Medical Chemistry Lecture PDF 2024

Week 13 Medical Chemistry Lecture 2024 Nitrogen-Containing Organic Compounds. Nitrogen-Containing Heterocycles. GenMed: Krisztina Tar, PhD Dentistry: Edit Mikó, PhD Department of Medical Chemist...

Week 13 Medical Chemistry Lecture 2024 Nitrogen-Containing Organic Compounds. Nitrogen-Containing Heterocycles. GenMed: Krisztina Tar, PhD Dentistry: Edit Mikó, PhD Department of Medical Chemistry UD Faculty of Medicine  Outline  Classification  Nomenclature  Synthesis  Physical properties – H bonding  Chemical properties – basicity  Chemical reactions  N-containing compounds and heterocycles with biological significance The biological significance of heterocyclic compounds (five- and six-membered, condensed) and ! alkaloids are discussed in the seminar, only knowledge of the structure of the basic compound (if not indicated otherwise on the slide) from which the particular biologically active compound is ! derived, and the biological effect in brief is required. The more detailed slides are primarily used to help study Medical Chemistry II and the later Biochemistry. © 2017 Pearson Education, Ltd. Nitrogen containing organic Chemical class Group Structural Formula Amide Carboxamide compounds Chemical class Group Structural Formula Amines Primary amine Imide Imide N 1s22s22p3 Secondary amine Azide Azide Azo Azo compound Tertiary amine Cyanates (Diimide) Cyanate 4° ammonium ion Nitrate Isocyanate Imine Primary ketimine Nitrile Nitrate RCN Nitrile RNC Secondary ketimine Nitrite Isonitrile Nitro Nitrosooxy compound Primary aldimine Nitroso Nitro compound Secondary aldimine AMINES N-CONTAINING aliphatic-, cyclic-, and aromatic HETEROCYCLIC COMPOUNDS Amide Carboxamide saturated and aromatic Aliphatic Saturated Aromatic Amines Primary amine Cyclic Secondary amine NH2 Tertiary amine Aromatic 4° ammonium ion NH2 Imine Primary ketimine Secondary ketimine  Classification of Amines The classification depends on how many groups (R) are bonded to the N. primary amine = one group bonded to the N secondary amine = two groups bonded to the N tertiary amine = three groups bonded to the N © 2017 Pearson Education, Ltd.  Classification of Amines versus Alkyl Halides and Alcohols © 2017 Pearson Education, Ltd.  The Structure of Amines - trigonal pyramidal structure The N in an amine has the same geometry as the N in ammonia. Note: Quaterner ammonium ions have tetrahedral shape. © 2017 Pearson Education, Ltd.  The Structure of Aromatic N-containing Heterocycles Resonance Contributors and the Resonance Hybrid © 2017 Pearson Education, Ltd.  The Structure of Aromatic N-containing Heterocycles – planar structure Hückel’s rule: 4n+2 delocalized electrons, n is the number of planar rings © 2017 Pearson Education, Ltd.  Electron densities: Benzene vs Pyridine and Pyrrole The aromatic ring of pyridine is less electron-dense than benzene because the nitrogen withdraws electrons from the ring. The aromatic ring of pyrrole is more electron-dense than benzene because the nitrogen donates electrons into the ring. © 2017 Pearson Education, Ltd.  Common Names of Amines Substituents are listed in alphabetical order followed by “amine.” They are written as one word. © 2017 Pearson Education, Ltd.  Quaternary Ammonium Salts When there are four groups bonded to the N, the groups are stated in alphabetical order followed by “ammonium” and then the name of the anion. © 2017 Pearson Education, Ltd.  Systematic Names of Amines The suffix “amine” denotes the amine functional group. The “e” at the end of the alkane name is replaced by “amine.” © 2017 Pearson Education, Ltd.  Nomenclature of Amines List substituents in alphabetical order, then add a number or N. © 2017 Pearson Education, Ltd.  Saturated and Aromatic Heterocyclic Compounds azabenzene 1-azacyclopenta pyridine -2,4-diene 1-azaindene 1,3-diazacyclopenta 1-azanaphthalene 1,3-diazabenzene pyrrole indole -2,4-diene quinoline pyrimidine imidazole © 2017 Pearson Education, Ltd.  Synthesis of Amines Alkylation, SN2 Reduction NH3, primary or alkyl halide primary, Catalytic reduction of nitrobenzene results in the secondary amine secondary, or tertiary amine formation of aniline through several intermediates. R1 , R2: H or alkyl group © 2017 Pearson Education, Ltd.  Physical Properties: Boiling Points nonpolar least polar most polar polar H-bond weaker H-bond The greater the attractive forces between molecules, the higher the boiling point. © 2017 Pearson Education, Ltd.  Hydrogen Bonds in Amines Hydrogen bonds are stronger in primary amines than in secondary amines because primary amines have stronger dipole–dipole interactions. Tertiary amines cannot form hydrogen bonds with each other. © 2017 Pearson Education, Ltd.  Physical Properties: Solubility of Amines in Water 1o 2o 3o 1o, 2o, and 3o amines with small alkyl groups are soluble in water due to hydrogen bonding. Note: Salts of quaterner ammonium ions dissociate to ions in water. © 2017 Pearson Education, Ltd.  Amines are Bases Amines are the most common organic bases. A base shares its lone pair with a proton R H R N+ + -O.. N H O H H R R R R + − 𝑅3𝐻𝑁 [𝑂𝐻 ] 𝑝𝐾𝑏 = −𝑙𝑜𝑔𝐾𝑏 𝐾𝑏 = [𝑅3𝑁] R: H or alkyl group © 2017 Pearson Education, Ltd.  Amines are Bases: Alkyl Amines Basicity of alkyl amines Name Structure Kb pKb H Ammonia NH3 1.8x10-5 4.74 Ammonia Primary amine.. O.. H PRIMARY AMINES R H H H H H Methylamine CH3NH2 4.4x10-4 3.36...... O N H O...... O N H O H H H H Ethylamine CH3CH2NH2 6.4x10-4 3.19 H H SECONDARY AMINES.O..O..... H H Dimethylamine (CH3)2NH 5.4x10-4 3.27 H H Diethylamine (CH3 CH2)2NH 9.6x10-4 3.02 Secondary amine Tertiary amine H H TERTIARY AMINES H R R Trimethylamine (CH3)3N 6.4x10-5 4.19...... N.. O N H O H O H R H R R Triethylamine (CH3CH2)3N 5.6x10-4 3.25 secondary amine > primary amine ≥ tertiary amine > ammonia © 2017 Pearson Education, Ltd.  Acid-Base Character: Cyclohexylamine vs Aniline No Delocalized Electrons: The base has greater delocalization energy than the conjugate acid. © 2017 Pearson Education, Ltd. Any delocalization of the electron pair weakens the base.  Amines are Bases: Cyclic vs Aromatic Amines Basicity of cyclic and aromatic amines Name Structure pKb Cyclohexylamine NH2 3.30 Decreasing base strength p-Methylaniline H3 C NH2 8.90 R: electron donating group R N: stronger base NH2 Aniline 9.37 R’: electron withdrawing group R’ N: weaker base p-Nitroaniline O2 N NH2 13.0 The basicity of aromatic amines is affected by the conjugative effect of the aromatic ring. In general, cyclic amines are stronger bases than aromatic amines. © 2017 Pearson Education, Ltd.  Amines are Bases: Heterocyclic Amines Basicity of heterocyclic amines Hybrid state of Name Structure pKb nitrogen Pyrrolidine NH sp3 2.73 pyrrole vs pyrrolidine Decreasing base strength Piperidine NH sp3 2.88 sp3 Cyclohexylamine NH2 pair is outside of 3.30 the ring sp2 pair is not Pyridine N involved in 8.75 forming the p- sextet sp2 NH pair is involved in Pyrrole 14.27 forming the p- sextet The lone pair of N in pyrrole is needed for its aromaticity. © 2017 Pearson Education, Ltd.  Acid-base character: Pyridine vs Imidazole pKb = 7 pKa = 14.9 pKb = 8.75 amphoteric base © 2017 Pearson Education, Ltd.  The Nitrogens are Equivalent in the Protonated Imidazole and in the Imidazole Anion © 2017 Pearson Education, Ltd.  Amines are Bases and Nucleophiles A base shares its lone pair with a proton. A nucleophile shares its lone pair with an atom other than a proton. δ+ δ- © 2017 Pearson Education, Ltd.  Amines are Nucleophiles 1. an SN2 reaction – alkylation of the amine δ+ δ- primary amine secondary amine 2. a nucleophilic acyl substitution reaction – acylation of the amine δ+ © 2017 Pearson Education, Ltd.  Amines are Nucleophiles 3. nucleophilic addition + elimination reactions , a Schiff base © 2017 Pearson Education, Ltd.  The Reaction of Aldehydes and Ketones with Primary Amines The product of the reaction is an imine. Imine formation replaces C═O with C═NR. © 2017 Pearson Education, Ltd.  Reactions of Amines with Nitrous Acid Primary amines O.. AN R NH 2 + N OH R N+ N OH- R OH + N2 -H2O Secondary amines O Can you tell the difference?.. AN R NH + N OH R N N O R' -H2O R' N-nitrosoamine (Nitrosamines and cancer) Tertiary amines no AN reaction, form salt with the acid © 2017 Pearson Education, Ltd.  Reactions of Amines with Nitrous Acid Arenediazonium Salts are Intermediates in the Synthesis of Substituted Aromatic Compounds © 2017 Pearson Education, Ltd.  Arenediazonium Salts are Intermediates in the Synthesis of Aromatic Compounds Production of azo compounds Methyl orange, an acid-base indicator azo linkage Benzenediazonium Phenol p-Hydroxyazobenzene chloride an orange dye Benzenediazonium Aniline p-Aminoazobenzene quinoid structure azo structure chloride a yellow dye Benzenediazonium ions are electrophiles in electrophilic aromatic substitution reactions. azo linkage red in acid yellow in base © 2017 Pearson Education, Ltd.  Aromatic Substitution Reactions of Pyridine and Pyrrole Pyrrole and pyridine undergo electrophilic aromatic substitution reactions, preferred sites C2 and C3, respectively: Pyridine undergoes nucleophilic aromatic substitution Pyridine can react as a nucleophile reactions, preferred sites C2 and C4: in SN2 reaction: Not mandatory © 2017 Pearson Education, Ltd.  Biologically Important Nitrogen Containing Compounds 1. Lipid components 2. Biogenic amines (mono- and polyamines) 3. Pyrimidine and purine bases 4. Sulfa drugs 5. Heterocycles (five- and six-membered, polycyclic compounds) 6. Alkaloids The biological significance of heterocyclic compounds (five- and six-membered, condensed) and alkaloids are discussed in the seminar, only knowledge of the structure of the basic compound from which the particular biologically active compound is derived, and the biological effect in brief is required (if not indicated otherwise on the slide). The more detailed slides are primarily used to help study Medical Chemistry II and the later Biochemistry. © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 1. Lipid components CH3 H 3C H2 Constituents of: HO C HO N+ C NH 2 CH 3 H2 H2 C CH2 glycerophospholipids ethanolamine choline OH H2 H H2 H2 H2 H2 H2 H2 sphingolipids C CH C C C C C C C H HO C C C C C C C C CH3 H H2 H2 H2 H2 H2 H2 NH2 sphingosine © 2017 Pearson Education, Ltd. Sphingosine structure is required in the second semester.  Important Nitrogen Containing Compounds 2. Biogenic amines (mono- and polyamines) Neurotransmitters Acetyl choline (Ach): a neurotransmitter H3C O H3C CH3 CH3 CH3 N+ OH + H3C C N+ O C + CoA-SH H3 C H3C H2C CH2 S CoA H2C CH2 O Choline Acetyl CoA Acetyl choline Reaction 9.16 Formation of acetyl choline from choline by an acylation reaction © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 2. Biogenic amines (mono- and polyamines) Neurotransmitters H Catecholamine neurotransmitters H H © 2017 Pearson Education, Ltd.  Antihistamines © 2017 Pearson Education, Ltd. Structures on this slide are not required.  Drugs for Ulcers Histamine production causes hypersecretion of H+, but antihistamines have no effect on acid production. another histamine receptor weak inhibition of HCl secretion © 2017 Pearson Education, Ltd. Structures on this slide are not required.  Important Nitrogen Containing Compounds 2. Biogenic amines (mono- and polyamines) Polyamines foul-smelling toxic substances NH 2 produced by decomposition of amino H 2N H 2N NH2 acids (arginine and lysine) in dead putrescine cadaverine organisms NH 2 growth factors for some H 2N N H microorganism and serve to stabilize spermidine membrane structures in bacteria as H well as structures of ribosomes, N NH2 some viruses, and the DNA of many H2 N N H organisms spermine © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 3. Pyrimidine and purine bases © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds Nucleotides, nucleic acids phosphate-pentose-base Watson and Crick © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 4. Sulfa drugs - Chemotherapy Ehrlich coined the term: chemotherapy. Modern chemotherapy began with his work early in the 20th century and particularly with his discovery of Salvarsan in 1909. Paul Ehrlich and Ilya Mechnikov The Nobel Prize in Physiology or Medicine 1908 “When the microbe causing syphilis is found, I must be prepared.” Prize motivation: "in recognition of their work on immunity." Chemotherapy: the use of chemical agents that bind and „transfer of blood serum with antibodies to treat and counteract diphtheria” specifically kill infectious organisms without destroying the host. © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 4. Sulfa drugs - Chemotherapy Gerhard Domagk Prontosil is a red dye, a „prodrug”. In living cells, it is converted. The Nobel Prize in Physiology or Medicine 1939 "for the discovery of the antibacterial effects of prontosil" © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 4. Sulfa drugs - Chemotherapy p-aminobenzoic acid Folic acid Not mandatory building block of folic acid inhibits folic acid synthesis © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 5. Heterocycles Heterocyclic Amino Acids © 2017 Pearson Education, Ltd. Chemical structures on this slide are not mandatory in the first semester.  Important Nitrogen Containing Compounds 5. Heterocycles –pyrrole Porphyrins 2+ 2+ chlorophyll © 2017 Pearson Education, Ltd. Chemical structures of porhin ring is required in the first semester.  Important Nitrogen Containing Compounds 5. Heterocycles –pyrrole Breakdown of heme Heme oxygenase O2 CO+Fe3+ Biliverdin NADPH NADP+ reductase M: methyl group P: propionate V: vinyl group © 2017 Pearson Education, Ltd. Chemical structures on this slide are not mandatory in the first semester.  Cofactors Many enzymes need a cofactor in order to catalyze a reaction. A cofactor can be a metal ion or an organic molecule. A cofactor that is an organic molecule is called a coenzyme. Coenzymes are derived from vitamins. © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 5. Heterocycles – pyridine Nicotinamide adenine dinucleotide, NAD+ vitamin B3 Oxidized substrate oxidized reduced NAD+ catalyzes oxidation reactions Only nicotinamide, niacin and NAD+/NADH conversion with © 2017 Pearson Education, Ltd. simplified formulas are mandatory in the first semester.  NAD+ is the Most Common Oxidizing Agent NADPH is the Most Common Reducing Agent catabolism: complex molecule simple molecules + energy Metabolism anabolism: simple molecules + energy complex molecule © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 5. Heterocycles – pyridine Vitamin B6 and pyridoxal phosphate Pyridoxal phosphate is attached to its enzyme by forming an imine with a lysine side chain. © 2017 Pearson Education, Ltd. Chemical structures on this slide are not mandatory in the first semester.  Important Nitrogen Containing Compounds 5. Heterocycles – pyridine Pyridoxal phosphate in transamination Pyridoxal phosphate is Enz attached to its enzyme by forming an imine with a lysine side chain. © 2017 Pearson Education, Ltd. Not required in the first semester.  Important Nitrogen Containing Compounds 5. Heterocycles –pyrimidine Barbituric acid and Barbiturates Tautomeric forms of barbituric acid O O OH HN HN N O N O O N OH HO N OH H H Johann Friedrich Wilhelm Adolf von Baeyer dilactam-oxo dilactam-enol dilactim-enol O O O The Nobel Prize in Chemistry 1905 was C2 H 5 awarded to Johann Friedrich Wilhelm Adolf von Baeyer "in recognition of his NH NH NH C 2 H5 services in the advancement of organic C2 H5 chemistry and the chemical industry, O N O O N O O N S through his work on organic dyes and H H H hydroaromatic compounds." Veronal Phenobarbital 2-thiobarbituric acid 5,5-diethylbarbituric acid 5-ethyl-5-phenylbarbituric acid © 2017 Pearson Education, Ltd. Chemical structure of barbituric acid is required.  Important Nitrogen Containing Compounds 5. Heterocycles – pyrimidine TPP is the coenzyme required by enzymes that catalyze the transfer of an acyl group. Vitamin B1 Thiamine deficiency: beriberi A Reaction That Requires TPP Christiaan Eijkman, 1896 The acyl group is transferred to CoA-SH. © 2017 Pearson Education, Ltd. Chemical structures on this slide are not mandatory in the first semester.  Important Nitrogen Containing Compounds 5. Heterocycles Fused heterocycles quinoline isoquinoline indole pteridine alloxazin © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 5. Heterocycles Cl NH NH N N I OH OH OH CH 3 8-hydroxyquinoline 5-chloro-7-iodo-8-hydroxy- 3-hydroxyindole 3-methylindole quinoline (Enteroseptol) By-products of tryptophan degradation Used in medicine against intestinal infection. excreted into urine and feces. © 2017 Pearson Education, Ltd.  Important Nitrogen Containing Compounds 5. Heterocycles-derivative of pteridine Folic acid, vitamin B9 One-carbon transfer Deficiency of folic acid causes a type of anemia in which red blood cells do not mature properly. Only the structure of pteridine and the names of the © 2017 Pearson Education, Ltd. three main structural parts of folic acid are mandatory in the first semester.  OH Important Nitrogen Containing Compounds HO CH H C CH2 OH 5. Heterocycles Riboflavin O Vitamin B2 H3 C N NH O H3 C N N O H3C N CH2 N NH HO NH2 CH O O H2 N H3C N N O CH H O C P P N HO C O O O N CH2 O HO O CH OH Deficiency causes OH HO OH inflammation CH H CH2 HO C Flavin adenine dinucleotide (FAD) of the skin a nucleotide co-enzyme OH Riboflavin Figure 9.17 Structure of riboflavin and the oxidized form of a flavin adenine dinucleotide (FAD) O H3 C N NH H3 C N N O CH2 N HO NH2 © 2017 Pearson Education, Ltd. CH O O H2 N Only the structure of alloxazin is mandatory in the first semester.  Important Nitrogen Containing Compounds 6. Alkaloids Alkaloids are N-containing (mostly heterocyclic) compounds in plants with strong biological actions on human. Coniin is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist. Coniine The first alkaloid the chemical structure of which was established (1881), and that was chemically synthesized (1886). Hemlock (Conium maculatum) Coniine's most famous victim is Socrates who was sentenced to death by poison chalice © 2017 Pearson Education, Ltd. Structure is not mandatory. containing poison hemlock in 399 BC.  Important Nitrogen Containing Compounds 6. Alkaloids Alkaloids from the opium poppy Codeine is Papaverine, a smooth used to treat muscle relaxant dry cough Morphine is used for the treatment of severe pain and dyspnoea. It primarily Codeine is approximately one- Morphine affects the CNS and the GI system. twelfth less potent than Tolerance development as well as strong morphine as an analgesic and physical and psychological dependence has a correspondingly lower occur in conjunction with the chronic oral dependence-liability than intake of morphine. morphine. © 2017 Pearson Education, Ltd. Structures are not mandatory.  Important Nitrogen Containing Compounds 6. Alkaloids Quinine, a Chinchona alkaloid to treat malaria © 2017 Pearson Education, Ltd. Structures are not mandatory  Important Nitrogen Containing Compounds 6. Alkaloids Nightshade Atropa Erythroxylon Nicotiana tabacum belladonna cocaine nicotine atropine A nitrogen containing alkaloid. Nature synthesizes its R isomer. Atropin blocks acetylcholine receptors and inhibits the parasympathetic nervous system. 64 © 2017 Pearson Education, Ltd. Image by NIDA Structures are not mandatory  Important Nitrogen Containing Compounds 6. Alkaloids Purine derivatives O CH3 O O CH3 H3C H H3C N N N N1 7 N1 HN 1 7 3 3 3 O N N O N N O N N CH3 CH3 CH3 Caffeine Theophylline Theobromine Figure 9.19 Structure of caffeine, theophylline, and theobromine © 2017 Pearson Education, Ltd. Structures are not mandatory