Comprehensive Stereochemistry Notes

History of Enantiomerism

  • Louis Pasteur's 1848 separation of a racemic salt of tartaric acid demonstrated enantiomerism, leading to the postage of the field of stereochemistry. Pasteur showed that optical activity is a property of the molecules themselves, not of the solution.
  • In 1874, van't Hoff and Le Bel proposed the tetrahedral (sp3) carbon geometry to explain stereoisomerism, linking molecular geometry to optical activity.
  • Historical example: Sodium ammonium tartrate used to illustrate enantiomerism.

Isomerism: Constitutional Isomers and Stereoisomers

  • Isomers are different compounds with the same molecular formula.
  • Subdivision of isomers:
    • Constitutional isomers: different connectivity of atoms (atoms connected in a different order).
    • Stereoisomers: same connectivity, but different three-dimensional arrangement of atoms in space.
  • Recap of terms:
    • Enantiomers: stereoisomers that are nonsuperposable mirror images of each other.
    • Diastereomers: stereoisomers that are not mirror images of each other.

Constitutional Isomers

  • 5.2A Constitutional Isomers: Have the same molecular formula but different connectivity; atoms are connected in different orders.

Stereoisomers

  • 5.2B Stereoisomers: Stereoisomers of 1,2-dichlorocyclopentane
    • The cis isomer has no enantiomers; it is achiral.
    • The trans isomer is chiral and can exist as two nonsuperposable enantiomers.
  • Stereoisomers are not constitutional isomers: they have the same constitution but differ in spatial arrangement.
  • Stereochemistry is the study of these spatial arrangements.

Enantiomers and Diastereomers

  • 5.2C Enantiomers and Diastereomers:
    • Stereoisomers can be divided into two categories: enantiomers and diastereomers.
    • Enantiomers: nonsuperposable mirror images of each other.
    • Diastereomers: not mirror images of each other.
    • Example: cis- and trans-1,2-dichloroethene are diastereomers.

Enantiomers and Chiral Molecules

  • Enantiomers occur only with chiral molecules.
  • A chiral molecule is one that is not superposable on its mirror image.
  • The trans isomer of 1,2-dimethylcyclopentane is chiral because its mirror image is non-superposable.
  • Enantiomers do not exist for achiral molecules.

Achiral Molecules

  • An achiral molecule is superposable on its mirror image.
  • The cis and trans isomers of 1,2-dichloroethene are both achiral because each is superposable on its mirror image.
  • Everyday analogy: shoes are chiral, socks are achiral (illustrative, not chemical).

Molecules Having One Chirality Center are Chiral

  • A chirality center is a tetrahedral carbon atom bonded to four different groups.
  • A molecule with one chirality center is chiral and exists as a pair of enantiomers.
  • Interchanging any two groups at the chirality center converts one enantiomer into the other.
  • A stereogenic center is any atom at which group interchange yields a stereoisomer; if the atom is carbon, it is called a stereogenic carbon.

More on Stereogenic Centers and Interconversion

  • Interchanging groups in a real molecule requires breaking covalent bonds, which requires energy; enantiomers do not interconvert spontaneously under normal conditions.
  • Some centers (e.g., cis-1,2-dichloroethene and trans-1,2-dichloroethene) have stereogenic carbons but are not chirality centers because they do not have four different groups attached.

Planes of Symmetry: How to Test for Chirality

  • The ultimate test for chirality is to compare a molecule with its mirror image (via models or 3D drawings).
  • If the two structures are superposable, the molecule is achiral.
  • If they are not superposable, the molecule is chiral.
  • Additional aids for recognizing chirality:
    • A molecule with a plane of symmetry is not chiral (plane of symmetry, or mirror plane).

Projection Formulas: Representation of 3D Molecules on 2D Paper

  • Sawhorse projections: show back and front carbon atoms with bonds projecting out of or behind the plane; useful for complex conformations.
  • Newman projections: show front and back carbon atoms with the interconnecting bonds; commonly used to analyze rotations about C-C bonds (staggered vs eclipsed).
  • Fischer projections: a convenient way to represent molecules with multiple chiral centers; horizontal bonds project out of the plane (toward you), vertical bonds project behind the plane.
  • Sawhorse, Newman, and Fischer projections are different representations of the same 3D structure; interconversion is possible through rotation and projection rules.

Fischer Projection Formulas

  • Fischer projections are especially useful for molecules with multiple chiral centers (e.g., sugars).
  • Rule for Fischer projections: For each chiral center, horizontal lines come out of the page toward you; vertical lines go behind the page.
  • The Fischer projection is designed to keep the main carbon chain in a vertical orientation; horizontal substituents stick out of the plane.

Interconversion of Projection Formulas

  • Interconverting between Fischer, Sawhorse, and Newman projections requires rotating the molecule while preserving stereochemistry.
  • Example relationships:
    • A meso compound like meso-tartaric acid can be represented in Fischer projection in a way that reveals symmetry and the presence of a plane of symmetry.
    • Different projection forms (eclipsed vs. staggered, line-wedge, sawhorse, Newman) illustrate the same stereochemical relationships from different viewpoints.
  • Interconversion rules emphasize that the projection formulas must be interpreted with the plane of the paper fixed; flipping the molecule over (without rotation) changes the representation but not the configuration.

Specific Projection Examples

  • 2,3-Dibromobutane (threo vs erythro forms):
    • (I) (2S,3S)-Dichlorobutane and (II) (2R,3R)-Dichlorobutane are enantiomers.
    • (III) (2S,3R)-Dichlorobutane is meso and achiral due to an internal plane of symmetry.
    • (III) is a diastereomer to (I) and (II).
  • 5.13 Fischer Projection Formulas: Interconversion and interpretation for molecules with multiple chiral centers.

Naming Enantiomers: The R,S System (CIP)

  • The two enantiomers of 2-butanol have the same simple IUPAC name if named only as 2-butanol; this is undesirable because they are distinct compounds.
  • R,S nomenclature resolves this by designating each enantiomer with (R) or (S): e.g., (R)-2-butanol and (S)-2-butanol.
  • CIP (Cahn–Ingold–Prelog) system assigns configurations at a chiral center by ranking substituents.
  • (R) and (S) refer to opposite configurations at the chirality center.

Rules of the CIP System

  • Rule 1: Look at the four atoms directly attached to the chirality center and rank them by atomic number; the highest atomic number gets priority 1, the lowest gets priority 4. If isotopes are present, heavier isotopes rank higher (e.g., \n^{2}\mathrm{H} > \mathrm{^{1}H}\,

d

  • Rule 2: If there is a tie at the first atoms, compare the second atoms away from the chirality center; continue to the third and fourth atoms until a difference is found.

  • Example: -CH2CH3 (ethyl) vs -CH3 (methyl): both have carbon as the first atom, so compare the second atoms; ethyl has a carbon (CH3-CH2) as its second atom, while methyl has hydrogen as its second atom; therefore ethyl ranks higher than methyl.

  • Practical use: By following Rule 1 and Rule 2, you assign priorities to the four substituents and determine whether the arrangement is R or S when the lowest-priority group is oriented away from you.

Examples and Applications

  • 2-butanol: The two enantiomers are designated (R)-2-butanol and (S)-2-butanol according to CIP.
  • 2,3-dibromobutane: Assignments as given above show how CIP distinguishes enantiomers and meso forms.
  • General point: The CIP system provides a unique, unambiguous way to name each individual enantiomer and to communicate configuration unambiguously in chemical literature and databases.