Paul Tinnemans

A New Ir-NHC Catalyst for Signal Amplification by Reversible Exchange in D2O

Abstract NMR signal amplification by reversible exchange (SABRE) has been observed for pyridine, methyl nicotinate, N‐methylnicotinamide, and nicotinamide in D2O with the new catalyst [Ir(Cl)(IDEG)(COD)] (IDEG=1,3‐bis(3,4,5‐tris(diethyleneglycol)benzyl)imidazole‐2‐ylidene). During the activation and hyperpolarization steps, exclusively D2O was used, resulting in the first fully biocompatible SABRE system. Hyperpolarized 1H substrate signals were observed at 42.5 MHz upon pressurizing the solution with parahydrogen at close to the Earths magnetic field, at concentrations yielding barely detectable thermal signals. Moreover, 42‐, 26‐, 22‐, and 9‐fold enhancements were observed for nicotinamide, pyridine, methyl nicotinate, and N‐methylnicotinamide, respectively, in conventional 300 MHz studies. This research opens up new opportunities in a field in which SABRE has hitherto primarily been conducted in CD3OD. This system uses simple hardware, leaves the substrate unaltered, and shows that SABRE is potentially suitable for clinical purposes.

Realising epitaxial growth of GaN on (001) diamond

By an extensive investigation of the principal growth parameters on the deposition process, we realized the epitaxial growth of crystalline wurtzite GaN thin films on single crystal (001) diamond substrates by metal organic chemical vapor deposition. From the influence of pressure, V/III ratio, and temperature, it was deduced that the growth process is determined by the mass-transport of gallium precursor material toward the substrate. The highest temperature yielded an improved epitaxial relationship between grown layer and substrate. X ray diffraction (XRD) pole figure analysis established the presence of two domains of epitaxial layers, namely (0001) 〈 101− 0〉 GaN∥ (001)[110] diamond and (0001) 〈 101− 0〉 GaN∥ (001) [11−0] diamond, which are 90∘ rotated with respect to each other. The presence of these domains is explained by the occurrence of areas of (2×1) and (1×2) surface reconstruction of the diamond substrate. When applying highly misoriented diamond substrates toward the [110] diamond direction, ...

Deracemization of a racemic allylic sulfoxide using viedma ripening

Despite the importance of enantiopure chiral sulfoxides, few methods exist that allow for their deracemization. Here, we show that an enantiopure sulfoxide can be produced from the corresponding racemate using Viedma ripening involving rearrangement-induced racemization. The suitable candidate for Viedma ripening was identified from a library of 24 chiral sulfoxides through X-ray structure determination. Starting from the racemic sulfoxide, an unprecedented application of a 2,3-sigmatropic rearrangement type racemization in a Viedma ripening process allowed for complete deracemization.

Additive Induced Formation of Ultrathin Sodium Chloride Needle Crystals

A multitude of ultrathin crystal needles are formed during the evaporation of saturated aqueous NaCl solution droplets in the presence of amide containing additives. The needles are as small as 300 nm wide and 100–1000 μm in length. Heating experiments, X-ray diffraction, and energy dispersive X-ray spectroscopy showed that the needles are cubic sodium chloride crystals with the needle length direction pointing toward [100]. This shape, not expected for the 43̅m point group symmetry of NaCl, has been explained using a model, based on tip formation by initial morphological instability followed by time dependent adsorption of additive molecules blocking the growth of the needle side faces. The latter also suppresses side branch formation, which normally occurs for dendrite growth.

Understanding the single-crystal-to-single-crystal solid-state phase transition of DL-methionine

The solid-state phase transition between the low temperature β and the high temperature α forms of DL-methionine was characterised in detail using DSC, SCXRD, thermal stage polarisation microscopy and solid-state NMR. The thermodynamic transition point of the α ↔ β transition of DL-methionine was determined to fall between 306 and 317 K. The transition is kinetically hindered, as is indicated by a large hysteresis. Moreover, the transition rate during cooling is significantly lower than during heating and there is a large temperature region of coexistence. The kinetic barriers involved are lower for single crystals than for powders. DL-Methionine crystals consist of 2D hydrogen-bonded bilayers interconnected by weak Van der Waals interactions. The crystals transform layer-wise, without complete delamination or deterioration, and with a transition front that propagates perpendicular to the layers and a relatively fast transition within one layer. The fast kinetics within the plane of the layers, combined with the faster kinetics in single crystals, indicate that cooperative motion could play a role in this single-crystal-to-single-crystal phase transition.

Direct Synthesis of Chiral Porphyrin Macrocyclic Receptors via Regioselective Nitration

Nitration of tetraphenylporphyrin cage compound 1, at −40 °C, leads to the regioselective formation of the chiral mononitro compound 2 (75% isolated yield) and, at −30 °C, to the achiral syn-dinitro-derivative 3 and the chiral anti-dinitro derivative 4 in a diastereomeric ratio of 5:2, which were separated by chromatography (46 and 20% yields, respectively). The structures of the compounds were confirmed by X-ray crystallography.

Racemic and Enantiopure Camphene and Pinene Studied by the Crystalline Sponge Method

The use of an achiral metal–organic framework for structure determination of chiral compounds is demonstrated for camphene and pinene. The structure of enantiopure β-pinene can be resolved using the crystalline sponge method. However, α-pinene cannot be resolved using enantiopure material alone because no ordering of guest molecules takes place in that case. Interestingly, enantiomeric pairs order inside the channels of the host framework when impure (+)-camphene is offered to the host, which is also the case when a racemic mixture of α-pinene is used. A mixture of (+)-α-pinene and (−)-β-pinene also leads to ordered incorporation in the host, showing the influence of the presence of an inversion center in the host framework. We further show that powder X-ray diffraction provides a direct view on incorporation of ordered guest molecules. This technique, therefore, provides a way to determine the optimal and/or minimal soaking time. In contrast, color change of the crystal only demonstrates guest uptake, not ordering. Moreover, we show that color change can also be caused by guest-induced host degradation.

The Rich Solid-State Phase Behavior of dl-Aminoheptanoic Acid: Five Polymorphic Forms and Their Phase Transitions

The rich landscape of enantiotropically related polymorphic forms and their solid-state phase transitions of dl-2-aminoheptanoic acid (dl-AHE) has been explored using a range of complementary characterization techniques, and is largely exemplary of the polymorphic behavior of linear aliphatic amino acids. As many as five new polymorphic forms were found, connected by four fully reversible solid-state phase transitions. Two low temperature forms were refined in a high Z′ crystal structure, which is a new phenomenon for linear aliphatic amino acids. All five structures consist of two-dimensional hydrogen-bonded bilayers interconnected by weak van der Waals interactions. The single-crystal-to-single-crystal phase transitions involve shifts of bilayers and/or conformational changes in the aliphatic chain. Compared to two similar phase transitions of the related amino acid dl-norleucine, the enthalpies of transition and NMR chemical shift differences are notably smaller in dl-aminoheptanoic acid. This is explained to be a result of both the nature of the conformational changes and the increased chain length, weakening the interactions between the bilayers.

Solid-Phase Conversion of Four Stereoisomers into a Single Enantiomer

Viedma ripening is an emerging method for the solid-phase deracemization of mixtures of enantiomers. Up to now, the scope of the method has remained limited to molecules with a single stereocenter. We show here that this method can be extended to obtain a single enantiomer from a mixture of stereoisomers with two different stereocenters. In addition, we show that by using tailor-made chiral additives, the conversion time can be reduced by a factor of 100. Among the 45 drugs that were approved by the FDA (Food and Drug Administration) in 2015, thirteen were achiral, three contained a single stereocenter, sixteen were small molecules containing multiple stereocenters, and thirteen were large biomolecules. Due to the different bioactivity of the enantiomers, all of them (with the exception of the achiral drugs) are marketed as a single enantiomer. This clearly shows that obtaining molecules in enantiomerically pure form is of vital importance to human healthcare. When synthesis yields a combination of enantiomers, diastereomeric salt formation is a frequently used method to separate the desired enantiomer from its unwanted mirror image isomer. This implies, however, that half of the product is discarded. Alternatively, deracemization methods can be used, in which the unwanted enantiomer is converted into the desired product. One such deracemization method is Viedma ripening. This process involves the solid-phase deracemization of a vigorously ground suspension of crystals, enabled by simultaneous solution-phase racemization. A key requirement for the process is that the two enantiomers crystallize in separate crystals, that is, as a racemic conglomerate. Over the past few years, various types of molecules have been deracemized using this approach. Up to now, only molecules with a single stereocenter have been deracemized using Viedma ripening. However, as mentioned, the majority of drug molecules are enantiopure and contain multiple stereocenters. Conversion of such compounds into a single enantiomer using such grinding experiments is obviously more challenging. This is due to the process involving 2 chiral compounds (with n the number of stereocenters), instead of only two. Of these 2 compounds, one set of enantiomers will be the thermodynamically most favorable one, whereas the other diastereomers will have a higher energy (or higher solubility). Sakamoto et al. used this difference in stability for a related experiment. They studied a system with two stereocenters, of which one was enantiopure and could not epimerize, while the second one could epimerize in solution, resulting in a solid-phase that contained only a single diastereomer. Other crystallization methods that lead to the formation of a single enantiomer exist as well. In the case of Viedma ripening, it is important that the thermodynamically more stable set of enantiomers crystallizes as a racemic conglomerate (Figure 1). The crystallization behavior of the less stable diastereomers is expected to be less important, since these compounds will eventually be eliminated from the solid phase. More challenging is the interconversion (racemization) of the two enantiomers, since this requires epimerization of all chiral centers. This can be achieved if the centers epimerize in a (near) identical way, or if the conditions for the different epimerization pathways are compatible. As a first step towards multiple stereocenters, we herewith show a successful demonstration on two molecules with two different stereocenters to which these conditions apply. From a total of four diastereomers, a single one was obtained using grinding experiments. To the best of our knowledge, this is the first example of conversion of a stereoisomeric mixture of a compound with multiple stereocenters into only one enantiomer using such grinding experiments. So far, experiments by Hachiya et al. approximate this goal most closely, but using total spontaneous resolution instead. They succeeded in partially converting molecules with two identical stereocenters (meaning their system consisted of only three stereoisoFigure 1. In order to successfully convert a compound with two stereocenters into a single stereoisomer using grinding experiments, epimerization of both stereocenters, as well as crystallization of the most stable pair of enantiomers as a racemic conglomerate, is

Stabilization of 2,6-Diarylanilinum Cation by Through-Space Cation−π Interactions

Energetically favorable cation−π interactions play important roles in numerous molecular recognition processes in chemistry and biology. Herein, we present synergistic experimental and computational physical–organic chemistry studies on 2,6-diarylanilines that contain flanking meta/para-substituted aromatic rings adjacent to the central anilinium ion. A combination of measurements of pKa values, structural analyses of 2,6-diarylanilinium cations, and quantum chemical analyses based on the quantitative molecular orbital theory and a canonical energy decomposition analysis (EDA) scheme reveal that through-space cation−π interactions essentially contribute to observed trends in proton affinities and pKa values of 2,6-diarylanilines.