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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 fac

Organic Chemistry

4th Edition Paula Yurkanis Bruice

Chapter 10

Substitution Reactions

of Alkyl Halides

lrene Lee Case Western Reserve University

Cleveland, OH

©2004, Prentice Hall

What is a substitution reaction?

Alkyl halides have relatively good leaving groups

How do alkyl halides react?

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

The Mechanism of an S,2 Reaction

Consider the kinetic of the reaction:

Rate = kA[alkyl halide][nucleophile]

a second-order reaction

Three Experimental Evidences Support

an S,2 Reaction Mechanism

_ 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

mechanism of the S,2 reaction

HP cH (te: — > CH;—OH + :Br?

Why does the nucleophile attack from the back side’?

empty o*

antibonding MO

filled o bonding MO

A bulky substituent in the alkyl halide reduces the

reactivity of the alkyl halide: steric hindrance

relative reactivities of alkyl halides in an S,y2 reaction

most methyl halide > 1° alkyl halide > 2° alkyl halide > 3° alkyl halide < least

reactive reactive

4 @ & €

Reaction coordinate diagrams for (a) the S,2 reaction of methyl bromide and (b) an S,2 reaction of a sterically

hindered alkyl bromide

Inversion of configuration (Walden inversion) in an S,2 reaction is due to back side attack

2° bonds are in the same plane

foe $e cey

5,2 Reactions Are Affected by the

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

relative basicities of the halide ions

L < Br < Cl < F

weakest base, strongest base,

most stable base least stable base

relative leaving abilities of the halide ions

best leaving [ > Br > Cr > F worst leaving group group

Carbon and iodide have the same electronegativity

Why is RI the most reactive?

relative reactivities of alkyl halides in an Sy2 reaction

most reactive —— RI > RBr > RCI > RF — least 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

The Nucleophile Affects an 5,2 Reaction

Nucleophilicity is a measure of how readily a

compound (a nucleophile) is able to attack an

When comparing molecules with the same attacking atom

When comparing molecules with attacking atoms of

approximately the same size,

relative acid strengths

best nucleophile

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

If the reaction is carried out in the gas phase, the stronger bases are the best nucleophiles

but, if a protic solvent is used

The Effect of Solvent on Nucleophilicity

Table 10.2 Relative Nucleophilicity Toward CH3l in Methanol

Consider the ion—dipole interaction

It is easier to break the ion-dipole interactions between

a weak base and the solvent than between a strong base and the solvent

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

Nucleophilicity ls Affected by Steric

Effects

oteric effects affect nucleophilicity, but not basicity

An S,2 reaction proceeds in the direction that allows the strongest base to displace the weaker base

Experimental Evidence for an S,1

Reaction

The rate of the reaction depends only on the

concentration of the alkyl halide

The rate of the reaction is favored by the bulkiness of the alkyl substituent

In the substitution of a chiral alkyl halide, a racemic mixture of product is obtained

Table 10.4 Relative Rates of S,1 Reactions for Several Alkyl Bromides

(solvent is HO, nucleophile is HjO)

mechanism of the Sy1 reaction

Reaction Coordinate Diagram for an

5,1 Reaction

relative reactivities of alkyl halides in an Sy1 reaction

most reactive = 3° alkyl halide > 2° alkyl halide > 1° alkyl halide < least reactive

The carbocation reaction intermediate leads to the

formation of two stereoisomeric products

inverted configuration same configuration as relative to the configuration the alkyl halide

of the alkyl halide

R R R

R Br HO-|-R + R-[-OH

if the leaving group in an Sy1 reaction is attached to a chirality center,

a pair of enantiomers will be formed as products

The Effect of the Leaving Group on an

When a reaction forms a carbocation intermediate,

always check for the possibility of a carbocation

The Stereochemistry of 5,2 Reactions

The Stereochemistry of 5,1 Reactions

(S)-2-bromobutane (R)-2-butanol (S)-2-butanol

product with product with inverted retained

Sometimes extra inverted product is formed in an S,1

reaction because

solvent | R—X — RX — RSS ?x- _—› 2 - SS x

undissociated intimate solvent-separated dissociated ions

molecule ion pair ion pz*~

The products resulting from substitution of cyclic

Both the cis- and trans-4-methylcyclohexanol are

obtained in the S,1 reaction

Benzylic and allylic halides readily undergo 8,2,

unless they are tertiary

1-bromo-2-butene 2-buten-1-ol

an allylic halide

Tertiary benzylic and tertiary allylic halides are

unreactive in S,2 because of steric hindrance

Benzylic and allylic halides also undergo S,,1

Benzylic and allylic halides form stable carbocations

More than one product may result from an S,1 reaction

Vinyl and aryl halides do not undergo S,,2 because

A bimolecular rate-determining step A unimolecular rate-determining step

No carbocation rearrangements Carbocation rearrangements

Product has inverted configuration Products have both retained and inverted

relative to the reactant configurations relative to the reactant

Table 10.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic

Substitution Reactions

1° and 2° benzylic and 1° and 2° allylic halides SNI and Š5q2

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

the concentration of the nucleophile,

the reactivity of the nucleophile,

and the solvent of the reaction

will determine which reaction will predominate

An 8,2 reaction is favored by a high concentration of a good nucleophile

An S,1 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

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

(CH:)2SO

CH;CN (CH;);NCHO

DMSO MeCN DMF HMPA

Me,CO

THF

EtOAc Et,O

30

21 9.1 7.6

189 81.6

153

ảo 56.3

40

66

TWA 34.6

80.1

68.7

Some Biological Methylating Reagents