Download Organic reactions and mechanisms

Lecture sheet
PHR122: Organic Pharmacy-II
Instructor: Dr. Biplab Kumar Das
Assistant professor, Pharmacy, NSU
Organic reactions and mechanisms
Representation of a typical organic reaction:
REACTANTS
conditions
PRODUCTS
Reactants = may be single molecule or more than one molecule i.e. the
attacking or reacting substances / reagents also act as reactants.
Products = principally single but by-products may also be formed.
Conditions = catalysts, temperature, pressure etc.
The classical structural theory of organic reactions
The reactions of organic compounds were explained based on their structural
formulae. They are essentially molecular in nature. The classical ‘structural
theory’ visualized that the chemical behavior of an organic compound was
determined by the functional groups present in its molecule. Thus the course
of an organic reaction could easily be interpreted by indicating the
interaction between the functional groups of the interacting molecules. The
incompetence of the classical structural theory became evident when it was
established that compounds having the same functional group behaved
differently under similar experimental conditions. Thus,
i. The carbonyl group (>C=O) in aldehydes (R-HC=O0 readily formed
addition compounds, cyanohydrins with HCN, while the carbonyl group
present in carboxyl group (-COOH) did not.
ii. The Br atom in ethyl bromide (C2H5Br) could be easily replaced by OH
group upon reaction with aqueous alkalies but the Br in phenyl bromide
(C6H5Br) could not be exchanged for OH under similar conditions.
Therefore it was proved that the structural theory of organic reactions was
made inadequate to offer satisfactory interpretation of the course of
reactions, and it was evident that the factors other than functional groups
played a significant role in determining the chemical behavior of organic
compounds.
Reaction mechanisms-Fundamental aspects
From a mechanistic approach, an organic reaction is believed to take place
by the attack of a reagent (Cl2, HBr, C2H5OH etc.) on a compound
containing carbon designated as a substrate (literally meaning a substance
lying below). Thus an organic reaction may be represented as:
ATTACKING REAGENT + SUBSTRATE
PRODUCTS
Substrate: A substrate may be defined as the reactant that contains carbon
atoms some of whose bonds with other atoms are broken and some new ones
formed as a result of reaction with the attacking reagent.
The carbon bonds in the substrate molecule are broken (or cleaved) to give
fragments, which are very reactive and constitute transitory intermediates.
At once they may react with other similar species or with molecules present
in their environments, thus establishing new bonds to give products.
Mechanism: The steps of an organic reaction depicting the breaking and
making of new bonds of carbon atoms in the substrate leading to the
formation of the final product through transitory intermediates are often
referred to as its mechanism.
SUBSTRATE
INTERMEDIATE (Transitory)
PRODUCTS
The attacking reagents bear either a positive or negative charge. Naturally
these would not attack the substrate successfully unless the latter somehow
possessed oppositely charged centers in the molecule. In other words, the
substrate molecule although as a whole electrically neutral must develop
polarity on some of its carbon atoms and substituents for linking with the
reagents.
This is made possible by the displacement of the bonding electrons (partially
or completely) resulting in the development of polarity in the molecule.
Such changes or effects involving the displacement of electrons in the
substrate molecule are often referred to as Electron displacement effects.
These displacement effects are of great significance in understanding
reaction mechanisms.
ELECTRON DISPLACEMENT EFFECTS
Four types of electron displacement mechanisms frequently observed in
organic molecules:
(a) Inductive effect
(b) Electromeric Effect
(c) Mesomeric effect
(d) Hyperconjugative effect
Inductive Effect: The permanent effect whereby polarity is induced on
the carbon atom and the substituent attached to it due to minor
displacement of bonding electron pair caused by their different
electronegativities, is known as Inductive effect or simply as I-effect.
When the substituent linked to carbon is electron attracting, it develops a
negative charge and it is said to exert a negative inductive effect or –I effect.
If the substituent bonded to carbon is electron releasing, it acquires a
positive charge and the inductive effect produced is called +I effect.
Examples:
(a) Common groups (electron-attracting) causing –I effects:
NO2 > F > COOH > Cl > Br > I > OH > C6H5
(b) Common groups (electron-releasing) causing +I effects:
(CH3)3C- > (CH3)2CH- > CH3CH2- > CH3Electromeric Effect: The effect which causes a temporary polarization in
the substrate molecule at the seat of a multiple bond by shift of an
electron-pair from one atom (or part) to the other under the influence of
an electrophilic reagent is called Electromeric effect (electro = electron;
meros = part).
This effect is very helpful in explaining polarization produced in a substrate
molecule containing multiple bonds. When a double or triple bond is
exposed to attack by an electrophilic reagent, a pair of bonding electrons is
transferred completely from one atom to the other. The atom that takes
charge of the electron-pair becomes negatively charged and the other
positively charged. Thus taking a general case we have:
A=B
Electrophilic reagent
added
A
B
Reagent removed
This a purely temporary effect and remains into play only in the presence of
the electrophilic reagent. As soon as the attacking reagent is removed, the
polarized molecule reverts to its original electronic state.
Mesomeric Effect: It affords another case of electron displacement in
the molecules causing permanent polarization. This electron
displacement relayed through pi electrons of multiple bonds in the
carbon chain of the molecule.
Unlike the inductive effect which operates in only those systems which have
an extended chain with conjugate double bonds (alternate sigma and pi
bonds). For this reason this effect is also referred to as Conjugative
effect. The pi electrons get delocalized as a consequence of mesomeric
effect, giving a number of resonance structures of the molecule. This leads
to a greater magnitude of the mesomeric effect than the corresponding
inductive effect for a given difference of electronegativities of the bonded
atoms.
When an electron pumping or electron withdrawing group is conjugated
with a pi bond or a set of alternately arranged sigma and pi bonds, the
electron displacement is transmitted through pi electrons in the chain.
Mesomeric effect like the inductive effect may be + or – and is usually
denoted by +M or –M. A group or atom is said to have +M effect when the
direction of electron displacement is away from it. Such groups as have lone
pair of electrons, furnish the pair for conjugation with an attached
unsaturated system. This extends the degree of deloclization bringing about
stability to the molecule. The groups are OH, OR. NH2, SR etc.
On the other hand, a group or atom is said to have –M effect when the
direction of electron displacement is toward it. The groups such as >C=O, NO2, -C=N, -SO3H etc. have –M effect owing to the presence of a highly
electronegative atom like oxygen or nitrogen functioning as an ‘electron
sink’.
Hyperconjugative effect or Hyperconjugation: When an unsaturated system
(>C=C<) is attached with the alkyl group, it becomes capable of releasing
electrons which is entirely different from the inductive effect. This
mechanism of electron release is known as hyperconjugation. For its
operation, hyperconjugation requires a carbon-hydrogen bond at the position to the double bond.
Hyperconjugative effect results in an electron displacement towards the
double bond carbon marked by as asterisk (*). Hyperconjugation effect takes
place through the interaction of sigma electrons of the carbon-hydrogen
bond with pi electrons of the double bond. The three C-H bonds of the
methyl group in the propylene molecule contribute to this effect as follows:
The order of hyperconjugative electron release for the alkyl groups will be:
Bond Fission (Breaking)
Homolytic bond fission: A covalent bond joining two atoms undergoes
hemolytic fission when each of the two departing atoms makes away with
one of the bonding pair of electrons.
Heterolytic bond fission: When a covalent bond breaks in a fashion that
both the bonding electrons are taken or withdrawn by one of the two
departing fragments (atoms or groups), it is said to have undergone
heterolytic bond fission.
The hemolytic bond fission results in the formation of free radicals (radical
with odd number of electron) and heterolytic bond fission gives rise to the
formation of ions.
Carbonium ion or carbocation
An ion containing a positively charged carbon center is called a carbonium
ion or carbocation.
Let us consider the heterolytic fission of the bond C-X present in an organic
molecule. If the atom X has greater electronegativity than the carbon atom,
the former takes away the bonding electron pair and becomes negatively
charged while an ion bearing a positive on carbon charge is produced which
is known as carbonium ion.
In general carbonium ions are named by adding the suffix –ium t the name
of the parent alkyl group i.e., alkylium. For example,