Photochemical and thermal isomerization processes of a chiral auxiliary based donor-acceptor substituted chiroptical molecular switch: Convergent synthesis, improved resolution and switching properties

Article abstract of DOI:10.1002/chem.200204660

A new type of chiroptical molecular switch is presented where irradiation employing different wavelengths of light induces a reversible helix inversion of a sterically overcrowded alkene bearing a second chiral entity in the form of a stereogenic center present in a pyrrolidine unit. The additional stereogenic center in the chiral auxiliary group has a distinct influence on the switching selectivity of this system and greatly facilitates the resolution of the different diastereoisomers, which is a considerable improvement compared with previously reported systems. In addition, the pyrrolidine stereogenic center causes small energetic differences between the various states of the switch system resulting in a small but significant directional preference in the helix inversion steps.

Full text of DOI:10.1002/chem.200204660

FULL PAPER
Photochemical and Thermal Isomerization Processes of a Chiral Auxiliary
Based Donor Acceptor Substituted Chiroptical Molecular Switch:
Convergent Synthesis, Improved Resolution and Switching Properties
Richard A. van Delden, Johannes H. Hurenkamp, and Ben L. Feringa*[a]
Abstract: A new type of chiroptical
molecular switch is presented where
irradiation employing different wave-
lengths of light induces a reversible helix
inversion of a sterically overcrowded
alkene bearing a second chiral entity in
the form of a stereogenic center present
in a pyrrolidine unit. The additional
stereogenic center in the chiral auxiliary
group has a distinct influence on the
switching selectivity of this system and
greatly facilitates the resolution of the
different diastereoisomers, which is a
considerable improvement compared
with previously reported systems. In
addition, the pyrrolidine stereogenic
center causes small energetic differences
between the various states of the switch
system resulting in a small but signifi-
cant directional preference in the helix
inversion steps.
Keywords: chirality ¥ isomerization
¥
molecular
devices
¥
nanotechnology ¥ photochromism
detectable change in for example chiroptical properties.
Examples include among others chiral diarylethylenes,[9]
azobenzenes,[10] spiropyrans,[11] and fulgides.[12] In those exam-
ples, the chirality of the systems itself does not change but the
photoinduced geometrical change has an effect on the chiral
properties (Figure 1B). Different wavelengths of light can be
employed for switching between two states (0-X* > 1-X*)
but the properties of the two forms of such a bistable
switching system, apart from the geometry-determined differ-
ence in chirality, are usually quite different due to the large
difference in shape. This type of switches also includes a large
variety of helically shaped polymer systems where a change in
helicity can be affected by switching an achiral side-chain.[13]
For these polymer systems the two forms of the bistable
switching system can be considered pseudoenantiomeric. Our
approach towards chiroptical molecular switches involves
switching of pseudoenantiomeric forms (P and M') of a
sterically overcrowded alkene (Figure 1C).[14] Switching, em-
ploying different wavelengths of light, completely changes the
chiral properties of the system. This has resulted in a number
of selective molecular switches which were successfully
applied as triggers for liquid crystal phase transitions.[15] The
molecular switches have evolved towards true molecular
motors in which consumption of photon energy results in
controlled unidirectional rotation.[16] This motion could
eventually enable a device to perform mechanical work.[17]
In a new versatile second-generation design of our molecular
motors the direction of rotation is solely governed by the
interplay of a single stereogenic center with the intrinsic
helical shape of the molecules.[18] The control of the direction
of a full rotary motion in these molecular type motors is a
Introduction
In the different approaches towards true nanoscale molecular
devices a variety of different functions have to be addressed at
the molecular level.[1] This requires delicate supramolecular
organization of different molecular components each capable
of performing a certain function. A variety of molecular,
mechanical type, components that might be part of the future
toolbox of nanotechnology have been developed, including
molecular counterparts of brakes,[2] gears,[3] turnstiles,[4] mus-
cles,[5] and switches.[6]
Optical molecular switches play an important role in this
endeavor.[6, 7] These photochromic systems might have poten-
tial use in applications such as optical data storage units,
trigger elements, or as switching devices in optical data
processing. In the pursuit of chiral optical (chiroptical)
molecular switches, the unique properties associated with
stereoisomers of chiral photochromic molecules and chiral
supramolecular systems are exploited. Different approaches
can be distinguished (Figure 1). The only approach resulting
in switching between true enantiomers (Figure 1A) involves
the use of circularly polarized light. The number of examples
in this case is limited.[8] For most chiral photochromic systems
known, switching, distant from the actual stereogenic center,
results in a geometrical change in the molecules leading to a
[a] Prof. Dr. B. L. Feringa, Dr. R. A. van Delden, J. H. Hurenkamp
Department of Organic and Molecular Inorganic Chemistry
Stratingh Institute, University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax : (‡31)50-3634296
E-mail: feringa@chem.rug.nl
Chem. Eur. J. 2003, 9, 2845 2853
DOI:10.1002/chem.200204660
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B. L. Feringa et al.
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basic requirement for the construction of (supra)molecular
machines.[1a]
Here, we report a newly developed pyrrolidine-based
donor acceptor switch where, in addition to the intrinsically
chiral switch structure, a second chiral unit in the form of a
stereogenic center in the pyrrolidine substituent is present.
This system can be considered a hybrid between types B and
C (Figure 1), where different wavelengths of light are used to
Scheme 1. Photochemical and thermal interconversion of four states of
chiroptical molecular switch 1.
Figure 1. Schematic representation of different types of chiroptical
molecular switches (X* ˆ chiral auxiliary group).
ized with a dimethylamine electron donating substituent and a
nitro electron withdrawing substituent. This asymmetric
substitution pattern results in relatively large differences in
the UV absorption characteristics of the two pseudoenan-
tiomers that can be employed for switching. For 1, switching
between photostationary states composed of 90% (M)-cis-1a
and 10% (P)-trans-1b using 435 nm light and 30% (M)-cis-1a
and 70% (P)-trans-1b using 365 nm light is achieved and the
switching process is reversible and repeatedly possible in n-
hexane solution. The same holds of course for the enantio-
meric couple (P)-cis-1a and (M)-trans-1b (Scheme 1bottom).
With compound 1, clear switching between pseudoenantiom-
ers is observed and in this way it is shown that molecular
chirality can be controlled by changing only the wavelength of
light used. This system has also been employed as a chiral
molecular trigger in liquid crystalline systems.[21] Heating the
system causes a thermal helix inversion to take place and
eventually leads to racemization of both pseudoenantiomers.
The target molecule for the present study is the sterically
overcrowded alkene 2, which closely resembles donor ac-
ceptor substituted switch 1. The key difference in this new
molecular switch is that an additional chiral unit is present.
Again, the intrinsically chiral overcrowded alkene is func-
tionalized with an electron withdrawing nitro and an electron
donating amine substituent. The amine in this case is the
proline-derived (S)-2-(methoxymethyl)pyrrolidine. This
amine has been used frequently as a chiral auxiliary in
asymmetric synthesis.[22] The additional stereogenic center in
this molecular switch, with fixed configuration, results in four
distinct diastereomeric forms, as depicted in Scheme 2, rather
than two diastereomeric pairs of enantiomers as found for 1.
As a result the two photoequilibria (path a, a') are now
different and also the helix inversion steps (path b, b') are no
longer racemizations. A mutual difference in energy for the
two separate cis ((S)-(M)-cis-2a/(S)-(P)-cis-2a) and trans
((S)-(M)-trans-2b/(S)-(P)-trans-2b) isomers of 2 can be
anticipated.
switch between two helically shaped forms of a sterically
overcrowded alkene bearing an additional chiral unit (Fig-
ure 1D). Some interesting features resulting from the inter-
play of the two chiral moieties (helix structure and asymmet-
ric carbon center) present in the molecule can be anticipated.
For example, where for previously reported chiroptical
molecular switches chiral resolution was troublesome in all
cases, we anticipated a positive influence of the chiral
pyrrolidine moiety in the present case. With a focus on the
influence of the chiral handle, the synthesis, resolution and
physical properties and stereochemical pathways of this
molecular switch are presented.
Our binary molecular switching system is based on the cis
and trans forms of a sterically overcrowded alkene with an
intrinsic helical chirality. The two pseudoenantiomeric[19]
forms of the molecular switch have an opposite helicity, that
is negative helicity (M) in case of the cis-form and positive
helicity (P) in case of the trans-form as illustrated for
compound 1 (Scheme 1top). Compound 1 is a typical
example of our chiroptical molecular switches and one of
the most successful switches developed so far.[20] For selective
switching of 1, the lower half of the molecules is functional
Abstract in Dutch: In dit artikel presenteren we een nieuw type
chiroptische moleculaire schakelaar waar bestraling met licht
van verschillende golflengtes een reversibele helix inversie
induceert van een sterisch gehinderd alkeen met een tweede
chirale groep in de vorm van een stereogeen centrum aanwezig
in een pyrrolidine substituent. Het extra stereogene centrum
heeft een subtiele invloed op de selectiviteit tijdens het
schakelen met het systeem en verbetert aanzienlijk de resolutie
van de verschillende diastereomeren, wat een nadeel was van
eerder gerapporteerde systemen. Daarbij komt dat de chirale
pyrrolidine eenheid kleine energie verschillen tussen de ver-
schillende toestanden van het schakelsysteem veroorzaakt wat
resulteert in een kleine maar significante voorkeur voor een
bepaalde richting in de helix inversie stappen.
Compound 2 offers some additional appealing features. The
(S)-2-(methoxymethyl)pyrrolidine moiety after deprotection
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Chiroptical Molecular Switches
2845 2853
extensively studied in recent
years and numerous examples
of successful arene substitutions
using different amines, aryl hal-
ides and palladium catalysts
have been reported.[24] We ap-
plied the Buchwald procedure in
the catalytic amination shown in
Scheme 3.[25]
The (S)-2-methoxymethylpyr-
rolidine was synthesized accord-
ing to a literature procedure[22]
starting from enantiomerically
pure (S)-proline providing (S)-4
with full retention of configura-
tion. The bromo-substituted al-
kene 3 was synthesized following
a route analogous to that em-
ployed for 1. A diazo-thioketone
coupling to form the central
double bond, which involves
Scheme 2. Four diastereoisomers of chiroptical switch 2 and their photochemical (path a, a') and thermal
interconversions (path b, b').
of the ether moiety might be suitable for attachment of the
chiroptical switch to, for example, peptide chains, which offers
an attractive route towards switchable biomaterials.[23] An-
other feature is that due to the diastereomeric relationship of
all four forms of molecular switch 2 chiral separation
techniques are no longer essential, whereas the resolution
of the four stereoisomers usually is the most delicate step in
our approaches towards chiroptical molecular switches and
Scheme 3. Functionalization of bromo-substituted overcrowded alkene 3 to form
2 involving a palladium catalyzed amination: [Pd2(dba)3], BINAP, NaOtBu,
toluene, 808C, yield: 58%.
molecular motors.
the corresponding episulfide 9, is the key step. Starting from
commercially available 2-bromothiophenol and 2-chloro-5-
nitrobenzoic acid the lower half thioketone 7 was obtained in
three steps (Scheme 4). This thioketone was coupled with the
upper half hydrazone, synthesized in three steps starting from
2-thionaphthol,[20a] via the Barton Kellogg method.[26] Using
this coupling procedure for upper and lower half, the
central–sterically hindered–double bond is formed via a
Results and Discussion
Synthesis and resolution: Compound 1 was synthesized via a
linear synthesis route starting from (N,N)-dimethylaniline.[20a]
Due to high stereoselectivity in the photochemical switching
process of this donor acceptor substituted compound direct
access to a variety of donor acceptor substituted chiral
switches, including target compound 2, to be able to fine tune
the switching properties would be highly desirable. Therefore
we altered our synthetic strategy
and rather than starting from
pyrrolidine functionalized start-
ing material in a similar linear
approach as for 1 a more flexible
and convergent synthetic route
was developed for switch 2. This
route is based on a palladium-
catalyzed amination of bromo-
substituted switch 3 with an
appropriate amine; in the pre-
sent case (S)-2-(methoxyme-
thyl)pyrrolidine 4 (Scheme 3).
The palladium-catalyzed amina-
tion of aryl halides has been
Scheme 4. Synthesis of bromo-substituted precursor 3: a) 2-chloro-5-nitro benzoic acid, NaHCO3, EtOH, D;
b) sulfuric acid, 1008C, 95%; c) P2S5, toluene, D, 76%; d) Ag2O, MgSO4, KOH/MeOH, CH2Cl2, À10 ! 08C,
60%; e) Ph3P, toluene, D, 97%.
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B. L. Feringa et al.
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stepwise increase of the steric constraints. First, 1,3-dipolar
cycloaddition of the thioketone lower half and diazo-upper
half results in the formation of a five-membered thiadiazoline
intermediate. Second, nitrogen is eliminated to form a three-
membered episulfide. After extrusion of sulfur the desired
sterically hindered alkene 3 is obtained.
Chiroptical switch 2 was obtained as a mixture of the four
diastereoisomers, as depicted in Scheme 2. Separation of
diastereoisomers was performed by HPLC using an achiral
silica column. Employing a gradient of n-heptane and
dichloromethane as an eluent, the four diastereomers were
readily separated with retention times of 16.9 min ((S)-(M)-
cis-2a), 17.4 min ((S)-(P)-cis-2a), 18.2 min ((S)-(P)-trans-2b),
and 18.8 min ((S)-(M)-trans-2b). The respective (P)- and (M)-
isomers could be assigned by CD spectroscopy (see below for
data) and comparison with previously reported sterically
overcrowded alkenes. The cis- and trans-isomers could readily
1
be distinguished by H NMR spectroscopy and most indica-
tive are: i) the MeO protons which are partly shielded by the
upper arene part of the molecule for the trans-isomers (d 3.17
and 3.21) but not for the cis-isomers (d 3.34 and 3.38) and
ii) the aromatic protons of the amine-substituted arene part of
the lower half which in case of the trans-isomer, where this
part of the molecule is shielded by the upper arene part, result
in distinct aromatic 1H NMR signals below d 6.50 (see
Experimental Section for full NMR data).
It should be emphasized that for the chiroptical switches
developed thus far, time-consuming and expensive chiral
resolution was necessary, whereas in the present case achiral
chromatography readily allows separation of the four stereo-
isomers. The accessibility of the enantiomerically pure forms
is an important advantage of compound 2 over all the other
chiroptical switches reported so far.[14]
Figure 2. UV/Vis and CD absorption spectra of the diastereoisomers (S)-
(M)-cis-2a and (S)-(P)-trans-2b in n-hexane. The solid curves correspond
to (S)-(M)-cis-2b and the dashed graphs to (S)-(P)-trans-2b. The thin
curves correspond to the photostationary states (solid thin: 463 nm PSS;
dashed thin: 380 nm PSS).
Switching selectivity: Due to presence of four diastereomers,
the discussion on the switching selectivity of compound 2 is a
little more complicated than for our previously reported
chiroptical molecular switches. Since the two photoisomeri-
zation processes in the present case are no longer enantio-
meric pathways (Scheme 2), they have to be analyzed
separately. For the pseudoenantiomeric couple (S)-(M)-cis-
2a and (S)-(P)-trans-2b (Scheme 5), UV/Vis and CD absorp-
tion spectra were determined (Figure 2).
(18610), 273 (16686), 368 (3385)) and (S)-(P)-trans-2b (UV
(n-hexane): lmax (e) ˆ 255 (17065), 275 (14981), 312 (6287),
327 (3882), 362 (1618), 402 (1681), with values comparable to
those of other donor acceptor switches,[20a] the ideal wave-
lengths for switching could be determined. The ideal wave-
lengths for switching are those where the ratio of the
extinction coefficients of cis-2a and trans-2b show maxima
and minima. Analysis of the UV spectra shows that 380 and
463 nm are the wavelengths where the highest selectivity can
be expected. The CD absorption curves confirm the respec-
tive (P)- and (M)-helicity for (S)-(M)-cis-2a (CD (n-hexane):
lmax (De) ˆ 241( À18.6), 256 (‡22.6), 280 (À36.7), 326 (À1.6),
362 (‡6.3)) and (S)-(P)-trans-2b (CD (n-hexane): lmax (De) ˆ
242 (‡4.4), 255 (À30.3), 275 (‡28.9), 325 (‡5.7), 354 (À3.9))
with De values comparable to those of the other donor ac-
ceptor switches (e.g. compound 1[20a]). The additional stereo-
genic center in the (S)-2-(methoxymethyl)pyrrolidine moiety
has only a minor effect on the CD spectra, which are mainly
determined by the exciton coupling of the upper and lower
half chromophores. The CD spectra of the enantiomerically
pure forms as well as the photostationary states (see below)
are depicted in Figure 2b. Irradiation of an n-hexane solution
of (S)-(M)-cis-2a with 380 nm light resulted in a photosta-
tionary state consisting of (S)-(P)-trans-2b and (S)-(M)-cis-2a
Scheme 5. Selective switching between two diastereoisomers (S)-(M)-cis-
2a and (S)-(P)-trans-2b.
From the differences in the UV/Vis spectra (Figure 2a)
between (S)-(M)-cis-2a (UV (n-hexane): lmax (e) ˆ 255
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Chiroptical Molecular Switches
2845 2853
in a ratio of 69:31, as determined by CD spectroscopy.
Subsequent irradiation at 463 nm led to a photostationary
state with excess (S)-(M)-cis-2a. An extremely high diaster-
eomeric ratio (S)-(M)-cis-2a: (S)-(P)-trans-2b of 96:4 was
found (see Figure 2b). The photochemical switching process is
comparable to that of other donor acceptor systems and was
found to be fully reversible. The basic features of the
chiroptical switching process are therefore retained despite
the presence of the additional chiral auxiliary and much to our
delight the stereoselectivity is improved compared with the
selectivity observed for the parent compound 1.
In a completely analogous way, the UV/Vis and CD spectra
of the other pseudoenantiomeric couple (S)-(P)-cis-2a (UV
(n-hexane): lmax (e) ˆ 257 (23552), 287 (13652), 369 (3058);
CD (n-hexane): lmax (De) ˆ 241( ‡20.7), 255 (À24.2), 280
(À37.7), 326 (‡1.8), 358 (À6.5)) and (S)-(M)-trans-2b (UV
(n-hexane): lmax (e) ˆ 257 (20005), 271 (14895), 312 (5942),
355 (2229), 398 (1681); CD (n-hexane): lmax (De) ˆ 243 (0),
255 (‡37.7), 275 (À37.4), 325 (À7.3), 353 (‡3.8)) were
determined (Scheme 6 and Figure 3). The most efficient
Scheme 6. Selective switching between two diastereoisomers (S)-(P)-cis-
2a and (S)-(M)-trans-2b.
Figure 3. UV/Vis and CD absorption characteristics of the (S)-(P)-cis-2a
and (S)-(M)-trans-2b diastereoisomers in n-hexane. The solid curves
correspond to (S)-(P)-cis-2a and the dashed graphs to (S)-(M)-trans-2b.
The thin curves correspond to the photostationary states (solid: 459 nm
PSS; dashed: 379 nm PSS).
switching wavelengths here, again derived from the ratio of
the two UV/Vis absorption curves (Figure 3a), are 379 and
459 nm for the trans and the cis photostationary state,
respectively. Irradiation at 379 nm resulted in a trans-enriched
photostationary state consisting of (S)-(M)-trans-2b and (S)-
(P)-cis-2a in a 66:34 ratio. Irradiation at 459 nm resulted in
the formation of a cis-enriched photostationary state with a
ratio of (S)-(P)-cis-2a:(S)-(M)-trans-2b of 95:5. Hence, UV/
Vis and CD absorption characteristics (Figure 3b) as well as
switching behavior are similar for the two diastereomeric
pairs of chiral photobistable molecules. This underlines the
minor influence of the (S)-2-(methoxymethyl)pyrrolidine
stereocenter on the photophysical properties. The stereo-
selectivity towards trans-2b in the PSS (379 nm) is, however,
slightly lower for (S)-(M)-trans-2b compared with (S)-(P)-
trans-2b. This is further illustrated in Figure 4 where both the
UV/Vis as well as the CD absorption spectra of the respective
cis- and trans-isomers are directly compared.
small differences in CD absorptions can be observed. The CD
spectra of the cis- and trans-compounds of opposite helicity
are, however, still roughly mirror images. The major differ-
ences are found in the UV absorption of the two isomers at
lower wavelengths with extinction coefficients e(l) for (S)-
(M)-cis-2a and (S)-(P)-cis-2a of 18610 (255) and 23552 (257),
respectively and for (S)-(P)-trans-2b and (S)-(M)-trans-2b of
17065 (255) and 20005 (257). These differences might be
assigned to different geometries of the chiral amine-substi-
tuted aryl moiety absorbing in this region but these effect
were not investigated further.
Thermal stability of the distinct diastereoisomers: A small but
significant effect of the additional stereogenic center in
compound 2 was observed in the photophysical behavior of
the four distinct diastereomers. Another important effect here
is the influence of the additional stereogenic center on the
thermal stability of the different stereoisomers. Where in the
case of the donor acceptor systems, thermal stability was
determined by monitoring the racemization at elevated
temperatures (Scheme 1), in the present system 2 one cannot
Subtle differences in UV absorption of the respective two
cis- and trans-isomers of 2 (Figures 3 and 4 top) result in the
slightly different ideal switching wavelengths (380 and 463 nm
for the (S)-(M)-cis-2a/(S)-(P)-trans-2b couple versus 379 and
459 nm for the (S)-(P)-cis-2a/(S)-(M)-trans-2b couple) as well
as the slightly different switching selectivity (92 and 38%
versus 90 and 32% diastereomeric excess, respectively). Only
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B. L. Feringa et al.
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respective pseudoepimers can
be determined. In case of (S)-
(M)-cis-2a, heating to equilibri-
um at 1008C resulted in a steady
state consisting of (S)-(M)-cis-
2a and (S)-(P)-cis-2a in
a
53.6:46.4 ratio. This steady state
ratio is not 50:50 indicating that
there is indeed an energy differ-
ence between the two cis forms
of 2. This equilibrium ratio com-
bined with the actual rate of the
pseudoracemization observed
gives the rate constants of the
two helix inversions: (S)-(M)-
cis-2a
!
(S)-(P)-cis-2a (k1)
and (S)-(P)-cis-2a ! (S)-(M)-
cis-2a (k2).[28] The observed
pseudoracemization rate in this
case is 9.9 Â 10À5 sÀ1 and the rate
constants of the two helix inver-
sion pathways were determined
to be 4.6 Â 10À5 and 5.3 Â
10À5 sÀ1, respectively, for k1 and
k2 (Scheme 7). In case of the (S)-
Figure 4. Comparison of UV/Vis and CD absorption characteristics of (S)-(M)-cis-2a and (S)-(P)-cis-2a (left)
and (S)-(M)-trans-2b and (S)-(P)-trans-2b (right), respectively. Solid curves correspond to both the (M)-
enantiomers; dashed curves correspond to both the (P)-enantiomers.
(P)-trans-2b solution at 1008C, an equilibrium state of (S)-
(P)-trans-2b and (S)-(M)-trans-2b in a ratio of 47.5:52.5 was
obtained. Also for the two trans forms of 2, the anticipated
energy difference is observed. Again, combining the equi-
librium ratio with the actual rate of the pseudoracemization
process (in this case 9.5 Â 10À5 sÀ1) gives the rate constants of
the two helix inversions. The rate constants for the two
processes (S)-(P)-trans-2b (S)-(M)-trans-2b (k3) and (S)-
(M)-trans-2b (S)-(P)-trans-2b (k4) were determined to be
5.0 Â 10À5 and 4.5 Â 10À5 sÀ1, respectively. From these k
values, the Gibbs energy of activation of the four distinct
thermal pathways, which is an indication for the relative
stability of the four isomers, can be determined.[28] The
calculated values are depicted in Scheme 7 and these values
again show a small but significant difference for the forward
and backward helix inversion for both cis-2a and trans-2b.
Although the additional stereogenic center clearly has an
effect on the relative stability of the distinct isomers the
effects are rather small. It should be noted that both for the
trans as well as the cis-isomers (M)-helicity is preferred,
however, no explanation for this behavior can be given at
this moment.
speak of a racemization but rather of a thermally induced
helix inversion (Scheme 2). The thermally induced intercon-
version between the diastereoisomers (S)-(M)-cis-2a and (S)-
(P)-cis-2a as well as between diastereoisomers (S)-(M)-trans-
2b and (S)-(P)-trans-2b was monitored in n-dodecane by CD
spectroscopy. These pairs of diastereoisomers that share the
same (cis or trans) geometry but show opposite helicity might
be called pseudoepimers.[27] Solutions of enantiomerically
pure (S)-(M)-cis-2a and (S)-(P)-trans-2b at known concen-
trations were heated for 10 h at 1008C. The change in CD
absorption was monitored in time, as depicted in Figure 5.
It might seem unexpected that the energy difference
between the two trans-nitro isomers is in fact smaller than
the difference for the two cis-nitro isomers. At first inspection
of the molecular structures it would seem that the influence of
the stereogenic center of the pyrrolidine substituent, which is
solely responsible for the observed energy differences be-
tween the cis-isomers (and the trans-isomers), is larger when
the pyrrolidine moiety is in close proximity to the sterically
demanding upper arene part of the molecule. It was, however,
previously observed that in these complicated helical struc-
tures the methylene group directly adjacent to the central
double bond in the upper half of the molecule has a
Figure 5. CD absorption (rescaled to show molar values De) in time for
heated samples of (S)-(M)-cis-2a (bottom) and (S)-(P)-trans-2b (top) at
1008C in n-dodecane.
Knowing the molar CD absorptions of all four diaster-
eoisomers in this solvent, which are identical to the absorp-
tions found in n-hexane, the equilibrium ratio of the two
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Chiroptical Molecular Switches
2845 2853
compared to the influence of the
stereogenic center in the molec-
ular motor systems, albeit far
less pronounced. The delicate
balance of chiral influences on
these intrinsically chiral helically
shaped overcrowded systems
and the stereochemical parame-
ters controlling the thermal and
photochemical processes re-
mains an interesting topic for
further studies.
Experimental Section
General methods: 1H NMR spectra
were recorded on a Varian Gemini-
200 (200 MHz),
(300 MHz) or
a
Varian VXR-300
Scheme 7. Thermal stabilities for the four distinct diastereoisomers of 2.
a
Varian Unity Plus
Varian-500 (500 MHz). 13C NMR spec-
tra were recorded on a Varian Gemini-
200 (50 MHz),
a Varian VXR-300
substantial steric effect on the lower half.[29] Whereas the two
hydrogens are restricted to their respective axial and equa-
torial orientation, the naphthalene moiety in the trans-isomer
can simply bend away thereby greatly reducing the steric
effect exerted on the lower half of the molecule. Therefore a
distinct difference exists between trans- and cis-isomers,
where the pyrrolidine-moiety is facing a naphthalene or CH2
group in the upper half, respectively.
(75 MHz) or a Varian Unity Plus Varian-500 (125 MHz). Chemical shifts
are denoted in d-unit (ppm) relative to CDCl3. The splitting patterns are
designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet) and br (broad) for 1H NMR. For 13C NMR the carbon atoms are
assigned as q (primary carbon), t (secondary carbon), d (tertiary carbon)
and s (quaternary carbon). CD spectra were recorded on a JASCO J-715
spectropolarimeter and UV measurements were performed on a Hewlett-
Packard HP 8453 FT Spectrophotometer using UVASOL grade solvents
(Merck). MS spectra were obtained with a Jeol JMS-600 spectrometer by
Mr. A.Kieviet. Column chromatography was performed on silica gel
(Aldrich 60, 230 400 mesh). HPLC analyses were performed on a Waters
HPLC system equipped with a 600E solvent delivery system and a 996
Photodiode Array Detector. Preparative HPLC was performed by Mr.
M. B. van Gelder on a preparative Gilson HPLC system consisting of a
231XL sampling injector, a 306 (10SC) pump, an 811C dynamic mixer, a
805 manometric module, with a 119 UV/Vis detector and a 202 fraction
collector, using the (chiral) columns as mentioned. Elution speed was
1mLmin À1, unless stated otherwise. Solvents were distilled and dried
before use, if necessary, by standard methods. Reagents and starting
materials were used as obtained from Aldrich, Acros, Fluka or Merck. (S)-
proline obtained from Acros and reported 99 ‡ % was used as purchased.
Irradiation experiments: Irradiations were performed with an 150 W Oriel
Xe lamp attached to an Oriel monochromator or a 180 W Oriel Hg lamp
adapted with a suitable Mercury line filter for 313, 365, 405 and 435 nm
irradiations (typical bandwidth 10 nm). Photostationary states are ensured
by monitoring composition changes in time by taking UV spectra at distinct
intervals until no changes were observed. Ratios of the different forms of
the molecular switches were determined by HPLC by monitoring at the
isosbestic point or by NMR analysis. HPLC elution times and NMR details
are denoted throughout the synthetic procedures. CD spectra were
recorded on a JASCO J-715 spectropolarimeter and UV measurements
were performed with a Hewlett Packard HP 8453 FT spectrophotometer
using UVASOL grade solvents (Merck). Thermal helix inversions were
also monitored by CD spectroscopy employing a JASCO PFD-350S/350L
Peltier type FDCD attachment with temperature control.
Conclusion
We presented a novel donor acceptor substituted molecular
switch 2 with excellent switching properties. A new and more
efficient synthetic route towards these systems was developed
which opens up the possibility of synthesizing a variety of
donor acceptor systems in one step starting from a mutual
bromo-substituted synthon 3. Compound 2 has some advanta-
geous properties compared with previously reported donor
acceptor switches. The improved resolution properties of the
system in combination with a high switching selectivity make
this compound a useful member of the chiroptical molecular
switch family. The additional stereogenic center only has a
minor effect on the photophysical properties and the thermal
stabilities of the different stereoisomers. Nevertheless, for a
comparable class of sterically overcrowded alkene the pres-
ence of a single stereogenic center, in addition to the intrinsic
chirality of the system, resulted in completely controlled
unidirectional rotation in two generations of molecular
motors. The key feature in these systems is unidirectionality
in the thermal helix inversion steps as a result of a relatively
large energy differences between the two pseudoenantiomeric
forms. Although the energy differences for compound 2,
shown in Scheme 7, are too small for a full control over the
directionality in these isomerization processes, the influence
of the additional stereogenic center in this molecule can be
2,3-Dihydro-1H-naphtho[2,1-b]thiopyran-1-one hydrazone (8):[20a] 2,3-Di-
hydro-1H-naphtho[2,1-b]thiopyran-1-one hydrazone was synthesized as
described before starting from 2-thionaphthol, via 3-(2-naphthylthio)-
propiononitrile
and
2,3-dihydro-1H-naphtho[2,1-b]thiopyran-1-one.
1H NMR: d ˆ 2.87 (s, 4H), 5.43 (brs, 2H), 7.31(d, J ˆ 8.4 Hz, 1H), 7.37
(ddd, J ˆ 8.1, 7.0, 1.1 Hz, 1 H), 7.46 (ddd,J ˆ 8.8, 7.0, 1.5 Hz, 1 H), 7.58 (d, J ˆ
8.4 Hz, 1H), 7.72 (dd, J ˆ 8.1, 1.5 Hz, 1 H), 8.65 (d, J ˆ 8.8 Hz, 1H);
13C NMR d ˆ 27.27 (t), 30.31 (t), 124.93 (d), 126.37 (d), 126.46 (d), 126.66
(d), 127.59 (d), 127.85 (d), 129.60 (s), 131.39 (s), 132.94 (s), 135.94 (s), 145.23 (s).
Chem. Eur. J. 2003, 9, 2845 2853
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2851

B. L. Feringa et al.
FULL PAPER
(S)-2-(Methoxymethyl)pyrrolidine (4):[22] Under exclusion of oxygen,
LiAlH4 (14 g, 0.4 mol) and anhydrous THF (600 mL) were heated under
reflux for 15 min. Without heating, (S)-proline (25 g, 0.25 mol) was added
in small portions and the mixture was subsequently heated for 1h under
reflux. Excess LiAIH4 was decomposed by cautiously adding a solution of
KOH (7 g) in H2O (28 mL). After stirring for 15 min the mixture was
filtered and the remaining salts were extracted with THF (200 mL). The
combined organic filtrates were dried (Na2SO4) and concentrated under
reduced pressure at 308C. Methyl formate (18 mL, 17 g, 0.28 mol) was
added at 08C over a period of 1h to the crude product and the mixture was
stirred for 2 h. Excess methyl formate was evaporated at 308C in vacuo
affording a dark oil which was taken up in CH2Cl2 (150 mL) and dried with
Na2SO4. The mixture was filtered and concentrated under reduced pressure
at 308C. The procedure yielded the crude N-formyl compound (28.3 g, ca.
0.22 mol), which was dissolved in anhydrous THF (350 mL). The solution
was cooled to À608C and MeI (18 mL, 0.26 mol) and NaH (6.26 g,
0.26 mol) were added carefully. The solution was allowed to warm to RT
(H2 gas evolves), heated under reflux for 15 min, quenched by slow
addition of 6m HCl (20 mL) and filtered. THF was evaporated under
reduced pressure yielding a dark oil. A solution of KOH (40 g) in H2O
(156 mL) was added to the crude product under vigorous stirring at RTand
the mixture was heated under reflux for 5 h. (S)-2-(Methoxymethyl)pyrro-
lidine was extracted in a 500 mL perforator over a period of 24 h with
diethyl ether. The organic layer was dried using Na2SO4, diethyl ether was
evaporated and product purified using bulb-to-bulb distillation (b.p. 628C
at 40 Torr). The procedure yielded 4 as a colorless liquid (10.56 g, 37%
overall yield) which was stored at À48C. Optical rotation was in
accordance with literature.[30] 1H NMR: d ˆ 1.23 1.30 (m, 1 H), 1.56 1.72
(m, 3H), 2.44 (s, 1H), 2.71 2.87 (m, 2H), 3.11 3.21 (s, 3H); 13C NMR:
d ˆ 23.72 (t), 26.27 (t), 44.82 (t), 56.11 (q), 57.36 (d), 74.58 (t).
column chromatography (silica gel, CH2Cl2/hexane 1:1), yielding 9 (510 mg,
60.1%) as a yellow powder as a 1:1 mixture of cis- and trans-isomers.
HRMS: m/z: calcd for C26H16BrNO2S3: 550.95060; found: 550.95225.
7-Bromo-2-nitro-9-(1',2',3',4'-tetrahydrophenanthrene-4'ylidene)-9H-thio-
xanthene (3): Triphenylphosphine (0.39 g, 1.5 mmol) was added to a stirred
solution of episulfide 9 (0.510 g, 0.92 mmol) in toluene (50 mL) and the
resulting solution was refluxed for 3 d. The solvent was evaporated and the
resulting orange solid was recrystallized from 96% EtOH to yield 3 as an
approximate 1:1 mixture of isomers as a yellow powder (491 mg, 97%).
1H NMR: d ˆ 2.30 2.40 (m, 3H), 3.45 3.64 (m, 8H), 6.53 (d, J ˆ 1.8 Hz,
1H), 6.87 7.16 (m, 10H), 7.32 7.71 (m, 22H), 8.14 (dd, J ˆ 8.4, 2.2 Hz,
1H), 8.37 (d, J ˆ 2.2 Hz, 1H); HRMS: m/z: calcd for C26H16BrNO2S2:
518.97853; found: 518.97674; elemental analysis calcd (%) for
C26H16BrNO2S2: C 60.24, H 3.11, N 2.70, S 12.37; found: C 60.33, H 3.05,
N 2.86, S 12.69.
7-((S)-2-(Methoxymethyl)pyrrolidine)-2-nitro-9-(1',2',3',4'-tetrahydrophe-
nanthrene-4'ylidene)-9H-thioxanthene (2): BINAP (15 mg, 0.0225 mmol)
and [Pd2(dba)3] (7.5 mg, 0.0063 mmol) were dissolved in dry toluene
(50 mL). This solution was stirred for 30 min at RT, whereupon it turned
from dark red to dark orange. After this period NaOtBu (125 mg,
1.3 mmol) was added, followed by bromo-substituted alkene 3 (100 mg,
0.19 mmol) and (S)-2-(methoxymethyl)pyrrolidine (4; 50 mg, 0.43 mmol).
The mixture was stirred at 808C for 2 d. Subsequently the reaction mixture
was poured into CH2Cl2 (50 mL). After filtration the solvents were
evaporated. The crude product was dissolved in a small amount of CH2Cl2
and purified using column chromatography (silica gel; CH2Cl2/n-hexane/
NEt3 50:50:1) to afford 2 as a red solid mixture of stereoisomers (60 mg,
58%). HRMS: m/z: calcd for C32H28N2O3S2: 552.15411; found: 552.15296.
Separation of stereoisomers was performed by HPLC (Econosphere Silica;
5 mm; 250 Â 4.6 mm). The following gradient of n-heptane and dichloro-
methane was used as an eluent: 0 3 min pure n-heptane; 3 15 min
gradient n-heptane/dichloromethane 100:0 to 0:100; 15 20 min pure
dichloromethane; 20 21min gradient n-heptane/dichloromethane 0:100
to 100:0. The four diastereomers are readily separated with retention times
of 16.9 min ((S)-(M)-cis-2a); 17.4 min ((S)-(P)-cis-2a); 18.2 min ((S)-(P)-
trans-2b); 18.8 min ((S)-(M)-trans-2b). The respective (M)- and (P)-
isomers were assigned by comparison of the CD spectra with other
sterically overcrowded alkenes synthesized. The respective cis- and trans-
2-[(4-Bromophenyl)sulfanyl]-5-nitrobenzoic acid (5): p-Bromothiophenol
(12 g, 64 mmol) and 2-chloro-5-nitrobenzoic acid (13.14 g, 64 mmol) were
added to a solution of NaHCO3 (10.8 g, 128 mmol) in dry ethanol (200 mL).
The reaction mixture was heated under reflux for 24 h under a nitrogen
atmosphere. After this period a 10% aq. HCl solution (150 mL) was added,
after which a precipitate was collected by filtration, yielding crude 5 (22.1g,
98%) as a yellow solid, which was used without further purification.
2-Bromo-7-nitro-9H-thioxanthen-9-one (6): A suspension of 5 (22.1g,
62 mmol) in sulfuric acid (400 mL) was stirred and heated at 1008C for 3 h.
The suspension was then poured onto ice (500 g) and left overnight. Next
the precipitate was filtered and washed with water (2 Â 50 mL), concen-
trated NaHCO3 (2 Â 100 mL) and ethanol (2 Â 50 mL). The yellow solid
was dried at 608C under reduced pressure, yielding 6 (20.2 g, 97%). m.p.
1
isomers were assigned by H NMR (see below).
1H NMR: (S)-(M)-cis-2a and (S)-(P)-cis-2a: d ˆ 1.92 2.06 (m, 8H), 2.24
2.31(m, 2H), 3.08 3.26 (m, 4H), 3.34 (s, 3H), 3.38 (s, 3H), 3.43 3.58 (m,
8H), 3.76 3.88 (m, 3H), 3.90 3.98 (m, 1H), 6.59 (t, J ˆ 2.2 Hz, 1H), 6.62
(t, J ˆ 2.2 Hz, 1H), 6.87 (t, J ˆ 2.6 Hz, 2H), 6.91 6.96 (m, 2H), 7.01 7.06
(m, 2H), 7.18 7.24 (m, 2H), 7.28 7.59 (m, 14H); (S)-(M)-trans-2b and (S)-
(P)-trans-2b: d ˆ 1.92 2.06 (m, 8H), 2.24 2.31 (m, 2H), 3.08 3.26 (m,
4H), 3.17 (s, 3H), 3.21 (s, 3H), 3.43 3.58 (m, 8H), 3.76 3.88 (m, 3H),
3.90 3.98 (m, 1H), 5.77 (d, J ˆ 2.2 Hz, 1H), 5.87 (d, J ˆ 2.2 Hz, 1H), 6.08
(dd, J ˆ 8.4, 2.2 Hz, 1H), 6.14 (dd, J ˆ 8.4, 2.2 Hz, 1H), 7.01 7.16 (m, 6H),
7.47 7.60 (m, 8H), 7.67 (d, J ˆ 8.4 Hz, 2H), 8.07 8.13 (m, 2H), 8.34 (d, J ˆ
2.2 Hz, 1H), 8.39 (d, J ˆ 2.2 Hz, 1H).
(S)-(M)-cis-2a: UV/Vis (n-hexane): lmax (e) ˆ 255 (18610), 273 (16686),
368 (3385); CD (n-hexane): lmax (De) ˆ 241( À18.6), 256 (‡22.6), 280
(À36.7), 326 (À1.6), 362 (‡6.3).
(S)-(P)-cis-2a: UV/Vis (n-hexane): lmax (e) ˆ 257 (23552), 287 (13652), 369
(3058); CD (n-hexane): lmax (De) ˆ 241( ‡20.7), 255 (À24.2), 280 (À37.7),
326 (‡1.8), 358 (À6.5).
1
288.1 290.5 8C; H NMR: d ˆ 7.46 (d, J ˆ 8.4 Hz, 1H), 7.70 (d, J ˆ 8.8 Hz,
1H), 7.76 (dd, J ˆ 8.4, 2.2 Hz, 1H), 8.39 (dd, J ˆ 9.2, 2.6 Hz, 1H), 8.72 (d,
J ˆ 2.2 Hz, 1H), 9.38 (d, J ˆ 2.2 Hz, 1H); no 13C data available due to low
solubility; HRMS: m/z: calcd for C13H6BrNO3S: 334.92512; found:
334.92661.
2-Bromo-7-nitro-9H-thioxanthene-9-thione (7): A suspension of xanthone
6 (5.1g, 15 mmol) and P 2S5 (8 g, 36 mmol) in dry toluene (150 mL) was
refluxed for 72 h. After this period additional P2S5 (3 g, 14 mmol) was
added and the suspension was heated under reflux for another 3 h. The
suspension was then allowed to cool to about 508C and filtered. The flask
was washed with hot toluene until the solvent was no longer green. From
the filtered solution the solvent was evaporated to leave a brown solid.
Recrystallization from toluene yielded 7 as dark brown crystals (4.0 g,
76%). M.p. 274.8 276.38C; 1H NMR: d ˆ 7.43 (d, J ˆ 8.4 Hz, 1H), 7.66 (d,
J ˆ 8.8 Hz, 1H), 7.73 (dd, J ˆ 8.4, 2.2 Hz, 1H), 8.34 (dd, J ˆ 9.2, 2.6 Hz, 1H),
9.00 (d, J ˆ 2.2 Hz, 1H), 9.68 (d, J ˆ 2.6 Hz, 1H); no 13C data available due
to low solubility; HRMS: m/z: calcd for C13H6BrNO2S2: 350.90228; found:
350.90238.
(S)-(M)-trans-2b: UV/Vis (n-hexane): lmax (e) ˆ 257 (20005), 271(14895),
312 (5942), 355 (2229), 398 (1681); CD (n-hexane): lmax (De) ˆ 243 (0), 255
(‡37.7), 275 (À37.4), 325 (À7.3), 353 (‡3.8).
(S)-(P)-trans-2b: UV/Vis (n-hexane): lmax (e) ˆ 255 (17065), 275 (14981),
312 (6287), 327 (3882), 362 (1618), 402 (1681); CD (n-hexane): lmax (De) ˆ
242 (‡4.4), 255 (À30.3), 275 (‡28.9), 325 (‡5.7), 354 (À3.9).
Dispiro[1,2,3,4-tetrahydrophenanthrene-4,2'-thiirane-3',9''-7-bromo-2''-ni-
tro))-9''H-thioxanthene (9): A stirred solution of hydrazone 8 (350 mg,
1.53 mmol) in dry CH2Cl2 (20 mL) was cooled to À208C, whereupon
MgSO4 (600 mg), Ag2O (531mg, 2.29 mmol) and a saturated solution of
KOH in dry MeOH (1.2 mL) were successively added and the mixture was
stirred at this temperature under a nitrogen atmosphere. After the solution
turned deep red it was filtered into another ice-flask containing thioketone
7 (445 mg, 1.53 mmol) and the mixture was then stirred for another 3 h
while warming to room temperature. The precipitated solid (excess 7) was
filtered off and the solvent was evaporated. The product was purified by
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2852
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2845 2853

Chiroptical Molecular Switches
2845 2853
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[28] The measured rate constant k for the process is a sum of the two
individual rate constants of the reversible helix inversion, for cis-2a:
(M)-cis-2a (P)-cis-2a rate: k1; (P)-cis-2a (M)-cis-2a rate: k2 then
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two equations with two unknown parameters that can be solved. For a
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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