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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

SN2 reactions are all about speed and precision. These substitution reactions depend on factors like substrate structure, nucleophile strength, and leaving group ability. Understanding these elements helps predict how fast reactions will occur and what products will form.

Solvent choice and reaction conditions also play crucial roles. Polar aprotic solvents speed things up, while protic solvents slow them down. By considering all these factors, you can become a master at predicting SN2 reaction outcomes and rates.

Factors Affecting SN2 Reaction Rates

Factors affecting SN2 reaction rates

  • Substrate structure significantly impacts reaction rate
    • Methyl and primary alkyl halides react fastest due to minimal steric hindrance (methyl bromide, ethyl chloride)
    • Secondary alkyl halides react more slowly as steric hindrance increases (isopropyl bromide)
    • Tertiary alkyl halides typically do not undergo SN2 reactions due to excessive steric hindrance preventing backside attack (tert-butyl chloride)
  • Nucleophile type influences reaction rate based on strength
    • Strong nucleophiles increase SN2 reaction rates by readily attacking the substrate (thiolates, cyanide, iodide)
    • Nucleophilicity increases with basicity and polarizability allowing for more effective backside attack (thiolates > cyanide > iodide)
    • Weak nucleophiles decrease reaction rates due to lower reactivity with the substrate (water, alcohols, fluoride)
  • Leaving group ability affects reaction rate
    • Good leaving groups increase SN2 reaction rates by readily departing from the substrate (iodide, bromide, chloride, tosylate)
    • Leaving group ability increases with stability of the conjugate base, facilitating departure (iodide > bromide > chloride)
    • Poor leaving groups decrease reaction rates due to stronger bonding to the substrate (hydroxide, alkoxides)
  • Solvent polarity and hydrogen bonding impact reaction rate
    • Polar aprotic solvents increase SN2 reaction rates by solvating cations and leaving the nucleophile more reactive (acetone, DMSO, DMF, acetonitrile)
    • Polar protic solvents decrease SN2 reaction rates by solvating the nucleophile through hydrogen bonding, reducing its reactivity (water, methanol, ethanol)

Nucleophile and leaving group reactivity

  • Nucleophile reactivity follows a general trend based on basicity and polarizability
    1. Thiolates ($\ce{RS-}$) are the strongest nucleophiles due to high polarizability of sulfur and strong basicity
    2. Cyanide ($\ce{CN-}$) is a strong nucleophile with high polarizability and moderate basicity
    3. Iodide ($\ce{I-}$) is a strong nucleophile due to its large size and polarizability
    4. Azide ($\ce{N3-}$) is a moderately strong nucleophile with resonance stabilization
    5. Bromide ($\ce{Br-}$) is a moderate nucleophile, less polarizable than iodide
    6. Chloride ($\ce{Cl-}$) is a weaker nucleophile compared to bromide and iodide
    7. Fluoride ($\ce{F-}$) is the weakest halide nucleophile due to its small size and strong solvation
  • Leaving group reactivity follows a trend based on the stability of the conjugate base
    1. Iodide ($\ce{I-}$) is the best leaving group as it forms the most stable conjugate base
    2. Bromide ($\ce{Br-}$) is a good leaving group, slightly less stable than iodide
    3. Chloride ($\ce{Cl-}$) is a moderately good leaving group, less stable than bromide
    4. Fluoride ($\ce{F-}$) is a poor leaving group due to the instability of its conjugate base
    5. Tosylate ($\ce{OTs-}$) is a good leaving group due to resonance stabilization of the conjugate base
    6. Water ($\ce{H2O}$) is a poor leaving group as hydroxide is a weak conjugate base
    7. Hydroxide ($\ce{OH-}$) and alkoxides ($\ce{OR-}$) are very poor leaving groups due to strong basicity and instability of their conjugate bases

Predicting SN2 reaction outcomes

  • The general mechanism for an SN2 reaction involves a nucleophile ($\ce{Nu-}$) attacking a substrate ($\ce{R-LG}$) and displacing the leaving group ($\ce{LG-}$) in a concerted process: $\ce{Nu- + R-LG -> R-Nu + LG-}$
  • Predict the reaction rate and product based on the substrate, nucleophile, leaving group, and solvent
    1. A primary alkyl halide substrate with a strong nucleophile in a polar aprotic solvent will react quickly: $\ce{CH3CH2Br + NaCN ->[\text{acetone}] CH3CH2CN + NaBr}$ (fast)
    2. A tertiary alkyl halide substrate with a strong base in a polar protic solvent will not react due to steric hindrance and nucleophile solvation: $\ce{(CH3)3CBr + NaOH ->[\text{ethanol}] No reaction}$
    3. A primary alkyl halide substrate with a poor leaving group and a weak nucleophile will react slowly: $\ce{CH3CH2CH2Cl + NaI ->[\text{acetone}] CH3CH2CH2I + NaCl}$ (slow)

Mechanism and Kinetics of SN2 Reactions

  • SN2 reactions follow a concerted mechanism, where bond breaking and bond formation occur simultaneously
  • The reaction proceeds through a transition state where the nucleophile and leaving group are partially bonded to the substrate
  • SN2 reactions are bimolecular, involving two species in the rate-determining step
  • The kinetics of SN2 reactions are second-order overall, first-order in both nucleophile and substrate
  • The stereochemistry of SN2 reactions involves inversion of configuration at the reaction center

Key Terms to Review (47)

SN2 reaction: In organic chemistry, an SN2 reaction is a type of nucleophilic substitution where a nucleophile strongly attacks an electrophilic center in one step, leading to the simultaneous displacement of a leaving group. This reaction mechanism is characterized by its bimolecular nature, involving two reacting species in the rate-determining step.
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.
Basicity constant, Kb: The basicity constant, \(K_b\), measures the strength of a base in solution, specifically how well an amine can attract and hold a proton (H+). It quantitatively expresses the equilibrium between the amine in its basic form and its corresponding protonated form in solution.
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.
Transition state: In organic chemistry, the transition state is a high-energy, temporary condition where reactants are transformed into products during a chemical reaction. It represents the point of maximum energy on the energy diagram before the formation of products.
Conjugate base: A conjugate base is the species that remains after an acid has donated a proton (H+ ion) during a chemical reaction. It is capable of gaining a proton in the reverse reaction, forming the original acid.
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.
Hydrogen Bonding: Hydrogen bonding is a special type of dipole-dipole interaction that occurs when a hydrogen atom covalently bonded to a highly electronegative element, such as nitrogen, oxygen, or fluorine, experiences an attractive force with another nearby highly electronegative element. This intermolecular force is stronger than a typical dipole-dipole interaction and has a significant impact on the physical and chemical properties of many organic compounds.
Resonance Stabilization: Resonance stabilization is a phenomenon where the delocalization of electrons in a molecule or ion leads to a more stable configuration compared to a single Lewis structure. This concept is crucial in understanding the behavior and properties of various organic compounds, including their acidity, basicity, reactivity, and stability.
Conjugate Base: A conjugate base is the species formed when an acid loses a proton (H+) in an acid-base reaction. It is the base that is left behind when an acid donates a proton to another substance, becoming the conjugate acid-base pair. This term is central to understanding acid-base chemistry, as well as its applications in organic reactions and biological systems.
Ethanol: Ethanol, also known as ethyl alcohol, is a colorless, volatile, and flammable liquid that is the principal type of alcohol found in alcoholic beverages. It is an important organic compound with diverse applications in various fields, including as a fuel, solvent, and chemical feedstock.
Acetone: Acetone is a simple organic compound with the chemical formula CH3COCH3. It is a colorless, volatile, flammable liquid that is widely used as a solvent and in various chemical processes. Acetone is a key term that is relevant in the context of several important organic chemistry topics.
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.
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.
Transition State: The transition state is a key concept in organic chemistry that describes the highest-energy intermediate along the reaction pathway. It represents the point where the reactants are being converted into products, with the system at its most unstable and energetically unfavorable configuration.
Backside Attack: A backside attack is a type of nucleophilic substitution reaction where the attacking nucleophile approaches the carbon atom from the opposite side of the leaving group. This orientation of the attack is a key characteristic that distinguishes the SN2 reaction mechanism from the SN1 reaction mechanism.
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.
Kinetics: Kinetics is the study of the rates and mechanisms of chemical reactions. It examines how quickly reactions occur and the factors that influence the speed of a reaction, such as temperature, pressure, and the presence of catalysts.
Concerted Mechanism: A concerted mechanism refers to a reaction that occurs in a single, continuous step without the formation of any discrete intermediates. In a concerted mechanism, the bonds that are being formed and broken happen simultaneously, leading to the product in a single, coordinated process.
Nucleophilicity: Nucleophilicity refers to the ability of a species to donate electrons and form a covalent bond with an electrophilic center. It is a key concept in organic chemistry that governs the reactivity and selectivity of many important reactions, including substitution, addition, and elimination reactions.
SN2 Reaction: The SN2 reaction, or bimolecular nucleophilic substitution, is a type of organic reaction where a nucleophile attacks the backside of a carbon atom bearing a leaving group, resulting in the displacement of the leaving group and the inversion of stereochemistry at the carbon center.
Ethyl Chloride: Ethyl chloride is a colorless, flammable gas with a sweet, ethereal odor. It is commonly used as a refrigerant, anesthetic, and in the production of other chemicals. In the context of organic chemistry, ethyl chloride is an important reactant in the SN2 reaction, a type of nucleophilic substitution reaction.
Tert-Butyl chloride: tert-Butyl chloride, also known as 2-chloro-2-methylpropane, is an organic compound with the chemical formula (CH3)3CCl. It is a colorless, volatile liquid that is used as a building block in the synthesis of various organic compounds and as a solvent in certain applications.
Isopropyl Bromide: Isopropyl bromide, also known as 2-bromoprpane, is an organic compound with the chemical formula $\text{CH}_{3}\text{CHCH}_{3}\text{Br}$. It is a colorless, volatile liquid that is commonly used as a precursor in the synthesis of other organic compounds.
Inversion of Configuration: Inversion of configuration refers to the stereochemical change that occurs when a carbon atom bearing four different substituents undergoes a nucleophilic substitution reaction, resulting in the reversal of the spatial arrangement of the substituents around that carbon.
Tosylate: A tosylate is a functional group or a salt derived from tosylic acid, which is a sulfonic acid. Tosylates are commonly used as leaving groups in $\text{S}_\text{N}2$ reactions, a key topic in organic chemistry.
Thiolates: Thiolates are the conjugate bases of thiols, which are organic compounds containing a sulfur-hydrogen (S-H) bond. Thiolates are important in the context of SN2 reactions, as they can act as nucleophiles in these substitution reactions.
Methyl Bromide: Methyl bromide is a colorless, odorless gas that is commonly used as a fumigant and soil sterilant. It is known for its ability to effectively kill a wide range of pests, including insects, weeds, and microorganisms, making it a widely used compound in the context of the SN2 reaction characteristics.
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.
Bromide: Bromide is a negatively charged ion with the chemical formula Br⁻. It is an important component in various chemical reactions, particularly in the context of the SN2 reaction, where it can serve as a nucleophile or a leaving group.
Cyanide: Cyanide is a chemical compound containing a carbon-nitrogen triple bond. It is a highly toxic substance that can interfere with cellular respiration and is found in various forms, including potassium cyanide and hydrogen cyanide. Cyanide is relevant in the context of SN2 reactions, hydration reactions, and the chemistry of nitriles.
Iodide: Iodide is the anion of the element iodine, with the chemical formula I-. It is an important ion in various chemical reactions and biological processes, particularly in the context of the SN2 reaction mechanism.
DMF: DMF, or dimethylformamide, is a versatile organic solvent that has applications in various chemical reactions and processes. It is a polar aprotic solvent that is widely used in organic chemistry, particularly in the context of nucleophilic substitution reactions, nucleophilic aromatic substitution, and the preparation of ethers and crown ethers.
Acetonitrile: Acetonitrile, also known as methyl cyanide, is a colorless, volatile, and flammable organic compound with the chemical formula CH3CN. It is widely used as a solvent in various chemical reactions and analyses, particularly in the context of organic chemistry and biochemistry.
Polar Protic Solvents: Polar protic solvents are a class of solvents that possess both polarity and the ability to donate a proton (hydrogen ion) to a solute. These solvents are characterized by the presence of hydrogen atoms bonded to highly electronegative atoms, typically oxygen or nitrogen, which allows for the formation of hydrogen bonds with other molecules.
Fluoride: Fluoride is a naturally occurring mineral that is essential for the development and maintenance of strong teeth and bones. It plays a crucial role in the context of the SN2 reaction, a type of nucleophilic substitution reaction, by acting as a powerful nucleophile.
Polarizability: Polarizability is a measure of how easily the electrons in an atom or molecule can be distorted or displaced from their normal positions by an external electric field. This property is particularly important in the context of the SN2 reaction, as it influences the reactivity and selectivity of the reaction. Polarizability is related to the size and electron density of an atom or molecule. Larger atoms and molecules with more diffuse electron clouds tend to have higher polarizabilities, which can impact the stability and reactivity of the species involved in an SN2 reaction.
Hydroxide: Hydroxide (OH-) is a negatively charged ion composed of one oxygen atom and one hydrogen atom. It is a key reactive species in many organic chemistry reactions, including the SN2 reaction and the dehydration of aldol products to form enones.
Methanol: Methanol, also known as methyl alcohol or wood alcohol, is a simple alcohol compound with the chemical formula CH3OH. It is a colorless, volatile, and flammable liquid that is widely used in various industrial and chemical applications. Methanol is particularly relevant in the context of the SN2 reaction, the naming of alcohols and phenols, and the spectroscopy of alcohols and phenols.
Solvent Polarity: Solvent polarity refers to the degree of polarity or charge distribution within a solvent molecule. It is a crucial factor in determining the solubility and reactivity of various compounds in organic chemistry, particularly in the context of the SN2 reaction.
Azide: An azide is a functional group consisting of a nitrogen atom triple-bonded to two other nitrogen atoms (N₃⁻). Azides are important in the context of the SN2 reaction, as they can act as nucleophiles in these substitution reactions.
Basicity: Basicity is a measure of the strength or ability of a chemical species to accept a proton (H+) and form a conjugate acid. It is a fundamental concept in organic chemistry that plays a crucial role in understanding the reactivity and properties of various organic compounds, including those involved in SN2 reactions, aromatic heterocycles, amines, and their reactions.
Bimolecular Reaction: A bimolecular reaction, also known as a second-order reaction, is a chemical reaction in which two reactant species collide and interact to form the products. This type of reaction is particularly relevant in the context of the SN2 (Substitution Nucleophilic Bimolecular) mechanism, which is a common pathway for organic substitution reactions.
Chloride: Chloride is a negatively charged ion (Cl-) that is essential for various physiological processes in the body. It is a key component in the regulation of fluid balance, acid-base balance, and nerve impulse transmission.
Polar Aprotic Solvents: Polar aprotic solvents are a class of organic solvents that are polar in nature but do not contain any hydrogen atoms bonded to highly electronegative atoms, such as oxygen or nitrogen. These solvents are widely used in organic chemistry due to their unique properties and ability to facilitate certain chemical reactions.
Alkoxides: Alkoxides are negatively charged species formed when an alkoxide group, consisting of an alkyl group bonded to an oxygen atom, replaces a hydrogen atom on a molecule. They are important intermediates in various organic reactions, particularly in the context of the SN2 reaction and the E1 and E1cB elimination reactions.
DMSO: DMSO, or dimethyl sulfoxide, is a highly polar organic solvent known for its ability to dissolve both polar and nonpolar compounds. Its unique properties make it a valuable reagent in various chemical reactions, particularly in nucleophilic substitution processes, where it enhances the solubility of reactants and facilitates the formation of intermediates.