I. Basic Principles I-L. Radicals & Carbenes 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; pp 715. A major difference between radicals and other reactive species that are employed in synthesis is that virtually all radicals react rapidly with themselves. The lifetime of a transient radical rarely exceeds 1 ms and is at the diffusion-controlled limit; the enthalpy of activation of most radicalradical reaction is close to 0 kcal/mol. In general, radical reactions are oxygen-sensitive but water-tolerant. Solvent effects are generally small, but hydrogen-atom abstraction can become a concern in radical reactions of slow or intermediate rates. The need to evaluate the relative rates of competing radical reactions pervades synthetic planning of radical additions and cyclizations. Concentrations are therefore very important. The following table contains some representative rate constants: 1
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 additions because of the low concentration of radicals. 2
Initiation can be accomplished by photochemical or redox reactions, but it is most often accomplished by homolytic bond cleavage of a chemical initiator. Some common initiators are: CAUTION: Heating AIBN (azobisisobutyronitrile) produces a deadly chemical, tetramethylsuccinonitrile (TMSN). TMSN is immediately dangerous to life and health (IDLH) at 5 ppm. Cyanide gas has an IDLH at 25 ppm. Organoboranes are readily oxidized by oxygen, a process that is inhibited by radical scavengers such as galvinoxyl. The accepted mechanism of the autoxidation is shown below (see also: Ollivier, C.; Renaud, P., "Organoboranes as a source of radicals." Chem. Rev. 2001, 101, 3415-3434). A homolytic substitution (S H 2) reaction between triplet oxygen and triethylborane serves as the initiation and lead to a peroxy radical that propagates the chain. The rate constant for the homolytic substitution at the boron center of triethylborane has been measured to be 2.010 6 M -1 s -1 at 30 C. 3
Atom and Group Transfer Reactions In this very broad class of reactions, a univalent atom (hydrogen or halogen) or a group (SPh, SePh) is transferred from a neutral molecule to a radical to form a new σ-bond and a new radical. Subsequently, C-C bonds are generally formed via addition reactions to alkenes and alkynes. 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 with electron rich are termed nucleophilic radicals. Conversely, those that react more rapidly with electron rich alkenes are termed electrophilic radicals. Certain radicals react more rapidly with both electron rich and electron poor alkenes than they do with alkenes of intermdiate electron density. These radicals are termed ambiphilic. The appropriate pairing of a radical and an acceptor is important for the success of an addition reaction. 4
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Roberts, B. P., "Polarity-reversal catalysis of hydrogen-atom abstraction reactions: Concepts and applications in organic chemistry." Chem. Soc. Rev. 1999, 28, 25-35. The rates and selectivities of the hydrogen-atom abstraction reactions of electrically-neutral free radicals depend on polar effects which operate in the transition state. Thus, an electrophilic species such as an alkoxyl radical abstracts hydrogen much more readily from an electron rich C-H bond than from an electron-deficient one of similar strength. The basis of polarity-reversal catalysis (PRC) is to replace a unfavorable single-step abstraction with a two-step process in 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* 6
Schematic potential energy diagram illustrating the principle of PRC for promoting hydrogen-atom transfer by a hydridic catalyst H-Nu: Two steps with low activation energies can lead to a faster overall reaction than is 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 methyl thioglycolate the yield was only 8%. 7
Stereochemistry The methyl radical is known to be planar. Alkyl- or heteroatom-substituted radicals are pyramidalized, but the inversion barrier is very low. Conjugating substituents favor planar structures. Accordingly, the stereochemistry of reaction at a radical center is controlled by the relative rates of the competing reactions: As with alkyl radicals, the stereochemical outcome of a reaction of a vinyl radical does not generally depend on the stereochemistry of the precursor. However, there are several examples in which a subsequent reaction of a vinyl radical has been proposed to be more rapid than its inversion. Thiohydroxamates (the Barton method) One of the most important chain methods that does nor revolve around the chemistry of the trialkyl radical is the Barton thiohydroxamate protocol. 8
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): 9
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). 10
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 free radical ring expansion." Tetrahedron Lett. 1992, 33, 7307-7310. 11
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. 12
Jung, M. E.; Kiankarimi, M., "Gem-dialkoxy effect in radical cyclizations to form cyclopropane derivatives: Unusual oxidation of a dialkoxyalkyl radical." J. Org. Chem. 1995, 60, 7013-7014. 13
Features of Carbene Reactions A carbene is a highly reactive organic molecule with a divalent carbon atom with only six valence electrons. The carbene comes in two varieties - a singlet and triplet. The singlet type has its carbon atom sp2 hybridized with an empty p-orbital extending above and below a plane containing R1 and R2 and the free electron pair. Typically these molecules are very short lived, although persistent carbenes are now known. Singlet carbenes have a pair of electrons and sp2 hybrid structure. Triplet carbenes have two unpaired electrons. They may be either sp2 hybrid or linear sp hybrid. Most carbenes have nonlinear triplet ground state 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., "Stereoselective cyclopropanation reactions." Chem. Rev. 2003, 103, 977-1050. 14
Halomethylzinc Additions to Alkenes Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B., "Stereoselective cyclopropanation reactions." Chem. Rev. 2003, 103, 977-1050. 15
Generally favored Schreiber s biscyclopropanation: 16
C,C-Bond Forming Cascade Reaction - Imine Additions - Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768. 5 new C,C-bonds Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1269.. 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 intramolecular insertion proceeds with retention of absolute configuration. 17
Davies, H. M. L.; Walji, A. M., "Direct synthesis of (+)-erogorgiaene through 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. 18
Davies, H. M. L.; Stafford, D. G.; Hansen, T.; Churchill, M. R.; Keil, K. M., "Effect of carbenoid structure on the reactions of rhodiumstabilized carbenoids with cycloheptatriene." Tetrahedron Lett. 2000, 41, 2035-2038. 19