Isomers are compounds that possess the same molecular formula but differ in the arrangement of their atoms. Within the broad category of isomerism, stereoisomers represent a specific class where atoms are connected in the same order, but their spatial arrangement differs. This spatial difference, which cannot be interconverted by simple bond rotation without breaking and reforming bonds, gives rise to distinct molecular shapes and properties. Stereoisomers are further subdivided into enantiomers and diastereomers, based on their specific relationship concerning mirror images.

Diastereomers are a fundamental concept in stereochemistry, critical for understanding the behavior, synthesis, and separation of complex organic molecules, especially those with multiple chiral centers. Unlike enantiomers, which are non-superimposable mirror images of each other and share identical physical properties in an achiral environment, diastereomers are stereoisomers that are not mirror images. This lack of a mirror-image relationship leads to significant differences in their physical and chemical properties, making them amenable to separation by conventional laboratory techniques. The intricate nature of diastereomerism plays a crucial role in diverse fields, ranging from drug discovery and development to asymmetric synthesis and natural product isolation.

What are Diastereomers?

Diastereomers are defined as stereoisomers that are not enantiomers. More precisely, they are stereoisomers that are not mirror images of each other and are non-superimposable. This definition implies several key characteristics:

  1. Multiple Stereocenters: For a compound to exhibit diastereomerism, it must possess at least two stereocenters (e.g., chiral carbons). If a molecule has only one chiral center, it can only exist as a pair of enantiomers. However, with two or more chiral centers, the possibility of diastereomers arises.
  2. No Mirror-Image Relationship: The defining feature of diastereomers is that they do not relate as an object and its mirror image. This means that if you have two stereoisomers, and they are not superimposable mirror images, they are diastereomers. For instance, if a molecule has two chiral centers, R,R and S,S are enantiomers of each other, and R,S and S,R are also enantiomers of each other. However, R,R is a diastereomer of R,S and S,R. Similarly, S,S is a diastereomer of R,S and S,R.
  3. Different Physical Properties: A direct consequence of their non-mirror-image relationship is that diastereomers possess distinct physical properties. This contrasts sharply with enantiomers, which have identical melting points, boiling points, densities, solubilities, refractive indices, and spectroscopic properties (NMR, IR, mass spectrometry) in an achiral environment. Diastereomers, however, will differ in these properties. For example, diastereomers will have different melting points, boiling points, solubilities, and chromatographic retention times. This difference in physical properties is paramount for their separation.
  4. Different Chemical Properties: Diastereomers also exhibit different chemical properties, particularly when reacting with chiral reagents or in chiral environments. They may react at different rates or produce different ratios of products. In an achiral environment with achiral reagents, their reactivity might be similar, but even then, subtle differences can exist.
  5. Optical Activity: Diastereomers can be optically active or inactive. An optically active diastereomer will rotate plane-polarized light. An optically inactive diastereomer might be a meso compound (which has chiral centers but is achiral overall due to an internal plane of symmetry) or an achiral molecule without chiral centers, though the term diastereomer strictly applies to stereoisomers of a chiral compound. A meso compound is a specific type of achiral stereoisomer that is a diastereomer of the other chiral stereoisomers in the set.

The maximum number of possible stereoisomers for a compound with ‘n’ chiral centers is 2^n. However, this rule is complicated by the presence of meso compounds, which reduce the total number of unique stereoisomers. For example, 2,3-dichlorobutane has two chiral centers (C2 and C3). The possible configurations are (2R,3R), (2S,3S), (2R,3S), and (2S,3R).

  • (2R,3R) and (2S,3S) are a pair of enantiomers.
  • (2R,3S) and (2S,3R) are identical and represent a meso compound due to an internal plane of symmetry, hence it is achiral.
  • Thus, (2R,3R) is a diastereomer of the meso (2R,3S) form.
  • (2S,3S) is also a diastereomer of the meso (2R,3S) form.

Threo and Erythro Diastereomers

The terms “threo” and “erythro” are historical descriptors used to classify diastereomers that arise from molecules possessing two adjacent chiral centers in an acyclic chain, particularly when these centers share common substituents. These terms originate from carbohydrate chemistry, specifically from the four-carbon sugars erythrose and threose, which themselves are diastereomers. While modern IUPAC nomenclature often prefers syn and anti or direct R/S assignment for clarity, threo and erythro are still commonly encountered, especially in older literature and in specific fields like carbohydrate and amino acid chemistry.

The assignment of threo and erythro is most easily visualized using Fischer projections, where horizontal lines represent bonds coming out of the plane of the page and vertical lines represent bonds going into the plane.

Erythro Diastereomers

An erythro diastereomer is characterized by having the two identical (or similar) substituents on the two adjacent chiral centers located on the same side of the Fischer projection. Conversely, the two other distinct substituents (often the bulkier ones) on these chiral centers will also be on the same side.

  • Visualization in Fischer Projection: If you draw the molecule in a Fischer projection, and the common groups (e.g., two hydrogens or two hydroxyls) on the adjacent chiral carbons are aligned on the same side (both left or both right), then it is an erythro isomer.
  • Corresponding Absolute Configurations: For compounds with two different end groups, the erythro pair typically corresponds to the (R,R) and (S,S) enantiomers. If the end groups are identical, the erythro form can be the meso compound (e.g., the (R,S) form of a symmetrical molecule like meso-tartaric acid where the two common groups are the -OH groups).
  • Analogy to syn: In terms of relative configuration, erythro isomers often correspond to a syn arrangement of similar substituents when viewed in a Newman projection or sawhorse representation.

Threo Diastereomers

A threo diastereomer, in contrast, is characterized by having the two identical (or similar) substituents on the two adjacent chiral centers located on opposite sides of the Fischer projection. This means the two other distinct substituents will also be on opposite sides.

  • Visualization in Fischer Projection: When drawn in a Fischer projection, if the common groups (e.g., two hydrogens or two hydroxyls) on the adjacent chiral carbons are on opposite sides (one left, one right), then it is a threo isomer.
  • Corresponding Absolute Configurations: For compounds with two different end groups, the threo pair typically corresponds to the (R,S) and (S,R) enantiomers.
  • Analogy to anti: In terms of relative configuration, threo isomers often correspond to an anti arrangement of similar substituents when viewed in a Newman projection or sawhorse representation.

Examples for Threo and Erythro Diastereomers

Let’s illustrate these concepts with specific examples.

Example 1: 2-Bromo-3-chlorobutane (CH3-CHBr-CHCl-CH3)

This molecule has two chiral centers at C2 and C3. The substituents on C2 are CH3, H, Br, and on C3 are CH3, H, Cl. The common substituent here is H.

  • Erythro-2-bromo-3-chlorobutane:

    • (2R,3R) and (2S,3S) are the erythro enantiomeric pair.
    • In their Fischer projections, the hydrogen atoms (or the CH3 groups, or the Br and Cl groups) on C2 and C3 are on the same side.
      • (2R,3R)-2-bromo-3-chlorobutane: 
          CH3
  |
H-C*-Br  (C2)
  |
H-C*-Cl  (C3)
  |
  CH3
        (Here, H’s are on the left, Br and Cl are on the right).
      • (2S,3S)-2-bromo-3-chlorobutane: (Mirror image of above, H’s on right, Br and Cl on left).

  • Threo-2-bromo-3-chlorobutane:

    • (2R,3S) and (2S,3R) are the threo enantiomeric pair.
    • In their Fischer projections, the hydrogen atoms (or the CH3 groups, or the Br and Cl groups) on C2 and C3 are on opposite sides.
      • (2R,3S)-2-bromo-3-chlorobutane: 
          CH3
  |
H-C*-Br  (C2)
  |
Cl-C*-H  (C3)
  |
  CH3
        (Here, H on C2 is left, H on C3 is right; Br on C2 is right, Cl on C3 is left).
      • (2S,3R)-2-bromo-3-chlorobutane: (Mirror image of above).

The erythro pair [(2R,3R) and (2S,3S)] and the threo pair [(2R,3S) and (2S,3R)] are diastereomers of each other. For instance, (2R,3R) is a diastereomer of (2R,3S) and (2S,3R).

Example 2: 2,3-Dihydroxybutanoic Acid (CH3-CHOH-CHOH-COOH)

This molecule also has two adjacent chiral centers, C2 and C3. The common substituents are the hydroxyl (-OH) groups and the hydrogen atoms.

  • Erythro-2,3-dihydroxybutanoic acid:

    • The (2R,3R) and (2S,3S) forms constitute the erythro pair.
    • In their Fischer projections, the two -OH groups (or the two H atoms) on C2 and C3 are on the same side.
      • (2R,3R)-2,3-dihydroxybutanoic acid: 
          COOH
  |
H-C*-OH (C2)
  |
H-C*-OH (C3)
  |
  CH3
        (Here, H’s are on the left, OH’s are on the right).

  • Threo-2,3-dihydroxybutanoic acid:

    • The (2R,3S) and (2S,3R) forms constitute the threo pair.
    • In their Fischer projections, the two -OH groups (or the two H atoms) on C2 and C3 are on opposite sides.
      • (2R,3S)-2,3-dihydroxybutanoic acid: 
          COOH
  |
H-C*-OH (C2)
  |
OH-C*-H (C3)
  |
  CH3
        (Here, H on C2 is left, H on C3 is right; OH on C2 is right, OH on C3 is left).

These two pairs are diastereomers of each other, exhibiting different physical and chemical properties.

Properties and Separation of Diastereomers

The practical significance of diastereomers stems from their differing properties, which allows for their separation.

  1. Distinct Physical Properties: As previously mentioned, diastereomers have different melting points, boiling points, solubilities, densities, dipole moments, and spectroscopic characteristics (NMR, IR, UV-Vis). This makes them separable by standard physical methods such as:

    • Fractional Crystallization: Exploiting differences in solubility in various solvents. As a solution cools, the less soluble diastereomer will crystallize out first.
    • Distillation: Utilizing differences in boiling points.
    • Chromatography: Taking advantage of differing affinities for a stationary phase in techniques like column Chromatography, thin-layer chromatography (TLC), gas chromatography (GC), and high-performance liquid chromatography (HPLC).

  2. Differential Chemical Reactivity: While not as pronounced as physical property differences, diastereomers can react at different rates or give different product ratios, especially when involved in diastereoselective reactions or interactions with chiral reagents. This difference in reactivity is crucial in asymmetric synthesis.

Relevance and Applications

The understanding and manipulation of diastereomers are central to numerous areas of chemistry and related fields:

  • Asymmetric Synthesis: In the synthesis of chiral molecules, particularly pharmaceuticals, it is often necessary to produce a single enantiomer. One common strategy is diastereoselective synthesis, where a reaction is designed to preferentially form one diastereomer over others. These diastereomeric products can then be separated and converted to the desired enantiomer.
  • Resolution of Enantiomers: Since enantiomers have identical physical properties in an achiral environment, their direct separation is challenging. A common method, known as resolution, involves reacting a racemic mixture of enantiomers with a pure chiral auxiliary (a “resolving agent”). This reaction forms two diastereomeric salts or adducts. Because these diastereomers have different physical properties, they can be separated by techniques like fractional crystallization. Once separated, the chiral auxiliary can be removed, yielding the pure enantiomers. This technique is indispensable for obtaining enantiopure compounds.
  • Drug Discovery and Development: Many biologically active molecules, including drugs, are chiral and often possess multiple stereocenters. Different diastereomers of a drug candidate can exhibit vastly different pharmacological activities, toxicities, absorption, distribution, metabolism, and excretion (ADME) profiles. Therefore, synthesizing, separating, and testing individual diastereomers is a critical step in drug development to ensure efficacy and safety. For example, some common over-the-counter decongestants exist as diastereomers (e.g., pseudoephedrine vs. ephedrine, which have distinct biological effects despite similar structures).
  • Natural Product Chemistry: Natural products are a rich source of complex chiral molecules, such as carbohydrates, amino acids, alkaloids, and terpenes. These molecules often contain multiple chiral centers, leading to numerous possible stereoisomers. Understanding diastereomeric relationships is essential for their isolation, structural elucidation, and synthesis. For instance, the naturally occurring amino acids like threonine and isoleucine are specific threo/erythro diastereomers.

Diastereomers are a crucial class of stereoisomers distinguished by their non-mirror-image relationship and, consequently, their differing physical and chemical properties. This fundamental distinction from enantiomers means that diastereomers can be separated by conventional methods. The specific classification of “threo” and “erythro” applies to diastereomers with two adjacent chiral centers, relating to the spatial arrangement of identical or similar substituents in their Fischer projections. Erythro forms typically have these groups on the same side, while threo forms have them on opposite sides. The ability to separate and differentiate diastereomers is immensely important in modern organic chemistry, underpinning advancements in asymmetric synthesis, the resolution of enantiomers, and the development of stereochemically pure pharmaceuticals. Their pervasive presence in complex organic molecules highlights their significance in both synthetic and natural systems.