Nickel-Catalyzed Three-Component Unsymmetrical Bis-Allylation of Alkynes with Alkenes: A Density Functional Theory Study.

Density functional theory (DFT) characterizations were employed to resolve the structural and energetic aspects and product selectivities along the mechanistic reaction paths of the nickel-catalyzed three-component unsymmetrical bis-allylation of alkynes with alkenes. Our putative mechanism initiated with the in situ generation of the active catalytic species [Ni(0)L2] (L = NHC) from its precursors [Ni(COD)2, NHC·HCl] to activate the alkyne and alkene substrates to form the final skipped trienes. This proceeds via the following five sequential steps: oxidative addition (OA), ß-F elimination, ring-opening complexation, C-B cleavage and reductive elimination (RE). Both the OA and RE steps (with respective free energy barriers of 24.2 and 24.8 kcal·mol-1) contribute to the observed reaction rates, with the former being the selectivity-controlling step of the entire chemical transformation. Electrophilic/nucleophilic properties of selected substrates were accurately predicted through dual descriptors (based on Hirshfeld charges), with the chemo- and regio-selectivities being reasonably predicted and explained. Further distortion/interaction and interaction region indicator (IRI) analyses for key stationary points along reaction profiles indicate that the participation of the third component olefin (allylboronate) and tBuOK additive played a crucial role in facilitating the reaction and regenerating the active catalyst, ensuring smooth formation of the skipped triene product under a favorably low dosage of the Ni(COD)2 catalyst (5 mol%).

Bioactivity of the cannabigerol cannabinoid and its analogues - the role of 3-dimensional conformation.

Cannabinoids are naturally occurring bioactive compounds with the potential to help treat chronic illnesses including epilepsy, Parkinson's disease, dementia and multiple sclerosis. Their general structures and efficient syntheses are well documented in the literature, yet their quantitative structure-activity relationships (QSARs), particularly 3-dimensional (3-D) conformation-specific bioactivities, are not fully resolved. Cannabigerol (CBG), an antibacterial precursor molecule for the most abundant phytocannabinoids, was characterised herein using density functional theory (DFT), together with selected analogues, to ascertain the influence of the 3D structure on their activity and stability. Results showed that the CBG family's geranyl chains tend to coil around the central phenol ring while its alkyl side-chains form H-bonds with the para-substituted hydroxyl groups as well as CH⋯π interactions with the aromatic density of the ring itself, among other interactions. Although weakly polar, these interactions are structurally and dynamically influential, effectively 'stapling' the ends of the chains to the central ring structure. Molecular docking of the differing 3-D poses of CBG to cytochrome P450 3A4 resulted in lowered inhibitory action by the coiled conformers, relative to their fully-extended counterparts, helping explain the trends in the inhibition of the metabolic activity of the CYP450 3A4. The approach detailed herein represents an effective method for the characterisation of other bioactive molecules, towards improved understanding of their QSARs and in guiding the rational design and synthesis of related compounds.

Aluminium catalysed oligomerisation in cement-forming silicate systems.

Alumino-silicates form the backbone of structural materials including cements and the concrete they form. However, the nanoscale aspects of the oligomerisation mechanisms elongating the (alumino-)silicate chains is not fully clarified; the role of aluminium in particular. Herein, we explore and contrast the growth of silicate and alumino-silicate oligomers by both neutral and anionic mechanisms, with focus on the influence of Al on oligomer structure and stability. Further, the spontaneity of chain lengthening in the absence and presence of Al of differing coordination (Al-IV, V, VI) was characterised. Result trends showed Al-IV facilitating oligomerisation in neutral conditions, with respect to Si only systems, effectively promoting longer chain formation and stabilisation. The anionic pathway similarly showed Al reducing the overall energetic barriers to oligomerisation. In both conditions, Al's coordinative and structural flexibility, at O-Al-O hinge points in particular, was responsible for the lowering of the energetic expense for oligomerisation. The results and implications resolved herein are informative for chain formation and stability for bulk material properties of alumino-silicate materials such as cements, where the aluminosilicate systems are dominated by short chains of 2-5 units in length.

Reduction Rate of 1-Phenyl Phospholane 1-Oxide Enhanced by Silanol Byproducts: Comprehensive DFT Study and Kinetic Modeling Linked to Reagent Design.

Important stoichiometric transformations like Wittig and Appel reactions have been implemented in a catalytic fashion in the past decade. The phosphine oxide generated in situ can be reintroduced as phosphine into the catalytic cycle using mild and selective silane reagents (redox-driven catalysis). While the field of experimental investigation has been fully expanding in the past decade, theoretical studies are still sparse. In this present work, density functional theory (DFT) has been used to characterize the free energy surfaces of the reduction of 1-phenyl phospholane 1-oxide with four different silanes. Found stationary points have been studied in-depth to highlight mechanistic peculiarities, like the effect of substituents at the silicon center and the parallel and competitive reactivity between the precursor silanes and their semioxidized byproducts. Calculated thermodynamic parameters in combination with "real" values for concentrations have been used in the formulation of rate equations for simple bimolecular and monomolecular steps of the mechanism. The deterministic integration concentrations versus time of such rate equations led to a realistic description of the systems under study and paved the way to strategic and rational design of new silanes with increased reactivity.

Systematic characterisation of the structure and radical scavenging potency of Pu'Er tea () polyphenol theaflavin.

The structure, energetics and radical scavenging potency of theaflavin (TF), a natural polyphenolic antioxidant found in oxidised tea, have been characterised by a series of density functional theory (DFT) determinations. Exploratory conformational searches yielded 153 distinct neutral structures. Results showed TF's structural preferences to be regulated by its unique fused double ring benzotropolone moiety, and its degree of planarity, with structural diversity, principally arising from variations of its nine -OH groups. The distinct 3D conformational 'poses' are shown to be stabilised by a complex network of intra-system interactions, damping overall structural floppiness. This rigidification, together with stability, is shown to be coupled with radical scavenging potency in the TF system. Radical scavenging via hydrogen atom abstraction (HAB) in H2O solution was determined to be spontaneous with very low reaction barriers (ΔGrel ∼ 4 kJ mol-1).

Reply to the 'Comment on "Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory"' by S. A. Glover, Phys. Chem. Chem. Phys., 2019, 21, 18012.

Herein we comparatively comment on the molecular metric 'amidicity', a descriptor of amide reactivity, and differing methods to determining it; with focus on lactam-rings. Specifically, our established amidicity percentage (AM%) approach is quantitatively contrasted with the transamidation (TA) method. This comment is organised into two sections, firstly addressing the differing methods in context of the computational bases of amidicity. This is followed by the quantitative demonstration that although both the AM% and HRS methods provide estimates of resonance enthalpy (ΔHRE), the former is more reliable across a wider set of systems. The robustness of the AM% approach is affirmed by quantitative matching of experimental NMR and kinetics measurements tracking changes in amide reactivities, including in Penicillin arising from modulation of its amide group and environmental effects.

Multi-Pathway Consequent Chemoselectivities of CpRuCl(PPh3 )2 /MeI-Catalysed Norbornadiene Alkyne Cycloadditions.

Chemoselectivities of five experimentally realised CpRuCl(PPh3 )2 /MeI-catalysed couplings of 7-azabenzo-norbornadienes with selected alkynes were successfully resolved from multiple reaction pathway models. Density functional theory calculations showed the following mechanistic succession to be energetically plausible: (1) CpRuI catalyst activation; (2) formation of crucial metallacyclopentene intermediate; (3) cyclobutene product (P2) elimination (ΔGRel(RDS) ≈11.9-17.6 kcal mol-1 ). Alternative formation of dihydrobenzoindole products (P1) by isomerisation to azametalla-cyclohexene followed by subsequent CpRuI release was much less favourable (ΔGRel(RDS) ≈26.5-29.8 kcal mol-1 ). Emergent stereoselectivities were in close agreement with experimental results for reactions a, b, e. Consequent investigations employing dispersion corrections similarly support the empirical findings of P1 dominating in reactions c and d through P2→P1 product transformations as being probable (ΔG≈25.3-30.1 kcal mol-1 ).

Simulations reveal the role of composition into the atomic-level flexibility of bioactive glass cements.

Bioactive glass ionomer cements (GICs), the reaction product of a fluoro-alumino-silicate glass and polyacrylic acid, have been in effective use in dentistry for over 40 years and more recently in orthopaedics and medical implantation. Their desirable properties have affirmed GIC's place in the medical materials community, yet are limited to non-load bearing applications due to the brittle nature of the hardened composite cement, thought to arise from the glass component and the interfaces it forms. Towards helping resolve the fundamental bases of the mechanical shortcomings of GICs, we report the 1st ever computational models of a GIC-relevant component. Ab initio molecular dynamics simulations were employed to generate and characterise three fluoro-alumino-silicate glasses of differing compositions with focus on resolving the atomic scale structural and dynamic contributions of aluminium, phosphorous and fluorine. Analyses of the glasses revealed rising F-content leading to the expansion of the glass network, compression of Al-F bonding, angular constraint at Al-pivots, localisation of alumino-phosphates and increased fluorine diffusion. Together, these changes to the structure, speciation and dynamics with raised fluorine content impart an overall rigidifying effect on the glass network, and suggest a predisposition to atomic-level inflexibility, which could manifest in the ionomer cements they form.

Competing Mechanisms, Substituent Effects, and Regioselectivities of Nickel-Catalyzed [2 + 2 + 2] Cycloaddition between Carboryne and Alkynes: A DFT Study.

Competing reaction mechanisms, substituent effects, and regioselectivities of Ni(PPh3)2-catalyzed [2 + 2 + 2] carboryne-alkyne cycloadditions were characterized by density functional theory using the real chemical systems and solvent effects considered. A putative mechanism involving the following steps was characterized: (1) exothermic carboryne-catalyst complexation and nucleophilic attack by the first alkyne; (2) insertion of the second alkyne, the rate-determining step (RDS) in all four reactions studied; (3) isomerization of reactant-bound complexes; and (4) product elimination and catalyst regeneration. The RDS in three reactions is mediated by free energy barriers of 27.2, 31.1, and 36.6 kcal·mol(-1), representative of the corresponding experimental yields of 67, 54, and 33%, respectively. A fourth reaction with 0% experimental yield showed representative RDS free energy barriers of 60.4 kcal·mol(-1), which are difficult to surmount even at 90 °C. Alternative pathways leading to differing isomers were similarly characterized and successfully reproduced experimentally determined product regioselectivities. Kinetic data derived from free energy barriers are in quantitative agreement (< ± 0.75-3.0 kcal·mol(-1)) of the experimental times, affirming the theoretical results as representative of the real chemical transformations. Complementary determinations show the use of truncated models (Ni(PMe3)2, Ni(PH3)2) causes the RDS to vary from step 2 (alkyne insertion) to step 1 (alkyne attack), highlighting the need to employ real chemical systems in modeling these reactions.

How the surface structure determines the properties of CuH.

CuH is a material that appears in a wide diversity of circumstances ranging from catalysis to electrochemistry to organic synthesis. There are both aqueous and nonaqueous synthetic routes to CuH, each of which apparently leads to a different product. We developed synthetic methodologies that enable multigram quantities of CuH to be produced by both routes and characterized each product by a combination of spectroscopic, diffraction and computational methods. The results show that, while all methods for the synthesis of CuH result in the same bulk product, the synthetic path taken engenders differing surface properties. The different behaviors of CuH obtained by aqueous and nonaqueous routes can be ascribed to a combination of very different particle size and dissimilar surface termination, namely, bonded hydroxyls for the aqueous routes and a coordinated donor for the nonaqueous routes. This work provides a particularly clear example of how the nature of an adsorbed layer on a nanoparticle surface determines the properties.

Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory.

Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).

Pd-NHC catalysed regioselective activation of B(3,6)-H of o-carborane - a synergy between experiment and theory.

Regioselective B-H activation of o-carboranes is an effective way for constructing o-carborane derivatives, which have broad applications in medicine, catalysis and the wider chemical industry. However, the mechanistic basis for the observed selectivities remains unresolved. Herein, a series of density functional theory (DFT) calculations were employed to characterise the palladium N-heterocyclic carbene (Pd-NHC) catalysed regioselective B(3,6)-diarylation of o-carboranes. Computational results at the IDSCRF(ether)-LC-ωPBE/BS1 and IDSCRF(ether)-LC-ωPBE/BS2 levels showed that the reaction undergoes a Pd(0) → Pd(II) → Pd(0) oxidation/reduction cycle, with the regioselective B(3)-H activation being the rate-determining step (RDS) for the full reaction profile. The computed RDS free energy barrier of 24.3 kcal mol-1 agrees well with the 82% yield of B(3,6)-diphenyl-o-carborane in ether solution at 298 K after 24 hours of reaction. The Ag2CO3 additive was shown to play a crucial role in lowering the RDS free energy barrier and facilitating the reaction. Natural charge population (NPA) and molecular surface electrostatic potential (ESP) analyses successfully predicted the experimentally observed regioselectivities, with electronic effects being revealed to be the dominant contributors to product selectivity. Steric hindrance was also shown to impact the reaction rate, as revealed by experimental and computational characterisation studies of substituents and ligand effects. Furthermore, computational predictions aligned with the experimental findings that NHC ligands outperform the phosphine ones for this particular reaction. Overall, the observed trends reported in this work are expected to assist in the rational optimisation of the efficiency and regioselectivity of this and related reactions.

CO2-mineralization and carbonation reactor rig: Design and validation for in situ neutron scattering experiments-Engineering and lessons learned.

CO2 mineralization via aqueous Mg/Ca/Na-carbonate (MgCO3/CaCO3/Na2CO3) formation represents a huge opportunity for the utilization of captured CO2. However, large-scale mineralization is hindered by slow kinetics due to the highly hydrated character of the cations in aqueous solutions (Mg2+ in particular). Reaction conditions can be optimized to accelerate carbonation kinetics, for example, by the inclusion of additives that promote competitive dehydration of Mg2+ and subsequent agglomeration, nucleation, and crystallization. For tracking mineralization and these reaction steps, neutron scattering presents unprecedented advantages over traditional techniques for time-resolved in situ measurements. However, a setup providing continuous solution circulation to ensure reactant system homogeneity for industrially relevant CO2-mineralization is currently not available for use on neutron beamlines. We, therefore, undertook the design, construction, testing and implementation of such a self-contained reactor rig for use on selected neutron beamlines at the ISIS Neutron and Muon Source (Harwell, UK). The design ensured robust attachment via suspension from the covering Tomkinson flange to stabilize the reactor assembly and all fittings (~25 kg), as well as facilitating precise alignment of the entire reactor and sample (test) cell with respect to beam dimension and direction. The assembly successfully accomplished the principal tasks of providing a continuous flow of the reaction mixture (~500 mL) for homogeneity, quantitative control of CO2 flux into the mixture, and temperature and pressure regulation throughout the reaction and measurements. The design is discussed, with emphasis placed on the reactor, including its geometry, components, and all technical specifications. Descriptions of the off-beamline bench tests, safety, and functionality, as well as the installation on beamlines and trial experimental procedure, are provided, together with representative raw neutron scattering results.

Simplification through complexity: the role of Ni-complexes in catalysed diyne-cyclobutanone [4+2+2] cycloadditions, a comparative DFT study.

A series of density functional theory (DFT) experiments carried out on selected nickel((0))-catalysed diyne-cyclobutanone [4+2+2] cycloadditions provided quantitative confirmation of proposed multistep mechanisms, while clarifying the catalytic role of Ni in the reactions. Geometric and energetic results of the Ni-catalysed process were compared to the one-step non-catalysed complement. Results show the first oxidation to be the rate-determining step, with the intramolecular reaction being the preferred one of the two competing pathways. Ligand-identity is also shown to greatly influence reaction barriers, leading to large deviation in product yields, in direct agreement with experimental observations.

Qualitative assessment of microstructure and Hertzian indentation failure in biocompatible glass ionomer cements.

Discs of biocompatible glass ionomer cements were prepared for Hertzian indentation and subsequent fracture analyses. Specifically, 2 × 10 mm samples for reproducing bottom-initiated radial fracture, complemented by 0.2 × 1 mm samples for optimal resolution with X-ray micro tomography (µCT), maintaining dimensional ratio. The latter allowed for accurate determination of volumetric-porosity of the fully cured material, fracture-branching through three Cartesian axes and incomplete bottom-initiated cracking. Nanocomputed tomography analyses supported the reliability of the µCT results. Complementary 2-dimensional fractographic investigation was carried out by optical and scanning electron microscopies on the larger samples, identifying fracture characteristics. The combined 3-D qualitative assessment of microstructure and fractures, complemented by 2-D methods, provided an increased understanding of the mechanism of mechanical failure in these cements. Specifically, cracks grew to link pores while propagating along glass-matrix interfaces. The methodological development herein is exploitable on related biomaterials and represents a new tool for the rational characterisation, optimisation and design of novel materials for clinical service.

Optimal Icosahedral Copper-Based Bimetallic Clusters for the Selective Electrocatalytic CO2 Conversion to One Carbon Products.

Electrochemical CO2 reduction reactions can lead to high value-added chemical and materials production while helping decrease anthropogenic CO2 emissions. Copper metal clusters can reduce CO2 to more than thirty different hydrocarbons and oxygenates yet they lack the required selectivity. We present a computational characterization of the role of nano-structuring and alloying in Cu-based catalysts on the activity and selectivity of CO2 reduction to generate the following one-carbon products: carbon monoxide (CO), formic acid (HCOOH), formaldehyde (H2C=O), methanol (CH3OH) and methane (CH4). The structures and energetics were determined for the adsorption, activation, and conversion of CO2 on monometallic and bimetallic (decorated and core@shell) 55-atom Cu-based clusters. The dopant metals considered were Ag, Cd, Pd, Pt, and Zn, located at different coordination sites. The relative binding strength of the intermediates were used to identify the optimal catalyst for the selective CO2 conversion to one-carbon products. It was discovered that single atom Cd or Zn doping is optimal for the conversion of CO2 to CO. The core@shell models with Ag, Pd and Pt provided higher selectivity for formic acid and formaldehyde. The Cu-Pt and Cu-Pd showed lowest overpotential for methane formation.

A Database of Solution Additives Promoting Mg2+ Dehydration and the Onset of MgCO3 Nucleation.

Formed via aqueous carbonation of Mg2+ ions, the crystallization of magnesite (MgCO3) is a promising route to carbon capture and reuse, albeit limited by the slow precipitation of MgCO3. Although magnesite is naturally abundant, forming at low temperature conditions, its industrial production is an energy-intensive process due to the temperatures required to prevent the formation of hydrated phases. The principal difficulty in aqueous conditions arises from the very strong Mg2+···H2O interaction, with high barriers to Mg2+ dehydration. Using atomistic simulations, we have investigated the influence of 30 additive anions (X n-, n = 1-3), ranging from simple halides to more complex molecules, on the first two steps of MgCO3 aggregation from solution, as follows: Mg2+ dehydration and subsequent prenucleative Mg2+···CO3 2- pairing. We have computed the thermodynamic stabilities of solvent shared ion pairs (Mg2+···H2O···X n-) and contact ion pairs (Mg2+···X n-) to reveal the propensity of solution additives to inhibit or promote Mg2+···CO3 2- formation. We have determined the stabilization of undercoordinated hydrated Mg2+ states with a vacant coordination site to which CO3 2- can bind, subsequently initiating MgCO3 nucleation or Mg2+ incorporation into the crystal lattice. Extensive molecular dynamics simulations of electrolyte solutions containing Na2CO3 with different sources of Mg2+ (i.e., MgCl2, MgSO4, and Mg(CH3COO)2) further show that the degree of dehydration of Mg2+ and the structure of prenucleation MgCO3 clusters change depending on the counterion identity. Through a fundamental understanding of the role of solution additives in the mechanism of Mg2+ dehydration, our results help to rationalize previously reported experimental observation of the effect of solvation environments on the growth of magnesite. This understanding may contribute to identifying the solution composition and conditions that could promote the low-temperature CO2 conversion into MgCO3 at industrially relevant scales.

Persistently folded circular aromatic amide pentamers containing modularly tunable cation-binding cavities with high ion selectivity.

In this work, we illustrated a novel design strategy that allows systematically tunable interior properties (effective cavity size, steric crowdedness, and hydrophobicity) contained within a novel class of shape-persistent aromatic pentamers to take place on a scale below 3 A. Such finely tunable structural features are complimented by experimentally observable functional variations in ion-binding potential. Results of the selective, differential binding affinities of three circular pentamers for Li(+), Na(+), K(+), Rb(+), and Cs(+), substantiated by metal-containing crystal structures and computational modeling, are detailed.

From Molten Calcium Aluminates through Phase Transitions to Cement Phases.

Crystalline calcium aluminates are a critical setting agent in cement. To date, few have explored the microscopic and dynamic mechanism of the transitions from molten aluminate liquids, through the supercooled state to glassy and crystalline phases, during cement clinker production. Herein, the first in situ measurements of viscosity and density are reported across all the principal molten phases, relevant to their eventual crystalline structures. Bulk atomistic computer simulations confirm that thermophysical properties scale with the evolution of network substructures interpenetrating melts on the nanoscale. It is demonstrated that the glass transition temperature (T g) follows the eutectic profile of the liquidus temperature (T m), coinciding with the melting zone in cement production. The viscosity has been uniquely charted over 14 decades for each calcium-aluminate phase, projecting and justifying the different temperature zones used in cement manufacture. The fragile-strong phase transitions are revealed across all supercooled phases coinciding with heterogeneous nucleation close to 1.2T g, where sintering and quenching occur in industrial-scale cement processing.

Density functional theory investigation of the alkyl-alkyl Negishi cross-coupling reaction catalyzed by N-heterocyclic carbene (NHC)-Pd complexes.

A novel mechanism is proposed for the Pd-1,3-(2,6-diisopropylphenyl)imidazolyl-2-ylidene (1) catalyzed Negishi reaction. DFT computations supported by atoms-in-molecules (AIM) analyses of non-truncated models show that a "steric wall" created by the N-substituent on the ligand guides reactants to and from the Pd center. Notably, transmetalation and not oxidative addition is found to be rate-limiting. Additionally, a key Pd-Zn interaction (approximately = 2.4 A, rho(b) approximately = 0.0600 au) is identified in the mechanism. This interaction persists beyond reductive elimination and, in combination with the ligand, facilitates reductive elimination by creating a highly sterically crowded environment in the coordination sphere of the Pd center.