Alkylations pyridines

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

Metal Cleaning. About 204 thousand metric tons of HCl (100% basis) was consumed in 1993 for steel pickling, wherein the hydrochloric acid readily dissolves all of the various oxides present in the scale formed during the hot rolling process. Using suitable inhibitors such as alkyl pyridines, HCl reacts very slowly with the base metal rendering the surface so clean that it must be passivated with a mild alkaline rinse. 

Commercial Manufacture of Pyridine. There are two vapor-phase processes used in the industry for the synthesis of pyridines. The first process (eq. 21) uti1i2es formaldehyde and acetaldehyde as a co-feed with ammonia, and the principal products are pyridine (1) and 3-picoline (3). The second process produces only alkylated pyridines as products. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

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. 

As with polybut-l-ene and many other vinyl monomers that contain an asymmetric carbon, isotactic, syndiotactic and atactic stmctures may be drawn. Using co-ordination catalysts such as mixtures of cobalt chlorides, aluminium alkyls, pyridine and water high-1,2 (high vinyl) polymers may be obtained. One product marketed by the Japan Synthetic Rubber Company (JSR 1,2 PBD) is 91% 1,2, and 51-66% of the 1,2 units are in the syndiotactic state. The molecular mass is said to be several hundred thousand and the ratio MJM is in the range 1.7-2.6. 

There are several reports that alkylated pyridine N-oxides react with Grignard reagents to give 2-alkylated pyridines (50,51). 

Heating the 9-methyl-9aH-quinolizine (83) with 2-methylpyridine in methanol causes isomerization to the corresponding 9-methyl-4H-quinolizine (84), but with 3-methylpyridine the isomeric 7-methyl-4H-quinolizine (86) is obtained. Similarly the 9-methyl compound (83) and the corresponding 7,9-dimethyl derivative (82) with pyridine yield tetramethyl 47f-quinolizine-l,2,3,4-tetracarboxylate (78) with loss of the original alkylated pyridine. The mechanism of these reactions has not been established but the addition-elimination isomerization sequence for 3-methylpyridine accounts for the known cases of exchange of the pyridine (see Scheme 1). 

The most thoroughly investigated compounds are the alkyl-pyridines. Coleman and Fuoss compared the reactions of pyridine, 4-picoline, and 4-isopropylpyridine with n-butyl bromide and found a steady increase in the rate in the order given the activation energies are 16.0,15.95, and 15.6 kcal per mole, respectively. Brown and Cahn carried out a detailed study of the reactions of 2-, 3-, and 4-alkyl-pyridines with methyl, ethyl, and isopropyl iodides in nitrobenzene the results are given in Table II. These data show the higher activation... 

In the absence of an added solvent, 3-alkyIpyridines, 4-alkyl-pyridines, and 3,4-dialkylpyridines all gave yields of substituted 2,2 -bipyridines that were up to three times greater than that of 2,2 -bipyridine from pyridine under similar conditions. With 3-ethyl-4-methylpyridine a marked improvement in yield was ob.served when the reaction was carried out at about 150°C in a vacuum, rather than at the atmospheric boiling point (195°C) of this base. This effect has also been observed with some other bases but the amount of 3,3, 5,5 -tetramethy 1-2,2 -bipyridine from 3,5-lutidine could not be increased in this way, and this pyridine was as unreactive as the 2-substituted pyridines. This finding is undoubtedly related to the reluctance of 3-substituted pyridines to form 3,3 -disubstituted 2,2 -bipyridines. 

Some characteristic ions in the mass spectra of quinolines include m/z 102, 128, 156, and so on. Again, as in alkyl pyridines, RCN is lost if the alkyl group is attached to the carbon atom adjacent to the nitrogen atom. 

The aerobic degradation of several azaarenes involves reduction of the rings at some stage, and are discussed in Chapter 10, Part 1. Illustrative examples include the degradation of pyridines (3-alkyl-pyridine, pyridoxal) and pyrimidines (catalyzed by dihydropyrimidine dehydrogenases). Reductions are involved in both the aerobic and the anaerobic degradation of uracil and orotic acid. 

A particularly elegant example of this approach is complex 10, which represents a very simple situation, namely that of an alkoxybenzoic acid and an alkyl pyridine and which shows a nematic phase at room temperature. There are, of course, very many examples of mesogens constructed in this was using pyridines, benzoic acids and even phenols these are helpfully collected in the relevant review literature [16,17]. 

B. striata, its secondary metabolic pattern, consisting of a series of uncommon polypropionates, is almost identical to that of its prey [36,37], On the contrary, if the mollusc, under maintenance in an aquarium, feeds on Haminoea navicula, it discharges [5] in the form of a yellow secretion two Haminoea metabolites, the haminols (8,9), structurally related to navenone-A (I), which possess alarm pheromone properties [38] for H. navicula. Studies on a third Aglajidae mollusc [39, 40], Philinopsis speciosa, led to the characterization of a 2-alkyl-pyridine, pulo upone (10), as a minor constituent co-occurring with two polypropionates closely related to the metabolites from the pair P. depicta-B. striata. 

Azomethine ylides such as 412 react with triafulvenes again by analogy with cyclopropenones. (3 + 2) Cycloaddition of the 1,3-dipole to the CVC2 bond and subsequent loss of C02 produces l,4-dihydro-4-methylene-N-alkyl pyridines 559, which as merocyanines show marked solvatochromic and thermochromic effects260. ... 

Scheme 11. Proton Loss and Tautomerism in Hydroxy, Amino, and Alkyl Pyridines...

Competitive ethylations were carried out by using 2- and 4-alkyl-pyridines to study inductive effects. Results of a study on this subject made by Notari and Pines 52) are reported in Table V along with results for alkylbenzenes. The 4-alkylpyridines closely parallel the alkylbenzenes in their relative reaction rates, whereas the 2-alkylpyridines have a different order. A solvation effect of the nitrogen may be the reason. 

R Ri 2-Alkyl- P3Tidines R.Ri 4-Alkyl- pyridines R.Il, Alkyl benzenes R Ri... 

Reductions of this type were applied to pyridine [442], alkyl pyridines and to many pyridine derivatives alcohols [443], aldehydes [443], ketones [443] and acids [444], In compounds containing both pyridine and benzene rings sodium exclusively reduces the pyridine ring [445]. Pyridine was not reduced by zinc and other similar metals. 

Double bonds in alkenyl pyridines may be hydrogenated under mild conditions (Raney nickel at room temperature) to give alkyl pyridines [450]. If the double bond is conjugated with the pyridine ring sodium in alcohol will reduce both the double bond and the pyridine ring in good yields [450]. 

R = CHj, R = and adenocarpine(16 R = CH=CHPh, R = H) ° are likewise dehydrogenated to 2,3 -bipyridine, and related dehydrogenation reactions afford substituted 2,3 -bipyridines. Ullmann and Grignard reactions have been used to synthesise 2,3 -bipyridine, whereas the Gomberg reaction of 3-pyridinediazonium chloride with pyridine and alkyl pyridines affords 2,3 -bipyridine, along with other isomeric bipyridines, and alkyl substituted 2,3 -bipyridines, respectively. " Photolysis of 3-... 

Alkylating agent Salt cation Solvent Overall conversion (%) N-Alkyl (%) O-Alkyl (%) Pyridin-2-one (%)... 

Selective o/t/io-acylation and orrfio-formylation of 2-alkyl pyridines is possible by [2,3] sigmatropic rearrangement (Sommelet-Hauser) of a-pyrrolidinyl-2-alkylpyridine sulfonates (268), prepared by treating the parent base with cyanomethyl benzenesulfonate (76JOC2658). Acid hydrolysis of the rearranged product (269 R = H) yields 3-formyl-2-methylpyridine (270). Methylation of (269 R = H) using NaH-Mel and acid hydrolysis of the reaction mixture gives 3-acetyl-2-methylpyridine (270 R = Me). 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

Trivial names for the methylpyndines are the picolines the dimethyl-pyridines are the lutidines-, and the trimethylpyridines (and in older literature the ethyldimethylpyndines) are the collidines. The refractive indices foi these alkyl pyridines and for pyridine itself fall in the range nD20 1-50-1.51. 

In the synthetic processes, mixtures of products are often obtained. Variation in the supply/demand balance of the alkyl pyridine isomers has led to much research on processes which may alleviate such imbalances, including development of the catalytic hydrodealkylation of alkyl pyridines to pyridine as well as the alkylation of pyndine. 

Surface Alkylated dimethyl aniline, Alkylated pyridine, Heparin content,... 

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