Resorcinarenes with Deepened Polyaromatic Lower Cavities: Synthesis and Structure

Full text of DOI:10.1021/jo9806557

J . Org. Chem. 1998, 63, 6065-6067
6065
resorcinarenes should embody ideal scaffolds for polyaro-
matic cavity enlargement without loss of structure. The
functionalization of the resorcinarene lower rim has
begun to attract attention as a means of enhancing the
properties of the parent macrocycles,6 but there is only
one example describing conjugation extension of the
lower rim.6a We previously reported the synthesis of a
new series of resorcinarenes embodying boronic acid
substituents.7 Herein, we detail the first direct, 4-fold
conjugation extension of the resorcinarene lower rim
employing Suzuki couplings featuring both octol and
cavitand macrocyclic substrates, including convenient,
nonchromatographic product isolation. Importantly, the
macrocycle conformation is preserved upon lower cavity
extension, resulting in the creation of a deepened, pol-
yaromatic lower rim cleft.
Suzuki coupling reactions have several advantages
over related methodologies, including tolerance of a wide
range of functionalities and relatively low toxicity.8 Two
resorcinarene substrates were chosen as Suzuki coupling
partners (Figure 1). Compound 1 is synthesized in 72.4%
yield via addition of a solution of the known precursor
octol tetrabromide6a (5.00 g, 4.51 mmol), DMF (150 mL),
and MeOH (10 mL) to a solution of K2CO3 (6.23 g, 45.1
mmol), DMF (100 mL), and CH2BrCl (1.32 mL, 20.3
mmol) over the course of 30 h. The temperature is
gradually increased from room temperature to 65 °C over
7 days, during which an additional 2 portions of CH2-
BrCl (1.32 mL, 20.3 mmol) is added. We observed that
methanolimproved the efficiencyofthe bridgingreaction,6d,9
presumably by aiding substrate solubility.
Resor cin a r en es w ith Deep en ed
P olya r om a tic Low er Ca vities: Syn th esis
a n d Str u ctu r e
Patrick T. Lewis and Robert M. Strongin*
Department of Chemistry, Louisiana State University,
Baton Rouge, Louisiana 70803
Received April 8, 1998
In Nature, interactions derived from π-systems are of
immense importance, influencing protein structure and
molecular recognition.1 Conjugated organic materials are
the basis of the burgeoning field of molecular electronics.2
Electronic organic materials embodying extended, semi-
rigid, and well-defined π-cavities might thus find use as
discriminating biomimetic molecular hosts for multipoint
π-π, CH-π, and ion-π interactions. Calixarenes are
attractive synthetic receptors with preorganized, electron-
rich π-cavities and versatile properties.3 They have been
employed as substrates for aryl-aryl coupling reactions
to lengthen their aromatic cavities with the goal of
promoting binding to larger guests.4 X-ray structure
analysis has shown, however, that severe conformational
distortion occurs upon 4-fold coupling to a biphenyl
substituent; the triphenyl arms exhibit skewed direc-
tionality, and a defined cavity is not attained.4c
Resorcinarenes have also been extensively studied as
π-rich, hydrogen bonding molecular hosts.5 Unlike calix-
arenes, which are typically obtained via formaldehyde
condensations, resorcinarenes are synthesized from sub-
stituted aldehydes. The aldehyde-derived appendages
reside on the lower rim of the macrocycles. Their steric
bulk prevents conformational interconversion; therefore,
Compound 1 undergoes 4-fold Suzuki coupling (Scheme
1) with arylboronic acids containing electron-donating or
-withdrawing groups to furnish the deepened lower cavity
cavitands 3a -c as the only observed macrocyclic reaction
products.10 A mixture of Pd(PPh3)4 (0.036 g, 0.031 mmol),
20 mL of DMF, compound 1 (0.300 g, 0.259 mmol), K2-
CO3 (0.286 g, 2.07 mmol), and ArB(OH)2 (0.139 g, 1.14
mmol) in 30 mL of a 2:1 solution of DMF/H2O is stirred
under N2 for 48 h at 65 °C. The solvent is removed in
vacuo, and the residue is stirred in water and methanol
(1) Leading references and reviews: (a) Burley, S. K.; Petsko, G. A.
Science 1985, 229, 23. (b) Principles of Nucleic Acid Structure; Saenger,
W., Ed.; Springer-Verlag: New York, 1984. (c) Hunter, C. A.; Sanders,
J . K. M. J . Am. Chem. Soc. 1990, 112, 5525. (d) Hunter, C. A. Chem.
Soc. Rev. 1994, 23, 101. (e) Ma, J . C.; Dougherty, D. A. Chem. Rev.
1997, 97, 1303, and references therein.
(2) (a) Molecular Electronic Devices; Carter, F. L., Ed.; Marcel
Dekker: New York, 1982. (b) Molecular Electronic Devices II; Carter,
F. L., Ed.; Marcel Dekker: New York, 1987. (c) Molecular Electronics:
Science and Technology; Aviram, A., Ed.; Conference Proceedings No.
262; American Institute of Physics: New York, 1992. (d) Miller, J . S.
Adv. Mater. 1990, 2, 378. (e) Molecular and Biomolecular Electronics;
Birge, R. R., Ed.; Advances in Chemistry Series 240; American
Chemical Society: Washington, DC, 1991. (f) Nanostructures and
Mesoscopic Systems; Kirk, W. P., Reed, M. A., Eds.; Academic: New
York, 1992. (g) Pearson, D. L.; J ones, L., III; Schumm, J . S.; Tour, J .
M. Synth. Met. 1997, 84, 303.
(3) (a) Calixarenes; Royal Society of Chemistry: Cambridge, U.K.,
1989. (b) Calixarenes: A Versatile Class of Macrocyclic Compounds;
Bohmer, V., Vicens, J ., Eds.; Kluwer: Dordrecht, The Netherlands,
1990.
(4) (a) Arduni, A.; Pochini, A.; Rizzi, A.; Sicuri, A. R.; Ungaro, R.
Tetrahedron Lett. 1990, 31, 4653. (b) Wong, M. S.; Nicoud, J . F.
Tetrahedron Lett. 1993, 34, 8237. (c) J uneja, R. K.; Robinson, K. D.;
J ohnson, C. P.; Atwood, J . L. J . Am. Chem. Soc. 1993, 115, 3818. (d)
Haino, T.; Harano, T.; Matsumura, K.; Fukazawa, Y. Tetrahedron Lett.
1995, 36, 5793. (e) Arduini, A.; McGregor, W. M.; Paganuzzi, D.;
Pochini, A.; Secchi, A.; Ugozzoli, F.; Ungaro, R. J . J . Chem. Soc., Perkin
Trans. 2 1996, 66, 839. (f) Larsen, M.; J orgensen, M. J . Org. Chem.
1997, 62, 4171.
(6) (a) Tucker, J . A.; Knobler, C. B.; Trueblood, K. N.; Cram, D. J .
J . Am. Chem. Soc. 1989, 111, 3688. (b) Botta, B.; Lacomacci, P.; Di
Giovanni, C.; Della Monache, G.; Gacs-Baitz, E.; Botta, M.; Tafi, A.;
Corelli, F.; Misiti, D. J . Org. Chem. 1992, 57, 3259. (c) Botta, B.; Di
Giovanni, C.; Delle Monache, G.; De Rosa, M. C.; Gacs-Baitz, E.; Botta,
M.; Corelli, F.; Tafi, A.; Santini, A.; Benedetti, E.; Pedone, C.; Misiti,
D. J . Org. Chem. 1994, 59, 1532. (d) Gibb, B. C.; Chapman, R. G.;
Sherman, J . C. J . Org. Chem. 1996, 61, 1505. (e) Botta, B.; Di Giovanni,
C.; Delle Monache, G.; Salvatore, P.; Gasparrini, F.; Villiani, C.; Botta,
M.; Corelli, F.; Tafi, A.; Gacs-Baitz, E.; Santini, A.; Benedetti, E.;
Caravalho, C. F.; Misiti, D. J . Org. Chem. 1997, 62, 932. (f) Botta, B.;
Delle Monache, G.; De Rosa, M. C.; Seri, C.; Benedetti, E.; Iacovino,
R.; Botta, M.; Corelli, F.; Masignani, V.; Tafi, A.; Bacs-Baitz, E.;
Santini, A.; Misiti, D. J . Org. Chem. 1997, 62, 1788. (g) Curtis, A. D.
M. Tetrahedron Lett. 1997, 38, 4295. (h) Akimoto, S.; Nishizawa, H.;
Yamakazi, T.; Yamakazi, I.; Hayashi, Y.; Fujimaki, T.; Ichimura, K.
Chem. Phys. Lett. 1997, 276, 405.
(7) Lewis, P. T.; Davis, C. J .; Saraiva, M.; Treleaven, D.; McCarley,
T.; Strongin, R. M. J . Org. Chem. 1997, 62, 6110.
(8) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(9) Moran, J . R.; Karbach, S.; Cram, D. J . J . Am. Chem. Soc. 1982,
104, 5826.
(10) Suzuki couplings at the upper rim of cavitands: (a) von dem
Bussche-Huennefeld, C.; Helgeson, R. C.; Buehring, D.; Knobler, C.
B.; Cram, D. J . Croat. Chem. Acta 1996, 69, 447. (b) Ma, S.; Rudkevich,
D. M.; Rebek, J ., J r. J . Am. Chem. Soc. 1998, 120, 4977.
(5) (a) Schneider, H.-J .; Schneider, U. J . Inclusion Phenom. 1994,
19, 67. (b) Container Molecules and Their Guests; Cram, D. J ., Cram,
J . M., Eds.; The Royal Society of Chemistry: Cambridge, U.K., 1994;
Vol. 4. (c) Bohmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (d)
Gutsche, C. D. Aldrichchim. Acta 1995, 28, 3. (e) Sherman, J . C.
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houdt, D. N. Tetrahedron 1996, 52, 2663.
S0022-3263(98)00655-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/25/1998

6066 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Sch em e 2
h at 65 °C. The solvent is removed in vacuo, and the
resultant residue is stirred in water and then methanol,
filtered, and dried. The solid is stirred in ether, filtered,
and dried, yielding compound 4a in 26% yield. This
compound was previously reported as a reaction mixture
component along with a stereoisomer via direct resorcinol
F igu r e 1.
and then filtered and dried. The resultant solid is then
stirred in ether, filtered, and dried, furnishing 3a in 71%
yield. In a similar fashion, compounds 3b and 3c are
synthesized in 79 and 42% yields, respectively.
1
condensation with 4-biphenylcarboxaldehyde.11 The H
NMR spectrum of 4a obtained via Suzuki coupling is
identical to that of the crown stereoisomer component of
the condensation reaction.
Sch em e 1
Compound 2 also undergoes Suzuki coupling with
4-bromobiphenyl, affording compound 4b which was
conveniently purified and characterized as the corre-
sponding octaacetate. In contrast to that for the tri-
phenyl calixarene analogue,4c 1H NMR evidence indicates
that all four resorcinarene triphenyl appendages reside
on the lower face of the macrocycle and that the macro-
cycle conformation is preserved. The octaacetate displays
the well-known, characteristic chemical shift pattern of
a typical acylated resorcinarene [acetate protons (2.12
and 2.14 ppm, 24 H), methine protons (5.66 ppm, 4 H),
and aromatic protons (6.52 and 6.62 ppm, 4 H; 7.07 and
7.21 ppm, 4 H)12 directly derived from a C4v crown octol.13
In conclusion, we have demonstrated the utility of
resorcinarenes with aryl halide or boronic acid lower
appendages as versatile 4-fold Suzuki coupling sub-
strates. Importantly, the integrity of the macrocyclic
conformation is preserved upon lower cavity deepening.
The upper rim is left free for host-guest interactions or
chemical modification. The extended compounds de-
scribed herein might not otherwise be readily attainable
via direct resorcinol/aldehyde condensation conditions
which are often sensitive to functionality and can afford
unfavorable or intractable stereoisomeric mixtures.5 The
Suzuki coupling strategy described herein should also be
amenable to the coupling of larger oligomers as well as
The great diversity of readily available aryl halides is
an advantage of employing tetraaryl boronic acid 2 and
congeners7 as Suzuki coupling substrates. Compound 2
undergoes 4-fold Suzuki coupling (Scheme 2) with iodo-
benzene to furnish a sole macrocyclic product as evi-
(11) Tunstad, L. M.; Tucker, J . A.; Dalcanale, E.; Weiser, J .; Bryant,
J . A.; Sherman, J . C.; Hegelson, R. C.; Knobler, C. B.; Cram, D. J . J .
Org. Chem. 1989, 54, 1305.
(12) Ho¨gberg, A. G. S. J . Am. Chem. Soc. 1980, 102, 6046.
(13) The isolated yields reported have not been optimized. We are
curently investigating variations in coupling methodology (e.g., solvent,
catalyst, base, and temperature) as well as further improvements in
the isolation of the products.
1
denced by H NMR. Pd(PPh3)4 (0.107 g, 0.093 mmol),
compound 2 (0.750 g, 0.774 mmol), K2CO3 (0.856 g, 6.19
mmol), and iodobenzene (0.38 mL, 3.41 mmol) in 50 mL
of a 4:1 solution of DMF/H2O are stirred under N2 for 48

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6067
2.28 mmol): yield 0.286 g (42%); mp >300 °C; 1H NMR (400
MHz, DMF-d7) δ 4.70 and 5.97 (d, J ) 7.6 Hz, 8 H), 6.40 (s, 4
H), 6.89 (s, 4 H), 7.60-8.45 (m, 36 H); 13C NMR (100 MHz,
(DMF-d7) δ 42.7, 117.8, 121.8, 123.0, 127.6, 129.8, 130.8, 131.4,
133.8, 136.6, 138.7, 142.5, 149.9, 157.0; IR (KBr) NO2 1533 and
1340 cm-1; UV λmax 277.5 nm (DMF); MALDI m/z (dithranol
matrix) calcd for C80H52O16N4 1325.3, found 1365.8 [(M + K)+].
P r oced u r e B. Octol 4a . To a three-neck 100 mL round-
bottom flask were added Pd(PPh3)4 (0.107 g, 0.093 mmol) and
20 mL of DMF under N2. Iodobenzene (0.38 mL, 3.41 mmol),
potassium carbonate (0.856 g, 6.19 mmol) dissolved in 10 mL of
water, and octol 2 (0.750 g, 0.774 mmol) dissolved in 20 mL of
DMF were added stepwise via a syringe to the reaction mixture.
The reaction mixture was stirred under N2 for 2 days at 65 °C.
The solvent was removed in vacuo, and the resultant solid was
stirred in 100 mL of water, 100 mL of MeOH, and 150 mL of
ether. The solid was filtered and dried, yielding 0.220 g (26%)
heteroaromatics and polyenes. The fabrication of con-
jugated π-cavities of increased complexity and the de-
tailed study of their properties are currently in progress
in our laboratory.
Exp er im en ta l P r oced u r es
Gen er a l. All solvents used for Suzuki coupling reactions
were degassed. All other chemicals were reagent grade (Aldrich
or Lancaster) and were used without further purification.
General methods of characterization have been described previ-
ously.7
Ca vita n d 1. The tetrabromo octol6a (5.00 g, 4.51 mmol) in
50 mL of DMF and 10 mL MeOH was added to a solution of
potassium carbonate (6.23 g, 45.1 mmol), 100 mL of DMF, and
bromochloromethane (1.32 mL, 20.3 mmol) via a syringe pump
over the course of 30 h. The reaction mixture was then stirred
at room temperature under nitrogen for 2 days. An additional
1.32 mL (20.3 mmol) of bromochloromethane was added. The
reaction mixture was heated to 45 °C and stirred for 24 h. An
additional 1.32 mL (20.3 mmol) of bromochloromethane was
added and the mixture heated for 2 days at 65 °C. The reaction
mixture was filtered and the resulting solid dried in vacuo and
stirred in 50 mL of water and 50 mL of ethyl ether. A total of
1
of product: mp >300 °C; H NMR (400 MHz, DMSO-d6) δ 5.72
(s, 4 H), 6.18 (s, 4 H), 6.86 (d, J ) 8.0 Hz, 8 H), 7.20 (d, J ) 8.0
Hz, 8 H), 7.28-7.34 (m, 24 H), 8.67 (s, 8 H); 13C NMR (100 MHz,
DMSO-d6) δ 41.0, 102.2, 120.2, 125.5, 126.3, 126.7, 128.8, 129.1,
136.7, 140.4, 145.4, 152.8; UV λmax 279.5 nm (DMF); MALDI m/z
(anthracene matrix) calcd for C76H56O8 1097.3, found 1098.0
(M+).
Octa a ceta te of 4b. Procedure B was used employing octol
2 (0.500 g, 0.517 mmol) and 4-bromobiphenyl (0.530 g, 2.27
mmol). Compound 4b was characterized as the corresponding
octaacetate; after being stirred in 150 mL of MeOH, the solid
purified by crystallization as detailed for octol 4a was refluxed
in 50 mL of Ac2O for 8 h. The solvent was removed in vacuo,
and the resultant solid was stirred in 100 mL of water, filtered,
dried, and recrystallized by slow diffusion from CHCl3 in an
acetonitrile atmosphere: yield of first crop of crystalline 4b 0.095
g (11%); mp >300 °C; 1H NMR (400 MHz, DMF-d7) δ 2.12 (s, 12
H), 2.14 (s, 12 H), 5.66 (s, 4 H), 6.52 (s, 2 H), 6.62 (s, 2 H), 7.07
(s, 2 H), 7.15 (d, J ) 8.3 Hz, 8 H), 7.21 (s, 2 H), 7.40-7.45 (m,
12 H), 7.58-7.65 (m, 32 H); 13C NMR (100 MHz, DMF-d7) δ 45.6,
127.7, 127.8, 128.2, 128.3, 128.5, 130.1, 130.7, 131.5, 133.8, 139.6,
140.2, 140.3, 141.1, 148.4, 148.6, 148.6, 169.4, 169.6; IR (KBr)
vCO 1771; UV λmax 284.0 nm (DMF); MALDI m/z (anthracene
matrix) calcd for C116H88O16 1736.6, found 1758.2 [(M + Na)+].
1
3.78 g (73.4%) of product was obtained: mp >300 °C; H NMR
(400 MHz, CDCl3) δ 4.58 and 5.86 (d, J ) 7.2 Hz, 8 H), 6.31 (s,
4 H), 6.70 (s, 4 H), 6.83 (s, 4 H), 7.18 (d, J ) 8.3 Hz, 8 H), 7.42
(d, J ) 8.4 Hz, 8 H); 13C NMR (100 MHz, CDCl3) δ 41.5, 99.8,
117.2, 121.0, 126.4, 130.5, 131.4, 137.7, 138.6, 156.2; UV λmax
288.5 nm (DMSO); FAB-MS m/ z (m-NBA matrix) calcd for
C
56H36Br4O8 1156.5, found 1156.1 (M+).
P r oced u r e A. Ca vita n d 3a . To a three-neck 100 mL round-
bottom flask were added Pd(PPh3)4 (0.036 g, 0.031 mmol) and
20 mL of DMF under N2. Cavitand 1 (0.300 g, 0.259 mmol)
dissolved in 10 mL of DMF, potassium carbonate (0.286 g, 2.07
mmol) dissolved in 10 mL of water, and phenylboronic acid
(0.139 g, 1.14 mmol) dissolved in 10 mL of DMF were added
stepwise via a syringe to the reaction mixture. The reaction
mixture was stirred under N2 for 2 days at 65 °C. The solvent
was removed in vacuo, and the resultant solid was stirred in 50
mL of MeOH and 50 mL of ether. The solid was filtered and
dried, yielding 0.210 g (71%) of product: mp >300 °C; 1H NMR
(400 MHz, CDCl3) δ 4.65 and 5.90 (d, J ) 7.1 Hz, 8 H), 6.48 (s,
4 H), 6.74 (s, 4 H), 7.13 (s, 4 H), 7.13-7.53 (m, 36 H); 13C NMR
(100 MHz, CDCl3) δ 41.7, 99.9, 117.0, 127.1, 127.3, 127.4, 128.9,
138.0, 138.9, 139.5, 140.8, 156.2; UV λmax 289 nm (DMSO); FAB-
MS m/ z (m-NBA matrix) calcd for C80H56O8 1145.3, found 1145.9
M+.
Ack n ow led gm en t. We thank Drs. Tracey D. Mc-
Carley and Wenzhe Lu for the acquisition of mass
spectra and Dr. W. Dale Treleaven for assistance in
obtaining NMR spectra. Acknowledgment is made to the
donors of the Petroleum Research Fund, administered
by the ACS, for partial support of this research as well
as to Louisiana State University. R.M.S. is the recipient
of an Arnold and Mabel Beckman Foundation Young
Investigator Award (1998-2000).
Ca vita n d 3b. Procedure A was used employing cavitand 1
(1.00 g, 0.865 mmol) and (4-methoxyphenyl)boronic acid (0.577
1
g, 3.80 mmol): yield 0.865 g (79%); mp >300 °C; H NMR (400
MHz, CDCl3) δ 3.84 (s, 12 H), 4.64 and 5.89 (d, J ) 6.9 Hz, 8 H),
6.46 (s, 4 H), 6.73 (s, 4 H), 6.86 (d, J ) 8.4 Hz, 8 H), 7.11 (s, 4
H), 7.37-7.47 (m, 24 H); 13C NMR (100 MHz, CDCl3) δ 41.7,
55.5, 99.9, 114.3, 116.9, 126.7, 127.1, 128.4, 129.3, 133.4, 138.1,
138.2, 139.1, 156.2, 159.2; UV λmax 341.0 nm (DMSO); MALDI
m/z (anthracene matrix) calcd for C84H64O12 1265.4, found 1265.4
(M+).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR,13C NMR,
and mass spectra of compounds 1, 3a -c, 4a , and 4b (octa-
acetate) (18 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.
Ca vita n d 3c. Procedure A was used employing cavitand 1
(0.600 g, 0.518 mmol) and (3-nitrophenyl)boronic acid (0.380 g,
J O9806557