Cyclophane Derivatives Research Articles

Photochemical Bromination of 2,5‐Dimethylbenzoic Acid as Key Step of an Improved Alkyne‐Functionalized Blue Box Synthesis**

AbstractCyclobis(paraquat‐p‐phenylene), also known as “blue box”, is a highly electron‐deficient macrocycle, widely used as a molecular receptor for small electron‐rich molecules. Inserting a reactive functional group onto the molecular structure of this cyclophane is paramount for its inclusion into complex architectures. To this aim, including an alkyne moiety would be ideal, because it can participate in click reactions. However, the synthesis of such alkyne‐functionalized cyclophane suffers from several drawbacks: the use of toxic and expensive CCl4, the need for high‐pressure reactors, and overall low yield. We have revised the existing synthesis of this cyclophane derivative bearing an alkyne moiety, to overcome all these limitations. In particular, photochemical radical bromination is adopted to obtain a sensitive intermediate. We demonstrated that the synthesized host molecule can be functionalized via click reactions and take part in radical‐radical interactions. Our work makes a key functionalized paraquat macrocycle more accessible, facilitating the development of novel redox‐responsive systems.

Dicyanoimidazole thermoset derived from [2.2]Paracyclophane: Synthesis, curing behavior and thermal properties

New functionalized cyclophane derivative (DCI-PcP) on the basis of [2.2]paracyclophane and dicyanoimidazole was designed and prepared. Fourier transform infrared spectrometer (FT-IR) suggested triazine and azaporphyrin can be observed in the cured product. DSC showed that DCI-PcP monomer revealed a melting point at 226 °C and exothermic transition at 312 °C. Rheological analysis showed that DCI-PcP possessed outstanding processability (melt viscosity <1 Pa s). DMA and TGA analysis indicated that cured resin showed excellent thermal properties and high glass transition temperature merely by a relatively low curing temperature of 300 °C.

A facile and efficient route to one-pot synthesis of new cyclophanes using vinamidinium salts.

In this study, an efficient method for the synthesis of new cyclophanes (5a–f, 6a–g) through the condensation of 1,4-phenylenedimethanamine (3) or 2,3,5,6-tetramethylbenzene-1,4-diamine (4) with 2-substituted vinamidiniums (2a–g) is described. The cyclophane derivatives are obtained in good to excellent yields in the presence of acetic acid in refluxing acetonitrile after 15 h. The structure of new compounds was validated based on their spectral data (1H NMR, 13C NMR, IR) and elemental analysis.

Synthesis of Branch-Type Cyclophane Tetramers Having a Multivalently Enhanced Guest-Binding Ability

A cationic branch-type cyclophane tetramer (1a) was synthesized by introducing three Boc-protected cyclophane derivatives into a N-acetylated tetraaza[6.1.6.1]paracy-clophane derivative as a core skeleton through DCC condensation, followed by removal of the external Boc-protecting groups. Cationic cyclophane tetramer 1a exhibited a high affinity toward an anionic and hydrophobic fluorescent guest, TNS, with binding constant of 4.8 × 105 M-1. This value of 1a was about 80-fold larger than that of the corresponding monomeric cyclophane for the identical guest, reflecting multivalent effect on the guest binding. As for electrostatic recognition, the obtained binding constant of 1a was one order of magnitude larger than that of an analogous anionic cyclophane tetramer (1b) for the identical guest. These enhanced guest-binding abilities of 1a were easily evaluated by fluorescence titration experiments.

A Combined Experimental and Theoretical Study on the Circular Dichroism of Staggered and Eclipsed Forms of Dimethoxy[2.2]-, [3.2]-, and [3.3]Pyridinophanes and Their Protonated Forms.

The circular dichroisms (CDs) of dimethoxy[2.2]-, [3.2]-, and [3.3]pyridinophanes and their protonated forms were investigated experimentally and theoretically. Characteristic multisignate Cotton effects (CEs), typical for planar chiral cyclophane derivatives, were observed. The CD spectral pattern was quite comparable for the staggered forms of [2.2]-, [3.2]-, and [3.3]cyclophanes, but significantly differed for the eclipsed forms. More interestingly, the patterns resembled, but the CE signs were practically opposite between staggered and eclipsed [2.2]pyridinophanes. Upon protonation, the signs of most CEs were inverted in both forms of cyclophanes, due to the reversal of dipole moment in the pyridine against the pyridinium moiety. Such a change in CD spectrum upon protonation was not apparent in [3.2]pyridinophane, and the CD spectral behavior was more complex in [3.3]pyridinophanes. The variation of CD caused by the protonation/deprotonation process was temperature-dependent and hence utilized as a thermal sensor. The protonated forms of the homologous pyridinophanes with different tether lengths in staggered and eclipsed forms served as a model system for systematically studying the cation-π interaction and its effects on chiroptical properties. A steady increase of electronic interaction became apparent for the smaller-sized cyclophanes from the increased excitation energy and electronic coupling element of the charge-transfer (CT) band, while the observed CE at the CT band was a more complex function of the original transition dipole of donor/acceptor pair and linker atoms, as well as the strength of the electronic interaction.

Theoretical simulations for vibrationally-resolved absorption spectra of naphthalenediimide cyclophane derivatives

In the present work we systematically investigated the vibrationally-resolved absorption spectra of three core substituted naphthalenediimide cyclophane derivatives. It has been performed by time-dependent density functional theory calculations using three different exchange-correlation functionals, including the conventional B3LYP functional and two long-range corrected functionals: CAM-B3LYP and ωB97XD. The solvent effects were also considered with the polarizable continuum model. Calculation results showed that long range corrections are needed to correctly describe the optical properties of the three molecules because of the strong charge transfer characteristic of the excited states. The core substitution induced red shift to the first absorption band is nicely explained by the theoretical calculations. It is found that this band mainly involves the transitions within the core substituted naphthalenediimide chromophore. The high energy absorption band, on the other hand, is generated mainly from the un-substituted chromophore. These characters result in different substitution dependence for those two main absorption bands. Furthermore, the simulated vibrational profiles of the first two absorption bands nicely reproduce the observed vibrational features in the measured spectra. The accuracy of the calculated results from different functionals and basis sets has been discussed.

Protonation-Induced Sign Inversion of the Cotton Effects of Pyridinophanes. A Combined Experimental and Theoretical Study.

The circular dichroisms (CDs) of planar chiral [2.2]- and [3.3]-pyridinophanes were investigated experimentally and theoretically. Strong multisignate Cotton effects, typical for cyclophane derivatives, were observed. The CD spectra of [2.2]- and [3.3]-paracyclophanes closely resembled in pattern each other, despite the much greater conformational variations in the latter. Upon protonation, both of the cyclophanes suffered dramatic CD spectral changes with accompanying complete sign inversion, which was attributed to the reversal of diploe moment of pyridinium versus pyridine moiety. This chiroptical property switching driven by protonation/deprotonation was temperature-dependent and hence applicable to thermal sensing. The protonated forms of pyridinophanes served as ideal model systems for studying the cation-π interactions and their effects on chiroptical properties. Thus, the molar CD (Δε) of the charge-transfer band of protonated [2.2]pyridinophane was 10-fold larger than that of protonated [3.3]pyridinophane, which exceeds the increased interplane electronic interactions assessed from the electronic coupling element values.

1,3-Alternate Tetraamido-Azacalix[4]arenes as Selective Anion Receptors.

Six tetraaza[1.1.1.1]cyclophane derivatives bearing peripheral amide groups were prepared according to two distinct synthetic strategies that depend on the connection pattern between the aryl units. NMR experiments combined with the X-ray structures of two tetraamide derivatives 4 b and 10 show that these cavitands adopt a 1,3-alternate conformation both in solution and in the solid state. Consequently, the four amide groups of the aza[1.1.1.1]-m,m,m,m-cyclophane isomer 10 can contribute to the same recognition process towards neutral water molecules or anion guests. NMR experiments, mass spectrometry analyses and single-crystal X-ray structures confirm the anion-binding ability of this receptor. Absorption spectrophotometric titrations in nonpolar solvents provided evidence for the selectivity of 10 to chloride anions in the halide series, with a corresponding association constant Ka reaching 2.5 × 10(6) m(-1).

Syn-6,15-Dihydroxy-2,11-dithia[3.3]metacyclophane ethyl acetate monosolvate

The title compound, C16H16O2S2·C4H8O2, is a cyclophane derivative, which was crystallized from an ethylacetate/methanol solvent system. The metacyclophane moiety exists with the benzene rings in thesynorientation, and with a pseudo chair–chair conformation for the dithia 12-membered ring. Both hydroxy groups are positioned on same side of this ring. In the crystal, the cyclophane and the lattice solvent are linked by O—H...O hydrogen bonds.

Synthesis of Phenanthroline and Indole Based Hybrid Cyclophane Derivatives via Ring-Closing Metathesis

Synthesis of Phenanthroline and Indole Based Hybrid Cyclophane Derivatives via Ring-Closing Metathesis

The preparation of new functionalized [2.2]paracyclophane derivatives with N-containing functional groups.

The two isomeric bis(isocyanates) 4,12- and 4,16-di-isocyanato[2.2]paracyclophane, 16 and 28, have been prepared from their corresponding diacids by simple routes. The two isomers are versatile intermediates for the preparation of various cyclophanes bearing substituents with nitrogen-containing functional groups, e.g., the pseudo-ortho diamine 8, the bis secondary amine 23, and the crownophanes 18 and 19. Several of these new cyclophane derivatives (18, 19, 22, 26, 28) have been characterized by X-ray structural analysis.

ChemInform Abstract: Diversity‐Oriented Approach to Cyclophanes via Claisen Rearrangement and Ring‐Closing Metathesis as Key Steps

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Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes

Nine novel symmetrical bispyridinium cyclophanes have been synthesized. They are rigid derivatives with an upper spacer which joins the two exocyclic amino groups, and a lower spacer joining the two positively charged nitrogen atoms. At least one of the two spacers is an aliphatic linker, such as an alkane or oxyalkane fragment. The activity of these compounds has been evaluated against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major. All the cyclophanes are more active against L.major, with EC50 in intracellular amastigotes of between 1 and 17μM, they exhibit very low toxicity against mammalian cells THP-1 and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs amphotericin B and miltefosine. Compound 9 [2,8-Diaza-1,9(4,1)-dipyridinacyclotetradecaphan-1(1),9(1)-bis(ilium) dibromide] is the most active one among cyclophane derivatives against intracellular amastigotes of L.donovani (EC50 7.6±0.2μM) while L.major amastigotes are 6-fold more susceptible to the compound (EC50 1.26±0.3μM). Compound 9 produces depolarization of the mitochondrial membrane and a decrease in the ATP levels that leads to death of the parasites. The anti-leishmanial activity of this macrocyclic salts is independent of the Leishmania enzymes ethanolamine kinase and choline/ethanolamine kinase.

Diversity-oriented approach to cyclophanes via Claisen rearrangement and ring-closing metathesis as key steps

Among numerous reactions to prepare cyclophane derivatives, Claisen rearrangement reaction is very useful. We have prepared cyclophanes containing ethylene oxy bridge by double Claisen rearrangement reaction and ring-closing metathesis reaction as key steps.

Synthesis and Guest-Binding Behavior of Water-Soluble Cyclophanes Bearing PEG Residues

A water-soluble cyclophane (1) having poly(ethylene glycol) (PEG) moieties has been prepared from a tetraazide-functionalized cyclophane derivative and four poly(ethylene glycol) methyl ether acetylenes by Cu(I)-catalyzed 1,3 dipolar cycloadditions (click chemistry). An analogous derivative having a pyrene moiety (2) was also prepared in a similar manner. The guest-binding behavior of 1 and 2 toward anionic guests such as 6-p-toluidinonaphthalene-2-sulfonate was investigated by fluorescence spectroscopy. The binding constants (K) of the host-guest complexes were evaluated.

ChemInform Abstract: Planar Chiral Triazole‐Based Phosphanes Derived from [2.2]Paracyclophane and Their Activity in Suzuki Coupling Reactions.

AbstractFour cyclophane derivatives with triazole‐phosphane moieties are synthesized and tested as ligands in Suzuki cross‐coupling reactions with compound (V) giving the best results.

Synthesis of Water-Soluble Cyclophane Pentamers Using Click Chemistry as a Multivalent Host for Daunorubicin and Doxorubicin

Abstract Cationic cyclophane pentamer 1 has been prepared from a tetraazide-functionalized cyclophane derivative and four acetylene-functionalized cyclophane derivatives by Cu(I)-catalyzed 1,3-dipolar cycloadditions (click chemistry) in a 87% yield, followed by a treatment with trifluoroacetic acid. Cationic host 1 showed effective guest-binding behavior toward fluorescent guests such as 6-p-toluidinonaphthalene-2-sulfonate, in comparison with those of monomeric cyclophane. On the other hand, anionic cyclophane pentamer 2, which was derived from 1 by a reaction with succinic anhydride, showed enhanced guest-binding affinity toward anticancer drugs such as daunorubicin hydrochloride, in comparison with those of the monomeric cyclophane.

Interplay of monomer, intra- and intermolecular excimer fluorescence in cyclophanes and selective recognition of methanol vapours

With an objective to develop simple organic systems for optoelectronic applications, we have investigated photophysical properties of water soluble cyclophane derivatives 1, 2 and model compound 3 in solution and solid state. Of these, the symmetrical cyclophane 1 exhibited monomer emission in methanol, whereas an intramolecular excimer emission was observed in the aqueous medium. Interestingly, in the solid state it showed a highly red-shifted emission maximum when compared to those in the solution. The unsymmetrical cyclophane 2, on the other hand, exhibited monomer emission in both organic and aqueous media, while a dual emission (monomer and excimer) was observed in the solid state. Insights into these unique fluorescence properties were gained by studying the molecular packing of the cyclophanes through single crystal X-ray structure analysis. The cyclophane 1 exhibited a unidirectional sandwich-type packing pattern thereby resulting in strong face-to-face π–π stacking interactions between the anthracene chromophores, whereas 2 exhibited both herringbone and sandwich-type pattern, wherein the interacting anthracene moieties are arranged in an intermolecular T-shaped fashion. By virtue of different molecular packing the cyclophane 1 showed visible fluorescence colour change from yellow to blue when exposed to methanol vapours as compared to ethanol, acetonitrile, hexane and water vapours. Uniquely, this system can detect as low as 1% of methanol in ethanol solution thereby demonstrating its usefulness as an optical probe for the detection of methanol vapours.

Ab Initio Molecular Orbital Study on the Excited States of [2.2]-, [3.3]-, and Siloxane-Bridged Paracyclophanes

Paracyclophanes are simple idealized model molecules for the study of interacting π-stacking systems. In this study, the excited states of [2.2]paracyclophane ([2.2]PCP), [3.3]paracyclophane ([3.3]PCP), and siloxane-bridged paracyclophane (SiPCP) are systematically investigated using the multiconfiguration quasi-degenerated perturbation theory (MCQDPT) method. The excited states of the alkyl- and silyl-substituted benzene monomers and benzene dimer, which can be regarded as the building blocks of paracyclophanes, are also examined at the same level of theory for more detailed understanding. The accuracy of the time-dependent density functional theory (TD-DFT) method required for excited state geometry optimization of the paracyclophanes is confirmed from calculations of the benzene dimer. The equilibrium distances between the benzene rings of the paracyclophanes in the first excited states are shorter than those in the ground state, and the benzene rings at the excited state optimized geometries are in an almost eclipsed parallel configuration, which indicates excimer formation. The calculated transition energies and oscillator strengths are generally in good agreement with the corresponding experimental results. A clear correlation between the excited state properties and the molecular structures is systematically demonstrated based on the calculation results for the substituted benzene monomers and benzene dimer. The transition energies of SiPCP are close to the corresponding absorption and fluorescence energies of the experimentally studied phenylene-silica hybrids, which indicates that the electronic properties of organic-silica hybrids, which is a new class of material with potential in photofunctional applications, can be approximated by simple siloxane-bridged cyclophane derivatives.

Diversity-Oriented Approach to Macrocyclic Cyclophane Derivatives via Ring-Closing Metathesis

A short synthetic approach to the macrocyclic framework of longithorone C is described via ring-closing metathesis using the Grubbs 2nd generation catalyst.