CHM-504 Organic Chemistry-II 4(3-1)

General term
Nucleophile: Nucleophiles are negatively charged or have lone pairs of electrons specie that
donates an electron pair to form a chemical bond with a target molecule. They are attracted to
positive or partially positive centers. For example: Cl⁻, Br⁻, I⁻, OH⁻, NH₃, RNH₂, H₂O, ROH,
RCO₂⁻etc.
Electrophile: Electrophiles are typically electron-deficient and are usually positively charged or
have a partial positive charge specie that accepts an electron pair from a nucleophile during a
chemical reaction. For example: R3C+, RCOCl, R-X and Carbonyl compounds.
Leaving group: A leaving group is an atom or group of atoms that detaches from the substrate
molecule during a chemical reaction, along with electrons from the bond it shared with the
substrate. A good leaving group is usually a weak base and can stabilize the negative charge once
it departs. For example: Tosylates (TsO⁻), Mesylates (MsO⁻), Cl⁻, Br⁻, I⁻ and R-OSO₃⁻.
Substrate molecule: A molecule on which nucleophile attacks is called substrate molecule. It
contains the electrophilic center that will be attacked by the nucleophile, and it holds the leaving
group, which will detach during the reaction.
Aliphatic nucleophilic substitution
Aliphatic nucleophilic substitution reactions are a type of organic reaction in which a nucleophile
replaces a leaving group on an aliphatic (non-aromatic) carbon chain. These reactions are quite
common and are fundamental in organic synthesis, especially when dealing with alkyl halides and
other similar substrates. In nucleophilic aliphatic substitution the attacking (electron donating)
reagent (the nucleophile) brings an electron pair to the substrate, using this pair to form the new
bond, and the leaving group (the nucleofuge) comes away with an electron pair:
R-X + Y: ⟶ R-Y + X:
Nucleophile Y may be neutral or negatively charged; RX may be neutral or positively charged, so
there are four charge types, examples of which are:

Type I R-I + OH- ⟶ R-OH + I-

Type II R-I + N(CH3)3 ⟶ R-N+(CH3)3 + I-
 Type III R-N+(CH3)3 + OH- ⟶ R-OH + N(CH3)3
Type IV R-N+(CH3)3 + H2S ⟶ R-S+H2 + N(CH3)3

Several distinct mechanisms are possible for aliphatic nucleophilic substitution reactions,
depending on the substrate, nucleophile, leaving group, and reaction conditions. The most common
are the SN1 and SN2 mechanisms.
SN2 Mechanism
In this mechanism, there is a backside attack having the nucleophile approaches the substrate from
a position 180° away from the leaving group. The reaction is a one-step process with no
intermediate. The C-Y bond is formed as the C-X bond is broken to generate transition state 1.
The energy necessary to break the C-X bond is supplied by simultaneous formation of the C-Y
bond. The position of the atoms at the top of the curve of free energy of activation is represented
as transition state 1. During the transition state the three non-reacting substituents and the central
carbon are approximately coplanar.

The SN2 mechanism proceed in a single concerted reaction (one step), where both the nucleophile
attacks the electrophile and the leaving group departs simultaneously. Primary substrate follow
this mechanism because of minimal steric hindrance. Polar aprotic solvents (e.g. DMSO and
acetone) enhance nucleophilicity by weakly solvating the nucleophile. This mechanism require a
strong nucleophile (OH-, CN-) and good leaving group to proceed one step mechanism.
The rate of reaction depends upon the concentration of both reactants (Bimolecular) and the
reaction is second-order with respect to the reactant.
Rate of reaction = K[substrate] [nucleophile]
If a large excess of nucleophile is present (for example, if it is the solvent) the mechanism may
still be bimolecular, although the experimentally determined kinetics will be first order. Such
kinetics are called pseudo-first order.
Rate of reaction = K[substrate]
The result of this backside attack is that the configuration of the carbon is 100% inverted in the
product. It show that if the carbon was originally R-configured, after the reaction, it will be S-
configured, this inversion of configuration is often referred to as the Walden inversion. No
rearrangement occur due to the concerted manner.

For example: Hydrolysis of methyl bromide with NaOH in acetone.

SN1 Mechanism
The SN1 mechanism (substitutional nucleophilic unimolecular) proceed in more than one step. The
first step is a slow ionization of the substrate and is the rate-determining step. The other step are
rapid reaction between the intermediate carbocation and the nucleophile. The reactive nature of
the carbocation can be expressed by its electrophilic character, or electrophlicity.

SN1 is a more than one step mechanism. The process involves the substrate first forming a
carbocation intermediate after the leaving group departs, followed by nucleophilic attack on the
carbocation in a subsequent step. Tertiary substrate follow this mechanism due to carbocation
stability. But Allylic/benzylic carbocation (resonance-stabilized) also favors S N1. Polar protic
solvents (e.g. ethanol and water) stabilize the ions by solvation. This mechanism require a weak
nucleophile (ROH, H2O) because carbocation is highly reactive and need good leaving group to
proceed this mechanism.
The rate of reaction depends upon the only concentration of substrate (unimolecular) and the
reaction is first order with respect to the substrate.
 Rate of reaction = K[substrate]
The result of this stepwise mechanism is that the configuration of the carbon are 50% retention
and 50% inverted in the product. It show that the racemization of product. The carbocation may
undergo hydride/alkyl shifts to form more stable intermediate carbocation (2 ° to 3° carbocation).

For example: Hydrolysis of ter-butyl chloride ((CH3)3CCl) in water.

The Neighboring-Group Mechanism

It is occasionally found with certain substrates in which the rate of reaction is greater than
expected, and the configuration at a chiral carbon is retained and not inverted or racemized. In
these cases, there is usually a group with an unshared pair of electrons group at ß position to the
leaving group (or sometimes farther away). The mechanism operating in such cases is called the
neighboring-group mechanism and consists essentially of two S N2 substitutions, each causing an
inversion so the net result is retention of configuration. In the first step of this reaction, the
neighboring group acts as a nucleophile, pushing out the leaving group but still retaining
attachment to the molecule. In the second step, the external nucleophile displaces the neighboring
group by a backside attack:
The group that involves in this have lone pair or pi electrons. The reaction obviously must go faster
than if Y were attacking directly, since if the latter process were faster, it would be happening. The
neighboring group Z is said to be anchimeric assistance. The rate law followed in the neighboring
group mechanism is the first-order law. Y does not take part in the rate-determining step. The
reason attack by Z is faster than that by Y is that the group Z is more available. In order for Y to
react, it must collide with the substrate, but Z is immediately available by virtue of its position. A
reaction between the substrate and Y involves a large decrease in entropy of activation (∆S) since
the reactants are far less free in the transition state than before.
Anchimeric assistance
If neighboring group participation results in an abrupt increase in the rate of reaction then
phenomenon is known as anchimeric effect or anchimeric assistance.
Role of Oxygen, Nitrogen, Sulphur, and Halogen in NGP
Oxygen as a Neighbouring Group
Oxygen being part of alcohols, ethers, esters, and other oxygen-containing functional groups, is
commonly involved in neighbouring group participation. Oxygen atoms due to their high
electronegativity and lone pairs, can readily participate in stabilizing the transition state or forming
cyclic intermediates.
Example:
In the case of ethers or alcohols, oxygen atoms can participate in NGP by forming a ring which
helps stabilize the leaving group departure. In ester reactions, oxygen atoms can assist by forming
a cyclic structure, accelerating nucleophilic substitution.
Nitrogen as a Neighbouring Group
Nitrogen, being electronegative and capable of forming lone pairs, can also participate in NGP.
Nitrogen-containing groups, such as amines, imines, and amides, can stabilize carbocations or help
in the transition state formation.
Example:
The lone pair of nitrogen in amides or amino groups can help in the stabilization of intermediates
by forming five- or six-membered rings with the electrophilic center. Nitrogen in aziridines (three-
membered nitrogen-containing rings) can act as a nucleophile, assisting in substitution reactions.

Sulphur as a Neighbouring Group

Sulphur, being a larger and less electronegative atom than oxygen and nitrogen, can participate in
NGP as well. This participation is observed in compounds like thiols, sulfides, and sulfoxides. The
lone pairs of sulfur in these compounds can form cyclic intermediates, assisting in leaving group
departure and stabilizing the transition state.
Halogens as Neighbouring Groups
Halogens (fluorine, chlorine, bromine, and iodine) can participate in neighbouring group
participation due to their ability to form bond-like interactions with the electrophilic center. They
can also stabilize transition states by providing partial negative charges through lone pairs. In some
cases, halogens can directly act as leaving groups.