Palladium(II)-catalyzed desulfitative synthesis of aryl ketones from sodium arylsulfinates and nitriles: Scope, limitations, and mechanistic studies

Article abstract of DOI:10.1021/jo501875n

A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle. (Figure Presented).

Full text of DOI:10.1021/jo501875n

Subscriber access provided by MCGILL UNIV
Article
Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium
Arylsulfinates and Nitriles: Scope, Limitations and Mechanistic Studies
Bobo Skillinghaug, Christian Sköld, Jonas Rydfjord, Fredrik Svensson,
Malte Behrends, Jonas Savmarker, Per J. R. Sjöberg, and Mats Larhed
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501875n • Publication Date (Web): 08 Oct 2014
Downloaded from http://pubs.acs.org on October 26, 2014
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.
The Journal of Organic Chemistry 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 55
The Journal of Organic Chemistry
Full Article
1
2
3
4
5
6
7
8
9
Palladium(II)ꢀCatalyzed Desulfitative Synthesis of
Aryl Ketones from Sodium Arylsulfinates and
Nitriles: Scope, Limitations and Mechanistic
Studies
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
†
†
†
†
Bobo Skillinghaug, Christian Sköld, Jonas Rydfjord, Fredrik Svensson,
†
‡
§
#*
Malte Behrends, Jonas Sävmarker, Per J. R. Sjöberg and Mats Larhed
†
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala
Biomedical Center, Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
Beijer Laboratory, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
Department of Chemistry, Uppsala University, BMC, Boxꢀ599, SEꢀ751 23, Uppsala,
Sweden
‡
§
#
Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala Biomedical
Center, Uppsala University, P. O. Box 574, SEꢀ751 23 Uppsala, Sweden
*
Corresponding author: Mats.Larhed@orgfarm.uu.se
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Graphical abstract
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ACS Paragon Plus Environment

Page 3 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Abstract
A fast and efficient protocol for the palladium(II)ꢀcatalyzed production of aryl ketones from
sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has
been developed. The wide scope of the reaction has been demonstrated by combining 14
sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional
example illustrated that through the choice of the nitrile reactant, benzofurans are also
accessible. The reaction mechanism was investigated by electrospray ionization mass
spectrometry (ESIꢀMS) and DFT calculations. The desulfitative synthesis of aryl ketones
from nitriles was also compared to the corresponding transformation starting from benzoic
acids. Comparison of the energy profiles indicates that the free energy requirement for
decarboxylation of 2,6ꢀdimethoxybenzoic acid and especially benzoic acid are higher than the
corresponding desulfitative process for generating the key aryl palladium intermediate. The
detected palladium(II) intermediates and the DFT calculations provide a detailed
understanding of the catalytic cycle.
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
Keywords: palladium, catalysis, desulfination, arylsulfinates, aryl ketones, microwave, ESI-
MS, density functional theory, mechanism
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Introduction
The aryl palladium precursor of choice for palladium(II)ꢀcatalyzed reactions has long been
aryl boronic acids since these are widely commercially available, tolerate a broad variety of
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
functional groups and are relatively nonꢀtoxic. However, the shelf life of aryl boronic acids is
limited as trimeric cyclic anhydrides are formed and many boronic acids are not easy to
2
handle due to their waxy appearance. Thus, different alternative aryl boron derivatives such
2
3
as aryl trifluoroborates and aryl MIDA esters have been investigated as improved and more
stable arylating agents.
Throughout the years we have investigated various aryl palladium precursors such as aryl
4,5
2,6
boronic acids , aryltrifluoroborates and more recently benzoic acids for Pd(II)ꢀcatalyzed
7
8
9
Heck arylations , synthesis of aryl amidines and aryl ketones . Although aryl carboxylic
acids may undergo decarboxylation to form an aryl palladium complex, the use of aryl
carboxylic acids for palladiumꢀcatalyzed decarboxylative coupling reactions is limited to
electron rich, sterically congested ortho substituted substrates or the use of a Cu
8,10,11
decarboxylative coꢀcatalyst.
The limitations of Pd(II)ꢀcatalyzed decarboxylative coupling
reactions prompted us to investigate alternative aryl palladium precursors. Based on a
1
2
literature report by Garves and preliminary DFT calculations we hypothesized that
arylsulfinic acids could be used as aryl palladium precursors through the loss of SO
the requirement of activating ortho substituents. The carbopalladation of nitriles by aryl
2
without
1
3–19
palladium complexes has been effected by employing different arylating agents
interesting route to aryl ketones. Thus, we initiated a preparative investigation and
communicated our initial findings concerning the use of sodium arylsulfinates and nitriles for
and is an
20
21
22
the Pd(II)ꢀcatalyzed synthesis of aryl ketones simultaneously as Wang and Deng .
After these initial reports sodium arylsulfinates have proven to be useful for different types
23
of reactions, ranging from the production of biaryls through homocoupling to the synthesis
4
ACS Paragon Plus Environment

Page 5 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
4
of caffeine analogues . Other examples of Pdꢀcatalyzed synthesis of biaryls using
25–27
28
arylsulfinates include coupling with aryl halides
or aryl triflates in addition to Hiyamaꢀ
29
type crossꢀcoupling reactions .
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
3
0–33
Desulfitative Heck type reactions have been developed
. Using different protocols
34,35
conjugate addition could be achieved instead
. Also, desulfitative hydroarylation has been
effected using sodium arylsulfinates as arylating agents in the presence of diarylacetylenes to
36
yield trisubstituted alkenes .
Recently, Pdꢀcatalyzed desulfitative arylation through CꢀHꢀactivation of heteroarenes such
3
7,38
39,40
as azoles
and indoles
has attracted notable attention. Also, CꢀH activation of electron
41
poor polyfluoroarenes and coupling with sodium arylsulfinates has been reported.
We have focused our efforts in investigating and optimizing the Pd(II)ꢀcatalyzed
desulfitative synthesis of aryl ketones. This functionality is a common functional group in
42–44
45–47
pharmaceuticals
and natural products
, and the introduction of a ketone functionality
also opens up for a range of subsequent reactions in multiꢀstep synthesis.
Herein, we report the mechanistic investigation and the scope of the microwave (MW)
assisted synthesis of aryl ketones by Pd(II)ꢀcatalyzed addition of sodium arylsulfinates to
organic nitriles and subsequent hydrolysis.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Results and discussion
Initial DFT investigation of arylsulfinates as arylating agents
Previous calculations of Pd(II)ꢀmediated decarboxylation of benzoic acid analogues have
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
shown that the
πꢀsystems of the carboxyl group and aryl group are approximately orthogonal
11,48,49
in the transition state (TS).
Thus, the energy required to reach the TS will include the
energy required to disrupt the stabilization obtained from the aryl–carboxyl conjugated
system. The sterical hindrance provided by ortho substituents in benzoic acid analogues
should hinder this stabilization and thus lower the required energy to reach the TS. In fact,
ortho substituents in benzoic acid analogues, such as 2,6ꢀdimethoxybenzoic acid, are a
prerequisite for productive reactions relying on Pd(II)ꢀmediated decarboxylation. We
hypothesized that arylsulfinic acids could be utilized as analogous aryl acids in the reaction
and thus avoid the strong stabilization from the aryl–carboxyl interaction, even without ortho
substituents. In order to investigate the difference in stabilization energy from the interaction
between the aryl group and the acidic group in benzenesulfinic acid (the corresponding acid
of 1e), benzoic acid, and 2,6ꢀdimethoxybenzoic acid the energy requirements for dihedral
angle rotation of the acidic groups in the aryl acids were investigated using DFT calculations.
The results of the calculations are presented in Figure 1.
6
ACS Paragon Plus Environment

Page 7 of 55
The Journal of Organic Chemistry
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
Figure 1. Energy diagram of the dihedral angle scan of benzenesulfinic acid, benzoic acid and
2,6ꢀdimethoxybenzoic acid.
From the dihedral scans it is clear that there is a substantial difference in energy
stabilization between the investigated aryl acids. In benzoic acid the lowest energy is obtained
when the phenyl ring and the carboxyl group are coplanar and the maximum energy is
reached when the groups are orthogonal. On the contrary, for 2,6ꢀdimethoxybenzoic acid the
coplanar geometry is the energy maximum while the orthogonal geometry is the energy
minimum in the calculations, as a consequence of the steric hindrance from the two ortho-
methoxy substituents. In line with the discussion above regarding the geometry of the
activated complex at the TS for decarboxylation the ortho substituents are clearly lowering
the required energy in Pd(II)ꢀmediated decarboxylation. The trigonal pyramidal geometry of
the sulfinic acid moiety makes a direct dihedral angle comparison to the trigonal planar
carboxylic acid moiety difficult. The calculated energy maximum for benzenesulfinic acid
occurs when the SO bond is orthogonal to the phenyl. However the energy requirement for
the dihedral angle rotation is substantially lower for benzenesulfinic acid with a maximum
ꢀ1
ꢀ1
energy requirement of 17 kJ mol compared to 30 kJ mol for benzoic acid. Because of the
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
lower energy requirement to arrange a suitable geometry in the activated complex towards the
TS, benzenesulfinic acid may be a more productive aryl source compared to benzoic acid.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
ACS Paragon Plus Environment

Page 9 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Optimization of reaction conditions
The starting point for optimizing the conditions for the desulfitative addition of 4ꢀ
methylbenzenesulfinate (1a) to acetonitrile (2a) was the protocol previously developed for
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
Pd(II)ꢀcatalyzed decarboxylative addition to nitriles. This protocol proved inefficient for the
transformation and only traces of the desired product 4aa was observed. Thus, the catalyst
loading was increased to 8% (12% ligand), the excess of the nitrile reactant was decreased to
5
equiv, the amount of water was increased, THF was used as a cosolvent and TFA was added
to effect in situ hydrolysis of the intermediate ketimine (see Table 1). The stoichiometry of
TFA proved to be crucial – the use of 1 equiv furnished 19% (entry 2) while increasing the
amount to 10 equiv yielded 87% of the desired aryl ketone 4aa (entry 4). Increasing the
amount of TFA further did not improve the yield of 4aa (entry 5).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Preparation of aryl ketone 4aa by palladium(II)-catalyzed desulfitative reaction
between 1a and 2a using varying amounts of TFA.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry
Amount of TFA
0 equiv
Yield
Traces
19%
b
1
2
3
4
5
1 equiv
5 equiv
72%
10 equiv
20 equiv
87%
83%
a
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged with
a (0.5 mmol), Pd(O CCF (0.04 mmol, 8%), 3a (0.06 mmol, 12%), H O/THF: 1/1 (1.4
1
2
3
)
2
2
mL), 2a (2.5 mmol, 5 equiv) and the specified amount of TFA. The sealed vial was heated in
b
a MW reactor at 100 °C for 1 h. According to GCMS.
Different solvents were screened and the solvent system with equal amounts of water and
tetrahydrofuran (THF) proved to be the most suitable for the reaction. However, the use of the
corresponding water/1,4ꢀdioxane system resulted in similar yield, see Table 2 (entries 4 and
5). More polar solvents seemed to favor the reaction. The use of neat water as the solvent
resulted in excessive hydrolysis of nitrile 2a under these conditions (analysis by LCMS
showed significant formation of the corresponding amide).
10
ACS Paragon Plus Environment

Page 11 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 2. Preparation of aryl ketone 3aa by palladium(II)-catalyzed desulfitative reaction
between 1a and 2a using different solvents.
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
a
a
Entry
Solvent
THF
Yield
39%
43%
28%
87%
77%
Entry
Solvent
Isobutanol
DMF
Yield
64%
54%
28%
17%
5%
1
2
3
4
5
6
7
Dioxane
Water
8
DME
Water/THF (1:1)
Water/Dioxane (1:1)
9
NMP
10
DMSO
a
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged
with 1a (0.5 mmol), Pd(O CCF (0.04 mmol, 8%), 3a (0.06 mmol, 12%), solvent (1.4 mL),
a (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). One equivalent of H O was added to the
reaction mixtures not using H O as solvent. The sealed vial was heated in a MW reactor at
00 °C for 1 h.
2
3 2
)
2
2
2
1
Having identified a suitable medium for the reaction, different palladium sources were
screened (see Table 3). Pd(O CCF was found to be more efficient than Pd(O CCH
compare entry 1 and 2), and as expected PdCl was not an efficient catalyst for the
2
3
)
2
2
3 2
)
(
2
transformation (entry 5). Although Pd(dba) is a palladium(0) complex the use of this
2
precatalyst provided a 32% yield of product 4aa under these conditions (entry 4). When no
palladium source was added to the reaction mixture no product formation was observed.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Preparation of aryl ketone 3aa by palladium(II)-catalyzed desulfitative reaction
between 1a and 2a using different palladium sources.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry
Preꢀcatalyst
Pd(O CCF
Pd(O CCH
Pd(OH)
Pd(dba)2
PdCl
Yield
87%
47%
47%
32%
5%
1
2
3
4
5
2
3 2
)
2
3 2
)
2
2
a
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged with
1a (0.5 mmol), the specified palladium source (0.04 mmol, 8%), 3a (0.06 mmol, 12%),
O/THF: 1/1 (1.4 mL), 2a (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed vial
H
2
was heated in a MW reactor at 100 °C for 1 h.
A number of common ligands used in transition metal catalysis were screened but only the
use of 6ꢀmethylꢀ2,2’ꢀdipyridyl (3a) as the ligand provided a satisfying yield, see Table 4. The
methyl group in 3a appears to be very important for high catalyst efficiency in the
9
corresponding decarboxylative reaction. Interestingly, the introduction of a second methyl
group drastically decreases the efficiency of the catalytic system. This difference also exists in
9
the decarboxylative coupling with nitriles but seems to be greater for sulfinates than
carboxylic acids. None of the phosphine ligands that were tested proved to provide effective
catalysts for the transformation.
12
ACS Paragon Plus Environment

Page 13 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 4. Preparation of aryl ketone 3aa by palladium(II)-catalyzed desulfitative reaction
between 1a and 2a using different ligands.
Pd(O CCF )
2
3 2
O
Ligand
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
SO Na
+
MeCN
2
TFA, THF/H O, MW
2
1a
2a
4aa
a
Entry
Ligand
Yield
Entry
6
Ligand
Yield
31%
1
87%
3a
3f
2
3
39%
8%
7
8
8%
3b
3c
3g
b
n.d.
3h
Dppf
b
4
5
15%
10%
9
n.d.
3i
3d
b
DMSO
10
No ligand
Traces
3e
a
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged with
1
a (0.5 mmol), Pd(O CCF ) (0.04 mmol, 8%), ligand (0.06 mmol, 12%), H O/THF: 1/1 (1.4
2
3 2
2
mL), 2a (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed vial was heated in a
b
MW reactor at 100 °C for 1 h. According to GCMS.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Investigation of scope and limitations
A limited number of sodium arylsulfinates have previously been evaluated for the
desulfitative addition to nitriles and therefore we decided to evaluate the scope of the reaction
by allowing various sodium arylsulfinates to react with acetonitrile under the optimized
conditions. As depicted in Table 5 both electron donating aryl substituents e.g. 4ꢀmethoxy
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(entry 1) and moderately electron withdrawing substituents e.g 4ꢀchloro (entry 6) are
tolerated. Compounds containing these substituents may be converted into the corresponding
aryl ketones in good yields (79% for either sodium arylsulfinate mentioned above). Reactions
were also performed under conventional heating, but consistently resulted in lower yield
(entries 1, 5 and 6). The difference is probably due to a higher reaction temperature using the
MW reactor than using conventional heating where the thermometer measures the
50,51
temperature of the metal block, not the temperature of the reaction mixture
. The reaction
mixture is also heated in situ using the MW reactor, in contrast to conventional heating where
the walls of the reaction vessel are heated which may result in decomposition of the
52,53
catalyst
.
Interestingly, sodium 2,4,6ꢀtrimethylbenzenesulfinate (entry 11), whose analogue is a
9
reactive substrate in the decarboxylative reaction , only affords 5% yield of the desired aryl
ketone. The reactivity of arylsulfinates seems truly orthogonal to carboxylic acids as orthoꢀ
substitution hinders the reaction while unsubstituted substrates work well. It is worth
mentioning that aryl halides are tolerated as compounds containing 4ꢀchloro and 4ꢀfluoro
substituents, respectively, give satisfying yields (entry 6 and 7). This indicates that competing
Pd(0)ꢀcatalyzed processes are not a significant issue. However, moving the chloro substituent
to the meta position drastically decreases the yield of the desired aryl ketone as the reaction
results in significant biaryl formation through homocoupling of the arylsulfinate. Very
14
ACS Paragon Plus Environment

Page 15 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
electron poor aryl sulfinates provided poor yields and analysis by GCꢀMS revealed that 4ꢀ
trifluoromethylbenzenesulfinate and sodium 4ꢀnitrobenzenesulfinate are even more prone to
biaryl formation.
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
It was observed that 4ꢀacetamidobenzenesulfinate is hydrolyzed and protodesulfinated to
form aniline under the optimized conditions. However, when the amount of water was
reduced to 0.2 mL and the amount of 2a was increased to 2 mL 57% of the desired product
could be isolated (entry 4). In addition to substituted benzenesulfinates, 1ꢀ and 2ꢀ
naphthylsulfinate can successfully be employed in the synthesis of the corresponding ketones
(entry 15 and 16).
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 5. Preparation of aryl ketones by palladium(II)-catalyzed desulfitative reaction
between different sodium arylsulfinates with 2a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry
ArSO
2
Na
Product
Yield
Entry
9
ArSO
2
Na
Product
Yield
ꢀ
b
7
9% /
1
c
Not detected
3
1%
1b
4ba
1i
b
b
2
51%
87%
10
66%
1
j
4ja
1
c
4ca
4aa
b
b
3
4
1a
11
12
5%
1
k
4ka
4la
b
Traces /
b
d
12%
5
7%
1l
1
d
e
4da
b
77% /
61%
e
5
6
7
c
13
14
15
Traces
ꢀ
1
4ea
1
m
b
7
4
9% /
b
c
18%
9%
1f
4fa
1n
1o
4na
4oa
b
b
73%
71%
1g
4ga
16
ACS Paragon Plus Environment

Page 17 of 55
The Journal of Organic Chemistry
1
2
3
4
b
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
Not detected
ꢀ
16
30%
1p
4pa
1
h
a
b
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with sodium arylsulfinate (0.5 mmol), Pd(O
2
CCF
)
3 2
(0.04 mmol, 8%), 3a (0.06 mmol, 12%),
2
H O/THF: 1/1 (1.4 mL), 2a (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed vial
c
b
was heated in a MW reactor at 100 °C for 1 h. Same conditions as , except heated in a
d
b
heating block at 100 °C for 16 h. Same conditions as , except performed in 2 ml 2a with 0.2
e
ml water. According to GCMS.
Next, the scope of the nitrile coupling partner was investigated. Aliphatic, benzylic and
aromatic nitriles were allowed to react with 1a to provide the corresponding products, see
Table 6. Aromatic nitriles with electron donating groups such as 4ꢀmethoxy (entry 6) or
electron withdrawing groups such as 4ꢀacetyl (entry 10) worked well (68% and 61%,
respectively), demonstrating the wide scope of the reaction. The use of 4ꢀformyl benzonitrile
resulted in a lower yield compared to 4ꢀacetyl benzonitrile, probably because of side reactions
of the formyl group (entry 11). Again, the Pd(II)ꢀcatalyzed reaction displayed excellent
chemoselectivity as reactions with arylhalide nitriles showed no traces of homocoupling or
dehalogenation. Also, no difference in reactivity between the regioisomers of
bromobenzonitrile was observed (entries 8, 12 and 13). The product from the reaction with
the bifunctional nitrile 2,2'ꢀ(1,2ꢀphenylene)diacetonitrile (entry 5) resulted in monocoupling
under these conditions and was isolated as the enol in 31% yield. The use of the sterically
hindered ethyl 2ꢀcyanoꢀ2ꢀphenylacetate (entry 15) afforded satisfying yield of the desired
product and no hydrolysis of the ethyl ester was observed.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Preparation of aryl ketones by palladium(II)-catalyzed desulfitative reaction
between 1a with different nitriles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry
RCN
Product
Yield Entry
RCN
Product
Yield
b
b
1
87%
9
62%
2a
4aa
2
i
j
4
ai
aj
b
9
8
1% /
b
2
c
10
51%
3%
2
2
2
b
c
d
4ab
2
4
b
b
3
4
91%
87%
11
12
42%
2
k
4ac
4ak
4al
b
b
b
b
62%
2
l
4ad
b
5
31%
68%
13
70%
2e
2m
2n
4am
4an
4ao
4ae
Br
CN
b
6
7
14
15
67%
2
f
4
af
b
8
7
9% /
b
c
42%
4%
2
g
4ag
2
o
18
ACS Paragon Plus Environment

Page 19 of 55
The Journal of Organic Chemistry
1
2
3
4
b
b
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
68%
16
49%
2
h
4ap
4
ah
4ap
a
b
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged
with 1a (0.5 mmol), Pd(O CCF (0.04 mmol, 8%), 3a (0.06 mmol, 12%), H O/THF: 1/1
1.4 mL), nitrile (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed vial was heated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
)
2
2
(
c
b
in a MW reactor at 100 °C for 1 h. Same conditions as , except heated in a heating block at
1
00 °C for 16 h.
To further demonstrate the usefulness of the reaction, different heterocyclic nitriles were
investigated. The synthesis of 2ꢀarylbenzofurans by desulfitative coupling with 2ꢀ(gemꢀ
54
dibromovinyl)phenols was recently reported and as shown in Table 7 the desulfitative
coupling of sodium arylsulfinate with (2ꢀhydroxyphenyl)acetonitrile 2v could also be used to
access this class of compounds. The product 4au is formed by aryl ketone formation and
subsequent intramolecular condensation.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 7. Preparation of heteroaryl ketones and benzofuran by palladium(II)-catalyzed
desulfitative reaction between 1a with different nitriles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry
RCN
Product
Yield
b
1
67%
53%
2
q
4aq
b
b
2
3
2
r
4ar
40%
2s
4as
b
b
4
5
50%
49%
2t
4at
2
u
4au
a
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged with
1a (0.5 mmol), Pd(O CCF (0.04 mmol, 8%), 3a (0.06 mmol, 12%), H O/THF: 1/1 (1.4
2
3
)
2
2
mL), nitrile (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed vial was heated in a
MW reactor at 100 °C for 1 h.
20
ACS Paragon Plus Environment

Page 21 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The results in Table 8 illustrates that electron rich and moderately electron poor sodium
arylsulfinates can be combined with any of a number of aromatic and aliphatic nitriles to give
the corresponding aryl ketones in 51ꢀ89% yields of 4bb-4jg. Aryl ketone 4bg was synthesized
in satisfying yield by combining 4ꢀmethoxybenzene sulfinate (1b) with benzonitrile (2g)
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
(
entry 3) and could also be synthesized from benzenesulfinate (1e) and 4ꢀmethoxybenzonitrile
(2f) (entry 9). However, using the more electron rich sodium arylsulfinate resulted in higher
yield which is consistent with the trend shown in Table 5. The consistently high yields
underscore the usefulness of this swift and straightforward reaction protocol.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 8. Preparation of aryl ketones by palladium(II)-catalyzed desulfitative reaction
between different sodium arylsulfinates and nitriles.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Entry ArSO
2
Na RCN
Product
Yield Entry ArSO
2
Na RCN
Product
Yield
b
6
6 /
b
1
2
3
4
1b
2b
12
13
14
15
1c
2l
62%
c
64%
4
el
4
bb
b
7
7% /
b
1b
1b
1b
2d
2g
2h
1c
1f
1f
2m
2b
2d
58%
c
56%
4
em
4
bd
bg
b
b
7
4% /
73% /
c
c
6
5%
73%
4
4fb
b
6
6% /
b
62%
c
58%
4
bh
4
fd
b
7
7% /
b
5
6
1b
1b
2l
62%
62%
16
17
1f
1f
2g
2h
c
55%
4
bl
4fg
4fh
b
b
2m
51%
4bm
22
ACS Paragon Plus Environment

Page 23 of 55
The Journal of Organic Chemistry
1
2
3
4
5
b
b
7
1c
1c
2b
2d
89%
18
19
1f
1f
2k
2l
53%
6
7
8
9
4eb
4
fk
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
b
7
6% /
b
8
9
89%
c
2
2%
4ed
4bg
4fl
b
b
b
b
1c
1c
2f
2g
2h
62%
70%
61%
20
21
22
1f
1j
1j
2m
2b
2g
54%
66%
84%
4fm
b
1
0
1
4eg
4jb
b
1
1c
4
jg
4eh
a
b
Isolated yield, > 95% purity. Reaction conditions: A 0.5ꢀ2 mL process vial was charged
with sodium arylsulfinate (0.5 mmol), Pd(O
2
CCF
3
)
2
(0.04 mmol, 8%), 3a (0.06 mmol, 12%),
2
H O/THF: 1/1 (1.4 mL), nitrile (2.5 mmol, 5 equiv) and TFA (5 mmol, 10 equiv). The sealed
c
b
vial was heated in a MW reactor at 100 °C for 1 h. Same conditions as , except heated in a
heating block at 100 °C for 16 h.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Mechanistic investigation
Density functional theory study
In order to further study the mechanism of the Pd(II)ꢀmediated desulfitative reaction and
compare with the corresponding decarboxylative reaction we initiated a theoretical
investigation by means of DFT calculations. Particularly we were interested in a
computational understanding of the desulfination step, which has not previously been
described. In addition to benzenesulfinic acid and benzoic acid, 2,6ꢀdimethoxybenzoic acid
was also included in the investigation since this is a wellꢀknown substrate in productive
decarboxylative reactions. A 1:1 THF:water mixture was used in the experimental reaction
protocol but since solvent mixtures were not supported in the calculations, water was chosen
as the solvent for the computational study.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The calculations were initiated from complex I (see Figure 2) in which 3a is associated to
2 3 2
Pd(O CCF ) . The calculated energies in the reactions are reported relative to this complex.
For the reaction employing benzenesulfinic acid stepwise ligand exchange via dissociation of
trifluoroacetate and association of 1b (complexes II to IVa) gave the positively charged
complex IVa as the lowest found energy minimum prior to the desulfination TS. In IVa both
oxygen atoms in the sulfinic moiety are coordinated to the two vacant sites on Pd(II). In order
to proceed over TS-Ia the binding mode of benzenesulfinate is altered into complex VIa to
ꢀ
allow for an interaction between Pd(II) and the phenyl group. From complex VIa 19.3 kJ mol
1
is required to reach TS-Ia. The total energy required for the desulfination step (IVa to TS-
ꢀ1
Ia) is calculated to 46.5 kJ mol . From TS-Ia the Pd–phenyl intermediate VIIa is formed and
replacing SO with the nitrile (2a) gives complex VIIIa, which was the lowest energy
minimum found after desulfination.
2
24
ACS Paragon Plus Environment

Page 25 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Comparisons of the energy profile for desulfination of benzenesulfinic acid with
decarboxylation of benzoic acid and 2,6ꢀdimethoxybenzoic acid in Figure 2 shows that the
ꢀ1
energy required for decarboxylation of benzoic acid (117.9 kJ mol , Vb to TS-Ib) is 2.5
ꢀ1
times higher than desulfination (46.5 kJ mol , IVa to TS-Ia). It should be noted that the
lowest energy minimum found prior to TS-Ib is the neutral complex Vb and that this energy
comparison of a neutral and a cationic complex is associated with a higher degree of
computational uncertainty, compared to the case of desulfination. However, the free energy
requirement for decarboxylation of benzoic acid should still be significantly higher compared
to desulfination because of the large energy difference between them. Decarboxylation of 2,6ꢀ
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
dimethoxybenzoic acid is also higher in energy than desulfination, at 66.1 kJ mol going from
VIc to TS-Ic. The geometries of the activated complexes at the TSs for decarboxylation and
desulfination are depicted in Figure 3. Studies on desulfination and decarboxylation of methyl
acids in Cuꢀcatalyzed systems have shown the same trend with desulfination having a lower
55
free energy requirement.
Figure 2. Free energy profiles of the Pd(II)ꢀmediated desulfination and decarboxylation steps.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a)
b)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Geometry of the activated complexes for a) desulfination of benzenesulfinic acid 1e
(TS-Ia), b) decarboxylation of benzoic acid (TS-Ib). Selected bond lengths (Å) are shown.
Complex VIII constitutes the starting point for the carbopalladation step (Figure 4). We
have previously shown that the carbopalladation of cyanamides is facilitated by a high
8
electron density on the aryl group. This trend seems to be consistent also with nitriles. The
free energy requirement for carbopalladation of acetonitrile (VIII to TS-II) with phenyl was
ꢀ1
calculated to 99.1 kJ mol and the corresponding carbopalladation with 2,6ꢀdimethoxyphenyl
ꢀ1
was calculated to 81.6 kJ mol , which shows a clear advantage when using 2,6ꢀ
dimethoxybenzoic acid as substrate. For the desulfitative reaction the free energy requirement
for the backward reaction from VIII, which leads back to Va, is lower in energy compared to
the forward carbopalladation step. However, the forward reaction from VIII leads to lower
free energy and thus provides a driving force for the reaction.
From complex IX, formation of the imine and subsequent hydrolysis proceeds to give the
aryl ketone product. In the calculated model reaction the imine released after IX and ammonia
26
ACS Paragon Plus Environment

Page 27 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
formed during hydrolysis leave the catalytic cycle as neutral species. In the experimental
desulfitative protocol the added 10 equiv TFA will protonate these species but this is not
computationally investigated herein. Finally, a new aryl acid is coordinated to Pd and this
constitutes the corresponding starting point for desulfination/decarboxylation (IVa,Vb or
VIc) in the next catalytic cycle.
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
Assuming that either desulfination/decarboxylation or carbopalladation provides the highest
energy requirements in the reaction the calculations suggest that the rate determining step of
the reaction depends on which aryl acid is used. For benzoic acid, which is not a productive
reactant in the reaction investigated herein, decarboxylation is clearly the rate determining
ꢀ1
ꢀ1
step with a required energy of 117.9 kJ mol compared to 99.1 kJ mol for carbopalladation.
On the other hand, carbopalladation of the nitrile is calculated to be the rate determining step
when using either benzenesulfinic acid or 2,6ꢀdimethoxybenzoic acid with a free energy
ꢀ1
ꢀ1
ꢀ1
requirement of 99.1 kJ mol and 81.6 kJ mol , respectively, compared to 46.5 kJ mol and
ꢀ1
6
6.1 kJ mol , respectively, for desulfination and decarboxylation.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 55
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Free energy profile for carbopalladation of acetonitrile followed by product release
and hydrolysis.
Electrospray mass spectrometry (ESI-MS) study
To give further experimental insight into the reaction pathway, an electrospray ionization
mass spectrometry (ESIꢀMS) study was conducted. This soft ionization technique only gives
few fragmentation products and can be a useful tool to directly detect and study charged
56–58
reaction intermediates
. In this case, most of the proposed organometallic intermediates in
the Pd(II)ꢀcatalyzed reaction are cationic and can be directly analyzed.
The reaction of 1a and 2a with 3a as the ligand was chosen as the model reaction. The
reaction mixture was heated at 100 °C for 10 minutes and an aliquot was diluted 10 times
with 2a and was analyzed directly by ESIꢀMS. The ESIꢀMS(+) spectrum showed signals with
the characteristic isotopic pattern of singly charged monoꢀpalladium complexes and few nonꢀ
28
ACS Paragon Plus Environment

Page 29 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
palladium complexes or ions were observed (see Figure 5). The signals that showed the
isotopic pattern of palladium were further analyzed by MSꢀMS selecting the isotopic peaks
106
108
3
containing Pd and Pd and some cases further analysis in MS mode was performed to
further assign the composition of the intermediates. Neutral loss experiments, monitoring the
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
loss of 41 Da and 64 Da corresponding to the loss of acetonitrile and SO respectively, were
also performed to verify the identity of some of the proposed Pd(II) complexes.
When the ESIꢀMS experiments were carried out with 1e as the substrate the corresponding
cations were also recorded. Similarly, when the reaction was carried out using phenanthroline
(4f) as the supporting ligand, the expected m/z ratios could also be detected although the
intensities were significantly lower (see supporting information). For all the reactions studied,
the major signal in the ESIꢀMS(+) spectrum corresponded to the complex with a free
coordination site where Pd(II) supported by the ligand binds the aryl group. This observation
is likely due to formation of the complex in the mass spectrometer since the coordination
2
strength of neutral SO and nitrile ligands to Pd(II) is weak.
The identified complexes were assigned (IV-IX) based on their proposed role in the
mechanism according to the DFT study. Complexes IV and VII were found independently
during the ESIꢀMS study through different techniques (i.e., neutral loss of arylsulfinate and
2
SO , respectively) and can therefore be differentiated despite the fact that they have identical
masses. When the corresponding ESIꢀMS(ꢀ) scan was performed no anionic palladium
complexes could be detected.
29
ACS Paragon Plus Environment