Carboxylic acids production

Acidic hydrolysis of 14 occurs via protonation of the nitrogen followed by attack of water on the resulting cationic intermediate. Proton transfer followed by ring-opening affords cation 15, which is trapped by a second equivalent of water. Another proton transfer followed by loss of the amino group affords protonated carboxylic acid 16, which loses to provide the carboxylic acid product. 

Expulsion of alcohol yields the free carboxylic acid product and regenerates the acid catalyst. 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

Trost et al.59 were the first to report enantioselectivity in the transition metal-catalyzed Alder-ene reaction. Several different acids were surveyed for the degree of efficacy in oxidizing the Pd(0) precursor to the active Pd(n) species and for compatibility with the catalyst, substrate, and product. Among acids surveyed were several chiral carboxylic acids products of reactions using these optically active acids were formed with modest enantioselectivity. (A)-binaphthoic acid gave the most promising result, with the cyclized product 83 obtained with 33% ee (Equation (52)). 

There are few drugs that are thioesters, but you may recall that one of the intermediates in the oxidation of aldehydes by aldehyde dehydrogenase is a thioester involving the thiol of the enzyme (Fig. 30 in Chapter 4), which is readily hydrolyzed back to the native form of the enzyme, a thiol, and the carboxylic acid product. Some drugs that are carboxylic acids, such as enaloprilate, are administered as ester prodrugs (enalopril), which are more readily absorbed from the intestine than the carboxylic acid and are then readily hydrolyzed to the active drug by esterases as mentioned in Chapter 1 (Fig. 1 in Chapter 1). 

Figure 18.12 Effect of fluorescent device exposure on carboxylic acid production in Spectar copolymer as determined by SF4 treatment 1816cm-1, aromatic acid peak 1841 cm1, aliphatic acid peak [11]. Reprinted from Polymer, 41, Grossetete, T., Rivaton, A., Gardette, J.-L., Hoyle, C. E., Ziemer, M., Fagerburg, D. R. and Clauberg, H., Photochemical degradation of poly(ethylene terephtha-late)-modified copolymer, 3541-3554, Copyright (2000), with permission from Elsevier Science...

These oxidations suffer from the fact that the high selectivities are only observed at low conversions (<7%). At higher conversions, the carboxylic acid products leach the transition metals out of the zeolite framework into solution where the selectivity index is much lower [63]. As these reactions proceed, the 3 -I- oxidation states of the metal ions return to their 2 -I- states, accompanied by their characteristic color change. In the case of MnAlPO-18, the spent catalyst (Mn ) was washed with methanol and reactivated in dry air at 550°C and successfully recycled (Mn Mn ) twice without appreciable loss of activity [64]. 

The reaction progresses because the amide anion, once a small amount is released, abstracts a proton from the carboxylic acid product. Again, we have an analogy with the last step in the base hydrolysis of esters, and the ionization becomes an essentially... 

Feedstock carboxylic acid Product Catalyst Temperature (°C) Pressure (bar)... 

While die above reactions will provide carboxylic acid products, each has problems associated with it. The cleavage of olefins to carboxylic acids [reaction (7.1)] can be carried out using potassium permanganate or by ozonolysis at low temperature followed by oxidative workup with hydrogen peroxide. Neither of diese mediods is very useful since only symmetric olefins provide a single carboxylic acid product. Unsymmetrical olefins give a mixture of two acids which must be separated. Furthermore the most useful synthetic processes are those which build up structures, whereas these reactions are degradative in nature. 

In fact, a closer examination of the products of decarboxylation from compound 4 and 10 led Zeng to conclude that, unless dioxygen is rigorously excluded, there is always perhaps 10-15% carboxylic acid product formed (along with the normal turnover products as discussed in Scheme 7) that can best be explained as resulting from dioxygen oxidation of the intermediate enamine in each case66, similar to the proposal by Abell and Schloss. 

Primary alcohols afforded the corresponding carboxylic acids via further oxidation of the aldehyde intermediate, e.g. 1-hexanol afforded 1-hexanoic acid in 95% yield. It is important to note, however, that this was achieved without the requirement of one equivalent of base to neutralize the carboxylic acid product (which is the case with supported noble metal catalysts). In contrast, when 1 mol% TEMPO (4 equivalents per Pd) was added, the aldehyde was obtained in high yield, e.g. 1-hexanol afforded 1-hexanal in 97% yield. Under cosolvent conditions using water/ethylene carbonate, Pd-neocuproine was found to be even more active (Fig. 4.65) [174]. This system is exceptional because of its activity (TOF 500h-1 could be reached for 2-octanol) and functional group tolerance, such as C=C bonds, C = C bonds, halides, a-carbonyls, ethers, amines etc. Thereby this system is expected to have a broad synthetic utility. 

The presence of both aldehyde and carboxylic acid products of ozonolysis indicates that both double and triple bonds are present in erythrogenic acid. 

During a synthesis of the protein kinase C inhibitor Balanol. Lampe and co-workers77 found that deprotection of the tert-butyl ester 30.1 [Scheme 6.30] with trifluoroacetic or formic acid was accompanied by substantial quantities of a debenzylated by-product. The same side reaction accompanied thermolytic cleavage of the terf butyl ester in neutral solvents presumably due to add catalysis by the carboxylic acid product 30.2. Thermolysis in quinoline at 205 °C led cleanly to the desired benzophenone carboxylic acid 30.2 in 68% yield. 

The mechanism of Orignard carboxylation is similfir to that of other Grignard reaction. a G bond of carbon dioxide in a typical nucleophilic addit ion reaction. Pro-tonotion of the carboxylaic by addilion of aqueous MCI in a separate step then gives the free carboxylic acid product... 

The production of carboxylic acids via carbonylation catalysis is the second most important industrial homogeneous group of processes. Reppe developed most of the basic carbonylation chemistry in the 1930s and 1940s. The first commercial carbonylation process was the stoichiometric Ni(CO)4-based hydroxycarbonylation of acetylene to give acrylic acid (see Section 3.5 for details). This discovery has since evolved into a trae Ni-catalyzed process, used mainly by BASF. The introduction of rhodium catalysts in the 1970s revolutionized carboxylic acid production, particularly for acetic acid, much in the same way that Rh/PPhs catalysts changed the importance of hydroformylation catalysis. 

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