Pyridine carboxylic acids, reactions

Pyridine carboxylic acid reactions) cADPR NAADP)... 

Shown in Figure 6-A are EELS spectra of the entire series of pyridine carboxylic acids and diacids adsorbed at Pt(lll) from acidic solutions at negative electrode potential. Under these conditions all of the meta and para pyridine carboxylic acids and diacids exhibit prominent 0-H vibrations (OH/CH peak ratio near unity). In contrast, at positive potentials only the para-carboxylic acids display pronounced 0-H vibrations, Figure 6-B. All of the 0-H vibrations are absent under alkaline conditions, Figure 6-C. This situation is illustrated by the reactions of adsorbed 3,4-pyridine dicarboxylic acid ... 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

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 involvement of zinc in nicotinamide-based hydride-transfer reactions has led to numerous studies of Group IIB complexes of pyridine carboxylic acid derivatives. Cadmium complexes of 2-pyridinecarboxylic acid, 5 3-pyridinecarboxylic add497 and 3-pyridinecarboxamide498 have been reported. The crystal structure of [Cd(HC02)2L2(H20)2] (L = 3-pyridinecarboxamide) has also been described the metal is in an octahedral environment in which the amide acts as a monodentate N donor.498... 

Tschitschibabin reaction,290 thus counteracting the example based on 3-hydroxypyridine. The second reaction to be discussed is that of 2-picoline with sodamide at a relatively high temperature, when 3,6-diamino-2-picoline (126) is one of the products isolated.293 If this is so, this represents another example of the type of orientation recently observed in the phenylation of pyridine with phenylcalcium iodide which gave some 2,5-diphenylpyridine.264 Alternatively, a 3,4-pyridyne intermediate (125) might perhaps actually be involved here. The evolution of hydrogen is not mentioned in this case. The decarboxylation of pyridine carboxylic acids under strongly basic conditions is unexceptional. 

In most of their reactions, the pyridine- and azinecarboxylic acids and their derivatives behave as any other acid (cf. Scheme 86). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. Esterification of pyridine carboxylic acids can be usefully achieved via in situ generation of the acid fluoride. For example, treatment of picolinic acid with a stoichiometric amount of N,N,N,A-tetramethylfluoroformami-dinium hexafluorophosphate (TFFH) in dichloromethane and triethylamine leads to generation of the acid fluoride, which reacts with (3-methyloxetan-3-yl)methanol to give the corresponding ester in 95% yield <2004S2485>. 

In acid solution the carbinol might be reduced further. Pyridine carboxylic acids,2812-carboxythiazoles,282and 2-carboxyimidazoles263 and their amide derivatives have been reduced in this way. The yields of aldehydes in some of these reactions are given in Table I.283... 

When the reduction is performed without control of the potential, a mixture of products results. Thus, reduction in sulfuric acid at lead or mercury cathodes of the pyridine carboxylic acids leads to a mixture of picolines andtetra- and hexahydropyridine derivatives.284-287 Derivatives of nicotinic acid are more apt to be reduced in the ring than the 2- and 4-carboxypyridines. Reduction of the corresponding pyridylcarbinoles under identical conditions produces a similar reaction mixture.287... 

The functional groups characterizing the sets of reactants are highlighted in grey. A stepwise procedure to construct the library described by Ugi s seven component reaction is given in [337]. Figure 5.6 shows how the pyridine-carboxylic acid is extended successively by the amine, aldehyde and isocyanide building blocks. The reaction schemes used are... 

Hofmaim degradations were carried out on 5pyridine carboxylic acids are treated with sodium azide in an oleum medium, a good yield (69%) of 3-aminopyridine and poorer yields (<30%) of 2- and 4-aminopyridine are realized. 3-Amino-5-nitropyridine is similarly prepared by the Schmidt reaction using 5-nitronicotinic and hydrazoic acid. ... 

Amdt-Eistert reaction, in the conversion of a pyridine-carboxylic acid to a pyri-dineacstic acid, 340 in the synthesis of pyridine side-chain carboxylic acids, 336... 

Derivatives of pyridine carboxylic acids form 1 1 complexes with Eu + in strongly acidic conditions. Whereas the complexes with nicotinic and picolinic acids are stable with respect to further reaction, isonicotinic acid and its Af-methyl derivative undergo reduction with an Eu + substrate stoicheiometry of 2 1. 

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 ready decarboxylation of pyridine-carboxylic acids was also early appreciated. Historically, the reaction played an important role in the orientation of quinoline, isoquinoline and the benzoquinolines . Decarboxylation occurs more readily than with benzene-carboxylic acids, and in the sequence 2 > 4 > 3 (see p. 367). The decarboxylation temperatures of solid pyridine-dicarboxylic acids depend roughly on their strengths as acids— the stronger the acid the lower the temperature . At 185 -190 , pyridine-2,3,4-tricarboxylic acid gives pyridine-3,4-dicarboxylic acid, which above... 

The rates of reaction of the pyridine-carboxylic acids with diphenyldia-zomethane fall in the order 4 >2 >3, the order of electron deficiency at the nuclear positions. Similarly, the rates of reaction of the pyridine-l-oxide carboxylic acids are in the order 3>4>2, pointing to an order of electron availability 2>4>3. 

The amides and hydrazides of pyridine-carboxylic acids arc of some importance, though their chemistry is not marked by unusual properties. Nicotinamide is, of course, an important compound, and isonicotinic acid hydrazide (isoniazid) is an antitubercular drug. Substituted derivatives are used as antidepressants. In general, however, these compounds show normal chemical behaviour. The amides undergo hydrolysis, dehydration and Hofmann bromination without difficulty. Their reduction has been much studied as a route to pyridine aldehydes. The Sonn-Muller reduction is not very satisfactory in this series, but the McFadyen-Stevens reaction is useful . Nicotinic acid diethylamide gives only poor yields of the aldehyde upon reduction with lithium aluminium hydride, but yields from the methyl-phenylamide are high. Most satisfactory is the reduction of nicotinic acid dimethylamide with lithium diethoxyaluminium hydride . 

The general reactions of the esters of pyridine-carboxylic acids are in no way exceptional their reduction has been mentioned (pp. 258, 263). 

Esters of pyridine-carboxylic acids react normally with compounds containing activated methylene groups. The reactions are valuable, for example as routes to acylpyridines. The ethoxide-catalysed condensation of ethyl pyridine carboxylates with ethyl acetate has often been described early work suggested that esters of nicotinic acid gave lower yields than their isomers, but this is not so . Many esters other than ethyl acetate have been used and a number of substituted pyridine esters > Condensations with picolines to give desoxypyridoins are of practical value (p. 380). 

Pyridine-carboxylic acid chlorides, usually prepared by the use of thionyl chloride [a reaction in which nuclear chlorination sometimes occurs (p. 227)], are in most respects normal though rather unstable. Their reactions with alcohols provide some of the best ester preparations in this series. The Rosen-mund reduction fails with all three of the pyridoyl chlorides i though it... 

Oxidations—4-Vinylpyridine can be oxidized to the glycol by cold permanganate solution333. When the acetic anhydride reaction (p. 340) is applied to 2-styryl- and 2-propenyl-pyridine 1-oxides, some of the glycol is produced in each case. Permanganate has more frequently been used to oxidize 2- and 4-styrylpyridines to pyridine-carboxylic acids i 35 ... 

Pyridine-carboxylic acids have been prepared by the reaction of the 3-pyridyl Grignard reagent 36a and of 2- and 3-pyridyl lithium with carbon dioxide. Nicotinic acid isotopically labelled in the carboxyl group has been obtained in this way . The reaction is especially useful for preparing pyridine-acetic acids and has been applied to 2-2t t and 4-picolyl lithium i. Under conditions where phenyl lithium adds to the azomethine linkage of 4-picoline, 2-phenylpyridine-4-acetic acid i is produced. 2,6-Lutidine gave 6-methylpyridine-2-acetic acid, but the reaction failed with 2-methyl-6-phenoxypyridine . ... 

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