The question of whether the L and D system represents absolute configuration is a long-standing point of confusion in organic chemistry and biochemistry. To understand the answer, one must first appreciate the concept of molecular handedness, a property known as chirality. Molecules that are chiral exist as non-superimposable mirror images of one another, much like a person’s left and right hands. This three-dimensional arrangement, or stereochemistry, is important because biological systems, such as enzymes and receptors, are also chiral. These mirror-image molecules are called enantiomers, and their differing interactions mean that one enantiomer may be biologically active while its mirror image is inactive or even harmful. Scientists developed various systems to label and communicate this precise three-dimensional structure.
Defining Relative Configuration (The D/L System)
The D/L system, developed in the late 19th and early 20th centuries, provides a way to describe the orientation of atoms in space relative to a single, chosen standard molecule. This historical nomenclature is based on the simplest sugar with a chiral center, glyceraldehyde. The system was established arbitrarily, with the dextrorotatory (+) form of glyceraldehyde being designated as D-glyceraldehyde. Any other molecule whose stereochemistry could be chemically related to D-glyceraldehyde was assigned the D designation, defining the D/L system as a method of determining relative configuration.
For carbohydrates and amino acids, the designation is determined by the configuration of the chiral center farthest from the main functional group. In a two-dimensional Fischer projection, the D configuration is assigned if the defining functional group (hydroxyl or amino) on the reference carbon is positioned on the right side. Conversely, the L configuration is assigned if that group is on the left side. This system is still widely used in biochemistry because it conveniently groups all the naturally occurring sugars (mostly D) and amino acids (mostly L).
Establishing Absolute Configuration (The R/S System)
The modern, universally accepted method for unambiguously describing three-dimensional structure is the Cahn-Ingold-Prelog (CIP) convention, known as the R/S system. This system provides the true absolute configuration by assigning a mathematical designation to each individual chiral center within a molecule. The R/S system does not rely on a comparison to a reference molecule like glyceraldehyde, making it independent and definitive.
The nomenclature works by assigning a priority rank from 1 to 4 to the four different groups attached to a chiral carbon atom. Priority is determined primarily by the atomic number of the atom directly attached to the chiral center; the atom with the higher atomic number receives a higher priority.
After assigning priorities, the molecule is mentally oriented in space so that the lowest priority group (4) points away from the viewer. A curved arrow is then traced from the highest priority group (1) to the second (2) and then to the third (3). If the path traces a clockwise direction, the configuration is labeled R, for Rectus. If the path is counter-clockwise, the configuration is labeled S, for Sinister. This convention precisely dictates the spatial orientation of the groups around the chiral center.
The Critical Distinction: L/D is Not Absolute Configuration
The core answer to the question is that the L/D system is fundamentally a system of relative configuration, not absolute configuration. While the R/S system provides an unambiguous description of the spatial arrangement around every chiral center, the D/L system only relates a molecule’s configuration to a single, historical reference compound: glyceraldehyde.
The designations D and L were initially assigned before the true spatial arrangement of atoms was known, based on a chemical correlation. It was a historical coincidence, later confirmed by X-ray crystallography, that D-glyceraldehyde happened to have the same absolute configuration, R, at its single chiral center. This initial match led to the understandable, but incorrect, assumption that D generally corresponds to R and L generally corresponds to S.
However, this simple correlation breaks down when considering more complex molecules with multiple chiral centers, such as long-chain sugars. The D/L designation for a sugar only specifies the configuration of the chiral center farthest from the main functional group, leaving the configuration of all other chiral centers unspecified by the D/L name alone. A D-sugar, for example, may have a mix of R and S configurations at its various chiral centers.
A further complication is seen with the naturally occurring L-amino acids. Nearly all L-amino acids have the S absolute configuration at their alpha-carbon. A notable exception is L-cysteine, which, due to the higher atomic priority of its sulfur-containing side chain, is designated with the R configuration. This inversion highlights that the D/L system describes a family relationship, while R/S is an independent, rule-based designation of spatial geometry.
Confusion with Optical Activity
A separate layer of confusion arises from the common practice of mistakenly linking the D/L and R/S configuration systems to the measured physical property of optical activity. Optical activity refers to a substance’s ability to rotate the plane of polarized light, a property measured experimentally with a polarimeter.
Molecules that rotate the light clockwise are called dextrorotatory and are denoted by a plus sign (+) or a lowercase d. Molecules that rotate the light counter-clockwise are called levorotatory and are denoted by a minus sign (-) or a lowercase l.
There is no reliable, predictable correlation between a molecule’s D or L configuration and the direction (+ or -) in which it rotates light. For instance, D-glyceraldehyde is dextrorotatory, but D-lactic acid is levorotatory, rotating the light in the opposite direction. The R/S system is similarly unrelated to optical activity; an R-configured molecule can be either dextrorotatory (+) or levorotatory (-). Configuration (D/L or R/S) is a naming convention based on the molecule’s spatial structure, while optical activity (+/-) is a measurable physical property. The sign of rotation must be determined experimentally and cannot be deduced from the molecule’s configuration label.