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2. Organic Chemistry Medical Chemistry and Biochemistry Winter term © Institute of Medical Biochemistry and Laboratory Diagnostics of the General University Hospital and of The First Faculty of Medicine of Charles University in Prague - 2005-2016

3. Org. chem. 2015/163 Synthesis of urea (Wöhler 1828) (Thermic rearrangement) Friedrich Wöhler (1800-1882): Organic compound formed from inorganic compounds Jan Horbaczewski (1854-1942): He graduated on the Faculty of Medicine in Wienna by prof. Ludwig; Founder of the Department of Medical Chemistry ONH 4 CN NH 2 NH 2 Teplo OC Heat Synthesis of uric acid Synthesis of uric acid ( Horbaczewski 1882 – age of 28) Urea + Glycine + (heat) = Uric acid (very low efficiency) (discovered by Schulz 1776) heat

4. Org. chem. 2015/164 During further experiments he proved that uric acid is formed by decomposition of nucleus-containing cells only, this process was not observed in cells without nucleus (e.g., erythrocytes) He successfully separated uric acid from xanthine and other purine bases and correctly supposed that uric acid is formed from these substances. Acrylic acidUric acid Synthesis of uric acid Synthesis of uric acid (Horbaczewski 1882)

5. Org. chem. 2015/165 The bond polarity depends on the difference of electronegativities. Presence of polar and non-polar bonds significantly affects the resulting character of the organic compound: Bind distance and binding energy - examples Bonds in organic compounds BondEnergy [kJ.mol -1 ]Distance [pm] C-C347154 C=C611133 CCCC 837120 C-H414106 C-N293147 CNCN 891116 C-O352143 C=O732122 N-H389101 O-H464100 Values of energy are approximate („average“). In molecules are influenced by surrounding structures, i.e., by other parts of the molecule. There are s. c. hybrid (partial) bonds (e.g., benzene – 1.5).

6. Org. chem. 2015/166 Constitution: Inner structure of the molecule of organic compounds Stereochemistry (Three-dimensional structure of organic compounds) – Formulas of organic compounds Molecular formulas are in organic chemistry practically inapplicable, because they do not yield the most important information about the inner structure of the molecule. e.g., C 2 H 6 O can be : 1)Ethanol (CH 3 -CH 2 -OH) 2)Dimethylether (CH 3 -O-CH 3 ) Therefore, the structural formulas are used, because they show all bonds among atoms. Disadvantage of such formulas consists in their complicity in case of more complicated compounds. Most frequently the rational formulas are used, in which are marked out only such bonds, which are necessary for unambiguous determination of the constitution – three dimensional configuration. For absolutely exact definition of 3D organization of the organic molecule, it is necessary to use perspective formulas (the bonds aiming upwards and downwards, forwards, backwards are differentiated). The use of models, which can help by solving of e.g. DNA structure (Watson and Crick - Nobel prize for chemistry), seems to be optimal. The computers can simplify significantly the work with such models.

7. Org. chem. 2015/167Isomers Isomers: Isomers are molecules, which have the same molecular formula, but they have a different arrangement of the atoms in space.

8. Org. chem. 2015/168 Isomers I. Basic types of isomerism: Constitutional (Structural) isomerism: Isomers have different constitution, i.e., they have a different arrangement of the atoms in space or in molecule. Chain: Butane, isobutene (arrangement of chain) Position: chains have variable amounts of branching (groups: 1-propanol, 2-propanol) (bonds: 1-buten, 2-buten) Tautomerism - Isomers differs in the position of the hydrogen and double bond, e.g., acetamide (Amide of acetic acid) The dynamic equilibrium is established between both tautomers.

9. Org. chem. 2015/169 Isomers II. Keto (oxo) formAcetoacetic acidenol form Keto-enol-tautomerism is best known Conformation of the molecule is given by the free rotation of molecules along single bonds. There are (theoretically) possible (by more complicated molecules) large amounts of conformations; they are limited by energy of the positions and by weak bonds (hydrogen bridges, ionic and non-polar interactions).

10. Org. chem. 2015/1610 Isomers III. Stereoisomerism (spatial): the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. Various configurations are given by double bond (cis-trans isomers) or by presence of a chiral center (an asymmetric carbon C*). cis-trans (geometric) isomerism is a result of the impossibility of the rotation along the double bond (it is caused by binding  -orbitals). cis-2-butenetrans-2-butene

11. Org. chem. 2015/1611 Isomers VI. Asymmetric carbon has each bond occupied by completely different single-bonded atom or group of atoms, therefore the structure has not any symmetry plane. There exit two possible space arrangements: subject and its mirror image. By their differentiation we go out from structure of glyceraldehyde: D- and L- isomers are characterized by equal chemical reactivity, but biochemically can differ mutually substantially (reactions with enzymes or antibodies) D-L- Compounds containing asymmetric carbon show optical rotation and they form optical antipodes - enantiomeres. Rotation is labeled: (+) – to the right and (-) – to the left. The aim of light rotation is not connected with the D- and L- labeling!!!!!

12. Org. chem. 2015/1612 Classification of organic compounds Organic compounds AliphaticCyclic Saturated (single bonds) Unsaturated (multiple bonds) Isocyclic (carbocyclic, C only) Heterocyclic (in ring are other atoms then C) Alicyclic Saturated Unsaturated Aromatic (conjugated double bonds in ring) SaturatedUnsaturatedAromatic

13. Org. chem. 2015/1613 Most important arenes I Benzene Naphtalene Anthracene Tetracene (partly hydrogenated „tetracycline“) Phenanthrene Cyclopentano perhydrophenanthrene - base of steroids

14. Org. chem. 2015/1614 Most important arenes II Pyrene Benzopyrene (carcinogenic) Benzo[a]pyrene Biphenyl (Polychlorated biphenyls - toxic for CNS of children) Diphenylmethane Base of DDT – p,p’-dichloro diphenyl trichloroethane 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane

15. Org. chem. 2015/1615 Halogen derivatives of hydrocarbons One or more hydrogens are substituted by a halogen (X = F, Cl, Br, I) Bond is weak polar – insoluble in water, good soluble in non-polar solvents. Most of these compounds are volatile liquids, which are very good non-polar („organic“ or „fat“) solvents. Chemically are very reactive, especially with nucleophilic substances. Application:  Solvents - Tetrachloromethane, CCl 4 (toxic, carcinogenic). It forms phosgene (COCl 2 ) with water  Freons (Fluorochloroalkanes) - CCl 3 F, CCl 2 F 2 and other in refrigerators – they damage ozonosphere  Plastics - PVC, synthetic rubber, Teflon  Chlorophorm CCl 3 H - toxic, Bromophorm CBr 3 H – against cough, Iodoform CI 3 H - disinfection, antiseptic agent, proof of acetone (iodoform reaction)  Anesthetic - local - earlier ethyl chloride CH 3 CH 2 Cl („kelene“ - freezing)  Anesthetic – general - Trichloroethylene CHCl=CCl 2 (narcotic) Halothane CF 3 -CHBrCl  Biologically active substances – thyroid gland hormones (triiodo-L- thyronine, Tetraiodo-L-thyronine=thyroxine)  Older insecticide - DDT, HCH (hexachlorocyclohexane - Lindane) – its use is prohibited at present

16. Org. chem. 2015/1616 Hydroxy derivatives (alcohols, phenols) Hydroxyl group -OH gives to hydrocarbons, especially to aromatic, weak acidic character (Attention – they are not hydroxides!!!) Bond C-OH is covalent, nevertheless strong polar, therefore the hydrogen bridges can be formed. Consequently, the simpler alcohols are good miscible with water, only by higher alcohols the non-polar character of side chain prevails (pentanol – amyl alcohol) Terminology: By aliphatic - hydrocarbon + -ol (methanol, ethanol) By aromatic compound used frequently more trivial

17. Org. chem. 2015/1617 Hydroxy derivatives (alcohols, phenols) Hydroxyl group of alcohols is strongly reactive. With alkali metals produces alkoxides C 2 H 5 OH + Na = C 2 H 5 ONa + 1/2H 2 The hydroxyl group with acids produces esters with mineral acids are formed: R-OH + H-X = R-X + H 2 O with organic acids are formed: Esterification is typical reversible reaction – (hydrolytic) dissociation of esters can be realized, producing alcohol and acid – common reaction in life organisms.

18. Org. chem. 2015/1618 Alcohols and phenols I Methanol: CH 3 OH toxic, blinding, danger of death Higher alcohols - propanol, butanol, pentanol have some isomers. Higher alcohols can be a part of lipids. Ethanol: CH 3 CH 2 OH - euphoric, narcotic effect. Habitudinal drug – most often toximania (drug addiction). More functional alcohols: 1,2-ethandiol (ethylene glycol) HO-CH 2 -CH 2 -OH toxic, heavy poisons, harmful for kidneys. Glycols are parts of antifreeze mixtures for cooling systems automobile radiator („Fridex“) - sweet –soluble in water. 1,2,3-propanetriol (glycerol) Part of most of lipids.

19. Org. chem. 2015/1619 Alcohols and phenols II Cyclohexanol (inositol): Cyclohexanol (inositol): Biologically important compound, similar type as vitamins Phenol: (weak acid) Toxic, corrosive !!! Hydroquinone (1,4-benzenediol) Para-benzoquinone (Redox = Oxidation – reduction systems)

20. Org. chem. 2015/1620 Biologically important alcohols I Sphingosine (sphingenine) (trans-D-erythro-)2-amino-4-octadecene-1,3-diol-18-carbon alcohol contained in complex lipids, especially in encephalic lipids Ethanolamine: HO-CH 2 -CH 2 -NH 2 Part of lipids Choline Part of lipids. Its ester with acetic acid is very important for transport of neural excitements. Strong basic, Quaternary ammonium base.

21. Org. chem. 2015/1621 Biologically important alcohols II We can classify also vitamins soluble in fats (exclusive vitamin K) as alcohols Vitamin A - retinol Vitamin E - tocopherol Vitamin D - cholecalcipherol and ergocalcipherol Fat-soluble vitamins are described in detail in chapter „Steroids and isoprenoids“

22. Org. chem. 2015/1622 Aldehydes and ketones (oxo-derivatives) I Carbonyl group Common group for ketones - carbonyl on secondary carbon aldehydes - carbonyl on primary carbon Aldehydes can be aliphatic or aromatic, ketones are mixed. Carbonyl group is polar, therefore the compounds have good miscibility with polar solvents. Character of the group does not enable formation of large clusters by means of hydrogen bridges. Therefore, the boiling point is lower than by alcohols, but higher than by corresponding hydrocarbons. Most of aldehydes and ketones are at normal temperature (laboratory temperature, in our country 25 o C- 298 K) (exclusive formaldehyde H 2 CO) liquid.

23. Org. chem. 2015/1623 Aldehydes and ketones (oxo-derivatives) II They exhibit very high reactivity. The addition on carbonyl is very easy realizable. The formation of hemiacetal is very important (see carbohydrates). Difference: Aldehydes have reducing character (reductants)– they are easy oxidized to carboxylic acids vs. ketones do not have reducing character. Aromatic aldehydes form with primary amines Schiff base Benzaldehyde MethylamineBenzylidenemethylamine (Schiff Base) Important by transamination – Schiff base forms pyridoxal-phosphate with ammonium group of amino acids

24. Org. chem. 2015/1624 ETHERS General formula: R 1 -O-R 2 Esters do not form hydrogen bridges. Therefore the boiling point is lower than by corresponding alcohols: CH 3 OHCH 3 -O-CH 3 Mol. mass [g.mol -1 ]3246 Boiling point [ o C]65-24 They are practically non-polar. Higher, e.g., diethylether, are used for extraction of non-polar compounds from aqueous solutions. Diethylether is the most frequently used ether: CH 3 -CH 2 -O-CH 2 -CH 3 Attention – the vapors are explosive. Explosive peroxides are formed on light and in the presence of air. It is necessary to store it in dark bottles and to stabilize (e.g., diphenylamine).

25. Org. chem. 2015/16 25 ETHERS II Important aromatic ethers, e.g.: 1-(2-methoxyphenoxy)-2,3-propanediol Medicine calming and lowering hypermyotonia (muscular stress) Guaiacol (1-hydroxy-methoxybezene) Part of cough-syrups. Guajacuran (Guaifenesin) 1-allyl-4-hydroxy-3-methoxybenzene Present in in clove bud oil. Source of clove odor. Eugenol

26. Org. chem. 2015/1626 Carboxylic acids I Characteristic group: Carboxyl group According to the number of these groups we call these compounds mono-, di-, tri- and polycarboxyl(s). They are relatively weak acids (pK A = 4-5). Carboxyls form mutually hydrogen bridges, and therefore the carboxylic acids exist mostly in form of dimers or of polymers.

27. Org. chem. 2015/1627 Carboxylic acids II Hydroxyl group of carboxyl dissociates proton (in consequence of the transfer of the electrons), therefore the carboxylic acids have character of acids. The strength of carboxylic acid is influenced also by the rest of molecule (e.g., number of carbons, number of carboxyls or of other substituents).

28. Org. chem. 2015/1628 Carboxylic acids III Labeling of carbons in the molecule: Properties: R-CH 2 -CH 2 -CH 2 -CH 2 -COOH  5432154321 1.Formation of salts 2.Possible decarboxylation, i.e., elimination of CO 2 under production of the one carbon shorter hydrocarbon (common reaction in biochemistry, in industrial organic chemistry very complicated process). 3.Reaction of carboxyl under formation of functional derivatives of carboxylic acids 4.Substitution on hydrocarbon part  substitution derivatives of carboxylic acids The radical formed by removing of -OH group from carboxyl is (generally) called ACYL. The names of radicals are derived from the name of the acid + ending -YL. Formyl Acetyl

29. Org. chem. 2015/1629 Monocarboxylic acids I FormulaTrivial English name - acid Systematic English name - acid Latin name acidum Salt name HCOOH*FormicMethanicFormicumFormiate CH 3 COOHAceticEthanicAceticumAcetate CH 3 CH 2 COOHPropionic Propionate CH 3 (CH 2 ) 2 COOHButyricButanicButyrate (CH 3 ) 2 CHCOOHIsobutyricIsobutanicIsobutyrate CH 3 (CH 2 ) 3 COOHValericPentanicValerate CH 3 (CH 2 ) 14 COOHPalmiticHexadecanoic Palmitate *Character of an aldehyde, i.e. reducing agent

30. Org. chem. 2015/1630 Uronic acids are a class of sugar acids with both carbonyl and carboxylic acid functional groups. They are sugars in which the terminal carbon's hydroxyl group has been oxidized to a carboxylic acid. β-D glucuronic (formed from glucose), salts: glukoronates -D-glucuronic acid is a component of many polysaccharides, present in pectins, slimes, component of hyaluronic acid, chondroitin sulfate acid, heparin and of a lot of microbial polysaccharides. -Formation of uronides supports solubility and excretion of many compounds. -Play very important role in synthesis of polysaccharides araban and xylan (parts of plant cell wall) -L-Ascorbic acid, Vitamin C, chemically lakton of 2-oxo-L-gulonic acid, formed in all animals except monkey and guinea pig, as well as in humans, from glucoronic acid.

31. Org. chem. 2015/1631 Monocarboxylic acids II FormulaTrivial English name - acid Systematic English name - acid Latin name acidum Salt name CH 3 (CH 2 ) 16 COOHStearicOctadecanoicStearate CH 3 (CH 2 ) 7 CH=CH- (CH 2 ) 7 COOH Oleic cis-9- Octadecenoic acid Oleate CH 2 =CHCOOHAcrylic2-en 1-propanic Acrylate Benzoic benzoicumBenzoate

32. Org. chem. 2015/1632 Dicarboxylic acids FormulaTrivial English name - acid Systematic English name - acid Latin name acidum Salt name HOOC-COOHOxalic1,2-EthandiicOxalicumOxalate HOOC-CH 2 -COOHMalonic*Propan-1,3-diicMalonicum*Malonate* HOOC-(CH 2 ) 2 - COOH SuccinicButan-1,5-diicSuccinicumSuccinate HOOC-(CH 2 ) 3 - COOH GlutaricPentan-1,5-diicGlutaricumGlutarate Maleic*cis-but-2-en-1,5- dioic Maleate* Fumarictrans-but-2-en-1,5- dioic Fumarate Phthalic o-Benzenedicarboxylic acid Phthalate Attention: malate – maleate - malonate

33. Org. chem. 2015/1633 Tricarboxylic acids cis-aconitic acid, important metabolite of Krebs cycle; salt: cis-aconitate citric acid, important metabolite of Krebs cycle; salt: citrate In detail: see substitution derivatives of carboxylic acids

34. Org. chem. 2015/1634 Substitution derivatives of carboxylic acids I 1)Halogen acids - trichloroacetic, monofluoroacetic – poison 2)Hydroxy acids – biochemically and medically important! lactic acid (lactate)pyruvic acid  -hydroxy propionic (pyruvate) Hydroxy propionic Ketoacid

35. Org. chem. 2015/1635 Substitution derivatives of carboxylic acids II  - and  -hydroxy acids are esterified within their molecules → a cyclic ester is formed - lactone  - lactone   E.g., Vitamin C = L-ascorbic acid = dehydrolactone of gulonic acid Carbonic acid The simplest hydroxy acid Carboxyl Hydroxyl

36. Org. chem. 2015/1636 Most important hydroxy acids I 1) Lactic acid, acidum lacticum, lactate ( L and D forms) 2,3-dihydroxypropionic acid Glycolysis (1 i 2) 2) Glyceric acid, salt: glycerate 3) Malic acid, acidum malicum, malate (2-hydroxybutandiic acid) (Krebs cycle) 4) Tartaric acid, acidum tartaricum, tartarate (+) Tartaric acid “right-handed“ tartaric (-) Tartaric acid “Left-handed“ tartaric Mesotartaric 

37. Org. chem. 2015/1637 Most important hydroxy acids II Isocitric acid, isocitrate 5) Citric acid, acidum citricum, citrate 6) Salicylic acidAcetylsalicylic acid p-aminosalicylic acid Wide application in medicine - Acylpyrin (in Czech) (Aspirin) Remedy against tuberculosis

38. Org. chem. 2015/1638 Most important hydroxy acids III Very sensitive reaction for the proof of peptides (principle denaturalization) Sulfosalicylic acid 7) Gentisic acid Anti-rheumatic effect

39. Org. chem. 2015/1639 Most important keto acids I 1) Pyruvic acid, acidum pyruvicum, Pyruvate Enol-form Keto-form (In biochemistry one of the most important acids!!!) (keto-, enol- tautomery)Acetone 2) Acetoacetic acid, acidum acetaceticum, acetoacetate Acetoacetate is formed by degradation of lipids (FA) 3) Oxalacetic acid, -, oxalacetate Important part of Krebs cycle CH 2 C COOH OH O COOH CCH 3

40. COOH CH 2 C COOH O Org. chem. 2015/1640 Most important keto acids II 4)  -ketoglutaric acid, -,  -ketoglutarate Very important metabolite of Krebs cycle, amino acids (glutamic acid) can be formed from this acid, as well as the compounds necessary for porphyrins synthesis (hem) connection between metabolism of peptides and of saccharides 5) Oxalsuccinic acid, ac. oxalsuccinicum, oxalsuccinate Metabolite of Krebs cycle, formed from iso-citrate and it is transformed by decarboxylation to  -ketoglutarate -CO 2 COOH CH 2 2 CCOOHO

41. Org. chem. 2015/1641 Nitrogen containing derivatives of hydrocarbons I. Nitro compounds R-NO 2 They are often toxic, important mainly in the industrial chemistry. Possibilities of poisons. Examples: Nitroethane: CH 3 -CH 2 -NO 2 Nitrobenzene: Trinitrotoluene: In nature are very rare. Exception: Chloramphenicol (Antibiotic from streptomyces venezuelae) Nitroglycerin: incorrect name, correctly it is glycerol nitrate - ester of glycerol with nitric acid, it is not nitro compound!

42. Org. chem. 2015/1642 Nitrogen containing derivatives of hydrocarbons II. Ammines Primary SecondaryTertiary Quaternary ammonium bases They are actually organic derivatives of ammonia, therefore they have mostly basic character. Amino group is strong polar. Ammines belong often to biologically important substances – amino acids, biogenic ammines (emphatic physiologic effect), alkaloids (toxic and pharmaceutical compounds of vegetative origin), synthetic pharmaceutical compounds.

43. Org. chem. 2015/1643 Reactions of secondary amines with nitrous acid (nitrites) in the presence of HCl  Nitrosamines Nitroso-amines exhibit carcinogenic effects!!! Nitroso-amine Some important amines Aniline – toxic – industrial poisons Ethylene Diamino Tetra Acetic acid EDTA - calcium salt of this acid is often administrated as antidote by heavy metals poisons Chelaton II and III – important in analytical chemistry Choline – Amino alcohol International Agency for Research on Cancer (IARC)

44. Org. chem. 2015/1644 Biologically important amines Noradrenaline … and similar alkaloids and drugs Dopamine Adrenaline Isoprenaline Amphetamine (Psychoton) EphedrineMescaline Synthetic drugs Alkaloids Similarity in structure and in effects!!!

45. Org. chem. 2015/1645 Functional derivatives of carboxylic acids Amide Acyl halide Nitril  Acyl halides – use in organic synthesis  Anhydrides - use in organic synthesis  Esters – low polarity, hydrogen bridges are not formed. Solvents of lipids!  Thioesters – acetyl coenzyme A  Amides - urea, nicotinamide, amides of amino acids  Nitril – hydrocyanic acid - nitril of formic acid - toxic! X-halogen Anhydrides Esters Thioesters

46. Org. chem. 2015/1646 Functional derivatives of carboxylic acids – derivatives carbonic acid (H 2 CO 3 ) I Dichloride of carbonic acid: 1) Halogen derivatives- phosgene - toxic!!! 2) Amides Diamide of carbonic acid = urea: Monoamide of carbonic acid = carbamic acid (Unstable, it exists only as phosphate) Important for biosynthesis Phosphate group of urea

47. Org. chem. 2015/1647 Functional derivatives of carboxylic acids – derivatives carbonic acid (H 2 CO 3 ) II they have sedative and sleeping (narcotic) effects, relatively toxic, and therefore they are not used at present (with one exception): 3) Esters carbamic acid = Urethanes 2-methyl-2-propyl-1,3-propanediolcarbamate MEPROBAMATE

48. Org. chem. 2015/1648 Derivatives of urea I 1) Biuret – is formed by heating up of the urea, ammonia is released biuret 2) Guanidine (iminourea)- oxygen is substituted by an imine group =NH Is formed by oxidative cleavage of guanine Its derivative – amino acid Arginine (see amino acids) Creatine - N–methyl-guanidine-acetic acid Very important for transport of energy in muscles

49. Org. chem. 2015/1649 Derivatives of urea II Creatinine is formed from creatine as its anhydride Creatinine is not utilizable for a muscle. It is excreted by urine (kidneys - diuresis) and therefore it is used in clinical biochemistry for monitoring of their functions („clearance“ of creatinine)

50. Org. chem. 2015/1650 Ureides I Ureides are derived from carboxylic acids by substitutions of the hydroxy group by the urea (analogy to amides): Many of ureides belong to important remedies, e.g.: Acetic acidUreaUreide of acetic acid (acetyl urea) Bromisoval (sedative) Ureide of  -bromoisovaleric acid

51. Org. chem. 2015/1651 Ureides II The cyclic ureides can be formed with dibasic acids. Such compound can be classified as heterocyclic compounds: Malonic acidUreaBarbituric acid Many drugs with sedative, hypnotic and in higher doses with narcotic effects are derived from barbituric acid - Barbiturates

52. Org. chem. 2015/1652 Thio derivatives I 2) Thioethers (sulfides): „yperite“ Mustard gas 1) Thioalcohols (and thiophenols): Dimercaptol (BAL) Bond with heavy metals Amino acid Cysteine 3) Disulfides: Disulphidic bridges (peptides)  -lipoic acid = (6,8-dithiooctanic acid)=1,2-Dithiolane-3-pentanoic acid Reduced form Oxidized form Amino acid Cystine

53. Org. chem. 2015/1653 Thiolic derivatives II sulfosalicylic acid (see hydroxy acids) 4) Sulfonic acids: 5) Sulfones: Sulfonamides (antimicrobial, chemotherapy) 6) Sulfur containing heterocycles: Thiophene (5member ring with 1-heteroatom S), thiazole, phenothiazine

54. Org. chem. 2015/1654 Sulfonamides (chemotherapeutics) Sulfones – derivatives of sulfanilic acid sulfoguanidine sulfothiazole which is antagonist of para-aminobenzoic acid (PABA) 4-aminobenzoic acid „vitamin H“ PABA is essential bacterial growth factor sulfanilamide

55. Org. chem. 2015/1655 Heterocycles – Basic structures I (usually 3 rd class of secondary (grammar, high) school)

56. Org. chem. 2015/1656 Heterocycles – Basic structures II (usually 3 rd class of secondary (grammar, high) school)

57. Org. chem. 2015/1657 Heterocycles – Basic structures III (usually 3 rd class of secondary (grammar, high) school)

58. Org. chem. 2015/1658 Heterocycles - Basic structures IV 5member ring Furan (furanoses) hydroxy derivatives - Sugars Thiophene hydrogenated base of biotin - vitamin H Pyrrole – base of cyclic and linear tetrapyrroles - porphyrines - hem, bilirubine (bile pigment) (In Czech žlučové barvivo) In combination with benzene: Benzopyrrole (indole) Amino acid Tryptophan Tryptamine 5-hydroxytryptamine „biogenic amines“ – physiologically very effective compounds Ergotic alkaloids (affect the tonus of smooth muscles (uterus-obstetrics) + LSD - diethylamide of lysergic acid (hallucinogenic compound (chemically prepared psychosis))

59. Org. chem. 2015/1659 Aflatoxin B 1 Toxic and carcinogenic compound from fungus Aspergillus flavus, which is growing on foods (especially groundnut – monkey nuts etc.). Biotin (vitamin H) Essential for carboxylation reactions (incorporation of CO 2 into organic acids) - prosthetic group of enzymes Dehydro-L-ascorbic acid Non-enzymatic transfer of hydrogen L-ascorbic acid - vitamin C

60. Org. chem. 2015/1660 Indole (1H-Benzo[b]pyrrole) Its diethylamide = LSD (hallucinogenic) Lysergic acid Ergometrine (ergot alkaloid)

61. Org. chem. 2015/1661 Five member heterocycles with two heteroatoms 1H-pyrazole  antipyretic (antipyrine, amidopyrine) imidazole Amino acid histidine  histamine („biogenic amine“) Vitamin B 1 thiamine and amiphenazole are derived from thiazole – drug increasing irritability of CNS (hyperirritability) Thiazole tetra hydrogenated base of penicillin structure

62. Org. chem. 2015/1662 Five member heterocycles with two heteroatoms – derived drugs I phenazon (antipyrine) aminophenazone (amidopyrine) and more complicated phenylbutazone and ketophenylbutazone (ketazone) From pyrazole:

63. Org. chem. 2015/1663 Five member heterocycles with two heteroatoms – derived drugs II Penicillins: From thiazole: G-penicillin -R=benzyl  -lactam ring – can be split by enzyme  -lactamase, which have some bacteria (gold staphylococcus). Thereby the effect of penicillin is destroyed, and therefore, in case of these bacteria, it has no any sense to administer it. Thiamine (vitamin B 1 ) (pyrimidine + thiazole)

64. Org. chem. 2015/1664 6-member heterocycles with one heteroatom  -pyran Sugars „pyranoses“ stable hyroxy derivatives Oxo derivative of  -pyran (2H pyran) Tetrahydropyran (4H-pyran) Benzo derivatives of  -pyran Chroman Vitamin E is derived of chroman  -pyron Benzo derivative  -pyron - coumarin Derived compound with (blood) anticoagulation effect (Warfarin)

65. Org. chem. 2015/1665 6-member heterocycles with one heteroatom – derived compounds Coumarin: Some derived compounds have anticoagulation effects – decelerate blood coagulation. This effect is medically used. Warfarin - antagonist to K vitamins: Vitamin K 2 K 1 Vitamin Vitamin K is necessary for synthesis of prothrombin in livers.

66. Org. chem. 2015/1666 6-member heterocycles with one heteroatom (nitrogen) Pyridine: Important derivatives Toxic. Alkaline, with acids produces salts. Nicotinic acid Medicament for blood- vessel extension Cl- Nicotine amide „vitamin PP“ part of NAD and NADP very important compound

67. Org. chem. 2015/1667 6-member heterocycles with one heteroatom (nitrogen) Isonicotinic acid INH – medicament against T.B. (tuberculosis) and its hydrazide Piperidine Formed from pyridine by hydrogenation Derived synthetic analog of morphine - pethidine (Dolsin) Benzo derivatives: Cinnoline is a part of alkaloid quinine and of other synthetic antimalaria drugs. CinnolineIsocinnolineAcridine

68. Org. chem. 2015/1668 Alkaloids and drugs with 6-member heterocycles with one heteroatoms Derived from pyridine diethylamide of nicotinic acid (central analeptics) nicotine Quinine (and other antimalarial drug ) QuinolineIsoquinoline Papaverine (spasmolytics, release spasms of smooth muscles) uvolňuje křeče

69. Org. chem. 2015/1669 6-member heterocycles with two heteroatoms I Pyridazine The most important: Some bases of nucleic acids are derived from pyrimidine Pyrimidine Pyrazine Cytosine Uracil Thymine Tautomerism of the uracil basis Lactim Lactam

70. Org. chem. 2015/1670 6-member heterocycles with two heteroatoms II Piperazine full hydrogenated derivative of pyrazine is used as medicament by goat (in Czech „dna“) (arthritis uratica) and furthermore as antihelminticum (medicament against pinworms and roundworms (in Czech „roupům a škrkavkám“) Thiazines ( the most important derivative Phenothiazine) Other derivatives: Methylene blue and neuroleptics – medicaments used in psychiatry

71. Org. chem. 2015/1671 Compounds with two condensed heterocycles Purine Some bases of nucleic acids are derived from purine Adenine (ATP!!!) Guanine Both compounds are degraded via hypoxanthine xanthine to uric acid Uric acid can crystallize in urine – gravel (urolithiasis) (in Czech „močové kameny“) Alkaloids derived from xanthine: caffeine, theophyline, theobromine Surplus – accumulation in tissues = gout (in Czech „dna“)

72. Org. chem. 2015/1672Phenothiazine Basic structure of phenothiazine neuroleptics Chlorpromazine 2-chlor-10-(3-dimethylaminopropyl) phenothiazine Caffeine 1,3,7-trimethylxanthine

73. Org. chem. 2015/1673 Heterocyclic vitamins Pteridine is formed by two aromatic azines: pyrimidine and pyrazine Pteridine Biopterine Reduced form Tetrahydrobiopterine Donor of hydrogen Pterine PABA- para-aminobenzoic acid (PABA) Glutamic acid Folic acid (ptero-glutamic) is derived from pteridine

74. Org. chem. 2015/1674 Heterocyclic vitamins II Benzopterine Alloxazine Pyridoxine, B 6 (derivative of pyridine) R= -CH 2 OH pyridoxol R= -CHO pyridoxal R= -CH 2 NH 2 pyridoxamine

75. Org. chem. 2015/1675 Organo-metallic compounds 1.Arsenic benzenes - salversan, neosalversan – formerly used as antiparasitics and antimicrobial drugs – not at present (toxic, carcinogenic) 2.War agent - Lewsit ClCH=CHAsCl 2 – used relatively recently (antidote BAL-dimercaptol) 3.Tetraethylplumban („tetraethyl lead“) anti-detonation additive into petrol – highly toxic (C 2 H 5 ) 4 Pb 4.Anti-tumoric compounds - carboplatin 5. Dimethylmercury (CH 3 ) 2 Hg – used in organic synthesis – highly toxic, possible industrial poisons (occupational medicine) 6. Organic compound of gold - antirheumatic agent gold sodium thiomalate

76. Org. chem. 2015/1676Organophophates Organophophates Soman: o-isopropyl methylfluorophosphate Blocker of acetylcholinesterase Parathione Malathione Insecticide - commonly used in agriculture (farming) – for man less toxic, but accidentally can occur the heavy professional poisons. antidote – antagonistic ACh - atropine aj.