10.3.1 Substitution Reactions (SN1 and SN2)

A. Nucleophilic Substitution

• Definition: A reaction in which a nucleophile (electron-rich species) replaces a leaving group (often a halide, tosylate, or other group that can depart with a pair of electrons) on a carbon center.

SN2 Mechanism (Bimolecular Nucleophilic Substitution)
- Concerted process: Bond forming and bond breaking occur simultaneously in a single transition state.
- Rate law: rate = k [substrate] [nucleophile] (second-order kinetics).
- Stereochemistry: Inversion of configuration (Walden inversion) at the carbon center, because the nucleophile attacks from the backside relative to the leaving group.
- Substrate preference: Primary alkyl halides react fastest; secondary are slower; tertiary rarely undergo SN2 due to steric hindrance. Methyl halides are most reactive.
- Common nucleophiles: OH–, CN–, N3–, RO–, RS–, NH3, amines, alkoxides, etc.
- Leaving groups: I– > Br– > Cl– > F– (in polar protic solvents, F– is a poor leaving group). Tosylate (–OTs), mesylate (–OMs), triflate (–OTf) are very good leaving groups.
- Example SN2: CH3–Br + OH– → CH3–OH + Br–. Hydroxide attacks methyl bromide from the backside, displacing Br– and yielding methanol. Reaction proceeds with inversion at carbon (not relevant for methyl since no stereocenter).

SN1 Mechanism (Unimolecular Nucleophilic Substitution)
- Stepwise process: First, the leaving group departs from the substrate to form a carbocation intermediate. Second, the nucleophile attacks the carbocation.
- Rate law: rate = k [substrate] (first-order kinetics). Nucleophile concentration does not appear in the rate law.
- Stereochemistry: Racemization occurs when substitution at a chiral carbon passes through a planar carbocation, which can be attacked from either face. However, slight preference for retention or inversion can arise if the leaving group or solvent blocks one face.
- Substrate preference: Tertiary alkyl halides react fastest (stable tertiary carbocation); secondary can react with strongly stabilized carbocations; primary and methyl rarely undergo SN1 because unstable carbocations.
- Nucleophile: Weaker nucleophiles (water, alcohols) can participate because carbocation formation is rate-determining.
- Solvent: Polar protic solvents (ethanol, water) stabilize the carbocation and the leaving anion, facilitating SN1.
- Example SN1: (CH3)3C–Cl dissolves in water; in the rate-determining step, chlorine leaves to form the tert-butyl carbocation. Water then attacks, yielding (CH3)3C–OH after deprotonation.

B. Electrophilic Substitution

• Aromatic electrophilic substitution (EAS): A class of reactions in which an electrophile (electron-deficient species) replaces a hydrogen on an aromatic ring, preserving aromaticity.
• Mechanism steps:
  a. Formation of electrophile (e.g., nitric acid + sulfuric acid generate nitronium ion NO2+).
  b. Electrophile attacks the aromatic pi system to form a nonaromatic carbocation intermediate (the arenium ion or sigma complex).
  c. Deprotonation of the sigma complex restores aromaticity.
• Common EAS reactions:
• Nitration: Ar–H + HNO3 (with H2SO4) → Ar–NO2 + H2O.
• Sulfonation: Ar–H + SO3 (in H2SO4) → Ar–SO3H (benzenesulfonic acid).
• Halogenation: Ar–H + X2 (Br2 or Cl2, with FeBr3 or FeCl3 catalyst) → Ar–X + HX.
• Friedel–Crafts Alkylation: Ar–H + R–Cl (with AlCl3) → Ar–R + HCl.
• Friedel–Crafts Acylation: Ar–H + R–CO–Cl (acid chloride, with AlCl3) → Ar–CO–R + HCl.
• Directing effects: Substituents already on the ring direct incoming electrophiles to ortho/para (if electron-donating) or meta (if electron-withdrawing). Steric hindrance can also influence regioselectivity (e.g., bulky substituents discourage ortho substitution).

10.3.2 Addition Reactions

A. Electrophilic Addition to Alkenes and Alkynes

• General pattern: An alkene (C=C) or alkyne (C≡C) acts as a nucleophile because its pi electrons are easily accessible. The first step is attack on an electrophile, breaking the pi bond and creating a carbocation (or a more stabilized vinyl cation in the case of alkynes). The second step is nucleophilic attack (often by a halide or anion of the electrophile), yielding the addition product.
• Typical reagents and products for alkenes:
• Hydrogen halides (HX, where X = Cl, Br, I):
• Markovnikov’s rule: H adds to the carbon bearing more hydrogens, X adds to the carbon bearing fewer hydrogens, because the more substituted carbocation intermediate is more stable.
• Example: CH3–CH=CH2 + HBr → CH3–CH(Br)–CH3 (2-bromopropane).
• Rearrangement can occur if the initially formed carbocation can rearrange to a more stable carbocation (hydride or alkyl shift).
• Halogenation (X2 addition):
• X2 (Br2 or Cl2) adds across C=C via a cyclic halonium ion intermediate. Stereochemistry is anti (the two halogen atoms add to opposite faces of the former double bond).
• Example: CH2=CH2 + Br2 → Br–CH2–CH2–Br (1,2-dibromoethane). Bromine adds in anti orientation.
• Hydration (addition of water):
• Acid-catalyzed hydration: alkene + H2O (H2SO4 catalyst) → alcohol. Follows Markovnikov’s rule.
• Oxymercuration-demercuration: alkene + Hg(OAc)2, H2O → organomercury intermediate → NaBH4 yields alcohol without rearrangement. Markovnikov product.
• Hydroboration-oxidation: alkene + BH3 or B2H6 → organoborane intermediate → H2O2, OH– yields alcohol with anti-Markovnikov regiochemistry and syn stereochemistry.
• Hydrogenation:
• H2 with a metal catalyst (Pt, Pd, or Ni) adds hydrogen across C=C to give alkane (syn addition).
• Alkynes hydrogenate stepwise to alkenes then to alkanes unless poisoned catalyst (e.g., Lindlar’s catalyst) yields syn cis-alkene.
• Polymerization: Radical or coordination polymerization of alkenes yields polymers. For example, ethene (CH2=CH2) in presence of Ziegler–Natta catalyst yields polyethylene.

10.3.3 Elimination Reactions (E1, E2)

General concept

• Elimination reactions remove atoms/groups from adjacent carbons in a substrate to form a double or triple bond. Typical elimination occurs from alkyl halides, alcohols, or amines, often producing alkenes or alkynes.

A. E2 Mechanism (Bimolecular Elimination)

1. One-step, concerted mechanism: a base abstracts a proton from the β-carbon while the leaving group (often a halide) departs from the α-carbon in a single transition state.
2. Rate law: rate = k [substrate][base].
3. Stereochemistry: The β-hydrogen being removed and the leaving group must be anti-periplanar (180°), ensuring optimal orbital overlap. This leads to the most stable alkene (often Zaitsev’s rule: the more substituted alkene is favored).
4. Base strength and substrate: Strong bases (OH–, OR–, tert-butoxide) favor E2. Tertiary alkyl halides often undergo E2 because SN2 is hindered, but secondary alkyl halides can undergo either E2 or SN2 depending on conditions.
5. Example: CH3–CHBr–CH2–CH3 + OH– → CH3–CH=CH–CH3 (but-2-ene) + Br– + H2O. The base removes a proton from the carbon adjacent to the one bearing Br, yielding the alkene.

B. E1 Mechanism (Unimolecular Elimination)

1. Stepwise process: leaving group departs first to form a carbocation. Then, a base removes a proton from the β-carbon, forming the double bond.
2. Rate law: rate = k [substrate]; independent of base concentration.
3. Stereochemistry: Since a planar carbocation intermediate forms, the base can remove a β-proton from either side, leading typically to a mixture of alkene stereoisomers (though most substituted alkene tends to dominate).
4. Substrate preference: Tertiary substrates favor E1 because they can form stable carbocations; secondary can also undergo E1 under weakly basic, polar protic conditions; primary rarely undergo E1.
5. Competing reactions: SN1 often competes with E1 if a nucleophile is present; for E1 to predominate, the base must be weak or in low concentration so that deprotonation of carbocation competes with nucleophilic attack.
6. Example: (CH3)3C–Br in ethanol (a poor nucleophile, poor base) forms tert-butyl carbocation, which then loses a proton to yield 2-methylpropene (isobutene).

10.3.4 Oxidation and Reduction Reactions

A. Oxidation of Organic Compounds

• Definition (organic context): Increase in oxidation state of carbon; often accomplished by increasing the number of carbon–oxygen bonds or reducing the number of C–H bonds.
• Common oxidizing agents:
• Potassium permanganate (KMnO4) in acidic, neutral, or basic medium.
• Potassium dichromate (K2Cr2O7) in acid (H2SO4) (orange solution turns green).
• Jones reagent (CrO3 in H2SO4).
• PCC (pyridinium chlorochromate) for mild oxidation, stopping at aldehyde stage.
• Ozone (O3) for oxidative cleavage of alkenes.
• Oxidation of alcohols:
• Primary alcohol → aldehyde → carboxylic acid:
• Mild oxidant (e.g., PCC) yields aldehyde selectively (no further oxidation to acid).
• Strong oxidant (KMnO4, K2Cr2O7/H2SO4) with heat yields carboxylic acid.
• Mechanism: Protonate –OH, form water leaving group, generate carbocation, deprotonate to form aldehyde; aldehyde is further oxidized by formation of geminal diol intermediate then acid.
• Secondary alcohol → ketone:
• Reagents such as KMnO4, K2Cr2O7, PCC will oxidize secondary alcohols to ketones (e.g., 2-propanol to acetone).
• Tertiary alcohols: Generally resist oxidation except under very strong conditions that cleave C–C bonds, yielding mixtures of smaller fragments.
• Oxidation of aldehydes and ketones:
• Aldehydes are easily oxidized to carboxylic acids by mild oxidizing agents (Tollens’ reagent [Ag(NH3)2]+, Fehling’s solution, Benedict’s solution, or mild dichromate).
• Ketones resist oxidation unless strong conditions break C–C bonds, yielding carboxylic acids or other fragments.
• Oxidation of alkenes and alkynes:
• Ozonolysis: O3, followed by reductive workup (e.g., Zn, H2O or Me2S), cleaves double bonds to yield carbonyl compounds (aldehydes or ketones). Oxidative workup (KMnO4, H+) cleaves further to acids.
• Example: CH3–CH=CH2 → O3, Zn/H2O → CH3–CHO (acetaldehyde) + HCHO (formaldehyde).
• Permanganate oxidation: KMnO4 (dilute, cold) oxidizes alkene to diol (cis-glycol, syn addition). Under strong or hot conditions, oxidative cleavage occurs to yield carboxylic acids (or ketones if the double bond is internal).

10.3.5 Rearrangement Reactions

• Definition: A molecular rearrangement involves the migration of an atom or group from one position to another within the same molecule, often via a reactive intermediate such as a carbocation, carbanion, or free radical.

A. Wagner-Meerwein rearrangements (common in carbocation chemistry)

• When a carbocation can rearrange to a more stable carbocation, a group (hydride or alkyl) shifts from an adjacent carbon to the carbocation center. The rearranged carbocation then continues along a reaction pathway (e.g., elimination or nucleophilic attack).
• Example: Tert-butyl methyl carbocation formation from isobutyl halide:
• CH3–CH2–CH(CH3)–Cl (isobutyl chloride) → via SN1 conditions forms CH3–CH2–C+(CH3)2 (secondary carbocation).
• A methyl shift from the adjacent carbon yields a more stable tertiary carbocation (CH3)3C+–CH2.

B. Pinacol rearrangement

• Vicinal diols (pinacols) under acidic conditions rearrange to ketones or aldehydes. The mechanism involves protonation of one –OH, loss of water to form a carbocation, and migration of a neighboring group to stabilize the adjacent positive charge, yielding a carbonyl after deprotonation.
• Example: 2,3-dimethyl-2,3-butanediol under acid yields 3,3-dimethyl-2-butanone (pinacolone).

C. Beckmann rearrangement

• Oximes (R–CH=NOH) under acidic conditions can rearrange to amides (R–C(=O)–NH–R′) with migration of a substituent anti to the leaving group (–OH) on the imine carbon.
• Example: Cyclohexanone oxime → ε-caprolactam (precursor to Nylon-6).

D. Claisen rearrangement

• A [3,3] sigmatropic rearrangement of allyl vinyl ethers to yield γ,δ-unsaturated carbonyl compounds. The concerted pericyclic mechanism passes through a six-membered transition state.
• Example: Allyl phenyl ether → 2-allylphenol on heating.

E. Other rearrangements

• Baeyer–Villiger oxidation: Ketones oxidized by peroxy acids rearrange to esters or lactones, with migration of the more substituted alkyl group to the oxygen.
• Sommelet–Hauser rearrangement, Favorskii, Curtius, Hofmann, and Stevens rearrangements are other named examples, each with specialized scope.