Hydrogen bonding heavily influences conformations, rate of reactions, and chemical equilibria. The development of a method to monitor hydrogen bonding interactions independent of polarity is challenging as both are linked. We have developed two solvatochromic dyes that detect hydrogen-bond-donating solvents. The unique solvatochromism of the triazine architecture has allowed the development of probes that monitor hydrogen-bond-donating species including water

Anfinsen

Bergen

Bock

Bohne

Bonn

Brian Creran

Carroll

Cuello

Fita

Graeme Cooke

Hemmateenejad

Huynh

Ihmels

Jordan

Kamlet

Mahdieh Yazdani

Matsubayashi

McDonald

Mehranpour

Pinheiro

Reichardt

Ryan F. Landis

Shie

Solnstev

Vikas Nandwana

Vincent M. Rotello

Vitha

Wolfshorndl

Xi Yu

English

Crossref

Chemical Communications

Solvatochromic probes for detecting hydrogen-bond-donating solvents

Landis, Ryan F.

Yazdani, Mahdieh

Creran, Brian

Yu, Xi

Nandwana, Vikas

Cooke, Graeme

Rotello, Vincent M.

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          Landis, Ryan F., Yazdani, Mahdieh, Creran, Brian, Yu, Xi, Nandwana, Vikas, Cooke, Graeme, and Rotello, Vincent M. (2014)Solvatochromic probes for detecting hydrogen-bond-donating solvents. Chemical Communications, 50 (35). p. 4579. ISSN 1359-7345   Copyright © 2014 The Authors     http://eprints.gla.ac.uk/94692/    Deposited on:  24 June 2014                     Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk This journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 4579--4581 | 4579Cite this:Chem. Commun., 2014,50, 4579Solvatochromic probes for detectinghydrogen-bond-donating solvents†Ryan F. Landis,a Mahdieh Yazdani,a Brian Creran,a Xi Yu,a Vikas Nandwana,aGraeme Cookeb and Vincent M. Rotello*aHydrogen bonding heavily influences conformations, rate of reactions,and chemical equilibria. The development of a method to monitorhydrogen bonding interactions independent of polarity is challengingas both are linked. We have developed two solvatochromic dyes thatdetect hydrogen-bond-donating solvents. The unique solvatochromismof the triazine architecture has allowed the development of probes thatmonitor hydrogen-bond-donating species including water.Solvatochromic probes are important in the study of solute–solvent interactions. The function of these probes depends onthe overall solvation process around the solute.1 Solvent char-acteristics, such as polarity and hydrogen-bonding, influencemolecular conformations, reaction rates, and system chemicalequilibria.2 In addition, both polarity and hydrogen bondingare major contributors to the stabilization of protein folding andbinding sites.3 Previously, organic fluorescent dyes possessingsolvatochromic properties have been used to investigate environ-mental changes in biomembrane imaging,4 ion sensing,5 andoil–water interface applications.6The spectral shifts of current solvatochromic dyes are influencedby both dipole interactions and hydrogen bonding.7 These dyescannot distinguish between the two interactions, which makesassessing the response of each interaction to environmental changediﬃcult. This lack of specificity complicates the use of the dyes inmonitoring hydrogen-bond strengths,8 hydrogen-bond-based con-formation changes,9 and detecting water and other hydrogen-bond-donating species.10 Development of a solvatochromic dye capableof monitoring how hydrogen bonding influences overall structure,independent of polarity, is therefore desirable.Here, we report the development of organic dyes, 6-(3-amino-phenyl)-1,3,5-triazine-2,4-diamine (MADAT) and its acetylated analog,AMADAT, which have the ability to detect hydrogen-bond-donatingsolvents. While the emission shift of both MADAT and AMADAT islargely unchanged in all aprotic solvents regardless of polarity, thesedyes show a significant bathochromic shift in protic solvents. Thisresult shows the potential of these solvatochromic dyes to monitorsmall changes in protic environments, independent of polarity, bymonitoring the bathochromic shift of their emission spectra.Scheme 1 outlines the synthesis of MADAT and the acetylatedanalogue, AMADAT. MADAT was synthesized by heating under reflux3-aminobenzonitrile with dicyandiamide in 1-butanol in the presenceof a catalytic amount of potassium hydroxide.11 AMADAT wassynthesized by treating 3-aminobenzonitrile with acetic anhydridein dichloromethane (DCM) to form N-(3-cyanophenyl)acetamide.Next, the acetamide and dicyandiamide was heated to reflux underthe same conditions used to synthesize MADAT to form AMADAT.By using commercially available materials, minimal steps, and asimple purification protocol, large-scale synthesis of these dyes canbe conveniently performed at a low cost.Scheme 1 Synthetic steps to (a) MADAT and (b) AMADAT.a Department of Chemistry, University of Massachusetts, 710 North Pleasant Street,Amherst, Massachusetts, USA. E-mail: rotello@chem.umass.edubWestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow,Glasgow, G12 8QQ, UK† Electronic supplementary information (ESI) available: Quantum yield ofMADAT in DCM and methanol. Emission of MADAT in phenol and trifluoro-ethanol. AMADAT emission in various solvents. Linear correlation betweenconcentration of thymine 1 and fluorescence intensity. Addition of N-Me thymine2 to MADAT in DCM. Linear relation between water concentration and fluores-cence intensity. Concentration versus emission plots for MADAT and AMADAT.See DOI: 10.1039/c4cc00805gReceived 29th January 2014,Accepted 14th March 2014DOI: 10.1039/c4cc00805gwww.rsc.org/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 17 March 2014. Downloaded on 24/06/2014 14:40:04.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal  | View Issue4580 | Chem. Commun., 2014, 50, 4579--4581 This journal is©The Royal Society of Chemistry 2014The influence of solvents on the spectroscopic properties ofMADAT was determined by UV-Vis absorption and fluorescencespectroscopy (Fig. 1). Minor changes in absorption spectra wereobserved (Fig. 1a) in either aprotic or protic solvents. In addition, theemission spectrum of MADAT (Fig. 1b) was largely unchangedin aprotic solvents; however a significant bathochromic shift wasseen in protic solvents. The same phenomenon was observedfor AMADAT (S1, ESI†). Protic solvents dramatically aﬀected theemission spectrum of these triazine dyes regardless of theirchemical structure. Interestingly, strongly hydrogen bonddonating solvents such as phenol and trifluoroethanol resultedin complete quenching of MADATs emission (S2, ESI†).Emission shifts of solvatochromic materials are the result ofenvironmental changes. As the material is excited by light, solventmolecules align their dipoles with the solute. This realignmentcan stabilize/destabilize and lower/raise the energy of emissionfrom the solute, causing diﬀerent light emissions from the samesolute in diﬀerent solvents. Since the emission of MADAT doesnot greatly shift in aprotic solvents regardless of polarity, theremay be no significant stabilization from the solvent or little chargeseparation within MADAT. The selective response of MADAT toprotic solvents could arise from hydrogen-bonding interactionsfrom the diamino units or the nitrogen atoms within the triazinering. We hypothesize that the triazine ring serves as a multiple-hydrogen-bond acceptor and is the cause of the large emissionshift. Attention was first directed towards the amino groups ofMADAT to rule out hydrogen bonding at these positions.MADAT was subjected to additions of thymine 1 in DCM (Fig. 2).As the concentration of 1 was increased, fluorescence quenchingalong with bathochromic shifts were observed in the emissionspectra. These eﬀects are attributed to the presence of three-pointhydrogen bonding between thymine 1 and the DAT ring ofMADAT.12 A linear correlation between the concentration of 1 andthe fluorescence intensity was observed (S3, ESI†). As a control, theimide group of 1 was methylated before addition to MADAT inDCM; in this case no quenching or shift was observed (S4, ESI†).Since 1 can only bind to one DAT ring nitrogen atom due to stericeﬀects, we believe that large bathochromic shifts require multiplehydrogen-bond interactions to occur with the triazine ring ofMADAT. The need for such multiple interactions would furthersupport the experimental results that showed a more significantemission shift in protic solvents due to the small size of the solventmolecules and their ease of access to the nitrogen ring atoms.Kamlet–Taft plots are used to distinguish intermolecularinteractions between solute and solvent.13 This method providesvaluable data on how a solute interacts with solvent through bothpolarity and hydrogen bonding. MADAT can distinguish hydrogenbonding from polarity without the need for Kamlet–Taft plots inboth a qualitative and quantitative manner. This solvatochromicphenomenon can be useful in the detection of water in othermedia. As a proof of concept, MADAT was used to monitor waterlevels in tetrahydrofuran (THF; Fig. 3). Emission of MADAT inanhydrous THF was observed while adding small aliquots ofwater. Addition of water resulted in fluorescence quenching anda bathochromic shift in the emission spectra. A linear relationbetween amount of water added and fluorescence intensity wasfound (S5, ESI†), with a detection limit of detection of 0.014 wt%and a quantification limit of 0.044 wt%.In conclusion, new solvatochromic dyes demonstrate largebathochromic shifts of their emission spectrum in hydrogen-bond-donating solvents only, caused by the presence of the1,3,5 triazine moiety. These new types of probes therefore have thepotential to monitor hydrogen-bonding interactions independentof environmental polarity. We believe that a range of new solvato-chromic materials can be readily constructed using the triazinearchitecture as modification of the aryl amine does not disrupt thesolvatochromic properties. This hydrogen-bond-selective solvato-chromic feature could prove very useful in developing sensors forhydrogen-bond-donating species.Fig. 1 (a) Normalized absorption and (b) emission spectra of MADAT [0.22 mM],[0.12 mM] (DCM) in various solvents. lex: aprotic = 330 nm, protic = 325 nm.Fig. 2 Thymine 1 additions to MADAT [0.12 mM] in DCM. lex = 330 nm.Communication ChemCommOpen Access Article. Published on 17 March 2014. Downloaded on 24/06/2014 14:40:04.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineThis journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 4579--4581 | 4581All solvents and reagents were purchased from commercialsources and were used as received, unless otherwise noted.Deionized water was used in all steps where water was required.1H and 13C NMR spectra were recorded using a Bruker 400 MHzspectrometer. mM concentrations were used for absorption andemission spectra, unless otherwise noted. Absorption and emissionmeasurements were performed on a Varian UV-Vis spectro-photometer and a PTI fluorometer respectively using a quartzcuvette.Synthesis of 6-(3-aminophenyl)-1,3,5-triazine-2,4-diamine (MADAT):To a solution of 3-aminobenzonitrile (1.0 eq., 5.0 g, 42.32 mmol)and dicyandiamide (1.2 eq., 4.27 g, 50.79 mmol) in 1-butanol(100 ml) was added solid potassium hydroxide (0.2 eq., 0.339 g,8.464 mmol). The mixture was heated to reflux under atmosphericconditions for 18 h. After the time allotted, the flask was cooled inan ice bath and water (50 ml) was added to fully precipitate theproduct. The precipitate was filtered oﬀ and suspended in hotwater (100 ml) and stirred for 5 min. The precipitate was filteredand lyophilized to yield MADAT (89%). Mp 210–211 1C; e2543 M1 cm1 (DCM), 1650 M1 cm1 (methanol); 1H NMR(CD3OD, 400 MHz) d: 7.6 (s, 1H), 7.56 (1H, J = 1.2 Hz, 1H), 7.19(t, J = 1.2 Hz, 1H), 6.88 (d, J = 1.8 Hz, 1H); 13C NMR (DMSO,400 MHz) d: 171.40, 167.82, 148.87, 138.24, 128.93, 117.09,116.20, 113.78; HRMS m/z (M + H)+ calcd for C9H10N6: 203.10.Found: M + H = 203.10.Synthesis of N-(3-cyanophenyl)acetamide: 3-aminobenzonitrile(1.0 eq., 5.0 g, 42.32 mmol) was dissolved in dichloromethane(50 ml). Acetic anhydride (1.1 eq., 4.75 g, 4.40 ml, 46.55 mmol)was added slowly to the stirred solution and allowed to reactovernight. The solution was concentrated under reduced pressureand the mixture dissolved in ethyl acetate (100 ml). The solutionwas cooled to 0 1C and saturated sodium bicarbonate was addedto the solution and allowed to stir for five minutes. The organiclayer was separated and washed twice with brine solution (50 ml).The organic layers were combined, dried with sodium sulfate,filtered, and concentrated under reduced pressure to yieldN-(3-cyanophenyl)acetamide (97%) and used without furtherpurification; 1H NMR (CD3OD, 400 MHz) d 7.71 (d, J = 1.2 Hz,1H), 7.66 (s, 1H), 7.65 (d, J = 0.6 Hz, 1H), 7.34 (t, J = 1.8 Hz, 1H),2.21 (s, 3H).Synthesis of AMADAT: N-(3-cyanophenyl)acetamide (1.0 eq.,3.0 g, 18.74 mmol) and dicyandiamide (1.2 eq., 1,891 g,22.49 mmol) were dissolved in 1-butanol (100 ml) and solidpotassium hydroxide (0.2 eq., 0.150 g, 3.75 mmol) was added.The mixture was heated to reflux under atmospheric conditionsfor 18 h and cooled in an ice bath. Water (50 ml) was added tofully precipitate the product. The precipitate was filtered oﬀand suspended in hot water (100 ml) and stirred for 5 min. Theprecipitate was filtered and lyophilized to yield AMADAT (93%).Mp 276–277 1C; e 1144M1 cm1 (DCM), 1089M1 cm1 (methanol);1H NMR (CD3OD, 400 MHz) d 8.41 (s, 1H), 8.0 (d, J = 1.2 Hz, 1H),7.74 (d, J = 1.2 Hz, 1H), 7.41 (t, J = 2.4 Hz, 1H), 2.17 (s, 3H); 13C NMR(DMSO, 400 MHz) d: 170.73, 168.83, 167.85, 139.60, 138.18,128.83, 123.11, 122.31, 119.25, 24.40; HRMS m/z (M + H)+ calcd forC11H12N6O: 245.10. Found: M + H = 245.5.VR acknowledges funding from the NSF (CHE-1307021 andCHE-1025889) and GC acknowledges the EPSRC.Notes and references1 (a) K. Solnstev and D. Huppert, J. Phys. Chem. A, 1998, 102,9599–9606; (b) C. Reichardt, Chem. Rev., 1994, 94, 2319–2358.2 (a) C. Bohne, H. Ihmels, M. Waidelich and C. Yihwa, J. Am. Chem. Soc.,2005, 127, 17158–17159; (b) A. Bergen, C. Bohne, D. Fuentealba,H. Ihmels, T. Waidelich, C. Yihwa and J. Bats, Photochem. Photobiol.Sci., 2012, 11, 752–767; (c) H. Ihmels, Eur. J. Org. Chem., 1999, 1595–1600.3 C. Anfinsen, Science, 1973, 181, 223–230.4 P. Yan, A. Xie, M. Wei and L. Loew, J. Org. Chem., 2008, 73,6587–6594.5 J. Wu, W. Liu, J. Ge, H. Zhang and P. Wang, Chem. Soc. Rev., 2011,40, 3484–3495.6 M. Vitha, ACS Symp. Ser., 2011, 1062, 51–97.7 (a) A. Mehranpour and S. Hashemnia, J. Chin. Chem. Soc., 2006, 53,759–765; (b) B. Hemmateenejad, M. Yazdani and H. Sharghi,Spectrochim. Acta, Part A, 2012, 91, 198–205.8 (a) P. Huynh, R. Walvoord andM. Kozlowski, J. Am. Chem. Soc., 2012,134, 15621–15623; (b) M. Hao, J. Chem. Theory Comput., 2006, 2,863–872; (c) A. Cuello, C. McIntosh and V. Rotello, J. Am. Chem. Soc.,2000, 122, 3517–3521; (d) J. Carroll, M. Gray, K. McMenimen,D. Hamilton and V. Rotello, Org. Lett., 2003, 5, 3177–3180;(e) K. Matsubayashi and Y. Kubo, J. Org. Chem., 2008, 73, 4915–4919.9 (a) H. Bock, N. Nagel and C. Na¨ther, Chem. – Eur. J., 1999, 5, 2233–2236;(b) P. Fita, M. Fedoseeva and E. Vauthey, J. Phys. Chem. A, 2011, 115,2465–2470; (c) D. Cui, X. Qian, F. Liu and R. Zhang, Org. Lett., 2004, 6,2757–2760; (d) M. Bonn, H. Bakker, A. Ghosh, S. Yamamoto, M. Sovagoand K. Campen, J. Am. Chem. Soc., 2010, 132, 14791–14978.10 (a) M. Wolfshorndl, R. Baskin, I. Dhawan and C. Londergan, J. Phys.Chem. B, 2012, 116, 1172–1179; (b) C. Pinheiro, J. Lima andA. Parola, Sens. Actuators, B, 2006, 114, 978–983.11 J. Shie and J. Fang, J. Org. Chem., 2003, 68, 1158–1160.12 (a) B. Jordan, M. Pollier, Y. Ofir, S. Joubanian, J. Mehtala, C. Sinkel,S. Caldwell, A. Kennedy, G. Rabani, G. Cooke and V. Rotello, Chem.Commun., 2008, 1653–1655; (b) N. McDonald, C. Subramani,S. Caldwell, N. Zainalabdeen, G. Cooke and V. Rotello, TetrahedronLett., 2011, 52, 2107–2110.13 M. Kamlet, A. Solomonovici and R. Taft, J. Am. Chem. Soc., 1979, 101,3734–3739.Fig. 3 Changes in fluorescence emission of MADAT [0.22 mM] in THFupon addition of water. lex = 330 nm.ChemComm CommunicationOpen Access Article. Published on 17 March 2014. Downloaded on 24/06/2014 14:40:04.  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Solvatochromic probes for detecting hydrogen-bond-donating solvents

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