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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. Calix[6]rotane adopts in the crystal and in solution a 1,3,5-alternate conformation. The presence of the spirocyclopropyl groups increases the rigidity of the macrocyclic ring.

p-tert-Butylcalix[6]arene hexamethyl ether was oxidized in one step to the corresponding ketocalix[6]arene via photochemical bromination (100 W spot lamp) with NBS in a chloroform/water mixture. A pentamethyl ketocalix[6]arene derivative was obtained by reaction of the ketocalix[6]arene hexamethyl ether with boron tribromide dimethyl sulfide complex, and characterized by X-ray crystallography. In the presence of base, the compound undergoes an intramolecular nucleophilic aromatic substitution reaction.

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.

Lithiation of the calix[6]arene methyl ether 2 followed by reaction with O2 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.

Reaction of the tert-butoxycarbonyl derivative of p-tert-butylcalix[6]arene (2) with excess NBS under irradiation yields a calixarene with four bromomethine bridges as the major product (3). On the basis of the number of signals in the NMR spectrum, to the product was assigned a 1,2,4,5-substitution pattern. X-ray crystallography indicates that the product possesses the rct2 configuration and crystallized as a mixture of two conformers. The major form in the crystal exists in a 1,2,3-alternate conformation where a single tert-butoxycarbonyl group is self-included in the cavity and all bromines are located at equatorial positions. A rotational barrier of 18.4 kcal mol–1 was measured for the intramolecular guest exchange rotational process that involves the mutual exchange between the unique self-included Boc group and the Boc group on the opposite ring (Boc = tert-butoxycarbonyl).

Alkylation of the tetrahydroxy-tetraoxocalix[4]arene 5 with n-butyl bromide proceeds in a stereoselective fashion and affords exclusively a single atropisomer of the tetraoxocalix[4]arene tetrabutyl ether derivative. Reaction with MeLi followed by fourfold acid-catalyzed elimination of water affords the rigid calix[4]radialene 8. The crystal structure of 8 corroborated the proposed calixradialene structure and indicated an 1,3-alternate arrangement of the rings.

Reduction of the carbonyl groups of tetrahydroxyketocalix[4]arene with NaBH4 in propan-2-ol, followed by heating the product to reflux in MeOH–H2SO4, yields a mixture of stereoisomers of the tetrahydroxycalix[4]arene derivative with all bridges monosubstituted by a methoxy group. To structurally characterize the compound, the mixture of isomers was derivatized by reaction with di-tert-butyl dicarbonate–DMAP. X-ray crystal structure analysis of the all-cis isomer of the product (obtained by fractional crystallization), corroborates the presence of Boc protecting groups at the lower rim (and thus underivatized OH groups in the starting material), and four methoxy groups at the bridges.

A calix[8]arene derivative substituted at the single methylene bridge by a chlorine atom reacts at the substituted bridge with O, N, and C nucleophiles under SN1 conditions. Thiscalix[8]arene can serve as a useful starting material for the preparation of calix[8]arene derivatives functionalized at a single methylene bridge.

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.

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.

The hexabromocalix[6]arene 5 reacts with p-tert-Bu-phenol, thymol and propargyl alcohol to afford the corresponding hexasubstituted methylene-functionalised calixarenes. The substituents at the bridges were further functionalised via acetylation or click chemistry. Reaction of the hexahydroxy derivative 10 with DAST afforded 11, a first example of a calixarene with all bridges monofluorinated.

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.

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.

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.

The different synthetic approaches for the preparation of “classical” calixarenes with one, part, or all bridges chemically modified are reviewed. The methods include the cyclization of fragments, the homologous anionic ortho Fries rearrangement, the spirodienone method, the lithiation/alkylation approach, the oxidation of the bridges followed by reaction of the carbonyl units with organolithium reagents, and the bromination of the bridges followed by reaction with nucleophiles.

[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.

[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.

The conformation of tetrahydroxycalix[4]arene derivatives substituted at two opposite methylene bridges or at a single bridge by an alkyl or aryl group is reviewed. The cone form with an equatorial substituent is the lowest energy conformation of calixarenes possessing one bridge substituted by an alkyl group, whereas both the axial and equatorial conformers are similarly populated if the substituent is an aryl group. In the cone conformation of calixarenes possessing two opposite bridges substituted in trans fashion by a pair of groups, one group must necessarily be located in an axial position. The steric interactions ensuing from the presence of an axial group destabilize the cone conformation, rendering the 1,2-alternate form the lowest energy conformation in some derivatives. Copyright © 2004 John Wiley & Sons, Ltd.

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 7.2EtOAc the dioxocalixarene adopts a partial cone conformation, whereas 9 adopts in the crystal a 1,2-alternate conformation. In both conformations, pairs of geminal rings connected to a carbonyl are oriented in an anti fashion. The relative stability of the partial cone and 1,2-alternate conformations of 7 and 9 is underestimated by MM3 calculations. The topomerization barriers of 7 and 9 are 12.8 and 13.6 kcal mol(-)(1), respectively.

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.

Hexaethylbenzene adopts a conformation with the ethyl groups perpendicular to the aromatic ring and oriented in a fully alternated up-down arrangement. The synthesis, stereochemistry and rotational barriers of systems possessing two polyethylaryl rings in spatial proximity (e.g., decaethylbiphenyl, octaethylbiphenylene) are reviewed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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.

Reaction of the calixarene derivative 7 with two exocyclic double bonds with carbon-, nitrogen-, oxygen-, or sulfur-containing nucleophiles afforded bis(spirodienone) derivatives substituted at two opposite methylene groups in a trans fashion. LiAlH(4) reduction of the bis(spirodienone) derivatives with two methylenes functionalized by thiomethoxy, diethyl malonate, or anilino substituents yielded trans methylene-substituted calix[4]arenes. Upon standing in solution, the calixarene derivative incorporating SMe groups on the bridges underwent trans right harpoon over left harpoon cis isomerization. An equilibration study performed on this calixarene derivative (tetrachloroethane-d(2), 430 K) indicated that the cis isomer is the form of lower free energy.

A new method for the regio- and stereoselective functionalization of two distal methylene groups of p-tert-butylcalixarene (1a) is described. Reaction of the meso bis(spirodienone) calixarene derivative 2a with bromine afforded the tetrabrominated product 3a derived from exo 1,4-additions of bromine to the diene subunits. A phase-transfer-catalyzed reaction of 3a with aqueous NaOH/CH2Cl2 yielded the exo bis(epoxide) calixarene derivative 4. Heating 3a in a vacuum eliminated two molecules of HBr and afforded a product (5b) that retained the C(i) symmetry of the starting material. X-ray analysis indicated that the calixarene derivative 5b possesses two exocyclic double bonds of E configuration. Calixarene 5b undergoes reaction with nucleophiles at the exocyclic double bonds, with concomitant bond shifts and expulsion of the bromine atoms. Selective trans monodeuteration of two methylene groups of 1 was achieved by reaction of 5b with NaBD4 followed by aromatization of the labeled spirodienol derivative. Reaction of 5b with RONa/ROH (R = Me, Et) afforded the methylene-substituted bis(spirodienone) derivatives 9a and 9b possessing two trans alkoxy groups. X-ray crystallography of 9b indicated that the two trans substituents are located at pseudoequatorial positions of the methylene groups. LiAlH4 reduction of the substituted bis(spirodienone) derivatives afforded calix[4]arenes incorporating trans alkoxy groups at two distal methylene positions.

The stereochemistry of the spherand-type calixarene 2a is analyzed in terms of the configuration of the three 2,2'-dihydroxybiphenyl subunits (R or S) and the disposition of the methylene groups (crown or twist). X-ray crystallography indicates that the neutral 2a and its mono- or dianion (in form of the salts 2a(-) x C(5)H(5)NH(+) and 2a(2)(-) x 2Et(3)NH(+)) exist essentially in the same conformation (RRS/SSR-twist). This asymmetric RRS/SSR-twist form is the lowest energy conformer according to molecular mechanics calculations. Low-temperature (1)H NMR data indicate the presence of a major conformer of C(1) symmetry, in agreement with a RRS/SSR-twist form. The lowest energy topomerization pathway mutually exchanges two pairs of methylene protons and is ascribed to an enantiomerization process involving rotation around an Ar-Ar bond.

Two chiral derivatives of a mesitylene-based calix[4]arene known to exist in the 1,3-alternate conformation were prepared by the attachment of homochiral residues to the four exo -hydroxy groups. Thus, the enantiotopic protons of the central scaffold became diastereotopic, leading to a doubling of their 1 H NMR signals in one example. From the temperature independence of the NMR spectrum, a lower limit of 24.2 kcal/mol could be estimated for the barrier of ring inversion. MM3 calculations confirm the 1,3-alternate conformation as the energy minimum, and estimate a barrier of 25.7 kcal/mol for the 1,3-alternate-to-1,3-alternate* interconversion process. This high barrier is due to the repulsive steric interactions between exo -methyl groups at vicinal rings when these groups pass each other.

Reaction of the monospirodienone derivative of p-tert-butylcalix[4]arene with methylene chloride/base in the presence of a phase transfer catalyst yielded the bridged monodioxamethylene derivative 6 which was characterized by X-ray crystallography. Treatment of 6 with NaBH4 resulted in exo-reduction of the carbonyl group and afforded the spiro alcohol 7, which rearranged thermally to the monodioxamethylene bridged calix[4]arene 3. Calixarene 3 exists in solution (CD2Cl2, 198 K) in three different conformations (a cone form with the dioxocine unit in a distorted boat conformation, and cone and partial cone forms with a boat-chair arrangement of the dioxocine) which interconvert with barriers in the 13.5−14.3 kcal mol-1 range. Molecular mechanics calculations indicate that the rate-limiting steps for the conformational interconversions of 3 involve transitions of the dioxocine subunit.

The static and dynamic stereochemistries of tricyclohexylmethane, tetracyclohexylmethane, and tetracyclohexylethene are reviewed. Chirality 10:159–168, 1998. © 1998 Wiley-Liss, Inc.

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.

The stereochemistry of decaethylbiphenyl (5) is analyzed. The potentially low-energy conformers of 5 were generated by formally linking two pentaethylphenyl subunits, and by assuming that no more that one syn interaction is present per ring. Molecular mechanics calculations (MM3 program) indicate that the forms “f”, “i”, “j”, and “m” represent the lowest energy conformations. As previously observed for decakis(bromomethyl)biphenyl, the “a” conformation (devoided of any syn arrangement of two neighboring ethyl groups) is destabilized by the mutual steric interactions of ortho ethyl groups at different rings. Decaethylbiphenyl (5) was synthesized by exhaustive ethylation of biphenyl. The compound exists in the crystal in three different conformations (“i”, “j”, and “m”). Low-temperature 13C NMR data show that the compound exists in CDCl2F at 149 K in two conformations in a 4:1 ratio, and the major conformer was assigned to the “m” form. Dynamic NMR data indicate that “m” undergoes ethyl rotation with a barr...

The first example of the replacement of hydroxyl groups of a calixarene by methyls is described. Reaction of the bis(spirodienone) calixarene derivative 3B with MeLi afforded the bis addition product 4 which is derived, as shown by X-ray crystallography, from attack on the face of the carbonyls which is anti to the ether oxygen. The reaction of the alternant bis(spirodienone) calixarene derivative 3A with excess MeLi resulted in addition to the CO groups, but with a concomitant cleavage of the spiro bonds. Ionic hydrogenation (CF3COOH/Et3SiH) of this product (5) yielded 5,11,17,23-tetra-tert-butyl-25,27-dihydroxy-26,28-dimethylcalix[4]arene (6) while ionic hydrogenation of 4 resulted in fragmentation of the macrocyclic ring. Calixarene 6 adopts a 1,3-alternate conformation both in solution and in the solid state. 6 is conformationally flexible, and an inversion barrier of 15.1 kcal mol-1 was measured for it by DNMR. The dimethyl ether derivative of 6 (i.e., 7) exists in a partial cone (paco) conformation ...

The synthetic methods by which the hydroxyl groups of calix[n]arenes have been formally dehydrated to afford xanthene derivatives, or have been replaced totally or partially by hydrogen, amino, halogen, alkyl, or mercapto groups are reviewed.

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. Keto[n]calixarenes (n = 5, 6) were prepared via hydrolysis of the bromocalixarenes 11 and 12, followed by CrO3 oxidation of the respective hydroxymethylene derivatives. Addition of MeLi to the ketocalix[n]arenes (n = 4, 5 and 6) followed by elimination of water yielded the corresponding calix[n]radialenes. Calix[5]- and calix[6]radialenes adopt in the crystal irregular alternate (i.e., noncone) conformations.

A conformational search procedure (HUNTER), in combination with the MM3(92) program, was used for the exploration of the conformational hypersurface of alkyl-substituted cyclohexanes and for the calculation of their chair/twist-boat (TB) energy gap. The systems studied were conformationally unconstrained polyalkylcyclohexanes (alkyl = methyl, ethyl, isopropyl, and tert-butyl) possessing either geminal and/or vicinal arrangements of the alkyl groups, but differing in the number of alkyl substituents and in their relative disposition (i.e., cis or trans). The calculations indicate that in 1,1,3,3,5,5-hexaisopropylcyclohexane the TB is the lowest energy form. Modification of the cis,trans relationship of vicinal alkyl groups changes the chair/TB energy gap, and in the minimum energy conformation of cis,trans,trans-1,2,3,4-tetraisopropylcyclohexane (23c) and cis,syn,cis-1,2,4,5-tetraisopropylcyclohexane (31c) the cyclohexyl ring adopts a TB conformation. The tetrasubstituted systems cis,syn,cis-1,2-diisopropyl-3,4-dimethylcyclohexane (46), cis,syn,cis-1,4-diisopropyl-2,5-dimethyl-cyclohexane (47), and cis,trans,trans-1,2-diisopropyl-3,4-dimethylcyclohexane (41) are the least crowded monocyclic unconstrained cyclohexanes found in which the TB conformation is of lower energy than the chair form. The present study indicates that two methyls and two isopropyl substituents are sufficient for stabilizing the TB form of a cyclohexyl ring relative to the chair form.

17O NMR spectra at natural isotopic abundance of two calix[n]arenes, (n = 4,6) and model phenols have been obtained in three different solvents. The difference in the hydrogen bond strength between calix[4]arene and calix[6]arene is manifested in the 17O NMR spectra.

Addition of MesMgBr to mesitylphenylketene 3 yields a ca. 3:1 mixture of the magnesium enolates 5-(E) and 5-(Z), whereas reaction of enol 1-(Z) with MesMgBr results in the exclusive formation of enolate 5-(Z). Acetylation of the configurationally stable 5-(E) and 5-(Z) yields the enol acetates 4-(E) and 4-(Z), respectively. The preference for the formation of the (E)-enolate from 3 indicates that the attack occurs preferentially from the side of the formally bulkier mesityl ring. Ketene 3 and the two diastereomeric transition states obtained by attack of MeLi on its CO were calculated by ab initio calculations. 3 adopts a conformation with a planar Ph-CC moiety while the mesityl is nearly perpendicular to this plane. Since the attack on the CO group occurs in the plane of the CC double bond, the coplanar Ph is effectively bulkier to the approaching nucleophile than the twisted Mes and the preferred attack is from the mesityl side. Similar stereoelectronic effects operate in 1,2-dimesityl-2-phenylvinyl cat...

The intraannular introduction of a halogen into a calixarene skeleton is described. Monoaminotetrahydroxy-p-tert-butylcalix[5]arene (2b) was diazotized by treatment with isoamyl nitrite/HCl/EtOH. Thermal dediazoniation of the salt in chloroform yielded monochlorotetrahydroxy-p-tert-butylcalix[5]arene (5a) and the xanthenocalix[5]arene 6. These products result from the capture of an intermediate phenyl cation derivative by chloride ion or intramolecularly, by a neighboring phenol ring. The product ratio 6:5a was not affected by the addition of excess external chloride, suggesting that the reacting intermediate exists as an ion pair. The dediazoniation reaction in the presence of bromide and iodide ions afforded the corresponding halocalixarenes 5b and 5c, while in the presence of a fluoride ion the calixindazole 8 was obtained. X-ray diffraction indicates that 5b exists in a distorted cone conformation (cone-in) in which the extraannular edge of the halophenyl ring is tilted toward the cavity center. The h...

1,2,3-Tricyclohexylcyclohexane (3) and 1,2,3,4-tetracyclohexylcyclohexane (4) were synthesized by catalytic hydrogenation of 1,2,3-triphenylbenzene and 1,2,3,4-tetraphenylbenzene, respectively. The...

In calix[4]arenes when one methylene bridge carries an alkyl or aryl substituent, two diastereomeric cone conformations are possible in which this substituent assumes the equatorial or axial position. Two diastereomers with cis or trans arrangement of the substituents exist for the corresponding compounds with two substituted bridges, and diastereomeric cone conformations have to be considered additionally in most cases. Molecular mechanics calculations predict an energetical preference of the equatorial position of the substituents in both systems. This preference is markedly more pronounced for alkyl groups than for aryl groups. To test these predictions a series of calix[4]arenes in which one (4) or two opposite (5) methylene bridges are substituted by alkyl or aryl groups was synthesized by fragment condensation. For these calixarenes the solution conformations, the equatorial/axial conformational equilibria, and the energy barriers for the cone to cone ring inversion were determined by 1H NMR spectro...

The isomerism of the tris(spirodienone) derivatives of p-tert-butylcalix[6]arene and bis(spirodienone) derivatives of p-tert-butylcalix[5]arene is analyzed. Oxidation of p-tert-butylcalix[6]arene with phenyltrimethylammonium tribromide/base afforded two chiral tris(spirodienone) calix[6]arene derivatives (3 and 4) which react with excess benzyne yielding the corresponding all-exo tris adducts 5 and 6. The structural characterization of the tris(spirodienone) derivatives was achieved by 2D NMR methods and in the case of 3, by X-ray crystallography. The main product 3 possess an alternant disposition of the ether and carbonyl functional groups and three spiro stereocenters of dissimilar configurations (RRS/SSR), while the disposition of the functional groups in 4 is nonalternant. Equilibration studies in toluene at 85 °C indicate that 3 is the thermodynamically most stable isomer. The tris adduct 5 exists in two nearly equally populated conformations which interconvert with a barrier of 12.1 ± 0.2 kcal mol-...