Molecular motors: new designs and applications
Roke, Gerrit Dirk
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Roke, G. D. (2018). Molecular motors: new designs and applications. Rijksuniversiteit Groningen.
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The work in this thesis was performed at the Stratingh Institute for Chemistry , University of Groningen, The Netherlands.
This work was financially supported by the Ministry of Education, Culture and Science (Gravitation program 024.001.035).
Printing : Ipskamp Printing, Enschede, The Netherlands ISBN: 978-94-034-1247-4 (printed version)
Molecular Motors: New Designs and
Applications
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector mangificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op vrijdag 14 december 2018 om 11.00 uur
door
Gerrit Dirk Roke
geboren op 12 februari 1991 te Zwolle
Prof. dr. W.R. Browne
Beoordelingscommissie
Prof. dr. T. Bach Prof. dr. S. Otto Prof. dr. E. Otten
Table of Contents
Table of Contents
5
Chapter 1 Molecular rotary motors: Unidirectional motion
around double bonds
9
1.1 Introduction 10
1.2 Motors based on overcrowded alkenes 11
1.2.1 Rotational speed adjustment 14
1.2.2 Shifting the excitation wavelength 18
1.2.3 Improvement of the photochemical efficiency 19
1.2.4 Redox-driven motors 20
1.3 Alternative motor designs 20
1.4 Outlook 23
1.5 Outline of this thesis 24
1.6 References 25
Chapter 2 A visible light driven molecular motor based on
pyrene
31
2.1 Introduction 32
2.2 DFT calculations 33
2.3 Synthesis 34
2.4 UV/vis and 1H-NMR studies 35
2.5 Conclusions 38
2.6 Experimental procedures 38
3.1 Introduction 48
3.2 DFT calculations 49
3.3 Synthesis 52
3.4 1H-NMR studies 52
3.5 UV/vis and CD studies 54
3.6 Conclusions 59
3.7 Experimental procedures 60
3.8 References 64
Chapter 4 Light-Gated Rotation in a Molecular Motor
Functionalized with a Dithienylethene Switch
67
4.1 Introduction 68
4.2 Synthesis 70
4.3 1H-NMR and UV/vis studies 71
4.4 Conclusions 75
4.5 Experimental procedures 76
4.6 References 80
Chapter 5 Photoresponsive supramolecular coordination
cage based on overcrowded alkenes
85
5.1 Introduction 86
5.2 Ligand synthesis and characterization 87
5.3 Cage formation and characterization 90
5.4 Photochemical isomerizations 97
5.5 Conclusions 98
5.6 Experimental procedures 98
Chapter 6 First generation molecular motors in polymers:
Towards photoswitchable foldamers
105
6.1 Introduction 106
6.2 Synthesis of linkers and model compounds 107
6.3 Switching studies of model compounds 109
6.4 Polymer formation and characterization 113
6.5 Conclusions 115 6.6 Experimental procedures 115 6.7 References 119
Chapter 7 Summary
123
7.1 English Summary 124 7.2 Nederlandse samenvatting 126Chapter 8 Popular science summary
129
8.1 English summary 130
8.2 Nederlandse samenvatting 131
Molecular rotary motors:
Unidirectional motion around
double bonds
The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self-assembled and nanostructured responsive materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, still many challenges need to be addressed. In this perspective, we focus on the design principles of rotary motors featuring a double bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input and environmental adaptability, will be crucial in order to fully exploit the opportunities that these rotary motors offer.
This chapter was published as: D. Roke, S. J. Wezenberg, B. L. Feringa, Proc. Natl. Acad. Sci.
10
1.1
Introduction
Control of motion at the molecular scale has intrigued chemists for a very long time. The quest for overcoming random thermal (Brownian) motion has culminated in the emergence of synthetic molecular machines,[1–7] including motors,[8–12] muscles,[13] shuttles,[14] elevators,[15] walkers,[16] pumps[17–19] and assemblers.[20] By taking inspiration from the fascinating dynamic and motor functions observed in biological systems (e.g. ATPase and bacterial flagella),[21] the field of synthetic molecular machines has evolved rapidly in recent years. This is due to major advances in supramolecular chemistry and nanoscience, the emergence of the mechanical bond[7] and the development of dynamic molecular systems.[22] A variety of potential applications is now being considered in areas ranging from catalysis[23] and self-assembly[24] to molecular electronics[25,26] and responsive materials.[27,28] Furthermore, translation of motion from the molecular scale to the macroscopic scale allows for dynamically changing material properties and the movement of larger objects. Cooperativity and amplification across several length scales can be achieved, for example, by incorporating molecular machines in gels,[29,30] liquid crystals,[27,31] polymers[32] or by anchoring them to surfaces,[33,34] allowing the control of a variety of properties including surface wettability,[33,34] contraction or expansion of gels[29] and actuation of nanofibers in response to their environment.[35] This leap from static to dynamic materials clearly demonstrates the potential of molecular machines. Although much effort has already been devoted to the development of molecular motors and machines as well as the elucidation of their operational mode, a great deal of design improvements are needed in order to fully exploit the potential in practical applications. Ideally, molecular motors can operate with high efficiency, durable energy input (fuel), can be easily adapted to a specific environment or application, are compatible with specific functions and can be synchronized and act in a cooperative manner.
Where the pioneering work of Sauvage, Stoddart, and others successfully led to stimuli-controlled translational and rotary motion in mechanically interlocked systems,[1,36–39] the induction of unidirectional rotary motion posed a major challenge. Distinct approaches, including those based on catenanes,[39] surface confined systems,[40] and aryl-aryl single bond rotation,[8,41,42] have been taken over the last two decades to develop molecular motors capable of such unidirectional rotation when supplied by energy in the form of light, chemical stimuli, or electrons.[11] In this perspective, we focus on rotary motors that contain a double bond axle (Figure 1.1). Although it may seem unusual to use a double bond as rotary axle since the rotation is restricted, stimuli such as light can induce rotation (cf. isomerization) as is most elegantly seen in the process of vision.[43] As such, autonomous and repetitive unidirectional rotation has been successfully achieved in multiple systems, all of them are driven by light. Here, we discuss the key design principles of these systems and furthermore, a perspective on key challenges and possible future developments is provided.
11
Figure 1.1. Schematic representation of unidirectional rotary motion around a double bond axle.
1.2
Motors based on overcrowded alkenes
At the very basis of overcrowded alkene-based molecular motors is a photochemical
cis-trans isomerization around their central carbon-carbon double bond. For stilbene, this
process has been studied already for more than half a century.[44] Due to the symmetry of stilbene, there is no directional preference in the isomerization process. It was shown in 1977 that the introduction of steric bulk around the double bond distorts the otherwise planar geometry giving rise to helical chirality.[45] This feature was further exploited to develop a chiroptical switch, in which two pseudoenantiomeric forms with opposing helical chirality could be selectively addressed.[46] This work formed the basis for the design and synthesis of the first molecule capable to undergo unidirectional 360° rotation around a double bond, which our group reported in 1999.[9] It is based on an overcrowded alkene, with two identical halves on each side of the double bond (the rotary axle)
((P,P)-trans-1 in Scheme 1.1a). Due to steric interactions between the two halves, in what is
referred to as the fjord region, the molecule is twisted out of plane resulting in a helical shape. The first molecular motor featured two stereogenic methyl substituents which are preferentially in a pseudo-axial orientation due to steric crowding. These stereocenters dictate the helical chirality in both halves of the molecule and hence, the direction of rotation. A full rotary cycle consists of four distinct steps: Two photochemical and energetically uphill steps and two thermally activated and energetically downhill steps. Starting from (P,P)-trans-1 (Scheme 1.1a), irradiation with UV-light (280 nm) induces a
trans to cis isomerization around the double bond leading to isomer (M,M)-cis-1 with
opposite helical chirality. This photoisomerization is reversible and under continuous irradiation a photostationary state (PSS) is observed in which for this particular case the ratio of cis to trans is 95:5. In (M,M)-cis-1 the methyl substituents end up in an energetically less favorable pseudo-equatorial orientation. To release the build-up strain, a thermally activated process occurs, in which both halves slide alongside each other inverting the helicity from left- (M,M) to right-handed (P,P) and allowing the methyl
12
substituents to readopt the energetically favored pseudo-axial orientation. The photogenerated states, which are prone to such a thermal helix inversion (THI) process, have often been referred to as ‘unstable’ or ‘metastable’ states. The THI is energetically downhill and effectively withdraws the higher-energy isomer such as (M,M)-cis-1 from the photoequilibrium mixture and hence, completes the unidirectional 180° rotary motion. The second part of the cycle proceeds in a similar fashion as a second photoisomerization step affords (M,M)-trans-1 (PSS trans to cis ratio of 90:10) with the methyl substituents again in the pseudo-equatorial position. A second THI then reforms (P,P)-trans-1 and a full 360° rotation cycle is completed.
The so called second generation light-driven molecular rotary motors, consisting of distinct upper (rotor) and lower (stator) halves and bearing only a single stereogenic center (Scheme 1.1c), was presented shortly after.[47] Analogous to the first generation motors, 360° rotary motion can be achieved by a sequence of a photochemical and thermal steps. The design, with non-identical halves, allowed for a much broader scope of functionalization, in particular for surface anchoring through the stator, and paved the way for many different applications,[12] as shown in Figure 1.2.
The development of second generation motors revealed that the presence of only one stereogenic center is sufficient to induce unidirectional rotation. This raised the question if unidirectional rotation can be achieved in the absence of any stereocenters.[48] To address this question, symmetrical motors were synthesized bearing two rotor units. These third generation motors only have a pseudo-asymmetric center and still unidirectional rotary motion around both axles was found to occur.
Since our first reports on molecular rotary motors based on overcrowded alkene, great effort has been dedicated to the understanding of their functioning, especially the key parameters that govern the isomerization processes, and the use of new insights to adapt the structural design.[11] This has resulted in a large collection of overcrowded alkene-based motors with different properties, which have been applied successfully to induce motion at the molecular scale as well as the nanoscale and macroscale.[27,34,49] The main aspects that have been investigated and will be discussed in the next sections are the speed of rotation, the excitation wavelength and the efficiency of the motors.
13
Scheme 1.1. (a) Rotary cycle of a first generation motor based on overcrowded alkene (b) Top view of the rotary cycle (c) Structures of second and third generation molecular motors.
14
Figure 1.2: Molecular motors based on overcrowded alkene in different types of applications.
1.2.1 Rotational speed adjustment
For every different application of molecular motors, for example in soft materials or biological systems, often a distinct frequency of rotation is desired. The photochemical steps proceed on a timescale of picoseconds, making the usually much slower THI the rate limiting step.[50] Considerable research effort in our group has been devoted to fully understand the THI and to altering the rotational speed by structural modifications. Throughout the years, DFT calculations have proven to be useful in predicting thermal barriers prior to the synthesis of new motors and in interpreting experimental results.[51,52] Although many factors may influence the rate of the THI, steric interactions within the molecule play a dominant role. Generally, two approaches have been taken to speed up the THI (Figure 1.3): (i) By lowering the thermal barrier through a decrease in the steric hindrance in the fjord region, or (ii) by raising the energy of the unstable state relative to the transition state. Additionally, electronic effects on the barrier of the THI were studied by introducing a strong push-pull system over the central double bond in a second generation motor.[53] A decrease in the barrier of the THI as well as for the thermal E-Z isomerization was observed. Consequently, upon generation of the unstable state, both a ‘forward’ THI and a competing ‘backward’ thermal E-Z isomerization took place in this push-pull system, reducing the efficiency of the resulting motor.
15
Figure 1.3. Approaches for speeding up the THI either through i) a decrease in steric hindrance in the fjord region or ii) by destabilization of the unstable state with respect to the transition state.
For first generation motors, the THI for unstable cis and trans isomers are different processes and therefore have different rates.[9] Modifications to the design of the molecular motor can have complex and sometimes opposite effects on these rates. For example, the introduction of more steric bulk at the stereogenic center, by replacing the methyl substituent in motor 4 with an isopropyl group, accelerates the rate of thermal isomerization from the unstable to the stable cis form, but decreases the rate going from the unstable to the stable trans isomer (Figure 1.4).[54] The latter process was found to be so slow that an intermediate state could be observed with mixed helicity, that is
(P,M)-trans-5, suggesting that the THI is a stepwise process. This kind of behavior was already
predicted for related overcrowded alkenes that do not have stereogenic methyl substituents, which according to calculations racemize between (M,M) and (P,P)-helical structures via an intermediate structure with (P,M)-helicity.[55] This example, however,
16
remains so far the only case in which such a stepwise mechanism for the THI in first generation motors is observed. To decrease the amount of steric hindrance in the fjord region and hence lower the energy barrier for THI, the central six-membered ring was changed to a five-membered ring (Motor 6 in Figure 1.4).[56] It has to be noted that upon reducing the ring size from six- to five-membered, conformational flexibility is lost. As a consequence, the unstable states are most likely further destabilized as the steric hindrance cannot be relieved by folding, which additionally contributes to increased rates for the THI.
Figure 1.4. Structural variations of first generation molecular motors and effects on t1/2 of THI process.
In an attempt to further destabilize the unstable states, overcrowded alkene 7 was synthesized, which has two tert-butyl instead of methyl substituents at the stereogenic center.[57] However, these substituents cause too much steric hindrance impeding the unidirectional motion. Another approach is to replace the naphthalene moieties with xylene moieties (motor 8).[58] In this design, the xylyl methyl substituents cause the necessary steric hindrance in the fjord region. X-ray analysis shows that these methyl substituents are more sterically demanding in the trans-isomer, forcing the molecule in a more strained conformation, also leading to destabilization of the unstable trans isomer. The barrier of the THI from unstable trans to stable trans was found to be lower in motor
8 with respect to motor 6. On the other hand, the increased steric hindrance in the fjord
region causes a higher barrier for the unstable cis to stable cis isomerization, reflecting the complex and opposite effect that (often subtle) changes in the molecular design may have on the rates of these two THI processes.
Similar systematic structural modifications have been made to second generation motors to alter their speed of rotation. Initial studies mainly involved motors of the general structure 9 (Figure 1.5) in which the bridging atoms (X and Y) where varied.[47,51,52] Half-lives of the unstable states ranging from 233 h (X = S, Y = C(CH3)) to 0.67 h (X = CH2, Y = S)
were measured. The conformationally flexible six-membered rings allow for the molecule to release some of the strain around the double bond that is build up in the
17 photoisomerization step. DFT calculations have shown that, in case of a six-membered ring, the THI is a stepwise process and multiple transition states have been identified.[51,52] Also here the change to a five membered ring in the stator makes the molecule more rigid. Again, this results in an increased barrier for the THI in compound 10, up to the point where a thermal E-Z isomerization becomes favored over the THI and a bistable switch is obtained.[59] When only in the upper half rotor a five-membered ring is introduced (motor
11), the rotational speed dramatically increases up to the MHz regime.[60] Motor 12, bearing two five membered rings, on the other hand, has a lower barrier in analogy to the first generation motors due to a decrease in the steric hindrance in the fjord region.[61] The steric hindrance, and as a consequence the THI barrier, was further reduced by replacing the naphthalene moiety in the upper half with xylene or benzothiophene (motor 13).[58,62] Furthermore, larger substituents have been placed at the stereogenic center to increase the rate of the THI[63,64] and DFT calculations showed that this decrease is due to destabilization of the unstable state, effectively lowering the barrier for THI.
Figure 1.5. Structural variations of second generation molecular motors.
The speed of the rotary motors is also dependent on the solvent.[65,66] In a systematic study of motors with pending arms of varying flexibility and length it was established that solvent polarity plays a minor role, but that in particular enhanced solvent viscosity for motor systems with rigid arms decreases THI drastically.[67] The results were analyzed in terms of a free volume model and it is evident that matrix effects (solution, surface, polymer, liquid crystal) comprise a challenging multiparameter aspect in applying molecular motors. In all these examples, changing the speed of rotation of a molecular motor requires a redesign of the molecule and multistep synthesis. Dynamic control of the rotational speed would be the next logical step in the development of molecular motors. Locking the rotation by employing an acid-base responsive self-complexing pseudorotaxane was the first example that allowed for such dynamic control over the rotary motion.[68] More recently, an allosteric approach was reported in which metal complexation was used to alter the speed of rotation.[69] Complexation of different metals to the stator part of a second generation molecular motor caused different degrees of contraction of the lower half. As a consequence the steric hindrance in the fjord region decreased, which resulted in a lower barrier for the THI.
18
Precise control of the speed of rotation in a dynamic fashion remains challenging but the first examples have shown that lengthy syntheses can be avoided and motor speed can be altered in situ. Controlling speed by external effectuators (metal/ion binding, pH, redox) or tuning in response to chemical conversions (catalysis) or environmental (matrix, surface) constraints offers exciting opportunities for more advanced motor functioning.
1.2.2 Shifting the excitation wavelength
A major challenge in the field of photochemical switches and motors is to move away from the use of damaging UV light because it limits the practicality in soft materials and biomedical applications.[70,71] For this reason, it is important to shift the irradiation wavelengths towards the visible spectrum.[72] The most straightforward method is to make changes to the electronic properties of the motors in such a way that the molecule is able to absorb visible light. However, such changes may be detrimental to the photoisomerization process. The first successful example of a visible light-driven molecular motor made use of a push-pull system to red-shift the excitation wavelength.[73] This second generation motor comprised a nitro-acceptor and a dimethylamine-donor substituent in its lower half, which allowed for photoexcitation with 425 nm light. An alternative strategy, that is often used to red-shift the absorption of molecular photoswitches, relies on the extension of the system. Indeed upon extension of the aromatic system of the stator half of second generation motors, unidirectional rotation could be induced by irradiation at wavelengths up to 490 nm.[74]
Apart from these methods that focus on altering the HOMO-LUMO gap, alternative strategies based on metal complexes are highly promising. For example, palladium tetraphenylporphyrin was used as a triplet sensitizer to drive the excitation of a molecular motor.[75] Isomerization of the motor was shown to occur by triplet-triplet energy transfer, upon irradiation of the porphyrin with 530-550 nm light. In a related example, a molecular motor was incorporated as a ligand in a Ruthenium(II)-bipyridine complex.[76] Irradiation with 450 nm into the metal-to-ligand charge transfer band resulted in unidirectional rotation.
These examples illustrate that there are multiple viable strategies to red-shift the excitation wavelength of molecular motors. However, the change of the wavelength region at which these motors can be operated is still modest. Moving further away from UV light towards red light or even near-infrared remains a major challenge. There are several strategies that have shown promising results for photoswitches, such as diarylethenes and azobenzenes, that have not been applied to molecular motors yet.[72] For example, multiphoton absorption processes using upconverting nanoparticles[77] or two-photon fluorophores[78] should be considered in future studies.
19
1.2.3 Improvement of the photochemical efficiency
Improving the efficiency of the photochemical isomerization process has proven to be difficult as it not as well understood as the thermal isomerization process. Typically, quantum yields below 2% are observed for E/Z photoisomerization of second generation motors.[52,79] To improve the yield, a detailed understanding of the excited state dynamics is required. Over the last decade, a combination of advanced spectroscopic studies and quantum chemical calculations have been used to gain insight in the mechanism of the photochemical isomerization. Using time-resolved fluorescence and picosecond transient absorption spectroscopy, a two-step relaxation pathway was observed after the initial excitation to the Franck-Condon excited state.[50,79,80] Within 100 femtoseconds, a bright (i.e. fluorescent) state relaxes to an equilibrium with a lower lying dark (i.e. non-fluorescent) state. Based on femtosecond stimulated Raman spectroscopy, supported by quantum chemical calculations, it has been postulated that this process is accompanied by elongation and weakening of the central double bond.[81–84] Solvent viscosity studies showed that this process is independent of solvent friction, which is consistent with a volume conserving structural change.[79,85] The dark excited state, formed after this first relaxation, has a lifetime of approximately 1.6 picosecond and relaxes back to the ground state to either the stable or unstable form via conical intersections (CIs). Relaxation to the ground state leaves excess vibrational energy which is dissipated to the solvent at the tens of picoseconds timescale.[81] The relative long lifetime of the dark state is attributed to the fact that a high degree of twisting and pyramidalization of one of the carbons of the central double bond is required to reach the CI.[84] Recent studies showed that this relaxation to the ground state, which is associated with twisting and pyramidalization, is not dependent on the size of the substituents,[85] while it is dependent on viscosity. This observation suggests that the motion that accompanies the relaxation to the ground state is not necessarily a complete rotation of the halves but rather occurs only at the core of the molecule.
The ability to control CIs could lead to major improvements, as they play an important role in the efficiency of the photochemical step. To improve the efficiency of molecular motors, Filatov and coworkers investigated the factors influencing the CIs in a theoretical study.[86,87] The calculations predict that by placing electron withdrawing groups close to the central axle, such as an iminium, the character of the CI changes from a twist-pyramidalization to a twist-bond length alteration. This effectively changes the mode of rotation from a precessional motion for current motors to an axial motion with higher efficiency. These computational designs have already inspired the development of new photoswitches with increased efficiency,[88] but have not yet been applied to motors and should be taken into account in attempts to increase the efficiency.
20
1.2.4 Redox-driven motors
As an alternative to the use of (UV-Vis) light to power molecular motors we considered designing an electromotor taking advantage of redox processes. Preliminary studies towards using overcrowded alkenes as redox-driven molecular motors are promising.[89] A rotary cycle is envisioned, in which consecutive oxidation/reduction cycles would electrochemically form the unstable state, which then undergoes a THI to afford the stable state, completing 180° rotation (Scheme 1.2). Unfortunately, the stereogenic center was found to be susceptible to deprotonation, leading to an irreversible double bond shift in which the central axis is converted to a single bond. As this type of degradation pathway impedes any successful directional motion, a different design has to be made. Quaternization of the stereogenic center by replacing the hydrogen for a fluorine atom would prevent deprotonation. It was recently shown that such fluorine-substituted molecular motors with quaternary stereocenters are still capable of unidirectional rotation when irradiated by light, making them excellent candidates to be studied as redox-driven molecular motors.[90]
Scheme 1.2. Proposed rotational cycle for a redox-driven molecular motor.
1.3
Alternative motor designs
In 2006, Lehn proposed a new type of light-driven molecular motor derived from imines.[91] The design is based on the two types of E/Z-isomerization processes that imines can undergo, namely a photochemical isomerization and a thermal nitrogen inversion. A two-step rotational cycle was proposed, starting with a light induced E/Z-isomerization, which has an out-of-plane rotational mechanism (Scheme 1.3). A thermally activated in-plane nitrogen inversion involves a planar transition state which would convert the system back to the original state. These two combined processes would lead to a net
21 rotational motion as both follow a different pathway. Placing a stereogenic center next to the imine leads to preferential rotation by favoring the direction of the photochemical isomerization. This is different from the other examples of double bond motors, as directionality is induced here in the photochemical step, rather than the thermal isomerization step.
Scheme 1.3. Proposed mechanism for an imine-based molecular motor.
Based on these design principles, Lehn and coworkers reported in 2014 on the synthesis of the first rotary motor based on imines,[92] i.e. N-alkyl imine 14 bearing a stereocenter next to the central imine (Scheme 1.4). Because of the twisted shape of the lower half and E-Z isomerism of the imine four stereoisomers are formed. A helicity inversion does not occur under the experimental conditions due to the relatively high barrier for this process compared to the nitrogen inversion. Under thermodynamic equilibrium, there is a preference for (S,M)-cis over (S,P)-trans, whereas there is not a major preference for either (S,P)-cis or (S,M)-trans. Photochemical isomerization occurs upon irradiation with 254 nm light and at PSS the ratio is shifted towards (S,P)-trans relative to (S,M)-cis, while the ratio of the other two isomers remains unaffected by irradiation. Heating up the mixture of isomers to 60° C for 15 h allows for the nitrogen inversion to occur, restoring the original distribution of diastereomers.
22
Scheme 1.4. A two-step molecular rotary motor based on imines.
Both processes are equilibrium reactions and therefore both forward and backward reactions can occur. However due to preferred formation of one of the isomers in each step, overall a net rotation occurs. During their investigations, it was found that annealing a benzene ring to the lower half is essential for this two-step motor as it effectively increases the thermodynamic barrier for the helicity inversion. Interestingly, when this inversion can occur, a molecular motor with a four-step rotary cycle is obtained, reminiscent of the cycle for motors based on overcrowded alkenes. That is, two photochemical isomerization steps and two thermally activated ring inversions give rise to 360° rotation. To show that imines can be used as two-step molecular motors in a more general sense and to provide more experimental and theoretical proof for the rotational behavior, camphorquinone imines were synthesized in a follow-up study.[93]
One of the major advantages of imine-based molecular motors is that many types of imines with different properties can be easily synthesized through simple condensation reactions starting from commercially available materials. Furthermore, fine-tuning of the speed of these motors can be achieved through controlling the barrier for N-inversion. The barrier for this process depends largely on the substituent at the N-atom, providing a good handle to alter the speed of rotation. The assumption that there is a preferred direction of rotation in the photochemical E/Z-isomerization in chiral imines due to the unsymmetrical excited state surface is very plausible, but further experimental support to unequivocally prove their preferred direction of rotation is warranted. These photoinduced isomerization processes often occur at the picosecond timescale, making it very difficult to obtain direct evidence. Potentially, quantum mechanical calculations can aid in exploring the excited state surface.
23 In 2015, Dube and coworkers introduced a light-driven molecular motor based on a thioindigo unit fused with a stilbene fragment (Scheme 1.5).[94] The design and rotational cycle resemble that of the molecular motors based on overcrowded alkenes with the distinct difference that a sulfoxide stereogenic center is present. Due to the steric crowding around the central axle, the substituents of the central double bond are twisted out of plane, giving the molecule a helical shape. The helicity is dictated by the chirality of the sulfoxide. The behavior of this motor was examined by UV/Vis and 1H-NMR spectroscopy showing that, in analogy to the overcrowded alkene motors, the rotational cycle consists of four steps: Two alternating sets of photochemical and thermal isomerization steps. The photochemical isomerization could be induced by light of wavelengths up to 500 nm and a frequency of rotation of 1 kHz at room temperature was determined. During the 1H-NMR studies, only the (E,S,M)-15 unstable state was observed, whereas the (Z,S,M)-15 state could not be detected, presumably because the THI is too fast. This hypothesis was supported by detailed DFT calculations showing a four-step unidirectional rotary cycle. More recently, a more sterically crowded and, therefore, slower motor was synthesized, which allowed for the direct observation of the fourth state.[95]
Scheme 1.5. Rotational cycle for hemithioindigo-based motors.
1.4
Outlook
Since the first development of light-driven molecular rotary motors two decades ago, great progress has been made in controlling unidirectional rotation around double bonds.
24
In particular, the overcrowded alkene-based molecular rotary motors have been thoroughly investigated. Various designs are now increasingly applied to control dynamic functions,[12] however, for a wider range of applications of these motors, further improvements are essential. For example, the use of longer irradiation wavelengths as usually the photochemical isomerization steps are induced by UV light, which is harmful and thus impedes application in chemical biology and materials science. The first visible-light-driven motors that can be powered with light up to 500 nm have recently been introduced, but more powerful strategies such as multiphoton absorption or photon upconversion need to be explored since they will afford a major red-shift in the irradiation wavelength, preferably even into the near-IR region. Although the influence of structural changes on the speed of rotation of these motors has been well established, supramolecular and metal-based approaches that allow for speed adjustments with multiple stimuli are highly promising. Increasing the efficiency of molecular motors is a more complex problem that offers another nice challenge also in view of potential use in nanoscale energy conversion and storage as well as performance of mechanical work by future rotary motor-based molecular machines. In this regard, theoretical studies could aid in improving the efficiency and motor design. Another major challenge for molecular motors that comprise a stereogenic center is to obtain sufficient quantities of enantiopure material, which is needed to explore new applications in particular towards responsive materials. Enantioselective synthetic routes towards first and second generation motors have been recently developed[29,96,97] and a chiral resolution method by crystallization of first generation motors offers important perspectives.[98]
All these fundamental challenges have to be considered in the perspective of molecular machines; control of functions and the design of responsive materials. Tuning molecular motors to operate in complex dynamic systems will require among others synchronization of rotary and translational motion, precise organization and cooperativity, as well as amplification of motion along length scales. A first approach towards coupled motion was recently reported by our group, in which the rotary motion of the molecular motor is transferred to the synchronized movement of a connected biaryl rotor.[99] The prospects for controlling motion at the nanoscale and beyond will continue to provide fascinating challenges for the molecular designer and many bright roads for the molecular motorist in the future.
1.5
Outline of this thesis
As outlined in the previous sections, for molecular motors to reach their full potential, challenges have to addressed. In this thesis, some of these challenges are addressed such as visible light addressability (Chapters 2 and 3) and dynamic control of rotary motion (Chapter 4). Additionally, making use of the intrinsic chirality of molecular motors, they
25 are incorporated in supramolecular coordination complexes and polymers as chiroptical multi-state switches.
Chapter 2 describes the synthesis and characterization of a second generation molecular motor based on pyrene. By extending the aromatic core of the motor, the excitation wavelength is red-shifted to the visible light region. Even though pyrene is well-known for its fluorescent behavior, the molecular motor retains its function without significant fluorescence.
The aim of Chapter 3 is red-shifting the excitation wavelength of molecular motors as well, but by developing a new type of molecular motor based on oxindole. Their four step rotation cycle is first explored using DFT. The motors are easily synthesized in one step using a Knoevenagel condensation. NMR and UV/vis studies show that these motors can be driven by visible light of wavelengths up to 505 nm.
Chapter 4 addresses the dynamic control of rotary motion in a multiphotochromic hybrid. A molecular motor is coupled with a dithienylethene switch, which allows gating of the rotary function. Photochemical ring closing of the dithienylethene switch moiety results in inhibition of the rotary motion.
In Chapter 5, molecular motors are used as photochromic ligands in a supramolecular coordination complex. A Pd2L4 complex is formed employing a first generation molecular
motor bearing pyridine moieties. X-Ray and CD studies supported by DFT calculations show that only homochiral cages are formed. Photochemical switching between different states of the molecular motor is possible, changing the morphology of the cage. Additionally, tosylate anions were shown to bind to in cavity of the cages.
Finally, Chapter 6 describes the incorporation of molecular motors in polymers. First generation molecular motors are copolymerized with fluorene moieties using a Suzuki polymerization, with the goal to control the conformation of the polymer using light. Unfortunately, photoswitching in the polymer appears to be inhibited to a large extent and instead fluorescence is observed.
1.6
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Chapter 2
A visible light driven molecular
motor based on pyrene
To red-shift the excitation wavelength of overcrowded alkene-based molecular motors, a visible light-driven motor with an extended aromatic core is presented. In this motor, the naphthalene moiety in the upper half is changed to pyrene. Its photochemical and thermal isomerization processes were initially studied using DFT calculations and were followed by NMR and UV/vis studies. Combined, these studies show that extension of the system on the upper half successfully shifts the excitation wavelength into the visible region, while retaining proper rotary function.
This chapter will be published as: D. Roke, S. J. Wezenberg, B. L. Feringa, Manuscript
32
2.1
Introduction
One of the major drawbacks for the field of photoresponsive switches and motors is that they are usually operated with harmful UV light.[1–3] To fully exploit their potential application in biology[4,5] or smart materials,[6–9] it is necessary to red-shift their excitation wavelength to the visible light region.[2,10] Various strategies for the visible light activation of existing photoswitches have been developed in recent years, mostly by making changes to the design in such a way that the photochromic unit can directly absorb visible light. Examples are push-pull systems,[11,12] extension of the system[13,14] and ortho-functionalization (applied to azobenzenes).[15–17] Alternatively, photosensitizers[18,19] or upconverting nanoparticles[20] have been used to operate photoswitches with visible light or even near infrared. Additionally, new types of photoswitches are emerging that allow for switching with visible light.[21–24]
Molecular motors based on overcrowded alkenes are unique photoswitches in the sense that they are able to perform rotary motion around their central double bond axle.[3,25,26] Their rotary cycle is based on two photochemical steps and two thermally activated steps (Scheme 2.1a). An initial light-induced E-Z isomerization yields a metastable isomer with opposite helicity. Subsequently, a thermal helix inversion (THI) occurs, in which the upper half passes the lower half. The photogenerated state is often referred to as an ‘unstable’ state. The second half of the cycle proceeds in a similar manner, resulting in 360° rotation. Owing to the unique properties of these molecular motors, they have found applications in diverse fields, such as responsive soft materials,[9,27–29] liquid crystals,[30,31] anion binding[32,33] and responsive catalysis.[34,35]
Scheme 2.1. a) Rotary cycle of second generation molecular motor 1. Note the isomer obtained after 180° rotation is identical to the initial isomer but viewed from the opposite side. b) Extension of the system of the upper half of the molecular motor to red-shift its excitation wavelength.
33 To red-shift the excitation wavelength of these motors, for example, a tetraphenylporphyrin triplet sensitizer was attached to a second generation molecular motor as a triplet sensitizer.[36] Hence, irradiation with 530 nm light resulted in triplet-triplet energy transfer from the porphyrin to the molecular motor, driving the rotation. In a related example, a molecular motor was incorporated into a Ru(II)-bipyridine complex.[37] Here, irradiation into the metal-to-ligand charge transfer band with 450 nm light resulted in rotation.
Other methods have been applied in which changes in the motor design were made in such a way that it absorbs visible light. Even though this seems to be a more straightforward method, these changes might also inhibit the rotary function. The earliest succesful example of a molecular motor able to absorb visible light features a push-pull substituent pattern.[38] The motor, bearing a nitro and a dimethylamino substituent, showed photoisomerization with 425 nm light. Recently, our group demonstrated that also by extending the system of the lower half, the excitation wavelength can be shifted to the visible region (up to 490 nm).[39] As this lower half aromatic extension led to successfully red-shifting of the excitation wavelength, we became interested in studying whether this strategy could be also applied the upper half. Overcrowded alkene 2 was designed (Scheme 2.1b), in which the naphthalene moiety in the upper half of parent motor 1 is changed to pyrene. Additionally, alkyl chains are attached to the lower half to improve solubility.
2.2
DFT calculations
To predict whether target compound 2 would function as a visible light-driven molecular motor, TD-DFT calculations were performed first. The structure was optimized and the vertical transitions were calculated using B3LYP/6-31G(d,p), which was shown before to be a reliable method for the prediction of geometries and UV/vis spectra of overcrowded alkene based molecular motors.[39,40] To reduce calculation time, methyl instead of hexyl substituents were introduced in the lower half. The first calculated transition at 431 nm has low oscillator strength (0.0038) and therefore most likely will not cause significant absorption. The second transition, being the HOMO-LUMO transition located at 420 nm, has a much higher oscillator strength (0.4818) (Figure 2.1a). Analysis of the orbitals involved showed a typical * transition located at the central double bond which is
likely to lead to photochemical isomerization.
The same functional and basis set were used to predict the thermal barrier for THI. The ground states and transition state geometries were identified and the geometries were optimized, and subsequently verified with a frequency analysis (Figure 2.1b). A barrier (⧧G
calc) of 90.9 kJ mol-1 was found, which is slightly higher than the experimentally
determined barrier for THI of parent motor 1 (⧧G
34
indicated that this pyrene-based overcrowded alkene would function as a visible light-driven motor, so we devised a strategy to synthesize this compound.
Figure 2.1. a) TD-DFT calculated HOMO-LUMO transition of motor 2. b) side and top views of optimized structures of motor 2.
2.3
Synthesis
The synthesis of 2 started with a palladium catalyzed Negishi cross-coupling of hexahydropyrene 6 with organozinc reagent 5 (Scheme 2.2). This organozinc reagent was prepared from ester 3, in which the bromide in 3 was substituted for iodide using a Finkelstein reaction to give 4. Subsequently, 4 was transformed into the organozinc reagent 5 by reaction with a zinc-copper couple, after which it was directly submitted to the cross-coupling reaction. The ester in 7 was then hydrolyzed and transformed into an acid chloride by using thionyl chloride, which was followed by an AlCl3 mediated
intramolecular Friedel-Crafts acylation to form ketone 9. Oxidation of 9 with DDQ afforded pyrene 10, which was subsequently converted into thioketone 11 and submitted to a Barton-Kellogg reaction with diazo compound 12 to provide overcrowded alkene 13. In the last step, hexyl chains were introduced on the lower half using a double
palladium-35 catalyzed organolithium cross-coupling, which was developed in our group.[42,43] The structure of motor 2 was determined with 1H and 13C-NMR and composition by HRMS.
Scheme 2.2. Synthetic route for pyrene-based molecular motor 2
2.4
UV/vis and
1H-NMR spectroscopy of motor 2
Next, the photochemical and thermal isomerization behavior of motor 2 were investigated using UV/vis spectroscopy. The UV/vis spectrum of motor 2 in CH2Cl2 showed an
absorption maximum in the visible region, at = 414 nm, which is close to the predicted maximum of = 420 nm (Figure 2.2). Upon irradiation at 455 nm at 0 °C, a clear bathochromic shift was observed, which is characteristic for the formation of the unstable state upon photochemical E-Z isomerization. A clear isosbestic point was observed at = 425, indicative of a unimolecular process. Notably, even though pyrene is well-known to be fluorescent,[44,45] no significant fluorescence was observed for motor 2. When the irradiated UV/vis sample was allowed to warm to room temperature, the original absorption spectrum was reobtained. The unstable state underwent thermal isomerization to afford the stable state. An Eyring analysis was performed to determine the activation parameters for this thermal process. The rate of isomerization was determined at five different temperatures between 0 °C and 20 °C by following the decrease in absorption at = 470 nm (Figure 2.3). The Gibbs free energy of activation was found to be (⧧G) 88.5 ± 0.1 kJ mol-1
, which is in good agreement with the calculated value of 91 kJ mol-1 for THI obtained by DFT. As expected, this value is also in the same range as the barrier for THI of parent motor 1 (⧧G = 85 kJ mol-1
36
Figure 2.2. Photochemical and thermal isomerization of motor 2 (top). UV/vis spectra of motor 2 in CH2Cl2 (c = 2.3 x 10-3 M) upon irradiation with max = 455 nm (bottom left) and
max = 395 nm (bottom right)
The photochemical and thermal isomerization were also followed by 1H-NMR spectroscopy. Irradiation of a sample of motor 2 in CD2Cl2 at 455 nm at -25 °C led to the
appearance of a new set of signals, indicative of the formation of the unstable state (Figure 2.4). The sample was irradiated until no further changes were observed and at this photostationary state (PSS) the ratio of unstable to stable was determined to be 28:72. Irradiation of the same sample at 395 nm led to a PSS ratio of 90:10, because the unstable state absorbs less strongly at this wavelength (vide infra). When the sample was allowed to warm to room temperature, the original spectrum was obtained, illustrating that the THI had taken place. Combined, these studies show that pyrene based motor 2 functions as a visible light-driven molecular motor.
37
Figure 2.3. Eyring plot analysis of the THI of unstable 2 to stable 2 monitored by the decrease in absorption at = 470 nm in CH2Cl2 (c = 2.6 x 10-5 M). ⧧G (20 °C) = 88.5 ± 0.1 kJ mol-1; ⧧H = 77.8 ± 1.6 kJ mol-1
;⧧S = -36.5 ± 5.6 J mol-1 K-1
Figure 2.4. Selected region of 1H-NMR spectra of motor 2 in CD2Cl2 (c = 1.7 x 10-3 M) at -25 °C. For atom labeling see Figure 2.2. i) stable 2 b) PSS max = 455 nm iii) THI, 20 °C.
Additionally, the quantum yield for the photochemical E-Z isomerization (s→u) was
estimated. By comparing the rate of formation of the unstable state to the formation of Fe2+ ions from potassium ferrioxalate under identical conditions (see experimental procedures for details), a quantum yield of 1.4% was determined. Using the PSS ratio, the quantum yield for the reverse photochemical isomerization (u→s) was calculated to be
38
2.5
Conclusions
In summary, aromatic extension of the upper half, from naphthalene to pyrene, is shown to be a viable method to shift the excitation wavelength of a molecular motor into the visible light region (irr = 455 nm). The photochemical and thermal isomerization processes
were first explored by DFT calculations, and was followed by the synthesis of this pyrene-based molecular motor. Combined UV/vis and 1H-NMR studies revealed that the excitation wavelength is shifted into the visible region, while proper rotary motion is retained. Interestingly, despite the well-known fluorescence of pyrene, no significant fluorescence was observed when it is incorporated in a molecular motor.
2.6
Experimental procedures
General procedures
Reagents were purchased from Sigma-Aldrich, Combi-Blocks or TCI and were used as provided unless stated otherwise. Anhydrous solvents were obtained from a solvent purification system (MBRAUN SPS systems, MBSPS-800). Solvents were degassed by purging with N2 for at least half an hour. All reactions involving air-sensitive reagents were
performed under a N2 atmosphere. Flash column chromatography was performed using
silica gel (SiO2) purchased from Merck (type 9385, 230-400 mesh) or on a Büchi Reveleris
purification system with Büchi cartridges. Thin-layer chromatography (TLC) was carried out on aluminum sheets coated with silica 60 F253 obtained from Merck. Compounds were visualized with a UV lamp (254 nm) or by staining with CAM. Melting points (m.p.) were determined using a Büchi-B545 capillary melting point apparatus. 1H and 13C NMR spectra were recorded on a Varian Mercury-Plus 400 MHz or a Varian Inova 500 MHz spectrometer at 298K unless indicated otherwise. Chemical shifts are quoted in parts per million (ppm) relative to the residual solvent signal (for CDCl3 δ 7.26 for 1H, δ 77.16 for 13C
and for CD2Cl2 δ 5.32 for 1H, δ 53.84 for 13C). For 1H-NMR spectroscopy, the splitting
pattern of peaks is designated as follows: s (singlet), d (doublet), t (triplet), m (multiplet), br (broad), or dd (doublet of doublets). High resolution mass spectrometry (ESI or APCI-MS) was performed on a LTQ Orbitrap XL spectrometer. UV/Vis absorption spectra were recorded on a Agilent 8453 or a Specord S600 UV/Vis Spectroscopy System in a 10 mm quartz cuvette. The CD spectra were recorded on a Jasco J-810 spectrometer. The UV/Vis and NMR irradiation experiments were performed with Thorlabs fiber-coupled LEDs. The Eyring analysis was performed by following the thermal isomerization step from unstable to stable 2 by monitoring the decrease in absorption at 470 nm. The rate constant (k) of the first order decay at five temperatures (0, 5, 10, 15 and 20 °C) were obtained by fitting to the equation Y = Ae(-k·t)+ Y0 using Origin Software. The obtained rates
were used to perform a least-squares analysis with the Eyring equation k = kBT/h ·e-(Δ‡G/RT)
