Q7(c). Birch reduction: mechanism and regiochemistry

Introduction. Birch reduction is the partial reduction of an aromatic ring by an alkali metal (Na, Li or K) dissolved in liquid ammonia in the presence of an alcohol (ethanol or tert-butanol) as proton source. Two electrons and two protons are added and the product is a non-conjugated cyclohexa-1,4-diene.

Mechanism (anisole)

Scheme: Electron, proton, electron, proton: the OMe ends on an unreduced C=C.

1. Na dissolves in NH₃: Na → Na⁺ + e-(NH₃) (solvated electron, deep blue).
2. The electron enters the lowest antibonding π* orbital of the ring: radical anion (rate-determining with the next step).
3. The radical anion is protonated by ethanol (not by NH₃, which is too weak an acid) at the carbon of highest electron density: ortho to OMe (C-2). A cyclohexadienyl radical forms.
4. A second electron gives the cyclohexadienyl (pentadienyl) anion.
5. This anion is protonated at its central carbon (C-5), where the charge density is highest (kinetic control). The two C=C bonds remain apart: 1,4-diene, with OMe on a C=C (an enol ether).

Why ortho and meta with an electron donor

1. In the radical anion the extra electron (and the negative charge) is distributed over the ring. An electron-donating group (OMe, CH₃, NH₂) destabilises negative charge on the carbon to which it is attached (ipso) and on the para carbon; the charge density is therefore highest at the ortho and meta carbons.
2. Protonation occurs where the charge is greatest, ortho; the second protonation, at the centre of the pentadienyl anion, is the carbon meta to OMe (C-5).
3. So the two new CH₂ groups are ortho and meta (C-2 and C-5); the donor is left on a remaining C=C (1-substituted 1,4-diene). An enol ether product hydrolyses (dilute acid) to cyclohex-3-enone and then cyclohex-2-enone.
4. An electron-withdrawing group (COOH) stabilises negative charge at ipso and para: protonation then occurs there, giving 2,5-dihydrobenzoic acid (cyclohexa-2,5-diene-1-carboxylic acid), with the substituent on an sp³ carbon.

Scheme: Electron-withdrawing group: the opposite regiochemistry.

Conclusion. Birch reduction (Na or Li/liq. NH₃/ROH) adds 2 e⁻ and 2 H⁺ to an arene by the sequence electron–proton–electron–proton, giving a 1,4-diene: anisole → 1-methoxycyclohexa-1,4-diene. An electron donor puts the highest negative charge of the radical anion at ortho and meta, so these are protonated and the donor stays on a C=C; an acceptor directs reduction to ipso and para.

Application. Birch reduction of the aromatic A ring of oestradiol methyl ether, then hydrolysis, gives the 19-nor-Δ⁴-3-ketone of the oral contraceptives norethindrone and norethynodrel.