Organophosphorus Chemistry 2018

Organophosphorus chemistry is an important discipline within organic chemistry. Phosphorus compounds, such as phosphines, trialkyl phosphites, phosphine oxides (chalcogenides), phosphonates, phosphinates and >P(O)H species, etc., may be important starting materials or intermediates in syntheses. Let us mention the Wittig reaction and the related transformations, the Arbuzov- and the Pudovik reactions, the Kabachnik–Fields condensation, the Hirao reaction, the Mitsunobu reaction, etc. Other reactions, e.g., homogeneous catalytic transformations or C-C coupling reactions involve P-ligands in transition metal (Pt, Pd, etc.) complex catalysts. The synthesis of chiral organophosphorus compounds means a continuous challenge. Methods have been elaborated for the resolution of tertiary phosphine oxides and for stereoselective organophosphorus transformations. P-heterocyclic compounds, including aromatic and bridged derivatives, P-functionalized macrocycles, dendrimers and low coordinated P-fragments, are also of interest. An important segment of organophosphorus chemistry is the pool of biologically-active compounds that are searched and used as drugs, or as plant-protecting agents. The natural analogue of P-compounds may also be mentioned. Many new phosphine oxides, phosphinates, phosphonates and phosphoric esters have been described, which may find application on a broad scale. Phase transfer catalysis, ionic liquids and detergents also have connections to phosphorus chemistry. Green chemical aspects of organophosphorus chemistry (e.g., microwave-assisted syntheses, solvent-free accomplishments, optimizations, and atom-efficient syntheses) represent a dynamically developing field. Last, but not least, theoretical approaches and computational chemistry are also a strong sub-discipline within organophosphorus chemistry

Syntheses, structure and stability of some alkylphosphonic acids and their metal complexes.

The protonation end complexetion behaviour of the a-aminomethylenephosphonic acids diethylaminomethylenephonosphonic acid (DEAMPH2), N-ethyliminobis(methylenephosphonic acid) (NEIBMPH4), (+-)-trans-l,2-diaminecyclohexane tetrakis(methylenephosphonic acid) (CDTMPN8) and 5,8-dioxadodecane-1,12-diaminetetrakis(methylenephosphonic acid) (DDDTMPH8) were studied by potentiometry and near spectroscopy

Tailored ligands for zinc coordination

Selective coordination to zinc over other members of the first row transition metal series is important for the commercial application of lipophilic ligands for the hydrometallurgic recovery of the metal. In order to achieve selectivity for zinc(n) over other ions, particularly copper(II) and iron(III), ligands have to be designed which take advantage of zinc's preferred tetrahedral coordination geometry and the borderline donor atom preference of the metal. With such ligands in mind, three new classes of ligand system have been designed and synthesised based on the benzimidazole, quinoline and pyridine ring systems with appended phosphinic and thiophosphinic acid anionic donor groups. Benzimidazole ligands which bind zinc in a 2:1 manner in solution have been made and their complexation ability assessed by ESMS, (^31)p NMR, liquid-liquid extraction, fluorescence and UV absorption spectroscopic methods. A bisbenzimidazole ligand with a C(_3) spacer in the 2,2' position was synthesised and shown to bind zinc initially in a 2:1 manner, at low metal concentrations, and predominantiy as a 1:1 species at higher metal concentrations. The formation constant for the ML complex was shown to be logK(_ML)=5 by analysis of the NMR titration curve, which was in close agreement with the value obtained from liquid-liquid extraction studies. A directly linked 2,2'- bisbenziraidazole system was also synthesised as an extension to previous work, however isolation of the target ligand proved to be difficult due to the insolubility of the desired bis-acid.8-(Quinolinyl)phenylphosphinic acid and 8-(2-metiiylquinolinyl)phenylphosphinic acid were also synthesised and their solution complexation behaviour studied in detail. The unsubstituted ligand appeared to form 1:1 complexes with zinc at all the metal concentrations studied, and the absence of the methyl substituent does not inhibit coordination to the ferric ion. In contrast the metiiyl substituted ligand initially forms a 2:1 L:M complex, and 1:1 complexes at higher metal concentrations. The initial ML(_2) complex probably involves coordination of two of the phosphinic acid moieties. Three pyridyl derived ligand systems were also synthesised varying the bulk of the C-6 substituent and the effect of the phosphinic versus the thiophosphinic acid moiety towards zinc coordination was examined. Both of the methyl appended ligands were shown to bind zinc in a 2:1 manner, with the thiophosphinic acid exhibiting a greater avidity for zinc. In contrast, the unsubstituted ligand predominantly forms 1:1 complexes at all metal concentrations

HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs

HuR/ELAVL1 is an RNA-binding protein involved in differentiation and stress response that acts primarily by stabilizing messenger RNA (mRNA) targets. HuR comprises three RNA recognition motifs (RRMs) where the structure and RNA binding of RRM3 and of full-length HuR remain poorly understood. Here, we report crystal structures of RRM3 free and bound to cognate RNAs. Our structural, NMR and biochemical data show that RRM3 mediates canonical RNA interactions and reveal molecular details of a dimerization interface localized on the α-helical face of RRM3. NMR and SAXS analyses indicate that the three RRMs in full-length HuR are flexibly connected in the absence of RNA, while they adopt a more compact arrangement when bound to RNA. Based on these data and crystal structures of tandem RRM1,2-RNA and our RRM3-RNA complexes, we present a structural model of RNA recognition involving all three RRM domains of full-length HuR. Mutational analysis demonstrates that RRM3 dimerization and RNA binding is required for functional activity of full-length HuR in vitro and to regulate target mRNAs levels in human cells, thus providing a fine-tuning for HuR activity in vivo.España, MINECO BFU2015-71017España, Junta de Andalucía CVI-BIO198; P11-CVI7216 to I.D.M

"2'-deoxy-6-thioguanosine :synthesis of monomer, oligomers and long DNA, and their binding with metal ions

PhD ThesisThe formation of one-dimensional (1D) coordination polymers using thiolated DNA nucleosides and nucleotides with transition metals was investigated. 2’-Deoxy-6- 1 13 thioguanosine was successfully synthesised and characterized by H-NMR, C-NMR, IR, MS and UV spectroscopy. Subsequently, the binding of several transition metal ions to 2’-deoxy-6-thioguanosine and 6-thioguanosine was studied. The binding ratio of thio-monomer with metal ions was shown to be three ligands to one metal in the case of cobalt (II) and nickel (II), whilst in the case of the cadmium (II)-complex with the thio-monomer, the results suggested that a 1D coordination polymer might be formed, although no crystal data was obtained to confirm this structure. Therefore, the oligonucleotides containing the thiolated monomer were synthesised to extend this study. The preparation of thiolated homo-guanosine oligomers involved standard solid phase synthesis of oligo-guanosine followed by on-column conversion of guanosine to 6-thioguanosine. The thiolated reaction was the same as that used for the monomer and yielded 2-, 3-, 4- and 5-mer thio-oligomers in good yield. The thio-oligomers were purified by HPLC and were fully characterized by mass spectrometry and UV. The interaction of thio-oligomers with cadmium (II) ions was investigated. For the dimer and tetramer, the binding ratio was two thio-bases bound to one cadmium, whereas for the trimer and pentamer the binding ratio showed more than one binding species in solution. In order to synthesise a long thiolated DNA polymer, an enzymatic slippage reaction was performed, where a short primer-template of poly (dG)-poly (dC) was 1010 - extended up to 300 bp using Klenow exo polymerase and nucleosides triphosphate (d-tGTP and d-CTP). The addition of cadmium ions to thio-modified DNA suggested a structure resembling M-DNA as coordination polymer is obtained according to UV titration data

Tetrahedrally coordinating ligands

Selective ligand coordination of zinc over other metals such as copper (II) and iron (III) is desirable and has potential commercial uses in hydrometallurgy. With this in mind ligands have been synthesised that impart a tetrahedral donor array. Binding to zinc which prefers a tetrahedral binding geometry may achieve selectivity over other non-tetrahedrally coordinating metals. Di-N-alkylated bisbenzimidazole-4,4'-dicarboxylic acids have been synthesised and shown by proton NMR, ESMS and IR analysis to bind zinc as an [L(_2)Zn(_2)] species with selectivity over copper, nickel, lead and cadmium. Hence a reversal of the Irving- Williams sequence is observed. Aqueous extraction tests using a lipophilic N-alkylated derivative indicated that the observed selectivity over copper and iron (III) was not reproduced under these experimental conditions. The ligand began to extract in the pH 2.3-3.8 region.2,9-Diphosphinoxymethyl phenanthroline derivatives were synthesised and shown to bind nickel, copper and zinc with similar stability constants, with only marginal enhancement over that of the parent phenanthroline. The 1:1 complexes were produced at acidities below pH 2. Increasing the length of the pendent arm donor groups by using phenylacetic acid moieties did not enhance zinc selectivity. The donor group was not ideal and [ML(_2)] species were generated (i.e. an N(_4) donor set)Two phenol substituted 12N(_3) ligands were synthesised (N-linked and β-C- linked). Complex stability order followed die Irving-Williams sequence Cu > Zn > Ni. The N-linked derivative formed a six membered chelate on binding and had larger metal-ligand stability constants than for the C-linked derivative which formed an eight membered chelate. The N-linked derivative bound the copper (II) cation in a near tetrahedral arrangement and imparted some copper (I) character to the meta

Complexation of divalent copper, zinc and calcium ions by phosphate esters in aqueous solution

The role of metal ions as catalysts for numerous biochemical reactions has been the subject of many investigations. One of the most important classes of ligands are phosphate esters. In this thesis I describe the investigation of some phosphate ester-metal ion equilibria. Formation constants for the complexation of p-nitrophenyl phosphate, phenyl phosphate, 1-naphthyl phosphate, α-D-glucose-1'-phosphate, glycerol-2-phosphate, methyl phosphate, 8-quinolyl phosphate, 8-quinolyl methyl phosphate, triphosphate and fluorotriphosphate with protons, copper, zinc and calcium ions were determined by potentiometry. In addition, the complexation of 1-naphthyl phosphate, 8-quinolyl phosphate and 8-quinolyl methyl phosphate with nickel and cobalt ions was also studied. Protonation enthalpies and copper complexation enthalpies of p-nitrophenyl phosphate, phenyl phosphate, 1-naphthyl phosphate, α-D-glucose-1'-phosphate, glycerol-2-phosphate and methyl phosphate were determined by calorimetry. A correlation between the nucleophilicity of the ester group and the magnitude of the stability constants of the proton, copper and zinc complexes of p-nitrophenyl phosphate, phenyl phosphate, 1-naphthyl phosphate, α-D-glucose-1'-phosphate, glycerol-2-phosphate and methyl phosphate is found and explained in terms of electronic induction effects, i.e. by polarisation of the phosphate oxygens by the ester group. The calorimetric results show that the desolvation of ligand and metal ion during the complexation plays an important role. The possibility of similar correlations for complexes of triphosphates is also discussed

Complexation behaviour of Aza-phosphink acids

An alkylphosphinate is an attractive isostere for a carboxylate. The acid is more acidic than a carboxylic acid, is amenable to (^31)P NMR analysis and is subject to easy structural modification by variation of the phosphorus alkyl or aryl substituent. Amino acid complexing agents incorporating carboxymethyl groups are ubiquitous, but the corresponding phosphinic acid analogues have been much less studied. On chelation of a metal ion to a ligand nitrogen and a phosphorus oxygen atom, a new stereogenic centre at phosphorus is created. In polydentate ligands diastereoisomeric complexes may form. A new family of acyclic ligands with phosphinic acid binding groups have been synthesised. The protonation constants have been determined and used for the determination of the stability constants for a range of metal complexes. A complexing agent based on a 9N(_3) macrocyclic skeleton incorporating pendant arm phosphinic acid donors, provides an octahedral site for metal complexation. The structures of seven complexes with a ligand of this type, have been determined by X-ray crystallography. They fall into two groups, those with a C(_3) axis (Cu (II), Co (II), Zn (II) and Ni (II)) and those with an approximate C(_3) axis (Ga (III), Fe (III) and In (III))

Tetraaza[14]macrocyclic transition metal complexes as DNA intercalators

Six tetraazamacrocyclic copper(II) and nickel(II) complexes have been synthesised and their interactions with double-stranded DNA (calf thymus DNA) have been studied using circular and linear dichroism, as well as other spectroscopic methods. The ability of these complexes to intercalate between DNA base pairs has been demonstrated qualitatively and confirmed by determining the stoichiometry and association constant values; these were found to range from 8.5 × 103 – 2.8 × 104 L mol–1. The nickel(II) complexes, being more electron-deficient, seem to have higher binding abilities than guests containing the copper ion. It has also been shown that not only CD, but also linear dichroism, can be a very useful tool for carrying out qualitative DNA interaction studies