Quinaldine

Quinoline derivatives may be synthesised by heating aii aromatic amine with an aldehyde or a mixture of aldehydes in the presence of concentrated hydrochloric or sulphuric acid this synthesis is known as the Doebner - Miller reaction. Thus aniline and paraldehyde afford 2-methylquinohne or quinaldine. 

The reaction probably proceeds as follows. Crotonaldehyde is first formed by oondensation of the depolymerised acetaldehyde in the presence of acid  

The aniline then reacts with the ap-unsaturated aldehyde by 1 4-addition the addition product, under the influence of strong acid, cyclises to form 1 2-dihydroquinaldine. The latter is dehydrogenated by the condensation products of aniline with acetaldehyde and with crotonaldehyde simultaneously produced ( .c., ethylideneaniline and crotonylideneaniline) these anils act as hydrogen acceptors and are thereby converted into ethylaniline and n-butyl-aniline respectively. 

The quinaldine is separated from any unreacted aniline and from the alkyl-anilines by treatment with acetic anhydride, basified with sodium carbonate and steam distilled. Only the primary and secondary amines are acetylated the acetylated amines are now much less volatile so that separation from the steam-volatile quinaldine (a tertiary amine) is facile. 

In a 1-litre round-bottomed flask, fitted with a condenser and trap (compare Fig. II, 13, 8), place 62 g. (61 ml.) of aniline. Cool the flask in an ice bath, add 120 ml. of concentrated hydrochloric acid slowly, followed by 90 g. of paraldehyde swirl the contents of the flask to ensure thorough mixing. Remove the flask from the ice bath and shake it frequently at 

C HsNH2 + OCHCH=CHCH3-------- - C6H5N=CHCH=CHCH3--------  

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On acetylation it gives acetanilide. Nitrated with some decomposition to a mixture of 2-and 4-nitroanilines. It is basic and gives water-soluble salts with mineral acids. Heating aniline sulphate at 190 C gives sulphanilic add. When heated with alkyl chlorides or aliphatic alcohols mono- and di-alkyl derivatives are obtained, e.g. dimethylaniline. Treatment with trichloroethylene gives phenylglycine. With glycerol and sulphuric acid (Skraup s reaction) quinoline is obtained, while quinaldine can be prepared by the reaction between aniline, paraldehyde and hydrochloric acid. 

Doebner-von Miller reaction Condensation of an aromatic amine with an aldehyde or ketone in the presence of hydrochloric acid to form a quinoline derivative. A general method, thus aniline and ethanal give 2-methyl-quinoline (quinaldine) and p-phenetidine. 

Quinaldine (or 2-methylquinoline) can be prepared by the Doebner.Miller Synthesis, which in some respects is closely similar to the Skraup Synthesis (p. 297) but has some significant differences. 

When a mixture of aniline, hydrochloric acid and acetaldehyde is heated (in the absence of an oxidising agent), a vigorous reaction occurs with the pro duction of quinaldine. In these circumstances, the main reactions are undoubtedly, (i) the acetaldehyde undergoes the aldol condensation, and the... 

The secondary amines present in the crude quinaldine are most effectively removed by acetylation. 

The pure quinaldine can now be isolated by either of the following methods, (a) Transfer the acetylated mixture to a Claisen flask (preferably having a short fractionating column below the side-arm) and distil the mixture slowly at water-pump pressure by heating the flask in an oil or silicone bath. The first fraction, of b.p. ca. 50715 mm., contains acetic acid and... 

Quinaldine Methiodide. Boil a mixture of 3 ml. of quinaldine, 2 ml. of methanol and 3 ml. of methyl iodide gently under reflux for hours, during which the methiodide will start to cry stallise. Cool the mixture thoroughly in ice-water, filter off the methiodide and recrystallise it from ethanol pale yellow crystals, m.p. 194". 

Dissolve a small quantity of the methiodide in cold water and add it with shaking to an excess of cold saturated aqueous sodium picrate solution. A yellow dovible salt of quinaldine niethoi icrate ami sodium picrafe. 

Mix 1 g. of quinaldine and 1 g. of powdered />-dimethylaminobenzab dehyde, add 2 -3 drops of 10% etl nolic zinc chloride solution, and heat under reflux in an oil-bath at 150 for 1 hour. Cool the product in ice-water, and reciystallise it from ethanol. p-Dimethylaminostyryl-quinoline (I) separates as bright yellow crystals, m.p. 177-178°. 

Bromination of quinaldine (I) (Section V,2) with bromine in glacial acetic acid in the presence of anhydrous sodium acetate aflFords dilute sulphuric acid gives quinaltiinic acid (III). 

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-p3nrole (V,12-V,13) 2-amino- and 2 4 dimethyl-thiazole (V,15-V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylp3rridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanop3n idine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi-oxylepidine (V,29). 

In 1923, Mills introduced thiazole for the first time in the synthesis of methine dyes through a somewhat indirect route. In order to demonstrate the 2,4 -cyanine mechanism of formation by quinoline and quinaldine quaternary salts reacting together, Mills used other pairs of quaternary salts as 2-methylthiazolium with either quinolinium or benzothiazolium (42, 43). 

Merocyanines with selenazolidine nuclei are obtained in 70 to 80°/o yield from the appropriate derivatives of lepidine or quinaldine (Scheme 79) (84). 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

A number of improvements have been made in these syntheses. For example, the use of ethanoHc ferric chloride and zinc chloride produces a good yield of 2-isopropylquinoline [17507-24-3] from isovaleraldehyde (46). The purification of 2-methylquinoline is facHitated through precipitation. A cmde quinaldine—hydrochloride and zinc chloride complex is prepared and then treated with aqueous base (47). 

Polymers. Quinoline and its derivatives may be added to or incorporated in polymers to introduce ion-exchange properties (see Ion exchange). For example, phenol—formaldehyde polymers have been treated with quinoline, quinaldine, or lepidine (81) (see Phenolic resins). Resins with variable basic exchange capacities have been prepared by treating Amherlites with 2-methylquinoline (82). 

A methylene base formed from quinaldine ethiodide, l-ethyl-2-methyl-ene-1,2-dihydroisoquinoline (129), exhibits a number of reactions characteristic of enamines (207,209). On treatment with benzoylchloride a dialkylated product (130) is produced by C and subsequent O benzoylation (210). 

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