Pharmaceutical Organic Chemistry-1 (PC 102) Lecture Notes

Pharmaceutical Organic Chemistry-1 (PC 102) 1 Pharmaceutical Organic Chemistry-1 (PC 102) DR. PETER AMIR HALIM Associate Professor of Pharmaceutical Organic Chemistry Faculty of Pharmacy...

Pharmaceutical Organic Chemistry-1 (PC 102) 1 Pharmaceutical Organic Chemistry-1 (PC 102) DR. PETER AMIR HALIM Associate Professor of Pharmaceutical Organic Chemistry Faculty of Pharmacy Cairo University Email : [email protected] Office Hours: Saturday: 08:30-12:30 Monday: 10:30-12:30 2  Pharmaceutical Organic Chemistry-1 (PC 102) Course Specifications The course aims to give general introduction to the fundamental concepts of organic chemistry. The course covers many classes of aliphatic and aromatic compounds regarding their nomenclature, physical properties, methods of preparation and different reactions. The aim of the course is to ensure that the graduated pharmacist achieved the competencies of integration of the knowledge obtained from studying this course with advanced courses to ensure that students understand the basics of organic chemistry. The knowledge and skills gained will help the students identify and synthesize organic compounds. 3  Pharmaceutical Organic Chemistry-1 (PC 102) Course Specifications, learning outcomes of the course 1.1.1.1. Understand the basics of aliphatic and aromatic organic chemistry science. 1.1.1.2. Recognize the concepts of aliphatic and aromatic organic chemistry reactions. 1.1.1.3. Classify different organic compounds with different functionalities. 1.1.2.1. Define basic and important scientific terms related to organic chemistry. 1.1.3.1. Apply the knowledge of different organic classes for their preparations using the appropriate synthetic routes. 4  Pharmaceutical Organic Chemistry-1 (PC 102) Course Specifications, learning outcomes of the course 2.2.1.1. Select the appropriate method of identification of organic compounds from both its physical properties and chemical reactions (reactions of functional groups) adopting the Good Lab. Practice (GLP) rules and regulations. 2.2.1.2. Synthesis of more complex compounds from simpler ones. 2.3.1.1. Performing the ecofriendly techniques and MSDS importance in dealing with labs. 4.2.1.1. Communicate effectively both in orally and in written way. 5  Pharmaceutical Organic Chemistry-1 (PC 102) Course Specifications, learning outcomes of the course No. of credit Topics hours General introduction (Electronegativity, Types of Chemical Bonds, Hybridization of carbon, 1 Classes of Carbons and Hydrogens, Electronic Effect Exerted by Substituents, Types of 2 Bond Cleavage, Carbon Containing Intermediates). General introduction continued (Types of Chemical Reagents, Families of Organic 2 Compounds, Types of Organic Reactions, Alkanes). 2 3 Alkanes (Nomenclature / Cycloalkanes ) 2 4 Alkenes (Nomenclature, Preparation and Reactions) 4 5 Alkynes + Reactions of Alkynes 2 6 Aromaticity 2 7 Electrophilic Aromatic Substitution Reactions 2 8 Orientation in Electrophilic Aromatic Substitution Reactions 2 9 Arenes 2 10 Revision 2 6 Pharmaceutical Organic Chemistry-1 (PC 102) Assessment Weighting Periodical 20 Marks Practical Examination 40 Marks Final-term Examination 75 Marks Oral Examination 15 Marks Total 150 Marks 7  Pharmaceutical Organic Chemistry-1 (PC 102) References Essential Books (Textbooks) Reference 1: R.T. Morrison and R. N. Boyed, 2011, Org. Chem. 9th. Edition. Reference 2: ‎T.W. Graham Solomon’s, 2013, Organic Chemistry 7th edition. Reference 3: T. W. Graham Solomons, 2014, Org. chem. 10th. Edition. Recommended Books 1-Advanced Practical Organic Chemistry. 2-Advanced Organic Chemistry 5th Edition, Francis A. Carey and Richard J. Sundberg PART A: Structure and Mechanisms. PART B: Reactions and Synthesis. 3-Experimental Organic Chemistry, James F. Norris, 2nd edition. 4-Organic Spectroscopy (NMR, IR, Mass and UV). 5-Organic Synthesis: Strategy and Control. 8  Pharmaceutical Organic Chemistry-1 (PC 102) Course Specifications, learning outcomes of the course 1.1.1.1. Understand the basics of aliphatic and aromatic organic chemistry science. 1.1.1.2. Recognize the concepts of aliphatic and aromatic organic chemistry reactions. 1.1.2.1. Define basic and important scientific terms related to organic chemistry. 2.2.1.2. Synthesis of more complex compounds from simpler ones. 4.2.1.1. Illustrate the structure elucidation of different organic compounds based on their spectral data. 9 Pharmaceutical Organic Chemistry-1 (PC 102) LECTURE 1: INTRODUCTION 10 Pharmaceutical Organic Chemistry-1 (PC 102) BASICS (GENERAL INTRODUCTION) i. ELECTRONEGATIVITY (EN) ii. TYPES OF CHEMICAL BONDS iii. HYBRIDIZATION iv. CLASSES OF CARBONS AND HYDROGENS v. ELECTRONIC EFFECT EXERTED BY SUBSTITUENTS (G) vi. TYPES OF BOND CLEAVAGE vii. CARBON CONTAINING INTERMEDIATES 11 What is the Organic Chemistry ?  Organic chemistry is the study of carbon compounds. But why is carbon special? The answer derives from the position of carbon in the periodic table. As a group 4A element, carbon atom can share four valence electrons and form four strong covalent bonds.  Furthermore; carbon atom can bond to another atom, forming long chains and rings. Of all elements, carbon alone is able to form an immense diversity of compounds, from simple methane, containing one carbon atom, to complex DNA, which can contain tens of billions of atoms. 12 Electronegativity measures the tendency or the ability of an atom to attract a bonding pair of electrons from a chemical bond. EN increases in the same period (horizontal row) of the periodic table with the increase in the atomic number (left to right). EN decreases as we go down in the group (vertical column). Periods Groups Groups 13 14. According to the difference in EN between 2 atoms, we can determine the type of chemical bond. 1. Ionic Bond 2. Covalent Bond:  Non-Polar Covalent Bond  Polar Covalent Bond 15 1- Ionic bond:  Is a type of chemical bond resulting from the transfer of one or more valence electrons from one atom, typically a “metal to  a nonmetal’’. Metal loses an electron‎to become +vely‎charged, called a cation while‎ Non-Metal gains an‎electron‎to become‎-vely‎charged, called an‎anion.  Usually formed between elements at the extreme of the periodic table, i.e. formed between atoms widely different in EN (> 2) e.g. Na + F Na+F- 16  2- Covalent bond: A class of chemical bonds where valence electrons are shared between two atoms, typically two nonmetals. Covalent Bonds are of 2 types: (a) Non-polar & (b) polar. (a) Non-polar covalent bond: A bond between 2 non-metal atoms that have the same electronegativity and therefore have equal sharing of the bonding electron pair. It is formed if EN difference between the 2 bonded atoms = Zero e.g. In chlorine molecule, 2 chlorine atoms are equal in EN, therefore, bond is non-polar. Cl Cl e.g. In ethane, the bond between carbon atoms is non-polar. 17  2- Covalent bond: (b) Polar covalent bond: A bond between 2 non-metal atoms that have difference in electronegativity and therefore have Unequal sharing of the bonding electron pair creating positive and negative poles (or charges). It is formed when the difference in the EN is < 2. The more electronegative atom pulls the electron pair towards it and acquires a partial negative charge (δ-) while the atom of lower electronegativity acquires a partial positive charge (δ+). e.g. 18 Summary 19. C6, Electronic configuration of ground state carbon: 1S2 2S2 2P2 (2px1 2py1 2pz)  Q. Does that mean that “C” forms 2 bonds bec. it has 2 unpaired e- orbitals (2px and 2py orbitals) ? No, C forms 4 bonds due to Hybridization. ‫تهجين‬ It is the concept of mixing atomic orbitals into new hybrid orbitals (with different energies, shapes, etc., than the component atomic orbitals) suitable for the pairing of electrons to form chemical bonds. 20. sp3 Hybridization Occurs only in compounds containing single bonds. e.g. methane, ethane, propane. In the excited state, one of the paired electrons in 2s atomic orbital is promoted to vacant 2p orbital. Then, the s orbital and the three p orbitals are combined or hybridized to give four equivalent atomic orbitals called sp3 hybrid orbitals. e- Promotion to 2pz and its hybridization to form Sp3 The four sp3 hybrid orbitals surround the carbon nucleus will arrange themselves in three dimensional space to get as far apart as possible (to minimize repulsion). The geometry that achieves this is: tetrahedral geometry which gives idealized bond angles of 109.5o. 21. sp3 Hybridization e.g. Methane, CH4 Four sp3 hybrid orbitals are overlapped (head to head overlap-sigma bonds) with 4 hydrogens 1s orbitals. yielding four σ (sigma) bonds (that is, four single covalent bonds) of equal length and strength. 4 (sp3-1s) bond. N.B. σ‎(sigma)‎bonds are very strong bonds. 22. sp2 Hybridization  When carbon atom is bonded to another atom by a double bond, the carbon is sp2 hybridized as in ethene.  Each carbon atom is sp2, trigonal planar with bond angle 120○. Promotion of an electron from the 2s to the 2p orbital then the 2s orbital mix with two of the three 2p orbitals to give three equivalent half-filled sp2 hybrid orbitals plus 1 p orbital left unhybridized (pure P orbital). 23. sp2 Hybridization Ethene: sp2 carbon atoms overlap with each other forming C-C σ-bond. Therefore, each carbon atom still has ‎ 2sp2 electrons, each of these overlap with 1S electron of hydrogen forming C-H‎σ-bond. The remaining Pz electron of each atom overlapping (lateral or side by side overlap) resulting in formation of pi bond. (𝜋) N.B. ‎𝜋-bond is very weak bond. 24. sp Hybridization Acetylene: (Ethyne)  When a carbon atom is joined to only two other atoms the carbon is sp hybridized as in acetylene C2H2.  Each carbon in acetylene is sp hybridized, linear with bond angle 180○. N.B. 1) Triple bond is formed of one  bond and two  bonds. 2) The shape of all hybridized orbitals are similar but the s character increase from sp3 to sp (sp> sp2 > sp3 in s character). 25. Determining The Hybridization Of An Atom In A Molecule Here’s what you should do: 1. Look at the atom. 2. Count the number of atoms connected to it (atoms – not bonds!) 3. Count the number of lone pairs attached to it. 4. Add these two numbers together. If‎it’s‎4, your atom is sp3. If‎it’s‎3, your atom is sp2. If‎it’s‎2, your atom is sp. (If‎it’s‎1,‎it’s‎probably‎hydrogen!) 26. 27. 28. ** Carbon atoms can be classified into: A Primary (1O) carbon: is the one that is bonded to only one other carbon. A Secondary (2O) carbon: is bonded to two other carbons. A Tertiary (3O) carbon: that is bonded to three other carbons. A Quaternary (4O) carbon: it is the carbon bonded to four other carbon atoms. Hydrogen atoms are classified on the basis of the carbon atom to which they are attached, primary (1°), secondary (2°), tertiary (3°) 29. 1- Inductive effect (I): It is the unequal sharing of electrons in  bond between 2 atoms, with Difference in EN. i.e. Electron displacement along the chains via  bond orbitals. (-I) effect: means electron withdrawing towards the substituent (G): when G = F, Cl, Br, I, OH, NH2, NO2 (electron withdrawing atom or group) e.g. (+I) effect: means electron donating away from (G): when G = Li, Mg ,Cd (electron donating atom or group) e.g. The effect becomes less as it proceeds away from the substituent (G) i.e. the effect decreases with the increase in distance from substituent. 30. 2- Mesomeric effect (M) or Resonance effect (R): It is the redistribution (delocalization) of electrons which takes place in unsaturated systems and especially in conjugated systems via their  bond orbitals to achieve a more stable structure. The mesomeric effect is‎positive (+M) when the substituent is an electron-releasing group. The mesomeric effect is negative (–M) when the substituent is an electron-withdrawing group. 31. 2- Mesomeric effect (M) or Resonance effect (R): + M effect : Electron Releasing Group e.g. - M effect: Electron Withdrawing Group e.g. Carbonyl group If the carbonyl group is conjugated with C = C bond, the above polarization can be transmitted further via the  - electrons. O O CH2=CH-CH=CH-C-H CH2-CH=CH-CH=C-H (- M) Delocalization takes place, so that an electron deficient atom results at C-5. 32. 2- Mesomeric effect (M) or Resonance effect (R): An example of delocalization via M effect in a conjugated system: H H C CH2 C CH2 H2C C 1,3-Butadiene H2C H C H (A) (B)  The essential differences between I & M effects: 1. Inductive effect occurs in saturated compounds (C-C), while the mesomeric effect occurs in unsaturated (C=C), specially conjugated systems. 2. (I) effect involves the electrons in  bonds, while the latter (M) effect in  bonds. 3. (I) effects are transmitted over only short distance in saturated chains whereas (M) effects may be transmitted from one end to the other of large molecules provided that conjugation is present through which they can proceed. 4. (M) effects are stronger than (I) effects specially in stability. 33. During chemical reaction bonds break in the reactants, and new bonds are formed in the products. Bond cleavage may occur‎(1) Homolytically or‎(2) Heterolytically. 1) Homolytic Cleavage: Each atom involved in the covalent bond receives one electron from the original shared pair. Cleavage homolytically leads to intermediate known as free radical. Free radical reactions occurs in: (Conditions) 1. Sunlight. Free radicals 2. At high temperature. 3. In the presence of free radical initiators‎e.g. (H2O2) or any peroxides ROOR'. Free radicals are neutral highly reactive species since they need to complete their outer shell of electrons. 34. Examples of Homolytic Cleavage: 2) Heterolytic Cleavage: Both electrons forming the covalent bond go to one atom. Heterolysis of a bond leads to the formation of carbocation and carbanion intermediates. A less electronegative Examples of Heterolytic Cleavage:. 1. Carbocations: They are positively charged species containing a carbon atom having only 6 electrons in 3 covalent bonds. Carbocation carbon is sp2 hybridized C and its shape is planar. +I effect of R groups stabilizes the carbocations. Order of stability of carbocations:  Tertiary carbocation is more stable as it is surrounded by 3 R groups (3 +I) than secondary surrounded by 2 R groups (2 +I) than primary carbocation surrounded by 1 R group (1 +I). 36. 2. Carbanions: They are negatively charged species containing carbon atom with 3 bonds and unshared pair of electrons. Carbanion carbon is sp3 hybridized C and its shape is tetrahedral. +I effect of R group destabilizes the carbaninon. Order of stability of carbanions:  Primary carbanion as it is surrounded by 1 R group (+I) more stable than secondary carbanion as it is. surrounded by 2 R groups (2 +I) more stable than tertiary carbanion as it is surrounded by 3 R groups (3 +I). 37. 3. Free radicals: They are electrically neutral species with one odd electron. Order of stability of free radicals: It needs electrons to complete Octet  Tertiary free radicals more stable as it is surrounded by 3 R groups (3 +I) than secondary surrounded by 2 R groups (2 +I) than primary free radicals surrounded by 1 R group‎(1 +I). 38 39