114. Birch and other (Dissolving) MetalReductionsMechanism of bond fission of single bonds with lithium-ammonia illustrated foralkyl halides:Mechanism of multiple bond saturation with lithium-ammonia illustrated for ketones:Mechanism of Birch reduction of benzene:P. Wipf - Chem 232013/1/200612Regioselectivity in the Birch reductionof aromatic rings:The radical and anion sites are always para to one another and tend to localize at sites on thering that stabilize charge. Regioselectivity is therefore controlled by the substituents on the ring.Electron-withdrawing groups stabilize the negative charge generated during the course of thereaction and increase the rate, leading to reduction at the position on the aromatic ring bearingthe stabilizing group. In contrast, electron donors are deactivating and direct protonation towardthe unsubstituted ortho- and meta-positions.Ring-fusions and electron-withdrawing groups have more influence in polysubstituted systems indirecting reduction than electron-donating groups. Of the electron-donating groups, the directingeffects of functional groups containing N or O outweigh alkyl groups. The empirical order ofdirecting power is carboxyl > amino, alkoxyl > alkyl. Hydrogen addition is para to an electron-withdrawing group and meta to the most strongly deactivating group, but preferentially not at aposition occupied by a deactivating substituent.The acidity of the proton source used in the first protonation step is important to theoutcome of the reduction. Sometimes, a more acidic proton source than NH3 (pKa =35) is advantageous. According to House, Modern Synthetic Reactions, alcohols(pKa = 16-19) or ammonium salts (pKa = 10) may be added to the reaction mixture.Generally, the more acidic the proton source, the faster the reduction. If theprotonation of the radical anion is the rate limiting step, NH3 can be too weak anacid to allow reaction. An unactivated benzene ring is only slowly reduced withoutan added proton donor.Reduction of an α,β-unsaturated ketone in NH3 stops at the saturated ketone stage; in thepresence of an added proton source, the saturated alcohol is obtained.P. Wipf - Chem 232023/1/200613The formation of dimerization products of the intermediate radical anion can beprevented by more acidic proton sources.Quenching: To avoid further reduction during the quenching step, NH4Cl or anotheracidic salt is used (not alcohol).The presence of bulky substituents on an aromatic ring retards reduction,presumably because of steric interference with solvation of the radical anion. Theorder of stability for the anion radical from alkyl substituted benzenes is:Stork, G.; Schulenberg, J. W. J. Am. Chem. Soc. 1962, 84, 284. Synthesis of dehydroabietic acid.Wipf, P.; Lim, S. Chimia 1996, 50, 157. P. Wipf - Chem 232033/1/200614Chemoselectivity:Ando, M.; Sayama, S.; Takase, K.Chem. Lett. 1981, 377.Stereoselectivity:Huang, P. Q.; Arseniyadis, S.; Husson, H.-P. Tetrahedron Lett. 1987, 28, 547.Truce, W. E.; Breiter, J. J. J. Am. Chem. Soc. 1962, 84, 1623.Boeckman, R. K.; Thomas, E. W. J. Am. Chem. Soc. 1977, 99, 2805.Stork, G.; Malhotra, S.; Thompson, H. J. Am. Chem. Soc. 1965, 87, 1148.Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs,S.; Wilcox, C. S. J. Am. Chem. Soc. 1983, 105, 1988.Ireland, R. E.; Wipf, P.; Miltz, W.; Vanasse, B. J. Org. Chem. 1990, 55, 1423. Use of a maskedaldol unit.P. Wipf - Chem 232043/1/200615Deoxygenation: Ireland, R. E.; Wipf, P. Tetrahedron Lett. 1989, 30, 919. Zinc reduction: Woodward, R. B. et al. J. Am. Chem. Soc. 1952, 74, 4223.McMurry Coupling: Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741.Reductive pinacol coupling.P. Wipf - Chem
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