None
2. Cinchomeronic Acid [fiy or 2, 3) is obtained from quinine, cinchonine and cinchonidine, by oxidation with nitric acid and by the oxidation of /3)'-methyl- pyridine carboxylic acid with potassium permanganate. It also results from pyridine tricarboxylic acid and from apophyllenic acid. It crystallizes from water in prisms containing hydrochloric acid, and melts at 266°, with decomposition into Cbj, y-pyridine carboxylic acid and a little nicotinic acid. When heated with acetic anhydride it yields its anhydride, C5H3N(CO)20, melting at 67°. Sodium amalgam decomposes it into NH3 and cinchonic acid, C,Hg05, which breaks up into COj, and dimethylfumaric anhydride (p. 430) on application of heat [Berichte, 18, 2968). Cotarnine, CijHiaNOg, boiled with nitric acid, yields Apophyllenic Acid, CgHjNO^ [Berichte, ig, Ref 706). This is methylated cinchomeronic acid, in which the methyl group is attached to the nitrogen atom, and has the formula, C5H3(C02H)N(CH3)^ T (comp. betaine, p. 316). It melts with decomposition at 242°, and when heated to 250° with hydrochloric acid decomposes into methyl chloride and cinchomeronic acid. 3. Lutidinic Acid (ay or 1,3) is produced together with isocinchomeronic acid by oxidizing ay-lutidine and picoline carboxylic acid with potassium perman- ganate [Annalen, 247, 37). It crystallizes with a molecule of water in micro- scopic needles, receives a blood-red color from ferrous sulphate, melts at 235°, and breaks up into COj and y-pyridine carboxylic acid. 4. Isocinchomeronic Acid (a/J' ^ i, 4) is obtained from pyridine tricar- boxylic acid (Berichte, ig, 131 1) and aldehyde colUdine. It crystallizes from acidulated hot water, with one or one and a half molecules of water, in microscopic leaflets, which melt at 236°, and when heated to 220° together with glacial acetic acid decomposes into CO2 and nicotinic acid. Ferrous sulphate imparts a reddish- yellow color to'the solution. 5. Dipicolinic Acid [aa' = 1,5) results when aa'-lutidine (p. 943) is oxidized with potassium permanganate [Annalen, 247, 33). It crystallizes in shining leaflets, melts at 225°, and at 227° decomposes into two molecules of carbon di- oxide and pyridine (together with a slight amount of picolinic acid). 6. Dinicotinic Acid (/3/3' := 2, 4) may be prepared from symmetrical pyridine tetracarboxylic acid, from (i, 2, 4)-pyridine tricarboxylic acid on boiling with glacial acetic acid [Berichte, ig, 286), and from /3/3-lutidine. (p. 943). It dis- solves with difficulty in water, consists of minute crystals, melts at 314°, and breaks down into carbon dioxide and nicotinic acid [Berichte, 23, 11 14). Oxypyridine Dicarboxylic Acids, C5H2(OH)N(C02H)j. a-Oxyquinolinic Acid (i, 2, 5 — OH in 5), obtained by fusing quinolinic acid with KOH [Berichte, 16,2158), also from amidocarbostyril by oxidation with per- manganate [Berichte, ig, 2432), consists of thick crystals, which char at 254°, but do not melt. When heated to 195° with water it decomposes into caibon dioxide and oxypyridine carboxylic acid (see above) ; the silver salt yields o-oxy-pyridine when heated. Ferric chloride colors it a deep red. Ammon-chelidonic Acid (i, 5, 3 — OH in 3), chelidamic acid, formed from chelidonic acid with ammonia, is a white, rather insoluble powder that breaks down into carbon dioxide and y-pyridone when heated above 230°. PYRIDINE TRICARBOXYLIC ACID. 949 Methyl Ammon-chelidonic Acid, C5HjO(N.CH3)(C02H)2, obtained by the aid of methylamine, yields «-methyl pyridone by decomposition (p. 945). Picoline Dicarboxylic Acids, C5H2(CH3)N(C02H)2. 1. Methyl-quinolinic Acid (i, 2, 3 — CH3 in 3) is produced upon oxidizing j'-raethylquinoline with potassium permanganate, as an intermediate product to the tricarboxylic acid. It crystallizes from water in plates or prisms, is colored yellow by ferrous sulphate, melts about 186° with decomposition, and yields (even on boiling with glacial acetic acid) carbon dioxide and /3y-methylpyridine car- boxylic acid (p. 947). 2. Uvitonic Acid is formed when ammonia acts upon pyrcracemic acid, con- sists of microscopic leaflets, is colored violet-red by ferrous sulphate, melts at 244°, and above 280° decomposes into COj and picoHne-carboxylic acid. ■* (i, 3, s)-TrimethyI-(2, 4)-pyridine Dicarboxylic Acid, C5(CH3)3N(COjH)2, Collidine dicarboxylic acid. The diethyl ester is prepared by tihe oxidation of di- hydro-collidine dicarboxylic ester (from aceto-acetic ester with aldehyde ammonia, (P' 939) in alcholic solution with nitrous acid. The free acid, obtained by saponi- fying the ester, crystallizes in little needles, and decomposes when strongly heated without melting. Dislilled with lime it yields a (l, 3, 5)-trimethyl pyridine (p. 943)- By successively oxidizing its methyl groups with potassium permanganate we obtain: lutidine tricarboxylic acid, C5(CH3)2N(C02H)3,picoline-tetra- carboxylic acid, C5(CH3)N(C02H)^, and pyridine pentacarboxylic acid, C5N(C02H)5. The separation of but one carboxyl from coUidine-dicarboxylic acid yields collidine-monocarboxylic acid, C5H(CH3)3N(C02H) (Annalen, 225. 133). which by successive oxidation forms lutidine-dicarboxylic acid, (C5H(CH3)2N(C02H)2, picoline-tricarboxylic acid, C5H(CH3)N(C02H)3, and pyridine-tetracarboxylic acid, C5HN(C02H)^. (3) Pyridine Tricarboxylic Acids, CgHsNOg = C5H2N(C02H)3. 1. a/?7-Pyridine Tricarboxylic acid (i, 2, 3) (tricarbopyridinic acid, carbo- cinchomeronic acid), is obtained by completely oxidizing quinine, cinchonine, quinidine and cinchonidine, with potassium permanganate, and by the same treat- ment of j-methyl quinoline, methyl-quinolinic acid (see above) and cinchoninic acid (p. 972). It is very soluble in hot water, crystallizes in plates with i^ molecules of HjO, becomes anhydrous at 115-120°, chars and melts when rapidly heated at 249-250°, with decomposition. At 180° it gradually breaks up (more readily on boiling with glacial acetic acid) into carbon dioxide and cinchomeronic acid. Ferrous sulphate gives it a faint red color. It is very probably identical with Ber- beronic Acid, formed from the alkaloid berberine by oxidation. 2. a;3/3'- Pyridine Tricarboxylic Acid (l, 2,4) is obtained from /3-ethyl quin- oline and /3-quinoline-carboxylic acid by oxidation with MnO^K. It is colored reddish-yellow,by ferrous sulphate, and softens with liberation of CO2, about 145° (p. 948). It IS very soluble in water and forms needles on crystallizing. 3. Symmetrical aay- Pyridine Tricarboxylic Acid (l, 3, 5) is obtained upon oxidizing symmetrical collidine (p. 943) and uvitonic acid (see above) with potas- sium permanganate. It crystallizes with two molecules of water. In an anhy- drous state it melts at 227°, with decomposition into carbon dioxide and isonico- tinic acid (Annalen, 228, 29). OMp-Pyridine Dicarboxylic Acid (l, 2, 5) results when the corresponding lutidine carboxylic acid is oxidized with potassium per- manganate. It crystallizes in leaflets containing two molecules of water. It melts at 100° in its water of crystallization, and at 130° breaks down into carbon dioxide and isocinchomeronic acid (Berichte, 19, 1309). 950 ORGANIC CHEMISTRY. 4. Pyridine Tetra-Carboxylic Acids, CgHjNOg = C5HN(C02H)^. The (m^y-Acid is produced in the oxidation of collidine carboxylic acid and flavenol (p. 971). It forms needles, containing two molecules of water. It loses water very slowly above 115°, and when anhydrous melts at 227°. Ferric chlor- ide colors it cherry-red {Berichte, 17, 2927). Symmetrical aa^^-acid is derived from the corresponding lutidine dicarboxylic acid (from aceto-acetic ester and iso- butylaldehyde etc.) by oxidation. It consists of minute needles, containing one molecule of water, and at 150° breaks down into carbon dioxide and dinicotinic acid. Ferrous sulphate imparts a blood-red coloration to its solution {Berichte, 19, 284). 5. Pyridine Pentacarboxylic Acid, C5N(COjH)5 = CnjHjNOi,,, is formed by the oxidation of synthetic collidine dicarboxylic acid and from the acids obtained in its oxidation. It crystallizes in microscopic needles, containing two molecules of vfater. It dissolves very readily in water, blackens at 200°, and de- composes, without melting, at 220°. Ferrous chloride imparts to its solutions a dark red color. C5H3N.CO2H Phenylpyridine Dicarboxylic Acids, . . There are two iso- CeH^.CO^H meric acids, u,- and /?-, which have been prepared by oxidizing a- and /J-naphtho- quinoline (p. 974) with potassium permanganate. They yield u- and /-phenyl- pyridine by the loss of two molecules of carbon dioxide. C5H3.N.CO2H Dipyridyl-dicarbonic Acids, . . Two isomeric acids, a- and CjHa.N.CO.H j8-, have been formed by oxidizing the two phenanthrolines with potassium per- manganate. Two dipyridyls are formed by the loss of two molecules of carbon dioxide (p. 942). Hydropyridine Derivatives. The pyridines yield hydrogen additive products, similar to those produced by benzene. They form when tin and hydrochloric acid act upon the pyridines, or more readily by the action of sodium upon the alcoholic solution ; the hexa-hydro- derivatives are then the direct products. Even oxypyridines are reduced by so- dium and alcohol to hexa-hydro pyridines [Berichte, 20, 250). Several natural alkaloids belong to this class of hydropyridines ; they are especially interesting. Hexahydro-pyridine, QH^N = CH2('^^''^g''')NH, Pi- peridine, occurs attached to piperic acid as piperine (see below) in pepper. It may be artificially prepared by reducing pyridine, also by distilling the hydrochloride of pentamethylene diamine (p. 313), or by the action of sodium upon an alcoholic solution of trimethy- lene cyanide (p. 311). Piperidine is a liquid that dissolves quite easily in water and alcohol. Its odor is like that of pepper. It boils at 106°. It shows a strong alkaline reaction. lis salts with the acids crystallize well. When piperidine is heated to 300° with sul- METHYL-PIPERIDINE. 95 1 phuric acid, or to 260° with nitrobenzene, or upon boiling it with silver oxide, it loses six hydrogen atoms and changes to piperidine. Nitrous acid converts it into the ni/roso compound, CjHjjiN.NO, boiling at 218°. Piperidine is very reactive with brom- and iodo-benzenes, forming «-phenyl- piperidines with them [Berichie, 21, 1921). This power of combination is mate rially diminished with a methyl piperidine {Berichle, 23, 1388). Potassium permanganate oxidizes piperidine to d-amidovaleric and 7-amidobuty- ric acids. The homologous piperidines are analogously oxidized {Berichte, 21, 2237 ; 22, 1035). (i-Amidovaleric acid loses water and yields oxypiperidine ox piperi- done, CjHgON (p. 945), a crystalline base, melting at 40° and boiling at 256°. It is a violent poison, resembling strychnine. The acid itself is not poisonous. Pyrrolidon, from y-amido-butyric acid, is also a strychnine-like poison (Berichte, 23, 2772). Dipiperidyls, C^HjjN.CjHiuN, are produced upon reducing the dipyridyls, (C5H^N)2, with sodium and absolute alcohol (^Berichte, 21, 2929). The same may be done with hexahydro-dipyridyls (p. 9S3). Piperidine is an imide base. It contains the NH-group and can form alkyl and acid derivatives. The alkyl compounds (the hydroiodides) result by the union of piperidine with alkyl iodides. »-Methylpiperidine, CjHjdN.CHj, and n-Etkyl Piperidine, CjHjjN.CjHj, are alkaline liquids, boiling at 107° and 128° respectively. With methyl iodide methyl piperidine forms dimethyl piperidine ammonium iodide, CjHjjNiCHjjjI. Potassium hydroxide, upon distillation with the latter, causes the decomposition of its ring structure and yields Dimethyl piperidine, Q^^[Ciii^^ = CHjiCH.CHj. CH2.CH2.N(CH,)2. This is a base, boiling at 118°. It reunites with methyl iodide to the ammonium iodide, C5Hg.N(CH3)3l ; silver oxide converts this into the hydroxide, C5Hg.N(CH3)3.0H, which on the application of heat breaks down into trimethylamine and Piperylene, C^Hg = CH2:CH.CH2.CH;CH2 (boiling at 42°). This is the method pursued by Hofmann in buildmg up the piperidine bases {^Berichte, 16, 2058; ig, 2628). «- Phenyl Piperidine, CjHjjiN.CgHj, from piperidine and brombenzene, is a liquid boiling about 250° (^Berichte, 21, 2279, 2287). «-Acetyl Piperidine, CjHuN.C^HgO, from piperidine by means of acetyl chloride, boils at 226°. Benzoyl Piperidine, CjHj^N.CO C5H5, is a solid. Piperidine urethanes, C5Hj5N.CO.OR, result from the action of chlorcarbonic ester. When these acid derivatives are oxidized the piperidine nucleus is torn asunder; saturated amido acids result (.5^nV^/^, 17, 2544; 19, 500)- Piperine, Ci^HjjNOg = CjHjoN.CijHjOj, the alkaloid, is an acid derivative of piperidine with piperic acid (p. 822). It occurs in different varieties of pepper {e.g., Papaver niger). It is artificially produced by the action of piperic acid chlo- ride upon piperidine. It crystallizes in prisms and melts at 128°- It dissolves with a deep-red color-in sulphuric acid. It is a very feeble base, and is decom- posed by boiling alcohol into piperidine and piperic acid. Sodium and alcohol reduce the homologous pyridines to homologous piperidines. They are known as Pipecolines, C5H9(CH3)NH, lupetidines, 05113(0113)2 NH, etc. (Ladenburg, Berichte, 18, 920). a-Methyl Piperidine, C5H9(CH3)(NH), o-Hydropicoline, boils at 118°. ;3-Methyl Piperidine, /3-Hydropicoline, boils at 126°. o-Ethyl Piperidine, 05Hg(C2H5)NH, boils at 143°. 952 ORGANIC CHEMISTRY. a-Propyl Piperidine, C5H9(C3H,)NH = CsHi,N, has been ob- tained by the action of sodium and alcohol upon a-allyl pyridine (p. 944). It boils at 167°. In properties and action it is very similar to conine. Its optical inactivity alone distinguishes it from the latter. By careful crystallization of its tartrate (induced by a small crystal of conine tartrate) it may be resolved (like inactive racemic acid, p. 478) into two optically active modifications, one of which is tevo-rotatory and the other dextro-rotatory. The latter is identical with conine — the first synthesis of an active alkaloid (Lsidenhmg, £erickte, 19, 2584; 22, 1405). Conine, QHi,N, dextro-rotatory a-normal propyl piperidine, C5H9(C3H,)NH, occurs in hemlock (Conium maculatum), chiefly in the seeds, and is obtained by extraction with acetic acid or distillation with soda. It is a colorless liquid, having the odor of hemlock, and boiling at 167-168°; its sp. gr. is 0.886 at 0°. It deviates the plane of polarization to the right (a„= 13-8°). Its hydrochloride melts at 217°. As secondary amine it yields alkyl and acid derivatives. If its nitrosamine, CgHi5N(N0) (azoconydrine), be digested with PjOj it forms Conylene, CgHjj, boiling at 125°. Benzoyl Conine, CgHj5N.CO.CgH5, is oxidized by permanga- nate of potassium to homo-coninic acid and amidovaleric acid. This nucleus is ruptured in the reaction [Berichte, 19, 506). Dimethyl conine iodide, CgHjgN (CHg).CH3l, obtained from methyl conine and methyl-iodide, manifests the same deportment as the piperidine derivative (see above), and finally decomposes into trimethylamine and conylene, CgH^. Conydrine, CgHj^NO, is an oxyconine and is intimately related to conine, occurring with the latter in hemlock and in the distillation it passes over last. It crystallizes in leaflets at 120°, distils at 226°, and sublimes about 100°. It reverts to conine when heated with hydriodic acid (Berichte, 18, 130). a-Isopropyl Piperidine, C5Hg(C3H,)NH, is derived from a-isopropyl pyri- dine by the action of sodium and alcohol. It is very similar to conine and boils at 160°. 7-Phenyl Piperidine, C5Hg(CgH5)NH, from y-phenyl piperidine, boils about 256° {^Berichte, 20, 2590). See Berichte, 23, Ref. 645 for the benzylpiperidines. Tetrahydropyridines, C5H5(H^)N, Piperidelnes. fl-Methyl Piperidelne, C5H8(CH3)N, and a-Ethyl Piperideine, C5H8(Cj H5)N, have been prepared by the action of bromine and sodium hydrate upon methyl and ethyl piperidine {Berichte, 20, 1645). A dipiperideine, Ci|,HjgN2, has been similarly derived from piperidine (Berichte, 22, 1322, 1377). a-Propyl Piperideine, C5H8(C3H,)N. The three isomeric bodies a-, /?-, 7-coniceSns, have been obtained from conydrine, CgH^NO (see above), by heating it with PjOj or to 220° with hydrochloric acid, and also by the action of bromine and sodium hydrate upon conine. They are again reduced to conine when heated with hydriodic acid {Berichte, 23, 680 and 2141). DIAZINES, OR AZINES. 953 Paraconine, CjHjsN, is a propyl tetrahydropyridine. It is formed from nor- mal butyraldehyde and butylidene chloride upon heating them with alcoholic ammonia. It is a colorless liquid, with stupefying odor. It boils at 168-170° (Berichte, 14, 2105). Tropine and tropidine are also tetrahydropyridine derivatives. Tropine, CaHijNO, obtained by the decomposition of the alkaloid atropine, crystallizes from ether in plates, melts at 63°, and boils at 229° When heated with concentrated hydrochloric acid or with glacial acetic acid to 180°, water separates, and it yields tropidine, CsHisN, which can also be produced by heating anhydroecgonine with hydrochloric acid to 280° {Berichte T.'^, 1389). It is an oil with an odor like conine. It boils at 162°. Hydro- bromic acid, acting upon it in the cold, causes it to revert to tropine. {Berichte 23, 1780, 2225). Tropine is an n-methyl-a-oxy-ethyl-tetrahydropyridine and belongs to the alkines (p. 315), while tropidine is an K-Methyl-a-vinyl-tetrahydropyridine (Ladenburg, Berichte 20, 1648; 23, 2587) : — C5H,N(CH3).CHj.CH,.OH ' and C5H,N(CH3).CH : CHj. Tropins. Tropidine. Tropidine forms hydrotropidine, CjHjsN, by reduction ; the distillation of its hydrochloride yields methyl chloride and Norhydrotropine, CjHjjN. The latter compound is isomeric with a-ethyl piperidine (see above) and when distilled with zinc yields a ethyl pyridine, C^H^N.CjIIj. Anhydroecgonine, CsHjN (CH3).CH : CH.COjH, is a carboxyl derivative of tropidine ; by the loss of car- bon dioxide it forms tropidine. Triacetonine is closely related to tropidine (p. 209). Nicotine, CioHuN^ = C5H4N. CsHjoN, is a hexahydrodipyridyl. It is found in the leaves of the tobacco plant, and may be obtained by distilling the residue from the aqueous extract with lime. It is an oil, readily soluble in water and alcohol. Its odor is very pene- trating. It becomes brown in color on exposure to the air. Its specific gravity at 15° is i.oii. It boils at 241°- It is a powerful diacid base and is poisonous. Chromic acid or potassium perman- ganate oxidizes it to nicotinic acid. Sodium, acting upon its alco- holic solution, converts it into dipiperidyl, CioH^oNj (p. 951). Nicotidine and Isonicotine, C^HuNj, are isomeric with nicotine. They result from the reduction oip- and »2-dipyridyl (p. 942) (Berichte, 16, 2521). DIAZINES, OR AZINES. These compounds bear the same relation to pyridine, that the " five-membered " diazoles or azoles bear to pyrrol (p. S51). They contain a " six-membered " ring, consisting of four C-atoms and two N-atoms — CjH^Nj. They may be considered pyridine derivatives, in which a CH-group has been replaced by nitrogen. There 80 954 ORGANIC CHEMISTRY. are three isomeric diaziue nuclei — the orthodiazines, meiadiazines and paradia- zmes, corresponding to the relative position of the two N-atoms. The usual desig- nations are pyridazine, pyrimidine and pyrazine* : — H N C N / V / \ / % HC CH N N N CH II I II II I HC CH HC CH HC CH \ ^ \ / \^^ N C C H H Paradiazine Metadiazine Orthodiazine Pyrazine. Pyrimidine. Pyridazine. I. Paradiazine or Pyrazine Compounds. These contain the two nitrogen atoms in the para position. They were formerly called ketines or aldines {Berichte, 19, 2524; 20, 431; 21, 20). They are pro- duced by the following methods : — 1. By reducing the isonitroso ketones and isonitroso acetoacetic esters with tin and hydrochloric acid. The amido-ketone compounds formed at first sustain an immediate condensation. Thus, isonitroso acetone (p. 206) yields dimethylpyra- zine (ketiue) {Berichte, 15, 1059) : — 2CH3.C0.CH{N.0H) + 6H = CJl2(CH3)2N2 -f 4H2O, CHj.CO.CHj.NH. CH3.C — CH = N -f 2H2O + H^. = II I -fNH2.CH2.CO.CH3 N — CH = C.CH3 Dimethyl Pyrazine. Again, isonitrosomethyl acetone, CH3.CO.C(N.OH).CH3 (p. 209) yields tetra- methyl pyrazine, C4(CH3)4N2 (dimethyl ketine), and isonitrosomethyl propyl ketone, CH 3. CO.C(N.OH).C2H5, gives rise to dimethyl ethyl pyrazine, C4(CH3)2 (C2H5)2N2 (diethyl ketine) [Berichte, 14, 1463). Dimethyl pyrazine dicarboxylic ester, C4(CH3)2N2(C02)R2> was similarly prepared from isonitroso acetoacetic ester (Berichte, 15, 1051). Tetraphenylpyrazine is obtained from benziloxime (p. 888). Isonitrosoaceto- phenone, C8H5.CO.CH(N.OH) (p. 728) may be condensed to isoamidoaceto- phenone, CgHj.CO.CHj.NH^, which ammonia will convert into diphenyl pyrazine (isoindol) {Berichte, 21, 1278, 1947; 22, 562). 2. By the action of ammonia upon brom- keto-derivatives, R.CO.CBr.HR. Thus, brom (chlor) acetophenone, CjHj.CO.CHjBr, yields diphenylpyrazine, C4H2(C8 H5)2N2, and brom- or oxy-l^vulinic acid, CHjCO.CHBr.CH^.COjH (p. 344) yields tetramethyl pyrazine with the simultaneous liberation of carbon dioxide. With aniline, on the other hand, the a-brom ketones form indol derivatives (p. 828) {Berichte, 21, 123). Pyrazines or paradiazines are diacid bases with a narcotic odor (resembling car- bylamine). They are mostly liquids and volatilize quite readily with steam. Free Pyrazine, C^H^Nj, appears to be produced when ammonia acts upon chloracetal, CH2Cl.CH(OR)2 {Berichte 21, 1481). *Widmann uses the texms piazine,miazine, oiazine {Jour. pr. Chem.,zi, 185). Compare Knorr, Berichte, 22, 2083; Hantzsch, Annalen, 249, 1. METADIAZINES OR PYRIMIDINE DERIVATIVES. 955 Dimethyl Pyrazine, C4H2(CH3)jN2, Ketine, from isonitrosoacetone (see above) boils with decomposition about 170-180°. Tetramethyl Pyrazine, C4 (CH3)4N2, Dimethyl Ketine, from isonitrosomethyl acetone and from Isevulinic acid, crystallizes with three molecules of water in brilliant needles. When an- hydrous it melts at 86° and boils at 190°. Diphenyl Pyrazine, C ^Ji ^i*^ e^ 5)1 N2, from bromacetophenone and amidoacetophenone,was formerly called isoindol {Berichie 21,1279). It forms shining needles or leaflets and melts at 195°- Dimethyl pyrazine DicarboxylicAcid,C4(CH3)2N2(C02H) 2, from isonitroso- aceto- acetic ester (see above) (ketine di-carboxylic acid), is produced by oxidizing, dimethyl ethyl pyrazine with potassium permanganate {^Berichie 20, 2524). It melts about 195° and decomposes into carbon dioxide and dimethyl pyrazine (?). Hydropyrazines. Piperazines. Diethylene diamine, described p. 313, may be claimed as a hexahydropyra- zinc, C^HijN, ^ HN^p j,2'_„2>NH. It sustains the same relation to pyrazine, that piperidine bears to pyridine, hence it is called Piferaaine. Formerly it was described as a liquid boiling at 170° [Berichte^ 23, 326). According to A. W. Hofmann it is a crystalline solie^^elting at 104°, and boiling at 145-146°. Ben- zoyl chloride converts it into the (/iiJ^wzoy/ derivative, melting at 191° {^Berichte, 23, 3297). It is identical with eihylenimine (C2HjNH)2, which was first obtained as a carbonate, a porcelanous mass, melting at 159-163° [^Berichte, 21, 75^! 23, 3303, 3718). Spermine on the contrary seems to have the simple formula C2H5.N. «-Diphenyl Piperazine, CjHs.N/^ j, jt'^Ptt^ ^N.CgHj, is a diethylene diphenyl diamine or diethylene aniline, resulting from the interaction of ethylene bromide and aniline [Berichte, 22, 1387, 177S; 23, I977). It melts at 163°. Dihydropyrazine, C^HgNj, derivatives are produced by the condensation of ethylene diamine with ortho diketones, just as the analogous quinoxalines and phenazines are obtained from the ortho phenylene diarnines (p. 593). For exam- ple, benzil yiiiis Diphenyldihydropyraaine {Berichte, 20, 267): — CH,.NH„ CO.C.H5 CHj.NiC.QHs I +1 =1 I +2H2O. CH2.NH2 CO.CeHj CHj.NrCCjHj A series of compounds which have been described as keto- or azi-piperazines are mainly amid-anhydrides of amido-acids or glycocoUs (p. 368). Thus, glycine anhydride may be termed a diketo-piperazine ; — (HN.CH2.CO)2 = Hn/^^^'^hJ/N^- Glycine Anhydride. Diketopiperazine. Phenylglycin- anhydride (CsH^.N.CHj.CO) is K-Diphenyldiketopiperazine, CeHj.N/'^Q-'^^^NH.CoHs, etc. For dif- ferent groups of similar derivatives see Abenius, Berichte, 21, 1664; 23, Ref. 244, and Bischof, Berichte, 22, 1810 and 23, 2005-2055; Berichte, 23, 1972. 2. Metadiazines or Pyrimidine Derivatives. These contain the two nitrogen atoms of the six-membered nucleus in the meta- position (p. 954). Thus far only amido- and oxy-derivatives have been prepared. i. Amido-pyrimidines are the so-called f^a«-a/i«««, formed by the polymeri- 956 ORGANIC CHEMISTRY. zation of the cyan-alkyls (nitriles) when heated to 150° with metallic sodium. Thus, cyanmethane, CHjCN, yields cyanmethine, CjHgN,, cyan-ethane, C2H5CN, cyanethine, C^Hj 5N3, and cyan-propane, C3H,.CN, yields cyan propine, CijlijiN,, etc. The constitution of the cyan-alkines was made evident by the fact that the oxy-base obtained by the action of nitrous acid upon cyanmethine is identical with dimethyl-oxypyrimidine (E. v. Meyer, Jr. pr. Chem., 39, 265 ; Berichte, 22, Ref. 328) :- CH, /C^s CH3.C/ \CH yields CH3.C/ ^CH. N — C N — C^ NH, OH Cyan-methine. Oxy-dimethyl-pyrimidine. Amido-dimethyl- Pyrimidine. The so-called cyan-ethine (see above) is amidodiethyl-methyl-pyrimidine, C,H = .C/S^^5??55)^C.CH,. A confirmation of this formula is afforded by the synthesis of acetyl cyan-ethine from acetamidioe, CH3.C(NH).NH2, on boiling the latter with acetic anhydride {Berichte, 22, 1600). Analogous cyan alkines are produced by the action of sodium upon a mixture of two alkylcyanides. The course of the reaction remains unexplained ; it may be that dicyanalkyls are pro- duced at first, and these then further combine with a cyanalkyl to form cyan- alkines {Berichte, 22, Ref. 327). The sodium alcoholates react in the same manner as metallic sodium {Berichte, 23, Ref. 630). The cyanalkines, or amido-pyrimidines, are crystalline and strongly, alkaline bases. They form salts with one equivalent of the acids. They are converted into oxypyrimidines by the action of nitrous acid upon heating them with hydro- chloric acid to 200°. Cyanmethine, C5H5N3, melts at 180°. Cyanethine, C9Hj5N3 = CgH,3N2.- NHj, crystallizes in white leaflets, melts at 189°, and boils with partial decomposition at 280°. The oxy-base, CgHjjNj.OH, melting at 156°, forms the chloride, CjHjjNjCl, by the action of PCI5. Nascent hydrogen converts the latter into cyanconine, CgHj^Nj, very similar to Conine. It is really methyl diethyl- pyrimidine {Berichte, 22, Ref. 328). Cyan methine-ethine, CgHjjNj, resulting from the action of sodium upon a mixture of cyanmethane and cyanethane, consists of shining leaflets, that melt at 165°, and begin to sublime about 100°. The character of the side-chains in this compound has not yet been established. (Jour. prk. Ch., 39, 267.) (2) The oxymetadiazines or oxypyrimidines are formed when the amidines of the paraffin and benzene series act upon acetoacetic ester and analogous P ketone derivatives (the hydrochlorides are mixed in equivalent quantity with acetoacetic ester and 10 per cent, sodium hydroxide) {Pinner, Berichte, 22, 1612, 1633; 23, 3820):— CH ,NH CO.CH3 N— C^ R.c<; +1 = R.cr: ^ch + r'.oh -fH^o. ^NH, CH,.CO,R' -\n=C( Alkyl methyl-oxy-pyriinidine. ^.y^s^See Berichte, 22, 2610 for the course of the reaction. Alkyl oxypyrimidine OXAZINE AND MORPHOLINE GROUP. 957 carboxylic acids are analogously derived by the use of oxalacetic ester, *"*^\ CH^ CO R Dibasic ketonic acids, such as aceto-glutaric ester and diaceto- succinic ester, react similarly, while succino-succinic ester forms a quinazoline derivative [BericA/e, 22, 2623 ; 23, 2934.) The oxypyrimidines are crystalline substances, soluble in nearly all solvents, and form salts both vfith acids and bJses. Dimethyl-oxypyrimidine, CH3.CNjC3H(OH).CH3, forms needles that melt at 192°. Phenylmethyl-oxypyrimidine, C5H5.CNjC3H(CH3).OH, from benzamidine, melts at 238°. Uracyl, C4HJN2O2, and its derivatives, as well as malonyl urea, alloxan and the analogous carbamides, may be viewed as ;J^^o-derivatives of the kydrometadiaaines [Berichte, 23, Ref. 643.) (3) All compounds obtained by the condensation of phenylhydrazine ( i molecule) with diaceto-succinic ester (a 7-diketone, p. 328), appear to be derivatives of ortho- diazine or pyridazine in which the two N-atoms of the " six-membered " ring are adjacent (p. 954) (Berichte, 18, 305, 1568) : — CH,.CO.CH.CO,R •I = CH,.CO.CH-CO,R C,H,.NH.NH,+ I =C,HN,(CeH,)(CH3),(CO,R),+2H,0. l.CI If the ester be saponified and two molecules of carbon dioxide eliminated phenyldimelhylpyridazine, CjH5N2(CgH5)(CHj)2, results. Acetophenone-ace- tone, CjH5.CO.CH2.CH2.CO.CH3, and phenylhydrazine yield an analogous compound (^Berichte, 17, 914). The benzoiriazines, CgH^iNjCH, are the only known derivatives oi triazine, C3H3N3 (p. 553). The osotetrazones described (p. 326) may be considered as tetrazines, CjH^Nj. OXAZINE AND MORPHOLINE GROUP. The oxazine ring is related in the same manner to the diazine and pyridine ring, as oxazole to diazole and pyrrol (p. 555) : — /CH:CH\q jj /CH2.CH2\o "^\CH:CH/'^ "^\CH2.CH2/^- Oxazine. Morpholine. Thus far an oxazine ring, similar to that just given, has only been shown to be present in the phen- or benzazoxines. Tetrakydro-oxazine, on the. other hand, does exist. It is called morpholine; verj probably because it is contained in mor- phine (Knorr, Berichte, 22, 2081). Morpholine, C^HjNO, tetrahydro-oxazine, is formed when dioxyethylamine, ^'^•V CH^ Ch" OH ' '^ lieated to 160° with hydrochloric acid, or boiled with alkali. re-Methyl Morpholine, C^H4(CH3)NO, is similarly formed from dioxyethyl- methylamine, CH3.N(CH2.CH2.0H)2. It is a liquid, boiling at 1 17°. It is very^ similar to methyl piperidine. »-Phenyl-morpholine, C^Hj(CjH5)N0, is obtained from dioxyethyl aniline, C5H,.N(CH,.CH2.0H),, melts at 53°, and boils at 270° {Benchte, 22, 2094). 958 ORGANIC CHEMISTRY. PYRONE GROUP. The pyrone ring contains six members. It is analogous to the furfurane ring ; but is less stable, owing to the influence of the CO-group, and in different reac- tions it readily breaks down into its components : acetone, acetic acid and oxalic acid. The conversion of most pyrone derivatives, by the action of ammonia, into derivatives of y-pyridone (p. 945) and pyridine, is considered rather re- markable : — =CO<CH=cg>0 CO<CH=CH>NH CH/Cg=CH\^ i i Pyrone. 7-Pyridone. Pyridine, The following compounds are probably derivatives of the pyrone nucleus : — Pyrone, CjH^Oj, Pyrocomane, is formed when comanic and chelidonic acids are heated to 250°. One or two molecules of carbon dioxide are eliminated (Be- richte, 17, Ref. 423). It is a neutral solid that dissolves quite readily in water. It melts at 32.5°, and boils about 315°. Dimethyl Pyrone, C5H202(CH3)2 (l, S), results upon heating dehydracetic acid (see below) with hydriodic acid. Two molecules of carbon dioxide are ex- pelled from the acid. Brilliant crystals, that melt at 132° and boil at 248°. It sublimes at 80° in long needles. It is very soluble in water ( Berichte, 22, 1570). Boiling baryta water converts it into diacetylacetone (p. 328), which ammonia changes to lutidone. Oxypyrone, C5H302(OH) (?), pyrocomenic acid, pyromeconic acid, is ob- tained by the elimination of one or two groups of carbon dioxide from comenic and meconic acids by distillation. It crystallizes in large plates, melting at 121°. It boils at 228°, and even sublimes at 100°. It forms unstable salts with one equivalent of the bases {Jour. pr. Chem., 27, 260). Comanic Acid, C15H4O4 = C5H3O2.CO2H, PyrOne Carboxylic Acid, is ob- tained from chelidonic acid l5y the loss of carbon dioxide (Berichte, 18, Ref. 381). It dissolves with difficulty in water. It melts at 250°, and deconiposes into carbon dioxide and pyrone. When boiled with lime it decomposes into acetone, oxalic acid and formic acid. It forms an oxypicolinic acid when digested with ammonia ; this breaks down into carbon dioxide and pyridone when it is heated. Chelidonic Acid, C^H^Og = CgH202(C02H)2, pyrone dicarboxylic acid, occurs together with malic acid in Chelidonium majus. (Preparation, Annalen, 57, 274). It crystallizes in silky needles with one molecule of H^O, and melts at 220°. It is a dibasic acid, and forms colorless salts. An excess of alkali converts it into xanthochelidonic acid, C^HgOj. This yields yellow-colored salts with three and four equivalents of the bases ; chelidonic acid is again liberated from them by the addition of acids [Berichte, 17, Ref. 424). The reduction of chelidonic acid gives rise to hydro-chelidonic acid, C,Hi„05, identical with acetone diacetic acid, CO(CH2.CH2.C02H)2 (p. 437; Berichte, 22, Ref. 681). Boiling hydriodic acid reduces chelidonic acid to apimelic acid (p. 421). It does not form an acetoxime with hydroxylamine. Ammonia converts it into an oxy-pyridine dicarboxylic acid, CjHjNOg (cheli- damic acid, p. 948). Coumalic Acid, CjH^O^, is identical with comanic acid. It is probably a CO— CH = C.COjH lactone carboxylic acid, with the following constitution, | | , O— CH = CH and may be regarded as a carboxylic acid of a-pyrone [Berichte, 22, 1419, 1705). DIMETHYL PYRONE DICARBOXYLIC ACID. 959 It is produced when malic acid is heated together with concentrated sulphuric acid or with zinc chloride (p. 465) (Berichte, 17, 936, 2385). It dissolves with difficulty in cold water, and melts with decomposition at 206°. With an excess of alkali it forms yellow- colored salts. Comenic Acid, CgH^Oj = CsHjOjCOHj.COjH, oxypyrone carboxylic acid. When meconic acid is heated to 1 20-200°, or boiled with water or hydrochloric acid, it decomposes into CO^ and Comenic Acid. The latter is rather insoluble in water, and crystallizes in hard, warty masses. When digested with ammonia it changes to dioxypicolinic acid (comenamic acid, p. 947). {Berichte, 17, Ref. 105, 167). Meconic Acid, C,H^O, = C5H02(OH)(C02H)2, oxypyrone dicarboxylic acid, occurs in opium in union with morphine. The opium extract is saturated with marble, and calcium meconate precipitated by calcium chloride [Annalen, 83, 352). The salt is afterwards decomposed by hydrochloric acid. The acid crys- tallizes with 3H2O in white laminae, which dissolve readily in hot water and alco- hol. When heated to 120° it decomposes into carbon dioxide and comenic acid. Ferric salts color the acid solutions dark red. In forming salts the acid generally combines with two equivalents of the bases, although with an excess of base, the salts are tribasic and yellow in color. Meconic acid also unites with ammonia, forming Comenamic Acid (Berichte, 17, 2081). Dehydracetic Acid, CgHgOi = CHj.C O C.CH3 II II ? i^te. Berichte, CH — CO — C.COjH. 23, Ref. 463; Annalen, 257, 253.) This is a by-product in the preparation of aceto-acetic ester. It can be obtained by long continued boiling of the ester, using at the time a return condenser. It dissolves with difficulty in cold water and alcohol. It crystallizes in needles from ether; these melt at 108° and boil at 269°. Being a ketonic acid it can unite with both hydroxylamine and pheayJhydrazine [Berichte, 18, 4.53).. It forms (l, 5)- dimethylpyrone on being heated with hydriodic acid. Iso-dehydracetic Acid, CgHjO^, is isomeric with the preceding and may be obtained by the decomposition of the condensation product, Cj3H2 209 (Annalen, 222,9), produced by the action of sulphuric acid upon acetoacetic ester. It is identical with carbaceto-acetic acid (Berichte, ig, 2402), derived from the aceto- acetic acid by means of hydrochloric acid. It is very probably mesiten-lactone carboxylic acid (Berichte, 23, Ref. 734). Dimethyl Pyrone Dicarboxylic Acid, C^HjOg Carbonyl Diacetic Acid. Its ethyl ester is produced when COClj acts upon the copper compound of aceto-acetic ester. Water is eliminated from the carbonyl diacetoacetic ester which is formed at first (Berichte, 19, 20) : — CH,.CO CO.CH3 CH3.C — O — C.CH3 I 1 yields II II RO,.C.CH — CO — CH.CO.R RO,C.C — CO — C.CO,R. The diethyl ester is crystalline, very readily soluble in alcohol and ether, and melts at 80°. Ammonia converts it into dimethyl pyridone-dicarboxylic ester {Berichte, 20, 154). g6o ORGANIC CHEMISTRY. 2. QUINOLINE GROUP— C,H2„_nN.* QUINOLINE, CjHjN. Lepidine, CioHgN = C9H5(CH,)N— Methyl quinoline. Cryptidine, CnHi,N = C9H5(CH3)2N — Dimethyl quinoline, etc. The quinoline bases occur with those of pyridine in bone-oil (p. 938), and are also obtained by distilling alkaloids (quinine, cinchonine, strychnine) with potassium hydroxide. The com- pounds leucoline, C9H7N, iridoline, C10H9N, etc., separated from coal-tar are identical with the quinoline bases {^Berichie, 16, 1847). As regards synthetic methods and isomerides, quinoline is a naphthalene in which a CH-group is replaced by N (p. 937). This was first shown by synthesizing quinoline from allyl aniline (p. 602), by passing the latter over ignited lead oxide. This is perfectly analogous to the syn- thesis of indol from ethyl-aniline (p. 827, and of naphthalene from phenyl bu- tylene (p. 905) (Konigs) : — .N =CH C,H5.NH.CH,.CH:CH, = C,H / | + 2H2. ^CH = CH Quinoline is also produced in the distillation of acrolein-aniline (p. 602). A more direct proof of the constitution of quinoline was effected through its forma- tion from hydrocarbostyril - (p. 755); PCI5 converts the latter into a dichloride, which upon heating with hydriodic acid yields quinoline (just as isatin yields indigo, p. 836) (A. Baeyer, Berichte, 12, 1320) : — CeH,/CH,.CH,\co C,H,(^H:CCl\cci G,^/^^^^CR. Hydrocarbostyril. a^-Dichlor-quinoIine. Quinoline. Here, as with naphthalene and pyridine, we represent the. three replaceable hydrogen atoms of the pyridine nucleus by a, /J and y; 4 r 2 I N those of the benzene nucleus with i, 2, 3 and 4.f The positions i, 2, 3 correspond to the ortho-, meta-, and para-positions of the benzene derivatives. 4 corresponds to the second meta position (referred to N), and is known as the .^«a-position. These posi- *A. Reissert, Das Chinolin und seine Derivate, 1889. f Another nomenclature designates the affinities of the pyridine nucleus as Py-I, -2, and -3; those of the benzene nucleus as B-i, -2, -3, and -4 (Berichte, 17, 960). QUINOLINE. 961 tions are designated as the affinities of the benzene nucleus with o-, m-, p- and a-. Consequently, seven mono-derivatives of quinoline are possible (^Berichte, ig, Ref. 443). Of the great number of new synthetic methods of preparing quinoline and its derivatives the following are the most important : 1. The condensation of the ortho-amido-compounds of such benzene derivatives as have an oxygen atom attached to the third carbon atom of the side-chain (p. 755) (A. Baeyer). In tbis way we obtain quinoline from o-amido-cinnamic aldehyde, a-methyl- quinoline from o-amido-cinnamic ketone, and a-oxy-quinoline from <7-amido- cinnamic acid (p. 812). Further, o-amido-benzyl acetone yields a-methyl-hydro- quinoline (p. 730), o-amido-phenyl valeric acid, ;3-ethyl hydrocarbostyril (p. 814), and from these compounds the normal quinoline derivatives — a-methyl quinoline and /3-ethyl quinoline — can be obtained by the withdrawal of 2H or O. 2. The production of quinoline and its derivatives by heating anilines (or amido-benzene compounds) with glycerol and sulphuric acid to about 190°. This method is of universal application and can be very readily executed (Skraup, Berichte 14, 1002) : — CeH,.NH, + C3H,03= C,H,N(C3H3) + ^H^O-f-H,. It is very probable that acrolein first results, this then combines with the aniline derivative yielding acroleln-aniline (see above), which is oxidized to the quinoline derivative by the elimination of two hydrogen atoms by sulphuric acid. Hence, the reaction proceeds more easily and rapidly by using a mixture of aniline with nitrobenzene, which only oxidizes. Similarly, from the three toluidines (and nitrotoluenes) we obtain the three methylquinolines (toluquinohnes), Cj|,HjN = C5H3(CH3)N(C3H3), from the naphthylamines (and nitronaphthalenes) the naphthoquinolines, Cj3HgN, and from the diamidobenzenes (and dinitrobenzenes) the phenanthrolines (p. 974). It is not necessary to apply the corresponding nitro-compounds together with the amido-derivatives; nitro-benzene mostly suffices as an oxidizing agent {Berichte, 17, 188). " Likewise, the chlor-, brom-, and nitro-quinolines result from the corresponding aniline derivatives. The nitranilines yield both nitro quinolines and phenanthro- lines [Berichte, 14, 2377). From the amido-sulphonic acids arise the quinoline sulphonic acids ; from the amido-benzoic acids, quinoline carboxylic acids ; from the amido-phenols oxyquinolines, etc. The Kekule benzene formula confirms the course of these quinoline syntheses - (p. 563) {Berichte, 23, 1020). 3. An analogous reaction is the condensation of anilines with paraldehyde, aided by sulphuric or hydrochloric acid. Here a-methyl quinolines (quinaldines) are produced (Doebner and v. Miller) : — .CH; CH CjH^.NH, + 2C,H,0 = C^H / | -f 2H,0 + H,. ^N:C(Crigj a-Methyl Quinoline. All aldehydes of the formula CHO.CHgR react like ferric 962 ORGANIC CHEMISTRY. aldehyde with anilines. The first step in the reaction consists in two molecules combining to unsaturated aldehydes, CHO.CR:CH. CHjR, or condensing to aldols corresponding to them. These then act upon the anilines and form quinoline bases. Two aldehyde molecules always act. Their condensation is due to the influ- ence of the CHj group attached to the aldehyde group. Acetaldehyde yields crotonaldehyde, CHO.CHiCH.CHj, propyl aldehyde yields methyl ethyl acrolein, CHO.C(CH3):CH(C2H5), and ethyl propyl acrolein is formed from normal butyraldehyde. These unsaturated aldehydes (or the aldols) then react with the anilines in such manner, that the aldehyde group attacks the benzene nucleus (and not the amido-group). Thus, u- or a/3-alkyl quinolines {^Berichte, 17, 1713 ; 18, 3360) result. Acetaldehyde (crotonaldehyde) forms a methyl quinoline (see above), a/3- ethyl- methyl quinoline [Berickte, zi, 299) is derived from propyl fildehyde : — C.H5.NH, + CH0.C(CH)3 .CH: C.CH, II =CeH/ I +H,0+H,. cii{c^n^) \n=c.qh5. a/S-Ethyl Methyl Quinoline. In oxidizing these dialkyl quinolines with a chromic acid mixture it is only the ffi-alkyl that is changed tfl carboxyl ; the resulting carboxylic acids eliminate carbon dioxide and yield /3-alkylquinolines [Berichte, 18, 3370). Unsaturated aldehydes, therefore, react (with one molecule) directly with the anilines. Acrolein (glycerol, see above) yields quinoline, while a-phenyl quino- line {Berichte, 16, 1664) is derived from cinnamic aldehyde, CHO.CHiCH.CjHj. z«-Nitrocinnamic aldehyde reacts similarly {Berichte, 18, 1902). Acetone (two molecules) reacts in the same manner as the aldehydes with aniline hydrochlorides when aided by heat. It is very probable that mesityl oxide, CH3.CO.CH:C(CH3)j, is the first product; therefore, as there is a simultaneous splitting off of one mesityl group, the products are ay-dimethyl quinolines {Berichte, 18, 3296; 19, 1394). The mixture of an aldehyde and ketone (each one molecule) re- acts the same as the aldehydes upon anilines. The intermediate products are unsaturated ketones, R.CO.CH:CH.R (or /J-aldol ketones, R.C0.CH2.CH(0H)R (C. Beyer, Berichte 20, 1767 ; ig, Ref. 327). In this way a;'-dialkyl quinolines are produced. Acetone and acetaldehyde, or acetylacetone, and aniline yield ay-dimethyl- c^vaoXxnt (Berichte, 21, Ref 138) : — CHj CH3 CjHj.NH^ -I- CO.CH3 =C^/ ^CH +2H.O-I-H,. \ I CHO.CH3 N=C.CH3 The /3-diketones react similarly {^Berichte, 20, 1 770; also a mixture of two different aldehydes, Berichte, 20, 1908, 1935). a-Alkyl-quinoline-y-carboxylic acids are produced by the interaction of a mixture QUINOLINE. 963 of pyroracemic acid and an aldehyde upon aniline (Berickte, 20, 277; 21, Ref. 12):— CO.H CO,H I C.Hj.NH, + CO.CH3 = C5H/ '''^CH + 2H,0 + Hj. CHO.R \ C.R N The carboxylic acids lose carbon dioxide and in this manner the a-alkyl quino- lines are produced. Pyroracemic acid alone when heated with aniline yields the same a-methyl quinoline-y-carboxylic acid (aniluvitonic acid, p. 972) ; this is be- cause aldehyde is formed from one molecule of the pyroracemic acid (Berickte, 20, 1769). 4. The direct condensation of amido-benzaldehyde with alde- hydes and ketones (by the action of caustic soda). The ortho- amido-derivatives of the unsaturated homologous benzaldehydes and ketones are the first products. These immediately give up water (see p. 721) (Friedlander, Berickte, 16, 1833). Thus, with acetone we get a-methyl-quinoline: — CfiHiC + I =C.H,'-"-^" +2H,0; ^NH, ^CO.CH^ " 'N :CCH3 ^ ^ with acetophenone, CHj.CO.CgHj, a-phenyl quinoline; with phenylethyl aldehyde, CgHj.CHj.CHO, /3-phenyl quinoline; with aceto-acetic ester, a-m ethyl quinoline-/3-carboxylic acid (Berichte, 16, 1833) ; with malonic ester a-oxyquino- line-|8-carboxylic acid [Berickte, 17, 456). tf-AmidObenzophenone (p. 859) reacts just like o-amidobenzaldehyde ; it yields ay-methyl phenyl quinoline with acetone and caustic soda [Berickte, 18, 2405) : — CeH / + I =C,H / I \nHj CO.CH3 ^N CCHg + aHjO. In acid solution it is only the amido group that takes part in the reaction ; ac- cording to Miller's reaction benzoyl-a-methyl quinoline results. 5. The condensation of aceto-acetic esters with primary and secondary anilines (L. Knorr, Berickte, 17, Ref. 147; Annalen, 236, 112). There are two phases in this reaction : (a) aceto-acetic anilide (from aniline and aceto-acetic ester when heated to 1 10°), when acted upon with concentrated acids, forms a-oxy-y- methyl quinoline (y-methyl carbostyril, p. 968) : — C0(CH3)CH, ,C(CH.):CH '\ ^ = C,h/ '' \ +H3O. CjH5(NH).C0 ^N . C(OH) Methyl aceto-acetic anilide by the same treatment yields /3y-dimethyl carbostyril [Berickte, 21, Ref. 628). [b) On the other hand /3-phenyl-amido-crotonic ester, formed at the ordinary 964 ORGANIC CHEMISTRY. temperatures, yields /-oxy-a-methyl quinoline (y-oxyquinaldine, p. 970) when heated to 240° (Conrad and Limpach, Berichte, 20, 945, 1397) : — .C(OH):CH = C,h/ I +C,H5.0H, CjHj.NH.C.CHj ^TST rCHj Phenyl-lutidone carboxylic ester is for(ned simultaneously. Anisidine, CjH^ (O.CH3).NH2, also affords methoxy-y-oxyquinaldine [Berichte, 21, 1649, 1655). Aceto-acetic ester and methylaniline condense to «-methyl lepidone (= pseudo- carbo-styril, p. 968) (Annalen, 236, 105; Berichte, ig, Ref. 827) : — CH3.CO.CH2 .C(CH3):CH ^^ =CeH/ I +H,0. C5H5.N(CH3).CO \N(CH3).C0 Acetone dicarboxylic ester (p. 435) reacts in an analogous manner with aniline (and methyl aniline) ; the products in this instance are esters of 7-oxyquinaldine- ^-carboxylic acid [Berichte, 18, Ref. 469). At the ordinary temperature benzoyl acetic ester and aniline yield /3-phenyl- amido-phenylacrylic ester, which heated to 250° forms y-oxy-a-phenyl quinoline (Berichte, 21, 521, 523). 6. By the rearrangement of the aniline malonates or the malonanilides with PCI5 ; triquinolines being produced (analogous to the formation of a-naphthol from phenylisocrotonic acid, Riigheimer, Berichte, 18, 2975) : — CC1=CC1 CeH5.NH.CO.CH2.CO2H yields CjH^/ |. \ N = CCl The toludines react similarly to aniline [Berichte, 18, 2979), and ethyl malonic acid deports itself the same as malonic acid [Berichte, 20, 1235). Hippuric acid, CjHj.CO.NH.CHj.COjH, under like treatment, yields chlorisoquinoline, (p. 976). 7. By rearranging the anil benzenyl compounds, from benzanilid-imide chlorides and sodium malonic or aceto-acetic ester, by the aid of heat (Just, Berichte, 19, 979, 1462, 1541):— RO.OC.CH.COjR /C(OH) = C.CO^R I =c,h/ / CeH5.N:C(C,H5) ^^=.Z.Q,Vi, a-Phenyl-7-oxy-/3-quinoline carboxylic acid. 8. The conversion of indol and alkyl indols into quinolines (p. 830) is rather re- markable. It occurs in consequence of the Introduction of methyl, dihydroquino- lines resulting (E. Fischer, Berichte, 21, Ref. 17). Chlor- and brom-quinolines are similarly obtained by heating methyl ketol with chloroform or CBrjH and sodium ethylate [Berichte, 21, 1940). The quinoline bases are liquids which dissolve with difificulty in water, alcohol and ether, and possess a penetrating odor. Like pyridine they are not readily attacked by nitric or chromic acid ; QUINOLINE. 965 potassium permanganate, however, destroys the benzene nucleus in them, with production of a/3-pyridine dicarboxylic acid (quinolinic acid, p. 947). The homologous quinolines, containing the alkyl groups in the pyridine nucleus (a, ^, ;-), and those containing the substitutions in the benzene nucleus {o, m, p, a), are oxidized by chromic acid in the presence of sulphuric acid to the corresponding quinoline car- boxylic acids, while potassium permanganate on the other hand usually oxidizes those substituted in the benzene nucleus, with the formation of pyridine carboxylic acids {Berichte, 19, 1194; 23, 2252). Potassium permanganate converts the ^- and y-alkyl quinolines (by decomposing the benzene nucleus) into the corresponding pyridine tricarboxylic acids, while the (z-alkyl quinolines have their pyridine nucleus destroyed, and acid derivatives of o-amidobenzoic acid result. By this treatment a-phenyl quinoline yields benzoyl anthranilic acid, CgH^/^jl r/-) r; jj {Berichte, ig, 1196). If two methyl groups are present in quinoline, the 7-position will be oxidized with the most ease, then the /3, and finally the a-position {Berichte, 23, 2254). In the case of the aj3-dialUylquinoIines, obtained by the action of aldehydes (2 molecules) upon the anilines, chromic acid only attacks the higher o-alkyl with the formation of ^-alkyl-a-carbonic acids (see above). Only the most important of the many derivatives of quinoline will receive notice in the succeeding paragraphs. Quinoline, CgHjN, occurs in bone oil and coal tar. It results when many alkaloids are distilled, and is best prepared syntheti- cally. In preparing quinoline, digest a mixture of 38 grams aniline, 100 grams sul- phuric acid, 24 grams nitrobenzene, and 120 grams glycerol, until the reaction commences. Boil them for several hours, dilute with water, distil off the nitro- benzene in a current of aqueous vapor, supersaturate with alkali, and distil the quinoline with aqueous vapor. To purify it thoroughly convert it into the acid sulphate {Berichte, 14, 1002). See Berichte, 14, 1769, for the reactions and physiological action of quinoline. Quinoline is a colorless, strongly refracting liquid, with pene- trating odor. It boils at 239°; its sp. gr. = 1.095 ^' 20°. It forms crystalline and very soluble salts with one equivalent of acids; the characteristic bichromate, (CgH,N2)Cr207H2, dissolves with difficulty and forms yellow needles, melting at 165°- With the alkyl iodides quinoline, as tertiary base, produces crystalline, yellow ammonium iodides, which may be converted into peculiar bases (ammonium hy- 966 ORGANIC CHEMISTRY. droxides), soluble in ether, on warming with caustic soda (Berichte, 17, 1953, and, 18, 410, 1015). Tertiary dihydroquinolines also afford bases soluble in ether, while the iodomethylates of tertiary tetrahydroquinolines are stable towards alkalies (^Berichte, 21, Ref. 17). Potassium permanganate oxidizes the ammonium chlo- rides, the pyridine nucleus being decomposed, and derivatives of o-amidobenzoic acid are produced (see above). Cyanine (C29H35N2I) is a blue dye, and was formerly prepared by heating quinoline amyl iodide with potassium hydroxide. It is only produced in the presence of a-methyl quinoline (Berichte, 16, 1501, 1847) ; the same is true of the red-dye (Berichte, 16, 1082) obtained from quinoline with benzotrichloride. Quinoline betaine, C^^(^^^Q,0 (the HCl-salt), is formed from quinoline and chlor-acetic acid; the free betaine melts at 171°. Nascent hydrogen (tin and hydrochloric acid) produces Dihydro.-quino- line, CgHgN (melting at 161°), and liquid Tetra-hydro-quinoline, CgHjjN = CsHj/^w'-^g^^, boiling at 245° (Berichte, 16, 727, 23, 1 142). Both are secondary bases and form nitrosamines. The tetrahydronitrosamine rearranges itself quite readily to the paranitroso compound, which yields p amidoquinoline when reduced (Berichte, 21, 862). The alkyl iodides and tetrahydroquinoline yield »-alkylhydroquinolines. M-Methyl tetrahydroquinoline, CjHi„N.(lIL, so-called Kairoline, obtained by means of methyl iodide, is said to have the same action as kairine — a febrifuge. Tetrahydroquinoline (unlike piperidine, p. 950), does not react with bromben- zene. 'When heated with nitro-benzene it is readily oxidized to quinoline (Be- richte, 22, 1389). In tetrahydroquinoline the four hydrogen atoms are attached to the pyridine nucleus, therefore like the ar-tetrahydro naphthylamines it possesses the character of an aromatic base (of an aniline). Decahydroquinoline, CgHjjN, of alicyclic "^aracter, is produced when the preceding compound is further reduced by heat- itig with hydriodic acid. It is strongly alkaline, with a penetrating, conine-like odor. It melts at 48° and boils at 204° (Berichte, 23, 1142). The diquinolyls, CgHjN.CfHjN, result from the union of two molecules of quinoline. They are analogous to the dipyridyls. They consist either of two pyridine nuclei, two benzene nuclei or one pyridine nucleus and one benzene nucleus. Seven isomerides have been prepared thus far, partly through the con- densation of quinoline by sodium, or by conducting it through a tube heated to redness. Skraup has succeeded in synthesizing them from benzidine and dipheny- lin (p. 961), or from amidophenyl quinolines. On heating quinoline with sodium in air we get a-Diquinolyl, melting at 176° (Berichte, 20, Ref. 327.) The two pyridine nuclei in it are united to each other at the a-positions (Py a-Py a) CjII^ : CjH^N— CjH^N : CjH^ (Berichte, 19, Ref. 7S5; 20, Ref. 471). The chlor-, brom-, and nitro-quinolines, with the substitutions in the benzene nucleus, are prepared synthetically, by Skraup's reaction, from the chlor-, brom-, and nitro-anilines. a-Chlorquinoline, C5H5CIN, is obtained from a-oxyquino- line with PCI5 and PCI3O ; it consists of long needles, fusing at 38°, and boihng at 266°. It is a feeble base. Its halogen atom, in the a-position, is very reactive. 