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I-L. Radicals & Carbenes

I. Basic Principles

Features of Radical Reactions

• Review: Curran, D. P. In Comprehensive Organic Synthesis; B. M.Trost and I. Fleming, Ed.; Pergamon Press: Oxford, 1991; Vol. 4; pp715.

• A major difference between radicals and other reactive species thatare employed in synthesis is that virtually all radicals react rapidly withthemselves. The lifetime of a transient radical rarely exceeds 1 ms and isat the diffusion-controlled limit; the enthalpy of activation of most radical-radical reaction is close to 0 kcal/mol. In general, radical reactions areoxygen-sensitive but water-tolerant. Solvent effects are generally small,but hydrogen-atom abstraction can become a concern in radicalreactions of slow or intermediate rates.

• The need to evaluate the relative rates of competing radical reactionspervades synthetic planning of radical additions and cyclizations.Concentrations are therefore very important. The following tablecontains some representative rate constants:

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The general pattern of a radical reaction is:

Chain reactions comprise initiation, propagation, and termination steps (ex.:Hunsdiecker reaction), and offer often an ideal way to conduct radical additionsbecause of the low concentration of radicals.

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Initiation can be accomplished by photochemical or redox reactions,but it is most often accomplished by homolytic bond cleavage of achemical initiator. Some common initiators are:

CAUTION: Heating AIBN (azobisisobutyronitrile) produces a deadly chemical,tetramethylsuccinonitrile (TMSN). TMSN is immediately dangerous to life andhealth (IDLH) at 5 ppm. Cyanide gas has an IDLH at 25 ppm.

Organoboranes are readilyoxidized by oxygen, aprocess that is inhibited byradical scavengers such asgalvinoxyl. The acceptedmechanism of the autoxidationis shown below (see also:Ollivier, C.; Renaud, P.,"Organoboranes as a sourceof radicals." Chem. Rev.2001, 101, 3415-3434). Ahomolytic substitution (SH2)reaction between tripletoxygen and triethylboraneserves as the initiation andlead to a peroxy radical thatpropagates the chain. Therate constant for the homolyticsubstitution at the boroncenter of triethylborane hasbeen measured to be 2.0106

M-1s-1 at 30 °C.

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Atom and Group Transfer Reactions

In this very broad class of reactions, a univalent atom (hydrogen orhalogen) or a group (SPh, SePh) is transferred from a neutral moleculeto a radical to form a new σ-bond and a new radical. Subsequently, C-Cbonds are generally formed via addition reactions to alkenes andalkynes.

The following decreasing order of reactivity is observed: R-I > R-Br > R-H > R-Cl>> R-F.

Radicals are often classified according to their rates of reactions with alkenes.Those radicals that react more rapidly with electron poor alkenes than withelectron rich are termed nucleophilic radicals. Conversely, those that react morerapidly with electron rich alkenes are termed electrophilic radicals. Certainradicals react more rapidly with both electron rich and electron poor alkenesthan they do with alkenes of intermdiate electron density. These radicals aretermed ambiphilic. The appropriate pairing of a radical and an acceptor isimportant for the success of an addition reaction.

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Roberts, B. P., "Polarity-reversal catalysis of hydrogen-atom abstractionreactions: Concepts and applications in organic chemistry." Chem. Soc.Rev. 1999, 28, 25-35.

The rates and selectivities of the hydrogen-atom abstraction reactions ofelectrically-neutral free radicals depend on polar effects which operate in thetransition state. Thus, an electrophilic species such as an alkoxyl radical abstractshydrogen much more readily from an electron rich C-H bond than from anelectron-deficient one of similar strength. The basis of polarity-reversal catalysis(PRC) is to replace a unfavorable single-step abstraction with a two-step processin which the radicals and substrates are polarity-matched.

e.g. Favored:

- (a) E + H-Nu → E-H + Nu

- (b) Nu + H-E → Nu-H + E

Disfavored:

- (c) E + H-E* → E-H + E*

- (d) Nu + H-Nu* → Nu-H + Nu*

PRC:

- (e) E + H-Nu → E-H + Nu

Nu + H-E* → Nu-H + E*

Overall: E + H-E* → E-H + E*

- (d) Nu + H-E → Nu-H + E

E + H-Nu* → E-H + Nu*

Overall: Nu + H-Nu* → Nu-H + Nu*

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Schematic potential energy diagram illustrating the principle of PRC forpromoting hydrogen-atom transfer by a hydridic catalyst H-Nu:

Two steps with low activation energies can lead to a faster overall reaction thanis achieved in a single-step process which has a much higher activation energy.

• Example:

The product was obtained in 80% yield, whereas in the absence of methylthioglycolate the yield was only 8%.

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Stereochemistry

The methyl radical is known to be planar.Alkyl- or heteroatom-substituted radicals are pyramidalized, but theinversion barrier is very low. Conjugating substituents favor planarstructures.Accordingly, the stereochemistry of reaction at a radical center iscontrolled by the relative rates of the competing reactions:

As with alkyl radicals, the stereochemical outcome of a reaction of avinyl radical does not generally depend on the stereochemistry of theprecursor. However, there are several examples in which a subsequentreaction of a vinyl radical has been proposed to be more rapid than itsinversion.

Thiohydroxamates (the Barton method)

One of the most important chain methods that does nor revolve around thechemistry of the trialkyl radical is the Barton thiohydroxamate protocol.

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Radical Cyclizations

The hexenyl radical cyclization:

A criss-cross strategy for modhephene (Jasperse, C.P.; Curran, D.P. J. Am. Chem.Soc. 1990, 112, 5601):

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Synthesis of dihydragarofuran (Buchi, G.; Wüest, H. J. Org. Chem.1979, 44,546. Karahana ether: Honda, T.; Satoh, M.; Kobayashi, Y.J. Chem. Soc., Perkin Trans. I 1992, 1557).

Synthesis of pyrrolizidine alkaloids (Hart, D. J.; Tsai, Y.-M. J. Am.Chem. Soc. 1984, 106, 8209. Burnett, D. A.; Choi, J.-K.; Hart, D. J.;Tsai, Y-M. J. Am. Chem. Soc. 1984, 106, 8201. Choi, J-K.; Hart, D. J.Tetrahedron 1985, 41, 3959).

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Cyclobutanone Ring Expansions:

Dowd, P.; Zhang, W. J. Am. Chem. Soc. 1992, 114, 10084. Zhang, W.; Dowd,P. Tetrahedron 1993, 49, 1965. Dowd, P.; Zhang, W. J. Org. Chem. 1992, 57,7163. Dow, P.; Zhang, W.; Geib, S.J. Tetrahedron 1995, 51, 3435. Dowd, P.;Zhang, W.; Mahmood, D. Tetrahedron 1995, 51, 39. Zhang, W.; Hua, Y.;Geib, S.J.; Hoge, G.; Dowd, P. Tetrahedron Lett. 1994, 35, 3865. Dowd, P.;Zhang, W.; Mahmood, K. Tetrahedron Lett. 1994, 35, 5563.

Zhang, W.; Dowd, P., "Unusual cyclopropane formation following freeradical ring expansion." Tetrahedron Lett. 1992, 33, 7307-7310.

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Cyclization/addition by tin hydride:

Stork, G.; Sher, P.M.; Chen, H.-L. J. Am. Chem. Soc. 1986, 108, 6384. Stork, G.;Franklin, P. Aust. J. Chem. 1992, 45, 275.

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Jung, M. E.; Kiankarimi, M., "Gem-dialkoxy effect in radicalcyclizations to form cyclopropane derivatives: Unusual oxidation of adialkoxyalkyl radical." J. Org. Chem. 1995, 60, 7013-7014.

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Features of Carbene Reactions

• A carbene is a highly reactive organic molecule with a divalentcarbon atom with only six valence electrons. The carbene comes in twovarieties - a singlet and triplet. The singlet type has its carbon atom sp2hybridized with an empty p-orbital extending above and below a planecontaining R1 and R2 and the free electron pair. Typically thesemolecules are very short lived, although persistent carbenes are nowknown.

• Singlet carbenes have a pair of electrons and sp2 hybrid structure.Triplet carbenes have two unpaired electrons. They may be either sp2hybrid or linear sp hybrid. Most carbenes have nonlinear triplet groundstate with the exception of carbenes with nitrogen, oxygen, sulfur atoms,and dihalocarbenes.

Carbene Additions to Alkenes

Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B., "Stereoselectivecyclopropanation reactions." Chem. Rev. 2003, 103, 977-1050.

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Halomethylzinc Additions to Alkenes

Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B., "Stereoselectivecyclopropanation reactions." Chem. Rev. 2003, 103, 977-1050.

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Generally favored

Schreiber’s bis-cyclopropanation:

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C,C-Bond Forming Cascade Reaction - Imine Additions

- Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768.

Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1269..

5 new C,C-bonds

Carbene Insertions - Intramolecular C-H Bond Insertion

Taber, D. F.; Yu, H.; Incarvito, C. D.; Rheingold, A. L., "Synthesis of (-)-isonitrin B." J. Am. Chem. Soc. 1998, 120, 13285. The intramolecularinsertion proceeds with retention of absolute configuration.

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Davies, H. M. L.; Walji, A. M., "Direct synthesis of (+)-erogorgiaenethrough a kinetic enantiodifferentiating step." Angew. Chem., Int. Ed.2005, 44, 1733-1735.

A combined C-H activation/Cope rearrangement strategy.

A combined C-H activation/Cope rearrangement strategy.

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Davies, H. M. L.; Stafford, D. G.; Hansen, T.; Churchill, M. R.; Keil,K. M., "Effect of carbenoid structure on the reactions of rhodium-stabilized carbenoids with cycloheptatriene." Tetrahedron Lett. 2000,41, 2035-2038.

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