What Is Birch Reduction Reaction?
The method of reducing aromatic compounds in liquid ammonia using metals (especially alkali metals and alkaline earth metals) under the condition of alcohol compounds is generally called Birch reduction.
Birch reduction is a powerful reduction method. In addition to reducing aromatic compounds, it can also reduce esters, ketones, and selectively reduce double bonds, alkynes, halides, sulfonates and other functional groups of α,β-unsaturated ketones. Since Birch reduction can effectively reduce aromatic compounds such as benzene derivatives, it provides an effective means to synthesize aliphatic compounds from aromatic compounds, making easily available aromatic compounds very useful synthetic building blocks in organic synthetic chemistry.
The usefulness of the Birch reduction of aromatic rings lies in the fact that its product is usually a non-conjugated 1,4-diene, and further functionalization or further transformation of the 1,4-diene can provide a series of useful synthons. Unlike catalytic hydrogenation, the Birch reduction selectively disrupts aromaticity, making it invaluable for synthesizing complex intermediates in pharmaceuticals, natural products, and materials science.
- Reagents: Alkali metal (typically sodium or lithium) in liquid ammonia or an amine solvent (e.g., ethylamine, tert-butylamine), and a proton source (e.g., alcohol like tert-butanol or ethanol, or water).
- Reactants: Aromatic rings (substituted benzenes, naphthalenes, other polycyclic aromatic hydrocarbons).
- Products: 1,4-Cyclohexadienes (non-conjugated dienes).
- Reaction type: Reduction reaction.
- Related reactions: Clemmensen reduction, Wolff-Kishner reduction.
- Regioselectivity: Electron-donating groups (EDGs, e.g., -OCH3) direct reduction to the meta position, while electron-withdrawing groups (EWGs, e.g., -COOH) favor para reduction. This selectivity arises from charge distribution in the radical anion intermediate.
Fig 1. Birch reduction reaction and its mechanism. [1]
Mechanism of Birch Reduction
The Birch reduction proceeds via a stepwise electron-transfer mechanism:
- Electron Donation: Alkali metals (e.g., Na) dissolve in liquid NH₃, generating solvated electrons (e⁻(NH3)).
- Aromatic Ring Reduction: The aromatic substrate accepts an electron, forming a radical anion intermediate. This disrupts aromaticity and localizes negative charge at positions with the highest electron density.
- Protonation: A proton source (ROH) quenches the radical anion, yielding a dihydroaromatic intermediate.
- Second Electron Transfer: A second electron is transferred to the intermediate, followed by another protonation step, producing the final 1,4-cyclohexadiene derivative.
Experimental Tips
- Solvent System: Liquid ammonia (BP: -33°C) is essential; reactions are typically conducted at -78°C (dry ice/acetone bath) to stabilize intermediates and minimize side reactions.
- Metal Choice: Sodium is cost-effective but less reactive than lithium. Lithium-ammonia systems enable faster reductions, especially for electron-deficient arenes.
- Proton Source: Use alcohols with low acidity (e.g., tert-butanol) to avoid premature protonation. Excess alcohol may lead to over-reduction.
- Safety: Alkali metals react violently with water; strict anhydrous conditions and inert atmospheres (N2/Ar) are mandatory. Quench residual metal with NH4Cl before workup.
Application Examples of Birch Reduction
- Example 1: In the total synthesis of Herqulines B and C, the l-tyrosine-based biaryl system is selectively converted to the common 1,4-diketone structural motif of Herqulines by initial hypervalent iodine-mediated dearomatization and subsequent targeted Birch reduction (achieved by an intramolecular H source). [2]
- Example 2: Justin P. Cole et al. reported a visible light-driven Birch reduction using benzo[ghi]perylene imides as organic photoredox catalysts. [3]
Fig 2. Synthetic examples via Birch reduction reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 41-43.
- Zhu, Xu, et al. Journal of the American Chemical Society, 2019, 141(8), 3409-3413.
- Cole, Justin P., et al. Journal of the American Chemical Society, 2020, 142(31), 13573-13581.
