Positional Variance in NMR Crystallography

Abstract

We propose a method to quantify positional uncertainties in crystal structures determined by chemical-shift-based NMR crystallography. The method combines molecular dynamics simulations and density functional theory calculations with experimental and computational chemical shift uncertainties. In this manner we find the average positional accuracy as well as the isotropic and anisotropic positional accuracy associated with each atom in a crystal structure determined by NMR crystallography. The approach is demonstrated on the crystal structures of cocaine, flutamide, flufenamic acid, the K salt of penicillin G, and form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butylpyrazol-1-yl]benzoic acid (AZD8329). We find that, for the crystal structure of cocaine, the uncertainty corresponds to a positional RMSD of 0.17 Å. This is a factor of 2.5 less than for single-crystal X-ray-diffraction-based structure determination.

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

“…Recently, modified NMR crystallography protocols that use genetic algorithms to generate trial structures and semiempirical calculations of 1 H chemical shifts to test the trial structures were described . Plane‐wave DFT and solid‐state NMR spectroscopy are also often applied to validate and/or refine structures determined by X‐ray diffraction …”

NMR Crystallography: Evaluation of Hydrogen Positions in Hydromagnesite by 13C{1H} REDOR Solid‐State NMR and Density Functional Theory Calculation of Chemical Shielding Tensors

“…[19] XRD suffers,h owever, from being insensitive to low atomic number (Z) nuclei, such as hydrogen;h ence,i ns ome cases,t he structural models produced by XRD are not sufficiently accurate for understanding how the resulting chemistry is directed by coordination. [20] Creative efforts in the emerging field of NMR crystallography [21][22][23][24][25] have pushed the use of NMR as ac omplementary tool for the elucidation of precise atomic coordinates,especially protons,int he unit cell.NMR crystallography,c ombines NMR, XRD,a nd computational chemistry, [26][27][28][29][30][31][32][33] to resolve atomic positions within crystals.Astrength of this scheme is using NMR chemical shifts and dipolar couplings between nuclei to validate ab initio quantum calculations for refining atom positions that are invisible to XRD. [34][35][36] Generally,i sotropic chemical shifts (d iso )a re used to identify spin-1/2 (nuclear spin, I = 1/2) NMR active species in structures,b ecause they are the most readily observed in NMR spectra.…”

“…[19] XRD suffers,h owever, from being insensitive to low atomic number (Z) nuclei, such as hydrogen;h ence,i ns ome cases,t he structural models produced by XRD are not sufficiently accurate for understanding how the resulting chemistry is directed by coordination. [20] Creative efforts in the emerging field of NMR crystallography [21][22][23][24][25] have pushed the use of NMR as ac omplementary tool for the elucidation of precise atomic coordinates,especially protons,int he unit cell.…”

Resolving alternative organic crystal structures using density functional theory and NMR chemical shifts

“…Given the importance of correctly positioned hydrogen atoms for describing hydrogen bonding arrangements, independent experimental evidence from a technique that is sensitive to hydrogen atom positioning would be highly desirable. Nuclear magnetic resonance (NMR) spectroscopy is highly sensitive to the local environment about the nuclei studied (for example, effective anisotropic displacement parameters derived from NMR chemical shis have been estimated to be consistently smaller than those associated with X-ray diffraction 7,8 ). "NMR crystallography" 9 is a rapidly developing eld that has recently been recognised by the IUCr in the form of a commission on NMR crystallography.…”