Regioselective Coordination toward Silver(I) Ions by Bis- and Tris(Tetra-Armed Cyclen)s via Differential Electron Density of Aromatic Side Arms.

Four types of bis- and tris(tetra-armed cyclen)s were prepared. 2MF is a bis(tetra-armed cyclen) with electron-rich side arms (three 4-methoxybenzyl groups) and electron-deficient side arms (three 3,5-difluorobenzyl groups), connected by a 4,4'-dimethyl-1,1'-biphenyl moiety. 3MFM is a tris(tetra-armed cyclen) with 4-methoxybenzyl and 3,5-difluorobenzyl groups introduced on both ends and the central cyclen, respectively. 4MFM is a V-shaped analogue of 3MFM. 3FMF is a tris(tetra-armed cyclen) where the aromatic side arms at both ends and the central cyclen of 3MFM are exchanged. The regioselective coordination of silver(I) ions by these ligands is reported. Initially, we added Ag+ ions to a compound (2MF) that consists of tetra-armed cyclen with 4-methoxybenzyl groups as an electron-donating substituent on the aromatic rings and 3,5-difluorobenzyl groups as an electron-withdrawing substituent. 1H NMR and 19F{1H} NMR spectroscopy exhibited that the cyclen with the 4-methoxybenzyl groups formed a complex with Ag+ ions first, followed by the cyclen with the 3,5-difluorobenzyl groups. Next, we employed a compound (3MFM) with three cyclen units, where the cyclen at each end was functionalized with three 4-methoxybenzyl groups, and the central cyclen was functionalized with two 3,5-difluorobenzyl groups. Upon adding Ag+ ions, we observed that the cyclen units at both ends formed complexes with Ag+ ions initially, followed by the central cyclen forming a complex with Ag+ ions. When we used 4MFM, which is a V-shaped compound, the Ag+-induced-1H NMR chemical shift changes are almost the same results as the 3MFM. Furthermore, we synthesized a compound (3FMF) by interchanging the substituents on the cyclen units at the ends and the center. Interestingly, the order of the complex formation was reversed in this compound. These results demonstrated that tuning the electron density on the aromatic side arms through substituents makes it possible to achieve regioselective coordination with Ag+ ions in bis- or tris(tetra-armed cyclen)s.

14- and 17-Membered Macrocycles Containing Amide, Amino, and Carbamate Groups in The Monocyclic Skeleton: An Accidental Byproduct Obtained from a Residue after Separation.

A 14-membered cyclic compound (3) containing amide, amino, and carbamate groups, which was serendipitously obtained in the oily residue after the separation of 4-benzyl-1,4,7,10-tetraazacyldododecane-2,6-dione (2a) and 4,16-dibenzyl-1,4,7,10,13,16,19,22-octaazacyclo-tetracosane-2,6,14,18-tetraone (2b), is reported. The structure of 3 is formally a CO2 insertion between positions 3 and 4 of the 12-membered ring in 2a. The CO2 insertion was confirmed in the synthesis of diethyl 2,2'-(benzylazanediyl)diacetate (1) by the reaction of benzylamine with ethyl bromoacetate using K2CO3 as the base. In addition, the selective synthesis of 3 and ethyl N-benzyl-N-((2-ethoxy-2-oxoethoxy)carbonyl)glycinate (5) and their kinetic behavior are reported. The reaction of 5 with triethylenetetramine afforded a 17-membered macrocycle (7), which was obtained in an 18% yield. Compounds 6 and 8 were prepared from 3 and 7 by introducing benzyl groups to improve their solubility in organic solvents. Titration experiments using 1H NMR showed that both 6 and 8 exhibit Li+ selectivity.

Argentivorous molecules with chromophores: dependence of their fluorescence intensities on the distance between a donor and an acceptor.

We have prepared new argentivorous molecules (L2 and L3) having different linker lengths between cyclen and anthracene units. The structures of Ag+ complexes with the new ligands were investigated in solution and solid states. The silver(I) ion-induced 1H NMR and UV-vis spectral changes of L2 and L3 showed the presence of 1 : 1 complexes. The solid-state structures of the Ag+ complexes with L2 and L3 are stable 1 : 1 complexes because four aromatic side-arms wrap the Ag+ incorporated in the cyclen unit. A photo-induced electron transfer (PET) effect that depends on the length of the linker connecting the nitrogen atoms of cyclen to the chromophore is also investigated. The result indicates a linear (log) correlation between the donor-chromophore average distances of the optimized structures calculated by DFT calculations and fluorescence intensities (log I), and the PET effect becomes ineffective at about 12 Å in this system.

A Structure-Adaptive Ligand: The Conformation Changes to Fit with the Lengths and Angles of Tetravalent Bis-Paraquat Guests.

A flexible cylindrical cryptand (1b) with two m-phenylene-26-crown-8 ethers has been prepared, and its complexing properties with respect to tetravalent cationic bis-paraquat guests have been investigated. Diffusion-ordered spectroscopy nuclear magnetic resonance (NMR) and titration experiments using cold electrospray ionization mass spectrometry and 1H NMR revealed that 1b has versatile complexing properties with respect to tetravalent cationic guests used despite the guest molecules' length and shape.

Bis-Argentivorous Molecules Bridged by Phenyl and 4,4'-Biphenyl Groups: Structural and Dynamic Behavior of Silver Complexes.

Bis-argentivorous molecules (La and Lb), which have phenyl and 4,4'-biphenyl groups as linkers, have been prepared. The structures of Ag+ complexes with the new ligands (La and Lb) were investigated in solution and the solid state. The CSI-MS and 1H NMR titration of La and Lb with Ag+ show 1:1 and 1:2 complexes depending on the [Ag+]:[L] ratios. In the solid-state structures, single crystals of La and Lb with 2 equiv of Ag+ were prepared. X-ray crystallography of the silver(I) complexes with La and Lb showed that an intramolecular racemic structure (Δ(δδδδ)Λ(λλλλ) form) and a racemic mixture of Δ(δδδδ)Δ(δδδδ) and Λ(λλλλ)Λ(λλλλ) forms were formed, respectively. The dynamic 1H NMR studies suggest the following: (i) the activation entropies (ΔS⧧) of the side arm rotations in the Ag+ complex with La were all negative, indicating restricted rotation of the side arms due to their shortness, and (ii) the ΔS⧧ values of the Ag+ complexes with Lb were negative only when the side arms of both cyclens rotated simultaneously, and the ΔS⧧ values for the 1:1 and 1:2 complexes were positive when one cyclen side arm was rotated. These values of ΔS⧧ indicate that the biphenyl side arms between the two cyclens are not long enough to rotate the ring freely.

Argentivorous Molecules with Oxyethylene Chains in Side-Arms: Silver Ion-Induced Selectivity Changes toward Alkali Metal Ions.

Argentivorous molecules with mono, di, tri, tetra, and penta-oxyethylene chains in aromatic side-arms were prepared (L1-L5). Titration experiments using proton nuclear magnetic resonance and cold electrospray ionization (cold-spray ionization, CSI) mass spectrometry showed that silver ions were trapped in the cyclen moiety and the arranged oxyethylene chains of the side-arms when two equivalents of silver ions were added. The silver complexes formed by adding one equivalent of silver ion to L2-L5 bind alkali metal ions using the oxyethylene chains; alkali metal ion-induced CSI mass spectral changes of L2-L5 were measured in the absence and presence of silver ions to compare the binding properties of the ligand for Li+, Na+, and K+ ions. As a result, the intensity ratios of [L + H + M]2+/[L + H]+ in L1-L3 were almost zero or very low. L4 and L5, which have tetra(oxyethylene) and penta(oxyethylene) chains, respectively, bind a larger size of alkali metal ions. On the other hand, in the presence of silver ions, the ratio for [L + Ag + M]2+/[L + H]+ (M = Li, Na, K) in L2-L5 was increased. The highest [L + Ag + M]2+/[L + H]+ ratios for K+ were observed in L4 and L5, while selectivity for Na+ was observed in the case of L2 and L3. These results indicate that the increased binding ability and selectivity by L2-L5 are due to the arrangement of oxyethylene chains by the conformational change of the aromatic side-arms. The Ag+-induced carbon-13 nuclear magnetic resonance spectral changes suggested that the second and third oxyethylene units, close to the benzene, are involved in the coordination of the second metal ion.

Argentivorous Molecules with Chromophores in Side Arms: Silver Ion-Induced Turn On and Turn Off of Fluorescence.

The synthesis of argentivorous molecules (L1 and L2) having two chromophores (4-(anthracen-9-yl)benzyl or 4-(pyren-1-yl)benzyl groups) and two benzyl groups and the fluorescence properties of their silver complexes in a solution and the solid state are reported. A crystallographic approach for the Ag+ complexes with L1 and L2 revealed that the observed fluorescence changes stem from the excimer formation and extinction of fluorescent. Furthermore, binding stabilities of L1 and L2 toward Ag+ ions were estimated by the Ag+-induced UV-vis and PL spectral changes.

Cosmosen: Octa-Armed 24-Membered Cyclic Octaamine Synthesized from a Byproduct in the Preparation of 4-Benzyl-2,6-dioxocyclen.

The synthesis of an octa-armed 24-membered cyclic octaamine (1) is reported. When 4-benzyl-1,4,7,10-tetraazacyclododecane-2,6-dione (3a) was prepared by the reaction of diethylenetriamine with diethyl N-benzyliminodiacetate (2), a dimeric macrocycle (3b) was obtained as a byproduct in a 5% yield. An octa-armed 24-membered cyclic octaamine (1), named Cosmosen, was prepared via the reductive amination and reduction of 3b. The binding constants for the 1:1 and 2:1 (Ag+/1) complexation of 1 were estimated to be ca. 7.9 and 13.9, respectively, by titration experiments using UV-vis spectrometry in methanol and chloroform (v/v, 9:1) solutions at 298 K.

Mole-Ratio-Dependent Reversible Transformation between 2:2 and Cyclic 3:6 Silver(I) Complexes with an Argentivorous Molecule.

A tetra-armed cyclen (L) with two substituted 3,5-difluorobenzyl and two substituted pyridine-4-yl methyl groups at the 1,4- and 7,10-positions of the cyclen ring as side arms was synthesized. When L was reacted with 1 equiv of the silver(I), dimetallo[3.3]paracyclophane-like 2:2 cyclic dimer, [Ag2(L)2](PF6)2, was obtained. The reaction of L with 2 equiv of silver(I) gave a 3:6 cyclic trimer, [Ag6(L)3(CH3CN)3](OTf)6·3CH3CN. Furthermore, reversible complexation between the 2:2 cyclic dimer and 3:6 cyclic trimer was confirmed by 1H NMR and the CSI mass in the addition of silver(I) or the [2.2.2]cryptand.

Pentacyclic Nano-Trefoil.

Tetra-armed cyclen (1) bearing two 4-(4'-pyridyl)benzyl and two 3,5-difluorobenzyl groups and its Ag+ complexes were prepared and structurally characterized. The complexes formed between 1 and Ag+ undergoes a reversible structural transformation between a 2:2 dimeric complex and a 3:5 pentacyclic trefoil complex with changes in the Ag+ /1 molar ratio. It was also revealed that the 3:5 trefoil complex could encapsulate benzene and [D6 ]benzene selectively in solid-state. The benzene-included structures are stabilized by C-H⋅⋅⋅F-C interactions between the benzene molecule and the ligand molecule.

1H NMR Study of a Chiral Argentivorous Molecule/Ag+ Complex: Assignment of Proton Signals of Four Aromatic Rings with Slightly Different Environments.

The proton signals at the 2'- and 6'-positions of the aromatic side arms of a silver(I) complex with a chiral tetra-armed cyclen ((S)-L2) are assigned by comparison with 1H NMR spectra and X-ray structure of Ag+ complexes with three analogues of (S)-L2: (S)-L23D having one benzyl group and three deuterium-substituted benzyl groups, (S)-L22D having two benzyl groups and two deuterium-substituted benzyl groups, and (S)-L2F having three benzyl groups and one 4'-fluorobenzyl group. An interaction factor is defined by using the X-ray structures. The chemical shift values of the proton signals in the aromatic side arms can be explained by using the interaction factors that are defined by the dihedral angles, the angles between two mean planes, and the CH···π distances from the X-ray data of the (S)-L2/Ag+ complex.

Argentivorous Molecules Exhibiting Highly Selective Silver(I) Chiral Enhancement.

We report the synthesis of chiral tetra-armed cyclens, having an asymmetric center at one side-arm, that show selective chiral enhancement with silver(I). When the chiral ligand forms a silver(I) complex, the side-arms cover the silver(I) incorporated into the cyclen. The asymmetric center controls the conformation of the side-arms in one direction, increasing the molar ellipticity of the CD spectrum. Chiral cyclens substituted with biphenyl groups exhibit large molar ellipticity values with strong exciton coupling effects.

Influence of the Molar Ratio and Solvent on the Coordination Modes of 1,7-Dibenzyl-4,10-bis(pyridin-4-ylmethyl)cyclen.

The synthesis of a tetra-armed cyclen (L) with two benzyl groups at the 1- and 7-positions and two pyridin-4-ylmethyl groups at the 4- and 10-positions as side arms and the solvent- and/or molar-ratio-dependent coordination modes in the formation of silver(I) complexes are reported. 1H NMR and cold-spray-ionization mass spectrometry studies suggest that a silver(I) complex with L gives different species depending on the molar ratio of silver ions used as the reactant. Furthermore, the conformation of cyclen in the one-dimensional (1D) coordination polymers, obtained using 2 equiv of silver(I), changes depending on the presence or absence of acetonitrile. When L was reacted with 1 and 2 equiv of silver(I) triflate in a mixed solvent system (CH2Cl2/CH3OH/CH3CN), a dimetallo[3.3]paracyclophane-like discrete cyclic dimer, [Ag2L2](OTf)2 (1), and a 1D coordination polymer, [Ag2L(OTf)2(CH3CN)]n (2), respectively, were obtained as single crystals. In the absence of acetonitrile, a zigzag 1D coordination polymer, {[Ag2L(OTf)]OTf·3CH2Cl2}n (3), was obtained when 2 equiv of silver(I) was used. Molar-ratio-dependent structural changes were not observed when L was reacted with AgBF4 or AgPF6 in the CH2Cl2/CH3OH/CH3CN mixed-solvent system. The solvent effect on the coordination modes can be explained by the coordination ability of the solvents toward the metal cation affecting the conformation of the cyclen.

Inclusion of alkyl nitriles by tetra-armed cyclens with styrylmethyl groups.

Synthesis of tetra-armed cyclens (2a-2e), with substituted styrylmethyl groups as side-arms, and their Ag+ complexes is reported. The Ag+ complex with a tetra styrylmethyl-armed cyclen (2a) incorporates alkyl nitriles in a pseudo-cavity formed by the four styrylmethyl side-arms. This prompted us to apply this system to the determination of the absolute configurations of chiral nitriles with low [α]D and low circular dichroism (CD) intensity. In the CD spectra of the 2a/Ag+ complex, (S)- and (R)-G1 did not show a specific Cotton effect, while when chiral nitriles were added to the 2a/Ag+ complex, drastic spectral changes were observed. The (S)-G1@2a/Ag+ system exhibited first a negative and then a positive Cotton effect, whereas the (R)-G1@2a/Ag+ system showed the mirror image of the Cotton effect of (S)-G1@2a/Ag+. We have, therefore, demonstrated a new technique for determining the absolute configurations of weak optical rotation molecules using the Ag+ complex with 2a.

Silver ion-induced chiral enhancement by argentivorous molecules.

Optically active tetra-armed cyclens with an asymmetric chiral centre in the cyclen moiety were synthesized and were shown to enhance chirality and control of enantiomers on complexation with Ag+. Binding studies of the Ag+ complex demonstrated that Ag+ preferentially interacts with electron-rich substituents over other aromatic substituents.

Synthesis and Aldose Reductase Inhibitory Activity of Botryllazine A Derivatives.

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).

Pillar[5]-bis-thiacrown: An Adaptive Tricyclic Host Selectively Recognizing an Organic Guest by Dimetalation.

Some biological receptors change their shapes and rigidity by metalation to recognize substrates precisely via adaptive guest binding process. Herein we present a semi-flexible tricyclic host molecule whose conformation is rigidified by dimetalation to uptake organic guests selectively. Considering two metal binding sites and an empty space between them, pillar[5]-bis-thiacrown (L) was synthesized. The tricyclic host L forms a disilver(I) complex [Ag2 L(NO3 )2 ], with an Ag⋅⋅⋅Ag separation of 9.976 Å. Binding studies based on 1 H NMR including 2D NOESY and DOSY experiments towards α,ω-dicyanoalkanes [CN(CH2 )n CN, n=2-6, shortly C2-C6] demonstrated that the dimetalated L, Ag2 L preferentially recognizes C2 over other guests than that of free L. Furthermore, the dimetalated the host only uptakes C2 in the presence of other guests. Crystal structures support the idea that the space between two silver(I) centers plays a decisive role on the selective guest binding forming an Ag-C2-Ag@L arrangement via the length-selective recognition. This work demonstrates the chemical example of the adaptive guest binding and presents a new perspective on the metallosupramolecules of pillararenes.

pseudo[1]Catenane-Type Pillar[5]thiacrown Whose Planar Chiral Inversion is Triggered by Metal Cation and Controlled by Anion.

Chiral inversion of single molecules has been a challenging task because chirality information controls structures and functions of various molecules, artificial nanostructures, DNA, and proteins. Herein we present a pseudo[1]catenane-type molecule whose planar chiral inversion is driven by a metal ion under the control of anions for the first time. Considering an in-out equilibrium of a fused thiacrown and the soft metal binding, pillar[5]thiacrown ( rac-L) was synthesized. Two planar-chiral enantiomers of rac-L ( in-pS-L and in-pR-L) were isolated and the absolute configuration was determined by circular dichroism and single crystal X-ray analysis. The in-pS-L recognizes Hg2+ to trigger the chiral inversion to out-pR-L, to our surprise; it takes place only in the presence of ClO4- or NO3- among the anions used. In the mercury(II) perchlorate complex solution, anion-exchange from ClO4- to I- or removal of Hg2+ by addition of S2- makes the system reversible. The crystallographic approach reveals that the anions act as coordination mode-directing species ( endo- or exo-coordination) which play a decisive role on the chiral inversion. For instance, the week coordinating ClO4- allows Hg2+ to locate inside the thiacrown ( endo-coordination) which causes the chiral inversion from in-pS-L to out-pR-L due to the expansion of the thiacrown unit upon endo-mode complexation. Oppositely, the strong coordinating I- takes Hg2+ out of the thiacrown ( exo-coordination) without large conformational changes of the thiacrown, resulting in no chiral inversion. A series of experimental works was also accomplished with the other enantiomer in-pR-L, which afforded identical results. Consequently, the chiral inversion is governed by steric factors that arise from the coordination modes depending on the coordinating ability of anions. This work demonstrates the first chiral inversion induced by combination of metal ion and anion and presents a new perspective on the supramolecular coordination chemistry of pillar[ n]arenes.

Thermal E/ Z Isomerization in First Generation Molecular Motors.

Determination of a thermal E/ Z isomerization barrier of first generation molecular motors is reported. Stable ( E)-1a directly converts to stable ( Z)-1c without photochemical E/ Z isomerization. The activation Gibbs energy of the isomerization was determined to be 123 kJ mol-1 by circular dichroism spectral changes. Density functional theory calculations show that ( Z)-1c is ∼11.4 kJ mol-1 more stable than ( E)-1a.

C-HCl- hydrogen bonds in solution and in the solid-state: HgCl2 complexes with cyclen-based cryptands.

Structural evidence is reported for C-HCl- hydrogen bonds in solution and in the solid state of HgCl2 complexes with cyclen-based cryptands. These cyclen-based cryptands (1) and (2) are bridged by di- and triethylene glycol units, respectively, between two aromatic rings. The X-ray structure indicates that the 2/HgCl2 complex contains an acetonitrile molecule in the cavity.