Macrocycle cavities

We do not discuss in detail the cases of tautomerism of heterocycles embedded in supramolecular structures, such as crown ethers, cryptands, and heterophanes, because such tautomerism is similar in most aspects to that displayed by the analogous monocyclic heterocycles. We concentrate here on modifications that can be induced by the macrocyclic cavity. Tire so-called proton-ionizable crown ethers have been discussed in several comprehensive reviews by Bradshaw et al. [90H665 96CSC(1)35 97ACR338, 97JIP221J. Tire compounds considered include tautomerizable compounds such as 4(5)-substituted imidazoles 1///4//-1,2,4-triazoles 3-hydroxy-pyridines and 4-pyridones. 

Recently considerable attention has been directed at anion binding ligands. Macrobicyclic 27 29) and macrotricyclic amines 30,31) were topologically designed to host anions such as spherical Cl-, linear Nf 32). These anion substrates are incorporated into macrocyclic cavities lined with appropriate anion-binding sites capable of forming hydrogen bonds like those of protonated amines (see /, below). 

Macrocyclic polyammonium cations containing more than one proton within the macrocyclic cavity have several unique features ... 

The importance of the relationship between the macrocycle cavity and the binding of two reagents is shown by the cycloadditions of cyclopentadiene with diethyl fumarate and ethyl acrylate in aqueous solution. The presence of jS-CD strongly accelerates the first cycloaddition, while it slows down the reaction rate of the second, probably because the cavity favors the binding of two molecules of either diene or dienophile [65c]. 

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. 

Consequences of unsaturation. Unsaturation in the macrocyclic ring may have major steric and electronic consequences for the nature of the ring. Extensive unsaturation will result in loss of flexibility with a corresponding restriction of the number of possible modes of coordination. Further, loss of flexibility tends to be reflected in an enhanced macrocyclic effect . For example, if the metal ion is contained in the macrocyclic cavity, the loss of flexibility reduces the possible pathways for ligand dissociation and this tends to increase the kinetic stability of the system. As explained in later chapters, enhanced thermodynamic stabilities will usually also result. 

Kinetic aspects of the use of alkali metals as templates for the formation of other crowns have been studied in some depth (Mandolini Masci, 1984). The results of such investigations parallel the previous observations - namely, that the catalytic efficiency of such ions in promoting cyclization shows a strong tendency to parallel their strength of binding with the crown products (this in turn often correlates with the fit of the metal ion for the macrocyclic cavity in the product). 

Complexes of the cryptands having 2 1 stoichiometries are also known for example, with Pb(n), 2.1.1 forms a species of type [Pb2(2.1.1)]4+ in which both Pb(n) ions appear to lie outside the macrocyclic cavity (Arnaud-Neu, Spiess Schwing-Weill, 1982). 

The symmetrical ring enniatin (304) forms a potassium complex (Figure 9.3) whose crystal structure indicates that the cation is contained in the macrocyclic cavity and is coordinated by the six carbonyl oxygen atoms which are orientated such that three lie above and three lie below the main plane of the molecule (Dobler, Dunitz Krajewski, 1969). Apart from those just discussed, it needs to be noted that a range of other structures of antibiotic molecules and their metal complexes have been determined (Hilgenfeld Saenger, 1982). 

Subsequent reaction of porphyrazines 170 and 171 with Cu(OAc)2 resulted in the selective metalation within the macrocyclic cavity to provide the corresponding copper complexes 166 (62%) and 172 (47%). Treatment of pz 170 with manganese acetate and iron sulfate in dimethyl sulfate gave the dmso adducts 173 (70%) and 174 (85%), respectively (168). Axial ligation was also observed when other metals were incorporated such as cobalt acetate, nickel acetate, and zinc acetate to give the metal complexes 175 (83%), 176 (70%), and 177 (90%) as the hydrates. The axial ligand of... 

The conversion of squaraine 19a to the rotaxane 18 D 19a causes a modest red-shift only in both absorption (10 nm) and emission (7 nm) but an approximately threefold decrease in quantum yield. The addition of two triazole rings (dye 19b) did not significantly alter the quantum yield of 17b (Table 4). A macrocycle-induced quenching effect was verified by fluorescence titration experiments adding aliquots of 18 to a solution of squaraine 17b in methylene chloride [58]. Treatment of the 18 d 17b psuedorotaxane system with the tetrabutylammonium salts of chloride, acetate, or benzoate leads to the displacement of squaraine 17b from the macrocyclic cavity and the nearly complete restoration of its fluorescence intensity. The 18-induced quenching of 17b does not support the utility of this system as a bioimaging probe however, the pseudorotaxane system 18 Z> 17b acts as an effective and selective anion sensor with NIR fluorescence. 

In the approach of Puddephatt et al., the P-phenyl-phosphonitocavitand 2 was obtained by the reaction of phenylphosphonous chloride on re-sorc[4]arene lb (1, R=CH2CH2C6H5) in presence of pyridine as base. The reaction is stereoselective and yielded the bowl-shaped molecule 2 with the four P-phenyl groups directed outwards and the four lone pairs directed inwards ini configuration) [45-49] (Scheme 6). Molecular mechanics calculations performed on the six possible isomers of 2, showed that the iiii isomer is preferred and the orientation of one phenyl group toward the macrocyclic cavity is probable iiio isomer), but two or more phenyl groups oriented inwards are highly unlikely [48]. 

Protonated forms of the large-ring macrocycle [24]Ng02 (5) and related compounds have been shown to be active as synthetic phosphorylation catalysts in ATP synthesis. It is likely that in this case the substrate enters the macrocyclic cavity to some extent, or is enveloped by it. Evidence for this possibility comes from the crystal structure of the chloride salt of 5-6H (Figure 1) in which a chloride ion is enveloped within a cleft formed by the boat-shaped conformation of the macrocy-cle. The crystal structure of the nitrate salt of 5-4H has also recently been determined and the host again adopts a boat-like conformation as it interacts with the anion. The hydrochloride salt of the smaller [22]Ng binds two chloride anions above and below the host plane in a similar way to 1. Molecular dynamics simulations indicate that the pocket-like conformation for 5-6H is maintained in solution, although Cl NMR experiments demonstrate that halide ions are in rapid exchange between the complexed and solvated state. 

In the previous section it was noted that hexacyclen 1 does not possess a macrocyclic cavity of sufficient size to encapsulate anionic guests such as Cl" and NO3. In contrast, the octaaza macrobicyclic analogue of hexacyclen (17) forms the fluoride cryptate [F" c 17-6H ] (Figure 7). Consistent with the observed high... 

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