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Organic Chemistry
Table of Contents
Unit 24 Overview: Amines and Heterocycles
24.1 Naming Amines
24.2 Structure and Properties of Amines
24.3 Basicity of Amines
24.4 Basicity of Arylamines
24.5 Biological Amines and the Henderson–Hasselbalch Equation
24.6 Synthesis of Amines
24.7 Reactions of Amines
24.8 Reactions of Arylamines
24.9 Heterocyclic Amines
24.10 Spectroscopy of Amines

Amines are versatile organic compounds with a nitrogen atom at their core. They can undergo various reactions, including alkylation and acylation, which add alkyl or acyl groups to the nitrogen. These reactions are crucial in synthesizing more complex molecules.

Elimination reactions of amines, like the Hofmann elimination, produce alkenes and amines. These processes follow specific rules and mechanisms, influenced by factors such as stereochemistry and substrate structure. Understanding these reactions is key to predicting and controlling amine transformations in organic synthesis.

Reactions of Amines

Alkylation and acylation of amines

  • Alkylation of amines involves reaction with alkyl halides (methyl iodide, ethyl bromide) to form substituted ammonium salts
    • Primary amines (methylamine, aniline) can undergo three successive alkylations to form quaternary ammonium salts (tetraethylammonium bromide)
    • Secondary amines (dimethylamine, piperidine) can undergo two successive alkylations to form quaternary ammonium salts
    • Tertiary amines (trimethylamine, pyridine) can undergo one alkylation to form quaternary ammonium salts
    • Alkylation reactions proceed through an SN2 bimolecular nucleophilic substitution mechanism where the amine nucleophilically attacks the alkyl halide
    • The nucleophilicity of amines affects their reactivity in alkylation reactions
  • Acylation of amines involves reaction with acyl chlorides (acetyl chloride, benzoyl chloride) or anhydrides (acetic anhydride) to form amides
    • Primary amines react with acyl chlorides to form N-substituted amides (N-methylacetamide)
    • Secondary amines react with acyl chlorides to form N,N-disubstituted amides (N,N-dimethylbenzamide)
    • Tertiary amines do not undergo acylation due to steric hindrance around the nitrogen atom and lack of an N-H bond
    • Acylation reactions proceed through a nucleophilic acyl substitution mechanism where the amine attacks the carbonyl carbon of the acyl chloride or anhydride

Mechanism of Hofmann elimination

  • Quaternary ammonium salts (tetraethylammonium bromide) undergo elimination when treated with a strong base (sodium hydroxide, silver oxide) to produce an alkene and tertiary amine
  • Mechanism involves:
    1. Formation of an ylide intermediate (triethylamine ylide) by deprotonation of the $\alpha$-carbon by the base
    2. Elimination of the ylide to form the alkene product, with the least substituted alkene (ethylene) being the major product (Hofmann product)
  • Hofmann product is favored due to:
    • Stereoelectronic preference for the least substituted alkene which allows for better orbital overlap in the transition state
    • Minimization of steric strain in the transition state by placing the smaller groups (hydrogen) closer to the leaving group
  • Hofmann elimination follows Hofmann's rule which states that the major alkene product will be the one that is least substituted
  • The basicity of the amine affects its ability to act as a leaving group in elimination reactions

Hofmann vs biological eliminations

  • Biological eliminations involve protonated ammonium ions (choline, betaine) undergoing elimination reactions similar to the Hofmann elimination
    • Occur in biosynthesis of compounds like neurotransmitter acetylcholine and osmoprotectant glycine betaine
    • Mechanism involves formation of an iminium ion intermediate by elimination of water, followed by elimination to form the least substituted alkene product
    • Also follow Hofmann's rule, producing the least substituted alkene as the major product
  • Comparison of Hofmann and biological eliminations:
    • Both eliminate a quaternary ammonium species to form an alkene and amine
    • Hofmann elimination uses a strong base to generate the ylide intermediate, while biological eliminations use an enzyme to generate the iminium ion intermediate
    • Both follow Hofmann's rule and produce the least substituted alkene as the major product due to stereoelectronic and steric factors favoring this pathway

Stereochemistry and Elimination Reactions

  • Elimination reactions of amines can result in changes to stereochemistry
  • The stereochemistry of the starting material influences the stereochemistry of the product
  • In E2 elimination reactions, the leaving group (often an amine) and the $\beta$-hydrogen must be in an antiperiplanar conformation
  • The stereochemistry of the alkene product is determined by the geometry of the transition state

Key Terms to Review (29)

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).
Hofmann elimination reaction: The Hofmann elimination reaction is a chemical process where an amine is converted into an alkene through the treatment with excess methyl iodide, followed by silver oxide (Ag2O), and then heating with water. This reaction involves the removal of a hydrogen atom and a leaving group from adjacent carbon atoms in a substrate, leading to the formation of a double bond.
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.
Nucleophilic acyl substitution reaction: A nucleophilic acyl substitution reaction is a type of chemical reaction where a nucleophile replaces the leaving group in an acyl compound. This reaction is fundamental in organic chemistry for modifying carboxylic acid derivatives into other functional groups.
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.
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.
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.
Nucleophilic Acyl Substitution: Nucleophilic acyl substitution is a type of organic reaction where a nucleophile attacks the carbonyl carbon of a carboxylic acid derivative, such as an acid chloride, anhydride, or ester, leading to the replacement of the leaving group with the nucleophile. This process is central to the reactivity and transformations of carboxylic acid derivatives.
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.
Hofmann Elimination: The Hofmann elimination is a type of elimination reaction that involves the removal of a hydrogen atom and a leaving group from a quaternary ammonium salt, resulting in the formation of an alkene. This reaction is particularly important in the context of preparing alkenes, understanding the structure and properties of amines, and the reactions of amines.
Elimination Reaction: An elimination reaction is a type of organic reaction in which two atoms or groups are removed from a molecule, typically resulting in the formation of a carbon-carbon double bond or a carbon-carbon triple bond. This process is an important step in the synthesis of alkenes and alkynes, as well as in various other organic transformations.
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.
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.
Hofmann's Rule: Hofmann's rule, also known as the Hofmann elimination, is a principle that predicts the major product in an elimination reaction involving a quaternary ammonium salt. It states that the elimination reaction will favor the formation of the alkene with the least substituted (most terminal) double bond.
Amides: Amides are a class of organic compounds that contain a carbonyl group (C=O) bonded to a nitrogen atom. They are derived from carboxylic acids and can be considered the result of replacing the hydroxyl group (-OH) of a carboxylic acid with an amino group (-NH2). Amides are important functional groups in many organic molecules, including proteins, and play a crucial role in various chemical reactions and processes.
SN2 Mechanism: The SN2 mechanism is a type of nucleophilic substitution reaction where a nucleophile attacks the backside of a carbon atom bearing a leaving group, resulting in the inversion of stereochemistry at that carbon center. This mechanism is particularly important in the context of the preparation of alcohols and the reactions of amines.
Acylation: Acylation is a chemical reaction in which an acyl group (such as an acetyl or benzoyl group) is introduced into a molecule, typically by the reaction of a carboxylic acid or its derivative with another compound. This process is central to the preparation of carboxylic acids, nucleophilic acyl substitution reactions, the chemistry of thioesters and acyl phosphates, and the reactions of amines.
Primary Amines: Primary amines are organic compounds containing a nitrogen atom bonded to two hydrogen atoms and one alkyl or aryl group. They are a class of amines that play a crucial role in various organic chemistry topics, including the chemistry of amides, the structure and properties of amines, the synthesis of amines, the reactions of amines, and the spectroscopy of amines.
Alkylation: Alkylation is the process of introducing an alkyl group (a hydrocarbon chain) into a molecule, typically through the reaction of a nucleophile with an alkyl halide or other alkylating agent. This versatile reaction is employed in various organic chemistry contexts, including the formation of new carbon-carbon bonds, the synthesis of more complex molecules, and the modification of existing functional groups.
Biological Eliminations: Biological eliminations refer to the process of removing waste products and other unwanted substances from the body through various physiological mechanisms. This term is particularly relevant in the context of the reactions of amines, as amines can undergo different types of elimination reactions during metabolic processes.
N-substituted Amides: N-substituted amides are a class of organic compounds derived from amides, where the hydrogen atom on the nitrogen is replaced by a substituent group. These compounds are important in organic chemistry, particularly in the context of reactions involving amines.
Tertiary Amines: Tertiary amines are a class of organic compounds where a nitrogen atom is bonded to three alkyl or aryl groups. They are an important subgroup of amines, which are organic compounds containing a nitrogen atom with a lone pair of electrons.
Hofmann Product: The Hofmann product is the major organic product formed in the reaction of a primary amine with a haloacetone or haloacetophenone. This reaction is an important method for the synthesis of ketones and is particularly useful in the context of amine reactions.
Iminium Ion: An iminium ion is a positively charged species formed by the reaction of an amine with a carbonyl compound, such as an aldehyde or ketone. It is a key intermediate in various organic reactions, including the Stork enamine reaction and the reactions of amines.
Quaternary Ammonium Salts: Quaternary ammonium salts are a class of organic compounds with a positively charged nitrogen atom surrounded by four alkyl or aryl groups. These salts are widely used as surfactants, disinfectants, and in various other applications due to their unique chemical properties.
Ylide: An ylide is a type of zwitterion, a molecule that contains both a positively and a negatively charged atom, typically carbon and a heteroatom like phosphorus or sulfur. Ylides are important intermediates in organic reactions, particularly in the Wittig reaction, which is used to form carbon-carbon double bonds.
N,N-disubstituted amides: N,N-disubstituted amides are a class of organic compounds where the nitrogen atom of an amide group is bonded to two alkyl or aryl substituents, rather than just one. This structural feature impacts the reactivity and properties of these compounds within the context of the reactions of amines.
Secondary Amines: Secondary amines are a class of organic compounds that contain a nitrogen atom bonded to two alkyl or aryl groups. They are characterized by the presence of two carbon-nitrogen bonds, distinguishing them from primary amines which have one carbon-nitrogen bond and tertiary amines which have three carbon-nitrogen bonds.