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Ipso and Cine Substitution

Understanding positional selectivity in Aromatic Substitution.

By chemca Team • Updated Jan 2026

In aromatic substitution reactions, the incoming group usually replaces a hydrogen atom (Electrophilic) or a leaving group (Nucleophilic). The position of entry defines the type of substitution: Ipso (same position) or Cine (adjacent position).

1. Ipso Substitution

Definition

Ipso substitution occurs when the incoming group attaches to the same carbon atom that bears the leaving group (a substituent other than Hydrogen).

A. In Nucleophilic Aromatic Substitution ($S_NAr$):
This is the standard direct substitution where the nucleophile attacks the carbon bearing the halogen.

$$ Ar-Cl + OH^- \xrightarrow{\text{Drastic Cond.}} Ar-OH + Cl^- $$

B. In Electrophilic Aromatic Substitution:
Usually, $H^+$ is replaced. However, groups like $-SO_3H$, $-SiR_3$, or $-Br$ can be replaced by a strong electrophile (like $NO_2^+$). This is Ipso attack.

$$ \text{p-Cresol Sulphonic Acid} + HNO_3 \rightarrow \text{2-Nitro-p-Cresol} + H_2SO_4 $$

Here, the $-SO_3H$ group at the ipso position is replaced by $-NO_2$.

2. Cine Substitution

Definition

Cine substitution occurs when the incoming group enters at a position adjacent (ortho) to the carbon atom that bore the leaving group.

Mechanism: Benzyne Intermediate
Cine substitution is the hallmark of the Elimination-Addition mechanism involving a Benzyne intermediate.

$$ \underset{\text{Chlorobenzene}}{C_6H_5Cl} + \underset{\text{Amide}}{NH_2^-} \xrightarrow{-HCl} \underset{\text{Benzyne}}{C_6H_4} \xrightarrow{NH_3} \underset{\text{Aniline}}{C_6H_5NH_2} $$

Proof (Isotopic Labeling):
If the carbon bearing chlorine is labeled ($^{14}C$), the product shows the nucleophile attached to both the labeled carbon (Ipso/Direct) and the adjacent carbon (Cine).

$$ [1\text{-}^{14}C]\text{-Cl} \rightarrow 50\% [1\text{-}^{14}C]\text{-NH}_2 \text{ (Direct)} + 50\% [2\text{-}^{14}C]\text{-NH}_2 \text{ (Cine)} $$

3. Comparison & Conditions

Feature	Ipso Substitution (Direct)	Cine Substitution (Indirect)
Position	Same carbon as Leaving Group	Adjacent carbon to Leaving Group
Mechanism	$S_NAr$ (Addition-Elimination)	Benzyne (Elimination-Addition)
Condition	Presence of EWG (like $NO_2$) ortho/para	Strong Base ($NaNH_2$) / High Temp, No strong EWG
Intermediate	Meisenheimer Complex (Carbanion)	Benzyne (Aryne)

4. Regioselectivity in Cine Substitution

Substituted Benzenes

When substituents are present on the ring, the major product of the benzyne mechanism depends on the inductive effect of the group stabilizing the carbanion intermediate.

Example: m-Bromoanisole + $NaNH_2$:
The nucleophile attacks to place the negative charge closer to the Electron Withdrawing Group ($-OCH_3$ exerts $-I$ effect at ortho position).

$$ \text{m-Bromoanisole} \rightarrow \text{m-Anisidine (Major via Cine)} $$

The meta product is formed via attack at the meta carbon (cine to the original bromine position if elimination happened towards para, or direct if elimination happened towards ortho).

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