Catalytic Formation of C(sp3)-F Bonds via Heterogeneous Photocatalysis

Article abstract of DOI:10.1021/acscatal.8b02844

Due to their chemical, physical, and biological properties, fluorinated compounds are widely employed throughout society. Yet, despite their critical importance, current methods of introducing fluorine into compounds suffer from severe drawbacks. For example, several methods are noncatalytic and employ stoichiometric equivalents of heavy metals. Existing catalytic methods, on the other hand, exhibit poor activity, generality, selectivity and/or have not been achieved by heterogeneous catalysis, despite the many advantages such an approach would provide. Here, we demonstrate how selective C(sp³)-F bond synthesis can be achieved via heterogeneous photocatalysis. Employing TiO₂ as photocatalyst and Selectfluor as mild fluorine donor, effective decarboxylative fluorination of a variety of carboxylic acids can be achieved in very short reaction times. In addition to displaying the highest turnover frequencies of any reported fluorination catalyst to date (up to 1050 h^-1), TiO₂ also demonstrates excellent levels of durability, and the system is catalytic in the number of photons required; i.e., a photon efficiency greater than 1 is observed. These factors, coupled with the generality and mild nature of the reaction system, represent a breakthrough toward the sustainable synthesis of fluorinated compounds.

Full text of DOI:10.1021/acscatal.8b02844

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Article
Catalytic formation of C(sp3)-F bonds via heterogeneous photocatalysis
Giulia Tarantino, and Ceri Hammond
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 20 Sep 2018
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ACS Catalysis
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Catalytic formation of C(sp3)-F bonds via heterogeneous
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photocatalysis
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Giulia Tarantinoa and Ceri Hammonda*
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aCardiff Catalysis Institute, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
* hammondc4@cardiff.ac.uk; http://blogs.cardiff.ac.uk/hammond/
Abstract. Due to their chemical, physical and biological properties, fluorinated compounds are widely
employed throughout society. Yet, despite their critical importance, current methods of introducing fluorine
into compounds suffer from severe drawbacks. For example, several methods are nonꢀcatalytic, and employ
stoichiometric equivalents of heavy metals. Existing catalytic methods, on the other hand, exhibit poor
activity, generality, selectivity, and/or have not been achieved by heterogeneous catalysis, despite the many
advantages such an approach would provide. Here we demonstrate how selective C(sp3)ꢀF bond synthesis
can be achieved via heterogeneous photocatalysis. Employing TiO2 as photocatalyst and Selectfluor® as
mild fluorine donor, effective decarboxylative fluorination of a variety of carboxylic acids can be achieved in
very short reaction times. In addition to displaying the highest turnover frequencies of any reported
fluorination catalyst to date (up to 1050 hꢀ1), TiO2 also demonstrates excellent levels of durability, and the
system is catalytic in the number of photons required i.e. a photon efficiency greater than 1 is observed.
These factors, coupled with the generality and mild nature of the reaction system, represent a breakthrough
toward the sustainable synthesis of fluorinated compounds.
Keywords: fluorination • photochemistry • heterogeneous catalysis • spectroscopy • photocatalysis
Supporting Information is available.
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ACS Catalysis
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Introduction
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Increasing demand for fluorinated compounds, widely employed as pharmaceuticals, agrochemicals,
materials1 or tracers for Positron Emission Tomography (as 18F),2 has prompted a surge of interest in the
development of new strategies to perform selective fluorination. However, whilst many breakthroughs have
been made,3 such as the development of safer electrophilic fluorinating agents such Selectfluor®, the
selective and catalytic formation of C(sp3)ꢀF bonds remains an immense challenge. Indeed, catalytic methods
for C(sp3)ꢀF bond formation are rare, and even when catalysis is achieved, other issues such as poor activity,
low selectivity and/or factors associated with scalability – particularly recovery and reuse of the catalyst –
are prevalent.
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Amongst various enabling technologies,4 recent studies have demonstrated the potential of using light to
facilitate fluorination chemistry, with Selectfluor® as fluorinating agent and homogeneous species as
photocatalysts.5 Combining fluorination with photocatalysis (photofluorination) represents a very powerful
and sustainable approach, and represents a major breakthrough for the field. However, several disadvantages
are observed with these previous methods. For example, the reaction mechanisms predominating during such
processes have not yet been clearly identified, prohibiting detailed structureꢀfunction relationships from
guiding catalyst design. More critically, the photocatalysts developed to date also suffer from severe
drawbacks, including the requirement for high loadings of scarcely available and/or prohibitively expensive
metal centres (Ir, Ru), poor levels of intrinsic activity, and/or difficulties associated with their molecular
complexity and homogeneous nature (recovery, reusability, scalability).5 Herein, we demonstrate that
commercially available titanium dioxide, TiO2, a nonꢀtoxic, stable and readily available semiconductor, can
be efficiently employed as a heterogeneous photofluorination catalyst. When combined with the
decarboxylative fluorination reaction – a powerful and sustainable method for C(sp3)ꢀF bond synthesis6 –
selective photofluorination of a variety of aliphatic carboxylic acids can be achieved under mild electrophilic
fluorinating conditions. Under 365 nm irradiation, remarkable fluorine yields can be achieved in very short
reaction times (< 10 minutes), resulting in turnover frequency (TOF) values over one order of magnitude
larger than previously reported (1050 hꢀ1). The employment of water as solvent, the avoidance of scarce
metals, and the facile recovery of TiO2 ꢀ reused up to 4 times ꢀ also dramatically increase the sustainability of
this method over alternative fluorination methods. Spectroscopic studies with Diffuse Reflectance Infrared
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ACS Catalysis
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Fourier Transform (DRIFT) spectroscopy, Temperature Programmed Desorption Mass Spectrometry (TPDꢀ
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MS), F Magic Angle Spinning (MAS) NMR and XꢀRay Photoelectron spectroscopy (XPS) are coupled to
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classical mechanistic studies and actinometry, allowing a preliminary reaction mechanism, in which a
combination of TiO2ꢀcatalyzed steps and freeꢀradical process combine, to be proposed.
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Results and discussion
Photocatalytic fluorination. Amongst a range of wellꢀknown photosensitive materials, we identified that
commercially available TiO2 (P25) possessed high levels of activity for the decarboxylative fluorination of
aliphatic carboxylic acids, such as 2,2ꢀdimethylglutaric acid (DMGA, 1a). Under classical decarboxylative
conditions (25 °C, Selectfluor®, aqueous phase, SI Section 1, Scheme 1)6 rapid fluorination of waterꢀsoluble
acids could be achieved when TiO2 was irradiated by a solar light simulator, or a 365 nm LED torch. Under
irradiation, selective monoꢀfluorination of DMGA to 4ꢀfluoroꢀ4 methyl pentanoic acid (4F4MPA, 1b) was
observed, in line with the radicalꢀbased mechanism recently reported for this reaction, for which tertiary
positions exhibit much higher activity than primary and secondary ones.6 Rapid reaction rates were observed,
with around 80% 4F4MPA yield achieved in only 5 minutes of reaction time, when 6.25 mol % of Ti,
relative to the substrate, was employed (triangles, Figure 1 (Left)). Control reactions were also performed, in
the absence of K2CO3, TiO2 and Selectfluor®. In the absence of the fluorinating agent, no 4F4MPA was
observed. Furthermore, in the absence of TiO2 or K2CO3, much lower levels of activity were observed. These
indicate the crucial role(s) played by the solid catalyst, the fluorine source and the base in the reaction
network. To further study the effect of base, a number of kinetic experiments at different base loading was
performed. Higher activity was observed at 1.16 equivalents of K2CO3 relative to DMGA (Figure 1 (Right)).
Interestingly, with higher amount of base (2.32 equivalents), a decrease of reaction rate was observed.
Notably, 4F4MPA selectivity > 95 % was observed in all reactions.
Scheme 1. Photocatalytic decarboxylative fluorination of 2,2ꢀdimethylglutaric acid (DMGA, 1a) to yield 4ꢀ
fluoroꢀ4 methyl pentanoic acid (4F4MPA, 1b).
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