21.5 Chemistry of Acid Anhydrides
2 min read•may 7, 2024
are versatile compounds in organic synthesis. They're less reactive than acid chlorides but more reactive than , making them useful intermediates in many reactions. Their balanced reactivity allows for controlled transformations in various synthetic processes.
Acid anhydrides play a crucial role in pharmaceutical synthesis. They're used to make common drugs like and through reactions. Understanding their reactivity and mechanisms is key for designing efficient synthetic routes in drug development.
Synthesis and Reactivity of Acid Anhydrides
Preparation of acid anhydrides
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- React carboxylic acids with in a
- Carboxylic acid acts as the attacking the electrophilic carbonyl carbon of the acyl chloride
- serves as the
- React a carboxylic acid with a dehydrating agent (, )
- Reaction proceeds through the formation of an intermediate
- Intermediate undergoes nucleophilic attack by another carboxylic acid molecule forming the acid anhydride and () as a byproduct
- This is an example of a
Acid anhydrides vs acid chlorides
- Acid anhydrides are less reactive than acid chlorides in nucleophilic acyl substitution reactions due to the better ability of the chloride ion compared to the
- Acid anhydrides are more reactive than carboxylic acids because the additional makes them more electrophilic
- Acid anhydrides undergo slower to form carboxylic acids compared to the hydrolysis of acid chlorides
- Acid anhydrides react with alcohols to form at a slower rate than the corresponding reaction with acid chlorides
- Acid anhydrides react with amines to form with lower reactivity than acid chlorides but higher than carboxylic acids
Acetic anhydride in pharmaceuticals
- Aspirin () synthesized using
- treated with acetic anhydride to acetylate the
- Nucleophilic acyl substitution reaction where the acts as the nucleophile
- Reaction typically carried out in the presence of a weak base () to catalyze the reaction
- Acetaminophen () synthesized using acetic anhydride
- acetylated using acetic anhydride to form acetaminophen
- Nucleophilic acyl substitution reaction with the amino group acting as the nucleophile
- Reaction usually performed in the presence of a weak base (sodium acetate) to catalyze the reaction and neutralize the acetic acid byproduct
Reaction Mechanism of Acid Anhydrides
- Acid anhydrides contain two carbonyl groups (carbonyl group) connected by an oxygen atom
- In nucleophilic acyl substitution reactions:
- The carbonyl carbon acts as the
- The incoming reactant acts as the nucleophile
- The carboxylate group serves as the leaving group
Key Terms to Review (34)
Acetaminophen: Acetaminophen, also known as paracetamol, is a widely used over-the-counter medication primarily used for its analgesic (pain-relieving) and antipyretic (fever-reducing) properties. It is a phenolic compound that is an important component in the context of both phenols and their uses, as well as the chemistry of acid anhydrides.
Acetic Anhydride: Acetic anhydride is a colorless, volatile liquid that is used as a reagent in organic synthesis, particularly in the formation of carboxylic acid derivatives. It is a key compound in various chemical reactions and processes, including those related to carboxylic acid derivatives, acid anhydrides, and DNA synthesis.
Acetylsalicylic Acid: Acetylsalicylic acid, commonly known as aspirin, is a medication used to reduce pain, fever, and inflammation. It is a type of acid anhydride that is widely used in the pharmaceutical industry and has a variety of applications in organic chemistry.
Acid Anhydrides: Acid anhydrides are organic compounds that contain two acyl groups bonded to a central oxygen atom. They are formed by the dehydration of two carboxylic acid molecules and serve as important intermediates in various chemical reactions, particularly those involving carboxylic acids.
Acyl Chlorides: Acyl chlorides are a class of organic compounds derived from carboxylic acids, characterized by the presence of a carbonyl group (C=O) bonded to a chlorine atom. They are highly reactive intermediates used in various synthetic reactions, particularly in the formation of other carboxylic acid derivatives.
Alcoholysis: Alcoholysis is a type of nucleophilic acyl substitution reaction in which an alcohol replaces a group attached to a carbonyl carbon, typically resulting in the formation of an ester. This process is also relevant in the chemistry of acid anhydrides, where alcohols can react with anhydrides to produce esters and carboxylic acids.
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.
Aspirin: Aspirin, also known as acetylsalicylic acid, is a widely used medication with a variety of therapeutic applications. It is a synthetic derivative of salicylic acid and is classified as a non-steroidal anti-inflammatory drug (NSAID) due to its ability to reduce inflammation, pain, and fever.
Carbodiimide: A carbodiimide is a functional group with the general formula R-N=C=N-R', where R and R' are organic substituents. Carbodiimides are versatile reagents used in various organic reactions, particularly in the context of acid anhydrides and peptide synthesis.
Carbonyl group: A carbonyl group is a functional group characterized by a carbon atom double-bonded to an oxygen atom, represented as C=O. This group is pivotal in organic chemistry as it forms the backbone of various important classes of compounds, influencing their chemical properties and reactivity.
Carboxylate Ion: The carboxylate ion is a negatively charged species formed when a carboxylic acid loses a proton (H+). It is a key intermediate in various organic chemistry reactions and plays a crucial role in understanding the structure and properties of carboxylic acids, as well as their reactions and the chemistry of acid anhydrides.
Carboxylic Acids: Carboxylic acids are a class of organic compounds containing a carboxyl functional group (-COOH) attached to an alkyl or aryl group. They are characterized by their acidic properties and play a crucial role in various chemical reactions and biological processes.
Carboxylic acids, RCO2H: Carboxylic acids are organic compounds characterized by the presence of a carboxyl group (-COOH), where "R" represents an alkyl or aryl group attached to the carbon atom of the carboxyl group. They are known for being acidic due to the ability of the hydroxyl (OH) part of the carboxyl group to release a proton (H+).
Chloride Ion: The chloride ion (Cl-) is a negatively charged ion composed of a single chlorine atom that has gained an extra electron, making it more stable. It is an important ion in various chemical processes and biological functions.
DCC: DCC, or dicyclohexylcarbodiimide, is a coupling agent commonly used in organic chemistry for the activation and coupling of carboxylic acids and alcohols, as well as in peptide synthesis and the preparation of acid anhydrides. It plays a crucial role in various reactions by facilitating the formation of new carbon-carbon or carbon-heteroatom bonds.
DCU: DCU, or Dicarboxylic Acid Anhydride, is a key functional group in the context of acid anhydrides. Acid anhydrides are organic compounds formed by the dehydration of two carboxylic acid groups, resulting in a cyclic structure that is widely used in various chemical processes and applications.
Dehydration Reaction: A dehydration reaction is a chemical process in which a molecule of water is removed from the reactants, resulting in the formation of a new product. This type of reaction is commonly observed in the context of acid anhydrides, where the removal of water leads to the creation of a cyclic anhydride structure.
Dicyclohexylcarbodiimide: Dicyclohexylcarbodiimide (DCC) is a reagent commonly used in organic chemistry, particularly in the context of reactions involving carboxylic acids and acid anhydrides. It serves as a coupling agent, facilitating the formation of new carbon-carbon or carbon-heteroatom bonds.
Dicyclohexylurea: Dicyclohexylurea is a chemical compound that is commonly used as a coupling agent in the synthesis of organic compounds. It is a derivative of urea, with two cyclohexyl groups attached to the nitrogen atoms, giving it a unique structure and properties.
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.
Esters: Esters are a class of organic compounds formed by the reaction between a carboxylic acid and an alcohol, resulting in the replacement of the hydroxyl group (-OH) of the acid with an alkoxy group (-OR). Esters are ubiquitous in nature and play a crucial role in various chemical processes and applications.
Hydrolysis: Hydrolysis is a chemical reaction in which a compound is cleaved into smaller molecules by the addition of water. This process involves the breaking of chemical bonds through the insertion of water molecules, often resulting in the formation of new functional groups or the decomposition of larger molecules.
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.
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.
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.
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.
O-acylisourea: O-acylisourea is an important reactive intermediate that arises in various organic reactions, particularly in the context of alcohol reactions, acid anhydride chemistry, and peptide synthesis. It serves as a key coupling agent, facilitating the formation of new bonds and enabling the transformation of starting materials into desired products.
P-Aminophenol: p-Aminophenol is an organic compound consisting of a phenol group with an amino group attached to the para position on the benzene ring. It is an important intermediate in the production of various pharmaceuticals, dyes, and other chemical products.
Paracetamol: Paracetamol, also known as acetaminophen, is a widely used medication that serves as an analgesic (pain reliever) and antipyretic (fever reducer). It is a common ingredient in many over-the-counter and prescription drugs, making it one of the most frequently consumed pharmaceuticals worldwide.
Phenolic Hydroxyl Group: The phenolic hydroxyl group is a functional group consisting of a hydroxyl (-OH) group attached directly to an aromatic (phenyl) ring. This group is an important structural feature in many organic compounds, particularly in the context of acid anhydrides.
Phenoxide Ion: The phenoxide ion is a negatively charged species formed when a phenol compound (an aromatic alcohol) loses a hydrogen atom from the hydroxyl group. This ion is an important intermediate in various organic reactions, particularly in the context of acid anhydrides.
Salicylic Acid: Salicylic acid is a naturally occurring organic compound that is classified as a phenolic acid. It is a key ingredient in many over-the-counter medications and is widely used in the treatment of various skin conditions, such as acne, warts, and psoriasis.
Sodium Acetate: Sodium acetate is a salt formed by the neutralization of acetic acid with sodium hydroxide. It is a common chemical compound with various applications in organic chemistry and related fields.