1,3-Phenyl linked urea-based receptors for anions and the facile cyclization to imidazolidinedione

Article abstract of DOI:10.1016/j.tetlet.2012.08.001

Amino acid-based molecules containing a bis-urea moiety have been synthesized and demonstrated for their anion binding affinities. Compound 1c binds phosphate and sulfate with binding constants of 3.6 × 10³ M^-1 and 4.3 × 10³ M^-1, respectively. These molecules undergo proton transfer upon treatment with fluoride, resulting in the formation of imidazolidinediones. The crystal structure of one such diimidazolidinedione displays self-assembly through nonconventional hydrogen bonding interactions. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.001

Tetrahedron Letters 53 (2012) 5523–5527
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,3-Phenyl linked urea-based receptors for anions and the facile cyclization to
imidazolidinedione
V. Haridas a, , Sandhya Sadanandan a, Geeta Hundal b, Cherumattathu H. Suresh c
⇑
a Department of Chemistry, Indian Institute of Technology, New Delhi 110016, India
b Department of Chemistry, Guru Nanak Dev University, Punjab 143005, India
c Computational Modeling and Simulation, National Institute for Interdisciplinary Science and Technology (NIIST-CSIR), Trivandrum 695019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Amino acid-based molecules containing a bis-urea moiety have been synthesized and demonstrated for
their anion binding affinities. Compound 1c binds phosphate and sulfate with binding constants of
3.6 Â 103 MÀ1 and 4.3 Â 103 MÀ1, respectively. These molecules undergo proton transfer upon treatment
with fluoride, resulting in the formation of imidazolidinediones. The crystal structure of one such diim-
idazolidinedione displays self-assembly through nonconventional hydrogen bonding interactions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 July 2012
Revised 30 July 2012
Accepted 2 August 2012
Available online 8 August 2012
Keywords:
Receptors
Urea
Anions
Cyclization
Imidazolidinedione
The design of molecular receptors is considered a way to under-
stand the workings of biological receptors and thus to understand
the underpinning mechanisms of molecular recognition in biolog-
ical systems. There are intricate examples of molecular recogni-
tion; the high accuracy in these processes are benchmark models
for synthetic chemists to imitate.1 Seventy percent of enzyme sub-
strates are anions,2 underscoring the importance of anion recogni-
tion in biological systems. Therefore, the design and synthesis of
anion receptors are of special significance. Nature has employed
various proteins and cyclic peptides for anion and cation transport
across biological membranes to maintain the ionic equilibrium
across the plasma membrane.3 The design and synthesis of ion-
binding artificial molecules may serve as a good chemical model
and also may have applications in biology and medicine.4 Such
molecules can also serve as sensors for the identification of various
trace anions.5
The recognition of anions by synthetic receptors is achieved by
incorporating various binding moieties like amide,6 pyrrole,7 urea,8
thiourea,9 or triazole.10 The success of the design depends on the
conformation of the receptor; this determines the type of anion
it can bind. Spherical anions (e.g., halides), linear anions (e.g., azide
and cyanide) and tetrahedral anions (e.g., phosphate) require
appropriate cavities, sizes and complementarities.11 Herein we
report a receptor molecule with urea linkages capable of binding
anions. The urea linkage is incorporated into the molecule using
a reaction between 1,3-phenyl diisocyanate and amino acid methyl
esters. The urea linkages are incorporated into the 1,3 positions of
the phenyl ring in order to bind anions in a cooperative fashion to
impart selectivity.12 With this notion, we designed and synthesized
various amino acid-based molecules 1a–c (Scheme 1). All of the
synthesized molecules were characterized by NMR and high
resolution mass spectrometric analysis (HRMS).
We envisioned that compounds 1a–c could potentially bind
anions, owing to the urea moieties present in the structure and this
notion was confirmed experimentally. The binding of anions was
studied by monitoring the 1H NMR spectrum after sequential
addition of tetrabutylammonium salts of anions to compound 1c
in chloroform. The high solubility of 1c in chloroform prompted
us to do detailed binding studies using 1c. The addition of tetrabu-
tylammonium salts to 1c showed a downfield shift of the NH pro-
tons (Ha and Hb) and the aromatic proton Hd (Figs. 1, S1, S3, S5, S6,
S7, S8 and S11). This supports the involvement of all four NHs in
binding to anions. Careful analysis of the NMR spectra showed that
the protons of the phenyl ring exhibit interesting characteristics.
Upon binding to halide (FÀ, ClÀ, BrÀ, and IÀ), the Hd protons
shifted downfield at first and then shielded upfield (Figs. S1, S3,
S6 and S8). These initial deshielding and later shielding are due
to the C–H polarization effect, it is an anion-induced through-bond
electrostatic effect first observed by Fabbrizzi et al.13 Interestingly,
our system deals with two urea moieties attached to a phenyl ring;
this led to some additional observations. The Hd proton was
⇑
Corresponding author. Tel.: +91 1126591380.
E-mail address: h_haridas@hotmail.com (V. Haridas).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.001

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V. Haridas et al. / Tetrahedron Letters 53 (2012) 5523–5527
O
H2N
OCH3
R2
O
O
R1
TBAF
HN
NH
NH
N
N
OCN
NCO
HN
R2
NH
R2
HN
O
O
O
O
R1
R2
R1
R1
R1
O
O
R2
OCH3
OCH3
2a-c
98-99%
1a-c
70-72%
R1=
a
R2=
CH3
CH3
H
b
c
CH3
H
CH2CH(CH3)2
Scheme 1. Synthesis of receptor molecules.
Figure 1. Change in 1H NMR (300 MHz, CDCl3) of receptor 1c with the addition of varying amounts of TBAHPO4 (0, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4 equiv). Peaks were assigned
using COSY analysis (Fig. S14).
deshielded during initial binding events as a result of polarization,
Table 1
and was later shielded because of the deprotonation of NH
(Fig. S2b). In fluoride binding (contrary to other halides), Hc was
first shielded and then deshielded (Fig. S2c), because of the first
dominant through-bond electrostatic effect. In the later stage of
binding, the Hc proton was majorly influenced by the polarization
effect, which resulted in a downfield shift of the Hc proton. In the
case of fluoride binding to 1c, the NH protons (Hb) have disap-
peared after the addition of 2.5 equiv of TBAF (Fig. S1) implying a
deprotonation event. The high basicity of the fluoride compared
to other halides, is the reason for deprotonation.
Association constants for receptor 1c with anions in
CDCl3. Anions used were in the form of their tetrabu-
tylammonium salts
Anions
Ka (MÀ1
)
FÀ
752
385
222
89
3610
4300
ClÀ
BrÀ
IÀ
À
H2POÀ4
HSO4

V. Haridas et al. / Tetrahedron Letters 53 (2012) 5523–5527
5525
Figure 2. X-ray crystal structure of 2b.
The NMR titrations and the non-linear regression analysis of the
data using WinEQNMR enabled us to calculate the binding con-
stants for each anion (Table 1).14 The receptor 1c could also bind
conditions of the binding studies, we observed no cyclization reac-
tions. Other halide anions did not induce cyclization under the
same reaction conditions. Among the compounds 1a–c, 1b showed
a strong tendency toward cyclization. This might be the effect of
À
to H2PO4 and HSO4À, as evident from the large downfield shift of
the amide NHs and aromatic protons. The binding studies showed
gem dimethyl substituents present on the Ca carbon atom, which
that 1c binds in the order HSO4À > H2PO4À > FÀ > ClÀ > BrÀ > IÀ.
facilitates easier cyclization to a five-membered ring than other
amino acids. Easy access to amino acid-based hydantoin is there-
fore a noteworthy observation.18 Hydantoin derivatives are biolog-
ically active and display diverse pharmacological properties such
as anticonvulsive, antiarrhythmic, antimicrobial, antidepressant,
antiviral, herbicidal, fungicidal, insectisidal etc.19 Moreover the
1,3-phenyl-linked hydantoin moieties are useful building blocks
for peptide design, as recently demonstrated by Jamieson and
Hamilton et al. by crafting beta strand mimetics.20
Compound 2b was crystallized from chloroform and methanol
(1:1) and the X-ray crystal structure shows that there are two crys-
tallographically independent molecules in the unit cell which are
rotated by 72.1(1)° with respect to each other (Fig. 2). Within each
molecule the five membered rings are almost gauche with respect
to the central phenyl ring (dihedral angles between them being
56.9(1), 55.1(1); 59.2(1) and 55.0(1)°). Each crystallographically
independent molecule is forming intermolecular H-bonding with
its symmetry related molecules via N–H. . .O type of H-bonds (Ta-
bles S1–S5) generating twisted ribbon like linear chains parallel
to b axis (Fig. 3). These chains are further connected to each other
by various C–H. . .O type of H-bonding interactions some of which
have been shown in Fig. 3, forming a two dimensional H-bonded
network.
It is noteworthy that the NH and carbonyl of 2b are used for
hydrogen bonding to form a linear chain, whereas the other oxygen
(not part of the amino acid) is used for C–H. . .O hydrogen bonding.
The imidazolidinedione unit of one molecule stacks with imidazo-
lidinedione of the other molecule and this trend continues to form
the string arrangement. The chemical structural representation is
given in Figure 3c, clearly shows the interactions.
In conclusion we have shown that 1,3-phenyl linked bis-urea
type molecules based on amino acids are good receptors for spher-
ical as well as tetrahedral anions. The receptors undergo base in-
duced deprotonation of the urea NH leading to cyclization to
provide hydantoin. This reaction may serve as new method for
The phosphate binding showed nearly equal downfield shifts (Dd)
for NHa and NHb, implying that phosphate is positioned between
these protons, perhaps because of its tetrahedral geometry. On
the other hand, the halide binding showed an increased binding
to NHb compared to NHa, implying the placement of halide well
within the cavity of the receptor near Hc. This is supported by the
downfield shift of the Hc proton.
In the case of phosphate, there was no significant change in the
Hc proton (Fig. 1) indicating that the anionic sites of the phosphatÀe
were far away from the Hc proton. The 1H NMR spectra of HSO4
binding showed similarity to phosphate binding, except that there
was a disappearance of NHa (Fig. S11), indicative of a proton transfer
event. The stronger binding and close proximity of the sulfate anion
to the NHa might be the reasons for the observed deprotonation.
À
À
The Job’s plot (Figs. S9 and S12) for the H2PO4 and HSO4
complexation by 1c indicated a 1:1 stoichiometry with a binding
constant of 3.6 Â 103 MÀ1 and 4.3 Â 103 MÀ1, respectively. The
unusual shift of Hd protons is a noteworthy feature of this type
of receptors.15 The tetrahedral phosphate anion binds to the four
urea NHs through O. . .H hydrogen bonds. The DFT modeling stud-
ies at PBEPBE/6-311G(d,p) level (Perdew-Burke-Ernzerh functional
for exchange and correlation)16 support the experimental findings
that the phosphate ion fits well in the cavity between the two urea
moieties (Fig. S15) of the receptor to form a 1:1 complex. The phos-
phate makes strong hydrogen bonds with all the N–H bonds of the
urea moieties as well as carbonyl group of one of the ester moieties
of the receptor and this leads to 44.7 kcal/mol stabilization of the
complex.
Interestingly, stirring a solution of 1a–c in acetonitrile with
TBAF gave 2a–c, namely, imidazolidinedione (hydantoin), which
was confirmed by 1H NMR and HRMS (Supplementary data). Alter-
natively, we noted that the receptors 1a–c slowly change to cyclic
analogs 2a–c, on stirring a methanolic solution of 1a–c in the pres-
ence of triethyl amine.17 It should be mentioned that, under the

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V. Haridas et al. / Tetrahedron Letters 53 (2012) 5523–5527
Figure 3. The self-assembly of 2b (a) packing diagram showing the ribbon-like linear chain. The chains are connected by CH. . .O hydrogen bonds to give rise to two
dimensional sheet (b) structural representation of the interactions present in the solid state. Methyl groups are omitted for clarity.
4. Talukdar, P.; Bollot, G.; Mareda, J.; Sakai, N.; Matile, S. Chem. Eur. J. 2005, 11,
6525–6532.
vealed a unique self-assembly through non-conventional hydrogen
5. (a) Sessler, J. L.; Gale, P. A.; Cho, W-S. Anion Receptor Chemistry; RSC publishing:
hydantoin synthesis. The crystal structure of hydantoin 2b re-
bonding interactions. Therefore, hydantoin units could be a prom-
ising motif for crystal engineering studies.
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We thank the Department of Science and Technology (DST),
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analysis. IIT Delhi and IIT Bombay for single crystal XRD.
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Supplementary data
Supplementary data associated with this article can be found, in
the onlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.001.
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