Wide rim urethanes derived from calix[4]arenes: Synthesis and self-assembly

Article abstract of DOI:10.1021/jo0524369

Calix[4]arenes 4, substituted at the wide rim by four N-tolyl-urethane groups, were synthesized, as well as derivatives 10a,b bearing two or three tolyl-urea groups beside of one or two urethane group(s). In contrast to tetra-tolyl urea 11, the urethane d

Full text of DOI:10.1021/jo0524369

Wide Rim Urethanes Derived from Calix[4]arenes: Synthesis and
Self-Assembly
Yudong Cao, Myroslav O. Vysotsky, and Volker Bo¨hmer*
Fachbereich Chemie, Pharmazie und Geowissenschaften, Abteilung Lehramt Chemie,
Johannes Gutenberg-UniVersita¨t Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
Vboehmer@mail.uni-mainz.de
ReceiVed NoVember 25, 2005
Calix[4]arenes 4, substituted at the wide rim by four N-tolyl-urethane groups, were synthesized, as well
as derivatives 10a,b bearing two or three tolyl-urea groups beside of one or two urethane group(s). In
contrast to tetra-tolyl urea 11, the urethane derivatives do not form hydrogen-bonded, dimeric capsules
in CDCl3 or benzene-d6, but the dimerization can be induced for the triurea 10b by tetraethylammonium
cations as guests. The quantitative formation of heterodimers is observed for all urethanes 4 and 10a,b
in benzene-d6 in mixtures with a “tetra-loop” tetraurea 14, while “bisloop” tetraureas 13 require di- or
triurea derivatives 10a,b for a clean heterodimerization.
Introduction
the nitrogen attached to the urea residue R (2.84-2.85 Å).5
Further X-ray structures confirmed this difference and showed,
in agreement with MD simulations, that some of these weaker
hydrogen bonds may not be present if a large cation (e.g.,
tetraethylammonium) is included as a guest.6
These results led to the idea of studying the association of
tetraurethanes in which the NHâ group is replaced by an
oxygen.7 Even if these tetraurethanes would not form ho-
modimers as a result of the lower number of hydrogen bonds,
heterodimers with tetraureas might be possible. This would add
an interesting novel selectivity to the self-organization of such
systems.
Calix[4]arenes bearing four urea functions at their wide rim
form dimeric capsules in aprotic, apolar solvents,1 which are
held together by a seam of hydrogen bonds between the
interdigitating urea functions of the two calixarenes. The
structure of these S8-symmetrical dimers (Figure 1) was first
deduced from their 1H NMR spectra,2 which typically show two
m-coupled doublets for the aromatic protons of the calix[4]arene
skeleton (∆δ ) ∼1.2-1.7 ppm) and two singlets for the NH
protons,3 which are usually found around 9.3 and 7.0 ppm for
aryl urea residues (R ) -Ar-X) in CDCl3.
This difference in their chemical shift suggests already two
-NH‚‚‚OdC hydrogen bonds of different strengths,3 although
the values for the aromatic protons show that shielding and
deshielding effects may have a strong influence, which is
difficult to predict. The first X-ray structure of a dimeric capsule4
revealed, however, that the N‚‚‚O distance for the calixarene
bound nitrogen is distinctly longer (3.10-3.16 Å) than that of
Results and Discussion
Syntheses. Tetraurethanes 4 were obtained in three steps from
the well-known tetraether, 1, unsubstituted in the para position
(Scheme 1). Tetra formylation by hexamethylenetetramine8 and
(5) One of the referees of ref 4 even suggested that there is no hydrogen
bond because the NH group must be in this distance as a result of the overall
geometry of the capsule.
(6) Thondorf, I.; Broda, F.; Rissanen, K.; Vysotsky, M. O.; Bo¨hmer, V.
J. Chem. Soc., Perkin Trans. 2 2002, 1796-1800.
(7) p-Nitrophenyl urethanes of calix[4]arenes, in which the other NH
group is replaced by O, were prepared and used for the synthesis of
tetraureas. They do not show self-association to dimers.
(1) Rebek, J., Jr. Chem. Commun. 2000, 637-643.
(2) Shimizu, K.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
12403-12407. Hamann, B. C.; Shimizu, K.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1326-1329.
(3) Vysotsky, M. O.; Bo¨hmer, V. Org. Lett. 2000, 2, 3571-3574.
(4) Mogck, O.; Paulus, E. F.; Bo¨hmer, V.; Thondorf, I.; Vogt, W. Chem.
Commun. 1996, 2533-2534.
10.1021/jo0524369 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/04/2006
J. Org. Chem. 2006, 71, 3429-3434
3429

Cao et al.
FIGURE 1. Molecular shape of a dimeric capsule (MD simulations are in agreement with X-ray structures) and schematic representation of the
hydrogen-bonded belt. As indicated by shorter distances, NHR‚‚‚OdC hydrogen bonds are stronger than NHâ‚‚‚OdC hydrogen bonds.
SCHEME 1. Synthesis of Calix[4]arenes Substituted at the Wide Rim by Urethane Functions, Alone or in Combination with
Urea Functions
Baeyer-Villiger oxidation9 with m-chloroperbenzoic acid in
analogy to literature procedures furnished the calix[4]arenes 3
in about 40-50% overall yield. They were reacted in the last
step with p-tolyl isocyanate in acetone in the presence of
potassium carbonate (35-40% of 4, not optimized).
In addition to 4, calix[4]arenes were synthesized, in which
urethane functions are combined with urea functions at the wide
rim. In these cases, the reaction sequence (Scheme 1) starts with
the (unspecific) partial nitration of the tetraether 1,10 followed
by formylation and oxidation, as described above. Hydrogena-
tion of the nitro groups with the use of Pd/C as catalyst leads
to compounds 8 bearing at their wide rim a combination of two11
or three amino groups with one or two11 hydroxy group(s). A
reaction with an appropriate isocyanate finally should give the
mixed urea/urethanes 10. As a result of the different reactivities
of amino and hydroxy groups, it was advantageous to do this
last acylation in two steps. First the amino groups were
converted to urea groups in CHCl3 at room temperature. After
purification of the intermediate ureas 9, the remaining hydroxy
groups were acylated in acetone in the presence of sodium/
potassium carbonate. It is evident that by this sequence (in
principle) easily two different carbamoyl residues could be
introduced.12
(8) Komori, T.; Shinkai, S. Chem. Lett. 1992, 901-904.
(9) Mascal, M.; Warmuth, R.; Naven, R. T.; Edwards, R. A.; Hursthouse,
M. B.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 1999, 1, 3435-3441.
Arduini, A.; Mirone, L.; Paganuzzi, D.; Pinalli, A.; Pochini, A.; Secchi,
A.; Ungaro, R. Tetrahedron 1996, 52, 6011-6018. Mascal, M.; Naven, R.
T.; Warmuth, R. Tetrahedron Lett. 1995, 36, 9361-9364.
All compounds described in Scheme 1 were unambiguously
characterized by NMR- and mass spectra. Only some typical
features will be discussed below.
(10) Brody, M. S.; Schalley, C. A.; Rudkevich, D. M.; Rebek, J., Jr.
Angew. Chem., Int. Ed. 1999, 38, 1640-1644. Kenis, P. J. A.; Noordman,
O. F. J.; Scho¨nherr, H.; Kerver, E. G.; Snellink-Ru¨el, B. H. M.; van Hummel,
G. J.; Harkema S.; van der Vorst, C. P. J. M.; Hare, J.; Picken, S. J.;
Engbersen, J. F. J.; van Hulst, N. F.; Vancso, G. J.; Reinhoudt, D. N.
Chem.sEur. J. 1998, 4, 1225-1234. Budka, J.; Lhota´k, P.; Michlova´, V.;
Stibor, I. Tetrahedron Lett. 2001, 42, 1583-1586.
(11) Only the 1,3-isomer was synthesized and studied here, but the 1,2-
isomer could be prepared analogously, as well as a mononitro-tri-hydroxy
derivative.
(12) Alternatively, it should be possible to acylate the hydroxy groups
before the nitro groups are hydrogenated.
3430 J. Org. Chem., Vol. 71, No. 9, 2006

Urethanes DeriVed from Calix[4]arenes
CHART 1
The formylation, for instance, is easily controlled by the
appearance of a signal at 9.55 ppm. Aromatic protons appear
as one singlet (8 H) for the C4V-symmetrical compounds 2-4,
as two singlets (4 H each) for the C2V-symmetrical compounds
6a-10a, while two singlets (2 H each) and two m-coupled
doublets (2 H each) should be seen for the Cs-symmetrical
compounds 6b-10b, a pattern which is characteristic even if
in routine spectra the m-coupling often is not resolved. The
symmetry is also reflected by the pattern of the methylene
protons, which appear as a pair of doublets with geminal
coupling for C4V- and C2V-symmetrical compounds (1-4 and
5a-10a), while two pairs of doublets are seen for the Cs-
symmetrical compounds (5b-10b).
For all compounds, the molecular peak was found in the FD
or ESI mass spectrum, and because these compounds are
prepared stepwise, according to the indicated synthetic strategy,
this information cannot be improved by high-resolution mass
spectrometry.
Dimerization Studies. While the 1H NMR spectra of 4, 10a,
and 10b in DMSO-d6 are sharp and in total agreement with the
expected structure of a “monomeric” calix[4]arene with C4V,
C2V, and Cs symmetry, respectively, broad unresolved spectra
are observed in CDCl3 or benzene-d6. This can be explained
by interactions via inter- and intramolecular hydrogen bonds,
but there is no indication for the formation of a dimeric capsule
or of any other well-defined species.
Attempts to induce the dimerization by adding a favorable
guest such as 1,4-difluorobenzene were also unsuccessful; for
tetraethylammonium cations, see below. Thus, we have to
conclude that not only do tetraurethanes 4 not form homodimers,
but that the usual dimerization is also impossible when just a
single urea group is replaced by an analogous urethane like in
10b. Obviously the “formalistic” picture that only two of the
eight weaker NH‚‚‚OdC hydrogen bonds are lacking in such a
dimer 10b‚10b in comparison with the dimer 11‚11 of the
corresponding tetraurea 11 is too simple. Potential explanations
(small differences in bond lengths and bond angles between
sNHs and sOs, lower basicity of the carbonyl group in
urethanes or repulsion between ArsOsC and OdC oxygens)
necessarily must be tentative.
1
FIGURE 2. Section of the H NMR spectra of a mixture of 10b and
13a (ratio 1:1.1) in (a) benzene-d6 and (b) CDCl3. Low field signals
for 16 protons (peaks marked by an asterisk have the double intensity)
indicate the formation of two regioisomeric heterodimers (two times
eight -NHR- groups) in nearly equal quantity (a).
arenes. However, stoichiometric mixtures of 4, 10a, or 10b with
the tetratolyl urea 11 or the tetratosyl urea 12 (known to form
exclusively heterodimers13 with tetraarylureas such as 11)
showed only sharp NMR signals for the homodimers 11‚11 and
12‚12, respectively, in benzene-d6 but no indication of het-
erodimers. The situation changes if the bis-loop compound 13
or the tetra-loop compound 14 are offered as a partner, which
cannot form homodimers for sterical reasons (Chart 1).14 In the
latter case, all urethane derivatives form heterodimers completely
in benzene-d6, but only the di- and triurea derivatives 10a and
10b do so in CDCl3. In benzene-d6, 10a and 10b form
heterodimers with 13b, and 10b will also form heterodimers
with 13a, which has smaller loops. From the number of NH
signals and from their relative intensity, we conclude that both
possible regioisomers with the urethane group(s) penetrating
the loops or being placed between the loops can be formed in
nearly equal quantity (see Figure 2). No definite species with
bisloop compounds are formed by 4, which contains no urea
(13) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am. Chem. Soc.
1997, 119, 12671-12672. Castellano, R. K.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 3657-3663.
(14) For the synthesis of 13 and 14, see: Bogdan, A.; Vysotsky, M. O.;
Wang, L.; Bo¨hmer, V. Chem. Commun. 2004, 1268-1269.
Heterodimerization. We, therefore, turned our attention to
the potential formation of heterodimers with tetraurea calix[4]-
J. Org. Chem, Vol. 71, No. 9, 2006 3431

Cao et al.
TABLE 1. Heterodimerization Studies of Urethane Derivatives 4,
10a, and 10b with Bis- and Tetra-loop Tetraureas 13 and 14a
4
10a
10b
13a
13b
14
((B))b
Bb/(C)b
Bb/(C)b
B/C
Bb
B
B/C
a B and C indicate the formation of dimers in benzene-d6 or CDCl3,
respectively. Weak ( ) and very weak (( )) signals for heterodimers are
indicated by parentheses. b Two regioisomers are possible.
FIGURE 4. Section of the methyl signals of the guest in the 1H NMR
spectrum (CDCl3, 400 MHz) of [10b‚Et4N+‚10b] PF6 at different
-
temperatures.
1
FIGURE 3. Section of the H NMR spectra of a mixture of 10a and
singlet (δ ) -1.51 ppm) at 57 °C and splits into two signals
(δ ) -0.06 ppm and δ ) -3.28 ppm) at -30 °C. This
splitting16 is due to the fact that the exchange between methyl
groups in the “equatorial plane” of the hydrogen-bonded belt
and methyl groups oriented toward the aromatic rings of the
calixarenes is now slow on the NMR time scale. When the
coalescence temperature of 0 °C is used, an energy barrier of
∆G ) 48.6 kJ mol-1 can be estimated.17 This value is lower
than the energy barrier observed for Et4N+, included in dimers
of 11 (∆G ) 54.8 kJ mol-1 at 305 K under analogous
conditions18), but corresponds to the value found for triurea-
monoacetamides (∆G ) 48.1 kJ mol-1).
14 (ratio 1:1.1) in (a) benzene-d6 and (b) CDCl3. Assignment of
peaks: filled circles, N-H (5 or 4 of 7 singlets); filled squares, tolyl
Ar-H (2 of 4 doublets); remaining peaks, calixarene Ar-H.
group at all. These results are summarized in Table 1, which
also contains some “borderline” cases. The low field section of
some typical H NMR spectra of such heterodimers is shown
1
in Figures 2 and 3.
The results show, that the tendency to form heterodimers with
multimacrocyclic tetraureas increases with the number of the
loops and with the number of urea functions in mixed urea-
urethanes. Benzene is more favorable for the dimerization than
chloroform, while the influence of the size of the loops in
bisloop compounds is less clear. Under the conditions studied,
the tetraurethane 4 is able to form dimers only with the tetraloop
tetraurea 14 and only in benzene.
Conclusions
Although the strength of the two NH‚‚‚OdC hydrogen bonds
formed by the urea functions in dimeric capsules of tetraurea
calix[4]arenes is quite different, urethanes obtained by the
(partial) replacement of the less strongly binding sNHs
attached to the calixarene part by sOs are not able to form
dimers under the usual conditions. Only in the case of
monourethane 10b can the dimerization be induced by tetra-
ethylammonium cations, known as favorable guests. The higher
mobility of the included cation, indicated by a lower energy
barrier ∆Gq, shows that the capsule is less tightly bound in this
case. Heterodimers are also not formed with partners, for
example, 11 or 12, which are also able to form homodimers.
Heterodimers are observed, however, with bis- or tetraloop
tetraureas 13 and 14, which are not able to homodimerize for
sterical reasons. Subtle effects due to the number and the size
Cationic Guests. Triurea-monoacetamide derivatives form
hydrogen-bonded, noncapsular tetramers in chloroform or
benzene,15 which can be “reorganized” to form the usual dimeric
capsules if tetraethylammonium cations are offered as guests.
Similar studies with compounds 4, 10a, and 10b in CDCl3 in
the presence of Et4N+PF6 show that the dimerization of the
-
monourethane 10b can also be induced. The 1H NMR spectrum
suggests that only one of the two possible regioisomers is
formed, but it is not possible to deduce if the urethane functions
are adjacent or in distal position. In the case of diurethane 10a,
a guest signal at approximately -1.5 ppm indicates encapsula-
tion, but the total spectrum remains rather broad, while no
significant spectral change is observed for tetraurethane 4 upon
addition of Et4N+PF6
.
-
The inclusion of the Et4N+ cations follows from the highfield
shift of its CH3 signal (see Figure 4), which appears as a broad
(16) A further splitting at lower temperature as a result of the direction-
ality of the hydrogen-bonded belt is not discussed.
(17) Gutowsky, H. S.; Holm, C. H. J. Chem. Phys. 1956, 25, 1228-
1234.
(18) Vysotsky, M. O.; Pop, A.; Broda, F.; Thondorf, I.; Bo¨hmer, V.
Chem.sEur. J. 2001, 7, 4403-4410.
(15) Shivanyuk, A.; Saadioui, M.; Broda, F.; Thondorf, I.; Vysotsky,
M. O.; Rissanen, K.; Kolehmainen, E.; Bo¨hmer, V. Chem.sEur. J. 2004,
10, 2138-2148.
3432 J. Org. Chem., Vol. 71, No. 9, 2006

Urethanes DeriVed from Calix[4]arenes
mg, 0.6 mmol) in dry acetone (40 mL) under nitrogen. The reaction
mixture was stirred at rt overnight and evaporated. CH2Cl2 (40 mL)
was added, the suspension was filtered, and the filtrate was washed
with saturated NH4Cl and dried (Na2SO4). After evaporation, the
residue was purified by column chromatography (hexane/ethyl
of the loops and the number of urea groups in mixed urea-
urethanes further demonstrate the delicate balance of weak
forces holding together such self-assembled dimers.
Experimental Section
1
acetate ) 4:1) to afford 4a (50 mg, 37%): mp 152-154 °C. H
3
NMR (300 MHz, CDCl3): δ 7.24, 7.08 (2 d, J ) 8.0 Hz, 16H),
5,11,17,23-Tetra-formyl-25,26,27,28-tetra-pentyloxy-calix[4]-
arene, 2a: A mixture of 1a19 (1.06 g, 1.5 mmol) and hexameth-
ylenetetramine (6.3 g, 45 mmol) was stirred in 60 mL CF3COOH
under reflux for 2 days. The pink solution was cooled to rt, diluted
with 1 M HCl (50 mL) and CH2Cl2 (50 mL), and vigorously stirred
for 1 h. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (50 mL). The combined organic layers
were washed with saturated aqueous Na2CO3 (50 mL) and brine
and dried over MgSO4. The solvent was removed in vacuo, and
the residue was purified by column chromatography (hexane/ethyl
acetate ) 2:1) to afford 2a as a white solid (0.9 g, 73%): mp 186-
188 °C. 1H NMR (300 MHz, CDCl3): δ 9.57 (s, 4H), 7.14 (s, 8H),
2
6.99 (br s, 4H), 6.49 (s, 8H), 4.44, 3.14 (2 d, J ) 13.7 Hz, 2 ×
3
4H), 3.83 (t, J ) 7.4 Hz, 8H), 2.29 (s, 12H), 1.87 (m, 8H), 1.37
3
(m, 16H), 0.94 (t, J ) 6.6 Hz, 12H). MS (FD) m/z: calcd for
C80H92N4O12, 1300.67; found, 1301.6. HRMS (ESI): [M + H]+
calcd for C80H93N4O12, 1301.6790; found, 1301.6746.
5,11,17,23-Tetra-tolylcarbamoyloxy-25,26,27,28-tetra-decyloxy-
calix[4]arene, 4b: Compound 4b was prepared and purified
1
analogously to 4a: yield 36%; mp 112-115 °C. H NMR (400
3
MHz, CDCl3): δ 7.24, 7.09 (2 d, J ) 8.6 Hz, 16H), 6.83 (br s,
4H), 6.51 (s, 8H), 4.44, 3.15 (2 d, 2J ) 13.7 Hz, 2 × 4H), 3.86 (t,
3J ) 7.0 Hz, 8H), 2.29 (s, 12H), 1.89 (m, 8H), 1.30 (m, 56H), 0.89
(t, 3J ) 6.7 Hz, 12H). 1H NMR (300 MHz, DMSO-d6): δ 9.82 (s,
4H), 7.31, 7.06 (2 d, 3J ) 8.1 Hz, 16H), 6.60 (s, 8H), 4.32, 3.32 (2
d, 2J ) 13.0 Hz, 2 × 4H), 3.84 (br t, 8H), 2.21 (s, 12H), 1.92 (m,
2
3
4.49, 3.34 (2 d, J ) 14 Hz, 2 × 4H), 3.96 (t, J ) 7.4 Hz, 8H),
1.87 (m, 8H), 1.39 (m, 16H), 0.94 (t, 3J ) 6.6 Hz, 12H). MS (FD)
m/z: calcd for C52H64O8, 816.46; found, 816.5.
3
8H), 1.25 (m, 56H), 0.85 (t, J ) 6.6 Hz, 12H). MS (FD) m/z:
5,11,17,23-Tetra-formyl-25,26,27,28-tetra-decyloxy-calix[4]-
arene, 2b: A mixture of 1b20 (1.97 g, 2 mmol) and hexamethyl-
enetetramine (8.4 g, 60 mmol) was stirred in 80 mL CF3COOH
under reflux for 2 days. The crude product was purified as described
above to afford 2b (1.24 g, 57%): mp 128-130 °C. 1H NMR (300
calcd for C100H132N4O12, 1580.98; found, 1584.9. HRMS (ESI): [M
+ Na]+ calcd for C100H132N4O12Na, 1603.9739; found, 1603.9772.
5,17-Di-nitro-25,26,27,28-tetra-pentyloxy-calix[4]arene, 5a: To
a solution of 1a (1.06 g, 1.5 mmol) in a mixture of CH2Cl2 (100
mL) and glacial acetic acid (14 mL) was added 65% HNO3 (7 mL),
and the reaction mixture was stirred at rt. After 15 min, the solution
became black (if not, a few drops of 100% HNO3 should be added).
The reaction was monitored by TLC and quenched after 2 h by the
addition of 100 mL of water. The organic layer was washed with
water and brine and finally dried over MgSO4. The solvent was
evaporated, and the residue was purified by column chromatography
(hexane/ethyl acetate ) 10:1) to afford 5a (490 mg, 41%) as yellow
2
MHz, CDCl3): δ 9.57 (s, 4H), 7.14 (s, 8H), 4.48, 3.33 (2 d, J )
3
13.6 Hz, 2 × 4H), 3.95 (t, J ) 7.4 Hz, 8H), 1.87 (m, 8H), 1.36
3
(m, 56H), 0.87 (t, J ) 6.3 Hz, 12H). MS (FD) m/z: calcd for
C72H104O8, 1096.77; found, 1096.9.
5,11,17,23-Tetra-hydroxy-25,26,27,28-tetra-pentyloxy-calix-
[4]arene, 3a: Compound 2a (816 mg, 1 mmol) and m-chloroper-
oxobenzoic acid (MCPBA, 2.4 g, 10.9 mmol) were stirred with 80
mL of chloroform at rt for 3 days until the starting material
disappeared. The solution was washed first with 2 M NaHSO3 to
remove the residual MCPBA and then twice with brine and dried
over MgSO4. The solvent was evaporated, the residue was dissolved
in 40 mL of methanol, and sodium hydroxide (400 mg, 10 mmol)
was added. The mixture was stirred at rt for 3 h. The solution was
concentrated, 1 M HCl (20 mL) was added, and the precipitate
was filtered and washed with water. The crude product was finally
purified by column chromatography (CHCl3/MeOH ) 30:1) to
afford 3a (520 mg, 68%) as a white solid: mp >300 °C (slow
1
powder: mp 141-143 °C. H NMR (400 MHz, CDCl3): δ 7.42
(s, 4H), 6.72 (s, 6H), 4.46, 3.24 (2 d, 2J ) 13.7 Hz, 2 × 4H), 3.94,
3.89 (2 t, 3J ) 7.4 Hz, 2 × 4H), 1.87 (m, 8H), 1.37 (m, 16H), 0.94
(t, 3J ) 7.0 Hz, 12H). MS (FD) m/z: calcd for C48H62N2O8, 794.45;
found, 795.4.
5,11,17-Tri-nitro-25,26,27,28-tetra-pentyloxy-calix[4]arene, 5b:
To a solution of 1a (0.7 g, 1 mmol) in a mixture of CH2Cl2 (60
mL) and glacial acetic acid (9.4 mL) was added 65% HNO3 (4.7
mL), and the reaction mixture was stirred at rt for 3 days. The
crude product was purified as described above to afford 5b (490
mg, 41%) as a yellow powder by column chromatography (hexane/
ethyl acetate ) 8:1): mp 139-141 °C. 1H NMR (400 MHz,
CDCl3): δ 7.79 (d, 4H), 7.23 (s, 2H), 6.35 (s, 3H), 4.50, 4.45 (2 d,
1
decomposition). H NMR (300 MHz, DMSO-d6): δ 8.49 (s, 4H),
6.11 (s, 8H), 4.20, 2.91 (2 d, 2J ) 12.2 Hz, 2 × 4H), 3.70 (t, 3J )
3
7.4 Hz, 8H), 1.86 (m, 8H), 1.37 (m, 16H), 0.91 (t, J ) 6.6 Hz,
12H). MS (FD) m/z: calcd for C48H64O8, 768.46; found, 770.0.
HRMS (ESI): [M + Na]+ calcd for C48H64O8Na, 791.4499; found,
791.4487.
3
2J ) 14.1 Hz, 2 × 2H), 4.08-4.00 (m, 4H), 3.89, 3.78 (2 t, J )
7.0 Hz, 2 × 2H), 3.34, 3.29 (2 d, 2J ) 14.1 Hz, 2 × 2H), 1.85 (m,
8H), 1.37 (m, 16H), 0.93 (m, 12H). MS (FD) m/z: calcd for
C48H61N3O10, 839.44; found, 839.4.
5,11,17,23-Tetra-hydroxy-25,26,27,28-tetra-decyloxy-calix[4]-
arene, 3b: A mixture of 2b (548 mg, 0.5 mmol) and MCPBA (1.2
g, 5.44 mmol) in 50 mL of chloroform was stirred at rt for 3 days
until the starting material disappeared. The crude product was
purified as described above to afford 3b (390 mg, 74%): mp 269-
5,17-Di-nitro-11,23-di-formyl-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 6a: A mixture of 5a (670 mg, 0.84 mmol) and
hexamethylenetetramine (1.76 g, 12.6 mmol) was stirred in 80 mL
CF3COOH under reflux for 5 h. The solution was cooled to rt,
diluted with aqueous 1 M HCl (30 mL) and CH2Cl2 (30 mL), and
vigorously stirred at rt for 1 h. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (30 mL). The
combined organic layers were washed with saturated aqueous Na2-
CO3 and dried (MgSO4). The solvent was evaporated, and the
residue was purified by column chromatography (hexane/ethyl
acetate ) 3:1) to afford 6a (640 mg, 89%) as a white solid: mp
1
271 °C. H NMR (300 MHz, DMSO-d6): δ 8.55 (s, 4H), 6.16 (s,
8H), 4.24, 2.95 (2 d, 2J ) 12.5 Hz, 2 × 4H), 3.73 (t, 3J ) 7.4 Hz,
8H), 1.91 (m, 8H), 1.38 (m, 56H), 0.89 (t, 3J ) 6.6 Hz, 12H). MS
(FD) m/z: calcd for C68H104O8, 1048.77; found, 1050.9. HRMS
(ESI): [M + Na]+ calcd for C68H104O8Na, 1071.7629; found,
1071.7645.
5,11,17,23-Tetra-tolylcarbamoyloxy-25,26,27,28-tetra-pent-
yloxy-calix[4]arene, 4a: Tolyl-isocyanate (80 mg, 0.6 mmol) was
added to a suspension of 3a (80 mg, 0.1 mmol) and K2CO3 (83
1
206-208 °C. H NMR (400 MHz, CDCl3): δ 9.55 (s, 2H), 7.62,
2
7.09 (2s, 8H), 4.49, 3.36 (2 d, J ) 13.7 Hz, 2 × 4H), 3.99-3.91
(br t, 8H), 1.85 (m, 8H), 1.38 (m, 16H), 0.93 (br t, 12H). MS (FD)
m/z: calcd for C50H62N2O10, 850.44; found, 852.3.
(19) Arnaud-Neu, F.; Barboso, S.; Bo¨hmer, V.; Brisach, F.; Delmau, L.;
Dozol, J.-F.; Mogck, O.; Paulus, E. F.; Saadioui, M.; Shivanyuk, A. Aust.
J. Chem. 2003, 56, 1113-1120.
(20) Ikeda, A.; Tsuzuki, H.; Shinkai, S. J. Chem. Soc., Perkin Trans. 2
1994, 2073-2080.
5,11,17-Tri-nitro-23-formyl-25,26,27,28-tetra-pentyloxy-calix-
[4]arene, 6b: A mixture of 5b (340 mg, 0.4 mmol) and hexa-
methylenetetramine (420 mg, 3 mmol) was stirred in 20 mL CF3-
J. Org. Chem, Vol. 71, No. 9, 2006 3433

Cao et al.
3
COOH under reflux for 6 h. The crude product was purified as
described above to afford 6b (340 mg, 98%) as a white solid: mp
226-229 °C. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.65
8.31, 8.22 (2s, 4H), 7.27, 7.05 (2 d, J ) 8.6 Hz, 8H), 6.92, 6.01
2
(2 s, 8H), 4.27, 3.01 (2 d, J ) 12.5 Hz, 2 × 4H), 3.86, 3.67 (2 t,
3J ) 7.4 Hz, 2 × 4H), 2.23 (s, 6H), 1.90 (m, 8H), 1.37 (m, 16H),
2
3
(s, 2H), 7.58 (br s, 4H), 7.29 (s, 2H), 4.37, 4.35 (2 d, J ) 14.1
0.94, 0.91 (2 t, J ) 7.0 Hz, 12H). MS (ESI) m/z: [M + Na]+
2
Hz, 2 × 2H), 4.00 (m, 8H), 3.68, 3.61 (2 d, J ) 14.1 Hz, 2 ×
calcd for C64H80N4O8Na, 1055.59; found, 1055.67. HRMS (ESI):
[M + H]+ calcd for C64H81N4O8, 1033.6054; found, 1033.6088.
5,11,17-Tri-tolylurea-23-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 9b: Tolyl-isocyanate (665 mg, 5 mmol) was added
to a solution of 8b (380 mg, 0.5 mmol) in chloroform (30 mL)
under nitrogen. The mixture was stirred at rt overnight and
evaporated, and the residue was purified by column chromatography
(hexane/THF ) 2:1) to afford 9b (290 mg, 50%): mp > 290 °C
2H), 1.85 (m, 8H), 1.38 (m, 16H), 0.91 (t, 3J ) 6.6 Hz, 12H). MS
(FD) m/z: calcd for C49H61N3O11, 867.43; found, 867.5.
5,17-Di-nitro-11,23-di-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 7a: A mixture of 6a (300 mg, 0.35 mmol) and
MCPBA (425 mg, 1.89 mmol) in 40 mL of chloroform was stirred
at rt for 3 days until 6a disappeared. Additional chloroform (20
mL) was added, and the solution was washed with 2 M NaHSO3
to remove the residual MCPBA and twice with brine and dried
(MgSO4). After evaporation, the residue was dissolved in methanol
(20 mL) and water (4 mL), NaOH (280 mg, 7 mmol) was added,
and the mixture was stirred at rt for 3 h. The solution was
concentrated in vacuo, 1 M HCl (20 mL) was added, and the
resulting precipitate was purified by column chromatography
(hexane/ethyl acetate ) 2:1) to afford 7a (220 mg, 75%): mp 202-
205 °C. 1H NMR (400 MHz, CDCl3): δ 7.89, 5.70 (2s, 8H), 4.70
(s, 2H), 4.42, 3.21 (2 d, 2J ) 13.6 Hz, 2 × 4H), 4.09, 3.70 (2 t, 3J
) 7.8 Hz, 2 × 4H), 1.85 (m, 8H), 1.38 (m, 16H), 0.90 (m, 12H).
MS (FD) m/z: calcd for C48H62N2O10, 826.44; found, 828.1. HRMS
(ESI): [M + Na]+ calcd for C48H62N2O10Na, 849.4302; found,
849.4296.
1
(partly decomposition). H NMR (400 MHz, DMSO-d6): δ 8.44
(s, 1H), 8.26 (s, 2H), 8.24 (s, 1H), 8.18 (s, 2H), 8.07 (s, 1H), 7.24,
7.03 (2 d, 3J ) 7.0 Hz, 12H), 6.89, 6.84, 6.72, 6.05 (4s, 8H), 4.32,
4.27 (2 d, 2J ) 12.9 Hz, 2 × 2H), 3.84 (t, 3J ) 7.4 Hz, 4H), 3.76,
3
2
3.71 (2 t, J ) 7.0 Hz, 4H), 3.09, 3.02 (2 d, J ) 12.5 Hz, 2 ×
2H), 2.22 (s, 6H), 2.20 (s, 3H), 1.89 (m, 8H), 1.39 (m, 16H), 0.93
(t, 3J ) 6.6 Hz, 12H). MS (ESI) m/z: [M + Na]+ calcd for
C72H88N6O8Na, 1187.66; found, 1187.74. HRMS (ESI): [M + Na]+
calcd for C72H88N6O8Na, 1187.6561; found, 1187.6542.
5,17-Di-tolylurea-11,23-di-tolylcarbamoyloxy-25,26,27,28-
tetra-pentyloxy-calix[4]arene, 10a: Tolyl-isocyanate (51 mg, 0.39
mmol) was added to a suspension of 9a (40 mg, 0.039 mmol) and
K2CO3 (54 mg, 0.39 mmol) in dry acetone (20 mL) under nitrogen.
The reaction mixture was stirred at rt overnight and evaporated.
CH2Cl2 (20 mL) was added, the suspension was filtered, and the
filtrate was washed with saturated NH4Cl and dried (Na2SO4). The
solvent was evaporated, and the residue was purified by column
chromatography (hexane/THF ) 3:1) to afford 10a (30 mg, 60%):
mp 198-200 °C. 1H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 2H),
8.36 (s, 2H), 8.27 (s, 2H), 7.28, 7.03 (2 d, 3J ) 7.8 Hz, 16H), 7.06,
6.33 (2 s, 8H), 4.34, 3.18 (2 d, 2J ) 12.9 Hz, 2 × 4H), 3.92, 3.76
5,11,17-Tri-nitro-23-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 7b: A mixture of 6b (360 mg, 0.42 mmol) and
MCPBA (250 mg, 1.12 mmol) in 50 mL of chloroform was stirred
at rt for 4 days until 6b disappeared. The crude product was isolated
and purified by column chromatography (hexane/ethyl acetate )
4:1) as described above to afford 7b (250 mg, 70%): mp 195-
197 °C. 1H NMR (300 MHz, CDCl3): δ 7.94 (d, 4H), 7.18 (s, 2H),
2
5.64 (s, 2H), 4.51, 4.40 (2 d, J ) 14.1 Hz, 2 × 2H), 4.18-4.06
(m, 4H), 3.85, 3.69 (2 t, 3J ) 7.0 Hz, 2 × 2H), 3.36, 3.24 (2 d, 2J
) 14.1 Hz, 2 × 2H), 1.90 (m, 8H), 1.51 (m, 16H), 0.97 (m, 12H).
MS (FD) m/z: calcd for C48H61N3O11, 855.43; found, 855.5. HRMS
(ESI): [M + Na]+ calcd for C48H61N3O11Na, 878.4204; found,
878.4215.
(2 t, J ) 8.2 Hz, 2 × 4H), 2.22 (s, 12H), 1.92 (m, 8H), 1.40 (m,
3
3
16H), 0.96, 0.93 (2 t, J ) 7.4 Hz, 12H). MS (ESI) m/z: [M +
Na]+ calcd for C80H94N6O10Na, 1321.69; found, 1321.78. HRMS
(ESI): [M + H]+ calcd for C80H95N6O10, 1299.7110; found,
1299.7150.
5,17-Di-amino-11,23-di-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 8a: Pd/C (106 mg, 0.1 mmol) was added to a solution
of 7a (410 mg, 0.5 mmol) in toluene (30 mL), and the mixture
was stirred at rt under H2 overnight. The catalyst was filtered
through Celite and washed with THF (2 × 30 mL), and the solvent
was evaporated in vacuo to afford 8a (310 mg, 81%): mp 276-
5,11,17-Tri-tolylurea-23-tolylcarbamoyloxy-25,26,27,28-tetra-
pentyloxy-calix[4]arene, 10b: Tolyl-isocyanate (210 mg, 1.5
mmol) was added to a suspension of 9b (175 mg, 0.15 mmol) and
Na2CO3 (160 mg, 1.5 mmol) in dry acetone (20 mL) under nitrogen.
The crude product was purified as described above to afford 10b
(100 mg, 51%), except using hexane/ethyl acetate (3:1) as eluent:
mp 204-206 °C. 1H NMR (400 MHz, DMSO-d6, 70 °C): δ 9.39
(s, 1H), 8.11 (s, 2H), 8.05 (br s, 3H), 7.90 (s, 1H), 7.24, 7.03 (2 d,
3J ) 8.2 Hz, 16H), 6.95, 6.91, 6.71, 6.45 (4 s, 8H), 4.40, 4.38 (2
d, J ) 12.9 Hz, 2 × 2H), 3.94 (m, 4H), 3.87, 3.81 (2 t, J ) 7.0
Hz, 4H), 3.18, 3.12 (2 d, 2J ) 13.3 Hz, 2 × 2H), 2.24 (s, 9H), 2.22
(s, 3H), 1.94 (m, 8H), 1.41 (m, 16H), 0.96 (m, 12H). MS (ESI)
m/z: [M + Na]+ calcd for C80H95N7O9Na, 1320.71; found, 1320.87.
HRMS (ESI): [M + H]+ calcd for C80H96N7O9, 1298.7270; found,
1298.7278.
1
278 °C. H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 6.14,
5.93 (2 s, 8H), 4.44 (br s, 4H), 4.18, 2.84 (2 d, 2J ) 12.1 Hz, 2 ×
4H), 3.78, 3.58 (2 t, 3J ) 8.2 Hz, 2 × 4H), 1.83 (m, 8H), 1.38 (m,
16H), 0.91, 0.90 (2 t, 3J ) 7.0 Hz, 12H). MS (FD) m/z: calcd for
C48H66N2O6, 766.49; found, 767.9.
2
3
5,11,17-Tri-amino-23-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 8b: Compound 7b (170 mg, 0.2 mmol) was
hydrogenated with Pd/C (96 mg, 0.09 mmol) in toluene (30 mL)
as described above to yield 8b (130 mg, 85%): mp > 270 °C (partly
1
decomposition). H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H),
Acknowledgment. Financial support by the European Com-
mission (Contract No. FI6W-CT-2003-508854) and by the
Deutsche Forschungsgemeinschaft (SFB 625; Bo523/14-4) are
gratefully acknowledged.
6.04 (s, 4H), 6.02 (s, 2H), 5.87 (s, 2H), 4.36 (br s, 6H), 4.17 (m,
2
4H), 3.72-3.63 (m, 8H), 2.85, 2.79 (2 d, J ) 12.5 Hz, 2 × 2H),
1.88 (m, 8H), 1.37 (m, 16H), 0.90 (t, 3J ) 7.0 Hz, 12H). MS (FD)
m/z: calcd for C48H67N3O5, 765.51; found, 766.7.
5,17-Di-tolylurea-11,23-di-hydroxy-25,26,27,28-tetra-pentyloxy-
calix[4]arene, 9a: Tolyl-isocyanate (120 mg, 0.9 mmol) was added
to a solution of 8a (70 mg, 0.09 mmol) in chloroform (20 mL)
under nitrogen. The mixture was stirred at rt overnight. The solvent
was evaporated, and the residue was purified by column chroma-
tography (hexane/ethyl acetate ) 2:1) to afford 9a (60 mg, 64%):
mp 176-178 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 2H),
Supporting Information Available: General experimental
information. Signal assignment for 1H NMR spectra of het-
1
erodimers. Selected H NMR spectra of newly synthesized com-
pounds and homo-and heterodimers. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0524369
3434 J. Org. Chem., Vol. 71, No. 9, 2006