Synthesis,coordination to Rh(I), and hydroformylation catalysis of new beta-aminophosphines bearing a dangling nitrogen group: an unusual inversion of a Rh-coordinated P center

Variants of the beta-aminophosphine L(1) [Ph(2)PCH(2)CH(Ph)NHPh] containing additional nitrogen donor functions have been prepared. These functions are branched off the C atom adjacent to the P atom, or the P atom itself. Ligand [Ph(2)PCH(o-C(6)H(4)NMe(2))CH(Ph)NHPh] has been obtained as a mixture of two diastereomers L(3A) and L(3B) by lithiation of L(2) [Ph(2)PCH(2)(o-C(6)H(4)NMe(2))] with n-BuLi followed by PhCH=NPh addition and hydrolysis. The diastereomers have been separated by fractional crystallization from ethanol. Ligand Et(2)NCH(2)P(Ph)CH(2)CH(Ph)NHPh has been obtained as a mixture of two diastereomers L(5A) and L(5B)(starting with P-Ph reductive cleavage of L(1) by lithium and subsequent hydrolysis to give PhP(H)CH(2)CH(Ph)NHPh (mixture of two diastereomers L(4A) and L(4B)). The latter reacts with diethylamine and formaldehyde to afford the L(5) diastereomeric mixture. Complexes RhCl(CO)(L) (L = L(3A), 1(A); L(3B), 1(B); L(5A/B), 2(A/B)) were obtained by reaction of [RhCl(CO)(2)](2) and the appropriate ligand or ligand mixture. Complexes 1(A), 1(B), and 2(A) have been isolated in pure form and characterized by classical techniques and by single-crystal X-ray diffraction. All structures exhibit a bidentate kappa-P,kappa-N(NHPh) mode similar to the complex containing L(1). While complexes 1(A) or 1(B) are stable in CDCl(3) solution, complex 2(A) slowly converts to its diastereomer 2(B). This unexpected epimerization appears to take place by inversion at the Rh-coordinated P center, an apparently unprecedented phenomenon. A mechanism based on a reversible P-C bond oxidative addition is proposed. The influence of the pendant nitrogen function of the diaminophosphines L(3A) and L(5A/B) on the rhodium catalytic activity in styrene hydroformylation has been examined and compared to that of the aminophosphines L(1) or L(2). The observed trends are related to the basicity of the dangling amine function and to its proximity to the metal center.     

Palladium-catalyzed pseudo-domino cyclizations: An easy entry toward polycondensed pyrrolidone derivatives

A new type I palladium-catalyzed pseudo-domino process is developed, in which a single Pd-based catalytic system promotes two mechanistically unrelated, sequential catalytic cycles in chronologically distinct order. Suitable precursors undergo an allylic alkylation and a Heck coupling in sequence, affording polycondensed pyrrolidone derivatives. Depending on the starting precursors, intra/inter or doubly intramolecular processes can be obtained. The allylic alkylation process takes place always very smoothly. On the other hand, the Heck coupling turns out to be rather difficult either when the process is intermolecular, or when an intramolecular process generates polycondensed structures featuring three fused bonds connected to a common carbon atom. In such difficult cases, use of the Herrmann-Beller phosphapalladacycle allowed to catalyze the coupling. This study demonstrates also that allylic alkylations can be catalyzed by the Herrmann-Beller phosphapalladacycle.     

The role of quality management system in the monitoring and continuous improvement of GMP-regulated short-lived radiopharmaceutical manufacture

The last decade has seen extraordinary growth in the clinical use of Positron Emission Tomography (PET), an in vivo molecular imaging modality widely used in oncology that requires the use of radiopharmaceuticals labeled with short-lived radionuclides. These medicinal products have found widespread application in Nuclear Medicine departments equipped with PET scanners. Due to the great increase in radiopharmaceutical demand, their production has been centralized and moved to industrial manufacturing sites in which Good Manufacturing Practice (GMP) principles and guidelines for medicinal products are to be applied. The production of PET radiopharmaceuticals features particular aspects such as the use of the lot before the completion of all tests, the multiplicity of batches produced per single day and the absence of product stock due to radionuclide short half-life. In this context, the application of quality principles to all stages of the process and the implementation of a quality management system (QMS) are of primary importance. This paper reports on the development of a QMS applied to a GMP manufacturing site of an in vivo PET diagnostic product, and on how its application can describe the performance of the site. Data were collected over a 6-year period (2008–2013) and demonstrate the ability of Key Performance Indicators, strictly related to the structure and organization of the QMS, and quality tools (data analysis, internal audit, etc.) to monitor process performance in terms of effectiveness, efficacy and stability.     

New Phenomena in Organometallic‐Mediated Radical Polymerization (OMRP) and Perspectives for Control of Less Active Monomers

The impact of reversible bond formation between a growing radical chain and a metal complex (organometallic‐mediated radical polymerization (OMRP) equilibrium) to generate an organometallic intermediate/dormant species is analyzed with emphasis on the interplay between this and other one‐electron processes involving the metal complex, which include halogen transfer in atom transfer radical polymerization (ATRP), hydrogen‐atom transfer in catalytic chain transfer (CCT), and catalytic radical termination (CRT). The challenges facing the controlled polymerization of “less active monomers” (LAMs) are outlined and, after reviewing the recent achievements of OMRP in this area, the perspectives of this technique are analyzed.     

Effect of the nature of the metal atom on hydrogen bonding and proton transfer to [Cp*MH3(dppe)]: tungsten versus molybdenum

The hydrogen-bonding and proton-transfer pathway to complex [Cp*W(dppe)H(3)] (Cp*=eta(5)-C(5)Me(5); dppe=Ph(2)PCH(2)CH(2)PPh(2)) was investigated experimentally by IR, NMR, UV/Vis spectroscopy in the presence of fluorinated alcohols, p-nitrophenol, and HBF(4), and by using DFT calculations for the [CpW(dhpe)H(3)] model (Cp=eta(5)-C(5)H(5); dhpe=H(2)PCH(2)CH(2)PH(2)) and for the real system. A study of the interaction with weak acids (CH(2)FCH(2)OH, CF(3)CH(2)OH, (CF(3))(2)CHOH) allowed the determination of the basicity factor, E(j)=1.73+/-0.01, making this compound the most basic hydride complex reported to date. A computational investigation revealed several minima for the [CpW(dhpe)H(3)] adducts with CF(3)CH(2)OH, (CF(3))(2)CHOH, and 2(CF(3))(2)CHOH and confirms that these interactions are stronger than those established by the Mo analogue. Their geometries and relative energies are closely related to those of the homologous Mo systems, with the most stable adducts corresponding to H bonding with M-H sites, however, the geometric and electronic parameters reveal that the metal center plays a greater role in the tungsten systems. Proton-transfer equilibria are observed with the weaker proton donors, the proton-transfer step for the system [Cp*W(dppe)H(3)]/HOCH(CF(3))(2) in toluene having DeltaH=(-3.9+/-0.3) kcal mol(-1) and DeltaS=(-17+/-2) cal mol(-1) K(-1). The thermodynamic stability of the proton-transfer product is greater for W than for Mo. Contrary to the Mo system, the protonation of the [Cp*W(dppe)H(3)] appears to involve a direct proton transfer to the metal center without a nonclassical intermediate, although assistance is provided by a hydride ligand in the transition state.     

Switchable Polymerization Triggered by Fast and Quantitative Insertion of Carbon Monoxide into Cobalt–Oxygen Bonds

A strategy that uses carbon monoxide (CO) as a molecular trigger to switch the polymerization mechanism of a cobalt Salen complex [salen=(R,R)‐N,N′‐bis(3,5‐di‐tert‐butylsalicylidene)‐1,2‐cyclohexanediamine] from ring‐opening copolymerization (ROCOP) of epoxides/anhydrides to organometallic mediated controlled radical polymerization (OMRP) of acrylates is described. The key phenomenon is a rapid and quantitative insertion of CO into the Co?O bond, allowing for in situ transformation of the ROCOP active species (Salen)Co^III‐OR into the OMRP photoinitiator (Salen)Co^III‐CO₂R. The proposed mechanism, which involves CO coordination to (Salen)Co^III‐OR and subsequent intramolecular rearrangement via migratory insertion has been rationalized by DFT calculations. Regulated by both CO and visible light, on‐demand sequence control can be achieved for the one‐pot synthesis of polyester‐b‐polyacrylate diblock copolymers (?<1.15).     

Dihydrogen to dihydride isomerization mechanism in [(C5Me5)FeH2(Ph2PCH2CH2PPh2)]+ through the experimental and theoretical analysis of kinetic isotope effects

The isomerization of complex [Cp*Fe(dppe)(eta2-H2)]+, generated in situ by low-temperature protonation of Cp*Fe(dppe)H with either HBF4 or CF3COOH, to the dihydride tautomer trans-[Cp*Fe(dppe)(H)2]+ is irreversible and follows first-order kinetics in the -10 to +15 degrees C range with Delta H double dagger = 21.6 +/- 0.8 kcal mol(-1) and DeltaS double dagger = 5 +/- 3 eu. The isomerization rate constant is essentially independent of the nature and quantity of a strong acid. Density functional theory (DFT) calculations on various models, including the complete system at both the quantum mechanics/molecular mechanics (QM/MM) and full QM levels, probe the relative importance of steric and electronic effects for the relative stability of the nonclassical and classical isomers and identify two likely isomerization mechanisms: a "direct" pathway involving simultaneous H-H bond breaking and cis-trans isomerization and a "via Cp" pathway involving agostic C5Me5H intermediates. Both pathways are characterized by activation energies in close correspondence with the experimental value (21.3 and 22.2 kcal mol(-1), respectively). Further kinetic studies were carried out for the Cp*Fe(dppe)H + CF3COOD and Cp*Fe(dppe)D + CF3COOD systems at 273 K. The [Cp*Fe(dppe)(eta2-HD)]+ complex establishes a very rapid isotope redistribution equilibrium with the eta2-H2 and eta2-D2 analogues. The equilibrium constant value (K = 3.3 +/- 0.3) indicates a significant equilibrium isotope effect. Simulation of the rate data provides access to the individual isomerization rate constants kHH, kHD, and kDD for the three isotopomers, yielding kinetic isotope effects: kHH/kHD = 1.24 +/- 0.01 and kHD/kDD = 1.58 +/- 0.01 (and, consequently, kHH/kDD = 1.96 +/- 0.02). The analysis of the DFT-calculated frequencies, using the [Cp*Fe(dhpe)H2]+ model system, for the [Cp*Fe(dhpe)(eta2-XY)]+ isotopomers as well as transition states for the "direct" (TSdir) and "via Cp" (TSrot) pathways (X = H, D) allowed the computation of the expected isotope effects. A comparison with the experiment strongly suggests that the mechanism occurs via the "direct" pathway for the present system, although the small difference in the calculated energy barriers suggests that the "via Cp" pathway may be preferred in other cases.     

Chemical fingerprinting of Equisetum arvense L. using HPTLC densitometry and HPLC

Equisetum arvense L. is a herbaceous medicinal plant, commonly known as horsetail, whose extracts have been reported to possess diuretic and haemostatic properties. The aim of this study was to evaluate the use of fingerprint chromatographic methods on commercially available raw materials or preparations of E. arvense L. in order to ascertain their quality and identify possible adulterants using HPLC and HPTLC densitometry. Two chromatographic methods were used to determine the chemical fingerprints of E. arvense and other allied species. The first was based on HPTLC identification followed by densitometric measurement at 350?nm. The second was based on HPLC separation. The ease of sample preparation and the possibility of simultaneous analysis of several samples in a short time make HPTLC a method of choice for the comprehensive quality evaluation of herbal products.