Coquerel, Gérard

Hoquante, Marine

Rietveld, Ivo B.

English

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Disappearing Conglomerates

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Disappearing conglomerates 
Marine Hoquante1, Ivo Rietveld1,2 Gérard Coquerel1 
marine.hoquante@univ-rouen.fr 
1 Normandie Université, Laboratoire SMS-EA3233, Université de Rouen, F76821, Mont Saint Aignan, 
France 
2 Université Paris Descartes, Faculté de Pharmacie, 4, av. de l’observatoire, 75006, Paris, France 
 
As the majority of active pharmaceutical ingredients are chiral, resolution methods to separate their 
enantiomers are of great importance for the pharmaceutical industry1. Preferential crystallisation, second 
order asymmetric transformation (SOAT) and deracemization are different processes for obtaining pure 
enantiomers;2 however, these methods all have in common the need for a conglomerate forming system. 
The system discussed in this work is an atropisomer couple of enantiomers understood to be a 
conglomerate forming system3. Indeed, in the CSD, 2'-(phenylmethoxy)-[1,1'-Binaphthalen]-2-ol] (Binol-
OBn) is reported with the space group P212121 (refcode UBULUB, CCDC 1443741) and the binary phase 
diagram with its two enantiomers possessing a ‘stable’ conglomerate has been established. However, 
upon crystallisation in our laboratory a stable racemic compound appeared. This new racemic compound 
was characterized by means of: Differential Scanning Calorimetry, IR spectroscopy, Second Harmonic 
Generation and single crystal X-ray diffraction.  
 
Figure 1 revisited binary system between enantiomers of 2'-(phenylmethoxy)-[1,1'-Binaphthalen]-2-ol] 
Discussion 
The conglomerate melts about 30 degrees lower than the newly identified racemic compound. Therefore, 
the metastable conglomerate will be difficult to obtain again. With such a large difference in melting 
points, one can wonder how the conglomerate could have been observed in different laboratories. An 
explanation can be found in the complexity of the racemic compound structure which contains three 
molecules in the asymmetric unit, each of them with a different conformation. The structure of the racemic 
compound will be compared to that of the enantiomer. The following open question should now be 
carefully considered: how to predict the threat that such a case would occur in an industrial setting, while 
using a conglomerate forming system? 
 References 
 (1)  Brooks, W. H.; Guida, W. C.; Daniel, K. G. The Significance of Chirality in Drug Design and Development. Curr. 
Top. Med. Chem. 2011, 11 (7), 760–770. 
(2)  Novel Optical Resolution Technologies; Sakai, K., Hirayama, N., Tamura, R., Eds.; Topics in Current Chemistry; 
Springer-Verlag: Berlin Heidelberg, 2007. 
(3)  Maria, T. M. R.; Marins, F. A.; Costa, J. B. S.; Silva, M. R.; Carrilho, R. M. B.; Monteiro, C. J. P.; Pereira, M. M.; 
Eusébio, M. E. S. Thermochim. Acta 2017, 648, 32–43.  


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Disappearing Conglomerates

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