Quinoline

1. المملكة العربية السعودية وزارة التعليم العالي جامعة أم القـــــرى كلية العلوم التطبقية قسم الكيمياء Quinoline • دلال ألناشري. • فخرية القرشي. • مريم عقيلي. • الفت رشيدي. • أحلام ألغامدي. أعداد الطالبات بإشراف د/ ناريمان محمد نحاس

2. الإهداء أرسل أبيات معطرة بعود منى لأغلي كيمياء حلقية حبها في قلبي دووم موجود وهي تبادليني نفس الإحساس . بأجمع من الإزهار باقة ورود وباهديها وأنا خاضع الرأس ربي عطاها حسن مفنود احد مركبتها ليمن تفاعل مع جمله الخود كأنة تشابه طير جرناس هو في قلبي والغير مطرود ربي يحميه من كل حسود بأية الكرسي وسورة الناس سلامي لك يالكنيولين عند النسيم هب نسناس.

3. N N 2. Isoquinoline 1.Quinoline 3. Quinolizinium 4.Benzopyrylium 6.4H-Benzopyran 5.2H-benzopyran Introduction The most investigated compounds of this group contain a nitrogen atom and theoretically can be derived from naphthalene by the substitution of a carbon or carbon and hydrogen atoms by a nitrogen atom .the same results can be obtained by fusing a benzene ring onto that of pyridine and three structures result. Derivatives of all three ring systems of quinoline(1) of isoquinoline(2). And of the quinolizinium cation(3) occur naturally in the from of alkaloids ,although those derived from the last-named system are comparatively rare. Quinoline and isoquinoline have received much attention from research workers for many years, but interest in simple quinolizinium salts is comparatively recent.These three types of compounds are essentially aromatic in character and to varying degree combine the properties of Pyridine and naphthalene. 4.BenzopyryliumO5.2H-benzopyran6.4H-BenzopyranThe oxygen analogues of naphthalene which are considered here are those derived from the benzopyrylium cation(4) and the benzopyrans(5and 6),In which the oxygen atom is adjacent to the carbocyclic rind .Derivatives of these system occur widely in plants and the anthocyanins, substitutes benzopyrylium saits are responsible for most red and blue flower colours .Very few sulphur analogues of these oxygen-containing compounds are known, and at present they are not of general interest.

4. 5 4 7 4a 6 3 β N N 7 2 α 8a 8 1 1 2 HO2C CHO CH3 NaOH H2O2 + Or KMnO4 HO2C NH2 CHO N N 4 3 QUINOLINE In 1834 Runge isolated crude quinoline from coal tar ,and in 1842 the same compound was obtained by heating the alkaloid cinchonine with alkali .Another 40 years elapsed before the identity of the materials from these two sources was establishes. The he positions of the quinoline ring are usually numberd(1),and the use of letters(2)has been virtually discontinused.A great many quinolines are known, And most have been obtained by direct synthesis invoving the building of the nitrogen –containing ring or by the transformation of existing substituents.the direct introduction of substituents into the nucleus ,and particularly into the carbocyclic ring ,is easier then in the pyridine series. A.Physical properties and structure Quinoline is a colourless liquid ,which turns yellow on standing and which possesses a characteristic odour resembling that of pyridine.it has f.p.-15.6OC,b.p. 237oC, and d154 1.097.It is miscible with most organic solvents ,dissolvent for many types pf organic compounds.The structure now accepted feo quinoline was first proposed by komer and was supported at an early stage by the oxidation to quinolinic acid (4)and by several syntheses,of which Friedlander's is shown.

5. + + N N 3a 3b 3 N N 3c 3d 0-988 0-932 1-361A 1-425A 1-008 1-003 1-410A 0-896 1-421A 0-984 N 1-013 1-216 Intcratomic distances in naphthalene π–Electron densities I quinoline N The resonance energy of quinoline [198kJ(47-3kcal)/mole],calculated by klages' method1 from heat of combustion data ,Is substantially less than that of naphthalene[255kj(6!-0kacl/mole];the method of calculation also gives an unexpectedly low vale for the resonance energy of pyridine .The interatomic distances in quinoline have not yet been determined but are probably between those of naphthalene2 and those of phridine. Quinoline is best considered considerd as a resonance hybrid that corresponds to that of naphthalene in regard to the uncharged contributing structures (3,3cand3d).As in the case of naphthalene, where bond-length determinations2 have confirmed the supposition thatsome bond fixation occurs,chemical evidence suggests that structure 3 with the symmetrical double-bond arrange-ment in the ring is probably the most important.The sipole moment (2-29D)

6. + N And the facile nucleophilic substitutions that take place at positions 2 and 4 (p.306)of quinoline indicate that chargrged structures .such as 3a,3b and similar structures with different bond arrangements in the carbocyclic ring ,must also contribute significantly to the resonance hybrid .All this is in agreement with the general, but not detailed ,similarity of the ultraviolet absorption spectra of quinoline and naphthalene. The π–electron densities and localization energies for electrophilic, uncleo-philic, and radical attack have been calculated3 by the huckel molecular orbital method for a wide range of Huckel parameters of reasonable values can be chosen to give pictures consistent with the observed substitution patterns, and the π -electron densities obtained from one set of parameters is shown above. Quinoline ,which has the benzene ring fused to pyridine in the 2,3-positon,is considerably more important than the isomer with the benzene ring fused at the 3,4-position.On account of the commercial importance of quinoline derivative ,considerable research in this area has been carried out in industrial laboratories .quinoline chemistry is of general interest in the study of organic chemistry because of the applicability of much basic aromatic and aliphatic chemistry .in particular ,enolate condensation become of great importance in the synthesis of quinolines by cyclization reaction. Structural Characteristics The basic structure of quinoline follows directly from its oxidation to quinoline acid (pyridine-2,3-dicarboxylic acid).The quinoline formula is ordinarily written with the double bonds placed as shown above ;however , the same resonance forms apply as discussed for naphthalene .In addition ,charged resonance forms are of importance ,as in pyridine, so substituents in the alpha and gamma positions exhibit the reactivity discussed in connection with pyridine chemistry .Interring charged forms such as the following,appear to be of such high energy as to make no significant contribution to the character of the molecule. Substituents in the 5-or 7-position have no unusual reactivity; they behave as normal aromatic substituents ,similar to naphthalene derivatives .the bond structure shown in the inter-ring resonance form ,with two double bonds at the ring juncture ,appears to be of high energy, in general.

7. * HO * CH=CH2 N H C * * CH3O N Quinine (asymmetric carbons marked with*) • CH3-CH-CH2-CH2-CH2-NH(C2H5)2+HBr • OHCH3-CH-CH2-CH2-CH2-NH(C2H5)2 • Br • And • CH3-CH2-CH-CH2-CH2-NH(C2H5)2 • Br Certain Important Compounds in the Quinoline Series Among the several alkaloids containing the quinoline ring system,perhaps the most well-known is quinine,long as a specific chemotherapeutic agent against malaria.Not only has the complex structure of quinine been worked out, but the compound has been synthesized, with the proper configuration for each of the four asymmetric carbon atoms. A feverish search was initiated in this country during world war П for synthetic substitutes for quinine .Although quinine was synthesized, the only practical source of the alkaloid in quantity is an Asiatic tree; so control of malaria during the war period depended entirely on synthetic drugs .The synthetic drug most widely used during the war was atabrine . The initial production of atabrine in the United States proved to be so highly toxic to man that it was of no value in chemotherapy .After expenditure of considerable time and money , it was finally established that the high toxicity resulted from presence in the atabrine of an isomer in which attachment of the ring-substituted nitrogen was to the 3-position in the amyl group .This isomer was introduced in an intermediate synthetic step in which a secondary alcohol had been converted to the bromide by a process involving a significant percentage of carbonium ion intermediate(cf.chap.5,SN1 mechanism).the reaction was the following:

8. CH3 CH3 C2H5 C2H5 H CH –(CH2)3-N H CH –(CH2)3-N C2H5 N C2H5 N H3CO Cl Cl Chloroquine N N Atabrine When there was employed a secondary bromide synthesis which eliminated ,or greatly minimized ,the SN1 component in the reaction ,the atabrine obtained as end-product showed the desired toxicity to the malaria with a sufficiently low toxicity to man. A particularly interesting feature of the experience with atabrine is that ,during the early nineteen-forties ,relatively few experienced research chemists were entirely familiar with reaction mechanisms now studied in elementary courses in organic chemistry. For control of malaria is called chloroquine .It is of interest to note that both of these drugs contain a substituent grouping in the 4-position of the quinoline nucleus, as does quinine. Atabrine may be regarded as chloroquine with an additional benz ring fused to quinoline. The three-ring system in atabrine is the acridine ring system. The search for anti-malarial drugs has continued ,on account of the facility of the malaria parasite for developing an acquired resistance to the drugs used against it .Chloroquine and atabrine have become virtually in effective ,and considerable resistance to quinine has been noted. The remarkable photosensitizing dyes are usually quinoline derivatives. The silver halides used in photographic emulsions are sensitive chiefly to light of short wavelength ,in the blue and ultraviolet. When a photosensitizing dye is included in the emulsion ,the film becomes sensitized to longer wavelengths .A film sensitive as far as the yellow and green in the spectrum is known as an orthochromatic film, while film sensitized as far as the red is called panchromatic. Sensitivity dyes absorb light of longer wavelength and emit energy in the spectral region to which silver halides are sensitive. A representative photosensitizing dye is pinacyanole , which is a panchromatic sensitizer.tow resonance forms of the cation of the ethiodide are shown:

9. N CH =CH-CH N N Pinacyanole C2H5 C2H5 C2H5 CH -(CH)=CN I- N C2H5 If the length of the resonance path in the cation is increased ,light of longer wavelengths will be absorbed by the photosensitizining dye .A dye with one more vinyl group(-CH=CH-)than contained by pinacyanole will give sensitization to the infrared. B.Chemical properties The chemical properties of quinoline are, in general, those that might be anticipated from an amalgamation of those of pyridine and naphthalene .the effect of the nitrogen atom is largely confined to its own ring, which possesses most of the chemical properties of the pyridine system. 1.Addition and ring-opening reactions With a few exceptions ,most of these concern the heterocyclic ring. Quinoline is a slightly weaker base(pKa=4.94) than pyridine (pKa=5.23),and forms many salts which are sparingly soluble in water .It readily forms a 1-oxide(p.307),and quaternary salts with reagents such as methyl iodide, methy1 suphate, and benzoy1 chloride.1-Alkylquinolinium salts ,such as 5, with alkali give the corresponding hydroxides(6). These are certainly in equilibrium with the corresponding pseudobases (e.g 7) but the position of equilibrium in water is not known with any certainty. Analogy with naphthalene and benzene, Where conversion into the corresponding dihydro derivatives (styrene and buta-1,3-diene)involves the loss of 88kJ(21 kcal)/mole and 136 KJ (33kcal0/mole of resonance energy ,respectively ,suggests that the position of equilibrium is further towards the pseudohydroxide than in the pyridine deries .The pseudohydroxide could also tautomerize to an open-chain form (8).the oxidation of 6 with alkaline potassium ferricyanide gives 1-methy 1-2-quinolone.

10. H CN + N + N + N NaOH N -OH Hl Me 12 6 Me Me Me 10 5 I- H C N N CH O- H NH Me CHO OH Me Me 7 8 N 9 ŌEt H OEt Me 11 I- 5 13 Me Me N N N CN CN KCN Beat to 200o I2 -Mel -HI Crystallization of the hydroxide (6~7)from ethanol gives the corresponding ethoxide ,which can have either an ionic(10)or covalent (11) structure. Treatment of 1-methylquinolinium iodide(5) with potassium cyanide gives a compound (12)corresponding to the pseudobase (7),but where the cyanide group has unexpectedly entered position 4.This is proved by successive oxidation and thermal decomposition ,when 4-cyanoquinoline is formed .The whole sequence is a useful synthetic procedure, and it is noteworthy that the decomposition of 1-alkylquinolinium halides(e.g. 5and 13) is quite general and may be carried out in vacuo or in a high-boiling such as ethyl benzoate.

11. - N N N N CO2H H CN 15 CO Ph Cl- + N - N - N Cl- H C=NH C-NH C=NH O O PhC PhC O PhCH CHO Cl- PhCHO+ CO Ph 14 17 NHCOPh 18 PhCOCl HCl HCl -HCl KCN 1-Benzoylquiniun chloride(14)behaves differently with potassium cyanide and ,perhaps more understandably, give 15 , where the double bond of the pyridine ring is still conjugated with the benzene system .Compounds such as 15,which are easily made ,are sometimes known as Reissert compounds after their discoverer. They have special interest , as on treatment with concentrated hydrochloric acid they break up as shown to give quinolone-2-carboxylic acids. The mechanism proposed4 is consistent with the facts that 2-cyanoquinoline is not an intermediate and that the reaction proceeds similarly with isoquinoline and phenanthridine but not with acridine where no cyclic intermediate is possible ,with the isolation of some quinoline-2-carboxyamide as a minor product, and with labeling studies which show that the asterisked hydrogen atom of the benzaldehyde 16 formed comes from the solvent. 1-Benzoylquiniun chloride(14)with sodium hydroxide may give initially the hydroxide corresponding to structure 7, but the product actually isolated is the trans aldehyde (18). In contrast ,the rings of 1-cyanoquinolinium salts do not open with alkali.

12. RL1 N N N N N N N Me 19 20 2Li+ Li+ R R 21 22 ClCOtEt CO2Et - 2Li NH2 2stages -NH2- The reduction of quinoline,2-quinolone ,or of 1-methylquinolinium iodide by lithium aluminium hydride yields the corresponding 1,2-dihydroquinoline.4a 1,2-Dihydroquinoline(23)is reported5 to be obtained in good yields from the sodium-liquid ammonia reduction of quinoline , but it disproportionates with acid and is easily oxidized .However , more recent work6 using lithium and liquid ammonia has shown that either the carbocylic or heterocyclic ring can be reduced ,depending on the proton source used, and conditions have been found7 where the intermediate anion (19) can be trapped by alkylating agents to give the 1-alkyl-1,4-dihydroquinolines (e.g 20)exclusively. Quinolines are attacked by organolithiums8 at position 2,to give salts(21).These yield stable 1-ethoxycarbonyl1-2,-dihyroquinolines(e.g 22) with ethyl chloroformate or can be protonated to 1,2-dihydroquinolines(,which are easily oxidized by air or nitrobenzene to the corresponding quinolines.

13. 1 N 160o at 15 mm L1AlH4 N N Na/Hg H2,Ni, or An/HCl 5 4 6 3 oxidatiun N Me2 H2Ni + N Me2 OH NMe2 7 2 8 25 27 26 H- H H 24 23 Quinoline is easily reduced to tetrahydroquinoline (24)by tin and hydrochloric acid, or by hydrogenation .This preferential reduction of the pyridine ring can be altered by substitution.1,2,3,4-Tetrahydroquinolin is a stronger base than quinoline ,it has most of the properties of a secondary aromatic amine, and it is dehydrogenated to quinoline by many oxidants, including even iodine. It gives a quaternary salt with excess methyl iodide. The corresponding hydroxide (26), contrary to earlier ideas ,does9 undergo the Hofmann degradation to 2-allylsimethlaniline (25) which must be dsitilled out in vacuo. As at ordinary pressures the degradation leads to methanol and 1-methyl-1,2,3,4-tetrahydroquinoline (cf.24)it appears that the formation of 25 from the quaternary hydroxide(26) is reversible. Reductin of the hydroxide with sodium amalgam giving 27 ,and is a useful complementlary procedure.1-Benzoy1-1,2,3,4-tetrahydroquinoline undergoes the normal von Braun ring.

14. N N KMnO4 NO2+ XNO2 + N N N N CO2H KMnO4 NRCOR R' OH 29 30 NO2 X Ph X R' NO2 28 31 NO2 NO2 X=NO2or AcO Powerful hydrogenation of quinoline in acetic acid over platinum gives a mixture of cis-and trans-decahydroquinoline. In other cases ,such as 2-phenlquinoline928)and pseudohydroxides (30),the nitrogen containing ring is split to give the corresponding acylanthranilic acid (29). 2.Substitution reactions In concentrates sulphuric acid , quinoline is converted almost entirely into the cation .Bromination10 and both chlorination and iodination11 with silver sulphate in this solvent yield a mixture of the 5-and 8-halogenated quinolines. Sulphonation at 220oC gives largely the 8-sulphonic acid ,which rearranges to the 6-sulphonic acid at 300oC,and fuming acid gives a mixture of the 5-,7-,and 8-sulphonic acids .Nitration in sulphuric acid at 0oC is rapid and also gives12 a mixture of 5-(52.3%)and 8-nitroquinolines(47.7%);no other isomers were detected by methods that would easily have estimated quantities of the order of 1%.The reaction Kinetics 13 show that the quinolinium cation is the species actually nitrated ,and that the proton is present in the transition state .These results are in agreement with molecular-orbital calculations,3 which show that the localization energies for electrophilic attack on the quinolinium cation are lowest at positions 5 and 8. Nitration in acetic anhydride14 however , gives 3-nitroquinoline(up to 6.6%) along with a little (0.9%)of the mixed 6- and 8-nitro isomers; the 3-nitro compound is not obtained if the reaction conditions preclude the formation of nitrous fumes .The same products are also obtained on nitration with dinitrogen tetroxide.

15. Br + N Br Br N 33 32 Me 4 5 Me 6 3 B A Me N N 2 7 36 35 37 1 8 34 The positions chosen by the entering groups do not suggest a free-radical attack .A possible course of reaction is through an initial addition ,giving compound 31 followed by electrophilic attack on position 3 and subsequent eliminations .This appears to be yhe reaction scheme that gives the highest electron density at the 3-position of the intermediate (e.g 31)which must be sub stituted.15 Bromine combines with quinoline to give initially a π-donor complex (32).16 This in hot carbon tetrachloride in the dark gives17 3-bromoquinoline (33,43%),but a much higher yield (82%)can be obtained along with a little 3,6-dibromoquinoline if pyridine is present.17 3-Bromoquinoline (25% yield)can also be formed by a vapour-phase bromination over pumice at 300oC, by bromination in the presence of suphur, sulphur chloride, and by heating quinoline in hydrochloric acid with bromine .The mechanism is probably similar to that of nitration at position 3.Heating 3-bromoquinolinium bromide to 300oC gives18 mainly quinoline(32%),bromine ,and 4-bromoquinoline.The remarkable debromination process may proceed by the reverse of the nitration mechanism leading to 3-nitroquinoline. Vapour-phase bromination of quinoline at 500oC gives 2-bromoquinoline (60%), probably via a radical attack. Phenyl radicals, obtained through the decomposition of benzoyl peroxide, attack quinoline ,giving a mixture of all the phenylquinolines.8-Phenyl-(30% yield) and 4-phenylquinoline (20%) are the major products. Benzyl radicals substitute mainly at positions 2 and 4 for both quinoline and its cation.19 The acetyl radical (CH3CO), from acetaldehyde and t-butylhydroperoxide ,attacks the quinolinium cation in sulphuric acid to dive about 60% of 2,3-diacetylquinoline.20 C.Derivatives of quinoline Substituted quinoline can be divided into two classes, depending on whether the substituent under consideration is attached to the carbocyclic (34,ring A)or heterocyclic (34,ring B)ring. In general ,substituents of these rings have properties corresponding to those of the analogous (lepidine, 37)occur to a small extent in coal tar and have methyl groups that are very reactive in an analogous way to those of 2-and 4-methylpyridine. N N

16. N + N KCN PhCOO Cl Cl- + N N H2O2,AcOH HNO3,H2SO4 H CN O- PhCOO PhCOO +PhCOO2H CN 5 NO2 + N O- N O- 38 N 3-methylquinoline(36)is similar and is comparatively unreactive. Quinoline 1-oxide is interesting ,as the products obtained on nitration depend on the temperature.21Between 0 and 20oCin sulphuric acid solution a mixture of 8-major and 5-nitroquinoline 1-oxides is obtained, while at 65-70oC 4-nitroquinoline 1-oxide is the main product and corresponds. Quinoline 1-oxide with benzoyl chloride and potassium cyanide gives benzoic acid and 2-cyanoquinoline quantitatively .The reaction probably proceeds through the formation of 1-benzoyloxyquinolinium chloride. The products of photolysis of quinoline 1-oxides22 depend on the solvent employed and are probably formed via an oxaziridine (38)intermediate. Ring opening to a charge species(38a) is thought22 more probable than to the corresponding diradical ,and tautomerism then gives 2-quinolone (38b),which is the main product using aqueous solvents. With acetone, 2-cyano-and 2-pjenylquinoline 1-oxides give stable oxazepines (40).In other cases the oxazepines are not isolable, and not isolable ,and if some water or ethanol is present ,hydrolysis occurs to give equilibrium mixtures (39 and 39a)of compounds that can dehydrate to corresponding 1-acylindoles. 2-and4-Chloro or bromoquinolines can be obtained from the quinolones (e.g 44)by treatment with phosphorus halides.3-bromoquinolines are unreactive .The rate of formation of bromide ion in the reaction of 5-,6-,7-, and 8-bromoquinoline with piperidine has been studied kinetically.23

17. + N O O O 38 38a O- N CHO + N H O R NH COR OH O- N COR 40 39 29a 38b N N N + N N 41 42 Although the activation energies for the four reactions are all very similar, the rates of reaction increases steadily for the compounds in the order given ,the rates of reaction increased steadily for the compounds in the order given .Hence structures 41 and 42 which can be written for quinoline and which would facilitate nucleophilic attack at positions 5 and 7,do not contribute greatly to the resonance hybrid .It can ,however, be concluded that 42 makes a larger contribution than 41,as 7-bromoquinoline reacts faster than 5-bromoquinoline in the above reaction because 7-aminoquinoline is a stronger base than 5-aminoquinoline.

18. CN CN 5 EtO O2N N O2N ? KCN2EtOH 7 8 N N 43 5 4 6 3 7 2 8 1 N Nitroquinolines can be obtained by direct nitration or by syntheses outlined later. 6_Nitroquinoline nitrates at position 8,and nucleophilic attack takes place at position 5,which corresponds to the active α-position of naphthalene ,In the example shown the initial nucleophilic attack is by the cyanide ion, to give 43 , and is followed by the displacement of the nitro group by an ethoxide ion; no attack appears to occur at position 7. 5-,6-,7-, and 8-Aminoquinoline can be obtained by the reduction of the corresponding nitro compounds or by one of the synthetic methods; 2-and 4-aminoquinoline are obtained by methods analogous to those of the pyridine series, while 3-aminoquinoline is prepared from 3-bromoquinoline and ammonia in the presence of copper. The chemical properties of the aminoquinolines, with the exception of the 20and 4-derivatives,which structurally and chemically resemble 2- and 4-aminopyridine, are comparable to those of aniline.6-and 7-Aminoquinoline with aromatic diazonium compounds at the 5-and 8-positions, respectively in conformity with the bond fixation of a naphthalene.2-and 4-Aminoquinolines are relatively strong bases because of additional ionic resonance. The fact that 7-aminoquinoline also shows enhanced basicity indicates that some additional ionic resonance involving both rings is possible (cf.42), and the low basicity of 8-aminoquinoline is probably due to interaction of the amino group with the nitrogen atom in the adjacent ring (Table 1). TABLE(The first dissociation constants(pKa)of the aminoquinolines in water)

19. H C + N KOH,250oC(80%yield) N CHH CL O- NO3 CO2H 44 H2pd NaOH HCL aq PCl3 H+l- O-SMe2 Me2SO CHO CH3 CL l- N O N COCO2H H NHCO OH NH2 O 46 45 H 47 N N Carbostyril or 2-quinolone(44), a colourless material of m.p.199oC,is very similar to 2-pyridone in chemical properties , and likewise does not tautomerize appreciably to 3-hydroxyquinoline (45);the lactam structure is supported by ultraviolet and infrared absorption spectrum measurements .The hydrolysis of 2-chloroquinolines to 2-quinolones in dimethyl sulphoxide24 is much easier then by acid alone.2-Quinolone is oxidized by potassium Permanganate to give isatin (47),through the intermediacy of isatinic acid (46),and it is nitrated ,via attack on the neutral molecule ,at position 6.

20. +4[H] (Na + EtOH) (1) N N H 1,2,3,4-Tetrahydroquinoline CH3 CH3 CH3 CH3 +4[H] (Na + EtOH) (2) CH3 CH3 2,3,4-Trimethyl-5,6,7,8-tetrahydroquinoline N N Reactions of the Quinoline Nucleus In general , the reaction of quinoline may be predicted with some reliability from the reactions previously studied for brnzene and for pyridine. Oxidation.It was pointed out (Eq.31-1)that the pyridine ring is much ,more stable to oxidation than is the benzene ring ;hence oxidation of quinoline give the 2,3-pyridinedicarboxylic acid. Reduction. Since chemical reduction of pyridine is relatively is relatively easy and chemical reduction of benzene is quite difficult, it would be expected that the hetero ring in quinoline would be more easily reduced . In the majority of quinoline derivatives, this is the fact(Eq. 1). It should be mentioned that in certain highly substituted quinoline derivatives the benz ring is preferentially reduced(Eq.2).

21. (4) NO2 +HNO3 (fuming) 200O fuming +HOH and H2SO4 heat (3) NO2 5-Nitroquinoline 8-Nitroquinoline SO2OH +H2SO4 (fuming) +H2O and SO2OH 300O HOO2S 6-Quinolinesulfonic acid N N N N N N N Thus the direction of reduction in substituted quinolines may not always b predicted with confidence, in absence of experimental information. Substitution. since there are seven monosubstitution positions in quinoline, the situation is considerably more complicated than is the case in naphthalene. A relatively limited number of monosubstitution derivatives may be obtained in a pure condition, and polysubstitution is of minor utility. There will be mentioned the derivatives which may be obtained relatively readily. Since the pyridine ring is substituted with such great difficully, substitution in quinoline would be expected to occur in the benz ring, and this is the case for orthodox substitution involving nitration and sulfonation. Bromination, however, gives substitution in the hetero ring ,and the reasons for this behavior are not understood. The rather unusual procedure used for bromination will be discussed. (1)NITRATION. This occurs under the rather vigorous conditions shown inEq.3. These two isomers can be separated, hence are available starting materials for synthesis. (2)SULFONATION. This also occurs under rather extreme conditions. The isomers shown in Eq.4 may be obtained under the conditions indicated, and they may be separated.

22. -NO2 -NH2 N2+ various group -SO2OH -OH -CN -CO2H -COCL various groups -Br -Li various groups Br Precipitate of a complex containing quinoline and bromine CCl4 reflux +Br2 solvent In CCl4 (5) N N It may be noted that there is some parallel with naphthalene chemistry, in that nitration occurs adjacent to a ring and sulfonation occurs similarly, while rearrangement of the sulfo group to the lower-energy β-position occurs under conditions permitting thermodynamic control of the product. The preference of substitution for the 5-position is an additional indication that inter-ring resonance forms are of no significance in quinoline. If this were not the case, the 5-position would be relaaticely positive, hence unattractive in electrophilic substitution. Under other conditions than those shown inEq.4, a small amount of 7-quinolinesulfonic acid is formed but isolation of an amount of this isomer sufficient to serve as a staring material in synthesis is not practical. In fact, it will be noted that substitution in the 7-position is not secured in either sulfonation or nitration. (3)BROMINATION OF QUINOLINE IN THE 3_POSITION. This substitution may be secured in yields as high as 80% by the sequence shown in Eq.5. the exact nature of the complex containing quinoline and bromine has not been determined, and the reasons for the unexpected substitution in the hetero ring are not known.2 This is an important entry to the 3-position in quinoline, however.The usefulness of the 3-bromoquinoline is considerably enhanced by the fact that it can be converted to the organolithium reagent, which gives reactions similar to those of the Grignard reagent. The substitution products shown in this section have typical aromatic character, and give such conversions as shown in outline form:

23. warm NH2 Cl +2NH3 +NH4Cl (6) -NH2 -OH -Cl -H N N If the reagents and conditions for these conversions cannot be recalled they should be reviewed by use of the index and reference to material on the chemistry of benzene and the derivatives of carboxylic acids. synthesis and reactions of 2-and 4-substituted Quinoline Derivatives In the preceding section have discussed methods for securing 3-,5-,6-, and 8-substituted quinolines. The 7-position is not readily attacked, but substituents in the 2-and 4-positions can be secured by methods dependent in large measure on the reactivity of these positions. Entry into the 2-position may be secured by use of lithium alkyls or sodium amide, by reactions essentially identical with those discussed for pyridine (cf. Eqs.31-13,31-28). Entry into both the 2-and 4-positions can be secured by way of the carboxylic acids or the hydroxyquinolines; methods for securing these derivatives will be discussed below. Since substituents in the 2-and 4-positions are active in the manner of pyridine substituents in these positions. The 2-and 4-hydroxyquinolines are available by independent syntheses; therefore, it is sometimes convenient to proceed from hydroxyl to halogen(cf.Eq.31-24). And thence to amino as in Eq.6. Of course such reactions as this do not apply in the 3-position.

24. CH=CH-CO2H CH CH- CO2H-H2O +P-isomer (separable) H2,Pt (8) NO2 Cinnamic acid (from Perkin condensation) CH CH CO2H NH2 (not isolable) +H2O H2SO4 O OH H 2-Quinolone O OH +HNO3 N (7) H N N N Synthesis of quinolones. The 2-and 4-hydroxyquinolines are called quinolones because of the existence of tautomeric equilibrium of the sort discussed for the pyridine series: As in pyridine, equilibrium favors keto form, hence use of the term quinoline. 2-Quinolone can be secured by the synthetic sequence in Eq.8. Several features of the sequence in Eq.8 are of interest. First may be mentioned the ortho, para-directing influence of the alkene group attached to the aromatic ring.

25. + CH H R H R CH C C H + H NO2 NO2 Since ortho, para-directors are those with a relatively negative atom attached to the ring, this type of directing influence indicates that the alkene grouping is a relatively negative one, in contrast with the polar multiple bonds in which the carbon attached to the ring is relatively positive. It will be recalled that normal attack of a regent on a double bond is an electrophilic attack, consistent with a relatively negative character for the double bond. Since the carbon double bond is ordinarily not highly polarized, this negative character would apply to both the carbon atoms and thus make the alkene grouping an ortho, para-director. In addition, energy of the transition state would be lowered to some extent by the electron delocalization indicated in the following resonance forms: This is in contrast to the situation in a meta-director where a resonance form of the type shown on the right would have the positive charge on the normally negative atom, hence be of high energy. A second point of interest in Eq.8 is preferential hydrogenation of the nitro group in presence of the carbon-carbon double bond. This selective hydrogenation goes especially well with a platinum catalyst, for the amino group appears to poison this catalyst towards hydrogenation of the alkene linkage. Thus, preferential hydrogenation of a nitro group in unsaturated compounds has found considerable application in synthesis.

26. O OH O C CH3 CHO -OH -OH H-CO2H (9) N N NH H O O O C CH3 CH3 CH3 HCl Heat Amide formation NO2 NO2 CHO N (10) H Finally, it should be noted that the cyclization, which amounts to amide formation, occurs spontaneously for the isomer cis geometry at the alkene linkage. Amide formation ordinarily occurs slowly with heation, but the gain in resonance energy on going to the quinoline ring system makes this cyclization occur very readily. In the discussion of more general types of cyclization reactions in a later section, there will appear other illustrationsof the ease with which reactions occur when an aromatic system is being formed. 4-Quinolone can also be formed by a cyclization reaction,Eq.9. This ready cyclization amounts to an aldol condensation, although the carbonyl group involved is actually that in a formamide. The starting material for this cyclization may be secured by the reactions shown. The starting material for this cyclization may be secured by the reactions shown in Eq.10.

27. C COCl CH3 CH3 CO2H N NO2 NO2 NO2 (11) C2H5 C + CH3+HOH NO2 (12) NO2 30-40O,acetic Heat (CH3)2cd PCl5 [O] OH OH +CO2 CO2H (13) O O N N Kynurenic acid Acid solvent Phenone, the starting material in Eq.10, may be secured by the reaction shown in Eq.11, however, it has also been found that the controlled oxidation shown in 12 may be accomplished in yields as high as 55%. This furnishes o-nitroacetophenone after a single reaction on a compound which is cheaply available commercially, so 4-quinolone become only slightly less readily available than the 2-isomer. Quinolones substituted in the benz ring may be obtained if the appropriately substituted benzene derivative can be synthesized. Another interesting source of 4-quinolone is from kynurenic acid, as shown in Eq.13. Decarboxylation of the 2-carboxylic acid occurs on simply heating.

28. +C6H5-COCl + + C6H5 C C6H5 C O O (14) H + CN CO2H CHO O+KCl C6H5 C Quinaldinic acid KCN H2O N N N N N H2SO4 heat Although most animals excrete urea and uric acid as end products of nitrogen metabolism, certain species of dogs excrete kynurenic acid instead. This can hardly be regarded as a practical source of large quantities of 4-quinolone. Synthesis of 2-and 4-quinolinecarboxylic. Since the methyl-quinolines are not available from coal tar, the carboxylic acid are usually made by routes other than oxidation of the methlquinolines.The 2- and 4-carboxylic acids may be prepared from quinoline by rather unusual but effective sequences. THE 2-CARBOXYLIC ACID is prepared by a sequence proceeding through the quaternary salt of quinoline and benzoyl chloride an shown in Eq.14.

29. + pyrolysis heat KCN I2 2H2O,H+ N N N N N + +CH3I N N I- CH3 H CN CH3 Methylquinolinium iodide (15) CN CN +CH3I +KI + CH3 I-+HI CO2H CH3 +NH4+ Cinchoninic acid It will be noted in the last step that as cyano is hydrolyzed to acid, benzaldehyde is eliminated. The mechanism of this reaction is not well understood, but it constitutes the final step in a usefl synthesis of quinaldinic acid. In certainreae instances, the process has been applied to synthesis of an aromatic aldehyde from the acid chloride, but other methods are usually superior. A consideration of the resonance forms of the quaternary salt makes it clear that attack of the negative group at the 2-position is quite reasonable, but it is not clear why there is selective attack at the 2-position in preference to the 4-position. Indeed, with a different quaternary salt, selective attack at the 4-position occurs(cf.Eq.15)A possible influencing factor is inductive with-drawal of electrons from the adjacent 2-position by the benzoyl group; however other less obvious effects are probably involved. 4-QUINOLINECARBOXYLIC ACID is available by way if the reactions outlined inEq.15.IN this sequence it will be noted that the dihydroquinoline is oxidized with iodine to give the quaternary iodide.

30. NO2 Other products + + +CH2-CH-CH2 OH OH OH CH2-CH-CH2 OH OH OH NH2 N (16) (or other aromatic amines) (or other mild oxidizing agent) O + 2H2O CH2=CH-C H Acrolein (16a) heat heat H2SO4 H2SO4 General Syntheses of Quinolines by Cyclization Since synthesis of monosubstitution derivatives of quinoline via substitution reactions is subject to some limitation, and pure disubstituted derivatives are rarely accessible by substitution, synthesis of quinolines by cyclization reactions becomes of considerable significance. More than thirty separate methods for synthesis of quinolines by cyclization have been developed, and we to a large variety of substituted quinolines. The Skraup synthesis. One of the best and most simple methods for preparation of quinolines substituted in the benz ring is the synthesis introduced by Skraup. The net result of this reaction is shown in (Eq. 11). The route which the reactants follow in order to eventually yield quinoline has been the subject of considerable study, and it is believed to well understood. The first step is the known reaction in which glycerol is dehydrated by hot sulfuric acid to give acrolein(Eq.11a).Acrolein may be used instead of glycerol as starting material.

31. HO CH CH [O] + H2O CH2 + N H H2O N H N (16c) NH2 HO O H CH C CH CH2 +CH2=CH-CHO CH2 CH2 N H N H (16b) H2C H2C CH CH 1,2-addition (side reaction) + H2O CH CH N H N OH (an anil, or Schiff's base) The next step in the sequence is 1,4-addition of the amine to acrolein,(Eq.11b). Cyclization of the product formed in (Eq.11b) leads to a dihydroquinoline, and the quinoline result from oxidation by nitrobenzene pr other mild oxidizing agent included in the reaction mixture(Eq.11c).

32. C6H5 C6H5 O N N H NH2 CH CH CH CH2 CH2 CH + CH2 CH2 CH2 N H N H N H NH2 (16d) + NH Skraup Skraup NH2 (17) N CH3 CH3 Br Br 8-Methylquinoline N NH2 (18) 6-Bromoquinoline It is known that the quinoline does not arise from cyclization of the Schiff's base shown as a side reaction product in Eq.11d)because substitution of crotonaldehyde. SCOPE AND LIMITATIONS OF THE SKRAUP AYNTHESIS. The Skraup method, using glycerol, cannot give substitution in the hetero ring; however, varied substitution in the benz ring can be secured by use of a suitably substituted aniline. One of the few substituted anilines that has failed completely in the Skraup synthesis is p-acetylaniline. An prtho- or para-substituted aniline give a single quinoline in the Skraup synthesis:

33. Br and N N N Br (19) Br Br N Br CH3 (20) (21) CH3 Skraup Skraup +2CH3-CHO heat HCl +2H2O +2[H] Or ZnCl2 CH3 NH2 NH2 NH2 On the other hand, if substitution in the difficulty accessible 7-position is sought, by use of a m-substituted aniline, a mixture, a mixture results (Eq.19). The possibility for closure in two directions naturally lowers the yield of the 7-isomer; however, the two isomers formed in a reaction such as Eq.19 can often be separated, especially since many of the quinoline derivatives are solids. On account of the difficulty of securing 7-subtituted quinoline, such reactions as in Eq.19 are often employed for lack of a better approach. Hindrance to closure ortho to a substituent favors formation of the desired 7-isomer. Disubstituted anilines of appropriate structure may by cyclized to yield only one product, as in Eq.20. A symmetrically substituted aniline, such as 3,5-dimethylaniline, will also give only one product. The Dobner-Miller synthesis. The yields in the Dobner-miller synthesis are usually inferior to those secures in the Skraup syntheses; however, the staring materials are often rather cheep, and the Dobner-Miller method permits substitution in either or both ring . It is probably the most versatile of all quinoline syntheses, but the relatively poor yields limit it in practice to amines and carbonyl compounds which are cheaply available. The over-all reaction in a simple Dobner-Miller synthesis is shown in Eq.21.

34. O O O CH3-CH=CH-C CH3-CH-CH2-C +2H2O 2CH3 C H H H OH (21a) + + CH3 CH N CH3 (21b) N N CH3 CH3 C4H9 C2H5 H H N N H H CH3 N CH CH 2 + 2 CH N N CH3 + (21c) H+ H+ heat heat Since no oxidizing agent is included in Eq.21, the hydrogen is indicated as reducing power that must be balanced by some oxidizing agent .The nature of the oxidizing agent is discussed in the following paragraph. The mechanism of the Dobner-Miller synthesis has much in common with that of the Skraup reaction. The first step is an acid-catalyzed aldol condensation, which leads to the unsaturated aldehyde(Eq.21a). The α,β-unsaturated aldehyde then proceeds to add 1,4- to the aniline just as shown in Eq.16b. and this product cyclizes as shown in Eq.16c or 16d. This sequence leads to the 1,2-dihydroquinoline, which is oxidized to yield the quinoline derivative. The identity of oxidizing agent has been rather well established as the Schiff's base shown as a side reaction product in Eq.16b and the similar Schiff's base from the starting aldehyde. In the preparation of quinaldine as in Eq.21. there have been isolated both ethylaniline (formed in Eq.21b)and n-butylaniline(Eq.21c).

35. CH3 Dobner- +CH3-CH2-CHO (22) Miller C2H5 2-Ethyl-3-methylquinoline H C O C-CH3 N NH2 CH-CH2-CH3 It may be noted, by examination of the equations involved in synthesis of quinaldine, that 3 moles of acetaldehyde and either moles (via Eq.21c) or 2 moles (via Eq.21b) of aniline are required to yield a mole of quinaldine. These ratios, coupled with linear polymerization of the aldehydes involved in the synthesis, leds to a relatively poor conversion factor in the Dobner-Miller process. SCOPE AND LIMITATIONS OF THE DOBNER-MILLER SYNTHESIS. Substitution in the benz ring is subject to considerations essentially identical to those elaborated in connection with the Skraup synthesis. Nearly any substituted aniline will give some yield, but certain of them will give two isomeric products. Substitution in the hetero ring is subject to considerable variation. (a)Most aliphatic aldehydes are satisfactory, and the commercially available normal aldehydes are practical for use. The type of substitution obtained with a higher aldehyde is shown in Eq.22. The quinoline produced may be visualized by considering the initial aldol condensation product, as it fits into the quinoline: (b)Two different aldehydes may often be used to give a practical amount of one quinoline resulting from a cross aldol condensation. Of course the yield is lowered still more by such a procedure, but the desired quinoline is separable in many instances. The predominant quinoline containing both aldehydes is determined by the aldol condensation that proceeds the fastest. This may be predicted from the fact that the reactivity of the carbonyl group decreases significantly with increase in molecular weight, up to four carbons in the alkyl group. Thus the favored aldol condensation will involve the carbonyl of the lower molecular weight aldehyde. For acetaldehyde and propionaldehyde, the favored cross aldol product would be

36. CH3-CH=C-CHO CH3 CH3 +CH3-CHO+C2H5-CHO (23) NH2 NH2 CH3 D-M D-M CHO + CH3-CHO + (24) 2-Phenylquinoline N N Quinoline formation from this aldehyde is shown in Eq.23. The other quinoline formed in about equal amount would be quinaldine, resulting from the aldol condensation of acetaldehyde with itself. The other two possible would be formed in considerably lesser amounts. In planning syntheses of this type, it is helpgul to remember that the carbonyl carbon of the lower molecular weight aldehyde becomes carbon-2 in the desired quinoline, while the α-carbon of the higher molecular weight aldehyde becomes carbon-3 in the quinoline. (c) If one of two different aldehydes is aromatic, yields are improved considerably, for only two aldol condensations can result, and the carbonyl of the aromatic aldehyde is the more reactive. Such a synthesis is shown in Eq.24.

37. CO2H (25) • + CH3-C-CO2H • O + Pyruvic acid 2-Phenl-4-quinoline-carboxylic acid NH2 D-M CHO N The by-product would be quinaldine, easily separable by distillation on account of its lower molecular weight. (d) Use of pyruvic acid with an aldehyde dives a rather favorable synthesis, for the carbonyl group in an aldehyde is much more reactive than that in a ketone, and the quinoline of the cross reaction is easily separated because it is an acid. The yield is especially good if the aldehyde is aromatic, as in Eq.25. 2-Phenyl-4-quinolinecarboxylic acid, Known as cinchophen, has been used as a drug for the treatment of gout. Various othe combinations can be successfully used to prepare quinolines by the Dobner-Miller synthesis; but the examples which have been discussed should be sufficient to indicate the considerable scope of this method of synthesis. Finally, it may be emphasized again that only relatively cheap staring materials are ordinarily used.

38. الخاتمة قصيدة إهداء من صديقات الكيمياء للدكتورة ناريمان كافكِ فحراً يا معلمة الكيمياء يا معلمة الأجيال الرموز الكيميائية يا شعاع زاح ظلام الجاهلية يا نور ساطعة في سماء الأبدية يا فخر مكة في المجالات العلية ياباني المجد بإصرار وعزيمة يا ناصرة السنة بين الأقلية أصبحنا بفضلك ِنوازن المعادلات ونطبق عملها على جميع المركبات أكانت حامضة او قاعدية أو تشآكلات ومانخاف من النتائج والتفاعلات . فكافكِ فخرا يا معلمة الكيمياء الله يهديكم السداد ويجعلكم للإسلام أوتاد ونرتقي بعلمكم البلاد وتكونون بظلالكم خير عماد يا الله يارب العماد أجعل معلمتنا نصرة للبلاد. شعاع الأمل