Chemical Reactions- Nucleophilic Substitution Reactions - JEE PDF Download

Introduction

Nucleophilic substitution reaction refers to a category of organic reactions in which one nucleophile replaces another. It shares similarities with displacement reactions observed in chemistry, where a more reactive element replaces a less reactive element in a salt solution. In this context, the "leaving group" is the group that accepts an electron pair and is displaced from the carbon atom, while the molecule undergoing substitution is referred to as the "substrate." The leaving group can depart as either a neutral molecule or an anion.

In nucleophilic substitution reactions, the reactivity or strength of nucleophile is called its nucleophilicity. So, in a nucleophilic substitution reaction, a stronger nucleophile replaces a weaker nucleophile from its compound. It can be illustrated roughly as follows:

Where,
R = Alkyl group
LG = Leaving group (less nucleophilic)

Stronger nucleophile

Example: Consider a reaction of methyl bromide with sodium hydroxide, gives sodium bromide as a side product with methanol as the main product.
CH3 – Br + O^–H → CH3 – OH + Br^–
Methyl bromide (Substrate)  + Hydroxide ion (Nucleophile)  → Methanol (Product) + Bromide ion

Nucleophilicity

Nucleophilicity is the characteristic that describes the capacity of nucleophiles to donate their lone pairs to a positively charged center. It represents a kinetic concept that pertains to the speed at which a nucleophile can attack substrates (R - LG). The nucleophilicity of various nucleophiles can be assessed by considering the following factors.

The Basic Strength of Nucleophiles

Basic strength again talks about the ability of a species to donate electron pairs. So the term’s basic strength and nucleophilicity are similar and are directly related. The only difference between nucleophilicity and basic strength is that nucleophilicity is a kinetic term, whereas basic strength is a thermodynamic term, meaning, it deals with how much the equilibrium is shifted towards the right for the reaction,

Therefore, generally strong bases are stronger nucleophiles, for example, let us take

and compare their nucleophilicities.

To compare the basic strengths of the above nucleophiles, the strength of their conjugate acids are determined and the opposite of that order will be the order of their basic strength (the conjugate base of strong acids are weak bases and vice-versa), and so the order of nucleophilicities can be found.
HF, HCl, HBr and HI are the conjugate acids of

respectively. Out of the four acids, the order of acidic strength is as follows:
HI > HBr > Hcl > HF (Bond enthalpy). Therefore, the order of basic strength and nucleophilicity is

Electronegativity of the Nucleophilic Atom

It is a common logic to understand that lone pair of electrons which are loosely held can be denoted easily. Therefore, nucleophiles having lone pairs on highly electronegative atoms are less nucleophilic or weaker nucleophiles.
For example,

SH^Θ is a better nucleophile than OH^Θ,
note that
OH^Θ is a stronger base than SH^Θ
So, basic nature is not the only criteria for deciding nucleophilicities.

Electron – Releasing Group Near Nucleophilic Centres

Presence of electron-donating groups in the nucleophiles increases their nucleophilicity. For example, CH3COO^Θ is a better nucleophile than HCOO^Θ  because CH₃ is an electron-releasing group, which increases the electron density on oxygen.

Steric Hindrance

• Highly hindered (crowded) nucleophiles have less ability to move, and therefore are weaker nucleophiles. For example, tertiary alkoxide ions are weaker nucleophiles than secondary and primary alkoxide ions due to steric hindrance.

Charged Or Uncharged

Two nucleophiles having the same nucleophilic atom, the one which is charged (negative) is more nucleophilic than the neutral one because – negative charge has more affinity towards a positive centre. For example,
OH^Θ  is a better nucleophile than H₂O,
even though in both cases oxygen is the nucleophilic atom.

Polar Solvents Effects

In the case of polar solvents likes, alcohol acids, H₂O, etc…., the effect of hydration (solvation) has a role in deciding the nucleophilicities of nucleophiles. The ionic mobility of an ion which is heavily hydrated is highly decreased, and therefore, decreases the nucleophilicity. Hydration is a phenomenon of crowding of water molecules surrounding an ion. Hydration and its effect on nucleophilicity can be explained taking

as examples.

We have already determined the order of nucleophilicities of the above nucleophiles wrt to the basic strength, but when these nucleophiles operate in a protic solvent like water, the extent of hydration happening to the nucleophile is also important. The following are the two factors on which the extent of hydration depends.

• Charge: Charge α extent of hydration
• Size:
  

(Because a smaller ion can be more easily crowded due to their high charge density)
Therefore, order at which the ions get hydrated is as follows:

Leaving Capacity of the Leaving Group

In a nucleophile substitution reaction, the rate of the reaction depends on the nucleophilicity of the incoming nucleophile and the leaving capacity of the leaving group which is replaced or substituted. The more the leaving capacity of the leaving group, faster the reaction is. The only thumb rule for deciding leaving capacities is that “weaker bases are better leaving group”.
For example,

is the order of leaving capacity.

Mechanisms of Nucleophilic Substitution

The rate of nucleophilic substitution reactions not only depends on nucleophiles and leaving capacities but also on the mechanism by which the reaction takes place. There are two mechanisms proposed for nucleophilic substation reactions.
SN₂ Mechanism

It is called substitution nucleophilic bimolecular mechanism. It follows 2nd order kinetics and the rate law for a reaction following the SN2 mechanism is as follows. For SN₂ reaction of the form

From the rate law, it is understood that the rate of SN2 reaction depends both on the concentration of the substrate and the nucleophile. Therefore, both nucleophilicity of the nucleophile and the leaving capacity of the leaving group increases the rate of the reaction. The mechanism for SN2 reaction is explained taking CH3 – X (methyl halide) and some nucleophile
(Nu^Θ)
as an example.
The overall reaction between the two is as follows.

 
Mechanism:

It is a single step process consisting of one intermediate. It proceeds through the backside (of the LG) attack of the incoming nucleophile to avoid repulsions, leading to an intermediate, which is indicated using two dotted lines between carbon – Nu and carbon-X. The two dotted lines in the intermediate indicate that the C – X bond is broken and the C – Nu bond is formed simultaneously. And at the end, C – x bond is completely broken and the c – Nu bond is completed formed.
Since it’s a backside attack of the nucleophile, the product will always have an inverted configuration wrt the substrate. Therefore, the SN2 mechanism always results in “inversion of configuration”. In case of t-butyl of chloride, SN2 mechanism becomes increasingly difficult as the nucleophile will find it difficult to attack from the backside due to the presence of bulky methyl.

Highly crowded substrates will be less reactive towards the SN₂ mechanism. The order of reactivity of 1°, 2°, 3° halides is as follows.
1° > 2° > 3° (steric hindrance). The rates of SN₂ reactions are enhanced if polar aprotic solvents such as DMF, DMSO, etc are used as reaction mediums.

S_N2 Transition State

In a transition state of SN2 reaction, a carbon atom and other atoms are in a planar arrangement.

Characteristics of Nucleophilic Substitution Bimolecular Reaction

• Prone to the influence of steric effects.
• Chiral center undergoes a reaction resulting in inversion.
• Methyl halides exhibit the highest reactivity, followed by primary compounds. Secondary halides may react, but tertiary halides lack reactivity.
• No reaction occurs at the C=C bond in the vinyl compound.
• When a negatively charged nucleophile reacts with the substrate, a neutral product is formed.
• When a neutral nucleophile reacts with the substrate, a positively charged product is produced.
• Leaving groups that are weak bases (possess stable anions) are considered good.
• Some compounds like alcohols, fluorides, ethers, and amines do not undergo SN2 reactions. Additionally, a very small leaving group can impede the SN2 mechanism.
• Solvents capable of donating hydrogen bonds slow down SN2 reactions due to their association with the reactants.

SN₁ Mechanism

It is called unimolecular nucleophilic substitution reaction. For SN1, mechanism having R – X as substrate and
Nu^Θas the incoming nucleophile,
the rate law can be presented as follows. R = k [R – x]
Where
r = rate of SN1 reaction
k = rate constant
{R – X} = concentration of substrate.
From the above equation, we can see that the rate of SN1 mechanism depends only on the concentration of the substrate and is independent of the concentration of the incoming nucleophile. Indirectly, the rate depends on leaving capacity of the leaving group but independent of the nucleophilicity of the incoming nucleophile.
Mechanism:

Example:
Stereochemistry of SN1 reaction

It is a two-step process, 1st being the breaking of C – X Bond heterolytically to form a carbocation andX^Θ
and 2nd being the attack of nucleophile onto the carbocation. In a multistep process such as this, the rate-determining step is given by the slowest step and of the two steps above, the formation of the carbocation is the slowest step, and therefore the rate-determining step.

Here, unlike SN₂, the incoming nucleophile can attack from both sides (opp and the same side as LG). Therefore, the product will always be a racemized product (50% – 50% enantiomers of the same compound).
For different substrates, the rate of SN₁ depends linearly on the stability of carbocation formed. Therefore, the order of reactivity of 1°, 2°, 3° alkyl halides will be
3° > 2° > 1° (stability of carbocation).
Rate is increased when a polar protic solvent is used since it increases the ionisation to form carbocations.

Characteristics of an S_N1 reaction

• In S_N1 mechanism tertiary alkyl halides are more reactive.
• The mechanism depends on the stability of the carbocation.
• In SN1 mechanism better-leaving groups are larger halide ions.
  OH^– < Cl^– < Br^– < I^–
• In this mechanism, the nature of the nucleophile does not matter much because nucleophilic addition takes place after the formation of a carbocation.
• Rate of the reaction is controlled by stabilizing the carbocation, which stabilizes the transition state of the reaction.