Martin U. Schmidt

Significant progress in predicting the crystal structures of small organic molecules – a report on the fourth blind test

We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.

Crystal structure prediction of small organic molecules: a second blind test.

The first collaborative workshop on crystal structure prediction (CSP1999) has been followed by a second workshop (CSP2001) held at the Cambridge Crystallographic Data Centre. The 17 participants were given only the chemical diagram for three organic molecules and were invited to test their prediction programs within a range of named common space groups. Several different computer programs were used, using the methodology wherein a molecular model is used to construct theoretical crystal structures in given space groups, and prediction is usually based on the minimum calculated lattice energy. A maximum of three predictions were allowed per molecule. The results showed two correct predictions for the first molecule, four for the second molecule and none for the third molecule (which had torsional flexibility). The correct structure was often present in the sorted low-energy lists from the participants but at a ranking position greater than three. The use of non-indexed powder diffraction data was investigated in a secondary test, after completion of the ab initio submissions. Although no one method can be said to be completely reliable, this workshop gives an objective measure of the success and failure of current methodologies.

A Two-Dimensional Polymer from the Anthracene Dimer and Triptycene Motifs

A two-dimensional polymer (2DP) based on the dimerization of anthraceno groups arranged in a triptycene motif is reported. A photoinduced polymerization is performed in the crystalline state and gives a lamellar 2DP via a crystal-to-crystal (but not single-crystal to single-crystal) transformation. Solvent-induced exfoliation provides monolayer sheets of the 2DP. The 2DP is considered to be a tiling, a mathematical approach that facilitates structural elucidation.

Crystal structures of quinacridones

The crystal structure of the αI-phase of quinacridone was determined from non-indexed X-ray powder data by means of crystal structure prediction and subsequent Rietveld refinement. This αI-phase is another polymorph than the α-phase reported by Lincke [G. Lincke and H.-U. Finzel, Cryst. Res. Technol. 1996, 31, 441–452.]. The crystal structures of the β and γ polymorphs were determined from single crystal data. The knowledge of the crystal structures can be used for crystal engineering, i.e., for targeted syntheses of pigments having desired properties, especially for the syntheses of new red pigments.

Bis(di-t-butylphosphino)methane complexes of rhodium: homogeneous alkyne hydrosilylation by catalyst-dependent alkyne insertion into RhSi or RhH bonds. Molecular structures of the dimer [(dtbpm)RhCl]2 and of the silyl complex (dtbpm) Rh[Si(OEt)3](PMe3)☆

The homogeneous, Rh-catalysed hydrosilylation of but-2-yne with triethoxysilane has been studied. All rhodium complexes employed as catalyst precursors contain tBu2PCH2PtBu2 (“dtbpm”) as a chelating ligand. The crystal and molecular structure of the dimer [(dtbpm)RhCl]2 (10) has been determined by X-ray diffraction. Complex 10 is shown to be a sluggish catalyst in hydrosilylation reactions of hex-1-ene, whereas but-2-yne is hydrosilylated more rapidly. A much more efficient and highly selective catalyst is 10 with added PPh3, equivalent to the use of monomeric (dtbpm)RhCl(PPh3). (E)-2-Triethoxysilylbut-2-ene is formed exclusively and with high turnover numbers in this case. For both 10 and its PPh3 derivative, the 14-electron fragment [(dtbpm)RhCl], formed by dissociation processes, is the most likely active intermediate in a Harrod-Chalk-type catalytic cycle. The PPh3 dissociation equilibrium has been studied in detail for (dtbpm)RhCl(PPh3) and its thermodynamic parameters have been determined. With rhodium alkyl complexes as catalyst precursors, a different type of alkyne hydrosilylation catalysis, involving direct alkyne insertion into the RhSi bond of an intermediate rhodium silyl complex, (dtbpm)Rh[Si(OEt)3](PMe3) (14), has been found. Complex 14 was synthesized independently from (dtbpm)RhMe(PMe3) and characterized by X-ray diffraction. It is an equally active catalyst itself, yielding (E)-2-triethoxysilylbut-2-ene as the major product (90%) from but-2-yne and HSi(OEt)3 (turnover number 1000 per 30 min). The insertion step of the alkyne into the RhSi bond of 14 and the formation of two stereoisomeric rhodium vinyl complexes were established independently for MeO2CCCCO2Me as a more reactive alkyne substrate. A catalytic cycle is proposed for this unprecedented hydrosilylation reaction. The synthesis of the ν3-benzyl complex (dtbpm)Rh(η3-CH2C6H5) (23) is described. This compound allows an alternative, more efficient access to the new silyl complex (dtbpm)Rh[Si(OEt)3](PMe3).

The Thermodynamically Stable Form of Solid Barbituric Acid: The Enol Tautomer

Barbituric acid, which has been known since 1863, is drawn in textbooks always as the keto tautomeric form 1 (Scheme 1). Indeed, this is the most stable form in the gas phase and in solution. Also in the solid state, the keto tautomer is observed in the metastable phase I, the commercial phase II, and a high-temperature phase III, as well as in its dihydrates. In contrast, we now observe that the recently discovered tautomeric polymorph IV consists of molecules in the enol form 2, and that this polymorph is actually the thermodynamically stable phase at ambient conditions. The preference for the enol form in the solid state is explained by the formation of an additional strong hydrogen bond in the crystal, leading to a more favorable lattice energy. Polymorph IV is obtained from phase II by grinding or milling. Solid-state NMR (SSNMR), IR, and Raman experiments revealed this to be a tautomeric polymorph, which does not consist of the keto tautomer 1, but of one of the enol forms. The spectroscopic data suggested the trienol tautomer, but other enol tautomers could not be ruled out. All attempts to obtain single crystals of phase IV by recrystallization failed, and dehydration of the dihydrate yielded only phase II. The grinding or milling processes resulted in powders of poor crystallinity. However, it was possible to index the laboratory X-ray powder data and to solve the crystal structure by simulated annealing, while refinement was carried out by the Rietveld method from synchrotron data (Figure 1). The bond lengths in the OCN framework revealed phase IV to consist of molecules in the enol form 2. Scheme 1. Barbituric acid in the keto (1) and enol (2) tautomeric forms.

Influence of the co-ligand on the magnetic and relaxation properties of layered cobalt(II) thiocyanato coordination polymers.

Reaction of Co(NCS)2 with 1,2-bis(4-pyridyl)-ethane (bpa) leads to the formation of [Co(NCS)2(bpa)2]n, which, on heating, transforms into the new layered coordination polymer [Co(NCS)2(bpa)]n. This compound can also be prepared in solution, but because no reasonable single crystals are available, its crystal structure was determined from X-ray powder data from scratch. In the crystal structure of [Co(NCS)2(bpa)]n, the cobalt(II) cations are coordinated by two S-bonded and two N-bonded thiocyanato anions and two N atoms of the bpa co-ligands in a distorted octahedral geometry. The cobalt(II) cations are linked into chains by pairs of μ-1,3 bridging thiocyanato anions. These chains are further connected into layers by the 1,2-bis(4-pyridyl)-ethane ligand. The compound was magnetically characterized, and, for comparative purposes, the complementary magnetic study of a known and very similar compound, [Co(NCS)2(bpe)]n (bpe = 1,2-bis(4-pyridyl)-ethylene), was also undertaken. The compounds differ in their interchain interactions, which are antiferromagnetic but significantly greater for [Co(NCS)2(bpe)]n. Magnetic measurements indicate that [Co(NCS)2(bpa)]n is a canted antiferromagnet with Néel temperature TN = 3.1 K and that Co(NCS)2(bpe) is an antiferromagnet with TN = 4.0 K. Both compounds show a metamagnetic transition with a critical field HC ∼ 40 Oe and ∼ 400 Oe, respectively. Magnetic relaxations were studied by means of dc and ac methods and analyzed using the Argand diagrams. Except for the thermally activated single chain and domain wall relaxations observed for both compounds, temperature-independent slow relaxations were observed for [Co(NCS)2(bpa)]n.

LOW GLUTATHIONE POOLS IN THE ORIGINAL PSO3 MUTANT OF SACCHAROMYCES CEREVISIAE ARE RESPONSIBLE FOR ITS PLEIOTROPIC SENSITIVITY PHENOTYPE

Abstract The original pso3-1 mutant isolate of the yeast Saccharomyces cerevisiae exhibits a pleiotropic mutagen-sensitivity phenotype that includes sensitivity to UVA-activated 3-carbethoxypsoralen, to UVC-light, to mono- and bi-functional nitrogen mustard, to paraquat, and to cadmium; on the other hand, it shows hyper-resistance (HYR) to nitrosoguanidine when compared to established wild-type strains. Also, the original pso3-1 mutant exhibits a low UVC-induced mutability and mitotic gene conversion and a high rate of spontaneous and UVC-induced petite mutations. Since the HYR to the nitrosoguanidine (MNNG) phenotype resembles that of low glutathione-containing yeast cells, the original pso3-1 mutant was crossed to a gsh1 knock-out mutant that lacks the enzyme for the first step in glutathione biosynthesis and the resulting diploid was tested for complementation. While there was none for HYR to nitrosoguanidine, and other low glutathione-related phenotypes, some other phenotypic characteristics of pso3-1, e.g. UVC sensitivity and UVC-induced mutability were restored to a wild-type level. Tetrad analysis of a diploid derived from a cross of the original haploid pso3-1 isolate with a repair-proficient, normal glutathione-containing, PSO3 GSH1 wild-type led to the separation of a leaky gsh1 mutation phenotype from that of the repair-deficient pso3-1 phenotype. Linkage studies by tetrad and random spore analyses indicated no linkage of the two genes. This shows that the low glutathione content in the original pso3-1 isolate is due to a second, additional, mutation in the GSH1 locus and is unrelated to the pso3-1 mutation. Thus, the original pso3-1 isolate is a pso3-1 gsh1 double mutant with most of the particular characteristics of the pleiotropic sensitivity phenotype contributed by either the pso3-1 or the gsh1-leaky mutant allele. The expression of a few phenotypic characteristics of pso3, however, were most pronounced in pso3-1 mutants with a low glutathione pool.

Overexpression of ADH1 confers hyper-resistance to formaldehyde in Saccharomyces cerevisiae.

Abstract In an attempt to clone genes involved in resistance to formaldehyde we have screened a genomic library based on the episomal plasmid YEp24 for the ability to increase resistance to formaldehyde in a wild-type strain. In addition to SFA, the gene encoding the formaldehyde dehydrogenase Adh5, an enzyme most potent in formaldehyde de-toxification, we isolated a second plasmid that conferred a less pronounced but significant hyper-resistance to formaldehyde. Its passenger DNA contained the gene ADH1, encoding alcohol dehydrogenase 1 (EC 1.1.1.1), which could be shown to be responsible for the observed hyper-resistance phenotype. Construction of an adh1-0 mutant revealed that yeast lacking a functional ADH1 gene is sensitive to formaldehyde. While glutathione is essential for Adh5-mediated formaldehyde de-toxification, Adh1 reduced formaldehyde best in the absence of this thiol compound. Evidence is presented that formaldehyde is a substrate for Adh1 in vivo and in vitro and that its cellular de-toxification employs a reductive step that may yield methanol.

Pair distribution function X‐ray analysis explains dissolution characteristics of felodipine melt extrusion products

Solid solutions of felodipine with EUDRAGIT E and EUDRAGIT E/NE were shown to dramatically increase the dissolution rate of felodipine in biorelevant media. Of the two polymer systems, extrudates containing 5% EUDRAGIT NE showed a faster dissolution rate and less recrystallization (no precipitation within 2 h). Although differential scanning calorimetry (DSC) and conventional X-ray powder diffraction (XRPD) were able to verify the amorphous state of the drug after melt extrusion, it was not possible to differentiate the two extrudate compositions further with these methods. We then applied pair distribution function (PDF) analysis to investigate extrudates. It was possible to more closely characterize the solid state of the amorphous extrudates in terms of local structural order: PDF analysis revealed that addition of minor amounts of EUDRAGIT NE to the main component EUDRAGIT E during extrusion changed the local structure of EUDRAGIT E in a nonadditive way. We conclude that local ordering can be important to the release characteristics of extrudates, even when the components are present in the amorphous state.