Heterocyclic Chemistry PDF

# Heterocyclic Chemistry ## Introduction: 1. Heterocyclic compounds are cyclic compounds in which one or more atoms of the ring are heteroatoms e.g. O, N, S, P........etc. 2. Heterocyclic compounds are present in many natural compounds (e.g. nucleic acid, hemoglobin, and antibiotics) and other syn...

# Heterocyclic Chemistry ## Introduction: 1. Heterocyclic compounds are cyclic compounds in which one or more atoms of the ring are heteroatoms e.g. O, N, S, P........etc. 2. Heterocyclic compounds are present in many natural compounds (e.g. nucleic acid, hemoglobin, and antibiotics) and other synthetic drugs such as indomethacin, antipyretic and phenytoin. - Indomethacin (analgesic and anti-inflammatory) ``` CH2COOH CH3 H3CO. -CH3 N Ο Cl ``` - Caffeine ``` Ο CH3 H3C N N C N N-CH3 N N CH3 ``` - Antipyrine (analgesic and antipyretic) ``` Ο CH3 N-CH3 ``` Heterocyclic compounds can be classified into aliphatic and aromatic compounds. - oxirane ``` ! Ο ``` - piperidine ``` 요 NH ``` - morpholine ``` N H ``` - pyrrole ``` NH H ``` - pyridine ``` N ``` - indole ``` 口 indole N H ``` Heterocyclic compounds can also be classified according to the number of cycles into: - **Monocyclic:** only one ring present in the structure e.g. pyrrole - **Bicyclic:** two fused rings contain one heteroatom at least e.g. indole - **Polycyclic:** more than two rings contain one heteroatom at least e.g. carbazole ## Monocycles can be classified according to: - Number of ring atoms or the ring size (3, 4, 5, 6,....) - Nature of the heteroatom in the ring [oxa (O), thia (S), aza (N)] - Position of the heteroatom to the ring. ## Nomenclature of heterocycles ### A) Nomenclature of monocycles #### IUPAC Nomenclature: The name of any heterocyclic ring is divided into prefix + stem + suffix. #### Prefix: - It refers to the type, number and position of heteroatoms. - When two or more heteroatoms of the same type are present, the prefix di, tri, tetra,......etc is used. - If the heteroatoms are different, their order of citation will be according to the periodic table through decreasing group number (O then N) and increasing atomic number in the same group (O then S) e.g. oxathiaza (O then S then N), dioxaza (20 then N). | Element | prefix | Order of priority | |---|---|---| | O | oxa | 1 | | S | thia | 2 | | Se | selena | 3 | | N | aza | 4 | | P | phospha | 5 | #### Stem: - It determines the ring size from 3-membered to 10-membered ring. | Ring size | Stem | |---|---| | 3 | ir (from tri) | | 4 | et (from tetra) | | 5 | ol | | 6 | in | | 7 | ep (from hepta) | | 8 | oc (from octa) | | 9 | on (from nona) | | 10 | ec (from deca) | #### Suffix: - It determines the state of the ring which may be unsaturation or unsaturation contain N or without N. - The saturated suffix apply only to completely saturated ring systems while the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double bonds. Systems having a lesser degree of unsaturation require an appropriate prefix such as "dihydro" or "tetrahydro" or "perhydro". | Ring size | With N in ring | Without N in ring | |---|---|---| | Unsat. | Sat. | Unsat. | Sat. | | 3 | irine | iridine | irene | irane | | 4 | ete | etidine | ete | etane | | 5 | ole | olidine | ole | olane | | 6 | ine | perhydro | in | ane | | 7 | epine | perhydro | epine | epan | | 8 | ocine | perhydro | ocine | ocane | | 9 | onine | perhydro | onine | onane | | 10 | ecine | perhydro | ecine | ecane | - **N.B.** The complete saturation is indicated by prefix "perhydro" which is added before the total name of the unsaturated ring. ## Numbering of monocycles 1. If monocycles containing one heteroatom, the numbering starts at heteroatom and the substituents take the least possible number. 2. If monocycles containing more than one different heteroatom, the numbering begins at heteroatom of higher order of priority and proceeds round the ring in order to give other heteroatoms the least possible numbers without regards to the substituents. ## Nomenclature of partially saturated ring: -i) If the saturated position is only one (obligatory saturation), we must mention its position by indicated hydrogen e.g. 1H, 2H, 3H,.....etc. -ii) If the number of the double bonds is less than maximum, prefix dihydro or tetrahydro are added to the same name of unsaturated state and the saturated positions are given the least number after heteroatom. ## The IUPAC and trivial names of most common monocycles: ### **1) Three membered rings (unsaturated)** - oxirene ``` ! C ``` - 1H-azirine ``` N H ``` - thiirene ``` ! S ``` - 1H-diazirine ``` N NH H ``` ### **2) Three membered rings (saturated)** - oxirane (ethylene oxide) ``` NH ``` - 1H-aziridine (ethylene imine) ``` NH S ``` - thiirane (ethylene sulfide) ``` ! S ``` - 1,2-oxaziridine ``` NH O ``` ### **3) Four membered rings (unsaturated)** - azete ``` Π ``` - 2H-oxete ``` Π ``` - 2H-thiete ``` Π S ``` - 1,2-dihydroazete ``` NH N ``` - 2,3-dihydroazete ``` NH N ``` ### **4) Four membered rings (saturated)** - azetidine ``` NH ``` - oxetane ``` O ``` - thietane ``` S ``` ### **5) Five membered rings (unsaturated)** - pyrrole (1H-azole) ``` N H ``` - furan (oxole) ``` O ``` - thiophene (thiole) ``` S ``` - imidazole (1H-1,3-diazole) ``` N NH H ``` - pyrazole (1,2-diazole) ``` N H ``` - oxazole (1,3-oxazole) ``` N O ``` - isoxazole (1,2-oxazole) ``` N O ``` - thiazole (1,3-thiazole) ``` N S ``` - 1H-1,2,4-triazole ``` N N-N H ``` - 1H-tetrazole ``` N N NH ``` - isothiazole (1,2-thiazole) ``` N S ``` - 2,5-dihydrofuran ### **6) Five membered rings (saturated)** - tetrahydrofuran (oxolane) ``` O ``` - pyrrolidine (azolidine) ``` ΝΗ ``` - tetrahydrothiophene (thiolane) ``` S ``` - imidazolidine (1,3-diazolidine) ``` NH H ``` - pyrazolidine (1,2-diazolidine) ``` N H ``` - oxazolidine (1,3-oxazolidine) ``` ΝΗ ``` - oxathiolane ``` S ``` - thiazolidine (1,3-thiazolidine) ``` S NH ``` ### **7) Six membered rings (unsaturated)** - pyridine (azine) ``` N ``` - pyridazine (1,2-diazine) ``` N N ``` - pyrimidine (1,3-diazine) ``` N ``` - pyrazine (1,4-diazine) ``` N ``` - 1,4-dihydropyridine (1,4-dihydroazine) ``` 口 ``` - 1,2-dihydropyridine (1,2-dihydroazine) ``` 에어 ``` - 2H-thiopyrane (2H-thiin) ``` S ``` - 4H-pyran (4H-oxin) ``` S ``` - 4H-1,4-oxazine ``` 110101101101 ``` - 1,2,4-oxathiazine ``` S N N ``` - 6H-1,2,5-thiadiazine ``` S ``` - 2H-pyran (2H-oxin) ``` Ο ``` - 4-pyrone (4H-pyran-4-one) ``` Ο ``` - 2-pyrone (2H-pyran-2-one) ``` Ο ``` ### **8) Six membered rings (saturated)** - piperidine (perhydroazine) ``` 오오오 ``` - piperazine (perhydro-1,4-diazine) ``` 오오오 ``` - morpholine (perhydro-1,4-oxazine) ``` 오오오 ``` - oxane ``` ``` - 1,4-dioxane ``` ``` ### **9) Seven and eight membered rings (unsaturated or saturated)** - 1H-azepine ``` 7 NH ``` - perhydroazepine ``` 7 NH ``` - oxepane ``` 70 ``` - thiepine ``` 7 S ``` - 1,4-thiazepine ``` 7 S ``` - 1,3-oxazepine ``` 7 N ``` - azocine ``` 8 N ``` - azocane (octahydroazocine) ``` 8 NH ``` ## B) Nomenclature of fused rings heterocycles **Trivial names of some fused heterocyclic rings:** - indole (benzo[b]pyrrole) ``` H ``` - benzofuran (benzo[b]furan) ``` O ``` - benzothiophene (benzo[b]thiophene) ``` S ``` - quinoline (benzo[b]pyridine) ``` N ``` - isoquinoline (benzo[c]pyridine) ``` N ``` - cinnoline (benzo[c]pyridazine) ``` N ``` - quinazoline (benzo[d]pyrimidine) ``` N ``` - quinoxaline (benzo[b]pyrazine) ``` N ``` - coumarin (benzo[b]pyran-2-one) ``` O ``` ## II) Two fused rings (benzene ring fused with a heterocycle) 1. The parent name (written at the end) is the name of the heterocyclic ring. 2. The fused name (written at first) is the name of the fused benzene called (benzo) 3. The side fusion of the parent ring with the benzene ring is indicated by alphabetical letters (a, b, c ......etc) and put such letters between square brackets in between the prefix and parent name. - benzo[d]isoxazole ``` a N ``` - benzo[d]thiazole ``` CNb N d a ``` - benzo[d]pyrimidine ``` a N d la N ``` - benzo[d]pyridazine ``` a N d la N ``` ## 4) Renumbering of all the fused system Total numbering of the complete fused system is done to determine the position of saturations and substituents on both cycles and fusion. - 5-methylbenzo[b]thiophene The numbering starts from the atom next to the fusion (from a, b, c, or d position) that gives: - 1st heteroatom the least possible number - If there is a choice, make numbering from a, b, c, or d that give 2nd, then 3rd heteroatom least possible number - If there is a choice, lowest number is given to senior heteroatom (O > S > N) then carbon in fusion than saturation then prior substituents. ## Two fused rings (heterocycle ring fused with another heterocycle) The IUPAC rules for naming such system are also composed of 4 points: A. The parent name is given to the more prior heterocycle and it is used as suffix B. The fused ring is given to the less prior heterocycle and it is used as prefix C. Numbering of the side of fusion for both rings D. Renumbering of all the fused system A) The selection of the parent ring (suffix) should be according to the following order of preferences: 1) The nitrogen containing ring must be taken as a parent ring. - 6H-furo[2,3-b]pyrrole - 5-methyl-6H-furo[2,3-b]pyrrole - thieno[3,2-d]pyrimidine 2) If both rings without N, the ring containing the more prior heteroatom (O > S in seniority) is considered as a parent ring. - thieno[2,3-b]furan 3) If both rings contain N or don't contain N, the largest ring size is taken as parent. - imidazo[3,2-b]pyridine - 6-methylfuro[3,2-b]pyridine - furo[3,2-b]oxepine 4) If there is a choice, the ring containing more number heteroatom is taken as parent. - 7-methylpyrido[2,3-b]pyrazine - 6-methylpyrido[2,3-d]pyrimidine 5) If there is a choice, the ring containing more variety of heteroatoms is taken as parent. - 4H-pyrimido[4,5-d][1,3]oxazine - 7-methyl-4H-pyrimido[4,5-d][1,3]oxazine 6) If there is a choice, ring having the more heteroatom is taken as parent. - 4,7-dihydro-[1,3]thiazino[4,5-d][1,3]oxazine - 2-methyl-4,7-dihydro-[1,3]thiazino[4,5-d][1,3]oxazine 7) If there is a choice, the ring containing lower locants for heteroatoms is taken as parent. - pyrimido[5,4-c]pyridazine - 6-methylpyrimido[5,4-c]pyridazine 8) The parent ring is the ring containing a more number of carbon atoms adjacent to the fusion. - pyrazino[2,3-d]pyrimidine - pyrazino[2,3-d]pyridazine ## B) The naming of the prefix of fused heterocycle (less prior) is given as: - furan= furo - thiophene= thieno - imidazole= imidazo - pyrrole= pyrrolo - pyrimidine= pyrimido - pyridine= pyrido - pyrazine= pyrazino - quinoline= quino - isoquinoline= isoqiuno ## C) The side of fusion with the parent ring is numbered alphabetically (takes letter a, b, c......etc) and the letter of fusion is placed between square brackets at the end. - The side of fusion of the prefix ring (less prior heterocycle) is indicated by two number, these two numbers are placed at first in the square bracket. - The order of writing of these two numbers conforms the directions of the lettering of the parent ring. ## D) The peripheral numbering of the total heterocyclic fused molecule is done to determine the position of saturation and substitution on both cycles and fusion by the same rules discussed before in two fused rings one of them is benzene ring. - **N.B.** The heteroatoms in the fusion side are numbered according to the sequence of numbering rules, but carbon atoms in the fusion take the previous number plus letter a, b, c, .........etc. - imidazo[1,2-b]1,2,4-triazine - 6-methylimidazo[1,2-b][1,2,4]triazine ## IV) Three fused rings or more: - Choose the parent ring which contains the greatest number of rings that: - Have trivial name - According to above rules (in two fused rings both of them are heterocycles)