A "Classical" Tetrahydroxycalix[4]arene Adopting the 1,2-Alternate Conformation

Article abstract of DOI:10.1021/jo035573j

The first example of a "classical" tetrahydroxycalixarene, which adopts the 1,2-alternate conformation both in solution and in the crystal, is described. Calixarene derivatives with two distal methylene groups substituted in a trans fashion by phenyl (5a)

Full text of DOI:10.1021/jo035573j

A “Cla ssica l” Tetr a h yd r oxyca lix[4]a r en e Ad op tin g th e
1,2-Alter n a te Con for m a tion
Samah Simaan and Silvio E. Biali*
Department of Organic Chemistry, The Hebrew University of J erusalem, J erusalem 91904, Israel
silvio@vms.huji.ac.il
Received October 27, 2003
The first example of a “classical” tetrahydroxycalixarene, which adopts the 1,2-alternate conforma-
tion both in solution and in the crystal, is described. Calixarene derivatives with two distal
methylene groups substituted in a trans fashion by phenyl (5a ) or mesityl (5b) groups were
synthesized via addition of PhMgBr/CuCN or MesMgBr/CuCN to the bis(spirodiene) derivative 3.
Whereas the phenyl-substituted calixarene derivative 5a adopts the usual “cone” conformation,
solution NMR data and X-ray crystallography indicate that the more crowded mesityl derivative
5b adopts a 1,2-alternate conformation with the two mesityl groups located at isoclinal positions
of the macrocycle.
SCHEME 1
In tr od u ction
One of the central conformational paradigms of “clas-
sical”1 tetrahydroxycalix[4]arenes (possessing phenol
groups interconnected by methylene bridges, e.g., 1a ) is
that their preferred conformation is the cone.2 This
conformation is stabilized over the other possible up-
down forms (partial cone, 1,3-alternate, and 1,2-alternate,
Scheme 1) by a circular array of hydrogen bonds between
the OH groups. The energy gap between the cone
conformation (possessing four intramolecular hydrogen
bonds) and the 1,2-alternate form (possessing only two
such bonds) of 1a has been estimated by MM3 calcula-
tions as 7.5-7.7 kcal/mol.3 A rather large number of
tetrahydroxycalixarene derivatives structurally related
to 1 and differing in the substituent at the aryl groups
and/or at the bridges have been reported so far. Polar
substituents may stabilize the noncone conformations by
formation of intramolecular hydrogen bonds with the OH
groups,4,5 and in some cases, dipole-dipole interactions
between substituents may destabilize the cone form.6,7
However, in all cases where the substituents on the calix
skeleton were alkyl or aryl groups, the preferred solution
conformation was the cone or the pinched cone. Here we
report the first example of a “classical” tetrahydroxycalix-
[4]arene, which as a result of the steric destabilization
of the cone form adopts the 1,2-alternate conformation.
Resu lts a n d Discu ssion
Ster ic Desta bliza tion of th e Con e Con for m a tion .
When two distal methylene groups of the calix scaffold
are substituted in a trans fashion (e.g., 1b-d ) the cone
conformation may be sterically destabilized relative to
other up-down forms. Necessarily, in the cone form, one
substituent must be located in an axial position and one
in an equatorial position. In the 1,2-alternate form, both
substituents can be located at diaxial, diequatorial, or
diisoclinal positions (Scheme 2, the hydroxyl groups are
omitted for clarity). A conformational change of the
macrocycle from cone to 1,2-alternate can reduce the
(1) We use the term “classical” to designate calixarenes possessing
pairs of phenol units connected by a single sp3 carbon as opposed to
“thiacalixarenes” (sulfur bridges) and “silacalixarenes” (silicon atoms).
(2) (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (b)
Gutsche, C. D. Aldrichimica Acta 1995, 28, 1. (c) Gutsche, C. D.
Calixarenes Revisited; Royal Society of Chemistry: Cambridge, 1998.
(d) Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J ., Vicens,
J ., Eds.; Kluwer Academic Publishers: Dordrecht, 2001. (e) Bo¨hmer,
V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester,
2003; Chapter 19.
(5) A tetranitrocalix[4]arene has been shown to adopt the 1,2-
alternate conformation in the crystal. Desroches, C.; Parola, S.;
Vocanson, F.; Perrin, M.; Lamartine, R.; Letoffe, J . M.; Bouix, J . New
J . Chem. 2002, 26, 651.
(6) p-Hexanoylcalix[4]arene undergoes a solid-phase transition upon
heating. In each phase, the calixarene adopts a different conformation
(cone and partial cone). See: Shinkai, S.; Nagasaki, T.; Iwamoto, K.;
Ikeda, A.; He, G.-X.; Matsuda, T.; Iwamoto, M. Bull. Chem. Soc. J pn.
1991, 64, 381.
(7) A calixarene derivative in which the methylene bridges have
been formally replaced by carbonyl groups (a “ketocalixarene”) adopts
the 1,3-alternate conformation both in solution and in the crystal. Seri,
N.; Simaan, S.; Botoshansky, M.; Kaftory, M.; Biali, S. E. J . Org. Chem.
2003, 68, 7140.
(3) (a) Harada, T.; Ohseto, F.; Shinkai, S. Tetrahedron 1994, 50,
13377. (b) Thondorf, I.; Brenn, J . J . Mol. Struct. (THEOCHEM) 1997,
398-399, 307.
(4) Calixarenes structurally related to 1 but with the methylene
bridges replaced by oxidized sulfur atoms (e.g., sulfoxides or sulfones)
adopt the 1,3-alternate conformation in the crystal. This conformation
is stabilized by intramolecular hydrogen bonds between the OH groups
and the sulfonyl or sulfone groups at the bridges. See: (a) Mislin, G.;
Graf, E.; Hosseini, M. W.; De Cian, A.; Fischer, J . Tetrahedron Lett.
1999. 40, 1129. (b) Mislin, G.; Graf, E.; Hosseini, M. W.; De Cian, A.;
Fischer, J . Chem. Commun. 1998, 1345.
10.1021/jo035573j CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003
J . Org. Chem. 2004, 69, 95-98
95

Simaan and Biali
SCHEME 2
SCHEME 3
repulsive steric interactions by allowing the groups to be
located at the less hindered diisoclinal or diequatorial
positions.8
ring can differ. For comparison purposes, the diphenyl
derivative 5a was also prepared.
Syn th eses of 5a a n d 5b. Several tetrahydroxycalix-
[4]arenes possessing a pair of aryl substituents at distal
methylene bridges have been prepared by the fragment
condensation method (i.e., cyclocondensation of two suit-
able fragments), which afforded a mixture of trans and
cis forms.11,12 In all cases, the preferred conformation was
the cone. For the preparation of 5a and 5b, the bis-
(spirodiene) derivative 39,13 was reacted with PhMgBr/
CuCN or MesMgBr/CuCN (Scheme 3). In the first case,
the reaction afforded the substituted calixarene deriva-
tive 5a , whereas in the reaction with MesMgBr/CuCN,
a mixture of the substituted bis(spirodienone) derivative
(4)14 and bimesityl was obtained, as judged from H NMR
spectroscopy. This mixture was reacted with LiAlH4, and
1
The formal introduction of a pair of trans alkyl sub-
stituents (e.g., isopropyl or tert-butyl) results in a change
of the conformational preferences of the 1,3-dimethyl
ether derivative from cone in the unsubstituted deriva-
tive 2a to 1,2-alternate in 2c and 2d .9 This is reminiscent
of the conformational behavior of some alkyl-substituted
cyclohexane derivatives where the preferred conforma-
tion is the twist form due to the unavoidable 1,3-diaxial
interactions in the chair conformation.10 However, in the
case of the tetrahydroxy calixarenes 1b-d , the repulsive
steric interactions ensuing from the presence of an axial
substituent are insufficient to overcome the stabilization
of the circular array of hydrogen bonds, and as in the
parent 1a , the preferred conformation is the cone.9
Since the cone form was preferred even in the presence
of the bulky tert-Bu groups (e.g., 1d ), we synthesized and
examined the conformational preferences of the mesityl
derivative 5b. Although both mesityl and tert-Bu are
bulky groups, they strongly differ in their shape, and
therefore their steric interactions with the macrocyclic
the resulting calixarene (5b) was isolated and purified.
1
NMR Sp ectr a of 5a a n d 5b. The H NMR spectrum
of 5a (400 MHz, 240 K, CDCl3) was fairly similar to those
reported for other calix[4]arene derivatives with trans
aryl substituents on opposite bridges.11 Calixarene 5a
displayed two signals for the methine groups (at 6.06 and
5.40 ppm, assigned to axial and equatorial methine
protons), two tert-butyl signals, and an OH signal at 10.3
ppm, in agreement with the presence of a “frozen” (on
the NMR time scale) cone conformation of Cs symmetry
(11) See: (a) Gru¨ttner, C.; Bo¨hmer, V.; Vogt, W.; Thondorf, I.; Biali,
S. E.; Grynszpan, F. Tetrahedron Lett. 1994, 35, 6267. (b) 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,
12938.
(12) For other examples of the use of the fragment condensation
method for the preparation of calixarenes substituted at the bridges,
see: (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. 1 1994, 1657. (c) Sartori, G.;
Bigi, F.; Porta, C.; Maggi, R.; Mora, R. Tetrahedron Lett. 1995, 36,
2311. (d) Biali, S. E.; Bo¨hmer, V.; Columbus, I.; Ferguson, G.; Gru¨ttner,
C.; Grynszpan, F.; Paulus, E. F.; Thondorf, I. J . Chem. Soc., Perkin
Trans. 2 1998, 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.
(8) The two trans substituents can be located at diequatorial
positions of the 1,2-alternate form since these positions are mutually
trans, whereas such an arrangement is impossible in the cone form
since diequatorial positions are in a cis relationship.
(9) (a) Simaan, S.; Biali, S. E. J . Org. Chem. 2003, 68, 3634. (b)
Simaan, S.; Biali, S. E. J . Org. Chem. 2003, 68, 7685.
(10) For a computational study of the chair/twist boat energy gap
of polyalkylcyclohexanes see: Weiser, J .; Golan, O.; Fitjer, L.; Biali,
S. E. J . Org. Chem. 1996, 61, 8277.
(13) (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.
(14) For a review on spirodienone calixarene derivatives, see: Biali,
S. E. Synlett 2003, 1.
96 J . Org. Chem., Vol. 69, No. 1, 2004

“Classical” Tetrahydroxycalix[4]arene
F IGURE 1. Stereoscopic view of the crystal structure of 5b (top view). The molecule adopts the 1,2-alternate conformation with
the two mesityl groups located at isoclinal positions of the macrocycle. The chloroform molecules that cocrystallized were omitted
for clarity.
SCHEME 4
possessing one phenyl located in an equatorial position
and one in an axial position. In contrast, the H NMR of
1
5b (CDCl3, 240 K) displayed a rather different pattern
of signals for the central macrocycle. A single signal at
6.06 ppm was observed for the methine protons, in
agreement with a structure in which both methines are
symmetry related. Notably, the OH signals of 5b reso-
nated at an unusually high field for a tetrahydroxycalix-
arene (5.75 and 7.67 ppm), suggesting that, in contrast
temperatures (308.5, 309.9, and 330.7 K, respectively),
to 5a , no circular array of hydrogen bonds is present. On
a rotational barrier of 15.2 kcal/mol was determined.16
the basis of the symmetry of the NMR pattern and the
The dynamic process is ascribed to a 1,2-alternate-to-1,2-
lack of a cyclic array of hydrogen bonds, we ascribe to
alternate inversion process (Scheme 4), which involves
calixarene 5b a 1,2-alternate conformation. Within the
rotation through the annulus of the four phenolic groups
1,2-alternate conformation, a pair of trans substituents
and mutually exchanges the methylene protons, the t-Bu
located at distal bridges can occupy diaxial, diequatorial,
groups, as well as pairs of aromatic protons ortho or para
or diisoclinal positions (cf. Scheme 2). The chemical shifts
to the substituted bridge. The cone-to-cone inversion
of the methylene protons (4.04 and 3.43 ppm in CDCl3)
barrier of 5a was somewhat lower (14.5 kcal/mol). In
and their separation (∆δ: 0.61 ppm) are characteristic
addition, coalescence phenomena were observed for the
of a pair of protons located at axial and equatorial
ortho methyl and aromatic protons of the mesityl groups.
positions of the macrocycle. By exclusion, the mesityl
Notably, the barrier determined from the mutual ex-
rings must be located at the diisoclinal positions of the
change of the o-Me groups (15.1 kcal/mol) was identical
within experimental error to the barrier determined for
the ring inversion process. This suggests that either both
1
calix skeleton.15 In the H NMR spectrum, the mesityl
groups of 5b displayed three aliphatic and two aromatic
signals, indicating a slow rotation around the CH-Mes
barriers are fortuitously similar or that a single process
bonds on the NMR time scale at 240 K.
is being followed. Addition of pyridine-d5 to the CDCl3
Cr ysta l Str u ctu r e of 5b. A single crystal of 5b was
solution allowed both alternatives to be distinguished.17
grown from CHCl3 and submitted to X-ray crystal-
The barrier for ring inversion of 5b in 4:1 (v/v) CDCl3/
lography. The molecule crystallized with two solvent
pyridine-d5 was 14.4 kcal/mol (0.8 kcal/mol lower than
molecules. As shown by the crystal data, the molecule
in pure CDCl3) but the barrier for mesityl rotation was
adopts a 1,2-alternate conformation of crystallographic
now also 14.4 kcal/mol. This suggests that the minimum
Ci symmetry (Figure 1) with the mesityl groups located
energy pathway for rotation of the mesityl ring requires
at isoclinal positions. In contrast to the cyclic array of
a conformational change of the calix macrocycle. In the
hydrogen bonds present in the cone conformation, only
crystal conformation of 5b, one ortho methyl is pointing
two intramolecular hydrogen bonds (between pairs of
toward the center of the calix annulus and the neighbor-
rings oriented syn) are present in 5b.
ing rings can restrict the rotations of the mesityl ring. It
may be possible that during the 1,2-alternate-to-1,2-
Rota tion a l Ba r r ier s of 5b. Upon raising the tem-
perature, signals of 5b broadened and coalesced. From
alternate interconversion process, these steric restrictions
the chemical shift difference under slow exchange condi-
are reduced, allowing the mesityl ring to rotate.
tions of pairs of aromatic, t-Bu, and methylene protons
(∆δ: 51.2, 52.0 and 254.1 Hz) and their coalescence
(16) Exchange rates at the coalescence temperatures (kc) were
estimated using the equations kc ) 2.22 ∆ν or kc ) 2.22 (∆ν2 + 6J 2)1/2
.
(15) One of the o-Me signals of the mesityl group displayed NOE
cross-peaks in the ROESY spectrum with an aromatic proton of a
neighboring phenol ring and the OH signal of a second phenol ring.
This is in agreement with an anti arrangement of the two phenol rings
vicinal to the mesityl group, i.e., with an isoclinal disposition of the
substituent.
See: J uaristi E. Stereochemistry and Conformational Analysis;
Wiley: New York, 1991; pp 253-254.
(17) The cone-to-cone inversion barrier of 1a is lower in pyridine-
5 (13.7 kcal/mol) than in CDCl3 (15.7 kcal/mol) since the circular array
of hydrogen bonds is disrupted by the pyridine molecules. See:
d
Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052.
J . Org. Chem, Vol. 69, No. 1, 2004 97

Simaan and Biali
(silica, eluent 2:1 hexane/CH2Cl2) yielding 0.24 g (24%) of 5a ,
mp 212 °C: 1H NMR (400 MHz, CDCl3, 240 K) δ 10.34 (br s,
OH), 7.39 (m, 3H, Ph), 7.28 (m, 9 H, Ph), 7.16 (br s, 2H, Ar-
H), 7.07 (d, J ) 1.9 Hz, 2H, Ar-H), 7.04 (d, J ) 1.9 Hz, 2H,
Ar-H), 6.06 (s, 1H, ax CHPh), 5.40 (s, 1H, eq CHPh), 4.26 (d,
J ) 13.9 Hz, 2H, CH2), 3.59 (d, J ) 14.0 Hz, 2H, CH2), 1.28 (s,
18H, t-Bu), 1.13 (s, 18H, t-Bu); 13C NMR (100.6 MHz, CDCl3,
260 K), δ 147.1, 147.0, 144.2, 144.1, 141.8, 138.9, 130.9, 129.4,
128.8, 128.7, 127.9, 127.8, 127.6, 127.2, 127.0, 126.9, 126.5,
125.9, 125.5, 125.2, 57.2, 41.1, 34.1, 34.0, 32.6, 31.5, 31.2 ppm;
CI MS (+DCI) m/z 801.3 (MH+).
P r ep a r a tion of 5b. The reaction with the organocopper
reagent was conducted as described above starting from 1 g
of 3 (1.25 mmol), 0.46 g (5.1 mmol) of CuCN, 10.5 mL of
mesitylmagnesium bromide (1.0 M solution in THF), and 50
mL of dry THF. After trituration with CHCl3/MeOH, 0.8 g of
a ca. 2:1 mixture of bimesityl and the substituted spirodienone
derivative was obtained. To a suspension of this mixture in
50 mL of dry THF were added 0.3 g of LiAlH4 under an inert
atmosphere. After treatment with water, phase separation,
and extraction of the aqueous phase with CH2Cl2, the combined
organic phases were evaporated. The residue was crystallized
from CHCl3/MeOH yielding 0.27 g of 5b. Recrystallization from
CHCl3 (100 mg requires 0.5 L of solvent) afforded 68 mg of
pure material (17% yield for the 3 f 5b conversion), mp 370
°C (dec): 1H NMR (400 MHz, CDCl3, 240 K) δ 7.67 (s, 2H,
OH), 7.17 (d, J ) 1.8 Hz, 2H, Ar-H), 7.14 (d, J ) 2.0 Hz, 2H,
Ar-H), 6.85 (s, 2H, Mes-H), 6.80 (s, 2H, Mes-H), 6.75 (d, J )
1.9 Hz, 2H, Ar-H), 6.62 (d, J ) 1.7 Hz, 2H, Ar-H), 6.06 (s,
2H, MesCH), 5.75 (s, 2H, OH), 4.04 (d, J ) 13.6 Hz, 2H, CH2),
3.43 (d, J ) 13.7 Hz, 2H, CH2), 2.28 (s, 6H, p-Me), 2.19 (s, 6H,
o-Me), 1.77 (s, 6H, o-Me), 1.18 (s, 18H, t-Bu), 1.05 (s, 18H,
t-Bu); 13C NMR (100.6 MHz, CDCl2CDCl2, 400 K) δ 149.3,
144.2, 138.0, 137.2, 135.5, 129.8, 128.4, 126.5, 126.0, 44.9, 33.9,
32.1, 31.3, 20.6, 20.5 ppm; CI MS (+DCI) m/z 885.1 (MH+).
In contrast to the calixarene dimethyl ether deriva-
tives, where in the 1,2-conformation the alkyl groups at
the bridges are located at equatorial positions, in the
solution and crystal conformation of 5b, the mesityl
substituents are located at the isoclinal positions of the
1,2-alternate form. This conformational preference indi-
cates that the repulsive steric interactions are larger in
the equatorial positions than in the isoclinal positions.
Assuming that the steric environments of the equatorial
positions at the cone and 1,2-alternate are similar, this
suggests that the cone conformation is destabilized not
only by the presence of the axial substituent but also by
the equatorial substituent as well.
Con clu sion s. The first example of a “classical” tet-
rahydroxycalixarene that adopts a 1,2-alternate confor-
mation in solution is described. The shift in the confor-
mational preferences from cone to 1,2-alternate is due
to the steric destabilization of the cone conformation as
a result of the presence of the bulky mesityl substituents
in the axial and equatorial positions of the macrocycle
in that conformation.
Exp er im en ta l Section
Cr ysta l d a ta for 5b. Data were collected in a Bruker Apex
CCD. Crystal dimensions: 0.24 × 0.22 × 0.08 mm, triclinic,
P1h, a ) 9.654(2) Å, b ) 12.542(2) Å, c ) 13.779(3) Å, R )
102.905(3)°, â ) 105.500(3)°, γ ) 107.444(3)°, V ) 1447.7(5)
Å3, Z ) 1, Fcalc ) 1.289 Mg m-3, 2θmax ) 56.26°, Mo KR
radiation, 0.71073 Å, temp ) 100(2) K, no. of measured and
independent reflections: 16 835/6766, no. of parameters ) 348,
R1 ) 0.0711, wR2 ) 0.1832, residual electron density: 0.816
e/Å3.
P r ep a r a tion of 5a . A mixture of 0.46 g (5.1 mmol) CuCN
and 6 mL of PhLi (1.8 M solution in 70:30 cyclohexane/ether)
was stirred in 50 mL of dry THF at 0 °C under an inert
atmosphere until a homogeneous solution was obtained. To
the mixture was then added 1 g of 3 (1.25 mmol), and the
mixture was stirred for 3 h and allowed to reach room
temperature. After treatment with water, the organic phase
was extracted with CH2Cl2 and the combined organic phases
were evaporated. The residue was triturated with a mixture
of CHCl3/MeOH. The product was purified by chromatography
Ack n ow led gm en t. We thank Dr. Shmuel Cohen for
the crystal structure determination of 5b. This research
was supported by the Israel Science Foundation (Grant
No. 44/01-1).
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 5b (CIF) and NMR spectra of 5a and 5b. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035573J
98 J . Org. Chem., Vol. 69, No. 1, 2004