The role of geometry on regioselectivity and rate of fluorination of fluorene and diphenylmethane with selectfluor F-TEDA-BF4

Article abstract of DOI:10.1039/b301652h

Diphenylmethane and fluorene were used as target molecules in an investigation of the effect of the geometry of aromatic molecules on the regioselectivity and rate of fluorination with 1-chloromethyl-4-fluoro-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF₄). In acetonitrile at 80°C ring fluorination of diphenylmethane was accompanied by oxidation of the saturated carbon atom, while in trifluoroacetic acid only ring fluorination with an ortho-para regioselectivity of 1.8:1 was observed. Fluorene was converted in acetonitrile as well as in trifluoroacetic acid into 2- and 4-fluoro substituted products in the relative ratio of 2:1 and 1.2:1, respectively. The reactions in acetonitrile obey a simple rate equation: v = d[F-TEDA]/dt=k₂ × [F-TEDA] × [Substrate] and the second order rate constants for the reactions in acetonitrile at 65°C were determined; values of 0.6 × 10^-4 M^-1 s^-1 for diphenylmethane and 35.5 × 10^-4 M^-1 s^-1 for fluorene were obtained. The reaction rates for the various functionalisations of fluorene relative to those for diphenylmethane were found to be considerably influenced by the type of functionalisation. Relative rate factors (k_rel=k_2(fluorene)/k_{2(diphenylmethane)}) with values between 59 for fluorination and 712 for chlorination were determined, while the corresponding data for the biphenyl/diphenylmethane pair were only slightly dependent on the type of functionalisation. A reaction pathway involving electron transfer, thus forming cation radical intermediates, was proposed as the main process in the case of fluorination of fluorene with F-TEDA-BF₄.

Full text of DOI:10.1039/b301652h

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The role of geometry on regioselectivity and rate of fluorination of
fluorene and diphenylmethane with Selectfluor F-TEDA-BF4
Jernej Iskra, Marko Zupan and Stojan Stavber*
Laboratory of Organic and Bioorganic Chemistry, “Jozef Stefan” Institute and Department of
Chemistry of the Faculty of Chemistry and Chemical Technology of the University of Ljubljana,
Jamova 39, 1000 Ljubljana, Slovenia
Received 12th February 2003, Accepted 12th March 2003
First published as an Advance Article on the web 2nd April 2003
Diphenylmethane and fluorene were used as target molecules in an investigation of the effect of the geometry of
aromatic molecules on the regioselectivity and rate of fluorination with 1-chloromethyl-4-fluoro-1,4-diazonia-
bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF4). In acetonitrile at 80 ЊC ring fluorination of
diphenylmethane was accompanied by oxidation of the saturated carbon atom, while in trifluoroacetic acid only ring
fluorination with an ortho–para regioselectivity of 1.8 : 1 was observed. Fluorene was converted in acetonitrile as well
as in trifluoroacetic acid into 2- and 4-fluoro substituted products in the relative ratio of 2 : 1 and 1.2 : 1, respectively.
The reactions in acetonitrile obey a simple rate equation:
v = d[F-TEDA]/dt = k2 × [F-TEDA] × [Substrate]
and the second order rate constants for the reactions in acetonitrile at 65 ЊC were determined; values of 0.6 × 10Ϫ4
M
Ϫ1 sϪ1 for diphenylmethane and 35.5 × 10Ϫ4 MϪ1 sϪ1 for fluorene were obtained. The reaction rates for the various
functionalisations of fluorene relative to those for diphenylmethane were found to be considerably influenced by the
type of functionalisation. Relative rate factors (krel = k2(fluorene)/k2(diphenylmethane)) with values between 59 for fluorination
and 712 for chlorination were determined, while the corresponding data for the biphenyl/diphenylmethane pair
were only slightly dependent on the type of functionalisation. A reaction pathway involving electron transfer, thus
forming cation radical intermediates, was proposed as the main process in the case of fluorination of fluorene with
F-TEDA-BF4.
[2.2.2]octane bis(tetrafluoroborate) (Accufluor NFTh), with
Introduction
various aromatic molecules8 or alkenes9 many mechanistic
Direct introduction of fluorine into aromatic molecules under
benefits could be obtained.
mild reaction conditions is still only a partly solved problem,
In our continuing interest in transformations of organic mol-
particularly if the aromatic ring is not activated.1 Valuable
ecules with F–L reagents we now report investigations on the
information about the role of the structure of the fluorinating
reactions of fluorene and diphenylmethane with F-TEDA-BF4.
reagent (F-L) in the fluorination of organic molecules could be
obtained if reactions are studied on several target molecules
Results and discussion
under comparable reaction conditions. Diphenylmethane
(DPM, 1a) and fluorene (1b) have been used several times as
tools for investigation of the effect of geometry, strain and con-
jugation in the target molecules on the type and regiochemistry
of their transformations.2–4 On the other hand, kinetic evalu-
ations of the mild introduction of an fluorine atom into organic
molecules with electrophilic F-L reagents are rather scarce,5
mainly due to the high reactivity of these reagents (elemental
fluorine, fluoroxy reagents) or the high sensitivity of their reac-
tions to reaction conditions (XeF2). The introduction and
broad synthetic application of organic molecules incorpor-
ating a reactive N–F bond as mild easy handling fluorinating
reagents with good stability/reactivity characteristics1d,6 opened
new possibilities for more extensive studies on the mild intro-
duction of fluorine into organic molecules also from a kinetic
point of view. It seems that from three types of N–F reagents,
namely neutral N-fluoro amines (R1R2NF type), N-fluoro-
pyridinium and related salts, and N-fluoro quaternary amine
salts (F–NϩR1R2R3 YϪ type), the latter, are the most convenient
tools for kinetic measurements since their reactivity could be
easily followed by iodometric titration.7 We have already
demonstrated that by following a kinetic evaluation of the
reactions of the two main representatives of this class of
N–F reagents, i.e. 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-
BF4) and its analogue 1-fluoro-4-hydroxy-1,4-diazoniabicyclo-
After a 48 hour reaction of diphenylmethane (DPM, 1a,
Scheme 1) with F-TEDA-BF4 in acetonitrile at 80 ЊC, beside
recovered starting material and some tar, only 13% of fluorin-
ated products were detected in the crude reaction mixture. The
main reaction process appeared to be the oxidation of the
benzyl position, which after consuming the traces of water
Scheme 1 Reaction conditions; i: F-TEDA-BF4, solvent (MeCN or
TFA), T = 50–80 ЊC, rt 2–48 h.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 8 – 1 5 3 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Effect of reaction conditions on ring fluorination of fluorene
and diphenylmethane with F-TEDA-BF4
Table 3 Effect of structure variation on the relative rates of ring
functionalization
Regioselectivity
kfluorene
kbiphenyl
Substrate
Solvent
Yielda (%)
3
4
Reaction
kdiphenylmethane
kdiphenylmethane
Ph2CH2
1a
MeCNb
MeCNd
TFAf
13c
14e
66
24
28
36
67
62
55
76
72
64
33
38
45
Fluorination
Nitration11
59
52
103
712
1.7
2.1
1.7
2.7
Detritiation11
Chlorination11,12
Fluorene
1b
MeCNg
MeCNh
TFAi
27
29
24j
bears a larger coefficient of electron density at C-2 (0.39) than
at C-4 (0.278) in its HOMO.15 The similar product distribution
in fluorination and nitration suggests that similar reaction
pathways should be involved in both processes, and that they
should be quite different from those concerning chlorination
and bromination where substitution at C-2 was exclusive or at
least predominant. A similar dichotomy in product distribution
in bromination on the one hand, and nitration and fluorination
on the other was already observed in the reactions of dibenzo-
furan,8a,10 where the latter ones also resemble the distribution
of HOMO electron density. This difference in regioselectivity
was explained by the different stability of the σ-complex (late
transition state) and π-complex (early transition state).
The rate of reactions of fluorene and diphenylmethane with
F-TEDA-BF4 was measured by following the progress of con-
sumption of the reagent by iodometric titration. The rate of the
reactions in MeCN at 65 ЊC obeyed a simple second order rate
equation:
a Yields of fluorinated products were calculated from 19F NMR of the
crude reaction mixture using octafluoronaphthalene as internal refer-
ence; product distributions were determined from 19F NMR. b 80 ЊC,
48 h. c 32% of benzophenone 2 was also formed. d 80 ЊC, 48 h, PhNO2.
e 14% of benzophenone 2 was also formed. f 60 ЊC, 4 h. g 80 ЊC, 4.5 h.
h 80 ЊC, 4.5 h, PhNO2. i 50 ЊC, 2 h. j 20% of unstable trifluoroacetyl
product was formed.
Table 2 Role of the type of ring functionalisation on the regio-
selectivity of substitution of fluorene, diphenylmethane (DPM) and
biphenyl (BP)
ortho–para-Substitution (4/3)
Reaction
Fluorene
DPM
BP
Fluorination:
F-TEDA-BF4
0.50
0.50
0.45
0.32
0.13
3.2
0.8
0.8
0.8
1.2
3.58a
1.1
2.2
1.2
0.6
10
XeF2
Nitration11
Detritiation11
Chlorination11,12
v = d[F-TEDA]/dt = k2 × [F-TEDA] × [substrate]
and the functionalisation of fluorene (Fig. 1) was found to be
much faster (k2 = 35.5 × 10Ϫ4 MϪ1 Ϫ1) than diphenylmethane
s
present in the solvent, resulted in 32% yield of benzophenone 2.
Fluorofunctionalisation at the ortho position prevailed over the
para one (Table 1). Reaction in the presence of nitrobenzene,
usually used as a radical scavenger, gave a very similar product
distribution of fluorosubstituted products but the oxidation
process was inhibited and only 14% of benzophenone was
formed. Side chain functionalization was eliminated and the
amount of fluorinated products increased when trifluoroacetic
acid was used as solvent (Table 1).
(k2 = 0.6 × 10Ϫ4 MϪ1 sϪ1) or biphenyl8a (k2 = 1.0 × 10Ϫ4 MϪ1 sϪ1).
Fluorene 1b was transformed with F-TEDA-BF4 at 80 ЊC in
acetonitrile to a mixture of two fluorinated products assigned
as 2-fluorofluorene 3b and 4-fluorofluorene 4b in 2 : 1 relative
ratio and 27% overall yield, while besides recovered 1b and
some tar material, no side chain functionalised product was
observed in the isolated crude reaction mixture. The presence of
nitrobenzene had no significant effect on the course of the reac-
tion, while the use of trifluoroacetic acid diminished the regio-
selectivity of the fluorination and up to 20% of an unstable
trifluoroacetyl substituted derivative was additionally detected
in the crude reaction mixture.
Further, we investigated the regioselectivity and kinetics of
various types of ring functionalisation of fluorene and com-
pared them with those of diphenylmethane and biphenyl. The
results are collected in Tables 2 and 3. Product distribution
in the case of fluorination of fluorene with F-TEDA-BF4 in
Fig. 1 Effect of substrate structure on the rate of fluorination with
F-TEDA-BF4 in acetonitrile at 65 ЊC.
10
MeCN as well as with XeF2 is very similar to nitration with
fuming HNO3 in Ac2O11 (Table 2). A much higher proportion
of 2-substitution was observed in the case of chlorination11,12
with Cl2 and detritiation in TFA,11 while bromination with Br2
proceeded almost regiospecifically to position 2.13 On the other
hand, quite different regioselectivity was observed in the fluorin-
ation of both biphenyl8a and diphenylmethane with F-TEDA-
BF4, where a high degree of ortho fluorination took place, con-
trary to the predominant para (relative to the biphenyl moiety)
functionalisation of fluorene.
By comparing the values for second order rate constants for
different types of functionalisation of fluorene, diphenyl-
methane and biphenyl (Table 3), we can see that the reagent
structure plays a very important role in the enhancement of the
reactivity of fluorene in comparison to diphenylmethane and
biphenyl. Again, the increase in the rate of fluorination with
F-TEDA-BF4 was found to be very similar to nitration, while
the relative reactivity of biphenyl compared to diphenyl-
methane was less affected by the type of reagent.
The regioselectivity of nitration of fluorene was rationalised
Organic compounds incorporating a reactive N–F bond are
by the fact that MNDO calculations14 showed that fluorene
also known as moderate to strong oxidants16 and F-TEDA-BF4
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 2 8 – 1 5 3 1
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is one of the strongest in the group. On the basis of extensive
studies, stressing especially nitration reactions, it has already
been proved that ion radical intermediates are involved in the
reaction of aromatic molecules with reagents of high oxidation
ability.17–21 On the basis of the present results and their com-
parison with relevant literature studies, the transformation of
fluorene could be ascribed as a competitive process between the
electron transfer formation of ion radicals B and ionic attack
leading to a σ-complex A (Scheme 2), while radical intermedi-
ates C are less probable. Since nitration of aromatic molecules
has been declared several times to be an electrophilic reaction
via cation radicals, the similar regiochemistry and kinetics of
fluorene transformation suggest that in the case of fluorination
with F-TEDA-BF4 the reaction pathway involving electron
transfer could be assumed to be the main process as well.
was heated at 50 to 80 ЊC for 4.5 to 48 hours (Table 1) until the
consumption of reagent, followed by KI starch paper, was
complete. The solvent was partially removed under reduced
pressure, the residue diluted with 30 mL of CH2Cl2, washed
with water (10 mL), a saturated solution of NaHCO3 (10 mL)
and dried over Na2SO4. After evaporating the solvent the
crude reaction mixture was analysed by 1H and 19F NMR
spectroscopy; yields of fluorinated products were determined
with octafluoronaphthalene as internal reference. Results are
presented in Table 1.
Pure products were isolated by preparative GLC (FFAP 30%
on Chromosorb W A/W 80/100, 180 ЊC) and the structures
determined on the basis of their spectroscopic data compared
with known data from the literature or those for independently
prepared samples: 4-fluorodiphenylmethane22 3a: δF = Ϫ117.7
ppm (dd), 2-fluorodiphenylmethane23 4a: δF = Ϫ118.5 ppm (m);
2-fluorofluorene24 3b: δF = Ϫ116.2 ppm (ddd), 4-fluoro-
fluorene24 4b: δF = Ϫ120.8 ppm (m).
In the crude reaction mixture obtained after fluorination of
fluorene in trifluoroacetic acid, a signal corresponding to tri-
fluoroacetate (δF = Ϫ76.5 (s), 20%) was observed in its 19F
NMR spectrum, but we were unable to determine the exact
structure due to the low stability of the product.
Kinetic measurements of reactions of aromatic molecules with
F-TEDA
To 25 mL of a thermostatted solution of 1 mmol of substrate
(1a,1b) in CH3CN, a thermostatted solution of F-TEDA in
CH3CN (25 mL 0.02 M) was added and stirred at 65 ЊC. After
various times 10 mL aliquots were mixed with 20 mL ice cold
0.02 M KI and the liberated iodine titrated with 0.05 M
Na2S2O3. The results are presented in the Fig. 1.
Acknowledgements
The financial support of the Ministry of Science and Tech-
nology of the Republic of Slovenia is acknowledged.
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