Notes

Nucleophilic Substitution Reactions

Some typical nucleophiles are the hydroxy group (OH), the alkoxy group (RO),
and the cyanide ion (C

N). Reaction of these nucleophiles with an alkyl halide

(R&bond;X) gives the following reactions and products:

The halogen ion that is displaced from the carbon atom is called the leaving
group,
and the overall reaction is called a nucleophilic substitution reaction.
Leaving Group
For a molecule to act as a nucleus or substrate in a nucleophilic substitution
reaction, it must have both a polar bond and a good leaving group. For an atom
or a group to be a good leaving group, it must be able to exist independently as

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a relatively stable, weakly basic ion or molecule. Groups that act as leaving
groups are always capable of accommodating the negative charge through a
high electronegativity or by delocalization. Because halogen atoms have high
electronegativities and form relatively stable ions, they act as good leaving
groups.
Nucleophilic Substitution Reactions: Mechanisms
Experimental data from nucleophilic substitution reactions on substrates that
have optical activity (the ability to rotate planepolarized light) shows that two
general mechanisms exist for these types of reactions. The first type is called
an SN2 mechanism. This mechanism follows secondorder kinetics (the reaction

rate depends on the concentrations of two reactants), and its intermediate

reactant), and its intermediate contains only the substrate molecule and is
therefore

unimolecular.

The

terminology

SN1

stands

for

substitution

nucleophilic unimolecular.
SN2 mechanism
The alkyl halide substrate contains a polarized carbon halogen bond. The SN2
mechanism begins when an electron pair of the nucleophile attacks the back
lobe of the leaving group. Carbon in the resulting complex is in pentavalent
(trigonal bipyramidal) shape. With the loss of the leaving group, the carbon
atom again regains a tetrahedral (pyramidal) shape; however, its configuration
is inverted.

Figure 1
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The SN2 mechanism can also be illustrated as shown below.

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Figure 2
Notice that in either picture, the intermediate shows both the nucleophile and
the substrate. Also notice that the nucleophile must always attack from the
side opposite the side that contains the leaving group. This occurs because the
nucleophilic attack is always on the back lobe (antibonding orbital) of the
carbon atom acting as the nucleus.
SN2 mechanisms always proceed via backward attack of the nucleophile on the
substrate. This process results in the inversion of the relative configuration,
going from starting material to product. This inversion is often called the
Walden inversion,

Figure 3
Steric hindrance
SN2 reactions require a rearward attack on the carbon bonded to the leaving
group. If a large number of groups are bonded to the same carbon that bears
the leaving group, the nucleophile's attack should be hindered and the rate of
the reaction slowed. This phenomenon is called steric hindrance. The larger or
bulkier the group(s)-greater the steric hindrance and slower the rate of
reaction. Table-1 shows the effect of steric hindrance on the rate of reaction for
a specific, unspecified nucleophile and leaving group. Different nucleophiles
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and leaving groups would result in different numbers but similar patterns of
results.
SN2 reactions give good yields on 1 (primary) alkyl halides, moderate yields on
2(secondary) alkyl halides, and poor to no yields on 3 (tertiary) alkyl halides.

Solvent effects
For protic solvents (solvents capable of forming hydrogen bonds in solution) an increase in the solvent's polarity results in a decrease in the rate of SN2
reactions. This decrease occurs because protic solvents solvate the nucleophile,
thus lowering its ground state energy. Because the energy of the activated
complex is a fixed value, the energy of activation becomes greater and,
therefore, the rate of reaction decreases.

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Polar aprotic solvents (solvents that cannot form hydrogen bonds in solution)
do not solvate the nucleophile but rather surround the accompanying cation,
thereby raising the ground state energy of the nucleophile. Because the energy
of the activated complex is a fixed value, the energy of activation becomes less
and, therefore, the rate of reaction increases.

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Figure 4 illustrates the effect of solvent polarity on the energy of activation and,
thus, the rate of reaction.

Figure 4
The smaller activation energy leads to the more rapid reaction.
SN1 mechanism
SN1 indicates a substitution, nucleophilic, unimolecular reaction, described by
the expression rate = k [R-LG]. This implies that the rate determining step of
the mechanism depends on the decomposition of a single molecular species.
This pathway is a multi-step process with the following characteristics:
Step-1: slow loss of the
leaving group, LG, to
generate a carbocation
intermediate, then
Step-2 : rapid attack of a
nucleophile
on
the
electrophilic carbocation
to form a new -bond

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Multi-step
reactions
have
intermediates and
a several transition
states (TS).
In an SN1 there is
loss of the leaving
group generates an
intermediate carbocation which is
then undergoes a
rapid reaction with
the nucleophile..
General case

SN1 reaction

Let's look at how the various components of the reaction influence the reaction
pathway:
Alkyl group (R-)
Reactivity order: (CH3)3C- > (CH3)2CH- > CH3CH2- > CH3In an SN1 reaction, the rate determining step is the loss of the leaving group to
form the intermediate carbocation. The more stable the carbocation is, the
easier it is to form, and the faster the SN1 reaction will be. Some students fall
into the trap of thinking that the system with the less stable carbocation will
react fastest, but they are forgetting that it is the generation of the carbocation
that is rate determining. Since a carbocation intermediate is formed, there is
the possibility of rearrangements (e.g. 1,2-hydride or 1,2-alkyl shifts) to
generate a more stable carbocation. This is usually indicated by a change in
the position of the substituent or a change in the carbon skeleton of the
product when compared to the starting material.
Leaving Group (LG)
The only event in the rate determining step of the SN1 is breaking the C-LG

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bond. Therefore, there is a very strong dependence on the nature of the leaving
group, the better the leaving, the faster the SN1 reaction will be.
Nucleophile (Nu)

Since the nucleophile is not involved in the rate determining step, the nature of
the nucleophile is unimportant in an SN1 reaction. However, the more reactive
the nucleophile, the more likely an SN2 reaction becomes.
Stereochemistry
In an SN1, the nucleophile attacks the planar carbocation.
Since there is an equally probability of attack on each face
there will be a loss of stereochemistry at the reactive center
as both products will be observed.

Solvent
Since the hydrogen atom in a polar protic solvent is highly positively charged, it can
interact with the anionic nucleophile which would negatively affect an SN2, but it does
not affect an SN1 reaction because the nucleophile is not a part of the rate-determining
step (See SN2 Nucleophile). Polar protic solvents actually speed up the rate of the
unimolecular substitution reaction because the large dipole moment of the solvent
helps to stabilize the transition state. The highly positive and highly negative parts
interact with the substrate to lower the energy of the transition state. Since the
carbocation is unstable, anything that can stabilize this even a little will speed up the
reaction.

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Sometimes in an SN1 reaction the solvent acts as the nucleophile. This is called a
solvolysis reaction (see example below). The polarity and the ability of the solvent to
stabilize the intermediate carbocation is very important as shown by the relative rate
data for the solvolysis (see table below). The dielectric constant of a solvent roughly
provides a measure of the solvent's polarity. A dielectric constant below 15 is usually
considered non-polar. Basically, the dielectric constant can be thought of as the
solvent's ability to reduce the internal charge of the solvent. So for our purposes, the
higher the dielectric constant the more polar the substance and in the case of SN1
reactions, the faster the rate.

Below is the same reaction conducted in two different solvents and the relative rate that corresponds
with it.

The figure below shows the mechanism of an SN1 reaction of an alkyl halide with water. Since water is
also the solvent, this is an example of a solvolysis reaction.

Summary

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This pathway is most common for systems with good leaving groups, stable
carbocations and weaker nucleophiles. A typical example is the reaction of HBr
with a tertiary alcohol.
SN1 Mechanism for Reaction of Alcohols with HBr

Step 1:
An acid/base reaction. Protonation of
the alcoholic oxygen to make a better
leaving group. This step is very fast and
reversible. The lone pairs on the oxygen
make it a Lewis base.
Step 2:
Cleavage of the C-O bond allows the loss
of the good leaving group, a neutral
water molecule, to give a carbocation
intermediate. This is the rate
determining step (bond breaking is
endothermic)
Step 3:
Attack of the nucleophilic bromide ion
on the electrophilic carbocation creates
the alkyl bromide.

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SN1 MECHANISM FOR REACTION OF ALKYL HALIDES WITH H2O

Step 1:
Cleavage of the already polar C-Br bond allows the loss of
the good leaving group, a halide ion, to give a carbocation
intermediate. This is the rate determining step (bond
breaking is endothermic)
Step 2:
Attack of the nucleophile, the lone pairs on the O atom of
the water molecule, on the electrophilic carbocation creates
an oxonium species.
Step 3:
Deprotonation by a base yields the alcohol as the product.
Note that this is the reverse of the reaction of an alcohol
with HBr.
In principle, the nucleophile here, H2O, could be replaced
with any nucleophile, in which case the final deprotonation
may not always be necessary.

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SN1 vs SN2 Reactions

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Whether an alkyl halide will undergo an SN1 or an SN2 reaction depends upon
a number of factors. Some of the more common factors include the natures of
the carbon skeleton, the solvent, the leaving group, and the nature of the
nucleophile.
Nature of the carbon skeleton
Only those molecules that form extremely stable cations undergo S

N1

mechanisms. Normally, only compounds that yield 3 (tertiary) carbonications

mechanisms. Carbocations of tertiary alkyl halides not only exhibit stability

due to the inductive effect, but the original molecules exhibit steric hindrance
of the rear lobe of the bonding orbital, which inhibits S N2 mechanisms from
occurring. Primary alkyl halides, which have little inductive stability of their
cations and exhibit no steric hindrance of the rear lobe of the bonding orbital,
generally undergo S N2 mechanisms. Figure 1 illustrates the tendencies of alkyl
halides toward the two types of substitution mechanisms.

Polar protic solvents such as water favor S N1 reactions, which produce both a
cation and an anion during reaction. These solvents are capable of stabilizing
the charges on the ions formed during solvation. Because S N2 reactions occur
via a concerted mechanism (a mechanism which takes place in one step, with
bonds breaking and forming at the same time) and no ions form, polar protic
solvents would have little effect upon them. Solvents with low dielectric
constants tend not to stabilize ions and thus favor S N2 reactions. Conversely,
solvents of high dielectric constants stabilize ions, favoring S N1 reactions.
In general, good leaving groups are those capable of forming stable ions or
molecules upon displacement from the original molecule. Conversely, poor
leaving groups form ions of poor to moderate stability. Strong bases, such as

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OH , NH

2 ,

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and RO , make poor leaving groups. Water, which is less basic

than a hydroxide ion, is a better leaving group. Poor bases usually make good
leaving groups. A poor base is an ion or group in which the electrons are tightly
bound to the molecule due to high electronegativity or resonance. Some good
leaving groups are the sulfate ion and the ptoluenesulfonate (tosylate ion).

The following list ranks atoms and molecules in order of their stability as
leaving groups, from most to least stable.

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