CHAPTER 25 Heterocycles: Heteroatoms in Cyclic Organic Compounds 25-1 Naming the Heterocycles kpl-forphosphoroug 分
1 CHAPTER 25 Heterocycles: Heteroatoms in Cyclic Organic Compounds Most physiologically active compounds owe their biological properties to the presence of heteroatoms, mainly in the form of heterocycles. 25-1 Naming the Heterocycles Saturated heterocycles will be treated as derivatives of the related carbocycles. A prefix will be used to denote the presence and identity of the heteroatom: aza- for nitrogen oxa- for oxygen thia- for sulfur phospha- for phosphorous etc. The substituent locations will be denoted by numbering the ring atoms, starting at the heteroatom. Hantzsch-Widman naming system 10 -ecine -ecin -ecane 9 -onine -onin -onane 8 -ocine perhydro- -ocin -ocane 7 -epine prefix -epine -epane 6 -ine -ine -ane 5 -ole olidine -ole -olane 4 -ete -etidine -ete -etane 3 -irine -iridine -irene -irane Ring unsaturated saturated unsaturated saturated member Nonnitrogencontaining Nitrogencontaining aza- for nitrogen oxa- for oxygen thia- for sulfur phospha- for phosphorous Boro- for boron
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2 The common names of unsaturated heterocycles will be used here since they are so firmly entrenched in the literature: 25-2 Non-aromatic Heterocycles Ring strain makes heterocyclopropanes and heterocyclobutanes reactive. Nucleophilic ring opening of the strained heterocyclopropane system leads to inversion at the less substituted center. Four-membered heterocycloalkanes are less strained than their three-membered analogs and therefore require more stringent reaction conditions to open. Heterocyclopentanes and heterocyclohexanes are relatively unreactive. Unstrained five- and six-membered heterocycles are relatively inert, although the heteroatoms in aza- and thiacycloalkanes allow for characteristic transformations. In general, ring opening occurs by conversion of the heteroatom into a good leaving group. Structure and Properties of Aromatic Heterocyclopentadienes 25-3 Pyrrole, furan and thiophene contain delocalized lone electron pairs. The electronic structure of pyrrole, furan and thiophene is similar to that of the aromatic cyclopentadienyl anion. The cyclopentadienyl anion can be thought of as a butadiene bridged by a negatively charged carbon whose electron pair is delocalized over the other four carbons. The heterocyclic analogs contain a neutral atom in that place bearing lone pair electrons. One of these pairs is delocalized providing the 2 electrons needed for aromaticity (4n+2)
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3 As a consequence of electron delocalization, pyrrole, furan and thiophene exhibit unusual stability, deshielded protons in their 1H NMR spectra due to ring currents and the ability to undergo electrophilic aromatic substitution. The electron delocalization in pyrrole can be described by resonance structures: Based on the charge distribution, the heteroatom should be electron poor and the ring carbons electron-rich. Pyrroles, furans and thiophenes are prepared from γ-dicarbonyl compounds. A general approach for the synthesis of heterocyclopentadienes is the Paal-Knorr synthesis (pyrroles) and its variations (for the other heterocycles). An enolizable γ-dicarbonyl compound is treated with an amine derivative (for pyrroles), P2O5 (for furans) or P2S5 (for thiophenes). Reactions of the Aromatic Heterocyclopentadienes 25-4 Pyrroles, furans and thiophenes undergo electrophilic aromatic substitution. There are two possible sites of attack, C2 and C3, in the 1-hetero- 2,4-cyclopentadienes undergoing electrophilic substitution. Attack at C2 leads to an additional resonance form and should be the preferred site of attack. Attack at C2 is generally observed, however, because C3 is also activated to electrophilic attack, mixtures of products may occur depending upon conditions, substrates and electrophiles. The relative nucleophilic reactivity series is: benzene << thiophene < furan < pyrrole Pyrrole is very non-basic compared to ordinary amines. Protonation occurs at C2 rather than N, and then only with very strong acids. Pyrroles are in fact relatively acidic. After losing a proton, the nitrogen atom rehybridizes from sp3 to sp2 and the negative charge becomes delocalized, as in the cyclopentadienyl anion
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4 1-Hetero-2,4-cyclopentadienes can undergo ring opening and cycloaddition reactions. Hydrolysis of furans to γ-dicarbonyl compounds under mild conditions can be viewed as the reverse of the Paal-Knorr-type synthesis of furans. Pyrrole polymerizes under these reaction conditions, whereas thiophene is stable. Sulfur-free acyclic compounds are formed upon Raney nickel desulfurization of thiophene derivatives. Furan, but not pyrrole or thiophene, possesses sufficient diene character to undergo Diels-alder cycloadditions. Indole is a benzopyrrole. Indole is the most important benzannulated derivative of the 1- herero-2,4-cyclopentadienes. It is found in many natural products including the amino acid tryptophan. Indole is related to pyrrole in the same way that naphthalene is related to benzene. It possesses many possible resonance forms, however those disturbing the cyclic six-π-electron of the fused benzene ring are less important. Structure and Preparation of Pyridine: an Azabenzene 25-5 Pyridine is aromatic. Of the two lone-pair electrons on the nitrogen atom, only one is in the p orbital perpendicular to the ring. The other is in the otherwise empty sp2 orbital pointing away from the ring. The nitrogen atom in pyridine is sp2 hybridized like the nitrogen atom in an imine. As a result, nitrogen does not donate excess electron density into the ring, but withdraws electron density, both inductively and by resonance. The 1H NMR spectrum indicates the presence of a ring current. The chemical shifts for the protons at C2 and C4 are more deshielded as is expected from the resonance picture. Pyridine is a weak base. The nitrogen lone pair is not tied up by conjugation as it is in pyrrole. The pKa of pyridinium is lower than that of an alkanammonium ion (~10) because the nitrogen atom is sp2 hybridized, not sp3 hybridized
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5 Higher aza analogs of pyridine behave in a similar manner but show the increasing effect of aza substitution: increasing electron deficiency. Pyridines are made by condensation reactions. Pyridine and simple alkylpyridines are obtained from coal tar. The more highly substituted pyridines are made from these compounds using both electrophilic and nucleophilic substitution reactions. Pyridines can be made by condensation reactions of acyclic starting materials, such as carbonyl compounds and ammonia. The most general of the methods is the Hantzsch pyridine synthesis: 25-6 Reactions of Pyridine Pyridine undergoes electrophilic aromatic substitution only under extreme conditions. Pyridine is electron-poor and therefore undergoes electrophilic aromatic substitution with great difficulty. The reaction is several orders of magnitude slower than for benzene and occurs only at C3. Pyridine undergoes relatively easy nucleophilic substitution. Pyridine is electron deficient and therefore undergoes nucleophilic substitution more readily than does benzene. Attack at C2 and C4 is preferred because the negative charge of the reaction intermediates is placed on the nitrogen atom. This reaction proceeds by the addition-elimination mechanism: attack by - :NH2 at C2, followed by expulsion of H:- from C2. Reactions similar to the Chichibabin reaction take place between pyridine and Grignard or organolithium reagents: Most nucleophilic substitutions of pyridines involve halides as leaving groups, the 2- and 4-halopyridines being particularly reactive
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6 25-7 Quinoline and Isoquinoline: the Benzopyridines Fusion of pyridine with a benzene ring results in either quinoline or isoquinoline: Both are liquids with high boiling points. Many of their derivatives are found in nature or have been synthesized in the search for physiological activity. Both substances are readily available from coal tar. Electrophilic substitutions on quinoline and isoquinoline take place on the benzene ring: pyridine is electron-poor compared to benzene. Substitution at carbons next to the ring fusion predominates, as in the naphthalene system. Nucleophiles react preferentially at the electron-poor pyridine nucleus. These reactions are analogous to those with pyridine itself. Representative higher aza analogs of naphthalene: Alkaloids: Physiologically Potent Nitrogen Heterocycles in Nature 25-8 Alkaloids are bitter-tasting, natural, nitrogen-containing compounds found primarily in plants. Alkaloids often have potent physiological activity. Several common stimulants are in the alkaloid family. Nicotine: 2-8% in dried tobacco leaves Caffeine and theobromine: found in coffee and tea or cocoa Cocaine: extracted from the leaves of the coca shrub
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7 Quinine, strychnine and many hallucinogens also belong to the quinoline or isoquinoline families: 25 Important Concepts 1. Heterocycloalkanes – named using cycloalkane nomenclature • Nitrogen - aza • Oxygen - oxa • Sulfur - thia • Many common names exist in the literature 2. Strained Cyclic Heterocycloalkanes – strained 3 and 4 heterocycloalkanes are easily opened by nucleophiles. 3. Aromatic Heterocycloalkanes – 1-Hetero-2,4- cyclopentadienes are aromatic (6 π electrons). • The heteroatom is sp2 hybridized and contributes 2 electrons to the π system. The diene unit is electronrich and reactive in electrophilic aromatic substitutions. 25 Important Concepts 4. Pyridine – formed by replacing a –CH= unit in benzene with sp2 nitrogen • Azabenzenes are electron-poor • Electrophilic aromatic substitution of azabenzenes is sluggish. • Nucleophilic aromatic substitution occurs readily. • Chichibabin reaction • Organometallic substitutions next to the nitrogen • Displacement of halide ion in halopyridines by nucleophiles 5. Azanaphthalenes (benzopyridines) – Quinoline and isoquinoline contain an electron-poor pyridine ring (subject to nucleophilic attack) and an electron-rich benzene ring (subject to electrophilic aromatic substitution, usually at positions closest to the heterocyclic unit)