Smart macrocyclic molecules: Induced fit and ultrafast self-sorting inclusion behavior through dynamic covalent chemistry

Article abstract of DOI:10.1002/chem.201001606

A family of macrocycles with oligo(ethylene glycol) chains, 4O, 5O, and 6O, was developed to construct a series of new incorporated macrocycles through dynamic covalent chemistry. These flexible macrocycles exhibited excellent "self-sorting" abilities with diamine compounds, which depended on the "induced-fit" rule. For instance, the host macrocycles underwent conformational modulation to accommodate the diamine guests, affording [1+1] intramolecular addition compounds regardless of the flexibility of the diamine. These macrocycles folded themselves to fit various diamines with different chain length through modulation of the flexible polyether chain, and afforded intramolecular condensation products. However, if the chain of the diamine was too long and rigid, oligomers or polymers were obtained from the mixture of the macromolecule and the diamine. All results demonstrated that inclusion compounds involving conformationally suitable aromatic diamines were thermodynamically favorable candidates in the mixture due to the restriction of the macrocycle size. Furthermore, kinetic and thermodynamic studies of self-sorting behaviors of both mixed 4O-5O and 4O-6O systems were investigated in detail. Finally, theoretical calculations were also employed to further understand such self-sorting behavior, and indicated that the large enthalpy change of H ₂NArArNH₂@4O is the driving force for the sorting behavior. Our system may provide a model to further understand the principle of biomolecules with high specificity due only to their conformational self-adjusting ability. All sorted out: A family of macrocycles composed of oligo(ethylene glycol) chains and diphenylbenzaldehyde residues was developed to construct a series of new incorporated macrocycles through dynamic covalent chemistry. These flexible macrocycles exhibit excellent "self-sorting" abilities with diamines, in accordance with the "induced-fit" rule (see schematic). Copyright

Full text of DOI:10.1002/chem.201001606

DOI: 10.1002/chem.201001606
Smart Macrocyclic Molecules: Induced Fit and Ultrafast Self-Sorting
Inclusion Behavior through Dynamic Covalent Chemistry
Ji-Min Han,[a] Jin-Long Pan,[a] Ting Lei,[a] Chenjiang Liu,*[b] and Jian Pei*[a]
Abstract: A family of macrocycles with
oligo(ethylene glycol) chains, 4O, 5O,
and 6O, was developed to construct a
series of new incorporated macrocycles
through dynamic covalent chemistry.
These flexible macrocycles exhibited
excellent “self-sorting” abilities with di-
amine compounds, which depended on
the “induced-fit” rule. For instance, the
host macrocycles underwent conforma-
tional modulation to accommodate the
diamine guests, affording [1+1] intra-
molecular addition compounds regard-
less of the flexibility of the diamine.
These macrocycles folded themselves
to fit various diamines with different
chain length through modulation of the
flexible polyether chain, and afforded
intramolecular condensation products.
However, if the chain of the diamine
was too long and rigid, oligomers or
polymers were obtained from the mix-
ture of the macromolecule and the di-
striction of the macrocycle size. Fur-
thermore, kinetic and thermodynamic
studies of self-sorting behaviors of both
mixed 4O–5O and 4O–6O systems
were investigated in detail. Finally, the-
oretical calculations were also em-
ployed to further understand such self-
sorting behavior, and indicated that the
AHCTUNGTRENNaGUN mine. All results demonstrated that
inclusion compounds involving confor-
mationally suitable aromatic diamines
were thermodynamically favorable can-
didates in the mixture due to the re-
large
enthalpy
change
of
H2NArArNH2@4O is the driving force
for the sorting behavior. Our system
may provide a model to further under-
stand the principle of biomolecules
with high specificity due only to their
conformational self-adjusting ability.
Keywords: dynamic
covalent
chemistry · host–guest systems ·
macrocycles · molecular recogni-
tion · self-sorting
Introduction
protein (host) recognition site has a different binding affini-
ty to a precisely specific ligand (guest) molecule was called
the “lock-and-key” principle by Fischer in 1894,[1] and is still
an important requirement for rational design of drugs or
host–guest systems. However, according to the “induced-fit”
hypothesis,[2] the hosts and guests need not exhibit precisely
complementary interaction, and different functions could be
achieved through a single interaction.[3] In these processes,
adaptation, such as dramatic conformation changes of flexi-
ble molecules upon complex formation, plays a very impor-
tant role. For example, the ubiquitin molecule is important
in many cellular signaling process such as protein degrada-
tion, and is recognized by a broad variety of proteins with
high specificity only by means of their conformational self-
adjusting ability.[4]
Many artificial host–guest systems are designed to mimic
biochemical processes in nature, which often exhibit excel-
lent recognition and high specificity. The notion that each
[a] J.-M. Han, J.-L. Pan, T. Lei, Prof. J. Pei
Beijing National Laboratory for Molecular Sciences
The Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of the Ministry of Education College of
Chemistry
and Molecular Engineering Department
Peking University, Beijing 100871 (China)
Fax : (+86)106-275-8145
E-mail: jianpei@pku.edu.cn
Considerable interest has been paid to artificial macrocy-
clic compounds[5] due to their intriguing topology,[6] which
mimics the biological process. These compounds have poten-
tial applications in molecular recognition,[7] ion transport,[8]
chemosensing and imaging,[9] and construction of molecular
machines.[10] However, to go beyond the lock-and-key prin-
ciple to reach high selectivity, the design of the cavity size
[b] Prof. C. Liu
Key Laboratory of Petroleum and Gas Fine Chemicals
Educational Ministry of China, College of Chemistry and
Chemical Engineering
Xinjiang University, Urumqi 830046 (China)
E-mail: pxylcj@126.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001606.
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and conformational flexibility of target macrocycles are
greatly limited. In addition, most host–guest systems are
mainly based on noncovalent interactions, but one drawback
of this strategy is their low stability. Because the association
constant is dependent on environment, any change in the
temperature, composition, or pH of the solution may affect
the equilibrium of the system.
5O, and 6O were designed to incorporate two 2,6-diphenyl-
benzaldehyde units and ethylene glycol fragments with vari-
able chain length. Scheme 1 illustrates the synthetic ap-
proach to macrocycles 4O, 5O, and 6O. a,w-Bis-OTs ethyl-
ene glycols were prepared by a modified literature proce-
dure[17] and subjected to nucleophilic reactions with 4-hy-
droxyphenylboronate to afford intermediates 1a, 1b, and
1c. Compound 2a was obtained by a Suzuki cross-coupling
procedure between 1a and 2,6-dibromobenzaldehyde in
moderate yield. The same Suzuki cross-coupling reaction be-
tween 1a and 4-hydroxyphenylboronate gave 3 in 90%
yield. Compound 4O was obtained by the ring-closing reac-
tions of 2a with 3 in highly dilute DMF solution in 75%
yield. Following the same procedures, 5O and 6O were also
obtained in moderate yields. These macrocyclic compounds
are readily soluble in common organic solvents, such as tolu-
ene, THF, and CH2Cl2. The structures and purity of all new
As a result, developing a smart artificial system mimick-
ing a biosystem by following the induced-fit principle is still
a challenge. Herein we report a facile route to a series of
flexible macrocycles containing two formyl groups, which
can condense with amino groups to give imines in the spirit
of dynamic covalent chemistry (DCC),[11] in which DCC
refers to the reversible formation of chemical bonds, which
tends to give the thermodynamically most stable products.
Encouraged by its “error-checking” nature, many efforts
have been devoted to constructing complex architectures by
DCC, including macrocycles,[12] rotaxanes or catenanes,[13]
and nanocages.[14] The series of macrocycles presented here
can be condensed with suitable diamine compounds to give
[1+1] inclusion products under both kinetic and thermody-
namic control. It is not surprising that the products are ther-
modynamically favored ones, but the fact that they are also
the kinetic ones is interesting. Moreover, owing to a length
limit, a specific macrocycle exhibits different behavior in in-
corporation of diamines. For example, if the diamine chain
is longer than the limit, flexible diamines may readjust their
conformation to fit the macrocycle cavity size and give
[1+1] inclusion products, while rigid ones can not. However,
when the chain length of the diamine is shorter than the
limit, all diamines afford inclusion products with these mac-
rocycles.
The term “self-sorting” has been discussed extensively in
recent years. Usually, “sorting” is defined as a process in
which different subunits are controlled with precise constitu-
tional and/or positional order according to certain features
or criteria. Thus “self-sorting” refers to not only the ability
to distinguish “self” from “nonself”, but also the operation
completed simultaneously and orthogonally within the mix-
tures.[15] Intuitively, the more similar the subunits are, the
more difficult self-sorting is, which is why self-sorting is very
common in biological systems but rare in synthetic sys-
tems.[16] Here we demonstrate rapid and highly accurate
self-sorting behaviors in a complex system, namely, a mix-
ture of two macrocycles and two diamines. Although their
reactive groups are completely the same, only two kinds of
conformationally suitable aromatic diamine@macrocycle
species are found. To the best of our knowledge, this is the
first example of self-sorting inclusion behavior controlled by
DCC. Our results provide a model system to mimic bio-
chemical systems.
1
compounds were fully characterized and verified by H and
13C NMR spectroscopy, elemental analysis, and ESI HRMS.
The condensation step (Scheme 2) was performed by two
procedures that differed in the amount of acid catalyst used.
For aliphatic amines, procedure A was preferred: Only
0.1 equivalents of trifluoroacetic acid (TFA) were used, but
a longer reaction time (ꢀ1 h) was used. Procedure B was
used for aromatic amines by adding 100 equivalents of TFA
and using a dramatically shorter reaction time (1 min), al-
though, as shown in the literature, this is not the optimum
method for establishing equilibrium.[18]
Several rigid aromatic amines with different length were
first chosen to study the flexibility of 4O, 5O, and 6O. Partial
1H NMR spectra (300 MHz, CDCl3, 298 K) of 4O treated
with three different linear aromatic amines are outlined in
Figure 1. Under the conditions of procedure A for 1 h, the
signal assigned to CHO at d=9.77 ppm in the 1H NMR
spectrum of 4O (Figure 1a) completely disappeared and a
new signal assigned to the protons of imino groups (CH=N)
emerged at d=8.33 ppm (Figure 1b). This, combined with
the fact that all signals assigned to aromatic protons of 4O
moved downfield and a new singlet appeared at d=
6.96 ppm, indicated that a [1+1] bicyclic compound was
formed in nearly quantitative yield on mixing 4O with
H2NArNH2.[19] Meanwhile, the ESI mass spectrum proved
the formation of the proposed structure. Only an ion peak
at m/z 881.4 for [M+H]+ was observed. Moreover, as
shown in Figure 1c, this reaction was went almost to comple-
tion without byproducts in only 1 min. The evenly downfield
shifted signals could be assigned to the salt form of the
Schiff bases. All characterization techniques verified the for-
mation and the purity of the [1+1] intramolecular product,
excluding the formation of any oligomers or polymers. Fig-
1
ure 1d illustrates the partial H NMR spectrum when aniline
was used instead of H2NArNH2. Apparently, because the
mono-amine could not form such a chelate-type bicyclic
1
Results and Discussion
product, clean H NMR spectra were hard to achieve. The
signals assigned to the imino groups split into two peaks due
to formation of two different imines. Moreover, the signal
assigned to CHO (d=9.42 ppm) still existed, but it moved
Synthesis of macrocycles 4O, 5O, and 6O, and formation of
aromatic amines@macrocycles: Our target macrocycles 4O,
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C. Liu, J. Pei et al.
Scheme 1. Synthetic approach to macrocyclic hosts 4O, 5O, and 6O.
Scheme 2. Condensation reaction between macrocycles and diamines. Conditions: A) TFA (0.1 equiv), 1 h, 708C; B) TFA (100 equiv), 1 min, RT.
upfield owing to the addition of TFA. Based on the above
facts, we speculate that the cavity size of 4O is sufficient to
accommodate a diamine with the length of phenyl and the
second aldehyde is still available if the cavity is not fully
filled.
With benzidine (H2NArArNH2), a white precipitate was
immediately generated after the addition of 100 equivalents
of TFA and the filtrate showed no clear H NMR signals,
with a few broad peaks indicating typical formation of oligo-
mers or polymers. This indicated that this process was so
1
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Smart Macrocyclic Molecules
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Figure 1. Partial 1H NMR spectra (300 MHz, CDCl3, 298 K) of a) 4O, b) 4O+H2NArNH2 (procedure A), c) 4O+H2NArNH2 (procedure B), d) 4O+
ArNH2 (procedure B), e) 4O+H2NArArNH2 (procedure A). All compounds were in equimolar concentrations (1ꢂ10À2 molLÀ1).
quick that we could hardly observe the formation of any in-
1
termediates. Figure 1e illustrates the partial H NMR spec-
trum, for which we simply combined the two reactants. The
1H NMR spectrum revealed that the intermediate exhibits
one signal assigned to CHO at d=9.58 ppm and an imine
signal at d=8.14 ppm, with integral ratio of 1:1. Further
comparison of aromatic protons revealed that Figure 1d cor-
responds to a mixture of the two starting materials and the
mono-condensed intermediate with both a free aldehyde
group and
a free amino group. We speculated that
H2NArArNH2 is too large to be contained inside the cavity
of 4O, so further intramolecular condensation was prevent-
ed. Therefore intermolecular reactions to give oligomers or
polymers were preferred.
The different inclusion behavior of 4O with various aro-
matic diamines is shown in Scheme 3, which is very similar
to the typical protein–protein interaction process.[20] For
short-chain diamines, the first imine bond is easily formed
after a diffusional encounter, then the macrocycle reshapes
its oligoethylene glycol chains to satisfy bonding of the
second imine before formation of the final bonds. Self-ad-
justment of the flexible oligoethylene glycol chains and for-
mation of the second imine bond can apparently considered
as a single step because the rate is very fast. However, for a
diamine with a long rigid chain, the energy for the confor-
mational changes is too high to promote the guestꢁs further
inclusion, so oligomers and polymers are easily generated
from these A2 and B2 systems.
Scheme 3. Inclusion behavior between 4O and linear aromatic amines.
inclusion compounds of 5O with aromatic diamines
H2NArNH2 and H2NArArNH2 were obtained in quantita-
tive yield. All protons were shifted downfield upon addition
of TFA. Meanwhile, ESI-MS shows the ion peak of [1+1]
addition products at m/z 969.4 for [M+H]+. Compared with
4O, 5O could contain the longer rigid diamine
H2NArArNH2 owing to the prolonged flexible ethylene
glycol chain, which self-adjusted the size of the cavity and
Similar results were obtained with macrocycles 5O or 6O
and various diamines. As shown in Figure 2, [1+1] bicyclic
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C. Liu, J. Pei et al.
Figure 2. Partial 1H NMR spectra (300 MHz, CDCl3, 298 K) of a) 5O, b) 5O+H2NArNH2 (procedure A), c) 5O+H2NArNH2 (procedure B), d) 5O+
H2NArArNH2 (procedure A), e) 5O+H2NArArNH2 (procedure B). All compounds were in equimolar concentrations (4ꢂ10À3 molLÀ1).
the distance between the two formyl groups of 5O. Once the
condensation reaction was completed at one site, the intra-
molecular reaction was preferred to the intermolecular reac-
tion in solution, and the [1+1] addition product was ob-
tained regardless of the reaction time and the amount of
TFA added. The same results were obtained with 6O
(Figure 3). Both 1H NMR and ESI-MS spectra confirmed
the production and purity of rigid diamines@6O. However,
for 4,4’’-diamino-p-terphenyl (H2NArArArNH2), the intra-
molecular reaction was prevented because the length of
three phenyl groups was too long for 6O. Therefore, the dis-
tance between the two formyl groups could not match the
rigid rod no matter how the flexible chain was stretched
(see the Supporting Information).
X-ray diffraction analysis of the single-crystal structure of
H2NArNH2@4O and H2NArArNH2@5O led to further iden-
tification of [1+1] inclusion products. As shown in Figure 4,
the diamine compounds are “stuck” in the cavity and the
phenyl groups show small torsion angles to ensure good con-
jugation of the Schiff bases. Meanwhile, the ethylene glycol
chains adopt the most stable helix form, with trans-gauche-
trans conformation around the successive O-C-C-O
bonds.[21] To sum up, rigid amines with various lengths react
with 4O, 5O, and 6O to give [1+1] inclusion compounds;
however, only oligomers or polymers were obtained when
the macrocycles were not large enough.
Study of flexible aliphatic amines@macrocycles: We further
chose to use ethane-1,2-diamine (C2), propane-1,3-diamine
(C3), butane-1,4-diamine (C4), pentane-1,5-diamine (C5),
and hexane-1,6-diamine (C6) to understand the behavior of
4O, 5O, and 6O when treated with flexible amines. Only in-
tramolecular [1+1] addition products were obtained even
though the lengths of the aliphatic amine in a stretched con-
formation were much longer than the distance between two
aldehyde groups in the macrocycle hosts. For 4O, for exam-
ple, an equimolar solution of the macrocyclic host and ali-
phatic diamine guest in CDCl3 showed almost unique aro-
matic protons, as illustrated in Figure 5. The signals assigned
to imines were at d=8.11 (C2@4O), 8.02 (C3@4O), 8.03
(C4@4O), 8.04 (C5@4O), and 7.96 ppm (C6@4O). The clean
1H NMR spectra definitely indicated formation and the
purity of intramolecular [1+1] addition products. We ob-
tained similar results for larger macrocycles as well (see the
Supporting Information). Therefore, if the diamine molecule
is small, the host undergoes conformational readjustment to
arrange its reactive sites to be complementary to the guest
regardless of whether the diamines were flexible or not.
However, relatively large and flexible diamine molecules
can fold themselves to give intramolecular condensation
products, whereas rigid ones give oligomers or polymers, as
shown in Scheme 4.
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Figure 3. Partial 1H NMR spectra (300 MHz, CDCl3, 298 K) of a) 6O, b) 6O+H2NArNH2 (procedure A), c) 6O+H2NArNH2 (procedure B), d) 6O+
H2NArArNH2 (procedure A), e) 6O+H2NArArNH2 (procedure B). All compounds were in equimolar concentrations (4ꢂ10À3 molLÀ1).
strong nucleophilicity. To ex-
clude this possibility, we chose
procedure A as the experimen-
tal conditions under which both
nucleophilic and less nucleo-
philic amines undergo a fast
condensation reaction. Fig-
1
ure 6a illustrates H NMR spec-
tra of 4O reacting with four dif-
ferent aliphatic amines. It could
be
concluded
that
H2NArNH2@4O was the major
product in the mixture, but the
broadness of the signals indicat-
ed that other condensation
products were also present.
However, these byproducts
gradually vanished after heating
Figure 4. Single-crystal structures of H2NArNH2@4O (left) and H2NArArNH2@5O (right).
1H NMR study of the reorganization ability of macrocycles:
It is interesting to examine what would happen if several
amines and a macrocycle were mixed in solution. To answer
this question, four typical amines were selected: aniline, C2
at 708C for 1 h. The sharp singlet at d=8.70 ppm, together
with other aromatic protons that perfectly match those in
Figure 6b, definitely showed that H2NArNH2@4O was the
dominant species in the mixture, whereas other unconsumed
amines finally became insoluble ammonium salts.
(representing
flexible
diamines),
H2NArNH2,
and
H2NArArNH2 (representing short and long rigid aromatic
diamines, respectively). Before the experiment, it might be
argued that these systems would be under kinetic control.
For example, C2 might be more reactive because of its
In summary, rigid aromatic amines with suitable lengths
are the most favorable candidates to be incorporated into
the cavity of the macrocycle. First, compared with aniline,
the aromatic diamines could form a “chelate-like” structure,
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C. Liu, J. Pei et al.
amines to investigate whether
the system is able to sort suita-
ble diamines. Surprisingly, these
flexible hosts also showed an
excellent self-sorting ability, as
usually observed in noncovalent
systems. At first, condensation
occurred immediately upon ad-
dition of 100.0 equivalents of
TFA to an equimolar mixture
of 4O, 6O, H2NArNH2, and
H2NArArNH2 in CDCl3, as in-
1
dicated by H NMR spectrosco-
py. As is characteristic of the
incorporation of amines into
macrocycles, three sets of imine
protons appeared at d=8.84,
8.77, and 8.73 ppm, indicating
that the mixture contained the
salt forms of the Schiff bases
H2NArNH2@6O,
rNH2@6O, and
H2NAr-
H2NAr-
AHCTUNGTRENNUNG
AHCTUNRTGEGNNUNN H2@4O, respectively. This
result was confirmed by ESI-
MS as well: peaks at m/z 881.4,
1057.5, 1093.5, and 1169.5, as-
Figure 5. 1H NMR spectra (300 MHz, CDCl3, 298 K) of 4O treated with five different linear aliphatic amines:
a) 4O+C2, b) 4O+C3, c) 4O+C4, d) 4O+C5, e) 4O+C6. All compounds were in equimolar concentrations
(2ꢂ10À3 molLÀ1).
signed
NH2@4O+H]+,
NH2@6O+H]+,
to
[H2NAr-
[H2NAr-
[H2NAr-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Scheme 5. Inclusion behavior between 4O and four amines.
ACHUTNGRENNUG CAHTUNGTRENNUGN
NH2@6O+2H2O]+, and [H2NAr rNH2@6O+2H2O]+, re-
spectively, were found. The ratio of matched pairs and mis-
matched pairs was estimated to be more than 90:10 from
the integrated intensity of the imine protons, which further
proved that rigid aromatic amines of suitable length are the
most favorable candidates for incorporation into the cavity
of the macrocycle: 4O matched with H2NArNH2, and 6O
with H2NArArNH2. This rapid and highly accurate self-sort-
ing behavior is remarkable in an artificial system. Inevitably,
because of the flexibility of the 6O macrocycle, mismatched
H2NArNH2@6O was also obtained as minor product after
rapid conformational readjustment. However, according to
the principle of DCC, these less stable products, or mis-
matched pairs, would finally transform into more stable
products after a so-called error-check process. After heating
Scheme 4. Inclusion behavior between 4O and linear aliphatic and aro-
matic amines.
which is thermodynamically much more favorable due to
the large energy gain on the formation of an additional
bond. Secondly, the formation of oligomers or polymers be-
tween H2NArArNH2 and 4O was prevented by a large en-
tropy loss. As a result, the most stable, highly conjugated
H2NArNH2@4O formed instead of the nonconjugated
C2@4O (Scheme 5).
Static study of self-sorting behavior: With the above results
in hand, we mixed different macrocycles and mixtures of di-
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Smart Macrocyclic Molecules
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are of very similar size, such as
4O and 5O, self-sorting still
proceeds efficiently (Scheme 6).
Similarly, a mixture of matched
and mismatched components
was obtained initially, but the
imine signals at d=8.83 ppm as-
signed to H2NArNH2@5O in
Figure 7c decreased dramatical-
ly after 1 h of heating, and only
H2NArNH2@4O and H2NAr-
AHCTUNTGRENNUNG rNH2@5O were produced, as
evidenced by the signals at d=
8.71 and 8.58 ppm, respectively
(Figure 7d). Meanwhile, ESI-
MS provided further confirma-
tion of the proposed structures:
peaks at m/z 881.4, 969.4, and
Figure 6. Partial 1H NMR spectra (300 MHz, CDCl3, 298 K) of a mixture of 4O, aniline, ethane-1,2-diamine,
1,4-diaminobenzene, and benzidine in the presence of TFA (100 equiv) after a) 1 min and b) 1 h. All com-
pounds were in equimolar concentrations (4ꢂ10À3 molLÀ1).
for 1 h, the matched pairs of H2NArArNH2@6O and
H2NArNH2@4O were finally obtained in nearly quantitative
yield (Figure 7b).
Scheme 6. Self-sorting behavior.
1081.5,
assigned
to
[H2NArNH2@4O+H]+,
[H2NArNH2@5O+H]+, and [H2NArArNH2@5O+2H2O]+,
repectively, were found.
Time-dependent 1H NMR study of self-sorting behavior:
1
Figure 8 shows time-dependent H NMR spectra of a mix-
ture of 4O, 6O, H2NArNH2, and H2NArArNH2 in CDCl3 at
348 K. The signals of formyl protons at d=9.83 and
9.76 ppm appeared, and finally all signals of formyl protons
1
disappeared over time. As the H NMR spectra show, there
are only two signals, which means that no intermediates are
formed other than inclusion products. Thus, we confirmed
that formation of the imine bonds is a self-accelerating pro-
cess. After one imine bond is formed, the reaction rate of
the other bond becomes much faster, even though the reac-
tivity of the second amino group dramatically drops after
the end of condensation of the first one.[23] In addition, the
formyl protons assigned to 6O at d=9.76 ppm decreased
faster than those of 4O, probably because 6O could react
with both H2NArNH2 and H2NArArNH2 with similar rates,
whereas the reaction rate between 4O and H2NArArNH2
was relatively slow, as shown before. As a result, “wrong”
structures are unavoidable, so the chemical shift assigned to
dynamic mismatched product H2NArNH2@6O at d=
8.32 ppm persists for the first 15 min. However, this peak
then gradually vanished over 1 h, which indicates that the
Figure 7. Partial 1H NMR spectra (300 MHz, CDCl3, 298 K) of a mixture
of 4O, 6O, H2NArNH2, and H2NArArNH2 in the presence of TFA
(100 equiv) after a) 1 min and b) 1 h, and of a mixture of 4O, 5O,
H2NArNH2, and H2NArArNH2 in the presence of TFA (100 equiv) after
c) 1 min and d) 1 h. All compounds were in equimolar concentrations
(4ꢂ10À3 molLÀ1).
We can then conclude that both kinetic and thermody-
namic self-sorting behaviors could be observed on a very
short timescale with high efficiency.[22] In this case, the ther-
modynamic product is also the kinetically favorable one,
and complete equilibrium can be reached after heating with
exclusion of mismatched products thanks to the inherent
“proof-reading” ability of DCC. Even when the macrocycles
Chem. Eur. J. 2010, 16, 13850 – 13861
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C. Liu, J. Pei et al.
derstanding of the process was gained by calculation of en-
thalpies (Table 1).[25]
The enthalpy contribution can be roughly divided into
two parts: 1) imine bond formation and 2) conformational
change of ethylene glycol. Although sizes are quite different
for these macrocycles and diamines, the reaction activities
for both aldehyde groups and amino groups are almost the
same. Therefore, model compound M served as a reference
to study the effects of imine bond formation, and the ener-
gies of condensation are relatively close: 15.4 kcalmolÀ1 for
H2NArNH2@M and 20.3 kcalmolÀ1 for H2NArArNH2@M.
These results also indicate the reversible nature of imine for-
mation.
Similar results were obtained on calculating 6O and its
relatives (Figure 10). The enthalpy changes of condensation
are 19.4 kcalmolÀ1 for H2NArNH2@6O and 21.8 kcalmolÀ1
for H2NArArNH2@6O, and solvent SPEs were calculated as
20.2 and 21.8 kcalmolÀ1, respectively. We can then conclude
that for small diamines, the enthalpy contribution of oligo-
Figure 8. Time-dependent partial 1H NMR spectra (300 MHz, CDCl3,
348 K) of self-sorting behavior of a mixture of 4O, 6O, H2NArNH2, and
H2NArArNH2 in the presence of TFA (0.1 equiv) after a) 5, b) 10, c) 15,
d) 45, and e) 60 min. All compounds were in equimolar concentrations
(1ꢂ10À2 molLÀ1).
AHCTUNGTREG(NNNU ethylene glycol) conformational changes is very small, so
that only slight increases are observed. However, when we
turned to 4O and its derivatives, only the H2NArNH2@4O
system showed the similar enthalpy changes both in vacuum
flexible smart macrocycles un-
dergo error-correction steps to
adjust their conformation and
accommodate the most suitable
guests, that is, to distinguish
“self” from “nonself”. Finally,
the clean signals assigned to
thermodynamically controlled
products
H2NArArNH2@6O
and H2NArNH2@4O at d=8.36
and 8.27 ppm indicate that the
reaction of the dynamic prod-
uct, either H2NArNH2@6O or
proposed oligomers generated
Figure 9. Computed structures of model imine intermediates.
by 4O and H2NArArNH2, is reversible, and equilibrium is
established to afford the most stable self-sorted products.
Although the imine bonds are the same, only the conforma-
tionally flexible side chains control the final equilibrium
state, which further confirms our induced-fit hypothesis.
Table 1. Calculated reaction enthalpies of condensation.
Compound
DHgas [kcalmolÀ1
]
DHsol [kcalmolÀ1
]
H2NArNH2@4O
H2NArArNH2@4O
H2NArNH2@5O
H2NArArNH2@5O
H2NArNH2@6O
H2NArArNH2@6O
H2NArNH2@M
15.8
27.2
17.1
20.4
19.4
21.8
15.4
20.3
18.0
31.0
22.4
23.9
20.2
21.8
–
Theoretical explanation of self-sorting: To understand the
origin of selectivity and how the flexible chains of macrocy-
cles control the self-sorting behavior by the induced-fit prin-
ciple, theoretical calculations were performed by using
Gaussian 03.[24] Geometry optimization and single-point
energy (SPE) calculations were done at the B3LYP/6-
31G(d) level (ZPE correction parameter: 0.9804) and calcu-
lations of solvent SPEs were based on the optimized gas-
phase geometry by using the CPCM model. Besides the pro-
posed structures of macrocycles and their relevant inclusion
compounds, model compounds without oligo(ethylene
glycol) units were optimized as well (Figure 9). In-depth un-
H2NArArNH2@M
–
and in solution. The H2NArArNH2@4O system exhibits a
very high enthalpy change of 27.2 kcalmolÀ1 in vacuum or
31.0 kcalmolÀ1 in solution, which means the enthalpy penal-
ty comes mainly from the oligo(ethylene glycol) chains
stretching. In the H2NArNH2@4O system, the macrocycle is
large enough to accommodate H2NArNH2 inside the cavity,
13858
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Smart Macrocyclic Molecules
FULL PAPER
compounds are observed. How-
ever,
rNH2@4O is not a thermody-
namically favored product, only
because
H2NAr-
AHCTUNGTRENNUNG
H2NAr
H2NArAHCNUTGTRENNUNG
ACHTUNGTRENNUNG
to transform into H2NAr-
NH2@6O, by virtue of reversi-
AHCTUNGTRENNUNG
ble DCC reaction. Finally, the
high enthalpy demand of
H2NArACHUTNGRNEUNG rNH2@4O is the key
element to ensure that self-sort-
ing can complete with high ac-
curacy in a short time.
Conclusion
In summary, we have developed
a series of “smart” macrocycles,
4O, 5O, and 6O, for self-sorting
the various diamines that fit
them by DCC. The investiga-
tions of their condensation
properties with different amines
indicate that although they
have nearly the same structure
except for the different side-
chain lengths, they exhibit rapid
and highly accurate self-sorting
behaviors. The cavity limit to-
gether with the flexible side
chains allow the macrocycles to
“intelligently” recognize confor-
mationally suitable aromatic di-
amines through the induced-fit
principle. The self-sorting be-
haviors of both 4O–5O and
4O–6O systems are controlled
by either kinetic or thermody-
namic conditions. Taking 4O–
Figure 10. Computed structures of 4O, 5O, 6O, and their imine intermediates.
6O, for example, two bicyclic
and the structure was similar to the most stable trans-
gauche-trans conformation, in accordance with the previous
single-crystal data. However, in the H2NArArNH2@4O
system, if the rigid diamine is incorporated into the cavity,
all oligo(ethylene glycol) chains are forced to be nearly
linear, so that the repulsion of the flexible chains dominates
the enthalpy contribution to prevent the generation of
H2NArArNH2@4O.
compounds H2NArNH2@4O and H2NArArNH2@6O are
formed as major products immediately after an excess of
acid is added, and the self-sorting effects are enhanced after
heating. Time-dependent 1H NMR analyses indicate that
multivalent bonds of these cooporations between aldehydes
and amines can be facilely and effectively constructed simul-
taneously. In the mixed DCC process, the matched pairs are
the main products not only under thermodynamic control,
but also under kinetic control. Theoretical calculation shows
the large enthalpy change of H2NArArNH2@4O may be the
driving force.
Because product formation occurs under thermodynamic
control, product distributions depend only on the relative
stabilities of the final products. It is speculated that in the
mixture of 4O, 6O, H2NAr
presence of TFA, the enthalpy contribution of oligo(ethy-
lene glycol) conformational changes is very similar between
NH2, and H2NAr
E
rNH2 in the
The DCC concept is known for its “error-checking”
nature. Our results demonstrate that although our “smart”
molecules make errors at first, they find their partners in
the end. Side-chain conformational readjustment is the key
H2NArACHTUNGTRENNUNGNH2@6O and H2NArCAHTUNGTERNNUGN rNH2@6O, so both inclusion
Chem. Eur. J. 2010, 16, 13850 – 13861
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13859

C. Liu, J. Pei et al.
143.79, 133.1, 132.9, 132.0, 131.4, 130.8, 130.1, 129.8, 127.9, 114.2, 70.7,
69.7, 69.2, 68.7, 67.4, 21.6 ppm; ESI-HRMS: m/z calcd for C45H54NO13S2:
880.3031; found: 880.3025 [M+NH4]+.
to self-sorting, which is common in nature but rare in syn-
thetic systems. This work helps to shed more light on the
nature of molecular recognition and selectivity. Further-
more, such a covalent approach to synthesizing interlocked
structures, such as rotaxanes[26] and catenanes,[27] is very dif-
ficult and examples are rare; a key reason for this is that a
bicyclic inclusion structure that is easy to build and to break
is hard to achieve. Finally, our systems may afford unique in-
sights into the formation process of DCC-based rotaxanes
and catenanes. The development of even “smarter” systems
is in progress.
Compound 2b: Yellow oil (yield: 59%). 1H NMR (CDCl3, 300 MHz):
d=9.93 (s, 1H), 7.78–7.81 (d, J=8.4 Hz, 2H), 7.53–7.55 (t, J=7.5 Hz,
1H), 7.32–7.36 (m, 6H), 7.25–7.28 (d, J=8.7 Hz, 4H), 6.95–6.98 (d, J=
8.4 Hz, 4H), 4.14–4.19 (m, 8H), 3.86–3.90 (m, 4H), 3.60–3.75 (m, 20H),
2.44 ppm (s, 6H); 13C NMR (CDCl3, 75 MHz, ppm): d=193.9, 158.5,
144.8, 143.9, 133.2, 133.0, 132.1, 131.4, 130.8, 130.1, 129.8, 127.9, 114.2,
70.8, 70.7, 70.7, 70.6, 69.7, 69.2, 68.7, 67.4, 21.6; ESI-HRMS m/z: calcd
for C49H59O15S2: 951.3290; found: 951.3284 [M+H]+.
Compound 2c: Yield: 44%, yellow oil. 1H NMR (CDCl3, 300 MHz): d=
9.93 (1H, s), 7.78–7.81 (2H, d, J=8.4 Hz), 7.53–7.55 (1H, t, J=7.5 Hz),
7.32–7.36 (6H, m), 7.25–7.28 (4H, d, J=8.7 Hz), 6.95–6.98 (4H, d, J=
8.4 Hz), 4.14–4.19 (8H, m), 3.86–3.90 (4H, m), 3.60–3.75 (20H, m), 2.44
(6H, s); 13C NMR (CDCl3, 75 MHz): d=194.0, 158.4, 144.8, 143.8, 133.1,
132.7, 131.9, 131.5, 130.8, 130.1, 129.8, 127.9, 70.8, 70.5, 69.6, 69.2, 68.6,
67.3, 21.6 ppm; ESI-HRMS: m/z calcd for C53H67O17S2: 1039.3814; found:
1039.3824 [M+H]+.
Experimental Section
General methods: Commercial chemicals were used as received. All air-
and water-sensitive reactions were performed under a nitrogen atmos-
phere. 1H and 13C NMR spectra were recorded by using a Mercury Plus
300 MHz at RT or 708C in appropriate deuterated solvents. All chemical
shifts are reported in parts per million (ppm); ESI HRMS spectra were
recorded on a Bruker Apex IV FTMS. X-ray diffraction was performed
by using a Bruker SMART-1000 diffractometer.
Compound 3:
2.95 mmol), (4-hydroxyphenyl)boronate pinacol ester (2.00 g, 8.85 mmol),
Na2CO3 (2m, 3.12 g, 29.5 mmol), and [Pd(PPh3)4] (0.340 g, 0.295 mmol) in
A
mixture of 2,6-dibromobenzaldehyde (0.778 g,
AHCTUNGTRENNUNG
THF (50 mL) and deionized water (18 mL) was heated at reflux over-
night under nitrogen. The mixture was extracted with ethyl acetate. The
combined organic extracts were dried over MgSO4. After removal of sol-
vent under reduced pressure, the residue was purified by column chroma-
tography (eluent: petroleum ether/ethyl acetate 2:1) to afford 3 (0.80 g)
as a white solid (yield 90%). 1H NMR (CD3COCD3, 300 MHz): d=9.96
(s, 1H), 8.63 (s, 2H), 7.56–7.61 (t, J=7.5 Hz, 1H), 7.33–7.35 (d, J=
7.5 Hz, 2H), 7.18–7.22 (d, J=8.7 Hz, 4H), 6.89–6.94 ppm (d, J=8.4 Hz,
4H); 13C NMR (CD3COCD3, 75 MHz): d=195.0, 158.8, 145.3, 135.5,
132.9, 132.6, 131.3, 116.6 ppm; ESI-HRMS: m/z calcd for C19H15O3:
291.1016; found: 291.1014 [M+H]+.
General procedure for the preparation of 1a, 1b, and 1c: A mixture of
an oligo(ethylene glycol) bis-toluenesulfonate (27.3 mmol), (4-hydroxy-
phenyl)boronate pinacol ester (9.09 mmol), [PdACTHNUGTRNEUNG(PPh3)4], and K2CO3
(13.6 mmol) in acetonitrile (200 mL) was heated at reflux overnight
under nitrogen. After filtration, the solvents were removed under re-
duced pressure to afford crude product. The residue was purified by
column chromatography (eluent: petroleum ether/ethyl acetate 1:1) to
afford the desired product.
Compound 1a: Colorless oil (yield: 85%). 1H NMR (CDCl3, 300 MHz):
d=7.78–7.80 (d, J=8.1 Hz, 2H), 7.72–7.75 (d, J=8.7 Hz, 2H), 7.31–7.33
(d, J=8.1 Hz, 2H), 6.88–6.90 (d, J=8.7 Hz, 2H), 4.11–4.17 (m, 4H),
3.80–3.83 (m, 2H), 3.60–3.70 (m, 6H), 2.42 (s, 3H), 1.33 ppm (s, 12H);
13C NMR (CDCl3, 75 MHz): d=163.9, 161.2, 144.7, 136.4, 132.9, 129.8,
127.9, 113.9, 83.5, 70.7, 69.6, 69.2, 68.6, 67.1, 24.8, 21.6 ppm; ESI-HRMS:
m/z calcd for C25H35BNaO8S: 529.2042; found: 529.2038 [M+Na]+.
Compound 1b: Colorless oil (yield: 77%). 1H NMR (CDCl3, 300 MHz):
d=7.78–7.81 (d, J=8.4 Hz, 2H), 7.72–7.75 (d, J=8.7 Hz, 2H), 7.32–7.34
(d, J=8.4 Hz, 2H), 6.88–6.91 (d, J=8.7 Hz, 2H), 4.13–4.16 (m, 4H),
3.83–3.85 (m, 2H), 3.58–3.71 (m, 10H), 2.43 (s, 3H), 1.33 ppm (s, 12H);
13C NMR (CDCl3, 75 MHz): d=161.3, 161.2, 144.7, 136.4, 132.9, 129.8,
127.9, 113.9, 83.5, 70.7, 70.6, 69.6, 69.2, 68.6, 67.1, 24.8, 21.6 ppm; ESI-
HRMS: m/z calcd for C27H39BO9S: 551.2485; found: 551.2483 [M+H]+.
Compound 1c: Colorless oil (yield: 65%). 1H NMR (CDCl3, 300 MHz):
d=7.78–7.81 (d, J=8.4 Hz, 2H), 7.72–7.75 (d, J=8.7 Hz, 2H), 7.32–7.35
(d, J=8.4 Hz, 2H), 6.88–6.91 (d, J=8.7 Hz, 2H), 4.13–4.17 (m, 4H),
3.85–3.87 (m, 2H), 3.58–3.71 (m, 14H), 2.44 (s, 3H), 1.33 ppm (s, 12H);
13C NMR (CDCl3, 75 MHz): d=160.9, 161.2, 144.8, 136.0, 132.5, 129.4,
127.5, 113.4, 83.1, 70.3, 70.1, 69.1, 68.9, 68.1, 66.7, 24.5, 21.2 ppm; ESI-
HRMS: m/z calcd for C29H43BO10S: 595.2748; found: 595.2738 [M+H]+.
General procedure for preparation of 4O, 5O, and 6O: A mixture of 3
(0.096 mmol), and 2a, 2b, or 2c (0.096 mmol), Cs2CO3 (0.288 mmol) in
DMF (100 mL) was heating at 1008C for 2 d under nitrogen. After filtra-
tion, the solution was concentrated under reduced pressure to afford resi-
dues, which were purified by column chromatography (eluent: ethyl ace-
tate) to afford the desired products.
Compound 4O: White solid (yield: 75%). 1H NMR (CDCl3, 300 MHz):
d=9.77 (s, 2H), 7.43–7.48 (t, J=7.5 Hz, 2H), 7.25–7.27 (d, J=7.5 Hz,
4H), 7.11–7.14 (d, J=8.7 Hz, 8H), 6.90–6.93 (d, J=8.4 Hz, 8H), 4.09–
4.17 (m, 8H), 3.89–3.92 (m, 8H), 3.78 ppm (s, 8H); 13C NMR (CDCl3,
75 MHz): d=193.7, 158.2, 143.7, 133.3, 131.9, 131.1, 130.8, 129.8, 114.4,
71.0, 69.7, 67.6 ppm; ESI-HRMS: m/z calcd for C50H48NaO10: 831.3140;
found: 831.3129 [M+Na]+.
Compound 5O: White solid (yield: 47%). 1H NMR (CDCl3, 300 MHz):
d=9.79 (s, 2H), 7.42–7.47 (t, J=7.5 Hz, 2H), 7.24–7.26 (m, 4H), 7.14–
7.16 (d, J=8.7 Hz, 8H), 6.89–6.92 (d, J=8.4 Hz, 8H), 4.12–4.15 (m, 8H),
3.89–3.92 (m, 8H), 3.74–3.77 ppm (m, 16H); 13C NMR (CDCl3, 75 MHz):
d=193.6, 158.3, 143.6, 133.0, 131.8, 131.2, 130.7, 129.8, 114.1, 70.7, 69.6,
67.4 ppm; ESI-HRMS: m/z calcd for C54H56NaO12
: 919.3664; found:
919.3655 [M+Na]+.
Compound 6O: White solid (yield: 40%). 1H NMR (CDCl3, 300 MHz):
d=9.85 (s, 1H), 7.44–7.49 (t, J=7.5 Hz, 2H), 7.27–7.29 (d, J=7.5 Hz,
4H), 7.17–7.20 (d, J=8.7 Hz, 8H), 6.91–6.94 (d, J=8.4 Hz, 8H), 4.15 (m,
8H), 3.87 (m, 8H), 3.69–3.72 ppm (m, 24H); 13C NMR (CDCl3, 75 MHz):
d=193.7, 158.5, 143.8, 133.3, 132.0, 131.3, 130.8, 130.0, 114.3, 70.9, 70.7,
General procedure for the preparation of 2a, 2b, and 2c: A mixture of
2,6-dibromobenzaldehyde (1.73 mmol), boronic ester 1a, 1b, or 1c,
Na2CO3 (2m, 6.90 mmol), and [PdACTHNURTGNEUNG(PPh3)4] (0.173 mmol) in THF (50 mL)
and deionized water (5 mL) was heated at reflux overnight under nitro-
gen. The mixture was extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4. After removal of solvent under reduced
pressure, the residue was purified by column chromatography (eluent:
petroleum ether/ethyl acetate 1:2) to afford the desired product.
Compound 2a: Yellow oil (yield: 75%). 1H NMR (CDCl3, 300 MHz):
d=9.93 (s, 1H), 7.79–7.82 (d, J=8.4 Hz, 2H), 7.52–7.55 (t, J=7.2 Hz,
1H), 7.32–7.36 (m, 6H), 7.25–7.28 (d, J=8.7 Hz, 4H), 6.95–6.98 (d, J=
8.4 Hz, 4H), 4.14–4.19 (m, 8H), 3.84–3.87 (m, 4H), 3.62–3.72 (m, 12H),
2.43 ppm (s, 6H); 13C NMR (CDCl3, 75 MHz): d=193.9, 158.4, 144.8,
69.7, 67.5 ppm; ESI-HRMS: m/z calcd for C58H64NaO14
found: 1007.4172 [M+Na]+.
: 1007.4188;
General procedure for preparation of single crystals of H2NArNH2@4O
and H2NArArNH2@5O: A phase-separation process was employed to
obtain single crystals. A mixture of macrocycle (0.002 mmol) and aromat-
ic diamine (0.002 mmol) was dissolved in CHCl3 (1 mL) and TFA (15 mL)
was injected before MeOH (2 mL) was added. One week later, colorless
crystals were finally collected from the mixture.
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Smart Macrocyclic Molecules
FULL PAPER
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Acknowledgements
This work was supported by the Major State Basic Research Develop-
ment Program (nos. 2006CB921602 and 2007CB808000) from the Minis-
try of Science and Technology and the National Natural Science Founda-
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Received: June 8, 2010
Published online: October 13, 2010
Chem. Eur. J. 2010, 16, 13850 – 13861
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