Pharmaceutical Organic Chemistry - III PDF

 A Text Book of PHARMACEUTICAL ORGANIC CHEMISTRY-III As per PCI Regulations Second Year B. Pharm. Semester – IV Dr. K. G. BOTHARA M. Pharm., Ph.D. Professor in Pharmaceutical Chemistry Sinhgad Institute of Pharmacy...

 A Text Book of PHARMACEUTICAL ORGANIC CHEMISTRY-III As per PCI Regulations Second Year B. Pharm. Semester – IV Dr. K. G. BOTHARA M. Pharm., Ph.D. Professor in Pharmaceutical Chemistry Sinhgad Institute of Pharmacy Narhe, Pune 411 041. N3961 PHARMACEUTICAL ORGANIC CHEMISTRY-III ISBN 978-93-88706-79-7 First Edition : January 2019 © : K. G. Bothara The text of this publication, or any part thereof, should not be reproduced or transmitted in any form or stored in any computer storage system or device for distribution including photocopy, recording, taping or information retrieval system or reproduced on any disc, tape, perforated media or other information storage device etc., without the written permission of Author with whom the rights are reserved. Breach of this condition is liable for legal action. Every effort has been made to avoid errors or omissions in this publication. In spite of this, errors may have crept in. Any mistake, error or discrepancy so noted and shall be brought to our notice shall be taken care of in the next edition. It is notified that neither the publisher nor the author or seller shall be responsible for any damage or loss of action to any one, of any kind, in any manner, therefrom. Published By : Polyplate NIRALI PRAKASHAN Abhyudaya Pragati, 1312, Shivaji Nagar, Off J.M. Road, PUNE – 411005 Tel - (020) 25512336/37/39, Fax - (020) 25511379 Email : [email protected]
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In spite this, errors may have crept in. Any type of error or mistake so noted, and shall be brought to our notice, shall be taken care of in the next edition. It is notified that neither the publisher, nor the author or book seller shall be responsible for any damage or loss of action to any one of any kind, in any manner, therefrom. The reader must cross check all the facts and contents with original Government notification or publications. [email protected] | www.pragationline.com Also find us on www.facebook.com/niralibooks  Preface Organic Chemistry deals with the name of composition of organic matter and more specifically the reasoning for the changes which it undergoes. In the last three decades the ever growing volume and ever changing nature of our understanding about reaction mechanisms are witnessed. Author aims to describe the fundamental principles of organic chemistry with an emphasis on the characteristic reactions of various functional groups. The text is divided into 5 units. Unit 1 and Unit 2 are devoted to isomerism and types of isomerism. Unit 3 and Unit 4 deals with the nomenclature, method of preparation, chemical reactions and uses of heterocyclic compounds. The last unit includes reactions of synthetic importance. However, the wide scope of the subject has necessitated restrictions to keep the size of the book within reasonable limits. I wish to place on record my sincere thanks to the publisher, Shri. D. K. Furia and Shri. Jignesh Furia for their kind co-operation. I am also indebted to my colleagues for giving many valuable suggestions, of which I have been glad to take advantage. Suggestions from all corners of the profession are welcome. Author is responsible for any deficiencies or errors that remain and would be grateful if readers would call them to his attention. Author Pune 1 January, 2019  Syllabus UNIT-I 10 Hours Stereoisomerism Optical isomerism – Optical activity, enantiomerism, diastereoisomerism, meso compounds, Elements of symmetry, chiral and achiral molecules. DL system of nomenclature of optical isomers, sequence rules, RS system of nomenclature of optical isomers Reactions of chiral molecules Racemic modification and resolution of racemic mixture. Asymmetric synthesis: partial and absolute UNIT-II 10 Hours Geometrical isomerism Nomenclature of geometrical isomers (Cis Trans, EZ, Syn Anti systems) Methods of determination of configuration of geometrical isomers. Conformational isomerism in Ethane, n-Butane and Cyclohexane. Stereoisomerism in biphenyl compounds (Atropisomerism) and conditions for optical activity. Stereospecific and stereoselective reactions UNIT-III 10 Hours Heterocyclic Compounds Nomenclature and classification Synthesis, reactions and medicinal uses of following compounds/derivatives Pyrrole, Furan, and Thiophene – Relative aromaticity, and reactivity of pyrrole, furan and thiopene. UNIT-IV 8 Hours Synthesis, reactions and medicinal uses of following compounds/derivatives: Pyrazole, Imidazole, Oxazole and Thiazole. Pyridine, Quinoline, Isoquinoline, Acridine and Indole. Basicity of pyridine, Synthesis and medicinal uses of Pyrimidine, Purine, azepines and their derivatives. UNIT-V 7 Hours Reactions of Synthetic Importance Metal hydride reduction (NaBH4 and LiAlH4), Clemmensen reduction, Birch reduction, Wolff Kishner reduction. Oppenauer-oxidation and Dakin reaction. Beckmanns rearrangement and Schmidt rearrangement. Claisen-Schmidt condensation.   Contents 1. Stereoisomerism 1.1 − 1.24 2. Geometrical Isomerism 2.1 − 2.24 3. Heterocyclic Compounds 3.1 − 3.18 4. Synthesis, Reactions and Medicinal Uses of Heterocycles 4.1 − 4.50 5. Reactions of Synthetic Importance 5.1 − 5.36  Unit...I STEREOISOMERISM ♦ SYNOPSIS ♦ 1.1 Introduction 1.7 Racemic Modification 1.2 Importance of Optical Isomerism 1.7.1 Methods of Racemic Modification 1.3 Diasterioisomerism 1.7.2 Resolution of Racemic Mixture 1.4 Meso Compounds 1.8 Reactions of Chiral Molecules 1.5 Elements of Symmetry 1.9 Asymmetric Synthesis (Partial and 1.6 Nomenclature of Optical Isomers Absolute) 1.6.1 The Cahn Ingold Prelog (CIP) Sequence Rule 1.1 INTRODUCTION Stereochemistry helps to define the structure of a molecule and orientation of the atoms and functional groups present, in three dimensions. Stereoisomers possess the same molecular and structural formulae and the same functional groups but differ in the three- dimensional spatial orientation of these atoms or groups within the molecule. Due to the difference in orientation of the functional group and geometry of the molecule, stereoisomers differ in their physical, chemical, physicochemical and biochemical properties. Based on symmetry and energy criteria, stereoisomers are divided into three classes. (a) Geometrical isomers (b) Optical isomers (c) Conformational isomers. (a) Geometrical isomers (cis-trans isomerism): Maleic acid (m.p. 130°C) and fumaric acid (m.p. 287°C) have the same molecular formula but differ in the arrangement of functional groups around double bond. They have different physical and, to some extent, chemical properties. This type of isomerism is known as geometrical isomerism. HOOC COOH HOOC H C C C C H H H COOH Maleic acid Fumaric acid (cis-butenedioic acid) (trans-butenedioic acid) (1.1) Pharamaceutical Organic Chemistry-III 1.2 Stereoisomerism The presence of a carbon-carbon double bond restricts the freedom of rotation about double bond. The designation cis (Latin word: same side), is used to denote the presence of like atoms or groups on the same side and trans (Latin word, across) is used when they are on opposite sides. Isomerism seen in non-cyclic, open-chain compound due to the presence of a double bond, is called as π diastereoisomerism while when it occurs in a cyclic skeleton lacking a double bond, it is termed as σ diastereoisomerism. (b) Optical Isomerism (enantiomerism): In 1815, Biot found that a number of organic and inorganic compounds in the solution form, have the ability to rotate the plane of polarized light in opposite directions but in identical amplitude, passing through them. Optical isomerism is seen in compounds that can rotate plane polarised light. A carbon atom connected to four chemically different functional groups is known as asymmetric or chiral carbon and the presence of at least one asymmetric carbon atom in the structure is the pre- requirement for a molecule to show optical isomerism. If there is one asymmetric carbon then two optically active isomers are possible. Isomer rotating plane of polarized light to the right is said to be dextrorotatory (Latin, dexter : right) while isomer showing rotation to the left is known as laevorotatory (Latin, laevus : left). Both isomers are mirror images of each other yet are not superimposable. They are called as enantiomers and the pair of enantiomers is called as enantiomorph. An enantiomer does not possess a plane or center of symmetry. For example, CHO CHO | | H — — OH C HO — — H C | | CH2OH CH2OH D-glyceraldehyde L-glyceraldehyde When the enantiomers are present together in equal concentration, the rotation of plane polarized light caused by laevo isomer will be neutralized by a dextro rotating isomer and the mixture will be optically inactive. Such mixtures are called as racemic mixtures. The conversion of an enantiomer into a racemic form is called as racemization. While the separation of racemic mixture into individual enantiomers is called as resolution. The maximum number of optically active isomers possible for a molecule having more than one asymmetric carbon atoms may be given by the formula N = 2n where, N = Number of optically active isomers, and n = Number of asymmetric carbon atoms. With the exception of rotation of plane-polarised light, enantiomers have identical physical and chemical properties like boiling point, melting point, solubility. Their chemical properties are same towards achiral reagents, solvents and conditions. Towards chiral reagents, solvents and catalysts, enantiomers react at different rates. Pharamaceutical Organic Chemistry-III 1.3 Stereoisomerism As per the rule given above, tartaric acid will have four optically active forms because of the presence of two asymmetric carbon atoms. COOH COOH COOH COOH | | | | HO − C − H H − C − OH H − C − OH HO − C − H | | | | HO − C − H H − C − OH HO − C − H H − C − OH | | | | COOH COOH COOH COOH (I) (II) (III) (IV) Forms (I) and (II) are identical and symmetrical. In these forms, the upper half is the mirror image of the lower half. This makes the molecule optically inactive through internal compensation. Such identical and symmetrical stereoisomers are called as meso-isomers. Forms (III) and (IV) are mirror images of each other but are not superimposable. They are enantiomeric forms. While if you compare (III) with (I) or (IV) with (I), these are not enantiomeric pairs. They are neither mirror images nor superimposable. Only one of the two halves of their molecules are identical while the remaining halves are mirror images. Such stereoisomers which are not mirror images and are non-superimposable are called as diastereomers. They have different physical and chemical properties, with both achiral and chiral reagents. The rates are different and the product may be different. 1.2 IMPORTANCE OF OPTICAL ISOMERISM Nearly all naturally occurring substances having asymmetric carbon atoms are in either the d or the l form rather than as racemic mixtures. In drugs and pharmaceuticals, most of the adverse effects and low potency may be related to the utilization of the drug in the form of its racemic mixture. Since, enantiomer in its pure form, is more active and selective, there is now an increasing interest to present the drug in the market in its active enantiomeric form instead of its racemic form. Optical isomerism has also been successfully utilized in elucidating the mechanism of many chemical reactions. The enantiomer that rotates a beam of polarised light in the clockwise direction is indicated by the prefix (+), formerly d (+) or dextro (–), the other enantiomer rotates light in a counter clockwise direction and is indicated by the prefix (–), formerly l(–) or levo. They have identical chemical and physical properties in an achiral environment but form different products when reacted with other chiral molecules and exhibit optical activity. 1.3 DIASTERIOISOMERISM Stereoisomers with two or more asymmetric or chiral carbons (stereocenter) will show diasterioisomerism. The stereoisomers that are neither mirror images of one another nor are superimposable, are known as diasterioisomers. Pharamaceutical Organic Chemistry-III 1.4 Stereoisomerism For example: Each stereocenter gives to two different configurations. It means if a molecule contains two asymmetric carbons, there are upto four possible conformations. When two diastereoisomers differ from each other at only one stereocenter they are known as epimers. e.g., D-threose and D-erythrose are epimers of each other. Unlike enantiomers, diastereoisomers have different physical and chemical properties. In case of 3-bromo-2-butanol, we have four possible combinations as SS, RR, SR and RS. Out of these, two molecules SS and RR are enantiomers of each other while the configurations RS and SR are diastereomers of SS and RR configurations. Thus in diastereoisomers, the chemical formula and atom connectivity remain the same but the three dimensional orientation or shape of the molecule is different e.g., 2-bromo-3- chloro ethane. Pharamaceutical Organic Chemistry-III 1.5 Stereoisomerism The molecules are different in the configuration of chlorine atoms but same with the bromine atoms hence they are diastereomers. Similarly in cyclic compound 3-ethyl-1- chlorocyclohexane, ethyl groups have same configuration but the chlorine atoms have opposite configuration. Hence, these molecules are diastereomers. Configurations differ at some stereocenters but not at others can not create mirror images. So they are not enantiomers, but are diastereomers. The dihydrotestosterone molecule contains seven stereocenters. Applying 2N rule, gives 128 possible configurations. Out of these, only one is enantiomeric pair while rest are diastereomers. 1.4 MESO COMPOUNDS When multiple stereocenters present in a molecule create an internal plane of symmetry, it leads to meso compounds. Tartaric acid contains two asymmetric centers which give rise to four configurations. But there are really only three stereoisomers of tartaric acid: a pair of chiral molecules (enantionmers of each other) and the achiral meso compound. In meso compound, we have internal mirror plane that splits the molecule into two symmetrical sides, the stereochemistry of both left and right side should be opposite to each other. This leads to auto cancellation of stereo activity of each other resulting into optical inactivity. Hence, meso compounds can not be assigned with either dextrorotatory (+) or levorotatory (–) designation. The internal mirror plane is simply a line of symmetry that bisects the molecule. Each half is a mirror image of the other half. Each half must contain a stereocenter in order to be a meso compound. These stereocenters must also have different absolute Pharamaceutical Organic Chemistry-III 1.6 Stereoisomerism configurations. Due to internal symmetry, they meso molecule is achiral. Hence, this configuration is not optically active. The meso form is also a type of diastereomer. The remaining two isomers are enantiomeric pair (D-and L-form). The melting point of both enantiomers of tartaric acid is about 170°C while the meso- tartaric acid has the melting point of 145°C. A meso compound is 'superimposable' on its mirror image. Examples in cyclic meso compounds include. In summary a meso compound should have two or more stereocenters, an internal symmetry plane and the stereochemistry should be R and S. Table 1.1: Difference between enantiomer and diasteromers Sr. No. Parameter Enantiomer Diastereomer 1. Number of stereocenters One Two or more 2. Mirror images Yes No 3. Superimposition No No 4. Physical properties Same Different 5. Chemical properties Same Different 1.5 ELEMENTS OF SYMMETRY A chiral object is not identical (i.e. non-superimposable) in all respects. An achiral object is identical (hence superimposable) with its mirror image. Chiral objects have a "handedness". Like gloves or shoes, chiral objects come in pairs, a right and a left. Achiral objects do not have a handedness just like a plain round ball. Thus, chirality of an object is related to its symmetry. Certain symmetry elements like a point, a line or a plane may be useful to check the symmetry of the molecule. The rotation or reflection around the symmetry element leaves the object in an orientation indistinguishable from the original. Reflection means the coincidence of atoms on one side of the plane with corresponding atoms on the other side, as though reflected in a mirror. Pharamaceutical Organic Chemistry-III 1.7 Stereoisomerism (i) Point of symmetry: In a chiral molecule, (E)-1,2,-dichloroethene, two lines drawn passing through point of symmetry ensure the same structural features at the opposite lines. Similarly the boat conformation of cyclohexane has two intersecting planes of symmetry (σ). A plane of symmetry divides the object in such a way that the points on one side of the plane are equivalent to the points on the other sides by reflection through the plane. The existence of a reflective symmetry (a point or plane of symmetry) indirectly proves the molecule is achiral. Chiral molecules however may have rotational symmetry axes and do not have any reflective symmetry elements. Table 1.2: Examples of rotational axis (360º/n) in the molecules Type n Angle Rotation Example C2 2 180° E isomers C3 3 120° Boron trifluoride C4 4 90° Cyclobutane C5 5 72° Cyclopentane C6 6 60° Benzene C∞ ∞ 0-360° Linear molecules O=C=C e.g. CO2, Acetylene HC ≡ CH Pharamaceutical Organic Chemistry-III 1.8 Stereoisomerism Table 1.3: Terms commonly used Sr. No. Terms Symbol 1. Plane of symmetry δ 2. Center or point of symmetry i 3. Rotational axis where the degrees of rotation that restore the Cn object is 360/n (C2 = 180° rotation; C3 = 120° rotation; C4 = 90° rotation; C5 = 72° rotation; At C1 = (i.e. 360° rotation), the molecule returns to its original orientation 4. Only a single plane of symmetry Cs 5. Only a single point of symmetry Ci 6. Vertical plan v Horizontal plan h Diagonal plane d Examples: (1) Methane: It is an example of a high symmetry molecule having 4 C3 axes, 3 C2 axes and 6 σ (planes). It belongs to the tetrahedral point group Td. It is achiral. (2) Cis-1,2-dichloroethane: This structure has two orthogonal planes of symmetry and C2 axis at their intersection. It is achiral. (3) Trans-1,2-dichloroethane: This structure has a plane of symmetry, an orthogonal C2 axis and a point of symmetry at their intersection. It is achiral. (4) Trans-1,2-dimethylcyclopropane: This structure has only a single C2 axis. It is a dissymmetric and chiral. (5) Cyclohexane (boat conformation): It has a C2 axis and two planes of symmetry. It is achiral. (6) Cyclohexane (chair conformation): It has planes, axes and a point of symmetry. The principle axis is C3. (ii) Plane of symmetry: A molecule with a zero strereocenters is always achiral. A molecule with odd number of stereoisomers (1, 3, 5 etc.) will always be chiral. A molecule with even number of sterocenters may be chiral or achiral due to meso compounds. Beside this planes of symmetry and inversion centers are the parameter to determine chirality of a molecule. Planes of symmetry are usually easier to identify than inversion centers. Pharamaceutical Organic Chemistry-III 1.9 Stereoisomerism Plane that cuts the molecule in half to get same things on both sides is known as plane of symmetry. It can be either perpendicular to the plane or within the plane. A molecule having a plane of symmetry in any conformation is usually achiral. (iii) Inversion center: The molecule (a) has a plane of symmetry through the central carbon. This is a mirror plane where one half of the molecule is a perfect reflection of the other half of the molecule. This molecule is achiral. The molecule (b) has a center of symmetry or an inversion center. An inversion center is a point in the molecule (may or may not be an atom) through which all other atoms can converted through 180° into another identical part. The molecule is achiral because of inversion center. 1.6 NOMENCLATURE OF OPTICAL ISOMERS The d/l system was developed by Fischer and Rosanoff in around 1900. Totally arbitrarily, (+) glyceraldehyde was defined as being D because the OH group attached to the C2 is on the right hand side of the molecule. While (–) glyceraldehyde was defined as L because the OH group is on the left hand side. Pharamaceutical Organic Chemistry-III 1.10 Stereoisomerism (1) The d/l system (named after Latin dexter and laevus, right and left) names the molecule by relating them to the molecule glyceraldehyde. This system of nomenclature represents an older system for distinguishing enantiomers of amino acids and carbohydrates. This arbitrary type of configuration (d/l system) is known as Relative Configuration. (a) To name complex amino acids and carbohydrates in Fischer projection, take carbonyl group (aldehyde, ketone or carboxylic acid) on the top and CH2OH on the bottom. (b) The D descriptor is used when the –OH or –NH2 on the 2nd carbon (from bottom) points to the right and L is used when the –OH or –NH2 points to the left. Thus, from stereochemistry of only one stereocenter (i.e. 2nd carbon from bottom) the stereochemistry of all other stereocenters in the molecule is defined. (c) The d/l nomenclature does not indicate which enantiomer is dextrorotatory and which is levoratatory. It just says that the compound’s stereochemistry is related to that of dextro - or levo - enantiomer of glyceraldehyde. For example, d-fructose is levorotatory. Hence, it is stated that all natural amino acids are L while natural carbohydrates are D. Thus, (+) glucose has the D-configuration and (+) ribose has the L-configuration. 1.6.1 The Cahn Ingold Prelog (CIP) Sequence Rule An absolute configuration refers to the spatial arrangement of the atoms of the chiral molecules and its stereochemical description using terms (R) or (S). Cahn, Ingold and Prelog introduce Sequence Rules to assign an order of priority to the atoms or the groups directly attached to a stereocenter. The absolute configuration of a given stereocenter is defined as either (R) or (S) by applying these rules. Rule 1: Atom of higher atomic number is given priority over those of lower atomic number e.g., I > Br > Cl > F >O > N > C > H. Rule 2: Isotope of higher atomic weight takes precedence. e.g., 3 H (tritium) > 2H (deuterium) > 1H (hydrogen) Rule 3: When two or more atoms directly attached to a stereocenter are same, the order of priority depends on the next atom along the chain. e.g., –CO2CH3 > –CO2H > CONH2 > COCH3 > CHO > CH2OH Pharamaceutical Organic Chemistry-III 1.11 Stereoisomerism Rule 4: If an atom is double bonded to another atom, treat it as if it were singly bonded to two of those atoms. If an atom is triply bonded to another atom, treat it as if it were singly bonded to three of these atoms. Convert the unsaturated group directly attached to the stereocenter into saturated group to decide order of priority e.g., Applying above sequence rules, assign the numbers to the functional groups as per order of priority. Draw a generic tetrahedral center and view the molecule so that the atom/group with lowest priority should project maximum away in space. A clockwise decreasing order is assigned the (R) - configuration while an anti-clockwise decreasing order is assigned the (S)-configuration. Examples: 1. As per sequence rule, the order of priority of the groups is OH > CHO > CH2OH > H 2. As per sequence rule, the order of priority of the groups is NH2 > CO2H > CH2OH > H Rule 5: A longer group may not necessarily have a higher priority over another smaller group. e.g. –CH2Cl has a higher priority than –CH2CH2CH2CH3. Rule 6: If a lowest priority group is in the front of the plane of the molecule then the assignment is reversed. i.e., clockwise is S and anticlockwise is R. Pharamaceutical Organic Chemistry-III 1.12 Stereoisomerism Rule 7: If there are multiple chiral carbons in a molecule, the configuration of entire molecule can be defined by using number that specifies the location of the stereocenter preceding configuration e.g., (1R, 4S). e.g., 1.7 RACEMIC MODIFICATION A racemic modification or racemate is a 1 : 1 mixture of (+) and (–) enantiomers. When enantiomers are mixed together in equal amount, the rotation caused by a molecule of one isomer is exactly cancelled by an equal and opposite rotation caused by a molecule of its enantiomer. Hence, the overall optical rotation of racemate is zero. A racemic modification is thus optically inactive. The prefix (±) is used to denote the racemic nature of the sample. e.g., (±)-2-methyl-1-butanol. When one of the starting material is chiral, the product of the reaction will always be formed as a racemate in the absence of chiral catalyst. However, biologically active pure enantiomer can be synthesized in the presence of chiral catalysts or agents. 1.7.1 Methods of Racemic Modification (a) Mixing: A racemic modification may be achieved by an intimate mixing of exactly equal amounts of dextro (+) and levo (–) isomers. (b) Chemical synthesis: When one of the starting material is chiral the product of reaction will always be formed as a racemate in the absence of chiral catalyst. e.g., when hydrogen cyanide reacts with acetaldehyde (chiral), equal number of mole of two enantiomeric forms of lactonitrile, CH3CHOHCN results. (c) Thermal recemization: Racemization may occur when an optically active material is heated. It leads to temporarily breaking one of the 4 bonds to a stereocenter. The atom/group separated exchanges the position and joins back to stereocenter to form another enantiomer e.g., the distillation of optically active enantiomer of α-phenethyl chloride leads to its racemization. Pharamaceutical Organic Chemistry-III 1.13 Stereoisomerism (d) Walden inversion: The racemization of 2-iodooctane by potassium iodide in refluxing acetone involves a process known as Walden inversion. (e) Epimerization: It is the change in the configuration at one asymmetric carbon atom in a compound having more than one stereocenters. It thus leads to interconversion of diastereomers. (f) Mutarotation: It is a spontaneous change with time, in the rotation of freshly prepared solutions of optically active substance till it reaches an equilibrium. Mutarotation is the result of either epimerization or a spontaneous structural change. The rate of mutarotation depends on temperature, solvent and catalyst. For example, the mutarotation of glucose is known to be acid-base catalysed. 1.7.2 Resolution of Racemic Mixture The process of separating a racemate into pure enantiomers is known as resolution. Enantiomers have identical physical properties (b.p., m.p., solubility) and hence it is difficult to separate enantiomers using conventional methods. If a pair of enantiomers is converted into a pair of diastereomers, the diastereomers can be separated easily utilizing the difference in their physical properties. Once separated, the pure enantiomer may be regenerated back from its respective diastereomer. For example, (i) A racemic mixture of enantiomers of an acid can be converted to a salt using a chiral base having D-configuration. The salt obtained contains a mixture of two diastereomers: (D acid, D base) and (L acid, D base). Due to difference in their physical properties, the diastereomeric salts are fully separated. Dissociation of separated diastereomeric salt leads to regeneration of D-acid and L-acid respectively. Fig. 1.1: Resolution of racemic mixture Racemic acids may be resolved using commercially available chiral bases like brucine, strychnine, l-phenyl ethanamine. Similarly racemic bases may be resolved using chiral acids such as (+) tartaric acid, (–) malic acid, (–) mandelic acid and (+) camphoric acid. A racemic alcohol may be resolved by converting the racemate into a mixture of diastereomeric esters using a chiral acid. The separation of these diastereomeric ester becomes difficult if they are liquid. In such cases, instead of full ester, half ester is synthesized containing one free carboxylic group. A chiral base, brucine then forms solid diastereomeric salts which can be later separated by crystallization. The pure enantiomer of 2-butanol is regenerated through hydrolysis of respective diastereomeric salt. Pharamaceutical Organic Chemistry-III 1.14 Stereoisomerism (ii) Resolution by biochemical means: Certain mold, bacteria or fungi selectively destroy one enantiomer at a faster rate than the other enantiomer. For example, the mold Pencillium glaucum if allowed to grow with racemic mixture, it selectively destroys the dextro isomer leaving pure levo isomer behind. Table 1.4: Pharmacological effects of Racemic drug mixtures Drug Biological response Enantiomer Terbutaline Trachea relaxation (–) Propranolol β-blockade (S) Amosulalol α-blockade (+) β-blockade (–) Warfarin Anticoagulation (S) Verapamil Negative chronotropic (–) Atenolol β-blocker (S) Nitrendipine Ca++ channel blocker (S) Zopiclone Sedation (R) Terfenadine Antihistaminic (S) Albuterol Antiasthmatic (S) Flurbiprofen Anti-inflammatory (S) Ketoprofen Anti-inflammatory (S) Thalidomide Immunosuppresive (S) Tetramisole Anthelmintic (S)-form (levamisole) Propoxyphene Analgesic Dextro form Antitussive Laevo form Tranylcypromine Antidepressant (–) Improvement in (+) performance Sotalol Antihypertensive (–) Antiarrhythmic (+) Pharamaceutical Organic Chemistry-III 1.15 Stereoisomerism Advantages of Resolution: (i) To avoid side effects of unwanted enantiomer leading to improved therapeutic profile and less chances of drug interaction. (ii) Reduction in the therapeutic dose and hence the cost of treatment. (iii) Lesser metabolic, renal and hepatic load of a drug on the body as the dose (for a pure enantiomer) reduces to the half of racemic mixture. 1.8 REACTIONS OF CHIRAL MOLECULES Chiral molecules react with the reagents in variety of ways and accordingly reactions are classified as follows: 1. Reactions where bonds with the chiral center are not broken. 2. Reactions leading to generation of chiral center. 3. Reactions of chiral compounds with optically active reagents. 4. Reactions where bonds with the chiral center are broken. 1. Reactions where bonds with the chiral center are not broken. These reactions can be used to relate configuration of one compound to that of another. Configuration is retained when reaction does not involve breaking of a bond to a chiral center. Here as the bond to the chiral center is not broken 'S' configuration is retained, because '–CH2–Cl' occupies same relative position as that was occupied by –CH2OH in the reactant. This retention of configuration can be utilized to determine configurational relationship between two optically active compounds by converting them into each other by reactions that do not involve breaking of a bond to a chiral center. Only relative configuration can be assigned than absolute configuration. Such reactions are used to get specific rotations of optically pure compounds. e.g. 2-methyl-1-butanol from fusel oil has specific rotation of –5.90° and is optically pure. Upon treatment with hydrogen chloride, 1-chloro 2-methyl butane has specific rotation of +1.67°. So if a sample has rotation equal to this value, compound is said to be pure. If rotation is about + 0.8º, compound is said to be only 50% optically pure. Pharamaceutical Organic Chemistry-III 1.16 Stereoisomerism 2. Reactions leading to generation of chiral center: Generation of first chiral center in a compound usually yields equal amounts of enantiomers (Racemic mixture) but reactions that form second/new chiral center yields unequal amounts of diastereomers depending on the side of attack. Retention of configuration(s) occurs as there is no bond breaking to the chiral center. For new chiral center, depending on side of attack from the same or opposite side, diastereomers are formed but in unequal amounts. This is because the intermediate 3-chloro-2-butyl radical contains a chiral center and it lacks symmetry. So two faces of the molecule for attack are not equal to each other. Here S isomer would yield the SS and meso compound in ratio of 29 : 71. In some reactions both configurations may not be actually generated but probability exists. Similarly R isomer would yield RR and meso compound in ratio of 29 : 71. If the reactant is optically inactive, it yields optically inactive products. 3. Reactions of chiral compounds with optically active reagents Such reactions are commonly used in resolution or separation of a racemic mixture/modification into individual enantiomers. Because enantiomers have similar physical properties (except optical rotation) they are not separated by usual methods of fractional distillation or crystallization. So to obtain pure enantiomers from racemic modification, use of optically active reagents is made. Such optically active reagent is easily obtained from natural sources or generated from naturally available reagents. Common reactions are reactions of organic acids and bases to form salts. Pharamaceutical Organic Chemistry-III 1.17 Stereoisomerism e.g. Reaction of racemic acid (+) HA with alkaloid reagent (–) B. Formed diastereomers have different physical properties and can be easily separated by fractional distillation or crystallization. Further by addition of mineral acid resolved enantiomers can be recovered from the solution. Alkaloid bases commonly used are (–) brucine, (–) quinine, (–) strychnine etc. Similarly, racemic bases can be separated with acid reagents e.g. (–) malic acid. Compounds other than acids, bases can also be resolved. Alcohols are weakly ionized and are not appreciably acidic or basic so their resolution is facilitated by attaching them with acidic handle which can be removed later. 4. Reactions where bonds with chiral center are broken Stereochemistry of such reactions depend on the mechanism of the reaction. Hence, stereochemistry can be helpful to give evidence of a particular mechanism. e.g. As the product is optically inactive and a racemic mixture, it implies second chlorine can be attached from either face of the intermediate, which can be a free alkyl radical with loss of chirality. Pharamaceutical Organic Chemistry-III 1.18 Stereoisomerism If there is simultaneous attack of chlorine while displacement of hydrogen, only the product from backside attack of chlorine would have been obtained instead of optically inactive product, so mechanism involving free alkyl radicals is correct. - A reaction is stereospecific when reactants exist as steroisomers and each isomeric reactant gives a different stereoisomeric product. - A reaction is stereoselective when reactant irrespective of any stereoisomerism produces predominantly or exclusively one stereoisomeric form of the product than other possible forms. 1.9 ASYMMETRIC SYNTHESIS (PARTIAL AND ABSOLUTE) De novo synthesis of a chiral substance from an achiral precursor such that one enantiomer predominates over the other is called as asymmetric synthesis. For reactions where molecules already contain chiral element and synthesis introduces a new chiral element, synthesis is referred as 'stereoselective or enantioselective' synthesis or diastereoselective synthesis. - Decarboxylation of ethyl methyl malonic acid to give α methylbutyric acid is one of the first recorded asymmetric synthesis. - Generally chiral reagents are used to carry out the reaction, if they are not available, chirality is acquired upon chelation, solvation etc. - Reactants are adsorbed onto chiral surfaces or within chiral crystals. - Chiral adjuvant or chiral auxiliary is temporarily attached to the achiral substrate which is cleaved after the synthesis by hydrolysis to recycle the adjuvant. - When a new stereogenic center is created in achiral molecule we get a racemic mixture while in diastereoselective synthesis, formation of any one of the desired diastereomer is preferred over the other. Typical asymmetric syntheses include - Asymmetric hydrogenation - Asymmetric epoxidation - Asymmetric dihydroxylation Partial term was used when optically active compounds are prepared from achiral compounds by intermediate use of optically active compounds as reagent without necessity of resolution, contrary to the 'absolute' asymmetric synthesis where physical reagent like circularly polarised light was used. Pharamaceutical Organic Chemistry-III 1.19 Stereoisomerism 1. Asymmetric Hydrogenation (Reduction): It is used for asymmetric synthesis of analgesic drug Naproxen. Reaction is carried out in presence of chiral catalyst to hydrogenate double bond. The catalyst selects a single enantiotopic face of the double bond and adds hydrogens across it. BINAP is a chelating diphosphine. Chirality is due to restricted rotation of the bond joining two naphthalene ring systems. Along with Ruthenium it acts as excellent catalyst for hydrogenation. For double bonds bearing amino group, better catalysts are based on rhodium. The catalyst is a cationic complex of rhodium with another diphosphine DI PAMP. - Important application of asymmetric hydrogenation is in synthesis of L menthol from (R) citronellal. Pharamaceutical Organic Chemistry-III 1.20 Stereoisomerism 2. Asymmetric epoxidation: Oxidation of alkenes by asymmetric epoxidation is one of the popular sharpless reaction. Catalyst is a transition metal, Titanium tetraisopropoxide with tertiary butyl hydroperoxide. The ligand is diethyl tartarate which is chiral and imparts selectivity to the reaction. Such metal catalysed epoxidation works only on allylic alcohols. Initially active complex is formed from two titanium atoms bridged by two tartrate ligands. Each titanium atom retains two of its isopropoxide ligands and is co-oridinated to one of the carbonyl group of the tartrate ligand. When oxidizing agent tBuOOH is added, it displaces one of the remaining isopropoxide ligands and one of the tartrate carbonyl groups. Further allylic alcohol is co- ordinated with the titanium displacing another isopropoxide ligand. Because of the shape of the complex of the reactive oxygen atom of the bound hydroperoixde has to be delivered to the lower face of alkene and epoxide is formed in high enantiomeric excess. Epoxides easily react with many nucleophiles to give 1,2, disubstituted products and thus used in synthesis of drugs e.g. Propranolol- used as β blocker. 3. Asymmetric dihydroxylation: Dihydroxylation of alkenes by osmium tetroxide in catalytic amount is carried out. - Osmium (VIII) act as oxidizing agent and K3Fe (CN)6 is commonly used to reoxidize the osmium after each catalytic reaction. - To increase rate of reaction K2CO3 and methanesulfonamide are added. - Chiral ligands are usually alkaloids dihydroquinidine and dihydroquinine based which must be attached to aromatic ring e.g. Phthalazine. Pharamaceutical Organic Chemistry-III 1.21 Stereoisomerism - Trans alkenes dihydroxylates more selectively than other alkenes because of alignement of ligand and catalyst. - Reaction has been successfully used for synthesis of antibiotic chloramphenicol in few steps. Energy Profile diagrams for asymmetric synthesis Fig. 1.2: Nucleophilic attack on ketone in achiral environment where enantiomeric products are produced in exactly equal amounts Fig. 1.3: Nucleophilic attack on a ketone in chiral environment where enantiomeric products are produced in unequal amounts. Pharamaceutical Organic Chemistry-III 1.22 Stereoisomerism QUESTIONS 1. What are diastereomers? Explain with suitable example? 2. What is conformational isomer? Explain with suitable example? 3. Assign R/S configuration of following: 4. Exaplain resolution of raecemic mixture. 5. Define enantiomer and mesocompound with structure. 6. Comment on resolution of racemic modification. 7. Define chirality and optical isomerism. 8. Explain significance of stereochemistry in biological activity. 9. Assign R and S configuration. Pharamaceutical Organic Chemistry-III 1.23 Stereoisomerism 10. What is resolution ? Give in brief any two methods? 11. Differentiate between enantiomers and diastereomers. 12. Explain various ways to represent chiral centre with example. 13. Write short note on methods of resolution of racemic mixture. 14. Draw and specify R or S a. 3-Chloro-2,2,5,trimethylhexane b. 3-bromohexane c. 1,3-dichloropentane 15. Explain with example stagged and eclipsed. 16. Give advantage of Z/E nomenclature over cis - trans with example. 17. Assign R and S nomenclature for following. 18. Differentiate between: a. Enantiomers and diastereomers b. Mesoform and racemic mixture 19. Write rules of R.S configuration. 20. Explain optical isomerism with examples. 21. What is racemic resolution ? Explain with suitable examples, various methods used. 22. Assign R and S Pharamaceutical Organic Chemistry-III 1.24 Stereoisomerism 23. Define configuration, conformation. Give example of each. 24. Write note on chirality in detail. 25. Optical isomerism is not exhibited by meso compounds, why ? 26. Define recemic mixture and give its examples. 27. What is Dihedral angle in stereoisomer? 28. Differentiate and give detail account on geometrical and optical isomerism.


Unit...II GEOMETRICAL ISOMERISM ♦ SYNOPSIS ♦ 2.1 Introduction 2.4.2 Conformations of n-Butane 2.2 Nomenclature of Geometrical Isomers 2.4.3 Conformations of Cyclohexane 2.3 Determination of Configuration of 2.5 Conditions for Optical Activity Geometrical Isomerism 2.6 Optical and Geometrical Isomerism 2.3.1 Chemical Methods 2.6.1 Optical Isomers and Biological 2.3.2 Physical Methods Activity 2.4 Conformational Isomerism 2.7 Stereospecific and Steroselective 2.4.1 Conformations of Ethane Reactions 2.1 INTRODUCTION Maleic acid (m.p. 130°C) and fumaric acid (m.p. 287°C) have the same molecular formula but differ in the arrangement of functional groups around double bond. They have different physical and, to some extent, chemical properties. This type of isomerism is known as Geometrical isomerism. HOOC COOH HOOC H C C C C H H H COOH Maleic acid Fumaric acid (cis-butenedioic acid) (trans-butenedioic acid) 2.2 NOMENCLATURE OF GEOMETRICAL ISOMERS (i) Cis-trans Nomenclature: The presence of a carbon-carbon double bond restricts the freedom of rotation about double bond. The designation cis (Latin word : same side), is used to denote the presence of like atoms or groups on the same side and trans (Latin word, across) is used when they are on opposite sides. Isomerism seen in non-cyclic, open-chain compound due to the presence of a double bond, is called as π diastereoisomerism while when it occurs in a cyclic skeleton lacking a double bond, it is termed as σ diastereoisomerism. (2.1) Pharamaceutical Organic Chemistry-III 2.2 Geometrical Isomerism (ii) E/Z System of Nomenclature: The simple convention of denoting the geometrical isomers by cis/trans is not possible when there are more than two different substituents on a double bond. Hence a new system of nomenclature known as the E/Z notation method is to be adopted. Except for very simple alkenes, the nomenclature for alkene officially uses E/Z notation. In cyclic alkanes, cis and trans terminology is retained. The E/Z notation is not used in cyclic alkanes. The group of highest priority on double bonded carbon atoms is first choosen according to Cahn-Ingold-Prelog (CIP) priority sequence rule. For example, in the following structure, Here, the priority of functional groups attached to both double bonded carbon atoms is Br > Cl and I > H. It means the highest priority functional groups are on the same side of the double bond (i.e., cis-isomer). Hence, it is named as Z-form (from German word, Zussamen meaning together). If the highest priority functional groups are on the opposite sides of the double bond (i.e., trans-isomer), it is named as E-form (from the German word, Entagagen meaning opposite). Thus, E stands for opposite side and Z for the same side. Generally cis- isomer is said to be Z-form and trans-isomer is said to be E-form with few exceptions. CIP Rules for determining priorities: (a) The atom which has the highest atomic number is given the higher priority, in the case of simple structure, and (b) In the most complicated molecule where group of atoms constitute the functional groups attached to the carbons of double bond, the priority depends on atomic weights of other atoms present in the group. For example, the priority in the given molecules is CH3CH2 – > CH3 and CHO > CH2OH. In case of CHO, oxygen is counted twice because of carbon oxygen double bond. Hence, the given structure has Z-form. If an atom is triply bonded to another atom, treat it as if it were singly bonded to three of those atoms. Pharamaceutical Organic Chemistry-III 2.3 Geometrical Isomerism (c) For molecules with multiple double bonds, it is necessary to indicate the alkene location for each E or Z symbol. For example, the prefix (2E, 4E, 6Z, 8E) used in IUPAC name of alitretinoin indicates that the alkenes starting at positions 2,4,8 are E while the alkene at position 6 is Z. (iii) Syn/Anti system of Nomenclature: The cis-trans isomerism in some classes (such as oximes, diazoates and azo) containing one or more carbon to nitrogen or nitrogen to nitrogen double bonds is designated by syn/anti-isomerism. Syn/anti nomenclature is based upon two substituents in an acyclic molecule. For example, in sterioisomeric oxime, configuration of oximes is usually denoted by prefixes “syn” and “anti” instead of cis and trans. The oximes may be of two types. (a) Aldoximes: These are derived when aldehydes are treated with hydroxyl amine. (either R or R’ is hydrogen), and (b) Ketoximes: These are derived when ketones are treated with hydroxyl amine (both R or R’ are alkyl/aryl groups). The geometrical isomerism in oximes occurs due to restricted rotation of C = N bond. In syn-aldoximes, both the hydrogen and the hydroxyl group are on the same side of the C = N and in anti-form, they are on the opposite side. However, in case of ketoxime, the syn and anti descriptors indicate the spatial relationship between the group (whose name appears first in the name of compound) and the hydroxyl group. For example, the ketoxime of butanone may be named as either syn methyl ethyl ketoxime (methyl and OH are syn) or anti-ethyl methyl ketoxime (ethyl and OH are anti). As per E-Z notation, the syn acetaldoxime is named as E-acetaldoxime whereas the anti form is named as Z-acetaldoxime. Pharamaceutical Organic Chemistry-III 2.4 Geometrical Isomerism Similarly, Syn/Anti nomenclature is also used for octahedral complex fused rings. The syn-isomer has adjacent fused rings whereas the anti-isomer has opposite fused rings. 2.3 DETERMINATION OF CONFIGURATION OF GEOMETRICAL ISOMERISM The methods of determination of configuration are classified as: (I) Chemical methods and (II) Physical methods 2.3.1 Chemical Methods These methods include: (a) Absolute method: This method is based on the following observations. (i) Functional groups in cyclic compound located cis to each other can be converted into cyclic lactones, anhydrides or amides. e.g., maleic acid containing two –COOH groups cis to each other forms anhydride easily. Hence, it can be identified as cis-(maleic acid). Similarly in fumaric acid the two –COOH groups are on the opposite side, it can not form anhydride easily. Hence, it can be identified as trans-form. (ii) Cis-isomers can be synthesized from the small rings but trans isomers can not be synthesized from small rings. (b) Through chemical reaction not affecting the configuration of the double bond: The synthesis of trisubstituted alkene of known configuration is possible by syn addition of organo-copper reagent to alkyne followed by alkylation. (c) If we synthesize a product from a starting material of known configuration, then the configuration of the product remains same as that of starting material. (d) The stereoselective reaction helps to predict the configuration of the resulting product. One such stereoselective reaction is Wittig reaction. Pharamaceutical Organic Chemistry-III 2.5 Geometrical Isomerism 2.3.2 Physical Methods The geometrical isomers differ from each other in their physical properties which include: (a) Boiling point, melting point, density, refractive index and dipole moment (b) Acid strength (c) UV-visible spectra (d) Vibrational (IR-Raman) spectra (e) NMR (1H, 13C both) (f) X-ray, microwave spectra and electron diffraction methods. (a) The parameters like boiling point, melting point, density and refractive index are not very reliable for prediction of configuration of the isomers. Dipole moment is variable for cis and trans isomer, sometimes higher for trans and at times for cis isomer. Similarly, trans isomer has greater symmetry than the cis. Therefore, trans has usually a higher melting point. e.g., (b) Acid Strength: The acid strength is strongly dependent on the configuration of the compound e.g. pKa of cis and trans isomers of crotonic acid are. The cis form (maleic acid) is more acidic in its first dissociation than trans form (fumaric acid) but the acidity of second proton is reversed. This is because of intramolecular H-bonding formed within the conjugate anion of maleic acid. It is stabilized to a greater extent than fumaric after first dissociation of proton. In the second dissociation, in cis-two negative anion species close to each other is not favourable as in fumaric, the trans form (the negative species further away). Hence, the trans form is more acidic than cis in second dissociation. Pharamaceutical Organic Chemistry-III 2.6 Geometrical Isomerism (c) UV-visible Spectra: Cis isomer has two bulky groups on the same side. Hence, internally the molecule is extremely crowded and thus has less resonance energy and less stable than trans isomer. The cis-isomer suffers distortion and is forced to be non-coplanar and thus has absorption maxima at slightly shorter wavelength than the trans isomer. (d) Infrared and Raman Spectra: The difference in the IR spectra of two isomers may be pointed out in the following regions. 1650 cm–1 (C = C), and 970 – 690 cm–1 (= C – H out of plane vibration). Similar for trans 1,2-dichloroethylene, dipole moment is zero, due to its symmetrical nature. Cis-isomer shows no IR absorption but shows Raman absorption at 1577 cm–1. While trans-isomer shows strong IR absorption at 1590 cm–1 but shows no Raman absorption. (e) NMR Spectra: Not only it gives you information regarding which functional groups are present, but NMR spectra are also capable of giving information about the position and configuration of atoms (environment) in the molecule. NMR spectra can differentiate chemcally unlike protons. In a disubstituted ethylene, RHC = CHR’, where R and R’ differ significantly in the way they influence the magnetic environment of the olefinic protons, thereby these protons experience a resonance condition at differnt field strengths. These olefinic protons are typically found in low field of the NMR spectrum and the hydrogens are said to be deshielded. Trans isomer is strongly coupled and hence has a coupling constant of 17-18 c.p.s. (cycles per second). While the coupling constant of cis-isomer ranges from 8-11 c.p.s. Similarly the difference in chemical shifts of cis- and trans- isomers may be used to identify the configuration of the isomer. (f) X-ray and Electron Diffraction: Single crystal X-ray diffraction is the most powerful tool for detailed structural characterization of crystalline compounds. It reveals the spatial atomic arrangement providing an image of the internal structure of the crystal. Single crystal Pharamaceutical Organic Chemistry-III 2.7 Geometrical Isomerism X-ray diffraction is the main source of information on the geometrical structure of the molecules including bond distances, bond angles, conformations of flexible molecules as well as intermolecular contacts. 2.4 CONFORMATIONAL ISOMERISM These are the isomers generated due to rotation around single bonds present in the molecule. They may be rapidly interconverted to each other again through further rotation around single bonds. There exists a rotational energy barrier that needs to be overcome to convert one conformer to another. Some important examples of conformational isomerism include: (i) Open chain alkane conformations: Staggered, eclipsed and gauche conformers. (ii) Ring conformation: Chair and boat conformers. (iii) Atropisomerism: A molecule can become chiral due to restricted rotation about a bond. (iv) Folding of molecule. 2.4.1 Conformations of Ethane Out of infinite conformations possible, most important conformers of ethane are: (i) Staggered conformation and (ii) Eclipsed conformation. Since the angle between the C – H bonds of 1st and 2nd carbons is 60º, the staggered conformation is the most stable conformation of ethane. In eclipsed form, the angle is 0º between two C – H bonds leading to repulsion in their electron cloud which raises the energy and decreases the stability of the molecule. The eclipsed conformation of ethane is less stable than the staggered conformation by 3 kcal/mol. In eclipsed conformation, the bulky substituents of the molecule are brought closer leading to repulsion amongst them. This hindrance causes resistance to rotation (torsional strain i.e., force that opposes rotation due to the repulsion of bonding electrons.) It is not possible to isolate either of ethane conformations due to their rapid interconversion at room temperature. Pharamaceutical Organic Chemistry-III 2.8 Geometrical Isomerism 2.4.2 Conformations of n-Butane Various conformations of n-Butane include, Dihedral angle: It is the angle created by two intersecting planes. Table 2.1: Types of interactions in conformers of n-butane Sr. No. Interaction Cause Energy cost kcal/mol. 1. H ←→ H eclipsed Torsional strain 1.0 2. H ←→ CH3 eclipsed Torsional strain 1.4 3. CH3 ←→ CH3 eclipsed Torsional and steric strain 2.6 4. CH3 ←→ CH3 gauche Steric strain 0.9 Table 2.2: Various strains contributing to rotational energy barrier Sr. No. Name Cause 1. Angle strain Expansion or compression of bond angles from the tetrahedral value of 109.5º. 2. Torsional strain Eclipsing of bonds on neighbouring atoms. 3. Steric strain Repulsive interactions between non-bonded atoms in close proximity. 4. Ring strain Combination of angle strain and torsional strain. Pharamaceutical Organic Chemistry-III 2.9 Geometrical Isomerism The gauche butane is less stable than antibutane by 3.8 kJ/mol. because of steric interference between H-atoms on the two methyl groups. Fig. 2.1: n-Butane torsional energy profile 2.4.3 Conformations of Cyclohexane In cyclohexane all carbon atoms are sp3 hybridized with a bond angle of 109º. This leads to two types of conformations. (i) Chair conformation: It is the most stable form having tetrahedron bond angle of 109º. It adopts staggered arrangement having least torsional strain. Chair cyclohexane has six axial hydrogens perpendicular to the ring (parallel to the ring axis) and six equatorial hydrogens near the plane of the ring. Pharamaceutical Organic Chemistry-III 2.10 Geometrical Isomerism Six membered rings are almost free of strain in a chair conformation. Fig. 2.2: Cyclohexane torsional energy profile Boat form can be obtained from chair conformation by bending of the bonds. This transformation of chair to boat form occurs through intermittant – half chair and twist boat form. In boat conformation, carbon 1 and 4 are bent towards each other while all hydrogens in the chair conformation are staggered, four hydrogens are eclipsed in the boat conformation. Hence, the boat conformation is less stable than a chair conformation by 6.5 kcal/mol. As a result of simultaneous rotation about all C – C bonds, chair conformations readily get interconverted, resulting in the exchange of axial and equatorial positions. It is known as ring inversion or ring flip. In this process, equatorial bonds become axial and axial becomes equatorial. Atropisomerism: Atropisomerism is stereochemistry arising from restricted bond rotation that creates a chiral axis. Atropisomers are stereoisomers resulting from hindered rotation about one or more single bonds between two planar moieties where the energy barrier to rotation is high enough to allow for isolation of individual conformers. The conformers are detectable by NMR if half lives of conformers exceed 10–2 sec. and can be isolated if their half lives are above 1000 sec. The name atropisomerism (from Greek, a = not and tropos = turn) was introduced by Kuhn in 1933 but it was first detected in 6,6-dinitro -2, 2’-diphenic acid by Christie in 1922. The bulkier groups on ortho position of the biphenyl ring restrict the rotation through C–C bond gives two enantiomers and resolvable at room temperature. Pharamaceutical Organic Chemistry-III 2.11 Geometrical Isomerism Atropisomers Newman projections Atropisomerism induces time dependent inversion of chirality via bond rotation generating atropisomers having different pharmacokinetic, biological and toxicological profiles. Nomenclature: The Cahn-Ingold-Prelog system suggested assigning stereo chemical descriptors (R, S descriptors) to molecules with axial chirality. All four groups are ranked with overall priority given to the groups on the front atom of the Newman projection. The two configurations are termed as Ra and Sa in analogy to the conventional R/S. In yet another nomenclature, if the sequence a-b-c-d of the substituents is clockwise, the configuration is called P or ∆. If it is counter clockwise, the configuration is called M or ^. Atropisomerism is also called as axial chirality. The chirality is not simply a centre or a plane but an axis. The simple symmetric biphenyl is achiral. Only biphenyl having different substitutents at ortho position contains a chiral axis. The biphenyl rings turn perpendicular to each other in order to minimize steric clashes the biphenyl bond restricted. For example, Pharamaceutical Organic Chemistry-III 2.12 Geometrical Isomerism 2.5 CONDITIONS FOR OPTICAL ACTIVITY (i) The planes of the two aryl groups must be non-planar. It is achieved by placing bulky groups in the ortho positions. (ii) In most of the cases, the enantiomers can be resolved. (iii) Ortho substitutents increase the restricted rotation by their steric repulsion. (iv) Mono ortho substituted biaryl compounds do not show atropisomerism at room temperature. e.g. (v) In addition to the substitutents at ortho position, the bulky groups adjacent to the ortho substitutents increase stability and isolatability of atropisomers. (vi) Heteroaromatic system provides chirality even though their ortho substituents are same. 2.6 OPTICAL AND GEOMETRICAL ISOMERISM Optical Isomerism (enantiomerism): In 1815, Biot found that a number of organic and inorganic compounds in the solution form, have the ability to rotate the plane of polarized light in opposite directions but in identical amplitude, passing through them. Optical isomerism is seen in compounds that can rotate plane polarised light. A carbon atom connected to four chemically different functional groups is known as asymmetric or chiral carbon and the presence of at least one asymmetric carbon atom in the structure is the pre- requirement for a molecule to show optical isomerism. If there is one asymmetric carbon then two optically active isomers are possible. Isomer rotating plane of polarized light to the right is said to be dextrorotatory (Latin, dexter : right) while isomer showing rotation to the left is known as laevorotatory (Latin, laevus : left). Both isomers are mirror images of each other yet are not superimposable. They are called as enantiomers and the pair of enantiomers is called as enantiomorph. An enantiomer does not possess a plane or center of symmetry. Pharamaceutical Organic Chemistry-III 2.13 Geometrical Isomerism For example, CHO CHO | | H — C — OH HO — C — H | | CH2OH CH2OH D-glyceraldehyde L-glyceraldehyde When the enantiomers are present together in equal concentration, the rotation of plane polarized light caused by laevo isomer will be neutralized by a dextro rotating isomer and the mixture will be optically inactive. Such mixtures are called as racemic mixtures. The conversion of an enantiomer into a racemic form is called as racemization. While the separation of racemic mixture into individual enantiomers is called as resolution. The maximum number of optically active isomers possible for a molecule having more than one asymmetric carbon atoms may be given by the formula N = 2n where, N = Number of optically active isomers, and n = Number of asymmetric carbon atoms. With the exception of rotation of plane-polarised light, enantiomers have identical physical and chemical properties like boiling point, melting point, solubility. Their chemical properties are same towards achiral reagents, solvents and conditions. Towards chiral reagents, solvents and catalysts, enantiomers react at different rates. As per the rule given above, tartaric acid will have four optically active forms because of the presence of two asymmetric carbon atoms. COOH COOH COOH COOH | | | | HO − C − H H − C − OH H − C − OH HO − C − H | | | | HO − C − H H − C − OH HO − C − H H − C − OH | | | | COOH COOH COOH COOH (I) (II) (III) (IV) Forms (I) and (II) are identical and symmetrical. In these forms, the upper half is the mirror image of the lower half. This makes the molecule optically inactive through internal compensation. Such identical and symmetrical stereoisomers are called as meso-isomers. Forms (III) and (IV) are mirror images of each other but are not superimposable. They are enantiomeric forms. While if you compare (III) with (I) or (IV) with (I), these are not enantiomeric pairs. They are neither mirror images nor superimposable. Only one of the two halves of their molecules Pharamaceutical Organic Chemistry-III 2.14 Geometrical Isomerism are identical while the remaining halves are mirror images. Such stereoisomers which are not mirror images and are non-superimposable are called as diastereomers. They have different physical and chemical properties, with both achiral and chiral reagents. The rates are different and the product may be different. A molecule is called as chiral if it is not superimposable to its mirror image. Many drugs bear one or more asymmetric carbon atoms on their skeleton. Due to non-identical 3D structures, the interaction of these chiral molecules with the target sites may differ. The resulting enantiomers have different pharmacokinetic profile and may elicit differentiated biological responses. The biological response induced by a pair of enantiomers can differ in potency or in nature. One enantiomer may act at one receptor site whereas another enantiomer is recognized by other target sites and possesses altogether different activity and toxicity profile. 2.6.1 Optical Isomers and Biological Activity Stereochemistry, enantiomers, symmetry, asymmetry and chirality are important concepts that help us to understand the therapeutic and toxic effects of drugs. The word 'chiral' is derived from the Greek word cheir which means 'hand'. A chiral drug consists atleast one asymmetric carbon atom and has two enantiomers. Although each enantiomer has identical chemical and physical properties, individually they may interact differently with receptors, enzymes and proteins in the body. A number of mechanisms (e.g. metabolism, protein binding, clearance) in the body can be stereoselective which may account for pharmacokinetic differences among enantiomers. Formulation factors such as the rate of dissolution, melting point, powder flow characteristics and solubility are all different for the racemate and to be taken into account to ensure bioequivalence of the formulations. Because the isomers have different three dimensional structures, they have different affinities for receptors and enzymes which are also three dimensional. This explains the reason for the different therapeutic and toxicological properties exhibited by different enantiomers. Generally one enantiomer is more potent than the other in exhibiting pharmacological response. The more potent enantiomer is called as eutomer and less potent enantiomer is termed as distomer. The ratio of activities of eutomer and distomer is called as 'eudismic ratio' which is a useful parameter to assess the relative potency of the enantiomers. This ratio is normally different at different receptor sites. The logarithm of this ratio is termed as eudismic index (EI). If two enantiomers of disopyramide are administered independently, they have the same pharmacodynamic and pharmacokinetic profile. If administered together, they have dramatically different pharmacokinetic profiles. This is the result of difference in protein binding. Pharamaceutical Organic Chemistry-III 2.15 Geometrical Isomerism Table 2.3: Plasma-protein binding of enantiomers Drugs % unbound Acidic Drugs: Indactinone R (–) 0.90 S (+) 0.30 Methobarbital R (–) 2.29 S (+) 0.13 Moxalactam R (+) 47.00 S (–) 32.00 Pentobarbital R (+) 36.60 S (–) 26.50 Phenprocoumon R (+) 1.07 S (–) 0.72 Warfarin R (+) 1.20 S (–) 0.90 Basic Drugs: Amphetamine (+) 84 (–) 84 Chloroquine (+) 33 (–) 51 Disopyramide (+) 27 (–) 39 Fenfluramine (+) 2.8 (–) 2.9 Methadone (+) 9.2 (–) 12.2 Propoxyphene (+) 1.8 (–) 1.8 Propranolol (+) 12 (–) 11 Tocainide (+) 86-91 (–) 83-89 Verapamil (+) 6.4 (–) 11 Similarly, the stereoselective clearance affects the plasma half-life of the drug. Upon administration of leucovorin calcium enantiomers, l-leucovorin is rapidly cleared from the body and has a plasma half-life of 32 minutes, whereas d-leucovorin is slowly cleared and has a plasma half-life of 45 minutes. S (–) Timolol is one of the few adrenoceptor blockers marketed as the pure enantiomer used clinically to treat systemic hypertension, angina pectoris and glaucoma. When this form is used topically in eyes for treating glaucoma, severe bronchoconstriction is noticed. In contrast R (+) timolol lowers intraoccular tension without causing significant bronchospasm. R (+) form is therefore safer for treating glaucoma than S (–) form. Similarly humans preferentially metabolise (+) fenfluramine while rats favour the (–) enantiomer. Table 2.4: Worldwide sales of single-enantiomer drugs Total market Single enantiomer ($) drugs ($) $ Billions 1999 2000 1999 2000 Analgesic 21.5 23.0 1.0 1.3 Antibiotics/Antifungals 29.3 31.7 23.9 23.9 Antiviral 17.7 19.1 6.2 6.5 Anticancer 13.7 15.6 9.4 10.4 Contd... Pharamaceutical Organic Chemistry-III 2.16 Geometrical Isomerism Cardiovascular 42.7 46.6 24.8 26.9 Central nervous system 47.7 53.9 8.6 9.0 Dermatological 17.9 18.4 1.3 1.2 Gastrointestinal 43.9 47.2 3.0 3.5 Hematology 16.5 15.4 8.6 9.1 Hormones 20.0 22.0 13.8 14.6 Ophthalmic 7.1 7.4 1.8 2.0 Respiratory 36.5 40.5 5.1 6.1 Vaccines 6.5 7.3 2.0 3.0 Others 39.0 41.9 5.5 5.6 Total 360.0 390.0 115.0 123.3 Table 2.5: Pharmacological effects of Racemic drug mixtures Drug Biological response Enantiomer Terbutaline Trachea relaxation (–) Propranolol β-blockade (S) Amosulalol α-blockade (+) β-blockade (–) Warfarin Anticoagulation (S) Verapamil Negative chronotropic (–) Atenolol β-blocker (S) Nitrendipine Ca++ channel blocker (S) Zopiclone Sedation (R) Terfenadine Antihistaminic (S) Albuterol Antiasthmatic (S) Flurbiprofen Anti-inflammatory (S) Ketoprofen Anti-inflammatory (S) Thalidomide Immunosuppresive (S) Tetramisole Anthelmintic (S)-form (levamisole) Propoxyphene Analgesic Dextro form Antitussive Laevo form Tranylcypromine Antidepressant (–) Improvement in (+) performance Sotalol Antihypertensive (–) Antiarrhythmic (+) Pharamaceutical Organic Chemistry-III 2.17 Geometrical Isomerism (1) Dexchlorpheniramine is highly stereoselective; the (S) - (+) - isomer is about 200 times more potent than the (R) - (–) - isomer. (2) d-Ketamine is a hypnotic and analgesic agent; the l-isomer is responsible for the undesired side-effects. In the case of local anaesthetic prilocaine, although both isomers are active, only one isomer contributes to the toxicity. (3) Both isomers of bupivacaine are local anaesthetics, but only the l-isomer shows vasoconstrictive activity. Indacrinone has a uric acid retention side-effect. The d-isomer is responsible for both the diuretic activity and the side-effect while the l-isomer acts as a uricosuric agent. (4) It also, is possible for the enantiomers to have opposite effects. The l-isomers of some barbiturates exhibit depressant activity and the d-isomers have convulsant activity. Similarly the d-isomer of the narcotic analgesic picenadol, is an opiate agonist, the l-isomer is a narcotic antagonist and the racemate is a partial agonist. H3C CH3CH2CH2 N — CH3 OH Picenadol (5) (+) - Butaclamol is a potent antipsychotic, but the (–) isomer is essentially inactive. The eudismic ratio (+/–) is 1250 for D2-dopaminergic receptor. (–) Baclofen is a muscle relaxant that binds GABA B receptors. The eudismic ratio (–/+) is 800. OH C(CH3)3 N H H Butaclamol (6) The eudismic ratio (l/d) for propranolol is about 100. However, propranolol also exhibits local anaesthetic activity for which the eudismic ratio is 1.0. Labetalol, as a result of two asymmetric carbon atoms, exists in four stereoisomeric forms, having the stereochemistries (RR), (SS), (RS) and (SR). This drug has α- and β-adrenergic blocking properties. The (RR) - isomer is predominantly the β-blocker and the (SR) - isomer is mostly the α-blocker. While other 50% of the isomers, the (SS) - and (RS)- isomers, are almost inactive. Pharamaceutical Organic Chemistry-III 2.18 Geometrical Isomerism (7) If you consider two enantiomers, such as R (–) and (S) (+) epinephrine, interacting with a receptor that has only two binding sites (Fig. 2.3), it becomes apparent that the receptor cannot distinguish between them. However, if there are at least three binding sites, the receptor easily can differentiate them. The R - (–) - isomer has three points of interaction and is held in the conformation shown to maximise molecular complementarity. The (S) - (+) - isomer can have only two sites of interaction (the hydroxyl group cannot interact with the hydroxyl binding site, and may even have an adverse steric interaction); consequently it has a lower binding energy. The chiral interactions help us to discover which parts of the molecule are involved in primary receptor interaction. Chirality may also be used to distinguish different states of activation of ion channel receptors. H H OH HO CH2NH2CH3 HO CH2NH2CH3 OH + + HO HO Ar – Ar – H H R-(–)-epinephrine S-(+)-epinephrine Fig. 2.3: Effect of stereochemical features on the biological activity Generally in a recemic mixture, one enantiomer is bioactive while other remains either inactive or possesses different activities. Hence in case of drug containing one asymmetric carbon, administration of a racemic form permits the delivery of 50% active compound. At present only about 12% of synthetic chiral drugs are available in pure chiral form in the market while remaining 88% are sold as racemates. An effort to make the drug commercially available in pure chiral form, add to the cost of the synthesis. Various options like, to reduce the number of asymmetric centers, replacing asymmetric carbon with nitrogen, adding symmetry to the molecule, are hence used to save this added cost. When a drug exists in stereoisomeric forms, the rate and routes of metabolism may differ between the enantiomers. The rate of metabolism of two enantiomers would be expected to differ where they form diastereomeric complexes with the metabolizing enzyme. Extra complications may arise because of ability of metabolic processes to interconvert chiral centers. Pharamaceutical Organic Chemistry-III 2.19 Geometrical Isomerism Conformational Factors: Various conformations are possible for a flexible drug structure. Besides drug, the receptor sites also exhibit flexible nature and can acquire conformation in adaptation to the mutual effect of drug. However, suitable steric features need to be present in a drug molecule if it is to have significant affinity and intrinsic activity at receptor site. The X-ray crystallographic spectrophotometry is routinely used to determine conformation of a drug molecule while NMR spectra provides information for geometric isomers when the compound is in liquid state. Optical isomers, particularly diastereoisomers (i.e. compounds with two or more asymmetric centres), exhibit similar chemical reactions but different physical properties. Since the physical properties are important in drug distribution, metabolism and interaction with the receptor, the biological properties of such isomers may also be different. We may expect from the definition of optical enantiomers (that compounds having identical physical and chemical properties except for their ability to rotate the plane of polarised light) that they may have the same biological activity. However, this is not the case with many of the enantiomers. Table 2.6: Stereoisomeric Drugs Cardiovascular Agents: Acebutolol Alprenolol Atenolol Betaxolol Bisoprolol Bopindolol Bucumolol Butefolol Bufuralol Bunitrolol Bupranolol Butofilolol Carazolol Carvedilol Curteolol Disopyramide Dobutamine Indenolol Mepindolol Metipranolol Metroprolol Nadolol Oxpranolol Pindolol Propranolol Quinidine Sotalol Toliprotol Verapamil Xibenolol Central Nervous System: Butaclomol Butorphanol Buprenorphine Codeine Dihydroergotoxine Dobutamine Fluoxetine Ketamine Lorazepam Meclizine Nalbuphine Nalfename Naloxone Naltrexone Oxaprotiline Oxymorphone Phenylpropanol amine Physostigmine Chloramphetamine Thioridazine Toloxaton Tomoxetin Vasopressin Viloxazin Contd... Pharamaceutical Organic Chemistry-III 2.20 Geometrical Isomerism Anti-inflammatory and Analgesics: Beclomethasone Betamethasone Cicloprofen Corticosteroid Dihydroxy thebane Fenbuphen Fenoprofen Flurbiprofen Ibuprofen Ketoprofen Indoprofen Minoxiprofen Norlevorphanol Oxycodone Pirpofen Stanozolon Steroids Suprofen Triamcinolon Anticancer: Bleomycin Cytarabine Doxorubicin Methotrexate Mitomycin C Antibiotics, Anti-infectives, Antiviral: Ciprofloxacin Norfloxacin Ofloxacin Genitourinary Hormones: Benzyl glutamate Bromocriptine Butoconazole Calcitonin Estradiol Flurogesterone Gonadorelin Ketodesogestrel Norgestrel Prednisolone Progesterone Testosterone Table 2.7: Geometrical Isomerism Sr. No. Drug Name Biologically active Therapeutic activity form 1. Diaminodichloroplatinum cis-platin Anticancer drug in testicular and ovarian cancers. 2. Diethylstilbestrol (DES) trans-DES Estrogenic activity 3. Thiothixene cis-thiothixene Antipsychotic acitivity 4. Vitamin K2 trans form 5. 3-methylfentanyl cis-mefentanyl Analgesic (Mefentanyl) 6. Resveratrol trans form Anticancer drug 7. Retinal 11-cis isomer Vision Pharamaceutical Organic Chemistry-III 2.21 Geometrical Isomerism 2.7 STEREOSPECIFIC AND STEROSELECTIVE REACTIONS (a) Stereospecific Reactions: Stereospecific reaction is a reaction where the stereochemistry of the starting material governs the stereochemistry of the product. Only a single stereoisomer is produced in a given reaction rather than a mixture. For example, bromination of cyclopentene occurs through stereospecific anti addition to give trans-1, 2-dibromocyclopentane only. During the addition of dichlorocarbene to 2-pentene, the cis-2-pentene gives only one product, substituted cis-cyclopropane while the trans-2-pentene gives only one product, substituted trans-cyclopropane. In yet another bromination reaction of 2-butene, two geometric isomers (cis and trans) of 2-butene gives three stereoisomeric products where cis-2-butene gives (S, S) and (R, R) 2,3-dibromobutane while trans-2-butene gives meso-2,3-dibromo butane. In above case, bromination of cis-2-butene, the stereochemistry of products is governed by cis-2-butene. Here it is stereospecific reaction. While bromination of trans-2-butene leads to formation of only one product (meso). Hence, it is stereoselective reaction. (b) Stereoselective Reactions: Stereoselective reaction is a reaction where one stereoisomer of a product is formed preferentially over another. If enantiomers of a chiral product are formed in unequal amounts, it is called as an enantioselective reaction. Pharamaceutical Organic Chemistry-III 2.22 Geometrical Isomerism (i) Enantioselective reaction: (ii) Diastereoselective reaction: Similarly when diastereoisomers are produced in unequal amounts, the reaction is called diastereoselective reaction. In this reaction two dia-stereoisomers could be formed but one is favoured. All stereospecific reactions are stereoselective but stereoselective reactions are not necessarily stereospecific. For example, the reaction of HCl with propene gives 1-chloropropane and 2-chloropropane. Since, one product is favoured over another, this reaction is said to be stereoselective. If above reaction yields only 2-chloropropane, then the reaction is called stereospecific. QUESTIONS 1. What is conformational isomer? Explain with suitable example. 2. Discuss chair, boat and twist boat conformation of cyclohexane molecule. 3. Give conformational isomerism in ethane. 4. Draw Fischer projection for i) 2-chlorobutane ii) (R)-2-Butanol 5. Why chair conformation is more stable than boat conformation ? Explain. 6. Define and classify stereoisomerism. Explain different types of representation of structure. 7. Assign Z and E form Pharamaceutical Organic Chemistry-III 2.23 Geometrical Isomerism 8. Explain conformation of n-butane. 9. Explain chair conformation is more stable than boat by using cyclohexane example. 10. Why trans-decalin is more stable than cis-decalin, explain with structure? 11. Explain any two stereospecific reactions and any two stereoselective reactions. 12. Explain stereochemistry of monosubstituted cyclohexane. 13. What is Atropisomerism ? Explain with respect to Biphenyls. 14. Draw Sawhorse projection of following a. Meso 2,3-dibromo butane b. 2-chlorobutane c. 2R, 3S 2-chloro butanol 15. Trans 1,2 dimethyl cyclohexane is more stable than its cis isomer. Why ? 16. What is isomerism involved in Allenes? 17. Write note on stereospecificity and write three examples. 18. Assign E and Z nomenclature for following: 19. Give configuration of following isomers: Pharamaceutical Organic Chemistry-III 2.24