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Redox Behavior of a Derivative of Vitamin K at a Glassy Electrode

Redox Behavior of a Derivative of Vitamin K at a Glassy Electrode
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  doi: 10.1149/2.032210jes2012, Volume 159, Issue 10, Pages G112-G116. J. Electrochem. Soc. Rehman, Hidayat Hussain and Suzanne K. LunsfordShamsa Munir, Afzal Shah, Fateen Zafar, Amin Badshah, Xuemei Wang, Zia-ur   Carbon ElectrodeRedox Behavior of a Derivative of Vitamin K at a Glassy serviceEmail alerting  click herein the box at the top right corner of the article or Receive free email alerts when new articles cite this article - sign up  go to: Journal of The Electrochemical Society  To subscribe to  © 2012 The Electrochemical Society  G112  Journal of The Electrochemical Society ,  159  (10) G112-G116 (2012) 0013-4651/2012/159(10)/G112/5/$28.00  ©  The Electrochemical Society Redox Behavior of a Derivative of Vitamin K at a GlassyCarbon Electrode Shamsa Munir, a Afzal Shah, a,z Fateen Zafar, a Amin Badshah, a Xuemei Wang, b Zia-ur Rehman, a Hidayat Hussain, c and Suzanne K. Lunsford d a  Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan b State Key Lab of Bioelectronics, Southeast University, Nanjing, China c  Department of Biological Sciences and Chemistry, University of Nizwa, Sultanate of Oman d  Wright State University, Dayton, Ohio 45435, USA The redox behavior of a novel derivative of vitamin K, (  E  )-2-((prop-1-enyloxy)methyl)naphthalene-1,4-dione (PMND) was inves-tigated in the pH range 1.2–12.7 by modern electrochemical techniques like cyclic voltammetry (CV), square wave voltammetry(SWV) and differential pulse voltammetry (DPV). PMND was found to reduce in a chemically irreversible pH dependent manner.The decrease in peak current with successive scans revealed PMND and its reduction product to desorb rapidly from the electrodesurface. The plot of   E   p  vs. pH exhibiting four linear segments provided compelling evidence of PMND reduction by differentmechanistic routes in acidic, neutral and alkaline media. The pKa of PMND with values of 6.67, 8.93 and 11.3 evidenced theexistence of three acid-base equilibria. The redox mechanism of PMND was proposed on the basis of voltammetric results.© 2012 The Electrochemical Society. [DOI: 10.1149/2.032210jes] All rights reserved. Manuscript submitted June 11, 2012; revised manuscript received July 12, 2012. Published August 29, 2012. Naphthoquinones are widespread in nature as they have a vitalrole in several biological electron transfer processes including respi-ration and photosynthesis. Many derivatives of naphthoquinones areof utmost importance as they have fungicidal, antibacterial and anti-cancerouspropertiesassociatedwiththem. 1 Twoimportantderivativesof naphthoquinones, menadione and  β  lapachone have achieved clini-cal status as anti tumor drugs. Such compounds are gaining mountingattention of chemists, biologists and pharmacologists because manyanticancerous drugs contain quinone functionality. As the availablequinones have diverse structures so it is difficult to generalize thebiological action mechanism of all of them. 2 A survey of literature re-vealedthatsomenaphthoquinoescausetheinhibitionofTopoIIbythestabilization of the intermediate forms of enzyme- DNA complexes. 3 Thebiologicalimportanceofnaphthoquinoesisduetotheirabilityof accepting electron/s to form radical anion or dianion. Their redoxpropertiesaregovernedbytheattachedelectrondonatingorwithdraw-ingsubstituents. 4 Inbiologicalsystemsnaphthoquinonetoxicityisas-sociatedwiththecatalyticreductionofquinonemoietytosemiquinoneradical which can subsequently result in the reduction of oxygen thusconverting it to superoxide anion radical. Vitamin K 3  is a prothrom-bin (a blood clotting protein) producing naphthoquinone in the body.Naturally occurring vitamin K 1  and K 2  are formed from provitaminK 3 . These vitamins play an integral part in bone calcification and theirdeficiency can lead to serious health problems like excessive bleedingand hemorrhage. Plumbagin and other structural analogs of vitaminK have been reported to have anticancerous properties. 5 Quinones-hydroquinones provide a prototypical example of re-dox systems in organic chemistry. Their electrochemical behavior hasbeen studied from the very beginning of the twentieth century. 6 Well-studied naphthoquinones include lapachol, 7 menadione, plumbaginand lawsone. 8 Menadione is a synthetic structural derivative of vita-min K which can be used as a nutritional component in some cases. 2 The involvement of quinone functionality of menadione in biologicaland physiological systems and its redox behavior at monolayer mod-ified gold electrode has been reported by the previous investigators. 9 Reduction of menadione at cellular level results in the forma-tion of reactive oxygen species (ROS), making it the very quinonesystem to be used for the investigation of ROS effects on variouscellular functions. 10 Electro-reduction of menadione has been docu-mented in aprotic media in which the semiquinone anion and dian-ion radicals are not protonated in the time scale of the voltammetricexperiments. 11 In view of the lack of reported articles on the redoxmechanism of menadione in protic solvent and narrow potential rangeof gold our research group investigated the electrode reaction mech- z E-mail: anism of a novel structural derivative of vitamin K 3 , (E)-2-((prop-1-enyloxy)methyl)naphthalene-1,4-dione (PMND) at a glassy carbonelectrode (having wide potential window) in different pH media us-ing modern voltammetric techniques. Owing to the importance of electrochemical studies in providing useful information, our researchteam recently started investigations on the establishment of electrodereaction mechanism of biologically important molecules. 12–16 Thepresent work was performed with the objective of providing usefulinsights into the understanding of unexplored pathways by whichPMND (Scheme 1) and its structural analogs exert their biochemicalactions. Experimental (E)-2-((prop-1-enyloxy)methyl)naphthalene-1,4-dione (PMND)was obtained from Sigma and used without further purification.2.5 mM stock solution of PMND was prepared in analytical gradeethanol and stored at 4 ◦ C. Working solutions of PMND were pre-pared in 50% ethanol and 50% aqueous supporting electrolytes. Thecomposition of supporting electrolytes prepared in doubly distilledwater is given in Table I. Microvolumes were measured using EP-10 and EP-100 Plus Motorized Microliter Pippettes (Rainin InstrumentCo. Inc., Woburn, USA). The pH measurements were carried out withaCrisonmicropH2001pH-meterwithanIngoldcombinedglasselec-trode. All experiments were done at room temperature (25 ± 1 ◦ C).Voltammetric experiments were performed using  µ Autolab run-ningwithGPES4.9software,Eco-Chemie,TheNetherlands.Aglassycarbon electrode (GCE) with electroactive area of 0.07 cm 2 was usedas working electrode, a Pt wire served as counter electrode and a sat-urated calomel electrode (SCE) was employed as the reference. Priorto every experimental assay the surface of GCE was polished with OOO (  E  )-2-((prop-1-enyloxy)methyl)naphthalene-1,4-dione Scheme 1.  Chemical structure of (  E  )-2-((prop-1-enyloxy)methyl)naphthalene-1,4-dione (PMND).   Journal of The Electrochemical Society ,  159  (10) G112-G116 (2012) G113 Table I. Supporting electrolytes of 0.1 M ionic strength. pH Composition pH Composition pH Composition1.2 HCl + KCl 5.8 NaH 2 PO 4  + Na 2 HPO 4  10.1 NaHCO 3  + NaOH2.1 HCl + KCl 7.4 NaH 2 PO 4  + Na 2 HPO 4  11.1 NaH 2 PO 4  + NaOH4.1 HAcO + NaAcO 8.0 NaH 2 PO 4  + Na 2 HPO 4  11.6 KCl + NaOH4.7 HAcO + NaAcO 9.1 NaH 2 PO 4  + Na 2 HPO 4  12.7 KCl + NaOH aluminapowderfollowedbythoroughrinsingwithdistilledwater.Forreproducible experimental results the clean GC electrode was placedin supporting electrolyte solution and various cyclic voltammogramswere recorded until achieving steady state baseline voltammogram.All the voltammetric experiments were conducted in a high purityargon atmosphere. Results and Discussion Cyclic Voltammetry.—   Cyclic voltammogram of 1 mM PMNDwas initially recorded in the potential range of   + 1.5 –  − 1.5 V at asweep rate of 100 mV s − 1 using supporting electrolyte of pH 7.4. Areduction peak (1c) at − 0.457 V with a counter oxidation peak (1a)was observed in the negative potential range of GCE. Therefore, fur-ther CV experiments were carried out at a starting potential of 0 V,first vertex potential of  − 1 V and second vertex potentials of  + 0.3 V.The absence of signal/s in the positive potential domain of GCE ruledoutthepossibilityofPMNDoxidationinpH7.4.Peakclippingexper-iment confirmed that peak 1a is related to 1c. By recording successivescans(Fig.1)withoutcleaningtheelectrodesurfaceverysmallchange in peak current was observed. The behavior is attributable to the quick desorption of PMND and its reduction product from the electrodesurface.In order to propose the redox mechanism, CVs of PMND wereobtainedinthepHrange1.2–12.7.Thepeakpotentialsoftheoxidationand reduction waves depended on pH and shifted to more negativepotentialswiththeincreaseinpHfrom1.22to5.8asshowninFig.2A.This behavior indicated the involvement of protons in the electrodeprocess. Change of pH from 5.8 to 7.4 resulted in a separate trendof pH dependence. The location of cathodic peak potential at lessnegative value of   − 0.49 V in pH 7.4 as compared to  − 0.63 V inpH 5.8 suggested facile reduction of PMND under slightly alkalineconditions. Moreover, the clogging of peak potential at a fixed valuein the pH range 7.4–9.1 indicated the reduction to proceed only bythe transfer of electrons. Shift in the peak potential continued for pHhigher than 9.1 until pH 11.0 where the shift of peak potential stoppedagain and persisted up to pH 12.7 (see Fig. 2B). Another reductionpeak at a potential more negative than the first peak but of very smallmagnitude appeared at pH 7.4, which corresponds to the addition of  Figure 1.  CVs (scan 1–3) of 1 mM PMND obtained at 100 mV s − 1 scan ratein a medium buffered at pH 7.4. secondelectrontotheproductofpeak1c.Theelectrochemicalprocesswas found different from the reported typical one-step addition of twoelectrons to naphthoquinones and its derivatives including vitamin Kinbufferedaqueousmedia. 17 ThisanomalousbehaviorofPMNDmaybe due to the electron donating effect of the side group attached to thequinone moiety that cause the addition of the second electron at morenegative potential (see Scheme 2). The second reduction peak occurs only in the pH range 7.4–9.1 and disappears at pH 10.1 indicatingchange of redox mechanism in strongly alkaline conditions.  Differential Pulse Voltammetry.—   DPV of 0.5 mM PMND solu-tionwascarriedoutfortheevaluationofnumberofelectronsinvolvedin the reduction process. The width at half peak height ( W  1/2  ) of 93 mV (close to the theoretical value of 90.4 mV) showed the elec-trochemical reduction to occur by the transfer of one electron. 12,18 The appearance of two cathodic peaks in the differential pulse Figure 2.  (A) CVs of 1 mM PMND obtained at  ν = 100 mV s − 1 in differentsupporting electrolytes of pH ranging from 1.22 to 5.8 (B) CVs obtained at aGCE in Ar saturated solution of 1 mM PMND at  ν = 100 mV s − 1 in differentsupporting electrolytes of pH 7.4–12.7.  G114  Journal of The Electrochemical Society ,  159  (10) G112-G116 (2012) OOO + OHOHO e2H + OH OH O Scheme 2.  Reduction mechanism of PMND in the pH range 1.22–5.8. voltammogramdisplayedinFig.3authenticatedtheCVresultsoftwostep reduction of PMND in pH 7.4. Square Wave Voltammetry.—   Square wave voltammetry (SWV) ispreferredoverotherelectrochemicaltechniquesinthefieldofanalysisdue to greater speed of analysis, little consumption of the analyte incomparison to DPV and reduced problems of electrode poisoning. 19 A greater advantage of SWV is that one can get evidence for thereversibility of electron transfer process in only one scan. Since thecurrent is sampled simultaneously inboth positive and negative-goingpulses so peaks corresponding to oxidation and reduction of the elec-troactivespeciescanbeobtainedinthesameexperiment.Inthepresentwork SWV was performed for getting information about the nature of redox process. The backward and forward peak currents ratio of lessthan 1 (see Fig. 4A) indicated the chemical irreversibility of the redox processowingtothechemicalstepsinvolvedinreductionmechanism.Successivesquarewavevoltammograms(Fig.4B)of0.5mMsolution of PMND were also recorded for monitoring the effect of number of scans.Almostnoeffectonthepeakcurrentexcludedthepossibilityof PMND to adsorb on the electrode surface. This square wave voltam-metric behavior correlates well with the results obtained from cyclicvoltammetry.  Redox Mechanism.—   Cyclic voltammetric results obtained in awide pH range were used to propose the redox mechanism of PMND.SWV was used to ensure the reversibility or irreversibility of the Figure 3.  First scan DPV of 0.5 mM PMND at  ν = 10 mV s − 1 and pH = 7.2. Figure 4.  (A) 1st scan SWV of 0.5 mM PMND recorded in pH 1.32, showing  I  t  – total current,  I  f   forward current,  I  b  – backward current;  f  = 20 Hz,   E  s = 5 mV,  ν eff   = 100 mV s − 1 and pulse amplitude = 50 mV (B) SWVs of firstfive scans of 0.5 mM PMND run at  ν eff   = 100 mV s − 1 in pH 1.32. redox process. DPV was employed for the determination of numberofelectronsinvolvedintheredoxprocess.  E  p  vs.pHplotsforreductionandoxidationpeaksareshowninFigs.5and6.Thedissimilartrendsof  bothplotsofferanotherevidenceoftheoverallchemicalirreversibilityof the redox process. The different slopes of straight line segmentsrevealedthechangeofredoxmechanismwithchangingpH.Therefore,the redox mechanism was explained separately for each pH range. Figure 5.  Plot of   E  pc  vs. pH.   Journal of The Electrochemical Society ,  159  (10) G112-G116 (2012) G115 Figure 6.  E  pa  as a function of pH.  pH 1.22–5.8.—  The slope of   E  p  vs. pH plot of 101.5 mV pH − 1 witha correlation coefficient of 0.987 in the pH range 1.22–5.8 indicatedthe electro-reduction of PMND to occur by the involvement of twoprotons and one electron. This behavior is consistent with the litera-ture reported CEC mechanism 20 in which an electron transfer step ispreceded and followed by homogeneous chemical steps.The mechanism shown in Scheme 2 was proposed on the basis of CV results. Addition of proton to the qunoid oxygen results in the for-mationofacationtowhichanelectronisaddedfromtheelectrodeandanother by bond cleavage of C = O group resulting in the formationof protonated semiquinone having single electron on oxygen atom(adjacent to side group). Following CEC mechanism another protonis added to this oxygen atom forming a cation radical stabilized byintramolecular hydrogen bonded six membered ring owing to the sidegroup attached at the quinone moiety. Formation of such intramolec-ular hydrogen bonded complex has also been reported for hydroxyquinones by the previous researchers. 21 Due to the unique side groupthe overall reduction of PMND followed 2H + , 1e − , pH dependent OOO + e O - OOO - OOO - OO +e O -- (H 2 O)nO -- (H 2 O)nOO - O - O Scheme 3.  Reduction mechanism of PMND in the pH range 7.4–9.1.  NQ + OH -  NQ  OH -  NQ  OH - + NQ+OH - e Scheme 4.  Reduction mechanism of PMND in the pH range pH 9.1–11.0. reduction under acidic conditions unlike the reported one-step 2H + ,2e − , reduction of vitamin K. 17  pH 7.4–9.1.—  The reduction potential of PMND was found indepen-dent of pH in the pH range of 7.4–9.1. In these conditions reductionoccurs with equal ease. Moreover, zero slope of   E  pc  vs. pH plot in thisrange theoretically predicts no involvement of proton which can be justifiedbythemechanismpresentedinScheme3.Gainofanelectron by the qunoid oxygen with the simultaneous bond breakage of C = Ogroup results in the formation of semiquinone radical. Appearanceof second reduction peak at pH 7.4 corresponds to the formation of quinone dianion. Formation of stable dianion of quinone in aproticmedia has already been documented in literature but this is the firstcase of dianion formation in protic solvent. This exceptional behav-ior of PMND can be related to the electron donating nature of theside group which hinders the addition of second electron causing itto occur at a more negative potential, thus giving two steps reduction.Hence, the side group seems to impart quiet different electrochemicalbehavior to this structural analog of vitamin K 3 . The dianion formedissuggestedtobestabilizedbyH 2 Omoleculesviahydrogenbonding.Behavior of PMND in this pH range is similar to quinones in aproticmedium i.e. two steps reduction with no protons involvement.  pH 9.1–11.0.—  Cyclic voltammetric results of   E  pc  as a function of pH in the pH range 9.1–11.0 gave a slope of 53 mV pH − 1 . This isattributedtotheformationofhydroxyadductofPMND,thusresultingin another acid-base equilibrium:PMND + OH −  PMND − OH − [1]The formation of hydroxy adduct of quinones has also been re-ported by other researchers in basic media. 22 The second cathodicpeakdisappearedatpH10.1.ThisvalidatedtheworkofSusanetal., 23 who found the same peak of some anthraquinones to disappear at pHclose to 10.1. From the disappearance of second reduction peak it canbe concluded that PMND gets reduced by the gain of one electron asverified by the slope value of 53 mV pH − 1 unit.The dramatic variation of   E  pc  vs. pH slopes in acidic, neutral andalkaline media can be attributed to the CEC mechanism (i.e. additionofprotontakesplacefirstfollowedbythetransferofelectron)inacidicconditions and its switching to EE mechanism (i.e. step wise additionofelectron)inneutralandbasicpHresultinginfasterkinetics. 24 AtpH > 9.1 the decrease in potential is caused by the formation of PMND–OH − adduct formation. The disappearance of second reduction peak may be due to the instability of dianion in highly alkaline media.Proposed mechanistic pathway of PMND in pH range 9.1–11.0 isrepresented in Scheme 4. The peak potential shift stopped again at pH ≥  11.0 indicating the stability of PMND –OH − adduct under theseconditions. The equilibrium shown by equation 1 shifts toward the O OH Oe O OH O Scheme 5.  Reduction mechanism in pH 11.0–12.7.
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