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On the use of a bow tie template and quinol-like ring-precursors in the covalently assisted synthesis of [2]rotaxanes

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Bachelor Thesis Scheikunde

On the use of a bow tie template and quinol-like

ring-precursors in the covalently assisted synthesis of

[2]rotaxanes

by

Finn McSorley

August 24, 2020

Student ID

11779470

Research institute

Van 't Hoff Institute for Molecular Sciences

Research group

Synthetic Organic Chemistry

Supervisor

Prof. Dr. Jan H. van Maarseveen

Daily supervisor

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Abstract

This thesis presents the utilisation of novel ring and thread components for the covalently assisted and template-directed synthesis of rotaxanes, which is a form of Mechanically Interlocked Molecule (MIM). This is done in the context of producing modular rotaxanes that do not contain pre-organisational motifs such as those found in non-covalent strategies, expanding the different possible architectures that are available. Furthermore, the novel components chosen have been designed with applications as molecular machines in mind. To this end, a modular and bulky tetraphenyl-terephthalic acid is utilised as the template, with its distinctive bow-tie shape. Two quinol-like ring-precursors with terminal alkynes were chosen to accommodate for a Glaser-Eglinton type macrocyclisation to afford the pre[2]rotaxane, thereby attempting to circumvent the bulkiness of the template. Furthermore, this could permit smaller 26-ring components instead of the 30-ring macrocycle used in previous publications, warranting the preparation of two ring-precursors, although the former is tested on a smaller model template as well. This thesis synthesized the ring-precursors and the activated ester of the template successfully. However, early attempts at functionalisation of the template with the introduction of bromides proved unsuccessful. Coupling of the template and the ring-precursors proved relatively successful, as NMR provided evidence for coupling, albeit in low amounts and with potential decomposition. Coupling with the simpler template and the 26-ring proved successful, although a follow-up Glaser reaction afforded no meaningful product. A preliminary Glaser reaction to produce a 30-ring macrocycle proved unsuccessful, indicating the difficulty of working with a bulky template. Conditions will need to be improved and optimised to improve conversion, prevent decomposition, and create a successful strategy.

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Populairwetenschappelijke samenvatting

Als men een draadvormige molecuul door een groot ringvormige molecuul arrangeert en vervolgens grote moleculaire groepen op de uiteinden van de draad plaatst zodat de componenten niet uit elkaar kunnen, dan wordt een zogenaamde rotaxaan gevormd: twee moleculen die op een mechanische manier verbonden zijn (Figuur 1). Dit wordt meestal bereikt door een motief op de ring of de draad te plaatsen, dat de andere component aantrekt en zo in de juiste positie plaatst. De rotaxanen die hieruit ontstaan kunnen mogelijk heel nuttig zijn voor het transporteren van moleculen en deeltjes, omdat de ring over de draad beweegbaar is.

Helaas blijven de motieven die gebruikt worden voor preorganisatie van de componenten vaak achter in de rotaxaan, waardoor de diversiteit van rotaxaan structuren enigszins wordt beperkt. Hierdoor kunnen sommige structuren met praktische applicaties niet gemaakt worden. Daarom is er ook interesse in een andere manier van rotaxanen maken, waarbij men één molecuul maakt dat bestaat uit een ring en een draad en vervolgens een binding tussen die twee componenten breekt, met als gevolg twee aparte componenten die op een mechanische manier zijn verbonden. Op deze manier blijft er geen motief achter op de ring of de draad en kan mogelijk een grotere diversiteit aan structuren bereikt worden.

Dit proefschrift probeert de eerste stappen te maken tot de synthese van een uniek soort rotaxaan (Figuur 1) volgens de eerdergenoemde methode. De X-vorm van de draad kan een groep op elk uiteinde toelaten, waardoor hij heel modulair overkomt. Bovendien bevat de ring twee groepen die van praktisch belang zijn. Op deze manier kan een rotaxaan gemaakt worden die aangepast kan worden voor de situatie of toepassing die zich voordoet. Deze thesis maakt gebruikt van methodes die eerder zijn geformuleerd en past ze aan voor de synthese van een X-vormige rotaxaan. Dit moet vooral omdat de draad een heel omvangrijke vorm heeft, die moeite kan opleveren als de ring eromheen gemaakt wordt. Verder is het belangrijk dat groepen op de uiteinden van de X-vorm ook relatief gemakkelijk geplaatst kunnen worden.

Figuur 1: Schematische representatie van een rotaxaan (links). De X-vormige rotaxaan (rechts) wordt gemaakt door (1) de ring delen op de draad te plaatsen en vervolgens (2) de ring te sluiten en de grijze bindingen te breken.

Met betrekking tot deze aspecten, probeert deze thesis erachter te komen of een omvangrijk X-vormige draad samengebracht kan worden met de unieke ring. Als bijvragen wordt er gekeken hoe eenvoudig de componenten gemaakt kunnen worden en of nuttige groepen op de draad geplaatst kunnen worden. Allerbelangrijkst echter is of de ring om de draad past, waardoor de aangepaste, oftewel nieuwe, methode praktisch kan zijn voor vervolgonderzoek. Om op deze vragen antwoord te geven, werden de benodigde ring en draad componenten gemaakt en werden pogingen gemaakt om ze samen te brengen.

Uit deze pogingen bleek dat de componenten relatief gemakkelijk gemaakt kunnen worden en dat de ring componenten enigszins succesvol op de draad kunnen worden geplaatst. Helaas was de laatstgenoemde reactie niet tot voltooiing gebracht, waardoor in vervolgonderzoek het belangrijk is om de reactie te optimaliseren. De vorming van de ring om de draad verliep heel moeizaam en zal ook optimalisatie vergen. Desondanks is het veelbelovend dat de componenten gemaakt kunnen worden en samengebracht kunnen worden. Er moet wellicht nog gesleuteld worden aan de grootte van de ringen, zodat ze passen om de draad.

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Introduction

Since the early 20th century, the increased understanding of non-covalent bonds and their occurrence in

nature has helped along the development of the field of supramolecular chemistry. Nowadays, these non-covalent bonds, or rather interactions, remain dominant in the field.1,2 None more so do these

interactions dominate, than in the field of the mechanical bond and the intriguing mechanical architectures associated with it. Using non-covalent motifs, a ring can for instance be arranged over a thread, securing the topology in place.3,4 Subsequent stoppering of the thread at either ends, creating a

dumbbell shape, prevents it from unthreading the ring, creating the mechanical bond.5 This is an

example of a rotaxane: one of a small group of Mechanically Interlocked Molecules (MIMs). This strategy, together with “capping”, “slipping” and the active template approach, form the mainstay of rotaxane synthesis (Scheme 1).6,7 Importantly, the motifs, or templates, used for preorganisation in most

strategies are maintained in these MIMs: they do not disappear after the mechanical bond has been formed. Often, these remaining motifs impart some form of functionality into the MIM, which can be a desired effect.8

Scheme 1: The common rotaxane synthetic strategies.6,7 The grey line represents the preorganisation induced by the motif, and the grey ball

for the active template method represents the metal ion. Note that the metal ion is not retained in the final rotaxane.

Indeed, it is not only aesthetics that drive chemists to arrange these mechanical architectures. Perhaps most intriguing of all are the molecular machines, inspired by their likenesses in nature, meant to imitate biological systems. The conformational flexibility of rotaxanes allows them to undergo significant changes in structure when prompted by external stimuli, such as charge and photo-induced changes.9–11 If these stimuli cause the ring from a rotaxane to move over the thread from one side to the

other, a molecular shuttle is created. In doing so, the properties of the rotaxane are changed as well, such as with photochromic rotaxanes, resulting in changes of colour, redox potential and dipolar moments.11 This has obvious applications for the fields of electronics, catalysis, bio-sensors and more,

and the potential for creating bio-inspired systems, such as those needed in pursuit of artificial photosynthesis, is immense. Photo-induced electron transporters are already a possibility and charge separated states have been achieved in the confines of a rotaxane.12 Moreover, light-induced electron

transport from the ring to the thread has already been attempted successfully.13All the rotaxanes used

for these transporters were made possible with the non-covalent templated approach.

However, ironically enough, the first successful, non-statistical based approach to rotaxane synthesis was actually covalently directed.14 Back in 1969, Schill published a paper detailing the

preparation of a rotaxane, whereby covalent-template-directed macrocyclisations were followed up by cleavage of temporary bonds between the macrocycle and the template.14 Although remaining moieties

can indeed sometimes be desired, they could also possibly interfere by limiting the structural diversity of the obtainable rotaxanes.15 Full control over which groups are present in the end-product will allow

one to tailor a rotaxane to one’s specific needs and desires. Certainly, if that desired product is a peptide, imitating those found in nature, the non-covalent motifs cannot remain. It is not surprising then that over the last few years covalent approaches have re-emerged on the stage as viable strategies.

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In contrast to the non-covalent methods, the cleavage of a labile bond between the ring and the thread yields the [2]rotaxane (n in [n]rotaxane represents how many components, such as a ring and a thread, are present in the final rotaxane). In order to obtain that bond, the synthesis must revolve around a template at its centre, upon which the various moieties are introduced: so-called template directed synthesis. The template is covalently attached to the macrocycle by labile bonds, such as esters, which are cleaved in the last step. In 2017, Steemers et al. published a letter detailing the use of a terephthalic acid template to direct the synthesis of an all-carbon 30-ring [2]rotaxane, which was based on an earlier report by the Höger group.15,16 It was found that the terephthalic acid template allowed for easy

installation of the stoppers and effective positioning of the ring-precursors prior to “clipping”. Following up on these results, in 2020, the Van Maarseveen group published a paper outlining how “capping” approaches using the terephthalic acid template can lead to a diverse class of homo- and hetero-[n]rotaxanes, providing a systematic and reproducible approach to the tailored design of rotaxanes.17

Scheme 2: Retrosynthetic scheme for the type of bow tie-shaped [2]rotaxane that forms the end-goal. Note that this scheme uses ring-precursor 3b as an example. The R-groups can be tailored to one’s liking and can theoretically be introduced onto the template 5.

Despite these pioneering efforts, rotaxanes prepared along covalently assisted strategies are still a niche effort and have not yet achieved their maturity and can be seen as a source of untapped potential for creating unique and practical rotaxanes. Using the template directed methods described above, this thesis attempts some of the steps required to preparing a [2]rotaxane suitable for those applications in electron transfer. The novel aspects included in these attempts are a modular bow tie-shaped template and quinol-like ring-precursors (Scheme 2), as these components can introduce and enhance the modularity of the rotaxanes and methods described previously.15,17 Together they form the eventual goal

of this undertaking, which is creating the type of [2]rotaxane presented in Scheme 2, with modular end-groups and quinone moieties in the macrocycle. The latter moieties can prove especially useful in the intended goal of electron transfer, and thus building them into the ring-precursors successfully is required. Furthermore, they could provide an alternative route to the covalent bond cleavage needed to form the [2]rotaxane from the pre[2]rotaxane. Instead of a difficult saponification of the sterically isolated esters, oxidation of the more exposed quinol moieties could yield the final rotaxane (Scheme 2).18 Not only this, but the bulkiness of the tetraphenyl-terephthalic acid, or bow tie template 5, will

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require these ring-precursors to be tailored to fit properly around the template. This, however, will require a different approach from what is typical of the established methods from the SOC group.

Instead of forming the macrocycle after a Grubbs ring closing metathesis (RCM) of the terminal alkenes, terminal alkynes have been installed in the precursors to permit a Glaser-Eglinton type reaction, as the latter method produces a straight chain of four carbons, which is more likely to happen around the template instead of small loops forming at the top and the bottom of the template, as illustrated in Fig. 1.19 This Glaser approach could therefore also permit the use of smaller macrocycles,

such as a 26-ring macrocycle instead of the previously employed 30-ring component shown in Scheme 2. However, the feasibility of such a small ring-precursor also requires testing on a simple 2,5-dimethoxyterephthalic acid template 9 as well, so as to illustrate any differences between a bulky and non-bulky template (Scheme 7). Using this theoretical background, it is hoped that the inevitable steric hindrance imposed by the template can be in effect limited, thereby permitting such [2]rotaxanes to be prepared. Of course, template 5 will require some form of functionalisation of the phenyl-groups to achieve such modularity.

Figure 1: This figure illustrates how cyclisations leading to two small rings is favored for when a Grubbs II ring closing metathesis is used, whereas with a Glaser-Eglinton reaction, the formation of small loops is unfavorable due to the straight chain of four carbons, which is very

straining in small rings.19 As a result, the larger macrocycle is favored instead.

Keeping the eventual goal of a modular bow tie-shaped [2]rotaxane in mind, this thesis poses the question of how feasible a covalently assisted, template-directed synthesis using a tetraphenyl-terephthalic acid and quinol-like ring-precursors can be to create modular [2]rotaxanes. The measure of this feasibility lies in three important aspects. Firstly, it depends on the ease with which its base components, namely the different ring-precursors and the template can be prepared, and for the latter component to be functionalised. Secondly, it depends on whether the ring-precursors can be coupled to the template successfully, which is expected to prove difficult due to the cumbersome template. Lastly, and perhaps most importantly, it depends on whether the Glaser-Eglinton approach for the macrocyclisation will provide a successful pathway to ring-closure around such a stubborn template, and whether smaller 26-ring macrocycles can successfully be formed. Again, this will prove difficult, and likely conditions will need to be refined to allow this to occur. In order to assess these aspects, the required components were synthesized, including two different ring-precursors 3a,b (Scheme 3) and the activated template 6

(Scheme 4)

, and preliminary attempts are made at functionalisation of the template 5 (Scheme 4). Couplings between the ring-precursors and the bulky tetraphenyl and simpler model template were performed (Schemes 5 and 6), which were followed up by attempts as Glaser-couplings (Schemes 7 and 8).

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Results & Discussion

There are two major components of a rotaxane that need to be synthesized: the ring and the thread. The ring is made up of two ring-precursors which are placed upon the template and subsequently cyclised. The synthesis of the ring-precursors 3a,b started with the ortho alkylation of 4-methoxyphenol, which required paraformaldehyde and sodium hydroxide, affording a 72% yield of the resulting tri-alcohol, similar to the yields found in literature (Scheme 3).20,21 Using a solution of HBr in acetic acid, the two

benzylic alcohols were selectively brominated, affording the dibromo product 2 in 64% yield, although it should be noted here that the 1H NMR showed that there was still a large presence of acetic acid in

the final product, even after drying in vacuo. The difficulty of removing the remaining acetic acid is exemplified by the attempts that were made to wash the product. The use of a bicarbonate solution initiated a reaction with the product. Washings with diethyl ether were ineffective, as the product is soluble in said solvent, and washings with petroleum ether were ineffective. Likely washings with water would yield better results, although extensive drying would be required after doing so.

Scheme 3: Synthesis of the ring-precursors.

In any case, the acetic acid may have proven troublesome in the preparation of the final ring-precursors 3a,b, considering that the reaction is sensitive to the presence of acids. This is because an alkoxide of the alkyne (propargyl alcohol or but-3-yn-1-ol) was first prepared using NaH, followed by addition of the dibromide 2. Acetic acid has the potential to react with the alkoxide and interfere with the desired reaction. This could be reflected in the yields for 3a and 3b of 20% and 19%, respectively. As a result, the overall yield for this synthetic route is about 12%, which is low for a three-step synthesis. The role that the acetic acid plays is however not definitive, as the yield can also potentially be lowered by a polymerisation side-reaction, resulting from the phenoxide reacting with neighbouring bromides. After all, the phenol is acidic, and will quickly be deprotonated by the alkoxide. To this end, a protection and deprotection step may be introduced to prevent such side-reactions from happening, with the drawback of adding more complications into the synthetic route. Despite these setbacks, enough of both the ring-precursors was prepared in order to continue.

The focus now shifts towards preparing the namesake and most distinctive part of this prospective bow tie rotaxane: the tetraphenyl-terephthalate template 5. This commences with the condensation reaction of 1,3-acetonedicarboxylate and benzil, whose product is reacted with diphenylacetylene in a cycloaddition that produces the tetraphenyl-terephthalate 4. These steps were performed according to literature by members of the SOC group prior to this thesis.22 With compound

4 in hand, the next required step was to hydrolyse the esters in order to prepare the active ester of the

template necessary for the subsequent coupling (Scheme 4). Hydrolysis in aqueous HBr in acetic acid under conditions of reflux for two days afforded a quantitative yield of the diacid template 5. This was further transformed into the shelf-stable bispentafluorophenyl esters 6 by treating the terephthalic acid with pentafluorophenol in presence of the coupling reagent HBTU and the organic base DIPEA, for a final yield of 60%.17 Pentafluorophenol is difficult to separate from the product using only column

chromatography, as it tends to elute together. Therefore, subsequent washing steps with petroleum ether and trituration were required to remove most of the phenol, leaving it only as a trace impurity, barely visible in the 19F NMR spectrum (Fig. S5, supplementary information).

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Scheme 4: a) Synthesis of the activated template, and b) the activation of the functionalised template.

Originally, one of the goals was to install bromides on the tetraphenyl template at the para positions to allow for stoppering later on in the synthesis. An attempt was made to brominate compound

4 using NBS in TFA, which resulted in a modest yield of 28% (Scheme 4). However, subsequent

attempts to hydrolyse the esters proved futile, despite the use of harsh conditions. Initially, the same conditions were used as for compound 4, which proved unsuccessful. The insolubility of the compound in most common solvents may have added to the difficulty, but an attempt at cleavage in toluene, in which the compound is soluble at reflux, also yielded no conversion. Also using a very concentrated solution of the HBr was ineffective. Thus, the continuation of this route was found to be in vain.

However, approaching the bromination from the diacid 5 of the template would circumvent this issue. Indeed, the terephthalic acid was brominated under the same conditions of NBS in TFA, but in a lower yield of only 12% (Scheme 4). This could potentially be improved by employing a longer reaction time. Despite the efforts to functionalise the template, the preparation of the pentafluorophenyl ester 7 was completely unsuccessful and yielded only starting material (Fig. S8). This suggests that either the formation of the activated ester of HBTU or the pentafluorophenol is too hindered by the presence of the bromides. These setbacks indicate that the bromide installation may have to come as a step after the coupling of the ring-precursors 3a,b and the PFP ester 6 has already occurred. However, this can introduce a multitude of complications, as there is the potential for reactivity with the newly introduced ring-precursors.

If the bromides are successfully installed, and no further problems are encountered, they can then be substituted by stoppers using the Pd-mediated Suzuki coupling. This thesis proposes using a biphenyl boronic acid, to create a large cross shape, preventing the ring from slipping off. However, as a result of the problems encountered with the bromide installation, it was decided that the unbrominated terephthalic acid 5 would serve as the template, in order to determine whether the coupling reaction and subsequent Glaser reaction are feasible even on this simpler template. Thus, two couplings were performed: one using the short ring-precursors 3a and one using the long ring-precursors 3b, eventually leading to a 26- and 30-member macrocycle, respectively (Scheme 5). In previous publications by the SOC group, 30-member macrocycles were utilized on simpler templates successfully, providing the basis for their use here.15,17

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Scheme 5: Coupling of the activated terephthalic acid template with the ring-precursors.

Already problems were encountered during the coupling of the template 6 with ring-precursor

3a. Firstly, an incorrect eluent was chosen to purify the crude reaction, affording a mixed fraction.

Despite this, further purification could still be carried out and a second column yielded a fraction as a single spot on TLC. The fraction contained ca. 100 mg of “product” relative to 1.04 g of template 6. The 1H NMR of this fraction shows characteristic peaks for the terminal alkyne and the adjacent

methylenes (Fig. 2; Figures S3 and S9). However, two triplets characteristic of a terminal alkyne are found, neither of which correspond to the terminal alkyne of the starting material, as illustrated in Fig. 2. Moreover, two peaks corresponding to the propargylic methylenes are also found. All four peaks show the same coupling constant of J = 2.4 Hz, indicating that the peaks are indeed related. The presence of two different sets of alkyne-related peaks is indicative of two possibilities: either there are two products present in the fraction, or there is one asymmetric product.

Figure 2: 1H NMR spectra of 8a (red) and ring-precursor 3a (blue). The shifts of the ring-precursor have been assigned (green) to the

structure for reference. Shifts are reported at the top and the areas at the bottom, both in blue. Note how the red spectrum differs from the blue spectrum. Furthermore, there are two sets of alkyne related peaks in the red spectrum with a 2:1 ratio of integrals.

The clue lies in the integration of the peaks, as one finds that the triplet (terminal alkyne proton) at 2.40 ppm integrates to 4.0, whilst the adjacent triplet at 2.46 ppm integrates to 2.0. Thus, there is a 2:1 ratio for these peaks. It is possible that the fraction consisted of a mixture of the mono-substituted product (i.e. one ring-precursor attached to the template, leaving one side with the PFP ester intact), and the di-substituted product. This would indeed yield a triplet integrating to 2.0 for the former product,

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and a triplet integrating to 4.0 for the latter product. If this is the case, 19F NMR would show the presence

of a PFP ester belonging to the mono-substituted product, and indeed this appears to be the case. (Fig. 3; Figures S5 and S9). Furthermore, as is illustrated in Fig. 3, the PFP ester peaks are shifted relative to those of the template 6, indicating that it is indeed a different compound. Based on these results, an initial conclusion would be that a 1:1 mixture of the mono- and di-substituted compounds was obtained.

Figure 3: 19F NMR spectra of suspected product 8a (red) and 6 (blue). Shifts are reported at the top of the spectrum in blue. Note how the

three major shifts in the red spectrum are similar to those in the blue spectrum, suggesting a similar structure, such as a mono-substituted template. Also note the presence of by-products (smaller peaks) from the PFP esters and/or pentafluorophenol.

If some of the remaining peaks of Fig. 2 are consulted, this conclusion is substantiated yet more. The aromatic peaks should integrate to a total of 20.0, accounting for the 20 aromatic protons in the template. Instead, they integrate to 43.0, which is in accordance with the suggested 1:1 mixture of products: two distinct compounds, each with 20 aromatic protons belonging to the template. Furthermore, two different possible methyl ether peaks at 3.76 and 3.69 ppm are also found, although their integration is slightly off. The same can be said for the peak of propargylic methylenes of the mono-substituted product, which integrates to 3.4 instead of 4.0. The equivalent peak of the di-substituted product at 3.82 ppm is significantly shifted to the right relative to the isolated ring-precursor (ca. -0.43 ppm). This raises the question of why the supposed di-substituted product has a much larger shift compared to the supposed mono-substituted product, suggesting that the coupling did not entirely yield what was wanted or expected.

The benzylic methylenes are altogether more elusive, considering three distinct singlets in the region of 5.3 to 4.5 ppm are visible. One of these most likely belongs to the mono-substituted product, but that leaves two peaks unaccounted for. These unaccounted peaks are possibly the result of by-products. Again, the equivalent peak for the di-substituted product at 3.26 ppm is shifted to the right of the isolated ring-precursor (ca. -1.45 ppm). The position of the benzylic group allows it to be directly in line with the phenyl rings of template, which would provide increased shielding due to ring current effects. However, this would be in contradiction with the expected conformation of the ring fragments; they would most likely prefer to be orthogonal relative to the centre of the template. Furthermore, such a shift would then also be expected in the mostly chemically equivalent mono-substituted product. Thus, some peaks are rather inconclusive as to what the outcome of the reaction was.

None more so than the peaks belonging to the aromatic protons of the ring fragments. Only one distinct singlet at 6.75 ppm is found, which integrates to 2.0, indicating its involvement in the mono-substituted product. However, no such peak belonging to the di-mono-substituted product is immediately evident, unless it has amalgamated with those protons of the template. Indeed, several sharp peaks are discernible at 7.22, 7.21 and 7.16 ppm. Nonetheless, it remains difficult to determine why these peaks

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would be shifted so far to the left. This, along with the large shifts to the right seen in the other peaks, most importantly the alkyne peaks, are indicative of something else having occurred during the reaction. Why would the alkyne of the supposed di-substituted product be shifted so far relative to the supposed mono-substituted product, considering the chemical environments of both alkynes are very similar, and the ring-precursors experience the same steric and electronic effects in both presumed products.

These observations, along with the emergence of several unaccounted singlets, indicate that some form of decomposition may have taken place. Considering that the alkyne and benzylic peaks shift far to the right, it is possible that the di-substituted product was formed in a maimed state. It is conceivable that the conditions used proved too harsh to allow for reliable formation of the desired product, instead forcing other side-reactions to take place. In any case, if this was a simple case of a mono- and a di-substituted product, the spectrum would have appeared much less complicated. Despite all this, the spectra still provide evidence that the ring-precursor 3a was attached to the template. Thus, follow-up conditions must focus on increasing the conversion, so as not to end up with mono-substituted product, and on preventing decomposition. Furthermore, this could also increase the relatively low-yielding reaction. To this end, lower temperatures and longer reaction times may prove fruitful. Sadly, for the sake of this thesis, as there was decomposition no meaningful isolated product of 8a was obtained to perform a Glaser coupling with.

Scheme 6: Coupling of the activated terephthalic acid template 9 with ring-precursor 3a.

This is exactly why it was chosen to couple 3a to the 2,5-dimethoxyterephthalic acid template

9, as it should prove less difficult due to the less constraining nature of this template. In this way, a

Glaser-Eglinton reaction could still be tested with 3a. The coupling was performed with Cs2CO3 in dry

ACN at 50 oC (Scheme 6). Considering that these conditions are less forcing than those of the coupling

with template 6, it is telling that an isolated di-substituted product was obtained according to the 1H

NMR and mass spectrum (Fig. S12), with a yield of 28%. No mix of products was obtained. In effect, this strongly suggests that the tetraphenyl template is indeed restricting the attachment of the ring-precursors, if even at increased temperature it remains difficult to attach. It should be noted that the reaction time was much longer for this coupling, being worked-up after 5 days instead of overnight. In fact, the solvent had unwittingly evaporated during that period. So, the yield could have been lowered due to the reaction stopping as soon as the solvent had evaporated, explaining the rather mediocre yield of 28%. In any case, this reaction yielded product suitable for a follow-up Glaser reaction in order to judge whether a 26-ring macrocycle can fit even over a simple terephthalic acid template.

Based on the results obtained for the preparation of 8a, a slightly lower temperature of 100 oC

was used for the coupling of the template 6 with ring-precursor 3b, which yielded a more promising 1H

NMR after purification of the reaction that afforded a possible 12% yield of product (Fig. 4; Figures S4 and S10). Interestingly, repeat experiments at 50 and 75 oC yielded the same 1H NMR spectra (Fig.

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glance of the 1H NMR spectrum presented in Fig. 4, there appears to be a shifted alkyne peak, along

with a shifted alkynyl methylene. Upon closer inspection, the shape is not characteristic of what is expected. Although a triplet of doublets is expected, the shape is more akin to a quartet of doublets, suggesting that there are two different peaks overlapping each other. The same is observed for the terminal proton of the alkyne, which has four peaks, instead of three. Interestingly, this is repeated for the aromatic shifts at 6.79 and 6.76 ppm, and the methoxy shifts at 3.71 and 3.70 ppm, where only one sharp singlet is expected. Perhaps there are two major conformations for the ring fragments, forced upon them by the template, which could yield two sharp yet very close peaks. The remaining methylene peaks appear to have shifted together into the group of singlets situated at 3.21 ppm. This could in fact be the result of ring current effects from the template shielding these protons.

Figure 4: 1H NMR spectra of 8b (red) and ring-precursor 3b (blue). The shifts of the ring-precursor have been assigned (green) to the

structure for reference, and an expansion of the peaks at 2.39 and 2.01 ppm has been provided. Shifts are reported at the top and areas at the bottom, both in blue. Note the sets of double singlets at 6.79/6.76 and 3.71/3.70 ppm, along with the cluster centred at 3.22 ppm.

Upon integration of the peaks, the areas of all the aforementioned peaks approximate what would be expected, with the glaring exception of the large multiplet in the aromatic region, integrating to 54.2. Although the integration will be slightly off due to the presence of the chloroform-d peak. This large area and the presence of two sets of peaks for each proton environment could yet again be indicative of two different products. However, unlike with the coupled product 8a with the ring-precursor 3a, the sets of peaks are very close to each other and not far away. Despite this, integrating the sets of peaks separately, with the larger one being twice as large as the smaller one, one does find an approximate ratio of 2:1. Though, as a result of doing this, the aromatic region integrates to 102.0, much too large for only two different products.

In summary, for this spectrum, there are two possibilities. Firstly, two products could have formed, a mono- and a di-substituted product, although the large aromatic area contradicts this. Secondly, the desired product was formed, and two major conformations are imposed by the template, resulting in the sets of two peaks. The latter conclusion is possible if the very demanding shape of the template is considered, whose pronounced phenyl groups could realistically prevent free movement of the ring fragments. In any case, the spectrum strongly suggests that the ring-precursors were coupled to the template to a certain degree, and importantly a mass spectrum (Fig. S10, not accurate mass) of the product showed a nominal mass of 1010.4452 Da relative to the calculated mass of 1010.4030 Da. Similar as with the results of the preparation of 8a, the focus now should lie on improving the conversion of the coupling. Again, longer reaction times could prove to be pivotal, and based on the couplings performed at lower temperatures, it would seem that higher temperatures could also be

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avoided, especially for the coupling using ring-precursor 3a. Lastly, it was decided that the spectrum in Fig. 4 looked promising enough to test a Glaser-Eglinton type coupling with the terminal alkynes, whose presence is still confirmed by the 1H NMR. Thus, a Glaser-Eglinton reaction would theoretically

still show conversion in terms of a smaller alkyne peak.

Scheme 7: Glaser-Eglinton coupling of model compound 10.

The first Glaser coupling was performed using model-compound 10, containing the smaller 2,5-dimethoxyterephtalic acid template 9 and ring-precursor 3a. It was carried out using CuCl and TMEDA in THF at a low concentration (Scheme 7). After 5 days the reaction was worked up and purified by column chromatography. The fractions obtained showed no conversion of the terminal alkynes based on 1H NMR (Fig. 5; Figures S12 and S13). Indeed, the other peaks line up with those

from the starting material both in terms of shift and area. Thus, the spectrum on initial interpretation suggests that no Glaser-Eglinton reaction had taken place, which is foreboding when the template in use here is the much less encumbering one.

Figure 5: 1H NMR spectra of Glaser coupling product (red, top) and of starting material 9 (blue, bottom). Note how the alkyne remains in

the red spectrum at 2.4 ppm, relative to the blue spectrum. Moreover, the peaks have become less sharp and well-defined and broadened.

Despite this, upon closer inspection of the red spectrum, it appears as though all the peaks have broadened due to the presence of a second singlet, shifted slightly to the right (ca. -0.016 ppm) of the main starting material peaks. It is expected that the starting material and the product have very similar shifts, with the latter only lacking an alkyne peak. Indeed, this is what can be observed in the spectrum, as there is no double-alkyne peak present. Thus, the presence of sets of peaks for all the other shifts indicates the possibility that a mixture of the desired product 11 and starting material 10 was obtained. However, these two compounds could not be separated from each other and the fraction that was used

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to take the 1H NMR appeared as one spot on TLC, even when varying eluents were tried. In fact, it

proved to be a difficult reaction to purify by column chromatography, as it had the tendency to stick to the baseline, even when very polar eluents were used. Considering that this problem was not encountered for the very similarly structured starting material, this is a very strong indicator that some type of polymerisation reaction occurred. Large polymers are practically incapable of being separated on a column. Thus, based on the experience of the purification steps, the coupling only resulted in the formation of a large structure.

It should be noted that this is an intramolecular Glaser coupling, meaning that there is also the possibility for intermolecular reactions. If the latter occurs, the result could be small oligomers of the starting material. This could explain why the peaks are broadened, as the product ends up having a set of very similar, yet unique proton environments. Furthermore, this would also explain the remaining presence of an alkyne, which would sit at the terminal ends of the oligomer. That the starting material prefers to polymerise over an intramolecular Glaser coupling could be evidence for the inability of a 26-ring macrocycle to form, which is substantiated based on the fact that very dilute conditions were used in an effort to circumvent such an issue. If this is an unfavourable reaction, the only other possible reaction pathway would be an intermolecular one, producing oligomers. As a result, the next step would be to use conditions that force the macrocyclisation to happen first before oligomerisation can occur.

Scheme 8: Glaser-Eglinton couplings.

The Glaser coupling of 8b may however prove more willing to occur due to the larger ring size. The reaction was performed using CuCl and TMEDA in THF at reflux (Scheme 8). A heightened reaction temperature was chosen to increase the speed of the reaction. After two days of reflux the reaction was worked up and purified by column chromatography. A 1H NMR was taken of the purified

fraction suspected to be product, but it showed very little change relative to the spectrum of the starting material (Fig. 6; Figures S10 and S11). Some of regions of the spectra are omitted here for the sake of clarity. In fact, the spectrum has resolved the issue of the double-peaks seen in Fig. 4., and now provides a much clearer picture. The splitting patterns have been resolved to clear triplets and doublets, and the triplet and singlets of the ether methylenes are now clearly separate. In effect, a seemingly purified product was obtained. This may not be too surprising if it is considered that the crude of this reaction was purified by column chromatography, rendering it feasible that any by-products from the previous reaction were removed.

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Figure 6: 1H NMR spectra of Glaser coupling (red, top) and of starting material 8b (blue, bottom). Note how no new peaks have formed in

the red spectrum, relative to the blue spectrum. Moreover, the patterns of the peaks have resolved and overlap, and "extra" singlets, are no longer visible.

Furthermore, if the starting material used for the Glaser-Eglinton did indeed contain a mixture of mono- and di-substituted products, the conditions used for the Glaser coupling could have caused the decomposition of the remaining PFP esters, whose by-products were then separated during the purification step. As a result, a fraction containing only the di-substituted compound could be obtained. In any case, the Glaser-Eglinton reaction showed no change in the area of the terminal alkyne peaks relative to the other peaks, indicative of no conversion having taken place. Glaser couplings are fairly robust reactions, and couplings with similar ring fragments can be found in the literature.23–25 Based on

these results, it seems that the steric encumbrance enforced by the tetraphenyl template is too severe to allow the ring fragments to cyclise. Also, the arms of the ring-precursors in this case are too small to form loops at the top and the bottom of the template.

To summarize, several results were obtained that indicate the difficulty of working with such an encumbering template. Firstly, the most likely outcome of the coupling reactions of the ring-precursors 3a and the template 6 was a mixture of mono- and di-substituted template, although most likely with decomposition as well. The coupling using 3b also most likely formed a mixture of mono- and di-substituted product, this case without any apparent decomposition. Furthermore, lowering the temperature appeared not to affect the conversion of the reaction. Secondly, the Glaser-Eglinton coupling reaction of the terminal alkynes resulted in no perceivable conversion taking place, which could suggest that the template prevents ring closure from taking place. Certainly, a Glaser reaction on

8a would have proven to be even less likely, as the results of model-compound 10 from Fig. 5 indicate

that the macrocyclisation is so unfavourable that an oligomerisation is preferred instead, despite the incredibly dilute conditions used. Based on these results, the main goal would be to improve reaction conditions in such a way that the coupling reactions go to completion, and that the Glaser-Eglinton reactions are forced intramolecularly and to completion. Perhaps harsher conditions need to be used to force the closure or a different copper/ligand combination needs to be used.

Conclusions

In summary, this thesis has reported several noteworthy results on the use of a tetraphenyl-terephthalic acid template alongside quinol-like ring-precursors in the preparation of a pre[2]rotaxane along a covalently assisted pathway. It has shown that the preparation of its base components, namely ring-precursors 3a,b and the activated template 6 can be accomplished relatively smoothly, although

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reactions encountered with the preparation of the ring-precursors may warrant the use of protecting groups to improve the overall yield of 12%. Furthermore, attempts at early functionalisation of the template by means of installing bromides on the para positions of the phenyl-groups, proved relatively unsuccessful. It was found that, aside from low yields, the bromides interfere with the installation of the pentafluorphenyl esters prior to the coupling step. Thus, functionalisation may have to come at a later stage, or a different activated ester can be prepared which permits installation of halide-groups. If successful, Pd-mediated Suzuki couplings could permit easy installation of functional groups of the template.

Continuing on with the unbrominated template 5, coupling of the activated template 6 to ring-precursors 3a,b in the conditions used resulted in the synthesis of both a mono- and a di-substituted template, with decomposition occurring with ring-precursor 3a, as indicated by NMR, suggesting that the ring-precursors find it difficult to position themselves in between the phenyl-groups of the template. Furthermore, a follow-up Glaser-Eglinton reaction on the product of the reaction between the template

6 and 3b, showed no coupling of the terminal alkynes as evidenced by 1H NMR. This reaction should

have resulted in a 30-ring macrocycle, and its failure to form indicates that the template is too sterically demanding for the macrocyclisation to occur, at least in the conditions used. Furthermore, the results obtained from model-compound 10 show that the smaller 26-ring macrocycle has little desire to form even on a less encumbering template.

Based on these results, the feasibility of a synthetic strategy involving a tetraphenyl template and quinol-like ring-precursors is promising when it is considered that successful coupling between the template and ring fragments was observed, and that the base components of the rotaxane can be synthesized with relative ease. However, the failure of the Glaser-Eglinton reaction to form 8b shows that the tetraphenyl template may prove too cumbersome to accommodate the ring sizes, and severe changes would need to be made to accommodate ring-precursor 3a in prerotaxane 8a as demonstrated by model-compound 10. Furthermore, the tetraphenyl template has proven to be difficult to brominate as well, warranting more investigation. These results of the Glaser-Eglinton reactions and functionalisation are however not definitive, nor defining, as the experiments performed in this thesis serve to benchmark the use of these novel components, and thus they are open to improvement. Future efforts will look to improving the conditions of both the coupling reactions and the Glaser reactions to achieve full conversion. Based on the results longer reaction times are required and lower temperatures may avoid the decomposition found with ring-precursor 3a, and thus it is wise to start here. Furthermore, improvements to the preparation of the ring-precursors in terms of yields will provide a robust pathway to the preparation of quinol-like ring components.

If these improvements are made, and a successful synthetic strategy is formulated, modular rotaxanes can be obtained with redox-reversible groups installed in the ring component and with the possibility for further groups to be installed on the template. This can all be placed in the context of achieving molecular architectures capable of electron transfer, in the imitation of biological systems involved in such processes as photosynthesis. Hopefully, covalent approaches such as the one presented in this thesis will find their niche amongst its non-covalent opposites for permitting the design and synthesis of molecular architectures unrestricted by pre-organisational motifs. Once the methods have been trivialised, the potential for designing molecular machines is immense, and the number of permutations is almost infinite. The applications in catalysis, electronics, biosensors and more could prove extremely useful and perhaps even important within the context of the energy issues we face today.

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Materials and Methods

All starting materials and reagents were obtained from commercial sources. Unless specified otherwise, the compounds used were of reagent grade or higher (≥95%), and no further purification was performed prior to use. Dry solvents were distilled from appropriate drying agents or stored over molecular sieves prior to use. All reactions involving air and moisture sensitive reagents were carried out under a nitrogen atmosphere. Thin-layer chromatography (TLC) was performed on 0.25 mm E. Merck silica gel plates (60F-254), and visualised with 254 nm UV light and a solution of KMnO4 in water. SilaFlash® P60

(particle size 40-63 µm) was used for flash column chromatography under a flow of compressed air. A Bruker DRX-300 MHz machine was used to record the 1H and 13C NMR spectra and a Bruker

DRX-400 MHz machine was used to record the 19F NMR spectra.Chemical shifts (δ) were measured in ppm

relative to residual undeuterated solvent peaks. 1H NMR spectra are reported as: chemical shift,

multiplicity (singlet = s, doublet = d, triplet = t, multiplet = m), coupling constant in Hz, integral and assignment. IR spectra were recorded using a Bruker Alpha FTIR machine. High-resolution mass spectra (HRMS) were recorded on an AccuTOF GC v 4g, JMST100GCV mass spectrometer (JEOL, Japan) and HR-ToF Bruker Daltonik GmbH (Bremen, Germany) Impact II, an ESI-ToF MS capable of resolution of at least 40,000 FWHM. The FD/FI probe was equipped with an FD Emitter, Carbotec, FD = 10 μm. Current rate = 51.2 mA/min over 1.2 min using field desorption (FD) as an ionization method.26

(2-hydroxy-5-methoxy-1,3-phenylene)Dimethanol: 4-Methoxyphenol (30.0 g, 242 mmol, 1.0 eq.)

and p-CH2O (26.1 g, 870 mmol, 3.6 eq.) were added to aqueous 2.5 M NaOH (160 mL). This mixture

was stirred at room temperature for 7 days and acidified to a pH of 5 using 37% HCl, causing precipitation of a white solid. The mixture was filtered and the solid was subsequently dried in vacuo. Yield: 97%. 1H NMR (300 MHz, DMSO-d

6): δ=6.75 (s, 2H; Ar-H), 4.52 (s, 4H; CH2), 3.68 (s, 3H;

CH3).

Dibromo-4-methoxy-2,6-xylenol (2): A solution of 16% HBr in acetic acid (50 mL) was cooled to 0

oC, before the (2-hydroxy-5-methoxy-1,3-phenylene)dimethanol (10.0 g, 54.3 mmol, 1.0 eq.) was added

portion-wise to said solution. This mixture was stirred for 2 minutes after which a thick paste formed, requiring it to be stirred by hand for another 30 minutes. The light-brown solid was collected by filtration and washed on the filter with cold acetic acid and petroleum ether, and subsequently dried in

vacuo. Yield: 64%. 1H NMR (300 MHz, CDCl

3): δ=6.58 (s, 2H; Ar-H), 4.56 (s, 4H; CH2), 3.80 (s, 3H;

CH3).

4-Methoxy-2,6-bis((prop-2-yn-1-yloxy)methyl)phenol (3a): A solution of propargyl alcohol (7.40

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bath, before NaH (1.55 g, 64.5 mmol, 4.0 eq.) was added slowly portion-wise. After 15 minutes, the ice-bath was removed and the dibromo-4-methoxy-2,6-xylenol 2 (5.02 g, 16.1 mmol, 1.0 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours, and then concentrated in

vacuo and partitioned between saturated aqueous NH4Cl solution (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic layer was dried over MgSO4, filtered, concentrated in vacuo and dry-loaded onto silica. Column chromatography

(PE/EtOAc 5:1 → 5:2) afforded a light-yellow oil. Yield: 20%. Rf=0.25 (PE/EtOAc 5:2); 1H NMR (300

MHz, CDCl3): δ=6.78 (s, 2H; Ar-H), 4.74 (s, 4H; CH2), 4.26–4.25 (d, 1JH,H=2.5 Hz, 4H; CH2), 3.79 (s,

3H; OCH3), 2.52 (t, 2JH,H=2.5 Hz, 2H; CCH); 13C NMR (75 MHz, CDCl3): δ=152.8 (Ar C), 147.8 (Ar

C), 123.9 (Ar C), 114.4 (Ar C), 79.1 (O-CH3), 75.2 (O-CH2), 68.6 (CCH), 57.5 (O-CH2), 55.8 (CCH);

IR: ν~=3420 (broad), 3287 (m), 1506 (s), 1193 (vs), 1153 (vs) cm–1 (Ar-OH, CC-H, C=C, C-O); HRMS

(FD+): m/z calcd for C

15H16O4: 260.2680 [M]∙+; found: 260.1041.

2,6-Bis((but-3-yn-1-yloxy)methyl)-4-methoxyphenol (3b): A solution of but-3-yn-1-ol (1.08 mL,

14.3 mmol, 3.2 eq.) in dry THF (40 mL) under a N2 atmosphere was cooled to 0 oC using an ice-bath,

before NaH (0.333 g, 13.8 mmol, 3.1 eq.) was added slowly portion-wise. After 15 minutes, the ice-bath was removed and the dibromo-4-methoxy-2,6-xylenol 2 (5.02 g, 16.1 mmol, 1.0 eq.) was added. The resulting mixture was stirred at room temperature for 2 hours, and then quenched with saturated NH4Cl solution (5 mL) and partitioned between saturated NH4Cl solution (100 mL) and ethyl acetate

(20 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL), and the combined organic layer was dried over MgSO4, filtered, concentrated in vacuo and dry-loaded onto silica. Column

chromatography (PE/EtOAc 9:1 → 8:2) afforded a colourless oil. Yield: 19%. Rf=0.34 (PE/EtOAc 8:2); 1H NMR (300 MHz, CDCl

3): δ=6.73 (s, 2H; Ar-H), 4.66 (s, 4H; CH2), 3.76 (s, 3H; OCH3), 3.66 (t, 2JH,H=6.6 Hz, 4H; CH

2), 2.53 (td, 2JH,H=6.7 Hz, 1JH,H=2.7 Hz, 4H; CH2), 2.02 (t, 2JH,H=2.7 Hz, 2H; CCH); 13C NMR (75 Hz, CDCl

3): δ=152.8 (Ar C), 147.6 (Ar C), 124.5 (Ar C), 113.5 (Ar C), 81.0 (O-CH3),

70.0 (O-CH2), 69.7 (O-CH2), 68.5 (CCH), 55.8 (CCH), 19.8 (CH2); IR: ν~=3398 (broad), 3290 (m),

1484 (s), 1153 (vs), 1057 (s) cm–1 (Ar-OH, CC-H, C=C, C-O); HRMS (FD+): m/z calcd for C

17H20O4:

288.3192 [M]∙+; found: Awaiting determination.

Tetraphenyl-terephthalic acid (5): Tetraphenyl-terephthalate (1.12 g, 2.13 mmol) was added to a

solution of 63% aqueous HBr (1.0 mL) in AcOH (10 mL) and refluxed at 120 oC for 48 hours. After

cooling to room temperature, the crude reaction mixture was filtered and subsequently dissolved in potassium carbonate solution, and promptly filtered again. The filter liquor was acidified with 37% HCl, causing the precipitation of a white solid, which was collected by filtration. Yield: quantitative. Spectral data matched those reported in literature.22

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PFP ester of tetraphenyl-terephthalic acid (6): Tetraphenyl-terephthalic acid 5 (1.31 g, 2.78 mmol,

1.0 eq.) was added to dry DCM (70 mL), followed by pentafluorophenol (1.28 g, 6.94 mmol, 3.0 eq.), HBTU (3.15 g, 8.33 mmol, 3.0 eq.) and DIPEA (1.93 mL, 11.1 mmol, 4.0 eq.). The mixture was stirred at 40 oC overnight. After cooling to room temperature, the mixture was dry-loaded onto silica. Column

chromatography (PE/DCM 3:7 → 2:8) afforded a white solid. A process of trituration washing in PE was used to remove any remaining pentafluorophenol. Yield: 60%. Rf=0.69 (PE/DCM 3:7); 1H NMR

(300 MHz, CDCl3): δ=7.35 (m, 10H; Ar-H), 7.26 (m, 10H; Ar-H); 19F NMR (400 MHz, CDCl3):

δ=-150.3 (d, 1JF,F=17.6 Hz, 4F; Ar-F), -157.9 (t, 2JF,F=21.8 Hz, 2F; Ar-F), -162.5 (t, 2JF,F=21.8, 4F; Ar-F).

Brominated tetraphenyl-terephthalate (4a): The tetraphenyl terephthalate 4 (1.29 g, 2.45 mmol, 1.0

eq.) was added to TFA (25 mL), alongside NBS (2.62 g, 14.7 mmol, 6.0 eq.) and concentrated sulfuric acid (0.50 mL), and stirred at 55 oC overnight. The mixture was poured into ice-cold water (30 mL),

causing precipitation of a red solid, before chloroform (50 mL) was added and the water layer was extracted with chloroform (2 x 50 mL). The combined organic layer was dried over MgSO4, filtered

and concentrated in vacuo. Recrystallization from DCM afforded a white solid. Yield: 28%. 1H NMR

(300 MHz, CDCl3): δ=7.34 (d, 1JH,H=8.5 Hz, 8H; Ar-H), 6.98 (d, 1JH,H=8.4 Hz, 8H; Ar-H).

Cleavage attempts of brominated tetraphenyl-terephthalate (4a):

1. Brominated tetraphenyl-terephthalate 4a (1.12 g, 2.13 mmol) was added to a solution of 63% aqueous HBr (1.0 mL) in AcOH (10 mL) and refluxed at 120 oC for 48 hours. After cooling to room temperature,

the crude reaction mixture was filtered and was subsequently insoluble in potassium carbonate solution. The resulting suspension was filtered again and a yellowish powder was collected.

2. Attempt 1 was repeated in chloroform at reflux. 3. Attempt 1 was repeated in toluene at reflux.

4. Attempt 1 was repeated in a 1:1:1 mixture of toluene/AcOH/63% HBr. None of the above attempts yielded the desired product.

Brominated tetraphenyl-terephthalic acid (5a): The tetraphenyl-terephthalic acid 5 (0.766 g, 1.63

mmol, 1.0 eq.) was added to TFA (20 mL), alongside NBS (1.74 g, 9.77 mmol, 6.0 eq.) and concentrated sulfuric acid (0.40 mL), and stirred at 55 oC overnight. The mixture was poured into ice-cold water (30

mL), causing precipitation of a red solid, before chloroform (50 mL) was added and the water layer was extracted with chloroform (2 x 50 mL). The combined organic layer was dried over MgSO4, filtered

and concentrated in vacuo. Recrystallization from DCM afforded a red solid. Yield: 12%. 1H NMR

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Attempted synthesis of the PFP ester of the brominated tetraphenyl-terephthalic acid (7):

Brominated tetraphenyl-terephthalic acid 5a (167 mg, 0.213 mmol, 1.0 eq.) was added to dry DCM (10 mL), followed by pentafluorophenol (97.8 mg, 0.531 mmol, 3.0 eq.), HBTU (242 mg, 0.638 mmol, 3.0 eq.) and DIPEA (0.15 mL, 0.850 mmol, 4.0 eq.). The mixture was stirred at 40 oC overnight. After

cooling to room temperature, the mixture was dry-loaded onto silica. Column chromatography (PE/DCM 96:4) yielded the starting material (see Fig. S8).

Compound 8a: 4-Methoxy-2,6-bis((prop-2-yn-1-yloxy)methyl)phenol 3a (674 mg, 2.59 mmol, 2.0

eq.) was added to a “bomb” flask containing dry ACN (25 mL), along with Cs2CO3 (1.68 g, 5.16 mmol,

4.0 eq.) and 4 Å molecular sieves (500 mg). After 10 minutes of stirring, the PFP ester of tetraphenyl-terephthalic acid (1.04 g, 1.29 mmol, 1.0) was added, and the flask was tightly capped and heated to 105 oC overnight. After cooling to room temperature, the crude reaction mixture was filtered over a

plug of Celite, concentrated in vacuo and dry-loaded onto silica. Column chromatography (PE/DCM 3:1 → 2:1 → 0:1 → EtOAc/DCM 1:9) yielded a mixed fraction. Further purification (PE/DCM 1:3 → 1:4), afforded a mixture of products based on 1H NMR found under Fig. S9, supplementary information.

Compound 8b: 2,6-bis((but-3-yn-1-yloxy)methyl)-4-methoxyphenol 3b (65 mg, 0.224 mmol, 3.0 eq.)

was added to a “bomb” flask containing dry CAN (6 mL), along with Cs2CO3 (97.5 mg, 0.299 mmol,

4.0 eq.) and 4 Å molecular sieves (200 mg). After 10 minutes of stirring, the PFP ester of tetraphenyl-terephthalic acid (60 mg, 0.0748 mmol, 1.0 eq.) was added, and the flask was tightly capped and heated to 100 oC overnight. After cooling to room temperature, the crude reaction mixture was filtered over a

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plug of Celite, concentrated in vacuo and dry-loaded onto silica. Column chromatography (PE/EtOAc 8:2 → 7:3) afforded a yellow solid. Yield: 25%. Rf=0.28 (PE/EtOAc 8:2). 1H-NMR found under Fig.

S10, supplementary information. The method was repeated at reaction temperatures of 50 and 75 oC. 1H NMR spectra are found under Fig. S10.

Model compound 10: 4-Methoxy-2,6-bis((prop-2-yn-1-yloxy)methyl)phenol 3a (170 mg, 0.653

mmol, 2.0 eq.), Cs2CO3 (430 mg, 1.31 mmol, 4.0 eq.) and 4 Å mol sieves (100 mg) were added to dry

MeCN (5 mL), and stirred for 10 minutes, before bis(perfluorophenyl) 2,5-dimethoxyterephthalate 9 (182 mg, 0.327 mmol, 1.0 eq.) was added. The mixture was stirred for 5 days, after which the solvent had evaporated. The remaining residue was partitioned between water (20 mL) and ethyl acetate (20 mL), and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over MgSO4, filtered, concentrated in vacuo and dry-loaded onto silica. Column

chromatography (PE/EtOAc 5:2) afforded a dark red solid. Yield: 29%. Rf=0.12 (PE/EtOAc 5:2); 1H

NMR (300 MHz, CDCl3): δ=7.64 (s, 2H; Ar-H), 7.02 (s, 4H; Ar-H), 4.61 (s, 8H; CH2), 4.15 (d, 1JH,H=2.4

Hz, 8H; CH2), 3.98 (s, 6H; OCH3), 3.85 (s, 6H; OCH3), 2.39 (t, 2JH,H=2.4 Hz, 4H; CCH). IR: ν~=3260

(m), 1724 (m), 1399 (m), 1214 (s), 1175 (s), 1071 (vs) cm–1 (CC-H, C=O, C-H, C-O, C-O, C-O). HRMS (FD+): m/z calcd for C

17H20O4: 710.2363 [M]∙+; found: 710.2363.

Glaser coupling of compound 8b: Coupled product (19.2 mg, 0.0188 mmol, 1.0 eq.), CuCl (40 mol%)

and TMEDA (40 mol%) were added to THF (4 mL) and refluxed for 2 days. The solvent was removed

in vacuo, and the residue was partitioned between water (10 mL) and ethyl acetate (15 mL), and the

aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over MgSO4, filtered, concentrated in vacuo and dry-loaded onto silica. Column chromatography (PE/EtOAc

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Glaser coupling of model compound 10: Model compound (40 mg, 0.056 mmol, 1.0 eq.), CuCl (20

mol%) and TMEDA (20 mol%) were added to THF (15 mL) and stirred for 5 days at room temperature. The solvent was removed in vacuo, and the residue was partitioned between water (10 mL) and ethyl acetate (15 mL), and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over MgSO4, filtered, concentrated in vacuo and dry-loaded onto silica. Column

chromatography (PE/EtOAc 1:3 → 1:1 → 1:0) yielded a crude solid. Further purification by column chromatography (EtOAc/DCM 5:95 → 10:90 → 15:85 → 20:80) yielded a white solid. 1H NMR (Fig.

S13) discussed under Results & Discussion.

Acknowledgments

The author would like to thank his supervisors Prof. Dr. Jan van Maarseveen and Simone Pilon MSc for making this project a possibility. Their incredible guidance and support made this both an enjoyable and educational experience. Furthermore, the staff of the Synthetic Organic Chemistry group were very welcoming and created an excellent working environment. The author would like to thank everyone involved.

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11. Yu, S.; McClenaghan, N. D.; Pozzo, J.-L. Photochem. Photobiol. Sci. 2019, 18, 2102–2111. 12. Kirner, S. V.; Henkel, C.; Guldi, D. M.; Megiatto Jr, J. D.; Schuster, D. I. Chem. Sci. 2015, 6, 7293– 7304.

13. Pasqual, S.; Stefano, D. S.; Masci, B. New J. Chem. 2010, 34, 426–431. 14. Schill, G.; Zollenkopf, H. Liebigs Ann. Chem. 1969, 721, 53.

15. Steemers, L.; Wanner, M. J.; Ehlers, A. W.; Hiemstra, H.; Van Maarseveen, J. H. Org. Lett. 2017,

19, 2342–2345.

16. Schweez, C.; Shushkov, P.; Grimme, S.; Höger, S. Angew. Chem., Int. Ed. 2016, 55, 3328–3333. 17. Cornelissen, M. D.; Pilon, S.; Steemers, L.; Wanner, M. J.; Frölke, S.; Zuidinga, E.; Jørgensen, S. I.; Van der Vlugt, J. I.; Van Maarseveen, J. H. J. Org. Chem. 2020, 85, 3146–3159.

18. Heathcock, C, H.; Pirrung, M. C.; Montgomery, S. H.; Lampe, J. Tetrahedron 1981, 37, 4087–4095. 19. Unpublished findings.

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20. Çay, S.; Köse, M.; Türner, F.; Gölcü, A.; Türner, M. Spectrochem. Acta. A 2015, 151, 821–838. 21. Moran, W. J.; Schreiber, E. C.; Behn, D. C.; Yamins, J. L. J, Am. Chem. Soc. 1952, 74, 127–129. 22. Ma, H.; Zhu, H.; Wang, Z. J. Polym. Sci. Pol Chem. 2019, 57, 1087–1096.

23. Rajakumar, P.; Murali, V. Tetrahedron Lett. 2002, 43, 7695–7698.

24. Yin, W.; He, C.; Chen, M.; Zhang, H.; Lei, A. Org. Lett. 2009, 11, 709–712.

25. Malik, N.; Babu, S. A.; Kaur, G.; Aslam, N. A.; Karanam, M. RSC Adv. 2014, 4, 18904–18916. 26. HRMS settings used were identical to those used in ref. 17.

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Supplementary Information

This contains all the 1H, 13C and 19F NMR spectra obtained for the relevant compounds. If applicable,

the HRMS spectra are also given. The relevant instruments and measurement settings are reported under the Materials & Methods section.

S1: (2-hydroxy-5-methoxy-1,3-phenylene)dimethanol

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S6: diethyl 4,4''-dibromo-4',5'-bis(4-bromophenyl)-[1,1':2',1''-terphenyl]-3',6'-dicarboxylate (4a)

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S8: bis(perfluorophenyl)

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S9: bis(4-methoxy-2,6-bis((prop-2-yn-1-yloxy)methyl)phenyl)

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S10: bis(2,6-bis((but-3-yn-1-yloxy)methyl)-4-methoxyphenyl)

4',5'-diphenyl-[1,1':2',1''-terphenyl]-3',6'-dicarboxylate (8b)

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Spectrum of 75 oC reaction:

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S11: Prerotaxane 1a (failed, mainly starting material)

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