1200 Chapter 25 eterocycles 7. Reactions of Quinoline and Isoquinoline (ection 25-7) Electrophilic substitution ucleophilic substitution Important Concepts 1. The heterocycloalkanes can be named using cycloalkane nomenclature. The prefix aza- for nitrogen, oxa- for oxygen, thia- for sulfur, and so forth, indicates the heteroatom. ther systematic and common names abound in the literature, particularly for the aromatic heterocycles. 2. The strained three- and four-membered heterocycloalkanes undergo ring opening with nucleophiles easily. 3. The 1-hetero-2,4-cyclopentadienes are aromatic and have an arrangement of six p electrons, similar to that in the cyclopentadienyl anion. The heteroatom is sp 2 hybridized, the p orbital contributing two electrons to the p system. s a consequence, the diene unit is electron rich and reactive in electrophilic aromatic substitutions. 4. Replacement of one (or more) of the C units in benzene by an sp 2 -hybridized nitrogen gives rise to pyridine (and other azabenzenes). The p orbital on the heteroatom contributes one electron to the p system; the lone electron pair is located in an sp 2 hybrid atomic orbital in the molecular plane. zabenzenes are electron poor, because the electronegative nitrogen withdraws electron density from the ring by induction and by resonance. Electrophilic aromatic substitution of azabenzenes is sluggish. Conversely, nucleophilic aromatic substitution occurs readily; this is shown by the Chichibabin reaction, substitutions by organometallic reagents next to the nitrogen, and the displacement of halide ion from halopyridines by nucleophiles. 5. The azanaphthalenes (benzopyridines) quinoline and isoquinoline contain an electron-poor pyridine ring, susceptible to nucleophilic attack, and an electron-rich benzene ring that enters into electrophilic aromatic substitution reactions, usually at the positions closest to the heterocyclic unit. 30. ame or draw the following compounds. cis-2,3-diphenyloxacyclopropane; 3-azacyclobutanone; 1,3-oxathiacyclopentane; (d) 2-butanoyl-1,3-dithiacyclohexane; C (e) C (f) (g) (h) 31. Identify by name (either IUPC or common) as many of the heterocyclic rings contained in the structures shown in Table 25-1 as you can. 32. Give the expected product of each of the following reaction sequences. ) [ 1. Lil 4, ( C 2 ) 2 2., 2 G ac 2, C 2, C 2 3 C Dilute Cl, 2
&C Chapter 25 1201 33. The penicillins are a class of antibiotics containing two heterocyclic rings that interfere with the construction of cell walls by bacteria (Chemical ighlight 20-2). The interference results from reaction of the penicillin with an amino group of a protein that closes gaps that develop during construction of the cell wall. The insides of the cell leak out, and the organism dies. uggest a reasonable product for the reactions of penicillin G with the amino group of a protein (protein 2 ). (int: First identify the most reactive electrophilic site in penicillin.) C 6 5 C 2 C &C Penicillin G &C &C C 2 Protein 2 a penicilloyl protein derivative Penicillin-resistant bacteria secrete an enzyme (penicillinase) that catalyzes hydrolysis of the antibiotic faster than the antibiotic can attack the cell-wall proteins. Propose a structure for the product of this hydrolysis and suggest a reason why hydrolysis destroys the antibiotic properties of penicillin. 2 penicillinase Penicillin G uuuuuuy penicilloic acid (ydrolysis product; no antibiotic activity) 34. Propose reasonable mechanisms for the following transformations. 1. ncl 4 (a Lewis acid), C 2 Cl 2 2., 2 C 2 1. C 2 C 2 C 2 Li, F 3 (C 2 ) 2, TF 2., 2 C 6 5 C 6 5 Mgr 2, CC 3 C C (int: ee ection 15-13.) ( ( ( 3 C ( r 35. Rank the following compounds in increasing order of basicity: water, hydroxide, pyridine, pyrrole, ammonia. 36. Each of the heterocyclopentadienes in the margin contains more than one heteroatom. For each one, identify the orbitals occupied by all lone electron pairs on the heteroatoms and determine whether the molecule qualifies as aromatic. re any of these heterocycles a stronger base than pyrrole? 37. Give the product of each of the following reactions. 2 P 2 5, 38. 1-etero-2,4-cyclopentadienes can be prepared by condensation of an a-dicarbonyl compound and certain heteroatom-containing diesters. Propose a mechanism for the following pyrrole synthesis. C 6 5 CCC 6 5 CC 2 C 2 C P 3 C C a,, 5 C 6 C C 6 5 ow would you use a similar approach to synthesize 2,5-thiophenedicarboxylic acid? C Pyrazole Thiazole Imidazole Isoxazole
1202 Chapter 25 eterocycles 39. Give the expected major product(s) of each of the following reactions. Explain how you chose the position of substitution in each case. C Cl 2 3, 2 4 C Cl C, lcl 3 (d) r r 2 (e) 2 Cl, a, 2 (int: basic conditions. First deprotonate nitrogen.) 40. Give the products expected of each of the following reactions. 3 C G D Fuming 2 4, 270 C, pressure K,, r (d) 1. C 6 5 CCl, ncl 4 2. Raney i, (e) ( ) 3 CLi, TF, 41. Propose a synthesis of each of the following substituted heterocycles, using synthetic sequences presented in this chapter. 3 C 3 C 3 C 5 C 6 C 6 5 (d) 3 C 42. The structures of caffeine, the principal stimulant in coffee, and theobromine, its close relative in chocolate, are given in ection 25-8. Propose an efficient synthetic method to convert theobromine into caffeine. Cl Cl Cl Cyanuric chloride 3 2 43. Melamine, or 2,4,6-triaminotriazine, is a toxic heterocyclic compound that has been implicated in the illnesses and deaths of both house pets and humans who ingested melamine-contaminated food. s its formula shows, melamine has a very high nitrogen content. Proteins (Chapter 26) are the main natural source of nitrogen in foods, and nitrogen analysis is commonly used to determine protein content in foods. The illegal addition of melamine to packaged foods increases their nitrogen content and makes them appear richer in protein; in reality, they are deadly. typical protein in food contains about 15% nitrogen. What is the % in melamine? Does this result explain the motivation behind the melamine doping of packaged foods? Melamine is synthesized by addition of ammonia to cyanuric chloride (2,4,6-trichlorotriazine, see equation in the margin). What kind of reaction is this? Formulate a mechanism and explain why cyanuric chloride displays this type of chemistry. 44. Chelidonic acid, a 4-oxacyclohexanone (common name, g-pyrone), is found in a number of plants and is synthesized from acetone and diethyl ethanedioate. Formulate a mechanism for this transformation. 2 Melamine 2 C 2 C 2 CCC 2 1. ac 2, C 2 2. Cl, C C Chelidonic acid
Chapter 25 1203 45. Porphyrins are polyheterocyclic constituents of hemoglobin and myoglobin, the molecules that transport molecular oxygen in living systems (ection 26-8), of the cytochromes, which also play central roles in biological redox processes (ection 22-9), and of chlorophyll (Chemical ighlight 24-2), which mediates photosynthesis in all green plants. Porphyrins are the products of a remarkable reaction between pyrrole and an aldehyde in the presence of acid: R R D P C G R R R porphyrin This reaction is complicated and has many steps. The simpler condensation of one molecule of benzaldehyde and two of pyrrole to give the product shown below, a dipyrrylmethane, is illustrative of the first stage in porphyrin formation. Propose a step-by-step mechanism for this process. 2 G C P dipyrrylmethane 46. Isoxazoles (Problem 36) have taken on increased significance as synthetic targets, because they are found in the structures of some recently discovered naturally occurring molecules that show promise as antibiotics (see Chemical ighlight 20-2). Isoxazoles may be prepared by reaction of alkynes with compounds containing the unusual nitrile oxide functional group: RCqCR RCq uggest a mechanism for this process. š itrile oxide R š š R R Isoxazole 47. Reserpine is a naturally occurring indole alkaloid with powerful tranquilizing and antihypertensive activity. Many such compounds possess a characteristic structural feature: one nitrogen atom at a ring fusion separated by two carbons from another nitrogen atom. ) ) C C ) Reserpine series of compounds with modified versions of this structural feature have been synthesized and also shown to have antihypertensive activity, as well as antifibrillatory properties. ne such synthesis is shown here. ame or draw the missing reagents and products through.
1204 Chapter 25 eterocycles C 2 C 2 f i 2 CC 2, C 2 C 2 C 2 C 8 14 2 Lil 4 C 8 16 2 48. tarting with benzenamine (aniline) and pyridine, propose a synthesis for the antimicrobial sulfa drug sulfapyridine. Indole enzimidazole ulfapyridine 49. Derivatives of benzimidazole possess biological activity somewhat like that of indoles and purines (of which adenine, ection 25-1, is an example). enzimidazoles are commonly prepared from benzene-1,2-diamine. Devise a short synthesis of 2-methylbenzimidazole from benzene-1,2-diamine. 2 Purine 2 2 enzene-1,2-diamine? 2-Methylbenzimidazole 50. The Darzens condensation is one of the older methods (1904) for the synthesis of three-membered heterocycles. It is most commonly the reaction of a 2-halo ester with a carbonyl derivative in the presence of base. The following examples of the Darzens condensation show how it is applied to the synthesis of oxacyclopropane and azacyclopropane rings. uggest a reasonable mechanism for each of these reactions. Cl KC( ) 3, ( ) 3 C f i C 6 5 C C 6 5 CCC 2 5 C 6 CCC 6 D 5 G CC 2 3 C 3 C r i r KC( ) 3, C 2 C 2 C 6 5 C 6 5 CPC 6 5 ClC 2 CC 2 C 6 5 CCCC 2 51. The compound shown in the margin, with the common name 1,3-dibromo-5,5-dimethylhydantoin, is useful as a source of electrophilic bromine (r 1 ) for addition reactions. Give a more systematic name for this heterocyclic compound. n even more remarkable heterocyclic compound (ii) is prepared by the following reaction sequence. Using the given information, deduce structures for compounds i and ii, and name the latter. f i 3 C G D CPC C 6 13 r 2 D G 3 C i 1,3-Dibromo-5,5-dimethylhydantoin, 98% 2 2 g C gr, C C 6 12 2 ii eterocycle ii is a yellow, crystalline, sweet-smelling compound that decomposes upon gentle heating into two molecules of acetone, one of which is formed directly in its n y p* excited state (ections 14-11 and 17-3). This electronically excited product is chemiluminescent. ii C C n * h 2 C eterocycles similar to compound ii are responsible for the chemiluminescence produced by a number of species [e.g., fireflies (see Chemical ighlight 9-1) and several deep-sea fish]; they also serve as the energy sources in commercial chemiluminescent products.
Chapter 25 1205 52. zacyclohexanes (piperidines) can be synthesized by reaction of ammonia with cross-conjugated dienones: ketones conjugated on both sides with double bonds. Propose a mechanism for the following synthesis of 2,2,6,6-tetramethylaza-4-cyclohexanone. 3 ( ) 2 CPCCCPC( ) 2 3 C 3 C 53. Quinolines (ection 25-7) are heterocycles that are widely used in medicinal chemistry because of the diversity of biological activity including anticancer utility that their derivatives display. short synthesis of 3-acyldihydroquinolines (which may be converted into 3-acylquinolines by mild oxidation) is shown below. Propose a mechanism for this process. (int: Review ection 18-10.) 2 ase catalyst 54. t which position(s) do you expect 3-acetylquinoline (margin) to undergo nitration in the presence of a mixture of sulfuric and fuming nitric acids? Will this reaction be faster or slower than nitration of quinoline itself? 55. Compound, C 8 8, exhibits 1 MR spectrum. Upon treatment with concentrated aqueous Cl, it is converted almost instantaneously into a compound that exhibits spectrum (p. 1206). What is compound, and what is the product of its treatment with aqueous acid? 3-cetylquinoline 1 MR 5 1 1 7.4 7.3 3.9 3.8 3.2 3.1 2.8 1 ( ) 4 i 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm (δ) δ
1206 Chapter 25 eterocycles 1 MR 5 7.4 7.3 4.9 4.8 3.8 3.7 3.6 1 1 1 2 ( ) 4 i 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm (δ) δ 56. eterocycle C, C 5 6, exhibits 1 MR spectrum C and is converted by 2 and Raney nickel into compound D, C 5 10, with spectrum D (p. 1207). Identify compounds C and D. (ote: The coupling constants of the compounds in this problem and the next one are rather small; they are therefore not nearly as useful in structure elucidation as those around a benzene ring.) 1 MR 3 7.4 7.3 6.3 6.2 6.1 6.0 2.4 2.3 1 1 1 ( ) 4 i C 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm ( δ)
Chapter 25 1207 1 MR 3 3.9 3.8 3.7 3.6 3.5 1.3 1.2 1.1 1.9 1.8 1.7 2 1 3 1 ( ) 4 i D 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm (δ) δ 57. The commercial synthesis of a useful heterocyclic derivative requires treatment of a mixture of aldopentoses (derived from corncobs, straw, etc.) with hot acid under dehydrating conditions. The product, E, has 1 MR spectrum E, shows a strong IR band at 1670 cm 21, and is formed in nearly quantitative yield. Identify compound E and formulate a mechanism for its formation. 1 MR 1 1 1 1 9.6 9.5 7.6 7.2 7.1 6.5 ( ) 4 i E 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm (δ) δ
1208 Chapter 25 eterocycles 1, D ldopentoses uuy C 5 4 2 E Compound E is a valuable synthetic starting material. The following sequence converts it into furethonium, which is useful in the treatment of glaucoma. What is the structure of furethonium? 1. 3, a 3 C 2. Excess I, ( C 2 ) 2 E uuuuuuuuuy furethonium 58. Treatment of a 3-acylindole with Lil 4 in ( C 2 ) 2 reduces the carbonyl all the way to a C 2 group. Explain by a plausible mechanism. (int: Direct 2 displacement of alkoxide by hydride is not plausible.) CR Excess Lil 4, ( C 2 ) 2, C 2 R (Compare CR C Lil 4 R) 1. 3, C 2 Cl 2 2. ( ) 2 3. 3 59. The sequence in the margin is a rapid synthesis of one of the heterocycles in this chapter. Draw the structure of the product, which has 1 MR spectrum F. 1 MR 1 1 1 1 3 9.2 8.5 8.4 7.9 7.8 7.7 7.6 7.5 ( ) 4 i F 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 300-Mz 1 MR spectrum ppm (δ) δ Team Problem 60. This problem introduces two literature syntheses of indole derivatives, and you are asked to come up with plausible mechanisms for them. Divide your team in two, each group concentrating on one of the methods.
Chapter 25 1209 Fischer Indole ynthesis of 2-Phenylindole 2 3 C 2 3 C C 4 i 2-Phenylindole In this procedure, a hydrazone of an enolizable aldehyde or ketone is heated in strong acid, causing ring closure with simultaneous expulsion of ammonia to furnish the indole nucleus. [ints: The mechanism of the reaction proceeds in three stages: (1) an imine enamine tautomerization (recall ection 17-9); (2) an electrocyclic reaction (a diaza-cope rearrangement; recall ection 22-7); (3) another imine enamine (in this case, benzenamine) tautomerization; (4) ring closure to the heterocycle; and (5) elimination of 3.] Reissert Indole ynthesis of Ethyl Indole-2-carboxylate 2 2-Methylnitrobenzene (o-itrotoluene) K C 2 2 2-oxopropanoate ester ( pyruvate ester) 2,Pt i C 2 C 2 Ethyl indole-2-carboxylate In this sequence, a 2-methylnitrobenzene (o-nitrotoluene) is first converted into an ethyl 2-oxopropanoate (pyruvate, Chemical ighlight 23-2) ester, which, on reduction, is transformed into the target indole. [ints: (1) The nitro group is essential for the success of the first step. Why? Does this step remind you of another reaction? Which one? (2) Which functional group is the target of the reduction step (recall ection 16-5)? (3) The ring closure to the heterocycle requires a condensation reaction.] Preprofessional 61. The proton decoupled 13 C MR spectrum of pyridine will display how many peaks? ne; two; three; (d) four; (e) five. 62. Pyrrole is a much weaker base than azacyclopentane (pyrrolidine) for which of the following reasons? The nitrogen in pyrrole is more electropositive than that in pyrrolidine; pyrrole is a Lewis acid; pyrrole has four electrons; (d) pyrrolidine can give up the proton on the nitrogen atom more readily than can pyrrole; (e) pyrrole is aromatic. 63. Which of the following compounds would you expect to be the major organic product of the two-step sequence shown here? š Pyrrole š zacyclopentane (Pyrrolidine) TF C 2 I ( C) 2 Li
1210 Chapter 25 eterocycles C 2 E C 2 C 2 (d) C 2 64. This reaction yields one main organic product. Which of the following compounds is it? 2-Phenylthiophene ncl 4, CCl C 6 5 C 3 CC C 6 5 3 C C 6 5 (d)