Organocatalyzed Fluoride Metathesis

Article abstract of DOI:10.1021/acs.orglett.0c03593

A new organocatalyzed fluoride metathesis reaction between fluoroarenes and carbonyl derivatives is reported. The reaction exchanges fluoride (F-) and alternate nucleophiles (OAc-, OCO2R-, SR-, Cl-, CN-, NCS-). The approach provides a conceptually novel route to manipulate the fluorine content of organic molecules. When the fluorination and defluorination steps are combined into a single catalytic cycle, a byproduct free and 100% atom-efficient reaction can be achieved.

Full text of DOI:10.1021/acs.orglett.0c03593

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Organocatalyzed Fluoride Metathesis
Daniel Mulryan, Andrew J. P. White, and Mark R. Crimmin*
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ABSTRACT: A new organocatalyzed fluoride metathesis reaction between fluoroar-
enes and carbonyl derivatives is reported. The reaction exchanges fluoride (F−) and
alternate nucleophiles (OAc−, OCO2R−, SR−, Cl−, CN−, NCS−). The approach
provides a conceptually novel route to manipulate the fluorine content of organic
molecules. When the fluorination and defluorination steps are combined into a single
catalytic cycle, a byproduct free and 100% atom-efficient reaction can be achieved.
luorine is ubiquitous in organic synthesis. From
modulating the bioavailability of agrochemicals and
complex.10 The finding builds upon the pioneering work of
Yamaguchi and co-workers who used [RhH(PPh3)3] to
establish exchange equilibria between fluoroarenes and esters
or thioesters to form functionalized arenes and carbonyl
fluorides.11,12 These papers suggest a general approach to
catalytic fluoride metathesis should be viable, but the current
systems are constrained to stoichiometric or expensive metals
and are limited in scope.
We became interested in the idea of using simple
nucleophilic catalysts to achieve fluoride metathesis. In 2005,
Sandford and co-workers reported the SNAr reaction of 4-
(dimethylamino)pyridine (DMAP) and pentafluoropyridine to
form a pyridinium fluoride salt (Figure 1a).13 This salt could
be isolated and used as a nucleophilic source of F− for the
fluorination of a limited scope of organohalides. The studies
form part of a broader set of work that targets the generation of
anhydrous F− by the combination of two organic compo-
nents.14−18 Interestingly, Schmidt et al. reported that the same
pyridinium fluoride salt served as an electrophile in reactions
with external nucleophiles.19 We envisaged that these two
modes of reactivity could be combined to create a catalytic
method for fluoride metathesis (Figure 1b).
F
pharmaceuticals to improving the chemical stability of
refrigerants and polymers, fluorine plays a key role in chemical
manufacturing.1−4 Despite their importance, our current
approach to the synthesis of fluorochemicals is not sustainable.
Inorganic fluoride (fluorspar, CaF2) is converted into HF,
which is ultimately used as the fluorine source for nearly all
synthetic organofluorine compounds. Current estimates
suggest that viable sources of fluorspar will sustain the
fluorocarbon industry for less than 100 years.5 Others have
begun to question the long-term strategy behind the use of this
finite resource.6 Fluorine containing molecules are often
treated as single use and can result in environmental
contamination, leading to significant issues such as ozone
depletion, global warming, and water contamination. In
addition to these concerns, our current approaches to install
and remove fluorine atoms into organic molecules are wasteful.
Fluorination reagents such as tetrabutylammonium fluoride
(TBAF), diethylaminosulfur trifluoride (DAST), and 1-
chloromethyl-4-fluoro-1,4-diazonoabicyclo[2.2.2]octane bis-
(tetrafluoroborate) (selectfluor) have low atom efficiency,
while defluorination methods often rely on stoichiometric
main group reagents such as silanes or boranes to provide a
thermodynamic driving force for breaking strong carbon−
fluorine bonds.7−9
In a series of experiments, we established the metathesis
reaction between pefluoroarenes and suitable partners (acid
anhydrides, dimethyl dicarbonate, S-phenyl thioacetate,
benzoyl chloride, benzoyl cyanide, benzoyl isothiocyanate).
Reactions were conducted with pentafluoropyridine as the
fluoroarene of choice, due to it being activated toward
reactions with nucleophiles by SNAr. Following an initial
screening of the conditions and substrates, a reaction scope
In this paper, we describe an alternative approach to
manipulate the fluorine content of molecules. We report an
organocatalyzed fluoride metathesis reaction that involves the
exchange of F− with a wide variety of functional groups
including acetate, carboxylate, thiol, chloride, cyanide, and
isothiocyanate (eq 1). The reaction transfers the fluoride group
between organic fragments.
Received: October 28, 2020
Very recently, Saunders and co-workers reported a
stoichiometric fluoride metathesis reaction promoted by a Rh
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conversion was observed when DMAP was used as a catalyst.20
DBU proved to be a poorer catalyst for other reactions in the
series, and no product was observed for fluoride metathesis of
pentafluorobenzene with benzoic anhydride using this catalyst.
Both the reaction products of fluoride metathesis are useful
chemical intermediates. Substituted polyfluoroarenes are
featured in liquid-crystal displays21,22 and conjugated polymers
for organic light-emitting diodes.23,24 They are also useful
building blocks for the synthesis of partially fluorinated arenes
relevant to drug discovery through a further hydrodefluorina-
tion step.25−27 Acyl fluorides are versatile fluorinating agents
for a variety of reactions including: oxidative addition to
transition metals,27,28 the enantioselective ring-opening fluori-
nation of epoxides,29 and the hydrofluorination of alkynes.30
A series of experiments and calculations were undertaken to
interrogate the proposed mechanism of fluoride metathesis.
Monitoring the reaction of pentafluoropyridine with benzoic
anhydride catalyzed by 5 mol % DMAP by 19F NMR
spectroscopy shows that 1a and 2a are formed at the same
rate (Supporting Information). In further experiments, the
direct reaction of DMAP with both pentafluoropyridine and
acetyl anhydride could be observed. Hence, the stoichiometric
reaction of DMAP with pentafluoropyridine forms the salt 3
through nucleophilic displacement of a fluoride group from the
arene. Experimentally, this salt was found to be catalytically
competent for the fluoride metathesis of pentafluoropyridine
and benzoic anhydride to form 1a and 2a. Similarly, the
stoichiometric reaction of DMAP with benzoic anhydride
forms the salt 4, which was again catalytically competent
(Figure 3a).
Kinetic analysis reveals the reaction to be first order in
fluoroarene, first order in acid anhydride, and second order in
DMAP. These findings were verified by both initial rates and
graphical analysis (VTNA; Supporting Information). The
second order behavior of the catalyst in the empirical rate
law is notable as it implies a turnover-limiting sequence
involving two equivalents of DMAP. The most sensible
interpretation of this finding is that the catalyst plays a dual
role in activating both components of the fluoride metathesis
reaction and turnover occurs by two intersecting catalytic
cycles, each of which relies on DMAP as a catalyst (Figure 3b).
Furthermore, while both nBu4NF and Me4NOAc could be used
as catalytic initiators, both gave reaction rates of approximately
half that recorded for DMAP.
DFT calculations were undertaken to gain a greater
appreciation of the key steps involved in substrate activation
in each of these intersecting cycles. The B3LYP functional and
a hybrid basis set were employed. Solvent (MeCN) and
dispersion corrections were considered during the optimization
of stationary points. This computational approach has been
used previously to model acetylization reactions catalyzed by
DMAP.31,32
The overall reaction of pentafluoropyridine and acetic
anhydride is calculated to be exergonic by −5.8 kcal mol−1.
The key steps of two intersecting catalytic cycles were
calculated. One involves the activation of the anhydride by
DMAP and the other, the activation of the fluoroarene by
DMAP. The transition states associated with both intersecting
pathways occur by either a concerted SNAr or a concerted
nucleophilic addition−elimination step. The catalyst activation
of both substrates is calculated to be facile under the reaction
conditions. Hence, the reaction of DMAP with both
pentafluoropyridine (TS-1, ΔG‡ = 18.0 kcal mol−1) and acetic
Figure 1. (a) Pyridinium salt from the SNAr addition of DMAP to
pentafluoropyridine and its established reactivity. (b) Proposed
catalytic cycle for fluoride metathesis.
was developed in which pentafluoropyridine was reacted with a
series of functional groups in the presence of 5 mol % DMAP
catalyst in acetonitrile at 100 °C. The fluoride metathesis
reaction creates two products, a new functionalization
fluoroarene (1a−q) and an acyl fluoride (2a−e), both of
which contain usable fluorine content. The formation of the
acyl fluoride provides a thermodynamic driving force for the
forward reaction. In all cases, yields were recorded for both
fluoride metathesis products and there is a clear and expected
correlation between the yields of 1 and 2. Both products could
be recovered from the reaction: 1a and 2a in 56% and 73%
isolated yields, respectively. The reaction scope includes a
variety of metathesis partners, meaning it can be used as a
general approach to create C−O, C−Cl, C−C, C−N, and C−S
bonds from high fluorine content arenes (Figure 2).
The observed regioselectivity is consistent with that
expected from a concerted or stepwise SNAr mechanism.
Yields of the reaction decreased for less stable nucleophiles
such as carboxylates (prone to eliminate CO2) and lower
fluorine content arenes. For the highly reactive substrates
pentafluorobenzonitrile and pentafluoronitrobenzene, a mix-
ture of mono- and disubstituted products was observed. In
most cases, the disubstituted species was the minor product.
The use of S-phenyl thioacetate to generate the highly
nucleophilic benzenethiolate anion enabled the expansion of
the scope and fluoride metathesis of the less activated
fluoroarenes pentafluorobenzene and 1,2,3,5-tetrafluoroben-
zene (1m and 1n, Figure 2). Interestingly, these reactions
required the presence of 5 mol % of DBU to proceed and no
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Figure 2. Fluoride metathesis reaction of fluoroarenes with a range of different carbonyl derived functional groups. [a]Internal NMR yield of the
tetrafluoropyridine product using 19F NMR (isolated yield after workup in parentheses). [b]Internal NMR yield of the corresponding carbonyl
fluoride using 19F NMR. Standard deviation calculated from three repeats at 99.9% confidence. [c]DBU was used as a catalyst.
anhydride (TS-2, ΔG‡ = 14.1 kcal mol−1) occurs by low
energy barriers. The calculations also show that DMAP
activated substrates are more susceptible to nucleophilic attack
by F− or OAc− than the parent reagents.
On the basis of the analysis, the turnover limiting step is
predicted to be associated with TS-3 and the nucleophilic
attack of the liberated fluoride anion on the acetylated DMAP
fragment of Int-2. While the complexity of modeling explicit
solvation in this system means that this conclusion should be
treated with care, if this step is turnover limiting, it would be
consistent with the empirical rate law and second order
dependence on the catalyst.
In summary, we have developed the first organocatalyzed
fluoride metathesis reaction. This approach is complementary
to more established and less efficient methods for the
fluorination and defluorination of organic molecules. When
the two steps are combined in a single catalytic cycle, a
conceptually new approach to manipulating the fluorine
content of organic molecules has been achieved. This approach
is 100% atom efficient and avoids the use of highly acidic or
toxic fluorinating agents. While the reaction is currently limited
to activated fluoroarenes, in the longer term, the development
of more active catalysts or alternative strategies, such as π-
activation of the arene, may allow fluoride metathesis to be
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Figure 3. (a) Generation and catalytic competence of the proposed intermediates 3 and 4. (b) Proposed reaction pathway for the reaction of
DMAP, C5F4N, and acetic anhydride.
established as a broad approach in the sustainable chemistry of
fluorocarbons.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03593.
Full details of the experiments and calculations (PDF)
Accession Codes
CCDC 2021812 and 2021813 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
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Corresponding Author
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Mark R. Crimmin − Department of Chemistry, Molecular
Sciences Research Hub, Imperial College London, London
W12 0BZ, United Kingdom; orcid.org/0000-0002-9339-
9182; Email: m.crimmin@imperial.ac.uk
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Authors
Daniel Mulryan − Department of Chemistry, Molecular
Sciences Research Hub, Imperial College London, London
W12 0BZ, United Kingdom
Andrew J. P. White − Department of Chemistry, Molecular
Sciences Research Hub, Imperial College London, London
W12 0BZ, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03593
Funding
We are grateful to the ERC (FluoroFix: 677367) for generous
funding.
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Notes
The authors declare no competing financial interest.
A preprint version of this article is available on ChemRxiv.33
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