Indian Journal of ChemistryVol. 17A, May 1979, pp, 456-460

Substitution Reactions of Au(III)-Nuc1eoside/Nuc1eotide Complexes InNon-aqueous Medium

D. CHATTERJI*j ~ S. K. PODDER.Department of Inorganic & Physical Chemistry and Department of Biochemistry, Indian Institute of SCience,

Bangalore 560012

Received 15 April 1978; revised and accepted 6 November 1978

A series of complexes of Au(III) with nucleosides and nuc1eotides in different stoichiometryhas been prepared and the rate of substitution of halide ions in these complexes measured inDMSO-methanol mixture (1: 9, v/v) at 250

• Substitution generally takes place in a stepwise'manner, as revealed by the change in absorbance at 490 nm, The observed pseudo-first orderrate constants obey two terms rate law found for other square planar dB systems. With (1: 1)Au(III)-guanosine, and (1: 1) Au-(III)-nucleotide complexes halide substitution can be describedby two time constants, indicating that both guanosine and nucleotldes act as bidentate Iigands.The logarithm of the ratio of different rate constants are correlated to pKa values of the groupsinvolved in coordination.

ITis well known that square planar complexes ofthe heavier transition metals with dS electronicconfigurations undergo ligand substitution (Eq. 1)

MLaX+ Y-+MLaY +X ••. (1)with it the kinetics of obeying a general rate lawof the form (2)

Rate = k1[complexJ+k2[complexJ[yJ ••.(2)

.A la-rge volume of literature suggestsv- stronglythat the kl path involves a slow bimolecular sub-stitution of X by a solvent molecule S, with theresulting solvent containing complex reacting rapidlywith Y. So far, the main emphasis has been onthe' Pt(II), Pd(II), and Ni(U) complexes, typicalat dS systems.

Au(III) complexes as a substrate for substitutionreactions are subject of interest for many years,though these have not been well studied like Pt (II)complexes mainly because of high reactivity ofAu(III) species". Cattalini and Tobe have describedthe reaction of AuC14 with pyridine, quinoline andtheir derivatives and that of AuClgAm (Am = aheterocyclic base) with halides+ They observedthat the bimolecular nucleophilic substitution isthe major pathway for the halide, substitution reo.action in the complexes of Au(III) with heterocyclicbases. We have prepared a series of complexesof Au(III) with nucleosides and nucleotides whichare heterocyclic base derivatives and monomericconstituents of nucleic acids. These complexeswere characterized by IR and NMR spectroscopictechniques as well as by elemental analysis''. Allthe nucleotides form a bidentate type of chelationthrough phosphate and base ring nitrogen withAu (III) whereas nucleosides behave either as uni-

+Present address: School rof Li£e~Sciences, University ofHyderabad, Hyderabad 500001.

456

1"

(

~entate or as bidentat.e depending on the type ofligand used and the ratio of metal to ligand. How-e~er, the preparation of the complexes is verydifficult unless the acid concentration in the mediumis extremely low. These observations led us tostudy the kinetics of halide substitution in Au(III)-nucleoside/nucleotide complexes. In contrast tothe observation of Cattalini and Tobe+, in thereplacement of nucleoside/nucleotide by halide,solvent dependent path contributes significantlyand is acid-catalysed.

Materials and MethodsComplexes of Au (III) with nuc1eosides and

nu~le~tides were synthesized according to the desiredstoichiometry and characterized as described pre-viously>,

Kinetic studies - The rate of substitution ofnucleosidejnucleorirls by halide ion in the presenceof acid was measured following the absorbancechange at 490 nm with time. This was done as -follow~: soluti?n (0·1 ml) of the complex in DMSOwas diluted ~lth methanol (0'9 ml) containing 1MNaCI04 at different concentrations of NaCl. Theionic strength of the medium was kept constantand the final absorbance of the solution was between0'5 and 1·0.. Spectral changes if any could not bedetected within. 10-15 min. The reaction was.tri~gered ?y adding 10-15 (1.1 of O'l-lM perchloricacid solution In methanol. The time dependentchange in A490 was recorded. There from thepseudo-first order rate constant of substitution·for the runs having both [H+] and [Cl-J in excesswas analysed, Pseudo-first order, rate constants,kij of the i-+j substitution step were calculatedfrom the relation (1)

ex = "J:.a'je-kijt

where aij is a constant... (1)

characteristic of each step

\

CHATTERJI & PODDER: REPLACEMENT OF NUCLEOSIDE/NUCLEOTIDE BY HALIDE

and is composed of molar extinction coefficientetc., and ex the fraction remaining _is defined asex=Ao-AdAo-A", where Ao' At, A", are absorbancesat time zero, t, and at infinity. In cases wherethe initial and final values were not known the rateconstants were calculated from the changes inabsorbance ~A during time interval ~t accordingto Guggenheim methods, Both the methods gaveidentical results within experimental errors.

ResultsIR and NMR data of complexes precipitated

from aqueous and DMSO solutions were identicalsuggesting that DMSO was not complexed withAu(III)5. Elemental analysis of the complex sug-gests that the present study refers to a reactionof the type

Cl-[Au(III)N"Clx] -7 [Au(III)N;;-_l Clx+1J+N

where 'N' denotes a nucleotide or a nucleoside andthe rate of substitution of 'N' is very much depen-dent on whether it acts as a bidentate or unidentateligand. The charge of the species [Au (III) (N)n]would vary depending wh=ther a proton is releasedor not. The study of the interaction of Au(III)with DNA suggests that one proton is released permole of Au(III) cornplexed".

Fig. 1 shows the change in absorbance at 490 nmwhen a small amount of perchloric acid ('" 10-3M)is added to a solution of 1:4 gold (III)-guano-sine complex in 1 :9 DMSO-methanol (vjv) containing1M NaCl04 and 10-2M NaCl. At low [H+] (10-3M)and [Au(III)] (10-3M) the reaction goes to comple-tion when kept overnight in the presence of.excessCl" ion. But at high [H+] (10-2M) initial phase ofthe substitution reaction is too fast to be measuredby Cary 14 spectrophotometer (shown in Fig. 1).However, absorbance value at infinite time alwayscorresponds to that of AuCl:i. In the 1:4 complexof Au(III)-guanosine, the ligand can take four cornerpositions of the square planar geometry of Au(III),each one of which is being replaced consecutively

(;!,)

0-7

0-6C-3

00-5

'"~« 0-4C.2C~---1~----'2'------!:---I

Time In minutes

0-3

0·2

0-1~ ..L... '-- -'- ""'"o 234

Time in hours

Fig. 1 - Change in absorbance at 490 nm and 25° withtime due to the stepwise substitution of Cl> ion in (1: 4)Au(III)-guanosine complex (a) [Au(IIl)] = 9-2 X 10-4M,[H+] = 9-9 X 10-4M, [CI-] = 4·45 X 10-2M. (b) [Au(Ill)]= 9'8 X 10-4M, [H+] = 1·71 X 10-2M, [Cl-] = 1'95 X 10-2M]

I

_by incoming Cl- ion, designated as 0~1, 1~2, 2~3.and 3~4 steps as shown in Scheme 1.

[Au(III) G.] +CI--+[Au(III)G3CI] +G ... (0-+1)[Au(III)G3Cl] + Cl--+[Au(III) G2Cl2] +G .. (1-+2)[Au(IIl)G2CI.] + Ct--+[Au(II I)GC13]+G (2....•..3)[Au(III)GC13] +CI-_[Au(III)CI.]- +G (3-+4)

Scheme 1/

The total charge on the various intermediatesdepends on the nature of coordinating atom andthe type of coordination. However, each inter-mediate species involved in this reaction schemecan be prepared very easily and each one of themhas different exti~ction value as expected. Whenthe total change III absorbance from zero time toinfinite time was divided into four different rangesit has, been observed that each range of valu~corr~sponds to t.he extinction of a particular inter-mediate depending on the extent of substitution.Therefore, assuming a linear relationship betweenthe extent of substitution and absorbance changepseudo-first order rate constant (under conditionwhere concentration of both Cl" and H+ Was 10-15fold in excess) was calculated either by Guggenheimplot or extent of reaction plot. Both these methodsgive identical br:aks in the curve indicating thepresence of a senes of consecutive reactions havingdifferent rate constants (not shown). However, these~reaks als? sugge~t that .the substitution takes placeIII a stepwise fashIOn: Similarly, for the replacementof a~l other nucleosides and nucleotides by Cl" orBe IOns from Au(III) complexes, stepwise reactionstake place. At high acid concentration 0~1 and~~2 substitutions in Au (III) complexes by halideions a.re too fast to be measured by this experimental!echmque. Based on the assumption that changesm absorbance at 490 nm are linear with the extentof the reaction over the entire range of substitution,the. calculate.d ra~e constant from the slope ofsemilog plot IS assigned to a particular substitutionaccording to the range of values of absobance used inthe semilog plot. Table 1 summarizes all the values.of rate constants for various steps of substitutionof Cl- and Be ions in different Au(III) complexes.

DiscussionIt has been observed that the replacement of

guanosine, 5'-dGMP, 5'-dCMP and 5'-dAMP from~:1 comple~es of Au(III) by ci- ion takes placeIII a, stepWl?e manner. This confirms very wellthat two-point attachments are involved in 1:1complexes as also suggested by our spectroscopicresults", In the case of two-point attachment,the rat~ constant corresponding to the first phaseof reaction may be referred to as 2~3 substitution.It is seen from the Figs. 2 and 3 and Table 1 thatkobs is given by k1[H+]+k2[Cl-] and k1[H+]+k2[H+J[Be].' All the values of kl and k2 are summarizedin Table 2.

It should be kept in mind that the analysis ofthe first order rate constant data (kobs) has beendone here in accordance with the rate equationavailable in the literature for other square planarcomplexes. It has been mentioned earlier that

457

INDIAN J. CHEM., VOL. 17A, MAY 1979

TABLE 1 - RATE CONSTANTSOF THE REACTION OFCHLORIDEION/BROMIDE ION WITH DIFFERENT Au (III)

COMPLEXESIN 1: 9 DMSO-CH.oH MIxTURE ('1/'1)CONTAINING1M NaClO, AT 25°

TABLE 1 - RATE CONSTANTSOF THE REACTION OFCHLORIDE ION/BROMIDE ION WITH DIFFERENT Au (III)

COMPLEXESIN 1-:9 DMSO-CH30H MJXTURE (v/v)CONTAINING1M NaCl04 AT 25° - contd

[Complexl [H+] X 103 [Cl-] X 10' kobs X 103 Type of [Complex] [H+] X 103 [Cl-] X 102 kobs X 103 Type ofM M M (sec-l) substi- M M M (sec-l) substi-

tution tution

Au (III)-GUANOSJNE (r = 0'25)* r· Au(III)-CYTIDINE (r =0'5)

9'8 X 10-4 17'1 0·98 7'9 l'96xl0-3 2·44 0·99 2·21·95 9'2 2~3 1·99 3'1 2~34'39 12-0 4'39 5'5

9'9 X 10-4 6·9 0'99 3·7 1·96 X 10-3 6·90 0'99 4·21'98 5·2 2~3 1·99 5·2 2~34·45 7'9 4'39 7'6

9'8x 10-' 11·0 0·99 5'5 l'96xl0-3 17·10 0'98 9·02·02 6·9 2~3 1·98 10·1 2~33'96 8·9 4·45 12'5

Au(III)-GUANOSINE (r = 0'25) Au(III)-5'-dCMP (r = l)t

9·8 X 10-:-4- 1·3 0·99 4·2 l'33xl0-3 1'80 0·99 4·21'99 6·6 1~2 - 1·99 6-0 2~3t4-45 13-0 4-45 10-3

9-8 X 10-4 2-44 0-98 4'9 1-33 X 10-3 2-44 0-99 5-01·95 7-4 1~2 1·99 6'8 2-+3t4-39 13-4 4-54 11-2

9-9x 10-4 6-99 0-99 9-4 l'33xl0-3 - 6-99 0'98 10-91-98 11'-8 1~2 1-98 12-6 2~3t4-39 18-0 4-39 17-0

Au(III)-GUANOSINE (r = 1) Au(IU)-GUANOSINE (r = 0-25)[Br-] X 102 M

1-96 X 10-3 2-44 0-98 1-62-44 3-0 2~3t 9_-8X 10-4 2·4 0-49 6-8

, 4-39 4-9 0·66 9-0 2-+31-96 X 10-3 17-10 0·98 5-2 0-98 12-7

2-44 6-7 2~3t 9-9 X 10-4 0-99 0-49 2-54·39 8-6 0-99 4-7 2~3

1·96.x 10-3 6-90 0-99 2-7 2-44 10-91-99 3-6 2-t3t·· 9-9 X 10-4 1-5 0-49 4-84'45 6-2 0'66 6'3 . 2~3

0-98 9-0Au(III)-5' -dGMP (r = 1)t

*r = Au(III)/nucleoside or nucleotide.

4-6x 10-' 2·44 0-49 4-2 t5'-dAMP = 2'-deoxyadenosine-5'-monophosphoric acid.1-46 6-1 2~3t 5-dGMP = 2'-deoxyguanosine-5'-monophosphoric acid.2-44 8-0 5'-dCMP = 2'-deoxycytidine-5'-monophosphoric acid.

4-6x 10-' 4-6Q 0-49· 7-0 tAssuming the formation of a 1: 1 bidentate type of1-46 8·9 2~3t complex, the first halide substitution is equivalent to 2~32·44 10-9 SUbstitution as other positions are already blocked by

4·6x 10-' 6'90 0-49 10·0 halide or hydroxyl ions. .1-46 11·9 2~Jt.2·44 13-8

.8'8 X 10-4 •

Au(III)-ADENOSINE (r = 0'33)

. 4-74 4'30 3-13'38 2-62·38 H

43-5 3-91 10-73·04 10-22-17 9-8

24'4 3-42 6-62-44 6-11'82 5'8

Au(III)-5' -dAMper = l)t

11'0 3'30 18'52-75 17-51-82 16-0

6'90 3-02 13·12·75 12-6 -1-82 11·2

1·7 3·57 7-72·90 6·62-22 5-6

the ligand substitution rate in square planar com-plexes obeys the general Eq. (3)Rate = k1[complex]+k2[complex][Y] ... (3)where Y is a substituting ligand. In our case, Figs.2 and 3 show that kl path is acid-catalysed andrate' equation follows the general rate law. Fromthe data in Tables 1 and 2 the following generali-zation can be made.

(a) The overall rate of substitution can beexpressed by a two..term .rate law: (i) a solvent de-pendent+path.t'which is acid-catalysed as observedwith-some -Pd(II} complexes", -and independentof the concentration of the ligand and (ii), ligandconcentration dependent path. In most of thecases of substitution in square planar complexesthe solvent dependent path is governed by SNImechanism and ligand concentration dependentpath is governed by SN2 mechanismv".

1'33 X 10-3

:8'8 x 10-'

8'4 x 10-4

5 X 10-'

458

«

CHATTERJI & PODDER: REPLACEMENT OF NUCLEOSIDE/NUC:LEOTIDE BY HALIDE,

Complex

TABLE 2 - RATE CONSTANTS FOR SUBSTITUTION OF HALIDES IN COMPLEXES

Atoms/groups- involved incoordination

Type of kl (see-I) _ka (M-I see-I)substitution

1--2 (CI-) 1-00 0·252--3 (Cl-) 0-40 0·122--3 (Br-) 0·41 1·20 ([H+] = 2'4xl0-3M)

0·41 0'85 ([H>]'= 1·50xl0-3M)0'41;;. 0'43 ([H+] =; 0'99 x 10-3M)

2--3 (Cl-) 0·25 0'102--3 (CI-) 1'30 0·20

2--3 (C1-) 0'20 0'052--3 (CI-) 1·20 0'16

2-+3 (CI-) 0;47 0'102-+3 (Cl") 1'30 0'18

Au(III)-guanosine (r =0'25)

Au(III)-guanosine (r = 1)Au(III)-5'-dGMP (r = 1)

Au(III)-adenosine (r = 0.33)Au(III)-5'-dAMP (r = 1)

Au(II Ij-cyfidine (y = O:5)Au(III)-5'-dCMP (r = 1)

C6 = 0 and N7N7and oxygen of phosphate

C6-NH2N, and oxygen of phosphate

NlN1and oxygen of phosphate

M:0 so><..a.~ 2-5•...c

15

x 10<II.0o

5

O~ ~ ~ -L ~ ~a 2 3 4 5

[CI]Xl02M

Fig. 2 - Dependence of kobs on [H>J for substitution of CI-ion in 2-+3 step of Au(III)-guanosine (r = 0'25) [Insetshows the evaluation of kl from the value of intercept.(1) [H>] =(17'1 x 10-3M; (2) [H+]= 11 X 10-3M; and (3) [H+]

= 6'9 X 10-3M]

8><~ 1'0•.u! 0-5c:

i2 o..,~ 10x

<II.0 8o~

6

4

2-00·5 1·0 1·5( Br-]X102M

Fig. 3 - Dependence of kobs on [H>]IJor the substitution ofBr- ion in 2--3 step of Au(III)-guanosine (r = 0'~5) [Insetshows the evaluation of k, from the value of mtercept.(1) [H+] = 2'4 X 10-3M; (2) [R>] = 1'5 X 10-3M; and (3) [H+]

= 0'99 X 1O-3M]

(

(b) The rate of entry of Be is faster and catalysedby H+ as observed in some Pt(II) complexese, Butthe values of kl' i.e, rate constant for acid-catalysed,solvent substitution remains constant for bothCl" ion and Be ions as expected.

(c) The values of kl and k2 differ among them-selves and depend on (i) type of substitution, and(ii) nature of coordinating atom.

The data reported in the literature show thatthe value of k2 is higher than kl in most of the cases",But in our case relative values of kl and k2 forany particular complex towards Cl: ion substi-tution show the opposite trend or in other wordskl>k2' i.e. acid-catalysed solvent substitution isthe predominant path. Because of this it is verydifficult to prepare Au(III)-nucleic acid complexesunless acid concentration is very low in the medium.

Finally, it is worthwhile to discuss the differencesin kl and k2 values in terms of structure, i.e. siteof coordination and stability of the complexes.Ligand substitution step being governed by SN2mechanism will .no~ ?e influenced by nonleavinggroup and also It IS independent of the nature ofthe solvent. Whereas, the kl pathway of substitu-tion will depend both on the nature of non-leavinggroup and solvent. The observation that theapparent rate by SN1 mechanism depends linearlyon [H"] suggests that unless bases are protonatedvery stable complexes are formed. It is clearlyevident from these results that kl for 2--+3 substitu-tion reaction by Cl" and Be is found to be same-whereas kl for 1--+2 substitution differs from thatof 2--+3 by a factor of 2·5. Similarly kl and k'!;.values for other complexes are significantly differentfrom each other; an increase in kl is concomitantwith the increase in k2 (Table 2).

The values of log k2/kl which are a measure of:the relative free energy of activations, have beenplotted against the PKa of the leaving nucleoside/nucleotide taking second ionization constant ofphosphoric acid. The nature of the curve is ingood agreement with that obtained for otheramines- (Fig. 4). Such a free energy relationship?et~een kinetic a~d equilibrium properties clearlyindicates a correlation between the rate of reactionand the strength of the gold-nitrogen bond. If

2·5

,\

INDIAN J. CBEM., VOL. 17A, M.AY 1979

1'0

0·6

0'4.x~'".x

0'2

a·'1 2 3 4 5 6 7

pKaFig. 4 - Variation of log k2/kl with pKa of coordinatinggroups in 2->-3 substitution by chloride ion [(1) Au(III)-guanosine (r = 0'25); (2) Au(III)-adenosine (r = 0'33);(3) Au(III)-cytidine (r = 0'5); and (4) Au(III)-nucleotide

(r = 1)]

kl and k2 values be taken as a measure of the stabilityof the complexes, data suggest that Au(III)-phosphate bond through oxygen is more labile thanthat between Au (III) and any of the ring nitrogenof nucleotides as one would expect. Attemptsto extend this relation alone with complexes of7-methylg'uanosine, inosine and thymidine werenot successful. There compounds isolated from

460

(

aqueous medium by alcohol precipitation werefound to be extremely unstable in DMSO. IR datasuggest that groups having PKa 7·1 and 8·2 areinvolved in complexation for 7-methylguanosineand inosine respectively", This again suggests k] >k

2•

The same conclusion can also be extended tothymidine.

It should be kept in mind that this observeddifference in k .values could also be partly due tocis and trans effect on the rate of substitution'.

References1. BASALO, F" Adv, Chent. s». 49 (1965), 81.2. ~L-\RTI:-<, D. S,' Inorg. chim, Acta Reviews, 1 (1967),

87,3. CATTALI:-<I, L., Progress in inorganic chelnistry, Vol. 13,

edited by J, 0, Edwards (Interscience, New York),1970, p. 263.

4. CATTALINI, L. & TOBE, M. L., Inorg, Chem., 5 (1966),1145.

5. CHATTERJI, D" NANDI, U. S. & PODDER, S. K, Bio-polymers, 16 (1977), 1863.

6. GUGGENHEIM, E. A., Phil. ivfag., 2 (1926), 538,7. PILLAI, C. K S. & NANDI, U. S., Biopolymers, 6 (1973),

1431.8. POE, A. J. & VAUGHAN, D. H., Lnorg: chim, Acta, 1 (1967),

255.

,