Development of a Six-Degree-of-Freedom Analog 3D Tactile Probe Based on Non-Contact 2D Sensors.

In this paper, a six-degree-of-freedom analog tactile probe with a new, simple, and robust mechanical design is presented. Its design is based on the use of one elastomeric ring that supports the stylus carrier and allows its movement inside a cubic measuring range of ±3 mm. The position of the probe tip is determined by three low-cost, noncontact, 2D PSD (position-sensitive detector) sensors, facilitating a wider application of this probe to different measuring systems compared to commercial ones. However, several software corrections, regarding the size and orientation of the three LED light beams, must be carried out when using these 2D sensors for this application due to the lack of additional focusing or collimating lenses and the very wide measuring range. The development process, simulation results, correction models, experimental tests, and calibration of this probe are presented. The results demonstrate high repeatability along the X-, Y-, and Z-axes (2.0 µm, 2.0 µm, and 2.1 µm, respectively) and overall accuracies of 6.7 µm, 7.0 µm, and 8.0 µm, respectively, which could be minimized by more complex correction models.

Weak Intermolecular CH···N Hydrogen Bonding: Determination of 13CH-15N Hydrogen-Bond Mediated J Couplings by Solid-State NMR Spectroscopy and First-Principles Calculations.

Weak hydrogen bonds are increasingly hypothesized to play key roles in a wide range of chemistry from catalysis to gelation to polymer structure. Here, 15N/13C spin-echo magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) experiments are applied to "view" intermolecular CH···N hydrogen bonding in two selectively labeled organic compounds, 4-[15N] cyano-4'-[13C2] ethynylbiphenyl (1) and [15N3,13C6]-2,4,6-triethynyl-1,3,5-triazine (2). The synthesis of 2-15N3,13C6 is reported here for the first time via a multistep procedure, where the key element is the reaction of [15N3]-2,4,6-trichloro-1,3,5-triazine (5) with [13C2]-[(trimethylsilyl)ethynyl]zinc chloride (8) to afford its immediate precursor [15N3,13C6]-2,4,6-tris[(trimethylsilyl)ethynyl]-1,3,5-triazine (9). Experimentally determined hydrogen-bond-mediated 2hJCN couplings (4.7 ± 0.4 Hz (1) and 4.1 ± 0.3 Hz (2)) are compared with density functional theory (DFT) gauge-including projector augmented wave (GIPAW) calculations, whereby species-independent coupling values 2hKCN (29.0 × 1019 kg m-2 s-2 A-2 (1) and 27.9 × 1019 kg m-2 s-2 A-2 (2)) quantitatively demonstrate the J couplings for these "weak" CH···N hydrogen bonds to be of a similar magnitude to those for conventionally observed NH···O hydrogen-bonding interactions in uracil (2hKNO: 28.1 and 36.8 × 1019 kg m-2 s-2 A-2). Moreover, the GIPAW calculations show a clear correlation between increasing 2hJCN (and 3hJCN) coupling and reducing C(H)···N and H···N hydrogen-bonding distances, with the Fermi contact term accounting for at least 98% of the isotropic 2hJCN coupling.

A GIPAW versus GIAO-ZORA-SO study of 13C and 15N CPMAS NMR chemical shifts of aromatic and heterocyclic bromo derivatives.

Theoretical simulation of NMR parameters in compounds bearing heavy atoms generally requires the application of relativistic corrections. We report herein the theoretical characterization of 13C and 15N CPMAS NMR of known bromo-derivative crystals by using both the GIPAW and the combined GIAO-ZORA-SO approximation methods. Several statistical analyses were performed to compare both approaches, with non-relativistic GIPAW method being more useful to predict the 13C and 15N chemical shifts. The problem of applying GIPAW to crystal structures showing static or dynamic crystalline disorder of the special class resulting in half-protons will be discussed in detail.

Experimental Approach for the Uncertainty Assessment of 3D Complex Geometry Dimensional Measurements Using Computed Tomography at the mm and Sub-mm Scales.

The dimensional verification of miniaturized components with 3D complex geometries is particularly challenging. Computed Tomography (CT) can represent a suitable alternative solution to micro metrology tools based on optical and tactile techniques. However, the establishment of CT systems' traceability when measuring 3D complex geometries is still an open issue. In this work, an alternative method for the measurement uncertainty assessment of 3D complex geometries by using CT is presented. The method is based on the micro-CT system Maximum Permissible Error (MPE) estimation, determined experimentally by using several calibrated reference artefacts. The main advantage of the presented method is that a previous calibration of the component by a more accurate Coordinate Measuring System (CMS) is not needed. In fact, such CMS would still hold all the typical limitations of optical and tactile techniques, particularly when measuring miniaturized components with complex 3D geometries and their inability to measure inner parts. To validate the presented method, the most accepted standard currently available for CT sensors, the Verein Deutscher Ingenieure/Verband Deutscher Elektrotechniker (VDI/VDE) guideline 2630-2.1 is applied. Considering the high number of influence factors in CT and their impact on the measuring result, two different techniques for surface extraction are also considered to obtain a realistic determination of the influence of data processing on uncertainty. The uncertainty assessment of a workpiece used for micro mechanical material testing is firstly used to confirm the method, due to its feasible calibration by an optical CMS. Secondly, the measurement of a miniaturized dental file with 3D complex geometry is carried out. The estimated uncertainties are eventually compared with the component's calibration and the micro manufacturing tolerances to demonstrate the suitability of the presented CT calibration procedure. The 2U/T ratios resulting from the validation workpiece are, respectively, 0.27 (VDI) and 0.35 (MPE), by assuring tolerances in the range of ± 20-30 µm. For the dental file, the EN < 1 value analysis is favorable in the majority of the cases (70.4%) and 2U/T is equal to 0.31 for sub-mm measurands (L < 1 mm and tolerance intervals of ± 40-80 µm).

Geometrical Characterisation of a 2D Laser System and Calibration of a Cross-Grid Encoder by Means of a Self-Calibration Methodology.

This article presents a self-calibration procedure and the experimental results for the geometrical characterisation of a 2D laser system operating along a large working range (50 mm × 50 mm) with submicrometre uncertainty. Its purpose is to correct the geometric errors of the 2D laser system setup generated when positioning the two laser heads and the plane mirrors used as reflectors. The non-calibrated artefact used in this procedure is a commercial grid encoder that is also a measuring instrument. Therefore, the self-calibration procedure also allows the determination of the geometrical errors of the grid encoder, including its squareness error. The precision of the proposed algorithm is tested using virtual data. Actual measurements are subsequently registered, and the algorithm is applied. Once the laser system is characterised, the error of the grid encoder is calculated along the working range, resulting in an expanded submicrometre calibration uncertainty (k = 2) for the X and Y axes. The results of the grid encoder calibration are comparable to the errors provided by the calibration certificate for its main central axes. It is, therefore, possible to confirm the suitability of the self-calibration methodology proposed in this article.

Design Optimization for the Measurement Accuracy Improvement of a Large Range Nanopositioning Stage.

Both an accurate machine design and an adequate metrology loop definition are critical factors when precision positioning represents a key issue for the final system performance. This article discusses the error budget methodology as an advantageous technique to improve the measurement accuracy of a 2D-long range stage during its design phase. The nanopositioning platform NanoPla is here presented. Its specifications, e.g., XY-travel range of 50 mm × 50 mm and sub-micrometric accuracy; and some novel designed solutions, e.g., a three-layer and two-stage architecture are described. Once defined the prototype, an error analysis is performed to propose improvement design features. Then, the metrology loop of the system is mathematically modelled to define the propagation of the different sources. Several simplifications and design hypothesis are justified and validated, including the assumption of rigid body behavior, which is demonstrated after a finite element analysis verification. The different error sources and their estimated contributions are enumerated in order to conclude with the final error values obtained from the error budget. The measurement deviations obtained demonstrate the important influence of the working environmental conditions, the flatness error of the plane mirror reflectors and the accurate manufacture and assembly of the components forming the metrological loop. Thus, a temperature control of ±0.1 °C results in an acceptable maximum positioning error for the developed NanoPla stage, i.e., 41 nm, 36 nm and 48 nm in X-, Y- and Z-axis, respectively.

A theoretical and experimental study of the NMR spectra of 4,5,6,7-tetrafluorobenzazoles with special stress on PCM calculations of chemical shifts.

The chemical shifts and several (19)F-(19)F, (13)C-(19) F and (1)H-(19)F spin-spin coupling constants (SSCSs) of eight 4,5,6,7-tetraflurobenzazoles (three benzimidazoles, three benzimidazolinones and two indazoles) have been determined. The chemical shifts were discussed using gauge including atomic orbital-density functional theory calculations taking into account solvent effects (polarizable continuum model) and, for the solid state, hydrogen bonds (clusters up to three molecules).

A facile method to determine the absolute structure of achiral molecules: supramolecular-tilt structures.

Achiral compounds 4-methoxy-4-(p-methoxyphenyl)cyclohexanoneethylene ketal (2), 4-hydroxy-4-(p-methoxy phenyl)cyclohexanoneethylene ketal (3), and 3,5-dimethyl-4-nitropyrazole (4) crystallized in chiral structures and the samples showed an enantiomeric excess. We have determined the absolute structures of these compounds by using X-ray diffraction with copper radiation at low temperatures. Moreover, we have also established the prevalent absolute structures in these samples, by comparing their calculated and solid-state vibrational circular dichroism (VCD) spectra. The consistency of this method was confirmed by using (R,R)-2,8-diiodo-4,10-dimethyl-6 H,12H-5,11-methano-dibenzo[b,f][1,5]diazocine, Tröger's base, (R,R)-1, as a chiral compound of known absolute configuration.

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring.

Two novel tetrafluorinated 1,5-benzodiazepinones were synthesized and their X-ray structures determined. 6,7,8,9-Tetrafluoro-4-methyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one crystallizes in the monoclinic P21/c space group and 6,7,8,9-tetrafluoro-1,4-dimethyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one in the triclinic P-1 space group. Density functional theory studies at the B3LYP/6-311++G(d,p) level were carried out on these compounds and on four non-fluorinated derivatives, allowing to calculate geometries, tautomeric energies and ring-inversion barriers, that were compared with the experimental results obtained by static and dynamic NMR in solution and in solid state.

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents.

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson's disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.

Regiospecific Synthesis and Structural Studies of 3,5-Dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones and Comparison with 1,3-Dihydro-2H-benzo[b][1,4]diazepin-2-ones.

Nine 3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones (17-25), some of which contain fluoro-substituents, have been regiospecifically prepared by reaction of 2,3-diaminopyridines with ethyl aroylacetates. In two cases, open intermediates have been isolated and these are related to the reaction pathway. The X-ray crystal structure of 1-methyl-4-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (23) has been solved (formula, C15H13N3O; crystal system, monoclinic; space group, C2/c). This is an asymmetric unit constituted by a single nonplanar molecule and its conformational enantiomer due to the presence of the seven-membered diazepin-2-one moiety, which introduces a certain degree of torsion in the adjacent pyridine ring. The 1H, 13C, 15N, and 19F NMR spectra were obtained and the chemical shifts, together with those of the previously published 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones (1-16), i.e., a total of 544 values, were successfully compared with the chemical shifts calculated at the gauge invariant atomic orbital (GIAO)/Becke, three-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level. The seven-membered ring inversion barrier in 5-benzyl-2-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (25) was determined and, in conjunction with the data from the literature, compared with the B3LYP/6-311++G(d,p) computed values. This allowed the determination of several structural effects. The rotation about the exocyclic N1-CR bond was also calculated and its dynamic properties were discussed.

Fluorinated indazoles as novel selective inhibitors of nitric oxide synthase (NOS): synthesis and biological evaluation.

In order to find new compounds with neuroprotective activity and NOS-I/NOS-II selectivity, we have designed, synthesized, and characterized 14 new NOS inhibitors with an indazole structure. The first group corresponds to 4,5,6,7-tetrahydroindazoles (4-8), the second to the N-methyl derivatives (9-12) of 7-nitro-1H-indazole (1) and 3-bromo-7-nitro-1H-indazole (2), and the latter to 4,5,6,7-tetrafluoroindazoles (13-17). Compound 13 (4,5,6,7-tetrafluoro-3-methyl-1H-indazole) inhibited NOS-I by 63% and NOS-II by 83%. Interestingly, compound 16 (4,5,6,7-tetrafluoro-3-perfluorophenyl-1H-indazole) inhibited NOS-II activity by 80%, but it did not affect to NOS-I activity. Structural comparison between these new indazoles further supports the importance of the aromatic indazole skeleton for NOS inhibition and indicate that bulky groups or N-methylation of 1 and 2 diminish their effect on NOS activity. The fluorination of the aromatic ring increased the inhibitory potency and NOS-II selectivity, suggesting that this is a promising strategy for NOS selective inhibitors.

NMR studies of ultrafast intramolecular proton tautomerism in crystalline and amorphous n,n'-diphenyl-6-aminofulvene-1-aldimine: solid-state, kinetic isotope, and tunneling effects.

Using solid-state NMR spectroscopy, we have detected and characterized ultrafast intramolecular proton tautomerism in the N-H-N hydrogen bonds of solid N, N'-diphenyl-6-aminofulvene-1-aldimine ( I) on the microsecond-to-picosecond time scale. (15)N cross-polarization magic-angle-spinning NMR experiments using (1)H decoupling performed on polycrystalline I- (15)N 2 and the related compound N-phenyl- N'-(1,3,4-triazole)-6-aminofulvene-1-aldimine ( II) provided information about the thermodynamics of the tautomeric processes. We found that II forms only a single tautomer but that the gas-phase degeneracy of the two tautomers of I is lifted by solid-state interactions. Rate constants, including H/D kinetic isotope effects (KIEs), on the microsecond-to-picosecond time scale were obtained by measuring and analyzing the longitudinal (15)N and (2)H relaxation times of I- (15)N 2, I- (15)N 2- d 10, and I- (15)N 2- d 1 over a wide temperature range. In addition to the microcrystalline modification, a novel amorphous modification of I was found and studied. In this modification, proton transfer is much faster than in the crystalline form. For both modifications, we observed large H/D KIEs that were temperature-dependent at high temperatures and temperature-independent at low temperatures. These findings are interpreted in terms of a simple quasiclassical tunneling model proposed by Bell and modified by Limbach. We obtained evidence that a reorganization energy is necessary in order to compress the N-H-N hydrogen bond and achieve a molecular configuration in which the barrier for H transfer is reduced and tunneling or an over-barrier reaction can occur.

Quantifying weak hydrogen bonding in uracil and 4-cyano-4'-ethynylbiphenyl: a combined computational and experimental investigation of NMR chemical shifts in the solid state.

Weak hydrogen bonding in uracil and 4-cyano-4'-ethynylbiphenyl, for which single-crystal diffraction structures reveal close CH...O=C and C[triple bond]CH...N[triple bond]C distances, is investigated in a study that combines the experimental determination of 1H, 13C, and 15N chemical shifts by magic-angle spinning (MAS) solid-state NMR with first-principles calculations using plane-wave basis sets. An optimized synthetic route, including the isolation and characterization of intermediates, to 4-cyano-4'-ethynylbiphenyl at natural abundance and with 13C[triple bond]13CH and 15N[triple bond]C labeling is described. The difference in chemical shifts calculated, on the one hand, for the full crystal structure and, on the other hand, for an isolated molecule depends on both intermolecular hydrogen bonding interactions and aromatic ring current effects. In this study, the two effects are separated computationally by, first, determining the difference in chemical shift between that calculated for a plane (uracil) or an isolated chain (4-cyano-4'-ethynylbiphenyl) and that calculated for an isolated molecule and by, second, calculating intraplane or intrachain nucleus-independent chemical shifts that quantify the ring current effects caused by neighboring molecules. For uracil, isolated molecule to plane changes in the 1H chemical shift of 2.0 and 2.2 ppm are determined for the CH protons involved in CH...O weak hydrogen bonding; this compares to changes of 5.1 and 5.4 ppm for the NH protons involved in conventional NH...O hydrogen bonding. A comparison of CH bond lengths for geometrically relaxed uracil molecules in the crystal structure and for geometrically relaxed isolated molecules reveals differences of no more than 0.002 A, which corresponds to changes in the calculated 1H chemical shifts of at most 0.1 ppm. For the C[triple bond]CH...N[triple bond]C weak hydrogen bonds in 4-cyano-4'-ethynylbiphenyl, the calculated molecule to chain changes are of similar magnitude but opposite sign for the donor 13C and acceptor 15N nuclei. In uracil and 4-cyano-4'-ethynylbiphenyl, the CH hydrogen-bonding donors are sp2 and sp hybridized, respectively; a comparison of the calculated changes in 1H chemical shift with those for the sp3 hybridized CH donors in maltose (Yates et al. J. Am. Chem. Soc. 2005, 127, 10216) reveals no marked dependence on hybridization for weak hydrogen-bonding strength.

Analysis of Surface Extraction Methods Based on Gradient Operators for Computed Tomography in Metrology Applications.

Among the multiple factors influencing the accuracy of Computed Tomography measurements, the surface extraction process is a significant contributor. The location of the surface for metrological applications is generally based on the definition of a gray value as a characteristic of similarity to define the regions of interest. A different approach is to perform the detection or location of the surface based on the discontinuity or gradient. In this paper, an adapted 3D Deriche algorithm based on gradient information is presented and compared with a previously developed adapted Canny algorithm for different surface types. Both algorithms have been applied to nine calibrated workpieces with different geometries and materials. Both the systematic error and measurement uncertainty have been determined. The results show a significant reduction of the deviations obtained with the Deriche-based algorithm in the dimensions defined by flat surfaces.

Electrospray mass spectrometry of 2-aminotroponimines and 2-aminotropones.

A series of aminotroponimine and aminotropone derivatives were studied by electrospray mass spectrometry. MS and MS/MS data were acquired according to automated procedures. In the case of mono- and di-halogenated compounds, their specific behavior upon collisionally-activated dissociation conditions provided rapid structural assignments through inexpensive isotopic labeling MS/MS experiments.

6-Aminofulvene-1-aldimine: A Model Molecule for the Study of Intramolecular Hydrogen Bonds.

An unusually substantial coupling is observed across the hydrogen bond of fully 15 N-labeled compound 1 when it is studied by 1 H and 15 N NMR spectroscopy. The structure was determined by X-ray diffraction and shown to correspond to tautomer 1 a (both in the solid state and in solution). These results open up a new field of hydrogen-bond research by NMR spectroscopic methods.

Synthesis and biological evaluation of indazole derivatives.

The inhibition of neuronal and inducible nitric oxide synthases (nNOS and iNOS) by a series of 36 indazoles has been evaluated, showing that most of the assayed derivatives are better iNOS than nNOS inhibitors. A parabolic model relating the iNOS inhibition percentage with the difference, E(rel), between stacking and apical interaction energies of indazoles with the active site of the NOS enzyme has been established.

15N-15N spin-spin coupling constants through intermolecular hydrogen bonds in the solid state.

A 2hJNN intermolecular spin-spin coupling constant (SSCC) of 10.2±0.4 Hz has been measured for the powdered tetrachlorogallate salt of pyridinium solvated by pyridine (pyridine-H+⋯pyridine cation 3). Density Functional Theory (DFT) calculations at the B3LYP/6-311++G(d,p) level reproduced this value and two others reported in the literature for 2hJ intermolecular SSCCs, which were measured for complexes in solution.