Cavitand-porphyrins

Article abstract of DOI:10.1021/ja010038r

The synthesis and characterization of new nanoscale container molecules 7 and 8 are described. They are covalent hybrids of deepened, self-folding cavitands and metalloporphyrins. In receptor 7, the Zn-porphyrin wall is directly built onto the cavitand skeleton. Host 8 features a large unimolecular cavity containing two cavitands attached with the Zn-porphyrin wall. Its dimensions, ～10 × 25 A, place it among the largest synthetic hosts prepared to date. A series of adamantyl- and pyridyl-containing guests 14-20 of various lengths were prepared and used to determine the hosts' binding abilities in solution using UV/vis and ^1H NMR spectroscopy. Intramolecular hydrogen bonds at the upper rims of the cavitands resist the unfolding of the inner cavities and thereby increase the energetic barrier to guest exchange. The exchange is slow on the NMR time scale (at ≤300 K), and kinetically stable complexes result. When the cavities and metalloporphyrins participate simultaneously in the binding event, very high affinities for guests are found (-ΔG²⁹⁵ up to 10 kcal mol^-1 in toluene), to which the porphyrin fragments contribute significantly (-ΔG²⁹⁵ up to 6 kcal mol^-1). The pairwise selection of two different guests by molecular container 8 is reported, and the termolecular complex formed raises the possibility of metal-catalyzed bimolecular reactions in these containers.

Full text of DOI:10.1021/ja010038r

J. Am. Chem. Soc. 2001, 123, 4659-4669
4659
Cavitand-Porphyrins
Stephen D. Starnes, Dmitry M. Rudkevich,* and Julius Rebek, Jr.*
Contribution from The Skaggs Institute for Chemical Biology and The Department of Chemistry,
The Scripps Research Institute, MB-26, 10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed January 3, 2001
Abstract: The synthesis and characterization of new nanoscale container molecules 7 and 8 are described.
They are covalent hybrids of deepened, self-folding cavitands and metalloporphyrins. In receptor 7, the Zn-
porphyrin wall is directly built onto the cavitand skeleton. Host 8 features a large unimolecular cavity containing
two cavitands attached with the Zn-porphyrin wall. Its dimensions, ∼10 × 25 Å, place it among the largest
synthetic hosts prepared to date. A series of adamantyl- and pyridyl-containing guests 14-20 of various lengths
1
were prepared and used to determine the hosts’ binding abilities in solution using UV/vis and H NMR
spectroscopy. Intramolecular hydrogen bonds at the upper rims of the cavitands resist the unfolding of the
inner cavities and thereby increase the energetic barrier to guest exchange. The exchange is slow on the NMR
time scale (at e300 K), and kinetically stable complexes result. When the cavities and metalloporphyrins
participate simultaneously in the binding event, very high affinities for guests are found (-∆G295 up to 10
kcal mol-1 in toluene), to which the porphyrin fragments contribute significantly (-∆G295 up to 6 kcal mol-1).
The pairwise selection of two different guests by molecular container 8 is reported, and the termolecular complex
formed raises the possibility of metal-catalyzed bimolecular reactions in these containers.
Introduction
encapsulated a single guest molecule, while catalysis most often
requires two molecules placed in close proximity. A second,
related limitation is functionality: how to provide space for a
guest or two and a functional group positioned to influence their
behavior? Here the central theme is the functionalization of
concave surfaces.
Synthetic molecular cavities are designed to more or less
completely surround smaller molecular guests. The motivations
for engineering the cavities depend on the tastes and appetites
of the researcher but frequently include molecular recognition,
sensing, delivery, and catalysis.1-3 However, compared to
alternatives such as imprinted polymers,4 catalytic antibodies,5
liposomes,6 and zeolites7 the accomplishments are modest, even
by the accommodating standards of the community. The
moderate dimensions of the synthetic cavities represent the most
serious limitations. First carcerandssthe container-molecules
with enforced interiors1a,bsaccommodated only one benzene-
sized guest. The more guest-accessible, self-assembling capsuless
“tennis balls”,8 calix[4]arene tetraureas,9 etc. - also generally
There has been progress on the problem of size. Very large
hemicarcerands 1 and 2 (Figure 1) were synthesized by Cram10
and Reinhoudt,11 respectively, in the mid 1990s, and at ∼20 Å
long, they are even now among the largest of unimolecular
cavities. Fullerene C60 and tetraphenylporphyrin appear ideal
guests for 1, while tetraphenylporphyrin, phthalocyanine, medium-
sized dibenzocrown ethers, and steroids can fit nicely within
the interior of 2. But attempts to sequester these large guests in
solution failed.10,11 Sherman et al. prepared “giant carceplex” 3
that incarcerated three DMF guest-molecules (Figure 1).12
Subsequently, the same researchers developed an approach
toward bis-capsules 4 (Figure 1) which entrapped two different
guestssEtOAc, benzene, THF, pyrazine, 1,4-dioxane, etc.sone
per each cavity.13 The 1H NMR chemical shifts of the
encapsulated species were clearly dependent on the presence
of the other guest in the neighboring cavity. Subsequently,
nanoscale self-assembled capsules have been synthesized which
reversibly bind a single sizable guest or even several guests.14
There is much less progress on interior functionality. Mo-
(1) (a) Cram, D. J.; Cram, J. M. Container Molecules and their Guests;
Royal Society of Chemistry: Cambridge, 1994. Carcerands and hemicar-
cerands: (b) Jasat, A.; Sherman, J. C. Chem. ReV. 1999, 99, 931-967. (c)
Warmuth, R.; Yoon, J. Acc. Chem. Res. 2001, 34, 95-105. Cryptophanes:
(d) Collet, A.; Dutasta, J.-P.; Lozach, B.; Canceill, J. Top. Curr. Chem.
1993, 165, 103-129. Cyclophanes: (e) Diederich, F. Cyclophanes; Royal
Society of Chemistry: Cambridge, 1991. Calixarene-based devices: (f)
Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97, 1713-1734. Catalysts: (g)
Sanders, J. K. M. Chem.-Eur. J. 1998, 4, 1378-1383.
(2) Self-assembled capsules: (a) Conn, M. M.; Rebek, J., Jr. Chem. ReV.
1997, 97, 1647-1668. (b) de Mendoza, J. Chem.-Eur. J. 1998, 4, 1373-
1377.
(3) (a) Rudkevich, D. M.; Rebek, J., Jr. Eur. J. Org. Chem. 1999, 1991-
2005. (b) Higler, I.; Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Eur.
J. Org. Chem. 1998, 2689, 9-2702. (c) Seel, C.; Vo¨gtle, F. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 528-549.
(4) (a) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812-1832.
(b) Whitcombe, M. J.; Alexander, C.; Vulfson, E. N. Synlett 2000, 911-
923. (c) Sellergren, B. Angew. Chem., Int. Ed. 2000, 39, 1031-1037.
(5) (a) Lerner, R. A.; Bencovic, S. J.; Schultz, P. G. Science 1991, 252,
659-667. (b) Schultz, P. G.; Lerner, R. A. Science 1995, 269, 1835-1842.
(c) Schultz, P. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14590-14591
and references therein.
(8) Branda, N.; Wyler, R.; Rebek, J., Jr. Science 1994, 263, 1267-1268.
(9) Hamann, B. C.; Shimizu, K. D.; Rebek, J., Jr. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1326-1329.
(10) von dem Bussche-Hu¨nnefeld, C.; Bu¨hring, D.; Knobler, C. B.; Cram,
D. J. J. Chem. Soc., Chem. Commun. 1995, 1085-1087.
(11) Timmerman, P.; Nierop, K. G. A.; Brinks, E. A.; Verboom, W.;
van Veggel, F. C. J. M.; van Hoorn, W.-P.; Reinhoudt, D. N. Chem.-Eur.
J. 1995, 1, 132-143.
(12) Chopra, N.; Sherman, J. C. Angew. Chem., Int. Ed. 1999, 38, 1955-
1957.
(13) Chopra, N.; Naumann, C.; Sherman, J. C. Angew. Chem., Int. Ed.
2000, 39, 194-196. Also see: Yoon, J.; Cram, D. J. Chem. Commun. 1997,
2065-2066.
(6) Lasic, D. D.; Papahadjopoulos, D. Science 1995, 267, 1275-1276
and literature therein.
(7) Corma, A.; Garcia, H. J. Chem. Soc., Dalton Trans. 2000, 1381-
1394.
10.1021/ja010038r CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/27/2001

4660 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Starnes et al.
Figure 1. Nanoscale unimolecular cavities 1-4 of a first generation.
lecular clefts, concave reagents, and endohedral functions all
testify to the existence of the problem15 but fail to provide
independent binding and functional group sites. An “introverted”
carboxyl group derived from Kemp’s triacid and a cavitand16
appears to provide such an environment and shows a special
behavior in the complexation of amines. Here we examine other
functionssmetalloporphyrins. Although porphyrins have been
attached to almost every type of macrocycle in seemingly every
type of way,17,18 their positioning on the host structures
developed below is uniquely suited for assessing the independent
contributions of the cavitand and porphyrin to the recognition
of guests. We describe here, then, our experiences with hybrids
of porphyrins fused to the self-folding cavitands.
The parent cavitand is so-called self-folding cavitand 5
(Figure 2), in which the cyclic array of eight intramolecular
secondary amide CdO‚‚‚H-N hydrogen bonds holds the four
aromatic walls together and stabilizes the “vase-like” conforma-
tion shown.19 The circle of hydrogen bonds resists the unfolding
of the vase required for guest exchange. This results in a slow
exchange between complexed and free guest species in solution
on the NMR time scale. Resonances for the complexed guest
species such as adamantanes, lactams, and cyclohexanes are
observed upfield of 0 ppm, as expected for inclusion in a
shielded magnetic environment, and their orientation in the
cavity and the stoichiometry of the complexes are easily
deduced. When two self-folding cavitands are covalently
attached, a rigid cylindrical host 6 (Figure 2) results, of
nanoscale dimensions: 10 × 23 Å and ∼800 Å3 internal
volume.20 The molecule resembles hemicarcerands, but the
internal cavity is held by a seam of intramolecular CdO‚‚‚H-N
(17) Cyclodextrin-porphyrins: (a) Kuroda, Y.; Hiroshige, T.; Sera, T.;
Shiroiwa, Y.; Tanaka, H.; Ogoshi, H. J. Am. Chem. Soc. 1989, 111, 1912-
1913. (b) Kuroda, Y.; Ito, M.; Sera, T.; Ogoshi, H. J. Am. Chem. Soc. 1993,
115, 7003-7004. Steroid-capped porphyrins: (c) Bonar-Law, R. P.; Sanders,
J. K. M. J. Am. Chem. Soc. 1995, 117, 259-271. (d) Bonar-Law, R. P.;
Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1 1995, 3085-3096.
Calixarene-porphyrins: (e) Rudkevich, D. M.; Verboom, W.; Reinhoudt,
D. N. Tetrahedron Lett. 1994, 35, 7131-7134. (f) Rudkevich, D. M.;
Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6585-6587. (g)
Nagasaki, T.; Fujishima, H.; Takeuchi, M.; Shinkai, S. J. Chem. Soc., Perkin
Trans. 1 1995, 1883-1888. Glycoluril-porphyrins: (i) Reek, J. N. H.;
Rowan, A. E.; Crossley, M. J.; Nolte, R. J. M. J. Org. Chem. 1999, 64,
6653-6663. (j) Elemans, J. A. A. W.; Claase, M. B.; Aarts, P. P. M.; Rowan,
A. E.; Schenning, A. P. H. J.; Nolte, R. J. M. J. Org. Chem. 1999, 64,
7009-7016. Cyclophane-porphyrins: (k) Benson, D. R.; Valentekovich,
R.; Knobler, C. B.; Diederich, F. Tetrahedron 1991, 47, 2401-2422. Cyclic
arrays of metalloporphyrins: (l) Anderson, S.; Anderson, H. L.; Bashall,
A.; McPartlin, M.; Sanders, J. K. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 1096-1099. Here, high kinetic and thermodynamic stability of the
complexes was demonstrated, however, through multiple ligand-metal
interactions.
(18) Diels-Alder reactions within cyclic, open-ended metalloporphyrin
hosts: (a) Nakash, M.; Clyde-Watson, Z.; Feeder, N.; Davies, J. F.; Teat,
S. J.; Sanders, J. K. M.. J. Am. Chem. Soc. 2000, 122, 5286-5293. (b)
Nakash, M.; Sanders, J. K. M.. J. Org. Chem. 2000, 65, 7266-7271.
(19) (a) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 12216-12225. (b) Rudkevich, D. M.; Hilmersson, G.;
Rebek, J., Jr. J. Am. Chem. Soc. 1997, 119, 9911-9912. (c) Ma, S.;
Rudkevich, D. M.; Rebek, J., Jr., Angew. Chem., Int. Ed. 1999, 38, 2600-
2602.
(14) (a) MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469-
472. (b) Ko¨rner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek,
Jr.; J. Chem.-Eur. J. 2000, 6, 187-195. (c) Lu¨tzen, A.; Renslo, A. R.;
Schalley, C. A.; O’Leary, B. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1999,
121, 7455-7456. (d) Cho, Y. L.; Rudkevich, D. M.; Rebek, Jr., J. J. Am.
Chem. Soc. 2000, 122, 9868-9869. (e) Fox, O. D.; Drew, M. G. B.;
Wilkinson, E. J. S.; Beer, P. D. Chem. Commun. 2000, 391-392. (f)
Gerkensmeier, T.; Iwanek, W.; Agena, C.; Fro¨hlich, R.; Kotila, S.; Na¨ther,
C.; Mattay, J. Eur. J. Org. Chem. 1999, 2257, 7-2262. For other covalently
linked nanosize host-molecules, see: (g) Higler, I.; Timmerman, P.;
Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1996, 61, 5920-5931. (h)
Higler, I.; Verboom, W.; van Veggel, F. C. J. M.; de Jong, F.; Reinhoudt,
D. N. Liebigs Ann./Recl. 1997, 1577-1586. (i) Gibb, C. L. D.; Stevens, E.
D.; Gibb, B. C. Chem. Commun. 2000, 363-364.
(15) Clefts: Rebek, Jr., J. Angew. Chem., Int. Ed. Engl. 1990, 29, 245-
255. Molecular bowls and capsules with an endohedral functionality: Goto,
K.; Okazaki, R. Liebigs Ann./Recl. 1997, 2393-2407. Concave reagents:
Lu¨ning, U. J. Mater. Chem. 1997, 7, 175-182.
(16) Renslo, A. R.; Rebek, Jr., J. Angew. Chem., Int. Ed. 2000, 39, 3281-
3283.

CaVitand-Porphyrins
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4661
Results and Discussion
Synthesis (Scheme 1, Scheme 2). The synthesis of 7 and 8
starts with the versatile diamine cavitands 9a and 9b. These
were described earlier in the context of nanoscale structure 6.20
In short, 9a,b were prepared by partial bridging of the hydroxyls
in the parent resorcinarene with three 1,2-dinitrophenylene walls,
followed by reduction of the NO2 groups. Acylation of the
resulting amino groups with either n-octanoyl or n-propanoyl
chloride gave the respective hexaamides. Now, by adding the
fourth, 1,2-dinitrophenylene wall and reduction of the NO2
groups, much as described for the other three, the final
o-phenylene diamine is in place. Condensation of 9a with
porphyrin dione 1022 in hot anhydrous toluene afforded the
metal-free porphyrin in 43% yield. Subsequent metalation with
Zn(OAc)2 in refluxing CHCl3/MeOH readily gave 7 as the only
product. Bis-cavitand 8 was prepared in the same way from
diamine 9b and porphyrin tetraone 11 and then subsequent
metalation. In this reaction the desired C-shaped isomer 8 was
obtained together with the S-shaped 8-S, in a ∼1:1 ratio. Prior
to the metalation, the isomers were separated by chromatogra-
phy. The assignment of the C- and S-shaped diastereomers was
performed through 1H NMR spectroscopy with their host-guest
complexes and will be described below. The simpler Zn-
porphyrin 13 was prepared analogously for comparison pur-
poses.Although 2,3,12,13-tetraone porphyrin 11 is known, no
experimental details have ever been published.23 We therefore
developed our own protocols and synthesized 11 through
tetrahydroxylation of commercially available tetraphenyl por-
phyrin with OsO4,24 followed by oxidation of the resulting
tetrahydroxybacteriochlorins 12a,b with o-iodoxybenzoic acid
(IBX) in DMSO25 (12% total yield). Guest molecules 14-19
were synthesized from the corresponding adamantyl- and
pyridyl-containing amines, alcohols, and carboxylic acids using
standard coupling protocols (see Experimental Section).
Figure 2. Self-folding container-molecules 5 and 6.
Spectroscopic Properties and Conformational Analysis.
1
According to the extensive FTIR, H and 13C NMR spectro-
scopic studies, molecular modeling, and single-crystal X-ray
analysis,19,26 the upper rim of self-folding cavitands 5 features
a seam of eight intramolecular hydrogen bonds formed by the
secondary amide groups. Four longer CdO‚‚‚H-N hydrogen
bonds bridge the neighboring aromatic walls, and four shorter
ones fix the orientations of the two amides on a given
o-phenylenediamine unit. The head-to-tail pattern gives rise to
two cycloenantiomers,27 with clockwise and counterclockwise
orientation of the amide bonds. The interconversion between
these is slow on the NMR time scale in CDCl3 and aromatic
Figure 3. Cavitand-porphyrins 7 and 8.
hydrogen bonds rather than covalent bonds. Access to the cavity
is facile under ambient conditions, and the uptake and release
of guests is reversible. High kinetic stability of the complexes
was achieved for long (∼18 Å) and rigid adamantyl- and
cyclohexyl-containing guests. The new cavitand-porphyrin
hybrids are 7 and 8 possessing one or even two deepened self-
folding cavities and a metalloporphyrin wall (Figure 3). The
Zn-porphyrin fragment presents an additional, strong binding
functionality for pyridine bases, so that caviplexes of unprec-
edented kinetic and thermodynamic stabilty result with guests
able to interact with both sites.21 Moreover, semi-capsule 8 is
among the largest of synthetic unimolecular hosts, featuring
cavity dimensions of 25 × 10 Å.
(22) Beavington, R.; Rees, P. A.; Burn, P. L. J. Chem. Soc., Perkin Trans.
1 1998, 2847-2851.
(23) (a) Crossley, M. J.; Govenlock, L. J.; Prashar, J. K. J. Chem. Soc.
Chem. Commun. 1995, 2379-2380. (b) Kozyrev, A. N.; Alderfer, J. L.;
Dougherty, T. J.; Pandey, R. K. Angew. Chem., Int. Ed. 1999, 38, 126-
128. While this manuscript was already under review, Promarak and Burn
published their own synthetic protocol to porphyrin 2,3,12,3-tetraone, see:
Promarak, V.; Burn, P. L. J. Chem. Soc., Perkin Trans. 1 2001, 14-20.
(24) Bruckner, C.; Dolphin, D. Tetrahedron Lett. 1995, 36, 9425-9428.
(25) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-
8022.
(26) For further structural details (X-ray, 1H and 13C NMR) of self-folding
cavitands 5, including the enantiomerically pure compounds, see: Shi-
vanyuk, A.; Rissanen, K.; Ko¨rner, S. K.; Rudkevich, D. M.; Rebek, J., Jr.
HelV. Chim. Acta 2000, 83, 1778-1790.
(27) Cycloenantiomerism: (a) Prelog, V.; Gerlach, H. HelV. Chim. Acta
1964, 47, 2288-2294. (b) Goodman, M.; Chorev, M. Acc. Chem. Res. 1979,
12, 1-7. (c) Yamamoto, C.; Okamoto, Y.; Schmidt, T.; Ja¨ger, R.; Vo¨gtle,
V. J. Am. Chem. Soc. 1997, 119, 10547-10548. In agreement with the
Prelog’s terminology, enantiomers 5 possess the clock- and counterclockwise
“directionality” of the eight secondary amide “building blocks” in an
otherwise identical “distribution pattern”, or the sequence or connectivity.
(20) (a) Tucci, F. C.; Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr.
Angew. Chem., Int. Ed. 2000, 39, 1076-1079. (b) Lu¨cking, U.; Tucci, F.
C.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 2000, 122, 8880-
8889.
(21) Preliminary communication: Starnes, S. D.; Rudkevich, D. M.;
Rebek, J., Jr. Org. Lett. 2000, 2, 1995-1998.

4662 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Starnes et al.
Scheme 1
Scheme 2
solvents but fast in more polar solvents. Accordingly, the vase-
shaped structure of C4 symmetry becomes averaged as C4ν
symmetry in cavitand 5 upon increasing solvent polarity. The
1H NMR spectrum of cavitand-porphyrin 7 is C2ν symmetrical;
three methine CH triplets in a 1:2:1 ratio and three porphyrin
â-pyrrole singlets in a 1:1:2 ratio are observed (Figure 4b). The
C(O)-NH resonances of 7 are found far downfield of 8 ppm
(CDCl3, benzene-d6, and toluene-d8), and the corresponding
FTIR spectrum shows hydrogen bonded N-H stretching
absorptions at 3240 cm-1 (toluene). Obviously, the secondary
amides form a seam of intramolecular hydrogen bonds, and their
arrangements should be cycloenantiomeric: again clockwise or
counterclockwise orientation of the head-to-tail amides is
possible. The interconversion between the two enantiomers is,
however, fast on the NMR time scale (600 MHz, at g273 K)
since the 1H NMR spectrum indicates a structure having a plane
of symmetry (Figure 4a,b). As in 5, the characteristic28 methine
(28) (a) Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler,
C. B.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 5707-5714. (b) Tucci, F.
C.; Rudkevich, D. M.; Rebek, J., Jr. Chem.-Eur. J. 2000, 6, 1007-1016.

CaVitand-Porphyrins
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4663
Figure 5. Energy-minimized structures (Amber* Force Field, Mac-
roModel 7.0 program) of host 7 (left, side and top views) and 8 (right,
side view). The extended porphyrin wall is not involved in hydrogen
bonding. Long alkyl chains and CH bonds have been omitted for
viewing clarity. For all cases, only one cycloenantiomeric arrangement
is depicted.
spectroscopy. In general, the cavities of 7 and 8 possess
typical18-20 affinities toward adamantanes, and the Zn-porphyrin
wall strongly complexes pyridines.17 A series of amide/ester-
linked guests, 14-20 (Figure 6), containing either adamantyl,
pyridyl, or both fragments were used in binding assays. Upon
complexation, both the UV/vis and the 1H NMR spectra of hosts
7 and 8 undergo changes (Figures 7 and 8). In the UV/vis
spectra, both Soret and Q-bands shift bathochromic. In particu-
lar, the Soret band of 7 at 412 nm shifts to ∼430 nm upon
complexation, while the Soret band of 8 at 470 nm shifts to
∼480 nm. Clear isosbestic points were found in the UV/vis
spectra upon titration, and integration of the corresponding NMR
spectra indicated a 1:1 stoichiometry for the complexes. Slow
exchange between the free and complexed guests 16-19 was
observed on the NMR time scale already at room temperature.
The bound guest signals were seen upfield of 0 ppm at e300
K. For the complexed 1-substituted adamantanes 16-19, all four
signals of the skeleton protons were clearly seen between 0 and
-2 ppm. The functional group at the adamantane’s 1-position
is generally not shifted upfield in the NMR spectra, indicating
that the adamantane skeleton is oriented toward the bottom of
the cavity in 7 and 8. The pyridyl signals of the complexed
guest were also seen shifted ∼2-3 ppm upfield.
Figure 4. Portions of the 1H NMR spectra (600 MHz) of: (a) metal-
free 7 in benzene-d6 at 330 K. (b) 7 in benzene-d6 at 330 K. (c) metal-
free 8 in CD2Cl2 at 295 K. (d) 8 in toluene-d8 at 330 K. In the downfield
8-10 ppm region, the amide C(O)NH singlets are marked as “O” and
the porphyrin â-pyrrole CH singlets are marked as “b”. The methine
CH triplets are situated at 5-6.5 ppm. The porphyrin NH is seen at
-2 ppm.
CH signals for the vase-shape are seen at ∼6 ppm for 7. The
internal cavity dimensions are estimated29 at 9 × 10 Å, and the
distance between the cavity’s bottom and the porphyrin’s metal
center is ∼14 Å (Figure 5). From molecular modeling and also
by analogy with cavitand 7, the C(O)-NH amides of each cavity
in 8 form a seam of five intramolecular hydrogen bonds within
a vase-like structure (Figure 5). Again, the methine CH signals
(1:2:1 ratio) are seen at ∼5.5-6 ppm, and three C(O)-NH
singlets are downfield 8 ppm; only one porphyrin â-pyrrole
singlet is observed (Figure 4c,d). Each cycloenantiomeric
cavitand in 8 possesses either clockwise or counterclockwise
arrangements of the head-to-tail amides. On the other hand, the
1H NMR spectrum exhibits an average C2ν symmetry that
indicates the rapid interconversion of the two cycloenantiomers.
The internal diameter of 8 was estimated by comparison with
5 and is ∼9-10 Å; the internal length of ∼25 Å was measured
from molecular modeling (Figure 5).29
The UV/vis spectra of compounds 7 and 8 are quite different
from each other and also from the spectra of normal tetra-
arylporphyrins; the conjugated quinoxaline fragment(s) change
the symmetry of the porphyrin. Thus, molecule 7 shows a broad
Soret band with two maxima at 412 and 450 nm and two
Q-bands at 570 and 612 nm, while molecule 8 exhibits large
bands at 415 and 470 nm (Soret) and small abrorption at 555,
605 (Q-bands), and 657 nm.
Neither model adamantane 14 nor model pyridine 15 showed
kinetically stable binding to 7 at 295 K (UV/vis, NMR control).
However, at 273 K, ln Kass ) 5.0 and -∆G273 ) 2.7 kcal mol-1
1
were determined for the 1:1 complex 7•14 from the H NMR
spectra in toluene-d8. This is in fair agreement with the binding
affinities (∼3 kcal mol-1) obtained for the complex 5 with
adamantanes.18 The interaction between the Zn-porphyrin wall
and pyridyl group in toluene was estimated from the titrations
with 7 and 15 or with model porphyrin 13 and 17b, respectively.
The affinity does not exceed -∆G295 ≈ 6.0 kcal mol-1
.
Host-Guest Properties. Binding studies with 7 and 8 were
performed in toluene solution using UV/vis and 1H NMR
At the same time, already 0.4 equiv of bidentate adamantyl-
pyridyl guest 17b was enough to give new signals for the
complex 7•17b (Figure 8a,b). Both adamantyl and pyridyl
signals of the complexed guest were shifted upfield, and separate
sets of signals for the free and bound host were apparent.
(29) MacroModel 7.0; Amber* Force Field. See: Mohamadi, F.;
Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.;
Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440-
467.

4664 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Starnes et al.
Figure 6. Guest-molecules 14-20.
Figure 8. Downfield and upfield portions of the 1H NMR spectra (600
MHz, toluene-d8) of 1:1 complexes: (a) 7•17b at 295 K. (b) 7•17b at
273 K. (c) 8•17b at 273 K. (d) 8•19 at 273 K. The complexed guest
signals are marked as “b”; the alkyl chain’s CH protons of the cavitand
exposed to the porphyrin ring current were assigned through NMR
experiments and are marked as “*”.
Accordingly, bidentate 1:1 binding occurred, with the adamantyl
fragment held within the cavity of 7 and the pyridine complexed
1
to the metal of the porphyrin wall (Figure 9). The H NMR
spectrum of complex 7•17b is rather broad at 295 K, but at
e280 K very sharp signals were observed. All amide N-H
signals were seen separately, indicating that the interconversion
between the cycloenantiomers within the complex is slow.30
Binding UV/vis studies with 7 and 17b in toluene gave the
association energy of -∆G295 ) 9.5 kcal mol-1 (Figure 7a and
Table 1), reflecting simultaneous participation of the cavity and
the Zn-porphyrin in the complexation event. Likewise, strong
Figure 7. Portions of the UV/vis titration spectra with guest 17b
(toluene, 295 K): (a) host 7, (b) host 8.
(30) In guest-free 7, cycloenantiomers interconvert fast even at lower
temperatures.

CaVitand-Porphyrins
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4665
Figure 9. Schematic representation of bidentate binding in cavitand-porphyrins 7 and 8.
Table 1. Association Constants (ln Kass) and Binding Energies
complex 8•19 and only one adamantyl was seen for the complex
8-S•19 ([8] ) [8-S] ) [19] ) 0.5 mM, 270-295 K temperature
range).
(-∆G,295 kcal mol-1) of Guests 14-19 by Porphyrins 7, 8, and
13a,b
complex
ln Kass
-∆G295
∆∆G295
Binding studies between 8 and monoadamantyl 17b and bis-
adamantyl 18 and 19 guests in toluene showed very strong
association: -∆G295 of 9.7, 7.5, and 9.2 kcal mol-1, respec-
tively. (Table). Obviously, the cavities and the Zn-porphyrin
wall were involved in the complexation (Figure 9). The fact
that diester 18 is less strongly complexed than diamide 19 once
again reflects the involvement of the guest’s C(O)-NH proton
in the hydrogen bonding with the cavity’s amide walls.19 At
the same time, the small difference in binding of 17b versus
19 indicates that the contribution of the second adamantyl is
not significant. This may involve the entropic cost of accom-
modating the more bulky 19 within the inner cavity of 8.31
For the complexed adamantyl-pyridine 17b, the set of the
adamantyl’s CH protons was doubled (Figures 8c, 10, and 11),
along with those of the amide NH’s and the aromatics of the
host’s skeleton. Integration showed only one cavity in 8 was
occupied with the adamantane. Accordingly, there are two
diastereomeric 1:1 complexes 8•17b.
7 + 14
c
c
7 + 15
10.3
10.5
11.8
13.6
12.9
12.0
9.5
16.2
16.5
13.6
15.8
8.9
6.0
6.1
6.9
7.9
7.5
7.0
5.6
9.5
9.7
7.5
9.2
5.2
0.0
0.1
0.9
1.9
1.5
1.0
-0.4
3.5
7 + 16a
7 + 16b
7 + 16c
7 + 16d
7 + 16e
7 + 17a
7 + 17b
8 + 17b
8 + 18
3.7
8 + 19
13 + 17b
a Determined by UV/vis in toluene at 295 K. [7] ) [8] ) [13] )
4.5 × 10-6 M, guest concentration 2.0 × 10-6 - 8.0 × 10-5 M. Error
(10%. b Data collected from at least two independent experiments.c No
visible complexation was detected by UV/vis in toluene at 295 K. No
kinetically stable complex was detected at 295 K by 1H NMR in
toluene-d8. At 273 K, ln Kass ) 5.0 and -∆G295 ) 2.7 kcal mol-1 was
1
calculated from the H NMR experiment in toluene-d8.
This was not unexpected. As in the topologically similar
nanostructures 6,20 molecule 8 possesses two cycloenantiomeric
cavities. In the absence of guests, the interconversion between
the two cycloenantiomeric forms is fast (see Figure 4c,d), and
the cyclodiastereomers were not thus observed. Upon complex-
ation, the interconversion of 8•17b (and 7•17b!) becomes slow.
Pairwise Guest Selection. In the complex 8•17b, not only
the occupied but also the “empty” (e.g., solvated with toluene)
binding (-∆G295 ) 7.9 and 7.5 kcal mol-1) was detected for
adamantyl-pyridines 16c and d, respectively, in which the
bound fragments are separated by two methylenes and a
secondary amide. This appears to be the optimal length for the
spacer; with the shorter 16a,b and 17a and longer 16e, lower
binding was measured (-∆G295 between 5.6 and 7.0 kcal
mol-1). Here, the cavity contributed less than 1 kcal mol-1 to
the overall complexation.
(31) Strong binding was also detected for the S-shaped diastereomer 8-S
and adamantyl-pyridines 17b, 18, and 19 (UV/vis, 1H NMR); the binding
energy values (-∆G295) of 9.9, 6.9, and 9.6 kcal mol-1, respectively, were
determined. However, unlike C-shaped 8, addition of more than 1 equiv of
these guests to the toluene solution of 8-S results in a disappearance (!) of
kinetically stable complexes in the corresponding 1H NMR spectra and also
causes an additional shoulder in the UV/vis spectra. The guest complexation
in 8-S may equally take place from both sides of the porphyrin plane; such
competition apparently results in the faster guest exchange. Similar
phenomena have been previously reported by Sanders and co-workers:
Hunter, C. A.; Meah, M. N.; Sanders, J. K. M. J. Am. Chem. Soc. 1990,
112, 5773-5780.
Container molecule 8 features cavities that are well preor-
ganized for cooperative binding, and it readily forms kinetically
stable complexes with long guests 18 and 19 containing two
adamantyl ends with a pyridyl in the center. All four 1-ada-
mantyl signals were clearly observed upfield of 0 ppm (Figure
8c,d), and aided the structure assignment to the C-shaped 8 and
the S-shaped diastereomer 8-S. Specifically, two adamantyl
1
fragments were integrated in the H NMR spectrum of the

4666 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Starnes et al.
from the interior. The following entrapment of adamantane 20
brings another 2-3 kcal mol-1 of energy and releases the second
solvent molecule from the remaining cavity. As a result, the
ternary complex 17b•8•20 is formed quantitatiVely.32 In another
experiment, both cavities of 8 were first saturated with ada-
mantane 20 (1H NMR control at 250 K), and then one of the
guest molecules was replaced upon addition of 1 equiv of 17b.
As in the previous case, the ternary complex 17b•8•20 was
formed exclusively.
Conclusions and Outlook
Molecular hosts surrounding their guests range from the
covalently sealed carcerands to reversibly self-assembled hy-
drogen-bonded capsules. The unimolecular, deepened cavities
in self-folding structures 5-8 are in-between in their properties.
They are open and bind guests reversibly, but strong and slow
on the NMR time scale. The cavities, lined with aromatic
surfaces, act as supramolecular NMR shift reagents. The internal
space is nanoscale, and the constant flow of substrates into and
products out of the cavity may be envisioned in their use is as
reaction chambers. In the cases at hand, the porphyrin functions
contribute to high binding affinities of appropriate guests and
raise the possibility of metal-catalyzed reactionssalkane hy-
droxylations or alkene epoxidationssin these containers. The
spectroscopic properties of the porphyrin wall promises energy
transfer to the appropriate guest molecules. The stoichiometric
pairwise selection of guests is unprecedented for unimolecular
hosts, and bimolecular reactions within the shielded interior are
likely. The synthesis of water-soluble and polymer-immobilized
versions of hosts 7 and 8 is also possible.33
Figure 10. Cartoon representation of cyclodiastereomerism in 8.
cavity exists as a mixture of cycloenantiomers, and they are in
slow NMR exchange. This implies some sort of communication
1
between these cavities. In the H NMR experiment, stepwise
addition of N-(1-adamantyl)acetamide 20 to the toluene-d8
solution of complex 8•17b resulted in the disappearance of the
doubled set of the adamantyl diastereomeric signals (Figure 11).
When g1 equiv of 20 is added, only one set for all groups of
the adamantane CH protons is clearly present. Obviously, guest
20 replaces the toluene molecule from the “empty” cavity of
8•17b; the signals for the encapsulated 20 were observed
simultaneously with the encapsulated 17b upon lowering the
temperature to ∼250 K. It is also known that N-(1-adamantyl)-
carboxamides accelerate the interconversion of the cycloenan-
tiomeric hydrogen-bonded seams in self-folding cavitands.19
Accordingly, upon complexation of 20 two cyclodiastereomers
are in a fast exchange on the NMR time scale.
These applications are currently under exploration and will
be reported in due course.
Experimental Section
General. Melting points were determined on a Thomas-Hoover
1
capillary melting point apparatus and are uncorrected. H NMR and
13C NMR spectra were recorded on Bruker DRX-600 spectrometer.
Chemical shifts were measured relative to residual nondeuterated solvent
resonances. FTIR spectra were recorded on a Perkin-Elmer Paragon
1000 PC FT-IR spectrometer. UV/vis spectra were recorded on a Perkin-
Elmer UV/vis Lambda 12 spectrometer. High-resolution matrix-assisted
laser desorption/ionization mass spectrometry (HR MALDI FTMS)
experiments were performed on a IonSpec HiResMALDI Fourier
transform mass spectrometer. For high-resolution mass spectral data
of compounds with molecular weight g2000, lower than 10 ppm
More intriguing is the pairwise selection of two different
guests by molecular container 8 (Figure 12). Complexation of
adamantyl-pyridine 17b produces ∼9 kcal mol-1 of binding
energy and doubtlessly replaces one solvent (toluene) molecule
1
Figure 11. Ternary complex 17b•8•20. Upfield portions of the H NMR spectra of the complexes (600 MHz, toluene-d8, 273 K): (a) 8•17b. (b)
8•17b and 1 equiv of 20. (c) 8•17b and 10 equiv of 20.

CaVitand-Porphyrins
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4667
Figure 12. Pairwise selection experiments: a cartoon representation. Two performed routes toward ternary complex 17b•8•20 are shown (1H
NMR experiment, 600 MHz, toluene-d8, 250-273 K).
resolution was achieved.34 Column chromatography was performed with
Silica Gel 60 (EM Science or Bodman, 230-400 mesh). All experi-
ments with moisture- or air-sensitive compounds were performed in
anhydrous solvents under a nitrogen atmosphere. Molecular modeling
was performed using the Amber* force field in MacroModel 7.0.29
cis- and trans-isomers were separated with Rf (trans-) ) 0.46 and Rf
(cis-) ) 0.35 (97:3 CH2Cl2:MeOH) as purple solids. Combined yield
257 mg (40%). cis-isomer 12a: 1H NMR (DMSO-d6, 330 K): δ 7.96
(d, 4H, J ) 1.8 Hz), 7.92 (br s, 8H), 7.61 (m, 12H), 5.98 (s, 4H), 4.80
(br s, 4 H, OH), -1.52 (s, 2H);1H NMR (CDCl3, 295 K, 600 MHz):
δ 8.13 (s, 4H), 8.07 (d, 4H, J ) 6.3 Hz), 7.86 (d, 4H, J ) 5.3 Hz),
7.66 (m, 12H), 6.21 (s, 4H), 2.95 (s, 4 H, OH), -1.79 (s, 2H); 13C
NMR (CDCl3, 295 K, 150 MHz): δ 158.5, 141.2, 137.4, 133.8, 131.9,
128.1, 123.7, 116.0, 74.0; HRMALDI-FTMS m/z 683.2651 ([M + H]+,
calcd for C44H34N4O4H 683.2653, error ) 0.3 ppm). trans-isomer
12b: 1H NMR (DMSO-d6, 330 K): δ 8.02 (d, 4H, J ) 1.6 Hz), 7.89
(br s, 8H), 7.61 (m, 12H), 5.88 (s, 4H), 4.86 (br s, 4 H, OH), -1.63 (s,
2H);1H NMR (CDCl3, 295 K): δ 8.15 (d, 4H, J ) 1.8 Hz), 8.04 (d,
4H, J ) 5.0 Hz), 7.85 (br d, 4H), 7.66 (m, 12H), 6.16 (s, 4H), 3.06 (s,
4 H, OH), -1.86 (s, 2H); 13C NMR (CDCl3, 295 K, 150 MHz): δ
158.1, 141.2, 137.4, 133.5, 132.1, 128.1, 123.7, 116.1, 74.2; HRM-
ALDI-FTMS m/z 683.2680 ([M + H]+, calcd for C44H34N4O4H
683.2653, error ) 4.0 ppm).
cis- and trans-2,3,12,13-Tetrahydroxybacteriochlorin, Mixture of
Isomers (12a, 12b). OsO4 (0.5 g, 2.0 mmol) (toxic!) was dissolved in
diethyl ether (5 mL) and pyridine (2 mL), and the resulting bright-
orange solution was added to tetraphenylporphyrin (580 mg, 0.94 mmol)
dissolved in CHCl3 (200 mL). The mixture was stirred in the dark under
a nitrogen atmosphere at 25-30 °C for 7 days. The solvent was
removed in vacuo, and the solid residue was dissolved in CH2Cl2 (250
mL). H2S was then bubbled through the solution for 15 min. The
solution was filtered through Celite; the flask and the Celite layer were
rinsed with CH2Cl2 (50 mL) and MeOH:CH2Cl2, 1:9 (200 mL). The
solvent was removed in vacuo and the product purified first by
extracting the solid residue with CH2Cl2 (2 × 20 mL). The cis- and
trans-tetrahydroxybacteriochlorins 12a,b are sparingly soluble in CH2-
Cl2; thus, the initial extraction provides a rough purification. The product
was further purified by column chromatography (gradient ranging from
CH2Cl2 then 99:1, 98:2, 97:3, and finally 96:4 CH2Cl2:MeOH). The
Porphyrin 2,3,12,13-Tetraone (11). IBX (492.4 mg, 1.76 mmol)
was suspended in DMSO (2 mL) and stirred for 1 h to achieve complete
dissolution of the oxidant. A mixture of the cis- and trans-isomers 12a,b
(150 mg, 0.22 mmol) in DMSO (3 mL) was then added. The reaction
mixture was stirred at room temperature, and the course of the
conversion was followed by TLC (SiO2, 98:2 CH2Cl2:MeOH). After
10-12 h, an additional of IBX (246.2 mg, 0.88 mmol) was added (e.g.,
3 equiv of IBX per alcohol), and the mixture was stirred at 50 °C for
2 h and then at room temperature overnight. Water (20 mL) was added,
resulting in precipitation of the desired product. The mixture was
filtered, and the solid residue was rinsed with water (5 × 20 mL). The
solid residue was then washed with CH2Cl2 to extract the porphyrin
product. The CH2Cl2 solution was evaporated in vacuo, and the product
was purified by column chromatography (CH2Cl2, Rf ) 0.44) to afford
11 as a purple solid. Yield 46.3 mg (31%, not optimized). Mp > 275
(32) Size-shape pairwise selection of two different guests by a self-
assembled cylindrical capsule: (a) Heinz, T.; Rudkevich, D. M.; Rebek,
J., Jr. Nature 1998, 394, 764-766. (b) Heinz, T.; Rudkevich, D. M.; Rebek,
J., Jr. Angew. Chem., Int. Ed. 1999, 38, 1136-1139. (c) Tucci, F. C.;
Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 4928-
4929. For the examples from the carcerand chemistry, see ref 13. In steroid-
capped porphyrins, see ref 17c.
(33) For the recent synthesis of water-soluble self-folding cavitands,
see: Haino, T.; Rudkevich, D. M.; Shivanyuk, A.; Rissanen, K.; Rebek, J.,
Jr. Chem.-Eur. J. 2000, 6, 3797-3805. Preliminary results on polymer-
supported self-folding cavitands: Rafai Far, A.; Rudkevich, D. M.; Haino,
T.; Rebek, J., Jr. Org. Lett. 2000, 2, 3465-3468.
(34) For details on high-resolution mass spectrometry, see: (a) Rose,
M. E.; Johnstone, R. A. W. Mass Spectrometry for Chemists and
Biochemists; Cambridge University Press: Cambridge, 1982. (b) Jennings,
K. R.; Dolnikowsi, G. G. Methods in Enzymology; McCloskey, J. A., Ed.;
Academic Press: New York, 1990; p 37 and references therein.
1
°C; H NMR (CDCl3, 295 K): δ 8.49 (s, 4H), 7.81 (d, 8H, J ) 7.2
Hz), 7.74 (t, 4H, J ) 7.3 Hz), 7.68 (t, 8H, J ) 7.3 Hz), -1.86 (s, 2H);
13C NMR (CDCl3, 295 K, 150 MHz): δ 186.9, 140.9, 139.6, 138.4,

4668 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Starnes et al.
132.5, 129.0, 128.7, 127.6, 117.4; FTIR (CH2Cl2, thin film, cm-1): ν
3426, 3053, 2986, 1728, 1637, 1417; UV/vis [CHCl3, λ max (log ꢀ)
383.9 (5.20), 630.0 (3.58), 774.20 (3.59); HRMALDI-FTMS m/z
674.1987 ([M]-, calcd for C44H26N4O4 674.1960, error ) 4.0 ppm).
Zn-Porphyrin (8). A Typical Procedure. Hexaamide diamine
cavitand 9b (152.7 mg, 0.082 mmol) and tetraone 11 (27.7 mg, 0.041
mmol) were dissolved in anhydrous toluene (20 mL), and nitrogen gas
was bubbled through the mixture for 15 min. The mixture was stirred
in the dark at 90 °C for 36 h. The solvent was removed in vacuo and
the product isolated by column chromatography (eluting with a gradient
ranging from CH2Cl2 then 99:1, 98:2, and finally 97:3 CH2Cl2:MeOH).
The S-isomer eluted prior to the C-isomer. The products were then
triturated with hexane and MeOH, affording 39 mg of the S-isomer
(22%) and 37 mg of the C-isomer (21%) as purple solids. S-isomer:
2H); HRMALDI-FTMS m/z 777.2951 ([M + H]+, calcd for C52H36-
1
N6O2H 777.2973, error ) 2.8 ppm). Zn-porphyrin 13: yield 33%; H
NMR (toluene-d8, 295 K): δ 9.00 (d, 2H, J ) 4.6 Hz), 8.95 (d, 2H, J
) 4.6 Hz), 8.91 (s, 2H), 8.33 (d, 4H, J ) 7.1 Hz), 8.25-8.23 (m, 4H),
7.85 (t, 2H, J ) 7.4 Hz), 7.79-7.75 (m, 4H), 7.55-7.52 (m, 6H), 7.27
(s, 2H), 3.51 (s, 6H); HRMALDI-FTMS m/z 839.2076 ([M + H]+,
calcd for C52H34N6O2ZnH 839.2107, error ) 3.7 ppm).
General Procedure for the Preparation of Ester and Amide
Guests (14, 15, 16a, 17a,b-19). The acid chloride (1 equiv) (2 equiv
for guest ester) was dissolved in EtOAc (2-3 mL) and added to a
rapidly stirred mixture of the amine (1 equiv) and K2CO3 (2 equiv) in
a 1:1 EtOAc/H2O mixture (50 mL). The guest precipitated from the
reaction mixture in each case. After 2 h, the mixture was filtered and
the solid residue recrystalized from toluene to give 14, 15, 16a, 17a,b,
18, and 19 as white solids in 27-90% yields.
1
mp > 275 °C; H NMR (CD2Cl2, 295 K): δ 9.46 (br s, 4H), 9.28 (br
s, 4H), 9.00 (s, 4H), 8.45 (br s, 4H), 8.17 (br s, 8H), 7.95 (t, 4H, J )
7.6 Hz), 7.82 (t, 8H, J ) 7.3 Hz), 7.72 (s, 4H), 7.58 (br s, 3H), 7.46
(s, 4H), 7.32-7.22 (m, 22H), 5.80 (t, 2H, J ) 8.3 Hz), 5.67 (t, 4H, J
) 8.2 Hz), 5.05 (br s, 2H), 2.48-2.14 (m, 32H), 1.9-1.7 (m, 8H),
1.45-0.95 (m, 173H), 0.90-0.80 (m, 34H), 0.80-0.70 (m, 4H), 0.54-
0.45 (m, 14H), -2.54 (s, 2H); MALDI-TOF m/z 4318 ([M + H]+,
calcd for C272H322N20O28H 4317.4). C-isomer: mp > 275 °C; 1H NMR
(CD2Cl2, 295 K): δ 9.47 (br s, 4H), 9.28 (br s, 4H), 8.99 (s, 4H), 8.45
(br s, 4H), 8.17 (br s, 8H), 7.95 (t, 4H, J ) 7.7 Hz), 7.82 (br t, 8H),
7.71 (s, 4H), 7.58 (br s, 3H), 7.46 (s, 4H), 7.27-7.24 (m, 22H), 5.79
(t, 2H, J ) 8.3 Hz), 5.67 (t, 4H, J ) 8.1 Hz), 5.01 (br s, 2H), 2.45-
2.13 (m, 32H), 1.9-1.7 (m, 8H), 1.46-0.92 (m, 174H), 0.91-0.80
(m, 34H), 0.80-0.65 (m, 4H), 0.59-0.45 (m, 14H), -2.54 (s, 2H);
MALDI-TOF m/z 4318 ([M + H]+, calcd for C272H322N20O28H 4317.4).
The free base S-isomer (20.5 mg, 0.0047 mmol) was added to a
solution of Zn(OAc)2 (7 mg) in CHCl3:MeOH, 2:1 (15 mL). Separately,
the free base C-isomer (21.8 mg, 0.0051 mmol) was added to a flask
containing Zn(OAc)2 (7.4 mg) in CHCl3:MeOH, 2:1 (15 mL). Each
solution was refluxed for 4 h (TLC control, SiO2, 98:2 CH2Cl2:MeOH).
The solvent was removed, and each mixture was taken up in CH2Cl2
and extracted with water and then brine. The organic layer was dried
over Na2SO4. The solvent was removed to give the metal-containing
8-S (19 mg, 91%), and C-isomer 8 (20 mg, 88%). 8-S: mp > 275 °C;
1H NMR (toluene-d8, 330 K): δ 9.65 (br s, 4H), 9.02 (s, 4H), 8.32-
8.0 (m, 9H), 7.75 (m, 30H), 6.30 (t, 2H, J ) 7.6 Hz), 6.14 (t, 4H, J )
7.6 Hz), 5.32 (br s, 2H), 2.50-2.12 (m, 22H), 1.85-0.58 (m, 264H);
UV/vis (toluene): λ 420, 480, 556, 606, 655; MALDI-TOF m/z 4378
([M + H]+, calcd for C272H320N20O28ZnH 4379.4). 8: mp > 275 °C;
1H NMR (toluene-d8, 330 K): δ 9.63 (br s, 4H), 9.02 (s, 4H), 8.35-
8.0 (m, 9H), 7.75 (m, 30H), 6.29 (br t, 2H), 6.13 (br t, 4H), 5.19 (br
s, 2H), 2.45-2.12 (m, 22H), 1.85-0.58 (m, 264H); UV/vis (toluene):
λ 415, 470, 555, 605, 657; MALDI-TOF m/z 4378 ([M + H]+, calcd
for C272H320N20O28ZnH 4379.4). Analogously, porphyrins 7 and 13 were
obtained.
2-(1-Adamantanyl)-N-benzyl-ethanamide (14): mp 167-168 °C;
1H NMR (CDCl3, 295 K): δ 7.29-7.26 (m, 2H), 7.23-7.19 (m, 3H),
5.57 (br s, 1H), 4.37 (d, 2H, J ) 5.6 Hz), 1.90 (s, 5H), 1.66-1.62 (m,
3H), 1.57 (s, 9H); 13C NMR (CDCl3, 295 K): δ 171.0, 138.6, 128.9,
128.1, 127.6, 52.0, 43.8, 42.8, 36.9, 33.0, 28.8; HRMALDI-FTMS m/z
284.2016([M]+, calcd for C19H25NOH 284.2009, error ) 2.5 ppm).
N-(Pyridin-3-ylmethyl)-hexanamide (15): mp 56-57 °C; 1H NMR
(toluene-d8, 295 K): δ 8.39-8.35 (m, 2H), 7.18-7.16 (m, 1H), 6.69-
6.65 (m, 1H), 4.56 (br s, 1H), 3.93 (d, 2H, J ) 6.1 Hz), 1.69 (t, 2H, J
) 7.7 Hz), 1.51 (p, 2H, J ) 7.4 Hz), 1.23-1.10 (m, 4H), 0.85 (t, 3H,
J ) 7.1 Hz); 13C NMR (CDCl3, 295 K): δ 173.5, 149.1, 148.7, 135.7,
134.5, 123.7, 40.9, 36.6, 31.5, 25.5, 22.5, 14.0; HRMALDI-FTMS m/z
207.1492 ([M]+, calcd for C12H18N2OH 207.1492, error ) 0.0 ppm).
N-(1-Adamantyl)-nicotinamide (16a): mp 164-165 °C; 1H NMR
(toluene-d8, 295 K): δ 8.92 (s, 1H), 8.50 (s, 1H), 7.87 (s, 1H), 6.72 (s,
1H), 5.25 (br s, 1H), 2.25-2.15 (m, 6H), 2.05-1.97 (m, 3H), 1.65-
1.58 (m, 6H); 13C NMR (CDCl3, 295 K): δ 164.8, 152.0, 147.8, 135.1,
131.7, 123.6, 52.9, 41.7, 36.4, 29.6; HRMALDI-FTMS m/z 257.1639
([M + H]+, calcd for C16H20N2OH 257.1648, error ) 3.5 ppm).
Adamantanecarboxylic acid N-(pyridin-3-ylmethyl)-amide (17a):
1
mp 120-122 °C; H NMR (toluene-d8, 295 K): δ 8.43 (s, 1H), 8.39
(d, 1H, J ) 5.0 Hz), 7.21 (d, 1H, J ) 7.6 Hz), 6.73-6.69 (m, 1H),
5.27 (br s, 1H), 4.05 (d, 2H, J ) 5.8 Hz), 1.78 (s, 3H), 1.66-1.60 (m,
6H), 1.58-1.45 (m, 6H); 13C NMR (CDCl3, 295 K): δ 178.3, 149.0,
148.8, 135.6, 134.6, 123.7, 40.9, 40.8, 39.4, 36.5, 28.2; HRMALDI-
FTMS m/z 271.1806 ([M]+, calcd for C17H22N2OH 271.1805, error )
0.4 ppm).
2-(1-Adamantyl)-N-pyridin-3-ylmethyl-ethanamide (17b): mp
1
131-132 °C; H NMR (toluene-d8, 295 K): δ 8.41 (s, 1H), 8.38 (d,
1H, J ) 4.0 Hz), 7.22 (d, 1H, J ) 7.8 Hz), 6.70-6.67 (m, 1H), 4.72
(br s, 1H), 3.96 (d, 2H, J ) 6.1 Hz), 1.88-1.85 (br s, 3H), 1.64-1.53
(m, 14H); 13C NMR (CDCl3, 295 K): δ 171.2, 149.3, 149.0, 135.9,
134.4, 123.7, 51.8, 42.8, 41.1, 36.8, 33.0, 28.7; HRMALDI-FTMS m/z
285.1953 ([M]+, calcd for C18H24N2OH 285.1961, error ) 2.8 ppm).
Porphyrin-monocavitand (7): metal-free porphyrin: yield 42%;
1H NMR (benzene-d6, 330 K): δ 9.82 (s, 2H), 9.28 (s, 2H), 8.96 (d,
2H, J ) 4.8 Hz), 8.85-8.82 (m, 4H), 8.17 (s, 4H), 8.10 (d, 4H, J )
6.7 Hz), 8.03 (s, 2H), 7.85 (br s, 2H), 7.71-7.52 (m, 12H), 7.51-7.43
(m, 10H), 7.40 (s, 2H), 7.28 (s, 2H), 6.37 (t, 1H, J ) 8.1 Hz), 6.23 (t,
2H, J ) 8.1 Hz), 5.20 (t, 1H), 2.50-2.22 (m, 14H), 2.21-2.12 (m,
2H), 1.97-1.80 (m, 8H), 1.70-1.50 (m, 6H), 1.53 (s, 10H), 1.51-
1.18 (m, 86H), 1.05-0.72 (m, 52H), 0.68-0.60 (m, 8H), -2.13 (s,
2H); MALDI-TOF m/z 2889 av ([M]+, calcd for C188H236N12O14 2889).
Zn-porphyrin 7: Yield 91%; 1H NMR (benzene-d6, 330 K): δ 9.81 (s,
2H), 9.28 (s, 2H), 9.05 (d, 2H, J ) 4.6 Hz), 8.98 (d, 2H, J ) 4.6 Hz),
8.93 (s, 2H), 8.28-8.22 (m, 8H), 8.11 (s, 2H), 7.90-7.80 (br s, 2H),
7.79-7.42 (m, 26H), 6.36 (t, 1H, J ) 8.1 Hz), 6.24 (t, 2H, J ) 8.1
Hz), 5.08 (br t, 1H), 2.45-2.10 (m, 20H), 1.98-1.80 (m, 8H), 1.75-
1.15 (m, 126H), 1.05-0.85 (m, 24H), 0.80-0.70 (m, 3H), 0.53-0.50
(m, 3H); FTIR (toluene, cm-1): ν 3240, 1666, 1277, 1223, 1123, 1006,
797; UV/vis (toluene): λ 412, 450, 570, 612; MALDI-TOF m/z 2952
av ([M]+, calcd for C188H234N12O14Zn 2952).
3,5-Pyridine diester (18): mp 90-92 °C; 1H NMR (toluene-d8, 295
K): δ 8.49 (s, 2H), 7.32 (s, 1H), 4.74 (s, 4H), 1.91 (s, 4H), 1.83 (s,
6H), 1.60-1.56 (m, 6H), 1.53-1.51 (m, 18H); 1H NMR (CDCl3, 295
K): δ 8.56 (s, 2H), 7.67 (s, 1H), 5.10 (s, 4H), 2.10 (s, 4H), 1.93 (br s,
6H), 1.68-1.64 (m, 6H), 1.60-1.55 (m, 18H).); 13C NMR (CDCl3,
295 K): δ 171.6, 149.4, 136.0, 131.9, 63.1, 48.8, 42.5, 36.9, 33.1, 28.7;
HRMALDI-FTMS m/z 492.3106 ([M + H]+, calcd for C31H41NO4H
492.3108, error ) 0.4 ppm).
3,5-Pyridine diamide (19): mp 193-194 °C; 1H NMR (CDCl3, 295
K): δ 8.42 (br s, 2H), 7.56 (s, 1H), 5.85 (br t, 2H), 4.41 (d, 4H, J )
6 Hz), 1.96 (s, 4H), 1.93 (br s, 6H), 1.68-1.64 (m, 6H), 1.60-1.55
(m, 18H); 13C NMR (CDCl3, 313 K): δ 171.4, 148.6, 135.4, 52.0,
43.1, 41.2, 37.1, 33.3, 29.0; HRMALDI-FTMS m/z 490.3415 ([M +
H]+, calcd for C31H43N3O2H 490.3428, error ) 2.7 ppm).
General Procedure for the preparation of Amide Guests (16b-
e). The corresponding acid (1 equiv), the amine (1 equiv), DCC (1
equiv), and a catalytic amount of DMAP (∼5 mg) were suspended in
anhydrous THF (75 mL). The mixture was stirred for 2 days at 35 °C.
The solvent was removed in vacuo, and the solid residue was dissolved
in EtOAc and washed with water and brine. The organic layer was
dried over MgSO4, the solvent was then removed in vacuo, and the
Model porphyrin (13): metal-free porphyrin: yield 47%; 1H NMR
(CDCl3, 295 K): δ 8.9 (dd, 4H, J ) 4.4 Hz, ∆ν ) 10.6 Hz), 8.70 (s,
2H), 8.20 (d, 4H, J ) 6.8 Hz), 8.15 (d, 4H, J ) 7.2 Hz), 7.85 (t, 2H,
J ) 7.5 Hz), 7.80-7.75 (m, 10H), 7.06 (s, 2H), 4.10 (s, 6H), -2.61 (s,

CaVitand-Porphyrins
J. Am. Chem. Soc., Vol. 123, No. 20, 2001 4669
product was purified by column chromatography (EtOAc) to give the
amides 16b-e as white solids in 40-70% yields.
(s, 1H), 6.72-6.69 (m, 1H), 2.80 (t, 2H, J ) 6.5 Hz), 2.70 (t, 2H, J )
7.4 Hz), 1.94 (t, 2H, J ) 7.3 Hz), 1.82 (s, 3H), 1.55 (dd, 6H, J ) 12.1
Hz, ∆ν ) 50.6 Hz), 1.22 (s, 6H); 13C NMR (CDCl3, 295 K): δ 171.5,
149.9, 147.8, 136.5, 136.3, 123.5, 51.1, 40.5, 38.2, 37.0, 33.7, 29.0,
28.3; HRMALDI-FTMS m/z 299.2129 ([M + H]+, calcd for C19H26N2-
OH 299.2118, error ) 3.7 ppm).
Determination of the Association Constant. Binding studies were
performed in toluene solution at 295 ( 1 K. An aliquot from the stock
solution of compounds 15-19 was added to the sample cell (1 mL)
containing hosts 7, 8, or 13 and after homogenization, the absorption
spectrum was recorded. Additional aliquots of 15-19 were added, and
the spectrum was recorded after each addition. Host concentration [7]
) [8] ) [13] ) 4.5 × 10-6 M, guest concentration range 2.0 × 10-6
- 8.0 × 10-5 M. The association constant was calculated from the
absorption intensity changes by nonlinear regression analysis. Error10%.
All experiments were performed at least in duplicate.
N-(1-Adamantyl)-2-(pyridin-3-yl)ethanamide (16b): mp 174-175
°C; 1H NMR (toluene-d8, 295 K): δ 8.39 (s, 2H), 7.27 (d, 1H, J ) 7.6
Hz), 6.72-6.68 (m, 1H), 2.85 (s, 2H), 1.82-1.77 (m, 9H), 1.49-1.43
(m, 6H); 13C NMR (CDCl3, 295 K): δ 168.9, 150.2, 148.4, 136.8,
131.4, 123.6, 52.3, 41.6, 41.6, 36.3, 29.4; HRMALDI-FTMS m/z
271.1798 ([M]+, calcd for C17H22N2OH 271.1805, error ) 2.6 ppm).
N-(1-Adamantyl)-3-(pyridin-3-yl)propanamide (16c): mp 148-
149 °C; 1H NMR (toluene-d8, 295 K): δ 8.41-8.36 (m, 2H), 7.09 (s,
1H), 6.72-6.69 (m, 1H), 2.65 (t, 2H, J ) 7.4 Hz), 1.87 (s, 9H), 1.79
(t, 2H, J ) 7.3 Hz), 1.55-1.48 (m, 6H); 13C NMR (CDCl3, 295 K):
δ 170.5, 149.9, 147.7, 136.6, 136.3, 123.5, 52.1, 41.7, 38.9, 36.4, 29.5,
28.9; HRMALDI-FTMS m/z 285.1954 ([M + H]+, calcd for C18H24N2-
OH 285.1961, error ) 2.5 ppm).
N-(1-Adamantylmethyl)-2-(pyridin-3-yl)ethanamide (16d): mp
1
108-110 °C; H NMR (toluene-d8, 295 K): δ 8.47 (s, 1H), 8.35 (d,
1H, J ) 4.7 Hz), 7.38 (d, 1H, J ) 7.7 Hz), 6.76-6.70 (m, 1H), 5.65
(br s, 1H), 3.10 (s, 2H), 2.84 (d, 2H, J ) 6.5 Hz), 1.81 (s, 3H), 1.54
(dd, 6H, J ) 12.1 Hz, ∆ν ) 46.1 Hz), 1.28 (s, 6H); 13C NMR (CDCl3,
295 K): δ 170.0, 150.4, 148.8, 137.0, 131.2, 123.8, 51.3, 41.0, 40.3,
37.0, 33.9, 28.2; HRMALDI-FTMS m/z 285.1953 ([M + H]+, calcd
for C18H24N2OH 285.1961, error ) 2.8 ppm).
Acknowledgment. We are grateful for financial support from
the Skaggs Research Foundation and the National Institutes of
Health. We thank Professor Dr. F. N. Diederich of ETH, Zu¨rich
for providing us with the curve-fitting program. Dr. A. Rafai
Far is acknowledged for experimental advice.
N-(1-Adamantylmethyl)-3-(pyridin-3-yl)propanamide (16e): mp
92-93 °C; 1H NMR (toluene-d8, 295 K): δ 8.41-8.35 (m, 2H), 7.10
JA010038R