Juyoung Yoon-CC2009=-光素-银离子探针

Manipulation offluorescent and colorimetric changes offluorescein derivatives and applications for sensing silver ions w zK.M.K.Swamy,y ab Ha Na Kim,y a Jung Huyn Soh,y a Youngmee Kim,a Sung-Jin Kim aand Juyoung Yoon*acReceived(in Cambridge,UK)3rd November2008,Accepted10th December2008First published as an Advance Article on the web13th January2009DOI:10.1039/b819538bThree structurally similar compounds,1–3,bearing a fluorescence chromophore to which are appended morpholine, thiomorpholine and methylpiperazine substituents,display oppositefluorescence responses to pH changes,in contrast to that observed forfluorescein;1and2have extremely high binding selectivity towards Ag+ions and show completely differentfluorescent and colorimetric changes upon addition of Ag+,and the differences are proposed to be associated with different binding modes of1and2to this metal ion.Sensors based on ion-induced changes influorescence intensities are particularly attractive owing to their potential simplicity and the high detection sensitivities that can be achieved.1 Among the variousfluorophores,those present influorescein derivatives have been extensively utilized in the design of fluorescent sensors for pH,2metal ions,3anions,4activity of enzymes5as well as redox events.6The enormous activity in this area is attributable to several unique advantages offluorescein derivatives,such as high water solubility,long wavelengths for excitation and emission,highfluorescence quantum efficiencies, and availability via short synthetic routes.Thefluorescence and colorimetric changes that take place withfluorescein in different pH regions is attributed to the interconversion of different prototropic forms.The absorption changes offluorescein were recently utilized for molecular logic gates.2a,b,7Even though a fewfluorescein derivatives bearing benzylic amine moieties have been utilized recently as metal ion3and anion sensors,4the colorimetric andfluorescent changes promoted by binding of these substances with metal ions is not well characterized and mechanisms associated with bind-ing have not been well defined.Fluorescein derivatives can display colorimetric andfluorescent changes that are induced by(1)spirolactone ring opening,(2)phenolate anion forma-tion,and/or(3)photoinduced electron transfer(PET)involving benzylic amine moieties.Manipulation of these three,potentially cooperative pathways could be a very important element in the design of newfluorescein based sensors.As far as we are aware,no reports exist describing the sensing application which involve manipulation of these three communicating inputs.Fluorescein,which is known to display unique absorption andfluorescence spectra at different pHs,can exist in four different ionization forms including a cation,neutral substance, monoanion and dianion.Absorption l max are observed at 437nm for the cation and neutral species,455and464nm for the monoanion,and at474nm for the dianion.2c,d Usually, the colorimetric change from colorless or light yellow to red or pink and the largefluorescence enhancement in the basic pH region is caused by the formation of the dianion.However,fluorescein derivatives bearing benzylic amine moieties display quite differentfluorescence changes as compared to that of fluorescein itself.The results of the studies described below,show that two structurally similar compounds,1and2,which have morpho-line and thiomorpholine substitutedfluorescein skeletons, have extremely high binding selectivities towards Ag+ions. Furthermore,upon the addition of Ag+these substances display completely differentfluorescence changes that are a consequence of different binding modes to Ag+.Thefluorescein derivatives1–3were synthesized by using Mannich reactions of20,70-dichlorofluorescein and iminium ions produced by condensation of formaldehyde with morpho-line(81%),thiomorpholine(84%)and1-methylpiperazine (90%),respectively(Scheme1and ESI z).All three compounds were obtained in very high yields and fully characterized by 1H NMR,13C NMR,high resolution FAB mass spectroscopy (Fig.S11to S16z)and X-ray crystallography(see ESI as well as Table S1&S2z).X-Ray crystal structures z(Fig.S1&S2)show that1and2 exist in the lactone ring closed forms and thathydrogen Scheme1Synthesis of compound1–3.a Department of Chemistry and Nano Science,Ewha WomansUniversity,Seoul120-750,Korea.E-mail:jyoon@ewha.ac.kr;Fax:+822-3277-3419;Tel:+822-3277-2400b Department of Pharmaceutical Chemistry,V.L.College ofPharmacy,Raichur584103,Indiac Department of Bioinspired Science,Ewha Womans University,Seoul120-750,Koreaw Dedicated to Professor Seiji Shinkai on the occasion of his65thbirthday.z Electronic supplementary information(ESI)available:Experimentaldetails and NMR spectra of1–DC707407and707406forcompounds1and2respectively.For ESI and crystallographic datain CIF or other electronic format see DOI:10.1039/b819538by These authors contributed equally to this work.1234|mun.,2009,1234–1236This journal is c The Royal Society of Chemistry2009 COMMUNICATION /chemcomm|ChemCommbonding interactions take place between phenolic hydrogensand nitrogens of the tertiary amine groups (1.89Afor both 1and 2,Table S2).The hydrogen bonding interactions likely serve as the reason why the fluorescent emission from the fluorescein chromophores in 1and 2(Fig.2and Fig.3)are not completely quenched via photoinduced electron transfer (PET)from the tertiary amine donors.1a In addition,a mirror plane of symmetry is present in the middle of these molecules (see Fig.S1&S2z )and the lactone ring in each substance is almost perpendicular to the central ring (86.201for 1and 82.671for 2).The fluorescence responses of the probes (1–3)in acidic and basic regions of the pH range were examined.Contrary to the behavior of 2,7-dichlorofluorescein (Fig.S3z ),1,2and 3exhibited strong fluorescence in the acidic region and their emission is almost quenched in the basic region (Fig.1).Based on plots of emission intensities vs.pH,the p K a ’s of 1,2and 3are calculated to be 7.13,7.20and 8.86,respectively.This finding suggests that the oxygen atom in morpholine derivative 1,sulfur atom in thiomorpholine derivative 2or methylamine moiety in piperazine can induce the significant differences in the p K a ’s of these substances,a factor that might be useful in desiging new fluorescein based pH probes.Ag +,Ca 2+,Cd 2+,Co 2+,Cs +,Cu 2+,Hg 2+,K +,Li +,Mg 2+,Mn 2+,Na +,Ni 2+,Rb +and Zn 2+ions were used to evaluate the metal ion binding properties of 1and 2.As shown in Fig.2and Fig.3,fluorescence emission changes of 1(3m M)and 2(1m M)were observed upon the addition of variousmetal ions at pH 7.4.Both fluorescein derivatives display an extremely selective response to Ag +among the metal ions examined.Interestingly,chemosensor 1displays a selective CHEF (chelation enhanced fluorescence enhancement)effect with Ag +but,in contrast,2shows a selective CHEQ (chelation enhanced fluorescence quenching)effect with this metal cation.Even though there is an increasing interest in finding the selective and sensitive detection of Ag +ions,there are only a few reports describing fluorescence chemosensors for Ag +ions.9,10To the best of our knowledge,there are only a couple of examples,in which fluorescent chemosensors display a significant selectivity for Ag +ions in aqueous solution.10In Fig.S4and S5is shown the results of competition experi-ments carried out with compounds 1and 2and Ag +and K +,Na +,Ca 2+,Mg 2+and Zn 2+.The opposite fluorescent changes of 1and 2promoted by the addition of Ag +are attributed to completely different metal cation binding modes of these substances.As the UV data shown in Fig.S6and S7and the Fig.4demonstrate,a colorimetric change occurs only for chemosensor 2upon the addition of Ag +.Specifically,a red shift of ca.15nm takes place when Ag +is added to a solution of 2(Fig.S7z ).This change is associated with the formation of a dianionic species.Obviously,in the absence of Ag +,both 1and 2exist in their monoanionic forms because the color of their solutions is light yellow.2c ,d Since the color change of 2promoted by Ag +is due to the formation of phenolate anion,it is likely that two Ag +ions chelate with sulfurs of the two thiomorpholine rings and the phenolic oxygens of fluorescein.The consequence of this complexation mode is that intramolecular hydrogenbondingFig.2Fluorescent changes of 1(3m M)with various metal ions (100eq.)at pH 7.4(0.01M HEPES :DMSO =95:5,v/v)(excitation at 504nm).Fig.3Fluorescent changes of 2(1m M)with various metal ions (100eq.)at pH 7.4(0.01M HEPES :DMSO =95:5,v/v)(excitation at 507nm).Fig.1Fluorescent pH titrations of 1–3in DMSO–water (5:95,v/v).Fig.4Colorimetric changes of 1(20m M)and 2(20m M)upon the addition of Ag +(300eq.)at pH 7.4(0.01M HEPES :DMSO =95:5,v/v).This journal iscThe Royal Society of Chemistry mun.,2009,1234–1236|1235between the phenolic hydrogens and the benzylic amines is eliminated.This releases tertiary amine groups that can now participate in photoinduced electron transfer(PET)quenching of emission from thefluorescein chromohore2(Scheme2). The addition of tetrabutylammonium chloride to the2–Ag+, complex and after removal of AgCl,changes the color of the solution back to yellow(Fig.S8z).This observation indicated that the sensor is active toward Ag+and provided evidence of a reversible process.On the other hand,thefluorescence enhancement and the absence of color change of1is likely caused by Ag+coordina-tion with nitrogens of the two morpholine donors(Scheme2). Strong interactions between the benzylic amines and Ag+ blocks the PET quenching and results in afluorescence enhancement.This binding mode is also the reason for the absence of the color change of1upon addition of Ag+.It is interesting that the strong affinity of sulfur towards Ag+ compared with oxygen results in such a huge difference in the binding mode as well asfluorescence and colorimetric changes seen with1and2.The data fromfluorescence titration experiments(Fig.S9and S10z)give respective association constants of3.5Â103MÀ1 (error o10%)and3.2Â109MÀ2(error o15%)for compounds 1and2with Ag+.8In conclusion,the studies described above,have led to the design,preparation and testing of newfluorescein derivatives bearing morpholine,thiomorpholine and methylpiperazine groups for sensing silver ions.These substances display oppositefluorescence responses to pH changes as compared to2,7-dichlorofluorescein.Furthermore,1and2display extremely selective binding of Ag+at pH7.4.Chemosensor 1shows a selectivefluorescence enhancement with Ag+.On the other hand,thefluorescence of chemosensor2is quenched and a light yellow to pink color change takes place upon addition of Ag+.Different binding modes in complex forma-tion between the two compounds and Ag+shown in Scheme2 are the cause of differences observed influorescent and colorimetric changes.It is remarkable that oxygen in the morpholine unit and sulfur in the thiomorpholine unit of 1and2,respectively,can induce this huge difference in binding with Ag+in aqueous solution.It is likely that the observations made in this effort will provide the basis for a new strategy for the design offluorescein basedfluorescent chemosensors. Studies exploring the detailed reasons for the large p K a differences between1/2and3,as well as how to use different metal ion binding modes for the design of newfluorescent chemosensors and pH sensors are currently under way.This work was supported by grants from the NRL program (R04-2007-000-2007-0),the SRC program of KOSEF/MEST (R11-2005-008-02003-0)and WCU(R31-2008-000-10010-0) program.H.N.K.and J.H.S.thank BK21.Notes and references1(a)A.P.de Silva,H.Q.N.Gunaratne,T.A.Gunnlaugsson, T.M.Huxley,C.P.McCoy,J.T.Rademacher and T.E.Rice, Chem.Rev.,1997,97,1515;(b)J.F.Callan,A.P.de Silva andD.C.Magri,Tetrahedron,2005,61,8551;(c)C.-H.Lee,H.Miyaji,D.-W.Yoon and J.L.Sessler,mun.,2008,24;(d)J.Yoon,S.K.Kim,N.J.Singh and K.S.Kim,Chem.Soc.Rev.,2006,35,355;(e)T.Gunnlaugsson,M.Glynn,G.M.Tocci, P.E.Kruger and F.M.Pfeffer,Coord.Chem.Rev.,2006,250, 3094;(f)P. 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