Trends in Structure and Ethylene Polymerization Reactivity of Transition-Metal Permethylindenyl-phenoxy (PHENI*) Complexes.

A family of ansa-permethylindenyl-phenoxy (PHENI*) transition-metal chloride complexes has been synthesized and characterized (1-7; {(η5-C9Me6)Me(R″)Si(2-R-4-R'-C6H2O)}MCl2; R,R' = Me, tBu, Cumyl (CMe2Ph); R″ = Me, nPr, Ph; M = Ti, Zr, Hf). The ancillary chloride ligands could readily be exchanged with halides, alkyls, alkoxides, aryloxides, or amides to form PHENI* complexes [L]TiX2 (8-17; X = Br, I, Me, CH2SiMe3, CH2Ph, NMe2, OEt, ODipp). The solid-state crystal structures of these PHENI* complexes indicate that one of two conformations may be preferred, parametrized by a characteristic torsion angle (TA'), in which the η5 system is either disposed away from the metal center or toward it. Compared to indenyl PHENICS complexes, the permethylindenyl (I*) ligand appears to favor a conformation in which the metal center is more accessible. When heterogenized on solid polymethylaluminoxane (sMAO), titanium PHENI* complexes exhibit exceptional catalytic activity toward the polymerization of ethylene. Substantially greater activities are reported than for comparable PHENICS catalysts, along with the formation of ultrahigh-molecular-weight polyethylenes (UHMWPE). Catalyst-cocatalyst ion pairing effects are observed in cationization experiments and found to be significant in homogeneous catalytic regimes; these effects are also related to the influence of the ancillary ligand leaving groups in slurry-phase polymerizations. Catalytic efficiency and polyethylene molecular weight are found to increase with pressure, and PHENI* catalysts can be categorized as being among the most active for the controlled synthesis of UHMWPE.

Towards designer polyolefins: highly tuneable olefin copolymerisation using a single permethylindenyl post-metallocene catalyst.

Using a highly active permethylindenyl-phenoxy (PHENI*) titanium catalyst, high to ultra-high molecular weight ethylene-linear-α-olefin (E/LAO) copolymers are prepared in high yields under mild conditions (2 bar, 30-90 °C). Controllable, efficient, and predictable comonomer enchainment provides access to a continuum of copolymer compositions and a vast range of material properties using a single monomer-agnostic catalyst. Multivariate statistical tools are employed that combine the tuneability of this system with the analytical and predictive power of data-derived models, this enables the targeting of polyolefins with designer properties directly through predictive alteration of reaction conditions.

The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.

Fully tuneable ethylene-propylene elastomers using a supported permethylindenyl-phenoxy (PHENI*) catalyst.

Using a highly active supported permethylindenyl-phenoxy (PHENI*) titanium catalyst, high molecular weight ethylene-propylene (EPM) and ethylene-propylene-diene (EPDM) elastomers are prepared using slurry-phase catalysis. Final copolymer composition was found to reflect the monomer feed ratio in a linear fashion, to access a continuum of material properties with a single catalyst. Post-polymerisation crosslinking of EPDM was also demonstrated in a model sulfur vulcanisation system.

Hydrogen-bonding and resonance stabilisation effects in cationic bis(iminium) phenoxide diacids.

The synthesis and characterisation of a bis(iminium)phenoxide diacid cation [4-tBu-C6H2-2,6-(HCN(H)Dipp)-1-O]+ ([H2tBu,DippL]+), is discussed. [H2tBu,DippL][BF4] (1) and [H2tBu,DippL][H2N{B(C6F5)3}2] (2) were synthesised in high yields via protonation of the bis(imino)phenol conjugate base with ethereal HBF4 or Bochmann's acid ([H(OEt2)2][H2N{B(C6F5)3}2]). Both species were fully characterised using NMR and IR spectroscopy as well as X-ray crystallography. The cationic fragment adopts an unusual tautomeric form in which both acidic protons are located on the nitrogen atoms: [HN〈O〉NH]+. This bis(iminium) phenoxide tautomer is stabilised by delocalisation of electron density from oxygen, into the extended π-system of the planar cation, and was found to be 22.6 and 263.1 kJ mol-1 lower in energy (ΔG) than the alternative [N〈OH〉NH]+ and [N〈OH2〉N]+ tautomers respectively. Topological analysis confirmed the presence of two electrostatic N+H⋯O- hydrogen bonds which contribute -111.2 kJ mol-1 towards the stabilisation of the diacid. The pKa values of the cations were estimated, from NMR experiments, to be 4.2 in THF (1) and 11.4 in acetonitrile (2).

SARS-CoV-2 Mpro Protease Variants of Concern Display Altered Viral Substrate and Cell Host Target Galectin-8 Processing but Retain Sensitivity toward Antivirals.

The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in Mpro may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 Mpro mutants provided structural insight into their altered functionality. Additionally, we show Mpro mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting Mpro will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.

Bimolecular Reductive Elimination of Ethane from Pyridine(diimine) Iron Methyl Complexes: Mechanism, Electronic Structure, and Entry into [2+2] Cycloaddition Catalysis.

The application of bimolecular reductive elimination to the activation of iron catalysts for alkene-diene cycloaddition is described. Key to this approach was the synthesis, characterization, electronic structure determination, and ultimately solution stability of a family of pyridine(diimine) iron methyl complexes with diverse steric properties and electronic ground states. Both the aryl-substituted, (MePDI)FeCH3 and (EtPDI)FeCH3 (RPDI = 2,6-(2,6-R2-C6H3N═CMe)2C5H3N), and the alkyl-substituted examples, (CyAPDI)FeCH3 (CyAPDI = 2,6-(C6H11N═CMe)2C5H3N), have molecular structures significantly distorted from planarity and S = 3/2 ground states. The related N-arylated derivative bearing 2,6-di-isopropyl aryl substituents, (iPrPDI)FeCH3, has an idealized planar geometry and exhibits spin crossover behavior from S = 1/2 to S = 3/2 states. At 23 °C under an N2 atmosphere, both (MePDI)FeCH3 and (EtPDI)FeCH3 underwent reductive elimination of ethane to form the iron dinitrogen precatalysts, [(MePDI)Fe(N2)]2(µ-N2) and [(EtPDI)Fe(N2)]2(µ-N2), respectively, while (iPrPDI)FeCH3 proved inert to C-C bond formation. By contrast, addition of butadiene to all three iron methyl complexes induced ethane formation and generated the corresponding iron butadiene complexes, (RPDI)Fe(η4-C4H6) (R = Me, Et, iPr), known precatalysts for the [2+2] cycloaddition of olefins and dienes. Kinetic, crossover experiments, and structural studies were combined with magnetic measurements and Mössbauer spectroscopy to elucidate the electronic and steric features of the iron complexes that enable this unusual reductive elimination and precatalyst activation pathway. Transmetalation of methyl groups between iron centers was fast at ambient temperature and independent of steric environment or spin state, while the intermediate dimer underwent the sterically controlled rate-determining reaction with either N2 or butadiene to access a catalytically active iron compound.

Data Ethics Club: Creating a collaborative space to discuss data ethics.

Awareness and management of ethical issues in data science are becoming crucial skills for data scientists. Discussion of contemporary issues in collaborative and interdisciplinary spaces is an engaging way to allow data-science work to be influenced by those with expertise in sociological fields and so improve the ability of data scientists to think critically about the ethics of their work. However, opportunities to do so are limited. Data Ethics Club is a fortnightly discussion group about data science and ethics whose community-generated resources are hosted publicly online. These include a collaborative list of materials around topics of interest and guides for leading an online data-ethics discussion group. Our meetings and resources are designed to reduce the barriers to learning, reflection, and critique on data science and ethics, with the broader aim of building ethics into the cultural fabric of quality data-science work.

Multimetallic Permethylpentalene Hydride Complexes.

The synthesis and characterization of group 4 permethylpentalene (Pn* = C8Me6) hydride complexes are explored; in all cases, multimetallic hydride clusters were obtained. Group 4 lithium metal hydride clusters were obtained when reacting the metal dihalides with hydride transfer reagents such as LiAlH4, and these species featured an unusual hexagonal bipyramidal structural motif. Only the zirconium analogue was found to undergo hydride exchange in the presence of deuterium. In contrast, a trimetallic titanium hydride cluster was isolated on reaction of the titanium dialkyl with hydrogen. This diamagnetic, mixed valence species was characterized in the solid state, as well as by solution electron paramagnetic resonance and nuclear magnetic resonance spectroscopy. The structure was further probed and corroborated by density functional theory calculations, which illustrated the formation of a metal-cluster bonding orbital responsible for the diamagnetism of the complex. These permethylpentalene hydride complexes have divergent structural motifs and reactivity in comparison with related classical cyclopentadienyl analogues.

Sterically rigid bismuth pincer complexes; observation of the growing polymer chain in polar monomer polymerisation.

A family of pyridine dipyrrolide bismuth complexes (Mes,PhL)MX (1-6) (M = Bi, X = O-2,6-Me-C6H3 = OXyl (1); M = Sb, X = OXyl (2); M = Bi, X = O-2,6-iPr-C6H3 = ODipp (3), O-2,6-tBu-C6H3 = OArtBu (4), OtBu (5) and OCMe2Et = OAm (6), N(SiMe3)2 = N'' (7) and CH2Ph (8)) have been prepared and investigated as initiators for the ring-opening polymerisation of lactide monomers. Bismuth lactate complexes (Mes,PhL)Bi{OC(H)(Me)C(O)OR} were prepared as models for the propagating species (R = tBu (9), Me (10), iPr (11)). The first insertion of the lactide monomer is rate limiting and the second and subsequent insertions are more rapid (kinit ≪ kLA2 < kprop), leading to a significant induction period. The sterically demanding, rigid pincer ligand affords a well-defined coordination environment at the metal centre and allows for the enchainment of two lactide monomers to be differentiated spectroscopically ((Mes,PhL)Bi{OC(H)(Me)C(O)}4OX (12-X)), with this species also implied to be the true initiator for the regime of propagation with first order kinetics. Well-controlled first order kinetic data for the polymerisation of L-, D-, rac- and meso-lactide are observed.

Supported permethylindenyl titanium catalysts for the synthesis of disentangled ultra-high molecular weight polyethylene (disUHMWPE).

Novel permethylindenyl-phenoxide (PHENI*) ansa-metallocene titanium complexes have been synthesised and immobilised on inorganic solid supports to afford highly effective catalysts for slurry-phase ethylene polymerisation. When supported on solid polymethylaluminoxane these complexes were both extremely active (up to 3.7 × 106 gPE molTi-1 h-1 bar-1) and produced substantially disentangled polyethylene with a weight-average molecular weight (Mw) of 3.4 MDa (disUHMWPE).

CO2 activation by permethylpentalene amido zirconium complexes.

We report the synthesis and characterisation of new permethylpentalene zirconium bis(amido) and permethylpentalene zirconium cyclopentadienyl mono(amido) complexes, and their reactivity with carbon dioxide.

Ring-opening polymerisation of l- and rac-lactide using group 4 permethylpentalene aryloxides and alkoxides.

A new family of group 4 permethylpentalene (C8Me62-; Pn*) aryloxide and alkoxide complexes have been synthesised and fully characterised by multinuclear NMR spectroscopy and single-crystal X-ray diffraction; (η8-C8Me6)Zr(OR)2 (R = tBu (1), 2,6-Me-C6H3 (2), 2,6-iPr-C6H3 (3) and 4-OMe-C6H4 (4)), (η8-C8Me6)Zr (OR) (R = 2,6-tBu-C6H3 (5) and 2,6-tBu-4-Me-C6H2 (6)), (η8-C8Me6)ZrCp(OR) (R = tBu (7), 2,6-Me-C6H3 (8) and 2,6-iPr-C6H3 (9)), (η8-C8Me6)TiCp(O-2,6-Me-C6H3) (10) and (η8-C8Me6)ZrCpMe(OR) (R = 2,6-Me-C6H3 (11), 2,6-iPr-C6H3 (12) and 2,4-tBu-C6H3 (13)). 2, 3, 6, 7, 9, 10 and 12 were studied as initiators for the ring-opening polymerisation (ROP) of l-lactide, and 2, 3, 6, 7 and 10 were studied as initiators for the ROP of rac-lactide. 3 was found to be the most active initiator for the ROP of l-lactide (kobs = 0.35 h-1) and 2 for the ROP of rac-lactide (kobs = 0.21 h-1). These initiators produced isotactic PLA for the ROP of l-lactide and moderately heterotactic enriched (maximum Pr of 0.69) or atactic PLA for the ROP of rac-lactide with polymer chains consisting of polylactic acid repeat units with -OR and -OH end groups.

Synthesis of zirconocene complexes and their use in slurry-phase polymerisation of ethylene.

A new family of zirconocene complexes of the type (3-RInd#)2ZrX2 (where Ind# = C6Me5H and R = Me, Et and Ph) have been synthesised and fully characterised. Six new crystal structures have been reported (meso-(3-EtInd#)2ZrBr2, rac-(3-EtInd#)2ZrCl2, rac-(3-EtInd#)2Zr(CH2Ph)2, meso-(3-EtInd#)2Zr(CH2Ph)2, meso-(3-MeInd#)2ZrBr2 and meso-(3-MeInd#)2Zr(CH2Ph)2). The complexes were studied for slurry-phase ethylene polymerisation when immobilised on solid polymethylaluminoxane (sMAO). Variation in the initiation group was found to have greater influence over polymerisation activity for meso-catalysts than rac-catalysts, with meso-alkyl catalysts showing higher polymerisation activities than meso-halide. Below 70 °C, polymerisation activity follows the order sMAO-meso-(3-EtInd#)2Zr(CH2Ph)2, sMAO-meso-(3-EtInd#)2ZrCl2 and sMAO-meso-(3-EtInd#)2ZrBr2 (activities of 657, 561, and 452 kgPE molM -1 h-1 bar-1, respectively). sMAO-meso-(3-EtInd#)2ZrBr2 produces HDPE with the highest molecular weight, followed by sMAO-meso-(3-EtInd#)2ZrCl2 and sMAO-meso-(3-EtInd#)2Zr(CH2Ph)2 (M w of 503, 406, and 345 kg mol-1, respectively, at 50 °C). sMAO-meso-(3-MeInd#)2ZrBr2 produced HDPE with almost identical molecular weights to sMAO-meso-(3-EtInd#)2ZrCl2 (395 kg mol-1 at 50 °C).

Ethnic disparity in access to the memory assessment service between South Asian and white British older adults in the United Kingdom: A cohort study.

BACKGROUND: Equality of access to memory assessment services by older adults from ethnic minorities is both an ethical imperative and a public health priority. OBJECTIVE: To investigate whether timeliness of access to memory assessment service differs between older people of white British and South Asian ethnicity. DESIGN: Longitudinal cohort. SETTING: Nottingham Memory Study; outpatient secondary mental healthcare. SUBJECTS: Our cohort comprised 3654 white British and 32 South Asian older outpatients. METHODS: The criterion for timely access to memory assessment service was set at 90 days from referral. Relationships between ethnicity and likelihood of timely access to memory assessment service were analysed using binary logistic regression. Analyses were adjusted for socio-demographic factors, deprivation and previous access to rapid response mental health services. RESULTS: Among white British outpatients, 2272 people (62.2%) achieved timely access to memory assessment service. Among South Asian outpatients, fourteen people (43.8%) achieved timely access to memory assessment service. After full adjustment, South Asian outpatients had a 0.47-fold reduced likelihood of timely access, compared to white British outpatients (odds ratio 0.47, 95% confidence interval 0.23-0.95, P value = .035). The difference became non-significant when restricting analyses to outpatients reporting British nationality or English as first language. Older age, lower index of deprivation and previous access to rapid response mental health services were associated with reduced likelihood of timely access, while gender was not. CONCLUSIONS: In a UK mental healthcare service, older South Asian outpatients are less likely to access dementia diagnostic services in a timely way, compared to white British outpatients.

Bismuth Pyridine Dipyrrolide Complexes: a Transient Bi(II) Species Which Ring Opens Cyclic Ethers.

A family of group 15 MIII pyridine dipyrrolide complexes has been prepared and fully characterized; the reduction of these complexes was investigated with traditional strong metal reductants, which led either to over-reduction in the case of Mg and Zn or to ligand redistribution and "ate" complex formation when KC8 was used. However, by utilizing organosilanes as soluble reductants, the ring opening and two electron reduction of thf solvent was observed with concomitant formation of Bi-C and Si-O bonds; this is an example of a main group complex that is capable of ring opening a cyclic ether in the absence of additional metal reducing agents. The proposed BiII intermediate in this mechanism could be trapped using the stable organic radical TEMPO.

Constrained geometry scandium permethylindenyl complexes for the ring-opening polymerisation of l- and rac-lactide.

The synthesis and characterisation of constrained geometry scandium permethylindenyl chloride, aryloxide and borohydride complexes Me2SB(tBuN,I*)Sc(Cl)(THF) (1), Me2SB(tBuN,I*)Sc(O-2,6-iPr-C6H3)(THF) (2), Me2SB(tBuN,I*)Sc(O-2,4-tBu-C6H3)(THF) (3) and Me2SB(tBuN,I*)Sc(BH4)(THF) (4) are reported. The activity of complexes 1-4 as initiators for the ring-opening polymerisation (ROP) of l- and rac-lactide is presented. The ROP of l- and rac-lactide using complexes 2 and 3 show first-order dependence on monomer concentration, and produced isotactic polylactide (PLA) and moderately heterotactic PLA (Pr = 0.68-0.72), respectively. Good agreement between experimental and theoretical molecular weights of PLA (Mn) and relatively narrow dispersities (Mw/Mn < 1.20) were obtained. Complex 4 showed higher activity for ROP of l- and rac-lactide than 2 or 3, with second-order dependence on monomer concentrations. However, poorly controlled molecular weights and lower heteroselectivity (Pr = 0.61-0.67) were observed. The effect of temperature and catalyst concentration for the ROP of l-lactide using 2 and 3 was also studied.

Synthesis, Structure, and Hydrogenolysis of Pyridine Dicarbene Iron Dialkyl Complexes.

Two methods for the synthesis of bis(imidazol-2-ylidene)pyridine iron dialkyl complexes, (CNC)Fe(CH2SiMe3)2, have been developed. The first route consists of addition of two equivalents of LiCH2SiMe3 to the iron dihalide complex, (CNC)FeBr2, while the second relies on addition of the free CNC ligand to readily-prepared (py)2Fe(CH2SiMe3)2 (py = pyridine). With aryl-substituted CNC ligands, octahedral complexes of the type ( Ar CNC)Fe(CH2SiMe3)2(N2) ( Ar CNC = bis(arylimidazol-2-ylidene)pyridine) were isolated, where the dinitrogen ligand occupies the site trans to the pyridine of the CNC-chelate. In contrast, the alkyl-substituted variant, (tBuACNC)Fe(CH2SiMe3)2 (tBuACNC = 2,6-(tBu-imidazol-2-ylidene)2pyridine) was isolated as the five-coordinate compound lacking dinitrogen. Exposure of the ( Ar CNC)Fe(CH2SiMe3)2(N2) derivatives to an H2 atmosphere resulted in formation of the corresponding iron hydride complexes ( Ar CNC)FeH4. These compounds catalyzed hydrogen isotope exchange between the deuterated benzene solvent and H2, generating isotopologues and isotopomers of ( Ar CNC)Fe(H n )(D4-n ) (n = 0-4). When (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2) (3,5-Me2 MesCNC = 2,6-(2,4,6-Me3-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) was treated successively with H2 and then N2, the corresponding reduced dinitrogen complex (3,5-Me2 MesCNC)Fe(N2)2 was isolated. The same product was also obtained following addition of pinacolborane to (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2).

Dialectical behavior therapy (DBT) for the treatment of stalking offenders: A randomized controlled study.

The objective was to evaluate the relative efficacy of dialectical behavior therapy modified for stalking offenders (DBT-S) versus a cognitive-behavioral anger management intervention for the treatment of stalking offenders. We expected DBT to result in significantly lower rates of renewed stalking behavior and significantly greater improvements in impulsivity, aggression, anger, and empathy. We randomly assigned individuals charged with stalking-related offences (N = 109) to one of two study interventions: DBT-S and anger management. Recidivism (renewed stalking, violence, and other offences) was monitored for 1 year following the baseline assessment, and participants completed a battery of self-report questionnaires before and after treatment and at a 1-year follow-up assessment. We found relatively low rates of reoffence when compared to past studies of untreated stalking offenders in the U.S., but type of treatment had no impact on the likelihood of reoffence, nor did completion of the treatment program. Likewise, there was no between-groups difference in rates of treatment completion, or on changes in self-report measures. Intensive treatment focused on reducing problematic behaviors in stalking offenders may be effective regardless of treatment modality, but the mechanism by which treatment impacts criminal behavior is not yet clear. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Synthesis, characterisation and redox properties of anti-bimetallic permethylpentalene complexes.

We report a series of anti-bimetallic transition metal complexes based on the permethylpentanyl (Pn*, C8Me6) ligand: anti-(MCpR5)2Pn* (where M = Fe, Co and Ni and R = H or Me). Compounds (FeCp*)2Pn* (1), (CoCp*)2Pn* (2), (NiCp*)2Pn* (3), (CoCp)2Pn* (4) and (NiCp)2Pn* (5) were fully characterised by NMR spectroscopy, X-ray crystallography, DFT calculations and cyclic voltammetry. All anti-(MCpR5)Pn* structures have diamagnetic ground states. 1, 2 and 4 have isolated non-degenerate ground states with closed shell configurations. A study of the magnetic properties of the dinickel complexes 3 and 5 reveal Boltzmann population of a Curie triplet state in the solution. Cyclic voltammetry reveals multiple reversible or quasi-reversible redox couples for all the dinuclear complexes.