Supramolecular aggregates of dendritic cyclophanes (dendrophanes) threaded on molecular rods with steroid termini

Article abstract of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3154::AID-ANIE3154>3.0.CO;2-W

Multinanometer-sized assemblies with molecular weights exceeding 14 000 are obtained by the threading of two dendritic cyclophanes (dendrophanes) onto molecular rods in which two testosterone termini are attached by rigid spacers to a central phenyl ring

Full text of DOI:10.1002/(SICI)1521-3773(19981204)37:22<3154::AID-ANIE3154>3.0.CO;2-W

COMMUNICATIONS
Poppe, J. Organomet. Chem. 1993, 454, 9; d) W. Uhl, U. Schutz, W.
Kaim, E. Waldhör, J. Organomet. Chem. 1995, 501, 79; e) R. J.
Wehmschulte, K. Ruhlandt-Senge, M. M. Olmstead, H. Hope, B. E.
Sturgeon, P. P. Power, Inorg. Chem. 1993, 32, 2983.
order structures in the absence of metal ions has only been
achieved in a few cases.[4±7] A particularly intriguing example
for dendritic self-association is the discrete hexameric assem-
bly of dendritic wedges through directional COOH ´´´ COOH
hydrogen-bonding interactions, which was reported by Zim-
merman and co-workers.[6] Hydrophobic nonstoichiometric
association of dendrimers in aqueous solution has been
observed on several occasions,[5, 8] yet apolar bonding inter-
actions and hydrophobic desolvation have not been previous-
ly employed to form structurally defined supramolecular
aggregates containing two or more dendritic components.
Here we report for the first time the formation of such
assemblies in aqueous solution by hydrophobically driven
threading of water-soluble dendrophanes (dendritic cyclo-
phanes)[9] onto the testosterone termini of suitably designed
molecular rods.
[2] a) W. Uhl, A. Vester, D. Fenske, G. Baum. J. Organomet. Chem. 1994,
464, 23; b) W. Uhl, R. Gerding, A. Vester, J. Organomet. Chem. 1996,
513, 163; c) W. Uhl, Coord. Chem. Rev. 1997, 163, 132.
[3] Crystal data were obtained on a Syntex P21 (3 ´ 3C6H6) diffractometer
or a Siemens P4-RA (4) diffractometer at 130 K with CuKa (l ˆ
1.54178 Š) radiation: 3 ´ 3C6H6: C108H156Ga4Na2, Mr ˆ 1779.2, a ˆ
13.203(3), b ˆ 30.381(6), c ˆ 25.928(5) Š, b ˆ 103.26(3)8, Vˆ
10,123(3) Š3, Z ˆ 4, space group P21/n, R1 ˆ 0.057 for 9826 (I >
2s(I)) data; 4, C90H138Ga4, Mr ˆ 1498.9, a ˆ 23.577(5), b ˆ 14.672(3),
c ˆ 24.513(4) Š, b ˆ 91.09(2)8, Vˆ 8478(3) Š3, Z ˆ 4, space group
P2/c, R1 ˆ 0.121 for 7384 (I > 2s(I)) data. Crystallographic data
(excluding structure factors) for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC-102712, CCDC-
102713. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
The initiator core cyclophane 1 (generation zero, G-0) and
the two dendrophanes of the first (2, G-1; Mr ˆ 2486) and
second generation (3, G-2; Mr ˆ 6318) had previously been
shown to form stable 1:1 complexes (DG8 at 298 K between
[4] A simplified analysis of the p orbitals, assuming approximate D3 point
group symmetry for the Ga4 array, affords two molecular orbitals (one
bonding, one antibonding) of A2 symmetry and two degenerate
nonbonding orbitals of E symmetry. In 3 the bonding A2 orbital is
occupied by a pair of electrons, whereas in 4 it is unoccupied.
[5] X.-W. Li, W. T. Pennington, G. H. Robinson, J. Am. Chem. Soc. 1995,
117, 7578; X.-W. Li, Y. Xie, K. D. Gripper, R. C. Crittendon, C. F.
Campana, H. F. Schaefer III, G. H. Robinson. Organometallics 1996,
15, 3798.
[6] F. A. Cotton, A. H. Cowley, X. Feng. J. Am. Chem. Soc. 1998, 120,
1795.
[7] P. J. Brothers, P. P. Power, Adv. Organomet. Chem. 1996, 39, 1.
[8] P. J. Brothers, K. Hübler, U. Hübler, B. C. Noll, M. M. Olmstead, P. P.
Power, Angew. Chem. 1996, 108, 2528 ± 2530; Angew. Chem. Int. Ed.
Engl. 1996, 35, 2355.
[9] N. Wiberg, K. Amelunxen, H. Nöth, H. Schwenk, W. Kaim, A. Klein,
T. Scheiring, Angew. Chem. 1997, 109, 1258 ± 1261; Angew. Chem. Int.
Ed. Engl. 1997, 36, 1213.
[10] D. Kost, E. H. Carlson, M. Raban, J. Chem. Soc. Chem. Commun.
1971, 656.
[11] Recent calculations on related Li Ar p-interactions show that they
can be as high as 21 kcalmol 1. M. Tacke, Eur. J. Inorg. Chem. 1998,
537.
1
3.9 and 4.3 kcalmol ) with testosterone in borate-buf-
fered D2O (pD 10.5)/CD3OD (1/1).[10] 1H NMR investigation
1 R = OH
R
COOH
O
O
O
O
HN
HN
2 R =
COOH
COOH
O
(CH2)4
O
O
COOH
COOH
COOH
COOH
R
O
O
O
O
O
R
O
O
N
O
O
O H
O
O
O
COOH
O
O
O
(CH2)4
3 R =
N
O
COOH
COOH
COOH
COOH
H
H
N
O
O
O
O
O
R
O
of the bonding provided clear evidence that the steroid binds
axially in the cyclophane cavity of 2 or 3 rather than in
nonspecific fluctuating voids in the dendritic shells.[11] The
molecular rods 4a and 4b consist of rigid oligo(phenylacety-
lene) spacers with terminal testosterone units for dendro-
phane complexation. Because of their different lengths, they
Supramolecular Aggregates of Dendritic
Cyclophanes (Dendrophanes) Threaded on
Molecular Rods with Steroid Termini**
Me3N
O
I
Benoît Kenda and FrancËois Diederich*
NH
Noncovalent association of dendrimers[1] promises to
provide a rapid, efficient way to construct higher molecular
architectures with properties and functions[2] that are absent
in the individual components. Whereas metal ion mediated
assembly of dendritic branches (dendrons) to form higher
generation compounds is well established,[1a, 3] the noncova-
lent networking[4a] of individual dendrimers to defined higher
5"
O
4 (4')
O
18
Me
O
O
Me
H
2 (2')
OEt
2"
19
Me
O
EtO
O
Me
O
HN
n
n
H
O
O
NMe3
4a n = 1
4b n = 2
I
[*] Prof. Dr. F. Diederich, Dr. B. Kenda
Laboratorium für Organische Chemie, ETH-Zentrum
Universitätstrasse 16, CH-8092 Zürich (Switzerland)
Fax: (‡41)1-632-1109
were expected to accommodate dendrophanes of different
generation and size. Solubility of the rods in aqueous solutions
represented a considerable challenge, which could be over-
come with the attachment of both glycol ether groups and
quaternary ammonium ions (to the central benzene ring).
These ions were expected to undergo ion pairing with the
E-mail: diederich@org.chem.ethz.ch
[**] This work was supported by the ETH Research Council and F.
Hoffmann-LaRoche, Basel.
3154
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3154 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 22

COMMUNICATIONS
surface carboxylate residues in 1 ± 3 and thus reduce the
undesired electrostatic repulsion between two anionic den-
drimers threaded onto one rod.
The attachment of testosterone (11) to 9a and 9b to yield
14a and 14b, respectively, was achieved by esterification with
pent-4-ynoic acid (!12), protection of the steroid enone
chromophore as dienol ether (!13),[16] and Sonogashira
coupling. Deprotection of the alkyne group afforded 15a
and 15b, which were coupled[17] to the 2,5-diiodoterephthal-
amide 16 (prepared in 30% yield by heating 2,5-diiodoter-
ephthalic acid[18] with SOCl2 to 1008C for 4 h, followed by
reaction with N,N-dimethyl-1,2-ethylenediamine in CH2Cl2 at
08). Hydrolysis of the dienol ethers to give enones 17a and
17b, and quaternization of the tertiary amino groups led to
the bis-steroid rods 4a and 4b (Table 1). Following a similar
synthetic route, the mono-steroid rods
The synthesis of the novel molecular rods 4a and 4b utilizes
in its key steps the elegant binomial strategy introduced by
Moore and co-workers for the construction of oligo(phenyl-
acetyene) sequences (Scheme 1).[1f, 12] The orthogonal doubly
protected arylacetylene 8a, which was obtained in three steps
from 5[13] via 6 and 7, was transformed into iodide 9a and the
deprotected alkyne 10.[14] Sonogashira cross-coupling between
9a and 10 in pyrrolidine[15] yielded 8b, which was converted
into aryl iodide 9b.
18a and 18b were prepared as controls.
O
Me
O
Me
O
c)
Me3N
O
I
b)
Me
a)
Et2N3
EtO
N
H
O
OR
NH
HN
O
7
5 R = H
6 R = CH2CH2OEt
O
Me
H
Me
O
EtO
O
d)
I
SiMe3
n
O
EtO
O
O
9a n = 1
9b n = 2
n
NMe3
18a n = 1
18b n = 2
I
Et2N3
SiMe3
n
EtO
O
The bis-steroid rods 4a and 4b are
e)
Et2N3
H
n
8a n = 1
8b n = 2
light yellow solids (Table 1) that fluo-
resce strongly (lexc ˆ 370 nm, lem ˆ 471
(4a) and 482 nm (4b) in H2O (0.15m
phosphate buffer, pH 6.9)/MeOH 1:1).
Therefore, complexation by threading
receptors 1 ± 3 could not only be studied
EtO
10 n = 1
f)
O
O
R
OR
Me
Me
O
O
Me
H
Me
H
EtO
O
Me
Me
h)
i)
1
n
by H NMR titrations in D2O, but also
H
O
EtO
EtO
by fluorescence titrations in H2O; all
data were evaluated by nonlinear
least-squares curve-fitting analysis
(Table 2).[19] Pure testosterone (11)
forms 1:1 complexes with the G-0 re-
14a R = SiMe3, n = 1
14b R = SiMe3, n = 2
13
11 R = H
g)
12 R = COCH2CH2C≡CH
j)
j)
15a R = H, n = 1
15b R = H, n = 2
1
Me2N
O
Me2N
ceptor 1 (DG8 ˆ 4.0 kcalmol ) and
the
G-1
receptor
2
(DG8 ˆ
NH
HN
4.4 kcalmol 1; entries 1 and 2 in Ta-
ble 2).[10] Apolar bonding interactions
and hydrophobic desolvation provide
the driving force for formation of these
complexes.[11] Much more stable 1:1
complexes are formed between 1 ± 3
and the mono-steroid rods 18a and
NH
O
I
O
O
O
k), l)
O
I
O
Me
H
Me
O
Me
EtO
O
Me
O
O
OEt
n
HN
n
H
O
17a n = 1
17b n = 2
NMe2
NMe2
m)
16
18b (DG8 between
5.9 and
4a n = 1
4b n = 2
6.4 kcalmol 1; entries 3 ± 8 in Table 2).
Since the complexation-induced shifts
(CIS) of the resonances for the steroid
methyl groups in the 1H NMR titrations
adopt similar values in complexes of 11
with both 18a and 18b, the inclusion
geometries must be similar. Thus, the
steroid A ± D rings of 18a and 18b,
rather than the phenylacetylene moiety,
are axially included in the cyclophane
cavities. Therefore, the significantly
Scheme 1. Synthesis of 4a and 4b. a) EtO(CH2)2OTos, K2CO3, DMF, 208C, 5 h, 75%; b) 10% aq HCl,
1008C, 81%, then NaNO2, 08C, 15 min, then Et2NH, 08C, 15 min, 65%; c) lithium 2,2',6,6'-
tetramethylpiperidide (1.1 equiv), THF, 788C, 30 min, then (EtO)2POCl, THF, 788C, then lithium
2,2',6,6'-tetramethylpiperidide (2.2 equiv), THF, 78 !208C, 1.5 h, then Me3SiCl (2 equiv), THF,
788C, 64%; d) MeI, 1308C, 17 h, 78% (9a), 97% (9b); e) K2CO3, MeOH, 208C, 1 h, 95%;
f) [Pd2(dba)3] (5 mol%), CuI (10 mol%), pyrrolidine, 208C, 97% (8b); g) pent-4-ynoic acid, N,N'-
dicyclohexylcarbodiimide, 4-(dimethylamino)pyridine, CH2Cl2, 208C, 96%; h) H(COEt)3, TosOH,
EtOH, 208C, 1 h, 100%; i) 9a or 9b, [PdCl2(PPh3)2] (5 mol%), CuI (10 mol%), pyrrolidine, 208C;
j) nBu4NF, THF, 08C, 30 min; k) 15a or 15b, [PdCl2(PPh3)2] (5 mol%), CuI (10 mol%), PhMe/Et3N
1/1, 1108C, 6 ± 17 h; l) 10% aq HCl/THF/MeOH 1/2/5, 08C, 2 h, then 208C, 1 h, 54% (17a) and
18% (17b) starting from 13; m) MeI/CH2Cl2 1/1, CaCO3 (traces), 208C, 2 h, 77% (4a), 95% (4b).
Tos ˆ p-toluenesulfonyl, dba ˆ dibenzylideneacetone.
Angew. Chem. Int. Ed. 1998, 37, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3155 $ 17.50+.50/0
3155

COMMUNICATIONS
Table 1. Selected physical data for the molecular rods 4a and 4b.
The binding of the G-0 derivative 1 to the bis-steroid rod 4a
was evaluated by fluorescence titrations, since precipitation of
the formed complex occurred at the higher concentration
ranges required for 1H NMR titrations. An excellent fit of the
titration data for a 2:1 binding model was obtained, with the
threading of the two cyclophanes through 4a occurring with
nearly identical association strength (DG8 ˆ 6.1, DG8 ˆ
1
4a: M.p. 1718C; IR (KBr): nÄ ˆ 3288, 1727, 1666 cm 1; H NMR (CD3OD,
500 MHz): d ˆ 7.93 (s, 2H; H(2''), H(5'')), 7.50 (d, J ˆ 8.0 Hz, 2H; H(5)),
7.13 (d, J ˆ 1.6 Hz, 2H; H(2)), 7.06 (dd, J ˆ 1.6, 8.0 Hz, 2H; H(4)), 5.74 (s,
ˆ
ˆ
2H; C CHC O), 4.74 (t, J ˆ 8.1 Hz, 2H; CHOCO), 4.28 (t, J ˆ 4.8 Hz,
‡
4H; ArOCH2), 3.95 (t, J ˆ 6.5 Hz, 4H; N CH2), 3.88 (t, J ˆ 4.78 Hz, 4H;
ArOCH2CH2O), 3.67 (q, J ˆ 7.0 Hz, 4H; OCH2CH3), 3.63 (t, J ˆ 6.8 Hz,
4H; NHCH2), 3.24 (s, 18H; NCH3), 2.78 (m, 4H; OOCCH2), 2.66 (m, 4H;
OOCCH2CH2), 2.05 ± 2.55 (m, 12H; steroid), 1.30 ± 1.95 (m, 20H; steroid),
1.25 (s, 6H; CH3(19)), 1.23 (t, J ˆ 7.0 Hz, 6H; CH3CH2O), 0.92 ± 1.20 (m,
6H; steroid), 0.92 (s, 6H; CH3(18)); ESI-MS (MeOH): m/z ˆ 1573 (1%,
1:1
2:1
5.9 kcalmol 1; entry 9 in Table 2). Clear evidence for the
proposed 2:1 stoichiometry was also obtained by Job analy-
sis.[21] Each cyclophane in the 2:1 complex (Mr ˆ 4117)
independently binds to one steroid terminus with similar
association strength to that measured for the 1:1 complexation
of 1 to the mono-steroid rod 18a.
‡
‡
[M I] ), 1431 (1%, [M Me 2I] ), 722 (100%, [M]2‡
)
1
4b: M.p. 888C; IR (KBr): nÄ ˆ 3288, 1727, 1655 cm
;
1H NMR (CDCl3,
500 MHz): d ˆ 8.50 (m, 2H; NH), 8.05 (s, 2H; H(2'')), 7.55 (d, J ˆ 7.9 Hz,
2H; H(5')), 7.38 (d, J ˆ 7.9 Hz, 2H; H(5)), 7.18 (dd, J ˆ 1.3, 7.9 Hz, 2H;
H(4')), 7.13 (d, J ˆ 1.3 Hz, 2H; H(2'), 6.96 (d, J ˆ 1.3, 7.9 Hz, 2H; H(4)),
In contrast to these findings, significant differences in the
driving force for the first and second binding event were
measured when the G-1 derivative 2 was threaded onto the
shorter bis-steroid rod 4a (entries 10 and 11 in Table 2).
Again, clear evidence for formation of a supramolecular
complex with 2:1 stoichiometry was obtained.[21] In this case,
ˆ
ˆ
6.93 (d, J ˆ 1.3 Hz, 2H; H(2)), 5.71 (s, 2H; C CHC O), 4.67 (t, J ˆ 8.1 Hz,
2H; CHOOC), 4.30 (m, 4H; ArOCH2), 4.19 (t, J ˆ 4.2 Hz, 4H; ArOCH2),
‡
3.98 ± 4.03 (m, 8H; NHCH2CH2N ), 3.86 (t, J ˆ 4.2 Hz, 4H; ArOCH2-
CH2O), 3.81 (t, J ˆ 4.2 Hz, 4H; ArOCH2CH2O), 3.66 (q, J ˆ 7.0 Hz, 4H;
OCH2CH3), 3.55 (q, J ˆ 7.0 Hz, 4H; OCH2CH3), 3.36 (s, 18H; NCH3), 2.74
(t, J ˆ 6.2 Hz, 4H; OOCCH2), 2.64 (t, J ˆ 6.2 Hz, 4H; OOCCH2CH2),
1.20 ± 2.50 (m, 32H; steroid), 1.22 (t, J ˆ 7.0 Hz, 6H; CH3CH2O), 1.17 (s,
6H; CH3(19)), 1.11 (t, J ˆ 7.0 Hz, 6H; CH3CH2O), 0.89 ± 1.10 (m, 6H;
steroid), 0.84 (s, 6H; CH3(18)); ESI-MS (MeOH): m/z ˆ 1949 (0.5%, [M
however, the driving force for the second association step
1
DG8 is between 2.1 (fluorescence) and 2.8 kcalmol
2:1
‡
‡
I] , 1807 (0.5%, [M Me 2I] , 911 (100%, [M]2‡
)
(1H NMR) smaller than for the first association step, which
with DG8 ˆ 6.7 kcalmol has a driving force of similar
1
1:1
magnitude to that for threading the G-0 derivative 1 on 4a,
18a, or 18b. The two dendrophanes once again prefer
inclusion of the tetracyclic steroid skeletons over the com-
plexation of the phenylacetylene moieties of 4a, as indicated
by a comparison of the complexation-induced shifts of the
1H NMR signals for steroid methyl groups CH3(18) and
CH3(19). At saturation binding, these resonances in the 2:1
complex of 4a with 2 (entry 10, Table 2) display strong upfield
shifts similar to those observed in the 1:1 complexes of 11
(entry 2) and the mono-steroid rods 18a and 18b (entries 6
and 7). The considerable reduction in thermodynamic driving
force for the second complexation step is undoubtedly a
enhanced association strength (D(DG8)11!18a/18b ꢀ 2.0 Æ
1
0.2 kcalmol ) measured for the complexes of 18a and 18b,
as compared to complexes of pure testosterone (compare
entries 1 and 2 with entries 3 ± 8 in Table 2), is mainly a result
of the additional ion pairing between the surface carboxylate
residues of dendrophanes 1 ± 3 and the quaternary am-
monium ions of the mono-steroid rods. The extra stabilization
1
of about 1 kcalmol provided by each of the two salt
bridges is in good agreement with results from previous
studies.[20]
Table 2. Association constants and binding free enthalpies for the complexes formed by dendrophanes 1 ± 3 with testosterone (11) and the molecular rods
1
4a/4b and 18a/18b as well as complexation-induced shifts at saturation binding of signals monitored during H NMR titrations.[a]
[b]
[b]
Entry
Titration
method
Steroid
substrate
Dendro-
phane
K1:1
[Lmol
DG18:1
K2:1
[Lmol
DG28:1
Ddsat [ppm]
CH3(19)
1
1
1
1
]
[kcalmol
]
]
[kcalmol
]
CH3(18)
CH3CH2O
1
2
3
4
5
6
7
8
NMR[c]
NMR
NMR
NMR
fluor.[e]
NMR
NMR
fluor.[e]
fluor.[f]
NMR
fluor.
11
11
G-0 (1)
G-1 (2)
G-0 (1)
G-0 (1)
G-0 (1)
G-1 (2)
G-1 (2)
G-2 (3)
G-0 (1)
G-1 (2)
G-1 (2)
G-1 (2)
G-2 (3)
G-2 (3)
900
1600
4.0
4.4
5.9
6.1
5.9
6.4
6.2
6.1
6.1
6.7
6.7
6.1
5.7
6.8
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
5.9
3.9
4.6
6.1
±
±
±
±
±
0.41
0.41
0.38
±
0.31
0.38
±
1.06
1.19
1.06[d]
±
1.50
1.02
±
18a
18b
18b
18a
18b
18b
4a
4a
4a
4b
4a
21000
30000
22000
47000
38000
32000
29000
79000
81000
31000
15000
91000
0.26
0.27, 0.28
±
0.21
0.14, 0.20
±
±
9
23000
700
2300
30000
±
±
±
10
11
12
13
14
0.40
±
±
±
±
1.39
±
±
±
±
0.20
±
±
±
±
fluor.
fluor.[g]
fluor.
4b
4000
4.9
[a] The thermodynamic data were determined by 500-MHz 1H NMR titration in D2O (0.15m phosphate buffer, pD 7.3)/CD3OD 1/1 at 300 K and/or by
1
fluorescence titrations in H2O (0.15m phosphate buffer, pH 8.7)/CH3OH 1/1 at 298 K.[19] [b] Uncertainties: Æ0.1 kcalmol for DG18:1 and Æ0.3 kcalmol 1 for
DG28:1. [c] Titration at constant dendrophane concentration; a titration at a constant concentation of 11 in D2O (0.1m borate buffer, pD 10.5)/CD3OD 1/1 gave
1
Ka ˆ 1350 Lmol as well as Ddsat
ˆ
0.24 (CH3(18)) and 0.81 (CH3(19)).[10] [d] Maximum shift. [e] The hypsochromic shift of the emission of 18b at
saturation binding was 43 nm (entry 5) and 40 nm (entry 8). [f] In H2O (0.15m phosphate buffer, pH 6.9)/CH3OH 4/6 for solubility reasons. [g] Formation
of a 1:1 complex with the given stability was also confirmed by 1H NMR titrations at constant concentration of 4a [Ddsat
(CH3CH2O)].
:
0.20 (CH3(18)); 0.16
3156
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3156 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 22

COMMUNICATIONS
[1] a) G. R. Newkome, C. N. Moorefield, F. Vögtle, Dendritic Molecules:
Concepts, Syntheses, Perspectives, VCH, Weinheim, 1996; b) D. A.
Tomalia, A. M. Naylor, W. A. Goddard III, Angew. Chem. 1990, 102,
119 ± 157; Angew. Chem. Int. Ed. Engl. 1990,29, 138 ± 175; c) D. A.
consequence of the Coulombic repulsion between the surface
carboxylate groups of the two threaded dendrophanes, which
are positioned in too close proximity on the small rod.
Computer modeling[22] suggests that the distance between
the junctions of the B and C rings of the two testosterone
termini is approximately 41 Š. When the rod size is extended
in 4b to about 55 Š, the driving forces for threading the first
and second dendrophane become identical again (entry 12 in
Table 2). Fluorescence titrations yielded for both 1:1 and 2:1
complexation between 4b and 2 a free enthalpy of formation
Â
Tomalia, Adv. Mater. 1994, 6, 529 ± 539; d) J. M. J. Frechet, Science
1994, 263, 1710 ± 1715; e) H. W. I. Peerlings, E. W. Meijer, Chem. Eur.
J. 1997, 3, 1563 ± 1570; f) J. S. Moore, Acc. Chem. Res. 1997, 30, 402 ±
413; g) O. A. Matthews, A. N. Shipway, J. F. Stoddart, Prog. Polym.
Sci. 1998, 23, 1 ± 56; h) H. Frey, C. Lach, K. Lorenz, Adv. Mater. 1998,
10, 279 ± 293.
[2] D. K. Smith, F. Diederich, Chem. Eur. J. 1998, 4, 1353 ± 1361.
[3] a) V. Balzani, S. Campagna, G. Denti, A. Juris, S. Serroni, M. Venturi
Acc. Chem. Res. 1998, 31, 26 ± 34; b) C. Gorman, Adv. Mater. 1998, 10,
295 ± 309; c) E. C. Constable, P. Harverson, Chem. Commun. 1996,
33 ± 34; d) R. J. Puddephatt, Chem. Commun. 1998, 1055 ± 1062; e) H.-
F. Chow, I. Y.-K. Chan, D. T. W. Chan, R. W. M. Kwok, Chem. Eur. J.
1996, 2, 1085 ± 1091; f) D. Tzalis, Y. Tor, Tetrahedron Lett. 1996, 37,
8293 ± 8296.
1
of DG8 ˆ 6.1 kcalmol , that is, nearly the same driving
force as measured for the complexation of one dendrophane 2
by the mono-steroid rods 18a and 18b.[23] Thus, a highly stable
supramolecular aggregate with a molecular mass of 6642 is
formed in which the two dendrophanes, through inclusion of
the testosterone termini, are placed at sufficient distance to
avoid charge repulsion.
[4] a) G. R. Newkome, R. Güther, C. N. Moorefield, F. Cardullo, L.
Â
Echegoyen, E. Perez-Cordero, H. Luftmann, Angew. Chem. 1995, 107,
2159 ± 2162; Angew. Chem. Int. Ed. Engl. 1995, 34, 2023 ± 2026; b) Y.
Tomoyose, D.-L. Jiang, R.-H. Jin, T. Aida, T. Yamashita, K. Horie, E.
Yashima, Y. Okamoto, Macromolecules 1996, 29, 5236 ± 5238.
[5] For a review on dendrimers in supramolecular chemistry, see F. Zeng,
S. C. Zimmerman, Chem. Rev. 1997, 97, 1681 ± 1712.
[6] a) S. C. Zimmerman, F. Zeng, D. E. C. Reichert, S. V. Kolotuchin,
Science 1996, 271, 1095 ± 1098; b) Y. Wang, F. Zeng, S. C. Zimmerman,
Tetrahedron Lett. 1997, 38, 5459 ± 5462.
[7] For recent examples of dendritic liquid crystalline phases, see a) S. D.
Hudson, H.-T. Jung, V. Percec, W.-D. Cho, G. Johansson, G. Ungar,
V. S. K. Balagurusamy, Science 1997, 278, 449 ± 452; b) D. J. Pesak, J. S.
Moore, Angew. Chem. 1997, 109, 1709 ± 1712; Angew. Chem. Int. Ed.
Engl. 1997, 36, 1636 ± 1639.
[8] a) D. A. Tomalia in Modular Chemistry, Nato ASI Series, Vol. 499
(Ed.: J. Michl), Kluwer, Dordrecht, 1997, pp. 183 ± 191; b) J. C. M.
van Hest, D. A. P. Delnoye, M. W. P. L. Baars, M. H. P van Genderen,
E. W. Meijer, Science 1995, 268, 1592 ± 1595; c) T. M. Chapman, G. L.
Hillyer, E. J. Mahan, K. A. Shaffer, J. Am. Chem. Soc. 1994, 116,
11195 ± 11196.
The bulky G-2 dendrophane 3 (Mr ˆ 6318 D) only forms a
1:1 complex with the smaller rod 4a, as evidenced by the curve
1
fitting of fluorescence and H NMR titration data and Job
analysis; the fluorescence data gave a maximum at mole
fraction x(3) ˆ 0.5 (entry 13 in Table 2). Formation of a stable
2:1 complex with a molecular mass of 14714 was, however,
observed again by fluorescence titrations and Job analysis for
the association between the longer rod 4b and G-2 dendro-
phane 3 (entry 14 in Table 2). The threading of the first
1
dendrophane is more favorable (DG8 ˆ 6.8 kcalmol ) than
1
that of the second (DG8 ˆ 4.9 kcalmol ) owing to charge
repulsion.[21, 23] Further extension of the phenylacetylenic
sequence in the bis-steroid rod is currently under way to
accommodate two G-2 dendrophanes with similar binding
free enthalpy. The successful threading of two third-gener-
ation dendrophanes (Mr ˆ 17813), which are already avail-
able,[10] to form 2:1 complexes with molecular weights
approaching 40000 will require the construction of bis-steroid
rods with even larger spacers.
[9] S. Mattei, P. Seiler, F. Diederich, V. Gramlich, Helv. Chim. Acta 1995,
78, 1904 ± 1912.
[10] a) S. Mattei, P. Wallimann, B. Kenda, W. Amrein, F. Diederich, Helv.
Chim. Acta 1997, 80, 2391 ± 2417; b) P. Wallimann, P. Seiler, F.
Diederich, Helv. Chim. Acta 1996, 79, 779 ± 788.
[11] For use of steroids in molecular recognition, see P. Wallimann, T.
Marti, A. Fürer, F. Diederich, Chem. Rev. 1997, 97, 1567 ± 1608.
[12] a) J. S. Zhang, J. S. Moore, Z. F. Xu, R. A. Aguirre, J. Am. Chem. Soc.
1992, 114, 2273 ± 2274; b) J. S. Zhang, D. J. Pesak, J. L. Ludwick, J. S.
Moore, J. Am. Chem. Soc. 1994, 116, 4227 ± 4239; c) Z. F. Xu, M. Kahr,
K. L. Walker, C. L. Wilkins, J. S. Moore, J. Am. Chem. Soc. 1994, 116,
4537 ± 4550.
We have demonstrated a novel, efficient dendrimer asso-
ciation process which takes advantage of apolar interactions,
hydrophobic desolvation, and ion pairing to produce supra-
molecules of defined structures with molecular weights
exceeding 14000. The experiments establish experimentally
an optimal distance for threading two anionic dendrophanes
in the thermodynamically most favorable way onto the steroid
termini of molecular rods with rigid phenylacetylene spacers.
For optimal binding, two G-0 dendrophanes 1 require an
intramolecular steroid ´´´ steroid distance of about 41 Š,
whereas in the case of the G-1 dendrophanes 2 this distance
is about 55 Š. From these data, the extensions of the
complexed dendrophanes, which are hard to obtain otherwise,
can be estimated. Thus, the bis-steroid rods 4a and 4b serve as
rulers on the molecular scale.
Â
[13] M. Julia, M. Baillarge, Bull. Soc. Chim. Fr. 1952, 639 ± 642.
1
[14] All new compounds were fully characterized by H NMR, 13C NMR,
and IR spectroscopy; EI, FAB, or MALDI-TOF mass spectrometry;
and elemental analysis or high-resolution mass spectrometry. The rods
4a/4b and 19a/19b were additionally characterized by UV/VIS and
fluorescence spectroscopy.
[15] a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34,
6403 ± 6406; b) K. Sonogashira in Metal-catalyzed Cross-coupling
reactions (Eds.: F. Diederich, P. J. Stang), WILEY-VCH, Weinheim,
1998, pp. 203 ± 229.
[16] R. Gardi, A. Eridi in Protecting Groups in Steroid Chemistry, Vol. 1
(Eds.: R. Gardi, A. Eridi), Van Nostrand-Reinhold, New York, 1972,
pp. 388 ± 390.
[17] Since 16 was only poorly soluble in the solvent mixture for the
Sonogashira coupling (PhMe/Et3N), long reaction times were applied
and homocoupling of the terminal alkynes 15a and 15b became a
competitive process.
Received: June 4, 1998 [Z11939IE]
German version: Angew. Chem. 1998, 110, 3357 ± 3361
[18] Q. Zhou, T. M. Swager, J. Am. Chem. Soc. 1995, 117, 12593 ± 12602.
[19] For the evaluation of 1:1 complexes, the program Associate V. 1.6 (B.
Peterson, Dissertation, University of California, Los Angeles, 1994)
was used. Complexes with higher stoichiometry (2:1) were analyzed
Keywords: cyclophanes ´ dendrimers ´ steroids ´ supra-
molecular chemistry
Angew. Chem. Int. Ed. 1998, 37, No. 22
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3157 $ 17.50+.50/0
3157

COMMUNICATIONS
with the program SPECFIT V. 2.10 (R. A. Binstead, A. D. Hunger-
bühler, Spectrum Software Associates, Chapel Hill, NC, 1997). This
program performs global least-squares fits which, in fluorescence
titrations, include the entire measured wavelength region (multiple
wavelength analysis). In the 1H NMR titrations at constant concen-
tration of the molecular rod (c(rod) ꢀ 0.1 ± 0.2mm, c(dendrophane) ꢀ
0.05 ± 1mm), the complexation-induced shifts of the steroid CH3(18)
and CH3(19) resonances and the CH3CH2O resonances were eval-
uated. In the fluorescence titrations at constant concentration of the
molecular rod (c(rod) ꢀ 0.01 ± 0.02mm, c(dendrophane) ˆ 0.005 ±
0.8mm), the emission intensity of the rod decreased upon addition
of dendrophane and the emission maxima of 4a/4b at saturation
binding shifted by 5 ± 16 nm to higher energy.
opments, and of the importance of redox centers to hetero-
geneous catalysis[4] and molecular recognition by electro-
chemical sensing,[5] we have synthesized an electrochemically
active organic species suitable for forming novel extended
molecular frameworks. Here we show how hydrogen bonding
and p ´´´ p nonbonding interactions can produce a micro-
porous framework of this species linked to a transition metal
complex. The material described displays remarkable flexi-
bility, and undergoes significant structural rearrangements
with desolvation to leave an empty-channel material that
shows selectivity to guest sorption.
By making use of slow diffusion in aqueous silica gels,
we have synthesized crystals incorporating the diprotonat-
ed, redox-active tetra(carboxyl)tetrathiafulvalene anion
H2(TC-TTF)2 , hexaaquacobalt(ii) cations, and solvent water
molecules. [CoII(H2O)6]H2(TC-TTF) ´ 2H2O (A) consists
[20] a) H.-J. Schneider, Angew. Chem. 1991, 103, 1419 ± 1439; Angew.
Chem. Int. Ed. Engl. 1991, 30, 1417 ± 1436; b) H.-J. Schneider, T.
Shiestel, P. Zimmermann, J. Am. Chem. Soc. 1992, 114, 7698 ± 7703.
[21] Multiple evidence for 2:1 complexation by 4a/4b was obtained: 1) An
1
excellent fit of the fluorescence and/or H NMR titration data to the
2:1 binding model was obtained. 2) Job plots of fluorescence data
showed clear maxima at x(dendrophane) ꢀ 0.66 (see D. V. Naik, W. L.
Paul, R. M. Threatte, S. G. Schulman, Anal. Chem. 1975, 47, 267 ± 270).
3) The complexation-induced shifts observed for the 1H NMR signals
for CH3(18) and CH3(19) of the steroids in solutions of 4a and 2 are
compatible with formation of a 2:1 complex; that is, they are of similar
magnitude to those observed for these resonances in the 1:1
complexes formed by testosterone (11) or the mono-steroid rods
18a and 18b.
of
a
three-dimensional hydrogen-bonded network of
[Co(H2O)6]2‡ and H2(TC-TTF)2 ions (Figure 1).[6] Short
[22] Insight II program, V. 97.0, Molecular Simulations Inc., San Diego
1997.
[23] Strong broadening of the resonances prevented the application of
1H NMR titrations to determine stabilities of the complexes formed
by 4b.
Desolvation of a Novel Microporous
Hydrogen-Bonded Framework:
Characterization by In Situ Single-Crystal
and Powder X-ray Diffraction**
Figure 1. Projection of A down the a axis. For clarity, only one oxygen
atom position of the disordered cavity water molecule is displayed.
Selected bond lengths [Š] and angles [8] (a fixed value of 0.86 Š was used
for O H distances in the cation): O11 ´´´ O1* 2.715(4), O12 ´´´ O3* 2.773(4),
O12 ´´´ O1* 2.802(4), O13 ´´´ O4* 2.685(4), O2 ´´´ O3 2.438(5), H2 ´´´ O3
1.47(8); O11 H11B ´´´ O1* 159(6), O12 H12B ´´´ O3* 173(8), O12
H12A ´´´ O1* 179(5), O13 H13A ´´´ O4* 174(6), O13 H13B ´´´ O11*
173(7), O3 H2 ´´´ O2 168(7).
Cameron J. Kepert, Dusan Hesek, Paul D. Beer,* and
Matthew J. Rosseinsky*
Attention has recently focused on the use of the hydrogen
bond,[1] and also the coordinate bond,[2] in the controlled
assembly of porous molecular frameworks. Studies into the
guest exchange and catalytic properties[3] of these materials
have led to a growing recognition of molecular frameworks as
zeolite analogues, many retaining their structural integrity
with desolvation or solvent exchange. Aware of these devel-
hydrogen bonds exist between eight of the twelve protons in
the hexaaquometal cation and six of the eight carboxyl oxygen
atoms. The two protons of the doubly deprotonated acid form
very short hydrogen bonds to neighboring carboxyl groups,
giving this unit a rigid planarity. Running along the a axis, and
lying parallel with slipped stacks of the TTF derivative and
hydrogen-bonded chains of [Co(H2O)6]2‡ ions, are one-
dimensional channels that are filled with zig-zag chains of
disordered water molecules. The sites occupied by these
molecules are defined by hydrogen bonding to the frame-
work, primarily to a water molecule coordinated to Co2‡
(O11) and to a lesser degree to O4 of the anion. Hydrogen
bonding between solvent molecules occurs along the channels,
the mean solvent separation being about 2.9 Š, compared
with 2.8(1) Š for a typical hydrogen-bonded O ´´´ O distance.
[*] Dr. P. D. Beer, Dr. M. J. Rosseinsky, Dr. C. J. Kepert, Dr. D. Hesek
Inorganic Chemistry Laboratory, Department of Chemistry
University of Oxford
South Parks Road, Oxford, OX1 3QR (UK)
Fax: (‡44)1865-272-690
E-mail: cameron.kepert@chem.ox.ac.uk
paul.beer@chem.ox.ac.uk
matthew.rosseinsky@chem.ox.ac.uk
[**] C.J.K. thanks Christ Church, Oxford, for a Junior Research Fellow-
ship. We thank Prof. C. K. Prout and Dr. D. J. Watkin for access to the
X-ray diffractometer and for useful discussions.
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the
author.
3158
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1433-7851/98/3722-3158 $ 17.50+.50/0
Angew. Chem. Int. Ed. 1998, 37, No. 22