Organic Compounds Guide: Alkanes, Alcohols, Aldehydes, Ketones, Acids, Amines, Phenols, Summaries of Pharmacognosy

Download Organic Compounds Guide: Alkanes, Alcohols, Aldehydes, Ketones, Acids, Amines, Phenols and more Summaries Pharmacognosy in PDF only on Docsity! · The content of this book is innovative and presented in 31 chapters with simple and uniform pattern of explanation along with all chemical reactions. · The book has covered the entire Pharmaceutical organic chemistry, starts from origin of organic chemistry to Heterocyclic chemistry and Stereochemistry. · The principles of Organic Chemistry, which is difficult to remember by the students is described in a student friendly manner and shall be reproduced well in examinations. · To make the learning comfortable and magnetize the attention we have used color in equations and diagrams. Salient Features: · In each chapter, a brief Introduction of the individual chapter, Importance, Detailed discussion of the Basic Theory, Preparations, Reactions, Test for identification and Applications of each class of compounds in Pharmacy are described which reflects the title of the book “Pharmaceutical Organic Chemistry”. · To inspire the readers, Interesting facts about great scientists and organic compounds and their discovery are given under each chapter. · As per PCI Revised syllabus the coverage is complete with the basics as well as B. Pharm. 2nd, 3rd and 4th Semesters portion. Pharmaceutical Organic Chemistry is a much awaited great work in the field of Chemistry and Pharmacy. Targeted mainly to B. Pharmacy students, this book will also be useful for Pharm-D, M. Pharmacy, B.Sc. as well as M.Sc. chemistry and pharmaceutical chemistry students. The main objective of this book is to attract the undergraduate Pharmacy students and make them to understand the basic principles of Organic Chemistry which can be applied in Pharmaceutical Chemistry and Medicinal Chemistry. Thus the book is aimed to eliminate the inadequacy in teaching and learning of Organic Chemistry by providing detailed information about the Organic compounds. About the Author Dr. V. Alagarsamy, M. Pharm., PhD, FIC, DOMH, is Professor and Principal of MNR College of Pharmacy, Sangareddy, Gr. Hyderabad. He received his D.Pharm., from Coimbatore Medical College, B.Pharm., degree from Madurai Medical College, M.Pharm., from LM College of Pharmacy, Ahmedabad, PhD from The MS University of Baroda. He has been teaching Pharmaceutical Organic Chemistry, Pharmaceutical Inorganic Chemistry, Chemistry of Natural Products and Medicinal Chemistry and performing research work in synthetic medicinal chemistry on novel heterocyclic bio-active compounds for two decades. For his research work, he has collaborated with various research laboratories/organizations like National Cancer Institute, USA; Rega Institute for Medical Research, Belgium; Southern Research Institute, USA; and Sudbury Regional Hospital, Ontario, Canada. He is a recipient of young scientist award from the Department of Science and Technology, New Delhi. He is the author/coauthor of over 160 papers, which includes the original research articles and presentations in various conferences and symposiums. He has also patented his Research findings. He become the co-editor of the International journal “Antiinfective Agents”, published by Bentham Science Publishers. His Books on the title of “Text Book of Medicinal Chemistry,” “Pharmaceutical Chemistry of Natural Products,” “Pharmaceutical Inorganic Chemistry,” “Organic Chemistry - A Comprehensive Approach”and “Practical Pharmaceutical Inorganic Chemistry” are well appreciated in the academic community. His research activities are supported by the funding agencies like CSIR, DST and DSIR. Dr. V. Alagarsamy is a member of All India Board of Pharmaceutical Education (AIB-PE), AICTE, New Delhi and a member of board of studies (Pharmacy) in Osmania University, Hyderabad and is a doctoral committee member and a recognized research guide for PhD scholars in various universities. Buy our eBooks on our App “BSP Books” To Download App Scan QR Code BSP B O O K S ISBN : 978-93-89354-77-5 C he m is tr y iContents Pharmaceutical Organic Chemistry Dedication My First & Best Teacher - Beloved Mother Gave me not only Respiration but also Inspiration Shrimathi. V. KAMUTHAI The inspirational words of my mother ringing in my ears are……. “The two most important days in your life are the day you are born and the day you find out why you are born. In your life either write something worth reading or do something worth writing. You should dedicate yourself to your profession and do your best that should answer why you are born.” Whatever the mind of man can conceive and believe, it can achieve. Challenges are what makes life interesting and overcoming them is what makes life meaningful. In order to succeed in your life, your desire for success should be greater than your fear of failure. It does not matter how slowly you go as long as you do not stop. We become what we think about; hence your thoughts should always be of high-quality. Definiteness of purpose is the starting point of all achievement. If you believe you can do it you are halfway there. Whatever you can do, or dream you can, begin it. Boldness has genius, power and magic in it. It will give you the required strength. “Nothing is Impossible in the world, because the word impossible itself says, I’m possible!” When everything seems to be going against you, remember that the aircraft takes off against the wind, not with it. That is why it is reaching the desired destination. If you compromise for others, you cannot reach your destination, instead you will reach others destination. Life shrinks or expands in proportion to one’s courage. Limitations live only in our minds. But if we use our imaginations, our possibilities become limitless. Hence you have enough opportunities in the world if you have courage. Do what you can, where you are, with what you have. You should have a dream in your life and to achieve it if you have good idea and clear plan with full devotion, it will fetch you sure success even if the God says impossible. Because the hard work has its own power, it will never fail. You should not be a product of your circumstances. You should be a product of your decisions. Pharmaceutical organic chemistry is the main branch of organic chemistry deals with the study of preparation, structure and reactions of organic compounds. As it deals with all the chemical reactions related to life, study of Pharmaceutical organic chemistry is important. Application of Organic chemistry in the development of pharmaceuticals, resulted in evolving Pharmaceutical organic chemistry. Hence studying Organic chemistry and applying this knowledge in Pharmaceutical substances is called as Pharmaceutical organic chemistry. Organic chemistry forms the basis of biochemistry, in which various aspects of health and diseases are studied. The biochemical knowledge is very important for the practice of nutritional, medical and related life sciences. In addition Organic chemistry paved way for the development of medicinal chemistry, Pharmaceutical organic chemistry, bioinformatics, biotechnology, gene therapy, Pharmacology, pathology, chemical engineering, dental science and so on. Organic substances play such a vital role in our daily life that all of us should know about organic chemistry in order to understand the manner how it influence our life process. In the given conditions, a specific compound is inert or reactive, and if it is reactive, how will it react? Such knowledge will be used to design the structure of a substance that will have a specifically desired property. We will then know what substance to be used for making the parts for various instruments? Which drug to be used for a specific disease? Many of careers such as Doctors, Engineers, Pharmacists, Veterinarians, Dentists, Pharmacologists and Chemists make use of the knowledge of this fundamental subject. Hence the study of this basic Organic chemistry subject will make you to become successful professionals. The field of organic chemistry is incredibly vast subject. Why is organic chemistry considered to be so difficult? in which “How to start” ? “What to study” ? and “How to study and remember the chemical reactions”? Is this either an antiquated misconception, or is absolutely true ? ? ? The book has been designed to meet the needs of the intended readers with reference to the above questions. Students should start learning organic chemistry by understanding only, not through mechanical memorization like “a poem learnt by rote in childhood”. Organic chemistry is not a difficult subject, and once you understand, it will become an enjoyable subject and you blast your way by proposing your own way of reaction one after another. This book is a product of my vision to design the best book on Pharmaceutical organic chemistry, which deals with the origin of organic chemistry, the concise description of structure of atom & organic molecules and their related properties, the nature of organic reactions & their mechanisms, nomenclature of organic compounds, clear classification of various organic compounds, preparation of each class of organic compounds by various routes, its chemical structure, physical properties and chemical reactions with the mechanism in a simplified manner and drugs derived from each class along with their applications in medicine. Swathing the entire features of Pharmaceutical organic chemistry, first of its kind, is the unique feature of this book. It facilitates the students to understand the subject more easily and make the subject interest. Preface Contentsviii As the students entering graduate course, understanding of Pharmaceutical organic chemistry is always been a difficult task especially the various chemical reactions with their mechanisms of different kind of organic compounds. Hence my efforts have been devoted to authoring a book by equipping with the challenging requirements of the subject for the new generations of the teachers all over India and is easy to read for students who are not necessarily of Pharmacy program, but mainly for the students of first time reading organic reactions, their mechanisms and their applications in science, Pharmacy and medicine. Methodical description of each chapter, enriching chemical and pharmaceutical background of the medicinally important organic compounds, proceeding each group of organic compounds in a systematic way in easy-to-understand style in the larger interest of the students without any difficulty and making the reader acquainted thoroughly with chemistry of organic compounds is the unique feature of this book. In preparing this text book, I have tried to enrich the importance of organic compounds in medicine and pharmacy, so that the anticipated audience of this book will feel the importance of organic compounds and made the book a comprehensive. The students of Pharmacy graduates of our country faced with the scarcity of books to serve their needs. Few of the authors dealt well about the basics of organic chemistry, but the reactions of organic compounds are not presented in a easy to understand manner which students felt difficult to learn. Some of the books of organic chemistry fail to give the chemical structures for all reactions, hence the students are unable to understand the reactions clearly. Hence the content of this book is made as a humble attempt to cater the needs of academicians belonging to all Indian Universities by incorporating the chemical structure of all reactions and enriching basic principles of each organic class of compounds. The book has covered the entire Pharmaceutical organic chemistry, starting from origin of organic chemistry to advanced topics like stereochemistry and heterocyclic compounds and it is divided into 31 chapters. Chapter 1 to 7 deals with the basics of the organic chemistry, wherein the fundamentals like origin and development of organic chemistry, structure of organic molecules and their related properties are described. Classification and nomenclature of organic compounds and general terms used are also presented in a systematic way, which is easy to understood and able to reproduce well in examinations. Chapter 8 to 25 deals with Aliphatic and Aromatic compounds which are further divided into different chapters and each chapter is dealt with Introduction, Importance of each class of compounds, Nomenclature, General methods of preparation, General physical and chemical properties and Pharmaceutically important organic compounds of each chapter are described in a easy to understand manner. Summary of methods of preparation and chemical reactions in a flow chart manner presented is unique and helps student to remember for exam which is the first of its kind. Chapter 26 to 28, Isomerism and detailed description of optical and geometrical isomerism is presented in a simplified manner. Chapter 29 to 30, Heterocyclic rings of various types and their utility in pharmaceutical chemistry is described well. The medicinal compounds derived from each heterocycles also exemplified which makes the reader inspiring. In Chapter 31, Important reactions and reagents used in organic chemistry and some of the special reactions are described with their mechanism and applications in Pharmaceutical organic chemistry. To inspire the readers and make them attracted, interesting facts about great scientists and Organic compounds and their discovery etc are given under each chapters. Preface Preface (vii) Acknowledgement (xi) 1. Introduction to Organic Chemistry Origin of Organic Chemistry 1 The Vital Force Theory “Essence of Life” 1 Definition of Organic Chemistry 2 Reasons for Treating Organic Chemistry as a Separate Branch of Chemistry 2 Rise of Organic Chemistry 5 Need for Studying Organic Chemistry 5 Classification of Organic Compounds 6 Organic Chemistry in the Service of Mankind 8 Probable Questions 8 2. Nomenclature of Organic Compounds Introduction 9 IUPAC System of Nomenclature 9 Steps Involved in Writing IUPAC name of the Compound 16 Writing the Structural Formula from the given IUPAC Name 18 Probable Questions 19 3. Structure of Organic Molecules and their Relative Properties Introduction to Atom/Molecule 21 Wave Nature of Electrons and Wave Equations 21 Quantum Mechanics 23 Atomic Orbitals Involved in Organic Molecules 23 Shells, Sub-Shells and Orbitals 24 Quantum Numbers 24 Shapes of Atomic Orbitals 26 Shape of s Orbital 26 Shape of p Orbital 26 Rules for Distribution of Electrons into various Shells, Subshells and Orbitals 27 Probable Questions 28 4. Bonds in Organic Compounds Introduction 31 The Nature of Bond between Atoms 31 Types of Bonds 31 Ionic Bond or Electrovalent Bond 31 Covalent Bond 31 Co-Ordinate Covalent Bond or Dative Bond 31 Electronic Theory of Valency 35 Characteristic Property of Covalent Bond 35 Bond Length 35 Bond Angle 36 Bond Energy 37 Bond Breaking 38 Bond Order 38 Polarity of Bond and Dipole Moments 38 Types of Orbital Overlapping and their Orbital Diagrams 39 s-s Overlapping 39 s-p Overlapping 40 p-p Overlapping 40 Hybridization 41 Salient Features of Hybridization 41 Conditions for Hybridization 41 Theory of Hybridization for the Formation of Covalent Bond (Sidwick – Powell Theory) 41 Source of Energy required for Hybridization 42 Types of Hybridization 42 sp3 Hybridization or Tetrahedral Hybridization 42 sp2 Hybridization or Trigonal Hybridization 43 sp Hybridization or Diagonal Hybridization 44 Effectiveness of Overlap 45 Molecular Orbital Theory 45 Probable Questions 46 5. Factors Influencing a Chemical Reaction or Electronic Displacements in Molecules Introduction 49 Inductive Effect 49 Types of Inductive Effect 50 Mesomeric and Resonance Effect 50 Types Mesomeric Effect 51 Electromeric Effect 52 Types of Electromeric Effect 53 Resonance 53 Hyperconjugation 55 Probable Questions 55 Contents Contentsxiv 6. Organic Reactions and Mechanism Introduction 57 Bond Breaking (Homolysis and Heterolysis) 57 Homolysis 57 Heterolysis 58 Organic Reagents (Nucleophiles and Electrophiles) 58 Nucleophiles (Nucleous Loving Species or Electron Rich Species) 58 Electrophiles (Electron Loving Species or Electron Deficient Species) 58 Types of Organic Reactions 59 Substitution Reactions 59 Addition Reactions 60 Elimination Reactions 61 Rearrangement Reactions 61 Reaction Mechanisms 62 Reactive Intermediates or Reaction Intermediates 62 Carbonium Ions or Carbocations 63 Carbanions 65 Carbon Free Radicals 65 Carbenes 67 Nitrenes or Imidogens 68 Vinylamines or Enamines or α,β-Unsaturated Amines 68 Probable Questions 69 7. General Terms used in Organic Chemistry General Terms Like Homologues Series 71 8. Alkanes Introduction 99 Importance of Alkanes 99 Nomenclature of Alkanes 100 General Methods of Preparation 104 Summary of General Methods of Preparation of Alkanes 107 Physical Properties 108 Structure 108 Chemical Properties 108 Summary of Chemical Reactions 114 Pyrolysis or Cracking of Alkanes 114 Probable Questions 115 9. Alkenes or Olefins Introduction 117 Importance of Alkenes 117 Nomenclature 119 Isomerism 120 General Methods of Preparation 120 Summary of Methods of Preparation 123 Structure 123 Physical Properties 124 Chemical Properties of Alkenes 124 Summary of Reactions of Alkenes 138 Probable Questions 139 10. Alkadienes or Dienes or Diolefins Introduction 141 Importance of Alkadienes 141 Nomenclature 142 Butadiene 144 Summary of Methods of Preparation 145 Relative Stability of Dienes 145 Stability of Conjugated Dienes 146 Summary of Chemical Reactions 155 Theory of Resonance 155 Resonance Stabilisation of Allyl Radicals - Hyper Conjugation 157 Allyl Cation as a Resonance Hybrid 157 Nucleophilic Substitution in Allylic Substrates: S N 1 Reactivity and Allylic Rearrangement 158 Nucleophilic Substitution in Allylic Substrates 159 S N 2 Reaction 159 Free Radical Addition Reactions of Conjugated Diene 159 Probable Questions 161 11. Cycloalkanes Introduction 163 Importance of Cycloalkanes 163 Nomenclature 164 General Methods of Preparation 165 Physical Properties 167 Chemical Properties 167 Summary of Chemical Reactions 169 Bayer’s Strain Theory or Stability of Cycloalkanes or Ring Strain 170 Molecular Orbital Theory of Cycloalkanes 171 Type of Strains 172 Sache-Mohr Theory 172 Structure of Two Forms of Cyclohexane 172 Axial Hydrogens 173 Equatorial Hydrogens 173 Conformations of Cycloalkanes 173 Drawing Chair Form of Cyclohexane Ring 173 Interconversion of Conformations of Cyclohexane 175 Conformations of Mono Substituted Cyclohexanes 175 xvContents Conformations of Disubstituted Cyclohexanes 176 Coulson and Moffit’s Theory of Maximum Overlapping of Carbon Orbitals 177 Probable Questions 177 12. Alcohols Introduction 179 Importance of Alcohols 179 Monohydric Alcohols 181 Introduction 181 Classification 181 Nomenclature 182 General Methods of Preparation 183 Summary of Methods of Preparation 188 Physical Properties 189 Chemical Properties 189 Structure 189 Reactions Involving Replacement of Hydrogen of the Hydroxyl Group 190 Reactions Involving Replacement of Hydroxyl Group 191 Reactions Involving both Alkyl Group and Hydroxyl Group 192 Chemical Tests for Alcohols 193 Distinction between Primary, Secondary and Tertiary Alcohols 194 Summary of Chemical Reactions 196 Dihydric Alcohols (or) Diols 197 Introduction 197 Nomenclature 197 Trihydric Alcohols (or) Triols 197 Introduction 197 Pharmaceutically Important Alcohols 198 Nitroglycerin 198 Unsaturated Alcohols 199 Vinyl Alcohol 199 Allyl Alcohol 199 Pharmaceutical Importance of alcohols Benzyl alcohol - 200 Cetostearyl alcohol - 200 Chlorbutol - 200 Ethanol - 200 Glycerol - 200 Propylene - 201 Methanol - 201 Qualitative Tests for Alcohols 201 Probable Questions 202 13. Halogen Derivatives or Alkyl Halides Introduction 205 Importance of Alkyl Halides 205 Classification 206 Nomenclature 207 General Methods of Preparation 208 Summary of Methods of Preparation 212 Structure 213 Physical Properties 213 Chemical Properties 214 Nucleophilic Substitution Reactions 215 Elimination Reactions 215 Miscellaneous Reactions 222 Summary of Chemical Reactions 224 Nucleophilic Substitution Reactions 224 Structure and Uses of Ethylchloride 225 Chloroform 225 Trichloroethylene or Trilene 225 Tetrachloroethylene or Perchloro Ethylene 225 Dichloromethane or Methylene Dichloride 225 Tetrachloro Methane or Carbon Tetrachloride 225 Iodoform or Triodomethane 226 Probable Questions 226 14. Nucleophilic Substitution and Elimination Reactions Introduction 227 Components of Nucleophilic Substitution 227 Reaction 227 Mechanisms 227 The S N 2 Mechanism 227 Stereochemistry of S N 2 Reaction 229 Factors Affecting S N 2 Reactions 230 First Order Nucleophilic Substitution Reaction (S N 1) or Unimolecular Nucleophilic Substitution Reaction 238 Stereochemistry of S N 1 Reactions 240 Factors Affecting S N 1 Mechanism 241 Carbocation Rearrangement in S N 1 Reaction 244 Competition between S N 2 and S N 1 244 Comparison between S N 1 and S N 2 Reactions 245 Elimination Reactions 246 Introduction 246 E 2 Mechanism or β-elimination 246 Zaitsev’s Rule 249 Stereochemistry of E 2 Reaction 252 E 1 Reaction or Unimolecular Elimination Reaction 254 Stereochemistry of E 1 Reaction 255 Competition between Substitution and Elimination Reactions 256 Conditions for S N 2/ E 2 257 Contentsxviii 21. Aromatic Amines Introduction 445 Importance of Aryl Amines 446 Nomenclature 448 Primary Amino Compounds 448 General Methods of Preparation 448 Summary of Methods of Preparation 453 Physical Properties 453 Chemical Properties 454 Basicity of Amines 462 Summary of Chemical Reactions 463 Tests for Distinguishing Primary, Secondary and Tertiary Amines 465 Probable Questions 466 22. Aryl Diazonium Salts Introduction 467 Preparation 467 Physical Properties 467 Chemical Properties 468 Summary of Chemical Reactions 476 Probable Questions 477 23. Phenols Introduction 479 Importance of Phenols 480 Phenol 481 Preparation 481 Summary of Methods of Preparation 483 Physical Properties 483 Chemical Properties 484 Acidity of Phenols 484 Summary of Chemical Reactions 496 Uses of Phenol 499 Tests for Identification 500 Homologues of Phenol 500 Methyl Phenols (Cresols) 500 Dihydric Phenols 500 Catechol 501 Resorcinol 501 Quinol 501 Trihydric Phenols 502 Pyrogallol 502 Hydroxyl Quinol 503 Phloroglucinol 503 Aromatic Alcohols 504 Benzyl Alcohol (Phenyl Methanol) 504 Amino Phenols 504 Aromatic Ethers 504 Structure and Medicinal uses of Phenol 505 Cresols 505 Resorcinol 505 Naphthols 505 Probable Questions 506 24. Aromatic Carboxylic Acids and their Derivatives Introduction 509 Importance of Aryl Carboxylic Acids 509 Nomenclature 511 General Methods of Preparation 511 Summary of Methods of Preparation 514 General Properties 514 Individual Members 514 Benzoic Acid 514 Summary of Chemical Reactions 519 Chemical Test for Benzoic Acid 519 Comparison of Benzoic Acid and Phenol 520 Acidity of Aromatic Carboxylic Acids 520 Probable Questions 520 25. Polynuclear Hydrocarbons Introduction 523 Types 523 Naphthalene 523 Manufacture of Naphthalene 523 Synthesis 524 Physical Properties 525 Chemical Properties 525 Uses 530 Anthracene 531 Preparation of Anthracene 531 Synthesis 531 Physical Properties 532 Chemical Properties 532 Uses 534 Phenanthrene 536 Preparation 536 Isolation 536 Synthesis 536 Physical Properties 536 Chemical Properties 537 Uses 538 Diphenyl Methane 539 General Methods of Preparations 540 Chemical Properties 540 Uses 541 xixContents Triphenyl Methane or Tritane 542 General Methods of preparations 542 Physical Properties 543 Chemical Properties 543 Uses 543 Probable Questions 544 26. Isomerism Introduction 545 Types of Isomerism 545 Structural Isomerism or Constitutional Isomerism 546 Tautomerism 549 Stereoisomerism 551 Probable Questions 552 27. Stereoisomerism Introduction 553 Optical Isomerism 553 Chiral Carbon 555 Enantiomers 555 Diastereomers 556 Meso Compounds 557 Chirality and Symmetry of Elements 558 Chiral Molecules 559 Achiral Molecules 560 DL System of Nomenclature 560 Nomenclature of Enantiomers or RS Nomenclature of Optical Isomers 562 Sequence Rules 562 Reactions of Chiral Molecules 567 Racemic Modification 572 Mechanism of Racemisation 572 Walden Inversion 573 Resolution or Separation of Racemic Mixture 573 Asymmetric Synthesis 575 Probable Questions 576 28. Geometrical Isomerism Introduction 577 Nomenclature of Geometrical Isomers 579 Determination of Configuration of Geometrical Isomers 581 Conformations of Alkanes 588 Conformational Isomerism in Ethane 589 Conformational Isomerism in n-Butane 590 Conformations of Cycloalkanes 592 Drawing Chair form of Cyclohexane Ring 592 Interconversion of Conformations of Cyclohexane 594 Conformations of Mono Substituted Cyclohexanes 594 Conformations of Disubstituted Cyclohexanes 595 Stereoisomerism in Biphenyl Compounds 596 Conditions for Biphenyls to show Optical Isomerism 597 Conditions for Optical Activity 598 Stereoselective and Stereospecific Reactions 598 Probable Questions 601 29. Heterocyclic Compound (Part 1) Introduction to Heterocyclic Compounds 603 Pharmaceutical Applications of Heterocyclic Compounds 604 Nomenclature of Heterocyclic Compounds 607 Classification of Heterocyclic Compounds 611 Pyrrole (Azacyclopenta-2,4-diene) 618 Introduction 618 Isolation 618 General Methods of Preparation 618 Structure 619 Physical Properties 620 Chemical Properties 621 Basic Nature of Pyrrole 621 Acidity of Pyrrole 621 Pyrrole Derivatives 626 Medicinal Compounds Containing Pyrrole (or) Pyrrole Derivatives Used in Medicine 627 Furan/Furfuran (Oxacyclopenta-2,4-diene) 628 Introduction 628 Isolation 629 General Methods of Preparation 629 Structure 629 Physical Properties 630 Chemical Properties 630 Furan Derivatives 634 Tetra Hydro Furan(THF)/ Oxolane/Oxacyclopentane 634 Medicinal Compounds Containing Furan (or) Furan Derivatives Used in Medicine 638 Thiophene (Thiocyclopenta-2,4-diene) 639 Introduction 639 Isolation 640 General Methods of Preparation 640 Structure 641 Physical Properties 641 Chemical Properties 641 Contentsxx Medicinal Compounds Containing Thiophene (or) Thiophene Derivatives Used in Medicine 646 Relative Aromaticity and Reactivity of Pyrrole, Furan and Thiophene 647 Probable Questions 648 30. Heterocyclic Compounds (Part 2) Azoles 649 Types of Azoles 649 Structure of all Azoles 650 Pyrazole 650 General Methods of Preparation 651 Synthesis of Substituted Pyrazoles 651 Physical Properties 652 Chemical Properties 652 Medicinal Compounds Containing Pyrazole (or) Pyrazole Derivatives used in Medicine 654 Imidazole (iminazoline) 655 General Methods of Preparation 655 Synthesis of Substituted Imidazoles 656 Physical Properties 656 Chemical Properties 656 Medicinal Compounds Containing Imidazole (or) Imidazole Derivatives used in Medicine 658 Oxazole 661 General Methods of Preparation 661 Synthesis of Substituted Oxazole 661 Chemical Properties 662 Medicinal Compounds Containing Oxazole Derivatives used in Medicine 663 Thiazole 663 General Methods of Preparation 664 Physical Properties 664 Chemical Properties 664 Medicinal Compounds Containing Thiazole (or) Thiazole Derivatives used in Medicine 665 Six Membered Heterocycles with One Hetero Atom 666 Pyridine 666 Nomenclature 666 Structure of Pyridine 667 General Methods of Preparation 668 Chemical Properties 669 Medicinal Compounds Containing Pyridine (or) Pyridine Derivatives used in Medicine 673 Quinoline (1-Azanaphthalene or Benzopyridine) 676 Introduction 676 General Methods of Preparation 677 Physical Properties 678 Structure 678 Chemical Properties 679 Medicinal Compounds Containing Quinoline (or) Quinoline Derivatives used in Medicine 683 Isoquinoline (2-Azanaphthalene (Or) Benzo[b]Pyridine) 684 General Methods of Preparation 684 Physical Properties 686 Chemical Properties 686 Medicinal Compounds Containing Isoquinoline (or) Isoquinoline Derivatives used in Medicine 688 Acridine 689 General Methods of Preparation 690 Physical Properties 691 Chemical Properties 691 Medicinal Compounds Containing Acridine (or) Acridine Derivatives used in Medicine 692 Indole (1H-1-Azaindine/Benzopyrrole) 693 General Methods of Preparation 693 Structure 695 Physical Properties 695 Chemical Properties 695 Indole Derivatives 700 Medicinal Compounds Containing Indole (or) Indole Derivatives used in Medicine 702 Pyrimidine 703 General Methods of Preparation 703 Medicinal Compounds Containing Pyrimidine (or) Pyrimidine Derivatives used in Medicine 703 Purine 706 General Methods of Preparation 707 Medicinal Compounds Containing Purine (or) Purine Derivatives used in Medicine 708 Azepines 710 General Methods of Preparation of Azepine and its Derivatives 710 Medicinal Compounds Containing Azepine (or) Azepine Derivatives used in Medicine 711 Probable Questions 712 31. Reactions and Reagents of Synthetic importance Sodium Borohydride (NaBH 4 ) 713 Method of Preparation 713 Advantages 713 Applications 713 Lithium Aluminium Hydride (LiAlH 4 ) 714 Preparation 714 Properties 714 Advantages 715 Applications 715 Pharmaceutical Organic Chemistry10 Rule 2: Lowest number for substituents rule: After selecting the longest chain, the numbering should be given from one end to the other end. While giving the number, the substituents should be given lowest possible number. For example, the compound given below is named in two ways. In first case, naming 4,7-dimethyl octane is not correct because 2,5-di methyl octane have lowest numbers for the substituents. If different alkyl groups are in equivalent positions in relation to the end of the chain, preference is given to the end where the radical has fewer carbon atoms (methyl, ethyl, etc). In the following example, the first case of naming is correct because methyl group is given preference over ethyl group. 11Nomenclature of Organic Compounds If identical radicals are at equal distance in the chain then the numbering starts from the end where it is more branched. In the following example, the first way of naming is correct where the branching end is given preference. If two sets of numbers are possible for the given chain, then order of prefix in the name will decide the numbering (alphabetical order of the substituents). For example, the given compound can be named as 1-bromo-4-chloro butane or 1-chloro-4-bromo butane. As the prefix bromo is first, the first name is correct. If chains of equal length are competing for selection as the parent chain in a branched alkane, the preference goes to the chain carrying more branches. For example, in the given organic compound first way of naming i.e., 3-ethyl-2,6-dimethyl heptane is correct where as 5-isopropyl-2-methyl heptane is wrong. Pharmaceutical Organic Chemistry12 Rule 3: Arrangement of prefixes: When there is more than one group attached in the chain, they should be arranged alphabetically. If same group is presented in two or three places of chain then the prefix di or tri etc are used. For example, the given organic compound is named as 5-ethyl-2,3-dimethyl heptane. Rule 4: Lowest number for functional group: When the functional group is present in the chain, it should be given first preference even if it violates lowest number rule 2. Double bond or triple bond also considered as functional groups. The order of preference of numbering is as follows. (i) To the principal functional group of a compound. (ii) To the double or triple bond. (iii) To the substituent atoms or groups. When more than one functional group present in the compound, then the order of preference is as follows. 1. Carboxylic acids 2. Carboxylic acid derivatives 3. Aldehydes 4. Nitriles 5. Ketones 15Nomenclature of Organic Compounds Table 2.4 Nomenclature of some unsaturated compounds of Simple Functions. Table 2.5 Nomenclature of some compounds of complex Functions. Pharmaceutical Organic Chemistry16 Rule 6: Treatment of “like things alike”: All groups of one kind which occurs in a single molecule should be given the same treatment as far as possible. For example, in the given example carboxylic acid is the main functional group, the parent compound should include two or three functional groups as possible. Rule 7: Functional groups and the selected chain: Maximum number of functional groups must be included in the carbon chain even if it violates longest chain rule (Rule 1), as shown in the following example. When there is a side chain with side chain, the latter is numbered and the name of the complex is considered to start with the first letter of its complete name, as shown in the following example. In addition to these rules, following points mentioned are also useful in writing IUPAC name of compound. Steps involved in writing IUPAC name of the compound Step 1: Locate the longest chain containing principal functional group and as many as secondary functional group and carbon-carbon multiple bonds. 17Nomenclature of Organic Compounds Step 2: Select the root word corresponding to the chain length. For example Hex for six carbon atom chain. Step 3: Number the longest chain selected from the end near to the principal functional group. Step 4: Based on the carbon-carbon bonds attach the suffix -ane, -ene or yne respectively to the root word of carbon chain. Step 5: Add suitable prefixes and suffixes with numerals to indicate the number and position of each side chain, substituent, or functional group. Example: Notes: 1. Position of numerals used in the enumeration of substituents: Numerals representing location of unsaturation or functional groups are placed before the name stem as 2-Pentene not pentene-2 1-Chloro-2-pentene not 1-chloropentene-2 1-hexene-3-yne Not hexenyne-3. 2. Writing names: The names of radical replacing hydrogen atom in compound are carried out. For example, Chlorotoluene (chlorine replaced “H” atom of toluene). Elision of vowels: To avoid ambiguity vowels, whether pronounced or silent are generally retained in systematic naming. This results in using of double vowels, e,g, cyclooctane. Pharmaceutical Organic Chemistry524 centrifugation or pressing out the oil in a hydraulic press. The crystals obtained are washed with water and with sodium hydroxide solution in a centrifuger to remove adhered oil and phenols. Then it is treated with conc. H2SO4 to remove the alkaline impurities, the crude naphthalene obtained is purified by sublimation and further purified by recrystallisation with petroleum ether. Nowadays the "hot processing process" is replaced by continuous washing or distillation. Synthesis 1. From petroleum fractions: Petroleum fractions are passed over a heated copper catalyst at 680 oC at atmospheric pressure to give naphthalene and methyl naphthalene and the later undergoes hydro dealkylation to give naphthalene. 2. Haworth synthesis: Benzene is treated with succinic anhydride followed by reduction to yield γ- phenyl butyric acid. The later one undergoes ring closure reaction in the presence of conc. H2SO4 to yield α-tetralone. Reduction of α-tetralone with Zn(Hg)/HCl yields tetrahydronaphthalene (tetralin) which upon further dehydrogenation yields naphthalene by heating with selenium or palladised charcoal. The sequence of the chemical reactions are as follows. Ring closure is also effected by Friedel-Crafts reaction on acid chlorides as shown below. 525Polynuclear Hydrocarbons 3. From 4-phenyl-1-butene: When 4-phenyl-1-butene is passed over red-hot calcium oxide naphthalene is obtained. 4. From 4-phenyl-3-butenoic acid: When 4-phenyl-3-butenoic acid is warmed with conc. H2SO4 1- napthol is formed which upon further distillation with Zn dust yields naphthalene. Physical Properties: It is a colorless crystalline substance with characteristic odour (moth ball odour). It is very volatile and readily sublimes on heating. It is insoluble in water but soluble in organic solvents. Chemical Properties: Chemical properties of naphthalene resembles to that benzene. It is less aromatic than benzene and forms substitution products more readily than benzene. Like alkenes it forms addition products readily than benzene. But as soon as one of the rings is saturated or destroyed by oxidation, the second ring is stable as the benzene ring. The important characteristic reactions of naphthalene are as follows. (I) Addition reactions. (II) Electrophilic aromatic substitution reactions. (I) Addition reactions 1. Addition of hydrogens: Naphthalene gives different kind of products depending upon the type of reducing agents used. (a) With catalytic reduction using nickel yields decalin or decahydro naphthalene (b) With sodium and alcohol, naphthalene gives 1,4-dialin (dihydronaphthalene). Pharmaceutical Organic Chemistry526 (c) With sodium and isopentanol naphthalene gives 1,2,3,4- tetrahydro naphthalene or tetralin. 2. Addition of chlorine: Solid naphthalene reacts with dry chlorine to give naphthalene di and tetra chlorides. Both of them undergo oxidation to yield phthalic acid. It indicates that the halogen atoms are present in the same ring. The naphthalene dichloride when heated at 310 K, loses one molecule of hydrogen chloride and gives 1-chloro naphthalene. Naphthalene tetrachloride on treatment with alkali gives dichloro naphthalene. 3. Addition of sodium: Naphthalene upon reaction with sodium gives 1,4-disodio naphthalene which reacts further with carbon dioxide with the formation of sodium salt 1,4-dihydro naphthalene-1,4-di carboxylic acid. 529Polynuclear Hydrocarbons But naphthalene reacts with ethyl bromide to yield 2-ethyl naphthalene. (b) With acetyl chloride: Naphthalene reacts with acetyl chloride and AlCl3 to yield a mixture of 1-naphthyl methyl ketone & 2-napthyl methyl ketone. The composition of mixture obtained depends upon the nature of the solvent and the temperature used. For example, in the presence of CS2 at 260 K, the 1 and 2 - derivatives are obtained in 3:1 ratio while in the presence of nitrobenzene at 298 K the product obtained is in 1:9 ratios. 5. Chloro methylation: Naphthalene reacts with formaldehyde/HCl and glacial acetic acid, gives 1-chloro methyl naphthalene with a small amount of 1,5-bis chloromethyl naphthalene. 6. Oxidation: Naphthalene gives different kind of products on oxidation. The products formed depend upon the nature of the oxidizing agents used. The various kind of oxidation reactions are as follows. (i) With potassium permanganate: Naphthalene reacts with acidic KMnO4 and alkaline KMnO4 to give phthalic acid and phthalonic acid respectively. (ii) With chromic acid: Naphthalene when oxidised with chromic acid yields 1,4-naphthaquinone. Pharmaceutical Organic Chemistry530 (iii) Naphthalene reacts with conc. H2SO4 and mercuric sulphate or air in the presence of vanadium pentoxide and yields phthalic anhydride. (iv) With ozone: Naphthalene is oxidized with ozone to give diozonide which upon hydrolysis gives phthalaldehyde. Uses: 1. It is used as an insecticide and for preventing moths in clothes. 2. Large amount of naphthalene is used in industry for the manufacture of various dye stuffs such as indigo, azo dye and eosin. 3. It is also used for manufacturing of phthalic anhydride, phthalic acid and phthalimide etc. 4. Local gas is carbureting with naphthalene. Medicinally useful compounds containing naphthalene Table Contd... 531Polynuclear Hydrocarbons Anthracene Anthracene is another example of fused aromatic hydrocarbons in which three benzene rings fused together in the o-positions. Anthracene is present in coal tar less than 1%. The name derives from the Greek word anthraz (means coal). High boiling point fraction of coal tar also contains anthracene, hence called as anthracene oil. Preparation of anthracene: Coal tar is a chief source of anthracene and it contains 0.25-0.45% of anthracene. It is present in anthracene oil or green oil along with phenanthrene, carbazole and other substances. Anthracene oil is allowed to stand in shallow tanks where by a viscous mass separates out and the crude anthracene (20%) is removed by filtration. During this, the anthracene content increases up to 35% and some amount of oil is removed by centrifuge when 50% anthracene is obtained. The resulting product is powdered and washed with solvent naphtha which dissolves out phenanthrene and then treated with pyridine which removes carbazole. Anthracene is finally crystallized out from benzene. Synthesis 1. Haworth synthesis: Benzene reacts with phthalic anhydride in the presence of AlCl3to yield o-benzoyl benzoic acid, which upon reaction with conc. H2SO4 to yield 9,10-anthraquinone. The later obtained is distilled with Zn, and yields anthracene. 605Heterocyclic Compounds (Part 1) Cimetidine is one of the major leading drug in 1970s and 1980s being the first non-surgical treatment of peptic ulcer. Further development of cimetidine analogues are promoted by changing the heteroyclic ring in the cimetidine molecule. Ranitidine, pyrrole ring of the cimetidine is replaced by furan, is also a successful drug for the treatment of peptic ulcer. Development of Nucleoside Analogues In the search for drugs to combat cancer and virus modification in the structure of DNA is the best approach by synthesizing the nucleosides. These analogues consists of pyrimidine and purine nucleus which is attached to a sugar moiety as shown in the following examples. Various nucleic acid analogues are developed by the structural modifications of heterocycles or sugar or both and yielded the important drugs as mentioned below. Pharmaceutical Organic Chemistry606 Development of Alkaloidal Drugs Development of Serotonin Analogues Serotonin: Vasoconstrictor drug obtained from natural source is widely distributed in nature but present only in very low concentration. It was first extracted from natural source in 1948. Synthesis of this drug was done in laboratories after few years and it is used for investigating the mechanism of action. The main pharmacological actions of serotonin includes constriction of brain arteries, behavourial changes in the body etc,. But the main drawback of serotonin is that it is too rapidly metabolised in the brain. This was overcome by designing the serotonin analogues and the simple indole derivative of serotonin such as sumatriptan was developed by researchers which acts as a selective agonist at serotonin receptor sites in the brain and used as a drug of choice for the treatment of migraine. Ergot alkaloids: Ergotamine: An indole alkaloid possesing aminoethyl side chain at 3rd position, is used in migraine at low doses. But the drug is highly toxic and not in use. But its synthetic analogue lysergic acid diethylamide (LCD) is discovered and it is now notorious as a hallucinogen. 607Heterocyclic Compounds (Part 1) Nomenclature of Heterocyclic Compounds Heterocyclic compounds are named by using trivial names as well as systematic names. Trivial name does not provide the detailed information about the structure but still it is used (In recent years the IUPAC has made efforts to systematize the nomenclature of heterocyclic compounds). According to the IUPAC system, following guidelines are used for naming the heterocycles. 1. The monocyclic compounds are named by a prefix which is derived from the nature of the hetero atom present in it (Eliding “a” where necessary). Some of the rings and their prefixes are indicated in the following Table 29.1. 2. If the same hetero atom is present more than one time, the prefixes di, tri etc are used. For example: dioxa, triaza etc. 3. If different heteroatoms are present in the ring, the naming starts from the atom which is high group in periodic table and as low in atomic number in that group. Hence the order of naming is as follows O, S, N, P, Si etc. 4. When the size of the monocyclic ring is from 3 to 10, they are indicated with suffixes which are mentioned in the Table 29.2. Table 29.1 Prefix for Hetero Atoms. Pharmaceutical Organic Chemistry610 Five membered rings: Six membered rings: Condensed heterocycles: 611Heterocyclic Compounds (Part 1) Classification of Heterocyclic Compounds I. Three membered heterocyclic compounds with hetero atom. (a) With nitrogen (b) With oxygen (c) With sulphur Pharmaceutical Organic Chemistry612 II. Three membered heterocyclic compounds with two hetero atoms. (a) With two nitrogen atoms (b) With one nitrogen and one sulphur atoms: (c) With one nitrogen and one oxygen atoms: III. Four membered heterocyclic compounds with one hetero atom. (a) With nitrogen (b) With oxygen atom 615Heterocyclic Compounds (Part 1) (d) With two oxygen atoms VI. Six membered heterocyclic compounds with one hetero atom. (a) With nitrogen atom (b) With oxygen (c) With sulphur Pharmaceutical Organic Chemistry616 VII. Six membered heterocyclic compounds with two hetero atoms. (a) With two nitrogen atoms (b) With oxygen and nitrogen atoms (c) With nitrogen and sulphur atoms (d) With three nitrogen atoms Fused rings 617Heterocyclic Compounds (Part 1) VIII. Seven membered heterocyclic compounds. IX. Bicyclic ring systems from pyrrole, furan and thiophene (fused five membered ring system). Heterocycles with Trivial names. X. Tricyclic heterocyclic compounds.