Engineering Flexible Metal-Phenolic Networks with Guest Responsiveness via Intermolecular Interactions.

Flexible metal-organic materials are of growing interest owing to their ability to undergo reversible structural transformations under external stimuli. Here, we report flexible metal-phenolic networks (MPNs) featuring stimuli-responsive behavior to diverse solute guests. The competitive coordination of metal ions to phenolic ligands of multiple coordination sites and solute guests (e.g., glucose) primarily determines the responsive behavior of the MPNs, as revealed experimentally and computationally. Glucose molecules can be embedded into the dynamic MPNs upon mixing, leading to the reconfiguration of the metal-organic networks and thus changes in their physicochemical properties for targeting applications. This study expands the library of stimuli-responsive flexible metal-organic materials and the understanding of intermolecular interactions between metal-organic materials and solute guests, which is essential for the rational design of responsive materials for various applications.

Site-Selective Coordination Assembly of Dynamic Metal-Phenolic Networks.

Coordination states of metal-organic materials are known to dictate their physicochemical properties and applications in various fields. However, understanding and controlling coordination sites in metal-organic systems is challenging. Herein, we report the synthesis of site-selective coordinated metal-phenolic networks (MPNs) using flavonoids as coordination modulators. The site-selective coordination was systematically investigated experimentally and computationally using ligands with one, two, and multiple different coordination sites. Tuning the multimodal Fe coordination with catechol, carbonyl, and hydroxyl groups within the MPNs enabled the facile engineering of diverse physicochemical properties including size, selective permeability (20-2000 kDa), and pH-dependent degradability. This study expands our understanding of metal-phenolic chemistry and provides new routes for the rational design of structurally tailorable coordination-based materials.

Electromagnetic bioeffects: a multiscale molecular simulation perspective.

Electromagnetic bioeffects remain an enigma from both the experimental and theoretical perspectives despite the ubiquitous presence of related technologies in contemporary life. Multiscale computational modelling can provide valuable insights into biochemical systems and predict how they will be perturbed by external stimuli. At a microscopic level, it can be used to determine what (sub)molecular scale reactions various stimuli might induce; at a macroscopic level, it can be used to examine how these changes affect dynamic behaviour of essential molecules within the crowded biomolecular milieu in living tissues. In this review, we summarise and evaluate recent computational studies that examined the impact of externally applied electric and electromagnetic fields on biologically relevant molecular systems. First, we briefly outline the various methodological approaches that have been employed to study static and oscillating field effects across different time and length scales. The practical value of such modelling is then illustrated through representative case-studies that showcase the diverse effects of electric and electromagnetic field on the main physiological solvent - water, and the essential biomolecules - DNA, proteins, lipids, as well as some novel biomedically relevant nanomaterials. The implications and relevance of the theoretical multiscale modelling to practical applications in therapeutic medicine are also discussed. Finally, we summarise ongoing challenges and potential opportunities for theoretical modelling to advance the current understanding of electromagnetic bioeffects for their modulation and/or beneficial exploitation in biomedicine and industry.

Origins of Structural Elasticity in Metal-Phenolic Networks Probed by Super-Resolution Microscopy and Multiscale Simulations.

Metal-phenolic networks (MPNs) are amorphous materials that can be used to engineer functional films and particles. A fundamental understanding of the heat-driven structural reorganization of MPNs can offer opportunities to rationally tune their properties (e.g., size, permeability, wettability, hydrophobicity) for applications such as drug delivery, sensing, and tissue engineering. Herein, we use a combination of single-molecule localization microscopy, theoretical electronic structure calculations, and all-atom molecular dynamics simulations to demonstrate that MPN plasticity is governed by both the inherent flexibility of the metal (FeIII)-phenolic coordination center and the conformational elasticity of the phenolic building blocks (tannic acid, TA) that make up the metal-organic coordination complex. Thermal treatment (heating to 150 °C) of the flexible TA/FeIII networks induces a considerable increase in the number of aromatic π-π interactions formed among TA moieties and leads to the formation of hydrophobic domains. In the case of MPN capsules, 15 min of heating induces structural rearrangements that cause the capsules to shrink (from ∼4 to ∼3 µm), resulting in a thicker (3-fold), less porous, and higher protein (e.g., bovine serum albumin) affinity MPN shell. In contrast, when a simple polyphenol such as gallic acid is complexed with FeIII to form MPNs, rigid materials that are insensitive to temperature changes are obtained, and negligible structural rearrangement is observed upon heating. These findings are expected to facilitate the rational engineering of versatile TA-based MPN materials with tunable physiochemical properties for diverse applications.

Predicting wavelength-dependent photochemical reactivity and selectivity.

Predicting the conversion and selectivity of a photochemical experiment is a conceptually different challenge compared to thermally induced reactivity. Photochemical transformations do not currently have the same level of generalized analytical treatment due to the nature of light interaction with a photoreactive substrate. Herein, we bridge this critical gap by introducing a framework for the quantitative prediction of the time-dependent progress of photoreactions via common LEDs. A wavelength and concentration dependent reaction quantum yield map of a model photoligation, i.e., the reaction of thioether o-methylbenzaldehydes via o-quinodimethanes with N-ethylmaleimide, is initially determined with a tunable laser system. Combined with experimental parameters, the data are employed to predict LED-light induced conversion through a wavelength-resolved numerical simulation. The model is validated with experiments at varied wavelengths. Importantly, a second algorithm allows the assessment of competing photoreactions and enables the facile design of λ-orthogonal ligation systems based on substituted o-methylbenzaldehydes.

Electrostatic Activation of Tetrazoles.

Photoactivation of tetrazoles to form nitrile imines primed for 1,3-dipolar cycloaddition reactions is of widespread utility in chemistry. In contrast, the corresponding thermal reactions usually possess prohibitively high barriers and have garnered significantly less attention. Here, computational chemistry at the M06-2X/6-31+G(d,p) level of theory with SMD solvent corrections is used to show that these thermal activation barriers can be significantly reduced through the use of nonconjugated charged functional groups (CFGs). For 2,5-dimethyl-tetrazole, a positive CFG on the N-methyl (2-position) lowers the fragmentation barrier by around 80 kJ mol-1 in the gas phase, while a negative charge has a smaller opposite effect. These CFG effects remain significant even in polar solvents, with barrier lowering on the order of 30 kJ mol-1 in dimethyl sulfoxide and acetonitrile. In practical terms, the positive CFG decreases the fragmentation half-life of 2,5-dimethyl-tetrazole in refluxing o-xylene from 300,000 years to 1 week. While the resulting nitrile imine is stabilized, its subsequent 1,3-cycloaddition with N-methylmaleimide remains highly facile. Electrostatic effects on a range of 2-phenyl-5-methyltetrazoles, 2-methyl-5-phenyl-tetrazoles, and 2,5-diphenyl-tetrazoles follow similar trends and are explicable largely in terms of the stabilization of the developing dipole in the transition state.

Computational Optimization of Alkoxyamine-based Electrochemical Methylation.

Computational chemistry at the G3(MP2)-RAD//M06-2X/6-31+G(d,p)//SMD level of theory was used to study the oxidation of a test set of methyl adducts of nitroxide radicals and methyl adducts of Blatter's radical, a Kuhn verdazyl and two oxo-verdazyls. The barriers and the reaction energies of the SN2 reactions of the oxidized species with pyridine were also studied with a view to identify species with both low oxidation potentials and low SN2 barriers, so as to broaden the functional group tolerance of in situ electrochemical methylation compared with TEMPO-Me (1-methoxy-2,2,6,6-tetramethylpiperidine). Within the alkoxyamines, the oxidation potentials covered a range of 0.5 V, with trends explicable in terms of electrostatics, ring strain, and charge transfer. The oxidation potentials of oxo-verdazyl adducts, verdazyl adducts, and particularly the methyl adducts of Blatter's radical were considerably low due to the ability of their extensive π-systems to stabilize a positive charge. As expected, the SN2 reaction energies of the oxidized substrate became less favorable as the oxidation potential decreases. Unfortunately, this also meant that the barriers increased due to the excellent Evans-Polanyi correlation (R2 = 0.92). Nonetheless, 7-methoxy-7-azadispiro[5.1.5.836]hexadecane, N,N-di-tert-butyl-O-methylhydroxylamine, and particularly 1-methoxy-2,2,5,5-tetramethylpyrrolidine were identified as suitable candidates for broadening the scope of in situ electrochemical methylation while maintaining comparable kinetics to known reagents.

Mechanistic Insights into N-Acyloxyamine-Initiated Controlled Degradation of Polypropylene: The Unexpected Role of Keto-Enol Tautomerization in Carboxylate Radical Chemistry.

Controlled degradation of polypropylene (PP) is used industrially to improve the properties of crude PP. While this degradation is traditionally initiated by organic peroxides, N-acyloxyamines are now preferred due to their greater stability. However, their mechanism of action remains unclear. Using high-level ab initio calculations, we show that N-O homolysis is the most likely fragmentation pathway available to N-acyloxyamines, in contrast to the more usual C-O homolysis observed for the closely related N-alkoxyamines. This would, in theory, generate aminyl and carboxylate radicals, with the latter undergoing decarboxylation to generate methyl radicals. However, the enol forms of N-acyloxyamines are significantly less thermally stable, having bond dissociation free energies that are over 50 kJ/mol below those of their keto equivalents. Under conditions where keto-enol tautomerism is feasible, enol N-O homolysis, which forms the more stable acetic acid radical, would be the dominant degradation pathway. This reveals the crucial and underappreciated role that polar impurities play in the initiation process of enolizable initiators and may explain contradictory observations in the experimental literature. The product aminyl radicals are susceptible to ß-fragmentation, releasing alkyl radicals and affording imines, which in turn are susceptible to allylic H-abstraction and further ß-fragmentation leading to dialkylpyridines as the ultimate degradation products.

Oriented Internal Electrostatic Fields Cooperatively Promote Ground- and Excited-State Reactivity: A Case Study in Photochemical CO2 Capture.

Oriented electrostatic fields can exert catalytic effects upon both the kinetics and the thermodynamics of chemical reactions; however, the vast majority of studies thus far have focused upon ground-state chemistry and rarely consider any more than a single class of reaction. In the present study, we first use density functional theory (DFT) calculations to clarify the mechanism of CO2 storage via photochemical carboxylation of o-alkylphenyl ketones, originally proposed by Murakami et al. (J. Am. Chem. Soc. 2015, 137, 14063); we then demonstrate that oriented internal electrostatic fields arising from remote charged functional groups (CFGs) can selectively and cooperatively promote both ground- and excited-state chemical reactivity at all points along the revised mechanism, in a manner otherwise difficult to access via classical substituent effects. What is particularly striking is that electrostatic field effects upon key photochemical transitions are predictably enhanced in increasingly polar solvents, thus overcoming a central limitation of the electrostatic catalysis paradigm. We explain these observations, which should be readily extendable to the ground state.

Rational Design of Highly Activating Ligands for Cu-Based Atom Transfer Radical Polymerization.

Atom transfer radical polymerization (ATRP) is the most commonly utilized technique in controlled radical polymerization. However, the identification of more active catalysts could further increase its scope, both for polymerization and small-molecule synthesis more generally. To this end, a series of novel ligands were designed on the basis of two strategies: replacing nitrogen-based ligands with their phosphorus equivalents and rigidifying the ligand cap of nitrogen-based ligands so as to enforce short Cu-cap distances. Each ligand was assessed using accurate computational chemistry, which was used to compute the thermodynamics and, in selected cases, kinetics of an ATRP reaction with a model methyl methacrylate propagating radical. In principle, the use of phosphorus ligand caps was found to be a powerful strategy for increasing catalyst activity. Unfortunately, in practice, speciation issues sacrificed much of their advantage. In contrast, cap rigidification increases the activity of nitrogen-based ligands, well beyond existing ATRP ligands such as TPMANMe2. The effectiveness of these ligands was further demonstrated for hard-to-activate initiating systems based on ethylene, vinyl chloride, and vinyl acetate polymerization. Several of these improved ligands are synthetically accessible, with rigid piperidine or quinuclidine analogues of TPMANMe2 possessing improved thermodynamic and kinetic activity by 2 to 3 orders of magnitude.

TEMPO-Me: An Electrochemically Activated Methylating Agent.

Bench- and air-stable 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO-Me) is relatively unreactive at ambient temperature in the absence of an electrochemical stimulus. In this report, we demonstrate that the one-electron electrochemical oxidation of TEMPO-Me produces a powerful electrophilic methylating agent in situ. Our computational and experimental studies are consistent with methylation proceeding via a SN2 mechanism, with a strength comparable to the trimethyloxonium cation. A protocol is developed for the electrochemical methylation of aromatic acids using TEMPO-Me.

Discrete and Stereospecific Oligomers Prepared by Sequential and Alternating Single Unit Monomer Insertion.

Natural biopolymers, such as DNA and proteins, have uniform microstructures with defined molecular weight, precise monomer sequence, and stereoregularity along the polymer main chain that affords them unique biological functions. To reproduce such structurally perfect polymers and understand the mechanism of specific functions through chemical approaches, researchers have proposed using synthetic polymers as an alternative due to their broad chemical diversity and relatively simple manipulation. Herein, we report a new methodology to prepare sequence-controlled and stereospecific oligomers using alternating radical chain growth and sequential photoinduced RAFT single unit monomer insertion (photo-RAFT SUMI). Two families of cyclic monomers, the indenes and the N-substituted maleimides, can be alternatively inserted into RAFT agents, one unit at a time, allowing the monomer sequence to be controlled through sequential and alternating monomer addition. Importantly, the stereochemistry of cyclic monomer insertion into the RAFT agents is found to be trans-selective along the main chains due to steric hindrance from the repeating monomer units. All investigated cyclic monomers provide such trans-selectivity, but analogous acyclic monomers give a mixed cis- and trans-insertion.

Effect of heteroatom and functionality substitution on the oxidation potential of cyclic nitroxide radicals: role of electrostatics in electrochemistry.

The oxidation potential of a test set of 21 nitroxide radicals, including a number of novel compounds, has been studied experimentally in acetonitrile and correlated with theoretical calculations. It was found that both Hammett constants (σp) of the substituents on the nitroxide radicals and hyperfine splitting constants of the respective nitrogen atoms (αN) were well correlated to their experimental oxidation potentials. Theoretical calculations, carried out at the G3(MP2,CC)(+)//M06-2X/6-31+G(d,p) level of theory with PCM solvation corrections, were shown to reproduce experiments to within a mean absolute deviation of 33 mV, with a maximum deviation of 64 mV. The oxidation potentials of the nitroxides examined varied over 400 mV, depending on ring size and substitution. This considerable variation can be rationalised by the ability of various substituents to electrostatically stabilize the oxidised oxoammonium cation. Importantly, this can be quantified by a simple predictive relationship involving the distance scaled dipole and quadrupole moments of the analogous cyclohexyl ring. This highlights the often-overlooked role of through-space electrostatic substituent effects, even in formally neutral compounds.

Electrochemical and Electrostatic Cleavage of Alkoxyamines.

Alkoxyamines are heat-labile molecules, widely used as an in situ source of nitroxides in polymer and materials sciences. Here we show that the one-electron oxidation of an alkoxyamine leads to a cation radical intermediate that even at room temperature rapidly fragments, releasing a nitroxide and carbocation. Digital simulations of experimental voltammetry and current-time transients suggest that the unimolecular decomposition which yields the "unmasked" nitroxide (TEMPO) is exceedingly rapid and irreversible. High-level quantum computations indicate that the collapse of the alkoxyamine cation radical is likely to yield a neutral nitroxide radical and a secondary phenylethyl cation. However, this fragmentation is predicted to be slow and energetically very unfavorable. To attain qualitative agreement between the experimental kinetics and computational modeling for this fragmentation step, the explicit electrostatic environment within the double layer must be accounted for. Single-molecule break-junction experiments in a scanning tunneling microscope using solvent of low dielectric (STM-BJ technique) corroborate the role played by electrostatic forces on the lysis of the alkoxyamine C-ON bond. This work highlights the electrostatic aspects played by charged species in a chemical step that follows an electrochemical reaction, defines the magnitude of this catalytic effect by looking at an independent electrical technique in non-electrolyte systems (STM-BJ), and suggests a redox on/off switch to guide the cleavage of alkoxyamines at an electrified interface.

Wavelength Dependence of Light-Induced Cycloadditions.

The wavelength-dependent conversion of two rapid photoinduced ligation reactions, i.e., the light activation of o-methylbenzaldehydes, leading to the formation of reactive o-quinodimethanes (photoenols), and the photolysis of 2,5-diphenyltetrazoles, affording highly reactive nitrile imines, is probed via a monochromatic wavelength scan at constant photon count. The transient species are trapped by cycloaddition with N-ethylmaleimide, and the reactions are traced by high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. The resulting action plots are assessed in the context of Beer-Lambert's law and provide combined with time-dependent density functional theory and multireference calculations an in-depth understanding of the underpinning mechanistic processes, including conical intersections. The π → π* transition of the carbonyl group of the o-methylbenzaldehyde correlates with a highly efficient conversion to the cycloadduct, showing no significant wavelength dependence, while conversion following the n → π* transition proceeds markedly less efficient at longer wavelengths. The influence of absorbance and reactivity has critical consequences for an effective reaction design: At high concentrations of o-methylbenzaldehydes (c = 8 mmol L-1), photoligations with N-ethylmaleimide (possible for λ ≤ 390 nm) are ideally performed at 330 nm, whereas at high light penetration regimes at lower concentrations (c = 0.3 mmol L-1), 315 nm irradiation leads to the highest conversion. Activation and trapping of 2,5-diphenyltetrazoles (possible for λ ≤ 322 nm) proceeds best at a wavelength shorter than 295 nm, irrespective of concentration.

TEMPO Monolayers on Si(100) Electrodes: Electrostatic Effects by the Electrolyte and Semiconductor Space-Charge on the Electroactivity of a Persistent Radical.

This work demonstrates the effect of electrostatic interactions on the electroactivity of a persistent organic free radical. This was achieved by chemisorption of molecules of 4-azido-2,2,6,6-tetramethyl-1-piperdinyloxy (4-azido-TEMPO) onto monolayer-modified Si(100) electrodes using a two-step chemical procedure to preserve the open-shell state and hence the electroactivity of the nitroxide radical. Kinetic and thermodynamic parameters for the surface electrochemical reaction are investigated experimentally and analyzed with the aid of electrochemical digital simulations and quantum-chemical calculations of a theoretical model of the tethered TEMPO system. Interactions between the electrolyte anions and the TEMPO grafted on highly doped, i.e., metallic, electrodes can be tuned to predictably manipulate the oxidizing power of surface nitroxide/oxoammonium redox couple, hence showing the practical importance of the electrostatics on the electrolyte side of the radical monolayer. Conversely, for monolayers prepared on the poorly doped electrodes, the electrostatic interactions between the tethered TEMPO units and the semiconductor-side, i.e., space-charge, become dominant and result in drastic kinetic changes to the electroactivity of the radical monolayer as well as electrochemical nonidealities that can be explained as an increase in the self-interaction "a" parameter that leads to the Frumkin isotherm.