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

Article abstract of DOI:10.1021/jo801187z

(Chemical Equation Presented) The bromine atoms of the hexabromo calixarene derivative 3 were replaced by other groups under S_N1 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). Solvolysis of 3 in TFE in the presence of strong nucleophiles (such as N₃^- and aniline) afforded the corresponding hexaazido and hexaanilino derivatives. Hydroxyl groups were incorporated into the calix[6]arene scaffold via acetolysis of 3, followed by LiAlH₄ reduction of the hexaacetate derivative obtained. Friedel-Crafts alkylations in the absence of Lewis acids were conducted by heating at reflux a mixture of 3, HFIP, and a substituted benzene derivative (e.g, m-xylene, p-methyl anisole, mesitylene). The calix[6]arene bridges were alkylated by heating at reflux a mixture of 3 and 2,4-pentanedione in TFE or HFIP. In all cases the reaction proceeded with high diastereoselectivity, and the major isomer isolated was assigned to the rc₅ (i.e., all-cis) form. NMR spectroscopy indicates that the conformation adopted by the macrocycle possesses 3-fold symmetry (a pinched cone ) that is rigid in the laboratory time scale in the mesityl-substituted derivative.

Full text of DOI:10.1021/jo801187z

Functionalization of the Methylene Bridges of the Calix[6]arene
Scaffold
Katerina Kogan, Ishay Columbus,*,† and Silvio E. Biali*
Institute of Chemistry, The Hebrew UniVersity of Jerusalem, Jerusalem 91904, Israel
ishayc@iibr.goV.il; silVio@Vms.huji.ac.il
ReceiVed June 25, 2008
The bromine atoms of the hexabromo calixarene derivative 3 were replaced by other groups under SN1
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). Solvolysis of 3 in TFE in the presence of strong
nucleophiles (such as N3- and aniline) afforded the corresponding hexaazido and hexaanilino derivatives.
Hydroxyl groups were incorporated into the calix[6]arene scaffold via acetolysis of 3, followed by LiAlH4
reduction of the hexaacetate derivative obtained. Friedel-Crafts alkylations in the absence of Lewis
acids were conducted by heating at reflux a mixture of 3, HFIP, and a substituted benzene derivative
(e.g, m-xylene, p-methyl anisole, mesitylene). The calix[6]arene bridges were alkylated by heating at
reflux a mixture of 3 and 2,4-pentanedione in TFE or HFIP. In all cases the reaction proceeded with high
diastereoselectivity, and the major isomer isolated was assigned to the rc5 (i.e., all-cis) form. NMR
spectroscopy indicates that the conformation adopted by the macrocycle possesses 3-fold symmetry
(a “pinched cone”) that is rigid in the laboratory time scale in the mesityl-substituted derivative.
Introduction
scaffold,1 a versatile method for the introduction of substituents
at all of the methylene groups has remained an elusive goal.2
Calix[6]arenes functionalized at one or two bridges have been
synthesized by the fragment condensation method,3 by a
spirodienone route,4 by an homologous anionic ortho-Fries
rearrangement,5 and via alkylation of a monolithiated tet-
ramethoxy p-tert-butylcalix[4]arene.6,7 Calix[4]arenes substituted
Although numerous synthetic methods have been developed
for the modification of the aromatic rings of the calixarene
† On sabbatical leave from the Israel Institute for Biological Research, P.O.
Box 19, Ness Ziona, Israel.
(1) For reviews on calixarenes see: (a) Calixarenes, a Versatile Class of
Macrocyclic Compounds; Vicens, J., Bo¨hmer, V., Eds.; Kluwer: Dordrecht, 1991.
(b) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (c) Gutsche, C. D.
Aldrichimica Acta 1995, 28, 1. (d) Pochini, A.; Ungaro, R. In ComprehensiVe
Supramolecular Chemistry; Vo¨gtle, F., Ed.; Pergamon Press: Oxford, UK, 1996;
Vol. 2, p 103. (e) Gutsche, C. D. Calixarenes ReVisited; Royal Society of
Chemistry: Cambridge, 1998. (f) Calixarenes 2001; Asfari, Z., Bo¨hmer, V.,
Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001. (g) Bo¨hmer, V. In
The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester, 2003; Chapter
19.
(2) For recent studies of aza[14]metacyclophanes substituted at the nitrogen
bridges see: (a) Ishibashi, K.; Tsue, H.; Tokita, S.; Matsui, K.; Takahashi, H.;
Tamura, R. Org. Lett. 2006, 8, 5991. (b) Tsue, H.; Ishibashi, K.; Takahashi, H.;
Tamura, R. Org. Lett. 2005, 7, 2165. (c) Zhang, E.-X.; Wang, D.-X.; Zheng,
Q.-Y.; Wang, M.-X. Org. Lett. 2008, 10, 2565. (d) Vale, M.; Pink, M.; Rajca,
S.; Rajca, A. J. Org. Chem. 2008, 73, 27. (e) Ito, A.; Inoue, S.; Hirao, Y.;
Furukawa, K.; Kato, T.; Tanaka, K. Chem. Commun. 2008, 3242.
10.1021/jo801187z CCC: $40.75
Published on Web 08/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7327–7335 7327

Kogan et al.
by phenyl groups at all of the bridges have been prepared via
addition of PhLi to a ketocalix[4]arene derivative followed by
ionic hydrogenation of the tetraalcohol product.8 The methylene
groups of calix[6]arene derivatives have been oxidized to
carbonyl groups9 and have been monobrominated,10 but no
general synthetic procedure has been reported for the preparation
of calix[6]arenes with all methylene bridges monosubstituted.
We have recently reported that the tetrabromocalix[4]arene
derivatives 1a and 1b are useful intermediates for the preparation
of methylene-functionalized calix[4]arenes. C-O, C-N, and
even C-C bonds can be readily formed at the four bridges under
mild solvolytic conditions.11 Here we describe the application
of this synthetic route to the large-ring calix[6]arene scaffold.
FIGURE 1. Stereoisomers arising from the different cis or trans disposi-
tion of identical substituents on the six bridges of a calix[6]arene. The
calixarene macrocycle is schematically represented as a hexagon.
substituent. These forms arise from the possible relative
dispositions (cis or trans) of the substituents at the bridges
(Figure 1). The eight diastereomeric forms of a substituted
calix[6]arene are analogous to those present in the classical case
of a 1,2,3,4,5,6-hexasubstituted cyclohexane (e.g., the inosi-
tols).12 The different forms can be designated by describing the
cis (c) or trans (t) disposition of the substituents relative to the
reference (r) substituent. For simplicity, a series of n substituents
on adjacent bridges in a cis or trans disposition relative to the
reference substituents are designated as cn and tn, respectively.
Although each descriptor unambiguously characterizes each
isomer, in some cases several descriptors are possible for a given
structure, depending on the identity of the substituent chosen as
reference and whether a clockwise or counterclockwise sequencing
order is used. In Figure 1, we chose arbitrarily the more “compact”
descriptor (e.g., rt5 and rtc3t, instead of rc4t and rc2tct, respectively).
Under a time scale of rapid internal rotations, only the rtc2t2 form
(which is stereochemically analogous to the “chiro” isomer of
inositol)12 is chiral, while the rest are achiral. Clearly, the
monofunctionalization of the six methylene bridges of a calix[6]arene
in stereoselective fashion is more challenging than the correspond-
ing transformation of a calix[4]arene due to the larger number of
possible diastereomeric products (eight for a substituted calix[6]arene
vs four for a calix[4]arene).
Hexabromo Calix[6]arene Derivative 3. The calixarene 3
was prepared by reaction of the corresponding hexamethoxy
derivative 2 with NBS under irradiation using a minor modifica-
tion of the reported literature procedure.10 The NMR spectrum
of 3 displays a simple pattern (one singlet each for the t-Bu,
methoxy, methine, and aromatic protons) indicating a highly
symmetric molecule. The NMR pattern could correspond to
either rc5 or rtctct configuration patterns. However, by analogy
with 1a and 1b, which according to the X-ray crystallography
possess the rccc configuration,11a,13 we tentatively ascribe to 3
the rc5 configuration.
Results and Discussion
Configurational Stereoisomerism in Methylene-Functional-
ized Calix[6]arenes. A calix[6]arene derivative monofunction-
alized at each methylene bridge possesses six stereocenters, and
several configurational isomers are possible. Under a time scale
of rapid rotation around the Ar-C bonds, the macrocyclic ring
of the calixarene can be depicted schematically by a planar
hexagon, with each corner representing a monosubstituted
bridge. Eight diastereomeric forms are possible for a calix[6]arene
derivative monosubstituted at all bridges by an identical
(3) (a) Tabatai, M.; Vogt, W.; Bo¨hmer, V. Tetrahedron Lett. 1990, 31, 3295.
(b) Sartori, G.; Maggi, R.; Bigi, F.; Arduini, A.; Pastorio, A.; Porta, C. J. Chem.
Soc., Perkin Trans. 1994, 1, 1657. (c) Sartori, G.; Bigi, F.; Porta, C.; Maggi, R.;
Mora, R. Tetrahedron Lett. 1995, 36, 2311. (d) Biali, S. E.; Bo¨hmer, V.; Cohen,
S.; Ferguson, G.; Gru¨ttner, C.; Grynszpan, F.; Paulus, E. F.; Thondorf, I.; Vogt,
W. J. Am. Chem. Soc. 1996, 118, 2261. (e) Bergamaschi, M.; Bigi, F.; Lanfranchi,
M.; Maggi, R.; Pastorio, A.; Pellinghelli, M. A.; Peri, F.; Porta, C.; Sartori, G.
Tetrahedron 1997, 53, 13037. (f) Tsue, H.; Enyo, K.; Hirao, K. Org. Lett. 2000,
2, 3071. For a review on the synthesis of calixarenes via the stepwise and
fragment condensation methods see: (g) Bo¨hmer, V. Liebigs Ann./Recueil 1997,
2019.
(4) (a) Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495. (b)
Simaan, S.; Agbaria, K.; Biali, S. E. J. Org. Chem. 2002, 67, 6136. (c) Simaan,
S.; Biali, S. E. J. Org. Chem. 2003, 68, 3634. (d) Simaan, S.; Biali, S. E. J. Org.
Chem. 2003, 68, 7685. For a review on spirodienone calixarene derivatives, see:
(e) Biali, S. E. Synlett 2003, 1.
(5) Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt, D. N.;
Snieckus, V. J. Org. Chem. 2000, 65, 667.
(6) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org. Lett. 2001, 3, 2741.
(7) For a review on the stereochemistry of calix[4]arene derivatives func-
tionalized at one or two bridges, see: Simaan, S.; Biali, S. E. J. Phys. Org. Chem.
2004, 17, 752.
(8) Kuno, L.; Seri, N.; Biali, S. E. Org. Lett. 2007, 9, 1577.
(9) (a) Matsuda, K.; Nakamura, N.; Takahashi, K.; Inoue, K.; Koga, N.;
Iwamura, H. J. Am. Chem. Soc. 1995, 117, 5550. (b) Kogan, K.; Biali, S. E.
Org. Lett. 2007, 9, 2393. A calix[6]arene possessing a single carbonyl bridge
was synthesized by Sone and co-workers by a stepwise route. See: (c) Ito, K.;
Izawa, S.; Ohba, T.; Ohba, Y.; Sone, T. Tetrahedron Lett. 1996, 37, 5959.
(10) Kumar, S. K.; Chawla, H. M.; Varadarajan, R. Tetrahedron Lett. 2002,
43, 7073.
(12) See for example: Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochem-
istry of Organic Compounds; Wiley: New York, 1994.
(13) Klenke, B.; Na¨ther, C.; Friedrichsen, W. Tetrahedron Lett. 1998, 39,
8967.
(11) (a) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927. (b) Columbus,
I.; Biali, S. E. J. Org. Chem. 2008, 73, 2598.
7328 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalization of Methylene Bridges of Calix[6]arene Scaffold
Reaction of 3 with Alcohols. Preparation of Hexaalkoxy
Derivatives. Heating at reflux a solution of 3 in primary (MeOH,
EtOH, 1-PrOH, 1-n-BuOH, 1-i-BuOH) or secondary alcohols
(i-PrOH, cyclopentanol, cyclohexanol) afforded in good yields
a single major hexaalkoxy product (4a-g, eq 1). By analogy
to 1b, we assume that these reactions take place via a SN1
mechanism involving heterolytic stepwise cleavage of the C-Br
bonds followed by reaction of the resulting benzhydryl-type
cation with the solvent. The reaction conditions for the solvolysis
of 3 are milder than those used for achieving a similar
transformation in the tetrabromo derivative 1b (an ionizing
solvent such as 2,2,2-trifluoroethanol (TFE) or hexafluoroiso-
propanol (HFIP) or higher temperatures are required). No
reaction was observed for the bulky t-BuOH. Reflux of 3 in
TFE afforded the corresponding hexakis(trifluoroethoxy) deriva-
tive 4i.
FIGURE 2. Crystal structure of 4a.
FIGURE 3. 1H NMR spectrum (500 MHz, CD2Cl2) of 4b at 170 K.
Two methylene signals are observed for the OCH2 groups (3.48 and
3.31 ppm). As a result of broadening effects, the ethoxy groups signals
display no measurable coupling.
Two alcohols required modified reaction conditions. Calix-
arene 3 is insoluble in HFIP, and only starting material was
obtained after reflux for 3 h in the fluorinated alcohol. The
hexakis(hexafluoropropoxy) derivative 4j was obtained when
the reaction was conducted in the presence of a base (i.e., 10%
v/v lutidine in HFIP). It seems likely that the role of the lutidine
is to increase the solubility of 3 in the reaction medium and to
generate hexafluoroisopropoxide, which is a better nucleophile
than HFIP. Solvolysis of 3 in ethylene glycol afforded a mixture
of products, but using a 3:1 mixture of the glycol and TFE
yielded 4k in low yield.14 In all cases a single major hexasub-
stituted isomer was obtained, which on the basis of its high
symmetry is ascribed to the rc5 form. X-ray crystallography
corroborated the rc5 configuration of 4a (Figure 2). The
macrocycle adopts a “pinched cone” conformation (see below).15
The possibility of selectively cleaving the lower rim methoxy
groups in the presence of the alkoxy substituents on the bridges
was briefly examined. We chose the hexaisopropoxy derivative
4d as substrate since we expected that the bulky isopropyl
groups should hinder the approach of the cleavage reagent to
the ether groups at the bridges, thus resulting in preferential
O-Me cleavage. However, treatment of 4d with BBr3/CH2Cl2
afforded the hexabromo derivative 3 as the major reaction
product. The calix-OPri bonds are apparently the more labile
ether bonds in the molecule. For the methylene-functionalized
calix[4]arenes we have observed previously that in some cases
the ether bonds to the calix scaffold can be quite labile.
Specifically, attempted recrystallization of the rccc form of a
tetramethoxy derivative of calix[4]arene (1c) resulted in a
mixture of the rccc, rcct, and rctt forms indicating that
isomerization took place, most likely proceeding via heterolytic
cleavage of the C-OMe bonds.11b
1
Low-Temperature NMR Studies of 4b and 4d. The H
NMR spectrum of the alkoxy derivatives displayed at room
temperature a broad signal for the lower-rim methoxy groups.
The hexaethoxy and hexaisopropoxy ether derivatives (4b and
4d, respectively) were chosen for low-temperature NMR studies.
Upon lowering the temperature of samples of 4b (500 MHz,
CD2Cl2) the broad signals decoalesced, and at 170.1 K (slow
exchange conditions on the NMR time scale) the t-Bu, aromatic,
and methoxy groups each appeared as a pair of signals (Figure
3). Notably, a large separation was present between the two
methoxy signals (ca. 2.3 ppm). One methoxy signal resonates
at an unusual high field for a methoxy group (1.61 ppm),
indicating that one type of methoxy group is located in the
shielding region of a neighboring aryl group. Two signals were
(14) A higher proportion of TFE yielded products (according to NMR
spectroscopy) containing bridges substituted by both 2-hydroxyethoxy and
trifluoroethoxy groups.
(15) Unfortunately, the structure could only be refined to a relatively high R
factor (R ) 0.1339).
J. Org. Chem. Vol. 73, No. 18, 2008 7329

Kogan et al.
SCHEME 1
observed for the methylene protons of the ethoxy groups.16
This pattern suggests that in the conformation adopted, the
six substituted bridges are equivalent, but no mirror planes
bisecting a pair of opposite bridges are present. On the basis
of the 3-fold symmetry indicated by the NMR data and the
shielding of only one type of methoxy groups, we propose
that in solution the molecule adopts a “pinched cone”
conformation of C3V symmetry, which can be viewed as
generated from a 3-fold distortion of the ideal cone confor-
mation of C6V symmetry. In this conformation the six bridges
are symmetry equivalent, but the rings at positions 1, 3, and
5 are less twisted than the rings at the 2, 4 and 6 positions
(cf. Scheme 1). The methoxy signal at 1.61 ppm is assigned
to the methoxy groups of the less twisted rings that are
pointing “in” (toward the cavity) and are shielded by the
neighboring aryl rings, while the methoxy signal at 3.91 ppm
is ascribed to the methoxy groups that are pointing “out”.
From the chemical shift difference of groups under slow
exchange conditions in CD2Cl2 at 500 MHz (∆ν ) 513.5, 86.0,
and 1150.5 Hz for the aromatic, methylene, and methoxy groups),
and their coalescence temperatures (206.0, 191.3, and 215.0 K,
respectively), a rotational barrier of 9.0 ( 0.1 kcal mol-1 was
calculated for 4b by means of the Gutowsky-Holm17 and Eyring
equations. This rotational process is ascribed to a pinched cone/
pinched cone interconversion, a process that exchanges the two
types of rings in the macrocycle (Scheme 1).
of reduced products containing methylene and CH-OR
bridges, whereas in the case of the HFIP/TFE only starting
material was recovered after 2 h reflux. Full reduction of
the bridges was obtained in the reaction of 3 with HFIP/
ethanol and HFIP/isopropanol mixtures (eq 2). The formation
of 2 can be viewed as resulting from hydride transfer between
the alcohol molecules and the carbocationic intermediates.
Since no reduced product was obtained in the reaction of 3
with pure TFE, EtOH or HFIP (eq 1), it seems likely that a
mixture of both HFIP and the nonfluorinated solvents is
required.
The low-temperature 1H NMR spectrum of the hexaisopropoxy
derivative 4d displayed two signals for the isopropyl methyl groups
(δ 1.30 and 1.20 ppm at 168 K). The coalescence data for 4d (∆ν
) 420 and 1100 Hz and Tc) 185.2 and 198.0 K, for the aromatic
and methoxy groups, respectively) afforded a lower barrier (8.2 (
0.2 kcal mol-1) than the one found for 4b. Thus, in the case of the
alkoxy substituents, increasing the bulk of the alkoxy groups
reduces the rotational barrier, most likely due to preferential steric
destabilization of the ground state.
Hydride Capture by Carbocation Intermediates. In an
attempt to introduce chiral groups on the calix[6]arene
bridges, calixarene 3 was reacted with R-(-)-2-butanol. The
reaction was conducted using a ca. 20:1 (v/v) mixture of HFIP
and the chiral alcohol. Surprisingly, the only product obtained
was the unsubstituted derivative 2. The reaction was exam-
ined using mixtures of HFIP with different alcohols. Reaction
with HFIP/MeOH or HFIP/ethylene glycol afforded a mixture
To determine the source of the hydride transferred to the
bridges of the calixarene, we conducted the reaction in a
mixture of HFIP and ethanol-d6. If the source of the hydride
is the HFIP, no labeling should be present in the final product,
whereas if the source is a C-D bond of the ethanol molecules,
the final product should incorporate a single deuterium atom
on each bridge.18 1H NMR analysis of the product indicated
that compound 5 was formed, possessing a deuterium atom
in each bridge (Figure 4). This demonstrates that the source
of the atom transferred to the carbocationic intermediates is
the ethanol molecules and not the fluorinated alcohol present
in excess.
(18) Upon mixing the two solvents, there is a fast exchange between the OD
group of the ethanol-d6 and the OH group of the HFIP molecules. For the ca. 20:1
mixture used, the labeling of the OH groups of both the ethanol and HFIP molecules
should be about 5%. If the source of the hydrogen transferred is the hydroxyl group
of either the ethanol or HFIP molecules (a mechanism not involving hydride transfer),
disregarding solvent isotope effects, it could be expected that only a small percent
of deuterium should be incorporated at the bridges.
(16) As a result of broadening effects, no coupling is observed for the signals
of the diastereotopic methylene and the methyl moieties of the ethoxy groups.
(17) Gutowsky, H. S.; Holm, C. H. J. Chem. Phys. 1956, 25, 1228.
7330 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalization of Methylene Bridges of Calix[6]arene Scaffold
azide and aniline. The incorporation of azido groups into the
calix scaffold is of interest since they may enable a large number
of chemical modifications, e.g., via 1,3-dipolar cycloaddition
to alkynes (click chemistry).20 The reaction of aniline, if
proceeding via C-N bond formation will result in calixarene
derivatives incorporating basic functionalities at the bridges.21
The reaction with azide was conducted by heating at reflux
a mixture of 3, NaN3, and TFE. 18-Crown-6 was added to the
mixture to increase the solubility of the azide salt in the solvent.
NMR and MS analysis of the product obtained after recrystal-
lization from CHCl3/MeOH indicated the formation of the
hexaazido derivative 6 (rc5 isomer, ca. 95% pure).22
FIGURE 4. 1H NMR spectrum (CDCl3) of the methoxy and methylene
groups of 2 (bottom) and 5 (top). The broadening of the CHD signal
is due to unresolved H-D coupling.
1
Hydride transfer reactions from alcohols to carbocations under
acidic conditions are known.19 However, the formation of 2 in the
solvolysis of 3 in the mixtures HFIP/EtOH and HFIP/i-PrOH was
unexpected, since only the hexaalkoxy derivatives were formed in
the reaction with the neat aliphatic alcohols. The formation of 2
can be rationalized if initially an ether bond is formed between
the aliphatic alcohol and the calix carbocation, but in the highly
ionizing and acidic solvent HFIP this bond undergoes a reversible
heterolytic cleavage, regenerating the carbocation. The competing
hydride transfer reaction, although slower than the ether formation
reaction, is irreversible, and eventually all of the bridges are reduced
(Figure 5). To test this hypothesis, a solution of the hexaisopropoxy
derivative 4d was heated at reflux for 2 h in a HFIP/i-PrOH mixture
(reaction conditions identical to those used in the reaction of 3).
Examination of the crude product indicated complete conversion
to 2, indicating that indeed the ether bonds of 4d are cleaved under
the experimental conditions. In the case of the reaction of 3 with
the neat aliphatic alcohols, most likely the lower ionizing power
and lower acidity of the alcohol (as compared to HFIP) are
sufficient for inducing the dissociation of the C-Br bonds but not
sufficient for the heterolytic cleavage of the C-O bonds at the
bridges, and therefore the reaction does not proceed beyond the
hexalkoxy stage. The aliphatic alcohols EtOH and i-PrOH are better
hydride transfer reagents than HFIP, since hydride transfer from
the latter would result in protonated hexafluoroacetone, in which
the positive charge in the protonated carbonyl group is destabilized
by the two electron-withdrawing CF3 groups. The reaction condi-
tions can be used for other systems generating relative stable
carbocations as shown by heating at reflux a solution of trityl
chloride in a HFIP/i-PrOH mixture, which afforded triphenyl-
methane.
Reaction of 3 with aniline was conducted in TFE. H NMR
analysis indicated that C-N bond formation took place, as
evidenced by a pattern characteristic of a monosubstituted
phenyl ring.
Hexaacetoxy and Hexahydroxy Derivatives. Incorporation
of hydroxy groups on the bridges was achieved by a two-step
process, involving acetolysis of 3, followed by LiAlH4 reduction
of the hexaacetoxy derivative 8 (eq 3). Hexahydroxycalix[6]arene
9 displayed a doublet for the OH protons (δ ) 5.50, J ) 6 Hz)
1
in the H NMR spectrum in DMSO-d6.
Friedel-Crafts Reactions. Solvolytic Friedel-Crafts alky-
lation reactions in the absence of a Lewis acid were recently
reported by Mayr and co-workers.23 We have shown that these
types of reactions can be conducted on the tetrabromocalixarenes
1a and 1b using TFE/butylene oxide (for 2-methylfuran) or
HFIP (for m-xylene) as solvents. Notably, the product obtained
in the reaction of 1a with m-xylene was partially de-
methylated.11b Apparently, the HBr released in the solvolytic
reaction is capable of cleaving the lower rim O-Me bonds. The
Friedel-Crafts reaction failed when the reaction was attempted
with the crowded mesitylene as the aromatic substrate.
We found that the solvolytic Friedel-Crafts reaction of
calixarene 3 proceeds readily with aryl rings substituted by
electron-donating groups. To avoid the formation of mixture
of products arising from substitution at different positions of
the ring (e.g., ortho and para to the electron-donating substitu-
ent), only aromatic rings expected to preferentially undergo
monosubstitution at a single position were used. In contrast to
(20) For an example of the utilization of the 1,3-dipolar cycloaddition of
azides for the preparation of water soluble calixarenes, see: Ryu, E.-H.; Zhao,
Y. Org. Lett. 2005, 7, 1035.
(21) For a calix[4]arene substituted at two bridges by dimethylamino groups,
see: Simaan, S.; Biali, S. E. Org. Lett. 2005, 7, 1817.
(22) The minor product formed is probably a pentaazido mono(trifluoroet-
hoxy) calix[6]arene derivative as evidenced by the small quartet at ca. 3.95 ppm
characteristic of the protons of a trifluoroethoxy group.
(23) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew Chem. Int.
Ed. 2004, 43, 5402.
Reaction with N-Nucleophiles: Azide and Aniline. We also
examined the reaction of 3 with N-nucleophiles, specifically
(19) Bartlett, P. D.; McCollum, J. D. J. Am. Chem. Soc. 1956, 78, 1441. See
also: Lu, Y.; Qu, F.; Moore, B.; Endicott, D.; Kuester, W. J. Org. Chem. 2008,
73, 4763.
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Kogan et al.
FIGURE 5. Hydride transfer versus capture by the nonfluorinated alcohol (ROH) in the solvolysis of 3 in a HFIP/ROH mixture.
that found for the other calixarenes indicating 3-fold symmetry
was observed.24
The NMR pattern under slow exchange conditions (on the
NMR time scale) of the macrocyclic rings of 10-14 indicating
3-fold symmetry suggests that the calix[6]arenes functionalized
at the bridges by aryl groups adopt also pinched cone conforma-
tions of 3-fold symmetry.25
Rotational Barriers of Arylated Calixarenes. The rotational
barriers of calixarenes 10, 11, and 13 were determined by
dynamic NMR. From the coalescence of the t-Bu and aromatic
protons of 10 (kc ) 136.6 and 261.0 s-1 and Tc ) 413.0 and
427.0 K), a barrier of 20.5 ( 0.1 kcal mol-1 was calculated by
means of the Eyring equation. For the p-xylyl derivative 11, a
barrier of 20.4 kcal mol-1 was determined from the coalescence
of the t-Bu groups. Calixarene 13 is significantly more flexible,
and from the coalescence data of the calix aromatic protons
and lower rim methoxy groups, a barrier of 14.1 ( 0.2 kcal
mol-1 was determined. The lower barrier of 13 suggests that
the barrier height is a function of the bulk of the substituent
the reaction of 1a and 1b, no demethylation was observed under
the reaction conditions, and the single major product was the
hexaaryl-substituted derivatives 10-13 (eq 4). Moreover, even
the crowded mesitylene reacted readily, affording the hexam-
esityl derivative 14. Since HFIP is relatively expensive, we
examined also the reaction in the presence of a cosolvent. We
found that the reaction proceeds readily even if a 4:1 mixture
of chloroform and HFIP is used instead of pure HFIP.
1
In the 500 MHz H NMR spectra of the calixarenes 10-12
and 14 at room temperature, each of the t-Bu, aromatic and
methoxy groups appeared as a pair of signals. In all cases the
aryl rings at the bridges displayed a single set of signals. The
1H NMR spectrum of calixarene 13 in CDCl3 displayed at room
temperature sharp signals for the aryl rings at the bridges, but
broad signals for the lower rim methoxy groups, t-Bu, and
aromatic protons of the calix[6]arene skeleton, suggesting that
this calixarene is the more flexible in the series 10-14. Upon
lowering the temperature of a sample of 13, a pattern similar to
(24) Notably, in the low temperature NMR spectrum of 13 in CD2Cl2 (278
K) both lower rim methoxy groups resonated at a relatively low field (4.26 and
4.08 ppm) compared to the other hexaaryl derivatives. This suggests that the
conformation adopted by 13 in that solvent is somewhat different. It may be
possible that in CD2Cl2 all of the lower rim methoxy groups are oriented in an
“out” fashion (i.e., pointing away from the cavity) and/or the twist angles of the
rings is different.
(25) X-ray crystallography of 14 (see Supporting Information) indicates that
the configuration of the substituents is rc5 and that the macrocycle adopts a
“pinched cone” conformation. Unfortunately, the structure could only be refined
to a relatively high R factor, but we believe the major structural features
mentioned above are trustworthy.
7332 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalization of Methylene Bridges of Calix[6]arene Scaffold
TABLE 1. Summary of Reactions Involving the Replacement of
All Bromine Atoms of 3
located ortho to the bond connecting the aryl substituent with
the calix macrocycle. The dynamic process is ascribed to a
pinched cone/pinched cone interconversion (cf. Scheme 1).
Notably, separate signals were observed in the room tem-
nucleophilic reagent
solvent
product
MeOH
EtOH
1-PrOH
2-PrOH
1-n-BuOH
1-i-BuOH
cyclopentanol
cyclohexanol
TFE
MeOH
EtOH
1-PrOH
2-PrOH
1-n-BuOH
1-i-BuOH
4a
4b
4c
4d
4e
4f
4g
4h
4i
1
perature H NMR spectrum of 14 for both the ortho methyl
groups and the aromatic protons of the mesityl groups. This
indicates that, at least for 14, both the internal rotations of the
macrocyclic ring and the rotations of the aryl substituents at
the bridges are slow at room temperature on the NMR time
scale. Heating a sample of 14 in C6D5NO2 up to 458 K did not
result in any appreciable broadening of the signals. From the
chemical shift difference between the t-Bu signals at 458 K (8
Hz at 500 MHz) and assuming that the coalescence of the signals
is at least 460 K, a lower limit of 24.6 kcal mol-1 was estimated
for the pinched cone-pinched cone interconversion of 14. The
rotational barrier of 14 could be measured by EXSY. From the
relative integration of the cross peaks between the methoxy
signals in an EXSY spectrum at 452.4 K, a rotational barrier of
27.8 kcal mol-1 was determined.26 The hexamesityl derivative
14 can be viewed as conformationally rigid at room temperature
in the laboratory time scale. Clearly, the introduction of bulky
aryl group at the bridges increases the rigidity of the pinched
cone conformation. This approach may be used when a reduction
in the flexibility (preorganization) of the calix[6]arene scaffold
is desirable.27
Alkylation of Calixarene Bridges. Although C(sp3)-C(aryl)
rings can be readily introduced at the bridges via the solvolytic
Friedel-Crafts reaction, it was not clear at first whether alkyl
substituents can be attached to the bridges by an analogous route
using a substituent possessing a double bond (i.e., a process
involving formation of C(sp3)-C(sp3) bonds). Carbonyl com-
pounds in equilibrium with a relatively highly populated enol
form were selected as nucleophiles, since reaction of the
intermediate carbocation with the enol form of the carbonyl was
expected to occur readily. The Lewis acid catalyzed alkylation
of benzhydryl cations with compounds possessing active me-
thylenes has been reported in the literature.28 Since the solvolytic
Friedel-Crafts reaction in the absence of Lewis acid work
efficiently for 3, we attempted the reaction with active methylene
compounds under similar reaction conditions (i.e., TFE or HFIP
as solvents without the introduction of an additional Lewis acid).
Initial experiments were conducted by heating at reflux a
solution of 3 and ethyl acetoacetate in HFIP or TFE. Since a
complex mixture of products was obtained, the reaction was
repeated in neat ethyl acetoacetate. Unexpectedly, the product
consisted of the hexaethoxy derivative 4b. It seems likely that
under the reaction conditions there is a partial hydrolysis of
the ethyl acetoacetate and the EtOH formed successfully
competes with the enolic form of the ethyl acetoacetate in the
cyclopentanol
cyclohexanol
TFE
HFIP
HFIPa
4j
ethylene glycol
3:1 ethylene glycol/TFE
20:1 HFIP/ethanol-d6
TFE
4k
5
6
NaN3
aniline
acetic acid
m-xylene
p-xylene
1,2,3,4-tetramethylbenzene
p-methylanisole
mesitylene
TFE
acetic acid
7
8 (9)b
10
11
12
13
14
15
4:1 CHCl3/HFIP
4:1 CHCl3/HFIP
4:1 CHCl3/HFIP
4:1 CHCl3/HFIP
4:1 CHCl3/HFIP
TFE or HFIP
acetylacetone
a In the presence of 10% lutidine. b Hexahydroxy calixarene 9 was
obtained after LiAlH4 reduction of the hexaacetoxy calix[6]arene 8.
reaction with the carbocation intermediate. No reaction was
observed when the hexaisopropoxy derivative 4d was heated
in neat ethyl acetoacetate.
To avoid the formation of alkoxy products, the reaction was
conducted with 2,4-pentanedione, which is highly enolic, but
in contrast to ethyl acetoacetate does not undergo hydrolysis.
The reaction proceeded in either HFIP or TFE, affording the
hexaalkylated calixarene 15 (eq 5).29 No signals corresponding
to the enol form of the diacetylmethyl substituents were detected
in both CDCl3 and DMSO-d6.
Conclusions
(26) We thank Dr. Roy Hoffman (Hebrew University) for conducting this
experiment.
Calix[6]arenes derivatives monosubstituted at all bridges can
be prepared by reaction under SN1 conditions of the hexabromo
calixarene derivative 3 with the appropriate nucleophile. The
reaction proceeds with a wide array of nucleophiles (alcohols,
azide ion, aniline, benzene derivatives) and even with acety-
lacetone (Table 1). The reaction in general is cleaner than the
one for the tetrabromo derivatives 1a and 1b, with fewer side
reactions (no demethylation was observed in the solvolytic
Friedel-Crafts reactions). In all cases a single major product
(27) For other approaches based on derivatizing the OH groups of a
calix[6]arene with bulky groups or via bridging, see: (a) Grynszpan, F.; Aleksiuk,
O.; Biali, S. E. J. Chem. Soc., Chem. Commun. 1993, 13. (b) Araki, K.; Akao,
K.; Otsuka, H.; Nakashima, K.; Inokuchi, F.; Shinkai, S. Chem. Lett. 1994, 1251.
(c) Otsuka, H.; Araki, K.; Shinkai, S. J. Org. Chem. 1994, 59, 1542. (d) Otsuka,
H.; Araki, K.; Matsumoto, H.; Harada, T.; Shinkai, S. J. Org. Chem. 1995, 60,
4862. (e) Otsuka, H.; Shinkai, S. J. Am. Chem. Soc. 1996, 118, 4271. See also: (f)
Janssen, R. G.; Verboom, W.; van Duynhoven, J. P. M.; van Velzen, E. J. J.;
Reinhoudt, D. N. Tetrahedron Lett. 1994, 35, 6555. (g) Kraft, K.; Bohmer, V.;
Vogt, W.; Ferguson, G.; Gallagher, J. F. J. Chem. Soc., Perkin Trans. 1 1994,
1221. (h) Chen, Y. Y.; Li, H. B. New J. Chem. 2001, 25, 340.
(28) (a) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823. (b)
Jana, U.; Biswas, S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4066. (c) Sanz, R.;
Miguel, D.; Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Org. Lett.
2007, 9, 2027.
(29) This reaction was also attempted with the tetrabromocalixarene 1b, but
reaction in either TFE or HFIP afforded only a complex mixture.
J. Org. Chem. Vol. 73, No. 18, 2008 7333

Kogan et al.
34.3, 31.3, 28.9, 19.8 ppm. HRMS (ESI) m/z 1513.0584 [(M +
was formed (assigned to the rc5 form) that could be purified by
simple recrystallization. Introduction of the substituents at the
bridges rigidifies the calix[6]arene scaffold.
Na)+, calcd for C96H144NaO12, 1513.0555].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexacyclopentyloxycalix[6]arene (4g). Yield 38 mg
1
(37%), mp 319-321 °C. H NMR (CDCl3, 500 MHz) δ 7.28 (s,
Experimental Section
12H), 6.21(s, 6H), 3.95 (m, 12H), 3.13 (br s, 18H), 1.59 (br m,
48H), 1.08 (s, 54H) ppm. 13C NMR (CDCl3, 125 MHz) δ 154.1,
145.6, 134.07, 125.8, 80.2, 69.9, 61.6, 34.4, 32.4, 31.4, 23.5 ppm.
HRMS (ESI) m/z 1585.0584 [(M + Na)+, calcd for C102H144NaO12,
1585.0555].
2,8,14,20,26,32-Hexabromo-5,11,17,23,29,35-hexa-tert-butyl-
37,38,39,40,41,42-hexamethoxy-calix[6]arene (3). A mixture of 2
(11.0 g, 10.4 mmol), NBS (13.6 g, 76.4 mmol), and CCl4 (500
mL) was heated at reflux for 22 h while being irradiated with a
spotlight (100 W). After the mixture cooled to room temperature,
aqueous Na2SO3 was added. The organic phase was filtered, and
the solid product was recrystallized from CHCl3/MeOH yielding
7.2 g (54%) of 3 as a white solid. If after the addition of aqueous
Na2SO3 there was no solid in the organic phase, it was washed
twice with water, dried (MgSO4) and evaporated. Recrystallization
was carried out in CHCl3/MeOH.
General Procedure for Preparation of the Hexaalkoxy Calix[6]ar-
ene Derivatives 4a-4i. If not stated otherwise, all of the reactions
were conducted under an open atmosphere without any moisture
protection. A mixture of 3 (0.10 g, 0.07 mmol) and 10 mL of the
appropriate alcohol was heated at reflux for two h. After evaporation
of the solvent, the residue was recrystallized from CHCl3/MeOH.
5,11,17,23,29,35-Hexa-tert-butyl-2,8,14,20,26,32,37,38,39,40,41,42-
dodecamethoxycalix[6]arene (4a). Yield 35 mg (43%). Mp 235-
238 °C. 1H NMR (CDCl3, 400 MHz) δ 7.26 (s, 12H), 6.06 (s, 6H),
3.74 (s, 18H), 3.11 (br s, 18H), 1.09 (s, 54H) ppm. 13C NMR
(CDCl3, 100 MHz) δ 154.5, 146.3, 133.4, 124.9, 73.2, 61.4, 57.3,
34.4, 31.3 ppm. HRMS (ESI) m/z 1259.7733 [(M + Na)+, calcd
for C78H108NaO12, 1259.7738].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexacyclohexyloxycalix[6]arene (4h). After evapora-
tion of the solvent, the crude product was dissolved in 50 mL of
chloroform and washed twice with water, and the organic phase
was dried with MgSO4. Recrystallization from CHCl3/MeOH
yielded 43 mg (40%) of the hexacyclohexyloxy derivative. Mp
1
315-317 °C. H NMR (CDCl3, 500 MHz) δ 7.34 (s, 12H), 6.33
(s, 6H), 3.26 (m, 6H), 3.18 (s, 18H), 1.97 (m, 12H), 1.70 (m, 12H),
1.53 (m, 12H), 1.32 (m, 12H), 1.06 (m, 12H), 1.08 (s, 54H) ppm.
13C NMR (HRMS (ESI) m/z 1669.1523 [(M + Na)+, calcd for
C
108H156NaO12, 1669.1494].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis(2,2,2-trifluoroethoxy)calix[6]arene (4i).
The reaction was carried out as described in the general procedure,
but the mixture was heated at reflux for 4 h. Recrystallization from
1
CHCl3/MeOH yielded 56 mg (52%). Mp 325-328 °C. H NMR
(CDCl3, 400 MHz) δ 7.31 (s, 12H), 6.26 (s, 6H), 3.83 (q, J ) 7.6
Hz, 12H), 3.08 (br s, 18H), 1.10 (s, 54H) ppm. 13C NMR (CDCl3,
125 MHz) δ 154.6, 147.1, 132.1, 128.9, 125.4 (q, J ) 278.8 Hz),
72.3, 66.6 (q, J ) 30.0 Hz), 61.7, 34.5, 31.2 ppm. 19F NMR (CDCl3,
376 MHz) δ -73.67 ppm. HRMS (ESI) m/z 1667.6976 [(M +
Na)+, calcd for C84H102F18NaO12, 1667.6981].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexaethoxy-calix[6]arene (4b). Yield 32 mg (37%).
1
Mp 242-244 °C. H NMR (CDCl3, 400 MHz) δ 7.25 (s, 12H),
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis-(1,1,1,3,3,3-hexafluoro-2-propoxy)calix[6]-
arene (4j). A mixture of 3 (0.10 g, 0.07 mmol), 10 mL of HFIP,
and 1 mL lutidine was heated at reflux for 2 h. After evaporation
of the solvent, the residue was recrystallized from CHCl3/MeOH
yielding 28 mg (21%) of 4j. Mp 187 °C (dec).1H NMR (CDCl3,
400 MHz) δ 7.51 (s, 12H), 6.52 (s, 6H), 4.25 (h, J ) 5.6 Hz, 6H),
3.53 (s, 18H), 1.14 (s, 54H) ppm. 13C NMR (CDCl3, 125 MHz) δ
153.6, 148.4, 131.0, 127.5, 121.6 ((CF3)2), 72.7, 72.4(CH(CF3)2),
61.8, 34.8, 31.2 ppm.30 19F NMR (CDCl3, 470 MHz) δ -74.11 (d,
J ) 5.6 Hz) ppm. HRMS (ESI) m/z 2075.6219 [(M + Na)+, calcd
for C90H96F36NaO12, 2075.6224].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis(2-hydroxyethoxy)-calix[6]arene (4k). A mix-
ture of 3 (0.50 g, 0.33 mmol), 15 mL of TFE, and 45 mL of ethylene
glycol was heated at reflux for 18 h. After evaporation of the TFE,
the crude product was dissolved in 50 mL chloroform and washed
twice with water, and the organic phase was dried (MgSO4).
Recrystallization from CHCl3/MeOH yielded 15 mg (3%) of 4k.
Mp 350 °C. 1H NMR (CDCl3, 500 MHz) δ 7.28 (s, 12H), 6.18 (s,
6H), 3.75 (t, J ) 4.5 Hz, 12H), 3.61 (t, J ) 5.0 Hz, 12H), 3.13 (br
s, 18H), 1.09 (s, 54H) ppm.13C NMR (CDCl3, 125 MHz) δ 154.1,
146.6, 133.4, 126.3, 71.8, 70.8, 62.0, 61.4, 34.4, 31.2 ppm. HRMS
(ESI) m/z 1439.8367 [(M + Na)+, calcd for C84H120NaO18,
1439.8372].
6.14 (s, 6H), 3.52 (q, J ) 6.8 Hz, 12H), 3.07 (br s, 18H), 1.21 (t,
J ) 6.8 Hz, 18H), 1.09 (s, 54H) ppm. 13C NMR (CDCl3, 100 MHz)
δ 154.4, 146.0, 133.7, 125.1, 71.6, 64.9, 61.3, 34.3, 31.3, 15.6 ppm.
HRMS (ESI) m/z 1343.8672 [(M + Na)+, calcd for C84H120NaO12,
1343.8677].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexa-1-propoxycalix[6]arene (4c). Yield 41 mg
1
(45%). Mp 303-305 °C. H NMR (CDCl3, 400 MHz) δ 7.25 (s,
12H), 6.12 (s, 6H), 3.43 (t, J ) 6.0 Hz, 12H), 3.06 (br s, 18H),
1.60 (m, 12H), 1.08 (s, 54H), 0.93 (t, J ) 7.6 Hz, 18H) ppm. 13C
NMR (CDCl3, 100 MHz) δ 154.4, 145.9, 133.8, 125.1, 71.6, 71.2,
61.3, 34.4, 31.4, 23.4, 11.1 ppm. HRMS (ESI) m/z 1427.9611 [(M
+ Na)+, calcd for C90H132NaO12, 1427.9616].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexa-2-propoxycalix[6]arene (4d). Yield 55 mg
1
(60%). Mp 303 °C. H NMR (CDCl3, 500 MHz) δ 7.31 (s, 12H),
6.31 (s, 6H), 3.61 (s, J ) 6.0 Hz, 6H), 3.14 (br s, 18H), 1.20 (d, J
) 6.0 Hz, 36H), 1.09 (s, 54H) ppm. 13C NMR (CDCl3, 100 MHz)
δ 154.2, 145.7, 134.0, 125.7, 69.5, 68.3, 61.8, 34.4, 31.3, 22.4 ppm.
HRMS (ESI) m/z 1427.9611 [(M + Na)+, calcd for C90H132NaO12,
1427.9616].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexa-1-n-butoxycalix[6]arene (4e). Yield 52 mg
(53%). Mp 228 °C.1H NMR (CDCl3, 400 MHz) δ 7.24 (s, 12H),
6.11 (s, 6H), 3.46 (t, J ) 6.4 Hz, 12H), 3.06 (br s, 18H), 1.57 (m,
12H), 1.38 (m, 12H), 1.08 (s, 54H), 0.88 (t, J ) 7.6 Hz, 18H)
ppm. 13C NMR (CDCl3, 100 MHz) δ 154.4, 145.9, 133.8, 125.1,
71.6, 69.4, 61.3, 34.3, 32.3, 31.3, 19.7, 14.0 ppm. HRMS (ESI)
m/z 1513.0584 [(M + Na)+, calcd for C96H144NaO12, 1513.0555].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexa-1-i-butoxycalix[6]arene (4f). Yield 43 mg
(44%). Mp 265 °C.1H NMR (CDCl3, 500 MHz) δ 7.25 (s, 12H),
6.10 (s, 6H), 3.25 (d, J ) 6.5 Hz, 6H), 3.06 (br s, 18H), 1.88 (m,
6H), 1.08 (s, 54H), 0.92 (d, J ) 6.5 Hz, 36H) ppm. 13C NMR
(CDCl3, 100 MHz) δ 154.4, 145.8, 133.8, 125.2, 76.4, 71.5, 61.2,
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexadeuterio-calix[6]arene (5). A mixture of 3 (0.10
g, 0.07 mmol), 10 mL of HFIP, and 0.5 mL ethanol-d6 was heated
at reflux for 2 h. After evaporation of the solvent, the residue was
recrystallized thrice from CHCl3/MeOH yielding 36 mg (52%) of
1
5, mp 218 °C. H NMR (CDCl3, 500 MHz) δ 7.01 (s, 12H), 3.91
(br s, 6H), 2.99 (s, 18H), 1.14 (s, 54H) ppm. 13C NMR (CDCl3,
(30) The signals for the OCH(CF3)2 group were detected in a 19F decoupled
13C NMR spectrum.
7334 J. Org. Chem. Vol. 73, No. 18, 2008

Functionalization of Methylene Bridges of Calix[6]arene Scaffold
125 MHz) δ 154.0, 145.7, 133.4, 126.0, 60.0, 34.1, 31.4 ppm.
HRMS (ESI) m/z 1085.7476 [(M + Na)+, calcd for C72H90D6NaO6,
1085.7475].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis(2,5-dimethylphenyl)calix[6]arene (11). Yield
1
86 mg (78%). Mp 383 °C (dec). H NMR (CDCl3, 500 MHz) δ
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexaazido-calix[6]arene (6). A mixture of 3 (0.10
g, 0.07 mmol), sodium azide (0.20 g, 3.08 mmol), 18-crown-6 (0.81
g, 3.08 mmol), and 10 mL of TFE was heated at reflux for 18 h.
After evaporation of the solvent, the residue was dissolved in 30
mL of chloroform and washed twice with 1 M aqueous HCl. Three
recrystallizations from CHCl3/MeOH yielded 18 mg (22%) of 6
6.96 (s, 6H), 6.89 (d, J ) 7.5 Hz, 6H), 6.80 (d, J ) 8.5 Hz, 6H),
6.76 (s, 6H), 6.59 (s, 6H), 6.38 (s, 6H), 2.88 (s, 9H), 2.50 (s, 9H),
2.15 (s, 18H), 2.02 (s, 18H), 1.05 (s, 27H), 0.95 (s, 27H) ppm. 13
C
NMR (CDCl3, 100 MHz,) δ 153.6, 153.2, 145.4, 145.1, 143.8,
136.4, 135.2, 134.1, 133.6, 130.0, 129.2, 126.3, 126.0, 125.9, 60.5,
60.0, 40.4, 34.2, 31.3, 21.2, 18.8 ppm. HRMS (ESI) m/z 1682.0991
(M+, calcd for C120H144NaO6, 1682.0962).
1
95% pure. Mp 182-185 °C. H NMR (CDCl3, 500 MHz) δ 7.30
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis(2,3,4,5-tetramethylphenyl)calix[6]arene (12).
A reaction was carried out as described in the general procedure.
After evaporation of the solvent, the residue was recrystallized from
(s, 12H), 6.42 (s, 6H), 3.33 (s, 18H), 1.10 (s, 54H) ppm.13C NMR
(CDCl3, 125 MHz) δ 152.9, 147.3, 132.2, 125.8, 61.7, 56.1, 34.5,
31.2 ppm. HRMS (ESI) m/z 1325.7183 [(M + Na)+, calcd for
C72H90N18NaO6, 1325.7188].
1
C6H6/MeOH yielding 69 mg (57%) of 12. Mp 376 °C (dec). H
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexaanilino-calix[6]arene (7). A mixture of 3 (0.20
g, 0.07 mmol), aniline (0.25 g, 2.74 mmol), and 30 mL of TFE
was heated at reflux for two h. Chloroform was added, and the
organic phase was washed twice with water. After drying (MgSO4)
and evaporation of the solvent, the residue was recrystallized from
CHCl3/MeOH yielding 36 mg (34%) of the hexaanilino derivative
NMR (C6D6, 400 MHz) δ 7.46 (s, 6H), 7.34 (s, 6H), 7.03 (s, 6H),
6.82 (s, 6H), 3.17 (s, 9H), 2.92 (s, 9H), 2.39 (s, 18H), 2.21 (s,
18H), 2.01 (s, 18H), 1.98 (s, 18H), 1.26 (s, 27H), 1.11 (s, 27H)
ppm. 13C NMR (C6D6, 125 MHz) δ 154.0, 153.8, 145.4, 145.1,
141.5, 137.6, 136.7, 135.2, 132.7, 132.3, 132.2, 128.5, 126.4, 60.5,
60.1, 41.2, 34.5, 34.2, 31.6, 31.3, 21.0, 16.2, 15.8, 15.6 ppm.
MALDI MS, m/z 1875.5 (M + Na)+.
1
7. Mp 383 °C. H NMR (CDCl3, 500 MHz) δ 7.28 (s, 12H), 7.08
(t, J ) 8.0 Hz, 12H), 6.64 (t, J ) 7.5 Hz, 6H), 6.54 (d, J ) 7.0 Hz,
12H), 6.47 (d, J ) 6.0 Hz, 6H), 4.08 (d, J ) 5.5 Hz, 6H), 3.14 (br
s, 18H), 1.04 (s, 54H) ppm. 13C NMR (CDCl3, 100 MHz) δ 153.7,
146.7, 146.5, 135.0, 129.0, 124.7, 117.5, 113.3, 61.5, 49.3, 34.3,
31.2 ppm. HRMS (ESI) m/z 1603.9767 [(M)+, calcd for
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis-(2-methoxy-4-methylphenyl)calix[6]arene
(13). Yield 68 mg (59%). Mp 390 °C (dec). 1H NMR (CDCl3, 400
MHz) δ 6.86 (d, Jo ) 8.4 Hz, Jm ) 2.0 Hz, 6H), 6.82 (br s, 12H),
6.62 (d, Jo ) 8.8 Hz, 6H), 6.55 (s, 6H), 6.51 (s, 6H), 3.48 (s, 18H),
2.13 (s, 18H), 0.99 (br s, 54H) ppm.13C NMR (CDCl3, 125 MHz,
238K) δ 155.0, 153.3, 152.9, 144.9, 144.2, 136.2, 134.0, 130.1,
128.5, 127.0, 125.7, 124.7, 111.0, 60.4, 60.0, 56.1, 34.2, 34.2, 31.5,
31.3, 21.1 ppm. HRMS (ESI) m/z 1801.0584 [(M + Na)+, calcd
for C120H144NaO12, 1801.0555].
C
108H126N6O6, 1603.9738].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexaacetoxy-calix[6]arene (8). Calixarene 3 (1.5 g,
0.98 mmol) and 200 mL of acetic acid were heated at reflux for
18 h. After cooling, the acetic acid was evaporated, and the residue
was recrystallized from CHCl3/MeOH to yield 0.38 g of the
hexaacetoxy derivative 8 (28%). Mp 392 °C (dec). 1H NMR
(CDCl3, 400 MHz) δ 7.52 (s, 6H), 7.26 (s, 12H), 3.66 (s, 18H),
2.08 (s, 18H), 1.12 (s, 54H) ppm. 13C NMR (CDCl3, 125 MHz) δ
169.5, 153.5, 146.6, 132.8, 125.3, 66.3, 61.7, 34.4, 31.3, 20.9 ppm.
HRMS (ESI) m/z 1427.7424 [(M + Na)+, calcd for C84H108NaO18,
1427.7433].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexahydroxy-calix[6]arene (9). To an ice-cold solu-
tion of 8 (0.36 g, 0.27 mmol) in 50 mL of dry THF was added
LiAlH4 (0.11 g, 2.89 mmol) under an inert atmosphere, and the
mixture was stirred for 30 min. Ethyl acetate was added to quench
the excess of LiAlH4, and the solution was washed with water,
and then with 1 M aq HCl. After drying (MgSO4) the organic phase
was filtered and evaporated. Recrystallization from CHCl3/MeOH
yielded 0.15 g of 9 (51%). Mp 348 °C (dec). 1H NMR (DMSO-d6,
500 MHz) δ 7.24 (s, 12H), 6.32 (d, J ) 6.0 Hz, 6H), 5.51 (d, J )
6.0 Hz, 6H), 3.01 (br s, 18H), 1.05 (s, 54H) ppm. 13C NMR
(CD3OD, 125 MHz) δ 152.4, 145.4, 135.6, 124.2, 63.0, 60.8, 33.6,
30.1 ppm. HRMS (ESI) m/z 1175.6794 [(M + Na)+, calcd for
C72H96NaO12, 1175.6799].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexamesityl-calix[6]arene (14). Yield 75 mg (66%).
1
Mp 405 °C (dec). H NMR (CDCl3, 500 MHz) δ 7.12 (s, 6H),
7.07 (s, 6H), 6.69 (s, 6H), 6.59 (s, 6H), 6.47 (s, 6H), 2.58 (s, 9H),
2.21 (s, 18H), 2.18 (s, 9H), 2.13 (s, 18H), 2.08 (s, 18H), 1.15 (s,
27H), 0.91 (s, 27H) ppm. 13C NMR (CDCl3, 100 MHz) δ 155.7,
152.7, 145.9, 143.3, 138.6, 138.0, 137.3, 135.9, 135.4, 134.9, 131.0,
129.5, 127.9, 126.2, 60.4, 60.3, 40.7, 34.3, 34.0, 31.4, 27.3, 21.0,
20.6 ppm. HRMS (ESI) m/z 1789.1828 [(M + Na)+, calcd for
C
126H156NaO6, 1789.1799].
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis-(2,4-pentanedione-3-yl)calix[6]arene (15). A
mixture of 3 (0.10 g, 0.07 mmol), 1 mL of 2,4-pentanedione, and
10 mL of TFE was heated at reflux for 2 h. After evaporation of
the solvents, the residue was recrystallized from CHCl3/MeOH
yielding 55 mg (51%) of 15. When HFIP was used instead of TFE
as a solvent the yield of 15 was 67 mg (62%). Mp 260-262 °C.
1H NMR (CDCl3, 400 MHz) δ 7.19 (s, 12H), 5.51 (d, J ) 12.0
Hz, 6H), 4.39 (d, J ) 11.6 Hz, 6H), 4.10 (s, 18H), 2.02 (s, 36H),
1.14 (s, 54H). 13C NMR (CDCl3, 125 MHz) δ 202.8, 152.7, 146.3,
133.8, 124.7, 77.6, 60.6, 36.7, 34.4, 31.0, 29.8 ppm. HRMS (ESI)
m/z 1668.9318 [(M + Na)+, calcd for C102H132NaO18, 1668.9311].
General Procedure for the Preparation of the Hexaaryl Deriva-
tives 10-14. A mixture of 3 (0.10 g, 0.07 mmol), 2 mL of HFIP,
8 mL chloroform, and 1 mL of the appropriate reagent was heated
at reflux for 2 h. After evaporation of the solvent, the residue was
recrystallized from CHCl3/MeOH.
Acknowledgment. We thank Dr. Shmuel Cohen (Hebrew
University) for the crystal structure determinations. This research
was supported by the Israel Science Foundation (grant No.
934/04).
5,11,17,23,29,35-Hexa-tert-butyl-37,38,39,40,41,42-hexamethoxy-
2,8,14,20,26,32-hexakis(2,4-dimethylphenyl)calix[6]arene (10). Yield
1
74 mg (67%). Mp 385 °C (dec). H NMR (CDCl3, 400 MHz) δ
6.97 (s, 6H), 6.81 (m, 12H), 6.78 (s, 6H), 6.73 (d, J ) 8.2 Hz,
6H), 6.37 (s, 6H), 2.84 (s, 9H), 2.45 (s, 9H), 2.20 (s, 18H), 2.06 (s,
18H), 1.04 (s, 27H), 0.92 (s, 27H) ppm. 13C NMR (CDCl3, 125
MHz, 233 K) δ 153.3, 153.1, 145.1, 144.9, 140.8, 136.2, 136.1,
135.0, 134.6, 131.0, 128.1, 126.0, 125.9, 125.6, 60.7, 59.7, 39.5,
34.3, 34.2, 31.4, 31.3, 21.1, 19.7 ppm. MALDI MS, m/z 1705.0
(M + Na)+.
Supporting Information Available: 1H and 13C NMR
spectra of 4a-k and 5-15 and molecular structures of 4a and
14. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801187Z
J. Org. Chem. Vol. 73, No. 18, 2008 7335