A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane

Article abstract of DOI:10.1002/ejoc.201500657

A non-symmetrical pH-sensitive bistable [2]rotaxane that bears a cholesterol unit and a tetraphenylmethane group as stopper groups was designed and synthesized in 18 steps. The successful formation of the rotaxane was proven by NMR spectroscopy and MS/MS. Besides a permanent cationic alkylated triazolium unit, the axle contains a secondary amine that can act as a second pH-sensitive binding site for a crown ether. Depending on the protonation state of this amine function, the crown ether reversibly changes its position by moving between the two binding sites along the axle, as revealed by NMR spectroscopy. A pH-sensitive bistable [2]rotaxane was synthesized and characterized by NMR spectroscopy and MS/MS. Besides an alkylated triazolium ion, the axle contains a secondary amine that acts as a second pH-sensitive binding site for a crown ether. Depending on the protonation state of this amine function, the crown ether reversibly changes its position by moving between two binding sites on the axles.

Full text of DOI:10.1002/ejoc.201500657

FULL PAPER
DOI: 10.1002/ejoc.201500657
A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
Martin Berg,[a] Senada Nozinovic,[b] Marianne Engeser,[a] and Arne Lützen*[a]
Keywords: Supramolecular chemistry / Molecular recognition / Rotaxanes / Crown compounds / Interlocked molecules /
Molecular shuttles
A non-symmetrical pH-sensitive bistable [2]rotaxane that
bears a cholesterol unit and a tetraphenylmethane group as
stopper groups was designed and synthesized in 18 steps.
The successful formation of the rotaxane was proven by
NMR spectroscopy and MS/MS. Besides a permanent cat-
ionic alkylated triazolium unit, the axle contains a secondary
amine that can act as a second pH-sensitive binding site for
a crown ether. Depending on the protonation state of this
amine function, the crown ether reversibly changes its posi-
tion by moving between the two binding sites along the axle,
as revealed by NMR spectroscopy.
the ring of which can undergo a shuttle-movement along
the axis depending on the protonation state of a suitable
functional group as depicted schematically in Scheme 1.
Several successful approaches can be found in the literature
that employ a permanent cationic function that can act as
a medium-strong binding site for an ionophore, such as a
crown ether and a secondary amine functionality that can
act as a strong binding site for an ionophore in the proton-
ated state but not in its neutral form.[12] Three permanent
cationic units have been used most in this context: dialkyl-
ated 4,4Ј-bipyridinium ions as pioneered by J. F. Stoddart
in the late 1990s[13] and more recently alkylated pyridinium
ions as employed by S.-H. Chiu,[14] F. Coutrot,[15] T. Ogo-
shi,[16] and U. Lüning,[17] or alkylated triazolium ions as
used by F. Coutrot,[18] Y. Liu,[19] C.-F. Chen,[20] P. D.
Beer,[21] and D. A. Leigh.[22] Among these, the latter one is
very appealing because the triazole unit can also act as a
key structural element to actually synthesis the rotaxane by
means of a copper-catalysed azide-alkyne cycloaddition
(CuAAC).[23]
Introduction
Control of mechanical motions on the molecular level is
a crucial point in the design of (supra-)molecular switches
and machines.[1,2] Among the different approaches, bistable
mechanically interlocked molecules, like catenanes and rot-
axanes, have attracted considerable attention to access func-
tional systems[3] because the mechanical bonds between the
molecular components offer a unique possibility to restrict
the freedom of motion to some well-defined pathways, such
as the translational motion of a rotaxane’s ring along its
axis in a shuttling manner.[4] In bistable rotaxanes this ring
displacement results from an external stimulus that alters
the non-covalent interaction patterns between the ring and
different parts of the axis. Among the repertoire of external
stimuli for actuating this movement, the application of
light,[5] redox-agents,[6] and changes of the pH[7] are proba-
bly used the most.
To affect stimulus induced motion, like a muscle-like
contraction or relaxation[8] or an opening or closing of a
channel, pore, or valve,[9] such systems need to be anchored
to a support.[10] Cholesterol can act as an anchor in lipid
membranes but so far there has only been a single report
that describes the synthesis of a bistable redox-sensitive
rotaxane that bears cholesterol as a stopper unit.[11]
Hence, we decided to develop another non-symmetrical
bistable pH-sensitive rotaxane with a cholesterol stopper on
the one end and another stopper group at the other end,
[a] Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
E-mail: arne.luetzen@uni-bonn.de
www.chemie.uni-bonn.de/oc/forschung/arbeitsgruppen/ak_lue
[b] Institut für Anorganische Chemie,
Scheme 1. Schematic representation of a bistable pH-sensitive [2]-
rotaxane shuttle.
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500657.
Therefore, we decided to follow this strategy to design
bistable [2]rotaxane 1 that contains a cholesterol and the
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A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
Scheme 2. Retrosynthetic analysis of bistable pH-sensitive [2]rotaxane 1·HBF4.
well-established tetraphenylmethane stopper which has a 2 and cholesterol derivative 3 that contains a terminal alk-
secondary amine function and a triazolium ion in its axis yne and a terminal azide function, respectively. These two
(Scheme 2). Its synthesis, structural characterization, and building blocks can be combined by means of a copper-
shuttling behaviour as analysed by NMR spectroscopic and catalysed Click-reaction to give rise to isolated axes 4,
ESI mass spectrometric means is reported here.
which is needed for comparison later on to prove the
threaded structure of the rotaxane.
Because the cholesterol group is not as bulky as the
tetraphenylmethane stopper, the size of the ring had to be
chosen with great care to ensure reasonable binding to the
triazolium ion or the secondary ammonium ion and to
Results and Discussion
Synthesis
The retrosynthetic analysis of 1 (Scheme 2) asks for the avoid dethreading of the axis. Dibenzo-24-crown-8 (db-24-
preparation of two half-axes: tetraphenylmethane stoppered c-8) perfectly fulfils these requirements because its cavity is
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small enough not to slip over the cholesterol but still offers with cholesterol derivative 3 was then planned to give rotax-
ample opportunities to interact with the axis through ane 6·HBF4, which could finally be transformed into de-
hydrogen bonds, cation-π, and CH-π interactions.[24] Hence, sired bistable rotaxane 1·HBF4 upon alkylation of the tri-
we thought to use half axis 2 to form pseudo-rotaxane azole moiety.
5·HBF4 upon subsequent treatment with acid and the
Schemes 3 and 4 show the syntheses of half-axes 2 and
crown ether moiety. Combination of this pseudo-rotaxane 3. Alkyne half-axis 2 was prepared in ten steps by starting
from 4-bromobenzoic acid (7) (Scheme 3). By following lit-
erature procedures, 7 was first transformed into corre-
sponding methyl ester 8 before it was subjected to a twofold
Grignard addition reaction to give tertiary alcohol 9. Com-
pound 9 was then condensed with phenol under acidic con-
ditions to give tetraphenylmethane derivative 10[25], which
was subsequently methylated to give tris(4-meth-
oxyphenyl)(4-bromophenyl)methane (11).[26]
Scheme 4. Synthesis of azide half axis 3: (a) pTsCl, pyridine, room
Scheme 3. Synthesis of alkyne half-axes 2: (a) MeOH, H2SO4, Δ,
24 h, 64%, (b) 4-MeOPhMgBr, THF, room temp., 18 h, 62%,
(c) PhOH, HBr, Δ, 18 h, 48%, (d) NaH, MeI, room temp., 78%,
(e) tBuLi, THF, 1 h, –78 °C, then DMF, HCl, 1.5 h, room temp.,
quant.; (f) 4-(aminomethyl)phenol, EtOH, 24 h, Δ, quant.;
(g) NaBH4, MeOH/THF, 1:1, 18 h, room temp., 64%; (h) di-tert-
butyl dicarbonate, CH2Cl2, 18 h, room temp., 83%; (i) 6-chloro-1-
hexyne, Cs2CO3, KI, DMF, 18 h, 70 °C, 77%; (j) HCl (2 n),
CH2Cl2, 18 h, room temp., then aq. NH4BF4, 18 h, room temp.,
74%.
temp., 1 h, 78%, (b) HOCH2CH2OH, 1,4-dioxane, Δ, 18 h, 86%,
(c) pTsCl, pyridine, 0 °C, 18 h, 76%, (d) NaN3, DMPU, 18 h,
50 °C, 90%.
To achieve formylation of 11 a bromine lithium exchange
had to be performed first. Interestingly, we found that this
could only be done with tert-butyllithium, whereas neither
n- nor sec-butyllithium was successful in this reaction. Ad-
dition of N,N-dimethylformamide to the lithium organyl
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A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
followed by quenching with aqueous HCl then gave rise to with dibenzo-24-crown-8, the counterion was finally ex-
desired aldehyde 12 in quantitative yield. Reductive amin- changed against the much weaker coordinating tetrafluoro-
ation upon reaction of 12 with 4-(aminomethyl)phenol in borate by using a saturated aqueous solution of ammonium
anhydrous ethanol, but without the typical use of an- tetrafluoroborate to give protonated alkyne-terminated
hydrous magnesium sulfate, and subsequent reduction of half-axis 2·HBF4 in 74% yield.
the intermediate imine by NaBH4 in tetrahydrofuran
Azide half-axis 3 was prepared in four steps starting from
(THF)/MeOH gave amine 13 in 64% yield over both steps. commercially available cholesterol (16; Scheme 4). By fol-
To be able to perform the desired alkylation with 6- lowing literature protocols,[27] 16 was first tosylated to give
chlorohex-1-yne regioselectively, as in a Williamson ether sulfonate 17 in 78% yield. Nucleophilic substitution with
synthesis, the more nucleophilic secondary amine had to be ethylene glycol then afforded chain-elongated alcohol 18
protected first. Therefore, base stable tert-butyloxycarbonyl with retention of stereochemistry in 86% yield. Another
(Boc) protecting group was introduced by reacting 13 with tosylation gave 19 in 76% yield, which was finally trans-
di-tert-butyl dicarbonate to give 14 in 83% yield. Boc pro- formed into desired azide 3 upon treatment with sodium
tected phenol 14 was then deprotonated with caesium carb- azide in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidin-
onate and the reaction with the chloroalkyne in the pres- one (DMPU). In this way cholesterol derivative 3 could be
ence of catalytic amounts of potassium iodide gave desired isolated in 90% yield after recrystallization from ethanol.
alkynylated ether 15 in 77% yield. Next, the Boc protecting
With both building blocks in hands the next task was to
group was removed by treatment with HCl (2 n) in diethyl prepare isolated axis 4 and the formation of rotaxane
ether to form the ammonium ion. To make this an even 6·HBF4 through CuAAC (Scheme 5). Therefore, alkyne-ter-
better template for the formation of the pseudo-rotaxane minated half-axis 2·HBF4 was mixed with dibenzo-24-
Scheme 5. Synthesis of rotaxane 6·HBF4 and isolated axis 4·HBF4: (a) dibenzo-24-crown-8, CH2Cl2, 2 h, room temp., (b) Cu(CH3CN)4
BF4, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), CH2Cl2, 2 d, 5%, (c) Cu(CH3CN)4BF4, CH2Cl2, 2 d, 55%.
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crown-8 and stirred for two hours in degassed dichloro-
(i) Evidence for the successful formation of the rotaxane
methane to achieve formation of pseudo-rotaxane 5·HBF4. structure in solution is available from NMR experiments.
1
This was treated with 3 for 2 d in dichloromethane with Figure 1 analyses the H NMR spectra of the free crown
Cu(CH3CN)4BF4 as catalyst and tris[(1-benzyl-1H-1,2,3- ether (trace a), rotaxane 6·HBF4 (trace b), free axis 4·HBF4
triazol-4-yl)methyl]amine (TBTA) as a copper(I) stabilizing (trace c), and a 1:1 mixture of crown ether and 4·HBF4
ligand[28] to afford desired rotaxane 6·HBF4 in a yield of (trace d) in CD2Cl2 at 293 K. Although the mixture of the
4% after recrystallization from ethanol and additional col- ring and the axle component more or less results in a sum-
umn chromatography. Interestingly, the same conditions mation of the individual spectra, some of the signals in the
were not successful to prepare the isolated axis from spectrum of the rotaxane show significant changes relative
2·HBF4 and 3 because we were unable to remove TBTA to the positions of these signals for the free components
from the desired product. Only when we repeated the syn- as a result of the threaded topology of the mechanically
thesis without the stabilizing ligand we were able to isolate interlocked structure. This could also be seen in (i) splitting
axis 4·HBF4 in a reasonable yield of 55% after column and (ii) a significant shift both aromatic protons (HAr, W
)
chromatography.
and aliphatic protons (CH2, W) of the dibenzo-24-crown-8
wheel. Furthermore the signals of the two different pairs of
benzylic protons k and m are shifted downfield Δδ = 0.64
and 0.62 ppm, respectively. This is most likely a result of C-
H···O hydrogen bonds between these protons and the oxy-
NMR Spectroscopic and Mass Spectrometric
Characterization
The threaded topology of rotaxane 6·HBF4 could be un- gen atoms on the crown ether.
ambiguously characterized in the gas phase, and in solu-
These changes clearly indicate that the preferred position
tion. Thus, two independent pieces of evidence for the rot- of the crown ether wheel is in close proximity to the
axane structure are available.
ammonium ion at room temperature. This interpretation is
Figure 1. 1H NMR spectra (400.1 MHz, CD2Cl2, 293 K) of (a) dibenzo-24-crown-8, (b) rotaxane 6·HBF4, (c) free axis 4·HBF4, and (d) 1:1
mixture of dibenzo-24-crown-8 and 4·HBF4. Dashed lines indicate changes in shifts between selected nuclei of the individual components
relative to the rotaxane (letters a–z mark protons of the axis, whereas CH2,W and HAr,W mark protons of the wheel).
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A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
further corroborated by the results of 2D NOESY experi- ether and protonated axis 4·HBF4 (Figure 2, f), and only a
ments (see the Supporting Information) that reveal NOE minor signal at m/z = 1530 is observed that results from
contacts between the benzylic protons k and m of the axis the corresponding non-threaded (most probably) hydrogen-
and the ethylene glycol protons (CH2, W) of the crown ether bonded complex [db-24-c-8·4+H]+.
unit.
Even better proof for this assignment comes from a series
(ii) Evidence for the interlocked structure also comes of positive ion MS/MS experiments shown in Figure 2
from the positive-mode ESI mass spectra of rotaxane (b–e and g–j).[29] In both cases we mass-selected the full
6·HBF4 and a 1:1 mixture of axle 4·HBF4 and dibenzo-24- isotope pattern of the ions at m/z 1530 and subjected the
crown-8 (Figure 2). The spectrum of the rotaxane (Figure 2, ions to collision-induced dissociation (CID). The molecular
a) does show a very intense signal at m/z = 1530 that corre- ion for rotaxane [6+H]+ proved to be remarkably stable and
sponds to the positive [6+H]+ ion, but no signal for the only decomposed by fragmentation of the axis after apply-
isolated protonated axis [4+H]+. In marked contrast, strong ing collision energies of about 50 eV. Upon fragmentation
signals for protonated axle [4+H]+ at m/z = 1082 and for of the axle the crown ether is released which is why we could
[db-24-c-8 + Na]+ at m/z = 471 are observed under the same only detect fragments that resulted from the axis, e.g. at m/z
conditions when we analysed the 1:1 mixture of the crown 536, but no signal for the intact protonated axle at m/z =
Figure 2. ESI mass spectra of 6·HBF4 (a) and a 1:1 mixture of 4·HBF4 and dibenzo-24-crown-8 (f, please note that the signal of the
crown ether sodium complex [db-24-c-8+Na]+ at m/z = 471 is so intense that the mass region below m/z = 500 had to be suppressed to
get observable intensities of the ion at m/z = 1531) and CID MS/MS spectra of [6+H]+ (b–e) and [db-24-crown-8·4+H]+ (g–j). The inset
shows the fragmentation pathways observed for the axis that gives rise to the signals at m/z 643, 537, and 367.
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1082. This can also be traced back to a significantly more Synthesis of the Bistable pH-Sensitive Rotaxane and Its
energy demanding cleavage of the covalent bonds of the Shuttling Behaviour
crown ether. Thus, fragmentation of covalent bonds within
After having confirmed the mechanically interlocked
structure of rotaxane 6·HBF4 by NMR spectroscopy and
mass spectrometry, the next task was to introduce a second
permanent cationic binding site within the axis to make the
rotaxane a bistable pH-sensitive molecular shuttling system.
Therefore, we decided to methylate the triazole moiety to a
triazolium ion by treatment with excess methyl iodide. A
prolonged reaction time of 3 d ensured quantitative methyl-
ation and finally we performed an anion exchange by treat-
ment with sodium tetrafluoroborate to obtain 1·HBF4 as a
white solid (Scheme 6).
the axle leads to simultaneous cleavage of the mechanical
bond.
The ion of the non-threaded axis-crown-ether complex
[db-24-c-8·4+H]+, when treated in the same way as the rot-
axane, behaves very differently. As expected for a noncova-
lently bonded species, the crown ether is lost very easily in
the CID experiments and positively charged axle [4+H]+ is
formed as the major product at m/z = 1082 upon applica-
tion of a collision energy of only ≈ 10 eV. The consecutive
fragmentations of the axle that start to occur at 50 eV are
similar to the fragments observed for the rotaxane. These
experiments confirm the threaded nature of the rotaxane
The permanent cationic function within the axis the rot-
and permit us to distinguish the mechanically bound spe- axane should undergo a shuttling motion upon deproton-
cies from a non-covalently-bonded complex of axis and ation of the secondary ammonium ion with a base. The
crown ether. They also reflect the much weaker bond resulting neutral amine has a significantly reduced binding
strength of the non-covalently assembled complex versus affinity towards the crown ether, and hence, the ring shifts
the strength of the mechanical bond of the rotaxane, which towards the triazole moiety that is a better binding site for
requires cleavage of a covalent bond for fragmentation.
the ionophore. Reprotonation of the amine function by ad-
Scheme 6. Synthesis of the rotaxane 1·HBF4: (a) MeI, 3 d, (b) NaBF4, quant. (top) and its pH-sensitive shuttling of the crown ether
(please note that the counterions might be exchanged upon the addition of base and acid).
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A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
dition of acid changes the affinity again, which causes the moiety (k, l, m, n, q, and r) are all significantly shifted. This
crown ether to move back to the ammonium ion.
indicates that the crown ether has shuttled to the triazole
This pH dependent shuttling of the crown ether along unit.
the axis could be easily monitored by NMR spectroscopic
This shuttling action is completely reversible, and ad-
experiments (Figure 3 and the Supporting Information). dition of HCl in diethyl ether leads to a reprotonation of
After addition of aq. NaOH to rotaxane 1·HBF4 the signal triazolene function, which causes the ring to move back to
that arises from the ammonium protons (l) at around δ = the ammonium ion and results in the same NMR spectrum
7.45 ppm disappears and a broad signal that arises from the as before (Figure 4). Further addition of base again results
secondary amine proton appears upfield at δ = 4.88 ppm in deprotonation of the ammonium ion and shuttling of
that indicates successful deprotonation.
the crown ether to the triazolium ion. This process can be
The shifts of the protons of the crown ether moiety (HAr, repeated several times (for four reversible shuttling motions
W, CH2, W) also change significantly to indicate that the see the Supporting Information).
crown ether is located in a different environment. The same
Although not the focus of our project, we also checked
is true for the shifts of the signals assigned to the nuclei whether rotaxane 1·HBF4 has some liquid crystalline prop-
around the triazolium ion. The proton of the triazolium erties and whether these are dependent on its protonation
ring (p) is shifted downfield by Δδ = 0.37 ppm, probably as state by using polarised optical microscopy. Unsurprisingly
a result of formation of C–H···O hydrogen bonding with with respect to their structures with the bulky arene and
the oxygen atoms of the crown ether. The signal of the cholesterol moieties, neither of the rotaxanes (1 or 1·HBF4)
protons of the methyl group that is bound to the tri- show any such phase transition but both rather become iso-
azolium nitrogen (NCH3) is shifted upfield owing to the tropic liquids upon heating and solidify into amorphous so-
shielding effect of the wheel, and finally, the signals of the lids without forming any observable structurally ordered
protons of the alkyl chains neighbouring the triazolium mesophase.
Figure 3. 1H NMR spectra (500.1 MHz, in CD2Cl2, 293 K) of (a) rotaxane 1·HBF4, (b) rotaxane 1 obtained by deprotonation of rotaxane
1·HBF4 through addition of NaOH (1 m; letters a–z mark protons of the axis, whereas CH2,W and HAr,W mark protons of the wheel).
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Figure 4. Reversible pH-sensitive shuttle motion of the crown ether moiety along the rotaxane axis. 1H NMR spectra (500.1 MHz, 293 K,
CD2Cl2) of (a) 1·HBF4, (b) 1 obtained after deprotonation of 1·HBF4, and (c) 1·HBF4 obtained upon reprotonation of 1.
Bruker DRX 500 spectrometer (300 K) operating at 500.1 and
125.8 MHz, a Bruker AM 400 (298 K) spectrometer operating at
Conclusions
We were able to synthesis rotaxane 6·HBF4 that con-
400.1 MHz and 100.6 MHz, or with a Bruker Avance 300 (298 K)
1
tained a crown ether threaded onto a non-symmetrical axis spectrometer operating at 300.1 MHz and 75.5 MHz. H and 13C
NMR chemical shifts are reported on the δ scale (ppm) relative to
signals of residual non-deuterated solvent (1H) or the deuterated
solvent (13C) as the internal standard. 19F NMR chemical shifts
are reported on the δ scale (ppm) relative to CFCl3 as an external
with a tetraphenylmethane and a cholesterol stopper unit
in a CuAAC reaction of an azide and an alkyne terminated
half axis through an ammonium-ion template effect. Its me-
chanically interlocked structure was unambiguously as-
signed by NMR spectroscopy and mass spectrometry.
Upon alkylation of the triazole ring we obtained pH-sensi-
tive bistable rotaxane 1·HBF4 in which the crown ether part
changes its preferred position on the axis as a result of the
protonation state of a secondary amine function. In the
1
standard. Signals were assigned on the basis of H, 13C, HMQC,
HMBC, and NOESY NMR experiments. For the numbering of the
individual nuclei in the compounds see Figures 1 and 3 and the
Supporting Information. Mass spectra were recorded with a Finni-
gan 95XL (EI) or a Bruker micrOTOF-Q (ESI). Argon was used
as collision gas for CID. The given collision energies are uncor-
protonated form the crown ether is located around the sec- rected values Elab because the isolated ions have the same mass in
this case, and Elab is sufficient for a relative comparison. Elemental
analyses were carried out with a Heraeus Vario EL. Please note
that our equipment does not allow for analysis of fluorine contain-
ing samples, therefore HRMS data is given in these cases. Polarized
optical microscopy measurements were performed on a Leica
DMLB microscope with a hot stage and a home-built control unit.
Images were acquired with a Canimpex digital camera connected
to a personal computer. Most solvents were dried, distilled, and
stored under argon in accordance with standard procedures. All
chemicals were used as received from commercial sources. 4-
Bromobenzoic acid methyl ester (8),[25] bis(4-methoxyphenyl)-
(4-bromophenyl)methane (9),[25] bis(4-methoxyphenyl)-(4-bromo-
phenyl)methane (10),[25] tris(4-methoxyphenyl)(4-bromophenyl)-
methane (11),[26] cholest-5-en-3β-tosylate (17),[27] cholest-5-en-3β-
oxyethanol (18),[27] and 2-(cholest-5-en-3β-oxy)ethyl tosylate (19)
ondary ammonium ion as the best binding site for the iono-
phore. Upon deprotonation of the ammonium ion the tri-
azolium ion becomes the better binding site, which causes
the ring to shuttle along the axis towards this position as
evidenced by NMR spectroscopy. After this proof of prin-
ciple, further studies will aim to develop amphiphilic bista-
ble rotaxanes with a lipophilic and a hydrophilic stopper
unit, to investigate their self-assembly and shuttling behav-
iour, or their implementation as functional devices in lipo-
philic barriers.
Experimental Section
[27]
General: Reactions under inert gas atmosphere were performed un-
der argon by using standard Schlenk techniques and oven-dried
glassware prior to use. Thin-layer chromatography was performed
on aluminium TLC plates (silica gel 60F254 from Merck). Detection
was carried out under UV light (254 and 366 nm). Products were
purified by column chromatography on silica gel 60 (70–230 mesh)
from Merck. 1H and 13C NMR spectra were recorded with a
were prepared in accordance to literature protocols.
4-[Tris(4-methoxyphenyl)methyl]benzaldehyde
(12):
tBuLi
(21.51 mL, 1.9 m in pentane, 40.87 mmol, 5.0 equiv.) were added to
dry THF (200 mL) at –78 °C and stirred for 10 min. To this solu-
tion tris(p-methoxyphenyl)(p-bromphenyl)methane (11; 4.00 g,
8.17 mmol, 1.0 equiv.) was added and stirred for another 1 h at
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A Cholesterol Containing pH-Sensitive Bistable [2]Rotaxane
–78 °C. Afterwards, dry dimethylformamide (DMF; 6.30 mL, tert-Butyl-4-hydroxybenzyl{4-[tris(4-methoxyphenyl)methyl]-
81.37 mmol, 10.0 equiv.) was added and the solution was warmed
to room temperature over 1.5 h. The reaction was quenched by
benzyl} Carbamate (14): Boc2O (0.62 g, 2.86 mmol, 1.0 equiv.) was
added to a stirred solution of 13 (1.56 g, 2.86 mmol, 1.0 equiv.) in
addition of aq. HCl (4N, 11.24 mL, 44.95 mmol, 5.5 equiv.) and anhydrous CH2Cl2 (50 mL). The solution was stirred overnight at
stirred for 0.5 h. The layers were separated and the organic layer room temperature and then washed with water (20 mL) and brine
was washed with aq. HCl (0.5 m, 150 mL), saturated aq. NaHCO3 (10 mL). The organic layers were dried with MgSO4 and concen-
solution (150 mL), and brine (150 mL), dried with MgSO4, and
concentrated in vacuo. The resultant white solid was used without
trated in vacuo. The residue was subjected to column chromatog-
raphy on silica gel with cyclohexane/ethyl acetate (1:1) as eluent to
further purification (3.35 g, 8.17 mmol, quant.). 1H NMR afford the desired product as a white solid (1.53 g, 2.36 mmol,
3
(400.1 MHz, CDCl3, 293 K): δ = 3.79 (s, 9 H, Ha), 6.79 (d, Jc,d
=
=
83%). 1H NMR (400.1 MHz, CD2Cl2, 293 K): δ = 1.47 (s, 9 H,
tert-butyl-H), 3.77 (s, 9 H, Ha), 4.27–4.40 (br., 4 H, Hk, Hm), 5.75
3
3
9.0 Hz, 6 H, Hc), 7.08 (d, Jd,c = 9.0 Hz, 6 H, Hd), 7.40 (d, Jh,i
3
8.4 Hz, 2 H, Hh), 7.76 (d, Ji,h = 8.4 Hz, 2 H, Hi), 9.98 (s, 1 H, (s, 1 H, O-H), 6.75–6.80 (m, 8 H, Hc, Hp), 7.06–7.11 (m, 10 H, Hd,
CHO) ppm. 13C NMR (75.5 MHz, CDCl3, 293 K): δ = 55.3 (Ca),
Hh, Hi), 7.14 (d, Jo,p = 8.4 Hz, 2 H, Ho) ppm. 13C NMR
3
63.4 (Cf), 113.1 (Cc), 128.9 (Ch), 131.6 (Ci), 132.0 (Cd), 134.2 (Cj), (100.6 MHz, CD2Cl2, 293 K): δ = 28.5 [C(CH3)3], 55.5 (Ca), 63.1
138.7 (Ce), 154.9 (Cg), 157.8 (Cb), 192.1 (Ck) ppm. MS (ESI): m/z (Cf), 80.3 [C(CH3)3], 113.1 (Cc), 115.6 (Cp), 127.1 (Ch), 131.2 (Co),
(%) = 461.2 (100) [C29H26O4 + Na]+. HRMS (ESI): m/z (%) calcd.
for [C29H26O4Na]+ 461.1723; found 461.1704. C29H26O4·0.5H2O
(438.51): calcd. C 77.84, H 6.17; found C 77.83, H 6.08.
132.2 (Cd), 139.9 (Ce), 146.9 (Cg), 155.6 (Cq), 156.3 (COO), 157.9
(Cb) ppm. MS (ESI): m/z (%) = 668.3 (100) [C41H43NO6 + Na]+.
HRMS (ESI): m/z (%): calcd. for [C41H43NO6Na]+ 668.2983; found
668.2983. C41H43NO6·0.5CH2Cl2 (645.78): calcd. C 72.42, H 6.44,
N 2.04; found C 72.91, H 6.70, N 1.96.
4-({4-[Tris(4methoxyphenyl)methyl]benzylideneamino}methyl)-
phenol: To a solution of 12 (3.35 g, 7.63 mmol, 1.0 equiv.) in anhy-
drous EtOH (153 mL), 4-(aminomethyl)phenol (0.94 g, 7.63 mmol,
1.0 equiv.) was added. The mixture was heated to reflux for 24 h.
After that the solvent was evaporated and the resultant yellowish
solid was used without further purification (4.15 g, 7.63 mmol,
tert-Butyl 4-(Hex-5-ynyloxy)benzyl{4-[tris(4-methoxyphenyl)-
methyl]benzyl}carbamate (15): A mixture of 14 (500 mg, 0.77 mmol,
1.0 equiv.), Cs2CO3 (505 mg, 1.55 mmol, 2 equiv.), KI (65 mg,
0.39 mmol, 0.5 equiv.), and 6-chloro-1-hexyne (136 mg, 1.16 mmol,
1.5 equiv.) in anhydrous DMF (8 mL) was heated to 70 °C over-
night. After cooling to room temperature, the mixture was diluted
with EtOAc (10 mL) and washed with water (3ϫ 15 mL) and brine
(3ϫ 15 mL). The organic layer was dried with MgSO4 and the
solvent was removed under reduced pressure. The residue was puri-
fied by flash column chromatography with silica gel and cyclohex-
ane/ethyl acetate (1:1) as eluent to give 15 as a yellow viscous oil
(430 mg, 77%). 1H NMR (500.1 MHz, CDCl3, 293 K): δ = 1.47 (s,
1
quant.). H NMR (400.1 MHz, CD2Cl2, 293 K): δ = 3.77 (s, 9 H,
3
Ha), 4.68 (s, 2 H, Hm), 6.70 (d, Jp,o = 8.0 Hz, 2 H, Hp), 6.78 (d,
3
3Jc,d = 8.4 Hz, 6 H, Hc), 7.09–7.11 (m, 8 H, Hd, Ho), 7.28 (d, Jh,i
3
= 8.1 Hz, 2 H, Hh), 7.65 (d, Ji,h = 8.1 Hz, 2 H, Hi), 8.36 (s, 1 H,
Hk) ppm. 13C NMR (100.6 MHz, CD2Cl2, 293 K): δ = 55.3 (Ca),
63.4 (Cf), 64.9 (Cm), 113.2 (Cc), 115.8 (Cp), 127.8 (Ch), 129.7 (Ci),
130.8 (Cn), 131.5 (Co), 132.2 (Cd), 133.9 (Cj), 139.5 (Ce), 151.2 (Cg),
156.0 (Cq), 158.0 (Cb), 162.0 (Ck) ppm. MS (ESI): m/z (%) = 544.2
(100) [C36H33NO4 + H]+, 566.2 (16) [C36H33NO4 + Na]+. HRMS
(ESI): m/z (%) calcd. for [C36H34NO4]+ 544.2482; found 544.2480.
C36H33NO4·0.5CH2Cl2·EtOH (543.65): calcd. C 73.14, H 6.38, N
2.22; found C 72.61, H 6.21, N 1.91.
3
9 H, tert-butyl-H), 1.72 (q, Jt,s = 7.0 Hz, 2 H, Ht), 1.88–1.90 (m,
4
3
2 H, Hs), 1.96 (t, Jw,u = 2.7 Hz, 1 H, Hw), 2.27 (td, Ju,t = 7.0 Hz,
4Ju,w = 2.7 Hz, 2 H, Hu), 3.78 (s, 9 H, Ha), 3.97 (d,3Jr,s = 6.4 Hz, 2
H, Hr), 4.27 (br., 2 H, Hm)*, 4.35 (br., 2 H, Hk)*, 6.78 (d, Jc,d
3
=
3
8.9 Hz, 6 H, Hc), 6.82 (d, Jp,o = 8.6 Hz, 2 H, Hp), 7.05–7.09 (m, 8
H, Hd, Hh), 7.10–7.12 (m, 4 H, Hi, Ho) ppm (* assignment of sig-
nals might be interchanged). 13C NMR (125.8 MHz, CDCl3,
293 K): δ = 18.3 (Cu), 25.2 (Ct), 28.4 (Cs), 28.6 [C(CH3)3], 48.7
(Ck)*, 49.0 (Cm)*, 55.3 (Ca), 62.7 (Cf), 67.4 (Cr), 68.7 (Cw), 80.1
[C(CH3)3], 84.2 (Cv), 112.7 (Cc), 114.5 (Cp), 126.8 (Ch), 128.9 (Cj),
129.5 (Ci) 130.1 (Cn) 131.1 (Co), 132.1 (Cd), 139.5 (Ce), 146.5 (Cg),
156.0 (COO), 157.5 (Cb), 158.3 (Cq) ppm (* assignment of signals
might be interchanged). MS (EI): m/z (%) = 725.4 (4) [C47H51NO6]+·,
669.3 (9) [C43H43NO6]+, 625.3 (4) [C42H43NO4]+, 439.2 (13)
[C29H29NO3]+, 333.1 (100) [C22H23NO2]+. HRMS (EI): m/z (%)
c a l c d . fo r [C4 7 H5 1 N O6 ]+ · 7 25 . 3 72 1; fo un d 7 25. 3721.
C47H51NO6·2H2O (725.91): calcd. C 74.09, H 7.28, N 1.84; found
C 73.80, H 7.63, N 1.94.
4-({4-[Tris(4-methoxyphenyl)methyl]benzylamino}methyl)phenol
(13): The Schiff Base derived from 12 (212 mg, 0.39 mmol,
1.0 equiv.) was dissolved in THF (5.8 mL) and MeOH (5.8 mL),
and then NaBH4 (59 mg, 1.56 mmol, 4.0 equiv.) was added slowly.
After stirring overnight at room temperature, the reaction was
quenched by addition of saturated aqueous ammonium chloride.
The solvents were removed under reduced pressure. The residue
was extracted with CH2Cl2 and dried with Na2SO4. Removal of
the solvent under reduced pressure and purification by column
chromatography with silica gel and a gradient of cyclohexane/ethyl
acetate (1:1 to 1:9) as eluent gave the target compound as a yellow-
ish amorphous solid, yield 136 mg (0.25 mmol, 64%). 1H NMR
(400.1 MHz, CD2Cl2, 293 K): δ = 3.72 (s, 2 H, Hk)*, 3.76 (s, 9 H,
3
Ha), 3.78 (s, 2 H, Hm)*, 6.65 (d, Jp,o = 8.4 Hz, 2 H, Hp), 6.77 (d, N-[4-(Hex-5-ynyloxy)benzyl]-1-{4-[tris(4-methoxyphenyl)methyl]-
3
3Jc,d = 8.9 Hz, 6 H, Hc), 7.11 (d, Jd,c = 8.9 Hz, 6 H, Hd), 7.13 (d,
phenyl}methanammonium Tetrafluoroborate (2·HBF4): HCl (2 m in
3Jh,i = 8.5 Hz, 2 H, Hh), 7.14 (d, Ji,h = 8.5 Hz, 2 H, Hi), 7.21 (d, Et2O, 5.17 mL, 10.33 mmol, 15.0 equiv.) was added to a stirred
3Jo,p = 8.4 Hz, 2 H, Ho) ppm (* assignment of signals might be solution of 15 (500 mg, 0.69 mmol, 1.0 equiv.) in anhydrous
interchanged). 13C NMR (100.6 MHz, CD2Cl2, 293 K): δ = 53.0 CH2Cl2 (20 mL) and stirred overnight at room temperature. The
(Ck)*, 53.1 (Cm)*, 55.5 (Ca), 63.1 (Cf), 113.0 (Cc), 115.8 (Cp), 127.7 solvent was evaporated and Et2O (30 mL) was added to the result-
3
(Ch), 130.0 (Ci), 131.2 (Co), 131.4 (Cn), 132.2 (Cd), 137.5 (Cj), 139.9
(Ce), 146.9 (Cg), 156.0 (Cq), 157.9 (Cb) ppm (* assignment of sig-
nals might be interchanged). MS (ESI): m/z (%) = 546.3 (100)
ant viscous oil. To this solution HCl (2 m in Et2O, 3 mL, 6 mmol)
was added and stirred until the mixture became clear. The solvents
were removed under reduced pressure. The residue was dissolved in
[C36H35NO4 + H]+, 568.2 (5) [C36H35NO4 + Na]+. HRMS (ESI): a 1:1 mixture of CH2Cl2 (40 mL) and saturated aqueous NH4BF4
m/z (%) calcd. for [C36H36NO4]+ 546.2639; found 546.2640.
C36H35NO4·0.5CH2Cl2·H2O (545.65): calcd. C 72.32 H 6.32 N
2.31; found C 72.18, H 6.45, N 2.18.
(40 mL) and stirred overnight. The layers were separated and the
organic layer was washed with water (100 mL), dried with MgSO4,
and concentrated in vacuo. The resultant pink solid was used with-
Eur. J. Org. Chem. 2015, 5966–5978
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5975

M. Berg, S. Nozinovic, M. Engeser, A. Lützen
FULL PAPER
out further purification (364 mg, 0.51 mmol, 74 %). 1H NMR 10BF4), –151.27 (br., 11BF4) ppm. MS (ESI): m/z (%) = 1081.7 (100)
3
(400.1 MHz, CD2Cl2, 293 K): δ = 1.69 (q, Jt,u, 3Jt,s = 7.2 Hz, 2 H, [C71H93N4O5]+, 1103.6 (23) [C71H92N4O5 + Na]+. HRMS (ESI):
3
3
4
Ht), 1.88 (q, Js,t, Js,r = 6.8 Hz, 2 H, Hs), 2.00 (t, Jw,u = 2.6 Hz,
m/z (%) calcd. for [C71H92N4O5Na]+ 1103.6960; found 1103.6980.
3
4
1 H, Hw), 2.25 (td, Ju,t = 7.2, Ju,w = 2.6 Hz, 2 H, Hu), 3.75 (s, 9
H, Ha), 3.91–4.02 (m, 6 H, Hk, Hm, Hr), 4.02–4.14 (br., 2 H, Hl),
6.75 (d, Jc,d = 8.9 Hz, 6 H, Hc), 6.87 (d, Jp,o = 8.6 Hz, 2 H, Hp),
Rotaxane·6·HBF4: A solution of 2·HBF4 (100 mg, 0.14 mmol,
1.0 equiv.) and db-24-C-8 (126 mg, 0.28 mmol, 2.9 equiv.) in de-
gassed CH2Cl2 (2 mL) was stirred at room temperature for 2 h un-
der argon. To this solution 3 (96 mg, 0.21 mmol, 1.5 equiv.),
Cu(CH3CN)4BF4 (9 mg, 0.03 mmol, 0.2 equiv.), and TBTA (15 mg,
0.03 mmol, 0.2 equiv.) were added and the reaction was stirred in
the dark for 48 h at room temperature. The reaction was diluted
with CH2Cl2 (21 mL) and washed with EDTA·2Na(aq.) solution
(0.1 m, 2ϫ 28 mL) and H2O (2ϫ 28 mL). The organic layer was
dried with MgSO4, and the solvent was removed under reduced
pressure. The crude product was recrystallized from ethanol and
further purified by flash column chromatography on silica gel with
a gradient of ethyl acetate to ethyl acetate/MeOH/CH2Cl2 (1:1:1)
as eluent to give 6·HBF4 as a yellowish solid (8 mg, 0.005 mmol,
3
3
3
7.05 (d, Jd,c = 8.9 Hz, 6 H, Hd), 7.24–7.27 (m, 6 H, Hh, Hi,
Ho) ppm. 13C NMR (100.6 MHz, CD2Cl2, 293 K): δ = 18.4 (Cu),
25.4 (Ct), 28.6 (Cs), 50.9 (Cm)*, 51.1 (Ck)*, 55.5 (Ca), 63.1 (Cf),
67.8 (Cr), 68.8 (Cw), 84.4 (Cv), 113.1 (Cc), 115.3 (Cp), 124.5 (Cn),
128.8 (Co), 130.2 (Cj), 131.3 (Ch), 131.9 (Ci), 132.2 (Cd), 139.4 (Ce),
149.3 (Cg), 159.0 (Cb), 160.1 (Cq) ppm (* assignment of signals
might be interchanged). 19F NMR (282.4 MHz, CD2Cl2, 293 K): δ
= –149.48 (br., 10BF4), –149.54 (br., 11BF4) ppm. MS (ESI): m/z
(%) = 626.4 (100) [C41H44NO6]+. HRMS (ESI): m/z (%) calcd. for
[C41H44NO6]+ 626.3265; found 626.3276.
3β-(2-Azido)ethoxycholest-5-ene (3): 2-(Cholest-5-en-3β-oxy)ethyl
tosylate (19) (500 mg, 0.85 mmol, 1 equiv.) was dissolved in DMPU
(24 mL) under an argon atmosphere. Sodium azide (111 mg,
1.71 mmol, 2 equiv.) was added and the mixture was stirred at
50 °C for 24 h. After this time Et2O (100 mL) was added and the
organic phase was washed with aq. HCl (10%; 2ϫ 30 mL) and
brine (50 mL), and dried with MgSO4. The solvents were removed
under reduced pressure. Crystallization from ethanol gave 3 as
white crystalline needles (430 mg, 90 %). H NMR (400.1 MHz,
CDCl3, 293 K): δ = 0.67 (s, 3 H, Hcholesterol) 0.85–2.29 (m, 38 H,
Hcholesterol), 3.17–3.25 (m, 1 H, Hz), 3.36 (t, Jx,y = 5.2 Hz, 2 H,
Hx), 3.66 (t, Jy,x = 5.2 Hz, 2 H, Hy), 5.33–5.38 (m, 1 H,
4%). 1H NMR (400.1 MHz, CD2Cl2, 293 K): δ = 0.67 (s, 3 H,
3
Hcholesterol) 0.85–2.29 (m, 42 H, Hcholesterol, Hs, Ht), 2.76 (t, Ju,t
=
7.0 Hz, 2 H, Hu), 3.08–3.15 (m, 1 H, Hz), 3.38–3.47 (m, 8 H, HCH2,
3
W), 3.66–3.76 (m, 8 H, HCH2, W), 3.77 (s, 9 H, Ha), 3.82 (t, Jy,x
=
3
5.5 Hz, 2 H, Hy), 3.88 (t, Jx,y = 5.5 Hz, 2 H, Hx), 4.03–4.13 (m, 8
H, HCH2, W), 4.45 (t, Jr,s = 6.0 Hz, 2 H, Hr) 4.53–4.55 (m, 4 H,
Hk, Hm), 6.64 (d, Jp,o = 8.7 Hz, 2 H, Hp), 6.76–6.79 (m, 10 H, Hc,
HAr, W), 6.87–6.90 (m, 4 H, HAr, W), 7.06 (d, Jd,c = 8.9 Hz, 6 H,
3
3
1
3
Hd), 7.15–7.19 (m, 6 H, Hh, Hi, Ho), 7.40–7.46 (br., 2 H, Hl), 7.49
(s, 1 H, Hw) ppm. 13C NMR (100.6 MHz, CD2Cl2, 293 K): δ =
12.0, 14.2, 18.9, 19.5, 21.4, 22.7, 22.9, 24.2, 24.6, 25.6, 26.4, 28.4,
28.5, 28.6, 29.0, 29.7, 30.1, 32.3, 36.2, 36.5, 37.1, 37.4, 39.5, 39.8,
40.2, 42.6, 50.6, 50.9, 52.6, 55.6, 56.5, 57.1, 63.2, 66.8, 68.0, 68.6,
70.1, 70.6, 71.0, 71.1, 80.0, 113.1, 113.2, 114.6, 122.0, 122.1, 122.2,
123.8, 128.8, 129.7, 131.2, 131.5, 132.1, 139.4, 140.9, 147.7, 147.9,
149.4, 158.0, 160.1 ppm (an individual assignment of the signals
3
3
Holefin) ppm. 13C NMR (100.6 MHz, CDCl3, 293 K): δ = 12.0, 18.8,
19.5, 21.2, 22.7, 22.9, 23.9, 24.4, 28.1, 28.3, 32.0, 32.1, 35.9, 36.3,
36.9, 37.3, 39.1, 39.6, 39.9, 42.4, 50.3, 51.7, 56.3, 56.9, 66.9, 79.8,
121.9, 140.8 ppm (individual assignment of the signals was not pos-
sible). MS (EI): m/z (%) = 455.2 (7) [C29H49N3O]+·, 440.2 (12)
[C28H46N3O]+, 425.2 (51) [C27H43N3O]+, 410.1 (28) [C26H40N3O]+,
368.2 (100) [C27H44]+, 353.2 (25) [C26H41]+, HRMS (EI): m/z (%)
calcd. for [C29H49N3O]+· 425.3668; found 425.3665.
was not possible). MS (ESI): m/z (%) = 1530.9 ([C95H125N4O13
–
– +
BF4 ] , 100). HRMS (ESI): m/z (%) calcd. for [C95H125N4O13]+
1530.9271; found 1530.9240.
N-[4-(4-{1-[2-(Cholest-5-en-3b-oxy)ethyl]-H-1,2,3-triazol-4-yl}but-
oxy)-benzyl]-1-{4-[tris(4-methoxyphenyl)methyl]phenyl}-
Rotaxane·1·HBF4. Method A from (6·HBF4): A solution of rotax-
ane (6·HBF4) (7 mg, 4.32ϫ10–3 mmol, 1.0 equiv.) in iodomethane
(0.5 mL) was stirred at room temperature for 3 d under argon. The
solvent was removed under reduced pressure and the residue was
dissolved in a 1:1:2 mixture of CH2Cl2/acetone/water (2 mL). An
excess of NaBF4 was added and the mixture was stirred for 18 h at
room temperature. CH2Cl2 (7 mL) and water (5 mL) were added,
the phases separated and the aqueous layer extracted with CH2Cl2
(2ϫ15 mL). The combined organic layers were washed with water
(5 mL), dried with MgSO4, and concentrated under reduced pres-
sure to afford 1·HBF4 (7 mg, quant.) as a yellowish solid.
methylammonium Tetrafluoroborate (4·HBF4):
A solution of
2·HBF4 (40 mg, 0.06 mmol, 1.0 equiv.), 3 (38 mg, 0.08 mmol,
1.5 equiv.), and Cu(CH3CN)4BF4 (3.53 mg, 0.01 mmol, 0.2 equiv.)
in degassed CH2Cl2 (2 mL) was stirred in the dark for 48 h at room
temperature. The reaction was diluted with CH2Cl2 (10 mL) and
washed with EDTA·2Na(aq.) solution (0.1 m, 2ϫ 14 mL) and H2O
(2ϫ 14 mL). The organic layer was dried with MgSO4 and the
solvent was removed under reduced pressure. The crude product
was purified by flash column chromatography with silica gel and
EtOAc/MeOH/CH2Cl2 (1:1:1) as eluent to give 4·HBF4 as a yellow-
1
ish solid (38 mg, 55%). H NMR (400.1 MHz, CD2Cl2, 293 K): δ Method B from 1: Rotaxane 1 (7 mg, 4.32ϫ10–3 mmol, 1.0 equiv.)
= 0.67 (s, 3 H, Hcholesterol) 0.85–2.30 (m, 42 H, Hcholesterol, Hs, Ht), was dissolved in CH2Cl2 (0.7 mL). HCl (2.5 μL, 2 m in Et2O,
3
2.73 (t, Ju,t = 6.6 Hz, 2 H, Hu), 3.04–3.15 (m, 1 H, Hz), 3.76 (s, 9 5ϫ10–3 mmol, 1.15 equiv.) was added and the mixture was stirred
3
H, Ha), 3.80 (t, Jy,x = 5.1 Hz, 2 H, Hy), 3.89 (s, 2 H, Hm)*, 3.91
at room temperature for 1 h. The solvent was removed under re-
(s, 2 H, Hk)*, 3.95 (t, 3Jx,y = 5.5 Hz, 2 H, Hx), 4.43 (t, 3Jr,s = 6.0 Hz, duced pressure and the residue was dissolved in a 1:4:2 mixture of
2 H, Hr), 6.76 (d, Jc,d = 8.9 Hz, 6 H, Hc), 6.84 (d, Jp,o = 8.5 Hz, CH2Cl2/acetone/water (2.3 mL). An excess of NaBF4 was added
3
3
3
3
2 H, Hp), 7.08 (d, Jd,c = 8.9 Hz, 6 H, Hd), 7.18 (d, Ji,h = 8.5 Hz,
and the mixture was stirred for 18 h at room temperature. CH2Cl2
(7 mL) and water (5 mL) were added, the phases separated and the
2 H, Hi), 7.25–7.29 (m, 4 H, Hh, Ho), 7.45 (s, 1 H, Hw) ppm. 13C
NMR (125.8 MHz, CD2Cl2, 293 K): δ = 12.0, 18.9, 19.5, 21.4, 22.7, aqueous layer extracted with CH2Cl2 (2ϫ15 mL). The combined
22.9, 23.1, 24.2, 24.6, 25.7, 26.4, 28.4, 28.6, 28.6, 29.2, 30.1, 32.2,
32.3, 36.2, 36.6, 37.1, 37.4, 39.3, 39.9, 40.2, 50.6, 50.9, 53.0, 53.1,
55.3, 56.6, 57.1, 63.0, 66.8, 68.0, 80.0, 113.0, 114.6, 122.1, 122.2,
127.5, 128.5, 129.3, 129.6, 131.1, 132.2, 139.9, 140.9, 146.6, 147.8,
157.9, 158.5 ppm (an individual assignment of the signals was not
possible). 19F NMR (282.4 MHz, CD2Cl2, 293 K) δ = –151.22 (br.,
organic layers were washed with water (5 mL), dried with MgSO4,
and concentrated under reduced pressure to afford 1·HBF4 (7 mg,
quant.) as a yellowish solid. 1H NMR (500.1 MHz, CD2Cl2,
293 K): δ = 0.67 (s, 3 H, Hcholesterol) 0.86–2.33 (m, 42 H, Hcholesterol
,
3
Hs, Ht), 2.96 (t, Ju,t = 7.6 Hz, 2 H, Hu), 3.16–3.22 (m, 1 H, Hz),
3.37–3.46 (m, 8 H, HCH2, W), 3.66–3.75 (m, 8 H, HCH2, W), 3.76 (s,
5976
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5966–5978

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9 H, Ha), 3.94–3.98 (m, 4 H, Hy, Hx) 4.03–4.12 (m, 8 H, HCH2, W),
3
4.23 (s, 3 H, NCH3) 4.52–4.55 (m, 4 H, Hk, Hm), 4.71 (t, Jr,s
5.0 Hz, 2 H, Hr) 6.72 (d, Jp,o = 8.6 Hz, 2 H, Hp), 6.77 (d, Jc,d
=
=
3
3
8.9 Hz, 6 H, Hc), 6.78–6.81 (m, 4 H, HAr, W), 6.87–6.90 (m, 4 H,
3
3
H
Ar, W), 7.05 (d, Jd,c = 8.9 Hz, 6 H, Hd), 7.15 (d, Ji,h = 8.6 Hz, 2
3
3
H, Hi)*, 7.18 (d, Jh,i = 8.6 Hz 2 H, Hh)*, 7.21 (d, Jo,p = 8.6 Hz,
2 H, Ho) 7.41–7.47 (br., 2 H, Hl), 8.39 (s, 1 H, Hw) ppm (* assign-
ment of signals might be interchanged). 13C NMR (125.8 MHz,
CD2Cl2, 293 K): δ = 12.0, 14.2, 18.9, 19.5, 21.4, 22.7, 22.9, 23.1,
23.3, 23.8, 24.2, 24.6, 27.3, 28.4, 28.5, 30.0, 30.1, 32.2, 32.3, 36.2,
36.5, 37.1, 37.3, 37.9, 39.1, 39.9, 40.1, 42.6, 50.5, 52.3, 52.6, 54.8,
55.6, 56.8, 57.1, 63.2, 64.9, 67.4, 68.7, 70.6, 71.0, 80.1, 113.1, 113.2,
114.8, 122.0, 122.3, 123.9, 128.8, 129.0, 129.8, 131.3, 131.4, 132.1,
139.4, 140.7, 144.8, 148.0, 149.3, 158.0, 159.7 ppm (an individual
assignment of the signals was not possible). 19F NMR (282.4 MHz,
CD2Cl2, 293 K): δ = –152.98 (br., 10BF4), –153.04 (m, 11BF4) ppm.
MS (ESI): m/z (%) = 772.5 (100) [C96H128N4O13 – 2BF4–]2+, 1633.0
– +
(7) [C96H128N4O13 – BF4 ] . HRMS (ESI): m/z (%) calcd. for
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[C96H128N4O13]2+ 772.9750; found 772.9747: calcd. for
[C96H128N4O13BF4]+ 1631.9506; found 1631.9522.
Rotaxane·1: Aq. NaOH (1 mL, 1 m) was added to a solution of
1·HBF4 (7 mg, 4.32ϫ10–3 mmol, 1.0 equiv.) in CH2Cl2 (0.7 mL)
and the mixture was stirred at room temperature for 1 h. The reac-
tion mixture was diluted with CH2Cl2 (10 mL), the layers sepa-
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combined organic layers were dried with MgSO4, and concentrated
under reduced pressure to afford rotaxane 1 as a yellow solid (7 mg,
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1
1950–1960.
quant.). H NMR (500.1 MHz, CD2Cl2, 293 K): δ = 0.69 (s, 3 H,
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H, Hz), 3.59–4.12 (m, 46 H, Ha, Hk, Hm, Hr, Hu, Hx, Hy, HCH2, W
,
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NCH3), 4.80–5.05 (br., 1 H, Hl), 6.73–6.90 (m, 16 H, Hc, Hp, HAr,
3
3
W), 7.09 (d, Jd,c = 8.7 Hz, 6 H, Hd), 7.14 (d, Ji,h = 8.2 Hz, 2 H,
3
3
Hi)*, 7.20 (d, Jh,i = 8.2 Hz, 2 H, Hh)*, 7.26 (d, Jo,p = 8.1 Hz, 2
H, Ho), 8.76 (s, 1 H, Hw) ppm (* assignment of the signals might
be interchanged). 13C NMR (125.8 MHz, CD2Cl2, 293 K): δ =
12.0,14.2, 15.5, 18.9, 19.5, 21.4, 22.7, 22.9, 23.1, 24.2, 24.6, 28.4,
28.6, 32.2, 32.3, 36.2, 36.6, 37.1, 37.5, 39.9, 40.2, 42.7, 50.6, 55.5,
56.6, 57.2, 66.0, 68.7, 70.4, 71.4, 79.9, 112.4, 113.0, 113.1, 114.4,
121.4, 127.4, 129.7, 130.7, 131.1, 132.2, 133.1, 138.5, 139.9, 146.7,
148.1, 157.9 ppm (an individual assignment of the signals was not
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,
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Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
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ˇ
Eur. J. Org. Chem. 2015, 5966–5978
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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M. Berg, S. Nozinovic, M. Engeser, A. Lützen
FULL PAPER
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Received: May 21, 2015
Published Online: August 6, 2015
5978
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5966–5978