Room-temperature nucleophilic aromatic fluorination: Experimental and theoretical studies

Article abstract of DOI:10.1002/anie.200504555

(Chemical Equation Presented) Taming the reagent: The use of anhydrous tetrabutylammonium fluoride (TBAF_anh) in nucleophilic aromatic substitution reactions, including variants of the selective halogen-exchange and fluorodenitration processes (see scheme), was investigated. It was shown that TBAF_anh permits these reactions to be performed under surprisingly mild conditions if it is used in relatively nonpolar media.

Full text of DOI:10.1002/anie.200504555

Communications
Synthetic Methods
DOI: 10.1002/anie.200504555
Room-Temperature Nucleophilic Aromatic
Fluorination: Experimental and Theoretical
Studies**
Haoran Sun and Stephen G. DiMagno*
Despite their rarity in nature,[1] organofluorine compounds
play a leading role in the life sciences.[2–11] The high electro-
negativity and small atomic radius of the fluorine atom mean
that its incorporation into biologically active compounds
[*] Dr. H. Sun, Prof. Dr. S. G. DiMagno
Department of Chemistry and
Center for Materials Research and Analysis
University of Nebraska–Lincoln
Lincoln, NE 68588-0304 (USA)
Fax: (+1)402-472-9402
E-mail: sdimagno1@unl.edu
[**] We thank the Nebraska Research Initiative for financial support of
this research, Rieke Metals Inc. for the gift of the substrates, and the
Research Computing Facility at the University of Nebraska for
supercomputer time.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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induces a relatively small structural perturbation, whereas
drastically altering the electronic properties and bioavailabil-
ity of the compounds.[9,12] Fluorine substitution is a partic-
ularly effective strategy for aromatic groups, as the electron-
withdrawing nature of the fluorine atom reduces the suscept-
ibility of an aryl ring to cytochrome P-450 catalyzed
À
hydroxylation, a common step in drug catabolism.[8] The
C
A
Scheme 1. A typical Halex reaction.[24] DMI=1,3-dimethyl-2-imidazoli-
dinone.
F dipole in fluoroaromatic groups can also lead to an increase
in molecular recognition through favorable, though generally
weak, electrostatic interactions.[3,6,10,11,13] Because of the
medicinal importance of fluorinated aromatic com-
pounds, mild and selective methods for their preparation
Table 1: Halex and fluorodenitration reactions of chloro- and nitroaromatic compounds
by TBAFanh
.
are desirable.
We recently reported the preparation of a soluble,
Entries Substrate
Conditions[a] Product
TBAFanh
Yield [%][b]
0
highly nucleophilic fluoride-ion source, anhydrous tetra-
butylammonium fluoride (TBAFanh).[14] TBAFanh can be
dissolved in dimethyl sulfoxide (DMSO) and CH3CN
(2m) and fluorinates primary alkyl halides and tosylates
rapidly at low temperature (À358C, 5 min, THF). The
rapid rate observed for SN2 reactions that feature
TBAFanh prompted us to investigate nucleophilic aro-
matic substitution (SNAr) reactions with this reagent.
Below we describe variants of the industrially important
selective halogen exchange (Halex) and fluorodenitra-
tion processes for aromatic fluorination.[15–18] We show
that TBAFanh permits these reactions to be performed
under surprisingly mild conditions.
1
2
3
4
5
(4 equiv)
14 days
TBAFanh
(4 equiv)
14 days
TBAFanh
(2.5 equiv)
1 h
no reaction
80
>95
>95
>95
TBAFanh
(2.5 equiv)
1.5 h
TBAFanh
(1.3 equiv)
20 min
Electron-withdrawing substituents are typically
required to activate chloroaromatic substrates toward
Halex chemistry. The usual reagents employed to effect
halogen exchange are spray-dried KF; a high-boiling-
point polar aprotic solvent, such as sulfolane; and a
phase-transfer catalyst to improve the solubility of the
fluoride ion (Scheme 1). Prolonged and vigorous heating
is often required. Such harsh conditions preclude syn-
theses in which the late introduction of fluorine sub-
stituents is desired. In contrast, many aromatic com-
pounds undergo Halex reactions at room temperature in
DMSO, CH3CN, or THF upon exposure to TBAFanh. In a
typical preparation, TBAFanh (1.3 equiv) and the chloro-
or nitroaromatic compound were simply stirred together
in DMSO.[19] Representative fluorinations are shown in
Table 1.
TBAFanh
(1.3 equiv)
30 min
6
>95
TBAFanh
(1.3 equiv)
1 h
TBAFanh
(2.5 equiv)
30 min
7
8
>95
>95
TBAFanh
(1.3 equiv)
30 min
9
>95
>90
TBAFanh
10
(1.4 equiv)
ꢀ30 min
The scope of the room-temperature reactivity of
TBAFanh with chloropyridines in DMSO is apparent from
inspection of Table 1. If the pyridine ring has no electron-
withdrawing groups, the nucleophilic substitution of
chloride is sluggish for the ortho position and does not
TBAFanh
(1.5 equiv)
2 days
TBAFanh
(1.5 equiv)
5 days
TBAFanh
(1.5 equiv)
18 h
11
12
13
80
2
occur at all with m-chloropyridine. Smooth nucleophilic
A
substitution occurs if mildly activating groups are pres-
ent. A comparison of the mono- and dichloropyridine
examples shows that a second electronegative substituent
accelerates substitution: fluorination of 2-chloropyridine
requires 14 days, whereas 2,6-dichloropyridine is exhaus-
tively fluorinated in 90 minutes under identical condi-
tions. In comparison, typical Halex fluorinations of 2,6-
dichloropyridine require heating at 1508C for ten
hours.[20–23] Chloropyridine substrates bearing more
strongly electron-withdrawing (trifluoromethyl or car-
>95
TBAFanh
(2.5 equiv)
20 min
14
15
>95
>85
TBAFanh
(1.4 equiv)
20 min
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Table 1: (Continued)
benzenes. Suzuki and Kimura synthesized fluorobenzoni-
triles from chlorobenzonitriles in a pressure reactor using
spray-dried KF and tetraphenylphosphonium bromide in
hot (2908C) DMI (Scheme 1).[24] TBAFanh fluorinated 2-
and 4-chlorobenzonitrile, albeit sluggishly, at room tem-
perature in DMSO. The meta isomer was recovered under
these conditions (Table 1). As in the case of pyridine,
addition of a second chlorine atom accelerates substitu-
tion; 3,4-dichlorobenzonitrile and 2,3-dichlorobenzoni-
trile yield 3-chloro-4-fluorobenzonitrile and 2-fluoro-3-
chlorobenzonitrile, respectively, within 20 minutes.
Entries Substrate
16
Conditions[a] Product
Yield [%][b]
TBAFanh
(2.5 equiv)
1 h
>90
TBAFanh
(2.5 equiv)
1.5 h
17
18
>90
>95
TBAFanh
(1.3 equiv)
30 min
Adams and Clark reviewed aromatic fluorodenitra-
tion and reported that NOÀ2 is superior to chloride as a
leaving group in SNAr;[15,18] thus, we assayed nitroaro-
matic compounds to expand the scope of room-temper-
ature fluorination with TBAFanh. The three isomeric
mononitrobenzonitriles are fluorodenitrated readily
with TBAFanh; the nitrite leaving group even facilitates
m-fluorination. TBAFanh performs fluorodenitration even
on relatively weakly activated arenes; for example, ethyl
4-nitrobenzoate is fluorodenitrated within 30 minutes.
Additional examples of fluorodenitration are summar-
ized in Table 2. There are no reported examples of
comparable, high-yielding fluorodenitration reactions
performed under similarly mild conditions. Entries 6, 9,
10, and 17–19(Table 2) show that various functional groups,
including aryl esters, ethers, aldehydes, ketones, and N-benzyl
protecting groups, are compatible with these fluorination
conditions.
While our experimental studies show that electron-with-
drawing groups are required for aromatic fluorodenitration
with TBAFanh in DMSO, previous work has shown that the
gas-phase reaction of nitrobenzene with fluoride ions is fairly
favorable (DH8 = À28.2 kcalmolÀ1) and has a very low
activation barrier (DH° = 3.5 kcalmolÀ1).[25] The reason for
the attenuated solution-phase reactivity is that fluoride, the
most densely charged monoanion, is tightly ion paired and
TBAFanh
(1.3 equiv)
30 min
19
>95
TBAFanh
(1.3 equiv)
10 min
TBAFanh
(1.3 equiv)
24 h
20
21
>95
>95
[a] Reaction conditions: in an anhydrous solution of DMSO ([substrate]=0.4m) at 208C
for the time indicated. [b] All yields are calculated from integration of 1H and 19F NMR
signals relative to an added internal standard.
bonyl) substituents are also fluorinated rapidly, as are several
other heterocyclic derivatives. It is noteworthy that N-benzyl-
6-chloropurine is fluorinated quantitatively within
30 minutes. However, 6-chloropurine is deprotonated by
TBAFanh if the amine is left unprotected, thus generating an
equivalent of bifluoride ion. Fluorination of the 6-chloropur-
ine anion requires excess TBAFanh (4 equiv) and an extended
reaction time (14 days, 65% yield).
Heterocyclic substrates are much more reactive than
simple arenes in Halex reactions. SNAr reactions were
attempted upon the three isomeric chlorobenzonitriles to
gauge the reactivity of anhydrous TBAFanh toward substituted
Table 2: Fluorodenitration of para-substituted nitrobenzenes
Entries
Substrate
Conditions[a]
Product
Yield [%][b]
sÀ
DGo [kcal molÀ1
(solution)
]
DG° [kcal molÀ1
(solution)
]
A
ACHTREUNG
TBAFanh (1.3 equiv)
<5 m in
1
2
3
4
5
6
>95
>95[c]
>90
0
1.27
À9.03
À8.00
À7.96
À4.33
À5.01
À3.97
24.5
29.8
33.9
42.6
42.5
45.3
TBAFanh (1.3 equiv)
10 min
1.00
0.65
TBAFanh (1.3 equiv)
2 h
TBAFanh (2.5 equiv)
>5 days
À0.03
0
TBAFanh (2.5 equiv)
>5 days
0
TBAFanh (2.5 equiv)
>5 days
0
À0.17
[a] Reaction conditions: in an anhydrous solution of DMSO ([substrate]=0.4m) at 208C for the time indicated. [b] All yields are calculated from
integration of 1H and 19F NMR signals relative to an added internal standard. [c] Yield of the isolated product was 69%.
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Chemie
strongly solvated.[15,26] Thus, we conducted computational
studies to explore the impact of solvent upon the potential-
energy surfaces of fluorodenitration reactions that feature a
variety of 4-substituted nitrobenzenes (Scheme 2).
energy relationship is produced. Extrapolation of this linear
plot suggests that fluorodenitration is thermodynamically
favorable for all para-substituted nitrobenzenes in the gas
phase. In contrast, calculated solution-phase DG8 and
DH8 values are only modestly negative for the free-ion
reaction. Inclusion of ion pairing would further lessen the
equilibrium constant for fluorodenitration as the fluoride ion
is expected to ion pair to a greater extent than the nitrite ion.
This suggests that the limitation of fluorodenitration to
electron-poor nitroaromatic compounds in polar solvents at
room temperature could arise from thermodynamic consid-
erations.
Scheme 2. The calculated fluorodenitration reactions.
For the transition-state (TS) search and activation-barrier
calculations, basis-set superposition error (BSSE) was cor-
rected by using the counterpoise method. It was found that
BSSE correction resulted in very modest adjustments to the
calculated activation barrier (0.7 kcalmolÀ1 for the gas-phase
fluorination of nitrobenzene). In the gas-phase calculations,
several stable fluoride–nitrobenzene complexes were found
in our extensive search of the TS geometry and reaction-side
local minima (RM), in agreement with previous theoretical
studies.[25] Our focus was limited to the RM which led directly
to transition states. Figure 2 shows typical structures of gas-
phase RM and TS structures for the fluorodenitration of
nitrobenzene and p-cyanonitrobenzene. If the para substitu-
ent is H or an electron-donating group, significant structural
changes are observed between the RM and the TS. The RM
Gas-phase structures and energies for all nitrobenzenes,
fluorobenzenes, the nitrite ion, and the fluoride ion were
calculated using density functional theory (B3LYP/6-311g +
+ (d,p)/6-311g + + (d,p)). Frequency calculations for all
molecular species were also performed to provide thermal
(298K) and ZPE corrections for the thermochemical analysis.
Polarizable continuum (PCM) and self-consistent isodensity
polarizable continuum models (SCI-PCM) were employed to
model the polar aprotic solvents used in the experiment. In
practice, the two models gave comparable potential-energy
diagrams and solvation energies.
The fluorodenitration reaction energies are shown in
Figure 1, in which they are plotted against Hammet
sÀ parameters. A comparison with the gas-phase experimen-
tal data shows that the DFT calculations correctly reproduce
the experimentally determined thermodynamic enthalpy for
the fluorodenitration of nitrobenzene;[25] thus, we deemed the
basis set and method to be sufficient for the study of
substituted nitrobenzenes. The gas-phase DG8 and DH8 val-
ues are large and negative for all fluorodenitration reactions
of substituted nitrobenzenes, and an excellent linear free-
À
has a weakly bound fluoride ion, little perturbation of the C
N bond length, and only a minor deflection of the nitro group
from the plane of the aromatic ring, whereas the TS shows a
“Meisenheimer-like” structure that indicates significant
charge injection into the aromatic ring. In contrast, elec-
tron-withdrawing groups lead to Meisenheimer intermediates
which require minimal structural reorganization to reach the
TS. The calculations for the gas-phase reaction predict an
excellent kinetic linear free-energy relationship; all gas-phase
fluorodenitration reactions of para-substi-
tuted nitrobenzenes should be rapid at room
temperature (Figure 1).
Solution-phase TS structures were
located using potential-energy surface scans,
in which optimizations were performed as the
À
C F length was stepped through several fixed
values. The optimized solution-phase TS
structures differ slightly from the gas-phase
À
TS structures; the former exhibit longer C F
À
and C N lengths. Removal of the solvent
model and recalculation of the optimized
solution-phase TS structures gave energies
within 2 kcalmolÀ1 of the gas-phase TS
energy for all of the substituted nitroben-
zenes, thereby indicating that the impact of
the solvent model upon the fluorodenitration
TS geometries and internal energies is quite
small. As strong solvation of the fluoride ion
results in calculated RMs that feature free
ions, activation energies (Table 2) were cal-
culated directly from the energy difference
between that of optimized TS structures and
Figure 1. A) Calculated thermodynamic free-energy relationships for gas- and solution-
phase fluorodenitration reactions. B) Calculated activation parameters for fluorodenitra-
tion reactions: a) DG° in CH3CN, b) DH° in CH3CN, c) DG° for gas-phase RM to TS,
d) DH° for gas-phase RM to TS, e) DG° for gas-phase dissociated reactants to TS,
f) DH° for gas-phase dissociated reactants to TS.
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fluorodenitration reactions. The initial results suggest that ion
pairing and solvation are the factors that limit the impressive
nucleophilicity of the fluoride ion under conditions typically
employed for nucleophilic aromatic substitution. Theoretical
calculations show that gas-phase fluorodenitration reactions
are both thermodynamically favorable and fast, whereas
preferential solvation of the fluoride ion leads to the large
activation barriers for the solution-phase reactions. It appears
that a further expansion in the scope of room-temperature
SNAr fluorination is possible, provided one can prepare highly
soluble, weakly ion-paired fluoride salts for use in relatively
nonpolar media.
Figure 2. Optimized structures (top), highest occupied molecular
Received: December 22, 2005
orbitals (HOMO; middle) and electrostatic potential surfaces (ESP;
bottom) for nitrobenzene (left) and p-cyanonitrobenzene (right) fluo-
rodenitration reactions.
Published online: March 20, 2006
Keywords: density functional calculations · fluorine ·
.
nucleophilic aromatic substitution · synthetic methods ·
tetrabutylammonium fluoride
the sum of the energies of nitrobenzene and the fluoride ion.
Preferential solvation of the fluoride ion is calculated to add
45–55 kcalmolÀ1 to the gas-phase free energy of activation.
Activation energies for the fluorodenitration of nitrobenzene
in cyclohexane, THF, and DMSO (DG° = 20.5, 37.5, and
42.5 kcalmolÀ1, respectively) were also obtained using the
PCM model; decreasing solvent polarity lowers the activation
barrier substantially. Thus, if one can prepare soluble, more
weakly ion-paired fluoride salts, it is expected that the scope
of room-temperature fluorodenitration reactions can be
expanded if nonpolar media are used.
[1] D. OꢀHagan, C. Schaffrath, S. L. Cobb, J. T. G. Hamilton, C. D.
Murphy, Nature 2002, 416, 279.
[2] G. Gerebtzoff, X. Li-Blatter, H. Fischer, A. Frentzel, A. Seelig,
ChemBioChem 2004, 5, 676 – 684.
[3] F. Hof, D. M. Scofield, W. B. Schweizer, F. Diederich, Angew.
Chem. 2004, 116, 5166 – 5169; Angew. Chem. Int. Ed. 2004, 43,
5056 – 5059.
[4] P. Jeschke, ChemBioChem 2004, 5, 570 – 589.
[5] I. Ojima, ChemBioChem 2004, 5, 628 – 635.
A comparison of experimental and theoretical results
shows that the calculated activation barriers for fluorodeni-
tration in CH3CN (or DMSO) are much too large. The
experimental data indicate that DG° = 20.5 and 21.5 kcal
molÀ1 for the fluorodenitration of p-cyanonitrobenzene and
p-trifluoromethylnitrobenzene, respectively, whereas the cal-
culated values are DG° = 29.8 and 33.9 kcalmolÀ1, respec-
tively. Additionally, the Hammett plots (Figure 1) appear to
be unrealistically steep (1 = À13). Three sources of error in
the PCM calculation are readily apparent. The calculated
solvation energy for the fluoride ion is too large (À90.7 kcal
molÀ1) relative to the experimental value (À82.6 kcalmolÀ1),
although it is in line with the stated error range of the solvent
model.[27,28] Secondly, the overestimated steepness of the
Hammett plot suggests that the solvent model cannot account
accurately for the localization of negative charge in the less
stable (more electron-rich) TS. The inadequacy of PCM to
account for the strong electrostatic effects that arise from
localized charge–solvent interactions has been highlighted by
Truhlar and co-workers.[29] Thus, we would expect the
experimental Hammett 1 value to be smaller than the PCM
calculation indicates. Finally, ion pairing of the TBA cation to
the fluoride anion and the TS have not been addressed herein,
nor is the nature of the actual reactive species (contact ion
pair, solvent-separated ion pair, free ion) known. Thus, this
relatively simple fluorodenitration reaction constitutes an
exceptionally challenging test case for computational solvent
models.
[6] J. A. Olsen, D. W. Banner, P. Seiler, U. O. Sander, A. DꢀArcy, M.
Stihle, K. Mueller, F. Diederich, Angew. Chem. 2003, 115, 2611 –
2615; Angew. Chem. Int. Ed. 2003, 42, 2507 – 2511.
[7] C. Pesenti, F. Viani, ChemBioChem 2004, 5, 590 – 613.
[8] H.-J. Bohm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Mueller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637 –
643.
[9] M. Schlosser, Enantiocontrolled Synthesis of Fluoroorganic
Compounds: Stereochemical Challenges and Biomedicinal Tar-
gets (Ed.: V. A. Soloshonok), Wiley, Chichester, 1999, 613 – 659.
[10] J. A. Olsen, D. W. Banner, P. Seiler, B. Wagner, T. Tschopp, U.
Obst-Sander, M. Kansy, K. Mueller, F. Diederich, ChemBio-
Chem 2004, 5, 666 – 675.
[11] J. C. Biffinger, H. W. Kim, S. G. DiMagno, ChemBioChem 2004,
5, 622 – 627.
[12] B. E. Smart, J. Fluorine Chem. 2001, 109, 3 – 11.
[13] H. W. Kim, P. Rossi, R. K. Shoemaker, S. G. DiMagno, J. Am.
Chem. Soc. 1998, 120, 9082 – 9083.
[14] H. Sun, S. G. DiMagno, J. Am. Chem. Soc. 2005, 127, 2050 – 2051.
[15] D. J. Adams, J. H. Clark, Chem. Soc. Rev. 1999, 28, 225 – 231.
[16] M. Maggini, M. Passudetti, G. Gonzales-Trueba, M. Prato, U.
Quintily, G. Scorrano, J. Org. Chem. 1991, 56, 6406 – 6411.
[17] S. D. Kuduk, R. M. DiPardo, M. G. Bock, Org. Lett. 2005, 7,
577 – 579.
[18] N. Boechat, J. H. Clark, J. Chem. Soc. Chem. Commun. 1993,
921 – 922.
[19] Product characterization and reaction progress were assayed by
1H, 19F and 13C NMR spectroscopic analysis; product purity and
identity were confirmed by GC mass-spectroscopic analysis;
commercially available fluoroaromatic compounds were used as
GC standards; and the NMR data are reported in the Supporting
Information.
In summary, TBAFanh in DMSO is a fluorinating reagent
with unprecedented activity in room-temperature Halex and
[20] M. Darabantu, T. Lequeux, J. C. Pommelet, N. Ple, A. Turck,
Tetrahedron 2001, 57, 739– 750.
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Chemie
[21] T. G. Muench (Dow Chemical Co., USA), US4071521, 1978,
p. 6.
[22] T. J. Giacobbe (Dow Chemical Co., USA), US4031100, 1977,
p. 7.
[23] M. M. Boudakian, J. Heterocycl. Chem. 1968, 5, 683 – 684.
[24] H. Suzuki, Y. Kimura, J. Fluorine Chem. 1991, 52, 341 – 351.
[25] T. Giroldo, L. A. Xavier, J. M. Riveros, Angew. Chem. 2004, 116,
3672 – 3674; Angew. Chem. Int. Ed. 2004, 43, 3588 – 3590.
[26] H. Plenio, ChemBioChem 2004, 5, 650 – 655.
[27] J. R. Pliego, Jr., J. M. Riveros, J. Phys. Chem. A 2001, 105, 7241 –
7247.
[28] J. R. Pliego, Jr., J. M. Riveros, Phys. Chem. Chem. Phys. 2002, 4,
1622 – 1627.
[29] C. P. Kelly, C. J. Cramer, D. G. Truhlar, J. Chem. Theory Comput.
2005, 1, 1133 – 1152.
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