SNAr catalysis enhanced by an aromatic donor-acceptor interaction; Facile access to chlorinated polyfluoroarenes

Article abstract of DOI:10.1039/c7cc03996d

Selective catalytic S_NAr reaction of polyfluoroaryl C-F bonds with chloride is shown. Stoichiometric TMSCl makes the reaction exergonic and allows catalysis, which involves ground state elevation of chloride, aromatic donor-acceptor interactions, and stabilization of the Meisenheimer complex. Traditional cross-coupling of the products is now possible and demonstrates the utility.

Full text of DOI:10.1039/c7cc03996d

ChemComm
View Article Online
View Journal
COMMUNICATION
SNAr catalysis enhanced by an aromatic donor–
acceptor interaction; facile access to chlorinated
polyfluoroarenes†
Cite this:DOI: 10.1039/c7cc03996d
Received 25th May 2017,
Accepted 14th June 2017
Sameera Senaweera and Jimmie D. Weaver
*
DOI: 10.1039/c7cc03996d
rsc.li/chemcomm
Selective catalytic SNAr reaction of polyfluoroaryl C–F bonds with
chloride is shown. Stoichiometric TMSCl makes the reaction exergonic
and allows catalysis, which involves ground state elevation of chloride,
aromatic donor–acceptor interactions, and stabilization of the
Meisenheimer complex. Traditional cross-coupling of the products
is now possible and demonstrates the utility.
Perfluoroarenes are widely available molecules and are typically
synthesized via the halogen exchange process (Halex), which
utilizes fluoride salts to substitute the corresponding poly- or
perchloroarenes.1 In fact, most commercially available mono-
and dichlorofluoroarenes are byproducts of incomplete halogen
exchange.2 As a consequence, such molecules bear chlorine at the
least activated position,3 typically meta- to an activating group.
As a result, the corresponding para-chlorinated products are not
accessible via partial Halex. However, if the synthetic strategy is
Scheme 1 Strategies of SNAr with fluoroarenes.
reversed (retro-Halex), and chlorination of a perfluoroarene metal center, which polarizes the substrate.12,13 In contrast, the
is performed, it takes place with the same regioselectivity.4 quadrupole of perfluoroarenes is inverted,14 and thus, this
Consequently, the inaccessible chlorination patterns become activation is not feasible.6,15 While SNAr addition of a variety of
accessible. Currently, attempts to perform such transformations traditional nucleophiles are prevalent in literature8,16 the use of
use forcing conditions (i.e., refluxing sulfolane, bp = 285 1C).5 chloride as a nucleophile to displace a fluoride is rather limited
Catalysis of such transformations could reduce the extreme condi- and to the best of our knowledge, catalytic reactions to selectively
tions and significantly increase the scope, allowing the retro-Halex substitute C–F with C–Cl are not known.17 In fact, in 2015,
to become synthetically useful.
Sanford and co-workers revealed a mild SNAr fluorination of
The stoichiometric SNAr of haloarenes is a well-studied class heteroaryl chlorides and nitroarenes using anhydrous tetra-
of reactions, typically requiring haloarenes with an activating methylammonium fluoride at room temperature, essentially
group which can facilitate the reaction (Scheme 1a).6,7 It is the reverse of the desired reaction.7 Exploiting the principle of
believed8 that the electron withdrawing group stabilizes the microscopic reversibility,18 we sought to develop the reverse
negative charge buildup in the Meisenheimer intermediate, reaction. Herein, we report conditions for the regioselective
and polarizes the C–X bond, facilitating the addition of the catalytic aromatic nucleophilic substitution of per- and poly-
nucleophile. Not surprisingly, strategies to catalyze SNAr reactions fluoroarenes which undergo selective substitution of the C–F
and increase scope have long been sought.9–11 Transition metal bond to give a C–Cl bond (Scheme 1c).
activation of haloarene C–X bonds toward nucleophilic substitu-
We began with pentafluoropyridine and trimethylsilyl
tion is achieved via complexation of the p-cloud of the arene to a chloride (TMSCl) in THF at 80 1C.19 We speculated that the
use of a chlorosilane would form a strong Si–F bond and serve as a
thermodynamic driving force (i.e., bond dissociation energies, PhF
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
127 kcal molꢀ1 vs. PhCl 97 kcal molꢀ120 and H3SiCl 109 kcal molꢀ1
E-mail: jimmie.weaver@okstate.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc03996d vs. H3SiF 152 kcal molꢀ1 21). However, attempts at 80 1C and
This journal is ©The Royal Society of Chemistry 2017
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Catalyst screen for the chlorination reactiona
150 1C failed to give any product. These results suggest that the
chlorosilane is incapable of substitution on its own. However,
Shipilov22 observed that hexaethylguanidinium chloride can be
used to substitute C–F bond with C–Cl bond, albeit as part of a
complex mixture of products. Nonetheless, this work led us to
consider the design of a catalyst that could facilitate transfer of
the chloride.
It is generally accepted that there are two transition states
(TS) associated with a SNAr reaction. The first is the nucleo-
philic addition which leads to a sigma-complex known as the
Meisenheimer intermediate, and the second TS being its
decomposition. We speculated that formation of a frustrated
ion pair23,24 could increase the nucleophilicity of the chloride.
We investigated different quaternary ammonium chloride salts
that varied in steric size. Consistent with the above hypothesis,
smaller ammonium chlorides gave little to no conversion,
but using tetrabutylammonium chloride (Bu4NCl), which was
completely homogeneous at 80 1C, gave the best reactivity. Some
limited success was observed using inorganic chlorides and
other silanes.19 We expect that Bu4NCl serves to increase the
concentration of soluble reactive chloride.
a
b
%conversion determined after 1 h, 20 h by 19F NMR. %conversion
determined after 3 h, 20 h by 19F NMR.
reasonable kinetics (vide infra). Characterization of the post-reaction
mixture revealed benzyl chloride is formed in significant amounts,
presumably from decomposition of the BnNBu3Cl catalyst. Given
the commercially availability and inexpensive nature of the catalyst,
we used 0.4 equiv. for the substrate screening to ensure reaction
completion.
After achieving moderate reactivity by destabilizing chloride,
we turned our attention to activation of the fluoroarene. The
negatively charged Meisenheimer complex is expected to be
electrostatically stabilized by the cation, while the neutral
perfluoroarene would not. Thus, significant molecular reorganiza-
tion must occur in the TS to take advantage of this stabilization.
By preorganizing the perfluoroarene and catalyst, we hoped to
reduce the entropic penalty, analogously to Zhang’s elegant
exploitation of this phenomenon.25 If designed appropriately,
this could bring the perfluoroarene into close proximity to the
positively charged ammonium ion, and reduce the entropic cost
during the TS. Simultaneously, it was expected that the nearby
positive charge would better stabilize the buildup of negative
charge in the Meisenheimer complex.
With optimum conditions in hand, we evaluated the scope of
the reaction (Table 2). We were pleased to see good to excellent
yields could be obtained starting with a variety of fluoroarenes.
Traditionally, incomplete Halex sequences provides access to meta-
chlorofluoroarenes (vide supra). We obtained the complimentary
para-chlorofluoroarene products with excellent regioselectivity.
Thus, this reaction provides access to new chemical space. The
reaction works well with activated fluoroarenes (2d–e, 2g–h).
However, relatively unactivated fluoroarenes could also be
engaged simply by elevating the temperature, (2f and 2k). In
fact, selective dichlorination of decafluorobiphenyl was achieved
simply by increasing the amounts of TMSCl and BnNBu3Cl (2k).
It should be noted that the highly fluorinated nature of the
In order to test these ideas, we synthesized analogs of benzyl-
tributylammonium chloride (BnNBu3Cl). A catalyst screen was
then performed in which the reaction progress was monitored at
both early and late time points (Table 1). If stabilization of the
Meisenheimer intermediate26 was the only important feature,
then it could be expected that catalyst 1n would have worked,
but it did not, suggesting other features are also important in
facilitating the entire reaction. Instead, the screen revealed that
catalysts with the neutral (1g) and donating (1e, 1f) arenes gave
the superior results when compared to Bu4NCl. In contrast,
electron withdrawing groups on the benzyl fragment (1a–1d)
retarded the rate. This is consistent with an aromatic donor–
acceptor (DA) interaction. While a number of more exotic analogs
were tested (1h–1m), of these only catalysts 1j and 1m offered
comparable conversions to Bu4NCl.
Table 2 Reaction scope for the catalytic chlorination
Catalyst loading experiments were performed (ESI,† Table S1,
entries 26 and 27), which indicated the relatively low catalyst
turnover number (TON) of B3. The low TON suggests either
catalyst deactivation/decomposition, or potentially is the result
of the involvement of more than one catalyst molecule during
the catalytic cycle, requiring higher catalyst loading to achieve
a
b
NMR yield (isolated yield after workup in parenthesis). Used BnNBu3Cl
c
(1.0 equiv.) and TMSCI (2.0 equiv.). Used BnNBu3Cl (0.5 equiv.) and
d
TMSCI (2.0 equiv.). Used BnNBu3Cl (0.8 equiv.) and TMSCI (2.0 equiv.).
e
Used BnNBu3Cl (1.0 equiv.) and TMSCI (2.4 equiv.).
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2017

View Article Online
ChemComm
Communication
products make them relatively volatile and can lead to difficult
isolation. In order to isolate the products with high purity, it
was necessary to develop an isolation method. This was accom-
plished via the decomposition of the remaining catalyst and
selective extraction of the product.19 Thus, this method allows
the isolation of pure products.
Next, we wanted to understand the mechanism and phenom-
ena which lead to the catalysis and specifically the observed rate
enhancement when BnNBu3Cl was used compared to NBu4Cl.
We postulated that an aromatic interaction between the per-
fluoroarene and the catalyst’s arene moiety, along with the
electrostatic interactions between the Meisenheimer intermediate
and charged ammonium of the catalyst are responsible for the
superior performance. Based on the compilation of evidence,
including UV-Vis, NMR, and kinetic experiments, we propose the
following mechanism for the catalytic retro-Halex of perfluoro-
arenes (Scheme 2).25 First, chloride transfer from the catalyst to
TMSCl generates the active chloride source, Me3SiCl2ꢀ (4b). Favor-
Fig. 1 (a and a0) UV-Vis spectra indicating formation of a DA complex.
(b) 19F NMR spectra of the titration between pentafluoropyridine and
BnNBu3Cl. (c) Formation of Me3SiCl2 observed by 1H NMR.
ꢀ
able aromatic DA interactions lead to complexation of the fluoro- to about 0.85 equiv., consistent with shielding of the fluorines on
arene with the BnNBu3Cl catalyst, which bring the catalyst and pentafluoropyridine, presumably, as a result of an interaction
substrate in close proximity. NMR titration experiments indicate with electron rich phenyl ring of BnNBu3Cl (Fig. 1b). However,
the formation of both a 1 : 1 complex as well as a 2 : 1 complex between 0.85–2.0 equivalents, the fluorine signals moved down-
(BnNBu3Cl : perfluoroarene). Initial rate analysis indicates the field. Finally, after 2 equivalents of BnNBu3Cl, the 19F chemical
reaction is greater than second order in catalyst concentration, shifts become constant. These results are consistent with initial
which is consistent with the necessary high catalyst loading. Via formation of a 1 : 1 and then a 1 : 2 complex between the
preorganization, the catalyst molecules facilitate the formation of fluoroarene and the catalyst, which results in more deshielding
the Meisenheimer complex (4c) upon chloride transfer from of the fluorines.
Me3SiCl2ꢀ. Next, TMSCl assisted extrusion27 of fluoride generates
The observation of a 1 : 2 perfluoroarene: BnNBu3Cl complex
the chlorofluoroarene (2a) which is associated with the ammonium in the NMR is consistent with a kinetic analysis which indicate
cation. The catalytic cycle is completed by displacement of 2a with a rate law that is 2.3 order with respect to the catalyst. This
another substrate molecule.
supports a transition state involving two catalyst molecules.
Preorganization of the transition state was further examined
To support the idea of an aromatic DA interaction, we carried
out an NMR titration experiment using pentafluoropyridine and by UV-Vis spectroscopy. When an aromatic DA interaction
BnNBu3Cl.25 Interestingly, we observed up-field shifts of the occurs, the HOMO–LUMO gap becomes smaller28 resulting in
fluorines signals with increasing BnNBu3Cl concentration up a new red shifted absorption band which may be observed via
UV-Vis spectroscopy.25 Such an experiment was carried out by
mixing pentafluoronitrobenzene (PFNB) and BnNBu3Cl (1 : 1
and 1 : 2 molar ratio) and PFNB : BnNBu3Cl : TMSCl (1 : 2 : 2
molar ratio) in DCM. Comparison of these mixtures with the
spectra of the individual components revealed the emergence
of a red shifted absorption band at 370–380 nm, consistent with
a formation of a DA complex.19,25,28 Overlap of PFNB’s absorp-
tion band with the newly formed band obscures identification of
the maximum absorption wavelength (lmax). However, the first
derivative analysis allows identification of the new red-shifted
lmax of both the 1 : 1 and 2 : 1 catalyst : PFNB complexes (Fig. 1a).
The observation of two different lmax values also supports the
formation of two distinct types of complexes.
We next investigated the nature of the silane in the reaction.19
To individuate effects from each reaction component, we evaluated
1
all possible combinations for 19F and H NMR spectral deviation.
Fluorinated catalyst 1d was used with pentafluoropyridine so that
19F NMR could be used to monitor the changes to both reaction
components. A concentration dependent change 41 ppm of the
19F catalyst signal was observed upon mixing 1d and TMSCl in a
1 : 1 mol ratio. Meanwhile, the 1H methyl signal of TMS signal
Scheme 2 Plausible mechanism of catalytic SNAr.
This journal is ©The Royal Society of Chemistry 2017
Chem. Commun.

View Article Online
Communication
ChemComm
facilitate the breakdown of the intermediate. These strategies are
general and thus provide future direction for SNAr catalysis.
Here, we demonstrated the feasibility of catalyzing the retro-
Halex reaction and have shown how it can provide access to new
chlorofluoroarenes. Furthermore, we demonstrated how these can
immediately be used with more traditional chemistry to access
derivatized multifluorinated arenes.
We acknowledge NIH NIGMS (R01GM115697) for support of
this work and thank JID for editing the manuscript.
Notes and references
1 R. E. Banks, B. E. Smart and J. C. Tatlow, Organofluorine Chemistry
Principles and Commercial Applications, Plenum, New York, 1994.
2 G. G. Yakobson and I. L. Knunyants, Syntheses of fluoroorganic
compounds, Springer-Verlag, Berlin, New York, 1985.
3 V. A. Petrov, Fluorinated Heterocyclic Compounds: Synthesis, Chemistry,
and Applications, John Wiley & Sons, Inc., Hoboken, New Jersey, 2009.
4 R. D. J. Froese, G. T. Whiteker, T. H. Peterson, D. J. Arriola,
J. M. Renga and J. W. Shearer, J. Org. Chem., 2016, 81, 10672.
5 T. A. Vaganova, S. Z. Kusov, V. I. Rodionov, I. K. Shundrina and
E. V. Malykhin, Russ. Chem. Bull., 2007, 56, 2239.
6 M. Otsuka, K. Endo and T. Shibata, Chem. Commun., 2010, 46, 336.
7 S. D. Schimler, S. J. Ryan, D. C. Bland, J. E. Anderson and
M. S. Sanford, J. Org. Chem., 2015, 80, 12137.
8 H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119.
9 M. F. Semmelhack, A. Chlenov and D. M. Ho, J. Am. Chem. Soc.,
2005, 127, 7759.
Scheme 3 Synthetic utility of chlorodefluorinated products.
undergoes an up-field shift (B0.4 ppm in 1H NMR) when
compared to TMSCl (Fig. 1c). Thus, we propose that upon
mixing the chloride catalyst and TMSCl, a penta-coordinated
silicate (Me3SiCl2ꢀ) is formed. Further evidence for this species
was obtained by HRMS and 1H-DOSY experiments, both of
which confirmed the mass of this anion. Furthermore, we have
observed that the BnNBu3Cl salt goes from being partially
to completely soluble upon addition of the TMSCl at room
temperature in THF. This may facilitate the reaction by simulta-
10 R. P. Houghton, M. Voyle and R. Price, J. Chem. Soc., Perkin Trans. 1,
1984, 925, DOI: 10.1039/P19840000925.
¨
11 S. Brase, Tetrahedron Lett., 1999, 40, 6757.
neously providing chloride and a TMSCl that can immediately 12 R. C. Cambie, G. R. Clark, S. L. Coombe, S. A. Coulson, P. S. Rutledge
facilitate the fluoride extrusion step.27
and P. D. Woodgate, J. Organomet. Chem., 1996, 507, 1.
13 A. J. Pearson, J. G. Park and P. Y. Zhu, J. Org. Chem., 1992, 57, 3583.
14 C. J. Pace and J. Gao, Acc. Chem. Res., 2013, 46, 907.
In addition to the fundamental interest in the development of
SNAr catalysis, this chemistry has the potential to be a straightfor- 15 J. W. Walton and J. M. J. Williams, Chem. Commun., 2015, 51, 2786.
16 J. Burdeniuc, B. Jedicka and R. H. Crabtree, Chem. Ber., 1997,
ward method to access starting materials for coupling reactions
that would be difficult or impossible with the fluoroarene starting
130, 145.
17 Shipilov was able to achieve retro Halex of hexafluorobenzene and
materials. To demonstrate the utility, Suzuki and Sonogashira
coupling reactions were performed, which proceeded smoothly to
5a and 5b in good yields (Scheme 3). In contrast to pentafluoro-
octafluorotoluene in the presence of catalytic hexaethylguanidinium
chloride. Unfortunately, the products were obtained as a mixture of
over addition products. See ref. 22.
18 R. C. Tolman, Proc. Natl. Acad. Sci. U. S. A., 1925, 11, 436.
pyridine which undergoes substitution with lithiates,29 2a under- 19 See ESI† for details.
20 S. J. Blanksby and G. B. Ellison, Acc. Chem. Res., 2003, 36, 255.
21 Y. R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC
Press, Boca Raton, Florida, 2007.
22 A. I. Shipilov, E. E. Zolotkova and S. M. Igumnov, Russ. J. Org. Chem.,
2004, 40, 1117.
23 C. L. Liotta and H. P. Harris, J. Am. Chem. Soc., 1974, 96, 2250.
24 J. W. Steed and J. L. Atwood, Supramol. Chem., John Wiley & Sons,
Ltd, United Kingdom, 2009.
goes halogen–lithium exchange, and gives smooth addition to
benzaldehyde to give 5c, and could be used as a method to access
fluorinated analogs of bioactive molecules.
In conclusion, we have demonstrated the first selective catalytic
SNAr of C–F bonds of perfluoroarenes with a Clꢀ. BnNBu3Cl was
determined to be the best chloride transfer catalyst and impor-
tantly provides insights into potential strategies that can facilitate
otherwise impossible SNAr reactions. This reaction is characterized
25 H. Lv, J.-H. Zhan, Y.-B. Cai, Y. Yu, B. Wang and J.-L. Zhang, J. Am.
Chem. Soc., 2012, 134, 16216.
26 F. Terrier, Chem. Rev., 1982, 82, 77.
by ground state elevation of the chloride and its conversion to a 27 TMSCl, formed upon delivery of the chloride may accept fluoride
before diffusing away, but this is not clear at this time.
28 C. R. Martinez and B. L. Iverson, Chem. Sci., 2012, 3, 2191.
29 A. K. Barbour, M. W. Buxton, P. L. Coe, R. Stephens and J. C. Tatlow,
silicate, transition state preorganization by aromatic DA inter-
action between the substrate and catalyst, a Coulombic interaction
that stabilizes the Meisenheimer complex, and the use of TMSCl to
J. Chem. Soc., 1961, 808, DOI: 10.1039/JR9610000808.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2017