HETEROCYCLIC COMPOUNDS
Heterocyclic compounds are carbon cyclic compounds in which one or more of the ring system atoms is a non-metal non-carbon (oxygen, nitrogen or sulfur). Like carbocyclic compounds, heterocycles can be divided into those with aromatic character and reduction products of such aromatic heterocycles, which, like alicyclic compounds, exhibit properties and reactions similar to the properties and reactions of aliphatic compounds. It is convenient to classify heterocycles a) by the number of atoms in the ring, b) by the number and nature of heteroatoms. Unsaturated heterocycles that exhibit the most aromatic character are taken as key representatives of each cyclic system.
A. FIVE-MEMBERED HETEROCYCLES
1. One heteroatom

2. Two heteroatoms

3. Three or more heteroatoms

The resonance (see "Resonance" at the beginning of Section IV-3) of five-membered rings includes a significant contribution from the following structures:

The resonance energy acquired in this way makes these systems very resistant to addition reactions at double bonds, and they enter into many typical aromatic substitution reactions.
B. SIX-MEMBER HETEROCYCLES
1. One heteroatom

2. Two heteroatoms

B. CONDENSED HETEROCYCLIC SYSTEMS
Important series of compounds in each class are prepared by condensation of a heterocyclic ring with one or more benzene rings, for example:

Heterocyclic systems are widespread in nature, especially in alkaloids, plant pigments (anthocyanins, flavones), porphyrins (hemin, chlorophyll) and B vitamins (thiamine, riboflavin, folic acid). Some heterocyclic compounds are discussed in more detail below.
D. PRACTICALLY IMPORTANT HETEROCYCLIC COMPOUNDS
Furan, a volatile liquid, resistant to alkalis but sensitive to acids

It is most easily obtained by decarboxylation of pyrosmucic acid (2,5-dicarboxyfuran), a product of the pyrolysis of mucus (tetrahydroxyadipic) acid. The most common method for preparing furan derivatives is the dehydration of g-diketones over zinc chloride:

Dry distillation of pentoses HOCH2(CHOH)3CHO gives furfural (a-formylfuran). Furfural exhibits many of the properties of an aromatic aldehyde. Thus, like benzaldehyde, it undergoes the Cannizzaro reaction and benzoin condensation. Coumarone (benzofuran) (see above "Condensed heterocyclic systems"), together with its homologues, is found in coal tar. It has some value for the production of coumaron resins, which are formed when it is treated with sulfuric acid. Coumarone derivatives can be obtained by decomposing dibromocoumarins with alkali:

or by the action of alkali on o-hydroxy-b-chlorostyrene, o-HO-C6H4-CH=CH-Cl. The coumarone structure is found in many natural plant substances that are potent insecticides and fish poisons, such as:

Thiophene (formula see above, bp 84°C) is contained in coal tar and accompanies benzene during its fractionation. It can be removed from benzene by precipitation of a complex with mercuric acetate, from which thiophene can be regenerated by treatment with hydrochloric acid. Sulfuric acid also removes it from benzene by forming a-thiophenesulfonic acid. Thiophene derivatives can be obtained by the following methods: 1) by distillation of succinic acids or g-keto acids from P2S3:

2) distillation of g-diketones from P2S5:

Thiophene and its homologues are very resistant to ring oxidation or reduction. Aromatic substitution reactions (sulfonation, nitration, etc.) occur in the a-position. Thionaphthene (benzothiophene) is obtained by oxidation of o-mercaptocinnamic acid with red blood salt (potassium ferricyanide). Its 3-hydroxy derivative, which is of great industrial importance in dye chemistry, is obtained by the action of acetic anhydride on o-carboxyphenylthioglycolic acid o-HOOCC6H4-S-CH2COOH. It combines readily with diazonium salts at position 2 to give azo dyes, and condenses with aldehydes and ketones to form thioindigoid dyes.

Pyrrole (formula see above), a colorless, pleasant-smelling liquid contained in coal tar, readily polymerizes in air. It has practically no base properties, it is resistant to oxidizing agents and alkalis, but easily polymerizes in the form of protein components (proline, tryptophan), alkaloids (nicotine, atropine) and porphyrins (hemin, chlorophyll). Pyrrole derivatives can be obtained: 1) by distillation of succinimides

With zinc dust; 2) heating g-diketones with ammonia; 3) heating mucus acid (see above) with ammonia or primary amines; 4) simultaneous reduction of equivalent amounts of b-ketoester and isonitrosoketone

Pyrroles undergo typical aromatic substitution reactions at the a-position. Treatment of Grignard reagents converts them to a-pyrrylmagnesium halides

which undergo typical Grignard reactions. Ring expansion with the formation of a pyridine system can be achieved: 1) treatment with chloroform and sodium ethoxide

2) passing a-alkylpyrroles through a tube heated to red heat

Reduction by catalytic hydrogenation under pressure leads, albeit slowly, to pyrrolidines:

Indole (benzopyrrole; formula see Table 4, Section III) is found in coal tar and essential oils of orange and jasmine flowers. Indole derivatives are obtained: 1) from o-aminophenylacetaldehyde o-H2NC6H4CH2CH=O by elimination of water; 2) heating o-oў-diaminostilbene hydrochlorides:

3) from phenylhydrazones by heating with copper or zinc halides

In its reactions, indole is similar to pyrrole, with the exception that the b-position is involved in substitution reactions. The following indole derivatives are worthy of mention: 1) skatole (b-methylindole), a substance with an unpleasant odor present in excrement; 2) tryptophan (b-(b-indolyl)alanine), an amino acid found in many proteins; 3) heteroauxin (b-indolylacetic acid or 3-indolylacetic acid), plant growth factor; 4) indigo

Oxazole (formula see above) is known in its pure form. Its derivatives can be obtained by condensation of amides with a-halogen ketones:

or the effect of phosphorus pentachloride on acylaminoketones:

Oxazoles are weak bases that are sensitive to cleavage by strong acids. Isoxazole

And its derivatives are of less interest. They can be prepared by dehydration of b-diketone monooximes. Thiazole and its homologues are weak bases in which the ring exhibits high resistance to oxidation, reduction and the action of strong acids

Thiazoles can be obtained from a-acylamine ketones by the action of P2S5, as well as by the reaction of thioamides with a-halogen ketones:

Strong acids convert thiazoles into salts (C3H3SN + HX(r)C3H3SNH+X-), which are stable but noticeably hydrolyze in aqueous solutions. With alkyl halides, N-substituted thiazolium salts containing quaternary nitrogen are formed:

The most important natural compound containing a thiazole ring is vitamin B1 (thiamine). The valuable chemotherapeutic drug sulfathiazole is obtained by the action of N-acetylsulfanyl chloride on 2-aminothiazole, followed by removal of the acetyl group by hydrolysis:

Imidazole (glyoxalin) and its homologues

Obtained from aldehydes, a-diketones and ammonia:

They can also be prepared by reacting amidines

With a-halogen ketones. Imidazoles are stronger bases than pyrroles. With alkyl halides they give N-alkylimidazoles. These substances, when passed through a tube at red heat, isomerize into 2-alkylimidazoles; upon interaction with a second alkyl halide molecule, they are converted into imidazolium salts containing quaternary nitrogen

The action of Grignard reagents RMgX on imidazoles leads to the corresponding 2-imidazolylmagnesium halides C3H3N2MgX, which undergo reactions common to Grignard reagents. The imidazole ring is found in many natural compounds, including the amino acid histidine (see Section IV-1.B.4, “Amino Acids”), pilocarpine alkaloids, and purine bases. Pyrazole and its derivatives are only synthetic compounds; pyrazole ring system

Not found in nature. Pyrazoles are prepared by reacting hydrazine with b-diketones:

or the action of diazoalkanes on acetylene:

The reaction of phenylhydrazine with a,b-unsaturated ketones or esters gives dihydropyrazoles, or pyrazolines:

These compounds are easily oxidized to the corresponding pyrazoles. The pyrazole ring is very resistant to oxidation, reduction and strong acids. Pyrazolinium salts, obtained by the action of strong acids on pyrazolines, are unstable and decompose in a vacuum. The most important class of pyrazoles are pyrazolones.

obtained by the action of hydrazine and its derivatives on b-ketoesters, for example,

Pyrazolones behave as a mixture of three tautomeric (i.e., in equilibrium) forms, for example:

1-Phenyl-3-methylpyrazole-5 is an important substance. Oxidation with red blood salt (potassium ferricyanide) transforms it into the indigoid dye pyrazole blue:

Methylation (CH3I at 100° C) converts it into the antipyrine drug antipyrine (1-phenyl-2,3-dimethylpyrazolone), the 4-N-dimethylamino derivative of which is a similar drug amidopyrine (pyramidon). Ring systems with three or more heteroatoms are of no practical interest. All of them are resistant to oxidation, reduction and strong acids. Furazans are obtained by dehydration of a-diketone dioximes. 1,2,3-Triazoles and tetrazoles also belong to this group of compounds.

Collier's Encyclopedia. - Open Society. 2000 .

See what "HETEROCYCLIC COMPOUNDS" are in other dictionaries:

- (heterocycles) organic compounds containing cycles, which, along with carbon, also include atoms of other elements. They can be considered as carbocyclic compounds with heterosubstituents (heteroatoms) in the ring. Most... ... Wikipedia

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HETEROCYCLIC COMPOUNDS- HETEROCYCLIC COMPOUNDS, an extensive class of organic compounds. compounds with a cyclic structure of molecules, the composition of which includes not only carbon atoms, but also atoms of other elements (heteroatoms). Cyclic compounds are known, in which the role... ... Great Medical Encyclopedia

HETEROCYCLIC COMPOUNDS, see CYCLIC COMPOUNDS ... Scientific and technical encyclopedic dictionary

Organic compounds containing a cycle in a molecule, which, along with carbon atoms, includes atoms of other elements, most often nitrogen, oxygen, sulfur (so-called heteroatoms). Natural heterocyclic compounds, for example... ... encyclopedic Dictionary

Org. compounds whose molecules contain cycles, including, along with carbon atoms, one or more. atoms of other elements (heteroatoms). Naib. are important. That is, the cycle includes atoms N, O, S. These include polycarbonates, alkaloids, vitamins,... ... Chemical encyclopedia

- (see hetero... + cyclic) organic compounds with a cyclic (ring) structure, the cycle of which includes atoms not only of carbon, but also of other elements (nitrogen, oxygen, sulfur, etc.). New dictionary of foreign words. by EdwART,… … Dictionary of foreign words of the Russian language

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- (from hetero... and Greek kyklos circle, cycle) organic. compounds containing a cycle in a molecule, the composition of which, in addition to carbon atoms, includes atoms of other elements (heteroatoms), most often nitrogen (see, for example, Pyridine), oxygen, sulfur, less often phosphorus, ... ... Big Encyclopedic Polytechnic Dictionary

Books

• Heterocyclic compounds with three or more heteroatoms. Study guide, Mironovich Lyudmila Maksimovna. The textbook outlines the basics of the chemistry of heterocyclic compounds containing three or more heteroatoms. The main methods for obtaining oxadiazoles, thiadiazoles,…

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Introduction

1. Heterocyclic compounds

1.3 Nucleophilicity

1.5 Electrophilic reaction

1.6 Heterocycles: Enzymes and vitamins

1.7 Heterocycles and medicine

2.4 Application: Antibiotics in medicine

2.5 Peptide antibiotics

Conclusion

List of used literature

Introduction

Nowadays, most educated people have at least a general understanding of proteins, fats and carbohydrates and the role of this triad of substances in life processes. Less awareness is manifested in relation to the so-called heterocyclic compounds, or heterocycles, the importance of which in the chemistry of living things, however, is no less, and the variety of manifestations is even noticeably wider than that of proteins, fats and carbohydrates. Heterocycles, and more specifically, some derivatives of purines and pyrimidines, play a fundamental role in the transmission of hereditary traits.

Antibiotics are substances that have toxic properties towards other microorganisms. The word "antibiotic" in Greek means "against life." In other words, antibiotics are specific waste products of certain types of fungi that delay or completely suppress the growth of other types of microorganisms. Therefore, antibiotics are considered to be toxins of bacteria and other microorganisms. (Lancini, 2005)

Based on the nature of their action, antibiotics are divided into bactericidal and bacteriostatic. The bactericidal effect is characterized by the fact that under the influence of the antibiotic, the death of microorganisms occurs. Achieving a bactericidal effect is especially important when treating weakened patients, as well as in cases of such severe infectious diseases as general blood poisoning (sepsis), endocarditis, etc., when the body is not able to fight the infection on its own. Antibiotics such as various penicillins, streptomycin, neomycin, kanamycin, vancomycin, and polymyxin have a bactericidal effect.

With a bacteriostatic effect, the death of microorganisms does not occur, only the cessation of their growth and reproduction is observed. When the antibiotic is removed from the environment, microorganisms can develop again. In most cases, when treating infectious diseases, the bacteriostatic effect of antibiotics in combination with the body’s defense mechanisms ensures the patient’s recovery. (Egorov, 2007 S.)

1. Heterocyclic compounds

Heterocyclic compounds (heterocycles) are organic compounds containing cycles, which, along with carbon, also include atoms of other elements. They can be considered as carbocyclic compounds with heterosubstituents (heteroatoms) in the ring. The most diverse and well studied are aromatic nitrogen-containing heterocyclic compounds. Limiting cases of heterocyclic compounds are compounds that do not contain carbon atoms in the ring, for example, pentazole.

1.2 Physico-chemical specificity of heterocycles

Various heterocyclic compounds participate in one form or another in many chemical processes occurring in living cells. Why heterocycles? - a completely reasonable question arises. To answer this, it is necessary to talk at least in general terms about the basic physicochemical properties of heterocycles.

The first thing to note is the extremely wide range of reactivity of heterocycles. Depending on the pH of the environment, they form anions or cations, some readily react with positively charged reagents (electrophiles), others with negatively charged ones (nucleophiles); some are easily reduced but difficult to oxidize, others, on the contrary, are easily oxidized but difficult to reduce. There are also amphoteric heterocyclic systems that simultaneously exhibit all of the listed properties. The ability of many heterocycles to form strong complexes with metal ions is of important biochemical significance. All these manifestations of reactivity are in one way or another related to the distribution of electron density in heterocyclic molecules.

Let's take pyridine as an example. The specificity of the pyridine nitrogen atom is that it attracts part of the electron cloud of the molecule. As a result, carbon atoms, primarily those in the ortho and para positions, acquire a partial positive charge. A deficiency of electron density on the carbon backbone is a characteristic property of all heterocycles containing pyridine-type heteroatoms. Their most important feature is the ease of interaction with negatively charged reagents - nucleophiles. A typical example is the reaction of pyridine with sodium amide, resulting in the formation of 2-aminopyridine. (Kochetkova 1986)

Hydrogen substitution reactions under the action of positively charged reagents for such heterocycles are very difficult or do not occur at all. However, electrophiles easily attach to the pyridine nitrogen atom due to its lone pair of electrons. For example, with acids and alkyl halides, pyridine forms pyridinium and N-alkylpyridinium salts, respectively. Pyridine actually acts as a base in such reactions.

It is known that the introduction of electron-withdrawing groups into an organic molecule causes a decrease in the energy of molecular orbitals. As a result, the compounds are more difficult to give up electrons (they are poorly oxidized), but they are easier to gain them (they are better reduced). The pyridine-type heteroatom is an electron acceptor, which means that the corresponding heterocycles should be prone to easy reduction. This is true. For example, 1-benzyl-3-carbamoylpyridinium chloride is reduced to 1-benzyl-3-carbamoyl-1,4-dihydropyridine, which can be oxidized back to the parent salt.

This reversible reaction underlies the action of many natural catalysts - enzymes, primarily those that provide the respiratory process and energy accumulation.

The opposite situation occurs in the case of pyrrole and other heterocycles with a pyrrole-type heteroatom. In the molecules of these compounds, there are formally six p-electrons per five ring atoms. As a result, the ring carbon atoms have an excess negative charge. Such heterocycles are no longer characterized by reactions with nucleophiles, but their interaction with electrophiles proceeds very easily. For example, pyrrole is brominated in the cold immediately to tetrabromopyrrole, and this reaction is difficult to stop at the monosubstitution stage.

A pyrrole-type heteroatom is practically devoid of basic properties. On the contrary, pyrrole and other NH heterocycles are characterized by acidity. Thus, under the action of bases they form N-anions. The latter easily react with various electrophiles, which is used to obtain a variety of N-derivatives, for example, 1-methylpyrrole. The molecular orbitals in such heterocycles have high energy, so they, in contrast to pyridine and its analogues, are difficult to reduce, but are easily oxidized. Thus, by controlled oxidation of pyrrole and its N-substitutes, polypyrroles can be obtained.

Compounds containing both pyrrole and pyridine heteroatoms respectively exhibit amphoteric properties. Imidazole is indicative in this regard.

This heterocycle is one of the most common, one might say key, in living organisms. It is part of purine bases, vitamin B 12, and many enzymes. The biological functions of imidazole are associated with the exceptional diversity and flexibility of its physicochemical properties. So, by removing a proton, it turns into an anion, and by adding a proton, it turns into an imidazolium cation. The acid-base properties of imidazole are such that in the body at pH = 7, about half of its molecules are in the form of a cation, the other half are in the form of neutral particles. Another feature of imidazole is its tendency to form intermolecular hydrogen bonds both with similar molecules and with water, amino acids, and other biomolecules.

Hydrogen bonds belong to the so-called non-valent interactions. Although the energy of one non-valent interaction is 1 - 2 orders of magnitude lower than the energy of ordinary covalent bonds, it is non-valent interactions and, above all, hydrogen bonds that provide flexibility, speed and diversity of biochemical processes. This is explained by the multiplicity of intermolecular interactions, which, when added up, become a determining factor in the chemistry of living things. Heterocyclic compounds, with their polarity, lone electron pairs, heteroatoms, and N-H bonds, have a unique ability for nonvalent interactions. In this regard, it should be recalled that the formation of multiple hydrogen bonds between complementary base pairs adenine-thymine and guanine-cytosine ensures fairly strong adhesion of polynucleotide helices in double-stranded DNA molecules. (Sherstnev, 1990)

1.3 Nucleophilicity

Nucleophile in chemistry (Latin nucleus “nucleus”, ancient Greek tsylEshch “to love”) is a reagent that forms a chemical bond with a reaction partner according to the donor-acceptor mechanism, providing an electron pair. Because nucleophiles donate electrons, they are by definition Lewis bases. Theoretically, all ions and neutral molecules with a lone electron pair can act as nucleophiles.

Nucleophile is an electron-rich chemical reagent capable of interacting with electron-deficient compounds (electrophiles). Examples of nucleophiles are anions (Cl?, Br?, I?) and compounds with a lone electron pair (NH 3, H 2 O).

Thus, for five-membered heterocycles with one heteroatom (pyrrole type), the aromatic sextet of electrons is distributed over the five atoms of the ring in such a way that leads to the high nucleophilicity of these compounds. They are characterized by electrophilic substitution reactions; they are very easily protonated at the pyridine nitrogen or ring carbon, halogenated and sulfonated under mild conditions. The reactivity during electrophilic substitution decreases in the order pyrrole > furan > selenophene > thiophene > benzene.

The introduction of pyridine-type heteroatoms into five-membered heterocycles leads to a decrease in electron density, nucleophilicity, and, accordingly, reactivity in electrophilic substitution reactions, that is, the effect is similar to the influence of electron-withdrawing substituents for benzene derivatives. Azoles react with electrophiles like pyrroles with one or more electron-withdrawing substituents in the ring, and for oxazoles and thiazoles it becomes possible only in the presence of activating substituents with a +M effect (amino and hydroxy groups).

Due to the mobility of p-electrons, molecules containing p-bonds also have nucleophilic properties: CH 2 =CH 2, CH 2 =CH-CH=CH 2, C 6 H 6, etc.

For six-membered heterocycles (pyridine type), the reduced electron density compared to benzene leads to a reduced nucleophilicity of these compounds: electrophilic substitution reactions occur under harsh conditions. Thus, pyridine is sulfonated with oleum at 220–270 °C.

1.4 Nucleophilicity of heteroatoms

Atomic position Electron density

2 (alpha) 0.84

3 (betta) 1.01

4 (gamma) 0.87

Accordingly, the attacks of electrophiles in this case are directed to the pyridine nitrogen atom. A variety of alkylating and acylating agents (quaternization reaction with the formation of the corresponding quaternary salts) and peroxyacids (with the formation of N-oxides) can act as electrophiles.

The pyrrole-type nitrogen atom is significantly less nucleophilic - alkylation of N-substituted imidazoles occurs predominantly at the pyridine-type nitrogen, however, when the unsubstituted pyrrole nitrogen is deprotonated, the direction of substitution is reversed. Thus, 4-nitroimidazole, when methylated under neutral conditions, produces mainly 1-methyl-5-nitroimidazole, and in alkaline solutions (where the substrate is its deprotonated form), the main reaction product is 1-methyl-4-nitroimidazole.

This increase in the nucleophilicity of pyrrole-type nitrogen upon deprotonation is typical for all heteroaromatic compounds, however, the direction of attack of the electrophile depends on the degree of dissociation of the resulting anion: if indolyl and pyrrolyl magnesium halides undergo electrophilic attack predominantly at carbon, then the corresponding alkali metal salts will react mainly at the nitrogen atom. Confirmation of the influence of dissociation of the N-anion-metal complex on the direction of the reaction is the reversal of the direction of electrophilic attack during the reaction of indolylmagnesium halides with methyl iodide in HMPTA due to the solvent-promoted dissociation of the magnesium complex.

1.5 Electrophilic reaction

Heterolithic r-tions org. conn. with electric reagents (electrophiles, from the Greek elektron - electron and phileo - love). Electrophiles include ions and molecules that have a fairly low energy vacant orbital (Lewis compounds) - H +, D+, Li+, Alk+, AlAlk3, Hal+, BF3, SO3H+, NO+, NO+2, etc. - and when interacting with the substrate, both bonding electrons are accepted by it.

The basis of the electophilic reaction is the electron-donating ability of olefins, acetylenes and aromatics. hydrocarbons in relation to electrophiles, as well as the possibility of heteroatoms and simple C - C and C - H bonds transferring their electron pairs.

The electrophilicity of heteroaromatic compounds increases with a decrease in n-electron density, that is, with an increase in the number of heteroatoms and, with their equal number, is higher for six-membered heterocycles compared to five-membered heterocycles. Thus, for pyrroles and indoles, nucleophilic substitution reactions are atypical; pyridine and benzimidazole are aminated with sodium amide, and 1,3,5-triazine is quickly hydrolyzed to ammonium formate already in an aqueous solution.

1.6 Heterocycles: Enzymes and vitamins.

Typically, enzymes are proteins with a large molecular weight. They often include several polypeptide chains intertwined with each other through nonvalent interactions. Thanks to this supramolecular organization, the enzyme molecule acquires a three-dimensional shape, on the surface of which there are all kinds of irregularities: depressions, niches, crevices. In one of these irregularities is the active zone of the enzyme, into which the reacting molecule enters, like a key in a lock. Like every good lock, the enzyme responds only to its “key”, that is, to molecules of a strictly defined substance - the substrate. Therefore, each type of transformation in the body requires the participation of its own specific enzyme.

The active centers of many enzymes include residues of heterocyclic compounds, in particular pyridine and imidazole. The imidazole fragment is part of the amino acid histidine. Along with the indole-containing amino acid tryptophan, it is one of the most important natural amino acids of the heterocyclic series.

Due to its unique acid-base properties, the imidazole ring can catalyze the addition of nucleophiles to the carbonyl group. This reaction is one of the most important both in laboratory practice and in living nature.

Along with purely protein enzymes, there are many enzymes that also contain a non-protein part, called a coenzyme. Most of the latter are derivatives of nitrogenous heterocycles: pyridine, pyrimidine, thiazole, etc. Many coenzymes cannot be synthesized in humans and animals, so they must be supplied with food. Finished coenzymes or their close chemical precursors are called vitamins. (Soldatenkov 2001)

1.7 Heterocycles and medicine

heterocycle microorganism antibiotic resistance

Few of us go through the day without a cup of tea or coffee. Their invigorating effect is caused by the purine group alkaloids present in tea leaves and coffee fruits - caffeine, theobromine and theophylline. All of them are stimulants of the central nervous system, increase the vital activity of tissues, and enhance overall metabolism. Theophylline and theobromine are used in medicine as vasodilators and diuretics. Of course, they are now prepared synthetically.

The twentieth century is sometimes called the century of the Great Medical Revolution. One of its brightest symbols, of course, should be considered b-lactam antibiotics - penicillin and cephalosporin, which saved millions of human lives. Both of them are also derivatives of heterocyclic compounds.

In recent years, there has been a breakthrough in solving such a complex problem as the creation of effective antiviral drugs. In 1988, American scientists G. Ellion and J. Hitchings were awarded the Nobel Prize for the creation of acyclovir, the first highly effective drug against herpes viral infections. Somewhat earlier, the same scientists obtained and introduced into clinical practice azidothymidine, used as a remedy against AIDS. Due to the fact that the action of acyclovir and azidothymidine is aimed at the genetic apparatus of viruses, it is not surprising that both drugs belong to purines and pyrimidines.

Successes in the fight against infectious diseases have moved them, as the main cause of mortality, to third place. At the same time, cardiovascular diseases and cancer took the first two places. Together with disorders of the nervous system, which are also extremely widespread, they are often called diseases of the twentieth century. The modern revolution in psychopharmacology began back in the 50s with derivatives of one of the heterocycles - phenothiazine. The classic and, perhaps, most striking representative of them is chlorpromazine (chlorpromazine). In the United States alone, the use of chlorpromazine in a short time has freed up several million hospital beds occupied by people with various mental disorders. In the 60s, another group of sedatives, also related to heterocycles, was introduced into clinical practice. We are talking about 1,4-benzodiazepine derivatives. The most famous of them are diazepam, nitrazepam, phenazepam, etc. In a short time, in terms of the number of tablets consumed, they have become one of the most common drugs in the world.

In the same way, in recent years, 1,4-dihydropyridine derivatives, for example, phenigidine, have taken first place among cardiovascular drugs. A common anticancer agent is 5-fluorouracil (Ivansky, 1978)

2. Antibiotics and their effects on microorganisms

The history of antibiotics began with a discovery made by the English bacteriologist Alexander Fleming. On September 15, 1928, when, during a long-term study devoted to studying the human body’s fight against bacterial infections, the scientist was conducting a routine experiment, he encountered an interesting phenomenon. In his laboratory he had a large collection of various microbes growing in Petre dishes on a nutrient medium. His attention was drawn to one of the cups, on the edge of which mold appeared, and all colonies of microorganisms nearby died. Fleming had the idea that mold spreads around itself a certain substance that can kill microbes. He began to deliberately introduce this mold into cups with colonies of microbes. They soon discovered that this mold actually had antimicrobial properties. He called the substance secreted by mold fungus penicillin. At that time, penicillin was not isolated in pure or concentrated form, and the mold itself produced a weak effect and was very inconvenient to use.

During the 1930s, unsuccessful attempts were made to improve the quality of penicillin and other antibiotics by learning how to obtain them in sufficiently pure form. It was only in 1938 that two Oxford University scientists, Howard Florey and Ernst Chain, managed to isolate a pure form of penicillin, which began to be used in 1941, and already in 1943, due to the great need for medicines during the Second World War, mass production began. production of this medicine.

In 1945, Fleming, Florey and Cheyne were awarded the Nobel Prize for their work.

Penicillin and other antibiotics have saved countless lives. In addition, penicillin was the first medicine to demonstrate the emergence of microbial resistance to antibiotics. (Goodman, 1977)

Antibiotics, depending on the concentration, can inhibit the growth of sensitive microorganisms (bacteriostatic effect), cause their death (bactericidal effect) or dissolve them (lytic effect). You cannot do without antibiotics for acute pyelonephritis, pneumonia, otitis, complicated sinusitis, abscesses, sepsis, chlamydia, infective endocarditis and other very serious diseases. Antibiotics are often prescribed to people after surgery. However, all antibiotics have a different spectrum of action. For example, penicillin is effective against pneumonia caused by staphylococcal infection, but for pneumonia caused by mycoplasma, it will not give any result.

Antibiotics came into our lives as a way to get rid of infections that have tormented humanity for thousands of years. However, after the emergence of new powerful drugs, people started talking about their harm. In the process of improving the drugs, it turned out that the drug kills only bacteria that are sensitive to it. The strongest of them survive, and mutation occurs in their cells. It turns out that every day the army of superbugs that are resistant to antibiotics is replenished. It turned out that with prolonged use, antibiotics “at the same time” kill the beneficial microflora of the gastrointestinal tract, contribute to the appearance of intestinal dysbiosis, toxic damage to the liver, kidneys, etc. Many people develop allergies to them. However, today we cannot do without antibiotics; they are still the “centre” in overcoming sepsis, intoxication, and tuberculosis. There are no other drugs yet that can so powerfully and quickly cope with a life-threatening infection. Scientists are constantly creating new drugs designed for new strains.

And so that antibiotics do not cause harm, they cannot be taken for a long time, much less “prescribed” to yourself; they must be prescribed by a doctor. A test - blood, urine or sputum culture for sensitivity to the drug - helps the doctor choose an antibiotic correctly and with the least risk to health. In addition, there are drugs that are taken in parallel with antibiotics as a cover. For example, suprastin, tavegil and other antihistamines can significantly reduce the risk of developing allergies. Bifikol or acylact reduce the likelihood of intestinal dysbiosis to almost nothing. In addition, dependence on antibiotics never develops. And bifidobacteria contained in fermented milk products and modern probiotic preparations help smooth out the negative effect of antibiotics on the body and restore the microflora.

2.2 Heterocyclic antibiotics

Antibiotics (from anti-against and Greek beos - life), substances of biological origin, synthesized by microorganisms and suppressing the growth of bacteria and other microbes, as well as viruses and cells. Many antibiotics can kill germs. Sometimes antibiotics also include antibacterial substances extracted from plant and animal tissues. Each antibiotic is characterized by a specific selective effect only on certain types of microbes. In this regard, antibiotics with a broad and narrow spectrum of action are distinguished. The former suppress a variety of microbes (for example, tetracycline acts on both gram-positive and gram-negative bacteria, as well as rickettsia); the second - only microbes of any one group (for example, erythromycin and oleandomycin suppress only gram-positive bacteria). Due to the selective nature of their action, some antibiotics are able to suppress the vital activity of pathogenic microorganisms in concentrations that do not damage the cells of the host body, and therefore they are used to treat various infectious diseases of humans, animals and plants. Microorganisms that form antibiotics are antagonists of the surrounding microbial competitors belonging to other species, and with the help of antibiotics they suppress their growth. The idea of ​​using the phenomenon of microbial antagonism to suppress pathogenic bacteria belongs to I.I. Mechnikov, who proposed using lactic acid bacteria that live in yogurt to suppress harmful putrefactive bacteria found in the human intestines. Until the 40s. 20th century Antibiotics with a therapeutic effect have not been isolated in pure form from microbial cultures. The first such antibiotic was tyrothricin, obtained by the American scientist R. Dubos (1939) from a culture of the soil spore aerobic bacillus Bacillus brevis. The strong therapeutic effect of tyrothricin was established in experiments on mice infected with pneumococci. In 1940, the English scientists H. Flory and J. Chain, working with penicillin produced by the mold Penicillium notatuip, discovered by the English bacteriologist Fleming in 1929, first isolated penicillin in its pure form and discovered its remarkable medicinal properties. In 1942, Soviet scientists G. F. Gause and M. G. Brazhtsikova obtained gramicidin C from a culture of soil bacteria, and in 1944 the American scientist Z. Vaksman obtained streptomycin from a culture of the actinomycete Streptomyces griseus. About 2000 different antibiotics from microbial cultures have been described, but only a few of them (about 40) can serve as therapeutic drugs; the rest, for one reason or another, do not have a chemotherapeutic effect. Antibiotics can be classified according to their origin (fungi, bacteria, actinomycetes, etc.), chemical nature or mechanism of action. Antibiotics from mushrooms. Antibiotics of the penicillin group, produced by many races of Penicillium notatum, P. chrysogenum and other types of molds, are of great importance. Penicillin inhibits the growth of staphylococci at a dilution of 1 in 80 million and is slightly toxic to humans and animals. It is destroyed by the enzyme penicillinase, produced by some bacteria. From the penicillin molecule, its “core” (6-aminopenicillanic acid) was obtained, to which various radicals were then chemically attached. Thus, new “semi-synthetic” penicillins (methicillin, ampicillin, etc.) were created that are not destroyed by cenicillinase and suppress some strains of bacteria that are resistant to natural penicillin. Another antibiotic, cephalosporin C, is produced by the fungus Cephalosporium. It has a chemical structure close to penicillin, but has a slightly wider spectrum of action and suppresses the vital activity of not only gram-positive, but also some gram-negative bacteria. From the “core” of the cephalosporin molecule (7-aminocephalosporanic acid), its semisynthetic derivatives (for example, cephaloridine) were obtained, which were used in medical practice. The antibiotic griseofulvin was isolated from cultures of Penicillium griseofulvum and other molds. It inhibits the growth of pathogenic fungi and is widely used in medicine. Antibiotics from actinomycetes are very diverse in their chemical nature, mechanism of action and medicinal properties. Back in 1939, Soviet microbiologists N. Krasilnikov and I. Korenyako described the antibiotic mycetin, formed by one of the actinomycetes. The first antibiotic from actinomycetes to be used in medicine was streptomycin, which suppressed, along with gram-positive bacteria and gram-negative bacilli, tularemia, plague, dysentery, typhoid fever, as well as tuberculosis bacilli. The streptomycin molecule consists of streptidine (a diguanidine derivative of mesoinositol) linked by a glucosidic bond to streptobiosamine (a disaccharide containing strentose and methylglucosamine). Streptomycin belongs to the group of antibiotics of water-soluble organic bases, which also includes aminoglucoside antibiotics (neomycin, monomycin, kanamycin and gentamicin), which have a wide spectrum of action. Antibiotics of the tetracycline group are often used in medical practice, for example chlortetracycline (aureomycin, biomycin) and oxytetracycline (terramycin). They have a wide spectrum of action and, along with bacteria, suppress rickettsia (for example, the causative agent of typhus). By exposing cultures of actinomycetes, producers of these antibiotics, to ionizing radiation or many chemical agents, it was possible to obtain mutants that synthesize antibiotics with an altered molecular structure (for example, demethylchlortetracycline, the antibiotic chloramphenicol-levomycetin), which has a wide spectrum of action, unlike most other antibiotics, is produced in recent years through chemical synthesis rather than biosynthesis. Another such exception is the anti-tuberculosis antibiotic cycloserine, which can also be produced by industrial synthesis. Other antibiotics are produced by biosynthesis. Some of them (for example, tetracycline, penicillin) can be obtained in the laboratory by chemical synthesis; however, this route is so difficult and unprofitable that it cannot compete with biosynthesis. Of significant interest are macrolide antibiotics (erythromycin, oleandomycin), which suppress gram-positive bacteria, as well as polyene antibiotics (nystatin, amphotericin, levorin), which have an antifungal effect. There are known antibiotics produced by actinomycetes (see Actinomycins), which have a suppressive effect on some forms of malignant neoplasms and are used in cancer chemotherapy, for example, actinomycin (chrysomallin, aurantine), olivomycin, bruneomycin, rubomycin C. The antibiotic hygromycin B, which has an anthelmintic effect, is also interesting . Antibiotics from bacteria are chemically more homogeneous and in the vast majority of cases are polypeptides. In medicine, tyrothricin and gramicidin C from Bacillus brevis, bacitracin from Bac. subtilis and polymyxin from Bac. polymyxa. Nisin, produced by streptococci, is not used in medicine, but is used in the food industry as an antiseptic, for example, in the manufacture of canned food. Antibiotic substances from animal tissues. The most famous among them are: lysozyme, discovered by the English scientist Fleming (1922); this is an enzyme - a polypeptide of a complex structure, which is found in tears, saliva, nasal mucus, spleen, lungs, egg white, etc., suppresses the growth of saprophytic bacteria, but has little effect on pathogenic microbes; interferon is also a polypeptide that plays an important role in protecting the body from viral infections; its formation in the body can be increased with the help of special substances called interferonogens. Antibiotics can be classified not only by origin, but also divided into a number of groups based on the chemical structure of their molecules. This classification was proposed by Soviet scientists M. M. Shemyakin and S. Khokhlov: antibiotics of an acyclic structure (polyenes nystatin and levorin); alicyclic structure; aromatic antibiotics; antibiotics - quinones; antibiotics - oxygen-containing heterocyclic compounds (griseofulvin); antibiotics - macrolides (erythromycin, oleandomycin); antibiotics - nitrogen-containing heterocyclic compounds (penicillin); antibiotics - polypeptides or proteins; antibiotics - depsipeptides. A third possible classification is based on differences in the molecular mechanisms of action of antibiotics. For example, penicillin and cephalosporin selectively inhibit cell wall formation in bacteria. A number of antibiotics selectively affect protein biosynthesis in the bacterial cell at different stages; tetracyclines disrupt the attachment of transport ribonucleic acid (RNA) to bacterial ribosomes; the macrolide erythromycin, like lincomycin, turns off the movement of the ribosome along the messenger RNA strand; chloramphenicol damages ribosome function at the level of the peptidyl translocase enzyme; streptomycin and aminoglucoside antibiotics (neomycin, kanamycin, monomycin and gentamicin) distort the “reading” of the genetic code on bacterial ribosomes. Another group of antibiotics selectively affects the biosynthesis of nucleic acids in cells also at various stages: actinomycin and olivomycin, interacting with the deoxyribonucleic acid (DNA) matrix, turn off the synthesis of messenger RNA; bruneomycin and mitomycin react with DNA as alkylating compounds, and rubomycin - by intercalation. Finally, some antibiotics selectively affect bioenergetic processes: gramicidin C, for example, turns off oxidative phosphorylation.

2.3 Microbial resistance to antibiotics

Resistance of microorganisms to antibiotics is an important problem that determines the correct choice of a particular drug for treating a patient. In the first years after the discovery of penicillin, about 99% of pathogenic staphylococci were sensitive to this antibiotic; in the 60s no more than 20-30% remained sensitive to penicillin. The growth of resistant forms is due to the fact that antibiotic-resistant mutants constantly appear in bacterial populations, which are virulent and spread mainly in cases where sensitive forms are suppressed by antibiotics. From a population genetic point of view, this process is reversible. Therefore, when a given antibiotic is temporarily removed from the arsenal of therapeutic agents, resistant forms of microbes in populations are again replaced by sensitive forms that multiply at a faster rate. Industrial production of antibiotics is carried out in fermenters, where antibiotic-producing microorganisms are cultivated under sterile conditions on special nutrient media. Of great importance in this case is the selection of active strains, for which various mutagens are first used to induce active forms. If the original strain of penicillin producer that Fleming worked with produced penicillin at a concentration of 10 U/ml, then modern producers produce penicillin at a concentration of 16,000 U/ml. These numbers reflect the progress of technology. Antibiotics synthesized by microorganisms are extracted and subjected to chemical purification. Quantitative determination of the activity of antibiotics is carried out by microbiological (according to the degree of antimicrobial action) and physicochemical methods.

Producers, chemical nature and spectrum of action of the most important antibiotics.

2.4 Application. Antibiotics in medicine.

The clinic uses about 40 antibiotics that do not have a harmful effect on the human body. To achieve a therapeutic effect, it is necessary to maintain so-called therapeutic concentrations in the body, especially at the site of infection. Increasing the concentration of antibiotics in the body is more effective, but may be complicated by side effects of the drugs. If necessary, to enhance the effect of an antibiotic, several antibiotics can be used (for example, streptomycin with penicillin), as well as eficillin (for pneumonia) and other drugs (hormonal drugs, anticoagulants, etc.). Combinations of some antibiotics have a toxic effect, and therefore their combinations cannot be used. Penicillins are used for sepsis, pneumonia, gonorrhea, syphilis, etc. Benzylpenicillin, ecmonovocillin (novocaine salt of penicillin with ecmolin) are effective against staphylococci; Bicillins-1, -3 and -5 (dibenzylethylenediamine salt of penicillin) are used to prevent rheumatic attacks. A number of antibiotics - streptomycin sulfate, pascomycin, dihydrostreptomycin pascate, pantomycin, dihydrostreptomycin pantothenate, streptomycin saluzide, as well as cycloserine, viomycin (florimycin), kanamycin and rifamycin - are prescribed for the treatment of tuberculosis. Syntomycin drugs are used in the treatment of tularemia and plague; tetracyclines - for the treatment of cholera. To combat the carriage of pathogenic staphylococci, lysozyme with ecmolin is used. Semi-synthetic penicillins with a broad spectrum of action - ampicillin and hetacillin - inhibit the growth of intestinal, typhoid and dysentery bacilli. Long-term and widespread use of antibiotics has caused the emergence of a large number of pathogenic microorganisms resistant to them. The emergence of microbes resistant to several antibiotics at the same time is practically important - cross-drug resistance. To prevent the formation of antibiotic-resistant forms, widely used antibiotics are periodically replaced and they are never applied topically to wound surfaces. Diseases caused by antibiotic-resistant staphylococci are treated with semisynthetic penicillins (methicillin, oxacillin, cloxacillin and dicloxacillin), as well as erythromycin, oleandomycin, novobiocin, lincomycin, leukocin, kanamycin, rifamycin; shincomycin and josamycin are used against staphylococci resistant to many antibiotics. In addition to resistant forms, when antibiotics are used (most often streptomycin), so-called dependent forms (microorganisms that develop only in the presence of an antibiotic) may appear. When antibiotics are used irrationally, pathogenic fungi in the body are activated, which leads to candidiasis. For the prevention and treatment of candidiasis, the antibiotics nystatin and levorin are used. In some cases, side effects develop during antibiotic treatment. Penicillin, when used for a long time in large doses, has a toxic effect on the central nervous system, streptomycin on the auditory nerve, etc. These phenomena are eliminated by reducing doses. Sensitization (hypersensitivity) of the body can manifest itself regardless of the dose and method of administration of the antibiotic and is expressed in an exacerbation of the infectious process (the entry of large quantities of toxins into the blood due to the massive death of the pathogen), relapses of the disease (as a result of suppression of the body’s immunobiological reactions), superinfection, as well as allergic reactions. Obtaining salts from antibiotics has made it possible to overcome the specific toxicity of some antibiotics. For example, the pantothenic salt of streptomycin - pantomycin, no different from streptomycin in its therapeutic effect, has a good effect on patients who cannot tolerate streptomycin. The ascorbic acid salt of dihydrostreptomycin also turned out to be significantly less toxic than streptomycin. If an allergy develops when using penicillins, cephalosporin antibiotics are used. When treating with antibiotics, it is necessary to simultaneously administer vitamins, the diet should be rich in proteins, since streptomycin reduces the amount of pantothenic acid (vitamin B3) in the body, and ftivazid and cycloserine - vitamin B6.

2.5 Peptide antibiotics

Peptide antibiotics, antimicrobial compounds whose molecules contain peptide bonds. Chemically, this is a very diverse group of substances, most of which are cyclic or linear oligo- and polypeptides containing substituents of a non-peptide nature (residues of fatty acids, aliphatic amines and alcohols, hydroxy acids, as well as sugars and heterocycles).

There are five main types of peptide antibiotics: 1) derivatives of amino acids (for example, cycloserine, b-lactam antibiotics) and diketopiperazine (gliotoxin, type I); 2) homomeric peptides - linear (gramicidin A, II) and cyclic (bacitracin A, III (here and below the letters of the Greek alphabet indicate the position of amino groups that are involved in the formation of bonds); viomycin, IV; capreomycin 1-A, V), as well as oligo-peptides (netropsin, VI; distamycin, VII); 3) heteromeric peptides (for example, polymyxins B, E and M, forms VIII, IX and X, respectively; R = 6-methyloctanoyl (B1, E1 and M1) or isooctanoyl (B2, E2 and M2); Dab -2 ,4-diaminobutyric acid), incl. chelating agents (bleomycins); 4) peptolides-chromopeptolides (actinomycins), lipopeptolides (stendomycin, XI; here and below the letter Me before the Latin designations of amino acids, except Pro, indicate the presence of a methyl group at the N atom; MePro 4-methylproline), heteropeptolides (mikamycin B, XII; staphylomycin S, XIII), simple peptolides (griselimicin A, XIV) and depsipeptides (valinomycin; see Ionophores); 5) macromolecular peptides, polypeptides (nisin, XV; sulfide bridges link b-C-atoms Ala and Abu), proteins (neocarcinostatin, containing 109 amino acid residues), proteins (asparaginase, lysostapnine with a molecular weight of 32000).

Homo- and heteromeric peptides, peptolides have a number of characteristic features that distinguish them from ordinary polypeptides and proteins: a) low content of some simple amino acids (arginine, histidine, methionine), the presence of D-configuration amino acids and amino acids of unusual structure (sulfur-containing, complex heterocyclic ., unsaturated, N-methylated, imino-, b- and g-amino acids, proline derivatives); b) the presence of non-peptide substituents in the molecules; c) predominantly cyclic or linear cyclic, structure without free carboxy and amino groups; cyclization between amino acid radicals themselves with the formation of thiazolines, oxazolines and other heterocyclic structures. In addition, peptide antibiotics, as a rule, are resistant to the action of hydrolases, although some of them (polymyxins, bleomycins) are sensitive to aminoacylases and peptidases of microbial and plant origin.

Peptide antibiotics are produced as a mixture of related compounds that differ from each other by one or more amino acid residues or variations in the structure of non-peptide components. Producers are various types of actinomycetes, bacteria and fungi. The biosynthesis of peptides and depsipeptides is carried out without the participation of ribosomes and RNA with the help of specific enzyme complexes, antibiotic synthetases, containing all the necessary information. For a number of peptide antibiotics, the molecular mechanism of biosynthesis has been elucidated or the composition of the synthetases has been established. During the polymerization process or after the formation of the peptide chain, cyclization of the molecule and modification of individual amino acids occurs. Biosynthesis of macromolecular peptide antibiotics (in particular, nisin) occurs on ribosomes as a result of modification of the precursor protein.

Peptide antibiotics have diverse biological properties. Among them are inhibitors of cell wall synthesis (bacitracin A) and lipoprotein synthesis of the outer membrane of gram-negative bacteria (bicyclomycin), inhibitors of replication and transcription (actinomycin D, bleomycins) and protein synthesis (viomycin), inhibitors of cell membrane functioning (polymyxins, gramicidin, valinomycin) , antimetabolites (alanosine, cycloserine). Peptide antibiotics have high antibiotic activity against gram-positive (bacitracin A) and gram-negative (polymyxins) bacteria, as well as mycobacteria (capreomycin 1-A, viomycin). A number of antibiotics exhibit antitumor (actinomycins, asparaginase) and antifungal activity; distamycin is very active against viruses.

Peptide antibiotics are widely used in veterinary medicine (mikamycin B, netropsin), as feed additives (bacitracin A, staphylomycins), as preservatives (nisin), and in biochemical studies (valinomycin, gramicidins, actinomycins). The use of peptide antibiotics in therapy is quite limited due to undesirable side effects, in particular nephrotoxicity. Only polymyxins B, E and M, certain antitumor drugs (bleomycin A2, actinomycin D, asparaginase) and anti-tuberculosis drugs (cycloserine, viomycin, capreomycin 1-A, lysostaphnin) are widely used. Peptide antibiotics, however, are being replaced from medical practice by less toxic antibiotics.

3. The problem of drug resistance of microorganisms

Antimicrobial resistance is not a new problem, but it is becoming more serious. We live in an era of dependence on antibiotics and other antimicrobials to treat diseases such as HIV/AIDS, which would have been fatal a few years ago. When microorganisms become resistant to them, known as drug resistance, these drugs become ineffective.

Currently, drug resistance of microorganisms is not only a purely microbiological, but also a huge national problem (for example, the mortality rate of children from staphylococcal sepsis is currently at approximately the same high level as before the advent of antibiotics). This is due to the fact that among staphylococci - the causative agents of various purulent-inflammatory diseases - quite often there are strains that are simultaneously resistant to several drugs (5-10 or more).

Among microorganisms that cause acute intestinal infections, up to 80% of the isolated dysentery pathogens are resistant to several antibiotics.

The development of drug resistance to antibiotics and other chemotherapeutic drugs is based on mutations of chromosomal genes or the acquisition of drug resistance plasmids.

There are genera and families of microorganisms that are naturally resistant to certain antibiotics; their genome contains genes that control this trait. For the genus Acinetobacter, for example, resistance to penicillin is a taxonomic feature. Many representatives of pseudomonas, non-clostridial anaerobes and other microorganisms are also multiresistant to antibiotics.

Such bacteria are natural banks (repositories) of drug resistance genes.

As is known, mutations, including those due to drug resistance, are spontaneous and always occur. During the period of massive use of antibiotics in medicine, veterinary medicine and plant growing, microorganisms practically live in an environment containing antibiotics, which become a selective factor contributing to the selection of resistant mutants that receive certain advantages.

Plasmid resistance is acquired by microbial cells as a result of genetic exchange processes. The relatively high frequency of transmission of R-plasmids ensures a wide and fairly rapid spread of resistant bacteria in the population, and the selective pressure of antibiotics ensures their selection and consolidation in biocenoses.

Plasmid resistance can be multiple, i.e., to several drugs, and at the same time reach a fairly high level. (Aksenova, 2003)

3.2 Biochemical basis of resistance

The biochemical basis of resistance is provided by different mechanisms:

1) enzymatic inactivation of antibiotics - is carried out using enzymes synthesized by bacteria that destroy the active part of antibiotics. One of these well-known enzymes is beta-lactamase, which ensures the resistance of microorganisms to beta-lactam antibiotics due to the direct cleavage of the beta-lactam ring of these drugs. Other enzymes are capable of not cleaving, but modifying the active part of the antibiotic molecule, as is the case with the enzymatic inactivation of aminoglycosides and chloramphenicol;

2) changing the permeability of the cell wall to the antibiotic or suppressing its transport into bacterial cells. This mechanism underlies tetracycline resistance;

3) a change in the structure of microbial cell components, for example a change in the structure of bacterial ribosomes, is accompanied by an increase in resistance to aminoglycosides and macrolides, and a change in the structure of RNA synthetases - to rifampicin.

Bacteria of the same species can exhibit several resistance mechanisms. At the same time, the development of one or another type of resistance is determined not only by the properties of bacteria, but also by the chemical structure of the antibiotic. Thus, 1st generation cephalosporins are resistant to the action of staphylococcal beta-lactamases, but are destroyed by beta-lactamase gram-negative microorganisms, while 4th generation cephalosporins and imipinemas are highly resistant to the action of beta-lactamase 1gram-positive and gram-negative microorganisms.

3.3 Combating drug resistance

To combat drug resistance, i.e. to overcome the resistance of microorganisms to chemotherapy drugs, there are several ways:

1) first of all, adherence to the principles of rational chemotherapy;

2) the creation of new chemotherapeutic agents that differ in the mechanism of antimicrobial action (for example, the recently created group of chemotherapy drugs - fluoroquinolones) and targets;

3) constant rotation (replacement) of chemotherapy drugs (antibiotics) used in a given medical institution or in a certain territory;

4) combined use of beta-lactam antibiotics together with beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam).

Conclusion

It is logical to expect that with such importance of heterocycles in the chemistry of living things, they should also find application in medicine. This is true. According to data at the beginning of the 90s, of the 1070 most widely used synthetic drugs, 661 (62%) were heterocycles.

Long before the development of pharmaceutical chemistry, people treated diseases using heterocyclic compounds from a natural pharmacy: leaves, fruits and bark of trees, roots and stems of herbs, extracts from insects, etc. Probably no other natural compound has as many stories surrounding it as quinine. Quinine is one of the representatives of a large family of alkaloids - nitrogen-containing organic compounds mainly of plant origin. Almost all alkaloids are derivatives of nitrogen heterocycles. Quinine played a historical role in the fight against malaria. An example of another alkaloid is papaverine, which is used in medicine as an antispasmodic and vasodilator.

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Heterocyclic compounds include organic compounds containing cycles in their molecules, in which, in addition to carbon, there are atoms of other elements (heteroatoms: O, N, S).

Heterocyclic compounds are classified:

a) by the number of atoms in the cycle (from three-membered to macrocyclic);

b) by the number and type of heteroatoms (–O, –N, –S);

c) according to the degree of unsaturation of the heterocycle (saturated and unsaturated).

Of particular interest are unsaturated heterocyclic compounds that satisfy the conditions of aromaticity: in terms of the number of π-electrons, they correspond to Hückel’s rule; have a flat structure and a closed system of π-electrons.

When naming heterocycles, trivial names are widely used:

The numbering in heterocycles is fixed and in most cases depends on the seniority of the substituents. A separate group includes heterocyclic compounds with fused nuclei:

Heterocyclic compounds play an important role in the life of organisms and have important physiological significance (DNA, RNA, chlorophyll, alkaloids, a number of vitamins, antibiotics).

FIVE-MEMBER SYSTEMS WITH ONE HETEROATOM

The most important representatives are furan, thiophene, pyrrole. All of them are aromatic compounds: they satisfy Hückel’s rule, 4 electrons of the carbon atom of the ring are in π-conjugation with the lone pair of electrons of the heteroatom, the ring itself has a flat structure. Therefore, as for benzene, their formulas can be depicted as follows:

WAYS TO OBTAIN

1. Cyclization of 1,4-dicarbonyl compounds (diketones, dicarboxylic acids or keto acids). When they are heated with a dehydrating agent (CaCl 2, H 2 SO 4, P 2 O 5), furan derivatives are formed; when carrying out dehydration in an NH 3 – pyrrole environment; in the presence of P 2 S 5 – thiophene:

2. Isolation from natural sources. Thiophene and pyrrole are contained in coal tar, furan is contained in pentosan-containing raw materials (sunflower seed husks, corn cobs) through the stage of producing furfural.

3. Interconversions of furan, thiophene, pyrrole (Yur’ev reaction) occur at t = 450 o C over Al 2 O 3:

4. Reaction of acetylene with hydrogen sulfide or ammonia. When a mixture of H 2 S is passed over Al 2 O 3, thiophene is formed

and mixtures with NH 3 – pyrrole

Physical properties

All three substances are colorless liquids, practically insoluble in water.

CHEMICAL PROPERTIES

Since these compounds are aromatic in nature, they are characterized by electrophilic substitution reactions (nitration, sulfonation, halogenation, acylation) occurring at position 2 (α-position) under very mild conditions.

Furan, thiophene and pyrrole are weak bases. Products of protonation of furan and pyrrole with mineral acids:

are unstable, the resulting cation quickly loses its aromaticity, acquires the properties of a conjugated diene, and easily polymerizes. This phenomenon is called acidophobia (“fear of acid”).

Thiophene is not acidophobic (due to the equality of electronegativities of the S and C atoms of the ring). Pyrrole is capable of exhibiting acidic properties at the N–H bond and replacing the hydrogen atom with a Na or K atom when interacting with metals or concentrated alkali KOH:

1. Halogenation. It is carried out by complexing Br 2 with dioxane, Br 2 at a low temperature (bromination) or Cl 2 at a low temperature, SO 2 Cl 2 (chlorination):

2. Sulfonation. It is carried out with pyridine sulfotrioxide C 5 H 5 N SO 3, since in this case there are no acidic compounds in the reaction mixture:

3.Nitration. Carried out with acetyl nitrate (a mixture of acetic anhydride and HNO 3):

4. Acylation. It is carried out by acid anhydrides in the presence of catalysts: AlCl 3, SnCl 4, BF 3 (Friedel-Crafts reaction):

5. Alkylation it is not possible to carry out the Friedel-Crafts test, but pyrrol potassium, when reacting with halogen derivatives, gives N-alkylpyrroles, which isomerize when heated into 2-alkylpyrroles:

6. Hydrogenation. Occurs in the presence of Ni or Pt catalysts for furan and pyrrole, Pd for thiophene:

SIX-MEMBERED HETEROCYCLES WITH ONE NITROGEN Atom

Of greatest interest is pyridine:

It is a heterocyclic analogue of benzene, in which one –CH= group is replaced by an sp 2 -hybrid carbon atom. It has an aromatic character. Since the lone pair of electrons of the nitrogen atom does not enter into π-conjugation, pyridine is not acidophobic and exhibits high basic properties. The electron density in the ring is reduced, especially at positions 2,4,6, so pyridine undergoes nucleophilic rather than electrophilic substitution reactions more easily.

WAYS TO OBTAIN

1. Isolation from natural sources. Pyridine and its homologues are obtained from coal tar.

2. Pyridine homologues can be obtained in the following ways:

2.1. Condensation of aldehydes with ammonia

2.2. Reaction of acetylene with ammonia (Repe method)

2.3. Condensation of β-diketones or β-ketoesters with aldehydes and ammonia (Hantzsch method). The 1,4-dihydropyridines formed intermediately are oxidized to pyridines with nitric acid or NO 2

Further hydrolysis and decarboxylation of the resulting product leads to trialkylpyridines.

Physical properties

Pyridine is a colorless liquid with a characteristic unpleasant odor. It is soluble in water and forms a mixture with it with a density of ρ = 1.00347 g/dm 3 .

CHEMICAL PROPERTIES

1. Basicity. Pyridine exhibits basic properties to a greater extent than furan, thiophene and pyrrole. Being a weak base, with strong mineral acids it gives pyridinium salts, which are aromatic in nature

2. Alkylation. Produced by halogen derivatives to form pyridinium salts, which when heated give 2- (or 4-) alkyl-substituted pyridines

3. Electrophilic substitution reactions. For pyridine, they flow with difficulty (since the nitrogen atom has acceptor properties) to position 3

4. Nucleophilic substitution reactions. Flows easily (due to depletion of the ring in electron density) in position 2

5. Recovery. Carried out with hydrogen under harsh conditions

6. Oxidation pyridine destruction occurs only under very harsh conditions. Homologues containing alkyl side chains are oxidized along them similarly to benzene homologues

Test

Heterocyclic compounds

Content

• 3. Structure of heterocycles
• 5. Azoles
• 6. Pyrrole
• 7. Indole
• 8. Furan
• 9. Thiophene
• 11. Pyridine
• Literature

1. General information, distribution and significance

Heterocycles are organic compounds whose cycle is built not only from carbon atoms, but also from atoms of other organogenic elements (nitrogen, oxygen, sulfur, phosphorus, etc.). Modern chemistry makes it possible to introduce an atom of almost any element of the Periodic Table into the cyclic skeleton of a molecule. Heterocycles can be saturated and unsaturated, among the latter there are aromatic and anti-aromatic.

Some saturated heterocyclic compounds were mentioned in previous chapters - these are cyclic secondary amines (piperidine, morpholine), lactones and lactams - derivatives of hydroxy and amino acids.

The importance of heterocycles in modern chemistry and biochemistry, molecular biology, and medicine can be assessed at least from the fact that about 50% of publications in scientific journals devoted to these areas of knowledge are in one way or another related to heterocycles.

Aromatic heterocycles, especially those containing one or more nitrogen atoms, are widespread in nature and are part of the complex chemical structures contained in every living cell. Thus, derivatives of the heterocyclic system of pyrimidine (uracil, thymine, cytosine) and imidazopyrimidine, called purine (adenine, cytosine), are part of DNA - the genetic apparatus of all living beings.

Heterocycles are part of a-amino acid molecules that form protein macromolecules

The heterocyclic pentanuclear porphyrin system is the main unit in the hemoglobin biomolecule, and the related heterocycle chlorin, which has one hydrogenated bond, is the basis of chlorophyll.

It is easy to see that these two systems have great structural similarity (even the substituents are similar), which suggests a common evolutionary origin.

To saturate the coordination number of the iron ion in hemoglobin, equal to six (distorted octahedron), in addition to four porphyrin nitrogen atoms (see heme formula), heterocyclic fragments of the protein part of hemoglobin or an oxygen molecule act as ligands. Both ligands are located on opposite sides of the macrocycle plane.

Heterocycles are part of vitamin molecules.

The macromolecule of vitamin B 12 (cyanocobalamin) is a cobalt complex of a very stable heterosystem - corrin. The vitamin B 12 molecule also contains the biologically active heterocycle benzimidazole.

A huge number of drugs are derivatives of heterocyclic compounds. These include, for example, numerous antibiotics of the penicillin series, sulfonamide drugs, substituted 5-nitrofurfurals with antiseptic activity, analgesics, tranquilizers, antiviral drugs, etc.

Many heterocyclic compounds are strong poisons, such as nicotine and LSD. In small quantities (active dose from 50 mcg), LSD is used as a psychotropic drug - a powerful hallucinogen ( use Not recommended !) .

A huge number of natural colored heterocyclic compounds are known, which determine the color of flowers, fruits, insects, etc. A large number of industrially important dyes have been synthesized based on heterocycles. Examples of synthetic dyes are indigo blue (used, in particular, for dyeing denim) and methylene blue (a water-soluble dye), thioindigo red, complex insoluble violet pigments - phthalocyanines.

In the plant world, dyes based on benzopyran derivatives are very common: flavones, flavonols and anthocyanidins. The color of these compounds varies over a wide range - from pale yellow to dark purple.

Flavones and flavonols give various shades of cream and yellow color to the flowers of fruit trees; salt forms of anthocyanidin determine the color of bright flowers (roses, lilies) and fruits (cherries, apples, strawberries).

2. Classification and nomenclature

Heterocyclic compounds are classified by ring size, type of heteroatoms and their number. The most common mononuclear unsaturated heterocycles have trivial names, which are used as the basis for the names of their derivatives and fused heterosystems. The basis is the name of the heterocycle that has the largest number of multiple bonds; often such a heterocycle is aromatic.

Many fully or partially hydrogenated heterocycles also have their own trivial names.

Aromatic six-membered heterocycles containing at least one nitrogen atom are collectively called “azines”; in accordance with the number of heteroatoms, mono-, di-, tri-, etc. are distinguished.

Five-membered nitrogen heterocycles with more than one heteroatom are called azoles. These include the following types of connections:

The numbering of atoms in the nucleus of heterocycles is carried out from the heteroatom so that the sum of the locants of the heteroatoms is the smallest; if there are options, then the highest heteroatom should have the lowest number. The rules of precedence for heteroatoms are: N > O > S, the nitrogen atom of the “pyrrole” type is older than that of the “pyridine” type.

The latter is determined by the type of bonds that the atom forms with its neighbors: if in the main boundary structure the heteroatom forms only s-bonds, then it is “pyrrole”; if it has two s-bonds and one p-bond, then it is “pyridine”.

Similar requirements apply to atoms of other elements.

An older nomenclature is also used: atoms are designated by letters of the Greek alphabet, starting from the one adjacent to the heteroatom. This numbering method is most often used for a heteroring of a symmetrical structure with one heteroatom and in the presence of one substituent to the ring.

A heterocyclic molecule can consist of two or more rings, carbocyclic and heterocyclic. Multinuclear heterocycles are named as follows:

1. The name of the older heterocycle is taken as a basis, the name of the younger one is added as a prefix ending with the letter “o”.

2. Rules of precedence: a) any heterocycle is older than benzene; b) the more heteroatoms, the older the heterocycle; c) with the same number of heteroatoms, the larger heterocycle is the eldest; d) if the heteroatoms are identical, then the closer they are, the older the cycle is (pyridazine is older than pyrimidine); e) with the same number of heteroatoms, the seniority is determined by the seniority of the heteroatoms.

3. The position of the connection along which the rings are annulated is indicated in square brackets separated by a hyphen. The connection of the senior cycle is designated by a letter of the Latin alphabet, the connection of the junior cycle is designated by the numbers of atoms separated by a comma, corresponding to the numbering in the isolated nucleus. The sequence of numbers is chosen in such a way that the direction of counting the bonds in both nuclei coincides:

4. The numbering of the atoms of the annulated heterocycle is carried out so that the sum of the numbers of the heteroatoms is the smallest, and if there are options, the smallest numbers should belong to older heteroatoms.

Examples :

3. Structure of heterocycles

Five-membered heterocycles with one heteroatom

Five-membered heterocycles with one heteroatom and two double C-C bonds meet the requirements for aromaticity. The nuclei of pyrrole, furan and thiophene are a flat ring with a conjugated system of electron orbitals, which includes 4n+2 p-electrons, two of which are supplied by the heteroatom.

Let us consider the delocalization of p-electrons in pyrrole. The nitrogen atom of the “pyrrole” type exists in the sp 2 hybrid state and formally forms three s-bonds: two with carbon, one with hydrogen or a substituent. s-Bonds are formed by hybrid orbitals, and the lone pair of electrons occupies a non-hybrid p-orbital. This makes it capable of conjugation with p_C-C bonds, resulting in the formation of an aromatic sextet. The electronic structure of pyrrole can be represented by resonance forms, five of which have the largest contribution to the resonance hybrid.

Thus, a "pyrrole" type heteroatom always provides two electrons to the p-system.

To understand the aromaticity of pyrrole, it can be compared with the isoelectronic cyclopentadiene anion.

It is easy to see that all five C-atoms of the cyclopentadinenide ion are equivalent: the lone electron pair, as in pyrrole, is located in the p-orbital and is delocalized.

The difference between pyrrole and the cyclopentadienyl anion is that not all boundary structures of pyrrole have the same contribution to the resonance hybrid. Their relative contribution can be assessed as follows: 1>3, 5>2, 4.

The electronic structure of furan and thiophene is qualitatively similar to the structure of pyrrole, only instead of the N-H s-bond there is a second lone pair of heteroatom electrons. This pair of electrons does not enter into conjugation with the p-system, because the axis of its orbital lies in the plane of the ring, i.e. perpendicular to the axes of the p-orbitals of the carbon atoms.

The existing significant differences in the distribution of electron density in the molecules of these three heterocycles can be assessed quantitatively on the basis of experimental data. When going from pyrrole to furan, the donor mesomeric effect of the heteroatom weakens, and the inductive acceptor effect increases, resulting in a change in the direction of the dipole moment.

Furan is therefore less p-excessive than pyrrole and is less aromatic and less stable. Thiophene is much more stable than both furan and pyrrole, and its chemical properties resemble benzene. It is interesting that the C-S-C bond angle in the thiophene molecule is close to 90°, which is not characteristic of an sp 2 hybrid atom in a five-membered ring (in a regular pentagon the angle is 108°).

These features of thiophene have led to two alternative proposals for the hybridization of the sulfur atom. According to the first of them, the sulfur atom is almost not hybridized, the s- and p-bonds are formed by pure p-orbitals. According to an alternative version, sulfur d-orbitals take part in the formation of C-S bonds, which can be expressed in terms of additional resonance structures:

In fact, the question of the true electronic structure of thiophene and the hybridization of the sulfur atom in its molecule remains controversial.

The bond lengths in the molecules of pyrrole, furan and thiophene have the following values:

Systems such as pyrrole, furan and thiophene, in which the number of aromatic electrons exceeds the number of atoms in the ring, and in the general concept, other heterocycles with heteroatoms only of the “pyrrole” type, are classified as p-excess. Despite the fact that the p-redundancy of these heterocycles is less than the p-redundancy of the cyclopentadienyl anion, it determines the main aspects of their reactivity.

An important factor characterizing the chemical behavior of five-membered heterocycles is their lower aromaticity compared to benzene. For a comparative assessment of the aromaticity of these compounds in relation to benzene, characteristics obtained as a result of quantum mechanical calculations are used: relative aromaticity, empirical resonance energy. You can find different values ​​for these parameters in different sources, but the following are currently accepted:

Based on the idea of ​​p-redundancy of pyrrole and its electronic analogues, it is logical to assume that these compounds are especially prone to participate in reactions with electrophiles. This is what is observed in reality. The properties of a compound containing a pyrrole heteroatom in the ring can be compared with the properties of aniline, in the molecule of which the amino group also activates the aromatic ring.

4. Six-membered heterocycles - azines and their analogues

Pyridine is an electronic analogue of benzene in which one CH group (methine group) is replaced by a nitrogen atom. Unlike pyrrole, the nitrogen atom in a neutral pyridine molecule forms two s-bonds and one p-bond, i.e. contributes one electron to the aromatic sextet. The lone pair of electrons of the nitrogen atom cannot enter into conjugation, because the axis of its orbital is oriented in space perpendicular to the axes of the orbitals of the p-electrons of the carbon atoms. This type of atom is called "pyridine". Being in the ring, a pyridine-type nitrogen atom cannot be a donor; it is an acceptor of p-electrons, since nitrogen is more electronegative than carbon. This is illustrated by the canonical structures of pyridine:

The inductive and mesomeric effects of the nitrogen atom in pyridine act in the same direction (-I - and - M), shifting the electron density towards the nitrogen atom. This is the reason that a partial positive charge is induced on the carbon atoms and the electron density in the nucleus is reduced. Therefore, pyridine is classified as a p-deficient aromatic heterocycle. The greatest positive charge is concentrated in the a- and g-positions. Here there is an analogy with the electronic structure of nitrobenzene, which has partial positive charges in ortho- And pair- provisions.

The oxygen and sulfur atoms may also be "pyridine" type atoms. The presence of such an atom in the cycle determines the existence of cationic isoelectronic analogues of benzene - pyrilium and thiopyrylium salts. Positively charged oxygen and sulfur atoms, like the pyridine nitrogen atom, contribute one electron to the p-system of the heteroring and have lone electron pairs that do not participate in conjugation with the p-electron system of the ring. Due to the fact that the electroacceptor properties of an atom with a total positive charge are greater than those of a neutral one, pyrilium and thiopyrylium salts are much more p-deficient than electrically neutral pyridine.

Six-membered heterocycles with several heteroatoms are also more p_deficient than pyridine. This is especially noticeable when the nitrogen atoms are located in the b-position to each other, for example, in pyrimidine and simm-triazine. The reason is that in these cases each heteroatom, independently of the other, places a positive charge on the same carbon atoms, as in the case of matched orientation, e.g. meta _dinitrobenzene.

five-membered heterocyclic organic compound

From the above it is obvious that pyridine, di- and triazines and, especially pyrilium salts, should easily react with nucleophilic reagents and be passive towards electrophiles.

5. Azoles

The molecules of diazoles (pyrazole and imidazole) contain heteroatoms of both “pyrrole” and “pyridine” types, and therefore compounds of this type, within the framework of the concept of p-excess (pyrrole) and p-deficient (pyridine) heterocycles, are called p-amphoteric . Among the polar boundary structures that describe the state of the imidazole and pyrazole molecules, there are structures with both positive and negative charges on the carbon atoms.

In fact, the chemical behavior of azoles illustrates their amphoteric nature—they are capable of reacting with both electrophiles and nucleophiles.

6. Pyrrole

Basicity

The lone pair of electrons of pyrrole nitrogen is largely involved in cyclic p-conjugation; it is inaccessible and therefore pyrrole exhibits very low basicity (pK a of the conjugate acid = - 3.8). Calculations show that among the possible pyrrolium cations, the resonance-stabilized cation is thermodynamically most favorable I- the result of protonation of the carbon atom in the a_positions. N-cation III least stable, because firstly, the charge in it is concentrated on one atom, and, secondly, the aromatic conjugation system is broken: it is actually a diene. Cation II occupies an intermediate position.

However, in an acidic environment, protonation of all nuclear atoms is possible. Crystalline salts corresponding to cations of the type I, can be isolated by passing dry HCl through solutions of polyalkylpyrroles in inert solvents. Evidence of cation formation III is an easy deuterium exchange of a proton at a pyrrole nitrogen atom in an acidic environment. Despite the fact that the cation III least stable, it is formed and destroyed faster than cations I And II, so the NH proton of pyrrole is deuterated faster than the CH protons. This phenomenon is called kinetic basicity. The kinetic basicity of nitrogen is always higher than that of carbon. C-cation II is responsible for the process of polymerization of pyrrole in an acidic environment, when a polymer of variable structure “pyrrole-red” is formed. The mechanism of the first stages of this reaction is confirmed by the structure of the isolated trimer.

The tendency of pyrroles to polymerize under the influence of acids imposes serious restrictions on the participation of pyrroles in reactions with electrophiles, because These transformations often occur in an acidic environment.

Reactions at the nitrogen atom

The acidity of pyrrole (pK a 17.0) is close to the acidity of ethanol (pK a 15.9) and strong bases can convert its pyrryl ion, which is a highly p_excess heteroanalogue of cyclopentadienyl. Sodium and potassium pyrrole salts obtained by the action of amides of metals or alkali metals easily interact with electrophiles - they are alkylated and acylated at the nitrogen atom, while mixed N-pyrrylmagnesium halides (the N-Mg bond is less ionic than N-Na) react predominantly at the a-position of the nucleus .

The kinetic acylation product N-acylpyrrole in the absence of a catalyst upon heating rearranges into a more stable thermodynamic product - 2-acetylpyrrole.

Reactions by carbon atoms

In neutral and acidic environments, pyrroles almost never react with electrophiles at the nitrogen atom. The electrophilic attack is directed mainly to the a_position of the nucleus. This is explained by the fact that the type I s-complexes formed in this case, as in the case of protonation, are the most stable among all possible ones.

Nitration

The nitrating mixture causes rapid decomposition of pyrrole, so special reagents are used for nitration: acetyl nitrate, prepared in advance from 70% HNO 3 and acetic anhydride, or crystalline nitronium tetrafluoroborate in non-aqueous solvents. In the second case (softer reagent) the yields are higher. The ratio of a- and b-isomers is approximately 4:1.

Sulfonation

Sulfonation of pyrrole due to its acidophobicity with oleum is impossible; however, pyrrole-2-sulfonic acid is formed in good yield using a complex of SO 3 with pyridine called pyridine sulfontrioxide.

Acylation

The acylation of pyrroles at carbon atoms, unlike benzene, does not require the use of catalysts usually used in the Friedel-Crafts reaction. Pyrrole is so active that it reacts with acetic anhydride when heated, and both 2-acyl and 2,5-diacylpyrroles can be easily obtained.

Friedel-Crafts alkylation of pyrrole is rarely used for synthetic purposes, because in this case, polyalkyl derivatives are quickly formed.

Halogenation

The interaction of pyrroles with molecular halogens leads, as a rule, to the substitution of all hydrogen atoms at free C-atoms, while at the same time, sulfuryl chloride, upon cooling, monochlorinates the pyrrole to the a-position.

Monohalopyrroles, unlike polysubstituted compounds, are unstable. The halogenation of pyrroles occurs so actively that it is often accompanied by the elimination of substituents, for example, the carboxyl group. In turn, a halogen atom, most often iodine, is easily removed during hydrogenation. This makes it possible to obtain an unsubstituted position in the nucleus in the case where a substituted pyrrole is more accessible as a starting compound, for example:

Reactions of pyrrole with weak electrophiles

Pyrrole, which is highly nucleophilic, easily reacts with weak electrophiles with which benzene does not react even under harsh conditions. For example, pyrrole enters into the Kolbe carboxylation reaction much more easily than even phenols - heating with ammonium carbonate is sufficient.

Pyrrole, like phenol, is formylated under the conditions of the Reimer-Tiemann reaction, when dichlorocarbene acts as the active reagent. However, this interaction is complicated by a parallel process - ring expansion occurs as a result of the introduction of dichlorocarbene into one of the p-bonds of the pyrrole ring, which leads to 3-chloropyridine. The explanation for this is that a cyclopropane derivative is formed intermediately, which is stabilized by two alternative pathways. The ratio of products depends on the reaction conditions.

In a weakly acidic environment, pyrrole is relatively stable, which makes it possible to introduce it, for example, into an azo coupling reaction, which once again confirms its high p_redundancy. If pyrrole is introduced into interaction with a diazonium salt in a weakly alkaline medium (pyrryl ion reacts), then 2,5- bis(phenylazo)pyrrole.

Pyrrole is capable of condensation with carbonyl compounds by its a-position, and the result of the reaction depends on the nature of the aldehyde or ketone. If the reaction with formaldehyde and aliphatic aldehydes in an acidic environment produces mainly polymers, then upon condensation with acetone the main product is methylated porphyrinogen. Mutual repulsion in space of methyl groups contributes to the planarization of the intermediate - trimer, therefore, during the next stage, a cyclic tetramer is more easily formed than a linear one.

When pyrroles interact with aromatic aldehydes, porphyrinogens are formed by a similar mechanism, which, however, are spontaneously oxidized by atmospheric oxygen into aromatic meso-tetraarylporphyrins.

In the case of condensation of pyrrole with pair-dimethylaminobenzaldehyde in a weakly acidic environment can isolate the primary condensation product - the red-violet arylidene pyrrolenium cation (Ehrlich color reaction).

To obtain unsubstituted porphyrinogen and porphyrin, it is advisable to first convert the pyrrole into a free Mannich base, and only then carry out condensation. Porphyrinogen under the action of most oxidizing agents, for example, when heated in chloroform with chloranil, is converted into unsubstituted porphyrin - porphin.

7. Indole

Indole is a condensed binuclear system consisting of a pyrrole nucleus and benzene. The systematic name for indole is benzo[ b] pyrrole. The chemical properties of pyrrole and indole are largely similar, but there are also differences.

Like pyrrole, indole has NH-acidity (pK a " 17), its N-anion, generated by strong bases (EtONa, t-BuOK, etc.), exhibits activity similar to the pyrryl ion: sodium and potassium salts alkylated and acylated at nitrogen, while mixed magnesium halide N-derivatives - at the C atom (3), i.e. at the b-position, but not at the a-carbon atom, as happens in pyrrole.

The latter circumstance is explained by the fact that in the anion, as in the neutral indole molecule, the negative charge is concentrated to a greater extent on the carbon atom in position 3 than on the C (2) atom. This can easily be seen in the set of resonance structures describing the indole N-anion:

Obviously, charge transfer to atom 2 is unfavorable (structure IV), because this disrupts the aromaticity of the benzene ring, while structures I and II contain an aromatic benzene ring.

The presence of electron-withdrawing substituents at position 3 greatly increases the acidity, and alkylation can be carried out in the presence of much weaker bases.

Indole exhibits high activity in reactions with a variety of electrophiles, and the substitution is also oriented towards position 3, but not along the a-carbon atom, as is the case in pyrrole. Resonance structures for indole s-complexes involving a- and b-carbon atoms lead to the same conclusions as the above scheme for N-anions: the s-complex formed as a result of the addition of an electrophile to atom 3 is more favorable.

Nitration

Indoles that do not have substituents in positions 2 and 3, similarly to pyrrole, polymerize under the influence of strong acids, therefore the nitration of such compounds is carried out with weak nitrating reagents - ethyl nitrate in the presence of sodium methoxide (indole anion reacts) or benzoyl nitrate in a neutral environment

2-Methylindole is more stable in an acidic environment than indole, so it is successfully nitrated under harsh conditions by the action of nitric acid. Up to three nitro groups can be introduced into the molecule, however, to synthesize a pure mononitro derivative, acyl nitrates should be used.

The reaction of 2-methylindole with a nitrating mixture proceeds interestingly: due to the fact that the compound is completely protonated, the reaction along the heterocyclic ring does not occur at all, and the intermediate covalent adduct with sulfuric acid reacts at position 5 of the benzene ring conjugated with the nitrogen atom.

Sulfonation

Sulfonation of indole, like pyrrole, is carried out by the action of the non-acidic reagent pyridine sulfotrioxide. If there is a substituent at position 3, for example a methyl group, then the reaction is oriented towards position 2.

Halogenation

Halogenation of indoles occurs very easily in position 3, however, the resulting haloindoles are not resistant to acids, therefore, for successful halogenation, reagents are used in the course of the reaction with which HHal is not released if possible: N-bromosuccinimide (NBS), SO 2 Cl 2, KI 3 , pyridinium perbromide.

If there is a substituent at the C-atom in position 3, then initially a cationic adduct with a halogen is formed at this atom, which is then transformed as a result of nucleophilic attack by the solvent, which leads to 2-hydroxyindoles or their derivatives.

In addition to the transformations listed above, indoles are capable of undergoing electrophilic acylation, Vilsmeier formylation, azo coupling, and condensation with carbonyl compounds. All reactions occur under mild conditions and are oriented towards position 3.

A substituent group at position 3, as a rule, does not prevent electrophilic attack at this position and the transformation is completed by the replacement of this group with electrophiles ( ipso-substitution).

The exception is diazonium salts, which do not enter into this reaction.

8. Furan

Of the three five-membered heterocycles considered, furan is the least aromatic and its diene character is noticeably manifested in many reactions.

Electrophilic aromatic substitution reactions for furan are known, but they require special reagents, because Under the action of protic acids, the furan ring is destroyed much more easily than pyrrole and, especially, indole.

But in general terms, furan in these reactions is significantly similar to pyrrole - it is very active and reacts predominantly with the a-positions.

Sulfonation

Sulfonation of furan, like pyrrole, can be carried out using pyridine sulfotrioxide in an organic solvent. The reaction produces a small impurity of furan-2,5-disulfonic acid.

The isolation of furan-2-sulfonic acid is carried out by destroying the resulting pyridinium 2-furylsulfonate with barium carbonate, and an insoluble barium salt is obtained.

Nitration

Like pyrrole, furan cannot be exposed to a nitrating mixture, but acetyl nitrate in pyridine can be used. The reaction proceeds more slowly than in the case of pyrrole, and a covalent product of the addition of the reagent to positions 2 and 5 is formed intermediately.

Furans having electron-withdrawing substituents are less acidophobic, so they are nitrated and sulfonated with conventional reagents.

Halogenation

The interaction of furan with halogens (bromine and, especially, chlorine) proceeds rapidly and leads to the formation of polyhalogen derivatives. Monohalofurans can be obtained only under mild conditions, for example, by the action of dioxane dibromide. There is disagreement about the mechanism of furan halogenation reactions: it is possible that they proceed as the addition of a halogen molecule to positions 2 and 5 and the subsequent elimination of a hydrogen halide molecule.

To confirm the addition-elimination mechanism, the action of bromine on furan in a methanol solution is considered, resulting in the formation of 2,5-dimethoxy-2,5-dihydrofuran.

The intermediate formation of adducts is also demonstrated by the example of the bromination reaction of 2,5-dibromofuran.

Formylation

Vilsmeier formylation of furan proceeds as smoothly as in the case of pyrrole, while acylation requires the mandatory addition of a Friedel-Crafts catalyst.

Diels-Alder reaction

There are transformations in which the diene character of furan is manifested. The most characteristic transformation is the reaction of diene synthesis (Diels-Alder). Furan itself and many of its derivatives react readily with maleic anhydride, dehydrobenzene and other dienophiles.

9. Thiophene

Among the heterocycles under consideration, thiophene is the most aromatic and its properties are in many ways similar to benzene. Thiophene derivatives accompany benzene derivatives in coal tar products and are very similar to them, often even having a similar odor.

Thiophene is much more resistant to acids than pyrrole and furan, so it can be introduced into a variety of electrophilic substitution reactions. which are oriented to the a-position.

When heated with 100% H3PO4, thiophene trimerizes, the reaction starting with the formation of an a-protonated cation, which is attacked by a neutral thiophene molecule.

Sulfonation

Thiophene reacts with electrophiles via the usual aromatic electrophilic substitution mechanism. It can be sulfonated with sulfuric acid at room temperature, which is used to separate thiophene from coal benzene in industry.

Nitration

To mononitrate thiophene into the a-position, it is best to use nitronium borofluoride: acetyl nitrate gives up to 20% 3-nitrothiophene impurity, while nitric acid reacts too violently, sometimes explosively. After the appearance of one nitro group in the nucleus, the activity decreases so much that further nitration requires the use of fuming HNO 3.

Halogenation

Thiophene is easily brominated and iodinated (unlike furan) to the a-position. The action of chlorine results in a mixture of products.

Acylation

Thiophene undergoes Friedel-Crafts acylation only in the presence of Lewis acids, and the reaction is accompanied by partial tarring due to self-condensation of the resulting ketones.

The Vilsmeier reaction proceeds with good yield, but at high temperature. The intermediate iminium salt can be isolated.

Condensation with carbonyl compounds

Similar to pyrrole and furan, thiophene actively condenses with carbonyl compounds, but the reaction can rarely be stopped at the stage of primary carbinol; di-, tri-, and polymers are often obtained.

Unlike furan, which decomposes under these conditions, thiophene can be converted into bis-chloromethyl derivative by the action of a large excess of formaldehyde and HCl.

The color “indophenine reaction” of thiophene with isatin in the presence of sulfuric acid, which is important from a historical point of view, deserves attention.

The intense blue indophenine led to the discovery of thiophene. Until 1882, it was believed that the indophenine reaction was characteristic of aromatic hydrocarbons, because The coal benzene used at that time always contained an admixture of thiophene. However, one day this beautiful experiment failed at W. Meyer’s lecture, because... at that time he used synthetic, not coal-burning, benzene. It became clear that the color reaction was caused by an impurity, which was later isolated and identified as a new compound - thiophene.

Loop extension

For substituted thiophenes, a ring expansion reaction is known, which is not typical for pyrrole and furan; the mechanism of this transformation is not known. Interestingly, as a result, a rather rare phenomenon is observed - the transformation of an aromatic compound into an anti-aromatic one.

Reactions on the sulfur atom

Thiophene undergoes peculiar reactions at the sulfur atom: alkylation and oxidation with peracids.

If S-alkylthiophene salts are stable and, judging by their spectral and chemical properties, aromatic compounds, then S,S-thiophene dioxides are not aromatic and can only be obtained for a,a-disubstituted substrates. These compounds react with dienophiles.

10. Interconversion of five-membered heterocycles

Under harsh conditions, pyrrole, furan and thiophene are capable of ring opening under the influence of nucleophiles, therefore, in the presence of a suitable reagent, they are able to convert into each other, which can be combined in the diagram:

This reaction is named after Yuryev; it occurs at 350°C in the presence of an Al 2 O 3 catalyst.

11. Pyridine

Transformations at the nitrogen atom

Pyridine is a base of medium strength with a pK a value of 5.2, measured in water (the basicity of aliphatic amines ranges from pK a 9-11). Pyridine forms crystalline salts with most protic acids and is often used as a basic catalyst or solvent that promotes the binding of acids released during a particular chemical reaction.

As a nucleophile, pyridine reacts with alkyl halides and other alkylating reagents via the S N 2 or S N 1 mechanism, depending on the nature of the substrate.

N_alkylpyridinium salts are aromatic compounds because the lone pair of electrons used to form a new bond does not participate in aromatic conjugation. These stable substances tend to react with nucleophiles due to their high p-scarcity. For example, nucleophilic hydroxylation by the action of potassium hydroxide gives a-pyridones.

When pyridines interact with acyl halides, N-acylium salts are formed. These compounds are not very stable and easily hydrolyze back.

It is precisely because of their low stability that acylpyridinium salts are important for synthetic chemistry as mild acylating reagents. For example, let us note the O-acylation of ketoenols - a reaction proceeding according to an unusual mechanism with the intermediate formation of an adduct at the a_position of the heterocycle.

When pyridine and its derivatives are treated with peracids, pyridine N-oxides are formed, the properties of which will be discussed separately.

Reactions by carbon atoms

Interaction with electrophiles

As shown above, pyridine is a p-deficient compound, so interaction with electrophiles is not typical for it, especially since electrophilic reactions occur in an acidic environment, where the pyridinium ion, which is even more p-deficient, interacts with the electrophile. These reactions are much more difficult than in benzene. Pyridine is attacked only by the strongest electrophiles, and under very harsh conditions. Electrophilic substitution is oriented toward position 3, which resembles the orientation of S E 2 reactions in nitrobenzene. This orientation is easily explained by the comparative stability of the face structures that describe cationic s_complexes resulting from the addition of an electrophile to the g-, b-, and a-positions of the pyridine ring. Obviously, only the s-complex II does not contain a contribution from a structure with a positively charged nitrogen atom.

As already mentioned, first an electrophile or proton attacks the nitrogen, which additionally passivates the substrate, converting it into a cation. If complexation at the heteroatom is prevented, the reaction of nuclear atoms with electrophiles proceeds more easily.

Nitration

Nitration of pyridine itself, especially with a nitrating mixture, when the heterocycle is completely protonated, is extremely difficult and has no practical significance.

2,6-Dimethyl and 2,4,6-trimethylpyridines, aminopyridines and pyridones are much more actively nitrated in the form of cations.

2,6-Dihalogen derivatives of pyridine, which as bases are weaker than pyridine, react more easily because the pyridine nitrogen atom is protonated to a lesser extent - the concentration of the free base is higher. Nitration proceeds more easily when using an aprotic nitrating reagent, for example:

Sulfonation

Sulfonation of pyridine with sulfuric acid is somewhat easier than nitration, but is also only possible under harsh conditions. At even higher temperatures, rearrangement into 4_sulfonic acid is possible.

An interesting product can be obtained by sulfonation of 2,6_di_ rubs _butylpyridine. Sulfonation itself proceeds easily, because bulky substituents prevent complex formation of SO 3 at the nitrogen atom. The resulting 2.6_di_ rubs When heated, _butylpyridine-3-sulfonic acid is converted into a cyclic sulfone due to one of the methyl groups rubs-butyl substituent.

Halogenation

Pyridines can be halogenated. It is not possible to introduce an iodine atom with satisfactory yield, but bromine and chloropyrimidines are synthesized quite simply.

Pyridine N-oxides exhibit greater activity in reactions with electrophiles than pyridine itself. There are two types of electrophilic substitution in N-oxides: the first option (without the addition of a nucleophile) leads mainly to N-oxides of 4-substituted pyridines. This, at first glance, strange circumstance is associated with the remarkable electronic nature of the N-oxide function, which can simultaneously manifest itself not only as an acceptor, but also as an electron donor. The diagram below illustrates this.

Therefore, the N-oxide of any substituted pyridine having a free position 4 can be nitrated with fuming HNO 3 in good yield.

Another approach to using N-oxides is to carry out the reaction in the presence of weak nucleophiles, which may be part of the reagent, for example, acetyl nitrate. In this case, the N-oxide is converted into a non-aromatic adduct, which is attacked by the electrophile. We can say that the pyridine nitrogen atom temporarily becomes an electron donor. The reaction allows one to obtain 3-nitro- and 3,5-dinitropyridines in good yields.

Similarly, another nitro group enters position 5

Nucleophilic substitution

Characteristic transformations of pyridine are nucleophilic substitution reactions. The amination reaction of pyridine when heated with sodium amide (Chichibabin reaction) leads to the formation of a-aminopyridine.

The reaction of replacing a hydrogen atom in pyridine with an amino group by the action of sodium amide is always oriented to position 2. The transformation has a complex mechanism: during the reaction, molecular hydrogen is released, which suggests the intermediate formation of sodium hydride. This fact, as well as the absence of hydrogen substitution products in position 4, is explained by the preliminary coordination of the sodium atom with the pyridine nitrogen atom.

Treatment of pyridines with freshly melted potassium hydroxide leads to hydroxylation to a_pyridones, which are a more stable form of existence of a- and g-hydroxypyridines.

Reactions of nucleophilic substitution of halogen in pyridine proceed by the same two alternative mechanisms as in halogenarenes - addition-elimination (AE) and elimination-addition (EA). The AE reaction (the addition of a nucleophile to form an s-complex and the elimination of a leaving group) occurs predominantly at atoms 2, 4 and 6, in which the maximum positive charge is concentrated. In addition, the nitrogen atom participates in the delocalization of the negative charge of the corresponding s-complexes, like the nitro group in the case of nitrochlorobenzenes. It is easy to see that the most stable are the anionic s-complexes I And III.

Using a reaction such as nucleophilic AE, a wide variety of substituents can be introduced into the pyridine molecule. Here are some examples:

Pyridine N-oxides and N-alkylpyridinium salts undergo the same reactions more easily than pyridine itself. Particularly interesting are the N-oxides of a-halopyridines, which immediately transform under the action of certain nucleophiles into condensed binuclear heterocycles, the formation of which occurs with the participation of the N-oxide group.

If the halogen is in position 3, then the reaction of pyridines with nucleophiles most often proceeds according to the EA mechanism through the intermediate formation of a heteroanalogue of dehydrobenzene - hetarine.

Free radical reactions

When atomic chlorine and (high temperatures) bromine act on pyridine, free radical halogenation occurs, which, unlike electrophilic, is oriented to positions 2 and 6.

For preparative purposes, the reactions of pyridine with nucleophilic radicals (Minisha reaction) are important. The sources of radicals are various organic compounds in the presence of peroxides and iron (II) salts, the cation of which serves as an electron carrier.

The reaction mechanism includes the stages of homolytic decomposition of peroxide, conversion of the reagent into a free radical and its addition to pyridine and subsequent aromatization.

In this way, a hydroxymethyl group, dialkylamide and other functional groups can be introduced into positions 2 and 4 of pyridine and quinoline.

Literature

1. Artemenko A.I., Tikunova I.V., Anufriev E.K. Workshop on organic chemistry. - M.: Higher School, 2007-187p.

2. Berezin B.D., Berezin D.B. Course of modern organic chemistry. Textbook for universities. - M.: Higher School, 2001. - 768 p.

3. Glinka N.L. General chemistry / Edited by V.A. Rabinovich. - L.: Chemistry, 1986. - 704 p.

4. Gradberg I.I. Practical work and seminars in organic chemistry. - M.: Bustard, 2011. - 352 p.

5. Collection of problems in organic chemistry. Textbook / Edited by A.E. Agronomova. - M.: Moscow State University Publishing House, 2010. - 160 p.

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Classification of N-containing heterocyclic compounds

- Five-membered heterocycles:

a) with one nitrogen atom (pyrrole and its derivatives)

b) with two nitrogen atoms (imidazole, pyrazole and their derivatives)

- Six-membered heterocycles:

a) with one nitrogen atom (pyridine and its derivatives)

b) with two nitrogen atoms (pyrimidine and its derivatives)

- Condensed (bicyclic) heterocycles (purine and its derivatives)

Pyrrole

Electronic structure of the molecule

The pyrrole cycle is aromatic in nature, since 4 unpaired electrons of the carbon atoms and a lone pair of electrons of the nitrogen atom form a single six-electron π-system. (Unlike benzene, a single π-system is usually not shown in the structural formulas of heterocyclic compounds.) The participation of the lone pair of electrons of the nitrogen atom in the formation of an aromatic bond explains why pyrrole practically does not exhibit basic properties (unlike amines). On the contrary, pyrrole has weakly acidic properties. properties.

Chemical properties

I. Acidic properties: interaction with active metals

II. Aromatic properties:

a) substitution reactions (usually in the α-position)

b) addition reactions (hydrogenation)

Pyrrolidine is a cyclic secondary amine and exhibits strongly basic properties. The pyrrolidine cycle is part of the heterocyclic amino acids proline and hydroxyproline:

Methods of obtaining

1. Preparation from furan and thiophene

2. Preparation from acetylene

Physical properties

Pyrrole is a colorless liquid with the odor of chloroform, boiling point 131°C, practically insoluble in water, soluble in alcohol and acetone

A pine splinter moistened with hydrochloric acid turns red with pyrrole vapor (hence the name pyrrol - “red oil”).

Biological role

Cycles of substituted pyrrole derivatives are part of chlorophyll and heme. In the chlorophyll molecule, four substituted pyrrole rings are associated with a magnesium atom, and in heme - with an iron atom

Pyridine

Electronic structure of the molecule

The pyridine cycle (like the pyrrole cycle) is aromatic in nature and is very similar to the benzene cycle. An aromatic six-electron π bond is formed by the unpaired electrons of five carbon atoms and a nitrogen atom. Unlike pyrrole, the lone pair of electrons of the nitrogen atom in pyridine does not participate in the formation of the π-system, and therefore can participate in the formation of a donor-acceptor bond with the NP. Consequently, pyridine exhibits basic properties.

Chemical properties

Basic properties

a) interaction with water

(An aqueous solution of pyridine turns litmus blue)

b) interaction with acids

II. Aromatic properties:

a) substitution reactions (usually in the β-position, since the nitrogen atom behaves as a substituent of the second kind)

b) addition reactions (hydrogenation):

Methods of obtaining

1. Isolation from coal tar (contains about 0.08% pyridine).

2. Synthesis from acetylene and hydrogen cyanide

Physical properties

Pyridine is a colorless liquid with a specific odor, boiling point 115°C, infinitely miscible with water, very toxic.

Biological role

Pyridine homologue - 3-methylpyridine (β-picoline) - upon oxidation forms nicotinic acid:

Nicotinic acid and its amide - nicotinamide are two forms of vitamin PP, which is used to treat pellagra (skin disease).

Imidazole

Electronic structure of the molecule. General characteristics of chemical properties

From the above formula it is clear that:

a) imidazole (like pyrrole and pyridine) is an aromatic compound;

b) imidazole has amphoteric properties, since N(1) determines the acidic properties, and N(3) determines the basic properties.

Physical properties

Imidazole is a colorless solid, melting point 90°C, soluble in water and alcohol.

Biological role

The imidazole core is part of one of the natural amino acids - histidine:

When decarboxylation (-CO 2) of histidine is formed, histamine is formed:

Histamine is found in bound form in various organs and tissues of humans and animals and is released during allergic reactions, shock, and burns.

Pyrimidine

General characteristics of electronic structure, chemical properties and biological role

Pyrimidine, like other heterocyclic compounds, has an aromatic character. The presence of two pyridine nitrogen atoms determines the basic properties of pyrimidine. Pyrimidine derivatives are called pyrimidine bases. Residues of three pyrimidine bases (uracil, thymine, cytosine) are part of nucleic acids (see “Nucleic acids”).

Purin

Molecule structure. Biological role

The purine molecule is a system of pyrimidine and imidazole rings having two common carbon atoms:

Purine derivatives are called purine bases. Residues of two purine bases (adenine and guanine) are part of nucleic acids (see “Nucleic acids”).