Uppsala University

Department of Chemistry - BMC Degree Project C in Chemistry, 1KB010

Development of synthetic methodology for non-symmetric dimers

Author: Fredrik Barn˚a

Supervisor: Prof. Helena Grennberg Merve Ergun Donmez¨

June 3, 2019 Abstract

This bachelor thesis covers the initial development of a synthesis of fullerene dimers using two different types of linking reactions. Different setups for [3+2] to (Prato reaction) were tested, and for that purpose, an N-alkylated amino acid was synthesised. Hydroarylation of fullerene using Rh- was also studied, using both MIDA protected and unprotected boronic acids, as well as by using products. A range of model compounds in form of fulleropyrrolidenes were synthesised. Products were purified with HPLC and analysed with MALDI-MS and 1H NMR. A range of new compounds were synthesised and characterisation of them was begun. With MALDI-MS, indica- tions that the fullerene dimer had formed were found. Using synthesised model compounds, by-products of the hydroarylation reaction were identified.

Sammanfattning

Denna kandidatuppsats behandlar p˚ab¨orjandet av syntesutvecklingen f¨or bildan- det av fullerendimerer genom anv¨andandet av tv˚aolika sorters l¨ankningskemi. Oli- ka f¨orh˚allandenoch reagens f¨or [3+2]-cykloaddition till fullerener (Pratoreaktio- nen) studerades, och i samband med det syntetiserades en N-alkylerad aminosyra. Hydroarylering av fullerener med hj¨alp utav rodiumkatalys studerades ¨aven, genom reaktioner med b˚adeskyddade och oskyddade borsyror, inklusive fulleropyrrolidi- ner. Produkter har renats upp med HPLC och analyserats med MALDI-MS och 1H NMR. En upps¨attning nya substanser har syntetiserts, men karakt¨ariseringen av dessa har inte slutf¨orts. Genom anv¨andning av MALDI-MS har indikationer att fullerendimer bildats framkommit. Genom att anv¨anda syntetiserade modell substanser har biprodukter fr˚anhydroaryleringsreaktionen identifierats.

1 Acknowledgements I would like to thank the entire AGHG group for this time, I have learned a lot and have had blast working in the group.

2 Abbreviations and symbols

MIDA = N-methyliminodiacetic acid o-DCB = ortho-dichlorobenzene cod = 1,5-cyclooctadiene DCM = dichloromethane MiW = Microwave rb = round bottom MeCN = acetonitrile TFA = triflouroacetic acid TEA = triethylamine MALDI-MS = Matrix Assisted Laser Desorption Ionization Mass Spectrometry HPLC = High Performance Liquid Chromatography t-BuOH = tert-butanol

3 Contents

1 Introduction 5 1.1 Discovery of fullerenes ...... 5 1.2 The properties and applications for fullerenes ...... 6 1.3 Reactivity ...... 7 1.4 Fullerene Dumbbells ...... 9 1.5 Project aim ...... 9

2 Results and discussion 10 2.1 Prato reaction with 4-bromobenzaldehyde ...... 10 2.2 Dumbbell using two Prato reactions ...... 11 2.3 Prato reaction with 4 and 8 ...... 12 2.4 Synthesis of 10 ...... 12 2.5 Prato reaction with N-octylglycine and MIDA ...... 13 2.6 Hydroarylation of C60 with 16 ...... 15 2.7 Forming the final dumbbell ...... 15 2.8 Identifying the unknown compounds ...... 18

3 Conclusions and future outlook 20

4 Experimental 22 4.1 Analysis ...... 22 4.2 List of reactions in the project ...... 23 4.3 Synthesis of 5 with the Prato reaction of 3 and 4 ...... 24 4.4 Attempted synthesis of 7 with the Prato reaction of 6 and 4 ...... 24 4.5 Synthesis of 9 with the Prato reaction of 8 and 4 ...... 24 4.6 Synthesis of 10 ...... 24 4.7 Synthesis of 14 by the Prato reaction with 10 and 8 ...... 25 4.8 Synthesis of 17 by hydroarylation of C60 with 16 ...... 25 4.9 Attempted synthesis of 2 by hydroarylation of C60 with 14 ...... 25 4.10 Treatment of 5 with [Rh(cod)(MeCN)2]BF4 ...... 26 4.11 Synthesis of 21 using the Prato reaction with 10 and 20 ...... 26 4.12 Synthesis of 19 using the Prato reaction with 10 and 18 ...... 26

A Mass spectra 30

B 1H NMR spectra 38

C HPLC chromatograms 42

4 1 Introduction

1.1 Discovery of fullerenes Elemental carbon exists in several different forms, so called allotropes. The two most well known are diamond and graphite, but in the last 40 years, new carbon allotropes have been discovered, such as carbon nanotubes [1], graphene [2] and Buckminsterfullerenes, more often referred to as fullerenes or Buckyballs (see Fig. 1).

Figure 1: Newly discovered allotropes of carbon: nanotube, buckminsterfullerene and graphene

The concept of a molecule consisting of sixty carbons shaped like a football was first explored in 1965, as a possibility for a hydrocarbon shaped like a geometric solid [3]. In 1970, the existence of such a structure consisting solely of carbon was predicted by Japanese chemists, but as it was never translated in English, it failed to have significant impact [4]. The underlying reasoning behind the prediction was the structure of the corannulene molecule, which has the same structure as a segment of the C60-molecule, and that it might be possible for there to be a fully enclosed molecule. Also in 1970, R.W. Henson, working at the Atomic Energy Research Establishment in the UK, noticed some unexpected patterns in x-ray diffraction measurements on carbon fibres. Based on the different possible structures that could give rise to such a pattern, he realised that the found molecule was the buckminsterfullerene C60. His findings were however never published [5]. In 1973, a computational study on stability of C60 was published, but this was still only theoretical evidence for its existence [6]. In the early 80s, a technique for vaporisation of carbon clusters using lasers was de- veloped by Rickard Smalley and Bob Curl at Rice University, Texas. Harry Kroto, at the university of Surrey, had during the 70s been studying unsaturated carbon chains, and he realised the potential of the new method. He therefore initiated a collaboration between the two groups [7]. The method utilised a Q-switch Nd:YAG laser to quickly vaporise carbon from a graphite target. The hot plasma formed was cooled, and allowed to form clusters of up to a few hundred carbon atoms. Mass spectrometry was then used to study the formed clusters. What was discovered was that the peak corresponding to a m/z-ratio of 720 (which is the weight of sixty carbon atoms) was far more prominent than other ions of similar size, meaning that C60 was for some reason a favoured cluster to form [8]. In their 1985 paper, the group hypothesised that the reason for this was due to the formation of a truncated icosahedron, which they named the ”Buckminster-

5 fullerene” after the American architect who popularised the shape [9]. The proposal that the molecule was spherical was not uncontroversial. A strong piece of evidence in favour of the suggested structure came in late 1985, when the group at Rice university managed to create a very stable complex between C60 and a lanthanum atom, arguing that the strong bond was due to the metal atom being enclosed in the fullerene [10], see Fig. 2.

Figure 2: Lanthanum atom enclosed in fullerene

However, the controversy about the structure of C60 was not yet over, as all evidence of the structure of the molecule was based on intensities of peaks in mass spectro- grams, which some groups argued was not sufficient evidence to infer the structure of the molecule with absolute certainty [11]. It was only in 1990, when a method for the creation of macroscopic amounts of fullerenes was developed, that the truncated icosa- hedron structure was confirmed [12]. In 1996 Kroto, Curl and Smalley were awarded the Nobel Prize in chemistry for their discovery of fullerenes [7].

1.2 The properties and applications for fullerenes

Fullerenes come in many different sizes, where C20 (a regular dodecahedron) up to C150 have been confirmed experimentally, and up to C3998 have been theorised to exist. The two most stable forms of fullerene are C60 and C70, of which C60 is the most common as well as the most studied [13]. Whether C60 is aromatic or not was for a long time subject for debate [14], when it was originally discovered, C60 was presumed to be aromatic [9], but later studies showed that that was not the case. In C60, there are two different types of bonds: 6:6 bonds, that fuse the six-membered rings together, and 6:5 bonds, that lie between the five-member and six-membered rings. These bonds have different characteristics: 6:5 bonds are more alike to single bonds and are of length 1.458A˚ whereas the 6:6 bonds behave more like double bonds and are shorter, 1.439A˚ [13, 15]. The 2.278 2 σ-bond hybridisation in C60 has been calculated to be sp , the deviation from sp - hybridization of graphene being due to the curvature of the molecule[16]. In 1999 de Broglie interference of C60 was observed, which at the time made it the largest and most complicated object for which wave-particle duality had been observed [17]. The electron affinity of C60 has been measured to be 2.65 eV [18], which means that it is highly receptive of additional electrons. Dissolved C60 has a distinct purple colour. It

6 does however only have low solubility in most organic solvents [19]. Fullerenes are insulators, but it is possible, via doping or derivatisation, to turn them into either semiconductors or superconductors. Their unique structure makes it possible to dope fullerenes in three different manners: endohedral, substitutional or exohedral doping. Endohedral doping is a consequence of the unique structure of fullerenes, as it entails one or more atoms being caught inside the fullerene during its formation process. The nomenclature for this uses @, for example, a lanthanum atom (see Fig. 2) enclosed in a C60-molecule would be written La@C60 . In substitutional doping, carbon atoms in the structure are replaced by other atoms, and in exohedral doping, heteroatoms are placed in empty spaces in the lattice [20]. Fullerenes have found use in several different applications. Their unique electronic prop- erties, such as endohedral doping, give them use in semi-conductor electronic, such as solar cells [21] and nanoelectronics [22]. They are also used in superconductor materials [23] as well as an additive to lubricants, where fullerenes act as nano-scale ball bearings [24]. Fullerenes also have medical applications, in differing roles such as photosensitiz- ers, antioxidants, transporting smaller molecules across fatty membranes as well as being able to complex with HIV protease [25].

1.3 Reactivity

Due to the large amount of conjugated double bonds in C60, one would expect it to be alike in reactivity to the electron-rich aromatic compounds, when in fact it behaves more like an electron-poor . The reason for this is most likely the presence of 12 pentagonal rings in the otherwise graphitic structure [26]. The fact that C60 is reversibly 6– reduced down to C60 and the existence of species with a formal charge of -12 support this explanation [27]. Another source of reactivity for C60 is its high ring strain. By saturating double bonds in the structure, said strain is reduced. As the [6,6]-bonds have more double-bond characteristics than the [6,5]-bonds, most reactions therefore occur there [14]. As fullerenes are highly electrophilic, they react readily with nucleophiles such as organo- lithiums and Grignard reagents [28], as well as with organocopper reagents [29]. It also reacts readily with radicals [26] and carbenes [30]. As it behaves as an electron- deficient alkene, C60 reacts readily as a dienophile in the Diels Alder-reaction [31]. It also reacts using many other types of cycloadditions, such as [2+2] cycloadditions [32], cyclopropanation (Bingel reaction)[33] and the [3+2] 1,3-dipolar cycloaddition (Prato reaction)[34]. The Prato reaction was discovered in 1993 by a group of Italian chemists, including Mau- rizio Prato, after whom the reaction is named. Within the mechanism, an azomethine ylide reacts with C60, forming a pyrrolidinofullerene. The azomethine ylide can be cre- ated in several different ways, among the easiest being the decarboxylation of an alpha amino acid (sarcosine is often used [34, 35]) by heating it the presence of an aldehyde.

7 Figure 3: Examples of reactions with C60

An alternative route for formation of azomethine ylides is by thermal ring opening of aziridines [34]. Another less studied group of reactions with fullerenes are organometallic additions using transition metal catalysis. In 2007, Nambo et. al. published a short paper showing a method for hydroarylation of fullerenes with boronic acids by using Rh-catalysis [36]. In this study, medium to high yields as well as high selectivity were reported, although the methodology used to calculate the yield has been called into question [37]. The reaction was performed in a bi-phase system consisting of water and ortho-dichlorobenzene (o- DCB), under an atmosphere of argon as well as a long reaction time [38]. Additionally, a mechanism for this reaction has been proposed by Mart´ınezet. al.[39], however it is solely based on a computational model and lacks experimental evidence. The reaction has been studied extensively by our group over the last couple of years. The reaction now takes place in a single-phase system instead of the original two-phase system, using [Rh(cod)(MeCN)2]BF4 as the catalyst[14]. Additionally, it has been con- cluded that high reaction temperatures or long reaction times are not necessary or in some cases even counter productive, as it facilitates the formation of disubstituted prod- uct. The reaction however has only low to middling yields, with no explanation discov- ered for this behaviour as of March 2019.

8 1.4 Fullerene Dumbbells A fullerene dumbbell is a molecule containing two fullerenes with some sort of linker in between them, see Fig. 4.

Figure 4: A generic fullerene dumbbell

These molecules have been studied since the 90s, and the general properties of them are known. Their solubility is known to be poor [40], which is why the linkers often contain long alkyl chains [41] or oligoether chains [42]. Many different types of linkers have been used over the years, such as ferrocene based ones [43], tetrathiafulvalene based ones [42], two pyrrolidinofullernes connected to a benzene in a para-configuration [41] as well as compounds connected by strong hydrogen bonding [44], see Fig. 5. As of March 2019, no literature had been published showing a fullerene dumbbell formed by hydroarylating a fullerene.

Figure 5: Example of dumbbells found in the literature

1.5 Project aim

The aim of the project was to synthesise a C60-dumbbell (see Fig. 6) consisting of two C60- molecules with a linker molecule in the middle. The linker will be connected to one of the fullerenes using the Prato reaction and to the other using boronic acid-hydroarylation. One of the main reasons for synthesising this compound was to test whether these two reactions are compatible.

9 (a) Original project ob- jective (b) Final project objec- tive

Figure 6: Project endgoal at different stages in the project 2 Results and discussion

2.1 Prato reaction with 4-bromobenzaldehyde After ordering the chemicals needed for the project, it was decided that the Prato reaction should be tested with already available chemicals while waiting for the delivery. Sarcosine (4) and 4-bromobenzaldehyde (3) were chosen as the reagents for the reaction. The reaction using those reagents is shown in Fig. 7. The reaction was performed five times with differing reaction conditions, see table 1.

Figure 7: Prato reaction with 3 and 4

Table 1: Reaction conditions for reactions with sarcosine and 4-bromobenzaldehyde as well as reaction turnover. More product is better.

Experiment Solvent Reaction time Product:C60 P1 o-DCB (110 °C) 2h 34:52 P2 o-DCB overnight 38:19 P3 o-DCB 2h 32:26 P4 4h 3.2:7.8 P6 toluene overnight 4:55

In the original paper describing the Prato reaction [34] the reactions conditions were reflux in toluene for 2h, which means that the reactions temperature would be 110 °C

10 as that is the boiling point for toluene. However, when trying this reaction, o-DCB was chosen as the solvent as it was more compatible with the hydroarylation supposed to take place after the Prato reaction. These reaction conditions were clearly sub-optimal for the reaction, as even though the crude solution was clearly much darker than the starting mixture, it retained a strong purple tint, signifying that a significant amount of C60 remained unreacted. Using MALDI-MS, it was shown that a compound with the same mass (m/z = 932) as 5 had formed, but also that much of the starting fullerene (m/z = 720) still remained. The same conclusion was made after analysing the product with HPLC, see table 1. To optimise the reaction conditions, the reaction was run several times in different solvents and for different times, see table 1. It was found that the best turnover was gotten if the reaction was performed in o-DCB at reflux temperature, and that the reaction was done in 2h. The reasoning behind trying the reaction with toluene was that o-DCB is very difficult to evaporate, and getting pure samples with toluene would therefore be easier. However, the reaction clearly seems to require the higher temperatures that o-DCB allows for, which is why that solvent was used for the remainder of the project. Due to a miscalculation, the reactions were run with only half the equivalents of aldehyde and amino acid as in the original paper. This means that the yields obtained were lower than what would otherwise have been possible, but there is no reason to believe that the results in table ?? would have been different if the correct amount of reagents had been used.

2.2 Dumbbell using two Prato reactions In an attempt to see whether or not a fullerene dumbbell with a linker similar to the one that the project strives towards would be soluble,and therefore possible to characterise and separate, it was decided to synthesise 7 using two Prato reactions with 4 and 6 as the linker instead of one Prato reaction and a hydroarylation. The reaction was done in o-DCB at 180 °C, as that had already been shown to work for a single Prato reaction. No product was detected with HPLC, most likely to due to low solubility of the product causing 7 to be filtered off in the workup of the crude. However, by washing the filter paper used in filtering of drying agent, a mass spectrum was collected, containing a peak with the expected mass to charge ratio (m/z = 1629)

Figure 8: Prato reaction with 4 and 6 to form 7

11 2.3 Prato reaction with 4 and 8 The originally proposed reaction was run, see Fig. 9, using the improved reaction condi- tions. The reaction seemed to have gone smoothly as the turned from purple to brown, but in the workup it became apparent that the product had very low solubility in organic solvents. 9 wasn’t confirmed with HPLC nor 1H NMR. However, in a mass spectrogram taken with MALDI-MS, there was a peak at the expected mass to charge ratio (m/z = 1008).

Figure 9: Prato reaction with 4 and 8 to form 9

A brown precipitate was formed in both the storage vial and in the the NMR tube, showing that some sort of reaction product had formed, but its identity could not be determined, other than with MALDI-MS. As the main method for separating the product from C60 and the bis-adduct is preparatory HPLC, the inability to confirm the product using that method was a big issue. For separation to be possible, increasing the solubility of 9 would be necessary.

2.4 Synthesis of 10 In order to solve the solubility issues of 9, it was decided to synthesise a new amino acid, that would exchange the N-methyl group found in 4 for a longer alkyl chain. Several different alkyl chains were considered. In earlier experiments in the group [13, 45], C18- chains were used. In another study where a fullerene dumbbell was synthesised using two Prato reactions, the C8-chains were used [41]. Based on this, it was decided to attempt to synthesise both types of amino acids.

Figure 10: Desired amino acids

12 In the literature, several studies for synthesising N-substituted was found [46, 47]. Based on these studies, a synthesis was proposed (see Fig. 11).

Figure 11: Reaction scheme for alkylated amino acids

In the proposed synthesis, 11 or 11’ is reacted with 12, forming the protected amino acid 13 and 13’ respectively. However, the solubility of 11’ turned out to be terrible in most solvents, and therefore only the reaction using 11 was worked up and only 13 was deprotected, although some 13’ had likely formed, as that amount was not deemed worth the trouble. The product of the first reaction was separated from the starting material and side products on a silica column. The progress of the column was observed with TLC and with ELSD. The deprotection of tert-butyl group to form the carboxylic acid was carried out in the next step by reaction with triflouroacetic acid (TFA). The TFA was then neutralised by addition of triethyl amine (TEA). The final product was the amino acid TEA salt containing some TEA/TFA salt as well. The proportion of these salts were determined using 1H NMR to be 1.8:6, with the amino acid salt being the latter. All in all 275.7 mg amino acid salt was prepared.

2.5 Prato reaction with N-octylglycine and MIDA ester With 10 synthesised, it was time to attempt the Prato reaction with it to see whether or not the solubility issues had been resolved by the extra alkyl chain.

Figure 12: Prato reaction with 8 and 10. Formation of 15 was unintentional

At first, a smaller batch (20 mg C60, reaction was called P8) was run. The reaction proceeded smoothly, as the solution lost its purple colour. A precipitate was formed in the reactions vessel, which had some solubility in toluene, but still pretty low. After

13 workup, it was still apparent that the solubility was low, as it didn’t fully dissolve in 3.7 ml CS2. The product was then studied with both MALDI-MS and HPLC. According to the mass spectrogram, both 14 and 15 had formed, and HPLC showed that some C60 remained unreacted and that it was viable to achieve peak separation for the mono- and disubstituted product, with the monoproduct assumed to have the longer retention time. This information was crucial for the project, as it means that purification of 14 using preparative HPLC is possible. With this information, it is decided to run the same reaction on a larger scale (reaction P9, using 50 mg C60) with the goal of purifying enough 14 to be able to proceed to use 1 it in the hydroarylation reaction with C60 to form the dumbbell. For 14, a H NMR was recorded. The reaction proceeded smoothly, and 114.1 mg of crude product was formed. The crude was dissolved in CS2 and a small amount of CDCl3 in order to make an NMR sample. The sample solution was amber coloured with some black particles. All product was then transferred to a bottle and all solvent was evaporated. The crude was then dissolved and diluted to 25 ml with HPLC mobile phase, giving a concentration of ≈ 4 mg/ml. However, this concentration was too high for the solvent system, and a brown precipitate was formed. The sample was centrifuged and the supernatant was then separated with preparative HPLC. As previously stated, the solubility of these compounds ranges from poor to outright terrible in most solvents, an issue that can be overcome in two different ways. Either you reduce the amount of compound that you try to dissolve, or you increase the amount of solvent used. However, for NMR, there is a max limit to the amount of solvent as well as a limit to how much compound that is needed, meaning that for a hardly soluble compound, getting a nice looking 1H NMR is difficult, and mono Prato product is definitely a compound whose solubility leaves a lot to be desired. In total, four different solvent systems were tried, see table 2.

Table 2: Solvent systems used for NMR sample of 14

Attempt Solvent 1 CDCl3 2 CS2 (CDCl3) 3 Toluene– d8 4 C6D6

1 Fig. 13 shows an expansion of the H NMR spectrum for 14 in C6D6. The three peaks are due to the three protons on the pyrrolidene ring. The singlet is the proton located on the carbon that binds to the aryl group, while the other two signals are from the other carbon with protons on the ring. As these protons are diastereotopic, they are not magnetically equivalent, which explains the two signals, and as they couple with each other from different chemical shifts, the peaks become doublets instead of singlets.

14 1 Figure 13: Expansion of H NMR spectrum for 14 in C6D6 showing signals from the pyrrolidene ring

2.6 Hydroarylation of C60 with 16 An alternate approach to the synthesis of the dumbbell was to start with the hydroaryla- tion reaction and then the Prato reaction. This entailed reacting C60 with 16 in o-DCB and wet t-BuOH. [Rh(cod)(MeCN)2]BF4 was used as a catalyst.

Figure 14: Hydroarylation of C60 with 16

This reactions was run mainly to try out the reaction with already available reagents in order to train before using the purified Prato product, but also to see if it was possible to perform the hydroarylation reaction with a boronic acid containing an aldehyde. The reaction went smoothly, and after the workup, 17 was confirmed using 1H NMR. Purification of the compound was then attempted. However, the solubility of 17 turned out to very low and and most of it was lost in the HPLC. Synthesising 2 this way seems to be impractical, but with more study, the issues might be worked out.

2.7 Forming the final dumbbell As 14 had been separated and identified, it was time to run the hydroarylation with it to form the dumbbell, see Fig. 16.

15 1 Figure 15: H NMR for hydroarylation of C60 with 16

Figure 16: Reaction to form 2

The reaction was run twice. The starting material for the reaction, 14, was made in another step, and the reaction chains are presented in the experimental part. To be able to run HPLC without damaging the column, the catalyst needed to be removed. In earlier studies in this group as well as in the reaction to form 17, this was done by filtering the reaction mixture through a silica column using toluene as the mobile phase. This was attempted on HA2. The contents of each fraction was evaluated using HPLC. The first two fractions collected had a distinct purple colour, showing that they contained a large amount of C60. At a later point in the project, the first collected fraction was analysed with MALDI-MS, giving a peak at the expected m/z-value (m/z = 1672). This analysis was however run after all other lab work had concluded, which is why the following work was done. On top of the column, there was a dark layer that didn’t move with toluene as the mobile phase. To make that layer move, methanol was used. Evaluating the contents of the first five fractions, no peak for the dumbbell could be discerned. Therefore, a last fraction

16 (Sil6) was eluted, this time using o-DCB. This fraction had a clear yellow-brownish colour. However, even this fraction didn’t have any peak that could be the dumbbell. The most likely candidate for the cause of the colour was [Rh(cod)(MeCN)2]BF4, the catalyst used in the reaction, as it is yellow in solution. Sil6 was therefore evaporated and a 1H NMR was taken to compare to a reference spectrum. The results from 1H NMR were ambiguous, and no further studies were made. As the dumbbell hadn’t been identified in any fraction at this point, it was believed that it likely remained undissolved on top of the silica. Another possibility was that no dumbbell had formed. To test this a second reaction was run, and NMR and MALDI-MS samples were prepared from the reaction mixture before any workup had been performed. The peak that was sought after in the 1H NMR (see Fig. 17) was a singlet somewhere between 6 and 7 ppm. This signal is caused by the hydrogen on the second fullerene. The existence of this peak would mean that a fullerene had been hydroarylated, and since the only available boronic acid present is the deprotected 14 hade reacted with a second fullerene, forming the dimer. Looking at the spectrum, there might be a small peak in the considered range (≈ 6.5 ppm), but the intensity is very low, and further proof was need to show that the dumbbell had formed.

1 Figure 17: Expansion of H NMR (C6D6) for reaction HA3 before any workup.

To get this further proof, MALDI-MS was used. One of the technique’s main advantages is that it doesn’t require the analyte to be in solution to be able to detect it. As the solubility of the dumbbell is expected to be very low, this makes MALDI-MS an amazing tool for analysis.

17 Looking at the mass spectrum in Fig. 18, the heaviest peak is at m/z = 1671.964, which is very similar to the weight of the dumbbell, at 1672.2 g/mol. Taken together, the mass spectrum and the 1H NMR spectrum show that the dumbbell had most likely formed. There were also peaks at m/z = 1318, 967 and 951.

Figure 18: MALDI-MS for the reaction HA3 before any workup.

However, to get definitive proof, a 1H NMR spectrum of the purified dumbbell was needed. In order to separate it, preparative HPLC was used. When preparing the sam- ples, a black precipitate was formed. Using MALDI-MS, it was shown to have a similar composition as crude reaction mixture, notably containing the suspected dumbbell peak. In the chromatogram of the supernatant solution, there were three non-injection peaks. One of them was easily identifiable as C60, but the other two were collected and char- acterised with 1H NMR and MALDI-MS. The compound with the shortest retention time (hereafter known as 19) had an m/z = 967.591 and the peak with the longer re- tention time (21) an m/z = 951.574. The 1H NMR gave no usable information on their structure due to the low concentration. The dumbbell wasn’t present in any of the two fractions.

2.8 Identifying the unknown compounds At this point in time, the project was nearing it’s end, and it was realised that separating out the dumbbell in the amount needed to get a nice 1H NMR spectrum would take more time than what was available. However, identifying 19 and 21 would probably be possi- ble in the given time frame. Knowing their structures would give important information on the mechanism of the Rh-catalysed hydroarylation of C60, as no mechanism based on experimental data have been published. There were several different proposal as to what these compounds could be. One idea was that the catalyst somehow interacted with the nitrogen on 14 and creating a new com- pound by breaking up the pyrrolidene ring. In order to try out this hypothesis, the prod-

18 uct from experiment P3 (crude solution of 5) was treated with [Rh(cod)(MeCN)2]BF4 under the same conditions as for reaction HA3 to see if any reaction takes place. By comparing the mass spectra of two sample of 5, before and after treatment, no difference could be discerned. This hypothesis was a long shot, as it was solely based on a line of reasoning that some sort of reaction could take place, but without any sort of suggestion as to the product of said reaction.

(a) 19 (b) 21

Figure 19: Hypothesised identities of compounds in collected fractions from HA3

Another possibility, which has more support in the experimental data, is that it is the boronic acid that has reacted and was replaced with, a hydroxygroup or a hydrogen atom. The second reaction is a well known reaction of boronic acids, known as pro- todeboronation. It is a reaction of boronic acids with water that can take place under either acidic or alkaline conditions, resulting with the replacement of the boronic acid with a proton, in this case resulting in 21. This reaction is also catalysed by base [48], which is present in the studied reaction in order to hydrolyse the MIDA ester. It is also catalysed by a number of metals [49]. The reaction to form the hypothesised 19 is more uncertain, no literature reports similar reaction conditions to the ones used is this study, there is however a newly published article reporting a similar reaction using CuO2 as a catalyst [50]. The main experimental support for these hypotheses is that the masses of proposed compounds match the experimental data. This is however not enough to definitively prove the suggestions, but it is a strong indication. In order to see if it was 21 that had formed, a Prato reaction with 10 and 20 was run. This was done in order to see if the retention time of the compound that was suggested to be 21 is the same as for a real sample of 21. Running the HPLC showed that the by-product of the hydroarylation reaction suspected of being 21 had the exact same retention time as 21 synthesised directly with the Prato reaction. This is very strong evidence that it is in fact 21 that was formed. The same process was performed for 19, by running a Prato reaction with 10 and 18. Running the HPLC, there is a peak in the crude Prato reaction mixture with the same retention time (5:55) as the peak suspected to be 19 in the chromatogram of reaction HA3, but there are several other peaks present as well, so running preparative HPLC to get a sample of pure 19 is likely needed to get definitive proof. However, the existence of two peaks with the same retention time is a strong indication that the hypothesis is correct, and it will be assumed to be for the purposes of further discussion in this report. Analysing both 19 and 21with MALDI- MS, they both show the same masses as the peaks in the mass spectra of the unknown

19 compounds, acting as further evidence for the hypotheses.

Figure 20: Reaction schemes for formation of 19 and 21

3 Conclusions and future outlook

The most interesting results from this project for the future is the discovery of the by- products for the hydroarylation reaction. The reaction mechanism of the reaction with rhodium acting as the catalyst is not known, meaning that the understanding of the behaviour of the reaction under different conditions is poor and that its full potential is not yet utilised. In this project, two of the main by-products of the reaction have been identified, shedding some light on the mechanism. How they are formed and how they relate to the hydroarylation reaction is still unknown, and merits further study. The reason as to why the by-products hadn’t been identified previously is that when the hydroarylation reaction was optimised, small boronic acids such as (4-metoxyphenyl)boronic acid or p-tolylboronic acid was used. The by-products in these systems are small molecules such as toluene, and they would either have been evaporated along with the o-DCB that was used as a solvent during the workup or eluted as part of the injection peak in HPLC analysis. By using larger compounds such as 14 as the source of the boronic acid, this issue is avoided. For further studies, it is however not necessary to use fullerene-containing compounds, as any sufficiently non-volatile boronic acid would fill the same function while being easier to work with. During the project, a range of compounds have been synthesised, some for the first time, other as replicates from other studies. Most of these are different fulleropyrrolidenes, but also 10 and 17. Synthesis of 10’ was also attempted, but that synthesis failed due to the low solubility of 11’.

20 One of the main conclusions drawn from this project is that the solubility of fullerenes and fullerene derivatives is low, and that fact will likely always be the main source of difficulty in the field of . The reactions themselves aren’t overly complex or difficult, but the yield might be hindered by solubility, solvents with annoying properties (e.g. o-DCB) might have to be used and workup and purification is difficult. As long as preparative HPLC is the best way of separating and purifying these compounds, the synthesis can only be done on a small scale, limiting the usability of them. Solubilising groups, such as alkyl or oligoether chains [42], might also have to added, which might solve some of of the previously mentioned issues, but it comes with it’s own set of problem regarding cost, the affinity for grease and the size of molecule. Enough of the dumbbell wasn’t synthesised during the project for it to be possible to extract it, characterise it or determine its electrochemical or photoelectrical properties. Analysis with MALDI-MS managed to show that the a compound with the same mass as the dumbbell formed, but attempts to detect and separate it using HPLC failed, a failure which could be due to several different factors. It might be that the amount of dumbbell simply wasn’t sufficient to be detected by HPLC, something that could be solved by either running the synthesis on a larger scale or by optimising the reaction to reduce the formation of by-product. It is also possible that the solubility of the dumbbell is to low to allow for analysis by HPLC. This could be solved in several ways. It could for example be that the dumbbell is insoluble enough that it can be purified by washing the precipitate that formed when preparing the HPLC-sample with solvent until only the dumbbell remains. Solubility could be increased by adding more solubilising groups or changing the structure of the linker. The length of the alkyl chain on the amino acid could be increased or some heteroatoms could be substituted onto the phenyl ring. An alternate synthetic pathway for obtaining the dumbbell is to run the synthesis ”back- wards”, by first performing the hydroarylation, forming 17, which can react with an amino acid and C60 to form 2. The first of the two reactions in this synthesis pathway was performed in this project, but there wasn’t enough time to carry out the full syn- thesis. The potential upside to forming the dumbbell in this manner is that the Prato reaction is more well behaved and understood, forming fewer by-products and using reagents that are easier to separate from the main product than the hydroarylation, potentially increasing the yield. However, the properties of the dumbbell would remain the same, meaning that if the main hurdle to separate and purify the dumbbell is its terrible solubility, said hurdles would remain even if the reaction pathway is changed. However, it is well worth further investigation in case the research into the dumbbell is continued. The immediate next step of the project would be to see if the formation of the identified by-products is due to the catalyst or if they are formed in the absence of it. This is important information, as if they are effected by the Rh-complex, they take part in the the catalytic cycle and therefore hold information about the reaction mechanics. The formation of 19 is especially interesting, as to be able to couple two electron-rich ligands, the catalyst would need to change its charge, something that Rh(I) usually does not do

21 [51]. If it turns out that 19 is formed as a by-product in the catalytic cycle, that would call the current state of knowledge on catalysis with Rh(I) into question. Another investigation that can be done is to try to figure out the identity of the compound causing the third unknown peak (m/z = 1318) in the mass spectrum of reaction HA3 (Figure 18). No hypothesis for its identity has been suggested, but a few things are known about it. It is quite a bit larger than 14, but it is also smaller than any C60-dimer.

4 Experimental

All starting materials and solvents whose synthesis was not covered in this report were available commercially. Solvent grades are presented in table 3. C60, the boronic acids and [Rh(cod)(MeCN)2]BF4 was purchased from Sigma-Aldrich. All reactions involving C60 took place in capped MiW bottles. All heating was done with oil baths.

Table 3: Table over solvent grades

Solvent Grade o-DCB 99% anhydrous toluene Reagent DCM Reagent MeCN Gradient

4.1 Analysis Analytical HPLC was run on a Gilson system with a Gemini NX-C18 4.6x250mm, 3µ m column with mobile phases consisting of a mixture of toluene:MeCN ≈ 1:1. For exact proportions, see table 4, with run names beginning with A. Preparative HPLC was run on a Gilson system with an ACE C18 150x21.2mm, 5µm column with mobile phases consisting of a mixture of toluene:MeCN ≈ 1:1. For exact proportions, see table 4, with run names beginning with P.

Table 4: Table over HPLC runs presented in the report

Run Analysed reaction Mobile phase (T:MeCN) A04051 P2 55:45 A04092 P3 55:45 A04181 P8 55:45 A05131 P11 and HA3 52.5:47.5 A05151 P12 and HA3 58:42 P04252 P9 45:55 P05031 P10 45:55 P05081 HA3 55:45

22 NMR samples were prepared by dissolution in either CS2/CDCl3 or C6D6. The relaxation time was set to 30 s for runs with 16 repetitions or 20 s for 1024 repetitions. The 400 MHz # 2 spectrometer at NMR Uppsala was used for all measurements1 All chemical shift are indirectly referenced to tetramethylailane via the residual solvent signals. MALDI-MS samples were prepared by mixing 20 µl of the analyte solution with 20 µl of trans-2-[3-(4-tert-Butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) in CHCl3. The new solution was mixed and 0.5 µl of it was loaded on the MALDI-MS target. The machine used was a BRUKER Daltonics Autoflex II.

4.2 List of reactions in the project Prato reactions In table 5 are presented all the Prato reactions that have been run in the project.

Table 5: Table over all Prato reactions in the project

Experiment Target molecule Amount of C60 used Solvent Reaction time P1 5 20mg o-DCB (110 °C) 2h P2 5 20mg o-DCB overnight P3 5 20mg o-DCB 2h P4 5 20mg toluene 4h P5 7 40mg o-DCB 2h P6 5 20mg toluene overnight P7 9 20mg o-DCB 2h P8 14 20mg o-DCB 2h P9 14 50mg o-DCB 2h P10 14 50mg o-DCB 2h P11 21 50mg o-DCB 2h P12 19 50mg o-DCB 2h

Hydroarylation reactions In table 6 are presented all hydroarylation reactions ran in this project.

Table 6: Reaction conditions for reactions with sarcosine and 4-bromobenzaldehyde

Experiment Target molecule Used boronic acid Prior reaction HA1 17 16 - HA2 2 14 P9 HA3 2 14 P10

1http://nmrcenter.kemi.uu.se/technical-information/

23 4.3 Synthesis of 5 with the Prato reaction of 3 and 4 2.5 mg (0.028 mmol, 1 eq.) sarcosine, 12.8 mg (0.069 mmol, 2.5eq.) 4-bromobenzaldehyde and 20 mg (0.028 mmol, 1 eq.) C60 was weighed in a microwave (MiW) bottle. A cross- bar stirrer was added and the bottle was sealed. 4 ml of o-DCB was added and the bottle was heated to reflux temperature if nothing else is stated with strong stirring under conditions presented in table 5. After the heating was finished, the o-DCB was evaporated. The product was then dissolved in DCM and extracted with 10% K2CO3. The organic phase was collected and dried using MgSO4. The drying agent was filtered off, and the DCM was evaporated in a bottle of known mass. The bottle was then weighed again and the product was dissolved in CS2 and CDCl3. A small amount of product was transferred to a small bottle and diluted in toluene.

4.4 Attempted synthesis of 7 with the Prato reaction of 6 and 4 1.9 mg (0.014 mmol, 1 eq.) of terephtalaldehyde, 7.6mg (0.085 mmol, 6 eq.) of sarcosine and 41.3 mg (0.057 mmol, 4 eq.) of C60 was weighed up in an MiW-bottle. The flask was sealed in and filled with N2 and 7 ml of o-DCB. The flask is heated to 180 °C for 2 hours under heavy stirring. The solvent is then evaporated, the product is redissolved in DCM and extracted with 10% K2CO3. It is then dried with MgSO4 and filtered. The DCM is evaporated and the product is dissolved in CS2 and CDCl3.

4.5 Synthesis of 9 with the Prato reaction of 8 and 4 5 mg (0.056 mmol, 2 eq.) of sarcosine, 36 mg (0.14 mmol, 5 eq.) of (4-formylphenyl)boronic acid MIDA ester and 20 mg (0.028 mmol, 1 eq.) C60 was weighed up in a MiW-bottle. The bottle was sealed and flushed with N2. 8 ml of o-DCB was added and the solu- tion formed was heated to 180 °C under heavy stirring for two hours. The solution was transferred to an rb-flask using 2 ml of toluene and the solvent was then evaporated. The crude product was dissolved in DCM and extracted with 10% K2CO3. The organic phase was then dried with MgSO4 and filtered. The DCM was then evaporated and the product was dissolved in CS2 and CDCl3. An HPLC-sample was prepared by adding a small amount of product solution to 30:70 acetonitrile:toluene solution.

4.6 Synthesis of 10 0.89g (6.9 mmol, 1.4 eq.) of 1-octylamine was dissolved in 15ml of MeCN. The flask was cooled in an ice bath while 1 g (5 mmol,1 eq.) t-butyl bromoacetate is added drop wise. 1.04g (10 mmol, 2 eq.) TEA was then added dropwise. 10 ml of MeCN is added. If a pink precipitate is formed, add more solvent. The reaction was performed in room temperature for two days. The crude product mixture had gotten a yellow colour. The product was separated on a silica column using pentane:EtOAc 19:1 in the beginning and 1:1 later on. The distubstituted amine formed as well in the reaction, and with

24 the wrong mobile phase, it will elute at the same time as the monosubstituted product begins to elute. The product was dissolved in 10 ml 1:1 TFA:DCM and stirred for 3h. 3ml of toluene was added and it was concentrated to dryness. Another 3ml of toluene was added and it was concentrated to dryness. 3ml of toluene and 2ml of TEA was added and it was concentrated to dryness. 6ml toluene was added and it was concentrated to dryness.

4.7 Synthesis of 14 by the Prato reaction with 10 and 8

50mg (0.07 mmol, 1.eq) C60, 49 mg (0.14 mmol, 2 eq.) N-octylglycine and 90.7mg (0.35 mmol, 5 eq.) of (4-formylphenyl)boronic acid MIDA ester is weighed up in a MiW- bottle. It is sealed and the air is evacuated of air and filled with N2 three times. It is then filled with 10ml of o-DCB and heated to 180 °C. The solvent is then evaporated. The product is dissolved in 10 ml DCM and extracted with 10% K2CO3, dried with MgSO4 and vacuum filtered. The DCM is evaporated and the product is dissolved in 55:45 MeCN:toluene and purified with preparative HPLC.

4.8 Synthesis of 17 by hydroarylation of C60 with 16

50 mg (0.07 mmol, 1 eq.) of C60, 12.5 mg (0.084 mmol, 1.2 eq.) of (4-formylphenyl)boronic acid (12.5mg) and 2.7 mg (0.007 mmol, 0.1 eq.) [Rh(cod)(MeCN)2]BF4 is weighed up in a MiW-bottle. A crossbar stirrer is added and the bottle is sealed. The air inside is removed with vacuum and replaced with N2. This was repeated 3 times. 7 ml of o-DCB and 1ml of t-BuOH containing 125 µl of water was added. The mixture was heated to 110 °C until that temperature was reached. The reaction solution was then filtered on silica with toluene as the mobile phase.

4.9 Attempted synthesis of 2 by hydroarylation of C60 with 14 The amount of 14 was dependent on the amount yield of the corresponding Prato reac- tion, as all the purified 14 was used. To the Miw-flask with 1 eq. of 14, 2.5 eq. (25 eq. for reaction HA2) C60 and 0.1 eq. (1 eq. for reaction HA2) of [Rh(cod)(MeCN)2]BF4 was added. A crossbar stirrer was added and the bottle was sealed. The air inside was removed and was replaced with N2 by applying a vacuum and then filling the bottle with N2 three times. 10 ml of o-DCB, and 1ml of t-BuOH containing 126µl of H2O and 8.4mg NaOH was added. For reaction HA2: The product solution was filtered on silica in order to remove the cat- alyst. Six fraction were collected, using different compositions of mobile phase, presented in table 7.

25 Table 7: Mobile phases for the collected fractions for reaction HA2

Fraction Mobile phase Sil1 Toluene Sil2 Toluene Sil3 Toluene Sil4 9:1 Toluene:methanol Sil5 Methanol Sil6 o-DCB

For reaction HA3: The solution was heated to 110 °C and then rotavaped. The crude product was dissolved in toluene and extracted with water five times in order to remove the catalyst and then dried with Brine. The products were separated with preparative HPLC.

4.10 Treatment of 5 with [Rh(cod)(MeCN)2]BF4 A MALDI-MS sample was prepared from the crude 5synthesised in reaction P3. The remaining part was evaporated and 7.5 mg (0.02 mmol) [Rh(cod)(MeCN)2]BF4 was added. A crossbar stirrer was added and the bottle was sealed and placed under an N2 atmosphere. 6 ml o-DCB and 1 ml t-BuOH containing 126µl H2O and 8.4 mg NaOH was added. The solution was heated to 110 °C. When that temperature was reached, the heating was removed. A MALDI-MS sample was prepared. The solution was rotavaped, redissolved in toluene and extracted three times with water and once with brine. The product was then rotavaped and NMR, HPLC and MALDI-MS samples were prepared.

4.11 Synthesis of 21 using the Prato reaction with 10 and 20

51.3 mg (0.071 mmol, 1 eq.) C60, 50.6mg (0.14 mmol, 2 eq.) N-octylglycine and 38.2 mg (0.036 mmol, 5 eq.) benzaldehyde were weighed up in a MiW-bottle, which was sealed and filled with N2. 9 ml o-DCB was added and the solution was stirred at 180 °C for 2 hours. The o-DCB was evaporated and the crude product was redissolved in DCM. The solution was extracted with 10% K2CO3, dried with MgSO4 and filtered. The DCM was evaporated and NMR and HPLC samples were prepared.

4.12 Synthesis of 19 using the Prato reaction with 10 and 18

50.9 mg (0.07 mmol, 1 eq.) C60, 53.2mg (0.16 mmol, 2.28 eq.) N-octylglycine and (0.35 mmol, 5 eq.) 4-hydroxybenzaldehyde were weighed up in a MiW-bottle, which was sealed and filled with N2. 8 ml o-DCB was added and the solution was stirred at 180 °C for 2

26 hours. The o-DCB was evaporated and the crude product was redissolved in DCM. The solution was extracted with 10% K2CO3, dried with MgSO4 and filtered. The DCM was evaporated and NMR and HPLC samples were prepared.

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29 A Mass spectra

Figure A.1: MALDI-MS mass spectrum for reaction P1

Figure A.2: MALDI-MS mass spectrum for reaction P5

30 Figure A.3: MALDI-MS mass spectrum for reaction P7

Figure A.4: MALDI-MS mass spectrum for reaction P8

31 Figure A.5: MALDI-MS mass spectrum for collected fraction in reaction P9

Figure A.6: MALDI-MS mass spectrum for precipitate in reaction P9

32 Figure A.7: MALDI-MS mass spectrum for first fraction from the silica column for reaction HA2

Figure A.8: MALDI-MS mass spectrum for the crude solution of reaction HA3

33 Figure A.9: MALDI-MS mass spectrum for precipitate in reaction HA3

Figure A.10: MALDI-MS mass spectrum of crude mixture of P3 before treatment with [Rh(cod)(MeCN)2]BF4

34 Figure A.11: MALDI-MS mass spectrum of crude mixture of P3 after treatment with [Rh(cod)(MeCN)2]BF4

Figure A.12: MALDI-MS mass spectrum for the first collected peak of preparative HPLC of reaction HA3 (Suspected of being 19)

35 Figure A.13: MALDI-MS mass spectrum for crude mixture of reaction P12 (Synthesis of 19)

Figure A.14: MALDI-MS mass spectrum for the second collected peak of preparative HPLC of reaction HA3 (Suspected of being 21)

36 Figure A.15: MALDI-MS mass spectrum for crude mixture of reaction P11 (Synthesis of 21)

37 B 1H NMR spectra

FB-P3-Cr_PROTON_01 0 8 1 0 7 0 9 9 3 2 . . . . .

5 4 4 4 4 800

750

700

650

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550

500

450

400

350 A (s) 4.91 300 B (d) C (d) 4.99 4.29 250

200

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50

0 1 8 0 0 9 0

. . . -50 1 0 1

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 f1 (ppm)

1 Figure B.1: H NMR spectrum (CDCl3) of of crude solution of reaction P3 (5)

38 1 Figure B.2: Expansion of H NMR spectrum (CDCl3) of of crude solution of reaction P3 (5)

FB-P9-Benzene-Night_PROTON_01

6500

6000

5500

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4500

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2500

2000

1500

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0 6 5 0 0 1 0 . . .

1 1 1 -500

14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 f1 (ppm)

1 Figure B.3: H NMR spectrum (C6D6) of (4-(1-octyl-1H-pyrrolidinofullerene-2- yl)phenyl)boronic acid MIDA ester

39 1 Figure B.4: Excerpt from H NMR spectrum (C6D6) of (4-(1-octyl-1H- pyrrolidinofullerene-2-yl)phenyl)boronic acid MIDA ester

1 Figure B.5: H NMR spectrum of (CDCl3) 4-[60]-fullererneylbenzaldehyde

40 1 Figure B.6: H NMR spectrum (CDCl3) of N-octylglycine

41 C HPLC chromatograms

Figure C.1: C60 reference for Fig. C.2 and C.3

42 Figure C.2: HPLC for crude mixture of 5 from reaction P2

43 Figure C.3: HPLC for crude mixture of 5 from reaction P3

44 Figure C.4: C60 reference for Fig. C.5

Figure C.5: HPLC for crude mixture of 14 from reaction P8

45 Figure C.6: C60 reference for Fig. C.8

Figure C.7: Second peak (HA3) reference for Fig. C.8

46 Figure C.8: HPLC for crude mixture of 21 from reaction P11

47 Figure C.9: C60 reference for Fig. C.11

Figure C.10: First peak (HA3) reference for Fig. C.11

48 Figure C.11: HPLC for crude mixture of 19 from reaction P12

49