Heterocyclic Compounds - Pharmaceutical Organic Chemistry III - PDF

HETEROCYCLIC CHEMISTRY N Heterocyclic S Compounds O Pharmaceutical Organic Chemistry III (PR 303) By Dr. Ola Abou-Ghadir Course Contents: Lecture...

HETEROCYCLIC CHEMISTRY N Heterocyclic S Compounds O Pharmaceutical Organic Chemistry III (PR 303) By Dr. Ola Abou-Ghadir Course Contents: Lecture Topic Lecturer (hr) Infrared Spectroscopy (IR) 4 Prof. Dr. Bahaa Mass spectrometry (MS) 2 Nuclear magnetic resonance 6 Prof. Dr. Samia (NMR) Chemistry of six-membered heterocycles (pyridine, quinoline, and isoquinoline chemistry) + Heterocyclic 6 Dr. Anber compounds with 2 heteroatoms (diazines) Nomenclature of heterocycles 3 Chemistry of five-membered Dr. Ola Abou- heterocycles (furan, thiophene, pyrrole, Ghadir 3 and indole) + Heterocyclic compounds with 2 heteroatoms (azoles) Total hours 24 CLASSIFICATION OF CYCLIC COMPOUNDS  Cyclic compounds Heterocyclic Homocyclic (Carbocyclic) *Cyclic organic compounds containing Compounds contain ring made at least one element other than up only of carbon atoms. carbon, within the ring system. (most commonly N, O, S) HO O N O H benzene cyclohexanol pyrrole 1,4-dioxane S cyclopentadiene 4 benzothiophene  WHY WE STUDY HETEROCYCLIC CHEMISTRY?  Importance of Heterocyclic Compounds 1. Used as solvents 2. Found as natural product HO OH OH HO N HO O O O OH pyridine HO HO sucrose (table sugar) 3. Found in Biomolecules: 4. Used as Drug NH2 O N 220px-Quinine-2D-skeletal Quinoline N as Anti malaria N N N HN Lactam as antibiotics http://upload.wikimedia.org/wikipedia/commons/thumb/9/99/Penicillin_core.svg/250px-Penicillin_core.svg.png N N N H N H2N N H N H purine Nitrogen adenine guanine bases in DNA & RNA Quinine Penicillin 6  Classification Aliphatic Aromatic heterocycles heterocycles N N O H H O ethylene oxide Tetrahydro-furan Pyrrolidine Piperidine Oxirane N S oxolane ethers amines Pyridine Thiophene Azine Thiole N N H H N ydro-furan Pyrrolidine H Piperidine 1H-Indole ne benzo(b)pyrrole amines  HETEROCYCLIC CHEMISTRY N Nomenclature of S Heterocyclic compounds O  Nomenclature of heterocyclic compounds Three systems for naming heterocylic compounds: 1) The common nomenclature: no structural information can be gained from name, but it still widely used. 2) The replacement method 3) The Hantzsch-Widman (IUPAC or Systematic) method which is designed so that one may deduce from it the structure of the compound. azine pyridine azabenzene N 12  I- Common Nomenclature ❖ Each compound is given the corresponding trivial name. This usually originates from the compounds occurrence, its first preparation or its special properties. ❖Has no structural information but it still widely used. 13  Most common Heterocyclic rings N - Heterocyclic rings Five-membered rings N N N Unsaturated N HN N N N N HN N N N N N H H H H pyrrole pyrazole imidazole 1,2,3-triazole 1,2,4-triazole tetrazole H O N NH Saturated N N H H pyrrolidine pyrazolidine lactam N - Heterocyclic rings Six-membered rings N N N N Unsaturated N N N pyridine pyrimidine pyridazine pyrazine H N Saturated N N H H piperidine piperazine O H3C O NH2 NH DNA bases N NH N H N N O H H O O uracil thymidine cytosine N - Heterocyclic rings Fused rings Pyrimidine –imidazole NH2 O N N (DNA bases) N N N HN N N N H N H2N N H N H purine adenine guanine Benzene fused N N H N 1H-indole quinoline isoquinoline  O- Heterocyclic rings O O O Five- membered O furan tetrahydrofuran lactone O O Six- membered O O O O O+ O 2-pyrone 4-pyrone 4H-pyran 1,4-dioxane pyrilium cation O Benzene fused O O O O benzofuran coumarin chromone  S - Heterocyclic rings S Unsaturated S S thiophene benzothiophene thiepine Heterocyclic rings with two different heteroatoms O N N N N and O N N N N N O O N O O O H oxazole isoxazole 1,2,3-oxadiazole 1,3,4-oxadiazole 1,2,4-oxadiazole morpholine S S S S S S N and S N N N N N N N N N N N 1,3-thiazole 1,2-thiazole 1,2,3-thiadiazole 1,3,4-thiadiazole 1,2,4-thiadiazole 1,2,3,4-thiatria  II- Replacement nomenclature Heterocycle’s name is composed of the corresponding carbocycle’s name and an elemental prefix for the heteroatom introduced if more than one heteroatom is present they should be listed according to the priority order shown in (table 1). Table 1 Atom Prefix O oxa Priority decreases S thia Se selena N aza P phospha 19  Oxygen Sulfur Selenium Nitrogen Phosphorus Element O S Se N P Valence 2 2 2 3 3 Prefix Oxa Thia Selena Aza Phospha priority Order of hetero atom is as high a group in periodic table and as low an atomic No. in that group Priority order decrease from left to right 20 II- Replacement nomenclature 21 II- Replacement nomenclature 22  III-HANTZSCH-WIDMAN NOMENCLATUREsystem III- the Hantzsch-Widman (IUPAC) (IUPAC) German chemists Arthur Hantzsch and Oskar Widman, proposed similar systematic naming of heterocyclic compounds in 1887 and 1888 respectively. Three to ten-membered rings named by combining the appropriate prefix (or prefixes) that denotes the type, No. and position of the heteroatom present in the ring Stem that determines the ring size and suffixes that determines the degree of unsaturation In addition, the suffixes distinguish between nitrogen- containing heterocycles and heterocycles that do not contain nitrogen IUPAC name = locants+ prefix + Stem + suffixes 23  Common name : thiophene S Systematic name : Thia + ole … Thiole prefix [stem+suffix] Common name : pyrrole NH Systematic name : Aza + ole … Azole prefix [stem+suffix] Common name : pyrimidine N Systematic name : [1,3]-diazine two aza at 1, 3 positions + ine N 25  Oxygen Sulfur Selenium Nitrogen Phosphorus Element O S Se N P Valence 2 2 2 3 3 Prefix Oxa Thia Selena Aza Phospha priority Priority order decrease from left to right 26  Hantzsch-Widman rules for fully saturated and fully unsaturated heterocycles Identify the hetroatom present in the ring and choose from (table 1) the corresponding prefix (Oxa, Thia, Aza, …….) ❖ The position of a single heteroatom control the numbering in a monocyclic compound. ❖ The heteroatom is always assigned position 1 and if substituents present are then counted around the ring in a manner so as to take the lowest possible numbers. 4 For example: N1 2 3 2-Methyl ……. CH3  Hantzsch-Widman rules ❖ A multiplicative prefix (di, tri, ect.) and locants are used when two or more similar heteroatoms contained in the ring (two nitrogen indicated by diaza) ❖ N.B.summation must be minimal. ❖ and the numbering preferably commenced at a saturated rather than an unsaturated atom, as depicted in the following example: 1,3-diaza…. 4 N3 5 2 1 N H 29  Hantzsch-Widman rules ❖The numbering is started from the heteroatom of the highest priority in such a way so as to give the smallest possible numbers to the other heteroatoms in the ring (the substituents are irrelevant). ❖For example the prefix corresponding to the following compound is 4-Methyl-1,3-Thiaza…. H3C Br 4 O N3 4 3 S 5 2 2 1 5 N S N 1 H2N O 5-Amino-4-bromo-1,2-oxaza……. [1,3,7]-oxathiaza….. 7, ep (from hepta); 8, oc (octa); 9, on (nona); 10, ec (deca). 32 33  Hantzsch-Widman rules ❖ Choose the appropriate suffix from (table 3) depending on: whether or not nitrogen atom is present in the ring the size of the ring and presence or absence of any double bonds ❖ Combine the prefix(s) and suffix together and drop the first vowel if two vowels came together.  Table 3. Stem Suffixes for Hantzsch-Widman names Stem +suffix ring size stem N : present N : absent Unsat. Sat. Unsat. Sat. 3 ir irine iridine irene irane 4 et ete etidine ete etane 5 ol ole olidine ole olane 6 in ine * in** ane*** 7 ep epine * epine epane 8 oc ocine * ocine ocane 9 on onine * onine onane 10 ec ecine * ecine ecane * use …….hydro- + name of unsaturated ** no suffix i.e. prefix + stem ** * no stem i.e. prefix +suffix The complete saturation is indicated by prefixing “perhydro” added before the total name of the unsaturated state. 35  Hantzsch-Widman rules Examples H N This ring contains (N) Prefix is aza The ring is 3-membered and fully saturated suffix is iridine By combining the prefix and suffix, two vowels ended up together (azairidine), therefore the vowel on the end of the first part should be dropped. This gives the correct name: Aziridine  Hantzsch-Widman rules HN O This ring contains (O ,N) And (o) has higher priority than (N) and by starting numbering the ring at (O) Prefix is 1,2-Oxaaza, but the first vowel must be omitted to give 1,2-Oxaza The ring is 4-membered and fully saturated suffix is etidine By combining the prefix and suffix, two vowels ended up together (1,2-oaxazaetidine), therefore the vowel on the end of the first part should be dropped. This gives the correct name: 1,2-oxazetidine 37  Hantzsch-Widman rules 4 3 5 N N2 O 1 ▪This ring contains (O) prfix1 (oxa), ▪ and two (N) prfix2 diaza Locants, since (O) is higher priority than (N) so it is in position 1 by default and the two (N) are therefore at positions 2 and 5, this gives the combined prefixes as 1,2,5-oxadiaza (note that the a in oxa is not dropped) It is 5-membered,fully unsaturated ring with (N) the suffix is ole ❖ By combining the prefixes and the suffix (1,2,5- oxadiazaole) and dropping the appropriate vowels we get the correct name as 38 1,2,5-Oxadiazole HANTZSCH-WIDMAN RULES N H ❖ The ring is 6-memberd, fully saturated with N Prefix perhydro followed by the name of fully unsaturated 6-memberd ring with nitrogen azine ❖ Thus the full name is perhydroazine The common name is piperidine 39  O O O N N S IUPAC name: 1,3-oxazole IUPAC name: 1,2-oxazole 1,2-oxathiolane Common name: oxazole Common name: isoxazole S CN H2N N N S H3C O N NH2 O 5- Amino-1,2,4-Oxathiazine 6-Methyl-1,4,3-oxathiazine 2-Amino-3-cyano azine 2-Amino-3-cyanopyridine 5 S 6 2 5 N N N N N N S 1 S N 2 N 1 [1,2,4]Triazine Pyrimidine H 1,3-diazine 6H-1,2,5-thiadiazine 2H,6H-1,5,2-dithiazine 2H, 6H-1,5,2-dithiazine 6H-1,2,5-thiadiazine 43  Hantzsch-Widman rules for partially saturated heterocycles ❖The saturated suffix applies only to completely saturated ring systems, and the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double bonds. ❖Systems having a lesser degree of unsaturation apply an appropriate roles. 44 45  Hantzsch-Widman rules for partially saturated heterocycles ❖ Partial saturation in heterocyclic compounds can be indicated by one of the following methods: A. The words dihydro, or trihydro, or tetrahydro are used if two or three or four atoms are saturated. ❖These words are preceded by numbers indicate the position of saturated atoms as low as possible and followed by the corresponding fully unsaturated Hantzsch-Widman name. 46 Hantzsch-Widman rules for partially saturated heterocycles 2,3,4,5-tetrahydroazine 2,3-Dihydrooxole 47  When a maximally unsaturated ring includes saturated atom (CH2 interrupts conjugation) its location may be designated by a "#H " prefix indicated hydrogen as in pyran and pyrrole. (indicated hydrogen). (Least number)). Saturated positions are given least numbers after the hetero atom. 48  Hantzsch-Widman rules for partially saturated heterocycles ❖ Partial unsaturation in heterocyclic compounds can be indicated by one of the following methods: B. The position of nitrogen or carbon atoms which bear extra hydrogen atoms must be indicated by numbers and italic capital H (e.g. 1H, 2H, etc.) followed by the name of maximally unsaturated ring. H N N N 3H-Azepine 1H-Azirine 2H-Azirine (not 6H- 49  N S N 6H-1,2,5-thiadiazine 2H-1,4-thiazine 2H-oxin Or 2H-pyran 4H-pyran  Hantzsch-Widman rules for partially saturated heterocycles Examples 3 N 4O 2 2,3-Dihydro-azete 2,3-Dihydro-oxole O OR 1-azetine 2-oxolene 1,2-Dihydro-azete 4-Methyl-2H-oxete O 2,5-Dihydro-furan 3 2,3-Dihydrooxole  -oxolene 55  Hantzsch-Widman rules for partially saturated heterocycles N H 2,3-Dihydro-1H-pyrrole 2 -1H-pyrroline 2H-1,3-Oxazine 6H-1,3-Oxazine 56  Exercise Explain how can you name the following heterocycles. Br N O O S N N N S 57 THANK YOU