Interplay of Steric Hindrance and Hydrogen Bonding to Restrict Mono-O-substituted p-tert-Butylcalix[6] arenes in Cone Conformation

Article abstract of DOI:10.1021/jo971443x

The simple mono-O-benzyl-p-tert-butylcalix[6]arene (2a) has been reported to display a cone conformation with a slow inversion rate at room temperature. Here, a series of mono-O-substituted p-tert-butylcalix[6]arenes (2a-g, 3-9) has been studied by 2D and variable-temperature NMR spectroscopies. Cone conformations with slow macrocyclic inversion were found for calix[6]arenes whose O-substituent was larger than butyl, whereas freezing of the conformation was observed for substituants larger than benzyl. Steric effects and preservation of the cyclic array of hydrogen bonds are suggested as the main cause for the high inversion barriers.

Full text of DOI:10.1021/jo971443x

J . Org. Chem. 1998, 63, 1079-1085
1079
In ter p la y of Ster ic Hin d r a n ce a n d Hyd r ogen Bon d in g To Restr ict
Mon o-O-su bstitu ted p-ter t-Bu tylca lix[6]a r en es in Con e
Con for m a tion
J . Oriol Magrans, Ana M. Rinco´n, Fe´lix Cuevas, J avier Lo´pez-Prados, Pedro M. Nieto,
Miquel Pons,† Pilar Prados,* and J avier de Mendoza*
Departamento de Quı´mica Orga´nica, Universidad Auta´noma de Madrid, Cantoblanco,
28049 Madrid, Spain, and Departament de Quı´mica Orga`nica, Universitat de Barcelona,
08028 Barcelona, Spain
Received August 4, 1997
The simple mono-O-benzyl-p-tert-butylcalix[6]arene (2a ) has been reported to display a cone
conformation with a slow inversion rate at room temperature. Here, a series of mono-O-substituted
p-tert-butylcalix[6]arenes (2a -g, 3-9) has been studied by 2D and variable-temperature NMR
spectroscopies. Cone conformations with slow macrocyclic inversion were found for calix[6]arenes
whose O-substituent was larger than butyl, whereas freezing of the conformation was observed for
substituents larger than benzyl. Steric effects and preservation of the cyclic array of hydrogen
bonds are suggested as the main cause for the high inversion barriers.
In tr od u ction
the methyl groups and three aromatic rings of the cavity.
The importance of this interaction has been pointed out
by Dougherty et al. with cyclophanes3 and, more recently,
cation-π interactions have been shown to play an
important role in the binding of choline derivatives in
biological systems, like Torpedo californica acetylcho-
linesterase.4
In a collaborative effort, we have described procedures
for the partial and selective functionalization of calix[6]-
arenes at either the lower and the upper rims.5 Other
functionalized calix[6]arenes have been recently reported
by others.6 These functionalization methods have opened
the way to use calix[6]arenes as building blocks for more
sophisticated receptors of choline derivatives.7
Calixarenes are useful building blocks in supramo-
lecular chemistry. In particular, calix[4]arenes can be
specifically obtained in any of their four well-defined
conformational families (cone, partial cone, 1,3-alternate,
and 1,2-alternate), with partial or full functionalization
at either the lower or upper rim positions.1 The resulting
shape- and size-controlled molecular platforms have been
employed mainly for the development of new selective
ionophores and chromoionophores, making use of the
available hydroxy groups at the lower rim.2 For the
smaller members of the series, the calix[4]arenes, the size
of the cavities, even in the cone conformation, is simply
too small to find extensive applications in host-guest
chemistry, and only some ions or small molecules can be
accommodated inside.1
To take advantage of the macrocyclic cavity for guest
inclusion, calix[6]arenes are more promising building
blocks. In an ideal cone conformation, calix[6]arenes
could encapsulate aromatic rings, as well as tert-butyl
or trimethylammonium groups, within their cavities.
Complexation of trimethylammonium groups is a par-
ticularly attractive issue since three well-oriented cation-
π-stabilizing interactions could be established between
However, a major problem of calix[6]arenes as cavities
for molecular recognition is their poor preorganization.
In general, calix[6]arenes display a much higher confor-
mational freedom than their tetramer analogues. Up to
90 energy minima have been calculated for the parent
(4) (a) Sussman, J . L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman,
A.; Toker, L.; Silman, I. Science 1991, 253, 872. (b) Harel, M.; Schalk,
I.; Ehret-Sabatier, L.; Bouet, F.; Goeldner, M.; Hirth, C.; Axelsen, P.
H.; Silman, I.; Sussman, J . L. Proc. Natl. Acad. Sci. U.S.A. 1993, 90,
9031. (c) Harel, M.; Quinn, D. M.; Nair, H. K.; Silman, I.; Sussman, J .
L. J . Am. Chem. Soc. 1996, 118, 2340.
(5) (a) J anssen, R. G.; Verboom, W.; Reinhoudt, D. N.; Casnati, A.;
Freriks, M.; Pochini, A.; Ugozzoli, F.; Ungaro, R.; Nieto, P. M.;
Carramolino, M.; Cuevas, F.; Prados, P.; de Mendoza, J . Synthesis
1993, 380. (b) J anssen, R. G.; Verboom, W.; Harkema, S.; van Hummel,
G. J .; Reinhoudt, D. N.; Pochini, A.; Ungaro, R.; Prados, P.; de Mendoza,
J . J . Chem. Soc., Chem. Commun. 1993, 506. (c) de Mendoza, J .;
Carramolino, M.; Cuevas, F.; Nieto, P. M.; Prados, P.; Reinhoudt, D.
N.; Verboom, W.; Ungaro, R.; Casnati, A. Synthesis 1994, 47. (d)
Casnati, A.; Domiano, L.; Pochini, A.; Ungaro, R.; Carramolino, M.;
Magrans, J . O.; Nieto, P. M.; Lo´pez-Prados, J .; Prados, P.; de Mendoza,
J .; J anssen, R. G.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1995,
51, 12699.
(6) (a) Rogers, J . S.; Gutsche, C. D. J . Org. Chem. 1992, 57, 3152.
(b) Kanamathareddy, S.; Gutsche, C. D. J . Org. Chem. 1992, 57, 3160.
(c) Neri, P.; Pappalardo, S. J . Org. Chem. 1993, 58, 1048. (d) Moran,
J . K.; Georgiev, E. M.; Yordanov, A. T.; Mague, J . T.; Roundhill, D. M.
J . Org. Chem. 1994, 59, 5990. (e) Otsuka, H.; Araki, K.; Shinkai, S.
Tetrahedron 1995, 51, 8757.
† Universitat de Barcelona.
(1) (a) Gutsche, C. D. Calixarenes, Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; Royal Society of Chemistry: Cam-
bridge, 1989. (b) Calixarenes: A Versatile Class of Macrocyclic Com-
pounds; Bo¨hmer, V., Vicens, J ., Eds.; Kluwer Academic Publishers:
Dordrecht, 1991. (c) Pochini, A.; Ungaro, R. Comprehensive Supramo-
lecular Chemistry; Atwood, J . L., Davies, J . E. D., Macnicol, D. D.,
Vo¨gtle, F., Eds.; Pergamon Press: 1996; Vol. 2, Chapter 2. (d) Bo¨hmer,
V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (e) Takeshita, M.;
Shinkai, S. Bull. Chem. Soc. J pn. 1995, 68, 1088.
(2) (a) Casnati, A.; Pochini, A.; Ungaro, R.; Ugozzoli, F. A.; Arnaud,
F.; Fanni, S.; Schwing, M.-J .; Egberink, R. J . M.; de J ong, F.;
Reinhoudt, D. N. J . Am. Chem. Soc. 1995, 117, 2767. (b) Diamond, D.;
McKervey, M. A. Chem. Soc. Rev. 1996, 15. (c) Matsumoto, H.; Shinkai,
S. Tetrahedron Lett. 1996, 37, 77. (d) Arnaud-Neu, F.; Barrett, G.;
Corry, D.; Cremin, S.; Ferguson, G.; Gallagher, J . F.; Harris, S. J .;
McKervey, M. A.; Schwing-Weill, M.-J . J . Chem. Soc., Perkin Trans. 2
1997, 575 and references therein.
(7) Magrans, J . O.; Ortiz, A. R.; Molins, M. A.; Lebouille, P. H. P.;
Sa´nchez-Quesada, J .; Prados, P.; Pons, M.; Gago, F.; de Mendoza, J .
Angew. Chem., Int. Ed. Engl. 1996, 35, 1712.
(3) (a) Dougherty, D. A.; Stauffer, D. A. Science 1990, 250, 1558.
(b) Dougherty, D. A. Science 1996, 271, 163 and references therein.
(8) Harada, T.; Shinkai, S. J . Chem. Soc., Perkin Trans 2 1995, 2231.
S0022-3263(97)01443-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

1080 J . Org. Chem., Vol. 63, No. 4, 1998
Magrans et al.
calix[6]arene.8 For O-unsubstituted calix[6]arenes, a full
array of hydrogen bonds results in a pinched cone
preferred conformation in the solid state9 and probably
also in solution.10 However, in solution, O-unsubstituted
calix[6]arenes display fast equilibria between degener-
ated conformations, leading to ring inversion. Addition-
ally, pseudorotation or pinched cone interconversion
produces Cn symmetric average structures from the
essentially asymmetric static structrures found at low
temperature.11 At very low temperature in CD2Cl2 upper
rim substituted trichlorocalix[6]arene shows a completely
unsymmetrical conformation compatible with the pinched
cone conformation but also with other conformations of
higher energy in vacuo.10a However, in CDCl3 at higher
temperature two exchange processes of similar energy
could be identified.10a We assigned them to pseudorota-
tion and inversion.12 In contrast to calix[4]arenes, full
substitution of the phenolic positions by bulky groups
does not result in immobilized calix[6]arenes,13 since
macrocycle inversion may occur as well by the passage
of the upper rim groups through the central cavity, even
when these groups are as large as tert-butyl residues.14
For this reason, a considerable effort has been devoted
to the synthesis of immobilized calix[6]arenes by means
of a covalent union of two or more phenolic hydroxyls
with appropriate bridging or capping subunits.15 Some
of these compounds have been shown to complex qua-
ternary ammonium salts with moderate efficiency.15d
Quite surprisingly, some simple substitution patterns
of p-tert-butylcalix[6]arene (1) (Chart 1) result in partially
Ch a r t 1
immobilized derivatives without the need of a syntheti-
cally costly covalent bridge between aromatic rings. For
example, many 1,3,5-tri-O-methyl-p-tert-butylcalix[6]-
arenes present a considerably slower rate of macrocycle
inversion than their O-unsubstituted analogues.14,16 This
effect has been attributed to CH-π interactions between
the methoxy groups pointing inside the cavity and the
corresponding aromatic rings in front of them. As a
result, the cavity size is significantly reduced by the self-
inclusion process. Even more interesting, the simple
mono-O-benzyl-p-tert-butylcalix[6]arene (2a ) has been
reported by Gutsche to show also a slow inversion rate
with a ∆Gq > 18 kcal/mol in C2D2Cl4.17 Apparently, the
substituent is not self-included, so the cavity remains free
for encapsulation of suitable guests, a fact that has yet
to be exploited in supramolecular chemistry. A similar
effect has been recently observed for mono- and di-O-
phosphorylated derivatives.18
The interplay between the steric hindrance of the
benzyl substituent and the conservation of an extended
array of intramolecular hydrogen bonds (five OH groups)
has been suggested by Gutsche as a rationale for the cone
“fixation” of this simple monosubstituted derivative.17
However, some questions remain to be answered: Is the
substituent effect purely steric, or is there some partici-
pation of the aromatic benzyl ring to stabilize the cone
conformation? What is the minimum size required for a
single O-substituent to “fix” the cone conformation? To
what extent does the intramolecular hydrogen bonding
network play a role? Herein, we address these questions
through an analysis of the conformational behavior of a
series of mono-O-substituted p-tert-butylcalix[6]arenes
(2a -g, 3-9) (Chart 1) studied by 2D and variable-
temperature NMR spectroscopies.
(9) (a) Andreetti, G. D.; Ugozzoli, F.; Casnati, A.; Ghidini, E.; Pochini,
A.; Ungaro, R. Gazz. Chim. Ital. 1989, 119, 47. (b) Halit, M.; Oehler,
D.; Perrin, M.; Thozet, A.; Perrin, R.; Vicens, J .; Bourakhoudar, M. J .
Inclusion Phenom. 1988, 6, 613.
(10) (a) Molins, M. A.; Nieto, P. M.; Sa´nchez, C.; Prados, P.; de
Mendoza, J .; Pons, M. J . Org. Chem. 1992, 57, 6924. (b) van Hoorn,
W. P.; van Veggel, F. C. J . M.; Reinhoudt, D. N. J . Org. Chem., 1996,
61, 7180.
(11) Inversion is the result of flipping the four phenol rings in an
“up” position to a “down” position and vice versa. This process
exchanges the relative position of the calixarene benzylic protons with
respect to the plane defined by the phenolic oxygens (see ref 10a).
Pseudorotation was defined by us (see ref 10a) as the process that
exchanges the phenolic rings that are projecting outside in a winged
cone conformation, all atoms being thus virtually rotated over an angle
of 120°. This process does not exchange the relative positions of the
calixarene benzylic protons with respect to the plane defined by the
phenolic oxygens. Pinched cone interconversion is a different pseu-
dorotation process implying the exchange of four methylene groups
between inside and outside positions. This process could be indepen-
dent from inversion, but energy calculations suggest that a combined
inversion-pseudorotation pathway has the lowest activation energy
in vacuo (see ref 10b).
(12) By comparison with energy calculations suggesting that pseu-
dorotation and inversion should be concerted in the pinched cone
conformation present in vacuo, the similarity of the two activation
barriers has been taken as experimental evidence for a single concerted
process.10b A detailed analysis of the exchange pattern does not support
this interpretation. We had previously suggested that CDCl3 could be
interacting with calix[6]arene’s stabilizing winged conformation.10a This
possibility was not considered in the calculations.10b
(13) (a) Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107,
6059. (b) Otsuka, H.; Araki, K.; Shinkai, S. Chem. Expr. 1993, 8, 479.
(14) van Duynhoven, J . P. M.; J anssen, R. G.; Verboom, W.; Franken,
S. M.; Casnati, A.; Pochini, A.; Ungaro, R.; de Mendoza, J .; Nieto, P.
M.; Prados, P.; Reinhoudt, D. N. J . Am. Chem. Soc. 1994, 116, 5814.
(15) (a) Kanamathareddy, S.; Gutsche, C. D. J . Am. Chem. Soc. 1993,
115, 6572. (b) Grynszpan, F.; Aleksiuk, O.; Biali, S. E. J . Chem. Soc.,
Chem. Commun. 1993, 13. (c) J anssen, R. G.; Verboom, W.; van
Duynhoven, J . P. M.; van Velzen, E. J . J .; Reinhoudt, D. N. Tetrahedron
Lett. 1994, 35, 6555 (d) Casnati, A.; J acopozzi, P.; Pochini, A.; Ugozzoli,
F.; Cacciapaglia, R.; Mandolini, L.; Ungaro, R. Tetrahedron 1995, 51,
591. (e) Otsuka, H.; Araki, K.; Matsumoto, H.; Harada, T.; Shinkai, S.
J . Org. Chem. 1995, 60, 4862. (f) Saiki, T.; Goto, K.; Tokitoh, N.;
Okazaki, R. J . Org. Chem. 1996, 61, 2924. (g) Ross, H.; Lu¨ning, U.
Liebigs Ann. 1996, 1367. (h) Kanamathareddy, S.; Gutsche, C. D. J .
Org. Chem. 1996, 61, 2511.
Resu lts a n d Discu ssion
Con for m a tion a l Stu d y. In unsubstituted p-tert-
butylcalix[6]arene (1), cone-cone inversion is fast at room
(16) (a) Casnati, A.; Minari, P.; Pochini, A.; Ungaro, R. J . Chem.
Soc., Chem. Commun. 1991, 1413. (b) Otsuka, H.; Araki, K.; Sakaki,
T.; Nakashima, K.; Shinkai, S. Tetrahedron Lett. 1993, 34, 7275.
(17) Kanamathareddy, S.; Gutsche, C. D. J . Org. Chem. 1994, 59,
3871.
(18) J anssen, R. G.; van Duynhoven, J . P. M.; Verboom, W.; van
Hummel, G. J .; Harkema, S.; Reinhoudt, D. N. J . Am. Chem. Soc. 1996,
118, 3666.

Restricted p-tert-Butylcalix[6]arenes in Cone Conformation
J . Org. Chem., Vol. 63, No. 4, 1998 1081
1
F igu r e 2. Methylene and OH regions of H NMR spectra of
compounds 2a , 8, 9 at low temperatures.
for the calixarene methylenes, whereas singlets and
broad singlets were observed for the same protons of
compounds 3 and 4, respectively. A 2D NMR study of
compounds 6 and 8 revealed that these compounds, and
presumably all the bulky-substituted compounds of the
series (2a -g, 5-9), display a close conformational simi-
larity to the benzyl derivative 2a . Indeed, (i) methylene
geminal protons did not show mutual exchange cross
peaks, (ii) each of the protons within a methylene group
showed ROEs only with either lower or upper rim protons
of the macrocycle. From this observation it may be
concluded that these compounds are also in a frozen cone
conformation at room temperature. Thus, the conforma-
tion of the mono-O-substituted p-tert-butylcalix[6]arenes
with bulky substituents does not appear to be dependent
on the aromatic or aliphatic nature of the substituent.
The lower limit for the size of the O-substituent chain to
freeze the macrocyclic ring inversion is established to be
the butyl substituent.
F igu r e 1. Selected through-space connectivities observed in
2a by a ROESY experiment in CDCl3 (298 K).
temperature, leading to complete coalescence of each
group of constitutionally equivalent nuclei.10a,19 In con-
trast, for mono-O-benzyl p-tert-butylcalix[6]arene (2a ), a
much lower conformational freedom has been reported.17
In agreement with these observations, the 1H NMR
spectrum of 2a in CDCl3 at room temperature shows
three AX systems for the methylene protons of the
macrocycle, indicative of a slow ring inversion on the
NMR time scale. The spectrum is in agreement with the
presence of an average symmetry plane bisecting the
O-substituted ring. Unambiguous assignment of most
signals was achieved by a set of 2D NMR experiments
(COSY-45, HMQC, and ROESY in CDCl3 at 298 K).
Unassigned signals correspond to calixarene aromatic
and tert-butyl protons which showed extensive overlap.
Pairs of methylene protons were unequivocally assigned
from ROESY experiments. Exchange peaks between
geminal methylene protons were not detected in ROESY
experiments with mixing times up to 300 ms, indicating
that inversion was also slow on this time scale.
1H NMR spectra of 2a , 8, and 9, forming a homologous
series with one, two, or three methylene groups acting
as spacers between the phenyl ring and the macrocycle,
were recorded in CDCl3 at 213 K (8 and 9) and 203 K
(2a ) (Figure 2). A clear trend was observed in the
methylene region of the three compounds. While 2a
shows only a slight broadening of one of the methylene
groups, 8 and 9 show a number of broad lines. Com-
pound 2a has considerably broader lines for the OH
signals than 8 and 9. On the other hand, signals arising
from a second conformation are barely visible in the OH
region of the spectra of 2a but can be observed in the
case of 8 and have a population of ca. 50% of the main
species in the calixarene 9 with a three-methylene spacer.
Reinhoudt has found that mono-O-phosphoryl-p-tert-
butylcalix[6]arene shows a rather complex spectrum at
low temperatures, due to the slow interconversion rate
Diagnostic ROE contacts of 2a are shown in Figure 1
(see Supporting Information for full ROESY spectra).
Protons a, b, and c present cross relaxation peaks only
with phenolic OH groups and substituent signals, whereas
protons a′, b′, and c′ show ROEs only with calixarene
aromatic signals. From this, it may be concluded that
the macrocycle is in a cone conformation. This is in
agreement with the corresponding 13C NMR signals for
the methylenic carbons appearing between 30 and 32
ppm, as is expected for a syn arrangement of the
neighboring aromatic rings.17,20 Other cross peaks of
medium to strong intensity are observed between lower
rim and substituent protons.21 These peaks were best
observed in the experiments recorded at longer mixing
times (τm ) 300 ms) and further confirm the overall
macrocyclic cone conformation. Since only protons b do
not have contacts with the substituent, a predominant
winged or pinched cone conformation, with the O-sub-
stituted ring and the ring in front of it pointing outward,
is suggested.
between pinched cone isomers by pseudorotation.18
A
similar effect is probably operating in the monosubsti-
tuted calixarenes studied by us. However, the length of
the spacer clearly affects the population of the nonsym-
metrical conformation. Presumably, the possible orienta-
tions of the substituted ring are restricted by the shorter
spacer (2a ). With a longer spacer with three methylene
groups as in 9, the energy difference between the two
conformations is around 1.2 kJ mol-1 at 213 K (calculated
from the integration of OH signals). Interestingly, this
shows that at room-temperature rapid pseudorotational
interconversion is taking place without inversion of the
cone. Thus, pseudorotation is not concerted with inver-
sion at least in the case of these monosubstituted calix-
[6]arenes.
1
The H NMR spectra of compounds 2b-g and 5-9, in
CDCl3 at room temperature, show also three AX systems
(19) Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052.
(20) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.; Sa´nchez,
C. J . Org. Chem. 1991, 56, 3372.
(21) For example, methylene proton a shows strong and medium
ROESY signals with protons I and II; phenol B with I, II, and III; and
phenol C and methylene proton c with III (Figure 1).

1082 J . Org. Chem., Vol. 63, No. 4, 1998
Magrans et al.
Ta ble 1. Coa lescen ce Tem p er a tu r e a n d F r ee En er gies of
Activa tion for th e Con for m a tion a l In ver sion of
Ca lix[6]a r en es 2-9
compd
solvent
Tc (K)
∆Gq (kJ /mol)
2a
C2D2Cl4
DMSO-d6
C2D2Cl4
DMSO-d6
C2D2Cl4
C2D2Cl4
C2D2Cl4
DMSO-d6
CDCl3
>396
320
>77
65
2b
2c
2d
2f
>396
>400
>396
>396
>396
>400
<300
300
>77
>79
>77
>77
>77
>79
<58
58
2g
3
4
5
CDCl3
C2D2Cl4
DMSO-d6
C2D2Cl4
DMSO-d6
C2D2Cl4
C2D2Cl4
DMSO-d6
C2D2Cl4
350
69
<300
>400
355
>400
>363
>363
>363
<58
>77
71
>77
>72
>72
>72
6
7
8
F igu r e 4. Hammett correlation between OH protons of B
rings and σp parameters in calix[6]arenes 2a -g (R2 ) 0.97; F
) -0.29).
9
with six hydrogen acceptors but only five hydrogen
donors. Monosubstitution reduces the inherent sym-
metry of the macroring, and the expected three signals
of relative intensities 2:2:1 for the OH resonances were
indeed observed at room temperature for the whole
series. Chemical shifts, in the range δ 8.70-9.19, 9.36-
9.95, and 9.80-10.15 ppm, respectively, are in accord
with highly chelated structures.23
The participation of the substituent’s oxygen as hy-
drogen acceptor in the hydrogen-bonded network was
clearly established by a simple Hammett correlation. In
general, calixarene 1H NMR (CDCl3) signals at room
temperature are quite independent of the benzylic sub-
stituent. This was not the case, however, for the OH
protons neighboring the substituted ring, whose chemical
shifts vary considerably depending on the nature of the
O-substituent. For example, these signals are 0.4 ppm
upfield shifted in 2g (p-nitrobenzyl) with respect to the
less basic 2c (p-methoxybenzyl), which presents a weaker
hydrogen bond.24 For the larger set of differently para-
substituted benzyl derivatives 2a -g a good correlation
with σp was observed (Figure 4).
Since hydrogen-bond strength with the neighboring
OH’s is likely to be dependent on the oxygen basicity,
this long distance Hammett correlation could only be
explained by assuming that the substituted oxygen
participates as a hydrogen acceptor with neighboring
phenols. Thus, the hydrogen bond network is only
partially destroyed when only one OH is replaced by an
ether substituent, and the cone conformation is still
stabilized. The highly preserved hydrogen-bond network
prevents monosubstituted p-tert-butylcalix[6]arenes from
inversion via the upper rim through the annulus, and
this could explain the high inversion barriers observed
for the compounds carrying a bulky substituent.
F igu r e 3. Methylene region of 1H NMR spectra of 2b in C2D2-
Cl4 at 396 K. (• minor impurities).
Ster ic Effect of th e Su bstitu en t. Variable-temper-
ature spectra of mono-O-substituted p-tert-butylcalix[6]-
arenes in CDCl3, C2D2Cl4, or DMSO were recorded.
Coalescence temperatures for methylene AX systems and
activation barriers (∆Gq) for calixarene inversion are
collected in Table 1. The parent compound 1, endowed
with a full cyclic array of hydrogen bonds, has an
inversion barrier of 53.5 kJ /mol in CDCl3.10a,19 In con-
trast, monomethyl derivative 3 appears to be more
flexible (no coalescence was observed above or at room
temperature). However, barriers raised significantly as
the size of the substituent was increased. For example,
coalescence is observed at 300 K (CDCl3) for propyl
derivative 4 (∆Gq ) 58 kJ /mol) and at 350 K (C2D2Cl2)
for the butyl homologue 5 (∆Gq ) 69 kJ /mol). The rest
of the compounds, bearing residues larger than benzyl,
can be considered “fixed” (∆Gq > 77 kJ /mol) (Figure 3).
For p-tert-butylcalix[5]arene O-derivatives, a single pro-
pyl group has been reported to fix the conformation.22
The fact that inversion barriers are so strongly de-
pendent on substituent size suggests that for monosub-
stituted p-tert-butylcalix[6]arenes inversion must occur
via the lower rim through the annulus. As for bridged
p-tert-butylcalix[6]arene derivatives, it is likely that
inversion is prevented under the usual experimental
conditions as the substituent becomes larger than the
available hole of the macrocycle.
(23) At room temperature phenol protons are differentially broad-
ened in the order B < C , D. The same trend is observed in
monosubstituted calix[6]arenes with a variety of substituents, includ-
ing those that produce “fixed cone” conformations (like 2a ) or mobile
structures (like 3). This suggests that differential broadening is a
property of monosubstituted calix[6]arenes reflecting differential
mobility, a range of chemical shift differences in the OH groups
between the exchanging species, or a combination of both.
(24) In hydrogen-bonded phenols, chemical shifts values are related
to the strength of hydrogen bonds, the stronger ones appearing at lower
fields. (See J ackman, L. M.; Sternhell, S. Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry, 2nd ed.;
Pergamon Press: New York, 1969.
In tr a m olecu la r Hyd r ogen Bon d in g. The intramo-
lecular cyclic array of hydrogen bonds stabilizing cone
conformations is perturbed when one or several OH
hydrogens are replaced by substituents. Thus, in calix-
[6]arenes, a single substituent results in a broken array
(22) Stewart, D. R.; Krawiec, M.; Kashyap, R. P.; Watson, W. H.;
Gutsche, C. D. J . Am. Chem. Soc. 1995, 117, 586.

Restricted p-tert-Butylcalix[6]arenes in Cone Conformation
J . Org. Chem., Vol. 63, No. 4, 1998 1083
9.72 (s, 1H, OH), 9.10 (s, 2H, OH), 7.63, 7.41 (AA′BB′ system,
4H, ArH), 7.26-7.06 (m, 12H, ArH), 5.14 (s, 2H, OCH2Ar), 4.42
(d, 2H, J ) 13.5 Hz, ArCH2Ar), 4.25 (d, 2H, J ) 14.0 Hz,
ArCH2Ar), 3.98 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 3.55 (d, 2H, J
) 14.0 Hz, ArCH2Ar), 3.52 (d, 2H, J ) 13.5 Hz, ArCH2Ar),
3.35 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 2.41 (s, 3H, CH3), 1.27 [s,
18H, C(CH3)3], 1.26 [s, 18H, C(CH3)3], 1.22 [s, 9H, C(CH3)3],
1.17 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT) δ 149.5,
149.3, 148.2, 147.9, 146.6, 144.3, 144.2, 143.5, 142.8, 138.3,
133.3, 132.5, 127.5, 127.0, 126.8, 126.7 (ArC), 129.7, 127.5,
126.2, 126.1, 126.0, 125.9, 125.7, 125.4 (ArCH), 78.0 (OCH2-
Ar), 34.2, 34.0, 33.91, 33.89, [C(CH3)3], 33.3, 32.7, 32.6 (ArCH2-
Ar), 31.6, 31.5, 31.4, 31.2 [C(CH3)3], 21.4 (CH3); HRMS (FAB+)
calcd for C74H92O6 (M+) 1076.6894, found 1076.6884.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-p en ta h y-
d r oxy-42-(4′-m eth oxyben zyloxy)ca lix[6]a r en e (2c). Calix-
[6]arene 2c was obtained with 4-methoxybenzyl chloride (0.6
mmol) as alkylating agent. Time for the reaction was 24 h, to
yield 31% (69 mg) after chromatography (hexane-CH2Cl2
1:1): mp 162-166 °C; 1H NMR (CDCl3) δ 9.95 (s, 2H, OH),
9.76 (s, 1H, OH), 9.16 (s, 2H, OH), 7.71 (AA′BB′ system, 2H,
ArH), 7.22-7.12 (m, 14H, ArH), 5.18 (s, 2H, OCH2Ar), 4.48
(d, 2H, J ) 13.4 Hz, ArCH2Ar), 4.30 (d, 2H, J ) 14.0 Hz,
ArCH2Ar), 4.03 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 3.90 (s, 3H,
OCH3), 3.60 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 3.58 (d, 2H, J )
13.4 Hz, ArCH2Ar), 3.44 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 1.33
[s, 18H, C(CH3)3], 1.31 [s, 18H, C(CH3)3], 1.27 [s, 9H, C(CH3)3],
1.23 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT) δ 159.8,
149.3, 149.2, 148.1, 148.0, 146.7, 144.2, 143.5, 142.9, 132.5,
128.3, 127.3, 127.2, 127.0, 126.7, 126.6 (ArC), 129.2, 126.1,
126.0, 125.9, 125.8, 125.3, 114.4 (ArCH), 77.5 (OCH2Ar), 55.3
(OCH3), 34.2, 34.0, 33.9, 33.8 [C(CH3)3], 33.1, 32.7, 32.5 (ArCH2-
Ar), 31.6, 31.5, 31.4, 31.2 [C(CH3)3]; MS (FAB+) m/z 1092.7
(M+). Anal. Calcd for C74H92O7‚CH3OH: C, 80.02; H, 8.60.
Found: C, 79.71; H, 8.74.
Participation of hydrogen bonding was further con-
firmed by the decrease of the inversion barriers of some
compounds (2a , 5, and 6) in DMSO. It is noteworthy
that, even in DMSO, the p-tert-butylcalix[6]arenes car-
rying the bulkier groups (2c, 2g, and 8) did not coalesce
even at 400 K, indicating that cone interconversion
follows the lower-rim-through-the-annulus pathway also
in DMSO (Table 1).
Con clu sion s
Mono-O-substitution of p-tert-butylcalix[6]arenes at the
lower rim with substituents as large as a butyl group
slows ring inversion, while substitution with groups
larger than benzyl freezes the conformation. Participa-
tion of the ether oxygen of the substituent as hydrogen-
bond acceptor has been demonstrated by the Hammett
correlation of the vicinal OH’s chemical shifts with σp for
a series of p-substituted benzyl derivatives. Steric effects
seem to be partly responsible for the high inversion
barriers. However, preservation of a cyclic hydrogen-
bond array is also a necessary requirement for their
effectiveness, as it raises the energy of the alternative
upper-rim-through-the-annulus pathway, which would
otherwise be insensitive to substitution at the lower rim.
In the case of monosubstituted calix[6]arenes, it has been
demonstrated that pseudorotation and inversion are not
concerted processes.
Exp er im en ta l Section
Solvents were dried before use by standard methods. Most
chemicals were purchased from Aldrich Co. and used as
received without further purification. 1H NMR and 13C NMR
spectra were recorded on a Bruker AMX 300 spectrometer at
300 and 75 MHz, respectively. ROESY (mixing times 300 and
500 ms), COSY-45, and HMQC were recorded using standart
Bruker microprograms using TPPI with TD ) 256 or higher.
The typical matrix size was 1K × 1K. Low-temperature
spectra were recorded in CD2Cl2 and/or CDCl3, and high-
temperature spectra were recorded in C2D2Cl4. Fast atom
bombardment (FAB, NBA matrix) spectra were recorded on a
VG AutoSpec instrument. TLC analyses were carried out on
Alugram Si G/UV254 (Macheray-Nagel). Chromatographic
separation was performed with flash grade silica gel SDS 60
(230-400 mesh). Compounds 1,25 2a ,5a and 35a were obtained
according to described procedures.
Gen er a l P r oced u r e for Mon oa lk yla tion . To a solution
of 200 mg (0.2 mmol) of 1 in acetone (15 mL) was added 30
mg (0.22 mmol) of K2CO3. After refluxing for 2 h and cooling
to room temperature, the corresponding halide was added and
the mixture was refluxed until the reaction was completed.
The reaction mixture was cooled to room temperature, quenched
with NH4OH (25%) (2 mL), and stirred for 1 h, HCl (1 N) was
added, and the solvent was removed under vacuum. CH2Cl2
(10 mL) was added and the aqueous layer was separated and
extracted with CH2Cl2 (2 × 5 mL). The combined organic layer
was washed with water and brine and dried (Na2SO4).
Evaporation of the solvent and treatment with hexane gave
some unreacted 1, which was filtered off. The filtrate was
evaporated and the residue treated with cold MeOH to give
the crude mono-O-alkylated product.
5,11,17,23,29,35-Hexa-ter t-bu tyl-42-(4′-ch lor oben zyloxy)-
37,38,39,40,41-p en ta h yd r oxyca lix[6]a r en e (2d ). Calix[6]-
arene 2d was obtained with 4-chlorobenzyl chloride (0.2 mmol)
as alkylating agent. Time for the reaction was 66 h, to yield
1
55% (120 mg): mp 195-196 °C; H NMR (CDCl3) δ 9.97 (s,
2H, OH), 9.84 (s, 1H, OH), 8.99 (s, 2H, OH), 7.68, 7.60 (AA′BB′
system, 4H, ArH), 7.00-7.14 (m, 12H, ArH), 5.14 (s, 2H, OCH2-
Ar), 4.39 (d, 2H, J ) 13.5 Hz, ArCH2Ar), 4.27 (d, 2H, J ) 13.9
Hz, ArCH2Ar), 3.99 (d, 2H, J ) 13.9 Hz, ArCH2Ar), 3.57 (d,
2H, J ) 13.9 Hz, ArCH2Ar), 3.49 (d, 2H, J ) 13.5 Hz, ArCH2-
Ar), 3.38 (d, 2H, J ) 13.9 Hz, ArCH2Ar), 1.27 [s, 18H, C(CH3)3],
1.26 [s, 18H, C(CH3)3], 1.22 [s, 9H, C(CH3)3], 1.17 [s, 9H,
C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT) δ 149.3, 149.1, 148.2,
148.1, 146.6, 144.4, 143.6, 143.0, 134.9, 134.4, 132.4, 127.5,
127.4, 127.0, 126.7 (ArC), 129.3, 128.6, 126.2, 126.1, 126.0,
125.7, 125.5 (ArCH), 77.0 (OCH2Ar), 34.3, 34.0, 33.92, 33.90
[C(CH3)3], 33.3, 32.6 (ArCH2Ar), 31.6, 31.5, 31.4, 31.2 [C(CH3)3];
HRMS (FAB+) calcd for C73H89ClO6 (M+) 1096.63477, found
1096.63280.
42-(4′-Br om oben zyloxy)-5,11,17,23,29,35-h exa -ter t-bu -
tyl-37,38,39,40,41-p en ta h yd r oxyca lix[6]a r en e (2e). Calix-
[6]arene 2e was obtained with 4-bromobenzyl bromide (0.6
mmol) as alkylating agent. Time for the reaction was 24 h, to
yield 30% (70 mg) after chromatography (hexane-CH2Cl2
2:1): mp 140-142 °C; 1H NMR (CDCl3) δ 9.98 (s, 2H, OH),
9.86 (s, 1H, OH), 9.03 (s, 2H, OH), 7.77, 7.66 (AA′BB′ system,
4H, ArH), 7.20-7.15 (m, 8H, ArH), 7.14 (s, 2H, ArH), 7.12 (s,
2H, ArH), 5.16 (s, 2H, OCH2Ar), 4.41 (d, 2H, J ) 13.4 Hz,
ArCH2Ar), 4.31 (d, 2H, J ) 14.0 Hz, ArCH2Ar), 4.03 (d, 2H, J
) 13.8 Hz, ArCH2Ar), 3.61 (d, 2H, J ) 14.0 Hz, ArCH2Ar),
3.56 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 3.41 (d, 2H, J ) 13.8 Hz,
ArCH2Ar), 1.31 [s, 18H, C(CH3)3], 1.30 [s, 18H, C(CH3)3], 1.26
[s, 9H, C(CH3)3], 1.20 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3,
DEPT) δ 149.3, 149.1, 148.2, 148.1, 146.6, 144.4, 143.6, 143.0,
135.4, 132.4, 127.5, 127.4, 127.1, 126.7, 122.6 (ArC), 132.2,
128.9, 126.2, 126.1, 126.0, 125.7, 125.5 (ArCH), 77.1 (OCH2-
Ar), 34.3, 34.0, 33.93, 33.91 [C(CH3)3], 33.3, 32.7 (ArCH2Ar),
31.6, 31.5, 31.4, 31.2 [C(CH3)3]; MS (FAB+) m/z 1139.4 (M+).
Anal. Calcd for C73H89O6Br: C, 76.75; H, 7.85. Found: C,
76.35; H, 8.33.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-pen ta h y-
d r oxy-42-(4′-m eth ylben zyloxy)ca lix[6]a r en e (2b). Calix-
[6]arene 2b was obtained with 4-methylbenzyl bromide (0.2
mmol) as alkylating agent. Time for the reaction was 66 h, to
yield 55% (117 mg) after chromatography (CH2Cl2-AcOEt
1:1): mp 210-215 °C; 1H NMR (CDCl3) δ 9.93 (s, 2H, OH),
(25) Gutsche, C. D.; Dhawan, B.; Leonis, M.; Stewart, D. Org. Synth.
1989, 68, 238.

1084 J . Org. Chem., Vol. 63, No. 4, 1998
Magrans et al.
5,11,17,23,29,35-Hexa -ter t-bu tyl-42-(4′-tr iflu or om eth yl-
ben zyloxy)-37,38,39,40,41-pen tah ydr oxycalix[6]ar en e (2f).
Calix[6]arene 2f was obtained with 4-trifluoromethylbenzyl
chloride (0.2 mmol) as alkylating agent. Time for the reaction
was 66 h, to yield 45% (100 mg) after chromatography
(hexane-AcOEt 15:1): mp 210-212 °C; 1H NMR (CDCl3) δ
9.96 (s, 2H, OH), 9.87 (s, 1H, OH), 8.94 (s, 2H, OH), 7.90 (s,
4H, ArH), 7.12-7.14 (m, 8H, ArH), 7.07-7.09 (m, 4H, ArH),
5.23 (s, 2H, OCH2Ar), 4.38 (d, 2H, J ) 13.2 Hz, ArCH2Ar),
4.24 (d, 2H, J ) 14.3 Hz, ArCH2Ar), 4.01 (d, 2H, J ) 14.0 Hz,
ArCH2Ar), 3.56 (d, 2H, J ) 14.3 Hz, ArCH2Ar), 3.54 (d, 2H, J
) 13.2 Hz, ArCH2Ar), 3.39 (d, 2H, J ) 14.0 Hz, ArCH2Ar),
1.27 [s, 18H, C(CH3)3], 1.26 [s, 18H, C(CH3)3], 1.22 [s, 9H,
C(CH3)3], 1.17 [s, 9H, C(CH3)3];13C{1H} NMR (CDCl3, DEPT)
δ 149.3, 149.1, 148.4, 148.1, 146.4, 144.5, 144.3, 143.7, 143.1,
140.5, 132.4, 126.6, 127.4, 127.1, 126.7 (ArC), 127.2, 126.2,
126.1, 126.06, 126.0, 125.7, 125.6 (ArCH), 76.9 (OCH2Ar), 34.3,
34.0, 33.9 [C(CH3)3], 33.3, 32.6, 32.5 (ArCH2Ar), 31.6, 31.5,
31.4, 31.2 [C(CH3)3]; MS (FAB+) m/z 1130.9 (M+). Anal. Calcd
for C74H89O6F3‚1.5H2O: C, 76.71; H, 8.01 Found: C, 76.63;
H, 8.10.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-p en ta h y-
d r oxy-42-(4′-n itr oben zyloxy)ca lix[6]a r en e (2g). Calix[6]-
arene 2g was obtained with 4-nitrobenzyl bromide (0.2 mmol)
as alkylating agent. Time for the reaction was 66 h, to yield
50% (112 mg). An analytical sample was obtained by chro-
matography (hexane-AcOEt 15:1): mp 230-235 °C; 1H NMR
(CDCl3) δ 9.92 (s, 2H, OH), 9.85 (s, 1H, OH), 8.83 (s, 2H, OH),
8.49, 7.94 (AA′BB′ system, 4H, ArH), 7.12-7.14 (m, 8H, ArH),
7.07-7.09 (m, 4H, ArH), 5.27 (s, 2H, OCH2Ar), 4.36 (d, 2H, J
) 13.5 Hz, ArCH2Ar), 4.24 (d, 2H, J ) 14.2 Hz, ArCH2Ar),
4.01 (d, 2H, J ) 13.8 Hz, ArCH2Ar), 3.58 (d, 2H, J ) 14.2 Hz,
ArCH2Ar), 3.55 (d, 2H, J ) 13.5 Hz, ArCH2Ar), 3.40 (d, 2H, J
) 13.8 Hz, ArCH2Ar), 1.27 [s, 18H, C(CH3)3], 1.26 [s, 18H,
C(CH3)3], 1.22 [s, 9H, C(CH3)3], 1.17 [s, 9H, C(CH3)3]; 13C{1H}
NMR (CDCl3, DEPT) δ 149.2, 149.0, 148.5, 147.9, 146.4, 144.5,
144.2, 143.8, 143.6, 143.2, 132.3, 127.4, 127.2, 127.0, 126.7,
126.6 (ArC), 127.6, 126.2, 126.0, 125.7, 125.6, 124.2 (ArCH),
76.2 (OCH2Ar), 34.3, 33.92, 33.90, 33.0 [C(CH3)3], 33.2, 32.6,
32.1 (ArCH2Ar), 31.53, 31.51, 31.4, 31.2 [C(CH3)3]; HRMS
(FAB+) calcd for C73H89NO8 (M+) 1107.65882, found 1107.65970.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-pen ta h y-
d r oxy-42-(p r op yloxy)ca lix[6]a r en e (4). Calix[6]arene 4
was obtained with 1-bromopropane (0.6 mmol) as alkylating
agent. Time for the reaction was 48 h, to yield 31% (65 mg)
after chromatography (hexane-CH2Cl2 1:1): mp 162-164 °C;
1H NMR (CDCl3) δ 9.91 (s, 2H, OH), 9.49 (s, 1H, OH), 9.17 (s,
2H, OH), 7.16-7.13 (m, 8H, ArH), 7.11 (s, 2H, ArH), 7.05 (s,
2H, ArH), 4.15 (t, 2H, J ) 7.3 Hz, OCH2), 4.5-3.6 (sa, 12H,
ArCH2Ar), 2.16-2.10 (m, 2H, OPr), 1.41 (t, 3H, J ) 7.3 Hz,
OPr), 1.31 [s, 18H, C(CH3)3], 1.29 [s, 18H, C(CH3)3], 1.24 [s,
9H, C(CH3)3], 1.22 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3,
DEPT) δ 149.5, 149.4, 148.2, 147.7, 146.6, 144.3, 143.5, 142.9,
132.5, 127.4, 127.3, 127.0, 126.79, 126.78 (ArC), 126.2, 126.0,
125.9, 125.8, 125.7, 125.4 (ArCH), 77.5 (OCH2), 34.2, 34.0,
33.94, 33.92 [C(CH3)3], 33.2, 32.6, 32.5 (ArCH2Ar), 31.6, 31.5,
31.4, 31.2 [C(CH3)3], 23.5 (OPr), 10.7 (OPr); MS (FAB+) m/z
1014.7 (M+). Anal. Calcd for C69H90O6‚MeOH: C, 80.26; H,
9.04. Found: C, 80.37; H, 8.79.
126.8, 126.7 (ArC), 126.2, 126.0, 125.9, 125.8, 125.7, 125.4
(ArCH), 75.8 (OCH2), 34.2, 34.0, 33.9, 33.8 [C(CH3)3], 33.2, 32.5,
32.3 (ArCH2Ar), 32.5 (OBu), 31.6, 31.5, 31.4, 31.2 [C(CH3)3],
19.6 (OBu), 14.1 (OBu); MS (FAB+) m/z 1028.7 (M+). Anal.
Calcd for C70H92O6‚CH2Cl2: C, 76.52; H, 8.50. Found: C,
75.64; H, 8.79.
5,11,17,23,29,35-H exa -ter t-b u t yl-42-(cycloh exylm et h -
yloxy)-37,38,39,40,41-p en t a h yd r oxyca lix[6]a r en e (6).
Calix[6]arene 6 was obtained with cyclohexylmethyl bromide
(0.8 mmol) as alkylating agent and acetonitrile as solvent.
Time for the reaction was 4 days, to yield 50% (111 mg) after
chromatography (hexane-CH2Cl2 2:1): mp 160-164 °C; 1H
NMR (CDCl3) δ 10.15 (s, 2H, OH), 9.95 (s, 1H, OH), 9.19 (s,
2H, OH), 7.17-7.11 (m, 8H, ArH), 7.08 (s, 2H, ArH), 7.01 (s,
2H, ArH), 4.36 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 4.25 (d, 2H, J
) 14.0 Hz, ArCH2Ar), 4.03 (d, 2H, J ) 13.8 Hz, ArCH2Ar),
3.95 (d, 2H, J ) 5.7 Hz, OCH2Cy), 3.54 (d, 2H, J ) 13.8 Hz,
ArCH2Ar), 3.47 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 3.39 (d, 2H, J
) 14.0 Hz, ArCH2Ar), 2.17-2.12 (m, 1H, Cy), 1.98-1.93 (m,
4H, Cy), 1.79-1.75 (m, 4H, Cy), 1.47-1.43 (m, 2H, Cy), 1.28
[s, 18H, C(CH3)3], 1.26 [s, 18H, C(CH3)3], 1.21 [s, 9H, C(CH3)3],
1.15 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT) δ 149.5,
149.4 148.2, 147.7, 146.5, 144.4, 143.6, 142.9, 132.4, 127.7,
127.5, 127.0, 126.8, 126.7 (ArC), 126.2, 126.1, 126.0, 125.9,
125.7, 125.5 (ArCH), 81.9 (OCH2), 39.1 (Cy), 34.0, 33.98, 33.93,
33.91 [C(CH3)3], 33.4, 32.7, 32.5 (ArCH2Ar), 31.6, 31.5, 31.4,
31.2 [C(CH3)3], 30.2, 26.5, 26.1 (Cy); MS (FAB+) m/z 1068.8
(M+). Anal. Calcd for C73H96O6‚1/2CH2Cl2: C, 79.39; H, 8.99.
Found: C, 79.59; H, 9.46.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-p en ta h y-
d r oxy-42-(2′-n a p h th ylm eth yloxy)ca lix[6]a r en e (7). Calix-
[6]arene 7 was obtained with 2-(bromomethyl)naphthalene
(0.26 mmol) as alkylating agent. Time for the reaction was
70 h, to yield 28% (60 mg) after chromatography (hexane-
AcOEt 25:1): mp 176-180 °C; 1H NMR (CDCl3) δ 9.91 (s, 2H,
OH), 9.58 (s, 1H, OH), 9.10 (s, 2H, OH), 8.25 (d, 1H, J ) 8.4
Hz, ArH), 8.12 (s, 1H, ArH), 8.10 (d, 1H, J ) 8.6 Hz, ArH),
8.03-7.96 (m, 2H, ArH), 7.57-7.54 (m, 2H, ArH), 7.22 (s, 2H,
ArH), 7.19-7.18 (m, 8H, ArH), 7.16 (s, 2H, ArH), 5.41 (s, 2H,
OCH2Ar), 4.58 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 4.20 (d, 2H, J
) 14.1 Hz, ArCH2Ar), 4.04 (d, 2H, J ) 13.8 Hz, ArCH2Ar),
3.62 (m, 4H, ArCH2Ar), 3.46 (d, 2H, J ) 13.8 Hz, ArCH2Ar),
1.35 [s, 18H, C(CH3)3], 1.33 [s, 18H, C(CH3)3], 1.30 [s, 9H,
C(CH3)3], 1.26 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT)
δ 149.53, 149.5, 148.2, 148.1, 146.6, 144.4, 143.6, 142.9, 133.8,
133.5, 133.4, 132.7, 127.6, 127.5, 126.8, 126.7, 126.3 (ArC),
129.3, 128.3, 128.0, 126.7, 126.3, 126.0, 125.9, 125.7, 125.4,
125.3 (ArCH), 78.4 (OCH2Ar), 34.3, 34.1, 34.0, 33.9 [C(CH3)3],
33.4, 32.8, 32.6 (ArCH2Ar), 31.7, 31.6, 31.5, 31.3 [C(CH3)3]; MS
(FAB+) m/z 1112.6 (M+). Anal. Calcd for C77H92O6‚1/2CH2Cl2:
C, 81.78; H, 8.24. Found: C, 81.37; H, 8.27.
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-p en ta h y-
d r oxy-42-(2′-p h en yleth yloxy)ca lix[6]a r en e (8). Calix[6]-
arene 8 was obtained with 2-chloro-1-phenylethane (1.05
mmol) and NaI (0.8 mmol). Time for the reaction was 5 days,
to yield 34% (73 mg) after chromatography (hexane-CH2Cl2
2:1) and trituration with methanol: mp 171-174 °C; 1H NMR
(CDCl3) δ 9.80 (s, 2H, OH), 9.51 (s, 1H, OH), 8.70 (s, 2H, OH),
7.47 (dd, 2H, J ) 6.9 Hz, J ) 1.4 Hz, ArH), 7.38 (t, 2H, J )
7.6 Hz, ArH), 7.23 (tt, 1H, J ) 7.2 Hz, J ) 1.4 Hz), 7.18-7.08
(m, 10H, ArH), 7.12 (s, 2H, ArH), 6.98 (s, 2H, ArH), 4.31 (t,
2H, J ) 6.9 Hz, OCH2), 4.24 (d, 4H, J ) 13.9 Hz, ArCH2Ar),
3.98 (d, 2H, J ) 13.9 Hz, ArCH2Ar), 3.63 (d, 2H, J ) 14.3 Hz,
ArCH2Ar), 3.50 (d, 2H, J ) 13.9 Hz, ArCH2Ar), 3.46 (d, 2H, J
) 13.8 Hz, ArCH2Ar), 3.38 (t, 2H, J ) 6.8 Hz, OCH2CH2Ar),
1.30 [s, 18H, C(CH3)3], 1.28 [s, 18H, C(CH3)3], 1.24 [s, 9H,
C(CH3)3], 1.14 [s, 9H, C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT)
δ 149.7, 149.3, 148.1, 147.7, 146.8, 144.3, 143.6, 142.9, 137.8,
132.2, 127.4, 127.2, 126.9, 126.8, 126.6 (ArC), 128.9, 128.7,
126.7, 126.1, 126.0, 125.9, 125.8, 125.7, 125.4 (ArCH), 76.8
(OCH2), 36.5 (OCH2CH2Ar), 34.2, 33.93, 33.89 [C(CH3)3], 33.1,
32.6, 32.3 (ArCH2Ar), 31.55, 31.52, 31.4, 31.2 [C(CH3)3]; MS
(FAB+) m/z 1076.6 (M+). Anal. Calcd for C74H92O6: C, 82.47;
H, 8.61. Found: C, 81.98; H, 8.64.
5,11,17,23,29,35-H exa -ter t-b u t yl-42-(b u t yloxy)-37,38,
39,40,41-p en ta h yd r oxyca lix[6]a r en e (5). Calix[6]arene 5
was obtained with 1-iodobutane (0.8 mmol) as alkylating
agent. Time for the reaction was 24 h, to yield 26% (56 mg)
after chromatography (hexane-CH2Cl2 3:2): mp 182-184 °C;
1H NMR (CDCl3) δ 9.97 (s, 2H, OH), 9.64 (s, 1H, OH), 9.15 (s,
2H, OH), 7.15-7.12 (m, 8H, ArH), 7.10 (s, 2H, ArH), 7.04 (s,
2H, ArH), 4.36 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 4.24 (d, 2H, J
) 14.4 Hz, ArCH2Ar), 4.17 (t, 2H, J ) 6.0 Hz, OCH2), 4.03 (d,
2H, J ) 13.9 Hz, ArCH2Ar), 3.59 (d, 2H, J ) 14.4 Hz, ArCH2-
Ar), 3.53 (d, 2H, J ) 13.4 Hz, ArCH2Ar), 3.47 (d, 2H, J ) 13.9
Hz, ArCH2Ar), 2.09-2.05 (m, 2H, OBu), 1.94-1.84 (m, 2H,
OBu), 1.30 [s, 18H, C(CH3)3], 1.28 [s, 18H, C(CH3)3], 1.23 [s,
9H, C(CH3)3], 1.22 (t, 3H, J ) 6.0 Hz, OBu), 1.18 [s, 9H,
C(CH3)3]; 13C{1H} NMR (CDCl3, DEPT) δ 149.5, 149.4, 148.2,
147.7, 146.6, 144.3, 143.5, 142.8, 132.4, 127.4, 127.3, 126.9,

Restricted p-tert-Butylcalix[6]arenes in Cone Conformation
J . Org. Chem., Vol. 63, No. 4, 1998 1085
5,11,17,23,29,35-Hexa -ter t-bu tyl-37,38,39,40,41-pen ta h y-
d r oxy-42-(3′-p h en ylp r op yloxy)ca lix[6]a r en e (9). Calix[6]-
arene 9 was obtained with 1-chloro-3-phenylpropane (1.04
mmol) and NaI (0.8 mmol). Time for the reaction was 5 days,
to yield 25% (74 mg) after chromatography (hexane-CH2Cl2
2:1) and trituration with methanol: mp 174-176 °C; 1H NMR
(CDCl3) δ 9.90 (s, 2H, OH), 9.36 (s, 1H, OH), 9.07 (s, 2H, OH),
7.40 (dd, 2H, J ) 7.0 Hz, J ) 1.4 Hz, ArH), 7.31 (t, 2H, J )
7.5 Hz, ArH), 7.20 (tt, 1H, J ) 7.2 Hz, J ) 1.3 Hz, ArH), 7.14
(d, 6H, J ) 1.9 Hz, ArH), 7.09 (d, 2H, J ) 1.3 Hz, ArH), 7.07
(s, 2H, ArH), 7.00 (s, 2H, ArH), 4.35 (d, 2H, J ) 13.6 Hz,
ArCH2Ar), 4.15 (d, 2H, J ) 14.4 Hz, ArCH2Ar), 4.14 (t, 2H, J
) 7.5 Hz, OCH2), 4.00 (d, 2H, J ) 13.9 Hz, ArCH2Ar), 3.55 (d,
2H, J ) 14.6 Hz, ArCH2Ar), 3.49 (d, 4H, J ) 13.7 Hz, ArCH2-
Ar), 3.15 (t, 2H, J ) 7.5 Hz, OCH2CH2CH2Ar), 2.46-2.37 (m,
2H, OCH2CH2CH2Ar), 1.30 [s, 18H, C(CH3)3], 1.27 [s, 18H,
C(CH3)3], 1.22 [s, 9H, C(CH3)3], 1.15 [s, 9H, C(CH3)3]; 13C{1H}
NMR (CDCl3, DEPT) δ 149.7, 149.4, 148.2, 147.8, 146.8, 144.3,
143.6, 143.0, 141.3, 132.3, 127.3, 127.2, 127.0, 126.8 (ArC),
128.7, 128.5, 126.2, 126.03, 126.01, 125.9, 125.8, 125.4 (ArCH),
75.2 (OCH2), 34.2, 33.97, 33.96, 33.94, [C(CH3)3], 33.2, 32.6,
32.5, 32.3, 31.9 (ArCH2Ar and OCH2CH2CH2Ar), 31.6, 31.5,
31.4, 31.2 [C(CH3)3]; MS (FAB+) m/z 1090.8 (M+). Anal. Calcd
for C75H94O6: C, 82.51; H, 8.68. Found: C, 82.49; H, 8.51.
Ack n ow led gm en t. We are grateful to DGICYT
(PB93-0283 and PB94-924) for financial support. Fel-
lowships (to J .O.M., F.C., and P.M.N.) by Ministerio de
Educacio´n y Ciencia (Spain) are gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1D 1H
NMR spectra of 3 and 4 at room temperature; 9, 8, 2a in CDCl3
at 213 and 203 K; 2g, 5 in DMSO-d6 at 300-400 K; 2f and 5
in C2D2Cl4 at 300-396 K and 2D NMR spectra of 6 and 2a
(27 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O971443X