Origin of the Macrocyclic Effect

It should now be possible to determine whether the macrocyclic effect is entropic or enthalpic in origin. Initial investigations were made on transition metal complexes and most workers had a prejudice towards an entropic origin, similar to that of the chelate effect. More recently, it has become apparent that there is no single cause to which the 

The value of log K for the copper complex of 6.24 is 4.3, whilst for that of 6.23 it is 1.97. The macrocyclic complex is thus about 100 times more stable than the open-chain complex, and this is presumably due to the macrocyclic effect. In this case, thermodynamic measurements have shown that Afor the macrocyclic and open-chain complexes are almost identical, and so the macrocyclic effect is due almost entirely to the entropy term. However, even with these ligands the involvement of solvation may not be neglected entirely. The stability values given above are for the complexes in aqueous solution if the measurements are repeated in 80 % aqueous methanol, the value of log K for the formation of the macrocyclic complex is only 3.5. A hole-size effect (section 6.6) is also apparent if we move to the larger thioether macrocycle 6.26. For the formation of the copper complex of 6.26 (again in 80 % aqueous methanol) log K is found to be 0.95. 

The thermodynamic stability of the macrocyclic complex provides one of the driving forces for cyclisation in template reactions. In a way, co-ordination of the macrocycle to the metal ion provides a thermodynamic sink into which the reaction product can fall. This is clearly of importance when we consider the reactions such as the formation of metal 

In addition to their thermodynamic stability, complexes of macrocyclic ligands are also kinetically stable with respect to the loss of metal ion. It is often very difficult (if not impossible) to remove a metal from a macrocyclic complex. Conversely, the principle of microscopic reversibility means that it is equally difficult to form the macrocyclic complexes from a metal ion and the free macrocycle. We saw earlier that it was possible to reduce co-ordinated imine macrocycles to amine macrocyclic complexes in order to remove the nickel from the cyclam complex that is formed, prolonged reaction with hot potassium cyanide solution is needed (Fig. 6-24). 

In terms of template reactions, this combination of kinetic and thermodynamic stability usually means that the metal ion remains co-ordinated to the macrocyclic ligand and the isolation of the metal complex of the macrocycle provides strong circumstantial evidence for the existence of a metal-directed process. This is particularly easy to establish if the incorporation of the metal ion into the macrocyclic ligand can be shown to be slower than the metal-directed formation reaction. 

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It is not easy to generahze about the origins of the macrocyclic effect. In considering comparable open- and closed-chain complexes such as 6.22 and 6.23, entropy factors tend, in most cases, to favour the formation of the macrocyclic complex. However, the enthalpy term does not always favour the macrocyclic complex, although the value of AG° (i.e. the ultimate arbiter) always favours the formation of the macrocycle. We shall consider the formation of macrocyclic compounds further in Chapter 10. 

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. 

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 presence of the cyclic backbone in ligands of this type makes a substantial contribution to their metal-ion complexing ability even though coordination involves donors which are not directly incorporated in the ring fragment. The origins of the enhanced stability of the metal-containing species may be considered to reflect the operation of an indirect macrocyclic effect (see Chapter 6) in these systems. 

Since binding in solution results from a compromise between interaction with the ligand and solvation, new insights into the origin of the cation recognition process and of the macrocyclic and cryptate effects can be gained from experimental gas phase studies [2.34, 2.35] as well as from computer modelling calculations in vacuo or in a solvent [1.35b, 1.42, 1.43, 1.45, 2.36, 2.37, A.37]. In particular, molecular dynamics calculations indicate that complementarity is reflected in restricted motion of the ion in the cavity [1.45, 2.36]. 

The macrocyclic effect is evident in the increase of 4.09 units in log K. It can be seen that the overall effect is of both enthalpic and entropic origin. The relative importance of these two contributions varies from case to case. 

In terms of thermodynamics, the role of entropy versus enthalpy has been hotly debated. Log K and thermodynamic values are provided in Table 2. As can be seen from the thermodynamic parameters provided in the table, it becomes evident that the macrocyclic effect is primarily enthalpic in origin. This is dependent, however, on comparing systems without steric strain, which naturally adds other mitigating factors to the thermodynamics. 

It is particularly interesting to compare the thermodynamic aspects of supramolecular chemistry with transition metal chemistry (Tables 2 and 6). If similar chemistry holds, the macrocyclic effect should be primarily enthalpic in origin. As can be seen from Table 6, the A AH) values show that the effect is primarily enthalpic for Na" ", Cs+, Ba +, and Pb +, ranging from negative teens for the... 

It is interesting to note that although the first examples of template effects were observed in nitrogen macrocycles (see chapter 2) no template effect appears to operate in the synthesis of 72. Richman and Atkins note this in their original report . The authors replaced the sodium cation with tetramethylammonium cations and still obtained greater than 50% yield of tetra-N-tosyl-72. Shaw considered this problem and suggested that because of the bulky N-tosyl groups, .. . the loss of internal entropy on cyclization is small He offered this as an explanation for the apparent lack of a template effect in the cyclization. 

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