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Chapter 8

Substitution Reactionsof Alkyl Halides

Organic Chemistry5th Edition

Paula Yurkanis Bruice

Irene Lee

Case Western Reserve University

Cleveland, OH

©2007, Prentice Hall

What is a substitution reaction?

The atom or group that is substituted or eliminated in these reactions is called a leaving group

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Alkyl halides have relatively good leaving groups

How do alkyl halides react?

Alternatively…

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The substitution is more precisely called a nucleophilicsubstitution because the atom or group replacing theleaving group is a nucleophile

The reaction mechanism which predominates depends on the following factors:

• the structure of the alkyl halide• the reactivity of the nucleophile• the concentration of the nucleophile

• the solvent of the reaction

The Mechanism of an SN2 Reaction

Consider the kinetic of the reaction:

a second-order reaction

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Three Experimental Evidences Support an SN2 Reaction Mechanism

1. The rate of the reaction is dependent on the concentration of the alkyl halides and the nucleophile

2. The rate of the reaction with a given nucleophiledecreases with increasing size of the alkyl halides

3. The configuration of the substituted product is inverted compared to the configuration of the reacting chiral alkyl halide

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As SN2 is a one-step reaction

A nucleophile attacks the back side of the carbon that isbonded to the leaving group

Why does the nucleophile attack from the back side?

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A bulky substituent in the alkyl halide reduces thereactivity of the alkyl halide: steric hindrance

Tertiary alkyl halides cannot undergo SN2 reactions

Reaction coordinate diagrams for (a) the SN2 reaction of methyl bromide and (b) an SN2 reaction of a stericallyhindered alkyl bromide

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Inversion of configuration (Walden inversion) in an SN2 reaction is due to back side attack

SN2 Reactions Are Affected by the Leaving Group

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The weaker the base, the better it is as a leaving group

Stable bases are weak bases

Carbon and iodide have the same electronegativity

Why is RI the most reactive?

Large atoms are more polarizable than small atoms

The high polarizability of a large iodide atom causes it toreact as if it were polar

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The Nucleophile Affects an SN2 Reaction

Nucleophilicity is a measure of how readily a compound (a nucleophile) is able to attack an electron-deficient atom

Nucleophilicity is measured by a rate constant (k)

UNLIKE

Basicity is a measure of how well a compound (a base)shares its lone pair with a proton

Basicity is measured by the acid dissociation constant (Ka)

When comparing molecules with the same attacking atom

stronger base,better nucleophile

weaker base,poorer nucleophile

OH– > H2OCH3O

– > CH3OH–NH2 > NH3

CH3CH2NH– > CH3CH2NH2

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When comparing molecules with attacking atoms ofapproximately the same size, the stronger bases are thebetter nucleophiles

When comparing molecules with attacking groups that are very different in size,

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Does the greater polarizability that helps the larger atomsto be better nucleophiles make up for the decreasedbasicity that causes them to be poor nucleophiles?

a hydrogen

bond donor

The Effect of Solvent on Nucleophilicity

In a protic solvent, the smallest atom is the poorest nucleophile even if it is the strongest base

How does a protic solvent make strong bases lessnucleophilic?

Protic solvents are hydrogen bond donors that shield thenucleophiles by ion–dipole interactions

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Consider the ion–dipole interaction

Therefore, fluoride is a better nucleophile in nonpolarsolvent

Also, aprotic polar solvents such as DMSO and DMF facilitate the reaction of ionic compounds because theysolvate cations

It is easier to break the ion–dipole interactions between a weak base and the solvent than between a strong baseand the solvent

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Nucleophilicity Is Affected by Steric Effects

Steric effects affect nucleophilicity, but not basicity

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An SN2 reaction proceeds in the direction that allowsthe strongest base to displace the weaker base

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The reaction will be reversible if the difference between the basicities of the nucleophile and the leaving group is not very large

Experimental Evidence for an SN1 Reaction

1. The rate of the reaction depends only on the concentration of the alkyl halide

2. The rate of the reaction is favored by the bulkiness ofthe alkyl substituent

3. In the substitution of a chiral alkyl halide, a mixture of stereoisomeric product is obtained

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An SN1 is a two-step reaction and the leaving groupdeparts before the nucleophile approaches

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Reaction Coordinate Diagram for an SN1 Reaction

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The carbocation reaction intermediate leads to the formation of two stereoisomeric products

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The Effect of the Leaving Group on an SN1 Reaction

The nucleophile has no effect on the rate of an SN1 reaction

The rate of the reaction is affected by:

1) the ease with which the leaving group dissociatesfrom the carbon

2) the stability of the carbocation that is formed

When a reaction forms a carbocation intermediate,always check for the possibility of a carbocationrearrangement

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The Stereochemistry of SN2 Reactions

The Stereochemistry of SN1 Reactions

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Sometimes extra inverted product is formed in an SN1reaction because…

The products resulting from substitution of cyclic compounds

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Benzylic and allylic halides undergo SN2, unless they are tertiary

Tertiary benzylic and tertiary allylic halides are unreactive in SN2 because of steric hindrance

Benzylic and allylic halides also undergo SN1

Benzylic and allylic halides form stable carbocations

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More than one product may result from an SN1 reaction of an allylic halide

Vinyl and aryl halides do not undergo SN2 because

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Vinyl and aryl halides do not undergo SN1 because

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When an alkyl halide can undergo either SN1 or SN2,

the concentration of the nucleophile,

the reactivity of the nucleophile,

and the solvent of the reaction

will determine which reaction will predominate

An SN2 reaction is favored by a high concentration of a

good nucleophile

An SN1 reaction is favored by a low concentration of a nucleophile or by a poor nucleophile

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The Role of Solvent in SN2 and in SN1 Reactions

one or more reactants charged

in the rate-limiting step

increase the polarity

of the solvent

decrease the rate of the reaction

none of the reactants is charged

in the rate-limiting step

increase the polarity

of the solvent

increase the rate of the reaction

Solvents Can Stabilize Organic Molecules

The dielectric constant is a measure of how the solventcan insulate opposite charges from one another

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Polar solvents have high dielectric constants and arevery good at insulating (solvating) charges

An SN1 reaction cannot take place in a non-polarsolvent or in the gas phase

The greater the charge on a solvated molecule, the stronger will be its interaction with a polar solvent and…

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If the charge on the transition state is greater than thecharge on the reactants, a polar solvent will stabilize thetransition state more…

The effect of a solvent on the rate of an SN1 reaction

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The effect of a solvent on an SN2 reaction

When a neutral halide reacts with a charged nucleophile,increasing the polarity of the solvent will decrease therate of the reaction

When a neutral halide reacts with a neutral nucleophile,increasing the polarity of the solvent will increase therate of the reaction

Intermolecular Versus

Intramolecular Reactions

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An intramolecular reaction is favored when a five- or six-membered ring product is formed

Some Biological Methylating Reagents