Conformation, Inversion Barrier, and Solvent-Induced Conformational Shift in Exo- and Endo/Exo-Calix[4]arenes

Article abstract of DOI:10.1021/jo970967u

Calixarenes 4a and 4b having hydroxyl groups in endo and exo positions and the ethanediyl-bridged exo-calixarene 5a were synthesized by a stepwise strategy. Single-crystal X-ray structures were obtained for 4a and for the exo-calixarene 3d, showing the molecules to exist in the 1,2-alternate conformation which is also found for 4a,b in solution. The inversion barriers of 4a and 4b (10.3 and 10.8 kcal mol^-1) are similar to that determined for the endo-dihydroxycalixarene 12, indicating that the additional intramolecular hydrogen bond between the exo OH groups does not decrease the flexibility of the molecule. In CDCl₃ solution exo-calixarene 5a adopts a 1,2-alternate conformation with the methyl group at the bridge located in an axial position, while in DMSO-d₆ the conformation adopted is the partial cone. Similar solvent-induced conformational shifts were found for the exo-calixarenes 3b and 3d. MM3 calculations predict that the cone form is the lowest energy conformation of 4 and the exo-calixarenes 3 and 5. The calculations suggest that the conformational preferences of the methyl group at the bridge for either the axial or equatorial positions are in large part determined by the repulsive steric interactions with the hydroxyl groups. The inversion barrier of 4b is satisfactorily reproduced by calculations, which indicate that the rotation of the exo rings is less energetically demanding than the rotation of the endo rings.

Full text of DOI:10.1021/jo970967u

8350
J . Org. Chem. 1997, 62, 8350-8360
Con for m a tion , In ver sion Ba r r ier , a n d Solven t-In d u ced
Con for m a tion a l Sh ift in Exo- a n d En d o/Exo-Ca lix[4]a r en es
Silvio E. Biali,*,† Volker Bo¨hmer,*,‡ J o¨rg Brenn,§ Michael Frings,‡ Iris Thondorf,*,§
Walter Vogt,‡ and J ens Wo¨hnert§
Department of Organic Chemistry, The Hebrew University of J erusalem, J erusalem 91904, Israel,
Institut fu¨r Organische Chemie, J ohannes-Gutenberg-Universita¨t, J .-J .-Becher-Weg 34, SB1,
D-55099 Mainz, Germany, and Institut fu¨r Biochemie, Fachbereich Biochemie/ Biotechnologie,
Martin-Luther-Universita¨t, Halle-Wittenberg, Kurt-Mothes-Strasse 3, D-06099, Halle, Germany
Received J une 2, 1997X
Calixarenes 4a and 4b having hydroxyl groups in endo and exo positions and the ethanediyl-bridged
exo-calixarene 5a were synthesized by a stepwise strategy. Single-crystal X-ray structures were
obtained for 4a and for the exo-calixarene 3d , showing the molecules to exist in the 1,2-alternate
conformation which is also found for 4a ,b in solution. The inversion barriers of 4a and 4b (10.3
and 10.8 kcal mol-1) are similar to that determined for the endo-dihydroxycalixarene 12, indicating
that the additional intramolecular hydrogen bond between the exo OH groups does not decrease
the flexibility of the molecule. In CDCl3 solution exo-calixarene 5a adopts a 1,2-alternate
conformation with the methyl group at the bridge located in an axial position, while in DMSO-d6
the conformation adopted is the partial cone. Similar solvent-induced conformational shifts were
found for the exo-calixarenes 3b and 3d . MM3 calculations predict that the cone form is the lowest
energy conformation of 4 and the exo-calixarenes 3 and 5. The calculations suggest that the
conformational preferences of the methyl group at the bridge for either the axial or equatorial
positions are in large part determined by the repulsive steric interactions with the hydroxyl groups.
The inversion barrier of 4b is satisfactorily reproduced by calculations, which indicate that the
rotation of the exo rings is less energetically demanding than the rotation of the endo rings.
In tr od u ction
adopt cone conformations, but they differ in the confor-
mational preferences of the alkyl groups: the alkanediyl
group of 1b prefers the equatorial position,6,7 while a
tetraaxial disposition of the alkyl substituents is exclu-
sively found in all-cis-2a .8
In recent years, two types of [14] metacyclophane
derivatives have been intensively studied as potential
molecular hosts: the calix[4]arenes1 (e.g., p-tert-butylcalix-
[4]arene, 1a ) and the resorcarenes2 (2a ). The calixarenes
possess an array of OH groups located at the intraan-
nular (endo) positions of the macrocyclic ring. These
groups are involved in a circular array of hydrogen bonds
in which each hydroxyl group serves both as a donor and
as an acceptor. In the resorcarenes the hydroxyl groups
are present in extraannular (exo) positions of the macro-
cycle, and therefore these and related compounds pos-
sessing a similar disposition of the hydroxyls may be
designated by the general term “exo-calixarenes” as
opposed to the “conventional” endo-calixarenes.3-5 Al-
though intramolecular hydrogen bonds may be formed
between adjacent OH groups, no circular array of hydro-
gen bonds is possible in resorcarenes. The all-cis res-
orcarenes and the alkanediyl derivatives of 1a (e.g., 1b)
Recently, resorcarenes with unsubstituted methylene
bridges (2b) were reported by Konishi and Morikawa.9
Although both 1a and 2b adopt cone conformations which
are held by four intramolecular hydrogen bonds between
the OH groups, the cone-to-cone inversion barrier of 1a
† The Hebrew University of J erusalem.
‡ J ohannes-Gutenberg-Universita¨t.
§ Martin-Luther-Universita¨t.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) For reviews on calixarenes see: (a) Gutsche, C. D. Calixarenes;
and 2b (R′ ) C6H13) in CDCl3 differ by 3.7 kcal mol-1
,
Royal Society of Chemistry: Cambridge, 1989. (b) Calixarenes:
A
q
being ∆Gc ) 15.710 and 12.0 kcal mol-1, respectively.9,11
Versatile Class of Macrocyclic Compounds; Vicens, J ., Bo¨hmer, V., Eds.;
Kluwer: Dordrecht, 1991. (c) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713. (d) Gutsche, C. D. Aldrichimica Acta 1995, 28, 1.
(2) For a recent review see: Timmerman, P.; Verboom, W.; Rein-
houdt, D. N. Tetrahedron 1996, 52, 2663.
(6) 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.
(3) Bo¨hmer, V.; Do¨rrenba¨cher, R.; Frings, M.; Heydenreich, M.; de
Paoli, D.; Vogt, W.; Ferguson, G.; Thondorf, I. J . Org. Chem. 1996, 61,
549.
(4) (a) Bo¨hmer, V.; Do¨rrenba¨cher, R.; Vogt, W.; Zetta, L. Tetrahedron
Lett. 1992, 33, 769. (b) Thondorf, I.; Brenn, J .; Brandt, W.; Bo¨hmer,
V. Tetrahedron Lett. 1995, 36, 6665. (c) Bo¨hmer, V.; Ferguson, G.;
Frings, M. Acta Crystallogr. C 1997, C53, 1293.
(7) For other studies of alkanediyl calix[4]arene derivatives see:
Sartori, G.; Maggi, R.; Bigi, F.; Arduini, A.; Pastorio, A.; Porta, C. J .
Chem. Soc., Perkin Trans. 1 1994, 1657.
(8) See for example: Abis, L.; Dalcanale, E.; Du vosel, A.; Spera, S.
J . Chem. Soc., Perkin Trans. 2 1990, 2075; Mann, G.; Hennig, I.;
Weinelt, F.; Mu¨ller, K.; Meusinger, R.; Zahn, G.; Lippmann, T.
Supramol. Chem. 1994, 3, 101.
(5) (a) Sartori, G.; Porta, C.; Bigi, F.; Maggi, R.; Peri, F.; Marzi, E.;
Lanfranchi, M.; Pellingheli, M. A. Tetrahedron 1997, 53, 3287. (b)
Sorrell, T. N.; Yuan, H. J . Org. Chem. 1997, 62, 1899.
(9) Konishi, H.; Morikawa, O. J . Chem. Soc., Chem. Commun. 1993,
34.
(10) Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052.
S0022-3263(97)00967-5 CCC: $14.00 © 1997 American Chemical Society

Conformation of Exo- and Endo/Exo-Calix[4]arenes
J . Org. Chem., Vol. 62, No. 24, 1997 8351
The preparation of exo-calixarenes possessing only four
exo hydroxyl groups (3) was recently described.3-5,12 X-ray
diffraction studies of 3a ‚CH3CN and 3a ‚CH2Cl2 indicate
that the exo-calixarene exists in a cone conformation3,5a
whereas 3c and a bis(dioxamethylene) derivative exist
in the crystal in a 1,2-alternate conformation.4c,5b In
solution all the exo-calixarenes 3 were found to be flexible
on the NMR time scale, even at -70 °C, and since the
dynamic processes could not be frozen, the solution
conformation could not be unambiguously determined.3
MM3 calculations suggest a ring inversion barrier as low
as 6.7 kcal mol-1 for 3c.4b
65% yield. In this step a stoichiometric amount of ZnCO3
was applied, which not only provides a mild Lewis acid,
but completely traps the HBr developed thus preventing
debutylation. Debromination was achieved by hydroge-
nation in alkaline solution (Raney-nickel, rt, normal
pressure) to yield 70-85% of 8, having two free ortho-
positions in the terminal o-tert-butylphenol unit. Their
condensation with paraformaldehyde in xylene at 175 °C
(autoclave) led to the calixarenes 4a ,b which were
obtained in 37 and 20% yield, respectively, after simple
recrystallization.
Starting with the ethanediyl-bridged dimer 9, the
analogous reaction sequence (eq 2) of bromomethylation
(55% of 10), condensation (50% of 11), and debromination
(90% of 12) furnished a linear tetramer which upon
cyclization with paraformaldehyde gave calix[4]arene 5a
in 38%.
Con for m a tion a l Descr ip tion of 3 a n d 4. For endo-
calixarenes (e.g., 1) usually four basic conformations are
discussed (cone, partial cone (“paco”), 1,2-alternate (“1,2-
alt”), and 1,3-alternate (“1,3-alt”))1 while for the resor-
carenes additional conformations are considered.2 No-
tably, although the four aryl rings of 3a ,c,e are identical,
two distinct 1,2-alt forms exist in which pairs of rings
with either convergent (“1,2-alt(conv)”) or divergent (“1,2-
alt(div)”) OH groups are oriented in a syn fashion. Only
in the 1,2-alt(conv) form are OH‚‚‚OH intramolecular
hydrogen bonds possible. Two different paco forms exist
for 4 in which either an endo or exo ring is oriented anti
to the rest of the rings.13 These forms will be dubbed
“paco(endo)” and “paco(exo)”, respectively.
In this paper we extend our conformational studies on
exo-calixarenes 3 to calixarenes possessing both endo and
exo hydroxyl groups (4a and 4b) and to the ethane-1,1-
diyl exo-calixarene 5a . Both structural modifications
desymmetrize the calixarene scaffold and may decrease
its flexibility, thus facilitating the determination of the
preferred conformation by NMR methods.
Resu lts a n d Discu ssion
Syn th esis. The exo/endo-calixarenes 4a and 4b were
prepared in a stepwise manner summarized in eq 1 which
is similar to the synthesis of 3b.3 Condensation of the
bis-bromomethylated dimers 6 with an excess of 2-bromo-
6-tert-butylphenol led to the linear tetramers 7 in 60-
[14] metacyclophanes (e.g., 1) adopting a cone confor-
mation possess methylene protons located in positions
commonly denominated, by analogy with the chair form
of cyclohexane, as axial or equatorial.1 For simplicity,
we propose that in all conformations where two adjacent
rings are oriented syn (i.e., both rings pointing “up” or
“down”) the protons on the bridging methylene which are
proximal or distal to the endo positions will be denoted
(11) The authors in ref 9 concluded that the energy gap between
the rotational barriers of 1a and 2b (R′ ) n-C6H13) is 4.4 kcal mol-1
.
This estimation was based on the value determined for 1a (16.4 kcal
mol-1) by simulation of the temperature-dependent NMR (Araki, S.;
Shinkai, S.; Matsuda, T. Chem. Lett. 1989, 581). However, the latter
barrier is most likely incorrect, the correct value being the one
determined by the coalescence approximation (15.7 kcal mol-1).10 See:
Van Gelder, J . M.; Brenn, J .; Thondorf, I.; Biali, S. E. J . Org. Chem.
1997, 62, 3511.
(13) For identification purposes, the aryl rings of 4 possessing endo
or exo hydroxyl groups will be denoted endo- and exo rings, respectively,
while the tert-butyl and Me substituted rings of 5a will be dubbed tert-
butylphenol and cresol rings.
(12) Sartori, G.; Bigi, F.; Porta, C.; Maggi, R.; Mora, R. Tetrahedron
Lett. 1995, 36, 2311.

8352 J . Org. Chem., Vol. 62, No. 24, 1997
Biali et al.
F igu r e 2. Molecular structure of calix[4]arene 4a .
F igu r e 1. Crystal structure of the exo-calixarene 3d .
Somewhat stronger differences can be seen in the incli-
nation of the phenolic rings where differences up to 43°
in 3d (rings C(1-6) and C(8-13)) and up to 32° in 4a
(rings C(15-20) and C(22-27)) are found. The folding
of the molecule leads even to a change in the sequence of
the signs of the torsion angles which is (+-,-+,-+,--)
for 3d and (+-,+-,-+,--) for 4a (both notations are
equivalent) while (+-,++,-+,--) is reported for a
“regular 1,2-alternate” conformation.
“axial” and “equatorial”. If the two rings are oriented
anti, we suggest for these protons, by analogy to the
twist-boat conformation of cyclohexane, the term “iso-
clinal”.14 The paco and 1,2-alt forms possess two kinds
of methylene groups, with axial/equatorial or isoclinal
positions available for substituents. In the paco form the
isoclinal positions within a methylene group are not
symmetry equivalent. In this case the isoclinal positions
pointing away or toward the unique ring oriented anti
to the rest of the rings will be denominated “iso I” and
“iso II”, respectively.
X-r a y Cr ysta llogr a p h y. Single crystals of 3d and 4a
were obtained by slow evaporation of solutions in aceto-
nitrile, a solvent which often favors a cone conformation
due to its tendency to be included into the molecular
cavity. However, in contrast to 3a ,3 both calixarenes
assume a 1,2-alt conformation (Figures 1-3).15 Equiva-
lent rings are in syn arrangement in both cases, which
means that the skeletal symmetry plane bisecting the
methylene carbons C7 and C21 is roughly found in the
crystal.
The 1,2-alt conformation allows intramolecular hydro-
gen bonds between the adjacent OH groups (O1‚‚‚O2 )
2.744 and O3‚‚‚O4 ) 2.748 Å for 4a ). A molecule of
acetonitrile is included in the crystal lattice of 4a , weakly
hydrogen bonded by one of the endo OH groups (O1‚‚‚N
) 2.878 Å), but this is the only intermolecular hydrogen
bond formed in this case. For 3d only the distance
O3‚‚‚O4 ) 2.756 Å is in agreement with an intramolecu-
lar hydrogen bond, while O1‚‚‚O2 ) 2.935 Å is even
longer than the intermolecular contacts O1‚‚‚O3′ ) 2.842
and O2‚‚‚O4′ ) 2.758 Å. The packing shown in Figure 4
suggests, however, that the molecules are arranged into
sheets linked together by infinite chains of intra- and
intermolecular hydrogen bonds (isodromic hydrogen bonds)
in which a given molecule is involved at both sides.
Similar arrangements were found for some dimers17a-c
(as well as linear trimers17a,c and tetramers17d). The
packing differs from the arrangement found for 3a and
3c where cyclic arrays of intra- and intermolecular
hydrogen bonds (including the solvent in the case of 3c)
lead to infinite ribbons of calixarene molecules.3,4c
Con for m a tion of 4a a n d 4b in Solu tion . The
determination of the conformation and rotational barrier
of calixarenes 4a and 4b is of interest since they share
structural features with both the endo-calixarenes and
the exo-calixarenes. The 181 K NMR spectrum of 4a in
CD2Cl2 is in agreement with a preferred conformation
or average structure in which a mirror plane bisects the
As found in 3c4c the methylene carbon atoms show
deviations up to 0.8 Å from their mean plane, which
therefore cannot be taken as a reference plane for the
description of the molecular conformation. The deviation
can be characterized by the interplanar angle of two
triangles formed by the methylene carbons, and these
triangles can be used then as reference planes for the
inclination of the adjacent phenolic rings. Alternatively
the molecular conformation can be described by the
torsion angles around the Ar-CH2-Ar bonds. This way,
proposed by Ugozzoli and Andreetti16 is unambiguous but
less pictorial. Both values are collected in Table 1.
In both molecules the usual “reference plane” of the
methylene carbons is folded nearly to the same extent.
(14) The term “isoclinal” is commonly used in the twist-boat
conformation of cyclohexane for the positions at the methylene groups
bisected by the C2 axis. See: Kellie, G. M.; Riddell, F. G. Top.
Stereochem. 1974, 8, 225.
(15) A preliminary X-ray diffraction study indicates that exo-
calixarene 4b also adopts a 1,2-alternate conformation in the crystal.
(16) Ugozzoli, F.; Andreetti, G. D. J . Incl. Phenom. 1992, 13, 337.
(17) (a) Casiraghi, G.; Cornia, M.; Sartori, G.; Bocchi, V.; Casnati,
G.; Andreetti, G. D. Makromol. Chem. 1982, 183, 2611. (b) Casiraghi,
G.; Cornia, M.; Ricci, G.; Balduzzi, G.; Casnati, G.; Andreetti, G. D.
Makromol. Chem. 1983, 184, 1363. (c) Casiraghi, G.; Cornia, M.; Ricci,
G.; Casnati, G.; Andreetti, G. D.; Zetta, L. Macromolecules 1984, 17,
19. (d) Paulus, E.; Bo¨hmer, V. Makromol. Chem. 1984, 185, 1921.

Conformation of Exo- and Endo/Exo-Calix[4]arenes
J . Org. Chem., Vol. 62, No. 24, 1997 8353
F igu r e 3. Stereoview of the crystal conformation of 4a .
Ta ble 1. Con for m a tion a l P a r a m eter s of Molecu les 3d
a n d 4a (in d egr ees)a
3d
4a
Interplanar Angles
C(7,28,21)-C(7,14,21)
148.4
145.3
105.0
147.7
130.5
130.9
144.6
140.8
121.2
125.8
142.4
110.5
C(14,7,28)-C(14,21,28)
C(14,7,28)-C(1-6)
C(14,7,28)-C(8-13)
C(14,21,28)-C(15-20)
C(14,21,28)-C(22-27)
Torsion Angles
C5-C6-C7-C9
73.3
-109.3
-156.2
96.4
-90.5
92.8
86.0
-88.3
92.5
-161.5
-102.9
77.6
C6-C7-C9-C10
C12-C13-C14-C16
C13-C14-C16-C17
C19-C20-C21-C23
C20-C21-C23-C24
C26-C27-C28-C2
C27-C28-C2-C3
-123.5
-155.7
-164.1
-106.2
a
For the interplanar angles only absolute values are given,
while the sign of the torsion angles follows the usual convention.
two methylene bridges connecting two exo or endo rings.
The NMR signals were assigned by COSY and NOESY
spectra. The endo and exo OH groups show similar
chemical shifts (6.88 and 6.46 ppm). The protons within
the two methylene groups connecting identical rings are
diastereotopic and display large chemical shift differences
(∆δ 0.61 and 0.85 ppm), suggesting that pairs of endo or
exo rings adopt syn arrangements. The signals at 3.44
and 4.05 ppm were assigned to the equatorial and axial
protons of the methylene group connecting the two endo
rings on the basis of their NOE’s with an aromatic proton
and with the OH protons of the endo ring, respectively.
This assignment is in agreement with the general
observation that in calix[4]arenes 1 the equatorial pro-
tons resonate at a higher field than the axial ones.18
However, according to the NOE data in the methylene
group connecting the exo rings the equatorial methylene
proton resonates at a lower field (3.89 ppm) than the axial
one (3.04 ppm). These shifts are easy to rationalize. In
a syn arrangement of the exo rings the equatorial
methylene proton will be in close proximity to the OH
group, and is located in a steric environment similar to
the axial protons of a “classic” endo-calix[4]arene and vice
versa, the axial proton of this methylene is in a similar
environment to the equatorial protons of an endo-calix-
arene. Thus, it could be generally expected that when-
ever a methylene group connects two exo rings existing
F igu r e 4. Section of the crystal lattice showing the chains of
intra- and intermolecular hydrogen bonding array of exo-
calixarene 3d .
in a syn arrangement, the equatorial proton will resonate
at a lower field than the axial one.
The presence of a mirror plane bisecting two methylene
bridges, the nonequivalence of the protons within each
methylene bridge as well as their large chemical shift
difference, and the NOE interactions, are all consistent
with either a 1,2-alt or a cone conformation. However,
the NMR data seem to fit better a 1,2-alt conformation,
in particular, the relatively high field resonance of the
intraannular aromatic protons (6.11 ppm) which indi-
cates that these protons are shielded by the ring current
of a neighboring ring, as expected for a 1,2-alt form.19
We therefore conclude that the 1,2-alt form is the major
conformer of 4a in CD2Cl2 solution. Increasing the
(19) A cross-peak between the extraannular aromatic protons of the
endo and exo rings which would unambiguously indicate the presence
of a cone conformation was not detected.
(18) See for example: Alfieri, C.; Dradi, E.; Pochini, A.; Ungaro, R.
Gazz. Chim. Ital. 1989, 119, 335.

8354 J . Org. Chem., Vol. 62, No. 24, 1997
Biali et al.
4b in CD2Cl2 are similar to that found for 13 in CDCl2F
21
(10.6 kcal mol-1
)
which indicates that the presence of
the additional extraannular hydrogen bond in 4 does not
reduce the conformational mobility of the system.
St a t ic a n d Dyn a m ic St er eoch em ist r y of t h e
Eth a n ed iyl exo-Ca lixa r en e 5a . The low inversion
barrier of the exo-calixarenes 3 precluded the unambigu-
ous experimental determination of their preferred con-
formation by NMR since the protons within the methyl-
ene groups remained isochronous even at the lowest
temperature studied. However, if one methylene proton
of 3 is replaced by an alkyl group, in the resulting system
(e.g., 5a ) the protons within the methylene groups are
also diastereotopic under fast ring inversion conditions.
Thus, it should be possible to obtain more detailed
conformational information from the NMR spectra in
solution. A priori it is not clear whether the preference
of the alkanediyl groups of 2a for the axial positions
applies also for the ethanediyl exo-calixarene 5a .
1
Con for m a tion of 5a in CDCl3. The H NMR spec-
trum of 5a in CDCl3 at 250 K displays single singlets for
the methyl and t-Bu groups, as well as four aromatic
signals and four methylene doublets. This is in agree-
ment with a structure in which a mirror plane bisects
the bridges connecting identical rings. The NMR pattern
can be rationalized either in terms of a mirror symmetric
conformation (e.g., 1,2-alt or cone) or an asymmetric
structure in which a fast rotational process (even at 250
K) renders the pairs of cresol and tert-butylphenol rings
symmetry equivalent.13 The large chemical shift differ-
ence observed between the equatorial and axial methyl-
ene protons connecting the two tert-butylphenol rings
(0.66 ppm) suggests that both rings exist in a syn
arrangement. Similarly, as indicated by NOE studies at
250 and 298 K, the two cresol rings exist in a syn
arrangement. This can be rationalized, since these
arrangements allow an intramolecular hydrogen bond
between OH groups facing each other across a methylene
bridge. Since the extraannular aromatic protons of the
cresol and tert-butylphenol rings (which resonate at 6.81
and 7.01 ppm, respectively) display NOE interactions
with a different proton of the methylene groups which
bridge both rings, it can be concluded that the solution
conformation in CDCl3 is the 1,2-alternate.22
F igu r e 5. 400 MHz 1H NMR spectra of the methylene region
of 4a in CD2Cl2 at different temperatures.
temperature resulted in a downfield shift of the intraan-
nular aromatic protons, which may indicate an increased
population of a second conformation (most likely, a cone
form) in fast equilibrium with the 1,2-alt form. The NMR
spectrum of 4b (CD2Cl2, 187 K) is similar to that of 4a ,
but the NOESY spectrum suggests that in addition to
the major 1,2-alt conformer, the cone conformer is also
present.
In the low-temperature NOESY spectrum, the OH
signal of the cresol ring shows a cross-peak with the
methine signal. This suggests that the latter proton is
located in an equatorial position. This assumption is
confirmed by a cross-peak between the signal at 7.07 ppm
(the intraannular proton of a cresol ring) and the methyl
group attached to the bridge. It can be concluded that,
as observed for the resorcarenes, the methyl group at the
bridge prefers an axial position. The equatorial confor-
mation is most likely destabilized by the steric interac-
tions between the alkyl group and the exo oxygens of the
neighboring rings.
Rota tion a l Ba r r ier . To determine the rotational
barrier of 4a , its 1H NMR spectra were recorded in
CD2Cl2 in the 181-295 K temperature range. Upon
raising the temperature, the three pairs of methylene
doublets coalesced into three singlets in a 2:1:1 ratio
(Figure 5). These findings can be explained by a dynamic
process involving the (stepwise) passage of the four rings
through the macrocyclic cavity which results in the
mutual exchange between the axial and equatorial
protons. On the basis of the chemical shift differences
under slow exchange (113.0, 245.6, and 348.7 Hz), the
mutual coupling constants (17.0, 13.8, and 14.3 Hz,
respectively), and the coalescence temperatures (221, 221,
and 229 K, respectively), a barrier of 10.3 ( 0.1 kcal mol-1
was calculated.20 Similarly, from the coalescence of the
methylene protons of 4b (∆δ ) 116.7 Hz, J ) 16.9 Hz, Tc
) 231 K) an inversion barrier of 10.8 kcal mol-1 was
determined for 4b in CD2Cl2. The barriers for 4a and
(21) Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J . Chem. Soc., Chem.
Commun. 1993, 11.
(22) The relative orientation of the two pairs of rings could be
derived in principle by examining the chemical shifts of the protons of
the methylene groups connecting a cresol with a tert-butylphenol ring.
In the endo-calixarenes small and large chemical shift differences
for the protons of a given methylene group can be taken as an
indication of an anti or syn orientation of the neighboring rings,
respectively. However, it is unlikely that a similar behavior will be
observed for the methylene protons between the tert-butylphenol and
the cresol rings, since in the syn and in the anti arrangements both
protons are expected to be located in rather similar chemical environ-
ments.
(20) The exchange rate at the coalescence temperature was calcu-
lated using the Kurland equation (Kurland, R. J .; Rubin, M. B.; Wise,
W. B. J . Chem. Phys. 1964, 40, 2426).

Conformation of Exo- and Endo/Exo-Calix[4]arenes
J . Org. Chem., Vol. 62, No. 24, 1997 8355
Axia l/Equ a tor ia l In ter con ver sion . In principle, a
ring inversion process in which all rings pass through
the macrocyclic annulus should interconvert the pre-
ferred 1,2-alt conformation with the methyl group located
in an axial position (1,2-alt(ax)) with a diastereomeric
1,2-alternate conformation in which the methyl group is
located in an equatorial position (1,2-alt(eq)). The 1H
NMR spectra of 5a were recorded in the 220-290 K
temperature range (CDCl3) and down to 190 K (CD2Cl2).
No line broadening, indicating a dynamic exchange
process with a second less populated conformation (a
hidden partner), was found.23 This suggests that the
equilibrium is so strongly biased toward one conformer
that no line broadening can be experimentally observed,
and/or that the rotational barrier is so low that even at
190 K the compound is rapidly undergoing a dynamic
process.
the association of both OH groups with the solvent
molecules. However, the anti arrangement is destabi-
lized for the o-cresol rings by the steric interactions
between the methyl at the bridge and one OH group and
the two rings retain their mutual syn arrangement, even
if they are no longer intramolecularly hydrogen bonded.25
Raising the temperature of a DMSO-d6 solution of 5a
resulted in changes in the methylene region. Notably,
the chemical shift difference (∆δ) between the protons
on the methylene connecting the two tert-butylphenol
rings increased with the temperature (∆δ: 0.13 (rt), 0.164
(338 K), 0.219 (383 K)). This may indicate that a second
conformation in which the tert-butylphenol rings are syn,
is in fast equilibrium with the preferred partial cone
conformation, the population of the second form increas-
ing with the temperature.
Solven t-In d u ced Con for m a tion a l Sh ift in exo-
Ca lixa r en es. To determine whether the solvent effect
observed for 5a is due to the presence of the ethanediyl
group or if it is an intrinsic property of the exo-calixarene
skeleton, we examined also the NMR spectra of the exo-
calixarenes 3b and 3d . Cooling a solution of 3b in
CDCl2F26 down to 140 K did not result in decoalescence
of the methylene signals, although some broadening due
to the increased viscosity was observed. Assuming that
the chemical shift difference between the protons of the
methylene group connecting the tert-butylphenol rings
is 230 Hz (this is the chemical shift difference observed
for the corresponding protons in 5a ), an upper limit of
Con for m a tion of 5a in DMSO-d 6. Since the relative
stabilities of the conformations of 5a are probably
determined by the intramolecular hydrogen bonds, we
examined the influence of a strong hydrogen bond-
accepting solvent (DMSO-d6) on the conformation of the
system. The COSY and NOESY NMR spectra of 5a in
DMSO-d6 were recorded at rt and at 338 K, taking
advantage of the better resolution obtained at this
slightly elevated temperature. The main differences of
1
the H NMR spectra in DMSO in comparison to CDCl3
are as follows: (i) The intraannular protons on the cresol
rings are shifted upfield by 0.39 ppm. (ii) The protons
on the methylene bridge connecting two tert-butylphenol
rings which displayed substantially different chemical
shifts in CDCl3 (∆δ ) 0.66 and 0.59 ppm at 250 K and
rt, respectively) display in DMSO rather similar chemical
shifts (∆δ ) 0.13 and 0.17 ppm at rt and 338 K) in
agreement with an anti orientation of the rings. (iii) The
two OH signals are shifted downfield in DMSO (7.95 and
8.14 ppm), suggesting hydrogen bonding with the solvent
molecules.
Conformational information was extracted from the
NOESY spectrum which suggests that both o-cresol rings
are in a syn arrangement, with the Me substituent of
the bridge located in the axial position. The two extraan-
nular aromatic protons on the different rings display
strong cross-peaks with the methylene proton at 3.55
ppm. In addition NOE interactions were observed for
the intraannular and the OH protons of the tert-butyl-
phenol ring and both protons of the methylene group
connecting the two tert-butylphenol rings. This is in
agreement with a preferred paco conformation with a
tert-butylphenol ring pointing in the opposite direction
than the rest of the rings. This indicates that changing
the solvent from CDCl3 to DMSO results in a conforma-
tional change from 1,2-alt to paco and that DMSO
disrupts selectively the syn arrangement of the two tert-
butylphenol rings.24 The similar chemical shift observed
for both OH signals in DMSO suggests that all OH
groups are hydrogen bonded to the solvent. In the case
of the tert-butylphenol rings, the conformation changes
from syn to anti since the latter arrangement facilitates
∆Gc < 6.6 kcal mol-1 can be estimated for the barrier of
q
ring inversion. Since this low barrier precludes the
determination of the slow-exchange spectrum, the rela-
tive orientation of the rings with respect to their adjacent
methylene protons could not be determined directly.
NOESY spectra were recorded for 3b in CDCl3 and
DMSO-d6 while the poor solubility of 3d in CDCl3
prevented conformational studies in that solvent. The
NOESY spectra of 3b in CDCl3 displayed cross-peaks
between the proton pairs “a”/“d”, “a”/“c”, “b”/“c” (for the
notation “a”-“d” see Figure 6). Assuming that in this
solvent the OH groups are intramolecularly hydrogen
bonded (thus inducing syn arrangements of two pairs of
neighboring rings), the NOE can be interpreted as
indicating the presence of both the cone and the 1,2-
alt(conv) conformations.
NOE cross-peaks were observed between the signal
pairs “a”/“d”, “a”/“c”, “b”/“c”, “b”/Me and “d”/R for both 3b
and 3d in DMSO-d6 (Figure 6). Although there are
several ways to rationalize the observed pattern,27 the
similarity of the chemical shifts observed in the NMR
spectra of 5b, 3b, and 3d in DMSO-d6 suggests that the
compounds adopt similar conformations. The similar
spectra and the NOE observed indicate that in DMSO-
d6 both 3b and 3d exist as a mixture of all possible partial
cone conformations which are in fast exchange on the
NMR time scale. The solvent-induced conformational
shift observed for 5a seems to be present also in the exo-
calixarenes 3b and 3d .
Molecu la r Mech a n ics Ca lcu la tion s. A comprehen-
sive search of the conformational space of several exo-
(23) Anet, F. A. L.; Basus, V. J . J . Magn. Reson. 1978, 32, 339. For
papers using this method see for example: Adams, S. P.; Whitlock, H.
W. J . Am. Chem. Soc. 1982, 104, 1602; Casarini, D.; Lunazzi, L.;
Macciantelli, D. J . Chem. Soc., Perkin Trans. 2 1985, 1839. For a recent
example of the use of this technique for measuring rotational barriers
of conformational biased calixarene systems see ref 6.
(24) Solvent effects affect the conformational stability of substituted
resorcarenes. See for example: Shivanuk, A. N.; Pirozhenko, V. V.;
Kalchenko, V. I.; Markovsky, L. N. J . Chem. Res. 1995, 374.
(25) The partial cone conformation of 5a is chiral, and a dynamic
process fast at the NMR time scale and resulting in enantiomerization
must be assumed. The observed NOE should correspond to the average
of the NOE present in the two enantiomeric conformations.
(26) Siegel, J . S.; Anet, F. A. L. J . Org. Chem. 1988, 53, 2629.
(27) For example, an additional explanation for the cross-peaks
would be that 3b and 3d exist in DMSO-d6 as a mixture of 1,2- and
1,3-alt conformations.

8356 J . Org. Chem., Vol. 62, No. 24, 1997
Biali et al.
Ta ble 2. Rela tive En er gies (in k ca l m ol-1) for th e Low
En er gy Con for m er s of Sever a l Ca lix[4]a r en e System s
partial cone
6.0
1,2-alt
compd
cone
0.0
1,3-alt
11.3
1a
7.7
conva
diva
4.8
4.6
5.7
5.6
3a
3b
3d
3e
0.0
0.0
0.0
0.0
3.2
3.3/2.7b
3.3/3.2
3.3
3.2
2.2
2.2
2.2
7.1
7.5
7.3
7.5
endo
exo
1.5
1.7
1.6
4a
4b
4c
0.0
0.0
0.0
0.0
2.4
2.8
2.3
0.5
1.0
0.4
4.8
5.8
5.6
5.9
6.1
6.6
1.8
14a
1.2
3.2
a
The terms converging (conv) and diverging (div) denote that
adjacent hydroxyl groups are in a syn and anti orientation,
b
respectively. Two different partial cone forms exist in which the
cresol and tert-butylphenol ring, respectively, assume an anti
orientation.
Ta ble 3. Rela tive En er gies (in k ca l m ol-1) for th e Low
En er gy Con for m er s of Eth a n ed iyl-Su bstitu ted
Ca lix[4]a r en es
cone
ax eq
partial cone
ax eq
isoa
1,2-alt
eq iso 1,3-alt
compd
ax
4d
4e
5a
5b
5c
0.0 2.3 2.2 4.5
2.6 0.0 4.5 1.9
0.0 2.9 2.7 5.5
0.0 2.6 3.3 6.0
0.0 3.3 3.2 6.6
0.0 0.3 0.5 1.0
4.1
1.9
5.2
5.3
5.3
0.3
0.1 2.5 4.1
3.3 0.4 4.9
1.6 5.0 4.4
1.7 4.9 5.3
2.9 6.3 4.3
0.9 1.8 1.0
7.9
6.3
7.5
8.6
7.3
0.9
14b
a
Two different orientations exist for the methyl substituent at
the bridge in the partial cone conformation (paco(iso I) and paco(iso
II)); values given here are for the lower energy conformer.
F igu r e 6. Top: schematic representation of the NOE interac-
tions observed in the NOESY spectra of 3b (R ) t-Bu) and 3d
(R ) H) in DMSO-d6. Bottom: 400 MHz 1H NMR NOESY
spectrum (aromatic region) of 3d in DMSO-d6.
cone over the 1,2-alt structure. In general, the energy
range between the basic conformations of 3 is narrower
than in 1a but wider than in 14a . The calculated
structure of the lowest energy 1,2-alt conformer of 3d is
very similar to that found in the crystal structure while
the structures of the cone and the 1,3-alt forms closely
resemble those found in various crystal structures of
endo-calix[4]arenes.33 The most stable cone conformers
assume a “pinched” shape which is somewhat lower in
energy (0.3-0.7 kcal mol-1) than a cone structure pos-
sessing nearly C4 symmetry. In the 1,2-alt and paco
forms of 3 the methylene carbons do not lie in a common
plane but adopt a folded arrangement.
The results of the calculations for 4a -c listed in Table
2 reveal that the cone and 1,2-alt(conv) possess the lowest
energies followed by a paco form, a relative stability
which parallels the number of possible hydrogen bonds.
The energy gaps between the cone and the 1,2-alt or paco
conformers are smaller than those found in 3, which
probably is the result of the destabilization of the cone
conformation by intraannular OH groups which cannot
form a complete cyclic array of hydrogen bonds. Fur-
thermore, the paco(exo) form is 0.7 to 1.1 kcal mol-1 lower
in energy than the paco(endo). This suggests that in the
context of the force field the hydrogen bond between endo
rings is somewhat stronger than the one between exo
rings. The geometric shapes of the lowest energy con-
formers of 4a -c resemble closely those described above
and endo/exo-calixarenes was accomplished using a ran-
dom search method based on the MM3 force field28,29
which was specially adapted to calixarenes (see Experi-
mental Section). Selected calixarenes were also calcu-
lated with the stochastic search routine included in
MM3.30 Tables 2 and 3 list the relative energies of the
most stable structures of each conformation obtained
from this approach.
(i) Un su bstitu ted exo-Calix[4]ar en es. From a struc-
tural point of view, 1a and the [14] metacyclophane 14a
represent two limiting cases in calixarene chemistry. As
shown by force field calculations, the stability and rigidity
of the cone conformer of 1a are largely determined by
the circular hydrogen bonding scheme and the bulk of
the intraannular substituents. In contrast, 14a exhibits
neither a pronounced energetical preference for a single
conformer nor a substantial rotational barrier.31,32
A
priori, it could be expected that the formation of two
extraannular hydrogen bonds in 3 should stabilize the
cone and the 1,2-alt(conv) conformers. Indeed, the
calculations indicate that these two forms are lower in
energy than the other conformers. However, in contrast
to the NMR and X-ray data, the computations favor the
(28) Allinger, N. L.; Yuh, Y. H.; Lii, J .-H. J . Am. Chem. Soc. 1989,
111, 8551. Allinger, N. L.; Rahman, M.; Lii, J .-H. J . Am. Chem. Soc.
1990, 112, 8293.
(29) MM3(92) is available from the Quantum Chemistry Program
Exchange, University of Indiana, Bloomington, IN 47405.
(30) Saunders, M. J . Am. Chem. Soc. 1987, 109, 3150.
(31) Thondorf, I.; Brenn, J . J . Mol. Struct. (THEOCHEM) 1997,
398-399, 307.
(33) E.g., the cone structure of tris(25,26,27,28-tetrahydroxycalix-
[4]arene)acetone clathrate (Ungaro, R.; Pochini, A.; Andreetti, G. D.;
Sangermano, V. J . Chem. Soc., Perkin Trans. 2 1984, 1979) and the
1,3-alt conformation of 25,27-bis(allyloxy)-26,28-bis(benzoyloxy)calix-
[4]arene (Georgiev, E. M.; Mague, J . T.; Roundhill, D. M. Supramo-
lecular Chemistry 1993, 2, 53).
(32) Harada, T.; Ohseto, F.; Shinkai, S. Tetrahedron 1994, 50, 13377.

Conformation of Exo- and Endo/Exo-Calix[4]arenes
J . Org. Chem., Vol. 62, No. 24, 1997 8357
is energetically dominating nor the axial or equatorial
arrangement of the methyl substituent is markedly
preferred.
In the calixarene series 5a -c the extraannular hy-
droxyl groups “direct” the substituent into an axial
position which is, for a given conformation of the calix
skeleton, approximately 3 kcal mol-1 lower in energy
than the equatorial one. The calculations favor the cone
over the 1,2-alt conformation in contrast to the NMR data
which indicate that 5a adopts in CDCl3 solution a 1,2-
alt arrangement with an axial disposition of the methyl
substituent.
Two 1,1-ethanediyl derivatives of 4 (4d and 4e) were
examined. The calculations predict that the substituent
will assume an axial arrangement if proximal to two exo
rings and an equatorial orientation if in the neighborhood
of two endo rings. For a given conformation of the
macrocyclic ring, the energy gaps between the forms are
F igu r e 7. Possible interconversion pathways and rotational
barriers (in kcal mol-1, relative to the lowest energy cone
structure) for 4c and (in parentheses) for 4b.
for the exo-calixarenes 3, with the exception of the paco-
(endo) form which exhibits a nearly planar arrangement
of the methylene carbon atoms.
in the range 2.3-2.9 kcal mol-1
.
The possible pathways for the cone-to-cone inversion
of 5c (a process which interconverts the cone(ax) with
the cone(eq) forms) were calculated assuming stepwise
ring rotations (Figure 8). The cone(eq) and cone(ax)
forms generate distinct paco conformations (paco(iso I)
and paco(iso II), respectively). Nearly all the rotational
barriers of a ring proximal to the alkanediyl group are
higher than for a distal ring (e.g., paco(ax) f 1,2-alt(iso):
11.8 kcal mol-1 vs paco(ax) f 1,2-alt(ax): 7.7 kcal mol-1).
This is probably due to the repulsive steric interactions
which exist between the exo hydroxyl of the rotating ring
and the alkyl group in the transition state of the first
process. However, in the case of the paco(iso) f 1,2-alt
interconversions, the barriers for rotation of the adjacent
rings are lower than those of the distal rings. Appar-
ently, the folded structure of these conformations circum-
vents the repulsive interactions during the ring rotation.
In addition, in the paco(iso I/II) f 1,2-alt(ax/eq) processes
a hydrogen bond is formed in the transition state,
whereas the rotation of the distal ring involves breaking
of a hydrogen bond.
The pathways of ring inversion of exo/endo-calixarenes
were studied using the coordinate driver method.31 To
characterize the influence of the extraannular alkyl
groups on the heights of the rotational barriers, 4b and
4c were chosen as examples (Figure 7). The complete
inversion of the calixarene scaffold leading to the to-
pomerization of the methylene protons of the cone
conformer necessarily requires the rotation of all four
rings through the macrocyclic annulus. In general, the
rotational barriers of the endo rings are higher than those
of the exo rings, probably because the passage of the
intraannular hydroxyl through the interior of the mac-
rocycle is sterically more demanding than the passage
of a hydrogen. The lowest energy pathway for the
interconversion of the cone into the paco(endo) form
involves the steps: cone f paco(exo) f 1,2-alt(conv) f
paco(endo). A single ring rotation may transform the
paco(endo) into a (topomerized) cone* form, with a barrier
of 11.7 kcal mol-1 (for 4c). However, a lower energy
topomerization pathway is available since the paco(endo)
form may topomerize via the 1,2-alt(div) conformation
(i.e., paco(endo) f 1,2-alt(div) f paco(endo)*). The
topomerization of the cone form can then be achieved by
reversal of the first three steps (paco(endo)* f 1,2-
alt(conv)* f paco(exo)* f cone*). The overall energy
barriers for this process are 9.1 and 8.0 kcal mol-1 for
4b and 4c, respectively, and are in reasonable agreement
with the experimental value of ∆Gq of 10.8 kcal mol-1
determined for 4b.34 The calculated values are higher
than those obtained for the metacyclophane 14a (4.4 kcal
Starting from the cone(ax) form, the lowest energy
pathway to the cone(eq) form involves the following se-
quence: cone(ax) f paco(iso II) f 1,2-alt(eq) f paco(eq)
f cone(eq) conformations with an overall energy barrier
of 9.5 kcal mol-1
.
This barrier is about 3 kcal mol-1
higher than that we have calculated for the unsubstituted
exo-calixarene 3c4b which means that the methyl sub-
stituent does not strongly reduce the flexibility of the exo-
calixarene. A previous DNMR study6 has also shown
that the incorporation of an alkanediyl bridge into 1 (e.g.,
1b) leads only to slightly higher barriers.
31
4b
mol-1
)
and the exo-calixarene 3c (6.7 kcal mol-1
)
but
Con clu sion s. Exo-Calix[4]arenes 3 are flexible on the
NMR time scale, as predicted by computational methods.
This flexibility is not significantly reduced by an alkyl
substituent at one of the bridges (like the methyl group
in 5a ), although such a substituent seems to favor the
axial position. Single-crystal X-ray analyses suggest a
slight preference of the 1,2-alternate conformation over
the cone conformation in the crystalline state for the
examples studied so far. The 1,2-alternate conformation
is predominant also in apolar solvents such as CDCl3,
while a polar, hydrogen bonding breaking solvent like
DMSO-d6 shifts the conformation toward partial cone.
Exo-endo-calix[4]arenes 4 show analogous conformational
preferences, but their inversion barrier is in a measurable
region of 10-11 kcal mol-1, a value to which the in-
tramolecular hydrogen bond of the exo-hydroxy groups
lower than for 1a (13.7 kcal mol-1).31
(ii) Eth a n ed iyl Br id ged exo-Ca lix[4]a r en es. By
analogy to the 1,1-alkanediyl-calixarenes 1b and resor-
carenes 2a it could be expected that the hydroxyl groups
of the correspondingly substituted exo- and exo/endo-
calixarenes should influence the axial/equatorial confor-
mational preference of the alkyl group. To test whether
the calixarene scaffold itself influences the orientation
of a 1,1-ethanediyl group we performed molecular me-
chanics calculations on the [14] metacyclophane 14b. The
relative energies listed in Table 3 indicate, however, that
neither a single conformation of the macrocyclic skeleton
(34) The calculated energies cannot be directly related to the
experimentally determined values of ∆Gq since the entropy term ∆Sq
is neglected in the computations.

8358 J . Org. Chem., Vol. 62, No. 24, 1997
Biali et al.
F igu r e 8. Pathways for the conformational interconversions of 5c. All energies (in kcal mol-1) are relative to the most stable
cone(ax) conformation. The peripheral black and white squares represent rings pointing “up” or “down”, respectively. Two different
partial cone forms are possible in which the methyl is in an isoclinal position (paco(iso I) and paco(iso II), see text) while only a
single 1,3-alt form exists.
-3 Å e z e +3 Å in steps of 0.5 Å, taking into account
symmetry considerations. This was followed by partial mini-
mization of the conformers under fixation of the corresponding
z-coordinates. Using the “coordinate calculation options” of
the MM3 force field, alkyl substituents were added, and their
arrangement was optimized. The conformers were subse-
quently energetically minimized without any constraints using
the block-diagonal Newton-Raphson method. The orientation
of the hydroxyl groups was studied using a systematic search
of the corresponding torsional angles in increments of 180°.
Finally, all conformers were optimized using the full-matrix
Newton-Raphson method.
For means of comparison, some compounds were calculated
using the stochastic search option of the MM3 force field. To
cover the entire conformational space different runs were
started from each of the basic conformations. No significant
differences with respect to low energy conformations were
detected in the results of both methods.
does not significantly contribute. Molecular mechanics
calculations predict for the methyl group at the bridge
an axial position in 4d and an equatorial position in 4e.
This tendency of alkyl substituents to avoid the neigh-
borhood of the hydroxy groups may be used to steer the
conformation in these types of calix[4]arenes.
Exp er im en ta l Section
Molecu la r Mech a n ics Ca lcu la tion s. All calculations
were done using the MM3(92) force field running on either
SGI Crimson or IBM RISC 6000 workstations. Each com-
pound was subjected to a comprehensive conformational
search. Starting from a cone conformation of the correspond-
ing calixarene, whose mean plane through the four methylene
carbons was aligned in the xy-plane of the Cartesian coordinate
system, possible orientations for all upper rim carbon atoms
were generated independently from each other in the range

Conformation of Exo- and Endo/Exo-Calix[4]arenes
J . Org. Chem., Vol. 62, No. 24, 1997 8359
The pathways of conformational interconversion were simu-
lated starting from the energetically most stable conformation
of a given compound. Ring inversions were performed by
modification of the z-coordinate of the aromatic para-carbon
in steps of 0.1 Å while two to four methylene carbon atoms
were kept fixed in their z-coordinates. The energy minima and
maxima were subsequently minimized with the option 6 and
7 of the MM3 force field, respectively, without any constraints.
Cr ysta llogr a p h y. The X-ray diffraction data were mea-
sured with a ENRAF-NONIUS CAD-4 computer-controlled
diffractometer. Cu KR (λ ) 1.54178 Å) radiation with a
graphite crystal monochromator in the incident beam was
used. All crystallographic computing was done on a VAX 9000
computer using the TEXSAN structure analysis software.35
Crystallographic data: 3d : C30H28O4, space group P1h, a )
11.670(2) Å, b ) 12.334(2) Å, c ) 8.971(1) Å, R ) 109.24(1)°, â
6,6′-Bis(3-br om o-4-h yd r oxy-5-ter t-bu tylben zyl)-4,4′-d i-
ter t-bu tyl-2,2′-m eth a n ed iyld ip h en ol (7b) was obtained
analogously from 6,6′-bis(bromomethyl)-4,4′-di-tert-butyl-2,2′-
methanediyldiphenol (6b). Yield: 67%; mp: 94-95 °C; 1H
NMR (CDCl3, 200 MHz) δ 7.23 (d, J ) 2.5 Hz, 2H), 7.15 (d, J
) 1.9 Hz, 2H), 7.11 (d, J ) 1.5 Hz, 2H), 6.98 (d, J ) 2.2 Hz,
2H), 5.93 (s, 2H), 5.72 (s, 2H), 3.91 (s, 4H), 3.87 (s, 2H), 1.37
(s, 18H), 1.28 (s, 18H) ppm. MS(FD), m/z 794.5 (M+).
6,6′-Bis(3-ter t-b u t yl-4-h yd r oxyb en zyl)-4,4′-d im et h yl-
2,2′-m eth a n ed iyld ip h en ol (8a ). Raney-nickel (10 g) was
added to a mixture of 7a (3.2 g, 4.5 mmol) and KOH (2.5 g, 40
mmol) in 200 mL of methanol. The flask was flushed with
hydrogen three times and the mixture stirred at room tem-
perature under a hydrogen atmosphere until the hydrogen
uptake was complete. The catalyst was removed by filtration
and washed with methanol and the washings combined with
the filtrate. Acidification with dilute HCl precipitated a crude
product which was recrystallized from petroleum ether to give
) 108.84(1)°, γ ) 97.35(2)°, V ) 1113.4(4) Å,3 z ) 2, Fcalc
)
1.35 g cm-3, µ(Cu KR) ) 6.67 cm-1, no. of unique reflections )
1
4115, no. of reflections with I G 3σI ) 3600, R ) 0.041, Rw
)
a white solid. Yield: 2.14 g (86%); mp: 97-98 °C; H NMR
0.069. 4: C38H44O4‚CH3CN, space group P1h, a ) 13.541(2) Å,
b ) 15.337(4) Å, c ) 9.240(3) Å, R ) 95.01(3)°, â ) 107.67(2)°,
(CDCl3, 200 MHz) δ 7.15 (br s, 2H), 7.00 (br s, 2H), 6.83 (br s,
2H), 6.79 (br s, 2H) 6.49 (d, J ) 8.0 Hz), 6.04 (s, 2H), 4.91 (s,
2H), 3.88 (s, 4H), 3.83 (s, 2H), 2.25 (s, 6H), 1.39 (s, 18H) ppm.
MS(FD), m/z 552.8 (M+).
γ ) 106.68(2)°, V ) 1719.2(9) Å,3 z ) 2, Fcalc ) 1.17 g cm-3
,
µ(Cu KR) ) 5.51 cm-1, no. of unique reflections ) 6513, no. of
reflections with I G 3σI ) 4974, R ) 0.044, Rw ) 0.070.
Syn th eses. Starting compounds were commercially avail-
able or prepared according to the literature. Dehydrogenation
reactions were carried out with Raney-nickel (Merck), but
other qualities can be used also according to our experience.
Melting points above 300 °C were determined under argon
using sealed capillary tubes. All melting points are uncor-
rected. All chromatographic separations were done using silica
gel 60, particle size 0.040-0.063 mm (230-400 mesh), as sta-
tionary phase. The eluent is indicated for the individual case.
All compounds were checked for purity by TLC (except the bro-
momethyl derivatives) and by 1H NMR spectroscopy. Elemen-
tal analyses were performed only for the new calixarenes.
6,6′-Bis(br om om eth yl)-4,4′-d im eth yl-2,2′-m eth a n ed iyl-
d ip h en ol (6a ). A mixture of 4,4′-dimethyl-2,2′-methanediyl-
diphenol36 (2 g, 8.8 mmol) and paraformaldehyde (0.6 g, 20
mmol) was stirred in 20 mL of HBr-acetic acid for 5 h. After
standing overnight, the product was filtered off and washed
several times with petroleum ether. Yield: 1.2 g (34%); mp:
138 °C: 1H NMR (CDCl3, 200 MHz) δ 7.05 (br s, 2H), 6.95 (br
s, 2H), 4.52 (s, 4H), 3.87 (s, 2H), 2.24 (s, 6H) ppm.
6,6′-Bis(3-ter t-bu tyl-4-h ydr oxyben zyl)-4,4′-di-ter t-bu tyl-
2,2′-m et h a n ed iyld ip h en ol (8b ) was obtained analogously
from 7b. Yield: 70%; mp: 104 °C; 1H NMR (CDCl3, 200 MHz)
δ 7.18 (d, J ) 2.4 Hz, 2H), 7.14 (d, J ) 2.0 Hz, 2H), 6.96 (d, J
) 2.4 Hz, 2H), 6.81 (dd, J ) 6.0, 2.0 Hz, 2H), 6.55 (d, J ) 8.0
Hz, 2H), 6.01 (s, 2H, OH), 4.76 (s, 2H, OH), 3.89 (s, 2H), 3.87
(s, 4H), 1.38 (s, 18H), 1.26 (s, 18H) ppm. MS(FD), m/z 636.7
(M+).
5,23-Di-ter t-b u t yl-11,17-d im et h yl-4,24,26,27-t et r a h y-
d r oxyca lix[4]a r en e (4a ). A mixture of 8a (3.0 g, 5.4 mmol)
and paraformaldehyde (0.18 g, 6 mmol) in 150 mL of xylene
was heated to 175 °C for 16 h in an autoclave. The solvent
was removed by evaporation and the residue recrystallized
from acetonitrile to give pale white crystals. Yield 1.15 g
1
(37%); mp: 315-319 °C; H NMR (CD2Cl2, 400 MHz, 181 K)
δ 7.10 (br s, 2H, ArH), 7.02 (br s, 2H, ArH), 6.88 (s, 2H, OH),
6.78 (br s, 2H, ArH), 6.40 (s, 2H, OH), 6.11 (br s, 2H, ArH),
4.05 (d, J ) 13.7 Hz, 1H, CH2), 3.96 (d, J ) 17.0 Hz, 2H, CH2),
3.89 (d, J ) 14.3 Hz, 1H, CH2), 3.67 (d, J ) 17.0 Hz, 2H, CH2),
3.44 (d, J ) 13.8 Hz, 1H, CH2), 3.04 (d, J ) 14.3 Hz, 1H, CH2),
2.18 (s, 6H, Me), 1.27 (s, 18 H, t-Bu). 1H NMR (CD2Cl2, 400
MHz, RT) δ 7.10 (d, J ) 1.9 Hz, 2H, ArH), 7.07 (d, J ) 2.1 Hz,
2H, ArH), 6.81 (d, J ) 1.8 Hz, 2H, ArH), 6.46 (s, 2H, OH),
6.31 (s, 2H, OH), 6.30 (d, J ) 2.1 Hz, 2H, ArH), 3.86 (s, 4H,
CH2), 3.83 (s, 2H, CH2), 3.56 (s, 2H, CH2), 2.24 (s, 6H, Me),
1.38 (s, 18H, t-Bu) ppm. MS(FD), m/z 564.6 (M+). Anal. Calcd
for C38H44O4: C, 80.82; H, 7.85. Found: C, 80.88; H, 7.93.
5,11,17,23-Tetr a-ter t-bu tyl-4,24,26,27-tetr ah ydr oxycalix-
[4]a r en e (4b) was obtained analogously from 4a . Yield: 20%;
6,6′-Bis(br om om eth yl)-4,4′-d i-ter t-bu tyl-2,2′-m eth a n e-
d iyld ip h en ol (6b). A mixture of 4,4′-di-tert-butyl-2,2′-meth-
anediyldiphenol37 (5 g, 16 mmol) and paraformaldehyde (1.2
g, 40 mmol) was stirred in 80 mL of HBr-acetic acid for 5 h
and then poured into water. The crude product was filtered
off and several times recrystallized from n-hexane at -18 °C.
Yield: 4.5 g (56%); mp: 152-153 °C; 1H NMR (CDCl3, 200
MHz) δ 7.29 (d, J ) 2.4 Hz, 2H), 7.12 (d, J ) 2.4 Hz, 2H), 6.56
(s, 2H), 4.55 (s, 4H), 3.93 (s, 2H), 1.26 (s, 18H) ppm.
1
mp: 360-364 °C; H NMR (CDCl3, 200 MHz) 7.32 (br, 2H),
6,6′-Bis(3-br om o-4-h yd r oxy-5-ter t-bu tylben zyl)-4,4′-d i-
m eth yl-2,2′-m eth a n ed iyld ip h en ol (7a ). A mixture of 6a
(6.0 g, 14.5 mmol), 2-bromo-6-tert-butylphenol (30 g, 0.131
mol), and ZnCO3 (4 g, 30 mmol) was kept at 60 °C for 16 h.
The mixture was treated with 100 mL of CHCl3 and filtered,
and the solvent was evaporated. The product was isolated by
column chromatography (toluene) as the second eluted com-
pound. A complete separation of the 2-bromo-tert-butylphenol
proved to be difficult in this case, and a crude product was
used for the debromination, after which o-tert-butylphenol was
easier to remove. Yield of crude 7a : 5.8 g (57%); mp: 76 °C;
1H NMR (CDCl3, 200 MHz) δ 7.11 (br s, 2H), 7.08 (br s, 2H),
6.98 (br s, 2H), 6.75 (br s, 2H), 5.80 (br, 2H), 5.70 (s, 2H), 3.85
(s, 2H), 3.83 (s, 4H), 2.24 (s, 6H), 1.36 (s, 18H) ppm. MS(FD),
m/z 710.4 (M+).
7.10 (br, 2H), 7.02 (br, 2H), 6.56 (s, 2H), 6.44 (br, 2H), 6.40 (s,
2H), 3.96 (s, 4H), 3.91 (s, 2H), 3.64 (s, 2H), 1.41 (s, 18H), 1.31
(s, 18H). MS(FD), m/z 649.0 (M+). Anal. Calcd for C44H56O4‚1.5
CH3CN: C, 79.45; H, 8.58. Found: C, 79.26; H, 8.88. CH3CN
could not be removed by drying in high vacuum at 50 °C in
this case, as shown also by the 1H NMR spectrum.
6,6′-Dim et h yl-4,4′-b is-(b r om om et h yl)-2,2′-et h a n ed iyl-
d ip h en ol (10). A mixture of 6,6′-dimethyl-2,2′-ethanediyl-
diphenol (9, 4.0 g, 16.5 mmol) and paraformaldehyde (1.0 g,
34 mmol) was stirred with 80 mL of a 33% solution of HBr in
acetic acid until complete dissolution was achieved. After
standing overnight the precipitate was filtered off and washed
several times with cold acetic acid. Yield: 4.02 g (57%); mp:
1
172 °C; H NMR (CDCl3, 200 MHz) 7.17 (d, J ) 2.0 Hz, 2H),
7.04 (d, J ) 1.8 Hz, 2H), 4.55 (q, J ) 7.1 Hz, 1H), 4.45 (s, 4H),
2.19 (s, 6H), 1.64 (d, J ) 7.1 Hz, 3H).
6,6′-Dim eth yl-4,4′-bis(3-br om o-4-h yd r oxy-5-ter t-bu tyl-
ben zyl)-2,2′-eth a n ed iyld ip h en ol (11) was prepared from 10
as described above for 7. The product was isolated by column
chromatography (CHCl3) as the second eluted compound.
Yield: 51%; mp: 87 °C; 1H NMR (CDCl3, 200 MHz) 7.07 (d, J
) 1.9 Hz, 2H), 7.01 (d, J ) 1.8 Hz, 2H), 6.97 (d, J ) 1.7, 2H),
6.75 (br s, 2H), 5.65 (s, 2H), 5.56 (s, 2H), 4.51 (q, J ) 7.1 Hz,
(35) The authors have deposited atomic coordinates for the struc-
tures with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(36) Zinke, A.; Hanus, F.; Ziegler, E. J . Prakt. Chem 1939, 152, 126.
(37) Zinke, A.; Kretz, R.; Leggewie, E.; Ho¨ssinger, K. Monatsh.
Chem. 1952, 83, 1213.

8360 J . Org. Chem., Vol. 62, No. 24, 1997
Biali et al.
1H), 3.76 (s, 4H), 2.16 (s, 6H), 1.59 (d, J ) 7.1 Hz, 3H), 1.35
(s, 18H). MS(FD), m/z 724.3 (M+).
1.37 (s, 18H, t-Bu) ppm. MS(FD), m/z 578.5 (M+). Anal. Calcd
for C39H46O4: C, 80.92; H, 8.02. Found: C, 80.79; H, 8.04.
The exo-calixarenes 3b and 3d showed the following spec-
troscopic data:
6,6′-Dim et h yl-4,4′-b is(3-ter t-b u t yl-4-h yd r oxyb en zyl)-
2,2′-eth a n ed iyld ip h en ol (12) was obtained from 11 as
described above for 8. Yield: 88%; mp: 98 °C; 1H NMR
(CDCl3, 200 MHz) 7.06 (d, J ) 1.8 Hz, 2H), 6.98 (d, J ) 1.3
Hz, 2H), 6.78 (dd, J ) 1.9, 7.0 Hz, 2H), 6.52 (d, J ) 7.9 Hz,
2H), 5.56 (s, 2H), 4.67 (s, 2H), 4.50 (q, J ) 7.1 Hz, 1H), 3.78
(s, 4H), 2.15 (s, 6H), 1.59 (d, J ) 7.1 Hz, 3H), 1.37 (s, 18H).
MS(FD), m/z 566.9 (M+).
3b: 1H NMR (DMSO-d6, 318 K) δ 8.32 (2H, OH), 8.27 (2H,
OH), 6.91 (2H, ArH), 6.79 (2H, ArH), 6.57 (2H, ArH), 6.56 (2H,
ArH), 3.74 (s, 2H, CH2), 3.74 (s, 2H, CH2), 3.58 (s, 4H, CH2),
2.13 (s, 6H, Me), 1.34 (s, 18H, t-Bu). 1H NMR (CDCl3, 400
MHz, RT) δ 6.99 (br s, 2H, ArH), 6.88 (br s, 2H, ArH), 6.84 (br
s, 2H, ArH), 6.61 (br s, 2H, ArH), 3.83 (s, 2H, CH2), 3.78 (s,
4H, CH2), 3.69 (s, 2H, CH2), 2.21 (s, 6H, Me), 1.40 (s, 18H,
t-Bu) ppm.
11,17-Di-ter t-bu tyl-2,5,23-tr im eth yl-4,12,16,24-tetr a h y-
d r oxyca lix[4]a r en e (5a ). A mixture of 11 (1.0 g, 1.76 mmol)
and paraformaldehyde (60 mg, 2 mmol) in xylene (150 mL)
was heated to 180 °C in an autoclave for 5 days. The solvent
was removed and the remaining oil dissolved in a small
amount of xylene. After standing for 2 days, the crude product
was filtered and recrystallized from xylene. Yield: 390 mg
(38%); mp: 269-272 °C; 1H NMR (CDCl3, 400 MHz, 250 K) δ
7.07 (s, 2H, ArH), 7.01 (s, 2H, ArH), 6.81 (s, 2H, ArH), 6.65 (s,
2H, OH), 6.48 (s, 2H, OH), 6.39 (s, 2H, ArH), 4.74 (q, 1H, J )
6.5 Hz, CH), 3.94 (d, 1H, J ) 14.1 Hz, CH2), 3.84 (d, 2H, J )
16.1 Hz, CH2), 3.78 (d, 2H, J ) 15.8 Hz, CH2), 3.28 (d, 1H, J
) 14.2 Hz, CH2), 2.04 (s, 6H, Me), 1.59 (d, 3H, J ) 6.5 Hz,
Me), 1.36 (s, 18H, t-Bu). 1H NMR (CDCl3, 400 MHz, RT) δ
6.99 (s, 2H, ArH), 6.95 (s, 2H, ArH), 6.81 (s, 2H, ArH), 6.50 (s,
2H, ArH), 4.69 (q, 1H, J ) 7.1 Hz, CH), 3.96 (d, 1H, J ) 14.4
Hz, CH2), 3.83 (d, 2H, J ) 15.7 Hz, CH2), 3.74 (d, 2H, J )
15.4 Hz, CH2), 3.37 (d, 1H, J ) 14.4 Hz, CH2), 2.21 (s, 6H,
Me), 1.54 (d, 3H, J ) 7.1 Hz, Me), 1.39 (s, 18H, t-Bu). 1H NMR
(DMSO-d6, 338 K) δ 8.14 (s, 2H, OH), 7.95 (s, 2H, OH), 6.92
(d, J ) 2.0 Hz, 2H, ArH), 6.76 (2H, ArH), 6.68 (d, J ) 1.8 Hz,
2H, ArH), 6.56 (d, J ) 2.0 Hz, 2H, ArH), 4.67 (q, J ) 7.2 Hz,
1H, CH), 3.88 (d, J ) 15.6 Hz, 1H, CH2), 3.71 (d, J ) 15.6 Hz,
1H, CH2), 3.64 (d, J ) 14.4 Hz, 2H, CH2), 3.55 (d, J ) 14.5
Hz, 2H, CH2), 2.11 (s, 6H, Me), 1.39 (d, J ) 7.2 Hz, 3H, Me),
3d : 1H NMR (DMSO-d6, 400 MHz, 318 K). δ 8.94 (2H, OH),
4
3
8.30 (2H, OH), 6.88 (dd, J ) 2.1 Hz, J ) 8.1 Hz, 2H, ArH),
6.78 (d, J ) 1.7 Hz, 2H, ArH), 6.69 (d, J ) 8.1 Hz, 2H, ArH),
6.55 (d, J ) 2.0 Hz, 2H, ArH), 6.50 (d, J ) 1.8 Hz, 2H, ArH),
3.71 (s, 2H, CH2), 3.67 (s, 2H, CH2), 3.54 (s, 4H, CH2), 2.12 (s,
6H, Me) ppm. The NMR data of 3d previously described3 were
obtained in acetone-d6 and not in CDCl3 as reported.
Ack n ow led gm en t. We thank Dr. Shmuel Cohen for
the crystal structure determinations. This research was
supported by grants from the German-Israeli Founda-
tion (GIF) for Scientific Research and Development and
the Deutsche Forschungsgemeinschaft.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
calixarenes 4a , 4b, and 5a and of compounds not characterized
by elemental analyses (14 pages). This material is contained
in libraries on microfiche, 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 O970967U