Template-directed syntheses of configurable and reconfigurable molecular switches

Article abstract of DOI:10.1055/s-2005-918468

Two self-complexing compounds based on donor-acceptor interactions, one comprised of a π-electron-deficient cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺) ring attached to a side-arm component containing π-electron-rich tetrathiafulvalene (TTF) and 1

Full text of DOI:10.1055/s-2005-918468

PAPER
3437
Template-Directed Syntheses of Configurable and Reconfigurable Molecular
Switches
T
emplate-Directed
i
S
yntheses
o
L
M
olecula
r
Sw
i
California NanoSystems Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard
Avenue, Los Angeles, CA 90095-1569, USA
Fax +1(310)2061843; E-mail: stoddart@chem.ucla.edu
Received 15 September 2005
This article is dedicated to Steven Ley on the occasion of his 60th birthday.
self-complexing compound 2·4PF6 has only one arm
Abstract: Two self-complexing compounds based on donor–ac-
which contains both a TTF and a DNP unit. Oxidation and
reduction of the TTF unit with an electrochemical stimu-
lus switches the favorable donor-acceptor charge transfer
ceptor interactions, one comprised of a p-electron-deficient cyclo-
bis(paraquat-p-phenylene) (CBPQT4+) ring attached to a side-arm
component containing p-electron-rich tetrathiafulvalene (TTF) and
1,5-dioxynaphthalene (DNP) units, and the other comprised of a (CT) interactions. Changes in the electronic properties of
CBPQT4+ ring carrying two side-arms, one containing a TTF unit
the molecules then trigger mechanical movements in both
and the other a DNP unit have been synthesized. 1H NMR spectros-
systems – an in-and-out motion8 of the TTF arm from the
copy and UV/Vis spectroelectrochemistry have revealed that, while
CBPQT 4+ ring’s cavity in the case of the two-armed, self-
the latter compound behaves as a reconfigurable redox-active mo-
complexing compound 1·4PF6, and a piston-like push-pull
lecular switch involving only the side-arm containing the TTF unit
in a self-complexing role with the CBPQT4+ ring (the side-arm con-
taining the DNP unit is essentially a ‘spectator’), the former com-
pound behaves as a molecular switch that is reversible and
reconfigurable when its starting self-complexing conformation is
retained, but becomes only configurable and irreversible when the
self-complexing conformation is partially transformed into ‘uncom-
plexed’ conformation on oxidation of the TTF unit.
movement in the case of the one-armed, self-complexing
compound 2·4PF6. The redox-induced mechanical behav-
iors of both these systems have been investigated by NMR
spectroscopy, electrochemistry, and spectroelectrochem-
istry and will be discussed in this paper along with a de-
scription of the synthesis of 1·4PF6 and 2·4PF6.
The synthesis of the two-armed, self-complexing, com-
pound 1·4PF6 is summarized in Scheme 1. Tosylation of
the alcohol 39 gave the monotosylate 4, which was reacted
Key words: molecular recognition, redox reactions, self-assembly,
spectroelectrochemistry, templation
Mechanically interlocked molecules – for example,
catenanes1 and rotxanes2 – have already established their
credentials as functional molecular machines3,4 by virtue
of the relative mechanical motions undergone by one
component relative to the other component(s) in response
to external stimuli in the form of chemical,5 electrochem-
ical,6 and photochemical7 inputs. Another class of me-
chanically interlocked molecules – the self-complexing
donor-acceptor macrocycles8 – have their donor units at-
tached covalently to an acceptor ring and is also depen-
dent on molecular recognition between the donor and
acceptor units for their unique ability to self-complex and
switch mechanically. In the donor-acceptor self-complex-
ing compounds 1·4PF6 and 2·4PF6 (Figure 1), the
CBPQT4+ ring is attached covalently to either one or two
flexible arm(s) which contain(s) p-donating units – name-
ly, TTF and DNP. In both compounds, the ground-state
co-conformations (GSCCs) comprise the stronger p-elec-
tron-donating TTF unit encircled by the CBPQT4+ ring.
The two-armed, self-complexing compound 1·4PF6 has
one of its two arms bearing a TTF unit, and the other, a
DNP unit. On the other hand, the stoppered, one-armed,
Figure 1 Structural formulas of the two-armed self-complexing
compound 1·4PF6 and the one-armed self-complexing compound
2·4PF6.
SYNTHESIS 2005, No. 19, pp 3437–3445
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918468; Art ID: C07705SS
© Georg Thieme Verlag Stuttgart · New York

3438
Y. Liu et al.
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with 4-hydroxybenzylaldehyde in the presence of K2CO3 The synthesis of the stoppered one-armed, self-complex-
to produce the alcohol 5 in 94% yield. Esterification of 5 ing compound 2·4PF6 is summarized in Scheme 2. The al-
with the carboxylic acid derivative 6,8b using 1,3-dicyclo- cohol 12 was obtained by reaction of the tosylate 118b with
hexylcarbodiimide (DCC) as the coupling agent, gave the the naphthol derivative 102e,f in the presence of K2CO3.
dibromide 7 in 76% yield. Heating of a MeCN solution of Esterification of 12 with the carboxylic acid derivative
7 and 4,4¢-bipyridine under reflux generated the 6,8b using DCC as the coupling agent, gave the dibromide
bis(hexafluorophosphate) salt 8·2PF6 after counterion ex- 13. The final product 2·4PF6 was isolated after reaction of
change. The final product 1·4PF6 was isolated in a yield of the dibromide 13 with the bis(hexafluorophosphate) salt
19% by reaction of 8·2PF6 with the TTF-containing dibro- 14.2PF6,10 followed by counterion exchange and column
mide 9,8b followed by counterion exchange and column chromatography.
chromatography.
K2CO3 / MeCN
18C6 (cat)
O
O
O
X
X = OH
3
4
TsCl / CH2Cl2
NEt3 / DMAP
HO
O
O
O
HO
CHO
X = OTs
94%
41%
HO
O
O
O
Br
Br
O
O
OH
O
O
O
O
O
O
CHO
DCC / CH2Cl2
DMAP (cat)
N
5
6
76%
O
O
O
CHO
7
Br
O
O
O
O
O
O
N
N
O
MeCN / reflux
81%
Br
N
O
O
O
O
CHO
N
N
N
O
O
O
O
O
O
–
2 PF6
N
8•2PF6
O
N
Br
Br
O
S
S
S
S
1. DMF / r.t.
2. NH4PF6 / H2O
N
O
O
O
OHC
O
O
O
O
O
9
19%
O
O
N
O
O
O
N
N
S
S
S
O
S
O
O
N
N
O
O
CHO
O
N
O
—
4 PF6
O
O
O
O
O
O
O
O
OHC
1•4PF6
Scheme 1 The synthesis of the two-armed, self-complexing compound 1⋅4PF6.
Synthesis 2005, No. 19, 3437–3445 © Thieme Stuttgart · New York

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Template-Directed Syntheses of Molecular Switches
3439
The chemically-induced switching of 2·4PF6 has been in- corresponding to two signals each for H-4/8, H-3/7 and H-
vestigated by 1H NMR spectroscopy. The initial spectrum 2/6, respectively. The large upfield shift of the H-4/8 pro-
(Figure 2a), which was recorded in acetone-d6 at 273 K, tons, in particular, is characteristic for complexation of the
revealed an extensive array of overlapping signals that DNP unit. Although it was not possible to determine the
were far from straightforward to assign because of the identity of the species responsible for the small peaks ob-
complex nature of the spectrum. Reasons for this com- served (Figure 2b) in the spectrum of the oxidized com-
plexity include the presence of multiple isomers arising pound, one possibility is the presence of a small amount
from two sources. The first one is the cis/trans isomeriza- of dethreaded 2·4PF6.
tion of the TTF unit. Secondly, the glycol chain, attached
A further experiment was performed to investigate the re-
to the unit encircled by the CBPQT4+ ring can be either
versibility of the switching process. A small amount of
endo or exo.8b This uncertainty leads to the possibility of
Zn-dust was added to the oxidized solution of 2·4PF6 in
four different isomers when the TTF unit is encircled by
order to reduce the species back to its starting state. The
the CBPQT4+. In search of reducing this complexity and
1H NMR spectrum was recorded (Figure 2c) once again.
forcing the equilibrium to favor solely encirclement of the
Aside from the appearance of two large signals, corre-
sponding to the reduced form of the oxidant, the spectrum
DNP unit, an oxidation of 2·4PF6 was carried out.
The oxidant, tris(p-bromophenyl)amminium hexafluoro- is qualitatively similar to the one observed (Figure 2a) be-
antimonate, was added (2.0–2.5 equiv) to an acetone-d6 fore oxidation. This observation suggests that switching
solution of 2·4PF6, and the 1H NMR spectrum (Figure 2b) has been reversed; however, we cannot confirm or rule out
was recorded. The number of signals present in the spec- the possibility that the relative ratios of the isomers
trum of the oxidized species (Figure 2b) was considerably present have changed as a result of the switching cycle.
1
reduced relative to those in the starting spectrum The relative complexity of the H NMR spectra, em-
(Figure 2a). As a result, it was possible to assign all the ployed for investigating the redox-driven chemical
signals. Characteristic signals were observed at 9.86 and switching process, provided us with the impetus to inves-
9.94 ppm and can be assigned to the TTF protons (HTTF
)
tigate its electrochemically controlled mechanical switch-
of the dication. Furthermore, evidence for encirclement of ing.
the DNP unit by the CBPQT4+ ring was found in the form
of signals at 2.80, 2.84, 5.95, 6.34, 6.51 and 6.56 ppm,
Electrochemical input is one of the most powerful and
‘waste-free’ stimuli that can induce mechanical motion in
mechanically interlocked molecules. The mechanical
motion within such molecules in response to electrons can
be monitored by cyclic voltammetry (CV) and/or spectro-
electrochemistry, in which UV-Vis absorption spectros-
copy is coupled with electrochemistry.
Electrochemically induced mechanical motion in the do-
nor–acceptor compound 1·4PF6 which contains two arms
– each bearing one donor unit, either TTF or DNP – was
investigated by both CV and spectroelectrochemistry. The
CV of 1·4PF6 at a scan rate of 200 mV s–1 shows
(Figure 3) anodic peaks at +390, +720, and +1280 mV –
the first two peaks corresponding to TTF oxidations to the
TTF+ radical cation and TTF2+ dication respectively,
while the third one being associated with the oxidation of
the DNP unit. Oxidation of 1·4PF6 was found to be fully
reversible over 20 cycles with negligible memory effect at
various scan-rates. The fact that the DNP unit is oxidized
at +1280 mV – an oxidation potential that is characteristic
of the uncomplexed DNP unit – clearly suggests that the
DNP-arm does not thread into the cavity of the CBPQT4+
ring even after dethreading of the TTF-arm induced by
TTF oxidations. This situation can be attributed to a steric
hindrance of the CBPQT4+ cavity by the phthalimide ad-
jacent to the TTF-arm. The relative intensity of the TTF+
anodic peak and its precise location in the scan-rate de-
pendent CV studies suggest8b that the TTF unit is in dy-
namic equilibrium between threaded and dethreaded
forms following its oxidation-reduction cycle. At a slower
scan rate (5 and 10 mV s–1), the first oxidation peak splits
into two features at +450 and +520 mV. It is not unreason-
able to suggest that the +450 mV peak corresponds to the
Figure 2 The 600 MHz 1H NMR spectra of 2·4PF6 in acetone-d6 at
273 K (a) before addition of oxidant, (b) after addition of 2.0–2.5
equivalents of the oxidant, tris(p-bromophenyl)amminium hexafluo-
roantimonate, and (c) after subsequent reduction using Zinc dust. See
Figure 1 for proton assignments.
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3440
Y. Liu et al.
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TsO
O
O
O
O
OH
S
S
S
S
O
O
O
+
10
11
K2CO3 / MeCN
18C6 (cat)
OH
74%
O
O
O
Br
O
N
6
HO
DCC / CH2Cl2
DMAP (cat)
O
O
O
O
O
O
OH
O
S
S
S
S
Br
60%
12
O
O
O
Br
O
N
13
O
O
O
S
S
S
S
O
O
O
O
O
Br
O
N
N
N
O
O
N
N
O
O
–
N
N
2 PF6
1. DMF / r.t.
—
4 PF6
S
S
O
2. NH4PF6 / H2O
S
O
S
N
21%
N
14•2PF6
O
O
O
2•4PF6
O
O
Scheme 2 The synthesis of the stoppered, one-armed, self-complexing compound 2·4PF6.
first oxidation of the uncomplexed TTF and the +520 mV diradical form when it encircles a TTF unit in a rotaxane.
peak arises from the oxidation of the complexed TTF unit. A second cathodic peak at –715 mV corresponds to the re-
duction of the ring component to the neutral CBPQT0
form. The first reduction is fully reversible, whereas the
The reduction of 1·4PF6 at 200 mV s–1 shows a split peak
at –260 and –330 mV – a feature which is characteristic of
second reduction leads to a small degradation of the sub-
the first reduction of a CBPQT4+ ring to the CBPQT2/2+
sequent anodic oxidation peaks – a phenomenon which
can be attributed to electrode adsorption.
Spectroscopic studies, coupled with electrochemical in-
puts, also shed light on the switching behavior of 1·4PF6.
The GSCC showed (Figure 4, green line) a characteristic
band centered on 840 nm on account of the TTF →
CBPQT4+ CT interaction confirming the encapsulation of
the TTF-arm into the CBPQT4+ cavity. Oxidation of the
TTF unit at an applied potential (Eap) of +750 mV resulted
(Figure 4, blue line) in the appearance of TTF+ radical cat-
ion’s absorption peaks at 450 and 600 nm, concomitant
with the disappearance of the 840 nm CT band. These fea-
tures confirm yet again that once the TTF unit is oxidized,
the TTF-arm dethreads from the CBPQT4+ cavity. The
second oxidation of the TTF unit to the TTF2+ dication
generated (Figure 4, red line) its characteristic peak at 375
nm. However, no DNP → CBPQT4+ CT band at 520 nm
Figure 3 Cyclic voltammetry of 1·4PF6 (0.1 mM solution in 0.1 M
appeared even after prolonged waiting at Eap = +1100
TBAPF6–MeCN) vs. standard calomel electrode (SCE) at a scan-rate
mV, suggesting that the DNP-arm does not complex with
of 200 mV/s.
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Template-Directed Syntheses of Molecular Switches
3441
the CBPQT4+ ring in 1·4PF6. Reduction of the TTF2+ di- (Figure 5, blue line) the characteristic absorption peaks of
cation back to its neutral TTF form regenerated (Figure 4, the radical cation at 450 and 600 nm, concomitant with the
black line) the 840 nm CT band, attaining almost its orig- disappearance of the 840 nm band – an observation which
inal intensity, indicating the rethreading of the TTF-arm suggests that the CBPQT4+ ring moves away from the ox-
into the CBPQT4+ cavity. A weak peak just below 500 nm idized TTF+ unit. Further oxidation of the TTF unit to its
in the final spectrum may be associated with a degradation TTF2+ dication at Eap = +1100 mV shows (Figure 5, red
product or a fraction of still uncomplexed TTF unit. In line) its absorption peak at 375 nm, and a concomitant de-
summary, the TTF-arm of the two-armed, self-complex- cay of the TTF+ radical cation’s absorption peaks reveals
ing, compound 1·4PF6 can be switched in and out of the a weak, but characteristic, CT band centered on 520 nm
CBPQT4+ ring by simply stimulating the TTF unit, how- which corresponds to the DNP → CBPQT4+ CT interac-
ever, the DNP-arm always remain uncomplexed irrespec- tion, confirming the ring’s relocation around the second-
tive of the TTF oxidation states.
ary electron-donating DNP unit. Complete reduction of
the TTF2+ dication back to its neutral TTF form at Eap = 0
V should regenerate the original spectrum, provided the
mechanical switching process has been completely re-
versible. After a prolonged reduction (12 h), however, the
spectrum displayed (Figure 5, black line) a modest loss of
ca. 40% in the intensity of the 840 nm band, implying that
fact that not all of the regenerated neutral TTF is encircled
by the CBPQT4+ ring. A new, weak band appears at
around 500 nm suggests that some of the CBPQT4+ ring
still encircles the DNP station rendering a higher stability
of its metastable state. In addition, a complete dethreading
of the side-arm component from the cavity of the
CBPQT4+ ring by a circumrotation of the phthalimide unit
through the ring cannot be ruled out – a process which
Electrochemically induced mechanical movement in the
one-armed, self-complexing, compound 2·4PF6 was best
monitored by spectroelectrochemistry of its 2 mM solu-
tion in MeCN with TBAPF6 (0.1 M) as the supporting
electrolyte. In the ground state of 2·4PF6, the side-arm
containing the two p-electron donating units – namely,
TTF and DNP – is folded in such a way that the stronger
electron-donating TTF unit is encircled by the electron-
accepting CBPQT4+ ring – a conformation that displays
(Figure 5, green line) a prominent charge-transfer (CT)
band centered on 840 nm, corresponding to a CT interac-
tion between a TTF unit and a CBPQT4+ ring. Upon one
electron oxidation of the TTF unit to the TTF+ radical cat-
ion at an applied potential of +800 mV, one observes
Figure 4 Spectroelectrochemistry and schematic representation illustrating in-and-out motion of the TTF-arm in 1·4PF6 in response to elec-
trochemical inputs. This motion constitutes a reconfigurable molecular switch. See the text for an explanation of the color-coded spectra.
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Y. Liu et al.
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does not require that the ring component slips over of the switching is irreversible, possibly because the tetrathiaful-
bulky 2,6-diisopropyl aryl stopper at the DNP end in a valene unit in the ‘uncomplexed’ conformation is perhaps
high-energy process. Once the self-complexing com- interacting in an external way with the p-electron-defi-
pound is dethreaded into the decomplexed ring plus side- cient bipyridinium units of the tetracationic cyclophane.
arm components, its rethreading process under diffusion In the case of the compound carrying two side-arms, the
control will be an extremely slow process, if possible at redox chemistry behaves in accordance with its being a re-
all.
configurable molecular switch in which only one of the
side arms – the one containing the tetrathiafulvalene unit
– participates in mechanical switching.
The donor-acceptor rings with one or two arms containing
electron-donating recognition sites are a unique class of
molecules that have the potential for self-complexation.
The integrity of these molecules is not solely dependent
on the supramolecular chemistry and molecular recogni-
tion as the electron-rich arms are covalently attached to
the electron-deficient ring. Nevertheless, their unique
self-complexing ability is based on noncovalent interac-
tions between the donor-acceptor units. Furthermore,
their redox-stimuli induced mechanical motions stem
The diol 3,9 the carboxylic acid derivative 6,8b the dibromide 9,8b the
naphthol derivative 10,2e,f the monotosylate 11,8b and the dicationic
10
salt 14·2PF6 were all prepared as reported in the literature. Sol-
vents were purified11 according to literature procedures. TLC was
carried out using aluminum sheets, precoated with silica gel 60F
(Merck 5554). The plates were inspected by UV-light prior to de-
velopment with iodine vapor. Melting points were determined on an
1
Electrothermal 9200 apparatus and are uncorrected. H NMR and
from noncovalent interactions between the recognition 13C NMR spectra were recorded on Bruker Avance 500, Avance
600 or ARX 500 spectrometers using the deuterated solvents as
units, which, in turn, allow the arm components to switch
locks and the residual protiated solvents as internal standards. High-
within or in and out of the ring’s cavity. In the case of the
resolution electrospray ionization mass spectra (HR-ESI-MS) were
obtained using an IonSpec Ultima 7.0T FT-ICR ESI mass spec-
compound carrying one side-arm that contains two recog-
nition units, the redox chemistry behaves in accordance
trometer. High-resolution matrix-assisted-laser-desorption-ioniza-
with its being a partially reconfigurable molecular switch,
reflecting the fact that one mode of switching leads to a
product which does not equilibrate back to its starting
conformation. This observation suggests that one mode of
tion mass spectra (HR-MALDI-MS) were recorded on an IonSpec
Ultima 7.0T FT-ICR MALDI mass spectrometer. The UV-Vis ab-
sorption spectra were recorded on a Varian Cary 100 Bio in MeCN
solution. The extinction coefficients were obtained from a single-
Figure 5 Spectroelectrochemistry and schematic representation illustrating the reversible and irreversible conformational changes involving
the TTF/DNP-containing side-arm in 2·4PF6 in response to electrochemical inputs. These reversible and irreversible conformational changes
correspond to a partially reconfigurable and partially configurable molecular switch, respectively. See the text for an explanation of the color-
coded spectra.
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Template-Directed Syntheses of Molecular Switches
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point determination. Electrochemical and spectroelectrochemical
experiments were carried out at r.t. in Ar-purged MeCN solutions at
specific concentrations of the compounds using a Princeton Applied
Research 263A Potentiostat/Galvanostat instrument, interfaced to a
PC (EG & G software). Cyclic voltammetric experiments were per-
formed using a glassy-carbon working electrode (0.018 cm2, Cy-
press Systems). Its surface was polished routinely with a 0.05
micron alumina/H2O slurry on a felt surface immediately before
use. The counter electrode was a Pt wire and the reference electrode
was either SCE or Ag/AgCl. Tetrabutylammonium hexafluoro-
phosphate (TBAPF6, 0.1 M in MeCN) was used as supporting elec-
trolyte. Cyclic voltammograms were obtained at scan rates ranging
from 2 to 1000 mV s–1. For reversible processes, E1/2 was calculated
from an average of the cathodic and anodic cyclic voltammetric
peaks. To establish the reversibility of a process, we used the crite-
ria of (i) 60 mV between cathodic and anodic peaks, and (ii) close
to unity ratio of the intensities of the cathodic and anodic currents.
Spectroelectrochemical experiments were made in a custom-built,
optically transparent, thin-layer electrochemical (OTTLE) cell with
an optical path of 1 mm, using a Pt grid as working electrode, a Pt
wire as counter electrode and a Ag wire pseudoreference electrode.
For spectroelectrochemistry, 1–2 mM solutions of the compounds
in 0.1 M TBAPF6/MeCN were used. Experimental errors: potential
values, 10 mV; absorption maxima, 2 nm.
Compound 7
A mixture of the alcohol 5 (300 mg, 0.57 mmol), the carboxylic acid
derivative 68b (244 mg, 0.62 mmol), 1,3-dicyclohexylcarbodiimide
(233 mg, 1.14 mmol) and 4-dimethylaminopyridine (cat.) in CH2Cl2
(15 mL) was stirred overnight at r.t.. The resulting suspension was
filtered and the filtrate was evaporated and subjected to column
chromatography (SiO2: hexanes–EtOAc, 1:1) to give the dibromide
7 as a white wax (0.389 g, 76%).
1H NMR (500 MHz, CDCl3, 298 K): d = 9.91 (s, 1 H), 7.88 (t,
J = 9.0 Hz, 2 H), 7.79 (d, J = 8.7 Hz, 2 H), 7.66 (s, 2 H), 7.35 (q,
J = 8.7 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 7.6 Hz, 1 H),
6.82 (d, J = 7.6 Hz, 1 H), 4.92 (s, 4 H), 4.36 (t, J = 4.5 Hz, 4 H), 4.32
(t, J = 4.5 Hz, 2 H), 4.29 (t, J = 4.5 Hz, 2 H), 4.18 (t, J = 4.5 Hz, 2
H), 4.04–4.00 (m, 4 H), 3.92 (t, J = 4.5 Hz, 2 H), 3.86–3.79 (m, 6
H), 3.76 (t, J = 4.5 Hz, 2 H), 3.72 (t, J = 4.5 Hz, 2 H).
13C NMR (125 MHz, acetone-d6, 298 K): d = 190.7, 167.0, 166.3,
163.7, 154.2, 154.1, 137.0, 137.4, 131.8, 129.9, 128.2, 126.6, 126.5,
125.0, 125.0, 114.7, 114.5, 114.4, 105.5, 105.5, 70.9, 70.8, 70.8,
70.7, 69.7, 69.4, 68.7, 67.8, 67.7, 67.6, 64.9, 38.7, 25.7.
HRMS (MALDI): m/z calcd for C41H43Br2NO12Na+ [M + Na]+:
922.1022; found: 922.1044.
Compound 8·2PF6
A solution of dibromide 7 (520 mg, 0.58 mmol) and 4,4¢-bipyridine
(540 mg, 3.46 mmol) in MeCN (10 mL) was refluxed for 5 h. The
resulting suspension was evaporated to dryness, followed by the ad-
dition of sat. aq NH4PF6 solution. The solid precipitate was collect-
ed by filtration. The excess of 4,4¢-bipyridine was removed by
washing with Et2O to give 8·2PF6 as a yellow solid (630 mg, 81%),
which was used directly for the next step of the synthesis.
Compound 4
A solution of TsCl (920 mg, 4.48 mmol) in CH2Cl2 (20 mL) was
added dropwise into a mixture of the diol 39 (2.16 g, 4.71 mmol),
Et3N (1.4 mL) and DMAP (cat.) in CH2Cl2 (80 mL) at 0 °C. The
mixture was allowed to stir overnight at r.t. after the addition was
complete. The solvent was evaporated and the residue was subject-
ed to column chromatography (SiO2: hexanes–EtOAc, 1:4) to give
4 as a colorless oil (880 mg, 41%).
1H NMR (600 MHz, CDCl3, 298 K): d = 7.85 (t, J = 9.8 Hz, 2 H),
7.77 (d, J = 8.5 Hz, 2 H), 7.35–7.32 (m, 2 H), 7.28 (d, J = 7.6 Hz, 2
H), 6.83 (t, J = 6.8 Hz, 2 H), 4.29 (t, J = 4.5 Hz, 2 H), 4.25 (t, J = 4.5
Hz, 2 H), 4.13 (t, J = 4.5 Hz, 2 H), 3.99 (t, J = 4.5 Hz, 2 H), 3.94 (t,
J = 4.5 Hz, 2 H), 3.80 (t, J = 4.5 Hz, 2 H), 3.73–3.68 (m, 8 H), 3.62–
3.60 (m, 4 H).
HRMS (ESI): m/z calcd for C61H59F12N5O12P2 [M – PF6]+:
1198.3797; found: 1198.3843.
Compound 1·4PF6
A solution of the dicationic salt 8.2PF6 (113 mg, 85.0 mmol) and the
dibromide 98b (78 mg, 85.0 mmol) in DMF (3 mL) was stirred at r.t.
for 10 d. Et2O (100 mL) was added to the green reaction mixture to
ensure the full precipitation of the reaction product. The green pre-
cipitate was filtered off under reduced pressure and subjected to col-
umn chromatography (SiO2: MeOH–NH4Cl (2 M)–MeNO2 7:2:1).
The green fractions containing the product were combined and con-
centrated. NH4PF6 was added to precipitate the product as a solid,
which was further purified by preparative TLC using MeOH–
NH4Cl (2 M)–MeNO2 (7:2:1) as the eluent. The band containing the
product was washed off the silica gel by using a solution of NH4PF6
in acetone. The solvent was evaporated off and the residue was
washed with H2O and Et2O separately to give pure 1·4PF6 as a green
solid (39 mg, 19%).
13C NMR (150 MHz, CDCl3, 298 K): d = 155.2, 155.1, 145.6,
133.8, 130.7, 128.8, 127.6, 127.6, 126.0, 126.0, 115.5, 115.4, 106.6,
106.5, 73.3, 71.9, 71.8, 71.7, 71.3, 70.7, 70.7, 70.1, 69.6, 68.7, 68.7,
62.7, 22.4.
Compound 5
A mixture of the monotosylate 4 (770 mg, 1.33 mmol), 4-hydroxy-
benzylaldehyde (194 mg, 1.60 mmol), K2CO3 (551 mg, 3.99 mmol),
LiBr (cat.) and 18-crown-6 (cat.) in MeCN (40 mL) was refluxed
for 24 h. The resulting suspension was filtered and the solid was
washed with acetone until the filtrate was colorless. The combined
organic solution was evaporated and subjected to column chroma-
tography (SiO2: hexanes–EtOAc, 1:5) to give 5 as a colorless oil
(660 mg, 94%), which slowly solidified upon storage.
1H NMR (500 MHz, acetone-d6, 298 K): d = 9.86 (s, 1 H), 7.83–
7.80 (m, 4 H), 7.34 (q, J = 7.8 Hz, 2 H), 7.05 (d, J = 7.8 Hz, 2 H),
6.94 (d, J = 7.6 Hz, 2 H), 4.30 (t, J = 4.5 Hz, 4 H), 4.19 (t, J = 4.5
Hz, 2 H), 3.96–3.94 (m, 4 H), 3.85 (t, J = 4.5 Hz, 2 H), 3.75–3.68
(m, 6 H), 3.63–3.50 (m, 6 H).
13C NMR (125 MHz, acetone-d6, 298 K): d = 190.1, 163.8, 154.4,
131.4, 130.1, 126.6, 125.0, 114.7, 114.1, 114.1, 105.6, 105.5, 72.6,
70.6, 70.6, 70.5, 70.2, 69.4, 69.4, 69.1, 67.8, 67.8, 61.0. 60.9.
MS (FAB): m/z (%) = 529.31 (75) [M + H]+.
HRMS (MALDI): m/z calcd for C29H36O9Na+ [M + Na]+: 551.2218;
1H NMR (500 MHz, acetone-d6, 323 K): d = 9.83 (m, 2 H), 9.58–
9.10 (m, 8 H), 8.58–8.16 (m, 12 H), 7.85–7.70 (m, 8 H), 7.30 (m, 2
H), 7.10–6.95 (m, 8 H), 6.48–6.40 (m, 6 H), 4.70–3.65 (m, 48 H).
HRMS (ESI): m/z calcd for C96H94F24N6O22P4S4 [M – 2PF6]2+:
1050.2288; found: 1050.2261; m/z calcd for [M – 3PF6]3+:
651.8310; found: 651.8295.
Compound 12
A mixture of 102e,f (170 mg, 0.42 mmol), the monotosylate 118b
(225 mg, 0.38 mmol), K2CO3 (105 mg, 0.76 mmol) and 18-crown-
6 (5 mg, cat.) in anhyd MeCN (20 mL) was refluxed for 16 h. The
mixture was filtered and the solid was washed with CH2Cl2. The
combined organic extracts were concentrated and the residue was
purified by column chromatography (SiO2: CH2Cl2–MeOH, 100:1)
to give 12 as a yellow semi-solid (231 mg, 74%).
found: 551.2252.
1H NMR (500 MHz, acetone-d6, 298 K): d = 7.94 (d, J = 8.5 Hz, 1
H), 7.91 (d, J = 8.5 Hz, 1 H), 7.48–7.39 (m, 2 H), 7.17–7.01 (m, 3
Synthesis 2005, No. 19, 3437–3445 © Thieme Stuttgart · New York

3444
Y. Liu et al.
PAPER
H), 6.98 (d, J = 8.5 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 6.55–6.44
(m, 2 H), 4.39 (d, J = 4.5 Hz, 2 H), 4.34–4.31 (m, 6 H), 4.10 (d,
J = 4.5 Hz, 2 H), 3.99–3.97 (m, 6 H), 3.77 (d, J = 4.5 Hz, 2 H),
3.66–3.19 (m, 12 H), 2.96 (s, 1 H), 1.26 (d, J = 8.5 Hz, 12 H).
13C NMR (125 MHz, acetone-d6, 298 K): d = 154.4, 154.3, 141.6,
134.8, 134.7, 134.7, 134.6, 126.7, 125.2, 125.1, 124.5, 123.8, 116.6,
116.5, 116.4, 114.3, 114.2, 109.9, 109.9, 109.8, 109.8, 105.7, 74.1,
72.6, 70.5, 70.1, 69.7, 69.4, 69.2, 69.2, 69.1, 68.1, 67.9, 67.6, 67.6,
67.6, 61.0, 25.9, 23.5.
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HRMS (MALDI): m/z calcd for C42H54O9S4 [M]+: 830.2636; found:
830.2645; m/z calcd for [M + Na]+: 853.2556; found: 853.2543.
Compound 13
A mixture of the alcohol 12 (174 mg, 0.21 mmol), the carboxylic
acid derivative 6 (90 mg, 0.23 mmol), 1,3-dicyclohexylcarbodiim-
ide (86 mg, 0.42 mmol) and 4-dimethylaminopyridine (cat.) in
CH2Cl2 (5 mL) was stirred overnight at r.t. The resulting suspension
was filtered and the filtrate was evaporated and subjected to column
chromatography (SiO2: hexanes–EtOAc, 1:2) to give the dibromide
13 as a brownish-yellow solid (150 mg, 60%).
1H NMR (500 MHz, acetone-d6, 298 K): d = 7.70 (s, 4 H), 7.38 (d,
J = 11 Hz, 2 H), 7.08–7.12 (m, 3 H), 6.98–7.02 (m, 2 H), 6.28–6.57
(m, 2 H), 5.07 (s, 4 H), 4.50 (s, 4 H), 4.36 (d, J = 15 Hz, 8 H), 4.11
(s, 2 H), 4.00 (s, 6 H), 3.61–3.79 (m, 10 H), 3.49–3.51 (m, 2 H), 1.20
(d, J = 6 Hz, 12 H).
13C NMR (500 MHz, acetone-d6, 298 K): d = 167.1, 166.2, 154.4,
154.3, 153.1, 141.6, 137.2, 136.6, 128.3, 126.6, 125.1, 125.0, 124.4,
123.7, 116.5, 114.2, 114.1, 105.6, 74.0, 70.5, 70.2, 69.7, 69.4, 69.2,
69.0, 68.5, 67.8, 64.7, 38.5, 31.3, 25.9, 22.3.
HRMS (MALDI): m/z calcd for C54H61Br2NO12S4 [M]+: 1201.1443;
found: 1203.1473.
Compound 2·4PF6
A solution of the dibromide 13 (149 mg, 0.124 mmol) and the di-
cationic salt 14·2PF610 (87.0 mg, 0.124 mmol) in DMF (3 mL) was
stirred at r.t. for 12 d. The solvent was removed under reduced pres-
sure and the residue was subjected to column chromatography
[SiO2: MeOH–NH4Cl (2 M)–MeNO2, 7:2:1]. The green fractions
containing the product were combined and concentrated. NH4PF6
was added to precipitate the product 2·4PF6 as a green solid (53 mg,
21%).
1H NMR (500 MHz, CD3CN, 348 K): d = 8.92–8.90 (m, 8 H), 7.00–
5.98 (m, 27 H), 5.73–5.60 (m, 6 H), 4.60 (s, 2 H), 4.52 (m, 2 H), 4.42
(m, 2 H), 4.30 (m, 2 H), 4.20 (m, 6 H), 4.18 (m, 4 H), 3.97 (m, 6 H),
3.75 (m, 4 H), 3.68 (m, 2 H), 3.42 (m, 2 H), 1.19 (m, 12 H).
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HRMS (ESI): m/z calcd for C82H85F24N5O12P4S4 [M – 2PF6]2+:
874.7175; found: 874.7162.
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Ackowledgment
This research was supported by the Defense Advanced Research
Projects Agency (DARPA) and the Institute of Cell Mimetic Space
Exploration (CMISE). Part of this work is based upon research sup-
ported by the National Science Foundation (NSF) under equipment
grant number CHE-9974928 and CHE-0092036.
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