21.7 Chemistry of Amides
3 min read•may 7, 2024
Amides are unique among carboxylic acid derivatives, resisting hydrolysis due to . Their reactions, from acid and base-catalyzed hydrolysis to reduction with , showcase their distinct reactivity compared to esters, anhydrides, and .
preparation often involves between amines and acid chlorides. The amide bond's partial double bond character leads to interesting structural features and rearrangements, like the Hofmann and Beckmann rearrangements, crucial in organic synthesis.
Amide Reactions
Hydrolysis of amides
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- Amides are more resistant to hydrolysis compared to other carboxylic acid derivatives (esters, anhydrides, acid chlorides) due to resonance stabilization
- Resonance structures involve donation of the nitrogen lone pair into the carbonyl, increasing the C-N bond order and decreasing the carbonyl electrophilicity
- mechanism:
- Protonation of the carbonyl oxygen activates the amide
- Water attacks the protonated carbonyl forming a
- Proton transfer from the oxonium ion to the nitrogen followed by C-N bond cleavage yields a carboxylic acid and an ammonium ion
- mechanism:
- Hydroxide attacks the carbonyl forming a tetrahedral intermediate
- Proton transfer from the nitrogen to the alkoxide followed by C-N bond cleavage yields a carboxylate and an amine
- Reactivity order of carboxylic acid derivatives towards nucleophilic acyl substitution: acid chlorides > anhydrides > esters > amides
Reduction of amides with LiAlH4
- Amide reduction with LiAlH4 yields while reduction of other carboxylic acid derivatives (esters, acid chlorides, anhydrides) yields primary alcohols
- Mechanism:
- Hydride () from LiAlH4 attacks the carbonyl carbon forming a tetrahedral intermediate
- Proton transfer from the nitrogen to the alkoxide yields an and an aluminum-coordinated amide
- The aldehyde is further reduced by LiAlH4 to yield a primary amine
- Workup involves quenching excess LiAlH4 with water, adding aqueous NaOH to convert aluminum salts to a white gelatinous solid, and extracting the primary amine product with ether or dichloromethane
Methods for amide preparation
- between an amine and an
- Amine acts as a nucleophile attacking the electrophilic carbonyl carbon of the acid chloride with chloride as the leaving group
- Reaction is rapid and exothermic, often performed at 0°C or below with a non-nucleophilic base () to neutralize the HCl byproduct
- Mechanism:
- Nucleophilic addition of the amine to the carbonyl carbon forms a tetrahedral intermediate
- Proton transfer from the ammonium ion to the chloride yields the amide product and HCl
- Primary and secondary amines readily form amides while tertiary amines cannot due to the absence of an
- Acid chlorides are highly reactive due to the excellent leaving group ability of chloride, but anhydrides and esters can also be used to prepare amides with lower reactivity
- is a method for preparing primary amines via an amide intermediate
Amide structural features and rearrangements
- Amide bond ( when part of a protein) exhibits partial double bond character due to resonance
- is restricted due to this partial double bond character, leading to cis/trans isomerism
- : conversion of primary amides to primary amines with one fewer carbon
- : conversion of oximes to amides, often used in the synthesis of
Key Terms to Review (22)
Acid Chloride: An acid chloride, also known as an acyl chloride, is a highly reactive organic compound derived from a carboxylic acid. It contains a carbonyl group (C=O) bonded to a chlorine atom, making it a versatile and important functional group in organic chemistry.
Acid chlorides: Acid chlorides are a class of organic compounds characterized by the presence of a carbonyl group (C=O) bonded to a chlorine atom. They are derived from carboxylic acids by replacing the hydroxyl group (OH) with a chlorine atom.
Acid-Catalyzed Hydrolysis: Acid-catalyzed hydrolysis is a chemical reaction where a compound is cleaved by the addition of water, facilitated by the presence of an acid catalyst. This process is particularly relevant in the context of protecting alcohols and the chemistry of amides.
Aldehyde Intermediate: An aldehyde intermediate is a transient chemical species that contains a carbonyl group (C=O) with a hydrogen atom attached to the carbon. These intermediates often arise in organic reactions and play a crucial role in the transformation of carbonyl compounds, such as the reduction of aldehydes to alcohols and the formation of amides from carboxylic acids.
Amide: An amide is a functional group consisting of a carbonyl group (C=O) linked to a nitrogen atom (N). Amides are important in organic chemistry and play a crucial role in various topics, including functional groups, elimination reactions, alcohol reduction, nitrile chemistry, amide chemistry, and the spectroscopy of carboxylic acid derivatives.
Amide Bond Rotation: Amide bond rotation refers to the restricted rotation around the carbon-nitrogen bond in amide functional groups, which is a key feature of the chemistry of amides. This rotational restriction arises from the partial double-bond character of the carbon-nitrogen bond, which gives the amide group a planar structure.
Base-Promoted Hydrolysis: Base-promoted hydrolysis is a chemical reaction in which a base, such as a hydroxide ion (OH-), facilitates the cleavage of a chemical bond, typically the carbonyl carbon-nitrogen bond in amides, to produce a carboxylic acid and an amine. This process is an important reaction in the chemistry of amides.
Beckmann Rearrangement: The Beckmann rearrangement is a chemical reaction that involves the conversion of an oxime (the product of the reaction between a ketone or aldehyde and hydroxylamine) into an amide. This reaction is an important tool in organic chemistry, particularly in the context of understanding the chemistry of amides.
Gabriel Synthesis: The Gabriel synthesis is a chemical reaction used to synthesize primary amines from phthalimide and an alkyl or aryl halide. It is a versatile method for the preparation of a wide range of primary amines, which are important building blocks in organic chemistry and have applications in the synthesis of various compounds, including amides, amino acids, and pharmaceuticals.
Hofmann Rearrangement: The Hofmann rearrangement is a chemical reaction that converts an amide into a primary amine. It involves the oxidation of an amide to an isocyanate intermediate, which is then hydrolyzed to form the primary amine product.
Hydrolysis of Amides: Hydrolysis of amides is a chemical reaction in which an amide bond is cleaved by the addition of water, resulting in the formation of a carboxylic acid and an amine. This process is an important step in the metabolism and degradation of proteins and other biomolecules containing amide linkages.
Lactams: Lactams are cyclic amides formed when a carboxylic acid group on one part of a molecule reacts with an amine group on another part of the same molecule, resulting in ring closure. They are important in organic chemistry because they serve as the core structure for many synthetic and naturally occurring compounds.
LiAlH4: LiAlH4, also known as lithium aluminum hydride, is a powerful reducing agent commonly used in organic chemistry reactions. It is particularly useful in the context of nucleophilic addition reactions of aldehydes and ketones, the chemistry of esters and amides, as well as the synthesis of amines.
N-H Bond: The N-H bond, also known as the amino group, is a covalent bond formed between a nitrogen (N) atom and a hydrogen (H) atom. This bond is an important structural feature in organic compounds, particularly in the context of the chemistry of amides.
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.
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.
Peptide bond: A peptide bond is a covalent chemical bond formed between two amino acid molecules when the carboxyl group of one molecule reacts with the amino group of another molecule, releasing a molecule of water (a condensation reaction). This bond is integral in forming the primary structure of peptides and proteins.
Peptide Bond: A peptide bond is a covalent chemical bond formed between the carboxyl group of one amino acid and the amino group of another amino acid, resulting in the creation of a peptide chain. This bond is crucial in the formation and structure of proteins, which are essential macromolecules for life.
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.
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.
Tetrahedral Intermediate: A tetrahedral intermediate is a key reaction step that occurs in many organic chemistry reactions, where a trigonal planar carbonyl carbon temporarily becomes a tetrahedral carbon with four bonded atoms. This transient intermediate is crucial for understanding the mechanisms of various nucleophilic addition and substitution reactions.
Triethylamine: Triethylamine is a colorless, flammable liquid with a distinctive fishy odor. It is a tertiary amine, meaning it has three ethyl groups attached to a central nitrogen atom. Triethylamine is a commonly used organic compound in various chemical reactions and processes, particularly in the context of oxidation of alcohols, protection of alcohols, and the chemistry of amides.