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ADDITION-ELIMINATION:
NITROGEN AND PHOSPHORUS
NUCLEOPHILES
Sections 16.12 - 16.14
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Compounds that bear an amino group
G
NH2
form Imines.
The G group can be one of many different
possibilities
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Addition-Elimination:
The Formation of Imines
G
..
NH2
R
R
C
+
R
O
HA
C
N
G
+
H2O
R
an imine
All of the imine reactions, regardless of G, go by the
same mechanism.
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Mechanism of Imine Formation
Step 1
H
R
G
..
NH2
C
+
slow
..
O
..
G
R
R
+
N C
H
R
.. _
O
.. :
G
R
..
N
C
H
R
..
OH
..
Step 2
R
G
..
N
C
H
R
..
OH
..
R
fast
+
HA
G
+
N
H
C
+
H2O
+
_
A
R
What is the mechanism of this step?
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Mechanism of Imine Formation
(Part Two)
Step 3
R
G
+
N
H
C
_
+
R
A
fast
G
..
N
R
C
+
H
A
R
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•This is Addition-Elimination
•The first step is carbonyl addition of an amine, and
the second step is a dehydration (elimination) to
yield the C=N double bond.
•HA is the catalyst
•Step #1 is rate-determining, unless the amine is
very basic (e.g., semicarbazide or aniline), in which
case step #2 becomes rate-determining.
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Carbonyl compounds react with:
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Formation of Simple Imines
R
R
C
R
O
..
+ H2N
R
acid
C
N
R
+
H2O
R
an imine
•Aldehydes and ketones react with simple primary
amines to yield imines.
•The equilibrium is unfavorable; the products are
much less stable than the reactants.
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A Simple Model for Enzyme-Substrate
Binding.
O
+
NH2
C
R
enzyme
R
substrate
R
N
C
R
enzyme-substrate complex
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O
H 2N
CH2
CH2
CH2
CH2
C
CH
OH
NH2
Lysine
If lysine is part of the protein chain of the
enzyme, the terminal amino group is available to
bind to carbonyl groups to form an imine.
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•Once the substrate (aldehyde or ketone) is bound
to the enzyme, the active site of the enzyme is in a
position to react with and modify the substrate.
•At the end of the reaction, because imines come
apart easily (remember the “unfavorable”
equilibrium?), the modified substrate can
dissociate from the enzyme and return to the
solution.
•As we can see, often biological substrates
possess carbonyl groups so that they can act as
a “handle” in enzyme-substrate binding. The
carbonyl group may have no other chemical
purpose than just this one!
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Formation of Oximes
R
R
C
R
O
+
..
H 2N
OH
hydroxylamine
acid
C
N
OH
+
H2O
R
an oxime
•Aldehydes and ketones react with hydroxylamine to
yield oximes.
•Oximes are important derivatives in qualitative
organic analysis.
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What’s a Derivative?
• One of the principal tests for the correct
identification of an unknown compound
comes in trying to convert the compound by
a chemical reaction into another known
compound -- a derivative
• If the melting point of the derivative
matches the expected value, according to
the literature, then one can assume that the
original substance had been correctly
identified.
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Formation of Hydrazones
R
R
C
R
O
+
..
H2 N
acid
C
NH R
a hydrazine
N
NH R
+
H2O
R
a hydrazone
•Aldehydes and ketones react with substituted
hydrazines to yield substituted hydrazones.
•The equilibrium is generally unfavorable.
•Exception: when R is an aromatic ring.
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2,4-Dinitrophenylhydrazones
NO2
R
C
O
..
H
N
+
2
NO2
NH
acid
R
2,4-dinitrophenylhydrazine
NO2
R
C
N
NH
NO2
+
H2O
R
2,4-DNP’s are the most
important of all
derivatives for aldehydes
and ketones.
a 2,4-dinitrophenylhydrazone
a 2,4-DNP
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Formation of Semicarbazones
O
R
C
R
O
..
+ H2N
NH C
acid
NH2
semicarbazide
•Aldehydes and ketones react
with semicarbazide to yield
semicarbazones.
•Semicarbazones are the
second-most important of the
derivatives of aldehydes and
ketones.
O
R
C
N
NH C
NH2
+
H2O
R
a semicarbazone
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Formation of Phenylhydrazones
R
HA
C
O
+
H 2N
NH
R
Phenylhydrazine
R
C
In most cases, the
equilibrium is unfavorable.
However, this reaction is
sometimes used to form
derivatives of the sugars.
R
N
+ H 2O
NH
a phenylhydrazone
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As we have already seen, substituted amines
can react with aldehydes and ketones to form a
variety of products.
Primary amines can yield imines by an additionelimination process.
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Addition-Elimination:
The Formation of Imines
R
G
..
NH2
R
C
+
R
O
HA
C
N
G
+
H2 O
R
an imine
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When secondary amines are allowed to react with
aldehydes or ketones, dehydration of the type
shown in the elimination step cannot take place
(there is no labile hydrogen on the nitrogen atom
of the addition product).
OH
R
CH2 C
R
N
R'
R'
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If the starting aldehyde or ketone has an ahydrogen, however, dehydration toward the
a-carbon can occur, yielding an enamine.
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Formation of Enamines
R
H
OH
C
C
Protonated by
HOTs catalyst
R
slow
R
R
H
H
OH2
C
C
R
R
N
R
R
N
R
R
H
R
C
C
R
R
C
C
R
+
O
H
N
R
R
R
An enamine
R
R
H
N
R
Resonance-stabilized
A proton goes back
to the reaction medium
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The equilibrium for the formation of
enamine is not favorable. It can be shifted
to the right, however, by removing the water
by azeotropic distillation as it is formed.
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The enamine is quite nucleophilic,
owing to resonance of the type:
R'
R
N
C
R
R'
R'
R
C
N
C
R
R
R'
C
R
As a consequence of this resonance, the a-carbon
of an enamine has a great deal of carbanion-like
(nucleophilic) character.
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Amines that are used typically to form enamines:
CH3 CH2
N
CH3 CH2
Diethylamine
H
N
H
Piperidine
O
N
H
N
Pyrrolidine
H
Morpholine
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Nucleophilic Character
of Enamines
R
R
:N
R
C
R
R
R
..
C
C
R
R
_
+N
R
C
R
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Reactions of Enamines
as Nucleophiles
R
:N
R
C
R
C
R
R
R
R
R
SN2
R
R
R
+N
C
C
R
R
R
R
:N
C
C
+
R
R
R
an iminium salt
X
_
+
X
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Hydrolysis of Iminium Salts
(Part One)
1)
R
R
R
+N
R
R
R
R
N:
C
C
R
+O :
R
R
+N
H
C
C
R
R
:O
..
H
slow
R
C
C
R
..
O
..
H
R
R
H
R
R
H
H
2)
R
R
R
R
+N
H
C
C
R
R
:O
..
H
R
R
R
C
C
R
R
+O
..
H
+
R
N
..
H
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Hydrolysis of Iminium Salts
(Part Two)
3)
R
R
R
C
C
R
R
+O
..
H
R
C
C
R
:O :
R
+
+
H
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O
O
N
N
HOTs
+
CH3 I
O
CH3
CH3
H2O
H+
from cyclohexanone
Enamines can react with alkyl halides -- Here’s an
example.
Apply the previous mechanisms to this synthesis.
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Another example:
O
N
O
CH2 CH
+
CH2 CH
CH2 Br
CH2
H2O
HOTs
H+
from cyclohexanone
Try to apply the mechanisms to this synthesis.
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In each of these reactions, the enamine,
acting as a nucleophile, displaces the halide
ion from the alkyl halide in an SN2 process.
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N
O
H
CH3
CH2 C
CH2 CH3
H2O
CH3I
HOTs
H+
O
CH3 CH2 C
CH
CH3
CH3
a-Alkylation of a Ketone
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O
N
O
H
Br CH2 C
O
CH2 CH3
HOTs
CH3 CH2 O
O
C
H2O
+
CH2
H
O
a-Alkylation of a Ketone
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Enamine Reactions -- Summary
R
R
R
N
O
R
+N
R
R2NH
R
X
HOTs
H2O
H+
O
R
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The nucleophilic behavior of enamines has been used to
prepare deuterium-labelled ketones.
O
O
O
O
D3PO4
D2O
+
D
N
N
HOTs
0 °C
H
O
+
1-Morpholinocyclohexane
N
D
This reaction demonstrates that enamines are basic.
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In the previous examples, we have been using
nitrogen as the nucleophilic atom.
Reasoning by analogy and using the periodicity that
we associate with position in the Periodic Table, what
would we predict if phosphorus were the
nucleophile?
When phosphorus is the nucleophilic atom, the
behavior is similar to that of amines, but there are
important differences.
The chief application of phosphorus chemistry in
this type of reaction is in the Wittig reaction.
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The Wittig Reaction
R3
R1
C
O
+
(C6H5)3P C
R2
R4
R2
R3
C
C
R4
P(C6H5)3
+
a betaine
: O:
.. _
an ylide
R1
This is a type of condensation
reaction -- we use it to “dock”
two large structures together.
R1
C
R2
R3
+
C
O
P(C6H5)3
R4
This is another example of
addition-elimination.
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Ylide
• A compound or intermediate with both a
positive and a negative formal charge on
adjacent atoms.
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Resonance in Ylides
R
(C6H5)3P
C
+
(C6H5)3P
_ R
..
C
R
R
The ylide is nucleophilic, owing to the negative
charge character on carbon (structure on the
right).
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Typical Solvents
• Ylides are highly reactive with water,
alcohols, acids, carbonyl compounds, and
esters.
• So, the solvents must exclude these classes
of compounds.
• That limits us to hydrocarbons (and perhaps
ethers). Toluene and xylene are used
frequently.
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Example of a Wittig Reaction
C
O
+ (C6H5)3P=CH2
C
CH2
O
P(C 6H5)3
C
+
CH2
(C6H5)3P=O
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Mechanism (???)
:O:
.. _
:O :
C
R1
R2
slow
R3
R1 C
+
(C6H5)3P C
(C6H5)3P C
R4
_
.. +
: O : P(C6H5)3
R2
R3
=
R1 C
C
R3
R2 R4
R4
R1
O
P(C6H5)3
+
C
R2
R3
C
..
:O
R1 C
R4
P(C6H5)3
C
R3
R2 R4
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Preparation of the Ylide
R2
R1
CH X
R1
+
(C6H5)3P
_
X
+
(C6H5)3P CH R2
a phosphonium salt
Typical bases:
base
•NaOCH3
R1
•NaH
•LiC4H9
This reaction is not stereospecific.
(C6H5)3P
C
R2
+ "HX"
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Preparation of trans,trans-1,4-Diphenyl-1,3-butadiene
CH2 Cl
CH2 P(C6H5)3
+ (C6H5)3P:
Cl
H
H
C O
NaOCH 3
C C
H
CH
H
H
H
Major product
C
C
H
C
C
H
H
trans,trans
+
H
C
C
P(C6H5)3
C
C
Minor product
H
trans,cis
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Green Chemistry Application
CH2 Cl
CH2 P(C6H5)3
+ (C6H5)3P:
Cl
H
H
C O
K3PO4
no solvent!
C C
H
CH
H
H
H
C
C
H
C
C
H
H
trans,trans
+
P(C6H5)3
H
C
C
More
grinding!
C
C
H
trans,cis
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The Wittig Reaction: A Reminder
R3
R1
C
O
+
(C6H5)3P C
R2
R4
R2
R1
R3
C
C
R4
P(C6H5)3
+
a betaine
: O:
.. _
an ylide
R1
C
R2
R3
+
C
O
P(C6H5)3
R4
This is a type of condensation
reaction -- we use it to “dock”
two large structures together.
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