A thermally-stable enzyme detection assay that amplifies signal autonomously in water without assistance from biological reagents
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1 A thermally-stable enzyme detection assay that amplifies signal autonomously in water without assistance from biological reagents Table of Contents Kimy Yeung, Kyle M. Schmid, and Scott T. Phillips* Department of Chemistry, The Pennsylvania State University, University Park, PA *Corresponding author Supporting Information General experimental procedures Instrumentation Synthesis of signal amplification reagent 1 Synthesis of activity-based detection reagent 2 HPLC studies showing consumption of reagent 1 when exposed to H 2 2 Photographic analysis of colorimetric output when reagent 1 is exposed to H 2 2 Calibration curve for quantifying hydrogen peroxide using 1 Detection of β-d-galactosidase using reagents 1 and 2 Quantification of β-d-galactosidase using reagents 1 and 2 References NMR spectra S1 S2 S2 S7 S10 S13 S20 S21 S23 S23 S24 General experimental procedures All reactions that required anhydrous conditions were performed in flame-dried glassware under a positive pressure of argon. Air- and moisture-sensitive liquids were transferred by syringe or stainless steel cannula. rganic solutions were concentrated by rotary evaporation (25 40 mmhg) at ambient temperature, unless otherwise noted. 4-Bromoisophthalic acid, 2,4- dihydroxybenzaldehyde, 2,4-diallyloxybenzaldehyde and all other reagents were purchased commercially and were used as received. Flash-column chromatography was performed as described by Still et al., 1 employing silica gel (60-Å pore size, µm, standard grade, Dynamic Adsorbents). Thin layer chromatography was carried out on Dynamic Adsorbants silica gel TLC (20Å~20 cm w/h, F-254, 250 µm). Deionized water was purified using a milliporepurification system (Barnstead EASYpure II UV/UF). Kinetics experiments were carried out in 1.5 ml plastic cuvettes. S1
2 Instrumentation Photographs were acquired using a Nikon digital camera (D40, D3100) and analyzed using Adobe Photoshop. Proton nuclear magnetic resonance ( 1 H-NMR) spectra and carbon nuclear magnetic resonance spectra ( 13 C-NMR) were recorded using a Bruker DRX-400 (400 MHz), Bruker CDPX-300 (300 MHz), or AV-360 (360 MHz) at 25 C. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to chloroform (CDCl 3, 7.26 ppm), methanol (CD 3 D, 3.31 ppm), acetonitrile (CD 3 CN, 1.94 ppm), or acetone ((CD 3 ) 2 C, 2.05 ppm). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances, br s = broad singlet, dd = doublet of doublet), integration, and coupling constant (J) in Hertz. Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to chloroform (CDCl 3, ppm), methanol (CD 3 D, 49.0 ppm), acetonitrile (CD 3 CN, 1.32 ppm), or acetone ((CD 3 ) 2 C, ppm). Synthesis of signal amplification reagent 1 Br MEM Br C 2 H C 2 H 5 1. BH 3 THF, THF 66 o C, 96% 2. HBr, H 2, H 2 S o C, 82% Br 6 Br Br MEM H MEM 7 K 2 C 3, acetone 57 o C 94% 8 MEM MEM MEM H B H MEM H B H H 1. nbuli, THF, -78 o C 2. B(Me) 3, -78 o C to rt M HCl 49% MEM MEM PTSA H 2, EtH 35 o C 39% H H 9 MEM 1 H S2
3 1-Bromo-2,4-bis(bromomethyl)-benzene (6): 4-Bromoisophthalic acid 5 (3.12 g, 12.7 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (32 ml), and the solution was cooled to 0 o C. Borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) was added dropwise slowly to the cooled solution, and the mixture was stirred at 0 o C for 15 min. The solution was warmed to room temperature and refluxed at 66 o C for 16.5 h. The reaction mixture was cooled to room temperature and quenched by slow addition of saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 50 ml). The combined organic layers were washed with saturated ammonium chloride (2 50 ml) and saturated sodium bicarbonate (2 50 ml). The organic layers were dried over sodium sulfate. The sodium sulfate was removed by filtration and the resulting solution was concentrated under reduced pressure, affording a white solid. The white solid was dried under reduced pressure and was without further purification. The white solid (1.0 g, 4.6 mmol, 1.0 equiv) was dissolved in aqueous hydrobromic acid (48%) (5.1 ml, 46.1 mmol, 10.0 equiv). Concentrated sulfuric acid (123 µl, 2.3 mmol, 0.5 equiv) was added dropwise. The reaction mixture was stirred at 122 C for 22 h. The solution was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water (1 30 ml), saturated sodium bicarbonate (2 30 ml) and brine (1 50 ml). The organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution 0 5% ethyl acetate/hexanes) to afford compound 6 as a white solid (1.29 g, 3.76 mmol, 82%). 1 H-NMR (360 MHz, CDCl 3 ): δ 7.55 (d, 1 H, J = 8.17), 7.48 (d, 1 H, J = 2.27), 7.20 (dd, 1 H, J = 8.25, 2.3), 4.57 (s, 2 H), 4.42 (s, 2 H). This 1 H-NMR data matches previously published data for ,4'-(((4-Bromo-1,3-phenylene)bis(methylene))bis(oxy))bis(1,3-bis((2- methoxyethoxy)methoxy)benzene) (8): An oven-dried two-necked round bottom flask equipped with a stir bar was charged with K 2 C 3 (237 mg, 1.72 mmol, 2.2 equiv), compound 6 (268 mg, 0.78 mmol, 1.0 equiv) and compound 7 3 (495 mg, 1.64 mmol, 2.1 equiv) in acetone (8 ml). The reaction mixture was heated to reflux at 57 ºC for 24 h. The solution was cooled to room temperature and the solvent was removed under S3
4 reduced pressure. The residue was purified by column chromatography (gradient elution with % ethyl acetate/hexanes) to obtain compound 8 as a yellow oil (588 mg, 0.75 mmol, 96%). IR (cm -1 ): , , 1082, 1000; 1 H-NMR (300 MHz, CDCl 3 ): δ 7.60 (d, 1 H, J = 1.96), 7.53 (d, 1 H, J = 8.17), 7.25 (dd, 1 H, J = 8.16, 2.18), 6.91 (d 1 H, J = 2.8), 6.89 (d 1 H, J = 2.8), 6.81 (d, 1 H, J = 16.68), 6.78 (d, 1 H, J = 16.69), 6.65 (dd, 1 H, J = 8.85, 2.82), 6.62 (dd, 1 H, J = 8.80, 2.76), 5.27 (s, 2 H), 5.24 (s, 2 H), 5.17 (s, 2 H), 5.16 (s, 2 H), 5.09 (s, 2 H), 4.99 (s, 2 H), (m, 8 H), (8 H), 3.35 (s, 3 H), 3.34 (s, 3 H), 3.33 (s, 6 H); 13 C-NMR (400 MHz, CDCl 3 ): δ 152.4, 152.2, 147.8, 147.8, 143.9, 137.0, 136.7, 132.5, 128.0, 127.7, 121.1, 116.0, 115.9, 109.5, 109.3, 107.3, 94.6, 94.6, 94.0, 71.5, 71.4,71.3, 71.2, 67.8, 67.8, 67.4, 58.8; MS (TF MS ES+, m/z): (+18, NH + 4 ); HRMS (TF MS ES+, m/z): calcd for C 36 H Br (M + 1) 784, found (+18, NH + 4 ). (2,4-Bis((2,4-bis((2-methoxyethoxy)methoxy)phenoxy)methyl)phenyl)boronic acid (9): Compound 8 (500 mg, 0.64 mmol, 1.0 equiv) was dissolved in dry tetrahydrofuran (6.4 ml) and the solution was cooled to 78 o C. n-butyl lithium (2.5 M solution in hexanes, 305 µl, 0.76 mmol, 1.2 equiv) was added slowly to the stirring solution, and the reaction mixture was stirred at 78 o C for 1 h. Trimethyl borate (357 µl, 3.2 mmol, 5.0 equiv) was added at 78 o C with continued stirring at 78 o C for 2.5 h. The solution was warmed to room temperature and was stirred at room temperature for 7 h. To this mixture was added 0.1 M HCl (6 ml) and the reaction mixture was stirred for 14 h. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with deionized water (1 10 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2 10 ml). The combined organic layers were dried over sodium sulfate. The sodium sulfate was removed by filtration and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution with % ethyl acetate/hexanes to 8% methanol/ethyl acetate) to obtain compound 9 as a light yellow oil (236 mg, 0.31 mmol, 49%). IR (cm -1 ): , , , , 1000; 1 H- NMR (300 MHz, (CD 3 ) 2 C): δ 7.80 (d, 1 H, J = 7.58), 7.61 (br s, 1 H), 7.43 (dd, 1 H, J = 7.6, 1.36), 7.39 (s, 2 H), 7.07 (d, 1 H, J = 8.87), 6.95 (d, 1 H, J = 8.89), 6.91 (dd, 2 H, J = 2.83, 0.92), 6.69 (dd, 1 H, J = 6.3, 2.83), 6.66 (dd, 1 H, J = 6.08, 2.63), 5.28 (s, 2 H), 5.25 (s, 2 H), 5.22 (s, 2 H), 5.18 (s, 2 H), 5.17 (s, 2 H), 5.04 (s, 2 H), (m, 8 H), (m, 8 H), 3.28 (s, S4
5 6 H), 3.26 (s, 3 H), 3.25 (s, 3 H); 13 C-NMR (300 MHz, (CD 3 ) 2 C): δ 153.3, 153.1, 148.9, 148.8, 142.5, 140.1, 135.8, 128.6, 127.2, 117.0, 116.7, 110.4, 110.3, 108.7, 108.0, 95.4, 95.3, 94.8, 73.3, 72.3, 72.3, 72.1, 68.6, 68.6, 68.3, 58.8; MS (TF MS APCI-, m/z): 749.0, MS (TF MS APCI+, m/z): (+18, NH + 4 ); HRMS (TF MS ES+) Calculated for C 36 H 55 BN 16 (M + NH + 4 ) ; Found: (2,4-Bis((2,4-dihydroxyphenoxy)methyl)phenyl)boronic acid (1): Compound 9 (81 mg, 0.19 mmol, 1 equiv) was dissolved in ethanol (200 proof, 2 ml) and the solution was stirred at room temperature. p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol, 2.2 equiv) was added to the stirred solution, and the reaction mixture was stirred at 35 o C for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was first purified by column chromatography (90 100% ethyl acetate/hexanes) to give a light brown oil residue. This residue was further purified using preparative HPLC to obtain 1 as an off-white solid (30 mg, 75 µmol, 39%). IR (cm -1 ): ; 1 H-NMR (400 MHz, CD 3 D): δ 7.48 (s, 1 H), 7.41 (t, 1 H, J = 10.98), 7.38 (d, 1 H, J = 20.15), 6.79 (d, 1 H, J = 18.52), 6.77 (d, 1 H, J = 18.53), 6.34 (s, 2 H), 6.20 (d, 1 H, J = 10.12), 6.17 (d, 1 H, J = 9.72), 5.07 (s, 2 H), 5.05 (s, 2 H). 13 C-NMR (400 MHz, CD 3 D): 153.8, 153.6, 149.3, 149.2, 142.3, 141.3, 141.0, 139.7, 132.6, 127.6, 127.4, 117.4, 117.2, 106.7, 106.6, 104.7, 73.6, 73.1; MS (TF MS ES+, m/z): 399.1; MS (TF MS ES-, m/z): 397.0; HRMS (TF MS ES-, m/z): calcd for C 20 H 18 8 B (M 1) , found Synthesis of 2,4 Dimethoxyethoxymethyloxyphenol (7) H H MEM-Cl, DIEA, CH 2 Cl 2 H MEM 1. m-cpba, CH 2 Cl 2 0 o C to 41 o C 2. KH, H 2, MeH 93 % 81% H MEM MEM H MEM 2,4 Dimethoxyethoxymethyloxybenzaldehyde (11): 2,4-Dihydroxybenzaldehyde 10 (2.0 g, 14.5 mmol, 1.0 equiv) was suspended in dry dichloromethane (29 ml), and the suspension was cooled to 0 ºC with stirring. N, N- S5
6 diisopropylethylamine (25 ml, mmol, 10.0 equiv) was added to the cooled suspension and the solution was stirred for 10 min at 0 ºC. Methoxyethoxymethyl chloride (9.9 ml, 87 mmol, 6.0 equiv) was added slowly to the cooled solution. The reaction mixture was stirred at 41 ºC for 24 h. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting solution was washed with water (3 50 ml) and brine (2 50 ml). The organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution with 20 50% ethyl acetate/benzene) to obtain compound 11 3 as a yellow oil (4.22 g, 13.4 mmol, 93%). 1 H-NMR (300 MHz, CDCl 3 ): δ (s, 1 H), 7.65 (d, 2 H, J = 8.7), 6.75 (d, 1 H, J = 2.18), 6.64 (dd, 1 H, J = 8.69, 1.85), 5.24 (s, 2 H), 5.18 (s, 2 H), (m, 2 H), (m, 2 H), (m, 4 H), 3.23 (s, 3 H), 3.22 (s, 3 H). This 1 H-NMR data matches previously published data for ,4 Dimethoxyethoxymethyloxyphenol (7): Compound 11 (1.84 g, 5.5 mmol, 1.0 equiv) was dissolved in dry dichloromethane (15 ml), and the solution was stirred at room temperature. meta-chloroperoxybenzoic acid (1.51 g, 8.74 mmol, 1.5 equiv) was added to the stirring solution. The reaction mixture was stirred at room temperature for 1.5 h. The solution was diluted with dichloromethane and the resulting solution was washed with 1:1 solution of saturated sodium thiosulfate and saturated sodium bicarbonate (30 ml). The organic layer was removed, and the aqueous layer was extracted using dichloromethane (3 20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2 30 ml) and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the resulting solution was concentrated under reduced pressure. The residue was dissolved in dry methanol (15 ml). A solution of potassium hydroxide (66 mg, 1.17 mmol, 0.2 equiv) in water (375 µl) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 3 h, after which the solvent was removed under reduced pressure. The residue was dissolved in water and the solution was carefully neutralized with 1 M HCl. The solution was extracted with ethyl acetate (3 30 ml). The combined organic layers were dried over sodium sulfate. The sodium sulfate was removed by filtration and the resulting solution was concentrated under reduced pressure. The residue was purified by column S6
7 chromatography (gradient elution with 25 50% ethyl acetate/benzene) to obtain compound 7 3 as a light yellow oil (1.43 g, 4.73 mmol, 81%). 1 H-NMR (300 MHz, CDCl 3 ): δ 6.82 (d, 1 H, J = 6.27), 6.79 (s, 1 H), 6.66 (dd, 1 H, J = 8.66, 2.92), 6.11 (br s, 1 H), 5.21 (s, 2 H), 5.14 (s, 2 H), (m, 2 H), (m, 2 H), (m, 4 H), 3.38 (s, 3 H), 3.35 (s, 3 H). This 1 H-NMR data matches previously published data for 7. 3 Synthesis of activity-based detection reagent 2 Ac Ac Ac H Ac Ac H H Ac Ac Ac H NaMe 1. PBr 3, CH 2 Cl 2 2. H,TBAI, K 2 C 3 MeH, CH 2 Cl 2 H 16 acetone, 70 o C 46% over 2 steps H H Pd(PPh 3 ) 4, Bu 3 SnH, ZnCl 2 DMF, THF 50% over 2 steps H H H H (2R,3S,4S,5R,6S)-2-(Acetoxymethyl)-6-(4-((2,4- bis(allyloxy)phenoxy)methyl)phenoxy)tetrahydro-2h-pyran-3,4,5-triyl triacetate (13): Compound 12 4 (0.57 g, 1.2 mmol, 1.0 equiv) was dissolved in dry dichloromethane (10 ml) and cooled to 0 C. Phosphorous tribromide (1.0 M solution in dichloromethane, 0.62 ml, 0.62 mmol, 0.5 equiv) was added dropwise and the solution was stirred at 0 C for 1 h. The reaction mixture was diluted with dichloromethane (50 ml), washed with saturated sodium bicarbonate (1 50 ml) and washed with brine (1 50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation and the residue was dried under reduce pressure, yielding a white solid. The white solid was dried under reduced pressure and used without further purification. The white solid, compound 16 (0.31 g, 1.5 mmol, 1.2 equiv), potassium carbonate (0.51 g, 3.7 mmol, 3.0 equiv), and tetrabutylammonium iodide (93 mg, 0.25 mmol, 0.2 equiv) were suspended in acetone (2.5 ml). The suspension was heated in a sealed vial to 70 C for 24 h. S7
8 The reaction mixture was filtered and the solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate (25 ml) and washed with saturated sodium chloride solution (1 25 ml). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (gradient elution with 30 50% ethyl acetate/hexanes) to afford compound 13 (0.35 g, 0.55 mmol, 46%) as a white solid. IR (cm -1 ): , (b), (b); 1 H-NMR (360 MHz, CDCl 3 ): δ 7.35 (d, 2 H, J = 8.7), 6.97 (d, 2 H, J = 8.6), 6.79 (d, 1 H, J = 8.7), 6.53 (d, 1 H, J = 2.8), 6.36, (dd, 1 H, J = 8.7, 2.8), (m, 2 H), (m, 4 H), (m, 2 H), 5.10 (dd, 1 H, J = 10.4, 3.4), 5.02 (d, 1 H, J = 8.0), 4.98 (s, 2 H), (m, 2 H), (m, 2 H), (m, 2 H), 4.05 (t, 1 H, J = 7.0), 2.16 (s, 3 H), 2.04 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H); 13 C-NMR (360 MHz, CDCl 3 ): δ 170.3, 170.2, 170.1, 169.4, 156.5, 153.9, 150.0, 142.7, 133.4, 133.2, 132.6, 129.0, 117.6, 117.6, 117.5, 116.8, 116.7, 105.0, 103.0, 99.7, 71.9, 71.0, 70.8, 69.7, 69.2, 68.6, 66.8, 61.3, 20.6; MS (TF MS AP+, m/z): (M + NH + 4 ); HRMS (TF MS ES+) Calculated for C 33 H 42 N 13 (M + NH4+): ; Found: (2S,3R,4S,5R,6R)-2-(4-((2,4-Bis(allyloxy)phenoxy)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol (14): Sodium methoxide (1.2 mg, 22 µmol, 0.04 equiv) was dissolved in dry methanol (100 µl) and was added to a stirring solution of compound 13 (0.35 g, 0.55 mmol, 1.0 equiv) in a mixture of dry dichloromethane (1 ml) and dry methanol (4 ml). The reaction mixture was stirred at 23 C for 2 h and an additional portion of sodium methoxide (1.2 mg, 22 µmol, 0.04 equiv, in 100 µl of methanol) was added. After 1 h, the solvent was removed by rotary evaporation to afford compound 14 as a white solid. Compound 14 was dried under reduced pressure and was used without further purification. (2S,3R,4S,5R,6R)-2-(4-((2,4-Dihydroxyphenoxy)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol (2): Compound 14 (0.14 g, 0.30 mmol, 1.0 equiv), tetrakis-(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol, 0.1 equiv), and zinc(ii) chloride (0.11 g, 0.8 mmol, 2.7 equiv) were dissolved in a mixture of dry tetrahydrofuran (4 ml) and dry N,N-dimethylformamide (1 ml). Tributyltin hydride (0.32 ml, 1.2 mmol, 4 equiv) was added slowly and the reaction mixture was stirred for S8
9 15 min. The suspension was then concentrated by rotary evaporation and dried under reduced pressure. The residue was dissolved in acetonitrile (20 ml), filtered through celite (eluting with 1:1 acetonitrile:methanol, 30 ml), and concentrated by rotary evaporation. The residue was purified by preparative HPLC, affording compound 2 (60 mg, 0.15 mmol, 50% over 2 steps) as an off white solid. IR (cm -1 ): , , , ; 1 H-NMR (360 MHz, CD 3 D): δ 7.36 (d, 2 H, J = 8.6), 7.10 (d, 2 H, J = 8.7), 6.71 (d, 1 H, J = 8.7), 6.31 (d, 1 H, J = 4.4), 6.16, (dd, 1 H, J = 8.6, 2.8), 4.94 (s, 2 H), 4.84 (s, 1 H), 3.89 (d, 1 H, J = 3.2), (m, 4 H), 3.59 (dd, 1 H, J = 9.72, 3.4); 13 C-NMR (360 MHz, CD 3 D): δ 158.9, 153.6, 149.3, 141.1, 132.9, 130.4, 117.7, 117.6, 106.6, 104.6, 102.9, 76.9, 74.8, 73.1, 72.3, 70.2, 62.4; MS (TF MS AP+, m/z): (M + NH + 4 ); HRMS (TF MS ES-) Calculated for C 19 H 21 9 (M H + ): ; Found: Synthesis of 2,4-diallyloxyphenol (16) CH KHS 4, H 2 2 H MeH 99% ,4-Diallyloxyphenol (16): 2,4-Diallyloxybenzaldehyde 15 (0.87 g, 4.0 mmol, 1.0 equiv) and potassium hydrogen sulfate (81 mg, 5.0 mmol, 1.25 equiv) were dissolved in methanol (8 ml). Hydrogen peroxide solution (35% in water, 0.49 ml, 5 mmol, 1.25 equiv) was added dropwise and the reaction mixture was stirred at 23 C for 1.5 h. A 1:1 solution of saturated sodium thiosulfate saturated sodium bicarbonate (1 ml) was added dropwise to the reaction mixture. The mixture was diluted with ethyl acetate (60 ml) and washed with saturated sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation. The residue was dried under reduce pressure, affording compound 16 (0.81 g, 3.96 mmol, 99%) as a white solid. IR (cm -1 ): , , ; 1 H-NMR (360 MHz, CDCl 3 ): δ 6.82 (d, 1 H, J = 8.68), 6.51 (d, 1 H, J = 2.74), 6.41 (dd, 1 H, J = 8.68, 2.77), (m, 2 H), S9
10 (m, 1 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 2 H); 13 C-NMR (360 MHz, CDCl 3 ): δ 152.3, 145.9, 140.1, 133.5, 132.6, 118.3, 117.5, 114.2, 105.9, 101.5, 69.7, 69.5; MS (TF MS AP+, m/z) (M + H + ). HPLC studies showing consumption of reagent 1 when exposed to H 2 2 General experimental procedure corresponding to Figure 2a: A solution of reagent 1 in dry acetonitrile was added to phosphate buffer (0.1 M, ph 7.3). Hydrogen peroxide in buffered water was added to the solution and solution was vortexed for 60 s, and the resulting solution was injected into an analytical reversed-phase HPLC coupled to a mass spectrometer. The column used was an Agilent Eclipse XDB-C-18 column ( mm, 5 µm). The mobile phase used was a mixture of 0.5 mm ammonium formate in H 2 (A) and CH 3 CN (B). The column was equilibrated with 9:1 A-B at a flow rate of 0.4 ml/min. The solvent gradient was as follows: Time (min) A (%) B (%) For the assay that contained water treated with catalase, the buffered water was prepared as follows: 1.3 mg of catalase (3691 units/mg) was added to phosphate buffer (10 ml, 0.1 M, ph 7.3) and the treated water was stirred gently for 15 min, after which the catalase was removed by filter centrifugation. The pre-treated buffered water was used without further purification. For the assay that contained water with catalase present, the buffered water was prepared using the same procedure, but the catalase was not removed, and the buffered solution was used without further purification. S10
11 Tables of HPLC data for Figure 2a: Table S1. HPLC data for consumption of reagent 1 with 0.5 equiv H 2 2. Time (min) Area of Reagent 1 % Conversion Table S2. HPLC data for consumption of reagent 1 with 0.25 equiv H 2 2. Time (min) Area of Reagent 1 % Conversion Table S3. HPLC data for consumption of reagent 1 with 0.1 equiv H 2 2. Time (min) Area of Reagent 1 % Conversion Table S4. HPLC data for consumption of reagent 1 with regular buffered water and no H 2 2. Time (min) Area of Reagent 1 % Conversion Table S5. HPLC data for consumption of reagent 1 with catalase-treated buffered water and no H 2 2. Time (min) Area of Reagent 1 % Conversion S11
12 Table S6. HPLC data for consumption of reagent 1 with buffered water containing catalase and no H 2 2. Time (min) Area of Reagent 1 % Conversion S12
13 Photographic analysis of colorimetric output when reagent 1 is exposed to H 2 2 General experimental procedure corresponding to Figure S1a: A hydrogen peroxide solution in phosphate buffered water (ph 7.3; 0.25 mm 2.5 mm, equivalents relative to amplification reagent 1) was added to a solution of the amplification reagent 1 in buffered water containing 1.5% DMF (2.5 mm). The colorimetric change of the solution was monitored via photography and image processing software. Figure S1. Amplified colorimetric response of 1 when exposed to hydrogen peroxide. (a) Intensity of color of the reaction mixture over time for experiments using 2.5 mm 1 and different initial quantities of hydrogen peroxide. The color of the solution was quantified from photographs using Adobe Photoshop. (b) An identical experiment as (a) with the exception that the amplification solution contained 0.5% Tween-20 (v/v), whereas the surfactant was not included in (a). The data points in both graphs are the average of three measurements, and the error bars represent the standard deviations from the averages. S13
14 Tables of Color Intensity for Figure S1a: Table S7. Color intensity data for 1 equiv H 2 2. Time Trial 1 Trial 2 Trial 3 (min) Table S8. Color intensity data for 0.5 equiv H 2 2. Time Trial 1 Trial 2 Trial 3 (min) S14
15 Table S9. Color intensity data for 0.25 equiv H 2 2. Time Trial 1 Trial 2 Trial 3 (min) Table S10. Color intensity data for 0.1 equiv H 2 2. Time Trial 1 Trial 2 Trial 3 (min) S15
16 Table S11. Color intensity data for no H 2 2. Time Trial 1 Trial 2 Trial 3 (min) S16
17 Table S12. Color intensity data for catalasetreated water with no H Time Trial 1 Trial 2 Trial 3 (min) General experimental procedure corresponding to Figure S1b: A hydrogen peroxide solution in phosphate buffered water (ph 7.3; 0.25 mm 1.25 mm, equivalents relative to amplification reagent 1) was added to a solution of the amplification reagent 1 in buffered water containing 1.5% DMF (2.5 mm) and 0.5% Tween-20 (v/v). The colorimetric change of the solution was monitored via photography and image processing software. S17
18 Tables of Color Intensity for Figure S1b: Table S13. Color intensity data for 0.5 equiv H 2 2 with 0.5% Tween-20. Time (h) Trial 1 Trial 2 Trial Table S14. Color intensity data for 0.1 equiv H 2 2 with 0.5% Tween-20. Time (h) Trial 1 Trial 2 Trial S18
19 Table S15. Color intensity data for no H 2 2 with 0.5% Tween-20. Time (h) Trial 1 Trial 2 Trial S19
20 Calibration curve for quantifying hydrogen peroxide using 1 General experimental procedure corresponding to Figure S2: A hydrogen peroxide solution in phosphate buffered water (ph 7.3; 0.01 mm 2.5 mm, equivalents relative to amplification reagent 1) was added to a solution of the amplification reagent 1 in buffered water containing 1.5% DMF (2.5 mm). After 30 min, the colorimetric change of the solution was monitored via photography and image processing software. Figure S2. Calibration curve for a 30 min assay in which (a) 2.5 mm 1 in 0.1 M phosphate buffer containing 1.5% DMF (ph 7.3) was exposed to various concentrations of hydrogen peroxide at 23 C. The intensity of color for each experiment was obtained using image analysis of photographs. The data points represent the averages of three measurements. (b) Expanded view of the dotted region of (a). The limit of detection was calculated as 3 (sd/s) where sd is the standard deviation at 0.01 mm and s is the slope of the calibration curve. Table S16. Color intensity data for the calibration curve (corresponding to Figure S2). Conc. of Trial 1 Trial 2 Trial 3 H 2 2 (mm) S20
21 Detection of β-d-galactosidase using reagents 1 and 2 Experimental procedure corresponding to Figure 3: For the assay containing both activity-based detection reagent 2 and signal amplification reagent 1 (denoted as ): A 5 µl solution of reagent 2 in DMF was mixed with 25 µl of Tween-20 in phosphate buffer (0.1 M, ph 7.3). To the solution was added 7.5 µl solution of reagent 1 in DMF and µl phosphate buffer, respectively. 25 µl solution of β-d-galactosidase in phosphate buffer was subsequently added. The colorimetric change of the solution was monitored via photography and image processing software. verall, the assay contained 2.5 mm of reagents 1 and 2, respectively, 194 nm of the β-d-galactosidase, 2.5% DMF, and 0.5% Tween-20 (v/v). For the assay containing only activity-based detection reagent 2 (denoted as ): A 5 µl solution of reagent 2 in DMF was mixed with 25 µl of Tween-20 in phosphate buffer (0.1 M, ph 7.3). To the solution was added 445 µl phosphate buffer, and 25 µl solution of β- D-galactosidase in phosphate buffer was subsequently added. The colorimetric change of the solution was monitored via photography and image processing software. verall, the assay contained 2.5 mm of reagent 5, 194 nm of the β-d-galactosidase, 1% DMF, and 0.5% Tween-20 (v/v). For the assay containing only activity-based detection reagent 1 (denoted as ): A 7.5 µl solution of reagent 1 in DMF was mixed with 25 µl of Tween-20 in phosphate buffer (0.1 M, ph 7.3). To the solution was added µl phosphate buffer, and 25 µl solution of β-d-galactosidase in phosphate buffer was subsequently added. The colorimetric change of the solution was monitored via photography and image processing software. verall, the assay contained 2.5 mm of reagent 1, 194 nm of the β-d-galactosidase, 1.5% DMF, and 0.5% Tween- 20 (v/v). For the assay containing only activity-based detection reagent 2 with no enzyme (denoted as ): A 5 µl solution of reagent 2 in DMF was mixed with 25 µl of Tween-20 in phosphate buffer (0.1 M, ph 7.3) and 470 µl phosphate buffer. The colorimetric change of the solution was S21
22 monitored via photography and image processing software. verall, the assay contained 2.5 mm of reagent 2, 1% DMF, and 0.5% Tween-20 (v/v). For all assays, the absolute intensities were calculated using the formula I I 0, where I = intensity at time t, and I 0 = intensity at time 0 min. Tables of Absolute Color Intensity for Figure 3: Table S17: Absolute color intensity data for the one-pot assay containing reagents 1 and 2, assay containing only 2, and assay containing only 1 Time (h) Table S18: Absolute color intensity data for activity-based detection reagent (2) with no enzyme Time (h) 2 (no enzyme) S22
23 Quantification of β-d-galactosidase using reagents 1 and 2 Experimental procedure corresponding to Figure 4: A 5 µl solution of reagent 2 in DMF was mixed with 25 µl of Tween-20 in phosphate buffer (0.1 M, ph 7.3). To the solution was added 7.5 µl solution of reagent 1 in DMF and β-dgalactosidase solution in phosphate buffered water (12.5 nm 250 nm) sequentially. After 10 h, the colorimetric change of the solution was monitored via photography and image processing software. verall, the assay contained 2.5 mm of reagents 1 and 2, respectively, 2.5% DMF, and 0.5% Tween-20 (v/v). Table of Absolute Color Intensity for Figure 4: Table S19. Color intensity data for the calibration curve (corresponding to Figure 4). Conc. of enzyme (nm) Trial 1 Trial 2 Trial References 1. W. C. Still, M. Kahn, A. Mitra. J. rg. Chem., 1978, 43, S-J. Lim, D. Y. Seok, B-K. An, S. D. Jung, S. Y. Park. Macromolecules, 2006, 39, S. Ramadas and G. L. D. Krupadanam. Tetrahedron Asymmetry, 2000, 11, A. K. Ghosh, S. Khan, D. Farquhar. Chem. Commun., 1999, 24, S23
24 Copies of spectra Br MEM MEM MEM 8 MEM S24
25 Br MEM MEM MEM 8 MEM S25
26 H B H MEM MEM MEM MEM 9 S26
27 H B H MEM MEM MEM MEM 9 S27
28 H B H H H H H 1 S28
29 H B H H H H H 1 S29
30 Ac Ac Ac Ac 13 S30
31 Ac Ac Ac Ac 13 S31
32 H H H H H 2 H S32
33 H H H H H 2 H S33
34 H 16 S34
35 H 16 S35
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