Free radical halogenation

Free radical halogenation is the result of chlorine or bromine added to an alkane in the presence of
uv light (hv). The reaction begins with an initiation step, the separation of the halide into two radicals
(atoms with a single unpaired electron) by the addition of uv light. Note the use of a single headed
arrow when representing the movement of a single electron.
Initiation Step:

Propogation Steps:

The initiation step, the formation of the chlorine radicals, is immediately followed by the propogation
steps--steps directly involved in the formation of the product. As an example, isobutane will be used.
The first step is the abstraction of the tertiary hydrogen atom (note that these are not protons, but
actual hydrogen atoms since they each have one electron), forming the tertiary radical.
Hydrogens attached to more highly substituted carbons (ie. carbons with the most other carbons
attached to them, like tertiary carbons) are kinetically more reactive because the radical they form is
stabilized by neighboring alkyl groups that have the ability to donate part of their electron density
inductively through the sigma framework to the electron-deficient radical carbon.

Here, the tertiary radical is stabilized by

electron donation from neighboring
alkyl groups.

A point of note about free radical processes is that the intermediates are so highly reactive and short
lived that usually there is a mixture of products. This is the major downfall of radical reactions, and
why they have been overlooked in industry for many years as mixtures of products are undesired,
although now these radical reactions are regaining popularity with new methods to control single
product formation. In our example, for instance, there would certainly be some formation of the
primary radical and, ultimately, isobutyl chloride, although it would be a minor product (assisted by
the fact that statistically there are nine primary hydrogens and only 1 tertiary hydrogen). Free radical
chlorination is less selective than bromination, so bromination more selectively adds bromine to the
more highly substituted carbons.

The tertiary radical then reacts with one of the chlorine radicals formed in the initiation step to form
the product. Notice that the chlorine radical is regenerated, so this reaction can, in theory, go on
forever as long as there are reagents. This is called a chain reaction.
Termination Steps:

Side

reactions

that

can

stop

the

chain

reaction

are

called

termination

steps.

Bromine reacts exactly the same way as chlorine; however, it is far more selective. If propane, for
example, was the substrate, 2-bromopropane would be the dominant product, and there would be
only a small amount of 1-bromopropane. Chlorine is not quite as selective, and there would be a
greater amount of the chlorination of the primary carbon.
So why can't the other halogens such as fluorine or iodine be used? Iodine reacts endothermically
and too slowly to be of much good, while fluorine is at the other pole--it reacts too violently and too
quickly to be selective, and can, if uncontrolled, break carbon-carbon bonds. To understand why this
is so, derive the H's for the 4 reactions (flourination is highly exothermic, iodonation is endothermic).

SN2 Mechanism
Overview:
The

general

form

of

the

S N2

mechanism

is

as

follows:

nuc:=nucleophile
X = leaving group (usually halide or tosylate)
The SN2 reaction involves displacement of a leaving group (usually a halide or a tosylate), by a
nucleophile. This reaction works the best with methyl and primary halides because bulky alkyl groups
block the backside attack of the nucleophile, but the reaction does work with secondary halides
(although it is usually accompanied by elimination), and will not react at all with tertiary halides. In the
following example, the hydroxide ion is acting as the nucleophile and bromine is the leaving group:

Because of the backside attack of the nucleophile, inversion of configuration occurs.

Solvents: Protic solvents such as water and alcohols stabilize the nucleophile so much that it won't
react. Therefore, a good polar aprotic solvent is required such as ethers and ketones and
halogenated hydrocarbons.
Nucleophiles: A good nucleophile is required since it is involved in the rate-determining step.
Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is involved
in the rate-determining step.

SN1 Mechanism
Overview:
The general form of the SN1 mechanism is as follows:

Because the mechanism goes through a carbocation, the leaving group must be attached to either a
tertiary or secondary carbon to stabilize the intermediate. A methyl or primary leaving group will not
form a carbocation. Since it goes through a carbocation intermediate, there are possibilities for alkyl
and hydrogen rearrangements (HINT: In mechanism problems if you see a change in the carbon
skeleton between the reactant and the product, automatically suspect a carbocation intermediate (ie,

E1, Sn1) stabilized by an alkyl or hydrogen rearangement). .

An example ofthe Sn1 Mechanism

Base Strength: Base strength is unimportant, since the base is not involved in the rate determining
step (the formation of the carbocation). .
Leaving groups: A good leaving group is required, such as a halide or a tosylate, since the leaving
group is involved in the rate-determining step.
Notes: Be wary of rearangements that can occur with the S N1 reaction. Because it goes through a
carbocation intermediate, both hydrogen shifts and alkyl shifts can occur!

E1 Mechanism
Overview:
The

general

form

of

the

E1

mechanism

is

as

follows:

B:=base
X = leaving group (usually halide or tosylate)
In the E1 mechanism, the the first step is the loss of the leaving group, which leaves in a very slow step,
resulting in the formation of a carbocation. The base then attacks a neighboring hydrogen, forcing the
electrons from the hydrogen-carbon bond to make the double bond. Since this mechanism involves the
formation of a carbocation, rearangements can occur.
An example of the E1 reaction:

Base Strength: A strong base not required, since it is not involved in the rate-determining step
Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is involved in the
rate-determining
step.
Rearangements: Since the mechanism goes through a carbocation intermediate, rearangements can
occur.

E2 Mechanism
Overview:
The

general

form

of

the

B:
X = leaving group (usually halide or tosylate)

E2

mechanism

is

as

follows:

base

In the E2 mechanism, a base abstracts a proton neighboring the leaving group, forcing the electrons
down to make a double bond, and, in so doing, forcing off the leaving group. When numerous things
happen simultaneously in a mechanism, such as the E2 reaction, it is called a concerted step.
An example of the E2 reaction:

Base Strength: A strong base is required since the base is involved in the rate-determining step.
Leaving groups: A good leaving group is required, such as a halide or a tosylate, since it is involved
in the rate-determining step.
Stereochemistry requirements: Must occur with antiperiplanar stereochemistry.

Electrophilic Addition to Alkenes Mechanism

Overview:
Electrophilic

addition

to

alkenes

takes

the

following

general

form:

nuc:=nucleophile
E+ = electrophile
Electrophilic addition to alkenes starts with the pi electrons attacking an electrophile, forming a
carbocation on the most stable carbon. A nucleophile then attacks the carbocation to form the
product. There are many different kinds of such addition, including:

Hydroxylation
Hydrogenation
Halogenation
Oxidative Cleavage
Hydration
Epoxidation
Cyclopropanation
Halohydrin Formation

Clearly, there are numerous kinds of products that can be formed as a result of this mechanism.
Orientation of Addition: Electrophilic Addition adds to give the Markovnikov Product, with the
nucleophile added to the more highly substituted carbon. This is because the carbocation
intermediate is significantly stabilized by alkyl substituents.

Example of electophilic addition to alkenes:

First, formation of the carbocation on the most highly substituted carbon

Followed by attack of Chlorine on the carbocation to give the addition product

Hydroboration of alkenes
Overview:
The

general

form

of

the

hydroboration

of

alkenes

mechanism

is

as

follows:

First step is the attack of the alkene on BH 3, which then forms a four membered ring intermediate of
partial bonds. It is because of this intermediate that hydroboration forms the anti-Markovnikov
product. The boron atom is highly electrophilic because of its empty p orbital (ie. it wants electrons),
and forms a slight bonding interaction with the pi bond. Since some electron density from the double
bond is going towards bonding with the boron, the carbon opposite the boron is slightly electron
deficient, left with a slightly positive charge. Positive charges are best stabilized by more highly
substituted carbons, so the carbon opposite the boron tends to be the most highly substituted. Once
the transition state breaks down, BH2 is attached to the least substituted carbon.

Peroxide then removes the borane and replaces it with the alcohol to form the anti-markovnikov
product.

An example of the hydroboration mechanism:

Nucleophilic addition to carbonyl groups

Overview:
The general form of the nucleophilic addition to carbonyl group mechanism is as follows:

First step is the attack of the nucleophile on the partially positive carbon to make the tetrahedral
intermediate with the full negatively charged oxygen. The oxygen then becomes protonated to yield
the alcohol.
Variety of nucleophiles:

Grignard Reagents
Alcohols
Amines
Alkyl Lithium Reagents
Acetylide Ions

Example of nucleophilic addition to carbonyl groups:

In this case, acetylide anion is acting as the nucleophile

Alcohol dehydration
Overview:
The general form of alcohol dehydrations is as follows:

The first step involves the protonation of the alcohol by an acid, followed by loss of water to give a
carbocation.

Elimination occurs when the acid conjugate base plucks off a hydrogen. Alcohol dehydrations
generally go by the E1 mechanism.
Example of alcohol dehydration:

Fischer esterification mechanism

Overview:
The general form of Fischer esterification mechanism is as follows:

The first step involves protonation of the carbonyl oxygen, followed by the nucleophillic attack of the

alcohol.

Then a loss and regain of a proton,

followed by loss of water as electrons from the alcohol oxygen kick down to form the double bond.
Loss of a proton yields the ester.
Example of fischer esterification:

Williamson ether synthesis

Overview:
The

general

form

of

the

Williamson

ether

synthesis

mechanism

is

as

follows:

Placing an alcohol in sodium metal forms the alcoxide plus hydrogen gas (because it forms
hydrogen, keep this away from any flame or it will explode!).

The alcoxide can then be added to a suitable alkyl halide (primary or secondary) to form the ether via
an SN2 mechanism.
An example of the Williamson ether synthesis:

Friedel-Crafts alkylation
Overview:
The general form of the Friedel-Crafts alkylation mechanism is as follows:

Adding an alkyl halide to the Lewis acid aluminum trichloride results in the formation of an organometallic complex. In this complex the carbon attached to the chlorine has a great deal of positive
charge character (in fact, for practical purposes when dealing with this reaction, you can think of the
partially positive charge as a carbocation).

The pi electrons in a benzene ring are mildly electrophilic, and can attack the partially positive carbon
to create a non-aromatic intermediate (note that this intermediate has several resonance structures,
so that it is not as unstable as it might appear). Elimination of a proton re-establishes the aromaticity
of the ring, and the aluminum trichloride catalyst is regenerated along with a molecule of hydrochloric
acid.

A word of caution about this reaction: because the aluminum trichloride generates what can
essentially be thought of as a carbocation, rearrangments can occur to produce a more highlysubstituted carbocation.
For example: Addition of 1-Chloro-2-Methylpropane to benzene with aluminum trichloride results in
the rearranged product, t-butyl benzene, and not the product that you might initially expect (work out
the mechanism if you cannot see how that product is attained).

An example of a Friedel-Crafts alkylation:

Claisen condensation
Overview:
The general form of a Claisen condensation is as follows:

The first step involves adding a strong base to an ester to generate an enolate at the carbon (note
that the enolate has an additional resonance structure).

The enolate can then add to another ester molecule by attacking the carbonyl to make the tetrahedral
intermediate. The carbonyl reforms with loss of the alcoxy group to make the -keto ester.

Example of a Claisen condensation:

This is an example of an intramolecular Claisen reaction, called a Dieckmann condensation

Baeyer-Villiger oxidation
Overview:
Baeyer-Villiger oxidations are a really handy way to make esters from ketones. The general form of this reaction
is as follows:

Under basic conditions, a peroxide can be deprotonated. This nucleophilic species can then attack a carbonyl
group to form a tetrahedral intermediate. Once the tetrahedral intermediate collapses, instead of kicking the
peroxide back off, the more highly substituted alkyl substituent makes a sigmatropic shift to the oxygen, kicking
off the alcoxide as the leaving group, forming the ester.
Example of a Baeyer-Villiger oxidation:

Here the common MCPBA (m-chlorobenzoic acid) is used as the peroxide. It is one of the most common
peroxides because it is cheap and crystalline, and can be used in stoichiometric quantities.