Schiff Base Formation and the Mannich Reaction

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

R-NH

primary amine

c=oh

equilibrium between protonated species; proton may be on N or O

R"NyC^OH2

elimination of water

imine or Schiff base

secondary

r' x quaternary Schiff base

(b) Schiff base hydrolysis nucleophilic attack on to imine or protonated imine

H2o:y

loss of amine leaving group; formation of carbonyl

(c) Mannich reaction nucleophilic addition on to iminium ion

iminium ion

carbanion-type nucleophile, e.g. enolate anion

Figure 2.12

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

protonated

aldol-type addition product aldol-type reaction between two imine systems behaving as enamine-iminium ion pair

Figure 2.13

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Responses

  • Fedra Udinesi
    How schiff base is formed in alkaloids?
    2 years ago
  • demet
    What are the importance of schiff base and mannich reaction in the biosynthesis of an alkaloid?
    12 months ago

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