Partial OH → Me Replacement in the Calixarene Scaffold: Preparation, Conformation, and Stereodynamics of Tetra-terf-butyl-25,27-dihydroxy-26,28-dimethylcalix[4]arene and Its Dimethyl Ether Derivative

Article abstract of DOI:10.1021/jo9623797

The first example of the replacement of hydroxyl groups of a calixarene by methyls is described. Reaction of the bis(spirodienone) calixarene derivative 3B with MeLi afforded the bis addition product 4 which is derived, as shown by X-ray crystallography, from attack on the face of the carbonyls which is anti to the ether oxygen. The reaction of the alternant bis(spirodienone) calixarene derivative 3A with excess MeLi resulted in addition to the C=O groups, but with a concomitant cleavage of the spiro bonds. Ionic hydrogenation (CF₃COOH/Et₃SiH) of this product (5) yielded 5,11,17,23-tetra-tert-butyl-25,27-dihydroxy-26,28-dimethylcalix[4]arene (6) while ionic hydrogenation of 4 resulted in fragmentation of the macrocyclic ring. Calixarene 6 adopts a 1,3-alternate conformation both in solution and in the solid state. 6 is conformationally flexible, and an inversion barrier of 15.1 kcal mol^-1 was measured for it by DNMR. The dimethyl ether derivative of 6 (i.e., 7) exists in a partial cone (paco) conformation and undergoes two distinct dynamic processes possessing barriers of 13.3 and 18.1 kcal mol^-1. Molecular mechanics calculations predict correctly the preferred conformation of 6 and 7 and indicate that the topomerization pathways resulting in the mutual exchange of the protons within a methylene group are the following: 1,3-alt → paco(CH3) → 1,2 alt → paco(CH3)* → 1,3-alt* for 6, and paco(CH₃) → 1,3-alt → paco(OCH₃) → 1,2 alt → paco(OCH₃)* → 1,3-alt* → paco(CH₃)* for 7 with calculated barriers of 15.0 and 16.1 kcal mol^-1, respectively.

Full text of DOI:10.1021/jo9623797

J . Org. Chem. 1997, 62, 3511-3519
3511
P a r tia l OH f Me Rep la cem en t in th e Ca lixa r en e Sca ffold :
P r ep a r a tion , Con for m a tion , a n d Ster eod yn a m ics of
Tetr a -ter t-bu tyl-25,27-d ih yd r oxy-26,28-d im eth ylca lix[4]a r en e a n d
Its Dim eth yl Eth er Der iva tive
J oel M. Van Gelder,† J o¨rg Brenn,‡ Iris Thondorf,*,‡ and Silvio E. Biali*,†
Department of Organic Chemistry, The Hebrew University of J erusalem, J erusalem 91904, Israel, and
Institut fu¨r Biochemie, Fachbereich Biochemie/ Biotechnologie, Martin-Luther-Universita¨t
Halle-Wittenberg, Kurt-Mothes-Strasse 3, D-06099, Halle, Germany
Received December 19, 1996X
The first example of the replacement of hydroxyl groups of a calixarene by methyls is described.
Reaction of the bis(spirodienone) calixarene derivative 3B with MeLi afforded the bis addition
product 4 which is derived, as shown by X-ray crystallography, from attack on the face of the
carbonyls which is anti to the ether oxygen. The reaction of the alternant bis(spirodienone)
calixarene derivative 3A with excess MeLi resulted in addition to the CdO groups, but with a
concomitant cleavage of the spiro bonds. Ionic hydrogenation (CF3COOH/Et3SiH) of this product
(5) yielded 5,11,17,23-tetra-tert-butyl-25,27-dihydroxy-26,28-dimethylcalix[4]arene (6) while ionic
hydrogenation of 4 resulted in fragmentation of the macrocyclic ring. Calixarene 6 adopts a 1,3-
alternate conformation both in solution and in the solid state. 6 is conformationally flexible, and
an inversion barrier of 15.1 kcal mol-1 was measured for it by DNMR. The dimethyl ether derivative
of 6 (i.e., 7) exists in a partial cone (paco) conformation and undergoes two distinct dynamic processes
possessing barriers of 13.3 and 18.1 kcal mol-1. Molecular mechanics calculations predict correctly
the preferred conformation of 6 and 7 and indicate that the topomerization pathways resulting in
the mutual exchange of the protons within a methylene group are the following: 1,3-alt f paco-
(CH3) f 1,2-alt f paco(CH3)* f 1,3-alt* for 6, and paco(CH3) f 1,3-alt f paco(OCH3) f 1,2 alt f
paco(OCH3)* f1,3-alt* f paco(CH3)* for 7 with calculated barriers of 15.0 and 16.1 kcal mol-1
,
respectively.
In tr od u ction . The calix[n]arenes are macrocyclic
compounds which are usually obtained by base-catalyzed
condensation of p-alkylphenols and formaldehyde and are
of interest as potential ligands and molecular hosts.1 One
of the most difficult synthetic tasks in calixarene chem-
istry is to replace (rather than to derivatize) the OH
groups. There are only few synthetic methodologies
capable of replacing a phenolic hydroxyl by another
group.2 At present, only the partial and/or total replace-
ment of the OH groups of calixarenes by H,3 SH,4 and
NH2 groups5 or their formal dehydration to afford xan-
thene derivatives5d,6 have been reported. Since the
preferred conformation and conformational rigidity of the
calixarenes are mainly due to a cyclic array of intramo-
lecular hydrogen bonds (“circular hydrogen bonding”), the
replacement of OH groups should influence both the
static and dynamic stereochemistries of the resulting
systems.
Several [14] metacyclophane systems which incorporate
intraannular methyl groups (e.g., 2a -d ) have been
described in the literature.7-10 These compounds were
prepared by tetramerization of suitable precursors, and
(3) See for example: (a) Goren, Z.; Biali, S. E. J . Chem. Soc., Perkin
Trans. 1 1990, 1484. (b) Grynszpan, F.; Goren, Z.; Biali, S. E. J . Org.
Chem. 1991, 56, 532. (c) de Vains, J .-B. R.; Pellet-Rostaing, S.;
Lamartine, R. Tetrahedron Lett. 1994, 35, 8147. (d) Harada, T.; Ohseto,
F.; Shinkai, S. Tetrahedron 1994, 50, 13377. (e) Matsuda, K.; Naka-
mura, N.; Takahashi, K.; Inoue, K.; Koga, N.; Iwamura, H. J . Am.
Chem. Soc. 1995, 117, 5550. (f) For additional synthesis of dehydroxy-
lated calixarenes see: Fukazawa, Y.; Deyama, K.; Usui, S. Tetrahedron
Lett. 1992, 33, 5803. Usui, S.; Deyama, K.; Kinoshita, R.; Odagaki, Y.;
Fukazawa, Y. Tetrahedron Lett. 1993, 34, 8127.
(4) (a) Gibbs, C. G.; Gutsche, C. D. J . Am. Chem. Soc. 1993, 115,
5338. (b) Ting, Y.; Verboom, W.; Groenen, L. C.; van Loon, J . D.;
Reinhoudt, D. N. J . Chem. Soc., Chem. Commun. 1990, 1432. (c)
Delaigue, X.; Harrowfield, J . McB.; Hosseini, M. W.; de Cian, A.;
Fischer, J .; Kyritsakas, N. J . Chem. Soc., Chem. Commun. 1994, 1579.
(d) Delaigue, X.; Hosseini, M. W.; Kyritsakas, N.; de Cian, A.; Fischer,
J . J . Chem. Soc., Chem. Commun. 1995, 609. (e) Gibbs, C. G.; Sujeeth,
P. K.; Rogers, J . S.; Stanley, G. G.; Krawiec, M.; Watson, W. H.;
Gutsche, C. D. J . Org. Chem. 1995, 60, 8394.
† Hebrew University of J erusalem.
‡ Institut fu¨r Biochemie.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) For reviews on calixarenes see: (a) Gutsche, C. D. Calixarenes;
Royal Society of Chemistry: Cambridge, 1989. (b) Calixarenes:
A
(5) (a) Ohseto, F.; Murakami, H.; Araki, K.; Shinkai, S. Tetrahedron
Lett. 1992, 33, 1217. (b) Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J .
Org. Chem. 1993, 58, 1994. (c) Grynszpan, F.; Aleksiuk, O.; Biali, S.
E. J . Org. Chem. 1994, 59, 2070. (d) Aleksiuk, O.; Cohen, S.; Biali, S.
E. J . Am. Chem. Soc. 1995, 117, 9645.
(6) Diazonium chemistry allowed the preparation of halo- and
xanthenocalix[5]arenes: Van Gelder, J . M.; Aleksiuk, O.; Biali, S. E.
J . Org. Chem. 1996, 61, 8419.
(7) Pappalardo, S.; Bottino, F.; Ronsisvalle, G. Phosphorus Sulfur
1984, 19, 327.
(8) Delaigue, X.; Hosseini, M. W. Tetrahedron Lett. 1993, 34, 8111.
(9) Pappalardo, S.; Ferguson, G.; Gallagher, J . F. J . Org. Chem.
1992, 57, 7102.
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. Aldrichim. Acta 1995, 28, 1.
(2) (a) According to the “replacement of the hydroxyl group” section
of the recent Rodd’s Chemistry of Carbon Compounds (Tyman, J . H.
P. In Second Supplements to the 2nd Edition of Rodd's Chemistry of
Carbon Compounds; Sainsbury, M., Ed.; Elsevier, Amsterdam, 1996,
Volume IIIA, p 247), phenolic hydroxyl groups can be replaced using
phosgene in o-xylene. As an example, it is stated that 4-hydroxyben-
zophenone reacts under these conditions, yielding 4-(chlorocarbonyl)-
benzophenone. However, the products obtained in the patent cited
(BASF AG, DE 384443; Chem. Abstr. 1991, 114, 6031e) are not the
chlorocarbonyls but the corresponding chloroformate derivatives. (b)
For a review on hydroxyl replacement in calixarenes see: Biali, S. E.
Isr. J . Chem., in press.
(10) Scha¨tz, R.; Weber, C.; Schilling, G.; Oeser, T.; Huber-Patz, U.;
Irngartinger, H.; von der Lieth, C.-W.; Pipkorn, R. Liebigs Ann. 1995,
1401.
S0022-3263(96)02379-1 CCC: $14.00 © 1997 American Chemical Society

3512 J . Org. Chem., Vol. 62, No. 11, 1997
Van Gelder et al.
for the mesityl calixarene 2c, it has been concluded that
the compound is conformationally rigid.9 Recent MM3
calculations have predicted that calixarene 2e possessing
intraannular methyl groups should only be moderately
more rigid than the corresponding OH-substituted sys-
tems.11 In this article we describe a first example of the
replacement of phenolic hydroxyl groups of p-tert-
butylcalix[4]arene (1) by an alkyl group (methyl) and an
experimental and computational study of the conforma-
tion and rotational barriers of the resulting system and
its dimethyl ether derivative.
F igu r e 1. Crystal structure of 4.
Sch em e 1
Resu lts a n d Discu ssion
Bis(sp ir od ien on e) Ca lixa r en e Der iva tives. Mild
oxidation of 1 results in the formation of bis(spirodienone)
calixarene derivatives.12,13 Three isomeric forms are
obtained (3A, 3A′, and 3B) which can be readily sepa-
rated by chromatography and were characterized by
X-ray crystallography.12 Previous work on monospiro-
dienone calixarene derivatives has shown that their
carbonyl group may undergo nucleophilic attack by amino
nucleophiles.5b,d The reactions of the two major spirodi-
enone products (3A and 3B) with MeLi were therefore
studied as a potential route for introducing two methyl
groups into the intraannular positions of the calixarene
scaffold. The addition to the carbonyl groups results in
the formation of two new stereocenters. However, it can
be expected that the less hindered carbonyl face will be
attacked preferentially.
75.74 ppm which is ascribed to a C(sp3)-OH group. The
methylene protons display in the 1H NMR spectrum three
pairs of doublets in a 2:2:1:1:1:1 ratio, which are consis-
tent with a structure which retains the Cs symmetry of
the starting material. The isolation of a single product
indicates that the addition to the carbonyl groups pro-
ceeded with high diastereoselectivity. The compound was
crystallized from CH3CN/CH2Cl2 and its structure de-
termined by X-ray crystallography. As shown by the
crystal structure (Figure 1), 4 is derived from the nu-
cleophilic attack of the MeLi to the exo face of the
carbonyl groups (anti to the spiro oxygens, cf. Scheme
1). The diastereoselectivity of the addition to the carbo-
nyl group is similar to that deduced for the Diels-Alder
addition of benzyne to the diene moieties of 3B.12 The
hydroxyl groups of 4 are oriented in an antiperiplanar
arrangement to the methyl groups with one OH group
serving as a donor and the second as an acceptor of an
intramolecular hydrogen bond.
Reaction of 3A with 2.2 equivalents of MeLi resulted
in an intractable mixture of products. However, the
reaction of 3A with a large excess of MeLi yielded a major
product.14 It displayed two distinct OH signals (7.85 and
2.90 ppm), a pair of doublets for the methylene protons
(integrating for four protons) and three signals at 5.97,
6.04, and 6.41 ppm. The last signals were assigned to
vinylic protons on the basis of their chemical shifts, and
a 2D H-C correlation spectrum which indicated that they
Rea ction of 3A a n d 3B w ith MeLi. Reaction of 3B
with excess MeLi in THF resulted in the formation of a
single major product (4) as judged by NMR spectroscopy.
The 13C NMR displays, in addition to a signal at 92.70
ppm characteristic of the spiro C-O bond, a signal at
(11) Thondorf, I.; Brenn, J . J . Mol. Struct. (THEOCHEM), in press.
(12) Litwak, A. M.; Grynszpan, F.; Aleksiuk, O.; Cohen, S.; Biali, S.
E. J . Org. Chem. 1993, 58, 393.
(13) For a review on spirodienone calixarene derivatives see: Ale-
ksiuk, O.; Grynszpan, F.; Litwak, M. A.; Biali, S. E. New J . Chem.
1996, 20, 473.
(14) This product was not detected in the reaction mixture when
the reaction was carried out using 2.2 equiv of MeLi in THF.

Partial OH f Me Replacement in the Calixarene Scaffold
J . Org. Chem., Vol. 62, No. 11, 1997 3513
Sch em e 2
Ch a r t 1
are attached to sp2 carbons. We assign to this compound
formula 5 of either Ci or C2 symmetry. The formation of
5 can be rationalized assuming that the MeLi acts both
as a nucleophile (adding to the carbonyl groups) and as
a base (abstracting a methylene proton with the con-
comitant cleavage of the spiro C-O bonds in an elimina-
tion reaction). Calixarene 5 slowly decomposed in solu-
tion, and it was used immediately in the next step.
In the case of 6 and 7, and disregarding the different
possible orientations of the hydroxyl or methoxy groups,
two distinct paco conformations must be considered in
which either the tolyl or the ArOH/ArOMe rings are
pointing in opposite directions (i.e., one “up” and one
“down”).17 These conformations will be dubbed “paco-
(CH3)” and “paco(OH)”/“paco(OMe)”, respectively.
Solu tion Con for m a tion of 6. The 1H NMR spectrum
of 6 at room temperature displays a broad signal for the
methylene protons, in agreement with a conformationally
mobile structure. At low temperature (400 MHz, CDCl3,
220 K) 6 displays a closely spaced AB system (3.77 and
3.86 ppm) for the methylene protons. The aromatic
protons of the tolyl and phenol groups each display a
NOESY cross peak with a different methylene proton,
in agreement with the presence in solution of a 1,3-alt
conformation in which neighboring rings are pointing in
opposite directions. This is also supported by the high
field chemical shift of the methyl groups (1.31 ppm),
indicating that they are under the influence of the
shielding effect of the neighboring aryl rings, as expected
for a 1,3-alt conformation. A similar solution conforma-
tion was deduced for the related dihydroxycalixarene
11,18 although in the crystal its methanol solvate exists
in a 1,2-alt conformation.3b The OH signals of 6 resonate
at a higher field (4.04 ppm) as compared with the parent
1 (δOH 10.2 ppm), as expected, since the disruption of the
cyclic array of hydrogen bonds in 1 and the shielding
effect of the neighboring rings should result in an up-
field shift of these protons.
Ion ic Hyd r ogen a tion . In principle, both 4 and 5
might be transformed to calixarene systems incorporating
proximal or distal intraannular methyl groups by reduc-
tion of the alcoholic OH groups followed by aromatization
(Scheme 2). Indeed, ionic hydrogenation (CF3COOH/Et3-
SiH/CH2Cl2)15 of 5 afforded the dimethyldihydroxycalix-
arene 6 in 35% yield.
In contrast to 5, treatment of 4 under ionic hydrogena-
tion conditions yielded fragmentation products (8-10)
1
which were characterized by H NMR and by GC-MS.16
The major product 10 could be isolated from the reaction
mixture. These products probably result from the acid
catalyzed opening of the spiro bond, followed by migration
of the methyl groups and fragmentation. Calixarene 6
was methylated by treatment with NaH/dimethyl sulfate
yielding the dimethoxy derivative 7.
Cr ysta l Str u ctu r e of 6. Calixarene 6 was crystallized
from CH2Cl2/CH3CN and submitted to X-ray crystal-
lography. The molecule exists in the crystal in a 1,3-alt
conformation (Figure 2) in which there is no hydrogen
bond between the two distal OH groups. One of the OH
groups is nearly coplanar with the corresponding phenol
ring, the torsional angle C(20)-C(15)-O(2)-H being 12°.
1,3-Alt conformations have been found in the crystal
structures of 2c9 and 2d .10
Con for m a tion of Ca lixa r en e System s. The confor-
mation of 1 is usually discussed in terms of four basic
conformers resulting from the possible “up”-“down”
arrangements of the phenol rings: cone, partial cone
(paco), 1,2-alternate (1,2-alt), and 1,3-alternate (1,3-alt)
(Chart 1).1 The preferred conformation of 1 is the cone
which is stabilized by a circular array of hydrogen bonds.1
Rota tion a l Ba r r ier of 6. In order to achieve site
exchange of the methylene protons all rings must pass
through the ring annulus. From the coalescence tem-
(15) Carey, F. A.; Tremper, H. S. J . Org. Chem. 1971, 36, 758.
(16) For an example of an acid-catalyzed fragmentation of the
macrocyclic ring of the monospirodienone derivative of calix[5]arene,
see reference 5d.
(17) For identification purposes, the aryl rings of 6 and 7 possessing
intraannular methyl or methoxy groups will be dubbed “tolyl” and
“anisyl”, respectively.
(18) Grynszpan, F.; Biali, S. E. Tetrahedron Lett. 1991, 32, 5155.

3514 J . Org. Chem., Vol. 62, No. 11, 1997
Van Gelder et al.
F igu r e 2. Crystal structure of tetra-tert-butyl-25,27-dihy-
droxy-26,28-dimethylcalix[4]arene (6). The large thermal el-
lipsoids of the methyls of the tert-Bu groups are due to
rotational disorder of the groups.
F igu r e 3. Molecular structure of tetra-tert-butyl-25,27-
dimethoxy-26,28-dimethylcalix[4]arene (7).
Con for m a tion a n d Ster eod yn a m ics of 7. Calix-
arene 7 displays in the 1H NMR spectrum at low
temperature (220 K, CDCl3) four aromatic protons, three
t-Bu signals, two pairs of doublets for the methylene
signals, and two methyl signals (at 1.40 and 0.70 ppm)
while in the 13C NMR spectrum (220 K, CDCl3) 11
aliphatic and 15 aromatic signals are present. This is
in agreement with the presence of the paco(CH3) confor-
mation in which the two tolyl rings are pointing in
opposite directions and are bisected by a mirror plane.
The high field methyl signal is ascribed to the Me group
on the single ring pointing in the opposite direction to
the rest, since this methyl is expected to be shielded by
the two vicinal anisyl rings. Notably, although the 6 f
7 transformation does not involve the disruption of strong
intramolecular hydrogen bonds between the hydroxyl
groups, the alkylation changes the conformational prefer-
ences of the system.
The structure of a single crystal of 7 grown from CH2-
Cl2/CH3CN was determined by X-ray crystallography.
The molecule adopts also in the crystal the paco(CH3)
conformation (Figure 3) deduced from the solution data
in which the methoxy groups are oriented in an “out”
fashion. The preferred conformation of the related p-tert-
butyl-tetramethoxycalix[4]arene 12 is also the paco.22
Upon raising the temperature, pairs of aromatic sig-
nals, one pair of t-Bu signals, and the two Me signals
coalesced while in the methylene region, the two pairs
of doublets coalesced and the signals then resharpened
perature of the methylene groups (302 K), the chemical
shift difference (35 Hz) and the mutual coupling constant
(15.05 Hz) a barrier of 15.1 kcal mol-1 was calculated for
the 1,3-alt h1,3 alt* exchange in CDCl3.19 This barrier
is comparable to the cone-to-cone inversion barrier of the
parent 1 (15.7 kcal mol-1 in CDCl3)20,21 and indicates that
the two systems are of comparable flexibility. The
absence of circular hydrogen bonding in 1 by the formal
OH f Me replacement seems to be compensated by the
larger bulk of the methyl groups.
(19) Exchanges rates (kc) at the coalescence temperatures were
calculated according to: Kurland, R. J .; Rubin, M. B.; Wise, W. B. J .
Chem. Phys. 1964, 40, 2426.
(20) Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052.
(21) A complete line shape analysis of the temperature dependent
1H NMR of 1 in CDCl3 (Araki, K.; Shinkai, S.; Matsuda, T. Chem. Lett.
1989, 581) provided a ∆G298q value of 16.4 kcal mol-1, a value 0.7 kcal
mol-1 higher than the one (15.7 kcal mol-1) obtained by the coalescence
approximation used in ref 20. This is rather puzzling, since the error
of the coalescence approximation in the case of 1 (two well resolved
singlets in a 1:1 ratio coalescing into a singlet) should be at most 0.1
kcal mol-1 (Kost, D.; Carlson, E. H.; Raban, M. J . Chem. Soc., Chem.
Commun. 1971, 656). Indeed, in our hands a complete line shape
analysis of the temperature dependent 1H NMR of 1 (DNMR5-program)
afforded a ∆Gcq value identical to the one obtained by the coalescence
approximation. We believe that the reason for this discrepancy is that
apparently the first simulation was carried out assuming a peak
separation according to 1 ppm ) 60 Hz instead of 1 ppm ) 400 Hz
(needed for simulating the 1H NMR spectrum taken with a 400 MHz
instrument). Indeed, using the 1 ppm ) 60 Hz equivalence we were
able to obtain all the (incorrect) lifetimes reported by Araki et al.
(22) Dhawan, B.; Levine, J . A.; No, K. H.; Bauer, L. J .; Gutsche, C.
D. Tetrahedron 1983, 39, 409. Grootenhuis, P. D. J .; Kollman, P. A.;
Groenen, L. C.; Reinhoudt, D.; van Hummel, G. J .; Ugozzoli, F.;
Andreetti, G. D. J . Am. Chem. Soc. 1990, 112, 4165. For calculations
on the conformational preferences of 12, see: Groenen, L. C.; van Loon,
J .-D.; Verboom, W.; Harkema, S.; Casnati, A.; Ungaro, R.; Pochini, A.;
Ugozzoli, F.; Reinhoudt, D. N. J . Am. Chem. Soc. 1991, 113, 2385.
Harada, T.; Rudzinski, J . M.; Shinkai, S. J . Chem. Soc., Perkin Trans.
2 1992, 2109. Nagasaki, T.; Sisido, K.; Arimura, T.; Shinkai, S.
Tetrahedron 1992, 48, 797. Iwamoto, K.; Ikeda, A.; Araki, K.; Harada,
T.; Shinkai, S. Tetrahedron 1993, 49, 9937.

Partial OH f Me Replacement in the Calixarene Scaffold
J . Org. Chem., Vol. 62, No. 11, 1997 3515
ppm broadened and resharpened at a chemical shift
similar to the original one. A similar behavior was
observed for the methoxy signal of 7. This behavior is
characteristic of the exchange of the major conformation
(1,3-alt and paco(CH3) for 6 and 7, respectively) with a
second form that cannot be detected by NMR due to its
low population. On the basis of the temperature of
maximum broadening of the methyl signal and its
broadening (284 K and 16.4 Hz, respectively), and as-
suming that the chemical shift of the methyl group in
the second conformation is 2.1 ppm (the “normal” chemi-
cal shift for the methyl of a tolyl group), a free energy
difference of 1.6 kcal mol-1 can be estimated for the
energy gap between the 1,3-alt and the low populated
conformer of 6 and a barrier of 14.0 kcal mol-1 for the
diastereomerization process.25 In principle, two diaster-
eomeric pathways are possible for this process, either
involving the rotation of two phenol or two p-tolyl groups
through the ring annulus. In order to determine the
rotational pathways followed by NMR for 6 and 7 we
resorted to molecular mechanics calculations.
In ter con ver sion Gr a p h of 6 a n d 7. The conforma-
tions and the barriers for the conformational intercon-
versions of 6 and 7 were calculated with the MM3(92)
force field.26 The calculated relative steric energies of
conformers of 6 and 7 and of the transition states for their
possible mutual interconversion via single-ring rotations
are collected in Tables 1 and 2.
F igu r e 4. 400 MHz 1H NMR spectra of the methylene protons
of 7 (in CDCl3) at different temperatures. From bottom to top:
at 230 K, 282 K, and 310 K.
Rela tive En er gies of Con for m er s of 6 a n d 7. The
calculations predict the relative order of conformational
stabilities of 6 as 1,3-alt > paco(OH) > cone > paco(CH3)
> 1,2-alt. The calculations predict correctly that the 1,3-
alt is the minimum energy conformation, although the
paco(OH) and cone conformers are calculated to lie only
0.2 kcal mol-1 above the 1,3-alt form. The cone confor-
mation (of calculated C2 symmetry) is stabilized by
hydrogen bonding between opposite phenol rings. From
the two possible paco conformations, the paco(OH) con-
former is energetically preferred, due to repulsive van
der Waals interactions between the methyl group and
the two adjacent hydroxyl groups in the paco(CH3)
conformer.
into a pair of doublets (Figure 4). From the frequency
difference under slow exchange conditions (∆ν ) 120.1,
154.0 Hz) and the coalescence temperature of a pair of
aromatic and methylene doublets (Tc ) 282 K) a barrier
of ∆Gc ) 13.3 kcal mol-1 (CDCl3) was calculated for the
q
rotational process.23 The methylene doublets coalesced
at 384 K (in CDCl2CDCl2), yielding a barrier of 18.1 kcal
mol-1 for the dynamic process. The lower barrier process,
which exchanges the two methyl groups, most likely
involves the stepwise rotation of the tolyl groups via a
symmetric intermediate (i.e., paco(CH3) f cone f paco-
(CH3)* or paco(CH3) f 1,3-alt f paco(CH3)*. The process
mutually exchanges signals corresponding to the un-
equivalent methylene groups, and signals on the two tolyl
groups, but since the two anisyl rings are not involved
in the rotational process the two protons within a given
methylene group remain diastereotopic. The high energy
process which results in topomerization of the methylene
protons must involve the stepwise rotation of all rings
through the annulus of the macrocycle.
For 7 the calculations predict the relative order of
stabilities paco(CH3) > 1,3-alt > paco(OCH3) > cone >
1,2-alt with the 1,3-alt and paco(OCH3) lying 0.5 and 2.2
kcal mol-1 above the paco(CH3). The most stable cone
conformer adopts a C2 symmetrical arrangement with
parallel orientations of the two tolyl rings. In all the
conformations calculated, “in” orientations of the methoxy
group (i.e., pointing to the molecular cavity) are of higher
energy than the “out” arrangements.
E xch a n ge w it h Low -P op u la t ed Con for m a t ion s.
In addition, spectral changes were observed in the
temperature-dependent NMR of both 6 and 7 which are
characteristic of the exchange with a “hidden partner”.24
For example, upon raising the temperature of a CDCl3
solution of 6 at 220 K, the sharp methyl singlet at 1.31
The calculations predict correctly the different pre-
ferred conformations for 6 and 7, but seem to underes-
timate the energy gaps between conformers. In both
cases, the calculated geometries are in good agreement
with the crystal conformation, with the exception of the
Cortho-Cipso-O-H torsional angles of 6 which are pre-
(23) The exchange rates at the coalescence temperature were
calculated by the Gutowsky-Holm equation. Gutowsky, H. S.; Holm,
C. H. J . Chem. Phys. 1956, 25, 1228.
(25) The maximum broadening of a given signal (ωmax) is defined
as (ωobs - ω0) where ωobs is the measured maximal line width and ω0 is
the line width in the absence of exchange. ωmax is a function of the
chemical shift difference of a given group in the exchanging conforma-
tions (∆ν) and the mole fraction of the less stable conformer (p) p (∆ν)
) ωmax (Hz). At the temperature of maximum broadening (Tm), the
rate constant for the conversion of the more stable to the less stable
conformer is given by k ) 2πp∆ν (ref 24).
(24) Anet, F. A. L.; Basus, V. J . J . Mag. 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 extracting conforma-
tional equilibria and rotational barriers of conformational biased
calixarene systems, see: 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.
(26) MM3(92) is available from the Quantum Chemistry Program
Exchange, University of Indiana, Bloomington, IN 47405.

3516 J . Org. Chem., Vol. 62, No. 11, 1997
Van Gelder et al.
Ta ble 1. MM3-Ca lcu la ted En er gies of th e Low En er gy Con for m er s a n d Activa tion Ba r r ier s (r ela tive to th e m ost sta ble
str u ctu r e) a lon g th e In ver sion P a th w a ys of 6 (in k ca l m ol-1
)
FSEa
∆E
Ecomp
Ebend
Etors
ΣEcross
ΣEvdW
Edipol
1,3-alt
paco(OH)
cone
paco(CH3)
36.71
36.87
36.94
38.15
40.57
44.99
54.96
42.97
52.24
45.50
51.71
0.00
0.16
0.24
1.45
3.86
8.28
18.25
6.26
15.53
8.79
15.00
6.25
6.23
6.41
6.81
6.73
6.55
7.93
6.64
7.94
6.52
7.71
8.09
8.40
9.10
-34.30
-33.17
-35.01
-39.30
-39.45
-33.81
-36.00
-34.62
-36.61
-32.57
-36.98
-1.19
-1.24
-1.24
-1.17
-0.99
-0.96
-1.06
-1.16
-1.08
-0.99
-0.96
39.10
37.84
37.59
41.90
43.59
41.67
51.14
42.13
50.43
41.98
50.01
18.76
18.82
20.09
19.95
19.20
19.78
20.03
19.82
19.35
19.74
19.11
9.98
1,2-alt
11.49
11.75
12.93
10.15
12.21
10.81
12.82
cone h paco(OH)
cone h paco(CH3)
paco(CH3) h 1,2-alt
paco(OH) h 1,2-alt
paco(OH) h 1,3-alt
paco(CH3) h 1,3-alt
a
FSE ) final steric energy; Ecomp ) bond compression energy, Ebend ) angle bending energy, ΣEcross ) sum of the energies from the
bend-bend, stretch-bend, and torsion-stretch cross terms, Etors ) torsional energy, ΣEvdw ) sum of the van der Waals energies, Edipol
) dipole-dipole interaction energy.
Ta ble 2. MM3-Ca lcu la ted En er gies of th e Low En er gy Con for m er s a n d Activa tion Ba r r ier s (r ela tive to th e m ost sta ble
str u ctu r e) a lon g th e In ver sion P a th w a ys of 7 (in k ca l m ol-1
)
FSEa
∆E
Ecomp
Ebend
Etors
ΣEcross
ΣEvdW
Edipol
paco(CH3)
1,3-alt
paco(OCH3)
cone
42.47
43.02
44.70
46.00
46.14
61.86
59.09
63.26
53.92
58.59
57.26
0.00
0.54
2.23
3.53
3.67
19.38
16.62
20.78
11.45
16.12
14.79
6.40
6.26
6.43
6.51
6.30
8.08
7.65
8.25
7.32
8.49
7.41
9.67
9.44
-34.03
-34.41
-34.11
-33.24
-33.02
-22.95
-30.79
-25.15
-30.70
-30.24
-32.17
-1.29
-1.20
-1.23
-1.26
-1.11
-1.33
-0.96
-1.18
-1.25
-1.19
-0.91
39.83
39.13
39.97
40.22
40.85
47.59
48.31
49.16
46.93
49.71
46.87
21.90
23.79
23.55
23.46
22.15
20.17
20.04
20.40
20.64
19.88
21.33
10.09
10.31
10.99
10.29
14.85
11.78
10.99
11.95
14.73
1,2-alt
coneh paco(OCH3)
coneh paco(CH3)
paco(CH3) h 1,2-alt
paco(OCH3) h 1,2-alt
paco(OCH3) h 1,3-alt
paco(CH3) h 1,3-alt
a
For footnotes see Table 1.
dicted to be 90° and in a “in” fashion while in the crystal
these angles are 12° and 46°.
barrier of 14.8 kcal mol-1 (experimental value: 13.3 kcal
mol-1). According to the calculations, the preferred
pathway for mutual exchange of the protons within a
methylene group is paco(CH3) f 1,3-alt f paco(OCH3)
f 1,2-alt f paco(OCH3)* f 1,3-alt* f paco(CH3)* with
a calculated barrier of 16.1 kcal mol-1 (experimental
value: 18.1 kcal mol-1). The calculations seem to un-
derestimate the rotational barrier of the anisyl groups,
although they indicate that the rotations of the anisyl
rings are energetically costlier than the rotation of tolyl
rings.
The MM3 calculations indicate that in the case of 6,
even at the lowest temperature examined by NMR, the
system should exist as a rapid equilibrium of the 1,3-
alt, paco(OH), and cone conformers, the NMR observed
being the weighted average of the spectra of the three
conformers. The exchange of the 1,3-alt form with a
“hidden partner” must correspond to a 1,3-alt h paco-
(CH3) interconversion.28 For the case of 7 we ascribe the
observed spectral changes to a paco(CH3) h cone ex-
change.
Rota tion a l P a th w a ys. The interconversion graphs
of the conformers of 6 and 7 via single aryl rotations and
the corresponding calculated barriers are displayed in
Figures 5 and 6. Additionally, for 7 the rotations of the
methoxy groups were also considered. The geometries
of the transition states of 6 are very similar to those
calculated for other calixarene systems. Thus, the struc-
tures of the transition states of the rotations of the
phenolic and tolyl rings of 6 resemble those of 1 and 2e11
(cf. Figure 7), while the transition states for the rotation
of the tolyl rings and anisyl groups of 7 resemble those
calculated for 2e11 and 12.27 In all cases the methoxy
group of the rotating ring adopts an “in” orientation.
Remarkably, the calculated barriers for the rotation of
the methoxy groups are only slightly lower than the ones
calculated for the ring rotations. Interestingly, as shown
by visual inspection of the structures, the rotation of the
methoxy group is accompanied by a simultaneous motion
of the calixarene scaffold.
Con clu sion s. The replacement of two opposite hy-
droxyl groups of 1 by methyl groups can be achieved via
As shown in Figure 5, the rotation of the phenol rings
of 6 has a substantially lower barrier than the rotation
of the tolyl rings. The rotational pathway of lowest
energy (threshold mechanism), which results in the
mutual exchange of the methylene protons of 6, involves
the 1,3-alt f paco(CH3) f 1,2-alt f paco (CH3)* f 1,3-
alt* with a calculated barrier of 15.0 kcal mol-1 in
excellent agreement with the experimentally determined
barrier (15.1 kcal mol-1). For 7 the lowest energy
pathway resulting in topomerization of the tolyl rings is
paco(CH3) f 1,3-alt f paco(CH3)* with a calculated
(28) There is a discrepancy of ca. 1 kcal mol-1 between the barriers
extracted from the broadening of the Me signal (exchange with a
hidden partner) and the topomerization of the methylene protons
(coalescence). This is due to the uncertainty in the chemical shift of
the signal of the “hidden” conformer. Moreover, in order to properly
compare the rate constants (and barriers) extracted from the two
methods a statistical correction factor must be introduced since the
first method measures directly the 1,3-alt f paco interconversion,
while the second method only follows the molecules in which the two
diastereotopic methylene had exchanged magnetic sites. Since the ring
inversion process involves a symmetrical intermediate (1,2-alt) which
may revert either to “reactant” or “product”, half of the molecules which
reach that conformation revert to the original 1,3-alt form without
topomerization of the methylene protons. The actual rate of the 1,3-
alt f paco interconversion (the rate-determining step in the process)
is therefore twice the rate derived by the coalescence approximation.
(27) Fischer, S.; Grootenhuis, P. D. J .; Groenen, L. C.; van Hoorn,
W. P.; van Veggel, F. C. J . M.; Reinhoudt, D. N.; Karplus, M. J . Am.
Chem. Soc. 1995, 117, 1611.

Partial OH f Me Replacement in the Calixarene Scaffold
J . Org. Chem., Vol. 62, No. 11, 1997 3517
F igu r e 6. Interconversion graph by single ring rotations of
the possible conformers of 7. Calculated steric energies are
relative to the lowest energy conformation (paco(CH3)). The
energies on the curved arrows represent the calculated barriers
for the rotation of the methoxy groups relative to the paco-
(CH3) conformation.
F igu r e 5. Interconversion graph by single ring rotations of
the possible conformers of 6. Calculated steric energies are
relative to the lowest energy conformation (1,3-alt). The
peripheral black and white squares represent rings pointing
“up” or “down”, respectively.
the bis(spirodienone) calixarene derivatives. The dihy-
droxydimethylcalixarene 6 adopts a 1,3-alt conformation
while its dimethyl ether derivative prefers the paco(CH3)
form. Both systems are conformationally flexible on the
laboratory timescale.
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.29
Exp er im en ta l Section
Crystallographic data: 4: C46H60O4‚0.5CH3CN, space group
P1h, a ) 14.424(3) Å, b ) 16.802(4) Å, c ) 9.945(4) Å, R )
100.41(3)°, â ) 91.77(3)°; γ ) 112.38(2)°, V ) 2179(1) Å3, z )
2, Fcalc ) 1.07 g cm-3, µ(Cu KR) ) 4.82 cm-1, no. of unique
reflections ) 6370, no. of reflections with I g 3σI ) 4986, R )
0.085, Rw ) 0.120. 6: C46H60O2, space group P21/n, a ) 18.593-
(3) Å, b ) 15.778(5) Å, c ) 14.325(3) Å, â ) 102.21(2)°; V )
Molecu la r Mech a n ics Ca lcu la tion s. In order to locate
the conformational minima on the energy hypersurface, a
stochastic search (MM3) was performed for each of the five
main conformations of each compound. Starting from the cone
conformation of 6 and 7, the pathways of the conformational
interconversion were simulated using the coordinate driver
method.11 For this purpose three methylene carbon atoms
were kept fixed in their z-coordinates, and ring inversions were
performed by modification of the z-coordinate of the aromatic
para-carbon atom in steps of 0.1 Å. The energy minima and
maxima were subsequently minimized with the options 6 and
7 of the MM3 force field, respectively, without any constraints.
This was followed by full matrix Newton-Raphson minimiza-
tion of the energy minima and transition states, which were
identified by means of their eigenvalues.
The rotations of the methoxy groups were calculated by
means of the dihedral driver option of the MM3 program in
5° steps. The rotational barriers were taken directly from the
block-diagonal optimization method without location of transi-
tion states and full-matrix Newton-Raphson optimization.
A comparison of the energy minimum structures obtained
by the stochastic search and by the coordinate driver method
indicated that all low energy conformations were found by both
methods, the energies differing by a maximum of 0.2 kcal mol-1
and the geometries being virtually identical.
4108(2) Å3, z ) 4, Fcalc ) 1.04 g cm-3, µ(Cu KR) ) 4.38 cm-1
,
no. of unique reflections ) 6283, no. of reflections with I g 3σI
) 4298, R ) 0.074, Rw ) 0.105. 7: C48H64O2, space group P21/
c, a ) 14.292(2) Å, b ) 15.225(2) Å, c ) 20.454(2) Å, â ) 104.11-
(1)°; V ) 4316(1) Å3, z ) 4, Fcalc ) 1.04 g cm-3, µ(Cu KR) ) 4.33
cm-1, no. of unique reflections ) 6682, no. of reflections with
I g 3σI ) 4177, R ) 0.073, Rw ) 0.099.
MeLi (1.4 M in ether) was purchased from Aldrich. All
reactions with this reagent were performed under nitrogen.
P r ep a r a tion of 4. To a solution of 1.65 g (2.56 mmol) of
3B in 300 mL of dry THF at 0 °C was added, with stirring, 13
mL of MeLi (1.4 M in ether, 18.2 mmol). The solution was
stirred for 30 min at rt and quenched with 5 mL of H2O. The
solution was extracted with CH2Cl2, the phases were sepa-
(29) 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.

3518 J . Org. Chem., Vol. 62, No. 11, 1997
Van Gelder et al.
F igu r e 7. Calculated geometries of the transition states for the 1,3-alt h paco and paco h1,2-alt conformational interconversions
of 6. Left: side view. Right: top view.
rated, and the organic phase was dried and evaporated. The
product was recrystallized from CH2Cl2/CH3CN, yielding 725
mg (42%) of 3B. Mp: 220-222 °C dec. 1H NMR (400.133
MHz, CDCl3, rt) δ 1.05 (s, 18H, t-Bu), 1.24 (s, 18H, t-Bu), 1.29
(s, 6H, Me), 2.83 (d, J ) 13.1 Hz, 1H, CH2), 2.86 (d, J ) 15.6
Hz, 2H, CH2), 3.23 (d, J ) 13.1 Hz, 1H, CH2), 3.40 (d, J )
13.1 Hz, 1H, CH2), 3.59 (d, J ) 15.5 Hz, 2H, CH2), 4.06 (d, J
) 13.1 Hz, 1H, CH2), 4.97 (s, 2H, OH), 5.47 (d, J ) 1.8 Hz,
2H, CdCH), 5.98 (s, 2H, CdCH), 6.95 (s, 2H, ArH), 7.11 (s,
2H, ArH). 13C NMR (100.62 MHz, CDCl3, rt) δ 22.01, 28.39,
30.22, 31.73, 33.98, 34.19, 35.92, 75.74 (CO), 92.70 (spiro CO),
119.59, 120.56, 120.95, 121.99, 125.28, 126.81, 143.62, 147.64,
148.11, 154.34. CI MS: m/z 677.0 (MH+)
Rea ction of 4 w ith TF A/Et3SiH. To a solution of 886 mg
(1.31 mmol) of 4 in 30 mL of CH2Cl2 at 0 °C was added, with
stirring, 6 mL of trifluoroacetic acid (TFA). The color of the
solution turned red. Et3SiH (4 mL) was added (discharging
the color of the solution), and the mixture was stirred for 3 h
at rt. The solvent was evaporated and the residue analyzed
by NMR, which indicated the presence of two main products
identified as 9 and 10. GC MS of the crude product indicated
also the presence of 2,6-Me2-4-tert-butylphenol 8 (m/z 178).
Trituration of the crude with CH3CN followed by filtration,
yielded 135 mg of pure 10 (21%). Mp: 194-196 °C. 1H NMR
(400.133 MHz, CDCl3, rt) δ 1.22 (s, 9H, t-Bu), 1.23 (s, 18H,
t-Bu), 2.20 (s, 6H, Me), 3.85 (s, 4H, CH2), 6.94 (d, 2H, ArH),
7.13 (br s, 4H, ArH), 8.33 (s, 2H, OH (220 K)), 9.44 (s, 1H, OH
(220 K)). 13C NMR (100.62 MHz, CDCl3, rt) δ 16.45, 31.45,
31.52, 31.87, 33.93, 33.98, 123.31, 125.18, 125.83, 126.19,
126.25, 127.19, 143.60, 144.24, 147.22, 148.59. CI MS: m/z
502.0 (MH+). Anal. Calcd for C34H46O3: C, 81.23; H, 9.22.
Found: C, 81.80; H, 9.36.
of MeLi (1.4 M in ether, 16.8 mmol). The solution was stirred
for 30 min at rt and then quenched by adding 5 mL of H2O.
After evaporation of the solvent, the residue was extracted
with ether, dried, and evaporated. The residue was dissolved
in MeOH, and the solid which precipitated was filtered yielding
225 mg (18%) of 5. The compound decomposes in solution. 1H
NMR (400.133 MHz, CDCl3, rt) δ 1.13 (s, 18H, t-Bu), 1.26 (s,
18H, t-Bu), 1.38 (s, 6H, Me), 2.90 (s, 2H, OH), 3.10 (d, J )
13.6 Hz, 2H, CH2), 3.53 (d, J ) 13.6 Hz, 2H, CH2), 5.97 (s, 2H,
CH), 6.04 (s, 2H, CH), 6.41 (s, 2H, CH), 6.95 (s, 2H, ArH), 7.06
(s, 2H, ArH), 7.85 (s, 1H, OH). 13C NMR (100.62 MHz, CDCl3,
rt) δ 28.83, 31.28, 31.46, 32.70, 33.93, 34.10, 120.76, 121.38,
123.49, 125.95, 126.47, 128.19, 128.94, 143.30, 143.87, 145.21,
145.41, 148.90, 149.12.
P r ep a r a t ion of p -ter t-Bu t yl-25,27-d ih yd r oxy-26,28-
d im eth ylca lix[4]a r en e (6). To a solution of 200 mg (0.30
mmol) of 5 in 30 mL of CH2Cl2 was added, with stirring, 2 mL
of TFA. The solution turned red, 3 mL of Et3SiH was added,
and the mixture was stirred for 3 h at rt. The solvent was
evaporated, and the residue was triturated with CH3CN and
filtered. Recrystallization from CH2Cl2/CH3CN yielded 68 mg
of 6 (35%). Mp: 267-269 °C dec. 1H NMR (400.133 MHz,
CDCl3, rt) δ 1.23 (s, 36H, t-Bu), 1.39 (br s, 6H, Me), 3.80 (s,
4H, CH2), 3.84 (s, 4H, CH2), 4.04 (s, 2H, OH), 7.00 (s, 4H, ArH),
7.17 (s, 4H, ArH). 13C NMR (100.62 MHz, CDCl3, rt) δ 16.80,
29.71, 31.34, 31.44, 33.77, 34.10, 40.69, 126.10, 126.95, 127.22,
133.59, 139.61, 141.52, 148.16, 151.79. CI MS: m/z 645.1
(MH+). Anal. Calcd for C46H60O2: C, 85.66; H, 9.38. Found:
C, 85.38; H, 9.30.
Syn th esis of 6 w ith ou t Isola tion of th e In ter m ed ia te
5. To a solution of 1.2 g (1.86 mmol) of 3A in 300 mL of dry
THF at 0 °C was added, with stirring, 20 mL of MeLi (1.4 M
in ether, 28 mmol). The solution was stirred for 30 min at rt,
and the reaction was quenched with 5 mL of water. After
P r ep a r a tion of 5. To a solution of 1.2 g (1.86 mmol) of 3A
in 400 mL of dry THF at 0 °C was added, with stirring, 12 mL

Partial OH f Me Replacement in the Calixarene Scaffold
J . Org. Chem., Vol. 62, No. 11, 1997 3519
evaporating the solvent, the residue was extracted with ether,
dried, and evaporated. The crude was dissolved in 50 mL of
CH2Cl2, 6 mL of TFA and 4 mL of Et3SiH were added to the
red solution, and the mixture was stirred for 3 h at rt. The
solvent was evaporated, and the residue was triturated with
CH3CN, yielding 157 mg of 6 (13%).
ArH), 7.08 (s, 2H, ArH), 7.27 (s, 2H, ArH). 13C NMR (100.62
MHz, CDCl3, 220 K) δ 12.78, 16.19, 30.90, 31.17, 31.37, 33.20,
33.53, 33.74, 33.96, 39.37, 61.13, 123.75, 125.14, 125.49,
126.20, 127.11, 131.25, 131.57, 132.02, 134.12, 137.57, 141.34,
143.86, 144.35, 144.66, 153.29. CI MS: m/z 673.2 (MH+).
5,11,17,23-Te t r a -t er t -b u t yl-25,27-d im e t h oxy-26,28-
d im eth ylca lix[4]a r en e (7). To a solution of 6 (75 mg, 0.115
mmol) in 15 mL of dry THF was added NaH (24 mg, 1 mmol).
The mixture was heated to reflux, and a solution of dimethyl
sulfate (0.1 mL, 1 mmol) in 2 mL of dry THF was added and
the reflux continued for 45 min. The excess of NaH was
neutralized with EtOH, CH2Cl2 was added, and the solution
was washed with water. The organic phase was evaporated,
and the product was recrystallized from CH2Cl2/CH3CN,
yielding 60 mg (77%) of 7, mp 282-284 °C.
Ack n ow led gm en t. We thank Dr. Volker Bo¨hmer for
helpful discussions, Dr. Shmuel Cohen for the crystal
structure determinations, and Dr. Flavio Grynszpan for
some preliminary experiments. This research was
supported by a grant from the German-Israeli Founda-
tion (GIF) for Scientific Research and Development.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4 and 7 (2 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.
1H NMR (400.133 MHz, CDCl3, 220 K) 0.77 (s, 3H, Me), 0.95
(s, 18H, t-Bu), 1.31 (s, 9H, t-Bu), 1.36 (s, 9H, t-Bu), 1.40 (s,
3H, Me), 3.25 (d, J ) 13.0 Hz, 2H, CH2), 3.64 (d, J ) 13.9 Hz,
2H, CH2), 3.68 (s, 6H, OMe), 3.89 (d, J ) 14.3 Hz, 2H, CH2),
3.96 (d, J ) 13.6 Hz, 2H, CH2), 6.55 (s, 2H, ArH), 6.86 (s, 2H,
J O9623797