Organic Chemistry I: Substitution Reactions

Substitution reactions involve the replacement of one atom or group of atoms in a molecule with another atom or group of atoms.

Alkyl Halide (Haloalkane): A compound containing a halogen covalently bonded to an sp3 hybridized carbon, symbolized as RX.
Vinyl Halide (Haloalkene): A compound containing a halogen bonded to an sp2 hybridized carbon.
Aryl Halide (Haloarene): A compound containing a halogen bonded to a benzene ring, symbolized as ArX.

Several polyhaloalkanes are common solvents and referred to by trivial names.
In perhalogenated molecules, all hydrogen atoms are replaced by halogens.
Alkyl halides are generally dense liquids and solids that are insoluble in water.

The C–X bond (where X denotes the halogen) is polar:
- Slight positive charge (24 δ+) on carbon end.
- Slight negative charge (24 δ-) on halogen end.
The bond strength of C-X decreases in the order:
C-F > C-Cl > C-Br > C-I
Alkyl fluorides are less reactive due to the strong C-F bond.

Bond Type and Length:
- CH3–H: Length = 0.11 nm, Strength = 414 kJ/mol.
- CH3–F: Length = 0.14 nm, Strength = 464 kJ/mol, Dipole Moment = 1.85 D.
- CH3–Cl: Length = 0.18 nm, Strength = 355 kJ/mol, Dipole Moment = 1.87 D.
- CH3–Br: Length = 0.19 nm, Strength = 309 kJ/mol, Dipole Moment = 1.81 D.
- CH3–I: Length = 0.21 nm, Strength = 228 kJ/mol, Dipole Moment = 1.62 D.

Alkyl halides have higher boiling points than alkanes of similar size and shape due to greater polarizability from halogen’s unshared electron pairs.
Polarizability: A measure of the ease of distortion of electron density; varies among halogens: fluorine has low polarizability while iodine has high polarizability.
Hydrocarbons and alkyl fluorides with similar weight and shape have comparable boiling points, but alkyl fluorides have lower boiling points due to fluorine's electron holding nature.

The transition state involves bond-making and breaking simultaneously:
- C–Br bond partially broken, C–O bond partially formed.
- The nucleophile and leaving group are oriented 180° apart in the transition state, leading to an inversion of configuration (Walden inversion).

SN2 Mechanism (Substitution Nucleophilic Bimolecular):
- One-step mechanism.
- Second-order kinetic equation: rate = k[nucleophile][electrophile]
- Higher steric hindrance decreases reaction rate.
- Polar aprotic solvents enhance SN2 rates by generating “naked,” reactive nucleophiles.

Nucleophilicity is a kinetic property measured by the rate of reactions under standard conditions.
Basicity is a thermodynamic property related to equilibrium in acid-base reactions.
Trends: Nucleophilicity increases from right to left across the periodic table and down a group.
- Charged nucleophiles are more reactive than their neutral counterparts.
- Sterically hindered bases may be poor nucleophiles but can still act as bases.

Stable leaving groups facilitate nucleophilic substitution reactions: lower activation energy.
Weak bases (e.g., I24, Br24): excellent leaving groups, whereas stronger bases (e.g., OH24, NH224) are poor leaving groups.
Common leaving group comparative stability:
- R-F < R-OH < R-NH2 < R-H < R-R
Additional leaving groups: tosylate (TsO24).

SN1 (Substitution Nucleophilic Unimolecular):
- Involves two steps: formation of a carbocation followed by nucleophilic attack.
- Reaction is first order; rate depends solely on alkyl halide concentration: rate = k[R–X]
- Reaction stereochemistry outcome is typically a racemic mixture since the carbocation is planar allowing nucleophilic attack from either side.
- Carbocation stability increases with substitution: 3° > 2° > 1° > methyl.

Carbocations are categorized based on the number of carbons connected to the positively charged carbon: 1°, 2°, or 3°.
Inductive Effect: Electron-donating nature stabilizes carbocations.
Hyperconjugation: Involves overlap of adjacent C–H or C–C bonds with the cation's empty p orbital, leading to charge stabilization.
Allylic and benzylic carbocations benefit from resonance, enhancing stability.

SN1 Reactions:
- Multiple steps; carbocation formation is rate-determining.
- More substituted halides react faster, weak nucleophiles required, and polar protic solvents are preferred.
SN2 Reactions:
- One-step, dependent on nucleophile and electrophile concentrations, favored with strong nucleophiles, and polar aprotic solvents.

SN1 Characteristics:
- Multiple steps (carbocation intermediate)
- Rate = k[R–X] (first order)
- Allows rearrangements and forms racemic mixtures.
SN2 Characteristics:
- Single step (direct attack by nucleophile)
- Rate = k[nucleophile][R–X] (second order)
- Stereospecific, leading to inversion of configuration.

Vinyl and aryl halides do not undergo SN1 or SN2 reactions due to instability in the resulting vinyl or aryl cation.

Understanding substitution reactions, their mechanisms, steric influences, and the nature of nucleophiles and leaving groups provides crucial knowledge for predicting chemical behavior in organic compounds.