A One-Dimensional Phase-Modulated (PM) NMR Experiment for Differentiating Spin Systems in Small Molecules Mixtures: With Application to Chiral Discrimination and Bicomponent Organic Systems.

A one-dimensional phase-modulated NMR experiment, which distinguishes the partially resolved peaks and accelerates the data acquisition due to reduced dimensionality, is reported for differentiating spin systems, with application to chiral discrimination. The multifarious utility of the technique is demonstrated in plenteous examples.

Correction: Mishra, S.K. and Suryaprakash, N. Intramolecular Hydrogen Bonding Involving Organic Fluorine: NMR Investigations Corroborated by DFT-Based Theoretical Calculations: Molecules 2017, 22, 423.

The authors wish to make the following corrections to their paper [...].

Intramolecular HB Interactions Evidenced in Dibenzoyl Oxalamide Derivatives: NMR, QTAIM, and NCI Studies.

Extensive NMR spectroscopic studies revealed information on the occurrence of bifurcated intramolecular hydrogen bond in the dibenzoyl oxalamide derivatives. One-dimensional NMR experiments, viz., solvent dilution, temperature perturbation, and two-dimensional experimental techniques, such as 15N-1H HSQC and 19F-1H HOESY, have been exploited to derive unambiguous confirmation of the participation of organic fluorine in the hydrogen-bonding interaction. The experimental NMR findings have been ratified by density functional theory based calculations, viz., NCI (noncovalent interaction) and QTAIM (quantum theory of atoms in molecules).

Intramolecular Hydrogen Bonding Appetency for Conformational Penchants in Oxalohydrazide Fluoro Derivatives: NMR, MD, QTAIM, and NCI Studies.

The conformational stability of synthesized diphenyloxalohydrazide and dibenzoyloxalohydrazide fluoro derivatives has been investigated by extensive NMR studies that are ascertained by various levels of theoretical calculations. Two-dimensional 1H-19F HOESY NMR experiments revealed the close spatial proximity between two NMR-active nuclei, confirming the hydrogen bond (HB)-mediated interaction between them, further aiding in establishing the probable stable conformations of these molecules. The relaxed potential energy scan disclosed the energy-minimized most stable structure among the several possible multiple conformations, which is in concurrence with NMR interpretations. Atomistic molecular dynamics simulations have been employed to unequivocally establish the conformational stability and the nature of HB formation at varied temperatures. With the possibility of occurrence of a number of probable conformations, the percentage of occurrences of different types of HBs in them was determined by MD simulations. Their population analysis was carried out using a Boltzmann distribution, in addition to deriving their Gibbs free energies. The molecular interactions governing the stable conformations have not only been ascertained by experimental NMR interpretations but also corroborated by other theoretical computations, viz., quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI).

Orchestrated approaches using pure shift NMR: Extraction of spectral parameters, ultra-high resolution, and sensitivity enhancement.

The limited chemical shift range of protons and pairwise interaction among all the abundant nuclear spins of a molecule makes 1 H spectrum too complicated. As a consequence, the straightforward analysis and the accurate extraction of their interaction strengths from the 1 H spectrum of a complex spin system are formidably difficult or often impossible. This problem persists in the determination of scalar couplings be it between two abundant homonuclear spins or between 1 H and an abundant heteronuclear spin (viz., 19 F and 31 P). Such problems are encountered in many situations where the determination of homonuclear and heteronuclear couplings is challenging. The several pure shift based one-dimensional and two-dimensional NMR strategies recently developed in our laboratory for the straightforward extraction of homonuclear and heteronuclear interaction parameters in diverse situations are discussed. Initially, the unique application of pure shift technique that paves the way for easy and straightforward extraction of magnitudes of heteronuclear couplings, namely, n JHX (where X stands for 19 F, 31 P, etc.), is discussed. Subsequently, several pure shift edited one-dimensional and two-dimensional NMR strategies that are developed for the direct extraction of homonuclear and heteronuclear couplings and for achieving ultra-high-resolved 1 H spectra with complete eradication of zero frequency peaks and the evolution of unwanted couplings. The enhancement in the sensitivity has also been achieved in the slice-selective pure shift experiments by the rapid acquisition of proton spectrum where the polarization from the adjacent protons is transferred to the selectively excited proton.

Intramolecular Hydrogen Bonding Involving Organic Fluorine: NMR Investigations Corroborated by DFT-Based Theoretical Calculations.

The combined utility of many one and two dimensional NMR methodologies and DFT-based theoretical calculations have been exploited to detect the intramolecular hydrogen bond (HB) in number of different organic fluorine-containing derivatives of molecules, viz. benzanilides, hydrazides, imides, benzamides, and diphenyloxamides. The existence of two and three centered hydrogen bonds has been convincingly established in the investigated molecules. The NMR spectral parameters, viz., coupling mediated through hydrogen bond, one-bond NH scalar couplings, physical parameter dependent variation of chemical shifts of NH protons have paved the way for understanding the presence of hydrogen bond involving organic fluorine in all the investigated molecules. The experimental NMR findings are further corroborated by DFT-based theoretical calculations including NCI, QTAIM, MD simulations and NBO analysis. The monitoring of H/D exchange with NMR spectroscopy established the effect of intramolecular HB and the influence of electronegativity of various substituents on the chemical kinetics in the number of organic building blocks. The utility of DQ-SQ technique in determining the information about HB in various fluorine substituted molecules has been convincingly established.

Two- and Three-Centered Hydrogen Bonds Involving Organic Fluorine Stabilize Conformations of Hydrazide Halo Derivatives: NMR, IR, QTAIM, NCI, and Theoretical Evidence.

The presence of two- and three-centered hydrogen bonds (HB) of the type H(N)···X-C and C═O···H(N)···X-C, respectively, involving organic fluorine in the synthesized hydrazide halo derivatives have been convincingly established by extensive multidimensional NMR studies. The stabilized conformation of the molecules involving two- and three-centered HBs derived by NMR studies have been further confirmed by density functional theory (DFT)-based calculations, such as quantum theory of atoms in molecules (QTAIM), noncovalent interaction (NCI), and relaxed potential energy scan.

J-edited pure shift NMR for the facile measurement of (n)J(HH) for specific protons.

We report a novel 1D J-edited pure shift NMR experiment (J-PSHIFT) that was constructed from a pseudo 2D experiment for the direct measurement of proton-proton scalar couplings. The experiment gives homonuclear broad-band (1)H-decoupled (1)H NMR spectra, which provide a single peak for chemically distinct protons, and only retain the homonuclear-scalar-coupled doublet pattern at the chemical-shift positions of the protons in the coupled network of a specific proton. This permits the direct and unambiguous measurement of the magnitudes of the couplings. The incorporation of a 1D selective correlation spectroscopy (COSY)/ total correlation spectroscopy (TOCSY) block in lieu of the initial selective pulse, results in the exclusive detection of the correlated spectrum of a specific proton.

RNA nucleosides as chiral sensing agents in NMR spectroscopy.

The study reports chiral sensing properties of RNA nucleosides. Adenosine, guanosine, uridine and cytidine are used as chiral derivatizing agents to differentiate chiral 1°-amines. A three component protocol has been adopted for complexation of nucleosides and amines. The chiral differentiating ability of nucleosides is examined for different amines based on the (1)H NMR chemical shift differences of diastereomers (Δδ(R,S)). Enantiomeric differentiation has been observed at multiple chemically distinct proton sites. Adenosine and guanosine exhibit large chiral differentiation (Δδ(R,S)) due to the presence of a purine ring. The diastereomeric excess (de) measured by using adenosine is in good agreement with the gravimetric values.

Intramolecular hydrogen bonds involving organic fluorine in the derivatives of hydrazides: an NMR investigation substantiated by DFT based theoretical calculations.

The rare examples of intramolecular hydrogen bonds (HB) of the type the N-H∙∙∙F-C, detected in a low polarity solvent in the derivatives of hydrazides, by utilizing one and two-dimensional solution state multinuclear NMR techniques, are reported. The observation of through-space couplings, such as, (1h)JFH, and (1h)JFN, provides direct evidence for the existence of intra-molecular HB. Solvent induced perturbations and the variable temperature NMR experiments unambiguously establish the presence of intramolecular HB. The existence of multiple conformers in some of the investigated molecules is also revealed by two dimensional HOESY and (15)N-(1)H HSQC experiments. The (1)H DOSY experimental results discard any possibility of self or cross dimerization of the molecules. The derived NMR experimental results are further substantiated by Density Function Theory (DFT) based Non Covalent Interaction (NCI), and Quantum Theory of Atom in Molecule (QTAIM) calculations. The NCI calculations served as a very sensitive tool for detection of non-covalent interactions and also confirm the presence of bifurcated HBs.

Three centered hydrogen bonds of the type C=O···H(N)···X-C in diphenyloxamide derivatives involving halogens and a rotating CF3 group: NMR, QTAIM, NCI and NBO studies.

The existence of three centered C=O···H(N)···X-C hydrogen bonds (H-bonds) involving organic fluorine and other halogens in diphenyloxamide derivatives has been explored by NMR spectroscopy and quantum theoretical studies. The three centered H-bond with the participation of a rotating CF3 group and the F···H-N intramolecular hydrogen bonds, a rare observation of its kind in organofluorine compounds, has been detected. It is also unambiguously established by a number of one and two dimensional NMR experiments, such as temperature perturbation, solvent titration, (15)N-(1)H HSQC, and (19)F-(1)H HOESY, and is also confirmed by theoretical calculations, such as quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) and non-covalent interaction (NCI).

RES-TOCSY: a simple approach to resolve overlapped ¹H NMR spectra of enantiomers.

Chiral auxiliaries are used for the NMR spectroscopic study of enantiomers. Often the presence of impurities, overlap of peaks, line broadening and the multiplicity pattern restrict the chiral analysis in the 1D (1)H NMR spectrum. The present study introduces a simple 2D (1)H NMR experiment to unravel the overlapped spectrum. The experiment separates the spectra of enantiomers, thereby allowing the unambiguous assignment of all the coupled peaks and the measurement of enantiomeric excess (ee) from a single experiment even in combinatorial mixtures.

In situ approach for testing the enantiopurity of chiral amines and amino alcohols by 1H NMR.

An in situ approach involving a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, chiral amino alcohols, by (1)H-NMR spectroscopy is developed. The protocol involves the in situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept was demonstrated convincingly on a large number of chiral and pro-chiral amines and amino alcohols, and also aids the precise measurement of enantiomeric excess. The protocol can be completed in a couple of minutes directly in the NMR sample tube, without the need for any physical separation.

"On-the-fly" kinetics of enzymatic racemization using deuterium NMR in DNA-based chiral oriented media.

We report the in situ and real-time monitoring of the interconversion of L- and D-alanine-d3 by alanine racemase from Bacillus stearothermophilus directly observed by (2)H NMR spectroscopy in anisotropic phase. The enantiomers are distinguished by the difference of their (2)H quadrupolar splittings in a chiral liquid crystal containing short DNA fragments. The proof-of-principle, the reliability, and the robustness of this new method is demonstrated by the determination of the turnover rates of the enzyme using the Michaelis-Menten model.

Discrimination of α-amino acids using green tea flavonoid (-)-epigallocatechin gallate as a chiral solvating agent.

We report a special, hitherto-unexplored property of (-)-epigallocatechin gallate (EGCG) as a chiral solvating agent for enantiodiscrimination of α-amino acids in the polar solvent DMSO. This phenomenon has been investigated by (1)H NMR spectroscopy. The mechanism of the interaction property of EGCG with α-amino acids has been understood as arising out of hydrogen-bonded noncovalent interactions, where the -OH groups of two phenyl rings of EGCG play dominant roles. The conversion of the enantiomeric mixture into diastereomers yielded well-resolved peaks for D and L amino acids permitting the precise measurement of enantiomeric composition. Often one encounters complex situations when the spectra are severely overlapped or partially resolved hampering the testing of enantiopurity and the precise measurement of enantiomeric excess (ee). Though higher concentration of EGCG yielded better discrimination, the use of lower concentration being economical, we have exploited an appropriate 2D NMR experiment in overcoming such problems. Thus, in the present study we have successfully demonstrated the utility of the bioflavonoid (-)-EGCG, a natural product as a chiral solvating agent for the discrimination of large number of α-amino acids in a polar solvent DMSO. Another significant advantage of this new chiral sensing agent is that it is a natural product and does not require tedious multistep synthesis unlike many other chiral auxiliaries.

Pure shift edited NMR methodologies for the extraction of Homo- and heteronuclear couplings with ultra-high resolution.

The scalar couplings that result in the splitting of the signals in the NMR spectrum arise due to the interaction of the nuclear spins, whereby the spin polarization is transmitted through chemical bonds. The interaction strengths depend inter alia on the number of consecutive chemical bonds intervening between the two interacting spins and on the molecular conformation. The pairwise interaction of many spins in a molecule resulting in a complex spectrum poses a severe challenge to analyse the spectrum and hence the determination of magnitudes and signs of homo- and heteronuclear couplings. The problem is more severe in the analysis of 1H spectra than the spectra of most of the other nuclei due to the often very small chemical shift dispersion. As a consequence, the straightforward analysis and the accurate extraction of the coupling constants from the 1H spectrum of a complex spin system continues to remain a challenge, and often may be a formidable task. Over the years, the several pure shift-based one-dimensional and two-dimensional methodologies have been developed by workers in the field, which provide broadband homonuclear decoupling of proton spectra, removing the complexity but at the cost of the very informative scalar couplings. To circumvent this problem, several one-dimensional and two-dimensional NMR experiments have been developed for the determination of homonuclear and heteronuclear couplings (nJHX, where n = 1,2,3) while retaining the high resolution obtained by implementing pure shift strategies. This review attempts to summarize the extensive work reported by a large number of researchers over the years for the accurate determination of homo- and heteronuclear scalar couplings.

Self-assembly of folic acid: a chiral-aligning medium for enantiodiscrimination of organic molecules in an aqueous environment.

Weak orienting medium: Self-assembly of alkaline salt of folic acid yielded a weak liquid-crystalline phase in an aqueous environment. This medium has the ability to discriminate enantiomers. The mesophase exists over a broad range and has the physical parameter dependent tunability of degree of alignment (see scheme).

Three-component chiral derivatizing protocols for NMR spectroscopic enantiodiscrimination of hydroxy acids and primary amines.

The novel three-component chiral derivatization protocols have been derived for (1)H and (19)F NMR spectroscopic discrimination of a series of chiral hydroxy acids by their coordination and self-assembly with optically active α-methylbenzylamine and 2-formylphenylboronic acid. In addition, the optically pure (S)-mandelic acid in combination with 2-formylphenylboronic acid permits visualization of enantiomers of primary amines. These protocols have been demonstrated on enantiodiscrimination of chiral amines and hydroxy acids.

Simple and efficient methods for discrimination of chiral diacids and chiral alpha-methyl amines.

The three-component chiral derivatization protocols have been developed for (1)H, (13)C and (19)F NMR spectroscopic discrimination of chiral diacids by their coordination and self-assembly with optically active (R)-α-methylbenzylamine and 2-formylphenylboronic acid or 3-fluoro-2-formylmethylboronic acid. These protocols yield a mixture of diastereomeric imino-boronate esters which are identified by the well-resolved diastereotopic peaks with significant chemical shift differences ranging up to 0.6 and 2.1 ppm in their corresponding (1)H and (19)F NMR spectra, without any racemization or kinetic resolution, thereby enabling the determination of enantiopurity. A protocol has also been developed for discrimination of chiral alpha-methyl amines, using optically pure trans-1,2-cyclohexanedicarboxylic acid in combination with 2-formylphenylboronic acid or 3-fluoro-2-fluoromethylboronic acid. The proposed strategies have been demonstrated on large number of chiral diacids and chiral alpha-methyl amines.

Competing HB acceptors: an extensive NMR investigations corroborated by single crystal XRD and DFT calculations.

A series of N-benzoylanthranilamide derivatives have been synthesized with the substitution of competitive HB acceptors and investigated by NMR spectroscopy and single crystal XRD. The interesting rivalry for HB acceptance between [double bond splayed left]C[double bond, length as m-dash]O and X (F or OMe) is observed in the investigated molecules which leads to an unusual increase in the electron density at the site of one of the NH protons, reflecting in the high field resonance in the 1H NMR spectrum. The NMR experimental findings and single crystal XRD are further reinforced by the DFT studies.