Author: Rimsha Nazir
INTRODUCTION
In organic chemistry, nucleophilic substitution reactions play a significant role in transforming molecules. Nucleophilic Substitution reactions are a group of reactions that involve the interaction of a nucleophile with an electrophile. The electron-rich nucleophile seeks out (attacks) the electron-deficient electrophile. These reactions are the characteristics of organic compounds containing a carbon atom with a good leaving group, such as haloalkanes (alkyl halides). However, not all nucleophilic substitution reactions follow the same pathway.
The two primary mechanisms—SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution bimolecular)-differ in kinetics and stereochemical effects. Both involve the breakage of the C-X bond and the formation of the C-Nu bond.
General Nucleophilic Substitution Reaction
The mechanism of the nucleophilic substitution reactions depends upon the timing of these two processes.
Understanding their kinetics and stereochemical outcomes helps to predict the reaction behavior and optimize synthetic strategies. In this blog we will explore the key differences between SN1 and SN2, their kinetics and stereochemical aspects.
NUCLEOPHILE VS ELECTROPHILE
| Property | Nucleophile | Electrophile |
|---|---|---|
| Meaning | Nucleus loving | Electron loving |
| Representation | Nu- | E+ |
| Electron Density | Electron Rich Specie | Electron Deficient Specie |
| Charge | Negative or No Charge | Positive or No Charge |
| Nature | Lewis’s Base | Lewis’s Bcid |
| Examples | Cl–, Br–, H2O, NH3, SCN–, etc. | H3O+, H+, CH3+, SO3, FeCl3 etc. |
NUCLEOPHILIC SUBSTITUTION BIMOLECULAR (SN2)
Key Features
- In SN2, S stands for Substitution, N for nucleophilic and 2 for bimolecular.
- It occurs in a single step, where the nucleophile attacks the electrophilic carbon of the substrate (the molecule with the leaving group), and at the same, the leaving group departs from it.
- It is a bimolecular reaction because both nucleophile and substrate molecules are involved in the rate-determining step. So, the rate of reaction depends upon the concentration of both substrate and nucleophile.
- It occurs in primary and secondary alkyl halides to avoid steric hindrance.
- For example, the hydrolysis of Methyl bromide with aqueous KOH.
- Order of reactivity of alkyl halides: Methyl > Primary > Secondary >>Tertiary (less reactive)
- It involves inversion of Configuration (Walden inversion).
- In this reaction, the hybridization of carbon atoms changes from sp3 (tetrahedral) in a substrate to sp2 (trigonal planar) in the transition state, and then back to sp3 in the product.
MECHANISM
It is a single-step mechanism.
- Backside Attack: The nucleophile attacks from the side opposite to the leaving group.
- Transition State Formation: A temporary transition State forms where both the nucleophile and leaving group are partially bonded.
- Product Formation: The leaving group fully departs, completing the reaction.
ENERGY PROFILE DIAGRAM OF SN2 REACTION
KINETICS OF SN2 REACTION
It is a second-order reaction, meaning that the rate of reaction depends upon the concentration of both the substrate (the molecule with the leaving group) and the nucleophile because both are involved in the rate-determining step.
The rate equation of nucleophilic substitution bimolecular is:
Rate = k [substrate] [Nucleophile]
Rate = k [ R-X] [Nu-]
Factors Affecting the Rate
1. Nucleophile Strength: A stronger nucleophile will speed up the rate of reaction.
2. Leaving Group Ability: A better leaving group will help to enhance the rate of reaction, but it not control the rate of reaction.
3. Structure of Substrate: Methyl and primary substrates react fastest due to minimal steric hindrance.
The general order of reactivity is
Methyl > Primary > Secondary >> Tertiary (less reactive)
| Substituent | Compound | Approximate Relative Rate |
|---|---|---|
| Methyl | CH3-X | 32 |
| Primary | R-CH2-X | 1.5 |
| Secondary | R2-CH-X | 0.04 |
| Neopentyl | R3C-CH2-X | 0.00001 |
| Tertiary | R3-C-X | ~0 |
Relative Rate of alkyl halides in SN2 reaction
4. Solvent Effect: Polar aprotic solvents (e.g., DMF, DMSO, etc.) enhance the reaction rate by stabilizing the nucleophile without solvation.
5. Temperature: Increased temperature generally increases the rate of reaction.
6. Concentration Of Nucleophile And Substrate: As the reaction is second-order, the rate of the reaction depends upon both the concentration of substrate and nucleophile.
STEREOCHEMISTRY OF SN2 REACTION
In this reaction, the nucleophile attacks the carbon center of the substrate from the side opposite to that of the leaving group, which inverts the configuration of the carbon center, a phenomenon known as Walden Inversion.
If the starting material is chiral (asymmetric), then the product will have the opposite configuration (R-Configuration becomes S-Configuration or vice versa).
NUCLEOPHILIC SUBSTITUTION UNIMOLECULAR (SN1)
Key Features
- In SN1, S stands for substitution, N for nucleophilic, and 1 for unimolecular.
- It is an unimolecular reaction because the rate of reaction depends only on the concentration of substrate, which is involved in the rate-determining step.
- It occurs in tertiary and secondary alkyl halides due to carbocation stability.
- For example, hydrolysis of tertiary butyl bromide with aqueous KOH.
- The order of reactivity is: Tertiary > Secondary > Primary >> Methyl.
- It involves the formation of the racemic mixture (50% inversion of configuration and 50% retention of configuration).
MECHANISM
Step1: Carbocation Formation
This involves the reversible ionization of alkyl halides in the presence of aqueous acetone or aqueous ethanol; as a result, a Carbocation is formed as an intermediate. This is the slowest and rate-determining step.
Step 2: Attack Of Nucleophile
In this step, the nucleophile attacks on Carbocation. This is a fast step. If the Nucleophile is neutral than the (e.g., H₂O, ROH), a proton transfer step may follow to give the final neutral product.
Step 3 (if applicable): Deprotonation
This step applies only if the nucleophile is neutral, then product may undergo deprotonation to give final product.
ENERGY PROFILE DIAGRAM OF SN1 REACTION
KINETICS OF SN1 REACTION
The rate of this reaction depends only on the concentration of substrate
(the molecule with the leaving group).
The rate equation of nucleophilic substitution unimolecular is:
Rate = k [Substrate]
Rate = k [R-X]
Where k is the rate constant.
Factors Affecting the Rate
1. Leaving Group Ability: A better leaving group enhances the rate of reaction.
2. Substrate Structure: Tertiary substrates are more reactive due to the formation of stable Carbocation, than those of secondary and primary
3. Solvent Effects: This reaction occurs best in polar protic solvents because they stabilize both the Carbocation and leaving group through hydrogen bonding. Polar protic solvents also solvate the nucleophile, reducing its reactivity.
4. Concentration of Substrate: As the reaction is first-order, the rate of this reaction depends only on the concentration of substrate.
STEREOCHEMISTRY OF SN1 REACTION
- This reaction involves the formation of Carbocation intermediate, which plays a significant role in stereochemical outcomes.
- In this reaction, the leaving group departs, forming a sp2-hybridized Carbocation with a trigonal planar structure. This allows the nucleophile to attack either from the front (same side as the leaving group) or from the back (opposite side to that of the leaving group), thus giving a racemic mixture (both R and S enantiomers in equal amounts).
- If the substrate was an active one, after substitution we get a di-mixture.
- It may show slight stereochemical bias due to solvent effects or ion pairing.
DIFFERENCE BETWEEN SN1 AND SN2 REACTIONS
| SN1 | SN2 |
|---|---|
| Two step reaction | Single step reaction |
| Follows first-order kinetics | Follows second order kinetics |
| Unimolecular reaction | Follows first-order kinetics |
| Carbocation is formed as an intermediate | No formation of Carbocation |
| The rate of reaction depends only on the concentration of substrate | The rate of reaction depends on the concentration of both substrate and nucleophile |
| 50% inversion and 50% retention of configuration (racemic mixture) | Inversion of configuration (Walden inversion) |
| No formation of transition State | Transition State is formed |
| Favored by the mild nucleophile | Favored by the strong nucleophiles |
| Nucleophiles attack from both sides either from the front or opposite side of the leaving group | Nucleophiles attack from the side opposite to that of leaving group |
| Possibility of rearrangement | No possibility of rearrangement |
| Favored in polar protic solvents | Favored in polar aprotic solvents |
CONCLUSION
SN1 and SN2 reactions follow distinct pathways with unique kinetics and stereochemical outcomes. SN2 is a one-step, bimolecular reaction favoring primary alkyl halides and leading to inversion of configuration. SN1 is a two-step, unimolecular process favoring tertiary alkyl halides, resulting in a racemic mixture. Understanding these mechanisms helps to optimize reaction conditions, predict outcomes, and improve efficiency in organic synthesis.
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