SYNTHESIS OF

1
SYNTHESIS OF ACID CHLORIDES
2
ACID CHLORIDE SYNTHESIS
THIONYL CHLORIDE
RECALL THIONYL CHLORIDE
Chapter 12, Section 12.4, pp. 12-24 to 12-27.
alcohol
alkyl chloride
The -OH group of an acid reacts the same way.
acid
acid chloride
RLi CO2
Recall how to make an acid?
3
REDUCTIONS OF ACID CHLORIDES
4
LiAlH4 with Acid Chlorides
ACID CHLORIDES REACT TWICE
two hydrides react
Acid Chloride
LiAlH4
LiCl AlCl3
cleaves
5
COLLAPSE OF THE INTERMEDIATE
bond is highly polar - not strong
AlH3
..
-
FIRST ADDITION
O


Cl- is lost
C
R
H
Cl
SECOND ADDITION
reacts again
6
LiAlH4 Reduction of an Acid Chloride

-
..
..


tetrahedral intermediate collapses

-
leaving group
Li Cl-
workup
aldehyde
TWO HYDRIDES REACT
7
REDUCTIONS OF ESTERS
.. ESTERS ALSO REACT TWICE
8
LiAlH4 with Esters
ESTERS REACT TWICE
two hydrides react
Ester
LiAlH4

two alcohols
cleaves
9
LiAlH4 Reduction of an Ester

-
..


tetrahedral intermediate collapses

-
..


-
leaving group

RO
workup
aldehyde

TWO HYDRIDES REACT
two alcohols
R-OH
workup
10
ROSENMUND REDUCTION
Converts Acid Chlorides to Aldehydes
11
This reaction allows you to stop the reduction
at the aldehyde stage and not continue to the
alcohol (which would be the result with LiAlH4).
stops here
Acid Chloride Aldehyde
one stage of reduction
X
Alcohol
second step does not occur
This is an older method. Yields are not
always adequate, but it is sometimes a useful
method.
12
Rosenmund Reduction
Ordinary catalysts would continue and reduce the
aldehyde.
SOCl2
Rosenmund catalyst
13
DIBAL-H
A Newer Method ...
14
DIISOBUTYL ALUMINUM HYDRIDE
( DIBAL-H )
SYNTHESIS
two moles
( iBuOH )
DIBAL-H
isobutyl alcohol
less active than LiAlH4
gas
Remember
-
..
H- H-O-R H-H
O-R
..
strong base
takes the place of hydride
15
Reduction of Esters to Aldehydes
DIBALH is soluble in hydrocarbon solvents because
of the isobutyl groups ethers must be used for
LAH.
At 20o C, LiAlH4 will reduce the aldehyde,
DIBAL-H stops at the aldehyde at the
lower temperature.
toluene
- 70o C
esters
some carboxylic acids may be reduced
RCOOH
NOTE
Sometimes LiAlH4 will also stop at the aldehyde
if the temperature is below -60o C. DIBAL-H is
more consistent.
16
DIBAL-H ALSO REDUCES ACID CHLORIDES TO ALDEHYDES
DIBAL-H
-70o
ether
This method gives better yields than
the Rosenmund reduction.
stable at -70o
Apparently the tetrahedral intermediate does not
collapse at -70o C (expel the leaving group).
This doesnt happen until you warm the solution
and add aqueous acid which destroys the DIBAL-H.

-
does not react again
17
HYDROLYSIS OF THE INTERMEDIATE
Aqueous acid breaks the complex apart.
..

LiCl
18
DIBALH ALSO REDUCES ALDEHYDES AND KETONES
The main feature of DIBALH is that it reacts only
ONCE to form a stable tetrahedral complex.
Since the complex doesnt fall apart until
workup, a second reduction is avoided.
Aldehydes and ketones only need one hydride to be
fully reduced ... therefore, DIBAL-H
reduces aldehydes and ketones.
With esters, acid chlorides and acids, more than
one hydride is required. Since DIBAL-H reacts
only once, they are not fully reduced, stopping
at the aldehyde.
19
ORGANOMETALLIC COMPOUNDS WITH ESTERS AND ACID
CHLORIDES
20
RLi with Esters and Acid Chlorides
( also RMgX )
REACT TWICE
two RLi react
Acid Chloride
RLi
ether
Ester
RLi

ether
two alcohols
cleaves
21
RMgX with Esters and Acid Chlorides
( also R-Li )
DECOMPOSES
..


Tetrahedral complex not stable - weak O-Mg bond.
..



ketone
R-OH
Reacts Twice !
22
COLLAPSE OF THE INTERMEDIATE
bond is highly polar - not strong
DECOMPOSES REACTS AGAIN
..
-
The tetrahedral intermediate collapses easily,
because the bond to Li is not strong.


The leaving group RO- is expelled.
The complexes formed from Grignard reagents react
in the same way. The bond to Mg is not strong.
breaks down and yields a ketone which reacts again
23
ORGANOCADMIUM REAGENTS
24
Ketone Synthesis Organocadmium Reagents
organocadmium compound R2Cd
Less active than RLi or RMgX
reacts once
25
ORGANOCADMIUM REAGENTS DO NOT REACT TWICE
WITH ESTERS
..
Cd-R
reacts once

workup
H3O
-
O-CH3
..
ketone
HO-CH3

Acid chlorides also react this way.
26
STABLE TETRAHEDRAL COMPLEX
The bond has more covalent character than a bond
to Li or Mg - it is stronger.
-
Apparently the tetrahedral intermediate does not
collapse (expel the leaving group) during the
reaction. It only breaks down on hydrolysis, and
then the leaving group is expelled.
The complex is stable and does not break
down and react again.
27
HYDROLYSIS OF THE INTERMEDIATE
Aqueous acid breaks the complex apart.
..
H
Cd
R

O
H3O
O
C
R
C
R
OR
OR
R
R
O
C
R
LiCl
R
Ketone is isolated.
28
LITHIUM DIALKYL CUPRATES
29
Ketone Synthesis Lithium Dialkylcuprates
ketone
Less active than RLi or RMgX
30
SUMMARY
31
MANTRA

• Aldehydes react with one mole of reducing
• agent to give a Primary Alcohol
• Ketones react with one mole of reducing
• agent to give a Secondary Alcohol
• Acid Chlorides react with two moles of reducing
• agent to give a Primary Alcohol
• Esters react with two moles of reducing
• agent to give a Primary Alcohol
• a second alcohol

32
BIOLOGICAL REDUCING REAGENTS
33
Nicotinamide Adenine Dinucleotide
NADH
adenine
..
..
..

..

..
nicotinamide
diphosphate
biological
COENZYME
ribose
ribose
works with an enzyme
34
Reduction of Acetaldehyde in
Fermentation
hydride transfer
ethanol
acetaldehyde
..
REVERSIBLE
This coenzyme can also oxidize depending on
the associated enzyme.
35
Reduction of Pyruvic Acid in Muscle
Tissue
formed when muscles contract
lactic acid
pyruvic acid
..