Cryptands protonation

The similarity between the cryptands and the first of these molecules is obvious. Compound 7 7 is a urethane equivalent of [2.2.2]-cryptand. The synthesis of 7 7 was accomplished using a diacyl halide and l,10-diaza-18-crown-6 (shown in Eq. 8.13). Since amidic nitrogen inverts less rapidly than a tertiary amine nitrogen, Vogtle and his coworkers who prepared 7 7, analyzed the proton and carbon magnetic resonance spectra to discern differences in conformational preferences. Compound 7 7 was found to form a lithium perchlorate complex. 

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. 

Two cryptands [6] show special behaviour [2.1.1] and [l.l.lj. In contrast to the larger cryptands where a fast proton exchange takes place between... 

The overall kineties of the mono- and double-protonation of cryptand [1.1.1] are even more complicated because the two ions [as for any other bimacroeyclic diamine (Alder, 1990)] may exist as different eonformers. Scheme 2 shows the protonated forms in five different eonformations ... 

For larger cryptands [6] (Cox et al., 1978), the protonation/deprotonation kinetics have also been measured. Table 4 lists the kinetic and the equilibrium data for such cryptands. When compared to the neutralization of protonated tertiary amines by OH, the reaction of the second smallest protonated cryptand [2.1.1] H is 10 to 10 times slower (Cox et al., 1978), indicating a strong shielding and possibly an i -orientation of the proton. For the [2.2.1] cryptand, no k and k-i values could be calculated, probably due to a fast pre-equilibrium between in,in- and m,OMt-conformations. 

Table 4 Kinetic and equilibrium data for the protonation of some cryptands [6].

Protonation of cryptands. Novel protonation behaviour has been observed for these (diaza) cryptands (Cheney Lehn, 1972 Kresge, 1975). Internal protonation of ligands such as 1.1.1 and 2.1.1 leads to species exhibiting very slow proton exchange rates. In contrast, for simple systems, proton exchange rates are invariably very fast. For 1.1.1, the... 

There is considerable interest in the properties of macrobicyclic cryptands, for example [78] to [81], and particularly in their ability to complex protons, metal ions, and small molecules (Lehn, 1978). In the proton cryptates there exists the possibility of intramolecular +N—H N hydrogen bonding as well as interaction of the proton with the oxygen atoms, and the properties are also strongly influenced by the size of the molecular cavity. In the [l.l.l]-cryptand [78] the molecular cavity is small (Cheney et al., 1978) and... 

For cryptands in which the molecular cavity is larger than in the case of the [l.l.l]-species [78], proton transfer in and out of the cavity can be observed more conveniently. Proton transfer from the inside-monoprotonated cryptands [2.1.1] [79], [2.2.1] [80], and [2.2.2] [81 ] to hydroxide ion in aqueous solution has been studied by the pressure-jump technique, using the conductance change accompanying the shift in equilibrium position after a pressure jump to follow the reaction (Cox et al., 1978). The temperature-jump technique has also been used to study the reactions. If an equilibrium, such as that given in equation (80), can be coupled with the faster acid-base equilibrium of an indicator, then proton transfer from the proton cryptate to hydroxide ion... 

Monoprotonation of the [2.1.1]-cryptand occurs rapidly but protonation of the monoprotonated species by hydronium ion and other acids can be followed kinetically in various solvents (Cox et al., 1982, 1983). In methanol, protonation of ii+ species by substituted acetic and benzoic acids to give i+i+ has been studied using the stopped flow technique with conductance detection. The values of the rate coefficients (kHA) for protonation (81) vary with the acidity of the donor acid from kHA = 563 dm3mol-1s-1 (for 4-hydroxy-benzoic acid) to kHA = 2.3 x 105 dm3mol 1s 1 (for dichloroacetic acid). 

The reactions, with rate coefficients well below the diffusion-limited values, are thought to occur by direct proton transfer from the donor acid into the molecular cavity. The kinetic isotope effect for proton transfer was observed to vary as a function of the pX-value of HA and to pass through a maximum value kHA/kDA 4.0, the maximum occurring for a reaction with ApA" = pA (HA) — pA ([2.1.1]H22+) = ca + 1. A similar large kinetic isotope effect kHA/kDA = 3.9 was observed for protonation of the cryptand by H20 and D20 in the isotopically different solvents (Kjaer et al., 1979). 

PET-5, PET-6 and PET-7 are examples of macrobicydic structures (cryptands) (Figure 10.12). The cavity of PET-6 and PET-7 fits well the size of K+. PET-6 has been successfully used for monitoring levels of potassium in blood and across biological membranes, but pH must be controlled because of pH sensitivity of this compound via protonation of the nitrogen atoms. This difficulty has been elegantly overcome in benzannelated cryptand PET-7, in which the aromatic nitrogens have lower pKa than those of aliphatic amines. 

Ellipsoidal cryptands can also be synthesized by direct alkylation procedures <77AG(E)720,80CB1487), obviating the need for a diborane or lithium aluminum hydride reduction step. In the case of [l.l.l]cryptand (15a) yields of the final amine alkylation step are enhanced by the amine proton itself acting as a template (81CC777). 

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