Exploring polymorphism and stoichiometric diversity in naproxen/proline cocrystals

We present naproxen/proline cocrystals discovered when combining enantiopure and racemic naproxen and proline. Using liquid-assisted grinding as the main method to explore the variety of crystal forms in this system, we found 17 cocrystals, of which the structures of only four of them were previously known. The naproxen/proline system exhibited multiple polymorphs of 1 : 1 stoichiometry as well as more rare cocrystals with 1 : 2 and 2 : 3 stoichiometries, two cocrystal hydrates and one cocrystal solvate. In situ ball-milling, used to monitor liquid-assisted grinding reactions, revealed that the solvent dictates the reaction intermediates even if the final reaction product stays the same. Synchrotron X-ray diffraction data collected in situ upon heating allowed us to monitor directly the phase changes upon heating and gave access to pure diffraction patterns of several cocrystals, thus enabling their structure determination from powder X-ray diffraction data; this method also confirmed the formation of a conglomerate in the RS-naproxen/DL-proline system. Proline in cocrystals kept its ability to form charge-assisted head-to-tail N–H⋯O hydrogen bonds, typical of pure crystalline amino acids, thus increasing the percentage of strong charge-assisted interactions in the structure and consequently providing some of the cocrystals with higher melting points as compared to pure naproxen. The majority of drugs are chiral, and hence, these data are of importance to the pharmaceutical industry as they provide insight into the challenges of chiral cocrystallization

Synthesis and post-functionalization of alternate-linked-meta-para-[2(n). 1(n)]thiacyclophanes

In recent decades, considerable research attention has been devoted to new synthetic procedures for thiacyclophanes. Thiacyclophanes are widely used as host molecules for the molecular recognition of organic compounds as well as metals. Herein, we report the selective and high-yielding synthesis of novel alternate-linked-meta-para-thiacyclophanes. These novel thiacyclophanes are selectively synthesized in high-yielding procedures. Furthermore, post-functionalization of the phenolic moieties was successfully performed. The 3D structure of the alternate-linked-meta-para-[22.12]thiacyclophane was further elucidated via X-ray crystallographic analysis

trans-Chlorido[6-chloro-4-(4-methoxy­benz­yl)-3-oxo-3,4-dihydro­pyrazin-2-yl]­bis­(triphenyl­phosphine)palladium(II)

The title compound, [Pd(C12H10ClN2O2)Cl(C18H15P)2], is the inter­mediate of the reduction of a 3,5-dichloro­pyrazinone [Loosen, Tutonda, Khorasani, Compernolle & Hoornaert (1991 ▶). Tetra­hedron, 47, 9259–9268]. This species is formed by oxidative addition of coordinatively unsaturated Pd0 to the reactive 3-position of the heterocycle. The coordination around the Pd atom is square planar, with two trans PPh3 ligands. π–π inter­actions are observed between the centroid of the pyrazinone ring and planes of two adjacent phenyl rings, one from each PPh3 group (3.25 and 3.078 Å), stabilizing the inter­mediate structure. This could explain the reduced reactivity towards substitution of the Cl atom by the formate anion, resulting in poor yield of the reduced compound. 3-Substituted pyrazinones are important precursors in the synthesis of 5-amino­piperidinone-2-carboxyl­ate (APC) systems

Stereoselective Syntheses and Application of Chiral Bi- and Tridentate Ligands Derived from (+)-Sabinol

A library of bidentate diols, as well as tridentate triols and aminodiols, derived from (+)-sabinol, was synthesized in a stereoselective manner. Sabinol was transformed into allylic trichloroacetamide via Overman rearrangement of the corresponding trichloroacetimidate. After changing the protecting group to Boc, the enamine was subjected to stereospecific dihydroxylation with OsO4/NMO, resulting in the (1R,2R,3R,5R)-aminodiol diastereomer. The obtained primary aminodiol was transformed to a secondary analogue. The ring closure of the N-benzyl-substituted aminodiol with formaldehyde was investigated and regioselective formation of the spiro-oxazolidine ring was observed. Hydroboration or dihydroxylation of sabinol or its benzyl ether with OsO4/NMO resulted in the formation of sabinane-based diols and triols following a highly stereospecific reaction. Treatment of sabinol with m-CPBA afforded O-benzoyl triol as a diastereoisomer of the directly dihydroxylated product, instead of the expected epoxy alcohol. The resulting aminodiols, diol, and triols were applied as chiral catalysts in the reaction of diethylzinc and benzaldehyde from moderate to good selectivity

Revisiting the planarity of nucleic acid bases: Pyramidilization at glycosidic nitrogen in purine bases is modulated by orientation of glycosidic torsion

We describe a novel, fundamental property of nucleobase structure, namely, pyramidilization at the N1/9 sites of purine and pyrimidine bases. Through a combined analyses of ultra-high-resolution X-ray structures of both oligonucleotides extracted from the Nucleic Acid Database and isolated nucleotides and nucleosides from the Cambridge Structural Database, together with a series of quantum chemical calculations, molecular dynamics (MD) simulations, and published solution nuclear magnetic resonance (NMR) data, we show that pyramidilization at the glycosidic nitrogen is an intrinsic property. This property is common to isolated nucleosides and nucleotides as well as oligonucleotides—it is also common to both RNA and DNA. Our analysis suggests that pyramidilization at N1/9 sites depends in a systematic way on the local structure of the nucleoside. Of note, the pyramidilization undergoes stereo-inversion upon reorientation of the glycosidic bond. The extent of the pyramidilization is further modulated by the conformation of the sugar ring. The observed pyramidilization is more pronounced for purine bases, while for pyrimidines it is negligible. We discuss how the assumption of nucleic acid base planarity can lead to systematic errors in determining the conformation of nucleotides from experimental data and from unconstrained MD simulations

Structure determination of cyclohexene nucleic acid (CeNA) duplexes by X-ray diffraction.

Het ontwikkelen van de cyclohexeennucleïnezuren kadert in het antisense-onderzoek. De antisense-methode biedt de mogelijkheid om niet alleen genetische ziekten zoals kanker, maar ook HIV te genezen. Een antisense geneesmiddel is een oligonucleotide dat selectief met mRNA bindt om zo de productie van bepaalde eiwitten te blokkeren. Deze oligonucleotiden moeten aan een aantal voorwaarden voldoen, zo moeten ze chemisch en enzymatisch stabiel zijn. De mogelijkheid om RNaseH te activeren is een pluspunt omdat RNaseH selectief de RNA-streng in DNA/RNA-hybriden afbreekt. In deze thesis is het effect van één of meer ingebouwde cyclohexeenresidu s op de driedimensionale structuur van nucleïnezuren nagegaan. In een eerste deel werd een cyclohexeenresidu ingebouwd in de welbekende Dickerson-sequentie CGCGAA*TTCGCG. Het cyclohexeenresidu (A*) veroorzaakte geen grote vervorming van de B-type structuur, wat een bewijs is voor de flexibiliteit van het cyclohexeenresidu. Deze Dickerson-sequentie met het gemodificeerde adenineresidu kristalliseerde uit in de ruimtegroep P2221, wat vrij uitzonderlijk is omdat nog geen enkele nucleïnezuursequentie tot nu toe in deze ruimtegroep uitkristalliseerde. Omdat het mogelijk is dat twee cyclohexeenresidu s in tegenoverstaande strengen elkaar conformationeel beïnvloeden, werd de heptameersequentie GCGT*GCG/CGCACGC (met T* een cyclohexeenresidu) onderzocht. Ondanks hoge-resolutie metingen op kristallen van de heptameersequentie, kon de structuur niet opgelost worden. Verscheidene technieken ( SAD phasing en direct methods ) zijn gepland om de nodige fase-informatie te verkrijgen. In een volgend hoofdstuk is de kristalstructuur van een volledig gemodificeerd cyclohexeenoctameer GTGTACAC beschreven. Fase-informatie werd bekomen door middel van moleculaire verplaatsings-technieken met de hexitolstructuur als model in de rhombohedrische ruimtegroep R32. Het octameer is echter opgebouwd uit linksdraaiende bouwstenen, wat aanleiding geeft tot een linksdraaiende helix. In het kristalrooster stapelen de helices op elkaar en vormen zo continue kolommen. Deze stapeling is ook de directe oorzaak van de geobserveerde wanorde. De structuur is verfijnd in twee delen die 4 baseparen ten opzichte van elkaar verschoven zijn. De biologische eenheid wordt bekomen door het toepassen van de kristallo grafische tweetallige as, net zoals bij de gemodificeerde Dickerson sequentie CGCGAA*TTCGCG. De linksdraaiende helix vertoont alle belangrijke karakteristieken van A-type DNA, zoals een grote x-displacement , geïnclineerde basenparen en typische waternetwerken. In het laatste hoofdstuk worden enkele algemene conclusies, evenals gelijkenissen en verschillen tussen de cyclohexeenresidu s belicht, samen met enkele mogelijkheden voor uitbreiding in de toekomst.LIST OF ABBREVIATIONS Chapter I DNA, RNA, and CeNA 1 1 Introducing DNA 1 1.1 Molecular Basis for Genetic Information 1 1.2 Conformational Parameters 3 1.3 The Double Helix 8 1.4 DNA Families 11 1.4.1 B type Helices 11 1.4.2 A type Helices 12 1.4.3 Z type Helices 13 2 Antisense Therapy 17 2.1 Biological Function of DNA 17 2.2 Antisense Strategy 18 2.3 Difficulties to Overcome 20 3 Cyclohexene Nucleic Acids 22 3.1 Chemical Structure of CeNA 22 3.2 Properties of CeNA 23 References 27 Chapter II Crystallography 31 1 X Ray Diffraction: Theoretical Background 31 1.1 The Direction of Diffraction: Bragg’s Law 32 1.2 The Intensity of the Diffracted Beam 34 2 Crystal Structure Determination of Macromolecules 37 2.1 Crystallization 37 2.2 Data Collection and Processing 39 2.3 Breaking the Phase Problem 42 2.4 Structure Refinement 46 2.4.1 Least-squares Method 47 2.4.2 Maximum Likelihood 49 2.4.3 Maximum Likelihood and Least-squares 51 2.5 Structure Analysis and Deposition 53 References 55 Scope and Outline of the Thesis 57 References 60 Chapter III The Dickerson Sequence with an Incorporated CeNA Residue 61 1 Experimental Procedure 62 1.1 Synthesis of the CGCGAA*TTCGCG Sequence 62 1.2 Crystallization 63 1.3 Data Collection and Processing 63 1.4 Structure Solution 65 1.5 Numbering Scheme 69 1.6 Structure Refinement 69 2 Results 73 2.1 Structural Features of the Helix 74 2.2 Base Stacking 88 2.3 Hydration and Thermal Parameters 90 2.4 Comparison between the Two Biological Units 97 2.5 The Modified versus the Native Dickerson Sequence 98 2.6 Crystal Packing 100 3 Conclusions 106 References 108 Chapter IV The Heptamer Sequence d(GCGT*GCG)/d(CGCACGC) 113 1 Experimental Procedure 114 1.1 Synthesis of the GCGT*GCG Sequence 114 1.2 Crystallization 114 1.3 Data Collection and Processing 115 1.4 Structure Solution 117 2 Conclusions 119 References 121 Chapter V The Left-Handed CeNA Sequence GTGTACAC 123 1 Experimental Procedure 123 1.1 Synthesis of the L-CeNA Sequence GTGTACAC 123 1.2 Thermal Denaturation of L-CeNA Sequences 124 1.3 Crystallization 125 1.4 Data Collection and Processing 126 1.5 Structure Solution 129 1.6 Numbering Scheme 129 1.7 Structure Refinement 130 2 Results 135 2.1 Structural Features of the Helix 135 2.2 Base Stacking 151 2.3 Hydration and Thermal Parameters 153 2.4 Comparison between the Two Static Disordered Parts 160 2.5 DNA, HNA, and CeNA 161 2.6 Crystal Packing 163 3 Conclusions 166 References 168 Chapter VI General Conclusions and Future Prospects 171 References 173 SUMMARY SAMENVATTING Appendix A ‘Refmac’ RESTRAINTS I Appendix B ‘SHELXL’ RESTRAINTS VI Appendix C LIST OF USED PROGRAMS VIIIstatus: publishe

Synthesis of water-soluble ruthenium clusters by reaction with PTA (1,3,5-triaza-7-phosphaadamantane)

In the search for new water-soluble ruthenium clusters, [Ru3(CO)12], [Ru5C(CO)15] and [Ru6C(CO)17] were reacted with ligand PTA (1,3,5-triaza-7-phosphaadamantane) to obtain compounds [Ru3(CO)12-x(PTA)x] (x ¼ 1 (4), 2 (5), 3 (6)), [Ru5C(CO)15-x(PTA)x] (x ¼ 1 (9), 2 (10), 3 (11), 4 (12), 5 (13), 6 (14)), and [Ru6C(CO)17-x(PTA)x] (x ¼ 1 (15), 2 (16), 3 (17), 4 (18), 5 (19), 6 (20)), respectively. The PTA ligand adds itself to ruthenium clusters very easily thanks to its low cone angle. Column chromatography purification under various conditions was necessary to obtain pure compounds. In total, fourteen new clusters could be synthesized and characterized. The water-solubility property is not reached after the addition of only one ligand but several are needed, the number depending on the core compound. For [Ru3(CO)12] derivatives, one phosphine per ruthenium atom is needed while it is less than one phosphine per ruthenium atom for the other compounds. It is postulated that the PTA forms a solubility envelope around the metal core: the number of PTA ligands necessary for water-solubility decreases proportionally as the nuclearity in the metal core increases. All new compounds were characterized by IR, NMR and HRMS and all analyses assessed the proposed formulae. Furthermore, clusters 4 [Ru3(CO)11(PTA)1], 5 [Ru3(CO)10(PTA)2], 9 [Ru5C(CO)14(PTA)1] and 10 [Ru5C(CO)13(PTA)2] were characterized by single crystal X-ray diffraction. It is observed that the phosphine occupies sites so as to minimize steric interactions. Degradation products of the reaction between [Ru3(CO)12] and PTA were found as a result of air exposure or high temperature treatment and were identified by crystal structure analysis as the mononuclear complexes 7 [Ru(CO)4(PTA)1] and 8 [Ru(CO)3(PTA)2]

Ontwikkelen en uittesten van een monitoringinstrument in de Vlaamse thuislozenzorg

nrpages: 241status: publishe

Solid-state thermo- and photochromism in N,N′-bis(5-X-salicylidene) diamines (X = H, Br)

Sixteen N,N′-bis(salicylidene)diamines of common formula (o-OHC 6H 4CN-) 2Z [Z = o-C 6H 4 (1a), m-C 6H 4 (2a), p-C 6H 4 (3a), O (4a), CH 2(p-C 6H 4) 2 (5a), O(p-C 6H 4) 2 (6a), S(p-C 6H 4) 2 (7a), SO 2(p-C 6H 4) 2 (8a)] and N,N′-bis(5-bromosalicylidene)diamines of common formula (2-OH-(5-Br)C 6H 3CN-) 2Z [Z = o-C 6H 4 (1b), m-C 6H 4 (2b), p-C 6H 4 (3), O (4b), CH 2(p-C 6H 4) 2 (5b), O(p-C 6H 4) 2 (6b), S(p-C 6H 4) 2 (7b), SO 2(p-C 6H 4) 2 (8b)] have been synthesized and characterized by elemental analysis, X-ray powder diffraction, NMR, diffuse reflectance, Raman, IR and fluorescence spectroscopy. Molecular structures of 2a, 6a, 7a, 8a and 4b were elucidated by single crystal X-ray diffraction. Their structures are stabilized by two intramolecular hydrogen bonds and weak intermolecular π⋯π stacking interactions. All molecules are thermochromic, while molecules 2a and 2b exclusively display photochromism upon irradiation at 450 and 365 nm, respectively, which is reversible and exhibits relatively slow thermal relaxation. © 2012 The Royal Society of Chemistry