Anthonius H. J. Engwerda

Computational (DFT) and Experimental (EXAFS) Study of the Interaction of [Ir(IMes)(H)2(L)3] with Substrates and Co-substrates Relevant for SABRE in Dilute Systems†

Signal amplification by reversible exchange (SABRE) is an emerging hyperpolarization method in NMR spectroscopy, in which hyperpolarization is transferred through the scalar coupling network of para-hydrogen derived hydrides in a metal complex to a reversibly bound substrate. Substrates can even be hyperpolarized at concentrations below that of the metal complex by addition of a suitable co-substrate. Here we investigate the catalytic system used for trace detection in NMR spectroscopy with [Ir(IMes)(H)2 (L)3 ](+) (IMes=1,3-dimesitylimidazol-2-ylidene) as catalyst, pyridine as a substrate and 1-methyl-1,2,3-triazole as co-substrate in great detail. With density functional theory (DFT), validated by extended X-ray absorption fine structure (EXAFS) experiments, we provide explanations for the relative abundance of the observed metal complexes, as well as their contribution to SABRE. We have established that the interaction between iridium and ligands cis to IMes is weaker than that with the trans ligand, and that in mixed complexes with pyridine and triazole, the latter preferentially takes up the trans position.

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.

Speeding up Viedma ripening

Viedma ripening allows the conversion of a solid state racemate into a single enantiomer. Using the gradual conversion of a metastable racemic compound into the conglomerate, the speed of deracemization for two amino acid derivatives could be considerably increased from several days to a few hours.

Deracemization of a Racemic Compound by Using Tailor-Made Additives

Viedma ripening is a process that combines abrasive grinding of a slurry of crystals with solution-phase racemization, resulting in solid-phase deracemization. One of the major disadvantages of Viedma ripening is that the desired compound needs to crystallize as a racemic conglomerate, accounting for only 5-10 % of all chiral molecules. Herein, we show that use of a chiral additive causes deracemization under conditions, in which the compound normally crystallizes as a racemic compound. Although this concerns a single example, it is envisioned that through this new approach the scope of Viedma ripening can be significantly expanded.

Solid Phase Deracemization of an Atropisomer

The scope of Viedma ripening and temperature cycling with respect to chiral molecules has remained mostly limited to molecules with a single stereogenic center, while racemization proceeds through inversion at that particular stereocenter. In this article we demonstrate for the first time that atropisomers, chiral rotamers that possess an axis of chirality, can be successfully deracemized in the solid phase by either applying temperature cycling or Viedma ripening.

Highly Stable and Selective Tetrazines for the Coordination-Assisted Bioorthogonal Ligation with Vinylboronic Acids

Bioorthogonal reactions are selective transformations that are not affected by any biological functional group and are widely used for chemical modification of biomolecules. Recently, we reported that vinylboronic acids (VBAs) gave exceptionally high reaction rates in the bioorthogonal inverse electron-demand Diels–Alder (iEDDA) reaction with tetrazines bearing a boron-coordinating pyridyl moiety compared to tetrazines lacking such a substituent. In this integrated experimental and theoretical study, we show how the reaction rate of the VBA-tetrazine ligation can be accelerated by shifting the equilibrium from boronic acid to the boronate anion in the reaction mixture. Quantum chemical activation strain analyses reveal that this rate enhancement is a direct consequence of the excellent electron-donating capability of the boronate anion in which the π HOMO is pushed to a higher energy due to the net negative potential of this species. We have explored the second-order rate constants of several tetrazines containing potential VBA-coordinating hydroxyl substituents. We observed an increase in rate constants of several orders of magnitude compared to the tetrazines lacking a hydroxyl substituent. Furthermore, we find the hydroxyl-substituted tetrazines to be more selective toward VBAs than toward the commonly used bioorthogonal reactant norbornene, and more stable in aqueous environment than the previously studied tetrazines containing a pyridyl substituent.

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

EXAFS and DFT studies on iridium catalysts for SABRE

Since it was first developed, Nuclear Magnetic Resonance (NMR) has become a powerful analytical tool that is now used widely in the fields of chemistry, materials science, and medicine. One way to overcome the intrinsic insensitivity of NMR is to use hyperpolarization techniques to produce non-Boltzmann spin-state distributions. One of these techniques is Signal Amplification By Reversible Exchange (SABRE),[1] in which hyperpolarization is achieved by the temporary association of parahydrogen and a substrate in the coordination sphere of a transition metal. The polarization can be transferred from the parahydrogen-derived hydride ligands to the bound substrate via scalar coupling, followed by dissociation of the hyperpolarized substrate into the bulk solution. We have investigated the efficiency of various iridium NHC complexes with aliphatic and aromatic R groups as SABRE catalysts.[2] The used metal centre is a six-coordinate iridium N-heterocyclic carbene complex, with three substrates and two hydrides, in which the exchange rate of substrate and parahydrogen at the metal centre determines the efficiency of the hyperpolarization. As solvent molecules compete with pyridine for coordination to iridium, the sensitivity of SABRE can be enhanced by displacement of solvent molecules by cosubstrates, i.e. proton-poor ligands such as methyltriazole.[3] In this exchange process, several mixed iridium complexes can be considered to exist, which were not all observed by NMR. Therefore, Density Functional Theory (DFT) calculations were performed on these complexes to better understand this phenomenon. While NMR itself is the best source of information on protons and dynamic processes involved in SABRE, we have found that Extended X-ray Absorption Fine Structure (EXAFS) studies in organic solutions provide interesting complimentary information on the complexes involved.