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Synthesis of Alcohols
 Reduction of Aldehydes and Ketones
 Common reducing agents and conditions:
 NaBH4 (sodium borohydride)
 alcohol, ether, or H2O as solvent
 (1) LiAlH4 (lithium aluminum hydride =LAH)
(2) H3O+
 Raney Ni
 finely divided H2-bearing form of Ni
 also reduces C=C to alkane
Synthesis of Alcohols
 Reducing agent:
 a substance that causes another to be
reduced.
 LAH
 NaBH4
 H2
 Mechanism of Hydride Reduction:
O
Synthesis
of Alcohols OH
R C R'
R C R'
 Reduction of Aldehydes and
H Ketones
O
R C H
O
R C R'
LiAlH4
or
NaBH4
LiAlH4
or
NaBH4
OH
R C H
H
OH
R C R'
H
 1o (from aldehyde) or 2o (from ketone) alcohol
O
OH
formed
as product
R C H
R C H
Synthesis of Alcohols
 Reduction of Acids and Esters using LAH
O
RCR'
O
RCOH
O
RCOR'
(1) LAH
+
(2) H3O
(1) LAH
+
(2) H3O
OH
RCR'
H
RCH2OH
Notice:
2 step process
(1) LAH
+
(2) H3O
RCH2OH
 LAH can reduce not only aldehydes and
ketones but also carboxylic acids and
esters.
Synthesis
O of
O (1)Alcohols
Hg(OAc) (aq)
2
OH
(1) LAH
CH3CHCH2CH2O
CH3CCH2COCH
CH3
+
2
(2)
NaBH
 Reduction of Acids and
Esters
4
(2) H3Ousing LAH
CH3
 Examples:
O
CO2H
CH2OH
(1) LAH
Raney Ni (2) H O+
3
O
O
CH3CCH2COCH2CH3
OH
(1) LAH
+
(2) H3O
CH3CHCH2CH2OH
CH3
(2) NaBH4
Synthesis of Alcohols
O
 NaBH4 is a weaker reducing agent than LAH.
Raney Ni
 NaBH4 reduces only aldehydes and ketones.
O
RCR'
O
(1) LAH
O
+
(2) H3O
CH3CCH2COCH2CH3
CO2CH3
OH
RCR'
NaBH
H
4
ether
NaBH4
ether
OH
O
CH3CHCH2COCH2CH3
No reaction
O
Synthesis of Alcohols OH
R C R'
R C R'
Example: Predict the majorHproduct formed in
each of the following reactions:
O
R C H
O
O
O 2C H
CH3CH
R C R'
NaBH4
CH3CH2OH R
C H
H
(1) LAH
OH
+
(2) H3O
R C R'
H
(1) BH3-THF
-
OCH3
OH
(2) H2O2, OH
Synthesis of Alcohols
Example: Predict the major product formed in
(1) Hg(OAc)reactions:
(aq)
each of the following
2
CH3
CH3
(2) NaBH4
(1) Hg(OAc)2 (aq)
(2) NaBH4
O
Raney Ni
O
NaBH4
ether
Synthesis of Alcohols
Example: Predict the product.
COCO
CHCH
2
3
2
3
(1) (1)
LAH
LAH
+
+
(2) (2)
H3O
HO
3
O
O
(1) LAH
+
(2) H3O
Synthesis of Alcohols
 Nucleophilic Addition of Organometallic
Reagents
 Organometallic reagent:
 An organic compound that contains a
covalent bond between a carbon atom and a
metal atom
 Carbon is more electronegative than most
metals
 C-M bond is polarized
 Carbon is nucleophilic
-

C M
+

R Li
Synthesis of Alcohols
 Two common organometallic reagents for
O
producing alcohols:
NaBH4
 Grignard Reagent
 Organomagnesium halide
+


R Mg X
 Organolithium compounds
+

R

Li
ether
Synthesis of Alcohols
 Preparation of Grignard Reagents
R X + Mg (s)
ether
R Mg X
 Alkyl halide:
 1o, 2o, or 3o
 Vinyl, R
allyl,Liaryl halides
 Ether must be used as a solvent to stabilize
the Grignard reagent
O
NaBH4
Synthesis of Alcohols
CH2CH2Br + Mg (s)
CH3CH2CH2CH2MgBr
Examples:
ether
CH3CH2CH2CH2Br + Mg (s)
Cl
Cl
CH3CH2CH2CH2MgBr
ether
+ Mg (s)
Mg (s)/ ether
MgCl
MgCl
Synthesis of Alcohols
Cl
+ Li (s)
Li
 Preparation of Organolithiums
solvent
R X + 2 Li (s)
 Alkyl halide:
 1o, 2o, 3o halide
 Vinyl, allyl, aryl
 Solvent:
 ether, alkanes
R Li + LiX
H2CH2Br + Mg (s)
CH3CH2CH2CH2MgB
Synthesis of Alcohols
Examples:
Cl
ether
+ 2 Li (s)
Phenyl lithium
solvent
R X + 2 Li (s)
CH3CHCH3 + 2 Li
Cl
Li
R Li + LiX
hexane
CH3CHCH3
Li
Synthesis of Alcohols
 Grignard reagents and organolithiums are
strong nucleophiles
 Behave
like
R
CH CHCH
+ 2 Li
CH CHCH + 2 Li
Cl
 Attack electrophilic
carbons
Cl
3
3
3
3
hexane
hexane
 Aldehydes, ketones
 Esters, acid chlorides
 Epoxides
-
O 
O
C
C
+

CH3C
CH3C
L
L
-

O
+

Synthesis of Alcohols
 Attack of R
on an aldehyde or ketone
produces an alkoxide ion which can be
protonated to form an alcohol.
-
Synthesis of Alcohols
 Addition of RMgX or RLi to Formaldehyde:
 forms primary alcohol
H
Cl
(1) Mg(s)/ether
(2) H-C-H
O
+
(3) H3O
C OH
H
Synthesis of Alcohols
 Addition of RMgX or RLi to Aldehydes
 forms secondary alcohol
Synthesis of Alcohols
H
 Addition of RMgX
or RLi to Aldehydes:
(1) Mg(s)/ether
Cl
Cl
Br
(2) CH3CH
(1) Mg(s)/ether
O
+
(2)
CH
(3) H3O3CH
O
+
(3) H3O
C OH
H
CH3
C OH
CH3
(1) Li (s)/ether
CH3
(2) CH3CH
C OH
H
O
+
(3) H3O
Synthesis of Alcohols
 Addition of RMgX or RLi to Ketones
 forms tertiary alcohol
Cl
(1) Mg(s)/ether
(2) CH3CCH3
O
+
(3) H3O
CH3
C OH
CH3
Synthesis of Alcohols
 Addition of RMgX or RLi to Esters
 forms tertiary alcohol with two identical R
groups
 identical R groups come from the
organometallic reagent
Synthesis of Alcohols
 The addition of RMgX or RLi to an ester
occurs in two steps:
 R- displaces an alkoxide group, forming a
ketone
 A second R- attacks the carbonyl, forming
the alcohol (after protonation)
Synthesis of Alcohols
 Addition of RMgX or RLi to Acid Chlorides
 forms tertiary alcohol with two identical R
groups
 identical R groups come from the
organometallic reagent
Synthesis of Alcohols
 The addition of RMgX or RLi to an acid
chloride occurs in two steps:
 R- displaces the chloride ion, forming a
ketone
 A second R- attacks the carbonyl, forming
the alcohol (after protonation)
Synthesis of Alcohols
Examples:
Cl
Cl
(1) Mg(s)/ether
(1)CH
Mg(s)/ether
(2)
CO2CH3
3
CH3
CCHOH
3
C OH
(2) CH3+CO2CH3
(3) H3O
+
(3) H3O
(1) Li (s)/ether
Br
Br
(1)CH
Li3C-Cl
(s)/ether
(2)
(2) CHO
C-Cl
3
+
(3) H3O O
+
CH3
CCH3
C
OH
OH
Synthesis of Alcohols
 Addition of RMgX or RLi to Epoxides
 forms primary alcohol with two more carbons
than the original alkyl halide
Cl
(1) Mg(s)/ether
(2)
O
+
(3) H3O
CH2CH2OH
Synthesis of Alcohols
Example: Predict the product of each reaction.
(1) Mg (s)/ether
CH3CH2CHCH3
Cl
(2)
CO2CH3
+
(3) H3O
(1) Mg (s)/ether
CH3CH2CHCH3
Cl
(2)
O
O
CH3CCH2CH2CCH3
+
(3) H3O
Synthesis of Alcohols
 Limitations/Side (1)
Reactions
of RMgX and RLi
Mg (s)/ether
RMgX
and RLi are strong nucleophiles
and
CH CH
CHCH
O
3
O
strong bases (2)
CH3CCH
CH2CCH3
2
Cl with acidic
 React
protons
+
(3) H3with
O
 Incompatible
water, ROH, RSH,
R-NH-R’, and RCO2H
2
3
MgBr + H2O
H + BrMgOH
Synthesis of Alcohols
 Limitations/Side Reactions of RMgX and RLi
 RMgX and RLi will react with any multiple
bond that contains a strongly electronegative
element.
 RMgX and RLi will react with C=O, S=O,
C=N, N=O and C
N present in the
solvent, organometallic reagent, or
substrate