4.5 Amides
7 min read•august 21, 2024
are crucial functional groups in organic chemistry, characterized by a carbonyl bonded to nitrogen. They play vital roles in protein structure and various synthetic applications due to their unique bonding characteristics and resonance stabilization.
Understanding amide structure, nomenclature, and reactions is essential in Organic Chemistry II. Their physical properties, synthesis methods, and biological significance make them important in drug design, neurotransmitters, and synthetic .
Structure of amides
- Amides represent a crucial functional group in organic chemistry characterized by a carbonyl group bonded to a nitrogen atom
- Understanding amide structure provides insights into their reactivity, physical properties, and biological importance in Organic Chemistry II
- Amides play a significant role in protein structure and various synthetic applications due to their unique bonding characteristics
Resonance in amides
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- Resonance stabilization occurs through electron delocalization between the carbonyl group and nitrogen atom
- Partial double bond character exists between the carbon-nitrogen bond due to resonance
- Resonance structures contribute to the planarity and stability of amides
- Resonance in amides affects their reactivity and makes them less susceptible to nucleophilic attack compared to other carbonyl compounds
Planar geometry
- Amides adopt a planar configuration around the carbon-nitrogen bond
- Planarity results from the partial double bond character caused by resonance
- Bond angles in amides typically measure close to 120° due to sp2 hybridization
- Planar geometry influences the reactivity and intermolecular interactions of amides
Bond lengths and angles
- Carbon-oxygen double bond in amides measures approximately 1.24 Å
- Carbon-nitrogen bond length falls between a single and double bond at about 1.32 Å
- Carbon-carbon single bond adjacent to the carbonyl group measures around 1.51 Å
- Bond angles deviate slightly from ideal 120° due to electronic and steric factors
- O=C-N angle typically measures 122-123°
- C-N-R angle (where R is an alkyl group) measures about 118-120°
Nomenclature of amides
- Amide nomenclature follows systematic rules established by IUPAC (International Union of Pure and Applied Chemistry)
- Proper naming of amides is essential for clear communication in organic chemistry and understanding their structural features
- Amide nomenclature considers the parent carboxylic acid and substituents on the nitrogen atom
Primary vs secondary amides
- Primary amides contain one alkyl or aryl group attached to the nitrogen atom
- Secondary amides have two alkyl or aryl groups bonded to the nitrogen
- Naming primary amides involves using the suffix "-amide" with the parent acid name ()
- Secondary amides use N-substituted nomenclature to indicate groups on the nitrogen (N-methylacetamide)
Cyclic amides (lactams)
- are cyclic amides formed by intramolecular condensation of amino acids
- Nomenclature for lactams uses prefixes to indicate ring size (γ-butyrolactam)
- Systematic names for lactams incorporate the parent heterocyclic ring system (2-pyrrolidone)
- Lactams play important roles in natural products and (penicillins)
N-substituted amides
- contain alkyl or aryl groups attached to the nitrogen atom
- Naming N-substituted amides involves using "N-" prefixes to indicate substituents on nitrogen
- Multiple substituents on nitrogen use numerical prefixes (N,N-dimethylacetamide)
- N-substituted amides exhibit different physical and chemical properties compared to unsubstituted amides
Physical properties of amides
- Amides possess unique physical properties due to their structure and intermolecular interactions
- Understanding amide physical properties is crucial for predicting their behavior in various chemical processes
- Physical properties of amides influence their applications in organic synthesis and biological systems
Hydrogen bonding
- Amides form strong hydrogen bonds through their N-H and C=O groups
- Hydrogen bonding in amides occurs both intermolecularly and intramolecularly
- Strength of hydrogen bonding in amides falls between alcohols and esters
- Hydrogen bonding affects various physical properties of amides (melting points, boiling points, solubility)
Boiling points
- Amides generally have higher boiling points compared to other organic compounds of similar molecular weight
- Extensive hydrogen bonding network contributes to elevated boiling points
- Boiling points increase with increasing molecular weight and number of hydrogen bond donors/acceptors
- N-substituted amides typically have lower boiling points due to reduced hydrogen bonding capability
Solubility
- Amides exhibit good solubility in polar solvents (water, alcohols) due to hydrogen bonding
- Solubility decreases as the hydrocarbon portion of the amide increases
- N-substituted amides show reduced water solubility compared to primary amides
- Amides with long alkyl chains may become insoluble in water but remain soluble in organic solvents
Synthesis of amides
- Amide synthesis represents a fundamental reaction in organic chemistry with numerous applications
- Various methods exist for amide formation, each with specific advantages and limitations
- Understanding amide synthesis techniques is crucial for designing efficient synthetic routes in Organic Chemistry II
From carboxylic acids
- Direct condensation of carboxylic acids with amines requires high temperatures
- Activating agents (DCC, EDC) facilitate amide formation under milder conditions
- Mechanism involves nucleophilic addition-elimination at the carbonyl group
- Carbodiimide-mediated coupling produces amides with good yields and minimal side reactions
From acid chlorides
- Acid chlorides react rapidly with amines to form amides under mild conditions
- Reaction proceeds via mechanism
- Base (triethylamine, pyridine) is often added to neutralize HCl byproduct
- Schotten-Baumann reaction uses aqueous conditions for amide synthesis from acid chlorides
From esters
- Esters undergo aminolysis with amines to form amides
- Reaction typically requires heating and extended reaction times
- Mechanism involves tetrahedral intermediate formation and elimination of alcohol
- Catalysts (sodium methoxide, enzymes) can accelerate ester aminolysis reactions
Reactions of amides
- Amides undergo various chemical transformations due to their unique electronic structure
- Understanding amide reactions is essential for predicting their behavior in complex organic syntheses
- Amide reactions play crucial roles in biological processes and pharmaceutical development
Hydrolysis
- Amide hydrolysis occurs under acidic or basic conditions to form carboxylic acids and amines
- Acid-catalyzed hydrolysis proceeds via protonation of the carbonyl oxygen
- Base-catalyzed hydrolysis involves nucleophilic addition of hydroxide to the carbonyl group
- Amide hydrolysis is generally slower than ester hydrolysis due to resonance stabilization
Reduction
- Amides can be reduced to primary amines using strong reducing agents
- Lithium aluminum hydride (LAH) effectively reduces amides to primary amines
- Mechanism involves hydride addition to the carbonyl group followed by elimination of alkoxide
- Partial reduction of amides to aldehydes can be achieved using DIBAL-H at low temperatures
Hofmann rearrangement
- Hofmann rearrangement converts primary amides to primary amines with one fewer carbon atom
- Reaction requires bromine and sodium hydroxide under aqueous conditions
- Mechanism involves formation of an isocyanate intermediate
- Curtius rearrangement and Lossen rearrangement are related reactions with similar outcomes
Spectroscopic analysis of amides
- Spectroscopic techniques provide valuable information about amide structure and purity
- Combining multiple spectroscopic methods allows for comprehensive characterization of amides
- Spectroscopic analysis is crucial for structure elucidation and quality control in amide chemistry
IR spectroscopy
- Amides exhibit characteristic IR absorption bands for C=O and N-H stretching vibrations
- C=O stretching frequency typically appears around 1630-1680 cm^-1^
- N-H stretching bands occur in the 3300-3500 cm^-1^ region for primary and secondary amides
- Amide II band (N-H bending + C-N stretching) appears around 1550 cm^-1^
NMR spectroscopy
- ^1^H NMR spectroscopy reveals information about proton environments in amides
- N-H protons in primary amides appear as broad singlets around 5-8 ppm
- ^13^C NMR shows characteristic carbonyl carbon peaks around 160-180 ppm
- 2D NMR techniques (COSY, HMQC) provide additional structural information for complex amides
Mass spectrometry
- Mass spectrometry allows for determination of molecular mass and fragmentation patterns
- Electron ionization (EI) often results in McLafferty rearrangement for amides
- Electrospray ionization (ESI) is useful for analyzing larger, more polar amides
- High-resolution mass spectrometry provides accurate mass measurements for molecular formula determination
Biological significance of amides
- Amides play crucial roles in various biological processes and structures
- Understanding the biological significance of amides is essential for applications in biochemistry and medicinal chemistry
- Amide chemistry forms the foundation for many important biomolecules and pharmaceutical compounds
Peptide bonds
- Peptide bonds are amide linkages that connect amino acids in proteins and peptides
- Formation of peptide bonds occurs through condensation of carboxylic acid and amine groups
- Peptide bonds exhibit partial double bond character due to resonance stabilization
- Hydrolysis of peptide bonds is a key step in protein digestion and degradation
Neurotransmitters
- Several important neurotransmitters contain amide functional groups
- Acetylcholine, a neurotransmitter at neuromuscular junctions, features an ester and amide group
- Melatonin, involved in regulating sleep-wake cycles, contains an indole ring with an amide side chain
- Understanding amide-containing neurotransmitters is crucial for developing drugs targeting neurological disorders
Synthetic polymers
- Amide linkages are present in various synthetic polymers with important applications
- Nylon, a versatile synthetic fiber, consists of repeating amide units
- Kevlar, a high-strength polymer, derives its properties from hydrogen-bonded amide groups
- Polyacrylamide gels are widely used in electrophoresis and water treatment applications
Amides in drug design
- Amide functional groups are prevalent in many pharmaceutical compounds
- Understanding amide chemistry is crucial for rational drug design and optimization
- Amides in drugs often contribute to target binding, metabolic stability, and pharmacokinetic properties
Amide prodrugs
- Amide prodrugs utilize the hydrolytic lability of amides for drug delivery
- Prodrug approach can improve solubility, stability, or absorption of active compounds
- Enzymatic or chemical hydrolysis of amide prodrugs releases the active drug in vivo
- Examples of amide prodrugs include levodopa and enalapril
Enzyme inhibitors
- Many enzyme inhibitors contain amide groups that mimic natural substrates
- Amide bonds in enzyme inhibitors often form hydrogen bonds with active site residues
- Peptide-based enzyme inhibitors (HIV protease inhibitors) utilize amide linkages
- Understanding amide interactions with enzymes is crucial for designing potent and selective inhibitors
Structure-activity relationships
- Structure-activity relationships (SAR) studies often involve modifications of amide groups
- Amide bond isosteres (e.g., thioamides, sulfonamides) can be used to probe SAR
- N-substitution patterns on amides can significantly affect drug potency and selectivity
- Computational modeling of amide-containing drugs helps predict binding affinities and optimize lead compounds
Key Terms to Review (17)
Acetamide: Acetamide is an organic compound with the formula CH3CONH2, classified as an amide derived from acetic acid. This compound is significant in organic chemistry due to its role as a building block in the synthesis of various pharmaceuticals and agrochemicals. It exhibits properties typical of amides, including participation in hydrogen bonding and acting as a polar solvent.
Amidation: Amidation is the chemical reaction that forms an amide from a carboxylic acid and an amine. This process involves the nucleophilic attack of the amine on the carbonyl carbon of the carboxylic acid, leading to the formation of a covalent bond and the release of water as a byproduct. Amidation is a key step in organic synthesis, as amides are important functional groups in many biological and industrial applications.
Amides: Amides are organic compounds derived from carboxylic acids, where the hydroxyl group is replaced by an amine or ammonia. They play a crucial role in various biological processes and are important in the formation of proteins, as they link amino acids together through peptide bonds. Understanding amides helps to connect the concepts of carboxylic acids and their derivatives in organic chemistry.
Benzamide: Benzamide is an organic compound derived from benzoic acid, where the carboxylic acid group (-COOH) is replaced by an amine group (-NH2), making it a type of amide. It features a benzene ring attached to a carbonyl group linked to a nitrogen atom, giving it distinct properties and applications in various fields, particularly in organic synthesis and pharmaceuticals.
Boiling point: The boiling point is the temperature at which a liquid's vapor pressure equals the external pressure surrounding it, causing the liquid to transition into a gas. This phenomenon is influenced by intermolecular forces, molecular weight, and the presence of functional groups in organic compounds, which can vary greatly among different classes of compounds.
Hermann Staudinger: Hermann Staudinger was a pioneering German chemist known for his groundbreaking work in polymer chemistry, particularly for proposing the existence of macromolecules and introducing the concept of polymers. His ideas revolutionized the understanding of large molecules, linking them to amides and organolithium compounds, which are critical in synthesizing various materials and studying reactions in organic chemistry.
Hydrolysis of Amides: The hydrolysis of amides is a chemical reaction where an amide compound reacts with water to produce a carboxylic acid and an amine. This process is important in organic chemistry as it helps in understanding how amides, which are derivatives of carboxylic acids, can be transformed into other functional groups. The reaction can occur under acidic or basic conditions, influencing the mechanism and products formed.
Lactams: Lactams are cyclic amides formed when the carbonyl group of an amide is part of a ring structure. These compounds are significant due to their presence in many biologically active molecules, including antibiotics and pharmaceuticals. The unique cyclic structure of lactams influences their reactivity and properties, making them an essential class of compounds in organic chemistry.
N-substituted amides: N-substituted amides are a class of organic compounds formed by replacing one hydrogen atom of the amine group in an amide with an alkyl or aryl group. This substitution creates variations in properties and reactivity, making n-substituted amides an important focus in organic chemistry, particularly in the context of amide derivatives and their applications in synthesis and biological systems.
Nucleophilic Acyl Substitution: Nucleophilic acyl substitution is a fundamental reaction in organic chemistry where a nucleophile attacks a carbonyl carbon of a carboxylic acid derivative, leading to the replacement of a leaving group with the nucleophile. This process is crucial for forming various functional groups, as it allows for the transformation of carboxylic acid derivatives into other compounds such as esters and amides. The stability of the carbonyl compound and the nature of the leaving group significantly influence the reaction's efficiency and outcome.
Pharmaceuticals: Pharmaceuticals are substances used in the diagnosis, treatment, or prevention of disease and are often derived from natural or synthetic compounds. These compounds play a crucial role in healthcare by providing therapeutic benefits, alleviating symptoms, and improving overall patient outcomes. They can be classified into various categories based on their chemical structure and biological activity, including esters, amides, aldehydes, and ketones, which contribute significantly to their efficacy and functionality in medical applications.
Polarity: Polarity refers to the distribution of electrical charge over the atoms in a molecule, which results in the formation of partial positive and negative charges. This concept is crucial in understanding the behavior of molecules, including their solubility, intermolecular interactions, and reactivity. In amides, polarity plays a significant role in their properties and how they interact with other substances.
Polymers: Polymers are large molecules composed of repeating structural units called monomers, which are covalently bonded together. These macromolecules can exhibit diverse physical and chemical properties, making them essential in various fields, including materials science and biochemistry. The versatility of polymers allows for their use in creating everything from plastics and fibers to natural substances like proteins and nucleic acids.
Primary Amide: A primary amide is a functional group characterized by a carbonyl group (C=O) attached to a nitrogen atom (N) that is bonded to only one alkyl or aryl group. This structure differentiates primary amides from secondary and tertiary amides, where the nitrogen is attached to more than one carbon group. The primary amide structure plays a significant role in organic chemistry, particularly in reactions involving nucleophiles and in the formation of peptides and proteins.
Robert H. Grubbs: Robert H. Grubbs is a prominent American chemist known for his work in the field of organic chemistry, particularly in the development of metathesis reactions. His research has significantly advanced synthetic methodologies, including the creation of catalysts that facilitate the formation of amides and other complex organic molecules, showcasing innovative strategies in synthetic chemistry.
Secondary amide: A secondary amide is a type of amide where the nitrogen atom is bonded to two carbon-containing groups and one hydrogen atom. This structure is significant because it plays a vital role in various chemical reactions and biological processes, often influencing the properties and reactivity of the compound. Secondary amides are important in organic synthesis and can be derived from the reaction of primary amines with carboxylic acids or acid chlorides.
Staudinger Reaction: The Staudinger Reaction is a chemical reaction that involves the conversion of an azide into an amine via a phosphine intermediate. This reaction highlights a crucial method for synthesizing amines from azides, and it’s particularly relevant in the context of amide chemistry, where amines can be derived from carboxylic acid derivatives such as amides and esters.