Configuration

Although configuration and conformation are listed as synonyms in the Oxford English Dictionary (1)  , in chemistry and biochemistry they have specific and separate meanings differentiated by time or energy. Both terms refer to the organization of atoms in space, but configuration refers to the element that remains invariant in time in the absence of any covalent bonds being altered, whereas conformation refers to the relative orientation in space of atoms that can vary by rotation about single bonds and consequently varies in real time for biological molecules. The absolute configuration identifies the arrangement of atoms that generates chirality in a molecule. Following Pasteurs identification of the two chiral forms of tartaric acid, it was only known that they differed by being nonsuperimposable mirror images. This ambiguity was resolved when the crystal structure of (+) tartaric acid was determined by Bijvoet and co-workers (2). By this means, the absolute configuration of many related molecules became identifiable.

The designation of the configuration of a chiral center was problematic for nearly a century. Fischer introduced a general procedure that identified enantiomers as either D- or L- (3) based on whether the nonhydrogen substituent was on the right or left when the molecule was drawn as a “Fischer projection” (Fig. 1). This nomenclature permeates biochemistry through the now colloquial names of amino acids, carbohydrates, and lipids.

Figure 1. A Fischer projection. By convention, it has the vertical bonds directed away from the viewer and horizontal bonds directed out toward the viewer. The configuration of each chiral carbon in D-ribose is D because the nonhydrogen substituent is drawn to the right. For sugars, the enantiomer is defined by the bottom chiral carbon when the carbon chain is oriented vertically with the carbonyl carbon at the top; thus, D-ribose is pictured.

The Fischer nomenclature leads to ambiguities (4). A rigorous and unambiguous method of identifying configuration proposed by Cahn et al. has been adopted for specifying absolute configuration as either (R) or (S) for chiral tetrahedral centers (5). The procedure requires the assignment of priority to the four substituents that generate a chiral center, followed by a procedure to identify the arrangement as either (R) or (S). The four rules for assigning priority are:

1. Substituents are assigned their priority in order of decreasing atomic number of the atom directly bonded to the chiral center.

2. If two or more atoms receive the same priority in step 1, the atoms bonded to each of the equal priority atoms are examined one at a time. If the two groups are not differentiated by the atom of greatest priority, the second and third atoms are compared successively.

3. Heavier isotopes take precedence over lighter isotopes, eg, ²H over ¹H and ¹⁴C over ¹²C.

4. Double bonds are counted as two bonds to the same atom.

Once the relative priorities of the four substituents are assigned, the bond to the lowest priority group is oriented directly away from the observer, and the remaining three groups are viewed in a plane. If the arc connecting the three groups in order of highest to lowest priority is clockwise, the chiral center is assigned the (R) configuration (from the Latin rectus), whereas if the arc is counterclockwise, the center is assigned the (S) configuration (from the Latin sinister). These assignments are shown in Figure 2.

Figure 2. Assignment of the relative priorities of the four substituents on the chiral a-carbon of serine. The carboxylate carbon takes precedence over the hydroxymethyl carbon because it has three bonds to oxygen. The assignment of the (S) configuration results from the counterclockwise arc that connects the substituents in order of precedence.

Assignment of the relative priorities of the four substituents on the chiral a-carbon of serine. The carboxylate carbon takes precedence over the hydroxymethyl carbon because it has three bonds to oxygen. The assignment of the (S) configuration results from the counterclockwise arc that connects the substituents in order of precedence.

References

1. Oxford English Dictionary, 2nd ed. (1989) Clarendon Press, Oxford. 

2. J. M. Bijvoet, A. F. Peerdeman, and A. J. van Bommel (1951) Nature 168, 271. 

3. E. Fischer (1891) Ber. Dtsch. Chem. Ges. 24, 2683. 

4. E. L. Eliel (1962) Stereochemistry of Carbon Compounds, McGraw-Hill, New York, Chap. "5".

5. R. S. Cahn, C. K. Ingold, and V. Prelog (1966) Angew. Chem. Int. Ed. 5, 385–415.