) are particularly well suited to these processes. As revealed in a series of reports by Bielawski and co-workers, these
latter NHCs are capable of activating small molecules such as NH3, while
NHCs as organocatalysts
Their propensity to coordinate to carbon-electrophiles has led to a third
major class of applications, in which NHCs act as organocatalysts
(Fig. 9)87,88. The majority of these processes are initiated by nucleophilic
attack of the carbene onto carbonyl groups present in organic substrates.
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Conjugated
umpolung98
Michael umpolung99
NHCs as
organocatalysts87,88
Umpolung93
MoritaBaylis
Hillman reactivity99
With aldehydes
With Michael
acceptors
Acyl
azolium96,97
Polymerization89
With esters
Transesterification
RESEARCH REVIEW
Y
O
+
R1
Y
X
N+
Y
R
R2
for R1 =
for R1 =
HO
R1
HO
or external
oxidant
R2
LG
R2
Acyl enolate
R2
N+
H+
29
Acyl azolium
R2
Breslow intermediate
Conjugate umpolung
O
O/NR3
O/NR3
+ Nuc
EWG
R4
R4
R2
R5
R3
R2
Nuc
O/NR3
XH
R2
R2
R4
R1
R1
O/NR3
EWG
DielsAlder-like
annulations
Azolium
substitution
X = O, NR3
(Aza)benzoin
condensation
R2
Stetter reaction
R4
+ CO2
R5
R2
Formal [3+2]
cycloaddition
R3
Decarboxylative
cyclopentene
formation
Additionelimination
OR1
OR1
Ar
R
H
-deprotonation
-deprotonation
O
HO
H
Ar
Ar
Ar
32
-CH2 acidic due to
electron-withdrawing
azolium, conjugation
30
31
Breslow-like
can react via
conjugate umpolung
O
OR1 33HBF (20 mol.%)
4
Ar
MeCN, 4 MS
RT, 2448 h
R2
R3
R2
R2
R3
Ar
Ar
O
NHC
1 equiv.
R2
R3
R3
CO2
Ar
3981%
d.r. = 5:1 to 20:1
e.r. = 91:1 to 97:3
Ph
tBu
33
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Despite the prevalence and widespread use of aliphatic esters as feedstocks
in organic chemistry, alternative synthetic methods of selectively activating the b-position of these substrates are scarce. Moreover, using the
chiral triazol-2-ylidene catalyst 33, this methodology allows for high levels
of enantiocontrol during the annulation reactions with five-membered
carbo- and heterocycles being delivered in enantiomeric ratios of up to
97:3, using enone, trifluoroketone or hydrazone electrophiles (the reaction with enones is shown in Fig. 11b).
10.
11.
12.
13.
14.
15.
Outlook
The discovery and development of N-heterocyclic carbenes is undoubtedly one of the greatest success stories of recent chemistry research. In
the 23 years since Arduengo and co-workers reported the first bottleable
NHC, seminal contributions from many different groups on the structure, coordination chemistry and reactivity of these compounds have led
to a multitude of applications across many different fields. NHCs are now
workhorses of organic and organometallic chemistry, rivalling phosphines
as ancillary ligands in transition metal catalysis and offering new possibilities in main-group chemistry and organocatalysis.
However, as we hope is clear from the examples of recent research touched
upon in this review, the meteoric rise of NHCs is far from complete. Alongside their other roles, NHCs are continuing to find many new applications
across the chemical sciences. One area of promise is the field of heterogeneous catalysis, where the strength of NHCmetal binding can allow
for enhanced stabilization of metallic colloids or surfaces, with the potential for modification of the catalyst properties via in situ functionalization
of the ligand. The strength and stability of the metalligand bond, and the
ability to readily fine-tune the properties of organometallic complexes
through structural modification of the ligand, also explain the increasing
use of NHCs in metallopharmaceuticals. Significant advances are also being
made in fields where the use of NHCs is more established. In organocatalysis, recent pioneering research has focused on the development of new
reactivity pathways which expand the range of suitable reaction partners
beyond the traditional aldehydes.
A major driver of current ground-breaking research is the development of new NHCs with different properties and reactivities. In the field
of homogeneous transition-metal catalysis, ruthenium catalysts featuring
novel chelating imidazolin-2-ylidene ligands have facilitated Z-selective
olefin metathesis, while recently developed chiral NHC ligands have shown
promise in asymmetric hydrogenation reactions. New classes of NHCs
such as DACs and CAACs have shown unprecedented reactivity in the
activation of small molecules and in the stabilization of hitherto inaccessible non-metallic species. CAACs are particularly suited to such stabilization, as exemplified by the recent report of a CAAC-stabilized bottleable
organic radical. Given the tremendous strides that have been taken over the
last two decades, and the high-quality research currently being conducted,
the future of NHCs looks very exciting.
Received 10 January; accepted 9 April 2014.
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Acknowledgements We thank the European Research Council under the European
Communitys Seventh Framework Program (FP7 2007-2013)/ERC grant agreement
number 25936, the Deutsche Forschungsgemeinschaft (Leibniz Award and SFB 858),
the Alexander von Humboldt Foundation (to M.N.H.) and the Fonds der Chemischen
Industrie (to M.S.) for financial support.
Author Contributions All authors worked together to outline the content of the review
and define its scope. The text was primarily written by M.N.H. and F.G. with
contributions from all authors. The figures were prepared by M.N.H., C.R. and M.S.
Editing of the manuscript, figures and references was done by all authors.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to F.G. (glorius@uni-muenster.de).
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