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LECTERE 5. THEME: Classification, structure and biological role of heterocyclic compounds. Lecturer: Yevheniya B. Dmukhalska. Plan. Classification and nomenclature of heterocycles compouns.
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LECTERE 5 THEME: Classification, structure and biological role of heterocyclic compounds. Lecturer: Yevheniya B. Dmukhalska
Plan • Classification and nomenclature ofheterocyclescompouns. • Five-membered heterocycles compouns with one heteroatom. Physical and chemical properties of furan, pyrrole, thiophene. The important derivatives of pyrrole, furan and thiophene. • Six-membered heterocycles compouns with one heteroatom. 4. Physical and chemical properties of indole.
Heterocyclic compounds are cyclic compounds in which one or more ring atoms are not carbon (that is, hetero atoms). • As hetero atom can be N, О, S, В, Al, Si, P, Sn, As, Cu. Bat common is N, О, or S.
Classification • Heterocycles are conveniently grouped into two classes, nonaromatic: and aromatic
By size of ring • Three-membered Four-membered • Five-membered Six-membered
Nonaromatic heterocycles Saturated monocyclic rings are named according to ring size as 3-, -iran; 4-, -etan; 5-, -olan; and 6-, -ane. Even this system does not apply to nitrogencontaining rings and finds only limited use in common practice.
Fivemembered heterocycles compounds with one heteroatom. The structures of these three heterocycles would suggest that they have highly reactive diene character. 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 bonds to its neighboring ring atoms, and each forms one sp² – s bond to а hydrogen.
H H C C H C C H 2 2 R C C R R C C R O H H O H S O c. O O 2 4 P S 2 5 N H 3 R R O R R S R R N H Methods of synthesis of five-membered heterocycles compounds with one heteroatom. 1. Cyclization of 1,4-dicarbones compounds (Paale-Knorr synthesis)
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-Клоrr 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.
Reciprocal transformation of furan, pyrrole, thiophene (Yurie`s cycle reactions) NH3 H2O O N Al O H2S 2 3 H H2O NH3 H2S S
Formation of furan: In laboratory conditions furan is produce by dry distillation of mucic acid. In the industry furan derived from aldopentozes
Formation of thiophene Thiophene is prepared industrially by passing а mixture of butane, butenes,or butadiene and sulfur through а reactor heated at 600' for а contact time of about 1 sec + H2 S n- C4H10 + S =
Physical properties of furan, pyrrole, thiophene At room temperature, thiophene is a colorless liquid with a mildly pleasant odor reminiscent of benzene, with which thiophene shares some similarities. Like benzene, thiophene forms an azeotrope with water. Furanis typically derived by the thermal decomposition of pentose-containing materials, cellulosic solids especially pine-wood. Furan is a colorless, flammable, highly volatile liquid with a boiling point close to room temperature. It is toxic and may be carcinogenic. Pyrrole is a heterocyclic aromatic organic compound. Substituted derivatives are also called pyrroles. Porphobilinogen is a trisubstituted pyrrole, which is the biosynthetic precursor to many natural products
Chemical properties of furan, pyrrole, thiophene The typical reaction of furan, pyrrole, and thiophene is electrophilic substitution. All three heterocycles are much more reactive than benzene. The reactivity order being is: To give some idea of the magnitude of this reactivity order, partial rate factors (reactivities relative to benzene) for tritium exchange with fluoroacetic acid.
1. Interaction with dilute mineral acids Pyrroles are polymerized by even dilute acids, probably by a mechanism such as the following . 2. Reactions of electrophilic substitution: This orientation is understandable in terms of the mechanism of electrophilic aromatic substitution. The / 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 -or -positions.
Nitration 2-nitropyrrole
Further substitution on 2-substituted furans tends to осcur at the other -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.
Acylation 2-acetylpyrrole Because of this high reactivity, even mild electrophiles to cause reaction. Substitution occurs predominantly at the α-position (С-2).
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 -position is more extensively delocalized than that for the cation resulting from attack at the -position. The following examples further demonstrate the generality of -attack.
Halogenation 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.
Reactions of reconstruction Thiophen are more stable and do not undergo hydrolysis. Reduction of pyrrole:
C H I 3 + C H N t o K NH 3 -NaCl sodium pyrrolide pyrrole 2-acetylpyrrole Potassium pyrrolide N-acethylpyrrole -KI, 2-methyllpyrrole
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.
For identification of pyrrole and furan used the method coloring of a pine chip. Couples of pyrrole painted a pine chip soaked in hydrochloric acid in the red colour and furan - in the green colour. Qualitative reaction on thiophene is indophenin`s reaction: a mixture of izathine with concentrated sulfuric acid painted in the blue colour.
Condensed of Pyrrole 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. 1 g of hemoglobin absorbs 1.35 ml of oxygen at STP, corresponding to exactly one molecule of О2 per iron.
VitaminB12 (cyanocobalamin), isanespeciallycommonvitamerofthevitamin B12family. Cyanocobalaminisusuallyprescribedforthefollowingreasons: aftersurgicalremovalofpart, orallofthestomachorintestinetoensurethereareadequatelevelsofvitamin B12inthebloodstream; totreatperniciousanemia; vitamin B12deficiencyduetolowintakefromfood; thyrotoxicosis, hemorrhage, malignancy, liverorkidneydisease. CyanocobamideisalsousedtoperformtheSchillingtesttocheckyourabilitytoabsorbvitamin B12
Derivatives of furan Furfuralisanindustrialchemicalcompoundderivedfromavarietyofagriculturalbyproducts, includingcorncobs, oatandwheatbran, andsawdust. Itisacolorlessoilyliquidwiththeodorofalmonds, butuponexposuretoairitquicklybecomesyellow.Furfural'sphysicalpropertiesaresummarizedinthetableatright. Furfuraldissolvesreadilyinmostpolarorganicsolvents, butisonlyslightlysolubleineitherwateroralkanes.
Chemically, furfural participates in the same kinds of reactions as other aldehydes and other aromatic compounds. The aromatic stability of furfural is not as great as in benzene, and furfural participates in hydrogenation and other addition reactions more readily than many other aromatics.
Derivatives of thiophene Biotin (vitamin H)isawater-solubleB-complexvitaminwhichiscomposedofanureidotetrahydroimidizalone) ringusedwithatetrahydrothiophenering.
Physical and chemical properties of indole Indole (benzo [b] pyrrole) 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 solid at room temperature. 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.
indole-3-sulfoacid 3-nitroindole indole 3-chlorindole 3-benzolazoindole
The importantderivatives of indole.a) indoxyl Indoxyl is isomeric with oxindol and is obtained as an oily liquid.Indoxyl is obtained from indican, which is a glycoside. The hydrolysis of indican yields β-D-glucose and indoxyl. Indigo dye is a product of the reaction of indoxyl by a mild oxidizing agent such as atmospheric oxygen.
Indigo is a powder, insoluble in water, with a melting point higher than 300C. It absorbs light in the yellow region of the spectrum (maximum at 602 nm), which gives it its intense blue colour.
For many organisms (including humans), tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. Amino acids, including tryptophan, act as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following compounds. Tryptophan, serotonin, β-indolyl acetic acid
H O С H С H N H 2 2 2 N H b Serotonin [5-hydroxy-3-( -aminoethyl)іndole] Serotonin Serotonin 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.
C H - C O O H 2 b a N H b- indolyl acetic acid (heteroauxin) It is a heterocyclic compound that is an phytohormone called auxins. This colourless solid is probably the most important plant auxin.
Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyridine. Heterocycles containing as a heteroatom atom of nitrogen, behave to the most widespread representatives of this group of connections (azynes): quinoline isoquinoline acridine pyridine
Pyridine is an analog of benzene in which one of the СН units is replaced by nitrogen. The nitrogen lone pair is located in an sp2 hybrid orbital which is perpendicular to the system of the ring. Various values have been deduced for the empirical resonance energy of pyridine, but it would appear to be roughly comparable to benzene. The resonance stabilization is shown by the two equivalent Kekule structures and the three zwitterionic forms with negative charge on nitrogen.
Derivatives of pyridine are biological active compounds, such as nicotine amide, nicotinic acid (vitamin PP). nicotinic acid
