Aromatic oligoamide macrocycles from the bimolecular coupling of folded oligomeric precursors

Article abstract of DOI:10.1039/b902495f

Aromatic oligoamide macrocycles consisting of six to ten meta-linked residues were prepared based on bimolecular coupling/cyclization of a pentameric diamine and oligomeric diacid chlorides, and adopt folded conformations enforced by intramolecular three-

Full text of DOI:10.1039/b902495f

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LETTER
www.rsc.org/njc | New Journal of Chemistry
Aromatic oligoamide macrocycles from the bimolecular coupling
of folded oligomeric precursorswz
Liuqing Yang,a Lijian Zhong,a Kazuhiro Yamato,b Xiaheng Zhang,a Wen Feng,a
Pengchi Deng,a Lihua Yuan,*a Xiao Cheng Zeng*c and Bing Gong*b
Received (in Montpellier, France) 5th February 2009, Accepted 17th February 2009
First published as an Advance Article on the web 16th March 2009
DOI: 10.1039/b902495f
Aromatic oligoamide macrocycles consisting of six to ten
meta-linked residues were prepared based on bimolecular
coupling/cyclization of a pentameric diamine and oligomeric
diacid chlorides, and adopt folded conformations enforced by
intramolecular three-center H-bonds.
having an odd number of residues and (3) the incorporation of
a single functional side chain into the macrocycle is not
possible. To address these limitations, we describe herein an
approach based on bimolecular coupling/cyclization involving
pentameric diamine 1 and a series of bifunctional oligomers
bearing terminal acid chloride groups.
The efficient preparation of various macrocycles1,2 has long
been an intriguing subject for creating well-defined and
functionally-adjustable structures. Of particular interest are
methods for forming shape-persistent macrocycles3 that may
be used for designing novel materials4 and catalysts.5 Known
approaches for preparing macrocycles include (a) templation,6
(b) high dilution7 and (c) dynamic covalent bond formation,
such as Schiff base-type cyclization,8,9 cross-coupling
cyclooligomerization,3,10 disulfide exchange11 and metathesis.12
Recently, we discovered the almost exclusive formation of a
series of six-residue oligoamide macrocycles from a one-step
condensation of monomeric diamines and diacid chlorides.13
This one-step condensation provided a highly efficient method
for preparing a novel series of shape-persistent macrocycles
consisting of meta-linked benzene rings, as exemplified by the
structure of 3a, as shown in Scheme 1.14 It was believed that
the observed high efficiency was due to folding15 of the
uncyclized oligomer precursors of these macrocycles into rigid,
crescent conformations. By bringing its two termini into close
proximity upon folding, the direct precursor of the macrocycle
is predisposed to undergo a highly favorable intramolecular
cyclization.
Results from our previous studies on analogous oligoamide
foldamers consisting of meta-linked benzene rings show that it
takes about 6.5 benzene residues to complete a turn,15 which
suggests that aromatic oligoamide macrocycles with seven
meta-linked residues may also be formed efficiently. While
seven-residue macrocycles cannot be formed from the
condensation of monomeric diacid chlorides and diamines,
coupling diamine 1 with dimeric 2b may get around this
limitation. Thus, based on a competition reaction, the forma-
tion of six- and seven-residue macrocycles was compared. A
mixture containing one equivalent (0.5 mM) each of diamine
1, and diacid chlorides 2a and 2b in CH2Cl2 (Scheme 1), was
stirred at 0 1C for 2 h, followed by warming up to room
temperature, stirring overnight and then heating under reflux
for 2 h. Based on the 1H NMR spectrum of the crude reaction
mixture, using p-xylene as the internal standard, a yield of
43.8% was determined for 3a, while the seven-residue 3b
formed in a surprisingly low yield of 5.9%.z This result
In spite its high efficiency, this one-step macrocyclization is
limited in that (1) only the six-residue macrocycle is formed,14
(2) the AB-type backbone is not compatible with macrocycles
a College of Chemistry, Key Laboratory for Radiation Physics and
Technology of Ministry of Education, Institute of Nuclear Science
and Technology, Analytical & Testing Center of Sichuan University,
Sichuan University, Chengdu 610064, Sichuan, China.
E-mail: lhyuan@scu.edu.cn; Fax: +86 28-85418755;
Tel: +86 28-85416996
b Department of Chemistry, University at Buffalo, The State
University of New York at Buffalo, Buffalo, New York 14260, USA.
E-mail: bgong@buffalo.edu; Fax: +1 716-6456800 x2243;
Tel: +1 716-6456963
c Department of Chemistry, University of Nebraska-Lincoln, Lincoln,
Nebraska 68588, USA. E-mail: xczeng@phase2.unl.edu
w This work is dedicated to Professor Seiji Shinkai on the occasion of
his 65th birthday.
z Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra, and MALDI spectra. See DOI:
10.1039/b902495f
Scheme 1 Competition reactions of pentameric diamine 1 with diacid
chlorides 2a and 2b.
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Scheme 2 Bimolecular coupling/cyclization involving 1 and diacid chlorides of various sizes.
demonstrated that the formation of six-residue macrocycles,
such as 3a, was overwhelmingly favored over macrocycles
of other sizes, even if the product, such as 3b, has a size that
is well accommodated by the geometry of the meta-linked
backbone.
The bimolecular coupling/cyclization shown in Scheme 1 is
particularly valuable for preparing macrocycles such as 3b and
3d, which have odd numbers of residues. These macrocycles,
with their unsymmetrical backbones, cannot be obtained
based on the direct coupling of monomeric diacid chlorides
and diamines. Given the usually difficult preparation of
macrocycles with expanded sizes, the successful synthesis of
3d and 3e shows great promise for preparing macrocycles of a
variety of sizes based on this bimolecular coupling/cyclization
method. In addition, this synthetic strategy should also allow
the site-specific incorporation of a single functional group into
a macrocycle, the product from which should serve as a
valuable building block for further derivatization and
modification.
One likely strategy to promote the formation of macrocycles
of other sizes involves ruling out the possibility of forming the
highly favorable six-residue macrocycle. This possibility was
first probed by carrying out coupling reactions involving 1 and
each of diacid chlorides 2a–2e under identical conditions
(Scheme 2). In addition to 3a and 3b, macrocycles 3c–3e,
which consist of eight to ten meta-linked residues, may also be
formed if ring closure happens in these condensation
reactions. One potential complication may arise from the
folding and rigidification of uncyclized precursors, which
could direct the reactive ends of uncyclized precursors of
3c–3e away from one another and thus retard the cyclization
reactions.
It was later found that the yields of individual coupling
reactions could be optimized by conducting the reaction at a
higher temperature and by controlling the way (e.g., rate and
duration of addition) the acid chlorides were added. For
example, the yield of macrocycle 3b was optimized to B70%
and that of 3e was raised to B15% when the coupling
reactions were carried out at around 20 1C in CH2Cl2,
followed by heating the reaction mixtures under reflux.
The structures of macrocycles 3a, 3b, 3c and 3e
were optimized by using an ab initio method at the
B3LYP/6-31(g)d level of theory. As shown in Fig. 1, the
energy-minimized conformations of six-residue 3a and
seven-residue 3b are nearly flat, with that of 3a resembling a
very shallow bowl and that of 3b being overall flat.
The flat conformations of 3a and 3b demonstrate that
these macrocycles are relatively strain-free, and that the
backbone-rigidifying three-center H-bonds undergo insignificant
twisting. In contrast, macrocycles 3c and 3e, with their
numbers of meta-linked benzene residues being well beyond
one full turn, are expected to have significant ring strain.
Indeed, neither 3c nor 3e has an overall flat shape. In fact,
both macrocycles adopt saddle-shaped conformations, with
that of 3c being reminiscent of a shallow saddle and the shape
of 3e being a deep saddle. To accommodate the ring
strain, some of the intramolecular H-bonded rings of 3c are
noticeably twisted. Consistent with significant ring strain,
parts of the backbone of 3e are twisted to such an extent that
some intramolecular H-bonds are completely interrupted.
In summary, we have investigated the formation of
aromatic oligoamide macrocycles consisting of six to ten
residues based on the bimolecular coupling and subsequent
cyclization of pentameric diamine 1 and diacid chlorides.
Pentamer 1 showed an overwhelming preference towards
Each of the coupling reactions was conducted under iden-
tical conditions, involving stirring a 1 : 1 mixture of diamine 1
(0.5 mM) and the corresponding diacid chloride 2 (0.5 mM) in
CH2Cl2 at 0 1C for 3 h, followed by warming up to room
temperature. After stirring for another 8 h, the reaction
mixture was heated under reflux for 1 h, after which methanol
and HCl was added.
It was found that six-residue 3a was obtained in a high
(84%) yield after purification. Coupling between 1 and dimeric
2b afforded macrocycle 3b in a reasonable (50%) yield. In
contrast, the eight-residue macrocycle, 3c, formed in a
significantly lower (14%) yield from the coupling of 1 and 2c.
The low yield of 3c indicates that as the ring size extends
beyond that of six-residue 2a, the formation of the
corresponding macrocycle becomes increasingly inefficient. It
was not clear, based on the same coupling and cyclization
reactions, whether macrocycles with sizes beyond that of 3c
could still form. Surprisingly, treating 1 and the corresponding
diacid chlorides 2d and 2e afforded the nine-residue 3d
and ten-residue 3e, respectively, which were revealed by
MALDI-TOF spectraz and subsequently isolated in yields of
10 and 6.2%, respectively.
The structures of macrocycles 3 were confirmed by 1H
and 13C NMR, ESI-HRMS and MALDI-TOF analysis.
Compared to the simplicity of the NH and aromatic 1H
NMR signals of symmetrical 2a, 2c and 2e, the presence of
multiple NH signals from 9.6 to 10.4 ppm in the 1H NMR
spectra of 3b and 3d is consistent with the unsymmetrical
nature of their structures.
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solution was then added immediately to a pre-cooled solution
at 0 1C of diamine salt 1 (1 equiv.) in CH2Cl2 containing DIEA
(5 equiv.). The final concentration of 1 was 0.5 mM. The
reaction mixture was stirred at 0 1C for 3 h and then at room
temperature for 8 h, followed by refluxing for 1 h. After
quenching with CH3OH and removing the solvent, the
residue was triturated with CH3OH and EtOAc. Filtration
provided the crude product. Further recrystallization with
CHCl3/CH3OH and/or purification by preparative
TLC (CHCl3/EtOAc/CH3OH, 10 : 1 : 1.5) provided the pure
product.
Six-residue macrocycle 3a. Prepared according to the
general synthetic procedure for macrocycles. 4,6-Dimethoxy-
isophthalic acid (17.5 mg, 0.077 mmol) and oxalyl chloride
(29.3 mg, 0.23 mmol) were used to prepare 2a. Diamine salt 1
(100.0 mg, 0.077 mmol), DIEA (50.0 mg, 0.39 mmol) and
CH2Cl2 (150 mL) were used for the macrocyclization. Yield
84.5%. 1H NMR (400 MHz, 90% CDCl3–10% CD3OD):
d 9.52 (s, 6 H), 9.43 (s, 3 H), 9.12 (s, 3 H), 6.46 (s, 3 H),
6.23 (s, 3 H), 4.04 (s, 18 H), 3.93 (m, 6 H), 3.83 (m, 6 H), 1.93
(m, 6 H), 1.49 (m, 6 H), 1.37 (m, 6 H), 1.14 (d, J = 6.5 Hz, 18
H) and 1.08 (t, J = 7.3 Hz, 18 H). 13C NMR (100 MHz, 90%
CDCl3–10% CD3OD): d 162.2, 160.5, 144.4, 138.8, 120.6,
116.0, 114.7, 96.1, 94.2, 74.1, 56.4, 35.1, 25.9, 16.6 and
11.2. MALDI-TOF MS (m/z) calc. for C68H92N6O18Na
(M + Na+) 1433.7; found 1434.1 (M + Na+). ESI-HRMS
(m/z) calc. for C68H93N6O18 (M + H+) 1411.7329; found
1411.7405 (M + H+).
Fig. 1 The top and side views of the structures of macrocycles (a) 3a,
(b) 3b, (c) 3c and (d) 3e optimized at the B3LYP/6-31(g)d level. The
hydrogen atoms are removed for clarity.
Seven-residue macrocycle 3b. Prepared according to the
general synthetic procedure for macrocycles. Diacid
9
monomeric diacid chloride 2a, which resulted in the highly
efficient formation of six-residue macrocycle 3a. Coupling 1
with diacid chlorides of increasing sizes led to the corresponding
macrocycles in yields that decreased as the ring size
expanded. The fact that macrocycles with more than eight
meta-linked residues were formed suggests that the
corresponding uncyclized oligomer precursors, in spite of their
H-bond-rigidified backbone, still possess a certain degree of
conformational flexibility to cyclize. Given the obvious large
ring strain, the formation of 3e is quite surprising and bodes
well for the construction of macrocycles of a variety of sizes
based on this strategy. The fact that no special effort was made
to optimize the reactions suggests that H-bond-enforced
folding of the oligomeric precursors may be promoting, rather
than hampering, the formation of macrocycles accompanied
by a large ring strain, and thus contain severely twisted
backbones.16 These macrocycles, with different cavity sizes
and unique conformations, provide a new series of structures,
upon which novel hosts and materials could be developed.
(31.3 mg, 0.077 mmol) and oxalyl chloride (29.3 mg,
0.23 mmol) were used to prepare 2b. Diamine salt 1
(100.0 mg, 0.077 mmol), DIEA (50.0 mg, 0.39 mmol) and
CH2Cl2 (150 mL) were used for the macrocyclization. Yield
49.7%. 1H NMR (400 MHz, 90% CDCl3–10% CD3OD): d
10.25 (s, 2H), 10.20 (s, 1H), 10.15 (s, 1H), 10.09 (s, 1 H), 9.94
(s, 2 H), 9.36 (s, 1 H), 9.16 (s, 1 H), 9.09 (s, 2 H), 8.97 (s, 3 H),
6.56–6.31 (m, 7 H), 4.17–3.86 (s, 36 H), 1.98 (m, 6 H), 1.64
(m, 6 H), 1.35 (m, 6 H), 1.10 (m, 18 H) and 1.01 (m, 18 H).
13C NMR (100 MHz, 90% CDCl3–10% CD3OD): d 162.4,
161.6, 161.4, 160.9, 154.2, 152.0, 144.1, 137.0, 122.1, 121.3,
121.0, 120.9, 120.5, 114.3, 114.1, 113.1, 112.6, 97.1, 96.4, 95.4,
95.1, 94.3, 74.7, 74.4, 57.1, 56.8, 56.7, 56.3, 35.2, 25.9, 16.5,
16.4 and 11.1. MALDI-TOF MS (m/z) calc. for
C87H111N7O21Na (M
+
Na+) 1612.8; found 1613.3
(M + Na+). ESI-HRMS (m/z) calc. for C87H112N7O21
(M + H+) 1590.7911; found 1590.7941 (M + H+). Anal.
calc. for C87H111N7O21: C, 65.68; H, 7.03; N, 6.16; found: C,
65.58; H, 7.07; N, 6.36%.
Eight-residue macrocycle 3c. Prepared according to the
general synthetic procedure for macrocycles. Diacid 7b
(26.9 mg, 0.039 mmol) and oxalyl chloride (14.7 mg,
0.12 mmol) were used to prepare 2c. Diamine salt 1
(50.0 mg, 0.039 mmol), DIEA (25.0 mg, 0.19 mmol) and
CH2Cl2 (75 mL) were used for the macrocyclization. Yield
13.8%. 1H NMR (400 MHz, 90% CDCl3–10% CD3OD):
d 10.18 (s, 8 H), 9.33 (s, 4 H), 8.99 (s, 4 H), 6.78 (s, 4 H),
Experimental
General synthetic procedure for macrocycles
A mixture of diacid (1 equiv.), dry CH2Cl2 (20 mL), oxalyl
chloride (3 equiv.) and DMF (4 mL) was stirred for 5 h at room
temperature. The solvent was then removed and the resulting
diacid chloride 2(a, b, c, d or e) dissolved in CH2Cl2. This
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6.64 (s, 4 H), 4.20 (s, 24 H), 4.00 (m, 8 H), 3.88 (m, 8 H), 1.98
(m, 8 H), 1.64 (m, 8 H), 1.37 (m, 8 H), 1.34 (m, 8 H), 1.10
(d, 24 H) and 1.08 (t, 24 H). 13C NMR (100 MHz, 90%
CDCl3–10% CD3OD): d 162.1, 161.5, 145.8, 136.7, 122.9,
120.7, 115.3, 99.1, 96.4, 74.8, 57.1, 35.1, 26.2, 16.7 and
11.3. MALDI-TOF MS (m/z) calc. for C104H136N8O24Na
(M + Na+) 1905.0; found 1905.8 (M + Na+). ESI-HRMS
(m/z) calc. for C104H137N8O24 (M + H+) 1882.9779; found
1882.9792 (M + H+).
Acknowledgements
The authors acknowledge the National Natural Science
Foundation of China (no. 20672078 to L. Y. and no.
20774059 to W. F.), the National Science Foundation of the
USA (CHE-0701540 to B. G. and X. C. Z.), the Nebraska
Research Initiative (to X. C. Z.) for their support of this
research, the Research Computing Facility at the University of
Nebraska-Lincoln and Holland Computing Center at the
University of Nebraska-Omaha. This work is also part of a
Project sponsored by SRF for ROCS, SEM. We also thank the
Analytical Center of Sichuan University for NMR analyses.
Nine-residue macrocycle 3d. Prepared according to the
general synthetic procedure for macrocycles. 11 (20.4 mg,
0.023 mmol) and oxalyl chloride (8.82 mg, 0.070 mmol) were
used to prepare 2d. Diamine salt 1 (30.0 mg, 0.023 mmol),
DIEA (15.0 mg, 0.12 mmol) and CH2Cl2 (45 mL) were used
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Experimental procedure of the competition reaction
A
mixture of 4,6-dimethoxy-isophthalic acid (8.7 mg,
0.039 mmol), diacid 9 (15.6 mg, 0.039 mmol), dry CH2Cl2
(20 mL), oxalyl chloride (39.2 mg, 0.309 mmol) and DMF
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diamine salt 1 (50.0 mg, 0.039 mmol) in CH2Cl2 (70 mL)
containing DIEA (54.9 mg, 0.42 mmol) at 0 1C. The reaction
was stirred in an ice bath for 2 h, warmed up to room
temperature, stirred overnight and then heated under reflux
for 2 h. After quenching with CH3OH and removing the
solvent, the residue was triturated with CH3OH and EtOAc.
Filtration provided the crude product.
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13 Known examples of the synthesizing of other cyclic amides:
(a) E. Schwartz, H. E. Gottlieb, F. Frolow and A. Shanzer,
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14 (a) L. H. Yuan, W. Feng, K. Yamato, A. R. Sanford, D. G. Xu,
H. Guo and B. Gong, J. Am. Chem. Soc., 2004, 126, 11120;
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