Indian Journal of Chemistry Vol. 40A, October 2001, pp. 1076-1081

Solution and molecular modeling studies on some bivalent metal complexes of higher analogues of biologically active 1,3-diaryl-4, 5, 6-pyrimidinetrione-

2-thioxo-5-oxime

Parvesh Sharma", Bablu Swaikab, Sachin Millalb

, R K Sharmab & S K Sindhwanib* "St. Stephen 's College, University of Delhi, Delhi 110007, India

bDepartment of Chemistry, University of Delhi, Delhi 110007, India

Received 20 October 2000; revised 9 Jllly 2001

Thermodynamic proton-ligand stability constants of 1,3-diethylphenyl-4,5,6- pyrimidinetrione-2-thioxo-S-oxime (and the thermodynamic metal ligand stability constants) with some bivalent metal ions were determined by potentiometric measurements in 75% (v/v) aqueous-dioxan medium at different temperatures rangi ng from 25° C to 35° C. The acidity and stability constants vary according to the kind of substitution at the 1- and 3- positions of the pyrimidine ring. The order of stability constants is UO/ +> Cu2+>Ni2+>C02+ >Zn2+ >Cdl + >M n2+ >Mg2+. The values of Smin (Xl) have also been calculated. The thermodynamic functions for the stepwise complexation processes are calculated at 25±0.5°C. Molect:l ar modeling studies have also been carried out on the ligand and complexes. the results of which corroborate the experimental findin gs.

Various N-substi tuted thiobarbiturates possess hypnotic, anaesthetic, intravenous, narcotic and antibacterial activit/ -4• Some derivatives are found to act as acricides, nematocides, molluscicides, fungi­cides5

.6 and anticancerous? The widespread interest in

thiobarbiturates is largely due to their pharmaco­logical activity, which in turn is mainly due to their enhanced lipid solubility compared with that of con'esponding parent barbiturates8

. 1,3-Diaryl-5-sub­stituted-2-thiobarbituric acids show considerable anti­inflammatory activity but less toxicitl. N,N'-ditolyl derivatives are capable of prevention and therapy of diseases caused by viruses 10. The knowledge of complexing properties of the derivatives of 5-nitroso barbituric acids (thiovioluric acids) is limited and a few data on their complex formation equilibria are known 1 1-13 . The acidity constants of some of the derivatives of thiovioluric acids vary according to the degree and nature of the substitution at the 1 and 3 positions of the pyrimidine ring.

The present paper reports the study of com­plexation equilibria of 1,3-diethylphenyl-2-thioxo-2H, 5 H -pyri midine-4,5 ,6-trione-5-oxime deri vati ves wi th bivalent metal ions by potentiometric method.

Materials and Me.;hods A digital pH-meter (ECIL, model pH 5651) with a

combined calomel .. glass electrode (0-14 pH range)

was used for pH measurements after standardisation with potassi um hydrogen phthalate and phosphate buffers. All measurements were made at a definite temperature maintained using MLW thermostat (NBE type, Germany). A personal computer PC-486 was used for the calculations.

1,3-Di(ethylphenyl)-1,3-dihydro-2-thioxo-2H, SHoo

pyrimidine-4,5,6-trione-5-oxime 4(a-c) were prepared

in three steps from ethyl anilines (Scheme I). N, N'­

di(ethylphenyl)thiourea 2(a-c), prepared by the

method of Vogel ll were reacted with malonic acid

and acetyl chloride to yield corresponding 1,3-di­

(ethylphenyl)thiobarbituric acid's 3 (a-c). It was

dissolved in NaOH and reacted with NaN02/dil.

H2S04 to give the oximes 4 15• The crucle product was

recrystallized form benzene/alcohol. The purity of the

compound was checked by TLC ancl characterized by

spectroscopic methods.

4a. IR V lllax (KBr) : 3489 (NO - H), 1719, 170 I

(C=O), 1649 (C=N), 1379, 1263 (C=S). IH NMR

(8Acetone - d6) : 1.32 (t, 6H, 2 x - CI-h), 2.65(q, 4H,

2 X-CH2)' 7.28 (m, 8H, Ar-H). Mass (mlz) : 381(M+).

4b. IR Vrnax (KBr) : 3504 (NO - H), 1737, 1706 (C=O), 1653(C=N), 1387, 1268 (C=S). IH NMR (8,

Acetone-cl6) : 1.35 (t, 6H, 2 x -CH3) 2.60 (q, 4H, 2 x

-CH2), 7.20 (m, 8H, Ar-H). Mass (mJz) : 381 (M+).

SHARMA el al.: METAL COMPLEXES OF 1,3-D1ARYL-4,5,6-PYRIMIDINETRIONE-2-THIOXO-5-0XIME 1077

Q ~I C2HsOH P-NH-~N~ ~ + cS2 ~

~ -H2S R R R

I. a.R= 2- b.R= 3- cR= 4- 2. a.R= 2- b. R= 3- c R=4-

C 2(COC 2 ! -

Q!x~ R s~Oo ;) aq.

I~ R

4. a .R= 2- b. R= 3- c R=4- 3. a .R= 2- b. R= 3- c. R=4-

Scheme 1

4c. IR V lllax (KBr): 3449 (NO-H), 1736, 1702 (C=O), 1655 (C=N), 1387, 1270 (C=S). I H NMR (8, Acetone - d6 ) : 1.30 (t, 6H, 2 x - CH3), 2.65 (q, 4H, 2x - CH2), 7.30 (m, 8H, Ar - H). Mass (nv'z) : 381 (M+) .

The solutions of the ligands were prepared in freshly distilled dioxan. The solutions of nitrates of bivalent metal ions namely U02(II), Pb(lI), Zn(II), Cd(II), and sulphates of Mn(II), Cu(ll), Ni(II), Co(II), Mg(II) were standardised by conventional gravimetric methods.

TMAH (Me4NOH) (Merck) in 75% dioxan (aqueous) was used as titrant. The solu tion was standardised with oxalic acid, (COOHh.2H20. Perchloric acid (HCI04) was standardised with Na2C03 and diluted to the required molarity (0.05 M). NaCI04 (Merck) was used to maintain the ionic strength constant. Dioxan (Merck) was freed from peroxide by refluxing with sodium metal for 24 hand was freshly distilled over sodium before use. All other chemicals were of reagent grade.Titrations were carried out at temperatures 25, 30 and 35 ± 0.5°C and ionic strength maintained at 0.02 M NaCI04. For each set of experiments, the final volume was made upto 20 ml, in 75% aqueous dioxan. The following

solutions were titrated potentiometrically against standard 0.05 M TMAH in 75 % aqueous dioxan (v/v) to determine nand pL values of the complexes formed in the solution:

(i) 0.8 ml of HCI04 (0.05 M) + 1.0 ml of NaCI04

(2.0 M) + 2.7 ml of H20 + 15.0 ml of dioxan + 0.5 ml of KN03 or K2S04 (0.02 M).

(ii) 0.8 ml of HCI04 (0.05 M) + 1.0 ml of NaCl04

(2.0 M) + 2.7 ml of H20 + 5.0 ml of dioxan + 10.0 ml of ligand solution (0.01 M) + 0.5 ml of KN03 or K2S04 (0.02 M).

(iii) 0.8 m! of HCI04 (0.05 M) + 1.0 ml of NaCI04

(2.0 M) + 2.7 ml of H20 + 10.0 ml ligand solution (0.01 M) + 5.0 ml of dioxan + 0.5 ml of metal nitrate or sulphate (0.02 M).

The titrations were carried out in a covered, double walled glass cell in an atmosphere of nitrogen gas, which was pre-saturated with the solvent (75 % aqueous dioxan) vapour before being passed into thetitration vessel. From the titration curves of solutions (i), (ii) and (iii), n H (average number of

protons bound to the ligand), n (average number of

1078 INDIAN J CHEM. SEC. A, OCTOBER 2001

ligand molecules bound per metal ion) and pL (free ligand exponent) values were calculated using the method of Bjerrum l6 and Calvin and Wilson l7 as modified by Irving and Rossotti 18. The procedure for calculation has been described earlier l9

. The nand pL data were analyzed usi ng the weighted least-squares technique developed by Sullivan el ai. to yield Bn values2o

. Smin has the same statistical distribution as X2

with ' K' degrees of freedom and weight defined in accordance with Sullivan et al.21 The stability constants thus calculated are given in Table I. The values of t::.H were calculated by the graphical method of Yatsimirskii and Vaslev22

, while the values of t::.G

and t::.S were calculated by conventional methods . From the stability constant values of complexes formed by metal ions having 3d5 and 3d lo

configurations, the 8H values were calculated accordin~ to the method described by George and McClure 3. The values are given in Table 2.

Molecular modeling In our experi ment molecular modeling software

'HyperChem' Suite release 5.1 Profess ional version, an interactive software that allows for rapid structure building, geometry optimization and molecular display, was used24

.

Table I-Stability constants of bivalent metal complexes of 1,3-diary l-4, 5, 6-pyrimidinetrione-2-thioxo-5-oxime faryl=2-ethylph enyl (D-o-EtPTO), 3-ethylpheny l (D-III-EtPTO) and 4-ethylphenyl (D-p-EtPTO)] at ionic st rength f..l=0.1O M NaCrO., and at different temperatures

H+

UO/+ Cu2+

Ni 2+

C02+

Pb2+

Zn2+

Cd2+

Mn2+

Mg2+

H+

UO/+ Cu2+

Ni 2+

C02+

Pb2+

Zn2+

C02+

Mn2+

Mg2+

H+

UO/+ Cu2+

Ni2+

C02+

Pb2+

Zn2+

C02+

Mn 2+ Mg2+

5.62

5.43 5.30 5.20 4.62

3.54 3.4 1

5.51

5.18 5.18 4.81 4.38

3.50 3. 14

5.44 5.14 5.05 4.32 4.08

2.55 2.33

D-o-EtPTO

4.33 5.14 4.19 4.35

4.73

4.44 4.64

3.26

log 1)2

9.76 10.44 9.39 8.97

3.54 3.41

5.18 9.91 4.81 4.38

3.50 3.14

9.58 9.69 4.33 7.34

2.55 2.53

0.39 0.02 0.Q2 0.02

0.00 0.00

0.03 0.04 0.03 0.00

0.00 0.00

0.23 0.33 0.03 0.00

0.00 0.00

D-m-EtPTO

Temp. 25 ± 0.5°C

6.00

5.89 5.87 5.81 4.54 4.43 3.61 3.43 2.98 3.00

5.14

5.36 4.18

3.99 3.59 2.31 2.24 1.29

11 .03 11 .23 9.99 8.53 8.02 5.92 5.67 4.27 3.00

Temp. 30 ± 0.5°C

5.93 5.33 5.63 5.59 4.55 4.27 3.41 3.18 2.80

5.96 5.20 4.69 3.54 3.42

2.35

11.29 10.83 10.28 8.09 7.69 3.41 3.18 5.15

Temp. 35 ± 0.5°C

5.88 5.30 5.35 5.24 4.49 4.18 2.76 2.76

5.58 4.85 4.74 7.1 I 3.46

10.88 10.20 9.98 7.60 7.64 2.76 2.26

0.50

0.00 0.02 0.04

0.07 0.00 0.00 0.00 0.00

0. 12

0.02 0.06 0.01 0.00 0.00 0.00 0.00

0.05 0.63 0.07 0.00 0.00 0.00 0.00

5.72 5.50 5.56 5.51 4.67 4.29 3.92 3.77 3.38

5.68 5.28 5.28

5.17 4.37

3.78 3.58 3.21 2.98

5.62 5.21 5.09 4.95 4.03 3.51 3.07

2.71 2.95

D-p-EtPTO

5.6 1 5.08 4.63

3.65 3.06

5.01 5.04 4.03 3.10 3.1 I 2.37 1.69 1.86

5.03 5.07 4.17 2.91 2.80

11.11 10.64 10.14 8.32 7.35 3.92 3.77 3.38

10.29

10.32 9.20 7.47 6.89 5.95 4.90 4.84

10.24 10. 16 9.12 6.94 6.31 3.07 2.71 2.95

0.02

0.06 0.01 0.01 0.00 0.00 0.00 0.00

0.01 0.00 0.02

0.00 0.00 0.00 0.00 0.00

0.12 0.02 0.00 0.05 0.00 0.00

0.00 0.00

SHARMA et at.: METAL COMPLEXES OF 1.3-D1ARYL-4.5.6-PYRIMID1NETRIONE-2-THIOXO-5-0XIME 1079

Table 2-Values of E, (Mn-Zn) and oH for complexes of D-m-EtPTO

log KOI ~F

~FR

~HH

~HL [(n-5/5))E,

oH

Mn2+

3.24 4.42

C02+

7. 14 9.73 5.31

43.00 48.31 19.50 28.81

Ni 2+

7.05 9.61 5. 19

62.00 67.19 29.25 37.94

Cu2+ Zn2+

6.72 4.53 9.17 6.18 4.74 1.75 63.00 47.00 67.74 48.75 39.00 48.75 28.74

Values of E, (Mn-Zn) and oH for complexes of D-p-EtPTO

Log KOI ~F

~FR

~HH

~HL [(n-5/5)) E,

oH

3.91 5.53

5.22 7.12 1.79

43.00 44.79 19.18 25.61

6.22 6.24 4.61 8.48 8.5 I 6.29 3.15 3.18 0.96

62.00 63.00 47 .00 65 .15 66.18 47 .96

28.78 38.37 47.96 36.37 27 .81

log KO I Thermodynamic stability constant values emoloyed for above calculations have been obtained by extrapolating the 10gKI vS.~lllinear plots to zero ionic strength

~F (kcal mor l) Free energy change on complexation. ~F = 2.303 RT log KOb where R. T & log KO I have their

usual significance and at T = 298K Free energy change relative to Mn2+. ~FR (kcal mor l

)

~HH (kcal mor l)

~Hdkcal mor l)

Heat of hydration of metal ions relative to Mn2+; Heat of Complexation referred to the metal ion in gaseous state and ligand in solution state. relative to value of Mn2+. number of electrons in 3d orbital. n

[(n-5/5))E, oH (kcal mor l

)

Lattice energy difference of Zn2+ and Mn2+ complexes.

Thermodynamic stabilisation energy(CFSE).

Results and Discussion

Prolonation constants of ligands The protonation constants of ligands and stability

constants of the complexes are given in Table 1. In the present study, it was noted that the protonation constants (PKa) follow the order: meta > para > ortllo. Singh et al .11 have made similar observations in the comparative study of the stability of Fe(lI) complexes with (0. m and p)-ditolyl thiovioluric acids (experiments performed spectrophotometrically).

The order of the basic strength of three diethyl thiovioluric acids still remains to be explained. It can be noted that generally the variation in the acid dissociation constants of aromatic ligands containing a dissociable proton is due to a combination of factors such as electronic effect of substitution (inductive effect of the alkyl substituent), steric effect (discussed using molecular modeling studies), the acidity of the solution, the stability of anionic species formed after the loss of proton25

. It is interesting to note that Roberts et aL?6 found that the ionic strength of

substituted anilines was influenced to a great extent when the substituent was present in the nearer mela position, than in the more distant para position. The inductive effect of a substituent group on an aromatic ring appears to be best regarded as falling off smoothly with distance. The present order is in accordance with the above view but for the ortllo derivative. This anomaly can be best explained by considering the enol form of orlllo-ethyl derivative I(b) where the negative change on the oxygen is stabilised by hydrogen bonding with the methylene protons of the ethyl group.

The stabilisation of the resultant anion therefore leads to decrease in pKa. This kind of stabilization of the anion will not be observed in the cases of meta and para derivatives due to increased spatial distance between ethyl protons and oxygen. Also, examples are found in the literature where the orlho derivative shows anomalous behavior as in the case of methyl anilines e.g., pKa of a-methyl anilines is less than those of l1l-and p-anilines27

• Also, irrespective of whether the group is ±I or ±R, nearly all orlllO

Ia Ib

substituted benzoic acids are stronger than benzoic acid28

. Molecular modeling studies reveal that the energy (global minimum) of the or/lIo ethyl derivative is max imum viz. 52.74 kcal morlas compared to meta ethyl derivative 30.31 kcal mor l and para ethyl derivative 28.57 kcal mor l thereby indicating maximum molecular strain in the or/ho isomer. and least in para isomer.

Stability cOllstants of complexes

From the examination of the reported data, in general , it is observed that the stability constants of the complexes (log K) of the ethyl-substituted ligands, with the same metal ion follow the same order as the proton ligand stability constants of the ligands i.e., lIIeta > para> ortho. The results are consistent with literature data I I on the corresponding methyl derivatives. This may be attributed to the different bas icities of the donor atoms of the ligands caused by the inductive substituent effects as discussed earlier. The low stability constant values of the ortho derivative can be attributed to the possible distortion of the chelate ring from its near planar structure (which is necessary for complete resonance) by the free rotation of the N-aryl substituent. Such kind of steric hindrance win thus lead to reduced stability of the chelate [1I(a) & lI(b)]. Molecular modeling stud ies carried out on the copper complexes of the ortho, meta and para derivative for energy minimi­zation (global minimum) show that the ortllo complexes have maximum energy i.e. 31.10 kcal marl followed by meta 30.80 kcal mor l and is least for para 30.22 kcal mOrl. The lower stability of the ortllO complex is thus explained. While the maximum stability for the meta derivative results from the net effect of two competing factors in opposite directions viz. inductive effect and steric effect (molecular modeling) i.e., the inductive effect falling off with distance whilst steric strain being reduced from ortho to para. The maximum stability constant for the meta-

substituted derivatives of salicylaldehyde and 8-hydroxyquinoline have been reported earlier29.

A linear relation between the logarithms of stability constants of a series of 1: 1 complexes M L, deri ved from one metal , M , with a set of simi lar ligands and the logarithms of the acid dissociation constant has also been suggested30

.3 1

, and such a li nearity has been observed in the present studies.

Order of stability constallt It has been noted that the values of acid

dissociation constant (PKa) and stability constants decrease with increasing temperature of the medium and with increasing acidity of metal ions. The order of stability constants (log K I ) of the three ethylphenyl derivatives with bivalent metal ions is found to be UO/+ > Cu2+ >Ni 2+ > C02+ > Pb2+ > Zn2+ > Cd2+ > Mn2+ > Mg2+.

The order IS 111 good agreement with the order found by Mellor and Malei2 and Irving and Williams33

.34 for complexes of ligands having O/N

donors. The decrease in stability with increasing temperature is in accordance wi th the result of

Pitzer35• The log KI, log K2 , log ~2 and Smin values at

different temperatures are given in Table I. In most of the cases, the value of log KI is greater than that of log K2, which is shown in the format ion curves (plots of nand pL), of various metal complexes of ethylphenyl derivative [at Jl= 0.1 M NaCI04 and at a temperature of 25 ± 0.5°C].

The regularity in stability constants can be correlated with a monotonic decrease in ionic radii and a monotonic increase in the second ionisation energy, which in passing from Mn to Cu, may be taken to indicate that either the coordination has not altered the electronic ground state of the metal ions or that any modifications are of secondary importance. For these chelates, n values greater than 2.0 have not been obtained. We, therefore, conclude that not more

SHARMA et al.: METAL COMPLEXES OF 1,3-DIARYL-4,5,6-PYRIMIDINETRIONE-2-THIOXO-5-0X IME 1081

Table 3--Thermodynamic parameters of bivalent metal complexes of D-o-EtPTO, D-m-EtPTO and D-p-EtPTO

11= 0. 10 M NaCI0 4 ; Temp. = 25 ±0.5°C

D-o-EtPTO

-6.G -6.H 6.S -6.G kcal mor l kcal mor l cal K"I mor l kcal mor l

U02 30.98 0.05 103.79 33.61 Cu 30.24 0.04 101.34 33.26 Ni 29.67 0. 16 99.02 37.15 Co 27.00 0. 11 90.23 26.42 Pb 25.28 Zn 20.20 0.18 67.18 20.54 Cd 19.40 0.09 64.79 19.57 Mn 17.00

than two chelates, 1: I and 1:2 (M:L) species are found in each system. Further, in view of the very low (5 x 10'4 M) concentration of metal ions used in the titration, it has been assumed that the possibi lity of formation of polynuclear complexes is negligible.

The thermodynamic parameters (!1G, !1H and !1S) were calculated using the relationships.

!1G= -RT In K

d (log K) / d (l/T)= -!1H 12.303R !1S=(!1H-!1G)/T

The overall free energy change, and the enthalpy and entropy changes at 25±0.50°C are reported in Table 3. The negative free energy change in each case indicates that the chelation is spontaneous. The change in entropy upon complexation is related both to changes in number of particles in the system and in mode of vibration of particles in the system.

Acknowledgement The authors, Parvesh Sharma thank the UGC, New

Delhi and Bablu Swaika and Sachin Mittal thank CSIR, New Delhi for awarding NET fellowship.

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