text: Until 1951, it was not possible to obtain the absolute configuration of chiral compounds. It was at some time decided that (+)-glyceraldehyde was the -enantiomer. The configuration of other chiral compounds was then related to that of (+)-glyceraldehyde by sequences of chemical reactions. For example, oxidation of (+)-glyceraldehyde (1) with mercury oxide gives (−)-glyceric acid (2), a reaction that does not alter the stereocenter. Thus the absolute configuration of (−)-glyceric acid must be the same as that of (+)-glyceraldehyde. Nitric acid oxidation of (+)-isoserine (3) gives (–)-glyceric acid, establishing that (+)-isoserine also has the same absolute configuration. (+)-Isoserine can be converted by a two-stage process of bromination and zinc reduction to give (–)-lactic acid, therefore (–)-lactic acid also has the same absolute configuration. If a reaction gave the enantiomer of a known configuration, as indicated by the opposite sign of optical rotation, it would indicate that the absolute configuration is inverted.
  In 1951, Johannes Martin Bijvoet for the first time used in X-ray crystallography the effect of anomalous dispersion, which is now referred to as resonant scattering, to determine absolute configuration. The compound investigated was (+)-sodium rubidium tartrate and from its configuration (R,R) it was deduced that the original guess for (+)-glyceraldehyde was correct. 
  Despite the tremendous and unique impact on access to molecular structures, X-ray crystallography poses some challenges. The process of crystallization of the target molecules is time- and resource-intensive, and can not be applied to relevant systems of interest such as many biomolecules (some proteins are an exception) and in situ catalysts. Another important limitation is that the molecule must contain "heavy" atoms (for example, bromine) to enhance the scattering. Furthermore, crucial distorsions of the signal arise from the influence of the nearest neighbors in any crystal structure and of solvents used during the crystallization process. 
  Just recently, novel techniques have been introduced to directly investigate the absolute configuration of single molecules in gas-phase, usually in combination with ab initio quantum mechanical theoretical calculations, therefore overcoming some of the limitations of the X-ray crystallography.