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Acid ChloridesAcid ChloridesPreparation and ReactionsPreparation and Reactions
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Preparation of an Acid ChloridePreparation of an Acid Chloride(“A” Method)(“A” Method)
+ SOCl2R C OH
O
R C Cl
O
+
+
O S O
H Clthionyl chloride
heat
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ExampleExample
C OH
O
C Cl
O
+ SOCl2 + SO2 (gas) + HCl (gas)
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Example #2Example #2
CH3
CH2CH2
CH2CH2
COH
O
CH3
CH2CH2
CH2CH2
CCl
O
SOCl2
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Preparation of Acid ChloridesPreparation of Acid Chlorides(“C+” Method)(“C+” Method)
R C OH
O
R C Cl
O
+ PCl5
heat
+ POCl3 + HCl
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Preparation of an Acid ChloridePreparation of an Acid Chloride(“C-” Method)(“C-” Method)
R C OH
O
+ PCl3
heatR C Cl
O
+ H3PO3
The single advantage to this method is that it does not produce HCl as a product. Use this method when your molecule can’t stand HCl.
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Hydrolysis of an Acid ChlorideHydrolysis of an Acid Chloride
+ H2O +
O
CR Cl
O
CR OH H Cl
•Notice the direction of the equilibrium arrow.
•Explain why you can’t make an acid chloride by reacting a carboxylic acid with hydrogen chloride.
•This explains why acid chlorides are very moisture-sensitive and why it is difficult to store them.
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Preparation of an EsterPreparation of an Ester(“A” Method)(“A” Method)
+
+
O
CR Cl
O
CR O R
H Cl
R OH
Because the ester is so much more stable than the acid chloride, this reaction proceeds at a rapid rate and in high yield.
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ExampleExample
C Cl
O
+ CH3 OH
C O
O
CH3
+ H Cl
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Preparation of an AmidePreparation of an Amide(“A” Method)(“A” Method)
+
+two equivalents " "
O
CR Cl
O
CR N
R
R
H Cl
H N
R
R
•Two equivalents of amine are required.
•The first equivalent acts as nucleophile to form the amide
•The second equivalent acts as a base and reacts with the HCl that is formed.
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Example #1Example #1(Ammonia is the Nucleophile)(Ammonia is the Nucleophile)
C Cl
O
+ 2 NH3
C NH2
O
+ NH4+ Cl-
Because the amide is so much more stable than the acid chloride, this reaction proceeds rapidly and in high yield.
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Example #2Example #2(Primary Amine is the Nucleophile)(Primary Amine is the Nucleophile)
CH3 CH2 C Cl
O
+ 2 CH3 NH2
CH2 C NH
O
+ CH3 NH3+ Cl-
CH3CH3
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Example #3Example #3(Secondary Amine is the Nucleophile)(Secondary Amine is the Nucleophile)
H
C
O
Cl
+H
NCH2 CH2
CH3 CH32
H
C
O
NCH2
CH3
+
NH2CH2 CH2
CH3 CH3 Cl
CH2
CH3
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Preparation of an Acid AnhydridePreparation of an Acid Anhydride
+
+
O
CR Cl
O
CR O C R
O
H Cl
O
CR OH
•This will also work with an acid chloride and a carboxylate anion.
•Because the acid chloride is less stable than the acid anhydride, this reaction proceeds rapidly and in good yield.
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ExampleExample
CH3 C Cl
O
CH3 C O
O
+
CH3 C O C CH3
O O
+
Cl
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Rosenmund ReductionRosenmund Reduction
+ H2
Pd/BaSO4
sulfurquinoline
R C Cl
O
R C H
O
Recall this from Chapter 17, Section 17.17
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ExampleExample
CH3 CH2 C Cl
O
CH3 CH2 C H
O H2 Pd
sulfurboiling quinoline
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Also...Also...
C Cl
O
C H
O
LiAlH[O-tert-Butyl]3
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By contrast, lithium aluminum hydride reduces acid chlorides all the way to alchols.
R C Cl
O
LiAlH4R CH2 OH
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ExampleExample
CH3
CH2CH2
CCl
O
1) LiAlH4
2) H2O CH3
CH2CH2
C
O
HH
H
Butanoyl chloride 1-Butanol
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•Acid chlorides react with enamines to yield 1,3-dicarbonyl compounds
•In this reaction, the first step involves formation of the enamine
•see Chapter 16, Section 16.13
•The enamine, being highly nucleophilic, reacts with the acid chloride in a nucleophilic acyl substitution process.
•Hydrolysis of the resulting iminium salt yields the final product.
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Acylation of an EnamineAcylation of an Enamine
1)
+
+
2) +
+ H2O
+
+
R C Cl
O
RCH C R
N
CH C R
N
C
R
R
O
CH C R
N
C
R
R
O
R C
O
CH C
R
R
O
N
HH
+
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Acylation of an Enamine -- Acylation of an Enamine -- Mechanism (Part 1)Mechanism (Part 1)
: :
:
slow
+ +
:..
:_
: :
NC
R
CR
R
C
O
R Cl
C C
R
R R
N NC
R
CR
R
C
O
R
O
CR Cl
+ Cl
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Acylation of an Enamine -- Acylation of an Enamine -- Mechanism -- Part 2Mechanism -- Part 2
+
: : : :
: :
:+
..NCCCR
O R
R
R
O
H
H
NCCCR
O R
R
R
OH H
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Acylation of an Enamine -- Acylation of an Enamine -- Mechanism -- Part 3Mechanism -- Part 3
: :
:+
..: :
:..
+
: :
: :
+
+
..
CCCR
O R
R
R
O
NCCCR
O R
R
R
O
H
H
NCCCR
O R
R
R
O H
H
NH
H+
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+HOTs
+ H2O..
:
:
+
+
+
+ H2O
+
+
..
R C C R
H
R
O
N
H
R C
O
C C
R
RR
N
C C
R
R R
N
C C
R
R R
N
R C Cl
O
R C
O
C C
R
RR
NR C
O
C C R
OR
RN
H
H+
Overall SequenceOverall Sequence
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ExampleExample
O N
H
HOTs
N
CH3 C Cl
O
N
CCH3
O
H2OO
CCH3
O
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Example #2Example #2
O
CCH3 CH3
N
O
H
HOTsN
O
CCH3 CH2
CH3 CH C Cl
O
CH3
N
O
CCH3 CH2
CCH
O
CH3
CH3
H2O
O
CCH3 CH2
CCH
O
CH3
CH3
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Also review...Also review...
• Conversion of acid chlorides to ketones– review material in Chapter 17, Section 17.18
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Using Dialkylcadmium ReagentsUsing Dialkylcadmium Reagents
CH3 C Cl
O
+
H3C Cd CH3
CH3 C CH3
O
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Using Lithium DialkylcupratesUsing Lithium Dialkylcuprates
C
Cl
O
CH3 CH2 CH2 CH2
C
CH2
O
CH2
CH2 CH3
+
2CuLi
0 °C
ether