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A New Auto-Inductive Cascade for the Optical Sensing of Fluoride: Application in the Detection of Phosphoryl Fluoride Nerve Agents Xiaolong Sun, Samuel D. Dahlhauser, and Eric Van Anslyn J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01008 • Publication Date (Web): 14 Mar 2017 Downloaded from http://pubs.acs.org on March 14, 2017
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A New Auto-Inductive Cascade for the Optical Sensing of Fluoride: Application in the Detection of Phosphoryl Fluoride Nerve Agents† Xiaolong Sun, Samuel D. Dahlhauser, and Eric V. Anslyn* Department of Chemistry, The University of Texas at Austin, Austin, TX 78712, USA. Supporting Information Placeholder ABSTRACT: A new auto-inductive cascade employing benzoyl fluoride as a latent source of fluoride is reported for signal amplification and optical detection of fluoride. The autoinduction leads to a maximum four-fold signal enhancement for each fluoride generated, as well as a self-propagating cycle that generates three fluorophores for each single fluoride released. A two-step integrated protocol creates a more rapid auto-inductive cascade than previously reported, as well as a highly sensitive diagnostic assay for the ultratrace quantitation of a phosphoryl fluoride nerve agent surrogate. The generation of methods for signal amplification is of 1 great utility in sensing protocols. Strategies involving a variety of catalysts, as well as auto-inductive cascades, are cur2 rently being pursued. For example, label amplification cre3,4 ates several signal-producing labels per recognition event. The wiring of chemosensory molecules in series provides a 5-7 general method. Another protocol relies upon deliberate deactivation of an organometallic reaction by an exogenous ligand, that catalytically creates a fluorophore or chromo8-10 phore upon addition of the analyte. In addition, by employing enzymes for amplified nucleic acid detection, several examples utilizing their conjugation to DNA have been 11,12 demonstrated. The protocols of self-immolative molecular amplification, as popularized by Phillips and Shabat, are attractive strate13-17 gies owing to their exponential signal amplification. For example, there are three systems reported which release two 18-20 fluorides from each fluoride trigger (Fig. 1). Further, we recently reported a six-fold release of fluoride for each trigger, amplifying both a colorimetric and fluorescence re21 sponse. The rate of signal accumulation resulting from these cascades depends on the hydrolysis of aromatic mono- or difluoromethyl groups that slowly release fluoride through quinomethide-like intermediates. Hence, while signal amplification is achieved with these systems, the total signal accumulation from complete disassembly requires hours to a 18-20 couple of days. Thus, creating new approaches toward self-immolative chemical probes, possessing faster rates, while also embodying ratiometric signal changes (colorimetric and fluorometric), high sensitivity, and low limits of detection (LOD), along with fluorophores offering longer wavelength emission, will further the utility of this form of signal amplification.
We postulated that the slow step of auto-inductive cascades resulting from the structures of Figure 1 is the release of fluoride, both because it is a poor leaving group and the initial creation of a high energy fluorinated quinomethide. Hence, we sought an approach to continuously generate fluoride avoiding this intermediate. In this regard, we took inspiration from acyl-transfer reactions. Levacher introduced a methodology for enantioselective protonation of enolates by using a combination of benzoyl fluoride (BF) and ethanol as 22 the latent source of HF. Kalow and Doyle developed a method for the in situ generation of an amine-HF adduct by the Lewis base-catalyzed alcoholysis of BF and applied it to 23-25 the opening of a meso-epoxide.
Figure 1. Structures of fluoride self-amplification systems from Shabat, Phillips, Huang.
Consequently, to generate a protocol for faster fluoride release in an auto-inductive cascade, a protocol introducing BF as a latent source of fluoride was explored. As described herein, combining compound 1 with BF creates a cascade which generates three fluorophores (4-amino-1,8naphthalimide, 3) upon fluoride cleavage of the TBS group. Our method still relies upon quinomethide intermediates to 26-28 generate 2,4,6-hydroxymethyl phenolate 2, as a reactive 1 core toward BF. The phenoxide and benzyl alcohols of compound 2 were anticipated to react with BF catalyzed by 1,5diazabicyclo(4.3.0)non-5-ene (DBN) to offer a mixture of products (labeled as 4) which would release at least one, but up to four fluorides, that re-trigger the propagation (Scheme 22,23,29 1). After disassembly, the visible color change from 3 allows for naked-eye detection in situ, and fluorescence for the quantitative detection of fluoride, as may be employed 21 for the analysis of phosphoryl fluoride nerve agents. Choosing a proper solvent for the auto-induction was our first study. In protic solvents, fluoride would be rendered less reactive for silyl-deprotection by solvation, and such solvents would also be expected to react with BF to produce fluoride
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and yield a false positive signal. Yet, to generate the benzylic alcohols in 2, a slight amount of water must be present (vida infra). Thus, we explored aprotic solvents that carry water: dimethyl sulfoxide, methyl tert-butyl ether (MTBE), tetrahydrofuran, and dimethylformamide. It was observed that probe 1 (20 µM) itself decomposed rapidly in the higher polarity solvents, such as DMSO and DMF (Fig. S2†). However, the self-propagation of probe 1 (20 µM) in the presence of DBN (4 µM), BF (100 µM) and fluoride (2 µM, TBAF as donor) caused nearly a 24-fold fluorescence increase in MTBE, while only a 4-fold increase in THF (all at 60 mins). Thus, MTBE was found to be superior (Fig. S3†), as was employed 23,29 in the synthetic applications of BF. 1 eq. F-
O N O
O N O
ON O
O N O
H 2O
O N O
H N O O Si
O NH O H O N O O
NH2
NH2 OH
O N O
HO O 2
1
DBN
NH2 3 CO 2
OH CO2 CO2
O F
(Bz,H)O > 1 eq. F-
(Bz,H)O
O(H,Bz) O
4
O
Scheme 1. First, cleavage of TBS-protected phenol by one equivalent of fluoride generates 4-amino-1,8-naphthalimide fluorophores 3 and 2,4,6-hydroxymethyl phenolate 2 through 1,4- and 1,6-quinone methide eliminations. Second, reaction of compound 2 and BF in the presence of DBN generates more fluoride. Third, the fluoride(s) released re-trigger self-immolation of probe 1 till complete decomposition.
Each silyl-group deprotection generates a phenoxide, and each release of 3 from 1 generates a benzyl alcohol and consumes one equivalent of water, thereby creating compound 2. The phenoxide/alcohol(s) in turn react with BF to generate a fluoride. However, due to the fact that each fluoride decomposes one equivalent of compound 1, not all alcohols created in 2 need be benzoylated for the complete decomposition of 1 to occur. Because a phenoxide is significantly more 30 nucleophilic than benzyl alcohols, it is expected to be benzoylated first. The benzoylation of the phenoxide of 2 by BF would be catalyzed by a base, while the benzoylation of the benzyl alcohols of 2 require an equivalent of base for neutralization of HF. Thus, we explored the amount of a base needed to play these roles. Indeed, we found that less than an equivalent was needed (vida infra) due to its partial catalytic property. We examined DBN due to its previous use with 23-25 BF, and found that a concentration of 4 µM facilitates full decomposition of probe 1 (20 µM), while a higher concentration (8 µM) barely increased the reactivity (Fig. S4†). However, the auto-induction is dependent upon DBN, as it is hampered without it and full decomposition of 1 does not occur (Fig. S4†). As discussed, the formation of the benzyl alcohols in 2 results from the reaction of an intervening quinone methide with water (Eq. 1). Thus, the ability of MTBE to carry water 27 facilitates the auto-inductive processes. To verify this, a Karl-Fischer titration was performed repeatedly alongside
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these experiments to measure the water content in MTBE, revealed to be 161.5 ppm (5.94 mM) on average. Because water reacts with the quinomethide past the rate determining release of 3, its concentration does not affect the kinetics. However, a large excess of water did decrease the fluorescence signal change (Fig. S5†), presumably due to solvation of fluoride that lowers its ability to deprotect the silylether in 23,31 compound 1.
Equation 1
To test the role of BF, we verified the chemical inertness of 3 in the presence of BF with DBN over 120 mins (Fig. S6†). However, reaction between 2,4,6-hydroxymethyl phenol and BF was detected by LCMS, demonstrating the generation of four possible products, with one, two, three and four benzoyl groups linked with the reactive core, respectively (Fig. S7†). Next, we turned to the detection of fluoride using a combination of probe 1 and BF. The UV-Vis absorbance spectra were recorded as a function of time at various equivalents of TBAF (Fig. 2). The absorbance decreased at 360 nm and increased at 425 nm (Fig. S8†). Each dose of fluoride reached the same level of absorbance with time that is commensurate with full release of three naphthalimide chromophores. It should be noted that there are two isosbestic points, at 390 nm first and then shifting to 365 nm. Thus, the spectroscopy indicates the release of fluorophores from 1 in a stepwise fashion. With one tenth equivalent of TBAF, the exponential decomposition of 1 with a signal at 425 nm results in complete disassembly within 100 min, while decreasing concentrations of fluoride led to slower exponential signal growth (0.04 equiv. TBAF at 160 min, 0.02 equiv. TBAF at 500 min). As a control, probe 1 without any TBAF displayed an even slower signal change, but still reached the same maximum absorbance over 800 mins. The fact that all three fluorophores are released upon deprotection of 1 gives mechanistic insight into the cyclic cascade. It means that benzoylation of the phenoxide generated is slower than fluorophore release. If it were faster, such benzoylation would halt release because the required quinomethide intermediates would then be prohibited. We similarly monitored fluorescence changes, in the time range of 0 – 200 min, at low equivalents of TBAF. The emission signal showed both an exponential decrease at 440 nm and an increase at 500 nm, until a plateau was reached corresponding to full release of 3 (Fig. S9†). As with absorbance, the speed of exponential signal growth depends upon fluoride concentration (Fig. 2b). Furthermore, it was verified that three equivalents of 3 were liberated from 1 by comparison to 32 an independently-made solution of 3 (Fig. S10†). The exponential turn-on, followed by a plateau in both absorbance and fluorescence, found with less than even one-tenth equivalent, is indicative of an auto-inductive cascade. To make a comparison with the previous auto-inductive system, e.g. the presence of 0.02 eq. fluoride (TBAF as donor) led half-lives of the two systems to 390 mins and 30 mins, respectively. There is more than ten times faster in the new amplified approach 21 which is very sensitive in situ detection.
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ESI†) through click chemistry (Scheme 2). Oximate compound 5-b (see Supp. Mat. ESI†), having a pKa of 11.6, was attached to the resin. The products of reaction 5 with DFP can be removed from the oximate through filtration. Thus, an integrated two-stage process with same solvent was developed which is superior to the solution method with two 21 separate steps in different medias. We employed the resinbound oximate to separately generate fluoride from DFP, followed by quantitation using 1 and BF auto-inductive cascades.
Absorption
Next, we turned to fluoride titrations with probe 1, with and without BF, to both verify the function of this acylating agent and to generate calibration curves. Because each selfimmolative system will disassemble to release all naphthalimide reporters over an extended period irrespective of the amount of fluoride trigger, the optical response must be measured at a set time to distinguish differing levels of the trigger. Thus, for samples of probe 1 (20 µM), including and excluding BF (200 µM) in MTBE, varying concentrations of fluoride (0 – 1.6 µM) were added to the two separate groups of samples and the optical signal was recorded at 60 mins (Fig. 3, Fig. S11†). Large optical differences, (e.g. ~ 8-fold from A425nm/A360nm and ~ 16-fold from emission F500nm/F440nm) for probe 1 between samples with and without BF at a set TBAF (1.6 µM) level at 60 mins verify the functional role of BF in promoting the auto-induction (more comparative data in Fig. S11†). Calibration curves were generated for absorbance 2 2 at 425 nm (R = 0.98) and for emission at 500 nm (R = 0.99) as a function of TBAF concentration (0 – 1.6 µM), with LODs calculated as o.06 µM (3σ/κ) and 0.16 µM (3σ/κ), respective33 ly.
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Figure 3. (a) UV-Vis spectra starting with probe 1 (20 µM) for fluoride titrations (0 – 1.6 µM) in the presence of DBN (4 µM) and BF (200 µM) in MTBE at a 6o mins time point. (b) Linear relationship for absorbance at 425 nm versus concentration of fluoride (0 – 1.6 µM). (c) Fluorescence spectra at the same conditions as part (a). (d) Linear relationship between fluorescence intensity at 500 nm as in part (b). Ex = 405 nm, Ex slit/Em slit: 2 nm/2 nm.
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Figure 2. (a) UV-Vis time kinetics for disassembly of 1 (20 µM) in the presence of DBN (4 µM) and BF (200 µM) with various concentrations TBAF in MTBE. The embedded figure shows the time-course during the first 60 mins. The reaction progress was monitored at 425 nm; (b) Fluorescence time kinetics and trendline for disassembly of 1 (20 µM) with DBN (4 µM) and BF (200 µM) in the presence of various concentrations of TBAF in MTBE. The reaction progress was monitored by conversion of F500 nm. Ex = 405 nm, Ex slit/Em slit: 2 nm/2 nm.
The species, sarin, soman and tabun are fluoridecontaining G series nerve agents, posing threats for society, particularly in a modern world facing the very real possibility of terrorist attacks (Scheme 2). The most common surrogate for these nerve agents is diisopropyl fluorophosphate (DFP). Fluoride is a product of the reaction between G series nerve agents (and DFP) and oximate reagents (Scheme 2), which are commonly used functional groups for nerve agent detec34,35 tion. Yet, due to their high reactivity, oximates are in part limited in real-life applications due to the potential to react in the presence of other strong electrophiles. For example, even in the auto-inductive procedure described herein, BF cannot be added to an oximate due to the expected sidereaction to release fluoride to give a false positive signal. A Wang resin-oximate conjugate was created (see Supp. Mat.
O P
F
O
sarin (GB)
O P
O
F
soman (GD)
O P
F O
cyclosarin (GF)
O P O O
Nerve agent surrogate, DFP
O O P O O N
OH N CF3 N
CF3
N
CF3
N H 2C H 2C
O
O
H 2C H C H2 H H2 N CH C N C C O O
O
Resin
F P
N N
P4-t-Bu
N
O
CF3
F-
H 2C H 2C H2 C
tBME
DFP
5 O
H C H2 H H2 N CH C N C C O O
Resin
Scheme 2. Structures of common G nerve agents and the surrogate DFP. Fluoride anion released from the chemical reaction between DFP and oximate on resin in the presence of P4 base (phosphazene base P4-t-Bu solution).
To start, solutions containing DFP were mixed with the Wang resin-oximate in the presence of P4-t-Bu base in MTBE for 30 mins (Fig. 4, vial 1), and after filtration, the filtrate was added to the auto-inductive system 1 (20 µM), DBN (4 µM) and BF (200 µM), followed by monitoring the emission (Fig. 4, vial 2). The exponential fluorescence time-course at 500 nm again confirmed an auto-inductive cascade in a dosedependent manner that corresponds with initial DFP con-
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Journal of the American Chemical Society centrations in the time range of 0 to 210 mins (Fig. 5a), whereas the background without any addition of DFP was minimal. At a set time point of 40 mins, a linear relationship was found between fluorescence conversions at 500 nm 2 emission wavelength and DFP concentrations (R = 0.994 and LOD = 14 ppb (3σ/κ)). The more rapid fluorescence signal response, linear calibration curves, and low ppb level detection limit, reveal that the new auto-inductive cascade herein represents an alternative with various improvements over previous systems.
ASSOCIATED CONTENT Supporting Information
1
13
General methods, probe 1 synthesis, H and C NMR, HRMS and supplementary spectra results. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Email:
[email protected] ACKNOWLEDGMENT This project received support from the Defense Threat Reduction Agency-Joint Science and Technology Office for Chemical and Biological Defense (Grant no: HDTRA1-16-10001) and the Welch Regents Chair (F-0046).
REFERENCES Figure 4. Schematic illustration of steps for fluoride generation sensing by the auto-inductive cascade. First, chemical reaction between resin-oximate and DFP releases fluoride. Second, filtering the reaction solution from vial 1 into vial 2 containing probe 1 + BF + DBN for optical signal amplification. (a)
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Y = 0.279 + 0.001X R-square = 0.994
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Figure 5. (a) Fluorescence time kinetics and trendline for disassembly of system 1 (20 µM) in the presence of DBN (4 µM) and BF (200 µM), under various concentrations of DFP after reaction with Wang resin-oximate in MTBE. The Y-axis represents the conversion of fluorescence intensity and the X-axis the time range for the detection. (b) Fluorescence linear relationship after titration for probe 1 (20 µM) between fluorescence change of F500nm and concentration of DFP at a set time point of 40 mins.
In summary, we introduce a methodology for optical detection of fluoride by employment of an auto-inductive cascade using benzoyl fluoride. Further, as a model, quantitation of DFP was achieved to establish a sensitive and precise diagnostic assay for ultratrace detection of G series nerve agents. Thus, the colorimetric and fluorometric off-on response, increased rate, low background, commercial availability of BF, and synthetic ease of probe 1, lends this autoinductive cascade potential practical utility. However, due to the fact that a non-polar solvent with a level of water may complicate use in a complex media, we are currently developing self-immolative systems that work in aqueous media. We are also incorporating auto-inductive protocols into portable devices for use in the field, and exploring potential interferents.
(1) Roth, M. E.; Green, O.; Gnaim, S.; Shabat, D. Chem. Rev. 2016, 116, 1309-1352. (2) Goggins, S.; Frost, C. G. Analyst 2016, 141, 3157-3218. (3) Nam, J.-M.; Thaxton, C. S.; Mirkin, C. A. Science 2003, 301, 18841886. (4) Taton, T. A.; Mirkin, C. A.; Letsinger, R. L. Science 2000, 289, 17571760. (5) Swager, T. M. Acc. Chem. Res. 1998, 31, 201-207. (6) Marsella, M. J.; Swager, T. M. J. Am. Chem. Soc. 1993, 115, 1221412215. (7) Zhou, Q.; Swager, T. M. J. Am. Chem. Soc. 1995, 117, 7017-7018. (8) Wu, Q.; Anslyn, E. V. J. Am. Chem. Soc. 2004, 126, 14682-14683. (9) Zhu, L.; Lynch, V. M.; Anslyn, E. V. Tetrahedron 2004, 60, 72677275. (10) Zhu, L.; Anslyn, E. V. Angew. Chem. Int. Ed. 2006, 45, 1190-1196. (11) Saghatelian, A.; Guckian, K. M.; Thayer, D. A.; Ghadiri, M. R. J. Am. Chem. Soc. 2003, 125, 344-345. (12) Gianneschi, N. C.; Ghadiri, M. R. Angew. Chem. Int. Ed. 2007, 119, 4029-4032. (13) Amir, R. J.; Pessah, N.; Shamis, M.; Shabat, D. Angew. Chem. Int. Ed. 2003, 42, 4494-4499. (14) Shamis, M.; Lode, H. N.; Shabat, D. J. Am. Chem. Soc. 2004, 126, 1726-1731. (15) Amir, R. J.; Popkov, M.; Lerner, R. A.; Barbas, C. F.; Shabat, D. Angew. Chem. Int. Ed. 2005, 117, 4452-4455. (16) Yeung, K.; Schmid, K. M.; Phillips, S. T. Chem. Commun. (Camb.) 2013, 49, 394-396. (17) Baker, M. S.; Kim, H.; Olah, M. G.; Lewis, G. G.; Phillips, S. T. Green Chem. 2015, 17, 4541-4545. (18) Perry-Feigenbaum, R.; Sella, E.; Shabat, D. Chem. Eur. J. 2011, 17, 12123-12128. (19) Baker, M. S.; Phillips, S. T. J. Am. Chem. Soc. 2011, 133, 5170-5173. (20) Gu, J.-A.; Mani, V.; Huang, S.-T. Analyst 2015, 140, 346-352. (21) Sun, X.; Reuther, J. F.; Phillips, S.; Anslyn, E. Chem. Eur. J. 2017, DOI: 10.1002/chem.201604474. (22) Poisson, T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem. Int. Ed. 2007, 46, 7090-7093. (23) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268-3269. (24) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133, 1600116012. (25) Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77, 4177-4183. (26) Gnaim, S.; Shabat, D. Acc. Chem. Res. 2014, 47, 2970-2984. (27) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002, 124, 6349-6356. (28) Toteva, M. M.; Moran, M.; Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 2003, 125, 8814-8819. (29) Birrell, J. A.; Desrosiers, J.-N.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 13872-13875. (30) Reeve, W.; Erikson, C. M.; Aluotto, P. F. Can. J. Chem. 1979, 57, 2747-2754.
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(31) Heuft, J.; Meijer, E. J. Chem. Phys. 2005, 122, 094501. (32) Individual solution of 4-amino-1,8-naphthalimide (60 µM) was made and tested in UV-Vis absorbance and fluorescence emission, in comparison with sample probe 1 (20 µM) after maximum disassembly (Fig. S8†). (33) Shrivastava, A.; Gupta, V. B. Chron. Young Sci. 2011, 2, 21. (34) Wallace, K. J.; Fagbemi, R. I.; Folmer-Andersen, F. J.; Morey, J.; Lynth, V. M.; Anslyn, E. V. Chem. Commun. (Camb.) 2006, 38863888. (35) Dale, T. J.; Rebek, J. Angew. Chem. Int. Ed. 2009, 48, 7850-7852.
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