Synthesis of Alcohols Reduction of Aldehydes and Ketones Common reducing agents and conditions: NaBH...
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Synthesis of Alcohols Reduction of Aldehydes and Ketones Common reducing agents and conditions: NaBH 4 (sodium borohydride) alcohol, ether, or H 2 O as solvent (1) LiAlH 4 (lithium aluminum hydride =LAH) (2) H 3 O + Raney Ni finely divided H 2 -bearing form of Ni also reduces C=C to alkane
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Transcript of Synthesis of Alcohols Reduction of Aldehydes and Ketones Common reducing agents and conditions: NaBH...
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 Nifinely divided H2-bearing form of Nialso reduces C=C to alkane
Synthesis of Alcohols
Reducing agent: a substance that causes another to be
reduced.LAHNaBH4
H2
Mechanism of Hydride Reduction:
Synthesis of Alcohols
Reduction of Aldehydes and Ketones
1o (from aldehyde) or 2o (from ketone) alcohol formed as product
R R
R R
C
O
H C
OH
H
H
C
O
R' C
OH
R'
H
R R
R R
C
O
H C
OH
H
H
C
O
R' C
OH
R'
H
LiAlH4
orNaBH4
LiAlH4
orNaBH4
RCOH(1) LAH
(2) H3O
+ RCH2OH
O
RCOR'(1) LAH
(2) H3O
+ RCH2OH
O
RCR'(1) LAH
(2) H3O
+ RCR'
O OH
H
Reduction of Acids and Esters using LAH
LAH can reduce not only aldehydes and ketones but also carboxylic acids and esters.
Synthesis of Alcohols
Notice: 2 step process
Synthesis of Alcohols
Reduction of Acids and Esters using LAH Examples:
(1) Hg(OAc)2 (aq)
(2) NaBH4
Raney Ni
CH3CCH
2COCH
2CH
3CH
3CHCH
2CH
2OH
(1) LAH
(2) H3O+
CH3
O
O O OH
(1) Hg(OAc)2 (aq)
(2) NaBH4
Raney Ni
CH3CCH
2COCH
2CH
3CH
3CHCH
2CH
2OH
(1) LAH
(2) H3O+
(1) LAH
(2) H3O+
CH3
O
O O OH
CO2H CH2OH
Synthesis of Alcohols
NaBH4 is a weaker reducing agent than LAH. NaBH4 reduces only aldehydes and
ketones.
(1) Hg(OAc)2 (aq)
(2) NaBH4
Raney Ni
CH3CCH
2COCH
2CH
3
NaBH4
etherCH
3CHCH
2COCH
2CH
3
CH3
O
O O OH ORCR'(1) LAH
(2) H3O
+ RCR'
NaBH4
ether
O OH
H
CO2CH
3No reaction
Synthesis of Alcohols
Example: Predict the major product formed in each of the following reactions:
R R
R R
NaBH4
CH3CH
2OH
CH3CH
2C
(1) LAH
(2) H3O
+
C
O
H C
OH
H
H
C
O
R' C
OH
R'
H
O
O
H
R R
R R
NaBH4
CH3CH
2OH
C
O
H C
OH
H
H
C
O
R' C
OH
R'
H
O
(1) BH3-THF
(2) H2O
2, OH
-
CH3
Synthesis of Alcohols
Example: Predict the major product formed in each of the following reactions:
(1) Hg(OAc)2 (aq)
(2) NaBH4
CH3
(1) Hg(OAc)2 (aq)
(2) NaBH4
Raney Ni
CH3
O
NaBH4
ether
O
Synthesis of Alcohols
Example: Predict the product.
(1) LAH
(2) H3O
+
CO2CH
3
(1) LAH
(2) H3O
+
(1) LAH
(2) H3O
+
CO2CH
3
O
O
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
NaBH4
ether
C- +
O
M
Synthesis of Alcohols
Two common organometallic reagents for producing alcohols:
Grignard ReagentOrganomagnesium halide
Organolithium compounds
NaBH4
ether
R- +
R
O
Li
Li
NaBH4
ether
R
- +R
O
Li
Mg X
NaBH4
ether
R
- +R
Rether
O
Li
Mg X
X + Mg (s) R Mg X
Synthesis of Alcohols
Preparation of Grignard Reagents
Alkyl halide:1o, 2o, or 3o
Vinyl, allyl, aryl halides
Ether must be used as a solvent to stabilize the Grignard reagent
Synthesis of Alcohols
Examples:
CH3CH
2CH
2CH
2Br + Mg (s) CH
3CH
2CH
2CH
2MgBr
ether
CH3CH
2CH
2CH
2Br + Mg (s) CH
3CH
2CH
2CH
2MgBr
ether
+ Mg (s)Cl MgCl
CH3CH
2CH
2CH
2Br + Mg (s) CH
3CH
2CH
2CH
2MgBr
ether
+ Mg (s)Cl MgCl
Cl MgClMg (s)/
CH3CH
2CH
2CH
2Br + Mg (s) CH
3CH
2CH
2CH
2MgBr
ether
+ Li (s)
Rsolvent
+ LiX
Cl Li
Cl MgCl
X + 2 Li (s) R Li
Synthesis of Alcohols
Preparation of Organolithiums
Alkyl halide: 1o, 2o, 3o halide Vinyl, allyl, aryl
Solvent: ether, alkanes
Synthesis of Alcohols
Examples:
CH3CH
2CH
2CH
2Br + Mg (s) CH
3CH
2CH
2CH
2MgBr
ether+ 2 Li (s)
Rsolvent
+ LiX
Cl Li
Cl MgCl
X + 2 Li (s) R Li
CH3CHCH
3 + 2 Li CH
3CHCH
3
hexane
Cl Li
Phenyl lithium
Synthesis of Alcohols
Grignard reagents and organolithiums are strong nucleophiles Behave like R -
Attack electrophilic carbonsAldehydes, ketonesEsters, acid chloridesEpoxides
CH3CHCH
3 + 2 Li CH
3CHCH
3
hexane
+
-
Cl Li
O
C
CH3CHCH
3 + 2 Li CH
3CHCH
3
hexane
+
-
Cl Li
O
C 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
(1) Mg(s)/ether
(3) H3O
+
(1) Li (s)/ether
(3) H3O
+
(2) H-C-HCl C
H
H
OH
Br (2) CH3CH
O
C
CH3
OH
H
O
Synthesis of Alcohols
Addition of RMgX or RLi to Aldehydes forms secondary alcohol
Synthesis of Alcohols
Addition of RMgX or RLi to Aldehydes:
(1) Mg(s)/ether
(3) H3O
+
Cl(2) CH
3CH
O
C
H
CH3
OH
(1) Mg(s)/ether
(3) H3O
+
(1) Li (s)/ether
(3) H3O
+
Cl(2) CH
3CH
O
C
H
CH3
OH
Br (2) CH3CH
O
C
CH3
OH
H
Synthesis of Alcohols
Addition of RMgX or RLi to Ketones forms tertiary alcohol
(1) Mg(s)/ether
(3) H3O
+
Cl(2) CH
3CCH
3
O
C
CH3
CH3
OH
Synthesis of Alcohols
Addition of RMgX or RLi to Esters forms tertiary alcohol with two
identical R groupsidentical 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 groupsidentical 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 AlcoholsExamples: (1) Mg(s)/ether
(3) H3O
+
(1) Li (s)/ether
(3) H3O
+
(2) CH3CO
2CH
3
(2) CH3C-Cl
Cl C
CH3
OH
BrC
CH3
O OH
(1) Mg(s)/ether
(3) H3O
+
(1) Li (s)/ether
(3) H3O
+
(2) CH3CO
2CH
3
(2) CH3C-Cl
Cl C
CH3
OH
BrC
CH3
O OH
Synthesis of Alcohols
Addition of RMgX or RLi to Epoxides forms primary alcohol with two more
carbons than the original alkyl halide
(1) Mg(s)/ether
(3) H3O
+
(1) Li (s)/ether
(3) H3O
+
(2) CH3C-Cl
(2)
Cl CH2CH
2OH
BrC
CH3
O OH
O
Synthesis of Alcohols
Example: Predict the product of each reaction.
CH3CH
2CHCH
3
(1) Mg (s)/ether
(2)
(3) H3O
+ClCO
2CH
3
CH3CH
2CHCH
3
(1) Mg (s)/ether
(2)
(3) H3O
+
CH3CCH
2CH
2CCH
3Cl
OO
Synthesis of Alcohols
Limitations/Side Reactions of RMgX and RLi RMgX and RLi are strong nucleophiles
and strong basesReact with acidic protons
Incompatible with water, ROH, RSH, R-NH-R’, and RCO2H
CH3CH
2CHCH
3
(1) Mg (s)/ether
(2)
(3) H3O
+
CH3CCH
2CH
2CCH
3
+ BrMgOH
Cl
OO
MgBr + H2O H
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
