Carboxylic acid amides reactivity with nucleophiles

Reductive carbonylation of 1,1-dibromocyclopropanes with tetracarbonylnickel in dimethyl-formamide in the presence of a nucleophile is a powerful method for direct introduction of carboxylic acid functions to cyclopropanes. Nucleophiles, such as alcohols, amines, and silylamines, are particularly reactive and give cyclopropyl esters and amides, respectively, in reasonable to good yields, e.g. formation of 5 and... 

The reactivity of different isocyanates varies widely, and the most reactive NCO groups can react with almost any compound that contains an active hydrogen [1, 2, 16]. The reactivity of the nucleophilic groups also varies primary amines are more reactive towards NCO than primary alcohols, followed by water, secondary and tertiary alcohols, other urethanes, carboxylic acids, and carboxylic acid amides in that order [16]. The isocyanate will, of course, react with the water present in the EPI formulation to form amines followed by further reactions producing urea and biuret. The mechanism of this reaction is shown in Pig. 5. As can be seen from the reaction mechanism CO2 is a byproduct of this reaction. 

The electrophilic reactivity of the carbonyl carbon in carboxylic acid derivatives is weakened by good electron-donating substituents. This effect, measurable by IR spectroscopy, is responsible not only for the decrease in the reactivity with nucleophiles and acid, but also for the increased basicity along the series acyl habdes-anhydrides-esters-amides. Electron donation by resonance from the nitrogen in amides is so pronounced that there is hindered rotation about the amide bond on the NMR time scale. 

A distinct order of reactivity is observed in these reactions with (1) carboxylate anion aliphatic amines 3> aromatic amines. This has led to slight variations in the practical procedures for preparing the amides but these are well documented in the literature. The first route involves a one-step procedure the second involves reaction of (1) with the carboxylate anion and subsequent treatment with the amine and is the preferred method for converting alkanamines to the amides since the first one-step method produces large amounts of phenyl phosphorodiamidates as well as the amide, by nucleophilic attack of (1) by the amine. The final method prevents the formation of phenyl phosphorodiamidates as the carboxylic acid first reacts with 0.5 equiv of (1) to... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

N-substituted carbodiimides can react with carboxylic acids to form highly reactive, o-acylisourea derivatives that are extremely short-lived (Reaction 11). This active species then can react with a nucleophile such as a primary amine to form an amide bond (Reaction 12)... 

Acid chlorides are the most reactive carboxylic acid derivatives, and easily converted to acid anhydrides, esters and amides via nucleophilic acyl substitutions (see Section 5.5.5). Acid chlorides are sufficiently reactive with H2O, and quite readily hydrolysed to carboxylic acid (see Section 5.6.1). 

The possible nucleophilic reactions for each carboxylic acid derivative depends on its reactivity with respect to the other acid derivatives (Following fig.). Reactive acid derivatives can be converted to less reactive (more stable) acid derivatives, but not the other way round. For example, an ester can be converted to an amide, but not to an acid anhydride. 

Figure 6.50 displays acylations of C nucleophiles with NMe(OMe) derivatives of carbonic instead of carboxylic acids. The discussion of acylation reactions with NMe(OMe) derivatives of carboxylic acids ( Weinreb amides ) in Figures 6.42 and 6.44 revealed that the NMe(OMe) group has two effects first, it increases the reactivity and second, it is responsible for the occurrence of clean acylations. Against this background we will leave you to your own studies of a picture without words, namely Figure 6.50. Convince yourself that the approaches A —4 C, D —> C and E —> C to Weinreb amides outlined in this figure work and find out why alternative ketone syntheses D —> H and E —> H are also possible ...

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

A major distinction for nucleophilic reactions with ambident anions is whether they proceed with kinetic or thermodynamic control.80 N-Substituted saccharins (10) should be thermodynamically more stable because of amide character than the isomeric pseudosaccharin (3) of imidate structure. In fact 3 may be rearranged thermally to 10 in an irreversible reaction.96 The threshold for thermodynamic control appears to be lowered for electrophiles with multiple bonds, e.g., formaldehyde, reactive derivatives of carboxylic acids, but also quaternary salts of N-heterocyclic compounds.80 It will be seen that in those cases substitution indeed occurs at the nitrogen, not necessarily through thermodynamic control. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

So far the reactivity of epoxides has involved their use as an electrophile. However, oxtranyl anions can serve as functionalized nucleophiles in their own right. Thus, the sulfonyl substituted epoxide 107 can be deprotonated with -butyllithium to provide a stabilized anion which engages in facile Sn2 reaction with triflate 108 <03JOC9050>. Other examples of such stabilized epoxide anions include those derived from oxazolinyloxiranes (e.g., 110), which react with nitrones to provide the spirotricyclic heterocycles of type 112, Hydrolysis provides the epoxy amino acids 113, in which the carboxylic acid moiety was provided by the oxazoline nucleus and the amine functionality was derived from the nitrone <03OL2723>. A recent report has demonstrated that oxiranyl anions can also be stabilized by the amide functionality <03H(59)137>. 

The direct conversion of a carboxylic acid to an amide with NH3 or an amine is very difficult, even though a more reactive acyl compound is being transformed into a less reactive one. The problem is that carboxylic acids are strong organic acids and NH3 and amines are bases, so they undergo an acid-base reaction to form an ammonium sait before any nucleophilic substitution occurs. 

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