Resolution by direct crystallization

Even a few seed crystals, mechanically separated, can be used to produce larger quantities of resolved enantiomerically pure material. A second method of resolution by direct crystallization involves the localized crystallization of each enantiomer from a racemic, supersaturated solution. With the crystallizing solution within the metastable zone, oppositely handed enantiomerically pure seed crystals of the compound are placed in geographically distant locations in the crystallization vessel. These serve as nuclei for the further crystallization of the like enantiomer, and enantiomerically resolved product grows in the seeded locations. 

A. Collet, M.-J. Brienne, J. Jacques, Optical resolution by direct crystallization of enantiomer mixtures, Chem. Rev. 80 (1980) 215-230. 

The second type of resolution by direct crystallization is knovm as entrainment. Here, the differences in the rate of crystallization of the enantiomers in a supersaturated solution give rise to a separation. Strict control of the conditionsforthe crystallization are required, with the system of crystals and solution not being allowed to come to equilibrium and time playing an important role. The occurrence of conglomerates has been estimated to be approximately 10% of all racemic compounds. We will now illustrate this phenomenon with some pertinent examples. 

Optical resolution by direct crystallization of enantiomer mixtures ... 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

Conglomerate solids are characterized by the presence of a single enantiomer within the unit cell of the crystal, even when the solid is obtained through crystallization of a racemic or partially resolved mixture. These solids consist of separate crystals, each of which consists entirely of one enantiomer or the other, which may be separated entirely on the basis of their physical properties. Compounds known to crystallize as conglomerates can be quite easily resolved, since the resolution step takes place spontaneously upon crystallization. The key to a successful resolution by direct crystallization lies in the means used to separate physically the crystals containing the opposite enantiomers. Jacques and coworkers have provided extensive summaries of the methods whereby direct crystallization can be used to effect the resolution of a racemic mixture [10,32]. 

For practical use the conglomerate is most favorable as pure enantiomers may be obtained by direct crystallization, either by localization of crystallization or by resolution by entrainment . 

The first method of enantiomeric separation by direct crystallization is the mechanical technique use by Pasteur, where he separated the enan-tiomorphic crystals that were simultaneously formed while the residual mother liquor remained racemic. Enantiomer separation by this particular method can be extremely time consuming, and not possible to perform unless the crystals form with recognizable chiral features (such as well-defined hemihedral faces). Nevertheless, this procedure can be a useful means to obtain the first seed crystals required for a scale-up of a direct crystallization resolution process. When a particular system has been shown to be a conglomerate, and the crystals are not sufficiently distinct so as to be separated, polarimetry or circular dichroism spectroscopy can often be used to establish the chirality of the enantiomeric solids. 

Ordinarily, the rate-determining step during phase conversion is the formation of nuclei of the new phase. If suitable nuclei cannot be formed at the conditions of study, then the phase transformation is effectively suspended until the nuclei either form spontaneously or are added by the experimenter. 8ynthetic chemists have long used seed crystals of their desired phase to obtain a sufficient crop of that material and to suppress the formation of unwanted by-products. This procedure is especially important during the resolution of enantiomers and diastereomers by direct crystallization. 

About 90% of all racemates are racemic compounds, consisting of a perfectly ordered array of R and S molecules. Conglomerates, on the other hand, consist of a mixture of crystals of the two enantiomers in equal amounts. Conglomerates are in principle amenable to resolution by direct crystallisation, a simple, non-waste producing technique. Where the racemate is available, the existence of conglomerates should always be... 

To solve a crystal structure by direct methods, difficult data are those which are incomplete in the sampling of reciprocal space, have non-atomic i.e. < 1.3A resolution) and are noisy with large (systematic) errors in the data measurements. As we have seen, this definition spans many electron diffraction data sets, but there are some of sufficient quality that they can be solved routinely using conventional direct methods packages. Often these are of inorganic materials or intermetallic compounds that are relatively resistant to radiation damage. 

The experiments were performed in stainless steel UHV chambers which were equipped with the instrumentation necessary to perform Auger Electron Spectroscopy (AES), X-ray Photoelectron Spectroscopy (XPS), UV Photoelectron Spectroscopy (UPS), Low Energy Electron Diffraction (LEED), work function measurements (A( )), High Resolution Electron Energy Loss Spectroscopy (HREELS), and Temperature Programmed Desorption (TPD). The Au(lll) crystal was heated resist vely and cooled by direct contact of the crystal mounting block with a liquid nitrogen reservoir. The temperature of the Au(lll) crystal was monitored directly by means of a... 

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