LECTURE 16

SECTION 3B

3.1.1b The SN2 reaction

 SN2 means substitution nucleophilic bimolecular (two molecules are involved in the rate-
determining step).
 Consider the reaction between a hydroxide ion and methyl iodide to yield methanol.

 The hydroxide ion is a good nucleophile since the oxygen atom has a negative charge and a
pair of unshared electrons.
 The carbon atom is electrophilic since it is bound to a halogen (more electronegative), which
pulls electron density away from the carbon, thus polarizing the bond.
 The nucleophile is attracted to the electrophile by electrostatic charges.
 The nucleophile attacks the electrophilic carbon through donation of 2 electrons.
 Since carbon can only have a maximum of 8 valence electrons, the carbon-nucleophile bond
forms while the carbon-leaving group breaks.
 Iodide is the leaving group since it leaves with the pair of electrons that once bound it the
carbon.

 The reaction is said to be concerted, taking place in a single step with the new bond forming
as the old bond is breaking.
 A potential energy diagram representing this process is shown below.

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Note: the transition state is a point of highest energy (not an intermediate).
 The study of kinetics allows us to determine how reaction mechanisms occur. In this case,
kinetic information tells us that the rate is doubled when the [CH3I] is doubled, and also
doubled when the [HO-] is doubled, i.e the rate is first order with respect to both reactants
and is therefore 2nd order overall.
Rate [CH3I][OH-]

3.1.1c The SN2 stereochemistry

 A productive collision (one that leads to the formation of the product) in an SN2 reaction
requires the nucleophile to hit the carbon on the side opposite to the side bonded to the
leaving group (backside attack) because the leaving group blocks the approach of the
nucleophile to the front side of the substrate. Therefore, every SN2 reaction of an alkyl halide
whose halogen is bonded to an asymmetric (chiral) carbon center occurs with complete
inversion of configuration with the formation of only one product.

 The SN2 reaction is, therefore, a stereospecific reaction since a certain stereoisomer reacts
to give one specific stereoisomer as product.

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Examples
a) Determine the product that would form in the following reaction

Exercises
a) Determine the product that would form in each of the following reactions:

3.1.1d Factors affecting SN2 reaction

a) The structure of the alkyl halide
 Because the nucleophile attacks the backside of the carbon bonded to the halogen, bulky
substituents attached to this carbon will decrease the nucleophile’s access to the backside of
this carbon, thereby decreasing the rate of an SN2 reaction. The order of reactivity in an SN2
reaction is as shown below.

 As larger alkyl groups replace the small H atoms, steric hindrance caused by bulky R groups
makes a nucleophilic attack from the backside more difficult, slowing the reaction.
 Apart from methyl, primary, secondary, and tertiary halides, allylic and benzylic halides
readily undergo SN2 reactions unless they are tertiary halides.

 On the other hand, aryl and vinylic halides do not undergo SN2 reactions because as the
nucleophile approaches the backside of the sp2
of the aromatic ring or the double bond.

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Exercise
i. Arrange the following alkyl bromides in order of decreasing reactivity in an S N2 reaction: 1-
bromo-2-methylbutane, 1-bromo-3-methylbutane, 2-bromo-2-methylbutane, and 1-
bromopentane
b) Stability of the leaving group
 If an alkyl fluoride, an alkyl chloride, an alkyl bromide, and an alkyl iodide all having the
same alkyl group were allowed to react with the same nucleophile under the same
conditions, the following reactivity order would be observed;

 The iodide ion is the best leaving group, while the fluoride ion is the worst; this is because
the iodide ion is a weak base, while the fluoride ion is a strong base. A weak base does not
share electrons well, and, therefore, it is not bonded as strongly to the carbon as a strong
base would be.
c) Strength of the nucleophile
 SN2 reactions require strong nucleophiles. Most strong nucleophiles have negative charges.
For example, a hydroxide ion is much more nucleophilic than a water molecule because the
negatively charged oxygen on the hydroxide ion carries greater electron density than the
oxygen atom of a neutral water molecule.

d) Type of the solvent

 Polar aprotic solvents (no O-H or N-H groups) such as acetone, acetonitrile, DMF, or
DMSO are popular choices for SN2 reactions because rates are generally faster than with
polar protic solvents (with hydrogen bond-donating capability) such as water, alcohols, etc.
But Why? Because polar protic solvent molecules form very strong ion-dipole interactions
with the negatively-charged nucleophile, essentially creating a ‘solvent cage’ around the
nucleophile.

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Example of SN2 reaction in biological systems
 In living cells, S-adenosylmethionine (SAM) acts as an efficient methylating agent.
Methylation reactions in the body regulate the biological activities of various hormones and
neurotransmitters. For example, SAM reacts with norepinephrine (noradrenaline) in the
presence of an enzyme to form epinephrine (adrenaline), which triggers a rise in blood
pressure and heart rate in the body.

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