Lourdes Infantes

Extended motifs from water and chemical functional groups in organic molecular crystals

The probability of organic compounds crystallising as hydrates increases with increasing number of polar chemical groups in the molecule. The extended patterns of H-bonding involving chemical groups and water molecules have been studied and classified. The most frequent ring, chain, tape and layer patterns displayed between the water molecules alone in organic molecular crystals are also predominant patterns in the larger H-bond network when other donor/acceptors are included.

Organic crystal hydrates: what are the important factors for formation

A database study of 34 770 accurate organic crystal structures reveals that the most important factor determining a higher frequency of hydrates is the sum of the average donor and acceptor counts for the functional groups. Different parameter forms for donor/acceptor properties were investigated for correlation with formation of hydrates, and are discussed. We did not find that the donor/acceptor ratio or the molecular weight significantly affects the hydrate formation. We also examined a wide range of calculated molecular properties and found that increasing polar surface is correlated with increasing hydrate formation. The water environment pattern of donor and acceptor hydrogen bonds in the crystal is influenced by the donor/acceptor ratio of the molecule.

New synthetic approaches to condensed pyridazinones: alkylpyridazinyl carbonitriles as building blocks for the synthesis of condensed pyridazinones

Abstract The pyridazinyl-5-carbonitriles (3a-d) were prepared via condensing the aryl hydrazones 2a-d with ethyl cyanoacetate. Similar condensation of 2a with malononitrile gives the pyrido[2,3-c]pyridazine derivative (8). Compounds 3a-d reacted with elemental sulphur in refluxing ethanolic solutions in the presence of triethylamine to yield the thieno[3,4-d]pyridazinones 9a-d. The 1,3,4-thiadiazaacenaphthene 12 was prepared via reacting 9e with diethyl fumarate. In contrast, only the phthalazines 14a-c were produced from the reaction of 13a-c with 9e. Compounds 9a-c reacted with acrylonitrile to yield the 1,3,4-thiadiazaacenaphthenes 18a, b. Compound 3a condensed with benzaldehyde to yield 19a. Condensation of 3a, c, d with dimethylformamide dimethylacetal afforded 19b-d. Compound 19b cyclized into 20b when refluxed in acetic acid in the presence of ammonium acetate. This same product was obtained from the reaction of the amide 3g with formaldehyde in refluxing pyridine. The reaction of 3a, c with arylidenemalononitrile (23a, b) gives the tetrahydrophthalazines 25a-c. The pyridazin-4-ones 26a-d were prepared from the reaction of 2a-d with dimethylformamide dimethylacetal in refluxing dioxane. The crystal and molecular structure of compound 18a was solved by X-ray analysis.

Hydrogen bond competition between chemical groups: new methodology and the Cambridge Structural Database

Abstract The probabilities of formation of intermolecular hydrogen bond interactions between chemical groups have been studied using new methodology to extract information from the Cambridge Structural Database (CSD). Data for 41052 crystal structures containing at least one strong hydrogen bond donor have been analysed using the RPluto program, assigning 108 chemical group codes to atoms, and creating tables of hydrogen contacts for subsequent analysis using the Access relational database software. This has enabled the study of competition effects where there are specified limited numbers of chemical groups in a structure, which is often difficult with the standard CSD search program, ConQuest. There are sufficiently high numbers of certain combinations of groups to make significant observations of the preference of a given donor for choices of acceptor atoms. For example, COOH…COOH contacts are frequently disrupted by groups such as keto carbonyl, whereas CONH…CONH is very robust and is seldom disrupted. There are a surprising number of structures that do not present any intermolecular hydrogen bond interactions, often due to intramolecular hydrogen bonding taking preference. There is a tendency to use as many groups as possible to build intermolecular hydrogen bond networks. An estimate is made of the relative strengths of self-association interactions which are, in decreasing order, CONH, COOH, alcoholic OH and phenolic OH. The frequency of preferred contacts in some cases allows one to predict the most probable contacts for a given molecule with a specific combination and ratio of chemical groups.

STRUCTURE AND TAUTOMERISM OF 3(5)-AMINO-5(3)-ARYLPYRAZOLES IN THE SOLID STATE AND IN SOLUTION : AN X-RAY AND NMR STUDY

Abstract The crystal and molecular structures of five 3(5)-amino-5(3)-arylpyrazoles differing in the nature of the substituent at the para position of the phenyl ring (1: X = H; 3.H2O: X = OCH3; 4: X = Cl; 5: X = Br and 6: X = NO2) have been determined by X-ray analysis. Three situations were detected in the crystal structures: the 3-tautomer is present in 1, 3 and 4; the 5-tautomer is only found in 6 and both tautomers (1:1) are observed in 5. The crystal packings are governed by NH… N O hydrogen bonds and also by OH…N interactions in the monohydrate of 3. It is worth noting that in 1, 3, 4 and 5 there are N-H…π(arene) contacts that might play a role in stabilizing the packing. Solid state 13C NMR results are consistent with the above crystallographic conclusions, thus allowing to determine that the only compound for which no good crystals have been obtained, the p-methyl derivative 2 should be a 3-amino tautomer. NMR solution studies (1H and 13C) allow to determine the 3-amino/5-amino tautomeric equilibrium constant, KT, which obeys a Hammett relationship with σp. Geometry optimizations of the 3 and 5-tautomers at semi-empirical level (AM1) were performed. In all compounds, the 3-tautomer has been found to possess a relatively lower energy by approximately 2 kcal mol−1. The potential energy surface as a function of the hybridization of the amino group and its conformation have also been analyzed.

A practical two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-yl)pyridin-2-amines.

The Sandmeyer reaction of differently C-2 substituted N-(prop-2-yn-1-ylamino)pyridines is an efficient, mild, new and practical method for the stereospecific synthesis of (E)-exo-halomethylene bicyclic pyridones bearing the imidazo[1,2-a]pyridine heterocyclic ring system.

Controlling Optical Properties and Function of BODIPY by Using Asymmetric Substitution Effects

Asymmetrically substituted BODIPY analogues of the dye PM567 have been synthesised from 2-acylpyrroles and pyrroles that bear indene, fluorene or difluorene units. The type of linkage between the fluorene and the BODIPY core plays an important role in the photophysics of the BODIPY chromophore. Indeed, an aliphatic bridge gives rise to an energy-transfer process between the chromophores, whereas a vinyl spacer allows an electronic interaction between them, leading to a large red shift of the spectral bands. The laser action of the new dyes has been analysed under transversal pumping at 10 Hz repetition rate, in both liquid phase and incorporated into solid polymeric matrices. Lasing efficiencies of up to 40% were reached with high photostabilities with the laser output remaining at the initial level after 1×10(5) pump pulses in the same position of the sample. The laser action of the new dyes outperforms the laser behaviour of commercial dyes that emit in the same spectral region. The replacement of fluorene by indene quenches the fluorescence and laser emission, but allows the development of an iron cation fluorescent sensor.

Knowledge-based approaches to crystal design

The 365 000 crystal structures recorded so far in the Cambridge Structural Database (CSD) have already been used extensively in the study of intermolecular interactions and crystal packing, providing fundamental knowledge that can be applied in crystal engineering and crystal design. However, as the scientific problems posed to the CSD become more sophisticated, there is a need to develop more extensive software facilities for database searching and for analysing search results. In this Highlight, we review a number of novel informatics approaches to the CSD, including derivative databases and new research software, and exemplify their use in providing further knowledge that is important in the design of novel crystalline materials.

Quaternary α,α-2-oxoazepane α-amino acids: synthesis from ornithine-derived β-lactams and incorporation into model dipeptides.

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple Pd-C-catalyzed hydrogenolysis of Orn(Z)-derived 2-azetidinones. The rearrangement from four- to seven-membered lactam ring is driven by the key intramolecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig ring closure from the NH(2) of the Orn side chain. The synthetic route is applied to the stereoselective preparation of enantiomerically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.

Further Evidence for 2-Alkyl-2-carboxyazetidines as γ-Turn Inducers

Reverse turns, a common motif in proteins and peptides, have attracted attention due to their relevance in a wide variety of biological processes. In an attempt to artificially imitate and stabilize these turns in short peptides, we have developed versatile synthetic methodologies for the preparation of 2-alkyl-2-carboxyazetidines and incorporated them into the i + 1 position of model tetrapeptides, where they have shown a tendency to induce gamma-turns. However, to ascertain the general utility of these restricted amino acids as gamma-type reverse turn inducers, it was then required to study the conformational preferences when located at other positions. To this end, model tetrapeptides R-CO-Ala-Xaa-NHMe, containing differently substituted azetidine moieties (Xaa = Aze, 2-MeAze, 2-BnAze) at the i + 2 position, were synthesized and subjected to a thorough conformational analysis. The theoretical and experimental results obtained, including the X-ray diffraction structure of a dipeptide derivative containing this skeleton, provide evidence that the 2-alkyl-2-carboxyazetidine scaffold is able to efficiently induce gamma-turns when incorporated into these short peptides, irrespective of their localization in the peptide chain.