S,S-Chiral Linker Induced U Shape with a Syn-facial Sensitizer and Photocleavable Ethene Group

Article abstract of DOI:10.1111/php.13000

There is a major need for light-activated materials for the release of sensitizers and drugs. Considering the success of chiral columns for the separation of enantiomer drugs, we synthesized an S,S-chiral linker system covalently attached to silica with a sensitizer ethene near the silica surface. First, the silica surface was modified to be aromatic rich, by replacing 70% of the surface groups with (3-phenoxypropyl)silane. We then synthesized a 3-component conjugate [chlorin sensitizer, S,S-chiral cyclohexane and ethene building blocks] in 5 steps with a 13% yield, and covalently bound the conjugate to the (3-phenoxypropyl)silane-coated silica surface.?We hypothesized that the chiral linker would increase exposure of the ethene site for enhanced?¹O₂-based sensitizer release. However, the chiral linker caused the sensitizer conjugate to adopt a U shape due to favored 1,2-diaxial substituent orientation; resulting in a reduced efficiency of?surface loading.?Further accentuating the?U shape was π–π stacking between the?(3-phenoxypropyl)silane and sensitizer. Semiempirical calculations and?singlet oxygen luminescence?data provided deeper insight into the sensitizer's orientation and release. This study has lead to insight on modifications of surfaces for drug photorelease and can help lead to the development of miniaturized photodynamic devices.

Full text of DOI:10.1111/php.13000

DR. ANDRÉS HÉCTOR THOMAS (Orcid ID : 0000-0002-8054-7799)
DR. S. MCFARLAND (Orcid ID : 0000-0002-8028-5055)
Article type : Special Issue Research Article
S,S-Chiral Linker Induced U-Shape with a Syn-facial Sensitizer
†
and Photocleavable Ethene Group
1
-3
2,3
2,3
2,3
Goutam Ghosh , Sarah J. Belh , Callistus Chiemezie , Niluksha Walalawela , Ashwini
2
,3
4
4,
1,5,
A. Ghogare , Mariana Vignoni , Andrés H. Thomas *, Sherri A. McFarland *,
6
,
2,3,
Edyta M. Greer *, and Alexander Greer *
1
Department of Chemistry, Acadia University, Wolfville, Nova Scotia B4P 2R6, Canada
2
3
4
Department of Chemistry, Brooklyn College of the City University of New York, Brooklyn,
New York 11210, United States
Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, 365
Fifth Avenue, New York, New York 10016, United States
INIFTA, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de
La Plata, CCT La Plata-CONICET, Argentina
5
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro,
North Carolina 27402, United States
6
Department of Natural Sciences, Baruch College of the City University of New York, New
York 10010, United States
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/php.13000
This article is protected by copyright. All rights reserved.

*
Corresponding authors’ e-mails: athomas@inifta.unlp.edu.ar (Andrés H. Thomas);
samcfarl@uncg.edu (Sherri A. McFarland); edyta.greer@baruch.cuny.edu (Edyta M. Greer);
agreer@brooklyn.cuny.edu (Alexander Greer)
†
This article is part of a Special Issue celebrating Photochemistry and Photobiology's
th
5
5 Anniversary.
ABSTRACT
There is a major need for light-activated materials for the release of sensitizers and drugs.
Considering the success of chiral columns for the separation of enantiomer drugs, we
synthesized an S,S-chiral linker system covalently attached to silica with a sensitizer ethene
near the silica surface. First, the silica surface was modified to be aromatic rich, by replacing
7
0% of the surface groups with (3-phenoxypropyl)silane. We then synthesized a 3-
component conjugate [chlorin sensitizer, S,S-chiral cyclohexane, and ethene building blocks]
in 5 steps with a 13% yield, and covalently bound the conjugate to the (3-
phenoxypropyl)silane-coated silica surface. We hypothesized that the chiral linker would
1
increase exposure of the ethene site for enhanced O -based sensitizer release. However, the
2
chiral linker caused the sensitizer conjugate to adopt a U-shape due to favored 1,2-diaxial
substituent orientation; resulting in a reduced efficiency of surface loading. Further
accentuating the U-shape was π–π stacking between the (3-phenoxypropyl)silane and
sensitizer. Semiempirical calculations and singlet oxygen luminescence data provided deeper
insight into the sensitizer’s orientation and release. This study has lead to insight on
modifications of surfaces for drug photorelease and can help lead to the development of
miniaturized photodynamic devices.
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INTRODUCTION
Photoreleased molecules are of considerable interest not only in the field of photochemistry
but also in site-specific delivery applications (1-23). Current literature on sensitizer and drug
photorelease has mainly focused on the use of direct UV, visible, and near-IR light to activate
1
1
the release mechanisms. However, a utility can be exploited with photogenerated O ( ∆ ) as
2
g
the drug release trigger agent, rather than light as a direct release trigger (24-32). Although
1
O -release reactions are becoming common, there is a need for heterogeneous surfaces in
2
this context to improve the selectivity of the process.
Heterogeneous surfaces have been used for photorelease reactions in the past (33-39).
However, this line of research is still in its infancy. Surface types that have been studied for
drug photorelease include chitosan particles (40), fluorinated silica (41), quantum dots (QDs)
(42), carbon and polymer dots (43-45), and gold nanoparticles (46,47). To our knowledge,
chiral surfaces that add control features to photorelease reactions have not been studied.
By contrast, many papers have been published reporting on chiral surfaces for the
chromatographic separation of enantiomers. Chiral compounds such as (–)-menthyl have
been covalently bonded to silica and shown to be useful as media for the separation of
enantiomers (48-52). Notably, there have been some chiral surface modifications adapted for
drug release. For example, porous chiral materials have been used to tune the release kinetics
of R- vs S-enantiomers (53). In another example, the antitumor drug doxorubicine was
released in a tunable, pH-dependent fashion to MCF-7 cells from chiral 3-N-aminopropyl-L-
tartaric acid triethoxysilane porous silica particles (54).
Due to the need for the further advancement of solid supports for the photorelease of
sensitizers and drugs, we sought to attach a photocleavable ethene linker to a sensitizer and
introduce a bend using a chiral S,S-cyclohexyl dicarboxylate group. This required the
assembly of a conjugate containing 3 types of monomer units: a sensitizer, a chiral
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cyclohexyl ring, and an ethene. This trimer was then attached to a 3-iodopropyl
trimethoxysilane enabling the 3-component conjugate to be covalently attached to a silica
surface and the sensitizer’s photorelease from the silica surface to be studied, for possible
PDT applications. Our detailed approach is shown in Figure 1.
In this paper, we report on the synthesis and testing of a bent [linked (1S,2S)-
cyclohexane-1,2-dicarboxylate group] ethene linker covalently bound to silica as a unique
system for the photorelease of a sensitizer. We hypothesized that the U-shape of the bridge
1
would increase the exposure of the ethene site for enhanced O -based sensitizer release. We
2
expected this system to be an improvement over our previous succinate (55) and
1
dimethylene-linked (56-58) sensitizer photorelease systems. In this system, the O , which
2
triggers the sensitizer release, is generated by the sensitizer surface. The rapid reaction
1
between O and the ethene linker, i.e. (Z)-1,2-dioxyethene, releases sensitizer molecules
2
upon cleavage of a dioxetane intermediate (55-58). We also hypothesized that the sensitizer
would be made to bend over by π–π stacking interactions with covalently bound (3-
phenoxypropyl)silanes close to the surface. It was thought that our surface modification
strategy would further reveal how sensitizer photorelease can be controlled, which also
connects to how these materials can be engineered for miniaturized photodynamic devices.
MATERIALS AND METHODS
General information. Reagents and solvents such as methanol, hexane, toluene, N,N-
dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (CH Cl ), chloroform
2
2
(
CHCl ), deuterated chloroform (CDCl ), carbon tetrachloride (CCl ), n-butanol, sodium
3 3 4
sulfate, sodium bicarbonate, sodium periodate, sodium borohydride, phenol, osmium
tetroxide, acetic acid, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride
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(EDC), N,N-dimethyl-4-aminopyridine (DMAP), 3-iodopropyl trimethoxysilane, and
trimethylsilyl diazomethane were purchased from Sigma-Aldrich. Chlorin e was purchased
6
from Frontier Scientific. The (1S,2S)-cyclohexane-1,2-dicarboxylic acid was purchased from
VWR. All the reagents and solvent were used as received from commercial suppliers without
further purification. Corning 7930 porous Vycor glass (PVG) was purchased from Advanced
Glass and Ceramics, Holden, MA. Silica samples were cleaned with refluxing methanol in a
1
1
Soxhlet extractor. H NMR spectra were collected using a Bruker Avance instrument for H
1
3
at 400 MHz and for C at 100.6 MHz. UV−vis spectra were collected on a Varian Cary-100
spectrophotometer. HPLC data were obtained on a Perkin-Elmer 200 series instrument
equipped with a bondclone 10 C18 column. HRMS data were collected at the mass
spectrometry facility in University of California, Riverside. Prior to covalent attachment,
PVG particles were dried using a muffle furnace (Fischer Scientific Isotemp.) for 24 h.
Synthesis of chlorin-e trimethyl ester 1. Yield 100.0 mg (93.4%). To a 10 mL mixed solution
6
(
6 mL MeOH and 4 mL toluene), 100.0 mg (0.167 mmol) of chlorin e was added and stirred
6
for 5 min under nitrogen. A 460 µL (0.924 mmol) 2 M hexane solution of trimethyl silyl
diazomethane was added to the reaction mixture drop wise. Reaction mixture was stirred
under N for 5 h. AcOH (10 mL 10% aqueous solution) was added to the reaction mixture to
2
quench excess diazomethane. MeOH was evaporated under reduced pressure. Reaction
mixture was diluted with 20 mL dichloromethane and organic layer was washed three times
with 10 mL water and dried on Na SO and evaporated to get crude product. Crude product
2
4
was separated by column chromatography using 0.2% MeOH in CH Cl . R = 0.85. HPLC
2
2
f
showed the purity of the compound is 99%: t = 19.2 min in gradient mixture of MeOH and
R
1
H O. H NMR (400.0 MHz, CDCl ) δ 9.72 (s, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 8.03 (dd, J =
2
3
1
8.0 Hz, 11.6 Hz, 1H), 6.34 (d, J = 18.0 Hz, 1H), 6.13 (d, J = 11.2 Hz, 1H), 5.44 (d, J = 18.8
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Hz, 1H), 5.33 (d, J = 13.6 Hz, 1H), 4.51 (m, 2H), 4.33 (s, 3H), 3.84 (s, 3H), 3.77 (m, 2H),
3
7
.70 (s, 3H), 3.64 (s, 3H), 3.48 (s, 3H), 3.29 (s, 3H), 2.63 (m, 1H), 2.26 (m, 2H), 1.83 (d, J =
.6 Hz, 4H), 1.75 (t, J = 11.2 Hz, 3H), -1.22 (br s, 1H), -1.37 (br s, 1H).
Synthesis of 3-formyl chlorin e trimethyl ester 2. Yield 52.0 mg (56%). To the 90.0 mg
6
(
0.141 mmol) of 1 in 25 mL THF, 15.36 mg (0.06 mmol) of OsO in 150 µL CCl was added
4 4
at 0 °C under N atmosphere. Reaction mixture was stirred within 0-5 °C temperature for 25
2
min. 254 mg (1.19 mmol) of NaIO , dissolved in 5% AcOH solution, was added to the
4
reaction mixture. Reaction mixture was stirred overnight at room temperature. THF was
evaporated out in rotavapor. Reaction mixture was extracted with 50 mL of dichloromethane
and washed with water. The organic layer was dried over sodium sulfate. After evaporating
organic solvent, residue was purified by column chromatography using 0.1% MeOH-CH Cl .
2
2
1
R = 0.62 in 1% MeOH-CH Cl . H NMR (400.0 MHz, CDCl ) δ 11.52 (s, 1H), 10.23 (s,
f
2
2
3
1
2
1
H), 9.67 (s, 1H), 8.97 (s, 1H), 5.43 (d, J = 19.2 Hz, 1H), 5.31 (d, J = 18.8, 1H), 4.51 (m,
H), 4.31 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.61 (s, 3H), 3.30 (s, 3H), 2.66 (m,
1
3
H), 2.30 (m, 2H), 2.19 (m, 4H), 1.79 (m, 3H), 1.72 (t, J = 7.6, 4H), -1.77 (br s, 1H); C
NMR (100.6 MHz, CDCl ) δ 188.3, 173.5, 172.8, 169.1, 168.9, 167.5, 155.1, 151.6, 145.0,
3
1
5
38.3, 138.2, 138.0, 136.5, 136.0, 134.0, 131.9, 128.5, 125.5, 103.2, 101.3, 100.7, 95.6, 53.5,
3.2, 52.2, 51.7, 48.7, 38.5, 31.0, 29.7, 29.3, 23.2, 19.6, 17.6, 12.4, 11.4, 11.3.
1
Synthesis of 3 -hydroxyl chlorin-e trimethyl ester 3. Yield 39.3 mg (98%). To the 10 mL
6
MeOH- CH Cl (4:1 mixture), 40.0 mg (0.062 mmol) of 2 and 9.0 mg (0.23 mmol) of NaBH
4
2
2
was added in ice cold temperature. Color of the solution was changed from red to emerald
green. Reaction was stirred in room temperature for 15 h. MeOH was evaporated by reduced
pressure. Reaction mixture was diluted with 25 mL CH Cl . Organic layer was washed with
2
2
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1
0 mL 5% AcOH followed by saturated sodium bicarbonate and water. Organic layer was
dried on Na SO and evaporated on rotavapor to get green solid. Crude product showed single
2
4
spot in TLC. Therefore, column chromatography was not performed. R = 0.32 in 1% MeOH-
f
1
CH Cl . H NMR (400.0 MHz, CDCl ) δ 9.69 (s, 1H), 9.52 (s, 1H), 8.77 (s, 1H), 5.83 (s, 2H),
2
2
3
5
3
4
1
1
2
.38 (d, J = 19.2, 1H), 5.30 (d, J = 11.2, 1H), 4.46 (m, 2H), 4.28 (s, 3H), 3.80 (s, 3H), 3.65 (s,
H), 3.60 (s, 3H), 3.43 (s, 3H), 3.27 (s, 3H), 2.59 (m, 1H), 2.21 (m, 3H), 1.78 (d, J = 7.2,
1
3
H), 1.71 (t, J = 7.6, 4H), -1.61 (br s, 1H); C NMR (100.6 MHz, CDCl ) δ 173.6, 173.0,
3
69.6, 169.4, 167.0, 154.3, 148.7, 145.0, 139.1, 136.7, 136.0, 135.6, 135.4, 135.1, 132.6,
29.4, 123.5, 102.4, 102.0, 98.2, 93.8, 56.3, 53.1, 53.0, 52.1, 51.7, 49.3, 38.6, 31.0, 29.7,
9.5, 22.9, 19.6, 17.6, 12.4, 11.3, 11.1.
Synthesis of trans-cyclohexyl monocarboxylate chlorin e trimethyl ester 4. Yield 30.0 (60%).
6
To the 40.0 mg (0.062 mmol) of 3 in 10 mL of dry dichloromethane under nitrogen
atmosphere, 42.8 mg (0.24 mmol) of (1S,2S)-cyclohexane-1,2-dicarboxylic acid, 23.79 mg
(0.12 mmol) of EDC and 15.07 mg (0.12 mmol) of DMAP was added. Reaction mixture was
stirred for 24 h under N in room temperature. CH Cl was evaporated and compound was
2
2
2
purified by 1-1.2% MeOH-CH Cl . R = 0.33 in 1.5% MeOH-CH Cl . HPLC showed the
2
2
f
2
2
1
purity of the compound is 87%: t = 16.0 min in gradient mixture of MeOH and H O. H
R
2
NMR (400.0 MHz, CDCl ) δ 9.70 (s, 1H), 9.56 (s, 1H), 8.80 (s, 1H), 6.49 (d, J = 12.8, 1H),
3
6
3
1
1
.31 (d, J = 12.8, 1H), 5.38 (d, J = 18.8, 1H), 5.26 (d, J = 18.8, 1H), 4.45 (m, 2H), 4.28 (s,
H), 3.79 (s, 3H), 3.64 (s, 3H), 3.58 (s, 3H), 3.48 (s, 3H), 3.32 (s, 3H), 2.72 (m, 2H), 2.55 (m,
H), 2.19 (m, 2H), 2.04 (m, 2H), 1.76 (d, J = 7.2, 3H), 1.69 (m, 6H), 1.23 (m, 8H), -1.64 (brs,
H).
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Synthesis of spacer (Z)-2-phenoxyvinyloxy)benzyl-(1S,2S)-cyclohexane-1,2-dicarboxyl-
ate chlorin-e trimethyl ester 5. Yield 17.7 mg (42%). To the 30.0 mg (0.04 mmol) of 4 in 10
6
mL of dry dichloromethane in nitrogen atmosphere, 30 mg (0.12 mmol) of spacer alkene
alcohol, 15.3 mg (0.08 mmol) of EDC and 9.7 mg (0.08 mmol) of DMAP was added.
Reaction mixture was stirred for 24 h under N in room temperature. CH Cl was evaporated
2
2
2
and compound was purified by 0.35-0.45% MeOH-CH Cl . R = 0.51 in 1.5% MeOH-
2
2
f
CH Cl . HPLC showed the purity of the compound is 95%: t = 18.5 min in gradient mixture
2
2
R
1
of MeOH and H O. H NMR (400.0 MHz, CDCl ) δ 9.74 (s, 1H), 9.58 (s, 1H), 8.80 (s, 1H),
2
3
7
.21 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 8.4
Hz, 2H), 6.46 (d, J = 12.8 Hz, 1H), 6.31 (d, J = 12.8 Hz, 1H), 5.80 (d, J = 3.6 Hz, 1H), 5.53
d, J = 3.2 Hz, 1H), 5.39 (d, J = 19.2 Hz, 1H), 5.27 (d, J = 18.8 Hz, 1H), 4.79 (d, J = 12.0 Hz,
H), 4.65 (d, J = 12.0 Hz, 1H), 4.55 (brs, 2H), 4.46 (m, 2H), 4.29 (s, 3H), 3.82 (m, 6H), 3.67
s, 3H), 3.61 (s, 3H), 3.48 (s, 3H), 3.34 (s, 3H), 2.78 (m, 2H), 2.60 (m, 1H), 2.15 (m, 4H),
(
1
(
13
1
.75 (m, 10H), 1.39 (m, 2H), 1.28 (m, 3H), -1.48 (brs, 1H), -1.79 (brs, 1H); C NMR (100.6
MHz, CDCl ) δ 175.0, 174.7, 173.7, 173.6, 173.4, 173.0, 169.4, 167.1, 156.8, 156.7, 154.7,
3
1
49.3, 145.1, 138.7, 136.6, 136.3, 135.4, 135.3, 134.0, 131.1, 129.9, 129.6, 129.3, 128.4,
28.2, 127.6, 123.7, 116.0, 115.6, 115.5, 115.4, 102.4, 102.0, 98.5, 94.0, 65.6, 64.7, 57.4,
3.1, 53.0, 52.1, 51.6, 49.3, 45.1, 45.0, 42.8, 42.7, 38.5, 31.1, 29.7, 29.5, 29.0, 28.9, 25.1,
1
5
+
2
2.9, 19.6, 17.7, 12.4, 11.3, 11.2. (+ESI) m/z calculated for C H N O [M+H] 1051.4699,
6
0
67
4
13
found: 1051.4716.
Covalent binding of conjugate 5 and phenoxypropylsilane to silica. Phenoxyproylsilane was
attached to silica following the methodology of nonafluorosilane
(CH O) SiCH CH CF CF CF CF ] attachment to silica (41). 3-Iodopropyl trimethoxysilane
[
(
3
3
2
2
2
2
2
3
0.783g, 2.62 mmol) and NaH (94.3 mg, 3.93 mmol) were added to 0.244 g (2.62 mmol) of
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phenol in 50 mL of dry THF. Mixture was refluxed at 70 °C for 24 h. THF was evaporated
completely after the reaction and 1.0 g of silica was added in situ and refluxed in toluene for
another 24 h. Silica particles were separated by filtration and washed with CH Cl , THF,
2
2
methanol, toluene, and hexane and then Soxhlet extracted with methanol for 24 h to get
phenol conjugated silica particle 6. Then, 5 mg (4.75 µmol) of 5 reacted with 3-iodopropyl
trimethoxysilane in THF in a round bottom flask. THF was completely evaporated and
phenol conjugated silica particle to that flask and toluene were added and refluxed for 24 h to
get chlorin trimethyl ester conjugated phenolic silica particle 7. It was then washed with
CH Cl , THF, methanol, and hexane followed by its Soxhlet extraction in methanol for 24 h
2
2
to remove any adsorbed sensitizer from the silica. No sensitizer leaching from the surface
was observed in the dark. Silica was dissolved by HF treatment and suspended green solid in
the aqueous solution was extracted with CHCl , evidence suggested the liberation of
3
sensitizer as characteristic Soret and Q-band was found at 400 and 660 nm, respectively, in
UV–vis of CHCl3.
Quantifying the loading of conjugate 5 on silica. Sensitizer loading on 7 was calculated by
the HF stripping method. 100.0 mg of sensitizer modified silica 7 was placed in 2.0 mL 50%
(v/v) HF solution and kept 3.0 h in room temperature. Sensitizer was extracted from aqueous
HF solution by CHCl . The concentration of sensitizer in CHCl was calculated based on a
3
3
calibration plot of 5 by monitoring the Soret absorption band (400 nm). Sensitizer loaded on
silica 7 is 378 nmol/g.
Singlet oxygen measurements. Time-resolved experiments were performed at room
temperature using a near-IR PMT Module H10330-45 (Hamamatsu, Iwata City, Japan)
coupled to FL3 TCSPC-SP (Horiba Jobin Yvon) single-photon-counting equipment, as
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described elsewhere (59). Steady-state experiments were conducted with samples in a quartz
cell irradiated with a CW 450W Xe source equipped with an excitation monochromator. The
o
luminescence, after passing through an emission monochromator, was detected at 90 with
respect to the incident beam using a near-IR photomultiplier tube. Emission spectra were
recorded between 950 and 1400 nm. For some steady-state experiments, a CW diode laser
with an output of 669 nm was used. The singlet oxygen quantum yield ( ) of silica 7 was

not determined due to complicating factors including: light scattering of the particles; small
1
O emission signal prior to sensitizer cleavage away from the particle; and interference from
2
1
the spacer ethene that acts as a O chemical quencher.
2
Computational details. Semiempirical PM6 method (60) available in Gaussian 09 program
package with revision D.01 (61) was used to generate scans by rotating dihedral angle Φ
(C1–O2–C3–C4) and dihedral angle θ (C1′–O2′–C3′–C4′) by 360 in increments of 60. The
PM6 method was selected was used successfully for modeling large systems, namely
proteins, where protein structures optimized with PM6 reproduced experimental X-ray
structures (62). The GaussView 5.0 program was used for visualization of the molecules (63).
RESULTS AND DISCUSSION
Our approach was to synthetically load the sensitizer conjugate onto silica, and to analyze
conformations and photorelease of the sensitizer from the silica surface.
Synthesis and characterization of compounds 1-5
The sensitizer–cyclohexyl–ethene trimer 5 was synthesized in five steps from chlorin e with
6
1
3% overall yield (Figure 2).
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Step 1: Chlorin e was reacted with trimethylsilyl diazomethane to reach chlorin e -
6
6
trimethyl ester 1 in 93% yield using a modified procedure from the literature, where
diazomethane gas was used for the conversion. Compound 1 was contained six distinct
singlets for six methyl groups (three from methyl esters, and other three from pyrrole moiety)
1
by H NMR. Compound 1 is known in the literature (64).
Step 2: Compound 1 was then reacted with OsO followed by a 10% acetic acid
4
solution of NaIO to yield 3-formyl chlorin e -trimethyl ester 2 with 56% yield using a
4
6
1
procedure of Shim et al. (65). H NMR showed four singlets (11.52, 10.23, 9.67 and 8.97
ppm), with the peak at 11.52 ppm assigned to the aldehyde and the others to
1
2
the meso hydrogens, which indicate the conversion of the 3 -3 vinyl bond to 3-formyl.
1
Step 3: NaBH reduction of the 3-formyl to its corresponding alcohol gave 3 -
4
hydroxyl chlorin e -trimethyl ester 3 in 98% yield based on the procedure of Pavlov et al.
6
(66). Formation of 3 was evidenced by proton NMR, where the aldehyde peak at 11.52 ppm
for 2 was absent in the spectrum of 3.
Step 4: (1S,2S)-cyclohexane-1,2-dicarboxylic acid was coupled to 3 using EDC-
DMAP, a common coupling reagent for esterification reaction (58,67), to afford
1
monoester 4 in 60% yield. Esterification of the 3 -hydroxyl group resulted in a downfield
1
shift of the two protons attached to 3 -carbon. Each of these two protons appeared as two
distinct doublets at 6.49 and 6.31 ppm with J = 12.8 Hz. The splitting of these hydrogens into
doublets suggests that attachment of the cyclohexane moiety produces a different electronic
environment for each proton.
Step 5: The (Z)-(ethene-bisphenylene)dimethanol was coupled to 4 using EDC-
DMAP to afford the 3-component conjugate 5 in 42% yield. (The (Z)-(ethene-
bisphenylene)dimethanol was synthesized in 5 steps following the literature procedure) (58).
1
The H NMR spectrum of trimer 5 exhibited eight phenyl protons (7.21, 6.90, 6.80 and 6.54
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ppm, J = 8.4 Hz). The alkene hydrogens gave rise to a doublet at 5.80 and 5.54 ppm. 2D
HSQC indicated that the four doublets produced by the phenyl hydrogens correlated to
carbon signals at 129.3, 128.4, 116.0, and 115.4 ppm and that the two alkene doublets
correlated to the carbons at 128.2 and 127.6 ppm (Figure S9, Supporting
Information). Following the synthesis of trimer 5, semi-empirical PM6 calculations were
performed, in order to gain insight on the preferred orientation of the sensitizer relative to the
ethene group. These calculations are described next.
Computed conformations show a bent-shaped three-component conjugate 5
In order to explore the conformations of trimer 5 connecting sensitizer, trans-cyclohexyl,
ethene together, PM6 calculations were carried out. In various conformations, trimer 5 was
found to fold into a U- or L-shape in order to reach its energetically preferred structure. When
straightened geometries were sought the energy increased, where optimized structures were
mainly bent structures. The conformers in Figures 3 and 4 show 14 optimized conformations
of trimer 5. Conformer F was the most stable. Conformers A-E and G-N were found to be
within 12 kcal/mol by C1–O2–C3–C4 bond rotations about the (1S)-cyclohexane group and
C1′–O2′–C3′–C4′ bond rotations about the (2S)-cyclohexane group. Thus, the conformers are
flexible and are expected to exist as a mixture in solution.
Table 1 shows the through-space distance from the center of the sensitizer to the
center of the ethene C=C bond in conformers A-N ranges from 7.7 Å to 14.9 Å. Table 1 also
shows the shapes of conformers due to the intervening chiral S,S-cyclohexyl group based on
PM6 computations. Furthermore, the calculation show a clear preference for a U-shape in
trimer 5, where the conformer F contains a 65° angle (center of the sensitizer—center of the
cyclohexyl—center of the ethene). The S,S-cyclohexyl group serves as the arced bend of the
U structure. The U-shape is based on a favored diaxial rather than diequatorial substituent
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orientation as shown in Figure 5. In contrast, previously reported sensitizer—ethene dimers
55-58) contain no such bending group and are thought to adopt linear conformations due to
(
their dimethylene or succinate connecting groups.
The U-shape of trimer 5 somewhat resembled structures found in literature (68-72). It
has been found that bent-shaped conformers in kibdelomycin bound to S. aureus (73), or arise
in aminomalonyl dipeptide esters (74) and fluorescent naphthalimide-cholesterol conjugates
in membranes (75). Next, the U-shape of the sensitizer conjugate was examined in both the
1
surface loading and O -based ethene cleavage relative to that reported in the literature. The
2
former effect is described next.
Covalent bonding of trimer conjugate to a phenoxypropyl-coated silica surface
Fine particles of diameters ranging from 75-150 µm were prepared by grinding and sieving
porous Vycor glass (PVG) according to our previously reported method (57). Next, phenol
molecules were covalently attached to the silica surface by a reaction with 3-iodopropyl
trimethoxysilane as seen in Figure 6. In our reaction, phenoxypropyl trimethoxysilane
(
MeO) SiCH CH CH OPh was formed in situ and bound with silica. The reaction resulted in
3 2 2 2
coverage of 70% of the silica surface (1.16 mmol/g silica) with OPh groups. The use of 3-
iodopropyl trimethoxysilane to covalently attach compound on a silica surface had been
previously successful (76-78). Sensitizer-coated surface 7 was then synthesized by
reacting trimer 5 with 3-iodopropyl trimethoxysilane and attaching it to the (3-
phenoxypropyl)silane coated silica surface by some of the remaining silanol groups. Soxhlet
extraction was used to remove any noncovalently bound compounds. The trimer’s silica
surface coverage was determined by obtaining UV-vis of the sensitizer liberated by
dissolving the silica 7 in aqueous HF, by a method previously reported (41,55,79,80). Based
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on the data gained through this HF treatment, the coverage of sensitizer molecules in 7 was
found to be 0.023% (0.38 µmol/g silica).
As noted in the computational studies reported above, the U-shape of trimer 5 may
discourage it from bonding to the silica surface by hindering the silane portion of 5 from
reaching the surface. Our results for the U-shape between the sensitizer and ethene suggest
the sensitizer would be directed toward the surface. This conformation could potentially
impact the photorelease chemistry, which we investigated next.
Singlet oxygen induced release of sensitizer 9 from the silica 7 (Figure 7)
1
Silica 7 was investigated by direct analysis of the O near-IR luminescence
2
(81,82). Silica 7 was stirred and irradiated simultaneously, while the near-IR emission spectra
were recorded after the sample was excited at the wavelengths of the Soret (400 nm) and the
1
Q-band (660 nm) of the sensitizer. The typical O phosphorescence band centered at 1270
2
nm was observed upon irradiation of silica 7 as seen in Figure 8, providing clear evidence of
1
1
O production. Interestingly, the O emission arises early in the reaction suggesting the
2
2
production of singlet oxygen while the sensitizer is bound to the particle, but this is very low
compared to when the sensitizer is photoreleased into solution. That is, the intensity of the
1
O phosphorescence increased as the irradiation time increased wherein the sensitizer is
2
released and diffused into solution.
In another set of experiments, silica 7 was irradiated at 400 nm for 2 h in chloroform
and then the particles were removed from solution by centrifugation. The resulting
1
chloroform solution (supernatant) produced O upon visible-light irradiation, indicating that
2
1
the sensitizer photorelease from the particles had occurred. The results suggest that O reacts
2
with the ethene and forms a dioxetane intermediate, which breaks its C–C and O–O bonds to
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1
give stable carbonyl-containing compounds. Because the total rate constant (k ) of O with
T
2
7
-1 -1
dialkoxyethene is ~4 × 10 M s (83), hundreds of collisions between the two are required
owing to its sub-diffusion control reactivity leading to sensitizer cleavage. The cleaved
1
sensitizer 9 dissolves in solution and leads to O luminescence in the solution phase. The
2
sensitizer release is shown not to occur in the dark by a reaction such as hydrolysis.
The results shown in Table 2 (entry 1) indicate a low sensitizer photorelease
efficiency of 5% after 1 h of irradiation at 669 nm, as determined by monitoring the
appearance of the released sensitizer’s Q-band absorption in n-butanol. The sensitizer
photorelease efficiency was greatly increased to 68-99% with a dimethylene or succinate
linker (Table 2, entries 2-4) (41,55-58). A previous report (58) also showed the optimal
photorelease rate was obtained with sensitizer loading of 4.4 µmol/g silica and a sensitizer-to-
sensitizer distance of 17 nm (Table 2, entry 2). Due to the limited surface coverage achieved
with the U-shape trimer 5, only 0.38 µmol/g silica, the sensitizer-to-sensitizer distance of 660
nm is less than optimal (Table 2, entry 1). Nonetheless, the dialkoxyethene group reacts
1
1
rapidly with O , where other successful O -based C=C and C=N bond types
2
2
(e.g., disulfidoethenes, aminoacrylates, oximes, vinylimines, and hydrazones) also cleave
apart as reported in the literature (84-88). Next, the mechanistic facets of the bent sensitizer
conjugate are analyzed.
Mechanistic considerations
Our computed and experimental results provided insight on how the bent orientation will
affect covalent attachment and sensitizer photorelease (Figure 9). We found that (i) the
sensitizer-cyclohexane-ethene trimer was successfully synthesized, and PM6 computations
show that it adopts a U-shape. (ii) The bonding of the sensitizer to the silica surface was low
when a (1S,2S)-cyclohexane linker was introduced. Table 2 provides information that its
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loading (entry 1) is 6-33 times lower loading compared to reports that use a dimethylene or
succinate linker on native silica (entry 2) and fluorinated silica (entries 3 and 4). (iii) Not only
does the curvature of the S,S-cyclohexane linkage restrict bonding of the silane to the surface,
it also restricts the sensitizer photorelease. Sensitizer particle 7 was 14-17–times less efficient
at photorelease, as can be seen in Table 2 when comparing to native silica (entry 2) and
fluorinated silica samples (entries 3 and 4). (iv) We surmise that sensitizer silica 7 is further
influenced by π-π stacking interactions between the phenoxypropyl and chlorin sites on the
surface. This is due to literature of porphyrin dimers that intercalate aromatic guests in a
sandwich-type complex (89-95). In our case the phenoxypropyl and chlorin heterodimer
would represent a half-sandwich system, where chlorin-chlorin homodimers could be
neglected as there are little to no interactions between the widely separated sensitizer
molecules. Additional weak C-H···π interactions may also exist. Such pairing between the
phenoxypropyl and sensitizer would further support the U-shape of the sensitizer by bending
to reach the phenoxypropyl site; negatively impacting the sensitizer photorelease chemistry.
Summary
A photoreleasable sensitizer has been successfully synthesized and attached to silica using a
chiral (1S,2S)-cyclohexane-1,2-dicarboxylate linker. The observed ~19-fold decrease in
sensitizer loading, as compared to similar sensitizers bearing succinate or dimethylene linkers
(55-58), can be attributed to a key problem. Namely, a bend in the S,S-linkage is found to
hinder the sensitizer silane from coupling to the silica surface. Computations show the
predominant form of the sensitizer trimer to be a U-shape, which along with possible π–
π stacking between the phenoxypropylsilane and the sensitizer can account for the reduced
efficiency of covalent bonding between the sensitizer and the silica surface.
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Future prospective
The system could possess an advantage in photoreleasing curve-shaped sensitizer molecules
that are potentially resistant to aggregation (96). Otherwise, we find that the U-shape of the
system only leads to downsides (pun intended), which should be avoided. We learned from
the study that the aromatic surface was not a good avenue to pursue. Alternative
modifications that increase sensitizer departure from the surface are a more favorable
venture. For example, Table 2 shows that the surface packing of the phenoxysilanes and the
fluorosilanes is nearly equal and does not appear to be restrictive enough to account for the
lower covalent bonding of the sensitizer. Therefore, the coverage was less dense than that of
the fluorosilane functionalized silica, where the fluorosilanes promoted the sensitizer to adopt
a vertical orientation by the repulsion of neighboring nonafluorosilanes. These
1
nonafluorosilanes also offered oxygen concentration increases, reduced O quenching, and
2
surface repelling properties that were advantageous in previous systems (41).
CONCLUSION
We have developed a five-step synthetic method to covalently attach a bent sensitizer
linkage to a silica surface by a (S,S)-cyclohexyl bridge. As we saw, the resulting bend led to
the less efficient covalent bonding of chlorin to silica. Co-doping of phenoxypropyl groups
1
on the silica dampened the yield of alkene bond photocleavage by O .
2
One can anticipate that (R,S) and (S,R) to enable linear chiral orientations, while (R,R)
will prompt diaxial substituent orientations, as we saw with the (S,S)-cyclohexyl. The
attachment of other chiral groups to the surface, such as tartaric acid derivatives, has been
seen for chiral surfaces for the tuning of enantiomer release kinetics. Retention of a
perfluorinated surface as we used done before will also be beneficial.
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1
These findings have led to our enhanced efforts to develop surfaces for O and
2
1
sensitizer delivery. Including, O -based sensitizer release reactions which we hope to take
2
down new avenues. The (S,S)-cyclohexyl, dimethylene, and succinate bridges we have
synthesized will add to the array of linkages designed to understand how compounds release
from photosensitive surfaces.
Our goal is to enable control over the linkage orientation as well as other aspects of
the bridge in order to enhance sensitizer release. Modifying surfaces is an excellent way
of revealing how drug photorelease can be tuned, which connects to how materials can be
engineered for use in miniaturized photodynamic devices.
ACKNOWLEDGEMENTS: GG acknowledges support from the Beatrice Hunter Cancer
Research Institute. GG and SAM acknowledge support from the Natural Sciences and
Engineering Council of Canada, the Canadian Institutes of Health Research, the Canadian
Foundation for Innovation, the Nova Scotia Research and Innovation Trust, and Acadia
University. SAM acknowledges support from the National Cancer Institute of the
National Institutes of Health under Award Number R01CA222227 (proviso: the content is
solely the responsibility of the authors and does not necessarily represent the official views of
the National Institutes of Health). SAM also acknowledges financial support from the
University of North Carolina at Greensboro. GG, SJB, CC, NW, AAG and AG acknowledge
support from the National Science Foundation (CHE-1464975). MV and AHT acknowledge
support from the Agencia de Promoción Científica y Tecnológica (ANPCyT-Grant PICT-
2
015–1988). We acknowledge support from Consejo Nacional de Investigaciones Cientıficas
y Tecnicas (CONICET) and the National Science Foundation (NSF) through the Bilateral
Cooperation Programme, Level I (PCB-I, Res.2172). EMG acknowledges support from the
donors of the Petroleum Research Fund of the American Chemical Society, PSC-CUNY, the
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Eugene Lang Foundation at Baruch College. Computational support was provided by the
Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by
the National Science Foundation Grant No. ACI01053575. We also thank Leda Lee for the
graphic arts work.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the online version of this article:
1
Figure S1. H NMR of compound 1 in CDCl .
3
1
Figure S2. H NMR of compound 2 in CDCl .
3
1
3
Figure S3. C NMR of compound 2 in CDCl .
3
1
Figure S4. H NMR of compound 3 in CDCl .
3
1
3
Figure S5. C NMR of compound 3 in CDCl .
3
1
Figure S6. H NMR of compound 4 in CDCl .
3
1
Figure S7. H NMR of compound 5 in CDCl .
3
1
3
Figure S8. C NMR of compound 5 in CDCl .
3
1
1
13
Figure S9. Expanded H NMR and H– C HSQC of compound 5 in CDCl .
3
Figure S10. HRMS (+ESI) of compound 5.
Figure S11. UV-vis spectrum of compound 5 in CHCl3.
Figure S12. Fluorescence spectrum of compound 5 in CHCl3.
Figure S13. UV-vis spectrum of compound 9 in n-butanol.
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