10.3. Types of Organic Reactions

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.

Substitution reactions involve replacing one functional group in a molecule with another. In the SN2 mechanism, a nucleophile directly attacks the substrate and replaces the leaving group in a single concerted step, leading to an inversion of configuration at the carbon atom due to the backside attack of the nucleophile. This means that if the carbon was chiral, the spatial arrangement is flipped. On the other hand, the SN1 mechanism is a two-step process where the leaving group first departs to form a carbocation (a positively charged carbon atom), and then a nucleophile attacks this intermediate. This often leads to racemization since the nucleophile can attack from either side of the planar carbocation. SN2 reactions are faster with primary substrates, while SN1 is typically faster with tertiary substrates because they form more stable carbocations.

Think of SN1 like a party where someone leaves the room (leaving group), creating an empty space (carbocation) at a table. Different friends (nucleophiles) can now take that chair—a few of them might even sit in different orientations, leading to a mix of outcomes (racemization). Similarly, SN2 can be likened to a friendly swap at the table: if you’re seated in a certain position and your friend wants to take your seat, you both have to coordinate your movements (the backside attack) to switch places, which directly changes how the seating looks (inversion of configuration).

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.

1. 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.

2. 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.

3. 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).

Electrophilic substitution is a crucial reaction type particularly for aromatic compounds. Here, an electrophile attacks the aromatic system, causing one hydrogen atom to be replaced without losing the aromatic character of the ring. The process begins with the generation of a reactive electrophile (like the nitronium ion in nitration), which then forms a non-aromatic carbocation intermediate upon attacking the aromatic ring. Finally, the removal of a proton restores the aromatic system. The outcome of these reactions can depend on existing substituents on the aromatic ring: electron-donating groups enhance electrophilic attack in ortho/para positions, while electron-withdrawing groups direct attacks to meta positions. This leads to key applications in developing new compounds.

Consider electrophilic substitution akin to a traditional dance at a family function where every dancer (the hydrogen atom in the aromatic ring) has to leave their place for the next generation of dancers (the electrophile). While one dancer leaves for a new pair (the electrophile replaces the hydrogen), the dance continues without breaking the rhythm (the ring preserves its aromatic nature). Each person’s dance style—a parent who likes to lead (an electron donating group)—can encourage more guests to join in the next dance (making it more likely for electrophiles to attack at certain positions) or make other guests leave the floor to avoid stepping on their toes (directing the reaction to less favored positions).