AFB QO I 2007/08 1

Química Orgânica I

Ciências Farmacêuticas

Bioquímica

Química

AFB QO I 2007/08 2

alcohols

� Adaptado de � Organic Chemistry, 6th Edition; Wade

� Organic Chemistry, 6th Edition; McMurry

AFB QO I 2007/08 3

Typical reactions of alcohols

� Two general classes of reaction� At the carbon of the C–O bond� At the proton of the O–H bond

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Types of Alcohol Reactions

� Dehydration to alkene

� Oxidation to aldehyde, ketone

� Substitution to form alkyl halide

� Reduction to alkane

� Esterification

� Tosylation

� Williamson synthesis of ether =>

AFB QO I 2007/08 5

Summary Table

=>

AFB QO I 2007/08 6

Oxidation States

� Easy for inorganic salts� CrO4

2- reduced to Cr2O3

� 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

=>

AFB QO I 2007/08 7

Oxydation

� 1º Carbons

� 2º Carbons

� 3º Carbons

=>

AFB QO I 2007/08 8

Oxidation of 1° Alcohols

� 1° alcohol to aldehyde to carboxylic acid

� Difficult to stop at aldehyde

� Use pyridinium chlorochromate (PCC) to limit the oxidation.

� PCC can also be used to oxidize 2° alcohols to ketones.

CH3CH2CH2CH2

OH N H CrO3Cl

CH3CH2CH2CH

O

=>

AFB QO I 2007/08 9

Oxidation of 2° Alcohols

� 2° alcohol becomes a ketone

� Reagent is Na2Cr2O7/H2SO4

� Active reagent probably H2CrO4

� Color change: orange to greenish-blue

CH3CHCH2CH3

OHNa2Cr2O7 / H2SO4

CH3CCH2CH3

O

=>

AFB QO I 2007/08 10

Mechanism of Chromic Acid Oxidation

� Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone

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3° Alcohols Don’t Oxidize

� Cannot lose 2 H’s

� Basis for chromic acid test

=>

AFB QO I 2007/08 12

Other Oxidation Reagents

� Collins reagent: Cr2O3 in pyridine

� Jones reagent: chromic acid in acetone

� KMnO4 (strong oxidizer)

� Nitric acid (strong oxidizer)

� CuO, 300°C (industrial dehydrogenation)

� Swern oxidation: dimethylsulfoxide, with oxalyl chloride and hindered base, oxidizes 2° alcohols to ketones and 1° alcohols to aldehydes. =>

Oxidation of Primary Alcohols with K2Cr2O7 (Jones)Oxidation of Primary Alcohols with K2Cr2O7 (Jones)

K2Cr2O7

H2SO4

K2Cr2O7

H2SO4

+ Cr3+

R CH2

OH R C H

O

R C OH

O

Jones Oxidation

Oxidation with Chromic Oxide and PyridineOxidation with Chromic Oxide and Pyridine

CrO3.

CH2Cl2

R CH R

OH

R C R

O

N

SarettSarett OxidationOxidation

Sarrett reaction: Primary alcohols get oxidized to aldehydesAldehydes are not further oxidized to carboxylic acids

AFB QO I 2007/08 15

The Swern Oxidation

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Mechanism of the Swern Oxidation

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The Tollens Reagent Oxidizes Only

Aldehydes

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Both aldehydes and ketones can be oxidized by

peroxyacid: The Baeyer–Villiger oxidation

AFB QO I 2007/08 19

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Mechanism of the

Baeyer–Villiger Oxidation

AFB QO I 2007/08 21

Therefore, the product of the Baeyer–Villiger oxidation of

cyclohexyl methyl ketone will be cyclohexyl acetate,

because a secondary alkyl group is more likely to migrate

than a methyl group

AFB QO I 2007/08 22

Biological Oxidation

� Catalyzed by ADH, alcohol dehydrogenase.

� Oxidizing agent is NAD+, nicotinamideadenine 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.

=>

AFB QO I 2007/08 23

Biological Oxidation–Reduction

Reactions

AFB QO I 2007/08 24

AFB QO I 2007/08 25

NAD+ oxidizes ethanol by accepting a hydride ion

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NADH reduces a carbonyl compound by donating a

hydride ion

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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

AFB QO I 2007/08 28

Alcohol as an Electrophile

� OH- is not a good leaving group unless it is protonated, but most nucleophiles are strong bases which would remove H+.

� Convert to tosylate(good leaving group) to react with strong nucleophile (base)

=>

CO

H

∂ +

C-Nuc bond forms,

C-O bond breaks

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Formation of Tosylate Ester

p-toluenesulfonyl chloride

TsCl, “tosyl chloride”

CO

H

CH3

S

Cl

OO N

CH3

S OO

OH

C

CH3

S

O

OO

C

ROTs,

a tosylate ester

=>

AFB QO I 2007/08 30

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

=>

AFB QO I 2007/08 31

Summary of Tosylate Reactions

=>

AFB QO I 2007/08 32

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

=>

AFB QO I 2007/08 33

Reaction with HBr� -OH of alcohol is protonated

� -OH2+ is good leaving group

� 3° and 2° alcohols react with Br- via SN1

� 1° alcohols react via SN2

H3O+

Br-

R O H R O H

H

R Br =>

AFB QO I 2007/08 34

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.

� 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.=>

AFB QO I 2007/08 35

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.

=>

AFB QO I 2007/08 36

Alcohols to halides

� 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)

=>

AFB QO I 2007/08 37

Mechanism with PBr3

� P bonds to -OH as Br-leaves

� Br- attacks backside (SN2)

� HOPBr2 leaves

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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

AFB QO I 2007/08 39

Dehydration Reactions

� Conc. H2SO4 produces alkene

� Carbocation intermediate

� Saytzeff product

� Bimolecular dehydration produces ether

� Low temp, 140°C and below, favors ether

� High temp, 180°C and above, favors alkene

AFB QO I 2007/08 40

Dehydration Mechanisms

CH3CHCH3

OHH2SO4

alcohol

CH3CHCH3

OH

H

CH3CHCH3

CH2 CHCH3H2O

CH3OH

H3O+

CH3OH CH3 OH2 CH3 O

H

CH3

H2OCH3OCH3

=>

AFB QO I 2007/08 41

Energy Diagram, E1

=>

AFB QO I 2007/08 42

Unique Reactions of Diols

� Pinacol rearrangement

� Periodic acid cleavage

AFB QO I 2007/08 43

Pinacol Rearrangement

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

AFB QO I 2007/08 44

Periodic Cleavage of Glycols

CH3 C

H

OH OH

CH3

C CH3

HIO4

CH3 CH

O+ C

OCH3

CH3

C C

H3C

H CH3

CH3

OsO4

H2O2

O3

(CH3)2S

AFB QO I 2007/08 45

Esterification

� Fischer: alcohol + carboxylic acid

� Tosylate esters

� Sulfate esters

� Nitrate esters

� Phosphate esters

=>

AFB QO I 2007/08 46

Fischer Esterification

� Acid + Alcohol yields Ester + Water

� Sulfuric acid is a catalyst.

� Each step is reversible.

CH3 C OH

O

+ CH2CH2CHCH3

CH3

OHH

+

CH3C

O

OCH2CH2CHCH3

CH3

+ HOH

=>

AFB QO I 2007/08 47

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+

=>

AFB QO I 2007/08 48

Sulfate Esters

Alcohol + Sulfuric Acid

+HO S

O

O

OH H O CH2CH3

H+

OCH2CH3

O

O

SHO

CH3CH2O H + OCH2CH3

O

O

SHOH

+

CH3CH2O S

O

O

OCH2CH3

=>

AFB QO I 2007/08 49

Nitrate Esters

+ H O CH2CH3H

+

N OH

O

OOCH2CH3N

O

O

CH2

CH2

CH2

O H

O H

O H

+ 3 HO NO2

CH2

CH2

CH2

O NO2

O NO2

O NO2

nitroglycerineglycerine =>

AFB QO I 2007/08 50

Phosphate Esters

P

O

OH

OH

HOCH3OH

P

O

OH

OH

CH3OCH3OH

P

O

OCH3

OH

CH3O

P

O

OCH3

OCH3

CH3O

CH3OH

=>

AFB QO I 2007/08 51

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

AFB QO I 2007/08 52

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

=>