Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms

Reactions of Alcohols

Oxidation

R-X, Ether, and Ester Preparation

Protection of Alcohols

Synthesis

The Logic of Mechanisms

Alcohols are Synthetically Versatile

Oxidation levels of oxygen- halogen- and nitrogen-

containing molecules

Reduction

Oxidation

CH3CH3

CH2=CH2 HC CH

[O] [O]CH3CH2OH CH3CH=O CH3CO2H

CH3CH2Cl CH3CHCl2 CH3CCl3

CH3CH2NH2 CH3CH=NH CH3CN

[O]

Oxidation - Reduction

Oxidation of 2o Alcohols with Cr(VI)

Mechanism

OH+ Cr

O

O

OHHO

OCrO3H

Chromate ester

+ H2O

Na2Cr2O7 + H2O + 2 H2SO4 2 H2CrO4 + 2 NaHSO4

Chromic Acid (Cr VI)

H

OCrO3H

OH2

O

+ H3O + HCrO3

2 alcoholo

ketone (Cr IV)

Oxidation of 1o Alcohols

PCC oxidizes 1o Alcohols to Aldehydes

N

H

CrO3Cl

pyridinium chlorochromatePCC

Pyridinium Chlorochromate (PCC)

• PCC is a complex of chromium trioxide, pyridine, and HCl.

• Oxidizes primary alcohols to aldehydes.

• Oxidizes secondary alcohols to ketones.

Oxidation of 1o Alcohols to Aldehydes: PCC

3° Alcohols Cannot Be Oxidized

• Carbon does not have hydrogen, so oxidation is difficult and involves the breakage of a C—C bond.

• Chromic acid test is for primary and secondary alcohols because tertiary alcohols do not react. Orange color of Cr(VII) turns green - Cr(III); 3o alcohol is not oxidized, therefore no color change.

© 2013 Pearson Education, Inc. Chapter 11 12

Sodium Hypochlorite (NaOCl)

• Sodium hypochlorite (household bleach) can oxidize alcohols without heavy metals or generating hazardous waste.

• This is a much better option for acid-sensitive compounds.


Swern Oxidation

• Dimethylsulfoxide (DMSO), with oxalyl chloride and hindered base, oxidizes 2 alcohols to ketones and 1 alcohols to aldehydes (same as PCC).

Oxidation Summary

CH2CH2OHNHCrO3Cl

Na2Cr2O7

H2SO4

CH2CHO

CH2CO2H

DMSO, ClCCCl

OO

(CH3CH2)3N, in CH2Cl2

CH2CHO

Reduction Summary

CH2CH2OH CH2CHO

CH2CO2H

CH2CHO

1) LiAlH4

2) H3O+

2) H3O+

1) NaBH4

or

H2, Raney Ni

Conversion of Alcohol into a Leaving Group

• Form Tosylate (p-TsCl, pyridine)

• Use strong acid (H3O+)

• Convert to Alkyl Halide (HX, SOCl2, PBr3)

Formation of p-Toluenesulfonate Esters

Substitution and Elimination Reactions Using Tosylates

Summary of Tosylate Reactions

Best to use p-TsCl with pyridine

OH

CH3

CH3ClS

O

O

p-toluenesulfonyl chloride

OS

O

O

CH3

CH3

N

H

Clpyridine reacts with

HCl as it forms

N+

Reactions of Tosylates:Reduction, Substitution, Elimination

OH

CH3

CH3ClS

O

O

OS

O

O

CH3

CH3

+pyr:

1) LiAlH4

CH3

H+ LiOTs

KI

CH3

I

CH3

NaOCH3

Reduction of Alcohols• Dehydrate with concentrated H2SO4, then add H2.

• Make a tosylate, then reduce it with LiAlH4.

Alcohols to Alkyl Halides

OH

3 alcoholo

HX (HCl or HBr)X + HOH

rapid SN1

OH HX

moderate SN1

X+ HOH

2 alcoholo


Reaction of Alcohols with Acids

• The hydroxyl group is protonated by an acid to convert it into a good leaving group (H2O).

• Once the alcohol is protonated, a substitution or elimination reaction can take place.

Reaction of Alcohols 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.

Step 1: Protonation.

Step 2: Formation of the carbocation.

Step 3: Bromide attacks the carbocation.

SN1 Mechanism

SN1: Carbocations can Rearrange

HO

HBrBr

+

Br

cis & trans

HO

H-BrBr

+

Br

cis & trans

HO

H

H- H2O

Br

Br

When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2-methylbutane. Propose a mechanism for the formation of this product.

The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a secondary carbocation.

Solved Problem 2

Solution

A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by bromide leads to the observed product.

Solved Problem 2 (Continued)

Solution (Continued)

Lucas Test

CH3COH

CH3

CH3

ZnCl212M HCl

CH3

CH3

CH3CCl

CH3

CH3

CH3C OZnCl2

H CH3

CH3

CH3CCl

forms in seconds

+ HOZnCl2


SN2 Reaction with the Lucas Reagent

• Primary alcohols react with the Lucas reagent (HCl and ZnCl2) by the SN2 mechanism.

• Reaction is very slow. The reaction can take from several minutes to several days.

Qualitative test for Alcohol Characterization

OHprimary

OH

secondary

OH

tertiary

ZnCl2, HCl

Cl

Cl

Cl

1-2 seconds

<5 minutes

>10 minutes(if at all)

Other Simple Qualitative Tests

AlkenesBr2

reddish-brown

Br

Br

colorless

AlcoholsOH

OH

Na2Cr2O7

H2SO4orange

O

CO2HCr(VI)

greenCr(IV)

1o and 2o Alcohols: best to use SOCl2, PBr3, or P/I2

OH

SOCl2pyridine

PBr3Br

Cl

P, I2I(in situ prep.

of PI3)

All are SN2 Reactions

Examples

Thionyl chloride mechanism in Pyridine – SN2, Inversion

OH

S

O

ClCl

O

H

S

O

Cl

ClO

H

SCl

O

OS

Cl

O

-H+

ClSOCl2

pyridine

N

Cl

+ SO2 + HCl


Dehydration of Alcohols

• Alcohol dehydration generally takes place through the E1 mechanism.

• Rearrangements are possible.• The rate of the reaction follows the same rate as the ease of

formation of carbocations: 3o > 2o > 1o.• Primary alcohols rearrange, so this is not a good reaction

for converting 1° alcohols into alkenes.

Dehydration of Alcohols – E1

OH

H2SO4 (aq)

OHH

cat.

H

H

+ H2O

HSO4or H2O

-H2O

Hregenerated

Methide Shift is Faster than Loss of H+

OHCH3

CH3

H2SO4 (aq)

distill

CH3

CH3

+

CH3

CH3

major minor+ H2O

Dimerization of Alcohols:Symmetrical Ethers

2 CH3CH2CH2OHH2SO4, 125-140 C

o

CH3CH2CH2OCH2CH2CH3

+ H2O

Dehydration

Mechanism

2 CH3CH2CH2OHH2SO4, 125-140 C

o

CH3CH2CH2OCH2CH2CH3

+ H2O

Dehydration, Acid-Catalyzed

CH3CH2CH2-OH

CH3CH2CH2OH

H

CH3CH2CH2OCH2CH2CH3

HH2O

loss of H2O

Esterification

• Fischer: Alcohol + carboxylic acid

• Tosylate esters

• Sulfate esters

• Nitrate esters

• Phosphate esters


Fischer Esterification

• Reaction of an alcohol and a carboxylic acid produces an ester.

• Sulfuric acid is a catalyst.• The reaction is an equilibrium between starting materials

and products, and for this reason the Fischer esterification is seldom used to prepare esters.


Nitrate Esters

• The best-known nitrate ester is nitroglycerine, whose systematic name is glyceryl trinitrate.

• Glyceryl nitrate results from the reaction of glycerol (1,2,3-propanetriol) with three molecules of nitric acid.

Phosphate Esters

Phosphate Esters in DNA

Protection of AlcoholsSuppose you wanted to carry out the following transformation:

CH2OH

O

1) CH3MgBr

2) H3O+

CH2OH

OHCH3

Would the following Grignard sequence work?

Nope.

Alcohol is acidic enough to react preferentially.

CH2OH

O

1) CH3MgBr

2) H3O+

CH2OMgBr

O

+ CH4

Chlorotrimethylsilane (TMS-Cl)

Protecting groups temporarily convert reactive functional

groups into unreactive groups in a simple, high-yielding reaction.

ROH + ClSi(CH3)3pyridine

TMS-ClROSi(CH3)3 + HCl

dilute H3O+

or Et3N

deprotection

Mechanism is SN2

OH Si Cl

CH3

CH3

CH3

OSi(CH3)3

H Cl

OSi(CH3)3

+ HCl

SN2

Protect as trimethylsilyl etherCH2OH

O

CH2OH

CH3

OH

1) ClSi(CH3)3in pyridine

CH2OSi(CH3)3

O

2) CH3MgBr

dry ether

CH2OSi(CH3)3

CH3

OMgBr

3) H3O+

protonates& deprotects

Give the Reagents…

O

OH OCH3

No Protection needed

O

OH OCH31) Na metal

2) CH3I

3) CH3CH2MgBr 4) H3O+

5) TsCl, pyridine6) LiAlH4 7) H3O+

Road Map Problem

Br MgBr

CH3CH2CH

O

A B

1)

2) H3O+ CNa2Cr2O7

H2SO4D

1) CH3MgBr

2) H3O+ E

Mechanisms Thinking Logically

• Do not use reagents that are not given.• Is the product a result of a rearrangement? Only

intermediates can rearrange.

• Is one of the reagents H3O+? If so, use it in the 1st step. Do not create negatively charged species in acid.

CH3H3CCH3

OHH+, heat

CH3H3C

CH2

+ H2O

Only Five Arrows

CH3H3CCH3

OHH+, heat

CH3H3C

CH2

+ H2O

CH3H3CCH3

OH

H

CH3H3CCH3

CH3H3C

CH2HH2O

Propose a Mechanism

OCH2CH3 H3O+ O

+ CH3CH2OH

Where do you protonate?

Both approaches seem logical

OCH2CH3

H+

H+

OCH2CH3

H

OCH2CH3

H

OCH2CH3

H

Take the Blue Route

OCH2CH3

H+

OCH2CH3

H

O

H

CH2CH3

O

H

HOCH2CH3

H

OH2

H2O

H3O+ O

+ CH3CH2OH

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Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms