Unique properties of fluorine lead to a boundless potential when introducing it into or-ganic molecules. As evidenced by the widespread presence of fluorine atoms in modern pharmaceutic compounds, the interest in controlled introduction and modification of fluorine moieties is unlikely to fade away. This sparkled immense progress in the de-velopment of versatile organofluorine reagents and reaction techniques. Still, taming fluorine for a specific application often brings unexpected challenges.
In the past 100 years, the arsenal of fluorination methods has expanded from brutal
2
use of elemental fluorine or hydrofluoric acid to more refined and targeted techniques, such as electrophilic fluorination and the fluorinated synthons approach. Having full ac-cess to such a knowledge base, and commercial availability of a plethora of fluorination reagents with different mechanisms of action, allows chemists to achieve the synthesis of organofluorine compounds easier than ever before. Of course, there is always room for improvement, and with such trends, the development of cost-effective, predictable, selective, and functional group-tolerant reagents can serve as a beacon for future gener-ations of organofluorine chemists.
In our work, we focused on pursuing the synthesis of organic materials with high dielectric constant (as discussed in Chapter 1) by utilizing unique electronegativity of fluorine atoms and aligning them in pendant, polarizable chains. To achieve this, we aimed to synthesize short PVDF-like fragments, that can be coupled to the monomer of choice.
Based on our previous experience, as well as thorough subject study (which was briefly described in this chapter) and literature precedents, we chose direct nucleophilic fluorination as the most straightforward, cost-effective, and versatile approach to reach the desired goal. Results of our efforts are further elucidated in Chapter 3.
B
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3
S YNTHESIS OF A H OMINAL B IS ( DIFLUOROMETHYL ) F RAGMENT
Abstract: This chapter describes the synthesis of a discrete unit of hominal bis(gem-CF2).
The controlled introduction of fluorine atoms is a powerful synthetic tool to introduce di-pole moments with minimal impact to sterics. Polyvinylidene fluoride (PVDF) is a striking example of the influence of fluorine atoms, which impart ferroelectric behavior from the alignment of the dipole moments of CF2units, however, it is prepared via direct polymer-ization of vinylidene difluoride. Thus, a different synthetic pathway is required to pro-duce synthons containing discrete numbers of CF2groups in a hominal relation to each other. 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 desulfur-ative 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, which can be used to install discrete chains of hominal bis(gem-CF2) on a variety of synthons and monomers.
The contents of this chapter were published in ACS Omega, American Chemical Society (10.1021/acso-mega.9b02131). I would like to thank Hans Smit for his contribution to this work.
3.1. I
NTRODUCTIONThe introduction of fluorine atoms into organic compounds has established itself as a powerful tool for tuning their chemical and physical properties with minimal impact on sterics. Fluorination often improves chemical resistance, thermal stability, biological and optical activity.[1] As a result, C-F bonds can be found in a wide variety of pharma-ceuticals, [2,3] agrochemicals, surfactants, dyes, and polymeric materials.[4,5]
The unique properties of the fluorine atom have drawn increasing attention to its potential application in the field of organic photovoltaics (OPV), where the introduc-tion of C-F bonds into the monomers of conjugated polymers can significantly improve their performance.[6,7] The systematic introduction of C-F bonds into the backbones of benzoditiophene-[8,9] and thiophene-containing[10–13] conjugated (co)polymers leads to an increase in power conversion efficiencies (PCEs) through a combination of subtle effects.[6] The utility of this approach is evident in the work of Zhao et al., where the combination of fluorinated donor and non-fullerene acceptors gave rise to OPV devi-ces with PCEs over 13 %.[14] In addition to direct backbone fluorination, several studies have explored the effects of introducing fluorinated pendant groups of semi-fluorinated alkyl chains.[15,16] Such modifications lead to favorable microstructural ordering and remarkably high electron mobilities. There is a growing focus on the electrostatics of pendant groups (i.e., permanent dipoles) in organic materials, from enhancing the dielec-tric constant of OPV materials[17,18] to stabilizing dopants in thermoelectrics.[19] A striking instance of the strong dipole moment created by C-F bonds is ferroelectricity in polyvinylidene difluoride (PVDF), which arises from the alignment of CF2groups en-abled by the – CH2CF2– repeating unit.[20–23]
We are interested in synthesizing discrete chains containing these hominal bis(gem-CF2) (i.e., CF2CH2CF2[24]) units that can be attached to small molecules and monomers to tailor their electrostatic properties. However, the synthesis of hominal CF2units has not been widely reported. Typically, such compounds are obtained in the mixture of telomers, as illustrated in Figure3.1.
Rf X
Haupschein et al. [25, 26] and other works [29, 31-35]
S S
Terjeson et al. [28]
5 days at 90 °C
Figure 3.1 Background for this study: telomerization approach
3
Haupschein et al. accomplished the telomerization of 1,1-difluoroethylene under thermal conditions, yielding telomer iodides and bromides containing the hominal bis-(gem-CF2) fragment.[25] In later work, they prepared fluorocarbon halosulfates, acids, and derivatives that also contained such units [26]. However, in both cases, the hom-inal bis(gem-CF2) fragment is formed in a mixture with perfluorinated moieties. The synthesis also required large autoclaves and long, extensive heating followed by difficult fractional distillations. Similar difficulties were observed by others, via a variety of syn-thetic approaches: photochemically initiated reactions of bistrifluoromethyl disulphide with olefins,[27] thermal polymerization of SF5Br with fluoroolefins,[28] modification of other telomers,[29] telomerization of VDF withα,ω-diiodoperfluoroalkanes[30] and iodoperfluoroalkanes.[31–35]
It is apparently impossible to control the number of CH2CF2units by means of telo-merization; a fully synthetic and controllable approach that does not require harsh con-ditions, achievable in a typical laboratory environment, and is easily reproduced would be ideal. As discussed in Chapter 2, there are numerous methods of introducing fluorine atoms into organic molecules. Their development over the years has built up an array of tools, each with its pros and cons. For our research, we chose several criteria that will dictate our choice of strategy: synthetic availability, substrate scope, ease of labor-atory handling, scalability, cost-effectiveness, and the number of literature precedents (depicted in Figure3.2). Based on these parameters, we chose deoxofluorination with dialkylaminosulfur trifluorides (see Scheme2.6) as a primary approach.
SF4 , HF
Stepanov et al. [36]
F F
... chain extension ...
5
R 2) acidic treatment
Hamel et al. [43]
Figure 3.2 Background for this study: synthetic approaches
3
Stepanov et al. demonstrated one of the first examples of synthetically-feasible com-pounds containing hominal bis(gem-CF2) fragment.[36] By treating pentane-2,4-dione with SF4for 3 h at 20◦C they managed to obtain a mixture that contained 8 % of 2,2,4,4-tetrafluoropentane and 70 % of 4,4-difluoropentan-2-one among other fluorinated prod-ucts. With increased reaction time (up to 40 h) and the addition of HF, they observed a shift toward the formation of 2,2,4,4-tetrafluoropentane as a predominant product. The same behavior was observed in the case of 2,2,4,4-tetrafluorohexane from hexane-2,4-dione. Even though this approach seems straightforward, reacting SF4 and HF in an autoclave is so dangerous that is forbidden nowadays in many (academic) laborator-ies (such as our own). As a result, more convenient and user-friendly reagents of in-troducing CF2groups have been developed,[37] largely as a class of dialkylaminosulfur tetrafluorides[38] and pyridinium poly(hydrogen fluoride) (PPHF, 70 % hydrogen fluor-ide, 30 % pyridine, also known as Olah reagent).[39]
Significant progress toward the user-friendly synthesis of hominal bis(gem-CF2 )-con-taining compounds using these methods has been done by O’Hagan and co-workers.
For example, Wang et al. introduced CF2groups into a palmitic acid analog by sequen-tial preparation of appropriate precursor ketones followed by deoxofluorination using diethylaminosulfur trifluoride (DAST).[40] The conversion to the CF2group occurred in modest yields and required neat DAST at elevated temperature. Jones et al. synthes-ized 2,2-dimethyl-5-phenyl-1,1,3,3-tetrafluorocyclohexane by means of the direct deox-ofluorination of a diketone precursor. [41] Attempts to use the same approach in the case of diketones, which did not have dimethyl-substituted methylene between keto groups were unsuccessful, yielding only complex and intractable products, which could be at-tributed to the high degree of enolization of such diketones. This behavior of diketones was also noted previously in the work by Singh et al.. [42] In both works by Stepanov et al.[36] and Wang et al.,[40] the route to compounds containing the hominal bis(gem-CF2) fragment included the formation of 3,3-difluoroketones as intermediates. 3,3-diflu-oroketones themselves are attractive building blocks, but are difficult to synthesize; how-ever, recent work by Hamel et al. demonstrated that the synthesis of 3,3-difluoroketones via a regioselective gold-catalyzed formal hydration of propargylic gem-difluorides.[43]
Given the relative scarcity of examples of the successful isolation of compounds con-taining hominal bis(gem-CF2) units, there does not appear to be any reasonable syn-thetic route to realizing our goal of incorporating them into pendant chains. In this work, we demonstrate an approachable, reproducible, and reliable strategy for synthes-izing compounds containing the hominal bis(gem-CF2) fragment from the precursor
Given the relative scarcity of examples of the successful isolation of compounds con-taining hominal bis(gem-CF2) units, there does not appear to be any reasonable syn-thetic route to realizing our goal of incorporating them into pendant chains. In this work, we demonstrate an approachable, reproducible, and reliable strategy for synthes-izing compounds containing the hominal bis(gem-CF2) fragment from the precursor