Faster initiation in the Friedel-Crafts reaction of benzyl fluorides using trifluoroacetic acid as activator

Article abstract of DOI:10.1016/j.jfluchem.2016.08.003

We report that the addition of a catalytic amount of trifluoroacetic acid (TFA) shortens the induction period associated with the 1,1,1,3,3,3-hexafluoroisopropoanol (HFIP)-promoted Friedel-Crafts reaction of benzylic fluorides. This faster initiation is d

Full text of DOI:10.1016/j.jfluchem.2016.08.003

Accepted Manuscript
Title: Faster initiation in the Friedel-Crafts reaction of benzyl
fluorides using trifluoroacetic acid as activator
´
Author: Remy Hemelaere Pier Alexandre Champagne Justine
Desroches Jean-Franc¸ois Paquin
PII:
S0022-1139(16)30237-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.08.003
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2-8-2016
5-8-2016
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Please cite this article as: Remy Hemelaere, Pier Alexandre Champagne, Justine
Desroches, Jean-Franc¸ois Paquin, Faster initiation in the Friedel-Crafts reaction of
benzyl fluorides using trifluoroacetic acid as activator, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.08.003
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Faster initiation in the Friedel-Crafts reaction of benzyl
fluorides using trifluoroacetic acid as activator
Rémy Hemelaere, Pier Alexandre Champagne, Justine Desroches and
Jean-François Paquin*
PROTEO, CCVC, Département de chimie, Université Laval, Québec, QC, Canada G1V
0A6
* Corresponding author. Tel.: +1 418 656-2131 ext. 11430; fax: +1 418 656-7916
E-Mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin)
1

GRAPHICAL ABSTRACT - PICTOGRAM
TFA cat.
Ar-H
- reduced activation period (< 10 min)
- enables lower temperature
F
Ar
R
R
- milder conditions for R = EWG
HFIP
GRAPHICAL ABSTRACT - SYNOPSIS
ABSTRACT: We report that the addition of a catalytic amount of trifluoroacetic acid
(TFA) shortens the induction period associated with the 1,1,1,3,3,3-
hexafluoroisopropoanol (HFIP)-promoted Friedel-Crafts reaction of benzylic fluorides.
This faster initiation is due to TFA’s strong hydrogen-bond donation capability, not its
Brønsted acidity. The improved reaction conditions were applied to a set of substrates,
demonstrating how they could improve yields and reliability of this transformation.
HIGHLIGHTS



The addition of trifluoroacetic acid drastically reduces the induction period.
Lower reaction temperature is enabled.
Milder conditions for benzylic fluorides bearing an electron-withdrawing group.
ABSTRACT: We report that the addition of a catalytic amount of trifluoroacetic acid
(TFA) shortens the induction period associated with the 1,1,1,3,3,3-
hexafluoroisopropoanol (HFIP)-promoted Friedel-Crafts reaction of benzylic fluorides.
This faster initiation is due to TFA’s strong hydrogen-bond donation capability, not its
Brønsted acidity. The improved reaction conditions were applied to a set of substrates,
demonstrating how they could improve yields and reliability of this transformation.
2

KEYWORDS: C-F bond activation, Friedel-Crafts alkylation, benzyl fluorides, hydrogen-
bonding
1.
Introduction
The activation and nucleophilic substitution of C–F bonds has been an increasingly popular
field of research over the last decades [1]. This interest is at least partially fuelled by the
fundamental challenge of breaking the strongest single bond that carbon can make with
any atom [2]. Furthermore, selective cleavage of C–F bonds has potentially important
applications in the synthesis of functionalized compounds or in environmental sciences.
To enhance the breadth of available methods, we recently reported an unusual strategy
towards C–F activation, using the ability of fluorine to act as hydrogen-bond acceptor [3].
For instance, we have demonstrated that activated alkyl fluorides could undergo a
bimolecular nucleophilic substitution reaction with various nucleophiles in the presence of
water as a hydrogen-bond donor [4]. In addition, we have reported on alcohol-promoted
amination of benzylic fluorides [5] . Finally, we have described the Friedel-Crafts reaction
of benzyl fluorides (Figure 1A) [6] . While benzylic fluorides were known to be somewhat
reactive, especially in strong acidic conditions [7], their activation using hydrogen bond
donors (HBD) was unprecedented. In this reaction, 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) [8] is used both as an activator and as a polar, ionizing solvent. However, this
reaction was plagued by an induction period of about 170 minutes for typical substrates,
which could vary according to the exact nature of the benzylic fluoride employed. In order
to provide a more reliable system, we decided to explore conditions that would
systematically allow for a faster initiation period. Herein, we report that the addition of a
3

catalytic amount of trifluoroacetic acid (TFA) can efficiently serve this purpose. In
addition, this mode of activation allows the reaction to be performed, with some substrates,
in milder conditions (Figure 1B).
2.
Results and discussion
This idea originally stemmed from our mechanistic rationale for the Friedel-Crafts reaction
of benzyl fluorides using HFIP as the activator, shown in Figure 2 [6, 9]. To initiate the
whole process, HFIP forms a hydrogen-bond with benzylic fluoride 1, forming complex 2
[10]. C–F bond ionization then occurs to form strongly stabilized fluoride 3 and
carbocation 4, which upon electrophilic aromatic substitution with Ar2–H generates the
desired diarylmethane 5 and a proton. This proton eventually leads to the formation of HF,
which we realize is a stronger HBD than HFIP thus acts as the active catalyst for the next
catalytic cycles [11]. Evidence in support of this mechanistic proposal was obtained
through various experiments that demonstrated the importance and involvement of HF, as
well as by the measurement of substrate conversion as a function of reaction time, for a
typical compound under standard conditions. Indeed, this experiment revealed an
unexpected induction period of about 170 minutes and a sigmoid increase of product
concentration (c.f. Figure 3), both effects hinting at an autocatalytic reaction promoted by
the generated HF.
Therefore, considering HFIP serves to initiate the first round of C–F cleavage through its
hydrogen-bond donating capacity ( = 1,96) [12] , we hypothesized that using instead a
catalytic amount of an even stronger HBD could trigger the reaction and release HF, which
in any case should be the strongest catalyst [13]. To this end, the Friedel-Crafts reaction of
benzyl fluoride 6 with p-xylene in CH2Cl2 was investigated, without HFIP, as a co-solvent,
4

but in the presence of 5 mol % of various dry acids (Table 1). No reaction took place when
using a catalytic amount of HFIP. In this case, we hypothesize that its concentration is too
low to provide an efficient activation. Unsurprisingly, no reaction occurred when acetic
acid (AcOH) was tried. Indeed, AcOH has a  value of 1.12 [11], so is a weaker HBD than
HFIP. Chloroacetic acid provided the same result. While its  value is unknown, we expect
that it should not be much higher than AcOH. Interestingly, those results also indicate that
the Brønsted acidity of the activator is not an important factor in the initiation step (i.e., the
initiation doesn’t involve the formal protonation of the C-F bond) as AcOH and
chloroacetic acid are much more acidic than HFIP [14]. Indeed, the pKa values in H2O for
AcOH, chloroacetic acid, and HFIP are respectively 4.76, 2.86 and 9.3[7]. However, when
trifluoroacetic acid (pKa = -0.25) was used, full conversion and a 50% isolated yield of the
desired product (7) was obtained after 18 h. The  value for TFA has not been measured,
but has been calculated to be 2.38 [15]. Hence, this result confirms our idea that stronger
hydrogen-bond donors than HFIP can initiate the Friedel-Crafts reaction of benzylic
fluorides.
At that point, although it was clear that HFIP could be replaced with TFA as the activator,
we realized that HFIP does play other beneficial roles, since much better yields
were obtained using our previous conditions (i.e. with HFIP, but no TFA) [6]. This is
likely because of HFIP’s polar nature, high-ionizing power and hydrogen-bonding
stabilization of charged species, a phenomenon also observed in our XtalFluor-E
mediated Friedel-Crafts reaction of benzylic alcohols [16]. To quantify this effect, a
reaction initiated by TFA, but in the presence of HFIP was run. Fewer by-products
5

were observed resulting in very good 89% yield in only 1 h. These optimized conditions,
depicted in eq 1, were used for the rest of the study.
We next examined the 1H NMR conversion vs time of the reaction between benzyl fluoride
6 with p-xylene with and without TFA to assess the effect on the initiation period (Figure
3). This experiment revealed a dramatic reduction in the induction period from ca. 170
minutes (without TFA) to ca. 10 minutes (with 5 mol % of TFA).
With optimized and reliable conditions in hand, we then sought to evaluate the scope of
the reaction (Table 2). Using the reaction of fluoride 6 with toluene, we obtained a 89%
yield in only 1.5 h, along with a 2.5:1 para:ortho selectivity (entry 1). Interestingly, we
could also run the reaction at 0 °C, leading to a better regioselectivity, albeit a longer
reaction time was required and a significantly reduced yield was observed (entry 2). This
is nonetheless interesting since without TFA, no reaction would occur at 0 °C. Other
nucleophiles, such as naphthalene (entry 3) or benzene (entry 4) could be employed.
Electron-rich benzylic fluorides, such as 9, spontaneously decomposed under the reaction
conditions, as was observed without TFA (entry 5) [17]. Electron-poor substrates, which
required harsh conditions to react in our previous conditions [6], benefitted from the
greatest improvements. Indeed, halogenated fluorides 10-12 promptly reacted at 45 °C, in
6

the presence of catalytic TFA (entries 6-8). Those milder conditions concomitantly
furnished better isolated yields of the diarylmethanes. Overall, while limitations of this
Friedel-Crafts procedure are similar with or without TFA, the use of this additive makes
all reactions occur faster, under more gentle conditions, more reliably, and with better
yields and selectivities. This is especially true for electron-poor substrates, which are less
prone to the initial C–F cleavage to liberate the strongest catalyst HF.
In conclusion, we have reported that the addition of catalytic TFA shortens the induction
period associated with the HFIP-promoted Friedel-Crafts reaction of benzylic fluorides.
While TFA helps initiate the catalytic cycle, HF still likely is the active catalyst, and HFIP
is still required for its polar and HBD capacities. Our improved reaction conditions were
applied to a set of representative substrates, demonstrating how they could improve yields,
reliability and initiation of this transformation. Study on the exploitation of the fastest
initiation using TFA in other C–F bond activation system are underway and will be
reported in due course.
3.
Experimental
3.1
General
Solvents were purified using a Vacuum Atmospheres Inc. Solvent Purification System. All
commercially available compounds were used as received. Thin-layer chromatography
(TLC) analysis of reaction mixtures was performed using Silicycle silica gel 60 Å F254
TLC plates, and visualized under UV or by staining with potassium permanganate. Flash
column chromatography was carried out on Silicycle silica gel 60 Å, 230–400 mesh. 1H,
7

19
13C and F NMR spectra were recorded in CDCl3 at ambient temperature using Agilent
1
DD2 500 and Varian Inova 400 spectrometers. H and 13C NMR chemical shifts are
reported in ppm downfield of tetramethylsilane and are respectively referenced to
tetramethylsilane (δ = 0.00 ppm) and chloroform (δ = 77.2 ppm). For 19F NMR, CFCl3 is
used as the external standard. High-resolution mass spectra were obtained on a LC/MS–
TOF Agilent 6210 using atmospheric pressure photoionization (APPI). Infrared spectra
were recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting points
were recorded on a Stanford Research System OptiMelt capillary melting point apparatus.
Benzyl fluorides 6, 8-12 were prepared following literature protocols [6].
3.1 Time-resolved analysis of the Friedel-Crafts reaction
A solution of 6 (14 mg, 0.075 mmol, 1 equiv.) in CD2Cl2 (270 μL, 90% of the volume
required for substrate concentration of 0.25 M) was prepared, to which p-xylene (46 μL,
0.375 mmol, 5 equiv.), then HFIP (30 μL, 10% of the volume required for substrate
concentration of 0.25 M, resulting in a 9:1 CD2Cl2/HFIP mixture) were added. This
solution was left standing for 35 minutes before being transferred into a NMR tube and
placed into the NMR spectrometer. 1H spectra were recorded every 2.66 minutes for 4.5
1
hours. Each H spectrum was then analyzed to calculate the conversion of 6 into 7. The
disappearance of the doublet of the starting material (5.48 ppm) was monitored, along with
the appearance of a singlet for the desired compound (4.07 ppm). Integrating both signals,
a conversion percentage was calculated for each spectrum and plotted against time.
8

3.2 General protocol for the Friedel-Crafts reaction of benzylic fluoride using TFA
To a stirred solution of the benzylic fluoride (1 equiv.) in CH2Cl2 (90% of the volume
required for substrate concentration of 0.25 M) were added the arene nucleophile (5 equiv.)
and HFIP (10% of the volume required for substrate concentration of 0.25 M, resulting in
a 9:1 mixture of CH2Cl2/HFIP). Finally, TFA (0.2 M in CH2Cl2, 5 mol % of TFA) was
added. The resulting solution was stirred for 1 h at room temperature. The reaction was
quenched with H2O and extracted with CH2Cl2 (3x). The combined organic extracts were
washed with brine, dried with MgSO4, filtered and evaporated under reduced pressure.
1
After silica gel chromatography, pure compounds are usually obtained. H NMR
spectroscopy was then used to measure ratios of regioisomers, where applicable.
3.2.1 4-(4-methylbenzyl)-1,1'-biphenyl (13).
Following the general protocol on 6 using toluene, 13 was obtained as a colourless oil
(yield 89%, 2.5:1 mixture of regioisomers). Following the general protocol, but at 0 °C, 13
was obtained as a colourless oil (yield 44%, 3:1 mixture of regioisomers). mp = 71–74 °C.
IR (ATR, ZnSe) ν (cm−1) = 3023, 2916, 2851, 1485, 1110, 1006, 742; 1H NMR (500 MHz,
CDCl3): δ (ppm) = 7.62–7.58 (m, 2.8H), 7.57–7.52 (m, 2.8H), 7.47–7.43 (m, 2.8H), 7.37–
7.33 (m, 1.4H), 7.30–7.27 (m, 2H), 7.24–7.17 (m, 2.5H), 7.15 (s, 3.6H), 4.06 (s, 0.8H,
minor), 4.01 (s, 2H, major), 2.35 (s, 3H, major), 2.31 (s, 1.2H, minor); 13C NMR (126 MHz,
CDCl3): δ (ppm) = 141.2, 141.1, 140.7, 139.6, 139.1, 138.99, 138.95, 138.1, 136.79,
135.76, 130.5, 130.1, 129.4, 129.34, 129.26, 129.0, 128.85, 128.84, 127.3, 127.3, 127.19,
127.18, 127.14, 127.12, 126.7, 126.2, 41.3 (major), 39.2 (minor), 21.2 (major), 19.9
(minor). HRMS (APPI) m/z calcd for C20H18 [M*]+ 258.1403 found 258.1403.
3.2.2 2-(4-(tert-butyl)benzyl)naphthalene (14).
9

Following the general protocol on 8 using naphthalene, 14 was obtained as a white solid
(yield 78%, 1.6:1 mixture of regioisomers). Spectral data were identical to those
previously reported [6].
3.2.3 1-benzyl-4-tert-butylbenzene (15).
Following the general protocol on 8 using a mixture of benzene/HFIP (9:1) as the solvent,
15 was obtained as a colourless oil (yield 86%). Spectral data were identical to those
previously reported [6].
3.2.4 2-(4-bromobenzyl)-1,4-dimethylbenzene (17).
Following the general protocol on 10 using p-xylene at 45 °C for 18 h, 17 was obtained as
a colourless oil (yield 78%). Spectral data were identical to those previously
reported [6].
3.2.5 2-(4-chlorobenzyl)-1,4-dimethylbenzene 1(8).
Following the general protocol on 11 using p-xylene at 45 °C for 18 h, 18 was obtained as
a colourless oil (yield 82%). Spectral data were identical to those previously
reported [6].
3.2.6 2-(2-bromobenzyl)-1,4-dimethylbenzene (19).
Following the general protocol on 12 using p-xylene at 45 °C for 18 h, 19 was obtained as
a colourless oil (yield 76%). Spectral data were identical to those previously
reported [6].
Acknowledgments
10

This work was supported by the Natural Sciences and Engineering Research Council of
Canada, the Fonds de recherche du Québec – Nature et technologies, and the Université
Laval.
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[4] P. A. Champagne, J. Pomarole, M.-E. Thérien, Y. Benhassine, S. Beaulieu, C. Y.
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Chem. 9 (2013) 2451–2456;
(b) P. A. Champagne, M. Drouin, C. Y. Legault, C. Audubert, J.-F. Paquin, J.
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[6] P. A. Champagne, Y. Benhassine, J. Desroches, J.-F. Paquin, Angew. Chem. Int. Ed.
53 (2014) 13835–13839.
11

[7] (a) J. Bernstein, J. S. Roth, W. T. Miller Jr., J. Am. Chem. Soc. 70 (1948) 2311–
2314. (b) C. G. Swain, R. E. T. Spalding, J. Am. Chem. Soc. 82 (1960) 6104–6107.
[8] J.-P. Bégué, D. Bonnet-Delpon, B. Crousse, Synthesis (2004) 18–29.
[9] J. Ichikawa, M. Yokota, T. Kudo, S. Umezaki, Angew. Chem. Int. Ed. 47 (2008)
4870–4873.
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(b) C. Dalvit, A. Vulpetti, Chem. Eur. J. 22 (2016) 7592–7601.
[11] Based on calculations performed by Chęcińska and Grabowski (L. Chęcińska, S. J.
Grabowski, Chem. Phys. 327 (2006) 202–208) and by Rosenberg (R. E. Rosenberg,
J. Phys. Chem. A 116 (2012) 10842–10849), we estimate that HF is approximately a
50% stronger donor than water in its interaction with alkyl fluorides.
[12] M. J. Kamlet, J. L. M. Abboud, M. H. Abraham, R. W. J. Taft, J. Org. Chem. 48
(1983) 2877–2891.
[13] Other groups have used catalytic amounts of Lewis acids to initiate the Friedel-Crafts
reaction of alkyl fluorides, see (a) M. Dryzhakov, J. Moran, ACS Catal. 6 (2016)
3670−3673.
(b) J. Zhu, M. Pérez, D. W. Stephan, Angew. Chem. Int. Ed. 55 (2016) 1417−1421.
[14] The direct protonation of benzyl fluoride has been proposed for its hydrolysis in the
presence of perchloric acid, see C. G. Swain, R. E. T. Spalding, J. Am. Chem. Soc.
82 (1960) 6104 – 6107. However, we discard this possibility here, as HFIP and HF
are considerably weaker acids than HClO4 (pKa (H2O) = -10).
[15] Y. Marcus, J. Solution Chem. 20 (1991) 929–944.
12

[16] J. Desroches, P. A. Champagne, Y. Benhassine, J.-F. Paquin, Org. Biomol. Chem.
13 (2015) 2243–2246.
[17] We suspect that decomposition occurs through Friedel-Crafts polymerization, such
decomposition pathway has been observed previously, see ref. 6..
13

A. Previous work
Ar-H
F
Ar
- long activation period (ca. 170 min)
- more forcing conditions for R = EWG
R
R
HFIP
B. This work: TFA-initiated Friedel-Crafts reaction of benzylic fluorides
TFA cat.
Ar-H
- reduced activation period (< 10 min)
- enables lower temperature
F
Ar
R
R
- milder conditions for R = EWG
HFIP
Figure 1. Previous work and current work
14

Figure 2. Mechanistic proposal for the Friedel-Crafts reaction of benzylic fluorides using
HFIP as the activator.
15

with TFA
100
90
80
70
60
50
40
30
20
10
0
without TFA
0
60
120
180
240
300
Time (minutes)
Figure 3. Examination of the conversion vs time by 1H NMR for the Friedel-Crafts reaction
of benzylic fluoride 6 with p-xylene with and without 5 mol % of TFA.
16

Table 2. Selected Examples for the TFA-initiated Friedel-Crafts Reaction of Benzylic
Fluorides.
Entry Benzylic Fluoride
1
Conditions Producta
rt, 1.5 h
Yield (%)b
89
2
3
6
0 °C, 18 h
rt, 1 h
13 (3 :1)
44
78
4c
8
rt, 1 h
rt, 1 h
86
0d
5
6
45 °C, 18 h
78
17

7
8
45 °C, 18 h
82
76
45 °C, 18 h
a
1
Ratio of regioisomers (determined by H NMR analysis) in parentheses with the major
isomer shown.
b Isolated yield.
c Solvent was benzene/HFIP (9:1).
d Decomposition with full conversion of the benzylic fluoride.
18

Table 1. Effect of the acid catalyst on the reactivity of benzyl fluoride 6 with p-xylene.
Entry
Acid
pKa (H2O)
Yield (%)a

1
2
3
4
HFIP
9.3
1.96
1.12
-
NRb
NRb
NRb
50
AcOH
4.76
2.86
-0.25
Chloroacetic acid
TFA
2.38c
a Isolated yield of 7
b NR = No reaction.
c Calculated value, see ref. 13 for details.
19