One-Pot Synthesis of Strained Macrocyclic Pyridone Hexamers and Their High Selectivity toward Cu2+ Recognition

Article abstract of DOI:10.1021/acs.orglett.5b02780

The removal of Cu²⁺ ions is relevant to environmental pollution control and neurodegenerative disease treatment. A novel family of strained macrocyclic pyridone hexamers, which exhibit highly selective recognition of Cu²⁺ ions and re

Full text of DOI:10.1021/acs.orglett.5b02780

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of Strained Macrocyclic Pyridone Hexamers and
2+
Their High Selectivity toward Cu Recognition
Changliang Ren, Jie Shen, and Huaqiang Zeng*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669
*
S Supporting Information
ABSTRACT: The removal of Cu2+ ions is relevant to environmental
pollution control and neurodegenerative disease treatment. A novel family
of strained macrocyclic pyridone hexamers, which exhibit highly selective
2
+
recognition of Cu ions and reduce copper content in artificial seawater by
9
7% at a very low [host]:[CuCl ] molar ratio of 2:1, is documented.
2
5
g
lthough copper is the third most abundant trace element
suggests the likely production of pyridone- or fluorobenzene -
based strained macrocyclic hexamers. This may lead to a new
class of ion-binding macrocyclic hexamers distinctively different
from the corresponding pentamers (Figure 1c) with an ability
A
after iron and zinc in the body with a typical blood
1a
concentration of up to 0.15 ppm and plays an important role
2
+
in many biological processes, excess intake of Cu ions might
1b
to recognize larger cations such as Cs , Ba and Tl+
preferentially over many other smaller metal ions. In this
communication, we show that BOP and only BOP can be used
to produce the strained macrocyclic pyridone hexamers via one-
pot macrocyclization and that the produced hexamers
specifically bind and efficiently remove Cu2+ ions from artificial
seawater. This constitutes the first report on the highly selective
+
2+
lead to liver damage and serious neurodegenerative diseases
1c
4e
including Wilson’s disease, Alzheimer’s disease and Parkin-
son’s disease. As a result of intensive industrial mining and
2
+
agricultural activities, hazardous Cu ions exceeding the
USEPA‘s recommended maximum contaminant concentration
of 1.3 ppm are often found in industrial wastewater, drinking
water or groundwater. Thus, highly selective removal of toxic
2
+
2+
6a
metal ions including Cu ions continuously presents a
recognition and removal of Cu ions by either aliphatic or
2
3
,6b
considerable challenge to the field.
aromatic
foldamers of great diversity and varying functions.
On the other hand, substantial progress has been made over
the years to develop H-bonded macrocyclic foldamers with3
aromatic backbones rigidified by intramolecular H-bonds.
Our initial attempt to use Al(Me)3 failed to produce
macrocyclic pyridone hexamers from their corresponding
monomers (Figure 1a). Starting from the dimers, however,
strained macrocyclic hexamers 1 and 2 both could be produced
with satisfactory yields of 31−56% by using BOP, but not
Al(Me) or POCl , in a mixed solvent containing anhydrous
dichloromethane (CH Cl ) and DMF (2:1, v/v). After many
unsuccessful attempts, the X-ray-quality single crystals were
eventually obtained by slowly diffusing 1 mL of acetonitrile into
mL of 2-containing DMSO solution for a few weeks at room
temperature. The determined structure reveals an expected
folding of 2 into a circular arrangement stabilized by a
continuous intramolecular H-bonding network (Figure 1b).
The folding convergently orients the six electron-rich carbonyl
O atoms inward to enclose a noncollapsible ion-binding cavity
of ∼4.6 Å in diameter exclusive of the atomic volumes of O
atoms. An intrinsic propensity for the monomeric pyridone
units to produce a planar macrocyclic pentagonal structure
Figure 1c) possibly explains why the macrocyclic hexameric
backbone is slightly distorted (Figure 1b) and energetically less
stable by 0.50 kcal/mol per building block than the pentamer.
3
Aside from their great structural diversity, many interesting
functions have also been demonstrated, including G-quad-
4
a
4b
4c−f
ruplext stabilization, ion transportation and recognition,
4
g,h
4i
3
3
solvent gelation,
reaction catalysis and liquid-crystallize
4
j
2
2
materials. In particular, a powerful H-bonding-assisted one-
pot macrocyclization strategy recently advanced by Gong and
3a
3
b,c
others
makes many such H-bonded macrocycles readily
1
available, greatly facilitating their further functional study and
applications.
Along the same line, our efforts toward developing “greener”
one-pot macrocyclization protocols led to discovery of POCl3
and BOP as the efficient macrocyclization reagents for rapid
production of H-bonded macrocyclic pentamers derived from
5
a−d
5e
alkoxybenzene
and pyridone units. In these protocols,
energetically more stable pentamers always are produced as the
dominant products with the corresponding energetically less
stable macrocyclic hexamers remaining either undetectable or
as a minor product. Our recent investigation, however,
5
f
(
identified trimethylaluminum [Al(Me) ] as a surprising macro-
3
cyclization reagent that selectively produces strained macro-
cyclic alkoxybenzene-based hexamers, rather than the more
Received: September 24, 2015
5f
stable pentamers, as the major product. This unusual finding
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02780
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Extraction Efficiencies of Cu2+ (0.72 Å) and Cs+
(
1.67 Å) Ions in Their Nitrate Salts by Host 1 at 25 °C at pH
.4 under Various Conditions As Determined by Inductively
Coupled Plasma Mass Spectrometry (ICP-MS)
6
2
+
[
1]/[Cu ]
metal
ions
concn
(mM)
entry
2
5
10
33
20
50 100
a
2+
1
Cu
0.01
13
23
50
90
7
93
14
d
a
+
2
Cs
b
2+
3
Cu
0.1
65
82
11
90
89
20
92
19
96
40
94
31
d
b
+
4
Cs
4.6
70
3.3
nonextractable ions
d
d
c
2+
5
Cu
d
d
c
+
6
Cs
8.9
d
d
a
+
+
2+
+
+
+
Rb (1.52 Å), Tl (1.50 Å), Ba (1.35 Å), K (1.38 Å), Ag (1.15 Å), Na
1.02 Å), Ca2 (1.00 Å), Cd (0.95 Å), Pb (0.86 Å), Mn (0.83 Å), Li+
+
2+
2+
2+
(
(
0.76 Å), Co2+ (0.75 Å), Zn (0.74 Å), Mg (0.72 Å), Ni (0.69 Å), Fe
2+ 2+ 2+ 3+
3+
(
0.645 Å), Cr3+ (0.62 Å), Al (0.535 Å)
a
Extractions carried out in a biphasic system using equal volumes of
H O containing 0.01 mM of individual metal ions and CHCl
2
3
b
containing 0.02−1.00 mM of1. Extractions carried out using H O
2
2+
+
containing 0.1 mM of Cu or Cs ions and CHCl containing 0.2−2.0
3
c
mM of 1. Extractions carried out using H O containing 20 metal ions,
2
d
each at 0.1 mM, and CHCl containing 0.2−2.0 mM of 1. Not
determined. Ions are 6-coordinate unless indicated.
3
9
with extraction efficiencies of 65%, 82%, 89%, and 95% at 1/
2+
Figure 1. (a) BOP-mediated H-bonding-assisted one-pot synthesis of
strained macrocyclic hexamers 1 and 2 under mild conditions and top
and side views of (b) the crystal structure of 2 deviating from planarity
and (c) the computationally determined planar structure of a pyridone
pentamer. In (b), the five tert-butyl groups were replaced by yellow
atoms for clarity of view, and the red balls refer to the carbonyl O
atoms. Computationally, hexamer is less stable than pentamer by 0.70
kcal/mol per building block at the B3LYP/6-31G(d,p) level in the gas
phase. For an ORTEP view of 2 at the 70% probability level, see
Figure S2.
Cu molar ratios of 2, 5, 10, and 20, respectively.
The selective recognition of Cu2+ and Cs+ ions in the
presence of other metal ions by 1 was then evaluated using an
aqueous solution containing a total of 20 metal ions including
2+
+
Cu and Cs . In this experiment, the concentration of each
metal ion is set to be 0.1 mM, and that of 1 is varied from 0.2 to
2
.0 mM. As summarized in entries 5 and 6 of Table 1, host 1, at
2+
2+
a low 1/Cu molar ratio of 5, is able to extract Cu by 90%
with Cs poorly extracted to 8.9%, and extractions of all the
+
other 18 metal ions remain undetectable. Comparison of the
extraction data of entry 3 with those of entry 5 confirms that
2+
Incorporation of one more building block, however, does
enlarge the cavity diameter from 2.8 Å as found in the pentamer
Cu removal by 1 is not adversely impacted by the 18 metal
+
2+
2+
2+
2+
2+
3+
3+
ions including Ag , Cd , Mn , Co , Zn , Ni , Fe , and Cr
(
Figure 1c) to 4.6 Å as in the hexamer (Figure 1b), thereby
ions. For comparison, at [1d] = 0.54 mM and [individual metal
ion] = 0.1 mM, the analogous dimer 1d (Scheme S1) displays a
suggesting differential ion-binding profiles between them.
The ion-binding profile of more soluble hexamer 1 toward 20
different metal ions (0.54−1.67 Å in radius) was evaluated by a
2+
moderate extraction of Hg ions (52%), very low extractions
+
+
toward K (10%) and Ag (18%), and no extraction of all the
4e
2+
biphasic water−chloroform extraction system. In a typical
other 17 metal ions including Cu ions.
experimental setup, the concentration of each individual metal
The above-demonstrated high selectivity of 1 in recognizing
and removing Cu2+ ions in the presence of many other
interfering ions led us to further explore its possible application
ion in H O is set constant at 0.01 mM or 0.1 mM, while that of
2
1
in CHCl is varied from 0.02 to 1.0 mM or from 0.2 to 2.0
3
2
+
+
+
mM. After the biphasic water−CHCl solution was shaken for
2
in the selective removal of Cu ions in the presence of Na , K ,
3
2+
2+
4 h at 25 °C, ion extractions from aqueous phase to
Ca , and Mg ions commonly found in groundwater (Figure
chloroform layer were measured by using inductively coupled
plasma mass spectrometry (ICP-MS). Averaging the data over
six runs gave the final extraction data with relative errors of
2). In this regard, artificial groundwater containing 10 ppm
2
+
+
+
(0.16 mM) Cu , 100 ppm of Na (4.3 mM), 5 ppm K (0.13
2+
2+
mM), 60 ppm of Ca (1.5 mM), 25 ppm Mg (1.0 mM), and
−
≤
1.5%. Among all the 20 tested metal ions, 1 selectively
349 ppm of Cl ions at pH 7.4 was prepared. It was found that
2+
2+
extracts only Cu ions with extraction efficiencies reaching
efficient removal of 89% Cu ions can be achieved using a low
2
+
9
3% when the molar ratio of [1]/[Cu ] is varied from 2 to 100
[1]:[CuCl ] molar ratio of 5:1, reducing copper content from
2
(
entry 1, Table 1). Under these conditions, extractions of 7%
10 ppm down to 1 ppm that meets the drinking water standard
of 1.3 ppm for Cu ions set by USEPA (Figure 2). By replacing
+
2+
and 14% Cs ions were also observed (entry 2, Table 1), while
the other 18 metal ions remain nonextractable at a high [1]/
chloride with nitrate salts, a much smaller [1]/[Cu(NO ) ]
molar ratio of 2:1 is sufficient to effect a 91% reduction of Cu
3
2
2
+
[
metal ion] molar ratio of 100 within the instrument’s
sensitivity range. When the concentration of metal ions is
increased from 0.01 to 0.1 mM (entry 3, Table 1), the
extraction ability of 1 toward Cu ions dramatically increases
ions (Figure S3).
Surprisingly, at the same [1]/[CuCl ] molar ratio of 5:1 but
in the absence of the other metal ions in solution, host 1 was
2
2
+
B
DOI: 10.1021/acs.orglett.5b02780
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
solution increases from 7.5% to 33%, 59%, 74% and 81% when
the solution pH increases from 0 to 2, 4, 6/ and 8, respectively.
+
The existence of a monovalent complex [1·Cu−H] and a
pH-dependent extraction of Cu2+ ions suggest the amide
groups in 1 to be significantly more acidic than they should be.
This increased acidity may result from a twisted hexameric
backbone enforced by a macrocyclic ring constraint. To verify
this hypothesis and to sensitively quantify the acidity of amide
7b
H atoms, we performed amide hydrogen−deuterium (H−D)
exchange experiments that were initiated by adding 20 μL of
D O into 600 μL of 5 mM sample in deuterated solvents
2
Figure 2. Cu2+ removal by 1 at varying [1]/[CuCl ] molar ratios from
artificial groundwater or seawater containing 10 ppm of Cu ions.
2
(
CDCl /DMSO-d , 2:1, v:v).
In addition to 1, pentamer 3 with a planar structure (Figure
c) and dimer 4 containing no H bonds at all (Scheme S1)
2+
3 6
1
were also subjected to comparative H−D exchange analyses.
Compared to the amide proton of 4 that resonates at 9.98 ppm,
a substantial downfield shift in chemical shift to 12.21 and
only capable of removing 64% instead of 89% of Cu2+ ions
when artificial groundwater was used. This suggests that 1-
2
+
1
3.54 ppm for the amide protons in 1 and 3, respectively,
mediated extraction of Cu ions be substantially promoted by
the noncopper ions possibly via a “salting out” effect. This
likelihood prompted us to study the performance of 1 in copper
removal from artificial seawater, which was prepared to contain
provides a clear indication of the involvement of the amide
protons from 1 and 3 in forming intramolecular H bonds,
which generally makes the H-bonded protons more difficult for
7b
2+
replacement by deuterium atoms from D O molecules.
1
0 ppm of Cu ions (0.16 mM CuCl ), 600 mM NaCl, 20 mM
2
2
Consistent with this expectation, the five equivalent amide
protons in 3 show an exceptionally high stability with a half-life
of 102.4 h, which is far much larger than the half-life value of
KCl, 20 mM CaCl , and 60 mM MgCl at pH 7.5. Remarkably,
2
2
use of stoichiometric amount of 1 results in a dramatic
reduction of CuCl from the artificial seawater by 88%, a value
2
0
.87 h for 4 that contains no H bonds (Figures S5 and S6). In
that compares very favorably with a mere 67% removal of
sharp contrast, strained hexamer 1 undergoes an even faster
H−D exchange than 4 by 0.21 h (Figure S5). This abnormal
finding, however, is in good accord with our above hypothesis,
speculating that a twisted conformation in 1 substantially
increases the acidity of the amide protons and its exchange rate
with deuterium atoms. This increased acidity works with the
surrounding six cation-stabilizing carbonyl O atoms to possibly
CuCl from the artificial groundwater at the same molar ratio
2
(
Figure 2). At a [1]/[CuCl ] molar ratio of ≥10, removal of
2
CuCl from the artificial seawater plateaus at 99%. As of now,
only a few ligands highly effective in removing Cu ions from a
2
2
+
solution as salty as seawater have been documented in the
2
literature. By switching the liquid−liquid extraction process to
a liquid−solid extraction method and using poorly soluble 2 in
2
+
its powder form, a [2]/[CuCl ] molar ratio of 10:1 results in a
allow deprotonation of 1 to take place upon binding of a Cu
2
2
+
very significant reduction of Cu ions by 98% from 10 ppm
down to 0.2 ppm in artificial seawater.
ion.
The structures of anionic complex [1·(CuCl
containing deprotonated anionic 1 (Figures S7a and S8) and
neutral complex [1·(CuCl )(H O)] containing neutral 1
(Figures S7c and S9) were computationally optimized at the
B3LYP/6-31G(d,p) level in chloroform. Due to possible
disturbances the crystal packing might have on the con-
formation of neutral 1, its computationally optimized structure,
rather than its crystal structure (Figure 1b), was used for
comparison (Figure S7a). The optimized structures show that
)(H
O)]‑
2
2
To elucidate possible structural origins accounting for this
unusual selectivity, matrix-assisted laser desorption/ionization
time-of-flight (MALDI-TOF) mass spectrometry was employed
to analyze the metal complexes formed in the chloroform layer.
A major peak at 1550.56 Da was identified and its identity is
unambiguously confirmed to be a monocationic complex [1·
2
2
7c
+
Cu] with one H atom lost from host 1 and with a molecular
formula of C H O N Cu via an excellent matching
8
4
119 12 12
between the experimental isotope distribution pattern and
that of the computer-simulated one (Figure S4). The existence
the cyclic hexameric backbone in anionic complex [1·
−
(CuCl
)(H
O)] (Figure S7b) is not more distorted than
2
2
+
of a monovalent cationic complex [1·Cu−H] points to a
that in neutral 1 (Figure S7a). Both of them, however, are
significantly less distorted than that of 1 in neutral complex [1·
2
+
plausible event where, upon binding of a Cu ion by 1, one of
the six amide protons in 1 was deprotonated to produce the
negatively charged 1, which subsequently interacts with the
(CuCl )(H O)] (Figure S7c). These differential distortions
2 2
between anionic and neutral complexes suggest that the cyclic
backbone of 1 be predisposed for forming an anionic complex,
rather than a neutral complex that comes with a considerable
entropic penalty. Enthalpywise, there might be more energy
gains in forming an anionic complex than a neutral complex
given that the Cu2+ ion appears to sit comfortably in the
binding pocket formed by two O atoms and one negatively
charged N atom in an anionic complex, and is stabilized by
three strong coordination bonds of ∼2.0 Å (Figure S7b).
EPR study of the solid sample prepared by mixing 1 and
CuCl ·2H O in a 10:1 ratio reveals a four line EPR spectrum
2
+
positively charged Cu ion. This scenario seems to be
7a
2+
consistent with our recent finding, demonstrating that Cu
ions promote metal ion-mediated deprotonation of phenolic
hydroxyl groups to the largest extent in aqueous solution
among 21 metal ions studied.
2+
The above hypothesis, which emphasizes the use of a Cu -
promoted deprotonation mechanism to account for a highly
2
+
specific and high-affinity recognition of Cu ions by the host,
2
+
suggests extraction of Cu ions by 1 to be pH dependent. The
data obtained from extractions carried out at different pH
indeed fit very nicely into the theory-derived pH-dependent
2
2
2+
for Cu (I = 3/2) with g = 2.27 being larger than g = 2.05
/
/
⊥
behavior. In more details, at a [1]/[CuCl ] molar ratio of 5:1,
the extraction efficiency of Cu ions from a plain water
(Figure S10), suggesting that the unpaired electron in the
2
2
+
2
2
copper center resides in the d
orbital and that the copper
x −y
C
DOI: 10.1021/acs.orglett.5b02780
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
center adopts a square-pyramidal geometry with elongation
115, 7398. (e) Li, F.; Gan, Q.; Xue, L.; Wang, Z.-M.; Jiang, H.
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(4) (a) Shirude, P. S.; Gillies, E. R.; Ladame, S.; Godde, F.; Shin-Ya,
along the z axis as similarly seen in the computationally
−
determined anionic complex [1·(CuCl )(H O)] but not the
2
2
K.; Huc, I.; Balasubramanian, S. J. Am. Chem. Soc. 2007, 129, 11890.
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2
2
(b) Helsel, A. J.; Brown, A. L.; Yamato, K.; Feng, W.; Yuan, L. H.;
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In summary, we have developed a novel class of circularly
folded macrocyclic pyridone hexamers with a noncollapsible
ion-binding cavity and demonstrated their excellent ability to
selectively recognize and efficiently remove copper ions in the
presence of many interfering transition metal ions and from
artificial seawater. This high selectivity may arise from a
distortion-enhanced acidity of the amide protons of the host.
Moreover, the copper removal capacity of these hexameric
hosts could be dramatically enhanced by other noncopper
metal ions, resulting in a highly efficient removal of Cu2+ ions
by 97% from artificial seawater at a [host]/[CuCl ] molar ratio
2
of 2:1. This outstanding selectivity in high-capacity recognition
of Cu2 ions may offer good opportunities in the making of
specialty high-performance nanofiltration membranes or solid
supports for water treatment and might also find uses as
innovative copper-chelating medicines, applicable in particular
2
323. (j) Li, X.; Li, B.; Chen, L.; Hu, J.; Wen, C.; Zheng, Q.; Wu, L.;
+
Zeng, H. Q.; Gong, B.; Yuan, L. Angew. Chem., Int. Ed. 2015, 54,
11147.
(5) (a) Qin, B.; Ong, W. Q.; Ye, R. J.; Du, Z. Y.; Chen, X. Y.; Yan, Y.;
Zhang, K.; Su, H. B.; Zeng, H. Q. Chem. Commun. 2011, 47, 5419.
1a,c
(b) Qin, B.; Shen, S.; Sun, C.; Du, Z. Y.; Zhang, K.; Zeng, H. Q. Chem.
to the treatment of Wilson’s disease.
-
Asian J. 2011, 6, 3298. (c) Qin, B.; Sun, C.; Liu, Y.; Shen, J.; Ye, R. J.;
Zhu, J.; Duan, X.-F.; Zeng, H. Q. Org. Lett. 2011, 13, 2270. (d) Liu, Y.;
Qin, B.; Zeng, H. Q. Sci. China: Chem. 2012, 55, 55. (e) Du, Z. Y.;
Ren, C. L.; Ye, R. J.; Shen, J.; Lu, Y. J.; Wang, J.; Zeng, H. Q. Chem.
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02780.
(
g) Ren, C. L.; Zhou, F.; Qin, B.; Ye, R. J.; Shen, S.; Su, H. B.; Zeng,
H. Q. Angew. Chem., Int. Ed. 2011, 50, 10612.
6) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Zhang, D.-
Synthetic procedures and characterization data including
(
1
13
H NMR, C NMR, MS, ICP-MS, MALDI-TOF, H/D
W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Chem. Rev. 2012, 112, 5271.
(7) (a) Liu, J. Q.; Sun, C.; Ma, W. L.; Lu, Y.-J.; Yu, L.; Zhang, K.;
Zeng, H. Q. RSC Adv. 2014, 4, 54469. (b) Yan, Y.; Qin, B.; Ren, C. L.;
Chen, X. Y.; Yip, Y. K.; Ye, R. J.; Zhang, D. W.; Su, H. B.; Zeng, H. Q.
J. Am. Chem. Soc. 2010, 132, 5869. (c) Ong, W. Q.; Zhao, H. Q.; Du,
Z. Y.; Yeh, J. Z. Y.; Ren, C. L.; Tan, L. Z. W.; Zhang, K.; Zeng, H. Q.
Chem. Commun. 2011, 47, 6416.
exchange experiment, crystal data, molecular modeling,
EPR, and UV−vis (PDF)
X-ray data for compound 2 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hqzeng@ibn.a-star.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for H.Z. by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency
for Science, Technology and Research, Singapore) is acknowl-
edged.
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