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Organic Chemistry
Table of Contents
Unit 11 Overview: Alkyl Halide Reactions: Substitutions & Eliminations
11.1 The Discovery of Nucleophilic Substitution Reactions
11.2 The SN2 Reaction
11.3 Characteristics of the SN2 Reaction
11.4 The SN1 Reaction
11.5 Characteristics of the SN1 Reaction
11.6 Biological Substitution Reactions
11.7 Elimination Reactions: Zaitsev’s Rule
11.8 The E2 Reaction and the Deuterium Isotope Effect
11.9 The E2 Reaction and Cyclohexane Conformation
11.10 The E1 and E1cB Reactions
11.11 Biological Elimination Reactions
11.12 A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

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11.12 A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

Citation:

Substitution and elimination reactions are key players in organic chemistry. They come in different flavors, each with its own set of rules and preferences. Understanding these reactions is crucial for predicting and controlling chemical outcomes.

Factors like nucleophile strength, solvent polarity, and substrate structure heavily influence reaction paths. Knowing how these elements interact helps chemists choose the right conditions to get desired products. It's all about manipulating the dance of molecules to our advantage.

Reaction Mechanisms and Conditions

Types of substitution and elimination reactions

  • SN1 (Substitution Nucleophilic Unimolecular)
    • Occurs with tertiary alkyl halides, allylic halides, and benzylic halides
    • Requires polar protic solvent (ethanol), weak nucleophile, and heat
    • Rate-determining step involves formation of a carbocation intermediate
  • SN2 (Substitution Nucleophilic Bimolecular)
    • Favored with primary alkyl halides and less favorable with secondary alkyl halides
    • Needs polar aprotic solvent (DMSO) and strong nucleophile
    • Backside attack of nucleophile on substrate is the rate-determining step
  • E1 (Elimination Unimolecular)
    • Occurs with tertiary alkyl halides, allylic halides, and benzylic halides
    • Requires polar protic solvent (methanol), weak base, and heat
    • Rate-determining step involves formation of a carbocation intermediate
  • E1cB (Elimination Unimolecular conjugate Base)
    • Occurs with alkyl halides containing acidic $\alpha$-hydrogens
    • Needs strong base and polar aprotic solvent (acetone)
    • Formation of a carbanion intermediate is the rate-determining step
  • E2 (Elimination Bimolecular)
    • Favored with primary and secondary alkyl halides
    • Requires strong base and polar aprotic solvent (acetonitrile)
    • Concerted elimination of $\beta$-hydrogen and leaving group is the rate-determining step

Mechanisms for different alkyl halides

  • Primary alkyl halides
    • SN2 favored with strong nucleophiles and polar aprotic solvents
    • E2 favored with strong bases and polar aprotic solvents
  • Secondary alkyl halides
    • SN2 favored with strong nucleophiles and polar aprotic solvents but slower than primary substrates
    • E2 favored with strong bases and polar aprotic solvents
    • SN1 and E1 possible with weak nucleophiles/bases and polar protic solvents but less favored than tertiary substrates
  • Tertiary alkyl halides
    • SN1 favored with weak nucleophiles and polar protic solvents
    • E1 favored with weak bases and polar protic solvents
    • SN2 and E2 not favored due to steric hindrance and instability of transition states

Factors Influencing Reaction Outcomes

Factors influencing alkyl halide reactions

  • Nucleophile strength
    • Strong nucleophiles (NaOH) favor SN2 and E2 mechanisms
    • Weak nucleophiles (H2O) favor SN1 and E1 mechanisms
  • Solvent polarity
    • Polar protic solvents (water, alcohols)
      • Stabilize carbocation intermediates favoring SN1 and E1
      • Solvate nucleophiles and bases reducing their reactivity
    • Polar aprotic solvents (DMSO, acetonitrile)
      • Do not stabilize carbocation intermediates
      • Enhance reactivity of nucleophiles and bases favoring SN2 and E2
  • Substrate structure
    • Degree of substitution (primary, secondary, tertiary)
      • Increasing substitution favors SN1 and E1 due to carbocation stability
      • Decreasing substitution favors SN2 and E2 due to reduced steric hindrance
    • Presence of resonance-stabilizing groups (allylic, benzylic)
      • Stabilize carbocation intermediates favoring SN1 and E1 (benzyl chloride)
    • Presence of electron-withdrawing groups (carbonyl, nitrile)
      • Increase acidity of $\alpha$-hydrogens favoring E1cB (ethyl acetoacetate)

Reaction Kinetics and Energy Considerations

  • Reaction kinetics: Describes the rate of chemical reactions and the factors that influence them
    • SN1 and E1 reactions follow first-order kinetics
    • SN2, E2, and E1cB reactions follow second-order kinetics
  • Transition state theory: Explains the rate of chemical reactions through the formation of a high-energy transition state
    • SN2 and E2 reactions proceed through a single transition state
    • SN1, E1, and E1cB reactions involve multiple transition states
  • Reaction energy diagrams: Visual representations of the energy changes during a reaction
    • Show the relative energies of reactants, intermediates, transition states, and products
    • Help in understanding the activation energy and overall thermodynamics of a reaction

Key Terms to Review (34)

First-order reaction: A first-order reaction in organic chemistry, specifically within the context of reactions of alkyl halides and nucleophilic substitutions and eliminations, is a chemical reaction whose rate depends on the concentration of only one reactant. These reactions have a rate constant that directly correlates with the lifespan of the reactive species involved, making their kinetics simple to analyze.
Hammond postulate: The Hammond postulate suggests that the transition state of a chemical reaction resembles the structure and energy of the nearest stable species, whether reactants or products. It is particularly useful in understanding the reactivity of alkenes in organic chemistry by predicting the outcome of reactions and their mechanisms.
Second-order reaction: A second-order reaction is one in which the rate of reaction depends on the concentration of two reactants or on the square of the concentration of a single reactant. In the context of SN2 reactions, this means that both the nucleophile and substrate concentrations affect the reaction rate.
Nucleophilic substitution reactions: Nucleophilic substitution reactions are a class of chemical reactions in organic chemistry where an electron-rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group. The reaction is characterized by the substitution of a nucleophile for a leaving group, which can occur via different mechanisms (SN1 or SN2).
Anti stereochemistry: Anti stereochemistry describes the spatial arrangement in a chemical reaction where two substituents are positioned on opposite sides of a double bond or ring structure after the reaction. It is particularly relevant in the halogenation of alkenes, resulting in products where the added atoms are located across from each other.
Leaving group: A leaving group in organic chemistry is an atom or group that detaches from the parent molecule during a nucleophilic substitution (SN2) reaction, forming a lone pair or negative ion. The ease with which a leaving group departs affects the rate and success of the reaction.
Stereochemistry: Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this arrangement affects the chemical and physical properties of the substance. It examines the spatial orientation of atoms and their relationship to one another, which is crucial in understanding many organic chemistry concepts.
Carbocation: A carbocation is a positively charged carbon atom that is part of an organic molecule. These reactive intermediates play a crucial role in various organic reactions, including electrophilic additions, nucleophilic substitutions, and elimination reactions.
Steric Hindrance: Steric hindrance, also known as steric strain or steric effect, refers to the repulsive forces that arise between atoms or groups of atoms in a molecule due to their physical size and spatial arrangement. This phenomenon can significantly impact the stability, reactivity, and conformations of organic compounds.
Reaction Kinetics: Reaction kinetics is the study of the rates and mechanisms of chemical reactions. It examines the factors that influence the speed and efficiency of a reaction, such as temperature, pressure, and the presence of catalysts. This concept is crucial in understanding organic reactions, as the rate and pathway of a reaction can have a significant impact on the products formed and the overall efficiency of the process.
SN2: SN2 is a type of nucleophilic substitution reaction in organic chemistry where a nucleophile attacks the backside of a carbon atom bearing a good leaving group, resulting in the displacement of that leaving group and the inversion of stereochemistry at the carbon center.
Electrophile: An electrophile is a species that is attracted to electron-rich regions and seeks to form new bonds by accepting electron density. Electrophiles play a crucial role in many organic reactions, including polar reactions, electrophilic aromatic substitution, and nucleophilic acyl substitution, among others.
SN1: SN1, or Nucleophilic Substitution Reaction, is a type of organic reaction mechanism in which a nucleophile attacks a neutral, trigonal planar carbocation intermediate to displace a leaving group, resulting in the substitution of one functional group for another. This mechanism is characterized by a stepwise process involving the formation of a carbocation intermediate.
E2: E2 (Elimination, bimolecular) is a type of organic reaction mechanism where a base removes two atoms, typically a hydrogen and a leaving group, from adjacent carbon atoms in a single step, resulting in the formation of a new carbon-carbon double bond.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Elimination: Elimination is a type of organic reaction in which two atoms or groups are removed from a molecule, typically resulting in the formation of a new double bond. This process is fundamental in understanding organic reaction mechanisms, oxidation-reduction reactions, and various types of substitution and elimination reactions.
E1: E1 is a type of organic reaction mechanism in which the first step involves the unimolecular elimination of a good leaving group from a substrate, resulting in the formation of a carbocation intermediate. This is then followed by the removal of a proton from an adjacent carbon, leading to the formation of a new carbon-carbon double bond.
Nucleophilic Substitution: Nucleophilic substitution is a fundamental organic reaction where a nucleophile (a species that donates electrons) replaces a leaving group attached to a carbon atom, resulting in the formation of a new carbon-nucleophile bond. This process is central to many organic transformations and is particularly relevant in the context of alkyl halides, alcohols, carboxylic acids, and amines.
Solvent Effects: Solvent effects refer to the influence that the surrounding solvent environment can have on the behavior and properties of chemical reactions, molecules, and spectroscopic measurements. The nature and polarity of the solvent can significantly impact the energetics, kinetics, and outcomes of various organic chemistry processes.
Leaving Group: A leaving group is a functional group or atom that is displaced or removed from a molecule during a chemical reaction. It is a key component in many organic reactions, particularly substitution and elimination reactions, as it facilitates the formation of a new bond or the creation of a new product.
Hammond Postulate: The Hammond Postulate is a principle in organic chemistry that describes the relationship between the structure of the transition state in a chemical reaction and the relative stability of the reactants and products. It states that if two transition states have similar energies, the one leading to the more stable product will be favored.
Transition State Theory: Transition state theory is a model used to describe the energy changes that occur during a chemical reaction. It explains the formation of an unstable, high-energy intermediate state, known as the transition state, which is the point at which the reactants are converted into products.
Alkyl Halides: Alkyl halides are organic compounds that consist of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). They are widely used in organic synthesis and have various applications in chemistry and biology.
Carbocation Stability: Carbocations are positively charged carbon atoms that are formed as intermediates in many organic reactions. The stability of a carbocation is a crucial factor in determining the mechanism and outcome of these reactions. Carbocation stability is a key concept that connects various topics in organic chemistry, including electrophilic additions, the SN1 reaction, and the reactivity of conjugated dienes.
Zaitsev's Rule: Zaitsev's rule is a principle in organic chemistry that predicts the major product of an elimination reaction. It states that the major alkene product will be the one with the most substituted (most stable) double bond.
NMR Spectroscopy: NMR (Nuclear Magnetic Resonance) spectroscopy is an analytical technique that uses the magnetic properties of atomic nuclei to provide detailed information about the structure and composition of organic compounds. It is a powerful tool for identifying and characterizing chemical compounds, particularly in the context of organic chemistry.
Second-Order: Second-order refers to the kinetic order of a chemical reaction, specifically the rate at which the concentration of reactants changes over time. In a second-order reaction, the rate of the reaction depends on the concentration of two reactants, with the overall reaction order being the sum of the individual orders for each reactant.
Substrate Structure: Substrate structure refers to the chemical composition and spatial arrangement of the molecule that undergoes a reaction. It is a crucial factor that determines the reactivity and mechanism of a chemical transformation, particularly in the context of substitution and elimination reactions.
First-Order: First-order is a kinetic term that describes a reaction where the rate of the reaction is directly proportional to the concentration of a single reactant. In other words, the rate of the reaction only depends on the concentration of one of the reactants.
$eta$-hydrogen: $eta$-hydrogen refers to the hydrogen atom that is located on the carbon atom adjacent to the reaction center in organic chemistry. This term is particularly relevant in the context of understanding the reactivity patterns associated with SN1, SN2, E1, E1cB, and E2 reactions.
Reaction Energy Diagrams: Reaction energy diagrams are graphical representations that illustrate the changes in energy that occur during a chemical reaction. They provide a visual understanding of the energetic pathway a reaction follows, including the relative stabilities of reactants, intermediates, and products, as well as the activation energy required to overcome the energy barrier and proceed from reactants to products.
E1cB: E1cB, or Elimination-Conjugate Base, is a type of elimination reaction where the leaving group is removed from the substrate in a concerted step with the abstraction of a proton by a basic nucleophile, resulting in the formation of a new carbon-carbon double bond.
$\alpha$-hydrogens: $\alpha$-hydrogens refer to hydrogen atoms attached to the carbon atom that is directly adjacent to a reactive functional group or a carbonyl carbon. These hydrogen atoms play a crucial role in determining the reactivity and reaction pathways in various organic chemistry reactions, including substitution and elimination reactions.
Carbanion: A carbanion is a negatively charged species that contains a carbon atom with three bonds and a lone pair of electrons, giving it a formal negative charge. This species is crucial in various organic reactions, as it acts as a strong nucleophile and can participate in forming new bonds by attacking electrophiles.