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Substitution Reactions
Organic Chemistry 4th Edition Paula Yurkanis Bruice Chapter 10 Substitution Reactions of Alkyl Halides 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? Alternatively …
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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
CH3Br + OH– CH3OH + Br– Consider the kinetic of the reaction: 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 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)
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When comparing molecules with the same attacking atom
stronger base, better nucleophile weaker base, poorer nucleophile OH– > H2O CH3O– > CH3OH –NH2 > NH3 CH3CH2NH– > 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 ion–dipole interaction
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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
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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 allows
the strongest base to displace the weaker base
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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 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
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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 …
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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
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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
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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
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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
none of the reactants is charged in the rate-limiting step increase the polarity of the solvent increase the rate of the reaction one or more reactants charged in the rate-limiting step increase the polarity of the solvent decrease the rate of the reaction
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Some Biological Methylating Reagents
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