Medical Chemistry Seminar 2024 PDF

Week 13 Medical Chemistry Seminar 2024 Nitrogen Containing Organic Compounds Nitrogen Containing Heterocycles Department of Medical Chemistry UD Faculty of Medicine...

Week 13 Medical Chemistry Seminar 2024 Nitrogen Containing Organic Compounds Nitrogen Containing Heterocycles Department of Medical Chemistry UD Faculty of Medicine 1  What are the main classes of N-containing organic compounds? 2 © 2017 Pearson Education, Ltd.  Define amines and give their classification. Amines are organic derivatives of ammonia. 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 3 © 2017 Pearson Education, Ltd.  Explain the difference between classification of amines and alkyl halides (1) and alcohols (2). 4 © 2017 Pearson Education, Ltd.  Give common names and classify the following amines. Substituents are listed in alphabetical order followed by “amine.” They are written as one word. 1o 2o 2o 3o 3o 3o 5 © 2017 Pearson Education, Ltd.  Give systematic names of these amines. The suffix “amine” denotes the amine functional group. The “e” at the end of the alkane name is replaced by “amine.” A substituent on the chain is indicated by a number. A substituent on the nitrogen is indicated by an “N.” 6 © 2017 Pearson Education, Ltd.  Give systematic names of these amines. List substituents in alphabetical order, then add a number or N. 7 © 2017 Pearson Education, Ltd.  Define quaternary ammonium salts and explain their naming. Quaternary ammmonium salts are substituted ammonium ion derivatives. 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. 8 © 2017 Pearson Education, Ltd.  Write general equation for the synthesis of amines from ammonia and alkyl halide. Give the type and mechanism of the reaction. NH3, primary or alkyl halide primary, secondary, secondary amine or tertiary amine R1 , R2: H or alkyl group SN2 9 © 2017 Pearson Education, Ltd.  Describe the structure of aliphatic amines. Nitrogen is sp3 hybridized. The N in an amine has the same trigonal pyramidal geometry as the N in ammonia. 10 © 2017 Pearson Education, Ltd. Amines with small carbon number are polar.  Describe the structures of aromatic N-containing heterocycles. Hückel’s rule: 4n+2 delocalized electrons, n is the number of planar rings 11 © 2017 Pearson Education, Ltd.  Compare boiling boints of propane, dimethylether, ethanol and ethylamine. London forces dipole-dipole H-bonding H-bonding propane < dimethylether < ethylamine < ethanol 12 © 2017 Pearson Education, Ltd.  Compare H-bonding in primary, secondary, and tertiary 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. 13 © 2017 Pearson Education, Ltd.  Are amines soluble in water? 1o, 2o, and 3o amines with small alkyl groups are soluble in water due to hydrogen bonding 14 © 2017 Pearson Education, Ltd.  Draw structures to illustrate H-bond formation between methylamine (1), dimethylamine (2), trimethylamine (3) and water. 15 © 2017 Pearson Education, Ltd.  Characterize acid-base properties of amines. Write an equation for the reaction of an amine with water and give the appropriate equilibrium constant expression. Amines are the most common organic bases. A base shares its lone pair of electrons with a proton. R H R N+ + -O.. N H O H H R R R R R: H or alkyl group + − 𝑅3𝐻𝑁 [𝑂𝐻 ] 𝐾𝑏 = [𝑅3𝑁] 𝑝𝐾𝑏 = −𝑙𝑜𝑔𝐾𝑏 16 © 2017 Pearson Education, Ltd.  Compare basicity of ammonia, ethylmethylamine and trimethylamine. + − 𝑅3𝐻𝑁 [𝑂𝐻 ] 𝐾𝑏 = Name Structure Kb pKb [𝑅3𝑁] Ammonia NH3 1.8x10-5 4.74 𝑝𝐾𝑏 = −𝑙𝑜𝑔𝐾𝑏 PRIMARY AMINES Methylamine CH3NH2 4.4x10-4 3.36 Ethylamine CH3CH2NH2 6.4x10-4 3.19 SECONDARY AMINES Dimethylamine (CH3)2NH 5.4x10-4 3.27 Diethylamine (CH3 CH2)2NH 9.6x10-4 3.02 TERTIARY AMINES Trimethylamine (CH3)3N 6.4x10-5 4.19 Triethylamine (CH3CH2)3N 5.6x10-4 3.25 secondary amine > primary amine ≥ tertiary amine > ammonia ethylmethylamine > trimethylamine > ammonia 17 © 2017 Pearson Education, Ltd.  Compare basicity of cyclohexylamine, aniline, p-methylaniline and p-nitroaniline. Name Structure pKb Primary amine Cyclohexylamine NH2 3.30 Decreasing base strength Aromatic amines p-Methylaniline H3 C NH2 8.90 R N: stronger base NH2 Aniline 9.37 O2 N NH2 R N: weaker base p-Nitroaniline 13.0 cyclohexylamine > methylaniline > aniline> p-nitroaniline 18 © 2017 Pearson Education, Ltd.  Draw the structure and compare basicity of the following heterocyclic amines. Hybrid state of Name Structure pKb nitrogen Saturated ring Pyrrolidine NH sp3 2.73 Decreasing base strength Piperidine NH sp3 2.88 sp3 Cyclohexylamine NH2 pair is outside of 3.30 the ring sp2 Heteroaromatic ring 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 19 © 2017 Pearson Education, Ltd.  Compare acid-base properties of pyridine and imidazole (1) and pyrimidine (2)... N NH+ + H+ + +H + 1N NH HN NH pKb = 7 pKb = 8.75 The lone pair of one N in imidazole is needed, the lone pair of the other N is not needed for its The lone pair (sp2 electrons) of N in aromaticity. Therefore, electron density around pyridine is not needed for its aromaticity. N-1 is slightly increased. Protonation of imidazole is also more favorable than protonation of pyridine because N NH+ the charge is delocalized to the second + H+ nitrogen atom. N N pKb = 12.77 The lone pairs (sp2 electrons) of Ns in pyrimidine are not needed for its aromaticity. Protonation of pyrimidine seems more favorable than protonation of pyridine because the charge is delocalized to the second nitrogen atom, however, the additional pyridine-like N is electron withdrawing and strongly 20 © 2017 Pearson Education, Ltd. decreases basicity.  Give the missing structures and name(s) in the following chemical reactions of amines. What is the mechanism of the reaction? AN+elimination: condensation H2 H3C H2 CH3 C + C CH3 H3C C N C H 3C NH 2 -H2O CH3 O ethylamine dimethylketone Schiff's base 21 © 2017 Pearson Education, Ltd.  Give the missing structures and name(s) in the following chemical reactions of amines. What is the mechanism of the reaction? AN+elimination: condensation H3C O H2 H2 H C + C Cl -HCl H3C C N C CH3 H 3C NH 2 O N-ethylacetamide ethylamine acetyl chloride primary amine N-alkylamide What is the mechanism of the reaction? AN+elimination: condensation H2 O C CH 3 H3C + H2 H 3C N C Cl H3C C N C CH 3 H -HCl O CH 3 ethylmethylamine acetyl chloride N-ethyl-N-methylacetamide secondary amine N,N-dialkylamide 22 © 2017 Pearson Education, Ltd.  Give chemical equation for nitrous acid reacting with ethylmethylpropylamine (1), propylamine (2), dimethylamine (3), and aniline (4). (1) Tertiary amine: NO REACTION with nitrous acid (2) Primary amine: alkyl diazonium ion → alcohol + nitrogen gas are produced O.. AN C3H 5 NH 2 + N OH C3H 5 N+ N OH- C3H 5 OH + N2 -H2O (3) Secondary amine: yellow product, nitrosoamine O.. AN H 3C NH + N OH H 3C N N O -H2O H3 C H3 C (4) Primary aromatic amine: arenediazonium salt is produced O AN.. NH 2 + N OH + HCl N+ N Cl- -2H2O 23 © 2017 Pearson Education, Ltd.  Practice Write the chemical equation for the following reactions: 1.ethylamine + methylchloride CH3 CH2 NH2 + Cl CH3 CH3 CH2 N CH3 + HCl H 2. Aniline + HCl + NH2 NH3 Cl- + HCl 3. Methyl fluoride + propylamine CH3F + CH3-CH2-CH2-NH2 ➔ CH3-CH2-CH2-NH-CH3 + HF 4. Butylamine + acetaldehyde CH3-CH2-CH2-CH2-NH2 + CH3-CHO ➔ CH3-CH2-CH2-CH2-N=CH-CH3 + H2O © 2017 Pearson Education, Ltd.  Practice Write the chemical equation for the following reactions: 1. o- toluidine + nitrous acid + NH2 HCl N N Cl- + 2 H O + HNO 2 2 CH3 CH3 2. dimethylamine + nitrous acid CH3 N CH3 + HNO 2 CH3 N CH3 + H2O H N O © 2017 Pearson Education, Ltd.  Compare the properties of A. ethanol and B. ethylamine according to the following questions. Write their structural formulas! A. CH3 CH2 O H B. CH3 CH2 NH2 Classify them according to their structure! A. 1o B. 1o Which one has the higher boiling point? A. d-.. O Hd+ N d- d+ O d+ Hd+ R d+H d+ R R H R H H d+ d+ N.... d- N d- d+ O d+ d+H d+ R R H H.. - Nd O d+H Hd R + H R d+ d+ © 2017 Pearson Education, Ltd.  Compare the properties of A. ethanol and B. ethylamine according to the following questions. Which one has a penetrating odor? B. (smells like fish) Characterize the acidity-basicity of the compounds! A. Acidic (very weak acid) CH3-CH2-OH + H2O → CH3-CH2-O- + H3O+ B. basic CH3-CH2-NH2 + H2O → CH3-CH2-NH3+ + OH- © 2017 Pearson Education, Ltd.  Compare the properties of A. ethanol and B. ethylamine according to the following questions. Which one reacts with acetic acid? A. & B. What are the products of the reactions? CH3 CH2 O H + H2O + CH3 CH2 O C CH3 CH3 - COOH O A. ethylacetate CH3 CH2 NH2 + [CH3 CH2 NH3 ]+ -OOC CH3 CH3 - COOH B. ethylammonium acetate © 2017 Pearson Education, Ltd.  Compare the properties of A. ethanol and B. ethylamine according to the following questions. Which one reacts with methylcloride? A. & B. What are the products of the reactions? CH3 CH2 O H + CH3 CH2 O CH3 + HCl CH3 - Cl A. methylethyl ether CH3 CH2 NH2 + CH3 CH2 NH CH3 + HCl CH3 - Cl B. methylethylamine CONCLUSION: FUNCTIONAL GROUPS DETERMINE THE PROPERTIES OF A COMPOUND! © 2017 Pearson Education, Ltd.  Arenediazonium Salts are Intermediates in the Synthesis of Aromatic compounds Production of azo compounds electrophilic substitution 30 © 2017 Pearson Education, Ltd.  Give the structure/name and function of the following nitrogen containing compounds. OH H2 H H2 H2 H2 H2 H2 H2 sphingosine C CH C C C C C C C HO H C C C C C C C C CH3 lipid component H H2 H2 H2 H2 H2 H2 NH2 H spermine N NH2 biogenic polyamine, binds to nucleic acids H2N N H p-aminobenzoic acid sulfanilamide building block of folic acid inhibits folic acid synthesis Sulfa drug 31 © 2017 Pearson Education, Ltd.  Give the structure/name and function of the following nitrogen containing compounds. N O nicotinamide Niacin-Vitamin B3 building block of NAD+ Essential for the nervous system, NH2 digestive system, and skin. porphyrin ring structural component of heme and chlorophyll 32 © 2017 Pearson Education, Ltd.  Draw structures of pyrimidine and purine bases present in nucleic acids. 33 © 2017 Pearson Education, Ltd.  Draw structures to illustrate H-bonding between pyrimidine and purine bases. 34 © 2017 Pearson Education, Ltd.  Select the molecule(s) which contain indole (1), imidazole (2), purine (3) or isoalloxazine ring (4). (4) (3) O O CH3 O CH3 H 3C CH3 H3C H H 3C H3C N N N N1 7 N1 HN 1 7 C O N+ 3 3 CH 3 3 O N N O N N O N N O H 2C CH2 CH3 CH3 CH3 Caffeine Theophylline Theobromine caffeine, an alkaloid acetyl choline, neurotransmitter Figure 9.19 Structure of caffeine, theophylline, and theobromine riboflavin, vitamin B2 NH (2) H2 (1) (2) C H2 N C N H2 histamine, neurotransmitter proline tryptophan histidine amino acids 35 © 2017 Pearson Education, Ltd.  MCQ1. Choose the correct statement about amines. A. There is a trigonal pyramidal geometry about the nitrogen in amines. B. All amines are weaker bases than ammonia. C. Tertiary amines have high boiling points because they can form H- bonding to each other. D. Amines have a pleasant smell. E. Secondary amines react with nitrous acid and produce nitrogen gas. MCQ2. Choose the strongest base. A. ammonia B. triethylamine C. methylamine D. ethylmethylamine E. aniline 36 © 2017 Pearson Education, Ltd.  MCQ3. When a primary amine reacts with an acyl chloride, the product is a(n) …. A. Schiff’s base B. imine C. N,N-alkylamide D. arenediazonium salt E. N-alkylamide MCQ4. Which method can be used for making a tertiary amine? A. reduction of nitrobenzene B. hydrolysis of acetonitrile C. reaction of aniline with methyl chloride D. reaction of ethyl methylamine with acetic anhydride E. reaction of diethylamine with methyl chloride 37 © 2017 Pearson Education, Ltd.  MCQ5. Select the starting material for the synthesis of aryldiazonium salt. A. N-methylaniline B. aniline C. 2-aminopropane D. tetramethylammonium chloride E. ethanamide MCQ6. In general, electron-donating groups …………, whereas electron attracting groups…………the basicity of the amino nitrogen of amines. A. increase, decrease B. decrease, increase C. both decrease D. both increase E. they have no effect 38 © 2017 Pearson Education, Ltd.  MCQ7. Which of the following inhibits the folic acid synthesis of bacteria? A. sulfanilamide B. penicillin C. histamine D. thiamine E. Salvarsan MCQ8. Epinephrine (adrenaline), norepinephrin and dopamine are… A. components of the cell membrane B. sulfa drugs C. catecholamines originated from tyrosine D. coenzymes 39 E. toxic alkaloids © 2017 Pearson Education, Ltd.  MCQ9. Which Vitamin B complex contains pteridine? A. Thiamine (vitamin B1) B. Riboflavin ( vitamin B2) C. Niacin (vitamin B3) D. Pyridoxine (vitaminB6) E. Folic acid (vitamin B9) Q10. Matching pairs Nicotine local anesthetic(syntetic) Cocaine CNS stimulant Novocaine stimulant, insecticid Morphine Strichnine local anesthetic analgestic 40 © 2017 Pearson Education, Ltd.