The Synergy between Nuclear Magnetic Resonance and Density Functional Theory Calculations.

This paper deals with the synergy between Nuclear Magnetic Resonance (NMR) spectroscopic investigations and DFT calculations, mainly of NMR parameters. Both the liquid and the solid states are discussed here. This text is a mix of published results supplemented with new findings. This paper deals with examples in which useful results could not have been obtained without combining NMR measurements and DFT calculations. Examples of such cases are tautomeric systems in which NMR data are calculated for the tautomers; hydrogen-bonded systems in which better XH bond lengths can be determined; cage compounds for which assignment cannot be made based on NMR data alone; revison of already published structures; ionic compounds for which reference data are not available; assignment of solid-state spectra and crystal forms; and the creation of libraries for biological molecules. In addition to these literature cases, a revision of a cage structure and substituent effects on pyrroles is also discussed.

Tautomerism of pyridinylbutane-1,3-diones: An NMR and DFT study.

The three possible 1-(n-pyridinyl)butane-1,3-diones (nPM) have been synthesized. Structures, tautomerism, and conformations are investigated by means of DFT calculations. 1 H and 13 C NMR spectra are assigned, and deuterium isotope effects on 13 C chemical shifts have been measured. Analysis of the isotope effects leads to the equilibrium constants of the keto-enol tautomers. Some interesting differences are seen between the three compounds and the phenyl analogs. The isotope effects can also rank the hydrogen bonds of the compounds, with the one with nitrogen in the three positions of the pyridine ring as the weakest. Structures, conformers, energies, and NMR nuclear shieldings are calculated using DFT calculations at the B3LYP/6-311++G(d,p) level.

Steerable photonic jet for super-resolution microscopy.

A promising technique in optical super-resolution microscopy is the illumination of the sample by a highly localized beam, a photonic jet (also called photonic nanojet). We propose a method of computation of incident field amplitude and phase profiles that produce photonic jets at desired locations in the near field after interaction with a fixed micro-scale dielectric lens. We also describe a practical way of obtaining the incident field profiles using spatial light modulators. We expect our photonic jet design method to work for a wide range of lens shapes, and we demonstrate its application numerically using two-dimensional micro-lenses of circular and square cross-sections. We furthermore offer a theoretical analysis of the resolution of photonic jet design, predicting among other that a larger lens can produce a narrower photonic jet. Finally, we give both theoretical and numerical evidence that the waist width of the achieved designed jets is increasing linearly and slowly over a large interval of radial distances. With uniform plane wave illumination, the circular two-dimensional micro-lens produces a similar-sized jet at a fixed radial distance, while the square lens does not form a jet at all. We expect our steerable optical photonic jet probe to enable highly localized adaptive real-time measurements and drive advances in super-resolution optical microscopy and scatterometry, as well as fluorescence and Raman microscopy. Our relatively weak peak jet intensity allows application in biology and health sciences, which require high resolution imaging without damaging the sample bio-molecules.

Isotope Effects on Chemical Shifts in the Study of Hydrogen Bonds in Small Molecules.

This review is giving a short introduction to the techniques used to investigate isotope effects on NMR chemical shifts. The review is discussing how isotope effects on chemical shifts can be used to elucidate the importance of either intra- or intermolecular hydrogen bonding in ionic liquids, of ammonium ions in a confined space, how isotope effects can help define dimers, trimers, etc., how isotope effects can lead to structural parameters such as distances and give information about ion pairing. Tautomerism is by advantage investigated by isotope effects on chemical shifts both in symmetric and asymmetric systems. The relationship between hydrogen bond energies and two-bond deuterium isotope effects on chemical shifts is described. Finally, theoretical calculations to obtain isotope effects on chemical shifts are looked into.

The best density functional theory functional for the prediction of 1 H and 13 C chemical shifts of protonated alkylpyrroles.

The prediction of 13 C chemical shifts can be challenging with density functional theory (DFT). In this study 39 different functionals and three different basis sets were tested on three neutral alkylpyrroles and their corresponding protonated species. The calculated shielding constants were compared to experimental data and results from previous calculations at the MP2. We find that the meta-hybrid functional TPSSh with either the Pople style basis set 6-311++G(2d,p) or the polarization consistent basis set pcSseg-1 gives the best results for the 13 C chemical shifts, whereas for the 1 H chemical shifts it is the TPSSh functional with either the 6-311++G(2d,p) or pcSseg-2 basis set. Including an explicit solvent molecule hydrogen bonded to NH in the alkylpyrroles improves the results slightly for the 13 C chemical shifts. On the other hand, for 1 H chemical shifts the opposite is true. Compared to calculations at the MP2 level none of the DFT functionals can compete with MP2 for the 13 C chemical shifts but for the 1 H chemical shifts the investigated DFT functionals are shown to give better agreement with experiment than MP2 calculations.

Azo-hydrazone molecular switches: Synthesis and NMR conformational investigation.

A series of five intramolecularly hydrogen-bonded arylhydrazone (aryl = phenol, p-nitrophenol, anisole, quinoline) derived molecular switches have been synthesized and characterized by NMR and HRMS techniques. It was found that the compounds exist as different isomers in solution. An investigation of both conformational and/or configurational changes of the azo-hydrazone compounds was carried out by 1D 1 H- and 13 C- spectra, 2D NOESY, COSY, HSQC, and HMBC techniques. It was found that these stimuli-responsive molecular switches exist mainly in the E form by intramolecularly hydrogen bonded between NH and the pyridine nitrogen at equilibrium. Deprotonation of the neutral E form yields the E' deprotonated isomer. Prediction of 13 C-NMR chemical shifts was achieved by DFT quantum mechanical calculations. Anions have traditionally been difficult to calculate correctly, so calculations of the anion using different functionals, basis sets, and solvent effects are also included. Deuterium isotope effects on the 13 C-NMR chemical shifts were employed in the assignments and furthermore utilized as indicators of intramolecular hydrogen bonding. Studies in various organic solvents including CDCl3 , CD3 CN, and DMSO-d6 were also performed aiming to monitor dynamic changes over several days. The effect of the hydrogen bonded solvents leads to Z forms.

A Spectroscopic Overview of Intramolecular Hydrogen Bonds of NH O,S,N Type.

Intramolecular NH…O,S,N interactions in non-tautomeric systems are reviewed in a broad range of compounds covering a variety of NH donors and hydrogen bond acceptors. 1H chemical shifts of NH donors are good tools to study intramolecular hydrogen bonding. However in some cases they have to be corrected for ring current effects. Deuterium isotope effects on 13C and 15N chemical shifts and primary isotope effects are usually used to judge the strength of hydrogen bonds. Primary isotope effects are investigated in a new range of magnitudes. Isotope ratios of NH stretching frequencies, νNH/ND, are revisited. Hydrogen bond energies are reviewed and two-bond deuterium isotope effects on 13C chemical shifts are investigated as a possible means of estimating hydrogen bond energies.

NMR of Natural Products as Potential Drugs.

This review outlines methods to investigate the structure of natural products with emphasis on intramolecular hydrogen bonding, tautomerism and ionic structures using NMR techniques. The focus is on 1H chemical shifts, isotope effects on chemical shifts and diffusion ordered spectroscopy. In addition, density functional theory calculations are performed to support NMR results. The review demonstrates how hydrogen bonding may lead to specific structures and how chemical equilibria, as well as tautomeric equilibria and ionic structures, can be detected. All these features are important for biological activity and a prerequisite for correct docking experiments and future use as drugs.

NH Stretching Frequencies of Intramolecularly Hydrogen-Bonded Systems: An Experimental and Theoretical Study.

The vibrational NH stretching transitions in secondary amines with intramolecular NH···O hydrogen bonds were investigated by experimental and theoretical methods, considering a large number of compounds and covering a wide range of stretching wavenumbers. The assignment of the NH stretching transitions in the experimental IR spectra was, in several instances, supported by measurement of the corresponding ND wavenumbers and by correlation with the observed NH proton chemical shifts. The observed wavenumbers were correlated with theoretical wavenumbers predicted with B3LYP density functional theory, using the basis sets 6-311++G(d,p) and 6-31G(d) and considering the harmonic as well as the anharmonic VPT2 approximation. Excellent correlations were established between observed wavenumbers and calculated harmonic values. However, the correlations were non-linear, in contrast to the results of previous investigations of the corresponding OH···O systems. The anharmonic VPT2 wavenumbers were found to be linearly related to the corresponding harmonic values. The results provide correlation equations for the prediction of NH stretching bands on the basis of standard B3LYP/6-311++G(d,p) and B3LYP/6-31G(d) harmonic analyses, with standard deviations close to 38 cm-1. This is significant because the full anharmonic VPT2 analysis tends to be impractical for large molecules, requiring orders of magnitude more computing time than the harmonic analysis.

One-bond 1 J(15 N,H) coupling constants at sp2 -hybridized nitrogen of Schiff bases, enaminones and similar compounds: A theoretical study.

1 J(15 N,H) coupling constants for enaminones and NH-forms of intramolecularly hydrogen-bonded Schiff bases as model compounds for sp2 -hybridized nitrogen atoms are evaluated using density functional theory (DFT) to find the optimal functionals and basis sets. Ammonia is used as a test molecule and its one-bond coupling constant is compared with experiment. A methylamine Schiff base of a truncated molecule of gossypol is used for checking the performance of selected B3LYP, O3LYP, PBE, BHandH, and APFD density functionals and standard, modified, and dedicated basis sets for coupling constants. Both in vacuum and in chloroform, modeled by the simple continuum model of solvent, the modified basis sets predict significantly better the 1 J(15 N,H) value in ammonia and in the methylamine Schiff base of a truncated molecule of gossypol than the standard basis sets. This procure is then used on a broad set of intramolecularly hydrogen-bonded molecules, and a good correlation between calculated and experimental one-bond NH coupling constants is obtained. The 1 J(15 N,H) couplings are slightly overestimated. The calculated data show for hydrogen-bonded NH interatomic distances that the calculated values depend on the NH bond lengths. The shorter the bond lengths, the larger the 1 J(15 N,H). A useful correlation between 1 J(15 N,H) and NH bond length is derived that enables realistic predictions of one-bond NH coupling constants. The calculations reproduce experimentally observed trends for the studied molecules.

Strong intramolecular hydrogen bonds and steric effects involving C═S groups: An NMR and computational study.

A number of 5-acyl rhodanines and thiorhodanines with bulky acyl groups (pivaloyl and adamantoyl), not previously available, have been synthesized. The compounds are shown to exist in the enol form. Structures have been calculated using both the MP2 approach and the B3LYP-GD3BJ functional and the 6-311++G(d,p) basis set. Hydrogen bond energies are estimated by subtracting energies of a structure with the OH group turned 180° from those of the intramolecularly hydrogen-bonded one. Properties such as OH chemical shifts, two-bond isotope effects on 13 C chemical shifts, electron densities at the bond critical point from atoms in molecules analysis, and the hydrogen bond energies show that the sterically hindered compounds have stronger hydrogen bonds than methyl or isopropyl derivatives. The combination of oxygen and sulfur derivatives enables a detailed analysis of hydrogen bond energies.

Computational Prediction of 1 H and 13 C NMR Chemical Shifts for Protonated Alkylpyrroles: Electron Correlation and Not Solvation is the Salvation.

Prediction of chemical shifts in organic cations is known to be a challenge. In this article we meet this challenge for α-protonated alkylpyrroles, a class of compounds not yet studied in this context, and present a combined experimental and theoretical study of the 13 C and 1 H chemical shifts in three selected pyrroles. We have investigated the importance of the solvation model, basis set, and quantum chemical method with the goal of developing a simple computational protocol, which allows prediction of 13 C and 1 H chemical shifts with sufficient accuracy for identifying such compounds in mixtures. We find that density functional theory with the B3LYP functional is not sufficient for reproducing all 13 C chemical shifts, whereas already the simplest correlated wave function model, Møller-Plesset perturbation theory (MP2), leads to almost perfect agreement with the experimental data. Treatment of solvent effects generally improves the agreement with experiment to some extent and can in most cases be accomplished by a simple polarizable continuum model. The only exception is the NH proton, which requires inclusion of explicit solvent molecules in the calculation.

Intramolecular Hydrogen Bonds in Normal and Sterically Compressed o-Hydroxy Aromatic Aldehydes. Isotope Effects on Chemical Shifts and Hydrogen Bond Strength.

A number of o-hydroxy aromatic aldehydes have been synthesized to illustrate the effect of steric compression and O···O distances on the intramolecular hydrogen bond and the hydrogen bond energies. Hydrogen bond energies have been calculated using the 'hb and out' method using either the MP2 method or the B3LYP functional with the basis set 6-311++G(d,p). However, several compounds cannot be treated this way. Hydrogen bond energies are also determined using electron densities at bond critical points and these results are in good agreement with the results of the 'hb and out' model. Two-bond deuterium isotope effects on 13C chemical shifts are suggested as an experimental way to obtain information on hydrogen bond energies as they easily can be measured. Isotope effects on aldehyde proton chemical shifts have also been measured. The former show very good correlation with the hydrogen bond energies and the latter are related to short O···O distances. Short O···O distances can be obtained as the result of short C=C bond lengths, conjugative effects, and steric compression of the aldehyde group. Short O···O distances are in general related to high hydrogen bond energies in these intramolecularly hydrogen-bonded systems of resonance assisted hydrogen bond (RAHB) type.

Replacing libraries in scatterometry.

Diffraction gratings have a wide array of applications in optics, diagnostics, food science, sensing, and process inspection. Scattering effects from defects can severely degrade the performance of such gratings. In this paper, we consider three classes of defects: Two classes introduced at the grating/air interface, as a change in line heights, and one class introduced as a sinusoidal variation of the grating/substrate interface. The scattering properties of the gratings are modelled using rigorous coupled wave analysis, and defects are approximated with a new semi-analytical model and a neural network. The new methods make it possible to avoid the time consuming library generation/search strategy commonly used in scatterometry. The method does not introduce new numerical parameters, and therefore no new parameter correlations. This work enables improved grating reconstruction, especially of non-diffracting short pitch gratings. It is found that two of the defect classes can be adequately described by the semi-analytical model, while the third defect is accurately reconstructed by a neural network. The network is demonstrated to be faster than a library search and more versatile for related structures.

NMR, MP2, and DFT study of thiophenoxyketenimines (o-thio-Schiff bases): Determination of the preferred form.

Five new thiophenoxyketinimines have been synthesized. 1 H and 13 C NMR spectra as well as deuterium isotope effects on 13 C chemical shifts are determined, and spectra are assigned. DFT and MP2 calculations of both structures, chemical shifts, and isotope effects on chemical shifts are done. The combined analysis reveals that the compounds are primarily on a zwitterionic form with an NH+ and a S- group and with a little of the neutral form mixed in. Very strong intramolecular hydrogen bonding is found and very high NH chemical shifts are observed. The theoretical calculations show that calculations at the MP2 level are best to obtain correct "C═S" chemical shifts.

Structure of a new usnic acid derivative from a deacylating Mannich reaction: NMR studies supported by theoretical calculations of chemical shifts.

In a conventional Mannich reaction using piperidine, hydroxypiperidines, morpholine, and N-methylpiperazine with usnic acid, a deacetylation was observed resulting in a substitution at C-2, a loss of an acetyl group, and a Mannich base with a stabilized enol. The enol has a hydrogen bond to the nitrogen of the secondary amine. The structure was investigated by nuclear magnetic resonance and deuterium isotope effects on 13 C chemical shifts as well as with density functional theory calculations to study the changed hydrogen bond pattern. It was found that the hydrogen bond involving the OH-9 group in chloroform forms a strong hydrogen bond than in usnic acid itself and that this hydrogen bond becomes even stronger in the more polar solvent, dimethylsulfoxide. Tautomerism was observed in the Mannich base as demonstrated by deuterium isotope effects on chemical shifts. The position of the tautomeric equilibrium depends on the solvent, and the position of the equilibrium governs the strength of the OH-9…O═C hydrogen bond.

NMR and IR Investigations of Strong Intramolecular Hydrogen Bonds.

For the purpose of this review, strong hydrogen bonds have been defined on the basis of experimental data, such as OH stretching wavenumbers, νOH, and OH chemical shifts, δOH (in the latter case, after correction for ring current effects). Limits for O-H···Y systems are taken as 2800 > νOH > 1800 cm-1, and 19 ppm > δOH > 15 ppm. Recent results as well as an account of theoretical advances are presented for a series of important classes of compounds such as ß-diketone enols, ß-thioxoketone enols, Mannich bases, proton sponges, quinoline N-oxides and diacid anions. The O···O distance has long been used as a parameter for hydrogen bond strength in O-H···O systems. On a broad scale, a correlation between OH stretching wavenumbers and O···O distances is observed, as demonstrated experimentally as well as theoretically, but for substituted ß-diketone enols this correlation is relatively weak.

Imaging scatterometry for flexible measurements of patterned areas.

Characterization of micro/nano-textured surfaces is time consuming using scanning probe and electron microscopy techniques. Scatterometry, where the intensity of scattered light is used as a 'fingerprint' to reconstruct a surface, is a fast and robust method for characterization of gratings. However, most scatterometry techniques are measuring the averaged signal over an area equal to the spot size of the light source. In this paper we present the imaging scatterometry technique, which is capable of locally measuring topographic parameters of gratings spanning an area down to a few µm(2) with nm accuracy. The imaging scatterometer can easily find areas of interest on the cm scale and measure multiple segments simultaneously. We demonstrate two imaging scatterometers, one built into an optical microscope and one in a split configuration. The two scatterometers are targeted characterization of mm(2) and cm(2) areas, respectively, and both setups are validated using nano-textured samples.

Alignment-free characterization of 2D gratings.

Fast characterization of 2D gratings is demonstrated using a Fourier lens optical system and a differential optimization algorithm. It is shown that the grating-specific parameters such as the basis vectors and the angle between them, along with the alignment of the sample, such as the rotation of the sample around the x, y, and z axis, can be deduced from a single measurement. More specifically, the lattice vectors and the angle between them have been measured, while the corrections of the alignment parameters are used to improve the quality of the measurement and, hence, reduce the measurement uncertainty. Alignment-free characterization is demonstrated on a 2D hexagonal grating with a period of 700 nm and a checkerboard grating with a pitch of 3000 nm. The method also can be used for automatic alignment and in-line characterization of gratings.

Chemical constituents from Sonneratia ovata Backer and their in vitro cytotoxicity and acetylcholinesterase inhibitory activities.

Sonneratia ovata Backer, Sonneratiaceae, is a widespread plant in mangrove forests in Vietnam, Cambodia, Thailand, Indonesia. Sonneratia ovata's chemical composition remains mostly unknown. Therefore, we now report on the structural elucidation of three new phenolics, sonnerphenolic A (1), sonnerphenolic B (2), and sonnerphenolic C (23), a new cerebroside, sonnercerebroside (3) together with nineteen known compounds, including nine lignans (5-13), two steroids (14, 15), two triterpenoids (16, 17), three gallic acid derivatives (18-20), two phenolic derivatives (4, 22) and a 1-O-benzyl-ß-d-glucopyranose (21) isolated from the leaves of Sonneratia ovata. Their chemical structures were established by spectroscopic data, as well as high resolution mass spectra and comparison with literature data. The in vitro acetylcholinesterase (AChE) inhibition and cytotoxic activities against HeLa (human epithelial carcinoma), NCI-H460 (human lung cancer), MCF-7 (human breast cancer) cancer cell lines and PHF (primary human fibroblast) cell were evaluated on some extracts and purified compounds at a concentration of 100 µg/mL. Compounds (5, 6, 23) exhibited cytotoxicity against the MCF-7 cell line with the IC50 values of 146.9±9.0, 114.5±7.2, and 112.8±9.4 µM, respectively, while they showed nontoxic with the normal cell (PHF) with IC50s >277 µM. Among 15 tested compounds, (S)-rhodolatouchol (22) showed inhibition against AChE with an IC50 value of 96.1±14.5 µM.