Mechanistic study of silver-catalyzed decarboxylative fluorination

Article abstract of DOI:10.1021/acs.joc.5b00826

The silver-catalyzed fluorination of aliphatic carboxylic acids by Selectfluor in acetone/water provides access to fluorinated compounds under mild and straightforward reaction conditions. Although this reaction provides efficient access to fluorinated alkanes from a pool of starting materials that are ubiquitous in nature, little is known about the details of the reaction mechanism. We report spectroscopic and kinetic studies on the role of the individual reaction components in decarboxylative fluorination. The studies presented herein provide evidence that Ag(II) is the intermediate oxidant in the reaction. In the rate-limiting step of the reaction, Ag(I)-carboxylate is oxidized to Ag(II) by Selectfluor. Substrate inhibition of the process occurs through the formation of a silver-carboxylate. Water is critical for solubilizing reaction components and ligates to Ag(I) under the reaction conditions. The use of donor ligands on Ag(I) provides evidence of oxidation to Ag(II) by Selectfluor. The use of sodium persulfate as an additive in the reaction as well as NFSI as a fluorine source further supports the generation of a Ag(II) intermediate; this data will enable the development of a more efficient set of reaction conditions for the fluorination.

Full text of DOI:10.1021/acs.joc.5b00826

Subscriber access provided by UNIV OF PITTSBURGH
Article
On the Mechanism of Silver-Catalyzed Decarboxylative Fluorination
Niki R. Patel, and Robert A Flowers
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00826 • Publication Date (Web): 30 Apr 2015
Downloaded from http://pubs.acs.org on May 4, 2015
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 30
The Journal of Organic Chemistry
1
2
3
4
On the Mechanism of Silver-Catalyzed Decarboxylative Fluorination
5
6
Niki R. Patel and Robert A. Flowers, II*
7
8
Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, United States
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
Abstract
The silverꢀcatalyzed fluorination of aliphatic carboxylic acids by Selectfluor in
acetone/water provides access to fluorinated compounds under mild and straightforward reaction
conditions. While this reaction provides efficient access to fluorinated alkanes from a pool of
starting materials that are ubiquitous in nature, little is known about the details of the reaction
mechanism. We report spectroscopic and kinetic studies on the role of the individual reaction
components in the decarboxylative fluorination. The studies presented herein provide evidence
that Ag(II) is the intermediate oxidant in the reaction. In the rateꢀlimiting step of the reaction,
Ag(I)ꢀcarboxylate is oxidized to Ag(II) by Selectfluor. Substrate inhibition of the process occurs
through the formation of a silverꢀcarboxylate. Water is critical for solubilizing reaction
components and ligates to Ag(I) under the reaction conditions. The use of donor ligands on
Ag(I) provides evidence of oxidation to Ag(II) by Selectfluor. The use of sodium persulfate as
an additive in the reaction as well as NFSI as a fluorine source, further support the generation of
a Ag(II) intermediate; data enabling the development of a more efficient set of reaction
conditions for the fluorination.
Introduction
Carbonꢀfluorine bond formation is becoming increasingly important in the synthesis of
fineꢀchemicals and pharmaceuticals.1 There has been a sharp increase in the development of
fluorination methods due to the importance of CꢀF bonds in a large number of compounds of
biological importance.2 Fluorine substitution into drugs and other compounds alters their
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
3
4
5
6
7
8
9
lipophilicity and metabolic stability, which can enhance the bioavailability and efficacy of a drug
compound.1a,3 In addition to pharmaceutical and agrochemical compounds, the presence of
fluorine is vital in polymers,4 materials,5 and for molecular positron emission tomography (PET)
imaging.6 Despite the abundance of fluorine in nature, as well as the vast utility of this functional
group, there are only a small number of naturally occurring organic compounds.7 For these
reasons, the development of facile and versatile fluorination methods is essential.
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
In recent years, significant progress has been made in the development of transition
metalꢀcatalyzed methods for the fluorination of aromatic8 and aliphatic substrates.9 In particular,
a great emphasis has been placed on the use of electrophilic fluorinating reagents in conjunction
with metal catalysts,8dꢀe,8gꢀh,9cꢀi as well as the reaction of radical intermediates with these
reagents.10 A greater understanding of metalꢀcatalyzed fluorinations would be of considerable
importance for the optimization of existing methods, expansion of substrate scope, enhancement
of chemoselectivity, as well as the development of new synthetic reactions. The recent
development of a silverꢀcatalyzed decarboxylative fluorination reaction using the electrophilic
fluorinating
reagent
1ꢀchloromethylꢀ4ꢀfluoroꢀ1,4ꢀdiazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (FꢀTEDAꢀBF4, Selectfluor®) is of particular importance due to its
procedural ease, mild reaction conditions, and extensive substrate scope.9d In addition,
carboxylic acids are ubiquitous in nature, widely available, and straightforward to synthesize. As
a consequence, there is a large pool of starting material available for conversion to CꢀF
containing compounds. It is our supposition that understanding the mechanism of this reaction
will aid synthetic chemists in the design of improved or novel protocols that proceed through
single electron oxidation.
2
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Herein we present a detailed mechanistic investigation of the silverꢀcatalyzed fluorination
of carboxylic acids to produce alkyl fluorides. We (1) determine the stability of the silver nitrate
catalyst during the course of the reaction, (2) present kinetic data describing the role of each of
the components in the reaction, providing evidence for the rateꢀdetermining step, (3) explore the
role of water as a coꢀsolvent, (4) discuss the identity of likely reaction intermediates in this
reaction, and (5) use the mechanistic information gleaned from our studies to develop an
efficient catalytic process.
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
Results and Discussion
The goal of this research was to explore the role of Ag(I) catalyst and Selectfluor in the
silverꢀcatalyzed fluorination of aliphatic carboxylic acids, a reaction recently developed by the Li
group.9d In the original report, fluorination of tertiary acid 1 proceeded in excellent yield.
Fluorination of this compound displayed selectivity of the tertiary carboxylic acid over the
primary acid moiety at room temperature.9d The reactions generally call for the use of 20 mol%
catalyst and 2 equivalents of Selectfluor in 1:1 acetone/water media (Scheme 1). After
examining a number of conditions, we found that increasing the concentration of 1 from 0.05 M
to 0.1 M enabled the reaction to proceed to completion in 2 hours. Using these synthetic reaction
conditions, kinetic studies were performed on the decarboxylative fluorination reaction of 1.
Scheme 1. Ag(I)-catalyzed fluorination of aliphatic carboxylic acid using Selectfluor
Catalyst Stability Studies. To study the mechanism of this system, we sought to first do
a thorough kinetic study of each component in the system. All kinetic studies were performed
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
under synthetically relevant conditions.11 Before beginning comprehensive studies, it was
important to determine catalyst stability during the course of the reaction. Using the reaction in
Scheme 1, we designated 1 as the limiting substrate with all other components added in excess
and extracted kinetic information by monitoring the [2] using 19F NMR and an internal standard.
(Figure 1). A significant amount of initiation was observed (approximately 600 seconds, Figure
1) in the reaction, a feature that will be discussed vide infra.
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
Under ideal conditions, at the first halfꢀlife of the reaction in Scheme 1, equivalent
amounts of 1 and Selectfluor are consumed and [AgNO3] remains constant. A second reaction
initiated at the concentrations of reaction components at the halfꢀlife of the first reaction should
follow the reaction profile of the first reaction and provide graphical overlay as long as [AgNO3]
is constant. Given the initiation period described above, reaction progress was monitored once
product formation commenced. The reaction shown in Scheme 1 was monitored under the
conditions shown in Table 1, Run 1. A second reaction was initiated at the first halfꢀlife of Run 1
(Table 1, Run 2). To do this, [1] was decreased to 0.05 M, oneꢀhalf of that in Run 1, and
[Selectfluor] was adjusted by an equivalent amount with respect to [1], decreased from 0.2 M to
0.15 M. The [AgNO3] in Run 2 was the same employed in Run 1. If [AgNO3] remained constant
during the course of the reaction, the rates of Runs 1 and 2 would be the same. If [AgNO3]
decreased as the reaction proceeded through catalyst deactivation, the rates of Runs 1 and 2
would be different and their rate profiles would not overlay. To compare the rate profiles of both
reactions on the same concentration scale, [2] was converted to [1]. When timeꢀadjusted, both
rate profiles show graphical overlay, consistent with constant [AgNO3] over the course of the
reaction (Figure 2).12 Catalyst stability during the course of the reaction suggested that AgNO3
loading could be lowered significantly. We were able to lower AgNO3 loading from 20 mol% to
4
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5 mol% to generate 2 in 90% yield by increasing concentration the concentration of 1 from 0.1
5
6
M to 0.2 M and allowing the reaction to proceed overnight.
7
8
9
0.12
0.1
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
0.08
0.06
0.04
0.02
0
0
1000
2000
3000
4000
5000
6000
7000
8000
Time (sec)
Figure 1. Growth of fluorinated product 2 over time monitored by 19F NMR
Table 1. Reaction conditions for catalyst stability studies
Run
[1] (M)
0.1
[AgNO3] (M)
0.02
[Selectfluor] (M)
Excess [Selectfluor] (M)
1 ꢀ 100%
2 ꢀ 50%
0.2
0.1
0.1
0.05
0.02
0.15
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
6
0.12
0.1
7
8
9
0.08
0.06
0.04
0.02
0
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
Run 1 (100%)
Run 2 (50%)
0
2000
4000
6000
8000
Time (sec)
Figure 2. Timeꢀadjusted profiles of [1] vs. time for Runs 1 and 2
Kinetic Order Studies. Next, the role of each substrate in the reaction was elucidated by
determining their rate orders. Kinetic orders of substrates were found by using reaction progress
kinetic analysis, in which the concentration of each substrate was varied individually to observe
its effect on the rate of reaction.11 When catalyst loading was increased from 20 mol% to 40
mol%, a firstꢀorder rate dependence was found for AgNO3. To determine the rate order of
Selectfluor, its concentration was adjusted to 0.15 M while keeping the concentration of all other
reactants constant. Decreasing [Selectfluor] resulted in a decrease of overall reaction rate, and a
first order rate dependence on Selectfluor was determined for the reaction. The order of 1 proved
to be more complex. When lowering the amount of 1 from 0.1 M to 0.075 M, an increase in
reaction rate was observed. The rate plots of each reaction were fit to straight lines, in which the
slope was equal to the rate (see Supporting Information).12a We observed an rate order of ꢀ1.5 for
1, suggesting that the substrate was inhibiting reaction progress.
Interaction of Carboxylic Acid with AgNO3. The formation of silverꢀcarboxylates is
wellꢀestablished in the literature.13 To investigate whether the inverse order found in carboxylic
6
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acids could be due to an interaction resulting in silverꢀcarboxylate formation, 1 was mixed with
silver nitrate and allowed to stir overnight, forming a solid precipitate. The precipitation is likely
a result of oligomers formed between diacid 1 and Ag(I). An FTIR spectrum of the precipitate
showed the loss of the –OH peak and shift of the carbonyl peak to lower wavenumbers,
consistent with the formation of a silverꢀcarboxylate.13 The formation of this product, along with
results found in the catalyst stability study and the inverse order found for the carboxylic acid,
are consistent with the interaction of substrate with Ag(I).
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
Kinetic studies were also performed on three other substrates to confirm the inverse order
observed for 1 was not a substrate specific effect. The substrates studied were 2,2ꢀ
dimethylbutyric acid (3a), 2,2ꢀdimethylpropanoic acid (4a), and isobutyric acid (5a), to form
products 3b, 4b, and 5b, respectively, in excellent yields (Scheme 2). In all cases, silver nitrate
and Selectfluor were first order and carboxylic acid was found to show inverse first order
dependency. The inverse orders observed for these monoꢀcarboxylic acids suggest that the order
of 1 is not a result of the presence of an additional carboxylic acid moiety, but rather is indicative
of a general phenomenon for all carboxylic acids examined in this study.
Scheme 2. Ag(I)-catalyzed fluorination of additional aliphatic carboxylic acidsa
a Yields determined by 19F NMR compared to α,α,αꢀtrifluorotoluene standard. b Reaction run for 4 h.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
8
9
Interaction of Selectfluor with AgNO3. The oxidation of Ag(I) to highꢀvalent
complexes is often the rateꢀlimiting step in silverꢀcatalyzed reactions.11f,14 To probe the role of
Selectfluor as both a fluorinating reagent as well as an oxidant, the interaction of silver nitrate
and Selectfluor was investigated by NMR. Upfield shifts of Selectfluor protons and carbons were
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
13
observed in the H and C NMR spectra, respectively, upon addition of an equivalent of silver
nitrate to Selectfluor in acetoneꢀd6/D2O. In addition, a disappearance of the NꢀF peak of
Selectfluor was observed in the 19F NMR under the same conditions. These spectroscopic results
are consistent with defluorination of Selectfluor. While the loss of the NꢀF signal was observed
19
in the F NMR, the appearance of another fluorine signal was not observed. This is consistent
with reaction between Selectfluor and silver. The resulting species may be paramagnetic (Ag2+,
d9). This could prevent observation of the product fluoride in the reaction. Attempts to
characterize the proposed highꢀvalent silver intermediate by a range of techniques including
XPS, LCꢀMS, or xꢀray crystallography were unsuccessful.
Activation Parameters. To obtain more insight into the transition state of the turnoverꢀ
limiting step of the catalytic cycle, activation parameters were obtained for the reaction of 1
o
under synthetic conditions at temperatures ranging between 23ꢀ40 C. The data were fit to the
linear form of the Eyring equation. The following activation parameters were found: ∆H‡ = 6.2 ±
0.5 kcal/mol, ∆S‡ = ꢀ51 ± 4 cal/Kꢁmol, and ∆G‡ = 21 ± 2 kcal/mol (at 23 C). The relatively
o
small enthalpy of activation (∆H‡) and the large negative entropy of activation (∆S‡) are
indicative of a highly ordered transition state.
Role of Water. In the original work of Li and coworkers, water was proposed to be
essential for reaction success.9d When the reaction was performed in neat acetone, 2 is formed in
9% yield; as shown in Scheme 1, 2 is formed in 95% yield when run in 50:50 ratio of
8
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acetone:water. To examine the impact of water on the reaction, various concentrations of water
in the reaction milieu were examined and the results are displayed in Table 2. While large
amounts of water in the medium correlated with an increase in formation of fluorinated product,
these studies showed that only a 9:1 ratio of acetone:water was necessary to produce 2 in 95%
yield. Under these conditions, solubility of the substrates is maintained. Given this finding, it is
our supposition that one role of water in the reaction is to solubilize the Selectfluor, which has
very limited solubility in acetone alone.
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
Table 2. Fluorination of 2 with increasing amounts of water
Ratio of water a
100% acetone
% Yield b
9
100% acetone + 0.1 mmol H2O
99.1/0.9 (acetone/water)
98.2/1.8 (acetone/water)
96.4/3.6 (acetone/water)
94.6/5.4 (acetone/water)
90/10 (acetone/water)
80/20 (acetone/water)
50/50 (acetone/water)
12
17
34
57
65
95
94
95
aReactions run at 0.1 M concentration of 2 bYields were determined
by 19F NMR with α,α,αꢀtrifluoromethyltoluene as a standard.
To further examine the role of water, AgNO3 was added to 9:1 solution of acetoneꢀd6:D2O
1
containing trace water. The H NMR of this solution displayed a downfield shift of the water
signal in the presence of AgNO3 compared to the spectrum in the absence of AgNO3, suggesting
that water is ligated to Ag, thus solvating the metal center (Supporting Information). Given the
critical role of water proposed by Li, these findings could allow for water to potentially be
replaced as a solvating ligand in this reaction.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
6
7
8
9
Induction Period. As previously mentioned, an induction period is observed in this
reaction. Since the oxidation of carboxylic acid substrate results in the generation of CO2 and H+
during conversion of starting material to product, the pH of the system was monitored over the
time course of the reaction (see supporting information). During the initial 600 seconds of the
reaction, the pH was found to increase from 3 to approximately 4.4. Interestingly, the time of the
pH increase correlates to the time required for initiation. Once the maximum pH is obtained, the
pH drops during the course of the reaction. In an attempt to obtain insight into the induction
period, 19F NMR was initiated at the start of the reaction. Interestingly, there is no loss of
Selectfluor observed during the induction suggesting that it is not involved in the initiation. This
leaves AgNO3 and carboxylic acid. The infrared spectroscopic experiments described above
indicate that the Ag and carboxylic acid form a Agꢀcarboxylate. We hypothesize the induction
period occurs as a result of Agꢀcarboxylate formation. In addition, the inverse order observed
for carboxylic acid is a result of an equilibrium of Agꢀcarboxylate and Ag(carboxylate)2
formation,15 in which Agꢀcarboxylate is the resting state. This point will be discussed vide infra.
Identification of Intermediates and Active Oxidant after Rate-Limiting Step.
Beyond substrate inhibition of the catalyst by carboxylic acid and the oxidation of Ag(I) by
Selectfluor, we wanted to explore the reaction mechanism after the rateꢀlimiting step. The
questions that arise are: (A) what intermediates are generated upon oxidation of Ag(I) by
Selectfluor, and (B) which of those intermediate species oxidize the carboxylic acid to generate
an alkyl radical after the rateꢀlimiting step? Based on the data obtained to this point and previous
literature reports, the mechanism likely proceeds through one of three pathways: (1) the twoꢀ
electron oxidation of Ag(I) to Ag(III) by Selectfluor, where Ag(III) oxidizes a carboxylic acid to
produce an alkyl radical,9d,9h,16 (2) single electron oxidation of Ag(I) to Ag(II) by Selectfluor to
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
10
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
also generate TEDAꢀBF4 radical cation, in which Ag(I) acts only as an initiator in the reaction
and the radical cation oxidizes the carboxylic acid, or (3) the oxidation of Ag(I) by Selectfluor to
generate Ag(II) and TEDAꢀBF4 radical cation, where Ag(II) oxidizes the carboxylic acid to
produce a radical (Scheme 3). We probed each of these hypotheses to determine the likely
intermediate and silver oxidation state in this reaction.
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
Scheme 3. Mechanistic possibilities for Ag(I)-catalyzed decarboxylation
Ag(III)-Intermediate. In the original report by the Li group, the reaction is proposed to
proceed through the oxidation of Ag(I) by Selectfluor to form Ag(III), followed by
decarboxylation of an acid to produce an alkyl radical through single electron oxidation.9d
Though Ag(III) complexes are capable of oxidizing carboxylic acids (Eo = 1.8 V, Ag3+/Ag2+),17
such complexes are known, but are typically generated under a narrow range of conditions.
Known complexes require specific ligands,18 including biguanidines,19 carbaporphyrins,20 and Nꢀ
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
heterocyclic carbenes,21 or generation under basic conditions,22 instances providing the electron
density required to stabilize Ag(III). In addition, several studies have demonstrated that
reduction of Ag(III) to Ag(I) is typically a oneꢀstep, twoꢀelectron process.23 Due to the
requirement of electron density, the lack of ligands other than TEDAꢀBF4, and acidic medium in
the present system, it is unlikely that Ag(III) is performing the oxidation of the carboxylic acid in
this reaction.
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
Ag(II) as Initiator. Several recent papers involving Selectfluor mediated fluorination
propose generation of TEDAꢀBF4 radical cation as a reaction intermediate.9g,24 In a recent paper
describing mechanistic studies of Cu(I)ꢀcatalyzed alkyl fluorination employing Selectfluor, the
Leckta group revealed the role of Cu(I) as an intiator, and TEDAꢀBF4 radical cation as the
intermediate responsible for Hꢀatom abstraction of an alkane to generate an intermediate radical
and chain propagation.9g To probe whether TEDAꢀBF4 radical cation could function as an
oxidant in this reaction, we employed triethylborane as an initiator to generate TEDAꢀBF4
radical cation in the absence of AgNO3 using a method similar to that described by Leckta.9g
When using a substoichiometric amount of triethylborane in oxygenated acetone/water, no
19
fluorination product was observed by F NMR after allowing the reaction to proceed overnight
(Scheme 4). This result suggests that TEDAꢀBF4 radical cation is likely not functioning as the
oxidant of carboxylic acid in this reaction, and that the presence of AgNO3 is critical for the
success of the decarboxylative fluorination.
Scheme 4. Decarboxylative fluorination reaction with triethylborane
12
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ag(II) intermediate. Since TEDAꢀBF4 radical cation is most likely not acting as an
oxidant responsible for conversion of the carboxylic acid to a radical, we sought to probe
whether Ag(II) could be performing the oxidation. Ag(I)ꢀpersulfate catalysis has a longꢀ
established history in the literature,14,25 in which Ag(II) is generated upon oxidation of Ag(I).14
Work performed by Kochi and coworkers in the early 1970s on the Ag(I)ꢀpersulfateꢀcatalyzed
oxidation of aliphatic carboxylic acids to produce alkyl radicals revealed that Ag(II) was the
active oxidant.14,26 Since the combination of AgNO3 and persulfate provides a rapid means for
producing Ag(II), we sought to probe the impact of persulfate on the decarboxylative
fluorination. Addition of Na2S2O8 resulted in acceleration of the reaction rate. The addition of
0.1ꢀ1.0 equivalents of Na2S2O8 (with respect to 1) to the reaction in Scheme 1 was examined.
The reaction rate was monitored by observing the appearance of 2 by 19F NMR. Exponential fits
were used to determine kobs for each reaction. In every case, the exponential fit was greater than
(R2 0.99). The reaction proceeded rapidly in the presence of Na2S2O8 and saturation was
observed at concentrations higher than 0.5 equivalents (Figure 3). To examine this further,
several other reactions were carried out by adding 0.5 equivalents of Na2S2O8.
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
0.01
0.009
0.008
0.007
0.006
0.005
0.004
0.003
0.002
0.001
0
0
0.2
0.4
0.6
0.8
1
1.2
Equiv Na2S2O8
Figure 3. Equivalent of Na2S2O8 vs. kobs for the fluorination of 1
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
5
6
7
8
9
When 0.5 equivalents of Na2S2O8 was combined with 2 equivalents of Selectfluor and 20 mol%
AgNO3, reaction time decreased from 2 hours to 15 minutes for all substrates, forming alkyl
fluorides in excellent yields (Scheme 5). The significant acceleration of rate in the
decarboxylative fluorination has led to a more efficient process, suggests that this approach may
be useful for 18F labeling.
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
Scheme 5. Decarboxylative fluorination reaction with Na2S2O8 as additive
a Yields determined by 19F NMR compared to α,α,αꢀtrifluorotoluene standard.
Since the addition of persulfate changes the system, kinetic studies were performed on
the reaction of 3a to determine the mechanistic role of persulfate in the reaction. Catalyst
stability studies showed that there was no deactivation of AgNO3 catalyst during the course of
the reaction. In addition, kinetic studies showed that AgNO3 and Na2S2O8 were consistent with a
first order dependence, and 3a and Selectfluor were zero order. The zero order observed for 3a
implies that in the presence of persulfate, Agꢀ(carboxylate)2 formation is slower than Ag(I)
oxidation by persulfate, and therefore does not result in substrate inhibition. The first order rate
dependence on silver and persulfate suggest that Ag(I) is oxidized to Ag(II) by persulfate. The
zero order dependence in Selectfluor for the reaction in Scheme 5 not only suggests that it does
not play a role before the rateꢀlimiting step, but that it is not oxidizing Ag(I) to Ag(II) under
14
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
these conditions; therefore, its role is likely that of a fluorine atom source after the alkyl radical
is produced by oxidation of the carboxylic acid by Ag(II) after the rateꢀlimiting step (Scheme 6).
The generation of Ag(II) by persulfate, along with the zeroꢀorder rate dependence on Selectfluor,
suggests that Ag(II), not TEDAꢀBF4 radical cation, is the oxidant responsible for
decarboxylation.
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
Scheme 6. Proposed catalytic cycle of Ag(I)-catalyzed fluorination using Na2S2O8 and
Selectfluor
One of the challenges with this system is that the absence of supporting ligands makes it
difficult to characterize the oxidation state of the metal. To probe the oxidation state of Ag and
gain further information on the active oxidant in this reaction, we chose to employ a strong donor
ligand with a characteristic 1H NMR signal. It was our supposition, that if Ag(II) was formed as
an intermediate upon mixing with Selectfluor, line broadening would occur, whereas if Ag(III)
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
was generated, no line broadening would occur.18,20a When an equivalent of Selectfluor was
added to a premixed equimolar combination of 2,9ꢀdimethylꢀ1,10ꢀphenanthroline and AgNO3,
3
4
5
6
7
8
9
1
significant line broadening was observed in the H NMR spectrum. Similar line broadening
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
occurred when terpyridine was employed as a donor ligand as well. These findings are
consistent with the formation of a paramagnetic (d9) Ag(II) complex (See Supporting
Information).
In the seminal work of Li, a Ag(II) fluoride is proposed as the active fluorine atom source
in the reaction as opposed to Selectfluor.9d To support this supposition, Li and coworkers heated
the combination of tertꢀbutylꢀ2ꢀethyltetradecaneperoxoate and Selectfluor in a sealed tube to 120
oC for 2 hours. When the reaction was run in acetone, a 22% yield of 3ꢀfluoropentadecane was
obtained, whereas when the reaction was run in 50:50 acetone:water, only a 4% of fluorinated
product was obtained. Based on these findings, Li proposed that fluorine atom transfer from
Selectfluor to alkyl radicals is unlikely to be involved in the Agꢀcatalyzed process. Selectfluor is
reported to be unstable in water at high temperature forming HF through reaction of the reagent
o
and water.27 To examine this, we heated Selectfluor in acetoneꢀd6:D2O to 120 C in a heated
1
tube for 2 hrs. After cooling to room temperature, a sample was removed and examined by H
NMR showing that 80% of the reagent decomposed to the defluorinated chloromethyl derivative
(See Supporting Information). This shows that the conditions of the experiment were likely not
conducive to testing whether radicals can abstract a fluorine atom from Selectfluor. In addition,
if a Ag(II)ꢀF intermediate was formed during the reaction, it can only be present in a catalytic
amount (at most). During its formation, radicals are also generated in a catalytic amount, so the
likelihood of a small amount of radical being fluorinated by a small amount of Ag(II)ꢀF in the
presence of excess Selectfluor is unlikely. Finally, there is a large body of evidence showing that
16
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
Selectfluor and similar electrophilic fluorinating reagents react with radicals to form CꢀF
bonds.10
7
8
9
The data presented to this point in the discussion are consistent with the following: 1) It
is unlikely that Ag(III) is an intermediate in the reaction, 2) Ag(II) does not act as an initiator in
the reaction, 3) the radical cation of Selectfluor does not oxidize the carboxylic acid, 4) water is
critical for solubilizing the reaction components and may ligate to Ag(I) under the reaction
conditions, 5) the addition of persulfate significantly accelerates the rate of the reaction and only
a half equivalent is required to achieve the highest rate of conversion to product, 6) the use of
donor ligands in conjunction with Ag(I) and Selectfluor provided spectroscopic evidence that
Ag(II), not Ag(III) is the intermediate in the reaction, 7) An alkyl radical is abstracting fluorine
from Selectfluor, not from a Ag(II)ꢀF intermediate.
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
If Ag(II) is the active oxidant in this reaction in the presence of persulfate, Selectfluor is
no longer required to oxidize Ag(I) to Ag(II), but should still function as a fluorine atom source.
Either the TEDAꢀBF4 radical cation produced by this process or the sulfate radical anion can turn
over (oxidize) Ag(I) to continue the catalytic cycle (Scheme 6). If this is the case, the alkyl
radical can abstract a fluorine from another NꢀF source. In the seminal report on this reaction, Li
showed that upon replacement of Selectfluor with Nꢀfluorobenzenesulfonimide (NFSI), no
reaction occurred.9d This finding is likely due to the fact that NFSI it is not a strong enough
oxidant to oxidize Ag(I) to Ag(II) (Eo = ꢀ0.78 V, NFSI; Eo = 1.98 V, Ag2+/Ag+).8a,9d,17 However,
in the presence of persulfate which can readily oxidize Ag(I), the addition of NFSI can
potentially result in alkyl fluoride formation through fluorine abstraction by the alkyl radical
formed after decarboxylation.10a,c In addition, the resulting sulfate radical anion formed after the
initial oxidation of Ag(I) by persulfate can carry out the subsequent oxidation of Ag(I) to Ag(II)
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
3
4
5
6
7
8
9
after the rateꢀlimiting step. A representation of this process is shown in Scheme 7. To test this
supposition, 1 was allowed to react with a catalytic amount of AgNO3 in the presence of 0.5
equiv Na2S2O8 and 2 equiv NFSI. After
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
Scheme 7. Proposed catalytic cycle of Ag(I)-catalyzed fluorination using NFSI and
Persulfate
19
reacting overnight, fluorinated product 2 was observed in 51% yield by F NMR (Scheme 8).
When increasing persulfate from 0.5 equiv to 1.1 equiv, yield of 2 increased to 63%. On the
basis of these findings, we propose that Ag(II) is the active oxidant in this decarboxylative
fluorination reaction.
Scheme 8. Decarboxylative fluorination reaction with NFSI and Na2S2O8
18
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Proposed Mechanism. Based on the kinetic and spectroscopic studies described above,
we propose a mechanism in which Ag(I) is oxidized to Ag(II) by Selectfluor to also generate
TEDAꢀBF4 radical cation in the rateꢀlimiting step of the reaction (Scheme 9). There is also
formation of Agꢀcarboxylate in the induction period, as well as substrate inhibition of silver
catalyst by carboxylic acid through formation of a Agꢀ(carboxylate)2 intermediate.15 Selectfluor
oxidizes the Agꢀcarboxylate and the resulting Ag(II) intermediate oxidizes the carboxylate ligand
to produce an alkyl radical. Fluorine abstraction from Selectfluor yields product and the TEDAꢀ
BF4 radical cation which can oxidize Ag(I) to Ag(II).
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
Scheme 9. Proposed catalytic cycle of Ag(I)-catalyzed fluorination using Selectfluor
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
Conclusions
5
6
7
8
The mechanistic studies described herein show the complex roles of AgNO3 and
Selectfluor in decarboxylative fluorination in acetone/water. In the turnoverꢀlimiting step of the
reaction, Ag(I)ꢀcarboxylate is oxidized to Ag(II) by Selectfluor, also generating TEDAꢀBF4
radical cation. In addition, substrate inhibition of the AgNO3 catalyst by the carboxylic acid is
proposed to occur as a result of Ag(carboxylate)2 formation. Catalyst stability enabled AgNO3
loading to be decreased significantly. Kinetic studies utilizing Na2S2O8 as an additive are
consistent with Ag(II) as the intermediate oxidant responsible for decarboxylation leading to a
radical that abstracts fluorine from an electrophilic fluorinating source. This supposition is
supported by the use of NFSI as a fluorine source in the presence of persulfate. While the
addition of persulfate enabled us to uncover the active oxidant in this reaction, it was also shown
to significantly accelerate the rate of decarboxylative fluorination leading to a more efficient
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
18
process. This suggests that this approach may be useful for F labeling. It is our supposition
that understanding the mechanism of this reaction will aid in the development of improved or
novel fluorination methods that proceed through single electron oxidation. We are currently
examining the use of this approach in other fluorinations that proceed through single electron
oxidations to produce free radical intermediates. The results of these studies will be reported in
due course.
Experimental Section
General Methods and Materials. Proton, carbon, and fluorine NMR were recorded on a 500
MHz instrument (1H: 500 MHz, 13C: 125 MHz, 19F: 470 MHz). GCꢀMS analyses were done with
a gas chromatograph with a mass selector detector. Chromatography was performed using an
automated system. Reaction products were separated using preꢀpacked silica gel columns with a
20
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
gradient elution of ethyl acetate and hexanes. The pH of the reaction was monitored using a pH
sensor and related software. AgNO3, Selectfluor, 1, 3a, 5a, BEt3 (1 M in THF), sodium
persulfate, and NFSI were purchased and used without further purification. Reagent grade
acetone and deionized water were used.
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
Synthesis of 2,2-dimethyl-3-phenylpropanoic acid (4a). To a round bottom flask equipped
with stir bar was added diisopropylamine and 30 mL dry THF under Ar. The solution was stirred
and cooled to approximately 0 oC. A solution of 2.2 M nꢀBuLi in hexanes was added over 30 min
via syringe pump and allowed to stir. Isobutyric acid was added over 10 min via syringe. The
solution was allowed to warm to room temperature and stirred for 1.5 h. The stirred solution was
o
cooled to approximately 15 C. Benzyl chloride was added over 30 min via syringe pump
o
maintaining temperature below 5 C. The resulting mixture was allowed to warm to ambient
temperature and stirred under argon overnight. The reaction mixture was partitioned between
200 mL diethyl either and 200 mL water. The aqueous layer was acidified by addition of conc.
HCl (36%, ca. 10 mL). The resulting mixture was extracted with 3 x 50 mL diethyl ether. The
combined organic phase was dried with Na2SO4, filtered and concentrated. The colorless oil was
then solidified under high vac. 1H NMR (500 MHz, CDCl3) δ (ppm): 7.29 (5H, m), 2.92 (2H, s),
1.22 (6H, s); 13C NMR (125 MHz, CDCl3) δ (ppm): 179.4, 132.5, 125.2, 123.0, 121.5, 40.8, 38.4,
19.6.
General Procedure for Synthesis of Fluorinated Products. The decarboxylative fluorination
reaction was performed in open air without the need for degassed solvents. In a vial equipped
with a magnetic stir bar was added carboxylic acid (1 mmol), Selectfluor (708 mg, 2 mmol), and
AgNO3 (34 mg, 0.2 mmol) . Acetone (5 mL) and DI water (5 mL) were added, and the mixture
was allowed to react between 2ꢀ4 h (depending on substrate). Reaction mixture was extracted
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
5
6
thrice with dichloromethane. Organic layer was dried with magnesium sulfate and concentrated
to obtain fluorinated product.
7
8
9
Due to the volatility of several of the fluorinated products, NMR spectra of products were
obtained by running the reaction in acetoned6/D2O. Upon completion of the reaction, CDCl3 was
added. The organic layer was extracted and analyzed by NMR.
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
General Procedure for Kinetic Studies. For kinetic studies, the concentration of reagents was
kept at synthetically relevant conditions. To an NMR tube, carboxylic acid and Selectfluor were
combined. To the tube was added 0.5 mL acetone and 0.5 mL of AgNO3 solution (in water), and
α,α,αꢀtrifluoromethyltoluene (10µL, internal standard). The tube was shaken and inserted into the
NMR. Reactions were monitored in situ by 19F NMR on a 470 MHz spectrometer. All reactions
o
were performed at 23 C. Peak integrations were analyzed using NMR processing software.
Concentrations at each time point were determined with respect to an internal standard.
General Procedure for IR studies. To a vial equipped with a magnetic stirrer were added 1 and
AgNO3. The reaction was allowed to react overnight, forming a small amount of precipitate. The
precipitate was isolated, washed with water, and allowed to dry under vacuum. An FTIR
spectrum was obtained.
General Procedure for Ag-Selectfluor NMR studies. To one NMR tube was added
Selectfluor, which was dissolved in 1:1 acetoneꢀd6:D2O . In a second NMR tube was added
AgNO3 (0.1 mmol) and Selectfluor (0.1 mmol), which were then dissolved in 1:1 acetoneꢀ
1
13
19
d6:D2O (0.25 mL each). The tubes were shaken and allowed to sit overnight. H, C, and F
NMR were obtained.
General Procedure for pH Studies. A pH probe was referenced with two buffer solutions of pH
4 and 7. To a vial was added 2,2ꢀdimethylgluatric acid (160.17mg, 1 mmol), AgNO3 (34 mg,
22
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
0.2mmol), and Selectfluor (708 mg, 2 mmol). The pH probe was inserted and acetone (5 mL)
and H2O (5 mL) were added. The reaction vial was then sealed. The pH of the reaction was
monitored over the course of 2 hours. The pH of acetone/water without any additives was also
monitored for 2 hours. No change in pH was observed.
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
General Procedure for Reaction with BEt3. To an NMR tube was added carboxylic acid (0.1
mmol), NFSI (63.1 mg, 0.2 mmol), and BEt3 (0.02 mmol, 1M soln in THF). Acetone (0.5 mL)
and DI water (0.5 mL) were then added. The mixture was allowed to react overnight. Product
yield was determined by 19F NMR using α,α,αꢀtrifluoromethyltoluene as an internal standard.
General Procedure for Fluorination Reaction using Sodium Persulfate. To a vial equipped
with a magnetic stir bar was added carboxylic acid (1 mmol), Selectfluor (708 mg, 2 mmol),
Na2S2O8 (119 mg, 0.05 mmol), and AgNO3 (34 mg, 0.2 mmol). Acetone (5 mL) and DI water (5
mL) were added. The mixture was allowed to react for 15 min. Reaction mixture was extracted
thrice with dichloromethane. Organic layer was dried with magnesium sulfate and concentrated
to obtain fluorinated product.
General Procedure for Fluorination Reaction using NFSI and Sodium Persulfate. To an
NMR tube was added carboxylic acid (0.1 mmol), NFSI (63.1 mg, 0.2 mmol), Na2S2O8 (11.9
mg, 0.05 mmol), and AgNO3 (3.4 mg, 0.02 mmol). Acetone (0.5 mL) and DI water (0.5 mL) was
added, and the mixture was allowed to react overnight. Product yield was determined by 19F
NMR using α,α,αꢀtrifluoromethyltoluene as an internal standard.
General Procedure for Selectfluor Heating/Decomposition Studies. A proton NMR spectrum
of Selectfluor from the commercially available bottle was obtained in CDCl3. Separately,
Selectfluor was subject to heating to 120 oC in acetoneꢀd6/D2O for 2 h in a sealed tube under the
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
1
conditions describe by Li.9d After 2 hours, an aliquot was taken and a H NMR spectrum
3
4
5
6
obtained.
7
8
9
Spectroscopic data for 2 (4-fluoro-4-methylpentanoic acid): 1H NMR (500 MHz,
CDCl3/acetoneꢀd6) δ (ppm): 2.34 (2H, m), 1.87 (2H, m), 1.26 (6H, d); 13C NMR (125 MHz,
CDCl3/acetoneꢀd6) δ (ppm): 174.7, 94.5 (d), 36.0 (d), 28.5, 21.4 (d) ; 19F NMR (470 MHz,
CDCl3/acetoneꢀd6): ꢀ135.4 (m).
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
Spectroscopic data for 3b (2-fluoro-2-methylbutane): 1H NMR (500 MHz, CDCl3/acetoneꢀd6)
13
δ (ppm): 1.55 (2H, m), 1.23 (6H, dd), 0.86 (3H, t); C NMR (125 MHz, CDCl3/acetoneꢀd6) δ
(ppm): 34.0, 25.9, 8.1 ; 19F NMR (470 MHz, CDCl3/acetoneꢀd6): ꢀ134.3 (m).
Spectroscopic data for 4b (2-fluoro-2-methylpropyl)-benzene: 1H NMR (500 MHz,
CDCl3/acetoneꢀd6) δ (ppm): 7.19 (5H, m), 2.82 (2H, d); 1.23 (6H, d); 13C NMR (125 MHz,
CDCl3/acetoneꢀd6) δ (ppm): 137.1, 130.4, 128.1, 126.5, 95.6, 94.3, 47.5, 47.4, 26.6, 26.4; 19F
NMR (470 MHz, CDCl3/acetoneꢀd6): ꢀ138.1 (m).
1
Spectroscopic data for 5b (2-fluoropropane): H NMR (500 MHz, CDCl3/acetoneꢀd6) δ
(ppm): 4.73 (1H, ds), 1.24 (6H, dd); 13C NMR (125 MHz, CDCl3/acetoneꢀd6) δ (ppm): 88.0,
22.7; 19F NMR (470 MHz, CDCl3/acetoneꢀd6): ꢀ162.9 (m).
Associated Content
Supporting Information
Experimental procedures, kinetic and spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
24
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3
4
rof2@lehigh.edu
5
6
Notes
7
8
9
The authors declare no competing financial interest.
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
Acknowledgments
The authors acknowledge partial support from the NIH (GM075960ꢀ03). NRP acknowledges
Lehigh University for the Newton and Constance Buch Research Fellowship. We thank Drs.
Lawrence Courtney and James Devery and Professor David Vicic for stimulating and fruitful
discussions. We also thank Professor Chaozhong Li of the Shanghai Institute of Organic
Chemistry for offering useful suggestions and criticisms concerning the work described in the
manuscript.
References
1. Pharmaceuticals: (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(b) Wang, J.; SánchezꢀRoselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A; Liu, H. Chem. Rev. 2014, 114, 2432–2506.
Agrochemicals (c) Jeschke, P. Chembiochem 2004, 5, 571–589.
2. (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305–321. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.
3. Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214ꢀ231.
4. Smith, D. W.; Iacono, S. T.; Boday, D. J.; Kettwick, S. C. Advances in Fluorineꢀ
Containing Polymers; ACS Symposium Series; American Chemical Society:
Washington, DC, 2013; Vol. 1106.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
3
4
5
6
7
8
9
5. (a) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati, G. Chem. Soc. Rev.
2012, 41, 31ꢀ42. (b) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J.
Chem. Soc. Rev. 2011, 40, 3496ꢀ3508.
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
6. (a) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501–1516. (b)
Miller, P.W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem. Int. Ed. 2008, 47, 8998.
7. Harper, D. B.; O’Hagan, D. Nat. Prod. Rep. 1994, 11, 123ꢀ133.
8. Reviews: (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. Engl. 2013, 52,
8214–8264. (b) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929–
2942. (c) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470–477. For examples:
(d) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135.
(e) Wang, X.; Mei, T.ꢀS.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2009, 131, 7520. (f) Watson, D.
A.; Su, M.; Teverovskiy, G.; Zhang, Y.; GarcíaꢀFortanet, J.; Kinzel, T.; Buchwald,
Stephen, L. Science 2009, 325, 1661–1665. (g) Tang, P.; Furuya, T.; Ritter, T. J. Am.
Chem. Soc. 2010, 132, 12150–12154. (h) Mazzotti, A. R.; Campbell, M. G.; Tang, P.;
Murphy, J. M.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012ꢀ14015.
9. (a) Liu, W.; Huang, X.; Cheng, M.ꢀJ.; Nielsen, R. J.; Goddard, W. A; Groves, J. T.
Science 2012, 337, 1322–1325. (b) McMurtrey, K. B.; Racowski, J. M.; Sanford. M. S.
Org. Lett. 2012, 14, 4094ꢀ4097. (c) Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.;
Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem. Int. Ed. Engl. 2012, 51, 10580–10583.
(d) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134, 10401–10404. (e)
Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. Org. Lett.
2013, 15, 1722ꢀ1724. (f) Xu. P.; Guo, S.; Wang, L.; Tang, P. Angew. Chem. Int. Ed.
2014, 53, 5955ꢀ5958. (g) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.;
26
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. J. Am. Chem. Soc. 2014, 136, 9780ꢀ9791. (h)
Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem. Soc. 2014, 136, 16439ꢀ16443. (i)
Mizuta, S.; Stenhagen, I. S. R.; Duill, M. O.; Wolstenhulme, J.; Kirjavainen, A. K.;
Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.;
Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett. 2013, 15, 2648–2651. (j) Emer, E.;
Pfeifer, L.; Brown, J. M.; Gouverneur, V. Angew. Chem. Int. Ed. 2014, 53, 4181ꢀ4185.
10. (a) RuedaꢀBecerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.;
Paquin, J.ꢀF.; Sammis, G. M. J. Am. Chem. Soc. 2012, 134, 4026–4029. (b) Barker, T. J.;
Boger, D. L. J. Am. Chem. Soc. 2012, 134, 13588. (c) Leung, J. C. T.; ChatalovaꢀSazepin,
C.; West, J. G.; RuedaꢀBecerril, M.; Paquin, J.ꢀF.; Sammis, G. M. Angew. Chem. Int. Ed.
2012, 51, 10804ꢀ10807. (d) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2015 (ASAP) DOI: 10.1021/jacs.5b02244.
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. (a) Mathew, J. S.; Klussman, M.; Iwamura, H.; Valera, F.; Futran, A.; Emanuelsson, E.
A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71, 4711. (b) Blackmond, D. G. Angew.
Chem., Int. Ed. 2005, 44, 4302. (c) Devery, J. J., III; Conrad, J. C.; MacMillan, D. W. C.;
Flowers, R. A., II. Angew. Chem., Int. Ed. 2010, 49, 6106. (d) Choquette, K. A.;
Sadasivam, D. V.; Flowers, R. A., II. J. Am. Chem. Soc. 2011, 133, 10655. (e) Gansäuer,
A.; Behlendorf, M.; Laufenberg, von, D.; Fleckhaus, A.; Kube, C.; Sadasivam, D. V.;
Flowers, R. A., II. Angew. Chem. Int. Ed. 2012, 51, 4739. (f) Patel, N. R.; Flowers, R. A.,
II. J. Am. Chem. Soc. 2013, 135, 4672.
12. (a) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J.ꢀQ.; Blackmond, D. G. J. Am. Chem. Soc.
2012, 134, 4600–4606. (b) Devery, J. J., III.; Douglas, J. J.; Nguyen, J. D.; Cole, K. P.;
Flowers, R. A., II.; Stephenson, C. R. J. Chem. Sci. 2015, 6, 537–541.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
5
6
7
8
9
13. Torroba, J.; Aynsley, J.; Tuzimoto, P. A.; Bruce, D. W. RSC Adv. 2012, 2, 12866.
14. Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92, 1651–1659.
15. (a) Chantooni, M. K.; Kolthoff, I. M. J. Phys Chem. 1973, 77, 1ꢀ7. (b) O’Hair, R. A. J.
Chem. Commun. 2002, 20ꢀ21. (c) Rohr, M. I. S.; Petersen, J.; Brunet, C.; Antoine, R.;
Broyer, M.; Dugourd, P.; BonacicꢀKoutecky, V.; O;Hair, R. A. J.; Mitric, R. J. Phys.
Chem. Lett. 2012, 3, 1197ꢀ1201.
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
16. (a) Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013, 135, 4640–4643. (b) Zhang, C.; Li,
Z.; Zhu, L.; Yu, L.; Wang, Z.; Li, C. J. Am. Chem. Soc. 2013, 135, 14082–14085. (c)
Zhu, L.; Chen, H.; Wang, Z.; Li, C. Org. Chem. Front. 2014, 1, 1299–1305.
17. CRC Handbook of Chemistry and Physics. 86th ed. CRC Press: Boca Raton, FL, 2005ꢀ
2006, 8ꢀ20.
18. Font, M.; AcunaꢀPares, F.; Parella, T.; Serra, J.; Luis, Josep, M.; LloretꢀFillol, J.; Costas,
M.; Ribas, X. Nat. Commun. 2014, 5, 4373.
19. (a) Simms, M. L.; Atwood, J.L.; Zatko, D. A. J. Chem. Soc. Chem. Comm. 1973, 2, 46.
(b) Sen, D. J. Chem. Soc. A. 1969, 1304–1305.
20. (a) Muckey, M. A.; Szczepura, L. F.; Ferrence, G. M.; Lash, T. D. Inorg. Chem. 2002,
41, 4840–4842. (b) Furuta, H.; Ogawa, T.; Uwatoko, Y.; Araki, K. Inorg. Chem. 1999,
38, 2676–2682. (c) Maeda, H.; Osuka, A.; Ishikawa, Y.; Aritome, I.; Hisaeda, Y.; Furuta,
H. Org. Lett. 2003, 5, 1293–1296.
21. Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 6877–6882.
22. Kirschenbaum, L. J.; Ambrus, J. H.; Atkinson, G. Inorg. Chem. 1973, 12, 2832ꢀ2837.
28
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
23. (a) Rush, J. D.; Kirschenbaum, L. J. Inorg. Chem. 1985, 24, 744–748. (b) Gupta, K. K.
Sen; Sanyal, A.; Ghosh, S. P. J. Chem. Soc. Dalt. Trans. 1995, 1229ꢀ1232.
24. (a) Pitts, C. R.; Ling, B.; Woltornist, R.; Liu, R.; Lectka, T. J. Org. Chem. 2014, 79,
8895–8899. (b) Kee, C. W.; Chin, K. F.; Wong, M. H.; Tan, C.ꢀH. Chem. Commun. 2014,
50, 8211ꢀ8214.
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
25. (a) Austin, P. C. J. Chem. Soc., Trans. 1911, 99, 262–266. (b) Yost, D. M. J. Am. Chem.
Soc. 1926, 48, 152–164. (c) Greenspan, F. P.; Woodburn, H. M. J. Am. Chem. Soc. 1954,
76, 6345–6349. (d) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M.
Tetrahedron 1971, 27, 3575–3579. (e) Seiple, I. B.; Su, S.; Rodriguez, R. A.;
Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
13194–13196. (f) Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Del Bel, M.;
Baran, P. S. J. Am. Chem. Soc. 2011, 133, 3292–3295.
26. Anderson, J. M.; Kochi, J. K. J. Org. Chem. 1970, 35, 986–989.
27. SelectfluorTM II ; MSDS No. 1277 [Online]; Air Products and Chemicals, Inc: Allentown,
PA, Apr 2000.
http://www.scottecatalog.com/images.nsf/Images/Selectfluor2msds/$FILE/Selectfluor2M
SDS.pdf (accessed Feb 27, 2015).
29
ACS Paragon Plus Environment