Ethylpyridine from pyridine

When pyridine is treated with zinc dust and acetic anhydride, a tyx e of reductive coupling occurs and the product is diacetyltetrahydrodipyridyl (I) this undergoes a curious change on heating yielding pyridine and a new diacetyl compound, 1 4-diacetyM 4-dihydropyridine (II). The latter is reduced by zinc and acetic acid to 4-ethylpyridine (III). 

Other 4-alkylated pyridines may be prepared by the use of the appropriate anhydride. 

Neutralise the cold contents of the flask with 500-600 ml. of 40 per cent, aqueous sodium hydroxide solution, equip the flask for steam distillation and steam distil until about 1 litre of distillate is collected. The steam distillate separates into two layers. Add sohd sodium hydroxide ( 100 g.) to complete the separation of the two layers as far as possible. Remove the upper (organic) layer and extract the aqueous layer with three 50 ml. portions of chloroform. Dry the combined organic layer and chloroform extracts with anhydrous potassium carbonate and distil the mixture through a short fractionating column (e.g., an 8 Dufton column) after a fore run of chloroform, followed by pyridine, collect the crude 4-ethylpyridine at 156-166° (49 g.). Redistil through a Fenske- 

The three picolines react with alkyl halides in liquid ammonia solution in the presence of sodamide to yield the corresponding monoalkylpyridines. a-Picoline also reacts with alkyl chlorides in the presence of sodamide either alone or in the presence of xylene to give a fair yield of monoalkylpyridine CjH N.CHjR. With y-picoliue under similar experimental conditions disubstitution of the alkyl group (CjHjN.CHRj) occurs to an appreciable extent. The preparation of tile three n-amylpyridines is described the 3- and 4-compounds by the liquid ammonia - sodamide method and the 2-compound by the sodamide-3 ene procedure. 

If much liquid ammonia is lost during the preparation of the sodamide, the volume should be made up to 500-600 ml. before adding the y-picoline. 

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Chapter V. Quinaldine (V,2) 2-methyl-, 2 5-dimethyl- and 2-acetyl-thiophene (V,8-V,10) 2 5-dimethyl- and 2 4-dimethyl-dicarbethoxy-pyrrole (V,12-V,13) 2-amino- and 2 4-dimethyl-thiazole (V,1 V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylpyridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanopyridine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi ox3depidine (V,29). 

The relative reactivities of pyridine, 3-picoline, and 3-ethylpyridine toward phenyllithium have been measured under various conditions by a competitive technique and found to be in the order 3-pico-line > pyridine > 3-ethylpyridine.252 By carrying out reactions using an equimolar mixture of pyridine and 3-picoline and a large excess of phenyllithium, it has been possible to obtain yields of the phenyl-pyridines of over 80%, provided short reaction times and low temperatures are used. It has also been shown that the low yields usually obtained in such reactions are due to the fact that the dihydropyridyl-lithium intermediates form by-products, probably by polymerization (the intermediate dihydropyridine is a ct s-butadiene-like system and, in the presence of a Ziegler-type catalyst, can be expected to polymerize readily). The a-complexes from 3-picoline and phenyllithium polymerize faster than that from pyridine and phenyllithium, but there is no selective removal of the isomeric dihydropicolyllithium intermediates to form by-products, both isomers undergoing side-reactions at virtually the same rate. 

Similarly, the reaction of Grignard reagents with quaternary salts from pyridine 1-oxides promises to be of practical value i. Thus, 1-ethoxypyri-dinium bromide reacts with ethyl magnesium bromide to give 78 per cent of 2-ethylpyridine. The picoline 1-oxide quaternary salts react equally efficiently in the case of l-ethoxy-3-methylpyridinium bromide, the product is almost exclusively the 2-alky 1-3-methylpyridine. The reaction probably proceeds as shown, but a side-reaction always generates some of the parent base ... 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

The alkyl pyridines (6) and (7) can be transformed either to nicotinic acid or nicotinonitrile. In the case of nicotinic acid, these transformations can occur by either chemical or biological means. From an industrial standpoint, the majority of nicotinic acid is produced by the nitric acid oxidation of 2-meth5i-5-ethylpyridine. Although not of industrial significance, the air oxidation has also been reported. Isocinchomeronic acid (10) (Fig. 2) is formed as an intermediate. 

Various alkyl-substituted pyridine derivatives are formed from the condensation of butyraldehyde with ammonia at high temperatures. For example, cocondensation of //-butyraldehyde with acroleia [107-02-8] and ammonia at 400°C over a borosiUcate 2eohte gives 3-ethylpyridine [536-78-7] ia 70% yield... 

There are now a reasonable number of reactions in which derivatives of pyrimidine are converted into pyridines. The tetrahydropyrimidine (792) is converted into a dihydropyridine by heating with silica and alumina (48HCA612). It was assumed that hydrolysis gave a ketoimine (also obtained directly from acetone and ammonia), which recydized. Pyrimidine itself is converted by hot (190 °C) aqueous ammonia or methylamine into 2-methyl-5-ethylpyridine (793) (71RTC1246), while 2-methoxy-5-arylpyrimidines (794) with... 

Synthetic Methods of Manufacture. Due to rising demand, production of the pyridine bases by large-scale synthesis passed the volume of tar bases extracted from coal tar in the 1960s. By the early 1970s. capacity in the United States for the synthetic manufacture of pyridine, the picolines, and 2-methyl-5-ethylpyridine (MEP) was in the tens of millions of pounds. All of these products can be made by condensation reactions of aldehydes and ammonia, MEP is no lunger made in the United Stales,... 

A heterocyclic sulfur-containing compound, 2-methyl-thiophene, was identified in boiled crayfish tail meat and pasteurized crabmeat. Thiazole and 3-methylthiopropanal were identified in the crayfish hepatopancreas. Heterocyclic sulfur-containing compounds play important roles in generating meaty aromas in a variety of meat products and are considered important volatile aroma components of marine crustaceans (12— 14). The 2-methylthiophene could be an important flavor cemponent in boiled crayfish tail meat. Both thiazole find 3-methylthiopropanal were important contributors to the desirable meaty aroma associated with crayfish hepatopancreas. The 3-methyl-thiopropanal, identified in boiled crayfish hepatopancreas, is derived from Strecker degradation of methionine (15), and has been considered to be an important cemponent in basic meat flavor (16). Pyridine was detected in the headspace of the hepatopancreas from freshly boiled crayfish. Pyridine and 2-ethylpyridine have been previously reported as components in the atmospheric distillate from a sample of crayfish hepatopancreas frozen for three months (2). 

Pyridine and its derivatives. The most unique pyridine derivative isolated from processed food is l,lt,5,6-tetrahydro-2-ace-topyridine. This compound was prepared by roasting proline and dihydroxyacetone at 92°C in presence of sodium bisulfate, and exhibited a strong odor reminiscent of freshly backed soda crackers (82). 2-Ethylpyridine and 2-pentylpyridine were reported in volatile flavor components of shallow fried (83). Pyridine, 2-methylpyridine, 3-methylpyridine, 2-ethylpyridine, 3-ethylpyri-dine, 5-ethyl-2-methylpyridine, 2-butylpyridine, 2-acetylpyridine, 2-pentylpyridine, 2-hexylpyridine, 3-pentylpyridine, 5-methyl-2-pentylpyridine, and 5-ethyl-2-pentylpyridine were identified in the volatiles of roasted lamb fat (8H). 2,5-Dimethylpyridine and... 

Figure 2-15. Retention of alkylpyridines on Phenomenex Luna-C18 column from methanol/water eluent, (diamonds, pyridine squares, 4-methylpyridine triangles, 4-ethylpyridine).

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