Connection of metallamacrocycles via dynamic covalent chemistry: A versatile method for the synthesis of molecular cages

Article abstract of DOI:10.1021/ja200580x

A modular approach for the synthesis of cage structures is described. Reactions of [(arene)RuCl₂]₂ [arene = p-cymene, 1,3,5-C₆H₃Me₃, 1,3,5-C₆H ₃(i-Pr)₃] with formylsub

Full text of DOI:10.1021/ja200580x

ARTICLE
pubs.acs.org/JACS
Connection of Metallamacrocycles via Dynamic Covalent Chemistry:
A Versatile Method for the Synthesis of Molecular Cages
Anton Granzhan, Clꢀement Schouwey, Thomas Riis-Johannessen, Rosario Scopelliti, and Kay Severin*
Institut des Sciences et Ingꢀenierie Chimiques, Ecole Polytechnique Fꢀedꢀerale de Lausanne, 1015 Lausanne, Switzerland
S Supporting Information
b
ABSTRACT: A modular approach for the synthesis of cage
structures is described. Reactions of [(arene)RuCl2]2 [arene =
p-cymene, 1,3,5-C6H3Me3, 1,3,5-C6H3(i-Pr)3] with formyl-
substituted 3-hydroxy-2-pyridone ligands provide trinuclear
metallamacrocycles with pendant aldehyde groups. Subsequent
condensation reactions with di- and triamines give molecu-
lar cages with 3, 6, or 12 Ru centers in a diastereoselective
and chemoselective (self-sorting) fashion. Some of the cages
can also be prepared in one-pot reactions by mixing
[(arene)RuCl2]2 with the pyridone ligand and the amine in
the presence of base. The cages were comprehensively analyzed by X-ray crystallography. The diameter of the largest dodecanuclear
complex is ∼3 nm; the cavity sizes range from 290 to 740 Å3. An amine exchange process with ethylenediamine allows the clean
conversion of a dodecanuclear cage into a hexanuclear cage without disruption of the metallamacrocyclic structures.
Scheme 1. Strategies for the Synthesis of Tetrahedral Cagesa
’ INTRODUCTION
Natural molecular cages such as viral capsids1 or ferritin2 are
formed by self-assembly of protein building blocks. In a related
fashion, synthetic molecular cages can be obtained by assembly of
molecular building blocks via reversible covalent3 or non-cova-
lent bonds.4,5 In terms of size, complexity, and functionality,
most synthetic cages cannot rival protein-based nanocages.
However, significant advances have been made in recent years,
and interesting applications have begun to emerge. For example,
synthetic cages have been used as nanoreactors for chemical
reactions,6 as transport vehicles for drugs,7 as containers for
reactive chemical species,8 and as organizing structures for
stacked π-systems.5m,9
The most widely used method for the preparation of synthetic
cages involves the connection of metal complexes or metal ions
via polytopic ligands.5 The thermodynamically controlled synth-
esis of metal-free cages has been achieved by linking organic
subunits via hydrogen bonds,10 chargeꢀcharge interactions,11
van der Waals forces,12 or dynamic covalent bonds such as
imines,13 boronate esters,14,15 and disulfides.16 Reversible ami-
neꢀaldehyde condensation reactions have also been used in
conjunction with metallasupramolecular chemistry.17 However,
the imine bonds are usually formed in the first coordination
sphere of the metal complex. Our group is interested in exploring
the possibility of combining dynamic covalent chemistry and
metalꢀligand interactions in an orthogonal fashion, i.e., the
reversible covalent bond is formed independently from the metal
complex.
a (a) Self-assembly of M4L6 coordination cages from metal ions and
organic ligands. (b) [4 þ 6] condensation reactions of trialdehydes with
diamines. (c) Assembly of trinuclear metallamacrocycles with pendant
aldehyde groups followed by [4 þ 4] condensations with triamines.
Cones, aldehyde groups; collars, amine groups; spheres, metal ions or
complexes.
Scheme 1 describes different approaches for the synthesis of
molecular cages with a tetrahedral geometry. Coordination cages
can be obtained by reaction of metal ions with ditopic bridging
Received: January 20, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Scheme 2. Synthesis of the Formyl-Substituted 3-Hydroxy-
2-pyridone Ligands 3 and 6a
Scheme 3. Synthesis of the Metallamacrocycles 7aꢀc and
8a,ba
a Reagents and conditions: (a) t-BuLi (2 equiv), THF, ꢀ80 °C; (b)
(CH2)5NCHO, ꢀ80 °C to room temp, 65%; (c) I2, ꢀ80 °C to room
temp, 61ꢀ67%; (d) 3-formylphenylboronic acid, Pd(PPh3)4, K2CO3,
PhMeꢀEtOHꢀH2O, reflux, 95%; (e) CF3COOHꢀCH2Cl2, room
temp, 82ꢀ89%.
ligands in the ratio 4:6 (Scheme 1a). This methodology has been
used by the groups of Raymond,6c,d,18 Ward,19 and others5 to
generate cages with different sizes and functionalities. Nitschke
et al. recently demonstrated that the metal-binding part of the
bridging ligandcan also be formed in situ by animinecondensation
reaction.20 Purely organic cages with a tetrahedral geometry have
been reported by Cooper,13b,c Gawronski,13h and Mastalerz.13i
[4 þ 6] polycondensation reactions of trialdehydes with dia-
mines (Scheme 1b) or of dialdehydes with triamines were shown
to result in the formation of cages in one step.
a Reagents and conditions: (a) [(arene)RuCl2]2, Cs2CO3,
CH2Cl2ꢀMeOH, room temp, 70ꢀ90%.
commercially available 2-chloro-3-hydroxypyridine. The ortho-
directing effect of the methoxymethoxy (MOM) group on the
lithiation of the pyridine ring is well-documented, and it is
supposedly due to the chelation of lithium by one or both of
the oxygen atoms of the protecting group.22 However, we
observed that 2 equiv of t-BuLi was necessary for a complete
conversion of 1, presumably because 1 equiv of the reagent is
chelated by the nitrogen atom and the benzyloxy group.
A reaction sequence which involves metallasupramolec-
ular chemistry and dynamic covalent chemistry is shown in
Scheme 1c. First, a trinuclear metallamacrocycle with three
pendant aldehyde groups is formed by self-assembly. Subsequent
condensation with a triamine gives the cage structure. Recently,
we demonstrated that reaction sequences of this kind can be
realized.21 Dodecanuclear coordination cages were obtained by
reaction of (arene)RuII complexes with 4-formyl-3-hydroxy-
2-pyridone followed by [4 þ 4] condensations with triamines.
Below we show that the synthetic concept to combine Ru-based
macrocycles containing formyl groups with amine linkers is
highly versatile. By variation of the three different building
blocks—the Ru complex, the formyl-substituted pyridone ligand,
and the amine linker—it is possible to change not only the size
and the solubility of the cages but also their topology. We will
describe the syntheses and the molecular structures of tri-, hexa-,
and dodecanuclear cages. It is shown that the cages, which
contain chiral metal centers, are formed in a diastereoselective
and chemoselective (self-sorting) fashion. Furthermore, we
demonstrate that simple one-pot reactions are possible, and we
will discuss the dynamic behavior of the complexes and how
exchange processes can be used to interconvert cage structures.
Reaction of lithiated 1 with N-formylpiperidine gave the 1,2-
diprotected isonicotinaldehyde 2, whereas quenching with
iodine gave the 4-iodopyridine derivative 4 in comparable yields
(60ꢀ67%). Reaction of 4 with 3-formylphenylboronic acid
under the standard conditions of Suzuki coupling (Pd(PPh3)4,
K2CO3, tolueneꢀwater) gave the diprotected aldehyde 5, which
may be considered as a phenyl homologue of isonicotinaldehyde
2. Both protecting groups of 2 and 5 were removed under acidic
conditions (50% trifluoroacetic acid in dichloromethane) to give
the formyl-substituted 3-hydroxy-2-pyridone derivatives 3 and 6
in good yields (80ꢀ90%) without the need for purification.
Synthesis and Structures of Metallamacrocyclic Trialde-
hydes. The base-induced self-assembly of (arene)RuII com-
plexes with 3-hydroxy-2-pyridone ligands was first described
in 2001.23 It was shown that trinuclear metallamacrocycles are
formed in which the (arene)Ru centers are bridged by two-fold-
deprotonated pyridone ligands. Subsequently, we and others
have used this structural motif for the construction of specific
receptors for cations24 and anions.25 In the course of these
investigations, it was found that substituents at position
4 of the 3-hydroxy-2-pyridone ligand do not interfere with
the self-assembly process.24b,g,i It was thus expected that the
ligands 3 and 6 are suited for the construction of trimeric (arene)
Ru complexes. Indeed, reactions of the chloro-bridged dimers
[(p-cymene)RuCl2]2, [(1,3,5-C6H3Me3)RuCl2]2, or [{1,3,5-
C6H3(i-Pr)3}RuCl2]2 with ligand 3 or 6 in the presence of base
(Cs2CO3) gave the trinuclear macrocyles 7aꢀc and 8a,b in
70ꢀ90% yield (Scheme 3). Overall, the spectroscopic properties
of the metallamacrocycles were similar to what has been
’ RESULTS AND DISCUSSION
Synthesis of 3-Hydroxy-2-pyridone Ligands. Our approach
for the synthesis of 4-substituted derivatives of 3-hydroxy-
2-pyridone relies on the regioselective lithiation of the pyridine
derivative 1 (Scheme 2). The latter is readily prepared from the
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Scheme 4. Synthesis of the C3-Symmetric Triamines 13, 14,
and 17a
Figure 1. Structures of the trinuclear complexes 7c (a) and 8b (b) in the
solid state. Solvent molecules and hydrogen atoms are omitted for
clarity. In the case of 7c, one of the isopropyl chains occupies two
alternate positions; the one with the higher occupancy factor (0.6) is
shown. Colors: C gray, N blue, O red, Ru orange.
described for other trimers of this kind.23ꢀ25 In addition,
1
characteristic signals for aldehyde groups were observed by H
and 13C NMR spectroscopy (δH = 10.0ꢀ10.3 ppm; δC ≈ 190
ppm; CDCl3).
a Reagents and conditions: (a) RMgCl, Et2O, room temp, 9, 64%, 10,
11%; (b) HNO3, H2SO4, 0 °C, 11, 36%, 12, 24%, 16, 70%; (c) H2 (1
atm), Pd/C, EtOH, 13 and 14, ∼quant., 17, 74%.
The molecular structures of 7b,21 7c (Figure 1a), 8a
(Supporting Information (SI), Figure S1b), and 8b (Figure 1b)
in the solid state were determined by single-crystal X-ray analyses
(SI, Table S1). The RuꢀO (2.04ꢀ2.10 Å) and RuꢀN (2.12ꢀ
2.15 Å) bond distances fall within the expected range.23ꢀ25 The
average distance between the oxygen atoms of the aldehyde
groups of the (1,3,5-C6H3Me3)Ru complex 7b is 7.8 Å, whereas a
value of 6.9 Å is found for the [1,3,5-C6H3(i-Pr)3]Ru complex 7c.
This difference can be attributed to the steric bulk of the π-ligand
[1,3,5-C6H3(i-Pr)3], which results in a distortion of the cone-
shaped macrocycle.
Synthesis of C3-Symmetric Triamines. The C3-symmetric
triamines 13 and 14 are derivatives of tris(4-aminophe-
nyl)methane with different alkyl substituents at the core carbon
atom (methyl vs tert-butyl). They were prepared in three steps by
reaction of trityl chloride with the corresponding Grignard
reagents, followed by nitration of the 1,1,1-triphenylalkanes 9
and 10 and catalytic hydrogenation of the 1,1,1-tris(4-nitrophe-
nyl)alkanes 11 and 12 (Scheme 4). In a similar fashion, 1,3,5-
tris(4-aminophenyl)adamantane (17) was prepared from the
readily available27 1,3,5-triphenyladamantane (15).
Tetrahedral Cages by [4 þ 4] Condensation Reactions. In a
recent communication we reported that 1,1,1-tris(4-aminophe-
nyl)pentane reacts with trimers 7a,b to give dodecanuclear
cages.21 The tris(4-aminophenyl)methane derivatives 13 and
14 and the adamantane-derived triamine 17 undergo similar
[4 þ 4] condensation reactions: when CH2Cl2ꢀMeOH solu-
tions (1.75:1 v/v) of equal amounts of either 7a or 7b and the
respective triamine were allowed to react for 5ꢀ7 days at room
temperature, the formation of cages was observed (Scheme 5).
The (1,3,5-C6H3Me3)Ru complexes 18b (yield, 45%) and 20b
(33%) precipitated from the reaction mixture, the former as an
orange powder and the latter in the form of orange, needle-like
crystals. The complexes 18a, 19a, 19b, and 20a were isolated in
35ꢀ50% yields as amorphous solids, which formed upon re-
moval of dichloromethane from the solutions adiabatically under
vacuum.
In the case of 8a,b, the aldehyde groups may adopt different
orientations due to rotation of the phenyl groups with respect to
the metallamacrocyclic framework. Thus, the distances between
the oxygen atoms of the aldehyde groups in 8a,b vary between
8.1 and 15.0 Å.
Metallamacrocycles with bridging 3-hydroxy-2-pyridone li-
gands are known to undergo ligand exchange reactions in polar
solvents such as methanol or water, a behavior which has been
used for the generation of dynamic combinatorial libraries.26
The formyl-substituted complexes 7aꢀc displayed reduced
lability, at least under the conditions employed. Due to low
solubility in pure methanol, ligand exchange reactions were
studied in CD2Cl2ꢀCD3OH (1.75:1 v/v). The 1H NMR
spectrum of an equimolar mixture of 7a and 7b (3 mM each)
showed no evidence for the formation of heterotrimeric species
after 7 days at room temperature. Under the same conditions, a
mixture of the trimers 8a and 8b contained about 25% of mixed
complexes, which indicates that complexes containing ligand 6
display a slightly higher lability. Since the additional phenyl
groups of 8a and 8b are well separated, we attribute the
difference in lability of complexes 7 and 8 to electronic rather
than steric effects. A mixture of 7a and 8b did not undergo
ligand exchange, in line with inertness of the former macrocycle
(SI, Figure S2).
Clear evidence for the formation of dodecanuclear [4 þ 4]
condensation products was obtained by high-resolution mass
1
spectrometry (ESI). The H and 13C NMR spectra of the
complexes 18ꢀ20 show only one set of signals for the 12 arene
π-ligands and one for the four bridging imine ligands (the latter
with apparent C3 symmetry). These data suggest that cage
formation proceeds in a diastereoselective fashion, an assump-
tion which is confirmed by the crystallographic analyses
described below.
Reactions of the triamines 13 and 14 with the [1,3,5-C6H3
(i-Pr)3]Ru complex 7c were also attempted. However, slow
decomposition of the metal complex during the course of the
It can be concluded that the macrocyclic trialdehydes 7aꢀc are
highly preorganized building blocks, which are essentially inert
under the conditions used for the synthesis of cages (vide infra).
The phenyl homologues 8a,b are largely inert as well, but their
functional aldehyde groups are less preorganized due to in-
creased conformational freedom.
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Scheme 5. Synthesis of Tetrahedral Cagesa
Table 1. Selected Structural Data for the Cages 18b, 20b, 21a,
and 21b
18b
20b
21a
21b
space group
C2/c
0.1260
500
C2/c
0.0800
740
P2/n
0.1109
290
Pcca
R1 (I > 2σ)
internal cavity volume (Å3)a
0.1557
290
maximal Ru Ru distance (Å) 23.434(5) 26.117(9) 20.391(3) 20.388(5)
3 3 3
a Calculated as described in ref 21. The error is (10%.
7c, albeit with low isolated yield (29%). The low yield is due
to the high solubility of 21c, which hampered its isolation.
The larger cages with phenyl groups in their walls (18ꢀ20) are
moderately or poorly soluble in halogenated solvents (CHCl3,
CH2Cl2, C6H5F), but their solubility dramatically increases in
the presence of small amounts of methanol as cosolvent (5ꢀ10%
v/v). At the same time, they are essentially insoluble in pure
methanol as well as in most other common solvents. The cages
21aꢀc display higher solubility in halogenated solvents and in
methanol, presumably due to the presence of polar tertiary amine
groups. Overall, the following trends were observed: with respect
to the nature of the triamine building block, the solubility of the
cage products decreases in the order N(CH2CH2)3 . nBu-
21
CPh3 > t-BuCPh3 > MeCPh3 > 1,3,5-triphenyladamantane;
with respect to the nature of the π-ligand, the solubility decreases
in the order 1,3,5-C6H3(i-Pr)3 > p-cymene > mesitylene. Thus,
complex 20b displays poor solubility in all solvents tested,
whereas 21c is well-soluble (g10 mg mLꢀ1) in CHCl3, THF,
and MeOH.
Large (1ꢀ2 mm) single crystals of the cages 18a,b and 19a,b
could be obtained by vapor diffusion of Et2O into CHCl3ꢀ
MeOH or CH2Cl2ꢀMeOH solutions (90:10 to 95:5 v/v).
However, most of these crystals diffracted X-rays very poorly,
and acceptable diffraction data sets could only be collected for
18b. Crystals of 20b, which were obtained directly from the
reaction mixture, and crystals of the smaller cages 21a,b
(obtained from C6H5FꢀMeOH or CHCl3) were also analyzed
successfully by X-ray diffraction (XRD). Selected refinement
details and structural features of the cages are given in Table 1
(for more details see SI, Table S2); the molecular structures of
the cages are shown in Figure 2.
Overall, the geometries of the cages 18b, 20b, 21a, and 21b are
similar: four trimeric Ru complexes are linked via imine bonds
with four organic ligands to give dodecanuclear cages of approx-
imate T symmetry (Figure 2). However, the sizes of the cages
differ substantially. For the TREN-based cages 21a and 21b, the
a Conditions: CH2Cl2ꢀMeOH (1.75: 1 v/v), room temp, 7 days
(18ꢀ20) or 24 h (21).
reaction was observed, as manifested by the formation of un-
bound triisopropylbenzene (detected by 1H NMR spectro-
scopy). The low stability of the [1,3,5-C6H3(i-Pr)3]Ru is likely
related to the steric bulk of the π-ligand. In fact, the facile
substitution of the 1,3,5-C6H3(i-Pr)3 ligand from RuII complexes
has already been observed in studies in the context of catalysis.28
Initially we assumed that the triamine had to be rather rigid to
prevent the formation of smaller (e.g., [1 þ 1] condensation)29,30 or
ill-defined condensation products (formation of a dynamic mixture
or of oligomers). We were thus surprised to discover that reactions
of 7a,b with the flexible triamine tris(2-aminoethyl)amine (TREN)
also resulted in the formation of [4 þ 4] condensation products
(21a,b). Moreover, the reactions with TREN were much faster, and
complete condensation was observed after just 24 h. The increased
reaction rate is presumably due to the higher nucleophilicity of the
aliphatic amino groups of TREN. The products 21a and 21b were
isolated as spectroscopically pure solids in 58% and 65% yield,
respectively. However, the crude yield of the reactions was more
than 90% according to 1H NMR. The very clean formation of 21a,b
is in contrast to what has been observed for reactions with the
triamines 13, 14, and 17, where significant amounts of imine side
products were detected in the crude reaction mixtures.
maximum Ru Ru distance is 20.391(3) and 20.388(5) Å,
3 3 3
respectively, whereas the corresponding value for the adaman-
tane-containing cage 20b is 26.117(9) Å (Table 1). Accordingly,
the cavity volume increases from ∼290 to ∼740 Å3.31 In each
case, highly disordered solvent molecules occupy the space in
and around the cages. The crystals thus diffracted poorly at high
angles and gave intensity data of limited quality. A more detailed
discussion of bond lengths and angles is therefore not given.
The 12 ruthenium atoms of the cages are stereogenic centers.
The metal atoms within the trimetric building blocks 7 have
necessarily the same relative configuration.23 Interestingly, the
cages are obtained in the form of a single diastereoisomer
(as evidenced by NMR), and the crystallographic analyses show
that the four Ru trimers have the same configuration. The
diastereoselectivity is particularly remarkable for the cages
The shorter reaction time also enabled us to obtain the [1,3,5-
C6H3(i-Pr)3]Ru-containing cage 21c from metallamacrocycle
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Figure 2. Structures of the dodecanuclear cages 18b (a), 20b (b), 21a (c), and 21b (d) in the solid state. Solvent molecules and hydrogen atoms are
omitted for clarity. Colors: C gray, N blue, O red, Ru orange.
21aꢀc, which are obtained in nearly quantitative yield from a
Scheme 6. Reactions of Metallamacrocycle 7a with 1,3,5-
Tris(aminoethyl)benzene Derivatives 22 and 23
highly flexible TREN.
Reactions with 1,3,5-Tris(aminomethyl)benzene: Cageꢀ
Cylinder Equilibria. After having found that an aliphatic amine
such as TREN is very reactive in condensation reactions with
the metallamacrocycles 7, we turned our attention to other
alkylamines, namely the 1,3,5-tris(aminomethyl)benzenes 22
(improved synthetic procedure, see Supporting Information)
and 23.32 Upon reaction of equimolar amounts of 7a and 22
under the conditions employed before (CD2Cl2ꢀCD3OH
1.75:1, v/v), 1H NMR monitoring of the reaction mixture
indicated the presence of several condensation products, with
equilibrium being established after ∼24 h. At this point, mass
spectrometric analysis revealed the presence of the expected
product of the [4 þ 4] condensation, along with unexpected
minor peaks for the products of the [2 þ 3] and the [3 þ 3]
condensations (SI, Figure S3). The attempted isolation of the
[4 þ 4] product failed to give the cage in pure form. However,
when the trialdehyde 7a and the triamine 22 were mixed in a 2:3
1
ratio instead of 1:1, H NMR analysis of the reaction mixture
indicated the formation of a single product (24; crude yield,
>95%). Complex 24 precipitated in the form of an orange
powder upon removal of dichloromethane under vacuum
aminomethyl group. On the basis of NMR and high-resolution MS
data, complex 24 was proposed to be a hexanuclear (p-cymene)Ru
complex resulting from the condensation of two metallamacrocyc-
lic units 7a with three molecules of triamine 22 (Scheme 6). This
proposition was confirmed by an XRD analysis of single crystals,
which were obtained by vapor diffusion of Et2O into a solution of
24 in fluorobenzene (Figure 3; refinement data, SI, Table S3).
Complex 24 displays a cylindrical shape with a length
1
(isolated yield, 32%). The H and 13C NMR spectra of 24
showed that the C3 symmetry of the metal trimers was main-
tained in the product. However, the 1,3,5-trisubstituted benzene
fragment displayed a lower symmetry. Two singlets at δ = 6.67 and
7.02 ppm with an integral ratio of 2:1 were observed in the aromatic
region of the 1H NMR spectrum, along with a singlet at δ = 3.17
ppm (66.2 ppm in 13C NMR), which was assigned to a “free”
of ∼2.5 nm (maximum C C distance). A unique feature of
3 3 3
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Scheme 7. Synthesis of Cylindrical Cages by [2 þ 3]
Condensationsa
Figure 3. Structure of the hexanuclear complex 24 in the solid state.
Solvent molecules and hydrogen atoms are omitted for clarity. Colors: C
gray, N blue, O red, Ru orange.
complex 24 is the presence of three “free” amine groups. Unlike
what was observed for the dodecanuclear cages, the two Ru
trimers have opposite chirality (achiral meso-form). Since the
crude reaction mixture did not contain other products in
1
significant amounts (as indicated by H NMR), it may be
concluded that the formation of 24 proceeds in a highly
diastereoselective fashion.
a Conditions: CH2Cl2ꢀMeOH (1.75:1 v/v), room temp, 18 h; alter-
native conditions for 26 and 27, CH2Cl2ꢀMeCN (1:1 v/v), AcOH (2
mol %), room temp, 48 h.
When a solution of 24 in CDCl3 was allowed to stand for 1ꢀ3
days, the NMR analysis showed the formation of a new complex
along with signals of the free triamine ligand 22. The new
complex was shown to be a [4 þ 4] condensation product (25,
Scheme 6) on the basis of NMR and high-resolution MS data (SI,
Figure S4). Cage 25 precipitated from solution, which allowed its
isolation (yield 41%). Remarkably, this rearrangement was not
observed if methanol was added as a cosolvent (5% v/v). A
plausible reason is that the “free” amine groups are stabilized by
hydrogen bonds to the protic cosolvent. It is interesting to note
that a related conversion of a cage into a cylindrical compound
with pendant amine groups was observed in the case of organic
rhombicuboctahedral nanocapsules synthesized from formyl-
substituted cavitands.13l
The reaction of 7a with the triethyl-substituted triamine 23
was also attempted. However, complex mixtures of products
were observed, regardless of the stoichiometry (1:1 or 2:3).
Apparently, the high rigidity of 23, which exists preferentially in
the alternate (ababab) conformation with all three amine groups
facing one side of the aromatic plane,33 is not favorable for the
formation of either cylindrical ([2 þ 3]) or tetrahedral ([4 þ 4])
cage structures.
Cylindrical Cages by [2 þ 3] Condensation Reactions. The
reaction with 1,3,5-tris(aminomethyl)benzene (22) demon-
strated that cylindrical cages can be obtained. The use of
diamines instead of triamines was expected to provide a more
straightforward access to such structures because [2 þ 3] con-
densations would give cylindrical cages without “free” amine
groups. However, it should be pointed out that polycondensation
reactions of C3-symmetric trialdehydes with diamines are poten-
tially very complex. For purely organic building blocks, it has been
observed that such reaction can give tetrahedral cages via [4 þ 6]
condensations,13c,h,i large cubic cages via [8 þ 12] condensations,13k
and interpenetrated structures13b as well as polymers.34
First, we performed reactions with p- and m-xylylenediamine,
as these amines are related to the benzylic triamine 22. Investiga-
tions of the [4 þ 4] condensations had shown that the trialde-
hyde 7c is potentially problematic because the π-ligand is easily
replaced from the Ru center, and complex 7b was found to give
compounds of rather low solubility. We therefore focused on
reactions with the (p-cymene)Ru trimer 7a. After a solution of
p-xylylenediamine and 7a (ratio 3:2) in a mixture of CH2Cl2 and
MeOH (1.75:1, v/v) was stirred for 18 h, NMR analysis of
the reaction mixture indicated the formation of two products
(ratio ∼1:5) whose spectra were similar. At the same time, the
mass spectrum showed several peaks, all of which corresponded
to the expected [2 þ 3] condensation product 26 (Scheme 7).
Similar results were obtained for reactions with m-xylylenedia-
mine (SI, Figures S5 and S6). These results suggested that the
complexes 26 and 27 were obtained as a mixture of diastereo-
isomers, in which the two Ru trimers have either the same (D3-
symmetric cylinder) or the opposite chirality (C3h-symmetric
cylinder; meso form). For complex 26 it was possible to separate
the D3-symmetric isomer from the meso form by selective
precipitation. However, this required a change of the reaction
conditions: instead of CH2Cl2ꢀMeOH we used CH2Cl2ꢀ
MeCN (1:1 v/v) and 2 mol % of acetic acid as a Brønsted acid
catalyst. Under these conditions, complex 26 precipitated after
40 h in 56% yield in the form of a single isomer. The assignment
of the isomer was achieved with the help of a single-crystal XRD
analysis (Figure 4a). In the case of the reaction with m-xylylene-
diamine, the use of CH2Cl2ꢀMeCN also led to a precipitation of
cage 27. However, the precipitate contained a mixture of the two
stereoisomers (ratio ∼1:1).
Reactions of 7a with either ethylenediamine or 2,7-bis-
(aminomethyl)-3,6-dimethoxynaphthalene (30; for synthesis
see SI, Scheme S1) in CH2Cl2ꢀMeOH (1.75:1 v/v) proceeded
rapidly and gave one main product in each case (28 and 29,
Scheme 7). The high-resolution MS data were in agreement with
structures resulting from a [2 þ 3] condensation, and the 1H and
13C NMR spectra pointed to the formation of a single diastereo-
isomer. A crystallographic analysis of cage 28 showed that it has a
cylindrical structure with D3 symmetry (Figure 4b), similar to
what was observed for cage 26. In the solid state, both 26 and 28
form columnar stacks, which are packed in a honeycomb-like
fashion (Figure 4c). As a result, one can observe thin channels
propagating along the crystallographic c-axis.
Self-Sorting and Amine Exchange Reactions. When multi-
plebuilding blocks withcross-reactive functionalities are employed
in self-assembly processes, the system can display a self-sorting
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Figure 4. Structures of the hexanuclear cages 26 (a) and 28 (b) in the solid state, and packing of 26 viewed along the crystallographic c-axis (c). Solvent
molecules and hydrogen atoms are omitted for clarity. Colors: C gray, N blue, O red, Ru orange.
Scheme 8. Condensation Reactions with a Mixture of
Ethylenediamine and TREN Occur under Self-Sortinga
Scheme 10. Synthesis of Small Cages 31a,b by [1 þ 1] Con-
densations of Extended Trialdehydes 8a,b with Triamine 23a
a Conditions: CH2Cl2ꢀMeOH (1.75:1 v/v), room temp, 18 h.
a Conditions: CD2Cl2ꢀCD3OD (1.75:1 v/v), room temp.
indicating that the system was in its thermodynamically most
stable state.
The imine bonds in the cage structures remain dynamic and
can participate in exchange reactions. When a solution of the
tetrahedral cage 21a was mixed with an excess of ethylenedia-
mine (10 equiv), a structural rearrangement took place, resulting
in the clean formation of cylindrical complex 28 along with free
TREN (Scheme 9; SI, Figure S8). It is interesting to note that we
did not observe any decomplexation of the pyridonate ligands
from the Ru centers despite the fact that we have used an excess
of ethylenediamine, which is known to be a good chelate ligand.
The ligand-induced reorganization of 21a into 28 is reminiscent
of the work of Nitschke, who has investigated extensively imine
exchange reactions in metallasupramolecular structures.17a,c
However, the imine bonds were situated in the first coordination
sphere of transition metal ions (mostly CuI), whereas 21a and 28
feature unsupported imines.
Scheme 9. Reaction of Cage 21a with an Excess of Ethyl-
enediamine Results in Clean Conversion to Cylinder 28
Small Cages via [1 þ 1] Condensation Reactions. The
reactivity of the extended trialdehydes 8a,b toward various
amines was also investigated. In the case of aromatic triamines
such as 13, 14, and 17, no condensation was observed, even in the
presence of acetic acid as a catalyst. Apparently, 8a,b display a
lower intrinsic reactivity when compared to the smaller alde-
hydes 7a,b. We attribute the diminished reactivity to steric rather
than electronic effects because the chemical shifts of the 1H and
13C NMR signals of the aldehyde groups in 7 and 8 are quite
similar.
behavior, i.e., homoaggregates are favored over heteroaggregates.
Self-sorting is frequently encountered in the area of metallasu-
pramolecular chemistry,35 but it is a rarely explored phenomenon
in the field of dynamic covalent chemistry.36 We were interested
in whether self-sorting of amine building blocks would take place
upon cage formation. Therefore, we examined the reaction of the
metallamacrocyclic trialdehyde 7a with a mixture of ethylene-
1
diamine and TREN (ratio 6:3:4). H NMR analysis of the
reaction mixture after 18 h revealed the exclusive formation of
two imine products: the cylindrical cage 28 and the tetrahedral
cage 21a (Scheme 8; SI, Figure S7). NMR analysis of the mixture
at a later stage revealed no changes in product distribution,
Reactions with more nucleophilic alkylamines such as 2,7-bis-
(aminomethyl)-3,6-dimethoxynaphthalene (30), p-xylylenedia-
mine, TREN, or 1,3,5-tris(aminomethyl)benzene (22) were also
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Scheme 11. One-Pot Self-Assembly Reactionsa
Figure 5. Structures of the trinuclear complexes 31a (a) and 31b (b) in
the solid state. Solvent molecules and hydrogen atoms are omitted for
clarity. Colors: C gray, N blue, O red, Ru orange.
inefficient, and incomplete condensation was observed after
extended periods of time. Only reactions with the conformation-
ally restricted triamine 23 gave in high yields single products
(31a,b). On the basis of NMR and high-resolution MS data, it
was deduced that 31a,b are [1 þ 1] condensation products
resulting from the “capping” of the concave metallamacrocycles
with the triamine (Scheme 10).
Single crystals of 31a,b were analyzed by XRD. In both
complexes, the hexasubstituted benzene ring is situated perpen-
dicular to the C3 axis of the metallamacrocycle (Figure 5). The
complexes feature small cavities, but neither appears to be of
sufficient volume to accommodate solvent molecules. Notably,
racemic 31a spontaneously resolves during crystallization, giving
an equal quantity of the two stereoisomers in enantiopure form.
However, the cubic morphology of the crystals (space group R3)
prevented naked eye distinction between the two enantiopure
forms, and the crystals could therefore not be manually
separated.
One-Pot Self-Assembly Reactions. All cage structures de-
scribed so far were obtained in a stepwise fashion, i.e., the amine
building blocks were mixed with preformed metallamacrocycles
7 and 8. Such a two-step procedure appeared advantageous
because—as discussed above—the metallamacrocycles are lar-
gely inert during the condensation reactions. Furthermore, it is
possible to perform the condensations in the presence of
Brønsted acid catalysts, whereas the formation of the metalla-
macrocycles requires the addition of base. Still, we were inter-
ested in exploring the possibility of obtaining cages in one-pot
reactions. As targets, we chose cylinder 29, the tetrahedral cages
21a,b, and the trinuclear complex 31a, because the condensation
reactions starting with the preformed metallamacrocycles had
given very good yields and stereoselectivities.
First, we investigated the one-pot reaction of the pyridone
ligand 3 with [(p-cymene)RuCl2]2 and the diamine 30 (ratio
6:3:3) in CD2Cl2ꢀCD3OH (1.75:1 v/v) in the presence
of Cs2CO3 as base (Scheme 11). An NMR analysis of the
reaction mixture after 18 h revealed the quantitative formation
of cylinder 29 (SI, Figure S8). The attempted one-pot synthesis
of the tetrahedral cages 21a,b was less successful. In reactions
with [(p-cymene)RuCl2]2, it was possible to detect the NMR
signals of cage 21a, but there were large amounts of unidentified
side products. Reactions with [(1,3,5-C6H3Me3)RuCl2]2 were
more selective and provided cage 21b with a crude yield of 37%
as determined by 1H NMR spectroscopy (SI, Figure S10). This
yield is lower than the overall yield for the two-step procedure
(65%), but it is still respectable, given that the assembly of 21b
requires the formation of 48 bonds (36 RuꢀL and 12 imine
bonds). Isolation of complex 21b from the reaction mixture was
a Conditions: CD2Cl2ꢀCD3OH (1.75:1 v/v), room temp, 18 h.
possible by selective precipitation (yield 13%). Finally,theone-pot
reaction of the extended pyridone ligand 6 with [(p-cymene)RuCl2]2
and triamine 23 was investigated. As in the case of cylinder 29,
a nearly quantitative formation of complex 31a was observed
(SI, Figure S10). From these selected examples it can be
concluded that one-pot reactions are feasible for simpler struc-
tures, but larger cages such as 21 are better obtained in a two-step
fashion.
’ CONCLUSIONS
We have demonstrated that the combination of metallasupra-
molecular chemistry with dynamic covalent chemistry can be
used for the rapid and efficient synthesis of molecular cages. Our
approach is based on three types of building blocks: (arene)RuII
complexes, formyl-substituted hydroxypyridone ligands, and
amine linkers. By variation of the building blocks, we were able
to change the size and the topology of the cages substantially. It
was thus possible to obtain small trinuclear cages, hexanuclear
cages with a cylindrical shape, and dodecanuclear cages with huge
cavities. Notably, all dodecanuclear and most hexanuclear cages
were formed in a highly diastereoselective fashion. A unique
feature of our approach is the fact that the dynamic covalent
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bonds are formed independently, i.e., the imine bonds are not
formed in the first coordination sphere of the metals. Reactivity
studies have shown that it is possible to address the imine bonds
selectively, as demonstrated by the conversion of a tetrahedral
cage into a cylindrical cage via an imine exchange reaction. The
goal of the present study was to establish the scope and the
limitations of the synthetic approach, with special focus on the
building blocks mentioned above. It appears likely, however, that
the basic concept of linking metallasupramolecular building
blocks via dynamic covalent bonds37 can be extended to other
metal complexes (e.g., PdII-based assemblies) and to different
types of organic linkers. Further investigations in this direction
are ongoing in our laboratory.
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’ AUTHOR INFORMATION
Corresponding Author
kay.severin@epfl.ch
’ ACKNOWLEDGMENT
This work was supported by funding from the Swiss National
Science Foundation and by the EPFL. We thank Dr. Laura Menin
(EPFL) for help with mass spectrometry. The figures were
produced using the UCSF Chimera package from the Resource
for Biocomputing, Visualization, and Informatics at the Univer-
sity of California, San Francisco.38
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