Amide Reactions
Amide reactions involve the chemical transformation of amides, which are compounds containing a carbonyl group bonded to an amine group. These reactions can include hydrolysis, reduction, and substitution, and are important in organic synthesis for creating a wide range of compounds. Amide reactions are widely studied and utilized in pharmaceutical, agricultural, and materials chemistry.
4 Key excerpts on "Amide Reactions"
eBook - ePub- J Fisher, J.R.P. Arnold, Julie Fisher, John Arnold(Authors)
- 2020(Publication Date)
- Taylor & Francis(Publisher)
...The most important reaction of amides is that of hydrolysis; this is the reverse reaction of amide formation (Section J3). The product of hydrolysis depends on the reaction conditions utilized. The acid catalyzed reaction results in the formation of an amine salt. The base catalyzed reaction results in the formation of an amine (Figure 3). Figure 3 The dependence of reaction conditions on the products of amide hydrolysis, (a) Acid catalyzed; (b) base catalyzed. Amide hydrolysis is very important in biology. It is a central reaction in the digestion of proteins. Biologically important amines and amides Many naturally occurring compounds and pharmaceutical agents contain amine or amide functions. Among the most important amine compounds are the neurotransmitters, such as dopamine and serotonin (Figure 4). These play an essential role in the transmission of nerve impulses throughout the body. Amphetamines, such as benzedrine, are generally powerful stimulators of the nervous system. Although many of these are used legally as drugs, they are also used illegally to heighten or stimulate emotions (Figure 4). Figure 4 Examples of biologically important amines. Alkaloids are amine-based compounds generally isolated from plants, and are among the most powerful psychotropic drugs. Some of these drugs are used to cure diseases, others, such as nicotine, cause them and are addictive (Figure 4). In addition to amides being the key structural and functional unit of peptides (Section L1), they are the core of numerous medicinal products (Figure 5). For example, acetaminophen, marketed under a number of names including Panadol, is an effective alternative to aspirin, without the side effects of gastrointestinal bleeding! However, acetaminophen has no anti-inflammatory activity, therefore unlike aspirin cannot be used for the treatment of rheumatoid arthritis. Figure 5 Examples of medically important amides....
- Wenyi Zhao(Author)
- 2016(Publication Date)
- CRC Press(Publisher)
...10 Reagents for Amide Formation N -Acylation reactions of nitrogen for the preparation of amides are frequently used in the synthesis of drug substances. Generally, the formation of C(O)−N amide bond 1 between acids and amines needs to activate the acids prior to coupling with amines. Among various activation methods, conversion of the acids into the corresponding acid chlorides is by far the most common approach. The use of mixed anhydrides provides an inexpensive and readily scaled process for preparation of amides that is particularly valuable for cases prone to epimerization. There has been increasing safety concern related to the use of triazole-based coupling agents, such as 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxid hexafluorophosphate (HATU) and O -(benzotriazol-1-yl)- N,N,N ′, N ′-tetramethyluronium hexafluorophosphate (HBTU), on a large scale due to the explosive nature of the reagents (>1500 J/g; maximum operating temperature approximately 50°C). 10.1 CDI-MEDIATED AMIDE PREPARATION Amide bond formation is one of the most valuable tools used to construct drug molecules. N,N- carbonyldiimidazole (CDI) as a coupling agent for amide bond formation is increasingly applied to the large-scale synthesis of a number of pharmaceutical products, for example, sildenafil, 2 darifenacin, 3 and sunitinib. 4 The evolution of a carbon dioxide by-product provides a driving force for the reaction. In addition, the imidazole by-product can be removed by acidic wash. A disadvantage of using CDI is that the resulting imidazolide intermediate is less reactive than the corresponding acid chloride. Consequently, CDI-mediated amide bond formation often requires a catalyst to promote the reaction. CDI 5 is a white crystalline solid and convenient to handle on scale. Compared with acid chlorides, CDI is less reactive and often used in the coupling of amino acids for peptide synthesis...
eBook - ePub- Greg T. Hermanson(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
...The water-insoluble carbodiimides can be used in peptide synthesis or for the synthesis of other organic compounds. Carbodiimides are used to mediate the formation of amide or phosphoramidate linkages between a carboxylate and an amine or a phosphate and an amine, respectively (Hoare and Koshland, 1966 ; Chu et al., 1986 ; Ghosh et al., 1990). Regardless of the type of carbodiimide, the reaction proceeds by the formation of an intermediate o -acylisourea that is highly reactive and short-lived in aqueous environments. The attack of an amine nucleophile on the carbonyl group of this ester results in the loss of an isourea derivative and formation of an amide bond (see Reactions 3.11 and 3.12). The major competing reaction in water is hydrolysis. 4 Hydroxyl Reactions Hydroxyl-reactive chemical compounds include not only those modification agents able to directly form a stable linkage with an –OH group, but also a broad range of reagents that are designed to temporarily activate the group for coupling with a secondary functional group. Many of the chemical methods for modifying hydroxyls originally were developed for use with chromatography supports in the coupling of affinity ligands. Some of these same chemical reactions have found application in bioconjugate techniques for crosslinking a hydroxyl-containing molecule with another substance, usually containing a nucleophile. For instance, carbohydrate-containing molecules such as polysaccharides or glycoproteins can be coupled through their sugar residues using hydroxyl-specific reactions. In addition, polymers and other organic compounds containing hydroxyls (such as PEG) may be conjugated with another molecule using these chemistries. 4.1 Epoxides and Oxiranes An epoxide or oxirane group can react with nucleophiles in a ring-opening process. The reaction can take place with primary amines, sulfhydryls, or hydroxyl groups to create secondary amine, thioether, or ether bonds, respectively...
eBook - ePub- Graham Patrick(Author)
- 2004(Publication Date)
- Taylor & Francis(Publisher)
...In both cases the rearrangement reaction involves the alkyl group being transferred from the carbonyl group to the nitrogen atom to form an isocyanate intermediate. Hydrolysis then results in loss of the original carbonyl group. The Hofmann rearrangement involves the treatment of a primary amide with bromine under basic conditions. The Curtius rearrangement involves heating an acyl azide. Arylamines Amino groups cannot be directly introduced to an aromatic ring. However, nitro groups can be added directly by electrophilic substitution, then reduced to the amine. Once the amine is present, reactions such as alkylation, acylation, or reductive animation can be carried out as described for alkylamines. Related topics (I4) Synthesis of mono-substituted aromatic rings (L6) Reactions of alkyl halides (O4) Chemistry of nitriles (K6) Reactions Reduction Nitriles and amides can be reduced to alkylamines using lithium aluminum hydride (LiAlH 4 ; Sections O4 and K6). In the case of a nitrile, a primary amine is the only possible product. Primary secondary and tertiary amines can be prepared from primary secondary and tertiary amides, respectively. Substitution with NH 2 Primary alkyl halides and some secondary alkyl halides can undergo S N 2 nucleophilic substitution with an azide ion (N 3 −) to give an alkyl azide (Section L6). The azide can then be reduced with LiAlH 4 to give a primary amine (Figure 1). The overall reaction is equivalent to replacing the halogen atom of the alkyl halide with an NH 2 unit. Another method of achieving the same result is the Gabriel synthesis of amines. This involves treating phthalimide with KOH to abstract the N–H proton (Figure 2). The N–H proton of phthalimide is more acidic (p K a 9) than the N–H proton of an amide since the anion formed can be stabilized by resonance with both neighboring carbonyl groups. The phthalimide ion can then be alkylated by treating it with an alkyl halide in a nucleophilic substitution (Section L2)...
