One-pot formation of large macrocycles with modifiable peripheries and internal cavities

Full text of DOI:10.1002/anie.200900584

Communications
DOI: 10.1002/anie.200900584
Macrocycle Synthesis
One-Pot Formation of Large Macrocycles with Modifiable Peripheries
and Internal Cavities**
Joseph S. Ferguson, Kazuhiro Yamato, Rui Liu, Lan He,* Xiao Cheng Zeng,* and Bing Gong*
Macrocycles with persistent shape and large, noncollapsible
lumens have attracted increasing interest because of their
unique properties and potential applications.[1] Although
most of the macrocycles with well-defined shape have hydro-
carbon backbones formed from the stepwise coupling of sp-
or sp2-hybridized carbon atoms,[1a,b,d,2] macrocycles with other
rigid backbones have also been reported.[3] For example, we
discovered a series of aromatic oligoamide macrocycles that
could be generated in high yield by a one-pot macrocycliza-
tion process.[4] These readily available macrocycles contain
hydrophilic cavities that are rich in carbonyl oxygen atoms.
With their persistent shape and noncollapsible cavities, these
macrocycles have demonstrated unique features such as
binding large cations with high affinity and specificity,[5] and
self-assembling into highly conducting transmembrane
pores.[6] The latest mechanistic study[4b] indicates that the
folding of uncyclized oligoamide intermediates and precur-
sors, which belong to a class of folding oligoamides with well-
defined crescent conformations and tapelike backbones,[7]
plays a critical role in the observed high efficiency of the
one-pot macrocyclization. The folding of the intermediates
and precursors facilitates the one-pot cyclization,[8] and at the
same time impedes the formation of “overshooting” oligom-
ers longer than the direct precursor of a macrocycle through
remote steric hindrance.[4b] Herein we report that macrocycles
with backbones other than aromatic oligoamides can also be
formed with very high efficiency. Specifically, macrocycles
with rigidified oligohydrazide backbones and nanosized
cavities containing well-positioned, modifiable convergent
sites can be obtained nearly exclusively in one step.
Similar to the crescent and helical oligoamides we had
previously synthesized, the aromatic oligohydrazides consist-
ing of meta-linked benzene rings are also known to fold into
conformations with tapelike, hydrogen-bond-rigidified back-
bones.[9] General structure 1 represents an unknown class of
aromatic oligohydrazides consisting of meta-linked benzene
and pyridine residues that should have a hydrogen-bond-
enforced, curved backbone. The basic unit of 1 consists of a
hydrogen-bonded hydrazide group flanked by pyridyl N and
ether O atoms that act as hydrogen-bond acceptors. The
planar conformation of such a basic unit is illustrated by the
optimized structure of hydrazide 1a.[10] The structure of 1a is
rigidified by two highly favorable, three-center hydrogen
bonds that are placed on either side of its hydrazide unit.
These three-center hydrogen bonds enforce 1a to be planar.
An oligomer consisting of such rigidified hydrazide units and
meta-linked aromatic rings will be forced to fold into a
crescent shape, which will allow cyclization to occur once it
reaches a length that brings its two ends into proximity. Thus,
oligomers based on 1 should have a folded, crescent-shaped
backbone that may facilitate macrocyclization, thus leading to
the corresponding macrocycle.
To test this possibility, acid chloride 2 (1 equiv) was
treated with hydrazide 3 (1 equiv) in CH2Cl2 in the presence
of 4-dimethylaminopyridine (DMAP) at 08C (Scheme 1).
The reaction mixture was allowed to warm to room temper-
ature, and was then heated under reflux for 24 h. The crude
product was precipitated by adding diethyl ether. The
MALDI mass spectrum of this product revealed a dominant
signal (m/z = 1515.0) that corresponded to the [M+Na+] ion
of the six-residue macrocycle 4. Purification by column
chromatography gave pure 4 as a pale yellow solid in 73%
yield. The 1H and 13C NMR spectra of 4 also revealed signals
that are fully consistent with the symmetrical structure of this
molecule.[10] The highly efficient, nearly exclusive formation
of 4 demonstrates that folding-assisted macrocyclization can
indeed be extended to the preparation of macrocycles with a
[*] Dr. J. S. Ferguson, Dr. K. Yamato, Prof. B. Gong
Department of Chemistry, University at Buffalo
The State University of New York, Buffalo, NY 14260 (USA)
Fax: (+1)716-645-6963
E-mail: bgong@chem.buffalo.edu
R. Liu, Prof. L. He, Prof. B. Gong
Colleges of Chemistry and Resources Science and Technology, and
State Key Laboratory of Earth Surface Processes and
Resource Ecology, Beijing Normal University
Beijing 100875 (China)
E-mail: helan1961@yahoo.com.cn
Prof. X. C. Zeng
Department of Chemistry, University of Nebraska-Lincoln
Lincoln, NE 68588 (USA)
E-mail: Zeng@phase2.unl.edu
[**] This work was supported by the US National Science Foundation
(CHE-0701540), the Changjiang Scholar Program and the Cultiva-
tion Fund of the Key Scientific and Technical Innovation Project,
Ministry of Education of China (grant 706009), the NSFC (grant
20672015 and 20772012), RFDP (grant 20070027038), Beijing
NSFC (grant 2073024), Beijing Municipal Commission of Educa-
tion, and Beijing New Medical Discipline Based Group
(XK100270569).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900584.
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The structure of 5 is supported by the X-ray structure of
5a[9] (Figure 1b), which adopts a completely planar confor-
mation that is enforced by two sets of highly favorable, three-
center hydrogen bonds.[12] The reported noncyclic aromatic
oligohydrazides were based on meta-linked benzene residues,
and thus trimer 5b was examined by 2D (ROESY) 1H NMR
to provide insights into the folding of the meta/para-linked 5.
The ROESY spectrum of 5b recorded at room temperature
Scheme 1. One-pot formation of oligohydrazide macrocycle 4 consist-
ing of meta-linked pyridine and benzene residues.
rigidified backbone besides that offered by aromatic oligo-
amides.
The six-residue 4 represents the first member of a new
series of macrocycles. An exciting possibility offered by
shape-persistent macrocycles involves the creation of modifi-
able internal cavities by placing well-positioned, multiple
functionalities in a convergent fashion. Unfortunately, most
currently known systems,[11] including the oligoamide macro-
cycles we reported previously and macrocycle 4 described
here, do not allow for easy modification of their internal
cavities. Shape-persistent macrocycles with internal cavities
of readily tunable size and properties could be formed in high
yields by choosing a rigidified, curved backbone that allows
the convergent placement of functional groups.
An oligohydrazide consisting of alternating meta- and
para-linked benzene residues, as exemplified by general
structure 5 (Figure 1a), should have a hydrogen-bond-
enforced, curved backbone with a convex edge and a concave
edge. Macrocycles based on such a backbone should have
both divergently (R1) and convergently (R2) placed side
chains. The size and, more importantly, the function of the
internal cavities can be tuned by adjusting the convergent
groups. An additional feature provided by this design is that
the presence of the para-linked residues leads to an overall
reduced curvature of the backbone of 5, macrocycles based on
which should have cavities of expanded sizes.
Figure 2. Partial ROESY 1H NMR spectrum of trimer 5b recorded in
CDCl3 (500 MHz, 298 K, mixing time=0.3 s).
(Figure 2) revealed significant
ROE interactions between
protons a and f, a and g, and
b and c, which suggests that 5b
indeed adopts the expected
crescent conformation that is
enforced by intramolecular
hydrogen bonds.
With the inclusion of para-
linked residues, it was not
clear whether the reaction
Figure 1. a) The general structure shared by oligohydrazides containing alternating meta- and para-linked
benzene residues connected by hydrogen-bond-rigidified hydrazide groups. Such an oligomer has a
concave edge and a convex edge, to which convergently and divergently side chains are attached. b) The
structure of 5 is supported by the known crystal structure of 5a, which shows a completely planar
conformation that is enforced by two sets of three-center hydrogen bonds.
between a diacid chloride and
dihydrazide (Scheme 2)
a
would lead to the formation
of cyclic product(s), linear
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The persistency of the three-center hydro-
gen bonds that rigidify the hydrazide groups and
thus the backbone of 8b was demonstrated by
intense NOE interactions between protons a
and e, b and c, and b and d in its NOESY
spectrum (Figure 4).
Compounds 6 and 7 can be readily prepared
by procedures previously described,[13] and
allows the preparation of other ten-residue
macrocycles that share the same backbone as
8a,b but carry a wide variety of divergent (R1)
and convergent (R2) groups. The preparation of
macrocycle 8c from diacid chloride 7b and
hydrazide 6c (Scheme 2) demonstrated that
neither R1 nor R2 had any effect on the
efficiency of the one-pot condensation. Crude
macrocycle 8c was obtained in 91% yield after
washing the reaction mixture in CH2Cl2 with
aqueous HCl and brine, and in 62% yield after
purification by column chromatography. The
cyclic structure of 8c was confirmed by the
[M+Na+] signal (m/z = 2804.5) in its MALDI
mass spectrum, along with the isotope distribu-
tion pattern of this signal.[10] However, attempts
1
to characterize 8c by H and 13C NMR spec-
troscopy have so far resulted in spectra with
either very poor resolution (1H NMR) or no
signals (13C NMR), which was most likely a
consequence of strong intermolecular aggrega-
tion of 8c.
Scheme 2. One-pot formation of oligohydrazide macrocycles 8 consisting of alternat-
ing meta- and para-linked benzene residues. Bn=benzyl.
A unique feature offered by the general
oligomers, or both. Thus, acid chloride 6a (1 equiv) was
treated with hydrazide 7a (1 equiv) in CH2Cl2 at room
temperature. The crude product was obtained in 72% yield
after removing the solvent, re-dissolving the solid residue in
CH2Cl2, simple washing, and recrystallization from methanol.
The crude product was analyzed by MALDI mass spectrom-
etry, which revealed a dominant signal (m/z = 3564.9) that
corresponded to the [M+Na+] ion of the ten-residue macro-
cycle 8a. Extensive purification by column chromatography
(silica gel, chloroform/methanol) yielded 8a in 54% yield.
The very high efficiency of this one-pot macrocyclization
reaction was further demonstrated by treating acid chloride
6b with hydrazide 7a under similar conditions. Examining the
crude products from this reaction by MALDI mass spectrom-
etry revealed that the corresponding macrocycle 8b (m/z =
4144.2, [M+Na+]) existed as the dominant species. Washing a
solution of the crude product in CH2Cl2 with aqueous HCl
design of 8 is that the multiple convergent sites in the internal
cavities of these macrocycles can be adjusted, either by
incorporating monomers carrying the desired side chains or
1
and NaCl afforded essentially pure (by H NMR spectrosco-
py) macrocycle 8b in 97% yield.[10]
In addition to the evidence provided by the MALDI mass
spectra, the cyclic structures of macrocycles 8a and 8b were
clearly demonstrated by the simplicity of their 1H NMR
spectra.[10] The 1H NMR signals corresponding to those of the
hydrazide and aromatic protons (6.0–12.0 ppm) of each
macrocycle can be unambiguously assigned to the two types
of monomeric residues (Figure 3). Consistent with the sym-
metrical nature of their structures, the 13C NMR spectra of
these compounds also exhibit similar simplicity.[10]
Figure 3. The 1H NMR spectra of a) 8a and b) 8b recorded in CDCl3
(500 MHz).
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Figure 5. Top and side views of the structures of macrocycles a) 4, and
b) 8 optimized at the B3LYP/6-31(g)d level. All side chains were
replaced with methyl groups to save computational time.
one-pot reactions use readily available starting materials and
should lead to large quantities of a variety of macrocycles.
Adjusting the divergent side chains allows the peripheries,
and thus the solubility, of the macrocycles to be tuned. With
their flat backbones and large diameters, these macrocycles
should undergo self-organization typical of disclike mole-
cules,[15] thereby leading to columnar aggregates containing
nanosized channels. The efficient formation of 8a–c has
opened up a new approach to constructing shape-persistent
macrocyles with internal cavities containing multiple con-
vergent sites. Incorporating different functionalities into these
convergent sites will lead to noncollapsible cavities with
systematically tunable sizes and properties, which will enable
hosts to be designed that are capable of targeting guests that
are otherwise difficult to recognize. Despite the kinetic nature
of the bond-forming reaction, the one-pot nearly exclusive
formation of 4 and the much larger 8, along with the
previously reported one-pot generation of aromatic oligoa-
mide macrocycles,[4] rival those observed for macrocyclization
reactions under thermodynamic conditions.[16] Thus, these
systems have established folding-assisted macrocyclization as
a new, general method for the efficient synthesis of shape-
persistent macrocycles from folded intermediates and pre-
cursors.
Figure 4. Partial 2D (NOESY) 1H NMR spectrum of 8b recorded in
CDCl3 (500 MHz, 293 K, mixing time=70 ms).
by performing a post-cyclization modification. For example,
removing the benzyl groups of 8a and 8b should expose the
hydroxy groups of the catechol moieties. Functional groups
could then be introduced through ester, ether, acetal, or other
linkages. Furthermore, the hydroxy groups of the catechol
moieties should provide multiple sites for the binding of metal
ions, thereby leading to cavities with catalytic capability.
The structures of macrocycles 4 and 8 (R replaced with
methyl) were optimized by using an ab initio method at the
B3LYP/6-31(g)d level of theory.[14] These macrocycles have
flat backbones rigidified by three-center hydrogen bonds
(Figure 5). The planar shape of both 4 and 8 reflects the high
strength of the three-center hydrogen bonds, which enforces
the hydrogen-bond donor and acceptors involved to be
coplanar. Macrocycle 4 has a triangular shape, with an
internal cavity of approximately 10 ꢀ diameter. Macrocycle
8 is much larger than 4, with an overall round shape and an
internal cavity that provides ten well-positioned, multiple
convergent sites. In the optimized structure of 8, the ten
convergent methyl groups project above and below the plane
of the macrocyclic backbone, thus leading to a cavity with a
diameter of about 21 ꢀ.
Received: January 31, 2009
Published online: March 25, 2009
Keywords: foldamers · hydrogen bonds · macrocycles ·
.
synthesis design
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