Electrophilic fluorination of aromatic compounds with NF type reagents: Kinetic isotope effects and mechanism

Article abstract of DOI:10.1016/j.tetlet.2006.02.016

H/D Isotope effects in fluorination of aromatic compounds with NF type reagents have been studied to reveal the reaction mechanism. The results obtained are consistent with a polar S_EAr mechanism. Small deuterium isotope effects (k_H/

Full text of DOI:10.1016/j.tetlet.2006.02.016

Tetrahedron Letters 47 (2006) 2639–2642
Electrophilic fluorination of aromatic compounds
with NF type reagents: kinetic isotope effects and mechanism
a,b
Gennady I. Borodkin,a,b, Pavel A. Zaikin and Vyacheslav G. Shubina
*
aVorozhtsov Novosibirsk Institute of Organic Chemistry, Acad. Lavrentiev ave. 9, 630090, Russia
bNovosibirsk State University, Pirogov st. 2, 630090, Russia
Received 8 September 2005; revised 24 January 2006; accepted 1 February 2006
Available online 21 February 2006
Abstract—H/D Isotope effects in fluorination of aromatic compounds with NF type reagents have been studied to reveal the reac-
tion mechanism. The results obtained are consistent with a polar SEAr mechanism. Small deuterium isotope effects (kH/kD = 0.86–
0.99) show that decomposition of a Wheland-type intermediate is not rate determining. The first example of a 1,2-hydrogen shift
accompanying electrophilic fluorination of arenes has been observed in the fluorination of 1,3,5-trideuterobenzene.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Fluorinated aromatic compounds are of increasing sig-
nificance for agrochemical, pharmaceutical and chemi-
cal uses.1 However, the selective direct introduction of
fluorine into aromatic molecules is still only a partly
solved problem.2,3 In the last two decades, various
types of N-fluoro compounds have been found to be
appropriate fluorine sources for milder and selective
fluorination of organic compounds.3–6 Interest in NF
type reagents was aroused with reports on N-fluoro-
benzenesulfonimide, 1-fluoropyridinium, 1,10-difluoro-
2,20-bipyridinium and 1-chloromethyl-4-fluoro-1,4-diazo-
niabicyclo[2.2.2]octane salts, which are commercially
available.3–6 Although details of the synthesis and char-
acterization of NF reagents have been published, little
information appears to have been reported concerning
the mechanism of their interaction with arenes.3–6
From the observed isomer distributions, which show
predominant ortho–para substitutions to electron-
donating ring substituents, the reactions are considered
to be the typical electrophilic aromatic substitu-
tions.4,7,8 Note that neither free nor solvated F+
cations are implicated in the reactions; the enthalpy
of F+ formation is very high compared with the values
for the other halonium ions (Cl+, Br+ and I+).4
At present two general possible pathways for electro-
philic fluorine transfer have been considered: nucleo-
philic displacement at fluorine (polar mechanism,
SEAr) and single electron transfer involving a radical
cation species as a discrete intermediate (SET mecha-
nism) (Scheme 1).3,6 The question of which of these
mechanisms is correct is, as yet, unresolved and it is pos-
sible that different arenes are fluorinated by different
mechanisms (cf. Refs. 6,7,9,10).
This letter reports a kinetic isotope study of the reaction
of NF reagents 1-chloromethyl-4-fluoro-1,4-diazoniabi-
cyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-
BF4) 1, 1,10-difluoro-2,20-bipyridinium bis(tetrafluoro-
borate) 2 and N-fluorobenzenesulfonimide 3 with
benzene, mesitylene and naphthalene. A reaction path-
way involving nucleophilic displacement at the fluorine
atom has been proposed as the main process. Such a
mechanism was determined from the fluorination of
mesitylene and durene with F-TEDA-BF4 in MeCN
and 1-ethyl-3-methylimidazolium triflate.7 As the
ionization potentials of benzene (9.24384 eV) and
naphthalene (8.1442 eV) are higher than that of durene
(8.025 eV), a SET mechanism for their fluorination
could hardly be operative.
Keywords: Fluorination; NF Reagent; Mechanism; Kinetics; Deute-
rium isotope effects; 1,2-Shift.
*
Corresponding author. Tel.: +7 383 330 7651; fax: +7 383 330
9752; e-mail: gibor@nioch.nsc.ru
Ionization potentials were obtained from the NIST Chemistry
WebBook (http://webbook.nist.gov/).
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.016

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G. I. Borodkin et al. / Tetrahedron Letters 47 (2006) 2639–2642
δ−
R2N
F
H
F
H
SEAr
+
δ+
-R2N-
F
-H+
X
X
R2NF
+
H
F
X
X
SET
+
R2N-F Ar
-R2N-
-H+
X
Scheme 1.
F
H
F
CH2Cl
CH2Cl
CH2Cl
+
+
+
k1
k-1
k2
N
N
N
-
-
-
+
-
+
2BF4
BF4
BF4
+
+
2BF4
N
N
N
+
+
F
H
Scheme 2.
First, we investigated the kinetics of the interaction of
mesitylene (MesH) with F-TEDA-BF4 1 in MeCN using
an iodometric titration method9 (Scheme 2).
value correspond to enthalpy control of the reaction
with the strong C–F bond formation in the rate-deter-
mining step.
The steady-state approximation, applied to the r-com-
plex, gives Eq. 1.
Kinetic isotope effects are widely used to elucidate the
mechanisms of electrophilic aromatic substitution.11
We measured kH/kD isotope effects in the reactions of
NF reagents with aromatic compounds using GC–MS
(Table 1). Competitive fluorinations of the correspond-
ing light and heavy hydrocarbons were carried out in
most cases. Small deuterium isotope effects showed that
decomposition of Wheland complexes is not a rate-
determining step. We observed smaller than unity iso-
tope effects (cf. Refs. 12–14). The effect was insensitive
to solvent variation. The source of the secondary deute-
rium isotope effect in the fluorination reactions under
study can be elucidated by the following analysis. A
hyperconjugative stabilization of the r-complex by the
Ca–H (Ca–D) bond should give kH/kD > 1 while an
sp2!sp3 rehybridization at the Ca-atom should result
in kH/kD < 1.14 An electron-donor effect of deuterium
should be important in the case when deuterium is at
positions 1, 3 or 5 of the r-complex ½cf. rþp ðDÞ ¼
ꢁ0:001ꢀ.15 In all cases, kH/kD < 1 can be attributed to
the prevalence of the sp2!sp3 rehybridization effect
and also to the electron-donor effect of deuterium. The
kH/kD values in the fluorination of mesitylene and naph-
thalene with F-TEDA-BF4 are smaller than those in the
fluorination of these compounds with N-fluorobenzene-
sulfonimide (Table 1). According to the Hammond
postulate,16 in the case of the more active reagent
F-TEDA-BF4, the transition state should be more
‘early’. It should result in a decrease of the hyperconju-
gative effect of C–H(D) bond.
lnð½MesHꢀ=½1ꢀÞ ¼ kð½MesHꢀ0 ꢁ ½1ꢀ0Þt þ lnð½MesHꢀ0=½1ꢀ0Þ
ð1Þ
where k = k1k2/(kꢁ1 + k2).
A good linear dependence of ln[MesH]/[1] on the time
(t) was observed (Fig. 1). The determination of the sec-
ond-order rate constants at different temperatures
[k273.2 K, (1.41 0.02) · 10ꢁ5, k303.8 K, (5.67 0.04) ·
10ꢁ4, k312.0 K, (1.85 0.01) · 10ꢁ3 and k323.0 K, (5.54
0.08) · 10ꢁ3 Mꢁ1 cꢁ1] gave the following values for the
activation parameters: Ea = 88 3 kJ/mol, lgA =
12.0 0.5, DH5 = 86 3 kJ/mol, DS5 = ꢁ24 9 J/
mol K. The high DH5 value and low absolute DS5
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
In order to obtain further information about the mech-
anism of electrophilic fluorination we studied the reac-
tion of F-TEDA-BF4 with benzene-1,3,5-d3. The
fluorobenzene-d3/fluorobenzene-d2 ratio (1.28) deter-
mined by GS–MS proved to be rather high, apparently
0
5000
10000
15000
20000
25000
t, c
Figure 1. Plot of ln([MesH]/[1]) versus time (t) at 303.8 K (r 0.9999).

G. I. Borodkin et al. / Tetrahedron Letters 47 (2006) 2639–2642
2641
Table 1. Kinetic isotope effects in the fluorination of aromatic compounds by NF reagents
NF Reagent
CH2Cl
ArH
Solvent
Temperature (ꢁC)
kH/kD
Benzene/benzene-d6
Benzene/benzene-d6
Mesitylene/mesitylene-1,3,5-d3
Naphthalene/naphthalene-d8
MeCN
110
110
60
0.92 0.06a
0.89 0.02a
0.89 0.02a
0.86 0.01a
[bmim][BF4]b
MeCN
N
N
MeCN
60
-
2BF4
F
1
F
N
-
Benzene/benzene-d6
Naphthalene/naphthalene-d8
MeCN
MeCN
110
60
0.86 0.03a
0.91 0.05a
2BF4
N
F
2
F
N
O
O
Mesitylene/mesitylene-1,3,5-d3
Naphthalene/naphthalene-d8
Naphthalene/naphthalene-d8
MeCN
MeCN
ClCH2CH2Cl
110
110
110
0.99 0.03a
0.895 0.007a
0.889 0.007a
S
S
O
O
Ph
Ph
3
a This value is given standard deviation of two measurements in mass spectra.
b [bmim]—1-Butyl-3-methylimidazolium.
due to 1,2-hydrogen and deuterium migrations in the r-
benzenes formed as a result of these migrations
followed by elimination of a proton and deuteron from
the respective r-complexes (Fig. 2). The present case, as
far as we are aware, constitutes the first example of 1,2-
shifts in Wheland intermediates formed in electrophilic
fluorination of aromatic compounds.
complexes (Scheme 3). This suggestion was confirmed
1
by H and 19F NMR spectra of the deuterated fluoro-
benzenes, particularly by the presence of a multiplet at
ꢁ116.3 ppm in the 19F NMR spectrum relevant to iso-
meric 2,4-dideuterofluoro- and 2,3,5-trideuterofluoro-
F
D
D
D
-H+
-H+
F
F
H
F
D
D
D
H
D
D
~1,2-H
+
H
+
-D+
D
D
D
D
D
+
F-TEDA-BF4
F
F
D
F
D
D
D
~1,2-D
+
+
H
-H+
D
D
D
D
D
D
F
-D+
-D+
D
D
Scheme 3.

2642
G. I. Borodkin et al. / Tetrahedron Letters 47 (2006) 2639–2642
Figure 2. 19F NMR spectrum (1) of deuterofluorobenzenes (470 MHz, CD3CN) formed in the reaction of benzene-1,3,5-d3 with F-TEDA-BF4 in
CD3CN at 110 ꢁC and computer simulation of the spectrum (2). Chemical shifts are referenced to CFCl3 with C6F6 as a secondary external standard
(ꢁ162.9 ppm). The ratio of A:B:C:D = 1.0:0.5:0.8:1.1.
7. Laali, K. K.; Borodkin, G. I. J. Chem. Soc., Perkin Trans.
2 2002, 953–957.
Acknowledgements
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We thank Dr. Z. Todres and a referee, for making con-
structive comments on our initial manuscript. Also, we
must thank Mr. M. M. Shakirov, for recording NMR
spectra and for helpful discussions.
11. Taylor, R. Electrophilic Aromatic Substitution; J. Wiley
and Sons: New York, 1990; pp 25–59.
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