Catalytic Carbon-Chlorine Bond Activation by Selenium-Based Chalcogen Bond Donors.

Chalcogen bonding is a noncovalent interaction based on electrophilic chalcogen substituents, which shares many similarities with the more well-known hydrogen and halogen bonding. Herein, the first application of selenium-based chalcogen bond donors in organocatalysis is described. Cationic bifunctionalized organoselenium compounds activate the carbon-chlorine bond of 1-chloroisochroman in a benchmark reaction. While imidazolium-based derivatives showed no noticeable activation, benzimidazolium backbones yielded potent catalysts. In all cases, syn-isomers were markedly more active, presumably due to bidentate coordination, which was confirmed by DFT calculations. Comparison experiments with the corresponding non-selenated as well as the non-cationic reference compounds clearly indicate that the catalytic activity can be ascribed to chalcogen bonding. The rate acceleration by the catalyst-compared to the non-selenated derivative-was about 10 fold.

Carbon-Halogen Bond Activation by Selenium-Based Chalcogen Bonding.

Chalcogen bonding is a little explored noncovalent interaction similar to halogen bonding. This manuscript describes the first application of selenium-based chalcogen bond donors as Lewis acids in organic synthesis. To this end, the solvolysis of benzhydryl bromide served as a halide abstraction benchmark reaction. Chalcogen bond donors based on a bis(benzimidazolium) core provided rate accelerations relative to the background reactivity by a factor of 20-30. Several comparative experiments provide clear indications that the observed activation is due to chalcogen bonding. The performance of the chalcogen bond donors is superior to that of a related brominated halogen bond donor.

Organocatalytic enamine-activation of cyclopropanes for highly stereoselective formation of cyclobutanes.

A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ*C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

A new organocatalytic concept for asymmetric α-alkylation of aldehydes.

The organocatalytic asymmetric α-alkylation of aldehydes by 1,6-conjugated addition of enamines to p-quinone methides is described. Employing a newly developed class of chiral secondary amine catalysts, α-diarylmethine-substituted aldehydes with two contiguous stereocenters have been synthesized in a simple manner with good diastereocontrol and excellent enantioselectivity.

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.

Activation of glycosyl halides by halogen bonding.

Halogen bonding is the formation of a non-covalent interaction between an electrophilic halogen substituent and a Lewis base, for instance, a halide. These kinds of relatively weak interactions have found applications in crystal engineering and initial applications in solution-phase chemistry are starting to appear. We report on the exploration of bis(iodoimidazolium) compounds as halogen-based Lewis acids in the activation of glycosyl halides. We show that these dicationic halogen-bond donors can be used to activate glycosyl halides if the carbohydrate core is sufficiently reactive enough. Furthermore, we provide comparison experiments which indicate that the mode of activation is indeed based on halogen bonding. This represents the first glycosylation reaction mediated by a (carbon-backbone-based) halogen-bond donor.

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.

Isothermal calorimetric titrations on charge-assisted halogen bonds: role of entropy, counterions, solvent, and temperature.

We have conducted isothermal calorimetric titrations to investigate the halogen-bond strength of cationic bidentate halogen-bond donors toward halides, using bis(iodoimidazolium) compounds as probes. These data are intended to aid the rational design of halogen-bond donors as well as the development of halogen-bond-based applications in solution. In all cases examined, the entropic contribution to the overall free energy of binding was found to be very important. The binding affinities showed little dependency on the weakly coordinating counteranions of the halogen-bond donors but became slightly stronger with higher temperatures. We also found a marked influence of different solvents on the interaction strength. The highest binding constant detected in this study was 3.3 × 10(6) M(-1).