Endowing Metal-Organic Coordination Materials with Chiroptical Activity by a Chiral Anion Strategy.

Recently, chiral metal-organic coordination materials have emerged as promising candidates for a wide range of applications in chiroptoelectronics, chiral catalysis, and information encryption, etc. Notably, the chiroptical effect of coordination chromophores makes them appealing for applications such as photodetectors, OLEDs, 3D displays, and bioimaging. The direct synthesis of chiral coordination materials using chiral organic ligands or complexes with metal-centered chirality is very often tedious and costly. In the case of ionic coordination materials, the combination of chiral anions with cationic, achiral coordination compounds through noncovalent interactions may endow molecular materials with desirable chiroptical properties. The use of such a simple chiral strategy has been proven effective in inducing promising circular dichroism and/or circularly polarized luminescence signals. This concept article mainly delves into the latest advances in exploring the efficacy of such a chiral anion strategy for transforming achiral coordination materials into chromophores with superb photo- or electro-chiroptical properties. In particular, ionic small-molecular metal complexes, metal clusters, coordination supramolecular assemblies, and metal-organic frameworks containing chiral anions are discussed. A perspective on the future opportunities on the preparation of chiroptical materials with the chiral anion strategy is also presented.

Circularly Polarized Luminescence of Thiophene-Bridged Macrocyclic pseudo-meta [2.2]Paracyclophanes.

Chiral organic molecules possessing high quantum yields, circular dichroism, and circularly polarized luminescence values have great potential as optically active materials for future applications. Recently, the identification of a promising class of inherently chiral compounds was reported, namely macrocyclic 1,3-butadiyne-linked pseudo-meta[2.2]paracyclophanes, displaying high circular dichroism and related gabs values albeit modest quantum yields. Increasing the quantum yields in an attempt to get bright circularly polarized light emitters, the high-yielding heterocyclization of those 1,3-butadiyne bridges resulting in macrocyclic 2,5-thienyls-linked pseudo-meta [2.2]paracyclophanes is herein described. The chiroptical properties of both, the previously reported 1,3-butadiyne, and the novel 2,5-thienyl bridged macrocycles of various sizes, are experimentally recorded, and theoretically described using density-functional theory.

Continuous nucleation of metallic nanoparticles via photocatalytic reduction.

Whether in organic synthesis or solar energy conversion, light can be a powerful reagent in chemical reactions and introduce new opportunities for synthetic control including duration, intensity, interval, and energy of irradiation. Here, we report the use of a molecular photosensitizer as a reducing agent in metallic nanoparticle syntheses. Using this approach, we report three key findings. (1) Nanoparticles produced by photocatalytic reduction form via a continuous nucleation mechanism, as opposed to burst and burst-like nucleation processes typically observed in metal nanoparticle syntheses. (2) Because nucleation is continuous, as long as the solution is irradiated (and there remains excess reagents in solution), nanoparticle nucleation can be turned on and off by controlling the timing and duration of irradiation, with no observable particle growth. (3) This synthetic method extends to the formation of bimetallic nanoparticles, which we show also form via a continuous nucleation pathway, and follow predicted patterns of metal incorporation as a function of the magnitude of the difference between the reduction potentials of the two metals. Taken together, these results establish a versatile synthetic method for the formation of multimetallic nanoparticles using visible light.

Classification and regression of stenosis using an in-vitro pulse wave data set: Dependence on heart rate, waveform and location.

BACKGROUND: Data-based approaches promise to use the information in cardiovascular signals to diagnose cardiovascular diseases. Considerable effort has been undertaken in the field of pulse-wave analysis to harness this information. However, the inverse problem, inferring arterial properties from waveform measurements, is not well understood today. Consequently, uncertainties within the estimation hinder the diagnostic application of such methods. METHOD: This work contributes a publicly available data set measured at an in-vitro cardiovascular simulator, focusing on a set of input conditions (heart rate, waveform) and stenosis locations. Furthermore, a first attempt is undertaken to perform classification and regression on this data set using standard machine learning methods on features extracted from four peripheral pressure signals. RESULTS: The locations of six different stenoses could be distinguished at high accuracy of 93%, where transfer function-based features outperformed features based solely on signal shape in almost all cases. Furthermore, regression on the stenosis position could be performed with a root mean square error of 2.4 cm along a 20 cm section of the arterial system using a shallow neural network. However, the performance difference between shape and transfer function features was not clear for this task. CONCLUSION: The data set contains 800 measurements and allows investigating the influence of different heart boundary conditions, such as heart rate and waveform shape, on classification and regression tasks. Extracting features that minimise this influence is a promising way of improving the performance of these tasks.

Modulation of Neutrophil Activity by Soluble Complement Cleavage Products-An In-Depth Analysis.

The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity was monitored by flow cytometry regarding cellular (electro-)physiology, cellular activity, and changes in the surface expression of activation markers. The study revealed no major effects induced by C3a or C4a on neutrophil functions. By contrast, exposure to C5a or C5a des-Arg stimulated neutrophil activity as reflected in changes in membrane potential, intracellular pH, glucose uptake, and cellular size. Similarly, C5a and C5a des-Arg but no other monitored complement cleavage product enhanced phagocytosis and reactive oxygen species generation. C5a and C5a des-Arg also altered the neutrophil surface expression of several complement receptors and neutrophil activation markers, including C5aR1, CD62L, CD10, and CD11b, among others. In addition, a detailed characterization of the C5a-induced effects was performed with a time resolution of seconds. The multiparametric response of neutrophils was further analyzed by a principal component analysis, revealing CD11b, CD10, and CD16 to be key surrogates of the C5a-induced effects. Overall, we provide a comprehensive insight into the very early interactions of neutrophil granulocytes with activated complement split products and the resulting neutrophil activity. The results provide a basis for a better and, importantly, time-resolved and multiparametric understanding of neutrophil-related (patho-)physiologies.

Reinterpreting the Fate of Iridium(III) Photocatalysts─Screening a Combinatorial Library to Explore Light-Driven Side-Reactions.

Photoredox catalysts are primarily selected based on ground and excited state properties, but their activity is also intrinsically tied to the nature of their reduced (or oxidized) intermediates. Catalyst reactivity often necessitates an inherent instability, thus these intermediates represent a mechanistic turning point that affords either product formation or side-reactions. In this work, we explore the scope of a previously demonstrated side-reaction that partially saturates one pyridine ring of the ancillary ligand in heteroleptic iridium(III) complexes. Using high-throughput synthesis and screening under photochemical conditions, we identified different chemical pathways, ultimately governed by ligand composition. The ancillary ligand was the key factor that determined photochemical stability. Following photoinitiated electron transfer from a sacrificial tertiary amine, the reduced intermediate of complexes containing 1,10-phenanthroline derivatives exhibited long-term stability. In contrast, complexes containing 2,2'-bipyridines were highly susceptible to hydrogen atom transfer and ancillary ligand modification. Detailed characterization of selected complexes before and after transformation showed differing effects on the ground and excited state reduction potentials dependent on the nature of the cyclometalating ligands and excited states. The implications of catalyst stability and reactivity in chemical synthesis was demonstrated in a model photoredox reaction.

Understanding Ir(III) Photocatalyst Structure-Activity Relationships: A Highly Parallelized Study of Light-Driven Metal Reduction Processes.

High-throughput synthesis and screening methods were used to measure the photochemical activity of 1440 distinct heteroleptic [Ir(C^N)2(N^N)]+ complexes for the photoreduction of Sn(II) and Zn(II) cations to their corresponding neutral metals. Kinetic data collection was carried out using home-built photoreactors and measured initial rates, obtained through an automated fitting algorithm, spanned between 0-120 µM/s for Sn(0) deposition and 0-90 µM/s for Zn(0) deposition. Photochemical reactivity was compared to photophysical properties previously measured such as deaerated excited state lifetime and emission spectral data for these same complexes; however, no clear correlations among these features were observed. A formal photochemical rate law was then developed to help elucidate the observed reactivity. Initial rates were found to be directly correlated to the product of incident photon flux with three reaction elementary efficiencies: (1) the fraction of light absorbed by the photocatalyst, (2) the fraction of excited state species that are quenched by the electron donor, and (3) the cage escape efficiency. The most active catalysts exhibit high efficiencies for all three steps, and catalyst engineering requirements to maximize these elementary efficiencies were postulated. The kinetic treatment provided the mechanistic information needed to decipher the observed structure/function trends in the high-throughput work.

Simultaneous Measurement of Changes in Neutrophil Granulocyte Membrane Potential, Intracellular pH, and Cell Size by Multiparametric Flow Cytometry.

Neutrophils provide rapid and efficient defense mechanisms against invading pathogens. Upon stimulation with proinflammatory mediators, including complement factors and bacterial peptides, neutrophils respond with changes in their membrane potential, intracellular pH, and cellular size. This study provides an approach to quantify these important changes simultaneously using multiparametric flow cytometry, thereby revealing a typical sequence of neutrophil activation consisting of depolarization, alkalization, and increase in cellular size. Additionally, the time resolution of the flow cytometric measurement is improved in order to allow changes that occur within seconds to be monitored, and thus to enhance the kinetic analysis of the neutrophil response. The method is appropriate for the reliable semiquantitative detection of small variations with respect to an increase, no change, and decrease in those parameters as demonstrated by the screening of various proinflammatory mediators. As a translational outlook, the findings are put into context in inflammatory conditions in vitro as well as in a clinically relevant whole blood model of endotoxemia. Taken together, the multiparametric analysis of neutrophil responsiveness regarding depolarization, alkalization, and changes in cellular size may contribute to a better understanding of neutrophils in health and disease, thus potentially yielding innovative mechanistic insights and possible novel diagnostic and/or prognostic approaches.

Activation of Neutrophil Granulocytes by Platelet-Activating Factor Is Impaired During Experimental Sepsis.

Platelet-activating factor (PAF) is an important mediator of the systemic inflammatory response. In the case of sepsis, proper activation and function of neutrophils as the first line of cellular defense are based on a well-balanced physiological response. However, little is known about the role of PAF in cellular changes of neutrophils during sepsis. Therefore, this study investigates the reaction patterns of neutrophils induced by PAF with a focus on membrane potential (MP), intracellular pH, and cellular swelling under physiological and pathophysiological conditions and hypothesizes that the PAF-mediated response of granulocytes is altered during sepsis. The cellular response of granulocytes including MP, intracellular pH, cellular swelling, and other activation markers were analyzed by multiparametric flow cytometry. In addition, the chemotactic activity and the formation of platelet-neutrophil complexes after exposure to PAF were investigated. The changes of the (electro-)physiological response features were translationally verified in a human ex vivo whole blood model of endotoxemia as well as during polymicrobial porcine sepsis. In neutrophils from healthy human donors, PAF elicited a rapid depolarization, an intracellular alkalization, and an increase in cell size in a time- and dose-dependent manner. Mechanistically, the alkalization was dependent on sodium-proton exchanger 1 (NHE1) activity, while the change in cellular shape was sodium flux- but only partially NHE1-dependent. In a pathophysiological altered environment, the PAF-induced response of neutrophils was modulated. Acidifying the extracellular pH in vitro enhanced PAF-mediated depolarization, whereas the increases in cell size and intracellular pH were largely unaffected. Ex vivo exposure of human whole blood to lipopolysaccharide diminished the PAF-induced intracellular alkalization and the change in neutrophil size. During experimental porcine sepsis, depolarization of the MP was significantly impaired. Additionally, there was a trend for increased cellular swelling, whereas intracellular alkalization remained stable. Overall, an impaired (electro-)physiological response of neutrophils to PAF stimulation represents a cellular hallmark of those cells challenged during systemic inflammation. Furthermore, this altered response may be indicative of and causative for the development of neutrophil dysfunction during sepsis.

Nickel(II) complexes based on dithiolate-polyamine binary ligand systems: crystal structures, hirshfeld surface analysis, theoretical study, and catalytic activity study on photocatalytic hydrogen generation.

To ascertain the influence of binary ligand systems [1,1-dicyanoethylene-2,2-dithiolate (i-mnt-2) and polyamine {tetraen = tris(2-aminoethyl)amine, tren = diethylene triamine and opda = o-phenylenediamine}] on the coordination modes of the Ni(ii) metal center and resulting supramolecular architectures, a series of nickel(ii) thiolate complexes [Ni(tetraen)(i-mnt)](DMSO) (1), [Ni2(tren)2(i-mnt)2] (2), and [Ni2(i-mnt)2(opda)2]n (3) have been synthesized in high yield in one step in water and structurally characterized by single crystal X-ray crystallography and spectroscopic techniques. X-ray diffraction studies disclose the diverse i-mnt-2 coordination to the Ni+2 center in the presence of active polyamine ligands, forming a slightly distorted octahedral geometry (NiN4S2) in 1, square planar (NiS4) and distorted octahedral geometries (NiN6) in the bimetallic co-crystallized aggregate of cationic [Ni(tren)2]+2 and anionic [Ni(i-mnt)2]-2 in 2, and a one dimensional (1D) polymeric chain along the [100] axis in 3, having consecutive square planar (NiS4) and octahedral (NiN6) coordination kernels. The N-HO, N-HS, N-HN, N-HS, N-HN, and N-HO type hydrogen bonds stabilize the supramolecular assemblies in 1, 2, and 3 respectively imparting interesting graph-set-motifs. The molecular Hirshfeld surface analyses (HS) and 2D fingerprint plots were utilized for decoding all types of non-covalent contacts in the crystal networks. Atomic HS analysis of the Ni+2 centers reveals significant Ni-N metal-ligand interactions compared to Ni-S interactions. We have also studied the unorthodox interactions observed in the solid state structures of 1-3 by QTAIM and NBO analyses. Moreover, all the complexes proved to be highly active water reduction co-catalysts (WRC) in a photo-catalytic hydrogen evolution process involving iridium photosensitizers, wherein 2 and 3 having a square planar arrangement around the nickel center(s) - were found to be the most active ones, achieving 1000 and 1119 turnover numbers (TON), respectively.

Interleukin 8 Elicits Rapid Physiological Changes in Neutrophils That Are Altered by Inflammatory Conditions.

A sufficient response of neutrophil granulocytes stimulated by interleukin (IL)-8 is vital during systemic inflammation, for example, in sepsis or severe trauma. Moreover, IL-8 is clinically used as biomarker of inflammatory processes. However, the effects of IL-8 on cellular key regulators of neutrophil properties such as the intracellular pH (pHi) in dependence of ion transport proteins and during inflammation remain to be elucidated. Therefore, we investigated in detail the fundamental changes in pHi, cellular shape, and chemotactic activity elicited by IL-8. Using flow cytometric methods, we determined that the IL-8-induced cellular activity was largely dependent on specific ion channels and transporters, such as the sodium-proton exchanger 1 (NHE1) and non-NHE1-dependent sodium flux. Exposing neutrophils in vitro to a proinflammatory micromilieu with N-formyl-Met-Leu-Phe, LPS, or IL-8 resulted in a diminished response regarding the increase in cellular size and pH. The detailed kinetics of the reduced reactivity of the neutrophil granulocytes could be illustrated in a near-real-time flow cytometric measurement. Last, the LPS-mediated impairment of the IL-8-induced response in neutrophils was confirmed in a translational, animal-free human whole blood model. Overall, we provide novel mechanistic insights for the interaction of IL-8 with neutrophil granulocytes and report in detail about its alteration during systemic inflammation.

High-Throughput Screening of Earth-Abundant Water Reduction Catalysts toward Photocatalytic Hydrogen Evolution.

Noble-metal photosensitizers and water reduction co-catalysts (WRCs) still present the highest activity in homogeneous photocatalytic hydrogen production. The search for earth-abundant alternatives is usually limited by the time required to screen new catalyst combinations; however, here, we utilize newly designed and developed high-throughput photoreactors for the parallel synthesis of novel WRCs and colorimetric screening of hydrogen evolution. This unique approach allowed rapid optimization of photocatalytic water reduction using the organic photosensitizer Eosin Y and the archetypal cobaloxime WRC [Co(GL1)2pyCl], where GL1 is dimethylglyoxime and py is pyridine. Subsequent combinatorial synthesis generated 646 unique cobalt complexes of the type [Co(LL)2pyCl], where LL is a bidentate ligand, that identified promising new WRC candidates for hydrogen production. Density functional theory (DFT) calculations performed on such cobaloxime derivative complexes demonstrated that reactivity depends on hydride affinity. Alkyl-substituted glyoximes were necessary for hydrogen production and showed increased activity when paired with ligands containing strong hydrogen-bond donors.

High-Throughput Screening and Automated Data-Driven Analysis of the Triplet Photophysical Properties of Structurally Diverse, Heteroleptic Iridium(III) Complexes.

Steady state emission spectra and excited state lifetimes were measured for 1440 distinct heteroleptic [Ir(C^N)2(N^N)]+ complexes prepared via combinatorial parallelized synthesis; 72% of the complexes were found to be luminescent, and the emission maxima of the library spanned the visible spectrum (652-459 nm). Spectral profiles ranged from broad structureless bands to narrow emissions exhibiting vibrational substructure. Measured excited state lifetimes ranged between ∼0.1-14 µs. Automated emission spectral fitting with successive Gaussian functions revealed four distinct measured classes of excited states; in addition to well understood metal-ligand to ligand-charge transfer (3MLLCT) and ligand-centered (3LC) excited states, our classification also identified photophysical characteristics of less explored mixed 3MLLCT/3LC states. Electronic structure features obtained from DFT calculations performed on a large subset of these Ir(III) chromophores offered clear insights into the excited state properties and allowed the prediction of structure/luminescence relationships in this class of commonly used photocatalysts. Models with high prediction accuracy (R2 = 0.89) for emission color were developed on the basis of experimental data. Furthermore, different degrees of nuclear reorganization in the excited state were shown to significantly impact emission energy and excited state lifetimes.

Dual-binding conjugates of diaromatic guanidines and porphyrins for recognition of G-quadruplexes.

The first conceptualised class of dual-binding guanine quadruplex binders has been designed, synthesised and biophysically studied. These compounds combine diaromatic guanidinium systems and neutral tetra-phenylporphyrins (classical binding moiety for guanine quadruplexes) by means of a semi-rigid linker. An extensive screening of a variety of guanine quadruplex structures and double stranded DNA via UV-vis, FRET and CD experiments revealed the preference of the conjugates towards guanine quadruplexes. Additionally, docking studies indicate the potential dual mode of binding.

Iron in a Cage: Fixation of a Fe(II)tpy2 Complex by Fourfold Interlinking.

The coordination sphere of the Fe(II) terpyridine complex 1 is rigidified by fourfold interlinking of both terpyridine ligands. Profiting from an octa-aldehyde precursor complex, the ideal dimensions of the interlinking structures are determined by reversible Schiff-base formation, before irreversible Wittig olefination provided the rigidified complex. Reversed-phase HPLC enables the isolation of the all-trans isomer of the Fe(II) terpyridine complex 1, which is fully characterized. While temperature independent low-spin states were recorded with superconducting quantum interference device (SQUID) measurements for both, the open precursor 8 and the interlinked complex 1, evidence of the increased rigidity of the ligand sphere in 1 was provided by proton T2 relaxation NMR experiments. The ligand sphere fixation in the macrocyclized complex 1 even reaches a level resisting substantial deformation upon deposition on an Au(111) surface, as demonstrated by its pristine form in a low temperature ultra-high vacuum scanning tunneling microscope experiment.

Photostable Helical Polyfurans.

This report describes the design and synthesis of a new class of polyfurans bearing ester side chains. The macromolecules can be synthesized using catalyst-transfer polycondensation, providing precise control over molecular weight and molecular weight distribution. Such obtained furan ester polymers are significantly more photostable than their alkyl analogues owing to the electron-withdrawing nature of the attached subunit. Most interestingly, they spontaneously fold into a compact π-stacked helix, yielding a complex multilayer cylindrical nanoparticle with a hollow, rigid, conjugated core composed of the polyfuran backbone and a soft, insulating outer layer formed by the ester side chains. The length of polymer side chains dictates the outer diameter of such nanoparticles, which for the hexyl ester groups used in the present study is equal to ∼2.3 nm. The inner cavity of the conjugated core is lined with oxygen atoms, which set its effective diameter to 0.4 nm. Furthermore, installation of bulkier, branched chiral ester side chains on the repeat unit yields structures that, upon change of solvent, can reversibly transition between an ordered chiral helical folded and disordered unfolded state.

Not Your Usual Bioisostere: Solid State Study of 3D Interactions in Cubanes.

Previous studies by Desiraju and co-workers have implicated the acidic hydrogen atoms of cubane as a support network for hydrogen bonding groups. Herein we report a detailed structural analysis of all currently available 1,4-disubstituted cubane structures with an emphasis on how the cubane scaffold interacts in its solid-state environment. In this regard, the interactions between the cubane hydrogen atoms and acids, ester, halogens, ethynyl, nitrogenous groups, and other cubane scaffolds were cataloged. The goal of this study was to investigate the potential of cubane as a substitute for phenyl. This could be achieved by analyzing all contacts that are directed by the cubane hydrogen atoms in the X-ray crystal structures. As a result, we have established several new cubane interaction profiles, such as the catemer formation seen in esters, the preferences of halogen-hydrogen contacts over direct halogen bonding, and the stabilizing effects caused by the cubane hydrogen atoms interacting with ethynyl groups. These interaction profiles can then be used as a guide for designing cubane bioisosteres of known materials and drugs containing phenyl moieties.

Nonconjugated Hydrocarbons as Rigid-Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry.

Nonconjugated hydrocarbons, like bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, triptycene, and cubane are a unique class of rigid linkers. Due to their similarity in size and shape they are useful mimics of classic benzene moieties in drugs, so-called bioisosteres. Moreover, they also fulfill an important role in material sciences as linear linkers, in order to arrange various functionalities in a defined spatial manner. In this Review article, recent developments and usages of these special, rectilinear systems are discussed. Furthermore, we focus on covalently linked, nonconjugated linear arrangements and discuss the physical and chemical properties and differences of individual linkers, as well as their application in material and medicinal sciences.

Chiral macrocyclic terpyridine complexes.

The syntheses of novel chiral M(ii) bis(terpyridine) cage complexes Fe(L1)2-c and Ru(L1)2-c are described. The extraordinary design of the precursors Fe(L1)2 and Ru(L1)2 allows perfect preorganization for the final closing step. Due to the rigidity of the spacers between the two terpyridine moieties, the two isolated enantiomers barely racemize at room temperature in solution. The stable and axially chiral bis(terpyridine) Fe(ii) and Ru(ii) complexes were fully characterized by NMR-spectroscopy, UV-Vis spectroscopy, electrochemical measurements, high resolution mass spectrometry, circular dichroism measurements, and X-ray structural analysis.

Optimization of Synthetically Versatile Pyridylidene Amide Ligands for Efficient Iridium-Catalyzed Water Oxidation.

The synthetic versatility of pyridylidene amide (PYA) ligands has been exploited to prepare and evaluate a diverging series of iridium complexes containing C,N-bidentate chelating aryl-PYA ligands for water oxidation catalysis. The phenyl-PYA lead structure 1 was modified (i) electronically through introduction of one, two, or three electron-donating methoxy substituents on the aryl ring, (ii) by incorporating long aliphatic chains to the pyridyl fragment of the PYA unit, and (iii) by altering the PYA positions from para-PYA to its ortho- and meta-isomers. Electrochemistry indicated no substantial electronic effect of the aliphatic chains, and only minor changes of the electron density at iridium when modifying the aryl ligand site, yet substantial alteration if the PYA ligand is the ortho- (E1/2 =+0.72 V), para- (E1/2 =+0.64 V), or meta-isomer (E1/2 =+0.56 V vs. saturated calomel electrode; SCE). In water oxidation catalysis, the long alkyl chains did not induce any rate enhancement compared with the phenyl-PYA lead compound, whereas MeO groups incorporated in the aryl group enhanced the catalytic activity from a turnover frequency (TOFmax )=1600 h-1 in the original Ph-PYA system gradually as more MeO groups were introduced up to a TOFmax =3300 h-1 for a tris(MeO)-substituted aryl-PYA system. The variation of the PYA substitution had only a minor impact on catalytic activity and revealed only a weak trend in the sequence ortho>meta>para. The high activity of the tris(MeO) system and the ortho-PYA isomer were attributed to efficient hydrogen bonding, which assists O-H bond activation and proton transfer. Remarkably, merging of the two optimized motifs, that is, an aryl unit with three MeO substituents and the PYA as the ortho isomer, into a single new aryl-PYA ligand system failed to improve the catalytic activity. Computational analysis suggests too much congestion at the active site, which hinders catalytic turnover. These results illustrate the complexity of ligand design and the subtle effects at play in water oxidation catalysis.