Nonaqueous solvents, hydration

Nonaqueous electrolyte solutions are analogous to aqueous solutions they, too, are systems with a liquid solvent and a solute or solutes dissociating and forming solvated ions. The special features of water as a solvent are its high polarity, e = 78.5, which promotes dissocation of dissolved electrolytes and hydration of the ions, and its protolytic reactivity. When considering these features, we can group the nonaqueous solvents as follows ... 

To summarize, the hydration status of the drug molecule and other components of a pharmaceutical formulation can affect mass transport. Solubility of drug crystals in an aqueous or nonaqueous solvent may depend on the presence or absence of moisture associated with the drug. Hydration may also determine the hydrodynamic radii of molecules. This may affect the frictional resistance and therefore the diffusion coefficient of the drug molecules. Diffusion of drugs in polymeric systems may also be influenced by the percent hydration of the polymers. This is especially tme for hydrogel polymers. Finally, hydration of... 

A fair number of mixed solvates, compounds containing molecules of crystallization of two different solvents, are also known. Generally, these are obtained either by recrystallizing halide hydrates from a nonaqueous solvent, or by crystallizing a halide from an appropriate solvent mixture, such as an alcohol intentionally or unintentionally containing significant amounts of water. Examples include... 

Strictly, the solubilities of salt hydrates in nonaqueous solvents, and of lanthanide trichlorides in 97% ethanol, mentioned in Section V,B,2,a,... 

The conventional preparative routes to anionic, neutral, or cationic complexes of indium start with the metal, which is dissolved in a suitable mineral acid to give a solution from which hydrated salts can be obtained by evaporation. These hydrates react with a variety of neutral or anionic ligands in nonaqueous solvents, and a wide range of indium(III) complexes have been prepared in this manner.1 Alternatively, the direct high-temperature oxidation of the metal by halogens yields the anhydrous trihalides, which are again convenient starting materials in synthetic work. In the former case, the initial oxidation of the metal is followed by isolation, solution reaction, precipitation, and recrystallization. 

The reduction of metal ions in higher oxidation states by CO and H20 has been known for many years. Work on the reduction of Hg2+, Ag+, Ni2+, Cu2 +, and Pd2+ has been summarized recently (4). The reduction of these metal ions does not proceed via a stable intermediate carbonyl. Since a metal carbonyl must be an intermediate in this reaction, however, the coordinated carbonyl must be very susceptible to attack by water, reacting as soon as it is formed. The ability of a metal in a higher oxidation state to activate a coordinated carbonyl to attack by as weak a nucleophile as water was noted previously in the description of the work by James et al., on the reduction of rhodium(III) by carbon monoxide and water (62). Here a stable rhodium(III) carbonyl, Rh(CO)Cl2-, can be observed as the initial product of reaction of RhCl3 3HzO with CO. The Rh(III) is then efficiently reduced to the rhodium(I) anion [RhCl2(CO)2], even in nonaqueous solvents such as dimethylacetamide, where the only water available for reaction is the water of hydration of the starting rhodium chloride. 

Grant and Higuchi (1990) commented on the solution behavior of solvates in their book on the solubility of organic compounds. The hydrated form will be more stable (less soluble) than the anhydrate in the general case. When the solvate is formed from a nonaqueous solvent that is miscibli in water, the free energy of solution of the solvent into the water reduces the activity of water and increases the apparent solubility of the solvate. An example is cited in which caffeine hydrate is less soluble in water than the anhydrate, but the solubility order reverses in ethanol. 

Lamivudine is an example of the effect of hydrates in nonaqueous solvents (Jozwiakowski et al., 1996). In distilled water at 25D, the anhydrate free base (form II) is 1.2 times as soluble as the 0.2 hydrate (form I). In ethanol at 26, the hydrate is 1.6 times as soluble as the anhydrate. The maximum solubility in ethanol-water mixtures was found to be at 40-60% water in ethanol, when form I is the most stable solid phase. The transition composition was with 18-20% water in ethanol in binary mixtures with more than 20% water, only the hydrate was found at equilibrium, and with less than 18% water, only the anhydrate was found at equilibrium. 

Another important area of dynamic studies in biological samples is the effect of hydration upon molecular mobility in proteins and carbohydrates. The reason for these studies is primarily that protein dynamics, in particular, are crucial to their function, and so examining factors, such as the degree of hydration, that affect their dynamics is very important. However, it is obviously near-impossible to study dynamics in aqueous solution as a function of degree of hydration, and, since most proteins are not soluble in nonaqueous solvents, solid-state studies must be used. The motions at three methionine (Met) residues in Streptomyces subtilisin inhibitor (SSI) were studied with 2H NMR using a sample in which the Met residues at two crucial enzyme recognition sites (PI and P4) were specifically deuterated, along with one in the hydrophobic core.114 The motions of the Met side-chains were then examined... 

The relationship between the hydration shell and folding is of some importance for the use of enzymes as catalysts for syntheses, especially in industrial reactors (Wong, 1989). Nonaqueous media are preferred or are necessary for some reactions. Enzymes appear to be active when partially hydrated, at low water activity. In some cases there is activity in nearly dry nonaqueous solvents (Klibanov, 1986 Zaks and Klibanov, 1984). Thus, one should expect that, generally, it will be possible to find nonaqueous conditions for a particular enzyme-catalyzed process. Knowledge of the hydration shell is important, of course, for other aspects of the design of enzyme catalysts or drugs. 

In acid-catalyzed reactions, the distinction between single-species and complex catalysis is not always clear-cut. The actual catalyst is the solvated proton, H30+ in aqueous solution, and H20 (or a molecule of the nonaqueous solvent) may thus appear as a co-product in the first step and as a co-reactant in the step reconstituting the original solvated proton, possibly also in other additional steps, e.g., if the overall reaction is hydrolysis or hydration. Moreover, the acid added as catalyst may not be completely dissociated, and its dissociation equilibrium then affects the concentration of the solvated proton. At high concentrations this is true even for fairly strong acids such as sulfuric, particularly in solvents less polar than water. Such cases are better described as acid-base catalysis (see Section 8.2.1). 

The ammines of cobalt(II) are much less stable than those of cobalt(III) thermal decomposition of [Co(NH3)6]Cl2 is characterized by reversible loss of ammonia, whereas that of [Co(NH3)6]Cl3 is not. In his classic dichotomy of complexes, Biltz regarded [Co (NH 3)3] Cl 2 as the prototype of the normal complex and [Co(NH3)6]Cl3 as that of the Werner or penetration complex. Hexaamminecobalt-(II) chloride has been prepared by the action of gaseous ammonia on anhydrous cobalt (II) chloride or by displacing water from cobalt(II) chloride 6-hydrate with gaseous ammonia. It may also be synthesized in nonaqueous solvents by passing dry ammonia through solutions of cobalt(II) chloride in ethanol, acetone, or methyl acetate. Syntheses in the presence of water include heating cobalt(II) chloride 6-hydrate in a sealed tube with aqueous ammonia and alcohol and the treatment of aqueous cobalt(II) chloride with aqueous ammonia followed by precipitation of the product with ethanol. The latter method is used in this synthesis. Inasmuch as the compound is readily oxidized by air, especially when wet, the synthesis should be performed in an inert atmosphere. 

This combination of Equations [5] and [16] is called the Generalized Born/Surface Area model (GB/SA), and it is currently available in the Macro-ModeP computer package. The speed of the molecular mechanics calculations is not significantly decreased by comparison to the gas phase situation, making this model well suited to large systems. Moreover, the model takes account of some first-hydration-shell effects through the positive surface tension as well as the volume polarization effects. A selection of data for aqueous solution is provided later (Table 2), and the model is compared to experiment and to other models. Nonaqueous solvents have been simulated by changing the dielectric constant in the appropriate equations, 8 but to take the surface tension to be independent of solvent does not seem well justified. 

Amines, hydrazines, and hydroxylamines. Amine complexes are known for tetravalent complexes of the earliest actinides (Th, U), particularly for the halides, nitrates, and oxalates. The complexes are generated either in neat amine, or by addition of amine to the parent compound in a nonaqueous solvent. Some of the known simple amine compounds are presented in Table 6. The molecular structure of ThCl4(NMe3)3 has been determined. The coordination environment about the metal is a chloride capped octahedron. A very limited number of adducts exist in which a tetravalent actinide is coordinated by a hydrazine or hydroxylamine ligand the parent compound is generally a halide or sulfate complex. Cationic metal hydrates coordinated with primary, secondary, or tertiary amines have also been isolated with acetylacetonate, nitrate, or oxalate as counterions. 

Ureas. Urea adducts (and those of the closely related A-alkylated derivatives) may be prepared from nonaqueous solvents alternatively, preparation in aqueous alcoholic solution leads to the formation of hydrates. In contrast to the carbamides discussed above, there is relatively little variability in the coordination number of reported urea adducts of tetravalent actinides. Most complexes are either six- or seven-coordinate higher coordination numbers are observed for the larger thorium ion (Table 15). 

One can assume that as the hydrate has already interacted intimately with water (the solvent), then the energy released for crystal break-up, on interaction of the hydrate with solvent, is less than for the anhydrous material. The nonaqueous solvates, on the other hand, tend to be more soluble in water than the nonsolvates. The n-amyl alcohol solvate of fludrocortisone acetate is at least five times as soluble as the parent compound, while the ethyl acetate solvate is twice as soluble. 

Englezos and Bishnoi developed a model to predict the formation conditions of gas hydrates for sparingly soluble gases in solutions of aqueous electrolytes. More recently, Clarke and Bishnoi proposed an equation of state for high-pressure aqueous systems, which may contain soluble gases, single or mixed electrolytes, and/or a second nonaqueous solvent. The equation of state was successfully used in conjunction... 

Typical oxidations of iron carbonyls are shown by reactions with halogens. In aqueous solution with CI2 or Br2, decomposition to Fe(III) is obtained due to the large hydration energy of the cation. However, under controlled conditions and in nonaqueous solvents, the dihalogenotetracarbonyl complexes of Fe(II) form ... 

Absolute values of free energies of hydration were made accessible by the work of Randles (7) who determined the absolute free energy of hydration of the K+ ion from measurements of Volta potentials. Since the absolute entropy of H+ is fairly well established (2), absolute values of enthalpy, free energy and entropy can be calculated for the hydration of ions. No comparable measmrements have been carried out in non-aqueous solvents. Application of extrapolation procedures to nonaqueous solvents is frequently restricted by the low solubility of salts in these solvents and lack of experimented data. 

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