Chapter 11

Reactions of
Alcohols,
Ethers,
Epoxides,
Amines, and
Thiols

Paula Yurkanis Bruice

University of California,
Santa Barbara
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More About the Families in Group II

The families in Group II all have an electronegative atom or group

that is attached to an sp3 carbon.
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Strongly Basic Leaving Groups

Cannot Be Displaced

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Acid Converts the Poor Leaving Group

into a Good Leaving Group

Alcohols have to be activated before they can react.

Only weakly basic nucleophiles can be used.
Strongly basic nucleophiles would react with the proton.
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Converting Alcohols to Alkyl Halides

Primary and Secondary alcohols require heat; tertiary alcohols do not.

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The Reactions of Secondary and Tertiary Alcohols

with Hydrogen Halides are SN1 Reactions

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An SN1 Reaction Creates a Carbocation Intermediate,

So Watch Out for Carbocation Rearrangements

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The Reactions of Primary Alcohols

with Hydrogen Halides are SN2 Reactions

Recall that Br is a good nucleophile in a protic solvent.

Alcohols undergo SN1 reactions unless they would have to form a primary carbocation.
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Cl is the Poorest Nucleophile of the Halide Ions

ZnCl2 increases the rate of the reaction

by creating a better leaving group than water.

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Why is It Important to Be Able

to Convert Alcohols to Alkyl Halides?

Alcohols are readily available but unreactive.

Alkyl halides are less available but reactive and
can be used to synthesized a wide variety of compounds.
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Other Methods to Convert

Alcohols into Alkyl Halides

phosphorus tribromide, phosphorus trichloride, thionyl chloride

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The Mechanism for the Reaction

with PBr3 or PCl3

A bromophosphite (chlorophosphite) group

is a better leaving group than a halide ion.
Pyridine is the solvent and acts as a base.
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The Mechanism for the Reaction with SOCl 2

A chlorosulfite group is a better leaving group than a halide ion.

Pyridine is the solvent and acts as a base.
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Converting Alcohols to Alkyl Halides

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Primary and Secondary Alcohols Can Be

Activated by Being Converted to Sulfonate Esters

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A Sulfonic Acid is a Strong Acid

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Common Sulfonyl Chlorides

tosyl chloride = TsCl

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The Mechanism

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A Sulfonate Ester Reacts with Nucleophiles

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Activating an Alcohol

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Two SN2 Reactions or

One SN2 Reaction?

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Dehydration of an Alcohol

Dehydration of an alcohol is an elimination reaction.

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Dehydration is a Reversible Reaction

To prevent the alkene from adding water and reforming the alcohol,
the water is removed as it is formed.

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Dehydration of Secondary and Tertiary Alcohols

are E1 Reactions

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Dehydration is a Regioselective Reaction

The major product is the more stable alkene.

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The More Stable Alkene Has the More Stable Transition State
Leading to Its Formation

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Tertiary Alcohols are

the Easiest to Dehydrate

The rate of dehydration reflects the ease of carbocation formation.

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An E1 Reaction Creates a Carbocation Intermediate,

So Watch Out for Carbocation Rearrangements

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Dehydration of a Primary Alcohol

is an E2 Reaction

Both E2 and SN2 products are obtained.

Alcohols undergo E1 reactions unless they would have to form a primary carbocation.
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The Major Product is 2-Butene

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Dehydration is Stereoselective

The major product is the stereoisomer with the

largest groups on opposite sides of the double bond.

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Dehydration Under Mild Conditions

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The Mechanism

The E1 dehydration has been changed to an E2 dehydration.

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Another Way to Do an E2 Dehydration

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Oxidation of Secondary Alcohols

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Oxidation of Primary Alcohols

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Tertiary Alcohols Cannot Be Oxidized

to a Carbonyl Compound

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Oxidation by Hypochlorous Acid (HOCl)

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The Mechanism

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Alcohols and Ethers Have Similar Leaving Groups

Alcohols and ethers have to be activated before the compounds can react.

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The Leaving Group of an Ether Can Be

Activated by Protonation

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The Mechanism

If a relatively stable carbocation is formed when ROH leaves,

it will be an SN1 reaction.
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The Mechanism

If a relatively stable carbocation would not be formed when ROH leaves,

it will be an SN2 reaction.

Ethers undergo SN1 reactions unless they would have to form a primary carbocation.
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Ethers Cannot Be Activated by Other Methods

An alcohol forms an intermediate that can lose a proton.

An ether forms an intermediate that cannot lose a proton.

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Ethers Are Common Solvents

Because They React Only with Hydrogen Halides

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Synthesis of an Epoxide

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Synthesis of an Epoxide

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Epoxides are More Reactive Than Ethers

Because of Ring Strain

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The Acid-Catalyzed Mechanism

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If the Epoxide is Not Symmetrical,

Which Carbon Does the Nucleophile Attack?

The nucleophile attacks the more substituted ring carbon.

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Under Acidic Conditions the Nucleophile Attacks

the More Substituted Ring Carbon

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Under Neutral or Basic Conditions the

Nucleophile Attacks the Less Substituted Carbon

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The Conditions Determine the Site of

Nucleophilic Attack

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Using Epoxides in Synthesis

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The Addition of Water to an Alkene

Carbocation rearrangements can occur during the acid-catalyzed addition of water.

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Adding Water to an Alkene

Without a Carbocation Rearrangement

The regioselectivity is the same as the acid-catalyzed addition of water

because the hydride ion adds to the sp2 carbon bonded to the most hydrogens.
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Forming a trans-1,2-Diol

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Forming a cis-1,2-Diol

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The Mechanism

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Arene Oxides

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Two Pathways for Reaction

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Mechanism for Formation of Phenol

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The Epoxide Opens Preferentially in the Direction

That Forms the More Stable Carbocation

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Addition Products Can Be Carcinogenic

If formation of the addition products is faster than formation of the phenol,

the arene oxide can be carcinogenic.
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Relative Reactivities

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Protonating an Amine Does Not Form

a Compound with a Good Leaving Group

Amines cannot undergo substitution and elimination reactions.

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Amines are Common Organic Bases

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Amines are Common Nucleophiles

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The Hofmann Elimination Reaction

A quaternary ammonium ion can undergo an elimination reaction

with a strong base such as hydroxide ion.
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The Hofmann Elimination is an E2 Reaction

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The Base Removes the H from the

-Carbon Bonded to the Most Hydrogens

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Because the Leaving Group is Poor,

the Transition State Is Carbanion-Like

Recall that alkyl fluorides have carbanion-like transition states

because the leaving group is poor.
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It Must Be a Quaternary Hydroxide

Aqueous silver oxide converts

a quaternary ammonium halide to a quaternary ammonium hydroxide.

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Thiols

Thiols used to be called mercaptans because they capture mercury.

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Nomenclature of Thiols

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Thiols are Good Nucleophiles

in a Protic Solvent

Thiolate ions are better nucleophiles in a protic solvent than alkoxide ions.
The product is a sulfur analogue of an ether (thioether or a disulfide).

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Thioethers are Also Nucleophiles

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A Sulfonium Salt is an Alkylating Agent

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The Families in Group II

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