JEE Chemistry Haloalkanes and Haloarenes Notes Set 05

Nucleophilic Substitution: Overview

In a nucleophilic substitution a nucleophile (Nu) replaces a leaving group (g) at an sp3 carbon: \( \ce{R-g + Nu- -> R-Nu + g-} \). The three common pathways are SN1 (unimolecular), SN2 (bimolecular) and SNi (internal return). Substitution on an aromatic ring that carries strong electron-withdrawing groups follows a different pathway, SNAr.

SN1 Reaction

Two steps: slow ionisation of R-g to a planar carbocation, then fast attack of the nucleophile. Rate = k[RX], first order, independent of the nucleophile.
Because of the carbocation, rearrangements (hydride or alkyl shifts) can occur and a chiral substrate gives racemisation.
Favoured by: tertiary, benzylic and allylic substrates (stable cations); weak or neutral nucleophiles; polar protic solvents (water, alcohols, which also act as the nucleophile in solvolysis); good leaving groups (I > Br > Cl > F).

SN2 Reaction

One concerted step through a single transition state in which the nucleophile attacks from the back side as the leaving group departs. Rate = k[RX][Nu], second order, so doubling both concentrations multiplies the rate by 4.
The configuration at the carbon is inverted (Walden inversion). Rate falls with steric hindrance: methyl > primary > secondary >> tertiary; branching on the carbon next to the reacting centre (neopentyl type) also slows it. Alpha-carbonyl and allylic or benzylic halides react fast.
Favoured by strong, unhindered nucleophiles and polar aprotic solvents (DMSO, DMF, acetone), which leave the anion bare. Williamson ether synthesis and the reaction of acetylide ions with primary halides are SN2 reactions.

SN1 and SN2 Compared

Alcohols to Alkyl Halides

With HX (Lucas reagent HCl/ZnCl2), tertiary alcohols react by SN1 at once, secondary alcohols slowly (with possible rearrangement) and primary alcohols by SN2. OH is a strong base and a poor leaving group, so it must be protonated first.
SOCl2 in the absence of base gives the chloride with retention of configuration (SNi, through the chlorosulphite and an internal return); with pyridine the mechanism changes to SN2 with inversion. PCl3 and PCl5 usually invert the configuration.

Allylic and Benzylic Systems

Allylic and benzylic halides ionise rapidly because the cations are delocalised. An allylic cation can be captured at either end, so allylic alcohols and halides give a mixture of isomeric products (allylic rearrangement), as when crotyl alcohol reacts with HBr. The 3-chlorocyclopropene cation is aromatic (2 pi electrons) and forms readily, while the cyclopentadienyl cation (4 pi electrons) is antiaromatic and does not.

Aromatic Nucleophilic Substitution (SNAr)

A halogen on a benzene ring can be replaced by a nucleophile when strong electron-withdrawing groups (NO2, CN, C=O) sit ortho or para to it. The nucleophile adds to the ipso carbon, giving a delocalised anionic Meisenheimer complex, and the halide then leaves (addition-elimination).
More ortho/para nitro groups give a faster reaction (2,4,6-trinitrochlorobenzene is far more reactive than chlorobenzene). Because the addition step is rate determining, the order for the halogen is F > Cl > Br > I, the reverse of SN2. A meta nitro group does not activate the ring.
Unactivated aryl halides do not react by SN1 or SN2, because the C-X bond has partial double-bond character and the carbon is sp2.

Ethers and Epoxides

Ethers are cleaved by HI or HBr. The oxygen is protonated and the halide attacks the carbon: with primary and methyl groups at the less hindered carbon (SN2); with a tertiary group at that carbon (SN1). Aryl alkyl ethers give a phenol and an alkyl halide, because the aryl C-O bond is not cleaved. Excess HX converts the alcohol formed into a second alkyl halide.
Epoxides open easily because of ring strain: with Grignard reagents and other strong nucleophiles the nucleophile attacks the less hindered carbon (SN2), while under acid catalysis the attack goes largely to the more substituted carbon, with inversion at the carbon attacked.
In the Williamson synthesis the halide must be primary (or methyl) and the alkoxide may be hindered: for a tert-butyl benzyl ether use benzyl chloride with sodium tert-butoxide.