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tnavratil@seznam.cz

The texts were not checked by a native speaker. All comments, suggestions and improvements are welcome and the authors will be very thankful for discovered errors, advices, recommendations and remarks. We are waiting for your messages on E-mail address:. tnavratil@seznam.cz. Organic Chemistry.

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  1. The texts were not checked bya native speaker. All comments, suggestions and improvements are welcome and the authors will be very thankful for discovered errors, advices, recommendations and remarks. We are waiting for your messages on E-mail address: tnavratil@seznam.cz

  2. Organic Chemistry Medical Chemistry and BiochemistryWinter 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 - 2005-2014

  3. Teplo Heat N H 2 O C O N H N C 4 N H 2 Synthesis of uric acid (Horbaczewski 1882 – age of 28) heat Urea + Glycine + (heat) = Uric acid (very low efficiency) (discovered by Schulz 1776) 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 Organic chemistry 2013/2014

  4. Synthesis of uric acid (Horbaczewski 1882) Acrylic acid Uric acid 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 fromxanthine and other purine bases and correctly supposed that uric acid is formed from these substances. Organic chemistry 2013/2014

  5. 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 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). Organic chemistry 2013/2014

  6. Molecular formulasare in organic chemistry practically inapplicable, because they do not yield the most important information about the inner structure of the molecule. • e.g., C2H6O can be : • Ethanol (CH3-CH2-OH) • Dimethylether (CH3-O-CH3) Stereochemistry (Three-dimensional structure of organic compounds) – Formulas of organic compounds Constitution: Inner structure of the molecule of organic compounds 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 formulasare 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 3Dorganization 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. Organic chemistry 2013/2014

  7. Isomers: Isomers are molecules, which have the same molecular formula, but they have a different arrangement of the atoms in space. Isomers Organic chemistry 2013/2014

  8. 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. Isomers I. Organic chemistry 2013/2014

  9. Isomers II. Keto-enol-tautomerism is best known Keto (oxo) form Acetoacetic acid enol form 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). Organic chemistry 2013/2014

  10. cis-trans (geometric) isomerismis a result of the impossibility of the rotation along the double bond (it is caused by binding-orbitals). cis-2-butene trans-2-butene 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*). Organic chemistry 2013/2014

  11. D- L- 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) 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!!!!! Organic chemistry 2013/2014

  12. Classification of organic compounds Organic compounds Aliphatic Cyclic Saturated (single bonds) Unsaturated (multiple bonds) Isocyclic (carbocyclic,C only) Heterocyclic (in ring are other atoms then C) Alicyclic Aromatic (conjugated double bonds in ring) Saturated Unsaturated Saturated Unsaturated Aromatic Organic chemistry 2013/2014

  13. Most important arenes I Organic chemistry 2013/2014

  14. 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane Most important arenes II Organic chemistry 2013/2014

  15. 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: Halogen derivatives of hydrocarbons • Solvents - Tetrachloromethane, CCl4 (toxic, carcinogenic). It forms phosgene (COCl2) with water • Freons (Fluorochloroalkanes) - CCl3F, CCl2F2 and other in refrigerators – they damage ozonosphere • Plastics - PVC, synthetic rubber, Teflon • Chlorophorm CCl3H - toxic, Bromophorm CBr3H – against cough, Iodoform CI3H - disinfection, antiseptic agent, proof of acetone (iodoform reaction) • Anesthetic - local - earlier ethyl chloride CH3CH2Cl („kelene“ - freezing) • Anesthetic –general - Trichloroethylene CHCl=CCl2 (narcotic)Halothane CF3-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 Organic chemistry 2013/2014

  16. Hydroxy derivatives (alcohols, phenols) Hydroxyl group-OHgives to hydrocarbons, especially to aromatic, weak acidic character(Attention – they are not hydroxides!!!) Bond C-OHis 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 moretrivial Organic chemistry 2013/2014

  17. The hydroxyl group withacids produces esters with mineralacidsare formed: R-OH + H-X = R-X + H2O with organicacidsare formed: Esterification is typical reversiblereaction – (hydrolytic) dissociation of esters can be realized, producing alcohol and acid – common reaction in life organisms. Hydroxy derivatives (alcohols, phenols) Hydroxyl group of alcohols is strongly reactive. With alkali metals produces alkoxides C2H5OH + Na =C2H5ONa + 1/2H2 Organic chemistry 2013/2014

  18. More functional alcohols: 1,2-ethandiol (ethylene glycol) HO-CH2-CH2-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. Alcohols and phenols I Methanol: CH3OH toxic, blinding, danger of death Ethanol: CH3 CH2OH - euphoric, narcotic effect. Habitudinal drug – most often toximania (drug addiction). Higher alcohols - propanol, butanol, pentanol have some isomers. Higher alcohols can be a part of lipids. Organic chemistry 2013/2014

  19. Phenol: (weak acid) Toxic, corrosive !!! Hydroquinone (1,4-benzenediol) Para-benzoquinone (Redox =Oxidation – reduction systems) Alcohols and phenols II Cyclohexanol (inositol): Biologically important compound, similar type as vitamins Organic chemistry 2013/2014

  20. Choline Part of lipids. Its ester with acetic acid is very important for transport of neural excitements. Strong basic, Quaternary ammonium base. 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-CH2-CH2-NH2 Part of lipids Organic chemistry 2013/2014

  21. 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“ Organic chemistry 2013/2014

  22. 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 oC- 298 K) (exclusive formaldehyde H2CO) liquid. Organic chemistry 2013/2014

  23. 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. Aldehydes and ketones (oxo-derivatives) II Aromatic aldehydes form with primary amines Schiff base Benzaldehyde Methylamine Benzylidenemethylamine (Schiff Base) Important by transamination – Schiff base formspyridoxal-phosphate with ammonium group of amino acids Organic chemistry 2013/2014

  24. ETHERS General formula: R1-O-R2 Esters do not form hydrogen bridges. Therefore the boiling point is lower than by corresponding alcohols: They are practically non-polar. Higher, e.g., diethylether, are used for extraction of non-polar compounds from aqueous solutions. Diethylether isthe most frequently used ether: CH3-CH2-O-CH2-CH3 Attention – the vapors are explosive.Explosive peroxides are formedon light and in the presence of air. It is necessary to store it in dark bottles and to stabilize (e.g., diphenylamine). Organic chemistry 2013/2014

  25. ETHERS II Important aromatic ethers, e.g.: (1-hydroxy-methoxybezene) Part of cough-syrups. Guaiacol Gujacuran 1-(2-methoxyphenoxy)-2,3-propanediol Medicine calming and lowering hypermyotonia (muscular stress) Organic chemistry 2013/2014

  26. 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 (pKA = 4-5).Carboxyls form mutually hydrogen bridges, and therefore the carboxylic acids exist mostly in form of dimers or of polymers. Organic chemistry 2013/2014

  27. 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). Organic chemistry 2013/2014

  28. 5 4 3 2 1 R-CH2-CH2-CH2-CH2-COOH     Labeling of carbons in the molecule: Carboxylic acids III Properties: • Formation of salts • Possible decarboxylation, i.e., elimination of CO2 under production of the one carbon shorter hydrocarbon (common reaction in biochemistry, in industrial organic chemistry very complicated process). • Reaction of carboxyl under formation of functional derivatives of carboxylic acids • 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 Organic chemistry 2013/2014

  29. Monocarboxylic acids I *Character of an aldehyde, i.e. reducing agent Organic chemistry 2013/2014

  30. Monocarboxylic acids II Organic chemistry 2013/2014

  31. Attention: malate – maleate - malonate Dicarboxylic acids Organic chemistry 2013/2014

  32. 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 Organic chemistry 2013/2014

  33. Substitution derivatives of carboxylic acids I • Halogen acids - trichloroacetic, monofluoroacetic – poison • Hydroxy acids – biochemically and medically important! lactic acid (lactate) pyruvic acid -hydroxy propionic (pyruvate) Hydroxy propionic Ketoacid Organic chemistry 2013/2014

  34. 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 Hydroxyl Carboxyl Organic chemistry 2013/2014

  35. 2) Glyceric acid, salt: glycerate 2,3-dihydroxypropionic acid Glycolysis (1 i 2) 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 1) Lacticacid, acidum lacticum, lactate ( L and D forms) Most important hydroxy acids I Organic chemistry 2013/2014

  36. 6) Salicylic acid Acetylsalicylic acid p-aminosalicylic acid Wide application in medicine - Acylpyrin (in Czech) (Aspirin) Remedy against tuberculosis Most important hydroxy acids II 5)Citric acid, acidum citricum, citrate Isocitric acid, isocitrate Organic chemistry 2013/2014

  37. 7) Gentisic acid Anti-rheumatic effect Most important hydroxy acids III Sulfosalicylic acid Very sensitive reaction for the proof of peptides (principle denaturalization) Organic chemistry 2013/2014

  38. COOH COOH CH C CH C 3 2 O OH 2) Acetoacetic acid, acidum acetaceticum, acetoacetate (keto-, enol- tautomery) Acetone Acetoacetate is formed by degradation of lipids (FA) 3) Oxalacetic acid, -, oxalacetate Important part of Krebs cycle Most important keto acids I 1) Pyruvic acid, acidum pyruvicum, Pyruvate Keto-form Enol-form (In biochemistry one of the most important acids!!!) Organic chemistry 2013/2014

  39. O C COOH CH 2 COOH CH 2 COOH O C CH COOH -CO2 COOH CH 2 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 Organic chemistry 2013/2014

  40. Nitrogen containing derivatives of hydrocarbons I. Nitrocompounds R-NO2 They are often toxic, important mainly in the industrial chemistry. Possibilities of poisons. Examples: Nitroethane: CH3-CH2-NO2 Trinitrotoluene: Nitrobenzene: In nature are very rare. Exception: Chloramphenicol (Antibiotic from streptomyces venezuelae) Nitroglycerin: incorrect name, correctly it is glycerolnitrate - ester of glycerol with nitric acid, it is not nitrocompound! Organic chemistry 2013/2014

  41. Ammines Nitrogen containing derivatives of hydrocarbons II. • Primary Secondary Tertiary Quaternary ammonium bases They are actually organic derivatives of ammonia, therefore they have mostly basic character. Amino group is strong polar. Ammines belong oftento biologically important substances – amino acids, biogenic ammines (emphatic physiologic effect), alkaloids (toxic and pharmaceutical compounds of vegetative origin), synthetic pharmaceutical compounds. Organic chemistry 2013/2014

  42. Some important amines Aniline – toxic – industrial poisons EthyleneDiamino Tetra Acetic acid EDTA - calcium salt of this acid is often administrated as antidote by heavy metals poisons Chelaton II andIII – important in analytical chemistry Choline – Aminoalcohol Reactions of secondary amines with nitrous acid (nitrites) in the presence of HClNitrosamines Nitroso-amine Nitroso-amines exhibit carcinogenic effects!!! International Agency for Research on Cancer(IARC) Organic chemistry 2013/2014

  43. Biologically important amines Dopamine Noradrenaline Adrenaline … and similar alkaloids and drugs IsoprenalineAmphetamine (Psychoton)EphedrineMescaline Synthetic drugs Alkaloids Similarity in structure and in effects!!! Organic chemistry 2013/2014

  44. Functional derivatives of carboxylic acids X-halogen Nitril Acyl halide Amide Anhydrides Esters Thioesters • 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! Organic chemistry 2013/2014

  45. 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 Functional derivatives of carboxylic acids –derivatives carbonic acid (H2CO3) I 1) Halogen derivatives- phosgene- toxic!!! Dichloride of carbonic acid: Organic chemistry 2013/2014

  46. Functional derivatives of carboxylic acids –derivatives carbonic acid (H2CO3) II 3) Esters carbamic acid = Urethanes they have sedative and sleeping (narcotic) effects, relatively toxic, and therefore they are not used at present (with one exception): 2-methyl-2-propyl-1,3-propanediolcarbamate MEPROBAMATE Organic chemistry 2013/2014

  47. 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 1) Biuret– is formed by heating up of the urea, ammonia isreleased Derivatives of urea I biuret Organic chemistry 2013/2014

  48. Creatinineis formed from creatine as its anhydride Derivatives of urea II 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) Organic chemistry 2013/2014

  49. Ureides are derived from carboxylic acids by substitutions of the hydroxy group by the urea (analogy to amides): Ureides I Acetic acid Urea Ureide of acetic acid (acetyl urea) Many of ureides belong to important remedies, e.g.: Bromisoval (sedative) Ureide of -bromoisovaleric acid Organic chemistry 2013/2014

  50. The cyclic ureides can be formed with dibasic acids. Such compound can be classified as heterocyclic compounds: Ureides II Malonic acidUreaBarbituric acid Many drugs with sedative, hypnotic and in higher doses with narcotic effects are derived from barbituric acid -Barbiturates Organic chemistry 2013/2014

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