The effect of ligand donor atoms on ternary complex stability

Polyhedron Vol. 4, No. 8, pp. 1451-1456.1985 Printed in Great Britain

THE EFFECT

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0277-5387/85 $3.00+ .OO 1985 Pergamon Press Ltd

OF LIGAND DONOR ATOMS ON TERNARY COMPLEX STABILITY

C. R. KRISHNAMOORTHY,* S. SUNIL and K. RAMALINGAM Department of Chemistry, Indian Institute of Technology, Madras 600036, India (Received 26 October 1984; accepted after revision 6 February 1985)

Abstract-Formation constants of mixed ligand complexes of Cu2+, Zn2+, Ni2+, Co2+, and Mn2+, with cytidine-S-monophosphoric acid (CMP) and various primary ligands such as 1,lo-phenanthroline (phen), gl ycylglycine (glygl y) and salicylic acid (Sal)have been determined in aqueous solution at 35°C and 0.1 M (KNO,) by potentiomeric measurements. The acid dissociation constants of all the above mentioned ligands together with their 1: 1 binary metal complex formation constants were also measured at 35°C. In general all the 1: 1 binary complexes follow the Irving-Williams order of stability. Further the binary metal complexes of primary ligands are more stable than their ternary complexes with CMP. For ternary complexes, A(log K) values seem to change from positive to highly negative as the coordinating atoms of the primary ligands were varied from N,N to N,O- to O-,0-. The higher stability of ternary complexes involving phen is due to its H-bonding interaction with the above metal ions and the relative decrease in the stability of other ternary systems is due to the coulombic repulsion of donor oxygen atoms of primary and secondary ligands. Thus for ternary complexes the stabilities follow a decreasing order of M-phen-CMP > M-glyglyCMP > M-sal-CMP.

Ternary complexes play a predominant role in many biological systems because of their involvement in enzyme-metal-substrate complexes and also due to their participation in the storage and transport of active substrates through membranes. Nucleotides and nucleosides are commonly used as ligands because many enzyme reactions need the presence of nucleotides like ATP, ADP, AMP, CMP, etc. In addition, metal ions seem to affect the structure of nucleic acids’ in uivo and also the structure of nucleic acid-protein complexes. Is2 Besides, specific interaction between nucleotides and amino acids must have been significant during the first steps of biochemical evolution.3 Several reviews2V4*5have appeared on these lines. But most of them are confined to adenine nucleosides and nucleotides.6-’ ’ In the present study CMP is chosen as the secondary ligand because of the relatively fewer studies done on cytosine nucleosides in comparison to adenine nucleosides. Choice of phen, glygly and sal as primary ligands is because of their tendency to form stable metal

* Author to whom correspondence is to be addressed at : Department of Chemistry, Georgia State University, Atlanta, GA 30303, U.S.A.

complexes even in high acid medium and also to assess the influence of factors such as : (1) nature of coordinating atom ; (2) steric factors; and (3) IIbonding effects on the stabilities of these metal complexes. Moreover stabilities of the 1: 1 binary complexes of the above mentioned primary ligands and metal ions are also determined for the sake of completion. Thus the present investigation is the first attempt to study the formation of binary and ternary complexes of transition metal ions such as Cu2+, Znzf, Nizf, Co2+, and MnZf and the above mentioned primary and secondary ligands in aqueous solution. EXPERIMENTAL Reagents. Chromatographically pure samples of cytidine monophosphoric acid (CMP), l,lO-phenanthroline (S. Merck), glycylglycine (BDH) and salicylic acid (BDH) were employed in this study. For each measurement fresh solid ligand was weighed out to avoid possible photochemical decomposition or hydrolysis. The metal nitrates were analar grade samples (BDH), and stock solutions of these metal nitrates were estimated volumetrically by EDTA

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titrations.’ 2 Carbonate free sodium hydroxide was prepared by known procedure and standardized by titration with pure potassium acid phthalate. Procedure. Potentiometric titrations of various ligands (1.5 x 10m3M) in the presence and absence of metal ions (1: 1 ratio) were carried out with standard sodium hydroxide solution to calculate the disssociation constants of various ligands and the stability of their 1: 1 binary metal complexes. The ionic strength of the solution was maintained at 0.1 M (KNO,). A stream of nitrogen was passed throughout the course of the experiment to exclude the adverse effect of atmospheric carbon dioxide and the temperature was maintained at 35+O.l”C. The reactants were equilibrated before commencing the titration and between each further addition of sodium hydroxide. The conditions used for the titration of ternary systems were the same as for binary ones (and for the determination of dissociation constants) but the solution contained both primary and secondary ligands and respective metal ions all in 1 : 1 ratio. An Elico model LI-120 digital pH meter with a combined electrode was used to measure the hydrogen ion concentration. The electrode system was calibrated as previously described.13 Calculations. Acid dissociation constants of the ligands are calculated by a direct algebraic method.‘4*‘5 The stability of 1: 1 binary complexes pertaining to equilibrium M + A + MA was calculated by the method developed by Martell.14 Stepwise formation of the ternary complex was assumed to take place as shown below and the respective formation constants were calculated by the method described earlier.16 KM* MA+B SMAB.

et al.

other species such as M(H-lL)OH, M(H-lL)(OH),, ML,, etc., are negligible in concentration at the pH employed in our calculations. RESULTS

AND DISCUSSION

Acid dissociation constants of both primary and secondary ligands calculated by a direct algebraic method are presented in Table 1. From the potentiometric titration curves shown (for Cu2+ alone) in Figs. 1-3, the stability of binary complexes were calculated assuming the equilibria indicated above and presented in Table 2. In all the cases the metal-ligand interaction was confirmed by checking the possibility of metal hydrolysis using titration procedure described earlier.l’*‘s Stabilities of the ternary complexes were calculated in the region of titration curve, a = 3-4 based on the reaction shown above and the values are given in Table 3. So also A(log K) values calculated from eqn (2) are presented in Table 4. Proton ionization sites of primary ligands are assigned to the two ring nitrogen atoms in phen, COOH and NH: groups in glygly and carboxylate and phenolic oxygens in sal respectively. The corresponding dissociation constants presented in Table 1 are consistent with earlier published results.‘9-2’ In the case of CMP the deprotonation takes place from N3 and phosphatic oxygen respectively and

(1)

The formation constants of 1: 1 binary metal complexes of the secondary ligand (CMP) were calculated by the usual algebraic method corresponding to the following reaction, M +BeMB. The stability of the ternary complex characterized by its A(log K) value can be defined by eqn (2). A(log K) = log Kg;,-log

K&,,

(2)

where M = Cu’+, Zn’+, Ni2+, Co2+ or Mn2+; A = primary ligands such as phen, glygly or sal ; B = secondary ligand, CMP. Charges on the complexes are omitted for simplicity. In the case of phen, sal and CMP the predominant equilibria involved in the binary complexation is M + L + ML, at the pH employed in our calculation. For glygly, the species M(H-1 L) is excluded in our calculation for the sake of simplicity, and all

0

1 2.0

I 1.0

I 3.0

4.

P

Fig. 1. Potentiometric titration curves of 1: 1 binary and 1: 1: 1 ternary complexes involving Cu2+, l,lOphenanthroline and cytidine-5’-monophosphoric acid (CMP). A = CMP; B = 1: 1 Cu2+-CMP; C = l,lOphenanthroline; D = 1: 1 Cu2+-l,lO-phenanthroline; E = 1: 1: 1 Cu’+-l,lO-phenanthroline-CMP;a = molesof base added per mole of ligand ; t = 35°C ; p = 0.1 M (KNW

Effect of ligand donor atoms on ternary complex stability

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Table 1. Acid dissociation constants of various ligands investigated. t = 35”C, p = 0.1 M (KNO,) Ligand

PK~.

PK.

Cytidine-S-monophosphoric l,lO-Phenanthroline Glycylglycine Salicylic acid

acid

4.27 + 0.01 1.95f0.02 3.16kO.02 2.75 +O.Ol

6.30 + 0.02 4.77 f 0.02 7.91 f0.02 12.87 kO.02

Table 2. Stability of 1: 1 binary complexes of transition metal ions with various ligands. t = 35°C p = 0.1 M (KNO,)

Metal ion

cu2+ co2+ Ni’+ Zn2+ Mn2+

M-phen log K

M-glygly log K

7.20+0.10 6.75 f 0.05 7.30+0.10 6.25 + 0.05 3.95 f 0.05

5.70+0.10 3.10*0.10 4.10+0.10 3.50+0.10 2.60 f 0.10

M-sal log K

MCMP log K

9.84 f 0.05 6.83f0.10 6.8OkO.10 7.10+0.10 6.10f0.10

Phen = l,lO-phenanthroline, glygly = glycylglycine, CMP = cytidine-5’-monophosphoric acid.

3.90 f 0.10 3.50+0.10 2.36+0.06 2.25kO.10 2.65 + 0.03

sal = salicylic

acid,

Table 3. Formation constants of the 1: 1: 1 ternary complex of transition metal ions with various primary ligands and CMP. t = 35°C p = 0.1 M (KNG,)

Metal ion

cu2+ co2+ Ni2 + Zn2+ Mn2+

M-phen-CMP log K 4.60+0.10 3.74_+0.10 3.77kO.10 3.76f0.10 3.65kO.10

M-glygly-CMP log K 4.30+0.10 1.59-to.10 2.15+0.10 2.06+0.10 1.44+0.10

Phen = l,lO-phenanthroline, glygly = glycylglycine, acid, CMP = cytidine-S-monophosphoric acid.

M-sal-CMP log K 2.84kO.10 0.84_+0.05 0.84 + 0.05 1.61 f0.05 0.15f0.03 sal = salicylic

Table 4. A(log K)values of the 1: 1: 1 ternary metal complexes of CMP with various primary ligands. t = 35°C p = 0.1 M (KNOB) Metal ion cl?+ co2+ Ni2 + Zn2+ Mn2+

M-phen-CMP to.70 to.24 + 1.41 + 1.51 +1.00

M-glygly-CMP +0.40 - 1.91 -0.21 -0.21 - 1.21

Phen = l,lO-phenanthroline, glygly = glycylglycine, acid, CMP = cytidine-S-monophosphoric acid.

M-sal-CMP - 1.06 - 2.66 - 1.52 -0.64 - 2.50 sal = salicylic

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et al.

tendency of these primary ligands using their donor atoms. For glycylglycine the presence of metal ion induces the deprotonation of the amide group proton. This makes the ionised amide nitrogen more basic than the amide oxygen and thereby metal chelation in glycylglycine occurs via aminonitrogen, deprotonated amide nitrogen and carboxylate oxygen.24 There are conflicting statements in literature about the metal ion binding sites in CMP especially in regard to the base nitrogen. Studies with Ni2+, Mn2+, and Mg2+ using magnetic resonance techniques have shown that there is a very weak interaction with the cytosine ring.25 So also in other I I I nucleotide-metal systems, the evidence for metal 2O 1.0 4.0 2.0 3.0 binding through the pyrimidine ring, apart from the II phosphatic oxygen is indicated.26 The relatively Fig. 2. Potentiometric titration curves of 1: 1 binary and higher stabilities of Cu2+ and Co’+ complexes of 1: 1 : 1 ternary complexes involving Cu2 +, glycylglycine and cytidine-5’-monophosphoric acid (CMP). A = CMP ; CMP may be due to the simultaneous binding of B = 1: 1 Cu’+-CMP. C = glycylglycine ; D = 1: 1 cytosine ring nitrogen and phosphate oxygen to the metal ions. Cu2 +-glycylglycine; E = 1: 1: 1 Cu*+-glycylglycineCMP ; a = moles of base added per mole of ligand ; t In the case of ternary complexes the stabilities = 35°C; /J = 0.1 M (KNO,). decrease in the order M-phen-CMP > M-glyglyCMP > M-Sal-CMP. The A(log K) values given in Table 4 show that in general the change is from the corresponding dissociation constants reported positive to weakly negative to highly negative when agree well with the previous studies.20 Stability of all the primary ligand is varied from phen, glygly to Sal. binary metal complexes follow the Irving-Williams This effect in turn is due to the change in the order and also agree well with earlier studies.1g-23 coordinating atoms from N,N to N,O - and 0 -,O The enhanced stabilities of all the primary ligandrespectively in these ligands. metal complexes are due to the chelate forming Thus M-phen-CMP systems uniformly show positive A(log K) in all the cases and this is expected when the primary ligand is an aromatic amine like phen or bipyridyl and the secondary ligand is a potential oxygen donor. 27 This is due to the backdonation from the metal d orbital into vacant IIorbital of the aromatic amine and when the secondary ligand has oxygen donor that will neutralize the charge on the central atom resulting in the enhancement of the stability of the ternary complexes. This increased stability of the ternary complexes can also be explained in another way, namely, that the aromatic amine and transition metal ions are borderline cases according to Pearson HSAB principle and the drain of electron from metal to aromatic amine ligands increases the effective nuclear charge on the central metal ion thereby I 1 I I I making it harder. This enables the metal ions to have 0 4.0 1.0 2.0 3.0 a selective interaction with harder oxygen ligands.28 [I Except in the case of Cu2+, the ternary systems of Fig. 3. Potentiometric titration curves of 1: 1 binary and M-glygly-CMP have weakly negative A(log K) 1: 1: 1 ternary complexes involving CL?+, salicylic acid values, which is due to the change ofligand donors to and cytidine-5-monophosphoric acid (CMP). A = CMP; N,O- in glygly. Similar observations were noticed B=l:lCu’+-CMP;C=sahcylicacid;D=l:lC~~+for other ternary systems of glygly.2g The positive salicylic acid ; E = 1: 1: 1 Cu2+-sahcylic acid_CMP; a A(log K) value for Cu-glygly-CMP may be due to = moles of base added per mole of ligand; t = 35°C; /I = 0.1 M (KNO,). the fact that Cu2+ can also bind to N, of cystosine I

1

Effect of ligand donor atoms on ternary complex stability ring and thus form stable square planar ternary chelate with glygly. This might also account for the weakly negative values for Ni2 + and Zn2 + which can form similar stable square planar and tetrahedral complexes respectively. The literature information available is scanty regarding the ternary metal complexes involving phenolic acids as primary ligands and biologically significant ligands such as nucleotides as secondary ligands. Hence, it is of interest to examine the effect of these primary ligands on the interaction of nucleotides with metal ions, as some of these phenolic compounds are known to occur in biological systems. In the present study it is noticed that there is very little interaction for CMP with metal ions already bound to salicylic acid as compared to its interaction with free (hydrated) metal ions. In fact the ternary systems of M-Sal-CMP show large negative A(log K) values in all the cases. This is because of the very high stability of the binary metal-Sal complexes due to chelation and conjugation effects which detract from its tendency to interact further. Another reason could be due to the increased coulombic repulsion between the donor oxygen atoms of sal and CMP resulting in the destabilization of their ternary complexes. The situation in which sal acts as primary ligand the electronic repulsion is maximum from its two donor oxygen atoms with that of the oxygen atoms of CMP. Thereby the stability of their ternary complex will be much less with A(log K) being most negative. However, glygly has only one such donor oxygen carrying a lone pair of electrons and their ternary complexes will be more stable [A (log K) small and negative]. Whereas phen has no such coulombit repulsion and the greater stability of its ternary systems are shown by its large positive value for A(log K). These marked differences in the stability of the ternary metal complexes could be directly related to the nature of primary ligands with varying donor atoms such as N,N, N,O- and O-,0- in phen, glygly and sal respectively. This discriminating behavior of M-CMP complexes towards other ligands will have a significant role in many biological systems.

repulsion of highly charged oxygen ions coming together to coordinate with the central metal ion thus leading to repulsion. Hence apart from IIbackbonding and chelation the nature of coordinating atoms of the primary ligands also influence the stabilities of the ternary systems. Since the stability of ternary complex is one of the major factors deciding its concentration in biological systems, the above discrimination of metal-CMP and similar systems towards primary ligands with varying donor atoms such as N,N, N,O- and O-,0- will be helpful to have selectivity of carrier bases in biological systems. Besides this will help in designing suitable model systems for various reactions involving metalloenzymes. Further study on similar systems is in progress in our laboratory.

Acknowledgements-The award of research fellowship to one of the authors (K.R.) by C.S.I.R. New Delhi, is gratefully recognized. We wish to thank Yueh-Hwa Wang ofGeorgia State University for drawing the figures and for carefully reading the manuscript.

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CONCLUSION

Thus as the donor atoms in the primary ligands are changed from N,N to N,O- to O-,0- the stability of their corresponding ternary complexes show a drastic decrease. The added stability in the case of ternary complexes involving aromatic N,N donor ligands is due to I-I-interaction with the central metal ion. The least stability seen in the ternary systems with O-,0- donor ligands is due to the coulombic

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