The Mannich Reaction

by James

Description: The Mannich reaction is similar to the Aldol reaction, except that instead of an enol (or enolate) adding to an aldehyde or ketone, it adds to an imine (or iminium).
1-headerNotes: The imine is usually formed “in situ” (in the reaction flask) by addition of a primary or secondary amine to an aldehyde or ketone. The addition of acid helps to catalyze formation of the enol from the ketone.
In this example, the imine will preferentially form fastest with the aldehyde (not the ketone) since aldehydes are more reactive towards nucleophiles (owing to less steric hindrance). For more details see the mechanism section below.

Examples: 

2-examples mannich

Notes: All of these examples show the amine being added at the same time as an aldehyde. An acid catalyst (such as HCl, but often just written “H+”) serves two functions: 1) increases rate of imine formation, and 2) catalyzes keto-enol tautomerism (forms the enol from the ketone, which is the nucleophile here).
In example 1, addition can happen at either side of the ketone (both are equivalent). In example 2, addition can only happen where shown, since the phenyl group does not have an enolizable proton. Example 3 shows a Mannich with an aldehyde and the iminium formed with formaldehyde. In example 4, the Mannich will occur at the carbon best able to form an enol (between the two carbonyls).
Not shown, but the byproduct in all these reactions is water (H2O).

Mechanism: There are several components to this mechanism and the first two are actually reactions shown in detail on other pages (but given again here).
Formation Of The Enol
The nucleophile in the Mannich reaction is an enol. Formation of the enol from an aldehyde or ketone (tautomerization)is shown below. In the first step, the carbonyl oxygen is protonated by acid (Step 1, arrows A and B). This makes the carbon adjacent to the carbonyl carbon (“alpha carbon”) considerably more acidic, and is deprotonated (Step 2, arrows C, D, and E) by a base. Here Cl- is shown as the base.

3-mech-1-enol

Imine (iminium) formation

The electrophile in the Mannich is an iminium (i.e. a positively charged imine). Formation of the iminium occurs through protonation of the aldehyde by acid (Step 1, arrows A and B) followed by addition of the secondary amine (Step 2, arrows C and D). A proton transfer occurs, leading to formation of OH2(+) and neutral nitrogen (Step 3, arrows E and F). Finally, water is expelled as a leaving group in an elimination reaction (Step 4, arrows G and H) leading to formation of the iminium.

3-mech-2-iminium

The Mannich Reaction

With these two components now in solution, the nucleophile (enol) attacks the electrophile (iminium) (Step 1, arrows A, B, and C). This is followed by deprotonation to give the neutral oxygen (Step 2, arrows D and E) to give the final product.

3-mech-3-mannich

Notes: Although Cl- is shown as the base here, pretty much any weak base (including another ketone oxygen, or neutral nitrogen from the product) will be competent to remove this proton.

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