Acid–base and metal ion binding properties of pyridine-type ligands in aqueous solution

Acid�/base and metal ion binding properties of pyridine-type ligandsin aqueous solution.

Effect of ortho substituents and interrelation between complexstability and ligand basicity

Larisa E. Kapinos, Helmut Sigel *

Institute of Inorganic Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland

Received 28 February 2002; accepted 19 April 2002

This study is dedicated to Professor Dr. Karl E. Wieghardt on the occasion of his 60th birthday with the very best wishes of the authors for all his

future endeavours

Abstract

The stability constants of the complexes formed between Mg2�, Ca2�, Sr2�, Ba2�, Mn2�, Co2�, Ni2�, Cu2�, Zn2� and Cd2�

(�/M2�) and two sets of pyridine-type ligands (�/L) were determined by potentiometric pH titration in aqueous solution (25 8C;

I�/0.5 M, NaNO3). One set consists of the simple and at the N1 site sterically unhindered pyridine-type ligands 3-chloropyridine, 4-

bromopyridine, 4-(chloromethyl)pyridine, pyridine, b-picoline (�/3-methylpyridine) and 3,5-lutidine (�/3,5-dimethylpyridine); the

other set includes the following pyridine derivatives with an ortho substituent, 2-methyl-5-bromopyridine, 2-amino-5-bromopyr-

idine, tubercidin (�/7-deazaadenosine), a-picoline (�/2-methylpyridine) and 2-aminopyridine. The acidity constants of the

monoprotonated ligands H(L)� were also measured. Plots of log KMM(L) versus pKH

H(L) give straight lines for each mentioned set of

pyridine derivatives. The equations for the corresponding least-squares lines allow calculation of the expected stability constant for a

complex of any pyridine-type ligand (with or without an ortho substituent) provided its pKHH(L) value is known (in the pKa range 3�/

7). The differences between the plots for these two sets of ligands reflect the steric influence of the ortho substituent on metal ion

binding at the N1 site of pyridine. It is shown that the steric effects of amino and methyl groups are equal. The extent of the steric

inhibition depends on the metal ion; it is most pronounced for Ni2� and nearly not existent for the alkaline earth ions. Furthermore,

for the latter ions complex stability is independent of the basicity of the pyridine nitrogen and this indicates that in these instances

outersphere complexes dominate. In the case of the divalent transition metal ions, the slopes of the straight lines are smaller for the

complexes of the ortho -substituted ligands, except for the Cu2� complexes where the slopes are identical; this indicates that Cu2�

forms with both sets of ligands mainly innersphere complexes, whereas for the other metal ions and their complexes with ortho -

substituted pyridine-type ligands outersphere binding becomes important. The present results permit in addition the determination

of the extent of the steric inhibition of the (C6)NH2 group on metal ion binding at N1 of the adenine residue.

# 2002 Elsevier Science B.V. All rights reserved.

Keywords: Acid�/base equilibria; Metal ion complexes; ortho -Substituted pyridine-type ligands; Pyridine derivatives; Stability constants; Steric

effects

1. Introduction

Pyridine and its derivatives are known to be suitable

ligands for d-transition metal ions and are therefore

often used in the design and synthesis of multifunctional

compounds [1]; studies involving Fe(II) [2], Ni(II),

Co(II) [3], and especially Cu(II) [4,5] are prominent.

Some of these pyridine derivatives are also of biological

and pharmacological relevance. For example, certain

peptide ligands with pyridine moieties seem to have a

potential as anti-HIV metal chelators [6], 4-methyl-2-

aminopyridine-palladium(II)-chloride inhibits the re-* Corresponding author. Fax: �/41-61-267 1017

E-mail address: [email protected] (H. Sigel).

Inorganica Chimica Acta 337 (2002) 131�/142

www.elsevier.com/locate/ica

0020-1693/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.

PII: S 0 0 2 0 - 1 6 9 3 ( 0 2 ) 0 0 9 9 3 - 3

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verse transcriptase of disrupted retroviruses [7], and

metal ion complexes of bis[di-1,1-(2-pyridyl)ethyl]amine

have been used in DNA cleavage studies [8].

In addition, the pyridine residue also occurs in several

molecules directly involved in biological processes [9],

like nicotinamide (pyridine-3-carboxamide), nicotina-

mide adenine dinucleotide (NAD) and its phosphory-

lated partner NADP, or vitamin B6, also named

pyridoxine [�/2-methyl-3-hydroxy-4,5-bis(hydroxy-

methyl)pyridine]. Furthermore, pyridine is structurally

and chemically related [10] to 1,3-diazine, which is a part

of pyrimidine and purine nucleobases. In fact, the N1

and N3 nitrogens of adenosine (Fig. 1) and cytidine,

respectively, are often addressed as pyridine-type nitro-

gen atoms [11�/14]. The importance of these nitrogens,

next to N7 of purines, as potential binding sites for

metal ions in their interactions with nucleotides or

nucleic acids, has long been recognized (for reviews see

[11,14�/17]).With the above situation in mind, it is surprising to

find [18�/20] that aside from some early data [21�/24],

including a study [25] dealing with the steric effect of

ortho substituents on the stability of Cu2��/pyridine

complexes, there are no comprehensive studies dealing

with the acid�/base properties of pyridine derivatives

and their corresponding metal ion affinities. The few

available attempts [11,13,14] to obtain a relation be-

tween nitrogen basicity and complex stability were based

on ‘mixed’ data, i.e. constants determined under differ-

ent conditions [12,21,22,25�/28].

To make the present study relevant for conclusions

regarding biological systems, we investigated not only

the acid�/base and metal ion binding properties of the

six simple pyridine derivatives seen in Fig. 2, but also of

the five ones given in Fig. 3, all of which have an ortho

substituent next to the N atom. This is important

because it is known [28] that the (C6)NH2 group in

adenosine (see Fig. 1) exerts a steric hindrance for metal

ion binding to N1. We have now quantified this steric

effect for the alkaline earth ions and the divalent 3d ions

Fig. 1. Chemical structure of adenosine (Ado), together with that of

1,4-dimethylbenzimidazole (DMBI), also named 6,9-dimethyl-1,3-

dideazapurine, a model compound for the adenine residue (see Section

4).

Fig. 2. Chemical structures of 3-chloropyridine (3ClPy), 4-bromopyr-

idine (4BrPy), 4-(chloromethyl)pyridine (4ClMPy), pyridine (Py), 3,5-

lutidine (�/3,5-dimethylpyridine, 3,5DMPy) and b-picoline (�/3-

methylpyridine, 3MPy).

Fig. 3. Chemical structures of ortho -substituted pyridine derivatives:

2-methyl-5-bromopyridine (2M5BrPy), 2-amino-5-bromopyridine

(2A5BrPy), a-picoline (�/2-methylpyridine, 2MPy), 2-aminopyridine

(2APy) and tubercidin (�/7-deazaadenosine, Tu).

L.E. Kapinos, H. Sigel / Inorganica Chimica Acta 337 (2002) 131�/142132

of Mn2�, Co2�, Ni2�, Cu2�, and Zn2�, as well as for

Cd2�. One among several interesting results is that the

extent of the steric inhibition also depends on the

basicity of the N liganding site, i.e. the log K versuspKa straight-line relations observed for the two series of

ligands (Figs. 2 and 3) are not parallel to each other for

most of the metal ions studied. It may be added that the

steric effect on the N7 site of the adenine residue has

recently been quantified [29] by studies with benzimida-

zole derivatives [30], including 1,4-dimethylbenzimida-

zole (DMBI). The use of this model compound allows

some interesting comparisons regarding the metal ionbinding sites N1 and N7 of the adenine residue (see

Section 4).

2. Experimental

2.1. Materials

3,5-Lutidine (�/3,5-dimethylpyridine, ]/97%), b-pi-coline (�/3-methylpyridine; ]/98%), pyridine (]/

99.8%), 4-(chloromethyl)pyridine hydrochloride (]/

98%), 4-bromopyridine hydrochloride (]/97%), 3-chlor-

opyridine (]/98%), a-picoline (�/2-methylpyridine; ]/

98%), tubercidin (�/7-deazaadenosine, ]/99%), 2-ami-

no-5-bromopyridine (]/97%), and 2-methyl-5-bromo-

pyridine (]/99%) were from Fluka, Buchs

(Switzerland), and 2-aminopyridine (]/99.9%) wasfrom Sigma�/Aldrich Co., Buchs (Switzerland). All these

substances were used as obtained; however, our poten-

tiometric pH titrations proved that they were free of any

acid�/base impurities.

The aqueous stock solutions of the ligands were

freshly prepared daily by dissolving the compounds in

deionized, ultrapure (MILLI-Q185 PLUS; from Milli-

pore S.A., F-67120 Molsheim, France) CO2-free waterand their exact concentrations were measured each time

by titrations with NaOH [31]. All the other chemicals

were the same as used previously [29,31], and the titres

of the metal ion stock solutions were also determined as

described [31].

2.2. Potentiometric pH titrations

The equipment, including the desk computers, was the

same as used recently [31,32]. All equilibrium constants

were calculated by curve-fitting procedures using a

Newton�/Gauss non-linear least-squares program.

The acidity constants determined [33] are so-called

practical, mixed or Brønsted constants [34]. Their

negative logarithms, given for aqueous solution at I�/

0.5 M (NaNO3) and 25 8C may be converted into thecorresponding concentration constants by subtracting

0.03 from the listed pKa values [34]. The ionic product of

water (Kw) does not enter into the calculations because

the differences in NaOH consumption between solutions

with and without ligand (see below) are evaluated. The

stability constants presented are, as usual, concentration

constants.

2.3. Determination of the acidity constants

The acidity constants KHH(L) of H(L)�, where L�/Py,

4BrPy, 4ClMPy, 3,5DMPy, 3MPy, 2M5BrPy, 2A5BrPy,

2MPy, 2APy or Tu (see Figs. 2 and 3), were determined

by titrating 50 ml 1.8 mM HNO3 (25 8C; I�/0.5 M,

NaNO3) in the presence and absence of 1.0 mM Py or

one of its mentioned derivatives under N2 with 1 ml of0.1 M NaOH and by using the differences in NaOH

consumption between such a pair of titrations for the

calculations. In the case of 3ClPy, because of its low

basicity, the acidity constant KHH(3ClPy) of H(3ClPy)� was

determined by titrating 25 ml of 7.2 mM HNO3 (25 8C;

I�/0.5 M, NaNO3) in the presence and absence of 2 mM

3ClPy with 1.85 ml of 0.1 M NaOH.

All acidity constants for monoprotonated species(KH

H(L)) were calculated as described [31] from the pH

range corresponding to about 3�/97% neutralization for

the equilibrium H(L)�/L. In the case of 3ClPy only the

pH range corresponding to about 20�/97% neutraliza-

tion for the equilibrium H(L)�/L was accessible. The

final results for the various acidity constants are the

averages of 16�/30 independent pairs of titrations.

2.4. Determination of the stability constants

The stability constants KMM(L) of the M(L)2� com-

plexes, where L�/Py, 4BrPy, 3ClPy, 4ClMPy,

3,5DMPy, 3MPy, 2M5BrPy, 2A5BrPy, 2MPy, 2APy

or Tu were determined under the same conditions as the

acidity constants, but NaNO3 was partly or fully

replaced by M(NO3)2 (I�/0.5 M, 25 8C).For the systems containing Mg2�, Ca2�, Sr2�, Ba2�,

and Mn2�, NaNO3 was always replaced completely by

M(NO3)2 because of the low stability of the correspond-

ing complexes; that is, [M(NO3)2] was equal to 0.1667 M

and consequently, the ratio for these systems was

M2�:L�/167:1, except for 3ClPy (see below).

For the other M2� complexes of pyridine and those

of its derivatives without an ortho substituent, thefollowing concentrations of M(NO3)2 were employed

and at least two different [M(NO3)2] were used for a

given ligand: 0.1667 M (M2�:L�/167:1 for Co2�,

Ni2�, Zn2�, and Cd2�), 0.0833 M (M2�:L�/83:1 for

Co2�, Cu2�, Zn2�, and Cd2�), 0.0417 M (M2�:L�/

42:1 for Co2�, Ni2�, Zn2�, and Cd2�), 0.0208 M

(M2�:L�/21:1 for Ni2�), 0.0104 M (M2�:L�/10:1 for

Ni2�). In the Cu2� systems also lower [Cu(NO3)2] wereused; i.e. 0.0083 M (M2�:L�/8.3:1), 0.0052 M

(M2�:L�/5.2:1), 0.0042 M (M2�:L�/4.2:1), 0.0033 M

(M2�:L�/3.3:1), and 0.0026 M (M2�:L�/2.6:1). For

L.E. Kapinos, H. Sigel / Inorganica Chimica Acta 337 (2002) 131�/142 133

the determination of the stability of the M(3ClPy)2�

complexes always the highest possible M2� concentra-

tion (0.1667 M) was employed for all metal ions giving

the ratio M2�:L�/83:1.In the case of the 2-methyl- or 2-amino-substituted

pyridines large M(NO3)2 concentrations were also

required because most of their metal ion complexes are

quite weak, except those containing Cu2�. Therefore,

NaNO3 was fully replaced by M(NO3)2 in most cases, so

that [M(NO3)2]�/0.1667 M and consequently,

M2�:L�/167:1. For the Ni2� and Zn2� systems with

tubercidin and 2-methylpyridine also half of the men-tioned concentration was used; i.e. [M(NO3)2]�/0.0083

M (M2�:L�/83:1). In the case of the Cu2� systems

further variations were possible, namely [Cu(NO3)2]�/

0.1333 M (133:1), 0.0834 M (83:1), 0.0417 M (42:1),

0.0333 M (33:1), 0.0167 M (17:1), and 0.0083 M (8.3:1).

The stability constants were calculated exactly as

described in [31]. The evaluations were carried out in

the pH range where no hydrolysis of M(aq)2� occurs;this was evident from the titrations of metal ion

solutions in the absence of ligand. The results showed

no dependence on the excess of the metal ion concen-

tration employed. The final results listed in the tables are

in each instance the averages of at least six independent

pairs of titrations. The relatively large error limits given

with the stability constants for the Cu2� and Zn2�

complexes of 2-aminopyridine (see Table 3, vide infra)are due to the relatively early M(aq)2� hydrolysis in

these systems which only allowed to reach a formation

degree of about 3% for the Cu(2APy)2� and

Zn(2APy)2� species.

3. Results and discussion

3.1. Acid�/base properties of pyridine and several

derivatives

Pyridine and all of the derivatives shown in Figs. 2

and 3 accept a proton at their endocyclic nitrogen giving

the monoprotonated species H(L)�, where L�/pyridine

or derivative. As far as aminopyridines and a possible

protonation of their exocyclic nitrogens are concerned,

already Sun and Brewer [22] had concluded: ‘‘Thebasicities of the �/NH2 groups in aminopyridines were

too weak to be detected and certainly had no effect on

the hydrogen ion concentration in a moderately acidic

pH range’’. This agrees with our own observations for 2-

aminopyridine and 2-amino-5-bromopyridine, that is,

pKHH2(L)51:3: Similarly, the most basic nitrogen in

tubercidin (Tu; Fig. 3) is N1, which undergoes proto-

nation by forming H(Tu)� [35]. No further protonationoccurs in the pH range down to 2 [35]. Neutral

tubercidin may release a proton from the ribose residue

[36], but this reaction only occurs at pH�/12 and does

not play a role in the physiological pH range. Hence, in

the present context, i.e. in the pH range 2�/12, only

H(Tu)� needs to be taken into account.

To conclude, for all pyridine ligands and pH rangesconsidered in this study only monoprotonated species

are of relevance and therefore, only equilibrium (1a) was

needed to explain the experimental data of the potentio-

metric pH titrations (25 8C; I�/0.5 M, NaNO3).

H(L)�XH��L (1a)

KHH(L)� [H�][L]=[H(L)�] (1b)

The results for the acidity constants (Eq. (1b)) of the

H(L)� species are given in Table 1. The value for

H(Tu)� has been determined before in this laboratory

and the result given in [28] is in excellent agreement with

the present one. This is also true, within the error limits,

for the ‘critically selected’ constants given in [18] for

H(Py)�, H(3MPy)�, H(3,5DMPy)�, H(2A5BrPy)�,

and H(2APy)�, as well as for the value of H(2MPy)�

given in Ref. [20]. For the acidity constants of

H(3ClPy)�, H(4BrPy)�, H(4ClMPy)�, and

H(2M5BrPy)� (Table 1, entries 1, 2, 3, 7) no values

are listed in Refs. [18�/20].

The results assembled in Table 1, together with some

literature data, allow several comparisons and conclu-

sions; a few are given: (i) as expected, halogen-contain-

ing substituents (entries 1�/3) decrease due to theirelectron-withdrawing properties the basicity of pyridine

(entry 4), whereas methyl (entries 5, 6, 10) and amino

(entry 11) groups enhance it in accordance with their

inductive (and resonance) effects [37]; the effect of the

amino group being more pronounced (cf. entries 10, 11).

(ii) Comparison of the acidity constants of the mono-

protonated ortho , meta , and para isomers of methylpyr-

idine with the pKa value of H(Py)�

[DpKa=ortho�pKHH(2MPy)�pKH

H(Py)�(6:1490:02)�(5:34/

/90:02)�0:8090:03; DpKa=meta�pKHH(3MPy)�pKH

H(Py)�(5:8190:02)�(5:3490:02)�0:4790:03; DpKa=para�pKH

H(4MPy) (from [18])�//pKHH(Py)�(6:0790:05)�(5:349

0:02)�0:7390:05] reveals that at the ortho and para

positions the electron-donating properties of the methyl

substituent are of a comparable size and more pro-

nounced than at the meta one; this order, meta B/

ortho �/para , agrees with theoretical expectations [37].

(iii) In contrast to the addition of an amino group,

which leads to the more basic aminopyridines (cf. entries

4, 11), the addition of a further endocyclic nitrogen

leading to the diazines, results in a decreased proton

affinity [38]. (iv) Annelation of pyridine to give quino-

line (Qu) has a relatively small effect, DpKa�pKHH(Py)

(from [39])�//pKHH(Qu) (from [40])�/(5.269/0.01)�/(4.979/

0.05)�/0.3, at least when compared to 1-methylimida-

zole and 1-methylbenzimidazole where the acidification

due to annelation amounts to DpKa�/1.5 [30].


The latter comparison, in which pKHH(Py)�5:2690:01

[39] was used, refers to 25 8C and I�/0.1 M. Since it is

of general interest to be aware of ionic strength effects,

we compare the values for H(Py)� at I�/0.1 and 0.5 M

and note that at the higher ionic strength the basicity is

increased by DpKa�/(5.349/0.02)�/(5.269/0.01)�/

0.089/0.02. This result is in excellent agreement with

comparisons that may be made for 2APy, 2MPy, and3MPy, based on the ‘critically selected’ values listed in

Ref. [18], and it agrees further with earlier values for Tu

[28]. An increase of the ionic strength from 0.1 to 1 M

enhances the basicity by DpKa#/0.15 based on the

values given for 2APy and 4APy in Ref. [18]. This latter

effect is somewhat smaller than the one observed

recently [41] for the deprotonation of a positively

charged (N)H� site in purine derivatives where thechange of I from 0.1 to 1 M resulted in a basicity

increase of DpKa�/0.299/0.09.

3.2. Stabilities of metal ion complexes formed with simple

and ortho-substituted pyridine-type ligands

All the experiments aimed to determine stability

constants of the metal ion complexes formed with the

ligands shown in Figs. 2 and 3 were carried out with the

metal ion (M2�) concentrations in excess of the

concentrations of the ligands (L). This means that underthese conditions only 1:1 complexes form and therefore

the experimental data of the potentiometric pH titra-

tions can be described completely by equilibrium (1a)

given above and equilibrium (2a)

M2��LXM(L)2� (2a)

KMM(L)� [M(L)2�]=([M2�][L]) (2b)

for complex formation. The only restriction is that the

evaluation of the experimental data is not carried into

the pH range in which hydroxo complex formationoccurs; however, this was evident from the titrations of

the metal ion solutions in the absence of ligand (see

Section 2.4). The results for the M(L)2� complexes of

Ba2�, Sr2�, Ca2�, Mg2�, Mn2�, Co2�, Ni2�, Cu2�,

Zn2�, and Cd2� are collected in Table 2.

Of the 110 stability constants listed in Table 2 only

about 25, the largest set for M2��/pyridine complexes at

varying conditions [18,19], have been measured before

[18�/20]. The early results by Sun and Brewer [22] for the

Cu2� complexes of Py, 3MPy, 3,5DMPy, 2MPy, and

2APy as well as for the Ni2� complexes of Py, 3MPy,

and 3,5DMPy are in excellent agreement with the

present ones. In general, there is also excellent agree-

ment with the ‘critically selected’ values given in [18] for

the Co2�, Ni2�, Cu2�, Zn2�, and Cd2� complexes of

3MPy, for the Ni2� and Cu2� complexes of 3,5DMPy,

and for the Cu2� complexes of 2MPy and 2APy. Aside

from the systems mentioned, there are also constants

listed in [19] for the Co2� and Cd2� complexes of

3,5DMPy, as well as for the Ni(2MPy)2�, Ni(2APy)2�,

and Zn(2APy)2� species. These earlier values [19] are at

least in part in fair agreement with the present ones; this

is also true for the M(Py)2� values given in Ref. [18].

Our own earlier determinations [28] of the stability

constants of the M(Tu)2� complexes are within the

error limits identical with the present results.

In a previous study we had determined in this

laboratory [39] the stability constants for the pyridine

1:1 complexes formed with Co2�, Ni2�, Cu2�, and

Zn2� at 25 8C and at I�/0.1 M (NaNO3). Comparison

of these earlier values, log KCoCo(Py)�1:2590:02;

log KNiNi(Py)�1:8790:01; log KCu

Cu(Py)�2:4990:02; and

log KZnZn(Py)�1:0090:03 [39], with those given in entry

4 of Table 2 for I�/0.5 M, gives the stability differences

Dlog KCo�/0.099/0.04, Dlog KNi�/0.079/0.02, Dlog

KCu�/0.119/0.04, and Dlog KZn�/0.159/0.04; i.e. these

M(Py)2� complexes are somewhat more stable at higher

ionic strength. The average increase in complex stability

of these examples, i.e. Dlog KM�/0.119/0.05 (3s), is

very close to the increased basicity of Py, i.e. DpKa�/

0.089/0.02, as described in Section 3.1, also due to the

change in ionic strength from 0.1 to 0.5 M. Hence, one

may conclude that the basicity increase (i.e. of pKHH(L))

due to an increased ionic strength leads in a first

Table 1

Negative logarithms of the acidity constants (Eq. (1)) of the simple and ortho -substituted protonated pyridine derivatives (H(L)�) shown in Figs. 2

and 3, respectively, as determined by potentiometric pH titrations in aqueous solutions at 25 8C and I�0.5 M (NaNO3) a,b

Simple pyridine derivatives ortho -Substituted pyridines

No. H(L)� /pKHH(L)/ No. H(L)� /pKH

H(L)/

1 H(3ClPy)� 3.0090.02 7 H(2M5BrPy)� 3.8690.02

2 H(4BrPy)� 3.9190.02 8 H(2A5BrPy)� 4.8790.01

3 H(4ClMPy)� 4.8390.01 9 H(Tu)� 5.2790.02

4 H(Py)� 5.3490.02 10 H(2MPy)� 6.1490.02

5 H(3MPy)� 5.8190.02 11 H(2APy)� 6.8690.01

6 H(3,5DMPy)� 6.2490.02

a The errors given are three times the standard error of the mean value or the sum of the probable systematic errors, whichever is larger.b So-called practical (or mixed) acidity constants [34] are listed; see Section 2.2.


Table 2

Logarithms of the stability constants for the 1:1 complexes (Eq. (2)) formed between several divalent metal ions (M2�) and the simple (a) or ortho -substituted (b) pyridine derivatives (L) shown in

Figs. 2 and 3, respectively, as determined by potentiometric pH titrations in aqueous solutions at 25 8C and I�0.5 M (NaNO3) a

No. L /Log KMM(L) for M2��

Ba2� Sr2� Ca2� Mg2� Mn2� Co2� Ni2� Cu2� Zn2� Cd2�

(a) Simple pyridine derivatives

1 3ClPy �0.1890.12 �0.1290.09 �0.0890.08 0.0290.05 0.1990.04 0.7990.03 1.3490.03 1.6090.03 0.5790.03 0.9390.03

2 4BrPy �0.0690.08 �0.0690.06 �0.0190.06 0.0790.06 0.3090.05 1.0390.02 1.5890.02 2.0390.02 0.7690.03 1.1490.05

3 4ClMPy �0.1290.06 �0.0690.06 �0.0690.05 0.0690.07 0.3790.04 1.2390.05 1.8490.02 2.4490.03 1.0190.05 1.3890.05

4 Py �0.2090.06 �0.1290.05 �0.1290.08 0.0390.06 0.4290.02 1.3490.04 1.9490.02 2.6090.04 1.1590.02 1.5190.05

5 3MPy �0.1690.16 �0.1990.09 �0.1290.07 0.0490.03 0.4790.03 1.3890.05 2.0090.02 2.7890.05 1.2490.04 1.5990.05

6 3,5DMPy �0.1890.13 �0.1690.08 �0.1190.15 0.0490.02 0.5490.02 1.5190.02 2.1290.02 2.9890.03 1.3790.02 1.7490.02

(b) ortho -Substituted pyridine -type ligands

7 2M5BrPy �0.2490.24 �0.1990.16 �0.0590.13 �0.0790.10 �0.0390.09 �0.0190.10 0.0190.10 0.6790.10 0.0090.12 0.4990.03

8 2A5BrPy �0.3490.11 �0.2490.13 �0.2190.12 �0.0890.08 �0.0390.08 0.0990.09 0.1790.05 0.9890.07 0.0790.07 0.5990.03

9 Tu �0.1490.13 �0.1390.09 �0.0790.09 �0.0590.12 0.1390.07 0.1390.09 0.3090.07 1.1990.06 0.1990.08 0.7190.07

10 2MPy �0.1990.10 �0.1590.08 �0.1590.07 �0.0290.06 0.0690.08 0.0590.08 0.2090.09 1.6290.03 0.2290.08 0.6890.03

11 2APy �0.2990.15 �0.2290.15 �0.1990.10 �0.0790.14 0.1390.10 0.2590.06 0.4290.07 1.8090.20 0.0590.20 0.9390.05

a For the error limits see footnote ‘a’ of Table 1. The entry numbers for the ligands correspond to those used in Table 1.

L.E

.K

ap

ino

s,H

.S

igel

/In

org

an

icaC

him

icaA

cta3

37

(2

00

2)

13

1�

/14

21

36

approximation to an equally large increase in complex

stability (i.e. of log KMM(L)): This observation promises to

be helpful for comparisons of data measured at different

values of I .

3.3. Relation between complex stability and ligand

basicity. Qualitative considerations

For families of structurally closely related ligands, a

linear relationship between log KMM(L) and pKH

H(L) is

expected [42] as expressed by Eq. (3):

log KMM(L)�m pKH

H(L)�b (3)

In Fig. 4, the values from Tables 1 and 2 for log KMM(L)

versus pKHH(L) of the simple pyridines (Fig. 2) are plotted

for six metal ions as examples. It is evident that the data

for a given metal ion fit excellently on a straight line.In an analogous way one may plot the data for the

ortho -substituted pyridine-type ligands (Tables 1 and 2,

entries 7�/11). This is done for four examples in Figs. 5

and 6 and also in these instances straight lines (filled

symbols) result.

From these two figures several conclusions are

immediately evident, i.e. without any further calcula-

tions: (i) in Fig. 5 the two lines due to the Cu2�

complexes are evidently parallel to each other and this

confirms an early observation [25]; of a similar paralle-

lism are the two lines for the Mg2� complexes, though

in this latter case the steric inhibition by the ortho

substituent is much smaller. However, (ii) from the two

examples shown in Fig. 6, it follows that this parallelism

is not a rule; the slopes due to the Ni2� and Cd2�

complexes formed with the ortho -substituted ligands are

lower than those of their complexes with the simple

pyridines. That is, for high pKHH(L) values the steric

inhibition is larger than for low pKHH(L) values. (iii) If one

compares the situations in Figs. 5 and 6 within the pH

range 3�/7, it is evident that the steric inhibition due to

an ortho substituent is most pronounced for the com-

plexes of Ni2�; indeed, for the four metal ions

considered in these two figures, the steric effect de-

Fig. 4. Relationship between log KMM(L) and pKH

H(L) for the 1:1

complexes of Mg2�, Mn2�, Ni2�, Cu2�, Zn2� and Cd2� with the

following simple and sterically unhindered pyridine-type ligands (k),

3-chloropyridine (3ClPy), 4-bromopyridine (4BrPy), 4-(chloro-

methyl)pyridine (4ClMPy), pyridine (Py), b-picoline (�/3-methylpyr-

idine, 3MPy) and 3,5-lutidine (�/3,5-dimethylpyridine, 3,5DMPy)

(from left to right) based on the results summarized in Tables 1 and

2 (entries 1�/6). The least-squares straight-reference lines are drawn

according to Eq. (3); these results are listed in Table 3, part (a). All

plotted equilibrium constants refer to aqueous solutions at 25 8C and

I�/0.5 M (NaNO3).

Fig. 5. Evidence for a reduced stability of the Mg2� (^,') and Cu2�

(k,m) 1:1 complexes of ortho -substituted pyridine-type ligands

(',m) compared with those of simple pyridine derivatives (^,k)

based on the log KMM(L) versus pKH

H(L) relationship. The reduced

complex stability reflects the steric inhibition due to an ortho -amino

or -methyl group. The sterically hindered pyridine-type ligands with an

ortho substituent (',m) are 2-methyl-5-bromopyridine (2M5BrPy), 2-

amino-5-bromopyridine (2A5BrPy), tubercidin (�/7-deazaadenosine,

Tu), a-picoline (�/2-methylpyridine, 2MPy) and 2-aminopyridine

(2APy) (from left to right). For the simple sterically unhindered

pyridine-type ligands (^,k) see Fig. 4 and its legend. All data pairs

are from Tables 1 and 2. The least-squares straight-reference lines are

drawn according to Eq. (3) and the results are listed in Table 3. All

plotted equilibrium constants refer to aqueous solutions at 25 8C and


creases in the order Ni2��/Cu2��/Cd2��/Mg2�. (iv)

A further important point that follows from Figs. 5 and

6 is that 2-methylpyridine and 2-aminopyridine and

their derivatives, including tubercidin, exert within the

error limits identical steric effects on metal ion binding

at the neighboring N site. An equal inhibitory effect of anon-bonding �/NH2 and a �/CH3 group on metal ion

binding at ortho -substituted pyridine-type ligands has

been suggested before [28,43] and this also agrees with

the recent conclusion about the shape complementarity

of the adenine and the 4-methylbenzimidazole residues

[44].

3.4. Quantitative evaluation of the log KMM(L) versus

pKHH(L) relations

Of course, the results listed in Tables 1 and 2 allow a

quantitative evaluation of the effects indicated in Sec-

tion 3.3; for each metal ion system five or six data pairs

are available. These were used to calculate by the least-squares procedure the straight-line equations summar-

ized in Table 3. From the plots of the equilibrium

constants of the Mg2� systems shown in Fig. 5, it is

evident that the data for the simple pyridines as well as

for the ortho -substituted ones can be fitted well to

straight lines. However, these two lines only show a

small dependence on pKHH(L); and this is the reason for

the low values obtained for the correlation coefficient R ,

i.e. 0.030 and 0.036 for the straight-line equations (4)

and (5), respectively:

log KMgMg(L)

�(0:00090:008) pKHH(L)�(0:04190:038) (4)

log KMgMg(L)ortho

�(0:00790:011) pKHH(L)�(0:09890:061) (5)

In fact, the slope m is in both equations zero within the

error limit (1s). This result agrees with a view on thestability constants listed in Table 2 for the Mg2�, Ca2�,

Sr2�, and Ba2� complexes; there is no dependence on

pKHH(L) observed and for a given series of complexes the

stability constants are identical within the error limits.

The results given in Table 2 for these ions are not very

precise, especially for the complexes of the ortho -

substituted pyridine-type ligands; this is understandable

because the stability of these complexes is very low.Clearly, within the error limits, the stability constants

for a given metal ion are independent of the ligand

considered, provided one stays within a given ligand

Fig. 6. Evidence for a reduced stability of the Ni2� (k,m) and Cd2�

(^,') 1:1 complexes of ortho -substituted pyridine-type ligands

(',m) compared with those of simple pyridine derivatives (^,k),

based on the log KMM(L) versus pKH

H(L) relationship. The reduced

complex stability reflects the steric inhibition due to an ortho -amino

or -methyl group. The sterically hindered pyridine-type ligands with an

ortho substituent (',m) are given in the legend of Fig. 5 and those of

the simple and sterically unhindered ones in the legend of Fig. 4. All

data pairs are from Tables 1 and 2. The least-squares straight-reference

lines are drawn according to Eq. (3) and the results listed in Table 3.

All plotted equilibrium constants refer to aqueous solutions at 25 8Cand I�/0.5 M (NaNO3).

Table 3

Straight-line parameters for M2� 1:1 complexes formed with simple

(a) and ortho -substituted (b) pyridine-type ligands, valid for aqueous

solutions at 25 8C and I�0.5 M (NaNO3) a,b

No. M2� m B R c

(a) Regression lines for simple pyridine -type ligands

1 Mn2� 0.10290.005 �0.11490.026 0.995

2 Co2� 0.21590.011 0.17090.054 0.995

3 Ni2� 0.23890.011 0.64790.057 0.995

4 Cu2� 0.41890.012 0.37490.058 0.998

5 Zn2� 0.24890.006 �0.19090.031 0.999

6 Cd2� 0.24690.006 0.18590.032 0.999

(b) Regression lines for ortho -substituted pyridine -type ligands

7 Mn2� 0.05290.026 �0.23090.145 0.754

8 Co2� 0.06690.030 �0.25490.167 0.782

9 Ni2� 0.11590.037 �0.40390.205 0.873

10 Cu2� 0.39790.027 �0.88990.146 0.993

11 Zn2� 0.10390.025 �0.39890.128 0.945

12 Cd2� 0.13190.031 �0.02890.172 0.925

a The slopes (m ) and intercepts (b ) for the straight reference lines

from plots of log KMM(L) versus pKH

H(L) were calculated by the least-

squares procedure from the experimentally determined equilibrium

constants listed in Tables 1 and 2.b Straight-line equation: y�mx�b , where x represents the pKH

H(L)

value of any (N1)-protonated pyridine derivative and y the calculated

stability constant (/log KMM(L)) of the corresponding M(L)2� complex

(Eq. (3)); the errors given with m and b correspond to one standard

deviation (1s ).c Correlation coefficient. In the case of small values for the slope

(m ) the values for R are also expected to be relatively small (see e.g.

entries 7, 8).


series. Thus, the stability constants for the complexes of

Mg2�, Ca2�, Sr2�, and Ba2� are probably best

represented in the pKHH(L) range from 3 to 7 by the

averages of the individual stability constants. Hence,from the six values listed in Table 2 for each metal ion

one obtains for the stabilities of simple pyridine-type

ligands the results given in Eqs. (6)�/(9):

log KMgMg(L)�0:0490:04 (6)

log KCaCa(L)��0:0890:07 (7)

log KSrSr(L)��0:1290:08 (8)

log KBaBa(L)��0:1590:10 (9)

For ortho -amino or ortho -methyl group-substituted

pyridine-type ligands, one obtains correspondingly the

results given in Eqs. (10)�/(13):

log KMgMg(L)ortho��0:0690:06 (10)

log KCaCa(L)ortho��0:1390:13 (11)

log KSrSr(L)ortho��0:1990:14 (12)

log KBaBa(L)ortho��0:2490:15 (13)

For the six metal ions for which finally straight-line

equations were calculated for simple and ortho -substi-

tuted pyridine-type ligands (see Table 3), it is interesting

to determine the deviation from the least-squares line for

the stability constant of each individual complex. It issatisfying to see from the results summarized in Table 4,

part (a), that all deviations of the data points from their

straight line are within 9/0.05 log unit. For complexes of

the ortho -substituted pyridine-type ligands (Table 4,

part (b)) all deviations are within 9/0.10 log unit. The

larger deviations observed in the latter cases are due to

the low stability of these complexes, which gives rise to

larger experimental errors as already indicated above.

To provide a reliable error limit for any stabilityconstant calculated with the equations of Table 3 and a

given pKHH(L) value for each of the 12 metal ion systems

listed in Table 3, the standard deviation of the six or five

data points from the relevant least-squares line was

calculated (Table 4, heading SD). Users of the results

described in this section are recommended to apply the

equations of Table 3 to simple and ortho -substituted

pyridine-type ligands in the pKHH(L) range 3�/7 and to

consider as error limits for the calculated stability

constants, log KMM(L) (Eq. (3)), two or three times the

standard deviation (SD) given in Table 4 for the

corresponding metal ion system. For calculated stability

constants in the pKHH(L) range 0�/3 and 7�/10, the error

limits given for b (intercept with the y -axis) should also

be taken into account.

No stability constants were determined in this studyfor the Fe2� complexes of these pyridine-type ligands,

despite the obvious biological significance of this metal

ion, because such measurements are difficult to carry

out and are rather error-prone if traces of Fe3� are

present or formed during the experiment. In fact, in the

three stability constant compilations [18�/20], only very

few constants for Fe2� complexes are given. If values

are needed, we recommend the following estimation:according to experience [45], based on the Irving�/

Williams sequence [46], one may propose the use of

the average of the results obtained for the Mn2� and

Co2� complexes; this view is also supported by recent

results [30].

Table 4

Logarithmic differences between the experimentally determined stability constants (/log KMM(L) of Table 2) of the M2� complexes for simple (entries 1�/

6; Fig. 2) and for ortho -substituted (entries 7�/12; Fig. 3) pyridine derivatives and the least-squares lines of the log KMM(L) versus pKH

H(L) plots (Table

3). a The column farthest to the right gives the standard deviation (SD) resulting from the listed differences.

(a) Simple pyridine -type ligands

No. M2� 3ClPy 4BrPy 4ClMPy Py 3MPy 3,5DMPy SD

1 Mn2� 0.00 0.02 �0.01 �0.01 �0.01 0.02 0.006

2 Co2� �0.03 0.02 0.02 0.02 �0.04 0.00 0.011

3 Ni2� �0.02 0.00 0.04 0.02 �0.03 �0.01 0.011

4 Cu2� �0.03 0.02 0.05 �0.01 �0.02 0.00 0.012

5 Zn2� 0.02 �0.02 0.00 0.02 �0.01 0.01 0.007

6 Cd2� 0.01 �0.01 0.01 0.01 �0.02 0.02 0.006

(b) ortho-Substituted pyridine-type ligands

No. M2� 2M5BrPy 2A5BrPy Tu 2MPy 2APy SD

7 Mn2� 0.00 �0.05 0.09 �0.03 0.00 0.024

8 Co2� �0.01 0.02 0.04 �0.10 0.05 0.027

9 Ni2� �0.03 0.02 0.10 �0.10 0.03 0.033

10 Cu2� 0.03 �0.06 �0.01 0.07 �0.03 0.023

11 Zn2� 0.00 �0.03 0.05 �0.01 �0.09 0.027

12 Cd2� 0.01 �0.02 0.05 �0.10 0.06 0.029

a The entry numbers for the various M2� systems correspond to those used in Table 3.


Another interesting observation is closely connected

with the quantitative evaluations given in this section.

We have already seen in Figs. 4 and 5, and expressed this

clearly in Eqs. (6)�/(12), that the stability of thecomplexes of the alkaline earth ions does not depend

on the basicity of the pyridine nitrogen. Why? The only

evident explanation for this experimental result is that in

these instances outersphere complexes are formed. If

there is a water molecule between the liganding N site

and the metal ion, then one expects that a change in the

basicity of the ligand is only little or not at all reflected

in the stability of the complexes. Such outerspherecomplexes are also expected to be of a low stability

and this is the case indeed. Furthermore, the steric

inhibition of the ortho substituent is very small in these

instances as is seen in Fig. 5 and as follows also from

Eqs. (6)�/(12); the inhibition only amounts to about

0.05�/0.10 log unit.

The only other example where the slopes of the

straight-line plots are identical for simple and forortho -substituted pyridine-type complexes are those of

Cu2� (see Fig. 5 and Table 3, entries 4, 10). The fact

that the slopes are identical indicates that Cu2� forms

innersphere complexes with both series of ligands; this is

also in accord with the relatively steep slopes, i.e., m #/

0.4. Indeed, from entries 1�/6 in Table 3 it follows that

the slope of the straight lines decreases for the M2�

complexes in the order Cu2��/Zn2��/Ni2��/

Co2��/Mn2�, the slope for Cd2� being close to those

for Zn2� and Ni2�. This indicates that in this order also

the amount of outersphere complexation increases; i.e.

the lower the slope, the higher the formation degree of

the outersphere species. Since an ortho -amino or ortho -

methyl substituent inhibits of course especially inner-

sphere complex formation, the slopes are expected to

decrease and this is exactly observed in all instances(except for Cu2�); however, the given order of the

slopes for the metal ions is hardly affected (Table 3,

entries 7�/12), as one would also expect. Moreover, the

slopes of the reference lines due to the Mn2� complexes

are very small (m�/0.10 and 0.05; Table 3, entries 1, 7),

that is, they are closest to the zero slopes of the Mg2�

complexes (Eqs. (4) and (6)) and this agrees with the

often described chemical kinship of these two metal ions[47�/49]; clearly, outersphere complex formation is of the

highest relevance for Mn2� among all the transition

metal ions studied here.

4. Conclusions

There are a few more stability constants available in

the literature [18�/20] of complexes of pyridine-typeligands, like 3-aminopyridine, 3,4-dimethylpyridine

(�/3,4-lutidine), and 4-methylpyridine (4MPy�/g-pico-

line). We select the latter ligand to demonstrate the

usefulness of the straight-line equations listed in

Table 3 because a relatively large number of complexes

of 4MPy has been studied before, even though these

results refer to different ionic strengths (25 8C; the errorlimits are estimates): log KCo

Co(4MPy)�1:5690:06 (I �0:5 M) [18], log KNi

Ni(4MPy)�2:1190:06 (I �0:1 M)

[21], log KCuCu(4MPy)�2:8890:06 (I �0:1 M) [21],

log KZnZn(4MPy)�1:4090:08 (I �0:1 M) [21], and

log KCdCd(4MPy)�1:6290:08 (I �1 M) [18]. Application

of the acidity constant, pKHH(4MPy)�6:1890:02/

/(I �0:1 M) [21] to the straight-line equations of Table

3 (entries 2�/6) provides the following calculatedstability constants for the five M(4MPy)2� comp-

lexes: log KMM(4MPy)�1:5090:03 (Co2�); 2:1290:03 /

/(Ni2�); 2:9690:04 (Cu2�); 1:3490:02 (Zn2�); and /

/1:7190:02 (Cd2�) (25 8C; I�/0.5 M). The agreement

between the experimental and calculated constants is

excellent, although some of these values were measured

nearly 40 years ago.

A similar excellent result is obtained for the Cu2�

complex of the ortho -substituted 2,5-dimethylpyridine

(2,5DMPy�/2,5-lutidine): the measured value,

log KCuCu(2;5DMPy)�1:7890:03 (25 8C; I�/0.5 M) [22], is

in excellent agreement with the calculated value based

on the acidity constant, pKHH(2;5DMPy)�6:63 (I�/0.6 M)

[22], and the straight-line equation for ortho -substituted

pyridine-type ligands (Table 3, entry 10), i.e.

log KCuCu(2;5DMPy)calc�1:7490:07 (I�/0.5 M).

That the (C6)-amino group of the adenine residue (see

Fig. 1) hinders metal ion binding at N1 and at N7 is

known [14], but an exact quantification of this inhibition

has remained elusive. The present study with its straight-

line relations for the complexes of ortho -amino or ortho -

methyl-substituted pyridine-type ligands allows now a

quantification of the effect of the (C6)NH2 group on

metal ion binding at N1 of an adenine moiety. Similarly,very recently we have studied [29] the metal ion binding

properties of DMBI, also named 6,9-dimethyl-1,3-di-

deazapurine; a model compound for the adenine residue

[44] (see Fig. 1). Assuming that the steric hindrance on

the N7 site by a (C6)NH2 or a (C6)CH3 group is equal,

which in fact has been proven (see Section 3.3), we are

now in the position to compare for the first time the

steric effect of the (C6)NH2 group on metal ion bindingat N1 and N7 for an adenine residue.

To this end we select the acidity constant pKHH(L)�

5:78; which also quantifies the deprotonation of

H(DMBI)� [29], because in this way the basicity of

the two N sites is kept equal and any differences possibly

observed in complex stability refer then to differences in

the steric hindrance. Application of the mentioned

acidity constant to the straight-line equations given inentries 1�/6 of Table 3 leads to the results listed in the

second column of Table 5; these stability constants

reflect the affinity of a pyridine nitrogen which is not

affected by any steric hindrance. Application of the


corresponding procedure to entries 7�/12 of Table 3

gives the stability constants of metal ion complexes

which suffer a steric hindrance of an ortho -ami-

no(methyl) group upon their coordination to the

pyridine nitrogen; these results are listed in column 3

of Table 5. In column 4, the stability differences

log DM(Py-type)ortho , which result from the two columns

to its left, are listed; these values quantify the steric

inhibition of the (C6)NH2 group on (N1)�/metal ion

binding of an adenine residue. The final column in Table

5 gives the log DM(DMBI) values, taken from [29], which

characterize the same effect on N7�/metal ion binding

also of an adenine residue (Fig. 1). As said above, the

basicity of N1 and N7 in this ‘hypothetical’ adenine

residue has been put equal to each other (pKHH(L)�5:78):/

Comparison of the values listed in columns 4 and 5 of

Table 5 allows several interesting conclusions: (i)

inhibition by the (C6)NH2 group, if reference is made

to an adenine residue, to binding of Mg2� at N1 or N7

is small and within the error limits identical. (ii) This

contrasts with the very large and within the error limits

again identical steric inhibition (approximately �/1.8 log

units), which is experienced by Ni2�, if binding to the

same two sites is considered. (iii) Cu2� binding to N1 is

also strongly affected by the (C6)NH2 group, but it

suffers less (by about 0.4 log unit) in its binding

tendency toward N7. (iv) This observation for Cu2�

contrasts with that for all other metal ions, i.e. Mn2�,

Co2�, Zn2�, and Cd2�, the binding of which at N1 is

less affected than that at N7 by the (C6)NH2 group.

These comparisons show that now the basic informa-

tion is available which should allow a re-evaluation of

the metal ion binding properties of cytidine [43] and of

adenosine [13]. Work on these aspects is in progress in

this laboratory.

Acknowledgements

The competent technical assistance of Mrs. Rita

Baumbusch and Mrs. Astrid Sigel in the preparation

of this manuscript is gratefully acknowledged. This

study was supported by the Swiss National Science

Foundation and within the COST D20 programme by

the Swiss Federal Office for Education and Science.

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Table 5

Comparison of the steric inhibition due to the (C6)NH2 group in an adenine residue on metal ion binding at N1 (�ortho -substituted pyridine-type

binding) and N7; the latter is based on results [29] obtained for DMBI (Fig. 1) a

M2�/Log KM

M(Py-type)b

/Log KMM(Py-type)ortho/

b Log DM(Py-type)ortho Log DM(DMBI)c

Mg2� 0.0490.04 �0.0690.06 �0.1090.07 �0.0690.13

Mn2� 0.4890.02 0.0790.07 �0.4190.07 �0.8690.08

Co2� 1.4190.03 0.1390.08 �1.2890.09 �1.5090.07

Ni2� 2.0290.03 0.2690.10 �1.7690.10 �1.8690.07

Cu2� 2.7990.04 1.4190.07 �1.3890.08 �0.9490.06

Zn2� 1.2490.02 0.2090.08 �1.0490.08 �1.2390.09

Cd2� 1.6190.02 0.7390.09 �0.8890.09 �1.3690.07

All values refer to aqueous solutions at 25 8C and I� 0.5 M (NaNO3).a The error limits are three times the standard errors and for the derived data (columns 4 and 5) they were calculated according to the error

propagation after Gauss.b Calculated with pKH

H(L)�5:78 (see text) and the straight-line equations listed in Table 3; the error limits are from Table 4 (�3�SD). The values

for the Mg2� complexes are those given in Eqs. (6) and (10).c These values are from Ref. [29].


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Acid–base and metal ion binding properties of pyridine-type ligands in aqueous solution

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Transcript of Acid–base and metal ion binding properties of pyridine-type ligands in aqueous solution