Towards improved characterisation of complex polyethylene glycol excipients using supercritical fluid chromatography-evaporative light scattering detection-mass spectrometry and comparison with size exclusion chromatography-triple detection array.

The application of supercritical fluid chromatography (SFC) coupled to an evaporative light scattering detector (ELSD) and mass spectrometer (MS) was evaluated for the characterisation of three analogues of functionalised polyethylene glycol (PEG) 2000 (m-PEG-OH, m-PEG-cm and cm-PEG-cm (where m = OCH3 and cm = OCH2COOH)). These polymers are common excipients in drug product formulations for pharmaceuticals as they help provide the desired pharmacokinetic profile for successful drug delivery. A SFC-ELSD-MS method was developed which was selective to all three polymers, and allowed visualisation of these low UV chromophore materials. The method provided baseline resolution of the individual oligomers which allowed facile calculation of the polymer dispersity. A number of molecular weight characteristics were calculated, which showed the SFC-ELSD-MS methodology to be comparable with the current standard of analysis using size exclusion chromatography (SEC) with a triple detector array (TDA). The increased resolving power of SFC compared to SEC revealed a bimodal distribution of oligomers in the cm-PEG-cm 2000 polymer, which was not observed using SEC-TDA and exemplified SFC-ELSD as an orthogonal approach for polymer characterisation with the potential for much simpler, reduced sample and instrument preparation, calibration-less dispersity determination. When combined with SEC-TDA data, this combination allows a more complete characterisation of complex formulations excipients.

Mono- and dinuclear Ni(i) products formed upon bromide abstraction from the Ni(i) ring-expanded NHC complex [Ni(6-Mes)(PPh3)Br].

Bromide abstraction from the three-coordinate Ni(i) ring-expanded N-heterocyclic carbene complex [Ni(6-Mes)(PPh3)Br] (1; 6-Mes = 1,3-bis(2,4,6-trimethylphenyl)-3,4,5,6-tetrahydropyrimidin-2-ylidene) with TlPF6 in THF yields the T-shaped cationic solvent complex, [Ni(6-Mes)(PPh3)(THF)][PF6] (2), whereas treatment with NaBArF4 in Et2O affords the dimeric Ni(i) product, [{Ni(6-Mes)(PPh3)}2(µ-Br)][BArF4] (3). Both 2 and 3 act as latent sources of the cation [Ni(6-Mes)(PPh3)]+, which can be trapped by CO to give [Ni(6-Mes)(PPh3)(CO)]+ (5). Addition of [(Et3Si)2(µ-H)][B(C6F5)4] to 1 followed by work up in toluene results in the elimination of phosphine as well as halide to afford a co-crystallised mixture of [Ni(6-Mes)(η2-C6H5Me)][B(C6F5)4] (4), and [6MesHC6H5Me][B(C6F5)4]. Treatment of 1 with sodium salts of more strongly coordinating anions leads to substitution products. Thus, NaBH4 yields the neutral, diamagnetic dimer [{Ni(6-Mes)}2(BH4)2] (6), whereas NaBH3(CN) gives the paramagnetic monomeric cyanotrihydroborate complex [Ni(6-Mes)(PPh3)(NCBH3)] (7). Treatment of 1 with NaOtBu/NHPh2 affords the three-coordinate Ni(i) amido species, [Ni(6-Mes)(PPh3)(NPh2)] (8). The electronic structures of 2, 5, 7 and 8 have been analysed in comparison to that of previously reported 1 using a combination of EPR spectroscopy and density functional theory.

Mono- and bimetallic zwitterionic chromium(0) and tungsten(0) allenyls.

A series of stable chiral (racemic), formally neutral, zwitterionic mono- and bimetallic M(CO)5[C(OEt)═C═CR(NHC)] (M = Cr, W) σ-allenyls are ready available by the addition of N-heterocyclic carbenes (NHCs) to Cr(0) and W(0) alkynyl Fischer carbene complexes. Different classes of NHCs, (e.g., 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene, and their six- and seven-membered analogues and 1,3-bis(dimethyl)imidazol-2-ylidene) were employed as nucleophiles in these C-C bond-forming reactions yielding the novel complexes in essentially quantitative yields. A systematic experimental and computational study of the electronic properties of the Cr- and W-allenyls shows that their UV-vis spectra are directly influenced by the structure of the heterocyclic moiety derived from the NHC (ring size, substituents on the N atoms) and by the nature of the metal fragment (Cr/W). The electron-releasing nature of these complexes allows them to participate in electron-transfer reactions in the ground state, leading to a type of charged α,ß-unsaturated Fischer carbenes that incorporate an NHC fragment in their structure.

Stereoelectronic effects in C-H bond oxidation reactions of Ni(I) N-heterocyclic carbene complexes.

Activation of O2 by the three-coordinate Ni(I) ring-expanded N-heterocyclic carbene complexes Ni(RE-NHC)(PPh3)Br (RE-NHC = 6-Mes, 1; 7-Mes, 2) produced the structurally characterized dimeric Ni(II) complexes Ni(6-Mes)(Br)(µ-OH)(µ-O-6-Mes')NiBr (3) and Ni(7-Mes)(Br)(µ-OH)(µ-O-7-Mes')NiBr (4) containing oxidized ortho-mesityl groups from one of the carbene ligands. NMR and mass spectrometry provided evidence for further oxidation in solution to afford bis-µ-aryloxy compounds; the 6-Mes derivative was isolated, and its structure was verified. Low-temperature UV-visible spectroscopy showed that the reaction between 1 and O2 was too fast even at ca. -80 °C to yield any observable intermediates and also supported the formation of more than one oxidation product. Addition of O2 to Ni(I) precursors containing a less electron-donating diamidocarbene (6-MesDAC, 7) or less bulky 6- or 7-membered ring diaminocarbene ligands (6- or 7-o-Tol; 8 and 9) proceeded quite differently, affording phosphine and carbene oxidation products (Ni(O═PPh3)2Br2 and (6-MesDAC)═O) and the mononuclear Ni(II) dibromide complexes (Ni(6-o-Tol)(PPh3)Br2 (10) and (Ni(7-o-Tol)(PPh3)Br2 (11)) respectively. Electrochemical measurements on the five Ni(I) precursors show significantly higher redox potentials for 1 and 2, the complexes that undergo oxygen atom transfer from O2.

Copper diamidocarbene complexes: characterization of monomeric to tetrameric species.

Treatment of CuCl with 1 equiv of the in situ prepared N-mesityl-substituted diamidocarbene 6-MesDAC produced a mixture of the dimeric and trimeric copper complexes [(6-MesDAC)CuCl]2 (1) and [(6-MesDAC)2(CuCl)3] (2). Combining CuCl with isolated, free 6-MesDAC in 1:1 and 3:2 ratios gave just 1 and 2, respectively, while increasing the ratio to >5:1 allowed the isolation of small amounts of the tetrameric copper complex [(6-MesDAC)2(CuCl)4] (3). Efforts to bring about metathesis reactions of 1 with MO(t)Bu (M = Li, Na, K) proved successful only for M = Li to afford the spectroscopically characterized ate product [(6-MesDAC)CuCl·LiO(t)Bu·2THF] (5). Attempts to crystallize this species instead gave a 1:1 mixture of 1 and the monomer [(6-MesDAC)CuCl] (6). The X-ray structures of 1-3 and 1 + 6, along with the cation [Cu(6-MesDAC)2](+) (4), have been determined.

Synthesis, electronic structure, and magnetism of [Ni(6-Mes)2]+: a two-coordinate nickel(I) complex stabilized by bulky N-heterocyclic carbenes.

The two-coordinate cationic Ni(I) bis-N-heterocyclic carbene complex [Ni(6-Mes)2]Br (1) [6-Mes =1,3-bis(2,4,6-trimethylphenyl)-3,4,5,6-tetrahydropyrimidin-2-ylidene] has been structurally characterized and displays a highly linear geometry with a C-Ni-C angle of 179.27(13)°. Density functional theory calculations revealed that the five occupied metal-based orbitals are split in an approximate 2:1:2 pattern. Significant magnetic anisotropy results from this orbital degeneracy, leading to single-ion magnet (SIM) behavior.

Three-coordinate nickel(I) complexes stabilised by six-, seven- and eight-membered ring n-heterocyclic carbenes: synthesis, EPR/DFT studies and catalytic activity.

Comproportionation of [Ni(cod)(2)] (cod = cyclooctadiene) and [Ni(PPh(3))(2)X(2)] (X = Br, Cl) in the presence of six-, seven- and eight-membered ring N-aryl-substituted heterocyclic carbenes (NHCs) provides a route to a series of isostructural three-coordinate Ni(I) complexes [Ni(NHC)(PPh(3))X] (X = Br, Cl; NHC = 6-Mes 1, 6-Anis 2, 6-AnisMes 3, 7-o-Tol 4, 8-Mes 5, 8-o-Tol 6, O-8-o-Tol 7). Continuous wave (CW) and pulsed EPR measurements on 1, 4, 5, 6 and 7 reveal that the spin Hamiltonian parameters are particularly sensitive to changes in NHC ring size, N substituents and halide. In combination with DFT calculations, a mixed SOMO of ∣3d z 2〉 and ∣3d x 2-y 2〉 character, which was found to be dependent on the complex geometry, was observed and this was compared to the experimental g values obtained from the EPR spectra. A pronounced (31)P superhyperfine coupling to the PPh(3) group was also identified, consistent with the large spin density on the phosphorus, along with partially resolved bromine couplings. The use of 1, 4, 5 and 6 as pre-catalysts for the Kumada coupling of aryl chlorides and fluorides with ArMgY (Ar = Ph, Mes) showed the highest activity for the smaller ring systems and/or smaller substituents (i.e., 1>4≈6≫5).