BL1012 Lecture - Bonding II Notes PDF

Lecture Remembering General Chemistry: Bonding II Non-covalent Bonds...

Lecture Remembering General Chemistry: Bonding II Non-covalent Bonds Joseph M. Hayes 1 © 2017 Pearson Education, Inc.  Covered in Today’s Lecture  Covalent Bonds (Introduction to Molecular Orbitals)  Non-covalent Bonds (Intermolecular Interactions) 2 © 2017 Pearson Education, Inc.  How do atoms form covalent bonds in order to form molecules?  According to Molecular Orbital (MO) theory, covalent bonds result when atomic orbitals combine to form molecular orbitals  Forming a sigma (σ) bond – “head-on” overlap of atomic orbitals A molecular orbital (MO) describes the volume of space around a molecule where an electron is likely to be found  Orbitals are conserved: # of Molecular Orbitals = # of Atomic Orbitals Combined  In above example, this is because H 1s orbitals of the same phase (colour) can overlap constructively (σ bonding MO) or of different phase (colour) overlap destructively (σ* antibonding MO) A sigma (σ) covalent bond is formed by the head on overlap of two atomic orbitals. © 2017 Pearson Education, Inc. 3  Atomic Orbitals Combine to Form Molecular Orbitals  When 2 AOs combine, 2 MOs are formed, one lower and one higher in E than the original AOs  Both electrons are in the σ bonding MO. The σ* antibonding MO is empty. Electrons are assigned to MOs using the same rules as for AOs  Electrons always occupy available orbitals with lowest E (Aufbau principle)  No more than two electrons can occupy a MO (Pauli exclusion principle) 4 © 2017 Pearson Education, Inc.  π Covalent Bonds Side-to-side overlap of p orbitals forms a π covalent bond Out-of-phase (different colour) overlap forms a π* antibonding MO In-phase (same colour) overlap π bonding MO. Note: there are another type of orbitals commonly involved in forming molecular orbitals in organic chemistry – hydrid orbitals – that can give side-to-side overlap and π covalent bonds © 2017 Pearson Education, Inc. 5  Type of Bonding > Geometry © 2017 Pearson Education, Inc. 6  Kekulé, Condensed & Skeletal Structures Kekulé structures are like Lewis structures except that lone pairs are normally omitted Condensed structures omit the covalent bonds and the lone pairs Skeletal structures show the carbon-carbon bonds as lines, and do not show the hydrogens that are bonded to the carbons* * each carbon is understood to be bonded to appropriate numbers of H atoms to give the carbon 4 bonds 7 © 2017 Pearson Education, Inc.  Covered in Today’s Lecture  Covalent Bonds (Introduction to Molecular Orbital Theory)  Non-covalent Bonds (Intermolecular Interactions) 8 © 2017 Pearson Education, Inc.  Drug Action  The main macromolecular targets for drugs are proteins (mainly enzymes, receptors & transport proteins) and nucleic acids (DNA & RNA)  The interaction of a drug with a molecular target involves a process known as ‘binding’  There is usually a specific area of the macromolecule where this takes places – this is known as the ‘binding site’  Most drugs bind to their targets by forming a network of intermolecular interactions (non-covalent bonds) 9 © 2017 Pearson Education, Inc. Binding of a Drug to its Target Drugs interact with their macromolecular targets by binding to binding sites Binding typically involve intermolecular interactions Binding regions between drug and target Regions within the target binding site involved in Drug binding interactions are called binding regions Binding groups Functional groups on the drug involved in binding interactions are called binding groups Intermolecular bonds Binding sites are sometimes a Binding site hydrophobic hollow/cleft on the Drugs are generally much macromolecular smaller than their targets Binding Drug surface site Drug Induced fit Macromolecular target Macromolecular target Unbound drug Bound drug Most drugs are in equilibrium between being bound and unbound to their target Binding interactions usually result in an induced fit where the binding site changes shape to accommodate © 2017 Pearson Education, Inc. the drug 10  Binding of a Drug to its Target  Binding interactions usually result in an induced fit where the binding site changes shape to accommodate the drug  The induced fit may also alter the overall shape of the drug target - important to the pharmacological effect of the drug  The study of how drugs interact with their targets through binding interactions is known as pharmacodynamics 11 © 2017 Pearson Education, Inc.  Intermolecular (non-covalent) bonding interactions Electrostatic or ionic bonds Hydrogen bonds van der Waals interactions Dipole-dipole interactions Ion-dipole interactions 12 © 2017 Pearson Education, Inc. Electrostatic ionic bonds  Ionic bonds are the most important initial interactions as a drug enters the binding site  Takes place between groups of opposite charge O Drug Drug NH3 O O H3N Target Target O  Ionic electrostatic interactions are generally the strongest of the intermolecular bonds (20-40 kJ mol-1)  The strength of interaction drops off much less rapidly with distance compared to van der Waals interactions – electrostatic interactions are considered long-range interactions 13 © 2017 Pearson Education, Inc. Hydrogen bonds  Vary in strength – typically 16-60 kJ/mol - + - - + - Drug Y H X X H Y Target Target Drug HBD HBA HBA HBD  A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (electronegative N or O)  The electron deficient hydrogen is usually attached to a heteroatom (O or N)  The electron deficient hydrogen is called a hydrogen bond donor (HBD)  The electron rich heteroatom has to have a lone pair of electrons and is called a hydrogen bond acceptor (HBA)  Hydrogen bond distances are typically 1.5 – 2.2 Å 14 © 2017 Pearson Education, Inc.  Hydrogen bonds  Some functional groups can act both as hydrogen bond donors and hydrogen bond acceptors Examples: –OH and –NH2  A good hydrogen bond acceptor has to be electronegative and have a lone pair of electrons. Nitrogen has one lone pair of electrons and can act as an acceptor for one hydrogen bond; oxygen has two lone pairs and can accept two hydrogen bonds 15 © 2017 Pearson Education, Inc. Relative Strengths of Hydrogen Bond Acceptors (HBA)  Any feature that affects the electron density of the HBA is likely to affect its ability to act as a HBA: the greater the electron density on the heteroatom, the greater its strength as a HBA  Examples of strong hydrogen bond acceptors © 2017 Pearson Education, Inc. Relative Strengths of Hydrogen Bond Acceptors (HBA)  Most HBAs present in drugs and binding sites are neutral  These groups will form moderately strong hydrogen bonds 17 © 2017 Pearson Education, Inc. Relative Strengths of Hydrogen Bond Acceptors (HBA)  These groups will form weak hydrogen bonds  S also forms weak H-bonds. Its lone pairs are in the 3rd shell, orbitals are more diffuse hence interact less efficiently with the HBD  F is more electronegative than N or S, it has three lone pairs of electrons, yet it is a weak HBA  The pi (π) system in alkynes and aromatic rings are electron rich and hence can act as “hydrogen bond acceptors” – electron density is diffuse so interactions weak 18 © 2017 Pearson Education, Inc. van der Waals interactions  Weak but very important interactions (2-4 kJ mol-1)  The overall contribution of van der Waals interactions to binding can be crucial  Occur between hydrophobic regions of the drug and the target DRUG Hydrophobic regions d+ d- Transient dipole on drug d+ d- van der Waals interaction d- d+ Binding site  Transient (temporary) areas of high and low electron densities cause temporary dipoles  Interactions drop off rapidly with distance (short-range interactions)  Drug must be close to the binding region for interactions to occur 19 © 2017 Pearson Education, Inc.  Dipole-dipole interactions  Can occur if the drug and the binding site have dipole moments d- O Dipole moment d+ C R R Dipoles align with each other as the drug enters the binding site/orientates the molecule in the binding site Localised dipole moment R O C R Binding site Binding site  Note that dipole-dipole interactions involve “localised” dipole moments in contrast to the “transient” (instantaneous) dipole moments we saw for van der Waals 20 © 2017 Pearson Education, Inc.  Ion-dipole interactions  Occur where the charge on one molecule interacts with the dipole moment of another  Stronger than a dipole-dipole interaction R O d- C d+ R R O d- C d+ O H 3N O C R Binding site Binding site 21 © 2017 Pearson Education, Inc.