Lecture No. 9
Relationship between structure and biological action
Pyridine: A highly toxic substance. Has a lone pair of electrons, a tertiary nitrogen atom, has strong basic properties
Dihydropyridine: a coronary dilator
Pyridine-3-carboxylic acid: anti-pellagic agent
Pyridine-4-carboxylic acid: has anti-tuberculosis activity
derivatives of pyridine methanol have B 6 vitamin activity.
Medicinal substances derivatives of pyridine methanol
Pyridoxine Hydrochloride
Methyl 3-hydroxy-4,5 dioxymethyl-pyridine hydrochloride
Vitamin B 6 is a white, odorless, fine-crystalline powder with a bitter-sour taste. T pl. - 204 - 206 ° С (with decomposition). Let's easily dissolve in water, it is difficult - in alcohol and acetone.
Pyridoxalphosphate
Phosphoric ester of 2-methyl-3-hydroxy 4-fornyl 5-hydroxymethyl pyridine.
Physical Properties: Light yellow crystalline powder. Slightly soluble in water, unstable in the light.
Emoxypine
Ethyl 3-hydroxy-6-methyl-pyridine hydrochloride
Physical properties: white fine crystalline powder, odorless. Easily soluble in water.
Authenticity:
General reactions
Reaction with 2,6 - dichloroquinone chlorimide - a blue indophenol dye is formed
3. Azo dye formation reaction (all preparations). Reaction to phenolic hydroxyl.
4. Reaction with FeCl 3 for phenolic hydroxyl
Reaction with general alkaloid reagents (silicotungstic and phosphotungstic acids form white precipitates).
Differentiation reactions
1. Pyridoxine hydrochloride and Emoksipin give a reaction to Cl - .
HCl + AgNO 3 AgCl + HNO 3
2. Pyridoxal phosphate contains an aldehyde group, which is found:
A-reaction with Felling's reagent 1 and 2
B- reaction with an ammonia solution of silver nitrate
Pyridoxal phosphate after hydrolysis gives a reaction to phosphoric acid. A yellow precipitate of silver phosphate is formed.
H 3 RO 4 + 3AgNO 3 Ag3PO4 + 3HPO4
Pyridoxine hydrochloride has blue fluorescence under UV light.
5. Spectrophotometric method (for all preparations). Record the UV spectrum of the test substance. Record the UV spectrum of the standard substance. They must be identical.
quantitation
For pyridoxine hydrochloride and emoxipine
Non-aqueous titration method
Method: direct titration
The method is based on the reaction of acid-base interaction in a non-aqueous medium
Medium: glacial acetic acid, add Hg (CH 3 COO) 2 - to bind the hydrochloric acid released during the titration
Chemistry
R 3 N HCl + HClO 4 R 3 NH ClO 4 + HCl
HCl + Hg (CH 3 COO) 2 → HgCl 2 +CH 3 COOH
Pyridoxal phosphate
Spectrophotometric in the UV region, through a standard solution.
Method Alkalimetric
Method of direct titration on the residue of phosphoric acid. The method is based on the reaction of acid-base interaction.
Argentometry
Mercuro- and mercurimeria
Application
Pyridoxine 0.02 and 0.1 g
Pyridoxal phosphate 0.01-0.02 g for toxicosis in pregnant women, various types of parkinsonism, pellagra and chronic hepatitis
Emoksipin is an antioxidant, has angioprotective activity.
Produced in the form of a 3% solution of 5 ml in ampoules.
Pyricarbate (Prodectin) 2,6-pyridine dimethanollabismethyl carbamate
Physical Properties: Odorless white crystalline powder. Poorly soluble in water.
T melt \u003d 137 - 140 ° C
Authenticity
1. With acetic anhydrin in the presence of citric acid when not heated → yellow coloration turning to cherry red.
Reaction to the pyridine ring with 2,4-dinitrochlorobenzene. A pyridine dye is formed.
Carry out alkaline hydrolysis. Methylamine is released. Red litmus paper turns blue.
| parmidine |
UV and IR Spectroscopy Methods
A. UV spectroscopy method.
Record the UV spectrum of the test substance.
Remove the UV spectrum of the standard substance. They must be identical.
In UV spectroscopy, electromagnetic radiation is absorbed by the electrons of the entire molecule, and on the spectrogram we observe one light absorption maximum.
λ, nm
B. Method of IR spectroscopy.
quantitation
Non-aqueous titration method
Method: direct titration
Derivatives of dihydropyridine
Nifedipine (Corinfar)
2,6-dimethyl-4-(2/-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester
Physical Properties: Greenish-yellow crystalline powder. Practically insoluble in water, difficult in alcohol. Decomposes in the world. T melt \u003d 169-174 about C.
Authenticity
UV spectroscopy method
IR spectroscopy method
quantitation
Get chromatograms.
H ,mm h ,mm
t,min t,min
Authenticity
quantitation
Authenticity
UV and IR spectroscopy
2. reaction to the aliphatic NH 2 - group with ninhydrin. A blue-violet color is formed.
quantitation
Lecture No. 9
Medicinal substances derivatives of pyridine
Pyridine is six-membered aromatic heterocycle with one nitrogen atom, colorless liquid with a sharp 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 that of benzene. The carbon and nitrogen atoms are in the state of sp2 hybridization. All C–C, C–H, and C–N σ bonds are formed by hybrid orbitals, the angles between them being approximately 120°. Therefore, the cycle has a flat structure. Six electrons located in non-hybrid p-orbitals form a π-electron aromatic system.
Of the three hybrid orbitals of the nitrogen atom, two form 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 the properties of a base. Its aqueous solution turns litmus blue. When pyridine reacts with strong acids, pyridinium salts are formed.
P iridine exhibits properties characteristic of tertiary amines: it forms N-oxides, N-alkylpyridinium salts, and is able to act as a sigma-donor ligand.
At the same time, pyridine has clear aromatic properties. However, the presence of a nitrogen atom in the conjugation ring leads to a serious redistribution of 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 are reacted.
The fundamental difference between pyridine and benzene is that, due to the greater electronegativity of nitrogen compared to carbon, in the case of pyridine, in the set of limiting structures describing the distribution of p-electron density, the contribution of structures with separated negative and positive charges is significant:
It can be seen from their consideration that the negative charge is localized on the nitrogen atom, and the positive one is distributed mainly between carbon atoms in positions 2,4 and 6 (a- and g-positions). In this regard, pyridine is classified as an electron-deficient aromatic heterocycle, in contrast to the above-considered furan, pyrrole, and thiophene. This means that the pyridine core, as an aromatic system, is deactivated with respect to the electrophilic system and, conversely, is activated with respect to the nucleophilic attack compared to benzene.
However, the fact that the nitrogen atom has a lone pair of electrons and an excess p-electron density 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 of it is always realized initially during an electrophilic attack.
Other possible directions of the reaction associated with the manifestation of C-nucleophilicity by pyridine - electrophilic attack on carbon atoms - are extremely difficult and very severe conditions are required for their implementation. In addition to the electron-deficient nature of the p-electron system indicated above, within the framework of the general approach to the qualitative explanation of the patterns of electrophilic substitution in the aromatic nucleus, this should be related to the fact that the presence of nitrogen in the ring, which is more electronegative than the carbon atom, destabilizes the intermediately formed cationic 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 commodity that is easily formed as a result of electrophilic attack on the nitrogen atom is often unstable and its formation, although kinetically preferable, is a reversible process. In contrast, electrophilic attack on carbon atoms is much more difficult, but leads to the formation of more stable substitution products that are 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, carbon atoms of the ring, 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. Similarly, N-alkylation of pyridine with alkyl halides occurs, leading to alkylpyridinium 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 reactions of carboxylic acid chlorides with pyridine proceed in a similar manner. However, the resulting N-acylpyridinium salt is such an active electrophilic, in this case an acylating reagent, that it cannot be isolated in the free state.
Pyridine is characterized by aromatic nucleophilic substitution reactions occurring predominantly at the ortho-para positions of the ring. This reactivity is indicative of 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 electrophilic substitution reactions - it is nitrated, sulfonated and brominated only at about 300 ° C with the formation of predominantly b-derivatives. Nucleophilic substitution occurs more easily than in benzene.
So, pyridine with NaNH2 gives a-aminopyridine, with KOH - a-hydroxypyridine. Pyridine is reduced by sodium in alcohol or H2 over Ni at 120°C to piperidine. Under the action, for example, of bases on a pyridinium salt, the pyridine ring is broken to form glutaconic dialdehyde HOCCH = CHCH2COH or its derivatives.
It forms stable salts with inorganic acids, pyridinium salts with alkyl halides, and complex compounds with metal halides, SO2, SO3, Br2, H2O.
Electrophilic substitution proceeds with great difficulty (pyridine is close to nitrobenzene in terms of its ability to electrophilic substitution) and goes to position 3. Most of these reactions proceed in an acidic environment, 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, draws electrons towards itself and reduces the density of the electron cloud in the ring, especially in positions 2, 4 and 6 (ortho and para positions).
Therefore, for example, the nitration reaction of pyridine takes place under harsh conditions (at 300 °C) and with a low yield. The orienting effect of the nitrogen atom on the introduction of a new substituent during electrophilic substitution in pyridine is similar to the effect 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 the properties of a secondary amine (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 with a small yield; sulfonated with oleum in the presence of Hg sulfate at 220-2700C to pyridine-3-sulfonic acid.
When pyridine is treated with mercury acetate 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 by a radical mechanism; reaction products - 2-bromo- and 2,6-dibromopyridines.
Radical reactions also include the interaction of pyridine with phenyldiazonium hydrate (the Gomberg-Bachmann-Hey reaction), resulting in a mixture containing 55% 2-phenyl-, 30% 3-phenyl- and 15% 4-phenyl-pyridine.
Nucleophilic substitution in pyridine proceeds at positions 2 and 4 and is easier than in benzene, for example, the synthesis of 2-aminopyridine by the reaction of pyridine with sodium amide. (Chichibabina reaction).
Pyridine, as a rule, is resistant to oxidizing agents; however, under the action of peracids, it easily forms pyridine N-oxide, in which the electron density on the C-2 and C-4 atoms is increased compared to pyridine.
At 300 0C, under the action of FeCl3, pyridine is oxidized to a mixture of isomeric dipyridyls of the general formula C5H4N-C5H4N.
Catalytic hydrogenation in the presence of Pt or Ni, reduction of Na in alcohol, as well as electrochemical reduction leads to piperidine (the latter method is used in industry). More severe reduction of pyridine is accompanied by ring splitting and deamination.
Nitration of pyridine occurs under the action of potassium nitrate and sulfuric acid at 370 ° C, leading to b-nitropyridine. Sulfation 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 a second substituent into the ring in this way. Pyridine does not enter into Friedel-Crafts reactions.
In the chemistry of pyridine in general, and in the part that concerns its functionalization with the help of electrophilic substitution reactions, the possibility of its transformation into the N-oxide is of great importance. Consider the electronic structure of this compound.
An analysis of these resonance structures leads to a surprising conclusion that the N-oxide group can act in relation to the p-electron system of the ring both as a donor (upper row of structures) and as an electron acceptor, that is, it can contribute to the occurrence of both electrophilic substitution reactions at a and g-positions, as well as the addition of a nucleophile at the same positions! What is actually observed?
The electronic influence actually exhibited by this group depends on the nature of the reagent. The nitration of pyridine N-oxide proceeds much more easily 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 those of pyridine itself, resulting in a b-sulfonic acid. This direction of the sulfonation reaction is explained by the coordination of SO3 to the oxygen atom of the N-oxide group, which turns this group into an acceptor and, consequently, a meta-orienting agent.
The conversion of pyridine to its N-oxide, carrying out electrophilic substitution reactions with it, and subsequent reductive removal of the N-oxide oxygen atom is a general approach to the synthesis of a wide range of functionally substituted pyridine derivatives that cannot be obtained directly from pyridine. Thus, the reduction of the N-oxide of g-nitropyridine with triphenylphosphine leads to the removal of the N-oxide oxygen atom, which makes it possible to obtain 4-nitropyridine in good yield. When the N-oxide of g-nitropyridine is reduced with iron in acetic acid, the nitro group and the N-oxide group are simultaneously reduced, leading to 4-aminopyridine. As noted earlier, the N-oxide group also facilitates the occurrence of nucleophilic substitution reactions. So, when the N-oxide of g-nitropyridine reacts with hydrogen chloride or hydrogen bromide, the N-oxide of g-halo-substituted pyridine is formed (suggest a mechanism for this reaction), the subsequent reaction with PCl3 to the elimination of the N-oxide group.
When pyridine N-oxide interacts with organometallic compounds, attachment occurs predominantly at position 2, that is, in this reaction, the N-oxide group actually activates this 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 reacts with alkalis in the presence of atmospheric oxygen (oxidizing agent), a-hydroxypyridine oxide is formed. Interestingly, this compound exists in tautomeric equilibrium with N-hydroxypyridone.
Alkyl pyridinium 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 a preparative value.
Pyridine itself is also capable of entering into nucleophilic addition reactions, but, of course, under more stringent conditions. Of these transformations, the Chichibabin reaction, the reaction with sodium amide at 130°C, has the greatest preparative significance. This reaction occurs by the mechanism of addition-cleavage and its product is a-aminopyridine. When pyridine reacts with potassium amide, along with a-aminopyridine, g-aminopyridine is also formed.
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.
The reduction of pyridine and its derivatives occurs either under the action of metallic sodium in alcohol, or under catalytic hydrogenation conditions. In this case, pyridine hexahydro derivatives are formed, and in the case of pyridine itself, piperidine.
b-Aminopyridine during diazotization forms fairly stable diazonium salts, which can enter into the usual transformations for this class of compounds, both with and without nitrogen evolution. In contrast, a- and g-aminopyridines do not readily form diazonium salts, and these salts themselves are highly unstable.
It is interesting to draw a parallel between the ability to exist in the tautomeric oxo form of hydroxypyridines and hydroxyarenes. 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 a hydroxy group to an aromatic or heteroaromatic ring. This process is not synchronous, but proceeds in two stages, the first of them, deprotonation, occurs with the participation of a solvent or another arene molecule and naturally proceeds the easier, the stronger the acid is the hydroxyl group. Taking into account the electron-deficient nature of the pyridine nucleus, it can be argued that the acidity of hydroxypyridines is noticeably higher than the acidity of hydroxyarenes and, therefore, the activation barrier in the case of pyridine derivatives will be lower. The second step 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 stage should also 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 stages of protonation-deprotonation leads to the keto form, with the b-position of the hydroxy group, such a transformation is impossible - it results in the formation of a zwitterion. Indeed, b-hydroxypyridine exists in this form, as evidenced by 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 transformation under consideration leads to the loss of aromaticity by 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, which facilitate protonation, the keto-enol tautomeric equilibrium is also realized for hydroxyarenes. So, phleroglucinol - 1,3,5-trihydroxybenzene - exists mainly in the keto form.
Pyridine is a weaker base than aliphatic amines (Kb = 1.7.10-9). Its aqueous solution turns litmus blue:
When pyridine reacts with strong acids, pyridinium salts are formed:
aromatic properties. Like benzene, pyridine enters into electrophilic substitution reactions, but 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 a low yield:
The nitrogen atom in electrophilic substitution reactions behaves as a substituent of the 2nd kind, therefore, electrophilic substitution occurs in the meta position.
Unlike benzene, pyridine is able to enter into nucleophilic substitution reactions, since the nitrogen atom draws electron density from the aromatic system, and the ortho-para positions with respect to the nitrogen atom are depleted in electrons. So, 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:
Pyridine homologues are similar in properties to benzene homologues. So, during the oxidation of side chains, the corresponding carboxylic acids are formed:
Pyridine is a representative of six-membered heterocycles with one heteroatom, which is the nitrogen atom
Monomethylpyridines are called picolines, dimethylpyridines are called lutidines, trimethylpyridines are called collidines. A saturated pyridine ring is called piperidine.
Pyridine has been known since 1851, when it was isolated from bone oil, and somewhat later from coal tar (1854).
Acquisition Methods. As already noted, pyridine is isolated from coal tar. Unfortunately, its content in this source does not exceed 0.1%.
Of the synthetic methods for obtaining pyridine, methods based on the transformations of acrolein and saturated and unsaturated aldehydes are important.
According to the method of Chichibabin (1937), substituted pyridines are obtained from aldehydes and ammonia (it is better to use aldehyde ammonia) by heating at 250 o C in the presence of ammonium acetate
Unsaturated aldehydes can also react with ammonia.
Practically important synthesis of substituted pyridines is based on heating a mixture of diene hydrocarbon and nitrile at 400 o C
A method for obtaining pyridine from acetylene and ammonia was developed Reppe. The reaction proceeds in the presence of complex nickel or cobalt catalysts
A compound with a saturated pyridine ring, piperidine, can be prepared by heating pentamethylenediamine hydrochloride.
From more complex syntheses, we present the synthesis of collidine according to Ganchu. In this synthesis, 2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester is obtained from acetoacetic ester and aldehyde (as aldehyde ammic). In the resulting product, two hydrogens are oxidized with nitrous acid, thereby creating a substituted pyridine ring. This is followed by the hydrolysis and decarboxylation step.
Chemical properties. Pyridine is an almost regular hexagon, all of whose atoms lie in the same plane. Geometrically, the pyridine ring is similar to the benzene ring.
The carbon atoms in pyridine are in sp 2 - hybrid state. For the formation of an aromatic sextet, five carbons give one p-electron each, and the sixth electron supplies a nitrogen atom, one that does not participate in hybridization. The axis of this orbital is perpendicular to the plane of location of all atoms and bonds of the pyridine ring. Of the three nitrogen hybrid orbitals, two are used to form σ -bonds with two neighboring carbon atoms, and the lone pair of electrons is in the third orbital
In accordance with the given structure, pyridine is a cyclic, planar formation with a Hueckel number R-electrons (4n+2=6 at n=1) and has an aromatic character. In addition, due to the lone pair of nitrogen electrons - basicity.
The picture of the structure of pyridine is supplemented by a significant dipole moment (2.26 D) pyridine, due to the high electronegativity of the nitrogen atom, as well as uneven density distribution π -electron cloud at heterocycle atoms. The Hückel molecular orbital method yielded the following distribution π -charges on atoms of the pyridine ring
Cyclic compounds in which cycles are formed not only by carbon atoms, but also by atoms of other elements - heteroatoms (O, S, N) - are called heterocyclic. Heterocyclic compounds are divided according to the size of the ring and the number of heteroatoms in the ring.
Among these compounds, five- and six-membered heterocyclic compounds are of the greatest importance. Typical heterocyclic compounds are aromatic. However, the presence of a heteroatom affects the electron density distribution. For example, in five-membered heterocycles (in furan, thiophene, pyrrole), the electron density is shifted from the heteroatom towards the ring and is maximum in the a-positions. Therefore, in a-positions, the reaction of electrophilic substitution (S E) most easily occurs.
In six-membered cycles (for example, pyridine), the heteroatom bound to carbon by a double bond draws the p-electron density of the cycle to itself, so the electron density in the pyridine molecule is lowered in the a and g positions. This is consistent with the preferred orientation to these positions of the reactants in nucleophilic substitution (SN). Since in pyridine the electron density is greater 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 nucleus is found in numerous natural products: vitamins, coenzymes and nucleic acids:
Electrophilic substitution for pyrimidine takes place 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 the purine core.
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-oxypurine).
Of interest is the oxygen derivative of purine - uric acid (2,6,8 - trioxypurine).
Lab #8
Goal of the work: study of the chemical properties of heterocyclic compounds
Reagents and equipment:
1) Antipyrine,
2) FeCl 3 - 0.1n,
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) bromthymol blue,
12) microscope,
13) test tubes.
Experience 8.1 Reactions of antipyrine and amidopyrine (pyramidone)
With iron(III) chloride
Place several crystals of antipyrine in a test tube, add two drops of water and a drop of 0.1 N. FeCl3. An intense and persistent orange-red color develops immediately and does not disappear on standing. For comparison, place several crystals of amidopyrine (pyramidone) in another test tube. Add two drops of water and one drop of 0.1N. FeCl3. A purple color appears and disappears quickly. Add three more drops of iron (III) chloride at once. The color will reappear, last a little longer, but gradually fade. The staining of antipyrine from iron (III) chloride is due to the formation of a complex compound - ferropyrine.
Amidopyrine is a derivative of antipyrine. The mobile hydrogen atom in position 4 is replaced 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.
Experience 8.2 Reactions of antipyrine and amidopyrine with nitrous acid
Place several crystals of antipyrine 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 purple color appears. If the color disappears too quickly, add a little more amidopyrine. The reaction with antipyrine proceeds according to the equation:
With amidopyrine, colored oxidation products are formed.
Like 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.
Experience 8.3 Precipitation of iron (III) hydroxide with an aqueous solution
Pyridine
Place two drops of an aqueous solution of pyridine in a test tube and add a drop of 0.1N FeCl 3 . Brown flakes of iron hydroxide Fe(OH) 3 precipitate immediately to form pyridine hydrochloride salt (pyridine hydrochloride), which is 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) during the interaction of pyridine oxide hydrate with iron (III) chloride.
Experience 8.4 Formation of pyridine picrin
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. On shaking, well-defined needle-like crystals of pyridine picrate gradually stand out. In an excess of pyridine, the crystals dissolve.
Place part of the crystals on a glass slide, examine them under a microscope and draw the shape of the crystals of the resulting preparation in the working journal.
The formation of a relatively sparingly 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.
Experience 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 into 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 worth, however, to add only 1 drop of 2n. NaOH, as a cloudy solution, instantly clears up due to the formation of a relatively easily soluble medium disubstituted sodium salt. Save the resulting solution for subsequent experiments.
Uric acid exists in two tautomeric forms:
From the lactim-enol form, the so-called salts of uric acid, or urates, are formed with alkali. In fact, these are not salts, but enolates.
The very weakly pronounced 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 salts of uric acid are unknown.
Experience 8.6 Formation of sparingly soluble ammonium urate
To four drops of a clear solution of a medium dibasic sodium salt of uric acid (experiment 8.5) add two drops of a saturated ammonium chloride solution. A white precipitate of ammonium urate immediately precipitated. Save this precipitate for the subsequent experiment on the isolation of free uric acid (experiment 8.7).
Write the reaction scheme, taking into account that both sodium ions are replaced in sodium urate by ammonium ions.
Experience 8.7 Decomposition of urates under the influence of mineral acid (isolation of crystalline uric acid)
Using a pipette, apply one drop of a cloudy solution containing ammonium urate to a glass slide (experiment 8.6). 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 clumps of ammonium urate that have not yet decomposed and newly formed characteristic uric acid crystals in the form of elongated prisms resembling whetstones are visible. Draw in the working journal the shape of the crystals of the resulting preparation.
The deposition of uric acid crystals 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 isolating uric acid from its salt.
Laboratory work number 9.
Separation of caffeine from tea
Goal of the work: 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.
Place 1 teaspoon of black tea crushed in a mortar and 2 g of magnesium oxide into a porcelain or metal crucible. Mix both substances and put the crucible on the tile. Heating should be moderate. Place a porcelain cup filled with cold water on top of the crucible. In the presence of magnesium oxide, caffeine sublimes. Once on a cold surface, caffeine settles to 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 off into a clean bottle.
Experience 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 on it dries. At the same time, caffeine is oxidized and turns into amalic acid, orange in color. Add ten drops of concentrated ammonia to it, a salt of red, turning into purple, color is formed. This salt is called murexide, and the reaction is called murexide.
Write the reaction equation.
Questions to control
1. What compounds are called heterocyclic?
2. Classification of heterocyclic compounds?
3. What is the aromaticity of heterocyclic compounds?
4. Write the formulas of the heterocycles that make up the amino acids.
5. The biological role of purine and pyrimidine.
Mol. m. 79.1; colorless liquid with special features. smell; m.p. -42.7 0 C, bp 115.4°C/760 mmHg 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 0 C); h 0.885 mPa s (25 0 C); With p 135.62 kJ / mol K) (17 0 C), - 2783 kJ / mol. Miscible in all respects with water and most org. r-guardians; forms an azeotropic mixture with water (bp 94 0 C, 58% by weight P.).
P.-base (
R K a 5.20). From inorg. to-tami forms stable salts, with alkyl halides -pyridinium salts ,
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 swarm because of the negative. induction effect of the N atom, the electron density of the C atoms, especially in positions 2, 4, and 6, is reduced (p-deficient heterocycle).
Electrof. substitution proceeds with great difficulty (P. is close to nitrobenzene in terms of its ability to electroph. substitution) and goes to position 3. Most of these districts proceed in an acidic environment, in a cut of the original Comm. P. is no longer himself, but his salt. P. is nitrated only under the action of NaNO 3 or KNO 3 in fuming H 2 SO 4 at t-re 300 0 C, forming 3-nitropyridine with a small yield; sulfonated with oleum in the presence of Hg sulfate at 220-270 0 C to pyridine-3-sulfonic acid. Under the action of mercury acetate on P. at 155 0 C, 3-pyridylmercuracetate is formed; at higher t-rah-di- and polysubstituted derivatives. The action of Br 2 in oleum at 300 0 C leads to a mixture of 3-bromo- and 3,5-dibromo-pyridines. At a higher t-re (approx. 500 0 C), the reaction proceeds according to a radical mechanism; p-tion products - 2-bromo- and 2,6-dibromopyridines. Radical reactions also include P.'s interaction with phenyldiazonium hydrate (the Gomberg-Bachmann-Hey reaction), resulting in a mixture containing 55% 2-phenyl-, 30% 3-phenyl-, and 15% 4-phenyl-pyridine.
nucleophilic substitution in P. proceeds at positions 2 and 4 and is easier than in benzene, for example, the synthesis of 2-aminopyridine during the interaction of P. with sodium amide (see. Chichibabina reaction
).
P., as a rule, is resistant to oxidizing agents, however, under the action of peracids, it easily forms pyridine N-oxide (see. Amine N-oxides)
in Krom, the electron density on the C-2 and C-4 atoms is increased compared to P. At 300 0 C, under the action of FeCl 3, P. is oxidized into a mixture of isomeric dipyridyls of the total f-ly C 5 H 4 N-C 5 H 4 N. Catalytic hydrogenation in the presence of Pt or Ni, reduction of Na in alcohol, as well as electrochemical. recovery leads to piperidine (the latter method is used in the industry). More rigid restoration of P. is followed by splitting of a cycle and deamination.
The addition of carbenes to P. or the deprotonation of N-alkylpyridinium ions leads to pyridinium ylides of general f-ly I, the interaction of P. with nitrenes or the deprotonation of N-aminopyridinium salts leads to pyridinium imines of general f-ly II.
Comm. of both types easily enter into p-tion cycloaddition, characteristic of 1,3-dipolar systems. P. allocate mainly from Kam.-ug. resin (content approx. 0.08%), dry distillation products of wood, peat or bone. Synthetically, he might. trace received. reactions:
P. and its derivatives-base pyridine alkaloids ,
as well as many others. medicinal Wed-in. P. is also used in the synthesis of dyes, insecticides, and is used to denature alcohol. P.'s complex with SO 3 - pyridine sulfotrioxide is a mild sulphurizing 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 -oxidizing agent. P. is a good solvent, incl. for many inorg. salts (AgBr, Hg 2 Cl 2, etc.). MPC vapor P. in the air ~ 0.005 mg / l, so flammable. 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.'s derivatives, see