Inner-sphere water

Figure 2 The molecular dynamics simulation picture of [Gd(DOTA)(H20)] in aqueous solution shows the inner sphere water, directly bound to the metal (its oxygen is dark) the second sphere water molecules, bound to the carboxylates of the ligand through hydrogen bridges (their oxygens are gray) and outer sphere or bulk water molecules without preferential orientation (in white).

Figure 5 Typical NMRD curves of monomer Gdm complexes with one ([Gd(DOTA)(H20)] and [Gd(DTPA)(H20)]2 ) and with two inner-sphere water molecules ([Gd(HTTAHAXH20)2]2 ).

Fig. 1. Schematic representation of a Gdm complex with one inner sphere water molecule, which is the origin of the inner sphere contribution to proton relaxivity. The complex is surrounded by bulk water, giving rise to the outer sphere relaxation mechanism.

In the case of Mn11 complexes as potential MRI contrast agents, the presence of a water molecule in the first coordination sphere is crucial to obtain reasonable relaxivity. Given the lower spin of Mn11, the outer sphere contribution to the overall relaxivity is lower than for Gdm complexes. Thus, for complexes that lack inner sphere water the relaxivity is less than 50% as compared to complexes with coordinated water (233-235). 

Table 1. Hydrolysis constants3 and exchange rate constants for substitution of inner-sphere water ligandsb...

In the course of our investigations to develop new chiral catalysts and catalytic asymmetric reactions in water, we focused on several elements whose salts are stable and behave as Lewis acids in water. In addition to the findings of the stability and activity of Lewis adds in water related to hydration constants and exchange rate constants for substitution of inner-sphere water ligands of elements (cations) (see above), it was expected that undesired achiral side reactions would be suppressed in aqueous media and that desired enanti-oselective reactions would be accelerated in the presence of water. Moreover, besides metal chelations, other factors such as hydrogen bonds, specific solvation, and hydrophobic interactions are anticipated to increase enantioselectivities in such media. 

S. Kobayashi, S. Nagayama, T. Busujima, Lewis Acid Catalysts Stable in Water. Correlation between Catalytic Activity in Water and Hydrolysis Constants and Exchange Rate Constants for Substitution of Inner-Sphere Water Ligands J. Am. Chern. Soc 1998, 120, 8287-8288. 

Molecular hydration in solution is described not only by the inner-sphere water molecules (first and second coordination spheres, see Section II.A.l) but also by solvent water molecules freely diffusing up to a distance of closest approach to the metal ion, d. The latter molecules are responsible for the so-called outer-sphere relaxation (83,84), which must be added to the paramagnetic enhancement of the solvent relaxation rates due to inner-sphere protons to obtain the total relaxation rate enhancement,... 

As an example of behavior of a typical Gd-complex and Gd-macromolecule we discuss here the NMRD profiles of a derivative of Gd-DTPA with a built-in sulfonamide (SA) and the profile of its adduct with carbonic anhydrase (see Fig. 37) 100). Other systems are described in Chapter 4. The profile of Gd-DTPA-SA contains one dispersion only, centered at about 10 MHz, and can be easily fit as the sum of the relaxation contributions from two inner-sphere water protons and from diffusing water molecules. Both the reorientational time and the field dependent electron relaxation time contribute to the proton correlation time. The fit performed with the SBM theory, without... 

The number of inner sphere water molecules has an obvious effect on the relaxivity. Doubling the value of q will imply a doubling of and then a substantial increase in the relaxation efficacy of the Gd(III) complex, as shown in Pig. 7. Knowing q is then crucial for a proper analysis of the NMRD profile, but this parameter cannot be extracted from a best fit procedure as, at best, only the term q/r can be obtained. Prom a qualitative point of view, for relatively small Gd(III) complexes and in the absence of... 

Fig. 7. NMRD profiles (25°C) of three Gd(III) complexes differing in the number q of inner sphere water molecules [GdDTPA(H20)] (open circles), [Gdtren-H0PY(H20)2] (squares), [GdCalix[4]arene(H20)2] (filled circles).

The search for Gd(III) complexes with an increased number of inner-sphere water molecules (q > 1), though sufficiently stable to be safely used in vivo has led to consider the model compounds shown in Chart 6. The relaxivity values of these complexes are significantly higher with respect to the Gd(III) chelates of similar size and q = 1. By taking as reference the ri values of [GdD0TA(H20)] and [GdDTPA(H20)] (4.7 s-VM ), the... 

The latter point is rather critical. In fact, whereas long xr values can be easily attained through a proper choice of the macromolecular system and the binding modality, it may not be an easy task to keep the relaxometric properties of the paramagnetic moiety unaltered, upon formation of the macromolecular adduct. In fact, this may result in a reduced hydration of the Gd(III) ion as donor groups such as aspartate or glutamate on the surface of a protein can replace coordinated water molecules (103 104). When the hydration state is maintained, the occurrence of a marked reduction of the exchange rate of inner-sphere water is very common (see next Section). 

Water molecules in the so-called coordination sphere of a metal ion complex can exchange with water molecules in the medium, and the rates depend largely on the nature of the metal ion and its electric charge, and to a lesser extent on the other coordinated substituents. The rate constants for substitutions of inner sphere water of various aqua ions were determined largely by Eigen s... 

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