Homologous carboxylic acids

The scope and mechanism of carboxylic acid homologation is examined here in relation to the structure of the carboxylic acid substrate, the concentrations and composition of the ruthenium catalyst precursor and iodide promoter, synthesis gas ratios, as well as 13C labelling studies and the spectral identification of ruthenium iodocarbonyl intermediates. 

In 1981, Texaco announced the ruthenium/H2/CO-catalyzed homologation of carboxylic acids. Homologation refers to a chain-extension reaction that increases the carbon number of the carboxylic acid see Homologation Reaction. The particular reaction that was initially studied was the conversion of acetic acid to propionic acid. The proposed mechanism shown in Scheme 22 is based on a Ru VRtf cycle, similar to that suggested by Knifton and coworkers at Texaco. 

Formic acid was first described by S. Fisher in 1670, who obtained it from the distillate of ants. The first nine members of the aliphatic carboxylic acids homologous series are liquids at room temperature. The first solid aliphatic carboxylic acid is decanoic acid, which has a melting point of 31.5°C. An unsaturated principal chain considerably lowers the melting point temperature. For example, c/s-oleic acid is a liquid at 5°C, and the cis and tram isomers have notably different melting temperatures. The tram isomer of oleic acid is eladic acid, which has a melting point of 44-45°C. The first three members of the aliphatic carboxylic acid homologous series are easy soluble in water. 

Arndt-Eistert synthesis A procedure for converting a carboxylic acid to its next higher homologue, or to a derivative of a homologous acid, e.g. ester or amide. 

One of the most sensitive tests of the dependence of chemical reactivity on the size of the reacting molecules is the comparison of the rates of reaction for compounds which are members of a homologous series with different chain lengths. Studies by Flory and others on the rates of esterification and saponification of esters were the first investigations conducted to clarify the dependence of reactivity on molecular size. The rate constants for these reactions are observed to converge quite rapidly to a constant value which is independent of molecular size, after an initial dependence on molecular size for small molecules. The effect is reminiscent of the discussion on the uniqueness of end groups in connection with Example 1.1. In the esterification of carboxylic acids, for example, the rate constants are different for acetic, propionic, and butyric acids, but constant for carboxyUc acids with 4-18 carbon atoms. This observation on nonpolymeric compounds has been generalized to apply to polymerization reactions as well. The latter are subject to several complications which are not involved in the study of simple model compounds, but when these complications are properly considered, the independence of reactivity on molecular size has been repeatedly verified. 

The reaction of diacetylene and its asymmetric homologs (penta-l,3-diyne, hexa-1,3-diyne) with semicarbazide (72ZOR2605) affords the amides of 3-methyl-pyrazole- 1-carboxylic acid (27) (80°C, EtONa, EtOH, 40 h). Amide 26 undergoes irreversible rearrangement to amide 27 at 80°C (EtONa, EtOH). 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

Another group of reactions with the predominant cleavage of the ring comprises catalytic hydrogenation of isoxazole derivatives and has been investigated only recently. The most commonly used catalyst has been Raney nickel,but use has sometimes been made of platinum catalysts. Hydrogenolysis of the 0—N bond (172—>173) occurs in isoxazole, its homologs,and their functional derivatives, for example, isoxazole carboxylic acids- and 5-aminoisoxazoles. ... 

The Arndt-Eistert synthesis allows for the conversion of carboxylic acids 1 into the next higher homolog 4. This reaction sequence is considered to be the best method for the extension of a carbon chain by one carbon atom in cases where a carboxylic acid is available. 

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted... 

Azetidine-2-carboxylic acid, the lower homolog of proline, has been isolated from Convallaria majalis (lily of the valley) 40,44), Polygonatum officinalis (Solomon s seal) 153), and Polygonatum multiflorum 45). Fowden and Steward 47) surveyed plants from 56 genera for nitrogenous compounds and found azetidine-2 -carboxylic acid to be restricted to members of the Liliaceae. In some species it was identified in leaf, stem, and root but was more commonly found in the seed. In Polygonatum, azetidine-2-carboxylic acid accounted for 75% or more of the total nonprotein nitrogen in the rhizome 45). There was no evidence that it occurred as a constituent of protein. 

Fowden and Richmond 46) found that azetidine-2-carboxylic acid was growth-inhibitory to Escherichia coli, but no inhibition was observed when both DL-proline and the homolog were present in the... 

Some members of the Liliaceae accumulate free azetidine-2-carboxylic acid in a much higher concentration than that found to be lethal to mung bean seedlings, but it is not incorporated into their proteins. Fowden (43) postulated that these plants either had a proline-incorporating system which was more specific than that found in other species, or some subcellular mechanism operated to prevent the homolog from reaching the sites involved in protein synthesis. Data which supported the first suggestion were subsequently obtained (116). 

The paraffin wax is oxidized by air in a liquid phase process at 110-130°C. Catalysts for this radical reaction are cobalt or manganese salts [54]. The quality of the obtained mixture of homologous carboxylic acids is impaired by numerous byproducts such as aldehydes, ketones, lactones, esters, dicarboxylic acids, and other compounds. These are formed despite a partial conversion of the paraffin and necessitate an expensive workup of the reaction product [50,55]. 

A two-step procedure was required for the preparation of a diverse set of pyrrole-3-carboxylic acid derivatives. The diketone 15 was prepared using a functional homologation of a 6-ketoester 14 with different aldehydes followed by oxidation with PCC. The Paal-Knorr reaction was carried out in AcOH in a sealed tube under microwave irradiation (180 °C, 5-10 min) to give differently substituted pyrroles with a COOMe group in position 3 (Scheme 5). This group was further transformed to expand the diversity of the products prepared with this method [32]. 

Examples of alkylation, dealkylation, homologation, isomerization, and transposition are found in Sections 1,17,33, and so on, lying close to a diagonal of the index. These sections correspond to such topics as the preparation of alkynes from alkynes carboxylic acids from carboxylic acids and... 

The main synthetic application of the Wolff rearrangement is for the one-carbon homologation of carboxylic acids.242 In this procedure, a diazomethyl ketone is synthesized from an acyl chloride. The rearrangement is then carried out in a nucleophilic solvent that traps the ketene to form a carboxylic acid (in water) or an ester (in alcohols). Silver oxide is often used as a catalyst, since it seems to promote the rearrangement over carbene formation.243... 

The chiral center would be installed from either Unear carbamate 15 or branched carbamate 16 via the asymmetric addition of malonate anion to the 7i-allyl Mo complex reported by Trost et al. [11] to afford the branched chiral malonate derivative 17. Decarboxylation of 17 should provide the mono-carboxylic acid 18. Masa-mune homologation with 18 affords our common precursor 14. Linear carbamate 15 was obtained from the corresponding cinnamic acid, and branched 16 was prepared in one pot from the corresponding aldehyde. 

Figure 3. A homologous series of three tyrosine dipeptide derivatives gave rise to three new polyiminocarbonates that differed only in the length of the alkyl chain attached to the carboxylic acid group of the dipeptide.

Reactions of 2,3-dioxo-l,2,3,5,6,7-hexahydropyrido[l,2,3-carboxylic acids and the homologous acetic and propionic acids, prepared by basic hydrolysis of the corresponding ester, with amines, 28% NH4OH, and hydroxylamine derivatives in the presence of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and hydroxybenztria-zole <1995BML1527>, 1995BML1533>, and in the presence of NEt3 and A, A -bis(2-oxo-3-oxazolidinyl)phosphinic... 

Addition of a silyl substituent into a-position of the a-(benzotriazol-l-yl)alkyl ether brings additional possibilities. Thus, lithiation of silyl ether 770 followed by treatment with an aldehyde or ketone gives unstable P-hydroxy-a-silyl-a-(benzotriazol-l-yl)alkyl ether 771 that spontaneously eliminates silanol to give vinyl ether 772 (Scheme 121). Treatment with ZnBr2 followed by hydrolysis with a diluted acid removes both the benzotriazolyl and the methyl groups to furnish carboxylic acid 773. In this way, in a simple manner, aldehydes and ketones are converted to one-carbon homologated carboxylic acid <1996S1425>. 

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