Methodical instruction

Methodical Instruction for Students of the 2 Course pharmaceutical Faculty

 

LESSON № 2 (PRACTICAL – 6 HOURS)

 

Themes:1.Condensed heterocyclic systems. Purine. Notion about alkaloids. Small practicum.

 

The aim: to formulate knowledge about the structure, classification, nomenclature, isomery, methods of obtaining and chemical properties of the condensed heterocyclic systems, sevenmember heterocycles and alkaloids.

 

Professional orientation of students.

Purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle iature. Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases.

Alkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications and recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste.

 

Professional orientation of students.

1. Solubility of uric acid and its salts in water.

Reagents: uric acid, 10% NaOH, saturated solution of NH₄Cl.

 Technique of the experiment. To the test tube on the end of pallet-knife bring uric acid and during the shaking by drops add water. After the adding of 10 drops of water determine the bad solubility of uric acid. To the received suspension add 1 drop of the 10 % solution of sodium hydroxide. The solution becomes transparent due to the formation of well soluble in water disodium salt of uric acid:

To resulting solution add 1 drop of the saturated solution of ammonium chloride and observe the formation of white sediment of diammonium salt of uric acid – ammonium urate:

Experiment 2. Murexide reaction.

Attention! Experiment is executed in a drawing cupboard!

Reagents: uric acid or caffeine, conc. HNO3, 10% NH₃.

Technique of the experiment. To a porcelain cup bring a few crystals of uric acid and 3 – 4 drops of concentrated nitrate acid. The resultant mixture is gently steamed over a flame torch to the dry state. Pink-red residue, which was formed after cooling, is wetted by 1-2 drops of 10 % ammonia solution. Observe the appearance of purple-violet color.

Experiment 3. Distinctive reaction for N-methylxanthines

Reagents: caffeine, theobromine, theophylline, 10% NaOH, 5% sol. of CoCl₂.

Technique of the experiment. To the three separate tubes containing a few crystals of caffeine, theobromine and theophylline add 2 drops of 10% solution of sodium hydroxide. Content of the tubes is shaken off for 2 min., then to each tube add 2 drops of 5% solution of cobalt (II) chloride.

 In the tube with caffeine visible changes aren’t observed. In the test tube with theobromine evanescent violet color appears and gray-blue precipitate of cobalt salt separates.

Theophylline in these conditions creates cobalt salt – white sediment with pink tinge:

Experiment 4. Interaction of alkaloids with general alkaloid (sedimentary) reagents.

Reagents: alkaloids, general alkaloid reagents (look table 1).

Technique of the experiment. On the subject glass put 1-2 drops of 1% alkaloid solution and 1 drop of general alkaloid reagent. Observe after the appearance of the painted sediment (Table.1).

Coloring products of alkaloids interaction with precipitate reagents.

Table. 1

 

Experiment 5. Alkaloids interaction with the special reagents.

Reagents: alkaloids, special alkaloid reagents (look table 2).

Technique of the experiment. On subject glass put 2-3 drops of 1% solution of alkaloid and 1 drop of the special reagent. Observe after the appearance of the painted sediment (Tab. 2).

Coloring products of alkaloids interaction with special reagents.

Table. 2

Experiment 6. Fluorescence of the dilute solutions of quinine hydrochloride.

Reagents: 1% solution of quinine salt.

Technique of the experiment. In test tube put 1-2 drops of 1% solution of quinine hydrochloride salt and add 10 ml of distilled water. The resulting solution is shaken off. Observe a weak blue fluorescence of the diluted solution of quinine salts. Fluorescence should be observed in a thick liquid layer on top with pale sunlight on the side of the tube.

Experiment 7. Thaleyoquine test (reaction of quinine with bromine water and ammonia).

Reagents: 1% solution of quinine salt, bromine water, 10% ammonia solution.

Technique of the experiment. In the test-tube put 1-2 drops of 1% solution of quinine hydrochloride salt, add 5 drops of water and 2 drops of the saturated brominewater solution. Shake the resulting solution and add 1 drop of 10% solution of ammonia. Observe after the gradual appearance of the emeraled-green coloring of thesolution –thaleyoquine forms.

This reaction is general qualitative reaction on quinine and its derivatives:

 

Individual Students Program.

I.Condensed heterocyclic systems.

1.   Classification and nomenclature of the condensed heterocyclic systems.

2.     Methods of obtaining, aromatic properties, tautomery of purine and its hydroxyderivatives (hypoxanthine, xanthine, uric acid).

3.     Physical and chemical properties of purine and its hydroxyderivatives:

—     acidic and basic properties;

—     tautomeric transformations (lactam-lactim and azol tautomery);

—     nucleophilic substitution (S _N).

4.     N-methyl derivatives of xanthine: Sources of obtaining, tautomery, acid-base properties, applications.

5.     Aminopurines: sources of obtaining and properties of purine bases (adenine, guanine).

6.     Identification of purine and its derivatives (murexide reaction).

7.     Pteridine: methods of getting, properties and derivatives.

8.     Condensed heterocyclic systems alloxazine and isoalloxazine groups: obtaining, properties (related to reduction).

II. Sevenmember heterocyclic compounds. Alkaloids.

1.   Sevenmember heterocycles with nitrogen atoms: the source of reception and chemical properties.

2.   Some representatives, aplication.

3.   Finding in the nature and methods of alkaloids allocation.

4.   Classification of alkaloids.

5.   Some representatives:

–     alkaloids of pyridine and pyperidine group (nicotine, anabasine, lobeline).

–     alkaloids of quinoline group (quinine).

–     alkaloids of isoquinoline and phenanthrene isoquinoline group (papaverine, morphine, codeine).

–     alkaloids of purine group (caffeine, theobromine, theophylline).

–     alkaloids of tropane group (atropine, scopolamine, cocaine).

–     alkaloids of indole group (reserpine, strychnine).

 

Seminar discussion of theoretical issues (12³⁰ – 14⁰⁰ hour).

Test evaluation and situational tasks.

Home task. 1, 2.

1.      Write the structural formulas of the following compounds: 1) 1,2-diazine; 2) 2,4,6-trihydroxypyrimidine; 3) pyrazine-N-oxide; 4) piperazine; 5) uracil; 6) thymine; 7) cytosine; 8) dibenzo [b, e]-4N-1,4-thiazine; 9) methyl blue.

2.      Give the correct names of the next structural formulas:

3.      Write the scheme of receiving of 8-methylpurine from 4,5-diaminopyrimidine (Traube’s method).

4.      Characterize electronic structure of purine. Write tautomeric forms of purine.

5.      Write the reaction schemes, which confirm amphoteric character of purine. Name the products.

6.      Write the structural forms of the natural compounds that include purine.

7.      Write the schemes of oxopurines tautomeric transformations. Name the tautomeric forms.

8.      Which reactions can be used to confirm amphoteric character of hypoxanthine and xanthine? Write the appropriate equations.

9.      Explain why uric acid is dibasic, not tribasic. Write the scheme of receiving of acidic and medium salts of uric acid.

10.  On the example of uric acid write the scheme of murexide reaction. What are the intermediate products of this reaction?

11.  Write the schemes of reactions that confirm presence of pyrimidine and imidazole cycles in uric acid molecules. Name the products.

12.  Point the equations of the consecutive reactions, which allow to get from 2,6,8-trichloropurine: 1) adenine, 2) guanine, 3) hypoxanthine 4) xanthine. What are the intermediate products of these reactions?

13.  Write the schemes of the chemical transformations that allow to convert: 1) uric acid in purine; 2) adenine in hypoxanthine; 3) 4,5-diaminopyrimidine in pteridine.What are the intermediate products of these reactions?

14.  Point the schemes of reactions, which confirm amphoteric character of N-methyl derivatives of xanthine (theobromine, theophylline). Why caffeine has only weak basic properties?

15.  Write the reaction equations, which allow identifying of N-methyl xanthine derivatives.

16.  Characterize the structure and chemical properties of pteridine.

17.  Point the tautomeric forms of alloxazine. Write the schemes of isoalloxazine reduction. Name the product.

18.  Write the scheme of reactions of 1,4-benzodiazepines with the following reagents: 1) HCl; 2) H2SО 4; 3) Br 2 (H2O). Name the products.

19.  Write the reaction equations of the following chemical transformations:

Name reagents and products.

20.  Write the structural formulas of the following compounds and write their trivial names: 1) 3,7-dimethylxanthine; 2) 2,6-dioxo-1,3,7-dimethylpurine; 3) 3-(2′-(N-methylpyrrolidyl))-pyridine; 4) 3-(α-piperidyl)-pyridine; 5) 6,7-dimethoxy-1-(3’4′-dimethoxybenzyl)-isoquinoline; 6) tropinic ester of tropic acid; 7) 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on; 8). 1-(3’,4’-dimethoxybenzyl)-6,7-dimethoxyisoquinoline.

21.  Write the structural formulas of the most important alkaloids groups of pyridine, piperidine, quinoline, phenanthrene isoquinoline, purine, indole and tropane.

22.  What connections have name alkaloids? Describe the methods of their selection from plants raw materials.

23.  Explain why alkaloids have basic properties? How can be confirmed the free alkaloid base?

24.  Write the scheme of interaction of nicotine with hydrochloride acid. Name the products.

25.  What chemical reaction is possible to distinguish morphine from codeine?

26.  Write the structural formula of morphine and put the numeration of the atoms. Indicate which condensed systems are present in morphine. What carbon atoms are common for these systems?

27.  Write the scheme of cocaine acidic hydrolysis. Name the products.

28.  Determine the chirality’s centers in the molecule of quinine. Write the schemes of quinine reactions with the following reagents:1) HCl; 2) excess of HCl; 3) Br₂(CCl₄).

29.  Give the correct names of the next structural formulas:

1).2).3).4)

5).6). 7).

30.  . Write the schemes of atropine interaction with hydrochloric acid.

31.  The most used method for alkaloids extraction is the following one:

A. Filtration

B. Extraction

C. Sublimation

D. Recrystallization

E.  Distillation

32.  From the following list choose general alkaloid reagent:

A. Frede

B. Lughole

C. Felling

D. Mayer

E.  Selivanov

33.  From the following list choose general alkaloid reagent:

A. Sheibler

B. Lughole

C. Frede

D. Felling

E.  Selivanov

34.  From the following list choose specific alkaloid reagent:

A. Felling

B. Selivanov

C. Lughole

D. Frede

E.  Mayer

Correct answers of test evaluations and situational tasks:

31. B; 32. D; 33.A; 34 D.

 

Individual student work (14¹⁵-15⁰⁰ hour) are checked by solving situational tasks for each topic, answers in test evaluations and constructive questions (the instructor has tests & situational tasks).

 

Student should know:

– structure, classification, nomenclature, isomery, methods of getting and chemical properties of condensed heterocyclic systems, sevenmember heterocycles andalkaloids.

 

Student should be able to:

– on the basis of functional groups to attribute matters to the certain class of organic compounds;

– to give the names organic connections with the help of rational and international (IUPAC) top- level systems;

– to conduct reactions which characterize of chemical properties of condensed heterocyclic systems, sevenmember heterocycles and alkaloids.

 

References:

Main:

1.   Clayden Jonathan. Organic Chemistry. Jonathan Clayden, Nick Geeves, Stuart Warren // Paperback, 2nd Edition. – 2012. – 1234 p.

2.   Bruice Paula Y. Organic Chemistry / Paula Y. Bruice // Hardcover, 6th Edition. – 2010. – 1440 p.

3.   Brückner Reinhard. Organic Mechanisms – Reactions, Stereochemistry and Synthesis / Reinhard Brückner // Hardcover, First Edition. – 2010. – 856 p.

4.   Moloney Mark G. Structure and Reactivity in Organic Chemistry / Mark G. Moloney // Softcover, First Edition. – 2008. – 306 p.

5.   Carrea Giacomo. Organic Synthesis with Enzymes in Non-Aqueous Media / Giacomo Carrea, Sergio Riva // Hardcover, First Edition. – 2008. – 328 p.

6.   Smith Michael B. March’s Advanced Organic Chemistry. Reactions, mechanisms, and structure / Michael B. Smith, Jerry March // Hardcover, 6th Edition. – 2007. – 2384 p.

7.   Carey Francis A. Advanced Organic Chemistry / Francis A. Carey, Richard A. Sundberg // Paperback, 5th Edition. – 2007. – 1199 p.

8.   http://intranet.tdmu.edu.ua/data/kafedra/internal/zag_him/classes_stud/pharmaceutical/pharmacy/full_time_study/organic_chemistry/2_course/lesson_21.Condensed heterocyclic systems. Purine. Notion about alkaloids.

9.   http://intranet.tdmu.edu.ua/data/kafedra/internal/zag_him/presentations/pharmaceutical/pharmacy/full_time_study/organic_chemistry/2_course/lecture_13.Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine.

Additional:

1.      Francotte Eric. Chirality in Drug Research / Eric Francotte, Wolfgang Lindner // Hardcover, First Edition. – 2006. – 351 p.

2.      Quin Louis D. Fundamentals of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of Pharmaceuticals / Louis D. Quin, John Tyrell // Hardcover, 1st Edition. – 2010. – 327 p.

3.      Zweifel George S. Modern Organic Synthesis – An Introduction / George S. Zweifel, Michael H. Nantz // Softcover, 1st Edition. – 2007. – 504 p.

4.      K. C. Nicolaou. Molecules that changed the World / Nicolaou K. C., Tamsyn Montagnon // Hardcover, First Edition. – 2008. – 385 p.

5.      Mundy Bradford P. Name Reactions and Reagents in Organic Synthesis / Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro // Hardcover, 2nd Edition. – 2005. – 886 p.

6.      Li Jie Jack. Name Reactions. A Collection of Detailed Reaction Mechanisms / Jie Jack Li // Hardcover, 4th Edition. – 2009. – 621 p.

7.      Gallego M. Gomez. Organic Reaction Mechanisms / M. Gomez Gallego, M. A. Sierra // Hardcover, First Edition. – 2004. – 290 p.

8.      Sankararaman Sethuraman. Pericyclic Reactions – A Textbook / Sethuraman Sankararaman // Softcover, First Edition. – 2005. – 418 p.

9.      Tietze Lutz F. Reactions and Syntheses / Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen // Paperback, First Edition. – 2007. – 598 p.

10.  Olah George A. Superelectrophiles and Their Chemistry / George A. Olah, Douglas A. Klumpp // Hardcover, First Edition. – 2007. – 301 p.

11.  Grossmann Robert B. The Art of Writing Reasonable Organic Reaction Mechanisms / Robert B. Grossmann // Hardcover, 2nd Edition. – 2003. – 355 p.

12.  Cole Theodor C.H. Wörterbuch Labor – Laboratory Dictionary / Theodor C.H. Cole // Hardcover, 2nd Edition. – 2009. – 453 p.

 

The methodical instruction has been worked out by: associate prof. Dmukhulska Ye.B., assistant Medvid I.I., assistant Burmas N.I.

 

 

 

 

Methodical instruction was discussed and adopted at the Department sitting

25.06.2013. Minutes N 11

 

Methodical instruction was adopted and reviewed at the Department sitting

27.08.2013. Minutes N 1