Phosphate selective alkylenebisurea receptors: Structure-binding relationship

Article abstract of DOI:10.1016/j.tet.2011.03.096

New host molecules for anions, adamantane, and alkyl urea derivatives substituted by naphthalene chromophores, were synthesized. Their binding with F^-, Cl^-, Br^-, OAc^-, HSO ₄^-, NO₃^-, and H₂PO ₄^- was investigated by UV-vis, fluorescence and NMR spectroscopy. The anion binding ability of adamantyl bisurea derivatives was compared with the analogous host molecules, wherein the urea moieties are separated by flexible alkyl linkers of the same length, and adamantane monourea derivative. The host molecules show the highest selectivity toward F^- and H₂PO₄^-. The binding stoichiometry and the values of the association constants depend on the basicity of anions, availability of H-bonding sites, preorganization, and rigidity of the hosts, as well as solvent polarity and H-bonding availability. Rigid adamantane receptors, compared to flexible analogues show increased selectivity for H ₂PO₄^-, whereas binding of OAc^- is better with flexible receptors. The binding of OAc^- and H ₂PO₄^- was investigated by microcalorimetry. The stoichiometries and the stability constants of the corresponding complexes obtained by this method were in good agreement compared to those determined by UV-vis titrations. In both cases the enthalpic contribution to the overall complex stability was predominant.

Full text of DOI:10.1016/j.tet.2011.03.096

Tetrahedron 67 (2011) 3846e3857
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Phosphate selective alkylenebisurea receptors: structure-binding relationship
a
b
a
a,
Vesna Bla ꢀz ek , Nikola Bregovi ꢁc , Kata Mlinari ꢁc -Majerski , Nikola Basari ꢁc
*
a
Department of Organic Chemistry and Biochemistry, RuCer Bo ꢀs kovi ꢁc Institute, Bijeni ꢀc ka cesta 54, 10000 Zagreb, Croatia
Department of Physical Chemistry, Faculty of Science, Horvatovac 102A, 10000 Zagreb, Croatia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
New host molecules for anions, adamantane, and alkyl urea derivatives substituted by naphthalene
Received 7 October 2010
Received in revised form 24 February 2011
Accepted 28 March 2011
Available online 2 April 2011
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
chromophores, were synthesized. Their binding with F , Cl , Br , OAc , HSO
4
, NO
3
, and H
2
4
PO was
investigated by UVevis, fluorescence and NMR spectroscopy. The anion binding ability of adamantyl
bisurea derivatives was compared with the analogous host molecules, wherein the urea moieties are
separated by flexible alkyl linkers of the same length, and adamantane monourea derivative. The host
ꢀ
ꢀ
molecules show the highest selectivity toward F and H
2
PO
4
. The binding stoichiometry and the values
Keywords:
Adamantanes
Ureas
Anion host molecules
NMR titration
UVevis titration
of the association constants depend on the basicity of anions, availability of H-bonding sites, pre-
organization, and rigidity of the hosts, as well as solvent polarity and H-bonding availability. Rigid
ꢀ
adamantane receptors, compared to flexible analogues show increased selectivity for H
2
PO
4
, whereas
ꢀ
ꢀ
ꢀ
binding of OAc is better with flexible receptors. The binding of OAc and H
2
PO was investigated by
4
microcalorimetry. The stoichiometries and the stability constants of the corresponding complexes ob-
tained by this method were in good agreement compared to those determined by UVevis titrations. In
both cases the enthalpic contribution to the overall complex stability was predominant.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
geometries. Urea and thiourea groups are very often used as
binding units in anion supramolecular chemistry. They have
6
Anions play an important role in a range of biological processes.1
They are essential in the formation of a variety of enzymeesub-
strate and enzymeecofactor complexes, as well as in the interaction
between proteins and nucleic acids. ATP and other high-energy
phosphate derivatives provide energy for most biological processes.
On the other hand, mis-regulation of anion transporting mechanisms
results in serious complications and diseases, such as cystic fibrosis.
Consequently, it is essential to develop reagents that can detect the
presence of various anionic analytes and regulate their transport in
the biological systems. This demand sparked significant progress in
two H-bond donating sites that point in the same direction and
hence provide the possibility of constructing highly preorganized
molecular hosts. The urea (or thiourea) moiety has been used as
7
8
a host by attachment to o-phenylene, m-phenylene and xanthene,
9
10
11
12
p-phenylene, naphthalene, anthracene, pyrene, chiral cyclo-
13
14
15
hexanediamine, calix[4]arenes, and anthraquinone. Although
some of the prepared host molecules are characterized by excep-
tional selectivity, there are not many reports where structure and
selectivity were correlated. Many questions remain unanswered,
particularly those related to the number of H-bonding sites and
molecular preorganization that are required for the selective
recognition of particular oxo-anions of different geometries.
Incorporation of urea moieties in rigid spacers, such as nor-
16
2
the field of anion supramolecular chemistry. However, the quest for
good anion hostmoleculesisnotover. Manyscientific groups work on
3
the development of novel hosts characterized by desired selectivity.
17
One way in which host molecules can recognize anionic guests
bornene prompted us to prepare a new class of anion receptors
that would have two urea moieties as a binding site, separated by
an adamantane rigid spacer and different chromogenic and fluoro-
4
is based on electrostatic interactions. However, due to non-di-
rectional properties of electrostatic interactions host molecules
that operate on that principle often suffer from the lack of selec-
1
8
genic groups. Herein we report an anion binding study of
1,3-adamantylenebisureas substituted with a naphthalene chro-
mophore, 3 and 4. The anion binding ability and selectivity of 3 and
4 were compared to the analogous derivatives 1 and 2, wherein the
urea groups are separated by flexible alkyl chains of the same
length. In addition, we investigated the anion binding of monourea
derivative 5. This investigation on specifically designed new host
molecules for anions was undertaken to increase general knowl-
edge in supramolecular anion chemistry regarding the relationship
5
tivity. On the other hand, a very important motif for anion
recognition is hydrogen bonding. Contrary to electrostatic in-
teractions, hydrogen bonding is directional, which is extremely
useful in designing selective hosts for anions with different
*
Corresponding author. Tel.: þ385 1 4561 141; fax: þ385 1 4680 195; e-mail
address: nbasaric@irb.hr (N. Basari ꢁc ).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.096

V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
3847
between selectivity and the number of available binding sites, as
well as to probe for the possibility of cooperativity and allosteric
effects. The results should be of special importance for the rational
design of new receptors characterized by better selectivity.
tetrabutylammonium salts. The following anions, characterized by
ꢀ
ꢀ
ꢀ
ꢀ
different size, basicity, and geometry were used: F , Cl , Br , OAc ,
ꢀ ꢀ ꢀ
HSO
rescence titrations were analyzed by the SPECFIT program,
4 3 2 4
, NO , and H PO . The data obtained by UVevis and fluo-
2
0
21
whereas for the analysis of NMR data we used EQNMR. The
UVevis titrations were performed in CH CN and DMSO, whereas
NMR titrations were performed in DMSO-d due to the low solu-
bility of the compounds in CH CN. The estimated binding constants
are compiled in Tables 1 and 3.
H
N
H
N
H
N
H
N
3
O
O
6
N
H
N
H
O
O
N
H
N
H
3
1
2
H
H
H
H
N
2
.2.1. UVevis titrations. UVevis titrations of the receptors with an-
N
N
N
O
O
ions in CH CN or DMSO after the correction for dilution generally
show an increase in absorbance, with a rather small bathochromic
shift of the maxima. For example, shifts of absorption maxima of only
3
N
H
N
H
N
H
N
H
O
O
3
4
ꢀ
ꢀ
w5 nm were seen in titrations with OAc , and H PO (Fig. 1). This
2 4
H
N
H
N
finding is in accordance with the formation of H-bonded complexes
that do not significantly perturb the electronic excitation of the
naphthalene chromophore. The observed small bathochromic shift
indicatesthatthenegativechargeonthe nitrogenatomincreasesonly
slightly, that is, there is no deprotonation of the urea moiety. The
observed findings are in accordance with the experimental and the-
O
5
2
2
. Results and discussion
.1. Synthesis
10d, 22
oretical investigation performed by Lee and Nam.
Dependences of absorption spectra on anion concentrations
were processed by multivariate non-linear regression analysis to
determine the complex stoichiometries and the association con-
stants (see Supplementary data). In some cases, fitting was difficult
since the addition of anions induced relatively small changes in
absorbance, particularly when the titrations were performed in
DMSO. Therefore, the constants were not determined precisely,
especially in cases where complexes of several stoichiometries
Urea derivatives 2e5 were prepared in moderate to good yields
according to a modification of the published procedure19 from the
corresponding carboxylic acids that were transformed to
isocyanates in situ and reacted with b-naphthylamine (Scheme 1).
However, in the preparation of 1, the same pathway afforded
a mixture of products. Therefore 1 was prepared by another
pathway, from naphthalene-2-carboxylic acid and propylene
diamine (Scheme 2), giving product 1 of higher purity.
ꢀ
were formed. Moreover, in the titration experiments with Cl and
NH2
2
H
N
H
N
DPPA
H
N
H
N
HOOC
COOH
CH2)n (CH2)n
OCN
NCO
(CH )
TEA
(
(CH )
(CH )
(CH )
2 n
O
2 n
2 n
O
2 n
1
2
3
n = 0
n = 1
n = 0
;
;
=
(CH2)3
80%
82%
=
(CH )
2 3
;
=
=
36%
45%
4
n = 1
;
Scheme 1.
ꢀ
3
in DMSO, small changes of absorbance were observed (<0.05)
NO
COOH
NCO
on addition of huge excess of anion (100 equiv), so the UVevis data
DPPA
TEA
2 2 3 2
1/2 NH (CH ) NH
1
73%
could not be used to reveal the association constants. Receptors
ꢀ
ꢀ
formed mostly 1:1 complexes, except with F and H PO . To ad-
2 4
DPPA = Diphenylphosphoryl azide
TEA = Triethylamine
ditionally verify the complexes stoichiometries Job plots were
performed (see Supplementary data). They indicated that 1:1
complexes prevailed in the solution. The constants compiled in
Scheme 2.
Table 1 reveal that receptors generally form more stable complexes
ꢀ
in CH
3
CN than in DMSO (except for F ). This finding is in accor-
2
.2. Anion binding
The anion binding ability of the urea receptors in the solution
dance with the stronger ability of the urea receptors to solvate with
DMSO. Since DMSO can engage as a hydrogen bonding acceptor,
solvent participation plays an important role in enthalpic and
enthropic contribution to the association of the complex. Thus,
DMSO competes for the hydrogen bonding with receptor molecules
9
b
was investigated by UVevis, fluorescence, NMR, and microcalori-
metric titrations. Anions used in the study were in the form of

3848
V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
Table 1
Cumulative stability constants of the complexes with anions determined by UVevis titrations [log (
11/M 1)] or [log (
ꢀ
b
12/M )]a
ꢀ2
b
Ion/Rec.
1
2
3
4
5
ꢀ
w5 (1:1)c,d
w5 (1:1)c,d
b
b
b
F
3.1 ꢁ 0.1 (1:1)
2.8 ꢁ 0.1 (1:1)
3.1 ꢁ 0.1 (1:1)
c,d
c,d
c,d
w4 (1:1)
w5 (1:1)
w5 (1:1)
ꢀ
ꢀ
c,e
c,e
b
b
b
b
b
Cl
d
d
3.08 ꢁ 0.02 (1:1)
3.87 ꢁ 0.02 (1:1)
2.57 ꢁ 0.04 (1:1)
c,e
c,e
c,e
d
d
d
Br
d
d
2.29 ꢁ 0.03 (1:1)
3.08 ꢁ 0.02 (1:1)
d
ꢀ
c
c
c
c
b
b
b
c
H
2
PO
4
5.5 ꢁ 0.7 (1:1)
3.47ꢁ0.04 (1:1)
5.2 ꢁ 0.2 (1:1)
6.2 ꢁ 0.1 (1:1)
3.16 ꢁ 0.01 (1:1)
2.91 ꢁ 0.09 (1:1)
b
b
8.7 ꢁ 0.7 (1:2)
9.4 ꢁ 0.1 (1:2)
10.6 ꢁ 0.1 (1:2)
c
c
c
2
6
.96 ꢁ 0.08 (1:1)
4.2 ꢁ 0.1 (1:1)
c
.04 ꢁ 0.08 (1:2)
7.2 ꢁ 0.3 (1:2)
ꢀ
b,e
b
b
c
HSO
OAc
4
ꢀ
d
d
d
2.87 ꢁ 0.02 (1:1)
4.29 ꢁ 0.05 (1:1)
3.18 ꢁ 0.04 (1:1)
d
c
b
b
c
3.30 ꢁ 0.03 (1:1)
3.39ꢁ0.04 (1:1)
4.9 ꢁ 0.2 (1:1)
3.64 ꢁ 0.02 (1:1)
2.73 ꢁ 0.06 (1:1)
c
2
.93 ꢁ 0.02 (1:1)
a
The anion is added in the form of tetrabutylammonium salt. Stoichiometries of the complexes are indicated in the parentheses (receptor:anion).
Titration performed in CH
Titration performed in DMSO.
b
c
3
CN.
d
The titration performed in DMSO strongly indicated formation of complexes of different stoichiometries but titration curves could not be well-fitted. The reported value
was obtained by fitting only the spectra corresponding to anion:receptor molar ratio from 0 to 3.
e
Very small changes were observed in the UVevis spectra and the data could not be used to estimate the association constants.
1
1
0
0
0
,6
,2
,8
,4
,0
2
1
1
0
0
,0
,5
,0
,5
,0
260
280
300
320
340
360
260
280
300
320
340
Wavelength / nm
Wavelength / nm
ꢀ
ꢀ
Fig. 2. UVevis titration of 3 with F in CH
3
CN. The bottom curve corresponds to the
Fig. 1. UVevis titration of 3 with H
2
PO
4
3
in CH CN. The bottom curve corresponds to
solution of 3, whereas the curves from bottom to top correspond to the solutions with
increasing concentration of Bu NF.
the solution of 3, whereas the curves from bottom to top correspond to the solutions
with increasing concentration of Bu NH PO
4
4
2
4
.
decreasing the affinity for the binding of the anions. In general, all
hand, in DMSO, the receptors formed in addition to 1:1 stoichiom-
etry other complexes, as clearly pointed from the titration data (see
the Supplementary data). However, precise determination of the
association constants was not possible since the data could not be
fitted to any model. Possible reason for such a behavior may be ag-
ꢀ
ꢀ
receptors showed the strongest binding with H PO , and F . Al-
2 4
though these are very basic anions, the association constants can-
not be correlated only to basicity.
ꢀ
It is well known that the addition of basic F can in principle
ꢀ
ꢀ
induce deprotonation of the urea moiety and the formation of HF
2
gregation of the molecules, which may be dependant on the F
2
3
ꢀ
species. In the examples reported by Fabbrizzi et al. the first F
concentration. Since deprotonation can be excluded based on the
small bathochromic shifts in the spectra, it is very likely that both
urea moieties participate in the formation of the complex, each
forms an H-bonded complex and the second induces deprotonation
ꢀ
due to the formation of a very stable HF
2
species (
DH
form¼39 kcal/
2
3
ꢀ
mol). The deprotonation is usually well-visualized by the for-
mation of red-shifted bands in the absorption spectra. Titration
binding one F . Although differences in the observed stoichiome-
2
3
tries in CH CN and DMSO cannot be rationalized at this point, they
3
ꢀ
of our receptors with F in CH
3
CN and DMSO, on the other hand,
are probably due to different solvations of the receptors in two in-
only induced an increase in absorbance (Fig. 2), and very small
bathochromic shifts were observed. This result suggests that the
vestigated solvents, and possibly due to varying trace amounts of
moisture in Bu NF and solvent.
4
ꢀ
b
-naphthyl NH on the urea moiety is not acidic enough to be
All investigated receptors form 1:1 complexes with Cl char-
ꢀ
deprotonatedbythe second equivalentof F and thatonly H-bonded
acterized by the association constants that are in some cases similar
or higher than the comparable association constants with more
complexes are formed. Namely, the pK
a
value of the naphthyl urea
ꢀ
NH is probably similar to the one of the unsubstituted diphenyl urea
basic F (comparing 1:1 complexes in CH CN). Formation of stable
3
2
4
ꢀ
in DMSO (pK
a
¼19.5). Hence, in bidentate host molecules 1e4, the
complexes with Cl in DMSO was in previous reports explained by
strong ion-dipole coupling with that solvent. In our case, how-
ever, the association constants with Cl in DMSO could not be es-
8
c
formation of 1:1 (host:anion) and 1:2 complexes should be possible
ꢀ
in principle. It is interesting to note that 3e5 in CH
3
CN form com-
ꢀ
plexes with F characterized only by stoichiometry 1:1 and similar
association constants (log K w3). This finding suggests that only one
urea moiety in 3 and 4 forms a complex with the anion, that is, the
second urea moiety does not participate in the binding. On the other
timated by UVevis titration. The stability of the complex is not only
a function of the solvation and the basicity of anions. Comparison of
ꢀ
the association constants with Cl (Table 2) can be related to the
molecular structure. The bidentate receptor 4 forms a complex,

V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
3849
Table 2
by urea derivatives have already been reported by Gunnlaugsson
et al. However, in Gunnlaugsson’s example, the binding of the first
Thermodynamic parameters for the complexation of Bu
4
NOAc and Bu
4
NH
2
PO
4
with
26
receptor 4a
anion by urea induced the binding of the second by an amide
Ion
log (K/M 1
ꢀ
)
D
r
G
ꢃ
kJ mol
ꢀ1
D
r
H
ꢃ
kJ mol
ꢀ1
T
D
r
S
ꢃ
kJ mol
ꢀ1
function. In our host molecules the first anion probably induces
26
ꢀ
OAc
4.6 ꢁ 0.1 ꢀ 26.36 ꢁ 0.05 (1:1) ꢀ 18.8 ꢁ 0.7 (1:1) 7.5 ꢁ 0.5 (1:1)
binding of the second to the same binding site (vide infra).
(
1:1)
ꢀ
UVevis titrations with HSO
4
were performed for receptors 3
ꢀ
H
2
PO
4
5.89 ꢁ 0.05
ꢀ33.6 ꢁ 0.3 (1:1) ꢀ22.0 ꢁ 0.1 (1:1) 9.7 ꢁ 0.2 (1:1)
and 4. However, the observed changes in the spectra of 3 were too
(
1:1)
ꢀ
small to estimate the binding constant. Although H
2
PO
4
and
4
.19 ꢁ 0.02 ꢀ23.93 ꢁ 0.03 (1:2) ꢀ26.2 ꢁ 0.4 (1:2) ꢀ18 ꢁ 4 (1:2)
ꢀ
(
1:2)
HSO
4
have similar geometry, the binding of the latter with 4 was
a
ꢃ
ꢀ1
CN at 25 C. The association constants [log (K/M )]
accomplished only in 1:1 stoichiometry with the association con-
Titration performed in CH
3
stants weaker by four orders of magnitude. Lower stability of the
and the thermodynamic parameters correspond to successive (not cumulative)
equilibria. Stoichiometries of the complexes are indicated in the parentheses
receptor:anion). The standard errors of the mean (N¼3) are reported.
ꢀ
complex is in line with lower basicity of the HSO
4
. The lack of 1:2
(
ꢀ
stoichiometry is probably due to the inability of HSO
4
to form H-
bonded dimeric structures and additionally stabilize the complex,
ꢀ
ꢀ
which is 20 times more stable than the corresponding complex of
the monodentate receptor 5, suggesting that both urea moieties
can participate in the binding, thus making the complex more
stable. It is interesting to note that the most stable complex with
as in the case of H
2
PO
4
. In addition, HSO
4
has a lower tendency of
ꢀ
forming H-bonds than H
the gas phase (5.9 and 7.6 kcal/mol, respectively).
It is well known that urea receptors form strong complexes with
acetate due to its Y-shaped geometry and formation of the contact
with the urea moiety with two well-positioned H-bonds. Can our
bidentate receptors form stable complexes with OAc wherein the
anion would be bound by both urea moieties? The association
3
constant of 4 in CH CN is 4.5 times higher than for 5 (in DMSO 2.8
2
PO
4
, based on their hydration energies in
27
ꢀ
Cl is formed with 4 wherein the urea moieties are separated from
the adamantane by the methylene spacers. This finding indicates
that both urea moieties in 4 participate in the binding, whereas the
binding by two urea moieties in 3 is probably hindered due to steric
ꢀ
ꢀ
reasons. The value of the association constant of 4 with Cl is in
accordance with both ureas participating in the binding since it is
times higher). This suggests that both urea moieties in 4 participate
in the binding. In addition, the association constants with OAc are
8
e
ꢀ
higher than the value for some tetradentate urea cyclic ligands, or
1
1f,g
7a
8b
bidentate urea ligands on anthracene,
or o-phenylenediamine.
higher than those for flexible m-phenylene bidentate urea ligands,
ꢀ
17b
Complexation with Br was analyzed only for receptors 3 and 4
or similar to those of bidentate norbornene
or anthracene urea
ligands, wherein it was shown that acetate is bound by two urea
However, much smaller binding constants than for
some other bidentate urea ligands, such as o-phenylenediamine or
xanthene (K¼1e3ꢂ10 M ), suggest that acetate does not form
a perfect fit with the clefts of receptors 1e4. In addition, flexible
receptors 1 and 2 form slightly more stable complexes than ada-
mantane receptors 3 and 4. It is probably the adamantane moiety in
3 and 4 that hinders the molecular motion necessary for adopting
11g
in CH
3
CN. The receptors form 1:1 complexes with association
ꢀ
11g
constants lower than for Cl . This finding is in accordance with the
lower basicity and hydration energy of Br . However, it is in-
teresting to note that 4 forms a rather stable complex with Br . That
moieties.
ꢀ
7b
ꢀ
8a
5
ꢀ1
suggests that both urea moieties participate in the binding of one
ꢀ
ꢀ
Br , similar to the complexes with Cl .
The investigated compounds form very stable complexes with
ꢀ
H
2
PO
4
. Receptors 2 and 5 form only 1:1 complexes, whereas other
ꢀ
receptors form both 1:1 and 1:2 stoichiometries. For 5 the finding is
logical since two urea moieties in a molecule are required for the
formation of a 1:2 complex, as seen with 1, 3, and 4. However, why
does receptor 2 form onlya 1:1 complex? It is interesting to note that
receptor 2 forms only 1:1 stoichiometries with all anions. Although
structural evidence is not available at the moment (vide infra, NMR
section) the observed stoichiometry may be due to the flexibility of
optimal geometry for the complexation with OAc .
ꢀ
Binding of NO
3
was investigated for adamantane receptors 3
and 4. However, very small changes were seen in the UVevis
spectra, precluding further analysis and estimation of association
constants.
2.2.2. Fluorescence titrations. A fluorescence titration was per-
2
5
ꢀ
2
.
Furthermore, it is interesting to note that 3 and 4 form more
formed for receptors 3 with F in DMSO. The emission spectrum of
stable complexes than 1 and 2, respectively, indicating that ada-
3 in DMSO has maximum at 370 nm and does not have a vibronic
structure. The excitation spectrum overlaps the absorption with
a vibronically structured band with the maximum at 285 nm and
a much weaker, broader band at w350 nm. The addition of the
anion to the DMSO solution quenched the fluorescence without
shifts to the maxima in the excitation and fluorescence spectra
(Fig. 3). Multivariate non-linear regression analysis of the fluores-
cence spectra suggested the same complex stoichiometry as in-
dicated by the UVevis titration. However, we observed slow
equilibration of the fluorescence intensity upon addition of the
anion aliquots. Usually fluorescence decreased in the intervals of
3e5 min. Therefore, fluorescence titrations could not be used to
precisely estimate the association constants. Similarly slow equili-
ꢀ
mantane preorganizes the host for binding with H
2
PO
4
. Receptor 4
forms the most stable complexes, suggesting that good pre-
organization for binding is achieved when the urea moieties are
separated from the adamantane by methylene groups. Very high
ꢀ
association constants for the complexes with H
2
PO
4
make the re-
ꢀ
ceptor 4 among the strongest H
2
PO
4
binders. However, it should be
recalled that UVevis titration is not reliable for determining high
6
ꢀ1
association constants (K>10
M
). Formation of 1:2 complexes
ꢀ
with H
2
PO
4
and urea bidentate ligands has already been reported
in several examples, albeit with lower stability constants.
8
e,10f,11d,e
ꢀ
Umezawa suggested that H
2
PO
4
forms a complex with m-phenyl-
enemethylene urea derivative wherein one of the oxygen atoms of
ꢀ
the H
2
PO
4
forms two hydrogen bonds, whereas the other oxygen
bration of the fluorescence intensity due to slow formation of the
ꢀ
atoms have only one H-interaction with the urea and one hydroxyl
complexes was observed in fluorescence titration of 3 with H
2
PO
4
.
8
b,c
group does not participate in the binding.
Furthermore, in Fab-
Contrary to the fluorescence titration, slow kinetics of the complex
formation was not observed with other techniques (UVevis and
NMR) where the concentration of the substrates was higher.
ꢀ
brizzi’s example of a bisurea receptor, two H
2
PO
4
are bound in
ꢀ
a complex wherein each H
2
PO
4
forms 2H-bonds with the urea, and
13b
2
H-bonds are formed between the anions. In our case, in the 1:2
ꢀ
ꢀ
complex, the first H
2
PO
4
can also probably contribute to the
2.2.3. Calorimetry. UVevis titration with H
2
PO
4
indicated the
binding of the second ion as a result of secondary hydrogen bonding
between the hydroxyl groups of the two anions (see Scheme 8).
The positive allosteric effects and cooperativity of anion binding
formation of 1:1 and 1:2 complexes and very high association
constants (e.g., with 4 K>10 M , Table 1). Therefore, calorimetric
titrations were performed to additionally verify these observations,
8
e
6
ꢀ1

3850
V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
260
280
300 320
Wavelength / nm
340
360
350
375
400
425
Wavelength / nm
450
475
500
ꢀ
Fig. 3. Fluorescence titration of 3 with F in DMSO (left: excitation spectra,
l
em¼370 nm, right: emission spectra,
NF.
l
ex¼295 nm). The top curve corresponds to the solution of 3,
whereas the curves from top to bottom correspond to the solutions with increasing concentrations of Bu
4
and get further insight into the thermodynamics of the complex-
2.2.4. NMR titrations. To verify the results obtained by UVevis ti-
trations and get more information about the geometry of the
complexes in solution, NMR titrations were carried out. The titra-
tions were performed for receptors 1, 3, and 4 with the following
ꢀ
ꢀ
ation. The complexation of two anions, H
was investigated by microcalorimetric titrations. The addition of
both Bu NH PO or Bu NOAc into the solution of 4 in CH CN
2
PO
4
and OAc with 4
4
2
4
4
3
ꢀ
ꢀ
ꢀ
ꢀ
resulted in exothermic changes as a consequence of the complex-
ation. The calorimetric titration curves were processed by non-
linear regression analysis to determine the stability constants of the
complexes and the reaction enthalpies. As an example, the exper-
imental and fitted data corresponding to the titration of 4 with
anions: F , Cl , OAc , and H
2
PO . Generally, in all titrations the
4
addition of anions induced significant downfield shifts of both
signals assigned to the urea NH protons, indicating that anions
formed H-bonded complexes with the urea moiety. Fitting the
dependence of the chemical shift of the aromatic NH signal on
the anion concentration by using the EQNMR program revealed the
complex stoichiometries and the association constants (compiled
4 4 2 4
Bu NOAc are shown in Fig. 4 (for the titration with Bu NH PO see
the Supplementary data).
ꢀ
4
ꢀ3
CN, T¼25 ꢃC. (a) Raw ITC data. (b) Dependence of successive enthalpy change per mole
Fig. 4. Calorimetric titration of 4 (c ¼ 1.598ꢂ10 M) with Bu
4
NOAc (c¼3.327ꢂ10 M) in CH
3
of titrant on Bu
4
NOAc/4 M ratio. - experimental values; dcalculated values.
ꢀ
The stoichiometry of the complex of 4 with OAc was found to be
in Table 3). In some cases characterized by the presence of com-
plexes of several stoichiometries, the fitting could not reveal as-
sociation constants accurately, so only approximate values are
reported. The values of the estimated constants are generally lower
ꢀ
1
:1, whereas in the case of H
2
PO
4
the formation of complexes with
both 1:1 and 1:2 (receptor:anion) stoichiometries was observed.
These findings are in agreement with the results of the above
described UVevis titrations. The values of the stability constants
Table 3
(
Table 2) agree relatively well with those obtained by UVevis titra-
Cumulative stability constants of the complexes with anions determined by NMR
tions. Standard reaction Gibbs energies and entropies were calcu-
ꢀ
1
ꢀ2 a
titrations [log (
b
11/M )] or [log (b12/M )]
ꢃ
ꢃ
ꢃ
ꢃ
D
r
lated using equations
D
r
G ¼RT ln K and
D
r
G ¼
D
r
H ꢀT
S ,
Ion/Receptor
1
3
4
respectively. By inspecting the data given in Table 2 it can be easily
concluded that for both anions the enthalpic and entropic contri-
butions to the overall stability of their 1:1 complexes with 4 are fa-
vorable, with the enthalpic one being predominant. On the other
ꢀ
2.36 (1:1)b
w4 (1:2)
2.29 (1:1)
2.60 (1:1)
F
w2 (1:1)
w6 (1:2)d
1.54 (1:1)
3.32 (1:1)
w 5 (1:2)
3.13 (1:1)
w 6 (1:2)
w2 (1:1)
w5 (1:2)d
1.66 (1:1)
2.77 (1:1)
c
ꢀ
Cl
ꢀ
OAc
hand, formation of the complex comprising compound 4 and two
ꢀ
ꢀ
H
2
PO
4
anions is completely enthalpy driven, with unfavourable
H
2
PO
4
w1 (1:1)
w4 (1:2)
w3 (1:1)
w5 (1:2)
ꢃ
reaction entropy (Table 2). The
D
r
H value for the 1:2 complex for-
mation is higher than the one corresponding to the 1:1 complex.
That can be tentatively rationalized by taking into account the
possibility of an additional energetical stabilization caused by
hydrogen bonding interactions between the two H
a
6
Titration performed in DMSO-d . The anion is added in the form of tetrabuty-
lammonium salt. The error is estimated atꢁ10%. Stoichiometries of the complexes
are indicated in the parentheses (receptor:anion).
b
ꢀ
Estimated H
2
O content 0.14 M.
O content 0.02 M.
2
PO
4
anions
c
Estimated H
2
bound to 4, whereas the preorganization of the receptor, which ac-
d
2
Both complex stoichiometries were formed, 1:1 and 1:2; estimated H O content
companies the binding process leads to the decrease in entropy.
0.02 M.

V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
3851
ꢀ
by 1e3 orders of magnitude than those obtained from the UVevis
titration. That is probably due to concentration of the receptor in
the NMR experiment higher by two orders of magnitude wherein
there is probably strong intermolecular interaction between the
urea moieties resulting in the formation of weaker complexes with
anions. In addition, the formation of higher molecular aggregates
than simple stoichiometries cannot be disregarded.
In the aliphatic part of the spectrum of 4, the addition of F
resulted in upfield shifts in signals by up to 0.1 ppm (Fig. 6). The most
pronounceddifferenceinthe aliphaticpartof the spectrum due tothe
complexationwas observed in the chemical shifts of the adamantane
signals, which are assigned to the endo- and exo-H on the C4,9 and
C8,10. For the neat receptor they appear as an ‘AB quartet’ (at
d 1.47
and 1.40 ppm, with the typical geminal coupling constant of 11.7 Hz).
In the complex they appear as a broad singlet, that is, they become
magnetically equivalent. This finding suggests that there is a free
rotational mobility of the arms bearing a urea naphthalene moiety in
the complex (Scheme 3). However, since there is an upfield shift of
the methylene signal at the position 2 of the adamantane, we pre-
sume that A-4$2F conformation is more populated than B-4$2F . In
the B-4$2F conformation, the F would probably induce anisotropic
deshielding (downfield shift) of the signal corresponding to the CeH
To investigate if aggregation of the receptors takes places, NMR
spectra were taken at different concentrations. For example, a 10-
fold increase of the concentration of 2 induced downfield changes
of the urea NH chemical shifts by 0.005 ppm (see Supplementary
data). The observed downfield shift is in accordance with in-
termolecular interactions between the urea moieties.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
The addition of F , the most basic anion, to the solutions of 1, 3,
and 4 induced the most pronounced shifts of the urea NH signals, in
accordance with the formation of stable complexes. However, it is
interesting to note that almost negligible changes in the spectra
ꢀ
at the position 2. In addition, in B-4$2F there would probably be
ꢀ
electronic repulsion between two F moieties that are close.
ꢀ
were observed until the addition of the second equivalent of F . The
ꢀ
fitting of the dependence of the Dd on the F concentration indicated
the formation of weak 1:1 complexes and much more stable 1:2
ꢀ
complexes. The titration with F can be demonstrated on the ex-
ꢀ
ample of receptor 4. Upon addition of the first equivalent of F
negligible changes were observed, which became more pronounced
ꢀ
on further increase of the F concentration. Since we observed only
shifts in signals without the appearance of new signals, the finding
indicates that there is a fast exchange between the complexed and
ꢀ
the noncomplexed species. Finally, on approaching the F concen-
tration equivalent to the ratio 1:4, the changes became smaller with
a tendency of reaching a plateau. Thus, upon the addition of the
ꢀ
fourth equivalent of F , the signal of the urea NH at the naphthalene
moiety shifted from the value of
d 8.63 ppm (corresponding to the
neat receptor) to w11.8 ppm. The signal of the urea NH connected to
the CH
2
group shifted from 6.25 to w7.8 ppm (Fig. 5). Since the ad-
ꢀ
dition of 4 equivalents of basic F did not result in the disappearance
of the NH signals, deprotonation of the urea probably does not take
place. Shifting of both NH signals suggests that F is being bound by
Fig. 6. Aliphatic part of the NMR spectra obtained on titration of 4 with Bu
bottom spectrum corresponds to H NMR spectrum of 4 in DMSO, whereas spectra
4
NF. The
ꢀ
1
from bottom to top correspond to 4 with the increased concentration of Bu
reaching the maximal ratio of anion:receptor¼4:1.
4
NF
two H-bonds to one urea moiety. Besides the shifting of the NH
signals, a smaller downfield shift of the CeH signal corresponding to
the naphthalene position 3 was observed (Dd w0.1 ppm), suggesting
ꢀ
its through-space interaction with the F . The other signals of the
aromatic part of the spectrum exhibited no change or very small
upfield shifts (up to Dd w0.05 ppm), in accordance with a small in-
crease in electron density on the naphthalene moiety due to the
partial formation of negative charge on the N atom in the complex.
Scheme 3.
ꢀ
Titration of the other two receptors, 1 and 3, with F resulted in
similar spectral changes. However, it should be noted that changes
ꢀ
of the chemical shifts upon addition of F (and accordingly, the
estimated stoichiometry and the association constants), depend
ꢀ
strongly on H
2
O content. For example, titration of 3 with F was
performed in DMSO containing different H
2
O content. Changes in
ꢀ
chemical shifts of the urea NH signals on F concentration are
presented in Fig. 7, being much smaller in moist DMSO than in dry
DMSO. The fitting of the data revealed the formation of a 1:1
complex in moist DMSO, whereas in dry DMSO 1:2 complex was
formed. This finding clearly shows the large influence of the solvent
polarity and the H-bonding ability to the complexation with ureas.
The influence of solvation and ability of the solvent to participate in
H-bonding to the complex stoichiometry has also been found for
Fig. 5. Aromatic part of the NMR spectra obtained on titration of 4 with Bu
4
NF. The
28
adamantane dipyrromethane anion receptors.
bottom spectrum corresponds to 1H NMR spectrum of 4 in DMSO, whereas spectra
To get further evidences about the structures of the complexes
with F , NOESY spectra of the 1:1 complexes with 2 and 3 were
from bottom to top correspond to 4 with the increased concentration of Bu
reaching the maximal ratio of anion:receptor¼4:1.
4
NF
ꢀ

3852
V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
signals, smaller downfield shifts of the CeH signals corresponding
to the position C1 (0.06 ppm) and C4 (0.1 ppm) of the naphthalene
ꢀ
moiety were observed. This suggests that OAc interacts through-
space with both CeH, that is, there is a free rotation around the NeC
bond between the urea and the naphthalene (giving rise to the
ꢀ
ꢀ
conformations A and C of the complexes 3$OAc and 4$OAc ,
Schemes 4 and 5, respectively). The flexible receptor 1 can form
ꢀ
a more stable complex with OAc than rigid adamantane de-
rivatives 3 and 4, as shown by the NMR and UVevis titration data.
ꢀ
Probably a relatively small OAc could not fit well into a cleft of the
ꢀ
rigid skeleton of the conformers D of the complex 3$OAc , or
ꢀ
conformers B and D of the complex 4$OAc , and hence, does not
3
ꢀ1
form very stable complexes (K<10 M ).
CH
3
-O
O
Fig. 7. Dependance of the chemical shift of the signal of the urea NH attached to the
HN
O-
O
ꢀ
H
N
H
N
H
H
O
NH
naphthalene in 3 on F concentration in DMSO at different H
2
O content (estimated
N
N
1
O
from the integral in H NMR spectra).
NH
HN
O
O
CH
3
A-4 OAc-
B-4 OAc-
taken. However, no interaction was observed between the signals of
the NH with the signals of the aliphatic or the aromatic part of the
molecule. In addition, the signals of the tetrabutylammonium group
and THF covered practically all aliphatic signals of the complexes.
Titration of 1, 3, and 4 with Cl induced very small changes in
the NMR spectra (see Supplementary data). The urea NH signals of
CH
3
ꢀ
-O
O
H
H
N
H
H
O
NH
HN
O-
O
N
N
N
O
NH
HN
1
, 3, and 4 shifted downfield by Dd 0.2, 0.1, and 0.2 ppm, re-
O
O
ꢀ
CH
3
spectively. The additions of Cl almost did not affect the other
C-4 OAc-
D-4 OAc-
signals and only a weak influence to the adamantane exo- and the
endo-H signals was observed, which became more magnetically
equivalent. The fitting with the EQNMR revealed rather small
values of the association constants of the complexes (Table 3).
Scheme 5.
ꢀ
ꢀ
NOESY spectra of the complexes 2$OAc and 3$OAc support
the findings observed in the titration experiments. For both com-
plexes, the NOE interactions were observed between the urea NH
proximal to the naphthalene and the naphthalene CH atoms at the
positions 1 and 3. The finding is in agreement with free rotation of
the naphthalene moiety and the existence of the conformers
ꢀ
The addition of OAc to the solutions of 1, 3, and 4 resulted in
downfield shifts of the urea NH signals by Dd w1e1.2 ppm. The
fitting of the data indicated the presence of 1:1 complexes (except
for 1). Furthermore, since both NH signals exhibited similar dif-
ꢀ
ferences in chemical shifts upon addition of OAc , it is reasonable to
ꢀ
assume that one urea moiety is forming a complex with OAc ,
ꢀ
ꢀ
ꢀ
A-3$OAc and C-3$OAc . Furthermore, in a spectrum of 3$AcO ,
whereas the other one is not involved in the binding (contrary to
the findings from the UVevis titrations). The finding is additionally
supported by the changes in the aliphatic part of the spectra
wherein the signals for 3 and 4 corresponding to the adamantane
exo- and endo-H changed the appearance from ‘AB quartet’ to sin-
a stronger NOE interaction was observed between the urea NH
(connected to the adamantane moiety) and the adamantane endo-
and exo-H atoms than between the urea NH and the adamantane
H-atoms at the position 2. The finding is in agreement with the
geometry of the complex where one arm holds anion as in
ꢀ
ꢀ
glet. That is, conformation B-3$OAc is more likely than D-3$OAc
Scheme 4). In addition, the observed changes in the aliphatic re-
ꢀ
ꢀ
ꢀ
ꢀ
A-3$OAc and C-3$OAc (or the corresponding A-4$OAc and
(
ꢀ
C-4$OAc ). In the NOESY spectrum of 2$OAc , the interactions were
gion of the spectrum suggest free rotation of the urea naphthalene
moiety. In the aromatic region, in addition to the shifts of the NH
observed between the NH connected to the aliphatic chain and the
CH at the a- and the b-position to the urea moiety. In addition,
2
a NOE interaction was observed between the acetyl group and the
urea NH connected to the naphthalene. The latter interaction
strongly suggests a folded conformation of the complex, as in
3
H C
O-
HN
H
N
H
N
O
O
O
ꢀ
B-2$OAc . Such an interaction would be less likely in a complex
HN
N
H
N
H
N
H
N
H
O
ꢀ
O
-
A-2$OAc (Scheme 6).
O
O
CH
3
A-3 OAc-
B-3 OAc-
O
NH
HN
O-
O
O
O
O
NH
HN
N
H
N
H
N
H
N
H
O-
CH
3
O
3
H C
O-
CH
3
H
N
H
A-2 OAc-
B-
2 OAc
-
O
HN
N
HN
O
O
O
O
Scheme 6.
N
N
H
N
H
N
H
H
O
O-
CH
ꢀ
The NMR titration with H
2
PO
4
induced different changes in the
3
spectra than titration with other anions. In the aromatic part of the
spectra, similarly to previous examples, the signal of the urea NH
connected to the naphthalene shifted to the lower magnetic field
C-3 OAc-
D-3 OAc-
Scheme 4.

V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
3853
w2 ppm, whereas the signal of the NH connected to the aliphatic
part of the molecule shifted w1 ppm (Fig. 8 and the Supplementary
data). In the aromatic part of the spectrum pronounced difference
was also observed in the signal of the CeH at the position 3 of the
naphthalene, whereas other signals exhibited almost no change.
The aliphatic part of the spectra observed on titration of 3 and 4
ꢀ
with H
2
PO
4
clearly indicated the formation of different complex
ꢀ
ꢀ
species depending on the H PO concentration. At lower H PO ,
2 4 2 4
up to the addition of 0.5 equiv of the anion, signals corresponding
to the exo- and the endo-H atoms of the C4,9 and C8,10 of the
The finding suggests prevalence of conformers A and D (compared
adamantane moiety become more magnetically equivalent (spectra
ꢀ
ꢀ
to C and B, respectively) for the complex 3$H
2
PO
4
(Scheme 7), and
1e3, Fig. 9). Further increase in H
2
PO
4
concentration induced
ꢀ
4
$H
2
PO
4
(Scheme 8).
differentiation of the signals, which started to appear as an ‘AB
ꢀ
quartet’, and finally upon addition of four H
2
PO
4
equivalents, as
two doublets with very large difference in chemical shifts
(
0.7 ppm). Fitting of the dependence of the NH chemical shifts on
ꢀ
the H
2
PO
4
concentration indicated the formation of 1:1 and 1:2
stoichiometries.
Fig. 8. Aromatic part of the NMR spectra obtained on titration of 3 with Bu
4 2 4
NH PO .
The bottom spectrum corresponds to 1H NMR of 3 in DMSO, whereas spectra from
4 2 4
bottom to top correspond to 3 with increased concentration of Bu NH PO reaching
the maximal ratio of anion:receptor¼4:1.
OH
P
Fig. 9. Aliphatic part of the NMR spectra obtained on titration of 3 with Bu
The bottom spectrum corresponds to H NMR of 3 in DMSO, whereas spectra from
4
NH
2
PO
4
.
-O
OH
1
bottom to top correspond to 3 with increased concentration of Bu
the maximal ratio of anion:receptor¼4:1.
4 2 4
NH PO reaching
H
N
H
N
O
O
O
H
N
H
N
N
H
N
H
N
H
N
H
O
O
O
P
OH
ꢀ
What is the geometry of the H
2
PO
4
complexes? The observed
HO
O-
ꢀ
changes in the aliphatic part of the spectrum at low H
2
PO
4
con-
-
-
A-3 H PO4
B-3 H
2
PO
4
centration strongly suggest that the anion is being bound by two
urea moieties forming a symmetric structure (conformers B and D of
2
OH
-O
ꢀ
ꢀ
OH
the complex 3$H
2
PO
4
, Scheme 7, or 4$H
2
PO , Scheme 8). The
4
P
O
O
other less likely option that cannot be disregarded is binding of the
anion byone urea moiety (conformations A and C) and fast exchange
between all conformations (Schemes 7 and 8). Large shifts in signals
corresponding to the endo- and exo-H of the adamantane on the
increase of anion concentration after addition of the first anion
H
N
O
H
N
H
H
N
N
H
N
H
N
N
N
H
H
O
P
OH
O
O
HO
O-
-
-
ꢀ
ꢀ
C-3 H
PO
D-3 H
PO
2
4
2
4
equivalent indicate that 3$2H
PO
or 4$2H
PO are characterized
2
4
2
4
by different geometry than the corresponding 1:1 complexes.
In addition to changes in the chemical shift of the endo- and exo-H
signals there is also a large upfield shift of the adamantane CeH
signal at the position 2 (0.4 ppm). These findings suggest that
Scheme 7.
two anions are not being bound in the cleft formed by two urea
ꢀ
moieties resulting in a symmetric structure like B-3$2H
2
PO
4
or
OH
P
ꢀ
-O
OH
B-4$2H
PO
(wherein the anions would induce a downfield shift
2
4
O
NH
HN
O
due to the anisotropic effect). Furthermore, taking into account that
O
H
H
N
H
N
H
N
O
P
ꢀ
8c
N
NH
HN
H
2
PO
4
has a tendency to form dimeric structures, the results
HO
O-
ꢀ
OH
from NMR titration suggest that two H
and 4 wherein one urea binds two H PO
2
PO
4
form complexes with 3
giving a bulky arm with
O
O
ꢀ
2
4
-
-
A-4 H
PO
4
B-4 H
PO
4
2
2
restricted rotation (structure D, Schemes 9 and 10). On the other
ꢀ
hand, the geometry of the complex represented by B-4$2H
2
PO
4
is
OH
P
suggested due to very high stability of the 1:2 complexes of 3 and 4
-O
OH
ꢀ
2
with H PO
4
. Namely, in conformation B, the complex should
O
NH
NH
HN
O
O
H
N
H
N
H
N
H
N
O
P
be very stable due to multiple H-bonds between the anion and
HN
HO
O-
OH
the ureas, as well as between the anions themselves. However,
O
O
ꢀ
the geometry wherein each H
2
PO
4
is being bound by one urea arm
-
-
C-4 H
PO
4
D-4 H PO
ꢀ
2
2
4
(
e.g., C-4$2H
2
PO
4
) is also possible in principle, although less likely.
To get answers to topological questions that arose from the NMR
Scheme 8.
ꢀ
titrations with H
2
PO
4
the NOESY spectra of the complexes

3854
V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
OH
P
O
OH
P
3. Conclusion
-O
-O
OH
OH
O
O
H
N
H
N
O
H
H
N
New alkylenebisurea derivatives 1e5 were synthesized and
N
N
H
N
H
N
H
N
H
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
their binding with anions, F , Cl , Br , AcO , HSO
4
, NO and
3
O
O
O
O
P
OH
ꢀ
2
H PO
4
3
was investigated. In CH CN or DMSO solutions, urea re-
P
O-
OH
O-
HO
HO
ceptors 1e5 form complexes with all anions studied. The strongest
binding is observed with H PO and F . Introducing an additional
ꢀ
ꢀ
2 4
A-3 2H PO4-
B-3 2H PO
-
2
2
4
urea binding site generally increases anion binding ability of the
adamantane-urea receptors, that is, the stability of the complexes
significantly depends on the number of possible H-bonding in-
teractions between the host and the receptor. The finding may be
due to the statistical reason because of dynamic exchange of the
complex conformations. However, the data strongly indicates that
the stability of the complexes depends on the geometry and pre-
organization of the hosts. The strongest binding and the best se-
lectivity can be attained with constrained receptors with some
molecular mobility. The most flexible receptor, on the other hand,
formed less stable 1:1 complexes due to probable intramolecular
OH
P
-O
OH
P
O
-O
OH
OH
OH
P
O
-
O
OH
O
H
N
H
N
N
H
N
H
H
N
O
H
N
H
N
H
O
O
P
N
O-
O
O
HO
OH
PO -
-
C-3 2H
D-3 2H
PO
2 4
2
4
Scheme 9.
urea interactions. Rigid adamantane receptors showed stronger
ꢀ
binding of H
2
PO
4
, compared to the flexible alkyl derivatives. On the
ꢀ
contrary, the binding of OAc was hindered by molecular rigidity.
The most stable complexes were formed with H
OH
P
OH
P
ꢀ
-O
OH
-O
OH
PO
4
and receptor
2
O
O
O
O
NH
HN
4, characterized by stoichiometry 1:2 and the association constant
among the highest reported for urea-anion complexes. Besides ge-
ometry, the solvent plays a pivotal role in the complexation. Change
in solvent polarity and H-bond donating ability induces changes in
complex stoichiometries and selectivity of an anion receptor. Ther-
H
N
H
N
H
N
H
N
O
P
OH
NH
HO
O HN
O
O-
HO
P
OH
O-
O
-
-
A-4 2H
PO
4
B-4 2H PO
2
2
4
ꢀ
ꢀ
HO
P
O-
OH
P
O
modynamics of the complexation of 4 with H
2
PO
4
and OAc in
-O
OH
HO
CH CN was examined by isothermal calorimetry. The enthalpic
3
OH
P
O
O
H
-O
H
OH
N
contribution to the overall complex stability was found to be the
predominant one. The changes in entropy for the formation of 1:1
complexes were positive, whereas for the formation of 1:2 complex
N
O
HN
O
O
H
N
H
H
N
H
N
N
HN
O-
P
O
O
ꢀ
ꢃ
D
r
HO
of H
2
PO
4
with receptor 4 the calculated
S had negative value.
OH
The binding results from this study provide some data, that is useful
in the rational design of the future molecular receptors for anions
currently underway in our laboratory.
-
-
C-4 2H PO
2 4
D-4 2H PO
2
4
Scheme 10.
4. Experimental
ꢀ
ꢀ
ꢀ
2
$H
2
PO
4
, 3$H
2
PO
4
, and 3$2H
2
PO
ꢀ
2 4
spectrum of 3$H PO , a stronger interactionwas observed between
4
were taken. In the NOESY
4.1. General
the urea NH atom (connected to the adamantane) and the ada-
mantane CH at the position 2, than with the adamantane endo- and
exo-H atoms. The finding suggests a prevalence of the conformers
1H and 13C NMR spectra were recorded on a Bruker Spectrom-
eter at 300 or 600 MHz. All NMR spectra were measured in CDCl
3
using tetramethylsilane as a reference. High-resolution mass
spectra (HRMS) were measured on an Applied Biosystems 4800
Plus MALDI TOF/TOF instrument. Melting points were obtained
using an Original Kofler apparatus and are uncorrected. IR spectra
were recorded on PerkineElmer M-297 and ABB Bomem M-102
spectrophotometers. Solvents were purified by distillation. Ada-
ꢀ
ꢀ
B-3$H
2
PO
4
and D-3$H
2
PO
4
(Scheme 7). In addition, NOESY spec-
trum showed interaction of the NH connected to the naphthalene
with the naphthalene CH atoms at the position 1 and 4. The latter
finding is in accordance with the free rotation of the naphthalene
ꢀ
ꢀ
moiety. Similar to 3$H
2
PO
4
, in the NOESY spectrum of 3$2H
2
PO
4
,
2
9
a stronger interactionwas observed between the urea NH connected
to adamantane and the adamantane CH at the position 2, than with
mantane diacids were prepared in the laboratory according to
known procedure. -Naphthyl amine and naphthalene-2-carboxy-
b
the endo- and the exo-H atoms. The finding indicates prevalence of
lic acid were obtained from the usual commercial sources.
ꢀ
the complex geometry B-3$2H
2
PO
4
(Scheme 9). However, the NH
0
connected to the naphthalene is also in a NOE interaction with
4.1.1. 1,1 -(Propane-1,3-diyl)-bis[3-(naphthalen-2-yl)urea] (1). A round-
the exo-H atoms of the adamantane. The latter interaction suggests
bottom flask (50 mL) equipped with a condenser and N
charged with naphthalene-2-carboxylic acid (200 mg, 1.16 mmol).
Under a stream of N the acid was suspended in anhydrous toluene
(10 mL). To the suspension triethylamine (180 L, 1.28 mmol) was
added, and the suspension was stirred at rt for 45 min, and than,
2
inlet was
ꢀ
ꢀ
that 3$2H
D-3$2H
2
PO
4
exists also in the conformations A-3$2H
2
PO
4
or
ꢀ
2
PO
4
. That is, the complexed species probably represent
2
a dynamic system wherein different conformers are engaged in fast
dynamicexchange. However, in thearomatic region of the spectrum,
a NOE interaction was observed between the NH and the naphtha-
lene CH at the position 3 (and not at the position 1), suggesting that
there is no free rotation of the naphthalene moiety in the complex
m
diphenylphosphoryl azide DPPA (290
reaction mixture was heated at 40 C for 1 h, and after that 4 h at reflux.
m
L, 1.34 mmol) was added. The
ꢃ
To the mixture, a solution of 1,3-propane diamine (50 mL, 0.58 mmol) in
ꢀ
ꢀ
3
$2H
2
PO
4
. In the NOESY spectrum of 2$H
2
PO
4
no interaction was
1 mL of dry toluene was added, and refluxing was continued for 16 h.
The solvent was removed on a rotational evaporator and the residue
treated with methanol. The white precipitate was filtered off, washed
observed between the aromatic or the NH signals with the aliphatic
CH atoms that would indicate prevalence of any complex
conformations.
ꢃ
with water and methanol, and dried in vacuum (100 mbar) at 60 C for

V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
3855
1
h to afford 175 mg (73%) of pure product 1. Colorless crystals, mp
J¼8.0 Hz), 7.39e7.43 (m, 4H), 7.30 (dt, 2H, J¼8.0, 1.1 Hz), 6.25 (t, 2H,
J¼6.0 Hz, NH), 2.90 (d, 4H, J¼6.0 Hz), 2.06 (br s, 2H), 1.59 (br s, 2H),
ꢃ
1
2
73e275 C; H NMR (DMSO-d
6
, 300 MHz)
.04 (d, 2H, J¼1.4 Hz), 7.68e7.81 (m, 6H), 7.37e7.50 (m, 4H), 7.31 (dt,
H, J¼7.5 Hz, J¼0.9 Hz), 6.30 (t, 2H, J¼5.7 Hz, NH), 3.15e3.26 (m, 4H),
, 75 MHz) /ppm 155.41 (s, 2C), 138.22
s, 2C), 133.79 (s, 2C), 128.68 (s, 2C), 128.14 (d, 2C), 127.34 (d, 2C), 126.71
d, 2C), 126.13 (d, 2C), 123.46 (d, 2C), 119.50 (d, 2C), 112.54 (d, 2C), 36.60
d/ppm 8.73 (br s, 2H, NH),
13
8
2
1
1.47 (d, 4H, J¼11.7 Hz), 1.40 (d, 4H, J¼11.7 Hz), 1.25 (br s, 2H);
C
6
(DMSO-d , 150 MHz) d/ppm 155.52 (s, 2C), 138.27 (s, 2C), 133.88 (s,
2C), 128.68 (s, 2C), 128.28 (d, 2C), 127.41 (d, 2C), 126.77 (d, 2C),
126.22 (d, 2C), 123.49 (d, 2C), 119.38 (d, 2C), 112.27 (d, 2C), 50.52 (t,
.59e1.71 (m, 2H); 13C (DMSO-d
d
6
(
(
2C), 42.49 (s, 2C), 39.39 (t, 4C), 36.09 (t, 1C), 34.14 (t, 1C), 27.85 (d,
ꢀ1
ꢀ1
(t, 2C), 30.72 (t, 1C); IR (KBr)
n
max/cm 1231 (m), 1279 (m), 1561 (s),
2C); IR (KBr)
n
max/cm 1243 (m), 1557 (s), 1645 (s), 2902 (m), 3309
þ
1623 (s), 2870 (w), 2939 (w), 3299 (m), 3338 (m); HRMS (MALDI):
(w), 3340 (m); HRMS (MALDI): MH found 533.2904. C34
37 4 2
H N O
þ
MH found 413.1980. C25
H
25
N
4
O
2
requires 413.1972.
requires 533.2911.
4
.2. General procedure for the preparation of ureas 2e5
4.2.4. 1-(Adamantane-1-yl)-3-(naphthalen-2-yl)methylurea
5). Obtained from adamantane-1-acetic acid (200 mg, 1.03 mmol),
triethylamine (160 L, 1.13 mmol), DPPA (260 mg, 1.18 mmol), and
2-aminonaphthalene (147 mg, 1.03 mmol), in 15 mL of dry toluene.
(
A round-bottom flask (50 mL) equipped with a condenser and
m
N
of N
2
inlet was charged with carboxylic acid (1 mmol). Under a stream
ꢃ
1
2
the acid was suspended in anhydrous toluene (10 mL). To the
Colorless crystals (43%, 143 mg), mp 217e219 C; H NMR (DMSO-
, 600 MHz)
suspension, triethylamine (2 mmol, 1 mmol for 5) was added, and
the suspension was stirred at rt for 45 min, and then, diphenyl-
phosphoryl azide DPPA (2.1 mmol, 1.1 mmol for 5) was added. The
reaction mixture was heated at 40 C for 1 h, and after that 4 h at
reflux. To the mixture, a solution of
d
6
d
/ppm 8.57 (br s, 1H, NH), 8.01 (d, 1H, J¼1.8 Hz), 7.77
(d, 2H, J¼8.6 Hz), 7.72 (d, 2H, J¼8.2 Hz), 7.38e7.43 (m, 2H), 7.30 (dt,
1H, J¼7.6, 1.0 Hz), 6.19 (t, 1H, J¼6.1 Hz, NH), 2.84 (d, 2H, J¼6.1 Hz),
1.96 (br s, 3H), 1.69 (d, 3H, J¼12.1 Hz), 1.61 (d, 3H, J¼12.1 Hz),
ꢃ
13
b
-naphthylamine (2 mmol,
6
1.46e1.50 (m, 6H); C NMR (DMSO-d , 150 MHz) d/ppm 155.43 (s,
1
mmol for 5) in 1 mL of dry toluene was added, and refluxing was
1C), 138.24 (s, 1C), 133.82 (s, 1C), 128.61 (s, 1C), 128.19 (d, 1C), 127.33
(d, 1C), 126.69 (d, 1C), 126.13 (d, 1C), 123.39 (d, 1C), 119.31 (d, 1C),
112.20 (d, 1C), 50.71 (t, 1C), 39.74 (t, 3C), 36.56 (t, 3C), 33.46 (s, 1C),
continued for 16 h. The solvent was removed on a rotational
evaporator and the residue treated with methanol. Product in the
form of precipitate was filtered off, washed with water and meth-
ꢀ
1
27.67 (d, 3C); IR (KBr)
n
max/cm 1241 (m), 1559 (s), 1647 (s), 2899
ꢃ
þ
anol, and dried in vacuum (10 mbar) at 40 C for 1 h.
(m), 3305 (w), 3350 (w); HRMS (MALDI): MH found 335.2115.
22 27 2
C H N O requires 335.2118.
0
4
.2.1. 1,1 -(Pentane-1,5-diyl)-bis[3-(naphthalen-2-yl)urea]
(
2). Obtained from pimelic acid (200 mg, 0.79 mmol), triethyl-
amine (245 L, 1.74 mmol), DPPA (395 L, 1.82 mmol), and 2-ami-
nonaphthalene (250 mg, 1.74 mmol), in 15 mL of dry toluene.
4
.3. UVevis titrations
m
m
3
The anion receptor was dissolved in CH CN or DMSO in the
ꢃ
1
Colorless crystals (82%, 450 mg), mp 264e265 C; H NMR (DMSO-
, 300 MHz)
/ppm 8.63 (br s, 2H, NH), 8.03 (d, 2H, J¼1.6 Hz),
.68e7.80 (m, 6H), 7.36e7.48 (m, 4H), 7.30 (dt, 2H, J¼7.5, 1.0 Hz),
ꢀ4
ꢀ5
concentration range 10 e10 M, corresponding to a absorbance
maximum in the range 0.5e1.5. A solution of the receptor was
d
7
6
4
2
1
2
n
6
d
placed in a quartz cuvette (1 mL) and small volumes (5e20
the following solutions of anion were added: Bu NF (1 M in THF,
CN or DMSO to
NHSO , Bu NNO or
CN or DMSO). After
mL) of
.25 (t, 2H, J¼5.6 Hz, NH), 3.13 (dd, 4H, J¼12.3 Hz), 1.44e1.57 (m,
4
13
H), 1.32e1.42 (m, 2H); C (DMSO-d
C), 138.26 (s, 2C), 133.84 (s, 2C), 128.67 (s, 2C), 128.20 (d, 2C),
27.37 (d, 2C), 126.75 (d, 2C), 126.17 (d, 2C), 123.47 (d, 2C), 119.48 (d,
C), 112.43 (d, 2C), 39.08 (t, 2C), 29.56 (t, 1C) 23.86 (t, 1C); IR (KBr)
6
, 75 MHz) d/ppm 155.29 (s,
containing <wt 5%
2 3
H O, diluted with CH
NCl, Bu
(from 1ꢂ10 to 1ꢂ10 M in CH
ꢀ3
1
Bu
ꢂ10
M), Bu
PO
4
4
NBr, Bu
4
NOAc, Bu
4
4
4
3
ꢀ2
ꢀ5
4
NH
2
4
3
each addition, UVevis spectra were recorded. The titrations were
performed at rt (20 C). The data were analyzed by SPECFIT pro-
gram to reveal the stability constants of the complexes.
ꢀ
1
max/cm 1252 (m), 1561 (s), 1625 (s), 2861 (w), 2934 (w), 3334
ꢃ
þ
(
m); HRMS (MALDI): MH found 441.2296. C27
29
H N
4
O
2
requires
4
41.2285.
0
.2.2. 1,1 -(Adamantane-1,3-diyl)-bis[3-(naphthalen-2-yl)urea]
4.4. Fluorescence titrations
4
(
0
2
1
3). Obtained from 1,3-adamantane dicarboxylic acid (200 mg,
3
The anion receptor was dissolved in CH CN or DMSO in the
concentration range 10 e10 M, corresponding to an absorbance
maximum in the range 0.08e0.1. The solution of the receptor was
.89 mmol), triethylamine (275
mL, 1.96 mmol), DPPA (440 mL,
ꢀ
5
ꢀ6
.05 mmol), and 2-aminonaphthalene (281 mg, 1.96 mmol), in
5 mL of dry toluene. Colorless crystals (36%, 160 mg), mp
ꢃ
1
placed in a quartz cuvette (2 mL) and small volumes (10
mL) of the
2
6
59e260 C; H NMR (DMSO-d , 300 MHz) d/ppm 8.46 (br s, 2H,
solutions of anion are added: Bu NF (1 M in THF, containing <wt 5%
4
NH), 8.04 (br s, 2H), 7.68e7.80 (m, 6H), 7.26e7.44 (m, 6H), 6.10 (br s,
H, NH), 2.28 (br s, 2H), 2.20 (br s, 2H), 1.97 (d, 4H, J¼11.3 Hz), 1.90
ꢀ3
ꢀ2
H
2
O, diluted with DMSO to 1ꢂ10 M), or Bu
4
NH
2
PO
4
(from 1ꢂ10
2
ꢀ5
13
to 1ꢂ10 M in DMSO). After each addition, fluorescence spectra
(
d, 4H, J¼11.3 Hz), 1.59 (br s, 2H); C NMR (DMSO-d
ppm 154.31 (s, 2C), 138.27 (s, 2C), 134.03 (s, 2C), 128.83 (s, 2C),
28.43 (d, 2C), 127.55 (d, 2C), 126.93 (d, 2C), 126.42 (d, 2C), 123.69
d, 2C),119.53 (d, 2C),112.50 (d, 2C), 51.68 (t,1C), 46.06 (s, 2C), 40.94
t, 4C), 35.23 (t, 1C), 29.59 (d, 2C); IR (KBr)
m),1557 (s),1681 (s), 2912 (m), 3299 (m), 3613 (s); HRMS (MALDI):
6
, 150 MHz) d/
were recorded, using the excitation wavelength at 295 nm, or
ꢃ
emission at 370 nm. The titrations were performed at rt (20 C).
1
(
(
(
ꢀ
1
n
max/cm 1222 (m), 1351
4.5. Calorimetry
þ
MH found 505.2562. C32
33
H N
4
O
2
requires 505.2598.
Microcalorimetric measurements were performed by an iso-
ꢃ
thermal titration microcalorimeter Microcal VP-ITC at 25.0 C. Or-
0
4
2
.2.3. 1,1 -[(Adamantane-1,3-diyl)dimethylene]-bis[3-(naphthalen-
igin 7.0 software, supplied by the manufacturer, was used for the
data acquisition and manipulation. The calorimeter was calibrated
electrically and its reliability was checked by carrying out the
complexation of barium(II) by 18-crown-6 in aqueous medium at
-yl)urea] (4). Obtained from 1,3-adamantane diacetic acid
L, 1.74 mmol), DPPA
L,1.82 mmol), and 2-aminonaphthalene (250 mg,1.74 mmol),
(
(
200 mg, 0.79 mmol), triethylamine (245
395
m
m
ꢃ
ꢀ1
in 15 mL of dry toluene. Colorless crystals (45%, 190 mg), mp
2
NH), 8.03 (d, 2H, J¼2.0 Hz), 7.77 (d, 4H, J¼8.9 Hz), 7.72 (d, 2H,
25 C. The results obtained (log K¼3.76,
D
r
H¼31.9 kJ mol ) were in
ꢃ
1
37e238 C; H NMR (DMSO-d
6
, 600 MHz)
d
/ppm 8.63 (br s, 2H,
good agreement with the literature values (log K¼3.77,
D
r
H¼31.4 kJ molꢀ1).30

3
856
V. Bla ꢀz ek et al. / Tetrahedron 67 (2011) 3846e3857
8. (a) Hamann, B. C.; Branda, N. R.; Rebek, J., Jr. Tetrahedron Lett. 1993, 34,
During titrations, the enthalpy changes were recorded upon
stepwise addition of the CH CN solution of Bu NOAc or Bu NH PO
V¼10 or 15 L) into solution of 4 (cz1.6ꢂ10 M, V ¼1.4182 cm ).
6
837e6840; (b) Nishizawa, S.; B u€ hlmann, P.; Iwao, M.; Umezawa, Y. Tetrahedron
3
4
4
2
4
Lett. 1995, 36, 6483e6486; (c) B u€ hlmann, P.; Nishizawa, S.; Xiao, K. P.; Ume-
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3
3
(
m
0
zawa, Y. Tetrahedron 1997, 53, 1647e1654; (d) Lee, K. H.; Hong, J. I. Tetrahedron
Lett. 2000, 41, 6083e6087; (e) Snellink-Ru e€ l, B. H. M.; Antonisse, M. M. G.;
Blank experiments were carried out in order to obtain heats of
dilution of salt solutions, which were subtracted from the heats
measured in the complexation experiments. The dependence of
successive enthalpy changes on the volume of the added titrant was
processed by non-linear least-square fitting procedure using Ori-
ginPro 7.5 program. All measurements were done in triplicate.
Engbersen, J. F. J.; Timmerman, P.; Reinhoudt, D. N. Eur. J. Org. Chem. 2000,
1
65e170; (f) Leung, A. N.; Degenhardt, D. A.; B u€ hlmann, P. Tetrahedron 2008, 64,
2
530e2536.
9. (a) Fan, E.; Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993,
15, 369e370; (b) Linton, B. R.; Goodman, M. S.; Fan, E.; van Arman, S. A.;
1
Hamilton, A. D. J. Org. Chem. 2001, 66, 7317e7319; (c) Benito, J. M.; G oꢁ mez-
García, M.; Blanco, J.; Ortiz Mellet, C.; García-Fern ꢁa ndez, J. M. J. Org. Chem. 2001,
6
6, 1366e1372.
0. (a) Hennrich, G.; Sonnenschein, H.; Resch-Genger, U. Tetrahedron Lett. 2001, 42,
805e2808; (b) Cho, E. J.; Moon, J. W.; Ko, S. V.; Lee, J. Y.; Kim, S. K.; Yoon, J.;
1
4
.6. NMR titrations
2
Nam, K. C. J. Am. Chem. Soc. 2003, 125, 12376e12377; (c) Qian, X.; Liu, F. Tet-
rahedron Lett. 2003, 44, 795e799; (d) Lee, J. Y.; Cho, E. J.; Mukamel, S.; Nam, K.
C. J. Org. Chem. 2004, 69, 943e950; (e) Cho, E. J.; Ryu, B. J.; Lee, Y. J.; Nam, K. C.
Org. Lett. 2005, 13, 2607e2609; (f) Kondo, S.-I.; Sato, M. Tetrahedron 2006, 62,
6
In an NMR tube was placed 0.5 mL of the DMSO-d solution of 3,
or 1. The concentration of the 3, 4 or 1 in the NMR experiment was
typically 0.05 M. To the solution in the tube was added a solution of
4
4
844e4850; (g) Jeong, H. A.; Cho, E. J.; Yeo, H. M.; Ryu, B. J.; Nam, K. C. Bull.
Korean Chem. Soc. 2007, 28, 851e854.
1. (a) Gunnlaugsson, T.; Davis, A. P.; Glynn, M. Chem. Commun. 2001, 2556e2557;
b) Kim, S. K.; Yoon, J. Chem. Commun. 2002, 770e771; (c) Gunnlaugsson, T.;
Bu
Bu
4
NF (1 M in THF, containing <wt 5% H
NHSO , Bu NH PO , Bu NOAc, Bu NNO
2
O) or Bu
(w0.5 M in DMSO-d
4
NCl, Bu
4
NBr,
).
1
4
4
4
2
4
4
4
3
6
(
The concentrations of the salt ranged from 0.01 to 0.1 M, reaching
the maximal ratio of anion:receptor¼4:1. After each addition, NMR
spectra were recorded. The association constants were determined
Davis, A. P.; Hussey, G. M.; Tierney, J. Org. Biomol. Chem. 2004, 2, 1856e1863; (d)
Kwon, J. Y.; Jang, Y. J.; Kim, S. K.; Lee, K.-H.; Kim, J. S.; Yoon, J. J. Org. Chem. 2004,
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C. M. G.; Glynn, M.; McCabe, T.; De Melo, J. S. S.; Burrows, H. D.; Gunnlaugsson,
T. Supramol. Chem. 2008, 20, 407e418; (g) Brooks, S. J.; Caltagirone, C.; Cossins,
A. J.; Gale, P. A.; Light, M. Supramol. Chem. 2008, 20, 349e355; (h) Dahan, A.;
Ashkenazi, T.; Kuznetsov, V.; Makievski, S.; Drug, E.; Fadeev, L.; Bramson, M.;
Schokoroy, S.; Rozenshine-Kemelmakher, E.; Gozin, M. J. Org. Chem. 2007, 72,
by fitting the dependence of the chemical shift of the NH signal (Dd
to the anion concentration, using EQNMR program.
)
21
Acknowledgements
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2. (a) Nishizawa, S.; Kaneda, H.; Uchida, T.; Terame, N. J. Chem. Soc., Perkin Trans. 2
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1
Financial support by the Ministry of Science, Education and
Sports of the Republic of Croatia (grant nos. 098-0982933-2911 and
1
119-1191342-2960) is gratefully acknowledged. We thank Prof. M. J.
Hynes for the EQNMR program and J. Ale ꢀs kovi ꢁc for the help in
applying the SPECFIT program. We also thank Prof. V. Tomi ꢀs i ꢁc for
13. (a) Albert, J. S.; Hamilton, A. D. Tetrahedron Lett. 1993, 34, 7363e7366; (b)
Amendola, V.; Boiocchi, M.; Esteban-G oꢁ mez, D.; Fabbrizzi, L.; Monzani, E.
Org. Biomol. Chem. 2005, 3, 2632e2639; (c) Costero, A. M.; Colera, M.;
Gavi n~ a, P.; Gil, S.; Kubinyi, M.; P aꢁ l, K.; K ꢁa llay, M. Tetrahedron 2008, 64,
3217e3224.
ꢀ
the critical reading of the manuscript and Mr. Z. Marini ꢁc and S. Roca
for recording NMR spectra.
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Supplementary data
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UVevis binding data (Job plots, UVevis titrations), NMR titra-
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mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2011.03.096.
13
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