Nucleophilic and Electrophilic Substitution Reactions

In a substitution reaction, one atom or group in a molecule is replaced by another: haloalkanes undergo nucleophilic substitution (S_N1 or S_N2), in which a nucleophile replaces the halogen, while aromatic compounds such as benzene undergo electrophilic substitution, in which an electrophile replaces a hydrogen atom. In brief: primary haloalkanes react by S_N2 in one step with inversion of configuration, tertiary ones by S_N1 through a carbocation, and benzene is nitrated to nitrobenzene by the nitronium ion, NO₂⁺.

Substitution is the way in which functional groups are exchanged, and it is central to the synthesis of alcohols, amines, nitriles and substituted aromatic compounds. This article compares the two mechanisms of nucleophilic substitution and the factors that decide between them, then explains electrophilic aromatic substitution and the directing effects of substituents, with tables and worked examples.

What is the S_N2 mechanism?

S_N2 stands for substitution, nucleophilic, bimolecular. The nucleophile attacks the carbon bearing the leaving group from the side opposite to the leaving group, and the new bond forms as the old one breaks, in a single step through a pentacoordinate transition state. The rate depends on both reactants: rate = k[RX][Nu⁻]. If the carbon is a stereocenter, the configuration is inverted, like an umbrella turning inside out (the Walden inversion). An example is CH₃CH₂Br + OH⁻ → CH₃CH₂OH + Br⁻.

What is the S_N1 mechanism?

S_N1 stands for substitution, nucleophilic, unimolecular. It takes place in two steps: (1) the slow, rate-determining ionization of the haloalkane into a carbocation and a halide ion; (2) rapid attack of the nucleophile on the carbocation. The rate depends only on the haloalkane: rate = k[RX]. The carbocation is planar, so a nucleophile can attack from either face, and a chiral starting material gives a racemic mixture. For (CH₃)₃CBr + H₂O → (CH₃)₃COH + HBr, the intermediate is the tert-butyl cation.

How do S_N1 and S_N2 compare?

How does structure affect the rate?

In S_N2, bulky groups on the carbon block the approach of the nucleophile, so primary haloalkanes react fastest and tertiary ones hardly at all. In S_N1, alkyl groups stabilize the carbocation, so the rate order is reversed. Approximate relative rates of solvolysis (S_N1 conditions) for alkyl bromides in water: CH₃Br 1, CH₃CH₂Br about 2, (CH₃)₂CHBr about 45 and (CH₃)₃CBr about 10⁸ times faster than methyl bromide. Secondary haloalkanes can react by either mechanism, depending on the conditions.

What is electrophilic aromatic substitution?

The delocalized π electrons of benzene attack strong electrophiles. The ring is first attacked to form a carbocation intermediate (an arenium ion), which loses H⁺ to restore the aromatic ring. The overall result is that a hydrogen atom is replaced by the electrophile. The main reactions are:

• Nitration: benzene + conc. HNO₃ and H₂SO₄ (50 °C) → nitrobenzene. The sulfuric acid generates the electrophile, the nitronium ion: HNO₃ + 2H₂SO₄ → NO₂⁺ + H₃O⁺ + 2HSO₄⁻.
• Halogenation: benzene + Br₂ with FeBr₃ (or Fe) → bromobenzene + HBr. The catalyst polarizes Br₂.
• Sulfonation: benzene + hot conc. H₂SO₄ or fuming H₂SO₄ → benzenesulfonic acid.
• Friedel–Crafts alkylation and acylation: benzene + RCl (or RCOCl) with AlCl₃ → alkylbenzene (or aryl ketone).

How do substituents direct the reaction?

Electron-donating groups stabilize the arenium ion when the attack is at the ortho or para position, so they make the ring more reactive. Electron-withdrawing groups destabilize it, and the meta attack is the least unfavorable.

Worked examples

Example 1: predicting the mechanism

What mechanism will 2-bromo-2-methylpropane follow with water? It is tertiary, the nucleophile is weak and the solvent is polar protic, so S_N1. For bromoethane with sodium cyanide in ethanol: primary, strong nucleophile, S_N2.

Example 2: the effect of concentration on the rate

For an S_N2 reaction, if both [RX] and [OH⁻] are doubled, the rate increases by a factor of 2 × 2 = 4. For an S_N1 reaction, doubling [OH⁻] has no effect on the rate, and doubling [RX] doubles it.

Example 3: stereochemistry

(R)-2-bromobutane reacts with OH⁻ in acetone (S_N2) to give (S)-butan-2-ol, with inversion. The same compound in aqueous ethanol under S_N1 conditions would give a mixture of (R)- and (S)-butan-2-ol, mainly racemic.

Example 4: nitration of toluene

The methyl group is activating and ortho/para directing, so toluene is nitrated faster than benzene, and gives mainly 2-nitrotoluene and 4-nitrotoluene (about 58 % and 38 %, with about 4 % meta product). From 10.0 g of toluene (M = 92.14 g/mol; 0.1085 mol), the maximum mass of mononitrotoluenes (M = 137.1 g/mol) is 0.1085 × 137.1 = 14.9 g.

Example 5: a two-step benzene synthesis

To prepare 3-nitrobenzoic acid from toluene: oxidize the methyl group first (KMnO₄) to give benzoic acid, whose –COOH is meta directing, then nitrate. If the order were reversed, nitration would give the ortho and para products.

Who worked out the mechanisms?

Paul Walden discovered in 1896 that a substitution can invert the configuration of a chiral center. The mechanisms S_N1 and S_N2 were established in the 1930s by Edward Hughes and Christopher Ingold at University College London, through kinetic studies and stereochemistry, and Ingold’s names for them are still used. Charles Friedel and James Crafts discovered their reaction in 1877. The arenium ion mechanism of aromatic substitution was supported by the work of G. W. Wheland in 1942.

Which mistakes are common?

• Mixing up the mechanisms: S_N2 is one step with inversion, S_N1 two steps via a carbocation.
• Expecting tertiary haloalkanes to react by S_N2: they are too hindered.
• Forgetting the catalyst in aromatic halogenation: benzene does not react with bromine without FeBr₃.
• Confusing the directing groups: –NO₂ directs meta, –OH directs ortho and para.
• Trying Friedel–Crafts on a strongly deactivated ring: nitrobenzene does not react.