Acyl chlorides, from carboxylic acids, with

The mechanism is similar to that for the formation of chlorides from alcohols and thionyl chloride. The hydroxyl group is converted to a good leaving group by thionyl chloride, followed by a nucleophilic acyl substitution in which chloride is the nucleophile (compare with Sec. 7.10). Phosphorus pentachloride and other reagents can also be used to prepare acyl chlorides from carboxylic acids. 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

It should be mentioned at this stage that instead of acyl chlorides, mixed anhydrides may also be used for the synthesis of acyl azides. From carboxylic acids and chloroformates/triethylamine, mixed anhydrides are formed, which can directly react with azide ions. Sterically hindered acids fail in this procedure (equation 31)." " The similar synthesis of /-butyl azidoformate by reaction of /-butylcarbonic diethylphosphoric anhydride with KN3 is described in Organic Syntheses. ... 

V-Dimethylchlorosulfitomethaniminium chloride (54), prepared from thionyl chloride and dimethyl-formamide, together with sodium azide is useful for the direct preparation of acyl azides from carboxylic acids (equation 35). ... 

Acyl chlorides are made from carboxylic acids with either thionyl chloride or oxalyl chloride. Look back at Chapter 10 if you need reminding of any of these reactions. 

Because acylation of amines with acyl chlorides and anhydrides yields an acid as one of the products (HCl from acyl chlorides, a carboxylic acid from an anhydride), the efficient synthesis of amides requires some attention to stoichiometry. 

Acyl chlorides are readily available They are prepared from carboxylic acids by reaction with thionyl chloride... 

The preparation of imidazolides by acylation of imidazole with acid chlorides is sometimes limited by the inaccessibility or instability of the required acid chlorides (e.g., formyl chloride, highly unsaturated acid chlorides, etc.) or by side-reactions in the case of multifunctional systems. For these reasons and due to the availability of an easy and convenient procedure involving very mild conditions, imidazolides today are usually prepared directly from the corresponding carboxylic acids with jV -carbonyldiimida-zole (CDI) or one of its analoga (see page 16). Use of these reagents has become more and more the preferred method for activation of carboxylic acids to azolides and their further transacylation to esters, amides, peptides, etc. (see subsequent Chapters). 

In addition to acyl chlorides and acyl bromides, there are a number of milder and more selective acylating agents which can readily prepared from carboxylic acids, hnidazolides, the /V-acyl derivatives of imidazole, are examples.108 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with... 

The coupling of the selone to racemic carboxylic acids with dicyclohexylcarbodiimide in dichloromethane with 4-dimethylaminopyridine at 0°C for 0.5-1 hour affords the acylated derivatives. Similar results are obtained using the acid chloride and triethyl amine. Figure 13 (upper part) shows the selenium spectrum for the diastereomeric. Y-acyl derivatives of the oxazo-lidine-2-selone with (A,A)-5-methylheptanoic acid. Clearly the shift difference of about (5 = 0.1 is sufficient for integration of the two singlets. The lower part of the figure shows the remarkably different 77Se resonances observed for four species derived from partially deuterated phenylacetic acid. The diastereomeric mixture of the monodeuteriated substance is easily detected (AS = 0.07, 5.0 Hz). 

Esters are produced by acid-catalysed reaction of carboxylic acids with alcohols, known as Fischer esterification. They are also obtained from acid chlorides, acid anhydrides and other esters. The preparation of esters from other esters in the presence of an acid or a base catalyst is called transesterification. All these conversions involve nucleophilic acyl suhstitu-tions (see Section 5.5.5). 

Initial efforts to prepare benzoic acid 28 from methyl or ethyl 4-aminobenzoate and biphenyl-2-carboxylic acid (27) afforded poor yields of 28 (48% and 7%, respectively). However, acylation of 4-aminobenzoic acid with biphenyl-2-carbonyl chloride was found to provide 28 in excellent yield (95%) when DMAP was employed as a base. Selective acylation of the anilinic nitrogen of 26 with benzoic acid 28 was accomplished in analogy with the first-generation process synthesis by conversion of 28 to the corresponding acid chloride (SOCl2, CH3CN) followed by acylation of 26 in acetonitrile. Subsequent addition of ethanolic hydrogen chloride to the reaction mixture resulted in the precipitation of conivaptan HCl (1), which was isolated in 90% yield. 

The acylation of carboxylic acids with 2,4,6-trichlorobenzoyl chloride gives mixed anhydrides A (Figure 6.14). Triethylamine must be present in this reaction to scavenge the released HC1. Anhydrides A contain two different acyl groups. In principle, both of them could be attacked by a nucleophile. However, one observes the chemoselec-tive attack on the acyl group that originates from the acid used. This is because the... 

Dihydrooxazoles are readily prepared from (V-acyl derivatives of /3-hydroxylamines by heating or by the action of thionyl chloride, sulfuric acid or phosphorus pentoxide (equation 167) (79JCS(P1)539>. The direct condensation of carboxylic acids with 13-hydroxylamines succeeds best with substituted compounds, such as norephedrine (equation 168). There are many variations of this general method, such as the use of imino ether hydrochlorides (equation 169) (78ACR375) and of cyanides (equation 170) (74LA996). 

Ammonia and amines react with acid chlorides to give amides, also through the addition-elimination mechanism of nucleophilic acyl substitution. A carboxylic acid is efficiently converted to an amide by forming the acid chloride, which reacts with an amine to give the amide. A base such as pyridine or NaOH is often added to prevent HC1 from protonating the amine. 

You remember, of course, that esters can be made from carboxylic acids and alcohols under acid catalysis, so you might expect them to use this type of method. On a small scale, it s usually better to convert the acid to an acyl chloride before coupling with an alcohol, using pyridine (or DMAP + Et3N) as a base this type of reaction might have been a reasonable choice too. 

One important application of this reaction is the chain extension of acyl chlorides to their homologous esters, known as the Amdt-Eistert reaction. Notice that the starting material for the Wolff rearrangement is easily made from RCO2H by reaction of the acyl chloride with diazomethane the product is RCH2CO2H—the carboxylic acid with one more carbon atom in the chain. A CH2 group, marked in black, comes from diazomethane and is inserted into the C-C bond between R and the carbonyl group. 

The reaction of a stannylanion with an acyl chloride also constitutes a general access to acylstannanes, but in low yields (equation 107) ". These can be improved by using other functions derived from carboxylic acids (see equation 118 below). 

Intramolecular acylation of alkylsilanes. Cyclopentanones can be prepared by ring closure of 5-(trimethylsilyl)alkanoyl chlorides mediated by AlCl,. The starting materials are readily available from alkylation of the dianion of a carboxylic acid with a 3-(trimethylsilyl)alkyl bromide or iodide (equation 1). 

The earliest, and most complex, protocol is presented by Burgess and cowoikers [66]. Starting from aspartic acid dimethylester, the amino group is acylated by adamantyl carboxylic acid chloride (see Figure 6.26). Reduction of the two ester groups, but not the amide function, with NaBH in ethanol followed by ring closure yields an oxazolineto-sylate that is transformed into the iodide. 

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