Conformations in Solution and in Solid-State Polymorphs: Correlating Experimental and Calculated Nuclear Magnetic Resonance Chemical Shifts for Tolfenamic Acid

Abstract

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Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

“…Previously, 70 at this point, we had calculated the solutionstate NMR chemical shift (δ solution calc ) by (1) systematically and exhaustively creating conformations by rotating each torsion upon the base geometry at 15°intervals, (2) calculating 1 H and 13 C NMR chemical shifts for each conformation using the GIPAW method in CASTEP for an "isolated box", 87 and then (3) calculating the overall solution-state value of each 1 H and 13 C chemical shift by combining the contribution of each conformation to its observed chemical shift, according to its calculated occupancy as per the measured solution dynamic 3D structure. While this approach was suitable for tolfenamic acid because it only had 1 rotatable bond, it was unfeasible for furosemide because its 6 rotatable bonds would have required isolated box CASTEP calculations on approximately 100 million conformations (24 6 ).…”

“…All Δδ experimental and Δδ calculated values for both 1 H and13 C are given in Table3. As noted previously,70 by effectively taking the difference of two…”

A toolbox for improving the workflow of NMR crystallography

“…If the difference is greater than 2 ppm, the atom is coloured red. If the difference is between 1 ppm and 2 ppm, a typical discrepancy for 13 C [28,[33][34][35][36][37][38],…”

“…Creating models of isolated molecules can be helpful, for instance, in finding fingerprints of intermolecular interactions, notably ring currents, and hydrogen bonds using NMR-calculated chemical shifts. [38,51,[125][126][127][128][129][130][131][132] To create models of isolated molecules, the space group is generally modified to P1 in order to eliminate symmetry-related molecules from the unit cell, and the unit cell size is usually increased to reduce the occurrence of throughspace interactions between unit cells. Due to the rising computational costs associated with increasing the size of the unit cell, it is undesirable to increase the cell size by more than 10 Å in all directions, as has been shown by Tatton et al [86] The script prompts the user to input the length to be added to the a, b, and c axes of the unit cell, whether to create the new structures in the P1 space group, and whether to isolate each molecule individually or to isolate the entire unit cell.…”

“…Gauge-including projector augmented wave (GIPAW) [26][27][28] density functional theory (DFT), as implemented in, e.g., CASTEP [29] and Quantum Espresso, [30][31][32] has been shown to reproduce chemical shifts typically within a 1% accuracy of the typical chemical-shift range, representing a discrepancy of 2 ppm for 13 C relative to experiment. [28,[33][34][35][36][37][38] Solid-state NMR is complementary to other solid-state characterization methods, notably diffraction. The combination of experimental solid-state NMR and DFT calculations has been termed NMR crystallography, [7,21,24,36,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]] finding application, for example, in crystallographic refinement.…”