Design and synthesis of a novel Rhodamine B [2]rotaxane

Article abstract of DOI:10.1039/c3ra40968f

The synthesis and characterization of a novel Rhodamine B [2]rotaxane is described. This species contains dibenzyl-24-crown-8 (DB24C8) as a wheel, which is threaded onto a sec-ammonium-containing axle. The axle has a Rhodamine B unit and a 2,2-diphenylethanamine unit as two bulky terminal stoppers to prevent unthreading.

Full text of DOI:10.1039/c3ra40968f

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Graphical Abstract
-
PF6
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O O
ONH
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O
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+
2
O
O
N
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Rhodamine B [2]Rotaxane
The synthesis and characterization of a novel Rhodamine B [2]rotaxane is described.

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Design and Synthesis of a Novel Rhodamine B [2]Rotaxane
,
Xiaofeng Bao† *, Duliang Liu †, Yanyan Jin, Xiaolu Liu, Wei Jiang
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract: The synthesis and characterization of a novel Rhodamine B [2]rotaxane is described. This species contains a dibenzyl-24-
crown-8 (DB24C8) as a wheel, which is threaded onto a sec-ammonium-containing axle. The axle has a Rhodamine B unit and a 2,2-
diphenylethanamine unit as two bulky terminal stoppers to prevent unthreading.
cells. In order to monitor the rotaxanes’ cellular permeability and
10 Introduction
determine its cellular locations with or without a guest, it is
necessary to develop a functional rotaxane that contains a
50 fluorophore. In this paper, we describe the first example of a
synthesis of a Rhodamine B [2]rotaxane. We converted the
rotaxanes into protein mimetics by replacing an aromatic rich
blocking group with a Rhodamine B. We considered that
Rhodamine-B [2]rotaxane will deliver materials as we have
55 previously observed, and its cellular location and permeability
may be monitored via fluorescence microscopy. Meanwhile, its
association with a guest can be determined by using fluorescence
quenching assays.
During the past few decades, dramatic progress has been made
in the synthesis of rotaxanes that consist of one or more wheels
encircling the rod portion of a dumbbell-shaped unit.1 Rotaxane
synthesis has become one of the most popular research fields due
15 to the novel supermolecular structures these complexes contain
and their potential applications in nanotechnology. The
applications include their use as components of molecular
machines,2 molecular switches,3 drug delivery devices,4 and
molecular electronic devices5. Rotaxanes that contain
a
20 fluorescent structure, such as naphthalimide6, Dipicolylamine7
and Diazapyrenium8 have made it possible to study the properties
of these supermolecules with electro-optical instruments and, in
some cases, even with the naked eye. However, to the best of our
knowledge, there are currently no reported examples of
25 fluorescent rotaxanes that contain a Rhodamine B moiety (Figure
1). Rhodamine derivatives, such as Rhodamine B, have been
extensively used both to derivatize biomolecules9 and as
fluorescent chemosensors10 for metal ions. These applications are
enabled by their excellent fluorescence properties.
60
65
70
30
35
75 Results and discussion
Rhodamine B [2]Rotaxane 1 (Figure 1) consists of a
dibenzyl-24-crown-8 (DB24C8) as a macrocyclic component, a
Rhodamine B and a 2,2-diphenylethanamine as the two bulky
terminal stoppers, and a sec-ammonium salt as the axle that links
80 the two stoppers. Rhodamine B aldehyde 8 was obtained via two
pathways (Scheme 1): the reduction of benzyl ester 6 (route A)
and the oxidation of alcohol 7 (route B). Specifically, the
hydrochloride salt 5 was prepared in 78% isolated yield through
the esterification of benzyl alcohol 4 with 3-aminopropanoic acid
40
We previously reported the successful preparation of a novel
type of Cleft-[2]Rotaxane (2) and Host-[3]Rotaxane (3, Figure 2),
containing one or two arginine-derivatized dibenzyl-24-crown-8
(DB24C8) rings as the wheel and a cleft or a cyclophane as a
blocking group. These rotaxanes can bind a variety of guests in
45 DMSO, water, and mixed solvent systems with large association
constants, and can efficiently transfer fluorescent materials into
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in HCl gas at 120 °C for 4 h. Other attempts to prepare 5 in the
presence of DCC/HOBt in refluxing SO2Cl2 afforded lower yields. 60
5
10
15
20
65
70
75
The synthesis of our Rhodamine B [2]rotaxane was based on
the known DCC-Rotaxane method11. Exposing DB24C8 to axle
Treatment of Rhodamine B (Route A) with 5 in the presence of
DCC (1 eq.), HOBt (1 eq.), and TEA (3 eq.) at rt. for 6 h in 80 10-H-PF6 in CHCl3 at -10°C for 30 min induced threading, which
CH2Cl2 gave Rhodamine B benzyl ester 6 in 81% isolated yield.
Ester 6 was reduced by slow addition of diisobutylaluminum
was followed by the addition of DCC and stirring for 2 h at rt. to
form crude DCC-[2]rotaxane 11-H-PF6. Reacting 2,2-
25 hydride (1.5 eq.). This reaction was performed in DCM at -83 °C
diphenylethanamine with crude 11-H-PF6 at rt. overnight,
under nitrogen for 2 h to provide aldehyde 8 in 56% isolated yield.
followed by removing the precipitated DCU in CHCl3, provided
Alcohol 7 was also isolated as a byproduct in ~8% yields due to 85 crude 12-H-PF6. This mixture was then purified by preparatory
over-reduction of 6. Alcohol 7 was prepared (Route B) in 48%
isolated yield by the coupling of Rhodamine B with 3-
30 aminopropan-1-ol in the presence of DCC/HOBt and TEA at rt.
silica gel chromatography, and 12-H-PF6 was isolated in 15%
yield as a pale-red solid. The product was characterized by H
1
NMR and ESI-MS (Figure 5). A byproduct, 11-H-PF6, was also
for
5
h., followed by treatment of
7
with pyridinium
isolated in trace amounts; its structure was determined by 1H
chlorochromate (PCC, 2 eq.) and silica gel (200-300 mesh, 2 eq.) 90 NMR and ESI-MS (m/s found, 1253.96; calcd. for [M-PF6]+,
in DCM at rt. under nitrogen for 24 h to obtain 8 in a 20%
isolated yield. Route A was employed to provide material for
35 further study because of the higher yields obtained and the
relative ease of purification performed during this route.
1253.75).
The ammonium salt 10-H-PF6 was prepared from aldehyde 8
as shown in Scheme 2. Specifically, acid 9 was prepared in 36%
yield by reduction of the corresponding Schiff base (generated by
40 condensation of aldehyde 8 with 5-aminopentanoic acid in MeOH)
with NaBH3CN or NaBH(OAc)3 in MeOH, followed by
95
treatment of 9 with HCl gas in EtOAc for 30 min to afford 10-H- 100
Cl salt. Anion exchange of 10-H-Cl in DCM with aqueous
NH4PF6 afforded sec-ammonium salt 10-H-PF6 in 97% isolated
45 yield as a pale-red solid.
105
Molecular dynamics simulations of the structure of our
Rhodamine B [2]rotaxane generated a folded model, as shown in
Figure 3. Because of stronger intramolecular hydrogen bonds
between the oxygen atoms of the macrocyclic DB24C8 (O1 -O4
110 shown in Figure 3) and two of the hydrogen atoms of the sec-
ammonium group (Ha and Hb shown in Figure 3), the crown
ether ring is pulled away from the aliphatic portion of the axle
and instead resides near the sec-ammonium group. Due to this
conformational restraint and corresponding intramolecular forces,
115 the chemical shifts of the hydrogen atoms on the thread change to
varying degrees.
50
55
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This research was supported by the Jiangsu Science Foundation
(BK2011704) and the Fundamental Research Funds for the
60 Central Universities (No. 2011ZDJH08).
5
10
15
Notes and references
1. Chemical Engineering Building B302, Department of Biochemical
Engineering, Nanjing University of Science & Technology, Nanjing,
210094, P. R. China
65 E-mail: baoxiaofeng@mail.njust.edu.cn
Fax: +86-(25)-84315945; Tel: +86-(25)-84315945
† These two authors contributed equally to this work.
‡ Electronic Supplementary Information (ESI) available: General
experimental procedures, copies of 1H NMR, 13C NMR, and HRMS
70 spectra are available. See DOI: 10.1039/b000000x/
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Figure 4 shows the H NMR spectra of DB24C8, 10-H-PF6 and
Rhodamine B [2]rotaxane 12-H-PF6. In spectrum b, the proton
signals of H3’ and H4’ that are adjacent to the sec-ammonium
20 group were observed at 2.80 ppm and 2.60 ppm, respectively.
Protons H3 and H4 produced signals in the spectrum of 12-H-PF6
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30 features and MS spectra of 12-H-PF6 (Figure 5) confirm the
interlocked nature of 12-H-PF6, which indicates the synthetic
approach presented here is an effective approach.
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50 Conclusions
In this study, we presented the construction of a Rhodamine B
[2]rotaxane. This represents
a new synthetic method for
producing fluorescent rotaxane. Further studies on the
a
application of this new system concerning its ability to deliver
55 materials into cells and its efficiency in reporting cellular
localization are currently underway.
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Acknowledgments
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