Dipartimento di Chimica e Centro di Eccellenza NIS, Università di Torino, v. P. Giuria 7, 10125 Torino, Italy.
Currently at Scuola di Scienze e Tecnologie, Centro di Ricerca ChIP, Università di Camerino, v. Madonna delle Carceri, 62032 Camerino, Italy.
Molecules. 2023 Feb 16;28(4):1876. doi: 10.3390/molecules28041876.
When it comes to crystal structure determination, computational approaches such as Crystal Structure Prediction (CSP) have gained more and more attention since they offer some insight on how atoms and molecules are packed in the solid state, starting from only very basic information without diffraction data. Furthermore, it is well known that the coupling of CSP with solid-state NMR (SSNMR) greatly enhances the performance and the accuracy of the predictive method, leading to the so-called CSP-NMR crystallography (CSP-NMRX). In this paper, we present the successful application of CSP-NMRX to determine the crystal structure of three structural isomers of pyridine dicarboxylic acid, namely quinolinic, dipicolinic and dinicotinic acids, which can be in a zwitterionic form, or not, in the solid state. In a first step, mono- and bidimensional SSNMR spectra, i.e., H Magic-Angle Spinning (MAS), C and N Cross Polarisation Magic-Angle Spinning (CPMAS), H Double Quantum (DQ) MAS, H-C HETeronuclear CORrelation (HETCOR), were used to determine the correct molecular structure (i.e., zwitterionic or not) and the local molecular arrangement; at the end, the RMSEs between experimental and computed H and C chemical shifts allowed the selection of the correct predicted structure for each system. Interestingly, while quinolinic and dipicolinic acids are zwitterionic and non-zwitterionic, respectively, in the solid state, dinicotinic acid exhibits in its crystal structure a "zwitterionic-non-zwitterionic continuum state" in which the proton is shared between the carboxylic moiety and the pyridinic nitrogen. Very refined SSNMR experiments were carried out, i.e., N-H Phase-Modulated (PM) pulse and Rotational-Echo Saturation-Pulse Double-Resonance (RESPDOR), to provide an accurate N-H distance value confirming the hybrid nature of the molecule. The CSP-NMRX method showed a remarkable match between the selected structures and the experimental ones. The correct molecular input provided by SSNMR reduced the number of CSP calculations to be performed, leading to different predicted structures, while RMSEs provided an independent parameter with respect to the computed energy for the selection of the best candidate.
当涉及晶体结构测定时，计算方法，如晶体结构预测（CSP），已经得到了越来越多的关注，因为它们提供了一些关于原子和分子在固态中如何堆积的见解，只需要非常基本的信息，而无需衍射数据。此外，众所周知，将 CSP 与固态 NMR（SSNMR）相结合，可以大大提高预测方法的性能和准确性，从而产生所谓的 CSP-NMR 晶体学（CSP-NMRX）。在本文中，我们成功地将 CSP-NMRX 应用于测定吡啶二羧酸的三种结构异构体，即喹啉酸、二吡啶酸和二烟酸的晶体结构，它们可以处于两性离子形式，也可以不处于固态。在第一步中，使用单维和二维 SSNMR 谱，即 H 魔角旋转（MAS）、C 和 N 交叉极化魔角旋转（CPMAS）、H 双量子（DQ）MAS、H-C HETeronuclear CORrelation（HETCOR），来确定正确的分子结构（即两性离子或非两性离子）和局部分子排列；最后，实验和计算的 H 和 C 化学位移之间的均方根误差（RMSE）允许为每个系统选择正确的预测结构。有趣的是，虽然喹啉酸和二吡啶酸分别在固态中为两性离子和非两性离子，但是二烟酸在其晶体结构中表现出“两性离子-非两性离子连续状态”，其中质子在羧酸部分和吡啶氮之间共享。进行了非常精细的 SSNMR 实验，即 N-H 相调制（PM）脉冲和旋转回波饱和脉冲双共振（RESPDOR），以提供准确的 N-H 距离值，确认分子的混合性质。CSP-NMRX 方法显示所选结构与实验结构之间的极好匹配。SSNMR 提供的正确分子输入减少了要执行的 CSP 计算数量，从而导致不同的预测结构，而 RMSE 则提供了一个与计算能量无关的独立参数，用于选择最佳候选结构。
