# Lecture 6: Stereochemistry: Diastereomers and Meso Compounds
## Organic Chemistry I
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Define diastereomers and distinguish them from enantiomers
2. Determine the maximum number of stereoisomers for molecules with multiple chirality centers
3. Identify meso compounds and explain why they are achiral despite having chirality centers
4. Assign configurations to molecules with two or more stereocenters
5. Identify and distinguish erythro/threo and syn/anti diastereomers
6. Explain the physical and chemical differences between diastereomers
7. Analyze Fischer projections and convert between representations
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## Lecture Content
### I. Molecules with Multiple Chirality Centers
Many organic molecules contain two or more chirality centers, and the maximum number of possible stereoisomers is 2^n, where n is the number of chirality centers. However, the actual count is sometimes lower than this maximum because of the existence of meso compounds, as discussed below.
For a molecule with two chirality centers, up to four stereoisomers are possible: (R,R), (S,S), (R,S), and (S,R). The relationships among these stereoisomers follow a clear pattern. Enantiomers have opposite configurations at all chirality centers, so (R,R) and (S,S) are enantiomers, as are (R,S) and (S,R). Diastereomers differ in configuration at some but not all chirality centers: (R,R) and (R,S) are diastereomers, (R,R) and (S,R) are diastereomers, and similarly for the pairs involving (S,S).
### II. Properties of Diastereomers vs. Enantiomers
While enantiomers share identical physical properties (differing only in the sign of their optical rotation), diastereomers have genuinely different physical properties. They differ in melting points, boiling points, solubilities, densities, specific rotations (both in sign and magnitude), and spectroscopic properties such as NMR and IR spectra. They also react at different rates with both chiral and achiral reagents.
This difference in physical properties has an important practical consequence: diastereomers can be separated using ordinary laboratory techniques such as column chromatography, distillation, and crystallization, whereas enantiomers require special chiral methods for separation. Tartaric acid illustrates these relationships well. The (2R,3R) and (2S,3S) isomers are enantiomers, sharing a melting point of 170 degrees C and specific rotations of +12 and -12 degrees, respectively. The meso form, a diastereomer of both, has a distinctly different melting point of 140 degrees C and a specific rotation of zero.
### III. Meso Compounds
A meso compound is a molecule that contains chirality centers yet is achiral overall. The defining feature of a meso compound is an internal plane of symmetry (or another improper symmetry element) that makes one half of the molecule the mirror image of the other half. The rotations at the chirality centers effectively cancel each other out.
To identify meso compounds, look for molecules with two or more chirality centers that have identical substituent patterns. If a plane of symmetry can be drawn so that one chirality center has the R configuration while the other has S, the molecule is likely meso. The (R,S) configuration of an internally symmetric molecule is meso, and its supposed enantiomer, (S,R), is actually the same compound.
Meso compounds are optically inactive, with a specific rotation of zero, despite possessing chirality centers. They are achiral because they are superimposable on their mirror images, and they are diastereomers of the chiral stereoisomers that share the same connectivity. The classic example is meso-tartaric acid, which has two chirality centers with one R and one S configuration and an internal plane of symmetry between C2 and C3. The existence of this meso form reduces the total stereoisomer count for tartaric acid from the expected four to three: (R,R), (S,S), and meso.
Panel A: The three stereoisomers of tartaric acid drawn as Fischer projections and 3D wedge-dash structures: (2R,3R)-tartaric acid, (2S,3S)-tartaric acid (its enantiomer), and meso-tartaric acid. The internal mirror plane of meso-tartaric acid is shown as a dashed horizontal line between C2 and C3. Panel B: A relationship diagram connecting the three stereoisomers with double-headed arrows labeled "enantiomers" (between R,R and S,S) and "diastereomers" (between the chiral pair and the meso form).
### IV. Fischer Projections
Fischer projections are a standardized two-dimensional representation developed by Emil Fischer for depicting molecules with multiple stereocenters, originally for use in carbohydrate chemistry. In a Fischer projection, the carbon chain is drawn vertically with the most oxidized carbon at the top. Horizontal bonds project toward the viewer (equivalent to wedge bonds), and vertical bonds project away from the viewer (equivalent to dash bonds). Each intersection of horizontal and vertical lines represents a chirality center.
Several rules govern the manipulation of Fischer projections. Rotating the entire projection by 180 degrees in the plane of the paper yields the same molecule, but rotating by 90 degrees produces the enantiomer. Swapping any two groups on a single chirality center inverts the configuration: an even number of swaps restores the original configuration, while an odd number gives the enantiomer.
To assign R/S configuration from a Fischer projection, first rank the four groups by CIP priority. If priority 4 sits on a horizontal bond (pointing toward the viewer), assign R/S normally and then reverse the answer. If priority 4 is on a vertical bond (pointing away), the assignment proceeds without reversal. Being able to convert fluently between Fischer projections, wedge-dash structures, and Newman projections is an essential skill.
### V. Erythro/Threo and Syn/Anti Nomenclature
The erythro and threo designations, named after the sugars erythrose and threose, provide an older but still widely used system for describing diastereomers with two adjacent stereocenters. In a Fischer projection, erythro diastereomers have like substituents on the same side, while threo diastereomers have them on opposite sides.
The syn/anti system is used in acyclic molecules and is especially common in aldol chemistry and modern synthetic contexts. Syn indicates that similar groups lie on the same side of the carbon backbone in its extended zigzag conformation, while anti places them on opposite sides. In cyclic systems, cis and trans designations describe substituents on the same face or opposite faces of the ring, respectively, and are particularly important for cyclopropanes, cyclobutanes, and cyclohexanes.
### VI. Stereoisomerism Summary and Flowchart
A systematic approach to determining the relationship between two molecules proceeds through a series of questions. First, do they have the same molecular formula? If not, they are not isomers of any kind. If yes, is the connectivity the same? If the connectivity differs, they are constitutional isomers. If the connectivity is identical, they are stereoisomers, and the next question is whether they are nonsuperimposable mirror images. If they are, they are enantiomers. If they are stereoisomers but not mirror images, they are diastereomers, a category that includes cis/trans isomers and compounds that differ at some but not all stereocenters. Two special cases deserve attention: molecules with the same configuration at all centers are simply the same compound, and a meso compound is superimposable on its mirror image and is therefore identical to it.
A comprehensive flowchart for classifying the relationship between two organic molecules. Starting at the top: "Same molecular formula?" branches to "Not isomers" (No) or continues (Yes). "Same connectivity?" branches to "Constitutional isomers" (No) or continues (Yes). "Same compound?" branches to "Identical" (Yes) or continues (No). "Mirror images?" branches to "Enantiomers" (Yes) or "Diastereomers" (No). Additional notes indicate that conformational isomers are interconvertible by bond rotation, while stereoisomers are not. The box for diastereomers includes sub-categories: cis/trans isomers, epimers, and anomers.
### VII. Chirality Without Chirality Centers
Although chirality centers are the most common source of molecular chirality, they are not the only one. Allenes, compounds with two cumulated double bonds (C=C=C), can be chiral when the two ends bear different substituents. The two planes of substituents are perpendicular to each other, and no chirality center is present, but the molecule is nonetheless nonsuperimposable on its mirror image. Allene chirality is described using the axial chirality designators Ra and Sa.
Atropisomers are molecules with restricted rotation about a single bond, where the rotational barrier is high enough that the individual isomers can be isolated. Substituted biphenyls with large ortho substituents are a classic example, and atropisomerism is common in pharmaceutical chemistry, as exemplified by the BINAP ligand. Helicenes are polycyclic aromatic compounds forced into a helical shape, described as left-handed (M) or right-handed (P). While these types of chirality are encountered less frequently in introductory courses, they are important for a complete understanding of stereochemistry.
### VIII. Resolution of Enantiomers
Resolution is the process of separating a racemic mixture into its individual enantiomers. Several methods are available. In the classical approach, the racemic mixture is reacted with an enantiopure reagent to form diastereomeric salts, which differ in physical properties and can be separated by fractional crystallization. The free acid or base is then regenerated from each diastereomeric salt.
Chiral chromatography, using HPLC or GC with a chiral stationary phase, is the most modern and widely used technique. The two enantiomers interact differently with the chiral stationary phase, resulting in different retention times that allow separation. Enzymatic resolution exploits the selectivity of an enzyme that reacts with only one enantiomer, leaving the other unreacted and available for recovery, though the maximum yield of the desired enantiomer is limited to 50% unless racemization can occur. Kinetic resolution uses a chiral catalyst that reacts faster with one enantiomer, enriching the remaining starting material in the slower-reacting enantiomer.
Panel A: Diagram showing the resolution of racemic 2-phenylpropanoic acid using (R)-1-phenylethylamine. The racemic acid reacts with the chiral amine to form two diastereomeric salts (R,R and S,R). These are separated by crystallization (different solubilities shown with a beaker and crystals). Each salt is then treated with HCl to regenerate the pure enantiomeric acids. Panel B: A schematic of chiral HPLC showing a column packed with a chiral stationary phase. A racemic mixture injected at the top separates into two peaks at the detector, one for each enantiomer, with different retention times labeled.
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