Medicinal Chemistry
Medicinal Chemistry

Medicinal Chemistry

Lead Author(s): Ronny Priefer

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This text explores how molecules exert their desired pharmacodynamic and pharmacokinetic effects.

      Chapter 1: Introduction

Structure and Bonding in Organic Chemistry (A Brief Review)

  • Atomic orbitals can combine to generate new orbitals:
    • Hybridization: combination of atomic orbitals of the same atom producing            new orbitals of lower energy
    • sp, sp2 and sp3 These orbitals explain the geometry of molecules
  • Molecular Orbitals:
    • Sigma bonding (σ): Hydrogen molecule
    • Sigma bond: is covalent (most common bond inorganic molecules)
  • 2 other types of bonds in organic molecules:
    • Pi (π) bond (DOUBLE BOND)
    • Hydrogen-bond (H-bond) (will discuss more later)
  • All single bonds are sigma bonds and all double or triple bonds contain only one sigma bond
  • Sigma bonds can be formed from atomic orbitals, hybridized or native, or a combination
  • π-bond: cannot exists if a σ-bond is not already present
    • Result from the overlap of p orbitals of two atoms. The π-bond is always perpendicular to the sigma bond connecting the nuclei
    • Occur in sp2 and sp hybridized atoms (double/triple bonds)
  • Double bond:


  • 4 electrons in the bonding region between the nuclei
    •      first pair forms the sigma bond
  •  Second pair forms the pi bond


  • Triple Bond:
    • 6 electrons in the bonding region between the nuclei
    • first pair forms the sigma bond
    • Second/third pairs form the pi bonds
  • Molecular shapes and 3-D drawings
    • Molecular shapes are related to hybridization of central atom sp3: only single bonds; 109.5o angle (methane) sp2: double bond; 120o angle (ethylene) sp: triple bond; 180o angle (acetylene)


Sigma and pi-1
question description

How many sigma and pi bonds exist in the molecule?

A

4 sigma 4 pi

B

8 sigma 4 pi

C

8 sigma 2 pi

D

4 sigma 2 pi


Sigma and pi-2
question description

How many sigma and pi bonds exist in the molecule?

A

16 sigma 3 pi

B

2 sigma 2 pi

C

8 sigma 4 pi

D

12 sigma 1 pi

E

15 sigma 5 pi


    • Only 4 general shapes are normally found in organic molecules:
      • Linear (sp hybridized atoms)
      • Trigonal planar (sp2 hybridized)
      • Trigonal pyramid or tetrahedral: (sp3 hybridized)



Hybridization

Click on the sp2 hybridized carbon


Bond angles

Click on the atom that has bond angles closest to 110 degrees.


Names of Organic Compounds

  • Names of Organic molecules are based on the names of Hydrocarbons.
  • The simplest hydrocarbons are the alkanes, all their names end by the suffix “ane” and is preceded by a prefix indicating the number of carbon atoms in the molecules.
  • Example:

Properties of Organic Molecules

  • Polarity of molecules Bond polarity can range from: 
    •  Non-polar covalent (C-C) 
    •  Ionic (NH4+ -Cl)
    •  Polar covalent (C-O) 

Example:

the dipole moment of a bond is the measure of its polarity (in Debye: D)

The molecular dipole moment is the dipole moment of the molecule taken as a whole. It is a good indicator of the overall polarity of molecules.

Its value is the vector sum of individual bond dipole moments

Examples:

  • Attractions and Repulsions: 3 major kinds of attractive forces cause molecules to associate into solids or liquids:
  • dipole-dipole forces
    • polar molecules
  • London forces (van der Waals)
    • affect all molecules
  • Hydrogen bonds
    • for molecules with NH or OH groups


Intermolecular forces

Arrange the three most common intermolecular forces in order of strongest to weakest.

A

dipole-dipole forces

B

Hydrogen bonding

C

van der Waals

  • Dipole-dipole forces:

     attractive intermolecular forces resulting from the attraction of the positive and      negative ends of polar molecules

result: polar molecules have higher boiling/melting point

  • London dispersion forces:

In non-polar molecules (alkanes), this is the principal attractive force

They arise from temporary dipole moments created by the proximity of other molecules

  • Result: molecules with larger surface area will have a higher boiling/melting point
  • Hydrogen bonding:

Not a true bond, but a very strong form of dipole-dipole attraction. An H atom can participate in H-bonding if it is bonded to O or N (-OH, -NH)

  • The O-H and N-H bonds are strongly polarized and the positive charge is located on H
  • Hydrogen bonds form between the hydrogen and the lone pair of the heteroatom from another molecule:
  • Example: Methanol
  • result: the stronger the H-bond, the higher the boiling/melting point
  • alcohols (OH) have higher boiling points than amines (NH) of similar molecular weights, because the OH bond is more strongly polarized than NH