Fluorine-Substituted Molecular Motors with a Quaternary Stereogenic Center

Article abstract of DOI:10.1002/chem.201700581

A series of unprecedented second generation molecular motors featuring a quaternary stereogenic center substituted with a fluorine atom has been synthesized. It is demonstrated that a seemingly benign replacement of the stereogenic hydrogen for a fluorine atom, regarded as a common substituent in pharmacology, resulted in a dramatic change in the energetic profile of thermal helix inversion. The barrier for the thermal helix inversion was found to increase considerably (by 20–30 kJ mol^?1), presumably due to destabilization of the transition state by increased steric hindrance when the fluorine atom is forced to pass over the lower half of the motor. This results in the activation barrier for the thermal helix inversion to be higher than the barrier for backward thermal E–Z isomerization, impairing the motor function. A fluorine-substituted motor capable of performing unidirectional rotation is successfully prepared when these limitations are considered in the design phase.

Full text of DOI:10.1002/chem.201700581

A Journal of
Accepted Article
Title: Fluorine-substituted molecular motors with a quaternary
stereogenic center
Authors: Peter Štacko, Jos C. M. Kistemaker, and Ben Lucas Feringa
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To be cited as: Chem. Eur. J. 10.1002/chem.201700581
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Fluorine-substituted molecular motors with a quaternary
stereogenic center
Peter Štacko[a], Jos C. M. Kistemaker[a] and Ben L. Feringa*[a]
Abstract: A series of unprecedented second generation molecular motors featuring a quaternary stereogenic center substituted with a
fluorine atom has been synthesized. It is demonstrated that a seemingly benign replacement of the stereogenic hydrogen for a fluorine atom,
regarded as a common substituent in pharmacology, resulted in a dramatic change in the energetic profile of thermal helix inversion. The
barrier for the thermal helix inversion was found to increase considerably (by 20−30 kJ·mol−1), presumably due to destabilization of the
transition state by increased steric hindrance when the fluorine atom is forced to pass over the lower half of the motor. This results in the
activation barrier for the thermal helix inversion to be higher than the barrier for backward thermal E-Z isomerization, impairing the motor
function. A fluorine-substituted motor capable of performing unidirectional rotation is successfully prepared when these limitations are
considered in the design phase.
application of the compound 1 as an electrochemically driven
unidirectional molecular motor. Potentially blocking this position
Introduction
with an additional substituent and thus preventing the undesired
On a daily basis, we are fortunate to witness the impressive
deprotonation step could alleviate this issue and allow for the
collection of molecular machines and nanosystems developed
construction of a reversible redox-active and unidirectional
by Nature to operate complex biological processes responsible
molecular motor.
for various key functions in living organisms.[1,2] Complimenting
the level of sophistication and elegance that evolved within the
design of these systems, the ability of Nature to harness the
proton gradient across a membrane to drive the rotation of the
axle in the ATPase motor[3–6] or to drive flagella of bacteria[7–10]
has served as inspiration for scientists to achieve redox-driven
molecular motion in a controlled fashion.[11–14] The importance of
achieving molecular machine functions utilizing redox
switching[15–21] was recognized as it promises to allow single or
small groups of molecules to be addressed more easily than
with a either chemical fuel or with light.[22–24]
Scheme 1. Olefinic double bond shift inside the ring of the upper half upon
For example, Sauvage and co-workers reported that changes
in the [copper(I)/(II)] redox state resulted in a change of the
electrochemical oxidation of the motor 1 to 2 in presence of traces of water.[34]
coordination number, leading to rotation of two interlocked rings
in a catenane.[15] An alternative approach adopted by Stoddard
Table 1. Selected thermodynamic and kinetic parameters for thermal helix
and co-workers exploited the change of the affinity of a moiety in
a rotaxane, inducing translational motion upon a change in its
redox state.[25] Alternatively, the structural changes observed
during photochemical isomerization being mimicked by redox
inversion of second generation motors with various substituents at the
stereogenic center.
switching has been demonstrated for a molecular nanocar[26]
,
dithienylethene[27,28], and spiropyran-based[29–31] switches as well
as dithienylethene switches immobilized[32,33] on surfaces.
In the recent attempt of Logtenberg et. al. to devise a
unidirectional electrochemically driven molecular motor based
on
a
second generation motor, it was observed that
R
∆‡G°
k (293 K)
[s−1
t1/2(293 K)
deprotonation at the stereogenic center results in double bond
migration inside the upper rotor half and this constitutes the
major degradation pathway since it leads to a release of the
strain around the overcrowded double bond axle (Scheme 1).[34]
In that study, the molecular motor 1 was electrochemically
oxidized to dication 2. However, in the presence of water, 2
underwent irreversible deprotonation to restore aromaticity of the
naphthalene moiety as confirmed by X-ray structure
determination. The formation of side product 3 hindered further
[kJ·mol−1
]
]
[s]
88
85
84
60
1.18 × 10−3
3.64 × 10−3
7.32 × 10−3
1.21 × 102
587
190
Ph
Me
i-Pr
tBu
95
5.74 × 10−3
[a]
P. Štacko, J. C. M. Kistemaker, Prof. Dr. B. L. Feringa
Centre for Systems Chemistry,Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG Groning en, The Netherlands
Fax:(+ 31) 50-363-4296
Additional studies on the impact of structural modifications of
the stereogenic center are imperative from other perspectives as
well. Numerous derivatives of the upper and lower halves of the
second generation motors have been made over the course of
years in our group. Both first and second generation motors with
five- and six- membered upper and lower halves have been
synthesized and the consequences of such structural alterations
on the motor properties have been evaluated.[35–39] Few
E-mail:b.l.feringa@rug.nl
Supporting information for this article is given via a link at the end of
the document.
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investigations into an important structural motif, the stereogenic
center, have been made. Substituents distinct from the typical
methyl group such as phenyl, t-butyl or methoxy groups have
been reported for second generation motors (Table 1).[35,38] From
these investigations, it could be concluded that the activation
barrier for the thermal helix inversion decreases as the relative
bulk of the substituent at the stereogenic center increases. To
the best of our knowledge, no reports with a quaternary
stereogenic center on first or second generation molecular
motors have been published.
oxidation of the starting material into the corresponding α,β-
unsaturated ketone, presumably via an SET mechanism.[41–44]
Therefore, a functional molecular motor featuring a quaternary
stereogenic center is valuable for certain applications that
require a higher stability of the overcrowded alkenes; such as
redox-driven systems or to serve as an additional tool for tuning
the rotary speed of the motors. Quaternarization of the
stereogenic center is not an easy task as an appreciable
difference in size of the two substituents must be preserved in
order to retain unidirectionality of the molecular motor. At the
same time, increasing the steric hindrance in this position
complicates synthesis; in particular functionalization of the
corresponding ketone intermediate as well as the Barton-Kellogg
coupling used for construction of the overcrowded alkenes.
Based on these consideration, replacement of the hydrogen
atom for fluorine was proposed since fluorine (71 pm) is “only”
twice the size of hydrogen atom (37 pm)[40] and is often
considered
a
suitable replacement for hydrogen in
pharmacology in order to improve stability or lipophilicity of lead
compounds. To this end, we set out to synthesize fluoro-
analogues of the second generation motor 4–6 (Figure 1).
Scheme 2. Reaction conditions: (i) methacrylic acid, Et3N, THF, 16 h, 79%; (ii)
1. (COCl)2, DCM; 2. AlCl3, DCM, 86%; (iii) 1. NaHMDS, toluene, −78 °C, 1 h;
2. NFSI, rt, 16 h, 67%; (iv) Lawesson’s reagent, P4S10, toluene, 110 °C, 3 h;
(v) THF, rt, 16 h; (vi) HMPT, toluene, 50 °C, 16 h, 17%.
With the fluorinated ketone 9 in hand, transformation of the
carbonyl into a hydrazone or a thioketone was investigated.
Reaction with NH2NH2.H2O led to a complex reaction mixture,
however, transformation of 9 into the thioketone 10 could be
carried out using a combination of P4S10 and Lawesson’s
reagent at reflux in toluene. Reaction times substantially longer
than 3 h led to decomposition of the product. The thioketone 10
was then reacted with freshly prepared diazo-compound 11 and
the resulting episulfide 12 was to be desulphurized to give the
target molecule 4. Since PPh3 was not reactive enough to
promote the desulphurization in this hindered system, alternative
methods had to be explored. After unsuccessful attempts with
Zn/Cu/(p-OMePh)3P, HMPT was employed as a more reactive
phosphine to facilitate the reaction. Interestingly, the resulting
overcrowded alkene was found to be prone to oxidation into the
corresponding dication during purification on silica gel.
Figure 1. Target fluoro-analogues of previously reported second generation
motors.
Results and Discussion
Synthesis
The upper halves 13 and 14 for the purpose of further
functionalization and synthesis of fluorinated motors 5a-b and 6
were synthesized by a reaction of p-xylene or naphthalene with
methacryoyl chloride in the presence of AlCl3 at low temperature.
The ketones 13 and 14 were fluorinated at the α-position using
LiHMDS/NFSI in toluene in 83% and 85% yield, respectively
(Scheme 3). Thionation of 15-16 with a mixture of P4S10 and
Lawesson’s reagent in toluene at reflux afforded the thioketones
17-18 that were immediately reacted with 9-diazo-9H-fluorene or
its 2-methoxy derivative. The episulfides 19a-b and 20 were
conveniently desulphurized in situ with HMPT at room
temperature. The motors 5a-b and 6 were isolated in 49%, 25%
and 50% yield, respectively, as yellow orange solids after
column chromatography (silica gel) of the reaction mixture
adsorbed on Celite. Prolonged exposure to silica gel, either
during adsorption or column chromatography, resulted in partial
The synthesis of the fluorinated analogue of the second
generation motor 4 started with preparation of the upper half 9
(Scheme 2). Previously, the synthesis of precursors started with
a Michael addition of naphthalene-2-thiol to methacrylonitrile.
However, due to safety issues, methacrylonitrile was no longer
commercially available and a different synthetic sequence had to
be conceived. Therefore, naphthalene-2-thiol was added in a
Michael reaction to methacrylic acid in the presence of Et3N
(Scheme 2). The resulting carboxylic acid 7 was treated with
oxalyl chloride and the resulting acyl chloride was subjected to
an intramolecular Friedel-Crafts acylation in the presence of
AlCl3 to give the upper-half ketone
8 in excellent yield.
Installation of the fluorine atom in the α-position was carried out
by deprotonation with NaHMDS at −78 °C, followed by a
reaction with NFSI in toluene. Different bases gave product 9 in
lower or negligible yield, and the use of THF as a solvent led to
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decomposition of the product. The motor 5b was isolated as
nearly pure E-isomer by repeated crystallization from ethanol.
The E- geometry was assigned based on H NMR absorption of
leads to partial separation of the regioisomers. Installation of the
fluorine atom proved to be not as straightforward as for previous
molecules. In general, the reaction of 21 with NFSI suffered from
poor and variable conversion, combined with poor separation of
the product from the starting material which substantially
lowered the yield. The yield was also highly dependent on the
quality of the solvent and NFSI. Different reagents used for
electrophilic fluorination such as N-fluoropyridinium salts or
Selectfluor did not lead to the desired product. At this point, the
ketone 22 was converted into the thioketone 23 with a mixture of
P4S10 and Lawesson’s reagent in toluene at reflux. After
purification by quick column chromatography, the thioketone 23
was immediately reacted with 9-diazo-9H-fluorene or its
2-methoxy derivative to give the episulfides 24a-b, which were
desulphurized in situ with HMPT to give the final motor 25a and
the desymmetrized analogue 25b with an Z-configuration. The
geometry of 25b was assigned based on the 1H NMR resonance
of the methoxy group (δ (ppm) = ~3.90 ppm) in analogy with
reported motors.[45,46]
1
the methoxy group (δ (ppm) = 2.92 ppm) in analogy with
reported second generation motors.[45,46]
Photochemical and thermal isomerizations
The photochemical and thermal behavior of 4 was examined in
solution using UV-vis absorption in order to understand the
influence of quaternarization of the stereogenic center on these
processes. The UV-vis absorption spectrum of the fluorinated
motor 4 in heptane at 293 K shows an absorption band centered
at 392 nm (Figure 2, black). Irradiation of the sample with UV
light (365 nm) under ambient conditions led to the formation of a
broad band between 500 and 550 nm with two local maxima.
Identical spectral changes were observed throughout the
electrochemical experiments of the parent desfluoro compound
1[34], suggesting a photooxidation to the dication 2 is taking place.
The solution of 4 was therefore deoxygenated with three freeze-
pump-thaw cycles and irradiation with UV light (365 nm) was
repeated. In this case, an increase of intensity of the band at
392 nm was observed (Figure 2, blue). This observation is
consistent with a formation of the unstable form of second
generation motors. The irradiation was continued until the
photostationary state (PSS) was reached. Leaving the sample to
stand in the dark or heating the sample to 363 K for 16 hours
resulted in a complete retention of the band at 391 nm (Figure 2,
red dashed). The initial spectrum was not recovered, indicating a
very high barrier for the anticipated thermal helix inversion (THI),
compared to the barrier of 105.6 kJ·mol−1 reported for the parent
compound.[46]
Scheme 3. Reaction conditions: (i) 1. LiHMDS, toluene, −78 °C, 1 h; 2. NFSI,
rt, 16 h, 83–85%; (ii) Lawesson’s reagent, P4S10, toluene, 110 °C, 1 h; (iii) 9-
diazo-9H-fluorene or 9-diazo-2-methoxy-9H-fluorene, toluene, rt, 16 h; (iv)
HMPT, toluene, rt, 16 h; 5a: 49%, E-5b: 49%, 6: 50% over 3 steps.
Scheme 4. Reaction conditions: (i) 1. LiHMDS, toluene, −78 °C, 1 h; 2. NFSI,
rt, 16 h, 38%; (ii) Lawesson’s reagent, P4S10, toluene, 110 °C, 1 h; (iii) 9-diazo-
9H-fluorene or 9-diazo-2-methoxy-9H-fluorene, toluene, rt, 16 h; (iv) HMPT,
toluene, rt, 16 h; 25a: 61%, Z-25b: 54% over 3 steps.
The upper half ketone 21 based on a benzo[b]thiophene moiety
was previously synthesized from benzo[b]thiophene and
methacrylic acid in PPA. This procedure leads to a mixture of
two regioisomers that are difficult to separate by column
chromatography and only the use of a slow gradient of eluent
Figure 2. UV-vis absorption spectra (heptane, 293 K, c = ~4×10-5 M). Stable 4
(black solid); irradiation to PSS at 293 K (blue solid); after heating the sample
to 363 K for 16 h (dashed red).
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Figure 3. UV-vis absorption spectra (heptane, 293 K, c = ~2–4×10-5 M). (a) stable 5a (black solid); irradiation to PSS at 293 K (blue solid); after heating the
sample to 353 K (dashed red). (b) stable 6 (black solid); irradiation to PSS at 293 K (blue solid); after heating the sample to 353 K (dashed red). (c) stable 25a
(black solid); irradiation to PSS at 273 K (blue solid); after heating the sample to 293 K (dashed red).
In order to verify the hypothesis that installation of the fluorine
atom at the stereogenic center leads to a large increase of the
barrier for thermal helix inversion, two fluoro-substituted motors
Table 2. Selected thermodynamic parameters of the thermal step for the
motors 5a-b, 6 and 25a and their corresponding desfluoro analogues.
5 and 6, derived from second generation motors with much
∆‡G°
∆‡H°
∆‡S°
lower barriers for THI, were proposed. It was assumed that since
the THI barrier for the desfluoro analogues is fairly low, the
measurement of activation parameters for THI will still be
possible despite the anticipated significant increase of the
barrier induced by the introduction of a fluorine atom in the
molecules.
The fluorinated analogues 5 and 6 were therefore synthesized
(Scheme 3, vide infra) and their photochemical and thermal
behavior was investigated in solution using UV-vis absorption,
1H and 19F NMR spectroscopy. The UV-vis absorption spectra of
the motors 5 and 6 in heptane at 293 K show absorption bands
centered at 387 and 363 nm, respectively (Figure 3a-b, solid
black). Irradiation of the samples with UV light (365 nm) under
Motor
t1/2(293 K)
[kJ·mol−1
]
[kJ·mol−1
]
[J·K−1·mol−1
]
5a
106.2±0.2
105.9±0.3
86.1
106.0±1.6
102.9±1.7
71.8
−0.8±4.5
−10.6± 4.9
−48.7
11.1±1.1 d
10.1±1.2 d
4.3 min
5b
desfluoro-5a[47]
6
104.3±0.3
79.1
97.7±1.9
n.d.
−22.6±5.7
n.d.
5.2±0.5 d
15 s
desfluoro-6[37]
25a
88.4 ± 0.0
71.1
65.1 ± 0.2
34.0
−79.5± 0.5
−126
642 ± 1 s
520 ms
ambient
conditions
resulted in
the
emergence of
desfluoro-25a[47]
bathochromically shifted absorption bands at 417 and 379 nm,
respectively, indicating the formation of the unstable forms of
motors 5 and 6 (Figure 2a-b, blue solid). Throughout the
irradiation, a single isosbestic point was observed in each case.
After the PSS was reached, the samples were heated at 353 K
for several hours and full reversal to the original UV-vis spectra
was observed, indicating that either the anticipated thermal helix
inversion or an undesired backward thermal E-Z isomerization is
taking place (Figure 3a-b, red dashed). The UV-vis absorption
spectra of the desymmetrized motor E-5b in heptane at 293 K
and its photochemical/thermal behavior was found to be nearly
identical to that of 5a (see SI, Figure S31).
The rate constants for the thermal isomerization were
measured at five different temperatures between 333 and 358 K
by following the change in UV-vis absorption spectra over time.
Multivariate analysis was performed on the array of the spectra,
providing the rate constant for each temperature. The Eyring plot
was then constructed and the activation parameters for the
thermal process were derived from the linear fit (see SI, Figure
S32 and S33). The Gibbs free energy of activation ∆‡G° for
thermal isomerization of the unstable 5a back to the stable 5a
was found to be 106.2±0.2 kJ·mol−1, corresponding to a half-life
of 11.1±1.1 days at room temperature (Table 2). In the case of 6,
the Gibbs free energy of activation ∆‡G° for thermal
isomerization of the unstable 6 back to the stable 6 was found to
be 104.3±0.3 kJ·mol−1, corresponding to a half-life of 5.2±0.5
days at room temperature (Table 2). Only a negligible influence
of the methoxy substituent on the activation parameters of the
thermal step was observed for 5b (Table 2, Figure S33).
The observed values for 5 and 6 are in a stark contrast with
those reported for the desfluoro[37,48] analogues which were
found to be 86.1 kJ·mol−1 and 79.1 kJ·mol−1, corresponding to
half-lives of 190 and 15 s, respectively, reaffirming the
hypothesis of a large increase of the THI activation barrier upon
substitution at the stereogenic center. In both cases, the ∆‡G° of
the thermal isomerization is increased by 21−25 kJ·mol−1 upon
fluorine substitution, presumably due to destabilization of the
transition state in which the pseudoaxially oriented fluorine atom
is forced to pass over the top of the lower half. Due to the
difference in size of the fluorine and hydrogen atom (and length
of the bond), it can be expected that the steric repulsion will be
higher for the former case, hence the increase in the energy of
the transition state, translating into an increase of ∆‡G°. At this
point, due to enhanced activation energy for the thermal step,
desymmetrization of the lower half was required to unequivocally
establish whether the thermal process being observed is a
backward thermal E-Z or indeed the thermal helix inversion. For
this purpose, a methoxy substituent was introduced in motor 5b.
The nature of the thermal step was probed using 1H and 19F
NMR spectroscopy. A sample of E-5b in d8-toluene (Figure 4a,
left) was prepared since in the preliminary experiments
decomposition in CDCl3 was observed upon irradiation and a
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Figure 4. 1H and 19F NMR spectroscopy (400 MHz, d8-toluene, 293 K, c = ~1×10-2 M). (a) 1H NMR (left) and 19F NMR (right) of the stable E-5b. (b) irradiation
(365 nm) to PSS and formation of the corresponding unstable Z-5b. (c) after heating to 323 K for 16 h mostly regeneration of the stable E-5b is observed.
higher temperature was required for the thermal isomerization.
The sample was irradiated with UV-light (365 nm) at 293 K until
PSS (85:15) was reached and 1H and 19F NMR spectra were
recorded. The most significant change that occurred was a shift
of the methoxy group resonance from 2.69 ppm to 3.53 ppm as
a result of a photochemical E-Z isomerization of stable E-5b to
unstable Z-5b. An upfield shift of Ha from 3.62 ppm to ~3.23 ppm
and a downfield shift of Hb from 2.83 ppm to ~3.23 ppm was also
observed (Figure 4b, left).
installation of a fluorine atom at the stereogenic center increases
the barrier for thermal helix inversion (>25 kJ·mol−1) to the extent
that backwards thermal E-Z isomerization now becomes
competitive.
The preceding experiments demonstrated that a scaffold with
even less steric hindrance in the fjord region is required to
preserve proper motor function upon introduction of fluorine. For
this purpose, a benzothiophene-based upper-half was chosen,
since it has been shown that the molecular motor featuring this
upper-half possesses an extremely low barrier for thermal helix
In the 19F NMR spectrum, the formation of an additional
resonance at −128.4 ppm was clearly observed (Figure 4b, right). inversion (∆‡G° = 71.1 kJ·mol−1, t1/2(298 K) = ~520 ms).[47] Such
These changes are consistent with formation of the unstable Z-
5b. The sample was then heated to 323 K for 16 h and H and
a low initial barrier should allow for considerable destabilization
(up to ~30 kJ·mol−1) of the transition state of thermal helix
inversion with respect to the unstable form, while still rendering
the thermal E-Z isomerization noncompetitive. Based on this
prediction, the fluorinated motor 25a and its desymmetrized
version 25b with a benzothiophene upper-half were synthesized
(Scheme 4, vide supra). Although less chemically stable than
the predecessors 5a-b or 6, their photochemical and thermal
behavior in solution was investigated using UV-vis absorption,
1H and 19F NMR spectroscopy.
1
19F NMR spectrum were recorded again (Figure 4c, left for 1H
NMR, right for 19F NMR). Unfortunately, only about 10% of the
expected stable Z-5b was observed and mostly regeneration of
the stable E-5b was detected. Heating the unstable Z-5b at
348 K, the proportion of stable Z-5b changed to ~27%. It could
be concluded that the thermal step observed at this temperature
can be attributed predominantly to the backwards thermal E-Z
isomerization, with the thermal helix inversion being a minor
pathway. As hypothesized earlier, it has been confirmed that the
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Figure 5. 1H and 19F NMR spectroscopy (400 MHz, CD2Cl2, 233 K, c = ~1×10-2 M). (a) 1H NMR (left) and 19F NMR (right) of the stable Z-25b. (b) irradiation
(365 nm) to PSS at 233 K and formation of the corresponding unstable E-25b; the mixture consists of stable Z-25b (38%), stable E-25b (4%), unstable E-25b
(50%) and unstable Z-25b (8%). (c) after heating to 293 K for 16 h. formation of stable E-25b is observed, confirming that thermal helix inversion is taking place.
The UV-vis absorption spectra of 25a in heptane at 273 K
shows an absorption band centered at 375 nm (Figure 3c, solid
black). Irradiation of the samples with UV light (365 nm) at 273 K
gave rise to a bathochromically shifted absorption band at
394 nm, indicating the formation of the unstable diastereoisomer
(Figure 3c, blue solid). A single isosbestic point was observed
throughout the irradiation. After the photostationary state (PSS)
was reached, the sample was warmed to 293 K for 30 min and
full reversal to the original UV-vis spectra was observed,
indicating that either the anticipated thermal helix inversion or
possibly the thermal backward E-Z isomerization is taking place
(Figure 3c, red dashed). Eyring analysis of the thermal step was
temperature. This is due to a relatively small difference in energy
between the stable Z-25b and its corresponding unstable Z-25b
(<10 kJ·mol−1) as confirmed by computations (vide infra).
Irradiation of the sample with UV-light (365 nm) at 233 K
resulted in the appearance of unstable E-25b according to both
1H and 19F NMR spectroscopy (Figure 5b). The most significant
change that occurred was a shift of the methoxy group
resonance from 3.89 ppm to 3.34 ppm as a consequence of the
photochemical E-Z isomerization of stable Z-25b to unstable
E-25b. In the region of the resonance of the stereogenic methyl
group of unstable Z-25b (~2.20 ppm), an additional methyl
resonance at ~2.35 ppm appeared, reinforcing the fact that the
performed using a procedure identical to compounds 5a-b and 6. minor compound observed in the initial sample is indeed
The Gibbs free energy of activation ∆‡G° for thermal
isomerization of the unstable 25a back to the stable 25a was
found to be 88.4±0.0 kJ·mol−1 (∆‡H° 65.1±0.2 kJ·mol−1, ∆‡S°
−79.5±0.5 J·K−1·mol−1), corresponding to a half-life of 642±1 s at
room temperature (Table 2). Just like in the previous cases, the
observed value for the thermal step is much higher than that
unstable Z-25b. A downfield shift of Ha/b from 3.40 ppm to
3.67 ppm was also observed (Figure 5b, left). Likewise, in
addition to the two original resonances in the 19F NMR spectrum
at −133.1 ppm (major, stable Z-25b) and −126.1 ppm (minor,
unstable Z-25b), an additional absorption at −126.8 ppm
emerged upon irradiation due to formation of unstable E-25b
(Figure 5b, right). When the PSS was reached, the mixture
consisted of stable Z-25b (38%), stable E-25b (4%), unstable E-
25b (50%) and unstable Z-25b (8%) as determined by
integration of the resonances in 19F NMR spectrum. The sample
was then heated to 293 K for 30 min and 1H and 19F NMR
spectrum were recorded again (Figure 5c, left and right
respectively). After performing the thermal step, the mixture
consisted of stable Z-25b (46%) and E-25b (54%) and residual
amounts of the unstable forms (see ratios before). These data
unequivocally demonstrate that the barrier for THI is lower than
for the backward thermal E-Z isomerization, facilitating the ability
reported for the desfluoro parent compound (∆‡G°
=
71.1 kJ·mol−1, t1/2(298 K) = 520 ms).[47]
While such a low barrier (∆‡G° < 100 kJ·mol−1) has not been
observed for
a thermal E-Z isomerization before, it was
necessary to exclude this possibility and assess the nature of
the thermal step by 1H and 19F NMR spectroscopy of the
desymmetrized motor 25b. A sample of Z-25b in CD2Cl2
(Figure 5a) was thus prepared. Interestingly, a minor amount
(~10%) of the unstable Z-25b (additional methyl resonance at
2.21 ppm and fluorine resonance at −126.1 ppm) was present in
the sample prior to irradiation and after extensive heating,
furthermore, the ratio was found to be dependent on
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of 25a-b to functional as photochemically driven unidirectional
molecular motors.
thermochemistry (Table 3) shows the barrier for THI to follow the
same trend as the parent desfluoro analogues, however, the
individual barriers of the motors 5a, 6 and 25a are significantly
higher (Table 2). The barriers for the motors 5a and 6 are of
such magnitude that high temperatures would be required to
bring about their THI, thus allowing backward thermal E-Z
isomerization to become a competing process. The increase in
energy is caused by additional steric hindrance of the fluorine
atom with the lower half. While the major part of the barrier
stems from the hindrance of the moieties in the fjord region, the
smallest substituent on the stereogenic center comes into close
proximity of the lower half as well (see TS’s in Figure 6). The
result is that the lower halves of the transition states require a
larger degree of folding than their hydrogen substituted
analogues. These results are consistent with the experimental
observations made for 5a and 6, for which a considerable
increase (>20 kJ·mol−1) of the THI barrier has been found,
resulting in thermal backward E-Z isomerization being the major
process (Table 2, Figure 4). At the same time, the calculated
barrier for THI of 25a (88.9 kJ·mol−1, Table 3) is in a perfect
agreement with the experimentally obtained value of
88.4 kJ·mol−1 (Table 2) and the observed forward thermal helix
inversion pathway
Computational results
The experimental study of the thermal behavior of the unstable
diastereoisomers (5, 6 and 25a) of the fluorinated motors was
supplemented with a computational investigation using DFT
calculations. Initial geometries were optimized using the semi-
empirical PM3 method after which the thermal helix inversion
was studied by scanning dihedral angles governing the aromatic
planes (indicated by bold bonds in the structures in Figure 6)
using the same method. The minima and transition states were
further optimized by DFT (B3LYP/6-31G(d,p)) and a frequency
analysis confirmed the identity of each geometry as well as
providing their thermochemistry.
Table 3. Calculated thermochemistry of motors 5a, 6 and 25a (DFT
B3LYP/6-31G(d,p)).
Motor
5a
8.7
2.8
133
124
6
25a
4.3
∆G° unstable[a] [kJ·mol−1
]
9.5
2.0
127
118
unstable [%][b]
15
∆G° TS [kJ·mol−1
]
93.2
88.9
∆‡G° TS [kJ·mol−1
]
[a] Energy difference between the stable and the corresponding unstable state.
[b] Boltzmann population of the unstable state at rt.
Due to the fluorine atom replacing the stereogenic hydrogen,
the difference in Gibbs energy between the stable and unstable
configurations of 25a-b has decreased, leading to a measurable
population (15% by DFT, Table 3) of the unstable 25a state
under equilibrium conditions, as has been observed
experimentally by both 1H and 19F NMR spectroscopy for
unstable Z-25b (~10%, Figure 5). The drop in the difference in
energy agrees well with the reduction in the difference in
substituent size on the stereogenic center, and suggests that a
population of the unstable configuration can be reduced by, for
example, a replacement of the methyl group by a tert-butyl
group.
Figure 6. Quaternarized second generation molecular motors 5a, 6 and 25a.
Side-view of the calculated geometries (DFT B3LYP/6-31G(d,p)) of the
unstable and stable diastereoisomers as well as the transition state (TS).
The calculated geometries of 5a, 6 and 25a are shown in
Figure 6, exhibiting a large consistency in configuration between
the different molecules. The global minimum, i.e. the stable
isomer, for all quaternarized motors is found to orient the fluorine
at the stereogenic center pseudo-equatorially towards the lower
half analogous to the orientation of the stereogenic hydrogen in
common second generation molecular motors.[46] In the same
way were all local minima, i.e. the unstable isomers, found to
orient the stereogenic fluorine pseudo-axially. The unstable
states of the studied motors (5a, 6 and 25a) were all connected
Conclusions
A series of fluorinated second generation motor analogues (4,
5a-b, 6 and 25a-b) with a quaternary stereogenic center have
been synthesized. A major increase (20–25 kJ·mol−1) in the
barrier for thermal isomerization compared to the parent
compounds has been observed for all the cases, presumably
due to destabilization of the transition state in which the fluorine
is forced to pass around the lower half. Being larger in size than
the original hydrogen, the steric penalty imposed on the
molecule is larger, leading to an increase in energy for the
to the corresponding stable state by
a transition state
constituting a thermal helix inversion pathway. The calculated
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transition state. It has been experimentally demonstrated (and
supported by calculations), that a motor with a sufficiently low
(d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 7.8,
7.8 Hz, 1H), 7.49 (dd, J = 7.4, 7.4 Hz, 1H), 7.21 (d, J = 8.7 Hz,
1H), 3.74 (dd, J = 13.1, 7.9 Hz, 1H), 3.25 (dd, J = 12.4, 12.7 Hz,
1H), 1.82 (d, J = 21.5 Hz, 3H).13C NMR (100 MHz, CDCl3): δ
(ppm) 193.3 (d, J = 19.0 Hz), 143.1, 134.5, 132.9, 131.7, 129.7,
128.7, 126.2, 125.4, 124.5, 123.6, 91.9 (d, J = 186.3 Hz), 35.5 (d,
J = 28.1 Hz), 20.9 (d, J = 25.1 Hz). 19F NMR (376 MHz, CDCl3):
δ (ppm) −149.6. HRMS (APCI+): calcd for C14H12FOS (M + H+)
247.0587 found 247.0589.
barrier for THI (25a-b) can still function as
a proper
unidirectional photochemically driven molecular motor upon
fluorination. This modification opens additional avenues in tuning
the speed and stability of the molecular motors leading to new
potential applications.
Note: Use of THF as a solvent instead of toluene drastically
decreases the yield of the desired product (<10%) due to
formation of 2-methyl-1H-benzo[f]thiochromen-1-one as the
major product.
2-Fluoro-2-methyl-1-(9H-thioxanthen-9-ylidene)-2,3-dihydro-
1H-benzo[f]thiochromene (4).
Experimental Section
2-Methyl-3-(naphthalen-2-ylthio)propanoic acid (7).
Methacrylic acid (4.2 ml, 50.0 mmol) was added slowly to a
stirred solution of naphthalene-2-thiol (4.0 g, 25.0 mmol) and
triethylamine (6.96 ml, 50.0 mmol) in THF (50 ml) at room
temperature. The resulting mixture was heated to reflux for 16 h.
Subsequently, it was quenched with aq. HCl (1 M) until the
mixture was acidic (pH = 2). The mixture was extracted with
ethyl acetate (3 × 50 ml). The combined organic extracts were
washed with brine (50 ml), dried over MgSO4 and the solvents
evaporated at reduced pressure. The residue was recrystallized
from heptane (~ 40 ml) to give the product 7. Yield: 4.86 g (79%).
Tan solid. Mp 89.3–90.5 °C. 1H NMR (400 MHz, CDCl3): δ (ppm)
10.3 (brs, 1H), 7.787.85 (m , 4H), 7.447.52 (m, 3H), 3.41 (ddd,
J = 13.4, 6.8, 1.8 Hz, 1H), 3.04 (ddd, J = 13.4, 7.0, 1.5 Hz, 1H),
2.78 (m, 1H), 1.45 (dd, J = 7.0, 1.5 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 181.6, 133.9, 133.0, 132.2, 128.8, 128.5, 128.1,
127.9, 127.4, 126.8, 126.1, 39.8, 37.1, 16.7.
2-Methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-one (8).
Oxalyl chloride (2.83 ml, 32.3 mmol) was added dropwise to a
solution of 7 (5.3 g, 21.5 mmol) and three drops of DMF in dry
CH2Cl2 (80 ml) at room temperature under N2 atmosphere. After
stirring for 1 h, the volatiles were evaporated at reduced
pressure and the residue was redissolved in dry CH2Cl2 (80 ml).
The solution was cooled to −10 °C and solid AlCl3 was added
portionwise over 10 min. The mixture was stirred for additional
2 h at −10 °C and then quenched by pouring into ice cold aq.
HCl (1 M, 100 ml). The mixture was extracted with CH2Cl2
(3 × 80 ml). The combined organic extracts were washed with
brine (50 ml), dried over MgSO4 and the solvents evaporated at
reduced pressure. The residue was purified by column
chromatography on silica gel (pentane : ethyl acetate  50 : 1) to
provide the title product 8. Yield: 4.86 g (86%). Pale yellow oil.
1H NMR (400 MHz, CDCl3): δ (ppm) 9.07 (d, J = 8.7 Hz, 1H),
7.75 (dd, J = 7.7, 7.7 Hz, 2H), 7.59 (dd, J = 7.7, 7.7 Hz, 1H),
7.44 (dd, J = 7.4, 7.4 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H),
3.073.28 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H).13C NMR (100 MHz,
CDCl3): δ (ppm) 199.1, 143.9, 133.0, 132.3, 131.5, 128.8, 128.2,
125.6, 125.4, 125.1, 124.9, 42.7, 32.5, 15.2.
A mixture of 9 (320 mg, 1.30 mmol), P4S10 (866 mg, 3.90 mmol)
and Lawesson’s reagent (1.58 g, 3.9 mmol) in toluene (20 ml)
was heated at reflux for 3 h. The mixture was allowed to cool
down to room temperature and was directly purified by column
chromatography on silica gel (pentane : ethyl acetate  20 : 1).
The fractions containing the thioketone were concentrated under
reduced pressure to a small volume. In the meantime, a stirred
solution of (9H-thioxanthen-9-ylidene)hydrazine[49] (552 mg,
2.44 mmol) in anhydrous THF (30 ml) was treated with MnO2
(1.06 g, 12.2 mmol) at 0 °C. After 30 min, the suspension was
filtered through a short plug of Celite. The pad was washed with
a small amount of anhydrous THF and the combined filtrates
cooled back to 0 °C. To this solution, the aforementioned
thioketone in small amount of solvents was added dropwise. The
resulting mixture was left stirring overnight after which the
solvents were evaporated at reduced pressure. The residue was
redissolved in toluene (10 ml), HMPT (222 l, 1.22 mmol) was
added and the mixture was heated to 50 °C overnight. The
crude reaction mixture was adsorbed on Celite and purified by
column chromatography (pentane : CH2Cl2  15 : 1). (Note: The
compound slowly oxidizes on silica gel, therefore the purification
should be performed swiftly.) The pale yellow solid afforded
thereafter was further purified by washing with cold pentane (3 ×
2 ml) to give the pure final compound 4. Yield: 87 mg (17%).
1
White solid. Mp 150–152 °C (dec.). H NMR (400 MHz, CDCl3):
δ (ppm) 7.78 (dd, 1H, J1= 8.4 Hz, J2 = 8.3 Hz), 7.66 (d, 1H, J =
8.4 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.58 (dd, 2H, J1= 7.5 Hz, J2 =
7.5 Hz), 7.44 (d, 1H, J = 8.5 Hz), 7.227.31 (m, 3H), 7.16 (dd,
1H, J1= 7.2 Hz, J2 = 7.2 Hz), 7.08 (dd, 1H, J1= 7.5 Hz, J2 = 7.5
Hz), 6.67 (dd, 1H, J1= 7.5 Hz, J2 = 7.4 Hz), 6.37 (dd, 1H, J1= 7.5
Hz, J2 = 7.5 Hz), 6.31 (d, 1H, J = 7.6 Hz), 3.68 (dd, 1H, J1= 23.1
Hz, J2 = 12.2 Hz), 3.29 (dd, 1H, J1= 12.7 Hz, J2 = 12.7 Hz), 1.35
(d, 3H, J = 21.5 Hz).13C NMR (100 MHz, CDCl3): δ (ppm) 139.3,
136.4, 136.4, 135.9, 135.3, 135.1, 134.4, 134.4, 134.2, 134.2,
134.1, 131.9, 131.0, 131.0, 131.0, 130.8, 128.6, 128.1, 127.7,
127.3, 127.3, 126.8, 126.7, 126.4, 126.0, 125.7, 125.3, 125.3,
125.3, 125.1, 124.6, 99.7 (d, J = 194.3 Hz), 43.0 (d, J = 26.6 Hz),
27.1 (d, J = 28.1 Hz). 19F NMR (376 MHz, CDCl3): δ (ppm)
−127.9 (m). HRMS (ESI): calcd for C27H20FS2 [M + H+] 427.0985
found 427.0983.
2-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one (14).
A mixture of AlCl3 (10.4 g, 78 mmol) and methacryloyl chloride
(3.8 ml, 39 mmol) in dry CH2Cl2 (100 ml) was cooled down to
−78 °C. Solid naphthalene was added portionwise to this mixture
over 10 min. The mixture was allowed to attain room
temperature overnight. The solution was then poured onto a
mixture of ice (~ 100 g) and aq. HCl (1 M, 50 ml). The resulting
mixture was extracted with diethyl ether (3 × 70 ml). The
combined organic extracts were washed with brine (50 ml), dried
over MgSO4 and the solvents evaporated at reduced pressure.
The crude product was purified by column chromatography on
2-Fluoro-2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-
one (9).
A solution of 8 (1.0 g, 4.38 mmol) in dry toluene (10 ml) was
added to a solution of NaHMDS (2.85 ml, 5.69 mmol, 2 M in
THF) in dry toluene (50 ml) at −78 °C under N2 atmosphere.
After stirring for 30 min at this temperature, NFSI (2.07 g,
6.57 mmol) was added portionwise over 10 min. The reaction
mixture was allowed to spontaneously warm up to room
temperature overnight. The reaction was quenched by addition
of aq. HCl (1 M, 60 ml). The mixture was extracted with CH2Cl2
(3 × 50 ml), the combined organic extracts were washed with
brine (50 ml) and dried over MgSO4. The solvents evaporated at
reduced pressure and the residue was purified by column
chromatography on silica gel (pentane : ethyl acetate  50 : 1) to
afford the desired product. Yield: 723 mg (67%). Yellow oil. 1H
NMR (400 MHz, CDCl3): δ (ppm) 9.10 (d, J = 8.8 Hz, 1H), 7.82
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A mixture of 16 (301 mg, 1.4 mmol), P4S10 (623 mg, 2.8 mmol),
Lawesson’s reagent (1.13 g, 2.8 mmol) in toluene (20 ml) was
silica gel (pentane : ethyl acetate  50 : 1) to provide the product
14. Yield: 4.71 g (62%). Pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ (ppm) 9.17 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H),
7.89 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 8.2, 7.1 Hz, 1H), 7.56 (dd,
J = 8.1, 7.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H,), 3.47 (dd, J =18.1,
8.1 Hz, 1H), 2.782.86 (m, 2H), 1.39 (d, J =7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 209.1, 156.1, 135.1, 132.2,
129.5, 129.0, 128.2, 127.6, 126.1, 123.44, 123.39, 41.8, 34.7,
16.2.
heated at reflux for
1 h. The dark green mixture was
concentrated under reduced pressure to ~5 ml and purified
directly on a short column of silica gel (pentane : ethyl acetate 
20 : 1) to give a dark green oil. In the meanwhile, (2-methoxy-
9H-fluoren-9-ylidene)hydrazine[38] (408 mg, 1.8 mmol) was
dissolved in THF (30 ml) and cooled down to 0 °C. MnO2 (1.22 g,
14.0 mmol) was added to the vigorously stirred solution. After
stirring for 30 min, the suspension was filtered through a short
plug of silica gel. The pad was washed with a small amount of
THF and the combined filtrates cooled back to 0 °C. To this
solution, the aforementioned thioketone in a small amount of
solvent was added dropwise. The resulting mixture was left
stirring overnight and HMPT (514 l, 2.8 mmol) was added
afterwards. The mixture was stirred for additional 24 h at room
temperature. The crude reaction mixture was adsorbed on Celite.
Purification by column chromatography on silica gel (pentane :
ethyl acetate  50 : 1), followed by two crystallizations from
heptane (~ 10 ml) afforded the product as a mixture of E/Z
isomers in 33:1 ratio. Yield: 135 mg (25%). Orange solid. Mp.
2-Fluoro-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-
1-one (16).
A solution of LiHMDS (6.6 ml, 6.6 mmol, 1 M in THF) in
anhydrous toluene (40 ml) was cooled down to −78 °C. A
solution of 14 (1.0 g, 5.1 mmol) in anhydrous toluene (5 ml) was
added dropwise. After stirring for 30 min, NFSI (2.25 g,
7.1 mmol) was added portionwise. The resulting mixture was
allowed to spontaneously warm up to ambient temperature
overnight. The reaction was quenched by addition of aq. HCl
(1 M, 60 ml). The mixture was extracted with CH2Cl2 (3 × 50 ml),
the combined organic extracts were washed with brine (50 ml)
and dried over MgSO4. The solvents were evaporated at
reduced pressure and the crude product was purified by column
chromatography on silica gel (pentane : ethyl acetate  15 : 1) to
provide the product as pale yellow oil (908 mg, 83%). 1H NMR
(400 MHz, CDCl3): δ (ppm) 9.05 (d, J = 8.3 Hz, 1H), 8.08 (dd, J
= 8.3, 4.8 Hz, 1H), 7.88 (m, 1H), 7.69 (m, 1H), 7.57 (m, 1H),
7.44 (m, 1H), 3.333.59 (m, 2H), 1.69 (d, J = 22.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 201.5 (d, J = 18.9 Hz) , 153.4
(d, J = 4.4 Hz), 137.5, 133.0, 129.7, 129.6, 128.5, 127.9, 127.2,
124.2, 123.7, 95.8 (d, J = 183.9 Hz), 41.0 (d, J = 24.7 Hz), 22.0
(d, J = 26.8 Hz). 19F NMR (376 MHz, CDCl3): δ (ppm) −151.2.
HRMS (ESI): calcd for C14H12FO [M + H+] 215.0867 found
215.0863.
1
(dec.) >210 °C. H NMR (400 MHz, CDCl3): δ (ppm) 8.20–8.11
(m, 1H), 7.92 (dd, J = 7.9 Hz, 2H), 7.70 (m, 2H), 7.59 (d, J = 8.2
Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.46 (dd, J = 7.4 Hz, 1H), 7.32
(m, 3H), 6.79 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 3.91 (dd, J = 15.8
Hz, 1H), 3.31 (d, J = 14.7 Hz, 1H), 2.92 (s, 3H), 1.96 (d, J = 19.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 158.5, 144.8,
144.6, 143.4, 143.3, 141.1, 139.1, 138.1, 134.8, 134.7, 133.8,
133.0, 132.4, 131.9, 129.2, 129.1, 127.8, 127.7, 127.3, 127.3,
127.1, 125.8, 125.8, 123.3, 123.3, 119.8, 118.8, 115.9, 110.3,
105.7 (d, J = 195.4 Hz), 48.7 (d, J = 24.5 Hz), 23.8 (d, J = 25.7
Hz). 19F NMR (376 MHz, CDCl3): δ (ppm) −138.7 (m) (Z-isomer),
−139.14 (pd, J = 19.0, 3.9 Hz) (E-isomer). HRMS (ESI): calcd for
C28H21O [M – F-] 373.1587 found 373.1599.
9-(2-Fluoro-2-methyl-2,3-dihydro-1H-
2-Fluoro-2,4,7-trimethyl-2,3-dihydro-1H-inden-1-one (15).
A solution of LiHMDS (3.7 ml, 7.5 mmol, 2 M in THF) in
anhydrous toluene (40 ml) was cooled down to −78 °C. A
solution of 2,4,7-trimethyl-2,3-dihydro-1H-inden-1-one (1.00 g,
5.7 mmol) in anhydrous toluene (5 ml) was added dropwise.
After stirring at −78 °C for 30 min, NFSI (2.35 g, 7.5 mmol) was
added portionwise. The resulting mixture was allowed to
spontaneously warm up to ambient temperature overnight. The
reaction was quenched by addition of aq. HCl (1 M, 60 ml). The
mixture was extracted with CH2Cl2 (3 × 50 ml), the combined
organic extracts were washed with brine (50 ml) and dried over
MgSO4. The solvents were evaporated at reduced pressure and
the crude product was purified by column chromatography on
silica gel (pentane : ethyl acetate  20 : 1) to provide the product
as a pale yellow oil (943 mg, 4.9 mmol, 85%). 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.28 (d, J = 7.5 Hz, 1H), 7.04 (d, J =
7.5 Hz, 1H), 3.29–3.04 (m, 2H), 2.57 (s, 3H), 2.25 (s, 3H), 1.58
(d, J = 22.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 202.2
(d, J = 18.2 Hz), 149.4 (d, J = 3.9 Hz), 137.4, 136.1, 132.9,
130.9, 130.1, 95.56 (d, J = 183.0 Hz), 39.0 (d, J = 24.5 Hz), 21.9
(d, J = 26.8 Hz), 17.8 (d, J = 57.0 Hz). 19F NMR (376 MHz,
CDCl3): δ (ppm) −150.5 (m). HRMS (ESI): calcd for C12H14FO (M
+ H+) 193.1029 found 193.1026.
cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene (5a).
A mixture of 16 (300 mg, 1.4 mmol), P4S10 (467 mg, 2.1 mmol),
Lawesson’s reagent (850 mg, 2.1 mmol) in toluene (20 ml) was
heated at reflux for
1 h. The dark green mixture was
concentrated under reduced pressure and purified directly on a
short column of silica gel (pentane : ethyl acetate  15 : 1) to
give a dark green oil. The oil was redissolved in toluene (20 ml)
and 9-diazo-9H-fluorene[38] (377 mg, 1.96 mmol) was added
portionwise over 5 min. The resulting mixture was left stirring
overnight and HMPT (514 l, 457 mg, 2.8 mmol) was added
afterwards. The mixture was stirred for additional 24 h at room
temperature. The crude reaction mixture (adsorbed on Celite)
was purified by column chromatography on silica gel (pentane :
ethyl acetate  50 : 1), followed by crystallization from ethanol
(10 mL) to give the motor 5a as a yellow solid (247 mg,
0.68 mmol, 49%). Mp. (dec.) >210 °C. 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.23 (m, 1H), 7.94 (dd, J = 9.0 Hz, 2H), 7.85–
7.79 (m, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H),
7.52 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 7.4 Hz, 1H), 7.44–7.36 (m,
2H), 7.33–7.20 (m, 2H), 6.77 (dd, J = 7.4 Hz, 1H), 6.72 (d, J =
7.8 Hz, 1H), 3.92 (dd, 1H, J =16.2 Hz), 3.30 (d, 1H, J =14.5 Hz),
1.93 (d, 3H, J =19.1 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm)
144.9, 144.7, 143.3, 143.2, 140.9, 140.4, 138.3, 137.9, 134.9,
133.0, 132.2, 131.9, 129.3, 129.1, 127.9, 127.7, 127.3, 127.2,
126.9, 126.2, 125.9, 125.9, 123.2, 123.2, 119.5, 119.1, 106.8,
105.8 (d, J = 195.5 Hz), 48.7 (d, J = 24.3 Hz), 23.8 (d, J = 25.7
Hz). 19F NMR (376 MHz, CDCl3): δ (ppm) −138.94 (pd, J = 19.0,
4.4 Hz). HRMS (ESI): calcd for C27H20 [M – F-] 343.1481 found
343.1488.
9-(2-Fluoro-2,4,7-trimethyl-2,3-dihydro-1H-inden-1-ylidene)-
9H-fluorene (6).
A mixture of 15 (358 mg, 1.9 mmol), P4S10 (623 mg, 2.8 mmol),
Lawesson’s reagent (1.13 g, 2.8 mmol) in toluene (20 ml) was
heated at reflux for
1 h. The dark green mixture was
concentrated under reduced pressure and purified directly on a
short column of silica gel (pentane : ethyl acetate  20 : 1) to
give a dark green oil. The oil was redissolved in toluene (20 ml)
and 9-diazo-9H-fluorene (501 mg, 2.6 mmol) was added
(E)-9-(2-fluoro-2-methyl-2,3-dihydro-1H-
cyclopenta[a]naphthalen-1-ylidene)-2-methoxy-9H-fluorene
(5b).
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10.1002/chem.201700581
Chemistry - A European Journal
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portionwise over 5 min. The resulting mixture was left stirring
overnight and HMPT (683 l, 608 mg, 3.7 mmol) was added
afterwards. The mixture was stirred for additional 24 h at room
temperature. The crude reaction mixture was purified by column
chromatography on silica gel (pentane : ethyl acetate  50 : 1),
trituration by hot methanol (2 × 7 mL) and recrystallization from
ethanol (20 mL) to provide 6 as a yellow solid (319 mg, 0.94
140.4, 138.5, 138.3, 133.9, 128.9, 128.0, 127.7, 127.2, 127.2,
127.1, 127.0, 126.9, 126.6, 126.4, 124.9, 124.87, 123.8, 120.0,
119.5, 108.2 (d, J = 198.6 Hz), 46.1 (d, J = 26.9 Hz), 24.1 (d, J =
25.1 Hz). 19F NMR (376 MHz, CDCl3): δ (ppm) −132.9 (m).
HRMS (ESI): calcd for C25H17S [M – F-] 349.1046 found
349.1049.
(Z)-2-Fluoro-1-(2-methoxy-9H-fluoren-9-ylidene)-2-methyl-
2,3-dihydro-1H-benzo[b]cyclopenta[d]thiophene (25b).
1
mmol, 50%). Mp. (dec.) >210 °C. H NMR (400 MHz, CDCl3): δ
A
mixture of 22 (195 mg, 0.89 mmol), P4S10 (295 mg,
(ppm) 8.17 (m, 1H), 7.86–7.72 (m, 2H), 7.37 (m, 4H), 7.22–7.07
(m, 3H), 3.69–3.52 (dd, J = 16.1 Hz, 1H), 3.18 (d, J = 14.5 Hz,
1H), 2.36 (s, 3H), 2.20 (s, 2H), 1.93 (d, J = 19.3 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 146.2, 146.0, 141.5, 141.4,
140.6, 140.4, 138.7, 138.2, 135.0, 132.0, 131.2, 131.0, 129.8,
128.0, 127.6, 127.2, 127.1, 126.8, 123.8, 119.5, 119.3, 105.1 (d,
J = 194.2 Hz), 46.6 (d, J = 24.0 Hz), 23.7 (d, J = 25.9 Hz), 21.4,
18.4. 19F NMR (376 MHz, CDCl3): δ (ppm) −139.9 (pd, J = 19.0,
4.4 Hz). HRMS (ESI): calcd for C26H23 [M – F-] 351.1743 found
351.1752.
1.33 mmol), Lawesson’s reagent (537 mg, 1.33 mmol) in toluene
(20 ml) was heated to 100 °C for 1 h. After TLC showed no
remaining starting material, the dark green mixture was
concentrated under reduced pressure and purified directly on a
short column of silica gel (pentane : ethyl acetate  20 : 1) to
give a dark green oil. The oil was redissolved in toluene (20 ml)
and freshly prepared 2-methoxy-9-diazo-9H-fluorene[38] (278 mg,
1.24 mmol) was added portionwise over 5 min. The resulting
mixture was left stirring overnight and HMPT (390 l, 347 mg,
2.12 mmol) was added afterwards. The mixture was stirred for
an additional 24 h at room temperature. The crude reaction
mixture was purified by column chromatography on silica gel
(pentane : dichloromethane  7 : 1) and recrystallization from
ethanol to give the desired motor Z-25b as a yellow solid
(190 mg, 0.48 mmol, 54%). Mp. (dec.) >200 °C. 1H NMR
(400 MHz, CD2Cl2): δ (ppm) 7.91 (d, J = 8.1 Hz, 1H), 7.76 (s,
1H), 7.70 (dd, J = 8.5, 8.5 Hz, 2H), 7.36 (dd, J = 7.5, 7.5 Hz,
1H), 7.27 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.8 Hz,
1H), 6.98–6.90 (m, 2H), 3.99–3.80 (m, 4H), 3.42 (d, J = 15.1 Hz,
1H), 1.95 (d, J = 19.0 Hz, 3H). 13C NMR (100 MHz, CD2Cl2): δ
(ppm) 159.7, 152.2 (d, J = 11.9 Hz), 143.9, 140.6, 140.4, 140.1,
138.5, 138.2, 134.3, 133.9, 129.0, 128.2, 127.0, 126.7, 125.3,
125.0, 124.9, 123.8, 120.6, 118.8, 113.8, 112.9 (d, J = 15.3 Hz),
108.2 (d, J = 198.5 Hz), 56.1, 46.1 (d, J = 26.9 Hz), 23.9 (d, J =
25.0 Hz).. 19F NMR (376 MHz, CD2Cl2): δ (ppm) −132.6 (p, J =
17.9 Hz). HRMS (ESI): calcd for C26H19SO [M – F-] 379.1151
found 379.1182.
2-Fluoro-2-methyl-2,3-dihydro-1H-
benzo[b]cyclopenta[d]thiophen-1-one (22).
A solution of LiHMDS (1.38 ml, 1.4 mmol, 1 M in THF) in
anhydrous toluene (40 ml) was cooled down to −78 °C. 2-
Methyl-2,3-dihydro-1H-benzo[b]cyclopenta[d]thiophen-1-one[50]
(200 mg, 0.99 mmol) in anhydrous toluene (5 ml) was added
dropwise to this solution. After stirring at −78 °C for 30 min, NFSI
(468 mg, 1.5 mmol) was added portionwise. The resulting
mixture was allowed to spontaneously warm up to ambient
temperature overnight. The reaction was quenched by addition
of aq. HCl (1 M, 60 ml). The mixture was extracted with CH2Cl2
(3 × 50 ml), the combined organic extracts were washed with
brine (50 ml) and dried over MgSO4. The solvents were
evaporated at reduced pressure and the crude product was
purified by column chromatography on silica gel (pentane : ethyl
acetate  30 : 1) to provide 22 as pale yellow oil (83 mg, 0,38
mmol 38%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.22 (d, J = 7.5
Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.47 (ddd, J = 7.8, 7.6, 1.1 Hz,
1H), 7.41 (ddd, J = 7.8, 7.6, 1.1 Hz, 1H), 3.68 – 3.32 (m, 2H),
1.70 (d, J = 23.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm)
192.2 (d, J = 19.6 Hz), 170.2 (d, J = 5.2 Hz), 143.8, 136.2, 131.4,
126.3, 126.2, 123.4, 123.1, 99.5 (d, J = 189.5 Hz), 39.8 (d, J =
27.0 Hz), 21.8 (d, J = 26.3 Hz). 19F NMR (376 MHz, CDCl3): δ
(ppm) −146.2 (qdd, J = 23.0, 19.6, 10.0 Hz). HRMS (ESI): calcd
for C12H10FOS [M + H+] 221.0436 found 221.0447.
Acknowledgements
This work was supported financially by the Netherlands
Organization for Scientific Research (NWO-CW), The Royal
Netherlands Academy of Arts and Sciences (KNAW),
NanoNextNL of the Government of the Netherlands and 130
partners, the European Research Council (ERC; advanced grant
no. 694345 to B.L.F.) and the Ministry of Education, Culture and
Science (Gravitation program no. 024.001.035). The authors
thank P. van der Meulen for assistance with NMR experiments.
1-(9H-Fluoren-9-ylidene)-2-fluoro-2-methyl-2,3-dihydro-1H-
benzo[b]cyclopenta[d]thiophene (25a).
A
mixture of 22 (100 mg, 0.45 mmol), P4S10 (151 mg,
0.68 mmol), Lawesson’s reagent (275 mg, 0.68 mmol) in toluene
(10 ml) was heated to 100 °C for 1 h. After TLC showed no
remaining starting material, the dark green mixture was
concentrated under reduced pressure and purified directly on a
short column of silica gel (pentane : ethyl acetate  20 : 1) to
give a dark green oil. The oil was redissolved in toluene (20 ml)
and 9-diazo-9H-fluorene[38] (122 mg, 0.64 mmol) was added
portionwise over 5 min. The resulting mixture was left stirring
overnight and HMPT (167 l, 148 mg, 0.91 mmol) was added
afterwards. The mixture was stirred for an additional 24 h at
room temperature. The crude reaction mixture was purified by
column chromatography on silica gel (pentane : CH2Cl2  7 : 1)
and recrystallization from ethanol to give the motor 25a as a
Keywords: fluorine • molecular motor • quaternary •
photoisomerization • unidirectional
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Fluorine-substituted molecular
motors with a quaternary stereogenic
center
A series of overcrowded alkenes with a quaternary stereogenic center substituted
with fluorine was investigated for application as unidirectional molecular motors.
Major increase of the thermal isomerization barrier was found as a consequence of
substituting hydrogen for fluorine atom.
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