A photoactivated molecular gate

Article abstract of DOI:10.1002/chem.201201127

An o-nitrobenzyl ester derivative bearing a cyclodextrin moiety that was selectively opened by the addition of specific enzymes and by UV irradiation was prepared. On methoxybenzylamine fragment, a compound, which , other than the photo-cleavable group, c

Full text of DOI:10.1002/chem.201201127

COMMUNICATION
DOI: 10.1002/chem.201201127
A Photoactivated Molecular Gate
Alessandro Agostini,[a, b] Fꢀlix Sancenꢁn,[a, b] Ramꢁn Martꢂnez-MꢃÇez,*[a, b]
Marꢂa D. Marcos,[a, b] Juan Soto,[a] and Pedro Amorꢁs[c]
The design and synthesis of mesoporous hybrid capped
materials, which can be selectively opened upon the applica-
tion of external stimuli and release an entrapped cargo,
have recently caught the interest of the scientific communi-
ty.[1] In general, these hybrid materials are composed of two
main subunits: an inorganic scaffold (with a porous network
in which certain chemicals can be stored) and molecular en-
tities grafted onto the outer surface, which act as molecular
gates (to control the delivery of the entrapped cargo).
As inorganic scaffolds, mesoporous silica nanoparticles
(MSNs) have been widely used because of their unique
properties, such as large load capacity, biocompatibility,
large surface area and well-known functionalisation proce-
dures.[2] In fact, gated MSNs have recently been used as sup-
ports for the development of on-command delivery nano-de-
vices using several physical and chemical triggers.[3] In this
area, MSNs showing controlled release features driven by
redox reactions,[4] pH changes[5] and biomolecular interac-
tions[6] have been described.
capped with PAMAM dendrimers (G1.5), and MSNs
capped with gold nanoparticles, which were opened using
light as a stimulus.[9] In contrast, only one photo-driven con-
trolled example using a photo-cleavable gate anchored on
the surface of MSNs has been reported.[10] In this work, Kim
and co-workers prepared an o-nitrobenzyl ester derivative
bearing a cyclodextrin moiety that was selectively opened
by the addition of specific enzymes and by UV irradiation.
In particular, the solid was able to release the entrapped
cargo (calcein) after UV irradiation at 350 nm due to the
photolysis of an o-nitrobenzyl ester fragment.
By considering our interest in developing gated materials
and the aforementioned ideas, we report herein the synthe-
sis and controlled release studies of a new nanoscopic meso-
porous system capped with a photo-cleavable o-methoxy-
benzylamine fragment. A schematic representation of the
controlled delivery paradigm is shown in Scheme 1. The o-
In this field, light is also a powerful tool for the control of
open/closed protocols in mesoporous systems. In particular,
by using light-driven gated systems, the release of the cargo
can be controlled spatially and temporally by finely tuning
the area and the time of the light stimulus. However, there
are relatively few examples of photochemically driven mo-
lecular gates,[7] some of which are based on reversible photo-
isomerisation reactions.[8] Recently, we described MSNs
functionalised with spiropyran photochrome units and
[a] A. Agostini, Dr. F. Sancenꢀn, Prof. R. Martꢁnez-MꢂÇez,
Dr. M. D. Marcos, Dr. J. Soto
Centro de Reconocimiento Molecular y Desarrollo Tecnolꢀgico
Unidad Mixta Universidad Politꢃcnica
de Valencia-Universidad de Valencia
Departmento de Quꢁmica, Universidad Politꢃcnica de Valencia
Camino de Vera s/n, 46022 Valencia (Spain)
Fax : (+34)96-387-93-49
E-mail: rmaez@qim.upv.es
[b] A. Agostini, Dr. F. Sancenꢀn, Prof. R. Martꢁnez-MꢂÇez,
Dr. M. D. Marcos
Scheme 1. Schematic representation of solid S1 and the photo-driven un-
capping mechanism.
CIBER de Bioingenierꢁa, Biomateriales y Nanomedicina
(CIBER-BBN) (Spain)
[c] Prof. P. Amorꢀs
methoxybenzylamine group was selected for its well-known
photo-cleavage properties, which have been used in a wide
range of applications.[11] Based on this methoxybenzylamine
fragment, we designed compound 7 which, other than the
photo-cleavable group, also contains two bulky tert-butyl
Institut de Ciꢄncia del Materials (ICMUV)
Universitat de Valꢄncia
P.O. Box 2085, 46071Valencia (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201127.
Chem. Eur. J. 2012, 00, 0 – 0
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moieties to obtain effective pore blockage in the final
hybrid material, as well as one trialkoxysilane moiety for an-
choring 7 on the external MSN surface. Compound 7 was
expected to be bulky enough to preclude the delivery of the
entrapped cargo but, at the same time, it was expected to
undergo photolysis upon UV irradiation. As a result of pho-
tolysis, the steric hindrance of the capping molecule would
decrease considerably, thus allowing the release of the en-
trapped dye.
The synthesis of 7 (see Scheme 2) began with a reaction
between 4-methoxyacetophenone (1) and aqueous formalde-
hyde in hydrochloric acid, which yielded compound 2. Then
a nucleophilic substitution reaction of 2 with amine 3 (pre-
pared following a well-known procedure)[12] gave the bulky
tertiary amine 4 equipped with two tert-butylamide moieties.
Treatment of tertiary amine 4 with bromine in chloroform
gave 5 through an a-bromination reaction. Finally, trialkoxy-
silane derivative 7 was prepared by a nucleophilic aliphatic
reaction between 5 and (3-aminopropyl)triethoxysilane (6)
in acetonitrile/K2CO3.
amine nitrogen appeared at d=2.51 ppm, whereas the meth-
ylene positioned between the aromatic ketone and the sec-
ondary amine gave a signal at d=3.60 ppm. Finally, the
methylene protons linked with amide nitrogen appeared as
triplets centred at d=3.30 ppm.
Prior to anchoring 7 on MSNs and to test the feasibility of
7 as a photo-cleavable molecule, photolysis studies were car-
ried out. Acetonitrile solutions of 7 were irradiated with a
mercury lamp (254 nm) and the photodegradation com-
pounds were studied by gas chromatography coupled with a
mass spectrometer. A complete photodegradation of 7 was
achieved in three hours, from which aldehyde 8 was the
major product of this reaction. Product 8 was isolated and
characterised by NMR spectroscopy (see Scheme 2 and the
Supporting Information).
After assessing 7 as a suitable photo-cleavable molecule,
preparation of the capped materials shown in Scheme 1 was
carried out. We selected mesoporous MCM-41 silica nano-
particles of approximately 100 nm in diameter as the inor-
ganic carrier vehicle. This support was prepared by follow-
ing well-known procedures using tetraethyl orthosilicate
(TEOS) as a hydrolytic inorganic precursor and the surfac-
tant hexadecyltrimethylammonium bromide. After surfac-
tant removal by calcination, MCM-41 nanoparticles were
obtained. The structure of the nanoparticulated calcined
MCM-41 starting material was confirmed by powder X-ray
diffraction analysis and TEM microscopy (Figure 1). The N2
adsorption–desorption isotherms of the prepared nanoparti-
cles showed a typical type-IV curve, with a specific surface
of 965.6 m2 gÀ1 and a pore volume of 0.77 cm3 gÀ1. From the
Scheme 2. Synthesis of trialkoxysilane derivative 7 that acts as a molecu-
lar gate and its photolysis reaction.
1
All the synthesised products were characterised by H and
13C NMR spectroscopy and HRMS (see the Supporting In-
1
formation). The H NMR spectrum of trialkoxysilane deriv-
ative 7 shows the presence of singlets centred at d=
1.10 ppm assigned to the methyl groups of both tert-butyl
subunits. The ethoxy moieties appeared as a triplet centred
at d=1.22 ppm and as a quadruplet centred at d=3.85 ppm,
whereas the aromatic signals were a pair of doublets centred
at d=6.89 and 7.88 ppm and a singlet at d=7.90 ppm. Meth-
ylene directly linked with the aromatic ring and the tertiary
Figure 1. Left: Powder-X ray diffractograms showing the MSN patterns
as synthesised (i), calcined MSNs (ii) and solid S1 (iii). Right: TEM
images of calcined MSN (a) and of final solid S1 (b).
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A Photoactivated Molecular Gate
COMMUNICATION
XRD, porosimetry and TEM studies, the a0 cell parameter
(4.34 nm), the pore diameter (2.67 nm) and a wall thickness
value (1.67 nm) can be determined.
To prepare the final capped material, the inorganic sup-
port was first loaded with the [RuACHTNUTRGNEUNG(bipy)3]Cl2 fluorophore,
which was used as a suitable dye for monitoring the light-
triggered protocol. Then, the surface of the solid was func-
tionalised with compound 7 to obtain the final hybrid mate-
rial S1. Finally, the charged orange solid was filtered, inten-
sively washed with acetonitrile and dried overnight at 368C.
Figure 1 shows the powder X-ray diffraction patterns of
the MSN material as synthesised, the calcined MSNs and
the final S1 nanoparticles. The hybrid material S1 displays
the expected features of the MCM-41 phase, indicating that
the mesopore in the inorganic scaffolding is preserved
throughout the filling process with the ruthenium complex
and the anchoring of bulky derivative 7 at the pore outlets.
Figure 1a and b provides TEM images of the MSN support
and of the final hybrid nanoparticles S1. Both TEM images
show the typical porosity associated with the inorganic sup-
port and their spherical form of about 100 nm in diameter.
Additionally, the N2 adsorption–desorption isotherm of S1
(see the Supporting Information) was typical of mesoporous
systems with filled mesopores, and the N2 volume adsorbed
and the surface area (53.6 m2 gÀ1) significantly decreased
when compared with calcined MSN samples. The contents
of ruthenium complex and capping molecule 7 in S1 were
determined by thermogravimetric analyses and amounted to
119 mmolgÀ1 SiO2 and 109 mmolgÀ1 SiO2, respectively.
After synthesising and characterising the capped MSNs,
the gating properties of S1 were studied. In a typical experi-
ment, solid S1 (3 mg) was suspended in anhydrous acetoni-
trile. Then the sample was stirred and exposed to 254 nm ir-
radiation in a closed photoreactor for a given time. As a
control experiment, dye release was also determined by
using suspensions of S1 under similar conditions but in the
absence of light (see the Supporting Information for de-
tails). Photo-triggered molecular gate performance was
monitored through the emission band (lem =619 nm, lex =
451 nm) of the ruthenium fluorophore delivered to the solu-
tion. The dye delivery versus time for both the irradiated
and non-irradiated samples is shown in Figure 2.
Figure 2. Kinetics of the [RuACHTNUGRTNEUNG
(bipy)3]2+ dye release from solid S1 in the
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absence of light ( ) and upon irradiation with UV light ( ).
irradiation. The photolysis of the methoxybenzylamine
group diminished the steric crowding around the pore out-
lets, which accounts for the dye delivery and the emission
enhancement observed. The design of light-responsive mate-
rials is a promising research field that may be of relevance
in the development of custom-made materials for advanced
delivery applications.
Acknowledgements
The authors thank the Spanish Government (project: MAT2009-14564-
C04), the Generalitat Valenciana (project: PROMETEO/2009/016) and
the CIBER-BBN for their support. A.A. also thanks the Generalitat Va-
lenciana for his Santiago Grisolia fellowship.
Keywords: controlled release
· mesoporous materials ·
molecular devices · nanoparticles · photochemistry
[1] a) A. B. Descalzo, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, K. Hoffmann,
K. Rurack, Angew. Chem. 2006, 118, 6068–6093; Angew. Chem. Int.
Ed. 2006, 45, 5924–5948; b) A. Cazacu, Y. M. Legrand, A. Pasc, G.
Nasr, A. Van der Lee, E. Mahon, M. Barboiu, Proc. Natl. Acad. Sci.
USA 2009, 106, 8117–8122; c) X. Hou, W. Guo, L. Jiang, Chem.
Soc. Rev. 2011, 40, 2385–2401; d) B. Zhu, J. Li, D. Xu, Phys. Chem.
Chem. Phys. 2011, 13, 10584–10592.
[2] a) J. S. Beck, J. C. Vartuli, W. J. Roth, M. E. Leonowicz, C. T.
Kresge, K. D. Schmitt, C. T. W. Chu, D. H. Olson, E. W. Sheppard,
S. B. McCullen, J. B. Higgins, J. L. Schlenker, J. Am. Chem. Soc.
1992, 114, 10834–10843; b) A. P. Wright, M. E. Davis, Chem. Rev.
2002, 102, 3589–3614; c) G. Kickelbick, Angew. Chem. 2004, 116,
3164–3166; Angew. Chem. Int. Ed. 2004, 43, 3102–3104; d) A.
Stein, Adv. Mater. 2003, 15, 763–775.
As explained above, compound 7 was expected to be
bulky enough to preclude the release of the entrapped dye
in S1. In fact, as Figure 2 illustrates, the release of the ruthe-
nium dye in the absence of light was completely inhibited
(the gate was closed). The profile obtained upon UV irradi-
ation clearly differed and a remarkable cargo release was
observed due to the photo-cleavage of the methoxybenzyl-
ACHTUNGTRENNUNGamine fragment. A maximum dye release was noted after
about 20 min of UV irradiation. Moreover, the presence in
the solution, upon irradiation, of the aldehyde 8 was also
confirmed.
To summarise, we report herein the synthesis of a new
photo-cleavable organic molecule which, when grafted on
the surface of MSNs, acts as a molecular gate by allowing
the controlled release of an entrapped cargo by simple UV
[3] E. Aznar, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, Expert Opin. Drug De-
livery 2009, 6, 643–655.
[4] a) B. G. Trewyn, S. Giri, I. I. Slowing, V. S. Y. Lin, Chem. Commun.
2007, 3236–3245; b) F. Torney, B. G. Trewyn, V. S. Y. Lin, K. Wang,
Nat. Nanotechnol. 2007, 2, 295–300; c) D. R. Radu, C. Y. Lai, K. Jef-
tinija, E. W. Rowe, S. Jeftinija, V. S. Y. Lin, J. Am. Chem. Soc. 2004,
126, 13216–13217; d) S. Giri, B. G. Trewyn, M. P. Stellmaker, V. S. Y.
Lin, Angew. Chem. 2005, 117, 5166–5172; Angew. Chem. Int. Ed.
Chem. Eur. J. 2012, 00, 0 – 0
ꢅ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

R. Martꢁnez-MꢂÇez et al.
2005, 44, 5038–5044; e) M. Fujiwara, S. Terashima, Y. Endo, K.
Shiokawa, H. Ohue, Chem. Commun. 2006, 4635–4637; f) R. Liu, X.
Zhao, T. Wu, P. Feng, J. Am. Chem. Soc. 2008, 130, 14418–14419;
g) T. D. Nguyen, Y. Liu, S. Saha, K. F. C. Leung, J. F. Stoddart, J. I.
Zink, J. Am. Chem. Soc. 2007, 129, 626–634.
E. Aznar, M. D. Marcos, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, J. Soto,
J. M. Barat, E. Pꢃrez-Payꢂ, C. Guillem, P. Amorꢀs, ACS Nano 2010,
4, 6353–6368; g) E. Climent, R. Martꢁnez-MꢂÇez, F. Sancenꢀn,
M. D. Marcos, J. Soto, A. Maquieira, P. Amorꢀs, Angew. Chem.
2010, 122, 7439–7441; Angew. Chem. Int. Ed. 2010, 49, 7281–7283;
h) C. Coll, L. Mondragꢀn, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, M. D.
Marcos, J. Soto, P. Amorꢀs, E. Pꢃrez-Payꢂ, Angew. Chem. 2011, 123,
2186–2188; Angew. Chem. Int. Ed. 2011, 50, 2138–2140.
[5] a) R. Casasffls, M. D. Marcos, R. Martꢁnez-MꢂÇez, J. V. Ros-Lis, J.
Soto, L. A. Villaescusa, P. Amorꢀs, D. Beltrꢂn, C. Guillem, J. La-
torre, J. Am. Chem. Soc. 2004, 126, 8612–8613; b) R. Casasffls, E.
Climent, M. D. Marcos, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, J. Soto, P.
Amorꢀs, J. Cano, E. Ruiz, J. Am. Chem. Soc. 2008, 130, 1903–1917;
c) S. Angelos, Y. W. Yang, N. M. Khashab, J. F. Stoddart, J. I. Zink, J.
Am. Chem. Soc. 2009, 131, 11344–11346; d) S. Angelos, Y.-W. Yang,
K. Patel, J. F. Stoddart, J. I. Zink, Angew. Chem. 2008, 120, 2254–
2258; Angew. Chem. Int. Ed. 2008, 47, 2222–2226; e) S. Angelos,
N. M. Khashab, Y.-W. Yang, A. Trabolsi, H. A. Khatib, J. F. Stod-
dart, J. I. Zink, J. Am. Chem. Soc. 2009, 131, 12912–12914; f) L. Du,
S. Liao, H. A. Khatib, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc.
2009, 131, 15136–15142; g) Q. Yang, S. Wang, P. Fan, L. Wang, Y.
Di, K. Lin, F. S. Xiao, Chem. Mater. 2005, 17, 5999–6003; h) C.
Park, K. Oh, S. C. Lee, C. Kim, Angew. Chem. 2007, 119, 1477–
1479; Angew. Chem. Int. Ed. 2007, 46, 1455–1457; i) L. Chen, J. Di,
C. Cao, Y. Zhao, Y. Ma, J. Luo, Y. Wen, W. Song, Y. Song, L. Jiang,
Chem. Commun. 2011, 47, 2850–2852.
ˇ
ˇ
´
[7] a) N. Z. Knezevic, B. G. Trewyn, V. S. Y. Lin, Chem. Commun. 2011,
47, 2817–2819; b) D. P. Ferris, Y. L. Zhao, N. M. Khashab, H. A.
Khatib, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2009, 131, 1686–
1688; c) J. L. Vivero-Escoto, I. I. Slowing, C. W. Wu, V. S. Y. Lin, J.
Am. Chem. Soc. 2009, 131, 3462–3463.
[8] a) N. K. Mal, M. Fujiwara, Y. Tanaka, Nature 2003, 421, 350–353;
b) Y. Zhu, M. Fujiwara, Angew. Chem. 2007, 119, 2291–2294;
Angew. Chem. Int. Ed. 2007, 46, 2241–2244; c) N. K. Mal, M. Fuji-
wara, Y. Tanaka, T. Taguchi, M. Matsukata, Chem. Mater. 2003, 15,
3385–3394.
[9] a) E. Aznar, M. D. Marcos, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, J.
Soto, P. Amorꢀs, C. Guillem, J. Am. Chem. Soc. 2009, 131, 6833–
6843; b) E. Aznar, R. Casasffls, B. Garcꢁa-acosta, M. D. Marcos, R.
Martꢁnez-MꢂÇez, F. Sancenꢀn, J. Soto, P. Amorꢀs, Adv. Mater. 2007,
19, 2228–2231.
[6] a) K. Patel, S. Angelos, W. R. Dichtel, A. Coskun, Y. W. Yang, J. I.
Zink, J. F. Stoddart, J. Am. Chem. Soc. 2008, 130, 2382–2383; b) A.
Schlossbauer, J. Kecht, T. Bein, Angew. Chem. 2009, 121, 3138–
3141; Angew. Chem. Int. Ed. 2009, 48, 3092–3095; c) P. D. Thornton,
A. Heise, J. Am. Chem. Soc. 2010, 132, 2024–2028; d) A. Bernardos,
E. Aznar, M. D. Marcos, R. Martꢁnez-MꢂÇez, F. Sancenꢀn, J. Soto,
J. M. Barat, P. Amorꢀs, Angew. Chem. 2009, 121, 5998–6001;
Angew. Chem. Int. Ed. 2009, 48, 5884–5887; e) E. Climent, A. Ber-
nardos, R. Martꢁnez-MꢂÇez, A. Maquieira, M. D. Marcos, N. Pastor-
Navarro, R. Puchades, F. Sancenꢀn, J. Soto, P. Amorꢀs, J. Am.
Chem. Soc. 2009, 131, 14075–14080; f) A. Bernardos, L. Mondragꢀn,
[10] a) C. Park, H. Kim, S. Kim, C. Kim, J. Am. Chem. Soc. 2009, 131,
16614–16615; b) C. Park, K. Lee, C. Kim, Angew. Chem. 2009, 121,
1301–1304; Angew. Chem. Int. Ed. 2009, 48, 1275–1278.
[11] R. S. Givens, C. H. Park, Tetrahedron Lett. 1996, 37, 6259–6262.
[12] M. J. Goldcamp, D. T. Rosa, N. A. Landers, S. M. Mandel, J. A.
Krause-Bauer, M. J. Baldwin, Synthesis 2000, 2033–2038.
Received: April 3, 2012
Revised: July 16, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

A Photoactivated Molecular Gate
COMMUNICATION
Light-controlled gate: A novel capped
silica nanoscopic mesoporous hybrid
material for photo-driven cargo release
applications has been designed and
prepared. The capped system, which
shows a zero release, contains a photo-
cleavable bulky o-methoxybenzyl-
Molecular Devices
A. Agostini, F. Sancenꢀn,
R. Martꢁnez-MꢂÇez,* M. D. Marcos,
J. Soto, P. Amorꢀs ........... &&&& — &&&&
A Photoactivated Molecular Gate
ACHTUNGTRENNUNGamine derivative. Upon irradiation at
254 nm, photo-degradation of the o-
methoxybenzylamine framework and
the subsequent delivery of a fluores-
cent cargo were observed (see figure).
Chem. Eur. J. 2012, 00, 0 – 0
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