para-Phenylenediamine Dimer as a Redox-Active Guest for Supramolecular Systems.

Redox-active components are highly valuable in the construction of molecular devices. We combined two p-phenylenediamines (p-PDA) with a biphenyl (BiPhe) unit to prepare a supramolecular guest 4 consisting of three binding sites for cucurbit[7/8]uril (CBn) and/or cyclodextrins (CD). Supramolecular properties of 4 were investigated using NMR, UV-vis, mass spectrometry and isothermal titration calorimetry. Our analysis revealed that 4 forms higher-order host-guest complexes, wherein a CD unit occupies the central BiPhe site, secured by two CBn units at the terminal p-PDA sites. Additionally, 1 : 1 complexes with α-CD and ß-CD, a 1 : 2 complex with γ-CD and 2 : 1 complexes with CB7 and CB8 were identified. Through UV-vis and cyclic voltammetry, redox processes leading to the formation of a stable, deep blue dication diradical of 4 are elucidated. Furthermore, it is demonstrated that CB7 selectively protects oxidised 4 from reduction in the presence of a reducing agent. The supramolecular and redox properties of the structural motif represented by 4 render it an interesting candidate for the construction of supramolecular devices.

Two Squares in a Barrel: An Axially Disubstituted Conformationally Rigid Aliphatic Binding Motif for Cucurbit[6]uril.

Novel binding motifs suitable for the construction of multitopic guest-based molecular devices (e.g., switches, sensors, data storage, and catalysts) are needed in supramolecular chemistry. No rigid, aliphatic binding motif that allows for axial disubstitution has been described for cucurbit[6]uril (CB6) so far. We prepared three model guests combining spiro[3.3]heptane and bicyclo[1.1.1]pentane centerpieces with imidazolium and ammonium termini. We described their binding properties toward CB6/7 and α-/ß-CD using NMR, titration calorimetry, mass spectrometry, and single-crystal X-ray diffraction. We found that a bisimidazolio spiro[3.3]heptane guest forms inclusion complexes with CB6, CB7, and ß-CD with respective association constants of 4.0 × 104, 1.2 × 1012, and 1.4 × 102. Due to less hindering terminal groups, the diammonio analogue forms more stable complexes with CB6 (K = 1.4 × 106) and CB7 (K = 3.8 × 1012). The bisimidazolio bicyclo[1.1.1]pentane guest forms a highly stable complex only with CB7 with a K value of 1.1 × 1011. The high selectivity of the new binding motifs implies promising potential in the construction of multitopic supramolecular components.

Convergent Assembly of the Tricyclic Labdane Core Enables Synthesis of Diverse Forskolin-like Molecules.

We report a new synthetic strategy for the flexible preparation of forskolin-like molecules. The approach is different from the previously published works and employs a convergent assembly of the tricyclic labdane-type core from pre-functionalized cyclic building blocks. Stereoselective Michael addition enabled the fragment coupling with excellent control over three newly created contiguous stereocenters, all-carbon quaternary centers included. Silyl enol ether-promoted ring-opening metathesis paired with ring closure were the other key steps enabling concise assembly of the tricyclic core. Late-stage functionalization sequences transformed the tricyclic intermediates into a set of different forskolin-like molecules. The modular nature of the synthetic scheme described herein has the potential to become a general platform for the preparation of analogs of forskolin and other complex tricyclic labdanes.

Adamantane-Substituted Purine Nucleosides: Synthesis, Host-Guest Complexes with ß-Cyclodextrin and Biological Activity.

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6. Additionally, the ability of the synthesized purine nucleosides to form stable host-guest complexes with ß-cyclodextrin (ß-CD) was confirmed using nuclear magnetic resonance (NMR) and mass spectrometry (ESI-MS) experiments. The in vitro antiproliferative activity of purine nucleosides and their equimolar mixtures with ß-CD was tested against two types of human tumor cell line. Six adamantane-based purine nucleosides showed an antiproliferative activity in the micromolar range. Moreover, their effect was only slightly suppressed by the presence of ß-CD, which was probably due to the competitive binding of the corresponding purine nucleoside inside the ß-CD cavity.

Highly Efficient and Selective Recognition of Dicyanoaurate(I) by a Bambusuril Macrocycle in Water.

Dicyanoaurate(I) anion, [Au(CN)2 ]- , plays a central role in the current industrial production of gold, as its extraction from crude ore samples represents the most money-consuming step. Herein, we present the strongest host-guest recognition of dicyanoaurate anion using the bambusuril receptor in water, a highly competitive solvent. The micromolar stability of such a complex facilitated the up to date most efficient supramolecular stripping of dicyanoaurate from activated carbon at ambient temperature. Thermodynamic characteristics of bambusuril binding with [Au(CN)2 ]- differing from binding of other inorganic chaotropic anions are rationalized, as well as the bambusuril selectivity for [Au(CN)2 ]- over [Ag(CN)2 ]- .

Stereocontrolled Synthesis of (-)-Bactobolin A.

A stereoselective synthesis of the ribosome-binding antitumor antibiotic (-)-bactobolin A is reported. The presented approach makes effective use of (-)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (-)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C-H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (-)-bactobolin A trifluoroacetate in 10% overall yield.

A Photochemical/Thermal Switch Based on 4,4'-Bis(benzimidazolio)stilbene: Synthesis and Supramolecular Properties.

Stilbene derivatives are well-recognised substructures of molecular switches based on photochemically and/or thermally induced (E)/(Z) isomerisation. We combined a stilbene motif with two benzimidazolium arms to prepare new sorts of supramolecular building blocks and examined their binding properties towards cucurbit[n]urils (n=7, 8) and cyclodextrins (ß-CD, γ-CD) in water. Based on the 1 H NMR data and molecular dynamics simulations, we found that two distinct complexes with different stoichiometry, i. e., guest@ß-CD and guest@ß-CD2 , coexist in equilibrium in a water solution of the (Z)-stilbene-based guests. We also demonstrated that the bis(benzimidazolio)stilbene guests can be transformed from the (E) into the (Z) form via UV irradiation and back via thermal treatment in DMSO.

Zwitterionic Ru(III) Complexes: Stability of Metal-Ligand Bond and Host-Guest Binding with Cucurbit[7]uril.

A wide range of ruthenium-based coordination compounds have been reported to possess potential as metallodrugs with anticancer or antimetastatic activity. In this work, we synthesized a set of new zwitterionic Ru(III) compounds bearing ligands derived from N-alkyl (R) systems based on pyridine, 4,4'-bipyridine, or 1,4-diazabicyclo[2.2.2]octane (DABCO). The effects of the ligand(s) and their environment on the coordination stability have been investigated. Whereas the [DABCO-R]+ ligand is shown to be easily split out of a negative [RuCl4]- core, positively charged R-pyridine and R-bipyridine ligands form somewhat more stable Ru(III) complexes and can be used as supramolecular anchors for binding with macrocycles. Therefore, supramolecular host-guest assemblies between the stable zwitterionic Ru(III) guests and the cucurbit[7]uril host were investigated and characterized in detail by using NMR spectroscopy and single-crystal X-ray diffraction. Paramagnetic 1H NMR experiments supplemented by relativistic DFT calculations of the structure and hyperfine NMR shifts were performed to determine the host-guest binding modes in solution. In contrast to the intramolecular hyperfine shifts, dominated by the through-bond Fermi-contact mechanism, supramolecular hyperfine shifts were shown to depend on the "through-space" spin-dipole contributions with structural trends being satisfactorily reproduced by a simple point-dipole approximation.

Locked and Loaded: Ruthenium(II)-Capped Cucurbit[n]uril-Based Rotaxanes with Antimetastatic Properties.

We report here the first coupling of Ru(II) units with cucurbit[6/7]uril-based pseudorotaxane ligands meant for biological application. The resulting ruthenium-capped rotaxanes were fully characterized, and a structure of one supramolecular system was determined by X-ray diffraction. Because the biological properties of Ru-based metallodrugs are tightly linked to the ligand-exchange processes, the effect of salt concentration on the hydrolysis of chlorides from the Ru(II) center was monitored by using 1H NMR spectroscopy. The biological activity of Ru(II)-based rotaxanes was evaluated for three selected mammalian breast cell lines, HBL-100, MCF-7, and MDA-MB-231. The antimetastatic activity of the assembled cationic Ru(II)-rotaxane systems, evaluated in migration assays against MCF-7 and MDA-MB-231 cell lines, is notably enhanced compared to that of RAPTA-C, a reference that was used. The indicated synergistic effect of combining Ru(II) with a pseudorotaxane unit opens a new direction in searching for anticancer supramolecular metallodrugs.

Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis.

Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors. The proof of principle was demonstrated on rotaxane synthesis, with near-quantitative yields observed in both the classical and "in situ" approach. The rotaxane formation was confirmed in the solid-state and solution by the X-ray and NMR studies. Our novel approach could be utilized in the fields of dynamic combinatorial chemistry, supramolecular polymers, or molecular machines, as well inspire further research on molecules that exhibit dynamic behavior, but owing to their high reactivity, have not been considered as constituents of more elaborate supramolecular structures.

Hyperfine Effects in Ligand NMR: Paramagnetic Ru(III) Complexes with 3-Substituted Pyridines.

NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transition-metal complexes. However, paramagnetic transition-metal complexes such as those with ruthenium in the +3 oxidation state are troublemakers because their unpaired electrons induce a fast nuclear spin relaxation that significantly broadens their NMR resonances. We recently demonstrated that the electronic and spin structures of paramagnetic Ru(III) systems can be characterized in unprecedented details by combining experimental NMR results with relativistic density-functional theory ( Novotny et al. J. Am. Chem. Soc. 2016 , 138 , 8432 ). In this study we focus on paramagnetic analogs of NAMI with the general structure [3-R-pyH]+trans-[RuIIICl4(DMSO)(3-R-py)]-, where 3-R-py stands for a 3-substituted pyridine. The experimental NMR data are interpreted in terms of the contributions of hyperfine (HF) NMR shielding and the distribution of spin density calculated using relativistic DFT. The DFT computational methodology is evaluated, and the effects of substituents, environment, and relativity on the hyperfine shielding are discussed. Particular attention is paid to the analysis of the fundamental Fermi-contact (FC), spin-dipole (SD), and paramagnetic spin-orbit (PSO) terms that contribute to the hyperfine 1H and 13C NMR shifts of the individual atoms in the pyridine ligands and the spin-polarization effects in the ligand system that are linked to the character of the metal-ligand bond. The individual HF shielding terms are systematically discussed as they relate to the traditional, but somewhat mixed, contact and pseudocontact NMR contributions used extensively by experimental spectroscopists in biomolecular NMR and the development of PARACEST magnetic-resonance contrast agents.

Bambusuril as a One-Electron Donor for Photoinduced Electron Transfer to Methyl Viologen in Mixed Crystals.

Methyl viologen hexafluorophosphate (MV2+·2PF6-) and dodecamethylbambus[6]uril (BU6) form crystals in which the layers of viologen dications alternate with those of a 1:2 supramolecular complex of BU6 and PF6-. This arrangement allows for a one-electron reduction of MV2+ ions upon UV irradiation to form MV+• radical cations within the crystal structure with half-lives of several hours in air. The mechanism of this photoinduced electron transfer in the solid state and the origin of the long-lived charge-separated state were studied by steady-state and transient spectroscopies, cyclic voltammetry, and electron paramagnetic resonance spectroscopy. Our experiments are supported by quantum-chemical calculations showing that BU6 acts as a reductant. In addition, analogous photochemical behavior is also demonstrated on other MV2+/BU6 crystals containing either BF4- or Br- counterions.

Interpreting the Paramagnetic NMR Spectra of Potential Ru(III) Metallodrugs: Synergy between Experiment and Relativistic DFT Calculations.

Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The central ruthenium atom can be in the oxidation state +2 (e.g., RAPTA, RAED) or +3 (e.g., NAMI, KP). In this study we focus on paramagnetic NAMI analogs of a general structure [4-R-pyH](+)trans-[Ru(III)Cl4(DMSO)(4-R-py)](-), where 4-R-py stands for a 4-substituted pyridine. As paramagnetic systems are generally considered difficult to characterize in detail by NMR spectroscopy, we performed a systematic structural and methodological NMR study of complexes containing variously substituted pyridines. The effect of the paramagnetic nature of these complexes on the (1)H and (13)C NMR chemical shifts was systematically investigated by temperature-dependent NMR experiments and density-functional theory (DFT) calculations. To understand the electronic factors influencing the orbital (δ(orb), temperature-independent) and paramagnetic (δ(para), temperature-dependent) contributions to the total NMR chemical shifts, a relativistic two-component DFT approach was used. The paramagnetic contributions to the (13)C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the (13)C isotropic hyperfine coupling constants, Aiso((13)C), for the individual carbon atoms. To analyze the mechanism of spin distribution in the ligand, the contributions of molecular spin-orbitals (MSOs) to the hyperfine coupling constants and the spatial distribution of the z-component of the spin density in the MSOs calculated at the relativistic four-component DFT level are discussed and rationalized. The significant effects of the substituent and the solvent on δ(para), particularly the contact contribution, are demonstrated. This work should contribute to further understanding of the link between the electronic structure and the NMR chemical shifts in open-shell systems, including the ruthenium-based metallodrugs investigated in this account.

Phenanthrylene-butadiynylene and Phenanthrylene-thienylene Macrocycles: Synthesis, Structure, and Properties.

A series of macrocycles consisting of 9,10-substituted phenanthrenes connected by butadiynylene linkers in positions 3 and 6 has been described as well as their transformation into the corresponding phenanthrylene-thienylene macrocycles. Structure and properties of the macrocycles, such as self-association in solution and optical and electrochemical properties, were studied and reported in a comparative manner with respect to the effects of the different sizes and shapes of the macrocycles and the character and length of their side chains.

Propanediurea-Based Molecular Clips Bind Halide Anions: An Insight into the Mechanism of Cucurbituril Formation.

The synthesis and supramolecular properties of the first methylene-bridged propanediurea-based dimers are described. These dimers, bearing an aromatic sidewall, have the shape of molecular clips. Unlike glycoluril-based dimers, these clips neither dimerize nor accept any organic guests, due to their small cavities. Both propanediurea- and glycoluril-based dimers bind halide anions on the convex side of the molecules, even in highly polar organic solvents. This observation brings new insights into the mechanism of cucurbituril formation.

Cooperative Binding of Cucurbit[n]urils and ß-Cyclodextrin to Heteroditopic Imidazolium-Based Guests.

Imidazolium-based guests containing two distinct binding epitopes are capable of binding ß-cyclodextrin and cucurbit[6/7]uril (CB) simultaneously to form heteroternary 1:1:1 inclusion complexes. In the final configuration, the hosts occupy binding sites disfavored in the binary complexes because of the chemically induced reorganization of the intermediate 1:1 aggregate. In addition, the reported guests are capable of binding two CBs to form either 1:2 or 1:1:1 ternary assemblies despite consisting of a single cationic moiety. Whereas the adamantane site binds CB solely via hydrophobic interactions, the CB unit at the butyl site is stabilized by a combination of hydrophobic and ion-dipole interactions.

Construction of larger molecular aluminophosphate cages from the cyclic four-ring building unit.

New molecular aluminophosphates of different nuclearity are synthesized by a stepwise process and structurally characterized. The alkane elimination reaction of bis(trimethylsiloxy)phosphoric acid, OP(OH)(OSiMe3)2, with trialkylalanes, AlR3 (R = Me, Et, (i)Bu), provides the cyclic dimeric aluminophosphates, [(AlR2{µ2-O2P(OSiMe3)2})2] (R = Me (1), Et (2), (i)Bu (3)). Unsymmetrically substituted cyclic aluminophosphonate [(AlMe2{µ2-O2P(OSiMe3)((c)Hex)})2] (cis/trans-4) is prepared by dealkylsilylation reaction of (c)HexP(O)(OSiMe3)2 with AlMe3. Molecules 1-4 containing the [Al2(µ2-O2P)2] inorganic core are structural and spectroscopic models for the single four-ring (S4R) secondary building units (SBU) of zeolite frameworks. Compound 1 serves as a starting point in construction of larger molecular units by reactions with OP(OH)(OSiMe3)2 as a cage-extending reagent and with diketones, such as Hhfacac (1,1,1,5,5,5-hexafluoropentan-2,4-dione) and Hacac (pentan-2,4-dione), as capping reagents. Reaction of 1 with 4 equiv of Hhfacac leads to new cyclic aluminophosphate [(Al(hfacac)2{µ2-O2P(OSiMe3)2})2] (5), existing in two isomeric (D2 and C2h) forms. Reaction of 1 with 2 equiv of OP(OH)(OSiMe3)2 and 1 equiv of Hhfacac provides a molecular aluminophosphate [AlMe{Al(hfacac)}2{µ3-O3P(OSiMe3)}2{µ2-O2P(OSiMe3)2}2{OP(OSiMe3)3}] (6), while by adding first the Hhfacac and using 3 equiv of OP(OH)(OSiMe3)2 we isolate [Al{Al(hfacac)}2{µ3-O3P(OSiMe3)}2{µ2-O2P(OSiMe3)2}2H{OP(O)(OSiMe3)2}2] (7). These molecules contain units in their cores that imitate 4=1 SBU of zeolite frameworks. Reaction with the order of component mixing 1, Hhfacac, OP(OH)(OSiMe3)2 at a 1:2:2 molar ratio lead to formation of a larger cluster [(Al(AlMe){Al(hfacac)}{µ3-O3P(OSiMe3)}2{µ2-O2P(OSiMe3)2}3)2] (8) containing both S4R and 4=1 structural units. Similarly, Hacac (pentan-2,4-dione) provides an isostructural [(Al(AlMe){Al(acac)}{µ3-O3P(OSiMe3)}2{µ2-O2P(OSiMe3)2}3)2] (9). Both molecules display Al centers in three different coordination environments.

Diethyl [4-(2,2':6',2''-terpyridine-4'-yl)phen-yl]phospho-nate.

The title compound, C25H24N3O3P, was obtained by catalytic phospho-nation of 4'-(4-bromphen-yl)-2,2':6',2''-terpyridine. The terpyridine moiety is nearly planar, the dihedral angles between the central and the outer rings being 4.06 (9) and 5.39 (9)°. The N atoms in the two pyridine rings are oriented nearly anti-periplanar to that of the central ring. The benzene ring is rotated out of the plane of the central ring of the terpyridine unit by 34.65 (6)°.

The double H-atom acceptability of the P=O group in new XP(O)(NHCH2C6H4-2-Cl)2 phosphoramidates [X = C6H5O- and CF3C(O)NH-]: a database analysis of compounds having a P(O)(NHR) group.

In the hydrogen-bond patterns of phenyl bis(2-chlorobenzylamido)phosphinate, C(20)H(19)Cl(2)N(2)O(2)P, (I), and N,N'-bis(2-chlorobenzyl)-N''-(2,2,2-trifluoroacetyl)phosphoric triamide, C(16)H(15)Cl(2)F(3)N(3)O(2)P, (II), the O atoms of the related phosphoryl groups act as double H-atom acceptors, so that the P=O···(H-N)(2) hydrogen bond in (I) and the P=O···(H-N(amide))(2) and C=O···H-N(C(O)NHP(O)) hydrogen bonds in (II) are responsible for the aggregation of the molecules in the crystal packing. The presence of a double H-atom acceptor centre is a result of the involvement of a greater number of H-atom donor sites with a smaller number of H-atom acceptor sites in the hydrogen-bonding interactions. This article also reviews structures having a P(O)NH group, with the aim of finding similar three-centre hydrogen bonds in the packing of phosphoramidate compounds. This analysis shows that the factors affecting the preference of the above-mentioned O atom to act as a double H-atom acceptor are: (i) a higher number of H-atom donor sites relative to H-atom acceptor centres in molecules with P(=O)(NH)(3), (N)P(=O)(NH)(2), C(=O)NHP(=O)(NH)(2) and (NH)(2)P(=O)OP(=O)(NH)(2) groups, and (ii) the remarkable H-atom acceptability of this atom relative to the other acceptor centre(s) in molecules containing an OP(=O)(NH)(2) group, with the explanation that the N atom bound to the P atom in almost all of the structures found does not take part in hydrogen bonding as an acceptor. Moreover, the differences in the H-atom acceptability of the phosphoryl O atom relative to the O atom of the alkoxy or phenoxy groups in amidophosphoric acid esters may be illustrated by considering the molecular packing of compounds having (O)(2)P(=O)(NH) and (O)P(=O)(NH)(N)groups, in which the unique N-H unit in the above-mentioned molecules almost always selects the phosphoryl O atom as a partner in forming hydrogen-bond interactions. The P atoms in (I) and (II) are in tetrahedral coordination environments, and the phosphoryl and carbonyl groups in (II) are anti with respect to each other (the P and C groups are separated by one N atom). In the crystal structures of (I) and (II), adjacent molecules are linked via the above-mentioned hydrogen bonds into a linear arrangement parallel to [100] in both cases, in (I) by forming R(2)(2)(8) rings and in (II) through a combination of R(2)(2)(10) and R(2)(1)(6) rings.

Synthesis of Organotitanium(IV) Fluoride Phosphates and the Crystal Structure of [(C5Me4Et)TiF(µ-F){µ-O2P(OSiMe3)2}]2.

The complexes [(C5Me4R)TiF(µ-F)µ-O2P(OSiMe3)2]2 [R = Me (1), Et (2)] were prepared from [(C5Me4R)TiF3]2, (R = Me, Et) and OP(OSiMe3)3. The molecular structure of 2 has been determined by single-crystal X-ray diffraction analysis. An eight-membered Ti2O4P2 metallacycle bridged by two fluorine ligands between two titanium centers is observed.