Acid halide nucleophiles

Nucleophilic substitution by ammonia on a halo acids (Section 19 16) The a halo acids obtained by halogenation of car boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac tive substrates in nucleophilic substitu tion processes A standard method for the preparation of a ammo acids is dis placement of halide from a halo acids by nucleophilic substitution using excess aqueous ammonia... 

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. 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

The above transformations show a few of the many inorganic esters that can be prepared by attack of an inorganic acid or, better, its acid halide or anhydride, on an alcohol. Although for convenience all these similar reactions are grouped together, these are not all nucleophilic substitutions at R. The other possible pathway is nucleophilic substitution at the inorganic central atom ... 

Acid halides react with vinylphosphoranes (56) to afford isolable N-acylaminophosphonium salts (57), which are hydrolyzed by alkali to N-vinylamides (58). By treatment with triethylamine and phenol the halogen in 57 can be nucleophilically exchanged for phenolate. Thiophenol, secondary amines, and hydrazones can be employed instead of phenol this leads to diverse 1-hetero-substituted 2-aza-1,3-dienes 59 (Scheme 31) (90TL3497). 

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

Oxetanes are much less susceptible to cleavage by nucleophiles than oxiranes, except in the presence of acids. Several types of acid-catalyzed nucleophilic reactions are described in the previous section, such as reaction of hydrogen halides to give 3-halogeno-1-propanols and various acid-catalyzed solvolysis reactions. Another example of this type is the reaction of thiourea with 2-alkyloxetanes in the presence of hydrochloric or perchloric acid to give excellent yields of 3-alkyl-3-hydroxybutylisothiouronium salts (equation 39) <67CR(C)(264)1309>. 

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. 

To capture electrophilic substrates such as acid halides, aldehydes, alkyl halides, isocyanates, and isothiocyanates, a variety of nucleophilic resins are commonly used. Some commercially available and representative examples are tris-(2-aminoethyl)amine (9), thiophenol (10), sulfonylhydrazide (11), triphenylphosphine (12), and methylthiourea (13) polymer resins (Fig. 6). 

Instead of carboxylic acids, other carbonyl compounds can be used acid halides, esters, amides, etc. The commonly accepted general mechanism for these reactions consists of the initial nucleophilic addition of an active hydrogen compound to the electron-poor carbonyl carbon atom of the R COOI I molecule, with the formation of a metastable intermediate that can undergo a subsequent elimination reaction ... 

Halonium ions are an important class of onium ions.43 The dialkylchloro, bromo, and iodohalonium ions can be prepared and even isolated as stable salts (i.e., 46), as shown by Olah et al. by reacting an excess of haloalkane with strong Lewis acid halides in solvents of low nucleophilic-ity (eq 14). In superacid solution, dialkylhalonium ions show enhanced alkylating reactivity.44 It is considered that this enhanced reactivity is due to further protolytic (or electrophilic) activation involving the non-bonded... 

Monocationic acyl ions are readily prepared as persistent species in solutions of low nucleophile strength.68 These acyl ions have been thoroughly characterized by IR and NMR spectroscopy, and several acyl ion salts have been characterized by X-ray crystallography. The monocationic acyl ions are often prepared in situ from carboxylic acids, esters, or anhydrides, by the action of a strong Brpnsted acid, or the ions can be prepared from ionization of an appropriate acid halide with a strong Lewis acid. Both methods have been used to prepare acyl-centered dications, some of which can be considered distonic superelectrophiles. As described previously, dicarboxylic acids cleave to the bis-acyl ions in superacid (FSChH-SbFs) provided that the acyl cations are separated by at least three methylene units (eq 54).55 The first bis-acyl dications were reported by Olah and Comisarow, being prepared by the reactions of dicarboxylic acid fluorides with superacidic SbFs (eq 72).69... 

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