Spontaneous Chiral Resolution of a MnIII Spin-Crossover Complex with High Temperature 80†K Hysteresis.

Non-centrosymmetric spin-switchable systems are of interest for their prospective applications as magnetically active non-linear optical materials and in multiferroic devices. Chiral resolution of simple spin-crossover chelate complexes into the Δ and Λ forms offers a facile route to homochiral magnetic switches, which could be easily enantiomerically enriched. Here, we report the spontaneous resolution of a new hysteretic spin-crossover complex, [MnIII (sal2 323)]SCN ⋅ EtOH (1), into Δ and Λ forms, without the use of chiral reagents, where sal2 323 is a Schiff base resulting from condensation of 1,2-bis(3-aminopropylamino)ethane with 2-hydroxybenzaldehyde. The enantiopurity of the Δ and Λ isomers was confirmed by single crystal X-ray diffraction and circular dichroism. Quantum chemistry calculations were used to investigate the electronic structure. The opening of a wide 80 K thermal hysteresis window at high temperature highlights the potential for good magneto-optical function at ambient temperature for materials of this type.

Proton-Induced Spin State Switching in an FeIII Complex.

Reversible proton-induced spin state switching of an FeIII complex in solution is observed at room temperature. A reversible magnetic response was detected in the complex, [FeIII (sal2 323)]ClO4 (1), using Evans' method 1 H NMR spectroscopy which indicated cumulative switching from low-spin to high-spin upon addition of one and two equivalents of acid. Infrared spectroscopy suggests a coordination-induced spin state switching (CISSS) effect, whereby protonation displaces the metal-phenoxo donors. The analogous complex, [FeIII (4-NEt2 -sal2 323)]ClO4 (2), with a diethylamino group on the ligand, was used to combine the magnetic change with a colorimetric response. Comparison of the protonation responses of 1 and 2 reveals that the magnetic switching is caused by perturbation of the immediate coordination sphere of the complex. These complexes constitute a new class of analyte sensor which operate by magneto-modulation, and in the case of 2, also yield a colorimetric response.

Domain Wall Dynamics in a Ferroelastic Spin Crossover Complex with Giant Magnetoelectric Coupling.

Pinned and mobile ferroelastic domain walls are detected in response to mechanical stress in a Mn3+ complex with two-step thermal switching between the spin triplet and spin quintet forms. Single-crystal X-ray diffraction and resonant ultrasound spectroscopy on [MnIII(3,5-diCl-sal2(323))]BPh4 reveal three distinct symmetry-breaking phase transitions in the polar space group series Cc → Pc → P1 → P1(1/2). The transition mechanisms involve coupling between structural and spin state order parameters, and the three transitions are Landau tricritical, first order, and first order, respectively. The two first-order phase transitions also show changes in magnetic properties and spin state ordering in the Jahn-Teller-active Mn3+ complex. On the basis of the change in symmetry from that of the parent structure, Cc, the triclinic phases are also ferroelastic, which has been confirmed by resonant ultrasound spectroscopy. Measurements of magnetoelectric coupling revealed significant changes in electric polarization at both the Pc → P1 and P1 → P1(1/2) transitions, with opposite signs. All these phases are polar, while P1 is also chiral. Remanent electric polarization was detected when applying a pulsed magnetic field of 60 T in the P1→ P1(1/2) region of bistability at 90 K. Thus, we showcase here a rare example of multifunctionality in a spin crossover material where the strain and polarization tensors and structural and spin state order parameters are strongly coupled.

Homochiral Mn3+ Spin-Crossover Complexes: A Structural and Spectroscopic Study.

Structural, magnetic, and spectroscopic data on a Mn3+ spin-crossover complex with Schiff base ligand 4-OMe-Sal2323, isolated in crystal lattices with five different counteranions, are reported. Complexes of [Mn(4-OMe-Sal2323)]X where X = ClO4- (1), BF4- (2), NO3- (3), Br- (4), and I- (5) crystallize isotypically in the chiral orthorhombic space group P21212 with a range of spin state preferences for the [Mn(4-OMe-Sal2323)]+ complex cation over the temperature range 5-300 K. Complexes 1 and 2 are high-spin, complex 4 undergoes a gradual and complete thermal spin crossover, while complexes 3 and 5 show stepped crossovers with different ratios of spin triplet and quintet forms in the intermediate temperature range. High-field electron paramagnetic resonance was used to measure the zero-field splitting parameters associated with the spin triplet and quintet states at temperatures below 10 K for complexes 4 and 2 with respective values: DS=1 = +23.38(1) cm-1, ES=1 = +2.79(1) cm-1, and DS=2 = +6.9(3) cm-1, with a distribution of E parameters for the S = 2 state. Solid-state circular dichroism (CD) spectra on high-spin complex 1 at room temperature reveal a 2:1 ratio of enantiomers in the chiral conglomerate, and solution CD measurements on the same sample in methanol show that it is stable toward racemization. Solid-state UV-vis absorption spectra on high-spin complex 1 and mixed S = 1/S = 2 sample 5 reveal different intensities at higher energies, in line with the different electronic composition. The statistical prevalence of homochiral crystallization of [Mn(4-OMe-Sal2323)]+ in five lattices with different achiral counterions suggests that the chirality may be directed by the 4-OMe-Sal2323 ligand.

Thermal and Magnetic Field Switching in a Two-Step Hysteretic MnIII Spin Crossover Compound Coupled to Symmetry Breakings.

A MnIII spin crossover complex with atypical two-step hysteretic thermal switching at 74 K and 84 K shows rich structural-magnetic interplay and magnetic-field-induced spin state switching below 14 T with an onset below 5 T. The spin states, structures, and the nature of the phase transitions are elucidated via X-ray and magnetization measurements. An unusual intermediate phase containing four individual sites, where 1 / 4 are in a pure low spin state, is observed. The splitting of equivalent sites in the high temperature phase into four inequivalent sites is due to a structural reorganization involving a primary and a secondary symmetry-breaking order parameter that induces a crystal system change from orthorhombic→monoclinic and a cell doubling. Further cooling leads to a reconstructive phase transition and a monoclinic low-temperature phase with two inequivalent low-spin sites. The coupling between the order parameters is identified in the framework of Landau theory.

In-vitro and in-vivo investigations into the carbene-gold anticancer drug candidates NHC*-Au-SCSNMe2 and NHC*-Au-S-GLUC against advanced prostate cancer PC3.

The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.

Modulation of Mn3+ Spin State by Guest Molecule Inclusion.

Spin state preferences for a cationic Mn3+ chelate complex in four different crystal lattices are investigated by crystallography and SQUID magnetometry. The [MnL1]+ complex cation was prepared by complexation of Mn3+ to the Schiff base chelate formed from condensation of 4-methoxysalicylaldehyde and 1,2-bis(3-aminopropylamino)ethane. The cation was crystallized separately with three polyatomic counterions and in one case was found to cocrystallize with a percentage of unreacted 4-methoxysalicylaldehyde starting material. The spin state preferences of the four resultant complexes [MnL1]CF3SO3·xH2O, (1), [MnL1]PF6·xH2O, (2), [MnL1]PF6·xsal·xH2O, (2b), and [MnL1]BPh4, (3), were dependent on their ability to form strong intermolecular interactions. Complexes (1) and (2), which formed hydrogen bonds between [MnL1]+, lattice water and in one case also with counterion, showed an incomplete thermal spin crossover over the temperature range 5-300 K. In contrast, complex (3) with the BPh4-, counterion and no lattice water, was locked into the high spin state over the same temperature range, as was complex (2b), where inclusion of the 4-methoxysalicylaldehyde guest blocked the H-bonding interaction.

Novel Anticancer NHC*-Gold(I) Complexes Inspired by Lepidiline A.

N-Heterocyclic carbene gold(I) complexes derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) represent a promising class of anticancer drugs. Complexes of the type NHC*-Au-L (L = Br-, I-, C≡C-R) and [NHC*-Au-L]+ (L = NHC*, PPh3) have been synthesised. The X-ray crystal structures of all gold(I) complexes are presented; aurophilic interactions were observed in five of the complexes. The anticancer activity was assessed via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based proliferation assays against the human colon carcinoma cell line HCT-116wt and the multidrug-resistant human breast carcinoma cell line MCF-7topo. Most complexes showed good cytotoxicity with IC50 values in the low micromolar range, while excellent sub-micromolar activity was observed for 2c, 3a and 3b. Generally, the activity of the ligands studied was as follows: carbene > phosphine > alkyne > halide, with an exception for the highly active iodido derivative 2c.

Stress-Induced Domain Wall Motion in a Ferroelastic Mn3+ Spin Crossover Complex.

Domain wall motion is detected for the first time during the transition to a ferroelastic and spin state ordered phase of a spin crossover complex. Single-crystal X-ray diffraction and resonant ultrasound spectroscopy (RUS) revealed two distinct symmetry-breaking phase transitions in the mononuclear Mn3+ compound [Mn(3,5-diBr-sal2 (323))]BPh4 , 1. The first at 250 K, involves the space group change Cc→Pc and is thermodynamically continuous, while the second, Pc→P1 at 85 K, is discontinuous and related to spin crossover and spin state ordering. Stress-induced domain wall mobility was interpreted on the basis of a steep increase in acoustic loss immediately below the the Pc-P1 transition.

Spin Crossover Behavior in a Homologous Series of Iron(II) Complexes Based on Functionalized Bipyridyl Ligands.

A series of bulky substituted bipyridine-related iron(II) complexes [Fe(H2Bpz2)2(L)] (pz = pyrazolyl) were prepared, where L = 5,5'-dimethyl-2,2'-bipyridine (bipy-CH3, 1), L = dimethyl-2,2'-bipyridyl-5,5'-dicarboxylate (MeObpydc, 2), L = diethyl-2,2'-bipyridyl-5,5'-dicarboxylate (EtObpydc, 3), or L = diisopropyl-2,2'-bipyridine-5,5'-dicarboxylate ( i-PrObpydc, 4). The crystal structures of five new iron(II) complexes were determined by X-ray diffraction: those of 1, 3, and 4 and two modifications of 3 (3B) and 4 (4B). Complexes 1 and 3B display incomplete spin crossover (SCO) behavior because of a freezing-in effect, whereas 3 and 4B undergo gradual and incomplete SCO behaviors. Complexes 2 and 4 show a completely gradual and steep SCO, respectively. Such different SCO behaviors can be attributed to an electronic substituent effect in the bipyridyl ligand conformation and a crystal packing effect. Importantly, the electronic substituent effect of the isopropyl acetate group and C-H···O supramolecular interactions in 4 contribute to a highly cooperative behavior, which leads to an abrupt thermally induced spin transition.

Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A.

Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3⁻5), p-mercaptobenzoate derivatives (12⁻14) and N-acetyl-l-cysteine derivatives (15⁻17). All complexes were synthesised in good yields of 57⁻78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116-/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 µM ± 0.03 µM. Complexes incorporating a Au⁻S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6⁻311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.

Mysterious Decomposition of Alkoxyphosphonium Chlorides: Postulated Involvement of the HCl2 Anion and Its Capture in the Solid State.

P-Alkoxyphosphonium (AP) chlorides were generated by reacting P-chlorophosphonium chlorides with alcohols. Their well-known spontaneous Arbuzov-type collapse leading to phosphine oxides was studied and its rate found to be dependent on a number of factors in an unexpected fashion: it is inversely proportional to the initial concentration and it shows strong dependence on the acidity of the media but is not very sensitive to the presence of base. To explain these observations, we evoke a self-inhibition model with the formation of the less nucleophilic hydrodichloride anion HCl2 in solution. Detailed analysis of the kinetic data yields the association constant (K=3×102 m-1 ) of the putative HCl2 species in chloroform. Experimental observations for the collapse of highly enriched diastereomeric alkoxyphosphonium (DAP) chlorides are fully analogous to the achiral AP also implying the involvement of HCl2 anions. Moreover, crystallisation of a highly enriched DAP salt derived from (-)-menthol furnished, for the first time, crystals of individual (RP )-DAP hydrodichloride as confirmed by X-ray diffractometry. Importantly, the P-configuration and detailed conformation of the DAP moiety is in good agreement with DFT-level computational results. The thermal collapse of (RP )-DAP⋅HCl2 proceeds with complete retention of the P-configuration furnishing the phosphine oxide of exceptional enantiomeric purity.

Two Independent Orthogonal Stereomutations at a Single Asymmetric Center: A Narcissistic Couple.

The energy barriers in our recently discovered Walden-type inversion of chlorophosphonium salts are similar to those for Cope rearrangements of caged cyclic hydrocarbons. Therefore, we have designed a molecular system that integrates the two processes, thereby producing the first embodiment of a chemical species that can undergo two entirely different and independent stereomutation mechanisms at the same nominal asymmetric center. Thus, the energy barrier to the rearrangement of 9-phenyl-9-phosphabarbaralane oxide, which is easily prepared by a new high-yielding synthesis, was found to be roughly 11 kcal mol-1 . This value is in contrast to the parent barbaralane (7.3 kcal mol-1 ) but in good agreement with our computational results for the rearrangement barriers. Crucially, in the corresponding chlorophosphonium derivative, two stereomutations occur simultaneously: a fast Cope rearrangement (barrier ≈12 kcal mol-1 ) and a slow Walden-type inversion of the phosphorus center (barrier ≈21 kcal mol-1 ). The computational model also revealed a relationship between the Cope rearrangement barrier and the bridgehead distance. The phenomenon of two independent and geometrically orthogonal stereomutations at a single asymmetric center provided important general insights into reaction pathway bifurcation, microscopic reversibility, and dynamic stereochemistry. This first example of coexisting alternative mechanisms that involve covalent bonds may encourage the design of new types of dynamic molecular structures.

Triazolylidene-Iridium Complexes with a Pendant Pyridyl Group for Cooperative Metal-Ligand Induced Catalytic Dehydrogenation of Amines.

Two iridium(III) complexes containing a C,N-bidentate pyridyl-triazolylidene ligand were prepared that are structurally very similar but differ in their pendant substituent. Whereas complex 1 contains a non-coordinating pyridyl unit, complex 2 has a phenyl group on the triazolylidene substituent. The presence of the basic pyridyl unit has distinct effects on the catalytic activity of the complex in the oxidative dehydrogenation of benzylic amines, inducing generally higher rates, higher selectivity towards formation of imines versus secondary amines, and notable quantities of tertiary amines when compared to the phenyl-functionalized analogue. The role of the pyridyl functionality has been elucidated from a set of stoichiometric experiments, which demonstrate hydrogen bonding between the pendant pyridyl unit and the amine protons of the substrate. Such Npyr ⋅⋅⋅H-N interactions are demonstrated by X-ray diffraction analysis, 1 H NMR, and IR spectroscopy, and suggest a pathway of substrate bond-activation that involves concerted substrate binding through the Lewis acidic iridium center and the Lewis basic pyridyl site appended to the triazolylidene ligand, in agreement with ligand-metal cooperative substrate activation.

Enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation.

The highly enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl-ß-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl-α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl-ß-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl-α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.

Donor-Flexible Nitrogen Ligands for Efficient Iridium-Catalyzed Water Oxidation Catalysis.

A pyridylideneamide ligand with variable donor properties owing to a pronounced zwitterionic and a neutral diene-type resonance structure was used as a dynamic ligand at a Cp* iridium center to facilitate water oxidation catalysis, a reaction that requires the stabilization of a variety of different iridium oxidation states and that is key for developing an efficient solar fuel device. The ligand imparts high activity (nearly three-fold increase of turnover frequency compared to benchmark systems), and exceptionally high turnover numbers, which indicate a robust catalytic cycle and little catalyst degradation.

Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations.

The benzylation of alcohols with the commonly used combination of benzyl bromide and sodium hydride in DMF can lead to the formation of an amine side product, N,N'-dimethyl-1-phenyl-1-(o-tolyl)methanamine. This amine coeluted with benzylated galactal during column chromatography and was found to be a catalyst poison in thiourea-catalyzed glycosylations of galactals. It may also be problematic for other base-sensitive reactions involving benzylated substrates. Solutions to this problem are described.

A Family of Chiral Ferrocenyl Diols: Modular Synthesis, Solid-State Characterization, and Application in Asymmetric Organocatalysis.

Readily available chiral diol scaffolds are useful as sources of chirality for asymmetric synthesis, however, few such scaffolds are readily available in enantiopure form. Reported herein is a cheap and modular synthesis of a novel family of chiral ferrocenyl diols in excellent yields with excellent enantio- and diastereoselectivity (>99 % ee and 99 % de). These diols possess not only planar and central chirality, but also axial chirality around the central iron atom. Characterization of these diols by X-ray crystallography revealed intra- and intermolecular hydrogen-bond networks depending on substitution at the carbinol positions. The potential of these diols as catalysts was subsequently demonstrated in an asymmetric hetero-Diels-Alder reaction which provided cycloadducts in up to 84 % yield with ee values ranging from -92 to +72 %.

A ferrocenyl kaleidoscope: slow interconversion of six diastereo-atropisomers of 2,6-di-tert-butyl-9,10-diferrocenyltriptycene.

The title triptycene, 6, has been isolated as the product of 9,10-cycloaddition of benzyne to 9,10-diferrocenyl-2,6-di-tert-butylanthracene, 5, whose X-ray crystal structure is reported. Each ferrocenyl unit in 6 has access to the same three non-equivalent molecular environments, and their rotations relative to the molecular paddlewheel give rise to six slowly interconverting atropisomers. Their dynamic behaviour in solution is a challenging NMR puzzle that can be successfully solved by taking advantage of the recently described very large diamagnetic anisotropy of the ferrocenyl moiety, together with the C2 symmetry of particular atropisomers. Application of one- and two-dimensional NMR techniques over a range of temperatures together, with a detailed analysis of the homo- and heteronuclear correlations in 6, resulted in unequivocal mapping of the 99 (1)H and 162 (13)C positions in the six interconverting systems. Variable-temperature 2D-EXSY measurements revealed that, while the stability of the atropisomers is almost identical, they are separated by energy barriers which the ferrocenyls must overcome in the course of their interconversions. The heights of two different rotational barriers have been identified and these experimental findings are in good agreement with DFT calculations.

Exploiting the gem-Disubstitution Effect in FcPHOX and HetPHOX P,N Ligands: Synthesis and Applications in Pd-Catalyzed Intermolecular Heck Reactions.

The synthesis of a range of novel gem-disubstituted and electronically varied thiophene-oxazoline (HetPHOX) ligands and ferrocene-oxazoline (FcPHOX) ligands and their application in the Pd-catalyzed intermolecular asymmetric Heck reaction (IAH) is described. These investigations show that gem-disubstitution of i-Pr-PHOX-type ligands can lead to effective and cost-efficient alternatives to the corresponding t-Bu-PHOX systems. The Pd complexes of these ligands were very effective in the IAH, providing phenylated products in up to 100% conversion with up to 97% ee.