Unit 5: Alkyl and Aryl Halides

Types of Nucleophilic Substitution Reactions (SN1, SN2, SNi)

Nucleophilic substitution reactions occur when an electron-rich species (nucleophile) replaces a leaving group (halogen atom) attached to a carbon atom.

1. SN1 Mechanism (Substitution Nucleophilic Unimolecular)

The SN1 reaction is a two-step mechanism where rate depends only on the concentration of the alkyl halide substrate.

Rate Law: Rate = k[R-X]

Step-by-Step Mechanism:

1. Formation of Carbocation (Slow, Rate-Determining Step): The C-X bond cleaves heterolytically, producing a planar carbocation intermediate and a halide ion.
2. Nucleophilic Attack (Fast Step): The nucleophile attacks the planar carbocation from either the front or back side with equal probability.

Key Characteristics of SN1:

• Stereochemistry: Results in racemization (50% inversion, 50% retention) due to the planar sp2-hybridized carbocation intermediate.
• Substrate Preference: 3° Alkyl Halides > 2° Alkyl Halides > 1° Alkyl Halides > CH3-X (driven by carbocation stability).
• Solvent Effect: Favored by polar protic solvents (e.g., H2O, ROH) which stabilize carbocations and halide ions through solvation.
• Rearrangement: Possible if a more stable carbocation can form via hydride or alkyl shifts.

2. SN2 Mechanism (Substitution Nucleophilic Bimolecular)

The SN2 reaction is a concerted, single-step mechanism without any intermediate.

Rate Law: Rate = k[R-X][Nu⁻]

Step-by-Step Mechanism:

• The nucleophile attacks the carbon atom from the side opposite to the leaving group (backside attack).
• A pentacoordinate transition state is formed where the bond to the nucleophile is partially formed while the bond to the leaving group is partially broken.
• The leaving group departs, yielding the product with inverted stereochemistry.

Key Characteristics of SN2:

• Stereochemistry: Complete inversion of configuration (Walden Inversion).
• Substrate Preference: CH3-X > 1° Alkyl Halides > 2° Alkyl Halides > 3° Alkyl Halides (driven by minimal steric hindrance).
• Solvent Effect: Favored by polar aprotic solvents (e.g., DMSO, DMF, Acetone) which do not solvate the nucleophile strongly, keeping it highly reactive.

3. SNi Mechanism (Substitution Nucleophilic Internal)

The SNi reaction is an internal nucleophilic substitution mechanism that occurs with retention of configuration.

Example: Reaction of alcohols with thionyl chloride (SOCl2) in the absence of pyridine.

R-OH + SOCl2 → R-Cl + SO2 + HCl

Mechanism:

1. Alcohol reacts with SOCl2 to form an alkyl chlorosulfite intermediate (R-O-S(=O)Cl) and HCl.
2. The intermediate decomposes, where chlorine from the chlorosulfite group attacks the carbon from the same side from which the leaving group departs.
3. Sulfur dioxide (SO2) gas is evolved, producing alkyl chloride with retention of stereochemical configuration.

Exam Note: If pyridine is added to the SOCl2 reaction, pyridine reacts with HCl to form pyridinium chloride, generating free chloride ions (Cl⁻) which attack from the backside, shifting the mechanism to SN2 with inversion.

Preparation of Alkyl Halides

1. From Alkenes

A. Addition of Hydrogen Halides (HX):

Alkenes react with HX (HCl, HBr, HI) via electrophilic addition.

Markovnikov's Rule: R-CH=CH2 + H-X → R-CH(X)-CH3

The hydrogen atom adds to the double-bonded carbon with more hydrogen atoms, forming the more stable carbocation intermediate.

Peroxide Effect (Anti-Markovnikov Addition): R-CH=CH2 + HBr + (RO)2O2 → R-CH2-CH2-Br

In the presence of organic peroxides, HBr adds via a free-radical mechanism to yield 1-bromoalkanes. Note: Peroxide effect is shown only by HBr, not HCl or HI.

B. Addition of Halogens (X2):

R-CH=CH2 + Br2 (in CCl4) → R-CH(Br)-CH2Br (Vicinal dihalide)

Decolorization of bromine water/CCl4 serves as a test for unsaturation.

2. From Alcohols

A. Reaction with Halogen Acids (HX):

R-OH + HX → R-X + H2O (catalyst: anhydrous ZnCl2 for HCl - Lucas Reagent)

Order of reactivity of alcohols: 3° > 2° > 1°.

B. Reaction with Phosphorus Halides:

3 R-OH + PX3 → 3 R-X + H3PO3 (where X = Cl, Br, I)

R-OH + PCl5 → R-Cl + POCl3 + HCl

C. Reaction with Thionyl Chloride (Darzens Process):

R-OH + SOCl2 → R-Cl + SO2(g) + HCl(g)

Important Observation: The reaction with SOCl2 is the preferred laboratory method for preparing pure alkyl chlorides because the gaseous side-products (SO2 and HCl) escape, leaving pure alkyl chloride.

Chemical Reactions of Alkyl Halides

1. Hydrolysis

Alkyl halides react with aqueous alkalis or moist silver oxide to yield alcohols.

R-X + KOH (aq) → R-OH + KX

R-X + AgOH (moist Ag2O + H2O) → R-OH + AgX

2. Nitrite and Nitro Formation

Nitrite ion (NO2⁻) is an ambident nucleophile (it can attack through nitrogen or oxygen).

• Reaction with Potassium Nitrite (KNO2): KNO2 is predominantly ionic (K⁺ ⁻O-N=O). The oxygen atom carries a negative charge and attacks carbon, forming an alkyl nitrite.

  R-X + KNO2 → R-O-N=O (Alkyl nitrite) + KX

• Reaction with Silver Nitrite (AgNO2): AgNO2 is predominantly covalent (Ag-O-N=O). The unshared electron pair on nitrogen acts as the nucleophile, forming a nitroalkane.

  R-X + AgNO2 → R-NO2 (Nitroalkane) + AgX

3. Nitrile and Isonitrile Formation

Cyanide ion (CN⁻) is also an ambident nucleophile.

• Reaction with Potassium Cyanide (KCN): KCN is an ionic compound supplying free cyanide ions (:C≡N:⁻). Attack mainly occurs through carbon to form an alkyl cyanide (nitrile).

  R-X + KCN → R-CN (Alkyl nitrile) + KX

• Reaction with Silver Cyanide (AgCN): AgCN is predominantly covalent (Ag-C≡N). Nucleophilic attack occurs via the lone pair on nitrogen, forming an alkyl isonitrile (isocyanide).

  R-X + AgCN → R-NC (Alkyl isonitrile) + AgX

Williamson's Ether Synthesis: Elimination vs. Substitution

Williamson's Ether Synthesis

Williamson's ether synthesis is an SN2 reaction between an alkyl halide and a sodium alkoxide or phenoxide to yield ethers.

R-X + R'-ONa → R-O-R' + NaX

Mechanism and Limitations:

• Works best with primary (1°) alkyl halides.
• If a tertiary (3°) alkyl halide is used with a strong alkoxide base, elimination (E2) dominates completely over substitution, producing an alkene instead of an ether.

(CH3)3C-Br + CH3ONa → (CH3)2C=CH2 (Isobutylene) + CH3OH + NaBr

To prepare tert-butyl ethyl ether, the halide must be primary and the alkoxide tertiary: (CH3)3C-ONa + CH3-Br → (CH3)3C-O-CH3 + NaBr.

Elimination vs. Substitution Competition

Alkyl halides can undergo substitution (SN1/SN2) or elimination (E1/E2) depending on several key factors:

Preparation of Aryl Halides

1. From Phenol

Phenol can be converted into chlorobenzene by reaction with phosphorus pentachloride (PCl5), though yields are typically low due to formation of triphenyl phosphate side product.

C6H5OH + PCl5 → C6H5Cl + POCl3 + HCl

Direct reaction of phenol with HX generally fails to produce aryl halides cleanly because the C-O bond in phenol has partial double bond character due to resonance.

2. Sandmeyer Reaction

A primary aromatic amine (aniline) is first converted into a benzene diazonium salt using nitrous acid (NaNO2 + HCl) at 0–5 °C (Diazotization).

C6H5-NH2 + NaNO2 + 2 HCl (0-5 °C) → C6H5-N2⁺ Cl⁻ + 2 H2O

The freshly prepared diazonium salt is treated with cuprous halides dissolved in corresponding halogen acids:

• Chlorobenzene: C6H5-N2⁺ Cl⁻ + Cu2Cl2 / HCl → C6H5Cl + N2
• Bromobenzene: C6H5-N2⁺ Cl⁻ + Cu2Br2 / HBr → C6H5Br + N2
• Iodobenzene: C6H5-N2⁺ Cl⁻ + KI → C6H5I + N2 + KCl (Does not require copper catalyst)

3. Gattermann Reaction

A modification of the Sandmeyer reaction where copper powder and halogen acid (Cu/HX) are used instead of cuprous halide salts.

C6H5-N2⁺ Cl⁻ + Cu / HCl → C6H5Cl + N2 + CuCl

C6H5-N2⁺ Cl⁻ + Cu / HBr → C6H5Br + N2 + CuCl

Reactions of Chlorobenzene & Effect of Nitro Substituents

Aromatic Nucleophilic Substitution (SNAr)

Chlorobenzene is extremely unreactive towards nucleophilic substitution compared to alkyl halides due to:

Replacement of -Cl by -OH Group (Dow's Process)

Drastic conditions are required for nucleophilic substitution of unsubstituted chlorobenzene:

C6H5Cl + 2 NaOH (623 K, 300 atm) → C6H5ONa + NaCl + H2O

C6H5ONa + HCl → C6H5OH (Phenol) + NaCl

Effect of Nitro (-NO2) Substituent

Electron-withdrawing groups (-NO2) at ortho and para positions dramatically increase the reactivity of chlorobenzene toward nucleophilic substitution by withdrawing electron density from the ring and stabilizing the anionic intermediate (Meisenheimer complex).

Important Note: Nitro groups at the meta position show negligible activating effect because the negative charge in the resonance structure cannot be delocalized directly onto the nitro group oxygen atoms.

Benzyne Mechanism

When unactivated aryl halides are treated with extremely strong bases (such as KNH2 or NaNH2 in liquid NH3), aromatic nucleophilic substitution proceeds via an Elimination-Addition (Benzyne) Mechanism.

Overall Reaction: C6H5Cl + KNH2 (in liquid NH3) → C6H5NH2 (Aniline) + KCl

Step-by-Step Mechanism:

1. Elimination Step (Formation of Benzyne): Strong amide ion (NH2⁻) abstracts a proton ortho to the halogen atom. Subsequent loss of halide ion forms a highly reactive benzyne intermediate containing a formal carbon-carbon triple bond inside the ring.
2. Addition Step (Attack on Benzyne): Amide ion attacks either of the two carbons of the benzyne triple bond, forming a carbanion intermediate.
3. Protonation: Carbanion accepts a proton from liquid NH3 to form the substituted aniline product.

Cine Substitution: Because the nucleophile can attack either of the two carbons of the triple bond in benzyne, substitution can occur at the carbon bearing the halogen or the carbon adjacent to it. This phenomenon is called cine substitution.

Reactivity and Relative Strength of C-Halogen Bond

The reactivity of different halides toward nucleophilic substitution depends heavily on the nature of the C-X bond and the stabilization of reactive intermediates.

Comparison of Halide Types

1. Alkyl Halides (R-CH2-X): Carbon is sp3 hybridized. Single C-X bond easily undergoes SN1 or SN2 reactions. High reactivity.
2. Allyl Halides (CH2=CH-CH2-X): Highly reactive in SN1 because the allylic carbocation intermediate formed is strongly stabilized by resonance [CH2=CH-CH2⁺ ↔ ⁺CH2-CH=CH2].
3. Benzyl Halides (C6H5-CH2-X): Highly reactive in SN1 because the benzylic carbocation is extensively stabilized by resonance across the aromatic ring. Highly reactive in SN2 as well due to favorable orbital overlap.
4. Vinyl Halides (CH2=CH-X): Extremely unreactive. Carbon is sp2 hybridized; C-X bond has partial double-bond character due to resonance [CH2=CH-X ↔ ⁻CH2-CH=X⁺]. Vinyl carbocation is extremely unstable.
5. Aryl Halides (C6H5-X): Extremely unreactive toward simple substitution due to resonance stabilization (partial double bond character), sp2 hybrid carbon, and steric/electronic repulsion of nucleophiles by the π-cloud.

Summary Table of Relative C-X Bond Strength and Reactivity