Reactive Intermediate Chemistry

314 SINGLET CARBENES

Note that despite the death of the carbene–alkene complex in the study of benzylchlorocarbene (53) (see above), benzene is able to modulate the intramolecular reactivity of tert-butylcarbene.150 Some sort of complex must be involved here. Benzene complexes with carbenes have been proposed before. Kahn and Goodman151 found a transient species on photolysis of diazomethane in benzene, and attributed it to a complex. Moss et al.152 found that benzene modulated the ratio of intramolecular rearrangement to intermolecular addition for three different carbenes (53), chloropropylcarbene, and chlorocyclopropylcarbene, and proposed that a carbene–benzene complex 70 favored the intramolecular rearrangement (Scheme 7.31). Their proposal was bolstered by ab initio calculations that found such stable complexes for CCl2 and CH3CCl.

Scheme 7.31

There are suggestions that carbene mimics are at work in intermolecular chemistry as well. The data are fragmentary and rare, but cannot be dismissed. For example, it was suggested long ago that excited diazomalonic ester apparently can undergo intermolecular insertions.153 There are some anomalies in this work— for example, allylic carbon–hydrogen bonds are apparently less reactive than unconjugated carbon–hydrogen bonds—but recent LFP work has supported the idea that intermolecular chemistry is possible for excited states of diazo compounds.154 If carbon–hydrogen insertion is possible, then it would seem that cyclopropanation, so far assumed to be a carbene reaction, might be similarly afflicted by reactions of carbene mimics. This is surely an area for further work, but there is an ancient suggestion that such is the case.155 Someone should make dicarbomethoxycarbene from a hydrocarbon source and compare its reactivity with that of the intermediate formed from the diazo compound.

2.5. The Phenylcarbene Rearrangement:

The Chemistry of an Incarcerated Carbene

In solution, phenylcarbene behaves normally; it undergoes routine intermolecular cycloadditions and insertions, for example.5,6 In the gas phase, in which intermolecular reactions are difficult or impossible, phenylcarbene produces a set of dimers

316 SINGLET CARBENES

As early as 1964, Vander Stouw and Shechter discovered that in the gas-phase p-tolylcarbene led to benzocyclobutene and styrene (Scheme 7.34). This work languished for some unknown reason in Vander Stouw’s dissertation and was not published in the primary literature until several years later.159

Scheme 7.34

Prompted by W. M. Jones’ work on the formation of heptafulvene from phenylcarbene in the gas phase,156 which implied a seven-membered ring intermediate, and by the implications of the possible reversibility of the process, Baron et al.160 rediscovered Vander Stouw’s cryptic work and showed that all three possible tolylcarbenes gave benzocyclobutene and styrene, albeit in different ratio from the ortho isomer than from the meta or para species.161 Baron et al.160 proposed a mechanism in which a methylcycloheptatrienylidene (CH3-71) was the active seven-membered species, and which additionally featured the intermediacy of methylbicyclo[4.1.0]- heptatrienes 73 and 730 (Scheme 7.35).

H3C

repeat process

Scheme 7.35

Over the years it became apparent, especially from matrix-isolation studies, that the seven-membered ring species was better formulated as cycloheptatetraene (72), a cyclic allene, rather than as the carbene (71). The question of the intermediacy of 73 remains unresolved: Theory supports Baron’s early suggestion, but the molecule itself has never been detected in a simple system.

The formation of benzocyclobutene and styrene in different ratios from the three isomeric tolylcarbenes is not easily explained by the Baron mechanism,160 and led to more than one clever (but ultimately wrong) alternative proposal.161 The question is best resolved by assuming that in the ortho system hydrogen atom transfer in the diazo compound leads to ‘‘extra’’ benzocyclobutene

(Scheme 7.36).162 Some ‘‘carbene’’ product in the ortho isomer (the excess benzocyclobutene) actually comes not from the carbene, but from the carbene precursor (see Section 2.4 for much more on this general subject).

Scheme 7.36

Ultimately, the seven-membered intermediate was identified as cyclohepta- 1,2,4,6-tetraene (72) or put more properly, this intermediate was indentified when phenyldiazomethane was photolyzed in an argon matrix.163 But the cycloheptatetraene (72) can be detected, not only at 10 K in argon, but even at þ100 C! The trick is to sequester the carbene precursor, in this case phenyldiazirine, inside a molecular cage.164 Reaction of the carbenes with the inside of the cage is discouraged by deuterating the cage, thus raising the barrier to insertion. If photolysis of the diazirine is carried out at low temperature, and reaction with the inside of the cage is thwarted by deuteration, the reactive carbene ring expands to give the twisted allene, cycloheptatetraene (72). The NMR studies in a chiral cage show

that the barrier to interconversion of the two allenes, over a transition state that must be the planar cycloheptatrienylidene (71), is >19.6 kcal/mol (Scheme 7.37).164,165

molecular cage (deuterated)

Scheme 7.37

2.6. Fragmentation of Alkoxycarbenes

Acyclic alkoxycarbenes can fragment by homolytic (radical) or heterolytic (ionic) pathways. For example, the allyloxymethoxycarbene (74) fragments in benzene at 110 C to a radical pair that recombines (Scheme 7.38).166 The radical pair can

Scheme 7.38

diffuse apart and the individual radicals can be trapped. Alternatively, recombination produces the allylic isomers 75 and 76 in a 2:1 ratio. When the initial carbene is 77, the allylic isomer of 74, fragmentation affords 75 and 76 in a 1:2 ratio. Thus, the radical pair intermediates generated by fragmentation of 74 and 77 retain some regiochemical ‘‘memory’’ of their origin; recombination is competitive with motional scrambling of the radicals (Fig. 7.20).

Ph

CH3OCOCHCH=CH2 C6H5CH2OCOCH3 C6H5CH2OCOCH2Ar

Figure 7.20

Related homolytic fragmentations were reported for benzyloxymethoxycarbene (78)167a and aryloxybenzyloxycarbenes (79, Fig. 7.20).167b The former fragments at 100 C to methoxycarbonyl and benzyl radicals, which can be trapped with tetramethylpyridinenitroxyl (TEMPO).167a Carbene 79 has two possible fragmentations: to C6H5CH2 and ArCH2OC O radicals or to C6H5CH2OC O and ArCH2 radicals. Electron-withdrawing substituents on Ar direct the fragmentation toward ArCH2

(r ¼ 0:7 vs. sþ), indicating that benzylic radicals are stabilized by electron withdrawal.167b

The fragmentation of bis(benzyloxycarbene) (79, Ar ¼ C6H5) is apolar and

homolytic,167 but the fragmentation of benzyloxychlorocarbene (80) appears to be polar and heterolytic.168,169 Loss of CO produces benzyl chloride in a process

likely to involve ion pair 81, at least in polar solvents such as CH3CN (Fig. 7.21).169 When fragmentation occurs in a nucleophilic solvent such as methanol, solvent capture competes with ion pair collapse yielding both C6H5CH2OCH3 (57%) and C6H5CH2Cl (43%).168 Note that fragmentation of 80 is faster than trapping of

this (ambiphilic) carbene by methanol. The LFP rate constant for the fragmentation is 4 105 s 1 in CH3CN,170 and the computed activation energy in simulated CH3OH is only 1.5 kcal/mol.171

320 SINGLET CARBENES

3. CONCLUSION AND OUTLOOK

In Conan Doyle’s ‘‘The Hound of the Baskervilles,’’ Dr. Mortimer, describing the death of Sir Charles Baskerville, informs Sherlock Holmes and Dr. Watson that footprints of the perpetrator were found beside the dead man’s body: ‘‘Mr. Holmes, they were the footprints of a gigantic hound.’’

Over the past one-half of a century, the chemistry of carbenes in particular (and reactive intermediates in general) has developed in parallel to the plot of Doyle’s tale. At first, only the ‘‘footprints’’ of the culprit were visible: the structure of reaction products, the relative rates of their formation, the fates of isotopic labels, and other, often ingenious, but still indirect indicators were used to construct an ident-a- kit portrait of the various reactive intermediates.

However, the advent of very fast spectroscopic techniques, such as nanosecond and picosecond LFP, now makes it possible to observe the ‘‘hound’’ itself, while the ever-increasing power of computational methods permits remarkably accurate calculations of the structures and energies associated with carbenes and other reactive intermediates, and often of the potential energy surfaces on which their reactions occur.

To what can we look forward in the future? The impact of spectroscopy and computation will strengthen. Reactions of excited-state singlet and triplet carbenes may be explored by very fast (ps) or even ultrafast (fs) spectroscopy. Solvent modulation of carbenic reactivity will be probed on a molecular level, and perhaps turned to synthetic advantage. The related problem of carbene–arene p complexes will be further elucidated. Dynamics will be increasingly applied to compute the reaction channels available to highly energetic carbenes reacting on relatively flat energy surfaces. Discrepancies between computed and experimental activation energies in such ‘‘simple’’ but fundamental carbenic reactions as the 1,2-carbon migration will be resolved. More precise experimental and computational descriptions will become available for excited-state carbene precursors (carbene mimics), and their reactivity will be better differentiated from that of the carbenes themselves. Continued studies of carbenes constrained in molecular capsules will provide NMR and other spectra of metastable carbenes, while the boundary between these species and stable, isolable singlet carbenes will blur.

Dr. Watson’s description of the final confrontation with the Hound of the Baskervilles is vivid and memorable: ‘‘A hound it was, an enormous coal-black hound, but not such a hound as mortal eyes have ever seen. Fire burst from its open mouth, its eyes glowed with a smoldering glare, its muzzle and hackles and dewlap were outlined in flickering flame. Never in the delirious dream of a disordered brain could anything more savage, more appalling, more hellish be conceived than that dark form and savage face which broke upon us out of the wall of fog.’’

Yet, in the end, the hound proved mortal, not supernatural; its unearthly ‘‘flickering flame’’ the result of a ‘‘cunning preparation’’ of phosphorus. (For other cunning preparations of phosphorus, see the discussion of phosphinidenes in Chapter 11 in this volume.) We too have peeled back much of the mystery and cleared away most of the fog that once surrounded the structures, electronic

REFERENCES 321

states, and reactions of carbenic intermediates. In doing so, chemists’ inductive and deductive powers have rivaled those of the master detective (himself a notable chemist). Our adventures will surely continue.

ACKNOWLEDGMENT

It is a pleasure to acknowledge the critical and helpful reading of this manuscript by Matthew S. Platz. Needless to say, any errors, and the inevitable infelicities that remain are our responsibility alone.

SUGGESTED READING

U. H. Brinker, Ed., Advances in Carbene Chemistry, Vol. 2, JAI Press, Stamford, CT, 1998.

U. H. Brinker, Ed., Advances in Carbene Chemistry, Vol. 3, Elsevier, Amsterdam, The Netherlands, 2001.

G.Bertrand, Ed., Carbene Chemistry: From Fleeting Intermediates to Powerful Reagents, FontisMedia, Lausanne, Dekker, New York, 2002.

R.A. Moss, ‘‘Carbenic Selectivity in Cyclopropanation Reactions,’’ Acc. Chem. Res. 1980, 13, 58.

R. A. Moss, ‘‘Carbenic Selectivity Revisited,’’ Acc. Chem. Res. 1989, 22, 15.

F.Mendez and M. A. Garcia-Garibay, ‘‘A Hard–Soft Acid–Base and DFT Analysis of SingletTriplet Gaps and the Addition of Singlet Carbenes to Alkenes,’’ J. Org. Chem. 1999, 64, 7061.

J.E. Jackson and M. S. Platz, in Advances in Carbene Chemistry, U. H. Brinker, Ed., ‘‘Laser Flash Photolysis Studies of Ylide-Forming Reactions of Carbenes,’’ Vol. 1., JAI Press, Greenwich CT, 1994, pp. 89ff.

K.N. Houk, N. G. Randan, and J. Mareda, ‘‘Theoretical Studies of Halocarbene Cycloaddition Selectivities. A New Interpretation of Negative Activation Energies and Entropy Control of Selectivity,’’ Tetrahedron, 1985, 41, 1555.

T.V. Albu, B. J. Lynch, D. G. Truhlar, A. C. Goren, D. A. Hrovat, W. T. Borden, and R. A. Moss, ‘‘Dynamics of 1,2-Hydrogen Migration in Carbenes and Ring Expansion in Cyclopropylcarbenes,’’ J. Phys. Chem. A 2002, 106, 5323.

A.Nickon, ‘‘New Perspectives on Carbene Rearrangements: Migratory Aptitudes, Bystander Assistance, and Geminal Efficiency,’’ Acc. Chem. Res. 1993, 26, 84.

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