Cyclometalated and NNN Terpyridine Ruthenium Photocatalysts and Their Cytotoxic Activity.

The cyclometalated terpyridine complexes [Ru(η2-OAc)(NC-tpy)(PP)] (PP = dppb 1, (R,R)-Skewphos 4, (S,S)-Skewphos 5) are easily obtained from the acetate derivatives [Ru(η2-OAc)2(PP)] (PP = dppb, (R,R)-Skewphos 2, (S,S)-Skewphos 3) and tpy in methanol by elimination of AcOH. The precursors 2, 3 are prepared from [Ru(η2-OAc)2(PPh3)2] and Skewphos in cyclohexane. Conversely, the NNN complexes [Ru(η1-OAc)(NNN-tpy)(PP)]OAc (PP = (R,R)-Skewphos 6, (S,S)-Skewphos 7) are synthesized in a one pot reaction from [Ru(η2-OAc)2(PPh3)2], PP and tpy in methanol. The neutral NC-tpy 1, 4, 5 and cationic NNN-tpy 6, 7 complexes catalyze the transfer hydrogenation of acetophenone (S/C = 1000) in 2-propanol with NaOiPr under light irradiation at 30 °C. Formation of (S)-1-phenylethanol has been observed with 4, 6 in a MeOH/iPrOH mixture, whereas the R-enantiomer is obtained with 5, 7 (50-52% ee). The tpy complexes show cytotoxic activity against the anaplastic thyroid cancer 8505C and SW1736 cell lines (ED50 = 0.31-8.53 µM), with the cationic 7 displaying an ED50 of 0.31 µM, four times lower compared to the enantiomer 6.

Assignment of individual structures from intermetalloid nickel gallium cluster ensembles.

Poorly selective mixed-metal cluster synthesis and separation yield reaction solutions of inseparable intermetalloid cluster mixtures, which are often discarded. High-resolution mass spectrometry, however, can provide precise compositional data of such product mixtures. Structure assignments can be achieved by advanced computational screening and consideration of the complete structural space. Here, we experimentally verify structure and composition of a whole cluster ensemble by combining a set of spectroscopic techniques. Our study case are the very similar nickel/gallium clusters of M12, M13 and M14 core composition Ni6+xGa6+y (x + y ≤ 2). The rationalization of structure, bonding and reactivity is built upon the organometallic superatom cluster [Ni6Ga6](Cp*)6 = [Ga6](NiCp*)6 (1; Cp* = C5Me5). The structural conclusions are validated by reactivity tests using carbon monoxide, which selectively binds to Ni sites, whereas (triisopropylsilyl)acetylene selectively binds to Ga sites.

3D electron diffraction analysis of a novel, mechanochemically synthesized supramolecular organic framework based on tetrakis-4-(4-pyridyl)phenylmethane.

Tetrakis-4-(4-pyridyl)phenylmethane (TPPM) is a tetrahedral rigid molecule that crystallizes forming a dynamically responsive supramolecular organic framework (SOF). When exposed to different stimuli, this supramolecular network can reversibly switch from an empty to a filled solvated solid phase. This article describes a novel expanded form of a TPPM-based SOF that has been mechanochemically synthesized and whose crystal structure has been determined by 3D electron diffraction analysis using a novel electron diffractometer.

Estimating the nonideality of eutectic systems containing thermally unstable substances.

Eutectic systems design requires an in-depth understanding of their solid-liquid equilibria (SLE). Modeling SLE in eutectic systems has as prerequisites, the melting properties and activity coefficients of components in the liquid phase. Thus, due to the unavailable melting properties of thermally unstable substances, it is impossible to estimate their activity coefficients from experimental SLE data and model the SLE phase diagram of their eutectic systems. Here, we evaluate the activity coefficients of thermally unstable constituents in the liquid phase, which were calculated independent of their melting properties by correlating the SLE data of their cocrystals. Differential scanning calorimetry and powder x-ray diffraction were employed to obtain the SLE phase diagram of three eutectic systems, i.e., tetramethylammonium chloride/catechol, tetraethylammonium chloride/catechol, and betaine/catechol systems, and identify the formation of nine cocrystals. The non-random, two-liquid equation was used to calculate the activity coefficients of the components in the liquid phase. The substantial negative deviation from ideality in the three studied systems indicated strong hydrogen bonding interactions in the liquid solution. Furthermore, modeling ion-ion interactions in eutectic systems containing ionic constituents is of utmost importance for understanding their nonideality.

Catalytic Alkyne Semihydrogenation with Polyhydride Ni/Ga Clusters.

The bimetallic, decanuclear Ni3 Ga7 -cluster of the formula [Ni3 (GaTMP)3 (µ2 -GaTMP)3 (µ3 -GaTMP)] (1, TMP=2,2,6,6-tetramethylpiperidinyl) reacts reversibly with dihydrogen under the formation of a series of (poly-)hydride clusters 2. Low-temperature 2D NMR experiments at -80 °C show that 2 consist of a mixture of a di- (2Di ), tetra- (2Tetra ) and hexahydride species (2Hexa ). The structures of 2Di and 2Tetra are assessed by a combination of 2D NMR spectroscopy and DFT calculations. The cooperation of both metals is essential for the high hydrogen uptake of the cluster. Polyhydrides 2 are catalytically active in the semihydrogenation of 4-octyne to 4-octene with good selectivity. The example is the first of its kind and conceptually relates properties of molecular, atom-precise transition metal/main group metal clusters to the respective solid-state phase in catalysis.

Metal-Metal Bonding in Late Transition-Metal [M2L5] Complexes: Exploring the Limits of the Isolobal Analogy between the CO and AlCp* Ligands.

Late dinuclear transition-metal (especially group 10 and 11) homoleptic carbonyl complexes are elusive species and have so far not been isolated. A typical example is the 30-electron species [Ni2(CO)5], the structure and bonding of which is still debated. We show that, by using the AlCp* ligand (isolobal to CO), it is possible to isolate and fully characterize [Ni2(AlCp*)5] (1), which inspired us to revisit by DFT calculations, the bonding situation within [Ni2L5] (L = CO, AlCp*) and other isoelectronic species. The short Ni-Ni X-ray distance in 1 (2.270 Å) should not be attributed to the existence of a typical localized triple-bond between the metals, but rather to a strong through-bond interaction involving the three bridging ligands via their donating lone pairs and accepting π* orbitals. In contrast, in the isostructural 32-electron [Au2(AlCp*)5] (2) cluster an orbital with M-M antibonding and Al...Al bonding character is occupied, which is in accordance with the particularly long Au-Au distance (3.856 Å) and rather short Al...Al contacts between the bridging ligands (2.843 Å). This work shows that, unlike late transition-metal [M2(CO)x] species, stable [M2(AlCp*)x] complexes can be isolated, owing to the subtle differences between CO and AlCp*. We propose a similar approach for rationalizing the bonding in the emblematic 34 electron species [Fe2(CO)9].

Total Synthesis of (+)-Prezizaan-15-ol, (+)-Jinkohol II, and (+)-Jinkoholic Acid.

A recently developed photochemical cascade reaction provides access to diastereomeric pentacyclic products, which display the carbon skeleton of prezizane natural products. The minor diastereoisomer with a 2ß-Me configuration was converted in 12 reaction steps into (+)-prezizaan-15-ol. The major diastereoisomer with a 2α-Me configuration gave in an analogous route (+)-jinkohol II, which was oxidized at C13 to (+)-jinkoholic acid. A previous ambiguity regarding the configuration of the natural products could be clarified by total synthesis.

Enzyme-like polyene cyclizations catalyzed by dynamic, self-assembled, supramolecular fluoro alcohol-amine clusters.

Terpene cyclases catalyze one of the most powerful transformations with respect to efficiency and selectivity in natural product (bio)synthesis. In such polyene cyclizations, structurally highly complex carbon scaffolds are built by the controlled ring closure of linear polyenes. Thereby, multiple C,C bonds and stereocenters are simultaneously created with high precision. Structural pre-organization of the substrate carbon chain inside the active center of the enzyme is responsible for the product- and stereoselectivity of this cyclization. Here, we show that in-situ formed fluorinated-alcohol-amine supramolecular clusters serve as artificial cyclases by triggering enzyme-like reactivity and selectivity by controlling substrate conformation in solution. Because of the dynamic nature of these supramolecular assemblies, a broad range of terpenes can be produced diastereoselectively. Mechanistic studies reveal a finely balanced interplay of fluorinated solvent, catalyst, and substrate as key to establishing nature's concept of a shape-selective polyene cyclization in organic synthesis.

"Dynamical Docking" of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes.

With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds' stabilization properties toward G4s of different topologies of physiological relevance. Initial structure-activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The binding modes and free-energy landscape of the most active xanthine derivative (featuring a propyl linker) with the promoter sequence cKIT1 have been studied by metadynamics. The atomistic simulations evidenced that the Au(I) compound interacts noncovalently with the top G4 tetrad. The theoretical results on the Au(I) complex/DNA Gibbs free energy of binding were experimentally validated by FRET DNA melting assays. The compounds have also been tested for their antiproliferative properties in human cancer cells in vitro, showing generally moderate activity. This study provides further insights into the biological activity of Au(I) organometallics acting via noncovalent interactions and underlines their promise for tunable targeted applications by appropriate chemical modifications.

Chiral Lewis acid catalysis in a visible light-triggered cycloaddition/rearrangement cascade.

Cascade (domino) reactions facilitate the formation of complex molecules from simple starting materials in a single operation. It was found that 1-naphthaldehyde derivatives can be converted to enantioenriched (82-96% ee) polycyclic benzoisochromenes via a cascade of ortho photocycloaddition and ensuing acid-catalysed rearrangement reactions. The cascade was initiated by irradiation with visible light (λ = 457 nm) and catalysed by a chiral AlBr3-activated 1,3,2-oxazaborolidine (14 examples, 65-93% yield). The absolute configuration of the products was elucidated by single crystal X-ray crystallography. Mechanistic experiments suggest that the ortho photocycloaddition occurs on the triplet hypersurface and that the chiral catalyst induces in this step the observed enantioselectivity.

Arene Activation through Iminium Ions: Product Diversity from Intramolecular Photocycloaddition Reactions.

While 2-alk-ω-enyloxy-sustituted benzaldehydes do not display any photochemical reactivity at the arene core, the respective iminium perchlorates were found to undergo efficient reactions either upon direct irradiation (λ=366 nm) or under sensitizing conditions (λ=420 nm, 2.5 mol% thioxanthen-9-one). Three pathways were found: (a) Most commonly, the reaction led to benzoxacyclic products in which the olefin in the tether underwent a formal, yet unprecedented carboformylation (13 examples, 44-99 % yield). The cascade process occurred with high diastereoselectivity and was found to be stereoconvergent. (b) If a substituent resides in the 3-position of the benzene ring, a meta photocycloaddition was observed which produced tetracyclic skeletons with five stereogenic centers in excellent regio- and diastereoselectivity (2 examples, 58-79 % yield). (c) If the tether was internally substituted at the alkene, an arene photocycloaddition was avoided and an azetidine was formed in an aza Paternò-Büchi reaction (2 examples, 95-98 % yield).

Terpyridine Diphosphine Ruthenium Complexes as Efficient Photocatalysts for the Transfer Hydrogenation of Carbonyl Compounds.

The cationic achiral and chiral terpyridine diphosphine ruthenium complexes [RuCl(PP)(tpy)]Cl (PP=dppp (1), (R,R)-Skewphos (2) and (S,S)-Skewphos (3)) are easily obtained in 85-88 % yield through a one-pot synthesis from [RuCl2 (PPh3 )3 ], the diphosphine and 2,2':6',2''-terpyridine (tpy) in 1-butanol. Treatment of 1-3 with NaPF6 in methanol at RT affords quantitatively the corresponding derivatives [RuCl(PP)(tpy)]PF6 (PP=dppp (1 a), (R,R)-Skewphos (2 a) and (S,S)-Skewphos (3 a)). Reaction of [RuCl2 (PPh3 )3 ] with (S,R)-Josiphos or (R)-BINAP in toluene, followed by treatment with tpy in 1-butanol and finally with NaPF6 in MeOH gives [RuCl(PP)(tpy)]PF6 (PP=(S,R)-Josiphos (4 a), (R)-BINAP (5 a)) isolated in 78 % and 86 % yield, respectively. The chiral derivatives have been isolated as single stereoisomers and 3 a, 4 a have been characterized by single crystal X-ray diffraction studies. The tpy complexes with NaOiPr display high photocatalytic activity in the transfer hydrogenation (TH) of carbonyl compounds using 2-propanol as the only hydrogen donor and visible light at 30 °C, at remarkably high S/C (up to 5000) and TOF values up to 264 h-1 . The chiral enantiomers 2, 2 a and 3, 3 a induce the asymmetric photocatalytic TH of acetophenone, affording (S)- and (R)-1-phenylethanol with 51 and 52 % ee, respectively, in a MeOH/2-propanol mixture.

C-H and Si-H Activation Reactions at Ru/Ga Complexes: A Combined Experimental and Theoretical Case Study on the Ru-Ga Bond.

Treatment of [Ru(COD)(MeAllyl)2 ] and [Ru(COD)(COT)] with GaCp* under hydrogenolytic conditions leads to reactive intermediates which activate Si-H or C-H bonds, respectively. The product complexes [Ru(GaCp*)3 (SiEt3 )H3 ] (1) and [Ru(GaCp*)3 (C7 H7 )H3 ] (2) are formed with HSiEt3 or with toluene as the solvent, respectively. While 1 was isolated and fully characterized by NMR, MS, IR and SC-XRD, 2 was too labile to be isolated and was observed and characterized in situ by using mass spectrometry, including labelling experiments for the unambiguous assignment of the elemental composition. The structural assignment was confirmed by DFT calculations. The relative energies of the four isomers possible upon toluene activation at the ortho-, meta-, para- and CH3 -positions have been determined and point to aromatic C-H activation. The Ru-Ga bond was analyzed by EDA and QTAIM and compared to the Ru-P bond in the analogue phosphine compound. Bonding analyses indicate that the Ru-GaCp* bond is weaker than the Ru-PR3 bond.

Memory, switches, and an OR-port through bistability in chemically fueled crystals.

The ability to store information in chemical reaction networks is essential for the complex behavior we associate with life. In biology, cellular memory is regulated through transcriptional states that are bistable, i.e., a state that can either be on or off and can be flipped from one to another through a transient signal. Such memory circuits have been realized synthetically through the rewiring of genetic systems in vivo or through the rational design of reaction networks based on DNA and highly evolved enzymes in vitro. Completely bottom-up analogs based on small molecules are rare and hard to design and thus represent a challenge for systems chemistry. In this work, we show that bistability can be designed from a simple non-equilibrium reaction cycle that is coupled to crystallization. The crystals exert the necessary feedback on the reaction cycle required for the bistability resulting in an on-state with assemblies and an off-state without. Each state represents volatile memory that can be stored in continuously stirred tank reactors indefinitely even though molecules are turned over on a minute-timescale. We showcase the system's abilities by creating a matrix display that can store images and by creating an OR-gate by coupling several switches together.

Diels-Alder Reaction of Photochemically Generated (E)-Cyclohept-2-enones: Diene Scope, Reaction Pathway, and Synthetic Application.

Upon irradiation at λ = 350 nm, cyclohept-2-enone undergoes an isomerization to the strained (E)-isomer. The process was studied by XMS-CASPT2 calculations and found to proceed by two competitive reaction channels on either the singlet or the triplet hypersurface. (E)-Cyclohept-2-enone is a reactive dienophile in thermal [4 + 2] cycloaddition reactions with various dienes. Ten different dienes were probed, most of which─except for 1,3-cyclohexadiene─underwent a clean Diels-Alder reaction and gave the respective trans-fused six-membered rings in good yields (68-98%). The reactions with furan were studied in detail, both experimentally and by DLPNO-CCSD(T) calculations. Two diastereoisomers were formed in a ratio of 63/35 with the exo-product prevailing, and the configuration of both diastereoisomers was corroborated by single crystal X-ray crystallography. The outcome of the photoinduced Diels-Alder reaction matched both qualitatively and quantitatively the calculated reaction pathway. Apart from cyclohept-2-enone, five additional cyclic hept-2-enones and cyclooct-2-enone were employed in their (E)-form as dienophiles in the Diels-Alder reaction with 1,3-cyclopentadiene (80-98% yield). The method was eventually applied to a concise total synthesis of racemic trans-α-himachalene (four steps, 14% overall yield).

Reduced Molecular Flavins as Single-Electron Reductants after Photoexcitation.

Flavoenzymes mediate a multitude of chemical reactions and are catalytically active both in different oxidation states and in covalent adducts with reagents. The transfer of such reactivity to the organic laboratory using simplified molecular flavins is highly desirable, and such applications in (photo)oxidation reactions are already established. However, molecular flavins have not been used for the reduction of organic substrates yet, although this activity is known and well-studied for DNA photolyase enzymes. We report a catalytic method using reduced molecular flavins as photoreductants and γ-terpinene as a sacrificial reductant. Additionally, we present our design for air-stable, reduced flavin catalysts, which is based on a conformational bias strategy and circumvents the otherwise rapid reduction of O2 from air. Using our catalytic strategy, we were able to replace superstoichiometric amounts of the rare-earth reductant SmI2 in a 5-exo-trig cyclization of substituted barbituric acid derivatives. Such flavin-catalyzed reductions are anticipated to be beneficial for other transformations as well and their straightforward synthesis indicates future use in stereo- as well as site-selective transformations.

Enantioselective crossed intramolecular [2+2] photocycloaddition reactions mediated by a chiral chelating Lewis acid.

In intramolecular [2+2] photocycloaddition reactions, the two tethered olefins can approach each other in a straight or in a crossed fashion. Despite the fact that the latter reaction mode leads to intriguing, otherwise inaccessible bridged skeletons, there has so far not been any enantioselective variants thereof. This study concerned the crossed [2+2]-photocycloaddition of 2-(alkenyloxy)cyclohex-2-enones to bridged cyclobutanes. It was found that the reaction could be performed with high enantioselectivity (80-94% ee) under visible light conditions when employing a chiral rhodium Lewis acid as a catalyst (2 mol%).

Visible Light-Mediated Dearomative Hydrogen Atom Abstraction/ Cyclization Cascade of Indoles.

The photochemical synthesis of yet unknown 2-oxospiro[azetidine-3,3'-indolines] (17 examples, 80-95 % yield), 2,4-dioxospiro[azetidine-3,3'-indolines] (eight examples, 87-97 % yield), and 1-oxo-1,3-dihydrospiro[indene-2,3'-indolines] (17 examples, 85-97 % yield) is described. Starting from readily accessible 3-substituted indoles, a dearomatization of the indole core was accomplished upon irradiation at λ=420 nm in the presence of thioxanthen-9-one (10 mol%) as the sensitizer. Based on mechanistic evidence (triplet energy determination, deuteration experiments, by-product analysis) it is proposed that the reaction proceeds by energy transfer via a 1,4- or 1,5-diradical intermediate. The latter intermediates are formed by excited state hydrogen atom transfer from suitable alkyl groups within the C3 substituent to the indole C2 carbon atom. Subsequent ring closure proceeds with pronounced diastereoselectivity to generate a 4- or 5-membered spirocyclic dearomatized product with several options for further functionalization.

Concise Total Synthesis of Agarozizanol†B via a Strained Photocascade Intermediate.

The prezizane-type sesquiterpene agarozizanol B was synthesized employing a photochemical cascade reaction as the key step. Starting from a readily available 1-indanone with a tethered olefin, a strained tetracyclic skeleton was assembled which contained all carbon atoms of the sesquiterpene with the correct relative configuration. The conversion into the tricyclic prezizane skeleton was accomplished by a strategic cyclopropane bond cleavage. Prior to the cyclopropane ring opening an adaption of the oxidation state was required, which could be combined with a reductive resolution step. After removal of two functional groups, the natural product was obtained both in racemic form or, if resolved, as the (+)-enantiomer which was shown to be identical to the natural product.

Investigation of Solvatomorphism and Its Photophysical Implications for Archetypal Trinuclear Au3(1-Methylimidazolate)3.

A new solvatomorph of [Au3(1-Methylimidazolate)3] (Au3(MeIm)3)-the simplest congener of imidazolate-based Au(I) cyclic trinuclear complexes (CTCs)-has been identified and structurally characterized. Single-crystal X-ray diffraction revealed a dichloromethane solvate exhibiting remarkably short intermolecular Au⋯Au distances (3.2190(7) Å). This goes along with a dimer formation in the solid state, which is not observed in a previously reported solvent-free crystal structure. Hirshfeld analysis, in combination with density functional theory (DFT) calculations, indicates that the dimerization is generally driven by attractive aurophilic interactions, which are commonly associated with the luminescence properties of CTCs. Since Au3(MeIm)3 has previously been reported to be emissive in the solid-state, we conducted a thorough photophysical study combined with phase analysis by means of powder X-ray diffraction (PXRD), to correctly attribute the photophysically active phase of the bulk material. Interestingly, all investigated powder samples accessed via different preparation methods can be assigned to the pristine solvent-free crystal structure, showing no aurophilic interactions. Finally, the observed strong thermochromism of the solid-state material was investigated by means of variable-temperature PXRD, ruling out a significant phase transition being responsible for the drastic change of the emission properties (hypsochromic shift from 710 nm to 510 nm) when lowering the temperature down to 77 K.