Materials preparation to the practical classes
for the students of pharmaceutical faculty
LESSON № 17
Theme 23. Fivemember heterocyclic compounds with one heteroatom (furan, pyrrole, thiophene).
Theme 24. The most important derivatives of the fivemember heterocyclic compounds with one heteroatom. Indole.
Fivemembered heterocycles connections with one heteroatom.
Furan, Pyrrole, and Thiophene.
The parent aromatic compounds of this family—pyrrole, furan, and thiophene—have the structures shown.
The structures of these three heterocycles would suggest that they have highly reactive diene character.
However, like benzene, many of their chemical properties are not typical of dienes. They undergo substitution rather than addition reactions, and they show the effect of а ring current in their nmr spectra. In short, these heterocycles have characteristics associated with aromaticity. From an orbital point of view, pyrrole has а planar pentagonal structure in which the four carbons and the nitrogen have sp2 hybridization. Each ring atom forms two sp2—sp2 s bonds to its neighboring ring atoms, and each forms one sp2 – s s bond to а hydrogen. The remaining рz, orbitals on each ring atom overlap to form а p molecular system in which the three lowest molecular orbitals are bonding. The six p electrons (one for each carbon and two for nitrogen) fill the three bonding orbitals and give the molecule its aromatic character. Pyrrole is isoelectronic with cyclopentadienyl anion, an unusually stable carbanion that also has а cyclic p electronic system with six electrons.
Furan and thiophene have similar structures. In these cases, the second lone pair on the heteroatom may be considered to occupy an sp2 orbital that is perpendicular to the p system of the ring.
The aromatic character of these heterocycles may also be expressed using resonance structures, which show that а pair of electrons from the hetero atom is delocalized around the ring.
This delocalization of the lone pair electrons away from the heteroatom can be inferred from the dipole moments of these aromatic heterocycles and their nonaromatic counterparts.
In the saturated compounds, the heteroatom is at the negative end of the dipole. In the aromatic heterocycles the dipole moment associated with the m system opposes the s moment. As а result, the net dipole moment of furan and thiophene is reduced. In pyrrole, the p moment is larger than the o moment so that the direction of the net dipole moment is actually reversed from its saturated counterpart.
Empirical resonance energies for furan, pyrrole, and thiophene may be computed from the heats of combustion for the compounds. In all cases, there is а substantial stabilization energy, although of considerably smaller magnitude than for benzene. Most of the simple derivatives are liquids. As mentioned earlier, furan, pyrrole, and thiophene show the effect of а ring current in their nmr spectra.
Although руrrole is an amine, it is an extremely nonbasic one because the nitrogen lone pair is involved in the aromatic sextet and is thereby less available for bonding to а proton. The pKa of its conjugate acid is 0.4. In fact, this pKa corresponds to а conjugate acid in which protonation has occurred predominantly on carbon rather than oitrogen.
Pyrrole compounds occur widely in living systems. One of the more important pyrrole compounds is the porphyrin hemin, the prosthetic group of hemoglobin and myoglobin. А number of simple alkylpyrroles have played an important role in the elucidation of the porphyrin structures. Thus, drastic reduction of hemin gives а complex mixture from which the four pyrroles, hemopyrrole, cryptopyrrole, phyllopyrrole, and opsopyrrole, have been isolated.
The function of hemoglobin in an organism is to transport oxygen;
The saturated derivatives are called pyrrolidine, tetrahydrofuran, and thiophane, respectively. The bicyclic compounds made of a pyrrole, furan, or thiophene ring fused to a benzene ring are called indole (or isoindole), benzofuran, and benzothiophene, respectively.
As mentioned in the introductory section, the nitrogen heterocycle pyrrole occurs in bone oil, in which it is formed by the decomposition of proteins upon strong heating. Pyrrole rings are found in the amino acids proline and hydroxyproline, which are components of many proteins and which are present in particularly high concentrations in collagen, the structural protein of bones, tendons, ligaments, and skin.
Pyrrole derivatives are widespread in the living world. Pyrrole compounds are found among the alkaloids, a large class of alkaline organic nitrogen compounds produced primarily by plants. Nicotine is the best-known pyrrole-containing alkaloid. The heme group of the oxygen-carrying protein hemoglobin and of related compounds such as myoglobin; the chlorophylls, which are the light-gathering pigments of green plants and other photosynthetic organisms; and vitamin B12 are all formed from four pyrrole units joined in a larger ring system known as a porphyrin, such as that of chlorophyll b, shown below.
The bile pigments are formed by decomposition of the porphyrin ring and contain a chain of four pyrrole rings. Bilirubin, for example, the brownish yellow pigment that gives feces its characteristic colour, is the end product of the breakdown of heme from destroyed red blood cells.
The phthalocyanines are a group of synthetic pigments that contain four isoindole units linked together in a large ring. A typical member of the family is phthalocyanine blue (Monastral Fast Blue).
Numerous compounds produced in plants or animals contain one or more indole units in their molecular structure. The important vat dye indigo, which contains two indole units, has been used for thousands of years and was formerly obtained from plants, but it is now synthesized on a large scale.
The closely related Tyrian purple, a dye obtained from species of snail and used in classical times, is 6,6′-dibromoindigo (with bromine atoms bonded to the numbered carbons in the structure above).
Tryptophan, an indole-containing essential amino acid found in most proteins, is used by the body to make several important substances, including the neurotransmitter serotonin and the B-complex vitamin niacin (see below Six-membered rings with one heteroatom). Skatole, a degradation product of tryptophan that retains the indole unit, contributes much of the strong odour of mammalian feces. Indole-3-acetic acid (heteroauxin or β-indolylacetic acid) is a plant-growth regulator and the most important member of the auxin family of plant hormones (see hormone: The hormones of plants). The structures of these compounds are:
Probably the best-known indole-containing compounds are the indole alkaloids, which have been isolated from plants representing more than 30 families. The mushroom hallucinogens psilocin and psilocybin, the ergot fungus alkaloids, the drugs reserpine and yohimbine, and the poison strychnine all belong to this group.
The simplest member of the furan family of oxygen heterocycles, furan itself, is converted industrially by hydrogenation to tetrahydrofuran. Tetrahydrofuran is used as a solvent and for the production of adipic acid and hexamethylenediamine, the raw materials for nylon-6,6, the most common form of nylon. Other furan derivatives of industrial importance are maleic anhydride and phthalic anhydride, which are constituents of resins and plastics. These compounds are prepared in bulk by the oxidation of benzene and naphthalene, respectively, as shown (V2O5 is a vanadium catalyst).
All carbohydrates, the biochemical family that includes the sugars and starches, are composed of one or more simple sugar (monosaccharide) units. These sugars are polyhydroxy aldehydes or polyhydroxy ketones that in aqueous solution exist as equilibrium mixtures of their open-chain and cyclized forms. Frequently the cyclized form of the sugar is a five-membered tetrahydrofuran ring called a furanose, as shown below for fructose, or fruit sugar, as a cyclized isomer (called a fructofuranose).
Other important examples of tetrahydrofuran ring systems are the sugars ribose and deoxyribose, which are present in furanose form in, respectively, RNA and DNA, the heredity-controlling components of all living organisms.
Dehydration of certain carbohydrates yields furan derivatives. Of great commercial importance is the conversion of a carbohydrate in corncobs, oat husks, and other agricultural waste into furan-2-aldehyde, or furfural, which is used extensively as a solvent, in the manufacture of plastics, and in the preparation of other furan derivatives. Many other furan derivatives occur naturally, including vitamin C. The structures of furfural and vitamin C are:
The sulfur heterocycle thiophene and related compounds are found in coal tar and crude petroleum. The most important biologically occurring thiophene derivative is the B-complex vitamin biotin.
Synthesis.
Furan, 2-furaldehyde (furfural), 2-furylmethanol, and 2-furoic acid are all inexpensive commercial items.
The ultimate source of these heterocycles is furfural, which is obtained industrially by the acid hydrolysis of the polysaccharides of oat hulls, corn cobs, or straw. These polysaccharides are built up from pentose units. Dehydration of the pentose may be formulated.
Pyrrole is prepared commercially by the fractional distillation of coal tar, or by passing а mixture of furan, ammonia, and steam over а catalyst at
n- C4H10 + S = + H2 S
Substituted furans, pyrroles, and thiophenes may be prepared by electrophilic substitution on one of the available materials discussed or by а variety of cyclization reactions. The most general is the Paal-Кnоrr synthesis, in which а 1,4-dicarbonyl compound is heated with а dehydrating agent, ammonia, or an inorganic sulfide to produce the furan, pyrrole, or thiophene, respectively.
Another general method for the synthesis of substituted pyrroles is the Knorr pyrrole synthesis, the condensation of an а-aminoketone with а p-keto ester. The method is illustrated in а synthesis of diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate.
Reactions:
The most typical reaction of furan, pyrrole, and thiophene is electrophilic substitution. All three heterocycles are much more reactive than benzene, the reactivity order being.
To give some idea of the magnitude of this reactivity order, partial rate factors (reactivities relative to benzene) for tritium exchange with fluoroacetic acid.
Because of this high reactivity, even mild electrophiles to cause reaction. Substitution occurs predominantly at the а-position (С-2).
This orientation is understandable in terms of the mechanism of electrophilic aromatic substitution. The a/b ratio is determined by the relative energies of the transition states leading to the two isomers. As in the case of substituted benzenes, we may estimate the relative energies of these two transition states by considering the actual reaction intermediates produced by attack at the a-or b-positions.
Of these structures, the most important are the two with the positive charge on sulfur because, in these two sulfonium cation structures, all atoms have octets of electrons. Nevertheless, as the sets of resonance structures show, the charge on the cation resulting from attack at the a-position is more extensively delocalized than that for the cation resulting from attack at the b-position. The following examples further demonstrate the generality of a–attack.
In the last example, note that 2-iodothiophene is the sole product of iodination, eyeu though the reaction is carried out in benzene as solvent; that is, thiophene is so much more reactive than benzene that no significant amount of iodobenzene is formed.
The position of second substitution in а monosubstituted furan, pyrrole, or lhiophene is governed by а combination о1 the directing effect of the group present and the inherent a-directing effect of the heteroatom. Substitution on 3-substituted compounds occurs exclusively at an a-position. When the substituent present is electron attracting (meta directing), reaction occurs at the nonadjacent a-position (that is, meta to the group present).
When the 3-substituent is electron donating (ortho, раrа directing), substitution occurs at the adjacent а-position (that is, ortho to the group present).
Further substitution on 2-substituted furans tends to оссш at the other a-position.
With 2-substituted pyrroles and thiophenes, attack can occur at С-4 or С-5 when the group present is meta directing, or at С-3 and С-5 when the group present is ortho, раrа directing.
When both a-positions are occupied, further substitution occurs at а b-position, the direction of attack being governed by the directing effect of the two groups present.
Pyrroles are polymerized by even dilute acids, probably by a mechanism such as the following.
Thiophen are more stable and do not undergo hydrolysis.
Reduction of pyrrole:
Furan
Furan is a colorless, flammable, highly volatile liquid with a boiling point close to room temperature. It is soluble in common organic solvents, including alcohol, ether and acetone, but is slightly soluble in water. It is toxic and may be carcinogenic. Furan is used as a starting point to other specialty chemicals.
History
The name furan comes from the Latin furfur, which means bran. The first furan derivative to be described was 2-furoic acid, by Carl Wilhelm Scheele in 1780. Another important derivative, furfural, was reported by Johann Wolfgang Döbereiner in 1831 and characterised nine years later by John Stenhouse. Furan itself was first prepared by Heinrich Limpricht in 1870, although he called it tetraphenol.
Health effects and prevalence in the diet
Furan at a dose of 2 mg/kg body weight (bw) and 4 mg/kg bw has been shown to cause bile duct cancer in rats and liver cancer in mice (National Toxicology Program, 1993; Moser et al. 2009). No long term trials on the adverse effects of furan on human health have been conducted. Furan is found in coffee and in canned and jarred food, including baby food.
Production
Industrially, furan is manufactured by the palladium-catalyzed decarbonylation of furfural, or by the copper-catalyzed oxidation of 1,3-butadiene:
In the laboratory, furan can be obtained from furfural by oxidation to furan-2-carboxylic acid, followed by decarboxylation. It can also be prepared directly by thermal decomposition of pentose-containing materials, cellulosic solids especially pine-wood.
Synthesis of furans
The Feist–Benary synthesis is a classic way to synthesize furans, although many syntheses have been developed. One of the simplest synthesis methods for furans is the reaction of 1,4-diketones with phosphorus pentoxide (P2O5) in the Paal–Knorr synthesis. The thiophene formation reaction of 1,4-diketones with Lawesson’s reagent also forms furans as side products. Many routes exist for the synthesis of substituted furans.
Chemistry
Furan is aromatic because one of the lone pairs of electrons on the oxygen atom is delocalized into the ring, creating a 4n+2 aromatic system (see Hückel’s rule) similar to benzene. Because of the aromaticity, the molecule is flat and lacks discrete double bonds. The other lone pair of electrons of the oxygen atom extends in the plane of the flat ring system. The sp2 hybridization is to allow one of the lone pairs of oxygen to reside in a p orbital and thus allow it to interact within the pi-system.
Due to its aromaticity, furan’s behavior is quite dissimilar to that of the more typical heterocyclic ethers such as tetrahydrofuran.
It is considerably more reactive than benzene in electrophilic substitution reactions, due to the electron-donating effects of the oxygen heteroatom. Examination of the resonance contributors shows the increased electron density of the ring, leading to increased rates of electrophilic substitution.
Furan serves as a diene in Diels-Alder reactions with electron-deficient dienophiles such as ethyl (E)-3-nitroacrylate. The reaction product is a mixture of isomers with preference for the endo isomer:
Pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3. Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.
Pyrroles are components of more complex macrocycles, including the porphyrins of heme, the chlorins, bacteriochlorins, chlorophyll, porphyrinogens.
Properties
Pyrrole has very low basicity compared to conventional amines and some other aromatic compounds like pyridine. This decreased basicity is attributed to the delocalization of the lone pair of electrons of the nitrogen atom in the aromatic ring. Pyrrole is a very weak base with a pKaH of about -1 to -2. Protonation results in loss of aromaticity, and is, therefore, unfavorable.
Like many amines, pyrrole slowly decomposes on exposure to air and light. It turns brown over time due to accumulation of impurities such as polypyrrole and various amine oxides. It is usually purified by distillation immediately before use.
Impure pyrrole being distilled to separate it from colored impurities
Pure pyrrole collected from the still is now colorless and transparent to all wavelengths of visible light due to the removal of impurities
Synthesis
Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid acid catalysts.
One synthetic route to pyrrole involves the decarboxylation of ammonium mucate, the ammonium salt of mucic acid. The salt is typically heated in a distillation setup with glycerol as a solvent.
Substituted pyrroles
Many methods exist for the organic synthesis of pyrrole derivatives. Classic “named reactions” are the Knorr pyrrole synthesis, the Hantzsch pyrrole synthesis, and the Paal-Knorr synthesis. More specialized methods are listed here.
The starting materials in the Piloty-Robinson pyrrole synthesis are 2 equivalents of an aldehyde and hydrazine. The product is a pyrrole with specific substituents in the 3 and 4 positions. The aldehyde reacts with the diamine to an intermediate di-imine
(R–C=N−N=C–R), which, with added hydrochloric acid, gives ring-closure and loss of ammonia to the pyrrole.
In one modification, propionaldehyde is treated first with hydrazine and then with benzoyl chloride at high temperatures and assisted by microwave irradiation:
In the second step, a [3,3]sigmatropic reaction takes place between two intermediates.
Pyrrole can be polymerized to form polypyrrole.
Reactivity
The NH proton in pyrroles is moderately acidic with a pKa of 16.5. Pyrrole can be deprotonated with strong bases such as butyllithium and sodium hydride. The resulting alkali pyrrolide is nucleophilic. Treating this conjugate base with an electrophile such as methyl iodide gives N-methylpyrrole.
Resonance Contributors of Pyrrole
The resonance contributors of pyrrole provide insight to the reactivity of the compound. Like furan and thiophene, pyrrole is more reactive than benzene towards electrophilic aromatic substitution because it is able to stabilize the positive charge of the intermediate carbocation.
Pyrrole undergoes electrophilic aromatic substitution predominantly at the 2 and 5 positions. Two such reactions that are especially significant for producing functionalized pyrroles are the Mannich reaction and the Vilsmeier-Haack reaction (depicted below), both of which compatible with a variety of pyrrole substrates.
Formylation of a pyrrole derivative
Pyrroles react with aldehydes to form porphyrins. For example, benzaldehyde condenses with pyrrole to give tetraphenylporphyrin. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as under Lewis acid catalysis, heating, or high pressure.
Pyrrole polymerizes in light. An oxidizing agent, such as ammonium persulfate, can also be used, typically at 0 °C and in darkness to control the polymerization.
Commercial uses
Pyrrole is essential to the production of many different chemicals. N-methylpyrrole is a precursor to N-methylpyrrolecarboxylic acid, a building-block in pharmaceutical chemistry. Although there is a claim that pyrrole is used as an additive to cigarettes[citation needed], it is typically listed as a constituent of tobacco smoke and not as an ingredient.
Analogs and derivatives
Structural analogs of pyrrole include:
· Pyrroline, a partially saturated analog with one double bond
· Pyrrolidine, the saturated hydrogenated analog
· Kryptopyrrole, a pyrrole derivative once thought to be associated with schizophrenia
· Heteroatom structural analogs of pyrrole include:
· Arsole, a moderately-aromatic arsenic analog
· Furan, an aromatic oxygen analog
· Phosphole, a non-aromatic phosphorus analog
· Pyrazole and imidazole, analogs with two nitrogen atoms
· Derivatives of pyrrole include indole, a derivative with a fused benzene ring.
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a common component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an indole ring are called indoles. The indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin.
General properties and occurrence
Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.
The corresponding substituent is called indolyl.
Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally occurring hallucinogen dimethyltryptamine (N,N-DMT).
The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum.
History
Baeyer’s original structure for indole, 1869
Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed a formula for indole (left).
Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole nucleus is present in many important alkaloids, as well as in tryptophan and auxins, and it remains an active area of research today.
Synthesis of indoles
Indole is a major constituent of coal-tar, and the 220–260 °C distillation fraction is the main industrial source of the material. Indole and its derivatives can also be synthesized by a variety of methods. The main industrial routes start from aniline.
Illustrative of such large-scale syntheses, indole (and substituted derivatives) form via vapor-phase reaction of aniline with ethylene glycol in the presence of catalysts:
In general, reactions are conducted between 200 and 500 °C. Yields can be as high as 60%. Other precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo cyclizations. Many other methods have been developed that are applicable.
Leimgruber-Batcho indole synthesis
The Leimgruber-Batcho indole synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are made up of specifically substituted indoles.
Fischer indole synthesis
One-pot microwave-assisted synthesis of indole from phenylhydrazine and pyruvic acid
One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis, developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions. Indole can still be synthesized, however, using the Fischer indole synthesis by reacting phenylhydrazine with pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.
Other indole-forming reactions
· Bischler-Möhlau indole synthesis
· Hemetsberger indole synthesis
· Baeyer-Emmerling indole synthesis
In the Diels-Reese reaction dimethyl acetylenedicarboxylate reacts with diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.
Chemical reactions of indole
Basicity
Unlike most amines, indole is not basic. The bonding situation is completely analogous to that in pyrrole. Very strong acids such as hydrochloric acid are required to protonate indole. The protonated form has an pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.
Electrophilic substitution
The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.
Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole acetic acid and synthetic tryptophan.
Nitrogen-H acidity and organometallic indole anion complexes
The N-H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or butyl lithium and water-free conditions are required for complete deprotonation. The resulting alkali metal derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon-3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C-3 attack.
Carbon acidity and C-2 lithiation
After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles.
Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.
Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.
Oxidation of indole
Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).
Cycloadditions of indole
Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al. have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes. The Pictet-Spengler reaction of indole derivatives, such as tryptophan, leads to a mixture of diastereomers as products. The formation of multiple products reduces the chemical yield of the desired product.
Applications
Natural jasmine oil, used in the perfume industry, contains around 2.5% of indole. Since 1 kilogram of the natural oil requires processing several million jasmine blossoms and costs around $10,000, indole (among other things) is used in the manufacture of synthetic jasmine oil (which costs around $10/kg).
Thiophene
Thiophene, also commonly called thiofuran, is a heterocyclic compound with the formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene rings, respectively. Compounds analogous to thiophene include furan (C4H4O) and pyrrole (C4H4NH).
Isolation, occurrence
Thiophene was discovered as a contaminant in benzene. It was observed that isatin forms a blue dye if it is mixed with sulfuric acid and crude benzene. The formation of the blue indophenin was long believed to be a reaction with benzene. Victor Meyer was able to isolate the substance responsible for this reaction from benzene. This new heterocyclic compound was thiophene.
Thiophene and its derivatives occur in petroleum, sometimes in concentrations up to 1–3%. The thiophenic content of oil and coal is removed via the hydrodesulfurization (HDS) process. In HDS, the liquid or gaseous feed is passed over a form of molybdenum disulfide catalyst under a pressure of H2. Thiophenes undergo hydrogenolysis to form hydrocarbons and hydrogen sulfide. Thus, thiophene itself is converted to butane and H2S. More prevalent and more problematic in petroleum are benzothiophene and dibenzothiophene.
Synthesis and production
Reflecting their high stabilities, thiophenes arise from many reactions involving sulfur sources and hydrocarbons, especially unsaturated ones, e.g. acetylenes and elemental sulfur, which was the first synthesis of thiophene by Viktor Meyer in the year of its discovery. Thiophenes are classically prepared by the reaction of 1,4-diketones, diesters, or dicarboxylates with sulfiding reagents such as P4S10. Specialized thiophenes can be synthesized similarly using Lawesson’s reagent as the sulfiding agent, or via the Gewald reaction, which involves the condensation of two esters in the presence of elemental sulfur. Another method is the Volhard–Erdmann cyclization.
Thiophene is produced on a scale of ca. 2M kg per year worldwide. Production involves the vapor phase reaction of a sulfur source, typically carbon disulfide, and butanol. These reagents are contacted with an oxide catalyst at 500–550 °C.
Properties
At room temperature, thiophene is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which thiophene shares some similarities. The high reactivity of thiophene toward sulfonation is the basis for the separation of thiophene from benzene, which are difficult to separate by distillation due to their similar boiling points (4 °C difference at ambient pressure). Like benzene, thiophene forms an azeotrope with ethanol.
The molecule is flat; the bond angle at the sulphur is around 93 degrees, the C-C-S angle is around 109, and the other two carbons have a bond angle around 114 degrees. The C-C bonds to the carbons adjacent to the sulphur are about 1.34A, the C-S bond length is around 1.70A, and the other C-C bond is about 1.41A (figures from the Cambridge Structural Database).
Reactivity
Thiophene is considered aromatic, although theoretical calculations suggest that the degree of aromaticity is less than that of benzene. The “electron pairs” on sulfur are significantly delocalized in the pi electron system. As a consequence of its aromaticity, thiophene does not exhibit the properties seen for conventional thioethers. For example the sulfur atom resists alkylation and oxidation. However, oxidation of a thiophene ring is thought to play a crucial role in the metabolic activation of various thiophene-containing drugs, such as tienilic acid and the investigational anticancer drug OSI-930. In these cases oxidation can occur both at sulfur, giving a thiophene S-oxide, as well as at the 2,3-double bond, giving the thiophene 2,3-epoxide, followed by subsequent NIH shift rearrangement.
Toward electrophiles
Although the sulfur atom is relatively unreactive, the flanking carbon centers, the 2- and 5-positions, are highly susceptible to attack by electrophiles. Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes; perhalogenation is easily accomplished to give C4X4S (X = Cl, Br, I).[9] Thiophene brominates 107 times faster than does benzene.
Chloromethylation and chloroethylation occur readily at the 2,5-positions. Reduction of the chloromethyl product gives 2-methylthiophene. Hydrolysis followed by dehydration of the chloroethyl species gives 2-vinylthiophene.
Desulfurization by Raney nickel
Desulfurization of thiophene with Raney nickel affords butane. When coupled with the easy 2,5-difunctionalization of thiophene, desulfurization provides a route to 1,4-disubstituted butanes.
Lithiation
Not only is thiophene reactive toward electrophiles, it is also readily lithiated with butyl lithium to give 2-lithiothiophene, which is a precursor to a variety of derivatives, including dithienyl.
Coordination chemistry
Thiophene exhibits little thioether-like character, but it does serve as a pi-ligand forming piano stool complexes such as Cr(η5-C4H4S)(CO)3.
Uses
Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals. The benzene ring of a biologically active compound may often be replaced by a thiophene without loss of activity.[14] This is seen in examples such as the NSAID lornoxicam, the thiophene analog of piroxicam.
Polythiophene
The polymer formed by linking thiophene through its 2,5 positions is called polythiophene. Polythiophene itself has poor processing properties. More useful are polymers derived from thiophenes substituted at the 3- and 3- and 4- positions. Polythiophenes become electrically conductive upon partial oxidation, i.e. they become “organic metals.”
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a common component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an indole ring are called indoles. The indolic amino acid tryptophan is the precursor of the neurotransmitter serotonin.
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine. Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar. The indole structure can be found in many organic compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in pigments. Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to develop with the study of the dye indigo. This was converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed the formula for indole (left) that is accepted today.
General properties and occurrence
Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.
The corresponding substituent is called indolyl.
Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. Other indolic compounds include the plant hormone Auxin (indolyl-3-acetic acid, IAA), the anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally occurring hallucinogen dimethyltryptamine (N,N-DMT).
The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum.
History
Baeyer’s original structure for indole, 1869
Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust. In 1869, he proposed a formula for indole (left).
Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole nucleus is present in many important alkaloids, as well as in tryptophan and auxins, and it remains an active area of research today.
Synthesis of indoles
Indole is a major constituent of coal-tar, and the 220–260 °C distillation fraction is the main industrial source of the material. Indole and its derivatives can also be synthesized by a variety of methods. The main industrial routes start from aniline.
Illustrative of such large-scale syntheses, indole (and substituted derivatives) form via vapor-phase reaction of aniline with ethylene glycol in the presence of catalysts:
In general, reactions are conducted between 200 and 500 °C. Yields can be as high as 60%. Other precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo cyclizations. Many other methods have been developed that are applicable.
Leimgruber-Batcho indole synthesis
The Leimgruber-Batcho indole synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are comprised of specifically substituted indoles.
Fischer indole synthesis
One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions.
Other indole-forming reactions
· Bischler-Möhlau indole synthesis
· Hemetsberger indole synthesis
· Baeyer-Emmerling indole synthesis
In the Diels-Reese reaction dimethyl acetylenedicarboxylate reacts with diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.
Chemical reactions of indole
Basicity
Unlike most amines, indole is not basic. The bonding situation is completely analogous to that in pyrrole. Very strong acids such as hydrochloric acid are required to protonate indole. The protonated form has an pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.
Electrophilic substitution
The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene. For example, Vilsmeier-Haack formylation of indole will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.
Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole acetic acid and synthetic tryptophan.
Nitrogen-H acidity and organometallic indole anion complexes
The N-H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or butyl lithium and water-free conditions are required for complete deprotonation. The resulting alkali metal derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon-3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C-3 attack.
Carbon acidity and C-2 lithiation
After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles.
Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.
Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.
Oxidation of indole
Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).
Cycloadditions of indole
Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al. have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes. The Pictet-Spengler reaction of indole derivatives, such as tryptophan, leads to a mixture of diastereomers as products. The formation of multiple products reduces the chemical yield of the desired product.
Applications
Natural jasmine oil, used in the perfume industry, contains around 2.5% of indole. Since 1 kilogram of the natural oil requires processing several million jasmine blossoms and costs around $10,000, indole (among other things) is used in the manufacture of synthetic jasmine oil (which costs around $10/kg).
Serotonin
Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.
Biosynthesis
1. Condensed furans, pyrroles, thiophenes.
Tetrapyrrole compounds
Benzofuran, indole, and benzothiophene are analogous to naphthalene. As with the simple heterocycles, the rings are numbered beginning with the heteroatom; carbazole is an exception.
Of the four systems, indoles are by far the most important. Many natural products have indole structures
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