Persistent carbene

Overview
A persistent carbene (also known as a stable carbene) is a particular carbene demonstrating particular stability despite being a reactive intermediate. 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 the more stable.

Introduction to persistent carbenes
The field of stable carbene research was initiated in 1991 by the discovery of the research group of Anthony J. Arduengo, III. who managed to isolate and obtain an X-ray structure of the stable carbene N,N'-diadamantyl-imidazol-2-ylidene:



However the first persistent carbene was first proposed by Breslow in 1957, first made but not isolated by Wanzlick in 1960,  first isolated by Guy Bertrand in 1989,  and finally isolated as a crystalline solid by Anthony J. Arduengo, III.

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 and in many cases these carbenes are thermodynamically stable in the absence of moisture and (in most cases) the absence of oxygen, and can be isolated and indefinitely stored. Some persistent carbenes dimerise slowly over days, whilst the least stable triplet state carbenes have half-lives measured in seconds, and thus can not be stored but merely observed.

Imidazol-2-ylidenes
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 most significant functionalizations has occurred with the 4,5-dichlorination of the imidazole moiety, resulting in 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°.

Triazol-5-ylidenes
The triazol-5-ylidenes pictured below were prepared by Enders and co-workers by vacuum pyrolysis 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 shows an N-C-N bond angles of ca. 101°. The 5-methoxytriazole precursor to carbene, was made by the treatment of a triazolium salt with sodium methoxide, which attacks as a nucleophile. Note 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.

Cyclic and acyclic diaminocarbenes
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 are not thermodynamically stable as shown by the dimerisation of some unhindered cyclic and acyclic examples. Dihydroimidazole carbenes were prepared via the desulfurisation of thioureas with molten potassium deprotonation of the respective dihydroimidazolium salts. The acyclic carbenes, as well as 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.

Heteroamino carbenes
Nucleophilic carbenes in which one of the nitrogen atoms has been replaced with an alternative heteroatom (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 the exact carbenic nature of this red oil when published was in debate.



An aromatic heteroamino carbene, thiazole based carbene (analogous to carbene postulated by Breslow) (R. Breslow, J. Am. Chem. Soc., 1957, 79, 1762.) 5 has been prepared and characterised by X-ray crystallography. Perhaps other formally aromatic α-heteroatom substituted carbenes have 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 disulphide 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 alpha to the carbene centre have been prepared e.g. thio- and oxy-iminium based carbenes being characterised by X-ray crystallography.

Since oxygen and sulphur 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.

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



Triplet state carbenes
In 2001, Hideo Tomioka and his associates were able to produce a comparatively stable triplet carbene, taking advantage of resonance. Triplet bis(9-anthryl)carbene has a half-life of 19 minutes.

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 one contains large bulky substituents, in this molecule bromine and the trifluoromethyl groups, that shield the carbene and prevent or slow down the process of dimerization 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.



History of stable carbenes
1957: Breslow proposed that a thiazol-2-ylidene was involved in the catalytic cycle of vitamin B1. This was the first example of a stable nucleophilic carbene being implicated in a reaction mechanism. In the catalytic cycle shown below two molecules of furfural react to give furoin, via a thiazol-2-ylidene catalyst, generated in situ by C2-deprotonation of a thiazolium salt moiety:



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 exchanged as a result of the generation of a stable thiazol-2-ylidene intermediate.

Wanzlick equilibrium
1960: Wanzlick et al. proposed that dihydroimidazol-2-ylidenes were generated from 2-trichloromethyl dihydroimidazoles, with the loss of chloroform by vacuum pyrolysis.

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 was the active species, reacting with electrophiles (E-X), whilst the dimer (tetraaminoethylene) was inactive to these electrophiles, and merely acted as a stable carbene reservoir.

Lemal and separately Winberg tested Wanzlick’s claims of a carbene-dimer equilibrium by heating together two differently N-aryl substituted tetraaminoethylenes:



This reaction did not produce a mixed dimeric product, and thus indicated that a carbene-dimer equilibrium does not exist for dihydroimidazol-2-ylidenes.

Lemal proposed a different mechanism to account for the reactions observed for Wanzlick’s so-called carbenes, by considering the reactivity of the electron rich tetraaminoethylenes.



Lemal believed that the tetraaminoethylene, not the carbene, reacted with the electrophile (E-X) to generate a transient cationic species, which then dissociated into the free carbene plus the reaction product salt. The free carbene can either re-dimerise (regenerating the tetraaminoethylene starting material) or react with E-X as Wanzlick originally predicted with both routes eventually giving the same reaction product 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, might be more stable than the 4,5-dihydro analogues, due to Hückel-type aromaticity. Unfortunately perhaps believing that these carbenes were still too sensitive to isolate, they resorted to trapping them with reagents like mercury and isothiocyanate:



1991: After nearly 30 years Arduengo et al. reinvestigated this area, and remarkably managed not only to isolate a stable carbene and but also to acquire an X-ray structure of it. Given the prevailing belief that all carbenes existed only as highly reactive, transient species, it is understandable that few attempts had been made to investigate isolation of these species. Simple deprotonation of an imidazolinium chloride gave the carbene:



It 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 feature of this molecule was a characteristic resonance in the 13C NMR spectrum at 211 ppm for the 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.



1992: Initially it was believed that this carbene owed its unique stability to the large N-adamantyl substituents, which prevented the carbene from dimerising due to steric hindrance. However, the Arduengo laboratory isolated and acquired an X-ray structure of an imidazol-2-ylidene, in which the bulky N-adamantyl groups had been replaced with methyl groups.



This proved that steric factors were not the predominant stabilising factors for these carbenes, and that imidazole-2-ylidenes were thermodynamically stable in their own right.

1995: Arduengo and co-workers then went onto obtain an X-ray structure of the first dihydroimidazol-2-ylidene:



This hindered molecule demonstrated that the aromatic imidazolium ring system, with its 4-5 carbon double bond, was also not critical to the stability of these carbenes. Later work performed by Denk et al. showed 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.

1996: Alder et al. isolated and acquired an X-ray structure of the first acyclic diaminocarbene:



This proved that diaminocarbenes without a cyclic backbone could be prepared. However, the real virtue of this carbene was its ability to rotate around the N-C carbene bonds. By measuring the barrier to rotation of these bonds, and thus the extent of double bond character, the ylidic nature of this carbene was determined. Like the cyclic diaminocarbenes, acyclic diaminocarbenes are not thermodynamically stable, with unhindered examples dimerising.

1997-1998: The preparation of thiazol-2-ylidene by Arduengo et al. and aminothiocarbene and aminooxycarbene by Alder et al., demonstrated that at least one nitrogen could be replaced by another heteroatom without endangering the stability of these molecules:



These carbenes are not thermodynamically stable with decomposition and dimeric species seen for unhindered examples.

Bertrand et al. some time before Arduengo’s initial discovery (1988), had isolated a red oil whose molecule structure 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. At the time of publication some doubt remained as to their exact carbenic nature.

1997: Arduengo and co-workers reported the synthesis of the first air-stable carbene, 1,3-dimesityl-4,5-dichloroimidazol-2-ylidene:



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 set to grow still further in the future.

General methods of preparing stable carbenes
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) 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). 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
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.

Metal Hydride bases
One might believe that sodium or potassium hydride 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 (in suitable solvents e.g. THF) due to the relative insolubility of the metal hydride and the salt.

The addition of soluble “catalysts” (DMSO, tBuOH) 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.

Potassium tert-butoxide
Arduengo and co-workers have used potassium tert-butoxide without the addition of a metal hydride to deprotonate precursor salts.

Alkyllithiums
The use of alkyllithiums as strong bases 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:



Lithium amides
Lithium amides like LDA and lithium tetramethylpiperidide (LiTMP) generally work well for the deprotonation of all types of salts, providing that not too much LiOH is present in the n-BuLi used to make the lithium amide. Titration of lithium amide can be used to determine the amount of hydroxide in solution.

Metal Hexamethyldisilazides
The deprotonation of precursor salts with metal hexamethyldisilazides 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
The preparation of carbenes free of metal ions has been a keenly sought reaction. This has been done in several ways:

Dechalcogenation
Another approach of preparing carbenes has relied on the desulfurisation of thioureas with molten potassium in boiling THF. A single example of the deoxygenation of a urea with a fluorene derived carbene to give the tetramethyldiaminocarbene and fluorenone has also been reported:  Potassium sulphide and molten potassium being insoluble, in the solvent. The elevated temperatures suggest that this method is not suitable for the preparation of unstable dimerising carbenes.



The desulfurisation of thioureas with molten potassium to give imidazol-2-ylidenes or diaminocarbenes has not been widely used.

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



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.

Bis(trimethylsilyl)mercury
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. e.g.: (CH3)3Si-Hg-Si(CH3)3 +  R2N=C(Cl)-NR2+Cl-   →   R2N-C:-NR2 + Hg(l) + (CH3)3Si-Cl

Photochemical decomposition
Persistent triplet state carbenes have been prepared by a photochemical decomposition of a diazomethane product with expulsion of nitrogen gas at a wavelength of 300 nanometers in benzene.

Basicity and nucleophilicity
The nucleophilicity and basicity of imidazol-2-ylidenes have been studied by Alder et al which revealed that these molecules are strong bases having a pKa of ca. 24 for the conjugate acid in DMSO:



Reaction of carbene 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.

Dimerisation
Imidazol-2-ylidenes and triazol-5-ylidenes are thermodynamically stable, and do not dimerise, and have been stored in solution 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 made a doubly tethered diimidazol-2-ylidene by deprotonating the respective diimidazolium salt. Only the deprotonating 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 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 like diaminocarbenes (e.g. R2N-C:-NR2) and have been shown to dimerise, albeit quite slowly, due to the high barrier to singlet state dimerisation:



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 of stable carbenes
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 outline 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 precede via deprotonation, resulting in the generation of a nucleophile (-XR) which can attack the generated salt giving the impression of a H-X insertion.

Carbene Complexation
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.
 * Green box = Carbene complex with element known.
 * Grey box = No carbene complex with element known.

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 phosphines ligands in several catalytic cycles. Whilst they have found that these ligands do not activate the metal catalyst as much as phosphines ligands they often result in more robust catalysts. Several catalytic systems have been looked into by Hermann and Enders with 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. .

Carbenes in organometallic chemistry
Carbenes can be stabilized 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.

Some persistent carbenes are used as ancillary ligand in organometallic chemistry. One of the most notable examples is in the second generation Grubbs' catalysts.

Triplet state carbene chemistry
Persistent triplet state carbenes are likely to have very similar reactivity as other triplet state carbenes.