Wouter A. Herrebout

A confidence level algorithm for the determination of absolute configuration using vibrational circular dichroism or Raman optical activity

Spectral comparison is an important part of the assignment of the absolute configuration (AC) by vibrational circular dichroism (VCD), or equally by Raman optical activity (ROA). In order to avoid bias caused by personal interpretation, numerical methods have been developed to compare measured and calculated spectra. Using a neighbourhood similarity measure, the agreement between a computed and measured VCD or ROA spectrum is expressed numerically to introduce a novel confidence level measure. This allows users of vibrational optical activity (VOA) techniques (VCD and ROA) to assess the reliability of their assignment of the AC of a compound. To that end, a database of successful AC determinations is compiled along with neighbourhood similarity values between the experimental spectrum and computed spectra for both enantiomers. For any new AC determination, the neighbourhood similarities between the experimental spectrum and the computed spectra for both enantiomers are projected on the database allowing an interpretation of the reliability of their assignment.

On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination.

Pyrido[1,2-a]benzimidazoles1, 2a are interesting compounds both from the viewpoint of medicinal chemistry2–7 (solubility,7 DNA intercalation3) and materials chemistry8 (fluorescence). Of note among the former is the antibiotic drug Rifaximin,5 which contains this heteroaromatic core. The classical synthetic approach for the assembly of pyrido[1,2-a]benzimidazoles is by [3+3] cyclocondensation of benzimidazoles containing a methylene group at C2 with appropriate bielectrophiles.2a However, these procedures are often low-yielding, involve indirect/lengthy sequences, and/or provide access to a limited range of products, primarily providing derivatives with substituents located on the pyridine ring (A ring, Scheme 1).2–4 Theoretically, a good alternative synthetic method for the synthesis of pyrido[1,2-a]benzimidazoles with substituents in the benzene ring (C ring) should be accessible by intramolecular transition-metal-catalyzed CN bond formation in N-(2-chloroaryl)pyridin-2-amines, based on chemistry recently developed in our research group.9 These substrates themselves are easily available through SNAr or selective Pd-catalyzed amination10 of 2-chloropyridine with 2-chloroanilines.11 If a synthetic procedure that eliminated the need for preactivation of the 2-position of the 2-chloroarylamino entity could be developed, this would be even more powerful, as anilines are more readily commercially available than 2-chloroanilines. Therefore the synthesis of pyrido[1,2-a]benzimidazoles (4) by a transition-metal-catalyzed intramolecular CH amination approach from N-arylpyridin-2-amines (3) was explored (Scheme 1).

Halogen Bonding from a Hard and Soft Acids and Bases Perspective: Investigation by Using Density Functional Theory Reactivity Indices

Halogen bonds between the trifluoromethyl halides CF(3)Cl, CF(3)Br and CF(3)I, and dimethyl ether, dimethyl sulfide, trimethylamine and trimethyl phosphine were investigated using Pearsons hard and soft acids and bases (HSAB) concept with conceptual DFT reactivity indices, the Ziegler-Rauk-type energy-decomposition analysis, the natural orbital for chemical valence (NOCV) framework and the non-covalent interaction (NCI) index. It is found that the relative importance of electrostatic and orbital (charge transfer) interactions varies as a function of both the donor and acceptor molecules. Hard and soft interactions were distinguished and characterised by atomic charges, electrophilicity and local softness indices. Dual-descriptor plots indicate an orbital σ hole on the halogen similar to the electrostatic σ hole manifested in the molecular electrostatic potential. The predicted high halogen-bond-acceptor affinity of N-heterocyclic carbenes was evidenced in the highest complexation energy for the hitherto unknown CF(3) I·NHC complex. The dominant NOCV orbital represents an electron-density deformation according to a n→σ*-type interaction. The characteristic signal found in the reduced density gradient versus electron-density diagram corresponds to the non-covalent interaction between contact atoms in the NCI plots, which is the manifestation of halogen bonding within the NCI theory. The unexpected C-X bond strengthening observed in several cases was rationalised within the molecular orbital framework.

In vitro selection and characterization of DNA aptamers recognizing chloramphenicol.

Chloramphenicol (Cam), although an effective antibiotic, has lost favour due to some fatal side effects. Thus there is an urgent need for rapid and sensitive methods to detect residues in food, feed and environment. We engineered DNA aptamers that recognize Cam as their target, by conducting in vitro selections. Aptamers are nucleic acid recognition elements that are highly specific and sensitive towards their targets and can be synthetically produced in an animal-friendly manner, making them ethical innovative alternatives to antibodies. None of the isolated aptamers in this study shared sequence homology or structural similarities with each other, indicating that specific Cam recognition could be achieved by various DNA sequences under the selection conditions used. Analyzing the binding affinities of the sequences, demonstrated that dissociation constants (K(d)) in the extremely low micromolar range, which were lower than those previously reported for Cam-specific RNA aptamers, were achieved. The two best aptamers had G rich (>35%) nucleotide regions, an attribute distinguishing them from the rest and apparently responsible for their high selectivity and affinity (K(d)∼0.8 and 1μM respectively). These aptamers open up possibilities to allow easy detection of Cam via aptamer-based biosensors.

C-2 arylation of piperidines through directed transition-metal-catalyzed sp3 C-H activation.

The development of transition-metal-catalyzed methods for the direct functionalization of C H bonds has attracted much attention during the past decade. While the direct functionalization of sp C H bonds is an active field of research, the corresponding knowledge on sp C H bonds is still limited and remains one of the current challenges in organic chemistry. Within the area of sp C H activation, the transformation of a C H bond in the a-position to the nitrogen atom of saturated cyclic amines is of particular importance, since such heterocyclic motifs can be found in an impressive number of natural products and marketed drugs. The intermolecular, direct transition-metal-catalyzed functionalization of saturated cyclic amines adjacent to nitrogen offers a simple and efficient synthetic approach towards valuable building blocks. To the best of our knowledge, only six articles are hitherto published on this topic, wherein the main focus is on five-membered cyclic subACHTUNGTRENNUNGstrates.[6,7a] In 2006, Sames and co-workers reported the first direct arylation of saturated cyclic amines through transition-metal-catalyzed sp C H activation, involving arylboronate esters as a coupling partner. Pyrrolidines were successfully arylated adjacent to nitrogen by using a Ru-catalyzed C-H activation process, directed by a pyrroline group and mediated by ketone (used also as a solvent). The authors suggested that the key role of the ketone (pinacolone) is to allow a transmetalation by transforming the initially formed metal hydride species into a metal alkoxide intermediate. The pyrroline directing group could be removed by treatment of the a-arylated pyrrolidines with NH2NH2/ AcOH. One example of a piperidine substrate also appeared in this work, which was C-2 p-methoxyphenylated in moderate yield (38 %). The six-membered piperidine ring is inherently less reactive than its five-membered analogue (pyrrolidine) due to its chair conformation. Consequently, there are very few examples in the literature of direct functionalization of piperidines by means of a transition-metalcatalyzed, sp C H activation process. We report here a novel method for the direct C-2 arylation of piperidines with arylboronate esters, resulting from a mechanistic study of the transmetalation step of the catalytic cycle. As part of our interest in C-2 functionalized 4-substituted piperidines, we first applied the conditions described by Sames and co-workers to 1-(pyrrolin-2-yl)-4-piperidinone ethylene ketal (Scheme 1, 1). Unfortunately, the reaction of 1 with phenylboronic acid pinacol ester resulted in a low conversion to the arylated product, and directing group in[a] Dr. H. Prokopcov , Dr. S. D. Bergman, Dr. K. Aelvoet, V. Smout, Prof. Dr. B. U. W. Maes Organic Synthesis, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) Fax: (+32) 32653233 E-mail : bert.maes@ua.ac.be [b] Prof. Dr. W. Herrebout, Prof. Dr. B. Van der Veken Cryospectroscopy, University of Antwerp Groenenborgerlaan 171, 2020 Antwerp (Belgium) [c] Dr. L. Meerpoel Johnson & Johnson Pharmaceutical Research & Development A Division of Janssen Pharmaceutica N.V. Turnhoutseweg 30, 2340 Beerse (Belgium) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001887. Scheme 1. 4-Piperidinone ethylene ketal bearing a pyrroline or pyridine directing group: substrates designed to explore the C-2 arylation process.

CX⋅⋅⋅O Halogen Bonding: Interactions of Trifluoromethyl Halides with Dimethyl Ether

The formation of weakly bound molecular complexes between dimethyl ether (DME) and the trifluoromethyl halides CF(3)Cl, CF(3)Br and CF(3)I dissolved in liquid argon and in liquid krypton is investigated, using Raman and FTIR spectroscopy. For all halides evidence is found for the formation of C-X...O halogen-bonded 1:1 complexes. At higher concentrations of CF(3)Br, a weak absorption due to a 1:2 complex is also observed. Using spectra recorded at temperatures between 87 and 125 K, the complexation enthalpies for the complexes are determined to be -6.8(3) kJ mol(-1) (DME x CF(3)Cl), -10.2(1) kJ mol(-1) (DME x CF(3)Br), -15.5(1) kJ mol(-1) (DME x CF(3)I), and -17.8(5) kJ mol(-1) [DME(x CF(3)Br)(2)]. Structural and spectral information on the complexes is obtained from ab initio calculations at the MP2/6-311++G(d,p) and MP2/6-311++G(d,p)+LanL2DZ* levels. By applying Monte Carlo free energy perturbation calculations to account for the solvent influences, and statistical thermodynamics to estimate the zero-point vibrational and thermal influences, the ab initio complexation energies are converted into complexation enthalpies for the solutions in liquid argon. The resulting values are compared with the experimental data deduced from the cryosolutions.

Solvent effects on IR and VCD spectra of natural products: an experimental and theoretical VCD study of pulegone.

The VCD spectra of pulegone, dissolved in CDCl3, CD2Cl2 and CS2 have been recorded in the frequency range from 1000 to 3000 cm(-1). The assignment of the absolute configuration was performed by comparing the experimental data with theoretical spectra computed at the B3LYP/6-311+G(d,p) level. Analysis of the agreement in several spectral regions revealed significant shortcomings when comparing with vacuum calculations. It is shown that the agreement improves when the solvent effects are taken into account by a continuum model. For the measurements in CDCl3 and CD2Cl2 further improvement was found when considering explicitly 1 : 1 complexes between a pulegone and a CDCl3 or CD2Cl2 solvent molecule in vacuo, while the best agreement was obtained when embedding these in a continuum model. The presence of the chiral solute was found to induce a VCD active C-D stretch band which could be modeled also at ab initio level.

A VCD robust mode analysis of induced chirality: The case of pulegone in chloroform†

Vibrational modes in an achiral molecule may acquire rotational strength by complexation to a chiral molecule, as happens for achiral solvent molecules complexed to a chiral solute. We investigate this transfer of chirality in vibrational circular dichroism for the pulegone molecule in CDCl(3) solvent from the point of view of the robustness concept introduced recently. It turns out that the transfer of chirality yields nonrobust modes, which means that, although they are observed in vibrational circular dichroism (VCD) experiments, the sign of these modes cannot be predicted reliably with standard (Density Functional Theory) VCD calculations. This limits the usefulness of the induced chirality phenomenon for obtaining information on the intermolecular interactions that give rise to it.

Van der Waals Complexes between Unsaturated Hydrocarbons and Boron Trifluoride: An Infrared and ab Initio Study of Ethene·BF3 and Propene·BF3

The mid-infrared (4000−400 cm-1) spectra of ethene/BF3 and propene/BF3 mixtures, dissolved in liquid argon (93−125K) and in liquid nitrogen (80−118K) are discussed. In all spectra, the formation of a 1:1 van der Waals complex, in which the electron deficient BF3 molecule binds to the CC double bond, was observed. Using spectra recorded at different temperatures, the complexation enthalpy ΔHo for ethene·BF3 was determined to be −10.0 ± 0.2 kJ mol-1 in liquid argon and −5.4 ± 0.3 kJ mol-1 in liquid nitrogen, while for propene·BF3 the ΔHo are −11.8 ± 0.2 and −6.9 ± 0.3 kJ mol-1, respectively. For both complexes a converged structure and the harmonic vibrational frequencies were calculated using ab initio calculations at the MP2/6-31+G* level.

Experimental characterization of C-X···Y-C (X = Br, I; Y = F, Cl) halogen-halogen bonds.

Using FTIR and Raman spectroscopy, we investigated the formation of halogen bonded complexes of the trifluorohalomethanes CF3Cl, CF3Br, and CF3I with the halomethanes CH3F and CH3Cl and the haloethanes C2H5F and C2H5Cl dissolved in liquid krypton. For CF3Br and CF3I, evidence was found for the formation of C-X···F and C-X···Cl halogen bonded 1:1 complexes. Using spectra recorded at different temperatures, we determined the complexation enthalpies for the complexes to be -7.0(3) kJ mol(-1) for CF3Br·CH3F, -7.6(1) kJ mol(-1) for CF3I·CH3F, -5.9(2) kJ mol(-1) for CF3Br·CH3Cl, -8.3(3) kJ mol(-1) for CF3I·CH3Cl, -7.1(1) kJ mol(-1) for CF3Br·C2H5F, -8.7(2) kJ mol(-1) for CF3I·C2H5F, -6.5(2) kJ mol(-1) for CF3Br·C2H5Cl, and -8.8(3) kJ mol(-1) for CF3I·C2H5Cl. For all halogen bonded complexes with a fluorine-electron donor, a blue shift ranging from +0.6 to +1.5 cm(-1) was observed for the C-X stretching mode. The results from the cyrospectroscopic study are compared with ab initio calculations at the MP2/aug-cc-pVDZ(-PP) level.