Curcumin is a natural product with antioxidant, anti-inflammatory, antiviral and antifungal functions. As it is known that the excited state intramolecular hydrogen transfer of curcumin are related to its medicinal antioxidant mechanism, we investigated its excited state dynamics by using femtosecond transient absorption spectroscopy in an effort to understand the molecule&apos;s therapeutic effect in terms of its photophysics and photochemistry. We found that stronger intermolecular hydrogen bonding with solvents weakens the intramolecular hydrogen bonding and decelerates the dynamical process of the enolic hydrogen. Exceptions are found in methanol and ethylene glycol due to their nature as simultaneous hydrogen bonding donor-acceptor and high viscosity solvent, respectively

Jin, Seung Min

Kang, Junhee

Kim, Hyung Min

Kim, Seong Keun

Ramanathan, Venkatnarayan

Suh, Yung Doug

Yang, Ilseung

Bulletin of the Korean Chemical Society

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3090     Bull. Korean Chem. Soc. 2011, Vol. 32, No. 8 Ilseung Yang et al.DOI 10.5012/bkcs.2011.32.8.3090Excited State Dynamics of Curcumin and Solvent Hydrogen Bonding†Ilseung Yang,‡ Seung Min Jin,§ Junhee Kang,# Venkatnarayan Ramanathan,‡ Hyung Min Kim,§ Yung Doug Suh,§ and Seong Keun Kim‡, #,*‡Department of Chemistry, Seoul National University, Seoul 151-747, Korea§NanoBio Fusion Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea#WCU Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151-747, Korea*E-mail: seongkim@snu.ac.krReceived March 29, 2011, Accepted July 8, 2011Curcumin is a natural product with antioxidant, anti-inflammatory, antiviral and antifungal functions. As it isknown that the excited state intramolecular hydrogen transfer of curcumin are related to its medicinalantioxidant mechanism, we investigated its excited state dynamics by using femtosecond transient absorptionspectroscopy in an effort to understand the molecule’s therapeutic effect in terms of its photophysics andphotochemistry. We found that stronger intermolecular hydrogen bonding with solvents weakens theintramolecular hydrogen bonding and decelerates the dynamical process of the enolic hydrogen. Exceptions arefound in methanol and ethylene glycol due to their nature as simultaneous hydrogen bonding donor-acceptorand high viscosity solvent, respectively.Key Words : Curcumin, Excited state intramolecular hydrogen transfer, Transient absorptionIntroductionCurcumin, a yellow-orange natural pigment found in therhizome of Curcuma longa, has drawn considerable interestin the past few decades due to its medicinal effects as ananti-inflammatory, anti-angiogenic, anti-cancer and anti-oxidant agent.1-4 The compound has been traditionally usednot only as a main ingredient in Indian and Arabic cuisinefor its distinctive flavor but also as a medicine for itstherapeutic effects.5 Curcumin is also reported to preventprotein aggregation that often leads to diseases such asAlzheimer’s and Parkinson’s.6,7Curcumin belongs to a group of β-diketonic compoundwhich exhibits keto-enol tautomerism at room temperature.Several isomeric structures have been proposed but thepredominant form in the ground state solution was found tobe the keto-enol structure by NMR spectroscopy.8 The keto-enol form has a strong intermolecular hydrogen bondinginteraction with the solvent through its hydrogen atoms.Excited state photophysics of curcumin has also beenextensively studied, perhaps partly prompted by theenhancement of its medicinal effects upon excitation withlight.9 The photogeneration of reactive oxygen species bycurcumin, which is strongly dependent on the chemicalnature of the solvent, has been speculated as the enhancementfactor for its chemo-therapeutic activities.10-12 Several intensivestudies have been reported about the connection betweenexcited state intramolecular hydrogen transfer (ESIHT) andthe medicinal properties of compounds such as hypericinand hypocrellin, both of which have a structural similaritywith curcumin.13-17 For such studies, a fundamentalunderstanding on solvation dynamics and its effect onESIHT is essential to elucidate the mechanisms involved.Several groups have studied the excited state photophysicsof curcumin in different kinds of solvents in the time domainof picoseconds to microseconds in organic solvents andmicellar systems.11,18,19 Recently, Adhikary et al. studied theexcited state photophysics of curcumin in protic solvent andsurfactant micelles by using femtosecond fluorescenceupconversion spectroscopy.20 They found that one of thedecay time constants, i.e., the longer one, changed significantlywhen the enolic hydrogen of curcumin was deuterated. Itwas thus assigned to the ESIHT process, whereas the shortertime constant that did not change was thought to beassociated with the process of solvation.Most recently, Ghosh et al. used subpicosecond time-resolvedtransient absorption (TA) and fluorescence upconversionspectroscopy to study the excited state dynamics of curcumin,21and reached basically the same conclusion as Adhikary etal.’s regarding the shorter time constant. For the longer timeconstant, however, they suggested that intermolecular hydrogenbonding between protic solvent and curcumin may sufficientlyperturb the intramolecular hydrogen bonding of curcumin.In view of these issues, we investigated in this paper therelationship between excited state dynamics of curcumin†This paper is dedicated to Professor Eun Lee on the occasion of his ho-nourable retirement.Figure 1. Chemical structures of curcumin, whose predominantform at room temperature is the enol form.Excited State Dynamics of Curcumin and Solvent Hydrogen Bonding  Bull. Korean Chem. Soc. 2011, Vol. 32, No. 8     3091and its hydrogen bonding with various solvents usingfemtosecond TA spectroscopy.ExperimentalWe used a typical TA setup to obtain femtosecond TA ofcurcumin in solution.22 A femtosecond pulse (130 fs, 120cm−1, 1 W, 1 kHz) centered at 800 nm was generated by atypical regeneratively-amplified Ti:Sapphire laser (SpitfirePro, Spectra Physics) seeded by a femtosecond Ti:Sapphireoscillator (MaiTai, Spectra Physics) running at 80 MHzrepetition rate. The continuum light was generated byfocusing the 800-nm light by a planoconvex lens (f = 10 cm)into a 1 mm-thick sapphire plate (Newport). To preventchirping of the continuum light, gold-coated metal mirrorsand concave mirrors were used. The pump pulses weregenerated using the second harmonic generator (TP-THG-F,Spectra Physics). The maximum power at the focal pointwas 100 µJ at 400 nm. The pump and continuum lights had adiameter of ~ 300 µm (f = 70 cm) and ~ 100 µm (f = 35 cm),respectively. The polarization angle of pump pulses wascontrolled using a zero-order half-waveplate for 400 nm(QWPO-400-06-2-R, CVI). We kept the polarization angleof pump pulses at the magic angle of 54.7o. The optical timedelay between the pump and continuum pulses was scannedby motorized translation stage (Daedal, Parker Hannifin Co.).The pump pulses were modulated using a synchronizedoptical chopper (MC1000, Thorlabs). The probe pulses ofsignal and reference beams were detected by photodiodesafter the wavelength selection using polychromator(SP2300i, Princeton Instruments). The signal and referenceintensity, which was generated using boxcar integrator(SR250, Stanford Research Systems), was divided using ananalog processor (SR245, Stanford Research Systems) tocompensate for the power fluctuation. The TA intensitieswere recorded using a lock-in amplifier (SR830, StanfordResearch Systems). The cross correlation of femtosecondTA was 340 ± 10 fs for the 400 nm pump.Curcumin (C1386, Aldrich) and HPLC-grade solvents(methanol, ethylene glycol, dimethyl formamide (DMF),acetonitrile, and chloroform, all from Aldrich) werepurchased and used without further purification. UV/Visabsorption and fluorescence spectra were recorded bycommercial instruments (Lambda 25, Perkin-Elmer andQM-3/2004SE, PTI, respectively) using a 1-cm path lengthquartz cell (111-QG, Hellma).Results and DiscussionTable 1 lists the absorption and emission maxima ofcurcumin in various solvents, indicating a significantdependence on hydrogen bonding. The Stokes shift isnoticeably smaller in non-hydrogen bonding solvent(chloroform) than in hydrogen bonding solvents (the topfour).12,18,23-25 Solvents that can both donate and accepthydrogen bonds generally yield a larger shift than those thatonly accept hydrogen bond.25In this work, we kept our probe wavelength at 850 nm toeffectively measure the lifetime of only the excited statewithout being affected by stimulated emission. Figure 2shows TA signal of curcumin in methanol at the probewavelengths of 775 and 850 nm. Temporal profile at 775 nmshows what appears to be a “negative absorption” thatresults from stimulated emission.Figure 3 shows the temporal profiles of photoexcitedcurcumin in various solvents at the pump and probewavelengths of 400 and 850 nm, respectively, at timeintervals of 166 fs up to 10 ps and 2 ps afterwards. We chosethe solvents to compare the strength of their hydrogenbonding with curcumin and the excited state decay rate. Thetemporal profiles were fitted with a biexponential function,whose time constants are listed in Table 2.In their earlier work, Adhikary et al. obtained a biexponentialdecay for hydrogen bonding solvents (methanol and ethyleneglycol) but only a single exponential decay for non-hydrogen bonding solvent (chloroform).20 They interpretedit as reflecting the absence of active solvation process withsolvents of non-hydrogen bonding character. The timeTable 1. Spectral and chemical properties of the various solventsused to dissolve curcuminSolvent H-bonding Absorption(nm)Emission(nm)Viscosity(Poise, 25 oC)26FunctionalgroupMethanolDonor-Acceptor434 545 0.55DMF Acceptor 429 526 0.80  Acetonitrile Acceptor 417 514 0.34  Ethylene glycolDonor-Acceptor435 541 13.76CholoroformNonH-bonding418 480 0.54Figure 2. Temporal profile for TA of curcumin in methanol probedat two different wavelengths (775 and 850 nm). At 775 nm, bothexcited state absorption and stimulated emission are convoluted inthe spectrum, while only the excited state absorption is observed at850 nm.3092     Bull. Korean Chem. Soc. 2011, Vol. 32, No. 8 Ilseung Yang et al.constant of 130 ps for their single exponential decay wasassigned to ESIHT.In our case, however, we found a biexponential decay forchloroform as well as all other solvents. Lack of hydrogenbonding does not necessarily preclude active solvation sincethere are other intermolecular interactions at play such asdipole-dipole interaction, and we think that our biexponentialdecay in chloroform indicates both solvation and ESIHT.From Table 2, we note that our shorter time constant τ1 forall solvents (regardless of their hydrogen bonding nature) iscomparable to the time constant for solvation dynamics ofcoumarin 153 of Horng et al.26 Since the dipole moment ofcurcumin (~6.1 D) is comparable to that of coumarin 153(~8 D), we find this to be reasonable.For the longer time constant, we note from Fig. 3 andTable 2 that a non-hydrogen bonding solvent (chloroform)gives a significantly shorter decay time constant τ2 thanhydrogen bonding solvents. It is to be noted that a very fastdecay of curcumin in non-hydrogen bonding solvents suchas cyclohexane and 1,4-dioxane (each with a time constantof 44 and 55 ps) in earlier studies18,21 was attributed to thefact that these solvents do not form intermolecular hydrogenbond with curcumin that would have weakened itsintramolecular hydrogen bond, which would decrease therate of its decay through ESIHT.We also note that our longer time constant τ2 is largest inDMF and acetonitrile, which have a stronger hydrogenbonding capability than chloroform. This is because formationof intermolecular hydrogen bonding would weaken theoriginal intramolecular hydrogen bond and also partially“lock” the enolic hydrogen involved in the intramolecularhydrogen transfer (as schematically shown in Fig. 4(a)),which acts as the main decay channel for the longer timeconstant. If this were the prevailing factor in determining τ2,methanol would have resulted in an even longer τ2 since itshydrogen bonding capability is the largest of all solvents weused. In reality, however, methanol gives a rather short τ2because it can act as both hydrogen bonding donor andacceptor, as schematically shown in Fig. 4 (b). Such astructure would provide an indirect pathway for ESIHT andtherefore partially compensate for the decrease in the decayrate based solely on intermolecular hydrogen bondingmodel. Ethylene glycol with its exceptionally high viscosityis a notable exception to the above discussion. There seems that a general correlation exists between thedecay time constant and the strength of intermolecularhydrogen bonding. In general, stronger intermolecularhydrogen bonding appears to decelerate the intramoleculartransfer of the enolic hydrogen represented by the longertime constant for decay, but certain solvents can make up forthe decrease in its rate by providing another, solvent-mediated, ESIHT pathway. These effects need to becarefully addressed to relate the strength of hydrogenbonding to the decay time constant via ESIHT.Figure 3. Temporal profile for TA of curcumin in various solvents. Table 2. Time constants associated with the relaxation of the excited state of curcumin and coumarin 153 in various solventsSolvent Hydrogenbonding strength27Coumarin CurcuminHorng et al.26 Ghosh et al.21 This workα β<τ>(ps)25<τ>solv(ps)τ3(ps)τ1(ps)τ2(ps)Methanol 0.98 0.66 5.0 6.9 130 6.26 172DMF 0.00 0.69 2.0 1.6 155 2.08 240Acetonitrile 0.19 0.40 0.26 0.44 300 0.9 255Ethylene glycol 0.91 0.52 15.3 10.5 231 16.25 333Choloroform 0.20 0.10 2.8 4.83 129α: hydrogen donating strength; β: hydrogen accepting strengthFigure 4. Schematic diagram showing the formation of intermolecularhydrogen bonding between curcumin and (a) hydrogen acceptingsolvents (b) hydrogen donating and accepting solvent.Excited State Dynamics of Curcumin and Solvent Hydrogen Bonding  Bull. Korean Chem. Soc. 2011, Vol. 32, No. 8     3093ConclusionsWe investigated the excited state dynamics of curcumin invarious solvents. All our temporal profiles showed a bi-exponential decay. We studied the effect of intermolecularhydrogen bonding strength between various solvents andcurcumin on the excited state relaxation dynamics. Wefound that intermolecular hydrogen bonding with solventsweakens the intramolecular hydrogen bonding in the keto/enol unit and “locks” the enolic hydrogen, therebydecelerating the transfer of the enolic hydrogen. Exceptionsare found in methanol due to its nature as simultaneoushydrogen bonding donor-acceptor and ethylene glycol dueto its high viscosity.Acknowledgments. We would like to thank ProfessorEun Lee of Seoul National University for years ofencouragement and support of our research on molecularspectroscopy of biological and medicinal compounds suchas the title molecule of this paper. This work was supportedby the Chemical Genomics Grant (M10526020002-08N2602-00210), the Star Faculty Program (KRF-2005-084-C00017), and the World Class University Program(R31-2010-100320) of the National Research Foundation ofKorea.References  1. Ruby, A. 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Excited State Dynamics of Curcumin and Solvent Hydrogen Bonding

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Excited State Dynamics of Curcumin and Solvent Hydrogen Bonding

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