Organic chemistry reactions Use of enamines in synthesis

1. USE OF ENAMINES IN
SYNTHESIS
T.Chikanda
T.Goto
I.Madoro
P.Muchemwa

2.  Enamines are unsaturated compounds formed by the
reaction of secondary amines with carbonyl
compounds(ketones and aldehydes)
 Common secondary amines used to form enamines
include pyrrolidine, piperidine, and morpholine.

3.  Because they have a significant resonance form
where there is a negative charge on the alpha
carbon, they are nucleophilic.
 Enamines undergo reactions with electrophiles
such as alkyl halides and Michael acceptors
 They are hydrolyzed with strong acid.

4. MECHANISM
 It follows the PADPED mnemonic – Protonation Addition
Deprotonation Protonation Elimination Deprotonation.
 The first step of enamine formation is Protonation of the
aldehyde/ketone oxygen, followed by Addition of the
secondary amine to the carbonyl carbon.
 Addition forms a new C-N bond and breaks the C-O pi
bond
 Proton transfer from nitrogen to oxygen is accomplished
through Deprotonation of nitrogen with base (e.g. excess
amine) followed by Protonation of the OH to give OH2(+).

7.  Now that there is a free lone pair on nitrogen and a
good leaving group (OH2) the stage is set for the
reverse of addition, that is Elimination of water to give
a new C–N pi bond.
 deprotonation step gives us our neutral enamine
species and a molecule of water.

8.  Cyclic amines are often used
 The reaction is catalyzed by acid
 Removal of water drives enamine formation to
completion

9. +
H
+
N
H
O
An enamine
-H2 O
N
OH
N
+
O
An enamine
N
O
OH
N
O
N
O
H
H
+
H
+
-H2 O
H
+

10.  Enamines react as nucleophiles, resulting in
alkylation at the position equivalent to the a carbon
atom of the original carbonyl compound.
 The reaction is restricted to displacement of halide
ion from primary alkyl halides. The product is an
alkylated imine.
 Upon hydrolysis, it gives an α alkylated carbonyl
compound
 Enamines react with electrophiles the same way
enolates do

11. REACTIONS OF ENAMINES: ALKYLATION
 an enamine treated with CH3I will form a new C-C
bond. This is an example of enamine alkylation. A new
carbon-carbon bond is formed
 water is often added because in the absence of
water, it’s possible for the enamine to re-form so step 2
shows hydrolysis
 This is an SN2 reaction at carbon, with the enamine
alpha-carbon as the nucleophile: formation of N-C (pi),
breakage of C-C (pi), formation of C-C and breakage
of C-X (iodine in this case).

13. REACTIONS OF ENAMINES: MICHAEL
ADDITION (CONJUGATE ADDITION)
 Enamines are also nucleophilic enough to perform
conjugate additions (“Michael additions”) with
alpha, beta unsaturated species eg the ketone
below (methyl vinyl ketone).

14.  As with alkylation, the usual procedure is to just add
aqueous acid after the reaction is complete,
resulting in hydrolysis of the enamine and formation
of a new ketone

15. REACTIONS OF ENAMINES: HYDROLYSIS WITH
AQUEOUS ACID
 Enamines are easily transformed back into
aldehydes/ketones though hydrolysis with using
aqueous acid (H2SO4/H2O is an alternative way of
depicting the same thing).
 we’re driving the reaction back towards the starting
aldehyde/ketone by using an excess of water.Steps to
follow :
 Protonation of the enamine at the alpha carbon,
followed by
 Addition of water to the resulting iminium ion.
 Deprotonation of oxygen
 Protonation of nitrogen (making it into a better leaving
group)
 Elimination of neutral HNR2
 Deprotonation of oxygen to give the neutral carbonyl.

17. SUMMARY
 Enamines can be formed through the addition of a
secondary amine to an enolizable aldehyde/ketone
in the presence of mild acid.
 The mechanism is PADPED.
 The nitrogen of enamines is a powerful pi-donor,
making the alkene particularly nucleophilic
 Enamines undergo alkylation at carbon with alkyl
halides. They can also perform conjugate addition
(“Michael reactions”).
 Enamines can be hydrolyzed back to
aldehydes/ketones with aqueous acid.