Macrocycles protonation

The possibility of using 2,6-disubstituted pyridines and 2,6,7-trisubstituted quinuclidines, where the substituents feature remote atoms with lone pairs to stabilize the hydrogen upon protonation, are proposed snperbases that have been explored by computational approaches. There is interest in synthesizing macrocyclic proton chelaters as catalytically active organic snperbases,and a new strnctnral motif for snperbases featuring caged secondary amines has been reported. The alkali metal hydroxides, of eqnal basicity in aqueous solution, have proton affinities in the order LiOH (1000 kJ/mol) < NaOH < KOH < CsOH (1118 kJ/mol). This order matches the increasing ionic character of the alkah metal-hydroxide bonds. 

The resulting macrocyclic ligand was then metallated with nickel(II) acetate. Hydride abstraction by the strongly electrophilic trityl cation and proton elimination resulted in the formation of carbon-carbon double bonds (T.J. Truex, 1972). 

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. 

Such modifications can be produced either in the kinetic aspects (proton transfer) or in the equilibrium constant. Both effects are mediated by intramolecular hydrogen bonds. For instance, Navarro et al. (93MI69) showed that the rate of proton transfer between the two nitrogen atoms of pyrazole (annular tautomerism) is considerably reduced in macrocycles containing oxygen or nitrogen atoms in the macroring. 

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). 

The characteristic property distinguishing macrocyclic polyamines from their linear counterparts is seen in successive protonation. One is the higher N basicity to the first proton and another is a sudden drop of N basicities in the later stages of protonation. Table 1 lists the protonation constants (Eq. 1) for the macrocyclic polyamines in comparison with the corresponding values for their linear homologues. When a linear triamine (e.g. dien) 36,37) is cyclized to, say, (9)aneN3, the basicity of the first amine increases (log Kt = 10.59 us 9.70), but the basicity of the second and especially the third amine diminish (log K2 = 6.88 vs 8.95, log K3 < 1 vs 4.25)36)... 

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

At pH 7, [13]aneN3 or [12]-[15]aneN4 accommodate only two nitrogen-bound protons and these dipositive ammonium cations are apparently unable to provide sufficient electrostatic attraction to polycarboxylate anions for ion-pair formation. In contrast, the macrocyclic spermines, pentaamines and hexaamines accommodate more than three nitrogen-bound protons at pH 7 and for these ligands 1 1 associations... 

The new macrocyclic hexaamine ligand X has the mixed protonation constants, log K of 10.10, 10.01, 8.96 and 8.02 at 25 °C and 1=0.2 M for the four most basic amines. The values for other weaker bases, including the six carboxylates, are all less than 5. From a comparison with logA values of the parent macrocycle [18]aneN6, it was deduced that the initial four protonations occur to the macrocyclic amine bases. Thus, the most abundant species of X at neutral pH is depicted as XI. 

For isolation of the fully protonated macrocycle, with known counterion composition, the CH,C12 soln of the free-base macrocycle was washed with an equal volume of a 1 M solution of the desired acid before briefly drying (Na2S04) and removing the solvent on the rotary evaporator yield 460 mg (44%) of 56 2HC1 (following treatment with 1 M HC1). The macrocyclic product and its diprotonated salts can be further purified by crystallization (CHCl3/hexane). 

The name amethyrin refers to the fact that the dull-purple color of the protonated form of the macrocycle is that of amethyst stones, Formal oxidation or reduction products are the aromatic [22]hexaphyrin(l.0.0.1.0.0) or the [26]hexaphyrin(l.0.0,1.0.0), respectively. However, none of these products could be observed either as reaction products or as direct products of oxidation or reduction reactions. 

Although [34]octaphyrin 80 fulfills Hiickel s rule, the II NMR spectrum indicates by the high-field shift of the methine protons that the system is nonaromatic. The X-ray structure analysis demonstrates clearly the reason for the lack of aromatic stabilization, namely the nonplanar loop conformation in which the whole macrocycle is twisted similarly to the [32]octaphyrin structure and which is also found for [36]octaphyrin and [40]decaphyrin structures (vide infra). 

Table 1 Equilibrium constants log K for the protonation of macrocyclic diamines [4] in water and methanol at 25°C.

The 1,3-xylyl trick was also used for the incorporation of phenols into crown ethers. Three classes of phenols [46a]-[46c] have been investigated. They differ by their substituents in the 4-position. In Table 22 the pX a values of different macrocyclic phenols [46a]-[46c] are compared. The data obtained for the phenol-containing crowns [46a] and [46b] show very little evidence for a macrocyclic effect. No extra stabilization of the protonated (acidic) form by a macrocycle of appropriate ring size was found. The acidities of the macrocyclic phenols [46a] and [46b] were independent of the ring size and comparable to non-macrocyclic analogues. However, the azo-substituted crowns [46c] showed a difference of 0.8 pACg units which was not expected from the pAfa values of [46a] and [46b]. TTiis different behaviour of [46c] is not yet understood. 

Dicarbonyl functions have been built into macrocyclic structures, and pKa values for the resulting macrocycles [60] have been determined (Alberts and Cram, 1979). When the open-chain model [62] is compared with the macrocycles [60], identical first pK values were found (pKa = 8.6). Thus for the diketones [60], no macrocyclic effect is noticeable. But for the dissociation of a second proton from the mono-aniorts of [60] much higher pKa values are found. To a certain extent. Coulomb repulsions (see Section 2) are probably the reason for this behaviour, but the large difference in the pKa values (ApKa = 2.9, see Table 26) argues for a special stabilization of the mono-anion. Again hydrogen bonds are not unreasonable. 

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