The Macrocyclic Effect

Why is it that these metal-directed reactions are so dominant in the preparative chemistry of macrocyclic ligands The answer to this lies in part in the great stability that is often associated with macrocyclic complexes. Very often, the complexes exhibit high kinetic and thermodynamic stabilities. 

Why are complexes with macrocyclic ligands particularly stable This question has generated considerable controversy over the years, and it is now clear that the factors 

The peraza macrocycles, in general, form more stable complexes with a variety of metal ions than do the open-chain polyamines containing the same number of amine groups. This characteristic is called the macrocyclic effect. Triaza-crowri macrocycles, in nearly every case, form 1 1 complexes with metal ions that are thermodynamically more stable than those with dieth-ylenetriamine. Only complexes of the open-chain triamine with and Hg- are more stable than those with the cyclic triamines (Bianchi et al., 1991). Triaza-9-crown-3 (23) forms stronger complexes with most cations than the larger triazacyclodecane (24), triazacycloundecane (25), or triazacyclo-dodecane (26) (Bhula et al., 1988 Chaudhuri and Wieghardt, 1987). 

The tetraazacycloalkanes, particularly the 14-membered cyclic tetraamine (cyclam) (10), exhibit the macrocyclic effect due to a more favorable enthalpy contribution to complex stability (Hancock and Martell, 1988). Complexes of the pentaaza-crown macrocycles have been studied extensively from a thermodynamic point of view (Bianchi et al., 1991). With the exception of Ni-, [15]Ns formed the most stable complexes with all the metal ions studied with the stability order as follows [15]N5(27) [16]N5(28) [17]N3(29) (Bianchi et al., 1991). 

The hexaazacycloalkanes have complexing properties that lie between those of the smaller peraza-crown macrocycles, which exhibit the macrocyclic effect and the large peraza macrocycles, which do not. Compound [18]N(,(22) forms complexes in water with the transition metals and also with K+, Sr, Ca-+, and La + ions. It is interesting that [18]N(,(22) has a higher affinity for Ca- than does [18]Of,(19) (Bianchi et al., 1991). 

---

Thioethers lack the capacity to neutralize positive charge and display weak donor properties. Consequently, they do not readily displace strong donor solvents (water) or strongly bonding anions (such as halides) from the coordination sphere. As a consequence, many thioether complex syntheses employ aprotic or alcoholic solvents and precursor complexes with weakly bound solvents (such as DMSO or acetone) or anions (such as C+3S03 ). Despite the synthetic challenges, a wide range of complexes has been reported, particularly with the cyclic poly-thioethers, where the macrocyclic effect overcomes many of the above difficulties. 

It is important to note that, even when the coordination geometry prescribed by the macrocyclic cavity is ideal for the metal ion involved, unusual kinetic and thermodynamic properties may also be observed (relative to the corresponding open-chain ligand complex). For example, very often the macrocyclic complex will exhibit both enhanced thermodynamic and kinetic stabilities (kinetic stability occurs when there is a reluctance for the ligand to dissociate from its metal ion). These increased stabilities are a manifestation of what has been termed the macrocyclic effect - the multi-faceted origins of which will be discussed in detail in subsequent chapters. 

The stability of cryptate complexes. The cage topology of the cryptands results in them yielding complexes with considerably enhanced stabilities relative to the corresponding crown species. Thus the K+ complex of 2.2.2 is 105 times more stable than the complex of the corresponding diaza-crown derivative - such enhancement has been designated by Lehn to reflect the operation of the cryptate effect this effect may be considered to be a special case of the macrocyclic effect mentioned previously. 

Table 6.1 summarizes the thermodynamic parameters relating to the macrocyclic effect for the high-spin Ni(n) complexes of four tetraaza-macrocyclic ligands and their open-chain analogues (the open-chain derivative which yields the most stable nickel complex was used in each case) (Micheloni, Paoletti Sabatini, 1983). Clearly, the enthalpy and entropy terms make substantially different contributions to complex stability along the series. Thus, the small macrocyclic effect which occurs for the first complex results from a favourable entropy term which overrides an unfavourable enthalpy term. Similar trends are apparent for the next two systems but, for these, entropy terms are larger and a more pronounced macrocyclic effect is evident. For the fourth (cyclam) system, the considerable macrocyclic effect is a reflection of both a favourable entropy term and a favourable enthalpy term. 

Table 6.1. Parameters illustrating the macrocyclic effect for the high-spin Ni(n) complex of the tetraaza macrocycles L, L4, L6 and L8 (Micheloni, Paoletti Sabatini, 1983). 

Crown polyethers. Macrocyclic effects involving complexes of crown polyethers have been well-recognized. As for the all-sulfur donor systems, the study of the macrocyclic effect tends to be more straightforward for complexes of cyclic polyethers especially when simple alkali and alkaline earth cations are involved (Haymore, Lamb, Izatt Christensen, 1982). The advantages include (i) the cyclic polyethers are weak, uncharged bases and metal complexation is not pH dependent (ii) these ligands readily form complexes with the alkali and alkaline earth cations... 

Finally, a discussion of the kinetic features of the macrocyclic effect (the kinetic macrocyclic effect ) mentioned in Chapter 1 is deferred until the next chapter. 

The dissociation kinetics of macrocyclic complexes have received considerable attention, especially during investigations of the nature of the macrocyclic effect. Before discussing the dissociation of cyclic ligand species, it is of benefit to consider some aspects of the dissociation of open-chain ligand complexes. 

For monocyclic crown ethers the data presented in Table 4 and the stability constants for glymes [43]—[46] determined by Chaput et al. (1975) can be combined to calculate the macrocyclic effect (Table 7). The data indicate that the gain in binding energy on ring closure shows the same pattern as the ion selectivity of the crown ether, being highest for Na+/15-crown-5, K+/18-... 

This kind of argument may also be invoked for some Cr(III)-azamacrocyclic complexes. In this regard, it is noted that the macrocycle effect (which is essentially an enhanced chelate effect) stabilizes metal ions entrapped in the cavity formed by macrocyclic organic ligands... 

The thermodynamic origins of the enhanced stabilities of macrocyclic ligands over their acyclic counterparts have been the subject of considerable debate since the term macrocyclic effect was first coined.83 Comparison of thermodynamic data for the several metal ion complexes of the [18]crown-6 and its acyclic counterpart are shown in Table 1. Enthalpy contributions to stabilization appear strongest for the K+ complex, while entropic contributions are stronger for the Na+ complex. Undoubtedly, the factors responsible for the thermodynamics will vary according to ion size, charge, solvation effects and structural preference. Hence, a single definable source of the macrocyclic effect is, in these systems at least, probably nonexistent. 

Varnek, A., Wipff, G., Solov ev, V.P. 2002. Assessment of the macrocyclic effect for the complexation of crown-ethers with alkali cations using substructural molecular fragments. J. Chem. Inf. Comput. Sci. 42 812-829. 

FIGURE 5.9 The macrocyclic effect contribution of stabilities of complexes (8 = ME/log K) for different macrocyclic scaffolds for the Na+ ( ), K+ ( ), and Cs+ ( ) crown ether complexes, respectively.77 25 Error bars show variation of 8 for a given type of ligand. 

Table 6-1. Thermodynamic stability data for copper(n) complexes of a series of nitrogen donor ligands, illustrating the macrocyclic effect.

---