Making an Amide

Not surprisingly, the hydrolysis of nitriles is the most atom economical reaction. The isohypsic transformations are the acid chloride-Schotten-Baumann sequence, carbodiimide and carbonyl-diimidazole methods, and the hydrolysis of nitriles. The oxidation of nitriles with hydrogen peroxide is hyperhypsic for the reasons mentioned in Section 9.1.1 for the nitrile to carboxylic acid transformation. The umpolung method, which electronically reverses the roles of the reacting partners, is hypohypsic since a net oxidation has occurred at the reactive carbon atom. This is a novel 

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Pantothenic acid, sometimes called vitamin B3, is a vitamin that makes up one part of a complex coenzyme called coenzyme A (CoA) (Figure 18.23). Pantothenic acid is also a constituent of acyl carrier proteins. Coenzyme A consists of 3, 5 -adenosine bisphosphate joined to 4-phosphopantetheine in a phosphoric anhydride linkage. Phosphopantetheine in turn consists of three parts /3-mercaptoethylamine linked to /3-alanine, which makes an amide bond with a branched-chain dihydroxy acid. As was the case for the nicotinamide and flavin coenzymes, the adenine nucleotide moiety of CoA acts as a recognition site, increasing the affinity and specificity of CoA binding to its enzymes. 

This loss in stabilization energy at the transition state makes an amide far less nucleophilic than an amine. 

Then the amino group of aspartate is transferred to the carboxyl, making an amide. This condensation uses ATP and the amide is cleaved to release fumarate, leaving behind the imidazole with a 5-amino group (left from the amidation of glycine four steps earlier) and a 4-carboxamide. (Note how this reaction is similar to the formation of arginine during the urea cycle.)... 

The chemists who first made amelfolide chose to make it from an amine and an acyl chloride because they knew that this reaction, the standard way of making an amide, had a very good chance of success. They chose to disconnect the C-N bond because this disconnection corresponds to a reliable reaction in a way that no other possible disconnection of this molecule does. 

To compare the basicity of an alkylamine (RNH2) and an amide (RCONH2), we must once again compare the availability of the nonbonded electron pair on nitrogen. With RNH2, the electron pair is localized on the N atom. With an amide, however, the electron pair is delocalized on the carbonyl oxygen by resonance. This decreases the electron density on N, making an amide much less basic than an alkylamine. 

The most important reaction of amino acids is the formation of peptide bonds. Amines and acids can condense, with the loss of water, to form amides. In the laboratory, we might make an amide simply by mixing the acid and the amine, then heating the mix-... 

Is there a way to make an amide from a carboxylic acid )... 

Preparation and Uses of Amides One way of making an amide is to treat a carboxylic acid with ammonia, forming an ammonium salt, followed by heating. The following sequence summarizes a pathway for making ethanamide. 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

A compound in which the —OH group of an acid is replaced by —NH2 is called an amide. When the —OH is replaced by —NHR, the product is called a nitrogen-substituted amide or, abbreviated, an N-substituted amide. One way to make amides is to react ammonia (or an amine) with an ester ... 

Itiswer The n-propyl group had best come from an amide (13) which could be the Ritter product if EtCM is used. Making (13) by more conventional methods Is fine, too. 

Note that for both examples, the metal/CCl4 interaction is dangerous whether an amide is present or not. This makes it difficult to interpret the role played by amide. 

As early as 1899, 8tieglitz proposed a tetrahedral intermediate for the hydrolysis of an imino ether to an amide. Thns it was clear qnite early that a complicated overall transformation, imino ether to amide, would make more sense as the result of a series of simple steps. The detailed mechanism proposed, althongh reasonable in terms of what was known and believed at the time, wonld no longer be accepted, but the idea of tetrahedral intermediates was clearly in the air. 8tieglitz stated of the aminolysis of an ester that it is now commonly snpposed that the reaction takes place with the formation of an intermediate prodnct as follows referring to work of Lossen. (Note that the favored tautomer of a hydroxamic acid was as yet unknown.)... 

Nature has developed exquisite catalysts for a variety of reactions, for example, the hydrolysis of an amide bond. In the absence of a catalyst, amide bonds are extremely stable, making them ideal bonds to link amino acids in order to create... 

If time or resource constraints do not allow for actual making or testing of certain compounds, use prophetic examples. A prophetic or "paper" example "describes a possible route to making an inventive embodiment that has not actually been carried out [9]." If prophetic examples are employed, it is very important that the verb tense of the prophetic examples always be in the present tense (e.g., acid (1) is reacted with amine (2) forming an amide). In the patent world, the present tense distinguishes prophetic examples from actual examples actual examples are written in the past tense. 

At this point, we can integrate much of what has been discussed above in a single case study. Antibody NPN43C9 was reported in 1988 as the first example of catalysis of hydrolysis of an amide bond, in fact of an active anilide. Its structure and mode of action have been well studied (Janda et al., 1988b), which makes it an appropriate example for this purpose. 

However, attempts to make an aqueous solution of the base sodium amide would result in the formation of sodium hydroxide and ammonia. The amide ion is a strong base and abstracts a proton from water, a weak acid. The reverse reaction is not favoured, in that hydroxide is a weaker base than the amide ion, and ammonia is a weaker acid than water. Take care with the terminology amide the amide... 

These reactions also provide us with a convenient way of making secondary and tertiary amines. Thus, a primary amine may be converted into an amide by reaction with an acyl chloride, then LAH reduction... 

This is an excellent method for making sodium amide for many i)urpo.ses. If the sodium amide is to be used in another... 

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