Control of translational and rotational movement at nanoscale
Stacko, Peter
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Chapter VI:
Overcrowded alkene-based amphiphiles:
Synthesis and Application
A series of amphiphiles based on the photoresponsive bisthioxanthylidene core bearing different hydrophilic and hydrophobic tails has been prepared. The effect of the structure on the morphology of the self-assembled structures along with processes such as photochemical control of surface pressure in a Langmuir-Blodgett monolayer or amplification of chirality were studied. Photochemical activity of the core unit has been preserved in all the derivatives thus providing a platform for development of responsive supramolecular systems and advanced materials.
Cheng, J.; Štacko, P.; Rudolf, P.; Gengler, R. Y. N.; Feringa, B. L Angew. Chem. Int. Ed., 2017, 56, 291. Štacko, P.; van Dijken, D. J.; Stuart, M. C. A.; Browne, W. R.; Feringa, B. L. Chem. Sci., 2017, 8, 1783. Erne, P. M.; Štacko, P.; van Dijken, D. J.; Chen, J. W.; Stuart, M. C. A.; Feringa, B. L. Chem. Comm.,
2016, 52, 11697
Erne, P. M.; van Bezouwen, L. S.; Štacko, P.; van Dijken, D. J.; Chen, J. W.; Stuart, M. C. A.; Boekema, E. J.; Feringa, B. L. Angew. Chem. Int. Ed., 2015, 54, 50, 15122–15127
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Introduction
Chemical self-assembly, inspired by numerous self-assembled system in Nature, continues to introduce challenges to the field of dynamic molecular systems and nanoscience.1,2 The supramolecular approach to directed self-assembly is an
important method to construct nanoscale objects including nanoparticles, molecules and polymers.3–10 Furthermore, higher-order architectures can be
constructed provided that the building blocks can co-assemble in distinct functional units.11,12 While naturally occurring amphiphiles play a major role in
this field, significant effort has been devoted to the development of artificial amphiphilic molecules; such as polymers13,14, copolymers15 or amphiphilic
peptides16,17, that are capable of self-assembling into nanotubes, vesicles, sheets,
ribbons or helices.18,19
To achieve dynamic and responsive systems, it is desirable to develop structures that not only create complex self-organized systems, but incorporate the ability to respond to external stimuli and translate this stimulus further to change, for example, their structure or physical properties. A lot of focus has been directed towards multicomponent20 systems including nanoparticles, gels or polymers
that adapt in response to light21–24, magnetic25 or electric fields26, temperature27,
pH changes28 or ultrasound29.
The group of Aida demonstrated formation of rigid nanotubes from an amphiphile based on hexa-peri-hexabenzocoronene central unit (Figure 1).30 The
nanotubes were found to have a wall thickness of 3 nm, suggesting a bilayer structure with interdigitating lipophilic chains. It is assumed that two graphitic layers of π-stacked 1D HBC column form the bilayer which then rolls-up into the observed nanotubes (Figure 2a). In subsequent work, Aida and co-workers also explored exploiting the “majority rules” principle to preferentially form chiral nanotubes by doping the system with a chiral amphiphile bearing stereogenic centers in either the lipophilic or hydrophilic chains (Figure 1).31 Interestingly,
when the stereogenic centers were embedded in the lipophilic chains, formation of the nanotubes was inhibited presumably due to distortion of the packing and disturbing the interdigitation mechanism. The molecules with the stereogenic centers located in the hydrophilic chains worked as intended.
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Figure 1. Hexa-peri-hexabenzocoronene amphiphile and the chiral analogues reported byAida and co-workers.
Figure 2. (a) Schematic illustration of the structure of the nanotube formed by rolling up
bilayer of 1D HBC column. (b) TEM image of the self-assembled ribbons. Scale bar represents 200 nm. (reproduced from ref. 31)
In previous work of the Feringa group, it has been shown that the amphiphile
6.1 based on an overcrowed alkene core featuring two lipophilic and two
hydrophilic chains is capable of self-assembly into rigid nanotubes (Figure 3).32
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chains resulting in a very stable bilayer. Addition of DOPC as a co-lipid due to solubility reasons facilitated preparation of DOPC end-capped nanotubes. DCS confirmed phase separation of the two lipids. Exploiting the remarkable stability of the nanotubes attributed to the interdigitating tails, the caps could be selectively removed by Triton X-100 without disturbing the nanotube structure. Alternatively, the nanotubes could be disassembled by UV light irradiation.
Figure 3. Schematic representation of assembly and disassembly of photoresponsive
self-assembled nanotubes from amphiphile 6.1. (reproduced from ref. 32)
Upon irradiation with UV-light, the nanotubes disassemble into amorphous aggregates due to formation of the cyclized product 6.2 (Scheme 1). This process was monitored using confocal microscopy. It is believed that the increased rigidity of the cyclized amphiphile compared to the anti-folded form disallows efficient packing of the molecules resulting in inhibition of nanotube formation.
Scheme 1. Transformation of the anti-folded form of 6.1 into the cyclized form 6.2 by
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We were interested to examine how different molecular structure, such as length of the aforementioned chains or the nature of the polar groups affects the aforementioned aggregation behavior.
Design of the amphiphiles
To that end, a set of amphiphiles with various lengths of the lipophilic and hydrophilic chains was proposed (Figure 4, 6.1‒6.4). To investigate the effect of polar head groups, it was decided to substitute the original oligoethylene glycol unit for a carboxylic acid (6.5) and tetraalkylammonium group (6.6). Under the assumption that both of these derivatives still form nanotubes, one could hypothesize that a mixture of such nanotubes could result in a self-assembly of the nanotubes into an array based on Coulombic interactions between the positively and negatively charged surface of the bilayers.
Figure 4. The proposed derivatives to study the effect of molecular structure on
self-assembly behavior.
At the same time, a derivative 6.7 with a stereogenic center located in the lipophilic chains was conceived for the purpose of chiral amplification of the point chirality into helical nanotubes. Potentially, a mixture of the chiral amphiphile 6.7 and the non-chiral amphiphile 6.1 could be investigated to establish a sergeants-and-soldiers effect.
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Synthesis of the amphiphiles
The synthesis of the derivatives with varying lipophilic and hydrophilic chain lengths started with a deprotection of 4,5-dimethoxy-9H-thioxanthen-9-one with BBr3 in DCM at 0 °C (Scheme 2). The product was purified by acid-base
extraction and the diol 6.8 was reacted with 1-iodododecane or 1-iodooctadecane in DMF to provide the liophilic parts of the amphiphile 6.9 and 6.10 in very good yields. To obtain the hydrophilic halves of the molecule
6.11 and 6.12, the diol 6.8 was substituted with oligoethylene glycol tosylates in
acetone.
Scheme 2. Alkylation of the diol 6.8 with 1-iodoalkanes and oligoethylene glycol
tosylates.
In order to perform the key Barton-Kellogg coupling used to construct the overcrowded alkene core, one of the halves had to be converted to a hydrazone and the other half into a thioketone. Prior to the thionation, the acidic hydroxyl groups of 6.11 and 6.12 had to be protected with TBDPS-Cl in presence of imidazole (Scheme 3). Reaction of the ketones 6.13-14 with Lawesson’s reagent in toluene gave the thioketones 6.15 and 6.16 in very good yields as green oils.
Scheme 3. Protection of the diols 6.11-12 and the subsequent thionation with Lawesson’s
reagent.
Transforming the ketone 6.9-10 into the corresponding hydrazones 6.19-20 was not as straightforward due to a low reactivity of the carbonyl towards
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nucleophiles such as hydrazine. Even prolonged heating at reflux in neat NH2NH2.H2O did not provide the desired product. Reaction of the ketones 6.9-10 with TBDMS-protected hydrazine33 was found to be poorly reproducible and
scale-up above 150 mg led to incomplete conversions under various conditions. The low reactivity of the carbonyl group was therefore circumvented by first transforming it into a more reactive thioketone, followed by a substitution with hydrazine at room temperature (Scheme 4). Using this method, multigram quantities of the hydrazones 6.19-20 were easily accessible.
Scheme 4. Transformation of 6.15-16 into the hydrazones 6.19-20 via thioketone
intermediates.
Subsequently, the hydrazones 6.19-20 were oxidized into the corresponding diazo-derivatives. Unlike in the synthesis of the original amphiphile 6.1, this was achieved by MnO2 at 0 °C instead of PIFA in DMF34,35 (Scheme 5). Following
the removal of MnO2 by filtration, the diazo intermediates 6.21-22 were reacted
with the thioketones 6.15-16 to give the desired episulfides 6.23-25. These improved conditions allowed for reproducible scale-up of the Barton-Kellogg coupling with no detrimental effects to the conversion or yield observed up to a gram scale. Desulphurization with PPh3 in p-xylene at reflux yielded the
overcrowded alkenes 6.26-28. Finally, the deprotection of the TBDPS protecting groups was accomplished by TBAF in THF at 0 °C and the final amphiphiles 6.1,
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Scheme 5. The Barton-Kellogg coupling followed by desulphurization and deprotection
of the silyl groups to give the final compounds 6.1, 6.3 and 6.4.
For the synthesis of the derivatives with different polar head groups such as trialkylammonium or carboxylate, the diol 6.8 was substituted with 1,4-dibromobutane or methyl 4-bromobutanoate (Scheme 6). Formation of oligo/polymeric structures was observed in the reaction with 1,4-dibromobutane. Regardless, the desired ketone 6.29 could be isolated in moderate 47 % yield. Thionation of 6.29-30 with Lawesson’s reagent provided the corresponding thioketones 6.31-32 in excellent yields. Remarkably, the ester groups of 6.30 remained intact in this transformation. In a similar vein to the preceding case, The Barton-Kellogg coupling with the diazo compound 6.21 provided the episulfides 6.33-34 in excellent yields.
Scheme 6. Synthesis of the episulfides 6.33-34 with hydrophilic halves bearing different
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Prior to desulphurization, the episulfide 6.33 was reacted with Me3N, since
reaction with PPh3 at elevated temperature would presumably result in a
concurrent formation of phosphonium salts (Scheme 7). The episulfide 6.35 could then be desulphurized with PPh3 in p-xylene at reflux to give, upon
recrystallization, the pure amphiphile 6.6.
Scheme 7. Synthesis of the trimethylammonium-substituted amphiphile 6.6.
The derivative with appending carboxylic acid moieties was synthesized in similar fashion by desulphurization of the episulfide 6.34 with PPh3 in p-xylene
(Scheme 8). The resulting ester 6.36 was hydrolyzed in an excellent yield with LiOH in a mixture of THF/MeOH/H2O. Acidification, washing of the
precipitate with acetone and trituration with MeOH provided the pure final carboxylic acid 6.5. The compound 6.5 displayed very poor solubility in all common solvents, and it was found to be soluble only in hot DMSO. Regrettably, this property precluded the use of the compound in further aggregation studies.
Scheme 8. Synthesis of the COOH-terminated amphiphile 6.5.
The chiral hydrophobic tail for the synthesis of 6.7 was synthesized starting from dodecanoyl acid by Evans methodology using oxazolidinone as the chiral auxiliary. In the first step, the oxazolidone was acylated with dodecanoyl chloride 6.37 (Scheme 9) to provide the carbamate 6.38 in excellent yield. Subsequent alkylation in the α-position provided the desired diastereomer 6.39 in >95:5 d.r. according to 1H NMR. Reductive cleavage of the chiral auxiliary
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group using NaBH4 provided the chiral alcohol 6.40 that was transformed into
the corresponding bromide 6.41 by Appel reaction in excellent yield. The chirality at the stereogenic centre was preserved throughout these two steps according to the optical rotation measurements and comparison with literature values.36
Scheme 9. Synthesis of the chiral alkyl bromide 6.41.
Employing the standard conditions, thioxanthone 6.8 was substituted with the chiral bromide 6.41 to afford the lipophilic half of the molecule bearing two stereogenic centres (Scheme 10). The ketone 6.42 was transformed into the required hydrazone 6.43 via thioketone prepared by thionation of 6.42 with Lawesson’s reagent. The diazo derivative 6.44 prepared by oxidation of 6.42 with MnO2 was immediately reacted in Barton-Kellogg coupling with
thioketone 6.15 to give the desired episulfide 6.45. Desulphurization with PPh3
in boiling p-xylene and deprotection of the silyl protecting groups provided the final chiral amphiphile 6.7 in excellent yield.
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Self-assembly studies by cryo-TEM
In order to test whether the ability to form self-assembled nanotubes has been retained for the derivatives 6.5-6.7, preliminary cryo-TEM experiments were conducted. The samples were prepared by sonicating a thin film of the amphiphile 6.5-6.7 and DOPC (1:1, 1 mg/mL) in water and subsequently the mixture was subjected to three freeze-pump-thaw cycles. Typically, this resulted in homogenous turbid solution that was then used in the cryo-TEM experiments.
The samples were deposited on a glow-discharged holy carbon coated grid (Quantifoil 3.5/1, QUNATIFOIL Micro Tools GmbH, Großlöbichau, Germany). After blottin at room temperature, the grid was rapidly frozen in liquid ethane (Vitrobot, FEI, Eindhoven, The Netherlands. The grids were observed in a Gatan model 626 cryo-stage in a Philips CM120 cryo-TEM operating at 120 keV. Images were recorded under low-dose conditions on a slow-scan CCD camera.
Figure 5. (a) Cryo-TEM image of the nanotubes generated from 6.7 and DOPC (1:1). (b)
Cryo-TEM image of the nanotubes generated from amphiphile 6.6 and DOPC (1:1). (c) Cryo-TEM image of nanotubes from 6.5 and DOPC (1:1) at pH = 10 (NaOH). Dark regions are the bilayer walls. The scale bar corresponds to 100 nm
(a) (b)
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Both amphiphiles 6.6 and 6.7 were capable of self-assembly into the rigid DOPC-capped nantubes just like the parent amphiphile 6.1 (Figure 5a and 5b, respectively). In case of the amphiphile 6.5, only very few nanotubes were observed, presumably due to a very poor solubility in all organic solvents and water (Figure 5c). The nanotubes could then be disassembled by UV (365 nm) irradiation in the same fashion as the original amphiphile. The experiments have shown that the nanotubes maintain the ability to self-assemble into defined nanotubes irrespective of the polar head group or presence of methyl groups in the lipophilic chains.
Osmosis induced loading of vesicles into soft amphiphilic
nanotubes
Osmosis-induced change in the shape of nanotube-attached vesicles has been observed for the amphiphile 6.1.32 This phenomenon proved to be a useful and
versatile method to encapsulate these vesicles into the nanotube, creating small separate compartments within the nanotube. In contrast to other studies where a shape change of vesicle formed by a synthetic amphiphile was observed upon osmotic pressure37–39, not only a change in shape of the vesicle attached to the
end of the nanotube is achieved, but in a conjunction with a geometrically restrictive environment, namely the rigid nanotube to which the vesicles is attached, a novel and unprecedented nanostructure is created. Shimizu and coworkers40 observed the formation of 1-3 µm wide tubes containing vesicles
where both the vesicles and tubes where comprised of the identical oligoglycine-based bola-amphiphile. In this case, no osmotic pressure was applied to obtain these structures, nor was a shape transformation of the vesicles to a cylindrical shape inside the microtubes observed.
In order to examine the behavior of the end-capped nanotubes under osmotic conditions, samples of end-capped nanotubes were prepared from a mixture of amphiphile 6.1 and DOPC in a ratio of 1:1 in a concentration of 1 mg/ml for each component in an aqueous 10 mM NaCl solution. To induce osmotic pressure a solution of 20 or 40 mM aq. NaCl was added in a volumetric ratio of 5:1 resulting in a final concentration of 12 or 15 mM “outside” the end-capped nanotubes. The presence of vesicles inside the nanotubes as a consequence of hyperosmotic conditions could be observed by cryo transmission electron microscopy (cryoTEM) (Figure 6c and d). The structure of the tube remains intact while an additional cylindrical bilayer structure with a bilayer distinct
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from the nanotube bilayer is found inside the nanotube. Different lengths of the cylindrical vesicles inside the nanotubes from sizes were observed, ranging from 50 nm up to several hundreds of nm. Some of the small vesicle caps still remain at the end of the nanotubes. It should be stressed that both in water and an aqueous salt solution end-capped nanotubes can be observed by cryoTEM (Figure 6b), and thus the presence of NaCl has no detrimental effect on formation of the nanotubes. Therefore, presence of salt during the formation of the nanotubes can be ruled out as a cause for the formation of vesicles inside the nanotubes. Increasing the concentration gradient (12−100 mM) between the inside and the outside of the nanotube revealed that even with increasing osmotic pressure small vesicles (below 30 nm) remained attached as caps to the end of the nanotubes. This can be attributed to the fact that the stress induced on a membrane while being deformed upon osmotic pressure due to a very high curvature of the bilayer would be too large and would not allow for the necessary shape transformation required for the small vesicle to be taken into the nanotube.41,42
Electron cryo-tomography43 was used to provide further experimental
support that the vesicles are located inside the nanotubes. A sample containing nanotubes loaded with vesicles was analyzed by electron cryo-tomography where a series of TEM images is being recorded at various tilt angles. In the region of interest (Figure 6a, marked with a circle) a nanotube with several small vesicles inside is analyzed. In the tomographic slice of the 3D reconstruction (Figure 6b) the DOPC vesicles inside the nanotube are highlighted in red whereas the nanotube bilayer is highlighted in a transparent blue (Figure 6c).44
Viewing the region of interest from a suitable angle in the 3D reconstruction (Figure 6d) shows that the vesicles are surrounded by the nanotube bilayer which demonstrates that the vesicles are indeed located inside the nanotube. If the capped vesicle was simply changing from a spherical shape into a cylindrical shape while located along the nanotube adapting to osmotic conditions, changing the viewing angle in the 3D reconstruction would readily reveal a geometry where the vesicles are located outside the nanotube.
The phenomenon is discussed, along with elucidation of the possible mechanism, in more detail in the thesis of Petra M. Erne.45
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Figure 6. (a) CryoTEM image of a sample DOPC:6.1 1:1 (1 mg/ml each) in 10 mM aq.
NaCl after addition of 200 mM aq. NaCl solution in a 5:1 ratio (v:v) with several DOPC vesicles inside the nanotube. The region of interest is marked with a circle (scale bar 200nm). (b) Tomographic slice of 3D reconstructed area obtained by electron cryo-tomography where both the nanotubes and the vesicles inside the nanotube are clearly visible. (c) Same region of the reconstructed area, the tomographic slice is visible in the background, with the enclosed vesicles surface rendered red and the nanotube surface rendered transparent blue. (d) Same region as in (b) and (c) shown in a 3D reconstruction at a different viewing angle with the same color rendering as in (c).
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Control of surface pressure in a monolayer
The amphiphile 6.3 was also investigated for formation of monolayers at the water-air interface for potential photoswitchable applications. Because of steric hindrance between the lower and upper halves, the stable isomer 6.3 preferentially adopts an anti-folded conformation with an absorption maxima at 355 nm for the π→π* transitions. The central double bond photoisomerizes when exposed to irradiation at 365 nm (Figure 7b). A noticeable decrease of the band at 355 nm with a concomitant increase of the band at 320 nm was observed under the irradiation, which corresponds to disappearance of the anti-folded isomer and formation of the unfavourable syn-folded 6.3.46 In addition, the
emission band at 480 nm disappears completely in the process (Figure 7c). Upon increasing the temperature to 5 °C, syn-folded 6.3 underwent complete thermal inversion back to the anti-folded 6.3 (Figure 7b) and a complete recovery of both the UV-vis spectrum and 1H NMR spectrum was observed. The
irradiation/thermal recovery cycle could be repeated multiple times without noticeable signs of fatigue (Figure 7b, inset).
Figure 7. (a) The conversion of anti-6.3 (blue) to syn-6.3 (red) in dichloromethane upon
irradiation at 365 nm and the thermal recovery (gray) monitored by UV/vis absorption spectroscopy. Inset: the irradiation (365 nm) of anti-6.3 for 10 min at -20 ºC followed by thermal relaxation at 5 ºC for 20 min monitored by absorption at 365 nm over 6 cycles. (b) Emission spectra during the irradiation process of anti-6.3 (λexc=365 nm) at -20 ºC.
A stable monolayer of anti-folded 6.3 was obtained by spreading a chloroform solution (0.07 mg/ml) onto the water-air interface. The surface pressure-area isotherm indicated a well-condensed monolayer with a collapse pressure of 45 mN/m for a molecular area of 70 Å/molecule (Figure 8a). First, the monolayer was compressed to 22.5 mN/m and the area was kept constant for the duration of the irradiation experiment. The compressed monolayer was sequentially exposed to UV irradiation (365 nm) for 30 sec and kept in the dark for 2 min to allow for thermal backward isomerization. Throughout each cycle, the
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configuration of 6.3 varied between an anti-folded and, syn-folded geometry, resulting first in an increase of the surface pressure by approximately 2 mN/m upon irradiation, followed by recovery of the original pressure when left standing in the dark (Figure 8c). Next, the behaviour of the Langmuir film was investigated at slightly increased initial surface pressure. Much to our surprise and contrary to the behaviour at lower pressures, in this case the UV irradiation (365 nm) led to a rapid decrease of the surface pressure, to 22.8 mN/m (Figure 8d). The pressure returned to the original value upon leaving the sample standing in the dark, with a slight fatigue observed over multiple cycles. [21b] The
fatigue was not observed at higher surface pressures (26 mN/m).
Figure 8. (a) Surface pressure versus area isotherm for a monolayer of 6.3 on the air-water
surface. (b) Absorption spectra of a monolayer of 6.3 on quartz deposited at different compressions; 23 mN/m (black) and 25 mN/m (red). (c and d) Kinetics of the anti-syn photoisomerization in monolayer of 6.3 as monitored by a surface pressure at the air-water interface at an initial molecular area of 92 Å2/molecule (c) and 101.5 Å2
Å2/molecule (d). The monolayers of the anti-folded 6.3 were compressed to a different
pressure and held at a constant area while being exposed to the radiation at 365 nm (30 s) and then left in the dark (120 s).
We have therefore shown that properly designed Langmuir films of a bis(thiaxanthylidene)-based molecule exhibits remarkable bidirectional
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response behaviour upon anti-syn folded photoisomerization which depends on the interfacial organization determined by the initial molecular density. The photoisomerization results in an increase of the surface pressure at low molecular density, while at higher molecular density, a decrease of the surface pressure is observed which can be ascribed to adopting a different, more favourable, stacking of syn-folded 6.3 under these conditions. Further insight into the behavior of 6.3 in monolayers as well as mixtures with other lipids can be found in the thesis of Jingling Cheng.47
Chirality controlled self-assembled nanotubes
After confirming that nanotubes could be formed at different ratios of 6.1 and 6.7, we studied their spectroscopic properties (vide infra, Figure 9). Self-assembled samples of pure chiral 6.7 show more scattering than those of pure achiral 6.1 (Figure 9a), indicating the formation of relatively large bundles of nanotubes, consistent with the observations by cryo-TEM (Figure 5). Plotting the absorption (λ = 303 nm) as a function of the fraction of chiral amphiphile 6.7 in the mixed nanotubes, reveals a significant increase in scattering when the fraction of 6.7 exceeds 40%, with an undulation point at 47% (calculated by fitting a sigmoidal curve; Figure 9b). Interestingly, the absorption remains nearly unchanged when increasing the fraction of chiral 6.7 from 50% to 100% (Figure 9b), which leads us to propose that a homogeneous population of bundled, shorter nanotubes is formed when chiral 6.7 is the major component, while the formation of longer, isolated nanotubes is favoured when the tubes mainly consist of achiral 6.1. This is in agreement with the observation of more bundled, shorter nanotubes for the same samples, as measured by cryo-TEM.48
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Figure 9. UV-vis absorption and CD spectra of nanotubes of 6.1 and 6.7. (a) UV-vis
absorption spectra of assemblies of pure 6.1 (solid line, 1.6·10-4 M in water) and pure 6.7
(dashed line, 1.6·10-4 M in water). (b) Absorption at λ = 303 nm as a function of the
fraction of 6.7 in co-assembled nanotubes of 6.1 and 6.7 (data was fitted to a sigmoidal curve). (c) CD spectra of nanotubes of 6.1 (solid line, 1.6·10-4 M in water) and 6.7 (dashed
line, 1.6·10-4 M in water) and a solution of 6.7 (dotted line, 2.5·10-5 M in CHCl3). (d) CD
maximum at λ = 303 nm as a function of the fraction 6.7 in co-assembled nanotubes of 6.1 and 6.7. Measurements were performed in triplo and standard error bars are shown.
We next set out to probe the induction of chirality based on the sergeant-soldier principle.49 It was found that a solution of 6.7 in CHCl3 is CD silent (Figure 9c,
dotted line), likely because the chromophore is remote from, or not influenced by, the presence of the stereogenic centers. This offers good prospects for the concept of reading and erasing chiral information.50,51 Nanotubes of achiral 6.1
are also CD silent, as expected (Figure 9c, solid line). On the other hand, CD spectroscopy shows that nanotubes of chiral amphiphile 6.7, exhibit Cotton effects with negative maxima at λ = 303, 256 and 225 nm and a positive maximum at λ = 208 nm (Figure 9c, dashed line). Subsequently, sergeant-soldier experiments were performed to investigate if a small fraction of chiral 6.7 is able to induce chirality into the otherwise achiral nanotubes of 6.1 To our delight, mixed nanotubes that mainly consist of achiral 6.1, with a small fraction of chiral
6.7 in the co-assembled aggregates, are indeed chiral (Figure 9d). Nanotubes
with less than 25% of 6.7, however, do not show any CD signal and plotting the CD maximum (λ = 303 nm) as a function of the fraction of chiral component 6.7 (Figure 9d), reveals a similar relation as between the absorption and the fraction
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of 6.7 (Figure 9b). Nanotubes in which chiral 6.7 is the major component (> 50%) show an approximately constant CD value, independent of the ratio of 6.7:6.1. In contrast to the absorption, which shows a sigmoidal relation with a sharp increase at 40% of 6.7, however, the CD signal increases when the fraction of chiral compound 6.7 exceeds 25% and reaches a maximum at 35%, after which it decreases and reaches a constant value. Above a fraction of 50% of 6.7, the nanotubes appear to be homogeneous and no differences could be observed for tubes that consist of 50–100% of 6.7 (Figure 9d).
Cryo-TEM showed that the mixed nanotubes are micrometers long (Figure 10) until 6.7 becomes the major component (> 50%) and it was hypothesized that mixtures of the amphiphiles, containing less than 50% 6.7, lead to the formation of long, chiral nanotubes (Figure 10), which causes a sharp increase in CD signal after exceeding a threshold of 20% 6.7 (Figure 9d). In the long nanotubes, the CD signal is more pronounced than in the short nanotubes. Apparently, the long nanotubes have a higher preference for the absorption of light of one handedness over the other, compared to the shorter nanotubes, which leads to a maximum value for the CD signal at 35% of 6.7. When 6.7 is the major component (> 50%) in the mixed tubes, both the UV-vis absorption (Figure 9b) and CD spectra (Figure 9d) become nearly constant, indicating that further increasing the fraction of chiral component 6.7 in the mixed nanotubes does not result in different self-assembled structures.
The ratio of chiral to achiral amphiphile provides a handle to control the dimensions of the self-assembled nanotubes and, importantly, the chirality of the molecular constituent can be amplified to the aggregates as a whole. In addition, the nanotubes can be disassembled48 with light and this responsive
feature offers another control element toward smart materials.
Conclusions
In conclusion, a series of different amphiphiles possessing various polar head groups and both lipophilic and hydrophilic chains have been synthesized. Based on cryo-TEM experiments, the amphiphiles 6.1 and 6.3‒6.7 retained the ability to form uniform, thin-walled nanotubes upon self-assembly in water.
The chiral amphiphile 6.7 was found to form chiral nanotubes as evidenced by CD spectra and could be used as a dopant with amphiphile 6.1 in chirality
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amplification experiments. The co-assemblies with 6.1 display nonlinear dependence of the CD with an optimum around 40% of the chiral amphiphile
6.7.
The amphiphile 6.3 was applied to photochemically control surface tension in Langmuir-Blodgett film on water-air interface. Osmosis induced loading of vesicles into the amphiphilic nanotubes prepared from amphiphile 6.1 was also observed.
The presented system based on the bisthioxanthylidene core unit retains the ability to self-assemble into uniform thin-walled nanotubes regardless of the length and nature of the hydrophilic and hydrophobic chains. It constitutes a versatile platform for development of responsive supramolecular systems and advanced materials.
Acknowledgment
Petra M. M. Erne, Marc C. A. Stuart, Laura S. van Bezouwen and Derk Jan van Dijken are acknowledged for performing the TEM and electron cryo-tomography experiments. Jinling Cheng performed the surface tension experiments described in this chapter and her contribution is gratefully appreciated.
Experimental section
General remarks
For general remarks regarding synthesis, characterization and experimental details see Chapter 2. All photochemical experiments were carried out using a Spectroline model ENB-280C/FE lamp at λ = 365 ± 30 nm. CD spectra were recorded on a JASCO J-715 spectropolarimeter and UV-vis measurements were performed on a Agilent 8453 UV-vis spectrometer.
cryoTEM: Samples for cryo-TEM were prepared by depositing typically 3 μL of
nanotube solution on holey carbon coated grids (Quantifoil 3.5/1, Quantifoil Micro Tools, Jena, Germany). After blotting the excess liquid at constant humidity of 100%, the grids were vitrified in liquid ethane (Vitrobot, FEI, Eindhoven, The Netherlands) and transferred to either a Philips CM 12 cryo-electron microscope operating at 120 kV, a Philips CM 120 cryo-cryo-electron
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microscope operating at 120 kV or a FEI Tecnai 20 microscope operating at 200kV. Micrographs were recorded under low-dose conditions with a slow-scan CCD camera.
Standard method for nanotube formation.44 A stock solution of amphiphiles in
chloroform was mixed with the desired amount of a stock solution of DOPC in chloroform and subsequently dried under nitrogen gas resulting in the formation of a thin film. After further solvent removal under high vacuum for 15 min, the sample was hydrated with aqueous 10 mM NaCl solution and the suspension was subjected to three freeze-thaw cycles. The concentration of amphiphiles was 1 mg/ml with an additional 1 mg/ml of DOPC.
Sergeant-soldier experiments: The amphiphiles and DOPC were dissolved in
chloroform and a thin layer was formed on the walls of a glass vial by flowing N2 over the sample, while rotating the vial. The resulting thin film was
rehydrated with water to give a total concentration of 1 mg/mL. The resulting suspension was subsequently subjected to five freeze-thaw cycles in liquid nitrogen and a water bath (40 °C), respectively, upon which a homogeneous, turbid solution was obtained
For the details on surface pressure measurements, see the thesis of Jinling Cheng.47
Synthesis of the amphiphiles
4,5-Bis(dodecyloxy)-9H-thioxanthen-9-one (6.9).
A mixture of 6.832 (7.52 g, 31 mmol), 1-bromododecane
(19.22 ml, 80 mmol), and K2CO3 (21.27 g, 154 mmol) in DMF
(150 mL) was heated at 100 °C for 36 h. The reaction was quenched with water (350 mL) and dichloromethane was
added (400 mL). The organic phase was separated and washed with water (4 x 400 mL). The solvents were evaporated at reduced pressure and the residue was recrystallized from ethanol (100 mL) to give the title product 6.9. Yield: 15.7 g (88%); yellow solid, mp 78.1‒79.2 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.24 (dd, 2H, J1 = 8.1 Hz, J2 = 0.9 Hz), 7.42 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 7.13 (d, 2H, J = 7.9 Hz), 4.19 (t, 4H, J = 6.5 Hz), 1.95 (m, 4H), 1.59 (m, 4H), 1.27 (m, 32H), 0.88 (t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 180.7, 154.6, 130.2, 128.7, 126.0, 121.5, 113.3, 69.7, 32.1, 29.9, 29.9, 29.88, 29.87, 29.6, 29.58, 29.3, 26.3, 22.9, 14.3.
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(4,5-Bis(dodecyloxy)-9H-thioxanthen-9-ylidene)hydrazine (6.19).
A mixture of 6.9 (11.6 g, 20.0 mmol) and Lawesson's reagent (15.0 g, 37.1 mmol) in toluene (250 mL) was heated at reflux under nitrogen atmosphere for 2 h. The resulting yellow solution was cooled to ambient temperature and filtered through a plug of silica gel (2 cm high). The plug was washed
with dichloromethane until the filtrate was colorless. The solvents were evaporated and the residue The volatiles were removed at reduced pressure and the residue was purified by flash column chromatography on silica gel (pentane : ethyl acetate - 10 : 1). The thioketone was redissolved in THF (150 mL). The solution was treated at room temperature with aq. hydrazine (40.0 ml, 70.0 mmol, 40%). The solution decolorized to an orange solution within several minutes. The solvent and excess hydrazine were removed at reduced pressure. The resulting solid was recrystallized from ethanol (100 mL) to give the title compound 6.19. Yield: 15.7 g (88%); yellow solid, mp 81.2‒82.7 °C. 1H NMR (400
MHz, CDCl3): δ (ppm) 7.64 (dd, 1H, J1 = 7.9 Hz, J2 = 0.9 Hz), 7.43 (dd, 2H, J1 = 7.9 Hz, J2 = 1.0 Hz), 7.28 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 7.24 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 6.89 (dd, 2H, J1 = 8.1 Hz, J2 = 0.8 Hz), 6.83 (dd, 2H, J1 = 8.1 Hz, J2 = 1.0 Hz), 5.84 (brs, 2H), 4.10 (m, 4H), 1.90 (m, 4H), 1.54 (m, 4H), 1.26 (m, 32H), 0.89 (t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 155.9, 154.3, 142.0, 135.3, 127.0, 126.7, 125.7, 121.8, 120.1, 118.4, 111.2, 110.2, 69.4, 32.2, 29.9, 29.6, 29.4, 26.3, 22.9, 14.4. 4,5-Bis(octadecyloxy)-9H-thioxanthen-9-one (6.10).
A mixture of 6.8 (500 mg, 2.05 mmol), 1-bromooctadecane (1.84 g, 5.53 mmol) and K2CO3 (1.414 g, 10.2 mmol) in DMF
(10 mL) was heated at 100 °C for 16 h. The DMF was evaporated at reduced pressure. Hot chloroform was added
(90 mL) and the residue dissolved. Water (40 mL) was added to the mixture and the organic phase separated. The solvents were evaporated at reduced pressure and the residue was recrystallized from ethanol (40 mL) to give the title compound 6.10. Yield: 1.40 g (91%); light yellow solid, mp 93.1‒94.2 °C. 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.24 (d, 2H, J = 8.1 Hz), 7.42 (dd, 2H, J1 = 8.0 Hz, J2 =
8.0 Hz), 7.13 (d, 2H, J= 7.9 Hz), 4.19 (t, 4H, J = 6.4 Hz), 1.95 (m, 4H), 1.59 (m, 4H), 1.26 (m, 64H), 0.89 (t, 6H, J = 6.7 Hz).13C NMR (100 MHz, CDCl3): δ (ppm) 180.7,
154.6, 130.2, 128.6, 126.0, 121.5, 113.3, 69.7, 32.2, 29.9, 29.89, 29.6, 29.3, 26.3, 22.9, 14.4. HRMS (APCI+): calcd for C49H81O3S [M + H+] 749.5906 found 749.5886.
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(4,5-Bis(octadecyloxy)-9H-thioxanthen-9-ylidene)hydrazine(6.20).A mixture of 6.10 (800 mg, 1.07 mmol) and Lawesson's reagent (648 mg, 1.60 mmol) in toluene (30 mL) was heated at reflux under nitrogen atmosphere for 2 h. The resulting yellow solution was cooled to ambient temperature and filtered through a plug of silica gel (2 cm high). The plug was
washed with CH2Cl2 until the filtrate was colorless. The solvents were
evaporated and the residue was redissolved in THF (40 mL). The solution was treated at room temperature with aq. hydrazine (2.0 ml, 25.5 mmol, 40%). The solution decolorized to orange solution within several minutes. The solvent and excess hydrazine were removed at reduced pressure. The resulting solid was recrystallized from ethanol (20 mL) to give the title compound 6.20. Yield: 647 mg (79%); yellow solid, mp 87.2‒88.8 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.62 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 7.8 Hz), 7.25 (m, 2H), 6.87 (d, 1H, J = 8.1 Hz), 6.81 (d, 1H, J = 8.0 Hz), 5.83 (brs, 2H), 4.07 (m, 4H), 1.88 (m, 4H), 1.54 (m, 4H), 1.26 (m, 64H), 0.88 (t, 6H, J = 6.8 Hz).13C NMR (100 MHz, CDCl3): δ (ppm) 155.9, 154.3, 141.0, 135.3, 127.0, 126.7, 125.7, 125.4, 121.8, 120.1, 118.4, 111.2, 110.2, 69.4, 69.3, 32.2, 30.0, 29.9, 29.89, 29.6, 29.6, 29.4, 29.36, 26.3, 26.3, 22.9, 14.3. HRMS (APCI+): calcd for C49H83N2O2S [M+H+] 763.6170 found 763.6159.
4,5-Bis(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-9H-thioxanthen-9-one (6.12).
A mixture of 6.8 (300 mg, 1.23 mmol), tetraethylene glycol p-toluenesulfonate (1.11 g, 3.19 mmol) and K2CO3 (849 mg, 6.14 mmol) in acetone (30 mL) was
heated at reflux for 24 h. The acetone was evaporated
under reduced pressure. Water (50 mL) and CH2Cl2 (100 mL) were added. The
water phase was washed with CH2Cl2 (2 x 50 mL). The solvents were evaporated
at reduced pressure and the residue was purified by column chromatography (ethyl acetate : methanol - 20 : 1) to give the compound 6.12. Yield: 645 mg (88%); yellow oil.. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.24 (d, 2H, J = 8.3 Hz),
7.42 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 7.18 (d, 2H, J = 7.9 Hz), 4.37 (m,4H), 4.00
(m, 4H), 3.82 (m, 4H), 3.57-3.83 (m, 20H). 13C NMR (100 MHz, CDCl3): δ (ppm)
180.4, 154.3, 130.0, 128.1, 126.1, 122.0, 113.9, 72.7, 71.3, 70.83, 70.81, 70.5, 69.7, 69.4, 61.8. HRMS (APCI+): calcd for C29H40O11S [M+H+] 597.2370 found 597.2364.
180 |
4,5-Bis((2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl)oxy)-9H-thioxanthen-9-one (6.14).
A mixture of 6.12 (600 mg, 1.01 mmol), TBDPSCl (1.19 g, 4.32 mmol) and imidazole (288 mg, 4.22 mmol) in dichloromethane (30 mL) was stirred for 24 h. The The reaction mixture
was filtered over Celite. The solvents were evaporated at reduced pressure and the residue was purified by column chromatography (pentane : ethyl acetate - 7 : 3) to give the compound 6.14. Yield: 930 mg (86%); yellow oil. 1H NMR (400
MHz, CDCl3): δ (ppm) 8.28 (dd, 2H, J1 = 8.1 Hz, J2 = 0.9 Hz), 7.71 (dd, 8H, J1 = 7.7
Hz, J2 = 1.8 Hz), 7.37-7.44 (m, 14H), 7.18 (dd, 2H, J1 = 8.0 Hz, J2 = 0.8), 4.35 (t, 4H, J = 4.9 Hz), 3.99 (t, 4H, J = 4.9 Hz), 3.83 (m, 8H), 3.72 (m, 4H), 3.68 (s, 8H), 3.62 (t, 4H, J = 5.3 Hz), 1.08 (s, 18H).13C NMR (100 MHz, CDCl3): δ (ppm) 180.3, 154.3,
135.7, 133.8, 130.1, 129.7, 128.4, 127.7, 126.0, 121.9, 113.9, 72.6, 71.2, 70.9, 70.9, 69.7, 69.3, 63.5, 27.0, 19.3. HRMS (APCI+): calcd for C61H77O11SSi2 [M + H+]
1073.4725 found 1073.4729.
4,5-Bis((2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl)oxy)-9H-thioxanthene-9-thione (6.16).
A solution of 6.14 (530 mg, 0.49 mmol) and Lawesson’s reagent (300 mg, 0.74 mmol) in toluene (30 mL) was heated at 130 °C for 2 h. The solvents were evaporated at reduced
pressure and the residue purified by column chromatography (pentane : ethyl acetate ‒ 1 : 1) to give the product 6.16. Yield: 511 mg (95%); dark yellow oil. 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.67 (dd, 2H, J1 = 8.4 Hz, J2 = 0.9 Hz), 7.68 (dd,
8H, J1 = 7.8 Hz, J2 = 1.6 Hz), 7.37-7.42 (m, 14H), 7.15 (dd, 2H, J1 = 7.9 Hz, J2 = 0.8),
4.35 (t, 4H, J = 5.0 Hz), 3.98 (t, 4H, J = 5.0 Hz), 3.81 (m, 8H), 3.69 (m, 4H), 3.64 (s, 8H), 3.59 (t, 4H, J = 5.3 Hz), 1.05 (s, 18H). 13C NMR (100 MHz, CDCl3): δ (ppm)
210.9, 154.4, 138.5, 135.8, 133.8, 129.8, 127.8, 126.5, 125.8, 123.8, 113.0, 72.6, 71.3, 70.9, 70.9, 70.88, 69.7, 69.6, 63.6, 27.0, 19.4. HRMS (APCI+): calcd for C61H77O10S2Si2 [M + H+] 1089.4497 found 1089.4499.
| 181
Episulfide(6.24).Solid MnO2 (203 mg, 2.34 mmol) was added to
a solution of 6.19 (167 mg, 0.28 mmol) in THF (40 mL) at 0 °C. The resulting solution was stirred for 1 h at 0 °C and filtered through a plug of silica gel. The silica gel pad was washed with a small amount of THF (10 mL). The light green solution was cooled back to 0 °C.
A solution of 6.16 (255 mg, 0.23 mmol) in THF (2.4 mL) was added dropwise and the resulting mixture was stirred overnight. The solvents were evaporated at reduced pressure and the residue purified by flash column chromatography (pentane : ethyl acetate – 3 : 1) to give the title product 6.24. Yield: 315 mg (81%); light yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.72 (dd, 8H, J1 = 7.7 Hz, J2
= 1.7 Hz), 7.33-7.42 (m, 12H), 7.33 (dd, 2H, J1 = 7.9 Hz, J2 = 0.8 Hz),7.29 (dd, 2H, J1 = 7.9 Hz, J2 = 0.8 Hz), 6.87 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 6.86 (dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 6.58 (dd, 2H, J1 = 8.1 Hz, J2 = 0.8 Hz), 6.53 (dd, 2H, J1 = 8.1 Hz, J2 = 0.7 Hz), 4.08 (m 2H), 3.91-4.03 (m, 4H), 3.57-3.83 (m, 30H), 1.79 (m, 4H), 1.49 (m, 4H), 1.29 (m, 32H), 1.08 (s, 18H), 0.91 (t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 154.0, 153.8, 135.8, 133.9, 132.5, 132.0, 129.8, 127.8, 125.9, 125.6, 125.1, 125.0, 124.0, 123.3, 111.6, 110.3, 72.6, 71.1, 70.88, 70.87, 70.84, 69.7, 69.5, 69.4, 66.64, 66.61, 63.6, 32.1, 29.9, 29.87, 29.86, 29.7, 29.6, 29.4, 27.0, 26.2, 22.9, 19.4, 14.3. HRMS (APCI+): calcd for C98H132O12S3Si2Na [M + Na+] 1676.8351 found
1676.8345.
15,15'-((4',5'-Bis(dodecyloxy)-[9,9'-bithioxanthenylidene]-4,5- diyl)bis(oxy))bis(2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecane)(6.27).
PPh3 (149 mg, 0.57 mmol) was added to a
solution of 6.24 (313 mg, 0.19 mmol) in toluene (30 mL). The resulting mixture was heated at 100 °C overnight. The solvents were evaporated at reduced pressure and the residue purified by flash column chromatography (pentane : ethyl
acetate ‒ 3 : 1) to give the title product 6.27. Yield: 264 mg (86%); light yellow solid, mp 62.8‒63.6 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.68 (dd, 8H, J1 = 7.5
Hz, J2 = 1.6 Hz), 7.33-7.44 (m, 12H), 6.80 (m, 4H), 6.65 (m, 4H), 6.42 (d, 2H, J =
7.8 Hz), 6.39 (d, 2H, J = 7.8 Hz), 4.28 (m 2H), 4.14 (m, 4H), 3.93-4.02 (m, 6H), 3.81 (m, 8H), 3.71 (m, 4H), 3.65 (m, 8H), 3.60 (t, 4H, J = 5.4 Hz), 1.90 (m, 4H), 1.57 (m,
182 |
4H), 1.28 (m, 32H), 1.05 (s, 18H), 0.89 (t, 6H, J = 6.7 Hz). 13C NMR (100 MHz,
CDCl3): δ (ppm) 155.3, 155.0, 137.0, 136.5, 135.7, 133.8, 133.2, 132.8, 129.7, 127.8,
125.9, 125.8, 124.9, 124.8, 122.7, 122.2, 109.5, 109.2, 72.6, 71.2, 70.9, 70.89, 70.86, 69.8, 69.1, 68.8, 63.6, 32.1, 29.9, 29.8, 29.83, 29.82, 29.7, 29.5, 29.4, 27.0, 26.3, 22.8, 19.3, 14.3. HRMS (APCI+): calcd for C98H132O12S2Si2Na [M + Na+] 1644.8630
found 1644.8625.
2,2'-((((((((4',5'-Bis(dodecyloxy)-[9,9'-bithioxanthenylidene]-4,5- diyl)bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))diethanol (6.3).
A solution of 6.27 (75 mg, 0.05 mmol) in THF (5 mL) was treated dropwise with TBAF (102 l, 0.10 mmol, 1M in THF). After 24 h of stirring, the solvents were evaporated at reduced pressure and the residue purified by flash column chromatography (CH2Cl2 :
methanol ‒ 10 : 1) to give the title product 6.3. Yield:
48 mg (91%); white solid, mp 96.3‒97.4 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.83 (dd, 2H, J1 = 8.0 Hz, J2 = 7.9 Hz), 6.82 (dd, 2H, J1 = 7.9 Hz, J2 = 7.9 Hz), 6.67 (m, 4H), 6.44 (dd, 2H, J1 = 7.7 Hz, J2 = 0.6), 6.39 (dd, 2H, J1 = 7.8 Hz, J2 = 0.7), 4.32 (m 2H), 4.11-4.20 (m, 4H), 3.93-4.05 (m, 6H), 3.89 (t, 4H, J = 4.6 Hz), 3.65-3.78 (m, 16H), 3.60 (t, 4H, J = 4.4 Hz), 3.06 (brs, 2H), 1.91 (m, 4H), 1.59 (m, 4H), 1.28 (m, 32H), 0.89 (t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 155.4, 155.0, 137.1, 136.5, 133.4, 132.8, 126.0, 125.8, 125.0, 124.8, 122.8, 122.2, 109.5, 109.3, 72.8, 71.3, 70.9, 70.8, 70.5, 69.8, 69.2, 68.9, 61.9, 32.1, 29.93, 29.89, 29.88, 29.87, 29.7, 29.6, 29.5, 26.3, 22.9, 14.3. HRMS (APCI+): calcd for C66H96O12S2 [M + Na+] 1167.6241
found 1167.6235.
Episulfide (6.25).
Solid MnO2 (203 mg, 2.34 mmol) was added to a
solution of 6.20 (214 mg, 0.28 mmol) in THF (50 mL) at 0 °C. The resulting solution was stirred for 1 h at 0 °C and filtered through a plug of silica gel. The pad was washed with a small amount of THF (10 mL). The light green solution was cooled back to 0 °C. A solution of
6.16 (255 mg, 0.23 mmol) in THF (2.4 mL) was added dropwise and the resulting
mixture was stirred overnight. The solvents were evaporated at reduced pressure and the residue purified by flash column chromatography (pentane :
| 183
ethyl acetate ‒ 3 : 1) to give the title product 6.25. Yield: 321 mg (70%); light yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.67 (dd, 8H, J1 = 7.5 Hz, J2 = 1.4 Hz), 7.33-7.39 (m, 12H), 7.30 (d, 2H, J = 7.9 Hz), 7.25 (d, 2H, J = 7.9 Hz), 6.84 (dd, 2H, J1 = 8.0 Hz, J2 = 7.9 Hz), 6.82 (dd, 2H, J1 = 8.0 Hz, J2 = 7.9 Hz), 6.54 (d, 2H, J = 8.1 Hz), 6.49 (d, 2H, J = 8.1 Hz), 4.06 (m 2H), 3.91-3.98 (m, 4H), 3.57-3.82 (m, 30H), 1.75 (m, 4H), 1.44 (m, 4H), 1.25 (m, 56H), 1.05 (s, 18H), 0.88 (t, 6H, J = 6.7 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 154.1, 153.8, 135.8, 133.9, 132.6, 132.1, 129.8, 127.8, 126.0, 125.6, 125.1, 125.0, 124.0, 123.3, 111.6, 110.3, 72.6, 71.1, 70.9, 70.89, 70.86, 69.7, 69.5, 69.4, 66.7, 66.6, 63.6, 32.1, 29.96, 29.93, 29.89, 29.87, 29.7, 29.6, 29.4, 27.0, 26.2, 22.9, 19.4, 14.3. HRMS (APCI+): calcd for C110H156O12S3Si2Na
[M + Na+] 1845.0229 found 1845.0223.
15,15'-((4',5'-Bis(octadecyloxy)-[9,9'-bithioxanthenylidene]-4,5- diyl)bis(oxy))bis(2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecane) (6.28).
PPh3 (134 mg, 0.51 mmol) was added to a
solution of 6.25 (310 mg, 0.17 mmol) in toluene (30 mL). The resulting mixture was heated at 100 °C overnight. The solvents were evaporated at reduced pressure and the residue purified by flash column
chromatography (pentane : ethyl acetate – 3 : 1) to give the title product 6.28. Yield: 241 mg (79%); light yellow solid, mp 82.6‒83.4 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.67 (d, 8H, J = 6.9 Hz), 7.38-7.44 (m, 12H), 6.84 (m, 4H), 6.70 (m, 4H), 6.47 (d, 2H, J = 7.7 Hz), 6.43 (d, 2H, J = 7.8 Hz), 4.33 (m 2H), 4.20 (m, 4H), 3.93-4.07 (m, 6H), 3.85 (m, 8H), 3.75 (m, 4H), 3.70 (m, 8H), 3.64 (t, 4H, J = 5.3 Hz), 1.96 (m, 4H), 1.62 (m, 4H), 1.31 (m, 56H), 1.09 (s, 18H), 0.93 (t, 6H, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 155.3, 155.1, 137.0, 136.5, 135.7, 133.8, 133.3, 132.8, 129.8, 127.8, 125.9, 125.8, 125.0, 124.9, 122.7, 122.3, 109.6, 109.3, 72.6, 71.3, 71.9, 70.91, 70.89, 69.8, 69.1, 68.8, 63.6, 32.1, 29.93, 29.90, 29.87, 29.85, 29.7, 29.55, 29.49, 27.0, 26.3, 22.9, 19.4, 14.3. HRMS (APCI+): calcd for C110H156O12S2Si2Na [M
184 |
2,2'-((((((((4',5'-Bis(octadecyloxy)-[9,9'-bithioxanthenylidene]-4,5- diyl)bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))diethanol (6.4).
A solution of 6.28 (75 mg, 0.04 mmol) in THF (5 mL) was treated dropwise with TBAF (92 l, 0.09 mmol, 1M in THF). After 24 h of stirring, the solvents were evaporated at reduced pressure and the residue purified by flash column chromatography (dichloromethane : methanol ‒ 10 : 1) to give 6.4. Yield:
48 mg (88%); white solid, mp 129.5‒131.0 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.83 (dd, 2H, J1 = 7.9 Hz, J2 = 7.9 Hz), 6.82 (dd, 2H, J1 = 7.9 Hz, J2 = 7.9 Hz), 6.68 (d, 2H, J = 8.7 Hz), 6.65 (d, 2H, J = 8.4 Hz), 6.44 (d, 2H, J = 7.8 Hz), 6.39 (d, 2H, J = 7.8 Hz), 4.32 (m 2H), 4.11-4.22 (m, 4H), 3.95-4.05 (m, 6H), 3.89 (t, 4H, J = 4.7 Hz), 3.65-3.78 (m, 16H), 3.61 (t, 4H, J = 4.6 Hz), 2.92 (brs, 2H), 1.92 (m, 4H), 1.59 (m, 4H), 1.27 (m, 56H), 0.89 (t, 6H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 155.4, 155.0, 137.1, 136.5, 133.4, 132.8, 126.0, 125.8, 125.0, 124.8, 122.8, 122.2, 109.5, 109.3, 72.8, 71.3, 70.91, 70.86, 70.6, 69.9, 69.2, 68.9, 61.9, 32.1, 29.9, 29.92, 29.89, 29.87, 29.7, 29.6, 29.5, 26.3, 22.9, 14.3. HRMS (APCI+): calcd for C78H120O12S2Na [M + Na+] 1335.8119 found 1335.8113.
(S)-4-Benzyl-3-dodecanoyloxazolidin-2-one (6.38):
A solution of (S)-4-benzyloxazolidin-2-one (3.20 g, 18.1 mmol, 1.0 equiv) in THF (100 mL) at -78 °C was treated dropwise with n-BuLi (12.4 ml, 19.9 mmol, 1.1 equiv) to give a colored light yellow solution. After 15 min, dodecanoyl chloride (4.54 g, 20.8 mmol,
1.2 equiv) was added. The resulting mixture was left to warm to room temperature over 1 h. The reaction was quenched by addition of 1 M aq. NH4Cl
(100 mL). Diethylether (100 mL) was added and the layers separated. The water phase was washed with diethylether (100 mL) and the combined organic phase was dried over Na2SO4. The solvent was evaporated under reduced pressure
and the residue purified by flash column chromatography (SiO2, n-pentane :
EtOAc ‒ 15 : 1) to give 6.38 as a white solid (6.24 g, 17.4 mmol, 96%). m.p. 46 – 47 °C; 1H NMR (300 MHz, CDCl3): δ = 7.26 – 7.33 (m, 3H), 7.21 (d, J = 7.2 Hz, 2H),
7.13 (d, J = 7.9 Hz, 2H), 4.68 (m, 1H), 4.18 (m, 2H), 3.30 (dd, J = 13.3, 3.1 Hz, 1H), 2.93 (m, 2H), 2.77 (dd, J = 13.3, 9.6 Hz, 1H), 1.69 (m, 2H), 1.27 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 173.6, 153.7, 135.5, 129.6,
| 185
ppm. Data is in accordance with literature.
(S)-4-Benzyl-3-((S)-2-methyldodecanoyl)oxazolidin-2-one (6.39):
A solution of 6.38 (6.20 g, 17.3 mmol, 1.0 equiv) in THF (150 mL) at -78 °C was treated with NaHMDS (22.4 mL, 22.4 mmol, 1.3 equiv, 1 M in THF) to give a light yellow colored solution. After 30 min, MeI (5.40 mL, 86.0 mmol, 5.0 equiv) was added and the resulting mixture was stirred at -78 °C for 30 min and then left
to warm to room temperature over 1.5 h. The reaction was quenched with 1 M aq. NH4Cl (100 mL) and the mixture was extracted with diethylether (2× 100
mL). The combined organic phase was dried with Na2SO4 and the solvents
evaporated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane : EtOAc ‒ 30 : 1 to 10 : 1) to yield 6.39 as a
colorless oil (4.54 g, 12.3 mmol, 71%, > 95% d.e. as determined by 1H NMR). 1H
NMR (300 MHz, CDCl3): δ = 7.26 – 7.33 (m, 3H), 7.21 (d, J = 7.2 Hz, 2H), 7.13 (d, J
= 7.9 Hz, 2H), 4.67 (m, 1H), 4.19 (m, 2H), 3.70 (m, 1H), 3.27 (dd, J1 = 3.3, 3.2 Hz,
1H), 2.93 (m, 1H), 2.77 (dd, J = 13.3, 9.6 Hz, 1H), 1.73 (m, 1H), 1.42 (m, 1H), 1.27 (m, 19H), 0.88 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 177.6,
153.3, 135.5, 129.6, 129.1, 127.5, 66.2, 55.6, 38.1, 37.9, 33.6, 32.1, 29.9, 29.8, 29.7, 29.5, 27.5, 22.9, 17.6, 14.3 ppm. Data is in accordance with literature.
(S)-2-Methyldodecan-1-ol (6.40).
To a solution of 6.39 (4.20 g, 11.2 mmol, 1.0 equiv) in THF (150 mL) at 0 °C, NaBH4 (735 mg, 33.7 mmol, 3.0 equiv) was added in
portions. After stirring for 2 h, the reaction was quenched with 1 M aq. Rochelle’s salt (100 mL) and extracted with diethylether (2 × 100 mL). The combined organic phase was dried over Na2SO4 and the solvents evaporated
under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane : EtOAc ‒ 10 : 1) to yield 6.40 as a colorless oil
(2.06 g, 10.2 mmol, 91%). []D = 7.8 (c 0.051, CHCl3); 1H NMR (300 MHz,
CDCl3): δ = 3.52 (dd, J = 10.5, 5.8 Hz, 1H), 3.42 (dd, J = 10.5, 6.6 Hz, 1H), 1.61 (m,
1H), 1.27 (m, 18H), 1.11 (m, 1H), 0.88 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (75.4
MHz, CDCl3): δ = 68.7, 36.0, 33.4, 32.1, 30.2, 29.9, 29.87, 29.86, 29.6, 27.2, 22.9,
16.8, 14.4 ppm. Data is in accordance with literature.
(S)-1-Bromo-2-methyldodecane (6.41):
To a solution of 6.40 (2.00 g, 10.0 mmol, 1.0 equiv) and CBr4 (3.97 g,
186 |
12.0 mmol, 1.2 equiv) was added in portions. The resulting solution was stirred for 2 h. Water (80 mL) was added and the layers were separated. The water phase was extracted with CH2Cl2 (80 mL). The combined organic extracts were
dried over Na2SO4, the solvents evaporated under reduced pressure and the
residue purified by flash column chromatography (SiO2, n-hexane) to yield 6.41
as a colorless oil (2.61 g, 9.90 mmol, 99%), []D = 0.27(c 0.407, CHCl3); 1H NMR
(300 MHz, CDCl3): δ = 3.41 (dd, J = 9.8, 4.9 Hz, 1H), 3.42 (dd, J = 9.8, 6.2 Hz, 1H),
1.78 (m, 1H), 1.44 (m, 1H), 1.27 (m, 16H), 1.02 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 41.9, 35.4, 35.1, 32.1, 29.9, 29.85,
29.81, 29.6, 27.1, 22.9, 19.0, 14.3 ppm. Data is in accordance with literature.
4,5-Bis(((S)-2-methyldodecyl)oxy)-9H-thioxanthen-9-one (6.42):
A mixture of 6.8 (0.93 g, 3.8 mmol, 1.0 equiv), 6.41 (2.6 g, 9.9 mmol, 2.6 equiv) and K2CO3 (2.6 g, 19 mmol, 5.0 equiv)
in DMF (20 mL) was heated to 100 °C for 24 h. The DMF was evaporated under reduced pressure and water (80 mL) and CH2Cl2 (150 mL) were added to the residue. The
organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane : EtOAc
‒ 10 : 1) to yield 6.42 as a yellow solid (2.1 g, 3.5 mmol, 91%). m.p. 63 – 64 °C; 1H
NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 7.6, 1.7 Hz, 8H), 7.32 – 7.40 (m, 12H), 7.30 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.83 (dd, J = 8.0, 8.0 Hz, 2H), 6.82 (dd, J = 8.0, 8.0 Hz, 2H), 6.55 (d, J = 8.1 Hz, 2H), 6.48 (d, J = 8.1 Hz, 2H), 4.04 (m 2H), 3.96 (m, 2H), 3.48 – 3.86 (m, 24H), 1.90 (m, 2H), 1.43 – 1.52 (m, 2H), 1.27 (m, 32H), 1.05 (m, 21H), 1.00 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 180.4, 154.5, 130.0, 128.6, 125.8, 121.2, 112.9, 74.3, 33.5, 33.3, 31.9, 30.0, 29.7, 29.68, 29.4, 27.0, 22.7, 17.1, 14.1 ppm; HRMS-APCI+ m/z calculated for C39H61O3S [M + H]+ 609.4341, found 609.4336.
(4,5-Bis(((S)-2-methyldodecyl)oxy)-9H-thioxanthen-9-ylidene)hydrazine (6.43):
A mixture of 6.42 (800 mg, 1.31 mmol, 1.0 equiv) and Lawesson's reagent (797 mg, 1.97 mmol, 1.5 equiv) in toluene (40 mL) was heated at reflux under nitrogen atmosphere for 2 h. The resulting yellow solution was cooled to room temperature and filtered through a plug of silica gel. The plug
| 187
evaporated and the residue was redissolved in THF (30 mL). The solution was treated with aq. 40% hydrazine (1.60 ml, 25.5 mmol, 19 equiv) at room temperature. The solution decolorized within several min. The solvent and excess hydrazine were removed under reduced pressure. The residue was purified by flash column chromatography (SiO2, n-pentane : EtOAc ‒ 10 : 1) to
yield 6.43 as a yellow oil (681 mg, 1.09 mmol, 83%). 1H NMR (300 MHz, CDCl3):
δ = 7.64 (dd, J = 7.9, 0.9 Hz, 1H), 7.44 (dd, J = 7.9, 0.9 Hz, 1H), 7.28 (dd, J = 8.0, 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 8.0 Hz, 1H), 6.88 (dd, J = 8.1, 0.8 Hz, 1H), 6.82 (dd, J = 8.1, 1.0 Hz, 1H), 5.85 (br s, 2H), 3.96 (m, 2H), 3.85 (m, 2H), 2.06 (m, 2H), 1.62 (m, 2H), 1.27 (m, 32H), 1.14 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H), 0.89 (t, J = 6.8 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 155.9, 154.4, 142.0, 135.2, 126.9, 126.6, 125.6, 125.6, 121.9, 120.0, 118.3, 111.0, 110.0, 74.2, 74.2, 33.7, 33.68, 33.5, 32.1, 30.2, 30.17, 29.9, 29.89, 29.6, 27.3, 27.26, 22.9, 17.4, 14.3 ppm; HRMS-APCI+ m/z calculated for C39H63N2O2S [M + H]+ 623.4610, found 623.4605.
Episulfide (6.45):
Solid MnO2 (347 mg, 4.00 mmol, 10 equiv) was
added to a solution of 6.43 (299 mg, 0.480 mmol, 1.2 equiv) in THF (50 mL) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C and filtered through a plug of silica gel. The plug was washed with a small amount of THF (10 mL). The light green solution was cooled back to 0 °C.
A solution of 6.15 (400 mg, 0.400 mmol, 1.0 equiv) in THF (2.4 mL) was added dropwise and the resulting mixture was stirred overnight. The solvents were evaporated under reduced pressure and the residue purified by flash column chromatography (SiO2, n-pentane : EtOAc ‒ 5 : 1) to yield 6.45 as a light yellow
oil (570 mg, 0.360 mmol, 90%). 1H NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 7.6, 1.7 Hz, 8H), 7.32 – 7.40 (m, 12H), 7.30 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.83 (dd, J = 8.0, 8.0 Hz, 2H), 6.82 (dd, J = 8.0, 8.0 Hz, 2H), 6.55 (d, J = 8.1 Hz, 2H), 6.48 (d, J = 8.1 Hz, 2H), 4.04 (m 2H), 3.96 (m, 2H), 3.48 – 3.86 (m, 24H), 1.90 (m, 2H), 1.43 – 1.52 (m, 2H), 1.27 (m, 32H), 1.05 (m, 21H), 1.00 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 154.2, 154.1, 153.81, 135.78, 133.9, 132.62, 132.60, 132.04, 132.00, 129.8, 127.8, 126.1, 126.0, 125.7, 125.1, 124.9, 124.01, 124.00, 123.2, 123.1, 113.9, 111.7, 111.6, 110.1, 110.0, 74.6, 74.5, 72.6, 71.2, 71.0, 69.7, 69.4, 69.38, 66.7, 63.6, 33.7, 33.6, 33.4, 33.36, 32.1, 30.2, 30.0, 29.95, 29.93, 29.90, 29.88, 29.6, 27.3, 27.1, 27.0, 22.9, 19.4, 17.5, 17.1, 14.3 ppm;
HRMS-188 |
APCI+ m/z calculated for C96H128O10S3Si2Na [M + Na]+ 1616.8139, found
1616.8134.
12,12'-((4',5'-Bis(((S)-2-methyldodecyl)oxy)-[9,9'-bithioxanthenylidene]-4,5-diyl)bis(oxy))bis(2,2-dimethyl-3,3-diphenyl-4,7,10-trioxa-3-siladodecane) (6.46):
PPh3 (407 mg, 1.55 mmol, 5.0 equiv) was added
to a solution of 6.45 (495 mg, 0.310 mmol, 1.0 equiv) in toluene (40 mL). The resulting mixture was heated at 100 °C overnight. The solvents were evaporated under reduced pressure and the residue purified by flash column chromatography (SiO2, n-pentane :
EtOAc ‒ 5:1) to yield 6.46 as a colorless oil (437 mg, 0.279 mmol, 90%). 1H NMR
(300 MHz, CDCl3): δ = 7.68 (dd, J = 7.6, 1.9 Hz, 8H), 7.31 – 7.39 (m, 12H), 6.78 (m, 4H), 6.62 (m, 4H), 6.42 (d, J = 7.7 Hz, 2H), 6.37 (dd, J = 7.8, 0.8 Hz, 2H), 4.26 (m 2H), 4.14 (m, 2H), 3.62 – 3.93 (m, 24H), 2.05 (m, 2H), 1.59 – 1.66 (m, 2H), 1.27 (m, 32H), 1.14 (m, 6H), 1.04 (s, 18H), 0.88 (t, J = 6.9 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 155.45, 155.43, 155.1, 137.04, 137.03, 136.49, 136.48, 135.8, 133.9, 133.3, 132.8, 129.8, 127.8, 125.9, 125.8, 125.2, 125.1, 124.9, 122.7, 122.3, 122.2, 109.6, 109.2, 109.1, 74.2, 74.0, 72.7, 71.3, 71.1, 69.9, 68.8, 63.6, 33.8, 33.6, 33.59, 33.5, 32.1, 30.2, 30.1, 30.0, 29.95, 29.91, 29.88, 29.87, 29.6, 27.3, 27.28, 27.0, 22.9, 19.4, 17.6, 17.3, 14.3 ppm; HRMS-APCI+ m/z calculated for C96H128O10S2Si2Na [M + Na]+
1584.8419, found 1584.8413.
2,2'-((((((4',5'-Bis(((S)-2-methyldodecyl)oxy)-[9,9'-bithioxanthenylidene]-4,5-
diyl)bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))diethanol (6.7):
A solution of 6.46 (75 mg, 0.050 mmol, 1.0 equiv) in THF (5 mL) was treated dropwise with TBAF (143 L, 0.140 mmol, 2.8 equiv, 1 M in THF) at room temperature. After 24 h, the solvents were evaporated under reduced pressure and the residue purified by flash column chromatography (SiO2,
EtOAc : MeOH ‒ 10:1) and recrystallized from
methanol (3 mL) to yield 6.7 as a white solid (45 mg, 0.040 mmol, 86%). Mp 150 – 152 °C; 1H NMR (300 MHz, CDCl3): δ = 6.84 (dd, J = 8.0, 8.0 Hz, 2H), 6.82 (dd, J =
| 189
Hz, 2H), 6.38 (d, J = 7.6 Hz, 2H), 4.31 (m 2H), 4.22 (m, 2H), 3.67 – 4.02 (m, 24H), 2.06 (m, 2H), 1.58 –1.68 (m, 2H), 1.28 (m, 32H), 1.15 (m, 6H), 1.04 (s, 18H), 0.89 (t, J = 6.6 Hz, 6H) ppm; 13C NMR (75.4 MHz, CDCl3): δ = 155.50, 155.48, 155.00, 137.32, 137.31, 136.393, 136.386, 133.5, 132.7, 126.1, 125.8, 125.2, 125.1, 124.7, 122.9, 122.23, 122.21, 109.5, 109.3, 109.2, 74.2, 74.04, 73.0, 71.4, 70.7, 69.9, 68.89, 61.9, 33.8, 33.7, 33.6, 33.5, 32.1, 30.2, 30.17, 29.99, 29.97, 29.94, 29.90, 29.89, 29.6, 27.4, 27.3, 22.9, 17.6, 17.4, 14.3 ppm; HRMS-APCI+ m/z calculated for C64H92O10S2Na [M + Na]+ 1107.6030, found 1107.6024.4,5-Bis(4-bromobutoxy)-9H-thioxanthen-9-one (6.29).
A mixture of 6.8 (1.0 g, 4.1 mmol), 1,4-dibromobutane (8.0 ml, 67.0 mmol) and K2CO3 (2.83 g, 20.5 mmol) in DMF
(20 mL) was heated at 100 °C for 24 h. DMF was
evaporated at reduced pressure. Water (80 mL) and dichloromethane (150 mL) were added to the residue. The organic phase was separated, the solvents were evaporated at reduced pressure and the residue was purified by column chromatography (pentane : ethyl acetate : DCM ‒ 7 : 1 : 1 switched to 5 : 1 : 1) to give the title compound 6.29. Yield: 993 mg (47%); yellow solid, mp 87.2‒88.5 °C.
1H NMR (400 MHz, CDCl3): δ (ppm) 8.22 (dd, 2H, J1 = 8.1 Hz, J2 = 1.0 Hz),7.40
(dd, 2H, J1 = 8.0 Hz, J2 = 8.0 Hz), 7.09 (dd, 2H, J1 = 7.9 Hz, J2 = 0.9 Hz), 4.20 (t, 4H,
J = 5.8 Hz), 3.59 (t, 4H, J = 6.5 Hz), 2.20 (m, 4H), 2.10 (m, 4H).13C NMR (100 MHz,
CDCl3): δ (ppm) 180.3, 161.1, 154.2, 130.1, 128.1, 126.1, 121.7, 113.1, 68.6, 33.8,
29.9, 27.9. HRMS (APCI+): calcd for C21H23Br2O3S [M + H+] 514.9714 found
514.9709.
4,5-Bis(4-bromobutoxy)-9H-thioxanthene-9-thione(6.31).
A solution of 6.29 (190 mg, 0.37mmol) and Lawesson’s reagent (224 mg, 0.55 mmol) in toluene (10 mL) was heated at 130 °C for 2 h. The solvents were evaporated at reduced
pressure, the residue adsorbed on silica gel from dichloromethane solution and purified by column chromatography (pentane : ethyl acetate ‒ 10 : 1) to give the product 6.31. Yield: 182 mg (93%); black thick oil. 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.64 (dd, 2H, J1 = 8.5 Hz, J2 = 0.9 Hz), 7.34 (dd, 2H, J1 = 8.2 Hz, J2 = 8.2 Hz),
7.06 (d, 2H, J = 8.0 Hz), 4.20 (t, 4H, J = 5.8 Hz), 3.60 (t, 4H, J = 6.5 Hz), 2.20 (m, 4H), 2.10 (m, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 210.6, 154.3, 138.3, 126.5,
125.5, 123.6, 112.2, 68.7, 33.8, 29.9, 27.9. HRMS (APCI+): calcd for C21H23Br2O2S2
