Silver(I)-Catalyzed C-X, C-C, C-N, and C-O Cross-Couplings Using Aminoquinoline Directing Group via Elusive Aryl-Ag(III) Species

Article abstract of DOI:10.1021/acscatal.8b03257

Cross-coupling transformations are a powerful tool in organic synthesis. It is known that this kind of transformation undergoes 2-electron redox processes, and, for this reason, silver has been nearly forgotten as catalyst for cross-couplings because silver is mainly considered as a 1-electron redox metal. Herein, we disclose effective Ag(I)-catalyzed cross-coupling transformations using bidentate aminoquinoline as a directing group toward different nucleophiles to form C-C, C-N, and C-O bonds. DFT calculations indicate the feasible oxidative addition of L₁-I substrate via the Ag(I)/Ag(III) catalytic cycle. Furthermore, ion spectroscopy experiments suggest a highly reactive aryl-Ag(III) that in the absence of nucleophiles reacts to form an intermolecular cyclic product [5d-Ag(I)-CH₃CN], which in solution forms 5a. This work proves that silver can undergo 2-electron redox processes in cross-coupling reactions like Pd and Cu.

Full text of DOI:10.1021/acscatal.8b03257

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Silver(I)-catalyzed C-X, C-C, C-N and C-O cross couplings using
aminoquinoline directing group via elusive aryl-Ag(III) species
Lorena Capdevila, Erik Andris, Anamarija Bris, Marius Tarres,
Steven Roldán-Gómez, Jana Roithová, and Xavi Ribas
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03257 • Publication Date (Web): 01 Oct 2018
Downloaded from http://pubs.acs.org on October 1, 2018
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 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 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.
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 8
ACS Catalysis
Silver(I)-catalyzed C-X, C-C, C-N and C-O cross couplings us-
ing aminoquinoline directing group via elusive aryl-Ag(III) spe-
cies
1
2
3
4
5
6
7
8
Lorena Capdevila,1 Erik Andris,2 Anamarija Briš,2,3 Màrius Tarrés,1 Steven Roldán-Gómez,1 Jana Roithová,2,4*
Xavi Ribas1*
9
1 Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Campus de Montilivi, E-
17071 Girona, Catalonia, Spain
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
2 Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague 2, Czech Republic.
3 Ruđer Bošković Institute, Bijenička 54, 10 000 Zagreb, Croatia.
4 Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, Netherlands.
ABSTRACT: Cross-coupling transformations are a powerful tool in organic synthesis. It is known that this kind of transformations undergoes
2-electron redox processes and, for this reason, silver has been nearly forgotten as catalyst for cross-couplings since silver is mainly considered
as a 1-electron redox metal. Herein, we disclose effective Ag(I)-catalyzed cross-coupling transformations using bidentate aminoquinoline as a
directing group towards different nucleophiles to form C-C, C-N and C-O bonds. DFT calculations indicate the feasible oxidative addition of
L1-I substrate via Ag(I)/Ag(III) catalytic cycle. Furthermore, ion spectroscopy experiments suggest a highly reactive aryl-Ag(III) that in ab-
sence of nucleophiles reacts to form an intermolecular cyclic product [5d-Ag(I)-CH3CN], which in solution forms 5a. This work proves that
silver can undergo 2-electron redox processes in cross-coupling reactions like Pd and Cu.
KEYWORDS. Silver, Cross-Coupling, Two-Electron Redox Catalysis, Mass Spectrometry, Infrared Photodissociation Spectroscopy.
exchange reactions, Ullmann-type C-N and C-O couplings, and
Hurtley-type C-C couplings with active methylene nucleophiles.12-14
The implication of putative aryl-Ag(III) species has been analyzed
by helium and D2 tagging infrared photodissociation (IRPD) spec-
troscopy15-19 and will be discussed in detail.
INTRODUCTION
The vast majority of C-heteroatom cross-coupling processes are
governed by palladium (C-N, Buchwald-Hartwig) and copper
(Ullmann-type) catalysis, constructing a myriad of scaffolds useful
as pharmaceuticals, materials, etc.1-5 However, there is continuous
need to discover new synthetic tools in order to have in hand versa-
tile solutions for a given cross-coupling transformation. Silver has
been completely forgotten in its use as catalyst for cross-coupling,6-7
which typically undergoes 2-electron redox processes, since it is gen-
erally believed that Ag only shows 1-electron redox chemistry.8-9
Nevertheless, albeit scarce, there are reports showing that silver cat-
alyzes Sonogashira-type couplings10 and Ullmann-type C-N and C-
O couplings,11 although with complete lack of mechanistic under-
standing. In that respect, our group reported the unprecedented ex-
perimental evidence that 2-electron redox Ag(I)/Ag(III) catalysis
can take place if the right coordination environment is provided to
stabilize the key aryl-Ag(III) intermediate species (Scheme 1a,b,c).9
It was shown that triazamacrocylic aryl-Br substrates enforced an
ideal square-planar environment to stabilize aryl-Ag(III) species
formed through facile oxidative addition at Ag(I). Strikingly, the
aryl-Ag(III) species reacted with O- and C-nucleophiles under mild
conditions via 2-electron reductive elimination, and the whole cross-
coupling process could be engaged in a catalytic mode.
a)
10 mol% AgI
30 mol% PPh3
R1
R1
I
R2
+
R2
K2CO3 (2.0 equiv.)
DMF, 100 ˚C, 8 h
b)
10 mol% AgNO3
10 mol% DMEDA
R1
R1
N/O-Nuc
I
H(N/O)-Nuc
+
tBuOK (2.0 equiv.)
DMSO, 160 ˚C, N2, 3 - 24 h
HN-Nuc : Heterocyclic Amines, Anilines, Benzamides
HO-Nuc : Phenols, alkylic Alcohols
c)
10-20 mol% AgOTf
10-20 mol% PPh3
O/C
NH
NH
+
H(O/C)-Nuc
NH
I
HN
Nuc
CD3CN, 50 ªC, 24 h
N2, absence of light
N
N
(ClO4)2
III
NH
Ag
N
In the present work, we aim at transferring the Ag-catalyzed cross-
coupling reactions into non-cyclic aryl-halide substrates by using bi-
dentate aminoquinoline (AQ) directing group, thus exploring the
limits of the transient stabilization of the putative aryl-Ag(III) in a
non-constrained system. To that end, we used L1-I as model sub-
strate (see Figure 1) and investigated the silver catalysis for halide
HN
HO-Nuc : pNO2-phenol, pCN-phenol
HC-Nuc : malononitrile
ACS Paragon Plus Environment

ACS Catalysis
Scheme 1. a) Ag-catalyzed Sonogashira-type coupling. b) Ag-cata-
Page 2 of 8
Given that the halide-exchange catalysis proved that the activation
of aryl-I and aryl-Br was feasible via silver-catalysis, we aimed at ex-
ploring the ability of generating C-N heteroatom bonds, using ali-
phatic amines as nucleophiles, as well as imidazole and anilines (Ta-
ble 2). Under optimized conditions (DMSO as solvent and CsF as
base), couplings with cyclohexanamine and cyclopentanamine af-
forded moderate yields of the coupling products (37- 53% yield), as
depicted in Table 2. Similarly, when imidazole was used, the cou-
pling product 2c was obtained in 59% yield. We then tested para-
substituted anilines (NO2- or MeO-), and they afforded a 79% yield
of 2d (NO2) and a moderate 33% yield of 2f (OMe). The beneficial
electron-withdrawing effect of the NO2 group suggested that the un-
derlying mechanism for C-N couplings might be related to a facile
deprotonation of the N-nucleophile.
1
2
3
4
5
6
7
8
lyzed Ullmann-type C-N and C-O reaction. c) Ag-catalyzed C-O
and C-C bond forming cross-coupling reaction.9
RESULTS AND DISCUSSION
We had previously shown that well-defined aryl-Ag(III) could un-
dergo reductive elimination with different halides to effectively af-
ford the halide exchange reaction within aryl-halide triazamacrocy-
cles.9 More importantly, the system was catalytic in Ag(I) for the
aryl-iodide to aryl-Br exchange. In this work we started by analyzing
the ability of Ag(I) to catalyze the halide exchange reactions using
non-cyclic aryl-halide substrates bearing an aminoquinoline biden-
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
tate Directing Group (DG), ligands L1- X,
L2–X (X = I, Br, Cl, F;
Figure 1). This non-cyclic model substrate enforces a square-planar
coordination upon oxidative addition at Ag(I), reduces from three
to two the number of N-coordination sites compared to the
triazamacrocyclic substrates, and loses the macrocyclic effect.
Table 1. Ag-catalyzed halide exchange reactions
2+
AgI
Yield (%)a
HN
AgIII NH
NH
X
N
HN
Entry
L1-X
L1-I
nBu4NX
nBu4NCl
N
(Yield in CH3CN)
82 % (95 %) L1-Cl
20 % L1-Cl
macrocylic model
crystallographic proof (XRD)[9]
1
2b
3
Oxidative Addition
open model system
nBu4NBr
74 % (46 %) L1-Br
0 % L1-Br
O
N
O
N
4b
5c
6
AgI
H
N
N
AgIII
nBu4NF·3H2O
nBu4NCl
0 % L1-F
X
R
X
R
L1-Br
L1-Cl
78 % L1-Cl
R = H (L1-X)
Me (L2-X)
putative intermediate
7b
8
0 % L1-Cl
nBu4NI
0 % (38 %,d 50 %e) L1-I
Figure 1. Macrocyclic model9 and open model system were com-
pared in oxidative addition step.
9
NaI
0 % L1-I
a
1
Yield calculated from H-NMR of crude using trimethoxybenzene
as internal standard. b The reaction was carried out without AgOTf.c Us-
ing 10 mol% of AgF. Side reaction was observed (34 % yield of
L -
Thus, we analyzed first the viability of this halide exchange catalysis
using L1-I with nBu4NX salts (X = Cl, Br). After optimization, we
found that the catalysis was effective at 100 ºC for the coupling with
Cl and Br using 10 mol % of Ag(I)OTf (see Table 1). The catalysis
can be performed in CH3CN or DMSO solvents, affording good-to-
excellent yields. The high reaction temperatures needed to achieve
the halide exchange suggested a significantly higher energy barrier
for the oxidative addition step in L1-I than in the triazamacrocyclic
aryl-I model substrate, where the reaction was conducted at room
temperature (in agreement with DFT study, see below). When L1-
Br was used as substrate with nBu4NX salts (X = Cl, I), the Br-to-Cl
exchange was optimized in DMSO affording up to 78% yield. On the
other hand, the Br-to-I exchange could only be optimized to afford a
38% yield in CH3CN when 20 mol% of AgOTf was used as catalyst.
This could be increased up to 50% when 20 mol% of PPh3 was used
as an additive (we also observed the beneficial use of PPh3 as additive
in cross-coupling catalysis using the triazamacrocyclic aryl-I sub-
strate).9 When L1-Cl was used as substrate, no halide exchange reac-
tion occurred and L1-Cl was fully recovered, presumably due to the
unsurmountable energetic barrier for the oxidative addition under
these conditions.
1
DMSO). d Using 20 mol% of AgOTf. e Using 20 mol% of AgOTf and 20
mol% of PPh3.
Table 2. Ag-catalyzed C-N bond forming reactions
O
O
AgOTf (20 mol%)
CsF (4 equiv.)
N
N
+
HN-Nuc
(12 eq.)
H
H
DMSO, 100 ˚C, 24 h
N2, absence of light
N
N
N-Nuc
I
2a-2e
L1-I
Entry
Nuc.
Yield (%)a
53 % (51 %) 2a
0 % 2a
Conv. (%)
>99 %
5 %
1b
2c
3b
37 % (31 %) 2b
59 % (54 %) 2c
>99%
71 %
4
ACS Paragon Plus Environment

Page 3 of 8
ACS Catalysis
which consists of an initial C-C coupling and a subsequent cycliza-
5
79 % (61 %) 2d
85 % (59 %) 2e
>99%
>99 %
1
2
3
4
5
6
7
8
tion by nucleophilic attack of the amide to one of the -CN groups
(entry 1). The blank experiment did not afford 4aa (entry 2). The
same product 4aa was obtained in 90% yield in CH3CN, but some
degree of decomposition of acetonitrile to form trimeric triazine-
coupled product was observed,20 thus the solvent of choice was
DMSO for the other C-nucleophiles. When ethyl 2-cyanoacetate
was used, 48% yield of 4b was obtained (entry 3), which is the C-C
coupling product without further intramolecular reorganization. In
this case, only 9% yield of 4ba, the intramolecular cyclization prod-
uct analogous to 4aa, was obtained. On the other hand, dimethyl ma-
lonate afforded 62% yield of 4ca which corresponds to the cyclic
product formed by a nucleophilic attack of the amide to one of the
carbonyl groups (with loss of MeOH). In the case of acetylacetone
and ethyl 2-nitroacetate, the catalysis was completely ineffective.
Surprisingly, nitromethane worked well as nucleophile yielding a
59% yield of 4fa, which bears an isoindolin-1-one formed after the
loss of the nitro group. Also, 16 % of L1-DMSO is obtained (coupling
of a deprotonated DMSO solvent molecule).
6d
7b
33 % (30 %) 2f
86 %
a
1
Yield calculated from H-NMR of crude using trimethoxybenzene
as internal standard (isolated yield in parenthesis).b Side reactions were
observed: 18 % of L1-H and 19 % of L1-L1 homocoupling (entry 1), 10
% of L1-H and 18 % of L1-L1 homocoupling (entry 3), traces of L1-H and
c
9
10 % of L1-L1 homocoupling (entry 7). The reaction was carried out
without AgOTf. d Using L2-I as a substrate.
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
We then explored the silver-catalyzed aryl-O cross-couplings with
phenols bearing different para-substituents (R = H, Cl, OMe, NO2)
(Table 3). In this case, reactions were optimized in DMSO and
tBuOK as a base. Good yields were obtained for phenol (73%, 3a
)
and p-Cl-phenol (74%, 3b), whereas low yield was obtained when
electron donating p-MeO-phenol was used (38%, 3c). Surprisingly,
the reaction was completely ineffective when p-NO2-phenol was
used as nucleophile. These results suggest that deprotonation is not
a key step in the C-O coupling reaction and that a correct electronic
balance is needed to achieve the desired coupling products. We also
attempted the cross-coupling catalysis with CH3OH as nucleophile,
but only stoichiometric amounts of the desired 3e coupling product
were obtained when 10 and 20 mol% of AgOTf were used (CH3OH
as solvent and tBuOK as a base).
Table 4. Ag-catalyzed C-C bond forming reactions
O
N
N
NH2
CN
4aa
O
O
O
AgOTf (20 mol%)
tBuOK (4 equiv.)
N
H
N
N
+
HC-Nuc
(2-4 eq.)
H
N
N
DMSO, 100 ˚C, 16h
N2, absence of light
N
OH
I
Table 3. Ag-catalyzed C-O bond forming reactions
C-Nuc
MeOOC
4a-4h
4ca
L
1-I
O
O
AgOTf (20 mol%)
O
tBuOK (4 equiv.)
N
N
+
HO-Nuc
(10 eq.)
N
H
H
DMSO, 100 ˚C, 16 h
N2, absence of light
N
N
N
CH2
4fa
O-Nuc
I
3a-3d
L1-I
Entry
Nuc.
Yield (%)a
Conv.(%)
Entry
Nuc.
Yield (%)a
74 % (73 %) 3a
12 % 3a
Conv. (%)
73 %
1
74 % (71 %) 4aab
0 % 4aa
99 %
16 %
1
2c
2b
19 %
48 % (41 %) 4b
9 % 4ba
3
4d
5e
6
99 %
63 %
64 %
19 %
99 %
3
4c
5
73 % (60 %) 3b
38 % (22 %) 3c
0 % 3d
94 %
71 %
12 %
62 % 4ca
0 % 4d
6d
7d
12 % 3e
66 %
73 %
0 % 4e
21 % (13 %) 3e
7e
59 % (47 %) 4fa
a Yield calculated from 1H-NMR of crude using trimethoxybenzene as
internal standard (isolated yield in parenthesis). b The reaction was car-
ried out without AgOTf. c 32 % of L1-H. d Using 2.5 mL of MeOH instead
of DMSO, 10 mol% of AgOTf was used (entry 6).
8f
9f
20 % (15 %) 4g
0 % 4h
57 %
71 %
Finally, C-C cross-couplings were explored using activated meth-
ylene-type substrates (Hurtley-type couplings), nitromethane and
p-MeO-phenylboronic acid (Table 4). Under the optimized condi-
tions (DMSO as solvent, tBuOK as a base and 20 mol% AgOTf),
aYield calculated from 1H-NMR of crude using trimethoxybenzene as
b
internal standard (isolated yield in parenthesis). 90 % of 4aa was ob-
c
tained using CH3CN as solvent. The reaction was carried out without
AgOTf. d The reaction was carried out using DMSO-d6. e Side reactions
were observed 15 % of L1-H (entry 5) and 16 % of L1-DMSO (entry 7).
malononitrile afforded a 74% yield of the coupling product 4aa
,
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 8
-1
f The reaction was carried out using 10 equiv. of arylboronic acid at 120
ºC.
L -Ag(III)-Cl
](I) species. The
1
24.7 kcal·mol , rendering the key [
1
2
3
4
5
6
7
8
latter shows a square-pyramidal geometry with I at the apical posi-
tion (dAg-I = 3.7 Å), conforming to a d8 electronic configuration for
Ag(III) in an analogous manner as well-defined aryl-Ag(III) species
isolated in triazamacrocyclic scaffolds.9
[
L1-Ag(III)-Cl](I) under-
goes subsequent aryl-Cl reductive elimination (TS2 = 28.1 kcal·mol-
1) to obtain the final (L1-Cl)AgI compound. The barrier of 28.1
kcal·mol-1 agrees with the high temperature (100 ºC) needed for the
reaction to take place. It is noteworthy that the reverse reaction, for-
mally the aryl-Cl oxidative addition, has a larger barrier (up to 32.5
kcal·mol-1) and conforms to the unobserved halide exchange when
L1-Cl is used as substrate.
Finally, arylboronic acids were also tested due to the effective reduc-
tive elimination observed using the triazamacrocyclic aryl-Ag(III)
species.9 In the non-cyclized substrate, only 20% yield of the biaryl
C-C coupling product 4g was obtained, suggesting that transmetal-
lation and reductive elimination occurred but the system could not
enter into catalytic turnover. When p-NO2-phenylboronic acid was
used no coupling product was obtained, presumably because of the
destabilizing effect of the electronwithdrawing group over the
Ag(III) center.
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
Discarding contamination of other metals. Given the unusual two-
electron redox Ag(I)/Ag(III) reactivity, we analyzed two AgOTf
commercial samples by ICP-MS searching the content of traces of
other possibly active metals in cross-coupling reactions, specifically
Pd and Cu. No traces of Pd were found, and 0.01% content of Cu
was determined in two batches of AgOTf. We then reproduced three
of the above coupling reactions using [Cu(CH3CN)4]OTf as cata-
lyst at 0.002 mol% (the content of Cu traces when using a 20 mol%
AgOTf). No significant product yields were found (Table 5). In ad-
dition, the coupling reactions were also tested in the presence of
Cu(OTf)2, which might have a role if Ag(0) was formed in situ and
was reoxidized to Ag(I). Again, no significant yields were obtained.
Therefore, yields obtained using 0.002 mol% [Cu(CH3CN)4]OTf
or Cu(OTf)2 in the coupling catalysis tested clearly discard any sig-
nificant role of Cu, and underlines silver as the main catalyst (Table
5).
Figure 2. Gibbs energy profile of the oxidative addition and reduc-
tive elimination steps in the L1-I-to-L1-Cl halide exchange reaction.
Experimental IRPD-MS analysis of operando catalysis. Aiming for
direct experimental proof of aryl-Ag(III) active species, we applied
high resolution mass spectrometry (HRMS) and helium tagging in-
frared photodissociation (IRPD) spectroscopy to our system.16-19 In-
itial HRMS analysis at short reaction times of the reactions using L1-
Table 5. Comparison of coupling reactions catalyzed by Ag or Cu
impurities.
Yield (Conv.)
I
and stoichiometric amounts of silver salt in CH3CN (suitable sol-
Cu(OTf)a
(0.002%)
Cu(OTf)2
(0.002%)
Ag(OTf)
(20 mol%)
Entry Nuc.
1
vent for the HRMS analysis) showed significant amounts of C-N ho-
mocoupling products. This result was a good indication of aryl-I ac-
tivation but complicated the analysis. To simplify the reaction and
the ulterior analysis, we designed the oMe-L1-I (L2-I) substrate to
minimize the formation of homocoupling products by steric hin-
drance. For instance, using L2-I as a substrate and pNO2-aniline as a
53 % of 2a
(99%)
6 % of 2a
(6%)
9 % of 2a
(24%)
79 % of 2d
(99 %)
24 % of 2d
(24 %)
2
3
-
nucleophile for the silver-catalyzed C-N coupling affords 85 % of 2e
.
0 % of
/
4a 4aa
(36 %)
Focusing in the MS study, no nucleophile was added to the reaction
in order to analyze only the putative [L2-Ag(III)]+ species formed by
aryl-I oxidative addition at Ag(I). The main peak observed at m/z
494.9088 presumably corresponded to [(L2-I)Ag]+ (Figure S1).
Noteworthy, small peak at m/z 366.9987 was detected, tentatively
74 % of 4aa
(99 %)
12% of 4aa
(37 %)
aUsing [Cu(CH3CN)4]OTf.
assigned to [L2-Ag(III)]+
.
To further discard the activity of other impurities, small contents of
HOTf, a typical impurity in triflate salts, were added in a AgOTf-cat-
alyzed halide exchange reactions. The reactions in Table 1, entries 3
and 6 were repeated using 10 mol% AgOTf and HOTf (5% with re-
spect to AgOTf), and smaller yields were obtained in both cases
(55% of L1-Br and 68% of L1-Cl, respectively), discarding any bene-
ficial role of triflic acid impurities.
In order to identify the structure of the detected silver complexes, we
have recorded their IRPD spectra. It turned out that the theoretically
predicted IR spectrum of [(L2-I)Ag]+ nicely reproduced the IRPD
spectrum of the ions with m/z 495 (Figure 3).21-26 It clearly con-
firmed that the detected m/z 495 ions peak correspond to the Ag(I)
complexation to L2-I. The putative silver(III) intermediate (m/z
367) was detected as a complex with acetonitrile at softer ionization
condition (m/z 408). We assumed that acetonitrile fills in the fourth
coordination site of the silver(III) complex and therefore stabilizes
this intermediate. However, the experimental IRPD spectrum of the
ions with m/z 408 and the theoretical spectrum of the proposed [L2–
Ag(III)–(CH3CN)]+ intermediate did not agree. In particular, the
Computational insight into the mechanism of the Ag-catalyzed
cross-couplings. In order to gain insight into the role of silver in the
catalysis mechanism, DFT studies (see SI for details) were per-
formed focusing on the I-to-Cl halide exchange reaction (Figure 2).
We determined that the aryl-I oxidative addition step (TS1) lies at
ACS Paragon Plus Environment

Page 5 of 8
ACS Catalysis
theoretical spectrum of this Ag(III) complex did not contain any
The theoretical IR spectrum for the complex [5d-Ag(I)-CH3CN]+
resulting from an intramolecular cyclization conformed to the exper-
imental spectrum (Figure 4).
1
2
3
bands that could be attributed to the experimental peaks at 1110 and
2770 cm-1. The search for alternative structures resulted in finding a
series of more stable complexes with the same mass (see Figure S4).
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
Figure 3. a) Helium tagging IRPD spectra of ions with m/z 495. b) Theoretical IR spectrum (
B3LYP21-24-D3BJ25-26/6-311+g(2d,p):SDD-
(Ag,I)) of [(L2-I)-Ag(I)]+. The scaling factor was 0.98 (below 2000 cm-1) and 0.96 (above 2000 cm-1). Predicted IR intensities above 2700 cm-
1 were multiplied by 10.
Figure 4. a) D2 tagging IRPD spectra of ions with m/z 408. b) Theoretical IR spectra (B3LYP-D3BJ/6-311+g(2d,p):SDD-Ag) of [L2-Ag(III)-
CH3CN]+ and [5d-Ag(I)-CH3CN]+. The harmonic IR spectra are in black; the scaling factor was 0.98 (below 2000 cm-1) and 0.96 (above 2000
cm-1). The anharmonic IR spectra (B3LYP-D3BJ/6-311+g(2d,p):SDD-Ag) are in red and were not scaled. Predicted IR intensities above 2700
cm-1 were multiplied by 10.
The formation of [5d-Ag(I)-CH3CN]+ was rationalized as depicted
in Scheme 2. The first species formed is the coordination of Ag(I) to
the substrate (m/z 495), which undergoes oxidative addition, formal
loss of HI and coordination of one CH3CN molecule to transiently
form the sought [L2-Ag(III)-(CH3CN)]+. Since IRPD analysis dis-
carded that m/z 408 corresponded to the latter species, [5d-Ag(I)-
CH3CN]+ was formed in the gas phase as an intramolecular cycliza-
tion of the transient aryl-Ag(III) via formation of a Ag(I) complex
bearing a cationic benzenylium moiety (a theoretical energy of 17
kcal·mol-1 was calculated for this intermediate), which rapidly col-
lapses to produce [5d-Ag(I)-CH3CN]+. In solution, further proton-
Scheme 2. Suggested mechanism of the formation of [5a-(Ag(I)-
CH3CN], the experimentally observed intermediate.
shuttle
affords
[5a-Ag(I)-CH3CN]+
,
isolating
10-
methylbenzo[c][1,10]phenanthrolin-6(5H)-one (5a) as the final
organic product.
ACS Paragon Plus Environment

ACS Catalysis
To clarify whether [5d-Ag(I)-CH3CN]+ was only formed in the gas
Page 6 of 8
+
+
O
O
1
2
3
4
5
6
7
Oxidative
Addition
phase or it was also formed in the reaction mixture, we repeated the
reaction at ~0.1 g scale in order to isolate the products of the reaction
of L2-I and AgClO4 in the presence of Na2CO3. Upon optimization
(100 ºC, 24 h), analysis by HRMS of the reaction crude indicated
that a compound at m/z 261 appeared mixed with starting L2-I and
byproducts. After chromatographic purification of the 261 peak,
NMR and HRMS characterization confirmed the formation of the
intramolecular cyclization organic product (5a) (Scheme 3), which
H
N
H
N
N
AgIII
I
N
I
AgI
[(L2-I)-Ag(I)]+
[(L2-Ag(III)-I]
- HI
+ CH3CN
8
9
+
O
results from a tautomerization of tautomer of 5d
.
N
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
AgIII
N
Global mechanism. The mechanistic proposal depicted in Scheme 3
is derived from all the experimental and theoretical results disclosed
in this work. The initial step of the reaction conforms to an aryl-hal-
ide oxidative addition that converges into the key aryl-Ag(III) spe-
cies. This species is at a crossroads depending on whether the nucle-
ophile is present in the reaction mixture. If present, nucleophile co-
ordination and reductive elimination affords the desired coupling
product following a 2-electron Ag(I)/Ag(III) catalysis. If absent, the
highly reactive aryl-Ag(III) species undergoes an intramolecular cy-
clization reaction to form the experimentally characterized 10-
methylbenzo[c][1,10]phenanthrolin-6(5H)-one (5a) species.
NCCH3
+ Nuc-
intramolecular
cyclization
reaction
Nuc-
- CH3CN
O
H
N
N
AgI
NCCH3
[5d-Ag(I)-CH3CN]
N
AgIII
N
O
Nuc
in solution
+ H+
-H+/+H+
proton shuttle
+
O
H
N
AgI
N
N
N
Nuc
AgI
OH
NCCH3
[5a-Ag(I)-CH3CN]
chromatographic
purification
O
N
N
H
N
NH
Nuc
O
5a
cross coupling product
Scheme 3. Global mechanistic proposal in solution.
CONCLUSIONS
The ability of silver to undergo non-canonical 2-electron redox
Ag(I)/Ag(III) cross-coupling catalysis for C-heteroatom and C-C
bond formation has been successfully proven for a non-cyclic sub-
strate bearing an aminoquinoline bidentate DG (L1-I). Contrary to
the rigid triazamacrocyclic model firstly used to isolate a well-de-
fined aryl-Ag(III) complex, the non-cyclic L1-I supports the same
kind of intermediate species but much more reactive. Despite our at-
tempts to directly detect organometallic aryl-Ag(III) species, those
remained elusive although their existence is clearly inferred experi-
mentally and theoretically in the four kinds of cross-coupling cataly-
sis studied (halide exchange, C-N, C-O and C-C couplings), and
also in the IRPD-MS studies without nucleophile. The sharply en-
hanced reactivity of this species in non-cyclic substrates compared
to macrocyclic substrates was also observed when studying Cu(III)
intermediate species.18 We envision that this work might trigger
more research efforts on Ag-catalyzed cross-couplings, to further
ACS Paragon Plus Environment

Page 7 of 8
ACS Catalysis
evaluate its use as an actual synthetic tool in organic synthesis, com- 12.
Rovira, M.; Soler, M.; Güell, I.; Wang, M.-Z.; Gómez, L.;
1
2
3
plementary to the well-known Pd(0)/Pd(II) and Cu(I)/Cu(III).
Ribas, X., Orthogonal Discrimination among Functional Groups in
Ullmann-Type C–O and C–N Couplings. J. Org. Chem. 2016, 81,
7315-7325.
13.
Ribas, X.; Güell, I., Cu(I)/Cu(III) catalytic cycle involved
4
5
6
7
8
9
AUTHOR INFORMATION
Corresponding Author
in Ullmann-type cross-coupling reactions. Pure Appl. Chem. 2014,
86, 263-467.
14.
Hurtley Coupling Catalysis that Operates through a Well-Defined
CuI/CuIII Mechanism. ChemCatChem 2013, 5, 687-691.
15.
* jana.roithova@ru.nl
* xavi.ribas@udg.edu
Rovira, M.; Font, M.; Ribas, X., Model Csp2-Csp3
ASSOCIATED CONTENT
Jašík, J.; Gerlich, D.; Roithová, J., Two-Color Infrared
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
Supporting Information. Detailed spectroscopic characterization of all
compounds is included. Also, computational DFT data and technical
details of the IRPD experiments are included. This material is available
free of charge via the Internet at http://pubs.acs.org.
Predissociation Spectroscopy of C6H62+ Isomers Using Helium
Tagging. J. Phys. Chem. A 2015, 119, 2532-2542.
16.
Jašík, J.; Žabka, J.; Roithová, J.; Gerlich, D., Infrared
spectroscopy of trapped molecular dications below 4 K. Int. J. Mass
Spectrom. 2013, 354–355, 204-210.
ACKNOWLEDGMENT
17.
ion spectroscopy. Chem. Soc. Rev. 2012, 41, 547-559.
18. Rovira, M.; Jasikova, L.; Andris, E.; Acuna-Pares, F.; Soler,
Roithova, J., Characterization of reaction intermediates by
This work was financially supported by grants from the European Re-
search Council (Starting Grant Project ERC-2011-StG-277801 to XR
and ERC-2015-CoG-682275 (IsoMS) to JR), the Spanish MICINN
(CTQ2016-77989-P to XR), and the Catalan DIUE of the Generalitat
de Catalunya (2017SGR264). X.R. thanks ICREA for an ICREA
Acadèmia award. We thank COST Action CHAOS (CA15106) and
STR from UdG for technical support.
M.; Guell, I.; Wang, M.-Z.; Gomez, L.; Luis, J. M.; Roithova, J.;
Ribas, X., A CuI/CuIII prototypical organometallic mechanism for
the deactivation of an active pincer-like CuI catalyst in Ullmann-type
couplings. Chem. Commun. 2017, 53, 8786-8789.
19.
Roithová, J.; Gray, A.; Andris, E.; Jašík, J.; Gerlich, D.,
Helium Tagging Infrared Photodissociation Spectroscopy of
Reactive Ions. Acc. Chem. Res. 2016, 49, 223-230.
REFERENCES
20.
Zhaoxiang, D.; Wenfeng, Q.; Weijia, L.; Yadong, L.,
Cyclotrimerization of nitriles catalyzed by Li_3N. Chin. Sci. Bull.
2004, 49, 127-130.
1.
Hickman, A. J.; Sanford, M. S., High-valent
organometallic copper and palladium in catalysis. Nature 2012, 484,
177-185.
21.
The role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652.
22. Lee, C.; Yang, W.; Parr, R. G., Development of the Colle-
Becke, A. D., Density‐functional thermochemistry. III.
2.
Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.,
Rational Development of Practical Catalysts for Aromatic Carbon-
Nitrogen Bond Formation. Acc. Chem. Res. 1998, 31, 805-818.
Salvetti correlation-energy formula into a functional of the electron
density. Phys. Rev. B 1988, 37, 785-789.
3.
Hartwig, J. F., Carbon-Heteroatom Bond-Forming
23.
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H., Results
Reductive Elimination of Amines, Ethers and Sulfides. Acc. Chem.
Res. 1998, 31, 852-860.
obtained with the correlation energy density functionals of becke
and Lee, Yang and Parr. Chem. Phys. Lett. 1989, 157, 200-206.
4.
Casitas, A.; Ribas, X., The role of organometallic
24.
Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch,
copper(III) complexes in homogeneous catalysis. Chem. Sci. 2013,
4, 2301-2318.
M. J., Ab Initio Calculation of Vibrational Absorption and Circular
Dichroism Spectra Using Density Functional Force Fields. J. Phys.
Chem. 1994, 98, 11623-11627.
5.
Coupling Reactions. John Wiley & Sons, Hoboken: 2014.
6. Weibel, J.-M.; Blanc, A. l.; Pale, P., Ag-Mediated
Evano, G.; Blanchard, N., Copper-Mediated Cross-
25.
Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H., A consistent
and accurate ab initio parametrization of density functional
dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem.
Phys. 2010, 132, 154104.
Reactions: Coupling and Heterocyclization Reactions. Chem. Rev.
2008, 108, 3149-3173.
7.
Unraveling Fundamental Coinage Metal Redox Processes. In The
Privileged Pincer-Metal Platform: Coordination Chemistry
Font, M.; Ribas, X., Pincerlike Cyclic Systems for
26.
Grimme, S.; Ehrlich, S.; Goerigk, L., Effect of the damping
function in dispersion corrected density functional theory. J.
Comput. Chem. 2011, 32, 1456-1465.
&
Applications, van Koten, G.; Gossage, R. A., Eds. Springer
International Publishing: 2016; Vol. 54, pp 269-306.
8.
Oxidation with Metal Complexes. Plenum Press: New York, 1986.
9. Font, M.; Acuña-Parés, F.; Parella, T.; Serra, J.; Luis, J. M.;
Mijs, W. J.; Jong, C. R. H. I. d., Organic Synthesis by
Lloret-Fillol, J.; Costas, M.; Ribas, X., Direct observation of two-
electron Ag(I)/Ag(III) redox cycles in coupling catalysis. Nat.
Commun. 2014, 5:4373.
10.
Sonogashira Coupling Reaction. Synlett 2006, 2006, 2261-2265.
11. Das, R.; Mandal, M.; Chakraborty, D., Silver-Nitrate-
Li, P.; Wang, L., A Novel Silver Iodide Catalyzed
Catalyzed N-Arylation of Amines and O-Arylations of Phenols and
Alcohols. Asian J. Org. Chem. 2013, 2, 579-585.
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 8
TOC
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
8
ACS Paragon Plus Environment