Convenient synthesis of 3,3,3-trifluoropropanoic acid by hydrolytic oxidation of 3,3,3-trifluoropropanal dimethyl acetal

Article abstract of DOI:10.1016/j.jfluchem.2007.08.007

A convenient and efficient method for preparing 3,3,3-trifluoropropanoic acid (1) is reported. The starting material is 1-chloro-3,3,3-trifluoropropene (2) that can be easily transformed into 3,3,3-trifluoropropanal dimethyl acetal (4) on treatment with methanol and KOH followed by acid-catalyzed addition of methanol. Direct transformation of 4 into 1 was efficiently achieved with 30% aqueous hydrogen peroxide (4.0 equiv.) in the presence of FeCl₃ (0.025 equiv.) and hydrochloric acid (0.5 equiv.).

Full text of DOI:10.1016/j.jfluchem.2007.08.007

Journal of Fluorine Chemistry 129 (2008) 35–39
www.elsevier.com/locate/fluor
Convenient synthesis of 3,3,3-trifluoropropanoic acid by hydrolytic
oxidation of 3,3,3-trifluoropropanal dimethyl acetal
Takeo Komata a,b, Shinya Akiba b, Kenji Hosoi b, Katsuyuki Ogura a,
*
a Diversity and Fractal Science, Graduate School of Science and Technology, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba-shi, Chiba 263-8522, Japan
b Chemical Research Center, Central Glass Co. Ltd., 2805 Imafuku-Nakadai, Kawagoe-shi, Saitama 350-1151, Japan
Received 28 July 2007; received in revised form 6 August 2007; accepted 10 August 2007
Available online 15 August 2007
Abstract
A convenient and efficient method for preparing 3,3,3-trifluoropropanoic acid (1) is reported. The starting material is 1-chloro-3,3,3-
trifluoropropene (2) that can be easily transformed into 3,3,3-trifluoropropanal dimethyl acetal (4) on treatment with methanol and KOH followed
by acid-catalyzed addition of methanol. Direct transformation of 4 into 1 was efficiently achieved with 30% aqueous hydrogen peroxide
(4.0 equiv.) in the presence of FeCl3 (0.025 equiv.) and hydrochloric acid (0.5 equiv.).
# 2007 Elsevier B.V. All rights reserved.
Keywords: 3,3,3-Trifluoropropanoic acid; Acetal; Hydrogen peroxide; Hydrolytic oxidation
1. Introduction
can be performed in an industrial scale. Here, we report a
convenient method for deriving 1 from 1-chloro-3,3,3-
trifluoropropene (2) that is commercially available as a raw
material of 1,1,1,3,3-pentafluoropropane (Scheme 1). The key
process of the present route is the direct conversion of 3,3,3-
trifluoropropanal dimethyl acetal (4) to 1.
Since 3,3,3-trifluoropropanoic acid (1) is an important
intermediate for the synthesis of some medicines [1a,b],
agricultural chemicals [2], and fluorinated polymers [3a–c],
several methods have been reported for preparing it; (i) the
trifluoromethylation of 3-bromo-1-propene with CF3CdBr
followed by oxidation with potassium permanganate and 18-
crown-6 [4a]; (ii) the radical addition of CF3I to the t-
butyldimethylsilyl enol ether of t-butyl acetate and the
subsequent acidic hydrolysis [4b]; (iii) the reaction of
monoethyl malonate with SF4 to give ethyl 3,3,3-trifluoropro-
panoate that is transformed by hydrolysis to give 1 [4c]; (iv) the
Bayer–Villiger oxidation of cyclohexyl 2,2,2-trifluoroethyl
ketone, which is derived by the AlCl3-mediated addition of
cyclohexylcarbonyl chloride to 1,1-difluoroethene, followed by
hydrolysis [4d]; (v) four-step derivation of 1,3-dithiane into 2-
(2,2,2-trifluoroethylidene)-1,3-dithiane that can be hydrolyzed
with sulfuric acid and mercury oxide to produce 1 [4e]. Most of
these methods involve many steps and utilize hazardous or
expensive reagents. Hence, we started our investigation to
develop an environmentally benign route leading to 1, which
2. Results and discussion
The key material, 3,3,3-trifluoropropanal dimethyl acetal (4)
was synthesized from 1-chloro-3,3,3-trifluoropropene (2) by
the substitution of chlorine atom with methoxyl group and the
subsequent addition of methanol. According to the literature
[5a], the reaction of 2 with methanol (5.58 equiv.) in the
presence of potassium hydroxide (1.06 equiv.) was performed
except for the reaction temperature (70 8C. Lit. temperature:
100 8C). After insoluble solid was filtered off, the obtained
filtrate was distilled. By the distillation, potassium hydroxide
was completely removed. After the addition of methanesulfonic
acid (0.20 equiv.), the distillate was heated at 70 8C for 4 h [5b].
By further distillation, we obtained the expected acetal (4) in
47% overall yield (from 2).
With the key intermediate (4) in hand, we initiated the
investigation to convert it to 3,3,3-trifluoropropanoic acid (1). It
is generally known that the aldehydes having strong electron-
withdrawing group(s) (for example, chloral) is so reactive to
* Corresponding author. Tel.: +81 43 290 3388; fax: +81 43 290 3402.
E-mail address: katsuyuki@faculty.chiba-u.jp (K. Ogura).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.08.007

36
T. Komata et al. / Journal of Fluorine Chemistry 129 (2008) 35–39
Scheme 1.
easily form the corresponding acetal or hydrate with an alcohol
or water, respectively. Therefore, we employed the reaction
path via 3,3,3-trifluoropropanal hydrate (5), which can be
produced by hydrolysis of 4. The concurrent oxidation of the
thus-formed 5 would give the expected 1.
The results that were obtained by GC analysis were
summarized in Table 1. The aldehyde (6) in Table 1 means that
it was detected by GC, but it is thought to exist as the hydrate
form (5) in the reaction mixture. It is likely that the formation of
the methyl ester (7) was attributable to the oxidation of the
intermediary hemiacetal (8). At the present time, we cannot
eliminate the possibility that a part of the methyl ester (7) was
formed by HCl-catalyzed esterification of 1 with methanol.
This is because methanol is produced in the hydrolysis of 4. The
best result was attained under the conditions using 4 equiv. of
hydrogen peroxide and 1 equiv. of HCl (Entry 4 in Table 1).
Next, we examined whether other cheap metal oxide and
metal salts can be employed instead of V2O5. The metal oxides
and metal salts examined here are listed in Table 2, which
showed the results using them. In the reaction using no metal
Direct conversion of a protected lactol to the corresponding
lactone was known to take place with a combination of m-
chloroperbenzoic acid and BF3 etherate [6]. The Jones
oxidation was also applied to this conversion [7]. Recently,
Patel et al. reported a mild and efficient method using a catalytic
amount of V2O5 and 30% aqueous hydrogen peroxide for the
oxidative transformation of acetals into the corresponding
esters [8]: when the reaction was performed in methanol at
about 5 8C, a methyl ester (III) was formed as shown Scheme 2
[8a]. The reaction seems to proceed through a V2O5-hydrogen
peroxide complex (II) to give III [8b]. In the absence of
methanol, the corresponding carboxylic acid was produced.
First, we applied this reaction system to the conversion of 4
to 1. But, the acetal (4) was too stable to react. Hence, we added
conc. hydrochloric acid to the reaction system in order to
promote the production of the hydrate (5). The oxidizing
reagent, which was prepared by mixing 30% hydrogen
peroxide, conc. hydrochloric acid, and V2O5 (0.05 mol-equiv.)
at À15 8C, was added to 4 and then the reaction mixture was
stirred. At an elevated temperature (60–80 8C), the reaction
occurred smoothly (Scheme 3).
Table 1
Oxidation of the acetal (4) with V2O2–H2O2 in the presence of HCla
Entry
H2O2
HClc
Temperature
Conversion
of 4 (%)c
Yield (%)d
b
(equiv.)
(equiv.)
(8C)
1
6
7
1
2
3
4
2
4
4
4
1
1
1
2
60
60
80
80
95
99
37
64
87
87
42
23
4
2
7
6
100
100
1
12
a
V2O5 (0.05 mol-equiv.) was used.
30% aq. H2O2 was used.
b
c
d
35% hydrochloric acid was used.
Determined by GC analysis.
Table 2
Oxidation of 4 with H2O2 and HCl in the presence of various metal compoundsa
Entry
Metal
Conversion
of 4 (%)b
Yield (%)b
compound
1
6
7
1
2
V2O5
–
100
93
87
12
85
91
70
56
87
91
53
49
24
50
9
4
6
22
1
31
9
3
Fe
100
100
100
99
Scheme 2.
4
FeCl3
Fe2O3
RuCl3
CuCl
Cu2O
AlCl3
ZnCl2
MoCl5
MnO2
WCl6
NiCl2
1
5
5
0
4
6
13
2
20
9
7
100
100
100
99
8
2
7
9
16
18
30
19
44
19
14
15
11
16
4
10
11
12
13
14
99
99
99
99
47
20
a
The reaction was performed with 30% aq. H2O2 (4 equiv.), 35% hydro-
chloric acid (1 equiv.), and the metal compound (0.05 mol-equiv.) at 80 8C.
Determined by GC analysis.
b
Scheme 3.

T. Komata et al. / Journal of Fluorine Chemistry 129 (2008) 35–39
37
compound (Entry 2), some unknown compounds were formed
except for 1, 6, and 7. Thus, the metal compound was confirmed
to play an important role in the present reaction. As shown in
Table 2, Fe, FeCl3, Fe2O3, CuCl, Cu2O, and V2O5 accelerated
the reaction to produce 1 in good to high yields. Probably, Fe,
Fe2O3, and Cu2O reacted with HCl to be converted to the
corresponding metal chlorides. Among the metal compounds
examined here, we selected FeCl3 because it is economically
advantageous and environmentally benign.
In the reactions listed in Tables 1 and 2, the required quantity
of hydrogen peroxide was 4 equiv. Although we made our effort
to reduce the amount of hydrogen peroxide, it was shown that
the best result was obtained with 4 equiv. of hydrogen peroxide.
The results are summarized in Table 3. As shown in Entries 1–3,
the yield of 3,3,3-trifluoropropanoic acid (1) became lower as
the amount of 30% aqueous hydrogen peroxide decreased. To
our surprise, the yield of methyl 3,3,3-trifluoropropionate (7)
increased with the decreasing amount of 30% aqueous
hydrogen peroxide. This tendency was also observed when
0.025 equiv. of FeCl3 and 15% aqueous hydrogen peroxide
were employed (Entries 5–7).
Scheme 4.
(4 equiv.) in the presence of FeCl3 (0.025 equiv) and conc.
hydrochloric acid (0.5 equiv.), as shown in Entry 4 of Table 3.
The yields of 1 was 95%.
The reaction mechanism is unclear at the present time, but
the reaction most likely proceeds via an intermediary
hydroperoxide (9), which is converted to 1 by the assistance
of FeCl3 and HCl. This is in analogy with the mechanism
proposed for the reaction of 2-halocyclohexanone with
hydrogen peroxide, which forms 2-halo-1-hydroxy-1-hydro-
peroxycyclohexane in the presence or the absence of mineral
acid [9] (Scheme 4).
3. Conclusion
We found the favorable reaction conditions for preparing
3,3,3-trifluoropropanoic acid (1) by the hydrolytic oxidation of
3,3,3-trifluoropropanal dimethyl acetal (4), which was easily
derived from 1-chloro-3,3,3-trifluoropropene. Thus, the hydro-
lytic oxidation of 4 with a high efficiency was attained with
30% aqueous hydrogen peroxide (4.0 equiv.) by the assistance
of FeCl3 (0.025 equiv.) and hydrochloric acid (0.5 equiv.).
As mentioned previously, water reacts with 4 to produce the
hydrate (5) via the hemiacetal (8). Since these reactions are
reversible, a large amount of water pushes the equilibrium
toward the hemiacetal site and then toward the hydrate site. If
the concentration of water becomes lower, the concentration of
the hydrate would be lower. As a result, the oxidation process
from the hemiacetal (8) should become more favorable.
Therefore, it is reasonably rationalized in terms of the amount
of water in the system that the yield of 7 increases with the
decreasing amount of aqueous hydrogen peroxide.
4. Experimental
1H NMR and 19F NMR spectra were recorded at 400 MHz on
aJEOLa-400andJEOLAL-400. 1H NMRdataaregiveninparts
per million (ppm) downfield from tetramethylsilane (TMS) as an
internal standard. 19F NMR data are given in ppm upfield from
CCl3F (an internal standard). The abbreviations used are as
follows: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad. Coupling constants (J values) are
given in hertz (Hz). MS analyses were performed using a
Shimadzu GCMS-QP2010 (EI at 70 eV). Gas chromatography
(GC) analyses were performed on a Shimadzu GC17A equipped
with J & W DB-5 capillary column (30 m) and a FID detector.
Finally, it should be noted that the best result was obtained in
the reaction of 4 with 30% aqueous hydrogen hydroperoxide
Table 3
Oxidation of 1 with FeCl3–HCl–H2O2
b
Entry
FeCl3
HCla
H2O2
Conversion
of 4c (%)
Yieldc (%)
4.1. Preparation of 3,3,3-trifluoropropanal dimethyl
acetal (4)
(equiv.)
(equiv.)
(equiv.)
1
6
7
1
2
3
4
5
6
7
0.05
1.0
1.0
1.0
0.5
0.5
0.5
0.5
4.0
100
100
99
91
54
34
95
92
84
65
1
–
1
–
–
–
2
5
Methanol (307 g, 9.6 mol), water (22.5 g), KOH (102 g,
1.8 mol), and 1-chloro-3,3,3-trifluoropropene (2, 225 g,
1.7 mol) were placed in a 1000 ml pressure-proof stainless
steel (SUS316) reactor equipped with a thermometer, a pressure
gauge, and a stirrer. The reactor was heated at 70 8C (internal
temperature) in an oil bath for 6 h under being stirred. It was
found by GC analysis that the reaction mixture involves 3,3,3-
trifluoro-1-methoxypropene (3), 1-chloro-3,3,3-trifluoropro-
pene (2), and 3,3,3-trifluoropropanal dimethyl acetal (4) in
0.05
3.0
44
58
3
0.05
2.0
0.025
0.025
0.025
0.025
4.0
100
100
100
99
4.0d
3.0d
2.0d
5
13
19
a
35% hydrochloric acid was used.
b
c
d
30% aq. H2O2 was used unless otherwise noted.
Determined by GC analysis.
15% aq. H2O2 was used.

38
T. Komata et al. / Journal of Fluorine Chemistry 129 (2008) 35–39
74%, 21%, and 5% yields, respectively. After insoluble solid
was filtered off, the filtrate was distilled to give a colorless
liquid (381.5 g). By this distillation, potassium hydroxide was
completely removed. After the addition of methanesulfonic
acid (33.0 g, 0.34 mol), the distillate was heated at 70 8C for
4 h. It was shown by GC analysis that the reaction mixture
contains 3,3,3-trifluoropropanal dimethyl acetal (4) and 3,3,3-
trifluoro-1-methoxypropene (3) in 96% and 1% yields,
respectively. After the reaction mixture was washed with
water (300 g), the organic layer was separated and dried over
[CF2CH2]+ (75), 63 [CF2CH]+ (10), 51 [CHF2]+ (3), 47 [COF]+
(3), 45 [CFCH2]+ (100), 42 [CH2CO]+ (19), 29 [CHO]+ (11), 28
[CO]+ (3). Anal. Calcd. for C3H3F3O2: C, 28.14; H, 2.36.
Found: C, 28.13; H, 1.91.
4.4. Independent synthesis of methyl 3,3,3-
trifluoropropionate (7)
Thionyl chloride (8.4 g, 0.071 mol) and a few drops of DMF
were placed in a 50 ml round-bottomed flask fitted with a
stirrer, a thermometer, a reflux condenser, and a dropping
funnel. After 3,3,3-trifluoropropanoic acid (7; 10.0 g,
0.078 mol) was dropwise added at 40 8C, the mixture was
stirred at 60–70 8C for 3 h. Then, methanol (2.3 g, 0.072 mol)
was added at room temperature and the mixture was stirred at
50 8C for 1 h. The reaction mixture was purified by distillation
(96–97 8C) to give methyl 3,3,3-trifluoropropionate (7; 7.5 g,
74% yield) as a colorless liquid; 1H NMR (CDCl3): d 3.19 (2H,
q, J = 10.6 Hz), 3.77 (3H, s); 19F NMR (CDCl3): d À64.16 (3F,
t, J = 10.6 Hz); EI-MS m/z (rel. int.): 142 [M]+ (9), 122 [M–
HF]+ (16), 111 [M–CH3O]+ (100), 91 [CF2CHCO]+ (25), 83
[CF3CH2]+ (26), 69 [CF3]+ (13), 64 [CF2CH2]+ (15), 63
[CF2CH]+ (5), 59 [C2H3O2]+ (47), 42 [CH2CO]+ (4), 31
[CH3O]+ (116), 29 [CHO]+ (12). Anal. Calcd. for C4H5F3O2: C,
33.81; H, 3.55. Found: C, 33.80; H, 3.14.
˚
MS 4 A (20 g). The obtained reaction mixture was purified by
distillation (89–90 8C) to give 3,3,3-trifluoropropanal dimethyl
acetal (7; 128 g; 47% yield) as a colorless liquid; H NMR
1
(CDCl3): d 2.51 (2H, dq, J = 10.6 and 5.6 Hz), 3.33 (6H, s), 4.70
(1H, d, J = 5.6 Hz); 19F NMR (CDCl3): d À63.34 (3F, d,
J = 10.6 Hz); EI-MS m/z (rel. int.): 158 [M]+ (0.05), 127 [M–
CH3O]+ (47), 83 [CF3CH2]+ (3), 75 [M–CF3CH2]+ (51), 69
[CF3]+ (5), 64 [CF2CH2]+ (5), 63 [CF2CH]+ (100), 59
[C2H3O2]+ (3), 47 [CH3O2]+ (15), 45 [CFCH2]+ (5), 43
[C2H3O]+ (4), 31 [CH3O]+ (17), 29 [CHO]+ (26), 28 [CO]+ (3).
Anal. Calcd. for C5H9F3O2: C, 37.98; H, 5.74. Found: C, 38.12;
H, 5.78.
4.2. General procedure for the hydrolytic oxidation of
3,3,3-trifluoropropanal dimethyl acetal (4)
The oxidizing reagent, which was prepared by mixing 35%
hydrochrolic acid, metal compound, and30%hydrogenperoxide
at À15 to À10 8C, were added to 3,3,3-trifluoropropanal
dimethyl acetal (4) at 60 8C or 80 8C and the reaction mixture
was stirred at the same temperature for 1 h. An aliquot of the
reaction mixture was taken out and analyzed by GC. The
isolation of 1 and its characterization are given in the following
section. The authentic sample of 6 was purchased from SynQuest
Labs., Inc. (Florida, U.S.A.) The structure of 7 was confirmed by
the independent syntheses that were described below.
Acknowledgement
We thank Dr. Yutaka Katsuhara (Central Gass Co., Ltd.) for
helpful discussions.
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