Annelated Calixarenes Composed of Calixarenes with Hydroxy Groups in the Endo and Exo Position

Article abstract of DOI:10.1021/jo9511197

Various phenol-derived calix<4>arenes (3) bearing four hydroxy groups in the exo position have been prepared by uncatalyzed condensation of suitable dimers or tetramers with formaldehyde in xylene in yields up to 44percent.The tetra-tert-butyl compound (3a) has been shown by X-ray analysis to adopt a regular cone conformation (nearly identical in shape with the endo isomer) with two intramolecular O-H...O hydrogen bonds, while the corresponding dimer (6c) prefers a conformation (not possible in the calixarene) with two intramolecular O-H...?(arene) interactions.Condensation of exo-calix<4>arenes 3f,g with free ortho positions (easily available by debutylation) with bisbromomethylated dimers gave annelated double (9) and triple (10) calixarenes consisting of endo- and exo-calix<4>arene substructures in yields up to 24percent and 10percent, respectively.Molecular dynamics calculations suggest that the exo-calixarene part in 9 is less mobile than the entirely flexible 3, while the endo-calixarene part shows a higher mobility than usual.A complete interconversion cone -> cone is impossible, however, which enables the construction of inherently chiral molecules.

Full text of DOI:10.1021/jo9511197

J . Org. Chem. 1996, 61, 549-559
549
An n ela ted Ca lixa r en es Com p osed of Ca lix[4]a r en es w ith Hyd r oxy
Gr ou p s in th e En d o a n d Exo P osition
Volker Bo¨hmer,*,† Ralph Do¨rrenba¨cher,† Michael Frings,† Mathias Heydenreich,‡
Diana de Paoli,† Walter Vogt,† George Ferguson,§ and Iris Thondorf|
Institut fu¨r Organische Chemie, J ohannes Gutenberg Universita¨t, J .-J .-Becherweg 34 SB1,
D-55099 Mainz, Germany, Fachbereich Chemie, Universita¨t Potsdam, Am neuen Palais 10,
D-14415 Potsdam, Germany, Department of Chemistry and Biochemistry, University of Guelph, Guelph,
Ontario, Canada N1G 2W1, and Institut fu¨r Biochemie, Fachbereich Biochemie/ Biotechnologie,
Martin-Luther-Universita¨t Halle-Wittenberg, Weinbergweg 16a, D-06099 Halle, Germany
Received J une 20, 1995 (Revised Manuscript Received October 2, 1995X)
Various phenol-derived calix[4]arenes (3) bearing four hydroxy groups in the exo position have
been prepared by uncatalyzed condensation of suitable dimers or tetramers with formaldehyde in
xylene in yields up to 44%. The tetra-tert-butyl compound (3a ) has been shown by X-ray analysis
to adopt a regular cone conformation (nearly identical in shape with the endo isomer) with two
intramolecular O-H‚‚‚O hydrogen bonds, while the corresponding dimer (6c) prefers a conformation
(not possible in the calixarene) with two intramolecular O-H‚‚‚π(arene) interactions. Condensation
of exo-calix[4]arenes 3f,g with free ortho positions (easily available by debutylation) with
bisbromomethylated dimers gave annelated double (9) and triple (10) calixarenes consisting of endo-
and exo-calix[4]arene substructures in yields up to 24% and 10%, respectively. Molecular dynamics
calculations suggest that the exo-calixarene part in 9 is less mobile than the entirely flexible 3,
while the endo-calixarene part shows a higher mobility than usual. A complete interconversion
cone f cone is impossible, however, which enables the construction of inherently chiral molecules.
The name calixarenes initially was coined by Gutsche
for the cyclic condensation products (1) which are ob-
tained by condensation of p-alkyl (mainly tert-butyl)
phenols and formaldehyde under alkaline conditions.1 It
seems reasonable, however, and justified especially by
various modifications and derivatives of 1 to use the
name calixarenes also in a more general sense for the
basic skeleton of 1n-metacyclophanes.2 With respect to
the macrocyclic ring system, the hydroxy groups in 1 are
in the endo position. However, each of the aromatic units
in a metacyclophane also has three exo positions, and
various macrocyclic molecules of the calixarene-type (1n-
metacyclophane type respectively) bearing exo-hydroxy
groups, like 23 or 3,4 have been synthesized meanwhile,
among them also compounds with hydroquinone units5
or resorcinol units.6 Here resorcarenes7 (4), cyclic tet-
ramers obtained from resorcinol and aldehydes other
than formaldehyde under acidic conditions, deserve
special mention.1,8
† J ohannes Gutenberg Universita¨t.
‡ Universita¨t Potsdam.
§ University of Guelph.
| Institut fu¨r Biochemie.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) For a recent review on calixarenes, see: Bo¨hmer, V. Angew.
Chem. 1995, 107, 785-818; Angew. Chem., Int. Ed. Engl. 1995, 34,
713-745.
Calix[4]arenes of type 1 may be synthesized by con-
densation of suitable dimers with bisbromomethylated
dimers,9 a strategy which enables also the synthesis of
compounds bearing different substituents in the para
position. If in this reaction a calix[4]arene of type 3 with
free ortho positions is used as the dimer, larger molecules
with annelated calix[4]arene structures are accessible.4
(2) Compounds 1 would be then hydroxycalixarenes, a name which,
however, is to be used only when a distinction from “non-hydroxy”
calixarenes is necessary.
(3) Pappalardo, S.; Ferguson, G.; Gallagher, J . F. J . Org. Chem.
1992, 57, 7102-7109.
(4) Bo¨hmer, V.; Do¨rrenba¨cher, R.; Vogt, W.; Zetta, L. Tetrahedron
Lett. 1992, 33, 769-772.
(5) See for instance: (a) Morita, Y.; Agawa, T.; Nomura, E.;
Taniguchi, H. J . Org. Chem. 1992, 57, 3658-3662. (b) Reddy, P. A.;
Gutsche, C. D. J . Org. Chem. 1993, 58, 3245-3251. (c) Casnati, A.;
Comelli, E.; Fabbi, M.; Bocchi, V.; Mori, G.; Ugozzoli, F.; Manotti
Lanfredi, A. M.; Pochini, A.; Ungaro, R. Recl. Trav. Chim. Pays-Bas
1993, 112, 384-392.
(6) For a calix[5]arene with resorcinol units linked via their 2- and
6-positions, see: Tabatabai, M.; Vogt, W.; Bo¨hmer, V.; Ferguson, G.;
Paulus, E. F. Supramol. Chem. 1995, 4, 147-152.
(7) Various names have been used for these cyclic tetramers among
which “resorcarenes” is shortest.
(8) (a) For a review on resorcarenes, see: Timmermann, P.; Ver-
boom, W.; Reinhoudt, D. N. Tetrahedron, in press. (b) For the first
resorc[6]arenes obtained from 2-alkyl resorcinols and formaldehyde,
see: Konishi, H.; Ohata, K.; Morikawa, O.; Kobayashi, K. J . Chem.
Soc., Chem. Commun. 1995, 309-310.
(9) Bo¨hmer, V.; Merkel, L.; Kunz, U. J . Chem. Soc., Chem. Commun.
1987, 896-897.
0022-3263/96/1961-0549$12.00/0 © 1996 American Chemical Society

550 J . Org. Chem., Vol. 61, No. 2, 1996
Bo¨hmer et al.
Sch em e 1
Sch em e 2
We report here on a more detailed study of the synthesis
of calixarenes 3 and of such larger systems.
Syn th eses
Symmetrically substituted calixarenes 3 are readily
prepared by condensation of suitable para-linked dimers
5 with formaldehyde in aprotic solvents like xylene at
175 °C in an autoclave, the first example (3c) being
reported by Chasar10 in 1985 (Scheme 1).
The driving force for the formation of the macrocycle
without high dilution conditions is obviously the forma-
tion of intramolecular OH‚‚‚OH hydrogen bonds in 3.
Thus, no cyclic material is obtained with dioxane as
solvent, and the yield is distinctly lower also for 3b (6%)
than for 3a (38%) where the directing influence exerted
by the bulky tert-butyl groups on the OH groups favors
such hydrogen bonds. (3f is detected only in traces if the
synthesis is tried with 4,4′-methylenediphenol which has
no ortho substituents. This may be caused, however, by
the formation of polymeric material by further condensa-
tion of 3f.) Finally, no calix[4]arene is formed if instead
of 5a ,b the isomeric compounds 6 are used. Here an
intramolecular hydrogen bond already exists in the dimer
and is not formed during the macrocyclization. If dimers
5 with a substituted bridge are used, the yield of 3
obviously decreases with increasing size of these sub-
stituents: 3a (38%), 3c (20%), and 3d (13%, mixture of
the two diastereomers). This could be interpreted in
terms of a steric hindrance of the cyclic conformation
necessary for the final cyclization step. Weaker hydrogen
bonds, expressed by an OH signal at 5.2 ppm in 3d , in
comparison to the signal at 6.3 ppm for 3a point in the
same direction.
direct condensation of the o-alkylphenols in apolar,
aprotic media.11 ) Bromomethylation of 6a (60-70% of
6b), condensation of 6b with excess 2-bromo-6-tert-
butylphenol (70-75% of 7a ), and dehalogenation of 7a
(hydrogenation in alkaline solution) leads in well-known
steps to 7b (75-80%). Condensation of 7b with formal-
dehyde gives here the calix[4]arene 3e in 43% yield. In
a similar way 3a was prepared starting from 6c, via 6d
(86%), 7c (72%), and 7d (69%). The yield of 44% in the
final cyclization step is (not unexpectedly) higher than
that in the direct condensation of the corresponding 5,
since no intermolecular connection of phenolic units is
necessary.
Transbutylation (AlCl3, toluene) of 3a and 3e gives
the unsubstituted calix[4]arene 3f with four and the
dimethylcalix[4]arene 3g with two reactive ortho posi-
tions, which are used as starting material for the
preparation of annelated calixarenes.
The calix[4]arenes 3f,g can be regarded as methylene-
bridged phenolic dimers (2,2′-methylenediphenols) con-
nected via their para positions (4-positions) by an addi-
tional bridge. Consequently they can be incorporated
into calix[4]arene systems with endo-OH groups by
condensation with bisbromomethylated dimers 8 accord-
ing to the well-established “2 + 2” strategy9 (Scheme 3).
Compounds 9a ,b are thus obtained in 24% yield if a
1.5-fold amount of 8a ,b is used. Such an excess, which
accounts for side reactions like the formation of quinone
methides and their di- and trimerization,12 cannot be
used with 3f, which has four reactive ortho positions. This
may be one reason for the lower yield (8%) observed for
Calix[4]arenes of type 3 having different substituents
R1/R2 are available as outlined in Scheme 2. Although
this synthesis has been carried out to date only for R1 )
CH3 or t-Bu and R2 ) t-Bu, there is, in principle, also
the possibility of having other substituents and even two
different residues R1/R1′ since the synthesis of various
dimers 6 is possible in a definite way, using for instance
halogen to protect the para positions. (The symmetrically
substituted dimers 6a ,c are obtained more easily by
(10) (a) Chasar, D. W. J . Org. Chem. 1985, 50, 545-547. (b) Recently
the BF3‚OEt2-catalyzed condensation of 6a with paraformaldehyde in
CH2Cl2 has been reported to yield 3a in 30% yield, while only linear
oligomers have been obtained from 6b: Sartori, G.; Bigi, F.; Porta, C.;
Maggi, R.; Mora, R. Tetrahedron Lett. 1995, 36, 2311-2314.
(11) Casiraghi, G.; Casnati, G.; Pochini, A.; Puglia, G.; Ungaro, R.;
Sartori, G. Synthesis 1981, 2, 143-146.
(12) E.g., Bavoux, C.; Perrin, M.; Goldmann, H.; Bo¨hmer, V. J .
Chem. Soc., Perkin Trans. 2 1989, 2059-2063.

Annelated Calix[4]arenes with Hydroxy Groups
J . Org. Chem., Vol. 61, No. 2, 1996 551
Sch em e 3
and should be available therefore from an appropriate
calix[6]arene by condensation with formaldehyde.
Calix[6]arene 11a , for instance, having two OH groups
in the endo and four OH groups in the exo position, would
be such a precursor for 9a . 11a can be obtained by
debutylation of 11b, which in turn was obtained by
condensation of 7b with 8a in dioxane in the presence of
TiCl4 in 7% yield. Under analogous conditions 11a could
be prepared by direct condensation of 7f with 8a in 13%
yield. This difference in yield can be understood, assum-
ing again a Ti-templated arrangement of the oxygen
functions of rings C-F in a calix[4]arene-like fashion
which is hindered in 11b by the two tert-butyl groups.
Such a template effect in the synthesis of 11 is further
corroborated by the fact that the calix[6]arene 12 with
six endo-OH groups from a linear tetramer of tert-
butylphenol and 8b is formed with only 3%. Although
9a could not be obtained from 11a and formaldehyde, the
compounds 11 are interesting, since they represent the
first calix[6]arenes with OH groups not only in the endo
but also in the exo position.8b
Tetraester derivatives of calix[4]arenes, easily obtained
by etherification with bromoacetates, form strong com-
plexes with Na+ ions, which are kinetically stable on the
NMR time scale.14 The hexaether ester obtained from
11a and ethyl bromoacetate could arrange four arms in
a similar way around a Na+ ion if the basic calixarene
skeleton assumes a conformation similar to that of 9a .
No complexation of NaSCN could be detected however
in CDCl3 by 1H NMR, which means that the coordination
around a Na+ cation is not sufficient to impart a conelike
conformation to the phenolic units C-F.
Con for m a tion
(a ) Cr ysta llin e Sta te. Single crystals suitable for
X-ray analysis were obtained for 3a by recrystallization
from acetonitrile/acetone (1:1). Although numerous crys-
tal structures of calix[4]arenes of type 1 have been
published,15 including examples for OH-depleted com-
pounds,16 this is the first structure determination for an
exo-calix[4]arene of type 3.17
Molecule 3a has crystallographic mm symmetry, as
shown in Figure 1, with an acetonitrile molecule enclath-
rated in the calix cup; the shortest C‚‚‚C contact is 3.752-
(3) Å between the acetonitrile methyl C22 and the endo
aromatic carbon C5. The calixarene assumes a regular
cone conformation, stabilized (see later) by pairs of
intramolecular OH‚‚‚O hydrogen bonds. This is not very
compound 9c under stoichiometric conditions. Seven
percent of 10a was obtained, on the other hand, with a
2.6-fold amount of 8a . However, all the factors deter-
mining the yield are not yet understood, since 9d (8%)
and 10b (mixture of the two isomers, 10%) were isolated
when a 1.7-fold amount of 8b was applied. A 1.5-fold
amount of 8c leads to 6% of 10c as the only identifiable
product. It should be noted that in all condensations with
3f the newly formed calix[4]arene has the four OH groups
in the endo position. A structure with two endo- and two
exo-OH groups was never observed. This may be due to
a template effect exerted by TiCl4 (one Ti being bound to
three adjacent oxygen atoms/functions) as discussed
earlier.13
(14) (a) Arnaud-Neu, F.; Collins, E. M.; Deasy, M.; Ferguson, G.;
Harris, S. J .; Kaitner, B.; Lough, A. J .; McKervey, M. A.; Marques, E.;
Ruhl, B. L.; Schwing-Weill, M. J .; Seward, E. M. J . Am. Chem. Soc.
1989, 111, 8681-8691. (b) For the X-ray structure of a similar complex,
showing the arrangement of the ligating groups, see: Arduini, A.;
Ghidini, E.; Pochini, A.; Ungaro, R.; Andreetti, G. D.; Calestani, G.;
Ugozzoli, F. J . Incl. Phenom. 1988, 6, 119-134.
(15) See for instance: (a) Andreetti, G. D.; Ungaro, R.; Pochini, A.
J . Chem. Soc., Chem. Commun. 1979, 1005-1007. (b) Andreetti, G.
D.; Pochini, A.; Ungaro, R. J . Chem. Soc., Perkin Trans 2 1983 1773-
1779. (c) Ehlinger, N.; Lecocq, S.; Perrin, R.; Perrin, M. Supramol.
Chem. 1993, 2, 77-82. (d) Rantsordas, S.; Perrin, M.; Gharnati, F.;
Lecocq, S.; Vogt, W.; Fey, W.; Bo¨hmer, V. J . Incl. Phenom. 1990, 9,
145-152. (e) Gharnati, F.; Perrin, M.; Rantsordas, S.; Goldmann, H.;
Bo¨hmer, V. J . Cryst. Spectr. Res. 1991, 21, 69-74. (f) Atwood, J . L.;
Orr, G. W.; Bott, S. G.; Robinson, K. D. Angew. Chem. 1993, 105, 1114-
1115. (g) J uneja, R. K.; Robinson, K. D.; J ohnson, C. P.; Atwood, J . L.
J . Am. Chem. Soc. 1993, 115, 3818-3819.
The annelated double calix[4]arenes 9 can be regarded
as calix[6]arenes with an additional methylene bridge
between opposite phenolic units (and compounds 10 cor-
respondingly as doubly methylene bridged calix[8]arenes)
(16) (a) Grynszpan, F.; Goren, Z.; Biali, S. B. J . Org. Chem. 1991,
56, 532-536. (b) For the basic 14-metacyclophane, see: McMurry, J .
E.; Phelan, J . C. Tetrahedron Lett. 1991, 32, 5655-5658.
(17) The X-ray structure of 2 which assumes the 1,3-alternate
conformation is reported in ref 3.
(13) Goldmann, H.; Vogt, W.; Paulus, E.; Bo¨hmer, V. J . Am. Chem.
Soc. 1988, 110, 6811-6817.

552 J . Org. Chem., Vol. 61, No. 2, 1996
Bo¨hmer et al.
Ch a r t 1
The packing of 1 (R ) t-Bu) and 3a in the solid state
is quite different. In 1 (R ) t-Bu) there is a cyclic array
of intramolecular hydrogen bonds and the toluene in the
calix cup is disordered about a 4-fold axis; intermolecular
contacts are of the van der Waals type. Compound 3a
has its hydroxy H atoms equally disordered over two
sites, and in each molecule there are pairs of intramo-
lecular O-H‚‚‚O bonds (across crystallographic mirror
planes) with O‚‚‚O 2.657(3) Å. The molecules are then
linked by pairs of intermolecular O-H‚‚‚O hydrogen
bonds (O‚‚‚O 2.712(3) Å) about inversion centers to form
infinite zig-zag ribbons as shown in Figure 2, which
extend along the ab cell diagonal.
Single crystals were also obtained from 6c, which is
representative of a structural motif that is present (twice)
in calix[4]arene 3a . Surprisingly molecule 6c forms
neither intra- nor intermolecular O-H‚‚‚O hydrogen
bonds between the two hydroxy groups, as has been found
in other X-ray structures published on phenolic dimers18a-c
or linear oligomers18 of this type. Molecule 6c has no
crystallographically imposed symmetry but has approxi-
mate 2-fold symmetry, with the 2-fold axis passing
through the central methylene carbon. The OH groups
found here are not syn as in 3a but are oriented anti with
respect to a plane through the methylene carbon and the
two adjacent aromatic carbon atoms. Both hydroxys are
involved in O-H‚‚‚π(arene) interactions, as shown in
Figure 3, with the hydroxy H atoms directed toward the
phenyl carbons of the adjacent rings and O1‚‚‚C22
2.987(1) and O2‚‚‚C12 2.959(2) Å. Intermolecular con-
tacts are of the van der Waals type with no unusual
interactions.
F igu r e 1. View looking into the cavity of 3a in the crystalline
state showing our numbering scheme and the acetonitrile in
the calixarene cavity. Ellipsoids are drawn at the 30% prob-
ability level. The molecule has mm crystallographic symmetry.
The hydroxyl H atoms are equally disordered over two sites;
the acetonitrile molecule also has mm symmetry and its
hydrogens are totally disordered.
surprising, although a 1,2-alternate conformation found
for instance in a 1,3-OH-depleted calix[4]arene would
allow also two intramolecular hydrogen bonds. Entirely
surprising, however, is the fact that the conformation of
the carbon framework of 3a is practically identical to that
of the isomeric tert-butylcalix[4]arene (1, R ) t-Bu)15a
which has crystallographic 4-fold symmetry. The unique
aromatic ring in 3a is inclined at 123.7(1)° to the plane
of the four CH2 groups; the corresponding angle in 1 (R
) t-Bu) is 123.0°. The conformational similarity of 3a
and 1 (R ) t-Bu) is further demonstrated by the fact that
fitting of the cyclophane skeleton of both compounds is
possible with a rms value of 0.071 Å, even although a
toluene molecule is included in the cavity of 1 (R ) t-Bu)
while acetonitrile is included in 3a .
A conformation analogous to 6c (stabilized by a pair
of OH‚‚‚π(arene) hydrogen bonds) was found for 2,2-bis-
(2-hydroxy-3-tert-butyl-5-methylphenyl)propane in the
crystalline state;19 this conformation effectively maxi-
mizes the intramolecular O‚‚‚C(methyl) separations. Our
structure analysis of 6c (which is devoid of methyl groups
F igu r e 2. View showing part of the zig-zag hydrogen-bonded ribbon in 3a ‚CH3CN. Hydrogen atoms are omitted for clarity.

Annelated Calix[4]arenes with Hydroxy Groups
J . Org. Chem., Vol. 61, No. 2, 1996 553
Four pairs of doublets (ratio 1:1:1:2) and a singlet (for
4H) are found for the methylene protons of the annelated
double calixarenes 9a and 9c, showing that the molecule
has the expected symmetry plane. No principal change
of this pattern is observed over a wide temperature range
(checked for 9c from 293 to 353 K in pyridine-d5 and from
293 to 193 K in CD2Cl2) which means that these
molecules are not flexible enough for all pairs of diaste-
reotopic methylene protons to change places. A signal
at 10.3 ppm for four OH groups indicates that the endo-
calix[4]arene part of the molecule assumes as usual a
cone conformation, stabilized by intramolecular hydrogen
bonds, which is confirmed further by NOEs observed
between aromatic protons of adjacent phenolic units. No
entirely convincing argument for a certain conformation
of the exo-calix[4]arene part can be given at the moment.
As discussed earlier for 9a , some results are in favor of
a 1,2-alternate conformation but a rapid equilibrium
between 1,2-alternate and cone cannot be ruled out.
As an additional example, the 1H NMR spectrum of
9b (in CD2Cl2) is discussed in some detail below. Due to
the difference of R2 and R3, no symmetry plane exists and
9b (as well as 9d ) is chiral. Three signals are found for
the methyl groups (2.11, 2.14, and 2.18 ppm), which is
best understood by a cone conformation of both calix[4]-
arene systems by which the methyl groups of A and B
are opposed to the methyl and tert-butyl group in E and
F. With a 1,2-alternate conformation of ABCD, these
groups would point in opposite directions, making the
difference between A and B less understandable. Two
signals for the OH groups at A and B (6.35 and 6.38 ppm
weak intramolecular H-bonding) suggest the same.
F igu r e 3. Molecular conformation of 6c in the crystalline
state, showing the O-H‚‚‚π hydrogen bonding and our num-
bering scheme. Thermal ellipsoids are at the 30% probability
level.
at the central C atom) shows that achieving this C‚‚‚O
separation is most probably not the main reason for
adopting this conformation. Probably in dimers with two
o-tert-butyl groups two intramolecular OH‚‚‚π(arene) give
better stabilization than a combination of intra- and
intermolecular OH‚‚‚O hydrogen bonds as found in linear
dimers and oligomers having at least one ortho position
unsubstituted.18 Only when the formation of OH‚‚‚π-
(arene) hydrogen bonds is precluded for other reasons,
as in the calixarene 3a , does OH‚‚‚O hydrogen bonding
become energetically attractive. We are presently study-
ing additional molecules of the 6c type with more and
less substitution to provide more examples of competitive
hydrogen bonding.
If a conformational arrangement as in 6c, which is
different from that in the calixarene molecule, would be
favored in compounds 7b,d , it is hard to see why a
cyclization should be favored over the polycondensation.
Thus, as in other areas of calixarene synthesis, further
work is necessary to elucidate entirely all the factors
determining the outcome of the cyclization reaction.
Unfortunately suitable crystals for X-ray analysis could
not yet be obtained for the annelated calixarenes 9 and
10.
9b
All seven methylene groups are different in 9b. For
a-d typical doublets (geminal coupling) for an endo-calix-
[4]arene in the cone conformation (confirmed also by the
OH signal at 9.98 ppm) are found in CD2Cl2 with axial
protons at 4.09 (b′), 4.17, 4.186, and 4.191 ppm and
equatorial protons at 3.26 (b), 3.43, 3.44, and 3.47 ppm,
where the slight high-field shift for b is remarkable and
could be due to shielding by A and B in the 1,2-alternate
conformation. Protons g/g′ are less separated (3.89, 3.54
ppm), an argument against a fixed cone conformation of
ABCD, while e,e′ (pseudosinglet at 3.71 ppm) and f,f′
(3.72, 3.65 ppm) are nearly identical. Doublets (m
coupling) are found for the aromatic protons s, t, o, r, p,
and q (7.06, 7.04, 6.95, 6.93, 6.55, 6.53 ppm) where the
high-field shift for p/q again indicates shielding by A and
B. The other aromatic protons n, m, u, v, w, and x appear
as pseudosinglets at 6.83 (3H), 6.78 (1H), and 6.76 (2H)
ppm. Thus, all these results, which are partly in favor
of a cone and partly in favor of a 1,2-alternate conforma-
tion of ABCD, are probably best understood in terms of
a flexible exo-calixarene part.
(b) Solu tion . Calixarenes 1 assume a cone conforma-
tion in solution; however a mutual conversion of opposite
cone conformations is possible on a time scale corre-
1
sponding to the H NMR time scale. Thus, methylene
protons are found as a singlet at high temperature and
as a pair of doublets at low temperature.1 In contrast,
the exo-calixarenes 3 are flexible, showing a singlet for
the protons of each of the different methylene groups.
No significant change which could be interpreted as
conformational freezing is observed upon cooling to -70
°C. This difference in flexibility arises from the absence
of intraannular substituents and also from the weaker
stabilization of two extraannular hydrogen bonds in
comparison to the complete array of four intraannular
hydrogen bonds in 1.
(18) (a) Casiraghi, G.; Cornia, M.; Sartori, G.; Bocchi, V.; Casnati,
G.; Andreetti, G. D. Makromol. Chem. 1982, 183, 2611-2633. (b)
Casiraghi, G.; Cornia, M.; Ricci, G.; Balduzzi, G.; Casnati, G.; Andreetti,
G. D. Makromol. Chem. 1983, 184, 1363-1378. (c) Casiraghi, G.;
Cornia, M.; Ricci, G.; Casnati, G.; Andreetti, G. D.; Zetta, L. Macro-
molecules 1984, 17, 19-28. (d) Paulus, E.; Bo¨hmer, V. Makromol.
Chem. 1984, 185, 1921-1935.
The chirality of 9d was also demonstrated by doubling
of the signals for the methyl and tert-butyl groups in the
presence of Pirkle’s reagent, which shows again that the
(19) Hardy, A. D. U.; MacNicol, D. D. J . Chem. Soc., Perkin Trans.
2 1976, 1140-1142.

554 J . Org. Chem., Vol. 61, No. 2, 1996
Bo¨hmer et al.
F igu r e 4. Possible conformational isomers of annelated triple calix[4]arenes of type 10 (substituents and hydrogen atoms omitted
for clarity). I: cone/1,2-alternate/cone. II: cone/cone/cone (not possible for large substituents R1, R2). In both isomers the endo-
calixarene systems can (in principle) be converted to 1,2-alternate, while a mutual interconversion of both isomers is impossible.
molecule exists in the form of enantiomers stable on the
NMR time scale. This means that a diphenylmethane
unit which belongs to two calix[4]arene substructures
cannot change its configuration.
adjacent phenolic units,20 allowing thus for determination
of the conformation. Table 1 contains these values for
the exo-calix[4]arenes 3 and the double and triple calix-
arenes 9 and 10. They demonstrate that similar conclu-
sions cannot be drawn in the present cases, since the
configurational factors are superimposed by constitu-
tional ones.
The triple calix[4]arenes 10a and 10c possess a highly
symmetrical conformation, as demonstrated by the 1H
NMR spectrum of 10c. One singlet for the tert-butyl
groups (1.22 ppm) and for the OH groups (10.55 ppm,
cone conformation!), four doublets (m coupling) for aro-
matic protons (7.11, 7.07, 6.90, 6.58 ppm), and a singlet
(3.78 ppm, 4H) and three pairs of doublets in the ratio
1:2:1 (geminal coupling, 4.31, 4.25 (4H), 4.08, 3.54, 3.50
(4H), 3.26 ppm) for the methylene protons are compatible
with a conformation with overall C2h symmetry (I), in
which the two endo-calix[4]arenes are in the cone and
the exo-calixarene in the middle of the molecule has an
1,2-alternate conformation (Figure 4).
Ta ble 1. Ch em ica l Sh ifts (δ, CDCl3) for Meth ylen e
Ca r bon Atom s
3a
3e
9a
9b
9c
9d
10a
10c
40.86 40.27b 39.45 39.54 39.33 39.44 39.54 39.48
34.30
34.22
32.29 34.09 32.28 34.10 32.46 34.10
32.08 32.33 32.09 32.33 32.25 32.81
31.57 32.25 31.61 32.25 29.69 31.68
30.83 31.89 30.83 31.90
3fa
3ga
31.68
31.73
41.19 41.18b
30.83
31.51
Although an all-cone conformation with C2v symmetry
(II) would have diastereotopic protons also at the meth-
ylene groups in the middle of the molecule, it cannot be
strictly ruled out by the observed singlet, since these
protons most probably would be isochronous. However,
such a conformation is sterically impossible for 10a and
highly unlikely for 10c, since the phenyl or tert-butyl
residues would point toward each other. The high-field
shift of one Ar-H doublet and one pair of Ar-CH2-Ar
doublets may be interpreted again in favor of I where
the 1,2-alternate conformation of the exo-calixarene in
the middle brings these protons in the shielding region
of the adjacent cone conformations. From the results
obtained with 9, it follows that an interconversion of I
and II is impossible.
a
b
Acetone-d6. Two signals superimposed.
(c) Com p u ta tion a l Stu d ies. In order to evaluate the
possible conformations of exo-calixarenes, we performed
an extensive conformational search of 3f as a model
compound. For this, the RANDOMSEARCH procedure
of the SYBYL21 program was used. All dihedral angles
around the aryl-methylene bonds were defined as rota-
ble and randomly perturbed followed by energy minimi-
zation using the TRIPOS force field.22 From this ap-
proach 31 conformers were obtained which served as
starting structures for subsequent minimizations using
the TRIPOS force field with decreased termination
criteria and the MM3(92) force field23 for means of
comparison. The 19 (TRIPOS) and 17 (MM3) unique
conformers obtained in this way were then classified by
analogy to the main conformations of the parent endo-
calix[4]arene’s cone (2/2 conformers with TRIPOS/MM3),
partial cone (10/5), 1,2-alternate (4/6), and 1,3-alternate
(2/4) (a boat-like conformation was found in addition with
The triple calix[4]arene 10b is obtained as a hitherto
inseparable mixture of two regioisomers, which, assum-
ing the cone-1,2-alternate-cone arrangement of the
calix[4]arene substructures, have Cs and Ci () S2) sym-
metry. Interestingly the signals of the methyl and tert-
butyl groups of both isomers (their integration leads to
a ratio of 1:1) are better separated in pyridine-d5 (∆δ )
0.12 ppm) than in CDCl3 (∆δ ) 0.01 ppm), which solvent
differentiates better the various methylene groups.
(20) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.; Sanchez,
C. J . Org. Chem. 1991, 56, 3372-3376.
(21) Sybyl (versions 5.4, 5.5, and 6.0), Tripos Associates, Inc., St.
Louis, MO 63144.
(22) Clark, M.; Cramer, R. D.; van Opdenbosch, N. J . Comput. Chem.
1989, 10, 982-1012.
(23) (a) Allinger, N. L.; Yuh, Y. H.; Lii, J .-H. J . Am Chem. Soc. 1989,
111, 8551-8556. (b) Allinger, N. L.; Rahman, M.; Lii, J .-H. J . Am
Chem. Soc. 1990, 112, 8293-8307.
It has been found for endo-calixarenes and their
derivatives that the 13C NMR signals of the methylene
carbons are diagnostic for the mutual arrangement of the

Annelated Calix[4]arenes with Hydroxy Groups
J . Org. Chem., Vol. 61, No. 2, 1996 555
Ta ble 2. Rela tive En er gies of th e Low est En er gy
Con for m er s of th e exo-Ca lixa r en e 3f Obta in ed by Usin g
th e TRIP OS a n d th e MM3 F or ce F ield s
We compared the most stable cone conformers of 3f
with the crystal structure of 3a by fitting of the meta-
cyclophane framework which led to rms values of 0.204
Å (TRIPOS conformer) and 0.426 Å (MM3 conformer).
The reason for these rather large deviations is the C2
symmetry of the calculated structures whereas the
crystal structure exhibits a (noncrystallographic) C4
symmetry of the metacyclophane skeleton. This is not
unexpected since in the crystal the C4 symmetry is
favored by incorporation of an acetonitrile molecule in
the cavity of the calixarene whereas the calculations of
the isolated molecule in vacuo neglect this effect.
Furthermore, we studied the conformational possibili-
ties of the annelated calixarenes 9 by using the entirely
unsubstituted compound (R1 ) R2 ) R3 ) H) as a model
(details of this study will shortly be submitted for
publication). This “naked” annelated calixarene was
again subjected to the RANDOMSEARCH procedure
followed by subsequent energy minimization using the
two force fields. Both methods yielded two, energetically
nearly equal, low-energy conformers, namely, a structure
showing the cone conformation for both the exo- and the
endo-calixarene part (ETRIPOS ) -25.44 kcal mol-1, EMM3
) 14.9 kcal mol-1) and a structure consisting of a cone
conformation in the endo-calixarene and a 1,2-alternate
conformation in the exo-calixarene part (ETRIPOS ) -25.07
kcal mol-1, EMM3 ) 16.96 kcal mol-1). These calculations
indicate that both conformers, having the maximum
number of intramolecular hydrogen bonds, may be present
under experimental conditions.
To study the conformational flexibility and the pos-
sibilities of interconversion of the annelated calixarene,
we performed a molecular dynamics simulation of 9 (R1
) R2 ) R3 ) H) and compared it with the corresponding
simulations of 1 (R ) CH3) and 3f. The results of the
MD runs are shown in Figure 5.
At the conditions chosen for the MD run the endo-
calixarene 1 shows only the C2v f C2v pseudorotation
whereas for 3f nonstop interconversions between the four
main conformations take place without any significant
preference of a single conformation. In contrast, in the
annelated calixarene there is a dynamic interplay be-
tween the exo- and the endo-calixarene part, that is, the
flexibility of the endo-calixarene part is enhanced and
the flexibility of the exo-calixarene part is diminished
when compared to the isolated molecules. As a result,
the presence of the cone, partial cone, and 1,2-alternate
conformation can clearly be distinguished for both parts.
conformation
energy in
kcal/mol
cone
1,2-alt
partl cone
1,3-alt
TRIPOS
4.73
-9.16
-8.58
-13.27
0.58
Ebond
Evdw
Eelec
Etotal
Erel
4.45
3.71
-9.49
-6.37
-12.16
1.69
4.19
-10.43
-3.64
-9.88
3.97
-9.76
-8.54
-13.85
0.00
MM3
-15.94
17.90
14.10
16.05
2.49
Ebond
Evdw
Eelec
Etotal
Erel
-18.55
16.56
15.55
13.56
0.00
-16.76
19.43
14.26
16.92
3.36
-16.57
22.06
15.49
20.97
7.41
the TRIPOS force field). These single conformers are
energetically different, mainly because of the differing
torsion angles around the methylene bridges, but also
because different orientations of the OH groups lead to
different numbers of intramolecular hydrogen bonds.
The following discussion is restricted to the most stable
conformers of each main conformation. Their relative
energies obtained with the two force fields are given in
Table 2.
With both methods the same energetical order cone >
1,2-alternate > partial cone > 1,3-alternate was obtained;
however, the energy differences between the conformers
differ considerably both with respect to the whole energy
range and to the energy differences between the conform-
ers. Whereas for the TRIPOS force field the energy
differences between the conformers result mainly from
the electrostatic term and hence from the number of
possible intramolecular hydrogen bonds, the MM3 energy
differences are due to both the bonding (essentially the
torsional term) and the van der Waals interactions. This
leads to a similar energy of the cone and 1,2-alternate
conformer within the TRIPOS force field resulting mainly
from the same number of hydrogen bonds whereas within
the MM3 force field the larger steric strain of the 1,2-
alternate conformer results in a larger energy difference.
The geometries of the energetically most stable con-
formers obtained with the TRIPOS force field correspond
to those known from the various crystal structures of
endo-calix[4]arenes. However, the partial cone and the
1,2-alternate conformer obtained with the MM3 force
field are characterized by the fact that the four methylene
carbons do not lie in a plane. Instead of using a single
mean plane, the spatial situation can be described by two
“reference planes” of two triangles formed by the meth-
ylene carbons, as was proposed by Harada et al.24 for
some 1,2-alternate conformers of OH-depleted calixare-
nes. These planes form dihedral angles of 147° and 128°
in the partial cone and 1,2-alternate conformation,
respectively. The “conventional” partial cone and 1,2-
alternate conformers are less stable by 0.4 and 3.2 kcal
mol-1, respectively.
Exp er im en ta l Section
(a ) Com p u ta tion a l Stu d ies. For the computational stud-
ies the SYBYL 6.1 software including the RANDOMSEARCH
module and the TRIPOS force field as well as the MM3(92)
force field were run on both a SGI Crimson Elan and an IBM
RISC/6000 workstation.
For the random conformational search procedure, a maxi-
mum of 10 000 cycles with an energy cutoff of 10 kcal mol-1
and rms gradient of 0.01 kcal mol-1 Å-1 was chosen. The
optimizations with the TRIPOS force field were performed
using some modified parameters25 with a distance-dependant
dielectric with e ) 1 until the rms energy gradient was less
than 0.001 kcal mol-1 Å-1 using the Powell minimizer included
in the SYBYL/MAXIMIN2 routine. The Gasteiger-Hu¨ckel
method26 was applied for the calculation of the partial charge
Additionally, with the TRIPOS force field a boat-like
structure was found where two phenolic rings are nearly
perpendicular whereas the other two lie in the mean
plane of the methylene carbons. However, the relative
energy of this conformer was 4.7 kcal mol-1 higher than
that of the most stable conformer.
(24) (a) Harada, T.; Rudzinski, J . M.; Osawa, E.; Shinkai, S.
Tetrahedron 1993, 49, 5941-5954. (b) Harada, T.; Ohseto, F.; Shinkai,
S. Tetrahedron 1994, 50, 13377-13394.
(25) Thondorf, I.; Hillig, G.; Brandt, W.; Brenn, J .; Barth, A.;
Bo¨hmer, V. J . Chem. Soc., Perkin Trans. 2 1994, 2259-2267.

556 J . Org. Chem., Vol. 61, No. 2, 1996
Bo¨hmer et al.
F igu r e 5. Molecular dynamics simulation for (a) 1 (R ) CH3), (b) 3f, (c) 9 endo part, (d) 9 exo part. The values a on the ordinate,
characterizing the conformation,25 are obtained for each snapshot conformer from the torsion angles at the methylene bridges as
a ) [(|∑æi| + |∑øi|) - ∑|æi + øi|]
The following values of a are characteristic for the four main conformations: cone, about 400 to 800°; partial cone, around 0°;
1,2-alternate, 0 to -200°; and 1,3-alternate, -200 to -500°.
distribution of the molecules. For the MM3 optimizations the
full-matrix Newton-Raphson method was used.
Figures 1 to 3 were produced with the aid of ORTEP31 (as
implemented in PLATON32 and NRCVAX28) and with PLU-
TON.33
The molecular dynamics simulations were done with the MD
module of SYBYL. For each molecule a 200 ps dynamics run
at 300 K using a time step of 1 fs and a snapshot every 50 fs
was performed. All bonds involving hydrogens were con-
strained by the SHAKE option; starting velocities were chosen
randomly. A constant dielectric of e ) 4 was applied.
(c) Syn th eses. Starting materials were commercially
available or prepared according to the literature prescriptions
indicated. Dehydrogenation reactions were carried out with
Raney nickel (Fa. Merck, Darmstadt), 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 uncorrected. All chromato-
graphic separations were done using silica gel 60, particle size
0.040-0.063 mm (230-400 mesh ASTH), as stationary phase.
The eluent is indicated for the individual case.
As is often found with calixarenes, the elemental analyses
deviate sometimes significantly from the values calculated for
the pure compounds. This may be caused, especially in the
case of low carbon values, by included solvent which is difficult
to remove. As shown below for the exo-calixarenes 3, the
experimental values may be matched by the assumption of a
certain fraction of the solvent used for recrystallization,
although this has only been exactly proved for 3a by X-ray
analysis. Such an adjustment frequently found in publications
is especially problematic if solvent mixtures (also petroleum
ether) have been used, and we therefore do not calculate such
arbitrary values for the double and triple calixarenes 9 and
10. All compounds are carefully characterized, however, by
NMR spectra and by their mass spectra.
(b) X-r a y An a lyses of 3a a n d 6c.27 Details of the crystal
data, data collection, structure solution, and refinement are
concisely summarized in Table 3. Diffraction data were
corrected for Lorentz and polarization effects using NRCVAX;28
no absorption correction was required. The structures were
solved with SHELXS86.29 In both 3a and 6c the hydroxy H
atoms were clearly located in difference maps before con-
strained refinement with the AFIX-147 option in SHELXL93.30
The unique hydroxy H atom in the asymmetric unit of 3a was
equally disordered over two sites. The acetonitrile molecule
in 3a is at the junction of two mirror planes, and the hydrogens
are necessarily disordered. A difference map section in the
expected locus of these H atoms showed a disk of density; these
H atoms were allowed for with a suitably disordered model.
The C-C molecular dimensions in 3a and 6c are entirely in
accord with expected values and are unexceptional.
(26) (a) Gasteiger, J .; Marsili, M. Tetrahedron 1980, 36, 3219-3226.
(b) Marsili, M.; Gasteiger, J . Croat. Chem. Acta 1980, 53, 601-614.
(27) The atomic coordinates for all the X-ray structures of 3a and
6a have been deposited with the Cambridge Crystallographic Data
Centre. The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK.
(28) Gabe, E. J .; Le Page, Y.; Charland, J .-P.; Lee, F. L.; White, P.
S. J . Appl. Crystallogr. 1989, 22, 384-387.
(29) Sheldrick. G. M. Shelxs86. Program for the solution of crystal
structures, 1986, University of Go¨ttingen, Germany.
5,11,17,23-Tetr a-ter t-bu tyl-4,12,16,24-tetr ah ydr oxycalix-
[4]a r en e (3a ). A solution of 5a 34 (10 g, 32 mmol) and
paraformaldehyde (1.2 g, 40 mmol) in 200 mL of xylene
(31) J ohnson, C. K. ORTEP-A Fortran Thermal Ellipsoid Plot
Program, Technical Report ORNL-5138, 1976, Oak Ridge National
Laboratory, Oak Ridge, TN.
(32) Spek. A. L. Platon Molecular Geometry Program, 1994, J uly
1994 version, University of Utrecht, Utrecht, Holland.
(33) Spek. A. L. Pluton Molecular Graphics Program, 1994, J uly
1994 version, University of Utrecht, Utrecht, Holland.
(30) Sheldrick. G. M. Shelxs93. Program for the refinement of crystal
structures, 1993, University of Go¨ttingen, Germany.

Annelated Calix[4]arenes with Hydroxy Groups
J . Org. Chem., Vol. 61, No. 2, 1996 557
0.88-0.82 (m, 6H); MS(FD), m/z 846.6 (M+, calcd 845.3). Anal.
Calcd for C58H84O4: C, 82.41; H, 10.02. Found: C, 81.56; H,
9.98.
Ta ble 3. Su m m a r y of Cr ysta l Da ta , Da ta Collection ,
Str u ctu r e Solu tion , a n d Refin em en t Deta ils
3a
6a
5,23-D i-t er t -b u t y l-4,12,16,24-t e t r a h y d r o x y -11,17-
d im eth ylca lix[4]a r en e (3e). 7b (6.0 g, 10.8 mmol) was
dissolved in 220 mL of xylene, paraformaldehyde (0.4 g, 13.4
mmol) was added, and the mixture was kept for 16 h at 180
°C in an autoclave. The solvent was removed, the remaining
brown oil was dissolved in 200 mL of CH2Cl2, silica (50 g) was
added, and the solvent was removed to adsorb the oil on the
silica. The product was extracted with CH2Cl2 (Soxhlet).
Removal of the solvent and recrystallization from CHCl3 gave
a pale brown solid: yield 2.9 g (47%); mp 240-243 °C; 1H NMR
(CDCl3) δ 7.00 (d, J ) 2.0 Hz, 2H), 6.90 (d, J ) 2.0 Hz, 2H),
6.84 (d, J ) 1.9 Hz, 2H), 6.61 (d, J ) 2.0 Hz, 2H), 6.30 (2H),
6.28 (2H), 3.84 (2H), 3.78 (4H), 3.69 (2H), 2.21 (6H), 1.40 (18H);
MS(FD), m/z 564.4 (M+, calcd 564.7). Anal. Calcd for
C38H44O4‚0.25CHCl3: C, 77.26; H, 7.50. Found: C, 77.63; H,
7.90.
(a) Crystal Data
C44H56O4‚CH3CN
689.94
formula
C21H28O2
312.43
colorless, block
molar mass
color, habit
crystal size, mm
crystal system
a, Å
colorless, plate
0.39 × 0.30 × 0.10 0.40 × 0.39 × 0.39
tetragonal
16.1990(14)
16.1990(14)
15.9570(13)
90
triclinic
9.3773(12)
10.5053(14)
11.0439(11)
106.971(10)
101.022(10)
107.371(10)
945.8(2)
P1h
b, Å
c, Å
R, deg
â, deg
90
90
γ, deg
V, Å3
4187.2(6)
P42/ncm
4
mm
1496
space group
Z
2
molecular symmetry
F(000)
none
340
1.097
0.069
dcalc, g cm-3
µ, mm-1
1.094
0.068
4,12,16,24-Tetr a h yd r oxyca lix[4]a r en e (3f). 3a (6 g, 9.2
mmol) was dissolved in 500 mL of toluene, AlCl3 (5.9 g, 44.4
mmol) was added, and the mixture was kept for 3 h at 50 °C
under argon. The volume was then reduced to 50 mL and the
mixture poured into water. The product was precipitated by
acidification with hydrochloric acid, recystallized from metha-
nol, and dried at 100 °C in vacuo: yield 2.8 g (71%); mp 350-
(b) Data Acquisitiona
294(1)
25 (8.9 13.8)
temp, K
unit-cell reflcns
(θ-range, deg)
294(1)
25 (17.8 24.2)
max θ (deg) for reflcns 26.9
27.0
hkl range of reflcns
variation in three
standrd reflcns
reflcns measd
unique reflcns
Rint
0 20; 0 14; 0 20
1.6%
-11 11; 0 13; -14 13
1.0%
1
357 °C; H NMR (acetone-d6) δ 8.50 (4H), 6.96 (m, 8H), 6.72
(m, 4H), 3.81 (4H), 3.70 (4H); MS(EI), m/z 424.2 (M+, calcd
424.5). Anal. Calcd for C28H24O4: C, 79.23; H, 5.70. Found:
C, 79.36; H, 5.78.
4663
2405
0.011
1069
4117
4117
4,12,16,24-Tet r a h yd r oxy-5,23-d im et h ylca lix[4]a r en e
(3g). 3e (2.9 g, 5.1 mmol) was dissolved in 200 mL of toluene,
AlCl3 (1.8 g, 13.5 mmol) was added, and the mixture was
heated to 50 °C for 3 h. After cooling, the mixture was poured
into 200 mL of water and the toluene removed by distillation.
Hydrochloric acid was added and the crude product filtered
off. Extraction with boiling methanol gave a white solid
residue: yield 1.78 g (77%); mp 346-349 °C; 1H NMR (CDCl3)
δ 8.62 (br, 2H), 8.12 (br, 2H), 6.96 (3H), 6.92 (d, J ) 2.1 Hz,
1H), 6.88 (d, J ) 1.9 Hz, 2H), 6.84 (2H), 6.71 (d, J ) 7.8 Hz,
2H), 3.97 (2H), 3.78 (2H), 3.66 (4H), 2.14 (6H); MS(FD), m/z
452.2 (M+, calcd 452.5). Anal. Calcd for C30H28O4‚0.5CH3-
OH: C, 78.18; H, 6.45. Found: C, 78.13; H, 6.43.
reflcns with I > 2σ(I)
3026
(c) Structure Solution and Refinementb
refinement on
solution method
H-atom treatment
F2
F2
SHELXS86
riding
SHELXS86
riding
no. of variables in L.S. 126
208
k in w ) 1/(σ2Fo + k)
(0.0777P)2
(0.0699P)2 + 0.0621P
2
[P ) (Fo + 2Fc2)/3]
2
R, Rw, gof
0.051, 0.149, 0.93
-0.144, 0.207
0.041, 0.132, 1.12
-0.148, 0.217
density range in final
∆-map, e Å-3
final shift, error ratio
sec. extnct type
sec. extnct corrctn
-0.003
SHELXL
0.0016(4)
-0.004
SHELXL
0.078(7)
4,4′-Bis(br om om eth yl)-6,6′-d im eth yl-2,2′-m eth a n ed iyl-
d ip h en ol (6b). Gaseous HBr was bubbled through an ice-
cooled suspension of 6a 35 (15 g, 65.7 mmol) and paraformal-
dehyde (7 g, 0.233 mol) in 60 mL of acetic acid to obtain a
clear, usually red solution. After 16 h at room temperature a
grey solid was filtered off, washed with petroleum ether, and
dried over KOH: yield 20 g (73.5%); mp 146-148 °C; 1H NMR
(CDCl3) δ 7.15 (d, J ) 2.1 Hz, 2H), 7.02 (d, J ) 1.8 Hz, 2H),
6.25 (br, 2H), 4.43 (4H), 3.87 (2H), 2.21 (6H); MS(EI), m/z 414
(M+, calcd 414.4). Anal. Calcd for C17H18Br2O2: C, 49.30; H,
4.38. Found: C, 49.31; H, 4.50.
4,4′-Bis(b r om om e t h yl)-6,6′-d i-t er t -b u t yl-2,2′-m e t h -
a n ed iyld ip h en ol (6d ) was synthesized as described for 6b,
starting with 6c36 (20 g, 64 mmol). 6d : yield 27.5 g (86%); mp
134 °C; 1H NMR (CDCl3) δ 7.18 (4H), 4.46 (4H), 3.89 (2H),
1.40 (18H).
a
Data collection on an Enraf Nonius CAD4 diffractometer with
b
graphite-monochromatized Mo KR radiation (λ ) 0.7107 Å). All
calculations were done on a Silicon Graphics 4D-35TG computer
system with the NRCVAX system of programs (Gabe, E. J .; Le
Page, Y.; Charland, J .-P.; Lee, F. L.; White, P. S. J . Appl.
Crystallogr. 1989, 22, 384-389) and with SHELXL-93 (Sheldrick,
G. M., 1993) for refinement with all data on F2.
was heated to 175 °C for 16 h in an autoclave. The solvent
was removed and the residue extracted into acetonitrile,
giving a yellow product which was recrystallized from acetone/
acetonitrile: yield 3.98 g (38%); mp 278-282 °C; 1H NMR
(CDCl3) δ 7.00 (d, J ) 1.9 Hz, 4H), 6.81 (d, J ) 1.8 Hz, 4H),
6.33 (4H), 3.81 (4H), 3.79 (4H), 1.41 (36H); MS(EI), m/z 648.5
(M+, calcd 648.9). Anal. Calcd for C44H56O4‚CH3CN: C, 80.08;
H, 8.62. Found: C, 79.90; H, 8.69.
5,11,17,23-Tetr a -ter t-bu tyl-8,20-d ih exyl-8,20-d im eth yl-
4,12,16,24-tetr a h yd r oxyca lix[4]a r en e (3d ). A solution of
5d (2.87 g, 7 mmol; prepared by acid-catalyzed condensation
of 2-tert-butylphenol and octanone-2) and paraformaldehyde
(0.27 g, 9 mmol) in 200 mL of xylene was heated to 180 °C for
15 h. After removal of the solvent, the remaining oil was
purified by flash chromatography (CHCl3 as eluent), giving 1.4
g of an orange oil which was recrystallized from petroleum
ether at -18 °C to give a white solid: yield 0.38 g (13%); mp
107-111 °C; 1H NMR (CDCl3) δ 7.18 (d, J ) 1.8 Hz, 4H), 6.36
(d, J ) 1.8 Hz, 4H), 5.22 (2H), 5.20 (2H), 3.67 (4H), 1.94-1.86
(m, 4H), 1.50 (4H), 1.42 (36H), 1.22 (14H), 1.15-1.00 (m, 4H),
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′-m eth a n ed iyld ip h en ol (7a ). A mixture of 6b
(6 g, 14.5 mmol), 2-bromo-6-tert-butylphenol (30 g, 0.131 mol),
and ZnCO3 (1.7 g, 3.1 mmol) was kept at 60 °C for 16 h. The
mixture was taken into 100 mL of CHCl3 and filtered, and
the solvent was removed. The product was isolated by column
chromatography as the second component. 7a : yield 5.9 g
1
(58%); H NMR (CDCl3) δ 7.07 (d, J ) 2.0 Hz, 2H), 7.01 (d, J
) 1.9 Hz, 2H), 6.91 (d , J ) 1.9 Hz, 2H), 6.76 (d, J ) 1.8 Hz,
2H), 6.00 (2H), 5.65 (2H), 3.85 (2H), 3.73 (4H), 2.17 (6H), 1.35
(18H); MS(FD), m/z 710.9 (M+, calcd 710.5).
(35) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J . Org. Chem. 1967,
32, 2358.
(34) Tashiro, M.; Fukata, G. Org. Prep. Proc. Int. 1976, 8(5), 231-
236.
(36) Casiraghi, G.; Casnati, G.; Pochini, A.; Paglia, G.; Ungaro, R.;
Satori, G. Synthesis 1981, 2, 143-146.

558 J . Org. Chem., Vol. 61, No. 2, 1996
Bo¨hmer et al.
4,4′-Bis(3-ter t-b u t yl-4-h yd r oxyb en zyl)-6,6′-d im et h yl-
2,2′-m eth a n ed iyld ip h en ol (7b). Raney nickel (10 g) was
added to a solution of 7a (10 g, 14 mmol) and KOH (5 g, 87.8
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
absorption was completed. The catalyst was removed by
filtration and washed with methanol, and the washings were
combined with the filtrate. Acidification with dilute hydro-
chloric acid gave a red oil which was separated and recrystal-
lized from petroleum ether to give a grey solid: yield 5.3 g
(68%); mp 146-149 °C; 1H NMR (CDCl3) δ 7.04 (d, J ) 2.0
Hz, 2H), 6.94 (d, J ) 1.8 Hz, 2H), 6.79 (m, 4H), 6.53 (d, J )
8.0 Hz, 2H), 4.70 (br, 4H), 3.84 (2H), 3.77 (4H), 2.16 (6H), 1.39
(18H); MS(FD), m/z 552.8 (M+, calcd 552.7). Anal. Calcd for
C37H44O4: C, 80.40; H, 8.02. Found: C, 79.86; H, 7.90.
4,4′-Bis(3-br om o-5-ter t-bu tyl-4-h yd r oxyben zyl)-6,6′-d i-
ter t-bu tyl-2,2′-m eth a n ed iyld ip h en ol (7c). A mixture of 6d
(4 g, 8 mmol) and 2-bromo-6-tert-butylphenol (20 g, 87 mmol)
was heated to 80 °C for 8 h. The excess of 2-bromo-6-tert-
butylphenol was removed by steam distillation, and the
remaining solid was recrystallized several times from petro-
leum ether: yield 4.6 g (72%); mp 137 °C; 1H NMR (CDCl3) δ
7.14 (d, J ) 2.0 Hz, 2H), 7.02 (d, J ) 1.8 Hz, 2H), 6.95 (d, J )
1.9 Hz, 2H), 6.89 (d, J ) 1.8 Hz, 2H), 5.82 (2H), 5.66 (2H),
3.86 (2H), 3.77 (4H), 1.358 (18H), 1.355 (18H).
6,6′-Di-ter t-bu tyl-4,4′-bis(3-ter t-bu tyl-4-h ydr oxyben zyl)-
2,2′-m eth a n ed iyld ip h en ol (7d ) was synthesized as described
for 7b, starting with 7c (4 g, 5 mmol). 7d : yield 2.21 g (69%);
mp 89 °C; 1H NMR (CDCl3) δ 7.1 (d, J ) 2.1 Hz, 2H), 6.97 (d,
J ) 2.0 Hz, 2H), 6.90 (d, J ) 1.8 Hz, 2H), 6.78-6.83 (dd, J )
7.9 Hz, J ) 2.1 Hz, 4H), 6.56 (2H), 6.52 (2H), 3.85 (2H), 3.79
(4H), 1.38 (18H), 1.35 (18H).
4,4′-Bis(3,5-di-ter t-bu tyl-4-h ydr oxyben zyl)-6,6′-dim eth yl-
2,2′-m eth a n ed iyld ip h en ol (7e). A mixture of 6b (14 g, 33.8
mmol), 2,6-di-tert-butylphenol (46 g, 0.223 mol), and ZnCO3
(4 g, 7.3 mmol) was heated to 60 °C for 16 h under argon.
Petroleum ether (300 mL) was added, and the solution was
filtered to remove inorganic materials. Silica (50 g) was added
and the solvent evaporated. In a Soxhlet apparature first the
excess of 2,6-di-tert-butylphenol was extracted with n-hexane
and then the product with CHCl3. A total of 15.5 g (69%) of
7e was obtained as a yellow oil solidifying as a glassy foam
when dried in vacuum. It was used without further purifica-
tion.
refluxed for 5 days under argon. Additional portions of 8a (1
g and 0.5 g) were added after 72 and 96 h, respectively. The
solvent was removed, and the residue was taken into 200 mL
of ethyl acetate and adsorbed onto 50 g of silica by evaporation
of the solvent. Extraction with ethyl acetate (Soxhlet) gave a
crude product which was purified by flash chromatography (4:1
CHCl3/acetone) to give a brownish oil. Further purification
by precipitation from CHCl3 with petroleum ether and recrys-
tallization from CHCl3/petroleum ether gave 0.893 g (24%):
1
mp >470 °C; H NMR (CDCl3) δ 10.32 (4H), 7.45 (d, J ) 1.8
Hz, 2H), 7.41 (d, J ) 1.6 Hz, 4H), 7.34 (2H), 7.30 (m, 6H), 6.97
(d, J ) 1.8 Hz, 2H), 6.80 (d, J ) 1.8 Hz, 4H), 6.45 (2H), 6.38
(d, J ) 1.8 Hz, 2H), 4.38 (d, J ) 14.8 Hz, 1H), 4.30 (d, J )
14.1 Hz, 2H), 4.11 (d, J ) 13.8 Hz, 1H), 4.07 (d, J ) 13.9 Hz,
1H), 3.75 (4H), 3.67 (d, J ) 14.2 Hz, 1H), 3.58 (d, J ) 14.0 Hz,
2H), 3.45 (d, J ) 14.0 Hz, 1H), 3.20 (d, J ) 13.9 Hz, 1H), 2.20
(6H); MS(FD), m/z 828.6 (M+, calcd 828.9). Anal. Calcd for
C
56H48O6: C, 82.33; H, 5.92. Found: C, 70.39; H, 5.58.
Dou ble Ca lixa r en e 9b. A mixture of 3g (2 g, 4.4 mmol)
and 8b (2 g, 4.4 mmol) was heated in 500 mL of dioxane to 50
°C. TiCl4 (4.93 g, 26 mmol) was added and the mixture
refluxed. After 3 days an additional quantity of 8b (1 g, 2.2
mmol) was added and the mixture refluxed for an additional
2 days. The solvent was then removed and the remaining oil
adsorbed onto 50 g of silica and extracted with ethyl acetate
as described above. The extract was purified by flash chro-
matography with 27:1 CHCl3/acetone and the product finally
recrystallized from CHCl3/acetone: yield 772 mg (24%); mp
1
>300 °C; H NMR (CDCl3) δ 10.24 (4H), 7.07 (d, J ) 2.3 Hz,
1H), 7.06 (d, J ) 2.3 Hz, 1H), 6.92 (d, J ) 1.8 Hz, 1H), 6.89 (d,
J ) 1.8 Hz), 6.83 (2H), 6.81 (2H), 6.77 (1H), 6.44 + 6.43 (3H),
6.34 (d, J ) 1.7 Hz, 1H), 6.32 (d, J ) 1.7 Hz, 1H), 4.22 (d, J )
13.8 Hz, 1H), 4.21 (d, J ) 13.9 Hz, 1H), 4.19 (d, J ) 13.6 Hz,
1H), 4.12 (d, J ) 13.9 Hz, 1H), 4.07 (d, J ) 13.7 Hz, 1H), 3.76
(2H), 3.75 (d, J ) 13.7 Hz, 1H), 3.69 (d, J ) 13.7 Hz, 1H), 3.49
(d, J ) 14.5 Hz, 1H), 3.47 (d, J ) 14.0 Hz, 1H), 3.45 (d, J )
14.3 Hz, 1H), 3.43 (d, J ) 13.9 Hz, 1H), 3.16 (d, J ) 13.8 Hz,
1H), 2.22 (3H), 2.19 (3H), 2.12 (3H), 1.24 (9H); MS(FD), m/z
746.8 (M+, calcd 746.9).
Dou ble Ca lixa r en e 9c a n d Tr ip le Ca lixa r en e 10a . TiCl4
(4 g, 21 mmol) was added to a solution of 3f (1.5 g, 3.5 mmol)
and 8a (1.9 g, 3.5 mmol) in 500 mL of dioxane at 60 °C. The
mixture was then refluxed for 2 weeks. During this time two
additional portions of 8a (0.8 g, 1.47 mmol each) were added.
The solvent was removed and the residue dissolved in 200 mL
of ethyl acetate and adsorbed on 50 g of silica by removing
the solvent again. Extraction with ethyl acetate (Soxhlet) gave
a crude product which was further purified by flash chroma-
tography (4:1 chloroform/acetone). The triple calixarene 10a
(Rf ) 0.98) was eluted first followed by fractions containing
the double calixarene 9c (Rf ) 0.85). Further purification by
flash chromatography (27:1 CHCl3/acetone) gave pure 9c (Rf
) 0.63) and 10a (Rf ) 0.98), which were finally recrystallized
from CHCl3/methanol: yield 9c, 224 mg (8%), mp >470 °C;
10a , 8 mg (0.2%), mp >470 °C.
6,6′-Dim e t h yl-4,4′-b is(4-h yd r oxyb e n zyl)-2,2′-m e t h -
a n ed iyld ip h en ol (7f). A mixture of AlCl3 (13 g, 98 mmol),
phenol (9.6 g, 0.102 mol), and 7e (15.5 g, 23 mmol) in 450 mL
of toluene was stirred at 0 °C for 1 h under argon and then at
room temperature for 9 h. The mixture was poured into 500
mL of HCl-water and extracted with diethyl ether. The
organic phase was dried with MgSO4 and the phenol removed
with boiling petroleum ether (80-100 °C). After evaporation
of the solvent the product was purified by flash chromatogra-
phy with 4:1 CHCl3/acetone (Rf ) 0.34) and recrystallized from
CH2Cl2: yield 3.0 g (50%); mp 168-169 °C; 1H NMR (acetone-
d6) δ 8.15 (2H), 7.93 (2H), 7.03-6.94 (m, 6H), 6.77-6.72 (m,
6H), 3.86 (2H), 3.70 (4H), 2.17 (6H); MS(EI), m/z 440.3 (M+,
calcd 440.5).
When a larger amount of 8a (1.9 g + 3 × 1.0 g) was used,
10a was the main product: yield 9c, 16 mg (0.4%); 10a , 288
mg (7%).
9c: 1H NMR (CDCl3) δ 10.33 (4H), 7.45 (dd, J ) 7.1 Hz, J )
1.3 Hz, 4H), 7.38 (d, J ) 6.5 Hz, 4H), 7.31 (d, J ) 2.0 Hz, 2H),
7.30 (d, J ) 2.2 Hz, 2H), 7.28 (m, 2H), 6.99 (d, J ) 7 Hz, 2H),
6.95 (d, J ) 1.9 Hz, 2H), 6.92 (dd, J ) 8.1 Hz, J ) 2.0 Hz, 2H),
6.80 (d, J ) 8.1 Hz, 2H), 6.28 (d, J ) 1.6 Hz, 2H), 4.62 (d, J )
14.0 Hz, 1H), 4.31 (d, J ) 14.0 Hz, 2H), 4.13 (d, J ) 14.4 Hz,
1H), 4.10 (d, J ) 14.3 Hz, 1H), 3.81 (4H), 3.69 (d, J ) 14.1 Hz,
1H), 3.59 (d, J ) 14.0 Hz, 2H), 3.43 (d, J ) 14.0 Hz, 1H), 3.17
(d, J ) 13.9 Hz, 1H); MS(FD), m/z 800.2 (M+, calcd 800.3).
Anal. Calcd for C55H44O6: C, 82.48; H, 5.30. Found: C, 75.41;
H, 5.36.
6,6′-Bis(br om om eth yl)-4-ter t-bu tyl-4′-m eth yl-2,2′-m eth -
a n ed iyld ip h en ol (8b) was synthesized as described for 6b,
starting with 4-tert-butyl-4′-methyl-2,2′-methanediyldiphenol
(15 g, 55.5 mmol; obtained by dehalogenation of 6′-bromo-4-
tert-butyl-4′-methyl-2,2′-methanediyldiphenol37 ). 8b: yield 6.0
1
g (24%); mp 126-128 °C; H NMR (CDCl3) δ 7.26 (d, J ) 2.4
Hz, 1H), 7.13 (d, J ) 2.4 Hz, 1H), 7.04 (d, J ) 1.7 Hz, 1H),
6.95 (d, J ) 1.7 Hz, 1H), 6.50 (br, 2H), 4.54 (2H), 4.52 (2H),
3.90 (2H), 2.22 (3H), 1.27 (9H); MS(EI), m/z 456 (M+, calcd
456.2). Anal. Calcd for C20H24O2Br2: C, 52.65; H, 5.30.
Found: C, 52.47; H, 5.39.
10a : 1H NMR (CDCl3) δ 10.45 (8H), 7.42 (dd, J ) 1.3 Hz, J
) 7.8 Hz, 8H), 7.34 (t, J ) 7.2 Hz, 8H), 7.33 (d, J ) 2.3 Hz,
4H), 7.30 (d, J ) 2.3 Hz, 4H), 7.28-7.26 (m, 4H), 6.94 (d, J )
1.9 Hz, 4H), 6.58 (d, J ) 1.7 Hz, 4H), 4.41 (d, J ) 14.0 Hz,
2H), 4.30 (d, J ) 13.9 Hz, 4H), 4.03 (d, J ) 13.8 Hz, 2H), 3.78
(4H), 3.70 (d, J ) 13.7 Hz, 2H), 3.58 (d, J ) 14.1 Hz, 4H), 3.25
Dou ble Ca lixa r en e 9a . TiCl4 (4.93 g, 26 mmol) was added
to a warm solution (60 °C) of 3g (2 g, 4.4 mmol) and 8a 9 (2.37
g, 4.4 mmol) in 500 mL of dioxane, and the mixture was
(37) Ka¨mmerer, H.; Happel, G. Makromol. Chem. 1978, 179, 1199-
1207.

Annelated Calix[4]arenes with Hydroxy Groups
J . Org. Chem., Vol. 61, No. 2, 1996 559
(d, J ) 13.8 Hz, 2H); MS(FD), m/z 1178.1 (M+, calcd 1177.3).
Anal. Calcd for C82H64O8: C, 83.65; H, 5.48. Found: C, 73.39;
H, 5.49.
described above. The product was extracted with ethyl
acetate, purified by flash chromatography (4:1 CHCl3/acetone),
and recrystallized from CHCl3/petroleum ether: yield 810 mg
(13%); mp 318-320 °C; 1H NMR (CDCl3) δ 9.86 (2H), 8.38 (2H),
7.47-7.45 (m, 4H), 7.41-7.35 (m, 8H), 7.31-7.26 (m, 2H), 7.05
(d, J ) 2.0 Hz, 2H), 6.83 (d, J ) 1.5 Hz, 2H), 6.78 (d, J ) 8.3
Hz, 2H), 6.67 (d, J ) 1.8 Hz, 2H), 6.43 (2H), 6.34 (dd , J ) 8.4
Hz, J ) 1.70 Hz, 2H), 4.00 (2H), 3.87 (4H), 3.73 (6H), 2.20
(6H); MS(FD), m/z 816.7 (M+, calcd 816.9).
16,24,28,36,41,42-Hexa k is[(eth oxyca r bon yl)m eth oxy]-
23,29-d im eth yl-5,11-d ip h en ylca lix[6]a r en e. A mixture of
11a (300 mg, 0.37 mmol), ethyl bromoacetate (736 mg, 4.4
mol), K2CO3 (617 mg, 4.4 mol), and 24 mL of acetonitrile was
refluxed for 16 h. The solvent was removed and the remainder
dissolved in 50 mL of CH2Cl2 and three times washed with
water. Removal of the solvent and recrystallization from hot
ethanol gave a colorless solid: yield 440 mg (90%); mp 78-80
°C; 1H NMR (CDCl3) δ 7.45 (d, 2H), 7.28 -7.19 (m, 10H), 7.09
(d, J ) 2.2 Hz, 2H), 6.79 (dd, J ) 8.3 Hz, J ) 1.9 Hz, 2H), 6.73
(d, J ) 1.6 Hz, 2H), 6.59 (d, J ) 8,3 Hz, 2H), 6.54 (d, J ) 1.1
Hz, 4H), 4.57 (4H), 4.48 (4H), 4.28-4.10 (m, 22H), 3.87 (2H),
3.34 (4H), 2.11 (6H), 1.27 (t, J ) 7.2 Hz, 6H), 1.22 (t, J ) 7.5
Hz, 6H), 1.18 (t, J ) 7.5 Hz, 6H); MS(FD), m/z 1332.8 (M+,
calcd 1333.5).
5,23-Di-ter t-bu tyl-4,12,16,24,36,37-h exa h yd r oxy-11,17-
d im eth yl-29,35-d ip h en ylca lix[6]a r en e (11b). A mixture of
7b (2.76 g, 5 mmol) and 8a (3.69 g, 6.9 mmol) in 500 mL of
dioxane was heated to 40 °C under argon. TiCl4 (2.31 mL, 21
mmol) was added and the mixture then refluxed for 3 days.
8a (1 g) was added and the reaction continued for 24 h. The
solvent was removed and the remainder adsorbed onto 50 g
of silica. The product was extracted with ethyl acetate and
then purified by flash chromatography (27:1 CHCl3/acetone).
Final recrystallization from CHCl3/petroleum ether gave 331
mg (7.2%): mp 310-312 °C; 1H NMR (CDCl3) δ 7.50 (br, 2H),
7.42-7.32 (m, 10H), 7.12 (d, J ) 2.0 Hz, 2H), 6.92 (d, J ) 1.8
Hz, 2H), 6.87 (d, J ) 1.5 Hz, 2H), 6.79 (d, J ) 1.7 Hz, 2H),
6.72 (d, J ) 1.4 Hz, 2H), 6.00 (br, 2H), 5.25 (br, 2H), 4.02 (2H),
3.93 (4H), 3.76 (2H), 3.74 (4H), 2.13(6H), 1.39 (18H); MS(FD),
m/z 928.7 (M+, calcd 929.2).
5,11,17,23-Tet r a -ter t-b u t yl-37,38,39,40,41,42-h exa h y-
d r oxy-29,35-d ip h en ylca lix[6]a r en e (12). A solution of 6,6′-
bis(5-tert-butyl-2-hydroxybenzyl)-4,4′-di-tert-butyl-2,2′-meth-
anediyldiphenol38 (3.18 g, 5 mmol) and 8a (2.69 g, 5 mmol) in
500 mL of dioxane was heated to 60 °C under an argon
atmosphere. TiCl4 (2.31 mL, 21 mmol) was added and the
reaction refluxed for 4 days. 8a (1 g) was added again and
the reaction continued for 3 days. The solvent was removed
and the remainder adsorbed onto 50 g of silica. The product
was extracted with ethyl acetate, purified by flash chroma-
tography with CHCl3 (Rf ) 0.96), and recrystallized from
CHCl3/petroleum ether: yield 120 mg (3%); mp 340-343 °C;
1H NMR (CDCl3) δ 10.64 (br, 2H), 10.52 (br, 4H), 7.48 (d, J )
7.5 Hz, 4H), 7.47 (t, J ) 7.5 Hz, 6H), 7.36 (2H), 7.28 (t, J )
7.3 Hz, 2H), 7.16 (8H), 4,1 (br, 12H), 1.259 (18H), 1.255 (18H);
MS(FD), m/z 1012.8 (M+, calcd 1013.3).
Dou ble Ca lixa r en e 9d a n d Tr ip le Ca lixa r en e 10b.
TiCl4 (4 g, 21 mmol) was added to a solution of 3f (2 g, 4.7
mmol) and 8b (3.84 g, 8 mmol) in 500 mL of dioxane at 70 °C
and the mixture refluxed for 7 days under an argon atmo-
sphere. After 2 days 8b (1 g) was added again and after an
additional 3 days another portion of 0.5 g was added. The
solvent was removed, and the residue was taken up in 200
mL of ethyl acetate and adsorbed on 50 g of silica as described
above. Extraction with ethyl acetate (Soxhlet) gave a black
oil which was purified first by flash chromatography with 4:1
CHCl3/acetone followed by flash chromatography of the crude
fractions using 27:1 CHCl3/acetone to give the pure products.
9d : 0.227 g (8.2%), Rf ) 0.47, mp 347-349 °C. 10b: 0.504 g
(10%), Rf ) 0.93, mp >470 °C. 9d : 1H NMR (CDCl3) δ 10.26
(4H), 7.26 (2H), 7.09 (d, J ) 2.3 Hz, 1H), 7.07 (d, J ) 2.3 Hz,
1H), 6.96 (d, J ) 1.9 Hz, 1H), 6.95 (d, J ) 2.0 Hz, 1H), 6.93 (d,
J ) 2.0 Hz, 1H), 6.91 (d, J ) 1.9 Hz, 2H), 6.88 (d, J ) 2.0 Hz,
1H), 6.85 (d, J ) 1.2 Hz, 2H), 6.80 (d, J ) 8.5 Hz, 1H), 6.78 (d,
J ) 8.3 Hz, 1H), 6.28 (dd, J ) 8.4 Hz, J ) 1.5 Hz, 2H), 4.24 (d,
J ) 13.5 Hz, 1H), 4.22 (d, J ) 13.9 Hz, 1H), 4.21 (d, J ) 12.5
Hz, 1H), 4.14 (d, J ) 14.0 Hz, 1H), 4.07 (d, J ) 13.8 Hz, 1H),
3.82 (d, J ) 16.1 Hz, 1H), 3.81 (2H), 3.74 (d, J ) 16.6 Hz, 1H),
3.48 (d, J ) 13.9 Hz, 1H), 3.47 (d, J ) 13.8 Hz, 1H), 3.47 (d,
J ) 13.8 Hz, 1H), 3.44 (d, J ) 13.5 Hz, 1H), 3.15 (d, J ) 13.9
Hz, 1H), 2.14 (3H), 1.25 (9H); MS(FD), m/z 718.5 (M+, calcd
718.8). Anal. Calcd for C48H46O6: C, 80.20; H, 6.45. Found:
C, 74.92; H, 7.39.
10b: 1H NMR (CDCl3) δ 10.45 (8H), 7.12-7.09 (m, 4H), 6.91
(d, J ) 1.9 Hz, 2H), 6.88 (d, J ) 1.8 Hz, 2H), 6.86-6.84 (m,
4H), 6.61 (d, J ) 1.8 Hz, 1H), 6.60 (d, J ) 1.8 Hz, 1H), 6.55 (d,
J ) 1.8 Hz, 1H), 6.54 (d, J ) 1.7 Hz, 1H), 4.27 (d, J ) 13.8 Hz,
2H), 4.25 (d, J ) 13.4 Hz, 1H), 4.24 (d, J ) 13.8 Hz, 1H), 4.23
(d, J ) 13.9 Hz, 1H), 4.21 (d, J ) 13.4 Hz, 1H), 4.07 (d, J )
13.8 Hz, 2H), 3.78 (d, J ) 13.9 Hz, 2H), 3.77 (1H), 3.74 (1H),
3.50 (d, J ) 14.0 Hz, 1H), 3.49 (d, J ) 14.0 Hz, 3H), 3.45 (d,
J ) 14.0 Hz, 1H), 3.44 (d, J ) 14.0 Hz, 1H), 3.27 (d, J ) 13.9
Hz, 2H), 2.13 (3H) 2.12 (3H), 1.244 (9H), 1.238 (9H); 1H NMR
(pyridine-d5) δ 8.55 (8H), 7.46 (2H), 7.45 (2H), 7.15 (2H), 7.11
(2H), 7.00 (1H), 6.87 (1H), 6.70 (1H), 6.60 (1H), 6.49 (1H) 6.40
(1H), 6.08 (1H), 5.93 (1H), 6.43 (d, J ) 16.6 Hz, 2H), 4.48 (d,
J ) 16.6 Hz, 4H), 4.26 (d, J ) 13.8 Hz, 2H), 3.76 (d, J ) 13.3
Hz, 2H), 3.70 (d, J ) 13 Hz, 2H), 3.61 (2H), 3.51 (d, J ) 14.2
Hz, 2H), 3.48 (d, J ) 13.3 Hz, 2H), 3.07 (d, J ) 13.5 Hz, 1H),
3.04 (d, J ) 13.4 Hz, 1H), 1.91 (3H) 1.79 (3H), 1.31 (9H), 1.20
(9H); MS(FD), m/z 1013.2 (M+, calcd 1013.2). Anal. Calcd for
C68H68O8: C, 80.60; H, 6.76. Found: C, 71.10; H, 6.28.
Tr ip le Ca lixa r en e 10c. A mixture of 3f (2 g, 4.7 mmol)
and 8c (2.34 g, 4.7 mmol) in 500 mL of dioxane was heated to
50 °C, TiCl4 (4 g, 21 mmol) was added, and the mixture was
heated to reflux. The next day additional 8c (1 g, 2 mmol)
was added and the mixture refluxed for 6 days. The solvent
was removed, and the remaining oil was dissolved in 200 mL
of ethyl acetate, adsorbed onto 50 g of silica, and extracted
with ethyl acetate to give a dark red oil which was purified by
flash chromatography (27:1 CHCl3/acetone) and finally by
recrystallization from CHCl3/methanol. 10c: yield 331 mg
(6%); mp 411-414 °C; 1H NMR (CDCl3) δ 10.55 (8H), 7.11 (d,
J ) 2.4 Hz, 4H), 7.07 (d, J ) 2.6 Hz, 4H), 6.90 (d, J ) 1.8 Hz,
4H), 6.58 (d, J ) 1.9 Hz, 4H), 4.31 (d, J ) 13.6 Hz, 2H), 4.25
(d, J ) 13.8 Hz, 4H), 4.08 (d, J ) 13.8 Hz, 2H), 3.78 (4H), 3.54
(d, J ) 13.9 Hz, 2H), 3.50 (d, J ) 14.0 Hz, 4H), 3.26 (d, J )
13.9 Hz, 2H), 1.22 (36H); MS(FD), m/z 1098.4 (M+, calcd
1097.4). Anal. Calcd for C74H80O8: C, 80.99; H, 6.85.
Found: C, 73.20; H, 7.02.
Ack n ow led gm en t . This investigation was sup-
ported by the Deutsche Forschungsgemeinschaft and
the German-Israeli Foundation.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectral
data of 23 compounds (5 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.
16,24,28,36,41,42-H e xa h yd r oxy-23,29-d im e t h yl-5,11-
d ip h en ylca lix[6]a r en e (11a ). 7f (3.28 g, 7.5 mmol) and 8a
(4 g, 7.5 mmol) were dissolved in 500 mL of dioxane under
argon. At a temperature of 50 °C TiCl4 (6 g, 31.5 mmol) was
added and the mixture refluxed for 48 h. The solvent was
removed and the remainder adsorbed onto 50 g of silica as
J O9511197
(38) Zinke, A.; Kretz, R.; Leggewie, E.; Ho¨ssinger, K. Monatsh.
Chem. 1952, 83, 1213.