Electrophilic aromatic aroylation with CF3-bearing arenecarboxylic acid derivatives: Reaction behavior and acidic mediator dependence

Article abstract of DOI:10.1080/00397910701465479

Triflic acid (TfOH) has been proven to be effective as a tolerant acidic mediator in electrophilic aromatic aroylation with CF3-bearing aroyl chlorides. The TfOH-mediated aroylation of fluorobenzene proceeds with high selectivity to give CF3-bearing aryl fluorophenyl ketones in good yields, which are hardly obtained with the aid of AlCl3 or direct condensation reagents. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701465479

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Electrophilic Aromatic Aroylation with
CF3‐Bearing Arenecarboxylic Acid
Derivatives: Reaction Behavior and Acidic
Mediator Dependence
Okamoto Akiko a , Maeyama Katsuya a , Oike Hideaki a & Yonezawa Noriyuki
a
a Department of Organic and Polymer Materials Chemistry , Tokyo University
of Agriculture and Technology , Koganei, Tokyo, Japan
Published online: 14 Aug 2007.
To cite this article: Okamoto Akiko , Maeyama Katsuya , Oike Hideaki & Yonezawa Noriyuki (2007)
Electrophilic Aromatic Aroylation with CF3‐Bearing Arenecarboxylic Acid Derivatives: Reaction Behavior and
Acidic Mediator Dependence, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 37:16, 2701-2715, DOI: 10.1080/00397910701465479
To link to this article: http://dx.doi.org/10.1080/00397910701465479
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Synthetic Communicationsw, 37: 2701–2715, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701465479
Electrophilic Aromatic Aroylation with
CF3-Bearing Arenecarboxylic Acid
Derivatives: Reaction Behavior and Acidic
Mediator Dependence
Okamoto Akiko, Maeyama Katsuya, Oike Hideaki, and
Yonezawa Noriyuki
Department of Organic and Polymer Materials Chemistry, Tokyo
University of Agriculture and Technology, Koganei, Tokyo, Japan
Abstract: Triflic acid (TfOH) has been proven to be effective as a tolerant acidic
mediator in electrophilic aromatic aroylation with CF3-bearing aroyl chlorides. The
TfOH-mediated aroylation of fluorobenzene proceeds with high selectivity to give
CF3-bearing aryl fluorophenyl ketones in good yields, which are hardly obtained
with the aid of AlCl3 or direct condensation reagents.
Keywords: acidic mediator, CF3-bearing aroyl chloride, CF3-bearing diaryl ketone,
regioselective electrophilic aromatic aroylation, triflic acid
INTRODUCTION
A great number of synthetic studies on organic compounds that have perfluor-
oalkyl groups have been reported by polymer chemists,[1–4] medicinal
chemists,[5] and organic synthetic chemists.[6–10] For example, aromatic
ring systems having CF3 groups and different electronically polarizable
groups have been of interest as potential functional compounds for
Received December 28, 2006
Address correspondence to Yonezawa Noriyuki, Department of Organic and
Polymer Materials Chemistry, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan. E-mail: yonezawa@cc.tuat.ac.jp
2701

2702
O. Akiko et al.
optoelectronic devices such as liquid-crystalline molecules[11–13] and
nonlinear optical materials.[14] As a natural consequence of this, diaryl
ketone skeletons having these substituents show unique chemical and
physical behaviors. For example, 4-fluoro-40-trifluoromethylbenzophenone
(5) possesses characteristic electronic structure.[15–18] It has been utilized as
an effective initiator for nucleophilic aromatic substitution polymerization
giving monodispersed poly(aromatic ether ketone)s,[19–21] a coating agent
for the toner-supplying part in one-component electrophotographic develop-
ing apparatus,[22–24] and a synthetic precursor for antimalarial radiopharma-
ceutical guanylhydrazones.[25,26]
For construction of such diaryl ketone structures, Friedel–Crafts
acylation would be the primary candidate. However, contrary to the
Friedel–Crafts alkylation, the corresponding acylation reaction often suffers
from intrinsic low reactivity and low selectivity, especially against the acyl-
acceptant arene substrates with low electron density. It is because acylium
cation intermediate is too inert to undergo smooth formation of the ketonic
carbonyl group–aromatic ring linkages with such arenes. Because of this dis-
advantage, the use of this well-known bond-formation reaction has been rather
restrictedly applied to diaryl ketone synthesis compared to transition-metal-
catalyzed coupling reaction.[27,28]
Furthermore, electrophilic aromatic acylation of the arenes bearing
CF3 groups is known to be troublesome. Such reactions often afford
complex mixtures. In addition, electrophilic aromatic aroylation with CF3-
bearing arenecarboxylic acid also demonstrates low selectivity. In the
course of the investigation of the synthesis of wholly aromatic polyke-
tones,[29–34] the authors have confirmed that electrophilic aromatic aroylation
with 3-trifluoromethylbenzoic acid or the aroyl chloride proceeds only with
low conversion and poor selectivity unless the highly activated arene is
employed as an acyl-acceptant substrate in the presence of phosphorus(V)
oxide–methanesulfonic acid (P2O5–MsOH)[35] as acidic mediator.[31]
Actually, electrophilic aromatic aroylation syntheses of trifluoromethylated
benzophenone homologues bearing other electron-withdrawing groups with
CF3-bearing arenecarboxylic acid derivatives have been scarcely reported
except for TfOH-mediated aroylation synthesis of 4-fluoro-40-trifluoromethyl-
benzophenone (5) by Ridd and Yousaf.[36]
Under such a circumstance, the authors have aimed to develop the general
synthetic protocol for CF3-bearing diaryl ketones via electrophilic aromatic
aroylation. Especially the synthesis of diaryl ketones having CF3 groups and
a fluorine group has been focused on because aryl–F bonds are valuable in
preparating of various organic compounds having a CF3-bearing aroylaryl
moiety via nucleophilic aromatic substitution. To estimate the influence of
CF3 groups of the aroyl moieties in electrophilic aromatic aroylation more
accurately and make the guideline of choice of the reagent for this transform-
ation, the authors have undertaken the reaction of arenecarboxylic acids/aroyl
chlorides with the aid of three different types of acidic mediators: typical

ArSE Synthesis of Diaryl Ketones that have CF3
2703
Friedel–Crafts catalyst, direct condensation mediator, and superacidic
mediator (TfOH).
In this article, the authors discuss the acidic mediator dependence and the
influence of the CF3 groups in the reaction of CF3-bearing arenecarboxylic
acid derivatives in electrophilic aromatic aroylation.
RESULTS AND DISCUSSION
Electrophilic Aromatic Aroylation of Toluene (2)/Fluorobenzene
(3) with 4-Trifluoromethylbenzoic Acid/4-Trifluoromethybenzoyl
Chloride (1)
To grasp the outline of the reaction feature, 4-trifluoromethylbenzoic acid (1a)/
4-trifluoromethylbenzoyl chloride (1b) were allowed to react with toluene (2)/
fluorobenzene (3) by the aid of three different types of acidic mediators: AlCl3,
P2O5–MsOH, and TfOH (Table 1). AlCl3 is one of the most conventional Lewis
acids for Friedel–Crafts reaction. P2O5–MsOH is known as an acidic mediator
for direct condensation, which has high solubilizing ability against various
organic compounds and sufficiently low viscosity as a reaction solvent in
comparison to the related phosphoric anhydride-based mediators such as poly-
phosphoric acid (PPA). TfOH is a Brønsted superacid having moderate super-
acidity (Hammett’s function: H0–14.1). The acidity of TfOH is situated
between those of 100% H2SO4 (H0–11.9) and magic acid (H0–24.3).
In the reaction of toluene (2) or fluorobenzene (3) with 4-trifluoromethyl-
benzoyl chloride (1b) by AlCl3, a complex mixture was obtained (entries 1,
7–9). Although the constituents of the complex mixture were unsatisfactorily
identified, the conversion of CF3 group in 4-trifluoromethylbenzoyl chloride
(1b) probably proceeded. In the reaction with 4-trifluoromethylbenzoic acid
(1a) by P2O5–MsOH, the aimed phenones were obtained in moderate yields
with a large amount of mesylated products and the starting material (entries
4, 5, and 10). The aroylation by P2O5–MsOH needed a long reaction
interval to achieve satisfactory conversion when fluorobenzene (3) was
employed as the acyl-acceptant arene (entry 10 vs. 11). On the other hand,
in the reaction by TfOH, the aimed phenones were obtained quantitatively
against both toluene (2) and fluorobenzene (3) without formation of
by-products, although the aroylation required a rather long interval against
fluorobenzene (3) (entry 6 vs. 16). Furthermore, the difference of the
reaction behavior between the combinations of the acidic mediator and arene-
carboxylic acid/aroyl chloride (1) is also demonstrated. When P2O5–MsOH
and arenecarboxylic acid 1a were treated with fluorobenzene (3), the yield
and the chemoselectivity were higher than those against aroyl chloride 1b
(entry 11 vs. 13). On the other hand, the reverse behavior was observed in
the reaction mediated by TfOH: arenecarboxylic acid 1a showed lower che-
moselectivity than the corresponding aroyl chloride (1b) (entry 14 vs. 15).

2704
O. Akiko et al.
Table 1. Electrophilic aromatic aroylation of arene 2/3 with 4-trifluoromethylbenzoic
acid/4-trifluoromethylbenzoyl chloride (1)a
Product
distributionb(%)
Entry
Substrate
Acidic mediator
Temp.
Time (h)
1
4/5
c
1
2
1b
1b
1a
1a
1a
1b
1b
1b
1b
1a
1a
1b
1b
1a
1b
1b
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
AlCl3
rt
24
48
0
0
—
Trace
Trace
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
TfOH (0.25 eq)
AlCl3
rt
3
rt
48
24
0
4
808C
Reflux
Reflux
rt
11
15
0
79 (10d)
58 (27d)
100
5
1.5
1.5
24
6e
7
c
0
—
—
c
8f
AlCl3
AlCl3
rt
24
24
0
c
9
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0
—
10
11
12
13
14g
15
16h
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
TfOH (0.10 eq)
TfOH (0.10 eq)
TfOH (0.50 eq)
24
32
0
36 (32d)
83 (17d)
24 (31d)
66 (34d)
Trace
192
24
45
0
192
144
144
144
0
60
2
40
98
aReaction conditions: arene (acidic mediator) against 1.0 mmol of 4-trifluoromethyl-
benzoic acid/aroyl chloride (1); 15 mmol: AlCl3 (3.0 mmol); 12 mmol: P2O5–MsOH
(2.0 mL); 12 mmol: TfOH (0.10 mmol); N2 atmosphere.
1
bCalculated on the basis of HNMR spectrum.
cA complex mixture was obtained.
dMesylated product was obtained.
eTfOH (0.25 mmol) was employed against 1.0 mmol of aroyl chloride 1b.
f1,2-Dichloroethane was employed as cosolvent.
gComplex mixtures were obtained.
hTfOH (0.50 mmol) was employed against 1.0 mmol of aroyl chloride 1b.
These results suggest that with the aid of TfOH, effective electrophilic
aromatic aroylation by CF3-bearing aroyl chloride might be performed
as general protocols. Hence, the generality of TfOH was evaluated by
investigating the reaction behavior of several homologous acid derivatives
in detail.

ArSE Synthesis of Diaryl Ketones that have CF3
2705
Electrophilic Aromatic Aroylation of Fluorobenzene (3) with
Arenecarboxylic Acids/Aroyl Chlorides Bearing Trifluoromethyl
Groups
To estimate the influence of the number and the position of CF3 substituents
on aroyl-donor species in electrophilic aromatic aroylation, the reaction of
several arenecarboxylic acids/aroyl chlorides was undertaken with the aid
of three acidic mediators (Table 2).
The reaction by AlCl3 gave complex mixtures against the CF3-bearing
aroyl chlorides (1b, 7b, 8b, 10b), whereas the aimed phenones were
obtained in high conversion in the reaction with the CF3-free aroyl
chlorides (6b, 9b) (entries 2–4, 6 vs. 1, 5). In the reaction of the CF3-
bearing aroyl chlorides (1b, 7b, 8b, 10b) by AlCl3, side reactions were
not suppressed even at low temperature. When P2O5–MsOH was
employed, the arenecarboxylic acids (except for acid 8a) gave the aimed
phenones in low conversions with a rather large amount of mesylated
compounds (entries 7–12). The amount of the mesylated products
increased with the number of CF3 groups (entry 7 vs. 9 vs. 10). On the
other hand, TfOH showed high regioselectivity and high chemoselectivity
whether the aroyl chlorides have CF3 groups or not (entries 13–18).
Especially when the CF3-bearing aroyl chlorides (1b, 7b, 8b, 10b) were
employed, the aimed phenones were obtained in high yields (entries 14–
16, 18). In addition, the substitution position of the CF3 groups against
the carbonyl group is shown to affect the conversion. 4-Trifluoromethylben-
zoyl chloride (1b) gave the aimed phenone (5) quantitatively. On the other
hand, the reaction of 3-trifluoromethylbenzoyl chloride (7b) proceeded with
a high but somewhat lower conversion (entry 14 vs. 15). Therefore, one
CF3 group substituted at the p-position against the carbonyl group is
more effective to obtain the aimed phenones in a high yield than one or
two m-positioned CF3 groups (entry 14 vs. 15, 16). As well as 4-trifluoro-
methylbenzoyl chloride (1b), 4-(4-trifluoromethylbenzoyl)benzoyl chloride
(10b) gave the aimed phenone (15) with a high conversion (entry 18).
This indicates that the electron-withdrawing effect of the CF3 group is
transmitted through the p-positioned ketonic carbonyl group of benzophe-
none unit.
The relationships among acidic mediators, number and substituted
position of CF3-groups, and yield in electrophilic aroylation of fluorobenzene
(3) are also summarized in Fig. 1. This chart shows the characteristics, scope,
and limitations of acidic mediators in the reaction. The reaction by P2O5–
MsOH yielded the aimed phenones with low conversion and low selectivity
against the arenecarboxylic acids (1, 6–10a), and the conversion descended
with number of CF3 groups of arenecarboxylic acids. In our previous study,
P2O5–MsOH has been proven an effective aroylation reagent for
o-terphenyl[30] and 2,20-dimethoxy-1,10-binaphthyl[37] as acyl-acceptant
arenes. In contrast, P2O5–MsOH was shown to be unsuitable against

2706
O. Akiko et al.
Table 2. Electrophilic aromatic aroylation of fluorobenzene (3) with arenecarboxylic
acids/aroyl chlorides 1, 6–10a
Product distributionb(%)
Acidic
mediator
Time
(h)
Entry
Substrate Temp.
Ketone Recoveryc By-product
1
2
AlCl3
AlCl3
AlCl3
6b
1b
7b
8b
9b
10b
6a
Reflux
rt
12
24
11 91
9
0
0
d
5
0
0
0
—
d
3
rt
24
24
12
13
0
—
—
d
4
AlCl3
AlCl3
AlCl3
rt
0
5
Reflux
rt
12
24
14 86
15
11 53
36
12 28
13
14
0
0
d
—
6
0
7
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
P2O5–MsOH
TfOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
24
24
19
32
30
43
29
45
21
2
28e
32e
42
57
39e
18e
0
8
1a
7a
5
9
24
24
10
11
12
13
14
15
16
17
18
8a
9a
0
24
24
14 32
15 37
11 79
10a
6b
1b
7b
8b
9b
10b
144
144
144
144
144
144
TfOH
TfOH
5
98
0
12 80
13 85
14 47
15 92
20
15
53
8
0
TfOH
TfOH
TfOH
0
0
0
aReaction conditions: arene 3 (acidic mediator) against 1.0 mmol of arenecarboxylic
acid/aroyl chloride; 15 mmol: AlCl3 (3.0 mmol); 12 mmol: P2O5–MsOH (2.0 mL);
12 mmol: TfOH (0.50 mmol); N2 atmosphere.
1
bCalculated on the basis of H NMR spectrum.
cStarting material (arenecarboxylic acid/aroyl chloride).
dA complex mixture was obtained.
eMesylated compound was obtained.
fluorobenzene (3). The reaction by TfOH yielded the aimed phenone with high
conversion against each aroyl chloride. Especially in the case of the CF3-
bearing aroyl chlorides (1b, 7b, 8b, 10b), TfOH gave excellent results,
which are in remarkable contrast with AlCl3.

ArSE Synthesis of Diaryl Ketones that have CF3
2707
Figure 1. Relationships among acidic mediators, structural factors of arenecar-
boxylic acids/aroyl chlorides and yields in electrophilic aromatic aroylation of fluor-
obenzene (3).
Postulated Reaction Mechanism
The susceptibility, the selectivity, and the structural dependence of the
reaction are interpreted on the basis of the speculated reaction mechanisms
described next (Schemes 1–3).
As shown in Table 2 (entries 1–6), the CF3-free aroyl chlorides (6b, 9b)
gave the corresponding phenones (11, 14) with excellent yields in the AlCl3-
mediated reaction, whereas the CF3-bearing aroyl chlorides (1b, 7b, 8b, 10b)
resulted in only complex mixtures. The distinct difference clearly manifests
because intermediates 17, formed from CF3-bearing aroyl chlorides 16, are
too reactive to give diaryl ketones selectively (Scheme 1). Furthermore, the
C—F bonds in the CF3 group have enough reactivity to cleave the connection
and form new bonds instead.[38]
Scheme 1.

2708
O. Akiko et al.
On the other hand, the active intermediate in P2O5–MsOH-mediated
aroylation is plausibly the mildest chemical species among those in three
types of aroylation reaction systems. In P2O5–MsOH-mediated system, the
rather stable intermediate (22), formed from arenecarboxylic acid 19 and
P2O5–MsOH complex, for example, structure 18, should gradually react
with arenes, probably via a possible concerted process (23) to give the
acylal-like derivatives (24) of diaryl ketones 25 (Scheme 2). In this system,
CF3-bearing arenecarboxylic acids 19 form ternary mixed anhydrides 21 so
slowly that the unimolecular decomposition of the primarily formed
complex (18) should precede to yield a methanesulfonium ion (20; mesyl
cation) equivalent, resulting in partial formation of mesylated products.
Furthermore, nonactivated arene reacts with complex 22 slowly. It is also
presumed to stimulate the mesylation of the arene. As a natural consequence,
P2O5–MsOH shows the best efficiency only against the electron-rich acyl-
acceptant compound. In other words, with nonactivated arenes, the P2O5–
MsOH-mediated aroylation system should lack the balance between the
reactivities of the acyl-acceptants and the acyl-donors.
In the TfOH-mediated aroylation system (Scheme 3), the active species is
anticipated to have a ortho-type acid anhydride/aroyl chloride structure or
Scheme 2.

ArSE Synthesis of Diaryl Ketones that have CF3
2709
Scheme 3.
acylal-like one (26). This species might have an intramolecular hydrogen-
bonded cyclic structure, which gradually eliminates the chloride ion to yield
another cationic species (27). This cation is considered to be an equivalent
of protoaroyl dication 28.[39] In the TfOH-mediated system, the intermediates
are presumably stable enough but more labile than those in the P2O5–MsOH-
mediated system. The intermediates in the P2O5–MsOH-mediated system
occasionally cleave by unimolecular mode to form mesyl cation (20),
resulting in formation of a substantial amount of mesylated by-products.
However, the intermediates in the TfOH-mediated system are essentially
free from scission, giving active species to yield by-products. In addition,
the participation of this highly cationic TfOH adduct probably promotes with-
drawal of the electron from the aromatic ring moiety, resulting in depression
of the cleavage of C—F bond in the CF3 group attached, which is unavoidable
in an AlCl3-mediated system. In consequence, cation 27 should undertake
concerted electrophilic attack (29) sufficiently slowly to achieve high
selectivity.
CONCLUSION
TfOH has been ascertained to be a tolerant acidic mediator against several
CF3-bearing aroyl chlorides for their aroylating function in electrophilic
aromatic aroylation. The electrophilic aroylation of fluorobenzene with CF3-
bearing aroyl chlorides has been demonstrated to proceed with high selectivity
by suppressing the side reactions that are unpreventable in AlCl3- and P2O5-
MsOH–mediated reactions, though the sufficient conversion needs a rather

2710
O. Akiko et al.
long reaction interval. According to this method, CF3-bearing aryl fluorophe-
nyl ketones are efficiently prepared.
EXPERIMENTAL
General
1H NMR spectra were recorded on a JEOL JNM-AL300 spectrometer
(300 MHz) and a JEOL JNM-A500 spectrometer (500 MHz). Chemical shifts
are expressed in parts per million (ppm) relative to internal standard of Me4Si
(d, 0.00). 13C NMR spectra were recorded on a JEOL JNM-AL300 spectrometer
(75 MHz) and a JEOL JNM-A500 spectrometer (125 MHz). Chemical shifts
are expressed in ppm relative to the internal standard of CDCl3 (d, 77.0). IR
spectra were recorded on a JASCO FR/IR-5300 spectrometer.
P2O5–MsOH was prepared according to literature.[35]
4-(4-Trifluoromethylbenzoyl)benzoic Acid (10a)
4-Methyl-40-trifluoromethylbenzophenone (4, 10.0 mmol, 2.64 g) and glacial
acetic acid (24 mL) were placed into a two-necked flask and refluxed for
30 min. Then a mixture of CrO3(IV) (5.00 g, 50.0 mmol), glacial acetic acid
(12 mL), and conc. H2SO4 (2.64 mL) was dropped into the reaction solution
for 30 min. After 12 h, it was poured into ice water (60 mL), and the
resulting mixture was extracted with diethyl ether (3 ꢀ 30 mL). The
combined extracts were washed with aqueous saturated NaCl solution (sat.
NaCl aq.) and dried over anhydrous sodium sulfate overnight. After
removal of diethyl ether, the residue was purified by recrystallization from
AcOEt (74% isolated yield).
Colorless plates; mp 238.5–2398C (lit. mp 82–838C[40]; though the
melting point differs from that reported in the literature, the formation of
the compound described is ascertained by the consistent spectroscopic data
and elemental analytical data after the derivation to aroyl chloride. IR n
1
(KBr): 1691, 1651, 1575, 1502 cm21; H NMR d (300 MHz, DMSO-d6):
7.85 (2H, d, J ¼ 8.4 Hz), 7.92–7.95 (4H, m), 8.09 (2H, d, J ¼ 8.1 Hz) ppm;
13C NMR d (75 MHz, DMSO-d6): 125.58, 125.63, 129.49, 129.85, 129.88,
130.34, 132.49, 134.50, 139.57, 139.59, 140.14, 166.56, 194.53 ppm.
4-(4-Trifluoromethylbenzoyl)benzoyl Chloride (10b)
Thionyl chloride (250 mmol, 29.5 g) and 4-(4-trifluoromethylbenzoyl)benzoic
acid (10a, 5.00 mmol, 1.47 g) were placed into a two-necked flask, and the
reaction mixture was refluxed for 2 h. After removal of thionyl chloride, the
residue was purified by recrystallization from hexane (95% isolated yield).

ArSE Synthesis of Diaryl Ketones that have CF3
2711
Colorless needles; mp 84–858C; IR n (KBr): 1777, 1661, 1510 cm21; 1H
NMR d (300 MHz, CDCl3): 7.80 (2H, d, J ¼ 8.1 Hz), 7.91 (2H, d,
J ¼ 8.4 Hz), 7.92 (2H, J ¼ 8.1 Hz), 8.27 (2H, d, J ¼ 8.1 Hz) ppm; 13C
NMR d (75 MHz, CDCl3): 121.64, 125.25, 125.59, 125.64, 125.69, 125.74,
130.11, 130.24, 131.31, 134.31, 134.75, 136.33, 139.37, 142.13, 167.80,
194.20 ppm. Anal. calcd. for C15H8ClF3O2: C, 57.62; H, 2.58. Found: C,
57.92; H, 2.68.
Electrophilic Aromatic Aroylation of Fluorobenzene (3) with
4-Trifluoromethylbenzoic Acid/4-Trifluoromethylbenzoyl
Chloride (1)
Typical Procedure of Friedel–Crafts Aroylation Mediated by AlCl3
Fluorobenzene (3, 15.0 mmol, 1.44 g) and 4-trifluoromethylbenzoyl chloride
(1b, 1.00 mmol, 208 mg) were placed into a two-necked flask. To the
solution thus obtained, AlCl3 (3.00 mmol, 400 mg) was added by portions
at rt under a nitrogen atmosphere. After the reaction mixture was stirred at
rt for 24 h, it was poured into ice water (20 mL), and the mixture was
extracted with CHCl3 (3 ꢀ 15 mL). The combined extracts were washed
with sat. NaCl aq. and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to give a viscous oil.
Typical Procedure of Direct Condensation Mediated by P2O5–MsOH
Fluorobenzene (3, 12.0 mmol, 1.15 g) and 4-trifluoromethylbenzoic acid (1a,
1.00 mmol, 190 mg) were placed into a two-necked flask. To the solution thus
obtained, P2O5–MsOH (2 mL) was added by portions at rt. After the reaction
mixture was stirred at 1008C for 24 h, it was poured into ice water (20 mL),
and the mixture was extracted with CHCl3 (3 ꢀ 15 mL). The combined
extracts were washed with sat. NaCl aq. and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give a powdery
product.
Typical Procedure of Modified Friedel–Crafts Aroylation Mediated by
TfOH[36]
Fluorobenzene (36.0 mmol, 3.46 g) and 4-trifluoromethylbenzoyl chloride
(1b, 3.00 mmol, 624 mg) were placed into a two-necked flask. To the
solution thus obtained, TfOH (1.50 mmol, 225 mg) was added by portions
at rt under nitrogen atmosphere. After the reaction mixture was stirred at
1008C for 144 h, it was poured into ice water (40 mL), and the mixture was
extracted with CHCl3 (3 ꢀ 30 mL). The combined extracts were washed
with sat. NaCl aq. and dried over anhydrous sodium sulfate. After removal

2712
O. Akiko et al.
of CHCl3, the residue was purified by recrystallization from EtOH to give
colorless needles (98% isolated yield).
Other reactions were undertaken by essentially the same procedure.
Spectral Data and Elemental Analyses
4-Methyl-40-trifluoromethylbenzophenone (4)[41]
Colorless plates (EtOH; 97% isolated yield.); mp 144–1458C (lit. mp 144.5–
1508C[41]); IR n (KBr): 1649, 1599, 1501 cm21 1H NMR d (300 MHz,
;
CDCl3): 2.46 (3H, s), 7.31 (2H, d, J ¼ 8.1 Hz), 7.71 (2H, d, J ¼ 7.8 Hz),
7.75 (2H, d, J ¼ 8.1 Hz), 7.87 (2H, d, J ¼ 8.1 Hz) ppm; 13C NMR d
(75 MHz, CDCl3): 21.715, 121.88, 125.19, 125.23, 125.29, 129.21, 129.99,
130.33, 134.02, 141.08, 144.09, 195.28 ppm.
4-Fluoro-40-trifluoromethylbenzophenone (5)[15,19]
Colorless needles (EtOH; 98% isolated yield); mp 100–1018C (lit. mp 100–
1
100.58C[15]); IR n (KBr): 1651, 1599, 1506 cm21; H NMR d (300 MHz,
CDCl3): 7.19 (2H, dd, J ¼ 8.7, 8.7 Hz), 7.76 (2H, d, J ¼ 8.1 Hz), 7.81–
7.88 (4H, m) ppm; 13C NMR d (75 MHz, CDCl3): 115.61, 115.90, 121.89,
125.39, 125.44, 125.49, 129.93, 132.68, 132.80, 132.98, 133.02, 134.02,
140.63, 164.06, 167.44, 193.98 ppm.
4-Fluoro-30-trifluoromethylbenzophenone (12)[15]
Yellow needles (EtOH; 76% isolated yield.); mp 44–458C (lit. mp 45–
468C[15]); IR n (KBr): 1652, 1598, 1507 cm21 1H NMR d (300 MHz,
;
CDCl3): 7.19 (2H, dd, J ¼ 8.7, 8.4 Hz), 7.64 (1H, t, J ¼ 7.5 Hz), 7.82–7.87
(3H, m), 7.95 (1H, d, J ¼ 7.8 Hz), 8.03 (1H, s); 13C NMR d (75 MHz,
CDCl3): 115.63, 115.92, 121.81, 125.42, 126.46, 126.51, 128.78, 128.83,
128.88, 128.92, 129.00, 130.83, 131.27, 132.58, 132.71, 132.88, 132.95,
132.99, 138.15, 163.99, 167.37, 193.68 ppm.
4-Fluoro-30,50-bis(trifluoromethyl)benzophenone (13)
Colorless oil; bp 110–1368C/4 mmHg (85% isolated yield.); IR n (KBr):
1672, 1601, 1508 cm21 1H NMR d (300 MHz, CDCl3): 7.24 (2H, dd,
;
J ¼ 8.4, 8.4 Hz), 7.82–7.87 (2H, m), 8.10 (1H, s), 8.19 (2H, s) ppm; 13C
NMR d (75 MHz, CDCl3): 116.06, 116.35, 120.98, 124.65, 125.70, 129.61,
131.93, 132.15, 132.19, 132.38, 132.65, 132.77, 139.29, 164.34, 167.73,
192.11 ppm. Anal. calcd for C15H7F7O: C, 53.59; H, 2.10. Found: C, 53.90;
H, 1.99.

ArSE Synthesis of Diaryl Ketones that have CF3
2713
4-(4-Fluorobenzoyl)-40-trifluoromethylbenzophenone (15)
Yellow needles (acetone; 88% isolated yield); mp 200–2018C; IR n (KBr):
1651, 1601, 1508 cm21 1H NMR d (300 MHz, CDCl3): 7.21 (2H, dd,
;
J ¼ 8.4, 8.4 Hz), 7.79 (2H, d, J ¼ 8.1 Hz), 7.88–7.95 (8H, m) ppm; 13C
NMR d (75 MHz, CDCl3): 115.63, 115.93, 125.59, 129.70, 129.86, 130.22,
132.72, 132.85, 139.67, 139.97, 141.16, 167.45, 194.30, 194.74 ppm. Anal.
calcd. for C21H12F4O2: C, 67.75; H, 3.25. Found: C, 67.87; H, 3.09.
REFERENCES
1. Kajiyama, M.; Kudo, J.; Mizumachi, H. Synthesis and characterization of aromatic
polymers derived from 5-perfluoroalkylisophthalic acid. J. Polym. Sci., Part A:
Polym. Chem. 1999, 37, 1135–1141.
2. Zhang, L.; Huang, W. Synthesis of polyfluorinated aromatic polyesters. J. Fluorine
Chem. 2000, 102, 55–59.
3. Chung, I.; Kim, S. Meta-activated nucleophilic aromatic substitution reaction:
Poly(biphenylene oxide)s with trifluoromethyl pendant groups via nitro displace-
ment. J. Am. Chem. Soc. 2001, 123, 11071–11072.
4. Salunke, A.; Madhra, M.; Sharma, M.; Benerjee, S. Synthesis and characterization
of poly(arylene ether)s derived from 4,40-bishydroxybiphenyl and 4,40-bishydrox-
yterphenyl. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 55–69.
5. Krafft, M.; Riess, J. Highly fluorinated amphiphiles and colloidal systems, and
their applications in the biochemical field. A contribution. Biochimie 1998, 80,
489–514.
6. McBee, E. T.; Resconich, S.; Belohlav, L. R. The reaction of ethylmagnesium
bromide with acetophenones and trifluoroacetophenones. J. Org. Chem. 1963,
28, 3579–3580.
7. Huang, Y.; Qing, F. Fluorous glycol derivatives: Novel carbonyl protective groups.
Tetrahedron 2004, 60, 8341–8346.
8. Zhdankin, V.; Kuehl, C. [Hydroxy(sulfonyloxy)iodo]perfluoroalkanes–New
hypervalent iodine species and promising reagents for organic synthesis. Tetrahe-
dron Lett. 1994, 35, 1809–1812.
9. Fuchigami, T.; Yamamoto, K. Electrolytic reactions of fluoro organic compounds,
7: Anodic methoxylation and acetoxylation of 2,2,2-trifluoroethyl sulfides: Prep-
aration of highly useful trifluoromethylated building blocks. J. Org. Chem.
1991, 56, 137–142.
10. Arnold-Stanton, R.; Lemal, D. M. Fluorinated bifunctional derivatives of
bisphenol A. J. Org. Chem. 1991, 56, 146–151.
11. Osawa, M.; Kusumoto, A.; Takehara, S. Methylenecyclohexane derivative, liquid
crystal composition containing it, and liquid crystal display device using the com-
position. Jpn. Kokai Tokkyo Koho 2002, JP 2002220356.
12. Takiguchi, T.; Nakamura, S.; Sato, K. Optically active aromatic compound, ferro-
electric/antiferroelectric liquid crystal composition and liquid crystal device using
it. Jpn. Kokai Tokkyo Koho 2001, JP 2001089410.
13. Sinta, R.; Gaudiana, R. A.; Rogers, H. G. Novel thermotropic poly(ester amides).
J. Macromol. Sci. Chem. 1989, A26, 773–785.

2714
O. Akiko et al.
14. Kimura, T.; Duan, X.; Kato, M. Synthesis and nonlinear optical properties of end-
group modified aromatic esters as chained chromophores. Macromol. Chem. Phys.
1998, 199, 1193–1199.
15. Pews, R. G.; Tsuno, Y.; Taft, R. W. A fluorine nuclear magnetic resonance
shielding study of substituent effects on p-charge distributions in benzophenone
and its Lewis acid adducts. J. Am. Chem. Soc. 1967, 89, 2391–2396.
16. Giam, C. S.; Taft, R. W. Evaluation of ground-state electronic energy from fluorine
nuclear magnetic resonance shielding. I. Prediction of enthalpies of reaction for
formation of Lewis acid adducts of benzophenones. J. Am. Chem. Soc. 1967, 89,
2397–2401.
17. Dayal, S. K.; Ehrenson, S.; Taft, R. W. Substituent effects, electronic transmission
and structural dependence of p delocalization as studied with the p-fluorophenyl
tag. J. Am. Chem. Soc. 1972, 94, 9113–9122.
18. Trost, B. M.; Weber, L. Regarding p-electron transmission of substituent polar
effects on fluorine nuclear magnetic resonance shielding. J. Am. Chem. Soc.
1975, 97, 1612–1615.
19. Yokozawa, T.; Suzuki, Y.; Hiraoka, S. Aromatic polyethers with low polydisper-
sities from chain-growth polycondensation. J. Am. Chem. Soc. 2001, 123,
9902–9903.
20. Suzuki, Y.; Hiraoka, S.; Yokoyama, A.; Yokozawa, T. Chain-growth polyconden-
sation for aromatic polyethers with low polydispersities: Living polymerization
nature in polycondensation. Macromolecules 2003, 36, 4756–4765.
21. Suzuki, Y.; Hiraoka, S.; Yokoyama, A.; Yokozawa, T. Solvent effect on chain-
growth polycondensation for aromatic polyethers. J. Polym. Sci., Part A: Polym.
Chem. 2004, 42, 1198–1207.
22. Minamitani, T.; Mochizuki, C. Electrophotographic developing apparatus having
aromatic fluoride-coated toner-supplying member. Jpn. Kokai Tokkyo Koho 1993,
JP 05011499.
23. Yamaguchi, K. One-component electrophotographic developer. Jpn. Kokai
Tokkyo Koho 1992, JP 04063357.
24. Yamaguchi, K.; Kawase, H. Toners for electrostatic image development compris-
ing suspension polymerization particle treated with fluorobenzophenone deriva-
tive. Jpn. Kokai Tokkyo Koho 1991, JP 03188465.
25. DoAmaral, J. R.; Blanz, E. J. Jr.; French, F. A. Antimalarial activity of guanylhy-
drazone salts of aromatic ketones, 1: Primary search for active substituent patterns.
J. Med. Chem. 1969, 12, 21–25.
26. Wang, T. S. T.; Fawwaz, R. A. Synthesis of 4-fluoro-40-trifluoromethylbenzophe-
none guanylhydrazone hydrochloride labeled with carbon-14. J. Label. Compd.
Radiopharm. 1985, 22, 405–409.
27. Moore, J. S. Poly(aryl ketones) via palladium-catalyzed cross-coupling.
Makromol. Chem., Rapid Commun. 1992, 13, 91–96.
28. Deeter, G. A.; Moore, J. S. A new polymerization reaction for the synthesis of
aromatic polyketones. Macromolecules 1993, 26, 2535–2541.
29. Yonezawa, N.; Kameda, A.; Jobashi, T.; Maruyama, S.; Maeyama, K. Synthesis of
sequential wholly aromatic polyketone composed of 2,20-dimethoxybiphenylene
unit. Polym. J. 2004, 36, 345–351.
30. Maeyama, K.; Ohe, T.; Nakamura, H.; Yonezawa, N. Synthesis of fully aromatic
polyketones without ether linkages in the main chain: Nickel complex-mediated
aromatic coupling polymerization of bis(chlorobenzoylated) o-terphenyls.
Polym. J. 2003, 35, 1009–1015.

ArSE Synthesis of Diaryl Ketones that have CF3
2715
31. Yonezawa, N.; Namie, T.; Ikezaki, T.; Hino, T.; Nakamura, H.; Tokita, Y.;
Katakai, R. Synthesis of aromatic polyketones by using biphenylene monomers.
React. Funct. Polym. 1996, 30, 261–268.
32. Maeyama, K.; Tagata, Y.; Yonezawa, N. 2,20-bis(4-benzoylphenoxy)biphenyl: A
novel efficient acyl-acceptant monomer yielding wholly aromatic polyketones
via Friedel–Crafts type polymerization with arenedicarbonyl chloride. Polym. J.
2004, 36, 146–150.
33. Yonezawa, N.; Mori, S.; Miyata, S.; Ueha-Anyashiki, Y.; Wu, S.; Maeyama, K.
Electrophilic aromatic acylation synthesis of wholly aromatic polyketones
composed of 2,20-dimethoxybiphenylene units. Polym. J. 2003, 35, 998–1002.
34. Yonezawa, N.; Ikezaki, T.; Nakamura, H.; Maeyama, K. Successful synthesis of
wholly aromatic polyketones via nickel-mediated aromatic coupling polymeriz-
ation. Macromolecules 2000, 33, 8125–8129.
35. Eaton, P. E.; Carlson, G. R. Phosphorus pentoxide–methanesulfonic acid: A con-
venient alternative to polyphosphoric acid. J. Org. Chem. 1973, 38, 4071–4073.
36. Ridd, J. H.; Yousaf, T. I. Polymerisation and related reactions involving nucleophi-
lic aromatic substitution. Part 1: The rates of reaction of substituted 4-halogenoben-
zophenones with the potassium salts of substituted 4-hydroxybenzophenones.
J. Chem. Soc., Perkin 2 1988, 1729–1734.
37. Maeyama, K.; Ogura, K.; Okamoto, A.; Sakurai, K.; Yoshida, Y.; Ogino, K.;
Yonezawa, N. P2O5–MsOH mediated regioselective diaroylation of 2,20-
dimethoxy-1,10-binaphthyl. Synth. Commun. 2004, 34, 3243–3250.
38. Fuchibe, K.; Akiyama, T. Low-valent niobium-mediated double activation of
C-F/C-H bonds: Fluorene synthesis from o-arylated a,a,a-trifluorotoluene deriva-
tives. J. Am. Chem. Soc. 2006, 128, 1434–1435.
39. Olah, G. A. Superelectrophilies. Angew. Chem. Int. Ed. Engl. 1993, 32, 767–788.
40. Zhong, J.; Wang, Y.; Deng, R. Syntheses of antimalarial drugs, derivatives of
substituted benzophenones. Yiyao Gongye. 1983, 8, 10–12, (in Chinese); Chem.
Abstr. 1983, 100, 138714.
41. DoAmaral, J. R.; French, F. A.; Blanz, E. J., Jr.; French, D. A. Antimalarial activity
of guanylhydrazone salts of aromatic ketones, 2: Development of active polyhalo
derivatives. J. Med. Chem. 197114, 862–866.