Inorganica Chimica Acta 418 (2014) 119–125

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Inorganica Chimica Acta

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Mediated kinetic medium effect in the reactionof bis-3,5-di-iso-propylsalicylatozinc(II) with tert-butylperoxyl radicals

http://dx.doi.org/10.1016/j.ica.2014.04.0240020-1693/� 2014 Elsevier B.V. All rights reserved.

⇑ Corresponding author. Tel.: +374 10 281 481; fax: +374 10 297 309.E-mail address: tavadyan@ichph.sci.am (L.A. Tavadyan).

Levon A. Tavadyan a,⇑, Makich Musaelyan a, Seyran H. Minasyan a, Frederick T. Greenaway b

a Institute of Chemical Physics, National Academy of Sciences, Republic of Armenia, 5/2 P. Sevak Street, Yerevan 375014, Armeniab Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St, Worcester, MA 01610-1477, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 January 2014Received in revised form 20 March 2014Accepted 15 April 2014Available online 30 April 2014

Keywords:bis-3,5-Di-iso-propylsalicylatozinc(II)DPVEPRAnti-radical activityHydrogen bondingMediated kinetic solvent (medium) effect

Absolute rate constants for the reaction of ZnII(3,5-di-iso-propylsalicylate)2 with tert-butylperoxyl radi-cals were determined by means of kinetic electron paramagnetic resonance measurements at �31.5 �Cin 10% (v/v) chlorobenzene in hexane, as well as with addition of approximately equivalent amountsof the Lewis base dimethylsulfoxide (DMSO). Differential pulse voltammetry was used to determinethe redox behavior of this chelate with different amounts of DMSO in a CH2Cl2 medium at 25 �C. A goodcorrelation was observed between the kinetic effect of the DMSO on the antiperoxyl radical reactivity ofthe zinc complex, which is due to transfer of a hydrogen atom from the ligand, and the redox behavior.These also correlated with changes in the 1H NMR and FTIR spectra of the chelate in these media. A med-iated kinetic medium (solvent) effect (MKME or MKSE) for DMSO has been established. The essence isthat electron pair donors such as DMSO at molar equivalent quantities do not directly impede the reac-tion center of radical scavenging (hydrogen atoms of salicylic OH groups that are not involved in intra-molecular hydrogen bonding), but act indirectly by bonding axially to the zinc, which changes thecoordination geometry in such a way as to increase intramolecular hydrogen bonding within the coordi-nated ligand and thus considerably diminish the fraction of OH groups available to transfer a hydrogenatom. As a result, the antiperoxyl radical H-atom donating reactivity of ZnII(3,5-di-iso-propylsalicylate)2

decreases upon coordination of DMSO.� 2014 Elsevier B.V. All rights reserved.

1. Introduction

Phenolic compounds can trap free radicals by donating ahydrogen atom. In this way they can regulate important chainperoxidation processes in lipid membranes, where peroxyl radicalsact as chain carriers. Similar reactions occur in various degenera-tive human diseases related to oxidative stress, a topic that hasattracted considerable interest [1–4]. It is precisely these reactionsthat have shown dramatic kinetic solvent (medium) effects (KSE orKME) in phenolic antioxidant activity [5–18]. The effect of a sol-vent is expressed through its electron donor impact on the reactivecenter of the phenol, viz., the phenolic hydroxyl group, and doesnot influence the reactivity of the abstracting radical [5,9]. Accord-ingly, experimentally detected effects of the solvent do not dependon the nature of the free radicals. The magnitude of the KSE isdetermined by hydrogen bonding between a substrate, XOH,representing a hydrogen bond donor (HBD), and a Lewis base,which is a hydrogen bond acceptor (HBA).

The influence of intermolecular hydrogen bonding onantiradical reactivity of phenolic antioxidants has been reportedin detail [5–18], including research on the mechanism of suchinfluences in elementary reactions of antioxidant phenolic com-pounds with chain carriers in lipid peroxidation reactions: peroxyl[9,11], alkoxyl and DPPH radicals [5–7,9–18]. Essentially, Lewisbase compounds considerably decrease the H-atom donatingactivity of various classes of antioxidants, which leads to adecrease in antioxidant activity during free-radical chain peroxida-tion of lipids [1–4].

The H-atom abstraction from a substrate by a free-radical (r�)taking into account the KSE may be represented by the followingscheme:

XOHþ : S)*XOH . . . SXOHþ r����!XO� þ rH

where :S is the HBA solvent.According to this scheme, which describes the experimental

data well, H-atom transfer is from the ‘‘free’’ substrate, XOH, andhydrogen bonding with a Lewis base solvent eliminates this

120 L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125

[8–18]. The higher the value of Kinter-HB, i.e., the stronger the Lewisbase solvent, the more dramatic is the kinetic solvent effect.

It should be noted that the reaction medium can influence thereaction rate of molecules with radicals without a direct strongintermolecular interaction between the medium and the reactioncenter, by influencing the reaction center indirectly. In this case aMKME is manifested. As shown in [10] the value of the absoluterate constant of the H-atom transfer reaction of peroxyl radicalswith amines decreases and increases in the presence of electro-philic and nucleophilic solvents, respectively. The kinetic effect ofsuch solvents is not a result of direct interaction with the reactioncenter, which is the H-atom of the C–H bond a to the heteroatom,but is manifested in the following manner. Electrophilic solventsinteract with the lone electron pair of the nitrogen atom, whilenucleophilic solvents interact with the amine hydrogen atom, thusinfluencing the electron-donor properties of the lone electron pairof the nitrogen atom, which in turn affects H-atom abstractionfrom the a-C–H bond of the amine.

tert-butylOO + H C R2

N

R1

R3H

tert-butylOOH + C R2

N

R1

R3H

A mediated kinetic medium effect was also observed in the reac-tions of para-substituted benzaldehydes with peroxyl radicals [10].Electrophilic solvents do not exhibit a direct kinetic effect on theC–H bond of an aldehyde participating in H-transfer reaction, butshow a MKME as a result of hydrogen bond formation with the lonepair of the heteroatom of the para-substituent, which considerablydecreases its electron-donor properties, thus indirectly decreasingthe hydrogen-donating ability of the aldehyde C–H bond.

Sorenson et al. have established that the lipophilic complex bis-3,5-diisopropylsalicylatozinc(II), ZnII(3,5-DIPS)2, and its solvatesdemonstrate anticonvulsant activity, as well as radioprotective,radiorecovery and antiinflammatory activities in animal models[19–23]. This observed biological activity of ZnII(3,5-DIPS)2 maybe related, at least in part, to its ability to react with peroxyl radi-cals generated in vivo. We hypothesize that ZnII(3,5-DIPS)2, byanalogy with substituted CuII and FeIII salicylates [11,24], will actas an antioxidant, scavenging peroxyl radicals by means of H-atomdonation by the OH groups of the 3,5-DIPS ligand.

It has also been shown experimentally that an axially coordi-nated Lewis base such as dimethylsulfoxide (DMSO) or ethylacetate leads to strengthening of the intramolecular hydrogenbonding between the salicylic OH hydrogen atom and a carboxyl-ate oxygen of the 3,5-DIPS ligand [25]. For this reason we expectthat Lewis base compounds present in drugs and in vivo can con-siderably influence the antioxidant activity of ZnII(3,5-DIPS)2.

It is of interest to identify the mechanism of the kinetic mediumeffect of Lewis bases for ZnII(DIPS)2, for which the H-atom donatingantiradical center is in the ligand of the complex. The main objec-tive of this research was to perform direct kinetic measurementsusing electron paramagnetic resonance (EPR) for reactions of tert-butylOO� with ZnII(DIPS)2 in non-polar lipophilic organic mediawith and without the addition of the strong Lewis base, DMSO.The interest in DMSO is additionally conditioned by the fact thatit is used as an efficient transporting agent for drugs and as a cryo-protectant [26].

Comparing kinetic data with the results obtained by differentialpulse voltammetry (DPV) and the data on 1H NMR and Fouriertransform infrared (FTIR) obtained previously [25]. we have clari-fied the mechanism of the kinetic solvent effect of Lewis bases suchas DMSO on the antiperoxyl radical activity of ZnII(3,5-DIPS)2 che-lates, as well as revealing the surprising effect of comparativelylow concentrations of Lewis bases on the radical scavenging abilityof the phenolic OH group present in the chelated 3,5-DIPS ligand.

2. Experimental

2.1. Materials

Heptane, chlorobenzene, DMSO and methylene chloride, werepurchased from Sigma–Aldrich Chemical Company (99.9% HMLCgrade) and purified according to known procedures [27]. Beforethese compounds were used, they were passed over a column ofactivated Al2O3. Azo-tert-butane (98%) was purchased fromSigma–Aldrich Chemical Company and tert-butylhydroperoxide(tert-butylOOH) was 99% pure and used without further purification.

bis-3,5-Di-iso-propylsalicylatozinc(II) was synthesized asdescribed elsewhere [19]. The hydrate was dried at 323 K and15 mmHg for 16 h before it was used. Acetonitrile (MeCN, 99.9%HPLC grade), tetra-butylammonium perchlorate (TBAP) and silvernitrate (AgNO3) were purchased from Aldrich.

2.2. Kinetic EPR measurements

Tert-butylOO� was generated by 300–450 nm photolysis of 10�3

to 10�2 M solutions of azo-tert-butane in 10% (v/v) chlorobenzenein heptane. Photolytic cleavage of the two C–N single bonds ofazo-tert-butane yields tert-butylOO� as shown below:

tert-butylAN ¼ NAtert-butyl! 2tert-butyl� þ N2

tert-butyl� þ O2 ! tert-butylOO�

Methods of kinetic EPR measurements with pulsed reagentintroduction are described in detail elsewhere [9–11]. This methodis based on the continuous temporal determination of free radicalconcentration changes as a result of their reactions with antioxi-dant (AO). Measurements of absolute rate constants for the reactionof tert-butylOO� with the bis-3,5-di-iso-propylsalicylatozinc(II)were performed at �31.5 �C. Kinetics of tert-butylOO� consumptionwere recorded using an EPR-B spectrometer (Institute of ChemicalPhysics, Moscow, Russia) operating at 9.4 GHz with 100-kHz mod-ulation. Fig. 1 shows plots of decreasing concentration of tert-buty-lOO� due to its reaction with added bis-3,5-DIPS-ZnII. By analyzingthese kinetic plots it was established that the rate of reaction oftert-butylOO� with ZnII(3,5-DIPS)2 is proportional to the concentra-tions of the reacting species and is described by the following equa-tion for a second-order reaction:

�d½tert-butylOO��dt

¼ keff ½tert-butylOO��½AO� ð1Þ

where keff = mst � kreact and mst is the stoichiometric coefficientshowing how many times the effective rate constant keff differsfrom the absolute rate constant kreact under the reaction conditions.Usually mst = 2 if one phenylic OH group reacts with tert-butylOO�.With an excess of [AO]0 the reaction is pseudo first-order withrespect to tert-butylOO�. Correspondingly, keff was calculated bythe following equation:

ln½tert-butylOO��0½tert-butylOO��t

� �¼ k0eff t ð2Þ

where k0eff ¼ keff ½AO�0.

2.3. Electrochemical measurements

DPV experiments were performed by using a Bioanalytical Sys-tems (BAS) 100B/W electrochemical analyzer with a conventionalthree-electrode system. The working electrode was a glassy carbonelectrode with an area of�0.09 cm2, which was cleaned before vol-tammetric measurements by polishing with alumina powder of0.5 lm size then rinsed with ultrapure deionized water and ace-tone. The reference electrode was filled with a solution containing

Fig. 1. (a) Kinetics of the change in concentration of tert-butylOO� due to reaction with added ZnII(3,5-DIPS)2 at �31.5 �C at the absence of DMSO (1) and in the presence ofDMSO in the reaction medium at [DMSO]/[ZnII(3,5-DIPS)2] ratios equal to 0.695 (2) and 1.39 (3). (b) The kinetic medium effect, showing the effect of addition of DMSO on thevalue of second-order rate constant of the reaction of tert-butylOO� with ZnII(3,5-DIPS)2. [ZnII(3,5-DIPS)2]0 = 3.5 � 10�2 M in 10% (v/v) chlorobenzene in heptane. Arrowsindicate the time of addition of antioxidant solution to the solution of tert-butylOO�.

L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125 121

0.01 M AgNO3 and 0.1 M TBAP in MeCN with platinum wire as theauxiliary electrodes. All electrodes were from BAS. Differentialpulse voltammograms were recorded from 200 to 2500 mV. TBAP(0.1 M) in methylene chloride was used as a supporting electrolyte.The solutions were purged by passing a stream of high-puritysolvent-saturated nitrogen (99.99%) for about 10 min and thenitrogen atmosphere was maintained during measurements. Back-ground currents for solvent and supporting electrolyte correctionwere obtained for all measurements. Experiments were performedin a thermostated electrochemical cell at 25.0 ± 0.1 �C. The opera-tion of the electrochemical analysis system was checked with aNa3Fe(CN)6 solution for which a linear calibration correlation coef-ficient of 0.9995 was obtained.

3. Results and discussion

3.1. Kinetics studies of reaction of tert-butylperoxyl radicals withZnII(3,5-DIPS)2

On the basis of data shown in Fig. 1, rate constants for thechemical reaction of tert-butylOO� with ZnII(3,5-DIPS)2 werecalculated and are presented in Table 1. Butylated hydroxytoluene(2,6-di-tert-butyl-4-methyl phenol, BHT) was used as a referencephenolic antioxidant. It follows from Table 1 that in a nonpolar,lipid-mimetic medium ZnII(3,5-DIPS)2 exhibits antiradical reactiv-ity with respect to tert-butylOO�. This chelate exhibited a reactivityapproximately two orders of magnitude less than BHT with respectto the reduction of tert-butylOO� to tert-butylOOH.

It was shown previously [11] that 3,5-DIPS acid has no measur-able antiperoxyl radical reactivity. Thus, the following rank of thereactivity was observed:

BHT >> ZnIIð3;5-DIPSÞ2 >> 3;5-DIPS acid:

This sequence is basically governed by the presence or absenceof intramolecular hydrogen bonding involving the H-atomdonating reaction center of a phenolic OH group. There is no

Table 1Second-order absolute rate constants for the reaction of tert-butylOO� with ZnII(3,5-DIPS)2 or BHT in 10% (v/v) toluene/n-heptane solution at �31.5 �C.

Antioxidant Rate constant, keff = mst � kreact (M�1 s�1)a

ZnII(3,5-di-iso-propylsalicylate) 9.0 ± 0.4BHTb 4886 ± 2153,5-Di-iso-propylsalicylate acidc <0.1

a mst � 2.b,c Data from Tavadyan et al. [11].

intermolecular hydrogen bond in BHT, while 3,5-DIPS acid has astrong intramolecular hydrogen bond between the hydrogen atomof the salicylic OH group and the oxygen atom of the carboxylgroup. This is the reason for the high antiperoxyl radical reactivityof BHT and absence of measurable reactivity for 3,5-DIPS acid.

The structures of zinc salicylate complexes in solution are notknown, but several crystal structures of zinc salicylates solids havebeen determined and there is evidence from related copper com-plexes that these are likely to prevail in non-coordinating solvents[28]. Crystal structures show that ZnII(3,5-DIPS)2(DMSO)2 has a tet-rahedral geometry with four oxygen ligands provided by twoDMSO molecules and monodentate coordination of two 3,5-DIPScarboxylate oxygen atoms [29]. The structure retains the intramo-lecular hydrogen bond between the salicylic OH hydrogen and thenon-coordinating carboxylate oxygen and we believe that thisstructure is retained in non-polar solvents as it is consistent withour observations.

While copper carboxylates often form dimeric complexes [28],the diamagnetic zinc carboxylates cannot form metal–metal bondsand are usually monomeric [30,31]. The crystal structure ofZnII(3,5-DIPS)2 has not been reported in the absence of otherligands, but it is likely that the carboxylate groups coordinatesymmetrically as bidentate ligands, a coordination geometryobserved for one of the salicylate ligands in [ZnII(salicylate)2(bipyr-idyl)(methanol)] [32]. No crystal structures have been reportedthat show metal coordination of the salicylic OH group as well asa carboxylate oxygen atom, and if one of the carboxylate oxygenatoms coordinates in an equatorial position, the geometry is suchthat the OH group cannot coordinate in an axial position.

When 3,5-DIPS binds to metal ions, there is experimentalevidence indicating that the 3,5-DIPS intramolecular hydrogenbonding is damped [11,24,27]. As a result, phenolic OH groups withreduced or free of intramolecular hydrogen bonding may appear((2) in Scheme 1), capable of directly participating in H-atom trans-fer reaction with peroxyl radicals. That is why ZnII(3,5-DIPS)2 isintermediate in antiperoxyl radical reactivity in the above ranking.

3.2. Influence of DMSO on the peroxyl radical scavenging reactivity ofZnII(3,5-DIPS)2

As shown in Fig. 1, addition of the electron-donating DMSO tothe reaction medium has a dramatic effect on the value ofsecond-order rate constant of the reaction between ZnII(3,5-DIPS)2

and tert-butylperoxyl radicals. It should be noted that at a 1:1molar ratio of DMSO/ZnII(3,5-DIPS)2 the value of second-order rateconstant falls by 80%, and at 2:1 molar ratio of DMSO/ZnII

(3,5-DIPS)2 it falls to a practically unmeasurable level.

weak (weakened)

OZnII

O

O H

(1) (2)

O

O

H

OH

Scheme 1. Illustration of intramolecular hydrogen bonding in 3,5-DIPS acid (1) andits reduction or loss resulting in an increase in the free phenolic OH group in goingfrom 3,5-DIPS acid to a metallochelate of 3,5-DIPS (2).

122 L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125

3.3. Voltammetric evidence for changes in hydrogen-bonding onaddition of DMSO

As shown in Fig. 2, differential pulse voltammetric (DPV) stud-ies clearly distinguish four distinct peak oxidation potentials foroxidation of the 3,5-DIPS ligand in the ZnII(3,5-DIPS)2 complex at+932, +1232, +1600 and +2183 mV versus Ag/Ag+. Occurrence ofmore than one peak for Zn(3,5-DIPS) indicates the presence ofOH bonds linked to the carboxyl group through different levels ofintermolecular hydrogen bonds. Here the first peak with the small-est value of oxidation potential, approximately 932 mV, is respon-sible for antiradical activity. Such a value is characteristic for the

Fig. 2. Differential pulse voltammograms of ZnII(3,5-DIPS)2 in CH2Cl2 in the absence (1) ain the relevant parts of the figure. [ZnII(3,5-DIPS)2] = 2.53 � 10�2 M, t = 22 �C, supportingrate: 20 mV s�1; pulse amplitude: 50 mV; pulse width: 50 ms; pulse period: 200 ms.

phenolic OH group exhibiting antiperoxyradical activity. An anodicpeak potential of +850 mV versus Ag/Ag+ was found for the pheno-lic OH group of BHT, which does not participate in hydrogen bond-ing, using our experimental conditions. The significantly highervalues of the peak oxidation potentials for 3,5-DIPS as comparedwith the model phenol, BHT, indicate the presence of some degreeof intramolecular hydrogen bonding involving the salicylic OHgroup when 3,5-DIPS is coordinated to zinc.

Fig. 3 shows that the anodic oxidation potential for the salicylicOH group at +932 mV increases as the [DMSO]/[ZnII(3,5-DIPS)2]molar ratio in the medium increases. As shown in Fig. 2, the valuesfor all four oxidation potentials shift concurrently to more positivevalues. At ratios of [DMSO]/[ZnII(3,5-DIPS)2] exceeding 1.2 only oneoxidation peak (with a higher potential) is observed. This indicatesthat upon coordination of DMSO with the central metal only onetype of OH bond is present in the ZnII(3,5-DIPS)DMSO complexand it is linked strongly by intramolecular hydrogen bond withthe carbonyl oxygen atom of the carboxylate group.

This indicates the strengthening of the intramolecular hydro-gen-bond between the salicylic carboxyl group and OH hydrogenatom, which participate in the anodic oxidation. This is consistentwith the data showing a MKME in the oxidation of ZnII(3,5-DIPS)2

by tert-butylOO� radicals shown in Fig. 1, where a decrease in theantiradical activity of ZnII(3,5-DIPS)2 was observed upon introduc-ing DMSO into the solution.

nd in the presence of DMSO (2) and (3). The [DMSO]/[ZnII(3,5-DIPS)2] ratio is shownelectrolyte: 0.1 mM TBAP, initial potential: 200 mV; final potential: 2500 mV; scan

Fig. 3. Dependence of the shift in the oxidation potential of the lower oxidationpeak potential for OH groups of the 3,5-DIPS ligand at +932 mV on the molar ratio of[DMSO]/[ZnII(3,5-DIPS)2]. [ZnII(3,5-DIPS)2]0 = 2.53 � 10�2 M. Experimental condi-tions are the same as those of Fig. 2.

L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125 123

3.4. Mechanism of the MKME for the Lewis base DMSO in the peroxylradical-scavenging reactivity of ZnII(3,5-DIPS)2

It has been previously shown [24] that introducing molar equiv-alent quantities of a Lewis base electron pair donating compoundsuch as DMSO into a nonpolar solution of ZnII(3,5-DIPS)2 resultsin axial bonding of the DMSO to ZnII. The shift in FTIR absorbancefor the salicylic OH group from 3240 to 3100 cm�1 is consistentwith a strengthening of the intramolecular hydrogen bond asDMSO is added (Scheme 2). Binding of DMSO to ZnII(3,5-DIPS)2

No measurable reactions

+tert-butylOO•

K intra

strongH

ZnII

OO

O O

OH

O

strong

ZnII

OO H

O O

H

O

O

S H3C CH3

O

S

H3C CH3

strong

+ tert-butylOO•

+2 O S(CH3)2

Scheme 2. Bonding of DMSO to ZnII(3,5-DIPS)2 increases the intramolecular hydrogen bthe reaction with the peroxyl radicals.

in CCl4 at an axial position is confirmed by observation of new sulf-oxide stretching frequencies at 1070 cm�1 in the FTIR spectra [25].

As a result of the strengthening of the intramolecular hydrogenbond the proportion of salicylic OH groups free of intramolecularbonding decreases significantly. Salicylic OH groups that are freeof hydrogen bonding or perhaps experiencing much weaker hydro-gen bonding are responsible for the anti-tert-butylOO� reactivity ofZnII(3,5-DIPS)2, which involves H-atom transfer from salicylic OHgroups of the salicylate ligands with the formation of intermediatesalicyloxyl radicals and subsequent formation of nonradical prod-ucts as shown in Scheme 2. Thus binding of DMSO to zinc reducesthe antiradical activity of the complex.

This is the origin of the MKME of the Lewis base DMSO on thecapability of ZnII(3,5-DIPS)2 to scavenge peroxyl radicals, shownin Fig. 1. When one molecule of DMSO bonds axially to formZnII(3,5-DIPS)2(DMSO) the value of the second-order rate constantfor the reaction between peroxyl radicals with the complex falls to80% (Fig. 1). In the case of axial bonding of two equivalents ofDMSO to form ZnII(3,5-DIPS)2(DMSO)2 the antiperoxyl radical reac-tivity becomes unmeasurable. Hence it follows that at axial coordi-nation of one molecule of DMSO a major reconfiguration of thebonds in ZnII(3,5-DIPS)2 takes place, leading to a strengthening ofthe intramolecular hydrogen bonding of the OH group of the 3,5-DIPS ligand.

Table 2 along with the MKME of DMSO demonstrates thechange in characteristics of physicochemical quantities forZnII(3,5-DIPS)2 using DPV measurements, as well as results from1H NMR and FTIR studies [25] for [DMSO]/[ZnII(3,5-DIPS)2] ratiosof 1:1 and 2:1, respectively. The change in measurable physico-chemical quantities characterizes the degree of bond reconfigura-tion resulting in the decrease in the fraction of ‘‘free’’ salicylic OH

kreact + tert-butylOO•

Non radical product

kreact + tert-butylOO•

O

Hweakened("free")

H

ZnII

OO

O O

O

Oweakened ("free")

•

H

ZnII

OO

O O

O

O

onding of the ligand and prevents the participation of salicylic phenol OH groups in

Table 2The changes in the rate constant and physicochemical characteristics (P) of the reaction of ZnII(3,5-DIPS)2 with tert-butylOO�, measured by various methods upon introducingDMSO into a nonpolar solution of ZnII(3,5-DIPS)2 in the mole ratios (m) of [DMSO]:[ZnII(3,5-DIPS)2] equal to 1:1 and 2:1.

Measurable quantity (P) Solvent PðmiÞ�Pðm¼0ÞPðm¼1Þ�Pðm¼0Þ � 100%

mi = 1 mi = 2

Second-order rate constant (keff) for the reaction ZnII(3,5-DIPS)2 + tert-butylOO� 10% (v/v) toluene in n-heptane 80 >98Shift of anodic potential for the lower potential DPV oxidation peak of salicylic OH groups CH2Cl2 �35 100*

1H NMR chemical shift of the 3,5-DIPS OH proton CDCl3 68 80Shift in m(OH) in FTIR spectra, from 3240 to 3100 cm�1 CCl4 78 100Shift in ma(COO-) in FTIR spectra, from 1560 to 1585 cm�1 CCl4 82 100

m =1 is the value m� 2, at which maximum value of P is achieved.* In this case the DPV measurement for m =1is that for m = 2.

124 L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125

groups due to the axial bonding of DMSO to the metal ion. A goodcorrelation was observed between changes of physicochemicalcharacteristics measured by the various methods. Addition of oneequivalent of DMSO leads to changes in the m(OH) and ma(COO�)frequencies in the FTIR spectra and in the 1H NMR chemical shiftof the OH proton of the 3,5-DIPS ligand by approximately 70–80%. The maximum change in the FTIR and 1H NMR characteristicsis achieved by addition of two equivalents of DMSO, in goodagreement with the observed MKME of DMSO on peroxyl radicalscavenging reactivity of ZnII(3,5-DIPS)2.

In the case of the DPV measurements, addition of one equiva-lent of DMSO leads to changes in the anodic potential for thesalicylic OH hydrogen atoms of only 35% while addition of twoequivalents of DMSO leads to changes of 100%. This suggests thatthe electrochemical properties are less dependent on the intramo-lecular hydrogen bonding, indicating that the redox reaction isonly partly affected by this, or possibly that the change in solventaffects the equilibria.

Thus, in the reaction of ZnII(3,5-DIPS)2 with tert-butylOO� radi-cal an unusual manifestation of the MKME is observed comparedto the examples of peroxyl radical reactions with aliphatic aminesand para-substituted benzaldehydes [10] discussed above. Theessence of this effect is that when molar equivalent quantities ofthe strong Lewis base, DMSO, are introduced into nonpolar solu-tions of ZnII(3,5-DIPS)2, the DMSO molecules do not act directlyat the radical reaction center, which is the salicylic OH hydrogenatom ‘‘free’’ (weakened) of intramolecular hydrogen bonding andresponsible for the reaction with the peroxyl radical. Instead DMSOshows a kinetically mediated effect, by axially coordinating withthe zinc, which causes a conformational change in the complexthat leads to increased intramolecular hydrogen bonding withinthe coordinating 3,5-DIPS ligands as shown in Scheme 2. Thisreduces hydrogen abstraction and results in a dramaticallydecreased reactivity of ZnII(3,5-DIPS)2 with peroxyl radicals.

4. Conclusions

In is established that ZnII(3,5-di-iso-propylsalicylate)2 exhibitsantioxidant reactivity by acting as a tert-butylOO� scavenger. Therole of the central metalloelement ZnII consists of considerablyenhancing the reactivity of OH hydrogen atoms by increasingmarkedly the fraction of available salicylic OH hydrogen atoms,which react directly with tert-butylOO�.

The presence of small quantities (close to molar equivalents) ofa strong Lewis base such as DMSO in the reaction medium dramat-ically decreases the value of the second-order rate constant for thereaction of ZnII(3,5-DIPS)2 with tert-butylOO�. At the same time, theoxidation potential due to the reactive salicylic OH group increasessignificantly. A good correlation was found between the kineticeffect of the electron-pair donor (DMSO) and the redox behaviorof ZnII(3,5-DIPS)2, as well as the change in the 1H NMR and FTIRspectra of the chelated ligand [24].

Thus, in the reaction of ZnII(3,5-DIPS)2 with tert-butylOO� radi-cal, a mediated kinetic medium (solvent) effect (MKME or MKSE)is observed. However it is manifested by a new and distinctivemechanism. The medium molecules act not directly with theorganic molecule, as previously observed [10], but instead by alter-ing the coordination geometry of the metal complex leading to achange in the nature of coordination of the ligand and results ina greatly reduced capability to donate hydrogen atoms to a freeradical.

A MKME (MKSE) may be widely encountered in free radicalreactions observed previously in the reactions of amines andpara-substituted benzaldehydes with peroxyl radicals [10].

Acknowledgments

The authors are most grateful to L. Harutyunyan and Z. Manukyanfor assistance in performing the electrochemical measurements.This work was supported by the Armenian State Committee ofScience (Grant No. 11-1d226, 2013).

References

[1] B. Halliwell, J.M.S. Gutteridge, Free Radicals in Biology and Medicine, OxfordUniversity Press, Oxford, 1999.

[2] E.T. Denisov, I.B. Afanasiev, Oxidation and Antioxidants in Organic Chemistryand Biology, CRC Press, Boca Raton, FL, 2005.

[3] G.W. Burton, K.U. Ingold, Acc. Chem. Res. 19 (1986) 194.[4] L. Tavadyan, A. Khachoyan, G. Martoyan, A. Kamal-Eldin, Chem. Phys. Lipids.

147 (2007) 30.[5] L. Valgimigli, J.T. Banks, K.U. Ingold, J. Lusztyk, J. Am. Chem. Soc. 117 (1995)

9966.[6] D.V. Avila, K.U. Ingold, J. Lusztyk, W.H. Green, D.R. Procopio, J. Am. Chem. Soc.

117 (1995) 2929.[7] P.A. MacFaul, K.U. Ingold, J. Lusztylk, J. Org. Chem. 61 (1996) 1316.[8] N.M. Emanuel, G.E. Zaikov, Z.K. Maizus, Oxidation of Organic Compounds:

Effect of Medium, Pergamon Press, Oxford, 1984.[9] L.A. Tavadyan, V.A. Mardoyan, A.B. Nalbandyan, Chem. Phys. 5 (1986) 1377 (in

Russian).[10] L.A. Tavadyan, V.A. Mardoyan, M. Musaelyan, Int. J. Chem. Kinetics 28 (1996)

555.[11] L.A. Tavadyan, H.G. Tonikyan, S.H. Minasyan, L.A. Harutyunyan, F.T.

Greenaway, S. Williams, R.A. Gray-Kaufman, J.R.J. Sorenson, Inorg. Chim.Acta 328 (2002) 1.

[12] L.R.C. Barclay, C.E. Edwards, M.R. Vingcist, J. Am. Chem. Soc. 121 (1999) 6226.[13] M.I. De Heer, P. Mulder, H.G. Korth, K. Ingold, J. Am. Chem. Soc. 122 (2000)

2355.[14] D.W. Snelgrove, J. Lusztyk, J.T. Banks, P. Mulder, K.U. Ingold, J. Am. Chem. Soc.

123 (2001) 469.[15] M.F. Nielsen, K.U, J. Am. Chem. Soc. 128 (2006) 1172.[16] P. Gaikwad, A. Barik, K.I. Priyadarsini, B.S.M. Rao, Res. Chem. Intermed. 36

(2010) 1065.[17] M. Bietti, M. Salamone, Org. Lett. 12 (2010) 3654.[18] M. Bietti, M. Salamone, G.A. Dilabio, S. Jockusch, N.J. Turro, J. Org. Chem. 77

(2012) 1267.[19] J.R.J. Sorenson, L.S.F. Soderberg, L.W. Chang, W.M. Willingham, M.L. Baker, J.B.

Barnett, H. Salari, K. Bond, Eur. J. Med. Chem. 28 (1993) 221.[20] G. Morgant, B. Viossat, J.C. Daran, D.M. Roch-Arveiller, J.P. Giround, N.H. Dung,

J.R.J. Sorenson, J. Inorg. Biochem. 70 (1998) 137.[21] P. Lemoine, B. Viossat, N.H. Dung, A. Tomas, G. Morgant, F.T. Greenaway, J.R.J.

Sorenson, J. Inorg. Biochem. 98 (2004) 1734.[22] J.R.J. Sorenson, Curr. Med. Chem. 9 (2002) 639.

L.A. Tavadyan et al. / Inorganica Chimica Acta 418 (2014) 119–125 125

[23] J. Sokolik, I. Tumova, M. Blanova, P. Svec, Acta Facultatis PharmaceuticalUniversitatis Comenianal 51 (2004) 192.

[24] L.A. Tavadyan, S.H. Minasyan, M.V. Musaelyan, L.H. Harutyunyan, H.G.Tonikyan, J.R.J. Sorenson, Int. J. Chem. Kinetics 28 (2010) 56.

[25] G.Z. Sedrakyan, F.E. Evans, S.H. Minasyan, L.A. Tavadyan, G.W. Wangila, R.B.Walker, J.R.J. Sorenson, J. Coord. Chem. 61 (2008) 2861.

[26] Z.W. Yu, P.J. Quinn, Biosci. Rep. 4 (1994) 259.[27] A.J. Cordon, R.A. Ford, The Chemist’s Companion, Wiley, New York, 1972.

[28] F.T. Greenaway, L.J. Norris, Inorg. Chim. Acta 145 (1988) 279.[29] G. Morgant, B. Viossat, J.C. Daran, M. Roch-Arveiller, J.P. Giroud, N.H. Dung,

J.R.J. Sorenson, J. Inorg. Biochem. 70 (1998) 137.[30] C.T. Dillon, T.W. Hambley, B.J. Kennedy, P.A. Lay, J.E. Weder, Q. Zhou, Metal

Ions Biol. Syst. 41 (2004) 253.[31] P. Lemoine, B. Viossat, N.H. Dung, A. Tomas, G. Morgant, F.T. Greenaway, J.R.J.

Sorenson, J. Inorg. Biochem. 98 (2004) 1734.[32] N.J. Brownless, D.A. Edwards, M.F. Mahon, Inorg. Chim. Acta 287 (1999) 89.