Unexpected intermediates and products in the C-F bond activation of tetrafluorobenzenes with a bis(triethylphosphine)nickel synthon: Direct evidence of a rapid and reversible C-H bond activation by Ni(0)

Full text of DOI:10.1021/ja8081395

Published on Web 12/02/2008
Unexpected Intermediates and Products in the C-F Bond Activation of
Tetrafluorobenzenes with a Bis(triethylphosphine)Nickel Synthon: Direct
Evidence of a Rapid and Reversible C-H Bond Activation by Ni(0)
Samuel A. Johnson,* Carla W. Huff, Ferheen Mustafa, and Mark Saliba
Department of Chemistry and Biochemistry, UniVersity of Windsor, Windsor, Ontario, Canada N9B 3P4
Received August 7, 2008; E-mail: sjohnson@uwindsor.ca
Scheme 1
The selective activation and functionalization of C-F bonds in
the commercially available polyfluorobenzenes is an attractive goal
because of potential use of these compounds as starting materials
for pharmaceuticals and agrochemicals containing partially fluori-
nated aromatic groups.1,2 The difficulties associated with the
oxidative addition of C-F bonds is similar to those encountered
with C-H bond activation,3 due in large part to the strength of the
C-F bond. However, the selective activation of C-F bonds in the
presence of C-H bonds generates additional issues, because many
second and third row late transition metal complexes that are
capable of the oxidative addition of C-F bonds display lower
activation barriers for C-H bond oxidative addition.4,5 Thus, despite
the efficacy of these heavier metals in the activation of perfluori-
nated aromatic substrates, they are of no utility with more
synthetically useful substrates such as penta-, tetra-, tri- and
difluorobenzene. Although this difficulty has been bypassed in a
few cases by utilizing metal complexes that react with aromatic
substrates via electron transfer or nucleophilic mechanisms,6 these
complexes produce activation products which cannot be con-
veniently incorporated into catalytic cycles.
A representative reaction between 1 and 2 equiv 1,2,4,5-
tetrafluorobenzene in d8-toluene is described; similar results were
The relatively low cost of nickel provides an impetus for its use
in lieu of its heavier congeners, and the potential of nickel(0)
obtained irrespective of solvent or equivalents of 1,2,4,5-
complexes in C-F bond activation and catalytic functionalization
tetrafluorobenzene utilized. The 19F NMR spectrum of this
mixture featured second order multiplets at δ -117.8 and -143.7
have been investigated extensively.7,8 It has been shown via
calculation that the oxidative addition of C-H bonds in C6H6 to a
for the small equilibrium amount of complex 2. In the 298 K
bis(phosphine)nickel(0) moiety is thermodynamically disfavored by
1H NMR spectrum a broad triplet was observed at δ -14.3, as
∼18 kcal ·mol-1, whereas C-F bond activation in C6F6 is favored.9
anticipated for a nickel hydride complex.11,12 Upon cooling to
In principle, this should allow for selective activation in a range of
233 K this broad resonance sharpened and could be modeled as
polyfluoroaromatics, but to date the selective activation of C-F
bonds using nickel complexes has been limited to perfluorinated
aromatics and nitrogen containing heterocycles. The reaction of
(PEt3)4Ni with pentafluorobenzene is reported to produce a mixture
of products,8 while no reactions with the tetrafluorobenzenes have
been described.
a multiplet with couplings to two 31P nuclei, two o-fluorine, and
2
two m-fluorine substituents. The relatively large JPH value of
67.7 Hz is diagnostic of a bis(phosphine)nickel hydride frag-
ment,11 and the remaining couplings identify the complex as 2.
The 298 K 31P{1H} NMR spectrum featured broad resonances
for 1 and 2 at δ 18.1 and 23.5, respectively. Cooling the solution
to 233 K resulted in the sharpening of these resonances in the
31P{1H} NMR spectrum, and in the 1H coupled 31P NMR
spectrum the peak at δ 23.5 was a doublet with a 68 Hz coupling
to the hydride.
The sodium reduction of Br2Ni(PEt3)2 in the presence of
phenanthrene provides a synthon for the unisolable Ni(PEt3)2
moiety, (PEt3)2Ni(η2-C14H10) (1).10 Complex 1 has been character-
ized by X-ray crystallography and NMR spectroscopy; details are
provided in the Supporting Information. Mixtures of 1 and 1-10
equiv 1,2,4,5-tetrafluorobenzene in pentane, d8-toluene, C6D6 or
THF all react over weeks to provide C-F bond activation products;
however, immediate characterization of these solutions revealed
an initial equilibrium producing the unexpected C-H bond activa-
tion product, (PEt3)2NiH-2,3,5,6-F4C6H, 2, as shown on the top of
Scheme 1. As expected for an equilibrium, the addition of
phenanthrene decreased the concentration of 2 and the addition of
1,2,4,5-tetrafluorobenzene increased the concentration of 2, as
monitored by 19F NMR spectroscopy.
1
The broad H hydride and 31P{1H} NMR resonances at 298
K are indicative of a fluxional exchange, and a 19F EXSY
spectrum with a mixing time of 0.5 s revealed positively phased
cross peaks between the 1,2,4,5-tetrafluorobenzene peak and the
19F resonances of 2. Further evidence for the reversible nature
of this C-H bond activation over a range of temperatures was
obtained by the reaction a d8-toluene solution of 1 and 2 equiv
of monodeuterated 1,2,4,5-tetrafluorobenzene, which was ana-
1
lyzed by H and 19F and 31P{1H} NMR spectroscopy. Signals
were observed for equilibrium amounts of the C-H and C-D
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C O M M U N I C A T I O N S
activation products 2a and 2b, shown in Scheme 2. An expansion
of the hydride region at 233 K is shown on the left side of Figure
1 and displays couplings and shifts identical to 2. Expansions
of the AA′MM′ spin system signals of this equilibrium species
in the 273 K 19F and 19F{1H} NMR spectra are shown on the
right side of Figure 1. These appear at δ -118.0 for the
overlapping o-fluorine resonances of 2a and 2b, whereas the
resolved resonances for the m-fluorines of 2a and 2b appear at
δ -144.1 and -143.8, respectively. This shift of ∼0.3 ppm for
fluorine nuclei adjacent to H versus D is typical for fluorinated
aromatics. The 19F NMR spectrum also exhibits the appropriate
couplings to the hydridic 1H; the Fortho resonance associated with
aromatic multiplets at δ -93.4, -145.4, and -146.6, as well as
a Ni-F environment at δ -378.5, which is a triplet of doublets
due to coupling to two equivalent 31P environments (2JPF ) 48.8
Hz) and a single o-F (2JFF ) 10 Hz). Complex 3 displays a
doublet 31P{1H} resonance at δ 12.1. As the reaction proceeds,
two other unanticipated C-F bond activation products are
observed. One product, which has 19F resonances at δ -119.2,
-143.2, and -390.1, the latter of which is a triplet of triplets
due to coupling to two 31P environments and two o-fluorine
substituents, can be identified as (PEt3)2NiF-2,3,5,6-F4C6H (4).
Complex 4 features a doublet in the 31P{1H} NMR at δ 13.6
2
with a JPF value of 46.5 Hz. This assignment was verified by
4
2a exhibits a JFH of 9.5 Hz and the Fmeta resonance associated
an alternate synthesis of 4 via the oxidative addition of 1-bromo-
2,3,5,6-tetrafluorobenzene to Ni(COD)2 in the presence of PEt3
to generate (PEt3)2NiBr-2,3,5,6-F4C6H, followed by reaction with
tetrabutylammonium fluoride hydrate. The second unexpected
product is (PEt3)2NiF-2,3,5-F3C6H2 (5), with 19F resonances at
δ -119.9, -121.3, -137.6, and -379.6, the latter of which
features coupling to two 31P nuclei and a single o-fluorine. The
31P{1H} NMR signal appears at δ 12.6 with a 2JPF value of 48.0
Hz. This assignment was verified by the reaction of 1,2,3,5-
tetrafluorobenzene with 1, shown in Scheme 3, which produces
5 as an isolable major product, but also features 3 as ∼3% of
the C-F bond activation products, by integration of the aromatic
19F resonances. Complex 5 was characterized by X-ray crystal-
lography and details are presented in the Supporting Information.
DFT calculations predict that isomer 5 is only slightly lower in
energy than 3, thus the conversion of 5 to small amounts of 3 is
thermodynamically viable, despite the observation of the mi-
croscopic reverse reaction with 1,2,4,5-tetrafluorobenzene.
5
1
with 2a exhibits a JFH of 4.2 Hz, consistent with the H NMR
spectral data. Additionally, a 3JFH of 9.3 Hz is observed between
the aromatic hydrogen and the Fmeta resonance associated with
2b. The temperature dependence of the integration of m-fluorine
resonances for 2a and 2b reveals that this C-H bond oxidative
addition is in kinetic equilibrium near room temperature. The
oxidative addition shown in Scheme 2 favors 2a over 2b, due
to the zero-point energy difference between carbon-H/D and
nickel-H/D bonds. At 298 K, the ratio of the integrals of these
peaks is 2.1:1. Cooling to 233 K gradually changes this ratio to
3.4:1. At temperatures lower than 233 K this reaction is slowed
sufficiently that the ratio of 2a to 2b does not change noticeably
within an hour. The 31P {1H} NMR spectrum at 233 K featured
2
a broad 1:1:1 triplet at 23.8 with a JPD of ∼10 Hz for 2b and
a singlet at 23.5 for 2a.
Scheme 2
Scheme 3
The major product in the reaction of 1,2,4,5-tetrafluorobenzene
and 1 depends on reaction conditions, but appears to thermo-
dynamically favor the formation of 4. For example, the addition
of an excess of phenanthrene to the initial reaction mixtures
slows the reaction and yields 4 and 1,2,4-trifluorobenzene as
the major products. The thermodynamic preference of 4 over 3
can be rationalized by the increased Ni-C bond strength as the
number of o-F substituents is increased.4
Scheme 4 depicts a viable mechanism for the formal
hydrodefluorination2,13 that results in the formation of 4 and
1,2,4-trifluorobenzene. The initial C-H bond activation product
2 is formed rapidly and is present in equilibrium with 1
throughout the reaction. The initial C-F bond activation product
3 is formed at a much slower rate and reacts with the equilibrium
amounts of 2 via transmetalation, which exchanges the fluoride
and hydride ligands to produce 4 and a new nickel hydride
complex, 6.14 The exact mechanism for this reaction is unknown
due to the paucity of data regarding the reactivity of bis(phos-
phine)nickel aryl hydrides, but it likely involves a binuclear
intermediate.15 Species 6 was not observed because it can rapidly
reductively eliminate a C-H bond to produce 1,2,4-trifluoroben-
zene. Complex 5 could be formed by a similar C-H bond
activation mechanism starting with 1,2,4-trifluorobenzene, al-
Over the course of 2 weeks these mixtures gradually convert
to C-F bond activation products and the concentration of 2
decreases as 1 is consumed. Despite the presence of a single
fluorine chemical environment in 1,2,4,5-tetrafluorobenzene,
these reactions provide a mixture of three C-F bond activation
products and 1,2,4-trifluorobenzene, as shown in Scheme 1.
Monitoringthereactionby19F{1H}NMRspectroscopy,(PEt3)2NiF-
2,4,5-F3C6H2 (3) is the only C-F activation product observed
at low conversion, typically within the first 8 h, with three
1
Figure 1. Hydridic signal in the 233 K H NMR spectrum with modeled
spectrum shown above (left) and selected peaks in the 273 K 19F and 19F{1H}
NMR spectra for an equilibrium amount of 2a and 2b prepared from a
mixture of 1 and 1,2,4,5-F4C6HD. Chemical shifts are in ppm and 19F shifts
are with respect to CFCl3.
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C O M M U N I C A T I O N S
though it is impossible to rule out other mechanisms,16 such as
the reversible deprotonation of the ortho hydrogen in 3, which
could convert 3 to 5 via a nickel aryne intermediate.17
Hitchcock, P. B.; Procopiou, P. A. Angew. Chem., Int. Ed. 2007, 46, 6339–
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These results provide insight into the steps required to utilize
these C-F bond activations into catalytic cycles; to generate
Ni catalysts for selective C-F bond functionalization in a wide
range of polyfluoroaromatics it will be necessary to alter the
choice of ancillary ligands to render C-F bond oxidative addition
significantly faster than ligand redistribution reactions, thus
avoiding unwanted byproducts that result from C-H bond
activation. Equally importantly, these low activation barrier C-H
bond activations could be exploited to extend the scope of Ni(0)
C-H bond activation and catalytic functionalization18 to include
polyfluoroaromatics19 and other weakly activated substrates,20
even when C-H bond activation products are thermodynamically
disfavored but kinetically accessible. Research toward both these
goals is currently underway.21
(10) A related anthracene adduct is known: Stanger, A.; Boese, R. J. Organomet.
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(14) In the reaction of 1 with isotopically pure 1,2,4,5-C6F4HD described, the
complete scrambling of labels to also provide C6F4H2 and C6F4D2 was also
observed over the course of days, presumably by a related ligand exchange
between 2a and 2b.
(15) It is possible that the Ni(PEt3)2 moiety in 1 plays a role in this reaction as
a Lewis acid capable of abstracting PEt3 from either square planar complex
2 or 3. The resultant electron-poor intermediate could increase the rate of
hydride/fluoride exchange. The Lewis acidic reactivity of a related source
of the Ni(PEt3)2 moiety has been previously reported in the coupling of
nickel arynes: Keen, A. L.; Doster, M.; Johnson, S. A. J. Am. Chem. Soc.
2007, 129, 810–819.
(16) Werkema, E. L.; Andersen, R. A. J. Am. Chem. Soc. 2008, 130, 7153–
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Chem., Int. Ed. 2004, 43, 3845–3847. Liang, L.-C.; Chien, P.-S.; Huang,
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Acknowledgment. Acknowledgement is made to the Petroleum
Research Fund, the Natural Science and Engineering Council
(NSERC) of Canada, and the Shared Hierarchical Academic
Research Network (SHARCNET) for their financial support.
(19) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 8754–8756. Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett.
2006, 8, 5097–5100.
(20) The increased metal-carbon bond strength for aryl groups bearing electron-
withdrawing groups versus unsubstituted phenyl rings provides a thermo-
dynamic advantage for the C-H bond activation of fluorinated aromatics
versus benzene, despite the fact that the C-H bonds are stronger in the
former (for a leading reference see ref 4).
Supporting Information Available: Coordinates and energies from
DFT calculations; full experimental details; CIF files for 1 and 5. This
material is available free of charge via the Internet at http://pubs.acs.org.
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