Absolute Configuration Assignment From a Single Reflection Using Resonant X-Ray Diffraction

Determination of the absolute configuration of chiral molecules is essential across multiple scientific disciplines, as handedness determines the chiroptical, biological, and pharmaceutical properties. For crystalline materials, single crystal x-ray diffraction is the standard technique for assigning the absolute configuration. However, its application typically requires a large number of reflections and analysis of Friedel pair intensities using the Flack parameter or related approaches, such as those of Hooft or Parsons. Here, we introduce a conceptually distinct approach for determining the absolute configuration of a known crystal structure, based on the x-ray energy dependent intensity of a single Bragg reflection that is sensitive to the absolute configuration. By monitoring the variation in the intensity of a Bragg peak across an absorption edge, this method provides an unambiguous probe of chirality. The proposed approach is demonstrated for the (Formula presented.) reflection of a 2-(3-bromophenyl)-N,N-diisopropyl-2-oxoacetamide single crystal, showing that the absolute configuration can be reliably determined from a single reflection. To confirm the assignment of chirality and assess potential limitations, the x-ray energy dependence of additional diffraction peaks was also investigated. This method is particularly advantageous for systems with a limited number of accessible reflections, where conventional statistical methods based on Flack parameter analysis are not reliable.