Highly selective one-pot synthesis of H-bonded pentagon-shaped circular aromatic pentamers

Article abstract of DOI:10.1039/c0cc05791f

One-pot, multi-molecular macrocyclization allows the highly selective preparation of pentagon-shaped circular aromatic pentamers mediated by an inward-pointing continuous hydrogen-bonding network.

Full text of DOI:10.1039/c0cc05791f

Chemical Communications
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Volume 47 | Number 19 | 21 May 2011 | Pages 5345–5636
ISSN 1359-7345
COMMUNICATION
Huaqiang Zeng et al.
Highly selective one-pot synthesis of
H-bonded pentagon-shaped circular
aromatic pentamers
1359-7345(2011)47:19;1-C

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COMMUNICATION
Highly selective one-pot synthesis of H-bonded pentagon-shaped circular
aromatic pentamersw
Bo Qin,a Wei Qiang Ong,a Ruijuan Ye,a Zhiyun Du,b Xiuying Chen,c Yan Yan,a Kun Zhang,b
Haibin Suc and Huaqiang Zeng*a
Received 26th December 2010, Accepted 20th January 2011
DOI: 10.1039/c0cc05791f
One-pot, multi-molecular macrocyclization allows the highly
selective preparation of pentagon-shaped circular aromatic
pentamers mediated by an inward-pointing continuous hydrogen-
bonding network.
some unique applications in such as targeting biological
pentamers.1a
Compared to one-pot macrocyclization systems involving
symmetric monomers,3d,g,k our system is further complicated
by (i) the presence of both acid and amine groups on the same
unsymmetrical bifunctional monomers, forcing us to look
beyond the classical conditions for acid chloride generation,
(ii) the H-bonding enforced, more curved backbone that
either lowers down the reactivity of both acid and amine or
introduces the steric hindrance in the backbone, rendering the
typical amide coupling agents (DCC, EDC, HATU, etc.;
Table 1) totally ineffective, and (iii) the additional steric
hindrance originating from five sticking-out interior methyl
groups,1a increasing the energetic barrier for macrocyclization
and possibly impeding its efficient cyclization, especially when
combined with the remote steric hindrance between the
end residues.3g This likelihood can be manifested by the
Recently, we1a–d and others1e,f described a series of folding
molecules with their helically or circularly folded structures
enforced by internally placed continuous H-bonding networks.
A unique structural feature shared by these folding molecules
and recently elucidated by us1a–d lies in an intrinsic peculiarity,
needing five identical repeating units to form either a macro-
cycle1a,b or helical turn.1c,d In particular, the nearly planar
pentagon shape found in these macrocyclic pentamers1a,b is
very unusual among shape-persistent macrocycles,2 and bears
no precedent among either H-bonded macrocycles3 or synthetic
foldamers4 except for very recently reported fivefold-
symmetric Schiff base macrocycles.5a Inspired by the prominent
examples of one-pot, H-bonding assisted multi-molecular
macrocyclization reactions,3d,g,k we became interested in
investigating the possibility to efficiently and selectively produce
H-bond rigidified pentagon-shaped macrocyclic pentamers in
one-pot from their monomeric building blocks. Our interest in
this work is not only due to the recurring challenges associated
with the efficient one-pot preparation of shape-persistent
macrocycles, in particular, H-bonded ones that are currently
very limited in scope and applicable to only a few monomer
building blocks, but also due to their proven ability to (i) bind
neutral3h,r or organic cationic species,5b (ii) serve as an ion
transporter across cell membranes,5c (iii) stabilize DNA
G-quadruplex structures5d and (iv) very recently selectively
recognize alkali metal ions.1b Additionally, the fivefold
symmetry built into the aromatic backbone should promise
Table 1 Searching suitable conditionsa for one-pot preparation of
circular pentamer 1 from monomer 1a
Entry Coupling reagent Base
Solvent
Yieldb (%)
c
d
1
2
3
4
5
6
7
8
DCC
EDC
HATU
BOP
HATU/HOBt
TSTU
CDI
P(OPh)3
Ph3PCl2
Ph3PCl2
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
—
—
CH2Cl2
CH2Cl2
—
c
d
—
DIEA
DIEA
DIEA
DIEA
DIEA
DMF/CH2Cl2 (1 : 1) —d
DMF/CH2Cl2 (1 : 1) —d
DMF/CH2Cl2 (1 : 1) Trace
DMF/CH2Cl2 (1 : 1) Trace
DMF/CH2Cl2 (1 : 1) Trace
d
Pyridine NMP
—
—
—
—
5
c
d
d
d
9
—
—
—
—
—
CHCl3
THF
THF
Toluene
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH3CN
c
c
c
c
10
11
12
13
14
15
16
17
18
19
20
21
6
DIEA
DIEA
TEA
10
36
25
46
a Department of Chemistry, National University of Singapore,
3 Science Drive 3, Singapore. E-mail: chmzh@nus.edu.sg;
Fax: +65 6779-1691; Tel: +65 6516-2683
TEA
Pyridine CH2Cl2 or CH3CN Trace
NMM CH2Cl2 or CH3CN Trace
DMAP CH2Cl2
DMAP CH3CN
b Faculty of Chemical Engineering and Light Industry,
Guang Dong University of Technology, Guang Dong, 510006, China
c Division of Materials Science, Nanyang Technological University,
50 Nanyang Avenue, Singapore 639798. E-mail: HBSu@ntu.edu.sg;
Fax: +65 6790-9081; Tel: +65 6790-4346
6
Trace
a
Reaction conditions: 1a (0.2 mmol), coupling reagents (0.4 mmol),
b
base (0.6 mmol), solvent (2.0 ml), room temperature, 12 h. Isolated
c
d
w Electronic supplementary information (ESI) available: Synthetic
procedures and a full set of characterization data including 1H
NMR, 13C NMR, MS, H–D exchange and molecular modelling. See
DOI: 10.1039/c0cc05791f
yield by flash column chromatography. No base is used. No
product can be detected. NMP = N-methylpyrrolidone; NMM =
N-methylmorpholine.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5419–5421 5419

when the amount of POCl3 was reduced from two to one
equivalents (entry 1). The use of either more of POCl3 (entry 3)
or less of TEA (entry 4) lowered down the chemical yields
significantly when compared to entry 2. Other solvents
permitting one-pot preparation of 1 include acetone (12%),
THF (14%), CHCl3 (20%) and toluene (17%). No cyclization
product 1 can be generated when DMSO is used as the solvent
possibly due to its strong H-bonding ability that disrupts
the crescent conformation in the intermediate oligomers, a
prerequisite for the efficient backbone cyclization.
Fig. 1 (a) Top view of crystal structure of 1 with methoxy methyl
groups in CPK representations,1a showing the steric crowding
involving the interior methyl groups. (b) Illustration of one-pot
synthesis of pentamer 1 from its monomer precursor 1a.
The general utility of one-pot macrocyclization conditions
was demonstrated by the satisfactory preparation of other
circularly folded aromatic pentamers 2–7, sharing the same
aromatic backbone but differing by interior (R1) and exterior
(R2) side chains (Table 3). Pentamer 5 with a poor solubility of
o0.04 mM in CH3CN was produced in a comparably much
lower yield of 24%. Bulky groups such as isopropyl groups
and ethyl groups decreased the production yields of 4 and 6
considerably to 31% and 32%, respectively. In addition to
bulky ethyl groups in its interior, the poor yield of 7 via
one-pot condensation possibly can be accounted for by its
poor solubility (o0.25 mM) in CH3CN. The evidences that
(i) no circular tetramers or heptamers were observed during
the synthesis of 1–7 and (ii) 6% of hexamer was only obtained
during the preparation of 1 but not 2–7 suggest that the
pentameric macrocycle consisting of five identical repeating
units is energetically more favored over other four-, six- and
seven-residue macrocycles. Consistent with this experimental
considerable difficulty we encountered during the last step
end-to-end amide coupling reaction that transforms the acyclic
pentamer precursor into circular pentamer 1 by intramolecular
cyclization (Fig. 1).w1a
Peptide coupling reagents first came to our mind because of
the simplicity in procedures and mild conditions under which
amide bonds form from carboxylic acids and amines. The well
known coupling reagents of varying types were tested that,
in some cases (entries 1–4 in Table 1), failed to produce
detectable amounts of circular pentamer 1, and in other cases
(entries 5–7) yielded 1 in a trace amount. The initial screening
of phosphorus-based reagents, allowing the in situ generation
of acid chloride, turned out to be unsuccessful (entries 8–11).
The subsequent screening of phosphoryl trichloride, POCl3, in
either toluene (entry 12) or dichloromethane (CH2Cl2, entry
13) gave rise to a very encouraging yield of 5% and 6%,
respectively. Addition of three equivalent organic bases such
as diisopropylethylamine (DIEA, entry 14) increased the
chemical yield to 10% in CH2Cl2. Replacement of CH2Cl2
with CH3CN further increased the chemical yield of 1 to 36%
(entry 15). A further screening of various bases (entries 16–23)
in both CH2Cl2 and CH3CN led to the discovery of triethyl-
amine (TEA) as the powerful organic base that allowed
the efficient production of 1 under a high concentration of
100 mM in good and excellent yields of 25% and 46%,
respectively. A chemical yield of 46% is considered excellent
with respect to the stepwise construction of 1 that gives an
overall yield of B5% after months of dedicated effort.1a
The one-pot macrocyclization reaction is influenced signifi-
cantly by the amount of coupling reagent (POCl3) and base
(TEA) used (Table 2). While 1 : 2 : 3 ratio of 1a : POCl3 : TEA
(entry 2) produced 1 with 25% and 46% yields in dichloro-
methane and acetonitrile, respectively, only a trace amount
or a low yield of 5% for 1 can be obtained in the same solvents
Table 3 One-pot preparationa of circular aromatic pentamers 1–7
from their respective monomers 1a–7a, and the half-lives (h) of H–D
exchangeb of amide protons in 1–7
Half-lifeb/h
Aromatic pentamer R1
R2 Yieldc (%)
Me 46 (6)d
2.0 mM 0.2 mM
1
2
3
4
5
6
7
H
On-C8H17 Me 42
OMe
Oi-Pr
Me
6.3
8.7
1.49
4.28
5.74
7.50
2.40
0.22
12.4
Table 2 Effects of coupling reagent (POCl3) and base (TEA)a on
one-pot preparation of circular pentamer 1 from monomer 1a
e
Me 45
Me 31
Me 24
Et 32
Et 26
—
31.6
e
Yieldb (%)
—
5.2
H
OMe
Nf
CH2Cl2
CH3CN
Entry
POCl3/equiv.
TEA/equiv.
a
1
2
3
4
1.1
2.0
3.0
2.0
3.0
3.0
3.0
2.0
Trace
25
21
5
46
35
28
Reaction conditions: na (0.2 mmol), POCl3 (0.4 mmol), TEA
b
(0.6 mmol), CH3CN (2.0 ml), room temperature, 12 h. Half-lives
of H–D exchange data were measured at 2.0 mM or 0.2 mM in 5%
D2O/47.5% DMSO-d6/47.5% CDCl3 (v/v) at room temperature.
18
c
d
a
Isolated yield by flash column chromatography. Yield of the
e
Reaction conditions: 1a (0.2 mmol = 1 equiv.), POCl3, TEA,
b
CH3CN (2.0 ml), room temperature, 12 h. Isolated yield by flash
f
hexamer. Not soluble at 2.0 mM. No H–D exchange was observed
over three days.
column chromatography.
c
5420 Chem. Commun., 2011, 47, 5419–5421
This journal is The Royal Society of Chemistry 2011

observation, theoretical treatments of circularly folded macro-
cycles containing from 4 to 7 residues at the B3LYP/6-31G*
level show that the relative stability per repeating unit
increases in the order of tetramer 9 o heptamer 11 o hexamer
10 o pentamer 1 with or without explicit solvents.w
H. Q. Zeng, Org. Lett., 2009, 11, 1201; (d) Y. Yan, B. Qin,
C. L. Ren, X. Y. Chen, Y. K. Yip, R. J. Ye, D. W. Zhang,
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(e) J.-L. Hou, H.-P. Yi, X.-B. Sha, C. Li, Z.-Q. Wu, X.-K. Jian,
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The strength of these internally located intramolecular
H-bonds in 1–7 was quantitatively measured by amide
proton–deuterium (H–D) exchange experiments carried out
at 2.0 mM (Table 3).1a,c,d Since the intermolecular aggregation
in 1–7 is an unlikely event,w1a the half-lives of H–D exchange
should enable the direct correlation between the H–D half-life
and H-bond strength. From entry 6, it is evidenced that the
steric crowding involving bulkier ethoxy groups in 6 does not
impede the efficient H–D exchange, and amide protons can be
accessed well by D2O molecules. The determined half-life
values show that the H-bond strength among 1–7 highly likely
increases in the order of 6 o 1 o 5 o 2 o 3 o 4 o 7.
A further examination of these H–D exchange values shows
that the exteriorly located electron-donating alkoxy side
chains (i) cause a large variation in H-bond strength and
(ii) make intramolecular H-bonds in pentamers 2–4 and 7
stronger than those found in pentamers 1 and 6 that carry no
side chains. These findings agree well with the similar trends
seen for a series of H-bonding stabilized crescent-shaped
oligomers recently reported by us.1d Comparison of H–D
exchange data for amide protons in 1 (t1/2 = 1.49 h) and 6
(t1/2 = 0.22 h) suggests much weakened intramolecular
H-bonds in 6 relative to those in 1. Largely, this may be due
to the bulkier interior ethyl groups in 6 that cause a larger
backbone distortion and so weaken the H-bonds in 6 more
than those in 1. Computationally, the aromatic backbone in 6
is more distorted than that in 1.w
Our current investigation makes possible the highly selective
production of circularly folded aromatic pentamers via
H-bonding assisted one-pot macrocyclization reactions with
excellent yields of B50% under mild conditions within a day.
This greener protocol is far more cost-effective and time-
saving than the lengthy step-by-step process, giving circular
pentamers in about 5% yields after months of effort
as previously reported by us.1a,b The established one-pot
macrocyclization protocol should enable a facile access to
diverse pentamers for targeting biological pentamers,1a and
for fine-tuning their already demonstrated high ion-binding
affinity and selectivity,1b especially when coupled with the
demethylating methodologies for the selective removal of
interior methyl groups that are currently under investigation.
Financial support of this work by the NUS AcRF Tier 1
grants (R-143-000-375-112 and R-143-000-398-112 to H.Z.),
A*STAR BMRC research consortia (R-143-000-388-305 to
H.Z.) and A*STAR SERC grant (M47070020 to H.S.) is
acknowledged.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5419–5421 5421