Improving palladium-catalyzed cyanation of aryl halides: Development of a state-of-the-art methodology using potassium hexacyanoferrate(II) as cyanating agent

Article abstract of DOI:10.1016/j.jorganchem.2004.08.020

Benzonitriles are easily accessible via palladium-catalyzed cyanation of aryl halides using potassium hexacyanoferrate(II) as cyanide source. This method is applicable on both activated and deactivated aryl and heteroaryl bromides and activated chlorides giving the corresponding benzonitriles in good to excellent yield. Advantageously, the used cyanating agent is non-toxic and cheap. The presented catalyst system is rather simple and it is not necessary to add expensive phosphines, making the novel method also attractive for industrial applications. Benzonitriles are easily accessible via palladium-catalyzed cyanation of aryl halides using potassium hexacyanoferrate(II) as cyanide source. This method is applicable on both activated and deactivated aryl and heteroaryl bromides and activated chlorides giving the corresponding benzonitriles in good to excellent yield. Advantageously, the used cyanating agent is non-toxic and cheap. The presented catalyst system is rather simple and it is not necessary to add expensive phosphines, making the novel method also attractive for industrial applications.

Full text of DOI:10.1016/j.jorganchem.2004.08.020

Journal of Organometallic Chemistry 689 (2004) 4576–4583
www.elsevier.com/locate/jorganchem
Improving palladium-catalyzed cyanation of aryl
halides: development of a state-of-the-art methodology
using potassium hexacyanoferrate(II) as cyanating agent
*
Thomas Schareina, Alexander Zapf, Matthias Beller
Leibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e.V., Buchbinderstr. 5-6, 18055 Rostock, Germany
Received 7 July 2003; accepted 3 August 2004
Available online 15 September 2004
Abstract
Benzonitriles are easily accessible via palladium-catalyzed cyanation of aryl halides using potassium hexacyanoferrate(II) as cya-
nide source. This method is applicable on both activated and deactivated aryl and heteroaryl bromides and activated chlorides giv-
ing the corresponding benzonitriles in good to excellent yield. Advantageously, the used cyanating agent is non-toxic and cheap. The
presented catalyst system is rather simple and it is not necessary to add expensive phosphines, making the novel method also attrac-
tive for industrial applications.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Aryl halides; Benzonitriles; Cyanation; Homogeneous catalysis; Palladium; Potassium hexacyanoferrate(II)
1. Introduction
[4]. In case of biologically active benzonitrile derivatives
another aspect is worth noting. By applying transition
metal-catalyzed cyanation of aryl halides using
K11CN, K13CN or K14CN isotope labelled compounds
are easily accessible [5–9]. The resulting products are
used in pharmacokinetic studies and investigations on
the metabolism of pharmaceuticals.
Clearly, benzonitriles can be prepared in numerous
ways [10–14]. Most often they have been synthesized
by the Rosenmund–von Braun reaction [15–19] from
aryl halides or diazotization of anilines and subsequent
Sandmeyer reaction [20–22] on laboratory as well as
on industrial scale. Drawbacks of the Rosenmund–von
Braun and the Sandmeyer reaction are the high temper-
ature (150–250 °C) and the use of stoichiometric
amounts of copper(I) cyanide as cyanating agent, which
leads to equimolar amounts of heavy metal waste.
On ton-scale the method of choice in industry is
ammoxidation, whereby the corresponding toluene
derivatives are reacted with oxygen and ammonia at
300–550 °C in the presence of heterogeneous fixed-bed
Benzonitriles are of considerable interest for organic
chemistry as integral part of dyes, herbicides, agrochem-
icals, pharmaceuticals, and natural products. The nitrile
group also serves as an important intermediate for a
multitude of possible transformations into other
functional groups. As an example the synthesis of
Fluvoxamine is shown in Scheme 1. Here, 4-(trifluoro-
methyl)benzonitrile, which is available from 4-chloro-
benzotrifluoride by nickel-catalyzed cyanation on
ton-scale, serves as an intermediate [1–3].
Benzonitriles themselves are also of significant inter-
est, e.g., as substructures in biologically active agents.
In Fig. 1 two selected examples of pharmaceuticals con-
taining an aromatic nitrile as part of the molecule are
shown along with their names, producers, and effects
*
Corresponding author. Tel.: +49 381 466930; fax: +49 381
4669324.
E-mail address: matthias.beller@ifok.uni-rostock.de (M. Beller).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.08.020

T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
4577
NH2
N O
F3C
Cl
F3C
O
[Ni]
NaCN
1. R-Mg-X
2. H3O+
O
F3C
F3C
CN
O
Scheme 1. 4-(Trifluoromethyl)benzonitrile – a key intermediate in the synthesis of Fluvoxamine.
CN
O
O
S
O
N
H
CF3
N
N
NC
HO
CH3
F
Bicalutamid
Casodex (Zeneca)
non-steroidal antiandrogen,
antineoplastic, anti(prostate)cancer
Fadrozole
Arensin (Ciba-Geigy)
antineoplastic, non-steroidal
aromatase inhibitor
Fig. 1. Examples of pharmaceutically active benzonitriles.
catalysts [23–25]. Unfortunately, the ammoxidation is
restricted to products such as benzonitrile, terephthalo-
dinitrile, and chlorobenzonitriles [26,27] because of the
high temperature and high pressure needed. In addition,
a limited supply of toluene derivatives is available on a
larger scale.
A useful alternative for the preparation of more-sub-
stituted benzonitriles is the transition metal-catalyzed
cyanation of aryl-X compounds (X = Cl, Br, I, OTf)
with cheap and readily available cyanation agents like
sodium or potassium cyanide (Scheme 2) [28–32]. The
order of reactivity of the aryl-X derivatives is opposite
to the bond-dissociation energy of the C–X bond (reac-
tivity: I ꢀ OTf > Br > Cl) [33,34]. Electron-withdrawing
substituents on the aryl ring increase the reactivity, while
electron-donating substituents decrease it. Catalysts for
coupling of aryl halides or triflates with cyanide are
transition metals complexes of the platinum group, espe-
cially palladium or nickel complexes. In general, palla-
dium catalysts tolerate a wider variety of functional
groups and are less sensitive to air and humidity com-
pared to nickel catalysts. The first palladium-catalyzed
cyanation of aryl-X derivatives was introduced in 1973
by Takagi et al. using aryl bromides and iodides with
potassium cyanide as cyanating agent (Scheme 3) [35].
Interestingly, palladium(II) cyanide or palladium(II)
acetate served as the catalyst without additional ligands
present. Typical reaction conditions were: DMF as sol-
vent, 140–150 °C and 2–12 h reaction time. Early studies
by Takagi et al. [36] led to a first mechanistic proposal.
One especially important point was the fact that an ex-
cess of cyanide ions inhibits the catalytic cycle. This
deactivation was explained by reaction of cyanide with
palladium(II) species, forming inactive palladium(II)
cyano compounds, which cannot be reduced to catalyt-
ically active palladium(0) species. Potassium tetracyano-
palladate(II) and palladium(II) cyanide were shown to
be almost inactive in the cyanation reaction, and a dra-
matic solvent effect was described which can be ex-
plained by the influence of the cyanide solubility in
different reaction media. The higher the solubility of the
cyanide salt, the lower the reaction outcome. Another
finding of this work is the positive effect of co-catalysts
like potassium hydroxide, sodium ethoxide, potassium
carbonate, or sodium phenoxide, which facilitate the
reduction of palladium(II) species [37,38].
+MCN
[catalyst]
X
CN
-MX
R
R
X = Cl, Br, I, OTf
Scheme 2. Transition metal-catalyzed cyanation of aryl halides.

4578
T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
2 mol% Pd(CN)2
or Pd(OAc)2
X
+
CN
+
KCN
KX
DMF, 140 ˚C
R
R
Scheme 3. First palladium-catalyzed cyanation of aryl bromides and iodides.
The reaction conditions have subsequently been
optimized, various ligated palladium complexes were
introduced, and the substrate scope of the method has
been considerably enhanced by different groups. In Ta-
ble 1 the different conditions of palladium-catalyzed cya-
nation reactions of aryl halides known prior to 2000 are
summarized. In general, the cyanation of aryl bromides
and iodides has been performed in the presence of an ex-
cess of KCN in dipolar aprotic solvents. In addition,
NaCN, Me3SiCN, n-Bu3SnCN and Zn(CN)2 were em-
ployed in selected examples as cyanide sources. Typi-
cally, a large amount of catalyst (1.5–20 mol% of Pd)
has to be applied in order to obtain significant conver-
sion and yield. Apparently using these catalyst loadings
there is no difference in applying palladium(II) or palla-
dium(0) pre-catalysts. In a few cases the cyanation of
chloroarenes was also performed. However, in all these
examples highly reactive heteroaryl chlorides were used.
Table 1 demonstrates that the palladium-catalyzed
cyanation of aryl bromides and iodides works with dif-
ferent palladium catalysts and cyanide sources (Scheme
4). Clearly, drawbacks of these procedures are the de-
scribed catalyst productivity, which is always quite low
(turnover numbers (TON) are in general 10–50), further-
more, many systems need additives or a special cyanide
source (e.g. Zn(CN)2) to enable good product yields.
In the last years new approaches have been made by
us and other groups in order to overcome the limitations
and drawbacks of the shown reactions, which will be
discussed below.
Regarding costs and availability aryl chlorides are
favorable substrates for catalytic refinement of aryl-X
derivatives [54–57]. So far the most versatile and practi-
cal procedure for the palladium-catalyzed cyanation of
aryl chlorides using potassium cyanide was published
by our group [58,59]. Here, as a catalyst system 2
mol% Pd(OAc)2, 1,5-bis(diphenylphosphino)pentane as
ligand and 20 mol% of N,N,N0,N0-tetramethylethylene-
[Pd]
X
CN
R
R
Scheme 4. Palladium-catalyzed cyanation of aryl halides.
Table 1
Evolution of the palladium-catalyzed cyanation of aryl halides
Entry
X
Catalyst (mol%)
Additive (mol%)
Cyanide (equiv.)
Solvent
T (°C)/t (h)
Ref.
1
2
I, Br
I
Pd(OAc)2 (2)
Pd(PPh3)4 (20)
–
KCN (2)
KCN (1.5)
KCN (2)
DMF
THF
HMPT
140/2–12
reflux/8
[35]
[39]
[40]
[41]
[41]
[42]
[43]
–
KOH (0.05) KI (9)
3
I, Br
I, Br
I, Br
Clb
Br
Pd(Oac)2 (1.5)
Pd(PPh3)4 (10)
60–90/2–9
80–100/2–40
80–100/2–40
reflux/2.5
100/65
4
–
Al2O3
NaCN on Al2 O3 (5)a Toluene
5
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
NaCN (5)
Toluene
DMF
Benzene
Et3N
6
–
KCN (1.5)
KCN (1)
Me3 SiCN (1.5)
7
Pd(PPh3)4 (20)
Pd(PPh3)4 (2)
18-C-6 (40)
–
8
I
reflux/0.17–0.5 [44]
9
Brc
Id
Pd(PPh3)4 (1.5)
Pd(PPh3)4 (n.g.)e
PdCl2 (PPh3)2 (2)
Pd2 (dba)3 (CHCl3) (0.5) dppfg (2)
Pd(PPh3)4 (2–6)
Pd(PPh3)4 (7)
18-C-6 (7.5) CuI (250) KCN (250)
–
DMF
DMF
DMF
NMP
DMF
NMP
RCNi
reflux/2
n.g.e
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
10
11
12
13
14
15
16
17
a
n-Bu3 SnCN (n.g.)
KCN (2)
KCN (2)
Clf
I
–
reflux/2
60–80/1–8
80/0.5–7
90/20
–
I, Br
Clf
–
Zn(CN)2 (0.6)
Zn(CN)2 (0.6)
NaCN (2)
–
I, Brh, OTf Pd(PPh3)4 (5)
CuI (10)
–
Zn (12)
reflux/1–6
Br
Cl
Pd2 (dba)3 (0.05–1), dppf
Pd2 (dba)3 (2)
Zn(CN)2 (0.6)
Zn(CN)2 (0.6)
DMF (wet) 120/20
DMA 120/1–12
5 mmol NaCN per g Al2O3.
Only chloropyrazines.
Only bromopyrazines.
b
c
d
e
f
Only 2-iodoadenosine.
Not given.
Only chloropurines.
g
h
i
1,10-Bis(diphenylphosphino)ferrocene.
One example of a vinyl bromide.
R = Me for iodides and triflates, R = Et for bromides.

T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
4579
loading of 0.1 mol% and the tolerance of low amounts
of oxygen, so that reagent grade solvent DMF without
special pre-treatment can be used.
CN
OH
+
O
HCN
Scheme 5. Acetone cyanohydrin, a useful HCN equivalent.
diamine (TMEDA) as additive work for most aryl chlo-
rides, either activated or deactivated.
2. Results
As discussed above various palladium species (palla-
dium(0) as well as palladium(II) species) are deactivated
by cyanide ions in solution. To overcome this problem
and to improve catalyst productivity (TON) it is neces-
sary to control the concentration of cyanide at a defined
low level, which allows the reductive coupling to pro-
ceed efficiently, but prevents catalyst deactivation at
the same time. An elegant and promising approach is
the defined dosage of a liquid cyanide source to the reac-
tion mixture using a syringe pump. One of the simplest
soluble cyanide sources for such reactions is acetone
cyanohydrin, which is commercially available on large
scale (Scheme 5).
The cyanation of aryl bromides with acetone cyano-
hydrin is possible in a very efficient manner [60].
Remarkable are the convenient reaction conditions,
the excellent nitrile selectivity and the low catalyst con-
centration. Until very recently, the highest turnover
number for palladium-catalyzed cyanation of aryl ha-
lides known has been reported by applying acetone
cyanohydrin as cyanating agent (TON = 129900). Simi-
larly, trimethylsilylcyanide (TMSCN) can be used to
control the concentration of cyanide ions in solution
[61].
Recent efforts by other groups which have been pur-
sued to further improve the reaction scope are mainly
based on the use of zinc salts. For example, a room tem-
perature aryl bromide cyanation with 2.5 mol%
Pd2(dba)3, tri-t-butylphosphine as ligand, 1.8 equiv.
Zn(CN)2 as the cyanide source and 0.12 equiv. Zn as
activating agent in DMF was presented by Maddaford
et al. [62]. Zinc was also used as activating agent, to-
gether with Zn(OAc)2, in a procedure by Chidambaram
[63]. The advantage of this method is a relatively low Pd
In continuation of our own work on the cyanation
reaction we have discovered earlier this year that slow
liberation of cyanide ions is also guaranteed by using
the extremely stable potassium hexacyanoferrate(II) as
cyanide source, with Pd(OAc)2 as catalyst and dppf
(1,10-bis(diphenylphosphino)ferrocene) as ligand [64].
An advantageous side effect of this procedure was the
high catalyst productivity achievable. Hence, a TON
of 9700 was reached for the cyanation of bromobenzene.
Keeping safety aspects in mind, the use of K4 [Fe(CN)6]
is significantly preferable compared to other highly toxic
cyanide sources. While KCN is extremely toxic (LDLo
(oral, human) = 2.86 mg/kg) and develops HCN on con-
tact with acidic water, K4[Fe(CN)6)] is non-toxic and
even used in food industry for metal precipitation. It
has also been used as anti-agglutinating auxiliary for
NaCl (table salt) [65]. It is soluble in water without
decomposition, even on addition of hydrochloric acid
HCN is developed only by boiling. Other previously
known cyanating agents such as NaCN, Zn(CN)2 and
CuCN are comparably toxic to KCN. In addition,
K4[Fe(CN)6)] is commercially available on ton-scale
and comparably in price to KCN [66].
Here, we report for the first time that palladium-cat-
alyzed cyanations using K4[Fe(CN)6)] also work highly
efficiently with simple palladium salts as catalyst! In gen-
eral there is no necessity to add an expensive phosphine
ligand, making this procedure highly attractive for
applications.
In Table 2 selected examples of catalyst variations for
our model reaction are shown. Initially, we discovered
that Pd/dppf gives excellent results in this reaction (Ta-
ble 2, entry 1). To our surprise in the presence of other
ligands such as PPh3, PCy3, bpephos and even carbenes
Table 2
Variation of reaction conditions for the cyanation of bromobenzene
Entry
Solvent
Pd(OAc)2 [mol%]
Ligand [mol%]
Conv. [%]
Yield [%]
TON
1
2
3
4
5
6
7
8
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
0.01
1
dppf (0.02)
PPh3 (4)
100
64
97
54
70
59
98
11
89
92
9700
54
1
PCy3 (4)
bpephos (2)a
84
73
70
59
1
0.01b
–
–
–
–
100
17
9800
11
1
0.05
0.01
97
95
1800
9200
Conditions: 2 mmol bromobenzene, 0.5 mmol dry K4[Fe(CN)6], 2 mmol Na2CO3, 2 ml NMP, Pd(OAc)2, 120 °C, 16 h.
a
2,20-bis(diphenylphosphino)diphenylether.
Pd(IMes)(dvds) = 1,3-dimesitylimidazole-2-ylidene-palladium(0)-g2,g2-1,1,3,3-tetramethyl-1,3-divinyldisiloxane [67].
b

4580
T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
Table 3
Cyanation of various aryl halides [68]
Entry
1
Aryl halide
Temp. [°C]
Pd(OAc)2 [mol%]
0.025
Conv. [%]
100
Yield [%]
69
TON
2760
Br
140
O
O
2
3
Br
140
140
0.025
100
97
98
75
3920
750
F3C
Br
F
0.1
F
4
5
6
Br
140
140
140
0.025
0.025
0.005a
100
92
92
90
91
3680
3600
Br
Br
100
18,200
7
Br
140
0.01a
100
98
9800
O
O
8
9
Br
140
140
0.025
0.025
100
100
95
92
3800
3680
Br
O
10
11
Br
140
140
0.1
0.1
100
99
>99
84
1000
840
N
Cl
N

T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
4581
Table 3 (continued)
Entry
12
Aryl halide
Temp. [°C]
Pd(OAc)2 [mol%]
0.1
Conv. [%]
85
Yield [%]
77
TON
770
Cl
120
O
a
20 mol% Na2CO3.
also a high yield of benzonitrile at relatively low catalyst
concentration was obtained (Table 2, entries 2–5). Be-
cause of the comparably low influence of the nature of
the ligand, next reactions without ligand were per-
formed. A blind test at 1 mol% Pd without phosphine
ligand shows only a low yield of the product benzonitrile
(Table 2, entry 6).
Nevertheless, reactions performed at lower Pd load-
ing resulted in activities comparable to the highest ones
achieved in the presence of phosphine ligands (Table 2,
entries 7–8). Due to the often high price of phosphine
ligands and the simplified process without any ligands
present this is an interesting feature worth further exam-
ination. Therefore, the new protocol was then applied to
the cyanation of various aryl halides (Table 3).
Compared to reactions with phosphine ligands
present, a slightly higher temperature of 140 °C has
to be used to obtain optimum results. In most cases
the yields of benzonitriles are higher or considerably
less Pd is needed, when performing the experiments
without additional phosphine ligand. Moreover, we
found that 1.2 equiv. of cyanide (20 mol%
K4[Fe(CN)6]) is sufficient to ensure a complete reaction
at high rate.
cyanated under these conditions. Some aryl chlorides,
for instance 4-chloroquinaldine (Table 3, entry 11) and
4-chloroacetophenone (Table 3, entry 12), are suffi-
ciently activated to react, while more electron rich ones,
like 4-chloroanisole, give so far only low conversion
(<10%). Most outstanding is the TON of >18.000 for
1-bromonaphthalene, which is an unprecedented high
productivity for a metal-catalyzed cyanation of aryl
halides.
What are the reasons for the high catalyst stability
and activity without phosphine ligands present? It is well
documented in literature that palladium catalysts used
in coupling reactions of aryl halides might be stabilized
by anions (halides, carboxylates) or even solvents. In
this context it is interesting to note that ‘‘naked’’ metal
catalysts can be sufficiently stable to perform a desired
reaction more efficiently than a ligand-modified catalyst
[69–73]. Even for some reactions with metal/ligand sys-
tems it is assumed that the ‘‘real’’ catalysts are ligand
free, solvent stabilized metal ions, clusters or colloids
[74]. Often, the defined ligand coordinated complexes
are considered merely as a storage pool for the metal
in a low oxidation state.
Regarding the dramatic increase of product yield at
lower catalyst concentration (compare Table 2, entries
6–8), we explain the observation by a decrease of
agglomeration of molecular palladium complexes to pal-
ladium black. A similar effect has been described by de
Vries et al. [73,75] for Heck olefinations of aryl iodides.
NMP and cyanide anions are well enough suited as
ligands to stabilize the intermediate Pd(0) and Pd(II)
species. Furthermore, stabilization of active Pd species
by binding to hexacyanoferrate(II) ions might occur,
which is in agreement to a mechanism proposed by Pra-
sad [76] for the Hg(II)-catalyzed ligand exchange in hex-
acyanoferrate(II) (Scheme 6).
3. Discussion
In general, we obtain good to excellent results for all
types of aryl bromides present in this reaction. Uni-
formly, electron poor (Table 3, entries 1–3) and electron
rich (Table 3, entries 4, 5, 7–9) bromoarenes give high
yields (69 to >99%) at low catalyst loadings (0.005–0.1
mol%). Ortho substituents such as fluoro or methyl
groups are well tolerated. Furthermore, heteroaryl bro-
mides, e.g., 3-bromopyridine (Table 3, entry 10) can be
4
4
4
N
Fe
N
N
Fe
N
N
Fe
N
N
N
N
N
N
N
N
N
N
N
X
Ar
Ar-PdX
X
+
Pd
Pd
Ar
CN
N
Scheme 6. Proposed Pd-catalyzed transfer of cyanide.

4582
T. Schareina et al. / Journal of Organometallic Chemistry 689 (2004) 4576–4583
[9] R.M. Carr, K.M. Cable, G.N. Wells, D.R. Sutherland, J. Labelled
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Another important factor for the high productivity
of our system may be contributed by the reductive prop-
erties of the reagent hexacyanoferrate(II). As has been
stated originally by Takagi, catalyst deactivation is
based on the fact that palladium(II) tetracyano com-
pounds cannot be reduced to catalytically active palla-
dium(0) species. Hexacyanoferrate(II) might be able to
perform this reduction and, moreover, reduce also
traces of oxygen and other impurities from the reaction
mixture.
[10] R.C. Larock, Comprehensive Organic Transformations, VCH,
New York, 1989, pp. 819–995.
[11] C. Grundmann, in: J. Falbe (Ed.), Houben-Weyl: Methoden der
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Stuttgart, 1985, pp. 1313–1527.
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4. Conclusion
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126.
We have developed an improved protocol for the cya-
nation of aryl halides. Our procedure relies on the use of
non-poisonous potassium hexacyanoferrate(II) and,
compared to our previous report, omits the necessity
of adding phosphines such as dppf, while keeping the
catalyst productivity and product yield at least constant
and in some cases even improving them. Using the de-
scribed catalyst system the best turnover number
(>18.000) for a transition metal-catalyzed cyanation of
aryl halides has been obtained. Combining the advan-
tages of the cyanide source and the simplicity of the cat-
alyst system we believe that the new procedure
constitutes the current state-of-the-art cyanation tech-
nology for aryl halides.
[18] K.W. Rosenmund, E. Struck, Chem. Ber. 52 (1919) 1749–1756.
[19] Meister, Lucius, Bruning, DE 271 790(1913).
¨
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