Acetals, imines and enamines

Reversible addition of weak nucleophiles

Water, alcohols and amines are weak nucleophiles, so their additions to C=O are reversible and usually need acid or base catalysis. Acid helps by protonating the carbonyl oxygen, which makes the carbon much more electrophilic.

Hydrates

Water adds to give a 1,1-diol (a hydrate, or gem-diol). Most hydrates cannot be isolated, but methanal in water is almost entirely hydrated, while propanone is barely hydrated at all. The more electrophilic and less hindered the carbonyl, the further the equilibrium lies towards the hydrate.

Hemiacetals and acetals

One molecule of alcohol adds to give a hemiacetal (an OH and an OR on the same carbon). With an acid catalyst and more alcohol, the OH is replaced by a second OR group, giving an acetal and water:

Removing the water drives the reaction forward; adding aqueous acid reverses it. Acetals are unaffected by bases, nucleophiles and reducing agents, which makes them useful protecting groups. The older terms hemiketal and ketal are still used for the products from ketones.

Sugars as cyclic hemiacetals

In glucose, the OH on C5 adds to the aldehyde at C1, forming a six-membered ring. The new OH on C1 can point down (\alpha) or up (\beta). The glycosidic bonds that link sugars into starch and cellulose are acetal linkages.

Imines

A primary amine adds to a carbonyl and then water is lost, giving an imine with a C=N bond:

Imine formation is fastest in weakly acidic solution, around pH 4–5. The orange precipitate formed between carbonyl compounds and 2,4-dinitrophenylhydrazine is a related condensation product (a hydrazone).

Thermodynamics of hydration

K_{\text{hyd}} reflects the stability of the carbonyl relative to the tetrahedral adduct. Electron-withdrawing substituents (CCl_3, CF_3) and ring strain (cyclopropanone) destabilise C=O and favour hydrates; alkyl and aryl groups (donation, conjugation, steric compression on sp^3) disfavour them. Exchange of ^{18}O from H_2^{18}O into a ketone reveals rapid, reversible hydration even when K_{\text{hyd}} is tiny.

Acetal formation: mechanism

1. Protonation of C=O, attack by ROH, deprotonation: hemiacetal. 2. Protonation of the hemiacetal OH, loss of water assisted by the lone pair on OR to give an oxocarbenium ion. 3. Attack by a second ROH and deprotonation: acetal.

Every step is reversible; the oxocarbenium ion is the key intermediate in both formation and hydrolysis. Acetal formation is entropically disfavoured (three molecules to two), so cyclic acetals from ethane-1,2-diol are preferred: the intramolecular second step is favoured, and water is removed with a Dean–Stark trap or a dehydrating agent such as trimethyl orthoformate. Acetals need acid to form and to hydrolyse, which is why they survive Grignard reagents, LiAlH_4 and base.

Worked example: to reduce the ester in ethyl 4-oxopentanoate with LiAlH_4 while keeping the ketone, protect the ketone as its ethane-1,2-diol acetal, reduce, then hydrolyse with aqueous acid to give 5-hydroxypentan-2-one.

Imines and the pH-rate profile

Primary amines add to give a carbinolamine (hemiaminal); acid-catalysed loss of water gives an iminium ion, then the imine. The rate is maximal at about pH 4–5: too acidic and the amine is protonated and non-nucleophilic; too basic and the carbinolamine OH is not protonated, so dehydration is slow. Related condensations with hydroxylamine (oximes), hydrazines (hydrazones) and semicarbazide (semicarbazones) give stable, often crystalline products.

Reductive amination reduces the imine or iminium in situ with NaBH_3CN or NaBH(OAc)_3, which react faster with C=N^+ than with C=O, making this a leading method for synthesising amines.

Enamines

Secondary amines (pyrrolidine, morpholine) give iminium ions that cannot lose an N–H proton, so they lose an \alpha-C–H instead, forming an enamine. Enamines are neutral enolate equivalents: the nitrogen lone pair makes the \alpha-carbon nucleophilic. In the Stork enamine synthesis they are alkylated with reactive halides or added to Michael acceptors, then hydrolysed to the substituted carbonyl. Organocatalysis by proline and its derivatives runs on the same enamine chemistry.

Biology

Pyridoxal phosphate forms imines with amino acids during transamination, and retinal forms a protonated imine (Schiff base) with a lysine in rhodopsin. Glycosidases cleave acetal bonds via oxocarbenium-like transition states.