Cationic Multidentate Halogen-Bond Donors in Halide Abstraction Organocatalysis: Catalyst Optimization by Preorganization.

In contrast to hydrogen bonding, which is firmly established in organocatalysis, there are still very few applications of halogen bonding in this field. Herein, we present the first catalytic application of cationic halogen-bond donors in a halide abstraction reaction. First, halopyridinium-, haloimidazolium-, and halo-1,2,3-triazolium-based catalysts were systematically tested. In contrast to the pyridinium compounds, both the imidazolium and the triazolium salts showed promising potency. For the haloimidazolium-based organocatalysts, we could show that the catalytic activity is based on halogen bonding using, e.g., the chlorinated derivatives as reference compounds. On the basis of these studies, halobenzimidazolium organocatalysts were then investigated. Monodentate compounds featured the same trends as the corresponding imidazolium analogues but showed a stronger catalytic activity. In order to prepare bidentate versions which are preorganized for anion binding, a new class of rigid bis(halobenzimidazolium) compounds was synthesized and structurally characterized. The corresponding syn isomer showed unprecedented catalytic potency and could be used in as low as 0.5 mol % in the benchmark reaction of 1-chloroisochroman with a silyl enol ether. Calculations confirmed that the syn isomer may bind in a bidentate fashion to chloride. The respective anti isomer is less active and binds halides in a monodentate fashion. Kinetic investigations confirmed that the syn isomer led to a 20-fold rate acceleration compared to a neutral tridentate halogen-bond donor. The strength of the preorganized halogen-bond donor seems to approach the limit under the reaction conditions, as decomposition is observed in the presence of chloride in the same solvent at higher temperatures. Calorimetric titrations of the syn isomer with bromide confirmed the strong halogen-bond donor strength of the former (K ≈ 4 × 10(6) M(-1), ΔG ≈ 38 kJ/mol).

Multiple Multidentate Halogen Bonding in Solution, in the Solid State, and in the (Calculated) Gas Phase.

The binding properties of neutral halogen-bond donors (XB donors) bearing two multidentate Lewis acidic motifs toward halides were investigated. Employing polyfluorinated and polyiodinated terphenyl and quaterphenyl derivatives as anion receptors, we obtained X-ray crystallographic data of the adducts of three structurally related XB donors with tetraalkylammonium chloride, bromide, and iodide. The stability of these XB complexes in solution was determined by isothermal titration calorimetry (ITC), and the results were compared to X-ray analyses as well as to calculated binding patterns in the gas phase. Density functional theory (DFT) calculations on the gas-phase complexes indicated that the experimentally observed distortion of the XB donors during multiple multidentate binding can be reproduced in 1:1 complexes with halides, whereas adducts with two halides show a symmetric binding pattern in the gas phase that is markedly different from the solid state structures. Overall, this study demonstrates the limitations in the transferability of binding data between solid state, solution, and gas phase in the study of complex multidentate XB donors.

Toward molecular recognition: three-point halogen bonding in the solid state and in solution.

A well-defined three-point interaction based solely on halogen bonding is presented. X-ray structural analyses of tridentate halogen bond donors (halogen-based Lewis acids) with a carefully chosen triamine illustrate the ideal geometric fit of the Lewis acidic axes of the former with the Lewis basic centers of the latter. Titration experiments reveal that the corresponding binding constant is about 3 orders of magnitude higher than that with a comparable monodentate amine. Other, less perfectly fitting multidentate amines also bind markedly weaker. Multipoint interactions like the one presented herein are the basis of molecular recognition, and we expect this principle to further establish halogen bonding as a reliable tool for solution-phase applications.

Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis.

TASK1 (KCNK3) and TASK3 (KCNK9) are two-pore domain potassium channels highly expressed in adrenal glands. TASK1/TASK3 heterodimers are believed to contribute to the background conductance whose inhibition by angiotensin II stimulates aldosterone secretion. We used task1-/- mice to analyze the role of this channel in adrenal gland function. Task1-/- exhibited severe hyperaldosteronism independent of salt intake, hypokalemia, and arterial 'low-renin' hypertension. The hyperaldosteronism was fully remediable by glucocorticoids. The aldosterone phenotype was caused by an adrenocortical zonation defect. Aldosterone synthase was absent in the outer cortex normally corresponding to the zona glomerulosa, but abundant in the reticulo-fasciculata zone. The impaired mineralocorticoid homeostasis and zonation were independent of the sex in young mice, but were restricted to females in adults. Patch-clamp experiments on adrenal cells suggest that task3 and other K+ channels compensate for the task1 absence. Adrenal zonation appears as a dynamic process that even can take place in adulthood. The striking changes in the adrenocortical architecture in task1-/- mice are the first demonstration of the causative role of a potassium channel in development/differentiation.

A halogen-bonding-catalyzed Michael addition reaction.

Only a few studies on the use of halogen bonding in catalysis have been published so far. Herein, (benz)imidazolium-based halogen bond donors are used as catalysts in a Michael addition reaction. The most potent catalyst, a rigid atropisomer featuring two iodobenzimidazolium moieties, provided a rate acceleration versus a reference compound of ca. 50.

Sex-dependent differences in the in vivo respiratory phenotype of the TASK-1 potassium channel knockout mouse.

TASK-1 potassium channels have been implicated in central and peripheral chemoreception; however, the precise contribution of TASK-1 for the control of respiration is still under debate. Here, we investigated the respiration of unrestrained adult and neonatal TASK-1 knockout mice (TASK-1-/-) using a plethysmographic device. Respiration in adult female TASK-1-/- mice under control (21% O2), hypoxia and hypercapnia was unaffected. Under acute hypoxia male TASK-1-/- mice exhibited a reduced increase of the respiratory frequency (fR) compared to wildtypes. However, the tidal volume (VT) of male TASK-1-/- mice was strongly enhanced. The volatile anesthetic isoflurane induced in male TASK-1-/- and male wild type mice (TASK-1+/+) a similar respiratory depression. Neonatal TASK-1-/- mice demonstrated a 30-40% decrease of the minute volume, caused by a reduction of the fR under control condition (21% O2). Under hypoxia, neonatal TASK-1-/- mice more frequently stopped breathing (apnea>3s) suggesting an increased hypoxia-sensitivity. As reported before, this increased hypoxia sensitivity had no influence on the survival rate of neonatal TASK-1-/- mice. In adult and neonatal mice, TASK-1 gene deletion induced a significant prolongation of the relaxation time (RT), which is a parameter for expiration kinetics. Additionally, screening for mutations in the human TASK-1 gene in 155 cases of sudden infant death syndrome (SIDS) was inconclusive. In conclusion, these data are suggestive for an increased hypoxia-sensitivity of neonatal TASK-1-/- mice, however, without causing an increase in neonatal lethality. In adult female TASK-1-/- mice respiration was unaffected, whereas adult male TASK-1-/- mice showed a modified breathing pattern. These results are suggestive for sex-specific mechanisms for compensating the inactivation of TASK-1 in mice.

Potent affinity material for tracing acetone and related analytes based on molecular recognition by halogen bonds.

Affinity materials based on halogen bonds turned out to be a powerful tool for the molecular recognition of acetone or related carbonyl compounds in the presence of ubiquitous protic molecules. The superior selectivity and sensitivity were found by the gravimetric detection of volatile organic compounds by quartz crystal microbalances.

Activation of a carbonyl compound by halogen bonding.

Using a prototypical Diels-Alder reaction as benchmark, we show that dicationic halogen-bond donors are capable of activating a neutral organic substrate. By various comparison experiments, the action of traces of acid or of other structural features of the halogen-bond donor not related to halogen bonding are excluded with high certainty.

5-Iodo-1,2,3-triazolium-based multidentate halogen-bond donors as activating reagents.

Bi- and tridentate polycationic halogen bond donors based on 5-iodo-1,2,3-triazolium groups have been synthesized by 1,3-dipolar cycloaddition reactions. These halogen-based Lewis acids have been evaluated as activators in a halide-abstraction benchmark reaction.