Introduction to Organic Intermediates and Carbocations

1. ORGANIC INTERMEDIATES
Presented by :
Swapna. M
I M.PHARM.
DEPT. OF PHARMACHEMISTRY
SJMCP
1

2. Heterolytic and homolytic bond fission results in
the formation of short-lived fragment called
reaction intermediates
(or)
If a reaction occurs in more than one step, it
must involve species that are neither the
reactant nor the final product is called reaction
intermediates. These are usually short lived .
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3. 3

4. CARBOCATION
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5. A carbocation is an ion with a positively
charged carbon atom. Among the simplest examples
are methenium 𝐶𝐻3
+
.
Properties
 It formed due to heterolytic bond cleavage
 Structurally trivalent compound
 It having empty p orbital
 𝑠𝑝2 hybridization
 It having 120⁰ bond angel
 Electrophile compound
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6. The different kinds of carbocations
Primary carbocations : In a primary (1°)
carbocation, the carbon which carries the positive
charge is only attached to one other alkyl group.
Examples
Secondary carbocations : In a secondary (2°)
carbocation, the carbon with the positive charge is
attached to two other alkyl groups, which may be the
same or different.
Examples:
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7. Tertiary carbocations : In a tertiary (3°) carbocation,
the positive carbon atom is attached to three alkyl
groups, which may be any combination of same or
different.
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8. Carbocation Formation:
1. Solvolysis : solvolysis is a type of nucleophilic
substitution reaction or elimination reaction where the
nucleophile is a solvent molecules.
The solvolysis of t-butyl chloride is an SN1reaction. It
involves the formation of a 3° carbocation
Example
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9. 2. By arenediazonium salt
 The greater stability of arenediazonium salts
compared with alkanediazonium salt to be related to
the difficulty of forming aryl carbocations . Even the
gain in energy with having nitrogen as the leaving
group is not sufficient to make aryl cations form
readily, solvolysis of arenediazonium ions in water
does proceed by an SN1 mechanism:

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10. 3. From super acid ( trifluoromethanesulfonic
acid (CF3SO3H), and fluorosulfuric acid (HSO3F)
Magic acid has low nucleophilicity, allowing for increased
stability of carbocations in solution. Many tertiary cycloalkyl
cations can also be formed in super acidic solutions. One
such example is the 1-methyl-1-cyclopentyl cation, which is
formed from both the cyclopentane and cyclohexane
precursor
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11. 4. Protonation followed by dehydration of alcohols
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.
Alcohol dehydrations generally go by the E1 mechanism.
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12. 5. Protonation of alkenes
Step 1: An acid/base reaction. Protonation of the
alkene to generate the more stable carbocation. The
p electrons act as a Lewis base.
Step 2:
Attack of the nucleophilic bromide ion on the
electrophilic carbocation creates the alkyl bromide.
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13. 6. Protonation of carbonyl compound
Protonation of carboxyl carbon of the carboxylic acid
forms cabocation and Nucleophilic attack of alcohol
molecule to form oxonium ion
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14. Carbocation Stability
1. increasing substitution by carbon stabilizes
carbocation
Alkyl groups – methyl, ethyl are weak electron donating
groups, and thus stabilize nearby carbocation. More
substituted carbocation are more stable. Primary
carbocation are highly unstable and not often observed as
reaction intermediates; methyl carbocation are even less
stable.
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15. 2. Electron releasing and electron withdrawing group.
Carbocation is very electron-poor, and thus anything
which donates electron density to the center of electron
poverty will help to stabilize it. A carbocation will be
destabilized by an electron withdrawing group.
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16. 3. Presence of double bond
The positive charge is delocalized around the aromatic
structure: this delocalization of charge results in stabilization.
As a result, benzylic and allylic carbocation are significantly
more stable than even tertiary alkyl carbocation.
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17. 4. presence of heteroatoms
heteroatoms such as oxygen and nitrogen are more
electronegative than carbon
This is due to the heteroatoms are electron withdrawing
groups by induction, they are electron donating groups by
resonance, and it is this resonance effect which is more
powerful.
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18. 5. Hyperconjugation
The interaction of electrons in a sigma bond with
an adjacent empty non-bonding p-orbital
In general greater the number of alkyl groups
attached to + vely charged C atom greater is the
hyper conjugation an greater will be stabilization of
cation.
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19. 6. Aromaticity
Electrophile (+E) attacks the aromatic ring. Leads to
the formation of a resonance stabilized carbocation
known as an arenium ion.
The positive charge on the carbocation is delocalized
throughout the molecule.
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20. Synthetic application
1. Sn1 and E1
The SN1 reaction is a substitution reaction in organic
chemistry. "SN" stands for nucleophilic substitution
and the "1" represents that the rate-determining step
is unimolecular. The reaction involves a carbocation
intermediate.
The reaction taking place with an SN1 reaction
mechanism is the hydrolysis of tert-butyl bromide
with water forming tert-butanol:
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21. Mechanism :This SN1 reaction takes place in three steps:
Formation of a tert-butyl carbocation by separation of a
leaving group (a bromide anion) from the carbon atom:
this step is slow and reversible.
Nucleophilic attack: the carbocation reacts with the
nucleophile. If the nucleophile is a neutral molecule a third
step is required to complete the reaction. When the
solvent is water, the intermediate is an oxonium ion. This
reaction step is fast.
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22. Deprotonation: Removal of a proton on the
protonated nucleophile by water acting as a base
forming the alcohol and a hydronium ion. This
reaction step is fast.
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23. Elimination (E1)
Unimolecular Elimination (E1) is a reaction in which
the removal of an HX substituent results in the formation
of a double bond. One being the formation of a
carbocation intermediate. Also, the only rate determining
(slow) step is the dissociation of the leaving group to
form a carbocation, hence the name unimolecular.
The general form of the E1 mechanism is as follows:
B: = base
X = leaving group (usually halide or tosylate)
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24. Mechanism
The first step is the loss of the leaving group, which is
very slow step, resulting in the formation of a
carbocation.
The base then attacks a neighbouring hydrogen,
forcing the electrons from the hydrogen-carbon bond
to make the double bond. Since this mechanism
involves the formation of a carbocation.
An example of the E1 reaction:
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25. Types of reaction mechanism
Carbocations are unstable due to their open octets and
positive charges. Thus, their reactions will be strongly
influenced by filling the octet of the carbon bearing the
positive charge, or at least making this positive charge
more stable. There are three common mechanism
pathways by which Carbocations may achieve this
stability.
(a) capture a nucleophile
(b) lose a proton to form a π bond
(c) rearrange.
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26. 1. Capture a nucleophile. The carbocation is
electrophilic because it has a positive charge and (in
most cases) a carbon atom with an open octet. The
positive charge is neutralized when an electron pair
is accepted and a new covalent bond is formed.
Because Carbocations are very reactive, even weak
nucleophiles such as water can be captured with
ease.
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27. 2. Lose a proton to form a π bond. Accepting an
electron pair from an adjacent bond to a hydrogen
atom neutralizes the positive charge or fills the open
octet and forms a new π bond. The hydrogen atom
must be removed by a base, but because
carbocations are generally very reactive species
and very strongly driven to dispose of the positive
charge even a weak base such as water or iodide
ion can accomplish this deprotonation.
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28. 3. Rearrangement. The bonding electrons of a
carbocation may shift between adjacent atoms to
form a more stable carbocation. For example,
rearrangement will occur if a secondary carbocation
can be formed from a primary carbocation because a
secondary carbocation is more stable than the
primary carbocation. There can be two types of
rearrangements. Shift of an alkyl group is called a
1,2-alkyl shift.
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29. Shift of a hydrogen atom is called a 1,2-hydride shift.
Hydride ion = H
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30. Pinacol rearrangement (1,2 diole rearrangement)
The Pinacol rearrangement is the acid-catalyzed
dehydration of glycols, which converts the glycol into
an aldehyde or a ketone.
Eg:
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31. Mechanism:
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32. 2. Wagner-Meerwein Rearrangements
Once formed, the ethyl Cation can only be
transformed by a substitution or elimination process.
The initially formed 1º-carbocation may be converted
to a more stable 3º-carbocation by the 1,2-shift of an
adjacent methyl group with its bonding electrons.
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33. 3. Markovnikov's rule
The rule states that with the addition of a protic
acid HX to an asymmetric alkene, the acid hydrogen
(H) becomes attached to the carbon with more
hydrogen substituents, and the halide (X) group
becomes attached to the carbon with more alkyl
substituents.
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34. Determination of carbocation
Formation of carbocation can be detected by
NMR spectroscopy as the cation formation shift
the proton signals appreciably downfield due to
deshielding of proton
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35. Synthetic application
1. Phenytoin : Phenytoin sodium is a commonly
used antiepileptic. Phenytoin is used to treat various
types of convulsions and seizures. Phenytoin acts on
the brain and nervous system in the treatment of
epilepsy. . Phenytoin is also used to control
arrhythmias (irregular heartbeat) and to treat
migraine headaches and facial nerve pain.
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36. 2. Benzopinacolone
The rearrangement of benzopinacol to
benzopinacolone
Mechanism
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