Isomers: Different compounds that have the same molecular formula but different properties.
1. Constitutional (or Structural) Isomers: Same formula, different connectivity (different atom-to-atom bonding sequence).
Chain Isomerism: Different carbon skeleton (e.g., n-butane and isobutane).
Position Isomerism: Same skeleton, different position of functional group or substituent (e.g., propan-1-ol and propan-2-ol).
Functional Group Isomerism: Same formula, different functional group (e.g., ethanol (C₂H₅OH) and dimethyl ether (CH₃OCH₃)).
Metamerism: Different alkyl groups on either side of a functional group (e.g., diethyl ether and methyl propyl ether).
2. Stereoisomers: Same formula, same connectivity, but different spatial arrangement of atoms.
Enantiomers: Stereoisomers that are non-superimposable mirror images of each other.
Diastereomers: Stereoisomers that are *not* mirror images of each other (e.g., cis-trans isomers).
Conformational Isomers (Conformers): Different spatial arrangements of a molecule that are inter-convertible by rotation about single bonds (e.g., staggered and eclipsed ethane). These are generally *not* considered true isomers as they cannot be separated.
Geometrical Isomerism
A type of stereoisomerism (specifically diastereomerism) that arises due to restricted rotation about a bond (usually a C=C double bond or a ring).
Cis-Trans Isomerism
Used for disubstituted alkenes or rings.
Cis: The two identical (or higher priority) groups are on the same side of the double bond/ring.
Trans: The two identical (or higher priority) groups are on opposite sides.
Example: But-2-ene exists as cis-but-2-ene and trans-but-2-ene.
Syn-Anti Isomerism
This is geometrical isomerism in compounds containing a C=N bond (like oximes).
Syn: The -H and -OH groups are on the same side.
Anti: The -H and -OH groups are on opposite sides.
E/Z Notations (Cahn-Ingold-Prelog Rules)
The cis-trans system fails for tri- or tetra-substituted alkenes. The E/Z system is a universal method based on priority.
Cahn-Ingold-Prelog (CIP) Priority Rules:
Assign priority to the two groups on *each* carbon of the double bond.
Priority is based on atomic number of the atom directly attached. Higher atomic number = higher priority. (e.g., Br > Cl > O > N > C > H).
If atoms are the same, move to the next atoms along the chain until a point of difference is found.
Multiple bonds count as multiple connections to that atom (e.g., C=O counts as C bonded to two O's).
Assigning E/Z:
Z (Zusammen - "Together"): The two high-priority groups are on the same side (cis-like).
E (Entgegen - "Opposite"): The two high-priority groups are on opposite sides (trans-like).
Optical Isomerism: Chirality and Enantiomers
Optical Activity
The ability of a substance to rotate the plane of
plane-polarized light. Compounds that do this are called optically active.
Specific Rotation [α]: A standardized measure of optical rotation.
[α] = (observed rotation α) / (concentration c * path length l)
Chirality and Chiral Centers
Chiral: An object or molecule that is non-superimposable on its mirror image. (e.g., your hands).
Achiral: An object that *is* superimposable on its mirror image (e.g., a simple sphere or cube).
A chiral center (or asymmetric carbon) is a carbon atom bonded to four different groups.
A molecule with one chiral center is *always* chiral.
Elements of Symmetry: A molecule is achiral if it possesses an element of symmetry, such as a plane of symmetry (σ) or a center of symmetry (i).
Enantiomers
Enantiomers: A pair of stereoisomers that are non-superimposable mirror images of each other.
Enantiomers have identical physical properties (boiling point, melting point, solubility) *except* for their interaction with plane-polarized light (they rotate it in equal but opposite directions) and their interaction with other chiral molecules.
Racemic Mixture (or Racemate): A 50:50 mixture of two enantiomers. It is optically inactive because the rotations cancel each other out (external compensation).
Resolution: The process of separating a racemic mixture into its pure enantiomers.
Optical Isomerism: Multiple Chiral Centers
Diastereomers
Diastereomers: Stereoisomers that are not mirror images of each other.
Occur in molecules with two or more chiral centers.
Unlike enantiomers, diastereomers have different physical properties (different melting points, boiling points, solubilities, etc.).
Geometrical isomers (cis/trans) are a type of diastereomer.
Rule of 2ⁿ: For a molecule with 'n' chiral centers, the maximum number of possible stereoisomers is 2ⁿ.
Meso Compounds
Meso Compound: An achiral compound that has chiral centers.
A meso compound is superimposable on its mirror image.
It must have two or more chiral centers AND a plane of symmetry.
Because it is achiral, it is optically inactive (due to internal compensation).
Example: Tartaric Acid It has 2 chiral centers (C2, C3). n=2, so max 2²=4 stereoisomers.
It exists as (+)-tartaric acid (2R,3R), (-)-tartaric acid (2S,3S), and meso-tartaric acid (2R,3S).
The (2R,3S) form has a plane of symmetry, so it is achiral. Its mirror image (2S,3R) is the same molecule.
Therefore, tartaric acid has only 3 stereoisomers, not 4.
(+)- and (-)- forms are enantiomers.
(+)- and meso- forms are diastereomers.
Configuration: D/L and R/S Systems
Configuration: The fixed, 3D arrangement of atoms that defines a stereoisomer. Can only be changed by breaking bonds.
D/L Designation (Relative Configuration)
Used mainly for carbohydrates and amino acids.
Based on the configuration of glyceraldehyde.
The molecule is drawn in a Fischer projection.
If the -OH group (for sugars) or -NH₂ group (for amino acids) on the highest-numbered chiral center is on the:
Right: D configuration
Left: L configuration
Note: D/L has no relation to the optical rotation (+)/(-). e.g., D-Glucose is (+), but D-Fructose is (-).
R/S Designation (Absolute Configuration)
A universal system that assigns an absolute configuration (R or S) to each chiral center, using the Cahn-Ingold-Prelog (CIP) priority rules.
Steps:
Assign priorities (1-4, 1=highest) to the four groups attached to the chiral center using CIP rules.
Orient the molecule so the lowest priority group (4) points away from you (to the back, on a dashed bond).
Trace the path from priority 1 → 2 → 3.
If the path is Clockwise: Configuration is R (from Latin, *Rectus* - right).
If the path is Counter-clockwise: Configuration is S (from Latin, *Sinister* - left).
Fischer Projection Trick: If the lowest priority group (4) is on a vertical line, R is clockwise and S is counter-clockwise. If group 4 is on a horizontal line, the rule is reversed (clockwise = S, counter-clockwise = R).
Conformational Analysis of Alkanes
Analysis of the different spatial arrangements (conformers) and their relative energies, arising from rotation around C-C single bonds.
Projections:
Sawhorse Projection: Views the C-C bond from an oblique angle.
Newman Projection: Views the C-C bond end-on. The front carbon is a point, the back carbon is a circle.
Ethane (CH₃-CH₃)
Staggered: H atoms on the back carbon are in the gaps between H atoms on the front. This is the most stable conformer (lowest energy). Dihedral angle = 60°.
Eclipsed: H atoms on the back carbon are directly behind the H atoms on the front. This is the least stable conformer (highest energy). Dihedral angle = 0°.
Torsional Strain: The 12 kJ/mol (3 kcal/mol) energy difference between them is due to electron-electron repulsion in the C-H bonds.
Butane (CH₃-CH₂-CH₂-CH₃)
Viewing along the C2-C3 bond:
Anti (Staggered): The two methyl groups are 180° apart. Most stable conformer. (0 kJ/mol).
Gauche (Staggered): The two methyl groups are 60° apart. This is stable, but 3.8 kJ/mol (0.9 kcal/mol) less stable than *anti* due to steric strain between the methyl groups.
Eclipsed: The two methyl groups are 0° apart. Least stable conformer (highest energy peak).
Partially Eclipsed: A methyl group is eclipsed with a hydrogen.
Conformational Analysis of Cycloalkanes
Baeyer Strain Theory
Baeyer proposed that cycloalkanes are planar.
He assumed the ideal bond angle is 109.5° (tetrahedral).
Angle Strain: The deviation from 109.5° causes instability.
e.g., Cyclopropane (60° angles) and Cyclobutane (90° angles) have severe angle strain.
Limitation: Baeyer's theory predicted cyclopentane (108°) would be most stable and cyclohexane (120°) would be highly strained. This is incorrect.
Strain-less Ring Theory (Sachse-Mohr)
Rings larger than cyclopropane are not planar. They "pucker" to relieve strain.
Angle Strain: Strain from bond angles deviating from 109.5°.
Torsional Strain: Strain from eclipsing C-H bonds.
Steric Strain: Strain from bulky groups being too close.
Conformations of Cyclohexane
Cyclohexane is the most stable cycloalkane because it can adopt a puckered chair conformation which has zero strain:
All C-C-C bond angles are 109.5° (no angle strain).
All C-H bonds are staggered (no torsional strain).
Conformers:
Chair: Most stable conformer.
Axial bonds (a): 6 bonds, parallel to the C3 axis (3 up, 3 down).
Equatorial bonds (e): 6 bonds, pointing out from the "equator" of the ring.
Boat: Less stable. No angle strain, but has:
Significant torsional strain from eclipsed C-H bonds.
Steric strain from "flagpole" hydrogens (C1 and C4) pointing at each other.
Twist-Boat: More stable than the boat (relieves some strain), but less stable than the chair.
Half-Chair: Highest energy, transition state between chair and twist-boat.
Monosubstituted Cyclohexane
A substituent (e.g., -CH₃) can be either axial or equatorial. The ring rapidly flips between two chair forms, interconverting axial and equatorial positions.
The equatorial position is more stable for bulky groups.
Reason: A bulky group in the axial position experiences 1,3-diaxial interactions (steric strain) with the two other axial hydrogens on the same side of the ring. This is absent in the equatorial position.
Disubstituted Cyclohexane
The stability depends on the (cis/trans) relationship and whether the groups are axial or equatorial.
1,2-disubstituted: cis = (a,e) or (e,a); trans = (a,a) or (e,e). The trans-(e,e) form is most stable.
1,3-disubstituted: cis = (a,a) or (e,e); trans = (a,e) or (e,a). The cis-(e,e) form is most stable.
1,4-disubstituted: cis = (a,e) or (e,a); trans = (a,a) or (e,e). The trans-(e,e) form is most stable.
Golden Rule: The most stable conformer of a substituted cyclohexane will have the maximum number of bulky groups in the equatorial position.