Lectures 5 & 6 - Intermolecular Forces I-II PDF

College of Pharmacy INTERMOLECULAR FORCES I-II PHARMACEUTICAL ORGANIC CHEMISTRY (PHBS-211) Third Term, AY23-24 Dr. Sahar S. Alghamdi, Pharmaceutical Sciences Department College of Pharmacy LECTURES 5 & 6 - Intermolecular Forces I-II 1 LECTURES’ LEARNING OUTCOMES At the end of the lectures, the stude...

College of Pharmacy INTERMOLECULAR FORCES I-II PHARMACEUTICAL ORGANIC CHEMISTRY (PHBS-211) Third Term, AY23-24 Dr. Sahar S. Alghamdi, Pharmaceutical Sciences Department College of Pharmacy LECTURES 5 & 6 - Intermolecular Forces I-II 1 LECTURES’ LEARNING OUTCOMES At the end of the lectures, the students must be able to: 1. Define concepts related to solubility and dissolution of organic compounds. 2. Describe the various types of intermolecular forces (covalent, dipole-dipole, ionic, ionic-dipole, hydrogen bonding, Van der Waal, etc.) 3. Distinguish between intra- and inter-molecular forces 4. Relate strength of intermolecular forces to the chemical nature of functional groups 5. Relate the intra-and intermolecular forces of amino acids, DNA and RNA bases to the shaping of biological molecules. 6. Relate the hydrophobic effect of water to the shaping of biological molecules 7. Describe the relative contribution of different reversible intermolecular forces to Drug-Receptor Interactions. 8. Relate intra-and intermolecular forces within a given medicinal agent to its physicochemical properties. 9. Predict the solubility/lipophilicity of a given medicinal agent. LECTURES 5 & 6 - Intermolecular Forces I-II 2 INTERMOLECULAR FORCES Intermolecular forces are the forces of attraction or repulsion which act between non-bonded functional groups. They are also known as noncovalent interactions, or Molecular interactions These forces are very important from a pharmaceutical and biological perspective, since they are responsible for the building up of biological macro-molecules(e.g. proteins ,nucleic acids) and determine to a large extent the physical properties of molecules (solubility ,melting point, boiling point etc.) LECTURES 5 & 6 - Intermolecular Forces I-II 3 Origin of Intermolecular Forces Intermolecular interaction originate from the attraction or repulsion between functional groups present in the molecules Functional groups present in the molecules and that are important in forming intermolecular bonds are called binding groups Intermolecular interactions can occur between different molecules,between molecules and the solvent and even between functional groups within the same molecule(in this case they are called intra molecular ) LECTURES 5 & 6 - Intermolecular Forces I-II 4 Types of Intermolecular Forces Van Der Waals interaction Hydrophobic interactions. Covalent bonding Ionic interactions Dipole – dipole interactions Ion- dipole interactions Hydrogen bonding Van Der Waals interaction LECTURES 5 & 6 - Intermolecular Forces I-II 5 Van der Waals interactions (London forces) They are weak interactions caused by momentary changes in electron density in a molecule. The electron cloud of an alkyl group, which can normally be expected to be equally distributed spatially. However, at any given moment the electron distribution may be uneven, resulting in an instantaneous dipole. This weak and temporary dipole subsequently influences neighboring functional groups through electrostatic attraction and repulsion by inducing a dipole on nearby functional groups The strength of these interactions falls off rapidly the further the two molecules are apart.(i.e. Van der Waals forces occur only when the molecules are very close) LECTURES 5 & 6 - Intermolecular Forces I-II 6 Van der Waals interactions (London forces) Alkyl functional groups and aromativc rings are the main functional groups responsible for Van der Waal interactions All compounds exhibit van der Waals forces. The surface area of a molecule determines the strength of the van der Waals interactions between molecules. The larger the surface area, the larger the attractive force between two molecules, and the stronger the intermolecular forces. LECTURES 5 & 6 - Intermolecular Forces I-II 7 Van der Waals interactions (London forces) Van der Waals forces play an important role in the folding of proteins Amino acids with nonpolar side chains get attracted to each other in water media (away from water molecules LECTURES 5 & 6 - Intermolecular Forces I-II 8 Hydrophobic interaction The repulsion between water molecules and nonpolar moieties is called hydrophobic interaction Oil doesn’t mix with water due to hydrophobic interactions LECTURES 5 & 6 - Intermolecular Forces I-II 9 Hydrophobic Interaction LECTURES 5 & 6 - Intermolecular Forces I-II 10 Ionic interactions An ionic bond is the strongest of the intermolecular bonds and takes place between groups having opposite charges such as a carboxylate ion and an alkylammonium ion The basic side chains of the amino acids Arginine and Lysine are protonated at physiologic pH. Thus provide cationic environment. Acidic groups (e.g.carboxylic acid side chains of Aspartic acid and Glutamic acid are deprotonated to give anionic groups. LECTURES 5 & 6 - Intermolecular Forces I-II ASPARTIC ACID GLUTAMIC ACID Negatively charged amino acids 11 ARGININE HISTIDINE Positively charged amino acids Dipoles Molecular dipoles occur due to the unequal sharing of electrons between atoms in a molecule. Atoms that are more electronegative pull the bonded electrons closer to themselves. The buildup of electron density around an atom or discreet region of a molecule can result in a molecular dipole In a molecular dipole one side of the molecule possesses a partially negative charge and the other side a partially positive charge. Molecules with dipoles that are not canceled by their molecular geometry are said to be polar. LECTURES 5 & 6 - Intermolecular Forces I-II 12 Haloalkanes Dipoles Many molecules have a permanent dipole moment resulting from the different electronegativities of the atoms and functional groups present. For example, a ketone has a dipole moment due to the different electronegativities of the carbon and oxygen making up the carbonyl bond. Aldosterone LECTURES 5 & 6 - Intermolecular Forces I-II 13 Hydrogen bonding A hydrogen bond is a special type of dipole-dipole attraction when a hydrogen atom bonded to a strongly electronegative atom exists in the vicinity of another electronegative atom with a lone pair of electrons. LECTURES 5 & 6 - Intermolecular Forces I-II 14 Hydrogen Bonding In BIOLOGICAL MOLECULES SERINE THREONINE ASPARAGINE GLUTAMINE Polar amino acids LECTURES 5 & 6 - Intermolecular Forces I-II 15 Hydrogen Bonding LECTURES 5 & 6 - Intermolecular Forces I-II The electron-deficient hydrogen is known as a hydrogen bond donor (HBD) The functional group that provides the electron rich atom to receive the hydrogen bond is known as the hydrogen bond acceptor (HBA). 16 Hydrogen Bonding Some functional groups can act both as hydrogen bond donors and hydrogen bond acceptors (e.g. OH, NH2). LECTURES 5 & 6 - Intermolecular Forces I-II 17 Covalent Bonding Sometimes a covalent bond can be formed The disulfide bridge in some proteins Cysteine LECTURES 5 & 6 - Intermolecular Forces I-II 18 Drug Targets The main molecular targets for drugs are proteins (mainly enzymes, receptors and transport proteins), and nucleic acids (DNA and RNA). The interaction of a drug with a macromolecular target involves a process known as binding. Binding site is the area in the macromolecule where the binding of a drug takes place LECTURES 5 & 6 - Intermolecular Forces I-II 19 Drug Receptor Interaction Drug Receptor Drug-Receptor complex Drug Receptor kd = Drug − Recetor complex The smaller the kd ,the larger the concentration of the D-R complex i.e. the greater the affinity of the drug to the receptor LECTURES 5 & 6 - Intermolecular Forces I-II 20 Covalent Bonding Some drugs react with the binding site and become permanently attached via a covalent bond e.g. organophosphorus compounds, penicillins Sarin gas Binds irreversibly to the enzyme choline-esterase LECTURES 5 & 6 - Intermolecular Forces I-II 21 Ampicillin( a penicillin) binds irreversibly to its bacterial target Covalent Bonding The formation of covalent bond with a receptor will lead to receptor deterioration. LECTURES 5 & 6 - Intermolecular Forces I-II 22 IonicInteractions Ionic interactions occur between negatively charged of a drug and a positively charged functional group in the receptor Or vise versa LECTURES 5 & 6 - Intermolecular Forces I-II 23 Dipole – Dipole Interactions LECTURES 5 & 6 - Intermolecular Forces I-II Occur when the drug and binding site contain carbonyl functional groups,or any other functional group with a dipole The positive side of the dipole binds to the negative side of the other dipole 24 Ion- Dipole Interactions An ion-dipole interaction is where a charged or ionic group in one molecule interacts with a dipole in a second molecule. Ion–dipole and dipole–dipole interactions are a weak form of electrostatic interaction LECTURES 5 & 6 - Intermolecular Forces I-II 25 Binding of Zaleplon δδ+ Dipole-dipole interaction δ+ Zaleplon δ- δδ+ Ion-dipole interaction LECTURES 5 & 6 - Intermolecular Forces I-II 26 HydrogenBonding HBD LECTURES 5 & 6 - Intermolecular Forces I-II HBA HBA 27 HBD Binding of Norepinephrine to its Receptor LECTURES 5 & 6 - Intermolecular Forces I-II 28 Charge Transfer Interactions When a group that is a good electron donor comes in contact with a group that is a good electron acceptor, the donor may transfer some of its charge to the acceptor. Donor groups may be groups that contain π electrons (e.g. aromatic moieties, alkenes)or a group that contains a pair of non-bonded electrons(e.g. O,N,S) Acceptor groups contain electron deficient π orbitals such as aromatic groups having electron withdrawing substituents. LECTURES 5 & 6 - Intermolecular Forces I-II 29 Binding of Chlorothalonil Chlorothalonil Charge transfer interactions LECTURES 5 & 6 - Intermolecular Forces I-II 30 π −π Interaction or Stacking 𝝅 −π stacking This type of interaction involves two aryl groups in a parallel arrangement Lacosamide LECTURES 5 & 6 - Intermolecular Forces I-II 31 Van der WaalsInteractions Van der Waals interactions arise when hydrophobic functional groups on the drug interact with hydrophobic functional groups on the receptor. Although the interactions are individually weak, there may be many such interactions between a drug and its target and so the overall contribution of van der Waals interactions can often be crucial to binding LECTURES 5 & 6 - Intermolecular Forces I-II L-Isoleucine Butamben 32 ADrug Molecule can haveMultiple Interactions with a Receptor LECTURES 5 & 6 - Intermolecular Forces I-II 33 Namethe Interactions you see LECTURES 5 & 6 - Intermolecular Forces I-II 34 Binding of Morphine LECTURES 5 & 6 - Intermolecular Forces I-II 35 Inter-and Intra-Molecular Interactions  Interaction between various functional groups can give rise to multiple types of bonding.  As discussed previously  If the interacting functional groups are on the same molecule, then it is called intramolecular bonding.  If the interacting functional groups are on two different molecules, then it is called intermolecular bonding. LECTURES 5 & 6 - Intermolecular Forces I-II 36 Intra-Molecular Bonding  For intramolecular bonding to occur , the functional groups must be near each other.  Or the molecule is flexible enough to bring the two functional groups into close proximity. LECTURES 5 & 6 - Intermolecular Forces I-II 37 Intra-Molecular Bonding  For a compound to be soluble in water these intra- and intermolecular interactions must be broken to allow bonding with water molecules. LECTURES 5 & 6 - Intermolecular Forces I-II 38 Intra-Molecular Bonding Intramolecular bonding is much stronger than intermolecular bonding. Intramolecular bonding may account for the insolubility of some polar compounds. LECTURES 5 & 6 - Intermolecular Forces I-II 39 Water Solubilizing Potential of Functional Groups in Polyfunctional Molecules LECTURES 5 & 6 - Intermolecular Forces I-II Functional group Number of Carbon atoms it can solubilize Alcohol 3C Phenol 3C Ether 2C Aldehyde 2C Ketone 2C Amine 4C COOH 3C Amide, Ester 3C Urea, Carbonate, Carbamate 2C 40 Predict the Solubility of the following: This compound has 3 ether x 2= 6C 1 phenol x 3= 3C 1 amine x 4 = 4C The functional groups can solubilize 13C The compound has 19C. So, it’s water insoluble LECTURES 5 & 6 - Intermolecular Forces I-II 41 Predict theSolubility of thefollowing: This compound has 2 phenol x3 = 6C 1 COOH X 3 = 3C 1 NH2 X 4 = 4C The functional groups can solubilize 13C α-Methyldopa LECTURES 5 & 6 - Intermolecular Forces I-II The compound has 9C. So, it’s water soluble 42 Calculated LogP  As we have seen Log P is a measure of the solubility characteristics of the whole molecule  One can use fragments of the whole molecule and assign a specific hydrophilic-lipophilic value( π-value)  A calculated log P can be obtained by the sum of these values. 𝐋𝐨𝐠 𝐏 = σ 𝛑(𝐟𝐫𝐚𝐠𝐦𝐞𝐧𝐭𝐬) LECTURES 5 & 6 - Intermolecular Forces I-II 43 π Values for Organic Fragments 𝛑 − 𝐯𝐚𝐥𝐮𝐞 Fragment C aliphatic C alkene Phenyl Cl ( halogen) S N amine O ( hydroxyl, ether, phenol) NO3 NO2 aliphatic NO2 aromatic O=C-O O=C-N LECTURES 5 & 6 - Intermolecular Forces I-II +0.5 +0.33 +2.0 +0.5 +0.0 -1.0 -1.0 +0.2 -0.85 -0.28 -0.7 -0.7 44 π Values for Organic Fragments  A positive value for π means the fragment is lipophilic.  A negative value for π means the fragment is hydrophilic.  A compound with a sum value over +0.5 is considered water insoluble.  A compound with a sum value less than soluble. LECTURES 5 & 6 - Intermolecular Forces I-II 45 +0.5 is considered water Predict the Solubility Using π Values for Organic Fragments Phenyl +2.0 6 aliphatic C X +0.5 = +3.0 2N X-1.0 = -2.0 O=C-O -0.7 Procaine  Total = +2.3  Prediction insoluble LECTURES 5 & 6 - Intermolecular Forces I-II 46 Partition Coefficient  Partition coefficient is a physical property of the drug used to measure its lipid solubility.  Partitioning is the movement of molecules from one phase to another.  Examples of partitioning include:  Drugs partition themselves between the aqueous phase and lipophilic membranes. Antibiotics partition from body fluids to microorganisms. Drugs can partition into plastic and rubber stoppers of containers. LECTURES 5 & 6 - Intermolecular Forces I-II 47 Partition Coefficient  If two immiscible phases are placed together, with one containing a solute soluble in it.  n-octanol is used as lipophilic phase.  Drugs must exhibit some degree of aqueous solubility.  The solute will distribute  This is essential because the itself between the immiscible availability of a drug in solution phases until equilibrium is form is a prerequisite for drug attained. absorption.  If we consider the concentration of the solute in High P High hydrophobicity water as Cw and in oil as Co Partition Coefficient P = LECTURES 5 & 6 - Intermolecular Forces I-II 𝑪𝒘 𝑪𝒐 = [Drug in octanol] [Drug in water] 48 Hydrophilic Drugs must begiven Parenterally Gentamicin Ceftriaxone LECTURES 5 & 6 - Intermolecular Forces I-II 49 Chemical Modification to EnhanceLipid Solubility Thiopental Pentobarbital Tetracycline LECTURES 5 & 6 - Intermolecular Forces I-II Chlortetracycline 50 PHBS 211 Pharmaceutical Organic Chemistry LECTURE 16Drug Solubility Prodrugs Haloperidol  A prodrug is an active drug linked to a carrier group that can be removed enzymatically.  Prodrugs are generally esters or amides.  Prodrugs have greatly modified lipophilicity due to the attached carrier. Haloperidol decanoate LECTURES 5 & 6 - Intermolecular Forces I-II  A prodrug is biologically inactive. 51