Lecture 4 Concept Notes Flashcards
Geometric Isomers
Isomers that arise to a restricted rotation around bonds like doublebonds (olefins)
and cyclic compounds
Properties of geometric isomers
Do not show optical isomerism unless they are chiral
Properties of geometric isomers:
physical and chemical properties
Geometric isomers exhibit differences in physical and chemical properties
E/Z terminology
Z= on the same side
E= on different sides
Usually used for complex structures
cis/trans
Cis = same side
Trans = different side
Conformational Isomers
Rotations about a single bond
Eclipsed and Staggered bonds
Eclipsed: H-bonds -> in a Newman projection, the bonds are all closer together
Staggered- H bonds -> in a Newman Projection, the bonds are spread apart equally
Eclipsed
High energy conformation
Less preferred because of how high energy it is
Newman projection: Bonds are close together
Staggered
Low energy conformation
More preferred because of how low energy it is.
Staggered: Bonds are far apart
Rank the Newman projections from most to least preferred
Most:
Staggered
Partially eclipsed
Gauche/skew
Fully eclipsed
Least
Sometimes a IMHB is more favorable than a projection confirmation. Why?
The H bonds are so favorable and stabilizing to the molecule, that it takes priority over the more preferred Newman projection conformation
Cyclic or ring hydrocarbons
They provide more rigidity to a drug than acyclic systems
Bioactive conformations
this is in relation to the receptor’s binding site
T/F: the bioactive conformer needs to be the lowest energy conformer
False. It can be a higher energy conformer.W
What problems do we run into when the bioactive conformer is a high energy conformer?
The drug does not have a high concentration of that conformer and the Kd of the molecule will be high, which means that the binding affinity is low
High Kd means what
Means that the binding affinity is low
Low Kd means
Binding affinity is high, and this is good for our drug
How can we fix when the bioactive conformer is a high energy conformer?
Synthesize a rigid analog of the drug
How can we synthesize a rigid analog of the drug?
Add ring structures
Add H bonding
Add double or triple bonds
Add more steric functional groups
Why do stereoisomers have diff. biological responses?
Active transport & binding involve asymmetric receptors which would prefer one isomer over another
enzymes or biological targets are also chiral and their active sites may exhibit stereospecificity.
In diastereomers, why are there different biological responses?
The diastereomers inherently have diff. physical and chemical properties anyway
Easson-Stedman hypothesis
3 intermolecular interactions are needed for an enantiomer to be considered the more active one.
R/S on Fischer Projections
Any time the lowest priority group is on a horizontal bond, make the switch.
Enantiomers can differ in activity. What does this mean?
One enantiomer may be the more active form.
Enantiomers may also interconvert to the more toxic form, which makes the drug unusable as a whole
Product selectivity
R and S enantiomers can affect which part of the drug are metabolized
Racemic switch
Purifying drugs into one enantiomer is expensive. Drug companies can use racemic mixes (50/50 mix, even if one is inactive) for a patent, and then as the patent expires, file a new one for a “new” drug that only contains one enantiomer of the drug.
Examples of racemic switch
Celexa to Lexapro
or
Zopiclone to Eszopiclone
Which will create a more rigid drug? A drug with a ring or a drug without?
A drug with a ring. Rings provide rigidity to the structure in comparison to a structure without a ring
The _____ the ring the _____ flexible
The bigger the ring, the more flexible
The smaller the ring, the more rigid
