Carboxamides nucleophilic attack

Nucleophilic attack by carbanion occurs in the reaction of 2-nitrobenzamides 154 treated with sodium ethoxide (72JCS(P1)835). The reaction mixtures usually contain small amounts of nitrile 155 and carboxamide 156, the product of decarboxylation 158 being usually the principal product (Scheme 24). The corresponding bromo derivatives under the used conditions did not react. 

From A(-substituted carboxamides, the 3-unsubstituted derivatives were formed, with loss of the corresponding amine. This reaction is to be expected from the mechanism of the ring closure amidine formation and subsequent nucleophilic attack of the amidine nitrogen on the carbonyl group. 

The transamidation mechanism starts with the nucleophilic attack by the thiol group of an active-site cysteine residue (the catalyhc triad is composed of Cys-276, His-334, and Asp-358) on the donor substrate y-carboxamide group, leading to loss of an equivalent of ammonia and formahon of a covalent thiolester intermediate. The acyl group of the transient thiolester is transferred to the acceptor amine substrate in the second step [45]. 

The fluoro substituents proved to induce changes in the reactivities of the methyl- (X = H) and trifluoromethyl-substituted (X = F) pyrido[3, 2 4,5]furo[3,2- [l,3]oxazin-4(47r)-ones 105 with nucleophiles. When methyl-substituted compounds 105 (X = H) were reacted with piperidine in toluene, Wacetylamino carboxamides 106 were formed by nucleophilic attack at the carbonyl group of the l,3-oxazin-4-one ring (Scheme 16). However, the similar reactions of the trifluoromethyl-substituted analogs 105 (X = F) resulted in formation of amidino carboxylic acids 107 by attack at electron-poor position 2 <1995JFC(74)1>. 

The electrochemical oxidation of hypoxanthine (261) in aqueous solution gave the intermediate 6,8-dioxopurine (262), which is more easily oxidized than 261, leading to 6,8-dioxopurinediimine (263).408 It is proposed that the nucleophilic attack of water occurs at the 4- or 5-position of 263, leading to the imino alcohols 264 or 265 [Eq. (138)]. These two compounds decompose by subsequent chemical or electrochemical reactions to the three major final products 5-imino-2,4-imidazoledione, 5-hydroxyhydantoin-5-carboxamide, and 4-amino-4-carboxyimidazol-5-one. 

Reaction via unstable acidic or basic intermediates can be promoted by proton transfer to a base or from an acid, respectively, thus giving rise to base or acid catalysis. The concept is illustrated for nucleophilic attack on carboxamide derivatives (Scheme 11.6). With base catalysis, deprotonation of the first-formed intermediate promotes the forward reaction, as does protonation of the first-formed intermediate with acid catalysis. 

In a strongly alkaline solution, the base abstracts a proton from the carboxamide A, and nucleophilic attack by carboxamide nitrogen can occur on the cyanamide B carbon atom prior to the attack of carboxamide oxygen, giving guanine C. 

The liquid range of HMPA is 7.2-235°C its dielectric constant is 30 (20" C). HMPA solvates cations strongly, whereas anions are less solvated. Unlike carboxamides, such as DMF, it is not attacked by aqueous alkali at t < SO C, and it is very resistant toward nucleophilic attack [377] but forms peroxides under the influence of light and oxygen [376]. 

The first step in the ring closure of carboxamide 107 (R=NH2) with imidates is the formation of an amidine intermediate, with subsequent nucleophilic attack of the imino group of the amidine on the carbonyl group this takes places with loss of the carboxamide iV-substituent [117]. This observation formed the basis of a simple synthesis of CHINOIN 143 enantiomers. From carboxamides 39 and 40 with ethyl m-chlorobenzimidate, 109 and 110 were obtained in high enantiomeric purity. The absolute configurations were determined by hydrolysis of 109 and 110 to the corresponding amino acid, which was identified by HPLC [79]. 

A nucleophilic attack by N occurs. Chloride ion is eliminated and a substitution product is obtained. Water, ammonia, and alcohols usually serve as the nucleophiles in the reactions with acyl chlorides. The products of these reactions are carboxylic acids, esters, or carboxamides. 

Nickel(II) compounds catalyze the hydration of organonitriles in basic and neutral media. For example, 2-cyano-l,10-phenanthroline is converted to the corresponding carboxamide by means of nucleophilic attack of OH on the nitrile carbon atom. The suggested mechanism is outlined in Scheme The same mechanism holds for the hydration reaction of... 

The cyclization reaction of 39 under basic conditions furnished a 1 1 mixture of diazepines 40 and 43. The unexpected formation of 43 has been rationalized by a Smiles rearrangement involving a nucleophilic attack of the deprotonated 3 -nitrogen at position 4 of the second pyridazine ring resulting in the displacement of a carboxamide anion followed by cyclization to afford 43. ... 

Coordination compounds with organonitrile ligands are of considerable interest due to the increased susceptibility of the coordinated nitrile to nucleophilic attack by reagents such as hydroxide ion. Rate accelerations of 10 in base hydrolysis (nitrile-> amide) have been observed. Two new aromatic organonitrile complexes of [Co(NH3)5] with 2- and 4-nitroben-zonitrile have been prepared, and their base hydrolysis to coordinated carboxamides studied. The second-order rate constants for base hydrolysis are 180 4 and 510 90 M s at 25°C and / = 1.0 M for the ortho and para isomers, respectively. Rate constants for the hydrolysis of 11 coordinated aromatic nitriles follow a Hammett-type correlation with log koH = l-93o- + 1.30 at 25 C and / = 1.0 M. Carbon-13 NMR studies of the free and coordinated nitriles indicate similar chemical shifts, so that the variation in the slope of the Hammett plots for free- and coordinated-nitrile hydrolysis is a transition-state effect rather than a ground-state phenomenon. 

However, the use of phenyl )V-phenylphosphoramidochloridate as a condensing agent for carboxylic acids and amines yields carboxamides in a one-step method (eq 7). The amide (12) is prepared from the carboxylic acid, 2 equiv of triethylamine, 1 equiv of amine, and 1 equiv of reagent (1) and isolated by filtration or evaporation of solvent and washing with water. Once again, a mixed anhydride intermediate (13) is presumed, which results from nucleophilic attack by the carboxylate anion on the phosphorus atom with elimination of a chloride ion a further nucleophilic attack by the amine on the carbonyl group of (13) and breakdown of the complex yields the amide (12) and phenyl Af-phenylphosphoramidate (14) which can be recycled to (1) by reaction with phosphorus pentachloride. 

Carboxypeptidase A"" (CPA, EC 3.4.17.1) is a proteolytic enzyme that cleaves C-terminal amino acid residues with hydrophobic side chains selectively. Several X-ray structures are available" The active site of CPA consists of a hydrophobic pocket (primary substrate recognition site) that is primarily responsible for the substrate specificity, a guanidinium moiety of Argl45 that forms hydrogen bonds to the carboxylate of the substrate, and Glu270, whose carboxylate plays a critical role, functioning either as a nucleophile to attack the scissUe carboxamide carbonyl carbon of the substrate or as a base to activate the zinc-bound water molecule, which in turn attacks the scissile peptide bond ". However, semiempirical calculations had shown that the direct attack of... 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

---