In this thesis, we will try to address the issue of increasing the dielectric constant, by util-izing high electronegativity of fluorine atoms.
In Chapter 2 we give a brief overview of existing fluorination methods and attempt to elucidate the general pathways of introducing the fluorine moieties into organic scaf-folds. We grouped the most common literature methods into three categories: direct fluorination (which is in turn sub-categorized by reaction mechanism), polyfuoroal-kylation (introduction of polyfluoroalkyl group directly into organic substrate, also sub-categorized by reaction mechanism), and synthon approach (formation of fluorine-con-taining compounds from simpler reagents, that readily contain desired fluorine moiet-ies).
In Chapter 3 we describe the synthesis of a discrete hominal bis(difluoromethyl) unit. We found out that, in the case of short chains, the consecutive deoxofluorination of sequentially introduced keto groups is inefficient, as it requires harsh conditions and decreasing yields at each step. To solve this problem, we combined the selective desul-furative fluorination of dithiolanes with pyridinium fluoride and the deoxofluorination of keto groups with morpholinosulfur trifluoride. This strategy is highly reproducible and scalable, allowing the synthesis of the hominal bis(gem-CF2) fragment as a shelf-stable tosylate, in order to introduce this unit on a variety of synthons and monomers.
In Chapter 4 we explore the effect of ether activation on deoxofluorination reactions.
To achieve this, we synthesized a small library of precursor ketones. We varied substitu-ents in direct proximity to the keto group and tested deoxofluorination reaction using several reaction conditions. This highlighted the activating effect of ether group located in 1,3 relation to ketone along the aliphatic chain, which allowed successful transforma-tion into the CF2group, whereas it was problematic, if even possible, for other substitu-ents. We also propose a plausible mechanism, which showcases the possible contribu-tion of the ether group in directing deoxofluorinating agents. We performed calculacontribu-tions
1
of intermediate and transition state structures and calculated their energetic profiles.
These calculations showed a clear effect of ether substituent in lowering the energy bar-rier of one of the transition states.
In Chapter 5 we attempt polymerization of monomers with fluorine-containing or TEG side-chains, in order to draw comparison with model P3HT polymer (used as a benchmark donor material in BHJ OPV devices). We encountered difficulties introdu-cing hominal bis(gem-CF2) fragment, so using the ether-activation approach, we syn-thesized 3-(1,1-difluoro-2-methoxyethyl)thiophene, and used it as a starting point of our tests. While electropolymerization technique succeeded, more conventional synthetic polymerization approaches failed. We postulate that attaching a CF2moiety next to the thiophene core leads to the withdrawal of electron density, which undermines oxidative addition steps of synthetic polymerization. Possible solutions, such as placement of CF2 group further from the core, use of dimer or copolymers of fluorinated monomers are proposed.
B
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2
A B RIEF O VERVIEW OF F LUORINATION M ETHODS
Abstract: The introduction of fluorine into organic compounds is a powerful tool for al-tering their properties. The rapid development of fluororganic compounds requires the use of right tools and techniques, and it is often difficult to pick the correct approach from a boundless amount of literature sources. We try to highlight important fluorination re-agents, and manners of their application based on three categories: direct fluorination, polyfluoroalkylation, and the fluorinated synthon approach.
The contents of this chapter are based on my BSc and MSc theses. I would like to thank Maksym Bugera, Igor Gerus and Karen Tarasenko for supervision, sharing their knowledge, and engaging my interest in this subject.
2.1. I
NTRODUCTIONFluorine is the 13thmost abundant element in Earth’s crust [1]. Despite such a high rank-ing, there are not too many compounds in nature that contain this element. Indeed, there are about five major mineral sources of fluorine [1,2], while its overall mineral di-versity is limited to 378 species [3]. Just as well, the number of organofluorines occurring in nature, while being subject to change in view of continuous exploration, still pales in comparison to other organohalogen compounds. A report from 2001 stated 3650 as a total of natural organohalides, of which organofluorines are only 30 [4], and this propor-tion is not likely to have drastically changed since.
While lacking in a variety of natural sources, what fluorine does possess is the par-ticular set of properties, most notable among which are record electronegativity (4.0 out of 4.0 possible), small atomic radius (1.35Å vs. 1.20Å for hydrogen), and large ionization potential (surpassed only by helium and neon)[5]. The combination of these factors sim-ultaneously causes extreme polarization and short bond length of C-F bond (depending on hybridization it can be 1.34 - 1.39Å vs. 1.08 - 1.09Å for C-H bond) [6].
As can be seen from the above-mentioned parameters, this story is prompting to draw comparison with the way replacing hydrogen with fluorine affects organic mo-lecules. And indeed, there are drastic consequences to such change: enhanced thermal stability, increased lipophilicity, mimicry of C-H bond, which in turn leads to modi-fication of chemical reactivity and causes blocking effect in metabolic transformations [2,5,7–9]. These effects lead to increasing interest in the development and application of organofluorine compounds for pharmaceuticals, agrochemicals, surfactants, and poly-meric materials [10].
In fact, despite the ongoing pandemic, in 2021, the US Food and Drug Administra-tion (FDA) approved 50 new drugs, 31 of which were small molecules (62% of the new drug pipeline), and 10 among them contained fluorine atoms [11]. A similar trend was observed for years in a row, like in 2020, when 13 out of 35 small-molecule drugs con-tained fluorine [12].
While over the last 100 years organofluorine chemistry has seen rapid growth, which sparked the development of numerous reagents, approaches, and techniques, introdu-cing fluorine in a right place and in the right manner often remain challenging. It is often hard to navigate in the sea of literature and to choose the correct fluorination approach for reaching the desired outcome. There is a plethora of comprehensive books and re-views on this topic [5,7,8,13–15], and this chapter is in no way claiming to give complete and straightforward guidelines. Still, we thought it is important to attempt giving a brief overview of existing fluorination methods and to elucidate the general pathways of in-troducing the fluorine moieties into organic scaffolds.
When contemplating the most common methods of introducing fluorine moieties that are reported in the literature, every author tends to group these methods using one of their features, be it fluorine source, bond hybridization, or reaction mechanism.
Each classification has its pros and cons, so we chose to generalize fluorination methods into 3 groups: direct fluorination (which in turn can be sub-categorized by the reac-tion mechanism into nucleophilic, electrophilic, and radical), polyfluoroalkylareac-tion and synthon approach (formation of fluorine-containing compounds from simpler reagents that readily contain desired fluorine moieties) [16–18]. But to simplify the reading, first
2
we will give a short tour of notable common fluorination reagents.