Pharmaceutical Organic Chemistry I PC101 Lectures PDF

Pharmaceutical Organic Chemistry I PC101_1 Introduction for Organic Chemistry Mona S. El-Zoghbi, Ph. D. Pharm. Sc. Associate professor of pharmaceutical Chemistry Pharmaceutical Chemistry Department [email protected] We...

Pharmaceutical Organic Chemistry I PC101_1 Introduction for Organic Chemistry Mona S. El-Zoghbi, Ph. D. Pharm. Sc. Associate professor of pharmaceutical Chemistry Pharmaceutical Chemistry Department [email protected] Week No. Topic Contact hours 1 Introduction to Organic Chemistry (Part 1) 2 2 Introduction to Organic Chemistry (Part 1I) 2 3 Alkanes (Nomenclature, preparation, reactions) 2 4 Cycloalkanes & Alkenes (Nomenclature, preparation, reactions) 2 5 Alkynes & Alkyl halides (Nomenclature, preparation, reactions) 2 6 Aromaticity 2 7 Mid Term Exams 8 Arene compounds 2 9 Arene compounds (Conti.) 2 10 Stereochemistry 2 11 Stereochemistry (Conti.) 2 12 Stereochemistry (Conti.) 2 13 Stereochemistry (Conti.) 2 14 Oral/ Practical Exams - 15 Final Exams -  Assessment schedules/semester Assessment’s methods Time of Assessments Grading Written exam 15th to 16th week 75 Marks Practical exam 11th week 40 Marks Oral exam 15th to 16th week 15 Marks Periodical exams 6th week 15 Marks 5 Marks Student activities weekly Content: What is the organic chemistry? The Periodic Table The atomic number The mass number Types of bonds Valence Electronegativity Sigma bond and pi bond Organic Chemistry It is the chemistry of all carbon compounds Four elements, hydrogen, carbon, oxygen and nitrogen, are the major components of most organic compounds. The Periodic Table A tabular arrangement of the chemical elements, ordered by their atomic number, electron configuration, and recurring chemical properties The atomic number It is the number of protons found in the nucleus of an atom. The mass number A of an atom The sum of the atomic number Z and the number of neutrons, N A period in the periodic table is a horizontal row. All elements in a row have the same number of electron shells. Each next element in a period has one more proton than its predecessor. A group is a column of elements in the periodic table of the chemical elements. There are 18 numbered groups in the periodic table. The elements in a group have similar physical or chemical characteristics of the outermost electron shells of their atoms Within one row (period) the elements are metals to the left, and non-metals to the right.  Electron shell #1 It has the lowest energy and its s-orbital is the first to be filled. Shell #2 It has four higher energy orbitals, the 2s-orbital being lower in energy than the three 2p-orbitals. (x, y & z). Valence shell The highest occupied electron shell Valence electrons Electrons occupying the highest shell An electron shell is the outside part of an atom around the atomic nucleus. It is a group of atomic orbitals. Electron shells have one or more electron subshells, or sublevels. Aufbau Rule, Pauli Exclusion Principle and Hunds Rule Aufbau principle It states that in the ground state of an atom or ion, electrons fill atomic orbitals of the lowest available energy levels before occupying higher levels. (Aufbau principle) building-up principle It states that in the ground state of an atom or ion, electrons fill atomic orbitals of the lowest available energy levels before occupying higher levels. Hunds Rule Electrons always enter an empty orbital before they pair up. Electrons are negatively charged and, as a result, they repel each other. Electrons tend to minimize repulsion by occupying their own orbitals, rather than sharing an orbital with another electron.  Pauli's Exclusion Principle states that no two electrons in the same atom can have identical values for all four of their quantum numbers. In other words, (1) no more than two electrons can occupy the same orbital and (2) (2) two electrons in the same orbital must have opposite spins Pauli Exclusion Principle ▪ The octet rule states that atoms tend to combine in such a way that each atom has eight electrons in its valence shell, giving it the same electron configuration as a noble gas. ▪ The chemical properties of the elements reflect their electron configurations. ▪ helium, neon and argon are exceptionally stable and unreactive ▪ The halogens (F, Cl, Br etc.) are one electron short of a valence shell octet, and are among the most reactive of the elements ▪ In their chemical reactions halogen atoms achieve a valence shell octet by capturing or borrowing the eighth electron from another atom or molecule. ▪ The alkali metals Li, Na, K etc. are also exceptionally reactive, but for the opposite reason. These atoms have only one electron in the valence shell, and on losing this electron arrive at the lower shell valence octet.  The inert gas elements of group 18 exist as monoatomic gases, and do not in general react with other elements. In contrast, other gaseous elements exist as diatomic molecules (H2, N2, O2, F2 & Cl2), and all but nitrogen are quite reactive. Types of bonds: 1. Ionic bond It is the complete transfer of valence electron(s) between atoms. It is a type of chemical bond that generates two oppositely charged ions. In ionic bonds, the metal loses electrons to become a positively charged cation, whereas the nonmetal accepts those electrons to become a negatively charged anion. 2. Covalent Bond It also called a molecular bond, is a chemical bond that involves the sharing of electron pairs between atoms. Multiple bonding The sharing of two or more electron pairs Double bond Triple bond Ex. ethylene and formaldehyde Ex. acetylene and hydrogen cyanide Valence The number of valence shell electrons an atom must gain or lose to achieve a valence octet is called valence. In covalent compounds the number of bonds which are characteristically formed by a given atom is equal to that atom's valence. Electronegativity The ability of an element to attract or hold onto electrons When two different atoms are bonded covalently, the shared electrons are attracted to the more electronegative atom of the bond, resulting in a shift of electron density toward the more electronegative atom. Such a covalent bond is polar, and will have a dipole (one end is positive and the other end negative). The degree of polarity and the magnitude of the bond dipole will be proportional to the difference in electronegativity of the bonded atoms. O–H bond is more polar than a C–H bond with the hydrogen atom of the former being more positive than the hydrogen bonded to carbon  The dipolar nature of these bonds is often indicated by a partial charge notation (δ+/–) or by an arrow pointing to the negative end of the bond. Although there is a small electronegativity difference between carbon and hydrogen the C–H bond is regarded as weakly polar, and hydrocarbons (composed of C&H only) in general are considered to be non-polar compounds. H ElectronegativityValues for Some Elements 2.20 Li Be B C N O F 0.98 1.57 2.04 2.55 3.04 3.44 3.98 Na Mg Al Si P S Cl 0.90 1.31 1.61 1.90 2.19 2.58 3.16 K Ca Ga Ge As Se Br 0.82 1.00 1.81 2.01 2.18 2.55 2.96 ▪ For bonds to hydrogen, If the bonding electron pair moves away from the hydrogen nucleus the proton will be more easily released as a proton (it will be more acidic). o A comparison of the acidities of methane, water and hydrofluoric acid is instructive. Methane is essentially non-acidic, since the C–H bond is nearly non-polar The O–H bond of water is polar, and it is at least 25 powers of ten more acidic than methane H–F is over 12 powers of ten more acidic than water as a consequence of the greater electronegativity difference in its atoms. ▪ Replacing hydrogen atoms of methanol by more electronegative atoms increases the acidity of the remaining O–H bond. Thus trifluoro- methanol, CF3–O–H is about ten thousand times more acidic than methanol, CH3–O–H. Inductive effect the effect of the transmission of unequal sharing of the bonding electron through a chain of atoms in a molecule, giving rise to a permanent dipole in a bond. Sigma bond: A covalent bond resulting from the formation of a molecular orbital by the end-to-end overlap of atomic orbitals, denoted by the symbol σ. Pi bond: A covalent bond resulting from the formation of a molecular orbital by side-to-side overlap of atomic orbitals along a plane perpendicular to a line connecting the nuclei of the atoms, denoted by the symbol π. Note: A single bond such as (C-H) has one sigma bond whereas a double (C=C) and triple (C≡C) bond has one sigma bond with remaining being pi bonds. Bond type No. of σ bond No. of π bonds Single (C-H) 1 0 Double (C=C) 1 1 Triple (C≡C) 1 2 ❑ Organic Functional Groups Functional groups are atoms or small groups of atoms that exhibit a characteristic reactivity when treated with certain reagents. 1. Carbon Functional Groups Group Specific Common Class Name IUPAC Name Formula Example Name C C Alkene H2C=CH2 Ethene Ethylene C C Alkyne HC≡CH Ethyne Acetylene Arene C6H6 Benzene Benzene 2. Functional Groups with Single Bonds to Heteroatoms Group Class Specific Common IUPAC Name Formula Name Example Name Methyl Halide H3C-I Iodomethane iodide Alcohol CH3CH2OH Ethanol Ethyl alcohol Ether CH3CH2OCH2CH3 Diethyl ether Ether Amine H3C-NH2 Aminomethane Methylamine Nitro H3C-NO2 Nitromethane Compound 3. Functional Groups with Multiple Bonds to Heteroatoms Group Class Specific IUPAC Name Common Name Formula Name Example Nitrile H3C-CN Ethanenitrile Acetonitrile Aldehyde H3CCHO Ethanal Acetaldehyde Ketone H3CCOCH3 Propanone Acetone Carboxylic H3CCO2H Ethanoic Acid Acetic acid Acid Ester H3CCO2CH2CH3 Ethyl ethanoate Ethyl acetate Acid Halide H3CCOCl Ethanoyl chloride Acetyl chloride N,N- N,N- Amide H3CCON(CH3)2 Dimethylethanamide Dimethylacetamide Acid (H3CCO)2O Ethanoic anhydride Acetic anhydride Anhydride lone pair It refers to a pair of valence electrons that are not shared with another atom and is sometimes called a non-bonding pair. Lone pairs are found in the outermost electron shell of atoms. The Shape of Molecules The three dimensional shape or configuration of a molecule is an important characteristic. Methane Ammonia Water 1. Shape of molecules without lone pair of electron Bonding Bond Configuration Example groups Angles Tetrahedral 4 109.5º Trigonal 3 120º Linear 2 180º Isomers Different compounds having the same molecular formula  Structural Formulas for C 4H10O Isomers (as example) Kekulé Formula Condensed Formula Structural Formula Short hand or line formula or skeletal formula Pharmaceutical Organic Chemistry I PC101 Introduction for Organic Chemistry Mona S. El-Zoghbi, Ph. D. Pharm. Sc. Associate professor of pharmaceutical Chemistry Pharmaceutical Chemistry Department [email protected] Intended learning outcomes of the course (ILOs) On successful completion of the course, you should be able to: ❖Recognize several organic terms. ❖Underline the different types of chemical bonds. ❖Recognize the different classes of organic compounds. ❖Assess the structural feature of organic compound and its IUPAC name. ❖Demonstrate alkanes, alkenes, alkynes and alkyl halides (nomenclature, physical and chemical properties, preparation and chemical reactions). ❖ Classify different reaction mechanism. ❖ Outline fundamental principles and applications of stereochemistry, stereo-dynamic, hydroxyl and carbonyl compounds. ❖ Identify the principles of aromaticity and benzenoid compounds. lone pair It refers to a pair of valence electrons that are not shared with another atom and is sometimes called a non-bonding pair. Lone pairs are found in the outermost electron shell of atoms. The Shape of Molecules The three-dimensional shape or configuration of a molecule is an important characteristic. Methane Ammonia Water 1. Shape of molecules without lone pair of electron Bonding Bond Configuration Example groups Angles Tetrahedral 4 109.5º Trigonal 3 120º Linear 2 180º Isomers Different compounds having the same molecular formula  Structural Formulas for C 4H10O Isomers (as example) Kekulé Formula Condensed Formula Structural Formula Shorthand or line formula or skeletal formula Resonance is a way of describing delocalized of pi electrons within certain molecules or polyatomic ions where the bonding cannot be expressed by one single structure. NB: The double headed arrow being the unique symbol for resonance. There are different groups of carbon atoms: A primary carbon (1º) is one that is bonded to no more than one other carbon atom. A secondary carbon (2º) is bonded to two other carbon atoms. Tertiary (3º) and quaternary (4º) carbon atoms are bonded respectively to three and four other carbons. Ex. What is the total number of tertiary carbons found in the following compound? Intermolecular Forces All atoms and molecules have a weak attraction for one another, known as van der Waals attraction forces. If there were no van der Waals forces, all matter would exist in a gaseous state. 1.Dipole–dipole attraction force. attractive forces between the positive end of one polar molecule and the negative end of another polar molecule. 2. Hydrogen Bond Electrostatic attraction between a hydrogen (H) which is bound to a more electronegative atom such as nitrogen (N), oxygen (O), or fluorine (F), and another adjacent atom bearing a lone pair of electrons. The hydrogen bond is weaker than an ordinary covalent bond but is much stronger than the dipole–dipole interactions.  Hydrogen bonding accounts for the fact that ethyl alcohol has a much higher boiling point (78.5°C) than dimethyl ether (24.9°C) even though the two compounds have the same molecular weight. ✓ Molecules of ethyl alcohol, because they have a hydrogen atom covalently bonded to an oxygen atom, can form strong hydrogen bonds to each other. ✓ Molecules of dimethyl ether, because they lack a hydrogen atom attached to a strongly electronegative atom, cannot form strong hydrogen bonds to each other. ✓ In dimethyl ether the intermolecular forces are weaker dipole–dipole interactions only. Q1. Which among the following compounds cannot form hydrogen bond? Solubility of organic compounds in Water Many organic compounds, especially alkanes and other hydrocarbons are nearly insoluble in water. Organic compounds that are water soluble, such as ethanol and acetone, generally have hydrogen bond acceptor and donor groups. Hydrophilic moiety polar, hydrogen bonding moieties Hydrophobic moiety nonpolar species Chemical Reaction: A transformation of the reactants into the reaction products Reactant It is the organic compound undergoing change in a chemical reaction. Product It is the final result of the chemical reaction Reaction Conditions The environmental conditions, such as temperature, pressure, catalysts & solvent, under which a reaction progresses optimally. Catalysts These are substances that accelerate the rate of a chemical reaction without themselves being consumed. Classes of Organic Chemical Reactions 1-Classification by Structural Change Addition, Elimination, Substitution and Rearrangement Addition: In an addition reaction the number of σ-bonds in the substrate molecule increases, usually at the expense of one or more π-bonds. Elimination reactions: the number of σ-bonds in the substrate decreases, and new π-bonds are often formed. Substitution: replacement of an atom or group (Y) by another atom or group (Z). In this reaction, the number of bonds does not change. A rearrangement reaction generates an isomer, and again the number of bonds normally does not change. Exercise: 2-Classification by Reaction Type Oxidation and Reduction Reactions If the number of hydrogen atoms bonded to a carbon increases, and/or if the number of bonds to more electronegative atoms decreases, the carbon in question has been reduced. If the number of hydrogen atoms bonded to a carbon decreases, or if the number of bonds to more electronegative atoms increases, the carbon in question has been oxidized. Reduced= blue Oxidized= red  3-Classification by Functional Group Functional Class Formula Characteristic Reactions Substitution (of H, commonly by Cl or Br) Alkanes C–C, C–H Combustion (conversion to CO2 & H2O) Addition Alkenes C=C–C–H Substitution (of H) Addition Alkynes C≡C–H Substitution (of H) Substitution (of X) Alkyl Halides H–C–C–X Elimination (of HX) Substitution (of H); Substitution (of OH) Alcohols H–C–C–O–H Elimination (of HOH); Oxidation (elimination of 2H) Ethers (α)C–O–R Substitution (of OR); Substitution (of α–H) Substitution (of H); Amines C–NRH Addition (to N); Oxidation (of N) Benzene Ring C6H6 Substitution (of H) Addition Aldehydes (α)C–CH=O Substitution (of H or α–H) Addition Ketones (α)C–CR=O Substitution (of α–H) Substitution (of H); Substitution (of OH) Carboxylic Acids (α)C–CO2H Substitution (of α–H); Addition (to C=O) (α)C–CZ=O Substitution (of Z); Substitution (of α–H) Carboxylic Derivatives (Z = OR, Cl, NHR, etc.) Addition (to C=O) Factors that Influence Reactions 1. Type of chemical bond: Compounds constructed of strong covalent bonds are more stable than compounds incorporating one or more relatively weak bonds. 2. Electronic Effects: The distribution of electrons at sites of reaction (functional groups) is a particularly important factor. An inductive effect A resonance effect 3. Steric Effects: Atoms occupy space. When they are crowded together, van der Waals repulsions produce an unfavorable steric hindrance. Ex. The steric effect of tri-(tert- butyl)amine makes electrophilic reactions, like forming the tetraalkylammonium cation, difficult. It is difficult for electrophiles to get close enough to allow attack by the lone pair of the nitrogen (nitrogen is shown in blue) 4. Solvent Effects: Most reactions are conducted in solution, not in a gaseous state. The solvent selected for a given reaction may exert a strong influence on its course.  Mechanisms of Organic Reactions Reaction mechanism A detailed description of the changes in structure and bonding that take place in the course of a reaction Chemical reactions involve the breaking and making of bonds In general, two kinds of curved arrows are used in drawing mechanisms: A full head arrow indicates complete movement or shift of an electron pair: A half headed arrow indicates the shift of a single electron: Homolysis If a covalent single bond is broken so that one electron of the shared pair remains with each fragment Heterolysis If the bond breaks with both electrons of the shared pair remaining with one fragment  In representing reaction mechanism, curved arrows must start from an electron rich species which may be a negative charge, a lone pair, or a bond. Arrowheads must direct towards an electron deficient species which may be positive charge, the positive end of polarized bond The Reaction Arrow The Equilibrium Arrow The Resonance Arrow Reaction Arrow 2 H2 + O2 2 H2O + Energy O O OH + H2O O + H3O Equilibrium Arrow H3C H3C H H Resonance Arrow C O C O H H Reactive Intermediates (Transient The products of bond breaking are not stable and cannot be intermediates) isolated for prolonged study Electrophiles An electron deficient atom or molecule that has an affinity for an electron pair, and will bond to a base or nucleophile. E.g. RCHO Nucleophiles An atom or molecule that has an electron pair that may be donated in bonding to an electrophile. E.g. R-NH2, R-O-H Electron deficient groups are attracted to electron rich groups. Carbocations are electrophiles Carbanions are nucleophiles  Carbenes have only a valence shell sextet of electrons and are therefore electron deficient so, it considered electrophiles. Carbon radicals (free radicals) have only seven valence electrons, and may be considered electron deficient; however, they do not in general bond to nucleophilic electron pairs, so their chemistry exhibits unique differences from that of conventional electrophiles. Examples for electrophiles and nucleophile Ex. Which of the following is an electrophile? A. CH3CH3 B. CH3CH2+ C. CH3CH2. D. H2O  Hybridization in organic compounds Hybridization is the term applied to the mixing electrons of atomic unequivalent orbitals in an atom to generate a set of new equivalent hybrid orbitals. 1.SP3 hybridization (CH4)  Mixing of the electron in 2S with the three electrons of 2P produced 4 SP3 hybrid orbitals available to make 4 sigma bonds form four sigma bonds with 4 hydrogen atoms through head to head overlapping have the tetrahedral shape. 2. SP2 hybridization (C2H4)  Ethylene molecule contains a C=C and has planner geometry Only 2Px and 2Py orbitals combine with the 2S orbital while the 2Pz orbital remains unchanged and appears perpendicular to the plane of the 3 hybrid orbitals Each carbon atom use the 3 SP2 hybrid orbitals to form 2 bonds with 2 Hydrogen atoms and the last orbital of SP2 type to form bond with the adjacent carbon by head to head overlapping The 2 unhybridized Pz orbitals form double bond (π bond) by sideway overlapping 3. SP hybridization (C2H2)  Acetylene molecule has a linear geometry, contains a carbon carbon triple bond hybridization take place between the remaining electron in 2S orbital and the electron in 2Px to produce 2 hybrid orbital of SP type. 2Py and 2Pz orbitals remains unhybidized. The 2 Sp hybrid orbitals of each carbon form sigma bond with one hydrogen atom and sigma bond with the adjacent carbon by head to head overlapping. An additional two bi bonds formed by the sideway overlapping between the two 2Py and 2PZ unhybridized orbitals of each carbon. Pharmaceutical Organic Chemistry I PC101 Alkanes & Cycloalkanes Mona S. El-Zoghbi, Ph. D. Pharm. Sc. Associate professor of pharmaceutical Chemistry Pharmaceutical Chemistry Department [email protected] Intended learning outcomes of the course (ILOs) On successful completion of the course, you should be able to: ❖Recognize several organic terms. ❖Underline the different types of chemical bonds. ❖Recognize the different classes of organic compounds. ❖Assess the structural feature of organic compound and its IUPAC name. ❖Demonstrate alkanes, alkenes, alkynes and alkyl halides (nomenclature, physical and chemical properties, preparation and chemical reactions). ❖ Classify different reaction mechanism. ❖ Outline fundamental principles and applications of stereochemistry, stereo-dynamic, hydroxyl and carbonyl compounds. ❖ Identify the principles of aromaticity and benzenoid compounds.  Organic Compounds Acyclic Cyclic Open chain aliphatic compounds Carbocyclic Heterocyclic Alicyclic Aromatic  Organic compounds: Are compounds containing carbon in C-C bonding. Organic comes from organism as they were first discovered in living organisms. Carbocyclic compounds: Are cyclic organic compounds containing carbon and hydrogen only. Alicyclic compounds: Are saturated cyclic organic compounds containing carbon and hydrogen only. They have the same properties of aliphatic compounds, they behave like alkanes eg. cyclopropane, cyclohexane. Aromatic compounds: Are carbocyclic compounds containing benzene ring or they are cyclic compounds having low H/C ratio. eg. Benzene, naphthalene.  Heterocyclic compounds: Are cyclic organic compounds containing one or more heteroatom as nitrogen, sulphur or oxygen. eg. N O S pyridine, furan, thiophen.  Aliphatic Hydrocarbons They are open chain organic compounds containing carbon and hydrogen. They are classified into: Saturated Unsaturated Alkanes Alkenes Alkynes Contain double bond Contain triple bond. I- Saturated Hydrocarbons "Alkanes" "CnH2n+2" where n is the number of carbon atoms Nomenclature of alkanes: common names “trivial names” I.U.P.A.C. system "International Union of Pure and Applied Chemistry" I.U.P.A.C. system "International Union of Pure and Applied Chemistry" No of carbons Name Formula 1 Methane CH4 2 Ethane C2H6 3 Propane C3H8 4 Butane C4H10 5 Pentane C5H12 6 Hexane C6H14 7 Heptane C7H16 8 Octane C8H18 9 Nonane C9H20 10 Decane C10H22 11 Undecane C11H24 12 Dodecane C12H26 13 Tridecane C13H28 14 Tetradecane C14H30  longest and continuous chain the parent CH2 CH2 CH3 CH3 CH2 CH CH2CH2 CH3 “4-Ethylheptane” more than one chain of equal length the more substituted chain CH3 CH3 CH CH3 CH CH3 CH3 CH2 CH2 C CH2 CH3 CH3 CH2 CH2 C CH2CH3 CH3 CH3 2- substituents only 3- substituents Number the chain and begin at the end that gives the lowest number to the substituents. CH3 CH CH3 CH3 CH2 CH2 C CH2CH3 CH3 "3- Ethyl-2,3-dimethyl hexane" Two or more identical groups prefixes di-, tri- and tetra- Ordering the groups in alphabetical order di-, tri- and tetra- are not considered in alphabetical order The numbers are separated by commas, while numbers and letters are separated by dashes. CH3 eg. CH3 CH2 C CH2 CH3 CH3 "3,3-Dimethylpentane "Iso" and "tertiary are considered in alphabetical order CH3 CH3 CH CH3 CH2 CH3 eg. CH3 CH CH CH CH2 C CH2 CH3 CH3 CH2CH3 "6,6-Diethyl-4-isopropyl-2,3-dimethyloctane" b) Common names “trivial names”: 1) Normal alkanes: "n" straight continuous chains with no branching eg. CH3–CH2–CH2–CH2–CH3. n-pentane 2) Isoalkanes: "iso" two methyl groups located at one end of the side chain CH3 CH2 CH3 CH CH3 CH3 CH CH2 CH2 CH2 CH3 "isobutane" isoheptane  3) Neoalkane : "neo" there are three methyl groups located at one end of the chain. CH3 CH3 CH3 C CH3 CH3 CH CH2 CH3 CH3 "neopentane" "isopentane" C) Alkyl groups: They are obtained by the removal of one hydrogen from alkane. Then remove the suffix "-ane" and replace it with “-yl". eg. Methane →methyl "CH3–" Ethane → ethyl CH3–CH2 - Propane → propyl -H eg. CH3 CH2 CH3 CH3 CH2 CH2 "n-propyl" -H CH3 CH "isopropyl" CH3  Preparation of alkanes I- From unsaturated hydrocarbons 1) By catalytic reduction Ni or Pd (a) C C + H2 CH CH Ni (b) C C + H2 CH2 CH2 II. From alkyl halides 1) Reduction of alkyl halides Zn/HCl or HAc R X R H or Mg/Hg/EtOH H2 / Ni R X or LiALH4 R H The same number of carbon atoms. 2) Wurtz reaction ether R X + Na solvent R R X CH3 CH3. Na CH3 CH CH3 CH3 CH CH CH3 ether Double the number of carbon atoms 3) From Gringard reagent: ether R X + Mg R MgX "alkyl halide" "alkylmagnesium halide" "Gringard reagent" H2O or H + R H + Mg(OH)X The same number of carbon atoms as alkyl halide. III- From carbonyl compounds: O reduction C CH2 The same number of carbon atoms Reduction is carried out either by Clemmenson reduction : Zn/Hg/HCl. Wolf-Kischner reduction: NH2–NH2/base (NaOH or NaOC2H5). IV- From carboxylic acids 1) By decarboxylation of carboxylic acids and their salts CaO/NaOH RCOOH R H + CO2 (Sodalime) or RCOO - Na+ one carbon less than the starting material  Reactions of alkanes sp3hybridized carbon atoms bond angle is 109.5º non-polar inert unreactive possessing strong sigma bonds I. Halogenation of alkanes A substitution reaction High temperature ( i.e. 250 - 400ºC) or in presence of light Free radical mechanism The rate of halogenation by fluorine is faster than chlorine than bromine than iodine Chlorine is more reactive and non selective, while bromine is less reactive but selective It reacts with 3º hydrogen rather than 2º than 1º light or CH4 + Cl2 CH3Cl + HCl high temp. "chloromethane" h.v h.v/Cl2 CH4 + Cl2 CH3Cl CH2Cl2 h.v/Cl2 CHCl3 h.v/Cl2 CCl4 It is called a chain reaction  CH3 CH3 Br2/h.v. eg. CH3 CH CH2 CH3 CH3 C CH2 CH3 3o 2o Br Cl2/h.v. "main product" CH3 CH2Cl CH3 CH3 C CH2 CH3 + CH3 CH CH2CH3 + CH3 CH CH CH3 Cl Cl CH3 CH CH2 CH2 Cl CH3 II. Nitration: The use of concentrated nitric acid at 500ºC Replace a hyrogen atom by a NO2 group Conc. HNO3 CH3 CH2 CH3 CH3 CH CH3 + CH3 CH2 CH2 500oC NO2 NO2 + CH3 CH2 NO2 + CH3 NO2 free radical mechanism "nitroethane" "nitromethane" III. Sulphonation: CH3 CH3 oleum or fuming sulphuric acid CH3 CH CH3 CH3 C CH3 (c.H2 SO4 /SO3) SO3H "1,1-dimethyl ethane sulphonic acid'" Substitution by sulphonic group occurs to tertiary hydrogen and to less extent to secondary hydrogen however, sulphonation may not occur to primary hydrogens IV. Oxidation: CnH2n+2 O2 or air CO2 + H2O + large amount of heat 500-700oC This reaction gives a large amount of heat that is why alkanes are used as fuel. V. Pyrolysis of alkanes "cracking". thermal decomposition of the compound occurs by heating at high temperature in absence of oxygen - H2 alkene 500oC CnH2n+2 rupture of C C bond absence of O2... smaller alkanes smaller alkenes eg. 600oC CH3 CH2 CH3 CH3 CH CH2 + CH3 CH3 + CH4 + CH2 CH2 Alicyclic compounds (Cycloalkanes)  Alicyclic compounds (Cycloalkanes) They are alkanes having the carbons arranged in a ring They have the general formula CnH2n Nomenclature: Name according to the number of carbon atoms, then give it the prefix “cyclo-”. CH2 CH2 CH2 cyclopropane Give the substituent number one unless there is more than one substituent, give them the lowest possible numbers. CH3 H 3C CH3 COOH CH2CH3 CH2CH3 "1-Ethyl-3-methylcyclohexane" "cyclohexane carboxylic acid'" 3-Ethyl-1,1-dimethylcyclo pentane"  If the side chain has greater number of carbon atoms than the ring the ring is considered as a substituent to the side chain. Remove the suffix "–ane”, and replace it by "–yl" to be a radical. Moreover, cyclo is considered in the alphabetical order. CH3 eg. CH2 CH CH2CH3 1-cyclopropyl-2-methylbutane Trivial names: They are named as polymethylene derivatives. eg. trimethylene, pentamethylene Preparation: 1- By dehalogenation of α, ω -dihalogen derivatives: internal Wurtz reaction the two halogen atoms must not be separated by more than six atoms if more than six atoms intermolecular Wurtz reaction Zn or Na eg. Br CH2 CH2 CH2 Br + ZnBr2 or 2 NaBr "1,3-dibromopropane" Zn eg. Br CH2 CH2 CH2 CH2 CH2 CH2 Br + 2 ZnBr2 Na eg. Br CH2 CH2 CH2 CH2 CH2 CH2 CH2 Br H3C (CH2)12 CH3 "tetradecane" 2. From other cyclic compounds: H2/Ni "cyclopentene" cyclopentane O Zn/Hg/HCl "Clemmenson reduction" "cyclopentanone" 3. Reduction of Benzene derivatives: H2/Ni eg. / pressure Benzene cyclohexane Double bonds of benzene are highly stable require high temperature and pressure to break the aromaticity. Reactions of cycloalkanes: “Baeyer Strain theory” they should have tetrahedral orientation Cycloalkanes have sp3 hybridized carbons the bond angle should be 109.5º three membered rings eg. cyclopropane will have bond angle They are cyclic equal to 60º four membered rings as cyclobutane their bond angle will be 90º five membered rings as cyclopentane their bond angle will be 108º six membered ring like cyclohexane their bond angle will be 120º As the difference from tetrahedral angle increase the strain will increase and the stability of the ring decreases  Three and four membered rings are highly strained they are very reactive and ring opening occur in order to remove the strain five membered rings have no strain six membered rings are very stable and are found in "puckered conformations". bond angle is 108o which or is not far from 109.5o boat conformation" "chair conformation" Five and six membered rings do not undergo ring opening as three and four membered rings do 1-Hydrogenation: 80oC + H2/Ni CH3 CH2 CH3 200oC + H2/Ni CH3CH2CH2CH3 or + H2/Ni no reaction 2-Electrophilic addition reactions: CH3 Br CH Br2 CH3 CH CH2 CH2 Br CH2 CH2 conc. HI CH3 CH CH2 CH3 I + H2O/H CH3 CH CH2 CH3 OH Reactions of five and six membered rings: They do not undergo ring opening but they carry out the normal substitution reactions of alkanes H Cl eg. + Cl2/h.v + HCl Cl OH NaOH Cyclohexanol. alc. KOH Cyclohexene CN KCN Pharmaceutical Organic Chemistry I PC101 Alkenes Mona S. El-Zoghbi, Ph. D. Pharm. Sc. Associate professor of pharmaceutical Chemistry Pharmaceutical Chemistry Department [email protected] Intended learning outcomes of the course (ILOs) On successful completion of the course, you should be able to: ❖Recognize several organic terms. ❖Underline the different types of chemical bonds. ❖Recognize the different classes of organic compounds. ❖Assess the structural feature of organic compound and its IUPAC name. ❖Demonstrate alkanes, alkenes, alkynes and alkyl halides (nomenclature, physical and chemical properties, preparation and chemical reactions). ❖ Classify different reaction mechanism. ❖ Outline fundamental principles and applications of stereochemistry, stereo-dynamic, hydroxyl and carbonyl compounds. ❖ Identify the principles of aromaticity and benzenoid compounds.  Unsaturated Hydrocarbons I. Alkenes CnH2n carbon-carbon double bond sp2 hybridized with bond angle 120º Nomenclature of alkenes: I. I.U.P.A.C. Nomenclature: Select the longest continuous chain containing double bond. Name the chain according to number of carbon atoms and replace the suffix “-ane” by “-ene”. Number the chain and give the double bond the lowest possible number The substituents are named and their positions are indicated. eg. CH3 CH2 CH2 CH CH2 CH2 CH3 CH CH2 3-propyl-1-hexene CH3 eg. CH3 CH2 CH CH CH2 CH CH3 6-methyl-3-heptene II. Common or trivial names: Naming the common name of the corresponding alkane and we replace the suffix “-ane" with “-ylene”. CH2=CH2 "ethylene" CH3–CH=CH2 "propylene" CH3–CH2–CH=CH2 "α-butylene or 1-butylene" CH3–CH=CH–CH3 "β-butylene or 2-butylene" CH3 CH3 C CH2 "Isobutylene" As derivatives of ethylene: CH3–CH=CH2 "methylethylene" CH3–CH=CH–CH3 "sym.dimethyl ethylene”. CH3 CH2 C CH2 "Asym. diethylethylene." CH2 CH3 Unsaturated alkyl groups: Remove the letter “e” from alkene and replace it by “–yl” to be alkenyl The attachment is always number one The number indicates the position of the double bond -H CH2 CH2 CH2 CH "ethene" "ethenyl" or "vinyl" -H CH3 CH CH2 CH2 CH CH2 "Propene" "2-propenyl" or "allyl" -H CH3 CH CH "1-propenyl"  Unsaturated Hydrocarbons containing two or more double bonds. Compounds containing two double bonds "CnH2n–2" Compounds containing three double bonds "CnH2n–4". I.U.P.A.C. nomenclature: Select the longest continuous chain containing the maximum number of double bonds Name the chain according to number of carbon atoms and replace the suffix “-ane” by “-diene” if two double bonds and by “- triene” if three double bonds Number the chain giving the double bonds the lowest possible numbers. CH3 CH2 eg. CH3 C C CH2 C CH2 CH3 CH3 "2-Ethyl-4,5-dimethyl-1,4-hexadiene"  Preparation of alkenes: I. By reduction of alkynes: R R H2/Ni2 B or C C H2/Pd-CaCO3 H H syn addition R C C R "cis-alkene" Na or Li/NH3 R H trans addition C C H R "Trans-alkene" II. By Elimination Reactions: 1. From alkyl halides: “Dehydrohalogenation" H alcoholic KOH/ C C C C - HX X alc. KOH eg. CH3 CH2 CH CH3 CH3 CH CH CH3 + - HBr Br "major" CH3 CH2 CH CH2 "minor" The order of reactivity and hence the elimination of halogen iodine more than bromine more than chlorine more than fluorine tertiary alkyl halides are more reactive than secondary than primary Saytzeff's rule: The predominant alkene is the most substituted one  Saytzeff's rule: 2. From dihalides: "dehalogenation" Zn/HAc C C C C - X2 X X vicinal dihalide Zn/HAc CH3 CH CH CH3 CH3 CH CH CH3 - Br2 Br Br "2,3-Dibromobutane" "2-butene" 3. From alcohols: "Dehydration" Conc. H2SO4 C C C C + H2O 160 - 180oC H OH