W. Bernd Schweizer

The Fluorine-Iminium Ion Gauche Effect : Proof of Principle and Application to Asymmetric Organocatalysis

The gauche effect that is induced upon reversible formation of an iminium ion (see structure: green F, blue N) provides a powerful method for the preorganization of transient intermediates that are central to secondary amine catalyzed processes. This phenomenon has been exploited in the design of a novel organocatalyst and is showcased in the stereoselective epoxidation of alpha,beta-unsaturated aldehydes.

Origin of intense intramolecular charge-transfer interactions in nonplanar push-pull chromophores.

Planar push–pull chromophores featuring intense intramolecular charge-transfer (CT) interactions have been extensively studied in view of their potential applications in molecular electronics and optoelectronics. In contrast, only a limited number of nonplanar low-molecular-weight donor– acceptor chromophores has been reported and the impact of nonplanarity on their p-conjugative and optoelectronic properties not been systematically investigated. Nonplanar CT chromophores tend to feature some desirable physical properties compared to their planar counterparts: they are usually more soluble, less aggregating, and more readily sublimable, forming amorphous, rather than crystalline films for potential use in optoelectronic devices. We showed recently that donor-substituted alkynes undergo a formal [2+ 2] cycloaddition with electron-accepting olefins, such as tetracyanoethene (TCNE), 7,7,8,8-tetracyanoquinodimethanes (TCNQs), as well as dicyanovinyl (DCV) and tricyanovinyl derivatives, followed by retroelectrocyclization, under formation of nonplanar push–pull chromophores featuring intense intramolecular CT and high third-order optical nonlinearities. Nonplanar, N,N-dimethylanilino (DMA) donor-substituted 1,1,4,4-tetracyanobuta-1,3-dienes (TCBDs), obtained by [2+ 2] cycloaddition of TCNE, produce high-optical quality amorphous films by vapor-phase deposition which in the meanwhile have found first application in silicon-organic-hybrid (SOH) waveguides. A key question raised was the origin of the intense intramolecular CT interactions in these push–pull chromophores, in view of their pronounced nonplanarity which is expected to lead to disruption of donor–acceptor p-conjugation and concomitant reduction in CT efficiency and optical nonlinearity. To investigate the effects of sterically enforced deconjugation on optoelectronic properties, we prepared two new series of push–pull chromophores (1 and 2, and 3–8), by adding TCNE or TCNQ to tetrathiafulvalene (TTF)or ferrocenyl (Fc)-substituted alkynes, respectively. These strong electron donors have found numerous applications in intermolecular and intramolecular CT systems, but have not seen much use for activating alkynes electronically for the cycloaddition of TCNE or TCNQ. TTF-appended TCBD 1 was obtained in 41 % yield as a deep blue solid by reaction of TCNE with TTF-substituted alkyne 9 in 1,2-dichloroethane at 80 8C (Scheme 1). The electronically more activated alkyne 10, with both TTF and DMA donor groups, reacted at room temperature to give 2 in 79 % yield. The ferrocene-substituted expanded TCNQs 3–8 were formed as black metallic-like solids in 41–81 % yield by regioselective cycloaddition between TCNQ and the acetylenic precursors 11–16. With the exception of 3 and 8, these push–pull chromophores are thermally stable up to 300 8C, as revealed by thermal gravimetric analysis (TGA); compound 6 can actually be sublimed without decomposition at about 250 8C/1 10 6 Torr. Single crystals of 1 and 3–5 suitable for X-ray analysis were grown from CH2Cl2/hexane at 15 8C (Figure 1 and Figure S1–S4 in the Supporting Information). Considerable nonplanarity is observed in the TCBD and expanded TCNQ acceptor moieties. Thus, the dihedral angle q (C1-C2-C17C18) between the two DCV planes in 1 (with two independent molecules) is 92.7(2)8. In the expanded TCNQ chromophores 3–5, the dihedral angle q between the DCV and the cyclohexa-2,5-diene-1,4-diylidene moiety changes from 51.9(4)8 (3, torsional angle C1-C2-C3-C4, Figure S2) to 68.6(2)8 (5, C5-C8-C9-C16, Figure S4), and to 94.0(2)8 (4, C1-C12-C13-C14). Sterically enforced p-deconjugation is [a] Dr. S.-i. Kato, Dr. M. Kivala, Dr. W. B. Schweizer, Prof. Dr. F. Diederich Laboratorium f r Organische Chemie, ETH Z rich Hçnggerberg, HCI, 8093 Z rich (Switzerland) Fax: (+41) 44-632-1109 E-mail : diederich@org.chem.ethz.ch [b] Prof. Dr. C. Boudon, Dr. J.-P. Gisselbrecht Laboratoire d’Electrochimie et de Chimie Physique du Corps Solide Intstitut de Chimie-UMR 7177, C.N.R.S. Universit de Strasbourg 4, rue Blaise Pascal, 67000 Strasbourg (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901630.

Property Tuning in Charge‐Transfer Chromophores by Systematic Modulation of the Spacer between Donor and Acceptor

A series of donor-acceptor chromophores was prepared in which the spacer separating 4-dimethylanilino (DMA) donor and C(CN)(2) acceptor moieties is systematically varied. All of the new push-pull systems, except 4 b, are thermally stable molecules. In series a, the DMA rings are directly attached to the central spacer, whereas in series b additional acetylene moieties are inserted. X-ray crystal structures were obtained for seven of the new, intensely colored target compounds. In series a, the DMA rings are sterically forced out of the mean plane of the residual pi system, whereas the entire conjugated pi system in series b is nearly planar. Support for strong donor-acceptor interactions was obtained through evaluation of the quinoid character of the DMA ring and by NMR and IR spectroscopy. The UV/Vis spectra feature bathochromically shifted, intense charge-transfer bands, with the lowest energy transitions and the smallest optical gap being measured for the two-dimensionally extended chromophores 6 a and 6 b. The redox behavior of the push-pull molecules was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In the series 1 b, 2 b, 4 b, 5 b, in which the spacer between donor and acceptor moieties is systematically enlarged, the electrochemical gap decreases steadily from 1.94 V (1 b) to 1.53 V (5 b). This decrease is shown to be a consequence of a reduction in the D-A conjugation with increasing spacer length. Degenerate four-wave mixing experiments reveal high third-order optical nonlinearities, pointing to potentially interesting applications of some of the new chromophores in optoelectronic devices.

Direct Photolysis of Human Metabolites of the Antibiotic Sulfamethoxazole: Evidence for Abiotic Back-Transformation

The presence of potentially persistent and bioactive human metabolites in surface waters gives rise to concern; yet little is known to date about the environmental fate of these compounds. This work investigates the direct photolysis of human metabolites of the antibiotic sulfamethoxazole (SMX). In particular, we determined photolysis kinetics and products, as well as their concentrations in lake water. SMX, N-acetyl sulfamethoxazole, sulfamethoxazole β-D-glucuronide, 4-nitroso sulfamethoxazole, and 4-nitro sulfamethoxazole were irradiated under various light sources and pH conditions. All investigated metabolites, except sulfamethoxazole β-D-glucuronide were found to be more photostable than SMX under environmentally relevant conditions. Between two and nine confirmed photoproducts were identified for SMX-metabolites through ultraperformance liquid chromatography/high-resolution mass spectrometry. Interestingly, photolytic back-transformation to SMX was observed for 4-nitroso-SMX, indicating that this metabolite may serve as an environmental source of SMX. Moreover, two human metabolites along with SMX were regularly detected in Lake Geneva. The knowledge that some metabolites retain biological activity, combined with their presence in the environment and their potential to retransform to the parent compound, underlines the importance of including human metabolites when assessing the effects of pharmaceuticals in the environment.

1,2,3-Triazoles as Conjugative π-Linkers in Push−Pull Chromophores: Importance of Substituent Positioning on Intramolecular Charge-Transfer

Isomeric charge-transfer chromophores using 1,2,3-triazol-diyl as linker have been studied experimentally and computationally. The instability of the polarized reactants precluded the use of the Huisgen reaction and alternative synthetic methodologies were employed. Charge-transfer absorptions between an N,N-dimethylanilino and a dicyanovinyl group are modest to strong, with maxima from lambda(max) = 400 to 453 nm depending on substituent positioning. TD-B3LYP/6-31G(d) calculations are within 0.6 eV of experiment and assign these bands as HOMO-LUMO transitions.

Derivatives of α,α,α',α'-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (TADDOL) containing nitrogen, sulfur, and phosphorus atoms. New ligands and auxiliaries for enantioselective reactions

Abstract α,α,α′,α′-Tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanols are converted to bicyclic phosphites and phosphonites (2a–2e) by reaction with Cl2PR and Cl2POR derivatives. - One or both OH groups of the parent TADDOL can be replaced by Cl (→, 4a, 5a), and the halide in turn substituted by azide (→ 4b, 5b), thiocyanide (→ 6), or sulfide (→ 8). Reduction of the azido group(s) to NH2 and N-alkylation or acylation furnishes a variety of amino alcohols (4c–4f) and diamines (5c–5f), as well as a bis(trifluoroacetamide) (5g). Cyclization of the aminoalcohol (4c) produces a bicyclic system (7), containing a pyrrolidine ring (structure determination by X-ray diffraction). - The new chiral compounds containing nitrogen and phosphorus atoms might be useful ligands and auxiliaries for enantioselective syntheses.

Regio-and stereoselective isomerization of hexabromocyclododecanes (HBCDs) : Kinetics and mechanism of γ-to α-HBCD isomerization

Hexabromocyclododecanes (HBCDs) are high production volume chemicals (>20000 ty(-1)) used as flame retardants for plastics and textiles. Lately, we reported on the stereoselective isomerization of beta-HBCDs. Herein we present insights into the mechanism and kinetics of (+)gamma- to (+)alpha- and of (-)gamma- to (-)alpha-HBCD isomerization. Only two of the six bromine atoms migrated, indicating that rearrangements of gamma- to alpha-HBCDs are regio- and stereoselective as well. The apparent first-order isomerization rate constants increased from 0.0013 to 0.0031 to 0.0070 min(-1) at 120, 130, and 140 degrees C, respectively, corresponding to half-lives of 540, 230, and 99 min. Thus, a thermal treatment of materials containing gamma-HBCDs at temperatures >100 degrees C may induce the formation of alpha-HBCDs and, hence, may alter the diastereomeric ratio of a HBCD mixture. The inversion of vicinal dibromides in like-configurations (RR/SS) prevailed, whereas unlike-configurations (RS/SR) were not affected. An intramolecular, stereoselective migration of neighboring bromine atoms via a four-center transition state would explain the observed stereoisomer pattern and first-order kinetics. Despite the fact that vicinal dibromides in HBCDs prefer synclinal (gauche) conformations, antiperiplanar (staggered) conformations are assumed to facilitate concerted 1.2-shifts of both bromine atoms. A conformation analysis revealed that under kinetic control, only those bromine atoms in the more flexible part of the molecules are migrating, whereas those in the conserved triple-turn motive were not affected. Thus, this structural motive, common to all alpha-, beta-, and gamma-HBCDs, is more rigid and less reactive than the flexible part, containing the reacting dibromides in like-configurations.

Redox-switchable resorcin[4]arene cavitands: molecular grippers.

Diquinone-based resorcin[4]arene cavitands that open to a kite and close to a vase form upon changing their redox state, thereby releasing and binding guests, have been prepared and studied. The switching mechanism is based on intramolecular H-bonding interactions that stabilize the vase form and are only present in the reduced hydroquinone state. The intramolecular H-bonds were characterized using X-ray, IR, and NMR spectroscopies. Guests were bound in the closed, reduced state and fully released in the open, oxidized state.

Self‐Assembly and Two‐Dimensional Spontaneous Resolution of Cyano‐Functionalized [7]Helicenes on Cu(111)

Birds of a feather flock together: STM and DFT studies provide the first example of spontaneous chiral resolution of a helicene on a surface. Racemic 6,13-dicyano[7]helicene forms fully segregated domains of pure enantiomers (2D conglomerate) on Cu(111). The propensity of the system to optimize intermolecular CN⋅⋅⋅HC(Ar) hydrogen bonding and CN⋅⋅⋅CN dipolar interactions translates into chiral recognition with preferential assembly of homochiral molecules.

Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines

The pentafluorosulfanyl (SF5) group is a perfectly stable building block under physiological conditions. Pioneering work on the synthesis and properties of SF5-containing aromatic compounds was carried out by Sheppard half a century ago. Thereafter, this novel substituent had been largely ignored by the chemical community for several decades. Due to the ACHTUNGTRENNUNGincreased availability of SF5-substituted derivatives, the organic chemistry of SF5-containing derivatives has come recently under more widespread investigation and has lead to multiple applications in material sciences. Fueled by the knowledge of the pronounced influence of fluorine on the physical and chemical properties 15] and therefore on the bioactivity of molecules, the interest of the life science industry in novel fluorine containing substituents is nowadays prevalent. Accordingly, the SF5 group has gained the attraction of crop ACHTUNGTRENNUNGscience in the recent years, as underlined by the growing number of patents and research articles 17, 18] for mainly agrochemicals containing this functional group. The SF5 group bears much similarity to the CF3 substituent, but it is even more electronegative (Hammett substituent constants: SF5 : sp =+0.68; CF3: sp =+0.54) [3] and has a higher lipophilicity (Hansch hydrophobicity constants: SF5 : p= 1.51, CF3 : p= 1.09). In addition, the SF5 group is distinguished by a higher thermal and chemical stability than its carbon relative 2] and has been characterized as a “super-trifluoromethyl” group in the literature. Its strong polarity in combination with high lipophilicity and thermal stability renders the SF5 group a highly interesting structural motif in medicinal chemistry. To the best of our knowledge, no structure–activity relationship (SAR) data on the target level have been reported for SF5containing derivatives to date. We selected the flavoenzyme trypanothione reductase (TR, EC 1.6.4.8), found in parasites of the trypanosomatid family, as a target for the design of SF5bearing inhibitors. Trypanosomatid parasites possess trypanothione [N,N-bis(glutathionyl)spermidine] and the enzyme TR instead of the nearly ubiquitous glutathione system composed of glutathione and the flavoenzyme glutathione reductase (GR, EC 1.6.4.2). TR, which is the key enzyme of the trypanothione-based antioxidant defence systems of parasitic trypanosomes and Leishmania, has been shown to be essential ; this renders the enzyme a promising target for the development of new drugs against antiparasitic drugs. Trypanosoma brucei is the causative agent of human African trypanosomiasis (African sleeping sickness), which threatens millions of people in ~36 countries of sub-Saharan Africa with an estimated number of current cases between 50 000 and 70 000. Trypanosoma cruzi is the pathogen of Chagas’ disease (American trypanosomiasis), an infection widespread in central and southern America and is responsible for 14 000 deaths each year. Another trypanosomatid-caused disease, leishmaniasis, is provoked by various species of Leishmania. The different forms of the disease range from cutaneous to visceral infections with millions of people infected. Around 50 000 deaths per year are quoted mainly due to L. donovani. New and improved drugs to fight these diseases are urgently needed, as current therapy for all forms of trypanosomiases and leishmaniases is problematic due to the severe adverse effects of the drugs in use, the long duration and high costs of treatment, and an increasing number of drug resistant pathogens. 24] In the search for new drugs against trypanosomatid-induced diseases, TR has become an increasingly popular target. Various compounds have been discovered over the last decade that moderately inhibit TR. Noticeably, several of them feature a basic or quaternary nitrogen connected through a flexible alkyl chain to a hydrophobic core. One of the prototypes of this inhibitor class are diaryl sulfide-based compounds, first reported by Sergheraert et al. and further explored by Douglas et al. In order to explore the eligibility of SF5 as a building block for TR inhibitors and to compare it with the corresponding CF3 or C ACHTUNGTRENNUNG(CH3)3 analogues, we designed and synthesized diarylamine derivatives 1–6, which are structurally related to the known class of diphenyl sulfide inhibitors (Scheme 1). In order to synthesize the diphenylamine core of the inhibitor scaffold, para-CF3-substituted aniline 7 was reacted with 2,5-dichloronitrobenzene, which delivered the desired diphenylamine 8 together with a considerable amount of triphenylACHTUNGTRENNUNGamine 9. This twofold coupled side product of the nucleophilic [a] Dr. B. Stump, C. Eberle, Dr. W. B. Schweizer, Prof. Dr. F. Diederich Laboratorium f r Organische Chemie, ETH Z rich, Hçnggerberg, HCI 8093 Z rich (Switzerland) Fax: (+ 41) 44-632-1109 E-mail : diederich@org.chem.ethz.ch [b] M. Kaiser, Prof. Dr. R. Brun Swiss Tropical Institute Socinstrasse 57, 4002 Basel (Switzerland) [c] Prof. Dr. R. L. Krauth-Siegel Universit t Heidelberg, Biochemie-Zentrum (BZH) Im Neuenheimer Feld 504, 69120 Heidelberg (Germany) [d] Prof. Dr. D. Lentz Institut f r Chemie und Biochemie, Anorganische Chemie Freie Universit t Berlin Fabeckstrasse 34/36, 14195 Berlin (Germany) Supporting information for this article is available on the WWW under http ://www.chembiochem.org or from the author.