P1252109247XYwGD

1
ADDITIONS OF AMINES TO CARBONYL GROUPS
Aldehydes and Ketones
2
MANTRA
(Memorization Jingle)
Reactions with CO
Primary amines yield imines
Secondary amines yield enamines
Tertiary amines do not react
we will come back to this again and again
AMINES
..
..
..
primary
secondary
tertiary
3
PRIMARY AMINES
IMINES
4
Addition-EliminationThe Formation of Imines
ketone or aldehyde
..
a carbinolamine intermediate
..

H
primary amine
Addition of the amine is followed by a loss of
water (elimination).
Imines are compounds with a CN bond
G is a primary alkyl group
5
Mechanism of Imine Formation
weak base addition - acid catalyzed
2
1
acid-catalyzed addition
proton exchanges
an imine
..


loss of water (elimination)
deprotonation
6
Formation of Simple Imines
overall result
remove
These reactions do not favor the formation of the
imine unless
- the product is insoluble (crystallizes or
precipitates) or
- water is removed to drive the equilibrium
7
Hydrolysis of Simple Imines
REVERSAL
In an excess of aqueous acid, simple imines
hydrolyze back to the aldehyde or ketone and the
amine from which they were orginally formed ..
H3O
Imines that are not soluble, however, are
difficult to hydrolyze.
8
CRYSTALLINE IMINES
HYDRAZONE AND OXIME DERIVATIVES
9
shown below
CRYSTALLINE IMINES
There are some special amines that yield
insoluble products (imines) that are easy to
crystallize ..
..
NH2OH
hydroxylamine
semicarbazine
..
..
R-NH-NH2
various hydrazine compounds
2,4-dinitrophenyl- hydrazine
10
Formation of Oximes
hydroxylamine
aldehyde or ketone
(usually crystallizes)
11
Formation of Hydrazones
a hydrazine
aldehyde or ketone
12
2,4-Dinitrophenylhydrazones
2,4-dinitrophenylhydrazine
2,4-dinitrophenylhydrazine
aldehyde or ketone
2,4-dinitrophenylhydrazone
(precipitates)
13
Formation of Semicarbazones
semicarbazine
semicarbazide
aldehyde or ketone
a semicarbazone
(usually crystallizes)
14
DERIVATIVES
CRYSTALLINE IMINES CAN BE USED AS DERIVATIVES
A derivative is a solid compound (formed from
the original compound) whose melting point can
help to identify the original compound.
What you will see in the tables of unknowns
semicarbazone
2,4-dinitrophenyl- hydrazone
bp mp
ketones
2-undecanone 231 12 122 63 4-chloroacetophenon
e 232 12 204 236 4-phenyl-2-butanone 235
- 142 127
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BIOLOGICAL REACTIONS
16
Pyridoxyl-5-phosphate (P-5-P)
Converts amino acids to a-ketoacids, and vice
versa.
Biologically important in transamination
reactions.
..
an amino acid

- H2O
pyridoxyl-5-phosphate
( P-5-P )
continued
formation of the imine

first imine
17
Enz
Enz-H
converts
tautomerism
H-Enz

Enz
a-ketoacid
first imine
H2O

new imine
Removing the amino group

hydrolysis of the new imine
pyridoxamine
18
TRANSFERRING THE AMINO GROUP
a different a-ketoacid
pyridoxamine
tautomerism
hydrolysis of the imine
These steps are the reverse of those on the
previous slides.
a different amino acid
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SUMMARY
TRANSAMINATION
( has NH2 )
( takes NH2 group )
a-Ketoacid-1
Amino Acid-1
pyridoxamine-NH2
pyridoxyl-5-phosphate
( has NH2 )
( has NH2 )
( gives NH2 back )
Amino Acid-2
a-Ketoacid-2

pyridoxyl- 5-phosphate
pyridoxamine-NH2
( has NH2 )
is a different a-ketoacid than
20
SECONDARY AMINES
ENAMINES
21
Formation of Enamines
b-hydrogen is required
secondary amine
..
benzene
carbinolamine
generally removed by azeotropic distillation
an enamine
22
COMPARISON
carbinolamine intermediates
PRIMARY AMINES
SECONDARY AMINES
hydrogen on the adjacent carbon
..
..
-H2O
-H2O
no hydrogen on nitrogen
hydrogen on the nitrogen
imine
enamine
When there is no hydrogen on nitrogen, one is
lost from carbon.
23
piperidine
SOME SECONDARY AMINES FREQUENTLY USED TO
FORM ENAMINES
pyrrolidine
Water must be removed
morpholine
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Enamine Formation
MECHANISM
continued .
25
Enamine Formation (cont)
MECHANISM

H2O
H
O-H
water must be removed to force the equilibrium
H3O

enamine
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Nucleophilic Character of Enamines
C
nucleophilic at carbon
X
SN2
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Reactions of Enamines as Nucleophiles
SN2
an iminium salt
hydrolysis
alkylation
28
ALKYLATION OF A KETONE
pyrrolidine
..
iminium salt
..

H
enamine
H3O
workup
remove water

29
Hydrolysis of Iminium Salts
MECHANISM
continued .
30
Hydrolysis of Iminium Salts
MECHANISM
31
SUBSTRATES FOR ENAMINE ALKYLATION
(and acylation)
alkylation
X Cl, Br, I
primary secondary allylic
acylation
enamine
acyl compounds may be used
32
CHLORIDES, BROMIDES AND IODIDES
In SN2 reactions you learned the rate sequence
R-I gt R-Br gt R-Cl and that iodides are better
substrates than chlorides.
This is true.
Based on this knowledge ..
many students assume that if acid chlorides are
good the acid bromides and iodides must be
better.
However acid bromides and iodides are
difficult to prepare, and the iodides are quite
unstable
.. you should use the chlorides.
They are easily prepared from the acid by
R-COOH SOCl2
33
Enamine Reactions -- Summary
secondary amine
alkyl or acyl halide
34
TERTIARY AMINES
DO NOT REACT
35
COMPARISON
PRIMARY AMINE
You need to lose two Hs, one to form the
intermediate, one to eliminate water.
loses H from N
..
H
SECONDARY AMINE
H is lost to form intermediate
loses H from C
TERTIARY AMINE

N-R
H is lost
R
..

unstable
The tertiary amine cant form the
carbinolamine intermediate because it lacks an H
on N.
reverses
N-R

R
R
no H to lose
36
FORMING RINGS
SOME GUIDELINES
37
DILUTE SOLUTION AND EXACT STOICHIOMETRY FAVOR
RING FORMATION
Problem 16-18 in in your textbook.
pH 5
Excess formaldehyde (gt21) and a more
concentrated solution favor the diimime.
Also remember that unstrained 5- and 6-rings
form easily, other sizes are difficult.
11 molar ratio and dilute solution favor the
ring formation
In dilute solution the molecule is more likely to
react internally with itself because encounters
with other molecules will be less frequent.
38
HINT ON THE MECHANISM ..
CN can undergo additions just like CO
Both are polar multiple bonds and both can
undergo acid- catalyzed nucleophilic addition.
protonation first

CRUCIAL STEP
forms ring
..
pH 5
mildly acidic
.. see if you can figure out the rest of the
mechanism for Problem 16-18 on your own.
39
WITTIG REACTION
40
Ylide
-
..

A compound or intermediate with both a positive
and a negative charge on adjacent atoms.
X
Y
BOND
Betaine or Zwitterion

A compound or intermediate with both a positive
and a negative charge, not on adjacent atoms,
but in different parts of the molecule.
Y
MOLECULE
-
X

41
Preparation of a Phosphorous Ylide
( WITTIG REAGENT )
precipitates
benzene

heat
-
..

O-CH3
..
..
strong base
ether
-

..
Triphenylphosphine
( Ph C6H5 )
an ylide
42
Resonance in Ylides
dp-pp BACKBONDING
..
Remember that Phosphorous is a Period III element
(d orbitals).
C
P
Backbonding to phosphorous reduces the formal
charges and stabilizes the negative charge on
carbon.
3d
2p
43
The Wittig Reaction
MECHANISM
-
..

ylide
betaine
INSOLUBLE
synthesis of an alkene
very thermodynamically stable molecule
oxaphosphetane
(UNSTABLE)
44
SYNTHESIS OF AN ALKENE - WITTIG REACTION
45
ANOTHER WITTIG ALKENE SYNTHESIS
46
Muscalure
Sex pheromone of the common house fly. Musca
Domestica
(Z)-9-tricosene
Wittig
The reaction can be made to give the cis alkene
(Z) by correct choice of solvent and
temperature, or by the separation of a mixture of
cis and trans.