Palladium catalyzed cyanation of o-dichloroarenes with potassium hexacyanoferrate(ii)

Article abstract of DOI:10.1007/s11172-012-0141-3

Cyanation of o-dichloroarenes with potassium hexacyanoferrate(ii) catalyzed by Pd(OAc)₂/PPh₃ system gave the corresponding phthalodinitriles in moderate yields. The method of competitive reactions revealed that activation rate of chl

Full text of DOI:10.1007/s11172-012-0141-3

Russian Chemical Bulletin, International Edition, Vol. 61, No. 5, pp. 980—983, May, 2012
980
Palladium catalyzed cyanation of oꢀdichloroarenes
with potassium hexacyanoferrate(II)
E. A. Savicheva and V. P. Boyarskiy
Department of Chemistry, Saint Petersburg State University,
26 Universitetsky prosp., 198504 Staryi Petergof, Russian Federation.
Fax: +7 (812) 428 6939. Eꢀmail: vadimpb@yahoo.com
Cyanation of oꢀdichloroarenes with potassium hexacyanoferrate(II) catalyzed by Pd(OAc)2/
PPh3 system gave the corresponding phthalodinitriles in moderate yields. The method of comꢀ
petitive reactions revealed that activation rate of chloroarenes by Pdꢀcatalyst increased in the
presence of the electronꢀwithdrawing groups in the arene core.
Key words: catalysis, Pdꢀcomplexes, cyanation, phthalodinitriles, the method of competiꢀ
tive reactions.
Aryl cyanides (benzonitriles) are widely used in drug
of orthoꢀdichloroꢀsubstituted arenes to give oꢀarenedicarꢀ
manufacturing, agrochemical industry, and as dyes and
their precursors.1 These compounds are also important
building blocks in organic chemistry and can easily be
transformed into diverse functionally substituted arenes.2
Numerous synthetic strategies to access aryl nitriles from
arenecarboxylic acid derivatives,3 aromatic aldehydes4 and
amines,5,6 alkyl arenes,7 aryl sulfonic acids,8,9 and aryl
halides10—13 have been developed. Aryl halides are apparꢀ
ently the most versatile and affordable starting materials
for aryl cyanides allowing direct displacement of the haloꢀ
gen atom by the nitrile group. It is known that the
C(sp2)—Hal bond is low reactive, therefore fairly harsh
conditions are required for the activation of these subꢀ
strates by common methods. Palladiumꢀcatalyzed cyanaꢀ
tion of aryl halides14,15 introduced in the 1970s makes this
approach promising. Cyanation of aryl chlorides,15—17
which are the most easy available compounds, is particuꢀ
larly attractive and at the same time particularly difficult
to accomplish.
bonitriles (phthalodinitriles) is of considerable interest.
The latter, for instance, are important intermediates for
the synthesis of phthalocyanines29 and organic lightꢀemitꢀ
ting materials.30,31
The present work presents the study of palladiumꢀcatꢀ
alyzed cyanation of dichloroarenes using potassium hexaꢀ
cyanoferrate(II) as a source of the nitrile group with the
aim to access phthalodinitriles.
Results and Discussion
For cyanation of 1,2ꢀdichlorobenzene (1a), 2,3ꢀdiꢀ
chlorobiphenyl (1b), and 3,4ꢀdichlorobiphenyl (1c), we
employed conditions used previously for Pdꢀcatalyzed
cyanation of monochlorobenzenes.27 These conditions
(e.g., atmospheric pressure and the use of triphenylphosꢀ
phine as cheap and affordable phosphine ligand) were choꢀ
sen taking in account potent practical application. The
results obtained are summarized in Table 1.
These data indicated that cyanation of dichloroarenes
(similar to cyanation of monochloroarenes27) requires relꢀ
atively severe conditions. The attempts to use the milder
reaction conditions (lower reaction temperature, various
solvents, and different reaction times) failed. Hence, in
contrary to our expectations, introduction of an additional
chlorine atom in the molecule does not increase considerꢀ
ably the reaction rate. Regardless of this issue, complete
conversion of aryl halide was achieved after prolonged
reaction time (Scheme 1).
One of the severe drawbacks of cyanation is the use of
highly poisonous metal cyanides as the cyanide ion sourꢀ
ces. Therefore, palladium catalyzed cyanation of aryl haꢀ
lides employing cheap and nonꢀtoxic potassium hexaꢀ
cyanoferrate(II), which was first developed in 2004,18 imꢀ
mediately attracted great attention. In less than 10 years,
approximately a dozen papers devoted to the synthetic
application of this approach for the cyanation of aryl chloꢀ
rides were published.19—27 Some of these papers19—22 deꢀ
scribed microwaveꢀaccelerated reactions; the other publiꢀ
cations are concentrated on the use of expensive and comꢀ
plicated ligands.23—26
It is of note that preparative yields of dinitrile were
significantly lower in all cases. Gas chromatography/
mass spectrometry revealed the presence of side products
resulting from reduction, which were formed upon cyanaꢀ
The data on the application of this method for cyanaꢀ
tion of polychloroarenes are virtually absent.28 Cyanation
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0974—0978, May, 2012.
1066ꢀ5285/12/6105ꢀ0980 © 2012 Springer Science+Business Media, Inc.

Cyanation of oꢀdichloroarenes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
981
Table 1. Cyanation of oꢀdichloroarenes with potassium hexaꢀ
cyanoferrate(II) catalyzed by Pd(OAc)2—PPh3
activation by Pdꢀcomplex in respect of the starting dichloꢀ
roarene. However, at the first glance, this explanation conꢀ
tradicts our observation that the reaction rate of diꢀ and
monochlorides are nearly equal. To approach this quesꢀ
tion, we studied the effect of the substituent on the activaꢀ
tion rate for a series of substituted chlorobenzenes. Since
we were interested in the reactivity of aryl chloride toꢀ
wards the catalyst, the method of competitive reactions
was used and the relative rate constants were calculated
from a decrease in the content of the starting substrates.
The data obtained are given in Table 2.
It is obvious that the presence of electronꢀwithdrawing
substituents accelerates the reaction. Estimation of a reꢀ
action parameter value  = 2.3 0.06 indicated that the
aryl halide activation is significantly sensitive to the elecꢀ
tronic effect of the substituents. This fact apparently exꢀ
plains why intermediate oꢀchlorobenzonitriles were not
detected in cyanation of oꢀdichloroarenes, viz., the nitrile
group in the ortho position being the strong electronꢀwithꢀ
drawing substituent accelerates cyanation of the halfꢀprodꢀ
uct by several times with respect to the starting oꢀdichloꢀ
roarene (see Table 2). It is worth of noticing that the small
size of the nitrile group introduced should also facilitate
the second cyanation.
Substrate
Solvent
T/C
/h Converꢀ Y (%)a
sion (%)b
1a
1a
1a
1b
1c
1c
DMF
DMF
DMF
DMF
DMF
DMF
140
140
140
140
140
140
6
24
72
24
6
30
62
>98
46
27
>98
17b
38b
55b
25c
15c
60c
(0d,e
0
24
)
1c
1c
1c
1c
DMF
Acetonitrile
Ethanol
Dioxane : water 100
(1 : 1)
100
85
80
24
24
24
24
0
0
0
0
0
0
0
a Y is the yield of dinitrile.
b Based on GC analysis.
c Preparative yield.
d Without Pd(OAc)2.
e Without PPh3.
Scheme 1
1,2ꢀDichlorobenzene (1a) is turned to be 6 times more
reactive than chlorobenzene (8) (see Table 2, based on the
number of reactive centers in a molecule). At the same
time, the cyanation conditions for compounds bearing the
second chlorine atom are not much milder. This suggestꢀ
Table 2. Relative reactivity of substituted chloroꢀ
arenes in cyanation with potassium hexacyanoꢀ
ferrate(II) catalyzed by Pd(OAc)2—PPh3
R = H (a), 3ꢀPh (b), 4ꢀPh (c)
tion of 1c at complete conversion (Scheme 2). Amounts
of the side products were determined by gas chromatoꢀ
graphy.
It should be emphasized that in all cases, products of
bisꢀcyanation of the corresponding dichloroarenes were
formed. Therefore, even on the initial stage of the reaction
(at conversions lower 50%), dinitrile was a major reaction
product, i.e., the cyanation involved both the chlorine
atoms at once.
Substrate
krel
4ꢀChloroanisole (6)
4ꢀChlorotoluene (7)
Chlorobenzene (8)
1,4ꢀDichlorobenzene (9)
1,3ꢀDichlorobenzene (10)
4ꢀChlorobenzonitrile (11)
1,2ꢀDichlorobenzene (1а)
2ꢀChlorobenzonitrile (12)
0.23
0.44
1.0
2.9*
7.6*
35
3.2*
43
This fact can be explained by the noticeably higher
reactivity of the intermediate oꢀchlorobenzonitrile towards
* Statistically corrected.
Scheme 2
i. K4[Fe(CN)6], [Pd], PPh3, Na2CO3, DMF, 140 C, 24 h. * Mixture of isomers in a 1 : 1 ratio.

982
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
Savicheva and Boyarskiy
Scheme 3
was washed with water, brine, and dried with Na2SO4. The
aliquot of the organic phase was analyzed by GC. The solvent
was removed in vacuo, the resulted residue was analyzed by
NMR 1H.
The products were purified by column chromatography (silꢀ
ica gel (Merck, 0.04—0.063 mm), elution with hexane—ethyl
acetate, 7 : 1).
ed that the harsh cyanation conditions is due to the transꢀ
metalation stage but not to the aryl halide activation stage as
for the majority of crossꢀcoupling reactions (Scheme 3).32
The transmetalation is involved destruction of a very stable
hexacyanoferrate(II) anion, which obviously required seꢀ
vere conditions.
In summary, we found that the electronꢀwithdrawing
substituents in the aromatic ring accelerate the aryl halide
activation in Pdꢀcatalyzed cyanation ( = 2.3 0.06). It was
shown that phthalodinitriles can be synthesized in moderꢀ
ate yields from oꢀdichloroarenes using nonꢀtoxic potasꢀ
sium hexacyanoferrate(II) as the source of the nitrile group.
This approach is promising for practical application.
In the case of cyanation of 1,2ꢀdichlorobenzene (1a), the
reaction products were identified by GC (by comparing the reꢀ
tention times of the analytes with that of 2ꢀchlorobenzonitrile
and phthalodinitrile) and NMR spectroscopy. Dinitriles 2b and
1
2c were identified by melting points, IR spectra, and H and
13C NMR spectra. The side products formed in cyanation of
compound 1c were identified by GC/MS and, in several cases,
by GC (by comparing the retention times of the analytes with
that of biphenyl (5), 3ꢀchlorobiphenyl (4a), and 4ꢀchlorobiꢀ
phenyl (4b)).
Experimental
Biphenylꢀ2,3ꢀdicarbonitrile (2b)28,35. Yield 103 mg (25%).
M.p. 136—137 C (cf. Ref. 34: 137 C). IR, /cm–1: 3064, 2926,
2854 (CAr—H); 2232 (CN); 1730, 1581, 1452 (Carom—Carom);
808, 761, 699 (Carom—Carom—H). 1H NMR (CDCl3), : 7.53—7.57
(m, 5 H, Ph); 7.78—7.82 (m, 3 H, C(4)H, C(5)H, C(6)H).
13C NMR (CDCl3), : 114.9; 115.5; 116.2; 117.5; 129.1; 129.8;
130.3; 132.5; 133.3; 134.8; 136.9; 147.9.
Biphenylꢀ3,4ꢀdicarbonitrile (2c)28,36. Yield 244 mg (60%).
M.p. 158—159 C (cf. Ref. 35: 158 C). IR, /cm–1: 3070,
2924, 2848 (Carom—H); 2233 (CN); 1714, 1595, 1481, 1391
(Carom—Carom); 1273, 913, 850, 766, 701 (Carom—Carom—H).
1H NMR (CDCl3), : 7.53—7.63 (m, 5 H, Ph); 7.88—7.96 (m, 2 H,
C(5)H, C(6)H); 8.03 (s, 1 H, C(2)H). 13C NMR (CDCl3), :
114.4; 115.8; 115.9; 116.9; 127.6; 129.9; 130.2; 131.8; 132.4;
134.4; 137.4; 146.9. MS (EI, 70 eV), m/z (Irel (%)): 204 [M]+
(100), 176 [M – HCN]+ (11), 102 (8), 88 (10), 75 (9).
Biphenylꢀ3ꢀcarbonitrile and biphenylꢀ4ꢀcarbonitrile (3). The
GC chromatogram contains two neighboring peaks, which were
not attributed to a particular product. MS of compound with
lower retention time (EI, 70 eV), m/z (Irel (%)): 179 [M]+ (100),
151 [M – HCN – H]+ (15), 89 (10), 76 (30). MS of compound
with higher retention time (EI, 70 eV), m/z (Irel (%)): 179 [M]+
(100), 151 [M – HCN – H]+ (13), 89 (12), 76 (25).
3ꢀChlorobiphenhyl and 4ꢀchlorobiphenyl (4). The GC chromaꢀ
togram contains two neighboring peaks, which were not attriꢀ
buted to a particular product. MS of compound with lower retenꢀ
tion time (EI, 70 eV), m/z (Irel (%)): 188 [M]+ (100), 152
[M – HCl]+ (50), 76 (35). MS of compound with higher retenꢀ
tion time (EI, 70 eV), m/z (Irel (%)): 188 [M]+ (100), 152
[M – HCl]+ (52), 76 (40). Characteristic molecular ion isotope
pattern revealed the presence of one chlorine atom in the moleꢀ
cules of both compounds.
1
H and 13C NMR spectra were run on a Bruker DPX 300
instrument at working frequencies of 300.13 (1H) and 75.03 MHz
13C) in CDCl3. Gas chromatography/mass spectrometry
(
(GC/MS) was performed on a Shimadzu QPꢀ5000 instrument
(EI (70 eV), SPBꢀ5 column, length of 6 m, diameter of 0.25 mm,
film of 0.25 m). IR spectra were obtained on a Shimꢀ
adzu FTIRꢀ8400S instrument in KBr pellets in the range
of 400—4000 cm–1. Gas chromatography was performed on
a Chromꢀ5 chromatograph (flame ionization detector, glass colꢀ
umn 3 mm in diameter and 2500 mm in length, stationary phase
either SEꢀ30 (10%) or OVꢀ225 (5%) on Chromaton NꢀSuper
(80—100 mesh)). Inorganic reagents (pure for analysis grade)
were used as purchased. The solvents were purified by standard
procedures. Substituted chlorobenzenes, triphenylphosphine,
1,2,4,5ꢀtetramethylbenzene, naphthalene, and acenaphthene
(pure for analysis grade) were used as purchased. Dichloroꢀ
biphenyls were synthesized by the known procedures,33,34 purity
of the products were monitored by GC and NMR 1H.
Cyanation of oꢀdichloroarenes (general procedure). The
Schlenk flask was charged with dichloroarene (2 mmol), potasꢀ
sium hexacyanoferrate(II) trihydrate (1.8 g, 4.2 mmol), acenaphꢀ
thene (0.077 g, 0.5 mmol; the GC internal standard), sodium
carbonate (1.1 g, 10 mmol), and DMF (10 mL). The mixture
was magnetically stirred and flushed with argon for 0.5 h. Then
the flushed with argon solution of palladium acetate (0.020 g,
0.09 mmol) and triphenylphosphine (0.080 g, 0.3 mmol) in DMF
(2 mL) was added. The mixture was heated at 140 2 C (bath
temperature) for specified time (see Table 1) under argon. After
completion of the reaction, the mixture was cooled to ambient
temperature and poured into a mixture of hexane—dichloroꢀ
methane (9 : 1, 20 mL) and water (20 mL). The organic layer

Cyanation of oꢀdichloroarenes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 5, May, 2012
983
Biphenyl (5). MS (EI, 70 eV), m/z (Irel (%)): 154 [M]+ (15),
153 [M – H]+ (100), 76 (53).
Gas chromatography (with calibration coefficients) was used
for quantitative analysis of the reaction mixtures. The relative
reactivity was determined by the method of competitive reacꢀ
tions; calculations were based on the consumption of the starting
substrates.
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Determination of relative rates of cyanation (general proceꢀ
dure). The 25 mL Schlenk flask was charged with a pair of studꢀ
ied aryl halides (2 mmol of each), the GC internal standard
(1,2,4,5ꢀtetramethylbenzene or naphthalene), potassium hexaꢀ
cyanoferrate(II) trihydrate (1.8 g, 4.2 mmol), sodium carbonate
(1.1 g, 10 mmol), and DMF (10 mL). The mixture was stirred
and aliquot for the GC analysis was taken. Then the mixture was
magnetically stirred and flushed with argon for 0.5 h. To the
mixture, the flushed with argon solution of palladium acetate
(0.020 g, 0.09 mmol) and triphenylphosphine (0.080 g, 0.3 mmol)
in DMF (2 mL) was added. The mixture was heated at 140 2 C
(bath temperature) for 10—12 h (conversion of the starting maꢀ
terial was 30—70%) with stirring. After completion of the reacꢀ
tion, an aliquot (0.5 mL) was taken, diluted with water (2 mL),
and unreacted starting compounds and internal standard were
extracted with hexane (2×2 mL). The organic layer was separatꢀ
ed, washed with brine (2 mL), and analyzed by GC.
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This work was financially supported by Ministry of
Education and Science of the Russian Federation (Federal
target program "Scientific and ScientificꢀPedagogical Perꢀ
sonnel of Innovative Russia", event 1.2.1, state contract
No. Pꢀ676 from 20.05.2010), SaintꢀPetersburg State Uniꢀ
versity (Grant for Scientific Research in 2011—2013), and
the Russian Foundation for Basic Research (Project
No. 11ꢀ03ꢀ00048ꢀa).
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Received May 18, 2011;
in revised form February 29, 2012