Reactions of carbenes

Carbenes are highly reactive and undergo insertion into a-bonds, cycloaddition reactions, dimerization, complex formation and intramolecular reactions. The singlet carbene, which often acts as an electrophile, gives different products than the triplet carbene, which behaves as a radical. Despite their very different nature, they manage to produce the same product in some reactions. 

The reaction of carbene with hydrocarbon is a single-step reaction involving a triangular transition state. This reaction is possible because the singlet is such a strong electrophile 

Singlet carbenes insert into alkyl C-H bonds randomly, with retention of configuration. Triplet carbenes insert into alkyl C-H bonds selectively, but not stereospecifically. 

Carbenes add on to multiple bonds like carbon-carbon double bonds, carbon-carbon triple bonds and carbon-nitrogen double bonds. 

Singlet carbenes add to carbon-carbon double bonds in one step in a stereospecific manner. Triplet carbenes add to carbon-carbon double bonds in two steps in a non-stereospecific manner. 

Transient carbenes display a rich and diverse chemistry as stoichiometric reagents, for example, in reactions such as olefin cyclopropanation, C-H insertion, dimerization, 1,2-migration, and so on. Carbenes are important in several synthetic methods and are growing in importance, especially the intramolecular versions. Carbenes are electron deficient, and unless strong resonance interaction is possible the reactions will be electrophilic. The chemical behavior of a carbene depends to some extent on its method of preparation, electronic state, and also on the presence or absence of certain metals or metallic salts. The state in which the carbene is produced depends on the method of generation, that is, singlets 

Carbenes and carbenoids undergo various reactions, that is, they can add to double and triple bonds, insert into C-H bonds, and undergo skeletal rearrangements. A carbon atom with only six electrons will do almost anything to get another two. Carbenes are too reactive to be isolated and stored they are trapped in frozen argon for spectroscopic study at very low temperatures. Alkyl carbenes insert much more selectively than methylene, which does not differentiate between primary, secondary, and tertiary C-H bonds. 

The reactivity of a carbene is strongly influenced by its multiplicity—that is, whether it is a singlet or triplet. As noted above, some carbenes are produced as singlets, while others are formed as triplets or may convert to triplets before reaction. Singlet and triplet carbenes exhibit similar reaction types, but there are some important differences between them. Because it has both an empty p orbital (like a carbocation) and a nonbonded pair of electrons (like a carbanion), the singlet carbene exhibits both carbocation and carbanion character. However, the triplet carbene behaves more as a diradical. These characteristics influence the types and stereochemistries of carbene reactions. 

One of the major reactions of carbenes is cycloaddition with double bonds  

A singlet carbene adds stereospecifically, meaning that reaction with a cis-alkene gives only ds-cyclopropane, and reaction with a frans-alkene gives trans-cyclopropane. The reaction of the triplet carbene is not stereospecific, however, and the product is a mixture of isomers. The difference in stereochemistry arises because the singlet carbene can add in one step (equation 5.39), 

If a triplet carbene were to add to an alkene in one step, there would be two unpaired electrons in one or bond that is, there would be an excited state of a o- bond, a very high energy species. For a summary of the reactions of triplet carbenes, see reference 167. 

1) spin flip 2) closure 1) spin flip 2) closure FIGURE 5.30 

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Weak to moderate chemiluminescence has been reported from a large number of other Hquid-phase oxidation reactions (1,128,136). The Hst includes reactions of carbenes with oxygen (137), phenanthrene quinone with oxygen in alkaline ethanol (138), coumarin derivatives with hydrogen peroxide in acetic acid (139), nitriles with alkaline hydrogen peroxide (140), and reactions that produce electron-accepting radicals such as HO in the presence of carbonate ions (141). In the latter, exemplified by the reaction of h on(II) with H2O2 and KHCO, the carbonate radical anion is probably a key intermediate and may account for many observations of weak chemiluminescence in oxidation reactions. 

The reactions of carbenes, which are apparently unique in displaying electrophilic character in strongly basic solutions, include substitution, addition to multiple bonds, and co-ordination with lone pairs of electrons to form unstable ylides. This last reaction is of obvious relevance to a consideration of the reactions of heterocyclic compounds with carbenes and will be summarized. 

Very few reactions of carbenes with heterocyclic systems containing more than one hetero atom have been studied. They are confined to variants of the Reimer-Tiemann formylation of thiazoles, pyra-zoles, iminazoles, and indolizines/ and ring expansion does not appear to have been observed. 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

The reactions of carbenes are more varied than those of the species previously discussed in this chapter. 

An unusual reaction of carbenes is that of insertion into C—H bonds (12-19). Thus. CH2 reacts with... 

It would seem that dimerization should be an important reaction of carbenes... 

Oxo-2,5-cyclohexadienylidene [83] was generated in solid argon at 9 K by irradiation of diazo compound [84] with visible light (A>495 nm) (Sander et al., 1988 Bucher and Sander, 1992 Bucher et al., 1992). The IR, UV, and esr spectra of [83] were in accord with a structure having a triplet state with one delocalized electron. In the IR spectrum of the carbene [83] the r (CO) mode was found at 1496 cm which indicates a bond order of the C—O bond considerably less than 2. The low-temperature reaction of carbene [83] with CO generated the keto-ketene [85]. Irradiation (A = 543 10 nm) of [83] led to its transformation into a very labile species, presumed to be [86], which rearranged back to [83] not only under UV or... 

Substituted benzenes are obtained from the reaction of carbenes with phosphorins. The phosphepin (123) is thought to be an intermediate because the related compound (124) decomposes to a substituted benzene. 

Using the pseudo-first-order equation A obsd = 0 + co2 [COiKwhere kcoi is the second-order rate constant for the reaction of carbene with CO2 and ko is the rate of carbene decay in the absence of CO2), solution-phase values of kcoi for phenylchlorocarbenes 9 and 12, and diphenylcarbenes 14 and 15 in dichloromethane were estimated (Table 4.1). (The concentration of CO2 in saturated dichloromethane solution at 25°C and 1 atm is 196mmol/L. ) The trend of these estimated second-order order rate constants agrees with that observed in low-temperature matrices by Sander and co-workers. ... 

Since the most direct evidence for specihc solvation of a carbene would be a spectroscopic signature distinct from that of the free carbene and also from that of a fully formed ylide, TRIR spectroscopy has been used to search for such car-bene-solvent interactions. Chlorophenylcarbene (32) and fluorophenylcarbene (33) were recently examined by TRIR spectroscopy in the absence and presence of tetrahydrofuran (THF) or benzene. These carbenes possess IR bands near 1225 cm that largely involve stretching of the partial double bond between the carbene carbon and the aromatic ring. It was anticipated that electron pair donation from a coordinating solvent such as THF or benzene into the empty carbene p-orbital might reduce the partial double bond character to the carbene center, shifting this vibrational frequency to a lower value. However, such shifts were not observed, perhaps because these halophenylcarbenes are so well stabilized that interactions with solvent are too weak to be observed. The bimolecular rate constant for the reaction of carbenes 32 and 33 with tetramethylethylene (TME) was also unaffected by THF or benzene, consistent with the lack of solvent coordination in these cases. °... 

Addition reactions with alkenes to form cyclopropanes are the most studied reactions of carbenes, both from the point of view of understanding mechanisms and for synthetic applications. A concerted mechanism is possible for singlet carbenes. As a result, the stereochemistry present in the alkene is retained in the cyclopropane. With triplet carbenes, an intermediate 1,3-diradical is involved. Closure to cyclopropane requires spin inversion. The rate of spin inversion is slow relative to rotation about single bonds, so mixtures of the two possible stereoisomers are obtained from either alkene stereoisomer. 

The addition of dichlorocarbene, generated from chloroform, to alkenes gives dichlorocyclopropanes. The procedures based on lithiated halogen compounds have been less generally used in synthesis. Section D of Scheme 10.9 gives a few examples of addition reactions of carbenes generated by a-elimination. 

The Reaction of Carbenes with Alkenes in Aqueous Medium... 

The reaction of carbenes or carbenoids with compounds containing S—S bonds is likely to begin with sulfonium ylide formation subsequent [1,2] rearrangement then produces a formal insertion product of the carbene moiety into the S—S bond152 b). 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

The reactions of carbenes are of great synthetic use in the preparation of compounds that have three-membered rings. 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

Synthesis, Properties, and Reactions of Carbene Complexes of Silver 203... 

The reaction of carbenes with alcohols can proceed by various pathways, which are most readily distinguished if the divalent carbon is conjugated to a tt system (Scheme 5). Both the ylide mechanism (a) and concerted O-H insertion (b) introduce the alkoxy group at the originally divalent site. On the other hand, carbene protonation (c) gives rise to allylic cations, which will accept nucleophiles at C-l and C-3 to give mixtures of isomeric ethers. In the case of R1 = R2, deuterated alcohols will afford mixtures of isotopomers. 

The pyridine ylide method also allows determination of the rate constants for the intermolecular reactions of carbenes with alkenes, alcohols, or other carbene... 

Fragmentation of 29 or 29 accounts for r-butylethene formation during the photolysis of 29. In thermolytic experiments, however, the yield of this olefin decreases as TME is added and carbene 20 is trapped. The inference is that fragmentation during thermolysis at 100°C is, at least partly, a reaction of carbene 20,46 with continued contribution from the fragmentation of 29. ... 

In contrast, 1,2-H shift to olefin 106 is the dominant reaction of carbene 104, and this process is slow enough to be measured by LFP r = 300 ns in cyclohexane and 560 ns in pentane at 25°C.117 There is a polar solvent effect the lifetime decreases to 52 ns in acetonitrile. However, at least in the case of cyclohexane, the lifetime is solvent limited, with a KIE of 1.5 on the lifetime in cyclohexane- (460 ns). Carbene 104 is much longer-lived than dimethylcarbene (r 21 ns in pentane) or methylcarbene (<1 ns).22,89... 

Another reaction of carbene la in an argon matrix is the carbonylation with CO to give ketene 10a.23 The carbonylation obviously proceeds with a very small barrier even at low temperature. The carboxylation with CO2, on the other hand, which is also a characteristic reaction of many carbenes, is not observed.70 The primary and rate-determining step of this reaction is the nucleophilic attack... 

The reaction of carbenes 1, generated either thermally or photochemically from the corresponding quinone diazides 2, with pyridine results in the formation of the deeply colored betaines which can be isolated in substance from the reaction mixture.73,62 This alternative synthesis of the betaines opens a general route to pyridine ylides unsubstituted at the pyridine ring. 

Compared to the parent system 3a, the barrier for formation of 3d is the highest in this series whereas the formation of 3b should be the most facile according to our computations. Although the reactions of carbenes la-c are initiated photochemically, the observed reactivity seems to be in line with the computed ground state properties. Thus, while methyl substitution in 3-and 5-position inhibits the vinylcarbene-cyclopropene rearrangement, methyl substitution in 2- and 6-position has the opposite effect. 

Figure 5. Reaction of carbene lh with acetylene, relative energies calculated at the B3LYP/6-31 G(d) level of theory.

Jackson, J.E. Platz, M.S. Laser Flash Photolysis Studies of Ylide-Forming Reactions of Carbenes. In Advances in Carbene Chemistry, U.H. Brinker, Ed. JAI Greenwich, CT, 1994 pp 89-160. 

The one-step mechanism, depicted in path a, consists simply of a 1,2-shift of an ortho carbon. While this process is an all-carbon version of the Wolff rearrangement, the bond order of the migrating bond is substantially greater than 1.0. Hence this would represent an unprecedented reaction of carbenes. 

There are several unique features about PAC. First, PAC and the related methods are the only experimental techniques currently available, which can measure the heats of reaction of carbenes on the microsecond and faster time scale. This usually allows for an accurate determination of the heats of formation of these reactive intermediates. Second, PAC can monitor the reactions of transients which are optically transparent, i.e. do not have an UV-VIS optical absorbance. Hence, in addition to thermodynamics, PAC can also provide important kinetic information about these invisible species. 

The heats and rates of reaction of carbenes with substituted pyridines to form ylides have been measured and used to calculate the ylides heats of formation.54 The heats of reaction of methylchloro- and phenylchlorocarbene with were found to correlate well with the pXa s and proton affinities of the pyridines. However, the correlation is not good for sterically demanding... 

In this chapter, we have described the application of photoacoustic calorimetry to determine the heats and rates of reaction of carbenes. It can also be readily... 

Among typical carbon-carbon bond (C-C) formation reactions with carbenes, the cyclopropanation reaction with olefins has been well studied including its application to industrial processes. The second typical reaction of carbenes is the insertion reaction into the carbon-hydrogen bond (C-H) which seems to be a direct and efficient C-C bond forming reaction. However, its use for synthetic purpose has often been limited due to low selectivity of the reactions.3... 

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