Persistent carbene

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A stable carbene: isolated 1,3-dimesitylimidazol-2-ylidene in a Schlenk flask (stir bar also present).

A persistent carbene (also known as stable carbene or Arduengo carbene) is a type of carbene demonstrating particular stability. The best-known examples are diaminocarbenes with the general formula (R2N)2C:, where the 'R's are various functional groups. The groups can be bridged so that the carbon with unfilled orbitals is part of a heterocycle, such as imidazole or triazole.

Carbenes have long been known as very reactive and short lived molecules that could not be isolated, and were usually studied by observing the reactions they undergo. Stable carbenes had been proposed to exist by R. Breslow in 1957,[1][2] and the first examples of stable carbenes coordinated to metal atoms were synthesized by H.-W. Wanzlick and collaborators.[3][4] The isolation of a stable liquid dicarbene was reported in 1989 by G. Bertrand and others.[5][6] In 1991, the group of A. Arduengo reported the synthesis of a stable, isolated, crystalline carbene.[7]

Persistent carbenes are still fairly reactive substances, and many will undergo dimerisation, sometimes reversibly.

Persistent carbenes can exist in the singlet state or the triplet state, with the singlet state carbenes being more stable. The relative stability of these compounds is only partly due to steric hindrance by bulky groups. Some singlet carbenes are thermodynamically stable in the absence of moisture and (in most cases) oxygen, and can be isolated and indefinitely stored. Others are not thermodynamically stable and will dimerise slowly over days. The less stable triplet state carbenes have half-lives measured in seconds, and therefore can be observed but not stored.

History[edit]

Conjectures[edit]

In 1957, Ronald Breslow proposed that a relatively stable nucleophilic carbene, a thiazol-2-ylidene derivative, was involved in the catalytic cycle of vitamin B1 (thiamine) that yields furoin from furfural.[1][8] In this cycle, the vitamin's thiazolium ring exchanges a hydrogen atom (attached to carbon 2 of the ring) for a furfural residue. Through a deuterium exchange experiment, Breslow demonstrated that under standard reaction conditions (in deuterated water) the C2-proton was rapidly exchanged for a deuteron in a statistical equilibrium.[2]

Deuterium exchange of the C2-proton of thiazolium salt

This confirmed that the C2-proton was readily removed, and Breslow claimed that the exchange occurred through the generation of a stable thiazol-2-ylidene intermediate. This was the first example of a stable carbene being implicated in a reaction mechanism. In 2012 a so-called Breslow intermediate was reported isolated [9][10]

In 1960, H.-P. Wanzlick and co-workers conjectured that carbenes derived from dihydroimidazol-2-ylidene were produced by vacuum pyrolysis of the corresponding 2-trichloromethyl dihydroimidazole compounds with the loss of chloroform.[3][4][11] They conjectured that the carbene existed in an unfavourable equilibrium with its corresponding dimer (a tetraaminoethylene derivative), in the so-called Wanzlick equilibrium. This conjecture was challenged by Lemal and co-workers in 1964, who presented evidence that the dimer did not dissociate;[12] and also by Winberg in 1965.[13] However, subsequent experiments by M. Denk, W. A. Herrmann and others have confirmed the reality of the equilibrium, in specific circumstances.[14][15]

First synthesis[edit]

In 1970, Wanzlick's group prepared the first imidazol-2-ylidene carbene, by the deprotonation of an imidazolium salt.[16] Wanzlick,[11] as well as Hoffmann,[17] believed that these imidazole-based carbenes, with a 4n+2 π-electron ring system, should be more stable than the 4,5-dihydro analogues, due to Hückel-type aromaticity. The carbenes were not isolated, but obtained as coordination compounds with mercury and isothiocyanate:

Preparation and trapping of an imidazol-2-ylidene

In 1988, G. Bertrand and others isolated a red oil, the molecular structure of which can be represented as either a λ3-phosphinocarbene or λ5-phosphaacetylene:[5][6]

Alkyne and carbene resonances structures of Bertrand’s carbene.

These molecules, nicknamed "push-pull carbenes" in reference to the contrasting electron affinities of the phosphorus and silicon atoms, exhibit both carbenic and alkynic reactivity. An X-ray structure of this molecule has not been obtained and at the time of publication some doubt remained as to their exact carbenic nature.

In 1991, a stable, isolated, and crystalline diaminocarbene, which can be represented as a carbene or a nitrogen carbon ylide, was obtained by A. Arduengo and co-workers,[7] by deprotonation of an imidazolium chloride with a strong base:

Preparation of N,N'-diadamantyl-imidazol-2-ylidene

This carbene, the forerunner of a large family of carbenes with the imidazol-2-ylidene core, was found to be indefinitely stable at room temperature (in the absence of oxygen and moisture), and melted at 240–241 °C without decomposition. Another interesting chemical property of this ylidic compound was a characteristic resonance in the 13C NMR spectrum at 211 ppm for the carbenic atom. The X-ray structure[18] revealed longer N–C bond lengths in the ring of the carbene than in the parent imidazolium compound, indicating that there was very little double bond character to these bonds.

The first air-stable ylidic carbene, a chlorinated member of the imidazol-2-ylidene family, was obtained in 1997.[19]

In 2000, Bertrand obtained additional carbenes of the phosphanyl type, including (phosphanyl)(trifluoromethyl)carbene, stable in solution at – 30°[20] and a moderately stable (amino)(aryl)carbene with only one heteroatom adjacent to the carbenic atom.[21][22]

Understanding their stability[edit]

Dimethyl imidazol-2-ylidene, a stable dicarbene with little steric hindrance.
(external viewer)

Initially many researchers believed that the unique stability of this carbene was due to the bulky N-adamantyl substituents, which prevented the carbene from dimerising due to steric hindrance. However, Arduengo's group later obtained an imidazol-2-ylidene in which the bulky N-adamantyl groups were replaced with smaller methyl groups.[23] This showed that steric hindrance was not the predominant stabilising factor, and that imidazole-2-ylidenes were thermodynamically stable.

1,3-Dimesityl-imidazol-4,5-dihydro-2-ylidene, a stable carbene without the aromatic imidazolium ring.
(external viewer)

It had been also conjectured that the double bond between carbons 4 and 5 of the imidazolium ring backbone, which gave aromatic character to that system, was important for the carbene's stability. This conjecture was disproved in 1995 by Arduengo's group, who obtained a derivative of dihydroimidazol-2-ylidene, lacking the double bond.[24] The thermodynamical stability in this compound, and the role of steric protection in preventing dimerisation, has been a topic of some dispute.[25][26]

Bis(diisopropylamino) carbene, the first acyclic stable carbene.

In 1996, Alder and others synthesized the first acyclic persistent carbene,[27] thus showing that a cyclic backbone was not necessary for their stability. Unlike previous examples, this molecule allowed rotation around the bonds of the carbenic atom. By measuring the barrier to rotation of these bonds, the extent of their double bond character could be measured, and the ylidic nature of this carbene could be determined. Like the cyclic diaminocarbenes, unhindered variants tend to dimerise.[26][28][29]

Until 1997, all stable carbenes known had two nitrogen atoms bound to the carbenic atom. This pattern was broken in 1997–1998 with the synthesis of a thiazol-2-ylidene derivative by Arduengo's group[30] and an aminothiocarbene and an aminooxycarbene by Alder's group.[31] In these stable compounds, the carbenic atom lies between a nitrogen atom and either a sulfur or oxygen atom:

Stable carbenes with oxygen or sulfur atoms bound to the carbenic atom. (External viewer)

However, these carbenes are not thermodynamically stable as decomposition and dimerisation have been observed for unhindered examples.

A more radical development was the synthesis in 2006 of bis(diisopropylamino)cyclopropenylidene by Bertrand's group. In this compound, stable at room temperature, the carbene atom is connected to two carbon atoms, in a three-member ring that retains the aromaticity and geometry of the cyclopropenylidene ring. This example demonstrated that the presence of heteroatoms next to the carbene is not necessary for stability, either.[32]

Classes of stable carbenes[edit]

The following are examples of the classes of stable carbenes isolated to date:

Imidazol-2-ylidenes[edit]

The first stable carbenes to be isolated were based on an imidazole ring, with the hydrogen in carbon 2 of the ring (between the two nitrogen atoms) removed, and other hydrogens replaced by various groups. These imidazol-2-ylidenes are still the most stable and the most well studied and understood family of persistent carbenes.

A considerable range of imidazol-2-ylidenes have been synthesised, including those in which the 1,3-positions have been functionalised with alkyl, aryl,[23] alkyloxy, alkylamino, alkylphosphino[33] and even chiral substituents:[33]

Stable imidazol-2-ylidenes.
1,3-Dimesityl-4,5-dichloroimidazol-2-ylidene, the first air-stable carbene.
(external viewer)

In particular, substitution of two chlorine atoms for the two hydrogens at ring positions 4 and 5 yielded the first air-stable carbene.[19] Its extra stability probably results from the electron-withdrawing effect of the chlorine atoms, which must reduce the electron density on the carbon atom bearing the lone pair, via induction through the sigma-backbone.

Molecules containing two and even three imidazol-2-ylidene groups have also been synthesised.[34][35]

Imidazole-based carbenes are thermodynamically stable and generally have diagnostic 13C NMR chemical shift values between 210–230 ppm for the carbenic carbon. Typically, X-ray structures of these molecules show N-C-N bond angles of 101–102°.

Triazol-5-ylidenes[edit]

Another family of persistent carbenes are based on the 1,2,4-triazole ring, with the unfilled orbitals in carbon 5 of this ring. The triazol-5-ylidenes pictured below were first prepared by Enders and co-workers[36] by vacuum pyrolysis through loss of methanol from 2-methoxytriazoles. Only a limited range of these molecules have been reported, with the triphenyl substituted molecule being commercially available.

Triazol-5-ylidenes

Triazole-based carbenes are thermodynamically stable and have diagnostic 13C NMR chemical shift values between 210–220 ppm for the carbenic carbon. The X-ray structure of the triphenyl substituted carbene above shows an N-C-N bond angle of ca. 101°. The 5-methoxytriazole precursor to this carbene was made by the treatment of a triazolium salt with sodium methoxide, which attacks as a nucleophile.[36] This may indicate that these carbenes are less aromatic than imidazol-2-ylidenes, as the imidazolium precursors do not react with nucleophiles due to the resultant loss of aromaticity.

Other diaminocarbenes[edit]

The two families above can be seen as special cases of a broader class of compounds which have a carbenic atom bridging two nitrogen atoms. A range of such diaminocarbenes have been prepared principally by Roger Alder's research group. In some of these compounds, the N-C-N unit is a member of a 5 or 6 membered non-aromatic ring,[24][25][37] including a bicyclic example. In other examples, the adjacent nitrogens are connected only through the carbenic atom, and may or may not be part of separate rings.[27][28][29]

Synthesised cyclic and acyclic diaminocarbenes

Unlike the aromatic imidazol-2-ylidenes or triazol-5-ylidenes, these carbenes appear not to be thermodynamically stable, as shown by the dimerisation of some unhindered cyclic and acyclic examples.[25][28] However more recent work by Alder[26] suggests that these carbenes dimerise via acid catalysed dimerisation (as in the Wanzlick equilibrium).

Diaminocarbenes have diagnostic 13C NMR chemical shift values between 230–270 ppm for the carbenic atom. The X-ray structure of dihydroimidazole-2-ylidene shows a N-C-N bond angle of ca. 106°, whilst the angle of the acyclic carbene is 121°, both greater than those seen for imidazol-2-ylidenes.

Heteroamino carbenes[edit]

There exist several variants of the stable carbenes above where one of the nitrogen atoms adjacent to the carbene center (the α nitrogens) has been replaced by an alternative heteroatom, such as oxygen, sulfur, or phosphorus.:[5][6][30][31]

Synthesised heteroamino carbenes (top and bottom right) and Bertrand's carbenes (bottom left).

In particular, the formal substitution of sulfur for one of the nitrogens in imidazole would yield the aromatic heterocyclic compound thiazole. A thiazole based carbene (analogous to the carbene postulated by Breslow)[38] has been prepared and characterised by X-ray crystallography.[30] Other non-aromatic aminocarbenes with O, S and P atoms adjacent (i.e. alpha) to the carbene centre have been prepared, e.g. thio- and oxy-iminium based carbenes have been characterised by X-ray crystallography.[31]

Since oxygen and sulfur are divalent, steric protection of the carbenic centre is limited especially when the N-C-X unit is part of a ring. These acyclic carbenes have diagnostic 13C NMR chemical shift values between 250–300 ppm for the carbenic carbon, further downfield than any other types of stable carbene. X-ray structures have show N-C-X bond angles of ca. 104 ° and 109 ° respectively.

Non-amino carbenes[edit]

Carbenes that formally derive from imidazole-2-ylidenes by substitution of sulfur, oxygen, or other chalcogens for both α-nitrogens are expected to be unstable, as they have the potential to dissociate into an alkyne (R1C≡CR2) and a carbon dichalcogenide (X1=C=X2).[citation needed]

A possible decomposition pathway for aromatic N-C-X (X = O, S) substituted carbenes

On the other hand, the reaction of carbon disulfide, CS2, with electron deficient acetylene derivatives gives transient 1,3-dithiolium carbenes (i.e. where X1 = X2 = S) which then dimerise. Thus it is possible that the reverse of this process might be occurring in similar carbenes.[39][40]

Bertrand's carbenes[edit]

In Bertrand's persistent carbenes, the unfilled carbon is bonded to a phosphorus and a silicon.[41] However, these compounds seem to exhibit some alkynic properties, and when published the exact carbenic nature of these red oils was in debate.[6]

Other nucleophilic carbenes[edit]

One stable N-heterocyclic carbene[42] has a structure analogous to borazine with one boron atom replaced by methylene. This results in a planar 6-electron compound.

In the second step of this reaction sequence the proton is abstracted by LiTMP; two cyclohexyl groups shield the carbene.

Cyclopropenylidenes[edit]

Another family of carbenes is based on a cyclopropenylidene core, a three-carbon ring with a double bond between the two atoms adjacent to the carbenic one. This family is exemplified by bis(diisopropylamino)cyclopropenylidene.[32]

Triplet state carbenes[edit]

In 2001, Hideo Tomioka and his associates were able to produce a comparatively stable triplet carbene (bis(9-anthryl)carbene, with a half-life of 19 minutes), by taking advantage of resonance.[43][44]

In 2006 the same group reported a triplet carbene with a half-life of 40 minutes.[45] This carbene is prepared by a photochemical decomposition of a diazomethane with expulsion of nitrogen gas at a wavelength of 300 nanometers in benzene.

A persistent triplet carbene (right), synthesised by Itoh (2006).

Exposure to oxygen (diradical) converts this carbene to the corresponding benzophenone and the diphenylmethane compound is formed when it is trapped by 1,4-cyclohexadiene. As with the other carbenes this species contains large bulky substituents, namely bromine and the trifluoromethyl groups, that shield the carbene and prevent or slow down the process of dimerisation to a 1,1,2,2-tetra(phenyl)alkene.

Based on computer simulations, the distance of the divalent carbon atom to its neighbours is claimed to be 138 picometers with a bond angle of 158.8°. The planes of the phenyl groups are almost at right angles to each other (the dihedral angle being 85.7°).

Mesoionic carbenes[edit]

Main article: Mesoionic carbene

Mesoionic carbenes (MICs) are similar to N-heterocyclic carbenes (NHCs) except that canonical resonance structures with the carbene depicted cannot be drawn without adding additional charges. Mesoionic carbenes are also referred to as abnormal N-heterocyclic carbenes (aNHC) or remote N-heterocyclic carbenes (rNHC). A variety of free carbenes can be isolated and are stable at room temperature. Other free carbenes are not stable and are susceptible to intermolecular decomposition pathways.

Chemical properties[edit]

Basicity and nucleophilicity[edit]

The nucleophilicity and basicity of imidazol-2-ylidenes have been studied by Alder et al.[46] who revealed that these molecules are strong bases, having a pKa of ca. 24 for the conjugate acid in dimethyl sulfoxide (DMSO):

Measurement of the pKa value for the conjugate acid of an imidazol-2-ylidene.

However, further work by Alder has shown that diaminocarbenes will deprotonate the DMSO solvent, with the resulting anion reacting with the resulting amidinium salt.

Using D6-DMSO as an NMR solvent can have unexpected results.

Reaction of imidazol-2-ylidenes with 1-bromohexane gave 90% of the 2-substituted adduct, with only 10% of the corresponding alkene, indicating that these molecules are also reasonably nucleophilic.

O'Donoghue and co-workers have determined pKa values for the conjugate acids of several NHC families in aqueous solution. pKa values of triazolium ions were found to lie in the range 16.5 - 17.8,[47] around 3 pKa units more acidic than related imidazolium ions.[48]

Dimerisation[edit]

At one time, stable carbenes were thought to reversibly dimerise through the so-called Wanzlick equilibrium. However, imidazol-2-ylidenes and triazol-5-ylidenes are thermodynamically stable and do not dimerise, and have been stored in solution in the absence of water and air for years. This is presumably due to the aromatic nature of these carbenes, which is lost upon dimerisation. In fact imidazol-2-ylidenes are so thermodynamically stable that only in highly constrained conditions are these carbenes forced to dimerise.

Chen and Taton[49] made a doubly tethered diimidazol-2-ylidene by deprotonating the respective diimidazolium salt. Only the deprotonation of the doubly tethered diimidazolium salt with the shorter methylene bridge (-CH2-) resulted in the dicarbene dimer:

Dimerisation of tethered diimidazol-2-ylidenes.

If this dimer existed as a dicarbene, the electron lone pairs on the carbenic carbon would be forced into close proximity. Presumably the resulting repulsive electrostatic interactions would have a significant destabilising effect. To avoid this electronic interaction, the carbene units dimerise.

On the other hand, heteroamino carbenes (e.g. R2N-C:-OR or R2N-C:-SR) and non-aromatic carbenes such as diaminocarbenes (e.g. R2N-C:-NR2) have been shown to dimerise,[50] albeit quite slowly. This has been presumed to be due to the high barrier to singlet state dimerisation:

"Least motion" (path A - not allowed) and "non-least motion" (path B) routes of carbene dimerisation.

However, more recent work by Alder [26] suggests that diaminocarbenes do not truly dimerise, but rather form the dimer by reaction via formamidinium salts, a protonated precursor species. Accordingly, this reaction can be acid catalysed. This reaction occurs because unlike imidazolium based carbenes, there is no loss of aromaticity in protonation of the carbene.

Unlike the dimerisation of triplet state carbenes, these singlet state carbenes do not approach head to head ("least motion"), but rather the carbene lone pair attacks the empty carbon p-orbital ("non-least motion"). Carbene dimerisation can also be acid or metal catalysed, and so care must be taken when determining if the carbene is undergoing true dimerisation.

Reactivity[edit]

The chemistry of stable carbenes has not been fully explored. However, Enders et al.[36][51][52] have performed a range of organic reactions involving a triazol-5-ylidene. These reactions are outlined below and may be considered as a model for other carbenes.

Reactions of triazol-5-ylidene.[52]
Triazol5ylidene reactions text.png

These carbenes tend to behave in a nucleophilic fashion (e and f), performing insertion reactions (b), addition reactions (c), [2+1] cycloadditions (d, g and h), [4+1] cycloadditions (a) as well as simple deprotonations. The insertion reactions (b) probably proceed via deprotonation, resulting in the generation of a nucleophile (-XR) which can attack the generated salt giving the impression of a H-X insertion.

Care must be taken to check that a stable carbene is truly stable. The discovery of a stable isothiazole carbene (2) from an isothiazolium perchlorate (1) by one research group [53] was questioned by another group [54] who were only able to isolate 2-imino-2H-thiete (4). The intermediate 3 was proposed through a rearrangement reaction. This carbene is no longer considered stable.[55]

Isothiazole carbene DeHope 2007

Carbene complexation[edit]

Imidazol-2-ylidenes, triazol-5-ylidenes (and less so, diaminocarbenes) have been shown to co-ordinate to a plethora of elements, from alkali metals, main group elements, transition metals and even lanthanides and actinides. A periodic table of elements gives some idea of the complexes which have been prepared, and in many cases these have been identified by single crystal X-ray crystallography.[37][56][57] Stable carbenes are believed to behave in a similar fashion to organophosphines in their co-ordination properties to metals. These ligands are said to be good σ-donors through the carbenic lone pair, but poor π-acceptors due to internal ligand back-donation from the nitrogen atoms adjacent to the carbene centre, and so are able to co-ordinate to even relatively electron deficient metals. Enders [58] and Hermann[59][60] have shown that these carbenes are suitable replacements for phosphine ligands in several catalytic cycles. Whilst they have found that these ligands do not activate the metal catalyst as much as phosphine ligands they often result in more robust catalysts. Several catalytic systems have been looked into by Hermann and Enders, using catalysts containing imidazole and triazole carbene ligands, with moderate success.[56][58][59][60] Grubbs [61] has reported replacing a phosphine ligand (PCy3) with an imidazol-2-ylidene in the olefin metathesis catalyst RuCl2(PCy3)2CHPh, and noted increased ring closing metathesis as well as exhibiting “a remarkable air and water stability”. Molecules containing two and three carbene moieties have been prepared as potential bidentate and tridentate carbene ligands.[34][35]

Periodic table (persistent carbene)
Group → 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
↓ Period
1 1
H

2
He
2 3
Li
4
Be

5
B
6
C
7
N
8
O
9
F
10
Ne
3 11
Na
12
Mg

13
Al
14
Si
15
P
16
S
17
Cl
18
Ar
4 19
K
20
Ca
21
Sc
22
Ti
23
V
24
Cr
25
Mn
26
Fe
27
Co
28
Ni
29
Cu
30
Zn
31
Ga
32
Ge
33
As
34
Se
35
Br
36
Kr
5 37
Rb
38
Sr
39
Y
40
Zr
41
Nb
42
Mo
43
Tc
44
Ru
45
Rh
46
Pd
47
Ag
48
Cd
49
In
50
Sn
51
Sb
52
Te
53
I
54
Xe
6 55
Cs
56
Ba
1 asterisk 72
Hf
73
Ta
74
W
75
Re
76
Os
77
Ir
78
Pt
79
Au
80
Hg
81
Tl
82
Pb
83
Bi
84
Po
85
At
86
Rn
7 87
Fr
88
Ra
1 asterisk 104
Rf
105
Db
106
Sg
107
Bh
108
Hs
109
Mt
110
Ds
111
Rg
112
Cn
113
Uut
114
Fl
115
Uup
116
Lv
117
Uus
118
Uuo

1 asterisk 57
La
58
Ce
59
Pr
60
Nd
61
Pm
62
Sm
63
Eu
64
Gd
65
Tb
66
Dy
67
Ho
68
Er
69
Tm
70
Yb
71
Lu
1 asterisk 89
Ac
90
Th
91
Pa
92
U
93
Np
94
Pu
95
Am
96
Cm
97
Bk
98
Cf
99
Es
100
Fm
101
Md
102
No
103
Lr
Legend
  Carbene complex with element known
  No carbene complex with element known

Carbenes in organometallic chemistry & catalysis[edit]

Carbenes can be stabilised as organometallic species. These transition metal carbene complexes fall into two categories:

  • Fischer carbenes in which carbenes are tethered to a metal and an electron-withdrawing group (usually a carbonyl),
  • Schrock carbenes; in which carbenes are tethered to a metal and an electron-donating group. The reactions that such carbenes participate in are very different from those in which organic carbenes participate.

Triplet state carbene chemistry[edit]

Persistent triplet state carbenes are likely to have very similar reactivity as other non-persistent triplet state carbenes.

Physical properties[edit]

Carbene peak in 13C NMR

Those carbenes that have been isolated to date tend to be colorless solids with low melting points. These carbenes tend to sublime at low temperatures under high vacuum.

One of the more useful physical properties is the diagnostic chemical shift of the carbenic carbon atom in the 13C-NMR spectrum. Typically this peak is in the range between 200 and 300 ppm, where few other peaks appear in the 13C-NMR spectrum. An example is shown on the left for a cyclic diaminocarbene which has a carbenic peak at 238 ppm.

Upon coordination to metal centers, the 13C carbene resonance usually shifts highfield, depending on the Lewis acidity of the complex fragment. Based on this observation, Huynh et al. developed a new methodology to determine ligand donor strengths by 13C NMR analysis of trans-palladium(II)-carbene complexes. The use of a 13C-labeled N-heterocyclic carbene ligand also allows for the study of mixed carbene-phosphine complexes, which undergo trans-cis-isomerization due to the transphobia effect.[62]

Applications[edit]

A second generation Grubbs' catalyst.

Some persistent carbenes are used as ancillary ligand in organometallic chemistry. Recently there have been practical application of these carbenes as metal ligands in catalysis, e.g. in the ruthenium-based Grubbs' catalyst and palladium-based catalysts for cross-coupling reactions.[63][64]

Preparation methods[edit]

Stable carbenes are very reactive molecules and so it is important to consider the reaction conditions carefully when attempting to prepare these molecules. Stable carbenes are strongly basic (the pKa value of the conjugate acid of an imidazol-2-ylidene was measured at ca. 24)[46] and react with oxygen. Clearly these reactions must be performed under a dry, inert atmosphere, avoiding protic solvents or compounds of even moderate acidity. Furthermore, one must also consider the relative stability of the starting materials. Whilst imidazolium salts are stable to nucleophilic addition, other non-aromatic salts are not (i.e. formamidinium salts).[65]

Consequently in these cases, strong unhindered nucleophiles must be avoided whether they are generated in situ or are present as an impurity in other reagents (e.g. LiOH in BuLi).

Several approaches have been developed in order to prepare stable carbenes, these are outlined below.

Deprotonation[edit]

Deprotonation of carbene precursor salts with strong bases has proved a reliable route to almost all stable carbenes:

Deprotonation of precursor salts to give stable carbenes.

Imidazol-2-ylidenes and dihydroimidazol-2-ylidenes, e.g. Imes, have been prepared by the deprotonation of the respective imidazolium and dihydroimidazolium salts. The acyclic carbenes[27][28] and the tetrahydropyrimidinyl[37] based carbenes were prepared by deprotonation using strong homogeneous bases.

Several bases and reaction conditions have been employed with varying success. The degree of success has been principally dependent on the nature of the precursor being deprotonated. The major drawback with this method of preparation is the problem of isolation of the free carbene from the metals ions used in their preparation.

Metal hydride bases[edit]

One might believe that sodium or potassium hydride[24][30] would be the ideal base for deprotonating these precursor salts. The hydride should react irreversibly with the loss of hydrogen to give the desired carbene, with the inorganic by-products and excess hydride being removed by filtration. In practice this reaction is often too slow, requiring the addition of DMSO or t-BuOH)[7][23] These reagents generate soluble catalysts, which increase the rate of reaction of this heterogeneous system, via the generation of tert-butoxide or dimsyl anion. However, these catalysts have proved ineffective for the preparation of non-imidazolium adducts as they tend to act as nucleophiles towards the precursor salts and in so doing are destroyed. The presence of hydroxide ions as an impurity in the metal hydride could also destroy non-aromatic salts.

Deprotonation with sodium or potassium hydride in a mixture of liquid ammonia/THF at -40 °C has been reported[33] for imidazole-based carbenes. Arduengo and co-workers[30] managed to prepare a dihydroimidazol-2-ylidene using NaH. However, this method has not been applied to the preparation of diaminocarbenes. In some cases, potassium tert-butoxide can be employed without the addition of a metal hydride.[23]

Alkyllithiums[edit]

The use of alkyllithiums as strong bases[7] has not been extensively studied, and have been unreliable for deprotonation of precursor salts. With non-aromatic salts, n-BuLi and PhLi can act as nucleophiles whilst t-BuLi can on occasion act as a source of hydride, reducing the salt with the generation of isobutene:

Reduction of formamidinium salts with tert-butyllithium

Amides bases[edit]

Lithium amides like the diisopropylamide (LDA) and the (tetramethylpiperidide (LiTMP))[27][28] generally work well for the deprotonation of all types of salts, providing that not too much LiOH is present in the n-butyllithium used to make the lithium amide. Titration of lithium amide can be used to determine the amount of hydroxide in solution. The deprotonation of precursor salts with metal hexamethyldisilazides[37] works very cleanly for the deprotonation of all types of salts, except for unhindered formamidinium salts, where this base can act as a nucleophile to give a triaminomethane adduct.

Metal-free carbene preparation[edit]

Stable carbenes readily coordinate to metals; in this case a diaminocarbene co-ordinates to KHMDS to form a complex.

The preparation of stable carbenes free from metal cations has been keenly sought to allow further study of the carbene species in isolation from these metals. Separating a carbene from a carbene-metal complex can be problematic due to the stability of the complex. Accordingly, it is preferable to make the carbene free from these metals in the first place. Indeed, some metal ions, rather than stabilising the carbene, have been implicated in the catalytic dimerisation of unhindered examples.

Shown right is an X-ray structure showing a complex between a diaminocarbene and potassium HMDS. This complex was formed when excess KHMDS was used as a strong base to deprotonate the formamidinium salt. Removing lithium ions resulting from deprotonation with reagents such as LDA can be especially problematic. Potassium and sodium salt by-products tend to precipitate from solution and can be removed. Lithium ions may be chemically removed by binding to species such as cryptands or crown ethers.

Metal free carbenes have been prepared in several ways as outlined below:

Dechalcogenation[edit]

Another approach of preparing carbenes has relied on the desulfurisation of thioureas with molten potassium in boiling THF.[25][66] A contributing factor to the success of this reaction is that the byproduct, potassium sulfide, is insoluble in the solvent. The elevated temperatures suggest that this method is not suitable for the preparation of unstable dimerising carbenes. A single example of the deoxygenation of a urea with a fluorene derived carbene to give the tetramethyldiaminocarbene and fluorenone has also been reported:[67]

Preparation of carbenes by dechalcogenation.

The desulfurisation of thioureas with molten potassium to give imidazol-2-ylidenes or diaminocarbenes has not been widely used. The method was used to prepare dihydroimidazole carbenes.[25]

Vacuum pyrolysis[edit]

Vacuum pyrolysis, with the removal of neutral volatile by-products (CH3OH, CHCl3), has been used to prepare dihydroimidazole and triazole based carbenes:

Preparation of carbenes via vacuum pyrolysis.

Historically the removal of chloroform by vacuum pyrolysis of d adducts was used by Wanzlick[4] in his early attempts to prepare dihydroimidazol-2-ylidenes but this method is not widely used. The Enders laboratory[36] has used vacuum pyrolysis of a c adduct to generate a triazolium-5-ylidene c.

Bis(trimethylsilyl)mercury[edit]

Bis(trimethylsilyl)mercury (CH3)3Si-Hg-Si(CH3)3 reacts with chloro-iminium and chloro-amidinium salts to give a metal-free carbene and elemental mercury.[68] For example, (CH3)3Si-Hg-Si(CH3)3 + R2N=C(Cl)-NR2+ Cl- → R2N-C:-NR2 + Hg(l) + (CH3)3Si-Cl

Photochemical decomposition[edit]

Persistent triplet state carbenes have been prepared by photochemical decomposition of a diazomethane product via the expulsion of nitrogen gas, at a wavelength of 300 nm in benzene.

Purification[edit]

Sublimation of a carbene

Stable carbenes are very reactive, and so the minimum amount of handling is desirable using air-free techniques. However, provided rigorously dry, relatively non-acidic and air-free materials are used, stable carbenes are reasonably robust to handling per se. By way of example, a stable carbene prepared from potassium hydride can be filtered through a dry celite pad to remove excess KH (and resulting salts) from the reaction. On a relatively small scale, a suspension containing a stable carbene in solution can be allowed to settle and the supernatant solution pushed through a dried membrane syringe filter. Stable carbenes are readily soluble in non-polar solvents such as hexane, and so typically recrystallisation of stable carbenes can be difficult, due to the unavailability of suitable non-acidic polar solvents. Air-free sublimation as shown right can be an effective method of purification, although temperatures below 60 °C under high vacuum are preferable as these carbenes are relatively volatile and also could begin to decompose at these higher temperatures. Indeed, sublimation in some cases can give single crystals suitable for X-ray analysis. However, strong complexation to metal ions like lithium will in most cases prevent sublimation.

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Further reading[edit]

Reviews on persistent carbenes:

For a review on the physico-chemical properties (electronics, sterics, ...) of N-heterocyclic carbenes:

  • T. Dröge, F. Glorius (2010). "The Measure of All Rings - N-Heterocyclic Carbenes". Angew. Chem., Int. Ed. Engl. 49 (39): 6940–6952. doi:10.1002/anie.201001865.  [Angew. Chem. 2010, 122, 7094-7107.]