Pyridine-2-carboxylic acid, formation

Pyridine and quinoline /V-oxides react with phosphorus oxychloride or sulfuryl chloride to form mixtures of the corresponding a- and y-chloropyridines. The reaction sequence involves first formation of a nucleophilic complex (e.g. 270), then attack of chloride ions on this, followed by rearomatization (see also Section 3.2.3.12.5) involving the loss of the /V-oxide oxygen. Treatment of pyridazine 1-oxides with phosphorus oxychloride also results in an a-chlorination with respect to the /V-oxide groups with simultaneous deoxygenation. If the a-position is blocked substitution occurs at the y-position. Thionyl chloride chlorinates the nucleus of certain pyridine carboxylic acids, e.g. picolinic acid — (271), probably by a similar mechanism. 

The formation of hydrated cobalt(n) complexes of pyridine carboxylic acids and the subsequent thermal decomposition to lower hydrates has been documented.82,83 Cobalt(n) halides react with 6-methylpicolinic acid (6-mpaH), picolinic acid (paH), nicotinic acid (naH), and pyridine-2,6-dicarboxylic acid (2,6-py) to form Co(6-mpa) (6-mpaH)X (X = Cl, Br, or NCS), Co(naH)nX2 (n = 2, X = Cl, Br n = 3, X = NCS), and Co(pa)(paH)X, EtOH (X = Cl, Br, or NCS) which are all probably octahedral.83 6-Methylpicolinic acid also formed Co(6-mpaH)4X2,2HX (X = Cl or Br) which were formulated [(6-mpaH)2H]2[CoX4], since the electronic spectra show absorptions characteristic of tetrahalogenocobaltate(n) ions.83... 

Electron-attracting substituents should assist this reaction. However, with acetic anhydride in acetonitrile, 2-picolinic acid 1-oxide gives mainly pyridine 1-oxide and carbon dioxide, whilst the same reaction carried out under ultra-violet irradiation proceeds similarly but with the formation of a little more 2-hydroxypyridine. The methyl esters of the pyridine-carboxylic acid 1-oxides behave normally, but there is no evidence that the methoxycarbonyl group promotes the reaction, and 2-cyanopyridine 1-oxide does not react with acetic anhydride . The results of a kinetic study of the rearrangement of pyridine 1-oxide in acetic anhydride exclude the intramolecular rearrangement of the free cation (113) and also a free radical process. There remain the two possibilities of nucleophilic substitution by reaction between... 

Concerning the pyridine-carboxylic acids Table 6.2), there has already been mentioned their tautomerism (p. 154), betaine and ester formation with alkylating reagents (p. 182), and the Hammick reaction (p. 163). 

The formation scheme of furfural is speculated as shown in Figure 3. An aldehyde group of furfural reacted with an amino group of lysine to form an imine. The double bond was migrated to form Amadori type compound, which was hydrolyzed to form alpha-keto carboxylic acid. The formed keto carboxylic acid reacted with an intra-molecular amino group to form tetrahydro-pyridine carboxylic acid or reacted with another furfural by aldol condensation, from which furpipate was formed by dehydration of 2 molecules of water. Another possible scheme is that lysine was converted to tetrahydropyridine carboxylic acid, which reacted with furfural to form furpipate. 

In the aromatic series, Nagy and Takacs-Novak [49] pointed out both theoretically and experimentally that the 3- and 4-COOH pyridine carboxylic acids (nicotinic and isonicotinic acids) form the zwitterionic species in aqueous solution. The distances of the -COOH groups from the pyridine nitrogens prevent the formation of a favorable dimeric form (except for the 3-COOH isomer with and anti carboxylic conformation) where a double-proton-relay... 

An example of this type of cyclization is the formation of 3-nitro-l,5-naph-thyridin-4(lH)-one (4) from 3-(/3-nitroethylideneamino)pyridine 2-carboxylic acid (3) by heating in acetic anhydride [56JCS(I)212]. No yields are given. 

Such an easy isomerization of acetylenylbenzoic acid amides implies the formation of a five-membered nonaromatic ring condensed with the pyrazole ring. However, the pyrazole analog of o-iodobenzamide (amide of 4-iodo-l-methylpyrazole-3-carboxylic acid) formed under heating with CuC=CPh in pyridine for 9 h only the disubstituted acetylene in 71 % yield is identical in all respects to the compound obtained from the corresponding acid by successive action of SOCI2 and NH3 (90IZV2089) (Scheme 126). 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

Within the wide range of phosphorus compounds described as activating agents for polyesterification reactions,2,310 triphenylphosphine dichloride and diphenylchlorophosphate (DPCP) were found to be the most effective and convenient ones. In pyridine solution, DPCP forms a A-phosphonium salt which reacts with the carboxylic acid giving the activated acyloxy A -phosphonium salt. A favorable effect of LiBr on reaction rate and molar masses has been reported and assumed to originate from the formation of a complex with the A-phosphonium salt. This decreases the electron density of the phosphorus atom... 

Similarly, triphenylphosphine dichloride (TPPCI2) can activate aromatic carboxylic acids in pyridine through the formation of acyloxyphosphonium salts (Scheme 2.30).313 A side reaction between tire intermediate acyloxyphosphonium species and a second carboxyl endgroup leading to the formation of anhydrides has been reported.313 This chain-limiting reaction decreases tire molar mass, while the presence of anhydride linkages in tire chains adversely affects the thermal and hydrolytic stability of the final polyester. 

Sulfur compounds have also been widely studied as activating agents for polyesterification reactions. p-Toluenesulfonyl chloride (tosyl chloride) reacts with DMF in pyridine to form a Vilsmeir adduct which easily reacts with carboxylic acids at 100-120° C, giving highly reactive mixed carboxylic-sulfonic anhydrides.312 The reaction is efficient both for aromatic dicarboxylic acid-bisphenol312 and hydroxybenzoic acid314 polyesterifications (Scheme 2.31). The formation of phenyl tosylates as significant side products of this reaction has been reported.315... 

Thionyl chloride is another activating agent employed for reactions between aromatic carboxylic acids and phenols in pyridine solution. The mechanism suggested does not involve the formation of an acid chloride but assumes the existence of an intermediary mixed sulfinic anhydride which undergoes reaction with phenolic endgroups (Scheme 2.32).311... 

If cobalt carbonylpyridine catalyst systems are used, the formation of unbranched carboxylic acids is strongly favored not only by reaction of a-olefins but also by reaction of olefins with internal double bonds ( contrathermo-dynamic double-bond isomerization) [59]. The cobalt carbonylpyridine catalyst of the hydrocarboxylation reaction resembles the cobalt carbonyl-terf-phos-phine catalysts of the hydroformylation reaction. The reactivity of the cobalt-pyridine system in the hydrocarboxylation reaction is remarkable higher than the cobalt-phosphine system in the hydroformylation reaction, especially in the case of olefins with internal double bonds. This reaction had not found an industrial application until now. 

Unsymmetrical as well as symmetrical anhydrides are often prepared by the treatment of an acyl halide with a carboxylic acid salt. The compound C0CI2 has been used as a catalyst. If a metallic salt is used, Na , K , or Ag are the most common cations, but more often pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. Mixed formic anhydrides are prepared from sodium formate and an aryl halide, by use of a solid-phase copolymer of pyridine-l-oxide. Symmetrical anhydrides can be prepared by reaction of the acyl halide with aqueous NaOH or NaHCOa under phase-transfer conditions, or with sodium bicarbonate with ultrasound. 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

Carboxylic acid esters of thiols are considerably more reactive as acylating reagents than the esters of alcohols. Particularly reactive are esters of pyridine-2-thiol because there is an additional driving force in the formation of the more stable pyridine-2-thione tautomer. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

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