Formation of C—N bonds is frequently achieved by condensation reactions between amines and aldehydes or ketones. A typical nucleophilic addition is followed by elimination of water to give an imine or Schiff base [Figure 2.12(a)]. Of almost equal importance is the reversal of this process, i.e. the hydrolysis of imines to amines and alde-hydes/ketones [Figure 2.12(b)]. The imine so produced, or more likely its protonated form the
(a) Schiff base formation nucleophilic attack on to carbonyl
equilibrium between protonated species; proton may be on N or O
elimination of water
imine or Schiff base
r' x quaternary Schiff base
(b) Schiff base hydrolysis nucleophilic attack on to imine or protonated imine
loss of amine leaving group; formation of carbonyl
(c) Mannich reaction nucleophilic addition on to iminium ion
carbanion-type nucleophile, e.g. enolate anion
iminium ion, can then act as an electrophile in a Mannich reaction [Figure 2.12(c)]. The nucle-ophile might be provided by an enolate anion, or in many examples by a suitably activated centre in an aromatic ring system. The Mannich reaction is encountered throughout alkaloid biosynthesis, and in its most general form involves combination of an amine (primary or secondary), an aldehyde or ketone, and a nucleophilic carbon. Secondary amines will react with the carbonyl compound to give an iminium ion (quaternary Schiff base) directly, and the additional protonation step is thus not necessary.
It should be appreciated that the Mannich-like addition reaction in Figure 2.12(c) is little different from nucleophilic addition to a carbonyl group. Indeed, the imine/iminium ion is merely acting as the nitrogen analogue of a carbonyl/protonated carbonyl. To take this analogy further, protons on carbon adjacent to an imine group will be acidic, as are those a to a carbonyl group, and the isomerization to the enamine shown in Figure 2.13 is analogous to keto-enol tautomerism. Just as two carbonyl compounds can react via an aldol reaction, so can two imine systems, and this is indicated in Figure 2.13. Often aldehyde/ketone substrates in enzymic reactions become covalently bonded to the enzyme through imine linkages; in so doing they lose none of the carbonyl activation as a consequence of the new form of bonding.
enamine imine-enamine tautomerism
aldol-type addition product aldol-type reaction between two imine systems behaving as enamine-iminium ion pair
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