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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
3
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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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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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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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