Defining Unidirectional Motions and Structural Reconfiguration in a Macrocyclic Molecular Motor

Abstract

The construction of sophisticated molecular machines requires not only precise control of energy fueled motions but their integration into larger functional architectures. Macrocyclization of molecular motors is a way to harness the intrinsic directionality of their rotation and use them to actively power different processes at the nano-scale. An effective concept in this regard uses a defined fragment of the molecular motor as a revolving door within the macrocycle. In this way, motor motions can be transmitted to distant structural entities, other rotations can be actively accelerated, or mechanical molecular threading events can be realized. In this work, a dual macrocyclization approach is presented, which not only allows to supersize the revolving door element but also structurally reconfigure the macrocycle in which the revolving door rotates. Unique possibilities for a multi-level precision control over integrated directional motions are thus opened up without deteriorating the functionality of the molecular machine.

Introduction

Central to the field of molecular machine research^1,2 is the control of molecular motions, either thermally induced ones in, e.g., rotors, molecular brakes, or molecular gears,³⁻⁵ or actively powered motions in, e.g., molecular motors,⁶⁻⁸ pumps,⁹ or the recently added photogears.¹⁰ For the latter types of energy-driven molecular systems, the next necessary step is transmission of directional motions to places further away from where these motions are initially generated.¹¹ This can be done in an up-scaling fashion by the transmission of the geometric state changes to an ordered environment, e.g., liquid crystals,^12,13 polymers,^14,15 or on surfaces.¹⁶ However, in less organized environments such as simple liquid solvents, transmission of motions at the molecular scale needs to be controlled more tightly in order not to diffuse the directional motion away by the action of the Brownian storm. Typically, close proximity of moving parts is needed as, e.g., in mechanically interlocked molecules,¹⁷⁻¹⁹ locked synchronous motions,²⁰ molecular gears,^{3−5,21−25} or photogearing systems.¹⁰ Macrocyclization of molecular motors is another powerful approach to harness the intrinsic unidirectionality of, for example, light-driven molecular motors and transmit this motion further away (Figure 1a,b). In a related approach, macrocyclization can be used to transfer the state changes of photoswitches (see refs (26–31) for some selected examples).

Figure 1.

Macrocyclic molecular motors provide advanced molecular machine functionality. (a) Examples for macrocyclic molecular motors. (b) Macrocyclic molecular motors with defined revolving doors. (c) Macrocyclic molecular motor system 1 with redefined and enlarged revolving door, the most stable isomeric state A is shown. Two different diastereomeric macrocycles 1-(R_a) and 1-(S_a) are available with revolving doors rotating in the same direction. Interchange between the macrocycles—namely, structural reconfiguration—is possible at high temperatures.

Different ways of motor macrocyclization are possible either containing only the stator or rotor moiety alone in the macrocycle^32,33 or interconnecting the two motor fragments within the macrocycle.³⁴⁻⁴² The latter approach allows to directly use the motor unidirectionality to perform work and wind up macrocyclic polymer chains, for example.^34,35,39,42 Work in our group (Figure 1b) has put forward a different setup in which one additional biaryl unit is incorporated into the molecular-motor architecture within the macrocycle.^36,37 In this way, a central “revolving door” unit could be defined, which is forced to perform an unidirectional rotation within the macrocycle once the motor is powered with light. When moving, the rotation direction created at the motors double bond is effectively transmitted to the remote single bond of the biaryl unit. Later elaboration has allowed us to actively accelerate this biaryl rotation in a sterically hindered derivative and measure the amount of energy useable to do work with such a nanomachine.³⁷ Another recent development is the coupling of this revolving door rotation to the active mechanical threading of an attached polyethylene glycol (PEG) chain through the macrocycle.³⁸ Such a behavior is akin to the threading of a macroscopic strand in weaving or sewing and represents the entry point to a nanoscopic counterpart of such processes. In this latter setup, a different section of the molecular motor—the indanone-based rotor fragment—was defined as the revolving door by conscious selection of the macrocycle attachment points. It thus becomes evident that macrocyclization is a powerful concept for advanced performances and applications of light-driven molecular motors, and the precise definition and dissection of motions and sub-motions in such architectures are key to unlock the full potential of this approach.

In this work, we first present a significant enlargement of a revolving door section in motorized macrocycle 1, which at the same time allows transmitting the unidirectional motion farther away from the motor double bond where it is generated (Figure 1c). The underlying design principles for revolving door enlargement are elucidated and influences of the macrocyclic setup on the motor rotation mechanism are scrutinized. Second, macrocycle system 1 comprised two different and individual diastereomeric macrocycles with their revolving doors rotating independently in the same direction under light irradiation. However, selective switching between these two macrocycles is possible at elevated temperatures, which represents the first example of structural reconfiguring a molecular machine and a motorized macrocycle in particular. In this process, the revolving door is dissected and a different type of motion, a sole atropisomerization, takes place leading to the macrocycle change. After the macrocycle switching, the enlarged revolving door can be operated again as a whole within the new macrocycle unidirectionally. This study thus presents an unprecedented level of multiple motion control in an integrated molecular machine setup and paves the way for more sophisticated macrocyclic motor applications in the future.

Results and Discussion

Macrocyclic setup 1 (Figures 1c and 2) consists of a hemithioindigo (HTI)⁴³ based molecular motor of the first type⁴⁴ incorporating a biaryl unit at the thioindigo fragment and a flexible PEG chain connecting the rotor indanone-fragment with the outer biaryl part. Two important elements need to be present to allow definition of the large revolving door element. First, strong steric hindrance is introduced directly at the biaryl axis by two methyl groups on the thioindigo fragment and one fluorine at the attached phenyl unit. The introduction of one additional fluorine raises the energy barrier for atropisomerization sufficiently to prohibit rotation of the biaryl axis and thus leads to the inclusion of the biaryl element within the movable entity. Second, a larger PEG-chain is introduced to provide enough space in the macrocycle for the enlarged revolving door motion. Thus, macrocyclic system 1 actually represents two different macrocyclic molecular motors termed 1-(R_a) and 1-(S_a) in the following (both with the same stereo configuration of the sulfoxide; note that only isomers with (S)-configuration of the sulfoxide stereocenter are shown in the figures, the corresponding enantiomers with (R)-configuration at the sulfoxide and opposite biaryl axis configuration are not discussed in the following for clarity reasons), which do not interconvert into each other at ambient temperatures. Both macrocycles 1-(R_a) and 1-(S_a) operate their revolving doors independently of each other and both revolving doors are rotating in the same direction (as dictated by the sulfoxide stereo configuration).

Figure 2.

Quantitative potential energy landscape of macrocyclic motors 1-(R_a) and 1-(S_a). The energetic order of states A–D was established by experiments and by theory [B3LYP-D3BJ/6–311G(d,p) IEFPCM (CH₂Cl₂) level]. THI and thermal DBI steps are depicted on the vertical- and structural reconfiguration steps via selective atropisomerization on the diagonal energy axis. Values for THI steps were obtained at −90 °C, DBI and structural reconfiguration steps at 80 °C, and the ground state isomer distribution and associated relative minimum energies were measured at 100 °C. Complete stereo assignments are given for all states. Stereodescriptors (E) and (Z) describe the double bond configuration, (S) and (R) the sulfoxide configuration, (M) and (P) the helicity of the motor part, and (R_a) and (S_a) the configuration of the atropisomers. Only states with (S)-configured sulfoxide are shown, and the corresponding enantiomers with (R)-configured sulfoxide are omitted for clarity.

A theoretical analysis was conducted to gain deeper insights into the structural and spectral changes in macrocycles 1-(R_a) and 1-(S_a) (for details, see the Supporting Information). All ground state structures were optimized at the DFT level of theory [B3LYP-D3BJ/6–311G(d,p) IEFPCM (CH₂Cl₂)] and the corresponding UV/vis and electronic circular dichroism (ECD) spectra were calculated for comparison with experimental spectra and identification of the different observed species (see below).

Synthesis of the macrocycle system 1 follows a previously established general approach (for details of synthetic conversions involving precursor molecules 2–11, see the Supporting Information), in which the PEG-chain is attached to a motor precursor via an azide–alkyne Huisgen click reaction. Intramolecular Suzuki cross coupling is used to form the macrocycle, after which an oxidation at the sulfur establishes the final integrated molecular machine 1.

Four different diastereomeric forms of 1, A-(R_a), A-(S_a), C-(R_a), and C-(S_a), could be isolated and were scrutinized for their molecular structures by a combined NMR, UV/vis, ECD spectroscopic, and theoretical approach (see Figure 2 and the Supporting Information for details). NMR studies and especially NOE spectra allowed elucidation of the double bond configuration for each isomer as well as establishing the tilt of the biaryl axis. Thus, isomers A-(R_a) and A-(S_a) could be shown to possess E configuration of the double bond, whereas isomers C-(R_a) and C-(S_a) possess Z configuration. Interestingly, a biaryl tilt toward the side of motor-indanone attachment is seen in isomers A-(R_a) and C-(S_a) but not for A-(S_a) and C-(R_a) in which the biaryl moiety assumes a 90° dihedral angle between the two aromatic planes (see the Supporting Information for details). For the latter, this gives an indication that no macrocyclic ring strain is present in the structures as opposed to the first two structures. The absence of ring strain in A-(S_a) and C-(R_a) but presence of it in A-(R_a) and C-(S_a) is well explained geometrically. In A-(R_a) and C-(S_a), the macrocycle attachment points are located on opposite sides with respect to the revolving door fragment, forcing the macrocycle to wind around the revolving door. In A-(S_a) and C-(R_a), the attachment points are located on the same side of the revolving door and thus are intrinsically less strained. A somewhat similar strain behavior was observed previously in the tense state of a smaller motorized macrocycle.³⁷ The distinct strain and conformational behavior in A-(R_a) versus A-(S_a) and C-(R_a) versus C-(S_a) directly shows the different local environments for the revolving doors in the two individual macrocycles 1-(S_a) and 1-(R_a).

ECD spectra of enantiomerically pure samples allowed to assign helicity of the motor unit for each isomer with the aid of theoretical calculations (see the Supporting Information and also below). Although a number of different conformers with various arrangements of the PEG chain part were observed in the theoretical description, the motor-biaryl unit was found to be very similar in all structures. The calculated ECD spectra revealed that the different PEG chain arrangements are not influencing the ECD spectra strongly, which are dominated by the particular motor helicity. The configuration of the biaryl axis could not be distinguished well by ECD spectra; however, the experimentally observed tilt of the biaryl axis in the strained structures as well as the specific energetic stability order of the four states (from most stable to least stable): A-(S_a) > C-(R_a) > C-(S_a) > A-(R_a) is matching again the theoretical description very well and allowed to complete the structural elucidation of the four isomers. The specific stereo assignments are given in Figure 2.

An additional theoretical description of the corresponding non-cyclic reference system 12 allowed us to compute the intrinsic energy landscape of the central motor fragment with enlarged revolving door element (see the Supporting Information for full details including the quantitative energy profile and isomeric structures). In this case, ΔG values for all four minima A to D as well as the corresponding Gibbs energies of activation ΔG^‡ for thermal helix inversions (THIs) and biaryl atropisomerizations could be obtained. Interestingly, the relative energetic order of isomers is different for the non-cyclic system 12 in the (S_a) atropisomer configuration, where C-(S_a) is more stable than A-(S_a). For the corresponding (R_a) atropisomers of 12, the isomer order is the same as in the macrocycle 1. It becomes thus apparent that the Z-configured C isomers are intrinsically more stable than the E-configured A isomers. In 1 however, the macrocycle imposes strain particularly to the C-(S_a) isomer and thus elevates its energy above that of the A-(S_a) isomer. This strain in C-(S_a) is in full agreement with the observed biaryl tilts discussed above.

After clarification of the four stable diastereomeric structures of 1, the thermal behavior of each isomer was scrutinized (Figure 3a,b). Heating experiments showed that the biaryl axis is thermally stable and only undergoes rotation at elevated temperatures above 60 °C in toluene-d₈ solution. Interestingly, a selective isomerization behavior is observed upon heating in which first the biaryl axis is interconverted, whereas the double bond is isomerized at a significantly slower rate. Furthermore, also the thermal atropisomerizations are selective and depend on the particular isomeric starting state. Thus, at higher temperatures of 80 °C, E isomeric A-(R_a) interconverts preferably to E isomeric A-(S_a) in up to 65% and the corresponding Z isomeric C-(S_a) to Z isomeric C-(R_a) in 66% maximum yield. Since a thermal equilibrium is finally established at elevated temperatures with all isomers A-(R_a), A-(S_a), C-(R_a), and C-(S_a) being present, their relative energy differences could also be quantified at 100 °C (see the Supporting Information). The most thermally stable isomer is A-(S_a) (62% in thermal equilibrium at 100 °C) followed by C-(R_a) (27%), C-(S_a) (6%), and finally A-(R_a) (5%). The two most stable isomers are also the two structures without ring strain as corroborated by no preferred biaryl tilt (see above). This experimentally observed order of isomers is perfectly matching with the theoretically predicted order of states (see Figure 2 and the Supporting Information for details). A comprehensive kinetic analysis of the heating experiments including all possible processes, i.e., thermal atropisomerizations (encountering lower energy barriers) as well as thermal double bond isomerizations (DBIs, higher energy barriers) allowed us to establish the corresponding Gibbs energies of activation ΔG^‡ as shown in Figure 2a (for further details, see the Supporting Information). The obtained ΔG^‡ values for the atropisomerizations are also in good agreement with the corresponding calculated values for the non-cyclic reference system 12. At the same time, the heating experiments established that at temperatures below 60 °C, no thermal atropisomerization takes place and a stable biaryl axis is present in both macrocycles 1-(R_a) and 1-(S_a). At ambient temperatures, the enlarged revolving doors are therefore stable and function as one single unit.

Figure 3.

Experimental elucidation of macrocycle 1-(R_a) and 1-(S_a) function. (a) Structures of 1-A-(R_a), 1-C-(R_a), 1-A-(S_a), and 1-C-(S_a). (b) Heating experiments (80 °C, toluene-d₈) evidencing selective macrocycle switching from A-(R_a) to A-(S_a) and conversely from C-(S_a) to C-(R_a). (c) ECD and (d) NOE or ROE ¹H NMR experiments (600 MHz, 25 °C, CD₂Cl₂) allowing assignment of species to individual isomers A-(R_a), C-(R_a), D-(R_a), A-(S_a), C-(S_a), and D-(S_a). (e,f) Low-temperature ¹H NMR (−90 °C, CD₂Cl₂) evidence for motor function in 1. In situ irradiation of A and C leads to the population of intermediate state D (first four spectra from top to bottom) which thermally converts completely into A (last three spectra from bottom). (e) Irradiation of pure A-(R_a) at −90 °C populates directly C-(R_a) first because intermediate B-(R_a) is thermally unstable and cannot be observed at this temperature. Only after C-(R_a) population is isomer D-(R_a) starting to accumulate as the direct photoproduct of C-(R_a). (f) Up to 89% of D-(S_a) can be accumulated by irradiation of 1-(S_a) at −90 °C. Again selective complete thermal conversion from D-(S_a) to A-(S_a) is observed.

Photochemical conversions were investigated next at ambient and low temperatures. Irradiation of isomer A-(S_a) with 490 nm light at 22 °C in CD₂Cl₂ leads to exclusive population of C-(S_a) reaching a photostationary state (PSS) with 34% A-(S_a) and 66% C-(S_a) being present. In toluene-d₈ solution, this isomer distribution can be improved to 11% A-(S_a) and 89% C-(S_a). Likewise, irradiation of A-(R_a) under the same conditions leads to a photoequilibrium with C-(R_a) until a final ratio of 31% A-(R_a) and 69% C-(R_a) is reached in the PSS. Irradiation with 385 nm light at 22 °C in CD₂Cl₂ solution delivers an opposite final isomer distribution in the PSS of 70% A-(S_a) and 30% C-(S_a), or 84% A-(R_a) and 16% C-(R_a), respectively.

To elucidate motor operation and distinguish it from a possible mere photoswitch behavior, low-temperature experiments were conducted. Cooling a solution of pure A-(R_a) to −90 °C and subsequent in situ irradiation within the NMR spectrometer led to population of C-(R_a) first and subsequently to a population of a new intermediate state in up to 39% yield. Subsequent warming up to −70 °C and re-cooling established thermal conversion of this intermediate exclusively to isomer A-(R_a). Kinetic analysis of this process at −90 °C established a corresponding Gibbs energy of activation ΔG^‡ = 13.5 kcal/mol (see the Supporting Information for details). This ΔG^‡ value is very similar to previously established ones for D to A THIs for E configured related HTI-based molecular motors.⁴⁴⁻⁴⁶ The value is also in very good agreement with the theoretically obtained value for the corresponding non-cyclic reference system 12, which evidences the absence of a macrocyclic effect on this THI. Additional low-temperature ECD spectroscopy revealed reversal of the Cotton effect sign at longer wavelengths accompanying the photoisomerization of C-(R_a) at −90 °C. The ECD spectral changes are in good agreement with the theoretical description of the different isomers of 1-(R_a) (see Figure 3 and the Supporting Information for details). The intermediate populated after irradiation of C-(R_a) could thus be assigned to isomer D-(R_a). Likewise, an intermediate D-(S_a) is observed when 1-(R_a) is irradiated at −90 °C, this time up to 89% of D-(S_a) can be accumulated (see the Supporting Information for details). Only a slightly different Gibbs energy of activation ΔG^‡ = 13.6 kcal/mol for the corresponding THI process from D-(S_a) to A-(S_a) was obtained. This energy difference reflects the different structures of the two diastereomeric macrocycles and establishes no major macrocycle effect on the motor operation in 1-(R_a) as compared to 1-(S_a). Note that both ΔG^‡ values are very close to the theoretically obtained values for the non-cyclic reference system 12, lending further evidence to the absence of a macrocyclic effect on these THIs. Since irradiation of isomers A-(R_a) and A-(S_a) at a low temperature resulted directly in population of isomers C-(R_a) and C-(S_a), respectively, no intermediate states B-(R_a) or B-(S_a) were observed at −90 °C. This behavior is typical for similar HTI-based molecular motors where the thermal B to C helix inversion process is significantly faster than the corresponding thermal D to A helix inversion and cannot be halted even at −90. However, the apparent contradiction of an isomer C undergoing two different photo-equilibria at the same time (with isomer D and separately with isomer A) indirectly evidences the presence of isomer B, which quickly undergoes THI. This interpretation is further supported by the theoretical description of the non-cyclic reference system 12, predicting low barriers of ΔG^‡ = 5.6 kcal/mol and ΔG^‡ = 6.0 kcal/mol for these THIs.

Taken together, the experimental thermal and photochemical analysis and the theoretical description of macrocycles 1-(R_a) and 1-(S_a) reveal full and independent motor functionality at ambient to low temperatures (Figures 2 and 3). The typical four-step motor cycle with alternating photoisomerization and THI steps can be observed under irradiation conditions. At the same time however, the biaryl axis does not undergo atropisomerization, which is only possible if its axial chirality remains stable during complete motor operation. Therefore, the revolving door element is significantly enlarged to include the biaryl moiety in its directional rotation through the macrocyclic ring in both 1-(R_a) and 1-(S_a).

At elevated temperatures however, it is possible to change the macrocyclic environment of the revolving door element by selective atropisomerization (Figure 4). A change from macrocycle 1-(R_a) to 1-(S_a) is possible when heating a toluene-d₈ solution of pure A-(R_a) at 80 °C to obtain predominantly A-(S_a) in 65% yield. Conversely, it is possible to change from macrocycle 1-(S_a) to 1-(R_a) when heating pure C-(S_a) at 80 °C to obtain predominantly C-(R_a) in 66% yield. It is noteworthy that there is a reversal of stability when moving from the A isomers [the (S_a) atropisomer is more stable] to the C isomers [the (R_a) atropisomer is more stable]. In each case, the oxygen attachment points of the macrocycle chain are on the same side respect to the revolving door fragment for the most stable structure. Thus, the macrocycle connectivity of 1 can be reconfigured by selective thermal atropisomerizations, a process that dissects the enlarged revolving door and establishes a different type of motion (sole single bond rotation within the revolving door).

Figure 4.

Structural reconfiguration of macrocyclic motors 1-(R_a) and 1-(S_a). The enlarged revolving doors in 1-(R_a) and 1-(S_a) are rotating independently and in the same direction under illumination at ambient temperatures within a different macrocycle environment. At elevated temperatures, selective macrocycle switching is possible specifically from A-(R_a) to A-(S_a) and conversely from C-(S_a) to C-(R_a) via specific atropisomerizations.

Conclusions

In summary, we present a macrocyclic molecular motor setup 1 inheriting a very large revolving door section, which is present in two independent macrocycle structures. The larger revolving door unit was consciously defined by deliberately locking the atropisomeric axis via steric overcrowding and overall enlargement of the macrocycle. At ambient temperatures, the revolving doors in both macrocycles individually rotate in the same direction powered by their respective molecular motor units. No large effect of the different macrocycle setups on the motor rotation mechanism was observed, evidencing full functionality of both molecular machines. A switching between the two macrocycles, and thus, the environment in which the revolving door is rotating, is possible by two highly selective atropisomerizations at elevated temperatures. In this way, the conjunct motion of the biaryl subunit as a part of an enlarged and unidirectionally revolving door section within the macrocycle can be abrogated and a sole single bond rotation of the biaryl axis (i.e., dissecting the revolving door) is taking place instead. Afterward, the resulting reconfigured macrocycle can be operated with an enlarged revolving door again at lower and ambient temperatures. We project that such controlled and multilevel structural reprogramming of a molecular machine will be of great value for future elaboration and design of nanoscale devices as well as their applications.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c01567.

• Details of synthesis; structural analyses; photochemical, photophysical, and thermal behavior; and theoretical description (PDF)

The authors declare no competing financial interest.