Bonding Environments and Conformational Analysis of Drug Structures

What are the features of benzene?

• Planar

• All C-C bonds are the same length (1.39 A)

• 6pi electrons are delocalised- p-orbitals overlap to form a delocalised ring, makes it stable

Select the shapes of the carbon atoms marked X and Y in paracetamol

X- planar Y- tetrahedral

Name the shapes of the carbon atoms marked X and Y in the HIV drug Efavirenz

X- linear Y- tetrahedral

Bonding of oxygen and it’s influence on shape

tetrahedral/ bent ( bond angle 104.5 degrees):

• Water (H2O)

• Alcohols (ROH)

• Ethers (ROR)

Planar (120 degrees):

Carbonyls:

• Carboxylic acid (RCOOH)

• Ester (RCOOR)

• Amide (RCONH2)

• Ketone (RCO-Alkyl)

• Aledehyde (RCOH)

• Acid Chloride (RCOCl)

• Anydride (RCOO(O)CR)

What are the conformations of a molecule? (General definition)

The conformations of a molecule are the different possible arrangements in space of the afk s that are inter-convertible by rotation about single bonds

• What are the 2 limiting conformations of ethane?

Staggered (most stable)

• Hydrogens are as far apart as possible

and eclipsed (least stable)

• Hydrogens are closer together

How can you show the conformations of ethane as wedge dash structures?

Wedges face towards us, dashes face away from us

How can you show the conformations of ethane using Newman projections?

Shows the view down the C-C bond

Explain the energy of ethane conformations

• All conformations don’t have the same energy, the staggered conformation is more stable with less energy than the eclipsed conformation

• Rotation around the C-C bond is very fast as it has a small energy barrier of 3 Kcal/mol

• For every 160 molecules of ethane, 159 are in the staggered most stable conformation and 1 in the eclipsed least stable conformation

Which dihedral angles have the highest energy?

0, 120, 240 and 360

Which dihedral angles have the lowest energy?

60, 180 and 300 degrees

• What are the different conformations of butane?

Syn (eclipsed)

• dihedral angles: 0, 360 degrees

• Methyl groups are eclipsing, least stable

Eclipsed:

• Dihedral angles: either 120 or 240 degrees

Gauche (staggered)

• Dihedral angles: either 60 or 300 degrees

Anti (staggered)

• Dihedral angles: 180 degrees

• Most stable as methyl groups are as far apart as possible

Select the. List stable conformation of the neurotransmitter GABA

• Bonds 3-4 staggered

• Bonds 2-3 staggered

What are the different conformations of cyclohexane?

Most stable is the CHAIR: hydrogens are as far apart as possible

What are axial and equatorial hydrogen atoms?

• Axial hydrogens point above and below the carbon atoms

• Equatorial hydrogens point parallel to the C-C bonds

Why is the boat conformation less stable than chair?

It has an eclipsed conformation, so it has more energy than the chair

What are the conformations of methyl-cyclohexane?

• Methylcyclohexane can adopt 2 chair conformations, interconverted by a boat

• Equatorial and axial

• Do these 2 chair conformations have the same energy?

• No the chair with the methyl group in the equatorial position is more stable, so it has less energy

• It is 7 Kj/mol more stable

• Axial is less stable because the axial methyl group clashes with the adjacent axial hydrogens- 1,3-diaxial interactions

Ritalin is used to treat ADHD. What is the most stable shape of the piperidine and phenyl rings?

Piperidine: chair

Phenyl: planar