Differential Recognition of Various Anions Utilizing Aromatic C?H Hydrogen Bonding

Article abstract of DOI:10.1002/bkcs.11646

Dihydrogen phosphate selective anion receptors 1, 2, and 3 that utilize amide N?H, and C?H for anion recognition have been designed and synthesized. For 1 and 2, aromatic C?H hydrogen bonding element is present on naphthyl rings (H_a). In additi

Full text of DOI:10.1002/bkcs.11646

Article
DOI: 10.1002/bkcs.11646
BULLETIN OF THE
E. Han et al.
KOREAN CHEMICAL SOCIETY
Differential Recognition of Various Anions Utilizing Aromatic C H
Hydrogen Bonding
†,
Eunbi Han,† Dae Hyup Sohn,† Seung Joo Cho,‡, and Jongmin Kang
*
*
†Department of Chemistry, Sejong University, Seoul 143-747, South Korea.
*E-mail: kangjm@sejong.ac.kr
‡Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, Gwangju
61452, South Korea. *E-mail: chosj@chosun.ac.kr
Received November 1, 2018, Accepted November 22, 2018
Dihydrogen phosphate selective anion receptors 1, 2, and 3 that utilize amide N H, and C H for anion
recognition have been designed and synthesized. For 1 and 2, aromatic C H hydrogen bonding element
is present on naphthyl rings (Ha). In addition, for receptor 1, this aromatic hydrogen bonding element is
further polarized by the nitro groups, which would enhance the hydrogen bonding ability. Partial charges
derived from Natural Population Analysis also supported the existence of this polarization. That is, posi-
tive partial charge of Ha in receptor 1 was more positive than that in receptor 2. As expected from the par-
tial charge values, receptor 1 consistently showed highest affinity among three receptors, followed by
receptor 2 regardless of the anions tested in this study. Therefore, we have shown that affinity modulation
of a receptor was possible by changing the nature of the aromatic C H hydrogen. In addition, the recep-
tors showed selectivity toward dihydrogen phosphate among various anions including acetate and
chloride.
Keywords: Dihydrogen phosphate selective anion receptor, C H hydrogen bonds, Polarization of
C H bond
Introduction
which induce higher polarity of C-Ha bonds compared to
receptor 2. Receptor 3 does not have naphthyl C–Ha bond.
Therefore, by comparing the associations of these receptors
with anions, the contribution and importance of aromatic
C–H hydrogen bonding would be studied. The binding phe-
nomena of receptors 1, 2, and 3 were studied by UV–Vis and
1H NMR spectra. Using these results the binding poses were
constructed by modeling studies.
There have been still a few examples of anion receptors uti-
lizing C H hydrogen bonds.1
although C H hydrogen bonds plays crucial roles in
nature.2 In many artificial anion receptors utilizing C H
hydrogen bonds, anion binding is assisted by additional
weaker interactions of the C H hydrogen bonds with
anions.3 As an attempt to develop new anion receptors that
have C H hydrogen bonds as an important binding factor,
Synthesis.
For the synthesis of receptor 1,
1,2-phenylenediacetic acid and 5-nitro-1-naphtylamine4
were reacted to give receptor 1 in 64% yield. For the syn-
thesis of receptor 2, 1,2-phenylenediacetic acid and naphty-
lamine were reacted to give receptor 2 in 82% yield. For
the synthesis of receptor 3, 1,2-phenylenediacetic acid and
aniline were reacted to give receptor 3 in 75% yield
(Scheme 1).
new receptors 1, 2, and
and synthesized. The receptors 1 and 2 have 1,2-
phenylenediamide scaffold and have amide N − H, α-C
3
have been designed
H
(aliphatic) to carbonyl group and naphthyl C–H (aromatic) as
hydrogen bond donors. In relation to anion recognition, the
main difference among these receptors is the aromatic C H
hydrogen bonding. For example, receptor 1 has nitro groups,
Bull. Korean Chem. Soc. 2018
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KOREAN CHEMICAL SOCIETY
Scheme 1. Synthesis of receptors 1, 2, and 3.
Results and Discussions
The binding ability of receptor 1 for dihydrogen phosphate
was studied in 60 μM DMSO solution using UV–Vis titra-
tion spectra. Receptor 1 showed strong absorption bands at
260 and 367 nm. On addition of increasing amounts of tetra-
butylammonium dihydrogen phosphate, the absorption band
showed slight bathochromic shift with multiple isosbestic
point at 267, 305, and 378 nm, which suggested the genera-
tion of a hydrogen bonding complex between receptor 1 and
dihydrogen phosphate (Figure 1(a)). In addition, standard 1H
NMR titration experiments in DMSO‑d6 showed the com-
plexation ability of receptor 1 to dihydrogen phosphate. Dur-
ing the experiments, the concentration of host was 2 mM
and the concentration of tetrabutylammonium dihydrogen
phosphate was increased. With the addition of tetrabutylam-
monium dihydrogen phosphate to the solution of receptor
1 in DMSO‑d6, downfield shifts of amide N H, aromatic
C H (Ha) and aliphatic CH2 (alpha to the carbonyl group)
peaks were observed. For example, amide N H peak moved
from 10.39 to 12.00 ppm, aromatic C H (Ha) moved from
8.43 to 8.69 ppm and aliphatic CH2 peak moved from 4.07
to 4.22 ppm (Figure 1(b)). This result indicates that the added
dihydrogen phosphate is complexed by receptor 1 through
amide N H, aromatic C H (Ha), and aliphatic C H.
The stoichiometry of receptor 1 to dihydrogen phosphate
was turned out to be 1:1 using 1H NMR Job plot in
DMSO‑d6 (Figure 2).
Figure 1. (a) Family of UV–Vis spectra recorded over the course
of titration of in DMSO solution of the receptor 1 with the stan-
dard solution tetrabutylammonium dihydrogen phosphate (b) 1H
NMR spectra of 1 with increased amounts of tetrabutylammonium
dihydrogen phosphate (0–4.7 equiv) in DMSO‑d6.
dihydrogen phosphate, the formation of a hydrogen bond-
ing complex was also observed with an isosbestic point at
336 nm (Figure 3(a)). Receptor 2 showed the hydrogen
bonded complex again in 1H NMR titration. Until 8.2 equiv
of dihydrogen phosphate were added, the amide N H peak
moved from 10.20 to 10.99 ppm, aromatic C H (Ha)
moved from 8.06 to 8.15 ppm and aliphatic CH2 peak
moved from 4.06 to 4.12 ppm (Figure 3(b)). These results
indicate that these hydrogens are also major hydrogens
involved in hydrogen bonding with anions during titration
and added dihydrogen phosphate is complexed by receptor
0.35
0.3
0.25
The change of 367 nm in the UV–Vis spectra was uti-
lized in plotting a Benesi–Hildebrand plot5 and hydrogen
chemical shifts in 1H NMR was utilized in EQNMR6 analy-
sis to give association constant. From the experiments, the
association constant for dihydrogen phosphate turned out to
be 1.5 × 103 (M−1) from UV–Vis titration and 1.3 × 103
(M−1) from 1H NMR titration respectively.
Receptor 2 and receptor 1 have similar structures except
that receptor 2 does not have nitro group that polarizes aro-
matic C-Ha group. Receptor 2 showed absorption bands at
297 nm in DMSO. On addition of increasing amounts of
0.2
1 + Dihydrogen phosphate
1 + Acetate
0.15
0.1
2 + Dihydrogen phosphate
2 + Acetate
0.05
0
0
0.2
0.4
0.6
0.8
1
[H]/([H]+[G])
Figure 2. Job plot analysis of receptor 1 and 2 with dihydrogen
phosphate and acetate.
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Contribution of Aromatic C-H Hydrogen Bonding
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Figure 4. H NMR spectra of 3 with increased amounts of tetra-
butylammonium dihydrogen phosphate (0–11.8 equiv) in
DMSO‑d6.
condition. Therefore, we were able to calculate association
constant between receptor 3 and dihydrogen phosphate. It
turned out to be 4.4 × 102 from 1H NMR titration.
The recognition of acetate with receptor 1 were also
studied in DMSO using UV–Vis titration spectra. Like
dihydrogen phosphate, the complex formation between
receptor 1 and acetate was observed from the slight batho-
chromic shift of absorption band and multiple isosbestic
point at 260 and 367 nm upon addition of tetrabutylammo-
1
nium acetate (Figure 5(a)). H NMR titration experiments
also showed complex formation between receptor 1 and
acetate. The addition of tetrabutylammonium acetate to the
solution of receptor 1 in DMSO‑d6 resulted in a downfield
shift of amide N H, aromatic C H (Ha), and aliphatic
CH2 (alpha to the carbonyl group) peaks. For example,
amide N H peak moved from 10.39 to 11.76 ppm, aro-
matic C H (Ha) moved from 8.43 to 8.56 ppm and ali-
phatic CH2 peak moved from 4.07 to 4.15 ppm
(Figure 5(b)).
Figure 3. (a) Family of UV–Vis spectra recorded over the course
of titration of in DMSO solution of the receptor 2 with the stan-
dard solution tetrabutylammonium dihydrogen phosphate (b) 1H
NMR spectra of 2 with increased amounts of tetrabutylammonium
dihydrogen phosphate (0–8.2 equiv) in DMSO‑d6.
2 through amide N H, aromatic C–Ha and aliphatic CH2.
The association constants calculated between receptor
2 and dihydrogen phosphate were found to be 8.8 × 102
from UV–Vis titration and 8.7 × 102 from 1H NMR
titration.
From the experiments, the association constant for ace-
tate was found to be 4.8 × 102 (M−1) from UV–Vis titra-
tion and 4.5 × 102 (M−1) from 1H NMR titration,
respectively. Similar behavior was observed when receptor
2 and 3 were titrated with acetate. Receptor 2 and 3 showed
relatively low association constants for acetate in both UV–
Receptor 3 has structure which does not have aromatic
C–Ha group to bind anions. Therefore, it has only amide
N H and aliphatic CH2 for anion binding. Interestingly,
receptor 3 did not show any changes in the spectrum in UV–
Vis titration. Probably, these hydrogens bonds are not strong
enough to make a complex with dihydrogen phosphate in
UV–Vis titration condition (60 μM), which indicates the
importance of polarization of C–Ha in receptors 1 and 2.
However, complex formation between receptor 3 and dihy-
drogen phosphate was observed in 1H NMR titration experi-
ments in DMSO‑d6 using a constant host concentration
(2 mM). The addition of tetrabutylammonium dihydrogen
phosphate to the solution of receptor 3 in DMSO‑d6 resulted
in a downfield shift of amide N H, and aliphatic CH2
peaks. For example, amide N H peak moved from 10.19 to
11.66 ppm and aliphatic CH2 peak moved from 3.81 to
3.89 ppm (Figure 4). The stoichiometry of receptor 1 to
1
Vis titration and H NMR titration (Table 1), which also
indicate the importance of polarization of C–Ha in these
receptors. Halides showed weak association constants with
these receptors although their association trend is same with
dihydrogen phosphate and acetate. Iodide, nitrate, hydrogen
sulfate did not show any affinities for these receptors. Cya-
nide and Fluoride showed only deprotonation of amide
N H. The binding constants calculated for all the anions
investigated are summarized in Table 1.
Computational Procedure. All the calculations have been
performed with Gaussian 09 suite of programs.7 We have
used popular hybrid B3LYP functional8 with extensive
basis sets of 6-311G(d,p). All the geometries were fully
optimized without any constraints and later confirmed to be
at the local minima in energy hypersurface by second deriv-
ative calculations with respect to coordinate. Solvation
effects were handled with polarizable continuum model
(PCM)9 using dielectric constant of DMSO. Partial charges
1
dihydrogen phosphate turned out to be 1:1 using H NMR
Job plot in DMSO‑d6 (Figure S11, Supporting information).
Although isosbestic point was not observed in UV–Vis titra-
tion, we were able to observe 1:1 binding in 1H NMR
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Contribution of Aromatic C-H Hydrogen Bonding
KOREAN CHEMICAL SOCIETY
1
O
O
N
H
H
N
HN
HN
HN: 0.383
H: 0.193
O2N
Ha
Ha
NO2
Ha: 0.192
2
O
O
N
N
H
H
HN
HN
HN: 0.383
H: 0.190
Ha
Ha
Ha: 0.184
3
O
N
O
N
Figure 5. (a) Family of UV–Vis spectra recorded over the course
of titration of in DMSO solution of the receptor 1 with the stan-
dard solution tetrabutylammonium acetate (b) H NMR spectra of
1 with increased amounts of tetrabutylammonium acetate (0–6.5
equiv) in DMSO‑d6.
H
H
1
HN
HN
HN: 0.378
H: 0.189
Figure 6. The partial charges of hydrogens involving anion recog-
nition, HN: Amide hydrogen, H: Aliphatic hydrogen, Ha: Aro-
matic hydrogen.
Table 1. Association constants (M−1) of receptors 1, 2, and 3 with
various anions in DMSO.
receptors showed selectivity toward dihydrogen phosphate,
the binding poses three receptors with dihydrogen phos-
phate are depicted in Figure 7. All the coordinates for opti-
mized anion and receptor complex structures were listed in
Supporting information.
As shown in Figure 7, all the complex structures possess
the hydrogen bonding interactions from NMR titration
experiments. It is very likely that these modeled structures
can be regarded as reasonable structures, although they are
only snap shots of dynamic molecular recognition pro-
cesses. However, the relative binding energies obtained
1
2
3
Anion
NMR
UV–Vis
NMR
UV–Vis
NMR
−
H2PO4
1.3 × 103 1.5 × 103 8.7 × 102 8.8 × 102 4.4 × 102
CH3COO− 4.5 × 102 4.8 × 102 3.8 × 102 4.0 × 102 2.1 × 102
Cl−
Br−
8.0 × 101 8.3 × 101 7.6 × 101 7.7 × 101 4.6 × 101
3.9 × 101 3.9 × 101 3.1 × 101 3.2 × 101 1.2 × 101
were evaluated using natural population analysis scheme.
For visual geometry inspection, GaussView5.0 was used
(Figure 6).
Modeling Results. Receptor geometries were optimized
and NPA partial charges are depicted as shown in Figure 6.
Here, only hydrogens which have shown to interact with
anions by NMR experiments are depicted. The biggest dif-
ference is the charge of Ha, which is positive for both
receptors 1 and 2. For receptor 1, the charge of Ha is signif-
icantly more positive via electron withdrawing effect of
NO2 functional groups. The partial charges of Ha nicely
explains why the affinity order of these hosts toward vari-
ous anions is 1 > 2 > 3.
-
-
-
1·H2PO4
2·H2PO4
3·H2PO4
Figure 7. Dihydrogen phosphate complexes with three receptors
1, 2, and 3; hydrogen bonding interactions which are responsible
to anion recognition are denoted by dotted lines. All the hydro-
gens except the ones involving anion recognition are omitted for
visual convenience.
Based on the NMR titration data, we have modeled bind-
ing poses those are listed in Table 1. Since all three
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Contribution of Aromatic C-H Hydrogen Bonding
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Conclusion
In conclusion, we have designed and synthesized anion
receptor 1, 2, and 3 based on 1,2-phenylenediamide scaf-
fold. For any anions tested, receptor 1 and 2 have higher
binding affinity than receptor 3, indicating positive involve-
ment to anion recognition of aromatic hydrogens which are
present only in receptor 1 and 2. Between receptor 1 and 2,
receptor 1 always showed higher binding affinity regardless
of the anions tested in this study. This notion was further
supported by the partial charge analyses using NPA (natural
population analysis) scheme based on the electron density
(B3LYP/6-311G**). More positive charges of Ha in recep-
tor 1 by electron withdrawing effect of NO2 group should
be responsible for higher anion affinity of receptor 1.
Therefore, the contribution of aromatic C H hydrogen
bond was demonstrated. And we could modulate anion
affinity via an aromatic C H hydrogen bonding element.
In addition, all the receptors (1, 2, and 3) are selective for
dihydrogen phosphate and acetate.
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Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Republic of Korea (NRF) funded by the
Ministry of Education, Science and Technology (2016R1D
1A1B01007177 and NRF-2016RlD1AlB01007060).
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Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
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