Stefan M. Huber

Organocatalysis by Neutral Multidentate Halogen‐Bond Donors

Over the last 15 years, hydrogen-bond donors, such as thiourea derivatives, have been used as noncovalent organocatalysts with ever-increasing sophistication. Yet, despite the large structural variety of the currently known noncovalent organocatalysts, virtually all are based on the same interacting atom: positively polarized hydrogen. Although it has been known for a long time that compounds featuring electrophilic halogen substituents also form adducts with Lewis bases, the corresponding interaction (“halogen bonding”) 4] was mostly ignored until the 1990s. An important difference between these two noncovalent interactions is the invariably high directionality of halogen bonds, with R X LB angles that are close to 1808 (X = Cl,Br,I; LB = Lewis base). Most studies involving halogen bonds are related to the solid state and to crystal engineering, but in recent years an increasing number of applications in solution-phase have been published, including fundamental studies and reports on anion receptors. In organocatalysis, the involvement of halogen bonds has only been postulated in two cases. Bolm et al. reported that iodoperfluoroalkanes catalyze the reduction of quinoline derivatives. The participation of halogen bonds in this reaction was derived from experimental observations. In a second example, iodine trichloride was reported to catalyze the ring-opening polymerization of l-lactide. The elucidation of the exact mode of action of this highly reactive interhalogen compound is not trivial, though, and in both reported cases the analysis is further complicated by the possible presence of traces of acid. One particular application of hydrogen-bonding organocatalysts is based on the coordination to anions and/or the abstraction of the latter from organic substrates (“anion binding mechanism”). Recently, we could show that halogen-bond donors may also serve as activators in a halide-abstraction benchmark reaction. To date, however, only dicationic compounds (based on either imidazolium, pyridinium, or 1,2,3-triazolium backbones) proved to be active, and stoichiometric amounts of the halogen-bond donor needed to be employed. As the use of cationic compounds comes along with several limitations (for example, concerning solubility, synthetic accessibility, and the presence of counteranions), our next goal was to design neutral halogen-bond donors for use as activators or, ideally, organocatalysts. At present, our studies have primarily proof-of-principle character to demonstrate the feasibility of halogen-bondbased organocatalysis. In the long term, we envision that halogen-based organocatalysts and hydrogen-bond donors will complement each other. Halogen-bond donors might be especially suitable for Lewis basic substrates featuring heavier elements (such as sulfur, phosphorous, or the halogens) or for certain reaction conditions. Furthermore, neutral fluorinated halogen-bond donors will likely allow the use of very nonpolar or fluorinated solvents in organocatalysis. Finally, the high directionality of halogen bonds might prove advantageous in future halogen-bond-catalyzed enantioselective transformations. In analogy to thiourea organocatalyst 1, we strove to develop multidentate halogen-based Lewis acids without further functional groups to study the isolated effect of halogen bonding. The 2,6-diiodo-3,4,5-trifluorophenyl group (Scheme 1) was chosen as building block for several reasons,

Measurement of accommodation after implantation of an accommodating posterior chamber intraocular lens.

Purpose: To analyze techniques of measuring accommodation after implantation of an accommodating posterior chamber intraocular lens (PC IOL). Setting: Department of Ophthalmology and University Eye Hospital, University Erlangen‐Nürnberg, Erlangen, Germany. Methods: This prospective study analyzed 23 eyes of 23 patients (aged 41 to 87 years) after cataract surgery and PC IOL implantation (1 CU®, HumanOptics) 4 weeks and 3 and 6 months after surgery. The results were compared to those in an age‐matched control group (n = 20) 6 months after surgery. The following methods were used to measure accommodation: dynamic with objective techniques (PlusOptix PowerRefractor® videorefractometry, streak retinoscopy) and subjective techniques (subjective near point [push‐up test, accommodometer], defocusing); static with pharmacologic stimulation after pilocarpine 2% eyedrops directly (conventional refractometry); indirectly (change in the anterior chamber depth [ACD] with Zeiss IOLMaster®). Results: Results at 6 months, given as mean ± SD (range), in the study and control groups, respectively, were as follows: near visual acuity (Birkhäuser reading charts at 35 cm) with distance correction, 0.32 ± 0.11 (0.20 to 0.60) and 0.14 ± 0.10 (0.05 to 0.30); accommodation amplitude (diopters) by PowerRefractor, 1.00 ± 0.44 (0.75 to 2.13) and 0.35 ± 0.26 (0.10 to 0.65), by retinoscopy, 0.99 ± 0.48 (0.13 to 2.00) and 0.24 ± 0.21 (–0.13 to +0.75), by subjective near point, 1.60 ± 0.55 (0.50 to 2.56) and 0.42 ± 0.25 (0.00 to 0.75), and by defocusing, 1.46 ± 0.53 (1.00 to −2.50) and 0.55 ± 0.33 (0.25 to 0.87). The mean ACD decrease (mm) was 0.78 ± 0.12 (0.49 to 1.91) and 0.16 ± 0.09 (0.00 to 0.34) after pilocarpine 2% eyedrops, indicating a mean accommodation of 1.40 D and 0.29 D, respectively, based on Gullstrands model eye (P = .001). The lowest fluctuation between follow‐ups was with the subjective near point and the defocusing techniques followed by ACD decrease with the IOLMaster. Conclusions: Accommodation after implantation of an accommodating PC IOL should be assessed with several techniques, including subjective and objective, to differentiate true pseudophakic accommodation from pseudoaccommodation. Researchers should be aware of the different variability and consistency of measurements with each technique over time.

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).

Halogen Bonding in Organic Synthesis and Organocatalysis

Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen-bonding-based organocatalysis is a well-established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen-bond donors in halide abstraction reactions or in the activation of neutral organic substrates.

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).

Time- and Space-Resolved Luminescence of a Photonic Dye–Zeolite Antenna

In a radiationless process, electronic excitation energy can be transported in the photonic antennae presented herein from the borders to the center of cylindrical zeolite L crystals (ca. 2 μm). These antennae are formed by supramolecular organization of a cationic and a neutral dye in the parallel channels of the crystal. The rectangles symbolize adsorption sites, for which the red ones are filled with red-emitting dyes and blue ones with blue-emitting dyes.

On the directionality of halogen bonding

The origin of the high directionality of halogen bonding was investigated quantum chemically by a detailed comparison of typical adducts in two different orientations: linear (most stable) and perpendicular. Energy decomposition analyses revealed that the synergy between charge-transfer interactions and Pauli repulsion are the driving forces for the directionality, while electrostatic contributions are more favourable in the less-stable, perpendicular orientation.

Unexpected trends in halogen-bond based noncovalent adducts.

Unexpected trends in the strengths of halogen-bond based adducts of CY(3)I (Y = F, Cl, Br, I) with two typical Lewis bases (chloride and trimethylamine) show that the halogen-bond donor strength (Lewis acidity) of a compound R-X is not necessarily increased with higher electronegativity of the (carbon-based) group R.

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.

Reduction of Nitrous Oxide to Dinitrogen by a Mixed Valent Tricopper-Disulfido Cluster

The greenhouse gas N(2)O is converted to N(2) by a mu-sulfido-tetracopper active site in the enzyme nitrous oxide reductase (N(2)OR) via a process postulated to involve mu-1,3 coordination of N(2)O to two Cu(I) ions. In efforts to develop synthetic models of the site with which to test mechanistic hypotheses, we have prepared a localized mixed valent Cu(II)Cu(I)(2) cluster bridged in a mu-eta(2):eta(1):eta(1) fashion by disulfide, [L(3)Cu(3)(mu(3)-S(2))]X(2) (L = 1,4,7-trimethyl-triazacyclononane, X = O(3)SCF(3)(-) or SbF(6)(-)). This cluster exhibits spectroscopic features superficially similar to those of the active site in N(2)OR and reacts with N(2)O to yield N(2) in a reaction that models the function of the enzyme. Computations implicate a transition state structure that features mu-1,1-bridging of N(2)O via its O-atom to a [L(2)Cu(2)(mu-S(2))](+) fragment and provide chemical precedence for an alternative pathway for N(2)O reduction by N(2)OR.