Binaphthyl-Based Simple Receptors Designed for Fluorometric

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(rac)-1,10 -Binaphthyl-Based Simple Receptors Designed for Fluorometric Discrimination of Maleic and Fumaric Acids Kumaresh Ghosh* and Tanushree Sen Department of Chemistry, University of Kalyani, Kalyani-741235, India

Amarendra Patra Department of Chemistry, University College of Science, 92 A. P. C. Road, Kolkata 700 009, India

John S. Mancini, Justin M. Cook, and Carol A. Parish* Gottwald Center for the Sciences, Department of Chemistry, University of Richmond, Richmond, Virginia 23173, United States

bS Supporting Information ABSTRACT: (rac)-1,10 -Binaphthylbased simple receptors 1 and 2 have been designed, synthesized and studied theoretically. The receptors utilize naphthyridine as the binding motifs for complexation of dicarboxylic acids in CHCl3. The emission of the BINOL moiety was monitored experimentally to ascertain the selectivity and sensitivity of the receptors. Receptor 1 distinguishes maleic acid from isomeric fumaric acid by exhibiting different fluorescence behavior and demonstrates stronger binding in the excited state. Modulation of the binding sites of 1 leads to a new receptor structure 2, which was found to be less efficient in distinguishing maleic from fumaric acid, fluorometrically. Both 1 and 2 also recognize other hydroxy di- and tricarboxylic acids. The binding interactions were monitored by 1H NMR, fluorescence and UVvis spectroscopic methods. Structures of apo-hosts, guests and hostguest complexes were determined using force-field based conformational searching. Low energy ensembles were grouped into geometrically similar families, and low energy structures from each family were verified using B3LYP/6-31G*/PB-SCRF(CHCl3) calculations. The atomistic calculations provide insight into the differential dicarboxylic acid binding behavior of receptors 1 and 2.

’ INTRODUCTION Molecule-to-molecule interaction is a fundamental process in biology. Synthetic receptors, comprised of simple hydrogen bonding synthons designed to discriminate between closely related guest molecules, have recently attracted significant interest in the supramolecular chemistry community.13 In this respect, recognition of closely related carboxylic acids (i.e., either isomeric or structurally similar) is a compelling research topic,4 particularly given their important role in biology. There is a great need in the field of molecular recognition for synthetic fluorescent sensors that utilize weak hydrogen bonding interactions for the selective recognition of such small molecules.57 During the past decade, considerable progress has been made in the fluorescent and nonfluorescent recognition of di- and tricarboxylic acids by a number of synthetic receptors of various architectures.2,4,811 Despite this significant progress, there is a continued need for synthesizing simple fluorescent receptors for recognition of di- and tricarboxylic acids because of the many advantages including multiple modes of detection (such as quenching, enhancing, lifetime), extremely high sensitivity, relatively low cost, and easy availability. In this context, we herein report rac-1,10 -binaphthyl-based naphthyridine receptors 1 and 2 r 2011 American Chemical Society

for selective sensing of maleic acid from isomeric fumaric acid and closely related hydroxy acids. Recently, very few studies on the colorimetric discrimination of isomeric dicarboxylates such as maleate versus fumarate and phthalate versus isophthalate have been reported in the literature.1214 In particular, to the best of our knowledge, fluorometric discrimination between maleic and fumaric acids is not known. The interest in selective sensing of maleate or maleic acid and fumarate or fumaric acid is twofold. First, they are π-diastereomeric, and second, they are structurally similar but participate in different biological processes. Fumarate is generated in the Krebs cycle, whereas maleate is the inhibitor of this cycle, and its implication in different kidney diseases has been widely described.15 In this work, receptors 1 and 2 have been synthesized and well characterized using spectroscopic and theoretical techniques. These receptors were designed using 1,10 -bi-2-naphthol (BINOL)based sensing moieties with napthyridine bonding pockets. Received: March 10, 2011 Revised: May 4, 2011 Published: June 10, 2011 8597

dx.doi.org/10.1021/jp202304k | J. Phys. Chem. B 2011, 115, 8597–8608

The Journal of Physical Chemistry B

Receptor 1 strongly binds maleic acid and distinguishes it from isomeric fumaric acid by exhibiting distinctly different fluorescence behavior. By contrast, the structural modification of 1 leads to receptor 2, which displayed poor selectivity for maleic and fumaric acids.

’ EXPERIMENTAL METHODS Synthesis. Receptors 1 and 2 were synthesized according to Scheme 1. 2,20 -Binol was initially reacted with µ-chloroethyl acetate to yield compound 3. The ester groups in 3 were then hydrolyzed to give the acid 416 in 87% yield. Reaction of the

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diacid 4 with oxalyl chloride followed by coupling of the naphthyridine amines 6 and 7 yielded the desired receptor molecules 1 and 2, respectively, in appreciable yields. Naphthyridine amine 7 was synthesized according to our previously reported method.17 All compounds were characterized using standard methods, and data were in agreement with the proposed structures. Diethyl 2,20 -(1,10 -Binaphthyl-2,20 -diylbis(oxy))diacetate (3). 2,20 -Binol (1.00 g, 0.003 mol), ethyl R-chloroacetate (1.28 g, 0.01 mol), and anhydrous K2CO3 (1.2 g, 0.009 mol) were dissolved in 60 mL of dry acetone. The mixture was refluxed for 8 h. After evaporation of the solvent, water was added to the mixture, and the solution was then extracted with 3 20 mL CHCl3. The organic layers were collected, dried over anhydrous Na2SO4, and evaporated. The residue was purified on a silica gel column (eluent: petroleum ether/ethyl acetate 4:1) to give the pure product 3 as a gummy liquid (1.1 g, 68% yield); FTIR: ν cm1 (KBr): 3034, 2913, 2821, 1742, 1614, 1415, 1123. 2,20 -(1,10 -Binaphthyl-2,20 -diylbis(oxy))diacetic acid (4)13. Compound 3 (1.00 g, 0.002 mol) was dissolved in 30 mL of a 20% KOH solution in ethanolwater (80:20 v/v), and the solution was refluxed for 2 h. Ethanol was evaporated and cooled, distilled water was added, and the pH was adjusted to 1 with concentrated HCl. The precipitated solid was dissolved in ethyl acetate, dried over anhydrous Na2SO4, and evaporated to dryness to give compound 4 as a white solid (0.8 g, 91% yield). Mp 92 °C (lit. mp 9496 °C); FTIR: ν cm1 (KBr): 3045, 2920, 1737, 1622, 1594, 1509, 1426, 1285, 1215, 1076. (rac)-2,20 -(1,10 -Binaphthyl-2,20 -diylbis(oxy))bis(N-(7-methyl1,8-naphthyridin-2-yl)acetamide) (1). Compound 4 (0.3 g, 0.0007 mol) was stirred in dry CH2Cl2 (15 mL) in the presence of oxalyl chloride (0.2 mL, 0.002 mol) for 10 h. Solvent was evaporated under reduced pressure, and the residue was dried in vacuum to give diacid chloride 5. It was then redissolved in dry CHCl3 (20 mL) and stirred under a nitrogen atmosphere. To this stirred solution, 2-amino-7-methyl-1,8-naphthyridine (0.24 g, 0.001 mol) was added followed by addition of Et3N (0.2 mL, 0.001 mol). Stirring was continued for 18 h at room temperature (rt), and the solvent was evaporated, washed with saturated NaHCO3 solution, and extracted with CHCl3 (3 30 mL). The combined organic phases were washed with distilled water, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel with 3% CH3OH in CHCl3 as eluent to give the pure product 1 as a yellow solid (47% yield).

Scheme 1. Syntheses of Receptors 1 and 2

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dx.doi.org/10.1021/jp202304k |J. Phys. Chem. B 2011, 115, 8597–8608

The Journal of Physical Chemistry B Mp 160 °C. 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 2H, NHCO), 8.27 (d, 2H, J = 8.7 Hz), 8.0 (d, 4H, J = 7.3 Hz), 7.91 (d, 2H, J = 8.2 Hz), 7.81 (d, 2H, J = 8 Hz), 7.55 (d, 2H, J = 8.9 Hz), 7.317.29 (m, 4H), 7.247.19 (m, 4H), 4.92 (d, 2H, J = 15.8 Hz), 4.82 (d, 2H, J = 15.8 Hz), 2.71 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 168.5, 163.2, 154.4, 153.0, 152.4, 138.7, 136.2, 133.8, 130.6, 130.2, 128.2, 127.2, 125.4, 124.6, 121.6, 120.3, 118.6, 115.6, 114.2, 69.7, 25.6; FTIR: ν cm1 (KBr): 3364, 3058, 1708, 1610, 1506, 1435; Mass (EI): 707.0 (M þ Na)þ, 685.3 (M þ H)þ; Anal. Calcd for C42H32N6O4: C, 73.67; H, 4.71; N, 12.27. Found: C, 73.76; H, 4.68; N, 12.21. N-(7-(Pyridin-2-ylmethoxy)-1,8-naphthyridin-2-yl)acetamide (7a)17. To a stirred solution of 2-hydroxymethyl pyridine (0.6 g, 0.005 mol) in dry tetrahydrofuran (THF), NaH (0.14 g, 0.006 mol) was added and refluxed for 3 h under a nitrogen atmosphere. After cooling the solution, 2-acetamido-7-chloro1,8-napthyridine (1.45 g, 0.006 mol) was added followed by the addition of a catalytic amount of Cu2O. Reflux was continued for an additional 18 h. The desired product was isolated after extraction with CHCl3 (3 25 mL) followed by purification through column chromatography using 35% ethyl acetate in petroleum ether (6080 °C). The desired amide derivative of 7 was isolated as a white solid (1.1 g, 60% yield), Mp 156 °C, 1H NMR (500 MHz, CDCl3): δ 8.66 (d, 1H, J = 4 Hz), 8.40 (br s, amide NH, 1H), 8.36 (d, 1H, J = 8.5 Hz), 8.12 (d, 1H, J = 9 Hz), 8.01 (d, 1H, J = 8.5 Hz), 7.72 (t, 1H, J = 10 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.25 (t, 1H, J = 10 Hz), 7.04 (d, 1H, J = 9 Hz), 5.72 (s, 2H), 2.25 (s, 3H); FTIR: ν cm1 (KBr): 3300, 2921, 1702, 1613, 1571, 1507, 1330, 1284, 1131; UVvis (CHCl3): λmax 335, 327, 320, 313, 306, 261, 232, 219, 216 nm. 7-(Pyridin-2-ylmethoxy)-1,8-naphthyridin-2-amine (7). Compound 7a (1.2 g, 0.004 mol) was dissolved in 20% KOH in aqueous ethanol (15 mL) and refluxed for 15 h. After reaction completion, the volume was reduced by evaporation of solvent and finally extracted with chloroform (3 20 mL). The extracts were dried (Na2SO4) and concentrated in vacuum. The crude amine was isolated as white solid, in 85% yield. Mp 170 °C. 1H NMR (400 MHz, CDCl3): δ 8.63 (d, 1H, J = 4.36 Hz), 7.80 (m, 2H), 7.69 (t, 1H), 7.48 (d, 1H, J = 7.8 Hz,), 7.22 (m, 1H), 6.82 (d, 1H, J = 8.56 Hz), 6.61 (d, 1H, J = 8.48 Hz), 5.69 (s, 2H), 4.96 (s, amine NH-, 2H); FTIR: ν cm1 (KBr): 3473, 3364, 3188, 2913, 1638, 1595, 1512, 1432, 1324, 1246, 1137. (rac)-2,20 -(1,10 -Binaphthyl-2,20 -diylbis(oxy))bis(N-(7-(pyridin2-ylmethoxy)-1,8-naphthyridin-2-yl)acetamide) (2). Compound 4 (0.3 g, 0.0007 mol) was stirred in dry CHCl3 (20 mL) in the presence of oxalyl chloride (0.2 mL, 0.002 mol) for 10 h. Solvent was evaporated under reduced pressure, and the residue was dried in vacuum to give diacid chloride 5. It was redissolved in dry CHCl3 (20 mL), and to this solution compound 7 (0.38 g, 0.001 mol) and Et3N (0.2 mL, 0.001 mol) were added. The reaction mixture was stirred overnight at rt. Solvent was evaporated, washed with saturated NaHCO3 solution, and extracted with CHCl3 (3 30 mL). The combined organic phases were washed with distilled water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (eluent: 3% CH3OH in CHCl3) to give the product 2 as yellow solid (0.365 g, 42% yield). Mp 250 °C; 1H NMR (400 MHz, CDCl3): δ 8.90 (s, NHCO, 2H), 8.67 (d, 2H, J = 4.5 Hz), 8.10 (d, 2H, J = 8.6 Hz), 7.977.89 (m, 6H), 7.787.70 (m, 4H), 7.567.50 (m, 4H), 7.277.18 (m, 8H), 6.99 (d, 2H, J = 8.7 Hz), 5.77 (dd, 4H, J1 = 13.7 Hz, J2 = 4.4 Hz), 5.10 (d, 2H, J = 15.4 Hz), 4.70 (d, 2H, J = 15.4 Hz); 13C NMR (100 MHz,

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CDCl3): δ 167.9, 164.5, 157.0, 153.9, 152.6, 152.0, 149.5, 138.7, 138.6, 136.7, 133.7, 130.6, 130.1, 128.3, 127.1, 125.3, 124.4, 122.7, 121.9, 119.7, 117.2, 116.4, 115.2, 111.9, 69.0, 68.6; FTIR: ν cm1 (KBr): 3310, 1715, 1580, 1445; Mass (EI): 871.1 (M þ H)þ, 893.2 (M þ Na)þ; Anal. Calcd for C52H38N8O6: C, 71.71; H, 4.40; N, 12.87. Found: C, 71.82; H, 4.46; N, 12.96. General Procedure of UVVisible (UVvis) Titration. Binding constants were determined by UVvis titration methods. Initially, the receptors were dissolved in dry UV grade chloroform and added to a cuvette. Following this, carboxylic acid guests dissolved in dry CHCl3 containing 0.7% dimethyl sulfoxide (DMSO), were individually added in different amounts to the receptor solution. The corresponding absorbance values during titration were noted and used for the determination of binding constant values. Binding constants were determined using the expression18 A0/A A0 = [εM/(εM εC)](Ka1 Cg1 þ 1), where εM and εC are molar extinction coefficients for the receptor and the hydrogen-bonding complex, respectively, at selected wavelengths. A0 denotes the absorbance of the free receptor at the specific wavelength, and Cg is the concentration of the carboxylic acid guest. The linear relationship that results when plotting A0/A A0 versus Cg1 indicates a 1:1 stoichiometry of the receptorcarboxylic acid complex and allows the determination of the binding constant Ka as the ratio of the intercept to the slope.18 General Procedure of Fluorescence Titration. Stock solutions of the hosts were prepared in CHCl3, and 2 mL of the individual host solution was taken in the cuvette. The solution was irradiated at the BINOL excitation wavelength of 320 nm maintaining the excitation and emission slits. Upon addition of guest acids, the change in fluorescence emission of the host was observed. The corresponding emission values during titration were noted and used for the determination of binding constant values using the same method as described above for UVvis titration experiments.

’ COMPUTATIONAL METHODS Conformational Analysis. The conformational ensembles generated in this study were calculated using the MacroModel V9.5 suite of software19 programs running on 3.2 GHz Athlons under the Red Hat WS4 operating system. The OPLS2001 force field20 was utilized because it contained only high quality torsional parameters for 12. (See Supporting Information for the analysis of 8 different force fields.) Solvent effects were included using the generalized Born/surface area (GB/SA) continuum model2125,26a in order to study the conformational behavior of the receptors (water and chloroform) and receptorguest complexes (chloroform) in solvent. The GBSA model has been shown to reproduce solvation free energies obtained with the more elaborate PoissonBoltzmann (PB) method and to determine hydration free energies to within 0.9 kcal/mol of experimental data for a series of compounds.26b The low mode (LM) search method27,28 was used in a 1:1 combination29 with the Monte Carlo (MC) search method30 to explore the potential energy surfaces (PESs) of receptors 12 as well as the PESs of 1 and 2 in complexation with the dicarboxylic acids maleic, malic, fumaric, succinic, citric, and tartaric acid. Details regarding each seach can be found in the Supporting Information. Searches utilized the usagedirected structure selection method31 that identifies the least used structure from among all known conformations and then uses this structure as 8599



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the starting point for a new search. This ensures that a variety of different starting structures from different regions of the PES are used to begin each block of searching. During the conformational search all structures were subjected to 1500 steps of the truncated Newton conjugate gradient (TNCG)32 minimization method to within a derivative convergence criterion of 0.05 kJ Å1 mol1. The XCluster program was used to determine geometric similarities of different conformations within each ensemble.33 Quantum Studies. Unrestrained quantum mechanical (QM) geometry optimization using Jaguar V7.734 and the B3LYP/631G* methodological treatment were performed with fine density girds on each of the lowest energy structures obtained from the conformational analysis and subsequent clustering of receptors 12 and 12 in complexation with guest acids maleic, malic, fumaric, succinic, citric, and tartaric acid. In addition, a QM geometry optimization was performed on the lowest energy structure obtained from a conformational search on each acid. These QM calculations were used to to verify the molecular mechanics (MM) structures, to provide structures for further analysis as well as complex, receptor, and guest energies for use in calculating binding energies. Quantum geometry optimizations included the effects of solvent (CHCl3 and water) using the selfconsistent reaction field (SCRF) model with a PB solver.35,36 QM Binding Energies. Binding enthalpies were computed in PB (chloroform) at the B3LPYP/6-31G* level of theory. The binding enthalpy is defined as Ebinding = Ecomplex Ehost Eguest. Basis set superposition error was not determined for hostguest complexes due to the size of the systems under consideration. It is expected that this effect will be small for the calculations in PB (chloroform) as the screening provided by the continuum solvent model should minimize such mathematical artifacts.37

Figure 1. Partial 1H NMR of 1 in CDCl3 (c = 2.30 102 M) (a) and its 1:1 complexes with fumaric acid (b), maleic acid (c), and citric acid (d).

’ RESULTS AND DISCUSSION 1

H NMR Study. Initially, 1H NMR was used as a qualitative

measure of binding between 1 and 2 and different carboxylic acid guests. Upon the addition of equivalent amounts of carboxylic acids such as maleic, fumaric, succinic, rac-malic, D-tartaric, and citric acids (dissolved in CDCl3 containing 0.7% d6-DMSO) to the CDCl3 solution of receptor 1, the amide protons of 1 underwent a downfield shift (see Table 1) and the extent of shifting varied with the nature of the carboxylic acid. This was true also for receptor 2. DMSO is a common solvent used in NMR and fluorescence studies of biosensors; however, it has also been shown to hydrogen bond with the amide protons of host molecules - and in some cases to provide solvent-assisted hydrogen bond fluorescence deactivation pathways.38 In order to ascertain the effect of 0.7% d6-DMSO on the complexes in the Table 1. Change in Chemical Shift (Δδ) of the Interacting Amide Protons in 1:1 Complexes of Receptors 1 and 2 with Guest Acids guests maleic acid fumaric acid

receptor 1

receptor 2

(Δδ in ppm) NH

(Δδ in ppm) NH

broad 0.06

0.30 0.05

succinic acid

0.06

0.32

(rac)-malic acid

0.06

0.60

D-tartaric

0.16

0.40

0.11

0.80

citric acid

acid

Figure 2. Partial 1H NMR of 2 in CDCl3 (c = 1.54 103 M) (a) and its 1:1 complexes with fumaric (b), maleic (c), and citric acids (d).

present study, the NMR of apo-hosts 1 and 2 were recorded in the presence of CDCl3 and CDCl3 with ∼2% d6-DMSO. The addition of DMSO did produce a downfield shift of the host amide protons, however, to a smaller extent than observed in the hostguest complexes (Δδapo = 0.010.02 ppm; Δδcomplexes = 0.060.80 ppm). The difference between these ranges is attributable to the interaction of host with guests and suggests that for these receptors, DMSO plays a small role in the binding event. During complexation of dicarboxylic acids, the protons of the linker CH2 moiety present between the BINOL ether oxygen and the naphthyridine amide group were also found to undergo a downfield shift, albeit somewhat smaller (Δδ = 0.010.13 ppm for receptor 1 and Δδ = 0.010.13 ppm for receptor 2) than the amide proton shift described above. These changes in chemical shift values for CH2 protons may be due to either weak unconventional CH 3 3 3 O hydrogen bonding interactions with the guest acids or a subtle change in conformation of the receptor molecules during complexation. Molecular modeling results confirm the later (vide infra). The change in 1H NMR of 1 and 2 upon complexation of maleic, fumaric, and citric acids are shown in Figures 1 and 2, respectively. In the presence of maleic and citric acids the amide protons of 1 were broadened and difficult to measure quantitatively (Figure 1). Fluorescence and UVvis Studies. With NMR data suggesting interactions between receptors and carboxylic acid guests, 8600



Figure 3. Fluorescence ratio (I I0/I0) of receptor 1 (c = 1.58 105 M) at 374 nm upon addition of 6.0 equiv of a particular acid in CHCl3.

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Figure 5. Change in emission spectra of 1 (c = 1.58 105 M) upon addition of fumaric acid in CHCl3; Inset. Change in absorbance of 1 (c = 1.58 105 M) upon addition of fumaric acid.

Figure 4. Change in emission spectra of 1 (c = 1.58 105 M) upon addition of maleic acid in CHCl3; Inset. Change in absorbance of 1 (c = 1.58 105 M) upon addition of maleic acid.

Figure 6. Fluorescence titration curves ([Guest]/[Host] vs change in emission) of 1 (measured at 374 nm). The absolute value of ΔI has been taken in the plot.

fluorescence titrations were performed in CHCl3 to better understand the sensing behaviors of 1 and 2. Increasing amounts of various carboxylic acids, dissolved in CHCl3 containing 0.7% DMSO, were added to the CHCl3 solution of 1 and excited at 320 nm. It should be noted that the naphthyridine and BINOL motifs in both 1 and 2 are present in two different nonconjugated fluorophores. While naphthyridine17 absorbs in the region 330 to 345 nm, BINOL16 absorption occurs around 320 nm. In the present examples, the absorbance peaks for these two motifs overlap somewhat leading to a broad absorption band. However, emission spectra of BINOL and napthyridine are distinguishable as the emission spectrum of the former is characterized as a nonstructured band at 370 nm,16 whereas for the latter the emission peaks occur at 365 and 410 nm.17 As shown in Figures 36, the fluorescence behavior of the BINOL moiety in these complexes was dependent upon the nature and concentration of the guest acid. For instance, the fluorescence ratio (I I0)/I0 exhibits a marked change in the presence of maleic, fumaric, and tartaric acids. By comparison, the saturated analogue succinic acid exhibited a negligible change in fluorescence. It is particularly noteworthy that significant quenching was observed in the presence of maleic

acid but in the presence of isomeric fumaric acid, emission of the BINOL moiety in 1 increased considerably. This opposite fluorescent signaling behavior of 1 may be useful in distinguishing maleic from fumaric acid. Figures 4 and 5 show the changes in emission of 1 in the presence of maleic and fumaric acids, respectively. Simultaneous UVvis titrations of 1 were also performed to probe the ground state behavior of 1 in the presence of the acids. In the ground state, maleic, and fumaric acid complexes also behaved oppositely as shown in the absorbance spectra in the insets of Figures 4 and 5, respectively. The stoichiometries of the complexes were estimated from the break of the fluorescence titration curves (Figure 6). The sharp break of the curve for maleic acid with 1 at [G]/[H] = 1 indicated a 1:1 stoichiometry. A Job plot additionally confirmed the 1:1 stoichiometry with maleic acid (Figure 7a). In the case of fumaric acid, the linear nature of the titration curve in Figure 6 suggests that the trans disposition of this carboxylic acid may be causing significant changes in the manner in which this acid interacts with 1. However, a Job plot performed for this complex suggests a 1:1 stoichiometry for fumaric acid with 1 (Figure 7b). The molecular nature of these interactions will be explored below using theoretical methods. 8601



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Figure 7. Fluorescence Job plots of 1 (c = 1.55 105 M) with maleic (a) and fumaric acids (b).

Figure 8. Fluorescence ratio (I I0/I0) of receptor 2 (c = 2.10 105 M) at 356 nm upon addition of 6.0 equiv of a particular acid in CHCl3.

Figure 9. Fluorescence titration curves ([Guest]/[Host] vs change in emission) of 2 (measured at 356 nm). The absolute value of ΔI has been taken in the plot.

The 1H NMR study described above also suggested that receptor 2 showed promising interactions with guest acids. Therefore, we also investigated the sensing capability of 2 in CHCl3 using fluorescence titration methods. On the addition of various carboxylic acids, a decrease in the fluorescence emission of the BINOL moiety (λex = 320 nm) of 2 was observed in all cases. Figure 8 displays the fluorescence ratio (I I0)/I0 upon addition of a particular carboxylic acid guest and exhibits a marked change in emission only in the presence of citric acid. The sensory response of 2 to maleic and fumaric acids was small compared to 1. Thus, the addition of the extra pyridine rings to the naphthyridine nucleus does not have any marked effect in improving the binding and/or sensing behavior of 2 in the presence of maleic or fumaric acid. Figure 9 presents the titration curves that suggest all acids formed 1:1 complexes with 2. Job plots also supported the stoichiometries of the complexes. The binding constants of 1 and 2 with the various acids were determined by both fluorescence and UV methods.18 In all cases the binding is thermodynamically favorable. However, the most exciting result is the selectivity displayed by receptor 1 for binding to maleic acid. As can be seen from the fluorescence results in Table 2, the excited state of 1 binds maleic acid much

more strongly than fumaric acid, and more strongly than all the other acids under study. Relative to the binding differences exhibited in fluorescence, the UV results suggest that the ground state of 1 is somewhat less selective; however, it does show the strongest preference for binding to tartaric acid, followed by maleic, malic and citric acids. Binding of 1 to fumaric and succinic acid was not experimentally detectable, further suggesting the applicability of 1 as a sensor for discriminating between the biologically important isomeric maleic and fumaric acid. Receptor 2 did not exhibit any measurable selectivity in either the fluorescence or UV study. While the measured binding constants indicate that binding is favorable, 2 binds tartaric and citric acids less tightly than our previously reported receptor for citric acid.14 Overall, the binding constants were smaller for 2 than for 1, in spite of 2 possessing a larger number of possible hydrogen bonding sites. This may be due to the lower basicity of the naphthyridine ring in 2 as compared to the methyl naphthyridine moiety of 1. The binding constants reported in Table 2 were additionally verified using a nonlinear least-squares method.39 Binding constants determined in this way were comparable to the values obtained from a linear fit. For instance, the values obtained by fluorescence for 1 with maleic 8602



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Table 2. Binding Constant (Ka) Values of Receptors 1 and 2 with the Acids in CHCl3 receptor 1 Ka in M1 guestsa

fluorescence

UV

receptor 2 Ka in M1 fluorescence

UV

CHCl3

maleic acid

2.56 10

1.44 10

3.94 10

5.69 10

fumaric acid

4.81 103

b

2.89 103

6.61 103

succinic acid (rac)-malic acid

5.02 103

1.53 104

4.16 103 1.72 103

4.60 103 6.43 103

D-tartaric

3.00 104

7.39 104

6.01 103

3.07 103

9.39 10

3.43 10

1.33 10

citric acid

acid

5

4

3

3

3

H2O

gas-phase

3

Number of Structures Found

b

acid were (K = 2.50 ( 0.12) 105 M1 (nonlinear) and K = 2.56 105 M1 (linear) and with fumaric acid (K = 3.79 ( 0.21) 103 M1 (nonlinear) and K = 4.81 103 M1 (linear). Nonlinear curve fits can be found in the Supporting Information. ROESY spectra recorded in CDCl3 containing 2% d6-DMSO indicated that there are short-range interactions between CH3 and the naphthyridine ring proton as well as between the bridging CH2 and BINOL ring protons (see Supporting Information). Upon complexation of equivalent amounts of maleic acid, a weak NOE interaction between the CH3 group of the receptor 1 and the olefinic proton of maleic acid was noted. However, this was not observed with fumaric acid (see Supporting Information). This suggests that receptor 1 follows different binding modes for maleic and fumaric acids. Similar experiments were attempted with the same acids using receptor 2; however, we were only able to record the ROESY spectrum of 2 in the presence of an equivalent amount of maleic acid. In this experiment, no cross peak from the interaction between maleic acid and receptor 2 was noted. During the ROESY experiment with fumaric acid, precipitation appeared and it was difficult to obtain accurate results. Atomistic modeling of receptors 1 and 2, individual guest acids, and all 12 complexes of 1 and 2 with each acid was conducted in order to gain a molecular level understanding of hostguest behavior.

’ COMPUTATIONAL RESULTS Receptor Shape and Flexibility. The conformational behavior of hosts 1 and 2 was determined using 125 000 LM:MC conformational search steps on the OPLS2001 force field surface, in the gas-phase and in combination with the GB/SA continuum solvent model for water and chloroform.40 The ensemble data in Table 3 suggest that host 1 is relatively rigid, adopting only 611 low energy conformers and exhibiting very similar flexibility in all three solvent environments. Host 2 is significantly more flexible in water (141 unique conformations) but displays very similar behavior in CHCl3 and in the gas-phase. The unusually large number of structures in the ensemble for 2 in water corresponds to the increased flexibility of the (methoxymethyl) pyridine groups. In all cases, except 2 in water, the lowest energy structures for apo-hosts are either “X”- or “U”-shaped with approximately perpendicular orientations between the naphthyl rings in the binol moiety, as well as perpendicular or parallel orientations between the 1,8-naphthyridine rings on the

1

6

11

8

2

10

141

15

Number of Conformational Families

3

Guests were dissolved in CHCl3 containing 0.7% DMSO. “” indicates that binding constants were not determined due to a minor change in signal. a

Table 3. The Number of Structures Found on the OPLS2001 Force Field Surface within a 12.5 kJ/mol Energy Window and the Results of Clustering the MM Ensembles for 1 and 2 in Gas-Phase, Water, and Chloroform

1

3

2

2

2

3

2

2

other side of molecule. This causes the hydrogen bond donating and accepting groups to point inward creating welldefined binding pockets in most low energy conformers. (Figure 10). For 2 in chloroform and water, the pendant pyridine units form a hinge-like region at the top of the binding pocket. These results suggest that the receptors are preorganized for guest binding, particularly in CHCl3, the solvent used in the experimental work described above. The hydrogen bonding cavity of 2 is more compact compared to the cavity of 1. For instance, for 1 and 2 in CHCl3, the distance between the two terminal (outermost) N atoms on the naphthyridine rings in the lowest energy conformers is 6.77 and 4.32 Å, respectively. The XCluster program and manual clustering were used to determine whether structures fit into structurally similar groups. Clustering by atomic root-mean-square (rms) after rigid body superposition of all heavy atoms showed that each ensemble could be grouped into at most three families (Table 3). To verify the MM results, QM minimizations were also performed on the lowest energy structures from each conformational family identified on the MM surfaces. Superposition of the MM and B3LYP/ 6-31G* structures resulted in rms deviation (rmsd) values ranging from 0.90 Å to 12.27 Å and averaging 1.50 Å, indicating that the majority of the minima were well described using the classical PES, and some necessitated a QM treatment. Visualization of the QM structures showed that most of the conformational families maintain the “X” or “U” shape with different orientations of the naphthyridine moieties the exception being the highest energy family of 1 in water. Further information regarding the structures and relative energies of the conformational families found for unbound 1 and 2 can be found in the Supporting Information. The experimental study described above was conducted in CHCl3; therefore, all remaining theoretical work on receptorguest complexes was performed in this solvent environment. It should be noted that the continuum solvent approach undertaken here is unable to describe explicit solventsolute interactions; however, it has been shown to adequately capture bulk solvent properties.26b While the NMR study described above indicated that the 0.7% d6-DMSO added to increase the solubility of the guests does not play a major role in the complexation, it should be noted that the theoretical study did not explore this effect, and the structures shown below do not include the molecular effects of low concentrations of DMSO. Analysis of HostGuest Conformational Behavior. A conformational search of each hostguest complex was also conducted by manually docking geometry optimized citric, fumaric, maleic, succinic, tartaric, and malic acid into the binding pocket of the lowest energy conformation of each receptor. These 8603



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Figure 10. Lowest energy structures found for 1 and 2. These structures were obtained by performing 125 000 LM:MC search steps on the OPLS-2001 PES in H2O, CHCl3, and gas-phase to generate an ensemble of low energy structures, which were verified by performing additional geometry optimizations using B3LYP/6-31G*. The SCRF-PBF solvent model was used to obtain QM results in CHCl3 and H2O.

Table 4. The Number of Statistically Significant Geometrical Families for Each HostGuest Complex in CHCl3a receptor

maleic

fumaric

succinic

malic

tartaric

citric

1

2

2

4

2

2

2

2

7

2

2

1

2

2

a

The lowest energy structure from each family is shown in Figures 11 and 12.

complexes were subjected to 125 000 LM:MC search steps in which the xyz coordinates and angular orientation of the guest (relative to the host) were sampled in addition to host and guest intramolecular torsional degrees of freedom. Detailed results of the complex conformational search can be found in the Supporting Information. The ensembles of low energy structures generated in this manner were subjected to geometrical clustering, and the lowest energy member of each cluster was subjected to B3LYP/6-31G*(PBF(CHCl3)) geometry optimizations. Superimpositions of the MM and QM structures yielded rmsd values no greater than 1.60 Å; therefore the remainder of this work will focus on the QM structures. The number of families found for each hostguest complex is shown in Table 4, and the structure of the lowest energy member of each family is shown in Figures 11 and 12. Detailed results of the superimpositions can be found in the Supporting Information. Analysis of HostGuest Interactions. The receptors 1 and 2 are surprisingly agile in their ability to adopt conformations that bind optimally with the differently sized guests. This is in spite of showing limited flexibility in the apo state. In many ways, this represents the ideal behavior for a receptor: flexible enough to accommodate a variety of guests, but not so flexible in the apo state that the binding cavity collapses preventing any possible binding.41 A detailed analysis of the receptorguest structures reveals that, in most cases, the host retains the “X” shaped conformation while also being flexible enough to wrap the naphthyridine “arms” around even the bulkiest guest. In complexes

with receptor 1, hostguest binding is generally characterized by hydrogen bonds between the hydroxyl groups of the guests and the amide protons and/or the nitrogen atoms on the naphthyridyl “arms” of the hosts. In contrast, hostguest binding involving receptor 2 is most often the result of guests interacting favorably with the carbonyl oxygen on the host. The best example of the host’s ability to interact with the guest is the lowest energy structure of 1 with fumaric (“fumaric A” in Figure 11). The host is able to spread its “arms” to great extremes in order to tightly bind to fumaric acid. However, in the lowest energy structure of the next family of 1 with fumaric acid, the host interacts less with the guest, forming only one hydrogen bond between a napthyridine lone pair and one of the acidic protons and instead forms hydrogen bonds to itself. However, the representative structure from this bonding motif lies almost 10 kcal/mol higher in energy than the more optimally oriented fumaric:1 complex. An examination of the structural differences between complexes containing hosts 1 and 2 provides insight into the tighter binding capabilities of host 1. In many cases, the methoxymethyl pyridine “hinge” units in 2 do not interact with the guest, the exception being with some of the maleic acid conformations. The “hinges,” in the cases of complexes with tartaric, fumaric, and maleic acids, wrap around to form intramolecular (within the host) hydrogen bonding interactions with the amide proton or establish π stacking interactions with the napthyridine rings, and this contributes to an overall smaller binding site in conformers of 2 versus 1. It was expected that the single bond between the naphthalene rings in the binol moiety in 1 and 2 could act as a “pivot” or “lever”, controlling the size of the binding cavity formed by the two naphthyridine arms; however, a detailed analysis of this dihedral angle in the resulting ensembles resulted in very similar average distances (78.5° and 78.9° for 1 and 2, respectively). Furthermore, a detailed analysis of the hydrogen bonding behavior exhibited in the theoretical structures suggest that receptor 1 is more likely or able to adopt conformations that involve both napthyridine rings in binding, whereas complexes of 2 typically involve only one napthyridine arm. These differences 8604



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Figure 11. Representative structures of each conformational family in hostguest complexes of 1. Structures increase in energy from left to right; relative energies reported in kcal/mol. These structures were obtained by performing 125 000 LM:MC search steps on the OPLS-2001/GBSA(CHCl3) PES, generating an ensemble of low energy structures that were clustered, and the lowest energy structure from each family was verified by performing additional geometry optimizations using B3LYP/6-31G*/ SCRF-PB (CHCl3).

in receptor flexibility may play a role in the overall tighter binding found for 1 both experimentally (Table 2) and theoretically (vide infra). Conserved Receptor Binding Motifs. There is a significant degree of structural conservation in the bound receptor conformations. In the lowest energy structure of citric, maleic, and succinic acids with 1 and higher energy “B” structure of malic acid with 1, the receptor naphthyridine moieties adopt a V-shape. The all-atom rmsd of these complexes of 1 with citric, malic, and succinic acid are all less than 0.37 Å. The complex between 1 and maleic acid is the mirror image of these structures. A second structural motif found in complexes with 1 is characterized by significant naphthyridinebinol ππ stacking. This conformation occurs for the complex of 1 with malic acid A, citric acid B, and succinic acid B (Figure 11). All-atom rmsd values for these structures were less than 0.85 Å. Alternate images highlighting these structural motifs may be found in the Supporting Information. Complexes with 2 display only one conserved structural motif characterized by hydrogen bonding between the guests and the naphthyridine moieties and intrahost ππ stacking between a pyridine ring from the “hinge” region and one of the naphthyridine moieties. The conserved structure is illustrated in the A conformers with citric, fumaric, and malic acid, the B structure with succinic acid and G structure with succinic acid (Figure 12). All-atom rmsd values after rigid-body superposition was less than 1.13 Å. A Molecular View of the Differences in Fluorescence Behavior in ReceptorAcid Complexes. Receptors 1 and 2

are fluorescent in the absence of guests presumably due to excitation and subsequent emission of the BINOL moiety. It is well-known that fluorescence lifetimes can be shortened or quenched by a ππ* or nπ* interaction with a neighboring chromophore.42,43 The molecular modeling results presented here did not study the excited states of the receptors, making it difficult to give a generalized mechanism for quenching. However, analysis of the QM structures strongly suggests that the spectroscopic behavior observed experimentally is controlled by conformational changes that occur upon guest binding and that allow for significant ππ stacking or nπ interaction between different regions of the host. When guest binding leads to receptor conformational changes where such intrahost electrostatic interactions are more numerous or more proximate, it results in fluorescence quenching. When guest binding leads to conformations where such interactions are less numerous or more distant, fluorescence in the complex may be enhanced relative to the fluorescence found in the apo-host. From a detailed comparison of the experimental spectroscopic data with the structures for each complex, we see a trend whereby naphthyridinenaphthyridine stacking is a more effective quencher of fluorescence than naphthyridinebinol interactions. For instance, experimental results show the greatest increase in fluorescence occurs for fumaric and tartaric acid with 1 and in these structural ensembles we see the least amount of naphthyridinenaphthyridine stacking. Analysis of the geometry optimized structures shows that the distance between the naphthyridine moieties in 1 with fumaric and tartaric are so large 8605



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Figure 12. Representative structures of each conformational family in hostguest complexes of 2. Structures increase in energy from left to right; relative energies reported in kcal/mol. These structures were obtained by performing 125 000 LM:MC search steps on the OPLS-2001/GBSA(CHCl3) PES, generating an ensemble of low energy structures that were clustered, and the lowest energy structure from each family was verified by performing additional geometry optimizations using B3LYP/6-31G*/ SCRF-PB (CHCl3).

(712 Å) as to exhibit no ππ interactions. Guest binding does cause some ππ interaction between a naphthyridine and a binol moiety in fumaric complexes with 1. However, binol naphthyridines stacking interactions appear to quench the system to a lesser degree than the naphthyridinenaphthyridine stacking found in other complexes. This is possibly due to lower electron densities in the binol moieties. Citric and malic acid enhance the fluorescence of 1, and these structures also show no naphthyridinenaphthyridine stacking and limited binol naphthyridine interactions. Maleic (to a great extent) and succinic (to a much lesser extent) are the only two acids that quench the emission of 1. These are also the only two acids that, when they bind to 1, cause a conformational change in the receptor that orients each naphthyridinenaphthyridine in an optimal stacking arrangement as best illustrated by the complexes with maleic B and succinic B and D as shown in Figure 11. Experimentally, the binding of any guest acid quenches the emission of receptor 2. An analysis of the theoretical structures indicates that in almost all cases, guest binding to 2 causes a conformational change that promotes face face ππ or maintains edgeface nπ stacking. Experimentally it was found that complexation of citric acid to 2 results in the greatest quenching, and the structural analysis indicates that this complex contains the most ππ interactions. Quantitative measurements of chromophore interactions and distances may be found in the Supporting Information. Theoretical Analysis of Binding Energies. Theoretical binding enthalpies (Ebinding = Ecomplex Ehost Eguest) were

Table 5. B3LYP/6-31G* Binding Energies (kcal/mol) Measured in CHCl3 1

ΔH

2

ΔH

citric A

19.0

citric A

7.9

citric B

16.1

citric B

2.5

fumaric A

11.0

fumaric A

5.1

fumaric B maleic A

0.7 17.8

fumaric B maleic A

4.9 20.4

maleic B

7.6

maleic B

19.1

malic A

11.7

maleic C

15.5

malic B succinic A

7.6

maleic D

15.1

18.8

maleic E

12.6

succinic B

14.8

maleic F

7.5

succinic C

13.6

maleic G

3.5

succinic D tartaric A

10.5 1.7

malic A succinic A

3.7 4.7

tartaric B

2.7

succinic B

4.2

tartaric A

5.4

tartaric B

4.3

determined in PB-SCRF(CHCl3) using B3LYP/6-31G* (Table 5). All complexes displayed favorable binding energetic, except for the B conformer of 1 with tartaric acid. According to these enthaplic results, receptor 1 binds most favorably to maleic, succininc, malic, and citric acids. Receptor 2 binds most favorably 8606


The Journal of Physical Chemistry B to maleic acid. These results are not in agreement with the UVvis experimental results, which indicate very little guest acid discrimination for either host in the ground state. It is not possible to compare these ground state theoretical results with the promising fluorescence behavior determined experimentally. The disagreement between our theoretical and ground state experimental data may well reflect weaknesses in the continuum solvent model employed, an inability of the density functional approach to capture some of the more subtle details of the intermolecular energetics, or the neglect of conformational entropy in the theoretical binding calculations.

’ CONCLUSION We have designed and synthesized (rac)-binol-based naphthyridine receptors 1 and 2 in the context of selective sensing of maleic acid from fumaric and other structurally similar hydroxy di- and tricarboxylic acids. The fluorescence sensory response of 1 to maleic acid is promisingly high compared to 2. To the best of our knowledge, fluorometric discrimination between maleic and fumaric acids by such a simple receptor is unknown in the literature. Two-dimensional NMR spectroscopic determination of binding constants and theoretically determined structures confirm that the hosts are interacting favorably with the guests. In the absence of the guests, the hosts are relatively rigid but adopt low energy conformations with well-defined binding pockets. In the presence of the guests, the hosts are able to undergo significant conformational adaptation in order to bind with the guests. Receptor 1 binds guest more favorably than receptor 2, likely due to increased flexibility that leads to optimal hostguest structural interactions. There is evidence that the selectivity of 1 for maleic acid is due to guest interactions that promote ππ stacking and subsequent quenching of fluorescence. ’ ASSOCIATED CONTENT

bS

Supporting Information. Computational results (force field analysis, geometries, energies, structurally related measurements, pairwise atomistic superpositions) and ROESY and NOESY spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*Email: [email protected] (K.G.); cparish@richmond. edu (C.A.P.).

’ ACKNOWLEDGMENT We thank CSIR, New Delhi, India, for financial support. T.S. thanks CSIR, New Delhi, India, for a fellowship. The work was also supported by the NSF RUI (Grant CHE-0809462) and the Henry Dreyfus Teacher Scholar Award (C.A.P.) programs, as well as the HHMI Undergraduate Science Education Program and the Floyd D. and Elisabeth S. Gottwald Endowment. Support is also acknowledged from the Donors of the American Chemical Society Petroleum Research Fund. ’ REFERENCES (1) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc., Perkin Trans. 1 2000, 3155.

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Binaphthyl-Based Simple Receptors Designed for Fluorometric

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