Organic Chemistry Unit 11 Review: Substitutions & Eliminations

Key Concepts

• Alkyl halides contain a carbon-halogen bond (fluorine, chlorine, bromine, or iodine) and are important in organic synthesis
• Substitution reactions involve the replacement of the halogen with another atom or group, while elimination reactions remove the halogen and an adjacent hydrogen to form a double bond
• The structure of the alkyl halide, the strength of the nucleophile or base, and the reaction conditions determine whether substitution or elimination occurs
• SN1, SN2, E1, and E2 are the main reaction mechanisms for substitution and elimination reactions
  • SN1 and E1 involve a carbocation intermediate and are unimolecular
  • SN2 and E2 occur in a single step and are bimolecular
• Factors such as the substrate structure, nucleophile/base strength, solvent, and temperature influence the reaction outcome
• Alkyl halides are versatile compounds used in the synthesis of various organic molecules (pharmaceuticals, polymers, and agrochemicals)

Alkyl Halide Structure

• Alkyl halides have the general formula R-X, where R is an alkyl group and X is a halogen (fluorine, chlorine, bromine, or iodine)
• The carbon-halogen bond is polar due to the electronegativity difference between carbon and the halogen
  • The polarity of the bond decreases in the order: C-F > C-Cl > C-Br > C-I
• Alkyl halides can be classified as primary (1°), secondary (2°), or tertiary (3°) based on the number of carbon atoms directly attached to the carbon bearing the halogen
• The reactivity of alkyl halides increases in the order: 1° < 2° < 3° for SN1 and E1 reactions, and 3° < 2° < 1° for SN2 and E2 reactions
• The leaving group ability of the halogens increases in the order: F < Cl < Br < I
• Steric hindrance around the carbon-halogen bond affects the accessibility of the substrate to nucleophiles or bases

Types of Reactions

• Alkyl halides undergo two main types of reactions: substitution and elimination
• Substitution reactions involve the replacement of the halogen with another atom or group, such as a nucleophile (Nu)
  • The general reaction is: R-X + Nu → R-Nu + X
• Elimination reactions remove the halogen and an adjacent hydrogen to form a double bond
  • The general reaction is: R-CHX-CH2-R → R-CH=CH-R + HX
• The reaction conditions, such as the choice of nucleophile or base, solvent, and temperature, determine the predominant reaction type
• Competing reactions can occur, leading to a mixture of substitution and elimination products
• Rearrangements, such as carbocation rearrangements, can also take place during the reaction

Substitution Reactions

• Substitution reactions involve the replacement of the halogen with a nucleophile (Nu)
• There are two main types of substitution reactions: SN1 and SN2
  • SN1 (Substitution Nucleophilic Unimolecular) reactions occur in two steps and involve a carbocation intermediate
  • SN2 (Substitution Nucleophilic Bimolecular) reactions occur in a single step, with the nucleophile attacking the carbon from the opposite side of the leaving group
• SN1 reactions are favored by tertiary alkyl halides, weak nucleophiles, polar protic solvents, and higher temperatures
• SN2 reactions are favored by primary alkyl halides, strong nucleophiles, polar aprotic solvents, and lower temperatures
• The stereochemistry of the product depends on the reaction mechanism
  • SN1 reactions lead to a mixture of stereoisomers (racemization)
  • SN2 reactions result in an inversion of stereochemistry (Walden inversion)

Elimination Reactions

• Elimination reactions remove the halogen and an adjacent hydrogen to form a double bond
• There are two main types of elimination reactions: E1 and E2
  • E1 (Elimination Unimolecular) reactions occur in two steps and involve a carbocation intermediate
  • E2 (Elimination Bimolecular) reactions occur in a single step, with the base removing a proton and the leaving group departing simultaneously
• E1 reactions are favored by tertiary alkyl halides, weak bases, polar protic solvents, and higher temperatures
• E2 reactions are favored by primary alkyl halides, strong bases, polar aprotic solvents, and higher temperatures
• The stereochemistry of the product depends on the reaction mechanism and the substrate structure
  • E1 reactions can lead to a mixture of stereoisomers
  • E2 reactions typically follow Zaitsev's rule, producing the more stable alkene (more substituted)
• Hofmann elimination, an E2 reaction with a bulky base and a less substituted alkene product, can occur under specific conditions

Reaction Mechanisms

• The reaction mechanisms for substitution and elimination reactions involve the interaction between the substrate, nucleophile or base, and solvent
• SN1 mechanism:
  1. Slow step: formation of a carbocation intermediate by the departure of the leaving group
  2. Fast step: nucleophilic attack on the carbocation to form the substitution product
• SN2 mechanism:
  1. Single step: concerted backside attack by the nucleophile and departure of the leaving group
• E1 mechanism:
  1. Slow step: formation of a carbocation intermediate by the departure of the leaving group
  2. Fast step: deprotonation of the carbocation by a base to form the alkene
• E2 mechanism:
  1. Single step: concerted removal of a proton by the base and departure of the leaving group to form the alkene
• The rate-determining step in SN1 and E1 reactions is the formation of the carbocation intermediate, while in SN2 and E2 reactions, it is the concerted step
• Carbocation rearrangements can occur during SN1 and E1 reactions, leading to unexpected products

Factors Affecting Reactions

• Several factors influence the outcome of substitution and elimination reactions
• Substrate structure:
  • Tertiary alkyl halides favor SN1 and E1 reactions due to the stability of the carbocation intermediate
  • Primary alkyl halides favor SN2 and E2 reactions due to less steric hindrance and the instability of the carbocation
• Nucleophile/base strength:
  • Strong nucleophiles favor SN2 reactions, while weak nucleophiles favor SN1 reactions
  • Strong bases favor E2 reactions, while weak bases favor E1 reactions
• Solvent:
  • Polar protic solvents (water, alcohols) favor SN1 and E1 reactions by stabilizing the carbocation intermediate
  • Polar aprotic solvents (DMSO, acetonitrile) favor SN2 and E2 reactions by enhancing the reactivity of the nucleophile or base
• Temperature:
  • Higher temperatures favor SN1 and E1 reactions by providing the energy needed to form the carbocation intermediate
  • Lower temperatures favor SN2 and E2 reactions by reducing the formation of the carbocation intermediate
• Leaving group:
  • Better leaving groups (I > Br > Cl > F) favor both substitution and elimination reactions
• Steric hindrance:
  • Bulky substituents around the reaction site hinder the approach of the nucleophile or base, favoring elimination over substitution

Applications and Examples

• Alkyl halides are versatile compounds used in the synthesis of various organic molecules
• Pharmaceuticals:
  • The synthesis of the local anesthetic procaine involves an SN2 reaction between 4-aminobenzoic acid and 2-diethylaminoethanol
  • The antidepressant fluoxetine (Prozac) is synthesized via an SN2 reaction between 3-chlorophenol and 3-methylamino-1-phenylpropan-1-ol
• Polymers:
  • Polyvinyl chloride (PVC) is produced by the free-radical polymerization of vinyl chloride, which is obtained from the elimination of 1,2-dichloroethane
  • Teflon (polytetrafluoroethylene) is synthesized by the polymerization of tetrafluoroethylene, which is derived from the elimination of chlorodifluoromethane
• Agrochemicals:
  • The herbicide 2,4-D is synthesized by the nucleophilic substitution of 2,4-dichlorophenol with chloroacetic acid
  • The insecticide DDT is produced by the Friedel-Crafts alkylation of chlorobenzene with chloral, followed by an SN2 reaction with chlorobenzene
• Other examples:
  • The Williamson ether synthesis involves an SN2 reaction between an alkoxide ion and an alkyl halide to form an ether
  • The Gabriel synthesis of primary amines uses potassium phthalimide as a nucleophile in an SN2 reaction with an alkyl halide, followed by hydrazinolysis to obtain the primary amine