SolutionsUmpolung (polarity inversion)
Exercise 1
Propose a synthesis of 1-phenylpentan-1-one (valerophenone) from benzaldehyde and 1-bromobutane using a dithiane. Compare it with the Friedel–Crafts route.
Benzaldehyde + propane-1,3-dithiol (BF3·OEt2) → 2-phenyl-1,3-dithiane; n-BuLi, THF, −30 °C, and 1-bromobutane → 2-butyl-2-phenyl-1,3-dithiane; HgCl2, CaCO3, aqueous MeCN → valerophenone. Friedel–Crafts acylation of benzene with pentanoyl chloride and AlCl3 does it in one step: the dithiane is kept for cases in which the ring does not tolerate Friedel–Crafts conditions or the electrophile is an epoxide, a carbonyl or a functionalized halide.
Exercise 2
Benzoin, PhCH(OH)COPh, is an α-hydroxy ketone. Explain why its disconnection calls for umpolung and how the cyanide ion achieves it in the benzoin condensation.
Disconnecting the C1–C2 bond gives two carbonyl carbons: one must be electrophilic (the aldehyde, a1) and the other nucleophilic (a benzoyl anion, d1), which does not have the natural polarity. Cyanide adds to benzaldehyde; in the cyanohydrin, the H on the benzylic carbon is acidic (stabilized by the nitrile and the ring) and the carbanion attacks another molecule of benzaldehyde. Final elimination of cyanide regenerates the carbonyl and the catalyst.