Bonding & Isomerism (Pharmaceutical Organic Chemistry) PDF

Pharmaceutical Organic Chemistry PHRM 102 1446H Dr. Mohammed Almaghrabi [email protected] Office: F 31  Attendance Class attendance and attendance recording...

Pharmaceutical Organic Chemistry PHRM 102 1446H Dr. Mohammed Almaghrabi [email protected] Office: F 31  Attendance Class attendance and attendance recording at Taibah University is MANDATORY. Students who fail to attend more than 75% (less than 25% absence) of scheduled classes\lab sessions will not be allowed to take the final exam pay attention to the two lectures on the same day. Attendance will be recorded 10 min after class or lab starts and according to the College\University’s policy Student who misses a class, lab session, quiz, or Exam; will need to file a petition to the office of the Vice-Dean for Academic Affairs. Only students with a valid petition will grant a make-up quiz, an examination, or a lab test Assessment, Evaluation and Grading  Text Books 1. Organic Chemistry: A Short Course 13th Edition by Harold Hart, David J. Hart and Leslie E. Graine, 2012, CENGAGE. 2. Chemistry for Pharmacy Students: General, Organic and Natural Product Chemistry, Wiley; 2nd edition (2019) Link to the TU library: https://dla.taibahu.edu.sa/uhtbin/cgisirsi.exe/?ps=AMFb6g2CLl/CLM/78590002/2/1000 Link to the Saudi Digital Library: https://sdl.edu.sa/SDLPortal/Publishers.aspx  Course Objectives Upon successful completion of the course, the students will be able to: - Explain the molecular properties of organic compounds. - Describe the nomenclature (IUPAC and common) and drawing structure of organic compounds. - Clarify the principal aspects of stereochemistry of organic reactions and their mechanisms. - Identify practically organic compounds. - Define the fundamentals of organic chemistry required for related courses in the Pharmacy curriculum.  What is Organic Chemistry? Organic chemistry is the chemistry of carbon compounds. It is a subject that studies structures, properties, and reactions of organic compounds and organic materials, which means materials that contain carbon atoms. Organic compounds don't just contain carbon also contain hydrocarbons or carbon bonded to hydrogen (C-H). Organic compounds refer to substances that are obtained from living (plants or animals) and non-living things ( synthesis).  Classification of Organic Compounds Organic Compounds Cyclic Aliphatic (Acyclic) Compounds Compounds Heterocyclic Homocyclic Compounds Compounds Alicyclic Aromatic Alicyclic Aromatic  Classification of Organic Compounds According to Molecular Framework The three main classes of molecular frameworks for organic structures are: 1. Acyclic compounds 2. Carbocyclic compounds 3. Heterocyclic compounds  Classification of Organic Compounds According to Molecular Framework 1. Acyclic compounds: Acyclic organic molecules have chains of carbon atoms but no rings.  Cont. 2. Carbocyclic compounds: Carbocyclic compounds contain rings of carbon atoms. The smallest possible carbocyclic ring has three carbon atoms, but carbon rings come in many sizes and shapes.  Cont. 3. Heterocyclic compounds: In heterocyclic compounds, at least one atom in the ring must be a heteroatom, an atom that is not carbon. The most common heteroatoms are oxygen, nitrogen, and sulfur.  Classification of Organic Compounds According to Functional group Functional groups are certain groups of atoms have chemical properties that depend only moderately on the molecular framework to which they are attached. The hydroxyl group (-OH) is an example of a functional group, and compounds with this group attached to a carbon framework are called alcohols. Periodic Table of Elements Bonding and Isomerism  Atomic structure An atom consists of a small, dense nucleus containing positively charged protons and neutral charge neutrons Nucleus and surrounded by negatively charged electrons. The atomic number of an element equals the number of protons in its nucleus. Atomic weight ((Mass Number)) is the sum of the number of protons and neutrons in its nucleus.  How Electrons are Arranged in Atom? Electrons are arranged in orbitals (s, p, d, and f). (N) (M) An orbital can hold a maximum of two electrons. (L) (K) Orbitals are grouped in shells designated by numbers 1, 2, 3, and so on. s Valence electrons are located in the outermost sp shell. Electrons in shells that are not completely spd filled. The kernel of the atom contains the nucleus and spdf the inner electrons (filled shells). Main Energy shell or level Cont.  Cont. The valence of an element is simply the number of bonds that the element can form. The number is usually equal to the number of electrons needed to fill the valence shell.  The Octet Rule Lewis noticed that : Inert gas helium (He) had only two electrons surrounding its nucleus and the next inert gas, Neon, had 10 such electrons (2 + 8). Atoms of these gases must have very stable electron arrangements because these elements do not combine with other atoms. Lewis suggested that other atoms might react in such a way in order to achieve these stable arrangements. This stability could be achieved in one of two ways: by Complete transfer of electrons from one atom to another or By sharing of electrons between atoms.  The Octet Rule The Octet Rule: states that elements gain or lose electrons to achieve an electron configuration of the nearest noble gas. In other words: Atoms transfer or share electrons in such a way that they can achieve a filled shell of electrons. This stable configuration of electrons is called an Octet. Loss Gain 1 4 8  Electronegativity Electronegativity (EN) is the ability of an atom that is bonded to another atom to attract electrons strongly towards it. EN increases from left to right and bottom to top in the periodic table. This competition for electron density is scaled by electronegativity values. If the EN difference is equal to or less than 0.5 the bond is Nonpolar covalent. If the EN difference between bonded atoms is 0.5–1.9 the bond is Polar covalent. If the EN difference between the two atoms is 2.0 or greater, the bond is Ionic. When two unlike atoms are covalently bonded, the shared electrons will be more strongly attracted to the atom of greater electronegativity. Such a bond is said to be polar. Cont. Fluorine, the most reactive non-metal, is assigned the highest value since it has the greatest attraction for the electron being shared by the other element. Oxygen is also highly electronegative and has a strong attraction for electrons. Metals have low electronegativities since they have weak attraction for any shared electrons.  Ionic and Covalent Bond 2.1 Ionic Compounds: Ionic compounds are composed of positively charged cations and negatively charged anions that form an ionic bond through electrostatic attraction. Ionic bonds are formed by the complete transfer of one or more valence electrons from highly electropositive atom to another highly electronegative one. Electropositive atoms (Na) give up electrons and form cations. Electronegative atoms (Cl) accept electrons and form anions.  Ionic and Covalent Bond 2.2 Covalent Compounds: Elements that are neither strongly electronegative nor strongly electropositive, or that have similar electronegativities, tend to form bonds by sharing electron pairs. A Covalent bond is formed when two atoms share one or more electron pairs. A molecule consists of two or more atoms joined by a covalent bond. Nonpolar and polar covalent bonds (Bond Polarity) Bond polarity is a useful concept for describing the sharing of electrons between atoms. The shared electron pairs between two atoms are not necessarily shared equally and this leads to a Bond polarity. Atoms, such as nitrogen, oxygen, and halogens, that are more electronegative than carbon tend to have partial negative charges. Atoms such as carbon and hydrogen tend to be more neutral or have partial positive charges. Thus, bond polarity arises from the difference in electronegativities of two atoms participating in the bond formation. Bond polarity of compounds is measured by dipole moment (µ) and its unit is Debye = D.  Nonpolar and polar covalent bonds If a bond is covalent, it is possible to identify whether it is a polar or nonpolar bond. In a nonpolar covalent bond, the electrons are shared equally between two atoms, e.g., H:H, Cl-Cl and H3C-CH3 A polar covalent bond between different atoms usually results in the electrons being attracted to one atom more strongly than the other (shared unequally). e.g., HCl This bond polarization is indicated by an arrow whose head is negative and whose tail is marked with a plus sign. Alternatively, a partial charge (read as “delta plus” or “delta minus”).  Multiple covalent bonds To complete their valence shells with eight electrons, atoms may sometimes share more than one electron pair (double bond). Carbon dioxide, CO2, is an example. Hydrogen cyanide, HCN, is an example of a simple compound with a triple bond, a bond in which three electron pairs are shared. In a double bond, two electron pairs are shared between two atoms. In a triple bond, three electron pairs are shared between two atoms. Nonbonding electrons or unshared electron pairs, reside on one atom.  Coordinate Covalent Bonding There are molecules in which one atom supplies both electrons to another atom in the formation of covalent bond. Example: Ammonium ion NH4+ H H N H + H+ H N H H H  Carbon-Carbon Single Bonds Catenation Carbon can share electrons not only with different elements but also with other carbon atoms. Less heat is required to break the carbon-carbon bond in ethane than is required to break the hydrogen–hydrogen bond in a hydrogen molecule. The carbon-carbon bond in ethane is longer (1.54 Å) than the hydrogen–hydrogen bond (0.74 Å). Bond energy is inversely proportional to Bond length.  Carbon-Carbon Single Bonds Break the carbon–carbon bond of ethane to give two CH3 fragments (called methyl radicals). A radical is a molecular fragment with an odd number of unshared electrons ( very reactive). The ability of an element to form chains as a result of bonding between the same atoms is called Catenation.  The Orbital View of Bonding 8.1. Sigma Bond (𝛔): The atomic orbitals (s, p, d and f) have definite shapes. The s orbitals are spherical. The three p orbitals are dumbbell shaped and mutually perpendicular, oriented along the three coordinate axes, x, y, and z. The shapes of the s and p orbitals used by the valence electrons of carbon. The nucleus is at the origin of the three coordinate axes.  The Orbital View of Bonding 8.1. Sigma Bond: Atoms approach each other in such a way that their atomic orbitals can overlap to form a Bond. A molecular orbital is the space occupied by electrons in a molecule. Molecular orbital can contain no more than two electrons. The orbital in the hydrogen molecule is cylindrically symmetric along the H-H internuclear axis. Such orbitals are called Sigma Orbitals, and the bond is referred to as a Sigma Bond. The molecular orbital representation of covalent bond formation between two hydrogen atoms contain only 2 electron.  The Orbital View of Bonding 8.1. Sigma Bond: Sigma bonds may also be formed by the overlap of an s and a p orbital or of two p orbitals (head-to-head overlapping of atomic orbitals).  The Orbital View of Bonding 8.2. Pi Bond(𝛑): Two properly aligned p orbitals can also overlap to form another type of bond called a p (pi) bond (lateral overlap of two atomic orbitals).  Hybridization Hybridization in Chemistry is defined as the concept of mixing two atomic orbitals to give rise to a new type of hybridized orbitals with redistribution of the energy of orbitals to give orbitals of equivalent energy. The atomic orbitals of comparable energies are mixed together and mostly involves the merging of two ‘s’ orbitals or two ‘p’ orbitals or mixing of an ‘s’ orbital with a ‘p’ orbital as well as ‘s’ orbital with a ‘d’ orbital. The new orbitals are known as hybrid orbitals. Type Of Shape Number Of Orbitals Hybrid orbitals are quite useful Hybridization Participating In Hybridization in explaining atomic bonding properties and molecular sp³ Tetrahedral 4 (1s + 3p) geometry. sp² Planar trigonal 3 (1s + 2p) sp Linear 2 (1s + 1p)  Hybridization 9.1. Carbon sp3 Hybrid Orbitals Ground State 6 x y z C 12 sp3 Excited State Hybridization State The angle between any two of the four bonds formed from x y z sp3 orbitals is approximately 109.5° (Tetrahedral)  Hybridization 9.1. Carbon sp3 Hybrid Orbitals Hybrid orbitals can form sigma bonds by overlap with other hybrid orbitals or with nonhybridized atomic orbitals.  Hybridization 9.1. Carbon sp3 Hybrid Orbitals (sp3 hybridization in Methane) sp3–orbital s-orbital A molecule of methane, CH4, is formed by the overlap of the four sp3 carbon orbitals with the 1s orbitals of four hydrogen atoms. The resulting molecule has the geometry of a regular tetrahedron and contains four sigma bonds of the sp3–s type.  Hybridization 9.2. Carbon sp2 Hybrid Orbitals (sp2 hybridization in Ethene) Ground State Hybridization between s orbital and 2 p orbitals yield x y z 3 hybrid orbitals Excited State Hybridization State z z z x y z A trigonal carbon showing three sp2 hybrid orbitals with a 120° angle between them. The remaining p orbital is perpendicular to the sp2 orbitals.  Hybridization 9.2. Carbon sp2 Hybrid Orbitals (sp2 hybridization in Ethene) z z Head overlap sp2 sp2 pz pz sp2 sp2 sp2 1s 1s : : H H Lateral overlap 1s : : 1s H H z  z sp2 sp2 sp2 sp2 sp2 sp2 The bonding in ethene consists of one sp2–sp2 carbon–carbon sigma bond, four sp2–s carbon–hydrogen sigma bonds, and one p–p  bond.  Hybridization 9.3. Carbon sp Hybrid Orbitals (sp hybridization in Ethyne) Ground State x z Hybridization between s orbital and one p orbitals y yield 2 hybrid orbitals. Excited State Hybridization State x y z The angle between two sp orbitals is 180°. (Linear)  Hybridization y 9.3. Carbon sp Hybrid Orbitals (sp hybridization in Ethyne) A triple bond consists of the head overlap z of two sp-hybrid orbitals to form a sigma bond and the lateral overlap of two sets of y parallel- oriented p orbitals to form two  bonds. z py 1 py pz pz H sp C  sp sp C sp H = 2  Hybridization sp³ sp² sp Shape Tetrahedral Trigonal Linear Bond Angle 109.5∘ 120∘ 180∘ Bond Length 1.5 Å 1.34 Å 1.2 Å Example Methane Ethene Ethyne  Tetrahedral Geometry of Carbon The geometry of carbon with four single bonds, as in methane, is commonly represented as: - Solid lines lie in the plane of the page (C and H in C—H lie in the plane), the dashed wedge goes behind the plane of the paper, and the solid wedge extends out of the plane of the paper toward you. Structures drawn in this way are sometimes called 3D Structures. - Ball-and-stick model shows the bonds that connect the atoms, each atom represented by Ball & each Bond represented by stick. - Space-filling model shows the space occupied by the atom. - Electrostatic potential map is sometimes used to show the distribution of electrons in a molecule. Red indicates partial negative charge (greater electron density), and blue indicates partial positive charge (less electron density).  Tetrahedral Geometry of Carbon Solid lines Ball-and-Stick Space-filling Electrostatic potential map  Nonbonding Intermolecular Interaction The physical properties, e.g., boiling points, melting points and solubilities of the molecules are determined by intermolecular nonbonding interactions (Molecules attract each other without forming chemical bonds). There are three types of nonbonding intermolecular interaction: 1. Dipole–dipole interactions, 2. Van der Waals forces 3. Hydrogen bonding. These interactions increase significantly with increase molecular weights, and increasing polarity of the molecules. Intermolecular Forces weaker than intramolecular forces (bonding).  Nonbonding Intermolecular Interaction 10.1. Dipole–dipole interactions: The interactions between the positive end of one dipole and the negative end of another dipole. Polar molecules are held together more strongly than nonpolar molecules. + - + - + - Dipole–dipole interactions  Nonbonding Intermolecular Interaction 10.3. Hydrogen bonding: Strong dipole-dipole attraction when H is covalently bonded to a highly electronegative atom. Hydrogen bonding occurs with hydrogen atoms covalently bonded to oxygen, fluorine or nitrogen. + - + O H + N H + + + H F H H H H - + H + H N H - F + - N - H O - O H F + - + + H H H H H H Water Hydrogen fluoride (HF) Ammonia (NH3)  Nonbonding Intermolecular Interaction Nucleus 10.2. Van der Waals forces (London dispersion): Van der Waals forces is a general term used to define the attraction of intermolecular forces between molecules. electrons The weakest of all intermolecular interactions. It is much weaker than the covalent bonds within + molecules. Exist between nonpolar molecules Electrons move continuously within bonds and molecules, so at any time one side of the molecule can have more electron density than the other + - + - side, which gives rise to a temporary dipole. Van der Waals forces (London dispersion)  Isomerism The molecular formula of a substance tells us the number of different atoms present, But a structural formula tells us how those atoms are arranged. H2O is the molecular formula for water. It tells us that each water molecule contains two hydrogen atoms and one oxygen atom. But the structural formula H-O-H tells us more than that. Isomers are molecules with the same number and kinds of atoms but different arrangements of atoms. Structural (or constitutional) isomers have the same molecular formula but different structural formulas.  Isomerism For the molecular formula C2H6O, two (and only two) structural formulas are possible that satisfy the valence requirement of 4 for carbon, 2 for oxygen and 1 for hydrogen. These structural formulas are: Structural isomers are different compounds. They differ in physical and chemical properties as a consequence of their different molecular structures.  Writing Structural Formulas Molecular formula C5H12 could be written as continuous chain, or written as a branched chain which give either isopentane or neopentane Pentane Isopentane Neopentane  Abbreviated Structural Formulas (Kekulé structure) Condensed structures Each formula clearly represents ethanol than its isomer methoxymethane (dimethyl ether), which can be represented by any of the following structures:  Abbreviated Structural Formulas The structural formulas for the three pentanes can be abbreviated in a similar fashion: Sometimes these formulas are abbreviated even further, they can be printed on a single line in the following ways: The ultimate abbreviation of structures is the use of lines to represent the carbon framework:  Abbreviated Structural Formulas Kekulé structure Condensed structures Line/Shorthand structures H H H H H C C C C OH CH3(CH2)3OH OH H H H H H H H O H H C C C C H CH3CH2CH(OH)CH3 OH H H H H H H H H C C C OH H C H (CH3)2CHCH2OH OH H H H H H H H H C C O C C H CH3CH2OCH2CH3 O H H H H Examples Examples  Resonance Resonance structures of a molecule or ion are two or more structures with identical arrangements of the atoms but different arrangements of the electrons. When resonance is possible, the substance is said to have a structure that is a resonance hybrid of the various contributing structures. Resonance is very different from isomerism, for which the atoms themselves are arranged differently in isomerism. Example: Carbonate ion, CO3 2-  Resonance In the real carbonate ion, the two formal negative charges are spread equally over the three oxygen atoms, so that each oxygen atom carries two-thirds of a negative charge. The carbonate ion does not physically alternate among three resonance structures but has in fact one structure—a hybrid of the three resonance structures. We use a double-headed arrow ( ) between contributing structures to represent resonance.  Arrow Formalism 1. Curved arrows are used to show how electrons are moved in resonance structures and in reactions. 2. Fishhook arrows is a curved arrow with half a head. This kind of arrow is used to indicate the movement of only a single electron. 3. Straight arrows point from reactants to products in chemical reaction equations. 4. Straight arrows with half-heads are commonly used in pairs to indicate that a reaction is reversible. 5. A double-headed straight arrow between two structures indicates resonance structures.