The Mechanism of Rh(I)-Catalyzed Coupling of Benzotriazoles and Allenes Revisited: Substrate Inhibition, Proton Shuttling, and the Role of Cationic vs Neutral Species.

Direct coupling of benzotriazole to unsaturated substrates such as allenes represents an atom-efficient method for the construction of biologically and pharmaceutically interesting functional structures. In this work, the mechanism of the N2-selective Rh complex-catalyzed coupling of benzotriazoles to allenes was investigated in depth using a combination of experimental and theoretical techniques. Substrate coordination, inhibition, and catalyst deactivation was probed in reactions of the neutral and cationic catalyst precursors [Rh(µ-Cl)(DPEPhos)]2 and [Rh(DPEPhos)(MeOH)2]+ with benzotriazole and allene, giving coordination, or coupling of the substrates. Formation of a rhodacycle, formed by unprecedented 1,2-coupling of allenes, is responsible for catalyst deactivation. Experimental and computational data suggest that cationic species, formed either by abstraction of the chloride ligand or used directly, are relevant for catalysis. Isomerization of benzotriazole and cleavage of its N-H bond are suggested to occur by counteranion-assisted proton shuttling. This contrasts with a previously proposed scenario in which oxidative N-H addition at Rh is one of the key steps. Based on the mechanistic analysis, the catalytic coupling reaction could be optimized, leading to lower reaction temperature and shorter reaction times compared to the literature.

A General Concept for the Electronic and Steric Modification of 1-Metallacyclobuta-2,3-dienes: A Case Study of Group 4 Metallocene Complexes.

The synthesis of group 4 metal 1-metallacyclobuta-2,3-dienes as organometallic analogues of elusive 1,2-cyclobutadiene has so far been limited to SiMe3 substituted examples. We present the synthesis of two Ph substituted dilithiated ligand precursors for the preparation of four new 1-metallacyclobuta-2,3-dienes [rac-(ebthi)M] (M=Ti, Zr; ebthi=1,2-ethylene-1,10-bis(η5-tetrahydroindenyl)). The organolithium compounds [Li2(RC3Ph)] (1 b: R=Ph, 1 c: R=SiMe3) as well as the metallacycles of the general formula [rac-(ebthi)M(R1C3R2)] (2 b: M=Ti, R1=R2=Ph, 2 c: M=Ti, R1=Ph, R2=SiMe3; 3 b: M=Zr, R1=R2=Ph; 3 c: M=Zr, R1=Ph, R2=SiMe3) were fully characterised. Single crystal X-ray diffraction and quantum chemical bond analysis of the Ti and Zr complexes reveal ligand influence on the biradicaloid character of the titanocene complexes. X-band EPR spectroscopy of structurally similar Ti complexes [rac-(ebthi)Ti(Me3SiC3SiMe3)] (2 a), 2 b, and 2 c was carried out to evaluate the accessibility of an EPR active triplet state. Cyclic voltammetry shows that introduction of Ph groups renders the complexes easier to reduce. 13C CPMAS NMR analysis provides insights into the cause of the low field shift of the resonances of metal-bonded carbon atoms and provides evidence of the absence of the ß-C-Ti interaction.

Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability.

The long-term stability of an active-pharmaceutical ingredient and its drug products plays an important role in the licensing process of new pharmaceuticals and for the application of the drug at the patient. It is, however, difficult to predict degradation profiles at early stages of the development of new drugs, making the entire process very time-consuming and costly. Forced mechanochemical degradation under controlled conditions can be used to realistically model long-term degradation processes naturally occurring in drug products, avoiding the use of solvents, thus excluding irrelevant solution-based degradation pathways. We present the forced mechanochemical oxidative degradation of three platelet inhibitor drug products, where the drug products contain thienopyridine. Model studies using clopidogrel hydrogen sulfate (CLP) and its drug formulation Plavix show that the controlled addition of excipients does not affect the nature of the main degradants. Experiments using drug products Ticlopidin-neuraxpharm and Efient show that significant degradation occurs after short reaction times of only 15 min. These results highlight the potential of mechanochemistry for the study of degradation processes of small molecules relevant to the prediction of degradation profiles during the development of new drugs. Furthermore, these data provide exciting insights into the role of mechanochemistry for chemical synthesis in general.

Solution and solid-state studies of hydrogen and halogen bonding with N-heterocyclic carbene supported nickel(II) fluoride complexes.

Nickel fluoride complexes of the type [Ni(F)(L)2(ArF)] (L = phosphine, ArF = fluorinated arene) are well-known to form strong halogen and hydrogen bonds in solution and in the solid state. A comprehensive study of such non-covalent interactions using bis(carbene) complexes as acceptors and suitable halogen and hydrogen bond donors is presented. In solution, the complex [Ni(F)(iPr2Im)2(C6F5)] forms halogen and hydrogen bonds with iodopentafluorobenzene and indole, respectively, which have formation constants (K300) an order of magnitude greater than those of structurally related phosphine supported nickel fluorides. Co-crystallisation of this complex and its backbone-methylated analogue [Ni(F)(iPr2Me2Im)2(C6F5)] with 1,4-diiodotetrafluorobenzene produces halogen bonding adducts which were characterised by X-ray analysis and 19F MAS solid state NMR analysis. Differences in the chemical shifts between the nickel fluoride and its halogen bonding adduct are well in line with data that were obtained from titration studies in solution.

How solvents affect the stability of cationic Rh(I) diphosphine complexes: a case study of MeCN coordination.

Cationic rhodium(I) diphosphine complexes, referred to as Schrock-Osborn catalysts, are privileged homogeneous catalysts with a wide range of catalytic applications. The coordination of solvent molecules can have a significant influence on reaction mechanisms and kinetic scenarios. Although solvent binding is well documented for these rhodium species, comparative quantifications for structurally related systems are not available to date. We present a method for systematic investigation and quantification of this important parameter, using MeCN which replaces diolefins and forms stable Rh(I) MeCN complexes. Using UV-vis and 31P{1H} NMR spectroscopy we determine and compare stability constants of different [Rh(PP)(NBD)]BF4 and [Rh(PP)(COD)]BF4 complexes (PP = diphosphine; COD = 1,5-cyclooctadiene; NBD = 2,5-norbornadiene) and discuss the influence of PP ligands and reaction temperature. A DFT study reveals the dependence of the stability on the thermodynamics of the exchange reaction. Using variable temperature NMR spectroscopy, the first mixed solvate complex could be verified as an intermediate in the MeCN-MeOH exchange.

Mono- and dinuclear zirconocene(iv) amide complexes for the catalytic dehydropolymerisation of phenylsilane.

The dehydropolymerisation of phenylsilane is investigated using group 4 metallocene amide complexes as catalysts. The dinuclear zirconocene amide complex Cp2Zr(NMe2)(µ-Me3SiC3SiMe3)Zr(NMe2)Cp2 (2) (Cp = η5-cyclopentadienyl) shows high activity in dehydrocoupling reactions, producing polyphenylsilanes with molecular weights ranging from 200 to 3000 g mol-1 and linear-to-cyclic product ratios of up to 80 : 20. Likewise, different ratios of oligomers and polymers with different tacticities could be described. Ansa-zirconocene amide complexes possessing the ebthi (ebthi = 1,2-ethylene-1,1'-bis(η5-tetrahydroindenyl)) ligand systems were prepared and evaluated for catalytic dehydropolymerisation in comparison to the dinuclear catalyst system.

Synthesis, Coordination Chemistry, and Mechanistic Studies of P,N-Type Phosphaalkene-Based Rh(I) Complexes.

The synthesis of P,N-phosphaalkene ligands, py-CH═PMes* (1, py = 2-pyridyl, Mes* = 2,4,6-tBu-C6H2) and the novel quin-CH═PMes* (2, quin = 2-quinolinyl) is described. The reaction with [Rh(µ-Cl)cod]2 produces Rh(I) bis(phosphaalkene) chlorido complexes 3 and 4 with distorted trigonal bipyramidal coordination environments. Complexes 3 and 4 show a pronounced metal-to-ligand charge transfer (MLCT) from Rh into the ligand P═C π* orbitals. Upon heating, quinoline-based complex 4 undergoes twofold C-H bond activation at the o-tBu groups of the Mes* substituents to yield the cationic bis(phosphaindane) Rh(I) complex 5, which could not be observed for the pyridine-based analogue 3. Using sub- or superstoichiometric amounts of AgOTf the C-H bond activation at an o-tBu group of one or at both Mes* was detected, respectively. Density functional theory (DFT) studies suggest an oxidative proton shift pathway as an alternative to a previously reported high-barrier oxidative addition at Rh(I). The Rh(I) mono- and bis(phosphaindane) triflate complexes 6 and 7, respectively, undergo deprotonation at the benzylic CH2 group of the phosphaindane unit in the presence of KOtBu to furnish neutral, distorted square-planar Rh(I) complexes 8 and 9, respectively, with one of the P,N ligands being dearomatized. All complexes were fully characterized, including multinuclear NMR, vibrational, and ultraviolet-visible (UV-vis) spectroscopy, as well as single-crystal X-ray and elemental analysis.

Iridium(III) bis(thiophosphinite) pincer complexes: synthesis, ligand activation and applications in catalysis.

Iridium(III) bis(thiophosphinite) complexes of the type [(RPSCSPR)Ir(H)(Cl)(py)] (RPSCSPR = κ3-(2,6-SPR2)C6H3) (R = tBu, iPr, Ph) can be prepared from the ligand precursors 1,3-(SPR2)C6H4 by C-H activation at Ir using [Ir(COE)2Cl]2 or [Ir(COD)Cl]2. Optimisation of the protocol for complexation showed that direct cyclometallation in the absence or presence of pyridine, as well as C-H activation in the presence of H2 are viable options that, depending on the phosphine substituent furnish the five-coordinate Ir(III) hydride chloride complexes 2-R or the base stabilised species 3-R in good yields. In case of the PhPSCSPPh ligand, P-S activation results in the formation of a thiophosphine stabilised Ir(III) hydride complex [(PhPSCSPPh)Ir(H)(Cl)(PPh2SH)] (4). Reaction of 2-tBu with H2 in the presence of base furnishes an Ir(III) dihydride complex (5) via a labile Ir(III) dihydride-dihydrogen complex (6). All complexes are inactive for transfer dehydrogenation of cyclooctane in the presence of NaOtBu and tert-butylethylene, likely due to decomposition of the Ir complex in the presence of base at higher temperature.

Model-based signal tracking in the quantitative analysis of time series of NMR spectra.

Hard modeling of NMR spectra by Gauss-Lorentz peak models is an effective way for dimensionality reduction. In this manner high-dimensional measured data are reduced to low-dimensional information as peak centers, amplitudes or peak widths. For time series of spectra these parameters can be assumed to be smooth functions in time. We suggest to model these time-dependent parameter functions by cubic spline functions, which makes a stable quantitative analysis of NMR series possible even for crossing, highly overlapping peaks. Applications are presented for the batch distillation of methanol and diethylamine, and the reaction of acetic anhydride with 2-propanol.

Molecular Catalysts for the Reductive Homocoupling of CO2 towards C2+ Compounds.

The conversion of CO2 into multicarbon (C2+ ) compounds by reductive homocoupling offers the possibility to transform renewable energy into chemical energy carriers and thereby create "carbon-neutral" fuels or other valuable products. Most available studies have employed heterogeneous metallic catalysts, but the use of molecular catalysts is still underexplored. However, several studies have already demonstrated the great potential of the molecular approach, namely, the possibility to gain a deep mechanistic understanding and a more precise control of the product selectivity. This Minireview summarizes recent progress in both the thermo- and electrochemical reductive homocoupling of CO2 toward C2+ products mediated by molecular catalysts. In addition, reductive CO homocoupling is discussed as a model for the further conversion of intermediates obtained from CO2 reduction, which may serve as a source of inspiration for developing novel molecular catalysts in the future.

Ball milling - a new concept for predicting degradation profiles in active pharmaceutical ingredients.

A method for forced oxidative mechanochemical degradation of active pharmaceutical ingredients (APIs) using clopidogrel hydrogensulfate as a model compound is presented. Considerable and selective formation of degradants occurs already after very short reaction times of less than 15 minutes and the nature of the products is strongly dependent on the used oxidant.

Reactivity of phospha-Wittig reagents towards NHCs and NHOs.

Phospha-Wittig reagents, RPPMe3 (R = Mes* 2,4,6-tBu3-C6H2; MesTer 2,6-(2,4,6-Me3C6H2)-C6H3; DipTer 2,6-(2,6-iPr2C6H3)-C6H3), can be considered as phosphine-stabilized phosphinidenes. In this study we show that PMe3 can be displaced by NHCs or NHOs. Interestingly, phosphinidene-like reactivity results in a subsequent C(sp2)-H activation of the exocyclic CH2 group in NHOs. This concept was further extended to allyl-apended NHOs, which resulted in phosphine-substituted allyl species.

1-Zirconacyclobuta-2,3-dienes: synthesis of organometallic analogs of elusive 1,2-cyclobutadiene, unprecedented intramolecular C-H activation, and reactivity studies.

The structure, bonding, and reactivity of small, highly unsaturated ring systems is of fundamental interest for inorganic and organic chemistry. Four-membered metallacyclobuta-2,3-dienes, also referred to as metallacycloallenes, are among the most exotic examples for ring systems as these represent organometallic analogs of 1,2-cyclobutadiene, the smallest cyclic allene. Herein, the synthesis of the first examples of 1-zirconacyclobuta-2,3-dienes of the type [Cp'2Zr(Me3SiC3SiMe3)] (Cp'2 = rac-(ebthi), (ebthi = 1,2-ethylene-1,1'-bis(η5-tetrahydroindenyl)) (2a); rac-Me2Si(thi)2, thi = (η5-tetrahydroindenyl), (2b)) is presented. Both complexes undergo selective thermal C-H activation at the 7-position of the ansa-cyclopentadienyl ligand to produce a new type of "tucked-in" zirconocene system, 3a and 3b, that possesses a η3-propargyl/allenyl ligand. Both types of complexes react with carbonyl compounds, producing enynes in the case of 2a and 2b, as well as η1-allenyl complexes for 3a and 3b. Computational analysis of the structure and bonding of 2a and 3a reveals significant differences to a previously described related Ti complex. All complexes were fully characterised, including X-ray crystallography and experimental results were supported by DFT analysis.

Dehydropolymerisation of Methylamine Borane and an N-Substituted Primary Amine Borane Using a PNP Fe Catalyst.

Dehydropolymerisation of methylamine borane (H3 B⋅NMeH2 ) using the well-known iron amido complex [(PNP)Fe(H)(CO)] (PNP=N(CH2 CH2 PiPr2 )2 ) (1) gives poly(aminoborane)s by a chain-growth mechanism. In toluene, rapid dehydrogenation of H3 B⋅NMeH2 following first-order behaviour as a limiting case of a more general underlying Michaelis-Menten kinetics is observed, forming aminoborane H2 B=NMeH, which selectively couples to give high-molecular-weight poly(aminoborane)s (H2 BNMeH)n and only traces of borazine (HBNMe)3 by depolymerisation after full conversion. Based on a series of comparative experiments using structurally related Fe catalysts and dimethylamine borane (H3 B⋅NMe2 H) polymer formation is proposed to occur by nucleophilic chain growth as reported earlier computationally and experimentally. A silyl functionalised primary borane H3 B⋅N(CH2 SiMe3 )H2 was studied in homo- and co-dehydropolymerisation reactions to give the first examples for Si containing poly(aminoborane)s.

A Comparative Study on the Thermodynamics of Halogen Bonding of Group†10 Pincer Fluoride Complexes.

The thermodynamics of halogen bonding of a series of isostructural Group 10 metal pincer fluoride complexes of the type [(3,5-R2 -tBu POCOPtBu )MF] (3,5-R2 -tBu POCOPtBu =κ3 -C6 HR2 -2,6-(OPtBu2 )2 with R=H, tBu, COOMe; M=Ni, Pd, Pt) and iodopentafluorobenzene was investigated. Based on NMR experiments at different temperatures, all complexes 1-tBu (R=tBu, M=Ni), 2-H (R=H, M=Pd), 2-tBu (R=tBu, M=Pd), 2-COOMe (R=COOMe, M=Pd) and 3-tBu (R=tBu, M=Pt) form strong halogen bonds with Pd complexes showing significantly stronger binding to iodopentafluorobenzene. Structural and computational analysis of a model adduct of complex 2-tBu with 1,4-diiodotetrafluorobenzene as well as of structures of iodopentafluorobenzene in toluene solution shows that formation of a type I contact occurs.

A general benzylic C-H activation and C-C coupling reaction of zirconocenes mediated by C-N bond cleavage in tert-butylisocyanide - unusual formation of iminoacyl complexes.

Reactions of the zirconocene alkyne complex [rac-(ebthi)Zr(η2-Me3SiC2SiMe3)] (rac-(ebthi) = rac-1,2-ethylene-1,1'-bis(η5-tetrahydroindenyl)) with tert-butylisocyanide and methylbenzenes were investigated. Depending on the stoichiometry, the solvent and the reaction temperature different products were obtained. Starting with the end-on coordination of the isocyanide to the zirconium centre (2), elevated reaction temperatures and an excess of tert-butylisocyanide resulted after the elimination of the alkyne in the formation of zirconocene η2-iminoacyl cyanide complexes 3a-d. These complexes are formed by coupling with a benzyl fragment through C-H bond activation of a methyl group of methylbenzene. The dimeric cyanide bridged zirconocene complex 4 is formed as a side-product of this process. The unexpected dimer and the heterometallacycles were fully characterised, including X-ray crystallography.

Nickel(ii) PE1CE2P pincer complexes (E = O, S) for electrocatalytic proton reduction.

Nickel(ii) chloride and thiolate complexes with iPrPE1CE2PiPr (E = O, S) pincer ligands were investigated as electrocatalysts for the hydrogen evolution reaction in CH3CN in the presence of acetic acid and trifluoroacetic acid. The bis(thiophosphinite) (S,S) chloride complex reduced protons at the lowest overpotential in comparison with the bis(phosphinite) (O,O) and mixed phosphinite-thiophosphinite (O,S) complexes. A combination of electrochemical, NMR and UV-vis spectroscopic and mass spectrometric experiments provides mechanistic insights into the catalytic cycle for proton reduction to dihydrogen.