Insights into the Crystallization and Structural Evolution of Glycine Dihydrate by In Situ Solid‐State NMR Spectroscopy

Abstract

In situ solid-state NMR spectroscopy is exploited to monitor the structural evolution of a glycine/water glass phase formed on flash cooling an aqueous solution of glycine, with a range of modern solid-state NMR methods applied to elucidate structural properties of the solid phases present. The glycine/water glass is shown to crystallize into an intermediate phase, which then transforms to the β polymorph of glycine. Our in situ NMR results fully corroborate the identity of the intermediate crystalline phase as glycine dihydrate, which was first proposed only very recently.

The importance of nuclear quantum effects for NMR crystallography

“…Error bars reflect ML uncertainties as well as, where applicable, statistical errors due to sampling. Experimental values [64][65][66][67][68][69] are indicated as black stars.…”

“…Fig. 2 shows a visual representation of the shifts for the polymorphs of succinic acid and glycine for which experimental data is available [64][65][66][67][68][69] (a full table is provided in the Supplemental Information). Even after internal calibration, NQEs lead to changes of the chemical shifts by up to 0.2 ppm for 1 H and 2 ppm for 13 C, in every case reducing the discrepancy with measurements.…”

“…This small difference is not reflected in significant changes in the predicted chemical shieldings for γ-glycine, indicating that the thermal expansion of the cell by around 1-2% in volume does not significantly affect σ. [65][66][67][68][69], as determined using the Bayesian framework of Ref. [59].…”

“…Even though the compounds we study here are usually considered too simple to be amenable to NMR crystallography, there is sufficient experimental data available for the three polymorphs of glycine to attempt structure determination, based on the distinct 1 H and 13 C shifts [65][66][67][68][69], so as to give an indication of the relevance of the NQEs-induced modulation of the chemical shieldings on NMR crystallography. First, we observe that even though there is a degree of cancellation between the changes in δ iso for pairs of polymorphs, the residual effect is still significant, up to 0.2 ppm for 1 H and 0.5 ppm for 13 C (Fig.…”

“…Experimental observations are indicated by black stars. b) Bayesian probabilities of matching the crystal structures of α, β, and γ-glycine to the respective experimentally measured 1 H (left) and 1 H and 13 C (right) chemical shifts[65][66][67][68][69], as determined using the Bayesian framework of Ref [59]…”