Hydrogen bonding-directed multicomponent dynamic covalent assembly of mono- and bimacrocycles. Self-sorting and macrocycle exchange

Article abstract of DOI:10.1021/jo801972s

(Chemical Equation Presented) This paper describes the multicomponent dynamic covalent assembly of macrocyclic structures by utilizing hydrogen bonding-driven zigzag anthranilamides as leading components. Two or three amino groups have been introduced to one side of hydrogen bonded anthranilamide oligomers. The preorganization of the frameworks enabled the amino groups to condense with structurally matched aldehydes to form mono-and bimacrocycles in good to quantitative yields. Reactions from up to five components have been investigated, which involved one-step formation of up to six imine bonds. The preorganization of the templates highly enhanced the stability of the macrocyclic structures. As a result, all the macrocycles could be purified by simply recrystallizing the crude products from suitable solvents. Coexisting experiments of three series of three to five components were also performed, which all revealed that the preorganized precursors possessed high self-sorting capacity. On the basis of the same approach, a hydrazone-based macrocycle was also prepared quantitatively, while an intermacrocycle hydrazone-imine exchange was revealed to facilitate the formation of the hydrazone-based macrocycle from an imine-based macrocycle.

Full text of DOI:10.1021/jo801972s

Hydrogen Bonding-Directed Multicomponent Dynamic Covalent
Assembly of Mono- and Bimacrocycles. Self-Sorting and Macrocycle
Exchange
Jian-Bin Lin, Xiao-Na Xu, Xi-Kui Jiang, and Zhan-Ting Li*
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
ztli@mail.sioc.ac.cn
ReceiVed September 7, 2008
This paper describes the multicomponent dynamic covalent assembly of macrocyclic structures by utilizing
hydrogen bonding-driven zigzag anthranilamides as “leading” components. Two or three amino groups
have been introduced to one side of hydrogen bonded anthranilamide oligomers. The preorganization of
the frameworks enabled the amino groups to condense with structurally matched aldehydes to form mono-
and bimacrocycles in good to quantitative yields. Reactions from up to five components have been
investigated, which involved one-step formation of up to six imine bonds. The preorganization of the
templates highly enhanced the stability of the macrocyclic structures. As a result, all the macrocycles
could be purified by simply recrystallizing the crude products from suitable solvents. Coexisting
experiments of three series of three to five components were also performed, which all revealed that the
preorganized precursors possessed high self-sorting capacity. On the basis of the same approach, a
hydrazone-based macrocycle was also prepared quantitatively, while an intermacrocycle hydrazone-imine
exchange was revealed to facilitate the formation of the hydrazone-based macrocycle from an imine-
based macrocycle.
Introduction
chemistry (DCC) has offered a new robust approach.4 With this
thermodynamically controlled strategy, two- and three-dimen-
sional macrocylic systems can be quickly constructed from
simple and multiple components.5-11 In this context, the
formation of the imine bond from various aldehyde and amine
precursors has been most extensively investigated.5-7 Owing
to the inherent instability of the imine bond, many imine-related
structures could not be purified from the solution and therefore
require being reduced to the corresponding amine derivatives.6,7
One strategy of overcoming this is to preorganize the precur-
Macrocycles of defined shape and size are useful architectures
for studies in molecular recognition, sensors, and porous
materials.1,2 Traditionally, this family of structures has been
mainly prepared by making use of kinetically controlled
cyclization strategy. This approach is able to allow precise
control over monomer composition and sequence selectivity,
but generally suffers the competition of more favorable poly-
merizing reactions. Although the template strategy has been
developed,3 frequently macrocyclic structures cannot be gener-
ated in acceptable yields. Recent advance in dynamic covalent
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10.1021/jo801972s CCC: $40.75
Published on Web 11/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9403–9410 9403

Lin et al.
In the past decade, foldamers, the linear molecules that are
induced by noncovalent forces to adopt compact conformations,
have received considerable attention.15-17 In particular, three-
center hydrogen bonding-driven aromatic amide foldamers
usually possess highly predictable secondary structures due to
the directionality of hydrogen bonding as well as the inherent
rigidity and planarity of aromatic amide units.16 Recently several
preorganized frameworks of this family have been utilized for
one-step synthesis of several cyclophanes by directing succes-
sive, ordered amide coupling.18 We previously developed a
family of zigzag anthranilamide oligomers, which may be
considered as a combination of short folded segments.19 More
recently, we demonstrated that such extended rigid structures
are useful frameworks in designing new preorganized supramo-
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FIGURE 1. Schematic diagram of hydrogen-bonding-driven preorga-
nized oligoanthranilamides (A) as templates for multicomponent
dynamic covalent assembly of macrocyclic structures. In principle, the
reactive sites may be amino, aldehyde, hydrazine, or any other groups
that undergo reversible reactions.
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9404 J. Org. Chem. Vol. 73, No. 23, 2008

CoValent Assembly of Mono- and Bimacrocycles
lecular synthons or synthetic receptors for guest recognition.20
Herein, we describe that, by using hydrogen bonded preorga-
nized frameworks that carry amino and/or aldehyde groups as
“leading” components,21 a variety of imine-based mono- and
bimacrocycles can be quickly assembled in high to quantitative
yields from up to five components. The new macrocycles are
all stable and therefore can be purified by simple recrystalli-
zation. Coexisting experiments reveal that the precursors also
possess high selectivity and fidelity in forming respective
macrocycles. In addition, preorganization can also accelerate
the formation of a hydrazone-based macrocycle through inter-
cyclehydrazone-imineexchangewithanimine-basedmacrocycle.
Results and Discussion
Design and Synthesis. We have previously demonstrated that
the framework of aromatic amide oligomers A adopts a rigid
zigzag conformation.19,20b It occurred to us that iterative
introduction of reversible reactive sites, such as amino or
aldehyde groups, at the para-positions of the alkoxyl groups of
the benzamide and isophthalamide moieties would produce
highly preorganized comb-styled structures (A, Figure 1).
Because all the reactive sites are located at the same side of the
backbones, they were expected to template the formation of
macrocyclic architectures by reacting with single or multiple
structurally matched molecules of complementary reactive sites
(B, Figure 1). To test this potential, discrete rigid and flexible
precursors of varying shape, length, and reactive sites were
synthesized. The synthetic details and characterization data are
provided in the Supporting Information.
FIGURE 2. Crystal structures of compounds (a) 1, (b) 2, and (c) 3.
SCHEME 1. Synthesis of Macrocycle 3 from [1+1]
Condensation Reaction of 1 and 2
Two-Component Condensation. Dialdehyde 1 and diamine
2(Scheme 1) were first prepared. Their crystal structures were
obtained, which exhibited the expected U-shaped conformations
stabilized by two pairs of three-center hydrogen bondings
(Figure 2a,b). It can be found that the distances between their
respective reactive sites are very close, which boded well for
efficient [1+1] condensation. The condensation reaction was
first performed in chloroform (Scheme 1). 1H NMR tracking in
CDCl3 showed that the reaction reached equilibrium within 15 h,
with a small amount of precursors unconsumed, to give
macrocycle 3 in 75% yield (Figure 3a-c). The macrocycle was
found to be stable in solution and solid state and therefore was
purified by simply recrystallizing the reaction residue from
chloroform and ethanol. In the presence of dry magnesium
sulfate or molecular sieve, the yield could be increased notably.
This was not unexpected because the reaction was of thermo-
dynamic control with water as one product. Macrocycle 3 was
comprehensively characterized by NMR, (HR)MS, and X-ray
crystallography (Figure 2c). Because it has been established that
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is the most widely used strategy for studies in intermolecular hydrogen bonding-
driven self-assembly. For representative reviews, see: (a) Zimmerman, S. C.;
Corbin, P. S. Struct. Bonding 2000, 96, 63–94. (b) Archer, E. A.; Gong, H.;
Krische, M. J. Tetrahedron 2001, 57, 1139–1159. (c) Brunsveld, L.; Folmer,
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the intermolecular three-center hydrogen bonding survives in
polar solvent,22 the reaction was also investigated in a binary
solution of chloroform and DMSO (4:1, v/v). Surprisingly, the
reaction afforded 3 in shorter time, but the selectivity was
increased substantially, as indicated by 1H NMR (Figure 3d,e),
possibly because the larger aggregation capacity of the macro-
cycle relative to the precursors stabilized the macrocycle, as
(22) (a) Parra, R. D.; Zeng, H.; Zhu, J.; Zheng, C.; Zeng, X. C.; Gong, B.
Chem. Eur. J. 2001, 7, 4352–4357. (b) Yi, H.-P.; Wu, J.; Ding, K.-L.; Jiang,
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J. Org. Chem. Vol. 73, No. 23, 2008 9405

Lin et al.
1
FIGURE 3. Partial H NMR spectra of (a) 1 + 2 (5 min), (b) 1 + 2
(15 h), and (c) 3 in CDCl3, and (d) 1 + 2 (5 h) and (e) 3 in CDCl3/
DMSO-d6 (4:1) ([1] ) [2] ) [3] ) 2.5 mM, see Scheme 1 for peak
marking).
revealed for m-phenylene ethynylene-based macrocycles.23 The
distance between the two imine units of 3 in the crystal structure
is approximately 1.08 nm, which is very close to those between
the reactive sites of precursors 1 and 2. This result implies that
no large tension was produced during the formation of 3 from
1 and 2. Therefore, the efficiency for the formation of 3 was
clearly a result of the highly structural matching of the
precursors. In contrast, under the same reaction conditions, no
macrocyclic products could be separated from the reaction of 2
with flexible dialdehyde 4,24 although mass spectrometry
indicated that the 1+1 macrocycle was formed from the reaction.
The result also illustrates the efficiency of the hydrogen bonding-
mediated preorganization of the precursors that not only
promoted macrocyclization but also stabilized the macrocyclic
product.
Compounds 5-7, which carry both NHBoc and CHO groups,
were also prepared for [1+1] condensation studies. This series
of precursors possess the same aromatic skeleton, but the number
of intramolecular hydrogen bonds is successively decreased.
Therefore, the role of the intramolecular hydrogen bonding
might be more reasonably revealed from their macrocyclization
results. The Boc group was introduced to these precursors
because molecules containing both amino and aldehyde units
would be difficult to manipulate. Trifluoroacetic acid (TFA, 10
equiv) was used to remove the Boc group and also to catalyze
1
the condensation process. H NMR indicated that the reaction
of 5 also selectively afforded [1+1] macrocycle 8 (Figure 4a-f).
After the reaction was finished, the solution was washed with
aqueous sodium bicarbonate solution and brine and dried over
sodium sulfate. Upon removal of the solvent, macrocycle 8 could
1
be obtained for analysis. H NMR tracking also showed that
the reaction first gave rise to 8 and other products. The latter,
however, were converted into 8 within approximately 1.5 h
(Figure 4b-d). Under the same conditions, 6 could also form
macrocyclic product (9), but in considerably lower yield (65%),
while macrocyclic product could not be separated from the
reaction mixture of 7. Mass spectrometry of the reaction mixture
of 7 did show the peak of the 1+1 macrocyclic product, which,
however, coexisted with Boc-removed 7, linear dimer, and
trimer (see the Supporting Information). These results again
illustrate that the intramolecular hydrogen bonding of the
FIGURE 4. Partial 1H NMR spectra of (a) 5, (b) 5 + TFA (0.5 h), (c)
5 + TFA (1.5 h), (d) 8 + TFA (1.5 h), (e) 8 (crude product), (f) 8
(after recrystallization), (g) 13, and (h) 18 ([5] ) 5 mM, the
concentration of other samples was 2.5 mM, [TFA] ) 50 mM, see the
structure of 8 for peak marking).
precursors not only highly facilitated the macrocyclization, but
also promoted the conversion of their amino and aldehyde units
into imines.
(23) Zhao, D.; Moore, J. S. Macromolecules 2003, 36, 2712–2720.
(24) Dyker, G.; Ko¨rning, J.; Stirner, W. Eur. J. Org. Chem. 1998, 149–154.
9406 J. Org. Chem. Vol. 73, No. 23, 2008

CoValent Assembly of Mono- and Bimacrocycles
SCHEME 2. Multicomponent Self-Assembly of Mono- and Bimacrocycles
SCHEME 3. Self-Assembly of Macrocycle 17 from [1+2+1]
Four-Component Condensation. Encouraged by the above
results, the possibility of creating macrocycles from more
components was then exploited. The first experiment concerned
the [2+2] condensation reaction of preorganized diamines with
dialdehydes. For this purpose, we replaced diamine 2 with 10a,
which carries two longer n-octyl groups, because the reactions
of 2 in this series of experiments were found to afford insoluble
residues that were difficult to characterize. The reaction of 10a
and oxaldehyde (40% aqueous solution) was conducted in
chloroform, which reached equilibrium after 6 h and afforded
macrocycle 11 in 65% isolated yield (Scheme 2). The reaction
of 10a with 12 was carried out in the mixture of chloroform
and DMSO (4:1). In this solvent system, no insoluble materials
were formed, which guaranteed that the formation of products
was thermodynamically controlled. The reaction reached equi-
librium in 12 h to afford macrocycle 13 exclusively. Addition
of TFA to the solution decreased the yield of the macrocycles,
implying that the reaction equilibrium was shifted to the left.
Increasing oxaldehyde to 3 equiv did not obviously affect the
yield of 11, indicating that the macrocycle was much more stable
than other possible products. The reactions of 10a with
isophthalaldehyde (14) or phthalaldehyde (15) were also inves-
tigated, which, however, did not generate corresponding [2+2]
macrocyclic products in isolatable yields, once again indicating
Condensation Reaction with Preorganized 2 as Template
that right geometry was indispensable for selective formation
of the macrocyclic products.
Next, we investigated if this approach could be used for
[1+2+1] macrocyclization. For this study, we chose compounds
2, 14, and 16 as precursors (Scheme 3). Stirring a solution of
the three compounds (1:2:1) in chloroform led to the formation
of macrocycle 17 in 91% isolated yield (Figure 6c, vide infra).
In contrast, in the absence of 2, the reaction of 14 and 16 (1:1)
J. Org. Chem. Vol. 73, No. 23, 2008 9407

Lin et al.
1
FIGURE 6. Partial H NMR of (a) reaction residue of 2, 14, 15, 16,
and 19 (1:2:1:2:2, after 24 h), (b) the product (17) after purification,
and (c) 17 in CDCl3. Partial 1H NMR of (d) reaction residue of 2, 14,
15, and 16 (1:2:1:2, after 24 h) and (e) 17 in CDCl3/DMSO-d6 (4:1).
The labeled signals belong to 15.
conducted at 60 °C. The reaction reached equilibrium after
1
approximately 12 h, to afford 18 (Scheme 2). The H NMR
1
FIGURE 5. Partial H NMR spectra of (a) 3, (b) 1 + 2 + 5 (1:1:2)
spectrum of 18 in CDCl3/DMSO-d6 (4:1) exhibited one set of
signals of good resolution (Figure 4h), although configurational
exchange of the three CdN bonds might give rise to different
isomers. In principle, more complicated ladder oligomers or even
polymers may be assembled from the longer multiamino
precursors. However, the side chains have to be modified to
provide enough solubility.
(CDCl3/DMSO-d6, 4:1), (c) 1 + 2 + 5 (1:1:2), (d) 3 + 8 (1:1), (e) 8,
(f) 8 + 17, and (g) 17 in CDCl3. The concentration was 5 mM. The
spectra of the crude products of 1, 2, and 5 were recorded after their
TFA-catalyzed reactions in chloroform reached equilibrium and TFA
was neutralized.
yielded no macrocyclic products but only simple linear mol-
ecules, as shown by the MS spectrum. Moreover, H NMR
Self-Sorting and Selectivity Experiments. Self-Sorting is
a stability-related behavior that features DCC in which multiple
products may be formed from a multicomponent system.4,26 For
the present structures, we chose three systems to study their
selectivity behavior. The first system involved macrocycles 3
and 8 and their formation from coexisting precursors. 1H NMR
showed that mixing 3 and 8 (1:1) in CDCl3 caused only a small
amount of other molecules to form (Figure 5a,d,e). Mass
spectrometry did not show the existence of larger products,
including the possible trimer or tetramer, indicating good
matching of the above precursors in macrocyclization. The
mixture of 8 and 17 also exhibited similar self-fidelity (Figure
5e-g). Coexisting experiments showed that the precursors also
possessed high self-sorting capacity in forming their respective
macrocycles. For example, 1H NMR indicated that, in the
presence of TFA (10 equiv), the reaction of 1, 2, and 5 (1:1:2)
in CDCl3 reached equilibrium in 2 h. The 1H NMR of the crude
product, obtained after neutralization with no further purification,
in CDCl3/DMSO-d6 (4:1) showed that 3 and 8 were formed as
the two major products (Figure 5b). The spectrum of the same
sample was also recorded in CDCl3, which showed that larger
amounts of other products were formed (Figure 5c). This result
is consistent with the above observation that higher macrocy-
clization selectivity could be achieved in the system of
chloroform and DMSO than in pure chloroform.
The second system concerned the reaction selectivity of five
molecules. Compounds 15 and 19 were chosen to compete with
14 for the reaction with 2 and 16 (Scheme 4). 1H NMR showed
that the reactions of 2, 14, 15, 16, and 19 (1:2:1:2:2) in CDCl3
reached equilibrium in 24 h, giving rise to macrocycle 17 as
the major product (Figure 6a). After recrystallizing the crude
product from THF, 17 could be obtained in 56% yield (Figure
6b,c). In the absence of 19, compounds 2, 14, and 16 could
react to afford 17 nearly exclusively (Figure 6d,e). In this case,
only isophthalaldehyde 14 was consumed, with phthalaldehyde
1
showed that, after the reaction reached equilibrium, most of 14
and 16 were left unconsumed. A similar result was also observed
for the reaction of 2 and 14 (1:1). However, when the two
mixtures of the same equivalent were mixed together, 17 could
be obtained in the same yield. The reaction of 2 and 16 with
12 or 15 was also attempted, from which no corresponding
macrocyclic product was isolated. The fact that 17 was
selectively formed from two distinct amine precursors should
also be ascribed to the preorganization of precursor 2.25 Also
owing to its high structural matching with 14 and 16, 17 is
expected to be much more stable than other cyclic or linear
products. Therefore, it could be gradually enriched by consum-
ing other less stable products.
Five-Component Condensation. The reaction of triamine
10b and 12 (2:3) was first performed in chloroform. The reaction
gave rise to precipitates immediately, which, however, did not
dissolve even at the reflux temperature. MS spectrometry
showed that the precipitates did contain bimacrocycle
18(Scheme 2). Therefore, discrete solvent systems were then
screened, and finally we found that the binary system of
chloroform and DMSO (4:1) yielded satisfactory results. In this
medium, no precipitate was formed when the reaction was
(25) Frischmann, P. D.; Jiang, J.; Hui, J. K.-H.; Grzybowski, J. J.;
MacLachlan, M. J. Org. Lett. 2008, 10, 1255–1258.
(26) For representative examples, see: (a) Jolliffe, K. A.; Timmerman, P.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. 1999, 38, 933–937. (b) Saur, I.;
Scopelliti, R.; Severin, K. Chem. Eur. J. 2006, 12, 1058–1066. (c) Wu, A.;
Chakraborty, A.; Fettinger, J. C.; Flowers, R. A., II.; Isaacs, L. Angew. Chem.,
Int. Ed. 2002, 41, 4028–4031. (d) Park, T.; Todd, E. M.; Nakashima, S.;
Zimmerman, S. C. J. Am. Chem. Soc. 2005, 127, 18133–18142. (e) Mukho-
padhyay, P.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2006, 128, 14093–
14102. (f) Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 14236–
14237. (g) Hutin, M.; Cramer, C. J.; Gagliardi, L.; Shahi, A. R. M.; Bernardinelli,
G.; Cerny, R.; Nitschke, J. R. J. Am. Chem. Soc. 2007, 129, 8774–8780. (h)
Legrand, Y.-M.; van der Lee, A.; Barboiu, M. Inorg. Chem. 2007, 46, 9540–
9547.
9408 J. Org. Chem. Vol. 73, No. 23, 2008

CoValent Assembly of Mono- and Bimacrocycles
SCHEME 4. Selective Formation of Macrocycle 17 from the
Reactions of Five Precursorsa
FIGURE 8. Hierarchical formation of macrocycles 3 and 17 from the
solution of precursors 1, 2, 14, and 16 in CDCl3/DMSO-d6 (4:1),
highlighting the high self-sorting capacity of the precursors in macro-
cyclization.
a In the absence of 19, 17 could be formed nearly exclusively from 2,
14, and 16.
formation of 17 (Figure 7c). As expected, simultaneously mixing
1, 2, 14, and 16 (1:2:2:1) gave rise to the same result after the
reactions reached equilibrium (Figure 8). These results indicated
that in this system the formation of 3 and 17 from 2 occurred
hierarchically. Only after the formation of the first favorable
macrocycle 17 was met could the second one, that is 3, be
generated. Whereas the ratio of the precursors was suitable, they
could both be simultaneously generated in high yields. These
results clearly indicate the high self-sorting capacity of the four
precursors. The fact that 17 was formed prior to 3 from this
four-component system does not imply that 17 was more stable
than 3. More reasonably, it should reflect the feature of DCC
that such thermodynamically controlled reactions prefer to afford
products with least reactive sites left.7b Additional evidence for
this came from the observation that treatment of 3 with 14 (2
equiv) and 16 (1 equiv) caused most of the former to decompose,
leading to the formation of 1 and 17 in approximately 80% yield
(Figure 7d,e).
1
FIGURE 7. Partial H NMR spectra of (a) the reaction mixture of 1,
Intermacrocycle Imine-Hydrazone Exchange. Hydrazones
are usually much more stable than imines because the mesomeric
effect of hydrazones remarkably decreases their electrophilic-
ity.27 As an extension of this preorganization-driven macrocy-
clization, we also prepared compound 20 to assess its capacity
of forming macrocycles. The related reactions were carried out
at 60 °C in CHCl3 and DMSO (4:1), in which both precursors
and products were soluble. 1H NMR showed that, in the absence
of Lewis acid, 20 could react with 1 to afford macrocycle 21
quantitatively in 10 h (Scheme 5). Several reactions of forming
hydrazone-based macrocycles have been reported to occur
within days or weeks even under the catalysis of Lewis acid.8,28
It is reasonable to assume that the formation of the first
hydrazone linkage is “normal”. Therefore, this result may be
ascribed to the preorganization of the precursors that facilitated
the formation of the second hydrazone bond intramolecularly,
making it much faster. Macrocycle 21 could also be generated
14, and 16 (1:2:1), (b) 1, 14, 16, and 2 (1:2:1:1), (c) 1, 14, 16, and 2
(1:2:1:2), (d) 3, and (e) 3, 14, and 16 (1:2:1) in CDCl3/DMSO-d6 (4:1)
(red triangle, 1; blue solid circle, 3; red solid circle, 17; [1] ) 15 mM).
All the spectra were recorded after the reactions reached equilibrium
after 12 h.
15 being left. The result illustrates well the high capacity of 2
and 16 in selecting 14 to form a macrocyclic product.
The third system concerned the coexisting experiments of
1
precursors 1, 2, 14, and 16. The H NMR spectrum of the
solution of 1, 14, and 16 (1:2:1) in CDCl3 displayed complicated
signals (Figure 7a), while the MS spectrum of the crude product
did not exhibit molecular ion peaks of simple macrocyclic
products but mainly those of linear imine species. These
observations reflect poor structural matching of the three
molecules. However, when 1 equiv of 2 was added (Figure 8),
macrocycle 17 was generated in approximately 80% yield after
the reaction reached equilibrium (Figure 7b). The yield was
estimated by comparing the integrated intensity of its signal at
6.37 ppm and that of inner reference dibromomethane. In
contrast, most of 1 was not consumed and thus only a small
amount of 3 (ca. 5%) was formed. When another equivalent of
2 was added, it could selectively react with the remaining 1 to
give 3 in approximately 85% yield, without affecting the
(27) Carey, F. A.; Sunderberg, R. J. AdVanced Organic Chemistry Part A;
Plenum Press: New York, 1990; pp 451-453.
(28) (a) Cousins, G. R. L.; Poulsen, S. A.; Sanders, J. K. M. Chem. Commun.
1999, 1575–1576. (b) Nguyen, R.; Huc, I. Chem. Commun. 2003, 942–943. (c)
Ramstro¨m, O.; Lohmann, S.; Bunyapaiboonsri, T.; Lehn, J.-M. Chem. Eur. J.
2004, 10, 1711–1715. (d) Giuseppone, N.; Schmitt, J.-L.; Lehn, J.-M. Angew.
Chem., Int. Ed. 2004, 43, 4902–4906.
J. Org. Chem. Vol. 73, No. 23, 2008 9409

Lin et al.
solvents,16a,e the reactions could be extended into polar solvents.
The high conformational predictability of this family of hydrogen
bonded aromatic amide oligomers also makes them potentially
useful as templating backbones for the synthesis of one-dimensional
nanoarchitectures.
A notable feature of this hydrogen bonding-directed DCC is that
the components can be readily expanded and functionalized,
whereas the size of the macrocyclic units can also be tuned by
regulating the distance of the reactive sites. In principle, any reactive
sites that undergo reversible covalent reactions can be introduced
to the amide backbones, while DCC of similar polymeric precursors
may lead to the construction of porous tapes of long-range order.
Therefore, the work also opens up a new possibility for quick
construction of more complicated porous systems.
FIGURE 9. Partial 1H NMR of (a) 20, (b) 3, (c) 3 + 20 (1:1, 5 min),
(d) 3 + 20 (1:1, 2 h, the labeled signals belong to 2), and (e) 21 in
CDCl3/DMSO-d6 (4:1). The concentration was 5 mM.
SCHEME 5. Hydrazone-Based Macrocycle 21 from 1+1
Macrocyclization and Intercycle Imine-Hydrazone
Exchange Reactions
Experimental Section
Compound 3. A solution of 1 (52 mg, 0.08 mmol) and 2 (51 mg,
0.08 mmol) in chloroform (8 mL) was stirred at room temperature for
15 h and then concentrated and dried under reduced pressure. The
resulting residue was recrystallized from acetonitrile and chloroform
to give compound 3 asa yellow solid (75 mg, 75%). 1H NMR (CDCl3)
δ 10.13 (s, 2 H), 9.89 (s, 1 H), 9.58 (s, 2 H), 9.35 (s, 1 H), 8.81 (s, 2
H), 8.78 (s, 2 H), 8.47 (d, J ) 1.5 Hz, 2 H), 8.22 (d, J ) 8.4 Hz, 2 H),
7.47 (dd, J1 ) 8.5 Hz, J2 ) 1.5 Hz, 2 H), 7.10 (d, J ) 8.4 Hz, 2 H),
7.05 (d, J ) 8.5 Hz, 2 H), 6.53 (d, J ) 11.8 Hz, 2 H), 4.44-4.09 (m,
8 H), 3.84 (d, 8 H), 2.17-2.14 (m, 4 H), 1.95-1.91 (m, 8 H),
1.64-1.34 (m, 8 H), 1.14-1.01 (m, 18 H), 0.99-0.96 (m, 12 H); 13
C
NMR (CDCl3) δ 162.8, 162.4, 159.5, 158.5, 155.1, 146.2, 145.3, 144.8,
137.7, 129.9, 129.8, 128.2, 124.1, 123.3, 123.0, 122.1, 121.0, 119.0,
115.9, 113.7, 113.1, 98.6, 98.1, 75.9, 69.9, 69.5, 31.0, 28.3, 19.4, 19.3,
19.1; MS (MALDI-TOF) m/z 1259 [M + H]+, 1281 [M + Na]+;
HRMS (MALDI-TOF) calcd for C74H95N6O12 1259.7035, found
1259.7003.
Compound 8. A solution of compound 5 (0.30 g, 0.40 mmol) and
TFA (0.46 g, 4.00 mmol) in chloroform (10 mL) was stirred at room
temperature for 1.5 h. To the solution was added saturated sodium
bicarbonate solution (10 mL). The mixture was stirred for 10 min and
the organic phase was separated with a separating funnel. The aqueous
solution was extracted with chloroform (3 × 5 mL). The organic phases
were combined and washed with water (10 mL) and brine (10 mL)
and dried over sodium sulfate. The solution was concentrated and the
resulting residue washed with ether and dried under vacuum to give
1
compound 8 as a yellow solid (0.26 g, 100%). H NMR (CDCl3) δ
9.92 (s, 2 H), 9.89 (s, 2 H), 9.76 (s, 2 H), 8.87 (s, 2 H), 8.83 (s, 2 H),
8.46 (s, 2 H), 8.27 (d, J ) 10.1 Hz, 2 H), 7.47 (d, J ) 8.8 Hz, 2 H),
7.12 (d, J ) 8.8 Hz, 2 H), 7.03 (d, J ) 10.1 Hz, 2 H), 6.53 (s, 2H),
4.35-4.27 (m, 8 H), 3.88-3.83 (m, 8 H), 2.19-2.13 (m, 4 H),
1.96-1.87 (m, 8 H), 1.49-1.47 (m, 8 H), 1.07-0.98 (m, 36 H); MS
(MALDI-TOF) m/z 1259 [M + H]+, 1282 [M + Na]+; HRMS
(MALDI-TOF) calcd for C74H94N6O12Na [M + Na]+ 1281.6822,
found 1281.6806. Anal. Calcd for C74H94N6O12 ·H2O: C, 69.57; H,
7.57; N, 6.08. Found: C, 69.41; H, 7.28; N, 6.50.
bytreatingmacrocycle3with20.Thisintercycleimine-hydrazone
exchange led to selective formation of 21 and 2 (Figure 9).
Furthermore, this exchange reaction was finished in much
shorter time (2 h). Because as electrophilic reagents aldehydes
are usually more active than relevant imines,27 this result appears
to imply that the two exchange reactions occurred simulta-
neously and therefore could accelerate each other.
Acknowledgment. We thank the National Science Founda-
tion of China (Nos. 20732007, 20621062, 20425208, 20572126,
20672137),theNationalBasicResearchProgram(2007CB808000),
and the Chinese Academy of Sciences (KJCX2-YW-H13) for
financial support.
Conclusion
In this paper, we have demonstrated that intramolecular hydrogen
bonding can be used to direct the thermodynamically controlled
formation of imine- and hydrazone-based macrocyclic structures
by modulating the conformation or shape of one or more molecular
components. This modulation is workable in less polar and polar
solvents and even in the presence of excess strong protonic acid
like TFA. The construction of the bimacrocycle through the
formation of six imine bonds from six components illustrates well
the efficiency of this new approach. Since the intramolecular
hydrogen bonding patterns have been evidenced to occur in polar
Supporting Information Available: General methods, de-
1
tailed synthesis and characterizations, H NMR spectra, MS
spectra of two reaction mixtures, and CIF files of 1-3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801972S
9410 J. Org. Chem. Vol. 73, No. 23, 2008