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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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Summary Table


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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1º, 2º, 3º Carbons

Note: carbon isgaining oxygen

Note: carbon islosing oxygen


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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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


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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3° Alcohols Don’t Oxidize

• Cannot lose 2 H’s (no alpha H to lose!)• Basis for chromic acid test


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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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

+


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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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


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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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)


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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Summary of Tosylate Reactions


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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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 =>


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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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.


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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Mechanism with PBr3

• P bonds to -OH as Br- leaves• Br- attacks backside (SN2)• HOPBr2 leaves• Note similarity to Swern!


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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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


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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Energy Diagram, E1


Unique Reactions of Diols

• Pinacol rearrangement• Periodic acid (HIO4) cleavage

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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

=>


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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Esterification

• Fischer: alcohol + carboxylic acid• Tosylate esters• Sulfate esters• Nitrate esters• Phosphate esters


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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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+

=>


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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Nitrate Esters

+ H O CH2CH3H+

N OH

O

OOCH2CH3N

O

O

=>


Phosphate Esters

=>

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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


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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End of Chapter 11Homework: 41, 42, 48, 52, 53, 55, 58,

62, 63

chapter 11 alcohol reactions - san diego miramar collegefaculty.sdmiramar.edu/choeger/chapter 11...

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