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SYNTHESIS OFSYNTHESIS OFACID CHLORIDESACID CHLORIDES
ACID CHLORIDE SYNTHESISACID CHLORIDE SYNTHESIS
R-OH + SOCl2 R-Cl + SO2 + HCl
benzene
THIONYL CHLORIDE
R C
O
OHR C
O
Cl+ SOCl2 + SO2 + HCl
benzene
The -OH group of an acid reacts the same way.
Chapter 12, Section 12.4, pp. 12-24 to 12-27.
RLi + CO2
RECALL THIONYL CHLORIDE:
Recall how tomake an acid?
alcohol alkyl chloride
acid acidchloride
REDUCTIONS OF REDUCTIONS OF ACID CHLORIDESACID CHLORIDES
Acid Chloride
LiAlH4 + LiCl + AlCl3
LiAlHLiAlH4 4 with Acid Chlorideswith Acid Chlorides
two hydrides reactACID CHLORIDES REACT TWICE
cleaves
CR
O
HCl
AlH3..: :
-
bond is highly polar- not strong
The tetrahedral intermediatecollapses easily, because thebond to Al is not strong.
COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE
R C
O
Cl
AlH3
H
R C
O
H
reacts again
Cl- is lost
FIRSTADDITION
SECONDADDITION
CR
O
ClCR
O
ClH
CR
O
H
CR
O
HH
CR
OH
HH
H3O+
LiAlH4
LiAlH4
AlH3
AlH3
Li
Li
..: :
workupreaction doesn’t stop here
aldehyde
TWO HYDRIDES REACT
-
..
+
+
tetrahedralintermediatecollapses
LiAlHLiAlH4 4 Reduction of an Acid ChlorideReduction of an Acid Chloride
+ Li+ Cl-leavinggroup
-
REDUCTIONS OF ESTERS REDUCTIONS OF ESTERS
….. ESTERS ALSO REACT TWICE
Ester
LiAlH4+
two alcoholscleaves
LiAlHLiAlH4 4 with Esterswith Esters
two hydrides reactESTERS REACT TWICE
LiAlHLiAlH4 4 Reduction of an EsterReduction of an Ester
TWO HYDRIDES REACT
+
+-
-
..
..
: :
+ R’O-: :
workupreaction doesn’t stop here
R’-OH
twoalcohols
aldehyde
leavinggroup
workup
+
CR
O
OR'CR
O
OR'H
CR
O
H
CR
O
HH
CR
OH
HH
H3O+
LiAlH4
LiAlH4
AlH3
AlH3
Li
Li
tetrahedralintermediatecollapses
ROSENMUND REDUCTIONROSENMUND REDUCTION
Converts Acid Chlorides to Aldehydes
Acid Chloride Aldehyde
Alcohol
X
one stage ofreduction
This reaction allows you to stop the reduction atthe aldehyde stage and not continue to the alcohol(which would be the result with LiAlH4).
stops here
This is an older method. Yields are not alwaysadequate, but it is sometimes a useful method.
second stepdoes not occur
R C Cl
O
R C H
O
+ H2
Pd/BaSO4
sulfurquinoline
Rosenmund ReductionRosenmund Reduction
Rosenmund catalyst
Ordinary catalystswould continue andreduce the aldehyde.
R C OH
O
SOCl2
.H
H
H H.
. .R C Cl
O
R C
O
H
Cl
H
DIBAL-HDIBAL-H
A Newer Method …...
DIISOBUTYL ALUMINUM HYDRIDEDIISOBUTYL ALUMINUM HYDRIDE( DIBAL-H )( DIBAL-H )
LiAlH4 + 2 CH CH2
CH3
CH3
OH Al OiBu
H
OiBu
H + 2 H2
( iBuOH )isobutyl alcohol DIBAL-H
less active than LiAlH4
Remember:
H:- + H-O-R H-H + :O-R....
-
strongbase
two moles
takes the placeof hydride
gas
SYNTHESIS
R C
O
O
R'
R C
H
O
+
H2O
HCl
R' OH
DIBAL-H
Reduction of Esters to AldehydesReduction of Esters to Aldehydes
At 20o C,LiAlH4 willreduce thealdehyde, DIBAL-Hstops at thealdehyde atthe lowertemperature.
esters
Sometimes LiAlH4 will also stop at the aldehyde if the temperature is below -60o C. DIBAL-H is more consistent.
- 70o C
toluene
DIBALH is soluble in hydrocarbon solvents because of the isobutyl groups;ethers must be used for LAH.
RCOOHsome carboxylicacids may be reduced
NOTE
R C Cl
O
R C H
O
+ H2
Pd/BaSO4
sulfurquinoline
DIBAL-H ALSO REDUCES DIBAL-H ALSO REDUCES ACID CHLORIDES TO ALDEHYDESACID CHLORIDES TO ALDEHYDES
DIBAL-H
This method gives better yields than theRosenmund reduction.
Apparently the tetrahedralintermediate does not collapse at -70o C (expel the leaving group). This doesn’t happenuntil you warm the solution and add aqueous acid whichdestroys the DIBAL-H.
CR
O
ClH
Al
H
Li+
-
does notreact again
-70o ether
stable at -70o
CR
O
ClH
Al
H
Li+
- H3O+
CR
O
ClH
H
CR
O
H
HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE
:..
Aqueous acid breaks thecomplex apart.
+ LiCl
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 doesn’t 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 onehydride is required. Since DIBAL-H reacts only once,they are not fully reduced, stopping at the aldehyde.
ORGANOMETALLIC COMPOUNDSORGANOMETALLIC COMPOUNDS WITH ESTERS AND ACID CHLORIDESWITH ESTERS AND ACID CHLORIDES
R CCl
O
R C
O
R'
R'
H
R CO
O
R"R C
O
R'
R'
H
R" O H
R’Li
ether
R’Li
ether+
Acid Chloride
Ester
RLi RLi with Esters and Acid Chlorideswith Esters and Acid Chlorides
two alcoholscleaves
( also RMgX )REACT TWICEtwo RLi react
RMgX with Esters and Acid Chlorides RMgX with Esters and Acid Chlorides
CR
O
OR'CR
O
OR'R"
R"MgX
CR
O
R"
CR
O
R"R"
R"MgX
MgX
MgX
CR
OH
R"R"
H3O+
Reacts Twice !
ketone
: :
: :
..
..
doesn’t stop here
+ R’O-
R’O-
R’-OH
( also R-Li )
Tetrahedralcomplex notstable -weak O-Mgbond.
DECOMPOSES
CR
O
ORR'
Li+
..: :
-
bond is highly polar- not strong
The tetrahedral intermediatecollapses easily, because thebond to Li+ is not strong.
The leaving group RO- isexpelled.
COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE
DECOMPOSES & REACTS AGAIN
The complexes formed fromGrignard reagents react inthe same way. The bond toMg is not strong.
breaks down andyields a ketone whichreacts again
ORGANOCADMIUM REAGENTS
2 + CdCl2 + 2 MgXCl
2
R MgX R Cd R
R C Cl
O
R C R
O
+ R Cd R 2 + CdCl2
Ketone Synthesis Ketone Synthesis Organocadmium ReagentsOrganocadmium Reagents
Less active than RLi or RMgX
organocadmiumcompound R2Cd
reacts once
C O
O
CH3 C O
O
CH3
CH3
CH3 Cd CH3
C CH3
O
:..reacts
once
:O-CH3..-
STOPS HERE
ORGANOCADMIUM REAGENTSORGANOCADMIUM REAGENTSDO NOT REACT TWICE WITH ESTERSDO NOT REACT TWICE WITH ESTERS
ketone
H3O+
Cd-R
workup
HO-CH3+
Acid chlorides also react this way.
Apparently the tetrahedralintermediate does not collapse (expel the leaving group) during the reaction. It onlybreaks down on hydrolysis, and then the leaving group is expelled.
Cd OR
CR
O
ORR'
-
The bond has more covalentcharacter than a bond to Lior Mg - it is stronger.
STABLE TETRAHEDRAL COMPLEXSTABLE TETRAHEDRAL COMPLEX
The complex is stable and does not break downand react again.
CR
O
ORR
CdH3O+
CR
O
ORR
H
CR
O
R
HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE
:..
Aqueous acid breaks thecomplex apart.
+ LiCl
R
Ketone is isolated.
LITHIUM DIALKYL CUPRATES
R C Cl
O
R C R
O
+ R2CuLi +
+ LiCl
0°
etherR Cu
Ketone Synthesis Ketone Synthesis Lithium DialkylcupratesLithium Dialkylcuprates
Less active than RLi or RMgX
ketone
SUMMARYSUMMARY
MANTRAMANTRA• Aldehydes react with one mole of reducing
agent to give a Primary Alcohol
• Ketones react with one mole of reducingagent to give a Secondary Alcohol
• Acid Chlorides react with two moles of reducingagent to give a Primary Alcohol
• Esters react with two moles of reducingagent to give a Primary Alcohol
+ a second alcohol
BIOLOGICALBIOLOGICALREDUCING REAGENTSREDUCING REAGENTS
N N
N N
NH2
O
H
OH
H
OH
HH
CH2 O P O
O
O
P O
O
O
CH2 O
H
OH
H
OH
HH
N
HHC NH2
O
_ _
Nicotinamide Adenine DinucleotideNicotinamide Adenine DinucleotideNADHNADH
adenine
ribose ribose
nicotinamide
diphosphate
..
..
..
..
..
:
:
COENZYMEbiological
works withan enzyme
N
C NH2
OH H
R
N
C NH2
O
R
H
H+CH3 C H
O
CH3 C H
OH
H
+
NADH NAD+
Reduction of Acetaldehyde Reduction of Acetaldehyde in Fermentationin Fermentation
..
This “coenzyme”can also oxidizedepending on theassociated enzyme.
REVERSIBLE
hydridetransfer
REDOX
ethanolacetaldehyde
N
C NH2
OH H
R
N
C NH2
O
R
H
H+
CH3 C
O
C OH
O
+
NADH NAD+
C OH
O
CH3 C
OH
H
Reduction of Pyruvic Acid Reduction of Pyruvic Acid in Muscle Tissuein Muscle Tissue
..
lactic acid
formed whenmuscles contract
pyruvic acid