Potentiometric and Thermodynamic Studies of Binaryand Ternary Transition Metal(II) Complexesof Imidazole-4-acetic Acid and Some Bio-relevantLigands

M. Aljahdali • Ahmed A. El-Sherif • Mohamed M. Shoukry •

Seham E. Mohamed

Received: 30 August 2012 / Accepted: 17 October 2012 / Published online: 28 May 2013� Springer Science+Business Media New York 2013

Abstract Proton–ligand association constants of imidazole-4-acetic acid (IMA) were

determined potentiometrically in aqueous solution at different temperatures in the range

15–35 �C. The stepwise stability constants of IMA with some selected bivalent transition

metal ions were also determined in 0.1 mol�dm-3 NaNO3. The stability of the complexes

follows the trend Cu2? [ Ni2? [ Co2? [ Mn2?, which is in agreement with the Irving–

Williams order of the metal ions. The thermodynamic parameters for Cu(II)–IMA complex

formation were derived and discussed. The ternary complexes Cu(IMA)L (IMA = imid-

azole-4-acetic acid, HL = amino acid, amides or DNA constituents) have been investi-

gated. Ternary complexes of amino acids or amides are formed by a simultaneous

mechanism. Amino acids form the complex Cu(IMA)L, whereas amides form two complex

species Cu(IMA)L and Cu(IMA)(LH-1). The DNA constituents form both 1:1 and 1:2

complexes. The stabilities of ternary complexes are quantitatively compared with their

corresponding binary complexes. The concentration distribution of the complexes in

solution was evaluated as a function of pH.

Keywords Imidazole-4-acetic acid (IMA) � Amino acids � Amides � DNA constituents �Potentiometry � Thermodynamics

M. AljahdaliDepartment of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589,Kingdom of Saudi Arabia

A. A. El-Sherif (&) � M. M. Shoukry � S. E. MohamedDepartment of Chemistry, Faculty of Science, Cairo University, Cairo, Egypte-mail: aelsherif72@yahoo.com

A. A. El-SherifDepartment of Chemistry, Faculty of Arts and Science, Northern Borders University, Rafha,Kingdom of Saudi Arabia

M. M. ShoukryDepartment of Chemistry, Faculty of Science, Islamic University, Madinah, Kingdom of Saudi Arabia

123

J Solution Chem (2013) 42:1028–1050DOI 10.1007/s10953-013-0015-9

AbbreviationsIMA Imidazole-4-acetic acid hydrochloride

GLuA Glutamine

Ino Inosine

Gly Glycine

Pyr Pyrocatecholate

1 Introduction

Binary and ternary chelations occur commonly in biological fluids, as millions of potential

ligands like amino acids, peptides or their derivatives or analogues, and heterocyclic

N-bases are likely to compete for biologically important transition metal ions such as

Cu(II), Ni(II) and Zn(II) found in vivo. These chelations, especially complexes that contain

the imidazole ring, have received much attention owing to the fact that the imidazole ring

serves as a metal binding site in a variety of biologically important molecules including

non-heme systems and several metalloproteins (one or more imidazole units are bound to

metal ions in almost all copper- and zinc metalloproteins or, e.g., in nickel-containing

urease) and thus has profound effects on their biological actions [1, 2].

It is well known that a number of imidazole derivatives have biological activity, e.g.

presenting pharmaceutical, biocidal or fungicidal properties [3]. The biological importance

of the imidazole moiety is connected with the co-ordination abilities of this system. The

metal complexes with several imidazole-containing ligands have also been widely studied

as structural model compounds of metal active sites [4]. Some of these ligands have been

found in living organisms as in the case of imidazole-4-acetic (IMA), which is a metabolite

of histamine [5] and histidine [6]. Low levels of IMA has also been found in human

cerebro-spinal fluid [7]. From the bioinorganic point of view, IMA may also interact with

several metal ions present in living cells.

Ternary complexes formed between metal ions and two different types of bioligands,

namely heteroaromatic nitrogen bases and amino acids (or peptides), may be considered as

models for substrate–metal ion–enzyme interactions and other metal ion mediated bio-

chemical interactions [8]. Among these compounds, copper(II) complexes of heterocyclic

amines are of great interest since they exhibit numerous biological activities such as

antitumor [9], anti-candida [10], antimycobacterial [11], and antimicrobial [12] activity,

etc. In a number of biochemical processes, Cu(II) is involved in mixed-ligand complex

formation and ligand catalyzed complex formation reactions [13]. Kinetic analysis showed

that the ternary complexes involving amino acids play an important role in the exchange

and transfer of copper(II) between amino acid and albumin [14].

In view of this it seems to be of considerable interest to conduct investigations covering

binary and ternary complexes of copper(II) involving the IMA ligand and amino acids,

amides or DNA units. IMA contains basic nitrogen (imidazole) and possesses p-accepting

properties, which are expected to display a stability-enhancement due to the hydrophobic

interaction with the substituted group of the amino acids or involved in aromatic ring p–pstacking effects with purine and pyrimidine bases. In this respect, it is very interesting to

refer to the work of Farrell et al. [15] who discovered a remarkable increase in the

cytotoxicity of trans-[Pt(py)2Cl2] complexes as compared to the inactive trans-

[Pt(NH3)2Cl2], formed by introducing aromatic nitrogen ligands. In continuation of the

J Solution Chem (2013) 42:1028–1050 1029

123

published work in the field of amino acids [16–18], amides [19–21] and DNA units [22–

24], we report in this paper a quantitative study of the formation equilibria of binary and

ternary complexes of copper(II) with IMA and some bio-active ligands.

2 Experimental

2.1 Materials and Reagents

Imidazole-4-acetic acid hydrochloride (IMA) was obtained from the Aldrich Chemical

Company. The amino acids: glycine, alanine, valine, proline, isoleucine, b-phenylalanine,

threonine, lysine, methionine, aspartic acid, histamine, and histidine, together with

methylamine hydrochloride and imidazole, were provided by the Sigma Chemical Com-

pany. The amides used were glycinamide, glycyl–glycine and glutamine, also provided by

Sigma Chemical Company. The DNA constituents as uracil, uridine, thymine, thymidine,

and inosine were supplied by BDH-Biochemicals Ltd. Cu(NO3)2 was provided by BDH.

The copper content of solutions was determined by complexometric EDTA titrations [25].

Carbonate-free NaOH (titrant) was prepared and standardized against potassium hydrogen

phthalate solution. All materials and reagents were used as provided by the chemical

companies without further purification. The purity of these reagents ranged from 98 to

99 %. All solutions were prepared in deionized H2O.

2.2 Instruments

Potentiometric measurements were made using a Metrohm 686 titroprocessor equipped

with a 665 Dosimat (Switzerland, Herisau). A thermostatted glass-cell equipped with a

magnetic stirring system was used, containing a Metrohm glass electrode, a thermometric

probe, a microburet delivery tube and a salt bridge connected with the reference cell filled

with 0.1 mol�dm-3 KCl solution in which a saturated calomel electrode was dipped. The

titroprocessor and electrode were calibrated with standard buffer solutions, potassium

hydrogen phthalate (pH = 4.008) and a mixture of KH2PO4 and Na2HPO4 (pH = 6.865)

at 25.0 �C.

2.3 Procedure and Measurements

The following mixtures were prepared and titrated potentiometrically with 0.05 mol�dm-3

NaOH solution.

(A) 40 mL of solution containing 1.25 9 10-3 mol�dm-3 ligand (IMA, amino acid, or

peptide, DNA constituents) of constant ionic strength 0.1 mol�dm-3 (adjusted with

NaNO3);

(B) 40 mL of solution containing 1.25 9 10-3 mol�dm-3 M(II) ion and 0.1 mol�dm-3

NaNO3;

(C) 40 mL of solution containing 1.25 9 10-3 mol�dm-3 M(II) ion, 2.5 9 10-3

mol�dm-3 ligand (IMA, amino acid, or peptide, DNA constituents) and

0.1 mol�dm-3, NaNO3;

(D) 40 mL of solution containing 1.25 9 10-3 mol�dm-3 Cu(II) ion, 1.25 9 10-3

mol�dm-3 IMA, 1.25 9 10-3 mol�dm-3 ligand (amino acid or peptide) and

0.1 mol�dm-3, NaNO3.

1030 J Solution Chem (2013) 42:1028–1050

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(E) 40 mL of solution containing 1.25 9 10-3 mol�dm-3 Cu(II) ion, 1.25 9 10-3

mol�dm-3 IMA, 2.5 9 10-3 mol�dm-3 ligand (DNA constituents) and

0.1 mol�dm-3, NaNO3.

The proton association constants of the ligands were determined potentiometrically by

titrating mixture (A). The hydrolysis constants of MII (M = Cu(II), Ni(II), Co(II) and

Mn(II)) were determined by titrating mixture (B). The formation constants of M(II)–IMA

and of Cu(II)–L (L = amino acid, peptide and DNA constituents) were determined by

titrating mixture (C). The stability constants of the mixed-ligand complexes of amino acids

and peptides were determined using the potentiometric data obtained for the mixture (D).

The stability constants of the ternary complexes of DNA constituents were determined

using potentiometric data obtained from mixture (E). All titrations were performed in a

purified N2 atmosphere, using aqueous 0.05 mol�dm-3 NaOH as titrant.

The general four component equilibria can be written as follows (charges are omitted

for simplicity):

lðCuÞ þ pðIMAÞ þ qðLÞ þ rðHÞ� ðCuÞlðIMAÞpðLÞqðHÞr ð1Þ

blpqr ¼½CulðIMAÞpðLÞqðHÞr�½Cu�l½IMA�p½L�q½H�r

ð2Þ

2.4 Data Processing

Calculations were performed using the computer program MINIQUAD-75 [26]. The

stoichiometry and stability constants of the complexes formed were determined by trying

various possible composition models. The model selected gave the best statistical fit and

was chemically consistent with the titration data without giving any systematic drifts in the

magnitudes of various residuals, as described elsewhere [26]. The fitted model was tested

by comparing the experimental titration data points and the theoretical curve calculated

from the values of the acid dissociation constant of the ligand and the formation constants

of the corresponding complexes. The results are summarized in Tables 1, 2 and 3. The

species distribution diagrams were obtained using the program SPECIES [27] under the

experimental conditions employed. All measurements were carried out in our laboratory in

Cairo University.

3 Results and Discussion

Knowledge of the protonation constants of biorelevant ligands is interesting and necessary

for a complete understanding of the physiochemical behavior of bio-ligands. Therefore,

stoichiometric protonation constants of the ligands were determined under the experi-

mental conditions of (25 ± 0.1) �C and a constant ionic strength of 0.1 mol�dm-3, which

were also used to determine the stability constants of the metal(II) complexes. Copper (II)

complexes with amino acids and peptides were previously investigated under different

experimental conditions, which did not allow a meaningful comparison of the reported

stability constants and definite stoichiometries. In the present study, we redetermined the

complex formation constants of Cu(II) with amino acids and peptides under the same

conditions used to study the ternary complexes. The values obtained are consistent with

data reported in the literature [28].

J Solution Chem (2013) 42:1028–1050 1031

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3.1 Acid–Base Equilibria of IMA

In order to calculate the stability constants of metal complexes, the acid dissociation

constant of the ligand was first determined. Analysis of the potentiometric data of (IMA) in

the diprotonated form yields two pKa values corresponding to the carboxylate and pro-

tonated imidazole groups (Table 1). The highest pKa value is attributed to the imidazole

group (pKa1 = 7.14) and the lowest one to the carboxylate group (pKa2 = 2.83) at 25 �C

as shown in Scheme 1. These results are in agreement with previous investigation carried

out on IMA in aqueous solution at 0.1 mol�dm-3 NaClO4 (pKa1 = 7.33 and pKa2 = 3.18,

at 25 �C) [29]. The pKimd value of IMA (pKimd = 7.14) is considerably greater than that of

the imidazole-4-acetamide (pKimd = 6.41) [30], which suggests the formation of a

Table 1 Association constantsof (IMA) in aqueous solution inthe presence of 0.1 mol�dm-3

NaNO3 at temperatures from 15to 35 �C

a Standard deviations are givenin parenthesesb Sum of squares of residuals

System Temp. (�C) log10 ba Sb

IMA

(1) L� þ Hþ � HL 15 7.38 (0.04) 3.2E-7

(2) L� þ 2Hþ � H2Lþ 10.29 (0.07)

IMA

(1) L� þ Hþ � HL 20 7.25 (0.05) 2.4E-7

(2) L� þ 2Hþ � H2Lþ 10.13(0.06)

IMA

(1) L� þ Hþ � HL 25 7.12 (0.04) 3.5E-7

(2) L� þ 2Hþ � H2Lþ 9.97 (0.07)

IMA

(1) L� þ Hþ � HL 30 6.95 (0.06) 4.8E-7

(2) L� þ 2Hþ � H2Lþ 9.77 (0.08)

IMA

(1) L� þ Hþ � HL 35 6.81 (0.07) 2.3E-7

(2) L� þ 2Hþ � H2Lþ 9.61 (0.09)

Table 2 Overall formation constants and derived results for the metal complexes of IMA (as their loga-rithms), I = 0.1 mol�dm-3 (NaNO3), t = 25 �C, and bpqr = [MlLpHr]/[M]l[L]p[H]r, with standard devia-tions in parentheses

System l p ra Cu(II) Ni(II) Co(II) Mn(II)

M2þ þ L� � MLþ 1 1 0 7.00 (0.03) 6.31 (0.06) 5.26 (0.06) 4.75 (0.05)

M2þ þ 2L� � ML2 1 2 0 11.08 (0.07) 9.78 (0.04) 8.46 (0.04) 7.69 (0.06)

log10 K1 – 7.00 6.31 5.26 4.75

log10 K2 – 4.08 3.47 3.2 2.94

log10 K1 - log10 K2 – 2.92 2.84 2.06 1.81

Sc – 3.5E-7 1.2E-6 2.6E-7 3.6E-6

N.P.d 297 272 283 291

a p, q and r are the stoichiometric coefficient corresponding to metal ion, IMA and H?, respectivelyb Standard deviations are given in parenthesesc Sum of squares of residualsd Number of experimental data points

1032 J Solution Chem (2013) 42:1028–1050

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hydrogen bond in the monoprotonated (LH) species, in this case between the carboxylate

and imidazole N3 nitrogen, increasing the pK of the more basic site.

3.2 Binary Complexes of Imidazole-4-acetic acid (IMA)

The stability constants of binary complexes of Mn2?, Co2?, Ni2? and Cu2? with (IMA)

were studied by applying potentiometric measurements. The resulting stability constants of

their complexes are shown in Table 2. These results are in agreement with a previous

investigation carried out on Ni2? and Cu2? complexation with IMA in aqueous solution

at 0.1 mol�dm-3 NaClO4. The literature log10 b values of Cu–IMA complexes are

(log10 b110 = 6.86 and log10 b120 = 12.43) and for Ni–IMA are (log10 b110 = 4.81 and

log10 b120 = 8.49), at 25 �C) [29]. The potentiometric titration curves for Mn2?, Co2?,

Ni2? and Cu2? with IMA were found to be below and well separated from that of the free

IMA ligand, confirming that complex formation occurs with liberation of protons [16, 20].

Potentiometric titration curves of IMA in the presence and absence of Cu(II) ion as a

representative example are shown in Fig. 1. The titration data as calculated for metal(II)

ions and IMA, taking into consideration all feasible theoretical models, were compared

with those experimentally obtained. The equilibrium patterns were chosen so as to lie

between the observed and the calculated data applying accurate statistical analysis

involving the sum of squares of residuals. At this point, all protonation constants were kept

constant, and the computer program MINIQUAD was applied for a second stage of

refinement. The whole titration data set obtained were fitted with different composition

models and the selected model with best statistical fit was found to consist of 1:1 and 1:2

complexes as shown in Scheme 2. This model was tested by comparing the experimental

titration data points and the theoretical curve calculated from the values of acid

O

NH

N

CH2

OH

O

NH

N

CH2

OO

NH

N

CH2

O

HH

+ H+

-

K1

+ H+

K2

++

-

Scheme 1 Acid–base equilibria of imidazole-4-acetic acid

Table 3 Atomic number, ionic radius, electronegativity and ionization potential of the investigated bivalentmetal ion

Metal ion Mn2? Co2? Ni2 Cu2?

Atomic number 25 27 28 29

Ionic radius (pm) 81 79 71 74

Electronegativity 1.55 1.88 1.91 2.00

Second ionization energy (kJ�mol-1) 1509 1646 1753 1958

Values from Ref. [28]

J Solution Chem (2013) 42:1028–1050 1033

123

dissociation constants of IMA and formation constants of the Cu2? complex. The good fit

is an indication of the validity of the complexation model.

3.3 Visible Electronic Spectra of the Cu–IMA Complex

The spectrum of the hydrated copper(II) ion (mixture A) consists of a broad, weak band

with a maximum wavelength at 817 nm, attributed to the 2T2g / 2Eg transition [31]. The

spectral band of the binary copper(II) complex with IMA is quite different from that of the

hydrated copper(II) ion in the position of the maximum wavelength. The spectrum of the

[Cu(IMA)] complex (mixture B) shows an absorption maximum at 744 nm (Fig. 2). The

shift toward shorter wavelength in the absorption spectrum (blue shift) may be taken as

evidence, supporting the potentiometric measurements, for the interaction of IMA with

copper.

3.4 Relationships Between the Properties of Central Metal Ion and Stability

of Complexes

In an attempt to explain why a given ligand prefers binding to one metal rather than

another, it is necessary to correlate the stability constants with characteristic properties of

the metal ions such as the ionic radius, ionization energy, electronegativity and the atomic

number. We have discussed relationships between the properties of central metal ions

reported in Table 3 [32] and the stability constants of complexes. The formation constants

of MII–complexes of bivalent 3d transition metal ions with IMA are in the order:

Mn2? \ Co2? \ Ni2? \ Cu2? in accordance with the Irving–Williams order [33]. The

correlation between log10 KML and the reciprocal ionic radii (1/r) of the studied bivalent

transition metal ions was found to be almost linear. Also, a good linear correlation has been

obtained between log10 KML and the electronegativities of the metal ions under study.

0

2

4

6

8

10

12

0 1 2 3 4 5 6

Volume of base added

pH

Fig. 1 Potentiometric titrationcurve of the Cu–thIMA system at25 �C

1034 J Solution Chem (2013) 42:1028–1050

123

This is in accordance with the fact that increasing electronegativity of the metal ions

{Mn2? (1.55) \ Co2? (1.88) \ Ni2? (1.91) \ Cu2? (2.0)} will decrease the electronega-

tivity difference between the metal atom and the donor atom of the ligand. Thus, the

metal–ligand bond will have more covalent character, which may lead to greater stability

of the metal chelates. A good linear relationship has been obtained between log10 KML and

the second ionization potential of the bivalent metal ions under study. In general, it is noted

that the stability constant of the Cu2? complex is quite large compared to the other metals.

The ligand field will give Cu2? some extra stabilization due to tetragonal distortion of the

octahedral symmetry [34]. Thus, the log10 K value for the Cu2? complex deviates sig-

nificantly when log10 K values of metal chelates are plotted against properties of the metal

ions (Fig. 3).

O

NH

N

CH2

O

OH2

Cu2+

NH

NCH2

COOH

O

NH

N

CH2

O N

NH

CH2

O

O

OH2

Cu+ Cu

IMA

(110) (120)

Scheme 2 Complex formation equilibria of Cu–IMA complexes

0

0.04

0.08

0.12

0.16

0.2

0.24

0.28

500 550 600 650 700 750 800Wavelength (nm)

Abs

orba

nce

Cu(II)

Cu(IMA)

Fig. 2 Electronic spectra ofCu(II) and the Cu(II)–IMAcomplex

J Solution Chem (2013) 42:1028–1050 1035

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3.5 Effect of Temperature and Thermodynamics

The values obtained for the thermodynamic parameters DH�, DS� and DG�, associated with

the protonation of IMA and its complex formation with Cu(II) species, were calculated

from the temperature dependence of the data in Tables 1 and 4. The values of DH� and DS�were obtained by a linear least-squares fit of ln K versus 1/T (ln K = -DH�/RT 1 DS�/R)

leading to the intercept DS�/R and slope -DH�/R, where K is the equilibrium constant, see

Figs. 4 and 5. The main conclusions from the data can be summarized as follows.

(I) The protonation reaction 1 of the N-site of IMA is exothermic with a net negative

DG� value (Table 5). Three factors affect the protonation reaction 1 in Table 5:

(i) the neutralization reaction, which is an exothermic reaction process;

(ii) desolvation of ions, which is an endothermic process;

0

24 25 26 27 28 29 30

1

2

3

4

5

6

7

8lo

g K

Atomic number

Fig. 3 Variation of the stability constants at 25 �C for the MII–IMA complexes with the atomic number ofthe divalent metal ions

Table 4 Formation constants forbinary complexes of (IMA) withCu(II) ions in aqueous solution inthe presence of 0.1 mol�dm-3

NaNO3 at different temperaturesfrom 15–35 �C

a Standard deviations are givenin parenthesesb Sum of squares of residuals

System Temp. (�C) log10 ba Sb

Cu–IMA 15

(1) Cu2þ þ L� � CuLþ 7.41 (0.02) 4.6E-7

(2) Cu2þ þ 2L� � CuL2 13.29 (0.04)

Cu–IMA 20

(1) Cu2þ þ L� � CuLþ 7.20 (0.04) 1.3E-7

(2) Cu2þ þ 2L� � CuL2 13.01 (0.03)

Cu–IMA 25

(1) Cu2þ þ L� � CuLþ 7.01 (0.01) 3.5E-7

(2) Cu2þ þ 2L� � CuL2 12.74 (0.03)

Cu–IMA 30

(1) Cu2þ þ L� � CuLþ 6.82 (0.02) 5.1E-7

(2) Cu2þ þ 2L� � CuL2 12.51 (0.04)

Cu–IMA 35

(1) Cu2þ þ L� � CuLþ 6.63 (0.03) 3.7E-7

(2) Cu2þ þ 2L� � CuL2 12.25 (0.05)

1036 J Solution Chem (2013) 42:1028–1050

123

(iii) the change of the configuration and arrangements of the hydrogen bonds around

the free and the protonated ligands.

(II) In most cases, the color of the solution after complex formation was observed to be

different from the colour of the ligand solution at the same pH.

0

1

2

3

4

5

6

7

8

0.0032 0.0033 0.0033 0.0034 0.0034 0.0035 0.0035

1/T

log

K

log K2

log K1

Fig. 4 Van’t Hoff plot of the protonation constants of (IMA) against 1/T

4

4.5

5

5.5

6

6.5

7

7.5

8

0.0032 0.0033 0.0033 0.0034 0.0034 0.0035 0.00351/T

log

K

log K1

log K2

Fig. 5 Van’t Hoff plot of the formation constants of Cu2? complexes with (IMA) against 1/T

J Solution Chem (2013) 42:1028–1050 1037

123

(III) The stability constants of the Cu(II) complexes formed at different temperatures

were calculated and the average values are included in Table 4. From these results

the following conclusions can be reached. These values decrease with increasing

temperature, confirming that the complexation process is more favorable at lower

temperatures. It is known that the divalent metal ions exist in solution as octahedral

hydrated species [35], and the obtained values of DH and DS can then be considered

as the sum of two contributions: (a) release of H2O molecules and (b) metal–ligand

bond formation. From these results the following conclusions can be made.

(1) Table 2 shows that the (log10 K1 - log10 K2) values are usually positive, since

the coordination sites of the metal ions are more freely available for binding of

the first molecule than for the second one.

(2) For the same ligand at constant temperature, the stability of the chelates

increase in the order Cu2? [ Ni2? [ Co2? [ Mn2? [33]. This order largely

reflects the changes in the enthalpy of complex formation across the series

from a combination of the influence of both the polarizing ability of the metal

ion [36] and the crystal field stabilization energies [35].

(3) All values of DG� for complexation are negative (Table 5), indicating that the

chelation process proceeds spontaneously.

(4) The negative values of DH� show that the chelation process is exothermic,

indicating that the complexation reactions are favored at low temperatures.

Furthermore, when a coordinate bond is formed between the ligand and the

metal ion, the electron density on the metal ion generally increases.

Consequently, its affinity for a subsequent ligand decreases, leading to

increases in DG� and DH� of complexation.

(5) It is noted that generally �DG�1 [ � DG�2 and� DH�1 [ � DH�2 (Table 5).

This may be attributed to the steric hindrance produced by the entrance of a

second molecule into coordination.

3.6 Species Distribution Curves of Cu–IMA Complexes

Estimation of equilibrium concentrations of metal(II) complexes as a function of pH

provides a useful picture of metal ion binding in solutions. All of the species distributions

were calculated with the aid of the Species computer program [27]. The concentrations of

Table 5 Thermodynamic parameters for the association equilibria of IMA and complex formation of Cu–IMA complexes

Equilibriuma DH� (kJ�mol-1) DS� (J�K-1�mol-1) DG� (kJ�mol-1)

IMA

(1) L� þ Hþ � LH -48.87 -27.95 -40.54

(2) LHþ Hþ � LHþ -9.52 22.59 -16.25

Cu-IMA

(3) Cu2þ þ L� � CuLþ -65.91 -86.98 -39.98

(4) CuLþ þ L� � CuL2 -21.76 36.95 -32.77

a L denotes imidazole-4-acetic acid (IMA)

1038 J Solution Chem (2013) 42:1028–1050

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metal–ligand complexes increase with increasing pH. The species distribution pattern for

the Cu–(IMA) complex, taken as a representative of metal ligand complexes, is given in

Fig. 6. The Cu(IMA) complex starts to form at pH * 1 and reaches its maximum con-

centration of 74 % at pH * 3.4, while Cu(IMA)2 complex species reaches a maximum

concentration of 97 % at pH * 8.5.

3.7 Ternary Complex Formation Equilibria Involving Amino Acids

Ternary complex formation may proceed either through a stepwise or simultaneous

mechanism depending on the chelating ability of IMA and the other ligands. The

formation constants of the 1:1 copper(II) complexes with IMA and amino acids are of

the same order of magnitude, Table 6. Consequently, the coordination of IMA and

amino acid (HL) will proceed simultaneously. The titration data of the ternary com-

plexes with amino acids and IMA are fit satisfactorily with formation of the species

Cu(IMA), Cu(IMA)2, Cu(L), Cu(L)2 and Cu(IMA)(L). Threonine forms, in addition to

the just mentioned complexes, the Cu(IMA)(LH-1) species. The latter complex is

formed through induced ionization of the b-alcoholato group, as mentioned in the

literature [37].

Phenylalanine forms a more stable complex than alanine, although the amino group of

the former molecule is less basic than that of the latter molecule. This may be due to some

stacking interactions between the phenyl group of phenylalanine and the aromatic moiety

of IMA as shown in structure (I). This will contribute to the stabilization of the formed

complex.

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12pH

% S

peci

es

Cu(II)

[Cu(IMA)]+

[Cu(IMA)2]

[Cu(OH)]+

Fig. 6 Concentration distribution of various species as a function of pH in the Cu–IMA system at theconcentration 1.25 9 10-3 mol�dm-3, I = 0.1 mol�dm-3 (NaNO3) and t = 25 ± 0.1 �C

J Solution Chem (2013) 42:1028–1050 1039

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Both imidazole and methylamine are monodentate ligands; the stability constant of the

monodentate methylamine complex is higher than that of the imidazole ligand. The

observed extra stability of the methylamine complex may be due to higher basicity of its

amino group (log10 b = 10.55) compared with that of the imidazole group (log10 b =

7.04).

The stability constants of Cu(IMA)–amino acid systems are larger than those for the

corresponding monodentate methylamine and imidazole complexes. This indicates that the

amino acids are coordinating as bidentate ligands through the amino and carboxylate

groups (Scheme 3).

Histamine and histidine have been shown to form both protonated (1111) and depro-

tonated (1110) complex species. The acid dissociation constants of the protonated species

are given by the following equation [38]:

pKH ¼ log10 b1111 � log10 b1110 ð4ÞThe pKa values for the histamine and histidine complexes are (5.23) and (5.73),

respectively, being lower than those of the protonated amino group (NHþ3 ) in histamine and

histidine ligands (pKa = 9.80 and 9.50, respectively), but closer to those of the protonated

imidazole in histamine and histidine ligands (pKa = 6.12 and 6.05) respectively, consid-

ering the increase in acidity due to complex formation. This reveals that the proton in the

protonated complex should be located mainly on the imidazole group.

Lysine forms the ternary complexes 1110 and 1111. The formation constant of the

species 1110 is in the same order of the ternary complexes of the amino acids, indicating

that lysine is a bidentate ligand and coordinates by both amino and carboxylate groups,

leaving the extra amino group susceptible to protonation. The pKa value of the protonated

species 1111 is 8.09 for Cu(IMA)–lysine.

3.8 Ternary Complex Formation Equilibria Involving Amides

Ternary complex formation of amides also proceeds through a simultaneous mechanism.

The species detected are Cu(IMA), Cu(IMA)2, Cu(L), Cu(LH-1), Cu(IMA)(L) and

Cu(IMA)(LH-1) and their formation constants are given in Table 6. The amide may form

the Cu(IMA)(L) complex by coordination through the amine and carbonyl groups. On

increasing the pH, the coordination sites should switch from the carbonyl oxygen to amide

nitrogen. Such changes in coordination centers are now well documented [39, 40].

The amide groups undergo deprotonation and Cu(IMA)(LH-1) complexes are formed.

The pKH values are calculated by the following Eq. 5

pKH ¼ log10 b1110 � log10 b111�1 ð5ÞThe pKH values of the amide complexes are 6.08, 6.32 and 9.83 for glycinamide,

glycylglycine and glutamine, respectively. It is noteworthy that the pKH for the

N

NH

Cu

O

OO

CH

O

NH2

CH2

(I)

1040 J Solution Chem (2013) 42:1028–1050

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Table 6 Stability constants of the ternary species in the CuII–IMA–amino acid, amide or DNA constituentsystems, and proton-association constants and their binary stability constants

System l p q ra log10 bblog10 bCu

CuL log10 bCuCuL2

Sc

Cu(H2O)2þ6

1 0 0 -1 -6.44 (0.07) – 9.6E-7

IMA 0 1 0 1 7.12 (0.04) 7.43 13.36 3.0E-7

0 1 0 2 9.97 (0.07)

1 1 0 0 7.01 (0.01) 3.5E-7

1 2 0 0 12.74 (0.03)

Glycine 0 0 1 1 9.6 (0.01) 8.19 14.96 1.5E-7

0 0 1 2 11.93 (0.03)

1 1 1 0 15.22 (0.06) 5.2E-7

Alanine 0 0 1 1 9.69 (0.01) 7.99 14.62 2.6E-6

0 0 1 2 11.88 (0.02)

1 1 1 0 15.68 (0.04) 5.3E-7

Proline 0 0 1 1 10.52 (0.01) 8.82 16.15 4.4E-8

0 0 1 2 12.03 (0.02)

1 1 1 0 15.33 (0.05) 1.2E-7

Iso-leucine 0 0 1 1 9.76 (0.01) 8.23 15.27 3.4E-8

0 0 1 2 12.22 (0.01)

1 1 1 0 15.41 (0.04) 2.2E-7

Valine 0 0 1 1 9.57 (0.01) 8.16 14.97 6.9E-8

0 0 1 2 11.70 (0.03)

1 1 1 0 15.60 (0.04) 1.7E-7

Phenylalanine 0 0 1 1 9.12 (0.01) 7.86 14.81 8.0E-8

0 0 1 2 11.01 (0.03)

1 1 1 0 17.14 (0.01) 1.7–7

Threonine 0 0 1 1 9.06 (0.01) 8.32 14.92 7.9E-8

0 0 1 2 11.03 (0.02)

1 1 1 0 14.45 (0.1) 1.1E-6

1 1 1 –1 4.94 (0.09)

Lysine 0 0 1 1 10.52 (0.03) 14.10 19.94 1.9E-8

0 0 1 2 19.65 (0.02)

0 0 1 3 21.91 (0.04)

1 1 1 0 16.99 (0.05) 5.3E-7

1 1 1 1 25.08 (0.35)

Histamine 0 0 1 1 9.80 (0.01) 9.55 16.10 1.8E-7

0 0 1 2 15.91 (0.01)

1 1 1 0 15.35 (0.02) 1.6E-7

1 1 1 1 20.58 (0.04)

Histidine 0 0 1 1 9.150 (0.01) 10.66 18.96 2.4E-8

0 0 1 2 15.55 (0.01)

1 1 1 0 17.92 (0.09) 1.5E-7

1 1 1 1 23.65 (0.1)

Methionine 0 0 1 1 9.10 (0.01) 7.86 14.60 8.9E-8

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glycinamide complex is lower than the pKHs of other amides, which signifies that a more

bulky substituent group on the amides may serve to hinder the structural change in going

from protonated to deprotonated complexes. The pKH of the glutamine complex, on the

other hand, is exceptionally, relatively higher than the others. This is due to the formation

Table 6 continued

System l p q ra log10 bblog10 bCu

CuL log10 bCuCuL2

Sc

0 0 1 2 11.08 (0.03)

1 1 1 0 14.33 (0.09) 8.6E-7

Aspartic acid 0 0 1 1 9.68 (0.01) 8.84 14.96 3.9E-8

0 0 1 2 13.35 (0.01)

1 1 1 0 15.04 (0.05) 2.6E-7

Methylamine 0 0 1 1 10.55 (0.004) 6.82 11.56 8.9E-9

1 1 1 0 12.21 (0.09) 3.6E-6

1 1 2 0 16.47 (0.1)

Imidazole 0 0 1 1 7.04 (0.02) 4.20 7.62 2.3E-7

1 1 1 0 9.71 (0.04) 7.4E-7

1 1 2 0 13.69 (0.06)

Glycinamide 0 0 1 1 7.60 (0.01) 4.70 – 8.5E-8

1 1 1 0 11.75 (0.08) 1.2E-6

1 1 1 –1 4.85 (0.04)

Glycylglycine 0 0 1 1 7.99 (0.006) 5.40 – 8.5E-8

1 1 1 0 12.80 (0.09) 1.6E-6

1 1 1 –1 6.48 (0.05)

Glutamine 0 0 1 1 8.95 (0.008) 7.69 – 4.5E-8

1 1 1 0 13.74 (0.07) 7.6E-7

1 1 1 –1 3.91 (0.08)

Thymine 0 0 1 1 9.53 (0.01) 5.77 – 3.4E-8

1 1 1 0 12.72 (0.05) 4.4E-7

1 1 2 0 16.57 (0.07)

Thymidine 0 0 1 1 9.50 (0.02) 5.87 – 6.2E-8

1 1 1 0 12.60 (0.07) 8.1E-7

1 1 2 0 16.39 (0.09)

Uridine 0 0 1 1 9.01 (0.02) 4.32 – 2.9E-8

1 1 1 0 12.11 (0.06) 3.4E-7

1 1 2 0 16.42 (0.04)

Uracil 0 0 1 1 9.28 (0.006) 5.49 – 3.4E-8

1 1 1 0 12.31 (0.04)

1 1 2 0 16.52 (0.07)

Inosine 0 0 1 1 8.55 (0.02) 4.01 – 5.6E-8

1 1 1 0 12.02 (0.03) 5.8E-6

1 1 1 1 18.28 (0.1)

a l, p, q and r are stoichiometric coefficients corresponding to CuII, IMA, other ligand and H?, respectivelyb Standard deviations are given in parenthesesc Sum of square of residuals

1042 J Solution Chem (2013) 42:1028–1050

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of a seven membered chelate ring, which would be more strained and less favored. The

speciation diagram of the glycylglycine complex is given in Fig. 7. The mixed ligand

species [Cu(IMA)L] (1110) starts to form at pH * 3.2 and, with increasing pH, its con-

centration increases reaching a maximum of 22 % at pH = 6. Further increase of pH is

accompanied by a decrease in [Cu(IMA)L] (1110) complex concentration and an increase

of [Cu(IMA)LH-1] (111-1) complex concentration.

3.9 Ternary Complex Formation Equilibria Involving DNA Units

In the ternary complexes of DNA constituents (HL), the formation of a ternary complex

was ascertained by comparing the experimental potentiometric data with the theoretically

calculated (simulated) curve. Figure 8 presents such a comparison for the inosine system,

where the experimental data coincide with the theoretical curve. This supports the

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 9 10 11 12pH

% S

peci

es

Cu(II)

[Cu(IMA)]+

[Cu(IMA)(glyglyH-1)]-

[Cu(IMA)2][Cu(IMA)(glygly)] [Cu(glyglyH-1)]

Fig. 7 Concentration distribution of various species as a function of pH in the Cu(IMA)–glycylglycinesystem at the concentration 1.25 9 10-3 mol�dm-3, I = 0.1 mol�dm-3 (NaNO3) and t = 25 �C

O ON

HN HN

O

O

OH2

Cu

N

NH

N

NH2O

Cu

O(1110)

CH2

(1110)

Scheme 3 Coordination modes of imidazole as monodentate ligand and glycine as bidentate ligand withthe CuII–IMA complex

J Solution Chem (2013) 42:1028–1050 1043

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formation of a mixed-ligand complex. Thus, the formation of ternary complex can be

described by the following equilibrium (charges are omitted for simplicity):

Cuþ IMAþ L� Cu IMAð ÞL ð6Þ

Inosine may become protonated at N(7) with formation of [N(1)H–N(7)H] monoca-

tions. In the present study, only the pKa of N(1)H was determined since the pKa of N(7)H is

too low to be detected by the potentiometric technique. In the acidic pH-range, N(1)

remains protonated while the metal ion is attached to N(7). The gradual change from N(7)-

binding to N(1)-binding for metal complexes with increasing pH has been rather exten-

sively documented by nuclear magnetic resonance (NMR) and electron paramagnetic

resonance (EPR) [41] spectroscopic measurements. This means that these binding sites are

pH-dependent therefore it is proposed that N(1) serves as a coordination site in the mixed

ligand complexes of inosine at higher pHs in agreement with Martin et al. [42]. The data

show the formation of the ternary complexes with stoichiometric coefficients 1110 and

1111. The pKa value of N(1)H group of the protonated complex (log10 b1111 - log10 b1110)

is 6.26. This indicates acidification of the N(1)H site by 2.17 units through coordination

with the Cu–IMA complex.

The pyrimidinic species (uridine, uracil, thymine and thymidine) have a dissociable

proton at N(3). The acid dissociation constants obtained from this study were compared

with that of the N(1) proton of inosine. The purinic derivative (inosine) is slightly more

acidic than the pyrimidinic species (uridine, uracil, thymine and thymidine). This can be

related to the existence of the anionic form of purinic derivatives in a higher number of

resonance forms due to the presence of two condensed rings in this ligand (inosine). Based

on the existing data, uracil, uridine, thymine and thymidine ligate in the deprotonated form

as monoanions, through N(3), and they do not form protonated complexes. The thymine

and thymidine complexes are more stable than those of uracil and uridine, most probably

01 1.5

Volume of base added

Experimental pH

Calculated pH

2 2.5 30 0.5

1

2

3

4

5

6

7

8

9

pH

Fig. 8 Potentiometric titration curve for the Cu(IMA)–inosine system

1044 J Solution Chem (2013) 42:1028–1050

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due to the higher basicity of the N(3) site of thymine and thymidine, resulting from the

inductive effect of the extra electron-donating methyl group. Mixed ligand complexes of

nucleosides are less stable than their corresponding bases as evident from the stability

constants given in Table 6. The presence of a sugar residue imposes steric hindrance in

nucleosides for their complexation with metal ions and reduces the overall basicity of

metal complexes of nucleosides considerably. No interaction with the ribose hydroxyls is

observed, showing preference of Cu2? for the soft bases N(7) and N(1).

3.10 Comparison of the Stability Constant of the Ternary Complexes with Those

of the Binary Complexes

Different methods are known that can be used to estimate the formation of mixed-ligand

complexes [43]. The relative stability of the mixed-ligand complexes as compared to those

of the corresponding binary species can be evaluated in different ways.

3.10.1 The Parameter (Dlog10 K)

Dlog10 K has been widely accepted and used for many years [44], and the advantages in

using Dlog10 K in comparing stabilities of ternary and binary complexes have been

reviewed. The parameter Dlog10 K expresses the effect of the bonded primary ligand

towards an incoming secondary ligand (L). One expects to obtain negative values for

Dlog10 K (Table 7) since more coordination positions are available for the bonding of

ligand (L) in the binary than in the ternary complexes. This indicates that the secondary

ligand (L), amino acid, peptide or DNA, form more stable complexes with the copper(II)

ion alone than with the CuII–IMA complex. The Dlog10 K values for deprotonated ternary

complexes are given by Eqs. 7 and 8:

Cu(IMA)þ Cu(L)� Cu(IMA)(L)þ Cu ð7Þ

Dlog10KCu IMAð ÞL ¼ log10bCu IMAð Þ Lð Þ � ðlog10bCuðIMAÞÞ � ðlog10bCu Lð ÞÞ ð8Þ

The Dlog10 K value for protonated ternary complexes is given by Eqs. 9 and 10:

Cu(IMA)þ Cu(HL)� Cu(IMA)(HL)þ Cu ð9Þ

Dlog10KCu IMAð ÞHL ¼ log10bCu IMAð Þ HLð Þ � ðlog10bCuðIMAÞÞ � ðlog10bCu HLð ÞÞ ð10Þ

The statistical value of Dlog10 Koh for a regular octahedral (oh) coordination sphere is

-0.4 [45]. For the distorted octahedron (do) of Cu(aq)2? with two different bidentate

ligands, the statistical value was deduced as being Dlog10 Koh/Cu ffi-0.9 [45]. All values of

Dlog10 K for the ternary complexes studied in this paper are listed in Table 7. The negative

values obtained for Dlog10 K are found to follow the order: tridentate (as orni-

thine) [ bidentate (as glycine) [ monodentate (as imidazole) ligand. This can be justified

by the fact that Cu–IMA provides only two available coordination sites.

The Dlog10 K value for the ternary complex of phenylalanine is positive. This may be

explained on the premise that the noncoordinating aromatic side groups of these amino

acids can approach the aromatic moiety of IMA and exert a stacking interaction, since the

presence of an aromatic ring above the Cu(II) coordination plane is probably essential for

preferential formation of ternary complexes.

The Dlog10 K value for the induced deprotonated amide complex can be calculated

using Eq. 11:

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Dlog10K ¼ log10b111�1 � log10b1100 � log10b101�1 ð11ÞThe Dlog10 K values for the induced deprotonated amide ternary complexes are more

negative than -0.9. This may be taken as an indication that the formation of the ternary

amide complexes is less favored than that of binary ones. This may be explained on the

premise that the inducely deprotonated amide is coordinated with the free CuII ion as a

tridentate ligand, whereas in the ternary complex, two coordination sites are available in

the Cu–IMA complex.

3.10.2 Disproportionation Constant (log10 X)

However, besides Dlog10 K, the ‘‘disproportionation’’ constant log10 X (Eqs. 12 and 13)

[46] can be used to quantify the stability of ternary complexes. The advantages and

disadvantages arising from the use of log10 X have been discussed [47]. The values of log10

X for Cu(IMA)L complexes are defined by Eqs. 12 and 13 (Table 7):

Table 7 Evaluated values of log10 b1110, log10 bstat, Dlog10 b, Dlog10 K, and log10 X for the formation of theternary complexes [Cu(IMA)(L)] at ionic strength 0.1 mol�dm-3 NaNO3 and t = 25 �C

Ligand log10 b1110

(experimental)log10 bstat

a

(calculated)Dlog10 bb Dlog10 Kc log10 Xd

Glycine 15.22 14.46 0.76 -0.40 2.12

Alanine 15.68 14.29 1.39 0.26 3.38

Phenylalanine 17.14 14.41 2.73 1.85 6.07

Isoleucine 15.52 14.62 0.70 -0.34 2.01

Valine 15.60 14.47 1.13 0.01 2.87

Proline 15.33 15.06 0.27 -0.92 1.15

Methionine 14.33 14.28 0.05 -0.96 0.70

Aspartic 15.04 14.46 0.58 -1.23 1.76

Threonine 14.45 14.44 0.01 -1.30 0.62

Histidine 17.92 16.46 0.23 -0.17 3.52

Lysine 16.99 16.95 0.04 -4.45 0.68

Glycinamide 11.75 – – -0.38 (-1.0)e –

Glycylglycine 12.80 – – -0.03 (-2.09)e –

Glutamine 13.74 – – -1.38 (-1.94)e –

Thymine 12.72 – – -0.48 –

Thymidine 12.60 – – -0.70 –

Uridine 12.11 – – 0.36 –

Uracil 12.35 – – -0.57 –

Inosine 12.02 – – 0.58

a log10 bstat = log10 2 ? (1/2)log10 b1020 ? (1/2)log10 b1200

b Dlog10 b = log10 b1110 - log10 bstat

c Dlog10 K = log10 b1110 - log10 b1100 - log10 b1010

d log10 X = (2 log10 b1110 - log10 b1020 - log10 b1200)e These Dlog10 K are for the induced deprotonated amide (Dlog10 K = log10 b111-1 - log10 b1100 -log10 b101-1)

1046 J Solution Chem (2013) 42:1028–1050

123

Cu IMAð Þ2þCu Lð Þ2 � 2 Cu IMAð Þ Lð Þ; XCu HMIð Þ Lð Þ ¼Cu IMAð Þ Lð Þ½ �2

Cu IMAð Þ2� �

Cu Lð Þ2� � ð12Þ

log10XCu IMAð ÞðLÞ ¼ 2 log10bCu IMAð Þ Lð Þ � ðlog10bCu IMAð Þ2 þ log10bCu Lð Þ2Þ ð13Þ

Here it is enough to note that for the calculation of log10 X (Eq. 13), the constants of the

binary 1:2 parent complexes must be known and these are often not available, e.g., for

nucleotides and peptides. However, for the following examples of ternary complexes

formed by simple bidentate ligand (IMA) and some selected bio-relevant ligands, the

values of Dlog10 K and log10 X lead to the same conclusions. On statistical grounds [43],

considerably more positive log10 X values indicate marked stabilities of the mixed com-

plexes. The statistical value for X is 4, i.e., log10 X = 0.6 (Eq. 11) [46]. A heteroaromatic

N base is essential for the high stability of a ternary complex [43, 47–49]. This was

attributed to p back-bonding from the metal ion to the aromatic ligand [50, 51]. This is in

accordance with the stabilities of the ternary complexes formed by Cu(Pyr) with 2-pic-

olylamine, bipyridyl and 2-aminomethylimidazole [49].

3.10.3 Stabilization Constant (Dlog10 b)

The stability of the ternary complexes studied is also interpreted using a statistical method

[43] according to Eq. 14:

log10bstat: calc:ð Þ ¼ log102þ 1=2ð Þlog10b1020 þ 1=2ð Þlog10b1200 ð14Þ

The stabilization constant (Dlog10 b), which results from the difference of the stability

constant measured for the mixed ligand complex and that calculated from statistical

grounds, was calculated using Eq. 15:

D log10 b ¼ log10 bmeas: � log10 bcalc: ð15ÞThe values of log10 bstat for the mixed ligand complexes detected in this study are

shown in Table 7. The large differences of Dlog10 b values (log10 b1110 - log10 bstat)

indicate that the Cu(IMA)L system is more stable than both Cu(IMA)2 and Cu(L)2, as

expected on the statistical basis.

4 Conclusions

The present investigation characterizes the formation equilibria of Cu(II) complexes

involving IMA and some selected bio-relevant ligands containing different functional

groups. It is hoped that the obtained data will be a significant contribution to workers

carrying out mechanistic studies in biological media. Combining the stability constants

data of such CuII complexes with amino acids, peptides and DNA constituents, it will be

possible to calculate the equilibrium distribution of the metal species in biological fluids

where all types of ligands are present simultaneously. This would form a clear basis for

understanding the mode of action of such metal species under physiological conditions.

From the above results it may be concluded that ternary complex formation proceeds

through a simultaneous mechanism. Amino acids form highly stable complexes, and the

substituent on the a-carbon atom has a significant effect on the stability of the formed

complex. The present study shows clearly that deprotonation of the peptide bond is pro-

moted by complex formation. Also, the slight difference in the side chain of the peptides

J Solution Chem (2013) 42:1028–1050 1047

123

seems to produce dramatic differences in their behavior upon complexation. The values of

log10 K1 - log10 K2 are positive, indicating that coordination of the first ligand molecule to

the metal ion is more favorable than the bonding to the second one. Complex formation in

solution was shown to be an enthalpy driven process.

Regarding biological systems, important conclusions may be drawn from this work.

(i) Coordination of amino nitrogens or oxygen donors to Cu2? is easily achieved in the

physiological pH range, while there is no such evidence for the coordination of an ionized

amide nitrogen. (ii) In a mixed-ligand complex an ionized amide group may be formed and

coordinates only if two equatorial coordination positions of Cu2? are accessible, namely,

for the terminal amino nitrogen and the neighboring ionized amide. (iii) More positive

log10 X and less negative Dlog10 K values indicate the marked stabilities of the ternary

complexes. (iv) The substituent on the a-carbon atom (side chain) has a significant effect

on the stability of the formed complex.

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