Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1H-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.

A new series of chiral 4,5-dihydro-1H-[1,2,4]-triazoline molecules, featuring a ß-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (8a-j) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative 8b provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the (S)-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative 8c showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.

Phenazine Cations as Anticancer Theranostics†.

The biological properties of two water-soluble organic cations based on polypyridyl structures commonly used as ligands for photoactive transition metal complexes designed to interact with biomolecules are investigated. A cytotoxicity screen employing a small panel of cell lines reveals that both cations show cytotoxicity toward cancer cells but show reduced cytotoxicity to noncancerous HEK293 cells with the more extended system being notably more active. Although it is not a singlet oxygen sensitizer, the more active cation also displayed enhanced potency on irradiation with visible light, making it active at nanomolar concentrations. Using the intrinsic luminescence of the cations, their cellular uptake was investigated in more detail, revealing that the active compound is more readily internalized than its less lipophilic analogue. Colocalization studies with established cell probes reveal that the active cation predominantly localizes within lysosomes and that irradiation leads to the disruption of mitochondrial structure and function. Stimulated emission depletion (STED) nanoscopy and transmission electron microscopy (TEM) imaging reveal that treatment results in distinct lysosomal swelling and extensive cellular vacuolization. Further imaging-based studies confirm that treatment with the active cation induces lysosomal membrane permeabilization, which triggers lysosome-dependent cell-death due to both necrosis and caspase-dependent apoptosis. A preliminary toxicity screen in the Galleria melonella animal model was carried out on both cations and revealed no detectable toxicity up to concentrations of 80 mg/kg. Taken together, these studies indicate that this class of synthetically easy-to-access photoactive compounds offers potential as novel therapeutic leads.

Ultrafast electronic, infrared, and X-ray absorption spectroscopy study of Cu(I) phosphine diimine complexes.

The study aims to understand the role of the transient bonding in the interplay between the structural and electronic changes in heteroleptic Cu(I) diimine diphosphine complexes. This is an emerging class of photosensitisers which absorb in the red region of the spectrum, whilst retaining a sufficiently long excited state lifetime. Here, the dynamics of these complexes are explored by transient absorption (TA) and time-resolved infrared (TRIR) spectroscopy, which reveal ultrafast intersystem crossing and structural distortion occurring. Two potential mechanisms affecting excited state decay in these complexes involve a transient formation of a solvent adduct, made possible by the opening up of the Cu coordination centre in the excited state due to structural distortion, and by a transient coordination of the O-atom of the phosphine ligand to the copper center. X-ray absorption studies of the ground electronic state have been conducted as a prerequisite for the upcoming X-ray spectroscopy studies which will directly determine structural dynamics. The potential for these complexes to be used in bimolecular applications is confirmed by a significant yield of singlet oxygen production.

2,2':4,4'':4',4'''-Quaterpyridine: synthesis, crystal-structure description, and Hirshfeld surface analysis.

The title compound, 2,2':4,4'':4',4'''-quaterpyridine (Qtpy), C20H14N4, crystallizes in the triclinic P space group and has half of the mol-ecule in the asymmetric unit, corresponding to 4,4'-bi-pyridine (4,4'-bpy) that serves as the building block for the mol-ecule. C4,4'-bpy-N-C4,4'-bpy and/or N-C4,4'-bpy-C4,4'-bpy bond-angle parameters show that the 4,4'-bpy ligands are highly rigid, displaying values lower than the linear bond angle of 180°. In the crystal, the 4,4'-bpy units are seen to be facing each other in relatively close proximity. The most important inter-actions on the Hirshfeld Surface of the compound are C-H⋯N/H⋯N-C inter-actions (constituting 10.6% and 7.6% of the total surface).

Photocatalytic Reduction of CO2 to CO in Aqueous Solution under Red-Light Irradiation by a Zn-Porphyrin-Sensitized Mn(I) Catalyst.

This work demonstrates photocatalytic CO2 reduction by a noble-metal-free photosensitizer-catalyst system in aqueous solution under red-light irradiation. A water-soluble Mn(I) tricarbonyl diimine complex, [MnBr(4,4'-{Et2O3PCH2}2-2,2'-bipyridyl)(CO)3] (1), has been fully characterized, including single-crystal X-ray crystallography, and shown to reduce CO2 to CO following photosensitization by tetra(N-methyl-4-pyridyl)porphyrin Zn(II) tetrachloride [Zn(TMPyP)]Cl4 (2) under 625 nm irradiation. This is the first example of 2 employed as a photosensitizer for CO2 reduction. The incorporation of -P(O)(OEt)2 groups, decoupled from the core of the catalyst by a -CH2- spacer, afforded water solubility without compromising the electronic properties of the catalyst. The photostability of the active Mn(I) catalyst over prolonged periods of irradiation with red light was confirmed by 1H and 13C{1H} NMR spectroscopy. This first report on Mn(I) species as a homogeneous photocatalyst, working in water and under red light, illustrates further future prospects of intrinsically photounstable Mn(I) complexes as solar-driven catalysts in an aqueous environment.

A Dinuclear Osmium(II) Complex Near-Infrared Nanoscopy Probe for Nuclear DNA.

With the aim of developing photostable near-infrared cell imaging probes, a convenient route to the synthesis of heteroleptic OsII complexes containing the Os(TAP)2 fragment is reported. This method was used to synthesize the dinuclear OsII complex, [{Os(TAP)2}2tpphz]4+ (where tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2''-h:2‴,3'''-j]phenazine and TAP = 1,4,5,8- tetraazaphenanthrene). Using a combination of resonance Raman and time-resolved absorption spectroscopy, as well as computational studies, the excited state dynamics of the new complex were dissected. These studies revealed that, although the complex has several close lying excited states, its near-infrared, NIR, emission (λmax = 780 nm) is due to a low-lying Os → TAP based 3MCLT state. Cell-based studies revealed that unlike its RuII analogue, the new complex is neither cytotoxic nor photocytotoxic. However, as it is highly photostable as well as live-cell permeant and displays NIR luminescence within the biological optical window, its properties make it an ideal probe for optical microscopy, demonstrated by its use as a super-resolution NIR STED probe for nuclear DNA.

Self-Assembly of Stimuli-Responsive [2]Rotaxanes by Amidinium Exchange.

Advances in supramolecular chemistry are often underpinned by the development of fundamental building blocks and methods enabling their interconversion. In this work, we report the use of an underexplored dynamic covalent reaction for the synthesis of stimuli-responsive [2]rotaxanes. The formamidinium moiety lies at the heart of these mechanically interlocked architectures, because it enables both dynamic covalent exchange and the binding of simple crown ethers. We demonstrated that the rotaxane self-assembly follows a unique reaction pathway and that the complex interplay between crown ether and thread can be controlled in a transient fashion by addition of base and fuel acid. Dynamic combinatorial libraries, when exposed to diverse nucleophiles, revealed a profound stabilizing effect of the mechanical bond as well as intriguing reactivity differences between seemingly similar [2]rotaxanes.

Chan-Lam Amination of Secondary and Tertiary Benzylic Boronic Esters.

We report a Chan-Lam coupling reaction of benzylic and allylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition-metal-mediated transformation of a tertiary alkylboron reagent. Initial investigation into the reaction mechanism suggests that transmetalation from B to Cu occurs through a single-electron, rather than a two-electron process.

Encoding Multiple Reactivity Modes within a Single Synthetic Replicator.

Establishing programmable and self-sustaining replication networks in pools of chemical reagents is a key challenge in systems chemistry. Self-replicating templates are formed from two constituent components with complementary recognition and reactive sites via a slow bimolecular pathway and a fast template-directed pathway. Here, we re-engineer one of the components of a synthetic replicator to encode an additional recognition function, permitting the assembly of a binary complex between the components that mediates replicator formation through a template-independent pathway, which achieves maximum rate acceleration at early time points in the replication process. The complementarity between recognition sites creates a key conformational equilibrium between the catalytically inert product, formed via the template-independent pathway, and the catalytically active replicator that mediates the template-directed pathway. Consequently, the rapid formation of the catalytically inert isomer kick-starts replication through the template-directed pathway. Through kinetic analyses, we demonstrate that the presence of the two recognition-mediated reactivity modes results in enhanced template formation in comparison to that of systems capable of exploiting only a single recognition-mediated pathway. Finally, kinetic simulations reveal that the conformational equilibrium and both the relative and absolute efficiencies of the recognition-mediated pathways affect the extent to which self-replicating systems can benefit from this additional template-independent reactivity mode. These results allow us to formulate the rules that govern the coupling of replication processes to alternative recognition-mediated reactivity modes. The interplay between template-directed and template-independent pathways for replicator formation has significant relevance to ongoing efforts to design programmable and adaptable replicator networks.

Ruthenium based antimicrobial theranostics - using nanoscopy to identify therapeutic targets and resistance mechanisms in Staphylococcus aureus.

In previous studies we reported that specific dinuclear RuII complexes are particularly active against pathogenic Gram-negative bacteria and, unusually for this class of compounds, appeared to display lowered activity against Gram-positive bacteria. With the aim of identifying resistance mechanisms specific to Gram-positive bacteria, the uptake and antimicrobial activity of the lead complex against Staphylococcus aureus SH1000 and other isolates, including MRSA was investigated. This revealed differential, strain specific, sensitivity to the complex. Exploiting the inherent luminescent properties of the RuII complex, super-resolution STED nanoscopy was used to image its initial interaction with S. aureus and confirm its cellular internalization. Membrane damage assays and transmission electron microscopy confirm that the complex disrupts the bacterial membrane structure before internalization, which ultimately results in a small amount of DNA damage. A known resistance mechanism against cationic antimicrobials in Gram-positive bacteria involves increased expression of the mprF gene as this results in an accumulation of positively charged lysyl-phosphatidylglycerol on the outer leaflet of the cytoplasmic membrane that electrostatically repel cationic species. Consistent with this model, it was found that an mprF deficient strain was particularly susceptible to treatment with the lead complex. More detailed co-staining studies also revealed that the complex was more active in S. aureus strains missing, or with altered, wall teichoic acids.

Sterically hindered Re- and Mn-CO2 reduction catalysts for solar energy conversion.

Novel molecular Re and Mn tricarbonyl complexes bearing a bipyridyl ligand functionalised with sterically hindering substituents in the 6,6'-position, [M(HPEAB)(CO)3(X)] (M/X = Re/Cl, Mn/Br; HPEAB = 6,6'-{N-(4-hexylphenyl)-N(ethyl)-amido}-2,2'-bipyridine) have been synthesised, fully characterised including by single crystal X-ray crystallography, and their propensity to act as catalysts for the electrochemical and photochemical reduction of CO2 has been established. Controlled potential electrolysis showed that the catalysts are effective for electrochemical CO2-reduction, yielding CO as the product (in MeCN for the Re-complex, in 95 : 5 (v/v) MeCN : H2O mixture for the Mn-complex). The recyclability of the catalysts was demonstrated through replenishment of CO2 within solution. The novel catalysts had similar reduction potentials to previously reported complexes of similar structure, and results of the foot-of-the-wave analysis showed comparable maximum turnover rates, too. The tentative mechanisms for activation of the pre-catalysts were proposed on the basis of IR-spectroelectrochemical data aided by DFT calculations. It is shown that the typical dimerisation of the Mn-catalyst was prevented by incorporation of sterically hindering groups, whilst the Re-catalyst undergoes the usual mechanism following chloride ion loss. No photochemical CO2 reduction was observed for the rhenium complex in the presence of a sacrificial donor (triethylamine), which was attributed to the short triplet excited state lifetime (3.6 ns), insufficient for diffusion-controlled electron transfer. Importantly, [Mn(HPEAB)(CO)3Br] can act as a CO2 reduction catalyst when photosensitised by a zinc porphyrin under red light irradiation (λ > 600 nm) in MeCN : H2O (95 : 5); there has been only one reported example of photoactivating Mn-catalysts with porphyrins in this manner. Thus, this work demonstrates the wide utility of sterically protected Re- and Mn-diimine carbonyl catalysts, where the rate and yield of CO-production can be adjusted based on the metal centre and catalytic conditions, with the advantage of suppressing unwanted side-reactions through steric protection of the vacant coordination site.

Unusual Magneto-Structural Features of the Halo-Substituted Materials [FeIII (5-X-salMeen)2 ]Y: a Cooperative [HS-HS]↔[HS-LS] Spin Transition.

X-ray structures of the halo-substituted complexes [FeIII (5-X-salMeen)2 ]ClO4 (X=F, Cl, Br, I) [salMeen=N-methyl-N-(2-aminoethyl)salicylaldiminate]at RT have revealed the presence of two discrete HS complex cations in the crystallographic asymmetric unit with two perchlorate counter ions linking them by N-Hamine ⋅⋅⋅Operchlorate interactions. At 90 K, the two complex cations are distinctly HS and LS, a rare crystallographic observation of this coexistence in the FeIII -salRen (R=alkyl) spin-crossover (SCO) system. At both temperatures, crystal packing shows dimerization through C-Himine ⋅⋅⋅Ophenolate interactions, a key feature for SCO cooperativity. Moreover, there are noncovalent contacts between the complex cations through type-II halogen-halogen bonds, which are novel in this system. The magnetic profiles and Mössbauer spectra concur with the structural analyses and reveal 50 % SCO of the type [HS-HS]↔[HS-LS] with a broad plateau. In contrast, [FeIII (5-Cl-salMeen)2 ]BPh4 ⋅2MeOH is LS and exhibits a temperature-dependent crystallographic phase transition, exemplifying the influence of lattice solvents and counter ions on SCO.

The first crystal structure of the pyrrolo-[1,2-c]oxazole ring system.

The title compound, C7H4F3NO2, 3-tri-fluoro-methyl-1H-pyrrolo-[1,2-c]oxazol-1-one, is the first crystal structure of the pyrrolo-[1,2-c]oxazole ring system: the fused ring system is almost planar (r.m.s. deviation = 0.006 Å). In the crystal, weak C-H⋯O and C-H⋯F hydrogen bonds link the mol-ecules into [001] chains and π-π stacking inter-actions consolidate the structure.

Structural Investigation into the Threading Intercalation of a Chiral Dinuclear Ruthenium(II) Polypyridyl Complex through a B-DNA Oligonucleotide.

Herein we report the separation of the three stereoisomers of the DNA light-switch compound [{Ru(bpy)2}2(tpphz)]4+ (tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2‴,3‴-j]phenazine) by column chromatography and the characterization of each stereoisomer by X-ray crystallography. The interaction of these compounds with a DNA octanucleotide d(GCATATCG).d(CGATATGC) has been studied using NMR techniques. Selective deuteration of the bipyridyl rings was needed to provide sufficient spectral resolution to characterize structures. NMR-derived structures for these complexes show a threading intercalation binding mode with slow and chirality-dependent rates. This represents the first solution structure of an intercalated bis-ruthenium ligand. Intriguingly, we find that the binding site selectivity is dependent on the nature of the stereoisomer employed, with Λ RuII centers showing a better intercalation fit.

Turning intercalators into groove binders: synthesis, photophysics and DNA binding properties of tetracationic mononuclear ruthenium(ii)-based chromophore-quencher complexes.

The synthesis of two new tetracationic mononuclear RuII complexes containing the tetrapyridyl [3,2-a:2',3'-c:3'',2''-h:2''',3'''-j] phenazine ligand in which the uncoordinated site has been converted into a dicationic ethylene-bipyridyldiylium unit is reported. The structure of the complexes is fully assigned through detailed NMR studies and, in one case, through an X-ray crystallography study. Voltammetry, optical spectroscopy and computational studies confirm that the bipyridyldiylium moiety has a low-lying reduction that quenches the 3MLCT-based emission usually observed in such systems. The new complexes interact with DNA in a quite different manner to their dicationic analogues: they both bind to duplex DNA with micromolar affinity through groove binding. These observations are rationalized through a consideration of their structural and electronic properties.

An Environmentally Responsive Reciprocal Replicating Network.

A reciprocal replication system is constructed from four building blocks, A, B, C, and D, which react in a pairwise manner through either a 1,3-dipolar cycloaddition or the condensation reaction between an amine and an aldehyde to create two templates, trans-TAB and TCD. These templates are equipped with complementary recognition sites-two carboxylic acids ( trans-TAB) or two 4,6-dimethylamidopyridines (TCD)-that enable each template to direct the formation of its complementary partner through two mutually reinforcing cross-catalytic pathways, in which the templates trans-TAB or TCD preorganize the appropriate building blocks within two catalytically active ternary complexes: [C•D• trans-TAB] and [A•B•TCD]. The template-directed processes within these complexes generate a heteroduplex [ trans-TAB•TCD], which is shown to possess significant stability through kinetic simulations and fitting. As a consequence, the individual cross-catalytic pathways perform more efficiently in template-directed experiments when the concentration of the template being formed is below that of the template added as instruction. Comprehensive analysis of the system in which A, B, C, and D are mixed together directly, using a series of 1H NMR spectroscopic kinetic experiments, demonstrates that the behavior of the reciprocal system is more than the simple sum of its parts-as part of the interconnected network, the product of each reaction clearly directs the fabrication of its reciprocal partner, facilitating both higher rates of formation for both templates and improved diastereoselectivity for trans-TAB. A simple change in experimental conditions (from dry to "wet" CDCl3) demonstrates the sensitivity of the replication pathways within the network to the reaction environment, which leads to a >10-fold increase in the contribution of a new minimal self-replicator, trans-TAB*, to the replication network.

Hydrogen bonding vs. halogen bonding: the solvent decides.

Control of intermolecular interactions is integral to harnessing self-assembly in nature. Here we demonstrate that control of the competition between hydrogen bonds and halogen bonds, the two most highly studied directional intermolecular interactions, can be exerted by choice of solvent (polarity) to direct the self-assembly of co-crystals. Competitive co-crystal formation has been investigated for three pairs of hydrogen bond and halogen bond donors, which can compete for a common acceptor group. These competitions have been examined in seven different solvents. Product formation has been determined and phase purity has been examined by analysis of powder X-ray diffraction patterns. Formation of hydrogen-bonded co-crystals is favoured from less polar solvents and halogen-bonded co-crystals from more polar solvents. The solvent polarity at which the crystal formation switches from hydrogen-bond to halogen-bond dominance depends on the relative strengths of the interactions, but is not a function of the solution-phase interactions alone. The results clearly establish that an appreciation of solvent effects is critical to obtain control of the intermolecular interactions.

The Contrasting Character of Early and Late Transition Metal Fluorides as Hydrogen Bond Acceptors.

The association constants and enthalpies for the binding of hydrogen bond donors to group 10 transition metal complexes featuring a single fluoride ligand (trans-[Ni(F)(2-C5NF4)(PR3)2], R = Et 1a, Cy 1b, trans-[Pd(F)(4-C5NF4)(PCy3)2] 2, trans-[Pt(F){2-C5NF2H(CF3)}(PCy3)2] 3 and of group 4 difluorides (Cp2MF2, M = Ti 4a, Zr 5a, Hf 6a; Cp*2MF2, M = Ti 4b, Zr 5b, Hf 6b) are reported. These measurements allow placement of these fluoride ligands on the scales of organic H-bond acceptor strength. The H-bond acceptor capability ß (Hunter scale) for the group 10 metal fluorides is far greater (1a 12.1, 1b 9.7, 2 11.6, 3 11.0) than that for group 4 metal fluorides (4a 5.8, 5a 4.7, 6a 4.7, 4b 6.9, 5b 5.6, 6b 5.4), demonstrating that the group 10 fluorides are comparable to the strongest organic H-bond acceptors, such as Me3NO, whereas group 4 fluorides fall in the same range as N-bases aniline through pyridine. Additionally, the measurement of the binding enthalpy of 4-fluorophenol to 1a in carbon tetrachloride (-23.5 ± 0.3 kJ mol(-1)) interlocks our study with Laurence's scale of H-bond basicity of organic molecules. The much greater polarity of group 10 metal fluorides than that of the group 4 metal fluorides is consistent with the importance of pπ-dπ bonding in the latter. The polarity of the group 10 metal fluorides indicates their potential as building blocks for hydrogen-bonded assemblies. The synthesis of trans-[Ni(F){2-C5NF3(NH2)}(PEt3)2], which exhibits an extended chain structure assembled by hydrogen bonds between the amine and metal-fluoride groups, confirms this hypothesis.

AAAA-DDDD quadruple hydrogen-bond arrays featuring NH···N and CH···N hydrogen bonds.

The X-ray crystal structure of a previously reported extremely strong quadruple NH···N AAAA-DDDD hydrogen-bond array [5·4] (K(a) = 1.5 × 10(6) M(-1) in CH3CN; K(a) > 3 × 10(12) M(-1) in CH2Cl2) features four short linear hydrogen bonds. Changing the two benzimidazole groups of the DDDD unit to triazole groups replaces two of the NH···N hydrogen bonds with CH···N interactions (complex [5·6]), but only reduces the association constant in CH3CN by 2 orders of magnitude (K(a) = 2.6 × 10(4) M(-1) in CH3CN; K(a) > 1 × 10(7) M(-1) in CH2Cl2). Related complexes without the triazole groups range in K(a) from 18 to 270 M(-1) in CH3CN, suggesting that the CH···N interactions can be considered part of a strong AAAA-DDDD quadruple hydrogen-bonding array. The NH···N/CH···N AAAA-DDDD motif can be repeatedly switched "on" and "off" in CDCl3 through successive additions of acid and base.

A simple network of synthetic replicators can perform the logical OR operation.

A small network of synthetic replicators is capable of responding to instructional inputs such that the output of the network is an excess of one of the replicators whenever the input contains either or both of the replicators, mirroring the OR boolean logic operation.