Photocleavable Surfactant for Two-Photon-Tuned Release
FULL PAPER
Synthesis and characterization of the compounds: The synthetic route is
shown in the Supporting Information, Scheme S1. The H NMR spectrum
of amphiphile 1 is shown in the Supporting Information, Figure S1.
NCH2), 1.71 (m, 4H; NCH2CH2), 1.55 (t, 3H; NCH2CH3), 1.48–1.28 (m,
1
44H), 0.89 ppm (t, 6H); IR (KBr pellet): n˜ =3265.2, 2921.7, 2851.5,
1739.4, 1709.9, 1607.6, 1434.3, 1259.2 cmÀ1
; MS (MALDI-TOF): m/z
calcd: 854.5 [M]+; found: 775.7 [MÀBr]+.
Synthesis of compound 2: 7-Amino-4-methylcoumarin (1.75 g, 10 mmol),
bromotetradecane (22 g, 80 mmol), K2CO3 (5.6 g, 40 mmol), and NaI
(0.38 g, 2.5 mmol) were mixed in MeCN (90 mL) and the mixture was
heated at reflux for 36 h. After the reaction mixture was cooled to RT,
the solvent was evaporated in a rotary evaporator. Then, the residue was
partitioned between CH2Cl2 and brine. The organic layer was dried over
MgSO4 and concentrated. The crude product was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 10:1 v/v) to
afford compound 2 (2.9 g, 52% yield). 1H NMR (CDCl3): d=7.37 (d,
1H), 6.55 (dd, 1H), 6.46 (s, 1H), 5.93 (s, 1H), 3.30 (t, 4H; NCH2), 2.33
(s, 3H; ArCH3), 1.59 (m, 4H; NCH2CH2), 1.31–1.25 (m, 44H), 0.89 ppm
(t, 6H); IR (KBr pellet): n˜ =2914.5, 2849.8, 1716.8, 1603.1, 1469.1, 1362.0,
1404.0 cmÀ1; MS (MALDI-TOF): m/z calcd: 567.5 [M]+; found: 568.5
[M+H]+.
Synthesis of 1,2-bis(2-azidoethoxy)ethane: Triethylene glycol (TEG, 1.5 g,
10 mmol) and CBr4 (7.1 g, 22 mmol) were dissolved in dry THF. PPh3
(5.3 g, 20 mmol) was added slowly under vigorous stirring. The reaction
mixture was stirred at RT for 1 h, filtered, and concentrated. The crude
material was purified by column chromatography on silica gel (petroleum
ether/EtOAc, 3:1 v/v) to afford 1,2-bis(2-bromoethoxy)ethane as a color-
less oil (2.5 g, 90% yield). 1H NMR (CDCl3): d=3.82 (t, 2H;
BrCH2CH2), 3.68 (t, 2H; BrCH2CH2), 3.46 ppm (t, 2H;
BrCH2CH2OCH2). Then, 1,2-bis(2-bromoethoxy)ethane (1.0 g, 3.6 mmol)
and sodium azide (0.5 g, 7.5 mmol) were mixed in DMF (40 mL) and stir-
red at 608C for 6 h. The mixture was filtered and the filtrate was concen-
trated in vacuum. The crude product was purified by column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 4:1 v/v) to afford 1,2-bis(2-
azidoethoxy)ethane as
a
colorless oil (0.6 g, 82% yield). 1H NMR
Synthesis of compound 3: Compound 2 (5.5 g, 10 mmol) and SeO2 (1.7 g,
15 mmol) were mixed in p-xylene (20 mL) and the mixture was heated at
reflux under an argon atmosphere for 6 h with vigorous stirring. Then,
the mixture was filtered, concentrated, and dissolved in ethanol/THF
(20 mL, 1:1 v/v). After NaBH4 (0.94 g, 25 mmol) was slowly added, the
reaction was stirred for 3 h at RT. The mixture was carefully neutralized
with 1m HCl and concentrated in a rotary evaporator to remove the sol-
vent. The residue was dissolved in CH2Cl2 (50 mL), washed with brine,
and dried over MgSO4. After evaporation of the solvent, the crude prod-
uct was purified by column chromatography on silica gel (petroleum
ether/EtOAc, 2:1 v/v) to give compound 3 (2.6 g, 44% yield). 1H NMR
(CDCl3): d=7.35 (d, 1H), 6.68 (dd, 1H), 6.58 (d, 1H), 6.30 (s, 1H), 4.84
(s, 2H; ArCH2OH), 3.32 (t, 4H; NCH2), 1.9 (br s; ArCH2OH), 1.59 (m,
4H; NCH2CH2), 1.31–1.28 (m, 44H), 0.89 ppm (t, 6H); IR (KBr pellet):
n˜ =3383.5, 2932.8, 1709.2, 1608.1, 1467.6, 1377.3, 1060.3, 1060.3 cmÀ1; MS
(MALDI-TOF): m/z calcd: 583.5 [M]+; found: 584.5 [M+H]+.
(CDCl3): d=3.69 (m, 4H; CH2OCH2), 3.41 ppm (t, 2H; N3CH2); MS
(ESI): m/z calcd: 200.1 [M]+; found: 223.1 [M+Na]+.
CAC determination: The CAC of amphiphile 1 was determined by using
the fluorescent-probe technique with a hydrophobic dye, Nile Red. A
certain amount of Nile Red was added to a series of aqueous solutions of
amphiphile 1 with different concentrations. These solutions were sonicat-
ed for 30 min and then left to stand for 2 h. The solutions were examined
by fluorescence spectroscopy. The emission intensity of Nile Red at
636 nm was plotted versus the logarithm of the concentration of amphi-
phile 1, thus showing a nonlinear relationship; the CAC was determined
as the inflection point (see the Supporting Information, Figure S2a). The
CAC was also determined by concentration-dependent conductivity ex-
periments. A plot of the conductivity of solutions of amphiphile 1 with
various concentrations versus the concentration of amphiphile 1 is shown
in the Supporting Information, Figure S2b. The CAC was obtained from
the extrapolated intersection of the two linear regions in the plot, as indi-
cated by an arrow.
Synthesis of compound 4:
A solution of propargyl bromide (8 g,
67 mmol) in dry CH2Cl2 (10 mL) was added dropwise to a stirring solu-
tion of ethanolamine (2 g, 33 mmol) and K2CO3 (9.5 g, 70 mmol) in dry
CH2Cl2 (30 mL) at 08C. The mixture was stirred at RT for 3 h and
poured into an excess amount of water. The crude product was extracted
with CHCl3 and the combined extracts were dried over MgSO4 and
evaporated. The crude product was purified by column chromatography
on silica gel (CH2Cl2/EtOAc, 1:1 v/v) to give compound 4 (3.6 g, 81%
yield). 1H NMR ([D6]DMSO): d=3.64 (t, 2H; HOCH2), 3.49 (d, 4H;
Preparation of the vesicles: A solution of amphiphile 1 in CHCl3 was
placed in a vessel and dried. Distilled water was added to the vessel to a
concentration of ꢀ10À3 m. The suspension was sonicated for about 15 min
and allowed to equilibrate for 2 h, thereby affording the vesicles.
Polymerization of the vesicles: 1,2-Bis(2-azidoethoxy)ethane, CuCl2
(2.5 mol%), and sodium ascorbate (25 mol%) were added to a solution
of the vesicles. Then, the mixture was stirred at RT for 24 h to afford the
click-polymerized vesicles.
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NCH2C CH), 2.76 (t, 2H; OCH2CH2N), 2.26 ppm (t, 2H; NCH2C CH);
MS (ESI): m/z calcd: 137.1 [M]+; found: 138.1 [M+H]+.
Preparation of the NR-loaded vesicles: A solution of Nile Red in CH2Cl2
(50 mL, 1 mgmLÀ1) was injected into the vesicular solution of amphiphile
1. The mixture was sonicated for 30 min to induce encapsulation and
then allowed to equilibrate for 2 h. The organic solvent and excess Nile
Red were removed by evaporation and filtration, respectively.
Synthesis of compound 5: 1,1’-Carbonyldiimidazole (CDI, 1.4 g,
11 mmol) was added to
a stirring solution of compound 4 (1.4 g,
10 mmol) in dry THF (20 mL) in an ice bath. After stirring at RT for 7 h,
compound 3 (5.9, 10 mmol) and a catalytic amount of KOH were added.
The mixture was stirred at ambient temperature for a further 4 h before
being concentrated. The residue was dissolved in CH2Cl2 (60 mL),
washed with brine, and dried over MgSO4. After removal of the solvent,
the crude product was purified by column chromatography on silica gel
(petroleum ether/EtOAc, 4:1 v/v) to give compound 5 (4.9 g, 66% yield).
1H NMR (CDCl3): d=7.28 (d, 1H), 6.54 (dd, 1H), 6.44 (s, 1H), 6.16 (s,
Encapsulation of Rh6G in the polymerized vesicles: An excess of Rh6G
was added to a solution of unpolymerized vesicles. The mixture was soni-
cated for 30 min to afford unpolymerized vesicles with entrapped Rh6G.
The polymerized vesicles that contained entrapped Rh6G were prepared
by click polymerization of the loaded unpolymerized vesicles (see
above). The polymerized vesicles were dialyzed for 24 h in the dark to
remove any free Rh6G.
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1H), 5.26 (s, 2H; ArCH2O), 4.34 (t, 2H; OCH2), 3.51 (d, 4H; NCH2C
ꢀ
CH), 3.31 (t, 4H; NCH2), 2.93 t, 2H; OCH2CH2N), 2.26 (t, 2H; NCH2C
CH), 1.59 (m, 4H; NCH2CH2), 1.31–1.24 (m, 44H), 0.89 ppm (t, 6H); IR
(KBr pellet): n˜ =3331.4, 2932.8, 2853.5, 1740.8, 1709.2, 1607.7, 1471.4,
1036.1 cmÀ1; MS (MALDI-TOF): m/z calcd: 746.5 [M]+; found: 747.1
[M+H]+.
Acknowledgements
Synthesis of amphiphile 1: Compound 5 (2 g, 2.6 mmol) and an excess
amount of bromoethane were mixed in distilled acetone and stirred for
2 days at 508C, before evaporating to dryness. The crude product was pu-
rified by column chromatography on silica gel (CH2Cl2/MeOH, 10:1 v/v)
to afford amphiphile 1 (1.2 g, 52% yield). 1H NMR (CD3OD): d=7.55
(d, 1H), 6.54 (dd, 1H), 6.44 (s, 1H), 6.16 (s, 1H), 5.26 (s, 2H; ArCH2O),
Financial support from the National Natural Science Foundation of
China (21233011, 21103210, 21172229, and 21002109) and the 973 Pro-
gram (2010CB934500, 2013CB834700, and 2013CB834505) is gratefully
acknowledged.
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4.83 (t, 2H; OCH2), 4.65 (d, 4H; NCH2C CH), 4.10 (t, 2H; NCH2C
CH), 3.86 (m, 2H; NCH2CH3), 3.71 (d, 2H; NCH2CH2O), 3.46 (t, 4H;
Chem. Eur. J. 2013, 19, 7931 – 7936
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7935