Broadband 1H homodecoupled NMR experiments: recent developments,methods and applications

In recent years, a great interest in the development of new broadband ¹H homonuclear decoupled techniques providing simplified J_HH multiplet patterns has emerged again in the field of small molecule NMR. The resulting highly resolved ¹H NMR spectra display resonances as collapsed singlets, therefore minimizing signal overlap and expediting spectral analysis. This review aims at presenting the most recent advances in pure shift NMR spectroscopy, with a particular emphasis to the Zangger–Sterk experiment. A detailed discussion about the most relevant practical aspects in terms of pulse sequence design, selectivity, sensitivity, spectral resolution and performance is provided. Finally, the implementation of the different reported strategies into traditional 1D and 2D NMR experiments is described while several practical applications are also reviewed. Copyright © 2015 John Wiley & Sons, Ltd.     

Band‐selective excited ultrahigh resolution PSYCHE‐TOCSY: fast screening of organic molecules and complex mixtures

Precise assignments of ¹H atomic sites and establishment of their through‐bond COSY or TOCSY connectivity are crucial for molecular structural characterization by using ¹H NMR spectroscopy. However, this exercise is often hampered by signal overlap, primarily because of ¹H–¹H scalar coupling multiplets, even at typical high magnetic fields. The recent developments in homodecoupling strategies for effectively suppressing the coupling multiplets into nice singlets (pure‐shift), particularly, Morris's advanced broadband pure‐shift yielded by chirp excitation (PSYCHE) decoupling and ultrahigh resolution PSYCHE‐TOCSY schemes, have shown new possibilities for unambiguous structural elucidation of complex organic molecules. The superior broadband PSYCHE‐TOCSY exhibits enhanced performance over the earlier TOCSY methods, which however warrants prolonged experimental times due to the requirement of large number of dwell increments along the indirect dimension. Herein, we present fast and band‐selective analog of the broadband PSYCHE‐TOCSY, which is useful for analyzing complex organic molecules that exhibit characteristic yet crowded spectral regions. The simple pulse scheme relies on band‐selective excitation (BSE) followed by PSYCHE homodecoupling in the indirect dimension. The BSE‐PSYCHE‐TOCSY has been exemplified for Estradiol and a complex carbohydrate mixture comprised of six constituents of closely comparable molecular weights. The experimental times are greatly reduced viz., ~20 fold for Estradiol and ~10 fold for carbohydrate mixture, with respect to the broadband PSYCHE‐TOCSY. Furthermore, unlike the earlier homonuclear band‐selective decoupling, the BSE‐PSYCHE‐decoupling provides fully decoupled pure‐shift spectra for all the individual chemical sites within the excited band. The BSE‐PSYCHE‐TOCSY is expected to have significant potential for quick screening of complex organic molecules and mixtures at ultrahigh resolution. Copyright © 2015 John Wiley & Sons, Ltd.     

Monitoring Conformational Changes in an Enzyme Conversion Inhibitor Using Pure Shift Exchange NMR Spectroscopy

We report the acquisition of 2D NMR EXSY spectra with ultrahigh resolution, which allows for probing the slow conformational exchange process in a pharmaceutical compound. The resolution enhancement is achieved by implementing interferogram based PSYCHE homonuclear decoupling to generate a pure shift proton spectrum along the direct domain of the resulting data. The performance of this pure shift EXSY pulse sequence is compared to the standard experiment recorded under identical conditions. It is found that although being less sensitive and requiring a longer acquisition time, the quality of pure shift spectra allows for extracting exchange rates values that are coherent with the ones determined by standard approach, on a temperature range that demonstrates the robustness of the chosen homonuclear decoupling method. The resolution enhancement provided by the simplification of proton line shape allows for probing a higher number of proton sites whose analysis would have been biased using a standard method. These results open the way to a thorough and accurate study of chemical exchange processes based on a multi-site analysis of 2D pure shift EXSY spectra     

纯位移核磁共振氢谱及其应用

J耦合引起的核磁共振(NMR)信号多重裂分的数目和耦合常数反映了磁性原子核之间的化学键数目和空间位置信息,是研究分子结构的重要依据之一.但是当分子中磁性原子核数目增加时,NMR谱图特别是一维核磁共振氢谱(1D ~1H NMR)中,J耦合所致的多重裂分造成谱图重叠,严重干扰结构指认和定量分析.利用纯位移(亦称宽带同核去耦)~1H NMR谱图可以消除J耦合效应(即将相邻质子间耦合所引起的多重裂分融合成一个单峰),得到与去耦碳谱相似的、只含化学位移信息的谱图.该文首先介绍了三种最受关注的获取纯位移核磁共振氢谱技术——BIRD、ZS和PSYCHE的基本原理,随后综述了纯位移~1H NMR谱图的典型应用.     

Synthesis of new cyano-substituted analogues of Tröger's bases from bromo-derivatives. A stereochemical dependence of long-range (nJHH,n = 4, 5, and 6) proton–proton and proton–carbon (nJCH,n = 1, 2, 3, 4, and 5) coupling constants of these compounds

A free-catalyst microwave-assisted cyanation of brominated Tröger's base derivatives ( 2a - f ) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds ( 3a - e, I ) in very good yields. Complete assignment of ¹H and ¹³C chemical shifts of 2a - f, I and 3a - d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton–proton coupling constants ⁿJ_HH (n = 4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the ¹H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and ¹H-¹⁵N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon–proton coupling constants ⁿJ_CH (n = 2, 3, and 4) and for assignment of ¹⁵N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6–311 + G(d,p) basis sets. For calculation of ¹H and ¹³C chemical shifts, ⁿJ_HH (n = 2, 3, 4, 5, and 6), and ⁿJ_CH (n = 1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range ⁿJ_HH (n = 4, 5, and 6) and ⁿJ_CH (n = 1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tröger's bases.     

Accurate measurement of JHH in overlapped signals by a TOCSY‐edited SERF Experiment

Selective refocusing (GSERF or the recent PSYCHEDELIC) experiments were originally designed to determine all proton–proton coupling constants (J_HH) for a selected proton resonance. They work for isolated signals on which selective excitation can be successfully applied but, as it happens in other selective experiments, fail for overlapped signals. To circumvent this limitation, a doubly‐selective TOCSY‐GSERF scheme is presented for the measurement of J_HH in protons resonating in crowded regions. This new experiment takes advantage of the editing features of an initial TOCSY transfer to uncover hidden resonances that become accessible to perform the subsequent frequency‐selective refocusing. Copyright © 2016 John Wiley & Sons, Ltd.     

Ultrahigh‐Resolution Diffusion‐Ordered Spectroscopy

Diffusion‐ordered spectroscopy (DOSY) is an effective method for the analysis of intact mixtures, but the quality of results is critically limited by resolution in the NMR dimension. A new experiment integrating diffusion weighting into the PSYCHE method for pure shift NMR spectroscopy allows DOSY spectra to be measured with ultrahigh NMR resolution at improved sensitivity.