Persistent carbene

Source: Wikipedia, the free encyclopedia.
1,3-Dimesityl-imidazol-4,5-dihydro-2-ylidene, a representative persistent carbene

A persistent carbene (also known as stable carbene) is an

resonance structure has a carbon atom with incomplete octet (a carbene), but does not exhibit the tremendous instability typically associated with such moieties. The best-known examples and by far largest subgroup are the N-heterocyclic carbenes (NHC)[1]
(sometimes called Arduengo carbenes), in which nitrogen atoms flank the formal carbene.

Modern theoretical analysis suggests that the term "persistent carbene" is in fact a

steric shielding
. Excitation to a carbene structure then accounts for the carbene-like dimerization that some persistent carbenes undergo over the course of days.

Persistent carbenes in general, and Arduengo carbenes in particular, are popular ligands in organometallic chemistry.

History

Early evidence

In 1957,

vitamin B1 (thiamine), was the catalyst involved in the benzoin condensation that yields furoin from furfural.[2]
deuteron in a statistical equilibrium.[4]

Deuterium exchange of the C2-proton of thiazolium salt.

This exchange was proposed to proceed via intermediacy of a thiazol-2-ylidene. In 2012 the isolation of the so-called Breslow intermediate was reported.[5][6]

In 1960,

dihydroimidazole compounds with the loss of chloroform.[7][8]
dimer, a tetraaminoethylene derivative, the so-called Wanzlick equilibrium. This conjecture was challenged by Lemal and coworkers in 1964, who presented evidence that the dimer did not dissociate;[10] and by Winberg in 1965.[11] However, subsequent experiments by Denk, Herrmann and others have confirmed this equilibrium, albeit in specific circumstances.[12][13]

Isolation of persistent carbenes

In 1970, Wanzlick's group generated imidazol-2-ylidene carbenes by the deprotonation of an

imidazolium salt.[14] Wanzlick as well as Roald Hoffmann,[9][15] proposed that these imidazole-based carbenes should be more stable than their 4,5-dihydro analogues, due to Hückel-type aromaticity. Wanzlick did not however isolate imidazol-2-ylidenes, but instead their coordination compounds with mercury and isothiocyanate
:

Preparation and trapping of an imidazol-2-ylidene.[14]

In 1988,

phosphaacetylene:[16][17]

Alkyne and carbene resonances structures of Bertrand's carbene

These compounds were called "push-pull carbenes" in reference to the contrasting electron affinities of the phosphorus and silicon atoms. They 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, Arduengo and coworkers crystallized a diaminocarbene by deprotonation of an imidazolium cation:[18]

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

This carbene, the forerunner of a large family of carbenes with the imidazol-2-ylidene core, is indefinitely stable at room temperature in the absence of oxygen and moisture. It melts at 240–241 °C without decomposition. The 13C NMR spectrum shows a signal at 211 ppm for the carbenic atom.

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.[20]

The first air-stable ylidic carbene, a chlorinated member of the imidazol-2-ylidene family, was obtained in 1997.[21]

In 2000, Bertrand obtained additional carbenes of the phosphanyl type, including (phosphanyl)(trifluoromethyl)carbene, stable in solution at -30 °C[22] and a moderately stable (amino)(aryl)carbene with only one heteroatom adjacent to the carbenic atom.[23][24]

Stabilization through adjacent orbitals

MO's
of the allylic system.

In the modern understanding, the superficially unoccupied p-orbital on a (meta)stable carbene is not, in fact, fully empty. Instead, the carbene Lewis structures are in

pi-bond orbitals.[25]

1,3,4,5-tetramethyl­imidazol-2-ylidene, a relatively unhindered carbene. (3D)

Early workers attributed the stability of Arduengo carbenes to the bulky N-

thermodynamically stable unhindered NHC.[26]

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

In 1995, Arduengo's group obtained a carbene derivative of

aromaticity of the conjugated imidazole backbone.[27] The following year, the first acyclic persistent carbene demonstrated that stability did not even require a cyclic backbone.[28] Unhindered derivatives of the hydrogenated[29][30] and acyclic[30][31][32] carbenes dimerized, suggesting that Me4ImC: might be exceptional, rather than paradigmatic. But the behavior of the acyclic carbenes offered a tantalizing clue to the stabilization mechanism. [citation needed
]

Unlike the cyclic derivatives, acyclic carbenes are flexible and bonds to the carbenic atom admit rotation. But bond rotation in the compound appeared

heteroatoms,[33][34] and room-temperature-stable bis(diisopropylamino)cyclopropenylidene, in which the carbene atom is connected to two carbon atoms in a three-member, aromatic, cyclopropenylidene ring.[35]

Stable carbenes with oxygen or sulfur atoms bound to the carbenic atom (3D)

Classes of stable carbenes

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

Imidazol-2-ylidenes

The first stable carbenes to be isolated were based on an

imidazol-2-ylidenes are still the most stable and the most well studied and understood family of persistent carbenes.[citation needed
]

A considerable range of imidazol-2-ylidenes have been synthesised, including those in which the 1,3-positions have been functionalised with

aryl,[26] alkyloxy, alkylamino, alkylphosphino[36] and even chiral substituents:[36]

Stable imidazol-2-ylidenes
1,3-Dimesityl-4,5-dichloroimidazol-2-ylidene, the first air-stable carbene.
(View the 3D structure with 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.[21] Its extra stability probably results from the electron-withdrawing effect of the chlorine substituents, which 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.[37][38]

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

Triazol-5-ylidenes

Depending on the arrangement of the three nitrogen atoms in triazol-5-ylidene, there are two possible isomers, namely 1,2,3-triazol-5-ylidenes and 1,2,4-triazol-5-ylidenes.

Triazol-5-ylidene isomers.

The

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.

Examples of 1,2,4-triazol-5-ylidenes.

Triazole-based carbenes are thermodynamically stable and have diagnostic 13C NMR chemical shift values between 210 and 220 ppm for the carbenic carbon. The X-ray structure of the triphenyl substituted carbene above shows an N–C–N bond angle of around 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.[39] 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.[citation needed]

Other diaminocarbenes

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 five- or six-membered non-aromatic ring,[27][29][40] 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.[28][31][32]

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.[29][31] Studies[30] suggest that these carbenes dimerise via acid catalysed dimerisation (as in the Wanzlick equilibrium).

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

Heteroamino carbenes

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.[16][17][33][34]

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)[41] has been prepared and characterised by X-ray crystallography.[33] Other non-aromatic aminocarbenes with O, S and P atoms adjacent (i.e. alpha) to the carbene centre have been prepared, for example, thio- and oxyiminium based carbenes have been characterised by X-ray crystallography.[34]

Since

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 and 300 ppm for the carbenic carbon, further downfield than any other types of stable carbene. X-ray structures have shown N–C–X bond angles of around 104° and 109° respectively.[citation needed
]

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).[42][43]

Non-amino carbenes

The reaction of

tetrathiafulvene. Thus it is possible that the reverse of this process might be occurring in similar carbenes.[42][43]

Bertrand's carbenes

In Bertrand's persistent carbenes, the unsaturated carbon is bonded to a phosphorus and a silicon.[44] However, these compounds seem to exhibit some alkynic properties, and when published the exact carbenic nature of these red oils was in debate.[17]

Other nucleophilic carbenes

One stable N-heterocyclic carbene[45] has a structure analogous to borazine with one boron atom replaced by a methylene group. This results in a planar six-electron compound.

In the second step of this reaction sequence the proton is abstracted by LiTMP, while the two cyclohexyl groups shield the carbene.[45]

Cyclopropenylidenes

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.[35]

Triplet state carbenes

Persistent carbenes tend to exist in the singlet, dimerizing when forced into triplet states. Nevertheless, Hideo Tomioka and associates used electron delocalization to produce a comparatively stable triplet carbene (bis(9-anthryl)carbene) in 2001. It has an unusually long half-life of 19 minutes.[46][47]

Although the figure below shows the two parts of the molecule in one flat plane, molecular geometry puts the two aromatic parts in

orthogonal
positions with respect to each other.

Delocalization in a stable triplet carbene reported by Tomioka (2001)

In 2006 a triplet carbene was reported by the same group with a

nm light in benzene with expulsion of nitrogen
gas.

Again the figure below is not an adequate representation of the actual molecular structure: both

hybridisation, the two remaining orthogonal p-orbitals
each conjugating with one of the aromatic rings.

A persistent triplet carbene (right), synthesized by Itoh (2006)

Exposure to oxygen (a triplet diradical) converts this carbene to the corresponding

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

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.[citation needed]

Chemical properties

Basicity and nucleophilicity

The imidazol-2-ylidenes are strong bases, having

pKa ≈ 24 for the conjugate acid in dimethyl sulfoxide (DMSO):[49]

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

However, further work showed that diaminocarbenes will deprotonate the DMSO solvent, with the resulting anion reacting with the resulting amidinium salt.

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

Reaction of imidazol-2-ylidenes with

nucleophilic
.

pKa values for the conjugate acids of several NHC families have been examined in aqueous solution. pKa values of triazolium ions lie in the range 16.5–17.8,[50] around 3 pKa units more acidic than related imidazolium ions.[51]

Dimerisation

At one time, stable carbenes were thought to reversibly

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

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

electrostatic interactions would have a significant destabilising effect. To avoid this electronic interaction, the carbene
units dimerise.

On the other hand, heteroamino carbenes (such as R2N–C–OR or R2N–C–SR) and non-aromatic carbenes such as diaminocarbenes (such as R2N–C–NR2) have been shown to dimerise,[53] 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.

Diaminocarbenes do not truly dimerise, but rather form the dimer by reaction via

formamidinium salts, a protonated precursor species.[30]
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

p-orbital
("non-least motion"). Carbene dimerisation can be catalyzed by both acids and metals.

Reactivity

The chemistry of stable carbenes has not been fully explored. However, Enders et al.[39][54][55] 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[55]
a 3,6-diphenyl-1,2,4,5-tetrazine, toluene 92% e 2 equiv., PhNCO, toluene, reflux 92%
b RXH, RT 95–97% f CS2, toluene, or PhNCS, THF, RT 71–90%
c O2, S8, or Se, toluene, reflux 54–68% g Maleimide, THF, RT 47–84%
d R1CH=CHR2, THF, RT 25–68% h Dimethylacetylene dicarboxylate, THF, reflux 21%

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.

The reported stable isothiazole carbene (2b) derived from an isothiazolium perchlorate (1)[56] was questioned.[57] The researchers were only able to isolate 2-imino-2H-thiete (4). The intermediate 3 was proposed through a rearrangement reaction. The carbene 2b is no longer considered as stable.[58]

Isothiazole carbene (2b) was proved to be unstable.[57]

Carbene complexation

Imidazol-2-ylidenes, triazol-5-ylidenes (and less so, diaminocarbenes) have been shown to coordinate to a plethora of elements, from

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.[40][59][60]
Stable carbenes are believed to behave in a similar fashion to
tridentate carbene ligands.[37][38]

Legend
  Carbene complex with element known
  No carbene complex with element known

Carbenes in organometallic chemistry & catalysis

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

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

Triplet state carbene chemistry

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

carbenes
.

Physical properties

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. 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 trans effect.[65]

Applications

A second generation Grubbs' catalyst.

NHCs are widely used as

NHC-Palladium Complexes for cross-coupling reactions.[66][67][68] NHC-metal complexes, specifically Ag(I)-NHC complexes have been widely tested for their biological applications.[69]

Preparation methods

NHCs are often strongly

formamidinium salts).[70]

In these cases, strong unhindered nucleophiles are avoided whether they are generated in situ or are present as an impurity in other reagents (such as 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:

Deprotonation of precursor salts to give stable carbenes.

Imidazol-2-ylidenes and dihydroimidazol-2-ylidenes, such

imidazolium and dihydroimidazolium salts. The acyclic carbenes[28][31] and the tetrahydropyrimidinyl[40]
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

One might believe that sodium 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[36] for imidazole-based carbenes. Arduengo and coworkers[33] 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.[26]

Alkyllithiums

The use of

isobutene
:

formamidinium
salts with tert-butyllithium

Amides bases

Lithium amides like the

hexamethyldisilazides[40]
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

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

formamidinium salt. Removing lithium ions resulting from deprotonation with reagents such as lithium diisopropylamide (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

Another approach of preparing carbenes has relied on the

THF.[29][71] 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:[72]

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.[29]

Vacuum pyrolysis

Vacuum pyrolysis, with the removal of neutral volatile byproducts i.e. methanol or chloroform, has been used to prepare dihydroimidazole and triazole based carbenes. Historically the removal of chloroform by

vacuum pyrolysis of adducts A was used by Wanzlick[8] in his early attempts to prepare dihydroimidazol-2-ylidenes but this method is not widely used. The Enders laboratory[39]
has used vacuum pyrolysis of adduct B to generate a triazol-5-ylidene.

Preparation of carbenes via vacuum pyrolysis.

Bis(trimethylsilyl)mercury

amidinium salts to give a metal-free carbene and elemental mercury.[73]
For example:

(CH3)3Si−Hg−Si(CH3)3 + R2N=C(Cl)−NR+
2Cl− → R2N−C−NR2 + Hg(l) + 2(CH3)3SiCl

Photochemical decomposition

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

Sublimation of a carbene.

Stable carbenes are very reactive, and so the minimum amount of handling is desirable using

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

Reviews on persistent carbenes:

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

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