Organic NMR crystallography: enabling progress for applications to pharmaceuticals and plant cell walls

Abstract

The application of NMR crystallography to organic molecules is exemplified by two case studies. For the tosylate salt of the active pharmaceutical ingredient, Ritlectinib, solid-state NMR spectra are presented at a ¹H Larmor frequency of 1 GHz and a magic-angle spinning (MAS) frequency of 60 kHz. Specifically, ¹⁴N-¹H heteronuclear multiple-quantum coherence (HMQC) and ¹H-¹H double-quantum (DQ) single-quantum (SQ) correlation experiments are powerful probes of hydrogen bonding interactions. A full assignment of the ¹H, ¹³C and ¹⁴N/¹⁵N chemical shifts is achieved using also ¹H-¹³C cross polarization (CP) HETCOR spectra together with gauge-including projector augmented wave (GIPAW) DFT calculation for the geometry-optimised X-ray diffraction crystal structure that is reported here (CCDC 2352028). In addition, GIPAW calculations are presented for the ¹³C chemical shifts in the two polymorphs of cellulose for which diffraction structures are available. For both case studies, a focus is on the discrepancy between experiment and GIPAW calculation.

Scheme 1

Fig. 1. (a) A ¹⁴N–¹H (600 MHz) HMQC MAS (60 kHz) NMR spectrum with skyline projections of 1 recorded with 16 rotor periods of phase-inverted R³ recoupling, τ_RCPL = 267.2 μs. (b) Comparison to a 1D ¹H (500 MHz)–¹⁵N CP (3.5 ms) MAS (12.5 kHz) NMR spectrum of 1 acquired with 10 240 co-added transients. The arrows indicate the difference between the ¹⁴N shift and the ¹⁵N chemical shifts for N1, N7 and N10.

Fig. 2. Intermolecular NH⋯O hydrogen bonds in the DFT (CASTEP) geometry optimised crystal structure of 1 (CCDC 2352028) between the oxygen atoms of the tosylate salt and the three NH protons of the API free base (see Table 2 for the hydrogen bond distances and angles).

Fig. 3. A ¹H (1 GHz) DQ–SQ 2D MAS (60 kHz) NMR spectrum of 1 with skyline projections recorded with one rotor period of BaBa recoupling. The base contour level is at 4% of the maximum peak height.

Fig. 4. (a) A 1D ¹H (600 MHz)–¹³C CP (2 ms) MAS (12.5 kHz) NMR spectrum (top) of 1 acquired with 2048 co-added transients. The asterisks denote spinning sidebands. The stick spectrum (bottom) represents the GIPAW calculated ¹³C chemical shifts for the DFT (CASTEP) geometry-optimised structure of 1 (CCDC 2352028, see Table 4). (b) and (c) Two-dimensional ¹H (1 GHz)–¹³C CP (500 μs) HETCOR MAS (60 kHz) NMR spectra with skyline projections for the aromatic and aliphatic regions, respectively. Here, the low-power ¹³C irradiation during CP was at an irradiation frequency of (b) 120 ppm and (c) 50 ppm. The black crosses in (b) and (c) represent the GIPAW calculated chemical shifts for the directly bonded CH connectivities up to 1.1 Å. The base contour level is at 17% and 14% of the maximum peak height for (b) and (c), respectively.

Fig. 5. 2D MAS (60 kHz) NMR spectra with skyline projections of 1 recorded at 1 GHz. Top: ¹H–¹³C CP HETCOR spectra for the high (left) and low (right) ppm regions repeated from Fig. 4b and c, respectively. Bottom: Corresponding regions of the ¹H–¹H DQ–SQ spectrum repeated from Fig. 3. Note that the ¹H–¹³C CP HETCOR spectra have been rotated through 90° so as to achieve the alignment of the ¹H SQ axis as horizontal for both sets of spectra.