Chapter 9

Substitution
Reactions of
Alkyl Halides

Paula Yurkanis Bruice

University of California,
Santa Barbara
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The Families of Group II

Substitution Reactions of Alkyl Halides

alkyl halides:
the first of the families
in Group II

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The Compounds in Group II Are Electrophiles

All the compounds in Group II

have an electron withdrawing atom or group
that is attached to an sp3 carbon.

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Because Group II Compounds are Electrophiles,

They React with Nucleophiles

Substitution reactionthe electronegative group is replaced by another group.

Elimination reactionthe electronegative group is eliminated along with a hydrogen.

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Alkyl Halides

This chapter discusses the substitution reactions of alkyl halides.

Alkyl halides have good leaving groups.

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A Substitution Reaction

More precisely called a nucleophilic substitution reaction

because the atom replacing the halogen is a nucleophile.

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What is the Mechanism of the Reaction?

The kinetics of a reactionthe factors that affect the rate of the reaction
can help determine the mechanism.

an SN2 reaction
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Relative Rates of an SN2 Reaction

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Inverted Configuration

If the halogen is bonded to an asymmetric center,

the product will have the inverted configuration.

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Summary of the Experimental Evidence

for the Mechanism of an SN2 Reaction
1. The rate of the reaction is dependent on the concentration
of both the alkyl halide and the nucleophile.
2. The relative rate of the reaction is
primary alkyl halide > secondary alkyl halide > tertiary alkyl halide.

3. The configuration of the product is inverted compared to

the configuration of the reacting chiral alkyl halide.

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The Mechanism

back-side attack

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Why Bimolecular?

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Why Back-Side Attack?

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If Front-Side Attack

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Why Do Methyl Halides React the Fastest

and Tertiary the Slowest?

steric hindrance
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Why Steric Hindrance Decreases the Rate

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Both are Primary Alkyl Halides

but They React at Different Rates

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Although it is Primary, it Reacts Very Slowly

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Why the Configuration of the Product

is Inverted

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The Weakest Base is the Best Leaving Group

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The Rate of an SN2 Reaction

is Affected by the Leaving Group

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Base Strength and Nucleophile Strength

If atoms are in the same row, the strongest base is the best nucleophile.

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Base Strength and Nucleophile Strength

A negatively charged atom is a stronger base and a better nucleophile

than the same atom that is neutral.
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Polarizability

As you go down a row in the

periodic table the larger
atoms are more polarizable,
so they are better
nucleophiles but they are
weaker bases.

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IonDipole Interactions

Stronger bases form stronger iondipole interactions.

Iondipole interactions have to be broken before the nucleophile can react.
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Base Strength and Nucleophile Strength

F is the best nucleophile in
a protic solvent because it is
the strongest base.

I is the best nucleophile in

an aprotic solvent because
it more polarizable and it is
poorly solvated.

The strongest base is the best nucleophile unless

1.they differ in size.
2.they are in a protic polar solvent.
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DMF and DMSO

They can solvate a cation (+) better than they can solvate an anion ().
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Steric Hindrance Decreases Nucleophilicity

Even though the tert-butoxide ion is a

stronger base, it is a poorer nucleophile
because nucleophilic attack is more
sterically hindered than proton removal.
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SN2 Reactions Can Be Used to Make

a Variety of Compounds

The reactions are irreversible because a strong base displaces a weak base.
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Synthesizing an Amine

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A Substitution Reaction

A tertiary alkyl halide and a poor nucleophile

The reaction is surprisingly fast, so it must

be taking place by a different mechanism.

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The Rate Depends Only on the

Concentration of the Alkyl Halide

an SN1 reaction

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Relative Rates of an SN1 Reaction

Generally only tertiary alkyl halides

undergo SN1 reactions.

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The Product is a Pair of Enantiomers

If the halogen is bonded to an asymmetric center,

the product will be a pair of enantiomers.
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Summary of the Experimental Evidence

for the Mechanism of an SN1 Reaction
1. The rate of the reaction depends only on the
concentration of the alkyl halide.

2. Tertiary alkyl halides react the fastest.

3. If the halogen is attached to an asymmetric center

the product will be a pair of enantiomers.

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The Mechanism

The leaving group departs before the nucleophile approaches.

Most SN1 reactions are solvolysis reactions; the nucleophile is the solvent.
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The Slow Step is Formation of the Carbocation

Tertiary alkyl halides react the fastest; they form the most stable carbocations.
Secondary and primary alkyl halides do not undergo SN1 reactions.
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Why a Pair of Enantiomers?

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Why More Inverted Product

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The Front Side is Partially Blocked

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The Weakest Base is the Best Leaving Group

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Benzylic and Allylic Halides

Undergo SN2 Reactions

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Benzyl and Phenyl Groups

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Benzylic and Allylic Halides

Undergo SN1 Reactions

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The SN1 Reaction of Allylic Halides

Can Form Two Products

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Vinylic and Aryl Halides

Cannot Undergo SN2 Reactions

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Vinylic and Aryl Halides

Cannot Undergo SN1 Reactions

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Comparing SN2 and SN1 Reaction

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Summary of Alkyl Halide Reactivity

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Rate Law for an SN2 Reaction + Rate Law for an SN1 Reaction

The rate law for a reaction that can undergo both SN2 and SN1 reactions.

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Common Solvents

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Solvation

The dielectric constant is a measure of how the solvent

can insulate opposite charges from one another.
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One of the Reactants is Charged

If a reactant is charged, the charge on the

reactants will be greater than
the charge on the transition state.

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If One of the Reactants is Charged,

Increasing the Polarity of the Solvent Decreases the Rate

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The Reactants are Neutral

If the reactants are neutral, the charge

on the reactants will be less than
the charge on the transition state.

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If the Reactants are Neutral,

Increasing the Polarity of the Solvent Increases the Rate

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The Rate of an SN1 Reaction of an Alkyl Halide Increases

as the Polarity of the Solvent Increases

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Intermolecular versus Intramolecular

SN2 Reactions

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The Intramolecular Reaction is Favored When

a Five- or Six-Membered Ring Can Be Formed

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3-Membered and 4-Membered Rings

are Less Stable

Three-membered rings are generally formed faster than 4-membered rings.

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Methylation by a Chemist

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Methylation by a Cell

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Nordrenaline to Adrenaline

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One Phospholipid is Converted

to Another Phospholipid

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