An unlockable-relockable iron cage by subcomponent self-assembly

Article abstract of DOI:10.1002/anie.200803066

(Chemical Equation Presented) In irons bound: Linear diamine and formylpyridine subcomponents form a tetrahedral cage with iron(II) in water (see scheme). This cage traps hydrophobic guests with high specificity within a rigid cavity, isolating them from the aqueous environment. The cage may be broken, releasing the guest, upon the addition of a triamine. It may also be unlocked by adding acid, allowing the guest to be reversibly released until base is added, relocking it within.

Full text of DOI:10.1002/anie.200803066

Angewandte
Chemie
DOI: 10.1002/anie.200803066
Host–Guest Systems
An Unlockable–Relockable Iron Cage by Subcomponent
Self-Assembly**
Prasenjit Mal, David Schultz, Kodiah Beyeh, Kari Rissanen,* and Jonathan R. Nitschke*
The study of hollow polyhedra prepared through metal–
[
1–3]
organic self-assembly,
tainer molecules,
within the wider context of con-
[
4–6]
has been a topic of great interest in
recent years. These structures provide an inner phase of
well-defined void space, within which the chemical reactiv-
[5]
[7,8]
[9]
ity
and dynamics of guest molecules have been altered
and studied in novel ways.
Herein we describe a new metal–organic cage complex
that is capable of tightly binding a hydrophobic guest
molecule in aqueous solution and in the solid state. Our
anionic cage exhibited high selectivity for appropriately sized
hydrocarbon guests (no affinity was detected for similarly
sized alcohols or organic cations), and the constrictive nature
of guest binding allowed a smaller guest to be selectively
removed from the cage in vacuo while a larger one remained
bound. A novel and potentially useful aspect of the cageꢀs
behavior is that it could be readily opened through the
application of either one of two chemical signals, releasing the
trapped guest molecule. One of these opening methods
proved reversible, allowing guest exchange through the
application of chemical signals.
Tetrahedral cage 1 was the unique product observed from
the aqueous reaction of the 4,4’-diaminobiphenyl-2,2’-disul-
fonic acid and 2-formylpyridine subcomponents shown in
Scheme 1 with iron(II) and base. Cage 1 contains exclusively
iron(II) in the low-spin state, as indicated by its sharp,
diamagnetic NMR spectra and dark purple coloration,
indicative of the intense metal-to-ligand charge-transfer
excitations associated with low-spin iron(II) in a hexaimine
Scheme 1. Preparation of tetrahedral cage 1 salt by aqueous subcom-
ponent self-assembly; the structure of only one edge is fully shown
for clarity.
[
14]
[
10]
ligand environment.
The strong binding and mutual
[11]
[10]
stabilization between iron(II) and imine ligands appear
to play an important role in the stability of 1. Neither
cobalt(II) nor zinc(II) produced well-defined products when
employed in place of iron(II). In keeping with the elegant
chiral M L cage motif discovered by Saalfrank and co-
4
6
[2]
[3,8,12]
workers and explored by several other groups,
1
displays tetrahedral symmetry in solution as detected by
NMR spectroscopy; only one set of ligand proton resonances
are observed.
Slow evaporation of a water/acetone (1:1 v:v) solution
permitted the isolation of single crystals of 1 as the
tetramethylammonium salt. In spite of the moderate quality
of the crystals, the crystal structure of 1 could be determined
by X-ray diffraction (Figure 1). This structure is consistent
[
+]
[
*] Dr. P. Mal, Dr. J. R. Nitschke
University of Cambridge, Department of Chemistry
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: jrn34@cam.ac.uk
3
with NMR spectra and revealed an internal cavity of 141 ꢁ ,
Homepage: http://www-jrn.ch.cam.ac.uk/
[13]
as calculated using PLATON VOIDS. The sulfonate groups
of 1 are symmetrically arrayed towards the exterior. We infer
that their presence and orientation contribute to the high
K. Beyeh, Prof. Dr. K. Rissanen
Nanoscience Center, Department of Chemistry
University of Jyvꢀskylꢀ
P.O. Box 35, 40014 JYU (Finland)
E-mail: kari.rissanen@jyu.fi
ꢀ
1
observed aqueous solubility of 1 (34 gL ).
When cage 1 was prepared in the presence of cyclohexane,
a new resonance attributed to cyclohexane within the cage
was observed at d = 0.37 ppm, that is, 1.03 ppm upfield of free
cyclohexane. Resonances corresponding to the cage were also
[
+]
Dr. D. Schultz
University of Edinburgh, School of Chemistry
The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ (UK)
+
[
] These authors contributed equally to this work.
shifted upon guest complexation, and a strong nuclear
[
**] This work was supported by the Walters–Kundert Charitable Trust,
the Royal Society, the Swiss National Science Foundation, and the
Academy of Finland (122350), the Graduate School of Organic
Chemistry and Chemical Biology (K.B.) and the Marie Curie IIF
Scheme of the 7th EU Framework Program (P.M.).
[15]
Overhauser effect
was observed between the resonance
corresponding to encapsulated cyclohexane and inward-
pointing H5 of the benzidinedisulfonate residues of the
1
cage. Integration of the H NMR spectrum indicated the
formation of a 1:1 complex. The cyclohexane guest proved to
be very tightly bound; in the solid state, finely powdered
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803066.
Angew. Chem. Int. Ed. 2008, 47, 8297 –8301
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8297

Communications
Scheme 2. Selective removal of smaller cyclopentane guests from
cages in vacuuo.
Figure 1. View of the crystal structure of 1; cations, hydrogen atoms,
and solvent of crystallization are not shown for clarity. Fe violet-gray,
N blue, S yellow, O red, C gray.
Following lyophilization of an aqueous 1.40:1 mixture of
C H ꢁ1 and C H ꢁ1 (see the Supporting Information),
5
10
6
12
1
C H ꢁ1 complex could be heated at 323 K for 24 h under
integration of the H NMR spectrum indicated a 1.35:0.07:1
6
12
dynamic vacuum (less than 0.01 Torr) without any appreci-
able degree of guest loss, as measured by subsequent solution
NMR spectroscopy.
mixture of free 1:C H ꢁ1:C H ꢁ1. Of the initial cyclopen-
5
10
6
12
tane, just 5% thus remained encapsulated, whereas less than
2% of the cyclohexane had escaped. The cyclohexane could
When excess cyclohexane was added to an aqueous
solution of preformed 1, the half-life for guest incorporation
was approximately 18 h at 298 K or 2 h at 323 K. We attribute
this slow guest exchange, in spite of high guest affinity, to the
rigidity of 1 together with the small size of the portals in the
faces of the cage: the largest sphere able to pass freely
through these apertures in the crystal structure, just in van der
Waals contact, would have a diameter of 2.04 ꢁ. Although
then readily be liberated from the cage (see below).
+
Neither [NMe ] nor tBuOH was observed to bind within
4
1 in solution or the solid state, despite their tetrahedral
geometries and 55% and 50.6% fill ratios. This high degree of
selectivity for neutral, hydrophobic guests may be attributed
[
20]
to the hydrophobic effect. This effect has been observed to
drive aqueous alkane binding by container molecules in the
[
18]
[21]
[22]
groups of Raymond, Gibb, and Rebek. The complete
[
16]
some degree of cage deformation
would be possible
lack of affinity of anionic 1 for tetraalkylammonium ions
+
+
+
without great energetic cost, the deformation required to
pass cyclohexane (approximate narrowest van der Waals cross
section of 6 ꢁ) through a portal of cage 1 is likely to be
([NMe Et] , [NMeEt ] , and [NEt ] cations were screened in
3 3 4
+
addition to [NMe ] ), which contrasts with their binding
4
[3]
within Raymondꢀs anionic tetrahedra, may be a conse-
quence of the lesser overall charge of 1 and the guestꢀs greater
screening from the externally directed sulfonates and the
[
17]
extensive. Guest binding is thus constrictive in nature.
Cyclopentane also served as a guest, forming a 1:1
complex with 1 more rapidly (t1/2 ꢂ 1.5 h at 323 K) than
cyclohexane, owing to its smaller size. When a competition
experiment was carried out in an aqueous solution saturated
in both cyclopentane and cyclohexane, an equilibrium
mixture of 1.40:1 C H ꢁ1:C H ꢁ1 was formed. This finding
II
apical Fe ions of 1. We thus attribute the selectivity observed
to the rigid and hydrophobic nature of the cavity of 1, which is
surrounded entirely by hydrophobic aryl rings.
[
23]
Both dynamic covalent (C=N) and coordinative (N!
Fe) bonds hold 1 together; 1 thus shares features with two
distinct classes of container molecules: metal–organic poly-
5
10
6
12
suggests that cyclohexane is slightly favored over cyclo-
pentane, since cyclopentane is 3.4 times more soluble in water
[
1–3,7–9,12]
[6,24]
hedra
and dynamic-covalent cages.
A feature of
[
18]
[14]
than cyclohexane.
the subcomponent self-assembly approach used to prepare
1 is that both coordinative and covalent linkages may be
independently addressed, providing two distinct means of
opening 1, thus allowing for the liberation of the more tightly
bound cyclohexane guest. These methods are described
below.
A cyclohexane guest molecule fills 61% of the available
space within the central cavity of 1, suggesting that this guest
is a good one following the Rebek rule that 55% occupation is
[
19]
optimal. Cyclopentane occupies 51% of the cavity volume;
the near-equal deviation of these two guests from 55%
occupation may explain the lack of selectivity between them
displayed by 1.
First, tris(2-ethylamino)amine 2 readily underwent imine
exchange with 1, resulting in the formation of mononuclear
II
The differing sizes of cyclohexane and cyclopentane
molecules led, however, to differing degrees of ease in
passing through the portals of 1, as reflected in the more
rapid formation of C H ꢁ1 than C H ꢁ1. This difference
Fe complex 3 and the liberation of the cyclohexane (or
[25]
cyclopentane) guest (Scheme 3). This imine exchange
reaction appears to have been driven to completion by both
enthalpic (electron-rich alkylamine replacing electron-poor
5
10
6
12
[
26]
was used as the basis of a novel separation of these two very
similar hydrocarbons (Scheme 2).
arylamine)
particles)
and entropic (increase in the number of
[
27]
factors. It was not possible to regenerate 1
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Angewandte
Chemie
Scheme 3. Liberation of the cyclohexane guest within 1 by the addition
of chelating amine 2.
1
Figure 2. H NMR spectra of a) cage 1, b) C H ꢁ1, c) C H ꢁ1 after
6
12
6
12
through the addition of acid to the mixture of 3 and
reaction with tosylic acid (10 equiv) and in presence of excess cyclo-
[
28]
diamine;
cage 1 appeared not to be stable under the
pentane, d) generation of complex C
sodium bicarbonate (15 equiv).
5
H10ꢁ1 after the addition of
acidic conditions required to induce the dissociation of 3. The
reaction of Scheme 3 might thus be considered as irreversibly
breaking open cage 1.
Second, variation of the solution pH could also be used to
reversibly open the cage. The addition of p-toluenesulfonic
and cyclopentane, the cyclohexane guest was observed to
have been released (Figure 2c) and had presumably parti-
tioned into the cyclopentane layer present in the NMR
tube. Following the addition of base, 1 was observed to re-
form as the cyclopentane adduct (Figure 2d).
(
tosylic) acid (10.0 equiv) to an aqueous solution of the
[
30]
C H ꢁ1 complex induced the cage to come apart, with
6
12
liberation of the cyclohexane guest (Scheme 4). In this case,
The tight, reversible, and selective encapsulation of
hydrophobic guest molecules within 1 might be exploited to
allow drug delivery uniquely to the vicinity of a target area,
where “opener” molecules would be selectively placed.
Conversely, potentially harmful hydrophobic molecules
might be safely sequestered within 1 after the addition of
base to the precursor subcomponents. A major practical
advantage of 1 is its low cost—its precursors are commercially
available and inexpensive. Current efforts are focusing on
investigating the reactivity of trapped guests and on the
preparation of longer linear diamines to allow for the
encapsulation of larger guests or multiple guest molecules
within more voluminous analogs of 1.
Scheme 4. “Unlocking” of cage 1 through the addition of acid and
subsequent base-driven “relocking” of cyclohexane within 1.
Experimental Section
1: 4,4’-diaminobiphenyl-2,2’-disulfonic acid (purity 70%, balance
water, 1.0 g, 2.03 mmol), 2-formylpyridine (0.435 g, 4.06 mmol),
tetramethylammonium
.06 mmol), and iron(II) sulfate heptahydrate (0.376 g, 1.35 mmol)
were added to a 100 mL Schlenk flask containing degassed water
25 mL) and a stir-bar. All starting materials dissolved, giving a dark
purple solution. The flask was sealed, and the atmosphere was
purified of dioxygen by three evacuation/argon fill cycles. The
reaction was stirred for 20 h at 508C. The product was then isolated
as dark purple crystals by slow vapor diffusion of acetone into the
hydroxide
pentahydrate
(0.737 g,
4
however, the dissociation of the cage was reversible. The
addition of sodium bicarbonate (15.0 equiv) induced C H ꢁ1
6
12
(
to re-form. Although the structural change involved in the
pH-driven “unlocking” of 1 is more radical than the portal-
opening organic system described by Diederich and co-
[
29]
workers, the pH-dependent behavior of 1 may similarly be
considered as switching.
aqueous solution of 1; yield of isolated product 0.734 g (83%);
1
H NMR (400 MHz, 300 K, D O, referenced to 2-methyl-2-propanol
The “payload” of 1 may thus be released in a desired
environment through opening with amine 2 or acid. If the
acid-opened cage is then closed with base, a different guest
molecule may be recovered from the environment.
Figure 2 documents this “capture-and-release” behavior
2
at 1.24 ppm as internal standard): d = 9.29 (s, 12H, imine), 8.68 (d, J =
7.6 Hz, 12H, 3-pyridine), 8.39 (t, J = 7.6 Hz, 12H, 4-pyridine), 7.75 (t,
J = 6.5 Hz, 12H, 5-pyridine), 7.50 (d, J = 7.6 Hz, 12H, 6-pyridine),
7
.12 (d, J = 7.0 Hz, 12H, 6,6’-benzidine), 6.43 (s, 12H, 3,3’-benzidine),
+
5
.82 (d, J = 7.0 Hz, 12H, 5,5’-benzidine), 3.18 ppm (s, [NMe ] );
4
1
13
by H NMR spectroscopy. After the addition of excess acid
C NMR (100.61 MHz, 300 K, D O, referenced to 2-methyl-2-prop-
2
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8299

Communications
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43.7, 140.5, 136.7, 132.7, 132.6, 130.5, 122.4, 121.6 ppm; ESI-MS: m/z:
2
ꢀ
4ꢀ
4ꢀ
2ꢀ
3
ꢀ
548.0 ([L Fe] ), ꢀ835.9 ([1] ꢃ [L Fe ] ), ꢀ1124.4 ([L Fe ] ),
2
6
4
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2ꢀ
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1412.8 ([L Fe ] ).
5
4
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4
4
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2
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[
31]
[32]
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[
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ꢀ1
=
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o
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Received: June 25, 2008
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Keywords: coordinationchemistry·dynamiccovalentchemistry·
host–guest systems · iron · self-assembly
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