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Nucleophilic Substitution Reactions: $S_N2$ and $S_N1$ Mechanisms

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Reactions

Energy Profile and Activation Energy

The (bimolecular nucleophilic substitution) reaction is characterized by a single transition state where bond formation and bond breaking occur simultaneously. The reaction requires an input of energy to overcome the activation barrier, which is the difference in free energy between the reactants and the transition state.

  • Activation Energy (): The energy difference between the starting material and the transition state.

  • Free Energy Change (): The difference in energy between starting materials and products.

  • Rate Equation:

  • Temperature Effect: A 10°C increase approximately doubles the reaction rate. Higher temperatures help more molecules reach the transition state.

Example: The reaction of CH3Cl with hydroxide has kJ mol−1, requiring heating to proceed at a reasonable rate.

Mechanism

The reaction is a concerted process where the nucleophile attacks the electrophilic carbon as the leaving group departs, all in a single step. This leads to inversion of configuration at the carbon center (Walden inversion).

  • Mechanism: Nucleophile attacks from the opposite side of the leaving group, forming a transition state with partial bonds to both nucleophile and leaving group.

  • Second Order Kinetics: The rate depends on both the nucleophile and the substrate.

  • Stereochemistry: Inversion of configuration occurs at the reaction center.

Example:

Effect of Substituents on Rates

The rate of reactions is highly sensitive to steric hindrance around the electrophilic carbon. Methyl and primary halides react much faster than secondary or tertiary halides.

Class of Halide

Example

Relative Rate

Methyl

CH3Br

>1000

Primary (1°)

CH3CH2Br

50

Secondary (2°)

(CH3)2CHBr

1

Tertiary (3°)

(CH3)3CBr

<0.001

n-Butyl (1°)

CH3CH2CH2CH2Br

20

Isobutyl (1°)

(CH3)2CHCH2Br

2

Neopentyl (1°)

(CH3)3CCH2Br

0.0005

Additional info: Bulky groups near the reaction center slow down reactions dramatically.

Solvent Effects

Solvents play a crucial role in reactions by influencing the nucleophilicity of the attacking species.

  • Protic Solvents: Contain acidic hydrogens (O–H or N–H) that can hydrogen bond with nucleophiles, reducing their reactivity. Nucleophilicity increases down the periodic table in protic solvents.

  • Aprotic Solvents: Lack acidic protons and cannot hydrogen bond with nucleophiles, allowing them to remain more reactive. Examples: acetonitrile, DMF, DMSO, acetone.

  • Effect: reactions proceed faster in polar aprotic solvents.

Structure of Substrate and Leaving Groups

The structure of the alkyl halide and the nature of the leaving group significantly affect rates.

Relative Displacement Rates of Halides ()

Average Relative Rate for Leaving Group

CH3CH2CH2CH2Cl: 40

PhSO2O−: 6

CH3CH2Cl: 120

I−: 3

CH3COOCH2Cl: 100

Br−: 1

CH3OCH2Cl: 400

H2O+: 1

Neopentyl: ~0.00001

(CH3)2S+: 0.5

CH3CH2CH2CH2Br: 30

Cl−: 0.02

CH3CH2Br: 1

F−: 0.0001

Additional info: Iodide is a better leaving group than bromide or chloride; fluorides are poor leaving groups.

Effect of Solvent Polarity and Nucleophiles

Solvent polarity and the strength of the nucleophile influence rates.

  • Increasing solvent ionizing power: Can accelerate or decelerate the reaction depending on the nucleophile and substrate.

  • Relative nucleophilicity in protic solvents:

Nucleophile

Relative Rate

PhS−

500

CN−

5

I−

4

Br−

1

CH3COO−

0.2

NO3−

0.01

Reactions

Energy Diagram and Mechanism

The (unimolecular nucleophilic substitution) reaction proceeds via a two-step mechanism involving the formation of a carbocation intermediate. The rate-determining step is the loss of the leaving group to form the carbocation.

  • Step 1: Formation of the carbocation (rate-limiting, endothermic).

  • Step 2: Nucleophile attacks the carbocation (fast, low activation energy).

  • Order of Reactivity: Follows carbocation stability: 3° > 2° > 1° >> CH3X.

  • Rate Equation:

  • Leaving Group: A better leaving group increases the rate.

Reaction Mechanism (Stepwise)

The mechanism involves the following steps:

  1. Loss of the leaving group to form a carbocation intermediate.

  2. Nucleophilic attack on the carbocation to form the product.

  3. If the nucleophile is neutral, a third step (deprotonation) may be required to yield the final product.

Example: Formation of a tertiary carbocation followed by attack by methanol and subsequent deprotonation to yield an ether.

Comparison of and Mechanisms

  • : Concerted, single-step, inversion of configuration, sensitive to steric hindrance, second order.

  • : Stepwise, carbocation intermediate, racemization possible, favored by stable carbocations and good leaving groups, first order.

Additional info: reactions are more common with tertiary alkyl halides, while reactions are favored by methyl and primary halides.

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