Concentration-dependent self-association

Some drugs exhibit concentration-dependent self-association in aqueous solutions. The dissociation constant of these compounds may change upon self-association. For example,... 

Surfactants having an appropriate hydrophobic/hydrophilic balance (sodium bis(-2-ethylhexyl)sufosuccinate, or AOT, for example) undergo concentration-dependent self association in apolar solvents to form reversed or inverted micelles (Fig. 33) [256-262]. Reversed micelles are capable of solubilizing a large number of water molecules (AOT reversed micelles in hexane are able to take up 60 water molecules per surfactant molecule, for example). Reversed-micelle-entrapped water pools are unique they differ significantly from bulk water. At relatively small water-to-surfactant ratios (w = 8-10, where w = [H20]/[Surfactant]), all of the water molecules are strongly bound to the surfactant headgroups. Substrate solubilization in the restricted water pools of reversed micelles results in altered dissociation constants [256, 257, 263-265], reactivities [256, 258, 266], and reaction products [267]. 

Figure 3. Static light scattering study of the concentration-dependent self-association of Pal-HI in the presence of a 0.35 mol ratio of Zn(II) protein (solid symbols), and metal-free Pal-HI (open symbols). The solutions were prepared in 25 mM Tris-HCl buffer pH 7.4.

The enzyme phosphofructokinase, isolated from a number of different sources including skeletal muscle, heart muscle, and erythrocytes, is known to undergo a concentration dependent self-association which is sensitive to pH as well as to added substrates and effector molecules. Various oligomers of phosphofructokinase have been observed to differ in specific activities and substrate affinities, suggesting that the self-association may be involved in regulation of the enzyme (ref. 13). 

The aniline-zinc porphyrin interaction has also been exploited to form dimers. Hunter (60) reported the dimerization of porphyrins functionalized at one meso position with ortho or meta aniline groups (47, 48, Fig. 15). Both compounds showed concentration-dependent H NMR spectra with large upfield shifts for the aniline protons. The dimerization constants are 160 and 1080 M-1 respectively for 47 and 48, and these values are an order of magnitude higher than the association constants of simple reference complexes (K — 10 and 130 M 1 respectively), which is indicative of cooperative self-assembly. The complexa-tion-induced changes in chemical shift were used to obtain three-dimensional structures of the dimers. 

Viscosity and molar mass measurements for 70 and 71 supplemented with broad H-NMR signals which depended on concentration, temperature, and solvent but independent of NMR frequency, strongly suggested self-association of these macromolecules (in a CHC13 solution). 

CS2 and acetone. The increases of 1.3-2.0 Hz depending on the temperature were about half the size of the temperature effects. Both were attributed to self association of the ethyl formate. Dhingra et al. 28> reported that /13 of tri-fluoroacetic acid increases with decreasing concentration in CC14, dioxane, acetone, water and acetonitrile. The change was apparently in order of the di-... 

The dependence of this phenomenon on temperature and concentration has been studied in detail (70,71,87) and treated mathematically (87). In principle any compound capable of self-association might be capable of self-induced nonequivalence. These cases should be sufficient to suggest due caution on the part of those who would establish the identity of a racemate (e.g., a synthetic natural product ), by comparison of its NMR spectrum with that of the naturally derived optically pure substance. This phenomenon is not restricted to solutes with aromatic substituents, as evidenced by Table 12. Self-induced nonequivalence may be eliminated by addition of polar solvents or by dilution of the sample. Under these conditions, as has been shown for dihydroquinine (14), spectra of racemic, optically pure, and enriched material become identical. 

Polymerization in aliphatic hydrocarbons is considerably slower than in aromatic hydrocarbons because of decreased dissociation of initiator and propagating ion-pair aggregates. The course of reaction in aliphatic hydrocarbons is complex compared to that in aromatic solvents. Initiation is very slow at the start of reaction hut proceeds with autoacceleration as cross- or mixed association of initiator and propagating ion pairs replaces self-association of initiator. Cross-association is weaker and results in an increased concentration of monomeric initiator. This effect may also explain the higher-order dependence of Rj on initiator (typically between and 1-order) in aliphatic solvents, especially for r- and f-butyllithium. Rp is still -order in initiator independent of solvent. 

Fluorescence quantum yield and emission maximum determinations as a function of peptide concentration may also permit the detection of peptide self-aggregation at concentrations below 10-4 M, because the peptide fluorophore is likely to be located in a different environment in the peptide aggregate. For example, the concentration-dependent changes in the tryptophan fluorescence emission maximum of mellitin were monitored to determine the equilibrium dissociation constant and thermodynamic parameters of the monomer-tetramer self-association reaction of this peptide. 25 Similarly, measurement of the changes in the tryptophan fluorescence intensity of gramicidin A as a function of its concentration permitted the determination of an average monomer-dimer equilibrium con-stant. 26 ... 

From the concentration dependence of the polyphenol chemical shifts as a function of the polyphenol concentration in the absence and presence of peptide, it is clear that polyphenol self-association is only weakly affected by the peptide. Thus, peptide-polyphenol binding probably involves noncovalent polyphenol oligomers that are more effective than the corresponding monomers at developing interactions with a second peptide molecule to trigger precipitation. 

Additional information <5> (<5> due to the capacity for self-association the enzyme can exist in different states of aggregation depending on the nature of the ligands and the concentration of phosphate buffer [5]) [5]... 

The concentration- and temperature-dependence of the hydrogen chemical shifts have been used to estimate the enthalpy for self-association as ca. —6.7 kJ mol-1 <69ZN(B)1365). Although the data are not definitive, the weight of evidence seems to favor the closed NH 7t-bonded dimeric structure (11) for associated pyrrole, at least in dilute solution. 

The reactions of poly(styryl)lithium in benzene with an excess of diphenyl-ethylene 272) and bis[4-(l-phenylethenyl)phenyl]ether158) also were found to proceed by a first order process. However, the reactions of poly(styryl)lithium with the double diphenylethylenes l,4-bis(l-phenylethenyl)benzene and 4,4 bis(l-phenyl-ethenyl)l,l biphenyl gave l58) non-linear first order plots with the gradients decreasing with time. This curvature was attributed to departure from a geometric mean relationship between the three dimerization equilibrium constants (Ka, Kb and Kab). The respective concentrations of the various unassociated, self-associated and cross-associated aggregates involved in the systems described by Equations (49) to (51) are dependent upon the relative concentrations of the two active centers and the respective rate constants which govern the association-dissociation events. 

When Tm is concentration dependent, an additional method" can be used to determine the thermodynamic quantities associated with melting. For example, consider the dissociation of a duplex that is formed from a self-complementary bimolecular process. The reverse reactions to those given in reactions (16.23) or (16.24) are specific examples of such processes. As Table 16.2 shows, the equilibrium constant for such a dissociation process is given by... 

Meijer et al. reported the self-aggregation behavior of a molecule in chloroform (Fig. 11.8) containing two units of 2-ureido-4-pyrimidone linked through a spacer (which self-associates in the DDAA-AADD pattern strongly with a dimerization constant >106 m ) [36], This compound formed viscous solutions in chloroform, and the viscosity observed was dependent on the concentration and temperature. 

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