1. Pharmaceutical Organic Chemistry By Dr. Mehnaz Kamal Assistant Professor Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

2. WELCOME WELCOME

4. 1-To know types of cyclic compounds 2- To know heterocyclic compounds 4- To know nomenclature of heterocyclic compounds 5-To understand methods of classification of heterocyclic compounds

5. Heterocyclic Compounds contain ring made up of carbon atoms and another kind of atoms. (most commonly N, O, S) homocyclic =( allicyclic = carbocyclic) Compounds contain ring made up only of carbon atoms. Cyclic compounds Homocyclic & Heterocyclic Aromatic Non aromatic

6. To be classified as aromatic, a compound must have 1 -Cyclic structure 2 -Coplanar structure. 3 -Each atom of the ring must have a p orbital to form a delocalized π system i.e. no atoms in the ring can be sp 3 hybridized instead all atoms must be sp 2 hybridized (N.B. carbocation and carbanions are sp 2 hybridized 4 -Fulfill Huckel rule i.e. the system must have 4n + 2= electrons : thus by calculating n value it will be an integral number i.e. n=0, 1, 2, 3, Conjugated (C=C-C=C-C=C) HETEROCYCLIC Erich Hückel

7. Examples of aromatic compounds Examples of non aromatic compounds HETEROCYCLIC

8. 8 10 6

9. What’s a heterocyclic compound? If the ring system is made up of carbon atoms and at least one other element, the compound can be classified as hetero cyclic (that is, hetero atoms). As hetero atom can be N, О, S, В, Al, Si, P, Sn, As, Cu. But The elements that are found most commonly together with carbon in a ring system are Nitrogen (N), Oxygen(O), and Sulfur(S). HETEROCYCLIC Definition: Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or non-aromatic Significance – Two thirds of all organic compounds are aromatic heterocycles. Most pharmaceuticals are heterocycles.

10. Pyrrole Is Aromatic

11. Furan Is Aromatic

12. Excercise Apply Huckel’s rule to the following

13. 1- Classification according to number of ring components :- 4) six-membered hetrocycles 3) five-membered hetrocycles HETEROCYCLIC a. Monocyclic: One ring structure 1) Three membered hetrocycles 2) Four membered hetrocycles rarer, because of the greater difficulty of preparing 4 member b. Bicyclic: Two rings fused with each other, one at least contains heteroatom c. Polycyclic: More than two rings, one at least contains heteroatom Classification

14. HETEROCYCLIC Classification 3. Classification according to position of heteroatoms to each other 2. Classification according to number of heteroatoms in a ring

15. Unsaturati on SaturationUnsaturationSaturation ireneirane eteetane oleolane ineane epineepane Heterocyclic Nomenclature Ring size Unsatu ration SaturationUnsaturationSaturation 3irineiridine 4eteetidine 5oleolidine 6ineprehydro 7epineprehydro Ring containing N Ring without N O=Oxa; S=Thia; N=Aza

16. There are two systems for naming heterocylic compounds: Heterocyclic Nomenclature 1- Trivial or Common names which convey little or no structural information but it still widely used. 2- Systematic ( IUPAC ) A )The Hantzsch-Widman (IUPAC or Systematic) method which in contrast is designed so that one may deduce from it the structure of the compound B) The replacement method

17.  trivial names are still preferred. Some monocyclic compounds of this kind are shown with the common (trivial). Some monocyclic compounds of this kind are shown in the following chart, with the common (trivial) name in bold and a systematic name in blue. Heterocyclic Nomenclature 1-Trivial or Common names

18. 1) 5-membered heterocycles with one or two heteroatoms 2) 6-membered heterocycles with one or two heteroatoms Heterocyclic Nomenclature 1-Trivial or Common names

19. 3) Fused heterocycles Heterocyclic Nomenclature 1-Trivial or Common names

20. 4) Saturated heterocycles Exercise : Give the common name of the following compounds: Heterocyclic Nomenclature 1-Trivial or Common names

21.  Hantzsch-Widman nomenclature is named after the German chemists Arthur Hantzsch and Oskar Widman, who proposed similar methods for the systematic naming of heterocyclic compounds in 1887 and 1888 respectively.  According to this system three to ten-membered rings are named by combining the appropriate prefix (or prefixes) that denotes the type and position of the heteroatom present in the ring with suffix that determines both the ring size (depending on the total number of atoms in the ring) and the degree of unsaturation (note that fully saturated and fully unsaturated have certain rules for nomenclature while partially unsaturation will be indicated in certain ways). In addition, the suffixes distinguish between nitrogen-containing heterocycles and heterocycles that do not contain nitrogen  IUPAC name = locants +Prefix + suffix Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman

22. Ring Size unsaturated saturated saturated ring with nitrogen 5 ole olane -olidine 6 ine inane (-ane) O Oxa S Thia N Aza Priority O ox S thi N az 1. Name Prefix- Suffix – ring size - saturation Rules for Systematic Nomenclature : 1- Generally The name consist of two parts, part 1 = prefix = indicate the type of the heteroatom in the ring ( N,O,S ) part 2 = suffix = indicate the size (3,4,5,…membered) of rin g Heterocyclic Nomenclature ?

23. Table 1 Atom O oxa S thia N aza Priority decreases Prefix Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman 1) Identify the hetroatom present in the ring and choose from (table 1) the corresponding prefix (e.g. thia for sulfur, aza for nitrogen and oxa for oxygen). 2) 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. and then they should be listed in alphabetical order. O=Oxa; S=Thia; N=Aza

24. 1,4-dithiane 1,2-dithiane1,3-dithiane 1,4-dithiine1,2-dithiine 1,2,3-triazole 1,3,5-Triazine 1,3,5-trioxane 1,2-dioxolane 1,4-dioxine Rules for fully saturated and fully unsaturated heterocycles Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman 3) 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) and the numbering preferably commenced at a saturated rather than an unsaturated atom, as depicted in the following example: 1,3-diaza….

25. 1,2-oxathiolane IUPAC name: 1,2-oxazole Common name: isoxazole IUPAC name: 1,3-oxazole Common name: oxazole 4 ) If more than one type of hetroatoms present in the ring the name will include more than one prefix with locants to indicate the relative position of the heteroatoms. Atom prefixes have a strict order of priority (preference) in which they are to be listed. For example,‘’Oxa’’(for oxygen) always comes before ‘’aza’’ (for nitrogen) in a name (see table 1). When combining the prefixes (e.g. oxa and aza) two vowels may end up together, therefore the vowel on the end of the first part should be omitted (oxaza). Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman Rules for fully saturated and fully unsaturated heterocycles 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). 4-Methyl-1,3-Thiaza …. Old Soldiers Never Cry (O > S > N > C)

26. Rules for fully saturated and fully unsaturated heterocycles Unsat sat N-presentN-absent irine iridine irene irane ete etidine etane ole olidine ole olane ine a in ane epin Table 2 a Ring size epine epane a: means use the prefix perhydro followed by the fully unsaturated name Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman 5) Choose the appropriate suffix from (table 2) 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 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 6) Combine the prefix(s) and suffix together and drop the first vowel if two vowels came together.

27. Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman Rules for fully saturated and fully unsaturated heterocycles 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-oxazaetidine), therefore the vowel on the end of the first part should be dropped. This gives the correct name:1,2-oxazetidine This ring contains (O) prefix1 (oxa), and two (N) prefix2 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 and dropping the appropriate vowels we get the correct name as : 1,2,5-Oxadiazole 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

28. Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman Rules for fully Partial unsaturation in heterocyclic compounds Partial unsaturation in heterocyclic compounds can be indicated by one of the following methods : 1) 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. 2)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

29. Heterocyclic Nomenclature 2-Systematic ( IUPAC ) A) Hantzsch-Widman Rules for fully Partial unsaturation in heterocyclic compounds Ring size 3) Alternatively, the partially unsaturated 4 and 5 rings (i.e. rings contain one double bond) are given special Hantzsch-Widman suffixes as in table 3 and the double bond is specified as ∆ 1, ∆ 2, ∆ 3, etc.. Which indicates 1 and ; 2 and 3; 3 and 4 atoms respectively have a double bond (i.e. Name : ∆ x + Prefix + special suffix ) ( x= locant of the double bond) Table 3 With N Without N -etine -oline -etene -olene

30.  Exercise: Explain how can you name the following heterocycles.

31. Definitions:  Fusion: This term is used to describe the process of joining two separate rings with the maximum number of non- cumulative double bonds via two atoms and one common bond.  Ortho-fused rings: are those rings that have only two common atoms and one bond, example; naphthalene  Ortho-and peri-fused rings: are those found in a polycyclic compound with a ring that is ortho- fused to different sides of two other rings that are themselves ortho-fused together (i.e. there are three common atoms between the first ring and the other two).  1H-phenalene is considered as being composed of three benzene rings, each is ortho-peri- fused to the other two.  Polycyclic compounds incorporating one heterocyclic ring or fused heterocylic system fused to benzene are known benzoheterocycles.  Also bicyclic compounds with two fused heterocyclic rings are well known.  Both types can be named according to certain rules Heterocyclic Nomenclature Nomenclature of Fused Systems

32. A.Nomenclature of benzofused compounds: Polycyclic compounds incorporating one heterocyclic ring or fused heterocylic system fused to benzene are known benzoheterocycles and is named by: 1. prefix: the word benzo 2. letter in square brackets: indicating the position of fusion 3. name of heterocyclic ring: (common or IUPAC name). Name= Benzo[letter]name of heterocyclic ring (the connected bond take letter ( a,b,c …) Heterocyclic Nomenclature Nomenclature of Fused Systems

33. 1.Numbering the H.C.R a. When numbering a ring with one heteroatom, the heteroatom is #1 and continues in the direction that is closer to the fused bond. b. When numbering a ring with more than one heteroatom, the highest priority atom is #1 and continues in the direction that gives the next priority atom the lowest number. 2. The bonds of the heterocyclic ring are assigned by alphabetical letters starting with the 1,2-bond Heterocyclic Nomenclature Nomenclature of Fused Systems For designating the position of fusion the following rule is followed

34. The name is formed of : name of substituent ring (minor ring)[number, number-letter] name of base ring (major ring B.Nomenclature of fused heterocylic compounds:  The name of the minor ring is derived by writing a contracted prefix for the substituent ring present Naming a fused heterocyclic systems composed of two monoheterocyclic units or benzoheterocycles (e.g. chromene) fused with another hetrocycle ring is based upon considering one system as the parent (base) and the second is considered as subsitituent Heterocyclic Nomenclature Nomenclature of Fused Systems

35.  The numbers indicate which atoms in the minor ring are common to the major ring (fusion sites in minor ring).  The order of the numbers indicates which atom of the minor ring is encountered closest to atom 1 in the major numbering system (i.e. these numbers may be written in ascending or descending order e.g. 2,3 or 3,2 )  The letter defines the position of attachment of the minor ring to the major ring (fusion sites in base component)  Finally a suffix indicate the name of the base ring is written.  The numbering system for the whole fused system is not the same as the numbers in the square brackets (i.e. there are three numbering systems; one for minor ring, one for major ring and the third is for the system as a whole) Heterocyclic Nomenclature Nomenclature of Fused Systems B.Nomenclature of fused heterocylic compounds:

36.  Selection of a parent or base ring is based on the following rules which are applied in order Rule 1: A heterocyclic ring containing the heteroatom occurring earliest in the order N, O, S, (i.e. ring containing N preferred to the rings does not contain N or containing O, or S) Priority order of component ring systems: Heterocyclic Nomenclature Nomenclature of Fused Systems Note: The numbering system for the whole fused system is not the same as the numbers in the square brackets (i.e. there are three numbering systems; one for parent ring, one for substituent ring and the third is for the system as a whol e) B.Nomenclature of fused heterocylic compounds:

37. Priority order of component ring systems: Heterocyclic Nomenclature Nomenclature of Fused Systems B.Nomenclature of fused heterocylic compounds: Rule 1: more example

38. Rule 2: A heterocyclic component containing the largest possible individual ring Heterocyclic Nomenclature Nomenclature of Fused Systems Priority order of component ring systems: Rule 3: A heterocyclic component containing the greater number of heteroatom of any kind Note: The whole molecule is numbered starting from pyridine ring to give the three heteroatom the lowest possible number (1,6,7), however, stating from oxazine ring will give them (2,3,5) or (2,3,8).

39. Note: The whole molecule is numbered starting from pyrazole ring to give the four heteroatom the lowest possible number (1,2,4,6). While starting from oxazole ring give them (1,3,4,5) or (1,3,5, 6). Rule 4: A heterocyclic component containing the greater variety of heteroatom Heterocyclic Nomenclature Nomenclature of Fused Systems Priority order of component ring systems: Rule 5: A heterocyclic component containing the greater number of heteroatoms most preferred when considered in order O, S,N,

40. Rule 6: A heterocyclic component with the lower possible number for heteroatoms Rule 7: If a position of fusion is occupied by a heteroatom the name of the component rings to be used are so chosen as both to contain the heteroatom. Heterocyclic Nomenclature Nomenclature of Fused Systems Priority order of component ring systems:

41. a) Give low numbers for the heteroatoms as a set Heterocyclic Nomenclature Nomenclature of Fused Systems Numbering the whole fused system should start from the first atom after fusion in any direction to fulfill the following rules in order: b) Give low numbers for heteroatoms of higher priority O,S, N c) Give low numbers to fusion carbon atom Fusion carbon 4a is preferred to 7a

42. D) Give low numbers to indicate hydrogen atom 4H-[1,3]dioxolo[4,5-d]imidazole Heterocyclic Nomenclature Nomenclature of Fused Systems B)- If there is a heteroatom at the position of the fusion …) divide the components such that the common heteroatom is a member of both component parts

43. Summary of Nomenclatures Rules Scheme for deriving the base component of' a fused ring system 1. Is there only one ring which contains nitrogen? (YES:. choose this as base component) 2. Are the two rings have the same heteroatoms but their size is different ? (Yes: choose the larger one ) 3. Are the two rings of the same size but have different heteroatoms? (YES: choose the ring containing a heteroatom of the highest priority i.e. O >S) 4. Are the rings of the same size but contain different numbers of heteroatoms? (Yes: choose the ring with the greater number ) 5. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose the ring with the greatest variety of heteroatoms 7-Are the two rings have the same size and the same number and type of heteroatoms? (Yes: choose the ring with the lower numbers for heteroatoms ) Heterocyclic Nomenclature

44.  In replacement nomenclature, the 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 According to this nomenclature, tetrahydrofuran, for instance, is called oxacyclopentane. Heterocyclic Nomenclature 2-Systematic ( IUPAC ) B-Replacement nomenclature

45. Heterocyclic Nomenclature 2-Systematic ( IUPAC ) B-Replacement nomenclature

46. Importantce and uses of Heterocyclic compounds:- Biosynthesized Essential for life ( haem, chlorophyll) In general various important compounds such as:- alkaloids, vitamins, antibiotics, essential amino acids, hormones, drugs and dyes contain heterocyclic structure. in general: nucleic acids, amino acids (proteins), feeding: proteins, carbohydrates, vitamins alkaloids: nicotine, caffeine Application: antibiotics (penicillins, sulfonamides) insecticides (triazoles) herbicides (triazines, pyridines) HETEROCYCLIC

47. Extra information please read it

48. Heterocyclic Nomenclature  Hetero-atom is to be counted as 1 or as low as possible  When there is more than one hetero-atom (and they are different), preference is given to O, then S, then N, then C. Also N-H presides over –N=.Mnemonic: Old Soldiers Never Cry (O > S > N > C) the first one in periodic take number 1 if the 2 element are the same we use; di,tri, tetra before the prefix  When there is more than one hetero-atom, numbering should be as direct as possible from one to the other  Substituents are numbered as low as possible  Acceptable prefixes include O=Oxa; S=Thia; N=Aza  Common suffixes for N- and non-N-heterocycles For partially unsaturated systems, H is(are) are used to indicate the location of saturation  Hantzsch-Widman System of systematic name of heterocyclic compounds  final of prefixes is dropped when followed by a vowel ( a,e,i,o and u) 2. IUPAC (systemic) Names ?

49. N - Heterocyclic rings Five-membered rings Saturated Heterocyclic (Most common ) Six-membered rings Unsaturated saturated DNA bases

50. Fused rings Pyrimidine –imidazole (DNA bases) Benzene fused Heterocyclic (Most common ) N - Heterocyclic rings

51. O- Heterocyclic rings Five- membered Six- membered Benzene fused Heterocyclic (Most common )

52. S - Heterocyclic rings Unsaturated Heterocyclic rings with two different heteroatoms N and O N and S Heterocyclic (Most common )

53. 1-Common 3-membered Those with two heteroatoms 2-Common 4-membered rings Those with one heteroatoms Heterocyclic Nomenclature Those with two heteroatoms

54. Heterocyclic Nomenclature Those with two heteroatoms Those with one heteroatoms Those with three heteroatoms 3-Common 5-membered rings

55. Those with one heteroatomsThose with two heteroatoms Heterocyclic Nomenclature 4-Common 6-membered rings : Those with three heteroatoms Those with four heteroatoms

56. Those with one heteroatomsThose with two heteroatoms Heterocyclic Nomenclature 5-Common 7-membered rings

57. Heterocyclic Nomenclature

58. Unsaturati on SaturationUnsaturationSaturation ireneirane eteetane oleolane ineane epineepane Heterocyclic Nomenclature Ring size Unsatu ration SaturationUnsaturationSaturation 3irineiridine 4eteetidine 5oleolidine 6ineprehydro 7epineprehydro Ring containing N Ring without N

59. Hantzsch – Widman Nomenclature (adopted by IUPAC) Ring Size Saturat ed Partly Saturated Unsatura ted 3-irane--irene 4-etane(dihydro)-ete 5-olane(dihydro)-ole 6-inane(di or tetrahydro) -ine 7-epane(di or tetrahydro) -epine 8-ocane(di, tetra, or hexahydro) -ocine Common name : ethylene oxide Systematic name : Oxa + irane …Oxirane Common name : furan Systematic name : Oxa + ole …. Oxole Common name : pyrrole Systematic name : H at 1 position + Aza + ole …. 1H-Azole Common name : piperidine Systematic name : Aza + inane …. 1H- Azinane Common name : pyrimidine Systematic name : two aza at 1, 3 positions + ine …. [1,3]-diazine Heterocyclic Nomenclature