Phosphinate selective hosts and importance of C–H hydrogen bonding for affinity modulation toward anion guests

Article abstract of DOI:10.1016/j.tetlet.2018.03.066

Even though phosphinate and its analogs are very important guests in nature, the artificial receptors which are capable of selective recognition of phosphinate are rare. Here, we report a series of acetate and phosphinate selective hosts (1, 2 and 3) which utilize amide N–H and aliphatic C–H groups as hydrogen bonding donors. In this series of receptors, even though the amide N–H hydrogen bonding element was found to be the most significant, by varying the polarity of C–H group, the magnitude of recognition could be modulated considerably. The affinities of host 3 against all the tested anion guests showed significantly higher affinities compared with those of hosts 1 and 2, and this could be attributed to the difference of C–H group polarities among the receptors 1, 2 and 3. C_α-H hydrogen in host 3 is the most highly polarized by the charged pyridinium group. Therefore, it is the strongest host in this series of hosts. From the experiments shown here, we demonstrated the importance of C–H hydrogen bonding element as a decisive modulating moiety for anionic recognition.

Full text of DOI:10.1016/j.tetlet.2018.03.066

Accepted Manuscript
Phospinate selective hosts and importance of C-H hydrogen bonding for affinity
modulation toward anion guests
Dae Hyup Sohn, Eunbi Han, Seung Joo Cho, Jongmin Kang
PII:
S0040-4039(18)30392-7
https://doi.org/10.1016/j.tetlet.2018.03.066
TETL 49835
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 February 2018
14 March 2018
22 March 2018
Please cite this article as: Sohn, D.H., Han, E., Cho, S.J., Kang, J., Phospinate selective hosts and importance of C-
H hydrogen bonding for affinity modulation toward anion guests, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.03.066
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Tetrahedron Letters
Phospinate selective hosts and importance of C-H hydrogen bonding for affinity
modulation toward anion guests
Dae Hyup Sohn†, Eunbi Han†, Seung Joo Cho*‡ and Jongmin Kang*†
†Department of Chemistry, Sejong University, Seoul 143-747, South Korea
‡Department of Cellular and Molecular Medicine, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
ARTICLE INFO
ABSTRACT
Even though phosphinate and its analogs are very important guests in nature, the artificial
receptors which are capable of selective recognition of phosphinate are rare. Here, we report a
series of acetate and phosphinate selective hosts (1, 2 and 3) which utilize amide N-H and
aliphatic C-H groups as hydrogen bonding donors. In this series of receptors, even though the
amide N-H hydrogen bonding element was found to be the most significant, by varying the
polarity of C-H group, the magnitude of recognition could be modulated considerably. The
affinities of host 3 against all the tested anion guests showed significantly higher affinities
compared with those of hosts 1 and 2, and this could be attributed to the difference of C-H group
polarities among the receptors 1, 2 and 3. C-H hydrogen in host 3 is the most highly polarized
by the charged pyridinium group. Therefore, it is the strongest host in this series of hosts. From
the experiments shown here, we demonstrated the importance of C-H hydrogen bonding element
as a decisive modulating moiety for anionic recognition.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Phosphinate selective host
Anion recognition
C-H hydrogen bonds
Polarity of C-H bonds
Anion receptor design
2018 Elsevier Ltd. All rights reserved.
OH
As an attempt to study anion receptors having weak C-H
hydrogen bonds, we have reported various new anion receptors
with C-H hydrogen bonds.1 Among them, we reported
phosphinate selective receptors, which utilized amide N-H,
pyrrole N-H and vinyl C-H as hydrogen bond donors.2 In these
receptors, the strength of association constants could be
controlled by the polarity of vinyl C-H. The receptors for
phosphinate have been rarely reported even though phosphinates
are related with antifolates3 and used for preventing and/or
treating metabolic diseases such as obesity, NASH (nonalcoholic
steatohepatitis), hypercholesterolemia and hyperlipidemia. They
are also associated with conditions such as atherosclerosis,
coronary heart disease, impaired glucose tolerance, metabolic
syndrome X and diabetes.4 In this work, we have designed and
synthesized receptors 1, 2 and 3 to develop new anion receptors
selective for phosphinate. These receptors utilize both amide N-H
and alpha C-H (C-H) to the carbonyl group. Since the difference
of three receptors (1, 2 and 3) is due to the substituent group
variation attached to the alpha carbon (C) to the carbonyl group,
the strength of association depends mainly on the polarity of C-
H bond. Receptor 2 has cyano group at the Cposition. Since this
group is an electron withdrawing group, enhanced molecular
recognition toward anion guest was expected. Receptor 3 has
positively charged pyridinium at the Cposition. Therefore, the
highest binding constant was expected. The binding phenomena
of these receptors were monitored by 1H NMR and fluorescence
spectra.
O
H
H
H
O
N
H
NH2
EDCl, HOBt
50 %
O
H
N
H
H
H
NH2
H
1
O
OH
NC
CN
N
H
O
POCl3, TEA
93 %
H
NH2
O
N
H
H
NH2
H
2
H
NC
O
H
N
1) chloroacetyl chloride, TEA
N
H
O
N
H
H
H
NH2 2) pyridine, NH4PF6
H
77 %
NH2
3
N
Scheme 1. Synthetic procedure for anion receptors 1, 2 and 3.
The ability of receptor 3 to recognize dimethyl phosphinate
was studied by standard 1H NMR titration experiments in
DMSO-d6 using a constant host concentration (2 mM) and
increasing concentrations of dimethyl phosphinate. The addition
of tetrabutylammonium dimethyl phosphinate salt to the solution
of receptor 3 in DMSO-d6 resulted in a downfield shift of amide
N-H, and C-H peaks. For example, amide N-H peak moved
from 10.10 ppm to 12.24 ppm and C-H peak moved from 5.62
ppm to 5.91 ppm (Figure 1). The stoichiometry between receptor
3 and
For the synthesis of receptors 1 and 2, 1,2-phenylenediamine
was reacted with acetic acid or cyanoacetic acid. For the
synthesis of receptor 3, the product from the reaction between
1,2-phenylenediamine and chloroacetyl chloride was reacted
further with pyridine (Scheme 1).

1
Figure 1. H NMR spectra of 2 mM DMSO-d6 solution of receptor 3 with increasing amounts tetrabutylammonium dimethyl
phosphinate
1
dimethyl phosphinate was determined to be 1:1 using H NMR
Job plot in DMSO-d6 (Figure 2)
can be explained with lower polarity of C-H bond. However, in
the case of receptor 1, only N-H bond was clear to participate in
the binding event. Since the contribution of C-H was very small,
it was not obvious whether this bond is involved (Figure 3). Only
N-H bond was clearly found to participate in the binding event.
Therefore, receptor 1 had the weakest affinity for the dimethyl
phosphinate. These results indicate that the strength of
association of dimethyl phosphinate depends on the polarity of
C-H bonds in these receptors
Analysis of chemical shift utilizing EQNMR5 gave the
association constant. The association constant calculated was 6.6
× 103 M-1 from 1H NMR titration, respectively.
Receptor 2 showed lower association constant for dimethyl
phosphinate than that of receptor 3 as expected. For example, the
association constant between receptor
2
and dimethyl
phosphinate calculated was 1.3 × 102 from 1H NMR titration. The
affinity of receptor 2 and 3 for the anion can be attributed to N-H
and C-H hydrogen bond and the lower association of receptor 2
0.5
0.4
0.3
0.2
0.1
0
Dimethyl phosphinate
Benzoate
Chloride
Nitrate
Nitrite
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
[H]/([H]+[G])
Figure 2. Job plots of receptor 3 with tetrabutylammonium anion salts obtained by 1H NMR spectroscopy
1
Figure 3. H NMR spectra of 2 mM DMSO-d6 solution of receptor 1 with increasing amounts tetrabutylammonium dimethyl
phosphinate

Host 1
Host 2
Host 3
Figure 4. Optimized geometries of phosphinate complexes with host 1, 2, and 3. Note that the structures were optimized in the gas
phase.
Figure 5. 1H NMR spectra of 2 mM DMSO-d6 solution of receptor 3 with increasing amounts tetrabutylammonium benzoate
Figure 6. 1H NMR spectra of 2 mM DMSO-d6 solution of receptor 3 with increasing amounts tetrabutylammonium nitrite
To understand more precisely how the binding events happened,
we studied the binding poses with computer simulations using
density functional theory. Initial geometries for phosphinate
complexes were set utilizing the information from experimental
spectra. All the calculations have been performed with Gaussian
09 suite of programs.6 We have used popular hybrid B3LYP
functional7 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 derivative calculations with respect to coordinate.
Solvation effects were considered with polarizable continuum
model (PCM)8 using dielectric constant of DMSO. Partial
charges were evaluated using natural population analysis
scheme.9 For geometry inspection, GaussView5.0 was used. For
host 1, the modelled structure might not be accurate since the
participation of C-H hydrogen in the binding event is not clear
from NMR experiments. There could be some intervention of
solvent molecules (DMSO). Since the structures are optimized in
the gas phase, in all modelled structures, C-H hydrogens seemed
to play roles in molecular recognition events. The optimized
geometries are shown in Figure 4. The average distance between
C-H hydrogen and complexed phosphinate oxygen are 2.249,
2.187 and 2.098 Å , for host 1, 2 and 3, respectively. Therefore, it
seems clear that as the polarity of C-H gets higher, the hydrogen
bonding distance (C-H---O-phosphinate) becomes shorter, and
the interaction between them gets stronger.
This is also consistent with calculated binding energy. In
DMSO solvent as well as in gas phase, host 3 has the highest
affinity toward phosphinate. The binding energies were
calculated using various models. Starting from mere electronic
energy, basis set superposition error correction was considered,
and thermal free energy was also considered. Finally, solvent
effect was also considered using polarization continuum model
approximation. The calculated relative complexation energies are
summarized in Table 1. As shown in Table 1, in every model,
host 3 has the highest affinity toward phosphinate, consistent
with experimental findings.
Phenyl phosphinate and diphenyl phosphinate gave similar
results with dimethyl phosphinate except that they showed lower
association constants than dimethyl phosphinate for the receptors
1, 2 and 3.
1H NMR titration of receptor 3 with benzoate in DMSO-d6
showed downfield shift of amide N-H, and C-H peaks. For
example, amide N-H peak moved from 10.10 ppm to 12.51 ppm
and C-H peak moved from 5.62 ppm to 5.82 ppm (Figure 5),
which suggests formation of hydrogen bonds

Table 1. The calculated complexation energies of phosphinate with three hosts (1, 2 and 3)
E
-43.3
-56.9
EBSSEC
-35.1
-49.1
-175.3
GBSSEC
-23.3
-36.1
-159.3
GDMSO
-7.9
-11.0
-129.9
Host 1
Host 2
Host 3
-184.0
E is electronic energy. EBSSEC is electronic energy with basis set superposition error correction (BSSEC). GBSSEC is Gibbs free
energy after thermal correction to EBSSEC GDMSO denotes binding energy in DMSO solution using polarizable continuum (PCM)
model. Units are in kcal/mol.
Table 2. Association constants (M-1) of receptors 1, 2 and 3 with various anions in DMSO
Anion
1
2
3
CH3COO-
1070
387
964
209
353
*NB
NB
2333
763
1321
239
975
NB
NB
NB
NB
*DP
5438
6671
2788
4188
841
215
448
67
C6H5COO-
(CH3)2POO-
(C6H5)HPOO-
(C6H5)2POO-
-
NO2-
NO3
Cl-
NB
NB
Br-
The numbers in the parenthesis are association constant from fluorescence titration. *DP: deprotonation, *NB: nonbinding
The stoichiometry between receptor 3 and benzoate was
determined to be 1:1 (Figure 2). The association constant
calculated from 1H NMR titration was 5.4 × 103 M-1.
showed consistent association phenomena between these
receptors and anions.(see supporting information). All
calculated binding constants for these anions are summarized
in Table 2.
1
Unfortunately, only deprotonation was observed from H NMR
titration of receptor 3 with acetate in DMSO-d6. Similar
behaviors were observed with receptors 1 and 2. Receptors 1 and
2 showed lower association constants for carboxylate than those
of receptor 3 and only N-H bond participated in the binding event
for the receptor 1. These results indicate that the strength of
association of carboxylate also depends on the polarity of C-H
bonds with these receptors
One notable trend is the difference between aliphatic anion guests
and aromatic anion guests. For example, acetate has higher
binding affinity compared with that of benzoate regardless of
hosts used. And for phosphinate series, dimethylphosphinate has
the highest binding affinity among the phosphinate guests. This
could be attributed to the electron delocalization of negative
charge into aromatic moieties. And this was also confirmed by
partial charges obtained from natural population analysis. For
acetate, the partial charge of oxygen is -0.792 and for
benzoacetate, -0.770. Therefore, the oxygens of benzoate are
slightly less negative compare with those of acetate. For
dimethylphosphinate, the partial charge is -1.156, while for
(C6H5)2POO- and (C6H5)HPOO-, -1.146 and -1.137, respectively.
Again, the oxygen charges of aromatic guests are less negative,
resulting in lower binding energies, as shown in Table 2.
In conclusion, Phosphinate and its analogous guests are very
important in nature. Since phosphinate-selective artificial
receptors are rare, we have developed acetate and phosphinate
selective hosts based on the hydrogen bonding interaction using
amide N-H and aliphatic C-H groups (hosts 1, 2 and 3). Since C-
H hydrogen in host 3 is the most highly polarized by the charged
pyridinium group, it is the strongest host in this series of hosts.
Amide N-H hydrogen bonding element was the most significant
one in anion recognition. However, by varying the polarity of C-
H group, the magnitude of interaction energy was changed
considerably. Host 3 showed one order of magnitude higher
affinities for most anion guests studied in this work compared to
those of host 1. This could be attributed to the difference of
polarities between C-H groups in host 1 and 3. In case of
receptor 3, the charge-assisted C-H hydrogen bonding
interactions were very crucial. Therefore, we report here the
importance of C-H hydrogen bonding element as a decisive
modulating moiety for anionic recognition.
The complexation abilities of receptor 3 to nitrite was also
1
measured by standard H NMR titration experiments in DMSO-
d6 using a constant host concentration (2 mM) and increasing
concentrations of nirtite anions. The addition of
tetrabutylammonium nirtite salts to the solution of receptor 3 in
DMSO-d6 resulted in downfield shifts of amide N-H peak and
C-H peak. For example, addition of tetrabutylammonium nitrite
moved amide N-H from 10.10 to 10.72 ppm and C-H from 5.62
to 5.74 ppm (Figure 5a). The downfield shifts of these protons
indicate the presence of a hydrogen bond interaction between
these hydrogens and nitrite ion.
The stoichiometry between receptor 3 and nitrite was
1
determined to be 1:1 using H NMR Job plot in DMSO-d6 (Fig.
2). The association constants for nitrite calculated were 8.4 × 102
from 1H NMR titration. The less polar nitrate gave lower
association constant for the receptor 3 as expected. The
association constants of nitrate for the receptor 3 turned out to be
2.0 × 102 from 1H NMR titration. Receptor 1 and 2 did not show
any affinities for the nitrite and nitrate and no shift of C-H peak
was observed. Chloride and bromide showed quite similar
behaviors like nitrate and nitrite.
The receptor 3 showed somewhat noisy fluorescence spectrum
due to low fluorescent phenyl moiety. The excitation and
emission wavelength were 250 and 460 nm respectively.
However, the intensity of emission spectrum from 60 µM
solution of the receptor 3 gradually increased as the concentration
of tetrabutylammonium dimethyl phosphinate was increased (1 -
10 equiv), which also indicates the association between the
receptor 3 and dimethyl phosphinate. As fluorescence titration
spectra of these receptors are noisy due to low fluorescent
phenyl moiety, we did not calculate association constants
from the fluorescence titration spectrum. However, they
Acknowledgements
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
(2016R1D1A1B01007177
and
NRF-
2016RlD1AlB01007060).
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Highlights
-
-
-
Phosphinate selective anion receptor
Control of recognition by varying C-H polarity
Importance of C-H hydrogen bonding

Graphical Abstract
Host 1
Host 2
Host 3