CHAPTER 1
Introduction
1.1 Importance of Anions in the Modern World
Although often overlooked in terms of their importance, anions are ubiquitous in the natural world. Chloride anions are present in large quantities in the oceans; nitrate and sulfate are present in acid rain; and carbonates are key constituents of biomineralized materials. Anthropogenic anions, including pertechnetate, a radioactive product of nuclear fuel reprocessing, and phosphate and nitrates from agriculture and other human activities, constitute major pollution hazards.
Anions are also critical to the maintenance of life as we know it. Indeed, without exaggeration, the recognition, transport, or transformation of anions is involved at some level in almost every conceivable biochemical operation. It is essential in the formation of the majority of enzyme–substrate and enzyme–cofactor complexes as well as in the interaction between proteins and RNA or DNA. ATP, phosphocreatine, and other high-energy anionic phosphate derivatives are at the centre of power processes as diverse and important as biosynthesis, molecular transport, and muscle contraction. They also serve as the energy currency for a host of enzymatic transformations. Anion channels and carriers are involved in the transport of small anions such as chloride, phosphate, and sulfate and thus serve to regulate the flux of key metabolites into and out of cells while maintaining osmotic balance.
On a less salubrious level, mis-regulation of various anion transport mechanisms can have serious consequences. For instance, a malfunctioning of the CFTR chloride transport channel is implicated in cystic fibrosis, one of the most commonly inherited diseases among Caucasians. Likewise, the so-called ATP binding cassette transport systems, multispecific organic anion transporters, can confer resistance to a variety of modern pharmaceutical agents and are responsible in part for one of the most pressing problems in medicine, namely multidrug resistance. On very different level, an inability to process or catabolize effectively xenobiotic anions, including such chemically simple species as cyanide, oxalate, arsenate, or nitrite, can produce symptoms of chronic or acute toxicity. Poor processing of naturally occurring phosphate and sulfate is also a serious problem for patients with renal failure. Likewise, an inability to remove excess superoxide and peroxynitrite is considered responsible for many of the symptoms associated with reperfusion injury following heart attacks and strokes. On the other hand, anionic species either administered directly as in the case of fluoride used to prevent dental caries, or produced in vivo from a wide range of prodrugs, running the gamut in complexity from aspirin to AZT, are key features of modern medicine. This dichotomy underscores the complexity and importance of anion recognition in biology; it also highlights the need for, and potential utility of, synthetic anion receptor chemistry.
Later in this chapter we provide a brief selection of biologically relevant paradigms. Needless to say, in a work of this size, an exhaustive treatment is not possible. However, it is hoped that the examples chosen as highlights will help illustrate how nature uses many of the tools, such as hydrogen bonding, electrostatics, size/shape complementarily, metal–anion complex formation, and hydrophobicity, that chemists are currently employing in their efforts to achieve anion recognition. In the remainder of this chapter, we provide an historical overview that is designed both to trace the origins of the field and introduce many of the molecular recognition motifs that are continuing to play a critical role in terms of the design and synthesis of current state-of-the-art synthetic receptor systems. But first we will start with an overview of the challenges that anion complexation presents to the supramolecular chemist.
1.2 The Challenges of Anion Complexation
The design of anion receptors (and receptors for ion-pairs) is particularly challenging when compared to the design of receptors for cations. There are a number of reasons for this. Anions are larger than the equivalent isoelectronic cations (see Table 1.1) and hence have a lower charge to radius ratio. The more diffuse nature of anions means that electrostatic binding interactions are less effective than they would be for the corresponding isoelectronic cation.
Anions may be pH sensitive (becoming protonated at low pH and so losing their negative charge). Thus, receptors must function within the pH window of their target anion. This is a particular problem when designing protonated receptors for anions (e.g., ammonium containing receptors) as the protonation window of the receptor (and the anion) must also be considered. It is, of course, less of a problem for neutral receptors, or those containing permanent built-in charges, designed to operate in aprotic media.
Anionic species have a wide range of geometries (Figure 1.1) and therefore generally a higher degree of design and complementarity is required to make receptors that are selective for a particular anionic guest than for most simplecations.
The nature of the solvent in which the anion-binding event occurs plays a crucial role in controlling anion-binding strength and selectivity. Electrostatic interactions generally dominate over other recognition forces and are particularly important in stabilizing anions in solution. However, hydroxylic solvents are also noted for their ability to form strong hydrogen bonds with anions. A potential anion receptor must, therefore, compete effectively with the solvent environment in which the anion recognition event is to take place. For example, a neutral receptor that binds anions solely through hydrogen-bonding interactions is less likely to be capable of competing with the polar protic solvation shell surrounding the target anion in a hydroxylic solvent and hence may only function as an anion receptor in aprotic organic solvents (in which the anion interacts more weakly with the solvent). A charged receptor, on the other hand, can benefit from electrostatic effects and thus may compete more effectively with polar protic solvents. For example, protonated polyammonium macrocycles are capable of binding anions in water. Of course, the anion receptor must not just compete with the solvent but also with the counter cation that is necessarily paired with the targeted anion.
Ion-pairing can be very significant, particularly in non-polar solvents. Therefore, when studying anion complexation there is a necessary trade–off associated with the choice of solvent. In non-polar solvents, the anion may be weakly solvated but there may be significant ion-pairing. In more polar solvents, the solvation may be stronger – but solvation of both the...
