The Preparation and Crystal Structures of Octaoxoketocalix[8]arene Derivatives: The Ketocalixarene Counterparts of the Largest "Major" Calixarene.

The purpose of this study was to synthesize and structurally characterize ketocalixarenes (i.e., calixarenes where the bridging methylene bridges are replaced by carbonyl groups) derived from the largest "major" calixarene, namely --butylcalix[8]arene .

Calixrotanes: Calixarenes Incorporating Spiro-Linked Cyclopropyl Groups.

Macrocyclic compounds (calix[4]- and calix[6]arene derivatives) with aryl rings interconnected by spirocyclopropyl groups have been synthesized and structurally characterized. The compounds were prepared by the reaction of dichlorocarbene with calixarenes possessing exocyclic double bonds at the bridges, followed by reductive perdechlorination of the spirocyclopropyl groups. In all systems, pairs of geminal rings connected to the quaternary spiro carbon atoms are oriented anti, and the methylene groups of the cyclopropyl rings are located in isoclinal positions.

C-Me Bond Formation at All Methylene Bridges of the Calix[4]arene Scaffold.

A reaction of a distal dibromo diketocalix[4]arene with excess MeLi, followed by acid-catalyzed dehydration, yields a derivative with a pair of opposite exocyclic double bonds, and a pair of trans methyl groups at the bridges. A reaction of a tetrabromo calix[4]arene derivative with excess MeLi yields a calix[4]arene derivative with all methylene bridges monomethylated in all- cis fashion.

The Lithiation/Oxygenation Approach to Calix[6]arenes Selectively Functionalized at a Pair of Opposite Methylene Bridges.

Lithiation of the calix[6]arene methyl ether 2 followed by reaction with O yields derivatives with two opposite methylene groups hydroxylated. Calix[6]arenes with two opposite bridges functionalized with alkoxy, azido, and m-xylyl groups were prepared via reaction of a dichlorocalix[6]arene derivative with nucleophiles.

Incorporation of three or two distal double bonds at the methylene bridges of the calix[4]arene scaffold.

Partial oxidation of the 1,3-alternate atropisomer of p-tert-butylcalix[4]arene tetraacetate with CrO3 afforded mainly a mixture of trioxo- and tetraoxo-calix[4]arene tetraacetate derivatives. The trioxotetrahydroxy derivative 6 was isolated from the mixture after hydrolysis of the crude product, followed by trituration with ethanol. Trioxocalix[4]arene adopts in the crystal a 1,2-alternate conformation.

Calixradialenes: calixarene derivatives with exocyclic double bonds.

Reaction of dioxocalix[4]arene 7 with MeLi followed by 2-fold elimination of water yielded calixarene 8 possessing exocyclic double bonds at two adjacent bridges. Calixarene 8 exists in tetrachloroethane-d2 solution at rt, as a 2.3:1 mixture of the 1,3-alternate and partial cone conformers.

Conformationally restricted calix[8]arenes substituted at all methylene bridges.

Reaction under S(N)1 conditions of the octabromocalix[8]arene derivative 2d with alcohols proceeds in nonstereoselective fashion, but all-cis octaryl derivatives are the single major products in the reaction with arenes. The incorporation of aryl substituents at the bridges rigidifies the calix[8]arene skeleton.

Calix[4]arenes with two different chemical modifications at the bridges.

Hexabromocalix[4]arene derivatives (3a and 3b) possessing pairs of dibromomethylene and bromomethylene groups located at distal or proximal positions of the calix scaffold were prepared via photochemical bromination of tetramethoxycalix[4]arene. The dibromomethylene groups undergo hydrolysis to afford calix[4]arenes possessing pairs of carbonyl groups and bromomethylene groups located at distal or proximal bridges (4a and 4b, respectively). The bromomethylene groups of 4 undergo reactions with nucleophiles under S(N)1 conditions to afford a wide array of derivatives possessing two different chemical modifications at the bridges.

Selective functionalization of a single methylene bridge of a calix[6]arene.

The monohydroxycalix[6]arene derivative 4a was prepared via photochemical bromination of hexamethoxycalix[6]arene 3a in aq THF. Monohydroxycalix[6]arene 4a and its chloro derivative 5 are useful synthetic intermediates for the preparation of structurally diverse calix[6]arenes functionalized at a single methylene bridge.

Incorporation of substituents at the methylene linkages of the Calix[5]arene skeleton.

Under S(N)1 reaction conditions, the bromine atoms of the pentabromo p-tert-butylcalix[5]arene 6 were replaced by alkoxy, electron-rich aryl, and acetylacetonate groups.

Restricted rotation of tert-butyl groups in sterically crowded methylene-functionalized calix[4]arenes.

The crowded methylene-functionalized calix[4]arenes 4 and 5 display restricted rotation of the tert-butyl substituents at the bridges. At low temperatures, separate signals were observed for the methyls of these groups in the (1)H NMR spectra.

Isotopic perturbation of the conformational equilibrium in methylene-functionalized calixarenes.

The 400 MHz 1H NMR spectrum of the tetramethoxycalixarene 2 (possessing hydroxyl groups at the bridges) in commercial acetone-d6 displays five signals (an isotopic multiplet) for a pair of methoxy groups. Inspection of the X-ray structures of 2 and its isomer 3 indicates that in the adopted 1,3-alternate conformation, the methoxy groups intramolecularly hydrogen bonded to neighboring OH groups are oriented "in" (pointing toward the cavity). Upon dissolution of 2 in acetone-d6, none, some, or all of the OH protons exchange with the deuterium atoms present in the residual water of the solvent.

Functionalization of the methylene bridges of the calix[6]arene scaffold.

The bromine atoms of the hexabromo calixarene derivative 3 were replaced by other groups under S(N)1 conditions, allowing the facile synthesis of calix[6]arene derivatives incorporating identical functionalities at all bridges. Heating at reflux a mixture of 3 and the appropriate alcohol incorporated primary and secondary alkoxy substituents. Hydride abstraction was observed when the reaction with EtOH and i-PrOH was conducted in hexafluoroisopropanol (HFIP).

Calix[4]arene derivatives monosubstituted at all four methylene bridges.

The scope of the reaction of the tetrabromocalixarene derivative 2b with alcohols under solvolytic conditions in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) was explored. The reaction proceeded readily with MeOH, EtOH, n-PrOH, ethylene glycol and i-PrOH affording preferentially the rccc isomer of the tetrasubstituted product. The methoxy derivative 6a undergoes isomerization upon attempted recrystallization from CHCl3/MeOH and its rcct and rctt forms were characterized by X-ray crystallography.

The nucleophilic substitution route. A facile method for the fourfold functionalization of the methylene bridges of calix[4]arene.

The radical bromination of p-tert-butylcalixarene tetramethyl ether was reinvestigated and the product (2b) characterized by X-ray crystallography. The tetrabromo calixarene derivatives 2a or 2b react with alcohols (TFE, EtOH), azide, and 2-methylfuran under solvolytic conditions affording calixarene derivatives functionalized at the four bridges. The reaction with alcohols and the aromatic compound proceeds in stereoselective fashion and affords the rccc isomer of the tetrasubstituted product.

Intramolecular SNAr reactions in a large-ring ketocalix[6]arene.

Ketocalix[6]arene 2e was prepared by CrO3 oxidation of the methylene groups of 2a, followed by hydrolysis of the acetate groups. 2e undergoes intramolecular SNAr reactions under the usual methylation conditions (MeI, base), yielding mono- and dixanthone calixarene derivatives.

Tetraaddition of PhLi to a ketocalixarene derivative.

[reaction: see text] Reaction of a ketocalixarene with 2.2 equiv or an excess of PhLi affords diaddition and tetraaddition products, respectively. Ionic hydrogenation of the tetraalcohol 8a yields a calix[4]arene monosubstituted by phenyl groups at all four methylene bridges.

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.

Preferential axial protonation in a zwitterionic calix[4]arene.

[structure: see text] Calixarene 3, substituted at two methylene bridges by dimethylamino groups, exists in the crystal and in polar solvents as a zwitterion, with the axial dimethylamino group protonated.

Preparation and conformation of dioxocalix[4]arene derivatives.

CrO(3) oxidation experiments conducted on atropisomeric forms of 2 (2(paco), 2(1,3)(-)(alt), and 2(1,2)(-)(alt)) indicate that under the reaction conditions only methylene groups located between pairs of geminal rings oriented in an anti disposition are oxidized to carbonyls. NMR data suggest that the tetrahydroxydioxocalix[4]arenes 7 and 9 adopt the partial cone and 1,2-alternate conformations, respectively. In the crystal structure of 7.

A "classical" tetrahydroxycalix[4]arene adopting the 1,2-alternate conformation.

The first example of a "classical" tetrahydroxycalixarene, which adopts the 1,2-alternate conformation both in solution and in the crystal, is described. Calixarene derivatives with two distal methylene groups substituted in a trans fashion by phenyl (5a) or mesityl (5b) groups were synthesized via addition of PhMgBr/CuCN or MesMgBr/CuCN to the bis(spirodiene) derivative 3. Whereas the phenyl-substituted calixarene derivative 5a adopts the usual "cone" conformation, solution NMR data and X-ray crystallography indicate that the more crowded mesityl derivative 5b adopts a 1,2-alternate conformation with the two mesityl groups located at isoclinal positions of the macrocycle.

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).

A conformationally flexible tetrahydroxycalix[4]arene adopting the unusual 1,3-alternate conformation.

The use of a chiral solvating agent enabled the determination of the NMR-silent ring-inversion process of the ketocalixarene 3. Spectroscopic and crystal data indicate that 3 adopts the unusual 1,3-alternate conformation.

Tris(arylmethyl) derivatives of 1,3,5-trimethoxy- and 1,3,5-triethylbenzene.

The hexasubstituted benzenes 7 and 9b were synthesized starting from 3 and 8b, respectively. In the crystal, 9b adopts the fully alternated conformation with all arylmethyl groups oriented syn.

Synthesis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges.

Reaction of the bis(spirodiene) calixarene derivative 9 possessing exocyclic double bonds with tetraethylammonium fluoride or chloride afforded bis(spirodienone) calixarene derivatives substituted by the corresponding halogen atoms (11 and 12). Reaction of 9 with alkyl cuprates yielded in one step p-tert-butylcalix[4]arene derivatives with opposite methylene groups substituted in a trans fashion by identical alkyl substituents (methyl, ethyl, or isopropyl). The isopropyl derivative 16 displayed the largest cone-to-cone inversion barrier of the series.