In the many scientific endeavors that are driven by organic chemistry, unambiguous identification of small molecules is of paramount importance. Over the past 50 years, NMR and other powerful spectroscopic techniques have been developed to address this challenge. While almost all of these techniques rely on inference of connectivity, the unambiguous determination of a small molecule’s structure requires X-ray and/or neutron diffraction studies. In practice, however, X-ray crystallography is rarely applied in routine organic chemistry due to intrinsic limitations of both the analytes and the technique. Here we report the use of the electron cryo-microscopy (cryoEM) method microcrystal electron diffraction (MicroED) to provide routine and unambiguous structural determination of small organic molecules. From simple powders, with minimal sample preparation, we could collect high-quality MicroED data from nanocrystals (∼100 nm, ∼10–15 g) resulting in atomic resolution (<1 Å) crystal structures in minutes.

<p>In the many scientific endeavors that are driven by organic chemistry, unambiguous identification of small molecules is of paramount importance. Over the past 50 years, NMR and other powerful spectroscopic techniques have been developed to address this challenge. While almost all of these techniques rely on inference of connectivity, the unambiguous determination of a small molecule’s structure requires X-ray and/or neutron diffraction studies. In practice, however, x-ray crystallography is rarely applied in routine organic chemistry due to intrinsic limitations of both the analytes and the technique. Here we report the use of the CryoEM method MicroED to provide routine and unambiguous structural determination of small organic molecules. From simple powders, with minimal sample preparation, we could collect high quality MicroED data from nanocrystals (~100x100x100 nm, ~10^–15g) resulting in atomic resolution (<1 Å) crystal structures in minutes.</p>

Here we apply microcrystal electron diffraction (MicroED) to the structural determination of transition-metal complexes. We find that the simultaneous use of 300 keV electrons, very low electron doses, and an ultrasensitive camera allows for the collection of data without cryogenic cooling of the stage. This technique reveals the first crystal structures of the classic zirconocene hydride, colloquially known as “Schwartz’s reagent”, a novel Pd(II) complex not amenable to solution-state NMR or X-ray crystallography, and five other paramagnetic and diamagnetic transition-metal complexes.

The first enantioselective Pd-catalyzed decarboxylative allylic alkylation of fully substituted N-acyl indole-derived enol carbonates generates acyclic all-carbon quaternary stereocenters in excellent yields (up to 99%) and enantioselectivities (up to 98% ee) using a new electron-deficient phosphinoxazoline (PHOX) ligand.