Anhydrides from ester carbonylation

Nucleophilic acyl substitutions at the ester carbonyl group are summarized m Table 20 5 on page 849 Esters are less reactive than acyl chlorides and acid anhydrides Nude ophilic acyl substitution m esters especially ester hydrolysis has been extensively mves tigated from a mechanistic perspective Indeed much of what we know concerning the general topic of nucleophilic acyl substitution comes from studies carried out on esters The following sections describe those mechanistic studies... 

The carbonyl group of an amide is stabilized to a greater extent than that of an acyl chlo ride acid anhydride or ester amides are formed rapidly and m high yield from each of these carboxylic acid derivatives... 

The Eastman acetic anhydride [108-24-7] process provides an extension of carbonylation chemistry to carboxyUc acid esters. The process is based on technology developed independendy in the 1970s by Eastman and Halcon SD. The Eastman acetic anhydride process involves carbonylation of methyl acetate [79-20-9] produced from coal-derived methanol and acetic acid [64-19-7]. 

Fluorinated Acids. This class of compounds is characterized by the strength of the fluorocarbon acids, eg, CF COOH, approaching that of mineral acids. This property results from the strong inductive effect of fluorine and is markedly less when the fluorocarbon group is moved away from the carbonyl group. Generally, their reactions are similar to organic acids and they find apphcations, particularly trifluoroacetic acid [76-05-1] and its anhydride [407-25-0] as promotors in the preparation of esters and ketones and in nitration reactions. 

The nucleus of the one-time widely prescribed prescribed COX-2 inhibitor, rofecoxib, better known by its trade name Vioxx , actually comprises a butenolide rather than a classical heterocycle. The drug was withdrawn from the market at full flood due to an unexpectedly high incidence of adverse cardiovascular side effects. The compound is included at this point to emphasize the breadth of the SAR for COX-2 anti-inflammatory agents. Reaction of phenylacetic acid (35-1) with ethyl bro-moacetate in the presence of triethylamine leads to the formation of the ester (35-2). Treatment of that intermediate with a strong base generates a carbanion at the benzyhc position in an intramolecular reaction, this attacks the terminal ester carbonyl to yield the butenolide (35-3). Reaction of that compound with triflic anhydride converts the... 

Acetylation of henningsoline (M+, 398) with [ He]-acetic anhydride gave a bistrideuteroacetyl derivative (M+, 488) indicating the presence of two hydroxyl groups in the alkaloid this was confirmed by the preparation of 0-benzoyl (ester carbonyl at 1709 cm i) and 0,0-di-benzoylhenningsoline (ester carbonyls at 1727 and 1721 cm i). The bistrideuteroacetyl derivative exhibited the m/e 190 and 176 peaks of the parent compound but these were weaker than new peaks at m/e 191 and 177. These must arise by transfer of deuterium from the 0-acetyl residue... 

Ozonolysis of the alkene of C frees the carboxylic acid of D which reacts with carbonyl diimidazole E (CDl) in a nucleophilic substitution at the carbonyl group, with the relatively stable imidazole anion as the leaving group. The product is an activated ester , like an anhydride, from which the anion of nitromethane displaces the second molecule of imidazole to give the product F. 

Lithium diisopropylamide N,N,N, N -tetramethylethylenediamine Maleic acid anhydrides from Y,6-ethylene-a-dicarboxylic acid esters via 1,2-carbonyl migration... 

Carbonylation may also be achieved by insertion of carbon monoxide into an existing bond, as for instance in the formation of anhydrides from carboxylic acid esters, of esters from ethers, or acids from alcohols. 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

Esters Like acid anhydrides the carbonyl group of an ester is stabilized by elec tron release from oxygen Because there is only one carbonyl group versus two m anhydrides esters are stabilized more and are less reactive than anhydrides... 

Section 20 21 Acyl chlorides anhydrides esters and amides all show a strong band for C=0 stretching m the infrared The range extends from about 1820 cm (acyl chlorides) to 1690 cm (amides) Their NMR spectra are characterized by a peak near 8 180 for the carbonyl carbon H NMR spectroscopy is useful for distinguishing between the groups R and R m esters (RCO2R ) The protons on the carbon bonded to O m R appear at lower field (less shielded) than those on the carbon bonded to C=0... 

Sulfur tetrafluoride [7783-60-0] SF, replaces halogen in haloalkanes, haloalkenes, and aryl chlorides, but is only effective (even at elevated temperatures) in the presence of a Lewis acid catalyst. The reagent is most often used in the replacement of carbonyl oxygen with fluorine (15,16). Aldehydes and ketones react readily, particularly if no alpha-hydrogen atoms are present (eg, benzal fluoride [455-31-2] from benzaldehyde), but acids, esters, acid chlorides, and anhydrides are very sluggish. However, these reactions can be catalyzed by Lewis acids (HP, BF, etc). 

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