Stereo Chemistry Course's Plan & Matrix PDF

 Stereo Chemistry  Course's Plan & Matrix Course Program Teaching and Week Course Contents learning Los Learning Meth...

 Stereo Chemistry  Course's Plan & Matrix Course Program Teaching and Week Course Contents learning Los Learning Methods s outcomes Theoretical: Introduction to stereochemistry & -Lectures representation of organic 1.1.1.2 -Interactive molecules in three 1.1.3.4 learning Week dimensional. 2.2.1.14 2,3,6,8,9 -Self-learning 5 2.2.3.19 Practical sessions. Practical: 4.2.2.46 -problem solving Preparation of - tetrahydrocarbazole & determine their the % of yield. 4 ISOMERS  They are the compounds that have identical chemical and molecular formulas but differ in the nature of sequence of bonding of their atoms or in their arrangement of atoms in space.  Classification of Isomers Structural or Stereo isomers Constitutional Structural (Constitutional) Isomers Skeletal Positional Functional Tutomers Tutomers Proton Valence Ring chain tautomerism Keto-Enol  Structural Isomers or constitutional isomers Compounds that have the same atoms present but differ in their order of connectivity. They have the same molecular formula but different structures.  Skeletal or Chain Isomers Compounds that have the same functional groups but differ in the length of the side chains. CH3 CH2 CH2 CH2 CH3 n- pentane CH 3 CH 3 CH 3 C CH 3 CH 3 C CH 2 CH 3 CH 3 H isopentane neopentane  Positional Isomers ▪ Compounds that have the same functional groups, but are present on different positions of the chain. CH 3 CH 2 CH 2 CH CH 2 CH3 CH2 CH CH CH 3 1-pentene 2-pentene CH 3 CH 2 CH 2 CH 2 CH CH 2 CH3 CH2 CH CH CH2 CH2 2-hexene 3-hexene  Functional Isomers Compounds that have different functional groups.  Tutomers Compounds whose structures differ in arrangement of atoms but which are in dynamic equilibrium with each other. O H OH CH 3 CH2 C C H CH 3 CH2 C C H H H H3C CH3 H3C CH3 O O OH O  Valence Tutomerism e.g. cycloocta-1,3,5-triene exists as equilibrium of 2 valence tautomers.  Ring Chain Tautomerism Tautomers of this type exists as equilibrim mixtures of two tautomers,one is open chain ststem and the other is cyclic system e.g. O OH HO CHO H O OH H OH OH OH HO H H OH O H H OH H H OH OH H HO OH H OH H OH H OH H OH OH -D-Glucopyranose -D-Glucofuranose D-Glucose  Stereo Isomers  Stereo Isomers Anomers Rotamers & Configurational Conformers Configurational Enantiomers Diastereomers Meso- Geometrical Geometrical Cis-isomers or Trans-isomer or Z-compounds E-compounds Stereoisomer Compounds that have the same chemical formula, same atoms, same connectivity and differ only in the arrangement of their atoms in space.  Configurational Isomers Have a chiral (stereogenic center). Chiral center refers to a carbon atom attached to four different groups. The molecule is said to possess chirality and to have a stereogenic center. Geometrical Isomers Cis- & Trans-  Geometric Isomers Stereoisomers, which are isomeric about double bonds and cycloalkane. If the bond is C=C, the terms are cis/trans or Z/E; if the bond is C=N, the terms are syn (cis- like) and anti (trans-like). CH 3 C2H5 H C2H5 C C C C H H CH 3 H cis-2-pentene trans-2 - pentene  Z-,E- System for Nomenclature of Alkenes and Cycloalkanes The cis – trans system of nomenclature can not be used for such a compound because there are four different groups on the two sp2 carbons forming the double bond. The E,Z system of nomenclature has devised for these kinds of compounds.  To name an isomer by the E,Z system Determine the relative priorities of the two groups bonded to one of the sp2 carbons and then the relative priorities of the two groups bonded to the other sp2 carbon. If the high – priority groups are on the same side of the double bond the isomers has the Z configuration (Z is for Zusammen, German word means "together") If the high priority groups are on opposite sides of the double bond, the isomer has the E Configuration (E is for entgegen, German for "opposite")  (CIP-Rules) Cahn – Ingold - Prelog rules  Rules for assigning priorities Rule (1) Atoms with higher atomic numbers have higher priority Example priorities: I > Br > Cl > S > F > O > N > 13C > 12C > 3H > 2H > 1H Low priority Low priority Low priority High priority C=C C=C High High priorty High Priority Low priority Z- isomer The E isomer Br Cl Br Cl C=C C=C H CH3 H CH3 Which isomer is cis and whic is trans? H CH3 CH3 H CH3 CH3CH2 CH3 H3C CH3  Rule (2) In case of ties, use the next atoms along the chain as tiebreakers. CH(CH3)2 > CH2CH2Br > CH3CH2 H C F CH3 CH2F H H CH2CH3 H C C H  Y Rule (3) Treat C Y double and triple bonds as if both atoms C Y C in the bond were duplicated or triplicated: Y C Y C Y C Y C Y C Y C C Y C Y Y C C Y Y C  Drawing Three Dimensional Structures  Flying-Wedge Representation A solid line is used for a bond in the plane. A wedge is used for a bond in front of the plane. A dashed line is used for a bond behind the plane. Fischer Projections “Sawhorse” Projection EVOLUTION OF THE CHO FISCHER PROJECTION HOCH2 OH H Fischer Projection Orient the main chain CHO CHO vertically with the most H OH H OH oxidized group at the top. CH2OH CH2OH Substituents will Main chain bends stick out toward away from you you like prongs  Fischer Projections Flat drawing that represents a 3D molecule A chiral carbon is at the intersection of horizontal and vertical lines. Horizontal lines are forward, out-of-plane. Vertical lines are behind the plane.  Rules for Fischer projections Flat drawing that represents a 3D molecule H Br Cl F Arrange the molecule so that horizontal bonds at chiral carbon point toward you and vertical bonds point away from you.  Rules for Fischer projections H Br Cl F Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.  Rules for Fischer projections H Br Cl F Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.  Fischer Rules Carbon chain is on the vertical line. Highest oxidized carbon at top. Rotation of 180 in plane doesn’t change molecule. Do not rotate 90! Do not turn over out of plane! => ANOMERS  Anomers Stereoisomers where the molecule is cyclized and the difference in configuration is about the anomeric carbon only. OH OH H O OH H OH H OH H H OH H HO OH HO H H OH H OH -D-Glucopyranose -D-Glucopyranose  Cyclization of D-Glucose CHO H OH H OH H OH HO HO HO HO H HO HO OH H OH HO H H OH H OH H H H OH H OH CH2OH nucleophilic addition of -OH on carbon 5 to the aldehyde functional group H OH CHO HO CH O HO H OH HO H H OH H OH HO H HO H H OH H OH  H OH H OH HOH2C H H OH CH2OH OH HO HO HO OH  rotate C-5 OH to rear H OH H H Cyclization of D-Glucose  Rotamers and Conformers  Rotamers and Conformers On the basis of spatial arrangement of atoms in the molecule that can be achieved by rotation (or torsion) around one or more single bonds, they are classified as: Conformers assume the chair/boat and equatorial/axial forms. H H H H H H H H H H H H H H H H H H H H H H H H  Rotamers assume the different Newman projections (staggered / eclipsed / ). Eclipsed conformation Staggered conformation H H H H H H H H H H H Front carbon H Back carbon Rotamers assume the different Newman projections (staggered / eclipsed / ) Rotamers assume the different Newman projections (staggered / eclipsed / ) Rotamers assume the different Newman projections (staggered / eclipsed / ) Chirality ◼48 49  IN PREVIOUS LECTURE  Drawing Three Dimensional Structures ANOMERS  Rotamers and Conformers  IN THIS LECTURE Chirality 7 ◼ Absolute (R-S) and Relative (D- L-) Configurations 8 ◼ Absolute Conformation Assign (R) or (S) IN Chiral compounds with one chiral carbon 9 ◼  Determination of Stereochemistry of Chiral Carbons in Flying-Wedge Representation. 10 ◼  Absolute Conformation Assign (R) or (S) Working in 3D, rotate molecule so that lowest priority group is in back. Draw an arrow from highest to lowest priority group. Clockwise = (R), Counterclockwise = (S) 11 ◼  Absolute Conformation Assign (R) or (S) 2 2 If the lowest prior 4 atom on front rotate the molecules 1 3 1 3 4 (S)-Lactic acid ◼12  (R) and (S) Treat double and triple bonds as if both atoms in the bond were duplicated or triplicated: Y C Y C Y C Y C Y C Y C Y C Y C Y C C Y C Y Y C 13 ◼ C Y  Assign Priorities O 2 OH 3 C 3 C Cl 4 H H 4 H3C 2 1NH2 * H Cl natural alanine 1 3 H CH2 (C) (C) C H C CH2 4 expands to O H C * C CH(CH3)2 *C CH(CH3)2 CH2OH C H CH2OH O O 1 2 C 14 ◼  (R) and (S) Nomenclature Example: Draw a 3-dimensional formula for (R)-2-chloropentane. Step 1: Identify the asymmetric carbon. Cl CH3 C CH2CH2CH3 H* Step 2: Assign priorities to each group attached to the asymmetric C carbon. 1 Cl 2 3 CH C CH2CH2CH3 3 15 ◼ H4  (R) and Cl (S) Nomenclature CH3 C CH2CH2CH3 Step 3: Draw a “skeleton” with the asymmetric H carbon in the center and the lowest priority group attached to the “dashed” wedge (i.e. Cl you). pointing away from CH3 C CH C H 2CH2CH3 Step 4: Place the highest priority group at H the top. Cl C H 16 ◼  (R) and (S) Nomenclature Cl CH3 C CH2CH2CH3 Step 5: For (R) configuration, H place the 2nd and 3rd priority groups around the asymmetric carbon in a clockwise direction.Cl C H CH3 CH2CH2CH3 Step 6: Double-check your structure to make sure that it has the right groups and the right configuration. ◼17 Draw (R)-2-butanol 1 2 2 4 3 4 1 3 18 ◼ Determination of Stereochemistry of Chiral Carbons in Fischer projections. ◼19  Determination of Stereochemistry of Chiral Carbons in Fischer projections. First, rules for allowed motions when manipulating 1. A Fischer projection can never be removed from the plane of the paper. 2. 1800 rotation is allowed, 900 or 2700 rotations are not allowed. 3. Hold one group stationary, rotate others either clockwise or counter clockwise. ◼20 So, how do you determine whether a Fischer projection is R or S? Using an allowed motion, place the lowest priority group either on the top or the bottom of the molecule. Then, look at the relationship of the other three groups Clockwise – R CH3 Counterclockwise - S 3 What is the stereochemistry of this molecule? HO2C OH 2 1 H What about this one? Clockwise R 4 CH3 H OH CO2H ◼21 Violating any of these rules during manipulation will result in a change in stereochemistry of the chiral carbon. The idea here is to manipulate without altering the stereochemistry. 2. CH3 CO2H 1800 H OH HO H R R CH3 CO2H CO2H H 900 H OH H3C CO2H R S CH3 OH ◼22 3. Hold one group stationary and rotate the other three groups either clockwise or counterclockwise. CO2H H H OH HO CO2H R R CH3 CH3 hold same as original – allowed motion ◼23  (R) and (S) Nomenclature Example: Given that the condensed structural formula for alanine is NH2CH(CH3)CO2H, draw (R)-alanine and (S)-alanine. ◼24 Absolute and Relative Configurations ◼25 Fischer-Rosanoff Convention: D and L Before 1951, only relative configurations could be known. Sugars and amino acids with same relative configuration as (+)-glyceraldehyde were assigned D and same as (-)- glyceraldehyde were assigned L. With X-ray crystallography, now know absolute configuration of : D is (R) and L is (S). No relationship to dextro- or levorotatory. ◼26 D and L Assignments CHO H OH CHO * CH2OH H OH D-(+)-glyceraldehyde HO H COOH H OH H2N H => * H * OH CH2CH2COOH CH2OH L-(+)-glutamic acid D-(+)-glucose ◼27 Chirality 28 ◼ Two or More Chiral Carbons 29 ◼ Two chiral carbons. What are their designations? 2 CO H 2 R S 1 * H on horizontal line 4 H NH2 2 must be on Vertical line 3 1 HO * H4 R S CH3 3 (2R,3S)-2-amino-3-hydroxybutanoic acids ◼30  Calculation of Number of Stereoisomers Maximum number is n 2, where n = the number of chiral carbons. => 31 ◼  Number of Stereogenic Centers in a Molecule Larger organic molecules can have two, three or even hundreds of stereogenic centers. 32 ◼ Molecules with Multiple Stereocenters More stereocenters = more stereoisomers possible One stereocenter OH Ibuprofen * R or S analgesic Two stereoisomers O OH O Two stereocenters Ascorbic acid O * * R,R; R,S; S,R; S,S vitamin C OH Four stereoisomers HO OH HO OH Three stereocenters O Deoxyribofuranose Eight stereoisomers * * in DNA * OH ◼ 33 Elements of Symmetry 34 ◼  Elements of Symmetry Chirality handedness not superposable on its mirror image symmetry = superposable types: plane imaginary plane through an object one half is the mirror image of the other center identical parts on an axis equidistant from a point 35 ◼  Elements of Symmetry Conformations of 2,3-butanediol* syn - plane of symmetry anti - point of symmetry H OH CH3 C C H CH3 H3 C. CH3 HO. C H C HO HO H If symmetry is present, the substance is achiral. *meso or R,S (later) 36 ◼  Elements of Symmetry Examples of molecules with presence of plane of symmetry If symmetry is present, the substance is achiral. 37 ◼ *meso or R,S (later)  Elements of Symmetry Examples of molecules with presence of center of symmetry If symmetry is present, the substance is achiral. *meso or R,S (later) 38 ◼ Chiral compounds with no chiral carbon  Allenes Contains sp hybridized carbon with adjacent double bonds: -C=C=C-  Allenes is achiral End carbons have not different groups.  Allenes is a chiral End carbons have different groups. H H H H C C C C C C Cl Cl CH3 CH3  Allenes is a chiral End carbons must have different groups. Biphenyl System =>  Biphenyl System If the conformer is sterically hindered, it may exist as enantiomers. => Spiro Compounds => Enantiomers, Diastereomers And Meso- Compounds 47 ◼  Enantiomers One of a pair of molecular species that are mirror images of each other and not superposable. They are mirror-image stereoisomers. CH3 CH3 H Cl Cl H Cl H H Cl CH3 CH3 48 ◼  Enantiomers nonsuperimposable mirror-image molecules 49 ◼  Physical Properties of Stereoisomers Enantiomers have identical physical properties, except for how they interact with plane-polarized light. Plane-polarized (polarized) light is light that has an electric vector that oscillates in a single plane. Plane- polarized light arises from passing ordinary light through a polarizer. A polarimeter is an instrument that allows polarized light to travel through a sample tube containing an organic compound. It permits the measurement of the degree to which an organic compound rotates plane-polarized light. ◼50  Diastereomers Stereoisomers that are not mirror images. Geometric isomers (cis-trans) Molecules with 2 or more chiral carbons. H H H CH3 C C C C H3C CH3 H3C H cis-2-butene trans-2-butene 51 ◼  Enantiomers & Diastereomers 52 ◼  COOH COOH H C OH HO C H Enantiomers: identical HO C H H C OH physical and chemical COOH COOH properties in achiral environments COOH COOH HO C H HO C H Diastereomers: different HO C H H C OH compounds different physical COOH COOH and chemical properties 53 ◼  Meso Compounds A meso compound is an achiral compound that contains tetrahedral stereogenic centers. All meso compounds contain a plane of symmetry. Compound C has two stereogenic centers but it contains a plane of symmetry, and is achiral; C is a meso compound. 54 ◼ Meso Compounds 55 ◼ 56 1 FIVE–MEMBERED RINGS 2  FIVE – MEMBERED RINGS Containing one Heteroatom 3  Structure Synthesis Reactions ELECTROPHILIC AROMATIC SUBSTITUTION 4 In this lecture 5  FORMYLATION REACTIONS Reimer-Tiemann Reaction : O CHCl3 + KOH Cl + N (: CCl2) N C H + H H N 6  FORMYLATION REACTIONS Reimer-Tiemann Reaction Mechanism: Cl -H -Cl CHCl 3 + KOH C Cl CCl 2 Cl Dichlorocarbene b CCl 2 Cl route (a) Cl b a a KOH Cl N - Cl N H N b a route (b) Cl Cl KOH C OH N Cl CH CH H N N Cl OH -H2O +H CHO CHO N N H 7  FORMYLATION REACTIONS Vilsmeier Reaction It is a generally applicable reaction, which provides the most effective way of introducing a formyl group. 8  FORMYLATION REACTIONS Vilsmeier Reaction It can be used with pyrrole it self, as the reagent does not cause polymerization. 9  REDUCTION Catalytic hydrogenation converts pyrrole and furan into the corresponding saturated heterocycles, pyrrolidine and tetrahydrofuran. 10  REDUCTION Clean reduction of thiophene to tetrahyfrothiophene is difficult to achieve catalytically because of the tendency of sulfur compounds to poison catalysts. Tetrahyrothiophene is synthesized instead from open- chain compounds. 11 DERIVATIVES OF PYRROLE, FURAN, AND THIOPHENE 12  DERIVATIVES OF PYRROLE, FURAN, AND THIOPHENE The aldehydic function of furan and thiophene behave normally in the sense that they undergo all the carbonyl reactions of benzenoid aldehydes. However the aldehydic function in pyrrole-2-aldehyde is less reactive than those of furfural and thiophen-2-aldehyde due to the strong +M effect of the heteronitrogen atom which decrease the positivity of the carbonyl carbon. 13  FURFURAL It is one of the most important derivatives of furan. A number of 5-nitrofurfural derivatives are important chemotherapeutic agents, nitofurazone, a bactericide, being a simple example. 14  FURFURAL SYNTHESIS Furfural is commercially manufactured from xylose, by acid catalysis (e.g. H2SO4) the overall loss of three moles of water from D-xylose in very good yield. 15  FURFURAL REACTIONS it can readily be reduced to the alcohol (Furfuryl alcohol) or oxidized to the acid (Furoic acid), is a key starting material for many furan syntheses. 2-Furfuryl alcohol 2-Furoic acid 16 Canizzaro's Reaction PERKIN CONDENSATION 3-(furan-2-yl)acrylic acid 17 BENZOIN_LIKE CONDENSATION: DECARBONYLATION: 18 FUSED 5- MEMBER HETEROCYCLIC COMPOUNDS 19  b c X a X a X= b Indole N Isoindole Benzo[b]thiophene S Benzo[c]thiophene Benzo[b]furan Benzo[c]furan O 20 neurotransmitter 21 22 INDOLE 23  Synthesis of indole A protic acid or a Lewis acid can be used to promote the reaction 24  Synthesis of indole -H2O H3C Ph ZnCl 2 + N NH2 N Ph N H N H COCH 3 H H 25 Fischer indole Synthesis Mechanism 26  GENERAL DISCUSSION AND A COMPARISON WITH PYRROLE BASIC PROPERTIES (Indole is an extremely weak base) Due to a lone pair on the indole nitrogen are part of the π cloud X X X X X X X X X X X X X X 27  Reactions Indole resembles pyrrole. It is basic and gives electrophilic substitution reactions, such as: nitration, sulphonation and halogenation in 3- position, this position has high electron density. The intermediate is more established in this position than the 2- position. 28 electrophilic substitution reactions at 3- position is more established than the 2- position, Why???? E E E E N H N N H H C2-Attak H H H I II III N less stable due to the aromatic sexet is destroyed in II & III i.e there are two less stable quinonoic rings H C3-Attak E E E H H N N H H more stable due to the aromatic sexet is preserved (Indoium cation) i.e benzonoid ring more stable 29 30 Nitration Sulphonation 31 N.B Acylation occurs at C before N because the N-acylated product does not react 32  Mannich Reaction A very useful reaction for the synthesis of 3-substituted indoles. The product (gramine) can be used to access a variety of other 3- substituted indoles Synthesis of Tryptophan from Gramine sodium acetamido bis(ethoxycarbonyl) methanide 33  BENZOFURANS AND BENZOTHIOPHENES 34  BENZOFURANS AND BENZOTHIOPHENES A Comparison of the rates of electrophilic substitution in the pairs furan / benzofuran and thiophene / benzothiophene shows that the effect of the annulation of a ring is to reduce the over all reactivity. 35 THE OVERALL PICTURE CAN BE SUMMARIZED Benzothiophene 36 37 Discussions 38 Anti-viral and anti-cancer Drugs Containing an pyrrole Containing an furan Containing an thiophene Containing an Indole Containing an Benzofuran Containing an Benzothiophene Published In last 10 years 39 40 1  Nomenclature of Fused Heterocyles Prefix + o [side of fusion] suffix (parent ring) Base Attached [Number, Number.- Letter ] component component Numbering of the complete fused system. 2 RENUMBER THE COMPLETE FUSED SYSTEM Order of Het. atom Order of Het. atom 1, 3, 4, 6, 7 1, 2, 4, 5, 7 Highest prior Order of Het. atom Het. Atom O, …. 1, 3, 4, 5, 7 lowest locant of Fused C 4’ Saturated H 3’ 3  The Following Exceptions Furan Furyl Quinoline Quinolyl Piperidine Pipreridyl Pyridine Pyridyl Thiophene Thienyl 4  IUPAC Nomenclature of Radicals Derived from Heterocycles The are named by remove e from heterocycles name and adding yl; prefixed by a number to indicate position of attachment EX 5 Homework Exercise 6  Common: 9H-Carbazole Common: 9H-purine 5H-Benzo[b]indole 3H-imidazolo[4,5-d]pyrimidine 5,7-dihydrothieno[3,4-d]pyridazine benzo[h]isoquinoline 7 In this lecture FIVE – MEMBERED RINGS 9  FIVE – MEMBERED RINGS Containing one Heteroatom 10  Five – MEMBERED RINGS Containing more than one heteroatom 11  is an amino acid. Amino acids are the building blocks of protein in our bodies N O2N N CH3 OH Metronidazole - Flagyl®, Protostat®, Metro IV® 12 Structure 13 Aromatic Five-Membered Heterocycles 14 15 16 Relative resonance energies of some aromatic compounds The resonance stabilization energies calculated form heats of combustion are: pyrrole 21 kcal/mole; and furan 16 kcal/mole; thiophene 29 kcal/mole. These values are considerably smaller than the resonance stabilization energy of benzene which is 36 kcal/mole. Thus pyrrole, furan and thiophene give electrophilic aromatic substitution reactions much more readily than benzene, the Aromaticity order being: Benzene, Thiophene, Pyrrole, and Furan 17 Synthesis 18 Poal – Knorr Sythesis A general way to synthesize heterocyclic compounds is by cyclization of a dicarbonyl compound using a nucleophilic reagent that introduces the desired heteroatom or atoms. P2O5 R R -H2O O P2S5 R R R R O O S R= CH3 Acetonyl acetone NH3 R R N H 19 20 Reactions 21  Unusual Reactivity ◼ Pyrrole, furan, and thiophene are conjugated dienes but they undergo electrophilic substitution (rather than addition) ◼ Pyrrole is an amine but it is not basic 22  Diene Characters (Diels-Alder Reaction) Furan only could be considered as a diene, which react with dienophiles to form addition product (Adduct) via (4+2) cycloaddtion O O O O O O O + 90% H O H 23 Diene Characters (Diels-Alder Reaction) 24  Basic Properties Pyrrole is an extremely weak base, Why? 1. The (+) M effect of its nitrogen atom that lead to formation of positive charge at this nitrogen atom. This will facilitates the expulsion of hydrogen as a proton. 2. The nitrogen in pyrrole is SP2 hybridized and is, therefore, more electronegative than the SP3 nitrogen of a saturated amine e.g. pyrrolidine. 3. Pyrrole's acidity also is increased as a result of its conjugate base being stabilized by electron delocalization 25  The Reaction of Mineral Acids The reaction of mineral acids with pyrrole or furan will lead to protonation at the heteroatom or mainly at C2 or C3 positions. This will lead to production of non-aromatic cation. This cation reacts easily as an electrophile and added to another non-protonated molecule leading to dimerization and polymerization. 26 Why the protonation of Pyrrole is taking place mainly at C2 ? 2H-pyrrolium cation the most 3H-pyrrolium cation stable 1H-pyrrolium cation But 27 some reactions that indicate the acidity of pyrrole and their synthetic applications 28  ELECTROPHILIC AROMATIC SUBSTITUTION 29  Relative reactivity towards electrophilic aromatic compounds ▪ +M effect of the heteroatom facilities attack of electrophiles at the ring carbons ▪ High electron density: Distribution of 6 π electrons on 5 atoms. ▪ The stability of δ complex. Since the lone pair on heteroatom can donate electrons into the ring by resonance 30  Rearrange the following heterocycles (furan, pyrrole and thiophene) more to less reactive towards electrophilic aromatic substitution reaction, Give reasons Pyrrole, Furan, Thiophene ▪ The oxygen of furan is more electronegative than the nitrogen of pyrrole, so the oxygen is not as effective as nitrogen in stabilizing the carbocation intermediate. ▪ Thiophene is less reactive than furan because sulfur's π- electrons are in 3P orbital, which overlaps less effectively than the 2P orbital of nitrogen or oxygen with the 2P orbital of carbon.. 31 ORIENTATION Electrophilic substitution in pyrrole, furan and thiophene The electrophilic substitution is more favored at the α-positions (C-2 & C5) rather than β-position (C-3 &C-4). This is most easily understood in terms of resonance stabilization or delocalization of positive charge in the intermediate cation X = O, NH, or S 32 Substitution in pyrrole. In the case of pyrrole , a structure in which nitrogen bears a positive charge is especially stable since every atom has an octet of electrons ; nitrogen accommodates the positive charge simply by sharing four pairs of electrons. E E E + E N N H N H N H N E H H H H H E E E H H + E N N N N H H H H 33 Nitration 34 Sulphonation 35 Halogenations 36 Friedel – Craft Acylation 37 Friedel – Craft Acylation 38 39 ‫بسم هللا الرحمن الرحيم‬ ‫‪1‬‬  Heterocyclic Chemistry N Nomenclature of Heterocyclic compounds S O 2  Exercise: 2H,6H-1,5,2-dithiazine 4H-1,2,4-triazole 1H-tetrazole 3  Hantzsch-Widman rules The presence of a carbonyl group is indicated by a suffix one and its position by a number, e.g. 4 In This Lecture 5  Nomenclature of Fused Heterocyclic Rings 6  Nomenclature of Fused Systems 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). 7  Nomenclature of Fused Systems ❖ For example : 1H-phenalene is considered as being composed of three benzene rings, each is ortho-peri-fused to the other two. 1H-Phenalene ❖ 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 8 The most important heterocycles having accepted trivial names 9 The most important heterocycles having accepted trivial names 10  Nomenclature of Fused Heterocyles Prefix + o [side of fusion] suffix (parent ring) Base Attached [Number, Number.- Letter ] component component Numbering of the complete fused system. 11  Nomenclature of Fused Heterocyles Benzo from Benzene Furo from Furan Imidazo from Imidazole pyrido from Pyridine Pyrimido from Pyrimidine Thieno from Thiophene Pyridazino from pyridazine Pyrazino from pyrazine Chromeno from chromene 12  Nomenclature of Fused Heterocyles Priority order of component ring systems: ❖ election of a parent component or attached component is based on the following rules which are applied in order A- If heterocyclic and carbocyclic rings are present, the parent ring should be heterocyclic (the greatest ring having accepted trivial name), b 1H-Benzo[b]pyrrole a 13  I-Nomenclature of Fused Heterocyles ❖ Examples 1 3 2 a O c b 2 4 4 3 a 5 b S1 b 5 d a 1 3 2 4 5 N 7 H 6 Benzo[b]furan Benzo[d]thiepine Benzo[b]pyrrole Indole b f 5 e 4 2 4a d c 3 b 2 a 1 6 3 a 1 N b c S 7 1 a 2 8a 4 Benzo[b]pyidine 8 N 5 Qunioline Benzo[f]qunioline Benzo[c]thiophene 14  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa ,Selena, thia, ….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 15  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > thia > aza, …… (first listed in table 1) 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) 16  Nomenclature of Fused Heterocyles Priority order of component ring systems: B- If both parent and fused rings are heterocyclic, the parent ring should be by order of preferences: 1- Nitrogen-containing ring parent ring b c a pyrazole [side of fusion] [2,3-c] Attached component pyrano pyrano[2,3-c]pyrazole 17 Nomenclature of Fused Heterocyles N O 5 3 4 1 c N 2 3 a 1 O b 2 Substituent ring Base or parent ring Chromeno because it has N pyrrole Chromeno[2,3-c]pyrrole 18  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 19  Nomenclature of Fused Heterocyles Priority order of component ring systems: 2- A component containing heteroatom (other than N) as high as possible oxa , selena, thia, aza, …… parent ring a furan b [side of fusion] [2,3-b] Attached component Thieno thieno[2,3-b]furan 20  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 21  Nomenclature of Fused Heterocyles Priority order of component ring systems: 3- A component containing the greatest number or rings (provided it has trivial name), c b parent ring a Carbazole [side of fusion] [2,3-c] Attached component pyrazino 7H-pyrazino[2,3-c]carbazole 22  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 23  Nomenclature of Fused Heterocyles Priority order of component ring systems: 4- A component containing the largest possible individual ring parent ring a pyridine [side of fusion] [4,3-a] Attached component [1,2,4]-triazolo [1,2,4]-triazolo[4,3-a]pyridine 24  Nomenclature of Fused Heterocyles A heterocyclic component containing the largest possible individual ring O Indicated H 1 2 b 3 a O 2H-Furo[3,2-b]pyran (pyran preferred to furan ) Numbering the whole system is started from O in furan ring to give the two heteroatoms locants 1,4 while starting from O in pyran ring gives them locants 1,5, thus the indicated H takes locant 2 25  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 26  Nomenclature of Fused Heterocyles Priority order of component ring systems: 5- A component containing the greatest number of heteroatoms, or greatest variety of heteroatoms b parent ring c d pyrimidine a [side of fusion] [2,3-d] Attached component pyrido pyrido[2,3-d]pyrimidine 27  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 28  Nomenclature of Fused Heterocyles Priority order of component ring systems: 6- A component containing the greatest number of heteroatoms first listed (oxa , selena, thia, aza, …… parent ring a thiazole b [side of fusion] [2,1-b] Attached component imidazolo imidazo[2,1-b]thiazole 29 NOMENCLATURE OF FUSED HETEROCYCLES S 1 N c 5 2 b d 4 3 a N O [1,3]Thiazolo[5,4-d][1,3]oxazole (N & O preferred to N & S) 30  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. Is there No, Nitrogen. Other heteroatoms? (YES:. Choose the base component, oxa , Selena, thia, aza….. 3. Are the component containing the greatest number of rings? (Yes: choose larger one (consists of two or more rings) has trivial name 4. Are the component have different rings size? (YES: choose the largest one (the largest possible individual ring) 5. Are the component containing the greatest number or variety of heteroatoms ? (Yes: choose it) 6. Are the two rings of the same size and the same number of different heteroatoms? (Yes: choose oxa > Selena > thia > aza, …… (first listed in table 1) 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) 31  Nomenclature of Fused Heterocyles Priority order of component ring systems: 7- If both components have the same size, the same number and kind of heteroatoms, the parent ring is one with lower numbers for heteroatoms before fusion b parent ring c d pyrimidine a [side of fusion] [2,3-d] Attached component pyrazino pyrazino[2,3-d]pyrimidine pteridine 32 RENUMBER THE COMPLETE FUSED SYSTEM (Numbering substituents on fused rings) 33  RENUMBER THE COMPLETE FUSED SYSTEM Numbering substituents on fused rings 1. Use rectangular coordinates. 2. As many rings as possible lie in a horizontal row 3. A maximum number of rings are in the upper right quadrant 34  RENUMBER THE COMPLETE FUSED SYSTEM Numbering substituents on fused rings 4. The system is numbered in a clockwise direction commencing with that atom which is not engaged in the ring fusion and is furthest to the left: in the uppermost ring or in the ring furthest to the right in the upper row 5. C atoms which belong to more than one ring are omitted 6. Heteroatoms in such positions are, however, included 7 7 1 1 2 6 2 6 3 5 5 4 4 3 2,7-dimethyl-2,3-dihydrofuro[2,3-c]pyridine 35 RENUMBER THE COMPLETE FUSED SYSTEM Order of Het. atom Order of Het. atom 1, 3, 4, 6, 7 1, 2, 4, 5, 7 Highest prior Order of Het. atom Het. Atom O, …. 1, 3, 4, 5, 7 lowest locant of Fused C 4’ Saturated H 3’ 36  RENUMBER THE COMPLETE FUSED SYSTEM Numbering substituents on fused rings 7. If there are several possible orientations in the coordinate system, a) the one in which the heteroatoms bear the lowest locants is valid,,,,,, b) or the one in which the C atom that belongs to more than one ring has the lowest locant 8 1 8 1 N N 7 N N 2 7 2 a)))) not N N 3 N 3 N 6 6 4 5 5 4 7 1 1 7 N N N b)))) 6 N 2 2 not 6 5 3 3' 3 5 4' 4 4 37  RENUMBER THE COMPLETE FUSED SYSTEM Numbering substituents on fused rings 7. If there are several possible orientations in the coordinate system, a) the one in which the heteroatoms bear the lowest locants is valid,,,,,, b) or the one in which the C atom that belongs to more than one ring has the lowest locant 38 Order of preference between alternative numbering system of the whole molecule ◼ Numbering the whole fused system should start from the first atom after fusion in any direction to fulfill the following rules in order: a) Give low numbers for the heteroatoms as a set H 6 N1 4 H3 H 4 N 3 N 2 2 5 5 2 5 O N 3 O N O N 4 1 6 6 1 1H-Furo[2,3-d]imidazole 6 1 (heteroatoms 1,3,4 is preferred to 1,3,6 or 1,4,6) S O 5 2 b) Give low numbers for heteroatoms of higher priority i.e. O, Se, S, N, P 4 3 4,5-Dihydro-thieno[2,3-b]furan 39  Order of preference between alternative numbering system of the whole molecule b) Give low 1 4 5 3 N numbers to 7 8 N 6 5 N 4 6 N 2 N 3 N fusion Not 7 2 6 Not carbon 3 2 N 8a N 7 N 4a N 8a atoms 5 N 4 8 N 1 8 1 Imidazo[1,2-b][1,2,4]triazine fusion C -4a is preferred to 8a 6 1 4 3 c) Give low N O N O 2  5 numbers to  Not  5 2 indicated 4N H O N O 3 H hydrogen 6 1 2H,4H-[1,3]dioxol[4,5-d]imidazole atom Indicated hydrogens 2,4 not 2,6 40 Exercise 41  NOMENCLATURE OF FUSED HETEROCYCLES b c N N 1 2 a d 3 N N Pyrazino[2,3-d]pyridazine (pyridazine [2N-1,2] preferred to pyrazine [2N-1,4] 1 O 6 1 5 2 2 b 3 4 5 S a 3 N H 4H-[1,3]oxathiolo[4,5-b]pyrrole 4 42  Nomenclature of Fused Heterocyles 1 8 N 8a 1 2 7N b c 2 a d 3 6 O 3 4a 5 4 5H-Pyrido[2,3-d][1,2]oxazine (Oxazine preferred to pyridine) N.B. to give the three heteratoms the lowest locants (1,6,7), however, stating from oxazine ring will give them locants (2,3,5) or (2,3,8). 43  NOMENCLATURE OF FUSED HETEROCYCLES N.B. The whole molecule is numbered starting from pyrazole ring to give the four heteratoms the lowest locants (1,2,4,6). While starting from oxazole ring give them locants (1,3,4,5) or (1,3,5,6). 44 NOMENCLATURE OF FUSED HETEROCYCLES 7 7 1 1 2 6 2 6 3 5 5 4 4 3 2,7-dimethyl-2,3-dihydrofuro[2,3-c]pyridine 45 45 IUPAC Nomenclature of Radicals Derived from Heterocycles 46  IUPAC Nomenclature of Radicals Derived from Heterocycles The are named by remove e from heterocycles name and adding yl; prefixed by a number to indicate position of attachment 47  The Following Exceptions Furan Furyl Quinoline Quinolyl Piperidine Pipreridyl Pyridine Pyridyl Thiophene Thienyl 48  IUPAC Nomenclature of Radicals Derived from Heterocycles The are named by remove e from heterocycles name and adding yl; prefixed by a number to indicate position of attachment Example 49  IUPAC Nomenclature of Radicals Derived from Heterocycles The are named by remove e from heterocycles name and adding yl; prefixed by a number to indicate position of attachment 2-(2-nitroimidazolidin-1-yl) thiazol-5(4H)-one 1-(5-nitrothiazol-2-yl) imidazolidin-2-one 50  IUPAC Nomenclature of Radicals Derived from Heterocycles 2-(2-oxoimidazolidin-1-yl) thiazole-5-carbaldehyde 2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)thiazole-5-carboxylic acid 51  IUPAC Nomenclature of Radicals Derived from Heterocycles 2-(2-oxoimidazolidin-1-yl) thiazole-5-carbaldehyde 2-(2-oxo-2,3-dihydro-1H-imidazol- 1-yl)thiazole-5-carboxylic acid 2-(piperidin-1-yl)-3H-pyrrole-4- carboxylic acid 3-(5-nitrofuran-2- yl)dihydrothiophen-2(3H)-one 52 Homework Exercise 53 ◼ Exercise Name the following compounds 54  NOMENCLATURE OF HETEROCYCLES ◼ Exercise Name the following compounds (a-d): N S H N O S N N N N N (a) (b) (c) (d) 55  IUPAC Nomenclature of Radicals Derived from Heterocycles 2-(2-oxoimidazolidin-1-yl) thiazole-5-carbaldehyde 2-(2-oxo-2,3-dihydro-1H-imidazol- 1-yl)thiazole-5-carboxylic acid 2-(piperidin-1-yl)-3H-pyrrole-4- carboxylic acid 3-(5-nitrofuran-2- yl)dihydrothiophen-2(3H)-one 56 NOMENCLATURE OF HETEROCYCLES 57 58 59  r your at fo t ks en n tio Tha n ! Th s an k ks a n T h 60 1 ◼ 2 Pharmaceutical Organic Chemistry II POC 303 ◼ 3  N S Heterocyclic Chemistry O & Stereochemistry 4  ‫الرؤية‬ Vision The college seeks to be an internationally distinguished institution in the field of pharmacy in order to develop the pharmacy profession and to achieve Egypt’s 2030 vision ◼ 5 ‫الرسالة‬ Mission ◼ 6  ‫الرسالة‬ Mission The College of Pharmacy- Misr University for Science and Technology aims to prepare pharmacists who adhere to the values and ethics of the pharmacy profession and who are able to compete locally and regionally through advanced academic programs that meet the needs of the labor market using modern technological techniques. The college is also keen to support applied scientific research in the fields of drug industry, patient health, provide community services, and achieve effective partnership with the internal and external community for sustainable development. ◼ 7  N S Heterocyclic Chemistry O & Stereochemistry 8  Basic Information Academic level / Semester Level 2 - Semester 1 Course title Pharmaceutical Organic Chemistry II Course code POC 303 Contact hours ( credit hours ) Lecture : 2 ( 2 ) , Practical : 2 (1), Total : 4(3) credit hours Course coordinator ◼ 9  Overall Aims of Course ☑ The aim of the course is to provide students with the fundamental principles of chemistry of heterocyclic compounds with particular reference to heterocycles of biological interest, stereochemistry of organic compounds. ☑ The laboratory work involves purification of organic compounds by different methods. ◼ 10 Competencies, learning outcomes of the course aligned with the learning outcomes of the program DOMAIN-1 FUNDAMENTAL KNOWLEDGE DOMAIN 2: PROFESSIONAL AND ETHICAL PRACTICE DOMAIN 4: PERSONAL PRACTICE ◼ 11 ◼ 12 ◼ 13 ◼ 14 Introduction 15  CHEMISTRY OF HETEROCYCLIC COMPOUNDS WHAT IS MEANT BY HETEROCYCLIC COMPOUNDS (HETEROCYCLES)? ✓ Heterocyclic compounds are cyclic compounds in which one or more of the atoms of the ring are heteroatoms. ✓ A heteroatom is an atom other than carbon. ✓ The name comes from the Greek word "heteros", which means "Different". ✓ The most common heteroatoms are nitrogen, oxygen, or sulfur. 16 Important of heterocyclic Chemistry WHY WE STUDY CHEMISTRY OF HETEROCYCLIC COMPOUNDS? Heterocyclic compounds occur so widely in nature. Heterocycles making up more than half of all known organic compounds, and are of such importance chemically that any discussion of organic chemistry will not get very far without mentioning them. 17  Important of heterocyclic Chemistry WHY WE STUDY CHEMISTRY OF HETEROCYCLIC COMPOUNDS? In the biological world, heterocyclic compounds are every where. Carbohydrates are heterocyclic; so are chlorophyll and heme, which make leaves green and blood red and bring life to plants and animals. Heterocycles form the sites of reaction in many enzymes and coenzymes. Heredity comes down, ultimately, to the particular sequence of attachment of a half-dozen heterocyclic rings to the long chains of nucleic acids. Furthermore, many natural and synthetic drugs are heterocyclic compounds. The chemistry of heterocyclic compounds is such an extensive field that this part of the course is by necessity a highly selective look at some of it. 18  Important of heterocyclic Chemistry Among the most important and interesting heterocycles are the ones that possess aromatic properties; we shall focus our attention on a few of these, and in particular upon their aromatic properties we can get some idea of the importance- as well as complexity – of heterocyclic systems from the following examples. 19 Important of heterocyclic Chemistry ↓ blood level TB of cholesterol anxiety 20  CLASSIFICATION OF HETEROCYCLIC COMPOUNDS 1. According to ring size : The most stable heterocycles are those containing five or six atoms in the ring. 2. According to the type of heteroatoms : the most common heteroatoms are N, O, or S. 3. Monocyclic and condensed or fused ring heterocycles. 4. Aliphatic and aromatic heterocycles. Examples of aromatic heterocycles 21  CLASSIFICATION OF HETEROCYCLIC COMPOUNDS Examples of aliphatic heterocycles 22  Nomenclature of Heterocyclic compounds 23  Nomenclature of heterocyclic compounds ◼ There are three systems for naming heterocylic compounds: 1) The common nomenclature: which convey little or no structural information but it still widely used. 2) The Hantzsch-Widman (IUPAC or Systematic) method which in contrast is designed so that one may deduce from it the structure of the compound. 3) The replacement method 24  I-Common Nomenclature ❖ Each compound is given the corresponding trivial name (which should be memorized, This usually originates from the compounds occurrence, its first preparation or its special properties. ❖ If there is more than one hetroatom of the same type numbering starts at the saturated one, 4 N3 ❖ e.g. imidazole. 5 2 1 N H 25  I-Common Nomenclature If there is more than one type of the heteroatoms, the ring is numbered starting at the hetroatom of the higher priority (O>S>N) and it continues in the direction to give the other hetroatoms the lower numbers as possible. If subsituents present, their Br 4 position should be identified 3 by the number of the atoms 5 N 2 1 bearing them and then they H2N O should be listed in alphabetical order. 5-Amino-4-bromoisoxazole 26  Common Nomenclature ❖ The words dihydro, or trihydro, H or tetrahydro are used if two or N three or four atoms are saturated. These words are preceded by numbers indicate the position of saturated atoms as low as 1,2-Dihydro-pyridine possible and followed by the corresponding fully unsaturated trivial name. 27  Trivial names 1) 5-membered heterocycles with one or two heteroatoms 2) 6-membered heterocycles with one or two heteroatoms Common azines-six-membered aromatic nitorgrn heterocycles N N N O O N N N N 2H-Pyran 4H-Pyran Pyridine Pyridazine Pyrimidine Pyrazine These are tautomers DNA/RNA bases Both are not aromatic 28  Trivial Names 3) Fused heterocycles O N NH N N NH2 Guanine 29  Trivial Names O O O O O O Ph Coumarine Chromen-4-one Flavone Chromen-2-one 8 9 1 5 6 4 7 2 3 7 6 10 3 2 N 8 9 5 4 N 1 H H 9,10-Dihydro-acridine 9H-Carbazole 30  Trivial Names 4) Saturated heterocycles Exercise : Give the common name of the following compounds: N H O N NH H2N N CH3 31  II-Hantzsch-Widman nomenclature (IUPAC) ◼ 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. 32  II-Hantzsch-Widman nomenclature (IUPAC) ◼ 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 33  II-Hantzsch-Widman nomenclature (IUPAC) ◼ appropriate prefix (or prefixes) that denotes the type and position of the heteroatom present in the ring (table 1). Table 1 Atom Prefix O oxa Priority decreases S thia Se selena N aza P phospha 34  Hantzsch-Widman rules Table 2 Ring size N-present N-absent Unsat sat Unsat sat iridine irene irane irine ete etane ete etidine ole olane ole olidine a in ane ine epine a epin epane ocine a ocin ocane 9 onine a onin onane 10 ecine a ecin ecane a: means use the prefix perhydro followed by the fully unsaturated name 35  Hantzsch-Widman rules for fully saturated and fully unsaturated heterocycles 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. 3) A multiplicative prefix (di, tri, etc..) 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, 36  Hantzsch-Widman rules for fully saturated and fully unsaturated heterocycles 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. 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 6) Combine the prefix(s) and suffix together and drop the first vowel if two vowels came together. 37  Hantzsch-Widman rules One Heteroatom H This ring contains (N) Prefix is aza N The ring is 3-membered and fully saturated suffix is iridine Aziridine 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