Hydrogen-bond-driven controlled molecular marriage in covalent cages

Article abstract of DOI:10.1002/chem.201303397

A supramolecular approach that uses hydrogen-bonding interaction as a driving force to accomplish exceptional self-sorting in the formation of imine-based covalent organic cages is discussed. Utilizing the dynamic covalent chemistry approach from three geometrically similar dialdehydes (A, B, and D) and the flexible triamine tris(2-aminoethyl)amine (X), three new [3+2] self-assembled nanoscopic organic cages have been synthesized and fully characterized by various techniques. When a complex mixture of the dialdehydes and triamine X was subjected to reaction, it was found that only dialdehyde B (which has OH groups for H-bonding) reacted to form the corresponding cage B₃X₂ selectively. Surprisingly, the same reaction in the absence of aldehyde B yielded a mixture of products. Theoretical and experimental investigations are in complete agreement that the presence of the hydroxyl moiety adjacent to the aldehyde functionality in B is responsible for the selective formation of cage B₃X₂ from a complex reaction mixture. This spectacular selection was further analyzed by transforming a nonpreferred (non-hydroxy) cage into a preferred (hydroxy) cage B₃X₂ by treating the former with aldehyde B. The role of the H-bond in partner selection in a mixture of two dialdehydes and two amines has also been established. Moreover, an example of unconventional imine bond metathesis in organic cage-to-cage transformation is reported. Marriage guidance: Controlled self-sorting in covalent cage formation, including cage-to-cage transformation, has been achieved by using hydrogen bonding as a driving force (see figure). Unconventional imine bond metathesis in organic cages is also reported. Copyright

Full text of DOI:10.1002/chem.201303397

DOI: 10.1002/chem.201303397
Full Paper
&
Cage Compounds
Hydrogen-Bond-Driven Controlled Molecular Marriage in Covalent
Cages
Koushik Acharyya and Partha Sarathi Mukherjee*[a]
Abstract: A supramolecular approach that uses hydrogen-
bonding interaction as a driving force to accomplish excep-
tional self-sorting in the formation of imine-based covalent
organic cages is discussed. Utilizing the dynamic covalent
chemistry approach from three geometrically similar dialde-
hydes (A, B, and D) and the flexible triamine tris(2-amino-
ethyl)amine (X), three new [3+2] self-assembled nanoscopic
organic cages have been synthesized and fully characterized
by various techniques. When a complex mixture of the di-
aldehydes and triamine X was subjected to reaction, it was
found that only dialdehyde B (which has OH groups for H-
bonding) reacted to form the corresponding cage B3X2 se-
lectively. Surprisingly, the same reaction in the absence of al-
dehyde B yielded a mixture of products. Theoretical and ex-
perimental investigations are in complete agreement that
the presence of the hydroxyl moiety adjacent to the alde-
hyde functionality in B is responsible for the selective forma-
tion of cage B3X2 from a complex reaction mixture. This
spectacular selection was further analyzed by transforming
a nonpreferred (non-hydroxy) cage into a preferred (hy-
droxy) cage B3X2 by treating the former with aldehyde B.
The role of the H-bond in partner selection in a mixture of
two dialdehydes and two amines has also been established.
Moreover, an example of unconventional imine bond meta-
thesis in organic cage-to-cage transformation is reported.
Introduction
ligand coordination to construct self-sorted metallacycles and
cages.[7]
Nature has demonstrated the magical artifices of making multi-
functional complex architectures with sheer selectivity and
utmost delicacy over millions of years. One such artifice is self-
sorting,[1] which is spontaneous association through mutual
recognition of complementary building units into a well-de-
fined ordered architecture, within a random reaction mixture.
In the biological regime this “order out of chaos” process is
a well-established synthetic protocol.[2] Formation of the DNA
double helix through hydrogen bonding is one of the proto-
types of biological self-sorting. To understand such a complex
biological phenomenon in a better way, immense efforts have
been made in the last few decades to construct numerous arti-
ficial elegant architectures. Noncovalent interactions, especially
metal–ligand coordination-driven self-recognition,[3] hydrogen
bonding,[4] charge–charge interaction,[5] and so forth, have
been employed for this purpose by Lehn, Stang, Schmittel,
and others. On the contrary, hitherto self-sorted systems utiliz-
ing covalent bonding have not been well studied.[6] Dynamic
covalent bonding has recently been coupled with metal–
In the last two decades, with profound advancement of dy-
namic covalent chemistry,[8] several sophisticated purely cova-
lent cages[9] have been synthesized. Such three-dimensional
(3D) cages have earned a substantial appreciation in recent
times from the scientific community owing to their potential
applications in sensing,[10] catalysis,[11] gas storage,[12] and sepa-
ration.[13] However, from the perspective of their synthetic
methodology, the self-sorting protocol has been overlooked.
The dynamic covalent bond, namely the imine bond, allows
the removal of errors during formation, which leads to a ther-
modynamically most stable combination in the majority of
cases.[8a] Does this dynamic nature of the imine bond allow
self-sorting in 3D organic cage formation? Indeed it does. In
our recent publication,[14] we were successfully able to show
how the dynamic nature of the imine bond maneuvered the
efficient formation of 3D self-sorted architectures. Additionally,
we also showed an example of a cage-to-cage transformation,
depending on the preference for a partner over another in
a complex reaction mixture. Therein, our main focus was to
look into the self-sorting behavior of two randomly selected al-
dehydes, irrespective of their geometrical background. After
having such unusual self-sorting behavior in the formation of
purely covalent cages from randomly chosen components, the
question that we asked is whether chemists can direct/control
such self-sorting. If so, what strategy can help chemists to con-
trol the outcome?
[a] K. Acharyya, Prof. Dr. P. S. Mukherjee
Department of Inorganic & Physical Chemistry
Indian Institution of Science
Bangalore 560 012 (India)
Fax: (+91)8023601552
E-mail: psm@ipc.iisc.ernet.in
It is a well-accepted fact that most of the self-sorting sys-
tems operate on the basis of difference in geometric shapes/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303397.
Chem. Eur. J. 2014, 20, 1646 – 1657
1646
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
sizes and electronic properties of the competing components.
Thus, increasing similarity makes the situation more complicat-
ed. To overcome this difficulty and to achieve an effective self-
sorting system, it is necessary to incorporate a structural ele-
ment that can modulate the reactivity of the reaction site. This
will aid in discriminating the reacting components, much like
in biological systems. In this regard, we turned our attention
towards a noncovalent interaction, particularly hydrogen bond-
ing. As already known, the H-bond plays a pivotal role in the
formation of several unprecedented abiological architec-
tures.[15] Herein, we report our investigation on the role of in-
tramolecular H-bonding in selective synthesis of a 3D organic
cage from a complex reaction mixture of four dialdehydes and
one triamine, in which the dialdehydes have similar geometri-
cal features. Furthermore, we also present our effort to achieve
exquisite control over a self-sorting process operating between
two dialdehydes and two triamines solely guided by H-bond-
ing to construct two selective cages out of myriad possibilities.
Moreover, we report unconventional imine bond metathesis in
transforming one set of cages to another set of cages, and in-
tramolecular H-bond-directed organic cage-to-cage transfor-
mation. To the best of our knowledge, this represents the first
example of systematic control of self-sorting in 3D organic
cage formation utilizing a secondary interaction such as H-
bonding as a driving force.
position) to an aldehyde/imine functionality is capable of form-
ing a stable six-membered ring through HOH···OCHO/HOH···NCHN in-
tramolecular hydrogen bonding.[16,17] We envisioned that such
supramolecular interaction can manipulate the fate of a reac-
tion in which competing components are present. Before per-
forming competitive experiments, all of the dialdehydes were
allowed to react separately with the triamine tris(2-amino-
ethyl)amine (X) in chloroform at room temperature under
dilute conditions. The purity and formation of all the newly
1
synthesized compounds were fully verified on the basis of H
1
and 13C NMR, H–1H COSY, HMQC, FTIR, ESI-HRMS, and single-
crystal X-ray diffraction analyses. These experimental results
unambiguously affirmed the formation of [3+2] imine-based
cages except in the case of C, for which we encountered the
formation of insoluble oligomeric or polymeric material. This
could be attributed to the steric bulk arising due to the pres-
ence of a methoxy group adjacent to the aldehyde functionali-
ty, which restricts it to preorganize during the reaction and
thus leads to the formation of undesired oligomeric or poly-
meric species.
After successful synthesis of the three cages (A3X2, B3X2, and
D3X2), our main objective was to investigate the selective for-
mation of one of them in a competitive reaction environment.
In this context, a mixture of dialdehydes A and D was subject-
ed to reaction with triamine X in a 3:3:2 molar ratio (amine X
was taken at a little less than 2 equiv) at room temperature in
chloroform for 48 h. From the experimental outcome it was as-
certained that although triamine X displayed a preference to
form a cage with aldehyde A, it also reacted with aldehyde D
to form the corresponding cage D3X2 (Scheme 2).
1H NMR tracking (Figure 1) of the reaction in CDCl3 revealed
that at the initial stage both the products A3X2 and D3X2 were
formed in almost equal amount.
Results and Discussion
Dialdehydes A, B, C, and D were selected for the present study
(Scheme 1). Among them, B is furnished with a hydroxyl
moiety adjacent to the aldehyde functionality. It is well docu-
mented in the literature that a hydroxyl group adjacent (ortho
This is suggested by the integra-
tion of the characteristic proton
NMR signals at d=5.60 and
5.99 ppm, respectively. But with
further progress of the reaction,
D3X2 was gradually converted
into A3X2 and finally reached
equilibrium within approximately
116 h (after that there was no
change in the product composi-
tion). From the integration of
the proton NMR signals it was
estimated that the equilibrium
product mixture contains 80%
of A3X2 and 20% of D3X2.
Quite surprisingly a different
picture emerged when, in a sepa-
rate set of experiments, a mixture
of dialdehydes B and D was
treated with triamine X. In this
case no peak corresponding to
D3X2 was observed rather than
cage B3X2. The same story iterat-
ed when aldehyde B was treated
Scheme 1. Schematic representation of the formation of [3+2] self-assembled organic cages A3X2, B3X2, D3X2, and
polymeric/oligomeric CnXm.
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1647
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
assigned to the aldehyde func-
tionality of B at d=9.90 ppm de-
creased selectively over time,
and the appearance of a new
proton NMR signal correspond-
ing to cage B3X2 at d=7.04 ppm
within 12 h (after that there was
no change in product composi-
tion) clearly supports the fact.
This selective formation of cage
B3X2 from a reaction mixture of
four aldehydes and an amine
can be considered as a 15-fold
(2+3) incomplete self-sorting ac-
cording to the classification of
Mahata and Schmittel,[3o] as only
Scheme 2. Formation of a mixture of cages A3X2 and D3X2 from a reaction mixture of two dialdehydes (A, D) and
amine X (3:3:2).
1
Figure 2. Time-dependent H NMR spectra recorded in CDCl3 during selec-
tive formation of cage B3X2 from a reaction mixture of aldehydes A–D and
amine X (3:3:3 3:2), with spectra of all three possible cages for comparison.
one type of discrete cage (B3X2) was formed from a five-com-
ponent reaction mixture (four dialdehydes and one triamine)
in which two components (B and X) were used and the other
three components (A, C, and D) remained unreacted.
Selective formation of hydroxyl-based aldehyde-containing
cage B3X2 from a complex reaction mixture encouraged us to
address the question: can a cage of non-hydroxy aldehyde
after formation be converted to B3X2? Thus, we performed an
experiment to check the possibility of transforming a nonpre-
ferred (non-hydroxy) cage into a preferred (hydroxy) cage. In
this context cage D3X2 was selected and its possibility of trans-
forming into cage B3X2 was investigated.
1
Figure 1. Time-dependent H NMR spectra recorded in CDCl3 during the for-
mation of cages A3X2 and D3X2 from a reaction mixture of dialdehydes A
and D and triamine X (3:3:2). The spectra of pure cages are also shown for
comparison.
with amine X in the presence of aldehyde A or C. In a final set
of experiments, a CDCl3 solution containing all four dialde-
hydes A–D was subjected to reaction with triamine X in
a 3:3:3:3:2 molar ratio (amine X was taken at a little less than
2 equiv). 1H NMR analysis of the reaction indicated that tria-
mine X again selectively picked up dialdehyde B as a preferred
partner, though other aldehydes were present in equal
amount in the mixture (Scheme 3). As shown in the spectrum
(Figure 2), there is no evidence of formation of any other possi-
ble products (A3X2, D3X2, or oligomeric species corresponding
to aldehyde C). Under the experimental conditions, the signal
First of all a solution containing dialdehyde D and triamine
X was stirred in CDCl3 for 24 h at room temperature to synthe-
1
size cage D3X2. H NMR spectra of the resulting reaction mix-
ture after 24 h clearly suggested the formation of the desired
cage with the presence of a very small amount of unreacted
dialdehyde D. The requisite amount of dialdehyde B was
added to this reaction mixture and the solution was stirred at
room temperature. The progress of the reaction was checked
1
periodically by H NMR spectroscopy. Although the transforma-
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1648
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
mixed with a solution of dialde-
hyde (A, B, or D) and immediate-
ly the 1H NMR spectrum of the
reaction mixture was recorded.
NMR spectra indicated that
within approximately 6 min after
mixing the reactants B and X, al-
dehyde was substantially con-
sumed unlike the other cases.
Letting the reaction proceed
without stirring or shaking for
another 80 min and checking
the spectra afterwards suggest-
ed ꢀ80% formation of cage
B3X2 (Figure S42 in the Support-
ing Information), whereas during
Scheme 3. Exclusive formation of cage B3X2 from a reaction mixture of four dialdehydes (A–D) and triamine X
(3:3:3:3:2).
tion was very slow, cage D3X2 gradually converted into cage
B3X2 and released dialdehyde D (Scheme 4). As depicted in the
spectra (Figure S38 in the Supporting Information), characteris-
tic proton NMR signals assigned to cage D3X2 and dialdehyde
B diminish with the appearance of signals corresponding to
cage B3X2 and dialdehyde D.
the same time lag yields of cages A3X2 and D3X2 reached only
ꢀ28 and ꢀ17%, respectively (Figures S40 and S44 in the Sup-
porting Information).
From the yields of the products it is quite clear that dialde-
hyde B has the fastest reaction kinetics towards triamine X
among the competing partners. Hence, cage B3X2 is kinetically
most favorable. The extremely fast reaction rate associated
with aldehyde B is consistent with the role of H-bonding in
the higher reactivity of salicylaldehyde over benzaldehyde re-
ported in the literature.[17a] As stated earlier, the O-hydroxyl
moiety can form a strong noncovalent interaction with the ad-
jacent aldehyde group, which makes it more nucleophilic to-
wards amine.
Kinetic and thermodynamic background of H-bonding assis-
tance in self-sorting
A self-sorting process is generally governed by either kinetics
or thermodynamics. When the outcome of the process is de-
termined by reaction rates of product formation then it is ki-
netically controlled, whereas if the penultimate stability of the
resulting assembly makes a difference then it is thermodynami-
cally controlled. To understand kinetic factors associated with
the self-sorting, the rate constant of individual cage formation
needs to be calculated. Unfortunately complications arose due
to the formation of several uncharacterized intermediates
during the reaction, which precluded us from such calculation.
To gain a brief overview of this subject, individual cage forma-
tion was monitored separately in CDCl3 at room temperature
for a certain period of time and the yield of the desired cage
after that time was calculated. A solution of triamine X was
To examine thermodynamic control, gas-phase DFT (B3LYP,
6-31G) calculations were executed to estimate roughly the
heat of reaction of individual cage formation (see Figure 3). All
the reacting components and products were optimized and
the energy differences between the products and the reactants
were calculated. Theoretical results are summarized in Table 1.
It is clearly evident that entropy plays a vital role in the cage
formation process, as the enthalpy of reaction is positive. Inter-
estingly, cage B3X2 formation required the least energy
(6.33 kcalmolꢁ1), which suggests that it is thermodynamically
the most stable product. The very high enthalpy of reaction
Scheme 4. Formation of nonpreferred cage D3X2 and its transformation to preferred cage B3X2 upon treatment with aldehyde B driven by intramolecular H-
bonding.
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1649
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
it could easily be rationalized that reaction rates
follow the order B3X2 >AB2X2 >A2BX2 >A3X2 >D3X2.
This means that the higher affinity of triamine X for
dialdehyde B leads to the fast formation of cages
B3X2, AB2X2, and A2BX2, which in turn regulates the
reaction equilibrium of the two parallel reactions (for-
mation of cages A3X2 and D3X2) and does not allow
completion of the reaction.
The above results suggest that the presence of the
hydroxyl moiety makes a commanding difference be-
tween dialdehyde B and the rest of the dialdehydes.
Motivated by this fact, the next question that we
asked was: what would be the consequence of a reac-
tion in which two aldehydes (one of which has a hy-
droxyl group neighboring the aldehyde functionality)
and two triamines are present in a mixture when
both the aldehydes have a preference for the same
amine? In such circumstances, can the aldehyde
bearing a hydrogen-bonding motif regulate the fate
of the competing dialdehyde? To address these ques-
tions a set of experiments was carried out in which
aldehydes E and F were selected for study and their behavior
towards amines X and Y was investigated.
In a recent report, we have shown that dialdehyde E prefer-
entially reacts with triamine X to form cage E3X2 and this affini-
ty did not alter even in a complex reaction mixture.[14] Dialde-
hyde F was employed for the present study as it fulfills the
necessary two criteria: 1) the presence of a hydroxyl group ad-
jacent to the aldehyde functionality and 2) preferential reaction
with triamine X in a mixture of triamines X and Y. A mixture of
dialdehydes E and F in chloroform was allowed to react with
triamines X and Y in a 3:3:2:2 molar ratio at room temperature
for 48 h. After completion of the reaction, the solvent was
completely removed and the composition of the as-obtained
solid mass was examined by 1H NMR spectroscopy in CDCl3.
The NMR spectra of the reaction mixture and all the possible
cages (E3X2, E3Y2, F3X2, and F3Y2) along with the starting alde-
hydes are assembled in Figure 4.
Figure 3. DFT (B3LYP, 6-31G) optimized structures of dialdehydes a) A, b) B, c) C, and
d) D, e) amine X, and cages f) A3X2, g) B3X2, h) C3X2, and i) D3X2.
Table 1. Calculated reaction enthalpies of formation of cages.
Entry
Reaction
Calculated reaction enthalpy (DHg)
[kcalmolꢁ1
]
1
2
3
4
3A+2X!A3X2 +6H2O
3B+2X!B3X2 +6H2O
3C+2X!C3X2 +6H2O
3D+2X!D3X2 +6H2O
30.65
6.33
65.54
32.51
(65.54 kcalmolꢁ1) associated with cage C3X2 justified why for-
mation of this cage was not feasible. These experimental and
theoretical results strongly recommend that the selectivity is
not guided solely by kinetics or thermodynamics; indeed, it is
the outcome of both. So, intramolecular H-bonding is playing
a dual role here: it increases the reactivity of the aldehyde
functionality, which is manifested in higher reaction kinetics or
kinetic stability, as well as providing higher thermodynamic
stability to the final assembly (cage B3X2).
Analysis of these spectra pointed out several facts: dialde-
hyde F was fully consumed during the course of the reaction
whereas some amount of dialdehyde E remained unreacted.
Most interestingly, spectra of the reaction mixture revealed the
formation of cages F3X2 and E3Y2, though the formation of
cage E3X2 was expected from earlier experience (Scheme 5).
This result demonstrates that fast and stable formation of
cage F3X2 forced dialdehyde E to react with triamine Y (which
is not a preferred choice) to form nonpreferred cage E3Y2,
though in the absence of dialdehyde F the same reaction
yielded exclusively E3X2. This result reflects that H-bonding
may play a crucial role in forcing an aldehyde to bind with its
nonpreferred partner.
With the above results in hand we were quite excited to test
another set of reactions in which triamine X was present in the
amount needed for the formation of all possible cages. A first
set of experiments was carried out between two aldehydes (A,
B) and amine X in 3:3:4 molar ratio. 1H NMR spectra (Fig-
ure S34 in the Supporting Information) recorded in CDCl3 with
time indicated formation of the desired two cages (A3X2 and
B3X2), but a considerable amount of dialdehyde A remained
unreacted along with the formation of uncharacterized prod-
ucts. A similar scenario was observed when triamine X was
treated with a mixture of dialdehydes A, B, and D in
1
6:3:3:3 molar ratio. In this case, though H NMR spectra (Fig-
ure S35 in the Supporting Information) indicated the formation
of the desired three cages (A3X2, B3X2, and D3X2), for further as-
sessment we employed ESI-MS analysis. Mass spectrometric
analysis (Figure S36 in the Supporting Information) revealed
the formation of three cages along with the hetero cages
A2BX2 and AB2X2 as byproducts. From the kinetic point of view
Partner exchange by imine bond metathesis
Exchange of Schiff bases, popularly known as imine metathe-
sis, has been a subject of interest to synthetic chemists for
a long time. According to the mechanism proposed by Ingold
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1650
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
and Piggott[18] in the early 20th century, it proceeds through
a symmetry-forbidden [2+2] cycloaddition reaction via the for-
mation of a concerted 1,3-diazetidine intermediate. A few de-
cades later Messmer[19] showed that catalyst is required for the
progress of the reaction as it goes through an ionic intermedi-
ate. So the next question that comes to mind is: would such
imine exchange be possible in covalent cages? If so, then
how? To reach this goal, we have revisited our recent work,[14]
and two previously synthesized non-self-sorted cages (E3Y2
and G3X2) have been selected. A solution containing cages
E3Y2 and G3X2 in CDCl3 was stirred at room temperature with-
out adding any catalyst (Scheme 6) and the progress of the re-
1
action was monitored by H NMR spectroscopy (Figure S36 in
the Supporting Information). Investigation throughout the re-
action progress suggested slow exchange of partners and the
formation of the desired two cages (E3X2 and G3Y2), but unex-
pectedly we also observed peaks assigned to aldehydes F and
G. This experimental outcome opposes the conventional imine
exchange pathway and rather we anticipated that it follows
a two-step process: disassembly into aldehydes and amines
followed by reassembly by the process of self-sorting. We be-
lieve that dissolved water in CDCl3 is responsible for the trans-
formation. Theoretical calculation (DFT, B3LYP, 6-31G) predicts
that thermodynamically this process is possible, as it gains
ꢁ3.84 kcalmolꢁ1 extra stability.
Figure 4. 1H NMR spectra of the self-sorting experiment recorded in CDCl3
after 48 h along with the spectra of all possible cages and reacting compo-
nents involved for comparison.
Scheme 5. Self-sorting (molecular marriage) of a complex mixture (E, G, Y, and X) and change in partner choice (controlled self-sorting) controlled by dialde-
hyde F due to H-bonding.
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1651
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 6. Imine bond metathesis in organic cage-to-cage transformation.
X-ray crystal structures
Colorless rodlike crystals suitable for X-ray diffraction of the
cage A3X2 were grown by slow cooling of a hot ethanolic solu-
tion to room temperature. Cage A3X2 crystallized in the mono-
clinic crystal system with space group C2/c. Three crystallo-
graphically independent cage molecules along with several
ethanol molecules were found to exist in the asymmetric unit.
Yellow block-shaped single crystals of the cage B3X2 were
grown in the same way from hot CH3CN solution. This com-
pound crystallized in the monoclinic crystal system with space
group P21/c. An asymmetric unit was found to have one cage
molecule along with one water molecule and two acetonitrile
molecules. Cage D3X2 crystallized in the orthorhombic crystal
system with Pccn space group. Colorless block-shaped single
crystals were grown by slow evaporation of an acetonitrile so-
lution. An asymmetric unit comprised two crystallographically
independent cage molecules and three water molecules. Inter-
estingly, these two cage molecules have different spatial ar-
rangements (conformations). One conformation can easily be
transformed into another by twisting the molecule around the
axis passing through the apical nitrogen atoms as shown in
Figure 5.
Figure 5. Two conformers of cage D3X2 present in the asymmetric unit.
Figure 6). Aldehyde groups adopted an antiparallel alignment
with respect to each other during the formation of the desired
cages. In the case of cage B3X2, strong intramolecular H···N hy-
drogen bonds are found to occur between imine nitrogen and
the hydroxyl groups. This fact is reinforced by the OꢁN distan-
ces between hydroxyl groups and the imine nitrogen atoms,
which are in the range of 2.52–2.58 ꢁ. The distance between
two central nitrogen atoms of amine X in cages A3X2 and B3X2
is ꢀ17 ꢁ whereas, due to lack of ethynyl functionality in alde-
hyde D, cage D3X2 is slightly smaller in size with a distance of
ꢀ14 ꢁ. Some of the selected bond lengths and angles are
listed in the Supporting Information (Table S1).
1
Observations of broad H NMR signals at room temperature
corresponding to ꢁCH2 protons in the case of cages A3X2 and
D3X2 indicate the higher conformational flexibility relative to
cage B3X2 (sharp ꢁCH2 proton signals). However, the expected
sharp signals due to the ꢁCH2 protons were found in the NMR
spectrum at very low temperature due to restricted flexibility
(Figures S31 and S33 in the Supporting Information).
Conclusion
We have successfully shown that intramolecular H-bonding
can play a decisive role in selective formation of an imine-
based organic cage out of several equally probable possibilities
from a mixture in which competitors (dialdehydes) are geo-
metrically identical. Both theoretical and experimental studies
support the fact that it provides extra stability to the final as-
Solid-state structural examination elucidates that in all cases
three molecules of aldehyde reacted with two molecules of
amine to form [3+2] self-assembled cages in which imine
bonds are, as expected, in the preferred trans conformation
with C=N bond lengths in the range of 1.26–1.28 ꢁ (see
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1652
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 6. Ball-and-stick diagrams of the single-crystal X-ray structures of the cages a) A3X2, b) B3X2 with intramolecular H-bonding indicated by green dotted
lines, and c) D3X2. d–f) Packing of the cages in the unit cell. Solvent molecules and hydrogen atoms are omitted for clarity.
were synthesized according to the reported procedures. Aldehydes
sembly by means of kinetics as well as thermodynamics. This
A, B, and D were synthesized according to modified synthesis pro-
concept of intramolecular H-bonding-guided selectivity has
cedures.[22] Triethylamine was dried over sodium prior to use for
been usefully exploited to achieve quite remarkable control
1
1
synthesis. H and 13C NMR, 2D H–1H COSY, and 13C–1H HMQC spec-
over a self-sorting process operational between two dialde-
hydes and two triamines to synthesize selectively two specific
combinations. Moreover, H-bonding has been used as a driving
force for the first time for covalent cage-to-cage transforma-
tion and partner exchange in a mixture of cages. Furthermore,
the dynamic nature of the imine bond has been used for
a fruitful purpose to reach the goal of exchange of partners
through unconventional imine bond metathesis. Experimental
results in our case ruled out the conventional concerted imine
exchange pathway, rather they pointed to a two-step process:
disassembly of the cages into starting aldehydes and amines
followed by self-sorting into preferred combinations.
tra for the characterization of the products were recorded on
a Bruker 400 MHz spectrometer. In H NMR spectra chemical shift
(d) values are reported in ppm relative to TMS (d=0.00 ppm) as an
internal standard in CDCl3. A Bruker ALPHA FTIR spectrometer was
used for recording IR spectra. High-resolution mass spectra were
recorded on a Q-TOF instrument by electrospray ionization (ESI).
1
Synthesis of aldehyde A
In a 100 mL flame-dried double-neck round-bottomed flask, 3-ethy-
nylbenzaldehyde (200 mg, 1.54ꢂ10ꢁ3 mol), 3-bromobenzaldehyde
(570 mg, 3.08ꢂ10ꢁ3 mol), Pd(PPh3)2Cl2 (50 mg, 7.04ꢂ10ꢁ5 mol), CuI
(10 mg, 5.26ꢂ10ꢁ5 mol), and PPh3 (10 mg, 3.82ꢂ10ꢁ5 mol) were
dissolved in triethylamine (30 mL). The reaction mixture was then
stirred under a nitrogen atmosphere at 758C for 24 h. After com-
pletion of the reaction, the solvent was completely removed. The
resulting solid mass was purified by silica gel column chromatogra-
phy in hexane/dichloromethane (1:3) to give a pale yellow solid.
Experimental Section
Materials and methods
1
Yield of isolated product: 152 mg (42%). H NMR (CDCl3, 400 MHz):
All chemicals and solvents were purchased from commercially
available sources and were used without further purification. 1,3,5-
Tris(aminomethyl)-2,4,6-trimethylbenzene (Y)[20] and aldehyde F[21]
d=7.56 (dd, 2H), 7.79 (d, 2H), 7.88 (d, 2H), 8.06 (s, 2H), 10.04 ppm
(s, 2H); 13C NMR (100 MHz, CDCl3): d=89.8, 124.4, 129.7, 129.9,
133.5, 137.0, 137.6, 191.9 ppm; FTIR: n˜ =1692 cmꢁ1 (C=O).
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1653
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
with ethanol to remove unreacted starting materials. Yield of iso-
lated product: 7.5 mg (85%). 1H NMR (CDCl3, 400 MHz): d=2.83
(br, 6H), 3.37–3.69 (br, 6H), 5.60 (s, 6H), 7.54 (m, 12H), 7.80 (d, 6H),
8.11 ppm (d, 6H); 13C NMR (100 MHz, CDCl3): d=56.6, 60.4, 90.1,
124.9, 125.4, 129.0, 133.7, 134.2, 137.0, 161.1 ppm; FTIR: n˜ =
1649 cmꢁ1 (C=N); ESI-HRMS (CHCl3/CH3CN, 1:3): m/z: calcd for
[M+H]+: 887.4505; found: 887.4654.
Synthesis of aldehyde B
In a 100 mL flame-dried double-neck round-bottomed flask, 5-ethy-
nylsalicylaldehyde (400 mg, 2.74ꢂ10ꢁ3 mol), 5-bromosalicylalde-
hyde (830 mg, 4.13ꢂ10ꢁ3 mol), Pd(PPh3)2Cl2 (100 mg, 1.40ꢂ
10ꢁ4 mol), CuI (20 mg, 1.05ꢂ10ꢁ4 mol), and PPh3 (20 mg, 7.63ꢂ
10ꢁ5 mol) were dissolved in triethylamine (50 mL). The reaction
mixture was then stirred under a nitrogen atmosphere at 808C for
36 h. The solvent was completely removed after the completion of
the reaction and the resulting solid mass was purified by silica gel
column chromatography in hexane/dichloromethane (1:3) to iso-
late the pale yellow solid. Yield of isolated product: 255 mg (35%).
1H NMR (CDCl3, 400 MHz): d=7.00 (d, 2H), 7.66 (dd, 2H), 7.75 (d,
2H), 9.90 (s, 2H), 11.14 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=
87.5, 115.3, 118.7, 121.0, 137.2, 140.1, 161.9, 196.4 ppm; FTIR: n˜ =
1686 cmꢁ1 (C=O).
Synthesis of cage B3X2
In an 8 mL glass vial, a chloroform solution (4 mL) of amine X
(2.9 mg, 1.98ꢂ10ꢁ5 mol) was added dropwise slowly to a stirred so-
lution of aldehyde B (7.9 mg, 2.99ꢂ10ꢁ5 mol) in chloroform (3 mL).
The resulting solution mixture was stirred at room temperature for
an additional 24 h. After completion of the reaction, the solvent
was reduced in volume and a yellow solid product was precipitat-
ed out by adding n-pentane. Yield of isolated product: 7.9 mg
1
(80%). H NMR: (CDCl3, 400 MHz) d=2.79 (t, 6H), 2.92 (t, 6H), 3.22
Synthesis of aldehyde C
(t, 6H), 3.79 (t, 6H), 5.60 (s, 6H), 7.04 (d, 6H), 7.60 (s, 6H), 7.65 (dd,
6H), 14.49 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=56.4, 58.4,
88.0, 115.4, 117.9, 118.6, 134.5, 136.0, 161.8, 166.1 ppm; FTIR: n˜ =
1631 cmꢁ1 (C=N); ESI-HRMS (CHCl3/CH3CN, 1:3): m/z: calcd for
[M+H]+: 983.4199; found: 983.4363.
In a 100 mL flame-dried double-neck round-bottomed flask, 5-eth-
ynyl-2-methoxybenzaldehyde (320 mg, 2.00ꢂ10ꢁ3 mol), 5-bromo-2-
methoxybenzaldehyde (650 mg, 3.00ꢂ10ꢁ3 mol), Pd(PPh3)2Cl2
(70 mg, 9.85ꢂ10ꢁ5 mmol), CuI (15 mg, 7.8ꢂ10ꢁ5 mol), and PPh3
(15 mg, 5.72ꢂ10ꢁ5 mol) were dissolved in triethylamine (40 mL).
The reaction mixture was then stirred under a nitrogen atmos-
phere at 808C for 48 h. The solid product was isolated after remov-
al of the solvent and the product was purified by silica gel column
chromatography in dichloromethane to isolate pure product as
Synthesis of cage D3X2
In an 8 mL glass vial, amine X (2.9 mg, 1.98ꢂ10ꢁ5 mol) was dis-
solved in acetonitrile (4 mL). This solution was added dropwise to
a stirred solution of aldehyde D (6.3 mg, 3.00ꢂ10ꢁ5 mol) in aceto-
nitrile (3 mL). The resulting solution mixture was stirred at room
temperature for an additional 24 h. After completion of the reac-
tion, the solvent was completely removed followed by addition of
a few drops of ethanol and then the product was precipitated out
by adding n-pentane. Yield of isolated product: 6.4 mg (78%).
1H NMR (CDCl3, 400 MHz): d=2.87 (br, 12H), 3.71 (br, 12H), 5.99 (s,
6H), 7.12 (d, 6H), 7.54 (t, 6H), 7.87 (s, 6H), 8.13 ppm (d, 6H);
13C NMR (100 MHz, CDCl3): d=56.3, 60.5, 125.0, 128.2, 128.8, 130.7,
137.6, 140.1, 162.1 ppm; FTIR: n˜ =1644 cmꢁ1 (C=N); ESI-HRMS
(CH3CN): m/z: calcd for [M+H]+: 815.4505; found: 815.4648.
1
a yellow powder. Yield of isolated product: 224 mg (38%). H NMR
(CDCl3, 400 MHz): d=3.96 (s, 3H), 6.98 (d, 2H), 7.68 (dd, 2H), 7.97
(d, 2H), 10.44 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=56.3,
88.1, 112.4, 116.2, 125.2, 132.3, 139.1, 161.9, 189.4 ppm; FTIR: n˜ =
1675 cmꢁ1 (C=O); ESI-HRMS (CHCl3/CH3CN, 1:3): m/z: calcd for
[M+H]+: 295.0925; found: 295.0958; calcd for [M+Na]+: 317.0789;
found: 317.0815.
Synthesis of aldehyde D
In a 100 mL flame-dried double-neck round-bottomed flask, 3-bro-
mobenzaldehyde (740 mg, 4.00ꢂ10ꢁ3 mol) and 3-formylphenylbor-
onic acid (900 mg, 6.00ꢂ10ꢁ3 mol) were taken in THF (50 mL) and
an aqueous solution (20 mL) of K2CO3 (1 g, 7.25ꢂ10ꢁ3 mol) was
added. The resulting solution mixture was stirred under a nitrogen
atmosphere at room temperature for 10 min followed by addition
of Pd(PPh3)4 (100 mg, 8.65ꢂ10ꢁ5 mol) and heating to 808C for
48 h. After completion of the reaction THF was completely re-
moved and the aqueous part was extracted with dichloromethane
(50 mLꢀ3). The organic part was dried over sodium sulfate and
the solvent was completely removed to obtain a pale yellow solid.
The resulting solid mass was purified by silica gel column chroma-
tography in dichloromethane to give a white powder. Yield of iso-
Synthesis of cage F3X2
In an 8 mL glass vial, a chloroform solution (4 mL) of amine X
(2.9 mg, 1.98ꢂ10ꢁ5 mol) was added dropwise slowly to a stirred so-
lution of aldehyde F (5.4 mg, 2.99ꢂ10ꢁ5 mol) in chloroform (3 mL).
The resulting solution mixture was stirred at room temperature for
an additional 24 h. After completion of the reaction, the solvent
was completely removed and the obtained yellow solid mass was
washed with ethanol to remove unreacted starting materials. Yield
of isolated product: 6.6 mg (91%). 1H NMR (CDCl3, 400 MHz): d=
2.14 (s, 9H), 2.71 (t, 6H), 2.86 (s, 6H), 3.23 (t, 6H), 3.72 (s, 6H), 5.46
(s, 3H), 7.50 (s, 6H), 15.18 ppm (s, 6H); 13C NMR (100 MHz, CDCl3):
d=7.8, 55.8, 56.2, 111.3, 113.1, 136.0, 166.2, 167.8 ppm; FTIR: n˜ =
1633 cmꢁ1 (C=N); ESI-HRMS (CHCl3/CH3CN, 1:1): m/z: calcd for
[M+H]+: 725.3730; found: 725.3860.
1
lated product: 824 mg (98%). H NMR (CDCl3, 400 MHz): d=7.67 (t,
2H), 7.91 (m, 2H), 8.16 (t, 2H), 10.11 ppm (s, 2H); 13C NMR
(100 MHz, CDCl3): d=128.4, 129.9, 130.2, 133.4, 137.5, 141.1,
192.5 ppm; FTIR: 1687 cmꢁ1 (C=O).
Synthesis of cage A3X2
Synthesis of cage F3Y2
In an 8 mL glass vial, a chloroform solution (4 mL) of amine X
(2.9 mg, 1.98ꢂ10ꢁ5 mol) was added slowly to a stirred solution of
aldehyde A (7 mg, 2.99ꢂ10ꢁ5 mol) in chloroform (3 mL). The result-
ing solution mixture was stirred at room temperature for an addi-
tional 24 h. After completion of the reaction, the solvent was com-
pletely removed and the obtained white solid mass was washed
In an 8 mL glass vial, amine Y (4.1 mg, 2.00ꢂ10ꢁ5 mol) was dis-
solved in chloroform (4 mL). This solution was added dropwise to
a stirred solution of aldehyde F (5.4 mg, 3.00ꢂ10ꢁ5 mol) in chloro-
form (3 mL). Pure solid product was isolated after removing the
solvent on completion of the reaction followed by washing with
acetonitrile. Yield of isolated product: 4.2 mg (58%). 1H NMR
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1654
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
(CDCl3, 400 MHz): d=2.11 (s, 18H), 2.18 (s, 9H), 5.01 (s, 12H), 6.27
(s, 3H), 7.52 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=7.7, 16.6,
30.1, 53.3, 111.8, 113.2, 130.5, 132.5, 139.6, 160.8, 164.4 ppm; FTIR
n˜ =1618 cmꢁ1 (C=N); ESI-HRMS (CHCl3/CH3CN, 1:1): m/z: calcd for
[M+H]+: 847.4138; found: 847.4215.
ing the H NMR spectrum. This process was repeated throughout
the transformation.
Imine metathesis experiment
In a 4 mL glass vial, cage E3Y2 (1.9 mg, 2.3ꢂ10ꢁ6 mol) was mixed
with cage G3X2 (2.0 mg, 2.3ꢂ10ꢁ6 mol) in CDCl3 (1 mL). Progress of
the reaction was monitored by transferring an aliquot into an NMR
tube and subsequently checking the H NMR spectrum. This pro-
cess was repeated throughout the transformation.
Self-sorting experiment (3A+3D+2X)
A solution of amine X (0.8 mg, 5.47ꢂ10ꢁ6 mol) in CDCl3 (0.5 mL)
was added to a CDCl3 solution (0.5 mL) containing aldehyde A
(2.3 mg, 9.82ꢂ10ꢁ6 mol) and aldehyde D (2.1 mg, 9.82ꢂ10ꢁ6 mol)
in a 4 mL glass vial. The resulting solution mixture was stirred at
room temperature and transferred into an NMR tube periodically
1
X-ray crystal data collection and structure solution
1
for H NMR monitoring of the reaction progress.
X-ray data of the cages A3X2, B3X2, and D3X2 were collected on
a Bruker SMART APEX CCD diffractometer equipped with a low-
temperature device, using the SMART/SAINT software.[23] All the dif-
fraction-quality crystals were mounted on a loop coated with
traces of viscous oil. The intensity data of A3X2 and B3X2 were col-
lected at 100(2) K, but at 110(2) K for D3X2 by using graphite-mono-
chromated MoKa radiation (0.7107 ꢁ). The structures were solved
by direct methods and refined by full-matrix least squares on F2 by
employing the SHELX-97[24] incorporated in WinGX.[25] Empirical ab-
sorption corrections were applied with SADABS.[26] All non-hydro-
gen atoms were refined anisotropically. Hydrogen atoms were
placed by using the riding models and refined isotropically. Crystal-
lographic data and refinement parameters are provided in Table 2.
Self-sorting experiment (3A+3B+3C+3D+2X)
A solution of amine X (0.8 mg, 5.47ꢂ10ꢁ6 mol) in CDCl3 (0.5 mL)
was added to a CDCl3 solution (0.5 mL) containing aldehydes A
(2.3 mg, 9.82ꢂ10ꢁ6 mol), B (2.7 mg, 9.82ꢂ10ꢁ6 mol), C (2.9 mg,
9.82ꢂ10ꢁ6 mol), and D (2.1 mg, 9.82ꢂ10ꢁ6 mol) in a 4 mL glass
vial. The resulting solution mixture was stirred at room tempera-
ture and transferred into an NMR tube periodically for 1H NMR
monitoring of the reaction progress.
Self-sorting experiment (3B+3D+4X)
In a 4 mL glass vial, aldehyde B (1.3 mg, 4.88ꢂ10ꢁ6 mol) and alde-
hyde D (1.0 mg, 4.88ꢂ10ꢁ6 mol) were dissolved in CDCl3 (1.0 mL).
Then a CDCl3 solution (0.5 mL) containing amine X (1.0 mg, 6.85ꢂ
10ꢁ6 mol) was added slowly. The resulting solution mixture was
stirred at room temperature and transferred into an NMR tube pe-
Computational methodology
Full geometry optimizations were carried out using the Gaussi-
an 09 package.[27] The hybrid B3LYP functional was used in all cal-
culations as implemented in the Gaussian 09 package, by mixing
the exact Hartree–Fock-type exchange with Becke’s expression for
the exchange functional[28] and that proposed by Lee–Yang–Parr
for the correlation contribution.[29] The 6-31G basis set was used
for all calculations. Frequency calculations carried out on the opti-
1
riodically for H NMR monitoring of the reaction progress.
Self-sorting experiment (3A+3B+3D+6X)
In a 4 mL glass vial, aldehyde A (1.1 mg, 4.88ꢂ10ꢁ6 mol), aldehyde
B
(1.3 mg, 4.88ꢂ10ꢁ6 mol), and aldehyde
D (1.0 mg, 4.88ꢂ
10ꢁ6 mol) were dissolved in CDCl3 (1.0 mL). Then a CDCl3 solution
(1.0 mL) containing amine X (1.5 mg, 1.02ꢂ10ꢁ5 mol) was added
slowly. The resulting solution mixture was stirred at room tempera-
ture and transferred into an NMR tube for 1H NMR analysis. This
process was repeated during the transformation.
Table 2. Crystallographic data and refinement parameters for cages A3X2,
B3X2, and D3X2.
A3X2
B3X2
D3X2
empirical formula
formula weight
T [K]
C129H108N16O4
1946.31
100(2)
C64H54N10O7
1075.17
100(2)
C54H54N8O2
847.05
110(2)
Self-sorting experiment (3E+3F+2X+2Y)
crystal system
space group
a [ꢁ]
b [ꢁ]
c [ꢁ]
monoclinic
C2/c
monoclinic
P21/c
orthorhombic
Pccn
In a 20 mL glass vial, aldehyde E (2.7 mg, 1.50ꢂ10ꢁ5 mol) and alde-
hyde F (5.0 mg, 1.50ꢂ10ꢁ5 mol) were dissolved in chloroform
(10 mL). Then a chloroform solution (8 mL) containing amine X
(1.5 mg, 1.02ꢂ10ꢁ5 mol) and amine Y (2.1 mg, 1.02ꢂ10ꢁ5 mol) was
added dropwise with stirring. The resulting solution mixture was
stirred at room temperature for another 48 h. The solvent was
completely removed and the composition of the solid mass was
34.3058(13)
34.3058(13)
20.9080(7)
90.000(0)
116.853(2)
90.000(0)
21540.7(14)
8
1.200
0.074
0.71073
8160.0
17.861(6)
17.674(5)
19.284(6)
90.000(0)
113.396(11)
90.000(0)
5587(3)
4
1.278
0.085
0.71073
2256.0
10.9552(4)
63.0820(17)
19.9511(4)
90.000(0)
90.000(0)
90.000(0)
13787.7(7)
12
1.224
0.076
0.71073
5400
a [8]
b [8]
g [8]
V [ꢁ3]
Z
1
checked by H NMR spectroscopy in CDCl3.
1calcd [gcmꢁ3
]
m (MoKa) [mmꢁ1
l [ꢁ]
]
Cage D3X2 to cage B3X2 transformation experiment
F(000)
In a 4 mL glass vial, aldehyde D (2.1 mg, 9.82ꢂ10ꢁ6 mol) and
amine X (1.0 mg, 6.85ꢂ10ꢁ6 mol) were stirred at room temperature
in CDCl3 (1 mL) for 24 h to synthesize cage D3X2. After that time
period, aldehyde B (2.7 mg, 1.01ꢂ10ꢁ5 mol) dissolved in CDCl3
(0.5 mL) was added slowly to the reaction mixture and the result-
ing solution was stirred. Progress of the reaction was monitored by
transferring an aliquot into an NMR tube and subsequently check-
collected reflns
unique reflns
171178
18873
1.174
0.0734
0.2526
56400
9835
0.893
0.0778
89513
12116
1.028
0.0858
goodness of fit (F2)
R1 [I>2s(I)][a]
wR2 [I>2s(I)][b]
0.2314
0.2094
1
2
2
[a] R1 =Sj jFo jꢁjFc j j/SjFo j. [b] wR2 =[S{w(Fo ꢁFc2)2}/S{w(Fo2)2}] =
.
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1655
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Harada, J. Am. Chem. Soc. 2009, 131, 12339–12348; g) A. S. Singh, S.-S.
Sun, Chem. Commun. 2012, 48, 7392–7394.
mized structures confirmed the absence of any imaginary frequen-
cies. Change in entropy had an impact on the cage formation pro-
cess. Release of water molecules was the main contributor to the
entropy change, so the entropy changes have similar contributions
in the overall process that are approximated.
[5] a) W. Jiang, W. I. Linder, F. Klautzsch, C. A. Schalley, Chem. Eur. J. 2011,
17, 2344–2348; b) W. Jiang, H. D. F. Winkler, C. A. Schalley, J. Am. Chem.
Soc. 2008, 130, 13852–1353; c) W. Jiang, D. Sattler, K. Rissanen, C. A.
Schalley, Org. Lett. 2011, 13, 4502–4505; d) W. Jiang, A. Schꢆfer, P. C.
Mohr, C. A. Schalley, J. Am. Chem. Soc. 2010, 132, 2309–2320; e) F.
Wang, C. Han, C. He, Q. Zhou, J. Zhang, C. Wang, N. Li, F. Huang, J. Am.
Chem. Soc. 2008, 130, 11254–11255; f) M. M. Safont-Sempere, P. Oss-
wald, M. Stolte, M. Grꢄne, M. Renz, M. Kaupp, K. Radacki, H. Braunsch-
weig, F. Wꢄrthner, J. Am. Chem. Soc. 2011, 133, 9580–9591; g) K. Tahara,
T. Fujita, M. Sonoda, M. Shiro, Y. Tobe, J. Am. Chem. Soc. 2008, 130,
14339–14345.
[6] a) S. J. Rowan, D. G. Hamilton, P. A. Brady, J. K. M. Sanders, J. Am. Chem.
Soc. 1997, 119, 2578–2579; b) J.-B. Lin, X.-N. Xu, X.-K. Jiang, Z.-T. Li, J.
Org. Chem. 2008, 73, 9403–9410; c) J. Han, J. Pan, T. Lei, C. Liu, J. Pei,
Chem. Eur. J. 2010, 16, 13850–13861.
[7] a) A. Granzhan, C. Schouwey, T. Riis-Johannessen, R. Scopelliti, K. Sever-
in, J. Am. Chem. Soc. 2011, 133, 7106–7115; b) M. M. J. Smulders, A. Ji-
mꢇnez, J. R. Nitschke, Angew. Chem. 2012, 124, 6785–6789; Angew.
Chem. Int. Ed. 2012, 51, 6681–6685.
[8] a) S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F. Stod-
dart, Angew. Chem. 2002, 114, 938–993; Angew. Chem. Int. Ed. 2002, 41,
898–952; b) S. Ladame, Org. Biomol. Chem. 2008, 6, 219–216; c) Dy-
namic Combinatorial Chemistry (Eds.: J. N. H. Reek, S. Otto), Wiley-VCH,
Weinheim, 2010; d) R. A. R. Hunt, S. Otto, Chem. Commun. 2011, 47,
847–858; e) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41,
2003–2024; f) J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455–2463; g) P. T. Cor-
bett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M. Sanders, S. Otto,
Chem. Rev. 2006, 106, 3652–3711; h) F. B. L. Cougnon, J. K. M. Sanders,
Acc. Chem. Res. 2012, 45, 2211–2221.
[9] a) M. L. C. Quan, D. J. Cram, J. Am. Chem. Soc. 1991, 113, 2754–1755;
b) X. Liu, Y. Liu, G. Li, R. Warmuth, Angew. Chem. 2006, 118, 915–918;
Angew. Chem. Int. Ed. 2006, 45, 901–904; c) D. Xu, R. Warmuth, J. Am.
Chem. Soc. 2008, 130, 7520–7521; d) Y. Liu, X. Liu, R. Warmuth, Chem.
Eur. J. 2007, 13, 8953–8959; e) N. Christinat, R. Scopelliti, K. Severin,
Angew. Chem. 2008, 120, 1874–1878; Angew. Chem. Int. Ed. 2008, 47,
1848–1852; f) B. IÅli, N. Christinat, J. Tçnnemann, C. Schꢄttler, R. Scopel-
liti, K. Severin, J. Am. Chem. Soc. 2009, 131, 3154–3155; g) T. Hasell, X.
Wu, J. T. A. Jones, J. Bacsa, A. Steiner, T. Mitra, A. Trewin, D. J. Adams,
A. I. Cooper, Nat. Chem. 2010, 2, 750–755.
Acknowledgements
K.A. gratefully acknowledges the Council for Scientific and In-
dustrial Research (CSIR), New Delhi, India, for the award of a Re-
search Fellowship. We thank Shubhadip Chakroborty and
Sanjoy Mukherjee for fruitful suggestions on theoretical calcu-
lations and Samya Banerjee for mass spectral analysis. P.S.M.
thanks the DST-funded ESI-MS facility in the Inorganic and
Physical Chemistry Department.
Keywords: aldehydes · cage compounds · hydrogen bonds ·
metathesis · self-sorting
[1] a) M. M. Safont-Sempere, G. Fernꢃndez, F. Wꢄrthner, Chem. Rev. 2011,
111, 5784–5814; b) M. L. Saha, M. Schmittel, Org. Biomol. Chem. 2012,
ˇ
´
10, 4651–4684; c) K. Osowska, O. S. Miljanic, Synlett 2011, 1643–1648;
ˇ
´
d) K. Osowska, O. S. Miljanic, J. Am. Chem. Soc. 2011, 133, 724–727; e) P.
Mukhopadhyay, A. Wu, L. Isaacs, J. Org. Chem. 2004, 69, 6157–6164;
f) Y. Rudzevich, V. Rudzevich, F. Klautzsch, C. A. Schalley, V. Bꢅhmer,
Angew. Chem. 2009, 121, 3925–3929; Angew. Chem. Int. Ed. 2009, 48,
3867–3871; g) M. Schmittel, K. Mahata, Chem. Commun. 2010, 46,
4163–4165; h) A. Wu, L. Isaacs, J. Am. Chem. Soc. 2003, 125, 4831–
4835; i) P. Mukhopadhyay, P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc. 2006,
128, 14093–14102.
[2] a) G. V. Oshovsky, D. N. Reinhoudt, W. Verboom, Angew. Chem. 2007,
119, 2418–2445; Angew. Chem. Int. Ed. 2007, 46, 2366–2393; b) A. L.
Lehninger, D. L. Nelson, M. M. Cox, Lehninger Principles of Biochemistry,
5th ed., W. H. Freeman, New York, 2008; c) R. C. Weisenberg, Science
1972, 177, 1104–1105.
[3] a) R. Kramer, J.-M. Lehn, A. Marquisrigault, Proc. Natl. Acad. Sci. USA
1993, 90, 5394–5398; b) J.-M. Lehn, Science 2002, 295, 2400–2403;
c) Y.-R. Zheng, B. H. Northrop, H.-B. Yang, L. Zhao, P. J. Stang, J. Org.
Chem. 2009, 74, 3554–3557; d) B. H. Northrop, Y.-R. Zheng, K.-W. Chi,
P. J. Stang, Acc. Chem. Res. 2009, 42, 1554–1563; e) H.-B. Yang, K.
Ghosh, B. H.Northrop, P. J. Stang, Org. Lett. 2007, 9, 1561–1564; f) L.
Zhao, B. H. Northrop, Y. R. Zheng, H. B. Yang, H. J. Lee, Y. M. Lee, J. Y.
Park, K.-W. Chi, P. J. Stang, J. Org. Chem. 2008, 73, 6580–6586; g) R. J.
Sarma, J. R. Nitschke, Angew. Chem. 2008, 120, 383–386; Angew. Chem.
Int. Ed. 2008, 47, 377–380; h) R. Chakrabarty, P. S. Mukherjee, P. J. Stang,
Chem. Rev. 2011, 111, 6810–6918; i) D. Samanta, P. S. Mukherjee, Chem.
Commun. 2013, 49, 4307–4309; j) K. Mahata, M. L. Saha, M. Schmittel, J.
Am. Chem. Soc. 2010, 132, 15933–15935; k) T. Kamada, N. Aratani, T.
Ikeda, N. Shibata, Y. Higuchi, A. Wakamiya, S. Yamaguchi, K. S. Kim, Z. S.
Yoon, D. Kim, A. Osuka, J. Am. Chem. Soc. 2006, 128, 7670–7678; l) S. J.
Lee, S.-H. Cho, K. L. Mulfort, D. M. Tiede, J. T. Hupp, S. T. Nguyen, J. Am.
Chem. Soc. 2008, 130, 16828–16289; m) M. A. Masood, E. J. Enemark,
T. D. P. Stack, Angew. Chem. 1998, 110, 973–977; Angew. Chem. Int. Ed.
1998, 37, 928–932; n) A. M. Johnson, R. J. Hooley, Inorg. Chem. 2011,
50, 4671–4673; o) K. Mahata, M. Schmittel, J. Am. Chem. Soc. 2009, 131,
16544–16554; p) S. Ghosh, P. S. Mukherjee, Inorg. Chem. 2009, 48,
2605–2613; q) A. K. Bar, G. Mostafa, P. S. Mukherjee, Inorg. Chem. 2010,
49, 7647–7649.
[10] a) M. Arunachalam, I. Ravikumar, P. Ghosh, J. Org. Chem. 2008, 73,
9144–9147; b) O. Francesconi, A. Ienco, G. Moneti, C. Nativi, S. Roelens,
Angew. Chem. 2006, 118, 6845–6848; Angew. Chem. Int. Ed. 2006, 45,
6693–6696; c) R. Alberto, G. Bergamaschi, H. Braband, T. Fox, V. Amen-
dola, Angew. Chem. 2012, 124, 9910–9914; Angew. Chem. Int. Ed. 2012,
51, 9772–19776; d) P. Mateus, R. Delgado, P. Branda~o, V. Fꢇlix, J. Org.
Chem. 2012, 77, 4611–4621.
[11] a) N. De Rycke, F. Couty, O. R. P. David, Tetrahedron Lett. 2012, 53, 462–
466; b) O. Perraud, A. B. Sorokin, J.-P. Dutasta, A. Martinez, Chem.
Commun. 2013, 49, 1288–1290.
[12] a) M. Mastalerz, W. Schneider, I. M. Oppel, O. Presly, Angew. Chem. 2011,
123, 1078–1083; Angew. Chem. Int. Ed. 2011, 50, 1046–1051; b) T.
Tozawa, J. T. A. Jones, S. I. Swamy, S. Jiang, D. J. Adams, S. Shakespeare,
R. Clowes, D. Bradshaw, T. Hasell, S. Y. Chong, C. Tang, S. Thompson, J.
Parker, A. Trewin, J. Bacsa, A. M. Z. Slawin, A. Steiner, A. I. Cooper, Nat.
Mater. 2009, 8, 973–978; c) T. Hasell, M. Schmidtmann, C. A. Stone,
M. W. Smith, A. I. Cooper, Chem. Commun. 2012, 48, 4689–4691;
d) M. W. Schneider, L. G. Lechnerb, M. Mastalerz, J. Mater. Chem. 2012,
22, 7113–7116.
[13] a) Y. Jin, B. A. Voss, A. Jin, H. Long, R. D. Noble, W. Zhang, J. Am. Chem.
Soc. 2011, 133, 6650–6658; b) T. Mitra, K. E. Jelfs, M. Schmidtman, A.
Ahmed, S. Y. Chong, D. J. Adams, A. I. Cooper, Nat. Chem. 2013, 5, 276–
281.
[4] a) K. A. Jolliffe, P. Timmerman, D. N. Reinhoudt, Angew. Chem. 1999, 111,
983–986; Angew. Chem. Int. Ed. 1999, 38, 933–936; b) P. S. Corbin, L. J.
Lawless, Z. T. Li, Y. G. Ma, M. J. Witmer, S. C. Zimmerman, Proc. Natl.
Acad. Sci. USA 2002, 99, 5099–5104; c) Y. G. Ma, S. V. Kolotuchin, S. C.
Zimmerman, J. Am. Chem. Soc. 2002, 124, 13757–13769; d) S. Ghosh, A.
Wu, J. C. Fettinger, P. Y. Zavalij, L. Isaacs, J. Org. Chem. 2008, 73, 5915–
5925; e) E. S. Barrett, T. J. Dale, J. Rebek, Jr., J. Am. Chem. Soc. 2008, 130,
2344–2350; f) N. Tomimasu, A. Kanaya, Y. Takashima, H. Yamaguchi, A.
[14] K. Acharyya, S. Mukherjee, P. S. Mukherjee, J. Am. Chem. Soc. 2013, 135,
554–557.
[15] a) L. R. MacGillivray, J. L. Atwood, Nature 1997, 389, 469–472; b) R.
Ahmed, A. Papmeyer, D. M. D’Souza, D. A. Leigh, K. M. Mullen, M. Pap-
meyer, A. M. Z. Slawin, J. K. Y. Wong, J. D. Woollins, J. Am. Chem. Soc.
2011, 133, 12304–12310; c) D. Ajami, H. Dube, J. Rebek, Jr., J. Am.
Chem. Soc. 2011, 133, 9689–9691; d) M. D. Tzirakis, N. Marion, W. B.
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1656
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Schweizer, F. Diederich, Chem. Commun. 2013, 49, 7605–7607; e) A. R.
Stefankiewicz, E. Tamanini, G. D. Pantos¸, J. K. M. Sanders, Angew. Chem.
2011, 123, 5843–5846; Angew. Chem. Int. Ed. 2011, 50, 5725–5728; f) N.
Ponnuswamy, G. D. Pantos, M. M. J. Smulders, J. K. M. Sanders, J. Am.
Chem. Soc. 2012, 134, 566–573; g) R. P. Sijbesma, F. H. Beijer, L. Bruns-
veld, B. J. B. Folmer, J. Hirschberg, R. F. M. Lange, J. K. L. Lowe, E. W.
Meijer, Science 1997, 278, 1601–1604; h) M. M. Conn, J. Rebek, Jr.,
Chem. Rev. 1997, 97, 1647–1668.
[25] L. J. Farrugia, WinGX: An Integrated System ofWindows Programs for
the Solution, Refinement and Analysis for Single Crystal X-ray Diffrac-
tion Data, version 1.80.01; Department of Chemistry: University of Glas-
gow, 2003. (L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838).
[26] G. M. Sheldrick, SADABS, Bruker Nonius Area Detector Scaling and Ab-
sorption Correction, version 2.05; University of Gottingen: Gottingen,
Germany, 1999.
[27] Gaussian 09 (Revision A.02), M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratch-
ian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F.
Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Strat-
mann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dan-
nenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz,
J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.
[16] a) A. Kovꢃcs, A. Szabꢈ, I. Hargittai, Acc. Chem. Res. 2002, 35, 887–894;
b) G. Gilli, F. Bellucci, V. Ferretti, V. Bertolasi, J. Am. Chem. Soc. 1989, 111,
1023–1028; c) G. Chung, O. Kwon, Y. Kwon, J. Phys. Chem. A 1998, 102,
ˇ
2381–2387; d) M. Cuma, S. Scheiner, T. Kar, J. Am. Chem. Soc. 1998, 120,
10497–10503; e) M. Palusiak, S. Simon, M. Sola’, J. Org. Chem. 2009, 74,
2059–2066; f) M. Palusiak, S. Simon, M. Sola’, J. Org. Chem. 2006, 71,
5241–5248.
ˇ ˇ
[17] a) P. Kovaricek, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134, 9446–9455;
b) B. E. Leach, D. L. Leussing, J. Am. Chem. Soc. 1971, 93, 3377–3384;
c) R. M. B. Singh, L. Main, Aust. J. Chem. 1983, 36, 2327–2332.
[18] C. K. Ingold, A. Piggott, J. Chem. Soc. Trans. 1922, 121, 2793–2804.
[19] G. Tꢈth, I. Pintꢇr, A. Messmer, Tetrahedron Lett. 1974, 15, 735–738.
[20] A. K. Mishra, S. Verma, Inorg. Chem. 2010, 49, 3691–3693.
[21] S.-Q. Wu, Q.-W. Xie, G.-Y. An, X. Chen, C.-M. Liu, A.-L. Cui, H.-Z. Kou,
Dalton Trans. 2013, 42, 4369–4372.
[28] A. D. Becke, Phys. Rev. A 1988, 38, 3098–3100.
[29] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[22] a) A. Vidal-Ferran, Z. Clyde-Watson, N. Bampos, J. K. M. Sanders, J. Org.
Chem. 1997, 62, 240–241; b) K.-L. Kuo, C.-C. Huang, Y.-C. Lin, Dalton
Trans. 2008, 3889–3898; c) E. F. Santos-Filho, J. C. Sousa, N. M. M. Bezer-
ra, P. H. Menezes, R. A. Oliveira, Tetrahedron Lett. 2011, 52, 5288–5291.
[23] SMART/SAINT; Bruker AXS, Inc., Madison, WI, 2004.
Received: August 29, 2013
Revised: October 14, 2013
[24] G. M. Sheldrick, SHELX-97, Program for the Solution and Refinement of
Crystal Structures; University of Gottingen: Gottingen, Germany, 1998.
Published online on December 30, 2013
Chem. Eur. J. 2014, 20, 1646 – 1657
www.chemeurj.org
1657
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim