Pharmaceutical Organic Chemistry I 2024-2025 PDF

PN701 Pharmaceutical Organic Chemistry I Prof. Naglaa Gamil Shehab, Pharmaceutical Sciences Department Learning Outcomes  Upon successful completion of this course the student will be able to:  1. LO- 1 Describe atomic structure, orbital theory and hybridization...

PN701 Pharmaceutical Organic Chemistry I Prof. Naglaa Gamil Shehab, Pharmaceutical Sciences Department Learning Outcomes  Upon successful completion of this course the student will be able to:  1. LO- 1 Describe atomic structure, orbital theory and hybridizations of organic molecule.  LO -2 Discuss different types of chemical bonding of organic compounds, physical forces within a molecule and their important bond characteristics.  LO- 3 Explain the effect of electronegativity on the polarity of organic compounds and the resonance effect of different types of functional group in an organic molecule.  LO- 4 Discuss different chemical reaction mechanism leads to the formation of intermediates as free radicals and the stability of free radicals.  LO- 5 Explain the concept of isomerism of organic compounds and its importance in medicinal chemistry. Important Notifications  1-Attendance  2-Study well Assessment and Evaluation Assessment Tool Mid Term Exam 25 Final Exam 40 Quiz 10 Assignment 25 Introduction to organic chemistry & Structure of atom  i. All organic compounds contain carbon.  ii. The compounds of carbon are far more numerous (over 3000000) than the known compounds of all the other elements put together.  iii. Carbon has the power to combine with other carbon atoms to form long chain. This property known as catenation, is not shown to such an extent by any other element.  CLASSIFICATION OF ORGANIC COMPOUNDS Hydrocarbons are (organic compounds composed of carbon and hydrogen). 1. Saturated Hydrocarbons. A hydrocarbon where valency of carbon atom is full and satisfied and the carbon atom is bonded to four atoms by single sigma bonds. Then this is called saturated hydrocarbons. e.g.: Methane Here nothing can be added to the carbon atom  CLASSIFICATION OF ORGANIC COMPOUNDS 2. Unsaturated Hydrocarbons. A hydrocarbon where valency of carbon atom is not full and not satisfied and the carbon atom is bonded to other atoms by double bonds or triple bonds. Then this is called an unsaturated hydrocarbons. e.g.: Ethene and Ethyne CLASSIFICATION OF ORGANIC COMPOUNDS Hydrocarbons Open chain or acyclic Closed chain or cyclic Alkanes Alkenes Alkynes Alicyclic Aromatic hydrocarbons hydrocarbons (i) Cycloalkanes (ii) Cycloalkenes (iii) Cycloalkynes  Alkanes, Alkenes and Alkynes are : Alkanes CH3 CH3 CH3 CH2 CH2 CH3 Ethane Butane CH2 = CH2 CH3 CH =CH2 Alkenes Ethylene Propylene CH  CH CH3 C  CH Alkynes Acetylene Propyne  Closed chain or cyclic hydrocarbons are characterized by the presence of a carbocyclic ring (ring containing all carbons). They can be further subdivided into two categories: (a) Alicyclic hydrocarbons (b) Aromatic hydrocarbons. Alicyclic hydrocarbons Cyclopropane Hydrocarbons in which the carbon atom form rings and are aliphatic in nature Cyclobutane i. Cycloalkanes (resembling alkanes). ii. Cycloalkenes (resembling alkenes). iii. Cycloalkynes (resembling alkynes). Cyclopropene Aromatic hydrocarbons  are composed of six membered carbocyclic rings containing a system of three conjugated double bonds. The presence of these double bonds confers special physical and chemical properties which are typical of the aromatic system.  OH Benzene Phenol  HETEROCYCLIC COMPOUNDS  besides carbocyclic hydrocarbons, there are cyclic compounds containing other elements like nitrogen, sulphur in place of carbon atom in the ring. These types of organic compounds are heterocyclic compounds. Furan Pyrrole Pyridine Polynuclear or Polyaromatic hydrocarbons These are compounds which have more than one aromatic ring fused or isolated. Biphenyl Naphthalene (Isolated) (Fused)  STRUCTURE OF ATOM According to modern theory: An atom consists of : 1- Nucleus which contains protons and neutrons and which is surrounded by electrons. 2- The mass of a proton is almost the same as that of a neutron, but whereas the proton carries a unit of positive charge, the neutron is electrically neutral. 3-The electrons has about 1/1850th of the mass of a proton, and carries a unit negative charge.  STRUCTURE OF ATOM 4 -The electron in an atom revolves round the nucleus only in certain selected orbits. 5- Each orbit is associated with a definite whole number quanta of energy. The orbits, therefore, are also known as energy levels or energy shells. 6- QUANTUM NUMBERS: The quantum numbers describe all characteristics of electrons in an atom i.e.the number of electrons in each shell, the energy associated with them, the position of electrons in each shell, their spin and their momentum. There are four quantum numbers: 1- Principal quantum number (n). 2- Angular momentum quantum number or orbital quantum number or azimuthal quantum number (l). 3- Magnetic quantum number (m). 4- Spin quantum number (s).  1- Principal quantum number - Denoted by (n): n has whole number values, 1,2,3, …., - What principal quantum number describes about an electron? - This quantum no. describes: (1) The electrons are arranged in shells around the nucleus, each shell being able to contain up to a maximum number of electrons, (2) This maximum depending on the number of the shell, n. n is known as the principal quantum number and indicates the main energy level of the electrons in that shell. (3) n has whole number values, 1,2,3, …., the shells corresponding to which are also denoted by the letters K, L, M, N … respectively. (4) This quantum number determines the energy of an electron as each shell is associated with a definite amount of energy. (5) It also describes the average distance of an electron from the nucleus. As the value of n increases, the electron gets farther away from the nucleus and its energy increases.  2- Angular momentum quantum number (l) What angular momentum quantum number describes about electron? An angular momentum quantum number describes the following: (1) In every principal quantum shell there are n energy sublevels or subshells and these are indicated by l, the angular momentum quantum number (also known as azimuthal quantum number) is the quantum number (2) An angular momentum quantum number tells about the orbital motion of an electron around the nucleus. (3) Just as the principal quantum number n can have values 1,2,3, …., so can l have values 0,1,2,3, n-1. (4) The value of l gives the sublevel or subshell in which the electron is located. Each value of l represents a particular sublevel or subshell. These sublevels are designated as s, p, d, f, g depending on the value of l as shown below.  2- Angular momentum quantum number (l) Value of l 0 1 2 3 4 Sublevel s p d f g If value of n = 1 it means K shell then I will have values 0 and upto n-1 (1-1) so I will have only one value zero. It means that Kshell has only one subshell s Now when n = 2 so I will have values 0 and 2-1 ie 0 and 1 Therefore L shell will have two subshells s and p (5) These s, p, d and f sublevels are subdivided into a number of orbitals and so on. The total number of orbitals that a principal quantum shell can contain is given by formula: n2.  2- Angular momentum quantum number (l) (6) * When n = 1 K shell I =0 and (1-1). l=0 * when n = 2 L shell I =0 and (2-1). l=0, 1 ( s and p subshells ) * When n = 3 M shell I =0,1 and (3-1). l=0, 1, 2 ( s p d)  3- Magnetic quantum number (m) What Magnetic quantum number describes about magnetic number ? It describes the following: (1) Since an electron has an angular momentum, its motion creates a magnetic field. (2) This field can interact with an external magnetic field. (3) As a result of such interaction, the electrons in a given energy sublevel orient themselves in certain specific regions of space around the nucleus. (4) These regions of space are called orbitals. (5) The number of orbitals in a given energy sublevel within a principal energy level is given by the number of values allowed to m, called the magnetic quantum number. (6) The number allowed to m depends on the value of l and ranges from –l through 0 to +l.  3- Magnetic quantum number (m) (7) Each value of m represents a particular orbital. e.g., if l = 0 ( i.e., the subshell is s), m can have only one value, 0. This means that s-subshell can have only one orbital, the s orbital i.e., there can be only one possible orientation of electrons in space. (8) If l = 1 (i.e., subshell is p), m can have three values m = -1, 0, +1. This means that p sublevel can have three orbitals i.e., there can be three possible orientations of electrons in space. (9) If l = 2 (i.e., the subshell is d), m can have five values –2, -1, 0, +1, +2. This means that d subshell can have five orbitals i.e., there can be five possible orientations of electrons in space. Thus, on the whole we can say that magnetic quantum number gives the allowed orientations of orbitals in an external magnetic field.  4- Spin quantum number (s) What Spin quantum number describes about an electron? It describes the following: (1) In addition to the energy levels of an electron described by quantum numbers n and l, electrons have spin about their axis, some spinning in one direction and other in the opposite direction. (2) This is indicated by the spin quantum number (s), and can have values of +0.5 and –0.5 depending on the direction of spin. The two values are often written as  and  for convenience. (3) Thus, on the whole the four quantum numbers specify completely the status of an electron in a given atom. They give its position in the main energy level (n), the sub-energy level (l), the orientation of the orbital (m) and direction of its spin (s). In other words, they serve as an address for the electron. CHEMICAL BONDING Learning outcomes:  After successful completion of this chapter , you should understand the followings:  What is an Electrovalent (or Ionic ) bond and its importance.  What is a Covalent bonds (Ordinary covalent bond and Dative covalent or co-ordinate covalent bond) and its importance.  What are the Sigma Bond and Pi Bond and their importance.  What is a Hydrogen Bond and its importance. CHEMICAL BONDING The forces that bind atoms together in elements and compounds are called a chemical bond. The rare or noble gases are very stable and difficult to be disturbed, i.e., they are self satisfied as they have their octet complete whereas the tendency of the other elements is to try and attain this inert octet structure possessed by the rare gases. This is achieved during chemical combination or bonding of the two atoms. There are two main types of chemical combination or bonds. Electrovalent (or Ionic ) bond Covalent bond – which is subdivided into a) Ordinary covalent bond b) Dative covalent or co-ordinate covalent bond  1.Electrovalent( or ionic) bond An ionic bond is formed when a metal atom transfers one or more electrons to a non metal atom. As a result of this transfer the metal atom becomes a positively charged ion (cation) and the non metal, a negatively charged ion (anion). These electrons which are transferred reside in the outermost shells (valence shell) and are known as “Valence electrons”. Those atoms which have only one or two valence electrons require less energy to give away these electrons to attain the stable octet structure of the nearest inert gas. Such elements are very active and readily combine with many other element and compounds. e.g., alkali metal Na has only one valence electron and it looses it to form a cation. Electronic configuration of first8 group elements. Na K2 L M1 or 1s2 2s2p6 3s1  1.Electrovalent( or ionic) bond The non metal element like chlorine (K2L8M7) will react readily with sodium, as it needs only one electron in order to achieve a stable electron octet and convert to anion. Thus sodium cation and chloride anion will combine together or form an electrovalent (ionic) bond to give sodium chloride molecule. Na + Cl Na+ + Cl- NaCl 2,8,1 2,8,7 2,8 2,8,8 Molecule atom atom Cation Anion Na Cl ．．． ． * Na+ + [Cl]- Na+Cl- Sodium atom Chlorine Atom Sodium ion Chloride ion Sodium chloride Na+, 2,8 Cl- 2,8,8  Characteristics of ionic/electrovalent compounds: 1. They do not contain molecules. Instead they consist of aggregates of charged particles called ions. 2. They dissolve in water to form electrolytes which readily conduct electricity. 3. They have high melting and boiling points because of the nature of crystal lattices. 4. They are mostly inorganic compounds. Hence they are usually insoluble in organic solvents (which are non polar) and will dissolve in water and other polar solvents.  2.Covalent bond: (a) Ordinary covalent bond 1. In ordinary covalent bond there is an equal sharing of a pair of electrons between two reacting atoms so that both can attain a stable octet structure. 2. This pair of electrons is referred to as the shared pair. 3. Sometimes, more than one pair of electrons may be shared between two reacting atoms. 4. The shared electrons may be regarded as revolving in orbits controlled by both nuclei, there-by forming the covalent bond. 5. Thus molecules are produced in covalent combination of atoms instead of ions. (a) Ordinary covalent bond 6. Diatomic molecules of elements are formed by covalent combination e.g., Cl2 and H2 molecules. 7. Organic compounds are also formed by this method. The shared pair is represented by a stroke between the two atoms in the association. e.g., formation of H2 molecule, in which a single pair of electrons shared between two bonded H atoms produce a single covalent bond. Each H atom donates, one electron in the shared pair. Single electron in outer shell H + H Shared electron pair Hydrogen atom Hydrogen atom H2 molecule (a) Ordinary covalent bond H + H H H or H 2 Atom Atom molecule 8. The sharing of two pair or three pairs of electrons between bonded atoms result in the formation of double and triple bond respectively. 9. Bonding between oxygen atoms to form a molecule of O2 which has a double bond between two oxygen atoms. 10. and in case of N2 there is a triple bond in between two nitrogen atoms. 2.Covalent bond: Characteristics of covalent compounds  The compounds exist as molecules and not as ions and therefore they do not conduct electricity, i.e., they are non electrolytes.  They are mainly organic compounds and soluble mostly in organic solvents usually not in polar solvent like water.  Simple covalent compounds are often either gases or volatile liquids because their molecules, being electrically neutral are not bonded by strong attractive forces. Some are solids also which have low melting and boiling points as they have weak vander waal’s forces of intermolecular attractions.  2.Covalent bond (b) Dative covalent or co-ordinate covalent bond1. In coordinate covalent bond there is a sharing of electrons between two atoms forming a bond, but both these electrons of the bond are donated by only one atom i.e. there is unequal sharing of electrons between two bonding atoms. This shared pair of electrons is called a lone pair of electrons e.g., the formation of NH4+ radical.  (b) Dative covalent or co-ordinate covalent bond + H 2. Formation of the NH+H4 (ion) + H H N H H N + H H co-ordinate NH3 molecule Hydrogen ion Ammonium ion bond H H H N H + H + H N H H Lone pair of electrons Co-ordinate bond is represented by an arrow pointing from the donor (who donate a lone pair ) to the acceptor (who accept an electron) atom. e.g: 3. These co-ordinate covalent bonded compounds have properties which are very similar to purely covalent compounds, except that the presence of co-ordinate bonds make the compound less volatile.  3.Sigma Bond and PI Bond  Sigma bond (bond): The bond formed by the overlap of atomic orbitals along the internuclear axis is called a sigma bond p - p Overlap s - s Overlap s - p Overlap Fig.1 Different types of  - overlaps  Pi bond (-bond): The bond formed by the lateral overlap of two p-orbitals oriented mutually parallel but perpendicular to the internuclear axis is called a pi bond. Y y x X p-Orbitals p-p Overlap ( bond) ( Bond ) +  3.Sigma Bond and PI Bond Differences between sigma bond and pi bond Sigma Bond (-bond) pi bond ( -Bond) 1. The bond formed by the overlap of 1. The bond formed by the lateral atomic orbitals along the internuclear overlap of the two p-orbitals mutually axis is called a sigma bond parallel but oriented perpendicular to 2. The bond is rotationally symmetrical the internuclear axis is called a pi around the intermuclear axis, i.e., the bond rotation of one of the atoms around 2. The bond is not rotationally the axis does not affect the amount of symmetrical around the internuclear the overlap and hence, the bond axis, i.e. the rotation of one of the strength. atoms around the internuclear axis 3. s-as well as p-orbitals can form this affects the amount of the overlap and type of bond hence, also the bond strength. 4. It is stronger than a pi bond 3. Only p-orbitals can form  bonds. 4. It is weaker than a sigma bond.  Hydrogen atom when it is covalently bonded to highly electronegative elements such as fluorine, oxygen and nitrogen, then the hydrogen atom will form a weak bond with an electronegative atom of another molecule. This weak bond is called a hydrogen bond. This may be represented as 4. Hydrogen Bond  The hydrogen bond is not a true bond but a particularly strong form of dipole- dipole attraction.  Where X and Y are electronegative atoms like F,O or N; the dotted line represents hydrogen bond and the solid line represents the original (covalent) bond present in the molecule. Hydrogen bond  Long chains of molecules are formed by intermolecular H- BONDING  H F H F H F (HF)n  n = 1, 2, 3, ……. 4. Hydrogen Bond Effect of H- bonding on the physical properties of molecules: 1. Molecules exhibiting the phenomenon of H-bonding have higher boiling than molecules of almost same molecular weight lacking H-bonds, e.g. ethanol has very high boiling point (78° C) whereas isomeric diethyl ether with same molecular weight has very low (-25° C) boiling point. Ethanol has intermolecular H- bonding and form long chains of molecules which requires high temperature to break, so boiling point is high, while diethyl ether has no H- bonding, so boiling point is less. 2. H-bond has also very significant effect on solute- solvent interaction. A molecule having H- bonded to F, O, or N may involve in H-bonding with solvents like H2O, NH3 etc, so it increases its solubility. H R O H O H H-Bond (Interaction of solvent with solute through H-bonds) 3. Interaction of solute alcohol with solvent water is responsible for fairly high solubility of alcohols in water. An increase in molecular weight of alcohols decreases its solubility. ELECTRONEGATIVITY AND POLARITY Learning outcomes:  After successful completion of this chapter , you should understand the followings:  1- What is Electronegativity & Polarity?  2- What is the effect of bond polarity on physical properties and chemical properties of molecules.  3- What is the relationship between polarity of molecules and dipole moments?  4- What is the effect of Dipole Moment on a chemical bond properties?  5- What are the Factors affecting dipole moment of molecules ?  6- Why water is highly polar molecule?  Electronegativity & Polarity Explain the relationship between polarity of a bond and electronegativity? Electronegativity is the tendency of an atom covalently bonded in a molecule to attract electrons of the bond towards itself. Polarity When covalent bonds are formed between two atoms with different electronegativities than they have property called polarity. Two atoms joined by a covalent bond share electrons; their nuclei are held by the same electron cloud. But in most cases the two nuclei do not share the electrons equally; the electron cloud is denser about one atom which is more electronegative than the other which is less electronegative. One end of the bond which has more electron density is thus relatively negative and the other end which has less electron density is relatively positive; that is, there is a negative pole and a positive pole. Such a bond is said to be a polar bond, or to possess polarity. Polarity can be indicated by using the symbols δ + and δ-, which shows partial + and – Polar Bonds charges.e.g.  Electronegativity Electronegativity of elements F > O > Cl > N > Br > C >H More is the differences in the electronegativity of two bonding atoms of a covalent bond, more will be the polarity of a bond.  What is an effect of bond polarity on physical properties and chemical properties: Bond polarities are intimately concerned with both chemical and physical properties. The polarity of a bond determines the kind of reaction that can take place at that bond, and even affects reactivity at nearby bonds. The polarity of bonds can lead to polarity of molecules, and thus profoundly affect melting point, boiling point, and solubility.  Relationship between polarity of molecules and dipole moments? What is a dipole? A covalent bond such as this, in which one atom has a larger share of the electron-pair, is said to possess partial ionic character and is called a polar molecule. H8+ CL8- (a dipole) Such a molecule is called a dipole. What is a dipole moment? The product of the electronic charge, e, and the distance d, between the charges (positive and negative centers) is called the dipole moment,  ; i.e.,  = e x d; e. The unit for measuring dipole moment is known as the Debye (D), in honour of Debye, who did a large amount of work on dipole moments.  Relationship between polarity of molecules and dipole moments? The dipole moment is a vector quantity (a quantity which has magnitude and direction), and its direction is often indicated by an arrow parallel to the line joining the points of charge, and pointing towards the negative end, e.g., H Cl. What is relationship between polarity of molecules and dipole moments? The greater the value of the dipole moment, the greater is the polarity of the bond and vice versa. Molecules like H2, O2, N2, Cl2 and Br2 have zero dipole moments means they are non polar because all are diatomic (consist of two similar atoms having the same electronegativity) and share electrons equally so e is zero and hence  is zero too. But the molecules like HF has a large dipole moment of 1.75 D. Although the HF is a small molecule, the very high electronegative fluorine pulls  What is an effect of Dipole Moment on a chemical bond properties? Greater the magnitude of dipole moment, greater will be the force of attraction between the atoms forming this bond and therefore higher will be the bond energy and smaller will be the bond length.  What are factors affecting dipole moment of molecules ? a) Arrangement of atoms in molecules affect the dipole moment ,the shape of the molecule, bond length and bond angles. This can be explained by the example of CH4 and CCl4. Molecules of methane(CH4) and carbon tetrachloride (CCl4) have zero dipole moments because of the very symmetrical tetrahedral arrangement, so they exactly cancel each other but in CH3Cl the polarity of δ− carbon-chloride bond is not cancelled and has a dipole moment as 1.86 D. δ+ δ+ δ+  = 1.75 D  = 0D  = 0D  =1.86 D  Factors affecting dipole moment of molecules ? What is the effect of presence of lone pair of electrons on atoms in the molecule on dipole moment? if any atom in a molecule has lone pair of electrons than it increases the dipole moment of a molecule. δ− H2O This can be explained by taking examples NH3 and N molecules. Ammonia, NH3 δ+ δ+  = 1.46 D H H H δ+ In ammonia (NH3) the observed dipole moment (1.46 D) is probably due to the presence of lone pair of electrons on nitrogen.  B)Presence of lone pair of electrons on atoms in the molecule: Why water is highly polar molecule? In water molecule H2O, both hydrogen and oxygen bonds are polar and shared pair of electron lies closer to oxygen than hydrogen atom. Its dipole moment is equal to 1.84 D, which is very large giving high polarity to water molecule. This indicates that H2O molecule is not linear but it is a bent structure. Because two lone pair of electrons on oxygen atom exerts a pull in the center bending the molecule and giving bond δ− angle of 110°. δ+ O δ+  = 1.84 D H 110 H ° Water molecule, H2O Thus the dipole moment can give valuable information about the structure of different molecules.