Synthesis, Prediction, and Determination of Crystal Structures of (R/S)- and (S)-1,6-Dinitro-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dione

Abstract

Spiro-cyclic compounds frequently have screw-type symmetry (C 2) and are therefore optically active even though they do not contain an asymmetric carbon atom. (R/S)-1,6-Dinitro-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dione is such a molecule. A blind crystal structure prediction study of structures containing one molecule in the asymmetric unit and considering all 230 space groups was undertaken using a dispersion-corrected density functional approach, which found a packing that matched the experimental structure of the (R/S) form as the lowest energy packing alternative. The densities of (R/S)- and (S)- or (R)-1,6-dinitro-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dione calculated for the optimized experimental crystal structures confirmed that there is a small difference in the densities of the racemate and the optically active compound, with the optically active material being slightly more dense (1.875 versus 1.842 g/cm3). (R/S)-1,6-Dinitro-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dione was synthesized as previously described. Synthesis of the pure (S)-stereoisomer was accomplished by resolution of the racemic dithiourethane using a previously described method, followed by reaction of the pure enantiomer with acetyl nitrate. The absolute configuration of the l-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dithione was established as (S)- by redetermining the crystal structure at 150 K. The racemate crystallizes in space group P21/n with a density of 1.835 g/cm3 (296 K). The (S)-compound crystallizes in space group P212121 with a density of 1.854 g/cm3 (296 K). This is the first demonstration of a difference in the density between the racemic mixture and the optically pure stereoisomer of an energetic material. It is also an apparent violation of Wallach’s rule, which states that racemic crystals tend to be denser than their optically active counterparts.

Crystal Structure Prediction of a Flexible Molecule of Pharmaceutical Interest with Unusual Polymorphic Behavior

“…No other experimental information is used to constrain the search, which explores the full conformational flexibility of the molecule. This approach to lattice energy calculations and CSP has been successful in a number of other studies, including the blind tests in CSP and related studies, ,,− a study of intermolecular and intramolecular hydrogen bonding in conformational polymorphs, predicting spontaneous racemate resolution, studies on the isostructurality relationships between molecular structure and crystal structure of small molecules, − as well as a study on an energetic material …”