Birch reduction

The Birch reduction is an organic reaction which is particularly useful in synthetic organic chemistry. The reaction was reported in 1944 by the Australian chemist Arthur Birch (1915–1995) working in the Dyson Perrins Laboratory in the University of Oxford.

Quotes

 * Alkali metals in liquid ammonia in the presence of an alcohol reduce aromatic systems to 1,4-cyclohexadienes. These can be further elaborated into a host of derivatives. The availability of a wide variety of substituted aromatic compounds, either commercial or via synthesis, makes the Birch reduction an important tool in organic synthesis.
 * George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 5 : Functional Group Transformations: The Chemistry of Carbon-Carbon π-Bonds and Related Reactions


 * The reduction is initiated by addition of a solvated electron to the aromatic system to generate a radical anion, which is then protonated by an alcohol cosolvent to furnish a pentadienyl radical. … The function of the alcohol in the metal -NH3 reduction is to provide a proton source… Furthermore, the presence of alcohol represses the formation of the amide ion NH2-, … is capable of isomerizing the 1,4-cyclohexadiene product…
 * George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 5 : Functional Group Transformations: The Chemistry of Carbon-Carbon π-Bonds and Related Reactions


 * Birch reduction of substrates containing methoxy or N,N-dimethylamino groups may be contaminated with appreciable amounts of conjugated products. In these cases, it is conceivable that the isomerization occurs during workup.
 * George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 5 : Functional Group Transformations: The Chemistry of Carbon-Carbon π-Bonds and Related Reactions


 * Birch reduction of monosubstituted benzenes could furnish either of two possible 1,4-cyclohexadienes … Generally, electron-donating groups (D) retard electron transfer and remain on unsaturated carbons. [D=-OH, -OR, -NR2, -SR, -PR2, -alkyl, -CH2OH, -CH2OR, -CO2R, -C(O)R, -CHO] … The reason why groups such as -C(O)R, -CHO, and -CO2R behave as electron-donating groups in this reaction is that they are reduced to -CH2O- … Electron-withdrawing groups (EWG) facilitate electron transfer and reside on saturated carbons.[EWG= -CO2H, -C(O)NH2, -aryl] … The carboxy group generally dominates the regiochemistry of the reduction when other substituents are present. The strong activation effect by the carboxyl group allows reduction to occur when only one equivalent of alcohol is present or even without an alcohol. In these cases, the intermediate dianion persists in solution and can be trapped with electrophilic reagents to generate a quaternary carbon center. … While ester groups are reduced competitively with the aromatic ring under the usual Birch conditions, addition of one or two equivalents of H2O or t-BuOH to NH3 before metal addition preserves the ester moiety.
 * George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 5 : Functional Group Transformations: The Chemistry of Carbon-Carbon π-Bonds and Related Reactions


 * Target molecules containing a 1,4-cyclodhexadiene unit are probably best prepared via the Birch reaction. These primary reduction synthons can be further elaborated into a variety of synthetically useful compounds … Isomerizations of l,4-cyclohexadienes with KOt-Bu in DMSO furnish the thermodynamically more stable conjugated 1,3-cyclohexadienes. … Hydrolysis of the initial enol ether (vinyl ether) formed from Birch reduction of anisole or substituted anisoles under mild acidic con- ditions leads to β,γ-unsaturated cyclohexenones. Under more drastic acidic condi- tions, these isomerize to the conjugated α,β-cyclohexenones. Birch reduction of anisoles followed by hydrolytic workup is one of the best methods available for preparing substituted cyclohexenone. It should be noted that Birch reduction of 4-substituted anisoles followed by acidic workup (aq HCl, THF) produces mixtures of isomeric cyclohexenones. … Selective cleavage of the more nucleophilic double bond of anisole-derived 1,4-cyclohexadienes by ozone provides highly function- alized acyclic compounds containing a stereodefined double bond. … Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence.
 * George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 5 : Functional Group Transformations: The Chemistry of Carbon-Carbon π-Bonds and Related Reactions