Download Reactions of Alcohols

KOT 222 ORGANIC CHEMISTRY II
CHAPTER 11
REACTIONS OF ALCOHOLS
KOT 222 Chapter 11
1
The hydroxyl group of alcohols can be
converted to almost any other functional
group.
R-OH
R-Y
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2
Types of Alcohol Reactions
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3
Oxidation of Alcohols
In organic chemistry, increasing the number of bonds to
oxygen is considered an oxidation.
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Oxidizing reagents:
Chromium reagent
Permanganate
Nitric acid
Even household bleach (NaOCl).
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o
Oxidation of 2 Alcohols
2o alcohols are oxidized to ketones.
Best oxidizing agent: Chromic acid reagent
(Na2Cr2O7 or CrO3)
Reactive reagent probably is chromic acid
(H2CrO4). Orange in color.
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Mechanism:
Observation:
Color change from orange to greenish blue.
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Cr3+
7
o
Oxidation of 1 Alcohols
1o alcohols is oxidized to aldehydes then to
carboxylic acids.
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Use pyridinium chlorochromate (PCC) to limit
the oxidation.
PCC also can be used to oxidized 2o alcohol to
ketones.
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o
Oxidation of 3 Alcohols
Can??
A tertiary alcohol lacks a hydrogen bonded to the carbon
attached to the OH group, therefore…
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3o alcohols do not undergo oxidation.
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Other Oxidation Reagents
Collins reagent: Cr2O3 in pyridine.
Jones reagent: chromic acid in acetone
KMnO4 (strong oxidizer)
Nitric acid (strong oxidizer)
Dehydrogenation (CuO, 300°C )
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Swern oxidation:
dimethyl sulfoxide, with oxalyl chloride and
hindered base.
oxidizes 2o alcohols to ketones and
1o alcohols to aldehydes.
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Alcohols as Nucleophiles
Alcohols are weak nucleophiles:
R
R
C
O
O
C
R
H
O
C
H
R
O
H
Alkoxide ions are strong nucleophiles:
Na
R
O
H
R
R
C
O
O
X
R
O
C
H
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Alcohols as Electrophiles
Alcohols are weak electrophiles as –OH is a
poor leaving group.
-OH becomes good leaving group (H2O) when
being protonated.
Example:
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Protonating the alcohols :
need a strong acidic solution.
and most nucleophiles are strong bases
which would remove H+ and protonated.
H
R
O
H
C
X
C
H
R
O
H
+ HC C
H
To overcome this, convert to tosylate (good
leaving group) to react with strong nucleophile
(base).
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Formation of Tosylate Ester
By condensation of alcohol with:
1.
p-toluenesulfonic acid (TsOH)
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2. tosyl chloride (TsCl)
H
C
O
C
C
H O
O
Cl
O
S
O
N
O
CH3
S
O
CH3
p-toluenesulfonyl chloride
TsCl, “tosyl chloride”
O
S
O
CH3
ROTs,
a tosylate ester
This reaction gives much higher yields than the reaction with
TsOH itself.
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Reactions of Tosylates
Tosylate group (-OTs) is a good leaving group.
The tosylate ester can undergo:
Elimination (R is a bulky group)
C
C
Substitution, SN2 (R is 1o or 2o alkyl)
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SN2 reactions of tosylates
inverted configuration
The tosylate ion is a resonance-stabilized anion
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SN2 reactions of tosylates
With hydroxide produces alcohol
With cyanide produces nitrile
With halide ion produces alkyl halide
With alkoxide ion produces ether
With ammonia produces amine salt
With LiAlH4 produces alkane
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Reduction of Alcohols
Two methods:
1. Dehydrate with conc. H2SO4 or H3PO4, then add H2
OH
CH3CHCH3
H2SO4
∆
alcohol
CH2
H2
CHCH3
Pt
alkene
E1 dehydration
CH3CH2CH3
alkane
hydrogenation
2. Tosylate, then reduce with LiAlH4
OH
CH3CHCH3
alcohol
TsCl
pyridine
OTs
CH3CHCH3
tosylate
KOT 222 Chapter 11
LiAlH4
CH3CH2CH3
alkane
22
Reactions of Alcohols with Acids
Alcohols react with hydrohalic acids (HX) to give
alkyl halides. (X=Br, Cl)
In acidic solution of hydrohalic
acid, alcohol is protonated.
Halide ions, X- react as
nucleophiles and attack
the protonated alcohol.
SN1: with 2o and 3o alcohols.
SN2: with 1o alcohols.
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Reactions with HBr
-OH of alcohols is protonated become a good
leaving group, -OH2+.
2o and 3o alcohols react via SN1.
1o alcohol react via SN2.
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Reactions with HCl
Chloride is a weaker nucleophile than bromide.
ZnCl2 is added to promote the reactions
- it bonds more strongly than proton.
The reagent composed of HCl and ZnCl2 =
Lucas reagent.
Lucas test: ZnCl2 in conc. HCl
– 1°alcohols react slowly or not at all.
– 2° alcohols react in 1-5 minutes.
– 3° alcohols react in less than 1 minute.
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Secondary and tertiary alcohols reacts with the Lucas
reagent (HCl and ZnCl2) by the SN1 mechanism.
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Primary alcohols react with the Lucas reagent (HCl and
ZnCl2) by the SN2 mechanism.
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Limitations of HX Reactions
HI does not react
Poor yields of 1°and 2°chlorides
May get alkene instead of alkyl halide
Carbocation intermediate may
rearrange.
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Reactions of Alcohols with
Phosphorus Halides
A better way to convert alcohols to alkyl halides.
Work well with 1o and 2o alcohols.
- no carbocation rearrangement.
Work poorly with 3o alcohol.
- alkyl groups hinder SN2 reaction.
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PCl3 for alkyl chloride (but SOCl2 better)
3 R-OH + PCl3 → 3 R-Cl + P(OH)3
R-OH + PCl5 → R-Cl + POCl3 + HCl
PBr3 for alkyl bromide
3 R-OH + PBr3 → 3 R-Br + P(OH)3
P and I2 for alkyl iodide (PI3 not stable)
6 R-OH + 2 P + 3 I2 → 6 R-I + 2 P(OH)3
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SN2 Mechanism with PBr3
• P bonds to -OH as Br- leaves
• Br- attacks backside (SN2)
• HOPBr2 leaves
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Reaction with Thionyl Chloride
SOCl2 is often the best reagent to give alkyl
chloride from an alcohol.
The reactant and product (RCl) have the same
configuration.
Byproducts (SO2 and HCl) are gaseous – no
reverse reaction.
Work best with 1o and 2o alcohols.
Also work with 3o alcohols.
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Mechanism (SN1):
Step 1: The oxygen atom attacks the sulfur of thionyl chloride. A chloride is
eliminated followed by the loss of a proton to give a chlorosulfite ester.
Step 2: This ester (when R = 2o or 3o) ionizes and the sulfur atom delivers a
chloride to the carbocation.
If the alkyl group is primary, ionization does not occur, instead the Cl probably
bonds to the carbon at the same time the C-O bond is breaking.
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Dehydration of Alcohols
A) Acid catalyzed dehydration:
E1 elimination of the protonated alcohol.
Ease of dehydration follows the ease of formation
of carbocation: 3o > 2o > 1o
Carbocation rearrangement especially with 1o
alcohol.
Follow Zaitsev rule: major product is the highly
substituted alkene.
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The major product is the most stable alkene product
The most stable alkene product has the most stable
transition state
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B) Bimolecular dehydration to form ethers:
synthesize symmetrical dialkyl ether from
simple, unhindered 1o alcohol.
Involve SN2 mechanism
CH3OH
H3O
+
CH3
OH2
CH3
O CH3
H
CH3OH
H2O
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CH3OCH3
36
Under acidic dehydration, E1 and SN2 compete:
SN2 when T ≤ 140 oC
2 CH3CH2OH
H2SO4
140
oC
CH3CH2-O-CH2CH3 + H20
E1 when T ≥ 180 oC
CH3CH2OH
H2SO4
180
oC
CH2=CH2 + H20
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Reactions of Diols
Pinacol rearrangement
Periodic acid cleavage of glycols
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Pinacol Rearrangement
vicinal diol converts to the ketone (pinacolone)
under acidic conditions and heat.
Formally an acid-catalyzed dehydration.
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Mechanism:
Step 1&2: Protonation of a hydroxyl group and loss of water.
CH3 CH3
CH3
C
C
CH3
OH
OH
H
CH3
CH3 CH3
+
CH3
C
C CH3
OH
OH
CH3
C
C
OH
CH3
CH3
H
Step 3: Methyl migration to form a resonance-stabilized
carbocation.
CH3
CH3
C
C
OH
CH3
CH3
CH3
CH3
C
C CH3
OH
CH3
CH3
CH3
C
C CH3
OH
CH3
CH3
Step 4: Deprotonation
CH3
KOT 222 Chapter 11
C
C
O
CH3
pinacolone
CH3
40
Periodic Acid Cleavage of Glycols
Glycols can be oxidatively cleaved by periodic
acid (HIO4) to form the corresponding ketones
and aldehydes.
CH3
H
CH3
C
C CH3
OH
OH
Hydroxylation alkene
HIO 4
CH3
H
C
O
O3
(CH3)2S
OsO 4
H2O 2
H
C
H3C
C
CH3
+
O
C
CH3
Ozonolysis-reduction of
the corresponding alkene
CH3
CH3
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Esterification of Alcohols
Fischer: alcohol + carboxylic acid
Tosylate esters
Sulfate esters
Esters of inorganic acids
Nitrate esters
Phosphate esters
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Fischer Esterification
Acid-catalyzed reaction between alcohols and
carboxylic acids to form esters + water.
Sulfuric acid is a catalyst.
The reaction is reversible.
O
CH3
C OH
CH3
+ H O CH2CH2CHCH3
+
H
O
CH3
CH3C OCH2CH2CHCH3
+ HOH
The equilibrium can be shifted to the right by adding excess
alcohol / acid or by adding dehydrating agent to remove the
water.
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Tosylate Esters
Alcohol + p-Toluenesulfonic acid, TsOH
Acid chloride is actually used, TsCl
O
CH3CH2
O H
+
HO
S
CH3
O
O
CH3CH2
O
S
O
CH3
+ HOH
Tosylate ester (ROTs)
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Sulfate Esters
Alcohol + Sulfuric acid.
O
HO
S
O
+
OH
H
+ H O CH2CH3
HO
O
S
OCH2CH3
O
O
CH3CH2O H + HO
O
+
S
OCH2CH3
H
CH3CH2O
O
H
H N
H
O
S
OCH2CH3
O
O
CH3CH2
S
H
O
CH2CH3
H
O
N
O
CH2CH3 O
H
ethylammonium ion
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S
O
CH2CH3
O
ethylsulfate ion
45
Nitrate Esters
Alcohols + nitric acid.
O
O
+
N OH
+
H O CH2CH3
H
O
N OCH2CH3
O
Glyceryl nitrate results from the reaction of glycerol (1,2,3propanetriol) with three molecules of nitric acid.
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Phosphate Esters
Alcohol + phosphoric acid.
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Phosphate esters in DNA
O CH2
base
O
H
H
H
O
O
CH2
O
H
P
O
base
O
H
H
O
O
CH2
O
H
P
O
base
O
H
H
O
O
CH2
O
H
P
Phoaphate ester linkage
– bond the individual
nucleotides together in
DNA
KOT 222 Chapter 11
O
base
O
H
H
O
O
P
O
O
48
Alkoxides Ions
How to form alkoxide ions?
R OH
O- +Na + 1/2 H2 (g)
+ Na
R
+ K
R 3C
1o/2o alcohol
R3C OH
O- + K
+ 1/2 H2 (g)
3o alcohol
R OH
+ NaH
THF
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R
O- +Na + H2 (g)
49
Reaction of Alkoxides
Williamson ether synthesis:
SN2 displacement reaction.
works better with primary alkyl halides to facilitate
back-side attack.
If a secondary or tertiary alkyl halide is used the
alkoxide will acts as a base and an elimination will
take place.
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