7.1 Carbonyl Additions and Condensations

7.1.1 Nucleophilic addition to C=O ★★

• C=O is polar, Cᵟ⁺–Oᵟ⁻; nucleophiles attack carbon at about 107° (Bürgi–Dunitz) to give a tetrahedral alkoxide. HCHO > RCHO > R₂CO: alkyl groups donate and crowd; aryl conjugation lowers reactivity further.SN
• Electron-withdrawing groups raise the reactivity (p-NO₂ or p-CF₃ benzaldehyde > PhCHO > p-MeO-, p-Me₂N-benzaldehyde). A Lewis acid (BF₃, Mg²⁺) or H⁺ on oxygen activates the carbonyl CSE 2021 Q1(d) 10m.SN
• Cyanohydrins: HCN with a little base (CN⁻ is the nucleophile). Hydrolysis gives α-hydroxy acids: ethanal → lactic acid, benzaldehyde → mandelic acid (racemic); with NH₄Cl/NaCN the iminium is attacked instead: Strecker α-amino acid Geo 2022 Q7(c) 5m Geo 2024 Q6(c) 10m.SN
• Acetals and thioacetals protect C=O: acid, diol or dithiol, water removed. 1,3-Dithiolanes are stable to acid and base; Raney Ni turns them into CH₂ Geo 2023 Q6(d) 4m. A 1,4-diketone in acid closes to a furan (Paal–Knorr): hexane-2,5-dione → 2,5-dimethylfuran Geo 2024 Q8(c).
• Grignard reagents add to give alcohols. A bulky one (t-BuMgBr) with a hindered ketone instead reduces it (β-H transferred through a six-membered transition state) or just enolises it IFoS 2024 Q4(a) 10m.
• Nitriles hydrolyse through the amide to the acid (CH₃CN → CH₃COOH + NH₄Cl) CSE 2024 Q3(a)(i) 10m.

7.1.2 Enols and enolates ★★★

• Kinetic: bulky strong base, low temperature, short time, no proton source: the less hindered α-H goes. Thermodynamic: weaker base in a protic solvent, higher temperature: the more substituted enolate IFoS 2025 Q3(d) 10m IFoS 2021 Q1(d).SN
• LDA turns all the ketone into enolate; with no C=O left the enolate cannot self-condense. NaOH leaves most ketone unenolised, so aldol follows Geo 2022 Q6(a) 4m.SN
• Enolisation destroys a stereocentre at the α-carbon: base-catalysed bromination of an optically active ketone racemises it, at the same rate as it exchanges H for D IFoS 2023 Q3(d).
• Malonic and acetoacetic ester syntheses: alkylate the stabilised enolate, hydrolyse, heat (β-keto or malonic acid loses CO₂ through a six-membered transition state). Malonate + 1,3-dibromopropane → cyclobutanecarboxylic acid IFoS 2021 Q6(a)(i) 5m. Ethyl acetoacetate, NaOEt (2 equiv) and 1,3-dibromopropane: after the first C-alkylation the ring closes through the enolate oxygen (six-membered ring) rather than carbon (four-membered): a dihydropyran, not a cyclobutane Geo Pre 2025 Q92.SN

7.1.3 Aldol addition and condensation ★★★

• Needs an α-H on the nucleophile partner. Aldol addition is reversible; dehydration (E1cB, on heating) gives the conjugated enone and drives it.SN
• Crossed aldol is clean only if one partner cannot enolise (HCHO, ArCHO, Me₃CCHO) and is the better electrophile: Claisen–Schmidt (ArCHO + ketone, OH⁻ → chalcone, benzalacetone).SN Two enolisable partners give up to four products; butanone + ethanal can give four β-hydroxy carbonyls in theory CSE 2023 Q4(c)(i) 10m.
• Which pairs give an α,β-unsaturated carbonyl in base? Only those where the aldol still has an α-H to lose: PhCHO + CH₃CH₂CHO gives PhCH=C(CH₃)CHO; HCHO + PhCHO (no α-H at all) gives Cannizzaro instead CSE 2021 Q4(c)(ii) 10m.
• Intramolecular aldol: five- and six-membered rings win; the more reactive aldehyde is the electrophile. CH₃CO(CH₂)₄CHO → 1-acetylcyclopentene IFoS 2021 Q3(b)(ii) 5m; 2-(2-oxohexyl)cyclopentanone → bicyclo[3.3.0]enone IFoS 2024 Q1(e) 5m.SN
• Reversibility decides between two rings: the aldol that can still dehydrate is drained off; one with a quaternary α-carbon cannot, and goes back Geo 2023 Q7(d) 5m.

Also asked: Geo 2021 Q9(a) PhCHO with NaOH, with CH₃CHO/NaOH and with Ac₂O/NaOAc (Cannizzaro, Claisen–Schmidt, Perkin).

7.1.4 Claisen ester condensation, Dieckmann and relatives ★★★ Geo-Scientist every year

1. Ester enolate (EtO⁻, matching the ester) adds to a second ester C=O; the tetrahedral intermediate expels EtO⁻: a β-keto ester.SN
2. Every step is reversible; the reaction is pulled over because the product's CH between two C=O (pKₐ ≈ 11) is deprotonated. So one full equivalent of base is needed, and an ester with only one α-H fails (no final deprotonation).SN
3. Dieckmann = intramolecular Claisen: 1,6-diesters give five-membered, 1,7-diesters six-membered cyclic β-keto esters. Diethyl adipate → ethyl 2-oxocyclopentanecarboxylate IFoS 2022 Q4(b) Geo 2025 Q9(a)(i) 5m Geo 2024 Q9(b) 5m.SN
4. Crossed Claisen works with an ester that cannot enolise: diethyl carbonate (gives β-keto esters), diethyl oxalate, ethyl formate, ethyl benzoate. A ketone is acylated on its CH₃ side, the side that leaves a CH₂ between the two C=O Geo 2022 Q7(b) 5m IFoS 2022 Q4(a).
5. Diethyl succinate cannot do a Dieckmann (three-membered ring); two molecules condense twice: diethyl succinylsuccinate → cyclohexane-1,4-dione after hydrolysis and decarboxylation IFoS 2021 Q5(a) 5m IFoS 2023 Q3(e).
6. A ketone enolate can attack a tethered ester (intramolecular Claisen) to give a cyclic 1,3-diketone IFoS 2025 Q1(h) 5m.

Also asked: CSE 2025 Q2(a) 15m a cyclic β-keto ester and NaOEt (retro-Claisen and recyclisation) · Geo 2022 Q9(d) · Geo 2023 Q9(d).