Medicinal substances are derivatives of pyridine. UV and IR spectroscopy methods

13.08.2020

Pyridine isa six-membered aromatic heterocycle with one nitrogen atom, a colorless liquid with a pungent unpleasant odor; miscible with water and organic solvents.

Pyridine is a weak base, gives salts with strong mineral acids, easily forms double salts and complex compounds.

The electronic structure of the pyridine molecule is similar to the structure of benzene. The carbon and nitrogen atoms are in a state of sp2 hybridization. All σ-bonds C – C, C – H, and C – N are formed by hybrid orbitals, the angles between them are approximately 120 °. Therefore, the cycle has a flat structure. Six electrons in non-hybrid p-orbitals form a π-electron aromatic system.

Of the three hybrid orbitals of the nitrogen atom, two form the C – N σ-bonds, and the third contains a lone pair of electrons that do not participate in the π-electron system. Therefore, pyridine, like amines, exhibits base properties. Its aqueous solution stains litmus blue. When pyridine reacts with strong acids, pyridinium salts are formed.

Piridine exhibits properties characteristic of tertiary amines: it forms N-oxides, N-alkylpyridinium salts, and is capable of acting as a sigma-donor ligand.

At the same time, pyridine has distinct aromatic properties. However, the presence of a nitrogen atom in the conjugation ring leads to a serious redistribution of the electron density, which leads to a strong decrease in the activity of pyridine in reactions of electrophilic aromatic substitution. In such reactions, predominantly the meta-positions of the ring react.

The fundamental difference between pyridine and benzene is that, due to the higher electronegativity of nitrogen in comparison with carbon in the case of pyridine, in the set of limiting structures describing the distribution of the p-electron density, the contribution of structures with separated negative and positive charges is significant:

From their consideration it can be seen that the negative charge is localized on the nitrogen atom, and the positive charge is distributed mainly between the carbon atoms in the 2,4 and 6 positions (a- and g-positions). In this regard, pyridine is referred to as electron-deficient aromatic heterocycles, in contrast to the above-considered furan, pyrrole, and thiophene. This means that the pyridine nucleus, as an aromatic system, is deactivated with respect to the electrophilic system and, conversely, is activated with respect to the nucleophilic attack in comparison with benzene.

However, the presence of a lone pair of electrons and an excess p-electron density in a nitrogen atom makes it a very active center of attack by an electrophile, especially since the formation of an s-bond does not affect the aromatic system. Thus, pyridine is an active N-nucleophile, and this property is always realized initially during electrophilic attack.

Other possible directions of the reaction associated with the manifestation of pyridine C-nucleophilicity - electrophilic attack on carbon atoms - are extremely difficult and require very harsh conditions for their implementation. In addition to the aforementioned electron-deficient nature of the p-electron system, within the framework of a general approach to a qualitative explanation of the regularities of electrophilic substitution in the aromatic nucleus, this should be associated with the fact that the presence of nitrogen in the ring, which is more electronegative than the carbon atom, destabilizes the intermediate cation s-complex ...

Thus, pyridine combines the properties of a highly active n-nucleophile and a substantially deactivated p-nucleophile. As will be seen from the examples below, a product that is easily formed as a result of an electrophilic attack on a nitrogen atom is often unstable and its formation, although kinetically preferable, is reversible. In contrast, the electrophilic attack on carbon atoms is much more difficult, but leads to the formation of more stable substitution products, thermodynamically preferable. As a result, many reactions of pyridine derivatives can be carried out under conditions of kinetic, that is, heteroatom, or thermodynamic, that is, ring carbon atoms, control, which makes them related to similar reactions of oxyarenes and aromatic amines.

As noted earlier, pyridine is a base and is protonated to form stable pyridinium salts. The N-alkylation of pyridine with alkyl halides proceeds in a similar manner, leading to alkyl pyridinium salts. Oxidation with peracids with the formation of pyridine N-oxide can also be attributed to similar reactions with electrophiles on the lone pair of electrons of the nitrogen atom.

In a similar way, pyridine interacts with bromine to form N-bromopyridinium salt - pyridinium bromide perbromide, and with oleum upon cooling to form pyridine sulfotrioxide.

The reaction of carboxylic acid chlorides with pyridine occurs in a similar manner. However, the resulting N-acylpyridinium salt is so active electrophilic, in this case an acylating reagent, that it cannot be isolated in a free state.

For pyridine, reactions of aromatic nucleophilic substitution are characteristic, proceeding mainly at the ortho-para positions of the ring. This reactivity indicates the electron-deficient nature of the pyridine ring, which can be summarized in the following rule of thumb: the reactivity of pyridine as an aromatic compound roughly corresponds to the reactivity of nitrobenzene.

Pyridine exhibits the properties of an aromatic compound, but, unlike benzene, it hardly enters into reactions of electrophilic substitution - it is nitrated, sulfonated, and brominated only at about 300 ° C with the formation of predominantly b-derivatives. Nucleophilic substitution is easier than in benzene.

So, pyridine with NaNH2 gives a-aminopyridine, with KOH - a-hydroxypyridine. Pyridine is reduced with sodium in alcohol or H2 over Ni at 120 ° C to piperidine. Under the action, for example, of bases on the pyridinium salt, the pyridine ring is broken to form glutacone dialdehyde HOCCH \u003d CHCH2COH or its derivatives.

Forms stable salts with inorganic acids, pyridinium salts with alkyl halides, metal halides, SO2, SO3, Br2, H2O - complex compounds.

Electrophilic substitution proceeds with great difficulty (pyridine is close to nitrobenzene in its ability to electrophilic substitution) and goes to position 3. Most of these reactions take place in an acidic medium, in which the starting compound is no longer pyridine itself, but its salt.

Along with the basic properties, pyridine exhibits the properties of an aromatic compound. However, its activity in electrophilic substitution reactions is lower than that of benzene. This is due to the fact that nitrogen, as a more electronegative element, attracts electrons towards itself and lowers the density of the electron cloud in the ring, especially in positions 2, 4, and 6 (ortho and para positions).

Therefore, for example, the pyridine nitration reaction proceeds under severe conditions (at 300 ° C) and with a low yield. The orienting influence of the nitrogen atom on the introduction of a new substituent upon electrophilic substitution in pyridine is similar to the influence of the nitro group in nitrobenzene: the reaction proceeds to position 3.

Like benzene, pyridine can add hydrogen in the presence of a Catalyst to form a saturated piperidine compound.

Piperidine exhibits secondary amine properties (strong base).

Pyridine is nitrated only under the action of NaNO3 or KNO3 in fuming H2SO4 at a temperature of 300 0C, forming 3-nitropyridine in low yield; sulfonated with oleum in the presence of Hg sulfate at 220-2700C to pyridine-3-sulfonic acid.

When mercury acetate acts on pyridine at 1550C, 3-pyridylmercuracetate is formed; at higher temperatures - di- and polysubstituted derivatives.

The action of Br2 in oleum at 3000C leads to a mixture of 3-bromo- and 3,5-dibromo-pyridines. At a higher temperature (about 5000C), the reaction proceeds according to a radical mechanism; the reaction products are 2-bromo- and 2,6-dibromopyridines.

Radical reactions include the interaction of pyridine with phenyldiazonium hydrate (Homberg-Bachmann-Hay reaction), resulting in a mixture containing 55% 2-phenyl-, 30% 3-phenyl- and 15% 4-phenyl-pyridine.

Nucleophilic substitution in pyridine occurs at positions 2 and 4 and is easier than in benzene, for example, the synthesis of 2-aminopyridine by the interaction of pyridine with sodium amide. (Chichibabin reaction).

Pyridine, as a rule, is resistant to oxidizing agents; however, when exposed to peracids, it readily forms pyridine N-oxide, in which the electron density at the C-2 and C-4 atoms is increased compared to pyridine.

At 300 0C, under the action of FeCl3, pyridine is oxidized into a mixture of isomeric bipyridyls of general formula C5H4N-C5H4N.

Catalytic hydrogenation in the presence of Pt or Ni, reduction of Na in alcohol, and electrochemical reduction leads to piperidine (the latter method is used industrially). More severe reduction of pyridine is accompanied by ring cleavage and deamination.

Pyridine nitration occurs by the action of potassium nitrate and sulfuric acid at 370 ° C, leading to β-nitropyridine. Sulfonation of pyridine is carried out with oleum in the presence of mercury sulfate at 220 ° C, bromination can be carried out by the action of a solution of bromine in oleum at 300 ° C. It is not possible to introduce the second substituent into the ring in this way. Pyridine does not enter the Friedel-Crafts reaction.

In the chemistry of pyridine in general, and in the part that concerns its functionalization by means of electrophilic substitution reactions, the possibility of its conversion into N-oxide is of great importance. Let's consider the electronic structure of this compound.

An analysis of these resonance structures leads to the surprising conclusion that the N-oxide group can act in relation to the p-electron system of the ring both as a donor (top row of structures) and as an electron acceptor, that is, it can promote both electrophilic substitution reactions at a and g-positions, and the addition of a nucleophile at the same positions! What is actually observed?

The actual electronic influence exerted by this group depends on the nature of the reagent. Nitration of pyridine N-oxide proceeds much easier than for pyridine itself - under the action of a mixture of fuming nitric acid and sulfuric acid at 90 ° C, leading to the g-nitro derivative with a yield of 90%, which is in accordance with the activating effect of the N-oxide group ... In contrast, the sulfonation reaction occurs under conditions similar to the conditions for sulfonation of pyridine itself, leading to β-sulfonic acid. This direction of the sulfonation reaction is explained by the coordination of SO3 at the oxygen atom of the N-oxide group, which converts this group into an acceptor and, therefore, a meta-orientant.

Conversion of pyridine into its N-oxide, carrying out electrophilic substitution reactions with it, and subsequent reductive removal of the N-oxide oxygen atom is a common approach to the synthesis of a wide range of functionally substituted pyridine derivatives that cannot be obtained directly from pyridine. Thus, the reduction of g-nitropyridine N-oxide with triphenylphosphine leads to the removal of the N-oxide oxygen atom, which makes it possible to obtain 4-nitropyridine in good yield. Reduction of g-nitropyridine N-oxide with iron in acetic acid leads to simultaneous reduction of the nitro group and the N-oxide group, leading to 4-aminopyridine. As noted earlier, the N-oxide group also facilitates nucleophilic substitution reactions. So, when the N-oxide of g-nitropyridine interacts with hydrogen chloride or hydrogen bromide, the N-oxide of g-halogenated pyridine is formed (suggest the mechanism of this reaction), the subsequent reaction with PCl3 leads to the elimination of the N-oxide group.

During the interaction of pyridine N-oxide with organometallic compounds, the addition occurs mainly at position 2, that is, in this reaction, the N-oxide group actually activates the indicated position with respect to the nucleophilic attack. After treatment of the reaction mixture with water, 2-substituted pyridine derivatives are formed in high yield.

When pyridine N-oxide interacts with alkalis in the presence of atmospheric oxygen (oxidizing agent), a-hydroxypyridine oxide is formed. It is interesting to note that this compound exists in tautomeric equilibrium with N-hydroxypyridone.

Alkylpyridinium salts interact even more easily with nucleophilic reagents.

The interaction of pyridinium salts with nucleophilic reagents can also lead to ring opening. So the reaction of methylpyridinium iodide with aniline leads to an acyclic conjugated heterotriene system. This reaction has preparative significance.

Pyridine itself is also capable of entering into nucleophilic addition reactions, but, naturally, under more severe conditions. Of these transformations, the Chichibabin reaction - interaction with sodium amide at 130 ° С has the greatest preparative value. This reaction occurs by the mechanism of addition-elimination and its product is a-aminopyridine. When pyridine reacts with potassium amide, g-aminopyridine is also formed along with a-aminopyridine.

When heated to 400 ° C, pyridine reacts with KOH to form a-hydroxypyridine, the reaction with phenyllithium occurs at 110 ° C for 8 hours and after treatment with water leads to a-phenylpyridine.

Reduction of pyridine and its derivatives occurs either under the action of metallic sodium in alcohol or under conditions of catalytic hydrogenation. In this case, hexahydro derivatives of pyridine are formed, and in the case of pyridine itself, piperidine.

b-Aminopyridine upon diazotization forms sufficiently stable diazonium salts, which can be converted into transformations, usual for this class of compounds, both with and without nitrogen evolution. In contrast, a- and g-aminopyridines form diazonium salts with difficulty, and these salts themselves are very unstable.

It is interesting to draw a parallel between the ability of hydroxypyridines and hydroxyarenes to exist in the tautomeric oxoform. Formally, the process of establishing such an equilibrium in pyridine and benzene derivatives should proceed according to the same mechanism and consists in the transfer of a proton from the hydroxy group to the aromatic or heteroaromatic ring. This process is not synchronous, but proceeds in two stages, the first of which is deprotonation, occurs with the participation of a solvent or one more arene molecule and naturally proceeds the easier, the stronger the acid is the hydroxyl group. Considering the electron-deficient nature of the pyridine nucleus, it can be argued that the acidity of hydroxypyridines is noticeably higher than that of hydroxyarenes and, therefore, the activation barrier in the case of pyridine derivatives will be lower. The second stage is protonation. Since the lone pair of electrons of the nitrogen atom in the pyridine ring is available for electrophilic attack, in particular for protonation, and there is a partial negative charge on the nitrogen atom itself (cf. p. 43), it can be assumed that this step should be carried out more easily in the case of derivatives pyridine. Let us consider what these transformations should lead to, depending on the position of the hydroxy group in the pyridine ring.

As can be seen from the presented scheme, in the case of a- and g-hydroxypyridines, the sequence of protonation-deprotonation stages leads to the keto form; with the b-arrangement of the hydroxy group, such a transformation is impossible - its result is the formation of a zwitter ion. Indeed, b-hydroxypyridine exists precisely in this form, which is evident from its abnormally high melting point and low solubility in organic solvents. Of course, both in the case of hydroxyarenes and in the case of hydroxypyridines, the considered transformation leads to the loss of aromaticity in the molecule, but for the reasons indicated above, this tautomeric equilibrium is much more characteristic of pyridine derivatives.

It should be noted that when additional donor groups are introduced into the aromatic ring that facilitate protonation, the keto-enol tautomeric equilibrium is realized for hydroxyarenes as well. So, fleroglucin - 1,3,5-trihydroxybenzene - exists mainly in the keto form.

Pyridine is a weaker base than aliphatic amines (Kb \u003d 1.7.10-9). Its aqueous solution stains litmus blue:

When pyridine interacts with strong acids, pyridinium salts are formed:

Aromatic properties. Like benzene, pyridine enters into electrophilic substitution reactions; however, its activity in these reactions is lower than that of benzene, due to the high electronegativity of the nitrogen atom. Pyridine is nitrated at 300 ° C with low yield:

The nitrogen atom in electrophilic substitution reactions behaves as a substituent of the second kind; therefore, electrophilic substitution occurs in the meta position.

Unlike benzene, pyridine is capable of entering into nucleophilic substitution reactions, since the nitrogen atom pulls off the electron density from the aromatic system, and the ortho-para positions with respect to the nitrogen atom are depleted in electrons. Thus, pyridine can react with sodium amide, forming a mixture of ortho- and para-aminopyridines (Chichibabin reaction):

Hydrogenation of pyridine produces piperidine, which is a cyclic secondary amine and is a much stronger base than pyridine:

The pyridine homologues are similar in properties to the benzene homologues. So, during the oxidation of side chains, the corresponding carboxylic acids are formed:

Mol. m. 79.1; colorless liquid with special features. smell; t. pl. -42.7 0 C, bp 115.4 ° C / 760 mm Hg. Art., 13.2 ° C / 10 mmHg; 0.9819: 1.5095; m 7.30 x x 10 -30 C · m; g 3.7 · 10 -2 N / m (25 ° C); h 0.885 mPa · s (25 0 C); C p135.62 kJ / mol K) (17 0 C), - 2783 kJ / mol. Mixes up in all respects with water and most org. p-eaters; with water forms an azeotropic mixture (bp 94 ° C, 58% by weight of P.).

P.-base ( r To a5.20). With neorg. to-tami forms stable salts, with alkyl halides -pyridinium salt , with metal halides, SO 2, SO 3, Br 2, H 2 O-complex compounds. Typical derivatives: (C 5 H 5 N HCl) 2 PtCl 2 (mp 262-264 0 C, with decomposition), C 5 H 5 N HCl 2HgCl 2 (mp 177-178 0 C ).

Possesses aromatic. St. you; contains 6p-electrons, forming a single closed system, in a cut due to negative. induction the effect of the N atom, the electron density of C atoms, especially in positions 2, 4, and 6, is lowered (p-deficient heterocycle).

Electroph. the substitution proceeds with great difficulty (P. is close to nitrobenzene by its ability to electrophysical substitution) and goes to position 3. Most of these districts take place in an acidic medium, in a cut with the initial connection. it is no longer P. himself, but his salt. P. is nitrated only under the action of NaNO 3 or KNO 3 in fuming H 2 SO 4 at temperature 300 0 C, forming 3-nitropyridine with a small yield; sulfonated with oleum in the presence of Hg sulfate at 220-270 ° C to pyridine-3-sulfonic acid. When mercury acetate acts on P. at 155 ° C, 3-pyridylmercuracetate is formed; at higher t-max-di- and polysubstituted derivatives. The action of Br 2 in oleum at 300 ° C leads to a mixture of 3-bromo- and 3,5-dibromo-pyridines. At a higher temperature (about 500 0 C), the reaction proceeds according to a radical mechanism; p-tions products - 2-bromo- and 2,6-dibromopyridines. Radical reactions include the interaction of P. with phenyldiazonium hydrate (the Gomberg-Bachmann-Hay reaction), resulting in a mixture containing 55% 2-phenyl-, 30% 3-phenyl- and 15% 4-phenyl-pyridine.

nucleophilic substitution in P. proceeds along positions 2 and 4 and is easier than in benzene, for example, the synthesis of 2-aminopyridine when P. interacts with sodium amide (see. Chichibabin reaction ).

P., as a rule, is resistant to oxidizing agents, however, under the action of peracids, it readily forms pyridine N-oxide. Amines N-oxides) in which the electron density on the C-2 and C-4 atoms is increased in comparison with P. At 300 0 C under the action of FeCl 3 P. is oxidized into a mixture of isomeric dipyridyls of total f-ly C 5 H 4 NC 5 H 4 N. Catalytic hydrogenation in the presence of Pt or Ni, reduction of Na in alcohol, as well as electrochem. recovery leads to piperidine (the latter method is used in the industry). More severe P.'s recovery is accompanied by cycle splitting and deamination.

The addition of carbenes to P. or the deprotonation of N-alkylpyridinium ions leads to pyridinium ylides of the total f-ly I, the interaction of P. with nitrenes or the deprotonation of N-aminopyridinium salts - to pyridinium imines of the total f-ly II.

Conn. both types easily enter into the reaction of cycloaddition, characteristic of 1,3-dipolar systems. P. is isolated mainly from Kam.-ug. resin (content approx. 0.08%), dry distillation products of wood, peat or bone. Synthetically, it can be. received a trace. reactions:

P. and its derivatives-basis pyridine alkaloids , as well as many others. medicinal medium. P. is also used in the synthesis of dyes, insecticides, and is used for denaturation of alcohol. P.'s complex with SO 3 -pyridine sulfotrioxide is a soft sulfonating agent; C 5 H 5 NBr 2 · HBr brominating agent; C 5 H 5 N · HCl-reagent for dehydration of epoxides and N-dealkylation, C 5 H 5 N · H 2 Cr 2 O 7 -oxidant. P. is a good solvent, incl. for many inorg. salts (AgBr, Hg 2 Cl 2, etc.). MPC of P. vapors in the air ~ 0.005 mg / l, i.e. ignition. 23.3 0 C.

P. was first isolated by T. Andersen in 1849 from bone oil; P.'s structure was established by J. Dewar and P. Kerner in 1869.

For P. derivatives, see

PYRIDINE , they say. m. 79.1; colorless liquid with special features. smell; t. pl. -42.70C, bp. 115.4 ° C / 760 mm Hg. Art., 13.2 ° C / 10 mmHg; 0.9819: 1.5095; m 7.30 x x 10-30 Cm; g 3.7 · 10-2 N / m (250C); h 0.885 mPa · s (250C); Сp 135.62 kJ / mol K) (170C), - 2783 kJ / mol. Mixes up in all respects with water and most org. p-eaters; with water forms an azeotropic mixture (bp 940C, 58% by weight of P.).
P-base (pKa 5.20). With neorg. to-tami forms stable salts, with alkyl halides - pyridinium salts, with metal halides, SO2, SO3, Br2, H2O-complex compounds. Typical derivatives: (C5H5N HCl) 2 PtCl2 (mp 262-2640C, decomp.), C5H5N HCl 2HgCl2 (mp 177-1780C).
Possesses aromatic. St. you; contains 6p-electrons, forming a single closed system, in a cut due to negative. induction effect of the N atom, the electron density of C atoms, especially in positions 2, 4, and 6, is lowered (p-deficient heterocycle).
Electroph. the substitution proceeds with great difficulty (P. is close to nitrobenzene by its ability to electrophysical substitution) and goes to position 3. Most of these districts take place in an acidic medium, in a cut with the initial connection. it is no longer P. himself, but his salt. P. is nitrated only under the action of NaNO3 or KNO3 in fuming H2SO4 at temperature 300 0C, forming 3-nitropyridine with a small yield; sulfonated with oleum in the presence. sulfate Hg at 220-2700C to pyridine-3-sulfonic acid. When mercury acetate acts on P. at 1550C, 3-pyridylmercuracetate is formed; at higher t-max-di- and polysubstituted derivatives. The action of Br2 in oleum at 3000C leads to a mixture of 3-bromo- and 3,5-dibromo-pyridines. At a higher temperature (approx. 5000C), the district goes to a radical mechanism; p-tions products - 2-bromo- and 2,6-dibromopyridines. The reaction of P. with phenyldiazonium hydrate (the district of Gomberg-Bachmann-Hey) also belongs to the radical regions, as a result of which a mixture is formed containing 55% 2-phenyl-, 30% 3-phenyl- and 15% 4- phenyl pyridine.
Nucleof. substitution in P. proceeds according to provisions 2 and 4 and is easier than in benzene, for example, the synthesis of 2-aminopyridine when P. interacts with sodium amide (see Chichibabin reaction).
P., as a rule, is resistant to oxidants, however, under the action of peracids, it readily forms pyridine N-oxide (see Amines N-oxides), in which the electron density on the C-2 and C-4 atoms is increased compared to P. At 300 0C under the action of FeCl3 P. is oxidized into a mixture of isomeric dipyridines of total f-ly C5H4N-C5H4N. Catalytic hydration in the presence. Pt or Ni, Na reduction in alcohol, as well as electrochem. recovery leads to piperidine (the latter method is used in the industry). More severe P.'s recovery is accompanied by cycle splitting and deamination.
The addition of carbenes to P. or the deprotonation of N-alkylpyridinium ions leads to pyridinium ylides of the total f-ly I, the interaction of P. with nitrenes or the deprotonation of N-aminopyridinium salts - to pyridinium imines of the total f-ly II.

Conn. both types easily enter into the reaction of cycloaddition, characteristic of 1,3-dipolar systems. P. allocate hl. arr. from Kam.-ug. resin (content approx. 0.08%), dry distillation products of wood, peat or bone. Synthetically, it can be. the trace is received. p-tions:

P. and its derivatives are the basis of pyridine alkaloids, as well as many others. lek. Wed-in. P. is also used in the synthesis of dyes, insecticides, and is used for denaturation of alcohol. P.'s complex with SO3-pyridine sulfotrioxide-soft sulfonating agent; C5H5NBr2 HBr brominating agent; C5H5N HCl reagent for epoxide dehydration and N-dealkylation, C5H5N H2Cr2O7 oxidizing agent. P. is a good p-reteller, incl. for many inorg. salts (AgBr, Hg2Cl2, etc.). MPC of P. vapors in the air ~ 0.005 mg / l, i.e. ignition. 23.3 0C.
P. was first isolated by T. Andersen in 1849 from bone oil; P.'s structure was established by J. Dewar and P. Kerner in 1869.
For P.'s derivatives, see Lutidines, Oxypyridines, Picolines, Pyridinium salts.
Lit .: General organic chemistry, trans. from English, vol. 8, M., 1985, p. 15-117; Pyridine and its derivatives. Suppl. ed. by R. A. Abramovitch, pt 1-4, N. Y., 1974; Pyridine and its derivatives, ed by E. Klingsberg, pt 1-4, L. - N. Y. - Sydney, 1960-64. L. N. Yakhontov.

Cyclic compounds in which the rings are formed not only by carbon atoms, but also by atoms of other elements - heteroatoms (O, S, N) - are called heterocyclic. Heterocyclic compounds are classified according to the ring size and the number of heteroatoms in the ring.

Among these compounds, the most important are five- and six-membered heterocyclic compounds. Typical heterocyclic compounds are aromatic in character. However, the presence of a heteroatom affects the electron density distribution. For example, in five-membered heterocycles (furan, thiophene, pyrrole), the electron density is shifted from the heteroatom towards the ring and is maximum in the a-positions. Therefore, in the a-positions the reaction of electrophilic substitution (S Е) proceeds most easily.

In six-membered rings (for example, pyridine), a heteroatom bonded to carbon by a double bond pulls off the p-electron density of the cycle; therefore, the electron density in the pyridine molecule is lowered at the a and g-positions. This is consistent with the preferred orientation to these positions of the reactants at nucleophilic substitution (S N). Since the electron density in pyridine is higher in the b - position, the electrophilic reagent is oriented in the b - position.

When studying heterocycles with two heteroatoms, pay special attention to pyrimidine and its derivatives: uracil, thymine, cytosine. The pyrimidine core is found in numerous natural products: vitamins, coenzymes and nucleic acids:

Electrophilic substitution for pyrimidine occurs at position 5; nucleophilic (as for pyridine) is difficult and the carbon atom in positions 4 and 6 is attacked.

A complex heterocyclic system consisting of two fused heterocycles - pyrimidine and imidazole is called a purine nucleus.

The purine group underlies many compounds, primarily nucleic acids, in which it is included in the form of purine bases: adenine (6-aminopurine) and guanine (2-amino-6-hydroxypurine).

Of interest is the oxygen derivative of purine - uric acid (2,6,8 - trioxypurine).

Laboratory work No. 8

Objective: study of the chemical properties of heterocyclic compounds

Reagents and equipment:

1) Antipyrine,

2) FeCl 3 - 0.1 n,

3) amidopyrine,

4) H 2 SO 4 - 2n,

5) NaNO 2 - 0.5n,

6) pyridine, NaOH - 2n,

7) uric acid, HCl - 2n,

8) NH 4 Cl saturated solution,

9) picric acid sat. solution,

10) litmus paper,

11) bromothymol blue,

12) microscope,

13) test tubes.

Test 8.1 Reactions of antipyrine and amidopyrine (pyramidone)

With iron (III) chloride

Place a few antipyrine crystals in a test tube, add two drops of water and a drop of 0.1N. FeCl 3. An intense and persistent orange-red color appears immediately and does not disappear upon standing. For comparison, place several crystals of amidopyrine (pyramidone) in another test tube. Add two drops of water and one drop of 0.1N. FeCl 3. A violet color appears, quickly disappearing. Add three more drops of iron (III) chloride at once. The color reappears, lasts a little longer, but gradually fades. The coloring of antipyrine from iron (III) chloride is due to the formation of a complex compound - ferropyrine.

Amidopyrine is an antipyrine derivative. The mobile hydrogen atom in position 4 is substituted in this case by a dimethylamino group.

The appearance of color is due to the oxidation of amidopyrine with iron (III) chloride. Therefore, the color is unstable, and an excess of iron (III) chloride harms the reaction.

These reactions are used in pharmaceutical practice to recognize antipyrine and amidopyrine and distinguish them from each other. In view of this, these reactions should be done for comparison in parallel in two test tubes.

Test 8.2 Reactions of antipyrine and amidopyrine with nitrous acid

Place several antipyrine crystals in a test tube, add two drops of water, one drop of 2N. H 2 SO 4 and one drop of 0.5N. NaNO 2. An emerald-green color will appear, gradually disappearing, especially quickly with a relative excess of sodium nitrite. For comparison, place several crystals of amidopyrine in another test tube, add two drops of water, one drop of 2N. H 2 SO 4 and one drop of 0.5N. NaNO 2. A very unstable violet color appears. If the color disappears too quickly, add some more amidopyrine. The reaction with antipyrine proceeds according to the equation:

Colored oxidation products are formed with amidopyrine.

Similar to the above reactions with iron (III) chloride, both reactions are used in pharmaceutical practice to recognize antipyrine and amidopyrine and distinguish them from each other. Therefore, they should be done in parallel in two test tubes.

Test 8.3 Precipitation of iron (III) hydroxide with aqueous solution

Pyridine

Place two drops of an aqueous solution of pyridine in a test tube and add a drop of 0.1 N FeCl 3. Brown flakes of iron hydroxide Fe (OH) 3 immediately precipitate with the formation of pyridine hydrochloride (pyridine hydrochloride) readily soluble in water.

The formation of iron (III) hydroxide confirms the basic properties of pyridine.

Write a scheme for the formation of pyridine hydrochloride (pyridinium chloride) in the interaction of pyridine oxide hydrate with iron (III) chloride.

Test 8.4 Formation of picrine pyridine

Using a pipette, place one drop of an aqueous solution of pyridine into a test tube and add three drops of a saturated aqueous solution of picric acid. With shaking, well-defined needle-like crystals of pyridine picrate are gradually released. In excess of pyridine, the crystals dissolve.

Place some of the crystals on a glass slide, examine them under a microscope and sketch the shape of the crystals of the resulting preparation in a work journal.

The formation of a relatively poorly soluble pyridine picrate also confirms the basic character of pyridine. This reaction is used to identify pyridine (pyridine picrate melts at 167 0 C).

Write a scheme for the formation of pyridine picrate.

Test 8.5Solubility of uric acid and its average sodium salt in water

Place a small amount (on the tip of a spatula) of uric acid in a test tube. Add water drop by drop, shaking the tube each time.

Pay attention to the poor solubility of uric acid in water. In cold water, uric acid is almost insoluble: 1 part of it dissolves in 39,000 parts of water.

After adding 8 drops of water, dissolution is still not noticeable. It is, however, worth adding only 1 drop of 2n. NaOH, as a cloudy solution, instantly clears up due to the formation of a relatively readily soluble average disubstituted sodium salt. Save the resulting solution for subsequent experiments.

Uric acid exists in two tautomeric forms:

The so-called uric acid salts, or urates, are formed with alkali from the lactimic-enol form. In fact, these are not salts, but enolates.

The very weakly expressed acidic nature of uric acid determines that of the three hydrogen atoms of the theoretically possible enol form, only two can be replaced by sodium. Trisubstituted uric acid salts are unknown.

Test 8.6 Formation of sparingly soluble ammonium urate

Add two drops of a saturated solution of ammonium chloride to four drops of a clear solution of an average disubstituted sodium uric acid salt (experiment 8.5). A white precipitate of ammonium urate precipitates immediately. Save this sediment for the subsequent experiment for the isolation of free uric acid (experiment 8.7).

Write a reaction scheme, taking into account that both sodium ions are replaced in sodium urate by ammonium ions.

Test 8.7 Decomposition of urates under the influence of mineral acid (excretion of crystalline uric acid)

Using a pipette, apply one drop of a cloudy solution containing ammonium urate (experiment 8.6) onto a glass slide. Add one drop of 2N to the center of the drop. HCl. Partial dissolution of the precipitate is observed.

When viewed under a microscope, yellowish lumps of not yet decomposed ammonium urate and newly formed characteristic crystals of uric acid in the form of elongated prisms resembling whetstones are visible. Sketch the shape of the crystals of the obtained preparation in the work journal.

The deposition of crystals of uric acid in the body (urinary stones, gouty nodes, etc.) occurs under the influence of a change in the reaction of the environment towards an increase in acidity.

Write a scheme for the release of uric acid from its salt.

Laboratory work No. 9.

Extraction of caffeine from tea

Objective:to isolate and study some of the chemical properties of a heterocyclic compound - caffeine

Reagents and equipment:

1) black tea

2) magnesium oxide powder

4) porcelain cup

5) concentrated solution of HNO 3

6) concentrated ammonia solution

Experience 9.1.Sublimation of caffeine.

In a porcelain or metal crucible, place 1 teaspoon of black tea crushed in a mortar and 2 g of magnesium oxide. Mix both substances and place the crucible on the hotplate. Heating should be moderate. A porcelain cup with cold water is placed on top of the crucible. In the presence of magnesium oxide, caffeine sublimes. Once on a cold surface, caffeine settles on the bottom of the cup in the form of colorless crystals. The heating is stopped, the cup is carefully removed from the crucible and the crystals are scraped into a clean bottle.

Test 9.2Qualitative response to caffeine.

Several crystals of caffeine are placed on a porcelain plate and one drop of concentrated nitric acid is added. Heat the plate until the mixture is dry on it. At the same time, caffeine is oxidized and turns into amalinic acid, orange in color. Add ten drops of concentrated ammonia to it, and a red salt turns into purple color. This salt is called murexide, and the reaction is murexid.

Write the reaction equation.

Questions for control

1. What compounds are called heterocyclic?

2. Classification of heterocyclic compounds?

3. What is the aromaticity of heterocyclic compounds expressed in?

4. Write the formulas of the heterocycles that make up the amino acids.

5. The biological role of purine and pyrimidine.

Heterocyclic compounds such compounds are called, the cycles of which, in addition to carbon atoms, include atoms of other elements (N, O, S, etc.), called heteroatoms.

Heterocyclic compounds are divided into groups: 1) according to the number of atoms in the cycle, 2) according to the number of heteroatoms in the cycle; 3) compounds with condensed cycles.

Five-membered heterocyclic compounds with one heteroatom:

furan pyrrole thiophene

Six-membered heterocyclic compounds with one heteroatom:

pyridine α-pyran γ-pyran

Heterocyclic compounds with two heteroatoms:

pyrazole imidazole thiazole pyrimidine

Heterocycles with condensed nuclei:

indole quinoline chromone

purine

Heterocyclic compounds are widespread in nature, are part of vitamins, alkaloids, pigments, some amino acids, dyes, antibiotics, etc. Purine and pyrimidine bases are part of nucleic acids.

Properties of some heterocyclic compounds. Five-membered heterocycles.

Pyrrole (C 4 H 5 N), the core of which is a part of many important natural compounds: hemoglobin, chlorophyll, tryptophan (an essential amino acid), etc., is an oily liquid with the smell of chloroform. In air, pyrrole turns brown due to oxidation, dissolves well in alcohol and ether, but poorly in water. It is obtained by dry distillation of fat-free bones or synthetically, for example, from succinic acid.

With a concentrated KOH solution, pyrrole forms pyrrole-potassium, exhibiting acidic properties.

+ H 2 O

Under the action of mineral acids, pyrrole undergoes polymerization.

When pyrrole is reduced, pyrrolidine is formed.

+ 2H 2

Pyrrolidine is a part of amino acids:

proline
hydroxyproline

Biologically active derivatives of pyrrole - hemoglobin and chlorophyll.

Hemoglobin – it is a complex protein consisting of a protein component and a non-protein part - heme, which includes pyrrole nuclei - a polycyclic system containing four pyrrole nuclei - porphin.

Porfin, having a Fe 2+ ion in the center is colored red, upon heat treatment forms a Fe 3+ ion and turns gray.

Chlorophyll – a green plant pigment containing a porphin core that is bound to Mg 2+. Chlorophyll takes part in the formation of organic compounds from CO 2 and H 2 O.

Oxygenated heterocyclic compounds.

Furan - - colorless liquid, soluble in water. The furan nucleus is found in furanose forms of carbohydrates (for example, ribose). The most important derivative of furan is furfural.

ribose furfural

Furfural - oily liquid with a pungent odor, in small concentrations it smells like rye bread. It is used for the production of nylon fiber, solvents, antiseptic agents, fungicides.

Compounds condensed with other cycles.

Benzopyrrole (indole) is a crystalline substance, in small concentrations it has the smell of jasmine, in the essential oil of which it is contained, in large concentrations it has a disgusting smell. In terms of chemical properties, indole is similar to pyrrole. The indole nucleus is found in heteroauxin (plant growth hormone), tryptophan (an essential amino acid), indigo (dye), and other compounds.

Six-membered heterocyclic compounds(oxygenated heterocyclic compounds).

Piran (α- and γ-) is an unstable substance, its derivatives are widespread in nature, γ-Piran and benzopyran (chromone) form the basis of the molecules of plant dyes and tannins - flavones, anthocyanins and catechins.

Flavones are yellow plant pigments (in flowers, fruits) and are found in plants in the form of glycosides.

flavone

Anthocyanins and catechins are very similar in structure to flavones. Anthocyanins are also plant pigments, their color varies from blue to purple. The color of the anthocyanin solution changes depending on the pH of the medium (in an acidic medium - red, in an alkaline medium - gray).

Flavones and anthocyanins are ginetically linked and are able to transform one into another.

flavone, quercetin anthocyanin, cyanidin

(yellow) chloride (red)

Catechins possess tanning properties (tea, hops, bird cherry, etc.), prevent the development of mold, being polyphenols.

Flavones, anthocyanins and catechins decompose, losing color and P-vitamin activity, under the influence of temperature and in the presence of metal ions (Fe 3+, Ag +, Cu 2+, etc.). СFeCl 3 give a dark color (qualitative reaction to phenolic hydroxyl).

Pyridine - colorless liquid with an unpleasant odor, readily soluble in water. It is obtained from coal tar and synthetically.

In reactions, pyridine exhibits basic properties:

C 5 H 5 N + HOH → OH - (pyridinium hydroxide);

C 5 H 5 N + HCl → Cl - (pyridinium chloride).

An aqueous solution of pyridine reacts with FeCl 3, forming iron hydroxide and pyridinium chloride

OH - + FeCl 3 → Fe (OH) 3 + 3Cl -

Reduction of pyridine produces piperidine:

Pyridine is resistant to oxidants, but side chains are oxidized upon oxidation of pyridine homologues.

β-picoline nicotinic acid

Nicotinic acid amide is a PP vitamin found in meat, potatoes, buckwheat, etc.

I AM nuclei of pyridine and pyrrolidine form nicotine, which is contained in tobacco in the form of a salt of citric and malic acids; is a heart poison.

Derivatives of pyrimidine and purine.

Six-membered heterocycles with two heteroatoms -pyrimidine derivatives:

uracil (U) thymine (G) cytosine (C)

Fused heterocycles -purine derivatives.

adenine (A) guanine (G)

All these heterocyclic nitrogenous bases are part of nucleic acids, which play an extremely important role in the life processes of organisms.

Nucleic acidsare polymers formed during the condensation of nucleotides - chemical compounds consisting of phosphoric acid residues, a carbohydrate component and one of the purine or pyrimidine bases. There are two types of nucleic acids. Deoxyribonucleic acid (DNA) contains deoxyribose as a carbohydrate component, and adenine, guanine, cytosine, and thymine are heterocyclic bases:

deoxyribose

R
ibonucleic acid (RNA) consists of the carbohydrate ribose and heterocyclic bases - adenine, guanine, cytosine, uracil.

RNA and DNA differ from each other not only in carbohydrates, but also in heterocyclic bases: ribonucleic acid contains uracil, and deoxyribonucleic acid contains thymine.

Polymerization of nucleotides occurs due to the formation of an ether bond between H 3 PO 4 of one nucleotide and the third hydroxyl of pentose:

nitrogenous base - sugar

residue H 3 PO 4

nitrogenous base - sugar

residue H 3 PO 4

Polynucleotide(DNA or RNA). The hereditary information of a cell is encoded by a specific sequence of bases in a DNA molecule, built in the form of an RNA double helix, and the sequence of nucleotides of one helix is, as it were, reflected in the other. RNA is formed in the form of a single helix.

HYDROCARBONS 8

Acyclic hydrocarbons 9

Alicyclic hydrocarbons 15

Aromatic hydrocarbons 17

Halogenated HYDROCARBONS 21

ORGANIC ELEMENTAL CONNECTIONS 22

ORGANIC ACIDS 33

OXYCIDS (HYDROXYACIDS) 39

Phosphatides 51

Stearins 54

CARBOHYDRATES 57

Monosaccharides 57