Into carboxylic acids

The conversion of primary alcohols and aldehydes into carboxylic acids is generally possible with all strong oxidants. Silver(II) oxide in THF/water is particularly useful as a neutral oxidant (E.J. Corey, 1968 A). The direct conversion of primary alcohols into carboxylic esters is achieved with MnOj in the presence of hydrogen cyanide and alcohols (E.J. Corey, 1968 A,D). The remarkably smooth oxidation of ethers to esters by ruthenium tetroxide has been employed quite often (D.G. Lee, 1973). Dibutyl ether affords butyl butanoate, and tetra-hydrofuran yields butyrolactone almost quantitatively. More complex educts also give acceptable yields (M.E. Wolff, 1963). 

The telomer obtained from the nitromethane 65 is a good building block for civetonedicarboxylic acid. The nitro group was converted into a ketone, and the terminal alkenes into carboxylic acids. The acyloin condensation of protected dimethyl dvetonedicarboxylate (141) afforded the 17-membered acyloin 142, which was modified to introduce a triple bond 143. Finally, the triple bond was reduced to give civetone (144)[120). 

Lithiated pyrazoles prepared from CtH or preferably from C-Br pyrazoles (B-76MI40402) can be transformed into carboxylic acids. In this way pyrazole-4-carboxylic acids (504 ... 

TheNef reaction of primary nitro compounds gives iildehydes or carboxylic acids, depending on the reaction conditions. Each transformation provides an important tool in organic synthesis. Primary nitro compotmds are converted into carboxylic acids vrith concentrated mineriil acids. Because such harsh conditions iilso lead to side reactions, a milder method is required inorganic synthesis. Basic phosphate-buffered KMnO rapidly converts primary nitroalkanes into carboxylic acids in 90-99% yield fEq. 6.13. "... 

Hydrolysis Conversion of Nitriles into Carboxylic Acids A nitrile is hydrolyzed in either basic or acidic aqueous solution to yield a carboxylic acid plus ammonia or an amine. 

Conversion of Esters into Carboxylic Acids Hydrolysis An ester is hydrolyzed, either by aqueous base or by aqueous acid, to yield a carboxylic acid plus an alcohol. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

CONVERSION OF TERMINAL ALKYNES INTO CARBOXYLIC ACIDS... 

Terminal alkynes can be converted by a process of hydrosilylation followed by oxidative cleavage into carboxylic acids (10). An alternative basic" cleavage yields the corresponding aldehydes. 

Such carbonyls may be further oxidized using potassium permanganate (KMnO and perchloric acid (HCIO4) to convert all of these groups into carboxylic acids. Once functionalized in this manner, the nanotubes can be fully dispersed in aqueous systems. Kordas et al. (2006) used these derivatives to print nanotube patterns on paper or polymer surfaces to create conductive patterns for potential use in electronic circuitry. The carboxylates also may be used as conjugation sites to link other ligands or proteins to the nanotube surface using a carbodiimide reaction as previously discussed (Section 1, this chapter Chapter 2, Section 1.11 Chapter 3, Section 1). 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

The ease of the Strecker synthesis from aldehydes makes a-aminonitriles an attractive and important route to a-amino acids. Fortunately, the microbial world offers a number of enzymes for carrying out the necessary conversions, some of them highly stereoselective. Nitrilases catalyze a direct conversion of nitrile into carboxylic acid (Equation (11)), whereas nitrile hydratases catalyze formation of the amide, which can then be hydrolyzed to the carboxylic acid in a second step (Equation (12)). In a recent survey, with a view to bioremediation and synthesis, Brady et al have surveyed the ability of a wide range of bacteria and yeasts to grow on diverse nitriles and amides as sole nitrogen source. This provides a rich source of information on enzymes for future application. 

You will recall that nitriles are easily converted into carboxylic acids by hydrolysis. This involves heating the nitrile with an aqueous acid. The hydrogen ions of the acid catalyse the reaction. 

Employing iminophosphoranes to protect a group labile under alkaline conditions can lead to a dramatic increase in yield. This is exemplified by the transformation of allylic azide 31 into the corresponding iminophos-phorane 32 shown in Scheme 16. Hydrolysis under basic conditions leads finally to 4-amino-3-hydroxycyclohexa-l,5-diene-l-carboxyclic acid (33) in 80% yield. However, when the same azide (31) is converted with a Lindlar catalyst, via allylic amine 34 into carboxylic acid 33, only 0-30% yields are found as a consequence of the low stability of the allylic amine [93JCR(S)148]. 

These reactants introduce either nitrile or nitro groups into the product. These groups may be converted into carboxylic acids or amines, as shown. 

Protons attached to the C atoms of the 1,2,4-trioxolane moiety of FOZs have chemical shifts at distinctly lower field than alcohols, ethers or esters. For example, the chemical shifts of the ozonide product in equation 100 (Section Vin.C.b.a) are S (CDCI3) 5.7 ppm for the H atoms of the trioxolane partial structure, and 4.1 ppm for the protons at the heads of the other ether bridge . Measurement of the rate of disappearance of these signals can be applied in kinetic studies of modifications in the ozonide structure. The course of ozonization of the methyl esters of the fatty acids of sunflower oil can be followed by observing in H and C NMR spectra the gradual disappearance of the olefinic peaks and the appearance of the 3,5-dialkyl-1,2,4-trioxolane peaks. Formation of a small amount of aldehyde, which at the end of the process turns into carboxylic acid, is also observed . 

Similarly, salts of carboxylic acids are converted into carboxylic acid fluorides, e.g. 4,41 or trifluoromethyl derivatives, e.g. 5,113 by treatment with sulfur tetrafluoride, with or without hydrogen fluoride in the latter case a sufficiently large excess of hydrogen fluoride is required. 

Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction... 

Most of these procedures are incompatible with common linkers, and are therefore unsuitable for the transformation of support-bound substrates into carboxylic acids. A more versatile approach for this purpose is the saponification of carboxylic esters. Saponifications with KOH or NaOH usually proceed smoothly on hydrophilic supports, such as Tentagel [19] or polyacrylamides, but not on cross-linked polystyrene. Esters linked to hydrophobic supports are more conveniently saponified with LiOH [45] or KOSiMe3 in THF or dioxane (Table 13.11). Alternatively, palladium(O)-mediated saponification of allyl esters [94] can be used to prepare acids on cross-linked polystyrene (Entries 9 and 10, Table 13.11). Fmoc-protected amines are not deprotected under these conditions [160],... 

Nitriles are converted by hydrolysis into carboxylic acids (see Reaction XXXVIII.), so that the former reaction affords a convenient method of synthesising aromatic carboxylic acids. 

Primary and secondary alcohols are readily oxidized by permanganate while tertiary alcohols are stable.284,311 Primary alcohols are transformed into carboxylic acid via the formation of aldehydes. Secondary alcohols are cleanly oxidized to ketones.294... 

The most important reaction of esters is their conversion by a carbonyl-group substitution reaction into carboxylic acids. Both in the laboratory and in the body, esters undergo a reaction with water—a hydrolysis—that splits the ester molecule into a carboxylic acid and an alcohol. The net effect is a substitution of -OC by -OH. Although the reaction is slow in pure water, it is catalyzed by both acid and base. Base-catalyzed ester hydrolysis is often called saponification, from the Latin word sapo meaning "soap." Soap, in fact, is a mixture of sodium salts of long-chain carboxylic acids and is produced by hydrolysis with aqueous NaOH of the naturally occurring esters in animal fat. 

Conversion of saturated, primary alkyl and aryl alkyl alcohols into the corresponding aldehydes can be achieved by this method provided that the alcohols are entirely dissolved in the organic phase. Relatively unstable protective groups are not affected, as in the oxidation of the acetonide of 1,2,6-hexanetriol, whereas conjugated and isolated double bonds give rise to side reactions which considerably decrease selectivities and yields.4 Some examples of aldehydes synthesized with this method are reported in Table 1. Under the same conditions, secondary alcohols are oxidized to ketones. Addition of catalytic amounts of quaternary onium salts allows fast and total conversion of primary alcohols and aldehydes into carboxylic acids making this methodology very versatile 4... 

This oxidant is a bright-orange solid that is soluble in organic solvents, and very convenient to store and manipulate, because of its lack of hydro-philicity. Pyridinium dichromate (PDC), which is normally used in dichlor-omethane at room temperature, is a very efficient oxidant able to transform alcohols in aldehydes and ketones in high yield. The absence of water in the reaction media prevents the over-oxidation of aldehydes into carboxylic acids. 

Jones oxidation is generally not useful for the transformation of primary alcohols into aldehydes. This is due to the equilibrium of the aldehydes with the corresponding hydrates in the aqueous media, leading to the subsequent oxidation of the aldehyde hydrates into carboxylic acids. In fact, kinetic studies support the assumption that chromic acid oxidizes aldehydes into carboxylic acids via the corresponding aldehyde hydrates.5... 

In the vast majority of cases, CH2CI2 is used as solvent in PCC oxidations. Occasionally, other solvents, including benzene,195 tetrahydro-furan,196 acetonitrile,197 chloroform,192 dioxane,198 hexane,199 acetone-CH2CI2200 or toluene,201 are used in PCC oxidations. The use of some of these alternative solvents may be advantageous in some substrates.202 Use of DMF tends to promote the over-oxidation of primary alcohols into carboxylic acids.203... 

Iodosobenzene diacetate [IBD, PhI(OAc)2] is able to oxidize benzylic alcohols to benzaldehydes when a solid mixture of iodosobenzene diacetate and the alcohol is irradiated with microwaves. Best results are obtained when iodosobenzene diacetate is supported on alumina.118 The use of polymer supported iodosobenzene diacetate (PSDIB) simplifies the work-up in the oxidation of benzylic alcohols to benzaldehydes.119 PSDIB can be employed in the presence of KBr and using water as solvent, resulting in the transformation of secondary alcohols into ketones and primary alcohols into carboxylic acids.117... 

Under the standard protocol, the over-oxidation of aldehydes into carboxylic acids is very slow. 

The electrocarboxylation of aldehydes and ketones leads to the corresponding a-hydroxycarboxylic acids that can easily be converted into carboxylic acids via a hydrogenation reaction [7]. It has been reported that the electrocarboxylation of aromatic ketones occurs through the reaction of C02 onto the activated carbon atom of the carbonyl group of the ketyl radical anion generated upon electron transfer to the ketone [7]. Otherwise, the aforementioned intermediate is likely to be a resonance hybrid (see Equation 12.23), and its electrophilic reaction with C02 may take place both at the carbon or the oxygen atom [42, 43]. 

The use of the haloform reaction for the conversion of methyl ketones into carboxylic acids (Sections 5.11.1, p. 667) is also applicable in the aromatic field. The conditions may be readily adapted from those described for the conversion of aliphatic methyl ketones into carboxylic acids (Expt 5.124). 

With these compounds the presence of the halogen will have been detected in the tests for elements. Most acid halides undergo ready hydrolysis with water to give an acidic solution and the halide ion produced may be detected and confirmed with silver nitrate solution. The characteristic carbonyl adsorption at about 1800 cm -1 in the infrared spectrum will be apparent. Acid chlorides may be converted into esters as a confirmatory test to 1 ml of absolute ethanol in a dry test tube add 1 ml of the acid chloride dropwise (use a dropper pipette keep the mixture cool and note whether any hydrogen chloride gas is evolved). Pour into 2 ml of saturated salt solution and observe the formation of an upper layer of ester note the odour of the ester. Acid chlorides are normally characterised by direct conversion into carboxylic acid derivatives (e.g. substituted amides) or into the carboxylic acid if the latter is a solid (see Section 9.6.16, p. 1265). 

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