MEDCHEM.01
Page 1: Introduction to Chirality
Title: Medicinal and Pharmaceutical Chemistry – MEDCHEM
Introduction to Chirality: Molecules in Three Dimensions
Dr. Marco Monopoli
Date: 20th of January 2025
Page 2: Learning Outcomes
Differentiate between structural and stereoisomers
Definitions:
Chirality
Chiral
Achiral
Stereogenic centre
Define enantiomers and discuss their physical properties, particularly optical activity.
Explain differentiation between enantiomers using a polarimeter.
Define terms:
Laevorotatory
Dextrorotatory
Specific rotation
Ability to calculate specific rotation of molecules.
Understand racemic mixtures.
Page 3: Importance of Stereochemistry and Chirality
Role in Drug Design and Action: Stereochemistry plays a critical role in the design of pharmaceutical compounds. The 3D arrangement of atoms within a drug molecule can profoundly influence its efficacy and safety. Chiral drugs, which exist in two enantiomeric forms, may have different interactions with biological targets, including receptors and enzymes. One enantiomer may exhibit desired therapeutic effects, while the other could be ineffective or even harmful, necessitating careful consideration of chirality in drug formulation.
Significance in Enzyme-Catalyzed Reactions: Enzymes are biological catalysts that are inherently chiral because they are composed of chiral amino acids. The stereochemistry of both the enzyme and its substrate can affect the binding affinity and reaction rate. Enzymes often exhibit specificity for one enantiomer over another, which can lead to the production of a singular product from a chiral substrate. Understanding the stereochemical relationships in enzyme-substrate interactions is essential for optimizing biochemical processes in both natural and synthetic pathways.
Importance of Chiral Amino Acids: Chiral amino acids serve as the fundamental building blocks of proteins, contributing to the chirality of all enzymes and proteins in biological systems. The L-forms of amino acids are predominantly utilized in protein synthesis, creating a homochiral environment necessary for the proper folding and functionality of proteins. This homochirality is crucial for the structural integrity and biological activity of proteins; any changes in chirality can result in misfolded proteins which may disrupt normal biological processes and lead to diseases. Therefore, the understanding of chirality in amino acids is significant in fields such as biochemistry, pharmacology, and molecular biology, emphasizing the importance of stereochemistry in life processes.
Page 4: Summary of Isomerism
Definitions:
Isomers - compounds with same molecular formula but different bond arrangements.
Types of Isomers:
Constitutional or Structural Isomers (e.g. C2H6O - alcohol/ether)
Stereoisomers: Different configurations due to spatial arrangements.
Types of Stereoisomers:
Conformational Isomers: Can be interconverted by rotation about single bonds.
Configurational Isomers: Cannot be interconverted without breaking bonds.
Page 5: Chirality Explained
Mirror image of a hand is different from the original
Chiral molecules: cannot be superimposed on their mirror images.
Achiral molecules: can be superimposed on their mirror images.
Example: A chair can be superimposed on its mirror image (achiral).
Concept of 'handedness' - right glove does not fit left hand.
Page 6: Optical Isomers
Chiral molecules cannot be superimposed on themselves.
Chiral molecules are chemically identical but with unique 3-dimensional shapes - significant in biological interactions (drug-enzyme/receptor).
Enantiomers: non-superimposable mirror images.
Page 7: When do Molecules Become Chiral?
A carbon atom with four different groups attached is termed a stereogenic centre, leading to two stereoisomers (e.g. 2-chlorobutane).
Definition of configuration: Arrangement of different substituents.
Enantiomers exhibit opposite configurations.
Chiral molecules lack a plane of symmetry; however, achiral molecules possess one.
Carbon has tetrahedral geometry.
Page 8: Enantiomers - A Closer Look
Enantiomers: Non-superimposable mirror images characterized by unique configurations about the chiral carbon.
Example: Drawing a carbon atom with four different substituents (colors) illustrating non-superimposability.
Page 9: Stereoisomers and 3-D Arrangement
Definition: Stereoisomers differ by their 3-dimensional arrangement of atoms in space.
Representation: Bold wedge for groups pointing towards viewer; dashed wedge for groups pointing away.
Example: 2-Chloro-2-hydroxyacetic acid structural representation.
Page 10: Importance of Chirality in Nature
Imagery: A hand as a drug analogy illustrates the concept of molecular interaction with biological targets. Just as a right hand can fit into a right glove, only one enantiomer of a chiral drug can properly fit into the active site of its corresponding chiral enzyme, thereby facilitating a biochemical reaction.
Chiral drugs typically exist in two enantiomeric forms, which are mirror images of each other. These enantiomers can possess vastly different pharmacological effects despite having the same molecular formula. For instance, while one enantiomer might be therapeutically active, the other may be completely inactive or could even induce undesirable side effects. This discrepancy is crucial in drug design and development, necessitating a thorough understanding of chirality in pharmacology to optimize efficacy and minimize adverse effects.
Moreover, when an incorrect enantiomer interacts with the enzyme or receptor, it can lead to ineffective treatment or harmful consequences, underscoring the importance of selecting the appropriate enantiomer in drug formulation. Therefore, the specificity of chiral drugs highlights the intricate relationship between molecular structure and biological function, making chirality a pivotal factor in the efficacy and safety of pharmaceutical compounds.
Page 11: Chiral Carbons Defined
Identification of chiral centers: Tetrahedral carbon attached to four distinct atoms/groups results in a unique enantiomeric form.
Definition of stereocenter.
Page 12: 2-Chloropropane Chiral Analysis
Structural Analysis: Draw out the structure to assess chirality.
Rule: Molecules with a plane of symmetry or center of symmetry are achiral.
Result: 2-Chloropropane is determined as achiral.
Page 13: 3-Methylpentane Chiral Analysis
Assessment: 3-Methylpentane shows achirality when rotated 180° about the C-CH3 bond.
Conclusion: Both structures are identical; only one form exists.
Page 14: 3-Methylhexane Chiral Analysis
Result: 3-Methylhexane is concluded to be chiral due to non-identical mirror images upon 180° rotation.
Distinction: There are two distinct 3-Methylhexanes derived from chirality.
Page 15: Generalization of Chirality
General Rule: Compounds with four different groups around a carbon atom create chiral molecules.
Terminology: The carbon atom bearing these groups is referred to as a chirality center or stereogenic center.
Page 16: Enantiomers Overview
Defining characteristic: Enantiomers are stereoisomers that exhibit non-superimposable mirror image properties.
Physical properties: Enantiomers possess identical melting and boiling points, density, etc.
Behavior: Each enantiomer rotates the plane of polarized light in opposite directions, establishing chirality as optically active.
Page 17: Plane-Polarized Light
Description: Nature of plane-polarized light, referenced in usage of sunglasses.
Page 18: Distinguishing Enantiomers with Polarized Light
Observations: Enantiomers rotate polarized light in opposing directions yet by equal degrees.
Page 19: Enantiomers and Optical Activity
If one enantiomer rotates plane-polarized light by x° clockwise, the other will rotate counterclockwise by x°.
Nomenclature:
Dextrorotatory (+) for clockwise rotation.
Levorotatory (-) for counterclockwise rotation.
Racemic mixture: A 50:50 mixture of enantiomers; such mixtures yield no net optical rotation because rotations cancel.
Page 20: Lactic Acid Enantiomers Example
Reference for example: Enantiomers of lactic acid found in sour milk.
Physical properties: (+)-lactic acid (melting point = 53°C, [α]25 = +3.33 (H₂O)); (-)-lactic acid (melting point = 53°C, [α]25 = -3.33 (H₂O)).
Page 21: Racemic Mixture Example - Lactic Acid
Definition recap: A racemic mixture consists of a 50:50 ratio of enantiomers.
Properties: Considered optically inactive due to balanced contributions from each enantiomer.
Page 22: Specific Rotation Basics
Factors Influencing Observed Rotation: Length of the cell, concentration of solution, optical activity strength, temperature, and wavelength of light.
Formula: [α] = α (observed rotation) / (conc x path-length (l))
Where:
α = rotation in degrees
c = concentration in g/ml
l = path-length in decimeters
T = temperature measurement
λ = wavelength of light used
Standard wavelength: 589 nm (sodium D line).
Page 23: Specific Rotation Calculation Example
Scenario: 1.00 g sample in 20.0 ml ethanol, 5.00 ml in a polarimeter tube at 25°C; observed rotation of 1.25° clockwise.
Calculation Setup: Derived from specified parameters for [α]D.
Additional Example: Calculation for coniline with [α]D = -16 in a 5.0 cm sample tube, needing observed rotation derived from specified mass/concentration.
Page 24: Specific Rotation Example Continued
Continuation of previous example involving the optical rotation calculations and application of the specific rotation formula in practice.
Page 25: Summary Points
Achiral molecules: can be superimposed on mirror images.
Chiral molecules: cannot be superimposed, are optically active.
Enantiomers: stereoisomers that are non-superimposable mirror images.
Racemic mixture: 50:50 mixture of enantiomers, optically inactive.
Page 26: Extended Summary
Recap:
Achiral molecules: optically inactive, can superimpose on mirror images.
Chiral molecules: optically active, cannot superimpose on mirror images, defined as tetrahedral carbon with four distinct groups.
Enantiomers: non-superimposable mirror image pairs.
Racemic mixture: optically inactive due to balanced enantiomers.
Page 27: Keep Up With Your Chemistry Studies!
Emphasis on maintaining consistency and diligence in chemistry studies at RCSI University of Medicine and Health Sciences.
Page 28: Acknowledgments
Closing remarks: Contact Dr. Marco Monopoli for more information.