Bis-Selenoureas for Anion Binding: A 1H NMR and Theoretical Study

Article abstract of DOI:10.1002/cplu.202000260

The anion binding ability of a family of bis-selenoureas L1-L3 obtained by the reaction of 1,3-bis(aminomethyl)-benzene and phenylisoselenocyanate, p-methoxyphenylisoselenocyanate and naphtylisoselenocyanate, for L1, L2, and L3, respectively, has been tested and compared to that of previously described bis-urea analogues. Results suggest that the introduction of selenium leads to an increase in the acidity of the urea NH hydrogen atoms, and therefore to a stronger affinity (more than three-fold higher) towards anion species, in particular dihydrogen phosphate, in DMSO-d₆. Theoretical calculations allowed for the optimization of the adducts receptors corroborating the experimental results.

Full text of DOI:10.1002/cplu.202000260

A Multidisciplinary Journal Centering on Chemistry
Accepted Article
Title: Bis-selenoureas for anion binding: a 1H-NMR and theoretical
study.
Authors: Giacomo Picci, Rita Mocci, Gianluca Ciancaleoni, Vito
Lippolis, Mariola Zielińska-Błajet, and Claudia Caltagirone
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To be cited as: ChemPlusChem 10.1002/cplu.202000260
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01/2020

10.1002/cplu.202000260
ChemPlusChem
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Bis-selenoureas for anion binding: a 1H-NMR and theoretical
study.
Giacomo Picci,*[a] Rita Mocci,[a] Gianluca Ciancaleoni,[c] Vito Lippolis,[a] Mariola Zielińska-Błajet[b] and
Claudia Caltagirone*[a]
[a]
Dr. G. Picci, Dr. R. Mocci, Prof. V. Lippolis, Prof. C. Caltagirone
Dipartimento di Scienze Chimiche e Geologiche
Università degli Studi di Cagliari
SS 554 Bivio per Sestu, 09042 Monserrato (CA), IT
E-mail: gpicci@unica.it, ccaltagirone@unica.it
Dr M. Zielińska-Błajet,
Department of Organic and Medicinal Chemistry
Faculty of Chemistry, Wrocław University of Science and Technology
Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Prof. G. Ciancaleoni
[b]
[c]
Dipartimento di Chimica e Chimica Industriale (DCCI)
Università di Pisa
Via Giuseppe Moruzzi, 13 - 56124 Pisa, Italy
Supporting information for this article is given via a link at the end of the document
Abstract: The anion binding ability of a family of bis-selenoureas
L1-L3 obtained by the reaction of 1,3-bis(aminomethyl)-benzene and
phenylisoselenocyanate, p-methoxyphenylisoselenocyanate and
naphtylisoselenocyanate, for L1, L2, and L3, respectively, has been
tested and compared to that of previously described bis-ureas
analogous. Results suggest that the introduction of selenium leads
to an increase in the acidity of the urea NHs and, therefore, to a
stronger affinity (more than three-fold higher) towards anion species,
dihydrogen phosphate in particular, in DMSO-d6. Theoretical
calculations allowed for the optimization of the adducts receptors
corroborating the experimental results.
VI group in the Periodic Table interesting trends can be
highlighted. For example, in analogous compounds containing
chalcolgen atoms, the electronic absorption and emission
maxima shift to longer wavelengths moving from oxygen to
sulfur to selenium as their softness increases.[14] Indeed,
selenium shows a borderline hard/soft nature that can be tuned
depending on the molecular scaffold, thus determining the
chemical properties of its compounds. In fact, due to the low
oxidation potential of selenium (Se(s)=>Se2-(aq) =-0.40 V) and its
capacity to change its valence state, organoselenium derivatives
are very effective as anti-oxidant against thiols and ROS.[15]
Selenoureas are
a class of organoselenium compounds
particularly interesting in the field of Supramolecular Chemistry.
They can be considered both as Lewis bases due to the lone
pairs on the selenium atom, which can act as a hydrogen bond
acceptor, and hydrogen bond donors at the –NH groups;
importantly, there is an electronic ‘‘communication’’ between the
two moieties through resonance.[16] Limited data on the
electronic structure of selenoureas suggests that compared to
analogous ureas and thioureas, the presence of the larger, more
polarizable selenium, affords a slightly higher delocalization of
the electron density.[17] Currently, the most common use of
selenourea compounds is in the antioxidant activity field,[18] as
well as in enzyme inhibition, and DNA binding properties where
anions play a crucial role.
Introduction
Selenium is a controversial element.[1] In the past, it was
described as a highly toxic element for biological systems
causing poisoning. However, in the last decades it has been
discovered that selenium is an essential nutrient for the correct
physiological processes in the human organism.[2] At this
purpose, a very important role in the self-defence mechanism
against oxidative stress is played by some selenoproteins such
as glutathione peroxidase,[3] in which selenium plays an active
role in important redox reactions with ROS species (Reactive
Oxygen Species).[4] Alterations in the equilibrium between the
oxidative stress and the selenium levels lead to several health
issues such as rheumatoid arthritis,[5] pancreatitis, diabetes[6]
and cardiovascular complications. Recent studies have
highlighted that many selenium derivatives show anticancer
properties being able to cause apoptosis of tumor cells and
induce a reduction of cancerous metastasis in animals.[7]
Moreover, a wide range of selenium compounds show anti-
inflammatory, antihypertensive, antiviral, antibacterial, and
antifungal properties.[8]
Following our interest in the Supramolecular Chemistry of anion
recognition, we have recently started exploiting selenoureas for
anion recognition and sensing. We have described the first
example of a chromo-fluorogenic chemosensor containing a
selenourea moiety that is able to colorimetrically sense the
presence of CN- and S2-; in this system the sensing mechanism
is based on the formation of a diselenide derivative.[19] We have
also proposed the first example of molecular logic gate based on
selenoureas/ anions host-guest interaction, that performs a
1
ternary logic operation using a H-NMR easy to read response
Due to these significant properties, the interest towards
selenium compounds has quickly developed. Indeed, the use of
organoselenium derivatives such as isoselenocyanates,[9]
selenocarbamates,[10]selenoheterocycles[11] and selenoureas[12]
as key synthetic intermediates and ligands in asymmetric
synthesis has become very popular.[13] Moving down along the
output and simple chemical inputs such as the steric hindrance
of the aryl substituents in selenoureas, and the geometry of the
anion guest.[20] Recently, the transmembrane anion transport
ability of tripodal selenoureas was studied.[21]
To the best of our knowledge, no examples of bis-selenoureas
have been reported so far in the literature. With this in mind, we
1
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the presence of several dehydrating reagents [TCT
(trichlorotriazine), T3P (1-propanephosphonic anhydride),
POCl3]. This brought us to follow a different approach, reported
in the synthetic procedure b) in Scheme 3, according to the
Hoffman carbylamines reaction that sees the formation of
isocyanide (3) directly from the aryl amine (1) using chloroform
and NaOH as reagents in a biphasic mixture.[24] This approach
allowed us to obtain the naphthyl isocyanide in satisfactory yield
(30%), to be reacted in the following reaction step (Scheme 3b).
All receptors were obtained in moderate yields (from 40% to
65%). Synthetic details are reported in the Experimental Section.
wished to investigate whether the presence of two selenourea
moieties within the structure of the receptor could be able to
improve the anion binding properties of the system and to tune
the dimension of the pseudo-cavity of the receptor. Indeed, we
now report the synthesis of a new family of functionalised bis-
selenourea-based receptors L1-L3 reported in Scheme 1 for
anion recognition.
1
Solution studies by means of H-NMR titrations in DMSO-d6 in
the presence of different anion species were performed.
Furthermore, theoretical calculations studies were carried out in
order to better understand the experimental results and support
them.
Scheme 2. Synthetic scheme for the preparation receptors L1-L3.
Scheme 1. Receptors studied in this paper
Results and Discussion
Synthesis. The synthesis of receptors L1-L3 (see Figures
S1-S6 in the Supporting Information for 1H- and 13C-NMR
spectra) was carried out following the synthetic procedures
reported in Scheme 2 by reacting at room temperature in DCM
and in the dark the 1,3-bis(aminomethyl)-benzene with the
corresponding isoselenocyanate previously synthesized. The
formation of the isoselenocyanate and isocyanide derivatives
was performed following literature procedures[22] (Scheme 3).
In the case of receptors L1 and L2, as reported in the synthetic
procedure a) in Scheme 3, the starting N-phenylformamide
and N-(4-methoxyphenyl)formamide (2) were prepared reacting
the corresponding aryl amines (1) with formic acid in toluene.
Afterward, the desired isocyanides (3) were prepared by
reacting the obtained formamides (2) with POCl3 in the presence
of NEt3.[23]
As far as the synthetic procedure to obtain the receptor L3 is
concerned, while the formation of the N-naphthylformamide
proceeds smoothly by microwave (MW) irradiation at 100 °C of a
solution of the N-naphthylamine in ethyl formate (see general
procedure for the synthesis of arylformamides (procedure b) in
the Experimental Section), the subsequent dehydration process
revealed to be not trivial and the product was not recovered in
Scheme 3. Synthetic procedures for the preparation of the isoselenocyanate;
a) i) formic acic, toluene, 70°C, 24 hs; ii) POCl3, Et3N, CH2Cl2, r.t., 24 hs; iii)
Selenium powder, CH2Cl2, r.t., 24 hs, dark; b) iv) CHCl3, NaOH,
Tetrabuthylamonium iodide (TBAI) as phase transfer; iii) Selenium powder,
CH2Cl2, r.t., 24 hs, dark.
1H-NMR anion binding studies. In order to evaluate the
anion binding affinity of L1–L3, 1H-NMR titrations in DMSO-d6 as
a solvent were performed with chloride (Cl-), benzoate (BzO-),
-
dihydrogen phosphate (H2PO4 ) and hydrogen pyrophosphate
(HPPi3-) as their tetrabutylammonium salts (see Figures S7-S10
in the Supporting Information). Stability constants from the
obtained 1H-NMR titration curves (see Figures S11-S19) were
calculated by fitting the data to a 1:1 binding model using
WinEQNMR[25] as shown in Table 1.
2
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A dramatic downfield shift (Δppm 1.97) of the signal attributed to
the “internal” selenourea NHs (in blue in Figure 1) was also
observed suggesting the formation of a 1:1 anion-receptor
adduct via the formation of H-bond. L1-L3 show a moderate
selectivity for dihydrogen phosphate, with stability constants
following the order L1>L3>L2.
Table 1. Association constants (Ka/M−1) for the formation of adducts of L1-L3
and A and B (Scheme 1) with anions added as tetrabutylammonium salts in
DMSO-d6 at 298 K. The downfield shift of the signal attributed to the “internal”
selenourea NH was followed to fit the titration data. All errors estimated to
be≤14%
HPPi3-
H2PO4
BzO-
Cl-
-
This trend is expected as the presence of the electron donating
p-methoxy group on the phenyl substituents of L2 should
decrease the acidity of the selenourea NHs, and thus their H-
bond donor properties.
In order to evaluate how the presence of selenium could affect
the anion binding properties of these systems, we compared the
results of the 1H-NMR titrations of L1 and L3 with those
previously reported by our group for the analogous bis-ureas A
and B (Scheme 1).[26]
1941
515
25
L1
L2
L3
A
Deprot.
315
1219
484
80
277[a]
65
16
Deprot.
Deprot.
5480
<10
-
B
>104
435
78
-
The stability constants reported in Table 1, highlight a stronger
affinity (more than three-fold higher) towards dihydrogen
phosphate for L1 and L3 than the analogous bis-ureas A and B.
This behavior is probably due to the increased positive charge
on the –NH group (i.e. a higher acidity) caused by the higher
polarizability of the selenium atom which tends to stabilize the
selenoamide group in the zwitterionic form (Se=C-NH- ↔ Se--
C=NH+-).
[a] This association constant is only indicative of the interaction as a partial decomposition of the receptor was observed
in the presence of an excess of anion (see SI, Figure S10B).
Under the experimental conditions considered, in the presence
of hydrogen pyrophosphate a large downfield shift followed by
1
the disappearance of the H-NMR signals attributed to the bis-
selenourea NHs was observed for all receptors upon the
addition of 0.2 equivs. of anion guest, accompanied by a
However, it is interesting to note that for the bis-ureas no
deprotonation is observed with pyrophosphate in agreement with
a lower acid character of the NHs hydrogen atoms in these
systems. Furthermore, the highest stability constants were
observed with B in presence of the hydrogen pyrophosphate,
and this was attributed to the possibility to establish an
additional H-bond between the anion species and one of the
dramatic colour change of the solution, suggesting
deprotonation for all the receptors with this anion. Moreover, the
precipitation of black selenium was observed.
As expected, on the base of the Lewis basicity of anions, L1-L3
displayed better binding properties towards oxoanions than
chloride (Table 1). In particular, L1-L3 showed a stronger affinity
towards dihydrogen phosphate compared to benzoate, less
pronounced in the case of L2 than L1 and L3.
a
-
naphtyl CHs that stabilised the adduct.[26] In the case of H2PO4 ,
-
the stability constants of A and B are almost identical and
significantly lower than those calculated for L1 and L3. This still
agree with the increased acid character of the NHs hydrogen
atom determined by the selenium atom.
The stack-plot for the titration of L1 in the presence of H2PO4 is
reported in Figure 1. Following the downfield shift of the signals
attributed to the selenourea NHs we observed the progressive
broadening and, eventually, in the presence of an excess of
anion (up to 5 equivalents), the disappearance of the signal
attributed to the NHs adjacent to the phenyl ring of the pendant
arm (in green in Figure 1) probably due to the possible partial
deprotonation of the receptor.
DFT studies. In order to shed more light on the
experimental results summed up in Table 1, the geometry of the
adducts between L1 or L3 and the various anions has been
optimized at DFT level (PBE-D3/def2-TZVP level of theory) by
taking into account the polarity of the solvent by using the
conductor-like polarizable continuum model (c-PCM, DMSO).
Firstly, the most stable geometry of the isolated L1 and L3
receptors have been computed. The two ligands have many
conformational isomers, but the most stable ones contain an
intramolecular π/π interaction between the two phenyl groups
(Figure 2).
L1
L3
Figure 1. Stack-plot of the 1H-NMR titration in DMSO-d6 at 298 K of L1
(0.005M) with dihydrogen phosphate added as tetrabutylammonium salt
(0.075M)
Figure 2. DFT-optimized geometries of L1 and L3 as free
receptors.
3
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The π/π interaction already prepares the ligand for the optimal
interaction with the anion, as all the NH groups are on the same
side with respect to the plane of the central phenyl ring.
Then, the DFT-optimized geometries of L1-Cl-, L1-BzO-, L1-
H2PO4- and L1-HPPi3- have been computed (Figure 3).
20.1 kcal/mol), but the receptor needs 6.0 kcal/mol to modify its
geometry (ΔEprep (L)). The most important of ΔEint is ΔEorb (-18.2
kcal/mol) (Table 2).
The interaction between L1 and the benzoate anion includes a
more stabilizing orbital contributions with respect to L1-Cl-. It is
worth to recall here that the orbital contribution contains both
charge transfer and polarization effects. In the case of the
anions studied here, and considering that hydrogen bonds are
mainly electrostatic in nature, the more negative ΔEorb is clearly
due to the larger polarizability of the benzoate than the chloride.
Also the dispersion forces are more important for L1-BzO- than
for L1-Cl-, which was expected as dispersion forces strengthen
as the molecular surface increases. On the other hand, the
geometry of the receptor is quite different from that of the
isolated L1, therefore ΔEprep (L) is more positive. Also ΔEst is
less favourable. The balance of all the elements makes the
strength of the L1-BzO- interaction only slightly larger than L1-Cl-.
-
For the L1- H2PO4 adduct, ΔEint is larger than previous ones (-
28.7 kcal/mol) mainly because of the more stabilizing orbital
contribution. Also in this case, it can be justified with the larger
polarizability of the dihydrogen phosphate anion.
The same is true for L1-HPPi3-, whose very high value of ΔEint (-
40.8 kcal/mol) is due to the even larger values of ΔEorb and
ΔEdisp. Also the destabilizing terms, ΔEst and ΔEprep, are larger
than in the previous cases, but to a lesser degree.
Figure 3. DFT-optimized geometries of the 1:1 adducts of L1 in presence of
the anions tested.
For L1-Cl-, the Mayer bond order[28] of the H…Cl bonds are
between 0.11 and 0.15 and there is a donation of electronic
density from the lone pairs of the chloride to the σ* orbital of the
N-H bond.
In L1-Cl-, L1-H2PO4- and L1-HPPi3- the anion locates at one side
of the receptor, which orients all the NH moieties in the same
direction. In addition, in these cases the two phenyl rings can
The second-order perturbation theory interaction energy
analysis (as implemented in the Natural Bond Order software,
NBO) gives a stabilization energy (E(2)) for the lp(Cl) → σ*(NH)
contributions of 10.7 kcal/mol.
interact with each other, establishing
a stabilizing CH/π
interaction which substitutes the π/π one present in the
geometry of the isolated receptor. The geometry of L1-BzO- is
slightly different, as the carboxylate group locates between the
two arms of L1, causing their divergence and the loss of
interaction between the two phenyl rings.
-
Similar values can be obtained analysing the L1-H2PO4 adduct:
the H…O bond orders are between 0.10 and 0.14 and E(2) for the
lp(O) →σ*(NH) donations is 6.5 kcal/mol.
On the contrary, for L1-HPPi3- gives different results: the H…O
Mayer bond order is slightly higher (0.12-0.18) and and E(2) for
the lp(O) →σ*(NH) terms is 15.1 kcal/mol.
The energy of the L1-anion interactions results to be -30.1, -24.7,
-
-19.5 and -17.6 kcal/mol for L1-HPPi3-, L1-H2PO4 , L1-BzO- and
L1-Cl-, respectively. The trend is in qualitative agreement with
experimental results (see Table 1). In the geometry of L1- HPPi3-
there is a higher polarization of the N-H bonds (see below) and
the interaction energy is markedly higher than the other cases
Table 2. Energy decomposition analysis for the adducts of L1 and L3 in
presence of the anions studied.
1
and justifies the large shift observed in the first part of the H-
NMR titration before the deprotonation occurs.
ΔE
ΔEint
ΔEst
2.0
ΔEorb
-18.2
-24.5
-27.2
-45.3
-18.8
-26.5
-24.4
-34.8
ΔEdisp
-3.9
ΔEprep
(L)
ΔEprep
(X)
These values can be decomposed in physically meaningful
contributions by using the Energy Decomposition Analysis,[27] in
order to better understand which term is more important in
determining the selectivity. This approach decomposes the
formation energy of the adduct (ΔE) into the preparation energy
(ΔEprep), which is the energy needed to distort the isolated
fragments from their relaxed geometry to the geometry they
assume in the adduct, and the interaction energy (ΔEint). The
latter, in its turn, can be decomposed in a term arising from the
electrostatic interaction between the two fragments (ΔEel), the
repulsive exchange (Pauli) interaction (ΔEPauli), a term deriving
from the orbital mixing and relaxation (ΔEorb), and, finally, a term
for the dispersion forces (ΔEdisp). The sum of ΔEel and ΔEPauli is
called the steric energy, ΔEst. Here, only the latter will be used,
as ORCA 4.1.0 does not allow its decomposition.
L1-Cl-
-14.1
-16.0
-21.1
-30.3
-13.1
-14.6
-19.7
-24.6
-20.1
-23.8
-28.7
-40.8
-20.9
-26.5
-24.1
-30.8
6.0
0.0
L1-BzO-
L1-H2PO4
9.0
-8.3
7.6
5.9
8.3
7.8
11.5
2.9
5.2
0.3
1.7
2.2
0.0
0.4
1.4
1.1
-
6.1
-7.6
L1-HPPi3-
L3-Cl-
15.5
2.2
-11.0
-4.3
L3-BzO-
11.3
9.1
-11.3
-8.8
-
L3-H2PO4
L3-HPPi3-
13.3
-9.4
For example, in the case of L1-Cl-, the adduct is 14.1 kcal/mol
more stable than the isolated fragments (L1 and Cl-). The
interaction between the fragments is stronger than this (ΔEint = -
Therefore, the stronger affinity for phosphate-bases anions can
be explained with their larger polarizabilities and surfaces factors
that enhance the orbital and dispersion terms of the interaction.
4
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In the case of L1-HPPi3-, the NH…O interaction showed also a
slightly larger “covalent” component with respect to the other
adducts.
TBACl a second set of experiments was conducted by titrating a
solution of the receptor (0.005M) in DMSO-d6 with
a
concentrated solution of the guest (2M) in DMSO-d6 (see SI,
Figures S20-S25). The values of the stability constants are
almost identical to those calculated when adding a smaller
excess of chloride.
For receptor L3, the framework is essentially the same, with
small yet significant differences. The intramolecular π/π
interaction in the geometry of the isolated receptor is more
extended and, consequently, the ΔEprep terms are larger for L3-
Cl- and L3-BzO-, leading to smaller ΔE and weaker interactions,
as experimentally evidenced. For the phosphate-based anions
this is not true and the preparation energy is quite small. For L3-
General procedure for the synthesis of the arylformamides
(A).[22] The aryl amine was dissolved in a mixture of 5 mL of
toluene and 2 mL of formic acid. The mixture was kept at 70°C
under vigorously stirring for 24 hs. Then, the solvent was
removed under reduced pressure, washed with water and
extracted with dichloromethane (3 x 10mL). The organic phase
was dried with Na2SO4 and then the solvent was removed under
reduced pressure collecting the product as a crude solid.
-
H2PO4 the smaller ΔEorb and the larger ΔEst concur in the
lowering of ΔEint, whereas for L3-HPPi3-, the main contribution
comes from the dramatic drop in ΔEorb, likely due to larger
receptor/anion distance in the optimized geometry. Indeed, in
L1- HPPi3-, the O…HN distances range from 1.679 to 1.740 Å,
whereas for L3- HPPi3- they are between 1.750 and 1.808 Å.
General procedure for the synthesis of the arylformamides
(B). In a microwave tube the aryl amine was dissolved in a
solution of ethyl formate. The mixture was kept in a microwave
equipment at 100°C for 2hs. After that time a precipitate was
observed. The mixture was filtrated and the solid was dried and
collected as a crude solid.
Conclusion
In conclusion, we have described the first examples of bis-
selenourea-based receptors bearing different aryl substituents
for anion binding. The results obtained in the solution studies by
1H-NMR spectroscopy show that L1 and L3 bearing phenyl and
naphthyl groups as substituents, respectively, strongly interact
with dihydrogenphosphate. In particular, the higher affinity
compared to the analogous bis-ureas previously reported, has
been highlighted in this work. In our hypothesis, this behaviour
could be attributed by the electronic properties of Selenium that
produce an improvement in the H-bond donor properties as
compared to the urea NHs. This fact, might provide valuable
guidance for future anionophore system design.
General
procedure
for
the
synthesis
of
the
isoselenocyanates (A).[22] To a solution of the arylformamide (1
equiv.) in dry dichloromethane (10 mL) under vigorously stirring
triethylamine (6 equivs.) and POCl3 (0.8 equivs.) were added
slowly. The reaction was kept at room temperature under argon
atmosphere for 24 hs. The progress of the reaction was
monitored by TLC. After that time 40 mL of a NaHCO3 saturated
solution was added dropwise (development of gas was
observed) and kept stirring for 2hs (till the gas development
stopped). Then the mixture was repeatedly extracted with
dichloromethane (4 x 10mL) and the organic phases were
combined and then dried over Na2SO4 and concentrated under
reduced pressure. The product obtained was then dissolved in
dry dichloromethane (5mL) and kept under argon atmosphere at
40°C. Selenium powder (3 equivs.) was then added. The
reaction was kept stirring at dark for 24hs and the reaction
progress monitored by TLC. After that time, the mixture was
filtrated over celite to remove the selenium powder in excess
and washed repeatedly with dichloromethane. The solvent was
then removed under vacuo and the residue purified by flash
chromatography on silica gel (eluent depending by the different
substrate used).
DFT studies highlighted that H2PO4 and HPPi3- strongly interact
with L1 and L3 because of dispersion forces and the
polarizability of the anions.
-
Experimental Section
All reactions were performed in oven-dried glassware
under a slight positive pressure of nitrogen. The synthesis of
isoselenocyanate and isocyanide derivatives was performed
following literature procedures.[22] 1H-NMR and 13C NMR spectra
were recorded on a Jeol 400yh and on a Bruker Avance 300
MHz. Chemical shifts for 1H-NMR are reported in parts per
million (ppm), calibrated to the residual solvent peak set, with
coupling constants reported in Hertz (Hz). The following
abbreviations are used for spin multiplicity: s = singlet, d =
doublet, t = triplet, m = multiplet . Chemical shifts for 13C NMR
are reported in ppm, relative to the central line of a septet at δ =
39.52 ppm for deuteriodimethylsulfoxide. Infrared (IR) spectra
were recorded on a NICOLET 5700 FT-IR spectrophotometer
and reported in wavenumbers (cm−1). Elemental analyses were
obtained using a PerkinElmer Series II – 2400. All solvents and
starting materials were purchased from commercial sources
where available. Proton NMR titrations were performed by
adding aliquots of the putative anionic guest (as the TBA salt,
0.075 M) in a solution of the receptor (0.005M) in DMSO-d6 to a
solution of the receptor (0.005M). The downfield shift of the
signal attributed to the “internal” selenourea NH was followed to
fit the titration data. In the case of L1 and L2 in the presence of
General
procedure
for
the
synthesis
of
the
isoselenocyanate (B). To a round bottom flask equipped with a
reflux condenser the aryl amine (1 equivs.) and
tetrabutylammonium Iodide (1 mol %) were dissolved in
chloroform (4 mL). A previous solution of NaOH 50% w/w (3.6
mL) was added to this solution. The reaction was monitored and
kept at 40 °C (exothermic) for 8 hours. The mixture was diluted
with water and the isonitrile extracted with DCM. The solvent
was then removed under vacuo and the residue purified by flash
chromatography on silica gel (gradient Hexane: Ethyl acetate
from 95:5 to 85:15) to collect the product as a crude solid. The
product obtained was then dissolved in dry dichloromethane
(5mL) and kept under argon atmosphere at 40°C. Selenium
powder (3 equivs.) was then added. The reaction was kept
stirring at dark for 24hs and the reaction progress monitored by
5
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10.1002/cplu.202000260
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TLC. After that time, the mixture was filtrated over celite to
remove the selenium powder in excess and washed repeatedly
with dichloromethane. The solvent was then removed under
vacuo and the residue purified by flash chromatography on silica
gel (eluent depending by the different substrate used).
frequencies have been obtained, due to the libration of the
terminal phenyl rings of L1 or L3.
Energy decomposition analysis. The EDA[6][27] has
been performed using the same computational details used for
geometry optimization. The EDA allows the decomposition of the
bond energy into physically meaningful contributions. The
interaction energy (ΔEint) is the difference of energy between the
adduct and the unrelaxed fragments. It can be divided into
contributions associated with the orbital, steric and dispersion
interactions, as shown in eqn (1)
General procedure for the synthesis of the bis-selenoureas
compounds (L1-L3). To a solution of 1,3-bis(aminomethyl)-
benzene (1 equiv.) in dry dichloromethane (4 mL) a solution of
the relative isoselocyanate (2 equivs.) in 2mL of dry
dichloromethane was added. The mixture was kept stirring at
room temperature under argon atmosphere for 24 hs. The
progress of the reaction was monitored by TLC. After that time a
precipitate was observed. Then the mixture was filtrated and the
solid dried collecting the product as a crude solid.
L1: Synthesized starting from 1,3-bis(aminomethyl)-benzene (1
mmol, 136 mg) and 1-phenyl isoselenocyanate (2 mmol, 364
mg) according to general procedure A. The product was
collected as a white solid. Yield 62% 1H NMR (400 MHz, DMSO-
d6) δH 10.05 (s, 2H), 8.50 (s, 2H), 7.34 (m, 9H), 7.22 (m, 5H),
4.81(s, 4H); 13C NMR (125 MHz, DMSO-d6) δC 159.27, 140.80,
138.12, 127.99, 127.69, 126.05, 125.35, 122.86, 120.33, 49.48.
+HR-ESI m/z found (calc.) 503.0257 (503.0253) [M-H]+;
Elemental Analysis: % found (% calc. for C22H22N4Se2): C, 52.79
(52.81); H, 4.41 (4.43); N, 11.18 (11.20).
ΔEint = ΔEst + ΔEorb + ΔEdisp
(1)
For the total interaction energy (ΔE), also the preparation energy
(ΔEprep), which is the energy difference between the relaxed
geometries of the fragments and the geometry they assume in
the adduct, has been calculated (eqn 2)
ΔE = ΔEint + ΔEprep
(2)
ΔEst is usually called the steric interaction energy and it is the
sum of ΔEel, the classical electrostatic interaction between the
unperturbed charge distributions of the fragments (ρA and ρB) at
their final positions in the adduct, and the Pauli repulsion
(ΔEPauli) that is the energy change associated with going from ρA
L2: Synthesized starting from of 1,3-bis(aminomethyl)-benzene
(0.8 mmol, 110 mg) and p-methoxy isoselenocyanate (1.6 mmol, + ρB to the antisymmetrized and renormalized wave function.
341 mg) according to general procedure A. The product was
collected as a grey solid. Yield 66% 1H NMR (400 MHz, DMSO-
d6) δH 9.85 (s, 2H), 8.22 (s, 2H), 7.16 (m, 8H), 6.90 (d, 4H),
4.79(s, 4H), 3.69 (s, 6H); 13C NMR (125 MHz, DMSO- d6) δC
162.50, 144.29, 136.19, 133.27, 132.12, 130.99, 120.11, 119.62,
60.49, 55.38. +HR-ESI m/z found (calc.) 563.0331 (563.0464)
The decomposition of ΔEst is not possible with ORCA 4.1.0. ΔEst
comprises the destabilizing interactions between the occupied
orbitals and is responsible for any steric repulsion. ΔEorb is the
contribution arising from allowing the wave function to relax to
the fully converged one, accounting for electron pair bonding,
charge transfer and polarization, while ΔEdisp is the contribution
of the dispersion forces. NBO analysis has been performed
using the NBO6 suite of software.[34]
[M-H]+; Elemental Analysis:
%
found (% calc. for
C24H26N4O2Se2): C, 51.36 (51.44); H, 4.60 (4.68); N, 9.92
(10.00).
L3: Synthesized starting from 1,3-bis(aminomethyl)-benzene
(0.5 mmol, 68 mg) and 1-naphthyl isoselenocyanate (1 mmol,
232 mg) according to general procedure A. The product was
collected as a white solid. Yield 42% 1H NMR (300 MHz, DMSO-
d6) δH 10.20 (s, 2H), 8.17 (s, 2H), 7.98 (d, 2H), 7.92 (t, 4H), 7.54
(m, 8H), 7.20 (d, 2H), 7.11 (s, 2H), 4.76(s, 4H); 13C NMR (75
MHz, DMSO- d6) δC 161.31, 140.79, 137.80, 135.29, 129.25,
127.98, 126.87, 126.14, 126.06, 125.44, 125.35, 123.44, 121.56,
112.5, 48.45. +HR-ESI m/z found (calc.) 603.0583 (603.0567)
[M+H]+; Elemental Analysis: % found (% calc. for C30H26N4Se2):
C, 59.95 (60.01); H, 4.32 (4.36); N, 9.30 (9.33).
Acknowledgements
C.C. G.P. and V.L. thank MIUR (PRIN 2017 project
2017EKCS35). C.C. and V.L. thank Università degli Studi di
Cagliari (FIR 2016-2019) and Fondazione di Sardegna (FdS
Progetti Biennali di Ateneo, annualità 2018) for financial support.
Keywords: • Anion binding • Chalcogens • DFT • Selenoureas •
Supramolecular Chemistry
Computational Details
All the geometries were optimized with ORCA 4.1.0,[29] using the
PBE functional in conjunction with a triple-ζ quality basis set
(def2-TZVP)[30] and def2/J auxialiry basis[31] for all the atoms
(final grid 5). Dispersion effects were accounted using the
Grimme D3-parametrized correction with Becke–Jonhson
damping to the DFT energy.[32] The solvent has been taken into
account by using the conductor-like polarizable continuum
model, CPCM [5],[33] with the parameters of DMSO, as
implemented in ORCA.
Thermodynamic parameters were computed at the same
theoretical level. In some cases, small unavoidable negative
6
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10.1002/cplu.202000260
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Entry for the Table of Contents
BzO-
-
H2PO4
HPPi3-
The first examples of bis-selenourea-based receptors bearing different aryl substituents for anion binding are described. The
introduction of selenium into the molecular skeleton of bis-ureas improves the anion binding properties of these receptors, towards
dihydrogen phosphate, in particular, as a result of an increase in the acidity of the selenourea NHs. Theoretical calculations
confirmed the experimental results obtained in solution.
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