Ag(I)-Catalyzed C-H Activation: The Role of the Ag(I) Salt in Pd/Ag-Mediated C-H Arylation of Electron-Deficient Arenes

Article abstract of DOI:10.1021/jacs.6b04726

The use of stoichiometric Ag(I)-salts as additives in Pd-catalyzed C-H functionalization reactions is widespread. It is commonly proposed that this additive acts as an oxidant or as a halide scavenger promoting Pd-catalyst turnover. We demonstrate that, contrary to current proposals, phosphine ligated Ag(I)-carboxylates can efficiently carry out C-H activation on electron-deficient arenes. We show through a combination of stoichiometric and kinetic studies that a (PPh₃)Ag-carboxylate is responsible for the C-H activation step in the Pd-catalyzed arylation of Cr(CO)₃-complexed fluorobenzene. Furthermore, the reaction rate is controlled by the rate of Ag(I)-C-H activation, leading to an order zero on the Pd-catalyst. H/D scrambling studies indicate that this Ag(I) complex can carry out C-H activation on a variety of aromatic compounds traditionally used in Pd/Ag-mediated C-H functionalization methodologies.

Full text of DOI:10.1021/jacs.6b04726

Subscriber access provided by UNIV MASSACHUSETTS WORCESTER
Communication
Ag(I)-catalyzed C-H activation: the role of the Ag(I) salt in
Pd/Ag mediated C-H arylation of electron-deficient arenes
Daniel Whitaker, Jordi Burés, and Igor Larrosa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Jun 2016
Downloaded from http://pubs.acs.org on June 15, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
Daniel Whitaker,† Jordi Burés†,‡,* and Igor Larrosa†,*
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.
‡ Imperial College London, Department of Chemistry Exhibition Road, South Kensington, SW7 2AZ London, UK
*e-mail: igor.larrosa@manchester.ac.uk; j.bures@imperial.ac.uk
Supporting Information Placeholder
enhanced heterobimetallic C-H activation.13 However, experi-
ABSTRACT: The use of stoichiometric Ag(I)-salts as additives
in Pd-catalyzed C-H functionalization reactions is widespread. It
is commonly proposed that this additive acts as an oxidant or as a
mental evidence for these proposals under catalytic conditions has
not been forthcoming.14
halide scavenger promoting Pd-catalyst turnover. We demonstrate
that, contrary to current proposals, phosphine ligated Ag(I)-
carboxylates can efficiently carry out C-H activation on electron-
deficient arenes. We show through a combination of stoichio-
metric and kinetic studies that a (PPh3)Ag-carboxylate is respon-
sible for the C-H activation step in the Pd-catalyzed arylation of
Cr(CO)3-complexed fluorobenzene. Furthermore, the reaction rate
is controlled by the rate of Ag(I)-C-H activation, leading to an
order zero on the Pd-catalyst. H/D scrambling studies indicate that
this Ag(I) complex can carry out C-H activation on a variety of
aromatic compounds traditionally used in Pd/Ag-mediated C-H
functionalization methodologies.
We report that Ag(I)-carboxylates on their own are, in fact,
highly efficient catalysts for the C-H activation of electron-
deficient arenes. We demonstrate that a Ag(I)-carboxylate — and
not a Pd(II) species as previously believed — is responsible for C-
H activation in a Pd/Ag mediated C-H arylation system, likely via
a concerted metalation-deprotonation similar to that proposed for
Pd. These results suggest that the role of Ag(I) in many other
Pd/Ag C-H functionalization processes may have been underesti-
mated.
Scheme 1. Pd/Ag-Mediated Direct Arylation of (2-
Fluorotoluene)Cr(CO)3 (1) with 4-Iodoanisole (2)
Over the last decade C-H functionalization has emerged as a
promising synthetic tool capable of significantly streamlining
access to complex materials from non-prefunctionalized starting
compounds.1 In particular, the functionalization of aromatic C-H
bonds is under intense development, and several transition metals
have been shown to catalyze C-H activation, including Pd,2 Ir,3
Rh,4 Cu,5 Ru6 and Au.7 Due to its versatility in mediating the C-H
functionalization of a broad range of aromatics, Pd has been one
of the most studied transition metals to date. While several mech-
anistic pathways have been proposed for Pd-mediated C-H activa-
tion, carbonate or carboxylate assisted concerted metalation-
deprotonation (CMD) stands out as a likely mechanism for a wide
variety of electron-rich and -poor aromatics, as well as those con-
taining directing groups.8 Often, Pd-catalyzed C-H functionaliza-
tions are carried out in the presence of stoichiometric Ag(I)-salts.9
The need for these Ag-additives is commonly attributed to one of
two secondary roles in these processes: as a terminal oxidant in
oxidative functionalizations, or as a halide scavenger, particularly
when iodoarenes are used as coupling partners.10 In both of these
roles, the Ag(I)-salts are needed to regenerate catalytically active
Pd species as the reaction proceeds. However, in many of these
processes the Ag(I)-salts cannot be successfully replaced with
other oxidants or halide scavengers. This raises the question of
whether silver-salts may play additional roles in these C-H func-
tionalization processes. Recent computational11 and deuteration12
studies on the oxidative coupling of pentafluorobenzene and ben-
zene suggested that silver could be performing the C–H activation
in this case, and a recent computational mechanistic study sug-
gested that Ag could interact with Pd in a cooperative manner for
Scheme 2. Mechanistic hypotheses
We recently reported a Pd-catalyzed methodology for the C-H
arylation of electron-deficient (arene)Cr(CO)3 complexes with
iodoarenes as coupling partners (Scheme 1).15 As is common in
this type of process, we found that stoichiometric Ag2CO3 was
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
required, nominally to scavenge the iodide formed during the
1
2
3
4
5
6
7
8
reaction. A typical Pd(0/II)-type catalytic cycle (mechanistic pro-
posal A in Scheme 2), as proposed in most C-H arylation method-
ologies could account for these results. The role of the Ag(I)-salt
would be simply to abstract I from Pd-species II, generating
Pd(II)-carboxylate III. Species III would then perform C-H acti-
vation of 1 via CMD, followed by reductive elimination to form
biaryl product 3. However, during optimization of this process we
observed that lower yields were obtained when the ratio PPh3:Pd
was decreased from 4:1 to 2:1 or 0:1.16 Intrigued by these results,
we now set out to investigate whether there was an alternative
species performing the C–H activation step in this reaction.
0.08
Prod - 0.32 mmol PPh3
0.08 M PPh3
Prod - 0.24 mmol PPh3
0.06 M PPh3
[3] (M)
Prod - 0.16 mmol PPh3
0.04 M PPh3
0.02 M PPh
Prod - 0.08 mmol PPh3
3
9
Pr0o.d00- nMo aPdPdhe3d PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.00
In order to identify the species performing the C-H activation
we attempted H/D exchange experiments on arene-complex 1
(Scheme 3). Treatment of 1 under the standard reaction conditions
in the presence of D2O, but in the absence of Ag2CO3, led to re-
covery of starting material after two hours. Similarly, treatment of
1 with, 0.75 equiv Ag2CO3 afforded no deuteration of the starting
material 1. The use of 0.5 equiv of AdCO2Ag, on the other hand,
led to a small amount of deuteration (5%). Interestingly, when 0.5
equiv of AdCO2Ag were used in combination with 0.5 equiv of
PPh3, 75% deuteration to d-1 was observed. This suggested that
the additional PPh3 needed in the arylation reaction was complex-
ing and solubilising an Ag-carboxylate species which then per-
0
t (h)
15
Figure 1. Determination of the saturation concentration of PPh3
using 5 mol % of Pd(PPh3)4.
Measuring the order in Pd is non-trivial because the precatalyst,
Pd(PPh3)4, liberates PPh3 which in turn has a positive effect in the
rate of the reaction. To avoid this interference, the order in Pd
must be measured under PPh3 saturation conditions. When the
reaction was performed adding 0.06 M of PPh3, the orders in io-
doarene 2 and arene 1 remained the same as under standard condi-
tions.20 Remarkably, the order in Pd was found to be zero, as
shown by the identical kinetic profiles of the reactions with 2.5, 5
and 10 mol % of Pd(PPh3)4 (Figure 2).
1
forms the C–H activation. H and 31P NMR experiments in d8-
PhCH3 confirmed that the highly insoluble AdCO2Ag is fully
solubilized upon addition of 1 equiv of PPh3, leading to the for-
mation of a 1:1 complex with the empirical formula Ad-
CO2Ag(PPh3).17 Accordingly, Scheme 2b outlines mechanistic
proposal B for the arylation reaction in which AdCO2Ag(PPh3)
species (VI) would carry out C-H activation, forming Ag(I)-aryl
species V. Subsequently, V would transmetalate with Pd(II)-
carboxylate III to form IV.
0.1
Pd(PPh3)4
Scheme 3. H/D exchange experiments on arene-Cr 1
2.5 mol %
5 mol %
10 mol %
[3] (M)
0.0
0
t (h)
15
Figure 2. Order zero in Pd under PPh3 saturation.
To the best of our knowledge, this is the first time that a null ef-
fect of the palladium concentration has been observed in a Pd-
catalyzed cross-coupling. A zero order in catalyst can be observed
in cases where a process external to the catalytic cycle is limiting
the rate of the overall reaction.21 In mechanistic proposal A
(Scheme 2a), the only out-cycle process that could limit the rate
of the overall reaction is the formation of AgO2CAd from Ag2CO3
and AdCO2H. This hypothesis would be consistent with the posi-
tive order in PPh3 because its coordination would increase the
solubility of Ag(I) salts. However, it would be incompatible with
the observed positive order in arene 1. On the other hand, mecha-
nistic proposal B has an additional out-cycle process that could
limit the rate of the overall reaction: the Ag(I)-mediated C-H acti-
vation. This scenario would be compatible with the positive effect
of PPh3, its saturation above the concentration of AdCO2H and the
positive order in arene 1 since it is a driving force of this step.,22
To confirm this hypothesis, we monitored the kinetics of the
arylation reaction with increasing amounts of added PPh3. We
found a positive effect of the phosphine on the rate of the reaction
reaching saturation at 0.04 M (Figure 1). Considering that the
precatalyst Pd(PPh3)4 can liberate two molecules of PPh3 into the
solution after formation of intermediate III, the amount of PPh3
available to coordinate AgO2CAd under those conditions is ap-
proximately 0.05 M. This value is the concentration of AdCO2H
used and therefore the upper limit concentration of VI that can be
formed. These results suggest that the AdCO2Ag(PPh3) complex
VI is involved in the rate determining step of the overall reaction.
To perform further mechanistic studies of such a complex sys-
tem, we used the experimental design of reaction progress kinetic
analysis (RPKA)18 and novel analysis methods for integrative data
recently developed.19. Under the standard conditions (Scheme 1),
same excess experiments analyzed by the time-adjusted method19a
showed neither significant deactivation nor product inhibition,
indicating that the system can be studied by these methods.20 Dif-
ferent excess experiments revealed a zero order in iodoarene 2
and a positive order in arene 1.20 A first order in arene 1 was fur-
ther determined by initial rate measurements.
The key species in the reaction is, therefore, AdCO2Ag(PPh3) VI.
It was not possible to measure the concentration of this complex
from reaction aliquots, and so order on this catalyst was evaluated
using the deuteration system (Scheme 3) as a simplified model.
The order on Ag was found to be 0.6, consistent with an inactive
dimeric resting state of the type [AdCO2Ag(PPh3)]2 and a low
concentration monomeric active species VI.23 The 0.6 order on
Ag, taken together with the positive order on arene 1 and the zero
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
order observed on Pd in the arylation reaction, provides strong
that Pd catalyst loadings could be significantly reduced below the
1
2
3
4
5
6
7
8
support for mechanistic proposal B in Scheme 2b.
5 mol % typically used. Gratifyingly, we found that in the pres-
ence of 60 mol % added PPh3 the reaction of 1 and 2 proceeded
efficiently with only 0.1 mol % Pd(PPh3)4, affording 3 in 61%
yield in 40 h. The longer reaction times and lower yield suggest
that at low Pd-catalyst loadings this cycle becomes kinetically
relevant. Indeed, under these conditions of PPh3 we observed an
order 1 for Pd at loadings below 0.5 mol %.20
In addition to the kinetic evidence supporting mechanistic pro-
posal B, we were also able to identify by 1H and 31P NMR trans-
(PPh3)2Pd(OCOAd)(p-C6H4OMe) (5, Figure 3) corresponding to
the trans isomer of proposed Pd(II)-carboxylate intermediate III,
as the major Pd-catalytic intermediate in the reaction. The identity
of 5 was confirmed by independent synthesis. This observation is
in agreement with mechanistic proposal B, where the Ag(I)-
mediated C-H activation is the rate limiting step of the entire cata-
lytic system. In this situation, the rate determining step of the Pd-
catalytic cycle must be the transmetallation of Ag(I)-aryl species
V with Pd(II) species III. Using species 5 as the Pd-precatalyst
instead of Pd(PPh3)4 for the arylation process led to identical reac-
tion kinetics, provided two additional equiv of PPh3 are added.20
Scheme 4. Stoichiometric reactions of aryl-Pd(II) 4 and
arene-Cr complex 2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Due to the ubiquity of Pd/Ag mediated C-H functionalization
methodologies we investigated whether AdCO2Ag(PPh3) may be
also able to mediate C-H activation on other commonly used
arenes. Gratifyingly, H/D exchange experiments using 50% of
this Ag(I)-salt showed significant deuteration after 3 h at 70 °C in
benzo[b]thiophene, pyridine-N-oxide, 1,3,5-trifluorobenzene and
1,3,4,5-tetrafluorobenzene (Scheme 5). On the other hand, fluoro-
benzene and 2-phenylpyridine did not undergo deuteration. These
results suggest that Ag(I)-salts may be the actual species perform-
ing C-H activation in several previously reported Pd/Ag C-H
functionalization methodologies. More studies will be necessary
to assess the extent of the contribution of Ag(I) to C-H activation
in these cases.
Figure 3. Comparison of 1H and 31P NMR of a reaction aliquot at
2 h with pure trans-(PPh3)2Pd(OCOAd)(p-C6H4OMe) (5, blue)
and in situ formed (PPh3)AgOCOAd (red). Cr-arene complex 1
and biaryl product 3 are highlighted in green and purple, respec-
tively.
This kinetic evidence points towards mechanistic proposal B
being in operation (Scheme 2b), with Ag(I)-mediated C-H activa-
tion as the rate limiting step in the process. A KIE of 2.3 had pre-
viously been measured for this reaction, in agreement with this
hypothesis.12 In order to gather further evidence we tested the
reactivity of Pd-species 5, a plausible resting state for Pd during
the reaction, with arene-Cr complex 1 (Scheme 4). As expected,
Pd-carboxylate 5 did not react with 1 under a variety of condi-
tions, including addition of 2 equiv of K2CO3. No reaction was
observed either when running the reaction under O2 atmosphere.24
On the other hand, addition of AdCO2Ag and PPh3 led to for-
mation of the C-H arylation product 3 in 26% yield. Decomposi-
tion of 5 is also observed, accounting for the low yield. We hy-
pothesized that this decomposition was accelerated by formation
of trace amounts of Pd(0). Indeed, when the reaction was carried
out in the presence of an iodoarene, 6, able to react rapidly with
any low valent Pd species, a yield of 72% of 3 was obtained.
These experiments reemphasize the need for the Ag(I)-
carboxylate in order for the C-H activation step to proceed. These
results are fully consistent with mechanistic proposal B (Scheme
2b) and inconsistent with mechanistic proposal A. 25
Figure 4. Computational studies for a plausible CMD-type C-H
activation step in the gas phase. Structures and energies calculated
by DFT (B3LYP/DGDZVP/SDD/6-31G(d)). Gibbs free energies
(G) in kcal/mol.
Further studies will be needed to understand the exact mecha-
nism of C-H activation by AdCO2Ag(PPh3). However, by analogy
with previous studies on Pd-O2CR, a plausible CMD can be pro-
posed. This was probed by DFT calculations of the CMD pathway
of (fluorotoluene)Cr(CO)3 with the simplified AcO-
Ag(PPh3)which revealed a feasible free energy barrier of 29.5
kcal/mol (Figure 4).26,27
In conclusion, with a combination of stoichiometric and kinetic
mechanistic studies we have demonstrated that phosphine ligated
Ag(I)-carboxylates are excellent catalysts for C-H activation of
electron-deficient arenes. These studies show that the ratio of
PPh3, AdCOOH and Pd determine the rate determining step of the
overall Pd/Ag mediated C-H arylation of (arene)-Cr(CO)3 com-
plexes with iodoarenes. Furthermore, deuteration studies suggest
that the role of Ag(I)-salts in C-H activation should be considered
in many other Pd/Ag mediated C-H functionalization reactions.
From a practical point of view, the observation of zero order
kinetics on the Pd-catalyst at PPh3 saturation conditions suggests
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (c) Hull, K. L.; Sanford,
Scheme 5. Ag(I)-catalyzed H/D exchange experiments on
arenes
M. S. J. Am. Chem. Soc. 2007, 129, 11904. (d) Stuart, D. R.; Villemure,
E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (e) Inamoto, K.;
Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931.
(f) Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506. (g) He, C.-Y.;
Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. (f) René, O.;
Fagnou, K. Org. Lett. 2010, 12, 2116. (h) Ano, Y.; Tobisu, M.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 12984. (i) Leow, D.; Li, G.; Mei, T.-S.;
Yu, J.-Q. Nature 2012, 486, 518. (j) Ozaki, K.; Zhang, H.; Ito, H.; Lei, A.;
Itami, K. Chem. Sci. 2013, 4, 3416. (k) Strambeanu, I. I.; White, M. C. J.
Am. Chem. Soc. 2013, 135, 12032. (l) Luo, J.; Preciado, S.; Larrosa, I. J.
Am. Chem. Soc. 2014, 136, 4109.
1
2
3
4
5
6
7
8
9
(10) Arroniz, C.; Denis, J. G.; Ironmonger, A.; Rassias, G.; Larrosa, I.
Chem. Sci. 2014, 5, 3509.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Tang, S.; Yu, H.; You, W.; Guo, Q. Chinese J. Chem. Phys. 2013,
26, 415
(12) H/D exchange on pentafluorobenzene mediated by Ag2O + PivOH
at 120 °C has been reported before. However, no control experiments
were carried out with other bases such as K2CO3. See: He, C.; Min, Q.;
Zhang, X. Organometallics 2012, 31, 1335.
(13) (a) Yang, Y.; Cheng, G.; Liu, P.; Leow, D.; Sun, T.; Chen, P.;
Zhang, X.; Yu, J.; Wu, Y.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344.
(b) Anand, M.; Sunoj, R. B.; Schaefer, H. F. J. Am. Chem. Soc. 2014, 136,
5535.
(14) For selected publications where C–H activation by silver has been
invoked see: (q) Patrick, S. R.; Boogaerts, I. I. F.; Gaillard, S.; Slawin, A.
M. Z.; Nolan, S. P. Beilstein J. Org. Chem. 2011, 7 , 892. (b) Zhang, X.;
Liu, B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem. 2012, 77, 501. (c)
Yang, L.; Wen, Q.; Xiao, F.; Deng, G.-J. Org. Biomol. Chem. 2014, 12,
9519.
Experimental procedures and characterization data for new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org
igor.larrosa@manchester.ac.uk
jordi.bures@imperial.ac.uk
We gratefully acknowledge the European Research Council for a
Starting Grant (to I.L.), and the Imperial College Junior Research
Fellowship Scheme (to J.B.).
(15) (a) Ricci, P.; Krämer, K.; Cambeiro, X. C.; Larrosa, I. J. Am.
Chem. Soc. 2013, 135, 13258. (b) Ricci, P.; Krämer, K.; Larrosa, I. J. Am.
Chem. Soc. 2014, 136, 18082.
(16) See Table 1 and page S2 in ref. 12a.
(17) Monomeric and dimeric RCO2Ag(PR3) complexes have been re-
ported before. See: (a) Ng, S. W.; Othman, a. H. Acta Crystallogr. Sect. C
Cryst. Struct. Commun. 1997, 53 (10), 1396. (b) Paramonov, S. E.;
Kuzmina, N. P.; Troyanov, S. I. Polyhedron 2003, 22 (6), 837. (c) Par-
tyka, D. V; Deligonul, N. Inorg. Chem. 2009, 48 (19), 9463.
(18) (a) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302. (b)
Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.;
Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71, 4711.
(c) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J.-Q.; Blackmond, D. G. J.
Am. Chem. Soc. 2012, 314, 4600.
(1) For reviews on C-H functionalization reactions, see: (a) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Ackermann,
L.; Vicente, R.; Kapdi, A. Angew. Chemie Int. Ed. 2009, 48, 9792. (c)
Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (d) C-H Bond
Activation and Catalytic Functionalization I; Dixneuf, P. H.; Doucet, H.,
Eds.; Topics in Organometallic Chemistry; Springer International Publish-
ing: Cham, 2016; Vol. 55. (e) Hartwig, J. F. J. Am. Chem. Soc. 2016, 138,
2.
(2) For recent reviews of Pd-catalyzed C-H activation of arenes, see:
(a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed.
Engl. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem. Int. Ed. Engl. 2009, 48, 5094. (d) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. Engl. 2012, 51,
10236.
(19) Burés, J. Angew. Chem., Int. Ed. 2016, 55, 2028.
(20) See supporting information.
(21) (a) Pandy, R. N.; Henry, P. M. Can. J. Chem. 1975, 53, 2223. (b)
Tanaka, Y.; Takahara, J. P.; Lempers, H. E. B. Org. Process Res. Dev.
2009, 13, 548. (c) Yayla, H. G.; Peng, F.; Mangion, I. K.; McLaughlin,
M.; Campeau, L.-C.; Davies, I. W.; DiRocco, D. A.; Knowles, R. R.
Chem. Sci. 2016, 7, 2066.
(22) This result would also be compatible with C-H activation by
K2CO3 or KO2CAd. We have discounted this hypothesis since we ob-
served no deuteration in the absence of Ag(I)-salt.
(23) For a reaction with a dimerization off-cycle equilibrium the order
on these species must be in the range 0.5 to 1. See ref. 19 and SI for
demonstration.
(24) Hartwig has shown that “ligandless” Pd(II)-aryl species, generated
through O2-oxidation of the phosphine ligands, can carry out C-H activa-
tion in DMA at 110 °C and in the presence of a large excess of benzene.
See: Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 3308. In our
case, only decomposition of Pd-complex 5 was observed under O2 atmos-
phere.
(25) A related study by Hartwig showed that a cyclometallated Pd(II)
phosphine carboxylate complex performed the C-H activation of electron
deficient arenes, and that the arene was then transferred to a second Pd(II)
complex containing the second arene coupling partner. This process is
very unlikely to be operating here due to the observed zero order on Pd.
See: Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2012,
134, 3683.
(26) Ground state and transition state for the CMD process were calcu-
lated by DFT using Gaussian 09. B3LYP and 6-31G(d) were used for
main-group atoms, DGDZVP was used for Cr and SDD for Ag.
(27) While direct comparisons are not possible due to the use of differ-
ent basis sets, the calculated barrier is comparable to those previously
(3) For recent reviews on Ir-catalyzed C-H functionalizations, see: (a)
Choi, J.; Goldman, A. S. In Iridium Catalysis; Andersson, P. G., Ed.;
Topics in Organometallic Chemistry; Springer Berlin Heidelberg: Berlin,
Heidelberg, 2011; Vol. 34, pp. 139–168. (b) Hartwig, J. F. Acc. Chem.
Res. 2012, 45, 864.
(4) (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (b)
Cheng, C.; Hartwig, J. F. Science 2014, 343, 853.
(5) For a recent review and selected examples of Cu-catalyzed C-H ac-
tivation of arenes, see: (a) Guo, X.; Gu, D.; Wu, Z.; Zhang, W. Chem. Rev.
2015, 115, 1622. (b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 15185. (c) Phipps, R. J.; Gaunt, M. J. Science
2009, 323, 1593.
(6) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879. (b) Juliá-Hernández, F.; Simonetti, M.; Larrosa, I. Angew.
Chem. Int. Ed. Engl. 2013, 52, 11458. (c) De Sarkar, S.; Liu, W.; Ko-
zhushkov, S. I.; Ackermann, L. Adv. Synth. Catal. 2014, 356, 1461.
(7) (a) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910. (b)
de Haro, T.; Nevado, C. Synthesis, 2011, 2530. (c) Ball, L. T.; Lloyd-
Jones, G. C.; Russell, C. A. Science 2012, 337, 1644 (d) Cambeiro, X. C.;
Ahlsten, N.; Larrosa, I. J. Am. Chem. Soc. 2015, 137, 15636.
(8) (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118 (b)
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658..
(9) For selected examples, see: (a) Zaitsev, V. G.; Shabashov, D.; Dau-
gulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Yang, S.; Li, B.; Wan,
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
calculated
for
Pd-mediated
CMD
using
the
simplified
[Pd(Ph)(PMe3)(OAc)]. See ref. 8b and Gorelsky, S. I. Coord. Chem. Rev.
2013, 257, 153.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 For reviews on C-H functionalization reactions, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chemie Int. Ed. 2009, 48, 9792. (c) Wencel-Delord, J.; Glorius, F.
Nat. Chem. 2013, 5, 369. (d) C-H Bond Activation and Catalytic Functionalization I; Dixneuf, P. H.; Doucet, H., Eds.; Topics in Organometallic Chemistry; Springer International Publishing: Cham, 2016; Vol. 55. (e) Hartwig, J. F. J. Am. Chem. Soc.
2016, 138, 2.
2 For recent reviews of Pd-catalyzed C-H activation of arenes, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. Engl. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. Engl. 2009, 48, 5094. (d) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. Engl. 2012, 51, 10236.
3 For recent reviews on Ir-catalyzed C-H functionalizations, see: (a) Choi, J.; Goldman, A. S. In Iridium Catalysis; Andersson, P. G., Ed.; Topics in Organometallic Chemistry; Springer Berlin Heidelberg: Berlin, Heidelberg, 2011; Vol. 34, pp.
139–168. (b) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864.
4 (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (b) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853.
5 For a recent review and selected examples of Cu-catalyzed C-H activation of arenes, see: (a) Guo, X.; Gu, D.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115, 1622. (b) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (c)
Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593..
6 (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (b) Juliá-Hernández, F.; Simonetti, M.; Larrosa, I. Angew. Chem. Int. Ed. Engl. 2013, 52, 11458. (c) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv.
Synth. Catal. 2014, 356, 1461.
7 (a) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910. (b) de Haro, T.; Nevado, C. Synthesis, 2011, 2530. (c) Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337, 1644 (d) Cambeiro, X. C.; Ahlsten, N.; Larrosa, I. J. Am.
Chem. Soc. 2015, 137, 15636.
8 (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118 (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658..
9 For selected examples, see: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007,
129, 11904. (d) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (e) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (f) Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506. (g)
He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850. (f) René, O.; Fagnou, K. Org. Lett. 2010, 12, 2116. (h) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (i) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012,
486, 518. (j) Ozaki, K.; Zhang, H.; Ito, H.; Lei, A.; Itami, K. Chem. Sci. 2013, 4, 3416. (k) Strambeanu, I. I.; White, M. C. J. Am. Chem. Soc. 2013, 135, 12032. (l) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109.
10 Arroniz, C.; Denis, J. G.; Ironmonger, A.; Rassias, G.; Larrosa, I. Chem. Sci. 2014, 5, 3509.
11
Tang, S.; Yu, H.; You, W.; Guo, Q. Chinese J. Chem. Phys. 2013, 26, 415.
12 H/D exchange on pentafluorobenzene mediated by Ag2O + PivOH at 120 °C has been reported before. However, no control experiments were carried out with other bases such as K2CO3. See: He, C.; Min, Q.; Zhang, X. Organometallics 2012,
31, 1335.
13 (a) Yang, Y.; Cheng, G.; Liu, P.; Leow, D.; Sun, T.; Chen, P.; Zhang, X.; Yu, J.; Wu, Y.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344. (b) Anand, M.; Sunoj, R. B.; Schaefer, H. F. J. Am. Chem. Soc. 2014, 136, 5535.
14 For selected publications where C–H activation by silver has been invoked see: (a) Patrick, S. R.; Boogaerts, I. I. F.; Gaillard, S.; Slawin, A. M. Z.; Nolan, S. P. Beilstein J. Org. Chem. 2011, 7 , 892. (b) Zhang, X.; Liu, B.; Shu, X.; Gao, Y.; Lv,
H.; Zhu, J. J. Org. Chem. 2012, 77, 501. (c) Yang, L.; Wen, Q.; Xiao, F.; Deng, G.-J. Org. Biomol. Chem. 2014, 12, 9519.
15 (a) Ricci, P.; Krämer, K.; Cambeiro, X. C.; Larrosa, I. J. Am. Chem. Soc. 2013, 135, 13258. (b) Ricci, P.; Krämer, K.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 18082.
16 See Table 1 and page S2 in ref. 12a.
17
RCO2Ag(PR3) complexes have been reported before. See: (a) Ng, S. W.; Othman, a. H. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 1997, 53 (10), 1396. (b) Paramonov, S. .; Kuzmina, N. .; Troyanov, S. . Polyhedron 2003, 22, 6, 837. (c)
Partyka, D. V; Deligonul, N. Inorg. Chem. 2009, 48 (19), 9463.
18 (a) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302. (b) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.; Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71, 4711.(c) Baxter, R. D.; Sale, D.; Engle, K.
M.; Yu, J.-Q.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 314, 4600.
19 Burés, J. Angew. Chem., Int. Ed. 2016, 55, 2028.
20 See supporting information.
21 (a) Pandy, R. N.; Henry, P. M. Can. J. Chem. 1975, 53, 2223. (b) Tanaka, Y.; Takahara, J. P.; Lempers, H. E. B. Org. Process Res. Dev. 2009, 13, 548. (c) Yayla, H. G.; Peng, F.; Mangion, I. K.; McLaughlin, M.; Campeau, L.-C.; Davies, I. W.;
DiRocco, D. A.; Knowles, R. R. Chem. Sci. 2016, 7, 2066.
22 This result would also be compatible with C-H activation by K2CO3 or KO2CAd. We have discounted this hypothesis since we observed no deuteration in the absence of Ag(I)-salt.
23 For a reaction with a dimerization off-cycle equilibrium the order on these species must be in the range 0.5 to 1. See ref. 19 and SI for demonstration.
24 Hartwig has shown that “ligandless” Pd(II)-aryl species, generated through O2-oxidation of the phosphine ligands, can carry out C-H activation in DMA at 110 °C and in the presence of a large excess of benzene. See: Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 3308. In our case, only decomposition of Pd-complex 5 was observed under O2 atmosphere.
25 A related study by Hartwig showed that a cyclometallated Pd(II) phosphine carboxylate complex performed the C-H activation of electron deficient arenes, and that the arene was then transferred to a second Pd(II) complex containing the second arene coupling partner. This process is very unlikely to be operating here due to the observed zero order on Pd. See: Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F.
J. Am. Chem. Soc. 2012, 134, 3683.
26 Ground state and transition state for the CMD process were calculated by DFT using Gaussian 09. B3LYP and 6-31G(d) were used for main-group atoms, DGDZVP was used for Cr and SDD for Ag.
27 While direct comparisons are not possible due to the use of different basis sets, the calculated barrier is comparable to those previously calculated for Pd-mediated CMD systems using the simplified [Pd(Ph)(PMe3)(OAc)]. See ref. 8b and Gorelsky, S. I. Coord. Chem. Rev. 2013, 257, 153.
ACS Paragon Plus Environment