Patterned recognition of amines and ammonium ions by a pyridine-based helical oligoamide host

Article abstract of DOI:10.1039/c2cc18182g

In response to binding to amine and ammonium guests of varying types, a pyridine-based folding oligomer displays fingerprint regions in its ¹H NMR spectra that allow for the easy identification and classification of the bound guests.

Full text of DOI:10.1039/c2cc18182g

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Professor Huaqiang Zeng, Department of Chemistry
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Patterned recognitions of amines and ammonium ions by a
pyridine-based helical oligoamide host
In response to binding to amine and ammonium guests of varying
types, a pyridine-based folding oligomer displays fingerprint
1
regions in its H NMR spectra that allow for the easy identification
and classification of the bound guests.
See Huaqiang Zeng et al.,
Chem. Commun., 2012, 48, 6343.
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COMMUNICATION
Patterned recognition of amines and ammonium ions by a pyridine-based
helical oligoamide hostw
a
a
a
a
a
a
Wei Qiang Ong, Huaiqing Zhao, Chang Sun, Ji’En Wu, Zicong Wong, Sam F. Y. Li,
b
a
Yunhan Hong and Huaqiang Zeng*
Received 31st December 2011, Accepted 20th March 2012
DOI: 10.1039/c2cc18182g
In response to binding to amine and ammonium guests of varying
types, a pyridine-based folding oligomer displays fingerprint
1
regions in its H NMR spectra that allow for the easy identifi-
cation and classification of the bound guests.
Selective recognition of amine and ammonium guests is a
considerably challenging issue particularly when given Nature’s
high selectivity towards ammonia sensing by using simple
1
organic or inorganic building blocks. For example, several
reported organic and coordination receptors capable of sensing
amines are unable to efficiently differentiate amines of varying
2
types, and amines from ammonium ions. Effective recognition
and differentiation of amines or ammonium ions is valuable not
only in environmental and industrial monitoring but also for
3
food quality control and clinical disease diagnosis. On the other
hand, aromatic foldamers of diverse structures have been elabo-
4
rated over the recent years. A wealth of functions derived from
5
these folding backbones have also been demonstrated. However,
Fig. 1 (a) NOE contacts in 1, illustrated by double headed pink
3
arrows. (b) Expanded 2D NOESY spectra of 1 (CDCl , 500 MHz, 300 K,
aromatic foldamers capable of recognizing functional groups as
simple as amines or ammonium cations appear to be very rare.
This communication demonstrates the functional utility of
pyridine-based foldamers such as tetramer 1 (Fig. 1a) as the host
for various amine and ammonium guests, exhibiting differential
binding patterns for easy detection and classification by using the
mixing time = 0.5 s), showing NOE contacts among amide protons b,
c and d and end-to-end NOE contacts among methyl protons e and
aromatic protons a. (c) Top and (d) side views of ab initio optimized
structure of 1 at the level of B3LYP/6-31G*.
1
corresponding H NMR fingerprint regions.
1
was synthesized in 7 steps using a step-by-step approach
We recently reported a series of pyridine-based foldamers
with their folded structures enforced by internally placed
with an overall yield of about 32% (Scheme S1, ESIw). The
crescent-shaped structure in 1 is evidenced by the experimentally
observed NOE contacts between amide protons c and b or d
and by the end-to-end NOE contacts between the end methoxy
protons e and protons a of the quinoline moiety (Fig. 1b). Its
helical geometry can be reliably established by the ab initio
calculation using density functional theory at the B3LYP/
5g,h,6
continuous H-bonding networks.
Results have shown
that this new set of backbone-rigidified pyridine-based folding
oligoamides requires Bfour repeating units to form a helical
˚
turn. The cavity enclosed by these pyridine foldamers is B2.5 A
in radius, and is decorated by both H-bond donors (amide
protons) and acceptors (pyridine N-atoms and ester O-atoms),
making these pyridine foldamers potentially suitable for accommo-
dating the amine or ammonium groups (Fig. 1a).
7
6-31G* level (Fig. 1c and d), and by the crystal structures
of analogous pyridine oligoamides that take up a helical
conformation starting from tetramers that contain bulkier
4
end groups such as an ester group. Such a helical geometry
in 1 is also in agreement with the above NOE results.
a
Department of Chemistry, National University of Singapore,
Singapore 117543. E-mail: chmzh@nus.edu.sg; Tel: +65-6516-2683
Department of Biological Sciences, National University of Singapore,
14 Science Drive 4, Singapore 117543
Using the soft electrospray ionization (ESI) method in a
high resolution format, the molecular ion peaks that represent
each of the host–guest complexes in a 1 : 1 ratio were obtained
with some representative aliphatic amine and ammonium
guests (Table 1), confirming the formation of the host–guest
complexes in a 1 : 1 ratio and their identities (Table 1).w
b
w Electronic supplementary information (ESI) available: Synthetic
1
13
C
procedures and a full set of characterization data including H/
NMR, HRMS, 2D NOESY, and molecular modelling. See DOI:
0.1039/c2cc18182g
1
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Chem. Commun., 2012, 48, 6343–6345 6343

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Table 1 List of amine and ammonium guests studied and the m/z of the
1ꢀguest] complexes determined using high-resolution mass spectroscopy
intramolecular hydrogen-bonding network in 1 and on its helical
structure. Selected 2D NOESY experiments on the 1 : 1 mixture
of 1 and octylamine or piperidine reveal the presence of strong
NOE contacts among amide protons of 1 that are indicative of
the persistence of its folded structure (Fig. S2 and S3, ESIw).
With the addition of increasing amounts of the amine guests
excluding tertiary and aromatic amines, the intensity or the height
of the NMR peaks for the amide protons progressively decreased,
and in most cases, the affected peaks also became broadened
(Fig. 2). Possibly, this occurs as a result of binding-induced
changes in the spin–spin relaxation time of amide protons that
interact with amine or ammonium protons in varying strengths,
altering both the intensity and shape of the NMR peaks. Except
for tertiary amines (Fig. 2d and Fig. S16–S18, ESIw) that contain
no protons and aromatic amines (Fig. 2e and Fig. S19, ESIw) that
are weak in basicity and thus do not elicit any change in NMR
signals, a few general patterns can be identified for primary and
secondary amines as well as ammonium cations.
[
Measured
m/z
a
S/N Guest
Molecular ion
Primary amine
+
1
2
3
4
Isopropylamine
1-Aminooctane
607.2440 [1ꢀC
677.3218 [1ꢀC
692.3311 [1ꢀC
696.2878 [1ꢀC
3
8
8
6
H
H
H
H
7
NH
17NH
16(NH
(NH
2
+ H]
+
2
+ H]
+ H]
+
1,8-Diaminooctane
0
2
)
2
+
2,2 -(Ethylenedioxy)-
bis(ethylamine)
Acyclic secondary amine
12
O
2
2
)
2
+ H]
+
5
6
7
Di-n-propylamine
Di-n-hexylamine
Di-n-octylamine
649.2891 [1ꢀ(C
733.3848 [1ꢀ(C
789.4458 [1ꢀ(C
3
6
8
7 2
H ) NH + H]
+
+
H
H
13
)
)
2
NH + H]
NH + H]
17
2
Cyclic secondary amine
+
8
9
1
Azetidine
Pyrrolidine
Piperidine
605.2265 [1ꢀC
619.2413 [1ꢀC
633.2578 [1ꢀC
3
H
4
H
5
H
6
NH + H]
NH + H]
+
8
+
0
10NH + H]
Tertiary amine
+
1
1
1
1
2
3
Triethylamine
Diisopropylethylamine 677.3224 [1ꢀC
649.2885 [1ꢀ(C
2
H
5
)
3
N + H]
+
+
8
H
H
19N + H]
13N + H]
1-Methylpiperidine
647.2752 [1ꢀC
Not detected
6
For primary amines, it was observed that amide proton b was
perturbed most as compared to the other two amide protons c
and d that remained very sharp throughout the titrations (Fig. 2a
and Fig. S6–S9, ESIw). It is highly likely that this is due to the
stronger binding of proton b than protons c and d with primary
amines. To assess this possibility, a series of possible structures
for the complex 1ꢀmethylamine were optimized at the level of
B3LYP/6-31G//6-311G+(2d,p). Expectedly, our calculations
show that the most stable complex formed between 1 and
methylamine indeed is the one where the amine sits in the cavity
Aromatic amine
Aniline
Ammonium salts
14
+
15
1-Octylammonium
perchlorate
677.3212 [1ꢀC
8
H
3
17NH ]
+
16
Di-n-octylammonium 789.4469 [1ꢀ(C
8
H
17
)
2
2
NH ]
perchlorate
a
HRMS obtained by using ESI method.
Titrating 1 at 2 mM in ‘‘normal’’ CDCl directly taken from
3
˚
of 1 with the amine N-atom forming a strong H-bond (1.84 A)
the bottle using various guests in varying equivalents does not
lead to noticeable changes in the chemical shift for all the three
amide protons b–d of 1 (Fig. 2 and Fig. S4–S21, ESIw), indicating
the minimal interference guest binding has on the high strength
with amide proton b in 1 (Fig. 3a), making proton b experience
1
the strongest influence of primary amines during the H NMR
titration experiments. The computational results also show that
placing methylamine on either side of 1 leads to energetically
almost equivalent 1ꢀmethylamine complexes with the ‘‘bottom’’
ꢁ
1
complex being 0.4 kcal mol more favored (Fig. 3a).
In the case of acyclic secondary amines, all the three amide
protons b–d become increasingly broadened roughly to an
equal extent (Fig. 2b and Fig. S10–S12, ESIw). Taking
dimethylamine as the test compound for ab initio calculations,
the most stable complex shown in Fig. 3b actually has the
methyl group and the amine N-atom from dimethylamine
˚
˚
forming weak intermolecular H-bonds of 2.52 A and 2.40 A
with the ester O-atom and the ester methyl proton from 1,
respectively, and no medium or strong H-bonds are found
Fig. 3 Top and side views of the computationally determined most
stable complex formed between 1 and (a) methylamine, (b) dimethyl-
amine, (c) piperidine and (d) methylammonium cation at the B3LYP/
6-31G//6-311G+(2d,p) level. Atoms involved in intermolecular H-bonds
of varying lengths are represented as small balls (gray = H, red = O and
blue = N). See Fig. 1a for the assignment of amide protons b–d.
1
Fig. 2 Representative H NMR (2 mM, CDCl
3
) fingerprint regions
for amide protons b–d and ester methyl protons e of 1 in the presence
of up to four equivalents of (a) 1-octylamine, (b) di-n-octylamine,
(c) piperidine, (d) triethylamine, (e) aniline, (f) 1-octylammonium
perchlorate and (g) di-n-octylammonium perchlorate.
6
344 Chem. Commun., 2012, 48, 6343–6345
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between dimethylamine and 1. The weakly interacting acyclic
secondary amines therefore exert unbiased influences over the
three amide protons b–d. Interestingly, a slightly different
trend was observed for cyclic secondary amines where proton
c becomes the most broadened and starts disappearing in the
presence of four equivalents of amine guests while the NMR
peaks for protons b and d are altered by both acyclic and
cyclic secondary amines almost to equal extents (Fig. 2c and
Fig. S13–S15, ESIw). Computationally, the cyclic secondary
amine (i.e. piperidine, Fig. 3c) interacts almost perpendicularly
with 1. The amine NH proton in piperidine forms a strong
Financial support to H.Z. by National Research Foundation
Competitive Research Programme Grant (R-154-000-529-281),
NUS AcRF Tier 1 grant (R-143-000-419-646) and Environment
and Water Industry Development Council and Economic
Development Board (SPORE, COY-15-EWI-RCFSA/N197-1)
is gratefully acknowledged.
Notes and references
1
S. Khademi, J. O’Connell, III, J. Remis, Y. Robles-Colmenares,
L. J. W. Miercke and R. M. Stroud, Science, 2004, 305, 1587.
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2
˚
H-bond of 2.14 A with the ester O-atom of 1 and a weak
˚
H-bond of 2.88 A with the pyridine N-atom of 1. On average,
2009, 3702; (c) C.-F. Chow, H.-K. Kong, S.-W. Leung, B. K. W.
Chiu, C.-K. Koo, E. N. Y. Lei, M. H. W. Lam, W.-T. Wong and
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M. A. O. Lourenc¸ o, M. J. F. Calvete, A. R. Abreu, M. T. S. Rosado,
the protons from the ring atoms of piperidine are closer to
˚
˚
amide protons b and c (B2.6 A) than to proton d (>3.3 A).
These electrostatic interactions among the protons may modify
the electron density around protons b and c, possibly resulting
H. D. Burrows and M. M. Pereira, Inorg. Chem., 2011, 50, 7916;
(e) C. G. Sun, Q. Lin and N. Y. Fu, Chin. Chem. Lett., 2012, 23, 217.
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T. Takase, W. L. Hinze, M. Butsugan and S. Igarashi, Analyst,
1
in the observed titration pattern of H NMR peaks where the
3
4
amide protons b and c are affected more than proton d by cyclic
secondary amines (Fig. 2c).
2
010, 135, 1417.
For reviews on foldamers, see: (a) S. H. Gellman, Acc. Chem. Res.,
998, 31, 173; (b) I. Huc, Eur. J. Org. Chem., 2004, 17; (c) B. Gong, Acc.
Lastly, the addition of ammonium ions into 1 leads to line
1
broadenings and a rapid decrease in the size of H NMR peaks
1
for all the three amide protons (Fig. 2f and g and Fig. S20
and S21, ESIw). Unseen for primary, secondary and tertiary
amines, ammonium ions additionally exhibit a dramatic influ-
ence over the size and shape of the ester methyl peaks (Fig. 2f
and g and Fig. S20 and S21, ESIw).
Chem. Res., 2008, 41, 1376; (d) I. Saraogi and A. D. Hamilton, Chem.
Soc. Rev., 2009, 38, 1726; (e) X. Zhao and Z. T. Li, Chem. Commun.,
2010, 46, 1601. For pioneering works on using H-bonds to rigidify
aromatic backbones, see: (f) Y. Hamuro, S. J. Geib and A. D.
Hamilton, Angew. Chem., Int. Ed., 1994, 33, 446; (g) V. Berl, I. Huc,
R. G. Khoury, M. J. Krische and J. M. Lehn, Nature, 2000, 407, 720;
(h) J. Zhu, R. D. Parra, H. Q. Zeng, E. Skrzypczak-Jankun, X. C. Zeng
It is known that ‘‘normal’’ CDCl slowly decomposes upon
3
and B. Gong, J. Am. Chem. Soc., 2000, 122, 4219; (i) V. Berl, I. Huc,
R. Khoury and J.-M. Lehn, Chem.–Eur. J., 2001, 7, 2798.
prolonged storage to produce trace amounts of DCl that may
protonate the amines or 1 to varying extents. To probe the
1
possible effect of DCl, the above H NMR-based analyses were
5 For cation-binding by pentamers, see: (a) B. Qin, C. L. Ren, R. J. Ye,
C. Sun, K. Chiad, X. Y. Chen, Z. Li, F. Xue, H. B. Su, G. A. Chass and
H. Q. Zeng, J. Am. Chem. Soc., 2010, 132, 9564; (b) C. L. Ren,
V. Maurizot, H. Q. Zhao, J. Shen, F. Zhou, W. Q. Ong, Z. Y. Du,
K. Zhang, H. B. Su and H. Q. Zeng, J. Am. Chem. Soc., 2011, 133, 13930.
For binding of organic cationic species, see: (c) A. R. Sanford, L. Yuan,
W. Feng, K. Yamato, R. A. Flowers and B. Gong, Chem. Commun.,
3
re-carried out in ‘‘neutralized’’ CDCl filtered with basic alumina.
For all the different types of amines studied, the fingerprint
regions identical to those shown in Fig. 2a–e were obtained
(Fig. S5a–e, ESIw). For primary ammonium salts, the broadening
2005, 4720. For water binding, see: (d) R. M. Meudtner and S. Hecht,
and disappearance of both amide and ester peaks take place with
Angew. Chem., Int. Ed., 2008, 47, 4926; (e) J.-M. Suk, V. R. Naidu,
X. Liu, M. S. Lah and K.-S. Jeong, J. Am. Chem. Soc., 2011, 133, 13938.
For anion recognition, see: (f) J. Garric, J.-M. Leger and I. Huc, Angew.
Chem., Int. Ed., 2005, 44, 1954; (g) W. Q. Ong, H. Q. Zhao, X. Fang,
S. Woen, F. Zhou, W. L. Yap, H. B. Su, S. F. Y. Li and H. Q. Zeng, Org.
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M. N. Hii, S. F. Y. Li, H. B. Su and H. Q. Zeng, Org. Biomol. Chem.,
addition of 10, rather than 4, equivalents of ammonium salts
8
(Fig. S5f, ESIw). Interestingly, addition of up to 12 equivalents
of secondary ammonium ions only leads to a slight decrease in
peak height with no observation of line broadening and dis-
appearance, suggesting that the combined use of ‘‘normal’ and
2
012, 10, 1172. For DNA G-quadruplex stabilizers, see: (i) P. S. Shirude,
‘
‘neutralized’’ CDCl
3
allows for a further differentiation between
E. R. Gillies, S. Ladame, F. Godde, K. Shin-Ya, I. Huc and
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7 (a) B. Qin, X. Y. Chen, X. Fang, Y. Y. Shu, Y. K. Yip, Y. Yan, S. Y.
Pan, W. Q. Ong, C. L. Ren, H. B. Su and H. Q. Zeng, Org. Lett., 2008,
primary and secondary ammonium ions.
1
While tetramer 1 displays up to six differential H NMR-based
patterns toward amines and ammonium ions (Fig. 2 and
Fig. S5, ESIw), similar analyses on shorter oligomers show
that both dimer 1b (Fig. S22, ESIw) and trimer 1d (Fig. S23,
ESIw) exhibit much less degenerated patterns. It is worthy to
note that primary and secondary ammonium ions also can be
confidently discriminated by both 1b and 1d. By combining
with 1, 1b further allows for the unambiguous differentiation
of primary from secondary amines.
6
10, 5127; (b) Y. Yan, B. Qin, Y. Y. Shu, X. Y. Chen, Y. K. Yip, D. W.
Zhang, H. B. Su and H. Q. Zeng, Org. Lett., 2009, 11, 1201; (c) Y. Yan,
B. Qin, C. L. Ren, X. Y. Chen, Y. K. Yip, R. J. Ye, D. W. Zhang,
H. B. Su and H. Q. Zeng, J. Am. Chem. Soc., 2010, 132, 5869.
8 In the computed structure that has a very high binding energy of
30.55 kcal mol , the primary ammonium ion is slightly nearer to the
ester side, forming strong H-bonds with 1 (1.79, 2.02 and 2.37 A,
Fig. 3d). In this case, our surmise is that the ammonium ion possibly
alters the NMR signals via chemical exchange involving ammonium
protons and protons from amide and ester groups of 1 by virtue of
forming a highly stable complex. The presence of DCl apparently
accelerates the exchange process, leading to much faster line broadening
1
The above observations from the H NMR experiments illustrate
ꢁ1
that varying amine and ammonium guests each displays a differ-
1
ential binding mode with host 1. By comparing H NMR finger-
˚
print regions involving the amide protons and the ester methyl
group in 1 and aided further by dimer 1b and trimer 1d, one could
possibly distinguish among various types of amines, between
ammonium ions, and between amine and ammonium guests.
3
and disappearance as seen in Fig. 2f when ‘‘normal’’ CDCl was used.
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6343–6345 6345