Novel anion receptors for selective recognition of dimethyl phosphinate and carboxylate

Article abstract of DOI:10.1016/j.tet.2016.11.076

We have designed and synthesized new anion receptors 1 and 2, which have amide N[sbnd]H, pyrrole N[sbnd]H and vinyl C[sbnd]H as hydrogen bond donors. These receptors are selective for dimethyl phosphinate and carboxylates. Due to electron withdrawing effect of the cyano group which is trans to the vinyl hydrogen with respect to carbon-carbon double bond, receptor 1 has higher binding constants for phosphinate and carboxylate than those of receptor 2. Modeling studies shows that cyano group polarized all three hydrogens through planar π-electron network. In addition, receptor 1 gave orange colored 1,4-addition product for cyanide.

Full text of DOI:10.1016/j.tet.2016.11.076

Accepted Manuscript
Novel anion receptors for selective recognition of dimethyl phosphinate and
carboxylate
Dae Hyup Sohn, Jong Il Park, Seung Joo Cho, Jongmin Kang
PII:
S0040-4020(16)31256-X
10.1016/j.tet.2016.11.076
TET 28290
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 October 2016
Revised Date: 22 November 2016
Accepted Date: 30 November 2016
Please cite this article as: Sohn DH, Park JI, Cho SJ, Kang J, Novel anion receptors for selective
recognition of dimethyl phosphinate and carboxylate, Tetrahedron (2017), doi: 10.1016/j.tet.2016.11.076.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Novel Anion Receptors for Selective recognition of Dimethyl Phosphinate and
Carboxylate
†
‡
†
§
Dae Hyup Sohn, Jong Il Park, Seung Joo Cho,*, and Jongmin Kang*,
†
Department of Chemistry, Sejong University, Seoul 143-747, South Korea
§
Department of Bio-nanomaterials Bio campus of Korea Polytechnics #48
Dongan-ro 112 ganggyeng-eup nonsan chungnam 32943 korea
‡
Department of Cellular and Molecular Medicine, College of Medicine, Chosun University,
75 Seosuk-dong, Dong-gu, Gwangju
01-759, South Korea
3
5
Abstract
We have designed and synthesized new anion receptors 1 and 2, which have amide N-H,
pyrrole N-H and vinyl C-H as hydrogen bond donors. These receptors are selective for
dimethyl phosphinate and carboxylates. Due to electron withdrawing effect of the cyano
group which is trans to the vinyl hydrogen with respect to carbon-carbon double bond,
receptor 1 has higher binding constants for phosphinate and carboxylate than those of
receptor 2. Modeling studies shows that cyano group polarized all three hydrogens through
planar π-electron network. In addition, receptor 1 gave orange colored 1,4-addition product
for cyanide.
Introduction
The design and synthesis of efficient receptors capable of binding anionic species is an
1
-5
emerging field in supramolecular chemistry . Most of researches have been directed to
biologically and environmentally important anions such as halides, carboxylates, dihydrogen
phosphate and cyanide. For example, as carboxylates are the most fundamental importance in
1

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6
-7
nature and in chemical technology , carboxylate anion sensor has enormous applications in
8
-9
pharmaceutical, biological areas . Cyanide is used in many industrial procedures, such as
1
0
fiber synthesis, resin synthesis, herbicide, and the gold-extraction process . Detection of
cyanide has drawn special interest due to its high toxicity to human health and environment
11-13
.
However, development of anion receptors capable of binding new anion species is still
necessary. For example, Phosphinates could be new target for the development of anionic
1
4
receptor as phosphinates are related with antifolates and used for preventing and/or treating
metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well
as associated conditions such as atherosclerosis, coronary heart disease, impaired
1
5
glucosetolerance, metabolic syndrome X and diabetes .
Generally, for the anion receptor, N-H hydrogen such as urea, thiourea, and amide had been
1
6-19
utilized
bond donors. For example, imidazolium
successfully utilized for anion recognition elements. In addition, aliphatic hydrogen bond
. However, various polarized C-H groups are proven to be effective hydrogen
2
0-23
24-30
31-33
, triazolium
, pyrimidium
groups are
3
4-36
3
7-39
and imine C-H
have been shown to be effective hydrogen bonding element in anion
recognition. Among various C-H groups, vinyl C-H rarely utilized as hydrogen bond donor.
As an attempt to have anion receptors with vinyl C-H as a hydrogen bond donor, we have
designed and synthesized new anion receptors 1 and 2, which have vinyl C-H as hydrogen
bond donors. These receptors have amide N-H, pyrrole N-H and vinyl C-H as hydrogen bond
donors. The only difference between receptor 1 and 2 is CN group, which will polarize vinyl
C-H group. Therefore, by comparing the association of receptor 1 and 2 with anions, the
contribution of vinyl C-H for anion binding could be estimated.
2

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1
The binding phenomena of receptor 1 and 2 were monitored by UV-vis and H NMR spectra.
H
H
N
H
H
N
H
H
N
O
NO2
N
O
NO
2
NC
H
1
2
Experimental Section
Materials
Tetra-n-butylammonium hydroxide, tetra-n-butylammonium fluoride, tetra-n-
butylammonium dihydrogen phosphate, tetra-n-butylammonium acetate (TBAA), tetra-n-
butylammonium benzoate, tetra-n-butylammonium bromide, tetra-n-butylammonium
chloride, tetra-n-butylammonium iodide, tetra-n-butylammonium cyanide, tetra-n-
butylammonium hydrogen sulfate, tetra-n-butylammonium nitrate were purchased from
SigmaAldrich Chemical Co., Inc., and used as received. The tetrabutylammomium
carboxylate salts of N-protected amino acids were prepared by neutralizing the corresponding
N-protected amino acid with 1.0 M tetrabutylammonium hydroxide in methanol solution,
o
followed by vaccum-drying at 40 – 50 C for 24 h.
Measurements
Absorption spectra were recorded using a biochrom Libra S70 spectrophotometer (Biochrom
Ltd, England). NMR spectra were recorded using a BRUKER spectrometer operated at 500
MHz. ESI MS spectra were obtained using a JMS 700 (Jeol, Japan) double focusing magnetic
3

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sector mass spectrometer. All measurements were carried out at room temperature (298 K).
Synthesis
For the synthesis of receptor 1, 2-cyanoacetic acid and 4-nitroaniline were reacted to give 2-
cyano-N-(4-nitrophenyl)acetamide 3 in 99% yield. The reaction between 3 and pyrrole-2-
carboxaldehyde in the presence of piperidine gave the receptor 1 in 75 % yield.
For the synthesis of receptor 2, chloroacetyl chloride and 4-nitroaniline were reacted to give
2
-chloro-N-(4-nitrophenyl)acetamide 4 in 93% yield. Wittig reaction of between 2-chloro-N-
(4-Nitrophenyl)acetamide 4 and pyrrole-2-carboxaldehyde gave the receptor 2 in 33% yield.
1
13
All compounds were characterized by H NMR, C NMR, and high-resolution mass
spectrometry (Scheme 1).
4

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H
NH
2
O
N
+
EDC, HOBT
DCM
NC
CN
HO
O
2
O N
NO
2
3
H
N
H
H
N
pyrrole-2-carboxaldehyde
piperidine, Etanol
NO
2
NC
O
1
H
NH
2
O
N
+
Cl
Cl
Cl
THF
O
2
O N
NO
2
4
H
N
H
H
1
) Ph3P
N
O
NO
2
2) 1H-pyrrole-2-carbaldehyde /4-DMAP
H
2
Scheme 1. Synthetic procedure for anion receptors 1 and 2.
Compound 3
To a solution of 4-nitroaniline (500mg, 3.6 mmol) in 30mL dichloromethane was added 2-
cyanoacetic acid (400mg, 4.7 mmol). Then, EDC (1041mg, 5.4 mmol) and HOBT (49 mg,
0
.4 mmol) were added. The reaction mixture was stirred for 16 hours in the room temperature.
Then, the precipitate was filtered and washed with cold ethanol. After drying the solid at
1
room temperature, a yellow solid 3(735mg) was obtained in 99% yield. H NMR (DMSO-d ,
6
1
3
5
00MHz) 4.00 (s, 2H), 7.79 (d, 2H, J=6.4), 8.25 (d, 2H, J=6.4), 10.90(s, 1H) C NMR
o
(
DMSO-d , 125 MHz) δ 162.5, 144.7, 143.0, 125.4, 119.4, 115.9, 27.5 Mp > 220 C. IR
6
_
1
(
cm ): 3282, 3230, 3168, 2915, 2265, 1673, 1566. HRMS (ESI), m/z calcd for
5

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+
C H O N +Na : 228.0380, Found: 228.0381
9
7
3
3
Receptor 1
To a solution of 2-cyano-N-(4-nitrophenyl)acetamide (100mg, 0.5 mmol) and piperidine
(10ꢀL, 0.1 mmol) in ethanol (2ml) were added pyrrole-2-carboxaldehyde (60mg, 0.63 mmol)
The reaction mixture was stirred at 40℃ for 6 hours. Then, the precipitate was filtered and
washed with cold ethanol. After drying at room temperature, a yellow solid 1 (104mg) was
1
obtained in 75 % yield. H NMR (DMSO-d , 500MHz) 12.03 (s, 1H), 10.60 (s, 1H), 8.25 (d,
6
1
3
2
H, J=9.1), 8.16 (s, 1H), 7.94 (d, 2H, J=9.1), 7.41 (s, 2H), 6.49 (d, 1H, J=1.8) C NMR
(
DMSO-d , 125 MHz) δ 162.0, 145.2, 142.7, 141.4, 127.9, 126.5, 125.0, 120.1, 117.5, 116.9, 113.1,
6
o
_1
9
4.8 Mp > 220 C. IR (cm ): 3283, 3134, 2212, 1663, 1508, 1305, 1149. HRMS (ESI), m/z
+
calcd for C H O N +Na : 305.0653, Found: 305.0647
1
4
10
3
4
Compound 4
To a solution of 4-nitroaniline (1g, 7.2 mmol) in tetrahydrofuran (5mL) was added solution of
chloroacetyl chloride (1.15ml in 5 ml tetrahydrofuran 14.5 mmol). After the reaction mixture
was stirred for an hour, 20mL of cold water was poured to the reaction mixture and the
mixture was stirred another 1 hour. The precipitate was filtered and washed with water. After
1
drying the solid at room temperature, a yellow solid 4 (1.43g) was obtained in 93 % yield. H
NMR (DMSO-d , 500MHz) 4.30 (s, 2H), 7.84 (d, 2H, J=9.25), 8.23 (d, 2H, J=9.25), 10.79(s,
6
1
3
o
1
H) CNMR (DMSO-d , 125 MHz) δ 166.0, 145.0, 143.0, 125.4, 119.5, 44.0 Mp > 220 C.
6
_
1
IR (cm ): 3276, 3230, 3165, 3105, 2943, 1684, 1566, 1334 HRMS (ESI), m/z calcd for
+
C H O N Cl+Na : 237.0035, Found: 237.0037
8
7
3
2
Receptor 2
To a refluxing solution of 2-chloro-N-(4-nitrophenyl)acetamide (2.14g, 10.0 mmol) in
benzene (25mL) was added triphenylphospine (2.62g, 10.0 mmol) solution in benzene(5mL).
6

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After the reaction mixture was refluxed for 8 hours, the temperature of reaction mixture was
reduced to room temperature. Filtration of reaction mixture and washing with ethyl acetate
gave triphenylphosphomium salt (4.0g) in 84% yield. To a solution of triphenylphosphomium
salt (2g, 4.2 mmol)) obtained above in chloroform (15mL) was added solution of 4-DMAP
(6.3 mmol, 800mg) in chloroform (5mL). After all starting materials were dissolved, 1H-
pyrrole-2-carbaldehyde (4.2 mmol, 200mg) was added. After the reaction mixture was stirred
for 8 hours at room temperature, the solvent was evaporated in vacuo. The residue material
was washed with diethyl ether, and purified by column chromatography (5% methanol in
1
dichloromethane). The desired product (213mg) was obtained in 40% yield. H NMR
(
DMSO-d , 500MHz) 11.53 (s, 1H), 10.63 (s, 1H), 8.22 (d, 2H, J=9.3), 7.94 (d, 2H, J=9.3),
6
7
.51(d, 1H, J=15.6), 7.02(s, 1H), 6.57(s, 1H), 6.39(d, 1H, J=15.6), 6.18(d, 1H, J=2.8)
1
3
CNMR (DMSO-d , 125 MHz) δ 165.7, 146.5, 142.4, 133.0, 128.9, 125.5, 123.4, 119.2,
6
o
_1
1
14.4, 113.2, 110.7 Mp > 220 C. IR (cm ): 3369, 3293, 1673, 1595, 1490, 1316, 1250
+
HRMS (FAB), m/z calcd for C H O N +H : 258.0880, Found: 258.0880
1
3
11
3
3
Results and discussion
Interaction with dimethyl phosphinate and dihydrogen phosphate
The ability of receptor 1 to recognize dimethyl phosphinate was studied in 40 µM DMSO
solution using UV-vis titration spectra. Receptor 1 displayed strong absorption bands at 391
nm. Upon addition of increasing amounts of dimethyl phosphinate, λmax moved from 391 nm
to 398 nm with multiple isosbestic point at 322, 349, 392, 435 nm, suggesting the formation
of a typical hydrogen bonding complex between receptor 1 and dimethyl phosphinate (Fig.
1
a)
7

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(a)
(b)
Figure 1. Family of UV–vis spectra recorded over the course of titration of in DMSO solution
of the receptor 1(a) and 2(b) with the standard solution tetrabutylammonium dimethyl
phosphinate.
8

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The complexation ability of receptor 1 to dimethyl phosphinate was also measured by
1
standard H NMR titration experiments in DMSO-d using a constant host concentration (2
6
mM) and increasing concentrations of dimethyl phosphinate. The addition of
tetrabutylammonium dimethyl phosphinate salt to the solution of receptor 1 in DMSO-d6
resulted in a downfield shift of amide N-H, pyrrole N-H and vinyl C-H peaks. For example,
pyrrole N-H peak moved from 12.02 ppm to 14.93 ppm, amide N-H peak moved from 10.60
ppm to 12.58 ppm, , and vinyl C-H peak moved from 8.15 ppm to 9.40 ppm. (Fig.2)
1
Figure 2. H NMR spectra of 2 mM of 1 with increased amounts of tetrabutylammonium
dimethyl phosphinate (0 –3.1 equiv) in DMSO-d6.
This result indicates that the added dimethyl phosphinate is complexed by receptor 1 through
amide N-H, pyrrole N-H and vinyl C-H. The stoichiometry between receptor 1 and dimethyl
1
phosphinate was determined to be 1:1 using H NMR Job plot in DMSO (Fig. S21 in
supporting information).
9

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40
A Benesi–Hildebrand plot drawn by plotting the change of λmax in the UV-vis spectrum and
4
1
1
EQNMR analysis of hydrogen chemical shifts in H NMR gave association constant. From
the experiments, the association constant for dimethyl phosphinate were found to be 5.0 X
3
-1
3
-1
1
1
0 (M ) V-vis spectrum and 4.3 X 10 (M ) from H NMR titration respectively.
Receptor 2 has similar structures with receptor 1 except that it does not have CN group which
polarizes vinyl C-H group. Figure 1b showed the family of UV–vis spectra obtained over the
course of the titration of 40 µM DMSO solution 2 with dimethyl phosphinate. When dimethyl
phosphinate was added to the solution of 2, movement of λmax from 379 nm to 388 nm with
two isosbestic point at 327, 387 nm also observed. These results suggest that a typical
1
hydrogen bonding complex forms between receptor 2 and dimethyl phosphinate. H NMR
titration of receptor 2 with dimethyl phosphinate in DMSO-d also showed downfield shift of
6
amide N-H, pyrrole N-H and vinyl C-H peaks. For example, pyrrole N-H peak moved from
11.52 ppm to 13.21 ppm, amide N-H peak moved from 10.62 ppm to 12.81 ppm and vinyl C-
H peak moved from 6.40 to 7.32 ppm. (Fig.3). we believe that such large downfield chemical
shifts are also caused by the formation of hydrogen bonds. However, the association constant
calculated was about 5 times smaller than that of receptor 1. For example, it was calculated
3
-1
3
-1
1
1
.0 X 10 (M ) from UV-vis titration, 1.1 X 10 (M ) from H NMR titration.
1
0

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1
Figure 3. H NMR spectra of 2 mM of 2 with increased amounts of tetrabutylammonium
dimethyl phosphinate (0 – 6.5 equiv) in DMSO-d6.
In the cases of dihydrogen phosphate, the Job plot was not symmetric and showed a
maximum when the mole fraction of the host was 0.6, which indicated a mixed stoichiometry.
(Fig. S22 in supporting information) Therefore, it was not possible to obtain accurate
association constants for dihydrogen phosphate. We also tried diphenyl phosphate. However,
it did not show any binding phenomena at all.
Interaction with carboxylates
Upon addition of increasing amounts of benzoate to the 40 µM DMSO solution of receptor 1,
moderate increases in absorption at 455 nm with isosbestic point at 417 nm were observed,
suggesting the formation of a typical hydrogen bonding complex between receptor 1 and
benzoate (Fig. 4a).
1
1

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(a)
(b)
Figure 4. Family of UV–vis spectra recorded over the course of titration of in DMSO solution
of the receptor 1(a) and 2(b) with the standard solution tetrabutylammonium benzoate
The stoichiometry between receptor 1 and benzoate was determined to be 1:1 using a UV-vis
1
2

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Job plot in DMSO (Fig. S23 in supporting information)
A Benesi–Hildebrand plot drawn by plotting the change at 455 nm in the UV-vis spectrum
gave the association constant for benzoate. From the UV-vis spectrum, the association
3
-1
constants for benzoate were found to be 1.4 X 10 (M )
1
H NMR titration of receptor 1 with benzoate in DMSO-d showed downfield shift of amide
6
N-H, pyrrole N-H and vinyl C-H peaks as expected. For example, pyrrole N-H peak moved
from 12.0 ppm to 13.5 ppm, amide N-H peak moved from 10.6 ppm to 11.3 ppm, , and vinyl
C-H peak moved from 8.2 ppm to 9.2 ppm. (Fig.5), which suggests formation of hydrogen
1
3
-1
bonds. The association constant calculated from H NMR titration was 4.3 X 10 (M )
1
Figure 5. H NMR spectra of 2 mM of 1 with increased amounts of tetrabutylammonium
benzoate (0–12.2 equiv) in DMSO-d6.
Figure 4b showed the family of UV–vis spectra obtained over the course of the titration of 40
µM DMSO solution 2 with benzoate. When benzoate was added to the solution of 2, the
intensity of absorption band at 383 nm decreased with isosbestic point at 402 nm. These
results suggest that a typical hydrogen bonding complex forms between receptor 2 and
1
3

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1
benzoate. H NMR titration of receptor 2 with benzoate in DMSO-d also showed downfield
6
shift of amide N-H, pyrrole N-H and vinyl C-H peaks. For example, pyrrole N-H peak moved
from 11.5 ppm to 12.0 ppm, amide N-H peak moved from 10.6 ppm to 11.7 ppm and vinyl C-
H peak moved from 6.4 ppm to 7.1 ppm. (Fig.6). We believe that such large downfield
chemical shifts are also caused by the formation of hydrogen bonds. However, the association
constant calculated was about 8 times smaller than that of receptor 1. The association
2
-1
2
-1
1
constants calculated were 1.7 X 10 (M ) from UV-vis titration, 1.8 X 10 (M ) from H
NMR titration.
1
Figure 6. H NMR spectra of 2 mM of 2 with increased amounts of tetrabutylammonium
benzoate (0–50.3 equiv) in DMSO-d6.
As receptor 1 and 2 showed affinities for carboxylates even in polar solvents such as DMSO,
we investigated affinities of more carboxylate salts for these receptors. Almost same
phenomena were observed with cyanoacetate, and acetate except that acetate showed peaks
of unknown compounds during NMR titration condition, all titration data for receptor 1 and 2
are summarized in Table 1.
1
4

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-1
Table 1 Association constants (M ) of receptors 1 and 2 with various anions in DMSO. UN
means unknown compound formed during titration
1
2
Anion
CH COO
NMR
UN
UV
NMR
2.0 × 10 ± 0.8 ×10
UV
-
4
3
2
1
2
3
2
1
0
2
3
2
1
0
2
1.3 × 10 ± 0.9 ×10
2.0 × 10 ± 0.5 ×10
3
-
3
2
1
2
3
2
2
1
1
4
.3 × 10 ± 0.9 ×10
1.4 × 10 ± 1.1 ×10
1.8 × 10 ± 0.6 ×10
1.7 × 10 ± 0.3 ×10
C H COO
6
5
-
2
2
1
1
.0 × 10 ± 0.7 ×10
1.2 × 10 ± 1.4 ×10
3.0 × 10 ± 1.5 ×10
1.5 × 10 ± 0.9 ×10
CNCH COO
2
-
3
3
3
3
.3 × 10 ± 0.9 ×10
5.0 × 10 ± 0.6 ×10
1.1 × 10 ± 0.2 ×10
1.0 × 10 ± 0.1 ×10
(
CH ) POO
3 2
Interaction with cyanide
When receptor 1 was titrated with cyanide in DMSO, movement of λmax from 391 nm to 461
nm with isosbestic point at 417 nm was observed (Fig. 7a) For example, when cyanide ions
were added to the 40 µM solution of 1, the intensity of the absorption peak at 391 nm
gradually decreased, while the intensity of the peak at 461 nm began to increase until it
reached a limiting value. In order to discriminate hydrogen bonding interaction from
deprotonation, UV-vis titration of receptor 1 with tetrabutylammonium hydroxide was carried
out. The UV-vis spectral changes of the receptor 1 upon addition of hydroxide were exactly
identical to those triggered by cyanide. (Fig. 7b). Furthermore, isosbestic points observed at
4
17 nm was also same observed those with cyanide. Therefore, we could conclude that
cyanide triggered only deprotonation of receptor 1 at this condition.
1
5

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(a)
(b)
Figure 7. Family of UV–vis spectra recorded over the course of titration of in DMSO solution
of the receptor 1 with the standard solution tetrabutylammonium cyanide (a) and
tetrabutylammonium hydroxide (b)
1
6

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1
However, in H NMR condition (2mM, DMSO-d ), as shown in Figure 8, upon addition of
6
-
CN (3 equiv.) to the 2 mM solution of receptor 1, completely new spectrum was observed.
For example, vinyl proton (H ) appearing at 8.16 ppm completely disappeared and new peak
4
appeared at 5.05 ppm was observed. These results could be explained from nucleophilic 1,4-
addition reaction between cyanide and receptor 1 (Fig. 8). Formation of nucleophilic 1,4-
addition product is also supported by the mass spectrum, which showed peak at 550.76 that
matched with mass of tetrabutylammonium salt of nucleophilic 1,4-addition product.
Furthermore, the yellow color of solution of receptor 1 was changed to orange color (Fig. 9).
This color change was not observed during UV titration. All of these results indicated that a
new compound was formed from the nucleophilic 1,4-addition reaction to the carbonyl group
of receptor 1.
1
Figure 8. H NMR spectra of 2 mM of 1 with 3 equivalents of tetrabutylammonium cyanide
in DMSO-d6.
1
7

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Figure 9. Color changes of solution of 1 in the presence of various anions (100 equiv.) in 400
µM DMSO solution.
Interaction with halides
Bindings of halides were not observed.
Modeling Studies
Based on the NMR titration data, we have constructed binding poses as shown in Figure 10.
The three hydrogens are close to bound anions. When acetate and phosphinate guests are
complexed, the complexes have very well defined three hydrogen bonding interactions.
However, when halides are complexed, the three hydrogen bonding structures are rather
strained. Consequently, the bound structures become more non co-planar compared to
corresponding free hosts. This may explain non detection of halides in experiments (UV and
NMR) and very low binding energy in theoretical calculations (DFT).
1
8

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phosphinate ꢀ1
acetateꢀ1
chlorideꢀ1
Figure 10. B3LYP/6-311G(d,p) - optimized structures of complexes with host 1. The three
hydrogens mainly involved in hydrogen bonding with guest anions are shown. Other
hydrogens are omitted for clarity. (From left, pyrrole H, vinyl H, and amide H are shown.)
Host
Guest Anion
∆E
∆EBSSEC
-66.31
-42.61
-40.26
-33.54
-54.32
-48.24
-45.33
-53.06
-59.86
-38.09
-36.12
-30.31
-49.76
-44.23
-41.76
-44.43
∆E(DMSO)
-6.85
-
F
-
100.03
-
Cl
-
43.96
42.48
34.72
63.82
55.72
52.98
58.89
93.47
39.38
38.28
31.44
59.15
51.49
49.32
51.66
-3.17
-
Br
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-2.82
-
I
-1.54
1
acetate
-16.12
-15.01
-13.85
-17.12
-2.51
benzoate
cyanoacetate
phosphinate
-
F
-
Cl
-1.34
-
Br
-1.21
-
I
-0.67
2
acetate
-13.31
-12.54
-11.59
-12.01
benzoate
cyanoacetate
phosphinate
Table 2. Binding Energies Calculated with B3LYP/6-311G(d,p)
E is electronic energy. ∆EBSSEC is electronic energy with basis set superposition error
∆
correction(BSSEC). ∆E(DMSO) denotes binding energy in DMSO solution using polarizable
continuum (PCM) model after BSSEC. Units are in kcal/mol.
1
9

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The binding Gibbs free energies could be obtained from the second derivative calculations
(Hessian). However, the values obtained using partition function were not reasonable,
probably owing to the floppy nature of complexes which give large errors to entropy terms.
Therefore in this work, we report only electronic binding energies(Table 2). The first column
(
∆E) is the binding energy before basis set superposition error correction. The second column
∆EBSSEC) is binding energy after BSSEC. The last column [∆E(DMSO)] is the binding
(
energy when the complexes are immersed in DMSO solvent using polarizable continuum
model (PCM). Since the experiments were performed in DMSO solvent, our discussion
would be based on these values unless otherwise noted. Two trends can be noted from Table
2
. The absolute magnitude of complexation energy with host 1 is always greater compared
with the corresponding anion guest with host 2. This should come from electron withdrawing
effect of the cyano group which is trans to the vinyl hydrogen with respect to carbon-carbon
double bond. The second trend is very large binding energy difference between
phosphinate/acetates and halides. The binding energies for halides are 1~4 kcal/mol, while 12
~
17 kcal/mol for acetates/phosphinate. This may come from strain when halides are
complexed to host 1 and 2. There are three H-bondings when an anion is complexed to host 1
or 2. Since in hydrogen bonding, the distances between donor hydrogen and acceptor anion
are important, the distances involving these structures (the dotted lines in Figure 10) are
-
-
tabulated in Table S1. Except that fluoride(F ) has shorter distance for amide H --- F for host
2
compared to host 1, all other H-bonding distances are shorter for anionꢀ1 complex than
-
the corresponding distances for anionꢀ2 complex. The reason why amide H --- F distance is
shorter for host 2 is not clear. Hydrogen binding is generally very strong for fluoride, the
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-
-
structures F ꢀ1 and F ꢀ2 are strained. As shown in Figure 10, the complexity involving the
convergence of three hydrogen bonding elements into one anion center could be responsible
for this anomaly. The overall hydrogen bonding distance data indicate stronger binding for
host 1 in all cases. Each anion guest was drawn closer to host 1 compared to host 2 when it
was complexed. The relative order of binding energy has better correlation with experimental
binding constants with ∆EBSSEC, rather than with ∆E(DMSO). This might reflect the
crudeness of PCM calculation schemes.
When we compare oxo-anions, the relative distances roughly reflect the relative binding
energy. As the H-bonding strength gets larger, the H-bonding distance becomes shorter. For
example, acetate and phosphinate has the distance of 1.63 and 1.62 ꢁ with pyrrole H of host
1
, while this H-bonding distances are significantly elongated with benzoate and cyanoacetate
(1.66 and 1.68 ꢁ).
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1

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Table 3. Partial Charges of Binding Hydrogens
Host
Guest Anion
Free Host
Pyrrole H
Vinyl H
0.210
0.247
0.239
0.237
0.228
0.239
0.237
0.233
0.243
0.197
0.235
0.231
0.229
0.220
0.231
0.229
0.225
0.235
Amide H
0.390
0.450
0.431
0.427
0.416
0.447
0.446
0.441
0.454
0.386
0.452
0.429
0.426
0.413
0.446
0.445
0.441
0.453
0.434
0.460
0.455
0.450
0.441
0.456
0.457
0.455
0.467
0.406
0.459
0.454
0.448
0.440
0.457
0.457
0.456
0.467
-
F
-
Cl
-
Br
1
-
I
acetate
benzoate
cyanoacetate
phosphinate
Free Host
-
F
-
Cl
-
Br
2
-
I
acetate
benzoate
cyanoacetate
phosphinate
Partial charges were obtained from natural population analysis (NPA)
The partial charges of three hydrogens in host 1 are bigger than those of the corresponding
hydrogens in host 2 (Table 3). When they are not complexed (free hosts), partial charges of
three hydrogens of host 1 are more positive than those of host 2 by 0.012, 0.004 and 0.028 for
vinyl H, amide H, and pyrrole H, respectively (Table 3). This electron depletion of all three
hydrogens indicates that the substitution of cyano group has an impact spanning all three
hydrogens probably through almost planar π-electron network.
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2

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Moreover, then they are complexed to an anion, all the hydrogens become more positive,
indicating electron depletion around the donor hydrogens which are involved in hydrogen
bonding. This is consistent with the down-field chemical shifts found for all three hydrogens
in host 1 and 2 in NMR titration experiments.
Computational Procedure
4
2
All the calculations have been performed with Gaussian 09 suite of programs . We have
4
3
used popular hybrid B3LYP functional with extensive basis sets of 6-311++G(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.
Since Gibbs free energy values were not reasonable, in this work we only reported electronic
44
binding energy. Solvation effects were handled with polarizable continuum model (PCM)
using dielectric constant of DMSO. Partial charges were evaluated using natural population
analysis scheme. For geometry inspection, GaussView 5.0 was used.
Conclusion
We have designed and synthesized new anion receptors 1 and 2, which have amide N-H,
pyrrole N-H and vinyl C-H as hydrogen bond donors. These receptors are selective for
dimethyl phosphinate and carboxylates. While most of anion receptor researches are
concentrated on well-known anions such as halides, carboxylates and dihydrogen phosphates,
anion receptor selective for dimethyl phosphinate is unprecedented as far as we know.
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3

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Furthermore, these receptors could discriminate dimethyl phosphinate from diphenyl
phosphate and dihydrogen phosphate. Due to the electron withdrawing effect of the cyano
group which is trans to the vinyl hydrogen with respect to carbon-carbon double bond,
receptor 1 has higher binding constant for carboxylate than receptor 2. The larger downfield
shift of hydrogen bonded hydrogens and the increase in binding constant for the receptor 1
result from the increased hydrogen bond ability of amide, pyrrole and vinyl hydrogen. The
partial positive charges of these hydrogens were increased by the cyano group in the receptor
1
. Modeling studies showed that cyano group seems to polarize all three hydrogens through
π-electron network. In addition, receptor 1 gave orange color 1,4 - addition product for
cyanide.
Conclusion
We have designed and synthesized new anion receptors 1 and 2, which have amide N-H,
pyrrole N-H and vinyl C-H as hydrogen bond donors. These receptors are selective for
dimethyl phosphinate and carboxylates. While most of anion receptor researches are
concentrated on well-known anions such as halides, carboxylates and dihydrogen phosphates,
anion receptor selective for dimethyl phosphinate is unprecedented as far as we know.
Furthermore, these receptors could discriminate dimethyl phosphinate from diphenyl
phosphate and dihydrogen phosphate. Due to withdrawing effect of the cyano group which is
trans to the vinyl hydrogen with respect to carbon-carbon double bond, receptor 1 has higher
binding constant for carboxylate than receptor 2. The larger downfield shift of hydrogen
bonded hydrogens and the increase in binding constant for the receptor 1 result from the
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4

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increased hydrogen bond ability of amide, pyrrole and vinyl hydrogen. The partial positive
charges of these hydrogens were increased by the cyano group in the receptor 1. Modeling
studies showed that cyano group polarizes all three hydrogens through π-electron network. In
addition, receptor 1 gave orange color 1,4 - addition product for cyanide.
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).
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