Chapter 5 Notes: Stereochemistry at Tetrahedral Centers
5.1 Enantiomers and the Tetrahedral Carbon
Tetrahedral carbon atoms and their mirror images.
Molecules of the type CH3X and CH2XY are identical to their mirror images.
A molecule of the type CHXYZ (four different substituents) is not identical to its mirror image.
A CHXYZ molecule is related to its mirror image in the same way a right hand is related to a left hand.
Enantiomers: Molecules that are not the same as their mirror image.
Enantiomerism arises from tetrahedral bonding to four different substituents.
Enantiomers are non-superimposable mirror images.
5.2 The Reason for Handedness in Molecules: Chirality
Symmetry plane concept:
A coffee mug has a symmetry plane cutting through it so that right and left halves are mirror images.
A hand has no symmetry plane; the right half is not a mirror image of the left.
Chiral: Molecules that do not have a plane of symmetry and are not superimposable on their mirror image.
Achiral: Molecules with a plane of symmetry that is the same as its mirror image.
5.3 Optical Activity
Optical activity is a property of organic compounds to rotate plane-polarized light.
Plane-polarized light: Ordinary light is composed of electromagnetic waves that can oscillate in many planes; polarizers convert it to oscillation in a single plane.
Optically active: Molecules rotate the plane of plane-polarized light.
Polarimeter: Instrument used to measure rotation.
Levorotatory (−): rotates plane of polarization counterclockwise.
Dextrorotatory (+): rotates plane of polarization clockwise.
The rotation is measured in degrees; the specific rotation [\alpha] characterizes the enantiomer.
Relationship between mixtures and pure enantiomer:
The specific rotation of a mixture of (+) and (−) enantiomers is linearly related to [\alpha] for the pure enantiomer and the enantiomeric excess (ee):
ee (enantiomeric excess) represents the excess of one enantiomer over the other in a mixture.
5.4 Pasteur’s Discovery of Enantiomers
Historical context: Pasteur distinguished enantiomers by seeding with helical crystals (not elaborated in detail in this transcript).
5.5 Sequence Rules for Specifying Configuration (Cahn–Ingold–Prelog, CIP)
Purpose: Determine configuration (R or S) at each chirality center.
General method: Specify configuration by relative positions of all groups around the chirality center.
Rule 1 (Priority): Look at the four atoms directly attached to the chirality center; rank by atomic number. Highest atomic-number gets priority 1; lowest gets 4.
Rule 2 (Tie-breaking): If a decision cannot be reached by the first atoms, look at the second, third, or fourth atoms in the substituents until a difference is found.
Rule 3 (Multiple bonds): Multiple-bonded atoms are treated as if they were the same number of singly bonded atoms.
5.6 Diastereomers
Diastereomers: Stereoisomers that are not mirror images of each other.
Example: 2-amino-3-hydroxybutanoic acid I, II, III, IV (I and II are enantiomers; I and III, I and IV, II and III, II and IV are diastereomers).
Diastereomers have different physical properties.
Epimers: Diastereomers that differ at only one stereocenter.
Example: Cholestanol and coprostanol include epimeric relationships.
5.7 Meso Compounds
Mesos are compounds with multiple stereocenters that are superimposable on one another due to an internal plane of symmetry.
Despite having stereocenters, meso compounds are achiral.
Example patterns show symmetry and rotation by 180° can map the molecule onto itself.
5.8 Racemic Mixtures and the Resolution of Enantiomers
Racemic mixture (racemate): A 50:50 mixture of two chiral compounds that are mirror images; such mixtures do not exhibit optical rotation.
Resolution: Separation of enantiomers via diastereomeric salts formed with a chiral resolving agent.
Common method: An acid–base reaction between the racemate of a chiral carboxylic acid and an amine base.
Example: Lactic acid racemate with achiral methylamine yields racemic ammonium salts.
Separation example: Reaction of racemic lactic acid with (R)-1-phenylethylamine yields diastereomeric ammonium salts that can be separated; subsequent steps regenerate enantiopure acids/bases.
7.4 Isomerism in Alkenes
Isomerism around C=C: The π bond must break to allow rotation around a carbon–carbon double bond.
Cis isomer: Two substituents of interest on the same side of the double bond.
Trans isomer: Two substituents of interest on opposite sides of the double bond.
7.4 Cis–Trans Isomerism (clarifications)
End groups must differ in pairs to be capable of cis–trans distinction.
Some structures are identical and not cis–trans isomers due to symmetry.
7.5 Alkene Stereochemistry and the E, Z Designation
E ( entgegen, opposite): Higher-ranked groups are on opposite sides of the C=C double bond.
Z ( zusammen, together): Higher-ranked groups are on the same side.
Rule: Higher-ranked groups are determined by CIP rules applied to the substituents attached to each double-bond carbon.
Examples:
(a) (E)-2-Chloro-2-butene: higher-ranked groups on opposite sides.
(b) (Z)-2-Chloro-2-butene: higher-ranked groups on the same side.
Visual cues: In drawings, high-priority substituents’ relative positions define E or Z.
7.6 Stability of Alkenes
General trend: Cis alkenes are less stable than trans alkenes.
Less stable isomer tends to be higher in energy and releases more heat upon conversion.
Substitution pattern ranking of stability: tetrasubstituted > trisubstituted > disubstituted > monosubstituted.
Hyperconjugation (a stabilizing interaction): Interaction between the C=C π orbital and adjacent C–H σ bonds on substituents; more substituents lead to greater stabilization of the alkene.
5.9 A Review of Isomerism
Constitutional isomers: Different carbon skeletons or different functional group arrangements.
Stereoisomers: Enantiomers and diastereomers.
Configurational diastereomers: Cis–trans diastereomers (on double bonds or rings).
Visual map: 2^N stereoisomers when N stereocenters exist; sometimes fewer when meso compounds are possible.
5.10 Chirality at Nitrogen, Phosphorus, and Sulfur
Nitrogen: Amine inversion; rapid interconversion between configurations.
Amines are usually drawn as trigonal planar in the average conformation due to rapid inversion; thus amines are typically achiral.
Implications: True chirality at nitrogen is rare under normal conditions because of fast inversion; quaternary ammonium salts can be chiral under certain constrained environments.
Connections to foundational principles and real-world relevance
Chirality and optical activity underpin drug design, as enantiomers can have different biological activities.
The CIP system provides a universal method to unambiguously assign configurations (R/S) across molecules.
E/Z designations are critical for describing stereochemistry in alkenes, which influences reactivity and properties.
Racemic mixtures and their resolution are foundational in pharmaceutical synthesis for obtaining enantiopure drugs.
Axial chirality and atropisomerism expand the concept of chirality beyond stereocenters, important in catalysis (e.g., BINAP ligand) and natural products.
Key definitions recap
Enantiomer: non-identical mirror image; non-superimposable.
Achiral: has a plane of symmetry; superimposable on its mirror image.
Chiral center (stereocenter): carbon with four different substituents.
Diastereomer: stereoisomer not related as a mirror image.
Epimer: diastereomer differing at one stereocenter.
Mesocompound: stereoisomer with internal symmetry; achiral despite multiple stereocenters.
Racemate: 1:1 mixture of enantiomers; optically inactive.
Hyperconjugation: interaction that stabilizes alkenes via σ–π overlap; more substituents increase stability.
E/Z designations: CIP-based method to describe the geometry around a C=C double bond.
Axial chirality: chirality arising from restriction of rotation about an axis (atropisomerism).
Notation and equations used
Optical activity relationship in mixtures:
where ee is the enantiomeric excess.CIP priority rules (summary):
Rule 1: Prioritize substituents by atomic number of directly attached atoms.
Rule 2: If needed, examine next atoms in the substituents.
Rule 3: Treat multiple bonds as equivalent to the same number of single bonds.
R/S assignment guideline: If the lowest-priority group (4) is oriented away from the viewer, tracing 1 → 2 → 3 clockwise yields R; counterclockwise yields S.
E/Z designations around C=C:
E: Higher-ranked groups on opposite sides of the double bond.
Z: Higher-ranked groups on the same side.
Enantiomers are non-superimposable mirror images of molecules, arising from tetrahedral carbons bonded to four different substituents (chiral centers). Chiral molecules lack a plane of symmetry, unlike achiral molecules. Optical activity, measured by a polarimeter, describes how chiral molecules rotate plane-polarized light (levorotatory for counterclockwise, dextrorotatory for clockwise). The specific rotation of a mixture follows the relationship . Configuration at chirality centers is assigned as R or S using Cahn–Ingold–Prelog (CIP) rules, prioritizing substituents by atomic number. Diastereomers are stereoisomers that are not mirror images, with epimers differing at only one stereocenter. Meso compounds possess multiple stereocenters but are achiral due to an internal plane of symmetry. A racemic mixture is a 1:1 mix of enantiomers with no optical rotation, and resolution separates them using chiral resolving agents. Alkene stereochemistry includes cis/trans isomers (substituents on the same/opposite sides of a double bond) and E/Z designations (E for higher priority groups opposite, Z for same side, determined by CIP rules). Trans alkenes are generally more stable than cis, with stability increasing with substitution due to hyperconjugation. While nitrogen typically undergoes rapid amine inversion, chirality in drugs and catalysts highlights the real-world significance of stereochemistry.