Mechanism of C-F reductive elimination from palladium(IV) fluorides

Article abstract of DOI:10.1021/ja909371t

The first systematic mechanism study of C-F reductive elimination from a transition metal complex is described. C-F bond formation from three different Pd(IV) fluoride complexes was mechanistically evaluated. The experimental data suggest that reductive elimination occurs from cationic Pd(IV) fluoride complexes via a dissociative mechanism. The ancillary pyridyl-sulfonamide ligand plays a crucial role for C-F reductive elimination, likely due to a K ³ coordination mode, in which an oxygen atom of the sulfonyl group coordinates to Pd. The pyridyl-sulfonamide can support Pd(IV) and has the appropriate geometry and electronic structure to induce reductive elimination.

Full text of DOI:10.1021/ja909371t

Published on Web 03/02/2010
Mechanism of C-F Reductive Elimination from Palladium(IV)
Fluorides
Takeru Furuya,† Diego Benitez,‡ Ekaterina Tkatchouk,‡ Alexandra E. Strom,†
Pingping Tang,† William A. Goddard III,‡ and Tobias Ritter*,†
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138, and Materials and Process Simulation Center, California
Institute of Technology, Pasadena, California 91125
Received November 4, 2009; E-mail: ritter@chemistry.harvard.edu
Abstract: The first systematic mechanism study of C-F reductive elimination from a transition metal complex
is described. C-F bond formation from three different Pd(IV) fluoride complexes was mechanistically
evaluated. The experimental data suggest that reductive elimination occurs from cationic Pd(IV) fluoride
complexes via a dissociative mechanism. The ancillary pyridyl-sulfonamide ligand plays a crucial role for
C-F reductive elimination, likely due to a κ3 coordination mode, in which an oxygen atom of the sulfonyl
group coordinates to Pd. The pyridyl-sulfonamide can support Pd(IV) and has the appropriate geometry
and electronic structure to induce reductive elimination.
Introduction
source of fluorine: either nucleophilic or electrophilic fluorinat-
ing reagents are employed. Nucleophilic fluorination using
Aryl fluorides are valuable compounds as pharmaceuticals,1
agrochemicals,2 and tracers for positron-emission tomography.3
Electrophilic4 and nucleophilic5 fluorination, as well as the
pyrolysis of diazonium tetrafluoroborates,6 are established
methods for the synthesis of fluoroarenes. However, conven-
tional fluorination reactions exhibit a limited substrate scope
with respect to the electronic structure of the arene and the
functional groups tolerated and are therefore typically not
applicable to late-stage introduction of fluorine into complex
functionalized molecules.7
Transition metal-catalyzed carbon-heteroatom bond forma-
tion for C-N8, C-O9, and C-S10 bonds has become increas-
ingly efficient over the past decade, with palladium being one
of the most common transition metals for catalysis. By contrast,
the development of transition metal-mediated C-F bond forma-
tion has been slower.11 Two general approaches have been
employed for Pd-mediated C-F bond formation: (1) Pd(0)/
Pd(II)-mediated nucleophilic fluorination as studied by
Grushin,12 Yandulov,13 and Buchwald,14 and (2) Pd-mediated
electrophilic fluorination as demonstrated by Sanford,15 Yu,16
Vigalok,17 and us.18 The two distinct approaches differ by the
fluoride anion is complicated by the high basicity of fluoride.
Protic functional groups such as alcohols, primary or secondary
amines, and N-H-containing amides that attenuate the nucleo-
philicity of fluoride can be problematic19 due to the strong H-F
hydrogen bonding20 and resulting bifluoride formation.21 Protic
functional groups are generally tolerated by electrophilic
fluorinating reagents, but electrophilic fluorination can be
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† Harvard University.
‡ California Institute of Technology.
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A R T I C L E S
Furuya et al.
problematic with basic functional groups such as amines and
sulfides due to unproductive reactions with the electrophilic
fluorinating reagent. As such, the two approaches are comple-
mentary.
A Pd(IV) trifluoride complex was reported by the Sanford
group in 2009 and afforded aryl fluoride in trace amounts upon
thermolysis. However, upon addition of various oxidants such
as XeF2, (PhSO2)2NF, and N-bromosuccinimide to the Pd(IV)
trifluoride complex, high-yielding C-F bond formation was
observed. The C-F bond formation may proceed by reductive
elimination from Pd(IV) and studies to gain further mechanistic
insight into the oxidant-promoted C-F coupling process are
ongoing in the Sanford lab.22
Currently, only two transition metal complex classess
Buchwald’s phosphine Pd(II) fluoride and our pyridyl-sulfon-
amide Pd(IV) fluorideshave been identified to afford C-F bond
formation via reductive elimination.11a,22 Here we report the
first systematic mechanism investigation of C-F bond formation
via well-defined reductive elimination from a transition metal
complex. C-F bond formation is a challenge in both nucleo-
philic and electrophilic transition metal-catalyzed fluorination
reactions and, hence, mechanistic understanding of C-F reduc-
tive elimination may support the rational development of more
efficient transition metal catalysts suitable for C-F bond
formation.
Mechanisms of C-C and C-heteroatom reductive elimina-
tion have been studied from Pd(II),23 Pd(III),24 and Pd(IV)25
complexes and have contributed to a better understanding and
rational reaction improvement. Mechanistic insight into C-F
bond reductive elimination has been elusive because no well-
defined reaction was available for systematic investigation.
We identified that a variety of functionalized arylboronic acids
can be converted to the corresponding aryl fluorides via
pyridylsulfonamide-stabilized Pd complexes (Scheme 1). Ad-
dition of the electrophilic fluorinating reagent F-TEDA-BF4 to
the arylpalladium complexes in acetone at 50 °C afforded aryl
fluorides, typically in 70 to 90% yield.18a
We hypothesized the intermediacy of Pd(IV) fluoride com-
plexes but could not spectroscopically observe them due to fast
C-F bond formation to afford the aryl fluoride products. To
study the mechanism of C-F bond formation, our strategy
entailed rigidifying the ligand environment on palladium to
retard reductive elimination from a putative Pd(IV) fluoride
intermediate. The strategy was executed by substitution of the
aryl and pyridine ligand of the aryl Pd(II) complex shown in
Scheme 1 with the bidentate benzo[h]quinolyl ligand. The more
rigid benzo[h]quinolyl ligand, when compared to independent
phenyl and pyridine ligands, allowed the synthesis of spectro-
scopically observable Pd(IV) fluoride complexes such as 1 (eq
1).18b The modular structure of the pyridyl-sulfonamide-
Aryl fluoride synthesis by confirmed C-F reductive elimina-
tion from any transition metal complex was not established until
our original report in 2008.18b Previously, independent efforts
by Grushin and Yandulov had focused on C-F reductive
elimination from aryl Pd(II) fluorides.12,13 Yandulov observed
the formation of 10% arylfluoride from a phosphine-stabilized
Pd(II) complex. Although the reaction mechanism has not been
elucidated, the mechanistic investigations by Grushin and
Yandulov significantly contributed to recognizing the challenges
associated with C-F reductive elimination. In 2009, Buchwald
reported a Pd(0)/Pd(II) catalyzed aromatic fluorination reaction
of functionalized aryl triflates and bromides in 57-85% yield.13
Buchwald also demonstrated C-F reductive elimination from
a discrete phosphine Pd(II) fluoride complex in up to 55% yield.
The development of bulky, monodentate phosphine ligands that
facilitate C-X reductive elimination from Pd(II) successfully
led to the first highly sought-after Pd(0)-catalyzed fluorination
reaction. Pd(II)-catalyzed electrophilic fluorination reactions are
less well understood. Although high-valent Pd(III) or Pd(IV)
fluoride intermediates seem reasonable, their relevance to
catalysis has not yet been mechanistically substantiated. Aside
from our initial report in 2008, mechanistic investigations of
C-F bond formation by confirmed reductive elimination from
high-valent Pd complexes have not yet been disclosed.
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Mechanism of C-F Reductive Elimination
A R T I C L E S
Scheme 1. Fluorination of Functionalized Arylboronic Acids via
Arylpalladium(II) Complexes by the Electrophilic Fluorination
Reagent F-TEDA-BF4
Figure 2. ORTEP diagram of the Pd(IV) difluoride 3 (left) and charac-
teristic 13C-19F coupling constants (right). Selected bond lengths [Å] and
angles [°]: Pd-F(1) 2.040(3), Pd-F(2) 1.955(3), Pd-C(35) 2.008(5),
Pd-N(13) 2.019(4), Pd-N(1) 2.027(5), Pd-N(26) 2.012(5), F(1)-Pd-F(2)
88.27(13)°, F(2)-Pd-N(13) 173.48(15)°.
and the neutral Pd difluoride complex 3 (Figure 1, for the
synthesis of 1-3, see Supporting Information). Complexes 1-3
feature the benzo[h]quinolyl ligand that was introduced to obtain
higher stability of the Pd(IV) fluoride complexes for mechanistic
analysis. For a meaningful discussion of the mechanism of C-F
reductive elimination, an unambiguous assignment of the
solution ground state structures of the Pd(IV) fluoride complexes
was essential. The complexes 1-3 have C1 symmetry, and six
coordination sites are occupied by six different ligands with
the exception of 3, which features two fluoride ligands. The
low symmetry of the complexes provides the opportunity to
investigate the effect of each ligand independently and gain
insight into the transition state for reductive elimination.
Solid State Structure of 3. Attempts to obtain X-ray quality
crystals for cationic complexes 1 and 2 were unsuccessful.
Complexes 1 and 2 could be observed in acetonitrile but
decomposed upon precipitation by addition of excess Et2O at
-20 °C. The difluoro Pd(IV) complex 3 was more stable than
cationic complexes 1 and 2, and its X-ray crystal structure was
obtained.18b UnlikemanyreportedPd(II)fluoridecomplexes,12,13,26
complex 3 is stable to moisture; it was synthesized from 1 and
tetramethylammonium fluoride tetrahydrate. Isolation and pu-
rification of 3 were carried out under ambient atmosphere.
Difluoro Pd(IV) complex 3 showed resistance to decomposition
by water; less than 10% of decomposition was observed when
a DMSO solution of 3 was kept at 23 °C for 1 day in the
presence of 10 equiv of water. The crystal structure of 3 is
shown in Figure 2. The two Pd(IV)-F bond lengths are 1.955
and 2.040 Å, respectively. The Pd-F(1) bond trans to the carbon
ligand is longer by 0.085 Å, which is consistent with the strong
trans influence27 of the carbon ligand. The Pd-F bond lengths
in 3 are 0.13 and 0.05 Å shorter than the average of Pd(II)-F
bond length of 2.09 Å, respectively,28 and similar in length to
Pd(IV)-F bond lengths in a Pd(IV) trifluoride reported by
Sanford in 2009 (1.923 and 1.931 Å).22,29
stabilized Pd(IV) fluoride 1 and its well-defined, high-yielding
reductive elimination to form a C-F bond permitted us to
address key questions that influence C-F bond formation. Is
the pyridyl-sulfonamide ligand special? What is the nature of
the transition state for C-F reductive elimination? What factors
accelerate C-F reductive elimination? Herein, we provide
experimental and computational evidence that supports reductive
elimination via a concerted pathway from a cationic, pentaco-
ordinate Pd(IV) fluoride. The pyridyl-sulfonamide ligand can
stabilize the high-valent, octahedral Pd(IV) fluoride by trico-
ordinate facial coordination and support the electronic require-
ments for reductive elimination.
Results
Structure Assignment of Pd(IV) Fluorides. Three Pd(IV)
fluoride complexes were investigated: the pyridyl-sulfonamide-
stabilized cationic Pd fluoride 1, complex 2, in which a pyridine
ligand occupies the coordination site trans to the carbon ligand,
Solution State Structure of 3. Solution state structures of the
three Pd(IV) fluoride complexes 1-3 were assigned by NMR
1
spectroscopy. The resonances in the H and 13C NMR spectra
1
1
of 1-3 were well resolved and, after H-1H COSY, H-13C
HSQC, H-13C HMBC, and H-1H NOESY analysis, could
1
1
(26) Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.;
Neumann, B.; Rothfeld, S.; Stammler, H.-G. Organometallics 2004,
23, 6140–6149.
(27) Landis, C. R.; Firman, T. K.; Root, D. M.; Cleveland, T. J. Am. Chem.
Soc. 1998, 120, 1842–1854.
(28) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2009, 131, 918–
919.
Figure 1. Pd(IV) fluoride complexes 1-3 analyzed in this study.
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A R T I C L E S
Furuya et al.
Figure 4. Characteristic NOE signals for configuration determination.
observed between F1 and HA, which is located in the 6-position
of the ortho-nitrobenzenesulfonamide moiety. Observation of
the F1-HA coupling constant confirmed that the conformation
of the ortho-nitrobenzenesulfonamide is similar in solution to
the conformation observed in the solid state (Figure 2) where
HA and F1 are 2.212 Å apart. Based on the combined structural
information, we assigned the solution structure of 3 to be similar
to the structure of 3 in the solid state. The assignment of the
solution structure of 3 was instructive for the elucidation of the
solution structures of 1 and 2 that lack crystallographic
characterization.
Figure 3. HOM2DJ spectrum and 1H-19F couplings. The 1H NMR is
shown in the X axis and the 1H-1H coupling constants are shown in the Y
axis. The doublet of doublets resulting from 1H-1H scalar coupling constants
are resolved in the Y axis. Two coupling constants (2 Hz, 8 Hz) out of
three shown in the Figure for the doublet of doublets of doublets are resolved
in the Y axis. The one remaining coupling constant (18 Hz) is resolved
1
only in the X axis and, hence, corresponds to a H-19F coupling.
be assigned (see Supporting Information). The observation of
1H-19F and 13C-19F coupling constants provided information
for the assignment of the configuration and solution conforma-
tion of the Pd(IV) fluoride complexes. As shown in Figure 2,
the vicinal trans C-Pd-F coupling constant (2JCF ) 63 Hz),30
and the C-F coupling constant (3JCF ) 2.1 Hz)31 indicate that
the benzo[h]quinolyl and the fluorine (F1) ligand are located in
the same plane. Coupling constants of the pyridyl 6-carbon of
the pyridyl-sulfonamide ligand were observed to both fluoride
ligands (3JCF ) 13.5 and 6.3 Hz), consistent with structure 3.
1H-19F coupling constants can provide further structural
information. 1H-1H coupling constants can often be similar in
Solution State Structure of 1 and 2. The solution state
structures of the monofluoro Pd(IV) complex 1 and pyridine
complex 2 were assigned by NMR analysis in comparison to
the analysis performed on 3. All 1H and 13C NMR signals of 1
1
1
and 2 were assigned based on H-1H COSY, H-13C HSQC,
1H-13C HMBC, and H-1H NOESY spectra. The analysis of
1
the 2D NMR spectra of the pyridine complex 2 was complicated
compared to the analysis of 1 due to signal overlap and required
an additional 1H-1H TOCSY spectrum for unambiguous
assignment. In a TOCSY experiment, each 1H spin system can
be identified separately. A 1H spin system includes all 1H
resonances that are mutually connected by an uninterrupted
32
1
size as H-19F coupling constants. Therefore, a HOM2DJ
spectrum33 was obtained to differentiate 1H-19F coupling
constants from H-1H coupling constants as shown in Figure
1
3. In a one-dimensional 1H NMR spectrum, chemical shift, and
coupling constants, 1H-1H and 1H-19F, are observed along the
same axis. A HOM2DJ experiment separates 1H-1H from
1H-19F coupling constants along two different axes. As can be
seen in Figure 3, 1H-1H coupling constants are resolved in the
ensemble of scalar couplings.34 Hence, the pyridine H spin
1
1
system in 2 could be identified because none of the H nuclei
1
of the pyridyl ligand has a scalar coupling to any H nucleus
1
outside the pyridine H spin system in 2. Assignments of the
configuration of complexes 1 and 2 were supported by two key
observations: (1) an NOE signal between HB and HC and (2)
the lack of a characteristic trans C-Pd-F coupling.
Y axis, whereas H-19F coupling constants are resolved in the
1
X axis. Two long-range 1H-19F couplings were identified from
the HOM2DJ spectrum. A 1H-19F through-space coupling was
The observed NOE signal between HB and HC is consistent
with the configuration shown in Figure 4 (left). A similar NOE
signal was observed for the difluoride complex 3, in which HD
and HE are 3.393 Å apart in the solid state (Figure 4, right).
The observation of the HB-HC NOE signal in 1 and 2 leaves
two possibilities for the configuration of complexes 1 and 2:
the fluoride and carbon ligands oriented cis or trans to one
another. Because no characteristic trans C-Pd-F coupling
constant was observed in the 13C NMR spectra of 1 and 2,
respectively, the fluoride ligand was assigned to be oriented cis
to the carbon ligand as shown for 2 in Figure 4. For the
hexacoordinate cationic complex 2, only one coordination site
remains for pyridine coordination, trans to the carbon ligand.
Complex 1 was prepared in MeCN and we originally assigned
structure 1b (Figure 5) to the cationic Pd(IV) fluoride, in which
an MeCN ligand occupies the sixth coordination site, analogous
to the pyridine ligand in 2. However, no evidence for MeCN
coordination could be obtained, even upon cooling to -30 °C.
While the lack of evidence for MeCN coordination in MeCN
(29) The third Pd-F bond length in the Pd(IV) trifluoride reported in ref
22 is longer (2.112 Å), presumably due to bifluoride (Pd-F-HF)
formation. For bifluoride formation, see: (a) Whittlesey, M. K.; Perutz,
R. N.; Moore, M. H. J. Chem. Soc., Chem. Commun. 1996, 787–788.
(b) Murphy, V. J.; Hascall, T.; Chen, J. Y.; Parkin, G. J. Am. Chem.
Soc. 1996, 118, 7428–7429. (c) Murphy, V. J.; Rabinovich, D.; Hascall,
T.; Klooster, W. T.; Koetzle, T. F.; Parkin, G. J. Am. Chem. Soc.
1998, 120, 4372–4387. (d) Whittlesey, M. K.; Perutz, R. N.; Greener,
B.; Moore, M. H. J. Chem. Soc., Chem. Commun. 1997, 187–188. (e)
Braun, T.; Foxon, S. P.; Perutz, R. N.; Walton, P. H. Angew. Chem.,
Int. Ed. 1999, 38, 3326–3329. (f) Jasim, N. A.; Perutz, R. N. J. Am.
Chem. Soc. 2000, 122, 8685–8693. (g) Roe, D. C.; Marshall, W. J.;
Davidson, F.; Soper, P. D.; Grushin, V. V. Organometallics 2000,
19, 4575–4582.
(30) For examples, see: (a) Marshall, W. J.; Thorn, D. L.; Grushin, V. V.
Organometallics 1998, 17, 5427–5430. (b) Flemming, J. P.; Pilon,
M. C.; Borbulevitch, O. Ya.; Antipin, M. Y.; Grushin, V. V. Inorg.
Chim. Acta 1998, 280, 87–98.
(31) Newmark, R. A.; Hill, J. R. Org. Magn. Reson. 1977, 9, 589–592.
(32) San Fabian, J.; Guilleme, J.; D´ıez, E. J. Magn. Reson. 1998, 133, 255–
265.
(33) (a) Aue, W. P.; Karhan, J.; Ernst, R. R. J. Chem. Phys. 1976, 64,
4226–4227. (b) Nagayama, K.; Bachmann, P.; Wuthrich, K.; Ernst,
R. R. J. Magn. Reson. 1978, 31, 133–148. (c) Nagayama, K. J. Chem.
Phys. 1979, 71, 4404–4415.
(34) Bruch, M. NMR spectroscopy techniques; M. Dekker: New York, 1996.
9
3796 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Mechanism of C-F Reductive Elimination
A R T I C L E S
Figure 5. Considered structures for the cationic Pd(IV) fluoride complex.
The data are consistent with structure 1.
cannot rule out structure 1b, significant evidence in favor of
structure 1 was obtained, in which the pro-S oxygen atom of
the sulfonyl group occupies the sixth coordination site trans to
the carbon ligand. While oxygen coordination in sulfonamide
complexes has been established crystallographically,35 the
tridentate κ3 coordination geometry of the pyridyl-sulfonamide
is not well-known, possibly due to the scarcity of pyridyl-
sulfonamide ligands in transition metal chemistry.
The observation of an NOE signal between hydrogen atoms
H23 and H30 is consistent with κ3 coordination of the pyridyl-
sulfonamide ligand and also rules out the diastereomer 1a as a
potential structure for the Pd(IV) fluoride. An analogous NOE
signal in the pyridine complex 2 was not observed. To further
bolster our assignment, we compared the 13C resonances of all
carbon atoms in 1 with the corresponding carbon atom
resonances in 2 and identified that the largest difference in shift
(6.9 ppm) was observed for the arenesulfonyl ipso carbon C25,
while the average difference in shift was only 1.1 ppm (see
Supporting Information for detail).
1
Figure 6. Comparison of the temperature-dependent H NMR spectra of
1 and 2.
More evidence for the structure of 1 was obtained by dynamic
NMR experiments. The pyridine complex 2 can be prepared
by addition of pyridine to 1 in MeCN. The equillibrium
constants Keq between 1 and 2 were calculated from data
obtained by comparing the integrations of NMR resonances in
the 1H NMR spectra acquired at temperatures between -35 and
25 °C. The free enthalpy, free entropy, and Gibbs free energy
of the reaction 1 f 2 (eq 2) were determined as follows: ∆H°
) -4.46 ( 0.28 kcal·mol-1, ∆S° ) -13.1 ( 1.1 eu, and
∆G°298 ) -0.57 ( 0.03 kcal·mol-1. The measured Gibbs free
energy of ∆G°298 ) -0.57 further supports the κ3 coordination
structural assignment of 1 over the MeCN coordinated structure
assignment 1b because a larger ∆G°298 would be expected if
an MeCN ligand from a hypothetical complex 1b was displaced
by a pyridine ligand to afford 2.36 Pyridine coordination is
significantly stronger than acetonitrile coordination and a larger
Keq and, hence, a more negative ∆G°298 would be expected.
For example, the Pd(II) complex 5 (vide infra) features a
pyridine ligand that is not replaced to any observable extent by
MeCN, even in MeCN as solvent.
1 were sharp from -30 to 25 °C; no dynamic behavior that
could be attributed to MeCN exchange was observed on the
1
NMR time scale. On the other hand, the H NMR resonances
for 2 were broad at 25 °C and became sharper when the
temperature was decreased to -5 °C, consistent with slow
pyridine exchange at -5 °C. To substantiate that the observed
dynamic behavior can be attributed to pyridine dissociation from
2, we determined the rate constant at equilibrium as well as the
activation parameters for the reaction from 1 to 2 shown in eq
1
2. The temperature-dependent rates were calculated from a H
NMR line-shape analysis experiment37 executed between -24
and 11 °C. The activation parameters were: ∆H‡ ) 14.0 ( 1.3
kcal·mol-1, ∆S‡ ) -3.99 ( 4.79 eu, ∆G‡ ) 15.1 ( 0.2
298
kcal·mol-1. As discussed later, the rate of exchange between 1
and 2 is about 106 times faster than the rate of C-F reductive
elimination. No pentacoordinate cationic complex was identified
by NMR spectroscopy at any temperature between -35 and 25
°C. Line-broadening around -35 °C for both 1 and 2 is
consistent with slowed rotation around single bonds such as
the sulfonamide C-S bond. Acquisition of NMR spectra at
lower temperatures was complicated by the melting point of
MeCN (-45 °C).
(35) For examples, see: (a) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.;
Walsh, P. J. J. Am. Chem. Soc. 1998, 120, 6423–6424. (b) Jamieson,
J. Y.; Schrock, R. R.; Davis, W. M.; Bonitatebus, P. J.; Zhu, S. S.;
Hoveyda, A. H. Organometallics 2000, 19, 925–930. (c) Wan, Z.-K.;
Choi, H.-w.; Kang, F.-A.; Nakajima, K.; Demeke, D.; Kishi, Y. Org.
Lett. 2002, 4, 4431–4434. (d) Lorber, C.; Choukroun, R.; Vendier, L.
Inorg. Chem. 2007, 46, 3192–3202.
1
(36) For examples, see: (a) Kickham, J. E.; Loeb, S. J. Inorg. Chem. 1994,
33, 4351–4359. (b) Bessire, A. J.; Whittlesey, B. R.; Holwerda, R. A.
Inorg. Chem. 1995, 34, 622–627.
The comparison of temperature-dependent H NMR spectra
of 1 and 2 provided additional circumstantial evidence for
structure 1. As shown in Figure 6, the 1H NMR resonances for
(37) Sandstrom, J. Dynamic NMR spectroscopy, London: New York, 1982.
9
J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 3797

A R T I C L E S
Furuya et al.
Figure 7. Energy minimized structure of 1. The computed energy difference
(∆H298) between 1 and 1b is 2.2 kcal ·mol-1 favoring 1.
Quantum mechanical calculations using the M06 functional38
of density functional theory (DFT) (see the Supporting Informa-
tion for computational details) also predicted structure 1 in favor
of structure 1b. Acetonitrile coordination to 1 to form 1b was
predicted to be endothermic by 2.2 kcal ·mol-1. In addition, the
computed Pd-N (MeCN) distance of 2.40 Å, compared to 2.27
Å for the Pd-N (pyridine) distance in 2 supports the lability of
the MeCN ligand in 1b. Figure 7 shows the energy minimized
structure of 1.
Figure 8. Methods employed in this mechanistic study.
Reductive Elimination from the Monofluoro Pd(IV)
Complexes 1 and 2. With established solution ground state
structures for the Pd(IV) fluoride complexes 1-3, we evaluated
the kinetic profile for C-F bond formation by reductive
elimination. Complexes 1 and 2 underwent C-F reductive
elimination following a first order rate law and afforded 10-
fluoro-benzo[h]quinoline (4) coordinated to Pd as the only
observable organic product (eq 3). The Pd complex after
reductive elimination is likely the cationic Pd(II) complex A.
While isolation and purification of A was not achieved,
1
presumably due to the weak coordination of 4 to Pd, H and
19F NMR spectroscopy is consistent with a structure in which
4 is bound to Pd. The 1H and 19F NMR resonances that
correspond to the 10-fluoro-benzo[h]quinoline ligand in A
differed from the resonances of isolated and purified 10-fluoro-
benzo[h]quinoline (4). In addition, computation predicted
structure A as the product of reductive elimination from 1 with
a Pd-F bond length of 2.22 Å. Addition of 4.0 equiv of pyridine
after complete consumption of the starting material 1 provided
Pd(II) complex 5, whose identity was confirmed by independent
synthesis from the corresponding acetato Pd(II) complex,
AgBF4, and pyridine.
Figure 9. Rate dependence on pyridine concentration.
1
23-61 °C and 28-65 °C by H NMR spectroscopy, respec-
tively. Reductive elimination from 1 proceeded with ∆H‡ )
26.5 ( 0.4 kcal ·mol-1, ∆S‡ ) 12.4 ( 1.3 eu, and ∆G‡
)
298
22.8 ( 0.02 kcal·mol-1, while reductive elimination from 2
proceeded with ∆H‡ ) 32.8 ( 2.5 kcal ·mol-1, ∆S‡ ) 30.7 (
7.8 eu, and ∆G‡ ) 23.7 ( 0.2 kcal·mol-1. The yield of 4
298
was only slightly affected by the reaction temperature; 4 was
obtained in 92-95% and in 79-85% from complexes 1 and 2,
respectively.
Rate Dependence for Reductive Elimination from
Complex 2 with Excess Pyridine. Complex 2 was heated at
50 °C in the presence of varying concentrations of pyridine and
the rate of C-F reductive elimination was measured by 1H NMR
spectroscopy as a function of pyridine concentration. The inverse
rate as a function of pyridine concentration is shown in Figure
9. A positive, linear dependence of the reciprocal of the rate of
C-F reductive elimination from 2 (1/k) vs pyridine equivalent
was observed as well as a nonzero intercept. The positive linear
dependence shows that pyridine slows the rate of reductive
elimination. The yield of fluorination was 90% for 2 without
additional pyridine and decreased to 74% with 1.0 equivalent
of added pyridine. The yield further decreased with addition of
more than one equivalent of pyridine. For example, addition of
two equivalents of pyridine afforded 4 in only 43% yield.
In the following section, we will systematically evaluate the
rate of reductive elimination from derivatives of 1 as a function
of temperature, polarity of the reaction medium, and electronic
structure of the ligands to collect data relevant to elucidating
the mechanism of reductive elimination (Figure 8).
Determination of Activation Parameters. We obtained activa-
tion parameters of C-F reductive elimination from both
complex 1 and pyridine complex 2 by measuring the rate of
C-F reductive elimination in the temperature range of
(38) (a) Zhao, Y.; Truhlar, D. G. Theo. Chem. Acc. 2008, 120, 215–241.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157–167.
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Mechanism of C-F Reductive Elimination
A R T I C L E S
Figure 10. Hammett study by independent modification of the sulfonamide,
benzo[h]quinolyl, and pyridine ligand substitution.
Therefore, the data with more than one equivalent of added
pyridine are not included in the analysis shown in Figure 9.
The rate of reductive elimination from 1 was independent of
MeCN concentration at high MeCN concentrations. While no
rate change was observed, the experiment could only be
executed in the presence of a large excess of MeCN (460-2298
equiv compared to complex 1) because 1 was prepared in MeCN
and not stable in the absence of MeCN. Therefore, saturation
kinetics cannot be excluded.
Rate Dependence for Reductive Elimination from Com-
plex 1 on the Polarity of the Reaction Medium. The rate of a
reaction can depend on the polarity of the reaction medium.39
Polar transition states are stabilized relative to the corresponding
ground states by polar solvents, and measurement of the reaction
rate as a function of solvent can give important information
about the mechanism. The monofluoro Pd(IV) complexes 1 and
2, however, were always prepared in acetonitrile because the
use of other solvents did not result in clean formation of the
Pd(IV) complexes. Thus, the polarity of the reaction medium
was modified by addition of tetra(n-butyl)ammonium tetrafl-
luoroborate (n-Bu4NBF4).40 Complex 1 was thermally decom-
posed at 53 °C in the presence of various amounts of
n-Bu4NBF4. The rate of reductive elimination reaction was
independent of the concentration of n-Bu4NBF4 from 0-
2.0 M. The yield of fluorination was not significantly influenced
by the addition of n-Bu4NBF4 and remained between 90 and
96%.
Figure 11. Hammett plot for sulfonamide substitution.
Effect of Sulfonamide Substitution on the Rate of C-F
Reductive Elimination from 1. Eight monofluoro Pd(IV) com-
plexes 6a-h with different sulfonamide substituents (R1 ) NO2,
CN, Cl, F, Ph, H, Me, and t-Bu) were synthesized. Complexes
6a-h were subsequently decomposed thermally at 49 °C in
MeCN and the rate of C-F reductive elimination was measured
by 1H NMR spectroscopy. The yield of fluorination was higher
for complexes featuring electron-withdrawing sulfonamides
(96%, when R ) NO2) than for complexes with electron-
donating sulfonamides (65%, when R ) t-Bu), but in all cases
both product formation and starting material consumption
followed first order rate laws. As shown in the Hammett plot
in Figure 11, a F value of -0.45 was obtained, which
demonstrates that electron-donating substituents at the para
position of the sulfonamide have an accelerating effect on the
rate of C-F reductive elimination.
Rate Dependence on Electronic Perturbation of Each
Ancillary Ligand (Hammett Plots41). A Hammett plot is helpful
for obtaining information on the magnitude and sign of charge
buildup in the transition state.41 A Hammett study of C-F
reductive elimination from 1 is particularly informative due to
the low symmetry of the complex and the resulting opportunity
to sequentially modify several ligands independently. We studied
the influence of three different ligand substitutions on the rate
of C-F reductive elimination from a total of 21 analogs of the
monofluoro Pd(IV) complex 1: 1) sulfonamide substitution R1,
2) pyridine (pyridyl-sulfonamide) substitution R2, and 3) ben-
zo[h]quinolyl substitution R3 (Figure 10). The synthesis and
characterization of the functionalized monofluoro Pd(IV) com-
plexes is described in the Supporting Information.
Effect of Pyridine (Pyridyl-Sulfonamide) Substitution on
the Rate of C-F Reductive Elimination from 1. The monofluoro
Pd(IV) complexes 7a-f were prepared from commercially
available 4-substituted 2-halopyridines (R2 ) CF3, CO2Me, Br,
H, Me, OMe). Complexes 7a-f were thermally decomposed at
51 °C in MeCN and the rate of C-F reductive elimination was
1
measured by H NMR spectroscopy. The yield of fluorination
did not correlate with substitution of the pyridine ligand of the
pyridyl-sulfonamide and was uniform between 92 and 96%. The
Hammett plot shown in Figure 12 afforded a F2 value of -0.52,
which illustrates that electron-donating groups at the para
position of the pyridine of the pyridyl-sulfonamide ligand
accelerate the rate of C-F reductive elimination. Our results
show that the sulfonamide aryl group substitution (R1) has a
stronger influence on the rate of C-F reductive elimination than
the pyridine substituent (R2). Similar F values for the two
Hammett plots for sulfonamide substitution (R1, F1) and pyridine
substitution (R2, F2) are observed but the aromatic bearing the
R1 substituent is separated from Pd by two additional bonds
compared to the aromatic bearing the R2 substituent.41b
(39) Christian, R. SolVents and SolVent Effects in Organic Chemistry, 3rd
ed.; Wiley-VCH: Weinheim, Germany, 2002.
(40) For example of salt effect, see: (a) Kinart, W. J.; Kinart, C. M.; Tylak,
I. J. Organomet. Chem. 2000, 608, 49–53.
(41) (a) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96–103. (b) Jaffe,
H. H. Chem. ReV. 1953, 53, 191–261.
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A R T I C L E S
Furuya et al.
Figure 12. Hammett plot for pyridine (pyridyl-sulfonamide) substitution.
Figure 13. Hammett plot for benzo[h]quinoline substitution for complexes
8a-g.
Effect of Benzo[h]quinoline Substitution on the Rate of
C-F Reductive Elimination from 1. A series of 7-substituted
benzo[h]quinolines was synthesized from 7-nitrobenzo[h]quino-
line.42 After cyclopalladation, pyridyl-sulfonamide ligand com-
plexation, and oxidation, the monofluoro Pd(IV) complexes 8a-g
(R3 ) NO2, CN, CHO, Cl, H, Me, OMe) were obtained.
Complexes 8a-g were subsequently thermally decomposed at
50 °C and the rate of C-F reductive elimination was monitored
by 1H NMR spectroscopy. The yield of the fluorination products
9a-g varied (70-94%) but did not correlate with the σ values
of the substituents. The Hammett plot shown in Figure 13 shows
a F value of +1.41, which shows that, unlike for the sulfonamide
and pyridine substituents, electron-withdrawing substituents on
the benzo[h]quinolyl substituent accelerate C-F reductive
elimination.
Effect of Benzo[h]quinoline Substitution on the Rate of
C-F Reductive Elimination from 2. The Hammett plot for
reductive elimination from 1 with respect to benzo[h]quinolyl
substitution is linear as shown in Figure 13. In contrast, a
nonlinear Hammett plot was observed for the identical experi-
ment with the pyridine complex 2. The pyridine complexes
10a-g were thermally decomposed at 50 °C in MeCN and the
rate of C-F reductive elimination was monitored by 1H NMR
spectroscopy. The yield of fluorination products 9a-g varied
(69-85%) but the kinetic data followed first order rate laws.
As shown in Figure 14, the Hammett plot shows two segments;
one for electron-withdrawing substituents (NO2, CN, CHO, Cl)
and one for electron-donating to -neutral substituents (OMe,
Me, H). The two F values for the two segments are -1.78 and
+4.47, respectively. In contrast to the rate of reductive elimina-
tion from 1, both electron-withdrawing and electron-donating
substituents slow the rate of reductive elimination from the
pyridine complexes 10.
Figure 14. Hammett plots of benzo[h]quinoline substitution for pyridine
complexes 10a-g.
Rate Dependence of Reductive Elimination from Deriva-
tives of Complex 2 with Excess Pyridine. The rate of reductive
elimination from complex 2 as a function of pyridine concentra-
tion is shown in Figure 9. The rate of reductive elimination as
a function of pyridine concentration was also determined for
the two derivatives of complex 2, in which the benzo[h]quinolyl
substituent in 2 was substituted with a 7-NO2 (10a) and a 7-OMe
(42) Barltrop, J. A.; MacPhee, K. E. J. Chem. Soc. 1952, 638–642.
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3800 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Mechanism of C-F Reductive Elimination
A R T I C L E S
Scheme 2. Pd(II) Product 11 after Reductive Eliminationa
a ORTEP representation of Pd(II) fluoride complex 11 with ellipsoids
drawn at 50% probability (hydrogen atoms omitted for clarity). Pd-F:
1.981 Å.
Figure 15. Rate dependence on pyridine concentration for the three
7-substituted benzo[h]quinolyl Pd(IV) pyridine complexes 2, 10a, and 10g.
(10g) substituent, respectively (Figure 15). A positive, linear
dependence of the reciprocal of the rate of C-F reductive
elimination (1/k) vs pyridine concentration was observed for
all three complexes, as well as a nonzero intercept. The positive
linear dependence shows that pyridine slows the rate of reductive
elimination for all investigated complexes.
Table 1. Dependence of Fluorination Yield on Reaction Conditions
entry
solvent
temperature [°C]
yield [%] 4:13a
1
2
3
50
75
100
<1:50
<1:57
<1:72
pyridine
Reductive Elimination from Difluoro Pd(IV) Complex 3.
Complex 3 afforded C-F bond formation product 4 in 97%
yield upon heating in DMSO at 150 °C for 10 min. Pd(IV)
complex 3 could also be pyrolyzed as a solid, without solvent,
and afforded product 4 at 100 °C in 4 h in 98% yield. After
addition of 1.0 equiv of pyridine after complete consumption
of 3, the Pd(II) fluoride complex 11 was isolated in 60% yield
4
5
6
7
50
75
100
150
38:60
48:50
66:32
97:1
DMSO
8
9
10
50
75
100
54:44
64:33
70:27
chloroform
1
from the reaction mixture and characterized by H, 13C, and
19F NMR spectroscopy and X-ray crystallography. Complex 11
was also independently synthesized from the corresponding iodo
Pd(II) complex 12 (Scheme 2).
11
12
13
75
100
150
95:<1
97:<1
98:<1
neat
Temperature and Solvent Dependency of C-F Reductive
Elimination from 3. When the difluoro Pd(IV) complex 3 was
thermally decomposed in DMSO at 50 °C, reductive elimination
to 4 was observed in only 38% yield. The major product was
the Pd(II) aryl complex 13 that is formally derived from
reduction of 3 by F2 elimination (eq 4). The fate of the fluorine
could not be determined; no 19F NMR resonances other than
those corresponding to 4 and 11 were observed. From a synthetic
standpoint, the formation of 13 is not desirable because the yield
of 4 is reduced by formation of 13. The ratio of 4:13 was
dependent on the solvent and the temperature (Table 1). Higher
temperatures favored the formation of 4 over the formation of
13. No correlation between the ratio of 4: 13 and solvent polarity
was observed. When 3 was heated as a solid in the absence of
solvent, 4 was formed exclusively, independent of temperature;
a
1
Yield determined by H and 19F NMR using an internal standard.
temperature dependent. Therefore, the Pd(IV) difluoride 3 was
decomposed at 100 °C without the use of solvent. The reaction
was stopped after different reaction times by cooling the reaction
mixture to 23 °C. The reaction mixtures were subsequently
dissolved in CDCl3 and 30 equivalents of pyridine-d5 with
respect to 3 were added to form 4 and 11. Product formation
and starting material disappearance were monitored by 19F NMR
spectroscopy. The rate of C-F reductive elimination from 3
was slower than the rates of reductive elimination from the
cationic complexes 1 and 2, respectively. The kinetic profile
for the reaction from 3 to 4 is shown in Figure 16 (shown with
squares). The rate of product formation was fitted to a logistic
curve of the general form y ) A/(1 + B exp(-Cx)) with an R2
value of over 0.99. Kinetic profiles of reactions that are
accelerated by autocatalysis follow sigmoid curves such as the
one shown in Figure 16.43 When 1.0 equiv of 4 (mp 50 °C)
were added before heating solid 3, significant rate acceleration
1
no 13 was detected by H NMR.
Kinetic Profile of C-F Reductive Elimination from 3. Rate
measurements of reductive elimination from 3 to form 4 in
solution were complicated by the fact that the yield of 4 was
9
J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 3801

A R T I C L E S
Furuya et al.
Table 2. Enthalpy of Activation for Reductive Elimination from 1
and 2 Determined Experimentally (exp) and Predicted
Computationally (pred)
∆H‡ [kcal·mol-1
]
compound
exp.
pred.
1
2
26.5 ( 0.4
32.8 ( 2.5
24.3
33.3
tion from 1 was underestimated computationally by 7.7
kcal·mol-1 (∆G‡298(exp) ) 22.8 ( 0.02 kcal·mol-1, ∆G‡
298(pred)
) 15.1 kcal ·mol-1) as a result of a deviation in the calculated
entropy of activation (∆S‡(exp) ) 12.4 ( 1.3 eu, ∆S‡(pred) ) 30.9
eu).45 This calculated entropy of activation was determined in
the absence of MeCN. The computationally determined entropy
of activation for the MeCN complex 1b was estimated at 1.7
eu. The calculated entropies of activation for 1 and 1b suggest
the involvement of a solvent molecule in the transition state of
reductive elimination from 1 in MeCN solution, in which MeCN
competes with O-coordination of the sulfonamide. The calcu-
lated activation parameters for reductive elimination from 2
(∆H‡ ) 33.3 kcal·mol-1, ∆S‡ ) 26.5 eu, and ∆G‡ ) 25.4
298
kcal·mol-1) are in agreement with the experimentally deter-
mined parameters (∆H‡ ) 32.8 ( 2.5 kcal ·mol-1, ∆S‡ ) 30.7
Figure 16. Kinetic data of C-F reductive elimination from 3.
( 7.8 eu, and ∆G‡ ) 23.7 ( 0.2 kcal ·mol-1).
298
was observed (Figure 16, shown with triangles). However, the
sigmoidal curve shown in Figure 16 is likely not due to
molecular autocatalysis of products 4 or 11 because rate
acceleration was also observed when naphthalene (mp 77 °C)
was added prior to heating to 100 °C. For more detail, see
Discussion Section and the Supporting Information.
Discussion
Structure of Pd(IV) Fluoride Complexes 1-3. Originally, we
proposed the structure 1b for the cationic Pd(IV) fluoride
complex, in which an MeCN ligand is coordinated to Pd. Based
1
on temperature-dependent line shape analysis of the H NMR
Computational Studies. Density functional theory calculations
were performed using the M06 functional,38 which has been
shown to be appropriate for the description of transition metal
complexes.44 The calculation of the structure of 3 was employed
to determine the level of theory necessary to accurately describe
palladium in the +IV oxidation state and the Pd-F bond
because a crystal structure of 3 was available for comparison
(for a comparison of relevant metrical parameters, see the
Supporting Information). Based on the structural method valida-
tion, we determined that geometry optimization with a triple-ꢀ
basis set was required for Pd and F. Energies computed at the
M06/LACV3P++**(2f) level of theory predicted the tridentate
coordination of the pyridyl-sulfonamide with N,O-κ3 coordina-
tion of the sulfonamide in 1. Binding of MeCN to 1 to afford
1b was calculated to be endothermic by 2.2 kcal ·mol-1. The
predicted result is supported experimentally as described in the
first section of this manuscript.
The calculated values for the enthalpies of activation for
reductive elimination from 1 and 2 are in good agreement with
the experimentally determined values (Table 2). The trends of
the rate changes of reductive elimination as a function of ligand
substitution (Hammett plots Figures 11-13) are correctly
predicted by computation (see the Supporting Information for
detail). The free energy of activation for the reductive elimina-
spectra of 1 and 2, the small equilibrium constant of Keq ) 2.61
for the equilibrium between 1 and 2 with added pyridine, the
13C resonance shift of the sulfonamide ipso carbon atom C,25
and computational support (Figures 5-7), we revised our
assignment to structure 1, in which the pyridyl-sulfonamide
ligand is tricoordinate facially with κ3-coordination to Pd of the
pro-S oxygen atom and the nitrogen atom of the sulfonyl group.
Pyridyl-sulfonamide ligands are not prevalent in transition metal
chemistry but we propose that they provide a suitable ligand
geometry to facilitate oxidation from Pd(II) to Pd(IV) and C-X
bond forming reactions through κ3-coordination.
The pyridyl-sulfonamide-stabilized aryl Pd(IV) fluoride com-
plexes are so far the only high-valent Pd complexes that have
been observed to undergo C-F bond reductive elimination.
While we do not suggest that pyridyl-sulfonamide ligands are
uniquely suited to promote C-F bond formation from Pd(IV),
we propose that the κ3-coordination mode, together with their
electronic properties, vide infra, may be responsible for facile
and efficient C-F bond formation. The pyridyl-sulfonamide
ligand in 1 may stabilize the high-valent oxidation state of Pd
because facial κ3-coordination can stabilize hexacoordinate
Pd(IV) complexes.46 Upon dissociation of the hemilabile oxygen
donor atom of the sulfonyl group, a pentacoordinate Pd center
is generated, from which C-F reductive elimination can occur.
We propose that the geometry of the ancillary ligand and the
capability to adopt bidentate coordination in the square planar
(43) For examples, see: (a) Soai, K.; Shibata, T.; Morioka, H.; Choji, K.
Nature 1995, 378, 767–768. (b) Mikami, K.; Yamanaka, M. Chem.
ReV. 2003, 103, 3369–3400. (c) Kovacs, K. A.; Grof, P.; Burai, L.;
Riedel, M. J. Phys. Chem. A 2004, 108, 11026–11031.
(45) We analyzed the vibrational entropies of activation computed from
the M06 analytic Hessian for reductive elimination from 1 and 2.
(46) (a) Canty, A. J.; Jin, H.; Roberts, A. S.; Skelton, B. W.; White, A. H.
Organometallics 1996, 15, 5713–5722. (b) Milet, A.; Dedieu, A.;
Canty, A. J. Organometallics 1997, 16, 5331–5341. (c) Canty, A. J.;
Jin, H. J. Organomet. Chem. 1998, 565, 135–140.
(44) (a) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A., III; Toste, F. D. Nat. Chem. 2009, 1, 482–486. (b) Benitez,
D.; Tkatchouk, E.; Goddard, W. A., III Organometallics 2009, 28,
2643–2645. (c) Benitez, D.; Tkatchouk, E.; Gonzalez, Z. A.; Goddard,
W. A., III; Toste, F. D. Org. Lett. 2009, 11, 4798–4801.
9
3802 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Mechanism of C-F Reductive Elimination
A R T I C L E S
and tridentate coordination in the octahedral complex with a
hemilabile oxygen ligand is the reason for the utility of the
pyridyl-sulfonamide ligand in C-F reductive elimination from
Pd(IV).
In the Pd(IV) fluoride complexes 1-3 the weakly σ-donating
ligandssκ3-sulfonamide oxygen, pyridine, and fluoride for 1,
2, and 3, respectivelysare placed trans to the strongly σ-donat-
ing aryl ligand. In all cases, fluoride and sulfonamide are
coordinated trans to each other. The trans orientation of the
fluoride ligand and the sulfonamide ligand can be rationalized
by ionic contributions to both Pd-ligand bonds. The fluoride
and sulfonamide ligands could strengthen the Pd-F and the
Pd-N bonds by mutually enhancing their ionic contribution to
the bonding.28,47,48
Potential Reaction Mechanisms of C-F Reductive Elimina-
tion from 1 and 2. As shown in Figure 17, we classified 15
potential reaction mechanisms of C-F reductive elimination
from 1 into two categories: (1) reductive elimination from a
hexacoordinate complex (direct mechanism) and (2) reductive
elimination from a pentacoordinate complex (dissociative mech-
anism). The dissociative mechanism class was further divided
into six subclasses, depending on the ligand that dissociates prior
to reductive elimination. In all six subclasses, there are at least
two distinct mechanisms depending on the rate-determining step:
(a) dissociation of the ligand to form a pentacoordinate complex
and (b) C-F bond formation from the pentacoordinate complex.
In our analysis, we disregarded the possibility of dissociation
of the benzo[h]quinolyl carbon ligand to form an aryl anion
(mechanisms 7a and 7b). Carbon ligand dissociation was
excluded due to the high pKa (ca. 43) of the hydrocarbon. We
also disregarded the possibility of the dissociation of two or
more ligands from the hexacoordinate Pd atom prior to reductive
elimination because formation of tetra or lower-coordinate
complexes for a Pd(IV) d6 would be energetically disfavored.49
Mechanism of C-F Reductive Elimination from 1. Through
analysis of the experimental and computational results, we
concluded that of the mechanisms shown in Figure 17, only
mechanism 2b is consistent with our data for C-F reductive
elimination from 1. Our rationale for proposing mechanism 2b
is described below.
First, the activation parameters obtained for the C-F reduc-
tive elimination from 1 do not support mechanisms 1 and 2a.
A process, in which reductive elimination proceeds from a
hexacoordinate complex (mechanism 1) should have an activa-
tion entropy close to zero.50 For example, in 2003, Goldberg
reported an activation entropy of ∆S‡ ) 3 ( 3 eu for C-H
reductive elimination from a PtIV complex via a direct
mechanism.50a We measured an activation entropy of ∆S‡ )
(47) (a) Mayer, J. M. Comments Inorg. Chem. 1988, 8, 125–135. (b)
Caulton, K. G. New J. Chem. 1994, 18, 25–41.
(48) (a) Klopman, G. In Chemical ReactiVity and Reaction Paths; Klopman,
G., Ed.; John Wiley and Sons: New York, 1974; p 55. (b) Drago,
R. S. Applications of Electrostatic-CoValent Models in Chemistry;
Surfside: Gainesville, FL, 1994. (c) Landis, C. R.; Firman, T. K.; Root,
D. M.; Cleveland, T. J. Am. Chem. Soc. 1998, 120, 1842–1854. (d)
Becker, C.; Kieltsch, I.; Broggini, D.; Mezzetti, A. Inorg. Chem. 2003,
42, 8417–8428. (e) Mezzetti, A.; Becker, C. HelV. Chim. Acta 2002,
85, 2686–2703.
Figure 17. Considered mechanisms for reductive elimination from 1. The
data are consistent with mechanism 2b.
(49) (a) Crabtree, R. H. The organometallic chemistry of the transition
metals; John Wiley & Sons: Hoboken, NJ, 2005. (b) Mitchell, P. R.;
Parish, R. V. J. Chem. Educ. 1969, 46, 811–814.
12.4 ( 1.3 eu for reductive elimination from 1, which would
be large for direct mechanism 1. Additionally, reductive
elimination from hexacoordinate metal complexes typically
requires that all ligands be tightly bound to the metal, as are
(50) (a) Crumpton-Bregel, D. M.; Goldberg, K. I. J. Am. Chem. Soc. 2003,
125, 9442–9456. (b) Bartlett, K. L.; Goldberg, K. I.; Borden, W. T.
Organometallics 2001, 20, 2669–2678. (c) Puddephatt, R. J. Coord.
Chem. ReV. 2001, 219, 157–185.
9
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A R T I C L E S
Furuya et al.
Scheme 3. Proposed Mechanism for C-F Reductive Elimination from 1
alkyl, hydrido, and bidentate phosphine ligands.51 In complex
1, however, the sulfonamide oxygen ligand is not tightly bound
as established by the rate of the equilibrium between complex
transition state structure compared to the structure of 1 (vide
infra). Therefore, we characterize mechanism 5b as unlikely.
Sixth, mechanism 6b cannot be excluded by our experimental
results. We were not able to synthesize the Pd(IV) complexes
with 4-substituted benzoquinolyl ligands. In addition, an attempt
to utilize analogs of 1, in which the benzo[h]quinolyl ligand of
1 was replaced by 2-phenylpyridyl substituents, for kinetic
analysis was not successful because the Pd(IV) complexes
resulting from the 2-phenylpyridine complexes could not be
prepared as cleanly as the corresponding benzo[h]quinolyl-
derived complexes. Therefore, the kinetic data would not be
accurate. Hence, we investigated mechanism 6b computationally
and did not identify a local minimum or a transition structure
where the Pd and the benzo[h]quinolyl nitrogen atom are not
involved in covalent bonding. Computationally, a bond length-
ening of the Pd-N (benzo[h]quinolyl) bond distance by only
0.05 Å at the transition structure was predicted.
1 and 2, which is as fast as 49 s-1 at 25 °C (∆G‡ ) 15.1 (
298
0.2 kcal/mol) compared to the rate of C-F reductive elimination
from 1 (8.2 × 10-5 s-1 at 23 °C). The fast dissociation of the
sulfonamide oxygen atom in 1 also excludes oxygen dissociation
as the rate-determining step (mechanism 2a).
Second, the rate of reductive elimination was independent
of the concentration of added n-Bu4NBF4 (0-2.0 M). Addition
of salts such as n-Bu4NBF4 increases the dielectric constant of
the reaction medium. The indifference of the rate on the
concentration of n-Bu4NBF4 suggests that the transition state is
not more ionic than the ground state and, hence, disfavors
mechanisms 3a and 3b.
Third, the F2 value of -0.52 for the rate dependence as a
function of pyridine substitution of the pyridyl-sulfonamide as
determined from the Hammett plot in Figure 12 renders
mechanism 4b unlikely. If pyridine dissociation preceded rate-
determining reductive elimination (mechanism 4b) a F2 value
smaller in size (closer to zero) would be expected because a
dissociated pyridyl ligand would only have a small influence
on the rate of C-F bond formation without being covalently
bound to Pd.
Fourth, the F3 value of +1.41, determined from the Hammett
plot in Figure 13, in which the rate was plotted as a function of
substitution on the benzo[h]quinolyl ligand, disfavors mecha-
nisms 4a, 5a, and 6a. A negative F3 value would be expected
for mechanisms 4a, 5a, and 6a because electron-donating
substituents should increase the rate of dissociation of the pyridyl
4a, sulfonamide 5a, or benzoquinoline nitrogen 6a ligands,
respectively, by increasing the electron density at Pd.
Fifth, the F1 value of -0.45 determined in the Hammett plot
shown in Figure 11, in which the rate is depicted as a function
of sulfonamide substitution, is inconsistent with sulfonamide
dissociation because sulfonamide substitution could not have a
significant influence on the rate if the sulfonamide were not
ligated to Pd during the rate-determining step. However,
dissociation of the sulfonamide nitrogen to afford the eight-
membered O-bound Pd sulfonamide shown in mechanism 5b
cannot be excluded by our experimental data. Computationally,
a local minimum with an O-bound, but not N-bound sulfonamide
could not be located. In addition, calculations predicted a
shortening of ∼0.05 Å of the Pd-N(sulfonamide) bond in the
All experimental and theoretical results are consistent with
reductive elimination from a cationic, pentacoordinate Pd(IV)
upon dissociation of the oxygen atom of the sulfonamide as
shown in mechanism 2b.
Proposed Transition State Structure for C-F Reductive
Elimination from 1. The Hammett studies not only provide
information about the operative mechanism for reductive
elimination but also about the structure of the transition state
for the C-F reductive elimination from complex 1. Based on
the data obtained, we propose a reaction mechanism via the
transition state 1‡ as shown in Scheme 3.
The three F values, F1-F3, obtained from the Hammett studies
(Figure 11-13) indicate charge build-up in the transition state.
The benzo[h]quinolyl carbon ligand is electrophilic at carbon
in the transition state, whereas the fluoride ligand is nucleophilic.
The positive F value of F3 ) 1.41 for benzo[h]quinolyl
7-substitution is consistent with an electrophilic carbon ligand
in the transition state; electron-withdrawing substituents ac-
celerate reductive elimination. Electron-donating ancillary ligands
on Pd accelerate reductive elimination. The negative values for
both F1 (sulfonamide substitution) and F2 (pyridine (pyridyl-
sulfonamide) substitution) are consistent with the ancillary ligand
supporting the Pd as it is being reduced to Pd(II). The Pd-F
bond is broken with nucleophilic fluoride participating in C-F
bond formation. The computed natural charges for the transition
state (see the Supporting Information) are in agreement with
the proposed charge distribution based on experimentally
determined values. The proposed mechanism of C-F bond
formation from 1 has similar electronic requirements as a
nucleophilic aromatic substitution reaction.41,52
(51) For examples, see: (a) Brown, M. P.; Puddephatt, R. J.; Upton, C. E. E.
J. Chem. Soc., Dalton Trans. 1974, 2457–2465. (b) Fekl, U.; Zahl,
A.; van Eldik, R. Organometallics 1999, 18, 4156–4164. (c) Bartlett,
K. L.; Goldberg, K. I.; Borden, W. T. J. Am. Chem. Soc. 2000, 122,
1456–1465. (d) Procelewska, J.; Zahl, A.; Liehr, G.; van Eldik, R.;
Smythe, N. A.; Williams, B. S.; Goldberg, K. I. Inorg. Chem. 2005,
44, 7732–7742.
Upon O-sulfonamide dissociation of the hexacoordinate
Pd(IV) complex 1 to form a cationic, pentacoordinate complex,
ligand rearrangement may take place for C-F reductive
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3804 J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010

Mechanism of C-F Reductive Elimination
A R T I C L E S
Figure 19. Computed transition state 1‡ for reductive elimination from 1
and predicted transition state based on Hammett analysis.
Figure 18. Two potential Y-shaped Pd(IV) transition states for C-F
reductive elimination.
(pyridines in 1‡), because the ligand-Pd orbitals of the ligand
in the Y-base are trans to the Pd-ligand orbitals of the two
substituents to be reductively eliminated. The analysis of the F
values is consistent with transition state 1‡.
elimination. Previously reported experimental and theoretical
data support that reductive elimination from pentacoordinate
transition metal complexes likely proceeds from distorted
trigonal bipyramidal structures, in which the three equatorial
ligands are in a Y-shaped arrangement. The two ligands to be
reductively eliminated are in equatorial positions.49 The Y-
shaped, distorted trigonal bipyramidal transition state positions
the two ligands to be reductively eliminated in close proximity
and, therefore, facilitates reductive elimination.
Computational analysis supported the proposed transition state
structure based on Hammett analysis shown in Figure 18 with
the two pyridine substituents in the apical positions of the
distorted trigonal bipyramidal structure and the nitrogen atom
of the sulfonamide in the basal position of the Y. The computed
transition state geometry is shown in Figure 19 (left) next to
the structure for the proposed transition state from experiment
(right). The computed bond length of the Pd-N (sulfonamide)
bond is about 0.05 Å shorter in the computed transition state 1‡
than in 1, consistent with a stronger bond of the sulfonamide
nitrogen to Pd in the transition state. No significant N-Pd
π-donation could be observed in the computed transition state
(for atomic and molecular orbital analysis, see the Supporting
Information).
Only two Y-shaped distorted trigonal bipyramidal transition
state structures are conceivable for reductive elimination from
1, under the assumption that the benzo[h]quinolyl ligand cannot
occupy two equatorial positions due to the large bond angle in
a Y-shaped arrangement (Figure 18): In one transition state,
the equatorial sulfonamide nitrogen ligand is coordinated in the
basal position of the Y-shaped transition state (1‡) and in the
other transition state, the pyridine of the pyridyl-sulfonamide
ligand is coordinated in the basal position of the Y (1′‡).
Previously, it has been argued that the ligand in the basal
position of a Y-shaped complex can have a strong influence on
the rate of reductive elimination due to π-donation.53 The
negative F1 value of -0.45 for p-sulfonamide substitution
(Figure 11) illustrates that more electron-rich sulfonamide
ligands accelerate reductive elimination. Potential π-donation
of the nitrogen atom of the sulfonamide to Pd in the transition
state 1‡ will be attenuated by the π-accepting sulfonyl group.
In the hypothetical transition state 1′‡, the pyridine of the
pyridyl-sulfonamide ligand is positioned in the basal position
of the Y. The F2 value for pyridine (pyridyl-sulfonamide)
substitution was determined to be F2 ) -0.52. While the values
for F1 and F2 are similar in size (F1 ) -0.45, F2 ) -0.52),
sulfonamide substitution has a larger electronic influence on the
rate of reductive elimination because the arene substituent of
the sulfonamide (R1) is remote from the Pd atom by two
additional bonds compared to the arene substituent of the
pyridine (R2). Therefore, increased electron-donation of the
sulfonamide substituent has a larger influence on the rate of
reductive elimination than increased electron-donation of the
pyridine substituent. The ligand in the basal position of the Y
(sulfonamide in 1‡) will have a larger effect on the rate of
reductive elimination than ligands in the apical positions
Mechanism of C-F Reductive Elimination from 2.54 Reduc-
tive elimination from 2 could proceed by a dissociative pathway
beginning with fast, reversible pyridine dissociation. A compet-
ing pathway could be a direct mechanism from hexacoordinate
2. Reductive elimination by both competing pathways with the
corresponding two-term rate law is shown in eq 5.
k2k3
rate ) kobs[2];
kobs ) k1 +
(5)
k-2[py] + k3
The linear dependence of the reciprocal of the rate of C-F
reductive elimination from 2 (1/k) vs pyridine concentration
(Figure 9) established that the rate constant for the direct
mechanism (k1) is significantly smaller than the rate constants
k2 and k3. If k1 is negligibly small compared to k2 and k3, kobs
simplifies to eq 6, which correctly describes the positive, linear
dependence (see the Supporting Information for detail). The
positive, linear dependence of the reciprocal of the rate of C-F
reductive elimination from 2 (1/k) vs pyridine concentration was
only measured for small pyridine concentrations because the
yield for C-F bond formation significantly decreased upon
addition of more than one equivalent of additional pyridine to
2. Therefore, our results cannot exclude mechanisms competing
with the dissociative mechanism via k2 and k3, such as the direct
mechanism from hexacoordinate 2.
(52) For a computationally determined tranistion state structure and energy
for C-I reductive elimination from a Pt(IV) complex, see: Yahav-Levi,
A.; Goldberg, I.; Vigalok, A.; Vedernikov, A. N. J. Am. Chem. Soc.
2008, 130, 724–731.
(53) (a) Ujaque, G.; Maseras, F.; Eisenstein, O.; Liable-Sands, L.; Rhei-
ngold, A. L.; Yao, W.; Crabtree, R. H. New. J. Chem. 1998, 23, 1493–
1498. (b) Hill, G. S.; Puddephatt, R. J. Organometallics 1998, 17,
1478–1486.
(54) We thank a reviewer for insightful comments that resulted in a
significantly improved manuscript.
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A R T I C L E S
Furuya et al.
Scheme 4. Proposed Rationale for the Dependence of Fluorination
on Solvent and Reaction Temperature
k2k3
k-2
1
kobs
1
k2
kobs
)
;
)
+
[py]
(6)
k-2[py] + k3
k2k3
The activation parameters for the reductive elimination from
2 were determined: ∆H‡ ) 32.8 ( 2.5 kcal ·mol-1, ∆S‡ ) 30.7
( 7.8 eu, and ∆G‡298 ) 23.7 ( 0.2 kcal ·mol-1. The activation
entropy for C-F reductive elimination from 2 was 30.7 ( 7.8
eu, which is about 20 eu higher than for the reductive elimination
from 1. The large activation entropy is consistent with a
dissociative mechanism, with pre-equilibrium pyridine dissocia-
tion before C-F bond formation. We have established that the
rate of pyridine dissociation is at least 106 times faster at 23 °C
than C-F bond formation by measurement of the rate of the
equilibrium between 1 and 2 (eq 2). A more thorough kinetic
analysis for the reductive elimination from 2 is complicated by
several pathways from 2 that are relevant on the time scale of
reductive elimination. For example, we have established that
the equilibrium between 2 and 1 is significantly faster than
reductive elimination from 2 (eq 2, free energy of activation
state geometries revealed that the Pd-N(pyridine) bond length
in 2‡ was longer by 0.2 Å than the Pd-N(pyridine) bond length
in 2, which was the most significant change in bond length from
2 to 2‡. For both 10a‡ and 10g‡ transition state geometries similar
to the geometry of 2‡ were found, respectively (see the
Supporting Information for details). Both our current experi-
mental and computational results cannot rationalize the nonlinear
Hammett plot shown in Figure 14, and additional studies are
required to elucidate the origin of the nonlinearity.
for equilibrium between 1 and 2: ∆G‡
) 15.1 ( 0.2
298
kcal·mol-1).
As shown in the Hammett plot in Figure 14, two different
segments are observed for the dependence of the rate of
reductive elimination from 2 as a function of 7-benzo[h]quinolyl
substitution. Nonlinear Hammett plots can be observed due to
a change in mechanism, in the rate-determining step, or in the
geometry of the transition state; Hammett plots with a large
change in F value such as observed for 2, +4.47 for electron-
donating substituents to -1.78 for electron-accepting substit-
uents, are rare.55
The analysis of the mechanism of reductive elimination from
pyridine complexes such as 2 is complicated by the fact that
the equilibrium constant between 1 and 2 changes with
substitution of the benzo[h]quinolyl substituent. For example,
the equilibrium constant for the reaction of 1 + py f 2 at
25 °C is Keq ) 2.6, whereas the equilibrium constant for the
reaction of the para-nitro-substituted Pd(IV) complex 8a + py
f 10a at 25 °C is Keq ) 3.1. Moreover, the Hammett plot
analysis for reductive elimination from complex 2 is convoluted
because the change in 7-benzo[h]quinolyl substitution not only
effects the electronic structure of the carbon ligand but also
influences the palladium-pyridine bond trans to the carbon
ligand.
Mechanism of C-F Reductive Elimination from 3. The
difluoride complex 3 is thermally more stable than 1 and 2.
Although C-F bond formation is significantly more efficient
for cationic monofluoro complexes such as 1 than it is for 3,
we briefly comment on C-F reductive elimination from 3.
Formation of the aryl Pd(II) product 13 decreases the yield of
product formation resulting from C-F reductive elimination.
The yield for reductive elimination from 3 is dependent on
solvent and temperature as shown in Table 1. At higher reaction
temperatures, the predominant formation of the desired product
4 is observed (Scheme 4). The temperature dependence of the
yield of C-F bond formation compared to formal reduction (4
versus 13) may be due to a large difference in activation
entropies between the two competing pathways. The mechanism
of C-F reductive elimination could take place by fluoride
dissociation via a similar or analogous cationic intermediate as
proposed for reductive elimination from 1. A dissociative
pathway, in which Pd-F ionization is concerted with C-F bond
formation, similar to the direct mechanism predicted for 2, is
also consistent with our results. The higher required temperature
for reductive elimination from 3 is consistent with a slower
dissociation of a fluoride ligand from a neutral Pd(IV) as
supposed to the dissociation of a neutral oxygen atom of the
sulfonamide in 1 or a pyridine ligand from 2. The preference
for the formation of 4 over the formation of 13 at high
temperatures indicates that the mechanistic pathway for the
formation of 4 has a large, positive activation entropy because
the Gibbs free energy of activation will be lower at high
temperatures for reactions with large entropies of activation.
As shown in Figure 16, the difluoro Pd(IV) complex 3 did
not undergo C-F reductive elimination following a first order
rate law. An induction period was observed and product
formation could be fitted to a logistic curve, which is typical
for reactions accelerated by autocatalysis.43 To obtain high
yields, the reaction had to be performed by heating solid 3
without solvent. The product 4, 10-fluorobenzo[h]quinoline, has
a melting point of 50 °C. At temperatures below 50 °C, the
Pd(IV) difluoride is stable in the solid state. At the reaction
Experimentally, we found that addition of pyridine inhibits
reductive elimination from 2 and also from its p-NO2 and
p-OMe-substituted derivatives 10a and 10g (Figure 15). Pyridine
dependence for reductive elimination was observed at the apex
and both extremes of the Hammett plot shown in Figure 14.
Because our experimental results could not explain the unusual
Hammett plot,55 we calculated the transition state energies and
geometries for 2‡, 10a‡, and 10g‡. Determination of the
solvation-corrected electronic energies of the three transition
states without thermodynamic corrections revealed that 10a‡ and
10g‡ are higher in energy than 2‡ by 2.7 and 3.1 kcal ·mol-1
,
respectively, in qualitative agreement with experiment. All of
the calculated transition states contained the pyridine ligand as
part of the transition state structure with increased Pd-N bond
lengths compared to 2, consistent with the possibility of a
competing direct mechanism (k1, eq 5) Analysis of the transition
(55) Williams, A. Free energy relationships in organic and bio-organic
chemistry; The Royal Society of Chemistry: Cambridge, U.K., 2003.
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Mechanism of C-F Reductive Elimination
A R T I C L E S
Scheme 5. Oxidation and Reductive Elimination Supported by the Pyridyl-Sulfonamide Ligand
temperature of 100 °C, 10-fluorobenzo[h]quinoline (4) melted.
The observation of reaction kinetics typically observed for
autocatalytic reactions may be explained by formation and
subsequent presence of 4 as a liquid. Addition of 1.0 equivalents
of 10-fluorobenzo[h]quinoline (4), accelerated the reaction of
reductive elimination from 3 and complete conversion of starting
material was observed at 100 °C within one hour, whereas only
12% of conversion of 3 was observed without additional 10-
fluorobenzo[h]quinoline (4) at 100 °C in one hour. A similar
rate acceleration was observed upon the addition of naphthalene,
which has a melting point of 77 °C. Although the sigmoidal
shape of product formation as a function of time (Figure 16) is
intriguing and can be fitted to a logistic curve as is common
for autocatalytic reactions, the experimental results suggest that
a medium effect is responsible for rate acceleration.
Intuitively, it could be expected that electron-withdrawing
substituents on the ancillary ligands of the Pd(IV) fluoride
complexes accelerate reductive elimination. Electron-withdraw-
ing substituents could increase the tendency of the resulting
electron-deficient, high-valent Pd to undergo a reductive elimi-
nation to attain the Pd(II) oxidation state. Instead, we found
that electron-donating ancillary ligands accelerated C-F bond
formation, presumably due to stabilization of the Pd as it is
being reduced to Pd(II) and increasing nucleophilic character
of fluoride as it attacks the electrophilic carbon substituent. On
the carbon ligand that participates in reductive elimination,
electron-withdrawing substituents accelerate reductive elimina-
tion. The electronic requirements for C-F bond reductive
elimination from the pyridyl-sulfonamide-stabilized Pd(IV)
fluoride complexes studied in this manuscript are comparable
to the electronic requirements of a nucleophilic aromatic
substitution reaction. The functional group tolerance, however,
of the Pd(IV)-F-mediated fluorination is larger than the
functional group tolerance of nucleophilic aromatic substitution
reactions.18a The identification of the influencing factors for C-F
reductive elimination and the identification of the pyridyl-
sulfonamide as an important ancillary ligand have potential to
support the successful future design of transition metal catalysts
for functional group-tolerant fluorination reactions.
Conclusion
We report a mechanism study of C-F reductive elimination
from Pd(IV) fluorides. A better understanding of aryl fluoride
formation by reductive elimination has previously been elusive
due to the absence of any transition metal fluoride complexes
that allowed the systematic investigation of high-yielding C-F
bond formation. To date, only two transition metal complex
classes have been identified that can provide aryl fluorides by
C-F reductive elimination. We identified that C-F reductive
elimination proceeds efficiently from aryl Pd(IV) fluoride
complexes, stabilized by pyridyl-sulfonamide ancillary ligands.
We propose that the pyridyl-sulfonamide ligand plays a crucial
role for facile and efficient C-F bond formation. The ability
of the pyridyl-sulfonamide ligand to function as a bidentate-
tridentate-bidentate coordinating ligand during oxidation and
reductive elimination, combined with the appropriate electronic
requirements of the sulfonamide to position the aryl substituent
trans to the sulfonamide ligand in the Pd(II) complex and the
fluoride ligand trans to the sulfonamide ligand in the Pd(IV)
complex, may be the reason for facile C-F bond formation
(Scheme 5). The pyridyl-sulfonamide ligand is, therefore, a
promising ancillary ligand for redox processes beyond C-F
bond formation, in which a transition metal changes its
coordination geometry and oxidation state.
Acknowledgment. We acknowledge NIH-NIGMS (GM088237)
for financial support of this project. We thank Dr. Shaw Huang for
NMR analysis, Dr. Douglas M. Ho and Jessica Y. Wu for X-ray
crystallographic analysis, Dr. Imhyuck Bae and Christian A.
Kuttruff for discussions, Chenghong Huang for experimental
contributions, and Air Products and Chemicals, Inc. for a generous
donation of F-TEDA-BF4. Computational facilities were funded by
grants from ARO-DURIP and ONR-DURIP.
Supporting Information Available: Detailed experimental
procedures and spectroscopic data for all new compounds.
Detailed computational methods and XYZ coordinates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA909371T
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J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 3807