New water-soluble iminecalix[4]arene with a deep hydrophobic cavity

We report the synthesis of a new water-soluble iminecalix[4]arene host 4c with a deep hydrophobic cavity. The negatively charged four carboxylate functions on the top of the cavity play a major role in the recognition of charged molecular species. The ¹H NMR titration experiments revealed that host 4c binds with cationic (10-12) and neutral guests (6-9) in water with high binding constants in the order of 10⁴-10⁵ M⁻¹. Cationic guest 9 showed highest binding constant of 2.81 × 10⁵ M⁻¹ with host 4c amongst all tested guests. Selectivity over anionic guests (13-17) is established by the presence of negative charges at the top of the deep hydrophobic cavity, as guests 15 and 17 were not recognized by host 4c. Neutral pyridine derivatives with hydrophobic chains at para positions showed high binding constants of 6.02 × 10⁴-2.23 × 10⁵ M⁻¹. The data obtained for the recognition of the guests by host 4c revealed that the ionic as well as the hydrophobic-hydrophobic interactions are crucial in the molecular recognition in aqueous medium.     

Binding studies of tetrathiafulvalene-calix[4]pyrroles with electron-deficient guests

The neutral meso-octamethylporphyrinogen derivative, tetraTTF-calix[4]pyrrole 1 (TTF=tetrathiafulvalene), acts as a multi-faceted receptor in that it interacts with an assortment of different guests in different ways. The conformation of receptor 1 can be reversibly switched between the 1,3-alternate conformation (i.e., 1, Fig. 1) and the cone conformation (i.e., 1·Cl⁻, Fig. 2) by the repetitive addition of chloride and sodium ions. In this paper, the results of detailed and systematic complexation studies involving both 1 and its chloride-bound complex, 1·Cl⁻, with a variety of guests are described. Receptor 1 binds quasi-planar nitroaromatic guests in its 1,3-alternate conformation, while release of these guests takes place upon addition of chloride anions. On the other hand, spherical fullerene guests are strongly bound by 1·Cl⁻. Finally, it was found that a bidentate guest, consisting of a quasi-planar 2,5,7-trinitro-9-dicyanomethylenefluorene moiety tethered to a spherical C₆₀ fullerene, could be recognized by receptor 1 in either its 1,3-alternate or its chloride-bound cone conformation, albeit through very different binding modes.     

A novel strapped porphyrin receptor for molecular recognition

A novel strapped porphyrin receptor Zn1, in which two electron-rich bis(p-phenylene)-34-crown ether-10 units are incorporated, has been designed and synthesized from the newly developed intermediate 7 for investigating new chemistry of molecular recognition. ¹H NMR and UV-Vis studies revealed that Zn1 displays relatively weak binding abilities to neutral electron deficient naphthalene-1,8,4,5-tetracarboxydiimide (NDI) derivatives 13 (no simple complexing stoichiometry was observed), 19 (K_a=48(±5) M⁻¹) and 30 (K_a=46(±5) M⁻¹) in chloroform-d, strong binding ability to pyridine derivative 25, (K_a=1.5(±0.12)×10³ M⁻¹) in chloroform, moderately strong binding ability to tetracationic compound 35·4PF₆ (K_a=475(±50) M⁻¹) in acetone-d₆, and very strong binding affinity to compound 22 (K_a=6.5(±0.7)×10⁵ M⁻¹), which consists of one pyridine and two NDI units, in chloroform. Remarkable cooperative effect of the intermolecular metal-ligand coordination and donor-acceptor interactions in complex Zn1·22 was observed by comparing the complexing behaviors between Zn1 and the appropriately designed guests. Complex Zn1·22 possesses an unique three-dimensional tri-site binding feature. For comparison, the complexing affinity of 1 toward compounds 13, 19, and 30 in chloroform-d and 35·4PF₆ in acetone-d₆ has also been investigated and the binding patterns in different complexes were explored. The results demonstrate that strapped porphyrin derivatives are ideal precursors for constructing new generation of three-dimensional multi-site artificial receptors for molecular recognition and host-guest chemistry.     

Molecular recognition of biotin, barbital and tolbutamide with new synthetic receptors

We have measured, by means of NMR titrations, the binding constants for the complexes between hosts N,N′-bis(6-methylpyridin-2-yl)-1,3-benzenedicarboxamide (7) and 4-chloro-N,N′-bis(6-methylpyridin-2-yl)-2,6-pyridinedicarboxamide (8, hydrated) with biotin methyl ester (1), N,N′-dimethylurea (2), 2-imidazolidone (3), N,N′-trimethylenurea (4), barbital (5) and tolbutamide (6) as guests. Molecular Mechanics calculations (Monte Carlo Conformational Search, AMBER and OPLS force fields, MacroModel v.8.1) on the complexes formed between the foregoing guests and hosts 7 and 8, comparatively with 4-oxo-N,N′-bis(6-methylpyridin-2-yl)-1,4-dihydro-2,6-pyridinedicarboxamide (9a) have been carried out in order to determine the correlation between experimental and theoretical results and to understand the behaviour of the designed new hosts. Finally we have performed single point DFT [B3LYP/6-31G(d,p)] calculations on the optimised Molecular Mechanics geometries for the complexes between hosts 7-9 and water.     

Studies on the Suzuki reaction on methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroaryl-pyrrolidin-2-carboxylate derivatives: synthesis of N-aryl modified monocyclic γ-lactam derivatives in search for newer antibacterial agents

A large number of novel N-aryl modified monocyclic γ-lactam derivatives have been prepared via Pd(0) catalyzed heteroarylation in the N-aryl part of (±) cis and (±) trans γ-lactam carboxylate derivatives 3(a–f) and 6(a–f), respectively, with furan-2-boronic acid and thiophen-2-boronic acid. (±) cis Methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroarylpyrrolidin-2-carboxylate derivatives 3(a–f), were prepared in good yields from 1(a–f) via hydrolysis, stereoselective decarboxylation, followed by esterification. Corresponding trans isomers 6(a–f) were prepared by the standard method already reported by us.     

New receptors for anions in water: Synthesis, characterization, X-ray structures of new derivatives of 5,11,17,23-tetraamino-25,26,27,28-tetrapropyloxycalix[4]arene

Syntheses and characterization of ten new compounds from the calixarene family, cone - 5,11,17,23- tetrakis(2-pyridylmethylamino)-25,26,27,28-tetrapropyloxycalix[4]arene 4a; cone - 5,11,17,23-tetrakis(3-pyridylmethylamino)-25,26,27,28-tetrapropyloxycalix[4]arene 4b; cone - 5,11,17,23-tetrakis(4-pyridylmethylamino)-25,26,27,28-tetrapropyloxycalix[4]arene 4c; cone - 5,11,17,23-tetrakis(ferrocenylmethylamino)-25,26,27,28-tetrapropyloxycalix[4]arene 4d; cone - 5,11,17,23-tetrakis(2-pyridylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3a; cone - 5,11,17,23-tetrakis(3-pyridylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3b; cone - 5,11,17,23-tetrakis(4-pyridylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3c; cone - 5,11,17,23-tetrakis(ferrocenylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3d; cone - 5,11,17,23-tetrakis(2-thienylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3e and cone - 5,11,17,23-tetrakis(2-pyrrolylmethimino)-25,26,27,28-tetrapropyloxycalix[4]arene 3f are reported. The target compounds 4a-4d were designed to form complexes with anions based on hydrogen bonds and electrostatic interactions in acidic aqueous solutions and the interaction constant 1770 mol⁻¹ dm³ of a 1:1 complex was obtained for the interaction of 4c with sulfate anion in 5 × 10⁻³ M aqueous HCl. The solid state structures of the compounds 3b, 3e and 3f were determined, their stereochemistry and the stereochemistry of the calix[4]arene frame is generally discussed. Raman, infrared and UV-vis spectra of the target compounds and some intermediates are reported, too.     

A close inspection of Ag(I) coordination to molecular baskets. A study of solvation and guest encapsulation in solution and the solid state

Four molecular baskets 1-4, each comprising a modular bowl-shaped platform and a set of distinctive aromatic gates, were synthesized. The gates were made to incorporate a nitrogen heteroatom at different positions, as in 2-4, or without a coordinating nitrogen, as in 1 (Fig. 1). For polydentate 3 and 4, the location of the nitrogen was revealed to have an effect on directing the basket's coordination to Ag(I) cation, and subsequent folding to enclose space. The folded geometries were shown to encompass a helical, Ag(I):3, or C_3v/C_2v symmetrical, Ag(I):4, dynamic arrangement of the gates (from density functional theory). For 2 and 1, however, the presence of Ag(I) caused the sole formation of oligomers and the absence of coordinating interactions, respectively. Variable temperature (VT) ¹H and ¹⁹F NMR measurements of Ag(I):3 did not provide direct evidence for the solvation of its inner space and the encapsulation of the BF_4⁻ counterion. Moreover, CH₃CN or CH₃NC substrates were not found inside of Ag(I):3. The finding is in contrast with the behavior of Cu(I):3, which is known to encapsulate these guests. The intriguing guest selectivity was accounted for by small structural and electronic differences of Ag(I)/Cu(I) folded baskets. The X-ray solid-state structural studies of 2, 3, and 4 revealed the basket's capacity to fill its inner space with small compounds. Thus, 3 was found with an ordered molecule of chloroform, while 4 contained molecules of CH₃OH and H₂O. The basket selectivity for enclosing and positioning guests, in the solid state, was deduced to be guided by their size and weak host-guest and guest-guest noncovalent interactions.     

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f subjected to hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a-6e or 7. Direct ring-closure of 6a-6e with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a-9e.     

Water-soluble aminocalix[4]arene receptors with hydrophobic and hydrophilic mouths

We report the new water-soluble aminocalix[4]arene hosts 1 and 2 with deep hydrophobic cavity facilitating hydrophobic mouth and hydrophilic mouth, respectively. The ¹H NMR titrations revealed that host 1 shows high selectivity for neutral guests 9 and 10, with log K of 4.2 and 4.6, respectively. The host 2 shows log K of 4.9 for binding with guest 15. Moreover, the binding ability of the host 2 for guest 14 is stronger by a factor of 1000 than that of the host 1.     

A clay-mediated, regioselective synthesis of 2-(aryl/alkyl)amino-thiazolo[4,5-c]carbazoles

The 3-aminocarbazoles 1a-e were condensed with phenyl and benzyl isothiocyanates on montmorillonite K10 clay or TLC-grade silica gel at room temperature to furnish efficiently the N-phenyl and N-benzylthioureidocarbazoles, 2a-e and 2f, respectively, within minutes. When adsorbed on montmorillonite K10 clay impregnated with para-toluene sulfonic acid (1:1, w/w) and heated at 60-70 °C, 2a-e and 2f furnished the 2-anilino and 2-benzylaminothiazolo[4,5-c]carbazoles, 3a-e and 3f, respectively, regioselectively in high yields. The cyclisation was also effective for the N-methylthioureidocarbazoles 2g-i.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Macrocycles with two exclusive hydrogen-bonding modes

A series of large, 44-membered macrocycles 7a-e were synthesized and characterized, which display two different diagonal binding modes. The unsubstituted macrocycle 7a strongly binds naphthalene-2,6-dicarboxylate through hydrogen bonds with the association constant (K_a ± 15%) of 4500 M⁻¹ in 40% (v/v) CD₃CN/CDCl₃ at 23 ± 1 °C. Introduction of an electron-withdrawing substituent (Cl) at all four corners increases the binding affinity (22,000 M⁻¹ for 7b), while that of an electron-donating substituent (pyrrolidinyl) greatly decreases it (150 M⁻¹ for 7c). The same propensity has been observed with macrocycles 7d and 7e bearing different substituents at two diagonal corners, suggesting that the relative population of the binding modes would be modulated by controlling the electron density of the aromatic ring.     

One-pot synthesis of macrocyclic compounds possessing two cyclobutane rings by sequential inter- and intramolecular [2+2] photocycloaddition reactions

Sensitized photocycloaddition reactions of 6,6′-dimethyl-4,4′-[1,3-bis(methylenoxy)phenylene]-di-2-pyrone (1) with electron-poor α,ω-diolefins such as ethylene diacrylate (2a) and polyoxyethylene dimethacrylates (2b-d) afforded site- and stereoselective macrocyclic dioxatetralactones (3a-d) and (4b) having 18- to 25-membered rings across the C5-C6 and C5′-C6′ double bonds, or C5-C6 and C3′-C4′ double bonds in 1, respectively. Similar photoreactions of 1 with electron-rich α,ω-diolefins such as poly(ethylene glycol)divinyl ether (2e and 2f) afforded crown ether-type macrocyclic compounds (5e and 5f) having 18- and 21-membered rings across the C3-C4 and C3′-C4′ double bonds in 1, respectively. The stereochemical features of 3b, 5e-xx, and 5e-nn were determined by the X-ray crystal analysis. The reaction mechanism was inferred by MO methods.     

Synthesis and characterization of boronates derived from non-symmetric amino-bis-phenols

The condensation of 2-[[(2-hydroxyphenyl)amino]methyl]-phenols (1a-1e) with different arylboronic acids led to 12 new monomeric boronates of the type 2-aryl-dibenzo[d,h]-6-aza-1,3-dioxa-2-boracyclononene (2a-2l). The boronates were characterized by ¹H-, ¹³C-, ¹¹B- and 2D-NMR experiments, FT infrared, mass spectra and elemental analyses. The stereochemistry of the H-N → B-Ph fusion is always cis, as established through the NMR spectra, as well as the X-ray structures of four boronates (2a, 2e, 2f and 2l). Hydrogen bonds between the amine proton and the oxygen ester of the five- membered ring are present in three X-ray structures (2a, 2e and 2f), while the supramolecular structure in the derivative possessing a primary amine (2l) is built up through the protons present in this moiety instead of the proton from the H-N → B-Ph fragment.     

Synthesis, structural characterisation and biological activity of novel N-(ferrocenylmethyl)benzene-carboxamide derivatives

A series of N-(ferrocenylmethyl)benzene-carboxamide derivatives (4a-f) have been synthesised by coupling ferrocenylmethyl amine 3 with benzoic acid and various substituted fluorobenzoic acids using the standard 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. All compounds were fully characterised using a combination of ¹H NMR, ¹³C NMR, ¹⁹F NMR, DEPT-135, ¹H-¹H COSY and ¹H-¹³C COSY (HMQC) spectroscopy and electrospray ionisation mass spectrometry (ESI-MS). The compounds 4a, 4d, 4e and 4f exhibited cytotoxic effects on the MDA-MB-435-S-F breast cancer cell line. Single crystal X-ray crystallographic data for 4d is also presented.     

‘Two-point’-bound supramolecular complexes from semi-rigidified dipyridine receptors and zinc porphyrins

Two linear compounds 1 and 2 have been designed and synthesized as new receptors for zinc porphyrins. Both compounds consist of two folded aromatic amide moieties, which are connected with an acetylene linker in 1 or directly in 2. The rigid conformations of their folded moieties are stabilized by intramolecular tri-centered hydrogen bonding, while the whole molecule adopts a ‘S’- or ‘C’-styled conformation depending on the relative orientation of the two rigid moieties. Two pyridine units are introduced at the ends of 1 and 2 for the complexation of zinc porphyrin guests. Although the ¹H NMR investigation indicated that both compounds can bind two zinc porphyrin guests at high concentrations (≥5 mM) in chloroform, the UV-vis studies revealed that, at low concentration of 1 and 2 (4 μM), both compounds complex one zinc porphyrin guest to form structurally unique ‘two-point’-bound 1:1 complexes. The association constants of the 1:1 complexes have been determined with the UV-vis titration experiments.     

Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

The synthesis of atropisomeric 2-substituted benzamides 2a-e, 3a-e, and 4a-e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic ¹H NMR spectroscopic studies of benzamides 2b-d, 3b-d, and 4b-d indicate that only two of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal mol⁻¹. Benzamides ArCON[(S)-phenethyl]₂ (2e, 3e, and 4e), exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal mol⁻¹. The highest rotation barriers were observed for the ortho-nitro derivatives 2a-e. Molecular calculations at the semiempirical level (PM3MM) gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal mol⁻¹, respectively, which are comparable to the experimental values.     

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximides with alkynes

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximide 1 with phenylacetylenes 2a-2c, cyclopropylacetylene 2d, diphenylacetylenes 2e-2f and 1-phenylpropyne 2g were investigated. In the case of phenylacetylenes 2a, 2b and cyclopropylacetylene 2c, photoreaction with 1 takes place at the naphthalene C(1)C(2) bond to give the cyclobutene products. For 4-methoxyphenylacetylene 1c, the cyclobutene 3c is obtained together with the 4-benzo[a]thebenidinone 4c derived from a primary oxetene product formed by [2+2] addition of the imide carbonyl with the alkyne. Similar to 2c, photocycloaddition of 1 with 2e and 2f gave the cyclobutenes 7e, 7f, 8f and the 4-benzo[a]thebenidinone products 9e, 9f and 10f, respectively, derived from the corresponding oxetenes. Photoreaction of 1 with 2g gave cyclobutene 7g and benzo[a]thebenidinone 9g. Sensitization experiment and internal heavy atom effect study showed that these reactions proceed from the ππ* singlet excited state of 1. Estimation of the free energy change for electron transfer between ¹1* and the alkynes and the calculation of charge and spin density distribution in the anion radical of 1 and the cation radical of the alkynes suggested that the cyclobutene products are formed by direct [2+2] cycloaddition of ¹1* with the alkyne, while the formation of the oxetene products is the result of electron transfer interaction between ¹1* and the alkyne. The regioselectivity in the oxetene formation is accounted for by charge and spin density distribution in the anion radical of 1 and the cation radical of the alkyne.     

Three-step pathway towards bis(1,2,3-triazolyl-γ-propylsilatranes) as Cu fluorescent sensor,via ‘Click Silylation’

A series of substituted aniline derivatized bis(1,2,3-triazolyl-γ-propylsilatranes) 3a–3f were designed in good yield from their triethoxysilane analogues via Cu(I) ‘Click Silylation’. All the silatranes 3a–3f were characterized by IR, NMR (¹H, ¹³C) and HRMS studies. All these compounds were explored for their thermal stability by thermogravimetric analysis (TGA)/differential thermal analysis (DTA)/differential scanning calorimetry (DSC) study and electronic properties by UV–vis spectroscopy and fluorescence study. The binding of silatranes 3a–3f to Cu²⁺ ion proves them to be good chemosensor. These silatranes were subjected to time dependent hydrolysis under normal atmospheric conditions. IR spectroscopic data support hydrolytic instability of 3a, 3c and 3e.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).