Comparison of Complexation-Induced p K a Shifts in the Ground and

Article pubs.acs.org/JPCB

Cite This: J. Phys. Chem. B 2017, 121, 11390−11398

Comparison of Complexation-Induced pKa Shifts in the Ground and Excited States of Dyes as Well as Different Macrocyclic Hosts and Their Manifestation in Host-Retarded Excited-Dye Deprotonation Alexandra I. Lazar,† Jana Rohacova,†,‡ and Werner M. Nau* Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany S Supporting Information *

ABSTRACT: 1-Aminopyrene and 1-naphthylamine-5-sulfonic acid were converted to the putrescine (1,4-diaminobutane)-substituted derivatives (dyes 1 and 2). The diaminobutyl anchor serves as a common binding motive for cation-receptor macrocycles such as cucurbit[n]urils (n = 6−8) and p-sulfonatocalix[4]arene. When protonated, they are prone to undergo a rapid deprotonation in their excited state to result in fluorescence from the unprotonated form (Förster cycle). The deprotonation can be suppressed by complexation with cation-receptor macrocycles, which allows the fluorescence of the locally excited (protonated) state to be dramatically enhanced (factor 12 for dye 1 and 83 for dye 2). This host-retarded excited-dye deprotonation is a direct consequence of the previously established complexation-induced pKa shifts that dyes undergo upon binding to a macrocyclic host. The data set also allows a systematic comparison of complexationinduced pKa shifts in the ground and excited state of a dye. The trends are comparable, which suggests that structural factors, that is, the geometry of the host−guest complexes, determine the magnitude of the shifts. In regard to the magnitude of the absolute pKa shifts on the size of the macrocycles, we observe for dye 2 that the complexationinduced pKa shifts decrease as the portals become larger along the cucurbit[n]uril series.

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INTRODUCTION The study of the interactions of fluorescent dyes with watersoluble macrocyclic host molecules has developed into an important area of supramolecular chemistry.1−32 Upon complexation, the fluorescent dye frequently changes significantly, rarely dramatically, its fluorescence properties, such that both its complexation as well as its decomplexation can be followed with high sensitivity. This fluorescence response provides a robust method to (i) measure and compare the binding propensities of different macrocycles at low dye concentrations,33−35 (ii) explore the physical properties of the inner cavities of macrocycles by means of solvatochromic effects,10,36−40 (iii) develop refined fluorescent switches for advanced supramolecular architectures6,10,13,17,41−43 or molecular logic gates,23,44−47 and (iv) monitor the reversible complexation of analytes to the macrocycles through indicator displacement strategies.48−54 The latter method, because it can be both miniaturized and scaled up to high-throughput screening format, has enormous application potential in the environmental, biological, and food sciences. It also forms the conceptual basis for selective fluorescent sensing ensembles operational in aqueous solution.17,35,54−62 A large fluorescence response of the dye upon complexation is invariably desirable. Hence the understanding of the mechanistic details, which lead to the fluorescence changes, and the quest for new mechanisms present a timeless endeavor. We now designed new dyes (1 and 2, Scheme 1) of the “anchor dye” type,6 which combine a common recognition motif for cation-receptor hosts with a basic nitrogen as © 2017 American Chemical Society

protonation site, such that ground-state pKa shifts can be systematically analyzed for a series of hosts, in particular, cucurbit[n]urils (CBn, n = 6−8)63−70 and p-sulfonatocalix[4]arene (CX4).57 In addition, we selected chromophores that are prone to undergo a Fö rster cycle, which, through the concomitant observation of unprotonated as well as protonated dye fluorescence, also allow the determination of excited-state pKa shifts. To our initial surprise, the excited-state deprotonation (Förster cycle) of dyes 1 and 2 was strongly suppressed by complexation. Closer inspection of the combination of the two phenomena (pKa shifts and Förster cycle) showed that the slower deprotonation kinetics, which manifests itself through an unexpectedly high fluorescence of the protonated complexed dye, is inevitably linked to the thermodynamics of the pKa shifts. The peculiar photophysical behavior can be considered as a distinct mechanism for switching on and off the fluorescence of dyes, which can be utilized for sensing. Effects of CB7 on excited-state protonation phenomena of dyes have been noted in different contexts and controversially discussed.10,71−74 Macartney and coworkers investigated 2aminoanthracene with CB771 and interpreted the phenomenon as a thermodynamic excited-state effect, that is, a much larger excited-state shift (ΔpKa* ca. 10 units) than the ground-state one (ΔpKa ca. 3 units).71 Scrutiny of their analysis revealed, however, an inconsistent treatment (see the Supporting Received: October 27, 2017 Revised: November 23, 2017 Published: November 23, 2017 11390

DOI: 10.1021/acs.jpcb.7b10651 J. Phys. Chem. B 2017, 121, 11390−11398

Article

The Journal of Physical Chemistry B

Scheme 1. Chemical Structures of Dyes 1 and 2 (in their protonated DH+ form) as Well as the Employed Macrocyclesa

a

First deprotonation sites of the two dyes (to afford the D form) are indicated by arrows.

Table 1. Thermodynamic Data of the Protonated and Unprotonated Dye 1a host none CB6 CB7 CB8 CX4 a

KDH (M−1) 2.0 1.3 6.3 2.8

× × × ×

108 104 106 104

KD (M−1)

pKa′

2.2 × 105 150 4.8 × 104 200

2.9b [3.4b,c] 5.7 5.5 6.6 6.3

ΔpKa

pKa′*

ΔpKa′*

2.8 2.6 3.7 3.4

−5.8d −3.6 −3.2 −2.1 −2.4

2.2 2.6 3.7 3.4

ΔpKa

pKa′*

ΔpKa′*

3.3 2.2 1.1 0.3

−13.5d −10.9 −11.5 −12.9 −12.9

2.7 2.0 0.7 0.7

Error in pKa values is 0.1. bpKa. cLiterature value for parent chromophore (1-aminopyrene) from ref 82. dpKa*.

Table 2. Thermodynamic Data of the Protonated and Unprotonated Dye 2a host none CB6 CB7 CB8 CX4 a

KDH (M−1) 1.3 3.1 2.2 1.8

× × × ×

108 104 104 103

KD (M−1)

pKa′

6.4 × 104 230 2.0 × 103 1.1 × 103

2.9b [3.7b,c] 6.2 5.1 4.0 3.2

Error in pKa values is 0.1. bpKa. cLiterature value for the parent chromophore (1-naphthylamine-5-sulfonic acid) from ref 81. dpKa*.

Information), and recalculation affords the same value for both ground- and excited-state pKa shifts. The analysis of Macartney formed the basis of Thomas and Bohne’s work.28 Hazra and coworkers also claimed a much larger ΔpKa* value of 8.1 units than the ΔpKa value of 0.6 units for topotecan with CB7.72 Inspection of their experimental data showed that they assigned the inflection point of the steady-state fluorescence titrations to the pKa* values; such direct assignment is not justified because fluorescence titration curves also report on pKa values.21,75 ́ et al. inspected the effect of CB7 on two dyes, namely, Basilio 4-methyl-7-hydroxyflavylium and β-naphthol, and found the apparent ΔpKa′* values to be 1.2 in the case of 4-methyl-7hydroxyflavylium and undetermined for β-naphthol because the excited-state proton transfer (ESPT) was completely suppressed by CB7 in the latter case.73 The authors did not provide a comprehensive interpretation, but they concluded instead that “This can be due to effective suppression of the ESPT or to a shift of pKa* to higher values”.73

Our present study for dyes 1 and 2, as well as one of our previous studies,10 show that the pKa shifts are actually comparable in the ground and excited states. Moreover, the observed apparent stabilization of the protonated complexed dye is a consequence of the reduction in deprotonation rate. This slow kinetics introduces a “metastability” of the excited state, allowing it to become fluorescent and observable even under pH conditions at which the unprotonated form would otherwise be thermodynamically favored.

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RESULTS Synthesis. Compound 1 was synthesized by coupling (reductive amination)76 of 1-aminopyrene with 4-phthalimidobutyraldehyde77 and final deprotection of the 4-aminobutyl group with an overall yield of 46% (see the Supporting Information). Compound 2 was synthesized analogously in similar overall yield (50%). The diaminobutyl chain of dyes 1 and 2 infers a high affinity for cation-receptor macrocycles such as CBn and CX4, which we have previously used as model hosts 11391


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The Journal of Physical Chemistry B to study complexation-induced pKa shifts (host-induced guest protonation) with other dyes.3,6,7,10,19,78,79 Physicochemical and Photophysical Properties. In contrast with the terminal alkylammonium groups of dyes 1 and 2 (pKa ca. 10), their arylamino groups are unprotonated at neutral pH but can be protonated at strongly acidic pH, as can be nicely followed through the interconversion of the broad long-wavelength absorption band at 360 and 335 nm, respectively, characteristic for the intramolecular charge-transfer transition (ICT, D → D*) of the amino form of the dyes, to a structured short-wavelength absorption at 340 and 283 nm, respectively, arising from the transition of the ammonium dyes to their locally excited states (LE, DH+ → DH+*). The corresponding UV and fluorescence titrations (see the Supporting Information) provide the same pKa values of the arylammonium groups of 1 and 2 (2.9, see Tables 1 and 2), falling slightly but systematically below the pKa values of the parent primary amino chromophores (3.4 and 3.7),81,82 an effect that is due to the electrostatic influence of the terminal ammonium group. However, regardless of which state is being populated (D* or DH+*) and regardless of at which pH the excitation is performed (pH 0−7), the fluorescence remains effectively the same for both dyes: a broad ICT-type emission from the D* state centered at 454 nm for 1 and at 507 nm for 2; Figure 1. This demonstrates that even when the DH+* state

Scheme 2. Förster Cycle for the Free (a) and Complexed (b) Dyes 1 and 2 (D)a

a

Bold arrows indicate the faster of two kinetically competitive processes.

Table 3. Lifetime Values (τF) for Dyes 1 and 2 as Well as Their Complexes with Macrocyclic Hosts τF (ns)

Figure 1. Absorption (black) and emission (red) spectra (λexc = 346 nm for 1 and λexc = 301 nm for 2, the respective isosbestic points) of dye 1 (a) and 2 (b) in their protonated (pH 1, solid line) and unprotonated (pH 7, dashed line) forms.

host

1H+a

1b

2H+c

2d

none CB6 CB7 CB8 CX4

5.20 156 154 135 16.5

4.60 4.44 4.93 5.53 5.35

1.50 14.3 9.47e 8.37

9.12 8.97 10.6e 7.45

λexc = 340 nm, λem = 375 nm, solutions deaerated with Ar. bλexc = 373 nm, λem = 455 nm. cλexc = 280 nm, λem = 330 nm. dλexc = 335 nm, λem = 505 nm. eAverage lifetime values (biexponential decay). a

is populated at very low pH, it undergoes a rapid deprotonation due to a dramatically lowered excited-state pKa* value (DH+* → D* → D + hυ). Such a phenomenon is well known as the Förster cycle and resembles the photophysics of the parent 1aminopyrene (pKa* ca. −5 in aqueous media).80,83−85 Close inspection of the spectra reveals, in fact, that there is a residual emission from DH+* but it is very weak (see Figure 1 and Scheme 2a) due to the short lifetime of the LE states (5.20 and 1.50 ns, see Table 3).

The concomitant observation of the absorption and fluorescence spectra of both unprotonated and protonated forms of the dyes allowed us to determine their excited-state pKa* values (−5.8 and −13.5 for dye 1 and 2, Tables 1 and 2) according to the common Förster cycle (see the Supporting Information), which are entropy-uncorrected values. The values 11392


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values according to the Förster cycle (−2 to −13, entropyuncorrected values, Tables 1 and 2). The entropy-corrected values remained negative and followed the same trend (Supporting Information). Accordingly, the deprotonated states of both dyes remain strongly thermodynamically favored even at the selected acidic pH (1.5). The observed fluorescence response of these two dyes upon macrocyclic complexation must therefore be due to a kinetic inhibition of the deprotonation of the complexed dyes in their excited states. To quantify the kinetic effect of encapsulation on deprotonation, time-resolved fluorescence measurements were performed.28,73,90 Indeed, the protonated dyes 1 and 2 in their complexes with CBs, and to a lesser degree in their complexes with CX4, showed drastic enhancements of their LE-state fluorescence lifetimes (Table 3); this reflects a higher kinetic persistence that also accounts for the enhanced fluorescence intensities (Figure 2) and fluorescence quantum yields (ϕF values in Table 4 for dye 1) corresponding to emission from

resulting from an empirical entropy correction developed by Shizuka86 differ systematically (−4.3 and −5.4 for dye 1 and 2, Supporting Information). Complexation by Cation-Receptor Macrocycles. The addition of the macrocyclic hosts CB6, CB7, CB8, and CX4 to solutions of dyes 1 and 2 at different pH values caused characteristic changes in their absorption and fluorescence spectra, attributable to the formation of inclusion complexes (Figure 2 and Supporting Information).6 The spectral changes

Table 4. Quantum Yields (ϕF), Excited-State Deprotonation Rates (kdeprot), and Radiative Fluorescence Decay Rates (kr) of Dye 1a with Macrocyclic Hosts DH+ (LE state)b host none CB6g CB7h CB8i CX4j

ϕF 0.02 0.55 0.33 0.43 0.04

6

−1 d

kdeprot (10 s ) 190 (2200) 2.9 4.4 4.2 58

f

D (ICT state)c

kr (10 s )

ϕF

kr (108 s−1)e

3.9 3.5 2.1 3.2 2.4

0.67 0.73 0.60 0.61 0.67

1.46 1.66 1.22 1.11 1.26

6

−1 e

a [1] = 5 μM. bpH 1.5. cpH 7.5. dApproximate values calculated as described in the Supporting Information. eCalculated with kr = ϕF/τF, with τF values from Table 3. fkdeprot value of 1-aminopyrene, the parent chromophore of dye 1, from ref 80. g[CB6] = 20 μM. h[CB7] = 100 μM. i[CB8] = 20 μM. j[CX4] = 200 mM.

Figure 2. (a) Fluorescence emission spectra of 0.5 μM 1 in the absence (dashed line) and presence (solid line) of 0.9 μM CB6, at pH 1.5, λexc = 347 nm. (b) Fluorescence emission spectra of 10 μM 2 in the absence (dashed line) and presence (solid line) of 1.6 mM CB7, at pH 1.5, λexc = 301 nm.

the protonated LE state. For example, the fluorescence lifetime increased from 5.20 ns for the protonated form of the free dye 1 to 156 ns for its CB6 complex (solutions were deaerated to eliminate oxygen quenching). Because the radiative decay rates (kr values in Table 4), calculated as the product of the quantum yield and the reciprocal fluorescence lifetime, were little affected, the increase in lifetime can be attributed to a reduction of the nonradiative decay rate upon complexation, namely, a suppression of the deprotonation of the protonated excited state. For comparison, the fluorescence quantum yield of the unprotonated ICT state, determined at higher pH values, was insignificantly affected by the macrocyclic complexation (Table 4). The ability to follow the deprotonation event (of the excitedstate) in real time offers the opportunity to substantiate the thermodynamic effect that macrocycles display on the pKa values of dyes in kinetic terms, that is, on the rate constants of (de)protonation (Scheme 2b). In detail, the fluorescence lifetimes (Table 3), along with the independently determined fluorescence quantum yields from the LE-state emission (Table 4), allow us to quantify the excited-state deprotonation rates (kdeprot) with the assumption that the nonradiative decay of the protonated form occurs exclusively by deprotonation. This analysis, which is detailed in the Supporting Information, affords kdeprot values that do indeed decrease by up to two orders of magnitude upon complexation (Table 4). Consideration of additional nonradiative decay pathways would affect

were used to determine the binding constants of the protonated and unprotonated forms of the dyes and their pKa values in the free and complexed forms (Tables 1 and 2, Supporting Information) by means of optical titrations. The corresponding analytical procedures to determine the associated complexation-induced pKa shifts in the ground state have already been abundantly documented in numerous previous studies.2,3,7,78,87−89 Dyes 1 and 2 display a special behavior when their characteristic fluorescence changes were investigated at pH 1.5 (see Figure 2 and the Supporting Information). This pH is sufficiently acidic to ensure virtually quantitative protonation of both the complexed and uncomplexed forms of dyes 1 and 2, such that variations in the optical spectra cannot be attributed to complexation-induced pKa shifts on the ground-state equilibria. Nevertheless, the addition of the different macrocyclic hosts led to dramatic changes in the fluorescence spectra, namely, an increase in the emission band of the protonated LE state (up to a factor of 83 for the CB6·2 complex) at the expense of a concomitant decrease in emission from the unprotonated ICT state. In view of the Förster cycle, it appeared that the protonated excited state is stabilized by the macrocycle. To evaluate the thermodynamic effect of encapsulation on the stability of the excited states, we also determined the pKa′* 11393



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the absolute kdeprot values but is unlikely to change the pronounced relative trends. By further assuming a constant protonation rate (Scheme 2), an independent estimate for the pKa* values can be obtained (“kinetic” calculation of the pKa* values; Table S3, Supporting Information). Although these were systematically higher than the pKa* values derived from the Förster cycle and the empirical entropy correction (Table S3, Supporting Information), the resulting values remain below the selected pH value, confirming that the protonated excited states of dyes 1 and 2 are not energetically more stable than the unprotonated excited forms but kinetically more persistent due to a retarded deprotonation in the complex. The combined optical spectroscopic data lead us to propose the state diagram in Scheme 2 as a summarized result, in which eight states (ground and excited, complexed and uncomplexed, protonated and unprotonated) are interrelated. The corresponding free-energy diagram is shown in Scheme 3, which

Article

DISCUSSION

This work provides a contribution to the understanding of the interaction of fluorescent dyes with supramolecular assemblies and applications of the resulting macrocycle·dye complexes. The novelty of our study with dyes 1 and 2 is two-fold. It comprises (i) a systematic comparison of ground- and excitedstate pKa shifts and their variation for different hosts and (ii) an investigation of the effects of macrocyclic complexation on the deprotonation kinetics. Compounds 1 and 2 are designer dyes in which classical fluorophores, namely, 1-aminopyrene and 5-aminonaphthalenesulfonate, were decorated with an aminobutyl tether. The latter serves as a common anchor to facilitate the complexation with a series of macrocyclic cation-receptor hosts: three homologous cucurbiturils (CB6, CB7, CB8) and p-sulfonato-calix[4]arene (CX4). Drawing from a previous exploratory utilization of this anchor strategy,6 the associated systematic investigation allowed us to obtain the first structure−activity relationship of ground-state pKa shifts for different macrocyclic complexes of the same dye, complementing the scattered data on pKa shifts available for different host·dye combinations in the literature. The state of affairs of pKa shifts induced by macrocyclic complexation was first summarized in 2006,2,87 and many more examples have become available in the following decade.6,7,10,19,21−23,28,74,78,91−94 As can be seen from Tables 1 and 2, all four receptors bind to the protonated forms of dyes 1 and 2 with high affinities (KDH ≈ 103 to 108 M−1), which confirms the validity of our anchor design. The selected putrescine is known to have the highest affinity for CB6 among the cucurbituril series, which is also reflected by the experimental KDH obtained for 1 and 2. The corresponding pH titrations, followed by both UV−vis and fluorescence spectroscopy, afforded the pKa values of the complexed dyes, which were markedly higher than those of the free dyes, as expected. The hosts “assist” the protonation of the dyes because of their known preference to bind cations.3,6,7,10,19,23,26,32,34,43,46,87,94−96 The pKa shifts induced by the macrocycles (ΔpKa) reached up to +4 pKa units, which falls in the reported range.87 Moreover, the rationally selected chromophores undergo a Förster cycle; that is, they have a known propensity to deprotonate from their excited state as a consequence of a lower pKa * compared with their pK a . The dominant fluorescence stems from the unprotonated excited state; that is, it occurs with a large Stokes shift at longer wavelengths. The pKa* values can be simply determined from the spectral properties (0−0 transitions in absorption and emission spectra) for the free and complexed forms (Tables 1 and 2). Compared with the pKa values, the pKa* values of dyes 1 and 2 become strongly negative (decreased by ca. 9 units for dye 1 and 16 units for dye 2), reflecting the high acidity of their excited states. However, the absolute values of both, pKa* and pKa, are offset to positive values by up to +4 units due to the macrocyclic complexation. In fact, through the Förster cycle it becomes possible to extract the complexation-induced pKa shifts in the excited state and compare them with these in the ground state (compare ΔpKa* with ΔpKa in Tables 1 and 2). The experimental data for dyes 1 and 2 allow us to derive the first structure−activity relationships on pKa shifts induced by macrocyclic complexation: (I) Complexation-induced pKa shifts are comparable in the ground and excited states. This is a

Scheme 3. Free-Energy Diagram for the Protonation and Complexation Equilibria of Dye 2, Depicted for CB6 as Host, the Experimentally Employed pH Value of 1.5, and a Typical Host Concentration of 20 μM

reveals that the origin of the observed fluorescence enhancement of the protonated form accompanying the complexation is not related to the fact that the protonated form becomes more stable than the unprotonated form, but rather that its interconversion to the unprotonated form is kinetically hindered. The protonated state becomes “metastable” on the excited-state time scale. Exploratory Chemosensing Applications. While the present study is devoted to photophysical aspects, it should be added that the fluorescence response of dyes 1 and 2 to macrocyclic complexation can be readily implemented into chemosensing applications. To illustrate, we have successfully employed the CB6·1 reporter pair for sensing of cadaverine as a reaction product of the enzyme lysine decarboxylase (see Supporting Information (Figure S32)); cadaverine binds tightly to CB6, and its presence or formation reverts the fluorescence response associated with the inclusion of 1 into the CB6 cavity. Independently, the CB6·2 reporter pair has already been communicated to serve as gas sensor60 because simple alkanes have a high affinity for this host and compete with 2 for inclusion into the CB6 cavity. 11394


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The Journal of Physical Chemistry B strong indication that the pKa shifts are due to “simple” geometrical (steric) reasons because no large coconformational changes are expected during electronic excitation or the short singlet excited-state lifetimes. Practically, the pKa shifts in the ground state are more important, but knowledge on the excited-state behavior is theoretically relevant because fluorescence is a popular method for pKa shift determination. In regard to pKa shifts in dependence on the type of macrocycle, dye 1 proved to be a less fortunate model because its hydrophobic pyrene moiety competed with the diaminobutyl anchor for binding to macrocycles with sufficiently large or flexible cavities, such as CB8 and CX4. Evidence of this propensity was obtained by 1H NMR complexation-induced chemical shifts and solvatochromic shifts (see the Supporting Information). This resulted in different coconformations and positions of the protonation site such that trends in dependence on the type of macrocycle were inconclusive for dye 1. This complication does not apply for dye 2, which carries a negatively charged sulfonato group at the naphthalene residue that suppresses binding to the selected cation-receptor macrocycles, confirmed as well by 1H NMR. Consequently, we used the thermodynamic data for dye 2 to advance a second structure−activity relationship: (II) Within the cucurbituril series (n = 6−8), when the inclusion mode is comparable, complexation-induced pKa shifts decrease as the portal becomes larger. This observation is consistent with expectations based on Coulombic attraction (ECoulomb ∝ n/RCBn), which increases with the number of interaction sites (n) but decreases with the distance between the charges (RCBn), that is, the protonation site and the carbonyl portal oxygens. A simple calculation with the assumption of a centrosymmetric charge in vacuum and the pKa shift of CB6 arbitrarily set to 3.0 (similar to the experimental values, see Table 2) predicts relative pKa shifts of 2.5 for CB7 and 2.3 for CB8 and thereby the correct trend. The fact that the experimental decrease is more pronounced than predicted can be attributed to at least two reasons, the first being a proximate interaction of the protonation site with one to two carbonyl groups and more distal ones with the others (rather than a centrosymmetric geometry) and the second one being an increased charge screening due to the better hydration enabled by the larger portals; recall that the relative dielectric constant, which is large for water, enters as a factor in the denominator of the Coulombic energy term. Even though our study allows us to understand the dependence of the complexation-induced pKa shifts on the electronic state and the macrocycle size, unknowns remain. These extend to the large variations of experimentally observed pKa shifts on the precise structure of the dyes, which have been noted before.19,87 The large differences of the complexationinduced pKa shifts between dye 1 and 2 with the larger macrocycles (CB8 and CX4) can be attributed to the different dye immersion pattern (see above). However, even when a common anchor motif is there to ensure that the protonation site is always an arylamino nitrogen such as in the CB6 complexes of dyes 1 and 2 as well as a previously studied carbazole dye,6 the corresponding pKa shifts differ significantly, from 2.8 to 4.5 (Tables 1 and 2 and ref 6). This suggests that minute variations in the precise positioning of the protonated site inside macrocyclesunavoidable when attaching different chromophoreshave a strong impact on the absolute pKa shifts achieved. While nature has optimized this subtle interplay and can realize pKa shifts up to five units in proteins,87,97−101

the rational design of synthetic host−guest complexes exceeding this benchmark remains a challenge. Beside the derived structure−activity relationships, the project afforded an element of surprise and practical importance; this refers phenomenologically to the unexpected presence of the protonated-state emission in the complexes and kinetically to a dramatically increased excited-state lifetime of the protonated state. This means that the macrocycles have a peculiar “photophysical function”; they apparently suppress the Förster cycle and induce a kinetic meta-stability of the protonated dye, which is otherwise known to undergo an efficient deprotonation to the excited unprotonated form, from where fluorescence conventionally predominates. The suppression of the Förster cycle, affected by the addition of cation receptors, in general, and cucurbiturils, in particular, establishes a distinct mechanism through which the fluorescent properties of dyes can be modulated. Such a selective chemoresponse is highly desirable for sensing applications and is superior to a less specific quenching or microenvironmental response of fluorescent dyes, such as the more commonly encountered dependencies on polarity, viscosity, or confinement.95 It also complements the use of ground-state complexation-induced pKa shifts of dyes as a previously established thermodynamical tool for optical response;3,6,7,10,19,23,26,32,34,43,46,74,87,92,94−96 these are operationally limited to pH values in between the pKa values of the complexed and uncomplexed dye. In contrast, the kinetic phenomenon of host-retarded excited-state deprotonation is also observed outside this pH range (Schemes 2 and 3).

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CONCLUSIONS The investigation of the anchor dyes 1 and 2 with a series of macrocyclic host molecules has exposed the first two structure−activity relationships on complexation-induced pKa shifts and thereby contributes to the partial understanding of the more than 100 experimental data that have been reported over the past 15 years (refs 3, 6, 7, 13, 14, 18, 19, 23, 26, 29, 50, 59, 62, 70, 71, 74, 87, 91, 92, 94, 95, and 102−107). In addition, a new mechanism, host-retarded excited-state deprotonation, which complements the abundantly documented host-assisted (ground-state) dye protonation (refs 3, 6, 18, 19, 21, 23, 32, 34, 43, 46, 74, 87, 92, and 94−96) as a tool to modulate the fluorescence, has been scrutinized. It rests on the stabilization of the excited dye, whose otherwise efficient deprotonation pathway is kinetically hindered in its complexed form. The new mechanism and the design approach can be implemented into a broad range of applications, such as indicator displacement assays.53,108 In fact, both dyes have already been used in enzyme assays (dye 1, see Results) and for chemosensing of gases60 (dye 2). From a photophysical point of view, the complexation of such dyes by macrocycles provides a unique approach to dramatically “shift” Förster cycles without changing the solvent, and this opportunity can be exploited, among others, to access otherwise elusive excited states, for example, for spectroscopic characterization.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.7b10651. Materials and methods, pKa* calculations, synthesis, and application example (PDF) 11395


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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +49 421 200 3233. ORCID

Alexandra I. Lazar: 0000-0003-1854-7920 Werner M. Nau: 0000-0002-7654-6232 Present Address ‡

J.R.: Teva Czech Industries s.r.o., Ostravská 29, 747 70 Opava, Czech Republic.

Author Contributions †

A.I.L. and J.R. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the financial support of the Deutsche Forschungsgemeinschaft (DFG, NA-686/11-1). REFERENCES

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Comparison of Complexation-Induced p K a Shifts in the Ground and

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