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Alkylation of enamines with alkyl halides

Description: Enamines are nucleophiles, and will react with alkyl halides to give alkylation products. Subsequent treatment with aqueous acid will give ketones.
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Notes: X here is a halide or sulfonate, such as Cl, Br, I or OTs

Examples:

Notes: Example 3 shows hydrolysis of the enamine to give the ketone.

Mechanism: Alkylation of the enamine occurs through attack of the enamine carbon on the alkyl halide through an SN2 reaction (Step 1, arrows A, B and C) which gives a positively charged iminium intermediate. This is deprotonated by a base (Step 2, arrows E, E and F) to give the alkylated enamine.

Hydrolysis mechanism: This s the reverse of enamine formation and is done with aqueous acid, such as H3O(+). Protonation of the enamine carbon (Step 1, arrows G, H, I) gives an iminium, which is attacked by water in a 1,2-addition (Step 2, arrows J and K). Proton transfer (Step 3, arrows L and M) followed by elimination of the amine in a 1,2-elimination (Step 4, arrows N and O) gives the protonated ketone, which is deprotonated (Step 5, arrows P and Q).

Notes: Acid can assist the reaction, making it faster in two ways. First, it makes the carbonyl more reactive for step 2, and it also allows for formation of OH2, which is a better leaving group than OH(–)

Also, nothing particularly important about Cl here – it’s just a counter-ion for H3O(+) here.

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