A persistent carbene (also known as a stable carbene or an Arduengo carbene) is a type of carbene demonstrating particular stability despite also being a reactive intermediate. The instability in these carbenes involves reactivity with substrates, or dimerisation (see Wanzlick equilibrium). Persistent carbenes can exist in the singlet state or the triplet state, with the singlet state carbenes being more stable.
The field of stable carbene research was awakened in 1991 with a landmark discovery by the research group of Anthony J. Arduengo, III., which managed to isolate and obtain an X-ray structure of the stable carbene N,N'-diadamantyl-imidazol-2-ylidene:
However, prior to this isolation, persistent carbenes had been proposed to exist by Ronald Breslow in 1957. The Hans-Werner Wanzlick group were the first group to make (but not isolate) a stable carbene. In 1989 Guy Bertrand's group were the first to make and isolate a stable carbene.
Typically, normal carbenes are very reactive short lived molecules that cannot be isolated, and are usually studied by observing the reactions they undergo. However, persistent carbenes are much more stable and considerably longer lived. This means that in many cases these carbenes are thermodynamically stable in the absence of moisture and (in most cases) oxygen, and can be isolated and indefinitely stored. Some persistent carbenes are not thermodynamically stable and dimerise slowly over days. The less stable triplet state carbenes have half-lives measured in seconds, and cannot be stored but merely observed.
Imidazol-2-ylidenes were the first (and the most stable) family of stable carbenes isolated, and hence are the most well studied and understood. A considerable range of imidazol-2-ylidenes have been synthesised, including those in which the 1,3-positions have been functionalised with alkyl, aryl, alkyloxy, alkylamino, alkylphosphino and even chiral substituents:
Arguably one of the more interesting functionalisations occurred with the 4,5-dichlorination of the imidazole moiety, resulting in an air-stable carbene. Molecules containing two and even three imidazol-2-ylidenes have also been synthesised.
Imidazol-2-ylidenes have been prepared by the deprotonation of imidazolium salts, and by the desulfurisation of thioureas with molten potassium. 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 ca. 101-102°.
The triazol-5-ylidenes pictured below were first prepared by Enders and co-workers 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.
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. 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.
A range of cyclic diaminocarbenes have been prepared principally by the Alder group in which the N-C-N unit is a member of a 5 or 6 membered ring, including a bicyclic example. The Alder group have prepared a range of 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. However more recent work by Alder suggests that these carbenes dimerise via acid catalysed dimerisation (see Wanzlick equilibrium). Dihydroimidazole carbenes were prepared via the desulfurisation of thioureas with molten potassium deprotonation of the respective dihydroimidazolium salts. The acyclic carbenes and the tetrahydropyrimidinyl based carbenes were prepared by deprotonation using strong homogeneous bases. Diaminocarbenes have diagnostic 13C NMR chemical shift values between 230-270 ppm for the carbenic carbon. The X-ray structure of dihydroimidazole carbene 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.
Stable nucleophilic carbenes in which one of the nitrogen atoms adjacent to the carbene center has been replaced by an alternative heteroatom (e.g. O, S or P) have been prepared, as well as a species in which both nitrogens have been replaced by phosphorus atoms. However, these phosphorus substituted “carbenes” seem to exhibit some alkynic properties, and when published the exact carbenic nature of these red oils was in debate.
An aromatic heteroamino thiazole based carbene (analogous to the carbene postulated by Breslow) has been prepared and characterised by X-ray crystallography. Other formally aromatic α-heteroatom substituted carbenes have perhaps not been synthesised as they have the potential to dissociate into alkynes (i.e. R1CCR2 as well as X=C=X,). The reaction of carbon disulfide with electron deficient acetylenes gives transient 1,3-dithiolium carbenes (i.e. where X = S) which then dimerise. Thus it is possible that the reverse of this process might be occurring in similar carbenes.
Acyclic non-aromatic carbenes 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.
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.
In 2006 the same group reported a triplet carbene with a half-life of 40 minutes. This carbene is prepared by a photochemical decomposition of a diazomethane with expulsion of nitrogen gas at a wavelength of 300 nanometers in benzene. As with the other carbenes this species contains large bulky substituents, in this molecule 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. In silico experiments show that the distance of the divalent carbon atom to its neighbours is 138 picometers with a bond angle of 158.8°. The dihedral angle is 85.7° which makes the phenyl groups almost at right angles to each other. Exposure to oxygen (diradical) converts the carbene to the corresponding benzophenone and the diphenylmethane compound is formed when it is trapped by 1,4-cyclohexadiene.
Evidence that the thiazol-2-ylidene was a stable intermediate in the above catalytic cycle was suggested by a deuterium exchange experiment. Breslow demonstrated that under standard reaction conditions (in deuterated water) the thiazolium C2-proton was rapidly exchanged for a deuteron in a statistical equilibrium.
This confirmed that the C2-proton of the salt was labile, and was proposed to be exchanged as a result of the generation of a stable thiazol-2-ylidene intermediate.
Wanzlick et al. believed that once prepared these carbenes existed in an unfavourable equilibrium with its corresponding dimer. This assertion was based on reactivity studies which they believed showed that the free carbene reacted with electrophiles (E-X). The dimer (tetraaminoethylene) was believed to be inactive to the electrophiles (E-X), and thought to merely act as a stable carbene reservoir.
Lemal and separately Winberg tested Wanzlick’s hypothesis of a carbene-dimer equilibrium by heating two differently N-aryl substituted tetraaminoethylenes together:
This reaction did not produce a mixed dimeric product, and accordingly indicated that a 'carbene-dimer equilibrium' did not exist for these dihydroimidazol-2-ylidenes.
Lemal proposed an alternative mechanism to account for the reactions observed by Wanzlick’s by considering the reactivity of the electron rich tetraaminoethylenes and not the then hypothetical stable carbenes.
Lemal believed that the tetraaminoethylene, not the carbene, reacted with the electrophile (E-X) to generate a transient cationic species. He proposed that this cation then dissociated into the free carbene plus the resultant salt. The free carbene could then either re-dimerise (regenerating the tetraaminoethylene starting material) or react with E-X (as Wanzlick originally predicted), with either route eventually giving the same reaction product, the dihydroimidazolium salt. More recent work by Alder has shown that unhindered diaminocarbenes form dimers by acid catalysed dimerisation as shown in the Lemal reaction above. In excess acid conditions the dimer forms the salt.
1970: Wanzlick et al. prepared but did not isolate the first imidazol-2-ylidene by the deprotonation of imidazolium salt. Wanzlick as well as Hoffmann 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. Unfortunately, perhaps believing that these carbenes were still too reactive to be isolated, they resorted to trapping these carbenes with reagents such as mercury and isothiocyanate:
1991: After nearly 30 years Arduengo et al. revisited this area, and remarkably managed not only to isolate a stable carbene but also to acquire an X-ray structure of it. Given the prevailing belief at that time that all carbenes existed only as highly reactive, transient species, it is understandable that few attempts had been made prior to this to isolate these species. Arduengo et al. found that simple deprotonation of an imidazolium chloride with a strong base gave the carbene:
This carbene 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 molecule was a characteristic resonance in the 13C NMR spectrum at 211 ppm for the deshielded carbenic carbon. The X-ray structure 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.
|1991: Hindered N,N'-diadamantyl-imidazol-2-ylidene. (external viewer)||1992: Less hindered tetramethyl-imidazol-2-ylidene||1995: Cyclic diaminocarbene 1,3-dimesityl-imidazol-4,5-dihydro-2-ylidene (external viewer)||1996: Acyclic diaminocarbene bis(diisopropylamino)carbene||1997: Air-stable 1,3-dimesityl-4,5-dichloroimidazol-2-ylidene. (external viewer)|
1992: Initially many researchers believed that this carbene's unique stability was due to the bulky N-adamantyl substituents, which prevented the carbene from dimerising due to steric hindrance. However, the Arduengo laboratory later also isolated and acquired an X-ray structure of an imidazol-2-ylidene in which the bulky N-adamantyl groups were replaced with smaller methyl groups.
1995: Arduengo and co-workers also went on to obtain an X-ray structure of the first dihydroimidazol-2-ylidene, a cyclic diaminocarbene. This hindered molecule demonstrated that the aromatic imidazolium ring system, with the 4-5 carbon double bond, was also not critical to the stability of these carbenes. Later work performed by Denk et al. suggested that these dihydroimidazole carbenes were in part reliant on steric protection to prevent dimerisation, and thus not thermodynamically stable, unlike their aromatic imidazol-2-ylidene analogues. However, in light of the work of Alder it would seem the dimerisation was acid (or metal) catalysed (see Wanzlick equilibrium).
1996: Alder et al. isolated and acquired an X-ray structure of the first acyclic diaminocarbene. This carbene showed that diaminocarbenes without a cyclic backbone could be prepared. However, the real virtue of this carbene was that it has the ability to rotate around the N-C carbene bonds. By measuring the barrier to rotation of these bonds, the extent of double bond character in these bonds could be measured. This allowed the ylidic nature of this carbene to be determined. Like the cyclic diaminocarbenes, unhindered examples tend to dimerise.
1997: Arduengo and co-workers reported the synthesis of the first air-stable carbene, 1,3-dimesityl-4,5-dichloroimidazol-2-ylidene:
1997-1998: The preparation of a thiazol-2-ylidene by Arduengo et al. and an aminothiocarbene and aminooxycarbene by Alder et al., demonstrated that at least one nitrogen adjacent to the carbene centre could be replaced by another heteroatom without destroying the stability of these molecules:
However, these carbenes are not thermodynamically stable as decomposition and dimerisation have been observed for unhindered examples.
Some time before Arduengo’s initial discovery in 1988, Bertrand et al. had isolated a red oil, the molecular structure of which can be represented as either a λ³-phosphinocarbene or λ5-phosphaacetylene:
These molecules 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. The carbene was made by the reaction of an imidazol-2-ylidene with carbon tetrachloride. This 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.
Arduengo’s initial publication has excited considerable interest in the field of stable carbenes. Since publication, this paper has been cited many hundreds of times. Work in this field has included a diverse range of topics from theoretical calculations, to the practical application of these carbenes as metal ligands in catalysis, e.g. the second generation Grubbs' catalyst:
With the establishment of some of the fundamental principles of this chemistry, it is clear that this subject is no longer a laboratory curiosity, but has established itself as a chemical research field in its own right, and is set to grow still further in the future.
Several approaches have been developed in order to prepare stable carbenes, these are outlined below.
Deprotonation of carbene precursor salts with strong bases has proved a reliable route to almost all stable carbenes:
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.
The addition of soluble “catalysts” (DMSO, t-BuOH) considerably improves 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 to work well by Hermann et al. for imidazole based carbenes. Arduengo and co-workers managed to prepare a dihydroimidazol-2-ylidene using NaH. However, this method has not been applied to the preparation of diaminocarbenes.
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 kryptanes or crown ethers.
Metal free carbenes have been prepared in several ways as outlined below:
Historically the removal of chloroform by vacuum pyrolysis of d adducts was used by Wanzlick in his early attempts to prepare dihydroimidazol-2-ylidenes but this method is not widely used. The Enders laboratory has used vacuum pyrolysis of a c adduct to generate a triazolium-5-ylidene c.
The nucleophilicity and basicity of imidazol-2-ylidenes have been studied by Alder et al. who revealed that these molecules are strong bases, having a pKa of ca. 24 for the conjugate acid in DMSO:
However, further work by Alder has shown that diaminocarbenes will deprotonate the DMSO solvent, with the resulting anion reacting with the resulting amidinium salt.
Chen and Taton 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 (-CH2-) linkage resulted in the dicarbene dimer:
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, albeit quite slowly. This has been presumed to be due to the high barrier to singlet state dimerisation:
However, more recent work by Alder suggests that diaminocarbenes do not truly dimerise, but rather form the dimer by reaction via formamidinium salts, a protonated precursor species (see Wanzlick equilibrium). 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.
The chemistry of stable carbenes has not been fully explored. However, Enders et al. 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.
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 was questioned by another group 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.
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.
Figure: Periodic Table featuring elements that have formed stable carbenes complexes.
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 and Hermann 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.Grubbs 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.
Persistent triplet state carbenes are likely to have very similar reactivity as other non-persistent triplet state carbenes.
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 left for a cyclic diaminocarbene which has a carbenic peak at 238 ppm.