University of Groningen
In Control of Motion
Feringa, Bernard
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Accounts of Chemical Research
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Feringa, B. (2001). In Control of Motion: From Molecular Switches to Molecular Motors.
Accounts of
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,
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(6), 504 - 513. https://doi.org/10.1021/ar0001721
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In Control of Motion: From
Molecular Switches to
Molecular Motors
†
BEN L. FERINGA
Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG, Groningen, The Netherlands
Received December 7, 2000
ABSTRACT
The design of molecular systems in which controlled linear and
rotary motion can be achieved under the influence of an external
signal is a major endeavor toward future nanoscale machinery. In
this Account we describe the development of molecular switches
and the discoveries that culminated in the first light-driven
molecular motor. Various chiral optical molecular switches and
their use as trigger elements to control organization and functions
will be discussed. The construction of the first and second
generation molecular motors is presented.
Introduction
The bottom-up construction of motors and machines of
nanosize dimensions offers a formidable challenge to
science, and its realization might have far-reaching con-
sequences in view of the impact of their macroscopic
analogues in daily life.
1,2
It is fascinating to see how Nature
has found elegant solutions to control movement at the
molecular level by the conversion of chemical energy into
mechanical energy.
3
Among the most prominent examples
of such biomolecular motors are the muscle linear and
ATP-ase rotary motors.
4
In approaches toward artificial
machinery, a variety of molecular and supramolecular
systems have been designed in recent years in which
changes in shape, switching processes, or movements
occur in response to external chemical, electrochemical,
or photochemical stimuli.
5,6
The efforts in our group that led ultimately to the first
light-driven molecular motor, which can undergo repeti-
tive 360° rotations in a unidirectional manner, started in
1989 with the challenge to construct chiral photobistable
molecules (chiroptical molecular switches) that could be
applied as molecular memory elements in optical data
storage systems.
6
But the molecular basis was already
established more than 10 years earlier, when the author
as a student synthesized the first sterically overcrowded
inherent dissymmetric alkenes of which both cis and trans
forms exist as stable enantiomers.
7
In this Account will be described how we came from
chiral molecular switches via triggering of the organization
and controlled motion of many molecules to the con-
struction of our present second generation light-driven
molecular motors.
Chiroptical Molecular Switches
Stimulated by the dazzling success of miniaturization in
information technology and the prophecy that molecular
memory elements for data storage and processing by light
are the ultimate goal, we embarked on the construction
of molecular switches. From the numerous early studies
on photochromic compounds, we soon learned that,
although the basic condition of photochemical bistability
is often fulfilled, several other requirements including
fatigue resistance, thermal stability, and nondestructive
read-out are essential for applications as trigger ele-
ments.
6,8
In our approach, we exploited the unique
properties associated with chiral photoresponsive mol-
ecules (Figure 1). The design is based on the intercon-
version by light of the right- (R or P) and left-handed (S
or M) forms of a chiral molecule which represent two
distinct states in a molecular binary logic element. Switch-
ing between diastereomeric (or pseudoenantiomeric)
photobistable molecules (P and M′) can be accomplished
at two different wavelengths λ
1
and λ
2
(Figure 1A). On the
other hand, two enantiomers (P and M) can, in principle,
be interconverted at a single wavelength using left or right
circular polarized light (l-orr-CPL) (Figure 1B).
We reasoned that a major advantage of such chiral
optical switches, compared to other photochromic sys-
tems, is nondestructive read-out of an optical recording
system containing these materials by monitoring the
change in optical rotation at wavelengths remote from the
wavelengths used for switching. In contrast, detection is,
at present, often based on UV/visible spectroscopy in or
near the absorption bands, leading to partial reversal of
the photochromic process used to store information.
9
The
principle of an information storage system based on
chiroptical molecular switches is shown in Scheme 1.
The design of the chiroptical switch, depicted in
Scheme 2a, involves a lower half, considered the static
†
Part of the Special Issue on Molecular Machines.
Ben L. Feringa received his Ph.D. degree from the University of Groningen in
1978 with professor Hans Wynberg. He was research scientist with Royal Dutch
Shell, both at the Shell Research Center in Amsterdam and at the Shell
Biosciences Laboratories in Sittingbourne, UK. In 1984, he joined the Department
of Chemistry at the University of Groningen as a lecturer and was appointed
professor at the same university in 1988. He is recipient of the Pino gold medal
of the Italian Chemistry Society. His research is focused on synthesis and
stereochemistry. His current research interests include asymmetric catalysis,
catalytic oxidation, self-assembly, and molecular switches and motors.
FIGURE 1. Chiroptical molecular switches. The right-handed helical
structure (
P
-isomer) and left-handed helical structure (
M
-isomer)
represent the 0 and 1 states in a binary logic system. The two states
can be interconverted by light irradiation. (A) Switching between
pseudoenantiomers
P
and
M
′ at two wavelengths λ
1
and λ
2
. (B)
Switching between enantiomers at a single wavelength with
l
- and
r
-CPL.
Acc. Chem. Res.
2001,
34,
504-513
504
ACCOUNTS OF CHEMICAL RESEARCH
/ VOL. 34, NO. 6, 2001 10.1021/ar0001721 CCC: $20.00 2001 American Chemical Society
Published on Web 05/04/2001
part, and an upper half, which turns from right to left
upon irradiation. The molecular structures (Scheme 2b)
comprise unsymmetric sterically overcrowded thioxan-
thenes 1-3.
To avoid unfavorable steric interactions at the fjord
region, these molecules adopt a helical shape. The mo-
lecular structure of cis-2-nitro-7-(dimethylamino)-9-(2,3′-
dihydro-1′H-naphtho[2,1-b]thiopyran-1′-ylidene)-9H-thiox-
anthene (P-cis-2a) is illustrative for the antifolded helical
shape of these chiral switches (Figure 2). The central
double bond has a normal bond length (1.353 Å), and only
slight deviation from planarity (dihedral angle 5.4°)is
observed. The extent of twisting and folding shows,
however, considerable variation among the approxi-
mately 50 different chiral overcrowded alkenes we have
synthesized so far. It was particularly rewarding that the
racemization barriers of symmetric overcrowded alkenes
could be tuned over a range from 12 to >30 kcal mol
-1
by modification of the bridging units X and Y in the upper
and lower halves. Typical data for nonsymmetric over-
crowded alkenes 1 are given in Table 1.
10
There appears
to be a delicate balance between ground-state distortion
due to twisting and folding of the molecules and helix
inversion. The ability to tune the barriers for the various
thermal and photochemical isomerization processes turned
out to be essential in our approaches toward the con-
struction of molecular switches and motors. It might not
come as a surprise that the photochemical properties can
also be readily tuned through the substituents R
1
-R
3
in
the upper and lower halves of 1-3.
A photochemically induced stilbene-type cis-trans
isomerization of 1 simultaneously results in reversal of the
helicity (from M to P and vice versa) (Scheme 2). The first
successful chiroptical switch was realized with 1 (X ) CH
2
,
Y ) S, R
1
) Me, R
2
) OMe, R
3
) H).
11
A stereospecific
interconversion of M-cis-1a and P-trans-1b was found.
Alternated irradiation with 250 and 300 nm light resulted
in a 4% shift of the photostationary state and modulation
of the ORD and CD signals. Taking advantage of the
helicene-like chirality, large changes in chiroptical proper-
ties occur in these systems, which allow easy detection.
We observed, however, about 10% racemization after 20
switching cycles.
Once we had realized our first goal of repetitive
chiroptical switching, we focused on the following key
issues: (i) improving the stability toward racemization;
(ii) tuning the wavelengths for photoisomerization; and
(iii) enhancing the stereoselectivity. Introduction of the
naphtho[2,1-b]thiopyran moiety in the upper half and
donor and acceptor substituents in the thioxanthene lower
half was particularly rewarding.
12
The synthesis of the
target switch 2 is outlined in Scheme 3. The coupling of
the lower and upper halves by formation of the central,
sterically demanding double bond is the crucial step in
the synthetic routes to the switches and motors described
here. After many failures with a plethora of olefination
procedures at our disposal, the diazothioketone coupling
method proved to be successful.
13
It should be emphasized
Scheme 1
Scheme 2
FIGURE 2. Pluto diagram of the crystal structure of
P
-
cis
-2a.
Table 1
XY
racemization barrier
(kcal mol
-1
)
O O 24.9 ( 0.3
CH
2
O 27.4 ( 0.2
S O 28.0 ( 0.2
S S 28.9 ( 0.1
S CHCH 29.0 ( 0.3
In Control of Motion
Feringa
VOL. 34, NO. 6, 2001 /
ACCOUNTS OF CHEMICAL RESEARCH
505
that steric constraints are introduced gradually via a
sequence involving 1,3-dipolar cycloaddition to give a five-
membered thiadiazoline. A three-membered episulfide
results from nitrogen elimination, and finally sulfur extru-
sion affords the alkene.
A remarkable enhanced stability (∆G
rac
) 29.2 kcal
mol
-1
) and a large bathochromic shift in the absorption
spectra, which allows switching to take place near the
visible wavelength region, were observed. M-cis-2a and
P-trans-2b (Scheme 4) have nearly mirror image CD
spectra (Figure 3), illustrating the pseudoenantiomeric
nature of these compounds and the fact that the overall
helicity is a dominant chirality factor. Note that the
naphthalene chromophore in the upper part is facing
either a donor or an acceptor moiety in the two isomers.
Large differences in isomeric composition, with ratios
of M-2a and P-2b of 30:70 (at 365 nm) and 90:10 (at 435
nm), in the photostationary states were readily achieved
upon irradiation (Scheme 4). The photomodulation of
chirality, as detected by CD, is illustrated in Figure 4.
Besides the reversal of helicity, it was possible to perform
80 switching cycles without deterioration or racemization.
Detailed studies of these and related chiroptical switches
revealed that the composition of the photostationary
states, and as a consequence the ratio of P and M helices,
depends on substituents, wavelength, and medium.
For instance, the difference in donor-acceptor inter-
actions in the bistable forms could be further enhanced
by the introduction of a dimethylamino donor moiety in
the upper part as shown in 3 (Scheme 2). A highly
stereoselective switching process in one direction was
observed using 435 nm light (M-cis-3a:P-trans-3b ) 99:
1), but irradiation at various wavelengths showed only
modest reversibility.
14
Photomodulation of chirality in thin polymer films,
using either covalently attached chiroptical switches or
doped systems, was also successful. However, matrix
effects play a prominent role, as these strongly influence
the diastereoselectivity and irradiation times required to
reach the photostationary states.
14,15
This aspect will be
particularly important in future applications as photo-
active materials or data storage systems.
The response time is another important issue in the
pursuit of molecular switches. Realizing the extremely fast
retinal cis-trans photoisomerization in the process of
vision,
16
we recently embarked on a femtosecond spec-
troscopy study.
17
For a number of symmetrically over-
crowded alkenes, we indeed found fast isomerization
(<300 ps) via a so-called phantom state.
18
The chiroptical switches described here represent the
first examples of synthetic systems in which unidirectional
rotary motion was accomplished (Scheme 2a). The relative
direction of the movement can be controlled by the
wavelength of the light and depends on the chirality of
the molecule.
But how do we switch between enantiomers, e.g., P and
M (Figure 1B)?
Scheme 3
Scheme 4
FIGURE 3. Circular dichroism spectra of
P
-
trans
-2b and
M
-
cis
-
2a.
FIGURE 4. Plot of ∆ at 280 and 350 nm versus the irradiation time
for the
M
-
cis
-2a-
P
-
trans
-2b isomerization. Irradiation alternately
at λ ) 435 and 365 nm.
In Control of Motion
Feringa
506
ACCOUNTS OF CHEMICAL RESEARCH
/ VOL. 34, NO. 6, 2001
Single Wavelength Switching
When the photochemical process involves the intercon-
version between two enantiomers, irradiation will always
lead to racemization, irrespective of the wavelength of the
light. Using chiral light (right- or left-circular polarized
light), enantioselective switching in either direction should,
in principle, be possible.
19
Facing the challenge to design
a suitable chiral molecule to demonstrate switching at a
single wavelength, we realized that the following factors
are decisive for success: (i) irradiation with CPL should
lead exclusively to interconversion of the enantiomers
without competing photochemical processes; (ii) the
enantiomers have to be thermally stable (∆G
rac
> 21 kcal
mol
-1
); (iii) the chiral photoactive compound should
exhibit a sufficiently high anisotropy factor g
20
(it should
be noted that the enantiomeric excess that can be
expected in the photostationary state is given by ee
pss
)
g/2 ) ∆/2, and for inherently dissymmetric alkenes g <
1% is usually found); and (iv) the quantum efficiency for
photoracemization should be high since the rate of
photoresolution is exponentially related to this quantity.
A large number of sterically overcrowded chiral alkenes,
comprising four distinct subclasses (type 1 through type
4, Figure 5), were synthesized, and the chiroptical proper-
ties and thermal and photochemical isomerization proc-
esses were examined. Compound 6 satisfied the require-
ments given above (Scheme 5).
The enantiomers of 6 show fatigue resistance, a stereo-
specific photoisomerization process that reverses the
helicity and sufficient stability at ambient temperature
(∆G
rac
) 25.9 kcal mol
-1
). A rapid photoracemization of
P-6 was found upon irradiation at 300 nm with unpolar-
ized light (Φ
rac
) 0.40, n-hexane), and the experimental g
value (g )-6.4 × 10
-3
at 314 nm) indicates that, under
ideal conditions, an ee of 0.3% might be observed. We
could, indeed, accomplish deracemization and switching
of P,M-6 by irradiation with l- and r-CPL at 313 nm (Figure
6).
21
At this wavelength, switching occurred between
photostationary states with ee values of 0.07% and -0.07%
for P and M helices, respectively. Upon irradiation of
either P-6 or M-6 at 313 nm with LPL, racemic P,M-6 was
obtained. Ways to reach more efficient CPL irradiation and
higher g factors are currently under scrutiny.
The system shown in Scheme 5 comprises a three-
position optical switch of racemic (P,M), P-enriched, and
M-enriched 6 with the distinct feature that all the switch-
ing processes can be performed at a single wavelength
simply by changing the chirality of the light employed.
Dual-Mode Photoswitching
It was anticipated that the incorporation of a kind of brake
in the photoswitch might enable us to use an additional
control element for the movement induced by irradiation.
We found that the photochemical process in the case of
donor-acceptor-substituted overcrowded alkenes 2 could
be regulated by reversible protonation of the N,N-di-
methylamine donor moiety.
22
Dual-mode photoswitching
with M-2a and P-2b is illustrated in Scheme 6.
The switching process was effectively blocked by ad-
dition of trifluoroacetic acid, for example. The presence
of a donor- and acceptor-substituted lower half in M-cis-
2a and P-trans-2b is essential for stereoselective photo-
isomerization, and protonation of the amine results in an
ineffective acceptor-acceptor (ammonium and nitro)-
substituted lower half. Therefore, by simple (de)protona-
tion, the on mode (switching) and off mode (no switching)
FIGURE 5. Different classes of chiral overcrowded alkenes.
Characteristic absorptions (λ, nm) and the corresponding ∆ and
g
factors are indicated (see text).
Scheme 5
FIGURE 6. Difference in CD absorption at 313 and 400 nm (∆
311
-
∆
400
) for a solution of 6 (9 × 10
-5
mol L
-1
)in
n
-hexane upon
alternating irradiation with
l
- and
r
-CPL at 340 nm (∆
400
is used as
an internal reference value to enhance accuracy).
In Control of Motion
Feringa
VOL. 34, NO. 6, 2001 /
ACCOUNTS OF CHEMICAL RESEARCH
507
