Rapid Structure Determination of Molecular Solids Using Chemical Shifts Directed by Unambiguous Prior Constraints

NMR-based crystallography approaches
involving the combination
of crystal structure prediction methods, ab initio calculated chemical shifts and solid-state NMR experiments are powerful
methods for crystal structure determination of microcrystalline powders.
However, currently structural information obtained from solid-state
NMR is usually included only after a set of candidate crystal structures
has already been independently generated, starting from a set of single-molecule
conformations. Here, we show with the case of ampicillin that this
can lead to failure of structure determination. We propose a crystal
structure determination method that includes experimental constraints
during conformer selection. In order to overcome the problem that
experimental measurements on the crystalline samples are not obviously
translatable to restrict the single-molecule conformational space,
we propose constraints based on the analysis of absent cross-peaks
in solid-state NMR correlation experiments. We show that these absences
provide unambiguous structural constraints on both the crystal structure
and the gas-phase conformations, and therefore can be used for unambiguous
selection. The approach is parametrized on the crystal structure determination
of flutamide, flufenamic acid, and cocaine, where we reduce the computational
cost by around 50%. Most importantly, the method is then shown to
correctly determine the crystal structure of ampicillin, which would
have failed using current methods because it adopts a high-energy
conformer in its crystal structure. The average positional RMSE on
the NMR powder structure is ⟨rav⟩ = 0.176 Å, which corresponds to an average equivalent
displacement parameter Ueq = 0.0103 Å2.