Organic Chemistry II: Mechanisms, Reactivity, and Stereochemistry – Exam Study Guide

Organic Reaction Mechanisms

Substitution and Elimination Reactions

Organic chemistry features several fundamental reaction types, including nucleophilic substitution (SN1 and SN2) and elimination (E1 and E2). Understanding the mechanisms, factors affecting rates, and product outcomes is essential for predicting reactivity and synthesis.

• SN2 Reaction: A bimolecular nucleophilic substitution where the nucleophile attacks the substrate in a single concerted step, leading to inversion of configuration.

• SN1 Reaction: A unimolecular nucleophilic substitution involving a carbocation intermediate; rate depends only on the substrate.

• E2 Reaction: A bimolecular elimination where base removes a proton as the leaving group departs, forming an alkene in a single step.

• E1 Reaction: A unimolecular elimination via a carbocation intermediate, followed by loss of a proton to form an alkene.

Key Factors Affecting Reaction Rates:

• Nucleophile strength: Stronger nucleophiles favor SN2 reactions.

• Substrate structure: Primary substrates favor SN2; tertiary favor SN1/E1/E2.

• Solvent effects: Polar aprotic solvents favor SN2; polar protic solvents favor SN1/E1.

• Base strength: Strong, bulky bases favor E2 over SN2.

Example: The reaction of 2-bromopropane with sodium methoxide in methanol can proceed via SN2 or E2, depending on conditions.

Ranking Reactivity and Stability

Nucleophile Reactivity in SN2 Reactions

In SN2 reactions, nucleophiles are ranked by their ability to attack the electrophilic carbon. Steric hindrance and electronic effects play major roles.

• Strong nucleophiles: Examples include alkoxides (RO-), thiolates (RS-), and cyanide (CN-).

• Weak nucleophiles: Water, alcohols, and carboxylates are less reactive.

Example: Methoxide (CH3O-) reacts faster than acetate (CH3COO-) in SN2 reactions.

Alkene Stability

Alkene stability is determined by substitution and conjugation. More substituted and conjugated alkenes are generally more stable.

• Tetrasubstituted alkenes > Trisubstituted > Disubstituted > Monosubstituted

• Conjugation: Alkenes conjugated with aromatic rings or other double bonds are stabilized.

Example: 2,3-dimethyl-2-butene is more stable than 1-butene due to higher substitution.

SN1 Reaction Rate

SN1 reactions proceed via carbocation intermediates. The rate is fastest for substrates that form the most stable carbocations.

• Tertiary carbocations > Secondary > Primary > Methyl

• Allylic and benzylic carbocations are stabilized by resonance.

Example: Benzyl bromide reacts faster than ethyl bromide in SN1 due to resonance stabilization.

Radical Halogenation and Photolysis

Mechanism of Radical Halogenation

Alkanes and alkenes can undergo halogenation via free radical mechanisms, especially under photolytic conditions (light, hv).

• Initiation: Formation of halogen radicals by homolytic cleavage.

• Propagation: Radical abstracts hydrogen, forms new radical and halogenated product.

• Termination: Radicals combine to end the chain reaction.

Major product: The most stable radical intermediate leads to the major product.

Example: Bromination of isobutane yields tert-butyl bromide as the major product.

Photolysis with Br2 and Cl2

Photolysis with Br2 or Cl2 selectively halogenates the most substituted carbon due to radical stability.

• Bromination: More selective for tertiary positions.

• Chlorination: Less selective, can yield multiple products.

Example: Chlorination of 2-methylpropane yields both 1-chloro-2-methylpropane and 2-chloro-2-methylpropane.

Stereochemistry of Alkenes

E/Z (cis/trans) Configuration

Alkenes are classified by the relative positions of substituents on the double bond using the Cahn-Ingold-Prelog priority rules.

• E (entgegen): Highest priority groups on opposite sides.

• Z (zusammen): Highest priority groups on the same side.

Example: 2-butene can be E (trans) or Z (cis) depending on methyl group positions.

Solvent and Nucleophile Effects

Solvent Effects on SN2 and E2

Solvents can dramatically affect reaction rates and mechanisms.

• Polar aprotic solvents (e.g., DMF, DMSO) increase SN2 rates by stabilizing cations but not anions.

• Polar protic solvents (e.g., water, alcohols) favor SN1/E1 by stabilizing carbocations.

Example: SN2 reaction of bromide with DMF is faster than in methanol.

Nucleophile Structure and Base Strength

The structure and strength of the nucleophile/base can shift the product ratio between substitution and elimination.

• Bulky bases (e.g., t-butoxide) favor E2 elimination over SN2 substitution.

• Strong nucleophiles (e.g., methanethiolate) favor SN2.

Example: Sodium t-butoxide yields more elimination product than sodium methoxide.

Product Prediction and Mechanism Drawing

Predicting Products of Substitution and Elimination

Given a substrate and reagent, predict the major product by considering mechanism, stereochemistry, and regiochemistry.

• SN2: Inversion of configuration at the reactive center.

• E2: Formation of the most substituted (Zaitsev) alkene, unless a bulky base is used (Hofmann product).

Example: Reaction of 1-bromo-2-methylcyclohexane with sodium ethoxide yields 2-methylcyclohexene via E2.

Multi-Step Reaction Sequences

Complex syntheses may involve several steps, each requiring correct reagent and mechanism selection.

• Track intermediates and products for each step.

• Apply correct stereochemistry and regiochemistry rules.

Example: Bromination followed by substitution and further bromination can yield polyhalogenated products.

Tabular Summary: Reaction Types and Conditions

Reaction Type	Mechanism	Favored by	Major Product
SN2	Concerted, backside attack	Strong nucleophile, polar aprotic solvent, primary substrate	Substitution, inversion of configuration
SN1	Carbocation intermediate	Weak nucleophile, polar protic solvent, tertiary substrate	Substitution, racemization
E2	Concerted elimination	Strong base, polar aprotic solvent, secondary/tertiary substrate	Alkene (Zaitsev or Hofmann)
E1	Carbocation intermediate	Weak base, polar protic solvent, tertiary substrate	Alkene (Zaitsev)

Key Equations

• SN2 Rate Law: $\text{Rate} = k[\text{Nucleophile}][\text{Electrophile}]$

• SN1 Rate Law: $\text{Rate} = k[\text{Electrophile}]$

• E2 Rate Law: $\text{Rate} = k[\text{Base}][\text{Electrophile}]$

• E1 Rate Law: $\text{Rate} = k[\text{Electrophile}]$

Additional info:

• Some questions require drawing products and mechanisms; practice with skeletal structures and curved-arrow notation is recommended.

• Assigning E/Z configuration uses Cahn-Ingold-Prelog rules: assign priorities to substituents on each alkene carbon.

• Radical halogenation selectivity: bromine is more selective than chlorine due to differences in activation energy and radical stability.