Thermodynamic and Structural Studies of NickelII Complexes of Amino Acids with Side Chain Donors

A large number of amino acids involve side chain donors which have the potential to form an additional bond to a metal ion, thus giving tridentate coordination. An obvious indication of tridentate coordination is a measurable increase in the stability constants relative to those of the truly bidentate amino acids. To quantify the extent of the side chain-metal ion interaction, a method was suggested by Martin [3] and also used in another review [16]. Based on this evaluation, no measurable intramolecular interaction is observed for nickel(II) and the gua-nidino side chain of Arg, or the e-amino group of Lys (which would be able to form only an eight-membered chelate), or the phenolic group of Tyr (where the coordination of the side chain donor is sterically not favored), or the y-amide O or N donor atoms of Gln.

The weak basicity of the indole group does not provide a real possibility for its coordination, hence, Trp is expected to coordinate in a 'normal' bidentate way via the a-amino-N and carboxylate-O atoms, but the result calculated in chapter III of [16] indicates some interaction. Deprotonation of the very weakly acidic alcoholic group of Ser or Thr (p^a > 14) is not induced by nickel(II), but a weak interaction of the non-deprotonated alcoholic group is suggested both in the solid state and in solution. As mentioned above, the y-amide of Gln does not play any measurable role in the interaction with nickel(II), but a weak interaction via the somewhat stronger y-carboxylate donor of Glu and a well measurable interaction via the much stronger y-amino-N donor of Orn occurs [29].

A six-membered chelate can be formed by coordination of the side chain amide function of Asn. However, because of the poor donor properties of a non-deprotonated amide group the stability increase of [NiL]+ and [NiL2] complexes is only ~0.4-0.5 log units per chelate. This weak coordination is the reason why a third coordinating Asn is able to displace the amide groups and the species [NiL3]", with a glycine-type coordination of the three ligands, is formed [30].

The rest of the amino acids contains strong side chain donors in suitable positions to form five- or six-membered chelates joined to the glycinate-type five-membered one. Together with the amino-N, a six-membered chelate can be formed by the coordination of the P-carboxylate of Asp, or p-amino group of Daba, or imidazole-N(3) of His, while five-membered chelates form by coordination of the a-amino group of Dapa or the thiol group of Cys. Alternatively, the side chain donor may coordinate together with the a-carboxylate.

Completely protonated forms of these ligands are able to release three dissociable protons in the measurable pH-range. The P-carboxylic acid group of Asp is quite acidic, but all the other side chain functions start to deprotonate only above pH 5 (His) or even higher (Table 1). As a consequence, the formation of proto-nated complexes is hardly important in the Ni(II)-Asp system, but with the other ligands, Daba, Dapa, His, and Cys it is important. Obviously, the monoprotonated ligands coordinate in a bidentate manner.

In the coordination of the nonprotonated form of these ligands the side chain donor plays a crucial role and a tridentate coordination via two joined chelates is expected. Although there is a strong tendency for tridentate coordination with all of these ligands, differences between their nickel(II)-binding ability can also be found. For example, tridentate chelation allows the coordination of two ligands at most to a nickel(II) ion in an octahedral complex. However, this is the case only with Asp and His; with Daba, Dapa, and Cys, the situation is more complicated. Although the formation of bis-complexes with tridentate coordination of two Daba or Dapa is favored, some 1:3 complex also appears at high ligand excess [29]. Moreover, with Dapa [29] and Cys [21], under certain conditions, even a change in the geometry from octahedral to planar occurs. Cysteine does not coordinate nickel(II) in a tridentate way at all, but (S,N)-chelation occurs and a diamagnetic planar 1:2 complex results. Sulfur-bridged [Ni3L4] species are also suggested in this system [16,21].

To compare the stability of the different types of chelates with each other, pH-dependent conditional constants were calculated for mono-chelated nickel(II) complexes of some selected models, such as a-Ala and P-Ala (models for five- and six-membered (N,O)-type amino-carboxylate chelates), 1,2-diaminoethane (en) and 1,3-diaminopropane (pn) (models for five- and six-membered (Namino, Namino)-chelates, respectively), and histamine (Hm) (a model for a six-membered


The conditional stability constant can be defined as:

where pNiL are the corresponding overall stability constants taken from [21, 31, 32], [L] is the totally deprotonated form of a-Ala, P-Ala, en, pn, and Hm; n is the number of protons competing with the formation of the chelate (this value is 2 in all of these models), and PHiL is the corresponding protonation constant taken from Table 1 and [33]. The calculated logarithmic K' values for the different chelates with Ni(II) as a function of pH are shown in Figure 1.

It can be seen in Figure 1 that although the five-membered glycine-type chelate (line 1) is somewhat preferred to the others (it has the highest log K' value) in the acidic region, there is no measurable formation of nickel(II) complexes in this pH

Figure 1. Conditional stability constants (log K') calculated for monochelated (1:1) Ni(II) complexes of a-Ala (5-N,O chelate, line 1), en (5-N,N chelate, line 2), Hm (6-Namino, Nim chelate, line 3), pn (6-N,N chelate, line 4), and P-Ala (6-N,O chelate, line 5) in dependence on pH.

Figure 1. Conditional stability constants (log K') calculated for monochelated (1:1) Ni(II) complexes of a-Ala (5-N,O chelate, line 1), en (5-N,N chelate, line 2), Hm (6-Namino, Nim chelate, line 3), pn (6-N,N chelate, line 4), and P-Ala (6-N,O chelate, line 5) in dependence on pH.

range (see the low numerical values of log K'). As expected, the six-membered amino-carboxylate chelate (line 5) is always less stable compared with the five-membered one. There is, however, a change in the order of log K' values for the Hm-, en-, and pn-containing 1:1 complexes at about pH 5, 5.5 and 9 (lines 3, 2, and 4), respectively. As a consequence, above pH ~5 His behaves more like a Hm derivative than an a-amino acid derivative. Above pH ~ 5.5 the en-type character of Dapa becomes more and more dominant, but the stability of the six-membered pn-type chelate is comparable to that of the five-membered amino-carboxylate one only above pH ~8 with Daba. A stable tridentate coordination mode of Dapa and especially Daba in their [NiL]+ complexes was indicated by the reduction potentials observed at dropping mercury electrode. From the redox potential of [Ni(His)]+, a n-acceptor behavior of the imidazole ring was also suggested [34].

The question of stereoselectivity in nickel(II) complexes of tridentate amino acids has been discussed in previous reviews [3,16,21]. While no stereoselectivity was found with potentially tridentate amino acids, such as Asn, Asp, Gln, Glu, a marked stereoselectivity was observed with His.

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