Efficient phosphorus catalysts for the halogen-exchange (Halex) reaction

Article abstract of DOI:10.1002/adsc.200800428

New families of monomeric to dendritic, and monocationic to multicationic (PNP) compounds have been prepared and tested as catalysts in halogen exchange (Halex) reactions. Some of them allow an increase in the efficiency of these reactions which are performed in some cases under the mildest conditions reported up to now.

Full text of DOI:10.1002/adsc.200800428

COMMUNICATIONS
DOI: 10.1002/adsc.200800428
Efficient Phosphorus Catalysts for the Halogen-Exchange (Halex)
Reaction
Marie-Agnꢀs Lacour,a Maria Zablocka,b,* Carine Duhayon,c
Jean-Pierre Majoral,c,* and Marc Taillefera,*
a
Institut Charles Gerhardt, AM2N, ꢁcole Nationale Supꢂrieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296
Montpellier Cedex 5, France
Fax : (+33)-467-144-319; e-mail: marc.taillefer@enscm.fr
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90363 Łodz, Poland
b
E-mail: zabloc@bilbo.cbmm.lodz.pl
Laboratoire de Chimie de Coordination, CNRS, UPR 8241, 205 route de Narbonne, 31077 Toulouse Cedex 04 France
c
E-mail: majoral@lcc-toulouse.fr
Received: July 10, 2008; Published online: November 14, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800428.
Abstract: New families of monomeric to dendritic,
and monocationic to multicationic (PNP) com-
pounds have been prepared and tested as catalysts
in halogen exchange (Halex) reactions. Some of
them allow an increase in the efficiency of these re-
actions which are performed in some cases under
the mildest conditions reported up to now.
cess consists of reacting an activated halogenated aro-
matic ring (chloronitrobenzene, for example) with a
source of fluoride via a nucleophilic aromatic substi-
tution. Generally, the Halex reaction is performed in
aprotic, strongly polar solvents with potassium fluo-
ride as fluorinating agent because it represents a good
compromise between cost and activity.[3–6] However,
because of the poor solubility of metal fluorides in or-
ganic solvents, high temperatures reactions (250–
3008C) are usually required,[7] which can pose prob-
lems for industrial applications. It has been demon-
strated that the use of phase-transfer catalysts gives
good results on activated aryl chlorides because it en-
ables one to extract and solubilize fluoride anion
Keywords: arylation; catalysts; fluorination; halo-
gen exchange (Halex) reaction; phosphorus
Fluorinated aromatic compounds are a very impor- from the solid to the solution.[8,9]
tant class of organic molecules due to their intensive
Catalysts generally used, tetraalkylammonium[10] or
use as pharmaceutical or agrochemical products and phosphonium[11,12] salts, are quite robust in mild condi-
for their biological applications.[1] A tremendous tions but tend to decompose at high temperature.
amount of work has been done both from the aca- Over the last years, guanidinium[13] or carbophospha-
demic world and the chemical industry concerning zenium salts were also used allowing one to decrease
their preparation. However, there are still numerous the temperature to 170–1908C, that is to say a drop of
drawbacks to overcome in order to propose milder 30–608C in the case of the conversion of 4-chloro- to
conditions to introduce fluorine on aromatic com- 4-fluoronitrobenzene in 96% yield.[14] Bis(phosphor-
pounds.[2] The halogen-exchange reaction (Halex reac-
anylidene)ammonium salts (PNP)+ are big lipophilic
ACHTUNGTRENNUNG
tion, Scheme 1) is one of the most important proce- cations, soluble in a number of solvents, easy to pre-
dures for the preparation of fluoroarenes. Such a pro- pare and to handle, and very stable at high tempera-
ture.[15,16] Therefore they may represent an alternative
as efficient catalysts for the Halex reaction. Having in
mind these observations we prepared numerous new
compounds of this type, playing with several factors
such as the constraint structure, i.e., the rigidity of the
molecule, the possibility to form dicationic salts in-
stead of monocationic ones, or even the possibility to
Scheme 1. The Halex reaction.
work with polycationic species, that is to say dendrim-
Adv. Synth. Catal. 2008, 350, 2677 – 2682
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2677

Marie-Agnꢀs Lacour et al.
COMMUNICATIONS
Scheme 2. Synthesis of (PNP)+ salts 8a–11a (counter-anion is BrÀ) and of the corresponding chlorides 8b–11b (counter-anion
is ClÀ).
ers bearing six or twelve terminal (PNP)+ cations. À27.9 (2JP, P =14.2 Hz) ppm for the phosphoradaman-
Syntheses of these salts by an original method are re- tane salt 9a, one singlet for the symmetrical salt 10a
ported as well as their catalytic properties in a model and two doublets at 4.45 and 21.1 (2JP, P =29.6 Hz)
1
reaction: the conversion of 4-chloronitrobenzene to 4- ppm for 11a. H and 13C NMR spectra and elemental
fluoronitrobenzene.
analysis are in full agreement with the proposed struc-
The synthesis of the monomeric (PNP)+ salts was tures. Additionally, X-ray diffraction studies on 9a un-
conducted as shown in Scheme 2 from the amino- ambiguously confirm the structure of this salt
phosphonium salt [Ph3PNH2]+ XÀ (X=Br, Cl) 1. Ad- (Figure 1). One unique feature of PTA 3 or THPA 5
dition of n-Buli (2 equivalents) in hexane to a suspen- is the ability to be chemoselectively protonated or al-
sion of 1 in THF followed by treatment with Br2 and kylated at nitrogen b to phosphorus rather than at the
addition of 1,2-dihydrophosphole (2)[17], 1,3,5-triaza-7- phosphorus center.[20] In the case of the corresponding
phosphaadamantane (3) (PTA)[18], triphenylphosphine salts 9a or 11a alkylation at one of the three or six
(4), and 4,6,9-trimethyl-1,3,4,6,7,9-hexaaza-5-phospha- cyclic nitrogen atoms takes place easily with trifluoro-
tricyclo[3.3.1.13,7] decane (5) (THPA)[19,20] led respec- methanesulfonate leading to the dicationic species
tively to the corresponding (PNP)+ salts 8a–11a. The 12a or 13a (Scheme 3). Alkylation with methyl iodide
structures were assigned on the basis of NMR data as proceeds smoothly for 9a affording the dicationic salt
well as X-ray diffraction studies for the salt 9a. All 12c while no reaction is observed for 11a.
complexes are air-stable solids. 31P NMR spectra dis-
Such a reaction induces in 31P NMR a deshielding
play two singlets at 51.7 and 20.7 ppm for the mono- effect for the signals of the two phosphorus atoms
cationic phospholene salt 8a, two doublets at 21.5 and from À27.9 to À18.6 (NPCN fragment) and from 21.5
Figure 1. ORTEP diagram of the monosalt 9a and of the disalt 12a.
2678
asc.wiley-vch.de
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2677 – 2682

Efficient Phosphorus Catalysts for the Halogen-Exchange (Halex) Reaction
COMMUNICATIONS
Scheme 3. Synthesis of dicationic (PNP) salts 12a–c, 13a, 13b.
to 27.8 (PPh3 unit) ppm with disappearance of the ini- tures, a very high local catalyst concentration on their
tial doublets observed for 9a on behalf of two singlets surface, the possibility to easily recover them and to
1
for 12a. The H NMR spectrum of 12a shows a new reuse them without significant loss of activity. For this
doublet at 2.94 (3JH,P =3.1 Hz) ppm corresponding to purpose, dendrimers 6 and 7 of generation 0 and 1, re-
the methyl group linked to a intracyclic nitrogen spectively, were prepared according to a method re-
atom, while the formation of N-CH3 unit is corrobo- ported by one of us.[37] The corresponding dendritic
rated in 13C NMR by the presence of a singlet at salts 14a and 15a (Br as counter-anion) incorporating
48.6 ppm. An ORTEP diagram of such a structure is six or twelve (PNP)+ units were obtained in excellent
shown in Figure 1. Two main features can be empha- yield ( 82–85%) by the same method which allows us
À
sized: lengthening of the cyclic N C bonds around to prepare the salts 8a–11a (Scheme 4). Their forma-
the alkylated nitrogen atom and a slight opening of tion is monitored by 31P NMR with disappearance of
the P1N1P2 angle (143.78 for 12a, 138.98 for 9a).
the singlet due to the terminal triphenylphosphine
As in the case of the monosalt 9a, the P1N1 and units in 6 on behalf of doublets at 23.8 (OC6H4PN)
2
N1P2 bond distances [1.569(3) and 1.582(3) ꢄ in 9a, and 24.8 (NP(Ph)3) ppm with JP, P =5.2 Hz for 14a.
1.565(3) and 1.583(3) ꢄ in 12a] clearly indicate a Similarly, the disappearance of the singlet due to ter-
strong delocalization of the charge along the P1N1P2 minal phosphine of 7 is observed simultaneously with
fragment. In order to extend the scope of the use of the appearance of two doublets at 23.9 and 24.7
(PNP)+ salts in Halex reaction, we investigated the (2JP, P =5.9 Hz) for 15a. Treatment of 14a and 15a with
possibility to prepare dendrimers bearing (PNP)+ AgCl leads to 14b and 15b (Cl as counter-anion).
salts on their surface. Indeed the role of dendritic cat-
Having in hands a number of monocationic and
alysts has been the subject of a lot of investigations as multicationic PNP molecules we investigated their
pointed out by the number of reviews published properties as catalysts in the Halex reaction and more
within the last two years[ 21–36] because such nano-ob- precisely for the transformation of 4-chloronitroben-
jects combine a unique set of characteristics due to zene to 4-fluoronitrobenzene, a very important mole-
their tailored size, their perfectly well-defined struc- cule for an industrial point of view. We performed the
Scheme 4. Synthesis of dendritic salts 14a and 15a (a: counter-anion is BrÀ). The corresponding (PNP)+ chlorides 14b and
15b are obtained by halide exchange (b: the counter-anion is ClÀ).
Adv. Synth. Catal. 2008, 350, 2677 – 2682
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2679

Marie-Agnꢀs Lacour et al.
COMMUNICATIONS
Scheme 5. ACHTUNGTRENNUNG
(PNP)+-catalyzed fluorination of 4-chloronitrobenzene.
Table 1.
ides.[a]
(PNP)+-catalyzed fluorination of aromatic chlor-
ACHTUNGTRENNUNG
tests in DMSO which is very often the solvent of
choice to promote this type of catalyzed fluorination.
The preliminary experiments showing that chlorides
salts were apparently more efficient we decided to
perform all the studies with them. They are obtained
from 8a–11a, 12a,c, 13a–15a via simple bromide-chlo-
ride, iodide-chloride and sulfonate-chloride exchanges
(the description of the exchanges is given in Experi-
mental Section). First experiments were conducted in
DMSO with (PNP)+ salts (4% mol.) at 1808C, that is
to say the usual conditions for Halex reactions. The
first run performed with 10b, giving quantitative yield
after 8 h, we then decreased the temperature to
1508C, a temperature which was previously never suc-
cessfully used and which prevents catalysts and sub-
strates from degradation. It can be mentioned that
the Halex reaction conducted without catalyst at
1508C is extremely slow (9% after 8 h). In marked
contrast the reactions performed with the monocat-
ionic derivatives 8b, 9b, 11b led to satisfactory results:
50 to 75% of fluorination of 4-chloronitrobenzene
after 8 h (Scheme 5). Surprisingly, since we were ex-
pecting a better solubilization of the fluorine anion,
the dicationic (PNP)+ salts 12b and 13b appeared to
be not effective at this temperature (while no appar-
ent degradation of the salts could be observed).
AHCTUNGTRENNUNG
Yield [%][b}
À
À
Entry
Ar Cl
T [8C]
Ar F
1
2
150
125
99 (93)
50
3
4
5
150
150
150
85 (76)
100 (91)
5
10
6
7
150
150
80 (68)
72 (65)
8
9
10
150
110
50
100
100
70
[a]
This reaction of SNAr type is not efficient with non-acti-
vated aromatic chlorides (bearing electron donating sub-
stituents.
GC yields determined with 1,3-dimethoxybenzene as in-
ternal standard (isolated yields in bracket).
More interesting are the results obtained starting
from the dendritic salt 14b as well as the monomer
10b: the transformation is close to 100%. This can be
considered as the best result reported so far for such
experimental conditions including results reported
[b]
with other charged species as Ph4P+, R4N+ or (CNC)+ cause of steric hindrance due to the nitro group in
,
compounds.[13,14] A negative dendritic effect is ob- ortho position, occurs at 1508C with 85% yield
served with the dendrimer of generation 1, 15b: in (entry 3), ii) monofluorination of 3,4-dichlonitroben-
this case, the 4-fluoronitrobenzene is obtained in 63% zene is quantitative and totally selective on chlorine
yield only. These encouraging results prompted us to in para position (entry 4): this opens new perspectives
investigate the catalytic activity of the most efficient for the selective functionalization of fluorinated aro-
system, that is to say the monomer 10b, for the Halex matic derivatives diversely substituted, a very impor-
reaction involving diversely substituted nitrobenzene tant class of compounds in the field of health,[1] iii) in
derivatives (Table 1). Worth noting is that the (PNP)+ marked contrast, full nucleophilic substitution of the
salt (14b), although a little bit less efficient, is howev- 2,4-dichloronitrobenzene is the main reaction leading
er also interesting taking into account the possibility to the difluorinated aromatic compound in 80% yield
to re-use it several times via a simple filtration (work after 8 h ; only 10% of the monofluorinated one is de-
is in progress in this field). Several key features can tected (entry 6), iv) quantitative yield of fluoro-2,4-di-
be emphasized i) fluorination of the ortho-chloroni- nitrobenzene is obtained at 1508C as well as at
trobenzene, a reaction usually difficult to perform be- 1108C. Remarkably the reaction also occurs at 508C
2680
asc.wiley-vch.de
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2677 – 2682

Efficient Phosphorus Catalysts for the Halogen-Exchange (Halex) Reaction
COMMUNICATIONS
gas chromatography. The yield was determined using 1,3-di-
methoxybenzene as a standard (results of Scheme 5).
leading to the final species in 70% yield (after 8 h at
this temperature): to our knowledge such conditions
are among the mildest ever reported for Halex reac-
tions ( entries 8–10).
Supporting Information
In conclusion, a unique family of monomeric to
dendritic, and monocationic to multicationic (PNP)
compounds have been prepared and fully character-
ized. Preliminary catalyst tests on Halex reactions of
industrial interest show that some of them are effi-
cient catalysts allowing one to increase the yield and
the chemoselectivity of the reactions which are per-
formed in some cases in the mildest conditions report-
ed up to now. Extension of the studies of the catalytic
properties of these (PNP)+ salts as well as the design
and use as catalysts of functionalized monomeric and
dendritic (PNP)+ salts of higher generations are
under active investigation.
Detailed experiments and characterisation of isolated prod-
ucts are available in the Supporting Information.
Acknowledgements
We thank the Ministꢀre de l’Education Nationale for a PhD
grant and financial support. M.Z. thanks the Ministry of Sci-
ence and Information Society Technologies Poland for finan-
cial support ( Grant No 3T0 9 A 158 29). M.Z. and J.P M.
thank the LEA (Laboratoire Europꢁen Associꢁ, Toulouse-
Lodz) for financial support.
Experimental Section
References
Synthesis of Triphenylphosphiniminophosphonium
Chloride 10b
[1] A. Tressaud, in: Advances in Fluorine Science Vols. 1 &
2, Elsevier, Amsterdam, 2006.
[2] L. Saint-Jalmes, J. Fluor. Chem. 2006, 127, 85.
[3] J. H. Clark, Chem. Rev. 1980, 80, 429.
[4] T. P Smyth, A. Carey, B. K. Hodnett, Tetrahedron 1995,
51, 6363.
[5] Houben-Weyl, Organo-Fluorine Compounds, Thieme,
Stuttgart, 1999, Vol. E10a, p 552.
[6] R. A. North, US Patent 4,287,374, 1981.
[7] R. A. Kunz, US Patent 4,069,262, 1978.
[8] C. M. Starks, C. Liotta, Phase Transfert Catalysis, Aca-
demic Press, New York, 1978.
[9] J. E. Gordon, R. E. Kutina, J. Am. Chem. Soc. 1977, 99,
3903.
[10] J. H. Clark, D. K. Smith, Tetrahedron. Lett. 1985, 26,
2233.
[11] J. H. Clark, D. J. Macquarrie, Tetrahedron. Lett. 1987,
28, 111.
[12] Y. Yoshida, Y. Kimura, Chem. Lett. 1988, 1355.
[13] A. Pleschke, A. Marhold, US Patent 2006,0009643,
2006.
[14] A. Pleschke, A. Marhold, M. Schneider, A. Kolomeit-
sev, G.-V. Rçschenthaler, J. Fluor. Chem. 2004, 125,
1031.
At À158C under dry nitrogen, a solution of n-butyllithium
(1.6M in hexane, 19.90 mL, 31.87 mmol) was added drop-
wise to a suspension of triphenylaminophosphonium chlo-
ride (1b) (5.00 g, 15.94 mmol) in anhydrous THF (80 mL) in
order to form Ph3PNLi. Upon addition, the mixture was
stirred for 2 h at À158C. In the same time, a solution of hexa-
chloroethane (3.77 g, 15.94 mmol) in THF (15 mL) was
added dropwise to a solution of triphenylphosphine (4)
(4.18 g, 15.94 mmol) in THF (15 mL) at 258C, and the mix-
ture was stirred for 2 h. The latter was added dropwise at
À158C to the solution of Ph3PNLi. After return to room
temperature, the mixture was stirred for 4 h. It was then fil-
tered and the beige residue obtained was diluted in di-
chloromethane (150 mL) and washed three times with an
aqueous solution of sodium chloride (10%, 50 mL). The or-
ganic layer was dried with sodium sulfate, filtered and
evaporated. Finally, the beige residue was dissolved in a di-
chloromethane/methanol mixture (7/3, v/v, 20 mL) and pre-
cipitated with diethyl ether (200 mL). Upon filtration and
rinsing with diethyl ether, 10b was obtained as a white solid;
1
yield: 6.09 g (67%); H NMR (200 MHz, CDCl3): d=7.35–
7.44 (m, 24H), 7.60–7.63 (m, 6H); 31P NMR (81 MHz,
CDCl3): d=21.7 (s, 2P); 13C NMR (62 MHz, CDCl3): d=
134.3 (s, 6C, C-p), 132.5 (m, 12C), 130.1 ( m, 12C), 127.3
[15] T. W. Rave, J. Org. Chem. 1967, 32, 3461.
[16] V. Schanen, H. J. Cristau, M. Taillefer, World Patent
WO 02092226, 2002.
3
1
(dd, JP, C =1.9 Hz, JP, C =107.7 Hz, 6C, C-o).
[17] V. Cadierno, M. Zabłocka, B. Donnadieu, A. Igau, J.-P.
´
Majoral, A. Skowronska, J. Am. Chem. Soc. 1999, 121,
11086.
General Procedure for Halex Reaction
After standard cycles of evacuation and back-filling with dry
[18] A. D. Phillips, L. Gonsalvi, A. Romerosa, F. Vizza, M.
Peruzzini, Coord. Chem. Rev. 2004, 248, 955.
[19] A. Dꢅaz-ꢆlvarez, P. Crochet, M. Zablocka, C. Duhay-
on, V. Cadierno, J. Gimeno, J.-P. Majoral, Adv. Synth.
Catal. 2006, 348, 1671.
[20] M. Zablocka, C. Duyahon, Tetrahedron. Lett. 2006, 47,
2687.
[21] B. Helms, J. M. J. Frꢂchet, Adv. Synth. Catal. 2006, 348,
1125.
and
pure
nitrogen,
4-chloronitrobenzene
(300 mg,
1.9 mmol), potassium fluoride (143 mg, 2.86 mmol), phase-
transfer catalyst (0.076 mmol) and dimethyl sulfoxide
(0.4 mL, 5.7 mmol) were charged in a Schlenk tube and
heated at Æ1508C for 8 h. After cooling, 5 mL of distilled
water were added and the mixture was extracted three times
with 5 mL of dichloromethane. Organic layers were com-
bined, dried with sodium sulfate, filtered and analyzed via
Adv. Synth. Catal. 2008, 350, 2677 – 2682
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2681

Marie-Agnꢀs Lacour et al.
COMMUNICATIONS
[22] J. K. Kassube, L. H. Gade, Topics Organomet. Chem.
2006, 20, 61.
[23] J. P. Majoral, A. M. Caminade, R. Laurent, ACS Sym-
[30] R. Van de Coevering, R. J. M. Klein Gebbink, G.
Van Koten, Prog. Polym. Sci. 2005, 30, 474.
[31] R. Andrꢀs, E. de Jesus, J.-C. Flores, New J. Chem. 2007,
31, 1161.
posium Series, 2006, 928, 230.
[32] S.-H. Hwang, C. D. Shreiner, C. N. Moorefield, G. R.
Newkome, New J. Chem. 2007, 31, 1192.
[33] T. Kehat, K. Goren, M. Portnoy, New J. Chem. 2007,
31, 1218.
[34] S. Nlate, L. Plault, D. Astruc, New J. Chem. 2007, 31,
1264.
[35] A. Gissibl, C. Padiꢂ, M. Hager, F. Jaroschick, R. Rasap-
pan, E. Cuevas-Yanes, C. O. Turrin, A.-M. Caminade,
J.- P. Majoral, O. Reiser, Org. Lett. 2007, 9, 2895.
[36] A.-M. Caminade, P. Servin, R. Laurent, J. P. Majoral,
Chem. Soc. Rev., 2008, 37, 56.
[24] D. Mꢂry, D. Astruc, Coord. Chem. Rev. 2006, 250, 1965.
[25] J. N. H. Reek, S. Arevalo, R. Van Heerbeek, P. C. J.
Kamer, P. W. N. M. Van Leeuwen, Adv. Catal. 2006, 49,
7.
[26] D. Astruc, K. Heuze, S. Gatard, D. Mery, S. Nlate, L.
Plaut, Adv. Synth. Catal. 2005, 347, 329.
[27] A. M. Caminade, J. P. Majoral, Coord. Chem. Rev.
2005, 249, 1917.
[28] A. Dahan, M. Portnoy, J. Polym. Sci. A, 2004, 2, 43,
235.
[29] C. Liang, J. M. J. Frꢂchet, Prog. Polym. Sci. 2005, 30,
385.
[37] V. Maraval, A.-M. Caminade, J.-P. Majoral, J.-C. Blais,
Angew. Chem. Int. Ed. 2003, 42, 1822.
2682
asc.wiley-vch.de
ꢃ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2677 – 2682