Active and Unidirectional Acceleration of Biaryl Rotation by a Molecular Motor

Article abstract of DOI:10.1002/anie.201913798

Light-driven molecular motors possess immense potential as central driving units for future nanotechnology. Integration into larger molecular setups and transduction of their mechanical motions represents the current frontier of research. Herein we report

Full text of DOI:10.1002/anie.201913798

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Accepted Article
Title: Active and Unidirectional Acceleration of Biaryl Rotation by a
Molecular Motor
Authors: Edgar Uhl, Peter Mayer, and Henry Dube
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10.1002/anie.201913798
Angewandte Chemie International Edition
Active and Unidirectional Acceleration of Biaryl Rotation by a
Molecular Motor
Edgar Uhl,† Peter Mayer,† Henry Dube†*
dedicated to Dr. Klaus Römer on the occasion of his 80th birthday
† Ludwig-Maximilians-Universität München, Department of Chemistry and Center for Integrated
Protein Science CIPSM, Butenandtstr. 5-13, 81377 München
E-mail: henry.dube@cup.uni-muenchen.de
Abstract
Light driven molecular motors possess immense potential as central driving units for future
nanotechnology. Integration into larger molecular setups and transduction of their mechanical motions
represents the current frontier of research. Here we report on an integrated molecular machine setup
allowing to transmit potential energy from a motor unit unto a remote receiving entity. The setup
consists of a motor unit connected covalently to a distant and sterically strongly encumbered biaryl
receiver. By action of the motor unit single bond rotation of the receiver is strongly accelerated and
forced to proceed unidirectionally. The transmitted potential energy is directly measured as the extent
to which energy degeneration is lifted in the thermal atropisomerization of this biaryl. Energy
degeneracy is reduced by more than 1.6 kcal/mol and rate accelerations of several orders of magnitude
in terms of rate constants are achieved.
Introduction
Molecular motors[1] allow to transform energy input at the molecular scale into directional molecular motions
and thus are envisioned to provide archetypal powering engines for future complex nanomachinery.[2] To date
a variety of molecular setups are available that deliver such powered directional motions[1a-m] and first attempts
have been made to transmit their motions at the molecular scale[3] or integrate them into larger structures to
perform macroscopic work.[4] However, at present there is only limited knowledge about the actual amount of
work that a single molecular motor can actively (against strain) perform and thus critical information for the
next leap in applicability is missing.[2b, 5] A different yet related pressing issue is the question how integration
of a molecular motor unit into a larger structure can be achieved such, that its directional motion is effectively
translated into potential energy raise at remote sites. Here we present a molecular machine setup 1 that allows
for the first time to effectively transmit potential energy raises from a powering motor unit unto a remote
receiver unit and thus actively accelerate the motion of the latter (Figure 1).[6] We use an axially chiral biaryl
as receiver unit, which in its nontethered form (model system 2) undergoes slow and nondirectional
atropisomerization rotation towards a 1:1 equilibrium of enantiomers (Figure 1a). Coupling of a molecular
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motor unit enables to drive this atropisomerization unidirectionally away from equilibrium. Different to an
earlier reported system[3a] we have now shifted the rate determining step of the machines operation cycle from
the motors helix inversion step to the atropisomerization step of the remote biaryl (see Supporting Information
for a direct comparison of both systems). As a result the biaryl atropisomerization is not passively following
motor operation anymore but represents an energy hurdle against which the motor has to work actively. In
machine 1 a rate acceleration of several orders of magnitude for the biaryl atropisomerization is achieved by
action of the motor, overpowering the intrinsic barriers for the isolated biaryl rotation (i.e. in model system 2
shown in Figure 1b and c). With this molecular setup critical design principles for advanced nano-machinery
are unraveled paving the way for effective generation and precise transmission of potential energy at the
smallest scales.
Figure 1
Integrated nano-machine 1 for potential energy transfer and active rate acceleration of biaryl
rotation. a) Biaryl rotation can be slowed down by increased steric hindrance via introduction
of two ortho-methyl groups. Atropisomerization proceeds nondirectionally towards a 1:1
equilibrium. In the integrated nano-machine 1 biaryl rotation is accelerated, proceeds
directional and is not reaching a 1:1 equilibrium. b) Molecular structure of biaryl 2 serving as
reference compound to determine the inherent biaryl atropisomerization rate. c) Molecular
structure of 2 in the crystalline state. d) Structure of AR-1 in the crystalline state. e) Structure
of CR-1 in the crystalline state. Structures in the crystalline state were determined from
racemic materials, only the (R) configured enantiomers are shown for clarity.
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Molecular setup 1 incorporates a molecular motor unit that is based on the parent hemithioindigo (HTI) dye[7]
(Figure 1). HTI belongs to the class of indigoid chromophores,[8] which are currently emerging as highly
promising visible light responsive photoswitches.[9] The motor unit is connected covalently to a remote biaryl
axis similar to an earlier described system that first evidenced the transmitted directional rotation from a
molecular motor to a different molecular entity.[3a] In the here presented setup 1 a sterically strongly
encumbered biaryl axis is introduced, which does not move in concert with the motor rotation. Different to the
earlier four-state system that is governed only by the motor rotation steps, additional steps are introduced
giving rise to an overall unidirectional six-step system (Figure 2). The six isomeric states are termed AT for
the tense state of A, AR for the relaxed state of A, and correspondingly BR, CT, CR, and DR for simplicity and
their exact stereo assignments are given in Figure 1 and 2. Five of these steps can be observed directly
experimentally, which also unequivocally proves existence of the sixth step and thus full directionality for the
whole coupled 360° rotation of both the motor and the biaryl unit.
Figure 2
Qualitative ground state energy profile of motor system 1. Six states with different stereo
configurations are populated during one full unidirectional 360° rotation. The covalent linkage
between the motor and the biaryl units is shown schematically for clarity reasons. The
enantiomer of 1 with (R) configured sulfoxide stereocenter is shown dictating
counterclockwise rotation of the motor as indicated by red and blue arrows.
Motor system 1 was synthesized in a convergent fashion from a brominated HTI-precursor to which the
covalent tether containing a boronic-ester function is attached via a copper-catalyzed click reaction. Afterwards
a Suzuki-type cross coupling reaction furnished macrocyclization, which was subsequently followed by
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oxidation to give the final structure 1. The synthesis of model system 2 is described in the Supporting
Information. For the two most stable states AR (E configured double bond) and CR (Z configured double bond)
of 1 and for the most stable state of 2 crystals suitable for structural analysis were obtained (the (R) configured
isomers of racemic AR and CR are shown in Figure 1d and e, respectively). The latter allowed to directly assign
the corresponding NMR spectra to specific molecular structures in solution. The conformations of the two
most stable states in solution were further analyzed by NMR spectroscopy confirming their close similarity to
the crystalline state. The only notable difference is the apparent presence of a minor isomer species, which is
in equilibrium with AR at ambient temperature in solution. A comprehensive spectroscopic analysis (see e.g.
ECD spectra in Figure 3a-d and Figures 17-19 and 50 in the Supporting Information for full details) revealed
this species to be the AT isomer possessing the same motor unit conformation but an atropisomerized biaryl
axis as compared to AR. Variable temperature assessment of the thermal equilibrium mixture allowed to
determine a free enthalpy difference G = 1.41 to 1.30 kcal/mol (0 °C to 35 °C) between the two states involved
using the Gibbs Helmholtz equation.
As AR/AT and CR could be separated using HPLC their behavior under heating and irradiation conditions at
different temperatures could be scrutinized independently. When heating a solution of racemic CR in (CDCl2)2
to 80 °C up to 140 °C the more stable AR was formed in up to 93%. This establishes a free enthalpy difference
G = 1.8 to 1.9 kcal/mol in this temperature range between these two states. The corresponding kinetic analysis
revealed a high energy barrier of 28.2 kcal/mol at 80 °C accompanying the thermal Z/E double bond
isomerization. When cooling pure CR down to -105 °C in CD2Cl2/CS2 (4/1) and in situ irradiating the solution
with 450 nm light at this temperature a new set of signals emerges, which is different to the known signal set
of AR and AT (Figure 3a). This new set of signals could be assigned to isomer DR by 2D NMR, and ECD
spectroscopy at low temperatures, which confirmed E configuration of the double bond, tilt of the biaryl unit,
and a helix inversion located in the motor unit, respectively (for the detailed analysis see Figure 3 and the
Supporting Information). The DR isomer signals decay to 75% within 28 min at -80 °C in the dark while at the
same time only the signals of the AT isomer are growing to the same extent (Figure 3e). Again a thermal
equilibrium between DR (12% remaining) and AT (88%) is observed at -60 °C, which translates into a free
enthalpy difference G = 0.84 kcal/mol between the two states. Kinetic analysis of the thermal decay revealed
an accompanying free activation enthalpy ‡G = 13.9 kcal/mol at -80 °C for this process. At -40 to 0 °C decay
of the AT signals and concomitant growth of the known signals of AR is observed until their equilibrium is
reached (see Supporting Information). Kinetic analysis of this process determined an associated free activation
enthalpy ‡G = 18.4 to 19.3 kcal/mol at -40 to 0 °C. Thus it was established that irradiation of pure Z configured
CR leads to a first photoisomerization product DR, which thermally converts into the AT isomer via a sole helix
inversion at the motor unit. Different to DR the AT isomer possesses a spring loaded covalent tether between
the rotor fragment and the biaryl unit owed to their large distance in this state. As a consequence the DR isomer
does not completely decay and an equilibrium concentration is established with this state still being populated.
At slightly more elevated temperatures AT decays further via atropisomerization of its biaryl axis thus
eliminating strain in the tether.
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When cooling the equilibrium solution of AR/AT in CD2Cl2/CS2 (4/1) to -105 °C and irradiating in situ with
450 nm light inside the NMR spectrometer the photoreaction of AR is observed predominantly owed to its
significantly larger abundance. A new set of signals emerges, which is different to the known signal set of CR
(Figure 3f). This set of signals is assigned to a rapidly interconverting mixture of BR and CT isomers based on
NMR and ECD spectroscopy and the behavior of this set of signals under irradiation conditions at very low
temperature (see below). Observation of this new set of signals as apparent photoproduct of AR therefore
directly confirms the expected photoisomerization directionality from AR to BR, which then stabilizes itself
further by undergoing fast helix inversion to CT even at the low temperature.
At -80 °C the signals of BR/CT decay in the dark almost completely while at the same time only the signals of
CR are growing to the same extent (Figure 3e). This gives a lower limit for the energy difference between CT
and CR of 0.98 kcal/mol at this temperature under the conservative assumption that 5% residual BR/CT are not
detectable by NMR. Kinetic analysis determined a free activation enthalpy ‡G = 13.4 to 13.5 kcal/mol for the
conversion of CT to CR at -90 to -75 °C, respectively. Compared to the corresponding atropisomerization
reaction of AT to AR (‡G = 18.4 kcal/mol at -40 °C) the atropisomerization activation energy for the CT to CR
conversion is significantly reduced. This experimental result can in part be attributed to the stronger strain in
CT as compared to AT, which is clearly evidenced by the presence of a thermal equilibrium between AR and
AT while such equilibrium is not present between CR and CT. Consequentially, the energy of CT lies
considerably higher than that of AT, but probably not high enough to account for the full effect. Therefore,
also the transition state for CT to CR conversion must be significantly stabilized by the tether strain. The larger
strain in CT versus AT can structurally be explained by the larger distance of the two phenolic oxygen atoms
serving as attachment points of the linker chain in the C structures as opposed to the A structures. In the
crystalline state of CR the distance between these two oxygen atoms is 10.6 Å whereas in AR the distance is
only 7.6 Å and a similar distance difference is seen in the theoretical description of the CT and AT states. This
gives the linker chain greater conformational freedom in the A structures as opposed to the C structures. Given
the free activation enthalpy for thermal conversion of CT to CR this process can be completely halted at -105
°C. It can thus be tested at -105 °C whether CT is strongly accumulated by light irradiation of AR. This should
be possible if 1. the energy difference between BR and CT is exceeding 2.0 kcal/mol prohibiting a significant
thermal equilibrium between the two states and 2. CT does not undergo productive photochemistry by itself.
Such accumulation is indeed observed in the analogous experiment for AT when irradiating pure CR at -60 °C.
However for CT there is no strong accumulation possible when irradiating AR at -105 °C. The most likely
explanation in this case is in fact a fast thermal equilibrium between CT and BR enabling establishment of a
photostationary state that includes photoreactions between BR and AR. Another indication for the presence of
a significant BR/CT equilibrium is the particular strong temperature dependence of the corresponding NMR
signals as opposed to the NMR signal shifts of all other isomers (Figure 3a and b) and the ECD changes
observed during irradiation of AR at low temperatures (see Supporting Information).
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Figure 3
ECD analysis and NMR experiments showing the sequence of isomer population under
irradiation conditions and at different temperatures. Experimental ECD spectra were recorded
for to enantiomerically pure solutions. Theoretical ECD spectra were calculated at the
B3LYP-D3BJ/6-311G(d,p) level of theory. a) Experimental (red) and theoretical (grey) ECD
spectrum of AR. b) Experimental (green) and theoretical (grey) ECD spectrum of CR. c)
Experimental (orange) and theoretical (grey) ECD spectrum of DR. d) Experimental (blue)
and theoretical (grey) ECD spectrum of AT. e) 1H NMR spectra (400 MHz, CD2Cl2/CS2 4:1)
recorded for 1: pure CR at -105 °C; 2: after 29 min of 450 nm irradiation at -105 °C; 3: after
55 min of 450 nm irradiation at -105 °C; 4: after warming to -80 °C in the dark; 5: after 23
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min at -80 °C in the dark. f) 1H NMR spectra (400 MHz, CD2Cl2/CS2 4:1) recorded for 1: pure
AR at -105 °C; 2: after 5 min of 450 nm irradiation at -105 °C; 3: after 34 min of 450 nm
irradiation at -105 °C; 4: after warming to -80 °C in the dark; 5: after 28 min at -80 °C in the
dark.
Table 1. Experimental quantitative data for operation of 1.
G(CR–AR)
[kcal mol-1]
(at T)
G(DR–AT)
[kcal mol-1]
(at T)
G(AT–AR)
[kcal mol-1]
(at T)
‡G(CR to AR)
[kcal mol-1]
(at T)
‡G(BR /CT to ‡G(DR to AT)
CR) [kcal mol-1] [kcal mol-1]
‡G(AT to AR)
[kcal mol-1]
(at T)
(at T)
(at T)
1.79
(80 °C)
0.93
(–80 °C)
1.41
(0 °C)
28.20 (80 °C)
13.35
(-100 °C)
13.90
(-80 °C)
19.25
(0 °C)
1.83
(110 °C)
0.84
(–60 °C)
1.31
(27 °C)
13.47
(-90 °C)
19.15
(-5 °C)
1.87
(140 °C)
0.75
(–40 °C)
1.30
(35 °C)
13.50
(-85 °C)
18.76
(-20 °C)
13.62
(-80 °C)
18.48
(-30 °C)
13.72
(-75 °C)
18.40
(-40 °C)
Taken together the above described measurements allow to establish a comprehensive mechanistic picture for
the 6-step transmission of unidirectional rotation in 1 (Figure 2 and 4). Variable temperature experiments for
selected processes further allowed to measure the temperature dependence of G between CR and AR/AT, DR
and AT, AT and AR, as well as of ‡G for the thermal BR/CT to CR, DR to AT, and AT to AR isomerizations
(Table 1). The corresponding H, S, ‡H and ‡S values are reported in the Supporting Information and allow
to extrapolate free enthalpies and kinetics to different temperatures. Different to the usual four step-mechanism
of the employed HTI motor unit two more steps are introduced during one full 360° rotation, which represent
the potential energy raise that is transmitted from the motor to the biaryl unit. In these steps the tethered biaryl-
unit is spring loaded by the energetically downhill process of the motors helix inversion (Figure 4b and 5). As
a consequence the biaryl atropisomers are not energetically nearly degenerate anymore as it is the case for the
non-tethered system 2 (Figure 5a and b, also see Supporting Information for determination of degeneracy).
Instead either atropisomer is energetically uplifted by the ratcheting steps of the motor unit during one full
360° rotation 1.41 kcal/mol in AT and by >1.5 kcal/mol in CT (Figure 5c and d, given values correspond to 0
°C). This uplift enables >90% atropisomer interconversion in the following thermally activated steps and thus
almost full rotation of the biaryl unit within one operation cycle of the machine. The change in degeneracy of
the biaryl atropisomers can thus be taken as measure for the potential energy raise – and thus the possible work
– that is performed by the motor unit (Figure 5). Interestingly the transmitted potential energy is significantly
smaller than the maximum potential energy raise created in the initial photoreaction fueling the whole system
when starting from CR. This initial potential energy raise corresponds to the energy of DR and amounts to 1.97
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kcal/mol, respectively (given values are extrapolated to 0 °C). Only about 72% of that (maximum possible)
energy are transmitted to the biaryl unit for the atropisomerization in our setup. When starting from AR/AT
more of the initial potential energy raise might be used as indicated by the complete conversion from BR/CT
to CR.
As a result of the motor units action, energy barriers for the thermal biaryl atropisomerization are significantly
reduced leading to a sizeable rate enhancement for this process. To obtain the intrinsic barriers of the
untethered biaryl unit model system 2 was synthesized and experimentally scrutinized in combination with a
theoretical description capturing the two transition states associated with either clockwise or counterclockwise
rotation in both the Z and the E isomeric state (for details see the Supporting Information). The corresponding
‡G values were found to be 20.74 kcal/mol for the experimentally observed atropisomerization of Z-2 at 0 °C,
which is close to the theoretical description giving 23.6 to 23.8 kcal/mol for Z-2 and 23.4 kcal/mol for E-2 as
shown in Figure 5. As expected clockwise and counterclockwise atropisomerizations of 2 do not encounter
significantly different energy barriers and the energy differences of atropisomer minima are very small with
G = 0.1 kcal/mol for both Z and E isomers. Atropisomerization barriers are thus lowered by up to 6.0 kcal/mol
(CT to CR transition versus Z-2 atropisomerization, values are extrapolated to 0 °C for the former and measured
at 0 °C for the latter) by the action of the molecular motor.
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Figure 4
Stepwise unidirectional rotation of motor system 1 powered by visible light irradiation. Only
structures with (R) configured sulfoxide stereocenter are shown for clarity. a) Schematic
representation of 1 to illustrate the relative rotations of different molecular fragments. b) Six-
step mechanism of the transmitted and accelerated unidirectional rotation.
From these results important design principles for increasing performance of such integrated molecular
machine can be derived. It seems evident that the length of the tether connecting motor and biaryl units
provides an efficient means of changing the effectiveness of energy transmission. It is thus straight forward to
assume that a more rigid or shorter tether will enable more of the potential energies of the BR and DR states to
be harnessed by raising the energies of the AT and CT states. Since both BR and DR states possess relaxed
tethers it is less likely that their energies would also be raised significantly by more rigid or shorter tethering.
In this regard our system behaves very differently from macrocyclic photoswitches that spring load directly in
the photoreaction.[10] In the latter cases tether lengths and rigidities have strong influences on the energy of the
metastable switching states initially populated after the photoreaction. In our case it is theoretically possible
to raise the energies of AT and CT beyond the energies of the initial photoproducts BR and DR. If ground state
barriers between BR and DR and the starting states AR and CR remain considerably higher than all other barriers
and the final states AR and CR still function as energy sinks the initial photoreactions would still be able to
power completely unidirectional rotation of the system.
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Figure 5
Rate acceleration of biaryl (orange) rotation by the molecular motor action and accompanying
potential energy changes during the unidirectional 360° rotation cycle of molecular machine
1. All values correspond to 0 °C (measured for Z-2 and AT-1, extrapolated from variable
temperature measurements for CT-1, and calculated (grey values) for E-2 and Z-2). a) and b)
Thermal biaryl rotation of 2 proceeds nondirectionally and encounters energy barriers in the
range of 20.7 to 23.4 kcal/mol. Atropisomer energies for 2 were obtaind from experiment
(enantiomerically pure Z-2, orange values) and from the theoretical description on the B3LYP-
D3BJ/6-311G(d,p) level of theory (E-2 and Z-2, grey values). c) and d) Action of the motor
unit results in sequential and alternating raise of the biaryl atropisomer energies enabling
>90% interconversion in each case. Biaryl rotation now proceeds unidirectionally and the
associated energy barriers are lowered by up to 6.0 kcal/mol leading to significant rate
acceleration of several orders of magnitude in terms of rate constants.
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In conclusion we present a molecular machine setup enabling to transmit the potential energy generated by a
molecular motor unit unto a remote biaryl receiver moiety. As a result of the motor action thermal
atropisomerization of the biaryl is forced to proceed unidirectionally and at the same time is significantly
accelerated by several orders of magnitude in terms of rate constants. Transmittance of potential energy
happens during the thermally activated ratcheting steps within the rotation mechanism and could
comprehensively be quantified. Up to 72% of the initial potential energy raise was found to be actually
transmitted, which directly corresponds to the amount of work that the motor unit would be able to perform
on the biaryl system. These findings therefore deliver a novel method for translating the power generated by a
molecular motor on the nano-scale, gives unprecedented insights into the working mechanism of such
integrated molecular machine, and allows to measure the potential energy usable in this system. It thus provides
a first quantitative answer to the long standing question of how much work a single molecular motor can
actually perform at the molecular scale. Finally, different isomeric states of this six-step molecular machine
can be accumulated separately at different irradiation conditions, which is a highly desirable property for
applications requiring multi-state molecular switching. Harnessing the transmitted potential energy to actually
performing work at the molecular scale will be the next big leap in this research line and our current efforts
are concentrated in this direction.
Acknowledgements
H. Dube thanks the “Fonds der Chemischen Industrie” for a Liebig fellowship (Li 188/05) and the Deutsche
Forschungsgemeinschaft (DFG) for an Emmy Noether fellowship (DU 1414/1-1). We further thank the
Deutsche Forschungsgemeinschaft (SFB 749, A12) and the Cluster of Excellence ’Center for Integrated
Protein Science Munich’ (CIPSM) for financial support.
Keywords: molecular machines • photochemistry • isomerization • hemithioindigo • physical chemistry
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