Chelate effects in sulfate binding by amide/urea-based ligands

Article abstract of DOI:10.1039/c5ob00618j

The influence of chelate and mini-chelate effects on sulfate binding was explored for six amide-, amide/amine-, urea-, and urea/amine-based ligands. Two of the urea-based hosts were selective for SO₄^2- in water-mixed DMSO-d₆ systems. Results indicated that the mini-chelate effect provided by a single urea group with two NH binding sites appears to provide enhanced binding over two amide groups. Furthermore, additional urea binding sites incorporated into the host framework appeared to overcome to some extent competing hydration effects with increasing water content.

Full text of DOI:10.1039/c5ob00618j

Volume 13 Number 25 7 July 2015 Pages 6881–7092
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PAPER
Kristin Bowman-James et al.
Chelate effects in sulfate binding by amide/urea-based ligands

Organic &
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Chelate effects in sulfate binding by amide/
urea-based ligands†
Cite this: Org. Biomol. Chem., 2015,
13, 6953
Chuandong Jia, Qi-Qiang Wang, Rowshan Ara Begum, Victor W. Day and
Kristin Bowman-James*
The influence of chelate and mini-chelate effects on sulfate binding was explored for six amide-, amide/
2−
amine-, urea-, and urea/amine-based ligands. Two of the urea-based hosts were selective for SO4 in
Received 29th March 2015,
Accepted 30th April 2015
water-mixed DMSO-d6 systems. Results indicated that the mini-chelate effect provided by a single urea
group with two NH binding sites appears to provide enhanced binding over two amide groups. Further-
more, additional urea binding sites incorporated into the host framework appeared to overcome to some
extent competing hydration effects with increasing water content.
DOI: 10.1039/c5ob00618j
www.rsc.org/obc
Selectively binding sulfate ions in aqueous solutions is of great revealed that while bulky end groups can prevent encircling a
significance in environmentally and biologically related appli- single anion (which would capitalize on the chelate influence),
cations, but challenging because of the extremely large they can induce the formation of helical structures, also of
hydration energy of the ion (Gh = −1080 KJ mol−1).1–3 One way interest due to biological implications.26
to attack this problem is to take advantage of extended hydro-
Here we report a comparative study of the influence of the
gen bonding sites, i.e., the chelate effect, in anion host design. chelate effect on anion binding for two widely used functional
In the most favorable scenario this strategy would include not groups, amides and ureas (Fig. 1). We further study the
only ligands that are functionalized with the highest possible effect of covalently linking these groups on their ability to
number of hydrogen bonding sites, but also those that are pre- bind anions. In order to circumvent the issues inherent in
organized in conformations readily positioned for binding a short or strained connections and bulky end groups, we
tetrahedral sulfate ion.4–14 In classical transition-metal coordi- have used N-methyldiethylene bridges and ethyl termini,
nation, the chelate effect has been extensively studied as a respectively.
major contributor to enhanced stabilities in transition metal
Six ligands were functionalized with increasing numbers of
complexes.15–21 In anion coordination, the chelate effect also either amide or urea hydrogen bond donor sites (Fig. 1).
plays an important role. The synergistic effect of appropriately Numbers of binding sites ranged from two to eight with the
positioned multiple hydrogen bonding sites can result not expectation that anion binding would increase along with the
only in more enhanced binding but also in more selective number of binding sites.1,22–25 While both 2,6-dicarboxamides
hosts for targeted anions.22–25
and ureas can be viewed as chelates, ureas can be considered
Urea-based acyclic hosts have previously been studied by
one of us (CJ) in order to probe the influence of the chelate
effect in anion coordination. Findings from those studies indi-
cated that while to some extent increasing the number of urea
groups tends to result in increased binding, this effect can be
tempered by steric strain depending on the linkages between
the ureas.5 Nevertheless, hosts with urea groups appear to be
capable of maintaining anion binding in mixed aqueous
systems, albeit with lower affinities. Previous findings also
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
E-mail: kbjames@ku.edu
†Electronic supplementary information (ESI) available: Experimental details,
X-ray data, spectral data, NMR spectra, binding studies. CCDC
1051283–1051285. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c5ob00618j
Fig. 1 Amide- and urea-based ligands 1–6.
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2−
Table 1 Binding constants (K, M−1 a
) of the SO4 (added as tetrabutyl-
as “mini chelates” due to the short separation between the
two NH groups. Such systematic variations in chelating frame-
works provide an opportunity for assessment not only of the
similarities and differences between ureas and amides, but
also of the influence of increasing numbers of hydrogen
bonding sites on binding affinities. Association constants
were determined in 0.5% to 50% H2O-mixed DMSO-d6 in order
to probe whether the power of additional hydrogen bonding
sites, and in particular the urea mini-chelating sites, could
compete with the large hydration energy of sulfate ion.
ammonium salts) complexes of ligands 1–6 at 298 K in water-mixed
DMSO-d6 in the presence of increasing percentages of H2Oa
Possible
coordination (0.5%
Complexes number (C.N.) H2O)
DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6
(10%
H2O)
(25%
H2O)
(50%
H2O)
2−
c
d
d
1·SO42−
2·SO42−
3·SO42−
4·SO42−
5·SO42−
6·SO4
2
4
2
4
4
8
744
—
—
—
c
d
5149
1405b
9630
>104
>104
52
82
307
3266
>104
—
—
c
d
—
—
c
68
294
7025
—
c
—
Ligands 1–6 can be readily synthesized in one to three steps
(see ESI†). Anion binding was studied by 1H NMR titrations
47
a All errors <10% except where noted. b Error = 12%. c Changes in the
1H NMR spectra are too small to calculate the association constants.
d Not determined.
in water mixed DMSO-d6, using the tetra(n-butyl)ammonium
(TBA+) salts of a broad range of anions (Cl−, SO42−, H2PO4
,
−
AcO−, NO3−, ClO4−, N3−). None of the ligands interacted to any
measurable extent with NO3−, ClO4−, and N3−, but 1–4 were
found to bind differing extents with Cl−, H2PO4−, and AcO−
(see ESI†). Notably, 5 and 6 were found to bind a majority of
the anions in DMSO-d6 with 0.5% H2O (Fig. 2, Table 1).
Binding constants were calculated based on 1 : 1 binding
modes, as confirmed for solution binding by Job’s plots (see
ESI†). Results can probably be attributed to both the larger
number of hydrogen bond donor groups (6) and the preorgani-
zation provided by the o-phenylene group (5 and 6). However,
1–6 all displayed affinity for SO42− over other anions.
As seen from the competitive titration experiments (Fig. 2,
spectrum in the presence of all anions), 5 and 6 selectively
bind SO42−, even in the presence of a mixture that includes
several different anions. It should be also noted that all of the
NH protons seem to participate in the binding to SO42−, as
suggested by the significant downfield shifts observed for all
NH protons in the 1H NMR spectra (Fig. 2). Job’s plots indi-
2−
cated that SO4 is held in a 1 : 1 mode in all cases, which was
also observed for three of the four crystal structures
2−
(vide infra). Thus, at least for this series of ligands, SO4
appears to be quite suitable as a target anion in an evaluation
of the chelate effect with increasing amounts of water.
2−
Association constants for SO4 (Table 1) were obtained by
fitting 1H NMR titration data with EQNMR (see ESI†). As
shown in the Table, the increasingly favorable influence of co-
valently linked chelates within each pair of hosts (1,2; 3,4; 5,6)
2−
2−
is clearly evident: K(1·SO4
) < ) <
K(2·SO42−); K(3·SO4
K(4·SO42−); and K(5·SO42−) < K(6·SO42−). In the DMSO-d6/0.5%
H2O studies, the ratio of binding constants in hosts progressing
from two to four binding sites (1 → 2 and 3 → 4) indicates an
almost seven-fold enhancement for the ligand with the larger
number of binding sites in each pair. Binding was so strong
with 5 and 6, it was beyond NMR capabilities (>104) for accurate
determination when in DMSO-d6/0.5% water.
A comparison of Table 1 with Fig. 3 illustrates the interde-
pendence of the NMR chemical shifts with binding strengths.
Binding precipitously decreased for all hosts in solutions with
increasing percentages of H2O. Even in only 10% H2O, we
found it to be immeasurably small for the very simple pyridine
dicarboxamide, 1. The lessened affinities are reflected in
decreases in the magnitudes of the chemical shift. However,
the urea-based hosts with four and eight binding sites still dis-
played at least some binding in 25% H2O.
The preorganization effect of the o-phenyl group appears to
enhance binding significantly (5 and 6). Doubling the poten-
tial number of donor groups from four to eight resulted in an
almost 25-fold increase in the binding of SO42− for 6 over 5 for
Fig. 2 Partial 1H NMR spectra (500 MHz, 298 K, 0.5% water-mixed
DMSO-d6) of ligands 5 and 6 in the presence of 1 equiv. of selected
anions and with all anions (NH signals are labelled by asterisks).
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Fig. 4 Perspective views of the crystal structures of (a)
(TBA+)2[4·(SO42−)] without the TBA+ counterions; (b) overhead view of
[52·(SO42−)] without the counterions, and (c) side view of [52·(SO42−)]
2−
with the two hosts on the left and right of the SO4 and with the TBA+
counterions above and below.
Fig. 3 Chemical shift changes of amide or urea NH protons in 1–6
2−
upon addition of (TBA+)2SO4 in DMSO-d6 containing v/v: (a) 0.5%,
(b) 10%, (c) 25% and (d) 50% H2O.
25% water in DMSO-d6 solution (K(6·SO42−)/K(5·SO42−) = 23.9).
greater conformational flexibility in 4, the two urea groups do
Comparatively, the dicarboxamide hosts were not nearly as not surround a single SO42−, as seen in the structures of the
2−
other, more preorganized ligands, 5 and 6.
effective in binding SO4
as the percentage of H2O was
In 5·SO42−, two of the ligands form a bis-chelate around a
increased. These findings tend to suggest the superior binding
2−
capabilities of the almost adjacent “mini-chelating” hydrogen single SO4 ion, resulting in a 2 : 1, 5 : SO42−, binding mode
(contrary to the results of the Job plot) (Fig. 4(b) and (c)). The
bis-chelate formation is reminiscent of an earlier report by one
bond donors in the urea hosts, at least in this instance. It
should be kept in mind, however, that in urea (and thiourea)
functionalities, the NH groups are usually oriented in the of us (CJ) of anion-templated dimeric host associations form
structure.5 The crystals were twinned and three of the four inde-
pendent SO4 complexes were disordered (see ESI†). Nonethe-
same direction, plus they are stronger acids than amides and
thus more effective at hydrogen bonding. An additional influ-
2−
ence, also a result of the proximal position of the urea NH less, all four independent complexes displayed the bis-chelate
structures, but with varying hydrogen bond distances, some
less strongly “coordinated” than others. Obviously, the
o-phenyl group plays a major role in the complex formation by
virtue of the preorganized urea groups. Just one of the inde-
pendent units is displayed in the Figure with its associated
groups, solvation/hydration of the anion may well be blocked,
as noted by Hamilton in a seminal paper.27 For the pyridine
dicarboxamide ligands, the two amide groups are not con-
strained to be pointed in the same direction, but are frequently
preorganized for chelation due to intramolecular hydrogen
bonding interactions with the pyridine nitrogen atom.28
Crystal structure results for the SO42− complexes of the urea
2−
hydrogen bond contacts. In this complex the SO4 is held by
eight hydrogen bonds from the two surrounding 5 hosts with
N⋯O distances ranging from about 2.8 Å to just under 3.0 Å.
The two TBA+ counterions form axial shields above and below
the complex. This axial positioning of the counterion essen-
tially boxes in the SO42− ion and serves to isolate it from neigh-
boring anions (Fig. 4(c)). The other three crystallographically-
independent (TBA)2[52·(SO4)] moieties have similar local
arrangements.
hosts 4, 5, and 6 tend, for the most part, to support the
binding conclusions. Crystals of the TBA+ salts of 4-SO4
,
2−
5-SO42−, and 6-SO4 were obtained by slow evaporation of
2−
DMSO solutions of the ligands in the presence of excess
2−
(TBA+)2SO42−. The structural results for the (TBA+)2SO4
complex with the simple diurea acycle 4 nicely illustrates the
conformational flexibility of a host that is not preorganized for
In the crystal structure of the most extended host ligand, 6,
with SO42−, the asymmetric unit contains three independent
[6·(SO42−)] complexes (Fig. 5). Each of the independent ligands
binding (Fig. 4(a)). The two urea binding sites of a single
2−
ligand are associated with two different SO4
ions. Each
2−
SO4 is also linked via hydrogen bonding to a neighboring
host, resulting in the formation of a host–guest chain that
extends throughout the crystal lattice. Although not shown in
the Figure for ease of viewing purposes, the single oxygen
atom that is not hydrogen bonded with a host appears to be
cushioned by the bulky TBA+ groups. Hence, as a result of the
2−
encircles a single SO4 anion and forms six hydrogen bonds
with N⋯O separations between 2.70 and 3.07 Å. Each ligand
uses the remaining two urea hydrogen atoms to form three
longer H-bonds with N⋯O separations between 3.13 and
3.33 Å. Shorter hydrogen bond distances are seen for the urea
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Acknowledgements
This material is based upon work supported by the
U. S. Department of Energy, Office of Science, Office of Basic
Energy Sciences, the Chemical Sciences, Geosciences and Bio-
sciences Division, DE-SC0010555. The authors also thank the
National Science Foundation CHE-0923449 for purchase of the
X-ray diffractometer. The authors would also like to thank
Drs Pedro Metola and Hanumaiah Telikepalli for helpful
discussions.
Notes and references
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