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Chapter 11Reactions of Alcohols
Chap 11 Alcohol Reactions Slide 11-2
Types of Alcohol Reactions
• Dehydration to alkene (Discussed in Chap 7)• Oxidation to aldehyde, ketone• Substitution to form alkyl halide• Reduction to alkane• Esterification• Tosylation• Williamson synthesis of ether
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Chap 11 Alcohol Reactions Slide 11-3
Summary Table
Chap 11 Alcohol Reactions Slide 11-4
Organic Redox
• Easy for inorganic saltsCrO4
2- reduced to Cr2O3 (Cr3+)KMnO4 reduced to MnO2
• Oxidation: loss of H2, gain of O, O2, or X2
• Reduction: gain of H2 or H-, loss of O, O2, or X2
• Neither: gain or loss of H+, H2O, HX
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Chap 11 Alcohol Reactions Slide 11-5
1º, 2º, 3º Carbons
Note: carbon isgaining oxygen
Note: carbon islosing oxygen
Chap 11 Alcohol Reactions Slide 11-6
Oxidation of 2° Alcohols
• 2° alcohol becomes a ketone• “Classic” reagent is Na2Cr2O7/H2SO4 (Chromic acid oxidn)• Active reagent probably H2CrO4
• Color change: orange to greenish-blue• BRUTAL
CH3CHCH2CH3
OHNa2Cr2O7 / H2SO4
CH3CCH2CH3
O
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Chap 11 Alcohol Reactions Slide 11-7
Oxidation of 1° Alcohols
• 1° alcohol to aldehyde to carboxylic acid using classic harshconditions
• Difficult to stop at aldehyde; need more gentle conditions• Use pyridinium chlorochromate (PCC) to limit the oxidation.• Made by adding CrO3 to HCl, followed by pyridine.• Stable, crystalline solid, easy to handle and use.• PCC can also be used to oxidize 2° alcohols to ketones.
CH3CH2CH2CH2
OH N H CrO3Cl
CH3CH2CH2CH
O
Chap 11 Alcohol Reactions Slide 11-8
PCC Preparation
• Tetrahedron Letters, No. 31, Corey, E.J. and Suggs, W.,'Pyridinium Chlorochromate. An Efficient Reagent forOxidation of Primary and Secondary Alcohols to CarbonylCompounds', 2647-2650, 1975
• To 184 ml of 6 M HCl (1.1 mol) was added 100 g (1 mol) ofCrO3 rapidly with stirring. After 5 min. the homogeneoussolution was cooled to 0o and 79.1 g (1 mol) of pyridine wascarefully added over 10 min. Recooling to 0o gave a yellow-orange solid which was collected on a sintered glass funneland dried for 1 hr in vacuuo (yield 180.8 g, 84%). The solid isnot appreciably hygroscopic and can be stored for extendedperiods at room temperature without change.
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Chap 11 Alcohol Reactions Slide 11-9
3° Alcohols Don’t Oxidize
• Cannot lose 2 H’s (no alpha H to lose!)• Basis for chromic acid test
Chap 11 Alcohol Reactions Slide 11-10
Other Oxidation Reagents
• Collins reagent: CrO3 in pyridine• Jones reagent: chromic acid in acetone• KMnO4 (strong oxidizer)• Nitric acid (strong oxidizer)• CuO, 300°C (industrial dehydrogenation)• Swern oxidation: dimethylsulfoxide (DMSO), with oxalyl
chloride and hindered base, oxidizes 2° alcohols to ketonesand 1° alcohols to aldehydes.
• Moffat oxidation: DMSO and dicyclohexylcarbodiimide(DCC); not as clean as the Swern
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Chap 11 Alcohol Reactions Slide 11-11
Swern Oxidation: Mechanism
Oxalyl chloride activates DMSO, chlorosulfonium ion reactswith alcohol, ylide formed decomposes to carbonyl compound
CH3
H3C S
OCl
C
C
OCl
OH3C
H3C
S O
CC
O
Cl
O
-78o
Cl-
H3C
H3C
S Cl
- CO2
- CO
H3C
H3C
S Cl
R1
R2
COH
H
CH3
CH2-H
S
R1
H
C
O
R2 Base
CH3
CH2
S
R1
H
C
O
R2H3C CH3
S
R1
C
O
R2
+
Chap 11 Alcohol Reactions Slide 11-12
Biological Oxidation
• Catalyzed by ADH, alcohol dehydrogenase.• Oxidizing agent is NAD+, nicotinamide adenine
dinucleotide.• Ethanol oxidizes to acetaldehyde, then acetic acid, a
normal metabolite.• Methanol oxidizes to formaldehyde, then formic acid,
more toxic than methanol.• Ethylene glycol oxidizes to oxalic acid, toxic.• Treatment for poisoning is excess ethanol.
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Chap 11 Alcohol Reactions Slide 11-13
Alcohol as a Nucleophile
• ROH is weak nucleophile• RO- is strong nucleophile• New O-C bond forms, O-H bond breaks.
CO
H
R X
Chap 11 Alcohol Reactions Slide 11-14
Alcohol as an Electrophile
• OH- is not a good leaving groupunless it is protonated, but manynucleophiles are strong baseswhich would remove H+.
• Convert to tosylate (good leavinggroup), or any other sulfonateleaving group, to react with strongnucleophile (base).
CO
H
δ+
C-Nuc bond forms, C-O bond breaks
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Chap 11 Alcohol Reactions Slide 11-15
Formation of Tosylate Ester
p-toluenesulfonyl chlorideTsCl, “tosyl chloride”
CO
H
CH3
S
Cl
OO N
CH3
S OO
OH
C
CH3
S
O
OO
C
ROTs,a tosylate ester
Can use any sulfonyl chloride (RSO2Cl)
Chap 11 Alcohol Reactions Slide 11-16
SN2 Reactions of Tosylates
• Sulfonate leaving groups are “kick-butt” leaving groups.• All SN2 reactions are available
With hydroxide produces alcoholWith cyanide produces nitrileWith halide ion produces alkyl halideWith alkoxide ion produces etherWith ammonia produces amine saltWith LiAlH4 produces alkane
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Chap 11 Alcohol Reactions Slide 11-17
Summary of Tosylate Reactions
Chap 11 Alcohol Reactions Slide 11-18
Reduction of Alcohols
• Dehydrate with conc. H2SO4, then add H2
• Tosylate, then reduce with LiAlH4
CH3CHCH3
OHH2SO4
CH2 CHCH3
H2
PtCH3CH2CH3
alcohol alkene alkane
alcohol
CH3CHCH3
OHTsCl
CH3CHCH3
OTsLiAlH4
alkane
CH3CH2CH3
tosylate
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Chap 11 Alcohol Reactions Slide 11-19
Reaction with HBr
• -OH of alcohol is protonated• -OH2
+ is good leaving group• Br- good nucleophile• 3° and 2° alcohols react with Br- via SN1; can get rearrangement!• 1° alcohols react via SN2
H3O+
Br-
R O H R O H
H
R Br =>
Chap 11 Alcohol Reactions Slide 11-20
Reaction with HCl
• Chloride is a weaker nucleophile than bromide.• Add ZnCl2, which bonds strongly with -OH, to promote the
reaction.• The chloride product is insoluble (solution turns cloudy).• 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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Chap 11 Alcohol Reactions Slide 11-21
Limitations of HX Reactions
• HI does not react• Poor yields of 1° and 2° chlorides• May get alkene instead of alkyl halide (good probability!)• Carbocation intermediate may rearrange.
Chap 11 Alcohol Reactions Slide 11-22
Reactions with Phosphorus Halides
• Good yields with 1° and 2° alcohols• PCl3 for alkyl chloride (but SOCl2 better)• PBr3 for alkyl bromide• P and I2 for alkyl iodide (PI3 not stable)
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Chap 11 Alcohol Reactions Slide 11-23
Mechanism with PBr3
• P bonds to -OH as Br- leaves• Br- attacks backside (SN2)• HOPBr2 leaves• Note similarity to Swern!
Chap 11 Alcohol Reactions Slide 11-24
Reaction with Thionyl Chloride
• Produces alkyl chloride, SO2, HCl• S bonds to -OH, Cl- leaves• Cl- abstracts H+ from OH• C-O bond breaks as Cl- transferred to C
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Chap 11 Alcohol Reactions Slide 11-25
Dehydration Reactions
• Conc. H2SO4 produces alkene• Carbocation intermediate• Zaitsev product• Bimolecular dehydration produces ether• Low temp, 140°C and below, favors ether• High temp, 180°C and above, favors alkene
Chap 11 Alcohol Reactions Slide 11-26
Dehydration Mechanisms
CH3CHCH3
OHH2SO4
alcohol
CH3CHCH3
OH
H
CH3CHCH3
CH2 CHCH3H2O
CH3OH
H3O+
CH3OH CH3 OH2 CH3 O
H
CH3
H2O
CH3OCH3
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Chap 11 Alcohol Reactions Slide 11-27
Energy Diagram, E1
Chap 11 Alcohol Reactions Slide 11-28
Unique Reactions of Diols
• Pinacol rearrangement• Periodic acid (HIO4) cleavage
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Chap 11 Alcohol Reactions Slide 11-29
Pinacol Rearrangement• Pinacol: 2,3-dimethyl-2,3-butanediol• Dehydration with sulfuric acid• Nothing special! Rearrangements lead to more stable
intermediates!
CH3 C
CH3
OH OH
CH3
C CH3H+
CH3 C
CH3
OH OH
CH3
C CH3
H
CH3 C
CH3
OH
CCH3
CH3
CH3 C
CH3
OH
CCH3
CH3
CH3 C
OH
CH3
C CH3
CH3
CH3 C
OH
CH3
C CH3
CH3
CH3 C
O
CH3
C CH3
CH3
pinacolone
=>
Chap 11 Alcohol Reactions Slide 11-30
Periodic Cleavage of Glycols
Same products formed as from ozonolysis of the correspondingalkene.
CH3 C
H
OH OH
CH3
C CH3
HIO4
CH3 CH
O
+ C
O
CH3
CH3
C C
H3C
HCH3
CH3
OsO4
H2O2
O3
(CH3)2S
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Chap 11 Alcohol Reactions Slide 11-31
Esterification
• Fischer: alcohol + carboxylic acid• Tosylate esters• Sulfate esters• Nitrate esters• Phosphate esters
Chap 11 Alcohol Reactions Slide 11-32
Fischer Esterification
• Acid + Alcohol yields Ester + Water• Sulfuric acid is a catalyst.• Each step is reversible.
CH3 C OH
O
+ CH2CH2CHCH3
CH3
OH
H+
CH3C
O
OCH2CH2CHCH3
CH3
+ HOH
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Chap 11 Alcohol Reactions Slide 11-33
Tosylate Esters
• Alcohol + p-Toluenesulfonic acid, TsOH• Acid chloride is actually used, TsCl
CH3CH2 O H + HO S
O
O
CH3
CH3CH2 O S
O
O
CH3
HOH+
=>
Chap 11 Alcohol Reactions Slide 11-34
Sulfate Esters
Alcohol + Sulfuric Acid
+HO S
O
O
OH H O CH2CH3H+
OCH2CH3
O
O
SHO
CH3CH2O H + OCH2CH3
O
O
SHOH+
CH3CH2O S
O
O
OCH2CH3
=>
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Chap 11 Alcohol Reactions Slide 11-35
Nitrate Esters
+ H O CH2CH3H+
N OH
O
OOCH2CH3N
O
O
=>
Chap 11 Alcohol Reactions Slide 11-36
Phosphate Esters
=>
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Chap 11 Alcohol Reactions Slide 11-37
Phosphate Esters in DNA
=>
OCH2
H
H
H
base
O
P
O
O O
OCH2
H
H
H
base
O
P
O
O O
OCH2
H
H
H
base
O
P
O
O O
O
OCH2
H
H
H
base
O
P
O
O O
Chap 11 Alcohol Reactions Slide 11-38
Alkoxide Ions
• ROH + Na (or NaH) yields sodium alkoxide• RO- + 1° alkyl halide yields ether (Williamson ether
synthesis)
CH3CH2CHCH3
O
CH3CH2 Br+ CH2CH2CH
CH3
O CH2CH3
=>
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Chap 11 Alcohol Reactions Slide 11-39
End of Chapter 11Homework: 41, 42, 48, 52, 53, 55, 58,
62, 63