Amide from anhydrides

The synthesis of a model library of 100 amides from anhydrides on microchips has been described with quality control indicating excellent yields of pure amides and no cross-contamination of the wells (199). This test validated the chip structure, the seals of the system, and the electrohydrodynamic pumping system in the presence of solvents such as DMF and methanol and reagents such as the anhydrides, piperidine, and DIPEA. More challenging chemistries and larger libraries have also been presented. 

The acylation takes place by the normal mechanism for the formation of amides from anhydrides, that is, by nucleophilic attack on the carbonyl group and loss of the most stable anion (acetate) from the tetrahedral intermediate. The two isomers of alanine are enantiomers. Enantiomers must react at identical rates with an achiral reagent like acetic anhydride. 

Acid derivatives are made directly from acids or by conversion from other acid derivatives depending on their stabihty. The most important are esters (RCOiEt), amides (RCO2NR2), anhydrides (RCOO COR) and add clilorides (RCOCI). Arrange these in an order of stabilily, the most reactive at the top of the list, the most stable at the bottom. 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

Conversion of Acid Anhydrides into Amides Acetic anhydride is also commonly used to prepare iV-substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts rather than the less nucleophilic -OH group. 

Acid anhydride, amides from, 807 eleclrostatic potential map of, 791 esters from, 807 from acid chlorides, 806 from carboxylic acids, 795 1R spectroscopy of, 822-823 naming, 786... 

Isocyanates react with carboxylic acids to form amides, ureas, anhydrides, and carbon dioxide, depending on reaction conditions and the structure of the starting materials (Scheme 4.13). Aliphatic isocyanates more readily give amides. Aromatic isocyanates tend to react with carboxylic acids to first generate anhydrides and ureas, which at elevated temperatures (ca. 160°C) may further react to give amides. In practice, the isocyanate reaction with carboxylic acid is rarely utilized deliberately but can be an unwanted side reaction resulting from residual C02H functionality in polyester polyols. 

G. Ketones from nitriles, thioesters, amides, and anhydrides... 

The deacetyl compound (26-6) is now used for the direct production of cephalexin (25-3) as well as several other related agents that incorporate similar amide side chains. For example, reaction of the protected 7-ADCA derivative (27-2) with the fert-BOC amide from D- flra-hydroxyphenylglyeine (27-1) by the mixed anhydride method gives the amide (27-3). Serial scission of the tert-BOC group and the silyl ester affords the antibiotic cefadroxyl (27-4) [32]. Exactly the same sequence starting... 

However, detection of the tetrahedral intermediate in the addition of a nucleophile to an ester, acid halide, amide or anhydride must be adduced from kinetic evidence, in particular the evidence of oxygen exchange in such an intermediate. Such tracer work has established the presence of symmetrical addition compounds in the hydrolysis of esters23, amides and acid chlorides24. Since the attempts to detect such intermediates have played a considerable part in the development of hydrolysis studies, it is worthwhile considering this point in some detail. 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

Few preparations of nitriles have been performed on insoluble supports (Table 13.19). Aromatic and heteroaromatic nitriles have been prepared on solid phase from the corresponding iodoarenes by metallation followed by reaction with tosyl cyanide (Entry 1, Table 13.19). Moreover, the reaction of chloromethyl polystyrene with NaCN has been used to prepare support-bound benzyl cyanide (Entry 2, Table 13.19). Cleavage with simultaneous formation of nitriles can be achieved by treating polystyrene-bound sulfonylhydrazones with KCN (Entry 3, Table 13.19) or by cleaving amides from a Rink or Sieber linker with TFA anhydride (Entry 10, Table 3.38 [262]). Support-bound benzaldehydes have been converted into 3-aryl-2-propenenitriles by means of a Horner-Emmons reaction with (Et0)2P(0)CH2CN [263]. 

Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N-bcnzyl-4-phenylbutan-amide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (I).1... 

Write equations for the preparation of a given amide from an acyl halide, acid anhydride, or ammonium salt. 

In one example sequence the technology has been used to synthesize a variety of amides from amines and acid anhydrides. It is currently also being used to optimize reactions through the variations of auxiliaries and solvents and might become an interesting and more direct alternative to solid-phase synthesis. 

Acid chlorides are often used in these syntheses because they are the most electrophilic of all acid derivatives and because they can be made from the acids themselves with PCI5 or SOCI2. The other important acid derivatives can all be made from acid chlorides or from any compound above them in the chart of reactivity. So you can make amides from acid chlorides, anhydrides or esters but it is very difficult to make any other derivatives from amides. All derivatives except amides can easily be made from the acids themselves. 

Trypsin was named more than 100 years ago. It and chymotrypsin were among the first enzymes to be crystallized, have their amino acid sequences determined, and have their three-dimensional structure outlined by x-ray diffraction. Furthermore, both enzymes hydrolyze not only proteins and peptides but a variety of synthetic esters, amides, and anhydrides whose hydrolysis rates can be measured conveniently, precisely and, in some instances, extremely rapidly. As a result, few enzymes have received more attention from those concerned with enzyme kinetics and reaction mechanisms. The techniques developed by the pioneers in these various fields have enabled other serine proteases to be characterized rapidly, and the literature on this group of enzymes has become immense. It might be concluded that knowledge of serine proteases is approaching completeness and that little remains but to fill in minor details. 

The formation of amides from acid anhydrides has been described in Section 1C(4). 

When we made acid anhydrides from acid chlorides plus car-boxylate salts, we used an anionic nucleophile RCO2 but, when we made amides from acid chlorides plus amines, we used a neutral nucleophile NH3, and not NH2. For proper comparisons, we should include in our table ROH (pXaH = -5 in other words, -5 is the pXa of ROH2) and NH3 (pXgH = 9 in other words, 9 is the pKaofNHj). 

From formylation reactions of CH-acidic compounds, which take place if mixtures of carboxylic acid amides and anhydrides are used as formylating agents, it was concluded that the latter compounds form similar adducts to those from amides and acid halides. ... 

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