The Crystal Sponge (CS) method is a highly promising, proven technique where gold standard single crystal X-ray diffraction (SCXRD) can be applied to samples that can either only be produced in minute amounts (those too small to grow a crystal) or those that cannot be crystallised (gases, liquids, and oils) to obtain atomic resolution chemical structures. The analyte (guest) is soaked into a crystalline porous framework (host) and the aggregate crystal structure is subsequently solved, revealing new structural information on the guest. The structures of ~450 analytes have been published using the CS method to date, while many times more have been studied in commercially sensitive projects or remain to be published.
However, there are ongoing problems with the CS-SCXRD method, including:
1.A lack of different sponges available, with most work carried out using a single generic sponge.
2. An associated limited analyte scope, due to inappropriate chemical compatibility and/or poor soaking, with a glaring lack of alternatives.
3. A lack of reliable synthetic methods to make suitable large, untwinned crystals of the known sponges.
4. Laborious solvent exchange and activation processes.
5. Long soaking times due to pore diffusion into large crystals and subsequent careful evaporation of loading solvent, with consequently poor reproducibility of analyte loading.
6. A relatively low hit-rate for successful data collections, meaning the process can be repetitious and time consuming.
7.Relatively poor data quality rendering structure refinements difficult and laborious.
8.Quality of results generally lower than the community accepted standard.
These problems have resulted in poor uptake and accordingly there are few experts and limited adoption as an 'analytical' method for determining chemical structure.
Electron Diffraction is a game changing technique that will improve this situation by offering structure determination on nanocrystals as small as 100nm in size, two orders of magnitude smaller than X-ray diffraction, as well as cryogenic loading and analysis of powders, fragile samples and solvates. We hypothesise that ED is, therefore, highly suited to CS analysis and our proposal focusses on developing the CS method for ED by demonstrating the following potential advantages:
1.Many more potential sponge materials will be explored (including highly inert sponges) as there is no longer a requirement for large single crystals.
2.Much more rapid and complete analyte soaking, due to ~6 orders of magnitude decrease in total sponge particle size, with concomitant decreases in required analyte amounts.
3.Quicker and simpler handling procedures, as there are minimal concerns about sponge nanocrystals drying out or cracking.
4.New soaking procedures and protocols become possible, e.g., soaking analytes into completely dry particles.
5.Novel sample preparation and presentation becomes possible, due to less technological constraints, e.g., multiple nanocrystals on sample grids (ED) versus individual crystals on a single pin-like mount (SCXRD).
6.Much faster data collection times, allowing analysis of multiple nanocrystals from one batch very quickly (potentially automated) on a single grid, therefore outrunning any sample/analyte instability.
7. Potential for screening multiple sponge materials on one grid with individual or multiple analytes, to rapidly determine which sponge is best for which material type.
In doing so, we will demonstrate the CS method is applicable to a broad subset of new sponges and analytes, ultimately rejuvenating the technique in the eyes of academia and industry and finally unleashing its potential to become the go-to technique for structure determination of uncrystallisable molecules.
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