Chaperone Compounds for Organic Molecule Co-crystallization

Many small organic molecules of interest are difficult to crystallize due to properties such as a high conformational flexibility, low symmetry or low polarity.

This crystallization challenge can prevent the application of SC-XRD analysis on such compounds, despite it being a strong technique for structural determination that delivers high-quality 3D structures in less than an hour. 

Chaperone compounds form stable complexes with small organic molecules, enabling the growth of ordered crystal lattices that meet the quality requirements for SC-XRD. This approach allows the crystallographic analysis and absolute structure determination of molecules that are otherwise resistant to crystallization using conventional methods.

Available Chaperone Compounds

• 1,3,5,7-Tetrakis(2,4-diethoxyphenyl)adamantane (TEO) P/N A30D250
• 1,3,5,7-Tetrakis(2,4-dimethoxyphenyl)adamantane (TDA) P/N A30D251
• 1,3,5,7-Tetrakis(2-bromo-4-methoxyphenyl)adamantane (TBro) P/N A30D252
  
• 1,3,5,7-tetrakis(2-fluoro-4-methoxyphenyl)adamantane (TFM) P/N A30D253

What Does Each Kit Contain?

• Selected chaperone compound
• 30 crystallization vials
• Instruction set on memory stick
• Reference publications

The Benefits of Using Chaperone Compounds

Our chaperone compound kits are a powerful method for chemist's and crystallographers's toolboxes.

• Chaperone compounds are fast and easy to use.
• Chaperone compounds are highly stable. 
• Produces crystals of excellent quality. 
• 100% analyte occupancy in the crystal guarantees reliable determination of the absolute configuration
• Co-crystallization enables absolute structure determination via SC-XRD, delivering in-depth data in often less than an hour.
• Only small quantities of analyte are required.

The crystals produced via co-crystallization are of a high quality.

In a sample screening of 52 small organic compounds in 88% of cases diffraction-quality crystals were produced and in 77% of cases high-resolution 3D structure determination was achieved. 

Recent research from the University of Stuttgart has demonstrated the use of chaperone compounds to promote the crystallization of large, conformationally flexible molecules such as vitamin K₂, even when the analyte is larger than the voids between individual chaperone molecules. In these cases, co-crystallization occurs in layers. 

Vitamin K₂ is a fat-soluble vitamin that regulates calcium levels during biological processes such as bone formation and blood coagulation. Its structure consists of a rigid menaquinone head group attached to a long terpenoid chain with a conformational flexibility that makes the crystallization of Vitamin K₂ particularly challenging.

To successfully crystallize vitamin K₂ the researchers employed chaperone-assisted crystallization, using the compound 1,3,5,7-tetrakis(2-fluoro-4-methoxyphenyl)adamantane (TFM) and a three-stage temperature protocol.

Diffraction measurements, using the D8 VENTURE METALJET, found that the resulting crystals were of a high quality, with diffraction patterns of 0.8 Å resolution. Structural analysis revealed that vitamin K₂ and the TFM chaperone compound form an ordered co-crystal of alternating layers (Figure 1), with vitamin K₂'s long terpenoid chain folding back within the lattice. Additionally, the co-crystal was found to be meta-stable, with storage over several weeks at low temperatures possible. 

These results demonstrate that chaperone compounds can promote ordered crystallization using mechanisms that that go beyond encapsulation in voids. Chaperones like TFM can adapt to the shape of the analyte, including the formation of separate layers that template the crystallization of large guest molecules. This highlights the potential of using chaperone compounds in the investigation of other larger, conformationally flexible organic molecules.

Learn more: 

• J. Hartenfels, G. L. Runge-Seither, T. Berking, J. Osterbrink, C. Wolf, C. Richert, Getting the Big Ones to Pack: Crystal Structure of Vitamin K2 With a Chaperone. Chem. Eur. J. 2026, e71741.

• F. Rami, J. Nowak, F. Krupp, W. Frey, C. Richert, Co-Crystallization of an organic solid and a tetraaryladamantane at room temperature. Beilstein J. Org. Chem. 2021, 17, 1476-1480.
• F. Krupp, M.-I. Picher, W. Frey, B. Plietker, C. Richert, Determining the Relative Configuration of Propargyl Cyclopropanes by Co-Crystallization. Synlett 2021, 32, 350-353.
• M. E. Casco, F. Krupp, S. Grätz, A. Schwenger, V. Damakoudi, C. Richert, W. Frey, L. Borchardt, Non-porous organic crystals and their interaction with guest molecules from the gas phase. Adsorption 2020, 26, 1323-1333.
• F. Krupp, W. Frey, C. Richert, Absolute Configuration of Small Molecules by Co-Crystallization. Angew. Chem. 2020, 132, 16009-16013; Angew. Chem. Int. Ed. 2020, 59, 15875-15879.
• F. Krupp, S. He, W. Frey, C. Richert, A crystalline ready-to-use form of cyclopentadiene. Synlett 2018, 29, 1707-1710.

• P.-E. Alexandre, A. Schwenger, W. Frey, C. Richert, High loading crystals of tetraaryladamantanes and the uptake and release of aromatic hydrocarbons from the gas phase. Chem. Eur. J. 2017, 23, 9018-9021.
• C. Richert, F. Krupp, Encapsulating organic crystals (EnOCs). Synlett 2017, 28, 1763-1766.
• A. Schwenger, W. Frey, C. Richert, Reagents with a crystalline coat. Angew. Chem. 2016, 128, 13910-13913; Angew. Chem. Int. Ed. 2016, 55, 13706-13709.
• A. Schwenger, W. Frey, C. Richert, Tetrakis(dimethoxyphenyl)adamantane (TDA) and its inclusion complexes in the crystalline state: A versatile carrier for small molecules. Chem. Eur. J. 2015, 21, 8781-8789.