Electrolytic reduction of pyridines

Few reports on the electrolytic reduction of pyridine mention the isolation of partially reduced products. The only one observed to date has been the 3-piperideine (5). Ferles attributed the presence of 5 to concurrent reduction mechanisms, one which led to this product and the other to piperidine (Scheme 2).3S Thus, if the first-formed intermediate was a 1,4-dihydro product, then full reduction to piperidine occurred, but if the intermediate was a 1,2-dihydro product, then the olefin was formed. The 3-piperideine (5) would not be further reduced under the conditions. The concept of competing pathways at an initial step in the reduction mechanism is probably sound, but the proposal of 1,2- versus 1,4-dihydro intermediates has not been fully substantiated. 

Pyridine.—Ahrens1 accomplished the electrolytic reduction of pyridine and the derivatives of pyridine, and obtained piperidine from pyridine, and a-pipecoline from a-picoline. In these electrolyses lead cathodes and 10% solutions of sulphuric acid were employed. 

The tetrahydro bases have been mentioned as possible by-products of electrolytic reduction of pyridines in some papers.55,58 Davies and McGee87 isolated 3-piperideine by fractional distillation of crude piperidine obtained by electrolytic reduction of pyridine. Appreciable amounts of 3-piperideines were obtained on reduction of pyridine and its homologs at activated lead electrodes in dilute sulfuric acid.47 The following tetrahydro bases were isolated (in addition to the corresponding hexahydro bases) 3-piperideine47 from the reduction of... 

Mixed Electrolytic Reduction of Pyridine Bases and Ketones... 

The mixed electrolytic reduction of pyridines substituted at position 4 leads exclusively to the unsaturated amino alcohols (e.g., 75).71... 

Properties Colorless liquid odor of pepper. D 0.862, bp 106C, fp -7 to -9C. Soluble in water, alcohol, and benzene strong base. Combustible. Derivation By electrolytic reduction of pyridine. Grade 95 and 98% pure. 

Piperidine. Hexahydropyridine. CjH N mol wt 85.15. C 70.52%, H 13.02%, N 16.45%. Found in small quantities in Piper nigrum L.. Piperaceae (black pepper). May be obtained from pipeline by henting with alcoholic KOH, or from 1,5-diaminopentane hydrochloride by cycli-zarion. Usually prepd by electrolytic reduction of pyridine. Forms complexes with salts of heavy metals. Because of its reactivity, piperidine is useful in the prepn of cryst derivatives of aromatic nitro compds contg nuclear halogen atoms Seikel, J, Am. Chem. Soc. 62, 750 (1940). Review of physical constants of piperidine and N-alkyl piperidines Magnus -... 

Piperidine, C5H10NH, is prepared by the electrolytic reduction of pyridine. It is one of the products of the hydrolysis of piperine the essential principle of pepper. Piperidine boils at 106° and possesses a pepper-like odor it has well characterized basic properties. It has recently been used as an accelerator in the vulcanization of rubber. 

The hydrogenation of pyridine to piperidine is difficult to perform both catalytically and electrochemically. However a study of the electrolytic reduction of pyridine at a Raney Ni cathode at atmospheric pressure resulted in near theoretical rates and good yields (90%), ... 

Electrolytic reduction of pyridine-2- and -4-carboxylic acids can be used to give methylpyridines 52 and zinc and acetic acid produce either the methylpyridines or the hydroxymethylpyridines. However, from nicotinic acid the second method produces piperidine, and electrochemical reduction of these acids can be conducted to give piperidine-carboxylic acids, tetrahydropyridine-carboxylic acids and tetrahydro-methylpyridinesi ". ... 

Colourless liquid with a characteristic ammo-niacal smell m.p. 9 C, b.p. 106°C. Miscible with water. It is present in pepper as the alkaloid piperine from which it can be obtained by healing with alkali. It can also be prepared by the reduction of pyridine, either electrolytically or by other means. Piperidine is a strong base, behaving like the aliphatic amines. 

Reduction of pyridine by electrolytic methods is the oldest reported industrial process involving pyridine compounds. Merck patented this process in 1896 however, catalytic hydrogenation has supplanted this process for virtually every piperidine manufacturer.8,14,13 The earliest report was by Ahrens, who described a process that others could not repeat.16 Up to 1934 the technology was to use an aqueous sulfuric acid electrolyte and a lead cathode. Many of these reports are conflicting.17-19 The interacting nature of electrochemical variables may be responsible in part for these discrepancies. Thus experimentation by an approach that attempts to hold all but one variable constant is bound to lead to different results depending on where the starting point was chosen or whether an important variable was, or was not,... 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

Reduction of aromatic heterocyclic bases and their quaternary salts is of particular interest. Reduction of pyridine with lithium aluminum hydride gives the unstable 1,2-dihydro derivative,403 whereas sodium in 95% ethanol yields 1,4-dihydropyridine. The latter is readily hydrolyzed with the formation of glutaric dialdehyde.404 Reduction of pyridine and its homologs with sodium in butanol affords a mixture of saturated and unsaturated bases d3-piperideines are formed405 only from those pyridine homologs which possess alkyl groups in positions 3 and 4. Electrolytic reduction always gives a mixture of both bases.406 A3-Piperideines have been obtained by reduction with a mixture of lithium aluminum hydride and aluminum chloride.407... 

Electrolytic reductions of 2- or 4-pyridylmethanol,58 4-formyl-pyridine,48 and 4-pyridinecarboxylic acid59,60 afford mixtures of the corresponding methylpyridine, methyl-3-piperideine, and methyl-piperidine. 

A mixture of 3-isopropylidenepiperidine (70), 5-isopropyl-3-piperideine (71), and 3-isopropylpiperidine was obtained in the electrolytic reduction of 3-pyridyldimethylcarbinol. No 3-isopropyl-pyridine was found in the reaction mixture.58... 

Electrolytic reductions of 2,3-dimethylpyridine,62 2,4-dimethyl-pyridine,63 2,5-dimethylpyridine,62 3,5-dimethylpyridine,62 2-methyl-... 

Preparation of 3-Piperideines by the Electrolytic Reduction of Methyl Methosulfates of Pyridine and Some of Its Homologs... 

Preparation of secondary (or tertiary) carbinols from pyridines and an aldehyde (or a ketone) in the presence of magnesium or aluminum and mercuric chloride is known in pyridine chemistry as the Emmert reaction. 7 70 For example, dimethyl-2-pyridylcarbinol is obtained in this way from pyridine and acetone. When a mixture of pyridine and acetone is subjected to an electrolytic reduction in dilute sulfuric acid at lead electrodes, a mixture of two main products results, namely, 2-(2-hydroxy-2-propyl)-3-piperideine and 4-(2-hydroxy-2-propyl)piperidine. Analogous compounds are obtained with the use of methyl ethyl ketone as the reactant. The mixed electrolytic reduction of 2-methylpyridine and acetone affords 2-(2-hydroxy-2-propyl)-6-methyl-3-piper ideine (74) and 2-methyl-4-(2-hydroxy-2-propyl)-piperidine.71... 

The aluminum hydride reduction of pyridine bases is very advantageous in the preparation of 3-piperideines since the amount of the corresponding accompanying hexahydro bases is small. The resulting tetrahydropyridines possess the same constitution as those obtained by the electrolytic or Ladenburg reduction (see Table III). 

Analogous results have been obtained in the electrolysis of the pyridine nucleotides134-141 the dimer has, however, been suggested to be a 4,4 -dimer.139 The coenzyme activity of the reduction product varies with the experimental conditions. Some reductions yielded totally inactive products, whereas others produced partly or fully active material. The highest activity was obtained by an indirect electrolytic reduction of triphosphopyridine nucleotide (TPN).141 Electrochemical reduction of methyl viologen in the presence of ferridoxin-TPN-reductase caused a reduction of TPN to a biochemically active product. 

There has been considerable research into the electrolytic reduction of aromatic carboxylic acids to the corresponding aldehydes. A general procedure has been described in which key elements are the use of the ammonium salt of the acid, careful control of the pH and the presence of an organic phase (benzene) to extract the aldehyde and thus minimize overreduction. The method appears to work best for relatively acidic substrates for example, salicylaldehyde was obtained in 80% yield. Danish workers have shown that, under acidic conditions, controlled electrolytic reductions are possible for certain pyridine-, imidazole- and thiazole-carboxylic acids. In these cases, it is thought that the product aldehydes are protected by geminal diol formation. A chemical method which is closely related to electrolysis is the use of sodium amalgam as reductant. Although not widely used, it was successfully employed in the synthesis of a fluorinated salicylaldehyde. ... 

Hirl] UHF calculation of spin densities using parameterization scheme of Beveridge and Hinze. i9 ) McLachlan calculation of spin densities. - ESR spectrum shown for corresponding radical generated from 2-vinylpyridine. 1 5 Or electrolytic reduction of 4-pyridine-carboxaldehyde N-oxide. 

Pyridone gives a small amount of piperidine, as well as some pyridine, but l-methyl-2-pyridone yields only a trace of methylpyridinium (picrate) Reduction of alkylpyridinium salts, electrolytically, with sodium amalgam or by x-ray irradiation in aqueous ethanol, can give l,r-dialkyl-l,r,4,4 -tetrahydro-4,4 -dipyridyls Electrolytic reduction of a mix-... 

The reduction of pyridine-carboxylic acids has been mentioned already (pp. 258, 263), and it has been seen that electrolytic reduction or reduction with zinc and acetic acid can give methyl- or hydroxymethylpyridines. Whilst the electrolytic reduction of benzoic acid to benzyl alcohol is well known, benzene-carboxylic acids are generally not so readily reduced as the pyridine-carboxylic acids. Two other additional cases might be quoted. A dichloropyridine-carboxylic acid has been reduced by phosphorus and hydriodic acid to a dichloromethylpyridine , and 2,6-dichloropyridine-4-carboxylic acid with zinc and acetic acid gives 2,6-dichloro-4-hydroxy-methylpyridine . Isonicotinic acid is reduced to the alcohol by tin and hydrochloric acid . 

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80°C (191), with acetic acid anhydride in pyridine at 100°C (192), with acetyl chloride and pyridine in toluene at 60°C (193), or by the action of ketene in alcohoHc suspension. 4-Hydroxyacetanihde also may be synthesized directiy from 4-nitrophenol The available reduction—acetylation systems include tin with acetic acid, hydrogenation over Pd—C in acetic anhydride, and hydrogenation over platinum in acetic acid (194,195). Other routes include rearrangement of 4-hydroxyacetophenone hydrazone with sodium nitrite in sulfuric acid and the electrolytic hydroxylation of acetanilide [103-84-4] (196). 

Electrolytic reduction using a lead cathode in 20% sulfuric acid converted pyridine a-carboxaldehyde to a mixture of 41% of a-picoline, 25% of a-pipecoline and 11% of 2-methyl-1,2,3,6-tetrahydropyridine [443]. 

Enantiomeric excess in pyridinylethanols from reduction of 2- and 4-acetyl-pyridine at mercury. The electrolyte contains an alkaloid (5 x 10 M) in aqueous acetate buffer (pH 4.5) - ethanol (1 1) at 0° C. Data from ref. [41]. 

Reduction of the carboxylic acid group passes through the intermediate aldehyde. For a number of examples in the heterocyclic series, the aldehyde becomes a major product because it is trapped as the hydrated vfc.-diol form. Examples include imidazole-2-caiboxylic acid [139], thiazole-2-carboxylic acid [140] and pyridine-4-carboxylic acid [141] reduced in dilute aqueous acid solution. Reduction of imidazole-4-carboxylic acid proceeds to the primary alcohol stage, the aldehyde intermediate is not isolated. Addition of boric acid and sodium sulphite to the electrolyte may allow the aldehyde intermediate to be trapped as a non-reducible complex, Salicylaldehyde had been obtained on a pilot plant scale in this way by... 

The possible mechanistic pathways can be shown using horizontal changes for electron transfer and vertical ones for proton transfer (Scheme 1). This scheme has been generalized and truncated to show only the reduction of A to AH2. Pyridine reduction would be extended from this scheme to reflect the six electrons and six protons involved. Of course, protonated monocationic species would probably be important only in acidic electrolytes, whereas dianions would normally be formed only in aprotic electrolytes at high junction potentials. The dication, AH22+ is an unlikely species when A is pyridine. 

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