Article pubs.acs.org/JACS
Self-Immolative Chemiluminescence Polymers: Innate Assimilation of Chemiexcitation in a Domino-like Depolymerization Samer Gnaim and Doron Shabat* School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel S Supporting Information *
ABSTRACT: Self-immolative polymers are distinctive materials able to disassemble in a domino-like mechanism from head-totail upon a triggering event induced by an external stimulus. We have developed an effective molecular method to intrinsically assimilate a chemiluminescence turn-ON mechanism with a domino-like fragmentation mechanism. A unique molecular unit was synthesized, which could combine the abilities of executing the duel function of quinone-methide elimination and chemiexcitation. Incorporation of this unit as a monomer, results with the first class of stimuli-responsive self-immolative polymers with amplified chemiluminescence output. Responsive groups for various analytes were introduced as a head-trigger during the polymer synthesis. The polymers were demonstrated as chemiluminescence probes for detection of different chemical analytes. The obtained polymers were able to amplify the intensity and the duration of the light emission signal by factors correlated to their length. We anticipate that the chemiluminescence self-immolative polymers described here will find use for various research topics such as signal amplification, light-emitting new materials, and molecular probes with long-lasting light emission and imaging capabilities.
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INTRODUCTION Functional polymeric molecules composed of self-immolative building blocks have found utility in numerous research areas.1 About a decade ago, our group developed a distinct kind of functional macromolecules, termed self-immolative polymers.2−4 Such polymers can undergo a domino-like disassembly from head to tail upon removal of a triggering substrate (Figure 1). The polymeric structure is based on a polycarbamate backbone, and the depolymerization mechanism occurs through the aza-quinone-methide elimination. Following our discovery, a burst of new reports has appeared in the literature.5,6 Several groups have used our original polymer design,7−15 while others developed alternative self-immolative depolymerization chemistries.16−28 Self-immolative polymers have been proven as effective molecular tools with utility in various research areas, such as signal amplification, molecular sensing, material chemistry, and more. In a previous report, we used a masked aniline derivative as a building block for a self-immolative polymer.2 Multiple copies of this aniline derivative are released through the quinonemethide elimination disassembly pathway of the polymer, to unmask a fluorescent dye. Therefore, the polymer disassembly could be conveniently monitored by the increase of the fluorescence signal produced by the aniline dye. A more beneficial signal, produced by the domino-like disassembly of © 2017 American Chemical Society
the polymer backbone could potentially be obtained by chemiluminescence output.29 Such output, when amplified by the self-immolative polymer, will produce superior signal-tonoise ratio and long-lasting light emission outcome. So far, chemiexcitation signal in regard to polymers was applied to demonstrate mechanical strain.30 Here we report how a chemiexcitation turn-ON mechanism can be innately assimilated in a domino-like fragmentation to produce the first class of stimuli-responsive self-immolative polymers with amplified chemiluminescence output. To design a chemiluminescence self-immolative polymer, a distinct probe that can serve as suitable building block for the polymer backbone was required. The Schaap’s adamantylidenedioxetane31 (Figure 2A, structure I) is equipped with an analyte-responsive substrate, that masks the phenol moiety of the probe. Removal of the substrate generates an unstable phenolate-dioxetane species II, which decomposes through a chemiexcitation process (chemically initiated electron-exchange luminescence or CIEEL) to produce the excited intermediate benzoate ester III and adamantanone. The excited intermediate decays to its ground-state through an emission of a blue photon. Received: May 10, 2017 Published: July 3, 2017 10002
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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Figure 1. Graphical illustration of domino-like disassembly of a self-immolative polymer upon the trigger activation.
Figure 2. (A) Activation pathway of Schaap’s dioxetane. (B) Mechanism of the quinone-methide elimination. (C) Probe combining the turn-ON mechanism of Schaap’s adamantylidene-dioxetane with quinone-methide elimination.
Figure 3. Molecular structure and activation mechanism of chemiluminescence self-immolative polymer.
We sought to integrate the distinct turn-ON mechanism of Schaap’s adamantylidene-dioxetane into the quinone-methide elimination (Figure 2B), which is used for the domino-like disassembly of the self-immolative polymer. Such integration could be achieved in a molecular structure like probe V (Figure 2C). Removal of the substrate from probe V should triggered initially the quinone-methide elimination to release quinonemethide VI. This quinone-methide can then react with an accessible nucleophile (e.g., a water molecule) to generate phenolate VII, which can then decompose through a chemiexcitation process to produce benzoate VIII, adamantanone, and a blue photon. Based on this strategy, we used unit VII as a building block for design of a new self-immolative polymer with a mode of action that amplifies chemiluminescence. The molecular
structure of such self-immolative polymer is composed of polycarbonate backbone with molecule VII as a monomer unit and a responsive substrate as a head-trigger (Figure 3). Removal of the substrate by an analyte of interest, initiates the polymer domino-like disassembly through multiple quinone-methide eliminations and decarboxylation sequence. The released quinone-methide units can react with an available nucleophile to generate a phenolate that can then decompose through the chemiexcitation process described in Figure 2C. Such a self-immolative polymer is expected to act as a molecular amplifier of light emission.
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RESULTS AND DISCUSSION The synthesis of the polycarbonate self-immolative polymers was achieved as outlined in Figure 4. Monomeric unit 1 was 10003
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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Figure 4. Synthesis of chemiluminescence self-immolative polymers 2b, 3b, and 4b.
Figure 5. Release of 4-nitroaniline from oligomers 5, 6, and 7 [100 μM] in DMSO/H2O (99:1), following 1 min after addition of TBAF (1 equiv). (Lower graph) UV−vis spectral change occurred for oligomers 5, 6, and 7 [100 μM] in DMSO/H2O (99:1), before and after addition of TBAF (1 equiv). (Upper graph) Quantification of 4-nitroaniline released from oligomers 5, 6, and 7 [100 μM] in DMSO/H2O (99:1), following 1 min after addition of TBAF (1 equiv).
Figure 6. (Left) Chemiluminescence kinetic profiles of polymer 2b and oligomers 5, 6, and 7 [50 μM] in DMSO/H2O (99:1) after activation by TBAF (1 equiv) at room temperature. (Right) Total emitted photons for 2b, 5, 6, and 7 (λmaxem = 499 nm).
suitable for activation by fluoride, polymer 3b was capped with an allyl substrate suitable for activation by palladium complex (Pd(0) or Pd(II)) and polymer 4b was capped with a phenyl boronic ester substrate suitable for activation by hydrogen peroxide.32 NMR and GPC analysis showed that polymer 2a, (and its counterpart dioxetane 2b), with the silyl-ether
subjected to polymerization conditions, in the presence of 5% equiv of the applicable capping head substrate, to produce polycarbonates 2a, 3a, and 4a. The enol-ether functionalities of the obtained polymers were oxidized with singlet oxygen to afford chemiluminescence self-immolative polymers 2b, 3b, and 4b. Polymer 2b was capped with a silyl-phenolic ether substrate 10004
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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Figure 7. (A) Left: Chemiluminescence kinetic profiles of polymer 3b [50 μM] in DMSO/H2O (99:1) in the presence and in the absence of Pd(0) (1 equiv) at room temperature. Right: Total emitted photons for 3b, and the indicated controls (λmaxem = 499 nm). (B) Left: Chemiluminescence kinetic profiles of polymer 4b [50 μM] in PBS, pH = 9.0, surfactant [25%] in the presence and in the absence 1 equiv of H2O2 at room temperature. Right: Total emitted photons for 4b, and the indicated controls (λmaxem = 499 nm).
triggering substrate, were obtained as 20-mers. Comparable chain-lengths were obtained for the polymers with other triggering substrates (see the Supporting Information, Figures S1−S3). To thoroughly understand the disassembly mechanism of the chemiluminescence self-immolative polymers, we initially prepared three self-immolative oligomers by stepwise synthesis (see the Supporting Information). Monomer 5, dimer 6, and trimer 7 were synthesized with silyl-ether headgroup and 4nitroaniline as tail reporter. Reaction of such oligomers with fluoride ion should activate the domino-like disassembly through the backbone to release the 4-nitroaniline tail reporter. Indeed, addition of tetrabutyl-ammonium fluoride (TBAF) to solutions of oligomers 5, 6, and 7 in DMSO resulted in rapid release (in about 60 s) of 4-nitroaniline (Figure 5). No release was observed in the absence of TBAF (see the Supporting Information, Figure S5). These observations clearly indicate that rapid domino-like disassembly of the self-immolative oligomer backbone occurs upon substrate triggering. Next, we studied the self-immolative disassembly of polymer 2b, via the programed mode of light-emission, in comparison to that of oligomers 5, 6, and 7. The chemiluminescence kinetic profiles of polymer 2b and its related oligomers are presented in Figure 6. The probes exhibited a typical chemiluminescent kinetic profile upon activation by TBAF with a steep initial signal increase to a maximum followed by a slow decrease within a time frame of minutes to hours. The signal produced by polymer 2b was about 20-times more intense than that obtained for monomer 5. Similarly, trimer 7 and dimer 6, respectively, showed 3-fold and 2-fold signal enhancement in comparison to monomer 5. No emission of light was observed for either the polymer or the oligomers in the absence of TBAF. These results suggest that enhancement of chemiluminescent signal can be produced through the activation mechanism assimilated in the polycarbonate self-immolative polymer. The activation of polymers 3b and 4b by their corresponding analytes was similarly monitored through their chemilumines-
cence (Figure 7). The allyl-ether substrate of polymer 3b was activated with Pd(0) to produce an amplified chemiluminescence signal (Figure 7A).33 Control experiments included incubation of the polymer in the absence of the Pd(0) and incubation of the polymer with TBAF and hydrogen peroxide; under these conditions, no emission of light was detected (Figure 7). The phenyl-boronic ester substrate of polymer 4b was activated with hydrogen peroxide under aqueous conditions (PBS, pH 7.4) using a commercialized surfactant as solubilizing agent.34 Chemiluminescence was observed after incubation of the polymer with hydrogen peroxide (Figure 7B). Only minor background signal was observed when the polymer was incubated in the solution without hydrogen peroxide. Expected signal enhancement was observed for polymers 3b and 4b in comparison to the signal produced by their corresponding monomers (see the Supporting Information, Figures S9 and S10). The disassembly of our chemiluminescence self-immolative polymers proceeds through two fragmentation reactions: a quinone-methide elimination and the chemiexcitation (CIEEL) leading to C−C bond cleavage and release of adamantanone. The phenolate species produced after removal of the triggering substrate can in principle disassemble through either of two routes: the quinone-methide elimination or the chemiexcitation. Kinetic studies of the polymers disassembly (Figures 5 and 6) indicated that the quinone-methide elimination is relatively fast, whereas the chemiexcitation fragmentation occurs over a longer time-scale. To obtain further evidence in support of this hypothesis, we conducted a kinetic experiment in which the disassembly of monomer 5 upon activation by TBAF was followed by NMR. In the 1H NMR spectrum of monomer 5, four characteristic signal peaks were monitored: two signals at chemical shifts of 8.2 ppm (H6) and 7.7 ppm (H7) that result from the pnitroanilne carbamate end-unit, a broad signal at chemical shift of 5.5 ppm (H4) that corresponds to the benzylic carbonate, and a broad signal at chemical shift of 2.9 ppm (H1) that corresponds to the adamantane moiety. Five minutes after 10005
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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Figure 8. (Left) 1H NMR kinetic Study of monomer 5 disassembly upon activation with TBAF. Conditions: 500 μL of DMSO-d6, 5 μL of D2O, 25 mg of monomer 5, and 1 equiv of TBAF. (Right) Kinetic data for monomer 5 disassembly. Correlation between the released adamantanone (the NMR signal as result of the chemiexcitation) and the measured total emitted light.
Figure 9. Chemiluminescence signal obtained from incubation of TBAF [50 μM] with polymer 2b [50 μM], trimer 7 [330 μM], dimer 6 [500 μM], and monomer 5 [1000 μM] in DMSO/H2O (99:1) at room temperature.
addition of TBAF, the peaks due to the p-nitroaniline carbamate had disappeared, and two new sets of sharp doublets appeared with a chemical shifts of 7.9 ppm (H6) and 6.6 ppm (H7). This observation indicates the release of free pnitroaniline and formation of quinone-methide species (5a). Over 20 min, the broad signals at chemical shifts of 5.5 ppm (H4) and 2.9 ppm (H1) gradually decreased, and three new singlet peaks appeared. The first new peak, at chemical shift of 4.6 ppm (H4), results from the two hydroxyl-benzylic hydrogens. The second, at chemical shift of 3.8 ppm (H3) corresponds to the three hydrogens of the methyl benzoate 5c. The third, at chemical shift of 2.4 ppm (H2) results from the free adamantanone obtained as a result of a nucleophilic addition of D2O to the p-quinone-methide (5a) followed by the CIEEL process to produce 5c. By approximately 60 min, the
singlet peak at chemical shift of 4.6 ppm (H4) had disappeared, and a new singlet peak at chemical shift of 5.2 ppm (H5) appeared as a result of an intramolecular trans-esterification at hydroxybenzyl alcohol 5c to generate lactone 5d. The NMR signal observed for the released adamantanone (2), as a result of the chemiexcitation, and the measured total emitted light were plotted as a function of time (Figure 8, right graph). Fairly good fit was obtained for both signals associated with the disassembly kinetics of monomer 5. Similar correlation was obtained for polymer 2b disassembly kinetics (see the Supporting Information, Figure S11). These NMR experiments clearly prove that the first step of the polymer disassembly occurs through the quinone-methide elimination, which breaks the polymeric backbone into its monomeric units. These monomeric units then undergo 10006
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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chemotherapeutic drug as a tail unit in probe V, a theranostic prodrug with chemiluminescence mode of action could be prepared.43 Very recently, our group reported the discovery of a new molecular methodology to significantly improve light-emission efficiency of Schaap’s adamantylidene-dioxetane under aqueous conditions.44 The chemiluminescence quantum yields of the new probes were up to 3 orders of magnitude higher than that of the known adamantylidene−dioxetane probes. Incorporation of these improved chemiluminescence molecules as building blocks into the polycarbonate self-immolative polymers described herein, would further improve the produced signal intensity and adaptability to aqueous conditions. Such new polymers could possibly be applied to compose new materials with imaging capabilities and long-lasting light emission effect (see the Supporting Information, Figure S12).
fragmentation through a chemiexcitation process to produce the chemiluminescence signal. To better explain the chemiluminescence amplification effect achieved by our self-immolative polymers, we performed a comparison evaluation of the signal generated by polymer 2b (a 20-mer) vs the signal generated by trimer 7, dimer 6, and monomer 5. Polymer 2b and its corresponding oligomers can be used as diagnostic probes for detection of fluoride. To make a comparison based on equivalent reporter units, experiments were conducted using 1 equiv of polymer 2b, 6.5 equiv of trimer 7, 10 equiv of dimer 6, and 20 equiv of monomer 5. All four probes were incubated with 1 equiv of fluoride, and chemiluminescence signals produced were measured over time. The total light emitted from each probe is presented in Figure 9. The signal produced by polymer 2b was about 20-fold higher than that obtained by monomer 5. Trimer 7 and dimer 6 produced signal intensities 3-fold and 2-fold higher than that of monomer 5. The kinetics of the light emission observed for the selfimmolative polymers and 4-nitroaniline oligomers disassembly involves a complex mechanism (see the Supporting Information Figure S6).35 The disassembly of the polymer backbone initially leads to release of multiple dioxetane quinone-methide units. However, this quinone-methide intermediate cannot yet undergo chemiexcitation. In the next stage an available nucleophile is reacted with the quinone-methide to generate a phenolate ion. Only then the chemiexcitation process is initiated through electron transfer from the phenoxy-ion to the peroxy-dioxetane bond. As a result, the relative concertation of the available nucleophile (1% water for oligomers 5, 6, 7 and polymer 2b) vs the number of quinone-methide units released, correspondingly affects the emission kinetics behavior. Increasing of the percentage of water in the solution would result in loss of chemilumincesence quantum yield through none-radiative energy transfer to water molecules. Therefore, the observed kinetic profiles for the 4-nitroaniline oligomers and polymer 2b (Figure 6) are not identical. Self-immolative polymer 2b was able to serve as a probe for fluoride sensing with a limit of detection at the low micromolar range. This experiment clearly demonstrates the amplification effect obtained by our designed chemiluminescence selfimmolative polymers. The incorporation of dioxetane in a polymer backbone was recently studied in the context of mechanical stimulation. In that example, light emission was observed when mechanical strain was applied on the polymer network with dioxetane cross-linkers.30 In our report, the chemiluminescence signal produced from the dioxetane was amplified through the domino-like disassembly of a self-immolative polymer backbone. The self-immolative quinone-methide elimination was embedded into the chemiexcitation mechanism of Schaap’s adamantylidene-dioxetane by design of a unique phenol monomeric building block. The distinct molecular structure of this phenol enables dual function: quinone-methide elimination and chemiexcitation of the dioxetane. Recent work described the attachment of Schaap’s dioxetane to AB2 self-immolative dendrons.36−38 With such molecules a moderate signal amplification (2-fold) of the produced chemiluminescence signal was obtained. Probe V (Figure 2C), which can undergo quinone-methide elimination and the chemiexcitation of Schaap’s adamantylidene-dioxetane, could be modified to harness other signal amplification techniques39,40 such as the dendritic chain reaction.41,42 In addition, by incorporating a
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CONCLUSIONS In summary, we have developed a new kind of self-immolative polycarbonate polymers with distinct chemiluminescence output signal. These polymers are able to disassemble in a domino-like manner from head to tail upon a triggering event by an external stimulus. Each of the polymers building blocks could combine the chemiexcitation mechanism of Schaap’s adamantylidene-dioxetane and the quinone-methide elimination, which is used for the domino-like disassembly of the selfimmolative polymer. The chemiluminescence output signal was effectively amplified by the disassembly property of the selfimmolative polymer. NMR studies showed that the fast step of the polymer disassembly occurs through the quinone-methide elimination, which breaks the polymeric backbone into its monomeric units. In a second step, each of the monomeric units undergoes additional fragmentation through a chemiexcitation process to produce the overserved chemiluminescence signal. Responsive groups for various analytes could be introduced as a head trigger during the synthesis of the polymer backbone. Similar polymers with altered triggering substrates were able to serve as chemiluminescence probes for detection of three different analytes. We anticipate that the chemiluminescence self-immolative polymers described here will find use in various research areas such as signal amplification, lightemitting new materials, and molecular probes with long-lasting light emission and imaging capabilities.
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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/jacs.7b04804.
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Detailed experimental information and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Doron Shabat: 0000-0003-2502-639X Notes
The authors declare no competing financial interest. 10007
DOI: 10.1021/jacs.7b04804 J. Am. Chem. Soc. 2017, 139, 10002−10008
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ACKNOWLEDGMENTS D.S. thanks the Israel Science Foundation (ISF), the Binational Science Foundation (BSF), and the German Israeli Foundation (GIF) for financial support. Special thanks go to Dr. Charles Diesendruck for assistance with GPC measurements and analysis.
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REFERENCES
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