wwu-chemistry the amides wwu-chemistry carboxylic acids can be converted directly to the...
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The AmidesThe Amides
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•Carboxylic acids can be converted directly to the corresponding amides by the reaction of an acid with the appropriate amine.
•The amine used in this reaction can be ammonia, a primary amine, or a secondary amine, depending on the degree of nitrogen substitution expected.
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Preparation of AmidesPreparation of Amides(“C+ Method”)(“C+ Method”)
+ +R NH2O
HH
COH
O
RC
O
R NHR
While this is not the best method of preparing amides, it has the advantage of being simple. It also serves to introduce the amides as a class of compounds.
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Preparation of AmidesPreparation of Amides(“A Method”)(“A Method”)
R C Cl
O
+ N H
H
H
R C N
O
H
H
R C Cl
O
+ N R
H
H
R C N
O
H
R
R C Cl
O
+ N R
R
H
R C N
O
R
R
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• REMEMBER: The previous image neglects to account for the H-Cl produced in the reaction.
• In each of the previous reactions, two equivalents of amine are required -- one to act as nucleophile and the second to act as a base. The second equivalent of amine reacts with the H-Cl to form the corresponding amine hydrochloride.
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Peptides and ProteinsPeptides and Proteins
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Amino acids have the general structure:
C
R
HH2N
O OH
•The correct Fischer projection for naturally-occurring amino acids is shown here.
•The R group is variable.
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•As can be seen, the amino acids possess both functional groups required to form an amide. Each amino acid is both a carboxylic acid and an amine simultaneously.
•Therefore, it should be possible to link amino acids together through the formation of amides.
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Peptide bond(an amide linkage)
H2N CH C
R1
OH
O
H2N CH C
R2
OH
O
H2N CH C
R3
OH
O
H2N CH C
R1
O
HN CH C
R2
O
HN CH C
R3
OH
O
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PeptidesPeptides
• When amino acids are linked together by amide linkages (biochemists call these “peptide bonds”), the resulting molecule is called a peptide.
• A peptide is a polymer formed from individual amino acid units.
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PeptidesPeptides
• Peptides are named according to the number of amino acids that are linked:– dipeptide: two amino acids– tripeptide: three amino acids– tetrapeptide: four amino acids– etc.
• The term oligopeptide refers an amino acid polymer with a moderate number of repeating amino acid units.
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Peptides and ProteinsPeptides and Proteins
• When a peptide grows to a length of about 70 amino acid units (molecular weight = approximately 10,000), the molecule begins to coil onto itself and assume a particular secondary structure.
• At this point, we no longer refer to the molecule as a “peptide”; we begin to call it a protein.
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alphaalpha-Helix-Helix
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Chateau de ChambordChateau de Chambord
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Chambord – Double Staircase by Chambord – Double Staircase by Leonardo DaVinciLeonardo DaVinci
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Other Amide PolymersOther Amide Polymers
H2NCH2
CH2
CH2CH2
CH2CH2
NH2Cl
CCH2
CH2CH2
CH2C
Cl
O
O
H2NCH2
CH2
CH2CH2
CH2CH2
NHC
CH2CH2
CH2CH2
CCl
O
O
NH (CH2)6 NH C
O
(CH2)4 C NH
O
(CH2)6 NH C
O
(CH2)4 C
O
+
repeat
NYLON!!!
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Hydrolysis of AmidesHydrolysis of Amides
• The most important reaction of amides is hydrolysis.
• The products of amide hydrolysis are the carboxylic acid and the amine.
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Hydrolysis of AmidesHydrolysis of Amides
R C N
R
RO
O
HH+acid
heatR C OH
O
+
H N
R
R
This reaction can also be run under basic conditions.
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Hydrolysis of AmidesHydrolysis of Amides
• In living organisms, the hydrolysis of peptides is accomplished through catalysis by enzymes.
• The enzyme-catalyzed hydrolysis of peptides and proteins is what happens to protein when we eat it.
• The protein is hydrolyzed into individual amino acids, which are then used to build new proteins.
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ExampleExample
C
N
O
H
CH3
+ H2OH+
C
OH
O
+ CH3 NH3
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Reduction of AmidesReduction of Amides
R C N
R2
R1O
LiAlH4 H2OR CH2 N
R2
R1
•If either R1 or R2 is hydrogen in the amide, the corresponding R groups will be hydrogen in the amine product. Notice that the carbonyl group is reduced to a methylene group.
•NaBH4 cannot reduce amides
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ExamplesExamples
CH3 CH2 CH2 C NH2
O
CH3 CH2 CH2 CH2 NH2
CH3 CH2 CH2 C NH CH3
O
CH3 CH2 CH2 CH2 NH CH3
1) LiAlH4
2) H2O
1) LiAlH4
2) H2O
CH3 CH2 CH2 C N
O
CH3 CH2 CH2 CH2 N1) LiAlH4
2) H2OCH3
CH3
CH3
CH3
a primary amine
a secondary amine
a tertiary amine
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NitrilesNitriles
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Formation of NitrilesFormation of Nitriles
+_: : +R CH2 Cl C N Cl R CH2 C N
This is an SN2 reaction. It works best with primary alkyl halides.
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Hydrolysis of NitrilesHydrolysis of Nitriles
+ H2O + NH4+
R CH2 C OH
O
R CH2 C N
The reaction can be conducted The reaction can be conducted in either acidic or basic in either acidic or basic solution.solution.
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ExampleExample
CH2 C N CH2 C OH
O
+ H2OH2SO4
heat
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ExampleExample
CH3 CH2 CH2 CH2 C N
+
NaOH
H2O
CH3CH2OH heat
CH3 CH2 CH2 CH2 C O
O
Na
H2O
H+
CH3 CH2 CH2 CH2 C OH
O
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Base-Promoted Hydrolysis of a Nitrile (Part One)Base-Promoted Hydrolysis of a Nitrile (Part One)
1)
:..
..
_
slow :.. _
: ..
2)..
_:
..
:
+ H2O
:..
.. + OH_
3):
..
..
:....
C N:R
CR
NH
OH
CR
NH2
O
C NR
O H
CR
N
OH
Tautomerism
O H
CR
NH
OH
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Base-Promoted Hydrolysis of a Nitrile (Part Two)Base-Promoted Hydrolysis of a Nitrile (Part Two)
4)
5)
6)
: :..
:..
..
_
: :.. _
..
:..
: :.. _
..
:..
: :
:..
+ NH2:..
_
: :..
.. + NH2:
.._
: :..
.. :_
+ NH3
..
O
CR NH2
O H
R C NH2
O
O H
R C NH2
O
O H
O
CR
O H
O
CR OH
O
CR O
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Acid-catalyzed Hydrolysis of a Nitrile (Part One)Acid-catalyzed Hydrolysis of a Nitrile (Part One)
1)
2)
3)
+fast + +
+
: :
slow ..
:+
..
:+
..
: :+
3 resonance forms
C N:R H+
C NR H C NR H
C NR H
OHH
C NR H
O
H
H
C NR H
O
H
H
C NR
O
H
H
H
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Acid-catalyzed Hydrolysis of a Nitrile (Part Two)Acid-catalyzed Hydrolysis of a Nitrile (Part Two)
4)
5)
6)
:..
+
: ::
:..
+
:
:..
+
:
:
..
+
:
:..
+
..
:
:..
+
..
+ NH4
+
O
CR NH2
H
OH H
O
CR NH2
H
O H
H
O
CR NH2
H
O H
H
O
CR NH2
H
O H
HO
CR NH2
H
O H
H
O
CR NH3
H
O H
O
CR OH
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Reduction of NitrilesReduction of Nitriles
R C N1) LiAlH4
2) H2OR CH2 NH2
NaBH4 does not reduce nitriles.
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Also:Also:
R C N + 2 H2
Ni
140°R CH2 NH2
(pressure)
CAUTION!!!
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ExampleExample
CH2 C N CH2 CH2 NH2
+ 2 H2 (pressure)
Ni
140°C
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ExampleExample
CH3 CH2 CH2 C NLiAlH4
etherCH3 CH2 CH2 CH2 NH2
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Reduction of a Nitrile to an Reduction of a Nitrile to an AldehydeAldehyde
O
O
C N
DIBALH H2O
H+
O
O
C O
H
85% yield
-78°