Divergent Reactivity of Stannane and Silane in the Trifluoromethylation of PdII: Cyclic Transition State versus Difluorocarbene Release

Article abstract of DOI:10.1002/anie.201808229

The transmetalation is a key elementary step in cross-coupling reactions. Yet, the precise nature of its mechanism and transition state geometry are frequently elusive. This report discloses our study of the transmetalation of [Pd^II]-F complexes with the silane- and stannane-based trifluoromethylation agents, R₃SiCF₃ and R₃SnCF₃. A divergent reactivity was uncovered, with the stannane showing selective R-group transfer, and the silane selective CF₃-group transfer. Using a combined experimental and computational approach, we uncovered a hitherto unrecognized transmetalation mechanism with the widely employed R₃SiCF₃ reagent, explaining its unique activity in metal-catalyzed trifluoromethylations. While the stannane reacts via a cyclic, 4-membered transition state, the silane undergoes a fundamentally different pathway and releases a difluorocarbene in the transmetalation event. Molecular dynamics studies clearly reinforced the liberation of a free CF₂ carbene, which reacts with [Pd^II]-F to ultimately generate [Pd^II]-CF_3.

Full text of DOI:10.1002/anie.201808229

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Divergent Reactivity of Stannane and Silane in the
Trifluoromethylation of Pd(II): Cyclic Transition State versus
Difluorocarbene Release
Authors: Maoping Pu, Italo Sanhueza, Erdem Senol, and Franziska
Schoenebeck
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808229
Angew. Chem. 10.1002/ange.201808229
Link to VoR: http://dx.doi.org/10.1002/anie.201808229
http://dx.doi.org/10.1002/ange.201808229

10.1002/anie.201808229
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Trifluoromethylation
Divergent Reactivity of Stannane and Silane in the Trifluoro-
methylation of Pd(II): Cyclic Transition State versus Difluorocarbene
Release
Maoping Pu, Italo A. Sanhueza, Erdem Senol and Franziska Schoenebeck*
be ligand displacement and associated over-trifluoromethylation of
the Pd-intermediates by reactive ‘CF3-anions’ that in turn are
liberated due to activating additives[6d,j,8] and (ii) side reactions due to
trace amounts of water may occur that are introduced through
reactivity enhancing fluoride salt additives (Figure 1).[9] As such, and
owing to the remarkable properties of highly fluorinated molecules as
well as the widespread interest in the CF3-motif,[ 10 ] there is a
significant demand to develop alternative strategies for the
introduction of ‘CF3’ in the context of Pd(0)/Pd(II) catalysis.
Abstract: The transmetalation is a key elementary step in cross-
coupling reactions. Yet, the precise nature of its mechanism and
transition state geometry are frequently elusive. This report discloses
our study of the transmetalation of [Pd(II)]-F complexes with the
silane- and stannane-based trifluoromethylation agents, R3SiCF3 and
R3SnCF3. A divergent reactivity was uncovered, with the stannane
showing selective R-group transfer, and the silane selective CF3-
group transfer. Using a combined experimental and computational
approach, we uncovered a hitherto unrecognized transmetalation
mechanism with the widely employed R3SiCF3 reagent, explaining its
unique activity in metal-catalyzed trifluoromethylations. While the
stannane reacts via a cyclic, 4-membered transition state, the silane
undergoes a fundamentally different pathway and releases a
difluorocarbene in the transmetalation event. Molecular dynamics
studies clearly reinforced the liberation of a free CF2 carbene, which
reacts with [Pd(II)]-F to ultimately generate [Pd(II)]-CF3.
 Proposed Transition States for Transmetalation:
 Challenges in introducing CF3 to Pd(II) with TMSCF3:
P
alladium-catalyzed cross-coupling reactions have had
a
tremendous and widespread impact in chemistry and related
disciplines. Mechanistically, these transformations proceed via multi-
step mechanisms, of which the transmetalation constitutes the key
elementary step which introduces the desired substituent to the metal
center that is ultimately installed in the target molecule (Figure 1).[1]
Through decades of delicate and diligent mechanistic work, insight
on the nature of this very step could be gleaned. [2,3] In this context, it
has been elucidated particularly by probing the stereochemical course
of the reaction that a cyclic transition state would be favored under
additive-free and non-polar conditions for the Stille cross-coupling
reaction (see Figure 1).[2f,3] In the presence of additives, an open
mechanism is more likely adopted.[2f, 4 ] By analogy, cyclic TS
arrangements have also been proposed for Hiyama, Suzuki couplings
and the introduction of other functionality (Figure 1).[5] In this context,
the introduction of a CF3 group via Pd(0)/Pd(II) catalysis belongs to one
of the most challenging transformations in the cross-coupling arena,
which is due to the difficult reductive elimination of ArCF3 from Pd(II)
on the one hand,[6] but primarily also to the transmetalation step.
Traces of H2O cause side-reactions
Ligand displacement
This Work
R transfer
CF3 transfer
 Divergent selectivity in transmetalation discovered – Stille vs. Hiyama
 Nature of transition state revealed with computation & experiment
Figure 1. Transmetalation: generally proposed TS geometries and key challenge
in Pd(0)/Pd(II) catalyzed trifluoromethylation.
As part of our ongoing program in organometallic and organofluorine
chemistry,[11] and the distant vision of developing fundamentally
novel transmetalation approaches, we set out to study this key
elementary step. To this end, we performed a comparative analysis of
the transmetalation reactions of trialkylsilane (R3SiCF3) and
trialkylstannane-based (R3SnCF3) CF3 reagents with LnPd(II)-F
complexes. In the course of our study, we observed divergent
selectivities of the stannane versus silane reagents, which in turn
served as mechanistic probe to gain insight on the favored
mechanisms and nature of transition states. Our experimental and
Trialkyl(trifluoromethyl)silanes, such as the Ruppert-Prakash
reagent TMSCF3,[7] commonly serve as transmetalating reagents to
LnPd(II)-X catalytic intermediates to produce LnPd(II)-CF3.[ 8 ] Two
major problems are associated with this step, however: (i) there can
[]
Dr. M. Pu, I. A. Sanhueza, E. Senol, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen, Germany
computational studies uncovered
transmetalation mechanism with R3SiCF3 that involves the
intermediacy of a difluorocarbene along the reaction pathway.
a
hitherto unrecognized
Mr. I. A. Sanhueza
We set out to study the transmetalation of the triphenylphosphine
bound Pd(II) complex 1 (Figure 2). Unlike other halogen-bound Pd(II)
complexes, LnPd(II)-F can be converted directly to LnPd(II)-CF3 upon
reaction with R3SiCF3 without the need for additives.[8] For the
corresponding stannane reagent, the reactivity with LnPd(II)-F in the
Laboratory for Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg
3, 8093 Zürich, Switzerland
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
1
This article is protected by copyright. All rights reserved.

10.1002/anie.201808229
Angewandte Chemie International Edition
absence of additives is unknown, but our group previously showed
that Bu3SnCF3 performs analogously to Me3SiCF3 in Cu-mediated
trifluoromethylations of aryl iodides and the synthesis of
trifluoromethyl alcohols.[ 12 ] However, to our surprise, when we
subjected Bu3SnCF3 to [(PPh3)2(Ph)Pd(II)-F] 1, we observed the
transfer of the butyl group instead of CF3, generating PhBu upon
reductive elimination from the generated LnPd(II)-Bu complex (Table
1, entry 1). The corresponding silane reagent, i.e. Me3SiCF3 or
Et3SiCF3, on the other hand led to selective CF3 transfer in reactions
with Pd(II)-F complex 1 under the analogous reaction conditions, i.e.
in the non-polar medium benzene and in the absence of additives
(entries 2 & 3).[13] Our further systematic study revealed that R3SiCF3
always transfers CF3, no matter the polarity of the medium or whether
an additive is present, while R3SnCF3 showcased a divergent
reactivity behaviour, giving butyl transfer under additive-free, non-
polar conditions and CF3 transfer in the presence of additives in polar
medium (entry 4).
For the stannane the closed 4-membered TS arrangement
significantly favours Me transfer over CF3 transfer (by ∆∆G‡ = 8.4
kcal/mol), in agreement with the experimental observations.
Interestingly, the analogous cyclic TS arrangement also significantly
favours Me over CF3 transfer for the corresponding silane (by ∆∆G‡
= 11.1 kcal/mol, see Figure 2). Yet, CF3 transfer was exclusively
observed experimentally. As such, the computational data support a
cyclic TS for the stannane-based reactivity but suggest that a different
mechanism must be at play for the corresponding silane.
Table 1. Divergent reactivity of R3SnCF3 vs. R3SiCF3 in transmetalation.
Figure 2. Computational prediction of selectivity of alkyl vs. CF3 transfer for cyclic
TS geometry [calculated at CPCM (benzene) B3LYP-D3/def2-TZVP//B3LYP-
D3/6-31G(d)/SDD(Sn,Pd)].
With the generally assumed mechanism ruled out for the silane-based
transmetalation, we subsequently set out to identify the underlying
mechanism and origin of preferential CF3 transfer. We hypothesized
that instead of the concerted CF3 transfer in a cyclic mechanism, a
more asynchronous or even stepwise alternative might also be
feasible. In the search of such alternatives, we computationally
discovered TSCF2, illustrated in Figure 3. Although this TS is also
cyclic in nature and the Si•••CF3 bond is broken, there is no concerted
formation of a Pd•••CF3 bond via a 4-membered arrangement. Instead,
a bond is formed between the Pd center and one of the fluorine atoms
of the transferred CF3 in a 5-membered arrangement. (An animated
Figure of TSCF2 that visualizes the bond making and breaking is
provided as SI). Following the reaction coordinate from this novel
TSCF2 an intermediate Pd-complex [LPd(F)(CF2)(Ph)] 3 is formed
that carries a phenyl, phosphine, fluoride and a difluorocarbene ligand.
Subsequently, a very facile fluoride shift from the Pd-center to CF2
takes place that is calculated to occur with a negligibly low barrier of
While the additive-containing, polar conditions appear consistent
with current assumptions that pentavalent silyl or stannane species
could be reactive via an open mechanism,[ 14 ] the results of the
additive-free conditions are unexpected. A cyclic mechanism would
be assumed under such conditions, as graphically represented in
Figure 1. However, if the same cyclic TS arrangements were to be
adopted for the silane and stannane reagents, why would different
selectivities result?
We subsequently turned to computational studies[15] to gain insight.
In this context, we considered the widely assumed 4-membered cyclic
TS arrangement and assessed methyl versus CF3 transfer for both, the
silane and stannane based reagents, i.e. Me3SiCF3 and Me3SnCF3 at
various levels of theory.[16] Previous studies demonstrated that one
phosphine ligand is lost prior to transmetalation,[17] which most likely
∆G‡
= 2.4 kcal/mol, giving the experimentally observed
occurs through
a mechanism that involves an associative
[LPd(Ph)(CF3)] 2 complex as the thermodynamically most stable
intermediate. The activation free energy barrier to reach the newly
discovered transition state TSCF2 is ∆G‡ = 9.8 kcal/mol, which is 2.6
kcal/mol lower in energy than the lowest energy competing pathway,
i.e. transfer of Me via a cyclic TS (Figure 2, bottom). Overall, this
new pathway suggests that no direct CF3 transfer takes place between
R3SiCF3 and a [Pd(II)]-F center. Instead there appears to be generation
displacement of a phosphine ligand by the transmetalating reagent.[18]
As all applied computational methods gave the analogous reactivity
trend (see SI for full data), we focus our discussion on the data set
obtained from CPCM (benzene) B3LYP-D3/def2TZVP energy
calculations (see Figure 2).
2
This article is protected by copyright. All rights reserved.

10.1002/anie.201808229
Angewandte Chemie International Edition
of a difluorocarbene along with concerted fluoride shifts in a 5-
membered arrangement (Figure 3).
fashion, ultimately binds to the Pd(II) intermediate as to generate a
palladium-carbene complex, i.e. [Pd]=CF2 3 (see Figure 3). However,
the dynamics suggest that 3 is by no means a “stable” or
experimentally observable intermediate. Instead, 3 spontaneously
undergoes further conversion towards the experimentally observed
[Pd(II)]-CF3 complex 2 as thermodynamic sink. Thus, the BOMD
simulation clearly demonstrated that the transmetalation of Pd(II) with
R3SiCF3 involves the generation of a ‘free’ difluorocarbene upon
concerted fluoride shifts between the silyl and Pd(II) moieties. This
exquisite mechanism is in line with the unique activity of trialkylsilyl
CF3-reagents in transition metal mediated trifluoromethylation
reactions. It is also consistent with observations of difluorocarbene-
derived side processes in catalytic transformations. Interestingly, for
Rh- and Os-metal complexes, relatively stable and long-lived CF2-
carbene bound metal complexes have previously been characterized
and were proposed to form from metal-CF3 precursors, or vice
versa.[19] As such, the mechanism of transmetalation revealed herein
may be of much greater generality and apply for a wider range of
metals.
We subsequently tested whether this novel pathway could also be
operative for the stannane analogue. However, in the case of
Me3SnCF3, the difluorocarbene path is calculated to be significantly
disfavoured over the direct Me transfer (by ∆∆G‡ = 8.3 kcal/mol),
which is in agreement with experimental observations of alkyl
transfer (see SI for information). Moreover, we also computationally
studied alternative ligands in place of PPh3, i.e. Brettphos and PtBu3-
derived Pd(II)-F complexes for their favoured mechanisms of
transmetalation. We obtained the analogous results; alkyl transfer is
favoured with the stannane but the difluorocarbene pathway is
favoured with silane (see SI). As such, these new mechanistic
findings appear to be independent of the employed ligand.
TSCF2
Given that difluorocarbenes have previously been generated, we
envisioned that it should be feasible to probe the novel mechanism
experimentally. If the uncovered pathway is indeed operating, we
Expansion TSCF2
& TS vibrations
would expect to be able to generate LnPd(II)-CF3 directly from LnPd(II)
-
TSCF2
F via subjection to a difluorocarbene. To this end, we utilized
(triphenylphosphonio)difluoroacetate (PDFA) well-known
9.8
–
a
precursor that generates difluorocarbene upon decarboxylation.[20] To
our delight, subjection of PDFA to [(PPh3)2(Ph)Pd(II)-F] 1 in CH2Cl2
gave quantitative formation of the complex [(PPh3)2(Ph)Pd(II)-CF3] 2
within 1 h at room temperature (see Scheme 1). Similarly, in DMF
and benzene we also observed efficient formation of 2. These
observations are a proof-of-principle that difluorocarbenes can
readily react with [Pd(II)]-F complexes, in line with the
computationally discovered mechanism of transmetalation.
TSF-shift
-9.8
3
-12.2
Me3SiF
0.0
-34.5
Scheme 1. Experimental test of new mechanism: reaction of in-situ generated
difluorocarbene with complex 1.
.
TSCF2
In summary, the discovery and in-depth mechanistic study of the
divergent transmetalation reactivity of R3SnCF3 and R3SiCF3 with
[Pd(II)]-F was disclosed herein. While selective trifluoromethylation
of the complex occurs with the silane, the stannane preferentially
transfers the alkyl (R) instead. The study of selectivity of R- versus
CF3-group transfer served as mechanistic probe to shed light on the
favoured reaction pathways using a combination of computations and
experiments. While the widely proposed cyclic mechanism is
consistent with the reactivity of R3SnCF3, this mechanism is not
operative for R3SiCF3 for the systems studied herein. Instead, our data
suggest that transmetalation with the silane reagent involves the
liberation of a difluorocarbene that eventually adds to the [Pd(II)]-F
complex to ultimately form [Pd(II)]-CF3. As such, the silane and its
stannane analogue react in fundamentally different ways. We
anticipate that follow-up developments from these fundamental
insights might arise, which likely are of relevance also more widely
for alternative metals. For example, practical alternatives to the
expensive and widely employed R3SiCF3 might be identifiable, e.g.
by employing the cheaper HCF3 (fluoroform) and harnessing its
Figure 3. New mechanism of transmetalation with R3SiCF3 via TSCF2 uncovered.
Top: static reactivity profile. Bottom: Born-Oppenheimer Molecular Dynamics
starting from TSCF2 showing free CF2 carbene.
Our newly discovered mechanism for transmetalation with R3SiCF3
suggests that a difluorocarbene is generated along the pathway. To
gain greater insight into the nature of transition state TSCF2, its
dynamical motions and the CF2 carbene generation, we subsequently
performed state-of-the-art Born-Oppenheimer molecular dynamics
(BOMD) simulations starting from TSCF2
. Snapshots of a
representative trajectory calculation are illustrated in Figure 3
(bottom) and a movie is provided in the supporting information. The
dynamics at B3LYP-D3/6-31G(d) [with SDD for Pd] level of theory
revealed a clear liberation of a CF2 carbene, which following a period
of about 2 ps of a rather random and ‘free’ motion in a roaming-like
3
This article is protected by copyright. All rights reserved.

10.1002/anie.201808229
Angewandte Chemie International Edition
Martin, F. M. Miloserdov, M. A. Novikov, J. A. Panetier, L. V. Romashov,
Organometallics 2012, 31, 1315; e) N. D. Ball, J. B. Gary, Y. Ye, M. S.
Sanford, J. Am. Chem. Soc. 2011, 133, 7577; f) P. Anstaett, F.
Schoenebeck, Chem. Eur. J. 2011, 17, 12340; g) E. J. Cho, T. D. Senecal,
T. Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010, 328,
1679; h) N. D. Ball, J. W. Kampf, M. S. Sanford, J. Am. Chem. Soc. 2010,
132, 2878; i) G. G. Dubinina, W. W. Brennessel, J. L. Miller, D. A. Vicic,
Organometallics 2008, 27, 3933; j) V. V. Grushin, W. Marshall, J. J. Am.
Chem. Soc. 2006, 128, 12644; k) D. A. Culkin, J. F. Hartwig,
Organometallics 2004, 23, 3398.
known propensity to convert to :CF2 via base-mediated
deprotonation,[21] followed by reaction with a catalytically generated
[Pd(II)]-F. Applications could also be envisioned in the context of PET
imaging,[22] as 18F together with :CF2 could yield in labelled [Pd(II)]-
CF2(18F) directly.
Acknowledgements
We thank the European Research Council (ERC-637993) for funding.
Calculations were performed with computing resources granted by
JARA-HPC from RWTH Aachen University under project ‘jara0091’.
[7] G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757.
[8] a) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475. b) For
a recent insightful study with AgCF3, see: S. Martínez de Salinas, A.
Mudarra, J. Benet-Buchholz, T. Parella, F. Maseras, M. H. Perez-
Temprano, Chem. Eur. J. 2018, DOI: 10.1002/chem.201802586.
Received: ((will be filled in by the editorial staff))
[9] V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 2006, 128, 4632.
[10] a) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell,
J. Med. Chem. 2015, 58, 8315; b) P. A. Champagne, J. Desroches, J.-D.
Hamel, M. Vandamme, J.-F. Paquin, Chem. Rev. 2015, 115, 9073; c) T.
Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214;
d) G. Landelle, A. Panossian, S. Pazenok, J.-P. Vors, F. R. Leroux,
Beilstein Journal of Organic Chemistry 2013, 9, 2476; e) R. Berger, G.
Resnati, P. Metrangolo, E. Weber, J. Hulliger, Chem. Soc. Rev. 2011, 40,
3496; f) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. Ed. 2011,
50, 11860; g) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320; h) K. Müller, C. Faeh, F. Diederich, Science 2007,
Published online on ((will be filled in by the editorial staff))
Keywords: transmetalation • trifluoromethylation • computations •
reaction mechanism • experiment
[1] a) T. J. Colacot, New Trends in Cross-Coupling: Theory and Applications,
RSC Catalysis Series, Cambridge, 2015; b) C. C. C. Johansson Seechurn,
M. O. Kitching, T. J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012,
51, 5062; c) F. Diederich, A. de Meijere, Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004; d) E.-i.
Negishi, A. de Meijere, Handbook of Organopalladium Chemistry for
Organic Synthesis, Wiley, New York, 2002.
[2] a) A. A. Thomas, S. E. Denmark, Science 2016, 352, 329; b) J. del Pozo,
G. Salas, R. Álvarez, J. A. Casares, P. Espinet, Organometallics 2016, 35,
3604; c) M. García-Melchor, A. A. C. Braga, A. Lledós, G. Ujaque, F.
Maseras, Acc. Chem. Res. 2013, 46, 2626; d) A. J. J. Lennox, G. C. Lloyd‐
Jones, Angew. Chem. Int. Ed. 2013, 52, 7362; e) M. Butters, J. N. Harvey,
J. Jover, A. J. J. Lennox, G. C. Lloyd‐Jones, P. M. Murray, Angew. Chem.
Int. Ed. 2010, 49, 5156; f) P. Espinet, A. M. Echavarren, Angew. Chem.
Int. Ed. 2004, 43, 4704; g) V. Farina, V. Krishnamurthy, W. J. Scott, The
Stille Reaction. In Organic Reactions, John Wiley & Sons, Inc., 2004; h)
T. J. Hiyama, Organomet. Chem. 2002, 653, 58; i) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457.
[3] a) C. Cordovilla, C. Bartolomé, J. M. Martínez-Ilarduya, P. Espinet, ACS
Catalysis 2015, 5, 3040; b) M. H. Pérez-Temprano, A. M. Gallego, J. A.
Casares, P. Espinet, Organometallics 2011, 30, 611; c) A. Ariafard, B. F.
Yates, J. Am. Chem. Soc. 2009, 131, 13981; d) R. Álvarez, O. N. Faza; C.
S. López, Á. R. de Lera, Org. Lett. 2006, 8, 35; e) A. Nova, G. Ujaque, F.
Maseras, A. Lledos, P. Espinet, J. Am. Chem. Soc. 2006, 128, 14571.
[4] a) J. Ye, R. K. Bhatt, J. R. Falck, J. Am. Chem. Soc. 1994, 116, 1; b) H.
Kurosawa, H. Kajimaru, S. Ogoshi, H. Yoneda, K. Miki, N. Kasai, S.
Murai, I. Ikeda, J. Am. Chem. Soc. 1992, 114, 8417; c) A. Vitagliano, B.
Aakermark, S. Hansson, Organometallics 1991, 10, 2592; d) H.
Kurosawa, S. Ogoshi, Y. Kawasaki, S. Murai, M. Miyoshi, I. Ikeda, J. Am.
Chem. Soc. 1990, 112, 2813; e) J. K. Stille, Angew. Chem. Int. Ed. 1986,
25, 508.
[5] For examples, see: a) H. Zheng, K. Semba, Y. Nakao, S. Sakaki, J. Am.
Chem. Soc. 2017, 139, 14065; b) S. A. Tymonko, R. C. Smith, A. Ambrosi,
M. H. Ober, H. Wang, S. E. Denmark, J. Am. Chem. Soc. 2015, 137, 6200;
c) A. Sugiyama, Y.-y. Ohnishi, M. Nakaoka, Y. Nakao, H. Sato, S. Sakaki,
Y. Nakao, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 12975; d) A. A. C.
Braga, N. H. Morgon, G. Ujaque, A. Lledós, F. Maseras, J. Organomet.
Chem. 2006, 691, 4459; e) A. A. C. Braga, N. H. Morgon, G. Ujaque, F.
Maseras, J. Am. Chem. Soc. 2005, 127, 9298.
317, 1881; i) G. Theodoridis, Chapter
4 Fluorine-Containing
Agrochemicals: An Overview of Recent Developments. In Advances in
Fluorine Science, Tressaud, A., Ed. Elsevier: 2006; Vol. 2, pp 121-175.
[11] For selected examples, see: a) S. T. Keaveney, F. Schoenebeck, Angew.
Chem. Int. Ed. 2018, 57, 4073; b) T. Scattolin, K. Deckers, F.
Schoenebeck, Org. Lett. 2017, 19, 5740; c) T. Scattolin, K. Deckers, F.
Schoenebeck, Angew. Chem. Int. Ed. 2017, 56, 221; d) A. B. Dürr, H. C.
Fisher, I. Kalvet, K. N. Truong, F. Schoenebeck, Angew. Chem. Int. Ed.
2017, 56, 13431; e) G. Yin, I. Kalvet, F. Schoenebeck, Angew. Chem. Int.
Ed. 2015, 54, 6809; f) G. Yin, I. Kalvet, U. Englert, F. Schoenebeck, J.
Am. Chem. Soc. 2015, 137, 4164.
[12] a) I. A. Sanhueza, K. J. Bonney, M. C. Nielsen, F. Schoenebeck, J. Org.
Chem. 2013, 78, 7749; b) I. A. Sanhueza, M. C. Nielsen, M. Ottiger, F.
Schoenebeck, Helv. Chim. Acta 2012, 95, 2231.
[13] The divergent reactivity is not limited to complex 1. For
(Xantphos)Pd(II)(Ph)(F) we also saw exclusive butyl transfer in reactions
with Bu3SnCF3 in benzene (see SI), while Pd(II)-CF3 is generated with
TMSCF3.
[14] For information on the various mechanistic roles of fluoride in catalysis,
see: C. Amatore, L. Grimaud, G. Le Duc, A. Jutand, Angew. Chem. Int.
Ed. 2014, 53, 6982.
[15] Calculations were conducted with Gaussian09, Revision D.01; M. J.
Frisch, et al. See Supporting Information for full reference and further
computational details.
[16] For ease of comparability, we calculated the Me3-substituted reagents.
However, Bu3SnCF3 was calculated to have same selectivity as Me3SnCF3.
See SI for more information.
[17] a) J. Louie, J. F. Hartwig, J. Am. Chem. Soc. 1995, 117, 11598; b) V.
Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585.
[18] A. L. Casado, P. Espinet, J. Am. Chem. Soc. 1998, 120, 8978.
[19] a) M. A. García-Monforte, S. Martínez-Salvador, B. Menjón, Eur. J.
Inorg. Chem. 2012, 4945; b) J. Goodman, V. V. Grushin, R. B. Larichev,
S. A. Macgregor, W. J. Marshall, D. C. Roe, J. Am. Chem. Soc. 2009, 131,
4236; c) D. Huang, P. R. Koren, K. Folting, E. R. Davidson, K. G. Caulton,
J. Am. Chem. Soc. 2000, 122, 8916.
[20] N. B. Heine, A. Studer, Org. Lett. 2017, 19 (15), 4150.
[21] C. S. Thomoson, Jr. W. R. Dolbier, J. Org. Chem. 2013, 78, 8904.
[22] M. Huiban, M. Tredwell, S. Mizuta, Z. Wan, X. Zhang, T. L. Collier, V.
Gouverneur, J. Passchier, Nat. Chem. 2013, 5, 941.
[6] Only a handful of ligands are known to trigger this step, see: a) D. M.
Ferguson, J. R. Bour, A. J. Canty, J. W. Kampf, M. S. Sanford, J. Am.
Chem. Soc. 2017, 139, 11662; b) M. C. Nielsen, K. J. Bonney, F.
Schoenebeck, Angew. Chem. Int. Ed. 2014, 53, 5903; c) A. Maleckis, M.
S. Sanford, Organometallics 2014, 33, 2653; d) V. I. Bakhmutov, F.
.
Bozoglian, K. Gómez, G. González, V. V. Grushin, S. A. Macgregor, E.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201808229
Angewandte Chemie International Edition
Layout 2:
 R Transfer via cyclicTS
 DifluorocarbeneRelease
Trifluoromethylation
M. Pu, I. A. Sanhueza, E. Senol, F.
Schoenebeck* __________ Page – Page
Divergent Reactivity of Stannane
versus Silane in the Trifluoro-
methylation of Pd(II) - Cyclic Transition
State vs. Difluorocarbene Release
1. (a) Colacot, T. J. New Trends in Cross-Coupling: Theory and Applications, RSC Catalysis Series, Cambridge, 2015; (b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062; (c) F. Diederich, F., de Meijere, A. Metal-Catalyzed Cross-CouplingReactions, 2nd ed., Wiley-VCH, Weinheim, 2004; d) Negishi, E.-i.; de Meijere, A. Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, New York, 2002.
2. (a) Thomas, A. A.; Denmark, S. E., Science 2016, 352, 329-332; (b) del Pozo, J.; Salas, G.; Álvarez, R.; Casares, J. A.; Espinet, P., Organometallics 2016, 35, 3604-3611; (c) García-Melchor, M.; Braga, A. A. C.; Lledós, A.; Ujaque, G.; Maseras, F., Acc. Chem. Res. 2013, 46, 2626-2634; (d) Lennox, A. J. J.; Lloyd‐Jones, G. C., Angew. Chem. Int. Ed. 2013, 52, 7362-7370; (e) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd‐Jones, G. C.; Murray, P. M., Angew. Chem. Int. Ed. 2010, 49, 5156-5160; (f) Espinet, P.; Echavarren, A. M., Angew. Chem. Int. Ed. 2004, 43, 4704-4734; (g) Farina, V.; Krishnamurthy, V.; Scott, W. J., The Stille Reaction. In Organic Reactions, John Wiley
& Sons, Inc., 2004; (h) Hiyama, T., J. Organomet. Chem. 2002, 653, 58-61; (i) Miyaura, N.; Suzuki, A., Chem. Rev. 1995, 95, 2457-2483.
3
4
5
(a) Cordovilla, C.; Bartolomé, C.; Martínez-Ilarduya, J. M.; Espinet, P., ACS Catalysis 2015, 5, 3040-3053; (b) Pérez-Temprano, M. H.; Gallego, A. M.; Casares, J. A.; Espinet, P., Organometallics 2011, 30, 611-617; (c) Ariafard, A.; Yates, B. F., J. Am. Chem. Soc. 2009, 131, 13981-13991; (d) Álvarez, R.; Faza, O. N.; López, C. S.; de Lera, Á. R., Org. Lett. 2006, 8, 35-38.
(a) Ye, J.; Bhatt, R. K.; Falck, J. R., J. Am. Chem. Soc. 1994, 116, 1-5; (b) Kurosawa, H.; Kajimaru, H.; Ogoshi, S.; Yoneda, H.; Miki, K.; Kasai, N.; Murai, S.; Ikeda, I., J. Am. Chem. Soc. 1992, 114, 8417-8424; (c) Vitagliano, A.; Aakermark, B.; Hansson, S., Organometallics 1991, 10, 2592-2599; (d) Kurosawa, H.; Ogoshi, S.; Kawasaki, Y.; Murai, S.; Miyoshi, M.; Ikeda, I., J. Am. Chem. Soc. 1990, 112, 2813-2814; (e) Stille, J. K., Angew. Chem. Int. Ed. 1986, 25, 508-524.
For examples, see: (a) Zheng, H.; Semba, K.; Nakao, Y.; Sakaki, S., J. Am. Chem. Soc. 2017, 139, 14065-14076; (b) Tymonko, S. A.; Smith, R. C.; Ambrosi, A.; Ober, M. H.; Wang, H.; Denmark, S. E., J. Am. Chem. Soc. 2015, 137, 6200-6218; (c) Sugiyama, A.; Ohnishi, Y.-y.; Nakaoka, M.; Nakao, Y.; Sato, H.; Sakaki, S.; Nakao, Y.; Hiyama, T., J. Am. Chem. Soc. 2008, 130, 12975-12985; (d) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledós, A.; Maseras, F., J. Organomet. Chem. 2006, 691, 4459-4466; (e) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F., J. Am. Chem. Soc. 2005, 127, 9298-9307.
6. Only a handful of ligands are known to trigger this step, see: (a) Ferguson, D. M.; Bour, J. R.; Canty, A. J.; Kampf, J. W.; Sanford, M. S., J. Am. Chem. Soc. 2017, 139, 11662-11665; (b) Nielsen, M. C.; Bonney, K. J.; Schoenebeck, F., Angew. Chem. Int. Ed. 2014, 53, 5903-5906; (c) Maleckis, A.; Sanford, M. S., Organometallics 2014, 33, 2653-2660; (d) Bakhmutov, V. I.; Bozoglian, F.; Gómez, K.; González, G.; Grushin, V. V.; Macgregor, S. A.; Martin, E.; Miloserdov, F. M.; Novikov, M. A.; Panetier, J. A.; Romashov, L. V., Organometallics 2012, 31, 1315-1328; (e) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S., J. Am. Chem. Soc. 2011, 133, 7577-7584; (f) Anstaett, P.; Schoenebeck, F., Chem. Eur. J. 2011, 17, 12340-12346; (g) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L., Science 2010, 328, 1679-1681; (h) Ball, N. D.; Kampf, J. W.; Sanford, M. S., J. Am. Chem. Soc. 2010, 132, 2878-2879; (i) Dubinina, G. G.; Brennessel, W. W.; Miller, J. L.; Vicic, D. A., Organometallics 2008, 27, 3933-3938; (j) Grushin, V. V.; Marshall, W. J., J. Am. Chem. Soc. 2006, 128, 12644-12645; (k) Culkin, D. A.; Hartwig, J. F., Organometallics 2004, 23, 3398-3416.
7. Prakash, G. K. S.; Yudin, A. K., Chem. Rev. 1997, 97, 757-786.
8. Tomashenko, O. A.; Grushin, V. V., Chem. Rev. 2011, 111, 4475-452.
9. Grushin, V. V.; Marshall, W. J., J. Am. Chem. Soc. 2006, 128, 4632-4641.
10. (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A., J. Med. Chem. 2015, 58, 8315-8359; (b) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F., Chem. Rev. 2015, 115, 9073-9174; (c) Liang, T.; Neumann, C. N.; Ritter, T., Angew. Chem. Int. Ed. 2013, 52, 8214-8264; (d) Landelle, G.; Panossian, A.; Pazenok, S.; Vors, J.-P.; Leroux, F. R., Beilstein Journal of Organic Chemistry 2013, 9, 2476-2536; (e) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J., Chem. Soc. Rev. 2011, 40, 3496-3508; (f) Zimmer, L. E.; Sparr, C.; Gilmour, R., Angew. Chem. Int. Ed. 2011, 50, 11860-11871; (g) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Chem. Soc. Rev. 2008, 37, 320-330; (h) Müller, K.; Faeh, C.; Diederich, F., Science 2007, 317, 1881-1886; (i) Theodoridis, G., Chapter
11. For selected examples, see: (a) Keaveney, S. T.; Schoenebeck, F., Angew. Chem. Int. Ed. 2018, 57, 4073-4077; (b) Scattolin, T.; Deckers, K.; Schoenebeck, F., Org. Lett. 2017, 19, 5740-5743; (c) Scattolin, T.; Deckers, K.; Schoenebeck, F., Angew. Chem. Int. Ed. 2017, 56, 221-224; (d) Dürr, A. B.; Fisher, H. C.; Kalvet, I.; Truong, K. N.; Schoenebeck, F., Angew. Chem. Int. Ed. 2017, 56, 13431-13435; (e) Yin, G.; Kalvet, I.; Schoenebeck, F., Angew. Chem. Int. Ed. 2015, 54, 6809-6813; (f) Yin, G.; Kalvet, I.; Englert, U.; Schoenebeck, F., J. Am. Chem. Soc. 2015, 137, 4164-4172.
12. (a) Sanhueza, I. A.; Bonney, K. J.; Nielsen, M. C.; Schoenebeck, F., J. Org. Chem. 2013, 78, 7749-7753; (b) Sanhueza, I. A.; Nielsen, M. C.; Ottiger, M.; Schoenebeck, F., Helv. Chim. Acta 2012, 95, 2231-2236.
4 Fluorine-Containing Agrochemicals: An Overview of Recent Developments. In Advances in Fluorine Science, Tressaud, A., Ed. Elsevier: 2006; Vol. 2, pp 121-175.
13
14 Reference fluroide effect
15. Frisch, M. J. et al., Gaussian 09, Revision D.01, Gaussian, Inc., Wallingford, CT, 2013 (see SI for full reference).
16. For ease of comparability, we calculated the Me3-substituted reagents. However, Bu3SnCF3 was calculated to have same selectivity as Me3SnCF3. See SI for more information.
17. (a) Louie, J.; Hartwig, J. F., J. Am. Chem. Soc. 1995, 117, 11598-11599; (b) Farina, V.; Krishnan, B., J. Am. Chem. Soc. 1991, 113, 9585-9595.
18. Casado, A. L.; Espinet, P., J. Am. Chem. Soc. 1998, 120, 8978-8985.
19. (a) García-Monforte, M. A.; Martínez-Salvador, S.; Menjón, B. Eur. J. Inorg. Chem. 2012, 4945–4966; (b) Goodman, J.; Grushin, V. V.; Larichev, R. B.; Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc. 2009, 131, 4236–4238; (c) Huang, D.; Koren, P. R.; Folting, K.; Davidson, E. R.; Caulton, K. G. J. Am. Chem. Soc. 2000, 122, 8916-8931.
20. Heine, N. B.; Studer, A., Org. Lett. 2017, 19 (15), 4150-4153
21. Thomoson, C. S.; Dolbier, Jr. W. R., J. Org. Chem. 2013, 78, 8904-8908
22. Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.; Zhang, X.; Collier, T. L.; Gouverneur, V.; Passchier, J., Nature Chemistry 2013, 5, 941.
5
This article is protected by copyright. All rights reserved.