C-F Activation in Perfluorinated Arenes with Isonitriles under UV-Light Irradiation

Article abstract of DOI:10.1002/chem.201502298

Due to the great value of fluorinated arenes in agrochemistry, medicinal chemistry and materials science, development of methods for preparation of fluorinated arenes is of high importance. They can be either accessed by arene fluorination or by partial arene defluorination. However, the carbon-fluorine bond belongs to the strongest σ-bonds, which renders C-F activation highly challenging. Here it is shown that aryl and alkyl isonitriles efficiently activate the strong C-F bond in perfluoroarenes by simple UV irradiation under mild conditions. Reactions proceed by formal direct insertion of the isonitrile into the C-F bond without any transition metal. Activation occurs at arene C-F bonds whereas aliphatic C-F bonds remain unreacted. For selected perfluoroarenes C-F activation occurs with high regioselectivity and resulting imidoyl fluorides are transformed into other valuable compounds. Theoretical studies give insights into the reaction mechanism.

Full text of DOI:10.1002/chem.201502298

DOI: 10.1002/chem.201502298
Communication
&
Photochemistry
CÀF Activation in Perfluorinated Arenes with Isonitriles under UV-
Light Irradiation
Abhishek Dewanji, Christian Mück-Lichtenfeld, Klaus Bergander, Constantin G. Daniliuc, and
Armido Studer*[a]
an alternative valuable strategy, cleavage of CÀF bonds in
Abstract: Due to the great value of fluorinated arenes in
highly fluorinated compounds to give partially fluorinated
agrochemistry, medicinal chemistry and materials science,
products has been realized.[7–9] However, due to the very
development of methods for preparation of fluorinated
strong CÀF bond (154 kcalmolÀ1 in perfluorobenzene)[7] this
arenes is of high importance. They can be either accessed
approach is highly challenging. F substituents are poor leaving
by arene fluorination or by partial arene defluorination.
groups in substitution reactions at carbon and they are poor
However, the carbonÀfluorine bond belongs to the stron-
Lewis bases which makes activation of the CÀF bond an ex-
gest s-bonds, which renders CÀF activation highly chal-
tremely difficult task.
lenging. Here it is shown that aryl and alkyl isonitriles effi-
Considering thermodynamic aspects of CÀF bond activation,
ciently activate the strong CÀF bond in perfluoroarenes
not focusing at activation mode and pathway, an atom or frag-
by simple UV irradiation under mild conditions. Reactions
ment has to be squeezed into the CÀF bond and the bond dis-
proceed by formal direct insertion of the isonitrile into the
sociation energies (BDE) gained from the novel CÀX and XÀF
CÀF bond without any transition metal. Activation occurs
bonds formed in the product CÀXÀF moiety should ideally
at arene CÀF bonds whereas aliphatic CÀF bonds remain
overcompensate the BDE of the strong CÀF bond to be
unreacted. For selected perfluoroarenes CÀF activation
occurs with high regioselectivity and resulting imidoyl flu-
orides are transformed into other valuable compounds.
Theoretical studies give insights into the reaction mecha-
nism.
cleaved.[9] This has been achieved by various transition metal
complexes which form rather strong metalÀF bonds.[7–10] The
most obvious and currently overlooked route to solve the ther-
modynamic problem is to use a carbon sextet where a novel
strong CÀF bond is formed on the product side along with
Fluorine has gained great atten-
tion in various disciplines of sci-
ence during the past decades.[1–5]
Fluorine is the most electronega-
tive element, is small and forms
the strongest s-bonds to carbon.
These parameters give F-con-
taining organic compounds
unique physical properties, ren-
dering them highly valuable for
development of agrochemicals,[4]
pharmaceuticals[1–3] and novel
organic materials.[5] An obvious
route for preparation of fluoro-
organic compounds is fluorina-
tion of parent nonfluorinated de-
rivatives, where great improve-
Scheme 1. A) Light-mediated insertion of isonitrile 1a into the CÀF bond of hexafluorobenzene (2a) to provide
3a. B) X-ray structure of imidoyl fluoride 3a[15] (thermals ellipsoids are shown with 30% probability).
ments have been achieved.[6] As
a CÀC bond which should ensure exothermicity of the overall
[a] A. Dewanji, C. Mück-Lichtenfeld, K. Bergander, C. G. Daniliuc,
Prof. Dr. A. Studer
process. We therefore decided to investigate reactivity of per-
fluoroarenes towards stable carbon sextets aiming at CÀF
bond activation and chose isonitriles as C-sextets, because aryl
and alkyl isonitriles are readily accessible stable compounds.
Whereas elegant hydrodefluorination using organic silylium–
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502298.
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carborane catalysts[11] and organofluorophosphonium salts[12]
were reported, a transition-metal-free CÀF bond activation[13]
keeping the F-atom in the product is currently unknown.
Initial reactions for CÀF activation in hexafluorobenzene (2a)
were conducted with isonitrile 1a and C6F6 as a solvent under
argon atmosphere. No reaction was observed even at elevated
temperature. However, conducting reaction in a quartz tube
under irradiation (254 nm at around 358C) for 18 h, isonitrile
1a in perfluorobenzene undergoes clean CÀF activation and
imidoyl fluoride 3a was obtained in 98% yield. Imidoyl fluo-
rides belong to a known compound class which has not been
intensely investigated to date.[14] We found that the amount of
hexafluorobenzene can be reduced to 50 equivalents upon ex-
tending the reaction time to 24 h using benzene as a co-sol-
vent without diminishing yield (97%, Scheme 1). With 30, 10
and 5 equivalents of 2a, the yield slightly dropped to 89, 84
and 72%, respectively (see Table S1 in the Supporting Informa-
tion for details on optimization studies). With trifluorotoluene
or THF as co-solvents the yield was slightly lower (81%, 83%).
Importantly, upon irradiation either with a 365 nm light source
or with visible light reaction did not occur. By using a photo-
reactor (254 nm) and conducting the reaction in a pyrex glass
which cuts light below 300 nm, no conversion was observed,
clearly revealing that the short wavelength is necessary for suc-
cessful CÀF bond activation.
We next tested the scope and limitations of the novel arene
CÀF activation method (Figure 1). The perfluoroarene was
varied first keeping the isonitrile 1a as reaction partner. Per-
fluoroarenes which showed low reactivity were used in larger
excess and depending on the solubility of the perfluoroarene,
benzene was replaced by trifluorotoluene as a co-solvent.
Treatment of 1a with perfluorotoluene was highly efficient
and imidoyl fluoride 3b was isolated in 96% as a mixture of re-
gioisomers with the ortho-compound as major product (ortho/
meta/para=1.0:0.65:0.10). Importantly, the benzylic CÀF bonds
in perfluorotoluene are not activated showing that the new
method is highly selective for aromatic CÀF activation. This is
in agreement with the observation that trifluorotoluene was
found to be a suitable co-solvent for that reaction. The ortho-
selectivity was also observed in the transformation of penta-
fluoromethyl-benzoate 2c to give ortho-imidoyl fluoride 3c
along with its minor para-isomer (76%, ortho/para=1:0.21). A
similar result was observed for isonitrile insertion of acetylated
perfluorobenzene 2e to give 3e. Likely for steric reasons, the
more hindered pentafluoro tert-butyl benzoate 2d provided
the para-isomer as major product (see 3d). For pentafluoro-
benzenes bearing an electron-donating group, formation of
the ortho-isomer was in most cases fully suppressed (see 3 f–i,
3k). Except for the methoxy-derivative 3k, products 3 f–j were
obtained in good yields (54–81%). Notably, perfluorobiphenyl
2l reacted with complete meta-selectivity to 3l (66%).
Figure 1. Light-mediated insertion of isonitriles into the CÀF bond of various
perfluoroarenes. A) Variation of the perfluoroarene with isonitrile 1a as the
reaction partner. B) Variation of the isonitrile with hexafluorobenzene as the
reaction partner. Only the major regioisomer of each product is presented;
[a] 100 equiv of perfluoroarene used; [b] reaction conducted in neat per-
fluoroarene; [c] the reaction was conducted over 44 h; [d] PhCF3 was used
as a co-solvent in place of benzene; [e] 200 equiv of perfluoroarene used;
[f] 0.2 mmol of the isonitrile and 50 equiv of C6F6 and 9.0 mL of benzene as
a co-solvent for 24 h.
arene as documented by the successful transformation of pyri-
dine 2o to imidoyl fluoride 3o which was formed in near
quantitative yield with complete meta-selectivity. In contrast to
transition-metal mediated CÀF activation of pentafluoropyri-
dine where activation occurs either at the ortho- or para-posi-
tion,[7–10] our metal-free approach is highly meta-selective.
Next the scope of the arene CÀF activation with respect to
the isonitrile component was investigated by using hexafluoro-
benzene (2a) as reaction partner. a-Isocyanonaphthalene and
ortho-isocyanobiphenyl worked well and the corresponding
As compared to hexafluorobenzene (2a), the less electro-
philic pentafluorobenzene (2m) turned out to be less reactive
and product 3m was isolated as a mixture of regioisomers.
Along these lines, 1,2,4,5-tetrafluorobenzene 2n showed lower
reactivity and 3n was isolated as a single isomer in 36% yield.
Pleasingly, CÀF insertion works also on a perfluorinated hetero-
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imidoyl fluorides 3p and 3r were isolated in good yields. With
the sterically more hindered ortho,ortho’-dimethylphenylisoni-
trile, CÀF insertion was achieved albeit the yield for 3q slightly
dropped. CÀF activation works also with more electron-rich ar-
ylisonitriles as shown for the three isomers of the methoxy-
substituted phenyl isonitrile (see 3s–u).[15] A near-quantitative
yield was obtained with the ester-functionalized isonitrile to
give imidoyl fluoride 3v. Aromatic isonitriles bearing halogen
substituents are tolerated as substrates as documented by the
successful reaction of a chloro and a bromo derivative to give
the products 3w and 3x in moderate to good yields. Pleasing-
ly, CÀF insertion is not restricted to aromatic isonitriles: the iso-
nitrile derived from glycine benzyl ester reacted with hexa-
fluorobenzene to afford imidoyl fluoride 3y in a good yield.
Yield was further improved with a phenyl alanine derived isoni-
trile to provide 3z in 80% yield.
action with pentafluoropyridine should lead regioselectively to
the ortho-product which was not formed in the experiment.
To gain further mechanistic insights, we analyzed a model
reaction between phenyl isonitrile (1b) and C6F6 (2a) with den-
sity functional theory (DFT) methods (Figure 2). The calculated
vertical excitation energy to the first excited singlet state of
isonitrile1b is 5.496 eV (126.7 kcalmolÀ1), in good agreement
with the experimental spectrum[18] and the activation wave-
length (254 nm) used in this work. Due to the energetic and
geometric similarity of S1 with at least two triplet states (T4 and
T5), intersystem crossing to an excited triplet state is likely to
occur rapidly. Exothermic reaction with C6F6 generates the trip-
3
3
let adduct 4. A transition structure TS4-6 for 1,2-migration of
F to the imidoyl carbon has been located, but the energetic
¼
barrier is rather high (DH =24.2 kcalmolÀ1) and that path
3
leads to an excited triplet state 6* of the product. The activa-
Regarding the mechanism of the arene CÀF activation, we
currently rule out that reactions occur by initial electron trans-
fer from a photoactivated isonitrile to the perfluoroarene fol-
lowed by fluoride ion fragmentation to give the corresponding
aryl radical with subsequent aryl radical trapping, since regio-
chemistry for functionalization of monosubstituted perfluoroar-
enes via electron transfer would be different from the experi-
mentally observed regioselectivities.[16,17] Nucleophilic addition
of the isonitrile to the perfluoroarene is also unlikely since re-
tion energy required for F migration to the ortho-position of
¼
the fluorinated arene is lower (3TS4-5, DH =16 kcalmolÀ1) and
3
3
intermediate 5 is formed exothermically. Thus, 5 is likely an
intermediate. We could not locate a transition structure for the
3
direct conversion of 5 to one of the triplet states of the prod-
uct, but it is reasonable to assume that a pathway involving
the mixing of p,p and n,p states exists. The lowest triplet inter-
3
mediate we could locate is 6, a p,p*-excited triplet state of
the product imidoyl fluoride. It will revert to the singlet state
Figure 2. TDDFT calculated vertical excitation energies (italics) of phenyl isonitrile (left), and DFT enthalpies of triplet intermediates for the reaction of phenyl
isonitrile (1b) with C6F6 (2a). Geometries, enthalpic corrections and excitation energies: wB97X/6-31G(d,p), electronic energies: PWPLYP-D3/def2-TZVP (see
the Supporting Information).
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(16) by intersystem crossing involving the rotation of the CÀN
bond.
in various fields. In particular, for preparation of liquid crystals
the novel method should be valuable.[22]
Notably, all attempts to activate the CÀF bond in hexafluoro-
benzene with N-heterocyclic carbenes (NHC)[19,20] as C-sextets
under photoirradiation failed. As compared to the isonitriles
the higher nucleophilicity[21] of the NHCs turned out to be
problematic.
Acknowledgement
We thank the University of Münster and the NRW Graduate
School of Chemistry for supporting our work.
Finally, to document the synthetic value of the product imi-
doyl fluorides, follow-up chemistry was investigated on 3a
(Scheme 2). Iminoether 7 was readily obtained upon treatment
of 3a with NaOMe in MeOH. The imidoyl functionality in 3a
can be either hydrolyzed or reduced to provide amide 8 or
amine 9, respectively. With a soft nucleophile such as potassi-
um phenylthiolate, regioselective nucleophilic aromatic substi-
tution to 10, keeping the imidoylfluoride moiety intact, was
achieved. This example shows that our light mediated CÀF ac-
tivation process can be combined with a classical nucleophilic
arene CÀF substitution reaction to provide regioselectively
a product of a double CÀF functionalization of the initial per-
fluoroarene.
Keywords: CÀF activation
· fluorine · perfluoroarene ·
photochemistry · transition-metal free
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In this work, we have presented a simple and efficient transi-
tion-metal-free CÀF activation in various perfluoroarenes with
readily accessible aryl and alkyl isonitriles to provide imidoyl
fluorides in good to excellent yields. CÀF activation in per-
fluorinated arenes is a valuable strategy for preparation of par-
tially fluorinated arenes which are important compounds in
various disciplines. CÀF insertion works upon simple UV irradia-
tion under mild conditions. We expect this method will find
application for preparation of perfluorinated arenes to be used
Received: June 12, 2015
Published online on July 17, 2015
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