Organocatalytic desymmetrization provides access to planar chiral [2.2]paracyclophanes.

Planar chiral [2.2]paracyclophanes consist of two functionalized benzene rings connected by two ethylene bridges. These organic compounds have a wide range of applications in asymmetric synthesis, as both ligands and catalysts, and in materials science, as polymers, energy materials and dyes. However, these molecules can only be accessed by enantiomer separation via (a) time-consuming chiral separations and (b) kinetic resolution approaches, often with a limited substrate scope, yielding both enantiomers. Here, we report a simple, efficient, metal-free protocol for organocatalytic desymmetrization of prochiral diformyl[2.2]paracyclophanes. Our detailed experimental mechanistic study highlights differences in the origin of enantiocontrol of pseudo-para and pseudo-gem diformyl derivatives in NHC catalyzed desymmetrizations based on whether a key Breslow intermediate is irreversibly or reversibly formed in this process. This gram-scale reaction enables a wide range of follow-up derivatizations of carbonyl groups, producing various enantiomerically pure planar chiral [2.2]paracyclophane derivatives, thereby underscoring the potential of this method.

Transition metal complexes of the (2,2,2-trifluoroethyl)phosphinate NOTA analogue as potential contrast agents for 19F magnetic resonance imaging.

A new hexadentate 1,4,7-triazacyclononane-based ligand bearing three coordinating methylene-(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent (Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and trivalent (Cr3+, Fe3+, Co3+) transition metal ions was studied. The ligand forms stable complexes with late divalent transition metal ions (from Co2+ to Zn2+) and the complexes of these metal ions are formed above pH ∼3. A number of complexes with divalent metal ions were structurally characterized by means of single-crystal X-ray diffraction. The complex of the larger Mn2+ ion adopts a twisted trigonally antiprismatic geometry with a larger coordination cavity and smaller torsion of the pendant arms, whereas the smaller ions Ni2+, Cu2+ and Zn2+ form octahedral species with a smaller cavity and larger pendant arm torsion. In the case of the Co2+ complexes, both coordination arrangements were observed. The complexes with paramagnetic metal ions were studied from the point of view of potential utilization in 19F magnetic resonance imaging. A significant shortening of the 19F NMR longitudinal relaxation times was observed: a sub-millisecond range for complexes of Cr3+, Mn2+ and Fe3+ with symmetric electronic states (t2g3 and HS-d5), the millisecond range for the Ni2+ and Cu2+ complexes and tens of milliseconds for the Co2+ complex. Such short relaxation times are consistent with a short distance between the paramagnetic metal ion and the fluorine atoms (∼5.5-6.5 Å). Among the redox-active complexes (Mn3+/Mn2+, Fe3+/Fe2+, Co3+/Co2+, Cu2+/Cu+), the cobalt complexes show sufficient stability and a paramagnetic-diamagnetic changeover with the redox potential lying in a physiologically relevant range. Thus, the Co3+/Co2+ complex pair can be potentially used as a smart redox-responsive contrast agent for 19F MRI.

Spatial arrangements of cyclodextrin host-guest complexes in solution studied by 13C NMR and molecular modelling.

13C NMR spectroscopic analyses of Cs symmetric guest molecules in the cyclodextrin host cavity, combined with molecular modelling and solid-state X-ray analysis, provides a detailed description of the spatial arrangement of cyclodextrin host-guest complexes in solution. The chiral cavity of the cyclodextrin molecule creates an anisotropic environment for the guest molecule resulting in a splitting of its prochiral carbon signals in 13C NMR spectra. This signal split can be correlated to the distance of the guest atoms from the wall of the host cavity and to the spatial separation of binding sites preferred by pairs of prochiral carbon atoms. These measurements complement traditional solid-state analyses, which rely on the crystallization of host-guest complexes and their crystallographic analysis.

Regular Arrays of Rod-Shaped Molecular Photoswitches: Synthesis, Preparation, Characterization, and Selective Photoswitching within Mono- and Bilayer Systems.

We assembled photoresponsive mono- and bilayer systems with well-defined properties from rod-shaped molecules equipped with different photoswitches. Using properly chosen chromophores (diarylethene-based switch and unidirectional light-driven molecular motor), we then selectively targeted layers made of the same types of photoswitches using appropriate monochromatic light. UV-vis analysis confirmed smooth and unrestricted photoisomerization. To achieve this, we synthesized a new class of triptycene-based molecular pedestals adept at forming sturdy Langmuir-Blodgett films on a water-air interface. The films were smoothly transferred to gold and quartz surfaces. Repeated deposition afforded bilayer systems: one layer containing diarylethene-based photoswitches and the other a unidirectional light-driven molecular motor. Structural analysis of both mono- and bilayer systems revealed the molecules to be tilted with carboxylic functions pointing to the surface. At least two different polymorphs differing in monolayer thickness and tilt angle (~40° and ~60°) were identified on the gold surface.

Enantioenriched 1,4-Benzoxazepines via Chiral Brønsted Acid-Catalyzed Enantioselective Desymmetrization of 3-Substituted Oxetanes.

Herein, we present a highly enantioselective desymmetrization of 3-substituted oxetanes enabled by a confined chiral phosphoric acid. This metal-free process allows effective access to chiral seven-membered 1,4-benzoxazepines with a high degree of enantiocontrol, under mild reaction conditions. The developed synthetic strategy tolerates a broad substrate scope and demonstrates its synthetic utility in various enantioselective product transformations, thus proving its effectiveness in diverse scenarios.

The Biomimetic Synthesis of Polyarylated Fluorenes, Relevant to Selaginellaceae Polyphenols, Leading to the Spontaneous Formation of Stable Radicals.

This work reports a biomimetic synthesis of polyarylated fluorene derivatives. The molecules are formed via intramolecular electrophilic aromatic substitution, resembling a cyclization leading towards the natural selaginpulvilins from selaginellins. The scope of the reaction was investigated, and the products were obtained in 60-95 % yields. Some of the compounds decompose to a stable radical. We investigated the nature and the origin of the radical using experimental methods, including EPR or electrochemical measurements, as well as theoretical methods, such as DFT calculations. Based on our observations, we hypothesize, that phenoxy radicals are formed in the first instance, which however undergo internal rearrangement to thermodynamically more stable carbon-centered radicals. The preliminary data also show the cytotoxic properties of some of the molecules.

Synthesis and reactivity of Pd(II) imidoyl complexes obtained by insertion of isocyanoferrocene into the Pd-C bonds of orthopalladated precursors.

While the multifaceted reactivity of organic isocyanides has been extensively demonstrated, that of their organometallic analogue, isocyanoferrocene (FcNC; Fc = ferrocenyl), has not yet been adequately explored. This contribution describes the syntheses of novel chelating Pd(II) imidoyl complexes, [(YCH2C6H4C(NFc)-κ2Y,C)PdCl(PR3)], by insertion of FcNC into the Pd-C bond of cyclopalladated precursors [(YCH2C6H4-κ2Y,C)PdCl(PR3)] (Y = Me2N, MeS, R = Ph, Me). The imidoyl complexes underwent facile alkylation with [Me3O][BF4] to produce the cationic aminocarbene complexes [{YCH2C6H4C(N(Me)Fc)-κ2Y,C}PdCl(PR3)][BF4]. All compounds were fully characterised using a combination of spectroscopic methods (NMR, FTIR and ESI MS), cyclic voltammetry and single-crystal X-ray crystallography. In addition, DFT calculations were used to describe the bonding in the two compound families. Analyses with intrinsic bond orbitals (IBOs) and the quantum theory of atoms in molecules (QTAIM) consistently pointed to the transformation of an X-type imidoyl C-ligand (σ-organyl) into an L-type carbene donor upon alkylation, which has only a minor structural consequence. Also reported is the unexpected conversion of the imidoyl complex [(Me2NCH2C6H4C(NFc)-κ2N,C)PdCl(PPh3)] into (Z)-2,2-dimethyl-1-(ferrocenylimino)isoindolin-2-ium tetrafluoroborate as a reductive elimination product, which was induced by Lewis and Brønsted acids.

Solvent-controlled formation of alkali and alkali-earth-secured cucurbituril/guest trimers.

Cucurbit[7]uril (CB[7]) encapsulates adamantyl and trimethylsilyl substituents of positively charged guests in dimethyl sulfoxide (DMSO). Unlike in water or deuterium oxide, addition of a selection of alkali and alkali-earth cations with van der Waals radii between 1.0 and 1.4 Å (Na+, K+, Ca2+, Sr2+, Ba2+ and Eu3+) to the CB[7]/guest complexes triggers their cation-mediated trimerization, a process that is very slow on the nuclear magnetic resonance (NMR) time scale. Smaller (Li+, Mg2+) or larger cations (Rb+, Cs+ or NH4+) are inert. The trimers display extensive CH-O interactions between the equatorial and pseudo-equatorial hydrogens of CB[7] and the carbonyl rim of the neighboring CB[7] unit in the trimer, and a deeply nested cation between the three interacting carbonylated CB[7] rims; a counteranion is likely perched in the shallow cavity formed by the three outer walls of CB[7] in the trimer. Remarkably, a guest must occupy the cavity of CB[7] for trimerization to take place. Using a combination of semi-empirical and density functional theory techniques in conjunction with continuum solvation models, we showed that trimerization is favored in DMSO, and not in water, because the penalty for the partial desolvation of three of the six CB[7] portals upon aggregation into a trimer is less unfavorable in DMSO compared to water.

Cyclopentadienyl Molybdenum(II) Compounds Bearing Ether and Thioether Functions in the Side Chain: Synthesis, Characterization, and Cytotoxic/Cytostatic Studies.

A series of molybdenum(II) compounds [(η5 -Cp')Mo(CO)2 (L2 )][BF4 ] (Cp'=C5 H4 (CH2 )2 SPh, C9 H6 (CH2 )2 OMe, L2= N,N-chelating ligand) have been synthesized and characterized by spectroscopic and analytical methods including X-ray crystallography. The in vitro assay on human leukemia cells MOLT-4 has shown that the substitution in the π-ligand in combination with suitable N,N-chelating ligand can lead to species with cytotoxicity considerably higher than reported to cisplatin. Unusually high activity was observed for compounds bearing phenanthroline ligands [{η5 -C9 H6 (CH2 )2 OMe}Mo(CO)2 (3,4,7,8-Me4 phen)][BF4 ] (IC50 =0.7±0.3 µM) and [{η5 -C9 H6 (CH2 )2 OMe}Mo(CO)2 (4,7-Ph2 phen)][BF4 ] (IC50 values 0.8±0.4 µM).

Synthesis, Structure, Reactivity, and Intramolecular Donor-Acceptor Interactions in a Phosphinoferrocene Stibine and Its Corresponding Phosphine Chalcogenides and Stiboranes.

Ferrocene-based phosphines equipped with additional functional groups are versatile ligands for coordination chemistry and catalysis. This contribution describes a new compound of this type, combining phosphine and stibine groups at the ferrocene backbone, viz. 1-(diphenylphosphino)-1'-(diphenylstibino)ferrocene (1). Phosphinostibine 1 and the corresponding P-chalcogenide derivatives Ph2P(E)fcSbPh2 (1E, fc = ferrocene-1,1'-diyl, E = O, S, Se) were synthesized and further converted to the corresponding stiboranes Ph2P(E)fcSb(O2C6Cl4)Ph2 (6 and 6E) by oxidation with o-chloranil. All compounds were characterized by spectroscopic methods, X-ray diffraction analysis, cyclic voltammetry, and theoretical methods. Both NMR spectroscopy and DFT calculations confirmed the presence of P → Sb and P═O → Sb donor-acceptor interactions in 6 and 6O, triggered by the oxidation of the stibine moiety into Lewis acidic stiborane. The corresponding interactions in 6S and 6Se were of the same type but significantly weaker. A coordination study with AuCl as the model metal fragment revealed that the phosphine group acts as the "primary" coordination site, in line with its higher basicity. The obtained Au(I) complexes were applied as catalysts in the Au-catalyzed cyclization of N-propargylbenzamide and in the oxidative [2 + 2 + 1] cyclization of ethynylbenzene with acetonitrile and pyridine N-oxides. The catalytic results showed that the stibine complexes had worse catalytic performance than their phosphine counterparts, most likely due to the formation of weaker coordination bonds and hence poorer stabilization of the active metal species. Nevertheless, the stibine moiety could be used to fine-tune the properties of the ligated metal center by changing the oxidation state or substituents at the "remote" Sb atom.

Stabilization of propene molybdenum and tungsten half-sandwich complexes by intramolecular coordination of a thioether function.

This study reports the stabilizing effect of an intramolecularly coordinated thioether function in propene complexes of the general formula [{η5:κS-C5H4(CH2)2SR}M(CO)2(η2-C2H3Me)][BF4] (M = Mo, W; R = Et, Ph). They are formed by protonation of allyl analogues [{η5-C5H4(CH2)2SR}M(CO)2(η3-C3H5)] by tetrafluoroboric acid in non-coordinating solvents. In contrast to analogues with unsubstituted Cp ligands, these propene complexes are isolable in a pure form and characterized by NMR spectroscopy. The molybdenum compounds are stable at low temperature and the propene ligand can easily be exchanged by thioethers or acetonitrile. Several representatives of the reaction products were characterized by X-ray structure analysis. The stabilization effect in tungsten complexes [{η5:κS-C5H4(CH2)2SR}W(CO)2(η2-C2H3Me)][BF4] (R = Et, Ph) was unusually high. The compounds are long-term stable at room temperature and do not undergo ligand exchange reactions even with strong chelators such as 1,10-phenanthroline. The molecular structure of the tungsten propene complex was confirmed by X-ray diffraction analysis on a single crystal.

Resolution by diastereomeric salts: Access to both enantiomers of racemic acid using the same enantiomer of resolving base.

Racemic carboxylic acid, a Diels-Alder cycloadduct derived from 5-bromo-3-phenyl-α-pyrone and acrylate dienophile, was resolved into enantiomers by diastereomeric salt crystallization. Quinidine was used as a sole resolving base. The salt of (+)-acid crystallized from aqueous acetonitrile solution. Once this salt was separated by filtration, quinidine salt with (-)-acid crystallized from mother liquor. As a result, both enantiomers of Diels-Alder cycloadduct were isolated in high enantiomeric purity.

Transition metal complexes of cyclam with two 2,2,2-trifluoroethylphosphinate pendant arms as probes for 19F magnetic resonance imaging.

A new cyclam-based ligand bearing two methylene(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent transition metal ions [Co(II), Ni(II), Cu(II), Zn(II)] was studied. The ligand was found to be very selective for the Cu(II) ion according to the common Williams-Irving trend. Complexes with all the studied metal ions were structurally characterized. The Cu(II) ion forms two isomeric complexes; the pentacoordinated isomer pc-[Cu(L)] is the kinetic product and the octahedral trans-O,O'-[Cu(L)] isomer is the final (thermodynamic) product of the complexation reaction. Other studied metal ions form octahedral cis-O,O'-[M(L)] complexes. The complexes with paramagnetic metal ions showed a significant shortening of 19F NMR longitudinal relaxation times (T1) to the millisecond range [Ni(II) and Cu(II) complexes] or tens of milliseconds [Co(II) complex] at the temperature and magnetic field relevant for 19F magnetic resonance imaging (MRI). Such a short T1 results from a short distance between the paramagnetic metal ion and the fluorine atoms (∼6.1-6.4 Å). The complexes show high kinetic inertness towards acid-assisted dissociation; in particular, the trans-O,O'-[Cu(L)] complex was found to be extremely inert with a dissociation half-time of 2.8 h in 1 M HCl at 90 °C. Together with the short relaxation time, it potentially enables in vitro/in vivo utilization of the complexes as efficient contrast agents for 19F MRI.

Synthesis of Hybrid Ligands with Nitrile and Cage Phosphane Donor Groups and their Applications in Gold-Mediated Reactions.

Altering the donor properties of phosphane ligands through substituent variation is an established tool in coordination chemistry and catalysis. This contribution describes the synthesis of two new hybrid donors (L) combining 1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane-8-yl (PCg) and nitrile donor groups at different molecular scaffolds, viz. ferrocene-1,1'-diyl (fc) and 1,2-phenylene. These ligands were used to prepare dimeric Au(I) complexes [Au2 (µ(P,N)-L)2 ][SbF6 ]2 , which were evaluated as silver-free, preformed catalysts in Au-mediated cycloisomerization of (Z)-3-methylpent-2-en-4-yn-1-ol to 2,3-dimethylfuran. The catalyst featuring the ferrocene-based ligand, viz., [Au2 (µ(P,N)-CgPfcCN)2 ][SbF6 ]2 , showed the best catalytic performance at low catalyst loading (0.5 or 0.15 mol.%), which exceeded that of its diphenylphosphanyl analog [Au2 (µ(P,N)-Ph2 PfcCN)2 ][SbF6 ]2 studied earlier and the prototypical Au(I) precatalyst [Au(PPh3 )(MeCN)][SbF6 ].

Cyclotrimerization Approach to Symmetric [9]Helical Indenofluorenes: Diverting Cyclization Pathways.

Catalytic cyclotrimerization routes to symmetrical [9]helical indenofluorene were explored by using different transition-metal complexes and thermal conditions. Depending on the reaction conditions, the cyclotrimerizations were accompanied by dehydro-Diels-Alder reaction giving rise to another type of aromatic compounds. Structures of both symmetrical [9]helical cyclotrimerization product as well as the dehydro-Diels-Alder product were confirmed by single-crystal X-ray diffraction analyses. Limits of enantioselective cyclotrimerization were assessed as well. DFT calculations shed light on the reaction course and the origin of diminished enantioselectivity.

Chlorinated Cubane-1,4-dicarboxylic Acids.

Herein, we report radical chlorination of cubane-1,4-dicarboxylic acid leading preferentially to one monochlorinated cubane dicarboxylate (ca. 70%) that is accompanied by four dichlorinated derivatives (ca. 20% in total). The exact positions of the chlorine atoms have been confirmed by X-ray diffraction of the corresponding single crystals. The acidity constants of all dicarboxylic acids in water were determined by capillary electrophoresis (3.17 ± 0.04 and 4.09 ± 0.05 for monochlorinated and ca. 2.71 ± 0.05 and 3.75 ± 0.05 for dichlorinated cubanes). All chlorinated derivatives as well as the parent diacid showed high thermal stability (decomposition above 250 °C) as documented by differential scanning calorimetry. The probable reaction pathways leading to individual isomers were proposed, and the energies of individual transition states and intermediates were obtained using density functional theory calculations (B3LYP-D3BJ/6-311+G(d,p)). The relative strain energies for all newly prepared derivatives as well as for hypothetical hexahalogenated (fluorinated, chlorinated, brominated, and iodinated) derivatives of cubane-1,4-dicarboxylic acids were predicted using wavefunction theory methods. The hexafluorinated derivative was identified as the most strained compound (57.5 kcal/mol), and the relative strain decreased as the size of halogen atoms increased (23.7 for hexachloro, 16.7 for hexabromo, and 4.0 kcal/mol for the hexaiodo derivative).

Stereoselective N-Heterocyclic-Carbene-Catalyzed Formal [4 + 2] Cycloaddition: Access to Chiral Heterocyclic Cyclohexenones.

The present study reports an asymmetric NHC-catalyzed formal [4 + 2] cycloaddition of heterocyclic alkenes containing a polarized double bond with an azolium-dienolate intermediate generated from α-bromo-α,ß-unsaturated aldehydes without external oxidation of the Breslow intermediate. Heterocyclic cyclohexenones were produced in good isolated yields (typically about 90%) with good stereochemical outcomes (in most cases, dr > 20/1, and ee = 70-99%). The synthetic utility of the protocol was exemplified by the scope of heterocyclic alkenes.

Access to Spirooxindole-Fused Cyclopentanes via a Stereoselective Organocascade Reaction Using Bifunctional Catalysis.

The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1-nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-to-good isolated yields (15-69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxindole compounds.

Beyond phosphorus: synthesis, reactivity, coordination behaviour and catalytic properties of 1,1'-bis(diphenylstibino)ferrocene.

Compared to their widely studied phosphine counterparts, ferrocene stibines have received only marginal attention thus far. This paper describes the synthesis of 1,1'-bis(diphenylstibino)ferrocene (1*), which is an antimony analogue of the ubiquitous dppf, and our investigations into the reactivity and coordination behaviour of this compound. Thus, distibine 1 was oxidised to stiboranes fc(SbPh2X2)2 (X = Cl, 2*; F, 6*; fc = ferrocene-1,1'-diyl) and to stibine-stiborane Ph2SbfcSbPh2F2 (5*). Compounds 2 and 6 were easily hydrolysed to produce ferrocenophanes fc[SbPh2XOSbPh2X] (X = Cl, 3*; F, 7*). Removing the halogen from 3 with silver(I) salts afforded the corresponding ferrocenophanes with O-bound oxyanions, fc[SbPh2ZOSbPh2Z] (Z = NO3, 4a*; ClO4, 4b*), which were alternatively prepared from 2 and also converted back to 2 by adding a chloride source. Through investigations into the coordination behaviour of distibine 1, the following compounds were isolated and characterised: [(µ-ClO4)2{Ag(1-κ2Sb,Sb')}2] (8*), [Ag(1-κ2Sb,Sb')2]X (X = ClO4, 9a; SbF6, 9b*), [(µ(Sb,Sb')-1){(arene)MCl2}2] (10*, 11*) and [(arene)MCl(1-κ2Sb,Sb')][PF6] (12*, 13*; 10, 12: M/arene = Ru/η6-p-cymene, 11, 13; Rh/η5-C5Me5), [(η5-C5Me5)RuCl(1-κ2Sb,Sb')] (14), [MCl2(1-κ2Sb,Sb')] (M = Pd, 15*; Pt, 16*), [Pd(1-κ2Sb,Sb')2]X2 (X = BF4, 17a; SbF6, 17b*), [Pd(η2-ma)(1-κ2Sb,Sb')] (18*; ma = maleic anhydride), [(µ(Sb,Sb')-1)(AuCl)2] (19*), and [Au(1-κ2Sb,Sb')2]X (X = AuCl2, 20a*; SbF6, 20b*). Inspection of the structural parameters suggested that complexes featuring 1 exhibit less sterically strained structures than their dppf analogues due to longer M-Sb and Sb-C bonds, which reduce crowding around the ligated metal centre. Cyclic voltammetry and DFT calculations revealed that the primary electrochemical oxidation of 1 is reversible and occurs at the ferrocene unit. Based on preliminary catalytic tests in Suzuki-Miyaura biaryl coupling, Pd-1 complexes exhibited a lower efficiency than their respective Pd-dppf analogues. (An asterisk indicates that the crystal structure has been determined.).

Copper(II) complexes of cyclams with N-(2,2,2-trifluoroethyl)-aminoalkyl pendant arms as potential probes for 19F magnetic resonance imaging.

A series of Cu(II) complexes with cyclam-based ligands containing two N-(2,2,2-trifluoroethyl)-aminoalkyl pendant arms in 1,8-positions (L1: 1,2-ethylene spacer, L2: 1,3-propylene spacer; L3: 1,4-butylene spacer) was studied in respect to potential use as contrast agents for 19F magnetic resonance imaging (MRI). A number of structures of the complexes as well as of several organic precursors were determined by single-crystal X-ray diffraction analysis. Geometric parameters (especially distances between fluorine atoms and the central metal ion) were determined for each complex and the identity of isomeric complex species present in solution was established. The NMR longitudinal relaxation times (T1) of 19F nuclei in the ligands at clinically relevant fields and temperatures (1-2 s) were significantly shortened upon Cu(II) binding to 7-10 ms for [Cu(L1)]2+, 20-30 ms for [Cu(L2)]2+ and 20-50 ms for [Cu(L3)]2+. The trend of the relaxation time shortening is in accordance with the distance and number of chemical bonds between fluorine atoms and the Cu(II) ion. The signals show promising T2*/T1 ratios in the range 0.25-0.55, assuring their good applicability to 19F NMR/MRI. The results show that even the Cu(II) ion, with a small magnetic moment, causes significant relaxation enhancement with a long-range effect and can be considered as a highly suitable metal ion for efficient 19F MRI contrast agents.