QUINOLINE, ISOQUINOLINE AND INDOLE

THIS PRESENTATION CONTAIN INTRODUCTION, STRUCTURE, PHYSICAL AND CHEMICAL PROPERTIES, SYNTHESIS AND APPLICATION OF FUSED HETEROCYCLIC COMPOUND CONTAINING ONE HETERO ATOM - QUINOLINE, ISOQUINOLINE AND INDOLE

1. FUSED HETEROCYCLES WITH ONE HETEROATOMS BY – VISHAL SINGH SOLANKI A.P. AT IDEAL INSTITUTE, POSHERI, WADA, PALGHAR, M.H. EMAIL – [email protected]

2. QUINOLINE ISOQUINOLINE INDOLE CONTENT

3. QUINOLINE

4. Quinoline  is a heterocyclic aromatic organic compound with the chemical formula C 9 H 7 N. It is a colourless hygroscopic liquid with a strong odour. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline itself has few applications, but many of its derivatives are useful in diverse applications. A prominent example is quinine, an alkaloid found in plants. Over 200 biologically active quinoline and quinazoline alkaloids are identified. 4-Hydroxy-2-alkylquinolines (HAQs) are involved in antibiotic resistance. INTRODUCTION

5. Quinoline , any of a class of  organic compounds  of the aromatic heterocyclic series characterized by a double-ring structure composed of a  benzene  and a  pyridine  ring fused at two  adjacent  carbon atoms. The benzene ring contains six  carbon  atoms, while the pyridine ring contains five carbon atoms and a  nitrogen  atom. The simplest member of the quinoline family is quinoline itself, a  compound  with molecular structure C 9 H 7 N. CONTI…

6. STRUCTURE

7. All ring atoms in Quinoline are SP2 hybridize. The nitrogen lone pair electrons reside in an SP2 orbital and not involved in the formation of the delocalized π molecular orbital. It shows aromatic properties because its π orbital contains ten electrons & satisfied the Huckel’s rule (n = 2 is 4n+2). RESONANCE

8. PHYSIAL PROPERTIES Chemical formula C 9 H 7 N Molar mass 129.16 g/mol Appearance Colorless oily liquid Density 1.093 g/mL Melting point −15 °C (5 °F; 258 K) Boiling point 237 °C (459 °F; 510 K) , 760 mm Hg; 108–110 °C (226–230 °F), 11 mm Hg Solubility in water Slightly soluble Solubility Soluble in alcohol, ether, and carbon disulfide Other IUPAC name 1-Benzopyridine, Benzo[ b ]pyridine

9. 1. Combes quinoline synthesis  using anilines and β- diketones. 2. Conrad- Limpach synthesis  using anilines and β- keto esters. 3. Doebner reaction  using anilines with an aldehyde and pyruvic acid to form quinoline- 4-carboxylic acids 4. Doebner -Miller reaction  using anilines and α,β- unsaturated carbonyl compounds. 5. Gould-Jacobs reaction  starting from an aniline and ethyl ethoxy methylene malonate 6. Skraup synthesis  using ferrous sulfate , glycerol, aniline, nitrobenzene, and sulfuric acid. 7. Friedländer synthesis  using 2-aminobenzaldehyde and acetaldehyde SYNTHESIS

10. CONTI…

11.  In the archetypal Skraup reaction, aniline is heated with sulfuric acid, glycerol, and an oxidizing agent such as nitrobenzene to yield quinoline. SKRAUP SYNTHESIS

12. MECHANISM

13. The  Doebner –Miller reaction   is the organic reaction of an aniline with α,β-unsaturated carbonyl compounds to form quinolines. The reaction is catalyzed by Lewis acids such as tin tetrachloride and scandium(III) triflate and  Brønsted acids such as  p - toluenesulfonic acid, perchloric acid, amberlite and iodine. DOEBNER–MILLER SYNTHESIS

14. CONRAD–LIMPACH SYNTHESIS The  Conrad– Limpach synthesis   is the condensation of anilines ( 1 ) with β- ketoesters ( 2 ) to form 4-hydroxyquinolines ( 4 ) via a Schiff base ( 3 ). The overall reaction type is a combination of both an addition reaction as well as a rearrangement reaction.

15. MECHANISM

16. The  Friedländer synthesis   is a chemical reaction of 2-amino benzaldehydes with ketones to form quinoline derivatives. This reaction has been catalysed by trifluoroacetic acid, toluene sulfonic acid, iodine, and Lewis acids. FRIEDLÄNDER SYNTHESIS

17. In the first mechanism 2-amino substituted carbonyl compound  1  and carbonyl compound  2  react in a rate-limiting step to aldol adduct  3 . This intermediate loses water in an elimination reaction to unsaturated carbonyl compound  4  and then loses water again in imine formation to quinoline  7 . In the second mechanism the first step is Schiff base formation to  5  followed by Aldol reaction to  6  and elimination to  7 . MECHANISM

18. MECHANISM

19. 1. ELCTROPHILIC SUBSTITUTION REACTION 2. NUCLEOPHILIC SUBSTITUTION REACTION 3. OXIDATION 4. REDUCTION 5. HETEROATOM REACTION CHEMICAL REACTION

20. Electrophilic substitution reactions occur on the ring C-atoms , mainly on those of the more activated benzene moiety. Electrophilic substitution reactions occur in positions 5 and 8 of quinoline. Nucleophilic substitution proceeds faster in quinoline than in pyridine. Nucleophilic substitution of quinoline occurs in the electron deficient pyridine ring, as a rule in the position 2 or 4 . Treatment of quinoline with nitrating mixture results in 5and 8-nitroquinolines. Sulphonation of quinoline produces different products depending on the reaction temperature. At 220°C quinoline8sulphonic acid is formed predominantly; At 300°C, quinoline6sulphonic acid is the sole product. When heating to 300°C quinoline8sulphonic acid is converted into quinoline6sulphonic, which is the thermodynamically favoured Sulphonation product. ELECTROPHILIC AND NUCLEOPHILIC SUBSTITUTION REACTIONS

21. The pyridine ring is hydrogenated prior to the benzene ring of quinoline. The product of reduction depends much upon the reaction conditions. The alkaline permanganate solution causes oxidative cleavage of the benzene ring in quinoline to give quinolinic acid (pyridine 2,3-dicarboxylic acid). The reaction of quinoline with per-oxy carboxylic acids leads to its N-oxide. Heteroatom reactions : The nitrogen in Quinoline, which undergoes protonation, alkylation, acylation, etc. Quinoline is a weaker base than pyridine. OXIDATION AND REDUCTION REACTIONS.

22. CONTI…

23. APPLICATION

24. ANY QUESTION ?

25. ISOQUINOLINE

26. Iso-quinoline   is a  heterocyclic   aromatic   organic compound . It is a  structural isomer  of  quinoline . Iso-quinoline and quinoline are  benzo-pyridines , which are composed of a  benzene  ring fused to a  pyridine  ring. In a broader sense, the term iso-quinoline is used to make reference to iso-quinoline  derivatives . 1-Benzylisoquinoline  is the structural backbone in naturally occurring  alkaloids  including  papaverine . The iso-quinoline ring in these natural compound derives from the aromatic  amino acid   tyrosine . INTRODUCTION

27. Iso-quinoline is a colourless hygroscopic liquid at room temperature. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon di- sulfide , and other common organic solvents. It is also soluble in dilute acids as the protonated derivative. Iso-quinoline is a crystalline substance with a quinoline like odour; Its melting point is 24.6°C. CONTI…

28. STRUCTURE OF ISOQUINOLINE

29. Chemical formula C 9 H 7 N Molar mass 129.162 g·mol −1 Appearance Colourless oily liquid; hygroscopic platelets when solid Density 1.099 g/cm 3 Melting point 24–26 °C Boiling point 242 °C (468 °F; 515 K) Acidity  ( p K a ) pK BH +  = 5.14 Other name Benzo[ c ]pyridine, 2-benzazine PHYSICAL PROPERTIES

30. 1. Pomeranz–Fritsch reaction 2. Bischler – Napieralski reaction SYNTHESIS

31. The  Pomeranz–Fritsch reaction   provides an efficient method for the preparation of iso-quinoline. This reaction uses a  benzaldehyde  and amino- acetoaldehyde diethyl acetal, which in an  acid   medium  react to form iso-quinoline.  Alternatively,  benzylamine  and a  glyoxal   acetal  can be used, to produce the same result using the Schlittler -Müller modification. 1. POMERANZ–FRITSCH REACTION

32. First the benzalamino -acetal  1  is built by the  condensation  of benzaldehyde and a 2,2-dialkoxyethylamine. After the condensation a  hydrogen -atom is added to one of the alkoxy groups. Subsequently, an alcohol is removed. Next, the compound  2  is built. After that a second hydrogen-atom is added to the compound. In the last step a second alcohol is removed and the bicyclic system becomes  aromatic . MECHANISM

33. The  Bischler – Napieralski reaction  is an intramolecular  electrophilic aromatic substitution  reaction that allows for the  cyclization  of β- aryl-ethyl amides or β- aryl-ethyl carbamates. The reaction is most notably used in the synthesis of dihydro iso-quinolines, which can be subsequently oxidized to iso-quinolines. 2. BISCHLER–NAPIERALSKI REACTION

34. Mechanism I involves a dichloro-phosphoryl imine-ester intermediate, while Mechanism II involves a nitrilium ion intermediate (both shown in brackets). This mechanistic variance stems from the ambiguity over the timing for the  elimination  of the  carbonyl  oxygen in the starting  amide . In Mechanism I, the elimination occurs with  imine  formation  after  cyclization; while in Mechanism II, the elimination yields the nitrilium intermediate  prior  to cyclization. Currently, it is believed that reaction conditions affect the prevalence of one mechanism over the other (see  reaction conditions ). In certain literature, Mechanism II is augmented with the formation of an  imidoyl chloride  intermediate produced by the  substitution  of chloride for the  Lewis acid  group just prior to the nitrilium ion. Because the dihydro iso-quinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated product. MECHANISM

35. MECHANISM

36. MECHANISM

37. The reactions of iso-quinoline are closely parallel to those of quinoline. Iso-quinoline reacts with strong mineral acids to form salts. Iso-quinoline is a stronger base than quinoline. 1. Alkylation and acylation occur on nitrogen 2. Reactions of electrophilic and nucleophilic substitution 3. Reduction reactions 4. Oxidation reactions CHEMICAL REACTION

38. 1. Alkylation and acylation occur on nitrogen

39. Similarly to quinoline electrophilic substitution reactions occur mainly in the 5 or 8 position of iso-quinoline 2. Reactions of electrophilic and nucleophilic substitution

40. Nucleophilic reactions take place on the heterocyclic ring, prefer ably in the 1-position . CONTI…

41. Reduction of iso-quinoline is more complicated than those for quinoline. 3. Reduction reactions

42. Oxidation of iso-quinoline with alkaline permanganate solution yields a mixture of phthalic acid and pyridine3,4-dicarboxylic acid . 4. Oxidation reactions

43. 1. Anasthetics ,   dimethisoquin  is one example. 2. antihypertension agents, such as  quinapril  and  debrisoquine  (all derived from 1,2,3,4-tetrahydroisoquinoline). 3. antiretroviral agents, such as  saquinavir  with an iso-quinolyl  functional group ,  4. vasodilators, a well-known example,  papaverine , shown below. APPLICATION

44. Quinoline & Iso-quinoline both have i . Have basic, pyridine like nitrogen atoms, which undergo electrophilic substitutions. ii. Are less reactive toward electrophilic substitution than benzene because of the nitrogen atom that withdraws electrons from the ring. iii. Electrophilic substitution occurs on the benzene ring rather than on the nitrogen-containing pyridine ring and a mixture of substitution products is obtained. In quinoline and iso-quinoline the N-atom withdrawn electron in pyridine ring thus few are available for Electrophilic Aromatic Substitution (EAS), therefore E + prefers to go to benzene . REACTIVITY OF QUINOLINE & ISO-QUINOLINE

45. INDOLE

46. INTRODUCTION Indole is an aromatic heterocyclic organic compound with formula C8H7N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environment and can be produced by a variety of bacteria. Indole is a solid at room temperature. It occurs naturally in human  feces  and has an intense fecal  odour. At very low concentrations, however, it has a flowery smell, and is a constituent of many perfumes. It also occurs in coal tar.

47. STRUCTURE

48. BASICITY Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that the lone pair of electrons on the nitrogen atom is not available for protonation. Strong acids such as hydrochloric acid can, however, protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the portion of the molecule located outside of the benzene ring. The protonated form has a  pKa  of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

49. PHYSICAL PROPERTIES Chemical formula C8H7N Molar mass 117.151 g·mol−1 Appearance White solid Odour Feces or jasmine like Density 1.1747 g/cm3, solid Melting point 52 to 54 °C (126 to 129 °F; 325 to 327 K) Boiling point 253 to 254 °C (487 to 489 °F; 526 to 527 K) Solubility in water 0.19 g/100 ml (20 °C) Soluble in hot water Acidity ( pKa ) 16.2 (21.0 in DMSO) Basicity ( pKb ) 17.6

50. SYNTHESIS 1. Fischer indole synthesis 2. Madelung synthesis 

51. 1. FISCHER INDOLE SYNTHESIS The Fischer indole synthesis is a chemical reaction that produces the aromatic heterocycle indole from a (substituted) phenyl hydrazine and an aldehyde or ketone under acidic conditions. The choice of acid catalyst is very important. Brønsted acids such as  HCl ,  H2SO4 ,  polyphosphoric acid  and p-toluene sulfonic acid have been used successfully.

52. MECHANISM The reaction of a (substituted) phenyl hydrazine with a carbonyl (aldehyde or ketone) initially forms a phenylhydrazone which isomerizes to the respective enamine (or ' ene -hydrazine’). After   protonation, a cyclic [3,3]-sigma tropic rearrangement occurs producing an imine. The resulting imine forms a cyclic amino-acetal (or  aminal ), which under acid catalysis eliminates NH3, resulting in the energetically favourable aromatic indole. Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenyl hydrazine is incorporated into the resulting indole.

53. CONTI…

54. 2. MADELUNG SYNTHESIS  The Madelung synthesis is a chemical reaction that produces (substituted or unsubstituted) indoles by the intramolecular cyclization of N-phenyl amides using strong base at high temperature.

55. MECHANISM The reaction begins with the extraction of a hydrogen from the nitrogen of the amide substituent and the extraction of a benzylic hydrogen from the substituent ortho to the amide substituent by a strong base. Next, the carbanion resulting from the benzylic hydrogen extraction performs a nucleophilic attack on the electrophilic carbonyl carbon of the amide group. When this occurs, the pi-bond of the amide is converted into a lone pair, creating a negatively charged oxygen. After these initial steps, strong base is no longer required and hydrolysis must occur. The negatively charged nitrogen is protonated to regain its neutral charge, and the oxygen is protonated twice to harbor a positive charge in order to become a good leaving group. A lone pair from the nitrogen forms a pi-bond to expel the positively charged leaving group, and also causes the nitrogen to harbor a positive charge. The final step of the reaction is an elimination reaction (specifically an E2 reaction), which involves the extraction of the other hydrogen that was once benzylic, before the bicyclic compound was formed, whose electrons are converted into a new pi-bond in the ring system. This allows the pi-bond formed by nitrogen in the preceding step to be converted back into a lone pair on nitrogen to restore nitrogen's neutral charge.

56. MECHANISM

57. CHEMICAL REACTION Electrophilic addition to N Electrophilic substitution Oxidation Reduction Mannich reaction

58. 1. ELECTROPHILIC ADDITION TO N

59. 2. ELECTROPHILIC SUBSTITUTION The most reactive position on indole for electrophilic aromatic substitution is C3, which is 10000000000000 times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan.  Vilsmeier –Haack formylation of indole will take place at room temperature exclusively at C3. Gramine, a useful synthetic intermediate, is produced via a  Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan.

60. CONTI…

61. 3. Oxidation of indole Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromo succinimide will selectively oxidize indole 1 to oxindole (4 and 5). The nitrogen containing ring of many substituted indoles can be opened by the action of per-oxy acid and ozone . PhC 2 O OH O 3 , H 2 O N H R R ' C O R N H C O R ' PhCO 2 OH O 3 , H 2 O N H C O H N H C O H

62. 4. REDUCTION

63. 5. MANNICH REACTION Indole undergo Mannich reaction with formaldehyde and dimethyl amine to give 3 – dimethylamine indole. -

64. MECHANISM OF MANICH REACTION

65. APPLICATION

66.   https://www.researchgate.net/publication/325080072_UNIT_-V_Heterocyclic_Chemistry_Quinoline_Isoquinoline_and_Indole https://en.wikipedia.org/wiki/Quinoline Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge:  The Royal Society of Chemistry . 2014. pp. 4, 211.  doi : 10.1039/9781849733069-FP001 .  ISBN   978-0-85404-182-4 . The name ‘quinoline’ is a retained name that is preferred to the alternative systematic fusion names ‘1-benzopyridine’ or ‘benzo[b]pyridine’. Brown, H.C., et al., in Baude , E.A. and Nachod , F.C.,  Determination of Organic Structures by Physical Methods , Academic Press, New York, 1955. Shang, XF; Morris- Natschke , SL; Liu, YQ; Guo, X; Xu, XS; Goto , M; Li, JC; Yang, GZ; Lee, KH (May 2018).  "Biologically active quinoline and quinazoline alkaloids part I." Medicinal Research Reviews.  38  (3): 775-828. doi : 10.1002/med.21466 .  PMC   6421866 .  PMID   28902434 .   Shang, Xiao-Fei; Morris- Natschke , Susan L.; Yang, Guan-Zhou; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto , Masuo ; Li, Jun-Cai; Zhang, Ji-Yu; Lee, Kuo-Hsiung (September 2018).  "Biologically active quinoline and quinazoline alkaloids part II" . Medicinal Research Reviews.  38  (5): 1614–1660.  doi : 10.1002/med.21492 .  PMC   6105521 .  PMID   29485730 .  F. F. Runge (1834)  " Ueber einige Produkte der Steinkohlendestillation "  (On some products of coal distillation),  Annalen der Physik und Chemie ,  31  (5) : 65–78 ; see especially p. 68: "3. Leukol oder Weissöl " (3. White oil [in Greek] or white oil [in German]). From p. 68: "Diese dritte Basis habe ich Leukol oder Weissöl genannt , weil sie keine farbigen Reactionen zeigt ."  (This third base I've named  leukol  or white oil because it shows no color reactions.)   Jump up to:   Gerd Collin; Hartmut Höke . "Quinoline and Isoquinoline ".  Ullmann's Encyclopedia of Industrial Chemistry Weinheim: Wiley-VCH.  doi : 10.1002/14356007.a22_465 . REFERENCE

67.  Gerhardt, Ch. (1842)  " Untersuchungen über die organischen Basen "  (Investigations of organic bases),  Annalen der Chemie und Pharmacie ,  42  : 310-313. See also: (Editor) (1842)  " Chinolein oder Chinoilin "  (Quinoline or quinoilin ),  Annalen der Chemie und Pharmacie ,  44  : 279-280.  Initially, Hoffmann thought that Runge's  Leukol  and Gerhardt's  Chinolein  were distinct. (See: Hoffmann, August Wilhelm (1843)  " Chemische Untersuchungen der organischen Basen im Steinkohlen-Theeröl "  (Chemical investigations of organic bases in coal tar oil),  Annalen der Chemie und Pharmacie ,  47  : 37-87 ; see especially pp. 76-78.) However, after further purification of his  Leukol  sample, Hoffmann determined that the two were indeed identical. (See: (Editor) (1845)  " Vorläufige Notiz über die Identität des Leukols und Chinolins "  (Preliminary notice of the identity of leukol and quinoline),  Annalen der Chemie und Pharmacie ,  53  : 427-428.)   O'Loughlin, Edward J.; Kehrmeyer , Staci R.; Sims, Gerald K. (1996). "Isolation, characterization, and substrate utilization of a quinoline-degrading bacterium". International Biodeterioration & Biodegradation.  38  (2): 107.  doi : 10.1016/S0964-8305(96)00032-7 .   GRIBBLE, Gordon W.; HEALD, Peter W. (1975). "Reactions of Sodium Borohydride in Acidic Media; III. Reduction and Alkylation of Quinoline and Isoquinoline with Carboxylic Acids". Synthesis.  1975  (10): 650–652.  doi : 10.1055/s-1975-23871 . ISSN0039-7881 .  Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C.  Chem. Commun. 2005 , 1390.   Reetz , M. T.; Li, X.  Chem. Commun .   2006 , 2159. "QUINOLINE (BENZOPYRIDINE)" . Chemicalland21.com. Retrieved 2012-06-14. Jump up to:   Chisholm, Hugh, ed. (1911).  "Quinoline"  .  Encyclopædia Britannica .  22  (11th ed.). Cambridge University Press. p. 759 . REFERENCE

68. 17.   Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge:  The Royal Society of Chemistry . 2014. p. 212.  doi : 10.1039/9781849733069-FP001 .  ISBN   978-0-85404-182-4 . 18. Jump up to: a   b  Brown, H.C., et al., in Baude , E.A. and Nachod , F.C.,  Determination of Organic Structures by Physical Methods , Academic Press, New York, 1955. 19. Gilchrist, T.L. (1997).  Heterocyclic Chemistry  (3rd ed.). Essex, UK: Addison Wesley Longman. 20 . Harris, J.; Pope, W.J. " iso Quinoline and the  iso Quinoline -Reds" Journal of the Chemical Society (1922) volume 121, pp. 1029–1033. 21 . Katritsky , A.R.; Pozharskii , A.F. (2000).  Handbook of Heterocyclic Chemistry  (2nd ed.). Oxford, UK: Elsevier. 22 . Katritsky , A.R.; Rees, C.W.; Scriven, E.F. (Eds.). (1996).  Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982–1995  (Vol. 5). Tarrytown, NY: Elsevier. 23. Nagatsu , T. " Isoquinoline neurotoxins in the brain and Parkinson's disease" Neuroscience Research (1997) volume 29, pp. 99–111. REFERENCE

69. REFERENCE 24. https://ars.els-cdn.com/content/image/1-s2.0-S092809871630207X-fx1_lrg.jpg 25. https://en.wikipedia.org/wiki/Indole 26. Houlihan, W. J., ed. (1972). Indoles Part One. New York: Wiley Interscience . [ ISBN missing ] 27. Sundberg, R. J. (1996). Indoles. San Diego: Academic Press.  ISBN   978-0-12-676945-6 . 28. Joule, J. A.; Mills, K. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science.  ISBN   978-0-632-05453-4 . 29. Joule, J. (2000). E. J., Thomas (ed.). Science of Synthesis.  10 . Stuttgart: Thieme . p. 361.  ISBN   978-3-13-112241-4 . 30. Schoenherr, H.; Leighton, J. L. (2012). "Direct and Highly Enantioselective Iso- Pictet -Spengler Reactions with α- Ketoamides: Access to Underexplored Indole Core Structures". Org. Lett.  14 : 2610.

70. THANK YOU