X‐ray Structure Analysis of N‐Containing Nucleophilic Compounds by the Crystalline Sponge Method

Abstract

Crystalline sponges (CS) used under a set of standard conditions have often failed to give viable N-containing nucleophilic compounds. Despite the high affinity of these nucleophiles to the binding sites of the CS, N-containing compounds considerably harm the coordination framework of the CS during the guest-soaking step. Herein, it is disclosed that these compounds are efficiently absorbed into the CS, without harming the host, under mild conditions (<4 °C, <2 μg) that normally do not work for common organic guests. Moreover, the use of ZnCl as the metal component of CS significantly improved the tolerance and robustness of the host framework toward N-containing compounds. Out of 22 drug (or drug-like) N-containing compounds chosen from the WHO model list of essential medicines, we succeeded in analyzing 17 analytes with the modified protocols and/or by using the ZnCl -noded CS. This demonstrates that the CS method is now a practical tool for drug-discovery research in pharmaceutical industries.

The Crystalline Sponge Method in Water

“…consists of ZnI 2 with 2,4,6‐tri(pyridin‐4‐yl)‐1,3,5‐triazine linkers. This MOF host easily decomposes when it comes into contact with solvents or (high concentrations of) guest molecules containing Lewis basic or protic substituents . Therefore, there is a clear need for more stable MOFs that can withstand a wider array of solvents and functional groups.…”

A high throughput screening method for the nano-crystallization of salts of organic cations

“… 14 , 15 Even the most recent optimisation of the crystal sponge method is still labour intensive, requires the analyte to be soluble in dichloromethane and can only in exceptional cases be used as an ab initio structure determination method without additional knowledge of the analyte. 16 A different MOF lattice has recently been developed by the group of Yaghi for the co-crystallization of carboxylates or alcohol containing molecules. 17 Summarizing the previous developments, a new method that could facilitate the crystallization of cationic, polar compounds would be highly desirable.…”

Determination of the Absolute Configurations of Chiral Alkanes – An Analysis of the Available Tools

“…An important limitation of the method is the lability of the host framework to Lewis bases in solvents and guest molecules though some improvements have been made using milder soaking conditions and/or ZnCl 2 as the metal component. [ 98 ]…”