Esters to Acid Halides

Ethyl alcohol also reacts with acid anhydrides or acid halides to give the corresponding esters. 

Conversion of Acid Halides into Esters Alcoholysis Acid chlorides react with alcohols to yield esters in a process analogous to their reaction with water to yield acids. In fact, this reaction is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HC1 formed. 

From Boron Halides. Using boron halides is not economically desirable because boron halides are made from boric acid. However, this method does provide a convenient laboratory synthesis of boric acid esters. The esterification of boron halides with alcohol is analogous to the classical conversion of carboxylic acid halides to carboxylic esters. Simple mixing of the reactants at room temperature or below in a solvent such as methylene chloride, chloroform, pentane, etc, yields hydrogen halide and the borate in high yield. 

Na-Protected a-amino aldehydes 4 are mainly obtained from their corresponding a-amino acid derivatives. Generally the synthetic route proceeds via acid halides, esters, or active amides of a-amino acids that are then reduced. The reduction of N -protected acid halides and esters is often accompanied by some overreduction to the respective alcohols. However, reduction of active amides is apparently free from overreduction. The different procedures described in this review are listed in Table 3. 

Carboxylic acids, acid halides, esters, and amides are easily reduced by strong reducing agents, such as lithium aluminum hydride (LiAlH4). The carboxylic acids, acid halides, and esters are reduced to alcohols, while the amide derivative is reduced to an amine. 

This general reaction allows the conversion of a halogen group to an ester group without the evolution of hydrohalogen acid and therefore without the corrosion problem that would attend such evolution. The reaction is particularly useful for changing organosilicon halides to esters in order to separate them more easily. 

A rapid survey of the contents of the previous four chapters, which dealt primarily with the synthesis of various types of phosphonic and phosphinic acids, is all that is necessary to realize that both classes of acids are synthesized by the direct formation of a limited selection of types of derivatives. Most often these are either esters as, for example, in the Michaelis-Arbuzov reaction, or acid halides, almost invariably the chloride as in the phosphorylation of alkenes with PCI5. In any multi-step synthesis, the interconversions of acids, acid halides and esters are consequently amongst the most important of translocations of ligands attached to phosphorus, and their success may even become of critical importance. 

Results of preparative nitration arenes, haloarenes, and nitroarenes are summarized in Tables XV XVII. Since HF and BF3 are the only by-products of the reaction, nitration with nitronium salts can be carried out under anhydrous conditions. This is advantageous in nitration of aromatics containing functional groups sensitive to hydrolysis. Thus aromatic nitriles, acid halides, and esters can be nitrated in high yield without difficulty (Tables XVIII-XIX). 

In this section, we will focus primarily on nucleophilic additions to carbonyl groups. The carbonyl substrate may be an aldehyde or ketone, as well as various carboxylic acid derivatives such acid halides and esters. Among the variety of nucleophiles that can participate in these reactions are hydride, hydroxide, alkoxide, and a variety of carbon-based nucleophiles. For carbonyl substrates, attack by a nucleophile typically results in an opening up of the C-O ar-bond, leading to a tetrahedral intermediate, as shown below for the addition of cyanide to a ketone in the presence of water. 

The most common reaction theme of acid halides, anhydrides, esters, and amides is the addition of a nucleophile to the carbonyl carbon to form a tetrahedral carbonyl addition intermediate. To this extent, the reactions of these functional groups are similar to nucleophilic addition to the carbonyl groups in aldehydes and ketones (Section 12.4). The tetrahedral carbonyl addition intermediate (TCAI) formed from an aldehyde or a ketone then adds H". The result of this reaction is nucleophilic addition to a carbonyl group of an aldehyde or a ketone ... 

The anion from a-trimethylsilylacetate reacts with aldehydes to give a,0-unsaturated esters, and it has been found that by employing magnesium as the counter-ion pure E-isomers are obtained. Another application of silicon-stabilized anions involves the addition of lithiated trimethylsilyl methane [produced in situ from tributyl(trimethylsilylmethyl)tin and Bu"Li] to acid halides to give silylmethyl ketones, and the cyclization by Bu4N F" of (123) to (124) avoids the problems arising from the corresponding base-induced reaction in the absence of silicon. ... 

Siloxy Isocyanates. Acyclic anhydrides react with TMSA in a manner similar to acid halides to give equal amounts of trimethylsilyl esters and isocyanates (eq 7). Similarly, cyclic anhydrides react with the azide to give < -trimethylsiloxycarbonyl alk(en)yl isocyanates (eq 8) which are further transformed into l,3-oxazine-2,6-dione derivatives (70-90%). ... 

The extent of resonance can be observed directly in the structures of carboxylic acid derivatives. In the progression from acyl halides to esters and amides, the C-L bond becomes progressively shorter, owing to increased double-bond character (Table 20-1). The NMR spectra of amides reveal that rotation about this bond has become restricted. For example, W,N-dimethylformamide at room temperature exhibits two singlets for the two methyl groups, because rotation about the C-N bond is very slow on the NMR time scale. The evidence points to considerable tt overlap between the lone pair on nitrogen and the carbonyl carbon, as a result of the increased importance of the dipolar resonance form in amides. The measured barrier to this rotation is about 21 kcal moF (88 kJ moF ). 

Group VI metal carbonyls catalyze the thermal or photochemical reaction of acyclic and cyclic ethers with acid halides to give esters (e.g., 4-chloropentylacetate, XLVIII) in good yields (Alper and Huang, 1973). The order of effectiveness for M(CO)g is Mo > W > Cr. Group V substituted... 

When LiAlH4, a lithium reagent (R-Li), or a Grignard (R-MgBr) is added to an acid halide or ester it is nearly impossible to stop the reaction at the aldehyde/ketone (see dotted box). 

Strictly speaking the alkyl halides are esters of the halogen acids, but since they enter into many reactions (t.g., formation of Grignard reagents, reaction with potassium cyanide to yield nitriles, etc.) which cannot be brought about by the other eaters, the alkyl halides are usually distinguished from the esters of the other inorganic acids. The preparation of a number of these is described below. 

The monosubstituted malonic ester still possesses an activated hydrogen atom in its CH group it can be converted into a sodio derivative (the anion is likewise mesomeric) and this caused to react with an alkyl halide to give a C-disubstituted malonic ester. The procedure may accordingly be employed for the synthesis of dialkyImalonic and dialkylacetic acids ... 

The xanthates react with alkyl halides to give the di-esters of dithiocarbonic acid 0=C(SH)2 S=C(SH)0H, for example ... 

Thiazolecarboxylic acid hydrazides are prepared by the same general methods used to prepare amides, that is, by treating acids, esters, amides, anhydrides, or acid halides with hydrazine or substitued hydrazines. For example, see Scheme 21 (92). The dihydrazides are obtained in the same way (88). With diethyl 2-chloro-4,5-thiazoledicarboxylate this reaction gives the mono hydr azide monoester of 2-hydrazine-4,5-... 

Substituted Amides. Monosubstituted and disubstituted amides can be synthesized with or without solvents from fatty acids and aLkylamines. Fatty acids, their esters, and acid halides can be converted to substituted amides by reaction with primary or secondary aLkylamines, arylamines, polyamines, or hydroxyaLkylamines (30). Di- -butylamine reacts with oleic acid (2 1 mole ratio) at 200—230°C and 1380 kPa (200 psi) to produce di-A/-butyloleamide. Entrained water with excess -butylamine is separated for recycling later (31). 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

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