chapter 10. substitution reactions of alkyl halides

7/29/2019 Chapter 10. Substitution Reactions of Alkyl Halides

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Chapter 10

Substitution Reactionsof Alkyl Halides

Organic Chemistry

4th Edition

Paula Yurkanis Bruice

Irene Lee

Case Western Reserve University

Cleveland, OH

2004, Prentice Hall


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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?

RCH2 X X= F, Cl, Br, I

Nu:-

+ C X C Nu + X-

+ -

+ -

Alternatively

Nu:- +

C X C++ -

+ X-

C+ C Nu


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Because a nucleophile substitutes for the halogen, these

reactions are known as nucleophilic substitution reactions

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


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The Mechanism of an SN2 Reaction

Consider the kinetic of the reaction:

CH3Br + OH CH3OH + Br

Rate = k[alkyl halide][nucleophile]

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 nucleophile

decreases 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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Why does the nucleophile attack from the back side?


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A bulky substituent in the alkyl halide reduces the

reactivity of the alkyl halide: steric hindrance


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Reaction coordinate diagrams for (a) the SN2 reaction of

methyl bromide and (b) an SN2 reaction of a sterically

hindered alkyl bromide


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Inversion of configuration (Walden inversion) in an SN2

reaction is due to back side attack


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SN2 Reactions Are Affected by the

Leaving Group


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


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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 to

react 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 anelectron-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)


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When comparing molecules with the same attacking atom

stronger base,

better nucleophile

weaker base,

poorer nucleophile

OH > H2

O

CH3O > CH3OH

NH2 > NH3CH3CH2NH

> CH3CH2NH2


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When comparing molecules with attacking atoms of

approximately the same size,


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When comparing molecules with attacking groups that

are very different in size,

more bonding

little bonding


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If the reaction is carried out in the gas phase, the stronger

bases are the best nucleophiles

but, if a protic solvent is used


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The Effect of Solvent on Nucleophilicity

How does a protic solvent make strong bases less

nucleophilic?


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Consider the iondipole interaction


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Therefore, fluoride is a better nucleophile in nonpolar

solvent

Also, aprotic polar solvents such as DMSO and DMF

facilitate the reaction of ionic compounds because they

solvate cations

It is easier to break the ion-dipole interactions between

a weak base and the solvent than between a strong base

and the solvent


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Nucleophilicity Is Affected by Steric

Effects

Steric effects affect nucleophilicity, but not basicity

A S 2 ti d i th di ti th t ll


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An SN2 reaction proceeds in the direction that allows

the strongest base to displace the weaker base

E i t l E id f S 1


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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 of

the alkyl substituent

3. In the substitution of a chiral alkyl halide, a racemic

mixture of product is obtained


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Reaction Coordinate Diagram for an

SN1 Reaction


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The carbocation reaction intermediate leads to the


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The carbocation reaction intermediate leads to the

formation of two stereoisomeric products


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ff f G


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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

Wh ti f b ti i t di t


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When a reaction forms a carbocation intermediate,

always check for the possibility of a carbocation

rearrangement


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The Stereochemistry of SN2 Reactions


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The Stereochemistry of SN1 Reactions


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Sometimes extra inverted product is formed in an SN1

reaction because

The products resulting from substitution of cyclic


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The products resulting from substitution of cyclic

compounds

Both the cis- and trans-4-methylcyclohexanol are

obtained in the SN1 reaction

Benzylic and allylic halides readily undergo SN2


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Benzylic and allylic halides readily 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 S 1


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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


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Vinyl and aryl halides do not undergo SN2 because

CC H

ClR

H

Nu

X

Br

NuX

Vinyl and aryl halides do not undergo SN1 because

RCH CH Cl RCH CHX + Cl-

Br

X + Br-


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When an alkyl halide can undergo either S 1 or S 2


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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 agood nucleophile

An SN1 reaction is favored by a low concentration of a

nucleophile or by a poor nucleophile

The Role of Solvent in S 2 and in S 1


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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


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S Bi l i l M th l ti R t


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Some Biological Methylating Reagents

chapter 10. substitution reactions of alkyl halides

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