rings of 1 this class can be utilized as a fluorosensor,
operating by either a photoinduced electron transfer (PET)
or an internal charge transfer (ICT) mechanism.6
Scheme 2. Synthesis of B(OMe)2 Derivatives
A significant drawback to covalent immobilization of
existing molecular fluorophores and sensors is the additional
synthetic steps required to make the fluorophore-particle
covalent bond. Typical approaches have utilized amide2a,f
or ester2e bond formation on polymer beads or
silicon-oxygen2d linkages on silica particles. It would be
distinctly attractive if a fluorophore linking method existed
that did not require any additional synthetic complexity.
Herein we report our first set of data acquired in pursuit of
this goal for the fluorophore class 1 with biologically inert
polystyrene beads of various sizes (5-150 µm). Our unique
linking strategy was to employ the reaction of alcohol-
functionalized polystyrene beads with 1 to effect an oxygen
for fluorine displacement, thereby generating a fluorophore-
boron-oxygen-polymer bead linked construct 2 (Scheme
1). Intramolecular oxygen-fluorine displacement reactions
on this compound class have recently been reported.7
We were pleased to observe that the spectral properties
of 3a-c did not significantly change from their correspond-
ing BF2 chelated derivatives 1a-c (Table 1, Supporting
Information).4b,6g Specifically, the λmax emissions for 3a and
3b were recorded at 674 and 711 nm, respectively, with
fluorescence quantum yields (φ) of 0.31 and 0.30 (Table 1;
entries 5 and 6). This shows little difference from the
corresponding BF2 analogues 1a and 2a (entries 1 and 2,
Supporting Information).4b We have previously reported that
the bis-anilino substituted 1c can act as a fluorosensor with
fluorescence signal modulated in response to acidic proton-
ation of both anilines (Table 1; entries 3 and 4).6g Similar
behavior was observed for 3c for which the fluorescence
output between 660 and 760 nm was virtually completely
quenched as a consequence of the donor-acceptor charge
transfer between the anilino lone pairs of electrons and the
fluorophore (Table 1; entries 7 and 8, Supporting Informa-
tion). Upon protonation to 3c-2H+, with TFA, the fluores-
cence spectrum showed a strong proton-induced fluorescence
enhancement with a wavelength of maximum fluorescence
at 684 nm (entry 8, Supporting Information). Significantly,
the fluorescence enhancement factor (FEF) was greater than
250-fold.
Scheme 1. Strategy for Covalent Linkage
Mild reaction conditions were first optimized for the
intermolecular fluorine displacement reaction of 1a-c with
methanol with the goal of utilizing these conditions for bead
functionalization.8 It was found that the treatment of a THF
solution of 1a-c with 3 equiv of NaH and 10 equiv of
MeOH at rt for 16 h was an efficient method for substitution
of both fluorine atoms to provide 3a-c, as bench-stable
solids, following chromatographic purification (Scheme 2,
Supporting Information).
Table 1. Comparative Spectral Characteristics of 1a-c and
3a-ca
entry
compd
abs λmax (nm) fluor λmax (nm)
φf
D. F. Chem. Commun. 2002, 17, 1862. (b) Gorman, A.; Killoran, J.; O’Shea,
C.; Kenna, T.; Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2004,
126, 10619. (c) McDonnell, S. O.; Hall, M. J.; Allen, L. T.; Byrne, A.;
Gallagher, W. M.; O’Shea, D. F. J. Am. Chem. Soc. 2005, 127, 16360. (d)
Gallagher, W. M.; Allen, L. T.; O’Shea, C.; Kenna, T.; Hall, M.; Killoran,
J.; O’Shea, D. F. Br. J. Cancer 2005, 92, 1702. (e) Hall, M. J.; McDonnell,
S. O.; Killoran, J.; O’Shea, D. F. J. Org. Chem. 2005, 70, 5571.
(5) Ntziachristos, V.; Ripoll, J.; Wang, L. V.; Weissleder, R. Nat.
Biotechnol. 2005, 23, 313.
1
2
3
4
5
6
7
8
1a4b
1b4b
1c6g
1c-2H+
3a
650
688
770, 625
650
649
674
733, 620
644
672
0.34
0.36
715
820b
684d
674
6g
0.31c
0.30c
3b
711
3c
822b
684d
3c-2H+
(6) (a) Killoran, J.; O’Shea, D. F. Chem. Commun. 2006, 14, 1503. (b)
Hall, M. J.; Allen, L. T.; O’Shea, D. F. Org. Biomol. Chem. 2006, 4, 776.
(c) McDonnell, S. O.; O’Shea, D. F. Org. Lett. 2006, 8, 3493. (d) Gawley,
R. E.; Mao, H.; Mahbubul Haque, M.; Thorne, J. B.; Pharr, J. S. J. Org.
Chem. 2007, 72, 2187. (e) Coskun, A.; Deniz Yilmaz, M.; Akkaya, E. U.
Org. Lett. 2007, 9, 607. (f) Loudet, A.; Bandichhor, R.; Wu, L.; Burgess,
K. Tetrahedron 2008, 64, 3642. (g) Killoran, J.; McDonnell, S. O.;
Gallagher, J. F.; O’Shea, D. F. New J. Chem. 2008, 32, 483.
(7) Loudet, A.; Bandichhor, R.; Burgess, K.; Palma, A.; McDonnell,
S. O.; Hall, M. J.; O’Shea, D. F. Org. Lett. 2008, 21, 4772.
a In CHCl3. b Very weak CT emission (Supporting Information).
c 1a,b used as references. d In CHCl3 with TFA.
To transfer these spectral features to polymeric beads, 1%
cross-linked polystyrene beads of 150 µm size (Wang resin
beads with 0.9 mmol/g loading) and smaller 5 µm variants
were used as illustrative examples. The developed protocol
treated a THF suspension of the beads with 1 equiv of NaH
for 20 min at rt followed by 0.5 equiv of 1a-c (Scheme 3).
(8) For conditions utilized in oxygen-fluorine displacements on BODIPY
dyes, see: (a) Gabe, Y.; Ueno, T.; Kojima, H.; Nagano, T. Anal. Bioanal.
Chem. 2006, 386, 621. (b) Tahtaoui, C.; Thomas, C.; Rohmer, F.; Klotz,
P.; Duportail, G.; Mly, Y.; Bonnet, D.; Hibert, M. J. Org. Chem. 2007, 72,
269.
Org. Lett., Vol. 11, No. 16, 2009
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