Pharmaceutical Chemistry for College students

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Substitution Reactions of Alkyl Halides
PCH 302

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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?

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Alternatively…

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The substitution is more precisely called a nucleophilic
substitution because the atom or group replacing the
leaving 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

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Experimental Evidence for the SN2
Reaction Mechanism
1. The rate of the reaction is dependent on the
concentration of both the alkyl halide and the
nucleophile.
2. The rate of the reaction with a given nucleophile
decreases with increasing branching of the alkyl
halide at the reacting center.
3. The configuration of the substituted product is
inverted compared to the configuration of the reacting
chiral alkyl halide.

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The Rate Law of an SN2 Reaction
Obtained experimentally:
Rate law includes both
the alkyl halide and the
nucleophile, a second-
order process

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The Influence of Branching on the SN2 Rate

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Because the nucleophile attacks the back side of the
carbon that is bonded to the leaving group:
Why Does Branching Lower the SN2 Rate?
Tertiary alkyl halides cannot
undergo SN2 reactions

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Why does the nucleophile attack from the back side?

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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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Good leaving groups are the conjugate bases of strong
acids, i.e., they are weak bases:

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List of Common Good Leaving
Groups
Anionic Leaving Groups:
Neutral Leaving Groups:

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Second-Row Nucleophiles in the SN2 Reaction
Second-row nucleophiles:
• Are approximately the same size.
• The stronger the base, the better the nucleophile.
stronger base,
better nucleophile
weaker base,
poorer nucleophile
OH– > H2O
CH3O– > CH3OH
H2N– > NH3
CH3CH2NH– > CH3CH2NH2

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Therefore the strength of second-row nucleophiles is
determined by conjugate acid strength:

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An SN2 reaction proceeds in the direction that allows
the stronger base to displace the weaker base:
Chloride is a weaker base than hydroxide and
the reaction is not reversible.

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Because of their small size, second-row nucleophiles
are solvated by polar solvents hindering back-side
attack:
Therefore water and alcohol
solvents are not suitable for
SN2 reactions with second-
row nucleophiles.

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SN2 reactions with second-row nucleophiles are carried
out in polar aprotic solvents:
Includes DMSO, DMF, and acetonitrile (CH3CN)
Consequently, the anionic
nucleophile is unsolvated
and reactive

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Bulk decreases
nucleophilicity,
but not basicity.
Non-nucleophilic bases: Uncoupling basicity from
nucleophilicity
Why? Nucleophilic attack
more sterically congested
than proton abstraction.

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Higher-Row Nucleophiles in the SN2 Reaction
Down a column of the
periodic table: nucleophiles
become larger and more
polarizable, but less
solvated and less basic.
Polarizability means that the
loosely held electron cloud of
iodide is readily distorted
The tightly held electron cloud
of fluoride is less polarizable.

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The Influence of Solvent on Higher-
Row Nucleophiles
In an aprotic medium,
fluoride is the best
nucleophile by virtue of
its basicity and lack of
solvation.
In an aprotic
medium, iodide
is the best
nucleophile by
virtue of its
polarizability and
lack of solvation.
Hydrogen Bonding
Solvents
CH3CH2OH
CH3OH
H2O
or mixtures thereof
Non-hydrogen Bonding
(Aprotic) Solvents
O
H3C CH3
Acetone
O
S
H3C CH3
DMSO
CH3CN
Acetonitrile
O
H N
CH3
CH3
DMF

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Synthetic Utility of the SN2 Reaction
A variety of functional groups can be prepared employing a good
nucleophile and an electrophile with a good leaving group:

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Iodide SN2 reactions are reversible because the basicities of
the nucleophile and leaving group are similar.
Solution: Use acetone as a reaction solvent.
Soluble in acetone
Insoluble in
acetone, reaction
goes to completion.

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Fluoride SN2 reactions are problematic because
fluoride salts are too ionic to dissolve in aprotic
solvents.
Solution, use a crown ether:

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Intermolecular Versus
Intramolecular SN2 Reactions

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

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Carrying out an internal SN2 reaction:
Use sodium metal to generate the oxygen anion.
Use a non-nucleophilic base to generate the oxygen
anion.
A nucleophilic base
would displace
chloride directly.

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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 increases with branching of
the alkyl halide at the reacting center.
3. An SN1 reaction with an enantiomeric pure alkyl
halide affords a racemic or partially racemic
product.

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Reaction Coordinate Diagram for an
SN1 Reaction

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An SN1 is a two-step reaction and the leaving group
departs before the nucleophile approaches:

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Influence of Alkyl Halide Branching
at the Reacting Center

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The carbocation reaction intermediate leads to the formation
of a racemic mixture:
The Stereochemistry of SN1
Reactions

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The SN1 reaction of an enantiomeric pure alkyl halide
affords a racemic mixture:
CH3OH

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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:
Inversion versus racemization

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The Rate of an SN1 Reaction
The nucleophile concentration has no effect on the
rate of an SN1 reaction because it is not in the rate-
determining step.
The rate of the reaction is affected by:
1) The better the leaving group, the larger the
rate.
2) The more stable the carbocation, the larger
the rate.
3) The higher the polarity of the solvent, the
larger the rate.

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

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The dielectric constant is a measure of how the solvent
can insulate opposite charges from one another:

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

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Rearrangement of the carbocation intermediate can occur:
SN1 Side Reactions
The carbocation intermediate can also lose a proton:
Called an E1
reaction

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Benzylic and allylic halides can undergo SN2 or SN1
reactions:
Tertiary benzylic and tertiary allylic halides are
unreactive in the SN2 reaction because of steric
hindrance.
Benzylic and Allylic Halides
SN2 conditions: Aprotic solvent and good nucleophile.

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Benzylic and allylic halides can undergo SN1 reactions
because benzylic and allylic carbocations are stable.
SN1 conditions: Protic solvent and poor nucleophile.

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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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Vinyl and aryl halides do not undergo SN1 because:

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S-Adenosyl methionine (SAM)
SAM, a Biological Methylating Agent
A sulfide leaving group

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Methyltetrahydrofolate, Another
Biological Methylating Agent
An amine
leaving group

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Hypoxanthine Guanine Phosphoribo
Transferase (HGPRTase): An SN2-Type
Enzymatic Reaction
HGPRTase deficiency: severe
mental retardation
(Lesch Nyhan Syndrome)
A pyrophosphate
leaving group

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Glutathione
Most
nucleophilic
site in an
aqueous media
This is the biological nucleophile that protects us from
electrophiles that react with proteins and DNA:
Highly
solvated
and not
nucleophilic
The glutathione SN2
product is highly polar
and readily excreted.

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Alkylating Agents: Cancer Drugs
These agents add alkyl groups to DNA by an SN2 reaction.
Leaving groups:
The presence of
two leaving
groups results in
DNA crosslinking,
a toxic event.

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Mechlorethamine, a Nitrogen Mustard
Mustard: refers to odor and color of the impure warfare agent.
Now used to treat lymphomas, breast and lung cancers.
Affects only rapidly dividing cells,
both normal and cancerous.

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Triethylenemelamine, an
Aziridinyl Triple Alkylating Agent
Used to treat Hodgkin’s lymphoma
Requires protonation to be activated as an alkylating agent
Protonation and ring opening:
Ring opening driven by:
•Amine leaving group
•Relief of ring strain

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Sulfur Mustard, Chemical
Warfare Agent

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Temozolomide: Used to Treat
Senator Kennedy’s Brain Tumor
Crosses
the Blood-
Brain
Barrier