Effect of competing alkali metal cations on neutral host's anion binding ability

Article abstract of DOI:10.1021/ol0063104

(matrix presented) Anion binding by neutral hosts in organic solvents can be inhibited by the presence of alkali metal cations. The binding inhibition is due to salt ion-pairing which increases in the order Cs⁺ < K⁺ < Na⁺.

Full text of DOI:10.1021/ol0063104

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3099-3102
Effect of Competing Alkali Metal Cations
on Neutral Host’s Anion Binding Ability
Rameshwer Shukla, Toshiyuki Kida, and Bradley D. Smith*
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556-5670
smith.115@nd.edu
Received July 10, 2000
ABSTRACT
Anion binding by neutral hosts in organic solvents can be inhibited by the presence of alkali metal cations. The binding inhibition is due to
salt ion-pairing which increases in the order Cs+ < K+ < Na+. The binding inhibition can be reversed by using heteroditopic hosts that
simultaneously bind both the metal cation and the anion. The largest cation-induced enhancements are observed with the less basic anions.
Since the first report of crown ethers in 1967,1 a large number
of neutral host compounds have been prepared and evaluated
for their ability to associate with inorganic cations or anions.2
Most of these ion binding studies have been conducted in
organic solvents and have used salt systems with noncom-
peting counterions. For example, cation binding studies often
use picrate salts,3 and anion binding studies often use
tetrabutylammonium salts.4 An obvious advantage with this
choice is the minimal interference due to ion-pairing of the
guest salt. In many real-life situations, however, the luxury
of noncompeting counterions is not available.5 While a
number of studies have shown that competing anions can
alter a neutral host’s affinity for its cationic guest, and in
some cases change the binding selectivity,6 much less
attention has been paid to the effect of competing cations
on a neutral host’s anion binding ability.6b In this paper, we
report anion association constants for hosts 1-4. The results
are presented in two parts. First, we show that competing
metal cations can inhibit the anion binding ability of urea 1;
then we show that cations can increase or decrease the anion
binding ability of crown-conjugates 2-4.
(1) Pederson, C. J. J. Am. Chem. Soc. 1967, 89, 7017-7036.
(2) Lehn, J. M. Supramolecular Chemistry, VCH: Weinheim, 1995.
(3) Cation Binding by Macrocycles, Inoue, Y., Gokel, G. W., Eds.; Marcel
Dekker: New York; 1990.
(4) The Supramolecular Chemistry of Anions; Bianci, A., Bowman-James,
K., Garcia-Espana, E., Eds.; VCH: Weinheim, 1997.
(5) ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies,
J. E. D., MacNicol, D. D., Vo¨gtle, F., Lehn, J.-M., Gokel, G. W., Eds.;
Pergamon: Oxford, 1996; Vol. 10.
Anion Binding Using Host 1.7 We find that the presence
of certain metal cations leads to significant reductions in
anion association constants, as determined by NMR titration
experiments in polar organic solvents.8 For example, titration
10.1021/ol0063104 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

of 1 in DMSO-d6 with tetrabutylammonium acetate leads to
Kacetate ) 310 M-1. Repeating the titration experiment in the
presence of 1 molar equiv of metal tetraphenylborate changes
Kacetate in the following way: Cs+ (340 M-1); K+ (200 M-1);
Na+ (90 M-1). A more dramatic example is reflected by the
1H NMR titration curves shown in Figure 1. Titration of 1
whereas cesium propionate exists as free ions in DMSO.11
Ion-pairing with a competing cation diminishes anion basic-
ity12 and can lower host/anion association constants by two
ways. (i) The metal cation can sterically hinder the host/
anion interaction. This steric effect increases with the degree
of ion-pair aggregation. (ii) The associated cation lowers the
anion’s effective charge by either a polarization or a shielding
effect. This electrostatic effect also increases with the degree
of ion-pair aggregation.
Anion Binding Using Hosts 2-4. One way to alleviate
cation-induced inhibition of host/anion binding is to use a
heteroditopic host that can simultaneously bind to both the
metal cation and the anion.13 In this case, there is the
possibility for positive cooperativity, that is, the presence of
metal cation increases anion association constants. Previous
designs of salt-binding systems have used allosteric effects
(induced fit)14 and/or through-bond electrostatic effects15 to
enhance anion association constants. In this section of the
paper we evaluate the effectiveness of an alternative design,
namely, heteroditopic hosts with juxtaposed binding sites that
(6) (a) Olsher, U.; Hankins, M. G.; Kim, T. D.; Bartsch, R. A. J. Am.
Chem. Soc. 1993, 115, 3370-3371. Olsher, U.; Feinberg, H.; Frolow, F.;
Shoham, G. Pure Appl. Chem. 1996, 68, 1195-199. (b) Lamb, J. D., in ref
5, p 90. (c) Moyer, B. A. In ComprehensiVe Supramolecular Chemistry;
Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Lehn, J.-M.,
Gokel, G. W., Eds.; Pergamon: Oxford, 1996; Vol. 1, p 401. (d) Danil de
Namor, A.; Ng, J. C. Y.; Llosa Tanco, M. A.; Salomon, M. J. Phys. Chem.
1996, 100, 11485-11491. (e) Arnecke, R.; Bo¨hmer, V.; Cacciapaglia, R.;
Dalla Cort, A.; Mandolini, L. Tetrahedron 1997, 53, 4901-4908. (f) Bartoli,
S.; Roelens, S. J. Am. Chem. Soc. 1999, 121, 11908-11909.
(7) The carboxylate binding abilities of 1 and related urea derivatives
are summarized in Hughes, M. P.; Smith, B. D. J. Org. Chem. 1997, 62,
4492-4501 and references therein.
(8) The detailed NMR titration procedures and the subsequent fitting of
the data to a 1:1 binding model using nonlinear computer methods are
described in ref 7. Dilution studies show that host aggregation is very weak
and so can be ignored. A number of other host/salt systems were examined,
but they could not be analyzed due to precipitation problems.
(9) (a) Swarc M. In Ions and Ion Pairs in Organic Reactions; Swarc,
M., Ed.; Wiley: New York, 1972; Vol. 1, Chapter 1. (b) Smid, J. Angew.
Chem., Intl. Ed. Engl. 1972, 11, 112-127. (c) Bordwell, F. G.; Branca, J.
C.; Hughes, D. L.; Olmstead, W. N. J. Am. Chem. Soc. 1980, 45, 3305-
3313. (d) Kaufman, M. J.; Streiwieser, A. J. Am. Chem. Soc. 1987, 109,
6092-6097. Krom, J. A.; Streitwieser, A. J. Org. Chem. 1996, 61, 6354-
6359.
Figure 1. Chemical shift (δ) for aryl-NH in 1 (initially 10 mM)
in CD3CN and 295 K upon addition of tetrabutylammonium
dihydrogen phosphate: 9, presence, and 0, absence, of potassium
tetraphenylborate (initially 10 mM). The signal for the alkyl-NH
in 1 shows the same behavior.
with tetrabutylammonium dihydrogen phosphate in CD3CN
results in the expected 1:1 binding isotherm, and an associa-
tion constant of 400 M-1 can be extracted by curve-fitting
methods.8 If the titration is repeated with the initial host
solution containing 1 molar equiv of potassium tetraphen-
ylborate, then a different isotherm is observed. The first 1
molar equiv of dihydrogen phosphate has no affinity for the
urea NH residues, but subsequent additions produce a
“normal looking” titration curve. The same result is also
obtained using DMSO-d6 as the solvent. Apparently, the
added K+ is able to stoichiometrically sequester the dihy-
drogen phosphate which prevents host/anion binding, an
observation that appears to have not been reported before.
We attribute this reduction in host/anion binding to the
ion-pairing equilibria shown in Figure 2. In most organic
(10) Olmstead W.; Bordwell, F. G. J. Am. Chem. Soc. 1980, 45, 3299-
3305.
(11) Dijkstra, G.; Kruizinga, W. H.; Kellogg, R. M. J. Org. Chem. 1987,
52, 4230-4234.
(12) Elimination of sodium acetylacetone ion-pairing in DMSO solution
(6.6 mM) by addition of [2.2.2]cryptand increases the anion basicity by
0.5 log unit.11 In addition to ion-pairing, anion basicity is further reduced
by ion-pair aggregation. For example, the less aggregated cesium salts of
carbon acids in ether solvents are generally 3-7 log units more basic than
the corresponding lithium salts.9d Since ion-pair aggregation is concentration
dependent, anions become less basic at higher salt concentrations.9d
(13) Reviews that discuss salt-binding hosts: (a) Antonisse, M. M. G.;
Reinhoudt, D. N. J. Chem. Soc., Chem. Commun. 1998, 443-448. (b)
Kimura, E.; Koike, T. J. Chem. Soc., Chem. Commun. 1998, 1495-1500.
(c) Stibor, I.; Hafeed, D. S. M.; Lhotak, P.; Hodacova, J.; Koca, J.; Cajan,
M. Gazz. Chim. Ital. 1997, 127, 673-685. (d) Reetz, M. T. In Compre-
hensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D.,
MacNicol, D. D., Vo¨gtle, F., Lehn, J.-M., Gokel, G. W., Eds.; Pergamon:
Oxford, 1996; Vol. 2, pp 553-562. For a recent listing of papers that
describe salt binding, see ref 17b.
(14) (a) Kubik, S.; Goddard, R. J. Org. Chem. 1999, 64, 9475-9486.
(b) Beer, P. D.; Hopkins, P. K.; McKinney, J. D. J. Chem. Soc., Chem.
Commun. 1999, 1253-1254.
(15) (a) Teramae, N.; Shigemori, K.; Nishizawa, S. Chem. Lett. 1999,
1185-1186. (b) Pelizzi, N.; Casnati, A.; Friggeri, A.; Ungaro, R. J. Chem.
Soc., Perkin Trans. 2 1998, 1307-1311. (c) Beer, P. D.; Cooper, J. B. J.
Chem. Soc., Chem. Commun. 1998, 129-130. (d) Tozawa, T.; Misawa,
Y.; Tokita, S.; Kubo, Y. Tetrahedron Lett. 2000, 41, 5219-5223.
Figure 2. Salts can exist as free ions, ion-pair,s and/or aggregated
ion-pairs in organic solvents.
solvents, the salts of alkali cations do not exist as free ions,
instead they are present as solvent separated ion pairs, contact
ion pairs, and/or aggregated contact ion pairs.9 Even in highly
polar organic solvents, the salts of localized ions exist as
associated ion pairs. For example, in DMSO (dielectric
constant 46.5) the ion-pair association constants for sodium
and potassium benzoate are 200 and 48 M-1, respectively,10
3100
Org. Lett., Vol. 2, No. 20, 2000

Table 1. Anion Association Constants in CD3CN at 295 K
metal
cationa
Kassn
ΝΗ ∆δmax
(ppm)c
b
entry
hosta
aniona
(M-1
)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
4
4
4
4
4
4
none
Na+ d
K+ d
Cs+ d
none
Na+
K+
Cs+
none
Cs+
none
Cs+
none
K+
acetate
acetate
acetate
acetate
nitrate
nitrate
nitrate
nitrate
acetate
acetate
chloride
chloride
nitrate
nitrate
nitrate
chloride
chloride
bromide
bromide
iodide
220
80
250
1670
35
130
140
310
1280
770
490
1280
90
3.12
3.20
3.08
2.92
1.33
1.32
1.08
0.92
3.91
3.76
2.52
2.20
1.21
1.42
1.11
2.11
e
Figure 3. Ion-pair recognition using heteroditopic salt-binding host.
allow the salt to bind to the host as an associated ion-pair
(Figure 3).16,17 Host structures 2-418 contain either an anion-
binding urea7 or 1,3-phthalamide19 connected to a cation-
binding crown ether; however, in each case the connecting
unit contains some single bonds and is not expected to
strongly transmit through-bond electrostatic effects. Hosts
3 and 4 each contain an N-methylanilide linkage which
adopts a cis conformation about the C-N bond and places
the benzocrown and the urea (or phthalamide in the case of
4) in close proximity.20,21
16
Cs+
none
K+
none
K+
140
2600
e
560
500
28
Hosts 2-4 were initially tested for their ability to bind
salts. They are able to extract solid KCl into CD3CN, as
judged by changes in host NMR spectra. Additional qualita-
tive evidence for heteroditopic binding was gained using
positive and negative ion FAB mass spectrometry. Samples
treated with KCl exhibited intense (M + K)+ signals and
weak (M + Cl)- signals. This reflects the ability of 2-4 to
bind cations strongly and anions relatively weakly. Solution-
1.74
1.51
1.03
0.79
none
K+
iodide
90
a Initially [host] ) [metal tetraphenylborate] ) 10 mM. The anion was
added as its tetrabutylammonium salt. b Uncertainty e15%. c Average
change in host NH chemical shift upon saturation with anion. d Metal picrate.
e Titration isotherm could not be fitted to a 1:1 binding model, but binding
was obviously very weak.
1
state association constants were determined by H NMR
titration experiments in CD3CN. The spectra are consistent
with a fast exchange between free and complexed species.
Titration isotherms, generated from the change in chemical
shift of the host NH signal(s) upon addition of tetrabuty-
lammonium anion, were fitted to a 1:1 binding model using
previously described computer methods.8 The derived as-
sociation constants (uncertainty e15%) are summarized in
Table 1. Examination of these data reveals a number of
trends. In certain cases, the presence of metal cation induces
changes in the order of association constants. For example,
in the absence of added metal cation, host 2 has an affinity
for acetate that is 6 times higher than that of nitrate (compare
entries 1 and 5), whereras in the presence of Na+ ions, host
2 binds nitrate 1.6 times better than acetate (entries 2 and
6). In the absence of metal cation, host 3 has an association
constant for acetate that is 2.6 times better than that of
chloride (entries 9 and 11), whereas in the presence of Cs+
ion host 3 binds chloride 1.7 times better than acetate (entries
10 and 12).
Cooperativity Factor. The data in Table 1 was used to
generate cooperativity factors (Figure 4). A cooperativity
(16) While hosts 2-4 were designed to bind contact ion pairs, the host
structures have enough flexibility to accommodate solvent-separated ion
pairs.
(17) For some recent X-ray structures of neutral hosts complexed with
solvent-separated ion pairs, see: (a) Levitskaia, T. G.; Bryan, J. C.; Saclebon,
R. A.; Lamb, J. D.; Moyer, B. A. J. Am. Chem. Soc. 2000, 122, 554-562.
(b) Deetz, M. J.; Shang, M.; Smith, B. D. J. Am. Chem. Soc. 2000, 122,
6201-6207.
(18) The syntheses of 1-4 are described in the Supporting Information.
(19) The anion binding abilities of 1,3-phthalamides are described in
ref 17b.
Figure 4. Cooperativity factors for hosts 2-4.
(20) (a) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J.
Am. Chem. Soc. 1992, 114, 10649-10650. (b) Krebs, F.; Larsen, M.;
Jørgensen, M.; Jensen, P. R.; Bielecki, M.; Schaumburg, K. J. Org. Chem.
1998, 63, 9872-9879. (c) Reference 17b.
1
factor is simply the anion association constant in the presence
of metal cation divided by the anion association constant in
the absence of metal cation. A value <1 indicates that host/
anion binding is inhibited by the ion-pairing shown in Figure
(21) In agreement with literature precedence, the H NMR spectra of 3
and 4 provide strong evidence for a cis C-N conformation.20 For example,
the aromatic signals in 3 and 4 are significantly upfield compared to
analogues that are not N-methylated, indicating that the two aromatic rings
in 3 and 4 are cofacial.
Org. Lett., Vol. 2, No. 20, 2000
3101

2, whereas a cooperativity factor >1 reflects host/anion
binding enhancement due to the ion-pair recognition shown
in Figure 3. Examination of Figure 4 reveals two host-
independent trends.22 First, the cooperativity factor for a
specific host/anion system increases with decreasing metal
cation charge to surface area ratio, i.e., Na+ < K+ < Cs+.
Second, the cooperativity factor for a specific host/cation
system increases with decreasing anion basicity, i.e., Cl- <
solvents can be reduced by the presence of competing alkali
metal cations. The binding inhibition is due to salt ion-pairing
which increases in the order Cs+ < K+ < Na+. In some
cases the effect is very dramatic, for example, K+ can
stoichiometrically sequester dihydrogen phosphate in polar,
aprotic solvents (Figure 1). The binding inhibition can be
reversed by using heteroditopic hosts that simultaneously
bind both the metal cation and the anion. In this case, we
find that the largest cation-induced enhancements (cooper-
ativity factors) are obtained with the larger and/or less basic
anions, a trend that is apparent in the results of other
studies.14b,15b Because of ion-pairing, it is inherently difficult
(but not impossible15c,d,17b) to obtain large cooperativity
factors in organic solvents using guest salts that are composed
of small, highly localized ions.
-
Br- < I- and CH3CO2- < NO3 . These trends are explained
in the following way. Host/anion affinity is reduced by salt
ion-pairing, and the ion-paring equilibria shown in Figure 2
are shifted to the right (i.e., ion-pairing increases) as the ions
become smaller and more charge-localized. In certain cases
(when one or both of the ions are small and charge-localized),
this inhibition effect is still observed with the crown-
containing hosts 2-4, which suggests that the crown-
encapsulated cation is still able to sequester the anion away
from the host’s NH residues. This is in agreement with the
abundant crystallographic literature showing anions axially
coordinated to metal cations that are simultaneously com-
plexed inside crown ethers.17a,23
Acknowledgment. This work was supported by the
National Science Foundation.
Supporting Information Available: Synthetic and ex-
perimental procedures, 1H NMR spectra of host compounds.
This material is available free of charge via the Internet at
http://www.pubs.acs.org.
In summary, anion binding by neutral hosts in organic
(22) Factors such as the strength and stoichiometry of the crown ether-
metal cation interactions (which depend on the host structures) will also
affect the observed cooperativity factors, but it appears with the nonen-
capsulating crown systems reported here that salt ion-pairing has a
dominating role.
OL0063104
(23) Steed, J. W.; Junk, P. C. J. Chem. Commun., Dalton Trans. 1999,
2141-2146 and references therein.
3102
Org. Lett., Vol. 2, No. 20, 2000