Reactions of HMPA with hexafluorobenzene, pentafluorochlorobenzene and pentafluorophenol

Article abstract of DOI:10.1016/j.jfluchem.2008.02.005

Hexamethylphophoramide (HMPA) reacted with hexafluorobenzene and its derivatives with good conversion to give dimethylaminated products and phosphorofluoridates, even in unfavorable reaction stoichiometries. An aromatic nucleophilic mechanism might be inv

Full text of DOI:10.1016/j.jfluchem.2008.02.005

Journal of Fluorine Chemistry 129 (2008) 424–428
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Reactions of HMPA with hexafluorobenzene, pentafluorochlorobenzene
and pentafluorophenol
*
Cheng-Pan Zhang, Qing-Yun Chen, Ji-Chang Xiao
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Hexamethylphophoramide (HMPA) reacted with hexafluorobenzene and its derivatives with good
conversion to give dimethylaminated products and phosphorofluoridates, even in unfavorable reaction
stoichiometries. An aromatic nucleophilic mechanism might be involved.
ß 2008 Elsevier B.V. All rights reserved.
Received 28 January 2008
Received in revised form 21 February 2008
Accepted 26 February 2008
Available online 4 March 2008
Keywords:
Hexafluorobenzene
Pentafluorochlorobenzene
Dimethylamination
Pentafluorophenol
Phosphorofluoridates
Aromatic nucleophilic substitution
1. Introduction
a N,N-dimethylamination of hexafluorobenzene with HMPA.
Herein, we present the results.
Generally, hexafluorobenzene is very stable in common
solvents, such as DMSO, THF and DMEU. Indeed, many nucleophilic
substitution reactions of hexafluorobenzene can be safely per-
formed in these solvents [1,2]. Hexafluorobenzene, as a solvent, is
very soluble, and could favor the intramolecular cyclization of
dialkynyl imidazoles and products separation in much higher
yields [3]. In some conditions, however, the cleavage of C–F bond of
hexafluorobenzene and its derivatives is known to occur in the
presence of nucleophiles. The nucleophilic replacement of the C–F
bond always need wild conditions like high temperature, strong
base or violent nucleophiles [1,4–8]. The use of HMPA to effect N,N-
dimethylamination of aromatic substrates has captured wide
interest previously, for example, the reaction of HMPA with
halogenated aromatics containing electron-withdrawing groups
[9–11]. The synthetic usefulness of the N,N-dimethylamination of
fluoroaromatics has been well documented [3,12–16]. However, to
the best of our knowledge, the reaction between HMPA and
hexafluorobenzene or its derivatives has never been reported. In
the investigation of the reaction of hexafluorobenzene with
nucleophiles in HMPA in our laboratory, we found unexpectedly
2. Results and discussion
The reaction between HMPA and hexafluorobenzene was
carried out in a sealed tube. 2a could be obtained in good yield
at 140 8C for 40 h (entry 4, Table 1), while 2b and 2c were formed at
160 8C for 82 h (entry 9, Table 1), which was determined by 19F
NMR.
As indicated in Table 1, this reaction is much influenced by the
reaction time, temperature and the ratios of the reactants. Lower
temperature and shorter reaction time will favor mono-substitu-
tion. 1-(N,N-dimethylamino)pentafluorobenzene was formed as
the main product at 140 8C for 40 h or at 160 8C for 12 h (entries 4
and 5). Increasing the ratio of HMPA to C6F6 resulted in rapid
conversion of hexafluorobenzene to 1,4-bis(N,N-dimethylamino)-
tetrafluorobenzene (entries 10 and 14). 1,2,4-Tris(N,N-dimethyla-
mino)trifluorobenzene still remains trace as the temperature
increases (entries 1 and 2, entries 3 and 6, entries 4 and 7, entry 13).
However, tetra-substitution were never observed in these condi-
tions even with prolonged reaction time (entries 7, 8, 9, 11 and 12).
The disubstituted product began to form substantially only in the
second 12 h at 160 8C (entries 5 and 6). Similarly, the formation
of trisubstituted product required longer reaction time (entries 7
and 8). This prompts us to assume that the first introduction of the
N,N-dimethylamino group deactivated the second substitution
* Corresponding author. Fax: +86 21 64166128.
E-mail address: jchxiao@mail.sioc.ac.cn (J.-C. Xiao).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.02.005

C.-P. Zhang et al. / Journal of Fluorine Chemistry 129 (2008) 424–428
425
Table 1
Reaction of C6F6 with HMPA
Entry
C6F6:HMPAa
Temperature (8C)
Time (h)
1a:2a:2b:2cb
1
1:5
120
140
140
140
160
160
160
160
160
160
160
160
180
160
120
140
160
160
160
160
180
180
180
180
8
11
23
40
12
24
41
63
82
14
38
65
15
6
100:0:0:0
75:25:0:0
30:70:0:0
5:94:1:0
2
1:5
3
1:5
4
1:5
5
1:5.3
1:5.3
1:5.3
1:5.3
1:5.3
1:20
1:20
1:20
1:20
1:50
1:5
2:95:3:0
6
0:79:21:0
0:50:44:6
0:12:77:11
0:12:69:19
0:45:43:12
0:5:77:18
0:0:83:17
0:54:36:10
0:15:85:0
100:0:0:0
98:2:0:0
7
8
9
10
11
12
13
14
15c
16c
17
18
19d
20d
21
22
23e
24e
9
1:5
23
2
1:5.3
1:5.3
1:5.3
1:5.3
1:5.3
1:5.3
1:5.3
1:5.3
79:21:0:0
69:31:0:0
77:23:0:0
68:32:0:0
10:88:2:0
0:91:9:0
4
2
4
2
4
2
9:89:2:0
4
0:90:10
a
Molar ratio.
Molar ratio, determined by 19F NMR.
b
c
NaF was added in the reaction system and the molar ratio of NaF to C6F6 was 1:1.
p-Hydroquinone was added and the molar ratio of p-hydroquinone to C6F6 was 1:5.
The reaction was conducted in darkness.
d
e
of hexafluorobenzene. And the second introduction of N,N-
dimethylamino group would intensively deactivate further sub-
stitution. Therefore, tri-substitution products always remain in
low yield (entries 7–13). Probably this can be explained in terms of
the strongly electron-donating effect of N,N-dimethylamino group
which retarded the further nucleophilic attack of N,N-dimethyla-
mino anion to 2a, 2b and 2c. Addition of fluoride ion could not
make the reaction condition milder but greatly inhibit the reaction
(entries 1 and 15, entries 3 and 16), which indicated that the
generation of dimethylamino anion would not be induced by
fluoride ion. Thermal cleavage of P–N bond was then assumed to be
the most probable way to dimethylamino anion. Furthermore, the
reaction could not be suppressed by the addition of free-radical
inhibitor, p-hydroquinone (entries 17 and 19, entries 18 and 20)
and could not be inhibited either even in dark environment
(entries 21 and 23, entries 22 and 24), which indicated that there
might be no free radical generated in these reactions. Even though
mono-, di-, and tri-substituted products were formed almost
simultaneously in most cases, the desired substitution type could
still be obtained by choosing proper reaction time, temperature
and the reactant ratios. These three dimethylaminated products
were easily separated by column chromatography.
[17–23]. There have been several approaches for the synthesis of
these P–F compounds, which required the use of some special
phosphorus precursors [19–21]. This reaction might thus become a
more practical and straightforward method to construct the
phosphorofluoridates. Treatment of hexafluorobenzene with HMPA
at 160 8C for 12 h could give 3a in 36% yield and 3b in 25% yield,
which were determined by 19F NMR using trifluoroacetic acid as an
internal standard (entry 5, Table 1).
In the case of pentafluorochlorobenzene, similar results were
achieved, as described in Table 2. Different products were also
observed at different reaction time, temperature and reactant
ratios (entries 1–3, entries 4 and 8). The para-substitution of
pentafluorochlorobenzene with HMPA occurred at 160 8C at first
(entry 3). The di-substitution and the subsequent tri-substitution
happened gradually with the extension of time (entries 5–7 and 8–
11). The product 4b and 4c were fully characterized by 1H NMR, 19
F
NMR, elementary analysis and MS. The substitution position of the
second and the third dimethylamino group was confirmed by the
19F NMR and 1H NMR, as mentioned in the literatures [24,25]. A
doublet with 5J (F–H) 2.1 Hz and a triplet with 5J (F–H) 1.8 Hz in the
1H NMR of 4b indicated that there exist two kinds of proton, in
which one was coupled with one fluorine and the other with two
[25]. This means that the first dimethylamino group was adjacent
to two fluorine. Only doublets or multiplets would be observed in
1H NMR specta if the substitution happened at C2. Therefore, the
introduction of the second dimethylamino group should be at C3
(4b) (Scheme 1). As for 4c, 5-substitution could be excluded for the
Besides the dimethylamination products, the phosphorofluor-
idates (3a and 3b), which have been demonstrated to be good
selective phosphorylating agents and efficient inhibitors of several
classesofenzyme [17–19], werealsoformed inthesereactions. They
were easily determined by 19F NMR, according to the literatures

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C.-P. Zhang et al. / Journal of Fluorine Chemistry 129 (2008) 424–428
Table 2
Reaction between C6F5Cl and HMPA
Entry
C6F5Cl:HMPAa
Temperature (8C)
Time (h)
1b:4a:4b:4cb
1
1:1.21
1:1.21
1:1.21
1:4.7
1:4.7
1:4.7
1:4.7
1:10
140
160
160
160
160
160
160
160
160
160
160
5
5
99:1:0:0
2
58:42:0:0
2:97:1:0
3
10
5
4
0:91:9:0
5
10
44
82
5
0:74:26:0
0:23:69:8
0:7:65:28
0:69:31:0
0:16:70:14
0:0:28:72
0:0:12:88
6
7
8
9
1:10
10
44
82
10
11
a
1:10
1:10
Molar ratio.
Molar ratio, determined by 19F NMR.
b
reason that two kinds of signals were found in the 19F NMR specta.
In addition, the signal appeared as a doublet with J (F–F) 7.8 Hz was
not from the ortho F–F coupling [25]. Thus the third dimethylamino
group should be bonded to C6 (4c) (Scheme 1). Besides, the 19F
chemical shifts confirmed further the substitution position of the
dimethylamino groups [24].
In order to gain deep insight into these reactions, we extended
our investigation to pentafluorophenol, as shown in Scheme 2.
Phosphordiamidates 5a and 5b (1:2) were formed when penta-
fluorophenol reacted with HMPA at 140 8C for 20 h. As for the
formation of 5a, 4-(N,N-dimethylamino)tetrafluorophenol (5c) was
presumed to be the most probable intermediate. The reaction
between 5c and 3a was very fast. Therefore, no 5c could be detected
by 19F NMR. On the other hand, the ortho-substituted phosphordia-
midate 5b was obtained as the major product in the reaction of
HMPA with pentafluorophenol (Scheme 2). An intramolecular
nucleophilic substitution was supposed to occur after the phos-
phorylation of pentafluorophenol with HMPA (Scheme 2).
Scheme 1.
Based on these observations, the single electron transfer (SET)
mechanism [26] was not supposed to be involved in these
substitution reactions. The product profile and the inhibition expe-
riments (entries 17–24 in Table 1) did not support a free radical
mechanism. The relative reactivity between hexafluorobenzene and
pentafluorochlorobenzene with HMPA (entry 5 in Table 1 and entry
4 in Table 2) and the preferential para-substitution of pentafluoro-
chlorobenzene and pentafluorophenol in HMPA (2a, 2b, 4a and 5c in
Scheme 2.

C.-P. Zhang et al. / Journal of Fluorine Chemistry 129 (2008) 424–428
427
Scheme 3.
Scheme 3 and 5a in Scheme 2) prompt us to assume that a typical
4.4. 1,4-Di(N,N-dimethylamine)tetrafluorobenzene and 1,2,4-
tri(N,N-dimethylamine)trifluorobenzene (2b, 2c)
nucleophilic aromatic substitution might be involved in these
reactions [27,28], as outlined in Scheme 3. The ortho-effect [27] was
also observed among them. Furthermore, the formation of 5a also
confirmed the existence of the phosphorofluoridate 3a, which was
found in the previous reactions of hexafluorobenzene and penta-
fluorochlorobenzene.
2b: Yield 63%, 1H NMR: d 2.88 (s, 12H) 19F NMR: d À152.8 (s, 4F).
2c: Yield 9.5%, 1H NMR: d 2.86 (t, J = 1.8 Hz, 6H), 2.83 (d, J = 1.8 Hz,
6H), 2.79 (d, J = 1.8 Hz, 6H) 19F NMR: d À136.0 (d, J = 6.3 Hz, 1F),
À151.2 (d, J = 20.4 Hz, 1F), À152.3 (dd, J = 20.4 Hz, 6.3 Hz, 1F).
3. Conclusion
4.5. 4-Chloro-1-(N,N-dimethylamine)tetrafluorobenzene (4a)
The aromatic nucleophilic substitution between HMPA and
hexafluorobenzene or its derivatives could occur smoothly, which
offers a simple and efficient method for the transformation of the
polyfluoroaromatics to the corresponding dimethylaminated
derivatives and a new procedure for the preparation of phosphor-
ofluoridates. When HMPA was used as the solvent for polyfluor-
obenzenes and other activated halo-aromatic compounds, the
potential reactions between them should be considered.
Yield 36%, 1H NMR: d 2.95 (t, J = 2.7 Hz, 6H) 19F NMR: d À143.9
(dm, J = 20.4 Hz, 2.7 Hz, 2F), À150.9 (d, J = 20.4 Hz, 2F).
4.6. 4-Chloro-2,5,6-trifluoro-N,N,N,N-tetramethylbenzene-1,3-
diamine and 5-chloro-3,6-difluoro-N,N,N,N,N,N-hexamethylbenzene-
1,2,4-triamine (4b, 4c)
4b: Colorless liquid. Yield 47%, 1H NMR: d 2.90 (t, J = 1.8 Hz, 6H),
2.83 (d, J = 2.1 Hz, 6H) 19F NMR: d À134.3 (s, 1F), À141.7 (dm,
J = 19.6 Hz, 1F), À149.2 (d, J = 19.6 Hz, 1F); ESIMS (m/e): 253.0
[M+H]+ (100); IR (KBr): 2933, 2852, 2803, 1499, 1452, 1432, 1060,
989, 914, 878, 801 cmÀ1. Anal. Calcd for C10H12ClF3N2: C, 47.54; H,
4.79; N, 11.09. Found: C, 47.92; H, 5.11; N, 10.92. 4c: Colorless
liquid. Yield 54%, 1H NMR: d 2.83–2.84 (m, 12H), 2.80 (d, J = 2.1 Hz,
6H) 19F NMR: d À126.6 (d, J = 7.8 Hz, 1F), À134.2 (s, 1F); ESIMS (m/
e): 278.0 [M+H]+ (100); IR (KBr): 2979, 2933, 2871, 2839, 2796,
1494, 1448, 1214, 1051, 1000, 927, 874, 776 cmÀ1. Anal. Calcd for
4. Experimental
4.1. General
NMR spectra were recorded in deuteriochloroform, unless
otherwise stated, on Mercury 300 at 300 MHz (1H NMR) and
282 MHz (19F NMR). Chemical shifts were reported in parts per
million relative to tetramethylsilane and trichlorofluoromethane
(positive for downfield shifts) as external standards. Mass spectra
were recorded on a Shimadzu LCMS instrument. The IR spectra were
recorded on a Shimadzu IR-440 spectrometer. Column chromato-
graphy was carried out on silica gel H (10–40 mm). All starting
materials were obtained commercially. HMPA was distilled from
CaH2 before use.
C12H18ClF2N3: C, 51.89; H, 6.53; N, 15.13. Found: C, 51.72; H, 6.51;
N, 14.72.
4.7. 4-(Dimethylamino)-2,3,5,6-tetrafluorophenyl-N,N,N,N-
tetramethylphosphordiamidate and 2-(dimethylamino)-3,4,5,6-
tetrafluorophenyl-N,N,N,N-tetramethylphosphordiamidate (5a, 5b)
4.2. Typical procedure
5a: Red liquid. Yield 15%, 1H NMR: d 2.89 (t, J = 2.4 Hz, 6H), 2.78
(d, J = 9.9 Hz, 12H) 19F NMR: d À153.0 (d, J = 19.2 Hz, 2F), À158.6 (d,
J = 19.2 Hz, 2F); ESIMS (m/e): 344.1 [M+H]+ (100); IR (KBr): 2938,
2901, 2858, 2814, 1519, 1497, 1459, 1438, 1312, 1234, 1123, 1027,
985, 866, 796, 761, 506, 475 cmÀ1. Anal. Calcd for C12H18F4N3O2P:
C, 41.99; H, 5.29; N, 12.24. Found: C, 42.40; H, 5.43; N, 12.06. 5b:
Red liquid. Yield 29%, 1H NMR: d 2.87 (t, J = 1.8 Hz, 6H), 2.78 (d,
J = 10.8 Hz, 12H). 19F NMR: d À143.5 (s, 1F), À149.8 (d, J = 21.9 Hz,
1F), À157.5 (d, J = 22.5 Hz, 1F), À165.2 (td, J = 22.5 Hz, 1F); ESIMS
(m/e): 344.1 [M+H]+ (100), IR (KBr): 2937, 2900, 2857, 2812, 1514,
1492, 1454, 1312, 1234, 1000, 987, 873, 792, 759, 474 cmÀ1. Anal.
Calcd for C12H18F4N3O2P: C, 41.99; H, 5.29; N, 12.24. Found: C,
42.42; H, 5.48; N, 11.98.
The polyfluorobenzene (4.67 mmol) was placed in a sealed tube
equipped with a magnetic stir bar. HMPA (4 ml) was added and the
system was flushed with nitrogen. The sealed tube was kept at
160 8C for 82 h. Then the reaction mixture was cooled and poured
into water (20 ml), extracted with ethyl acetate (30 ml), washed
with water (4 ml  15 ml) and dried over anhydrous Na2SO4. The
crude products were purified by column chromatography.
4.3. 1-(N,N-dimethylamine)pentafluorobenzene (2a)
Yield 69%, 1H NMR: d 2.90 (t, J = 2.4 Hz, 6H) 19F NMR: d À150.8
(dm, J = 22.4 Hz, 2F), À164.1 (tm, J = 22.4 Hz, 22.2 Hz, 2F), À164.8
(tm, J = 22.2 Hz, 1F).

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C.-P. Zhang et al. / Journal of Fluorine Chemistry 129 (2008) 424–428
[12] V.E. Platonov, A. Haas, M. Schelvis, M. Lieb, K.V. Dvornikova, O. Osina, J. Fluorine
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We thank the Chinese Academy of Sciences (Hundreds of
Talents Program) and the National Natural Science Foundation
(20772147) for financial support.
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