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This review covers the binding and selectivity aspects of halide anions in positively charged polyammonium hosts including monocyclic, bicyclic and tricyclic systems. The binding affinity and selectivity of host molecules for halides are largely depended on the shape, charges, and ring size of the host molecules. In general, a monocycle that has a flexible cavity binds an anion from both side, however a bicyclic or tricyclic molecule tends to bind a single anion in its cavity.
Research in molecular recognition field involving synthetic receptors has its origin in biological systems which are highly dependent on non-covalent interactions to function. A molecular receptor is capable of binding and recognizing a guest species selectively to form a supramolecular complex by virtue of hydrogen bonding or electrostatic interactions (Scheme 1).
Anion binding process which involves non-covalent interactions, namely electrostatic and hydrogen bonding interactions between a receptor and a negatively charged species, constitute a major challenge as compared to the cation binding. A number of factors which make the anions more difficult for binding to synthetic receptors than the cations, are size, shape and free energy of solvation. Anions are structurally diverse and are larger than their isoelectronic cations. In an isoelectronic pair of anion/cation (for example, F− and Na+), the lower atomic number causes a decrease in effective nuclear charge of an ionic radius of the anion, therefore, the electron clouds spread in size. This effect results in lower charge density of the anion and makes anions less efficient for electrostatic binding interactions than smaller cations. The free energy of solvation also constitutes another problem for anion binding. In general, an anion has higher free energy of hydration than the cation of comparable size. Therefore, an anion is required to overcome the high hydration energy for binding with a receptor.
Among the various anions, halides represent one of the most informative series that have been widely investigated for binding with various types of synthetic receptors. Halides play an important role in the field of chemistry and biology. For instance, the high concentration of fluoride in water or food is toxic and can have negative health effect, e.g. dental fluorosis, if consumed over an extended period of time (Colquhoun, 1997). Chloride is an essential component that is transported to different organs (lungs, kidney and pancreas), and disruption of chloride transport causes cystic fibrosis (Akabas, 2000). The bromide can be converted into the bromate (BrO3−) during water purification process with ozone as a disinfecting agent. Bromate is highly toxic, and is suspected to be a genotoxic carcinogen (Bonacquisti, 2006). The presence of iodide in drinking water causes low taste and an unpleasant odor due to formation of iodoform with natural organic matter (Bichsel and von Gunten, 1999). Nitrate and sulfate are contaminants in water, and have been implicated in high incidences of lymphoma if present in larger quantities (Ward et al., 2005).
Macrocyclic polyamines are known to coordinate cations though the lone pairs of elcetrons. These ligands can be protonated in presence of an acid to form polyammonium ions that are capable of binding negatively charges species. Such binding patterns and affinities are highly dependent on the degree of protonation, solvent pH and ring sizes. Depending on the cycles, theses ligads are classified an monocycle, bicycle and tricycles.
A monocyclic ligand can interact with anions from both sides of the cavity leading to the formation of a ditopic complex. For instance, a monocyclic ligand 1 formed complexes with halides at low pH (Warden et al., 2004). The resulting X-ray analysis indicated that the ligand formed 1:2 complexes regardless of the sizes of halides. The ligand was hexaprotonated in chloride salt, while it was tetraprotonated in bromide and iodide complexes. Figure 1 shows the crystal structure of the chloride and bromide complex of 1 showing two anions bonded with macrocyclic ring though the protonated amines. These findings, however, are not consistent with the previously reported data in solution, where the ligand in its hexaprotonated form was shown to complex chloride and bromide with 1:1 binding mode (Cullinane et al., 1982).
Monolicyclic ligands 2 and 3 were synthesized from K2CO3 templated cyclization of 1.3-bis(bromomethyl)benzene with corresponding tosylated amides and examined their for anion binding (Illioudis and Steed, 2005). The ligand 2 was shown to form ditopic complexes with chloride (Figure 2). It was observed that the two macrocycles formed a dimer sandwiching a pair of chloride anions. The structures of the bromide and iodide complexes of 2 are similar with the short anion…centroid distances of 3.77 and 4.22 Å resulting from the conformational changes of the aromatic ring that adopts almost perpendicular to the pane of macrocyclic ring. Regardless of the sizes, the anions interact with the ligand through amide hydrogens from both faces of the macrocycles. On the other hand, in the fluoride complex of the relatively smaller ligand 3, the two fluoride ions interact with the macrocycle from the same side, where one of the fluoride ion is held by three NH hydrogens of the macrocycle. The ligand also forms a dimer similar to the chloride complex of 2’, sandwiching a HF2−.
A bicylic octaazacryptand 4, consisted of two 18-membered cycles was found to bind fluoride very strongly in water giving the association constant, K >1010 M−1 (Dietrich, 1989 and 1996). This ligand showed high fluoride/chloride selectivity. In the crystal structure of 4 with the fluoride anion showed that the small anion is held with six ammonium hydrogens into the cavity (Figure 3a). Modeling studies of this ligand indicated that the cavity is small to encapsulate other halide ions (Reilly et al., 1995).
However, at low pH (below 2.5) this ligand was also found to form a complex with chloride (Hossain et al., 2000). The resulting X-ray structure is shown in Figure 3. The chloride anion is coordinated with the six protons of the secondary nitrogens with an average N···Cl− distance of 3.10 Å. The distance between the two bridgehead nitrogens is 6.59 Å, slightly shorter than in the fluoride complex (N+ ··· N+ = 6.65 Å). The ligand, however, was too small to bind larger bromide or iodide anion as examined by 1H NMR studies.
Slightly expanded ligand 5 in its hexaprotonated ligand formed strong 1:1 complexes (ligand to anion) with fluoride and chloride in water (Dietrich et al., 1996). This ligand also exhibited some selectivity for chloride over bromide or iodide due the perfect fitting of the chloride into the cavity. The crystal structure of the chloride complex of H66+, showed that one anion is encapsulated with six secondary NH protons with an average N···Cl− of 3.23 Å. The two bridgehead nitrogens are placed at a distance of 7.60 Å, that is longer than 6.08 Å seen in the free ligand (Dietrich et al., 1996).
There is a good number of examples of ditopic complexes of the transition metal ions (Jazwinski et al., 1987; Bazzicalupi et al., 1997). A macrocyclic ligand is also capable of forming a ditopic complex with anions, if the size of the ligand is sufficiently large to allow multiple guest species. In the case of an anion ditopic complex, one guest species is anion and the other is an anion or a water molecule (Aguilar et al., 2001; Morehouse et al., 2003; Hossain et al., 2005).
The first anion ditopic complex was reported for the ligand 6 in its hexaprotonated form with fluoride anion (Mason et al., 2000). The crystal structure showed that one fluoride anion and one water molecule are encapsulated into the cavity (Figure 4). The fluoride is tetrahedrally bonded with three NH groups of a given tren and one OH group of water. The anionic species and the water molecule are located near the two tren units with the distances of 3.16 and 3.46 Å, respectively from the tertiary nitrogen atoms. In water, the ligand 6 binds fluoride with the association constant K > 3500 M−1, in its hexaprotonated form. When the ligand was heptaprotonated, the association constant was significantly increased to 19500 M−1 due to the strong electrostatic interactions (Aguilar et al., 2001).
The ligand 7 with p-xylyl linkers has slightly larger cavity as compared with 6, was also found to form ditopic complexes with both chloride and bromide (Hossain et al., 2005). The coordination environment of encapsulated halide is similar as it is in the fluoride structure of 6. In the case of chloride complex, the anion and the water are located in the cavity with the distances of 3.58 and 3.32 Å, respectively from the bridgehead nitrogens. The apical central nitrogens are apart by 10.09 Å. For the bromide structure, this distance is longer (10.37 Å), because of the larger size of the encapsulated anion compared with fluoride or chloride.
The ligand 7, however, showed different binding behavior with fluoride when studied in solid state. The single crystal analysis of 7 with fluoride revealed that the ligand holds two fluoride anions and one water molecule in a cascade fashion (Hossain et al., 2002, 2005). Two fluorides are located on the axis of two tertiary amines, and are tetrahedrally bonded with three NH’s of one tren unit and a water molecule. The distances of N···F− are within the ranges of 2.60–2.72 Å, while that of O-H···F− is 2.71 Å. Inclusion of the three guests in the cavity causes an elongation of N+ ···N+ distance (10.717Å) compared to the corresponding distance in chloride or bromide complexes. The inclusion of two fluoride anions was further confirmed in solution studies performed by potentiometric experiments at low pH.
The synthesis of tricyclic ligands is not straight forward as monocycles and tricycles, and often requires multistep synthetic procedures. In an earlier work, Lehn and coworkers synthesized a spherical tricyclic aminopolyether 9 that was found to be very selective for chloride over bromide (Graf and Lehn, 1976). Treating with hydrochloric acid, the ligand formed a chloride complex. The crystal structure showed of H44+ that the anion was nicely encapsulated into the macrotricyclic cavity (Mets, 1976). A pyridine based ligand 10 was synthesized from the coupling of 2,6-bis(bromoethyl)pyridine and 1,5-diamino-3-oxapentane, and investigated for anion binding in solution (Takemura et al., 1999). 1H NMR titration experiments in 10% D2SO4, suggested that the compound exhibited weak binding for chloride and bromide with the association constants of 24 and 23 M−1, respectively. However, this ligand did not bind bromide or iodide under the similar experimental conditions.
In this review polyamine based halide receptors with different dimensionality and sizes have been highlighted. The ligands form complexes with negatively charged anions by means of electrostatic and hydrogen bonding interactions. Although polyamines are good candidates for anions, however their binding is limited to a certain pH ranges where the protonation of amino groups is occurred. The degree of protonation contributes not only to the strong affinity for a particular anion, but also changes the selectivity patterns for different anions. A solvent also plays a significant role in governing the magnitude of the binding constant. In a competitive polar solvent ligands tend to exhibit weak binding for anions. Depending on the size, a ligand can form different stoichiometric complexes with halides. In general a monocyclic compound has a tendency to form 2:1, however, bicyclic or tricyclic ligands form mostly 1:1 with halides. The higher degree of complexation is observed for larger ligands.
This work was supported by National Institutes of Health, Division of National Center for Research Resources, under the Grant Number G12RR013459.