Alkyl Halides

Bimolecular nucleophilic substitution (SN2) is a reaction in which a nucleophile attacks an alkyl substrate, displacing a leaving group. It is a concerted single-step process: nucleophile attack and leaving-group expulsion occur simultaneously.

Kinetic characteristics: the rate depends on the concentration of both reactants: $v = k[\text{RX}][\text{Nu}^-]$ (second order, bimolecular).

Stereochemistry: Walden inversion. The nucleophile attacks from the side opposite the leaving group (back-side attack), causing inversion of configuration at the stereogenic carbon. It is like an umbrella turning inside out.

Factors affecting SN2 rate:

• Substrate (steric effect): CH₃X (methyl, fastest) > 1° > 2° >> 3° (tertiary, no SN2). Bulky groups prevent back-side attack. Order: $mathrm{CH_3X > RCH_2X > R_2CHX > R_3CX}$.
• Nucleophile: stronger and negatively charged gives faster rate. Nucleophilicity order (in polar aprotic solvents): $mathrm{-S^- > Gamma > -CN^- > -OH^- > CH_3COO^- > Cl^- > Br^- > H_2O}$.
• Leaving group: more stable as an anion is better. Order: $mathrm{OTs^- > Gamma > Br^- > Cl^- > F^- >> OH^-}$.
• Solvent: polar aprotic solvents (acetone, DMSO, DMF, CH₃CN) accelerate SN2 because they do not solvate the nucleophile. Polar protic solvents (H₂O, ROH) slow SN2 by solvating the nucleophile.

Real-world applications: SN2 is used to synthesize a wide range of compounds: alcohols from halides (with OH⁻), nitriles (with CN⁻, chain elongation), ethers (Williamson synthesis: alkoxide + 1° alkyl halide). Walden inversion is exploited in stereoselective synthesis.

Unimolecular nucleophilic substitution (SN1) occurs in two steps, with formation of a carbocation intermediate:

1. Dissociation (slow, rate-determining step): the C—X bond breaks heterolytically, forming a carbocation R⁺ and anion X⁻. Rate depends only on substrate concentration: $v = k[\text{RX}]$ (first order).
2. Nucleophilic attack (fast step): the nucleophile (often the solvent) quickly attacks the carbocation from either side, yielding a racemic mixture (racemization) if the carbon is chiral.

Characteristics:

• Kinetics: first order, $v = k[\text{RX}]$ (independent of [Nu⁻])
• Substrate: 3° > 2° >> 1° ≈ CH₃X (no SN1). Carbocation stability is crucial: tertiary > secondary >> primary ≈ methyl
• Stereochemistry: racemization (nucleophile attacks from both sides of the planar carbocation). If the starting substrate is enantiomerically pure R, an R/S mixture is obtained
• Rearrangements: the carbocation intermediate may undergo rearrangements (1,2-hydride or alkyl migration) to form a more stable carbocation, leading to unexpected products
• Leaving group: same order as SN2: better anion = easier dissociation
• Solvent: polar protic solvents (H₂O, alcohols, acids) favor SN1 because they stabilize the carbocation
• Nucleophile: nucleophile strength is not critical (fast step). Even weak nucleophiles (H₂O, ROH) react if the carbocation is stable enough

SN1 vs SN2 comparison: SN2 favored by 1° substrate, strong nucleophile, aprotic solvent; SN1 favored by 3° substrate, good leaving group, protic solvent. With 2° substrates, the outcome depends on conditions.

Real-world applications: SN1 is involved in solvolysis reactions (hydrolysis of tertiary halides with H₂O to form alcohols). Carbocation rearrangements are important in synthesis (pinacol rearrangement, Wagner-Meerwein) and in the biosynthesis of terpenes and steroids.

Elimination reactions compete with substitution and lead to alkene formation by HX loss (dehydrohalogenation). Two main mechanisms:

Bimolecular elimination (E2):

• Concerted single-step process: a strong base (e.g., HO⁻, RO⁻) abstracts a eta proton while the leaving group X⁻ departs. The C=C $pi$ bond forms simultaneously.
• Kinetics: $v = k[\text{RX}][\text{B}^-]$ (second order)
• Antiperiplanar stereochemistry: the H and the leaving group must be anti (180° apart) to allow orbital overlap leading to $pi$ bond formation
• Substrate: 1° < 2° < 3° (E2 elimination is favored by more substituted halides because the alkene formed is more stable — Saytsev rule)
• Requires a strong base and steric hindrance blocking SN2

Unimolecular elimination (E1):

• Two steps: (1) substrate dissociates to carbocation (same as SN1), (2) deprotonation of the carbocation by a weak base (often the solvent).
• Kinetics: $v = k[\text{RX}]$ (first order, independent of [B⁻])
• Direct competition with SN1: every carbocation can be attacked by a nucleophile (SN1) or lose a proton (E1). At higher temperatures, E1 is favored.
• Follows the Saytsev rule: the more substituted (more stable) alkene is the major product
• May give carbocation rearrangements

Saytsev (Zaitsev) rule: in elimination, the more stable alkene (with the more substituted double bond) is the major product. Exception: with sterically hindered bases (potassium tert-butoxide, t-BuOK) Hofmann elimination occurs (less substituted alkene, terminal alkene).

Real-world applications: dehydrohalogenation of alkyl halides is a common method for preparing alkenes in the lab and industry. The E2 reaction is used in monomer synthesis (e.g., vinyl chloride from dichloroethane).

The competition between substitution (SN1/SN2) and elimination (E1/E2) is a central aspect of alkyl halide reactivity. Factors determining the reaction course:

1. Substrate structure:

• 1° substrates: SN2 (if nucleophile is good) or E2 (if base is strong and bulky). SN1/E1 do not occur for 1° (carbocations too unstable).
• 2° substrates: can undergo SN2, SN1, E2 or E1 depending on base, nucleophile, and solvent. Competition is greatest (most studied case).
• 3° substrates: SN2 impossible (steric hindrance). E2 (strong base) or SN1/E1 (neutral/acidic conditions) prevail.

2. Base/nucleophile strength and bulk:

• Strong, small base (HO⁻, CH₃O⁻) → E2 on 3°, SN2 on 1°
• Strong, bulky base (t-BuOK) → E2 (Hofmann elimination, less substituted product)
• Weak nucleophile, weak base (H₂O, ROH) → SN1/E1 (solvolysis conditions)

3. Temperature: higher temperatures favor elimination (higher activation energy, greater entropic contribution). Elimination produces more molecules (entropy increase), so it is favored at high T.

4. Solvent: polar protic solvents favor SN1/E1 (stabilize the carbocation). Polar aprotic solvents favor SN2/E2.

Empirical rules: 1° + strong base/nucleophile → SN2; 3° + strong base → E2; 3° + H₂O/ROH → SN1/E1 (solvolysis, mixture). 2° is the intermediate case: with strong base (HO⁻) in ethanol → E2 ≥ SN2.

Real-world applications: understanding SN/E competition is crucial for designing efficient syntheses. For example, to obtain an ether from an alcohol (Williamson synthesis) a 1° halide with a strong alkoxide is used: SN2 is favored and elimination minimal.