Thionyl chloride method, acyl chlorides

A modification of the thionyl chloride method for making acyl chlorides uses oxalyl chloride plus catalytic DMF. The oxalyl chloride reacts with the... 

Carboxyl Activation Synthesis of Esters and Amides from Carboxylic Acids. 4-(Dimethylamino)pyridinium chlorosulfite chloride is more reactive than either thionyl chloride or thionyl chloride/pyridine for carboxyl activation. Aliphatic and aromatic, as well as amino acids (in racemic form), undergo activation (via the acyl halide) and subsequent esterification by reaction with an alcohol at — 20 °C (eq 1). The esterification step requires the addition of a second equivalent of DMAP and this method has been applied to a range of functionalized carboxylic acids. 

The chemical transformations of the carboxyl group include formation of halo[ C]acetyl halides, amides, imides, alcohols, aldehydes and amines. Methods for the preparation of halo[ " C]acetyl halides from [ " C]acetic acid have already been mentioned. In addition, chloro[ " C]acetyl chloride has become available through treatment of chloro[ C]acetic acid with thionyl chloride or phthaloyl chloride, whereas for bromo[ " C]acetyl chloride, thionyl chloride or phosphorus pentachloride is recommended. Numerous applications of halol Clacetyl halides have been published, out of which the following C-, N- and 0-acylations may illustrate their versatility. 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

The acyl chloride (the crude material prepared by the thionyl chloride method is quite satisfactory) is added dropwise to well-stirred concentrated aqueous ammonia cooled in a freezing mixture. The amides of the higher carboxylic acids crystallise out on standing and need only to be filtered and recrystallised. Water-soluble amides are isolated by extraction with hot ethyl acetate following removal of water on a rotary evaporator. 

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). 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

This method is usually used for producing small amounts of valuable acyl chlorides—oxalyl chloride is much more expensive than thionyl chloride. DMF... 

Some of the starting compounds were commercially available only as acids or anhydride. The respective acyl chlorides were obtained according to the thionyl chloride method of Smith et al. (1991). Reactions with cyanotrimethylsilane were completed under water-free conditions and in an argon atmosphere (Hiinig and Schaller, 1982). Glassware was dried in an oven directly before use. 

N-Acylsaccharins (13) possess a certain potential as acylating agents. They will acylate amines, but will react with water or alcohols only when acid or base is present.167 The method was used to acylate a-amino-penicillanic acid.170 Micheel162-165 has based a peptide (38) synthesis on the acyl transfer from 31 [Z = carbobenzoxy, obtained through reaction with DCC or with pseudosaccharin chloride (6) or with thionyl chloride and imidazole] to amino acids. Pseudosaccharin anhydride 323, lee js thg product of a condensation between 6 and 1, mostly from hydrolysis of 6. Formation of 32 tends to occur in nonprotic solvents with base catalysis, even when practical precautions are taken to exclude moisture. Water and protic solvents seem to shield the anion 19 and prevent attack on 6. 

Pentafluorophenyl 61 and 4-oxo-3,4-dihydrobenzotriazin-3-yl 65 esters (see Table 16) can be obtained from acid 59 and hydroxy compounds using thionyl chloride the intermediate is the Fmoc amino acid chloride 64 (Scheme 17). In the case of the pentafluorophenyl esters 61, the acid chloride 64 is generated in the absence of the nucleophile and acylation is promoted in the presence of pyridine. While in the case of the 4-oxo-3,4-dihydrobenzotriazin-3-yl esters 65, condensation is achieved by heating the reactants in refluxing dichloromethane. The method is not applicable to derivatives with acid-sensitive side-chain protectors. 

The Vilsmeier (or Vilsmeier-Haack or Vilsmeier-Haack-Arnold) reaction is primarily a mild method for formylating a wide variety of substrates.1 It has limited application to higher acylation and involves the reaction of a Vilsmeier reagent derived from a tertiary amide and an acid chloride (or occasionally a bromide). The most commonly employed amide is jV,N-dimethylformamide (DMF) and the acid chloride is generally phos-phoryl chloride, though phosgene and thionyl chloride are also employed. 

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Sodium Azide Pathway The free carboxyl group-containing compound was dissolved in thionyl-chloride and refluxed for 10 hours, followed by vacuum evaporation. To a solution of acyl chloride in 1,2-dimethoxyethane was added, under stirring, an excess of freshly activated sodium azide in solid form ("dry method"), or in aqueous solution ("wet method"). In the dry method, the mixture was refluxed overnight, filtered, and evaporated to dryness. In the wet method, the mixture was stirred for 20 minutes and precipitated by the addition of water (10 times its original volume). The precipitate was filtered, washed, and freeze-dried. The organic azide was either heated for 1 hour to 100-120°C (oil bath) as a dry powder ("dry method"), or refluxed for 1 hour in dioxane- or DMF-solution ("solution method"), which was followed by vacuum evaporation. 

Another chemical method (6) of synthesizing amino acid esters is to form acyl halides by reacting amino acids with thionyl chloride first. Then the appropriate alcohol is added to produce ester. A facile synthetic method under mild conditions was studied via cesium salts to yield amino acid esters (7). This process not only involves expensive cesium salts, but it also produces amino acid esters with one enantiomer in rich. 

For acylation in pyridine by Einhorn s method it is not always necessary to start with preformed acyl chloride. Its preparation and reaction can be effected in one operation by dissolving the amine and carboxylic acid together in pyridine, adding the calculated amount of thionyl chloride with cooling, and after some time pouring the mixture into water the amide is precipitated and is washed successively with dilute acid, dilute alkali hydroxide, and water. 

The grafting to method was used for the preparation of composites with the polymers containing reactive functional groups. One of the first examples of the grafting to approach was published by Fu et al in 2001. In this work, carboxylic acid groups on the nanotube surface were converted into acyl chlorides by refluxing the samples in thionyl chloride. Then the acyl chloride functionalised CNTs have been reacted with hydroxyl groups of dendritic PEG polymers via esterification reactions. 

Carboxylic acids can be converted to the corresponding acyl chlorides, which react with an amine containing chromophore. A few methods have been developed for conversion of acids to acyl chlorides. Hoffman and Liao [107] used a mixture of triphenylphosphine and carbon tetrachloride or polystyryldiphenylphosphine to prepare acyl chlorides of fatty acids. The reaction was carried out at 80 °C for 5 min. The intermediate acyl chlorides were then converted to amides with p-nitroaniline or p-melhoxyaniline. Thionyl chloride [108] and oxalyl chloride [109] were also applied to prepare acyl chloride. The conversion with oxalyl chloride was quantitative in 30 min at 70 °C. The commonly used amines were 1-naphthylamine [109] and p-chloroaniline [110]. The final derivatives were separated by RP-HPLC with either gradient [108] or isocratic elution [109,110]. 

Acid chlorides or acid anhydrides provide rapid and reliable acylation. The usual method of forming saturated acid chlorides is by reaction of the unesterified fatty acid with thionyl chloride (cf. Jensen and Pitas, 1976). Unsaturated fatty acid chlorides are best made with oxalyl chloride (Mattson and Volpenheim, 1962). Notes on precautions to be taken during the preparations are detailed in Buchnea (1978). 

---