Thiourea-linked upper rim calix[4]arene neoglycoconjugates: synthesis,conformations and binding properties

The thiourea group has been exploited to link two or four carbohydrate units at the upper rim of tetrapropoxycalix[4]arene derivatives in the cone conformation. Two synthetic methodologies were used, the first one consisting of the condensation of di- and tetraminocalix[4]arenes with the isothiocyanate of monosaccharides in dry CH2Cl2 at room temperature and the second one exploiting the condensation of an aminolactoside with a calixarene isothiocyanate. The first method allows the glycoconjugates to be obtained in 75-80% overall yields. The disfunctionalized derivatives exist in a closed flattened cone conformation in CDCl3 and CD3OD due to the formation of intramolecular hydrogen bonds involving the thiourea groups which are broken in DMSO-d6 to give an open flattened cone conformation. The thiourea groups act not only as linkers but also as binding units for anionic substrates as evidenced by solution 1H NMR and ESI-MS experiments. Turbidimetric analysis indicates that the tetraglucoside and tetragalactoside clusters give specific interactions with Concanavalin A (Con A) and peanut lectin (PNA), respectively. Both features show that the neoglycoconjugates could also be used as site specific molecular delivery systems.     

Solvent effects on IR and VCD spectra of natural products: an experimental and theoretical VCD study of pulegone

The VCD spectra of pulegone, dissolved in CDCl3, CD2Cl2 and CS2 have been recorded in the frequency range from 1000 to 3000 cm(-1). The assignment of the absolute configuration was performed by comparing the experimental data with theoretical spectra computed at the B3LYP/6-311+G(d,p) level. Analysis of the agreement in several spectral regions revealed significant shortcomings when comparing with vacuum calculations. It is shown that the agreement improves when the solvent effects are taken into account by a continuum model. For the measurements in CDCl3 and CD2Cl2 further improvement was found when considering explicitly 1 : 1 complexes between a pulegone and a CDCl3 or CD2Cl2 solvent molecule in vacuo, while the best agreement was obtained when embedding these in a continuum model. The presence of the chiral solute was found to induce a VCD active C-D stretch band which could be modeled also at ab initio level.     

A combined NMR, DFT, and X-ray investigation of some cinchona alkaloid O-ethers

Structures and conformational behavior of several cinchona alkaloid O-ethers in the solid state (X-ray), in solution (NMR and DFT), and in the gas phase (DFT) were investigated. In the crystal, O-phenylcinchonidine adopts the Open(3) conformation similar to cinchonidine, whereas the O-methyl ether derivatives of both cinchonidine and cinchonine are packed in the Closed(1) conformation. Dynamic equilibria in solutions of the alkaloids were revealed by combined experimental-theoretical spin simulation/iteration techniques for the first time. In the (1)H NMR spectra in CDCl3 and toluene-d8 at room temperature, Closed(1) conformation was observed for the O-silyl ethers as a separate set of signals. For O-methyl ether derivatives Closed(1) could be separated only at -30 degrees C in CDCl3 or toluene-d8 and for O-phenylcinchonidine at -70 degrees C in CDCl3/CD2Cl2. The ratio between the Closed(2) and Open(3) conformers was estimated by analyzing the vicinal coupling constant (3)J(H9,H8) at ambient and low temperatures. The observed conformational equilibria of O-(tert-butyldimethylsilyl)cinchonidine in CDCl 3 and toluene-d8 are in good agreement with the theoretically estimated equilibrium populations of the conformations according to Boltzmann statistics. The conformational equilibria of four cinchona alkaloid O-ether solutes in CDCl3 and toluene-d8 are discussed in the light of their relevance to the mechanism of 1-phenyl-1,2-propanedione (PPD) hydrogenation over cinchona alkaloid modified heterogeneous platinum catalysts. It was demonstrated that the conformation found to be abundant in the liquid phase has no direct correlation with the enantioselectivity of the PPD hydrogenation reaction.     

Enhanced thermodynamic and kinetic stability of calix[4]arene dimers locked in the cone conformation

Wide rim tetraurea derivatives (2a,b) have been prepared from a calix[4]arene rigidified in the cone conformation by two diethyleneglycol ether bridges between adjacent oxygens. In comparison to the analogous tetraurea derivatives (3a,b) of a tetrapentoxy calix[4]arene, 2a,b show an increased thermodynamic stability in mixtures of CDCl(3) and DMSO-d(6). Their kinetic stability as expressed by the rate of guest exchange (benzene or cyclohexane against the solvent benzene-d(6)) is also strongly increased by factors of 30-38. Noticeable differences for the inclusion of selected guests are found.     

Metal-switching and self-inclusion of functional cavitands

Cavitands bearing both eight (5) and two (13) metal-ligating carboxymethylphosphonate groups on their rims were synthesized by Arbuzov reaction of the corresponding bromoacetamido cavitands with trialkyl phosphites. These exist in the vase conformation in CDCl(3) and are stabilized by a cyclic seam of hydrogen bonds. This structure was also found in the solid state for the octabromoacetamide 4a and diphosphonate cavitand 13 by single-crystal X-ray analysis. Cavitands 5 and 13 form caviplexes in CDCl(3), CD(2)Cl(2), and alcohol solutions with adamantane derivatives 15a,b, quinuclidine 15d, ammonium and phosphonium salts 14, and drugs like ibuprofen 15c, all of which are stable on the NMR time scale at 295 K. NMR spectroscopy reveals that at 223 K octaphosphonate 5b exists in two forms: the major C(4)-symmetrical compound is filled with solvent while the minor species shows intramolecular inclusion of a dialkoxyphosphoryl group. In methanol-d(4) 5 and 13 exist in a lower symmetry vase conformation with self-inclusion of one alkyl group. Interaction of these complexes with La(OTf)(3) results in a change in the conformation of the cavitand from vase to kite with concomitant and quantitative release of the encapsulated guests. Two to three equivalents of the lanthanide salt per equivalent of cavitand 5a-d is necessary for the complete decomplexation of the included guest. The kite and the vase conformers equilibrate slowly on the NMR time scale at 295 K. The addition of good ligands for metal cations (nitrate or CMPO calixarene 16) shifts the equilibrium to the vase-shaped caviplex and allows quantitative control of the binding and release of the guest. The lanthanide complexes of octaphosphonates 5 in methanol-d(4) are velcraplex-like dimers held together by four metal cations.     

Vibrational circular dichroism study of optically pure cryptophane-A

Vibrational circular dichroism (VCD) measurements and density functional theory (DFT) calculations were used to obtain the absolute configuration of optically pure cryptophane-A molecule. This large molecule (120 atoms) that possess a globular shape, but no chiral centers, exceeds the molecular size of published structures for which VCD has been used to determine the absolute configuration. VCD spectra recorded in CDCl(3) solution for the two resolved enantiomers are near mirror images, and very good agreement between the observed IR and VCD spectra and intensity calculations performed at the DFT (B3PW91/6-31G) level establish, besides the absolute configuration, the preferential anti conformation of the aliphatic linkers of the chloroform-cryptophane-A complex. Experiments performed in CD(2)Cl(2) and C(2)D(2)Cl(4) solutions show no significant modifications in the IR and VCD spectra, indicating that the conformation of the aliphatic linkers is similar for empty (C(2)D(2)Cl(4) solution) and encaged (CDCl(3) and CD(2)Cl(2) solutions) cryptophane-A molecules.     

Conformational analysis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges: destabilization of the cone form by axial alkyl substituents

The stereochemistry of calix[4]arenes substituted by a pair of identical alkyl substituents in a trans fashion at two distal bridges is analyzed. MM3 calculations suggest that increasing the bulk of the alkyl group at the bridges destabilizes those conformations possessing an axial disposition of the substituent. In contrast to the 1,3-dimethyl ether of p-tert-butylcalix[4]arene, which adopts a cone conformation, solution NMR data indicate that the 1,2-alternate conformation is preferred in the dimethyl ether derivatives 5b (alkyl = i-Pr) and 5c (alkyl = t-Bu). In the derivative substituted by the less bulky methyl substituent (5a), both the cone and 1,2-alternate forms coexist in CDCl3. Increasing the polarity of the solvent increases the relative population of the cone form of 5a and 5b. The steric destabilization ensuing from the presence of the axial substituent is so large in the cone conformation of 5c that the 1,2-alternate conformer is the major form even in polar solvents. The cone --> 1,2-alternate interconversion barrier of 5a is 18.2 kcal mol(-1), indicating that the presence of an axial methyl group both destabilizes the cone conformation and decreases its rigidity.     

Complexation of quaternary ammonium ions by tetraester derivatives of [3.1.3.1]homooxacalixarene in mobile and in fixed conformation

In the tetraalkylation of p-tert-butyl[3.1.3.1]homooxacalixarene with BrCH2CO2R and K2CO3 in acetone, the initially formed cone conformer is converted into the more stable 1,4-alternate conformer when R = Me or Et, but not when R = i-Pr or t-Bu. In the case of R = i-Pr, derivatives in fixed 1,4-alternate conformation and in partial cone conformation were also isolated. Compounds in fixed cone conformation are good ligands for tetramethylammonium, acetylcholine, and N-methylpyridinium salts in CDCl3, but the partial cone isomer proved to be somewhat better and even the 1,4-alternate conformer turned out to be active. The possible involvement of the ester functions as additional binding sites is discussed; moreover, an insight into the energetics of the complexation and conformational isomerization processes is given.     

The first solid enols of anhydrides. Structure, properties, and enol/anhydride equilibria(1)

Reaction of beta-methylglutaconic anhydride with NaOMe followed by reaction with methyl or phenyl chloroformate gave the corresponding O-methoxy (and O-phenoxy) carbonylation derivatives. Reaction of the anhydride with MgCl2/pyridine, followed by methyl chloroformate gave C-methoxycarbonylation at C3 of the anhydride. The product (4) was previously suggested by calculation to be the enol of the anhydride 5 and this is confirmed by X-ray crystallography (bond lengths: C-OH, 1.297 A; C1C2 1.388 A; HO...O=C(OMe) distance 2.479 A) making it the first solid enol of an anhydride. In CDCl3, CD3CN, or C6D6 solution it displays the OH as a broad signal at ca. 15 ppm, suggesting a hydrogen bond with the CO2Me group. NICS calculations indicate that 4 is nonaromatic. With D2O in CDCl3 both the OH and the C5H protons exchange rapidly the H for D. An isomeric anhydride 5a of 5 is formed in equilibrium with 4 in polar solvents. In solution, anhydride(s)/enol equilibria are rapidly established with Kenol of 6.40 (C6D6, 298 K), 0.52 (CD3CN, 298 K), 9.8 (CDCl3, 298 K), 22.8 (CDCl3, 240 K), and decreasing Kenol in CDCl3:CD3CN mixtures with the increase in percent of CD3CN. The percentage of the rearranged anhydride in CDCl3:(CD3)2CO increases with the increased percent of (CD3)2CO. In DMSO-d6 and DMF-d7 the observed species are mainly the conjugated base 4- and 5a. Deuterium effects on the delta(13C) values were determined. An analogous C2-OH enol of anhydride 15 substituted by 3-CO2Me and 4-OCO2Me groups was prepared. Its structure was confirmed by X-ray crystallography (CO bond length 1.298 A, O...O distance 2.513 A); delta(OH) = 12.04-13.22 ppm in CDCl3, THF-d8, and CD3CN, and Kenol = > or = 100, 7.7, and 3.4 respectively. In DMSO-d6 enol 15 ionizes to its conjugate base. Substantial upfield shifts of the apparent delta("OH") proton on diluting the enol solutions are ascribed to the interaction of the H+ formed with the traces of water in the solvent to give H3O+, which gives the alleged "OH proton" signal.     

Diffusion and NOE NMR studies on the interactions of neutral amino-acidate arene ruthenium(II) supramolecular aggregates with ions and ion pairs

The interaction between [RuCl(AA)(cymene)]n supramolecular aggregates (1, AA = alpha-amino-acidate = alpha-aminoisobutyrate; 2, AA = N,N-dimethyl-Gly; 3, AA = Ala; 4, AA = Pro; cymene = 4-isopropyltoluene) and ionic species derived from NBu4PF6 and KPF6 is investigated through diffusion NMR measurements and 19F,1H-hetero-nuclear Overhauser effect spectroscopy experiments in CDCl3 and CD2Cl2. Aggregates containing the -NH2 functionality (1 and 3) interact strongly with NBu4PF6 as demonstrated by the observation of intense nuclear Overhauser effects between the fluorine atoms of PF6(-) and the protons of [RuCl(AA)(cymene)]n. Unexpectedly, diffusion NMR measurements indicate that the average size of the aggregates increases when a small amount of NBu4PF6 is added (Csalt/CRu < 0.1) in CD2Cl2. At higher concentration levels of NBu4PF6 or in CDCl3, NBu4PF6 exerts a destructive effect that reduces the average size of the aggregates. [RuCl(AA)(cymene)]n aggregates with NR-H (4) and NR2 (2) functionalities are little affected by the addition of NBu4PF6. KPF6 also interacts with [RuCl(AA)(cymene)]n aggregates as demonstrated by the fact that it becomes noticeably soluble in CDCl3 and CD2Cl2. Diffusion1H-NMR experiments show that the addition of KPF6 does not markedly alter the average size of [RuCl(AA)(cymene)]n supramolecular aggregates. Interestingly, the average size of PF6(-)-containing supramolecular aggregates is, in some cases, slightly higher than that of the ones that do not contain PF6(-). This was deduced by independent measurements of the hydrodynamic volume of the anion and of the ruthenium complexes by diffusion 19F- and 1H-NMR experiments, respectively.     

Environmental control of solution speciation in cobalt(II) 2,2':6',2'-terpyridine complexes: anion and solvent dependence

In methanol or chloroform/methanol solutions, reactions of Cltpy or MeOtpy (Rtpy = 4'-R-2,2':6',2'-terpyridine) with CoX(2)·xH(2)O (X(-) = Cl(-), [OAc](-), [NO(3)](-) or [BF(4)](-)) result in the formation of equilibrium mixtures of [Co(Rtpy)(2)](2+) and [Co(Rtpy)X(2)]. A study of the solution speciation has been carried out using (1)H NMR spectroscopy, aided by the dispersion of signals in the paramagnetically shifted spectra; on going from a low- to high-spin cobalt(II) complex, proton H(6) of the tpy ligand undergoes a significant shift to higher frequency. For R = Cl and X(-) = [OAc](-), increasing the amount of CD(3)OD in the CD(3)OD/CDCl(3) solvent mixture affects both the relative proportions of [Co(Cltpy)(2)](2+) and [Co(Cltpy)(OAc)(2)] and the chemical shifts of the (1)H NMR resonances arising from [Co(Cltpy)(OAc)(2)]. When the solvent is essentially CDCl(3), the favoured species is [Co(Cltpy)(OAc)(2)]. For the 4'-methoxy-2,2':6',2'-terpyridine, the speciation of mono- and bis(terpyridine)cobalt(II) complexes depends upon the anion, solvent and ligand:Co(2+) ion ratio. The (1)H NMR spectrum of [Co(MeOtpy)(2)](2+) is virtually independent of anion and solvent. In contrast, the signals arising from [Co(MeOtpy)X(2)] depend on the anion and solvent. In the case of X(-) = [BF(4)](-), we propose that the mono(tpy) complex formed in solution is [Co(MeOtpy)L(n)](2+) (L = H(2)O or solvent, n = 1-3). The formation of mono(tpy) species has been confirmed by the solid state structures of [Co(Cltpy)(OAc-O)(OAc-O,O')], [Co(MeOtpy)(OAc-O)(OAc-O,O')], [Co(MeOtpy)(NO(3)-O)(2)(OH(2))] and [Co(MeOtpy)Cl(2)]. The single crystal structure of the cobalt(III) complex [Co(Cltpy)Cl(3)]·CHCl(3) is also reported.     

Raman spectrum of [Ru(CNBu t)(CO)(eta2-C6H4-2-CHO)(PPh3)2][BF4].2CDCl3 shows that the crystallographically determined bifurcated hydrogen-bonding interaction Cl3CD...F2BF2- is an example of a blue-shifting hydrogen bond

Raman data suggest that a crystallographically determined Cl3CD...F2BF2- interaction in the solid-state structure of [Ru(CNBut)(CO)(eta2-C6H4-2-CHO)(PPh3)2][BF4].2CDCl3 is an example of a blue-shifting bifurcated hydrogen bond. The nu(C-D) band blue-shifts 5 cm-1 to 2269 cm-1 compared to 2264 cm-1 for CDCl3 in the gas phase and 20 cm-1 from frozen CDCl3 at 2249 cm-1. A conventional interpretation of these band shifts would suggest that the CCl2 fragment of DCCl3 is a stronger hydrogen-bond acceptor than the BF2 fragment of a BF4- group.     

Calix[6]arene derivatives selectively functionalized at alternate sites on the smaller rim with 2-phenylpyridine and 2-fluorenylpyridine substituents to provide deep cavities

The synthesis is described of calix[6]arene derivatives 4, 9, and 14 functionalized at alternate sites on the smaller rim with 4'-(pyrid-2' '-yl)phenylmethoxy, (6'-phenylpyrid-3'-ylmethoxy), and {6'-[2-(9,9-di-n-hexylfluorenyl)]pyrid-3'-ylmethoxy} substituents, respectively. They were obtained by 3-fold reactions of 2-[4-(bromomethyl)phenyl]pyridine (3), 5-(bromomethyl)-2-phenylpyridine (8), and 5-(bromomethyl)-2-(9,9-di-n-hexylfluorenyl)pyridine (13) with the 1,3,5-trimethylether of the t-Bu-calix[6]arene in the presence of sodium hydride in THF in 56-75% yields. Detailed analysis of the 1H NMR spectra (including variable-temperature data for 4) has established that 4, 9, and 14 exist predominantly in the C3v cone conformation with minor Cs isomers also observed. The X-ray crystal structure of 4 reveals two molecules of similar cone conformation, with all three 4'-(pyrid-2' '-yl)phenylmethoxy substituents stretched in the axial direction. Molecule I has a dimeric capsule structure with (pyrid-2' '-yl)phenylmethoxy substituents of one molecule interpenetrating those of its inversion equivalent to form a deep enclosed intermolecular cavity, which contains a CH2Cl2 guest molecule. Molecule II forms no such pair: the intramolecular cavity is filled with solvent molecules.     

Conformational features and anion-binding properties of calix[4]pyrrole: a theoretical study

The conformational preference of calix[4]pyrrole and its fluoride and chloride anion-binding properties have been investigated by density functional theory calculations. Geometries were optimized by the BLYP/3-21G and BLYP/6-31G methods, and energies were evaluated with the BLYP/6-31+G method. To model the effect of medium, the SCIPCM solvent model was also employed. Four typical conformations of the parent substituent-free calix[4]pyrrole were studied. Both in the gas phase and in CH(2)Cl(2) solution, the stability sequence is predicted to be 1,3-alternate > partial cone > 1,2-alternate > cone. The cone conformation is predicted to be about 16.0 and 11.4 kcal/mol less stable in the gas phase and CH(2)Cl(2) solution, respectively. This is mainly due to electrostatic repulsions arising from the all-syn pyrrole/pyrrole/pyrrole/pyrrole arrangement present in this conformer. The existence of possible 1:1 and 1:2 anion-binding modes were explored in the case of fluoride anion, and the factors favoring the 1:1 binding mode are discussed. The calculated binding energy for fluoride anion is about 15 kcal/mol larger than that for chloride anion. The calculated binding energy for chloride anion agrees with the experimental value very well. The presence of meso-alkyl substituents destabilizes the cone conformer with respect to the 1,3-alternate conformer and, therefore, reduces the anion-binding affinity by 3-4 kcal/mol. The strength of N-H- - -anion hydrogen bonds in the various structures subject to study were estimated on the basis of the calculated anion-binding energies and the predicted structural deformation energies of substituent-free calix[4]pyrrole.     

Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides

Heptapeptides containing residues with terminal olefin-derivatized side chains (3 and 4) have been treated with ruthenium alkylidene 1 and undergone facile ring-closing olefin metathesis (RCM) to give 21- and 23-membered macrocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 were based upon a previously studied heptapeptide (2), which was shown to adopt a predominantly 3(10)-helical conformation in CDCl(3) solution and an alpha-helical conformation in the solid state. Circular dichroism, IR, and solution-phase (1)H NMR studies strongly suggested that acyclic precursors 3 and 4 and the fully saturated macrocyclic products 7 and 8 also adopted helical conformations in apolar organic solvents. Single-crystal X-ray diffraction of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up to the fifth residue. Solution-phase NMR structures of both acyclic peptide 4 and cyclic peptide 8 in CD(2)Cl(2) indicated that the acyclic diene assumes a loosely 3(10)-helical conformation, which is considerably rigidified upon macrocyclization. The relative ease of introducing carbon-carbon bonds into peptide secondary structures by RCM and the predicted metabolic stability of these bonds renders olefin metathesis an exceptional methodology for the synthesis of rigidified peptide architectures.     

Conformational changes in cryptophane having C1-symmetry studied by vibrational circular dichroism

Vibrational circular dichroism (VCD) measurements and density functional theory (DFT) calculations were used to obtain the absolute configuration of a cryptophane molecule having C1-symmetry (labeled cryptophane-H). This molecule exhibits chiroptical properties different from those published for cryptophane-A having D3-symmetry [Brotin et al. J. Am. Chem. Soc. 2006, 128, 5533-5540]. In particular, we have shown that the conformation of the aliphatic linkers is very dependent on the solvent used and its ability to enter (CDCl3 solution) or not (C2D2Cl4 solution) in the cryptophane cavity. Calculations performed at the DFT (B3PW91/6-31G*) level establish, besides the absolute configuration, the preferential anti and gauche conformations of the aliphatic linkers of the chloroform@cryptophane-H complex and the empty cryptophane-H molecule, respectively. Polarimetric measurements performed in several solvents reflect also the change of conformation of the bridges upon guest encapsulation.     

Proximal regioselectivity of the O,O'-dialkylation of tetrahydroxyketocalix[4]arene

The only dialkylated products obtained in the reaction of tetrahydroxyketocalixarene 2a with MeI/K(2)CO(3) or PhCH(2)Br/K(2)CO(3) are the corresponding proximal (i.e., 1,2) O,O'-dialkyl ethers, in contrast to the parent tetrahydroxycalix[4]arene 1a which affords the distal (1,3) dialkyl ether derivatives. Pairs of geminally alkylated phenoxy groups in the conformationally rigid dibenzylated and tetrabenzylated derivatives are oriented in an anti fashion. These results can be rationalized assuming that the 1,3-alternate arrangement of the rings preferred by 2a is adopted during all the intermediate stages of the alkylation. The NMR spectra (in CDCl(3)) of the monomethyl, dimethyl, trimethyl, and tetramethyl ether derivatives of 2a are in agreement with a 1,3-alternate conformation.     

Partially O-alkylated thiacalix[4]arenes: synthesis, molecular and crystal structures, conformational behavior

NMR spectroscopy, X-ray diffraction analysis, and quantum chemical calculations were used for conformational behavior study of partially alkylated thiacalix[4]arenes bearing methyl (1), ethyl (2), or propyl (3) groups at the lower rim. The conformational properties are governed by two basic effects: (i) stabilization by intramolecular hydrogen bonds, and (ii) sterical requirements of the alkoxy groups at the lower rim. While the monosubstituted derivatives 1a and 3a adopt the cone conformation in solution, distally disubstituted compounds 1b, 1'b, 2b, 2'b, 3b, and 3'b exhibit several interesting conformational features. They prefer pinched cone conformation in solution, and, except for 3'b, they form also 1,2-alternate conformation, which is flexible and undergoes rather fast transition between two identical structures. The crystal structures of the compounds 1b, 2b, 2'b, and 3b revealed yet quite rare 1,2-alternate conformation forming molecular channels held together by pi-pi interactions. Different channels-with hexagonal symmetry, 0.26 nm wide-are formed in the crystal structure of the pinched cone conformation of 3b. An uncommon hydrogen bonding pattern was found in dimethoxy and dipropoxy derivatives 1'b and 3'b that adopt distorted cone conformations in crystal. Trialkoxy-substituted compounds 1c and 3c adopt the partial cone conformation in solution. A higher mobility of methyl derivative 1c enables also existence of the cone conformer.     

Synthesis of 2-alkyl- and 2-carboxy-p-tert-butylcalix[4]arenes via the lithiation of tetramethoxy-p-tert-butylcalix[4]arene

[reaction: see text]. Tetramethoxy-p-tert-butylcalix[4]arene reacts readily with n-butyllithium to give a putative monolithiated intermediate that is substituted with alkyl halides and carbon dioxide to give in 60-75% yield conformationally mobile calix[4]arenes monosubstituted at the methylene bridge (2-position). 2-Alkyl- and 2-benzyl-substituted tetramethoxycalix[4]arenes are converted in 62-68% overall yield to the corresponding tetrahydroxy-p-tert-butylcalix[4]arenes by treatment with boron tribromide. The tetrahydroxy-p-tert-butylcalix[4]arenes exist in the cone conformation at room temperature in CDCl3 as judged by NMR spectroscopy.     

Conformation, Inversion Barrier, and Solvent-Induced Conformational Shift in Exo- and Endo/Exo-Calix[4]arenes

Calixarenes 4a and 4b having hydroxyl groups in endo and exo positions and the ethanediyl-bridged exo-calixarene 5a were synthesized by a stepwise strategy. Single-crystal X-ray structures were obtained for 4a and for the exo-calixarene 3d, showing the molecules to exist in the 1,2-alternate conformation which is also found for 4a,b in solution. The inversion barriers of 4a and 4b (10.3 and 10.8 kcal mol(-1)) are similar to that determined for the endo-dihydroxycalixarene 12, indicating that the additional intramolecular hydrogen bond between the exo OH groups does not decrease the flexibility of the molecule. In CDCl(3) solution exo-calixarene 5a adopts a 1,2-alternate conformation with the methyl group at the bridge located in an axial position, while in DMSO-d(6) the conformation adopted is the partial cone. Similar solvent-induced conformational shifts were found for the exo-calixarenes 3b and 3d. MM3 calculations predict that the cone form is the lowest energy conformation of 4 and the exo-calixarenes 3 and 5. The calculations suggest that the conformational preferences of the methyl group at the bridge for either the axial or equatorial positions are in large part determined by the repulsive steric interactions with the hydroxyl groups. The inversion barrier of 4b is satisfactorily reproduced by calculations, which indicate that the rotation of the exo rings is less energetically demanding than the rotation of the endo rings.