Functionalized and Partially or Differentially Bridged Resorcin[4]arene Cavitands: Synthesis and Solid‐State Structures

We report the synthesis and structural characterization of modified Cram‐type, resorcin[4]arene‐based cavitands. Two main loci on the cavitand backbone were selected for structural modification: the upper part (wall domain) and the lower part (legs). Synthesis of unsymmetrically bridged cavitands with different wall components (i.e., 7, 8 , and 14 – 18 ) was performed by stepwise bridging of the four couples of neighboring, H‐bonded OH‐groups of octol 1a (Schemes 1, 2, 4, and 5). Cavitands with modified legs (i.e., 20, 24, 27 , and 28 ), targeted for surface immobilization, were synthesized by short routes starting from suitable aldehyde starting materials incorporating either the fully preformed leg moieties or functional precursors to the final legs (Schemes 7–10). The new cavitand substitution patterns described in this paper should enable the construction of a wide variety of functional architectures in the future. X‐Ray crystallography afforded the characterization of cavitands 2c (Fig. 3) and 24 (Fig. 7) in the vase conformation, with 2c featuring a well‐ordered CH₂Cl₂ guest molecule in its cavity. A particular highlight is the X‐ray crystal‐structure determination of octanitro derivative 19 (Scheme 6), which, for the first time, shows a cavitand, lacking substituents in the ortho‐position to the two O‐atoms of the four resorcinol moieties, in the kite‐conformation (Fig. 5).     

Clathrate tetraldehyde cavitand: single-crystal structure and NMR study

The tetraldehyde cavitand, C₁₀₀H₈₈O₂₀, was synthesised as the penultimate stage of a procedure to obtain cavitand-capped porphyrins. The complete structural characterisation was performed by single-crystal X-ray diffraction studies, NMR and IR spectroscopy. The inclusion phenomena of the solvent molecules were confirmed using NMR spectroscopy. The structure is the first example of a clathrate having an aromatic tetraldehyde cavitand grown as a single crystal with acetonitrile at the lower rim of the molecule and methanol at the upper rim of the molecule.     

Expanding cavitand chemistry: the preparation and characterization of [n]cavitands with n>=4

The preparation of cavitands composed of 4, 5, 6, and 7 aromatic subunits ([n]cavitands, n=4-7) is described. The simple, two-step synthetic procedure utilized readily available starting materials (2-methylresorcinol and diethoxymethane). The two cavitand products having 4 and 5 aromatic subunits exhibited highly symmetric cone conformations, while the larger cavitands (n = 6 and 7) adopt conformations of lower symmetry. 1H NMR spectroscopic studies of [6]cavitand and [7]cavitand revealed that these hosts undergo exchange between equivalent conformations at room temperature. The departure of these two cavitands from cone conformations is related to steric crowding on their Ar-O-CH2-OAr bridges and is predicted by simple molecular mechanics calculations (MM2 force field). X-ray diffraction studies on single crystals of the [4]cavitand, [5]cavitand, and [6]cavitand hosts afforded additional experimental support for these conclusions.     

Synthesis and NMR elucidation of novel amino acid cavitand derivatives

The synthesis of seven novel protected amino acid cavitands is reported. All have four pendant n-undecyl chains and ‘headgroups’ connected by a two-carbon spacer at four positions on the aromatic rings. The amino acids employed are glycine, alanine, phenylalanine, leucine, proline, tryptophan, serine, glutamine and lysine. The structures of the compounds were elucidated using one- and two-dimensional NMR techniques, which verified that all tetra-substituted cavitands have symmetrical C_4v conformation. This is the first example of a complete study for amino acid cavitand derivatives.     

Structural Studies of Self‐Folding Cavitands

Resorcinarene‐based cavitands 1a – c fold into a deep open‐ended cavity by means of intramolecular hydrogen bonds in both apolar solutions and the solid state. The X‐ray crystal‐structure analysis of cavitand 1a features a seam of secondary amide C=O⋅⋅⋅H−N interactions that bridge adjacent rings and are held in place by intra‐annular hydrogen bonds. This results in a cavity of 9.2×7.0 Å dimensions. The arrangement of the amides in 1a – 1c is cycloenantiomeric, with clock‐ and counterclockwise orientation of the head‐to‐tail amide sequence. Interconversion rates of the two enantiomers are controlled by solvent polarity: the rate is slow on the NMR time‐scale in aromatic solvents and CDCl₃, but fast in (D₆)acetone. The ¹H‐ and ¹³C‐NMR‐spectral analysis is in agreement with the crystallographic data. Chiral cavitand 1b with eight HN−C(O)−C*HMeEt ((+)‐(S)) groups on its upper rim exists as two cyclodiastereoisomers (in a ca. 3 : 1 ratio) in apolar solution. A `library' of 512 diastereoisomeric cavitands 1c is obtained as a mixture by using the corresponding racemic acid chloride.     

Synthesis and characterization of upper and lower rim functionalized [6]cavitands

A [6]cavitand has been selectively derivatized on both the lower and upper rims. On the lower rim, two out of six potential sites were oxidized to produce a 1,4 substituted [6]cavitand bisketone, which was converted to a corresponding diol as well as a bisacetate [6]cavitand. The crystal structures of the bisketone and the diol were solved. On the upper rim, all six ArCH(3) groups were selectively brominated to ArCH(2)Br groups to produce the hexabromomethyl [6]cavitand, which was converted to the corresponding hexabenzylthiol and hexabenzylthioacetate [6]cavitands. The conformational properties of all compounds are discussed.     

Rim,Side Arms,and Cavity: Three Sites for the Recognition of Anions by Tetraazolium Resorcinarene Cavitands

Two tetrabenzoimidazolium‐resorcinarene cavitands were prepared and used for the recognition of chloride, bromide, iodide, cyanide, nitrate, perchlorate, hexanoate, benzenesulfonate, and p‐toluenesulfonate. Binding affinities of the two cavitands were determined by ¹H NMR titration and computational analysis. The observed spectral changes were related to specific interaction sites, which were supported by the computational studies. In the case of the C2?H tetrabenzoimidazolium‐resorcinarene, the recognition region of the inorganic anions and hexanoate was located at the rim of the cavitand, although chloride and bromide also interacted with the aromatic C?H bonds located between adjacent arms of the cavitand. By contrast, the recognition of the two anions with an aromatic ring (benzenesulfonate and p‐toluenesulfonate) results from encapsulation of the aromatic part of the anions inside the hydrophobic cavity of the host. In the case of the C2?Me tetrabenzoimizazolium‐resorcinarene receptor, the ability of the molecule to bind all inorganic anions and hexanoate was suppressed, but the receptor maintained its ability to strongly bind benzenesulfonate and p‐toluenesulfonate. This is interpreted in terms of suppression of the ability of the cavitand to form hydrogen bonds at the rim of the molecule due to replacement of the C2?H proton by a methyl group, while the hydrophobic pocket of the molecule maintains its binding abilities.     

Cavitand-porphyrins.

The synthesis and characterization of new nanoscale container molecules 7 and 8 are described. They are covalent hybrids of deepened, self-folding cavitands and metalloporphyrins. In receptor 7, the Zn-porphyrin wall is directly built onto the cavitand skeleton. Host 8 features a large unimolecular cavity containing two cavitands attached with the Zn-porphyrin wall. Its dimensions, approximately 10 x 25 A, place it among the largest synthetic hosts prepared to date. A series of adamantyl- and pyridyl-containing guests 14-20 of various lengths were prepared and used to determine the hosts' binding abilities in solution using UV/vis and (1)H NMR spectroscopy. Intramolecular hydrogen bonds at the upper rims of the cavitands resist the unfolding of the inner cavities and thereby increase the energetic barrier to guest exchange. The exchange is slow on the NMR time scale (at < or =300 K), and kinetically stable complexes result. When the cavities and metalloporphyrins participate simultaneously in the binding event, very high affinities for guests are found (-DeltaG295 up to 10 kcal x mol(-1) in toluene), to which the porphyrin fragments contribute significantly (-DeltaG295 up to 6 kcal x mol(-1)). The pairwise selection of two different guests by molecular container 8 is reported, and the termolecular complex formed raises the possibility of metal-catalyzed bimolecular reactions in these containers.     

A New Tubular Arrangement of a Dimethylsilyl Bridged Calix[4]resorcinarene

Abstract

The functionalization of calix[4]resorcinarene 1 (R ₁=H, R ₂=Me) with dichlorodimethylsilane leads to the formation of the dimethylsilyl-bridged cavitand 2 which, during the work up of the reaction product, encapsulates a molecule of water 2·H₂O crystallizes in the C2/c system (a = 23.892 Å, b = 8.493 Å, c = 43.035 Å, β = 100.05°, reflections: 5385, 2376 (F>4.0 [sgrave](F)), R=9.17%, calculated density=1.213 Mg/m³) with eight molecules per unit cell. The main feature of the crystal packing is the alternating pairs of up-down disposed cavitands along the c direction and well developed columns in the b direction. The molecules of water are completely encapsulated, but there are some close contacts with the methylene bridge from the upper molecule. Molecular orbital calculations show that the lowest energy conformer of cavitand 2 is that with all four silicon atoms oriented inward and the energies of the other conformers are so high that they cannot be accessed at normal temperature. Ab initio calculated electrostatic potentials correlate well with the relative positions of the cavitands in the crystal structure.     

Recognition of C60 by tetra- and tri-quinoxaline cavitands

Abstract

Molecular recognition of C₆₀ fullerene by two cavitands, bearing four and three quinoxaline walls, is reported here. Fluorescence titrations show the recognition ability of the receptors with high binding constant values. The formation of a stable 1:1 supramolecular complex was also confirmed by DOSY, EI-MS and X-ray analysis. The crystal structure analysis of tetraquinoxaline cavitand and C₆₀ shows a crystal packing, where C₆₀ molecules are intercalated between bilayers of cavitand molecules, on the ideal fourfold symmetry axis of the receptor, and are arranged in a zigzag motif.     

Versatile Syntheses of Hemi‐Cryptophanes and a Metallo‐Cryptophane from a Hexa‐Functionalized C3v‐Symmetrical Tribenzotriquinacene (TBTQ) Derivative

A number of three‐fold C_3v‐symmetrical tribenzotriquinacene (TBTQ) cavitands were synthesized by a “metamorphosis‐to‐half” strategy, employing six‐fold etherification reactions between the hexakis(chloromethyl)‐TBTQ intermediate 2 a and various 5‐functionalized resorcinols. X‐ray structure analyses of single crystals of the cavitands revealed limited rotational flexibility of the resorcinol bridging units, which enables an apical, nearly co‐axial orientation of the three functional groups and, as a consequence, the construction of nanoscale cage‐like molecules via covalent or coordination bonding. On this basis, two TBTQ‐based hemicryptophanes were prepared from the TBTQ cavitands via covalent bond formation in good yields. A dumbbell‐shaped TBTQ‐based metallo‐cryptophane was also synthesized in 34 % yield by a solvothermal reaction between cadmium nitrate and two equivalents of the TBTQ‐cavitand triacid, as confirmed by single‐crystal X‐ray diffraction and MALDI‐ToF mass spectrometry.     

Me3Ga-mediated alkynylation of aldehydes

The trimethylgallium reagent was found to promote the addition of phenylacetylene to various aromatic and aliphatic aldehydes. This reaction was efficiently carried out in anhydrous CH₂Cl₂ at room temperature under mild conditions and the corresponding propargylic alcohols were obtained in good to excellent yields up to 98%.     

Cavitands as Reaction Vessels and Blocking Groups for Selective Reactions in Water

The majority of reactions currently performed in the chemical industry take place in organic solvents, compounds that are generally derived from petrochemicals. To promote chemical processes in water, we examined the use of synthetic, deep water‐soluble cavitands in the Staudinger reduction of long‐chain aliphatic diazides (C₈, C₁₀, and C₁₂). The diazide substrates are taken up by the cavitand in D₂O in folded, dynamic conformations. The reduction of one azide group to an amine gives a complex in which the substrate is fixed in an unsymmetrical conformation, with the amine terminal exposed and the azide terminal deep and inaccessible within the cavitand. Accordingly, the reduction of the second azide group is inhibited, even with excess phosphine, and good yields of the monofunctionalized products are obtained. In contrast, the reduction of the free diazides in bulk solution yields diamine products.     

Conformational Switching of Resorcin[4]arene Cavitands by Protonation,Preliminary Communication

The synthesis of the quinoxaline‐bridged resorcin[4]arene cavitand 1 was accomplished from 2‐[3,5‐di(tert‐butyl)phenyl]acetaldehyde via formation of the intermediate octol 2 . Such cavitands are known to occur in an open `kite' conformation at low temperature (<213 K) but to adopt a `vase' conformation at elevated temperatures (>318 K). We discovered that protonation of cavitand 1 at room temperature by common acids, such as CF₃COOH, also causes reversible switching from `vase' to `kite', and that this conformational change can be conveniently monitored by both ¹H‐NMR and UV/VIS spectroscopy.     

Cavitands bearing four fluorophores

The synthesis of novel cavitands containing four fluorophores [tert-butoxycarbonyl protected 2,2′-bis(furyl)benzidine (t-BOC FurylBz) or 5,5′-bis(4-aminophenyl)-2,2′-bifuryl (t-BOC PFDA)] and ionophoric functional groups on the upper rim is reported. The cavitands bearing the four fluorophores emit blue light photoluminescence. In particular, the cavitand containing PFDA moieties exhibits a high photoluminescence quantum yield.     

Effect of Temperature and Solvent on the Structure of Amide Cavitands

Conformational changes of amide cavitands A – C were investigated at varied temperatures and in several solvents. While cavitands A and B , with comparatively smaller substituents such as Et and ⁱPr, were always in vase conformation in non‐polar solvents such as CDCl₃, CD₂Cl₂, (D₈)THF, and C₆D₆, their thermoswitching (vase to kite) was observed in polar solvents such as (D₇)DMF and (D₆)DMSO or in the presence of acid (TFA) and H‐bonding inhibitor (TFE). Intra‐ and interannular H‐bonds of A and B were clearly observed by low‐temperature ¹H‐NMR spectra in CDCl₃. No conformational change of cavitand C with bigger substituent (^tBu) was observed under any tested temperature range and in polar or non‐polar solvents; C was always in the kite conformation.     

Hydrogen‐Bond and Metal–Ligand Coordination Bond Hybrid Supramolecular Capsules: Identification of Hemicapsular Intermediate and Dual Control of Guest Exchange Dynamics

Hybrid supramolecular capsules self‐assemble by simultaneously forming hydrogen and metal–ligand coordination bonds on mixing a C₂‐symmetrical cavitand (calix[4]resorcinarene‐based cavitands with ureide and terminal 4‐pyridyl units) with platinum or palladium complexes ([Pt(OTf)₂] or [Pd(OTf)₂] with chelating bisphosphines) in 1:1 ratio. Hemicapsular assemblies formed in the presence of excess amounts of cavitand relative to the platinum or palladium complexes are identified as intermediates in the above self‐assembly process by 2D‐NOESY spectroscopy. External‐anion‐assisted encapsulation of a neutral guest, 4,4′‐diiodobiphenyl, inside the hybrid supramolecular capsules accompanied conformational changes in the hydrogen‐bonding moieties. The in/out exchange ratio of the encapsulated guest depends on the bite angle of the bisphosphine ligand. Addition of DMSO accelerates guest exchange by weakening the hydrogen bonds in the encapsulation complex. Therefore, variations in the structure of the metal complex and amount of polar solvent exert dual control on the dynamics of the guest exchange.     

Metal-free synthesis of calixsalen-type cavitands for the recognition of fluoride ion

Novel calixsalen-type cavitands have been synthesized using metal-free synthesis from simple and inexpensive materials, such as ethylenediamine and 5,5′-methylene-bis-salicylaldehyde derivatives. The cavitand 1 containing salen functionality recognizes fluoride ion. Fluoride ions switch on fluorescence on binding with the cavitand 1. Substitution on bis-salicylaldehyde part of calixsalen-type cavitand shows change in recognition behavior. On the attachment of electron withdrawing substituent, such as nitro group, the cavitand lost its fluorescence properties but proved to be a better colorimetric probe showing marked color change from pale yellow to red on addition of tetrabutyl ammonium salt of fluoride ion to the solution of cavitand. The nitro substituted cavitand is highly sensitive and selective for fluoride anion and hence is a promising candidate for development of colorimetric chemosensor. The binding of the cavitands with fluoride ion is investigated using ¹H NMR-titration experiments.     

Tetrathiafulvalene (TTF)‐Bridged Resorcin[4]arene Cavitands: Towards New Electrochemical Molecular Switches

We report the synthesis of novel resorcin[4]arene‐based cavitands featuring two extended bridges consisting of quinoxaline‐fused TTF (tetrathiafulvalene) moieties. In the neutral form, these cavitands were expected to adopt the vase form, whereas, upon oxidation, the open kite geometry should be preferred due to Coulombic repulsion between the two TTF radical cations (Scheme 2). The key step in the preparation of these novel molecular switches was the P(OEt)₃‐mediated coupling between a macrocyclic bis(1,3‐dithiol‐2‐thione) and 2 equiv. of a suitable 1,3‐dithiol‐2‐one. Following the successful application of this strategy to the preparation of mono‐TTF‐cavitand 3 (Scheme 3), the synthesis of the bis‐TTF derivatives 2 (Scheme 4) and 19 (Scheme 5) was pursued; however, the target compounds could not be isolated due to their insolubility. Upon decorating both the octol bowl and the TTF cavity rims with long alkyl chains, the soluble bis‐TTF cavitand 23 was finally obtained, besides a minor amount of the novel cage compound 25a featuring a highly distorted TTF bridge (Scheme 6). In contrast to 25a , the deep cavitand 23 undergoes reversible vase → kite switching upon lowering the temperature from 293 to 193 K (Fig. 1). Electrochemical studies by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) provided preliminary evidence for successful vase → kite switching of 23 induced by the oxidation of the TTF cavity walls.     

New cavitand derivatives bearing four coumarin groups as fluorescent chemosensors for Cu and recognition of dicarboxylates utilizing Cu complex

New cavitand derivatives (1, 2) bearing four coumarin groups were synthesized, and the binding properties of these cavitands towards metal ions were examined through their fluorescent changes. Cavitand 1 effectively recognized the Cu²⁺ ions among the metal ions examined. The recognition of cavitand 1-Cu²⁺ with dicarboxlyates is also described.