MEDCHEM_02_2425
Page 1: Introduction
Medicinal and Pharmaceutical Chemistry - MEDCHEM.2 Chirality II
Focused on the Assignment of R- and S- configurations
Presenter: Dr. Declan Gaynor
Page 2: Recommended Reading
Organic Chemistry with Biological Applications (3rd Ed) by John McMurry
Chapter 5:
Section 5.4 - Pasteur’s discovery of enantiomers
Section 5.5 - Sequence rules for specifying configuration
Chapter 21:
Section 21.1 - Classifying carbohydrates
Section 21.2 - Representing carbohydrate stereochemistry: Fischer Projections
Page 3: Learning Outcomes
Distinguish between 3-D drawings and 2-D Fischer projections
Name Fischer projections using the Cahn-Ingold-Prelog system of nomenclature
Assign absolute configuration (R or S) from 3-D drawings or Fischer projections
Page 4: Stereoisomers
Definition: Differ by their 3-D arrangement of atoms in space
Representation: Bold wedge = towards viewer; Dashed wedge = away from viewer; Solid line = in the plane of the screen
Example: 2-Chloro-2-hydroxyacetic acid
Interaction with chiral molecules influenced by tetrahedral carbon arrangement
Page 5: Enantiomers
Defined as stereoisomers that are non-superimposable mirror images
Physical properties: Identical melting point, boiling point, density, etc.
Page 6: Optical Activity of Chiral Molecules
Optical Activity: Chiral molecules rotate polarized light
Clockwise = dextrorotatory = (+)
Anti-clockwise = laevorotatory = (-)
Enantiomers rotate light in opposite directions but by the same magnitude
Page 7: Example - Lactic Acid
Different enantiomers rotate plane-polarized light oppositely
Configuration categorized as (R) or (S) does not correlate with rotational direction
(+)-lactic acid:
Melting point = 53 °C, [𝛼]25 = +3.33 (H2O)
(-)-lactic acid:
Melting point = 53 °C, [𝛼]25 = -3.33 (H2O)
Page 8: Assigning (R) and (S)
Absolute configuration indicates spatial arrangement of atoms
Use Cahn-Ingold-Prelog rules for configuration assignment
Page 9: Cahn-Ingold-Prelog Rules
Locate the chiral carbon (indicated by *)
Assign priority (1 to 4) based on atomic numbers:
Higher atomic number = higher priority
Page 10: Priority Assignment
Higher atomic number corresponds to higher priority
Visual representation of increasing priority
Page 11: Identical Atoms in Priority Assignment
For identical atoms, consider the next bonded atom in determining priority
Continue until a distinction is found
Page 12: Handling Multiple Bonds
For multiple bonds:
Double bonds take precedence over single bonds
Prioritize based on overall structure
Page 13: Further Rules for Assigning Priority
Highest priority items considered first in the assignment process.
Page 14: Assigning Enantiomer Configuration
Rotate molecule so lowest priority group is in the back
Draw arrow from highest to lowest priority:
Clockwise = (R) enantiomer
Anti-clockwise = (S) enantiomer
Page 15: Orientation Guidance
Visualization of lowest priority group orientation
Tip: Think of positioning like a steering wheel during assignment
Page 16: Orientation Methods
Steps on how to orientate for configuration assignment
Page 17: Example Assignment of Configuration
Rotate so that the lowest priority group is away from view
Assign clockwise or anti-clockwise to derive R or S
Page 18: Example 2 - Assigning Configuration
Similar procedure as above
Page 19: Configuration Assignment Steps
Maintain lowest priority group orientation to distinguish S and R
Page 20: Final Steps for R and S Assignment
Confirm orientation to assign correct configuration
Page 21: Summary of R and S Assignment
Last orientation adjustments for configuration assessment.
Page 22: Double-Switch Method
Double-Switch Trick: Helps in manipulating structure on paper
Switching lowest group puts it in the appropriate position
Effective in notation without altering stereochemistry
Page 23: Double-Switch Variations
Indicating the flexibility in application of the double-switch technique
Page 24: Exercises & Practice
Opportunities to practice R & S configuration assignment
Page 25: Quick Manipulation Instructions
Ensure proper positioning of groups for assignment
Visualize manipulations effectively for accurate configuration assessment
Page 26: Carousel Method Application
Details on applying carousel method for configurations
Page 27: Fischer Projections
Representation of 3-D molecules as flat structures
Crossed lines illustrate tetrahedral z orientation
Page 28: Fischer Projection Technique
Expand on the 3-D mapping as flat for molecular models
Page 29: Fischer Projection Rotation
Viewing manipulation strategies for Fischer projections
Clarifying allowed 180° rotations vs illegal 90° rotations
Page 30: Fischer Projection Adjustments
Discuss allowed manipulations while maintaining correct stereochemistry
Page 31: Assigning R and S via Fischer Projections
Step-by-step for priority assignment followed by manipulations
Page 32: Conclusion & Contact Information
Thank you for participating!
For further information:
Dr. Declan Gaynor
Email: dgaynor@rcsi-mub.com