University of Groningen · 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

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Molecular motors: new designs and applicationsRoke, Gerrit Dirk

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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) ISBN: 978-94-034-1246-7 (electronic 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

Promotores Prof. dr. B.L. Feringa 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

2.7 References 44

Chapter 3 Tunable visible light driven molecular motors based on oxindole 47

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


3.8 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


4.6 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


5.7 References 101

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


6.7 References 119

Chapter 7 Summary 123

7.1 English Summary 124

7.2 Nederlandse samenvatting 126

Chapter 8 Popular science summary 129

8.1 English summary 130

8.2 Nederlandse samenvatting 131

Acknowledgements 133

Chapter 1

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.

U.S.A. 2018, 115, 9423 – 9431.

10

Chapter 1

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

Molecular rotary motors: Unidirectional motion around double bonds

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

Chapter 1

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

Chapter 1

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

Chapter 1

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

Chapter 1

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

Chapter 1

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

Chapter 1

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

Chapter 1

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 References

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Chapter 1

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28

Chapter 1

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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 submitted for publication

32

Chapter 2

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

A visible light driven molecular motor based on pyrene

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

(⧧Gcalc) of 90.9 kJ mol-1

was found, which is slightly higher than the experimentally

determined barrier for THI of parent motor 1 (⧧Gexp = 85 kJ mol-1

).[41]

As these results

34

Chapter 2

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

Chapter 2

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

0.38%.

38

Chapter 2

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)

using direct weighting (1/k2) to obtain the activation parameters. Subsequently, the

39


standard errors were obtained from a Monte Carlo error analysis on the linearized Eyring

equation using calculated standard errors on rates an estimated standard error on

temperature of 0.5 K.

methyl-3-iodo-2-methylpropanoate (4)

NaI (375 mg, 2.5 mmol) was added to a solution of methyl (R)-3-bromo-2-

methylpropanoate (0.25 ml, 2.0 mmol) in acetone (1.5 ml). The mixture was stirred while

heated at reflux for 2 h, after which water was added (5 ml). The mixture was extracted

three times with Et2O and the combined organic layers were dried over MgSO4. The

volatiles were carefully removed in vacuo (>500 mbar) and the residue was filtered over a

plug of silica (Et2O) and dried in vacuo to yield 4 (417 mg, 92%) as a red oil. 1H-NMR (400

MHz, CDCl3) δ 3.73 (s, 3H), 3.38 (dd, J = 9.8, 6.6 Hz, 1H), 3.26 (dd, J = 9.8, 6.2 Hz, 1H), 2.80

(h, J = 6.8 Hz, 1H), 1.28 (d, J = 7.0 Hz, 3H). Spectroscopic data are in agreement with those

reported in the literature.[46]

methyl-3-(1,2,3,6,7,8-hexahydropyren-4-yl)-2-methylpropanoate (7)

A solution of iodide 4 (240 mg, 1.05 mmol) in dry toluene/DMA (15:1, 4.3 ml) was added

to Zn-Cu couple (126 mg) under a N2 atmosphere. The mixture was stirred at 60 °C for 4 h

after which it was cooled to rt. Then, 4-bromo-1,2,3,6,7,8-hexahydropyrene (271 mg,

0.945 mmol), Pd2dba3 (11 mg, 0.012 mmol) and QPhos (17 mg, 0.024 mmol) were added

and the mixture was stirred overnight at rt. The suspension was filtered over celite

(washed with CH2Cl2) and the volatiles were removed in vacuo. The residue was purified

by column chromatography (SiO2, pentane/EtOAc 30:1) to yield 7 (208 mg, 71%) as a

yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.16 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H),

7.06 (s, 1H), 3.70 (s, 3H), 3.29 – 3.18 (m, 1H), 3.15 – 3.02 (m, 8H), 2.91 – 2.79 (m, 2H), 2.13

– 2.03 (m, 4H), 1.23 (d, J = 6.3 Hz, 3H). 13

C-NMR (100 MHz, CDCl3) δ 176.9, 134.0, 134.0,

133.7, 132.2, 131.3, 130.4, 129.1, 126.4, 123.7, 123.0, 51.6, 40.5, 36.9, 31.5, 31.5, 31.4,

27.7, 23.3, 23.1, 16.8. HRMS (ESI+, m/z): Calcd for C21H25O2+: 309.18491 [M+H]

+, found

309.18478.

3-(1,2,3,6,7,8-hexahydropyren-4-yl)-2-methylpropanoic acid (8)

40

Chapter 2

Methyl ester 7 (364 mg, 1.18 mmol) was dissolved in a mixture of 25 ml THF and 25 ml

aqueous 0.1M NaOH. The solution was stirred overnight at rt. and acidified with 2M aq.

HCl. The mixture was extracted with CH2Cl2 and the combined organic layers were dried

over MgSO4. The volatiles were removed in vacuo to yield 8 (340 mg, 97%) as a colorless

oil. 1H-NMR (400 MHz, CDCl3) δ 7.14 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 7.05 (s, 1H),

3.33 – 3.20 (m, 1H), 3.07 (q, J = 5.4 Hz, 8H), 2.94 – 2.75 (m, 2H), 2.12 – 2.00 (m, 4H), 1.22

(d, J = 6.5 Hz, 3H). 13

C-NMR (100 MHz, CDCl3) δ 182.9, 134.2, 134.2, 133.9, 132.0, 131.5,

130.5, 129.3, 126.5, 123.9, 123.2, 40.6, 36.6, 31.6, 31.5, 27.8, 23.4, 23.2, 16.6. HRMS (ESI+,

m/z): C20H22O2+: 295.16926 [M+H]

+, found 295.16913.

10-methyl-1,2,3,6,7,8,10,11-octahydro-9H-cyclopenta[e]pyren-9-one (9)

Acid 8 (340 mg, 1.15 mmol) was dissolved in dry CH2Cl2 (25 ml) under N2 atmosphere.

Thionyl chloride (0.20 ml, 2.74 mmol) was added and the mixture was stirred at reflux for

4h. The volatiles were removed in vacuo and the residue was redissolved in dry CH2Cl2 (25

ml) under N2 atmosphere. AlCl3 (231 mg, 1.73 mmol) was added in portions at 0 °C and the

mixture was stirred at reflux for 3h. The mixture was allowed to cool to rt overnight after

which water was carefully added. The layers were separated and the aqueous layer was

extracted with CH2Cl2. The combined organic layers were washed with water and dried

over MgSO4. The volatiles were removed in vacuo and the residue was purified using

column chromatography (SiO2, pentane/EtOAc 20:1) to yield 9 (200 mg, 63%) as a

colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.0 Hz, 1H), 7.11 (d, J = 7.0 Hz, 1H),

3.62 (t, J = 6.3 Hz, 2H), 3.39 (dd, J = 16.7, 8.4 Hz, 1H), 3.07 (t, J = 6.2 Hz, 4H), 3.03 – 2.95

(m, 2H), 2.83 – 2.71 (m, 1H), 2.67 (dd, J = 16.7, 4.9 Hz, 1H), 2.14 – 1.99 (m, 4H), 1.36 (d, J =

7.3 Hz, 3H). 13

C-NMR (100 MHz, CDCl3) δ 211.6, 142.6, 137.4, 137.2, 133.7, 133.0, 129.6,

129.5, 128.1, 126.4, 123.5, 43.0, 32.9, 31.2, 31.2, 27.0, 26.6, 22.9, 22.6, 16.9. HRMS (ESI+,

m/z): Calcd for C20H21O+: 277.15869 [M+H]

+, found 277.15903

10-methyl-10,11-dihydro-9H-cyclopenta[e]pyren-9-one (10)

41


Ketone 9 (280 mg, 1.01 mmol) was dissolved in dry toluene (50 ml) under N2 atmosphere

and DDQ (722 mg, 3.18 mmol) was added. The mixture heat at reflux for 2h and then

allowed to cool to rt. The suspension was filtered over celite (washed with CH2Cl2) and the

volatiles were removed in vacuo. The residue was purified by column chromatography

(SiO2, CH2Cl2) to yield 10 (225 mg, 82%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 9.50 (d,

J = 7.7 Hz, 1H), 8.37 – 8.31 (m, 2H), 8.22 (d, J = 7.5 Hz, 1H), 8.14 – 8.03 (m, 4H), 3.86 (dd, J

= 17.6, 7.3 Hz, 1H), 3.16 (dd, J = 17.6, 3.1 Hz, 1H), 3.02 (pd, J = 7.4, 3.0 Hz, 1H), 1.51 (d, J =

7.5 Hz, 3H). 13

C-NMR (100 MHz, CDCl3) δ 212.8, 160.3, 134.0, 133.4, 132.1, 131.0, 130.7,

130.5, 129.6, 129.2, 128.8, 128.7, 128.4, 128.4, 126.8, 125.0, 124.7, 124.7, 44.5, 36.0, 19.5.

HRMS (ESI+, m/z): Calcd for C20H15O+: 271.11174 [M+H]

+, found 271.11092

9-(2,7-dibromo-9H-fluoren-9-ylidene)-10-methyl-10,11-dihydro-9H-cyclopenta[e]pyrene

(13).

Ketone 10 (196 mg, 0.725 mmol) and Lawesson reagent (441 mg, 1.09 mmol) were

dissolved in dry toluene (5 ml) under N2 atmosphere. The resulting suspension was

heated to 95 °C and the conversion was followed by TLC. After 2.5h the mixture was

allowed to cool to rt. and directly purified using column chromatography (SiO2,

pentane/CH2Cl2 4:1 – 2:1) to yield the corresponding thioketone (161 mg, 78%), which was

used directly in the following reaction.

Thioketone 11 (160 mg, 0.559 mmol) and diazo 12 (294 mg, 0.839 mmol) were dissolved

in dry toluene under a N2 atmosphere. The mixture was stirred 16h at rt and subsequently

24h at 70 °C after which full conversion of the thioketone was observed by TLC. HMPT

(0.17 ml, 0.923 mmol) was added and the mixture was stirred for 4h at 70 °C, after which

water was added and the layers were separated. The aqueous layer was extracted twice

with CH2Cl2 and the combined organic layers were washed with brine and dried over

MgSO4. The volatiles were removed in vacuo and the resulting solid was washed with

EtOAc. The crude product was used in the following reaction without further purification.

42

Chapter 2

9-(2,7-dihexyl-9H-fluoren-9-ylidene)-10-methyl-10,11-dihydro-9H-cyclopenta[e]pyrene

(2).

Compound 13 (50 mg, 0.087 mmol) and Pd[P(tBu)3]2 (4.4 mg, 0.0087 mmol) were loaded

in a dry Schlenk flask under N2 atmosphere. Dry toluene (4 ml) was added) and the

mixture was purged with O2 and stirred overnight. In a separate dry Schlenk flask, n-

hexyllithium (2.2M, 0.5 ml) was diluted with toluene (4.5 ml) to reach a final concentration

of 0.22M. The diluted n-hexyllithium (0.8 ml) was added over 1h via a syringe pump to the

mixture of compound 13 and catalyst at rt and stirred for an additional 30 min. The

reaction mixture was treated with MeOH (0.1 ml) and the volatiles were removed in

vacuo. The residue was purified by column chromatography to yield 2 (33 mg, 65%) as a

dark yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.7 Hz, 2H), 8.21 (d, J = 7.9 Hz,

1H), 8.18 – 8.07 (m, 4H), 7.88 (s, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.60

(d, J = 7.6 Hz, 1H), 7.22 (dd, J = 7.8, 1.3 Hz, 1H), 6.96 (dd, J = 7.6, 1.5 Hz, 1H), 6.39 (s, 1H),

4.57 (p, J = 6.5 Hz, 1H), 3.87 (dd, J = 15.2, 5.6 Hz, 1H), 3.31 (d, J = 15.2 Hz, 1H), 2.79 (t, J =

7.6 Hz, 2H), 2.04 – 1.86 (m, 2H), 1.77 (p, J = 7.5 Hz, 2H), 1.54 (d, J = 6.6 Hz, 3H), 1.50 – 1.31

(m, 6H), 1.10 (p, J = 6.9 Hz, 2H), 1.05 – 0.68 (m, 12H). 13

C NMR (101 MHz, CDCl3) δ 153.0,

148.8, 143.9, 142.9, 142.7, 140.8, 140.1, 140.0, 138.8, 134.3, 134.1, 133.6, 132.0, 130.8,

130.0, 130.0, 129.9, 129.5, 129.4, 128.8, 128.7, 128.6, 128.5, 127.8, 127.6, 127.0, 126.9,

125.0, 121.8, 120.9, 47.6, 43.0, 39.2, 38.4, 34.5, 34.5, 34.2, 33.4, 31.7, 31.5, 25.4, 25.1,

22.3, 16.8, 16.8. HRMS (ESI+, m/z): Calcd for C45H47+ [M+H]

+: 587.36723, found 587.36603

Quantum yield determination

The photon flux of the Thorlabs M420F2 LED was estimated by measuring the production

of ferrous ions from potassium ferrioxalate.[47]

An aqueous 0.05 M H2SO4 solution

containing 12 mM K3[Fe(C2O4)3] (2 mL, quartz cuvette) was irradiated at 20 °C for 2, 4, 6, 8

and 10 min in the dark at 420 nm at 20 °C. At every time interval, a volume of 10 μL was

taken and diluted to 2.0 mL with an aqueous 0.5 M H2SO4 solution containing

phenanthroline (1 g/L) and NaOAc (122.5 g/L). The absorption at = 517 nm was

measured and compared to an identically prepared non-irradiated sample. The

concentration of [Fe(phenanthroline)3]2+

complex was calculated using its molar

absorptivity ( = 11100 M-1

cm-1

). This concentration corresponded to the concentration of

Fe2+

ions that had formed upon irradiation divided by 200. The difference in Fe2+

ion

concentration was plotted versus time and the following slope, obtained by linear fitting

43


to the equation y = ax + b using Origin software, equals the rate of formation at

standardized conditions (Figure 2.5). This rate can be converted into a photon flux by

taking into account the quantum yield (420 = 1.12) of the formation of the Fe2+

ion,

resulting in a flux of 5.31 x 10-5

mmol photons per second.

0 100 200 300

0.000

0.004

0.008

B

Linear Fit of B

[F

e2

+]

time (s)

Equation y = a + b*x

Adj. R-Square 0.95666

Value Standard Error

B Intercept 8.73359E-5 5.11417E-4

B Slope 2.97088E-5 2.81526E-6

Figure 2.5. Linear fit of the photochemical formation of Fe2+

ions over time by irradiation

with max = 420 nm. The slope, obtained from the linear fit, corresponds to the rate of

formation of Fe2+

ions (2.97 x 10-5

M s-1

or 5.94 x 10-5

mmol s-1

).

A sample of motor 2 was irradiated at 420 nm under identical conditions as with the

actinometry at a concentration high enough to absorb all incident light (Abs420 > 2, c = 2.28

x 10-4

M in CH2Cl2) at 0 °C. The formation of the unstable state was monitored over time

by following the absorbance increase at = 475 nm. The molar absorptivity of the

unstable state at = 475 nm (= 1.56 x 104 M

-1 cm

-1) was used to calculate the

concentration increase. The initial concentration increase was plotted versus time (Figure

2.6) and the slope, the rate of formation of the unstable state, was obtained by linear

fitting to the equation y = ax + b using Origin software. The photochemical quantum yield

(s→u = 1.4%) was then calculated using the photon flux of this specific light source

previously determined at identical conditions in the actinometry. The quantum yield of

the reverse reaction (u→s = 0.38%) at = 420 nm can then be calculated using equation

1, in which [stable]/[unstable] is the ratio of both states at PSS420.

44

Chapter 2

[stable]

[unstable]=

Φ(𝑢→𝑠) 𝑢

Φ(𝑠→𝑢) 𝑠 (1)

30 60 90

0.0

1.0x10-5

2.0x10-5

3.0x10-5

[un

sta

ble

2] (M

)

time (s)




B Intercept -7.57077E-6 2.23654E-6

B Slope 3.8532E-7 3.24512E-8

Figure 2.6. Linear fit of the photochemical formation of unstable 2 over time by irradiation

of a sample of motor 2 with max= 420 nm. The slope, obtained from the linear fit

corresponds to the rate of formation of the unstable state (3.84 x 10 -7

M s-1

or 7.71 x 10-7

mmol s-1

).

2.7 References

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[23] S. Helmy, F. A. Leibfarth, S. Oh, J. E. Poelma, C. J. Hawker, J. Read de Alaniz, J. Am. Chem. Soc. 2014, 136, 8169–8172.

[24] M. M. Lerch, W. Szymański, B. L. Feringa, Chem. Soc. Rev. 2018, 47, 1910–1937.

[25] B. L. Feringa, N. Koumura, R. W. J. Zijlstra, R. A. van Delden, N. Harada, Nature 1999, 401, 152–155.


[27] J. Chen, F. K.-C. Leung, M. C. A. Stuart, T. Kajitani, T. Fukushima, E. van der Giessen, B. L. Feringa, Nat. Chem. 2017, 10, 132–138.



46

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[31] T. Orlova, F. Lancia, C. Loussert, S. Iamsaard, N. Katsonis, E. Brasselet, Nat. Nanotechnol. 2018, DOI 10.1038/s41565-017-0059-x.

[32] S. J. Wezenberg, M. Vlatković, J. C. M. Kistemaker, B. L. Feringa, J. Am. Chem. Soc. 2014, 136, 16784–16787.

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47

Tunable visible light driven molecular motors based on oxindole

Chapter 3 Tunable visible light driven molecular motors based on oxindole

Molecular rotary motors based on oxindole which can be driven by visible light are

presented. This novel class of motors can be easily synthesized in a Knoevenagel

condensation and the choice of different upper halves allows for the facile tuning of their

rotational speed. Their four-step rotational cycle was explored using DFT calculations and

the expected photochemical and thermal isomerization behavior for molecular rotary

motors was confirmed by NMR, UV/vis and CD spectroscopy. These oxindole motors are

offer attractive prospects for functional molecular materials.

This chapter will be published as: D. Roke, M. Sen, W. Danowski, S. J. Wezenberg, B. L. Feringa, Manuscript in preparation

48

Chapter 3

3.1 Introduction

The emergence of artificial molecular machines has allowed chemist to control movement

at the molecular scale.[1–7]

Among these machines, molecular rotary motors are drawing a

lot of attention owing to their unique ability to undergo repetitive unidirectional

rotational motion.[8–10]

Overcrowded alkene-based motors, which are driven by light, have

shown great potential in a number of fields, such as soft materials,[11–14]

catalysis[15]

and

surface chemistry.[16]

They were first reported by our group in 1999,[17]

and since then,

second and third generation molecular motors have been developed and their functioning

has been thoroughly investigated.[18,19]

Through synthetic modification, their rotational

speed can be tuned,[8,20,21]

and recently methods to control their speed dynamically have

been developed.[22–24]

A major challenge that remains is to drive the rotation with visible

light instead of harmful UV light.[25]

Strategies to shift the excitation wavelength to the

visible range have been developed by, for example, making use of photosensitizers,[22,26]

extended systems,[27]

or push-pull substituents.[28]

However, for molecular motors to

fully reach their potential, there are a number of challenges that still need to be

addressed.[9,10]

They should, for example, be powered with a sustainable energy source.

Apart from adapting the design of existing motors, new types of light driven molecular

motors have appeared. Lehn and coworkers reported easily accessible molecular motors

based on imines,.[29,30]

and the group of Dube developed molecular motors based on

hemithioindigo, which can be operated with visible light.[31,32]

Here we present a design

that is based on arylidene oxindoles, which are easily accessed by a condensation reaction

and can be operated by visible light.

The group of Luňák Jr. has shown that some arylidene oxindoles undergo E-Z isomerization

when exposed to sunlight, but the potential of these compounds as photoswitches was

not explored.[33]

Inspired by the facile synthesis and the interesting spectroscopic

properties of arylidene oxindoles, we envisioned a new design for a molecular rotary

motor (Scheme 3.1).

49


Scheme 3.1. a) Oxindole-based molecular motors b) Representative rotational cycle of

motor 1

3.2 DFT calculations

Initially, DFT calculations were performed to predict the structural parameters and the

relative energies of the different isomers of oxindole-based motors 1-4 (Figure 3.2). All

structures were optimized using the B3LYP functional with a 6-31+G(d,p) basis set.

Additionally, a IEFPCM, DMSO solvation model was chosen as previous studies with

arylidene oxindoles were carried out in DMSO.[33]

The calculated relative Gibbs free

energies of all stable and unstable states, as well as the transition states (TS) for THI are

shown in Figure 3.1. In all cases, two unstable states are found that are much higher in

energy than their respective stable states with opposite helicity. This energy difference is

crucial to assure unidirectionality in the rotary cycle of molecular motors. The relative

energy barriers for THI of all motors are summarized in Table 3.1.

50

Chapter 3

Figure 3.1. Calculated relative Gibbs free energies of motors 1 (black), 2 (blue), 3 (purple)

and 4 (red).

Similar to what has been reported for their overcrowded alkene-based counterparts,[34,36]

motors 1-3 with a central six membered ring in the upper half have higher barriers than

motor 4 with a five membered ring. The latter has less steric hindrance in the fjord region,

making it easier for the two halves to slip along each other. In all cases, the barrier for THI

of unstable-Z is lower than for unstable-E which can also be explained by less steric

hindrance in the fjord region as here the upper half needs to pass the smaller carbonyl

instead of the bulkier aromatic ring. Furthermore, the calculated barriers for THI in motors

1-3 scale with the size of the bridging atom X (S > C > O). The upper half is pushed closer

towards the lower half as the size of X increases, causing more steric hindrance in the fjord

region. As a consequence, the upper half folds away from the lower half, resulting in an

increased dihedral angle 1-2-3-4 in unstable-Z (Table 3.1). A similar effect has been

observed in structurally related molecular motors.[35]

The results of these calculations

indicate that oxindole-based molecular motors 1-4 will operate as unidirectional rotary

molecular motors.

51


Figure 3.2. DFT optimized structures of motor 1 as a representative example.

‡Gcalc (Z)

(kJ mol-1)

‡Gcalc (E)

(kJ mol-1)

Dihedral

anglea

1 98.8 110.3 43.1

2 87.6 100.4 41.2

3 108.5 120.2 48.1

4 53.3 66.8 23.9

Table 3.1. DFT calculated barriers for THI of 1-4. a Dihedral angle 1-2-3-4 as shown in

Scheme 3.1 of unstable Z.

52

Chapter 3

3.3 Synthesis

Oxindole motors 1-4 were synthesized in a single step by a Knoevenagel condension of

commercially available N-methyloxindole and the corresponding ketone, mediated by a

combination of TiCl4 and DBU (Scheme 3.2). The ketones were synthesized in one to four

steps following well-established literature procedures,[35,37]

thus making these molecular

motors very easily accessible. In all cases the E-isomer was exclusively obtained. According

to DFT calculations, this isomer is the most stable one (vide infra). The structures of the

molecular motors 1-4 were determined by 1H and

13C-NMR, and UV/vis spectroscopy and

composition by HRMS.

Scheme 3.2. Representative synthesis of molecular motor 1 and isolated yields of 1-4.

3.4 1H-NMR studies

With these four different motors in hand, the photochemical and thermal isomerization

behavior was first monitored by 1H-NMR spectroscopy with 365 nm light. Upon irradiation

of an NMR sample of E-1 in DMSO-d6 at room temperature, a new set of signals appeared

(Figure 3.3). The most distinct shifts were observed for protons Ha (1.02 -> 1.39) and Hb

(4.48 -> 4.02) at the stereogenic center (see Scheme 3.1 for the atom labeling). Hence,

these 1H-NMR spectral changes were ascribed to formation of the unstable Z-isomer. The

sample was irradiated until no further changes were observed and at this photostationary

state (PSS) the ratio of unstable Z-1 to stable E-1 was 76:24. Heating this sample to 60 °C

resulted in the disappearance of the signals assigned to this photogenerated isomer. A

new stable state was obtained and isolation and characterization of the newly obtained

isomer on preparative scale revealed that this isomer is the stable Z-isomer. This confirms

that the oxindole-based motor undergoes an E-Z-isomerization upon irradiation which,

followed by a subsequent THI to complete 180° rotation, identical to other molecular

motors based overcrowded alkenes.[17]

53


Figure 3.3. 1H-NMR spectra of a sample of 1 in DMSO-d6 (c = 2.2 x 10

-3 M). See Scheme 3.1

for the atom labeling. i) E-1 before irradiation. ii) PSS 365 nm iii) 60 °C, 1h iv) PSS 365 nm.

v) 100 °C, 120 min.

When the NMR sample containing stable Z-1 was once again irradiated at 365 nm, a new

set of signals appeared indicative of unstable E-1, with a PSS365 ratio of 96:4. Upon heating

to 100 °C, this unstable state was converted to the original isomer (stable E-2), and as a

consequence, a 360° rotation was successfully achieved.

A similar rotational cycle was observed for motor 2 in THF-d8. THF was chosen as low

temperature studies were needed. Irradiation of a sample of 2 at 365 nm at -25 °C

revealed the emergence of unstable Z-2 (PSS365 = 77:23), which underwent THI to stable Z-

2 when the sample was allowed to warm to room temperature. Subsequent irradiation

afforded unstable E-2 (PSS365 > 99:1), which converted to the original isomer (stable E-2)

when the sample was heated to 55 °C.

For motor 3, for which the highest barriers for THI was calculated (vide infra), the first part

of the cycle was found to be identical to that of motors 1 and 2. Irradiation of an NMR

sample of 3 in DMSO-d6 at 365 nm at room temperature (PSS365 = 79:21) and subsequent

heating to 100 °C showed the formation of stable Z-3. The sample was again irradiated to

show the appearance of unstable E-3 (PSS365 = 95:5), however, when it was heated,

complete degradation was observed. Most likely, degradation is due to the high

temperature required to trigger THI, owing to the high energy barrier for this compound.

54

Chapter 3

Due to the low barrier for THI, unstable Z-4 could only be observed when irradiated at -90

°C, which was performed in CD2Cl2. Even at this low temperature, unstable Z-4 was

observed to already undergo slow THI to form stable Z-4. At the same time, this isomer

then undergoes a photochemical E-Z isomerization, forming unstable E-4 over time. When

warming the sample to -45 °C, stable E-4 is again reformed, completing a 360° rotary

cycle.

3.5 UV/vis and CD spectroscopy of 1-4

Next, the photochemical and thermal isomerization behavior of motors 1-4 were studied

using UV/vis spectroscopy. All compounds show a broad absorption band with max

between 350 and 400 nm, which extends into the visible region (Figure 3.4). Very little

solvatochromism (≤ 5 nm) was observed over a range of different solvents, including

aromatic and protic solvents. The rotational cycle of motor 2 was additionally studied

using CD spectroscopy. Its enantiomers were therefore separated using chiral supercritical

fluid chromatography. The enantiomers could be identified by comparing their CD

spectrum to the DFT calculated spectrum, generated using CAM-B3LYP/6-31+G(d,p) and a

IEFPCM, DMSO solvation model (Figure 3.5). When a UV/vis sample of stable E-(S)-1 in

DMSO was irradiated at 365 nm, a bathochromic shift in both the UV and CD spectra

could be observed, signifying the formation of unstable Z-(S)-1. Interestingly,

isomerization could also be achieved with visible light of wavelengths up to 455 nm, albeit

with a lower PSS, which is most likely due to the stronger absorption of the unstable

isomer at longer wavelengths. Heating the sample to 60 °C leads to a blue shift of the

band as unstable-Z is converted to stable-Z. The helicity is inverted in this step and as a

consequence the sign of the CD absorption belonging to the * band is changed.

Subsequent irradiation of this sample at 365 nm yields the unstable E-isomer, which is

again accompanied by a characteristic bathochromic shift. The unstable E-isomer has the

opposite CD sign as the starting stable E-isomer, which is expected as they have opposite

helicity. Heating the sample to 100 °C completes the cycle, i.e. stable E is formed, which is

accompanied by a hypsochromic shift.

55


Figure 3.4.Normalized UV/vis spectra of 1 (top left), 2 (top right), 3 (bottom left) and 4

(bottom right) in different solvents.

Figure 3.5. Comparison of the DFT calculated spectrum of E-(S)-1 with the experimentally

obtained spectrum.

56

Chapter 3

Figure 3.6 CD and UV/vis spectra of the isomers in the rotation cycle of motor (S)-1 in

DMSO.

UV/vis studies of motor 2 showed the same spectral changes as for motor 1, with a

bathochromic shift upon irradiation of the stable E isomer (Figure 3.7). In this case,

isomerization was observed upon irradiation with wavelengths up to 505 nm, well into the

visible region. Characterization of the isomerization behavior of motor 4 with UV/vis is

more challenging due to its fast THI steps. Nonetheless, a bathochromic shift could be

observed upon irradiation with wavelengths up to max= 455 nm at -30 °C, most likely

originating from the unstable E isomer (Figure 3.7). The unstable Z isomer undergoes THI

which is too fast to follow at -30 °C (note that the calculated half-life at -30 °C is 38 ms).

57


Figure 3.7. UV/vis spectra of rotational cycle of motor 2 in THF (c = 3.5 x 10-5

M) (left),

UV/vis spectra of stable E-4 in CH2Cl2 (c = 4.7 × 10‒5

M) at -30 °C upon irradiation with

max= 365 nm (right).

Eyring analysis was performed to determine the activation parameters of the THIs of

motors 1, 2 and 4. For compounds 1 and 2 the rate of THI was determined by following

the change in absorbance at = 470 nm. For motor 4, low temperature 1H-NMR was used

and only the barrier of from unstable E-4 to stable E-4 could be obtained as the THI of

unstable Z-4 is too fast to be measured. In each case, the rate of THI was determined at

five temperatures, after which the activation parameters were obtained by using the

Eyring equation (Table 3.2 and Figure 3.8). The Gibbs free energy barriers and half-lives of

the respective unstable states are summarized in Table 3.2. All experimentally obtained

barriers match those predicted by DFT, within a reasonable margin (≤ 3.4 kJ mol-1

). As

predicted, the barriers for THI of the unstable Z isomers is lower for both motors 1 and 2,

and as a result the THI of unstable E is the rate limiting step in the rotational cycle. These

results show that half-lives ranging from ms to days can be readily achieved by choosing

the appropriate upper half.

58

Chapter 3

Figure 3.8. Eyring plots of THI of a) Z-1, b) E-1, c) Z-2, d) E-2, e) E-4.

59


‡H (Z)

(kJ mol-1

)

‡S (Z)

(J mol-1

K-1

)

‡G (Z)

(kJ mol-1

)

t1/2 ‡H (E)

(kJ mol-1

)

‡S (E)

(J mol-1

K-1

)

‡G (E)

(kJ mol-1

)

t1/2

1 95.6

± 2.3

-22.3

± 6.9

102.2

± 0.3

50

± 7h

106.7

± 2.4

-17.1

± 6.6

111.7

± 0.5

105

± 21d

2 79.7

± 1.7

-26.9

± 6.2

87.6

± 0.1

455

± 14s

97.8

± 3.5

-12.0

± 11.0

101.3

± 0.3

35

± 5h

4 - - - - 64.6

± 3.2

-17.7

± 14.6

69.8

± 1.1

305

±148ms

Table 3.2. Gibbs free energy barriers of THI and half-lives of the respective unstable states

of motors 2-4. All values of ‡G and t1/2 are at 20 °C.

Additionally, quantum yields of the photochemical isomerization steps (s→u) were

estimated for motors 1 and 2 (Table 3.3). The rate of formation of the unstable states was

determined by following the absorption increase at = 475 upon irradiation of a sample

with a high enough concentration to absorb all incident light. To assess the efficiency of

these motors with visible light, max= 420 nm irradiation was used. The rates thus obtained

were then compared to the rate of formation of Fe2+

from potassium ferrioxalate under

identical condition to estimate the quantum yields (Table 3.3, see Experimental

Procedures for details). The quantum yield for the reverse photochemical isomerization

(u→s) could then be calculated using the PSS420 ratio and extinction coefficients at this

wavelength. The obtained quantum yields are lower than those obtained with max= 365

nm for second generation molecular motors based on overcrowded alkenes (5-20%).[38]

stable E →

unstable Z

unstable Z

→ stable E

stable Z →

unstable E

unstable E

- stable Z

1 2.3 0.67

2.1 0.32

2 1.2 0.35 3.0 0.18

Table 3.3. Quantum yields (%) of photochemical isomerization steps

3.6 Conclusions

In summary, a new, readily accessible, with easy to control rotary motion, molecular

motor based on oxindole is presented which can be driven by visible light. A four-step

rotation cycle was proposed based on DFT calculations and confirmed by a combination of

60

Chapter 3

NMR, UV/vis and CD spectroscopy. Motors with four different upper halves were easily

synthesized by a Knoevenagel condensation, allowing tuning of the half-life for THI and

the overall motor speed from the millisecond regime to multiple days. Additionally, the

oxindole scaffold provides an interesting handle for further functionalization, opening up

new possibilities for application in biology and materials science.


For general remarks regarding experimental procedures see Chapter 2.

Ketones 5-7[35]

and 8[37]

were synthesized according to literature procedures.

General procedure for the synthesis of oxindole-based motors

The appropriate ketone (0.50 mmol) was dissolved in dry THF (2 ml) under N2 atmosphere

and the solution was cooled to 0 °C. TiCl4 (0.75 mmol, 0.08 ml) was added dropwise and

the resulting suspension was stirred for 5 min. N-methyloxindole (0.75 mmol, 110 mg) in

THF (1 ml) was added and subsequently DBU (0.75 mmol, 0.11 ml) was added dropwise.

The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction

was treated with 1M aq. HCl and extracted three times with EtOAc. The combined organic

layers were washed with H2O and brine, and dried over MgSO4. The volatiles were

removed in vacuo and the residue was purified by flash column chromatography (SiO2,

pentane/EtOAc 3-10%) to yield the corresponding motor.

(E)-1-methyl-3-(3-methyl-2,3-dihydrophenanthren-4(1H)-ylidene)indolin-2-one (E-1)

Motor E-1 was isolated as a yellow solid (93 mg, 55%). 1H NMR (400 MHz, DMSO-d6) 8.00

(d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H) 7.65 (dd, J = 8.5, 1.2 Hz, 1H), 7.54 (s, 1H), 7.43 (d,

J = 16.2 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.28

(t, J = 7.1 Hz, 1H), 5.51 (d, J = 7.7 Hz, 1H), 4.83 (dq, J = 13.7, 7.0 Hz, 1H), 3.22 (s, 3H), 2.85 –

2.75 (m, 1H), 2.46 – 2.40 (m, 1H), 2.36 – 2.23 (m, 1H), 1.07 – 0.94 (m, 1H), 1.00 (d, J = 6.8

Hz, 3H). 13

C NMR (101 MHz, DMSO-d6) δ 166.6, 154.2, 142.2, 140.6, 131.6, 130.8, 129.7,

129.6, 128.7, 128.2, 127.2, 126.0, 125.2, 124.2, 122.4, 122.1, 121.2, 120.7, 107.9, 31.5,

61


28.9, 25.6, 20.7.HRMS (ESI+, m/z) Calcd for C24H22NO (M+H)+ = 340.16959, found

340.17004.

(E)-1-methyl-3-(2-methyl-2,3-dihydro-1H-benzo[f]chromen-1-ylidene)indolin-2-one (E-2)

Motor E-2 was isolated as an orange solid (79 mg, 63%). 1H NMR (600 MHz, CDCl3) δ 7.85

(d, J = 8.9 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.31 (ddd, J = 8.1, 6.8, 1.2

Hz, 1H), 7.23 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 7.10 (td, J = 7.6, 1.2 Hz,

1H), 6.78 (d, J = 7.6 Hz, 1H), 6.47 (td, J = 7.7, 1.1 Hz, 1H), 6.06 (d, J = 7.6 Hz, 1H), 5.21 (qdd,

J = 6.9, 3.7, 1.7 Hz, 1H), 4.46 (dd, J = 11.4, 3.7 Hz, 1H), 4.40 (dd, J = 11.4, 1.7 Hz, 1H), 3.33

(s, 3H), 1.26 (d, J = 6.9 Hz, 3H).13

C NMR (151 MHz, CDCl3) δ 168.2, 155.1, 149.0, 142.3,

132.9, 130.2, 128.7, 128.6, 128.2, 127.3, 125.0, 124.5, 123.7, 122.3, 121.2, 118.2, 112.8,

107.3, 72.9, 29.3, 25.8, 16.2. HRMS (ESI+, m/z) Calcd for C23H20NO2 (M+H)+ = 342.14886,

found 342.14920.

(E)-1-methyl-3-(2-methyl-2,3-dihydro-1H-benzo[f]thiochromen-1-ylidene)indolin-2-one

(E-3)

Motor E-1 was isolated as an orange solid (122 mg, 68 %). 1H NMR (400 MHz, CDCl3) δ 7.84

(d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H),

7.39 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.03 (td, J = 7.7, 1.2 Hz, 1H), 6.71 (d,

J = 7.8 Hz, 1H), 6.34 (td, J = 7.7, 1.1 Hz, 1H), 5.65 (p, J = 6.7 Hz, 1H), 5.60 (d, J = 7.8 Hz, 1H),

3.33 (dd, J = 12.1, 6.8 Hz, 1H), 3.30 (s, 3H), 2.74 (dd, J = 12.0, 6.0 Hz, 1H), 1.16 (d, J = 6.7

Hz, 3H). 13

C NMR (101 MHz, CDCl3) δ 167.9, 153.2, 142.6, 137.3, 131.6, 131.3, 130.4, 129.3,

128.7, 128.6, 127.7, 126.9, 125.5, 124.3, 124.0, 123.4, 121.9, 121.6, 107.5, 36.0, 33.4, 26.0,

18.2. HRMS (ESI+, m/z) Calcd for C23H20NOS (M+H)+ = 358.12601, found 358.12648.

(E)-1-methyl-3-(2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)indolin-2-

one (E-4)

62

Chapter 3

Motor E-1 was isolated as an orange solid (36 mg, 22%). 1H NMR (400 MHz, CDCl3) δ 7.99


7.52 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.85 (d, J = 7.8 Hz,

1H), 6.66 (t, J = 7.7 Hz, 1H), 6.39 (d, J = 7.7 Hz, 1H), 4.66 (p, J = 6.6 Hz, 1H), 3.50 (dd, J =

15.7, 5.9 Hz, 1H), 3.37 (s, 3H), 2.77 (d, J = 15.7 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H). 13

C NMR

(101 MHz, CDCl3) δ 171.4, 164.6, 153.2, 145.3, 137.5, 135.5, 135.3, 131.8, 131.5, 130.3,

130.1, 129.5, 128.3, 127.7, 126.7, 124.8, 123.2, 122.4, 109.8, 46.3, 44.2, 28.5, 22.1. HRMS

(ESI+, m/z) Calcd for C23H20NO (M+H)+ = 326.15394, found 326.15443.

(Z)-1-methyl-3-(3-methyl-2,3-dihydrophenanthren-4(1H)-ylidene)indolin-2-one (Z-1)

Motor E-1 (10 mg, 0.029 mmol) was dissolved in 20 ml CH2Cl2 and irradiated with max =

365 nm for 3 h at 5 °C. CH2Cl2 was removed in vacuo and the residue was dissolved in

EtOAc. The mixture was heated at reflux for 2 h in the dark. The volatiles were removed in

vacuo and the residue was purified by flash column chromatography (SiO2, pentane/EtOAc

3-10%) to yield motor Z-1 (5 mg, 50%) as an yellow solid. 1H NMR (600 MHz, CDCl3) δ 7.97


7.41 (t, J = 8.1 Hz, 1H), 7.38 – 7.31 (m, 3H), 7.13 (td, J = 7.7, 1.1 Hz, 1H), 6.85 (d, J = 7.7 Hz,

1H), 3.97 (h, J = 7.2 Hz, 1H), 2.73 (ddd, J = 14.3, 4.2, 2.9 Hz, 1H), 2.55 (td, J = 13.7, 4.7 Hz,

1H), 2.38 (dddd, J = 12.7, 7.7, 4.7, 2.8 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.13 (tdd, J = 13.0,

7.4, 4.2 Hz, 1H). 13

C NMR (151 MHz, CDCl3) δ 165.6, 153.5, 143.7, 139.3, 132.9, 131.9,

131.7, 129.3, 128.4, 128.3, 126.3, 125.4, 124.9, 124.5, 123.9, 123.4, 122.7, 121.6, 107.8,

35.2, 29.8, 29.7, 25.8, 20.4. HRMS (ESI+, m/z) Calcd for C24H22NO (M+H)+ = 340.16959,

found 340.16997.

(Z)-1-methyl-3-(2-methyl-2,3-dihydro-1H-benzo[f]chromen-1-ylidene)indolin-2-one (Z-2)

63


Motor E-2 (10 mg, 0.029 mmol) was dissolved in CH2Cl2 (20 ml) and the mixture was

degassed by purging with N2 for 20 min. After cooling to -50 °C, the mixture was irradiated

with max = 365 nm overnight. It was allowed to warm to room temperature and stirred for

1h. The volatiles were removed in vacuo and the residue was purified by flash column

chromatography (SiO2, pentane/EtOAc 3-10%) to yield motor Z-2 (5 mg, 50%) as an orange

solid. 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.75 (d, J

= 7.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.37 – 7.28 (m, 3H), 7.10 (t, J = 8.2 Hz, 1H), 7.04 (d, J

= 8.9 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.45 (dd, J = 11.4, 3.8 Hz, 1H), 4.33 (dd, J = 11.6, 1.9

Hz, 1H), 3.97 – 3.89 (m, 1H), 3.17 (s, 3H), 1.40 (s, 3H). 13

C NMR (151 MHz, CDCl3) δ 165.3,

153.9, 147.0, 143.3, 133.2, 132.9, 128.7, 128.3, 128.3, 126.6, 124.5, 123.7, 123.1, 123.0,

122.2, 121.5, 117.7, 113.0, 108.1, 71.4, 32.4, 26.0, 15.9. HRMS (ESI+, m/z) Calcd for

C23H20NO2 (M+H)+ = 342.14886, found 342.14934.


The photon flux of a Thorlabs model M420F2 LED was determined by measuring the

production of ferrous ions from potassium ferrioxalate as described in Chapter 2 (5.31 x

10-5

mmol photons per second).

A sample of motor 1 or 2 was irradiated with max = 420 nm light under identical conditions

as with the actinometry at a concentration high enough to absorb all incident light (Abs420

> 2). In the case of E-2, the sample was irradiated at -15 °C to prevent the THI to occur.

The formation of unstable states was monitored over time by following the absorbance

increase at = 475 nm. The molar absorptivity of the unstable states at = 475 nm was

used to calculate the concentration increase. The initial concentration increase was

plotted versus time (Figure 3.9) and the slope, the rate of formation of the unstable state,

was obtained by linear fitting to the equation y = ax + b using Origin software. The

photochemical quantum yield (s→u) was then calculated using the photon flux of this

specific light source previously determined at identical conditions in the actinometry. The

quantum yield of the reverse reaction (u→s) at = 420 nm can then be calculated using

equation 1, in which [stable]/[unstable] is the ratio of both states at PSS420 (Table 3.4).

[stable]

[unstable]=

Φ(𝑢→𝑠) 𝑢

Φ(𝑠→𝑢) 𝑠 (1)

64

Chapter 3

PSS420 (unstable/stable) 420 (stable)

(M-1

cm-1

)

420 (unstable)

(M-1

cm-1

)

E-1 51:49 2.53 x 103

8.73 x 103

Z-1 67:33 5.61 x 103

1.77 x 104

E-2 62:38 8.25 x 103

1.72 x 104

Z-2 94:6 1.60 x 104

1.66 x 104

Table 3.4. PSS ratios and molar absorptivities of motors 1 and 2 at 420 nm.

Figure 3.9 Linear fit of photochemical formation of unstable states by irradiation with =

420 nm. a) stable E-1 (c = 1.6 x 10-4

M in DMSO) b) stable Z-1 (c = 5.7 x 10-4

M in DMSO) c)

stable E-2 (c = 1.6 x 10-4

M in THF) d) stable Z-2 (c = 3.4 x 10-4

M in THF).

3.8 References

[1] V. Balzani, A. Credi, F. M. Raymo, J. F. Stoddart, Angew. Chem. Int. Ed. 2000, 39, 3348–

65


3391.

[2] K. Kinbara, T. Aida, Chem. Rev. 2005, 105, 1377–1400.


[4] E. R. Kay, D. A. Leigh, Angew. Chem. Int. Ed. 2015, 54, 10080–10088.


[6] J. P. Sauvage, P. Gaspard, Eds. , From Non-Covalent Assemblies to Molecular Machines, Wiley-VCH, Weinheim, 2010.

[7] C. J. Bruns, J. F. Stoddart, The Nature of the Mechanical Bond: From Molecules to Machines, John Wiley & Sons, Inc., Hoboken, NJ, 2016.


[9] D. Roke, S. J. Wezenberg, B. L. Feringa, Proc. Natl. Acad. Sci. U. S. A. 2018, 201712784.

[10] T. van Leeuwen, A. S. Lubbe, P. Štacko, S. J. Wezenberg, B. L. Feringa, Nat. Rev. Chem. 2017, 1, 0096.









[19] J. C. M. Kistemaker, P. Štacko, J. Visser, B. L. Feringa, Nat. Chem. 2015, 7, 890–896.


[21] M. Klok, N. Boyle, M. T. Pryce, A. Meetsma, W. R. Browne, B. L. Feringa, J. Am. Chem. Soc. 2008, 130, 10484–10485.


66

Chapter 3


[24] T. van Leeuwen, W. Danowski, S. F. Pizzolato, P. Štacko, S. J. Wezenberg, B. L. Feringa, Chem. - Eur. J. 2018, 24, 81–84.





[29] L. Greb, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 13114–13117.

[30] L. Greb, A. Eichhöfer, J. M. Lehn, Angew. Chem. Int. Ed. 2015, 54, 14345–14348.

[31] M. Guentner, M. Schildhauer, S. Thumser, P. Mayer, D. Stephenson, P. J. Mayer, H. Dube, Nat. Commun. 2015, 8406.

[32] L. A. Huber, K. Hoffmann, S. Thumser, N. Böcher, P. Mayer, H. Dube, Angew. Chem. Int. Ed. 2017, 56, 14536–14539.

[33] S. Luňák, P. Horáková, A. Lyčka, Dye. Pigment. 2010, 85, 171–176.


[35] J. C. M. Kistemaker, S. F. Pizzolato, T. van Leeuwen, T. C. Pijper, B. L. Feringa, Chem. - Eur. J. 2016, 22, 13478–13487.


[37] U. Dietrich, M. Hackmann, B. Rieger, M. Klinga, M. Leskelä, J. Am. Chem. Soc. 1999, 121, 4348–4355.


Chapter 4 Light-Gated Rotation in a Molecular Motor Functionalized with a Dithienylethene Switch

A multiphotochromic hybrid system is presented in which a light-driven overcrowded

alkene-based molecular rotary motor is connected to a dithienylethene photoswitch. Ring

closing of the dithienylethene moiety, using an irradiation wavelength different from the

wavelength applied to operate the molecular motor, results in the inhibition of the rotary

motion as is demonstrated by detailed 1H-NMR and UV/Vis experiments. For the first time,

a light-gated molecular motor is thus obtained. Furthermore, the excitation wavelength of

the molecular motor is red-shifted from the UV into the visible light region upon

attachment of the dithienylethene switch.

This chapter was published as: D. Roke, C. Stuckhardt, W. Danowski, S. J. Wezenberg, B. L.

Feringa, Angew. Chem. Int. Ed. 2018, 130, 10515-10519.

Parts of the work described in this chapter was performed by C. Stuckhardt under the

guidance of D. Roke.

68

Chapter 4

4.1 Introduction

Inspired by the wealth of molecular machines found in Nature, which drive and regulate a

wide range of processes such as muscle contraction and ATP synthesis, a large collection

of synthetic molecular machines has been developed over the last decades.[1–8]

Prominent

examples of such artificial machines include a molecular elevator,[9]

a molecular brake,[10]

a nanocar,[11]

an adaptive catalyst,[12]

a molecular walker[13]

and a synthesizer,[14]

which are

all powered by either chemical fuel, redox processes or light. The use of light as a stimulus

offers the advantage that it is non-invasive and does not produce any waste products.[6,8]

Moreover, it can be easily tuned in terms of wavelength and intensity and it can be

applied with high spatio-temporal control. These advantages have stimulated the

application of light-driven molecular switches[15]

and motors in functional materials[8,16–21]

and in biological systems.[22–25]

However, potentially harmful UV light is typically used for

their operation while, for practical applications, the use of visible light is often desired.[26–

32]

One of the major contemporary challenges in the development of light-driven switches

and motors is to design systems that can be controlled by more than one stimulus,

offering a higher level of control. Gated photochromism, which is the ability to turn

photoswitching processes on and off using a stimulus that is complementary to light,

provides such control. Different stimuli have been used in the past to achieve gated

photochromic systems, for example by ion complexation,[33–36]

pH change,[37,38]

redox

processes[39–41]

or host-guest interactions.[42]

We envisioned that the use of light, of a

different wavelength than the wavelength that is used for photoswitching, could be a

viable alternative. However, to our best knowledge, no successful examples of light-gated

photochromism have been reported so far, which is most probably due to a lack of

orthogonality.[43]

Light-driven molecular motors based on overcrowded alkenes represent unique

photoresponsive systems in the sense that they undergo unidirectional rotation around

their central double bond (Scheme 4.1 a) Full 360° rotary cycle of molecular motors 1 and

2 (note that the isomer generated after 180° rotation is identical to the starting isomer,

but has a different viewpoint). b) Representation of light-gated rotary motion via

switching between the open and closed form of the appending DTE moiety.a).[44–46]

Promising applications have been demonstrated in nanotechnology,[11,47,48]

catalysis[12,49]

and anion binding,[50,51]

amongst others. Unidirectional rotation is achieved by sequential

photochemical E-Z-isomerization and thermal helix inversion steps (Scheme 4.1a). In the

first step, an unstable isomer is generated photochemically in which the methyl-

substituent at the stereocentre adopts an energetically unfavored pseudo-equatorial

orientation. The strain that is built up around the double bond is subsequently released

by a thermal helix inversion (THI) process, in which the aromatic moieties of the upper and

lower half slide along each other. After this thermal step, the thermodynamically favored

69

Light-Gated Rotation in a Molecular Motor Functionalized with a Dithienylethene Switch

pseudo-axial orientation of the methyl group is restored. A second photochemical E-Z-

isomerization, followed by a THI, completes a full 360° rotation.

Scheme 4.1 a) Full 360° rotary cycle of molecular motors 1 and 2 (note that the isomer

generated after 180° rotation is identical to the starting isomer, but has a different

viewpoint). b) Representation of light-gated rotary motion via switching between the open

and closed form of the appending DTE moiety.

Several approaches have been taken to dynamically control the rotary behavior of

molecular motors with a second stimulus, all of which required chemical additives.

Illustrative examples are the locking of rotation using an acid-base responsive self-

complexing pseudorotaxane[52]

and the reversal of the rotary direction by base-catalyzed

epimerization.[53]

More recently, we reported an allosteric approach in which the

rotational speed can be regulated by metal complexation.[54]

Whereas all of these

approaches rely on chemical additives, we considered the development of a non-invasive

approach an important next step. We now present the first example in which the rotary

behavior of a light-driven molecular motor can be controlled by an additional light source.

70

Chapter 4

In our design, a second generation molecular motor is connected to a dithienylethene

(DTE) switch to give a multiphotochromic hybrid system (Scheme 4.1b). Interestingly, the

molecular motor can be operated with visible light (irr = 455 nm) instead of the generally

used UV light. Upon closing of the DTE switch by UV light (irr = 312 nm), the rotation of

the molecular motor is inhibited, a process which can be reversed by irradiation with light

of a longer wavelength (irr = 528 nm), which opens the switch.

4.2 Synthesis

For the synthesis of target molecule 2, the molecular motor moiety was first synthesized

using a Barton-Kellogg reaction (Scheme 4.2). Coupling partners diazo 3 and thioketone 4

were freshly prepared following literature procedures.[47,55]

For the synthesis of the DTE

switch moiety, unsymmetric dithienylethene 6 was first synthesized according to literature

procedures.[56]

Due to the poor reactivity of chlorides in Sonogashira coupling reactions,

the chloride was first exchanged for an iodide by lithium-halogen exchange followed by

quenching with iodine. The TMS protected acetylene moiety could then be installed using

a Sonogashira coupling, yielding switch 8. Subsequent TMS deprotection followed by a

second Sonogashira coupling with bromo-substituted motor 5 afforded hybrid 2.

71


Scheme 4.2 Synthetic route towards hybrid 2.

4.3 1H-NMR and UV/vis studies

The possible photochemical and thermal isomerization steps of 2, as illustrated in Scheme

4.3, were first followed by 1H-NMR spectroscopy. Figure 4.1i shows the

1H-NMR spectrum

of the stable open (so) isomer of hybrid 2 in CD2Cl2. Upon irradiation at 455 nm at ‒25 °C,

a new species appeared (Figure 4.1ii). In analogy to the unsubstituted parent motor 1,[57]

the clear shifts of 1H-NMR signals Ha, Hc and Hc’ are characteristic for the photochemically

induced formation of the unstable 2uo (Scheme 4.3). Moreover, the doublet signal for Hd

has a clearly distinct chemical shift for each isomer. The sample was irradiated until no

further changes were observed, that is, the photostationary state had been reached. The

ratio of unstable:stable at this photostationary state (PSS455) was found to be 66:34. When

the sample was warmed up to room temperature, the THI was allowed to take place,

resulting in quantitative conversion to the stable state (that is, isomer 2so). The same

NMR sample was then irradiated at 312 nm at room temperature to isomerize the DTE

moiety to its closed isomer 2sc (Figure 4.1iii). The expected formation of isomer 2sc was

evident from the shifts of protons He, belonging to the methyl substituents of the

72

Chapter 4

thiophene moieties, and proton Hd. At the PSS312, the ratio of closed:open isomer was

found to be approximately 70:30.[58]

The sample was subsequently irradiated at 455 nm at

‒25 °C to test whether the closed hybrid 2sc could be isomerized to the unstable state 2uc

(Figure 4.1iv). If isomerization would be allowed, the unstable 2uc should be observed

beside the unstable 2uo, which are the photochemical isomerization products of 2sc and

2so respectively, which were present in a 70:30 ratio. After irradiation the sample

contained 2uo, but 2uc was absent, revealing inhibition of isomerization in the closed

form. It should be noted that at the same time also some opening of the DTE switch

occurs when the sample is irradiated at 455 nm which is unusual for DTE switches at this

wavelength. The rate of the opening of the DTE switch is, however, significantly lower

than when the sample is irradiated at 528 nm.

Figure 4.1. 1H-NMR spectra of 2 in CD2Cl2. (i) before irradiation; (ii) PSS 455 nm; (iii) PSS

312 nm; (iv) sample of iii irradiated at 455 nm; (v) sample of ii irradiated at 312 nm.

73


The unstable closed isomer 2uc could be accessed via another route. That is, by first

irradiating a sample of 2so at 455 nm at ‒25 °C, to give isomer 2uo, and subsequently at

312 nm at the same temperature to close the DTE switch (Scheme 4.3). Figure 4.1v

corresponds to this experiment and reveals a fourth doublet of Hd belonging to the

unstable closed isomer. Allowing the sample to warm up to room temperature leads to

quantitative conversion of 2uc back to 2sc and of the remaining 2uo back to 2so. These

combined NMR experiments reveal that the motor functions as usual when the DTE switch

is in the open state, but that rotation is impeded when it is closed. Thus, the rotary

function can be controlled by light of a different wavelength than the wavelength that is

used to operate the molecular motor. This gated photochromic behavior is most likely due

to an energy transfer process from the motor to the DTE moiety in analogy to other

multiphotochromic systems.[43,59]

Scheme 4.3 Photochemical and thermal isomerization steps of hybrid 2.

The isomerization behavior of hybrid 2 was additionally studied by UV/Vis spectroscopy.

The UV/Vis spectrum of a solution of 2so in CH2Cl2 shows an absorption band with a

maximum at = 423 nm (Figure 4.2). This absorption band is bathochromically shifted

compared to the parent unsubstituted molecular motor 1, which has an absorption

maximum at = 395 nm.[56]

Most likely, this bathochromic shift is caused by the extension

of the π system. Aromatic extension has been shown before to be suitable to shift the

excitation wavelength of molecular motors into the visible light region.[60]

74

Chapter 4

Figure 4.2 a) UV/Vis spectra of hybrid 2 upon irradiation at 455 nm. b) Eyring plot analysis

of the thermal isomerization step from unstable to stable 2. c) UV/vis spectra of hybrid 2

upon irradiation at 455 nm (-9 °C) followed by 312 nm (-9 °C) and 528 nm (20 °C). c) after

irradiation at 312 nm (20 °C) followed by 455 nm (-9 °C) and 528 nm (20 °C).

Upon irradiation of a UV/Vis sample of 2so with 455 nm light at ‒9 °C a bathochromic shift

was observed (Figure 4.2a,), which is characteristic for the formation of the unstable

isomer 2uo.[57]

A clear isosbestic point at = 447 nm revealed that this photochemical

isomerization is a unimolecular process. The quantum yield for this photochemical step

(so→uo) was estimated by comparing the rate of formation of 2uo, which was determined

by following the absorption increase at = 505 nm at a concentration high enough to

absorb all incident light, with that of Fe2+

ion formation from potassium ferrioxalate, under

identical conditions (see Experimental Procedures for details). A quantum yield of so→uo =

5.6% was measured and the quantum yield for the reverse photochemical isomerization

step (uo→so) was then calculated using the PSS455 ratio, giving uo→so = 3.3%. These values

are in similar range as the quantum yields that have been measured for structurally

related molecular motors with and without substituents in the same position.[61]

When the

UV/Vis sample was allowed to warm to room temperature, the original spectrum was

recovered, indicating that the THI had taken place. The rates for this thermal

isomerization step were determined at five different temperatures (ranging from 0 to 20

75


°C) by monitoring the decrease in absorption at 500 nm. Using the Eyring equation

(Figure 4.2b), the activation parameters for this process were determined (⧧H = 74.9 ±

1.7 kJ mol-1

; ⧧S = -41.5 ± 5.9 J mol-1

K-1

). The Gibbs free energy barrier (Δ⧧G(20 °C)) was

found to be 87.1 ± 0.1 kJ mol‒1

, corresponding to a half-life (t1/2(20 °C)) of 370 s. These

values are in the same order of magnitude as the ones determined for the unsubstituted

parent molecular motor 1, for which an energy barrier of 85 kJ mol‒1

and a half-life of 190

s have been reported.[57]

Moreover, multiple cycles of these photochemical and thermal

isomerization steps could be performed without any major signs of fatigue.

When a UV/vis sample of 2so was first irradiated at 312 nm at 20 °C, a broad band around

max = 602 nm appeared (Figure 4.2c, green line). This band is characteristic for the

formation of the closed, more conjugated isomer of the DTE switch (isomer 2sc),[58]

of

which the formation was also observed by 1H-NMR spectroscopy (vide supra). This closed

state of the DTE switch is thermally stable under the experimental conditions used and

multiple close/open isomerization cycles showed only minor signs of fatigue. Subsequent

irradiation of this sample, containing a mixture of 2so and 2sc, at 455 nm at ‒9 °C caused

relatively small changes in the absorption band located around max = 423 nm. The broad

band in the visible region decreased, revealing some concomitant opening of the DTE

switch. These results are fully consistent with the 1H-NMR studies, showing that only the

open isomer 2so is able to undergo E-Z-isomerization whereas this process is inhibited for

the closed isomer 2sc. Subsequent irradiation at 528 nm triggered almost quantitative

opening of the DTE switch as is clear from the disappearance of the absorption around

max = 602 nm.

As also described for the 1H-NMR studies, isomer 2uc could be accessed by irradiation of a

sample containing 2so at 455 nm to afford 2uo, followed by irradiation at 312 nm,

showing the emergence of a broad band in the visible region (Figure 4.2d, red line). The

emergence of this band is indicative of the formation of the closed DTE moiety. Again,

opening of the DTE switch could be triggered by irradiation at 528 nm.

4.4 Conclusions

In summary, we have presented a photochromic hybrid system consisting of an

overcrowded alkene-based molecular motor and a DTE switch. Interestingly, by aromatic

extension, the excitation wavelength is red-shifted into the visible region. Visible light

excitation leads to the usual rotary motor behavior when the DTE is in the open form.

However, when closed, the rotary motion is inhibited and thus, light-gated

photochromism is observed. This is the first system in which the rotary function can be

switched on and off in a non-invasive manner by using an additional light source. Gated

systems, like the one presented here, offer an increased level of control over

photoswitching processes, which will prove essential for the development of more

complex and sophisticated molecular machinery in the future. Studies on the exact

76

Chapter 4

mechanism of the inhibition of the rotary motion by the closed isomer of the DTE switch,

which require detailed investigation of the electronic coupling of both photochromes,[59]

are underway in our lab.



Compounds 3,[55]

4,[47]

and 6[62]

were synthesized according to literature procedures and

all spectroscopic properties were in agreement with reported spectra.

9-(5-bromo-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ylidene)-9H-fluorene

(5)

Freshly prepared diazo compound 3 (405 mg, 2.11 mmol) and thioketone 4 (613 mg, 2.11

mmol) were dissolved in dry toluene (80 ml) under N2 atmosphere in a flame-dried

Schlenk flask and stirred overnight at rt. HMPT (0.44 ml, 2.41 mmol) was added and the

resulting mixture was stirred for 3h at 50 °C. The volatiles were evaporated and the

residue was purified using column chromatography (SiO2, pentane/EtOAc 20:1) followed

by layered crystallization with CH2Cl2/MeOH to yield 5 (520 mg, 57%) as yellow crystals.

M. p. 213 °C; 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 8.6 Hz, 1H), 7.98 – 7.94 (m, 1H), 7.92

(s, 1H), 7.86 – 7.81 (m, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.57 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.43

– 7.38 (m, 2H), 7.36 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.22 (td, J = 7.5, 1.0 Hz, 1H), 6.79 (td, J =

7.6, 1.2 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.34 (m, 1H), 3.58 (dd, J = 15.1, 5.7 Hz, 1H), 2.74

(d, J = 15.2 Hz, 1H), 1.39 (d, J = 6.7 Hz, 3H); 13

C NMR (101 MHz, CDCl3): δ 149.9, 147.5,

140.3, 139.9, 139.8, 137.1, 136.8, 131.3, 131.0, 130.8, 128.4, 128.1, 128.0, 127.5, 127.4,

127.3, 127.2, 126.9, 126.2, 125.9, 125.5, 124.3, 119.9, 119.2, 45.6, 41.8, 19.4; HRMS

(APCI+, m/z): Calcd for C27H20Br [M+H+]: 423.07429, found: 423.07431.

3-[3,3,4,4,5,5-Hexafluoro-2-(2-methyl-5-phenyl-3-thienyl)-1-cyclopenten-1-yl]-5-iodo-2-

methylthiophene (7)

77


Under a N2 atmosphere, dithienylethene 6 (50 mg, 0.10 mmol, 1.0 equiv.) was dissolved in

dry THF (2 mL) in a flame dried schlenk tube and the mixture was cooled to –78 °C. t-Butyl

lithium (1.9 M in hexane, 0.12 mL, 0.23 mmol, 2.2 equiv.) was slowly added and the

mixture was stirred for 45 min at the same temperature. Then, iodine (58.4 mg,

0.23 mmol, 2.2 equiv.) was added and the mixture was stirred for 45 min at –78 °C and

then at rt for a further 30 min. The mixture was diluted with CH2Cl2 and the organic layer

was washed with water, Na2S2O3 and brine. The organic phase was dried (MgSO4) and

volatiles were removed in vacuo The residue was purified using column chromatography

(SiO2, pentane) to give aryl iodide 7 (53 mg, 90%) as a blue oil. 1H-NMR (400 MHz, CDCl3):

δ 7.54 (dd, J = 7.4, 1.6 Hz, 2H), 7.39 (dd, J = 7.6, 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 (s,

2H), 1.95 (s, 3H), 1.93 (s, 3H). 19

F NMR (376 MHz, CDCl3): δ -110.16 (t, J = 5.5 Hz), -131.90

(p, J = 5.6 Hz).

Spectroscopic data are in agreement with those reported in the literature.[56]

3-[3,3,4,4,5,5-Hexafluoro-2-(2-methyl-5-phenyl-3-thienyl)-1-cyclopenten-1-yl]-2-methyl-

5-trimethylsilylethynylthiophene (8)

Under a N2 atmosphere, aryl iodide 7 (40 mg, 0.07 mmol, 1.0 equiv.), tetrakis(triphenyl-

phosphine)palladium(0) (6.0 mg, 5.3 μmol, 0.075 equiv.), copper(I) iodide (1.0 mg, 5.3

μmol, 0.075 equiv.) and triethylamine (3 mL) were placed into a Schlenk flask and the

mixture was degassed. Then, trimethylsilylacetylene (20 μL, 0.014 mmol, 2.0 equiv.) was

added and the mixture was stirred at 70 °C overnight in the dark. The progress of the

reaction was followed by TLC and once the reaction was completed, the mixture was

diluted with EtOAc and washed with aq. NH4Cl, water and brine. The organic phase was

dried (MgSO4) and concentrated in vacuo. The residue was purified using column

chromatography (SiO2, pentane) to give alkyne 8 (30 mg, 79%) as a blue oil. 1H-NMR (400

MHz, CDCl3): δ 7.56 – 7.51 (m, 2H), 7.39 (dd, J = 8.4, 6.8 Hz, 2H), 7.34 – 7.28 (m, 1H), 7.25

(s, 2H), 1.93 (s, 3H), 1.89 (s, 3H), 0.25 (s, 9H). 19

F NMR (376 MHz, CDCl3): δ -110.2 (s), -

131.9 (s).

Spectroscopic data are in agreement with those reported in the literature.[56]

5-Ethynyl-3-[3,3,4,4,5,5-hexafluoro-2-(2-methyl-5-phenyl-3-thienyl)-1-cyclopenten-1-yl]-

2-methylthiophene (9)

78

Chapter 4

Alkyne 8 (30 mg, 55.4 μmol, 1.0 equiv.) was dissolved in THF (1 mL), potassium hydroxide

(100 mg, 1.78 mmol, 32 equiv.), water (1 mL) and MeOH (1.5 mL) were added and the

mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2 and

the organic layer was washed with water and brine. The organic phase was dried (MgSO4)

and concentrated in vacuo to give alkyne 9 (25 mg, quant) as a purple oil. 1H-NMR (400

MHz, CDCl3): δ 7.53 (dd, J = 7.6, 1.6 Hz, 2H), 7.38 (dd, J = 8.4, 6.8 Hz, 2H), 7.34 – 7.29 (m,

1H), 7.27 (s, 1H), 7.24 (s, 1H), 3.35 (s, 1H), 1.93 (s, 3H), 1.92 (s, 3H); 19

F NMR (376 MHz,

CDCl3): δ -110.23 (t, J = 5.7 Hz), -131.91 (p, J = 5.1 Hz); 13

C NMR (101 MHz, CDCl3) δ (16

signals were observed, signals of the central perfluorocyclopentene are not observed as is

commonly found in the literature[56]

) 143.8, 142.7, 141.4, 133.4, 132.9, 129.2, 128.1,

125.8, 125.7, 125.0, 122.3, 120.5, 82.3, 76.0, 14.7, 14.6. HRMS (APCI+, m/z): Calcd for

C23H15F6S2 [M+H+]: 469.05139 found: 469.05060.

5-((1-(9H-fluoren-9-ylidene)-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-5-

yl)ethynyl)-2-methyl-3-(3,3,4,4,5,5-hexafluoro-2-(2-methyl-5-phenylthiophen-3-

yl)cyclopent-1-en-1-yl)thiophene (2)

Compound 5 (14 mg, 32 μmol, 1.0 equiv.), alkyne 9 (15 mg, 32 μmol, 1.0 equiv.), and

triethylamine (2 mL) were placed into a Schlenk flask under N2 atmosphere and the

mixture was degassed. Then, tetrakis(triphenyl-phosphine)palladium(0) (2.0 mg, 1.6 μmol,

0.05 equiv.) and copper(I) iodide (0.30 mg, 1.6 μmol, 0.05 equiv.) were added and the

mixture was stirred at 70 °C in the dark overnight. The mixture was diluted with CH2Cl2

and the organic layer was washed with aq. NH4Cl, water and brine. The organic phase was

dried (MgSO4) and concentrated in vacuo. The residue was purified using column

chromatography (SiO2, pentane) to give hybrid 2 (20 mg, 77%) as a yellow solid. m.p. 145

°C (dec.); 1H-NMR (400 MHz, CDCl3): δ 8.46 (d, J = 8.4 Hz, 1H), 8.02 – 7.94 (m, 1H), 7.87 –

79


7.82 (m, 3H), 7.76 (d, J = 7.5 Hz, 1H), 7.55 – 7.62 (m, 3H), 7.45 – 7.28 (m, 8H), 7.22 (t, J =

7.4 Hz, 1H), 6.82 – 6.75 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 4.31 – 4.39 (m, 1H), 3.57 (dd, J =

15.1, 5.7 Hz, 1H), 2.77 (d, J = 15.1 Hz, 1H), 2.02 (s, 3H), 2.00 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H); 19

F NMR (376 MHz, CDCl3): δ -110.08 (t, J = 5.5 Hz), -110.15 (t, J = 5.5 Hz), -131.85 (tt, J =

5.5 Hz); 13

C NMR (101 MHz, CDCl3) δ (43 signals were observed, signals of central

perfluorocyclopentene are not observed as is commonly found in literature[56]

) 150.2,

146.3, 144.0, 142.7, 141.5, 140.4, 139.9, 139.8, 138.0, 137.1, 133.4, 132.4, 131.9, 131.8,

129.8, 129.2, 128.3, 128.1, 128.1, 127.4, 127.4, 127.3, 127.2, 126.9, 126.5, 126.2, 126.0,

125.8, 125.8, 125.5, 124.4, 122.4, 122.3, 121.8, 119.9, 119.2, 93.1, 88.1, 45.4, 41.8, 19.4,

14.8, 14.7. HRMS (APCI+, m/z): Calcd for C50H33F6S2 [M+H+]: 811.19224, found: 811.19286.


The photon flux of the Thorlabs M455F1 LED was estimated by measuring the production

of ferrous ions from potassium ferrioxalate.[63]

0 10 20 30 40 50 60

0.0

1.0x10-3

2.0x10-3

3.0x10-3

concentration difference

linear fit

[F

e2

+ io

n] / M

Time / s




Delta conc Intercept -1.11873E-5 5.54379E-5

Delta conc Slope 4.81244E-5 1.53757E-6

Figure 4.3 Linear fit of the photochemical formation of Fe2+

ions over time by irradiation

with max = 455 nm. The slope, obtained from the linear fit, corresponds to the rate of

formation of Fe2+

ions (4.81 x 10-5

M s-1

or 9.62 x 10-5

mmol s-1

).

A sample of 2so was irradiated with max = 455 nm light under identical conditions as with

the actinometry at a concentration high enough to absorb all incident light (Abs455 > 2, c =

6.9 x 10-5

M). The formation of 2uo was monitored over time by following the absorbance

increase at = 505 nm. The molar absorptivity of 2uo at = 505 nm ( = 2.17 x 104 m

-1 cm

-

1) was used to calculate the concentration increase. The initial concentration increase was

plotted versus time and the slope, the rate of formation of 2uo, was obtained by linear

fitting to the equation y = ax + b using Origin software. The photochemical quantum yield

80

Chapter 4

of 2so (so-uo = 6.3%) was then calculated using the photon flux of this specific light source

previously determined at identical conditions in the actinometry. The quantum yield of

the reverse reaction at = 455 nm (so-uo = 3.3%) can then be calculated using equation 1,

in which [2so],[2uo] are the concentrations at PSS455.

[𝟐𝐬𝐨]

[𝟐𝐮𝐨]=

𝜙(𝑢𝑜→𝑠𝑜) 𝑢𝑜

𝜙(𝑠𝑜→𝑢𝑜) 𝑠𝑜 (eq. 1)

0 1 2 3 4 5 6

6.0x10-6

1.2x10-5

1.8x10-5

concentration difference

Linear fit

[2so

] / M

time (s)




delta conc Intercept 4.62265E-6 4.95553E-7

delta conc Slope 2.77755E-6 1.27246E-7

Figure 4.4 Linear fit of the photochemical formation of 2so over time by irradiation max =

455 nm. The slope, obtained from the linear fit, corresponds to the rate of formation 2so

(2.78 x 10-6

M s-1

or 5.56 x 10-6

mmol s-1

).

4.6 References

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[13] D. A. Leigh, U. Lewandowska, B. Lewandowski, M. R. Wilson, Top. Curr. Chem. 2014, 354, 111–138.

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[30] N. M.-W. Wu, M. Ng, W. H. Lam, H.-L. Wong, V. W.-W. Yam, J. Am. Chem. Soc. 2017, 139, 15142–15150.

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[32] C.-C. Ko, V. W.-W. Yam, Acc. Chem. Res. 2018, 51, 149–159.

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[34] C.-T. Poon, W. H. Lam, V. W.-W. Yam, J. Am. Chem. Soc. 2011, 133, 19622–19625.

[35] Y. Wu, S. Chen, Y. Yang, Q. Zhang, Y. Xie, H. Tian, W. Zhu, Chem. Commun. 2012, 48, 528–30.

[36] S. Wang, X. Li, W. Zhao, X. Chen, J. Zhang, H. Ågren, Q. Zou, L. Zhu, W. Chen, J. Mater. Chem. C 2017, 5, 282–289.

[37] F. Pina, M. J. Melo, M. Maestri, R. Ballardini, V. Balzani, J. Am. Chem. Soc. 1997, 119, 5556–5561.

[38] G. Szalóki, G. Sevez, J. Berthet, J.-L. Pozzo, S. Delbaere, J. Am. Chem. Soc. 2014, 136, 13510–13513.

[39] S. H. Kawai, S. L. Gilat, R. Ponsinet, J. M. Lehn, Chem. Eur. J. 1995, 1, 285–293.

[40] M. C. Moncada, A. J. Parola, C. Lodeiro, F. Pina, M. Maestri, V. Balzani, Chem. - Eur. J. 2004, 10, 1519–1526.

[41] L. Kortekaas, O. Ivashenko, J. T. van Herpt, W. R. Browne, J. Am. Chem. Soc. 2016, 138, 1301–1312.

[42] M. Lohse, K. Nowosinski, N. L. Traulsen, A. J. Achazi, L. K. S. von Krbek, B. Paulus, C. A. Schalley, S. Hecht, B. Kirchner, C. A. Schalley, Chem. Commun. 2015, 51, 9777–9780.

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[44] N. Koumura, R. W. Zijlstra, R. A. van Delden, N. Harada, B. L. Feringa, Nature 1999, 401, 152–155.

[45] N. Koumura, E. M. Geertsema, A. Meetsma, B. L. Feringa, J. Am. Chem. Soc. 2000, 122, 12005–12006.

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83


[50] S. J. Wezenberg, M. Vlatković, J. C. M. Kistemaker, B. L. Feringa, J. Am. Chem. Soc. 2014, 136, 16784–16787.

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[58] Irradiation with 312 nm also causes isomerization of the molecular motor to form isomer 2uo. The THI is however relatively fast at this temperature and as a result only the stable isomer is observed.

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Chapter 5 Photoresponsive supramolecular coordination cage based on overcrowded alkenes

Supramolecular coordination cages with a Pd2L4 composition are formed using molecular motors based on overcrowded alkene as a ligand. Characterization of these cages with NMR, HRMS, CD and X-Ray shows that the cages self-sort into homochiral assemblies, which are energetically favored over the diastereomeric complexes as shown by DFT calculations. The photochromic ligands can be switched between three states, each of them having the potential of forming discrete cage complexes, allowing cage-to-cage transformation. Moreover, the complexes were shown to bind a tosylate anion in their cavity.

This chapter will be published as: C. Stuckhardt, D. Roke, W. Danowski, S. J. Wezenberg, B. L. Feringa, manuscript in preparation

The experimental work described in this chapter was performed by C. Stuckhardt as a part

of his Master’s thesis under the guidance of D. Roke.

86

Chapter 5

5.1 Introduction

Supramolecular coordination complexes (SCC’s) represent an exciting class of compounds

which have been used in sophisticated molecular systems.[1–6]

Making use of the vacant

cavity inside these complexes, SCC’s have found applications for drug delivery,[6–8]

supramolecular catalysis,[9–12]

X-ray structure determination[13,14]

and stabilization of

reactive guests.[15–17]

The use of reversible and hence dynamic bonds in supramolecular

chemistry gives rise to systems that allow for error correction, a necessity for self-

sorting,[18–20]

and for adaption to external stimuli such as pH, anions, electric potential,

concentration and light.[4,8,21–24]

Using light to control the shape and function of SCCs is a

very promising strategy as light is a non-invasive stimulus that can be easily controlled in a

spatial and temporal manner as well as in terms of intensity and wavelength, without

producing any waste. The field of photoswitchable SCC’s is, however, underdeveloped.

Systems have been reported where photoisomerization of azobenzene-derived anions

encapsulated in supramolecular palladium complexes caused immediate crystallization.[25]

Moreover, azobenzenes have been used to functionalize both the interior[26]

and

exterior[27]

of SCC’s to photochemically control guest binding and release. Incorporation of

photoswitches into the backbone of the ligands has only been shown with

dithienylethenes, which can be switched between an open and a closed state.[28–30]

These

ligands were used to control host-guest interactions,[31]

structural composition of

coordination cages[32]

and sol-gel transitions.[33]

However, up to now, these are the only

examples of SCCs bearing photoswitchable ligands in the backbone and they are limited to

the use of dithienylethene switches. Introducing photoswitches that have a larger

geometric change upon switching has the potential to induce larger changes in properties.

Employing molecular motors as ligands in SCCs is therefore an interesting strategy, as they

feature a large geometric change upon switching and have the potential to induce chirality

in the complex.[34]

Herein, we report a new photochromic coordination cage with ligands based on molecular

motors (Scheme 5.1a). Cages with a Pd2L4 composition are formed from bent bidentate

bispyridyl ligands and Pd(II) ions with a square planar geometry, which have been widely

studied.[6,35–37]

The photochromic ligands can be switched between three states, each of

them having the potential of forming separate discrete cage complexes, allowing cage-to-

cage transformations (Scheme 5.1b). Moreover, the assemblies were found to be self-

sorting, as only homochiral cages are formed. In addition, two of the cage isomers can

bind a tosylate anion in solution by formation of a host-guest complex.

87

Photoresponsive supramolecular coordination cage based on overcrowded alkenes

Scheme 5.1 a) Schematic representation of a photoresponsive cage with ligands based on

overcrowded alkenes. b) Cage formation of overcrowded alkene switches 1 and 2 and their

isomerization behavior.

5.2 Ligand synthesis and characterization

Ligands Z-1a and E-2a were synthesized by a Suzuki cross-coupling reaction of 3-

pyridinylboronic acid with an E/Z mixture of reported overcrowded alkene precursors

(Scheme 5.2).[38]

The E and Z isomers were readily separated by column chromatography

and identified using 2D NOESY NMR spectroscopy. Enantiopure ligands were synthesized

in the same manner, starting from enantiopure motor 7, which was prepared according to

literature procedures.[38]

88

Chapter 5

Scheme 5.2. Synthesis of overcrowded alkene-based ligands Z-1a and E-2a.

The photochemical and thermal isomerization steps of ligands Z-1a and E-2a were

characterized by detailed 1H-NMR studies (Figure 5.1), revealing the same behavior as

structurally related molecular motors.[39]

When a sample of stable Z-1a was irradiated at

312 nm at -55 °C, a new set of signals appeared, belonging to unstable E-2b (Figure 5.1ii).

This can be seen most clearly for the signals of the protons on the central five membered

ring (Ha-c). The sample was irradiated until no further changes were observed, and at this

photostationary state (PSS) the ratio of E-2b to Z-1a was 91:9. When allowing this sample

to warm to room temperature, this photogenerated isomer undergoes a thermal helix

inversion (THI), quantitatively forming stable E-2a. An Eyring analysis was performed to

obtain the activation parameters for this process. The THI was followed at five different

temperatures ranging from -46 to -26 °C using NMR spectroscopy. A Gibbs free energy

barrier of 72.9 kJ mol-1

was obtained (Table 5.1), slightly lower than the barrier reported

for the unsubstituted parent motor (‡G = 80 kJ mol

-1).

[40]

89


Figure 5.1. 1H-NMR spectrum of switching cycle of ligand 1 in CD2Cl2 at -55 °C. i) Stable Z-

1a. ii) PSS 312, unstable E-2b. iii) THI, stable E-2a.

When a 1H-NMR sample of E-2a was irradiated at 312 nm in CD2Cl2, the formation Z-1b

could be observed (Figure 5.2). A slightly lower PSS ratio is obtained at this step: 77:23.

Leaving this sample for 5 days at room temperature leads to the formation of Z-1a

through a THI process. The activation parameters for this step were determined using an

Eyring analysis as well. The THI of Z-1b to Z-1a was followed with UV/vis spectroscopy, by

monitoring the increase in absorption at = 320 nm of a sample in heptane at five

different temperatures ranging from 60 to 90 °C. A Gibbs free energy barrier of 101 kJ mol-

1 was obtained (Table 5.1), slightly higher than the barrier reported for the unsubstituted

parent motor (93 kJ mol-1

).[40]

Figure 5.2. 1H-NMR spectra of switching cycle of ligand 2 in CD2Cl2. i) stable E-2a ii) PSS 312

nm, unstable Z-1b. iii) THI, stable Z-1a.

‡H (kJ mol

-1)

‡S (J mol

-1 K

-1)

‡G (kJ mol

-1)

E-2b 70.5 ± 2.4

-6.7 ± 10 72.9 ± 0.5

Z-1b 67.7 ± 2.0 -106 ± 5.6 101 ± 0.1

90

Chapter 5

Table 5.1. Activation parameters for the THI of isomers E-2b and Z-1b. Values are given at

20 °C.

5.3 Cage formation and characterization

Heating a 2:1 mixture of racemic ligands Z-1a or E-2a with Pd(NO3)2 in acetonitrile at reflux

lead to the quantitative formation of cage 3 or 4, respectively, as evidenced by 1H NMR,

DOSY and HRMS. The 1H-NMR signals of the pyridine moieties of the ligands (Ha-d) in the

assembled cages are shifted downfield compared to those of the free ligands, as expected

due to metal coordination (Figure 5.3).[31]

As the ligand exchange in Pd2L4 complexes is

slow on the NMR timescale, the discrete signals do not represent an average of quickly

interconverting isomers.[41,42]

Using a racemic mixture of ligands, four different

diastereomeric cages can be formed ((S,S)4, (S,S)3(R,R), (S,S)2(R,R)2 and (S,S)(R,R)(S,S)(R,R)

and their enantiomeric pairs). However, in both cases, only one set of signals is observed,

which is a strong indication that only one species with high symmetry is formed by chiral

self-sorting without any sign of the formation of diastereomeric mixtures. The formation

of cage complexes using enantiopure ligands (S,S)-Z-1a or (S,S)-E-2a, resulted in the exact

same 1H-NMR spectrum as was obtained with the racemic ligands, indicating that the

racemic ligands also form homochiral cages.

Figure 5.3. Aromatic region of stacked 1H-NMR spectra (in CD3CN) of Z-1a and cage 3 (top)

and E-2a and cage 4 (bottom).

Additionally, DOSY NMR spectroscopy revealed that the signals correspond to a single

type of assembly in each case (Figure 5.4). The measured diffusion coefficients (D =

8.7 · 10-10

m2 s

-1 for cage 3 and D = 7.9 · 10

-10 m

2 s

-1 for cage 4 in CD3CN at 23 °C) can be

91


translated into hydrodynamic radii of rH = 7.2 Å for cage 3 and rH = 8.0 Å for cage 4 by

using the Stokes-Einstein equation.[43]

By means of ESI high resolution mass spectrometry,

we were able to identify the Pd2L4 constitution of both cages. The spectrum of cage 3

shows the signals for the cations Pd2-Z-1a4(NO3)3+, Pd2-Z-1a4(NO3)2

2+, Pd2-Z-1a4(NO3)

3+,

Pd2-Z-1a44+

(Figure 5.5). For cage 4, the peaks corresponding to the cations Pd2-E-

2a4(NO3)22+

and Pd2-E-2a4(NO3)3+

were observed (Figure 5.5). For both isomers, the

experimental isotopic patterns and exact m/z values match the simulated patterns.

Figure 5.4. DOSY NMR spectra of cage 3 (top) and cage 4 (bottom) in CD3CN.

92

Chapter 5

Figure 5.5. HRMS spectra of cage 3 (top) and cage 4 (bottom); Insets: comparison of

simulated and measured isotopic patterns of Pd2L4(NO3)3+

ions

Formation of single crystals suitable for X-ray structure determination of the cages proved

to be challenging and many attempts at obtaining suitable crystals were unsuccessful.

Finally, one single crystal of cage 4 formed from a racemic mixture of ligand E-2a suitable

for X-ray structure determination was grown by vapor diffusion of a 1:1 mixture of

benzene and diethyl ether into a solution of the cage in a 1:1 mixture of acetonitrile and

chloroform. The crystal structure shows cages with a Pd2L4 stoichiometry and one NO3-

counter ion and one molecule of acetonitrile are located inside each cage (Figure 5.6). In

addition, a chloride ion is located close to the metal centers outside of the cage. This

counter ion most likely originates from the solvent, as chloroform can contain

considerable amounts of HCl. The crystal structure belongs to the P 4/n space group and

the unit cell is occupied by a pair of enantiomeric cages in which the Pd-Pd axis of each

cage is located at the 4-fold rotation axis. This means that the crystal structure represents

a racemic mixture of cages which either only contain the (R,R) enantiomer or only the (S,S)

enantiomer of the ligand.

93


Figure 5.6. Crystal structure of cage 4 (top left) and DFT optimized structures of cages 3-5.

Color coding: C – Black, H – White, N – Blue, Pd – Cyan, Cl – Green, O – Red.

To further support that homochiral cages 3 and 4 are formed by chiral self-sorting, giving

rise to only one diastereomer (and its enantiomer), DFT calculations were performed. The

structures of all possible cage diastereomers were optimized using B3LYP/6-31G(d) for

C,H,N and LANL2DZ with ECP for Pd in the gas phase without counter ions. The optimized

structure of (E-2a)4Pd24+

is in good agreement with the solved X-ray structure (Figure 5.6).

Moreover, the calculations revealed that the homochiral cage [(S,S)-E-2a]4Pd24+

(and its

enantiomer) are energetically favored by at least 61 kJ mol-1

compared to the other

possible diastereomers (Table 5.2). Similar calculations on the diastereomers of cage 3

revealed that the homochiral cage diastereomers [(S,S)-Z-1a]4Pd24+

are energetically

favored as well, by at least 19 kJ mol-1

(Table 5.3).

94

Chapter 5

Cage 4 diastereomer Relative Gibbs free energy (kJ mol-1

)

Pd2[(S,S)-E-2a]4 0

Pd2[(S,S)-E-2a]3[(R,R)-E-2a] +60.9

Pd2[(S,S)-E-2a]2[(R,R)-E-2a]2 +75.8

Pd2[(S,S)-E-2a][(R,R)-E-2a][(S,S)-E-2a][(R,R)-E-2a] +113.8

Table 5.2. DFT calculated relative Gibbs free energy of possible diastereomers of cage 4.

Cage 3 diastereomer Relative Gibbs free energy (kJ mol-1

)

Pd2[(S,S)-Z-1a]4 0

Pd2[(S,S)-Z-1a]3[(R,R)-Z-1a] +18.5

Pd2[(S,S)-Z-1a]2[(R,R)-Z-1a]2 +27.4

Pd2[(S,S)-Z-1a][(R,R)-Z-1a][(S,S)-Z-1a][(R,R)-Z-1a] +32.4

Table 5.3. DFT calculated relative Gibbs free energy of possible diasteomers of cage 3.

These calculations support that the cage is formed by chiral narcissistic self-sorting which

was then probed experimentally by CD spectroscopy. Since the two homochiral

enantiomers of cage 3 are expected to be the only optically active species in solution, we

argue that the difference in the extinction coefficient (Δε) should have a linear

dependency on the ee of the cage solution. On the other hand, if several different

diastereomers were present, they should have different individual CD spectra which

would all contribute to the overall obtained CD spectrum. As the ratio of these

diastereomers would depend on the ee of the cage, this situation would cause a deviation

from the linear dependency of Δε on the ee. To test this hypothesis, stock solutions of

racemic and enantiopure cage 3 were mixed in different ratios to obtain a range of ee’s. In

accordance to our expectations, we found that the amplitude in CD spectra of solutions

containing cage 3 show a linear dependence on the ee of ligand Z-1a (Figure 5.7). Plotting

the values for Δε found around the extrema at λ = 258, 320 and 360 nm versus the ee of Z-

1a used to form the cage gave linear curves for each wavelength. Our predictions based

on the DFT calculations were hence further supported experimentally.

95


260 280 300 320 340 360 380 400

-60

-40

-20

0

20

40

60

80

[mo

l-1cm

-1]

[nm]

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Figure 5.7. CD spectra of cage 3 formed from ligand Z-1a (c = 1.1 x 10-5

M) with varying ee

(left). Plot of versus ee, showing a linear dependency (right).

Next, we were interested in the guest binding abilities of cages 3 and 4. The tosylate anion

has an appropriate size to fit inside the cages. 1H-NMR titrations with

tetrabutylammonium tosylate was performed and the data was fitted against a 1:1

binding model using BindFit software (Figure 5.8).[44]

The fitting revealed that both cages

show equally strong binding towards OTs- (KB= 1604 ± 39 M

-1 for 3; KB = 1758 ± 39 M

-1 for 4

at 293 K). The binding constants were determined by titration of a stock solution of cage 3

(c = 3.0 x 10-4

M) or 4 (c = 2.7 x 10-4

M) with a stock solution of tetrabutylammonium

tosylate (c = 4.0 x 10-3

M) that contained the guest in the same concentration to exclude

dilution effects. A Job plot analysis was performed by plotting the host-guest

concentration ([HG]) versus the molar fraction of the host (), revealing a 1:1 binding

stoichiometry between both cage isomers and OTs- (Figure 5.9). This is in line with the

idea that OTs- serves as a guest molecule which is encapsulated inside the cages.

0 20 40 60 80 100

-60

-40

-20

0

20

40

60

80

258 nm

320 nm

360 nm

[mo

l-1cm

-1]

ee [%]

96

Chapter 5

Figure 5.8. Top: Fitting of 1H-NMR titration data of cage 3 (a) and 4 (b) with

tetrabutylammonium tosylate using protons Ha-He as shown in figure 5.3. Bottom: residual

plots of fitting of 1H-NMR titration data of cage 3 (c) and 4 (d).

0.0 0.2 0.4 0.6 0.8 1.0

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

[HG

] (m

M)

x

Figure 5.9. Job plot of tosylate binding to cage 3 (left) and cage 4 (right).

0.0 0.2 0.4 0.6 0.8 1.0

0.00

0.02

0.04

0.06

0.08

[HG

] (m

M)

x

97


5.4 Photochemical isomerizations

The photochemical and thermal isomerizations of cages 3 and 4 were followed by 1H NMR

studies (Scheme 5.3 and Figure 5.10). Irradiation of cage 3 in CD3CN:CD2Cl2 1:1 mixture at

312 nm at -70 °C was performed to isomerize ligand Z-1a to E-2b (vide infra), followed by

allowing the sample to warm up to room temperature to form E-2a (Figure 5.10ii). The 1H-

NMR spectrum of this newly formed complex is identical to the spectrum of cage 4

prepared directly from E-2a (Figure 5.10iii), showing that cage 3 is effectively converted to

cage 4. An intermediate complex containing ligands E-2b was never observed, even at low

temperatures, most likely due to the low barrier for THI of this isomer. Conversion of cage

4 to cage 5 by photochemical E-Z isomerization of ligand E-2a to Z-1b was performed by

irradiation of cage 4 at 312 nm at -20 °C (Figure 5.10iv). Signals of cage 4 disappeared and

the formation of a new set of signals was observed. DOSY NMR confirmed the formation

of an assembly with a similar hydrodynamic radius. Precipitation of the metal centers in

this assembly using sodium glutamate liberates the organic ligands and they were

identified as Z-1b. This confirms that the photogenerated complex is indeed cage 5,

formed from ligand Z-1b. Subsequent irradiation of this sample containing cage 5 at -20 °C

at 365 nm converts the Z-1b ligands back to E-2a, reforming cage 4 (Figure 5.10v). These

experiments highlight the reversible formation of cage 5 through photochemical E-Z

isomerization of the ligands.

On the other hand, allowing the THI of ligands Z-1b in cage 5 to take place by leaving the

solution at room temperature for 5 d did not lead to the formation of cage 3, but to

disassembly of the cage and formation of ill-defined complexes. Precipitation of the metal

centers in these complexes identified the ligands as a mixture of both Z-1a and E-2a

(originating from the PSS mixture), indicating that the THI does take place. A possible

explanation could be that the mixture of Z-1a and E-2a does not form separate well-

defined cage structures, but form mixed complexes.

Scheme 5.3. Photochemical isomerization behavior of cages 3-5.

98

Chapter 5

Figure 5.10. Aromatic region of stacked 1H NMR spectra (CD3CN/CD2Cl2 1:1) of i) cage 3

formed from Z-1a; ii) cage 4 generated by irradiation of cage 3; iii) cage 4 prepared from

E-2a; iv) cage 5 generated by irradiation of cage 4; v) cage 4 generated by irradiation of

cage 5.

5.5 Conclusions

In summary, a new photoresponsive supramolecular coordination complex based on

overcrowded alkenes is presented, allowing switching between three different cage

structures. Interestingly, the cage structures with Pd2L4 constitution were shown to be

homochiral, forming single diastereomers as shown by NMR, CD and X-ray studies,

supported by DFT calculations. Additionally, the cage structures were able to bind OTs-

inside their cavity. Although photoswitching affords a large geometric change of the

ligands, only minor changes were observed in binding constants of the different cage

structures. These results show that by incorporation of overcrowded alkenes into SCCs the

geometry of cage structures can be controlled by light. Different designs might be

considered to translate these geometrical changes to changes in properties such as guest

binding.



Racemic and enantiopure ketone 6 and motor 7 were synthesized according to literature

procedures.[38]

99


(Z)-3,3'-(2,2',4,4',7,7'-hexamethyl-2,2',3,3'-tetrahydro-[1,1'-biindenylidene]-5,5'-

diyl)dipyridine (Z-1a) and (E)-3,3'-(2,2',4,4',7,7'-hexamethyl-2,2',3,3'-tetrahydro-[1,1'-

biindenylidene]-5,5'-diyl)dipyridine (E-2a)

A 1.5:1 mixture of motors Z-7 and E-7 (700 mg, 1.48 mmol, 1.0 equiv.), 3-pyridinylboronic

acid (454 mg, 3.69 mmol, 2.5 equiv.), PdCl2dppf complex with CH2Cl2 (60 mg, 73.8 μmol,

0.05 equiv.) and K2CO3 (1.40 g, 10.1 mmol, 6.8 equiv.) were dissolved in a mixture of water

(7.4 mL) and THF (21 mL). The mixture was degassed by purging with N2 for 30 min and

then stirred at 70 °C for 2 d. Then, the mixture was diluted with CH2Cl2 (50 mL) and

washed with brine (50 mL). The organic phases were combined and dried over Mg2SO4,

volatiles were removed in vacuo and the residue was purified using column

chromatography (SiO2, CH2Cl2 + 2.5% MeOH) to give ligands Z-1a (343 mg, 0.73 mmol,

82%) and E-2a (233 mg, 0.49 mmol, 83%) as off-white solids.

Z-1a: Mp 269 °C. 1

H NMR (400 MHz, CDCl3) δ (ppm) = 8.64 (s, 2H), 8.58 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.37 (s, 2H), 6.86 (s, 2H), 3.43 (t, J = 6.6 Hz, 2H), 3.18 (dd, J = 14.9, 6.4 Hz, 2H), 2.53 (d, J = 15.4 Hz, 2H), 2.20 (s, 6H), 1.61 (s, 6H), 1.15 (d, J = 6.8 Hz, 6H).

13C NMR (101

MHz, CDCl3) δ (ppm) = 150.2, 147.7, 145.6, 141.0, 140.9, 138.0, 136.9, 136.8, 133.4, 130.0, 128.3, 123.1, 41.9, 39.6, 20.8, 20.7, 16.4. HRMS (ESI+): calcd for C34H35N2

+ [M+H]

+:

471.2795, found 471.2763.

E-2a: Mp 235-237 °C. 1

H NMR (400 MHz, CDCl3) δ (ppm) = 8.66 (s, 2H), 8.59 (s, 2H), 7.73 (d,

J = 7.7 Hz, 2H), 7.38 (s, 2H), 7.00 (s, 2H), 3.22 – 2.89 (m, 2H), 2.79 (dd, J = 14.7, 5.7 Hz, 2H),

2.50 (s, 6H), 2.34 (d, J = 14.6 Hz, 2H), 2.13 (s, 6H), 1.17 (d, J = 6.5 Hz, 6H). 13

C NMR (101

MHz, CDCl3) δ (ppm) = 150.3, 147.9, 144.0, 141.7, 141.0, 137.8, 136.9, 136.8, 131.3, 130.5,

129.1, 123.0, 42.2, 39.8, 22.0, 19.7, 16.3. HRMS (ESI+): calcd for C34H35N2+ [M+H]

+:

471.2795, found 471.2764.

The enantiopure ligands (S,S)-Z-1a and (S,S)-E-2a were prepared according to the same

procedure employing a mixture of enantiopure precursors (S,S)-Z-7 and (S,S)-E-7. The ee

for (S,S)-Z-1a >99% as was determined by chiral HPLC analysis, Chiralpak AD-H (90%

heptane/10% i-PrOH), 0.5 mL/min, retention times (min) 12.4 (major) and 15.5 (minor).

The ee for (S,S)-E-2a >99%, Chiralpak AD-H (90% heptane/10% i-PrOH), 0.5 mL/min,

retention times (min) 11.3 (major) and 12.6 (minor).

100

Chapter 5

Cage formation

A solution (c ≤ 2.5 mM) of 1.0 equiv. of Pd(NO3)2 in CD3CN, alternatively in a mixture with

CD2Cl2, was added to 2.0 equiv. of either Z-1a or E-2a in a closed vial and the mixture was

heated at reflux until a clear solution was obtained to yield either cage 3 or cage 4 in

solution.

Cage 3: 1H NMR (500 MHz, CD3CN) δ (ppm) = 8.81 (s, 8H), 8.67 (d, J = 5.8 Hz, 8H), 7.99 (d, J

= 8.4 Hz, 8H), 7.55 (dd, J = 8.1, 5.7 Hz, 8H), 7.00 (s, 8H), 3.52 – 3.31 (m, 8H), 3.05 (dd, J =

14.8, 6.2 Hz, 8H), 2.48 (dd, J = 14.9, 7.7 Hz, 8H), 1.97 (s, 24H), 1.61 (s, 24H), 1.02 (d, J = 6.7

Hz, 24H). HRMS (ESI+): calcd for C136H136N11O9Pd2+ ([Pd2Z-1a4](NO3)3

+): 2280.8644, found

2280.8893; calcd for C136H136N10O6Pd22+

([Pd2Z-1a4](NO3)22+

): 1109.4380, found 1109.4513;

calcd for C136H136N9O3Pd23+

([Pd2Z-1a4](NO3)3+

): 718.9625, found 718.9712; calcd for

C136H136N8Pd24+

([Pd2Z-1a4])4+

): 523.7248, found 523.7303.

Cage 4: 1H NMR (500 MHz, CD3CN) δ (ppm) = 9.56 (br, 8H), 9.16 (d, J = 5.7 Hz, 8H), 8.13 –

7.85 (m, 8H), 7.67 (dd, J = 7.7, 5.8 Hz, 8H), 6.88 (s, 8H), 2.93 (t, J = 6.3 Hz, 8H), 2.55 – 2.47

(m, 8H), 2.43 (s, 24H), 2.12 (d, J = 12.7 Hz, 8H, *covered by solvent signal), 1.52 (s, 24H),

1.08 (d, J = 6.4 Hz, 24H). HRMS (ESI+): calcd for C136H136N10O6Pd22+

([Pd2E-2a4](NO3)22+

):

1109.4380, found 1109.4378; calcd for C136H136N9O3Pd23+

([Pd2E-2a4](NO3)3+

): 718.9625,

found 718.9613.

Binding studies

The binding constants were determined by NMR titrations at 20 °C. Titration of a stock

solution of cage 3 (c = 3.0 x 10-4

M) or 4 (c = 2.7 x 10-4

M) with a stock solution of

tetrabutylammonium tosylate (c = 4.0 x 10-3

M) in a 1:1 mixture of CD2Cl2 and CD3CN that

contained the guest in the same concentration to exclude dilution effects was performed.

The chemical shifts of Ha-d (cage 3) and Ha,c-e (cage 4) were plotted against the host to

guest ratio and fitted against a 1:1 binding model using BindFit software (Figure 5.8).

Binding constants of 1604 ± 39 M-1

for 3 and 1758 ± 39 M-1

for 4 were obtained.

A Job plot analysis was performed by plotting the host-guest concentration ([HG]) versus

the molar fraction of the host (). Different molar fractions were obtained by mixing stock

101


solutions (c = 3.4 · 10-4

M) of TBAOTs and cage 3 or 4 in a 1:1 mixture of CD3CN and CD2Cl2.

The host guest concentration ([HG]) was then determined by equation 1, in which [H]0 is

the total concentration of host, δobs is the measured chemical shift of proton Ha in the host

guest mixture, δ0 is the chemical shift of proton Ha for the pure host and δcomplex is the

chemical shift of proton Ha in the host guest complex which is assumed to be formed

completely for a host guest ratio of 1:9. Plotting [HG] versus the molar fraction of the host

(x) yielded curves with maxima for x = 0.5, confirming a 1:1 binding stoichiometry (Figure

5.9).

[HG] = [H]0 ·𝛿obs−𝛿0

𝛿complex−𝛿0 (1)

5.7 References

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[2] M. M. J. Smulders, I. A. Riddell, C. Browne, J. R. Nitschke, Chem. Soc. Rev. 2013, 42, 1728–1754.

[3] T. R. Cook, P. J. Stang, Chem. Rev. 2015, 115, 7001–7045.

[4] K. Harris, D. Fujita, M. Fujita, Chem. Commun. 2013, 49, 6703–6712.

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[6] A. Schmidt, A. Casini, F. E. Kühn, Coord. Chem. Rev. 2014, 275, 19–36.

[7] Z. Ma, B. Moulton, Coord. Chem. Rev. 2011, 255, 1623–1641.

[8] J. E. M. Lewis, E. L. Gavey, S. A. Cameron, J. D. Crowley, Chem. Sci. 2012, 3, 778–784.

[9] D. M. Vriezema, M. C. Aragonès, J. A. A. W. Elemans, J. J. L. M. Cornelissen, A. E. Rowan, R. J. M. Nolte, Chem. Rev. 2005, 105, 1445–1489.

[10] M. D. Pluth, R. G. Bergman, K. N. Raymond, Acc. Chem. Res. 2009, 42, 1650–1659.

[11] M. Yoshizawa, J. K. Klosterman, M. Fujita, Angew. Chem. Int. Ed. 2009, 48, 3418–3438.

[12] D. M. Kaphan, M. D. Levin, R. G. Bergman, K. N. Raymond, F. D. Toste, Science 2015, 350, 1235–1238.

[13] Y. Inokuma, S. Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora, K. Takada, S. Matsunaga, K. Rissanen, M. Fujita, Nature 2013, 495, 461–466.

[14] K. Yan, R. Dubey, T. Arai, Y. Inokuma, M. Fujita, J. Am. Chem. Soc. 2017, 139, 11341–11344.

[15] M. Ziegler, J. L. Brumaghim, K. N. Raymond, Angew. Chem. Int. Ed. 2000, 39, 4119–4121.

[16] M. Kawano, Y. Kobayashi, T. Ozeki, M. Fujita, J. Am. Chem. Soc. 2006, 128, 6558–6559.

[17] P. Mal, B. Breiner, K. Rissanen, J. R. Nitschke, Science 2009, 324, 1697–1699.

[18] M. M. Safont-Sempere, G. Fernández, F. Wurthner, Chem. Rev. 2011, 111, 5784–5814.

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[19] C. Gütz, R. Hovorka, G. Schnakenburg, A. Lützen, Chem. - Eur. J. 2013, 19, 10890–10894.

[20] Z. He, W. Jiang, C. A. Schalley, Chem. Soc. Rev. 2015, 44, 779–789.

[21] A. J. McConnell, C. S. Wood, P. P. Neelakandan, J. R. Nitschke, Chem. Rev. 2015, 115, 7729–7793.

[22] K. Mahata, P. D. Frischmann, F. Würthner, J. Am. Chem. Soc. 2013, 135, 15656–15661.

[23] M. Scherer, D. L. Caulder, D. W. Johnson, K. N. Raymond, Angew. Chem. Int. Ed. 1999, 38, 1587–1592.

[24] P. Mal, D. Schultz, K. Beyeh, K. Rissanen, J. R. Nitschke, Angew. Chem. Int. Ed. 2008, 47, 8297–8301.

[25] G. H. Clever, S. Tashiro, M. Shionoya, J. Am. Chem. Soc. 2010, 132, 9973–9975.

[26] T. Murase, S. Sato, M. Fujita, Angew. Chem. Int. Ed. 2007, 46, 5133–5136.

[27] J. Park, L.-B. Sun, Y.-P. Chen, Z. Perry, H.-C. Zhou, Angew. Chem. Int. Ed. 2014, 53, 5842–5846.

[28] B. L. Feringa, W. R. Browne, Molecular Switches, Second Edition, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2011.

[29] M. Irie, T. Fukaminato, K. Matsuda, S. Kobatake, Chem. Rev. 2014, 114, 12174–12277.

[30] H. Tian, S. Yang, Chem. Soc. Rev. 2004, 33, 85–97.

[31] M. Han, R. Michel, B. He, Y.-S. Chen, D. Stalke, M. John, G. H. Clever, Angew. Chem. Int. Ed. 2013, 52, 1319–1323.

[32] M. Han, Y. Luo, B. Damaschke, L. Gómez, X. Ribas, A. Jose, P. Peretzki, M. Seibt, G. H. Clever, Angew. Chem. Int. Ed. 2016, 55, 445–449.

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104

Chapter 5

Chapter 6 First generation molecular motors in polymers: Towards photoswitchable foldamers

With the goal of forming photoswitchable foldamers, first generation molecular motors are copolymerized with fluorene and m-phenylene ethylene linkers. Initially, model compounds consisting of a single motor with linkers on both halves are synthesized, showing that appending these linkers does not impede the photoswitching. Unfortunately, the copolymer of motors with fluorene were showing very little photoswitching, but show fluorescence instead. The Sonogashira polymerization to form polymers with m-phenylene ethylene linkers was unsuccessful, as no polymeric material was obtained.

106

Chapter 6

6.1 Introduction

Foldamers are oligomers or polymers that are able to adopt a specific compact

conformation in solution.[1–6]

Inspired by Nature’s broad collection of structurally well-

defined macromolecules, the folding of synthetic analogues such as peptoids,[7]

-

peptides[8,9]

and polyamide nucleic acids[10]

were initially studied. Soon thereafter, the

scope was expanded to aromatic foldamers, such as oligo(meta-phenylene ethylene)s

(OmPEs)[11,12]

and polyamides.[13]

Although many conformations can be adopted, helices

are by far the most studied. As such, foldamers have shown promising applications in

various fields, such as molecular recognition,[14,15]

biomedicine[16–18]

and catalysis.[19,20]

Incorporation of photoswitches in foldamers offers the possibility to dynamically control

folding using light.[21,22]

Azobenzenes are mainly used, as the photochemical E-Z

isomerization results in a large geometry change. They have been attached as side

chains,[23]

tethers[22]

or incorporated in the backbone.[24]

In most cases they have been

introduced in aromatic foldamers, such as OmPEs,[25,26]

polyamides[27]

and aryl-triazole

foldamers.[28,29]

Studies on OmPEs showed that the photoswitching is cooperative, in

which the terminal azobenzene moieties isomerize first, leading to unfolding at the

termini.[30]

Subsequent isomerization of the internal azobenzenes is then facilitated by

unfolding of the helix. This unique feature of foldamers allows for the amplification of the

photoswitching event.

The incorporation of overcrowded alkene-based molecular motors as chiroptical switches

in foldamers would be highly beneficial, as they possess helical chirality, which can be

transferred to the helix of the polymer,[31,32]

allowing control over the folding and the

helical chirality (Figure 6.1). Second generation molecular motors have been incorporated

in polymers by copolymerizing them with xanthone or fluorene with the aim to perform

light-driven movement.[33]

The motor function was retained in the polymers, but no

significant movement was observed. The motors were polymerized at the lower halves,

and therefore isomerization does not lead to a large geometry change of the polymer. In

our current design, first generation molecular motors[34,35]

were chosen to achieve a large

geometric change upon photoisomerization (Figure 6.1). Isomerization of the trans isomer

to the unstable cis isomer upon irradiation at 312 nm should convert the linear polymer

chain to a helix. Unfolding of the helix could be achieved by irradiation at 365 nm to

isomerize the unstable cis to the stable trans.

107

First generation molecular motors in polymers: Towards photoswitchable foldamers

Figure 6.1. A light switchable foldamer employing intrinsic overcrowded alkene-based

molecular motors.

6.2 Synthesis of linkers and model compounds

Two designs of polymers were considered (Figure 6.2), both bearing a first generation

molecular motor in their backbone. In polymer P1 the motor is copolymerized with

dioctylfluorene. The linkers in polymer P2 are based on m-phenylene ethynylene (mPE),

which have been widely studied as foldamers.[11,12]

To investigate the effect of appending

these linkers to molecular motors on their switching behavior, model compounds 1 and 2

were first synthesized, bearing a linker at both the upper and lower half (Scheme 6.1).

Figure 6.2: Designs for molecular motor containing polymers

For model compound 1, commercially available fluorene 3 could be converted to the

corresponding boronic ester via halogen-lithium exchange and quenching with tributyl

borate. Boronic ester 4 was then in situ coupled to motor 5 in a Suzuki cross coupling.

Even though motor 5 was used as a mixture of cis and trans, the resulting product was

108

Chapter 6

isolated exclusively as the trans isomer as determined by 2D NOESY NMR (Figure 6.3). A

correlation was observed between Ha and Hd, as well as between Hb and Hd and only in the

trans isomer these protons are in close proximity to each other. Alongside di-substituted

motor 1, mono-substituted product was isolated after column chromatography, as a

mixture of cis and trans. Most likely, the cis isomer is too hindered to undergo a second

coupling. The mPE linker was synthesized starting from 3,5-dibromobenzoic acid, which

was first esterified using hexanol according to a literature procedure.[36]

The alkyne linkers

were installed by performing a double Sonogashira coupling with 2-methylbut-3-yn-2-ol,

providing 8 in high yield. The acetonide protecting groups can then be removed using

NaH, giving a mixture of 9 and 10. Linker 10 could be used for the synthesis of model

compound 2, which is synthesized using a double Sonogashira cross-coupling. Essential in

this reaction is the use of iodide substituted motor 11,[37]

as the bromide substituted

motor proved to be unreactive in this cross-coupling. Model compound 2 was, as in the

case of 1, isolated exclusively as the trans isomer.

Scheme 6.1: Synthesis of model compounds 1 and 2.

109


Figure 6.3. Partial ROESY spectrum of model compound 1.

6.3 Switching studies of model compounds

The UV/vis spectra of model compounds 1 and 2 show a strong absorption band in the UV

region, similar to the unsubstituted parent motor (Figure 6.4).[38]

Upon irradiation with

max = 312 nm light in both cases a clear bathochromic shift is seen, characteristic for the

formation of the unstable cis state. When these samples are irradiated at 385 nm, the

motor isomerizes back to the stable trans isomer and the UV/vis spectra almost

completely return to the original state. Both model compounds show clear isosbestic

points, indicative of a unimolecular process (Figure 6.5 and Figure 6.6).

110

Chapter 6

Figure 6.4: UV/vis spectra of model compounds 1 (left, CH2Cl2, c = 8.1 x 10-6

M) and 2 (right,

DMSO, c = 9.7 x 10-6

M)

Figure 6.5. UV/vis spectra of model compound 1 (CH2Cl2, c = 8.1 x 10-6

M) upon irradiation

at 312 nm (left) and 385 nm (right) with isosbestic points (inset).

111


Figure 6.6. UV/vis spectra of model compound 2 (DMSO, c = 9.7 x 10-6

M) upon irradiation

at 312 nm (left) and 385 nm (right) with isosbestic points (inset).

To confirm that the switching behavior of the motor is retained in these model

compounds, its isomerization behavior was followed using 1H-NMR (Figure 6.7). An NMR

sample containing motor 1 in THF-d8 was irradiated at 312 nm, showing the disappearance

of the stable trans isomer and the emergence of a new isomer: unstable cis (Figure 6.7ii).

The most clear changes are seen for Ha, Hb and Hc. The sample was irradiated until no

further changes were observed and at this photostationary state (PSS) the ratio of

unstable cis to stable trans was 79:21. When this sample is irradiated at 385 nm, the

stable trans isomer is again obtained as is seen in Figure 6.7iii. At the PSS, the ratio of

stable trans to unstable cis is 93:7. In the same manner, the isomerization behavior of

model compound 2 was followed (Figure 6.8). Upon irradiation at 312 nm clear changes

are seen for the aromatic protons on the linker, Hb, Hc and Hd (Figure 6.8ii). A PSS of

unstable cis to stable trans of 85:15 is obtained. Irradiation at 385 nm isomerizes this

photogenerated isomer back to stable trans as the original spectrum is reobtained (Figure

6.8iii). Combined, these results show that appending either mPE or fluorene linkers does

not impede the switching behavior of this first generation molecular motor, making them

promising candidates to be used as switchable polymers.

112

Chapter 6

Figure 6.7. Selected regions of 1H-NMR spectrum of model compound 1 in THF-d8 (c = x 10

-4

M). i) start ii) PSS 312 nm iii) PSS 385 nm.

Figure 6.8: Aromatic region of 1H-NMR spectrum of model compound 2 in DMSO-d6 (c = 8.5

x 10-4

M). i) start ii) PSS 312 nm iii) PSS 385 nm.

113


6.4 Polymer formation and characterization

Polymer P1 was synthesized using a Suzuki polymerization, which is proposed to proceed

via a chain-growth mechanism, leading to a narrow weight distribution.[39,40]

Initially,

polymerization of (S,S)-trans-5 with commercially available linker 12 was carried out using

Pd(PPh3)4 as a catalyst (Scheme 6.2).[33]

After stirring for 24 h, the polymer was end-

capped at both ends with 4-iodoanisole and 4-methoxyphenyl boronic acid. The polymer

was then purified by sequential precipitation in MeOH and acetone, and P1 was isolated in

70% yield. GPC analysis in CHCl3 using a polystyrene standard showed a relative low

polydispersity (1.3) and a number average molecular weight of 7.5 kDa, which

corresponds to 11 units per chain (Table 6.1). End-group analysis with 1H-NMR showed an

average of 46 units per chain. The large difference between the GPC and 1H-NMR could

suggest that not all polymers are end-capped. Unfortunately, attempts to polymerize

(S,S)-cis-5 failed. Most likely, the mono-substituted motor is too hindered to undergo a

second cross-coupling, in analogy to model compounds 1 and 2 (vide infra).

Scheme 6.2. Polymerizations towards polymers P1 and P2.

Mn 7.5 kDa

Mw 9.7 kDa

PI 1.3

n 11 units/chain

n (1H-NMR) 46 units/chain

Table 6.1. Analysis of polymer P1

For polymer P2, a Sonogashira polymerization was envisioned, using racemic iodo-

substituted motor trans 11 and and dialkyne 9. Unfortunately, different polymerization

conditions gave a complex mixture and did not yield any high weight polymeric material

114

Chapter 6

upon precipitation with MeOH. As the presence of trace amounts of oxygen could cause

significant homocoupling of linker 9, the polymerization was carried out under strict

oxygen-free conditions using an argon atmosphere, but this did not lead to a significant

improvement.

The UV/vis spectrum of P1 in THF is slightly red-shifted compared to model compound 1,

most likely due to extended conjugation (Figure 6.9). Upon irradiation at 312 nm only

small changes are seen in the UV/vis spectrum, suggesting that only very little

photoswitching occurs. The same is seen in the CD spectrum, which shows a small

increase in the CD signal (Figure 6.9). On the other hand, fluorescence with a maximum at

em = 399 nm was observed when P1 was excited at 312 nm, even in the nanomolar range

(Figure 6.10). It was shown before that molecular motors incorporated in gels show

increased fluorescence[41]

and that the introduction of rigid arms leads to increased

fluorescence.[42]

Interestingly, negligible fluorescence was observed in polymers

containing second generation molecular motors, in which photoisomerizaiton does not

lead to a geometry change in the polymer chain.[33]

Incorporation of a motor in a rigid

polymer might hamper the photoswitching as the whole chain needs to be reoriented in

order to achieve the E-Z isomerization. Instead, fluorescence is observed, similar to the

blue fluorescence of polyfluorenes.[43]

The small degree of isomerization might be

originating from motors in polymers in the low molecular weight fraction, or from the

chain ends.

Figure 6.9. UV/vis (left) and CD (right) spectra of P1 in THF (c = 1.5 x 10-6

M) upon

irradiation at 312 nm.

115


Figure 6.10. Fluorescence spectrum of P1 in THF (c = 4.5 x 10-9

M) with ex = 312 nm.

6.5 Conclusions

In summary, a polymer containing first generation molecular motors was synthesized

using a Suzuki polymerization. Although UV/vis and NMR studies on model compounds

showed promising results, photoswitching of the motors embedded in the polymer main

chains was very poor. Instead, fluorescence is observed. Possibly, photoswitching is

inhibited as the whole polymer chain needs to be reoriented upon E-Z isomerization of the

motor unit. To confirm this, low molecular weight oligomers might be synthesized, in

which photoswitching should be easier as fewer units have to be rearranged to facilitate

isomerization.



2-Bromo-9,9-dihexylfluorene (3) was bought from Sigma-Aldrich. Ester 7 was synthesized

according to literature procedures.[36]

Racemic motors 5[44]

and 11[37]

were synthesized

according to literature procedures. Enantiopure motor 5 was synthesized from

enantiopure ketone 12, obtained via an enantioselective protonation following literature

procedures (Figure 6.11).[35]

Cis and trans isomers were subsequently separated by layered

crystallization with CH2Cl2/MeOH.

116

Chapter 6

Figure 6.11. Synthesis of enantiopure motor 5.

(E)-2,2'-(2,2',4,4',7,7'-Hexamethyl-2,2',3,3'-tetrahydro-[1,1'-biindenylidene]-6,6'-

diyl)bis(9,9-dihexyl-9H-fluorene) (1)

2-Bromo-9,9-dihexylfluorene (3) (109 mg, 0.263 mmol) was dissolved in dry THF (3 mL)

under N2 atmosphere and the solution was cooled to -78 °C. n-BuLi (2.5 M in hexanes, 0.12

mL, 0.29 mmol) was added dropwise and the resulting solution was stirred for 30 min.

B(OBu)3 (78 L, 0.29 mmol) was added and the mixture was allowed to warm to room

temperature and stirred for an additional 30 min. Dioxane (3 mL) and 1M aq. K2CO3 (5 mL)

were added the mixture was purged with N2 for 30 min. PdCl2dppf (4.3 mg, 0.0053 mmol)

and motor 5 (50 mg, 0.11 mmol) were added the resulting mixture was stirred at 95 °C for

2 d. After cooling to rt., water was added and the mixture was extracted three times with

CH2Cl2. The combined organic layers were washed with water and brine, dried over MgSO4

and the volatiles were removed in vacuo. The residue was purified by flash column

chromatography (SiO2, pentane/CH2Cl2 0-10%) to yield 1 as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 10.0, 7.3 Hz, 4H), 7.42 – 7.28 (m, 10H), 7.07 (s,

2H), 3.12 (p, J = 6.3 Hz, 2H), 2.84 (dd, J = 14.5, 5.6 Hz, 2H), 2.38 (d, J = 10.8 Hz, 2H), 2.34 (s,

, 6H), 2.30 (s, 6H), 2.11 – 1.92 (m, 8H), 1.23 – 0.97 (m, 24H), 0.85 – 0.60 (m, 20H). 13

C NMR

(101 MHz, CDCl3) δ 151.1, 150.6, 142.4, 142.3, 141.9, 141.8, 141.6, 141.2, 139.7, 131.3,

129.7, 129.1, 128.3, 127.0, 126.9, 124.4, 123.0, 119.7, 119.4, 55.2, 42.7, 40.6, 40.6, 39.2,

117


31.7, 31.7, 29.9, 24.0, 23.9, 22.7, 22.7, 21.6, 19.3, 18.4, 14.2, 14.1. HRMS (ESI+, m/z): Calcd

for C78H93 [M+H]+: 981.72718, found 981.72452.

Hexyl 3,5-bis(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate (8)

Ester 7 (5.95 g, 16.3 mmol), PdCl2(PPh3)2 (458 mg, 0.652 mmol) and CuI (124 mg, 0.652

mmol) were dissolved in THF/Et3N 3:1 (160 mL) and the mixture was degassed by purging

with N2 for 30 min. 2-methylbut-3-yn-2-ol (4.7 mL, 49 mmol) was added and the resulting

mixture was refluxed o.n. After cooling to rt. the volatiles were removed in vacuo, H2O

was added to the residue and extracted three times with CH2Cl2. The combined organic

layers were washed 2x with 1M aq. HCl, 2x with H2O and brine. The combined organic

layers were dried over MgSO4 and the volatiles were removed in vacuo. The residue was

purified by flash column chromatography (SiO2, pentane/EtOAc 10-40%) to yield 8 (5.81 g,

96%) as an off-yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 1.6 Hz, 2H), 7.61 (t, J =

1.6 Hz, 1H), 4.31 (t, J = 6.8 Hz, 2H), 2.08 (bs, 2H) 1.76 (dq, J = 7.9, 6.8 Hz, 2H), 1.61 (s, 12H),

1.48 – 1.29 (m, 6H), 0.95 – 0.86 (m, 3H). 13

C NMR (101 MHz, CDCl3) δ 168.0, 141.0, 134.8,

133.6, 126.1, 97.9, 83.1, 68.3, 68.2, 34.1, 34.0, 31.3, 28.3, 25.2, 16.7. HRMS (ESI+, m/z):

Calcd for C23H29O3 [M-OH]+: 353.21112, found: 353.21152. Calcd for C23H30O4Na [M+Na]

+:

393.20363, found 393.20371.

Hexyl 3-ethynyl-5-(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate (9)

NaH (130 mg, 3.24 mmol, 60% dispersion in mineral oil) was dissolved in dry THF (10 mL)

under N2 atmosphere. Ester 8 (1.00 g, 2.70 mmol) was added in THF (2 mL) and the

mixture was heated to 50 °C for 2 h. After cooling to rt., 1 M aq. HCl was added carefully

and the layers were separated. The aqueous layer was extracted twice with EtOAc and the

combined organic layers were dried over MgSO4. The volatiles were removed in vacuo and

the residue was purified by column chromatography to yield alkyne 9 (30%, ) as a red oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (t, J = 1.6 Hz, 1H), 8.03 (t, J = 1.7 Hz, 1H), 7.69 (t, J = 1.6

118

Chapter 6

Hz, 1H), 4.31 (t, J = 6.7 Hz, 2H), 3.12 (s, 1H), 1.81 – 1.71 (m, 2H), 1.62 (s, 6H), 1.47 – 1.38

(m, 2H), 1.40 – 1.29 (m, 4H), 0.94 – 0.87 (m, 3H). 13

C NMR (101 MHz, CDCl3) δ 165.1, 144.0,

138.8, 132.7, 132.6, 131.1, 123.6, 122.8, 95.4, 81.8, 80.3, 78.6, 65.7, 65.5, 31.4, 31.3, 28.6,

25.6, 22.5, 14.0. HRMS (ESI+, m/z): Calcd for C20H23O2 [M-OH]+: 295.16926, found:

295.16971. Calcd for C23H30O4Na [M+Na]+: 335.16177, found 335.16207.

Dihexyl 5,5'-((2,2',4,4',7,7'-hexamethyl-2,2',3,3'-tetrahydro-[1,1'-biindenylidene]-6,6'-

diyl)bis(ethyne-2,1-diyl))(E)-bis(3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate) (2)

Motor 11 (57 mg, 0.10 mmol), alkyne 9 (65 mg, 0.21 mmol), CuI (1.5 mg, 0.0078 mmol)

and PdCl2(PPh3)2 (5.6 mg, 0.0080 mmol) were dissolved in degassed DMF/iPrNH 3:1 (2 mL)

and stirred at 50 °C on. After cooling to rt., H2O was added and the mixture was extracted

3x with CH2Cl2. The combined organic layers were washed with 2M aq. HCl, H2O and brine

and dried over MgSO4. The volatiles were removed in vacuo and the residue was purified

by flash column chromatography (SiO2, pentane/EtOAc 5-40%) to yield 2 (25 mg, 27%) as a

white solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 1.6 Hz, 2H), 8.01 (t, J = 1.6 Hz, 2H), 7.76

(t, J = 1.6 Hz, 2H), 7.27 (s, 2H), 4.34 (t, J = 6.7 Hz, 4H), 2.90 (p, J = 6.4 Hz, 2H), 2.68 (dd, J =

15.0, 5.7 Hz, 2H), 2.61 (s, 6H), 2.27 (d, J = 14.9 Hz, 2H), 2.20 (s, 6H), 1.79 (p, J = 6.8 Hz, 4H),

1.65 (s, 12H), 1.51 – 1.41 (m, 4H), 1.41 – 1.31 (m, 8H), 1.13 (d, J = 6.4 Hz, 6H), 0.95 – 0.89

(m, 6H). 13

C NMR (101 MHz, CDCl3) δ 168.1, 146.5, 144.3, 143.9, 140.7, 136.1, 134.7,

134.6, 134.4, 134.2, 133.7, 127.3, 126.1, 123.6, 97.8, 93.6, 93.4, 83.3, 68.3, 68.3, 44.6,

41.9, 34.1, 34.1, 31.3, 28.3, 25.2, 23.5, 21.7, 20.7, 16.7. HRMS (ESI+, m/z): Calcd for

C64H72O6 [M+H]+: 936.5323, found: 936.5326.

Suzuki Polymerization

Motor (S,S)-trans-5 (57 mg, 0.12 mmol), fluorene 12 (78 mg, 0.12 mmol) and Aliquat 336

(20 mg) were dissolved in toluene (6 mL) and 2M aq. K2CO3 (1 mL). The mixture was

119


degassed by purging with N2 for 30 min. Pd(PPh3)4 (4.2 mg, 0.0036 mmol) was added and

the resulting mixture was stirred at 95 °C for 24h. 4-methoxyphenyl boronic acid (18 mg,

0.12 mmol) was added and the mixture was stirred o.n. Then, 4-bromoanisole (15 L, 0.12

mmol) was added and the mixture was stirred for an additional 8 h. After cooling to rt. the

mixture was precipitated in MeOH and washed with MeOH and H2O. The residue was

redissolved in CHCl3, precipitated in acetone and washed with acetone. After drying

overnight, polymer P1 (57 mg, 70%) was obtained as a grey solid. GPC analysis: Mn= 7.6 kg

mol-1

Mw = 9.7 kg mol-1

(PI: 1.3).

6.7 References

[1] S. Hecht, I. Huc, Foldamers: Structure, Properties, and Applications, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007.

[2] S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180.

[3] D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893–4011.

[4] G. Guichard, I. Huc, Chem. Commun. 2011, 47, 5933–5941.

[5] E. Yashima, K. Maeda, H. Iida, Y. Furusho, K. Nagai, Chem. Rev. 2009, 109, 6102–6211.

[6] B. A. F. Le Bailly, J. Clayden, Chem. Commun. 2016, 52, 4852–4863.

[7] R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D. Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg, C. K. Marlowe, et al., Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 9367–71.

[8] D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell, S. H. Gellman, J. Am. Chem. Soc. 1996, 118, 13071–13072.

[9] D. Seebach, J. L. Matthews, A. Meden, T. Wessels, C. Baerlocher, L. B. McCusker, Helv. Chim. Acta 1997, 80, 173–182.

[10] P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science 1991, 254, 1497–1500.

[11] J. C. Nelson, J. G. Saven, J. S. Moore, P. G. Wolynes, Science 1997, 277, 1793–1796.

[12] L. Brunsveld, E. W. Meijer, R. B. Prince, J. S. Moore, J. Am. Chem. Soc. 2001, 123, 7978–7984.

[13] D.-W. Zhang, X. Zhao, J.-L. Hou, Z.-T. Li, Chem. Rev. 2012, 112, 5271–5316.

[14] A. Tanatani, T. S. Hughes, J. S. Moore, Angew. Chem. Int. Ed. 2002, 41, 325–328.

[15] H. Juwarker, J. M. Suk, K. S. Jeong, Chem. Soc. Rev. 2009, 38, 3316–3325.

[16] R. Gopalakrishnan, A. I. Frolov, L. Knerr, W. J. Drury, E. Valeur, J. Med. Chem. 2016, 59, 9599–9621.

[17] W. S. Horne, S. H. Gellman, Acc. Chem. Res. 2008, 41, 1399–1408.

[18] C. M. Grison, J. A. Miles, S. Robin, A. J. Wilson, D. J. Aitken, Angew. Chem. Int. Ed.

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[19] M. M. Müller, M. A. Windsor, W. C. Pomerantz, S. H. Gellman, D. Hilvert, Angew. Chem. Int. Ed. 2009, 48, 922–925.

[20] Z. C. Girvin, S. H. Gellman, J. Am. Chem. Soc. 2018, jacs.8b05869.

[21] Z. Yu, S. Hecht, Chem. Commun. 2016, 52, 6639–6653.

[22] G. A. Woolley, Acc. Chem. Res. 2005, 38, 486–493.

[23] A. Natansohn, P. Rochon, Chem. Rev. 2002, 102, 4139–4175.

[24] M. Irie, Y. Hirano, S. Hashimoto, K. Hayashi, Macromolecules 1981, 14, 262–267.

[25] A. Khan, C. Kaiser, S. Hecht, Angew. Chem. Int. Ed. 2006, 45, 1878–1881.

[26] Z. Yu, S. Hecht, Angew. Chem. Int. Ed. 2013, 52, 13740–13744.

[27] C. Tie, J. C. Gallucci, J. R. Parquette, J. Am. Chem. Soc. 2006, 128, 1162–1171.

[28] Y. Hua, A. H. Flood, Chem. Soc. Rev. 2010, 39, 1262–1271.

[29] Y. Hua, Y. Liu, C.-H. Chen, A. H. Flood, J. Am. Chem. Soc. 2013, 135, 14401–14412.

[30] Z. Yu, S. Hecht, Chem. - Eur. J. 2012, 18, 10519–10524.

[31] D. Pijper, B. L. Feringa, Angew. Chem. Int. Ed. 2007, 46, 3693–3696.

[32] T. van Leeuwen, G. H. Heideman, D. Zhao, S. J. Wezenberg, B. L. Feringa, Chem. Commun. 2017, 53, 6393–6396.

[33] A. Kulago, Nanotechnological Tools Built on Synthetic Light-Driven Molecular Motors, University of Groningen, 2011.



[36] K. Suda, K. Akagi, Macromolecules 2011, 44, 9473–9488.

[37] A. S. Lubbe, Q. Liu, S. J. Smith, J. W. de Vries, J. C. M. Kistemaker, A. H. de Vries, I. Faustino, Z. Meng, W. Szymanski, A. Herrmann, et al., J. Am. Chem. Soc. 2018, 140, 5069–5076.


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[42] J. Conyard, P. Stacko, J. Chen, S. McDonagh, C. R. Hall, S. P. Laptenok, W. R. Browne, B. L. Feringa, S. R. Meech, J. Phys. Chem. A 2017, 121, 2138–2150.

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Chapter 7 Summary

124

Chapter 7

7.1 English Summary

This thesis focusses on molecular motors based on overcrowded alkenes, molecules which

are able to rotate when irradiated with light. Their structures consist of a lower half

(stator) and an upper half (rotor) which are connected through a central axle. When these

motors are irradiated, the upper half rotates with respect to the lower half around this

central axle, exclusively in one direction. One full rotation proceeds in four distinct steps,

all of which can be followed using various techniques. First, upon irradiation, a

photochemical E-Z isomerization of the central double bond occurs. This rotation causes

tension to build up in this newly formed state which strain can be released by slipping the

two halves past each other. This process is often referred to as a thermal helix inversion.

The second half of the rotational cycle is basically the same as the first half; it starts with a

light induced isomerization of the double bond which is then followed by a second

thermal helix inversion.

Scheme 7.1: Rotational cycle of a molecular motor

Over the years, the exact mechanism of rotation of these motors has been studied

thoroughly and the factors influencing their properties such as the rotational speed, light

absorption and efficiency have been investigated. Molecular motors have been

incorporated into various smart materials to dynamically change the properties. For

example, they have been used to form contracting gels, surfaces that change their

wettability and even a small muscle-like fiber. However, if we want to find real-life

applications for molecular motors, there are some challenges that remain. For example,

molecular motors are often powered by high energy UV light, which can be damaging for

many materials but also for cells when considering biomedical applications. It is therefore

important to develop motors that are able to perform rotational motion with visible light,

which is much milder. Moreover, many motors have low quantum yield; typically only 5-

125

Summary

20% of the light that is absorbed contributes to the rotation, the rest is just converted into

heat. Improving the efficiency of these motors will open up new possibilities, especially

when considering applications in nanoscale energy converters and energy storage. In

addition to this, synthesizing molecular motors in the lab can be a long and tedious

process, so the development of motors that can be easily made and which are readily

adapted to the desired environment would be highly beneficial. Finally, one of the major

challenges is to translate the motion of these motors (which is happening at the molecular

scale) to power functions at the macroscale. This requires a certain organization and

cooperativity. In this thesis, some of these challenges are addressed.

In Chapter 2, a molecular motor is designed and synthesized that can be operated using

visible light. The aromatic system of the upper half is extended by incorporation of a

pyrene moiety, allowing the motor to directly absorb visible light. UV/vis and NMR

spectroscopy show that the rotational function of this motor is retained. Chapter 3 also

deals with visible light driven rotation of molecular motors, but uses a different approach.

A new type of molecular motor is developed with a lower half based on an oxindole

scaffold, allowing the easy synthesis of different molecular motors with a range of rotation

speeds. Their rotational cycle is similar to that of molecular motors previously described,

as it is first established by DFT calculations and then subsequently confirmed by 1H-NMR,

CD and UV spectroscopy. Rotational motion can be achieved by irradiation with light of

wavelengths up 505 nm.

Chapter 4 describes the synthesis and characterization of a molecular motor with a

dithienylethene switch attached to the upper half. When the dithienylethene switch is in

the open state, the motor functions as usual, and can be driven with visible light.

Interestingly, when the dithienylethene is switched to the closed state, the rotation of the

molecular motor is inhibited. In this way, the rotation of the molecular motor can be

switched on and off by switching of the dithienylethene.

In Chapter 5, molecular motors are used to form a supramolecular coordination cage. Four

motors coordinate to two palladium ions and form a hollow, spherical shaped structure.

Both cis and trans isomers efficiently form cages and the structures were determined with

(DOSY) 1H-NMR and X-ray and composition by HRMS. The cages are self-sorting, meaning

that even when using a racemic mixture of motors, only cages are formed with four

ligands of the same chirality. DFT calculations show that cages formed from mixtures of

enantiomers are significantly higher in energy. Upon irradiation with light, isomerization

of the ligands is observed, allowing switching between the different cage structures.

Finally, the cavity inside the cages can be used to bind small molecules, as is demonstrated

with a tosylate ion.

Chapter 6 discusses the incorporation of molecular motors into polymers. When

attempting to translate the motion of molecular motors from the molecular scale to the

macroscale, it is essential for the motors to be ordered in a specific structure and ideally

126

Chapter 7

to cooperate with eachother. This chapter explores the possibility to use motors in light

responsive foldamers, which are polymers that can fold into a specific structure. First

generation motors were polymerized with fluorene, but unfortunately the photoswitching

appears to be inhibited and instead fluorescence is observed.

7.2 Nederlandse samenvatting

De focus in dit proefschrift zijn moleculare motoren, moleculen die kunnen roteren

wanneer ze met licht bestraald worden. Ze bestaan uit een onderkant (stator) en een

bovenkant (rotor) die verbonden wordt door een centrale as. Wanneer deze met licht

bestraald worden, draait de bovenkant ten opzichte van de onderkant om deze centrale

as. Eén volledige rotatie bestaat uit vier stappen, welke allemaal gevolgd kunnen worden

met verschillende technieken. De eerste stap is een fotochemische E-Z isomerisatie van de

centrale dubbele binding. Deze isomerisatie zorgt ervoor dat er spanning binnen het

molecuul ontstaat. Deze sterische hinder kan worden verlost door de twee helften langs

elkaar heen te laten schuiven. Dit proces wordt vaak aangeduid als de thermische helix

inversie. De tweede helft van de cyclus is eigenlijk identiek aan de eerste helft: eerst een

licht geïnduceerde isomerisatie, gevolgd door een tweede thermische helix inversie.

Scheme 7.2: Rotatie cyclus van een moleculaire motor

Door de jaren heen zijn het rotatiemechanisme van deze moleculaire motoren en de

factoren die hun eigenschappen beïnvloeden, zoals rotatie frequentie, licht absorptie en

efficiëntie, nauwkeurig bestudeerd. De motoren zijn in verschillende materialen verwerkt

om zo de eigenschappen van deze zogenaamde ‘slimme materialen’ te kunnen

beïnvloeden. Zo zijn motoren bijvoorbeeld gebruikt in gels die krimpen, oppervlaktes die

hun bevochtigbaarheid kunnen veranderen en zelfs vezels die als kleine spiertjes

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Summary

fungeren. Voordat we moleculaire motoren kunnen gebruiken in toepassingen die we in

ons dagelijks leven gebruiken, zijn er nog wat uitdagingen die overwonnen moeten

worden. De meest motor worden bijvoorbeeld aangedreven met UV licht, wat schadelijk is

voor veel materialen, maar ook voor cellen als we over biomedische toepassingen

nadenken. Het is daarom essentieel dat motoren worden ontwikkeld die met zichtbaar

licht kunnen worden aangedreven, wat lang niet zo schadelijk is. Daarnaast hebben

motoren veelal een laag rendement: 5-20% van het licht dat opgenomen wordt, wordt

maar gebruikt voor rotatie, de rest wordt omgezet in warmte. Het verbeteren van het

rendement open de deur voor nieuwe toepassingen, zoals de opslag en conversie van

energie op nanoschaal. De synthese van motoren is vaak een lang proces. Het ontwikkelen

van nieuwe motoren die gemakkelijk gesynthetiseerd kunnen worden en snel aangepast

kunnen worden verschillende omgevingen is daarom een belangrijke uitdaging. Een van

de grootste uitdagingen is wel het overbrengen van beweging op de moleculaire schaal

naar functies op de nanoschaal. Als we dit willen bereiken is het nodig dat de motoren op

een bepaalde manier georganiseerd worden en samenwerken. In dit proefschrift worden

een paar van deze uitdagingen behandeld.

In hoofdstuk 2 worden een moleculaire motor ontworpen en gemaakt die aangedreven

kan worden met zichtbaar licht. Het aromatische systeem van de bovenste helft van de

motor is uitgebreid door er een pyreen in te verwerken. Gecombineerde UV/vis en NMR

spectroscopie laten zien dat de motor functie hierbij is behouden. In hoofdstuk 3 is het

doel ook om een motor met zichtbaar licht aan te drijven, maar er is gekozen voor een

andere strategie. Een nieuw type motor is ontworpen, gebaseerd op oxindole. De

rotatiecyclus is eerst bestudeerd met DFT berekeningen en daarna experimenteel met

UV/vis, CD en NMR studies. Motoren met verschillende snelheden kunnen gemakkelijk

gesynthetiseerd worden doormiddel van een Knoevenagel condensatie.

In hoofdstuk 4 is een moleculaire motor gekoppeld met een dithienylethene schakelaar.

Wanneer deze schakelaar in de open positie is werkt de motor zoals gebruikelijk en kan

met zichtbaar licht aangedreven worden. Echter, wanneer de dithienylethene in de

gesloten positie staat, werkt de motor niet meer. Op deze manier kan de motor functie

gecontroleerd worden door de dithienylethene schakelaar.

In hoofdstuk 5 worden moleculaire motoren gebruikt als liganden in een supramoleculaire

coördinatie complex. Vier liganden coördineren aan twee palladium ionen en vormen zo

een kooi structuur, die gekarakteriseerd is met (DOSY) NMR, X-ray en HRMS. De cis en

trans isomeren vormen beide verschillende structuren en zijn zelf sorterend. Ze vormen

uitsluitend structuren met vier liganden van dezelfde chiraliteit wanneer racemische

mengsels gebruikt worden. DFT berekeningen laten zien dat deze homochirale structuren

stabieler zijn dan de andere mogelijke diastereomeren. Verder laten UV/Vis en 1H-NMR

studies zien dat isomerisatie met licht van de liganden de structuur van de kooi kan

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Chapter 7

veranderen. Hierdoor kan er efficiënt geschakeld worden tussen drie verschillende

structuren.

In het laatste hoofdstuk zijn moleculaire motoren gepolymeriseerd. Om de beweging van

motoren van de moleculaire schaal naar de macro schaal te vertalen, is het essentieel dat

ze georganiseerd worden en samen werken. In dit hoofdstuk wordt de mogelijkheid

onderzocht om motoren in licht responsieve foldameren te verwerken. Foldameren zijn

oligomeren of polymeren die in een bepaalde structuur vouwen. Eerste generatie

motoren zijn gepolymeriseerd met fluoreen, maar het lijkt erop dat de motoren maar zeer

beperkt schakelen in deze structuur.

Chapter 8 Popular science summary

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Chapter 8

8.1 English summary

For chemists, it has been a long outstanding quest to control movement on the molecular

scale. This might seem rather trivial at first, but considering the size of molecules (one

billionth of a meter, hundred thousand times smaller than the diameter of a hair), this is

certainly not an easy task. On top of that, molecules are moving around randomly at high

speeds, constantly bumping into each other, creating a chaos. Therefore, controlling

movement on the molecular scale has sometimes been compared to trying to walking in a

hurricane. However, with the development of molecular machines, chemist are now able

to do just that. A range of tiny machines that are able to do various tasks on the molecular

scale has been developed, but the focus in this thesis is molecular motors: molecules

which are able to rotate when irradiated with light. Their structure consist of a lower half

(stator) and an upper half (rotor) which are connected through a central axle. When these

motors are irradiated, the upper half rotates with respect to the lower half around this

central axle, exclusively in one direction. One full rotation proceeds in four distinct steps,

all of which can be followed using various techniques.

Over the years, the exact mechanism of rotation of these motors and the factors

influencing their properties (such as the rotational speed, light absorption and efficiency)

have been investigated. They have been incorporated in various materials to dynamically

change the properties of so-called ‘smart materials’. For example, molecular motors have

been incorporated in gels that are able to shrink, surfaces that change their wettability

and even a small muscle-like fiber. However, if we want to find real-life applications for

molecular motors, there are some challenges that remain. Some of these challenges are

addressed in this thesis.

For example, molecular motors are often powered by high energy UV light, which can be

damaging for many materials, but also for cells when considering biomedical applications.

It is therefore important to develop motors that are able to perform rotational motion

with visible light, which is much milder. In chapters 2 and 3, new motors are designed

which can be powered with visible light. Moreover, changing the speed of rotation of a

molecular motor can be quite tedious, as it often requires making a whole new motor in

the lab. In chapter 4, a switch is attached to a molecular motor that can be switched

between two states with light. When irradiating this switch, the rotary function of the

motor can be easily switched on and off.

In the final chapters in this thesis, new areas are explored to apply molecular motors.

Chapter 5 describes the formation of hollow spheres (or cages) formed by four molecular

motors. The structures of these motors change upon irradiation with light and as a result

the structure of the cage changes. Controlling the shape and size of cages with light is a

very promising strategy to for example release drugs loaded inside the cavity of these

spheres. In chapter 6, molecular motors are incorporated into polymers, which are long

chains in which the same unit is repeated many times. The aim is to change the structure

131

Popular science summary

of the polymer by shining light on them, potentially changing its properties. In this way,

movement on the molecular scale can be translated to the macro scale by making all the

motors in the chain work together. Unfortunately, the rotary function of the motors

appeared to inhibited when incorporated in the polymers.

8.2 Nederlandse samenvatting

Al jarenlang proberen chemici beweging op de moleculaire schaal te controleren. Op het

eerste oog lijkt dit misschien niet zo moeilijk, maar als je de grootte van moleculen in

ogenschouw neemt (één miljardste van een meter, tienduizend keer zo klein als de

diameter van een haar) dan is dit geen gemakkelijke opgave. Daarnaast bewegen

moleculen willekeurig en op hoge snelheid en botsen voortdurend op elkaar. Sommigen

vergelijken daarom het controleren van beweging op moleculaire schaal wel eens met

proberen te lopen in een orkaan. Met de komst van moleculaire machines is het chemici

toch gelukt om precies dit te doen. Verschillende moleculaire machines zijn ontwikkeld,

maar de focus in dit proefschrift is moleculaire motoren. Dit zijn moleculen die kunnen

roteren wanneer ze met licht bestraald worden. Ze bestaan uit een onderkant (stator) en

een bovenkant (rotor) die verbonden wordt door een centrale as. Wanneer deze met licht

bestraald worden, draait de bovenkant ten opzichte van de onderkant om deze centrale as

in één richting.

Door de jaren heen zijn het rotatiemechanisme van deze moleculaire motoren en de

factoren die hun eigenschappen beïnvloeden, zoals rotatie frequentie, licht absorptie en

efficiëntie, nauwkeurig bestudeerd. De motoren zijn in verschillende materialen verwerkt

om zo de eigenschappen van deze zogenaamde ‘slimme materialen’ te kunnen

beïnvloeden. Zo zijn motoren bijvoorbeeld gebruikt in gels die krimpen, oppervlaktes die

hun bevochtigbaarheid kunnen veranderen en zelfs vezels die als kleine spiertjes

fungeren. Voordat we moleculaire motoren kunnen gebruiken in toepassingen die we in

ons dagelijks leven gebruiken, zijn er nog wat uitdagingen die overwonnen moeten

worden.

De meeste motor worden bijvoorbeeld aangedreven met UV licht, wat schadelijk is voor

veel materialen, maar ook voor cellen als we over biomedische toepassingen nadenken.

Het is daarom essentieel dat mot oren worden ontwikkeld die met zichtbaar licht

kunnen worden aangedreven, wat lang niet zo schadelijk is. In hoofdstukken 2 en 3 zijn

nieuwe motoren ontworpen en gemaakt die aangedreven kunnen worden met zichtbaar

licht. Daarnaast kan het soms lastig zijn om de snelheid van rotatie van een motor aan te

passen. Vaak is het nodig om een nieuwe motor te maken in het lab. In hoofdstuk 4 is er

een schakelaar aan een motor gezet die kan worden geschakeld met licht. Wanneer deze

schakelaar bestraald wordt met licht kan de rotatie functie van de motor uit en aan

worden gezet. Op deze manier kan de rotatie van de motor gecontroleerd worden.

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Chapter 8

In de laatste hoofdstukken worden nieuwe velden onderzocht waar moleculaire motoren

toegepast kunnen worden. Bijvoorbeeld, in hoofdstuk 5 worden vier motoren gebruikt om

holle structuren (kooien) te maken. Door deze structuren met licht te bestralen verandert

de structuur van de motoren en daardoor de kooi. Het controleren van de structuur van

kooien is een interessante strategie om bijvoorbeeld medicijnen die in de holle structuren

zit los te laten op de plek van bestemming. In het laatste hoofdstuk worden motoren

verwerkt in polymeren, lange ketens waarin dezelfde structuur zich steeds herhaalt. Het

doel is om de structuur van de polymeer te veranderen door het te bestralen. Op deze

manier kan de beweging op de moleculaire schaal van alle motoren in een keten

gebundeld worden om zo de eigenschappen van de polymeer te veranderen op de macro

schaal. Helaas leek de rotatie van de motoren grotendeels verhinderd te zijn wanneer ze

in de polymeren verwerkt waren.

Acknowledgements

134

Over the years there have been so many people that have contributed in some way to this

thesis that I would like to thank. I am very grateful that I had the pleasure to work in such

an amazing place with lovely coworkers and made many friends along the way. Some

people say a PhD is 4+ years of agony, working your way through endless experiments,

meetings and papers. I can just say I’ve really enjoyed this period, because of all the great

people I’ve met in this time.

First of all, I would like to thank my promotor, Ben. Thank you for allowing me to do my

PhD in your group. You’ve managed to create a place with a very diverse group of people

where the members don’t see each other as competition but work together, making it

such a great environment to work and (maybe even more important) to learn. Your

enthusiasm for chemistry is unrivaled and has been a great inspiration.

Sander, I would like to thank you for all the guidance you’ve given me over the years. In

the beginning you really helped me getting started with molecular motors and throughout

the years you’ve helped me a lot with all your advice and corrections, including this thesis.

It’s great to see that your own group is now forming, I’m sure you will do great as a

supervisor. I wish you and your family all the best for the future.

I would like to thank my second promotor Prof. Browne and my reading committee for

taking the time to read my thesis and giving valuable suggestions: Prof. Bach, Prof. Otto

and Prof. Otten.

A great thanks is owed to all the people that are keeping the group running, and have

allowed me and all the other group members to focus on the chemistry. Tineke and Inge,

thank you for letting the whole group run so smoothly. It has been mentioned more often,

but without you I think we would be running around not knowing what to do like savages.

Thanks to all the support staff for their help with various instruments and analysis:

Monique, Theodora, Hans, Renze, Pieter and Johan.

I would like to thank my Paranimphs Mickel and Dorus, first of all for getting me through

the big day. Mickel, it’s so great that we started together 9 years ago and can now defend

on the same day (I’m just a bit earlier than you, but that’s ok). Your work ethics have

always impressed me, from the first practical courses to the final stages of your PhD. Apart

from that I’ve really enjoyed the coffee breaks, lunches and party’s (nog eem kneiterhard

ouwehoeren) we shared over the course of the last years. I hope our friendship will

continue, even though (for the first time in almost 10 years) we won’t be studying or

working together anymore. Dorus, your presence in the lunchroom is already legendary,

we really share the same sense of humor (to the point where it got scary). Sharing desks at

the beginning of our PhD was maybe not the most productive, but it was a lot of fun.

I would like to thank the students that I’ve guided and who in that way contributed to this

thesis. I cannot say this without a special mention to Constantin. When a new student

arrives, it can be a bit of a lottery. Sometimes you get lucky and a good one arrives,

135

Acknowledgements

sometimes they’re a bit less talented. With you I hit the jackpot, you contributed a great

deal to this thesis and for that I owe you a massive thanks. Especially in your second stay

in Groningen I hardly felt that I was your supervisor, as we were just discussing as peers.

Apart from that it was great to have you in the lab, shouting at your pc (Arschmachine!)

and yourself (Why are you so shit?!). You were also Berlin’s best and worst tour guide. I

wish you the best of luck with the remainder of your PhD, but I’m sure you’ll do fine.

I would like to thank all the colleagues I’ve worked with over the years and have

contributed in some way. Sometimes for their collaborations, advice and help, others for

the great times during coffee breaks, borrels and trips. They are too many to mention all

of them here, and I would probably forget half, but you know who you are! I do want to

name a few special people here.

Wojtek, I’ve learned a great deal from you. You are an excellent chemist with a broad

knowledge and I’m sure you will do a great job finishing your PhD soon! Thanks for the

interesting discussions and advice but also for your friendship! Hugo, your sound effects

have lightened up many lunches and cycling trips. Thanks for your humor. Filippo, your

honest (and sometimes savage) reviews of basically anything that you see are

unprecedented. Thanks for your sassy comments and coffee breaks. Hennie, thanks for all

the coffee breaks, lunches and trips we shared. Sometimes it seems that you are one of

the few that is not affected by the C-wing, but it only makes those few moments that it

does come out so much better. Franco, thank you for the all the beers that you bought

and the beer that you bought and OMG more beer?

To the old group members: Anouk, you are by far the craziest person I’ve met. Apart from

that, you are also a lovely person that will go out of her way to help your friends. Thanks

for the coffee breaks, organizing trips and crazy borrels. Jos, thanks for the advice on

motors early in my PhD, it helped getting me started. A massive thanks also for the house,

it is a lovely place. Jiawen (although you are still here), it was a great experience starting

my BSc in this group, seeing you and Martín play basketball in the lab. I wish you and your

family all the best when you are moving back to China soon! Martín, a great thanks for

guiding me during my BSc and MSc. I learned a lot from you which greatly contributed to

the work I did described in this thesis.

Pap & Mam, jullie hebben me de basis gegeven waarop ik verder kon bouwen. Ik ben

dankbaar voor de onbezorgde opvoeding die ik heb gehad en goede voorbeeld dat jullie

me blijven geven op zoveel vlakken. Bedankt voor alles.

Het beste bewaar je altijd voor het laatst. Marlies, ik ben dankbaar voor je steun de

afgelopen tijd. Je weet soms beter wat er in me om gaat dan ik zelf. Ik kijk uit naar onze

toekomst samen. Wat we ook gaan doen en waar we ook belanden, zolang we samen zijn

komt het allemaal wel goed! Ik hou van je.

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Documents

University of Groningen · 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