Features of the reaction of 2,3-dihalopropanoic acids with pyridines and nucleophilic addition to N-vinylpyridinium salts

Article abstract of DOI:10.1134/S107036320807030X

The example of vinylpyridinium salts to establish for the first time the possibility of nucleophilic addition to the vinyl group in quaternary ammonium salts, which provides evidence against the concept that such reactions involve d orbitals. The nucleoph

Full text of DOI:10.1134/S107036320807030X

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 7, pp. 1452–1457. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © R.Dzh. Khachikyan, S.L. Davtyan, M.G. Indzhikyan, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 7, pp. 1219–
1224.
Features of the Reaction of 2,3-Dihalopropanoic Acids
with Pyridines and Nucleophilic Addition
to N-Vinylpyridinium Salts
R. Dzh. Khachikyan, S. L. Davtyan, and M. G. Indzhikyan
Institute of Organic Chemistry, National Academy of Sciences of Armenia,
ul. Zakhariya Kanakertsi 167-А, Yerevan, 375091 Armenia
fax: (374+1)283511
e-mail: nara7777@mail.ru
Received November 16, 2007
Abstract—The example of vinylpyridinium salts to establish for the first time the possibility of nucleophilic
addition to the vinyl group in quaternary ammonium salts, which provides evidence against the concept that
such reactions involve d orbitals. The nucleophilic addition reaction was accomplished with triphenylphosphine
and pyridine. In the latter case, the suggested reaction scheme was confirmed by the observation of the Wittig
reaction under the action of carbon dioxide and the Stevens reaggangement involving the double bond of the
pyridinium ring and migrating 2-phosphonioethyl group. Procedures for preparing the starting vinylpyridinium
salts. Reaction schemes were siggested.
DOI: 10.1134/S107036320807030X
We previously established [1] that vinylpyridinium
chloride (I) reacts with triphenylphoshine in boiling
acetonitrile to form ethylenebis(triphenylphospho-
nium) dichloride (II). A scheme of the reaction was
suggested, involving nucleophilic addition of the
phosphine followed by anion exchange, β-cleavage,
and addition of a further phosphine molecule to the
resulting triphenylphsophonium chloride.
(C6H5)3P
+
_
+
N
+
+
N
CH−CH2−P(C6H5)3
CH=CH2
_
_
Cl
Cl
I
_
+
N
(C6H5)3P−CH=CH2
_
+
_
+
CH2−CH−P(C6H5)3
N
Cl
_
Cl
_
initial salt
+
(C6H5)3P
+
+
+
(C6H5)3P−CH−CH2−P(C6H5)3
(C6H5)3P−CH2−CH2−P(C6H5)3
_
_
_
Cl
Cl
Cl
II
Proceeding with this research we found that 3,5-
dibromo-1-vinylpyridinium halides III and IIIa form
[2-(3,5-dihalopyridin-2-yl)ethyl]triphenylphosphonium
halides V and Va, along with ethylenebis(triphenylphos-
phonium) dihalides II and IIa (II : V and IIa : Va ratios
~1 : 1). With 2-methyl-1-vinylpyridinium chloride (IV),
[2-(6-methylpyridine-2-yl)ethyl]triphenylphosphonium chlo-
ride (VI) is formed along product II (II : VI ratio 16 : 3).
1452

FEATURES OF THE REACTION OF 2,3-DIHALOPROPANOIC ACIDS
1453
X
X
X
X
+
+
+
(C6H5)3P−CH2−CH2−+P(C6H5)3
(C6H5)3P
Z_
Z_
+
CH2−CH2−+P(C6H5)3
N
N_
Y
Y
CH2=CH2
Z_
Z
III, IIIa, IV
V, Va, VI
II, IIa
II, Z = Cl; IIa, Z = Br; III, V, X = Br, Y = H, Z = Cl; IIIa, Va, X = Z = Br, Y = H; IV, VI, X = H, Y = CH3, Z = Cl.
Products V, VI are probably formed via anion
exchange in the initially formed ammonium ylides
followed by the Stevens rearrangement involving the
double bond of the pyridinium ring.
X
Y
X
X
X
Y
X
Y
X
_
_
+
+
N
+
+
+
N CH−CH2−P(C6H5)3
N
CH2−CH2−P(C6H5)3
CH2−CH2−P(C6H5)3
Z_
Z_
Z_
The structure of compound Va was confirmed by
1H NMR data, as well as the iodomethylation of the
mixture obtained from compound IIIa and triphenyl-
phosphine, which provided a mixture of compounds
IIa, Va, and VII in a 4 : 1 : 4 ratio.
The reaction of salt I with triphenylphosphine in a
mixture of acetonitrile and HBr unexpectedly gave
acid VIII (isolated yield 44%) formed, probably, by
Scheme 1.
As seen from the scheme, the intermediate ylide
undergoes the Wittig reaction under the action of CO2
formed by hydrolysis of acetonitrile and subsequent
decarboxylation. Evidence for the decarboxylation of
acetate ion in such conditions was provided by the
formation of calcium carbonate in reactions of
acetonitrile with HBr in the presence of calcium salts.
The formation of acid VIII in the reaction of
triphenylphosphine with salt I, like the Stevens
rearrangement observed with compounds III, IIIa, and
IV, provides conclusive evidence for the suggested
Br
Br
Va
+ CH3I
+
+
_
N
CH2−CH2−P(C6H5)3
I
Br_
CH3
VII
We found that salt II is also formed by the reaction
of compound I with triphenylphosphine in the pres-
ence of HBr in aqueous medium.
Scheme 1.
O
HBr
CH3
CH3
C
N
CO2 + NH4Br
C
_CH4
H2O
_
+
O NH4
O_
CO2
O
C
_
CH
+
+
+
+
+
N
N
N
CH2
CH2
CH
CH2
O
CH
C
CH
C
P(C6H5)3
P(C6H5)3
P(C6H5)3
O
Cl_
Cl_
Cl_
H2O
_(C6H5)3P=O
+
+
N
N
CH2
O
CH2
CH2
COOH
Cl_
Cl_
VIII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

1454
KHACHIKYAN et al.
reaction scheme involving nucleophilic addition into
the β-position of the vinyl group and ylide formation.
reactions has been explained in [2] in terms of “d-
orbital resonance,” i.e. the stabilization of intermediate
α-carbanions in the measomeric ylene, which takes
place in phosphonium and sulfonium salts and is
impossible in vinylphosphonium salts.
We made an attempt to react triphenylphosphine
with salt I in the presence of benzaldehyde. However,
the reaction gave phosphonium salt II as a single
product, and unreacted salt I was recovered. These
results are probably explained by a lower electro-
philicity of benzaldehyde compared to CO2, which
makes β-cleavage more competitive.
R3P=CH−R'.
R3P−CH−R'
Our present results provide the first reliable
example of nucleophilic addition to vinylammonium
salts. Interesting data were obtained when salt Ia was
reacted with pyridine in boiling acetonitrile. The
reaction gave acetoxyvinylphosphonium bromide IX
in a yield of ~36%. The reaction is mpst likely to
follow a nucleophilic addition scheme. The ylide
formed is stabilized by reaction with CO2 followed by
β-cleavage.
Vinylphosphonium and vinylsulfonium salts are
known to readily react with nucleophiles to form
compounds with a β-substituted ethyl group. Reliable
information concerning similar reactions of
vinylammonium salts is lacking from the literature.
The inertness of vinylammonium salts in these
+
_
CH
+
N
+
+
+
N
N
N
CH
CH2
CH2
Br_
Br_
Ia
O_
C
CO2
O
COOH
+
_
CH
+
N
+
+
+
N
N
N
CH
N
CH COOH
CH
CH
CH2
Br_
Br_
Br_
IX
However, theoretically, the reaction may take an
alternative route to form, under the action pf pyridine,
a C-betaine which than stabilizes by reacting with
CO2.
compounds III and IIIa. The reaction was accom-
panied by strong tarring. Presumably, the reaction
involves amine attack on the α position of the
pyridinium ring and subsequent cleavage of the latter,
as observed by Krohnke [6] in the reaction of
vinylpyridinium salts with potash in acetone.
The tendency of pyridine to formation of betaine
structures is well known. A lot of pyridinium ylides
and imines were reported [3, 4]. The reaction of
pyridine with dimethyl acetylenedicaroxylate, involv-
ing C-betaine formation, was described [5]. In this
respect pyridine differs from aliphatic tertiary amines,
since in the latter case such structures are almost as
unstable as in phosphorus compounds. It is supposed
that phosphonium betaines are stabilized due to d
orbitals, whereas the stability factor in pyridinium salts
is the electron-acceptor nature of pyridine.
We previously prepared vinylpyridinium salts by
the reaction of pyridine with 2,3-dihalopropanoic acids
in boiling acetonitrile [7]. Compounds III and IIIa
were prepared in a similar way [1]. On repeated study
we found that the reaction with the bromine analog
gives acetoxyvinylpyridinium bromide IX as a minor
product. The Ia : IX ratio is 15 : 2. In the reaction with
2,3-dibromopropanoic acid at room temperature the
fraction of acid IX unexpectedly proved to be much
greater (Ia : IX ~6 : 5).
We also reacted vinylpyridinium salts with di- and
triethylamines. As a result, the corresponding amine
hydrochlorides were isolated in yields of 50 and 52%
for compound I and nearly quantitative yields for
The formation of products of I and Ia from 2,3-
dihalopropanoic acids was previously explained in
terms of a scheme involving nucleophilic substitution
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

FEATURES OF THE REACTION OF 2,3-DIHALOPROPANOIC ACIDS
1455
followed by decarboxylation and hydrogen halide
release, probably, by a synchronous mechanism [1, 7]
(Scheme 2).
A special experiment showed that pyridine fails to
react with salt Ia at room temperature. Consequently,
our results in experiments with 2,3-dibromopropanoic
Scheme 2.
CH CH COOH
+
2
_CO2, _HX
+
_
X
O
+
N
CH=CH2
I, Ia
X
X
N_ CH C
N
O H
X
CH2 X
I, X = Cl; Ia, X = Br.
acid suggest two independent reaction routes. The first
we described above and the second involves
preliminary dehydrobromination followed by reaction
of the resulting α-bromoacrylic acid with pyridine, like
in a similar reaction with triphenylphosphine [8]
(Scheme 3).
Scheme 3.
CH2
Br
H2C
COOH
+
CH COOH
Br
C
_
N
Br
HBr
N
N
_
CH
_
C
+
N
+
N
+
N
CH2
COOH
CH COOH
Br
CH
CH COOH
IX
Br_
Br
2,3-Dichloropropanoic acid was reacted with
picoline in pyridine under reflux under conditions used
for the preparation of vinylpyridinium salts to isolate
salt IV in a yield of 6.4%. The precipitate comprised a
mixture of salt IV, acid X, and picoline hydrochloride
in a 1:1:1 ratio.
CH2
Cl
COOH
+
CH
Cl
+
H3C
N_
Cl
H3C
N
CH
CH2Cl
COOH
_CO2
+
+
H3C
N
H3C
N
CH
C
CH2
CH2
Cl_
Cl_
COOH
IV
X
The same reaction with 2,3-dibromopropanoic acid
gave acid XI as a single product (yield 50%) (Sche-
me 4).
Attempted synthesis of N-vinylquinolinium salt by
reacting quinoline with 2,3-dibromopropanoic acid
failed. The only product was quinoline hydrobromide
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

1456
KHACHIKYAN et al.
Scheme 4.
+
CH2 CH COOH
Br
+
_
H3C
H3C
N
CH=CH COOH
N
Br
Br
XI
isolated in nearly quantitative yield. Such a difference
in the behavior of quinoline and pyridine is probably
explained by steric reasons.
7.5 Hz, p-H-picoline); 8.65 d (1H, J 6.3 Hz, picoline
m-H). 31P NMR spectrum: δP 30.30 ppm.
1H NMR spectrum of salt IV (DMSO-d6 + CCl4, 1 : 3),
δ, ppm: 3.00 s (3H, Me); 5.00–5.40 m (3H, CH=CH2);
EXPERIMENTAL
3
3
8.00 d.d (1H, J 1 7.5, J2 6.3 Hz, picoline m-H); 8.15
d (1H, 3J 7.5 Hz, picoline m-H); 8.60 d.d (1H, 3J1 = 3J2
1
31
The H and P NMR spectra were measured on a
Varian MERCURY-300 instrument at 300 MHz,
internal reference TMS.
3
7.5 Hz, p-H-picoline), 9.20 d (1H, J2 6.3 Hz, о-H-
picoline).
Reaction of the mixture of salts, obtained from
compound IIIa and triphenylphosphine, with
methyl iodide. To 0.10 g of the mixture, a triple molar
excess of methyl iodide in acetonitrile was added at
room temperature. A day after, the reaction mixture
was poured into ether, the crystal that formed were
filtered off, washed with ether, and poured into ether to
obtain 0.11 g of a mixture of products IIa, Va, and VII
Reaction of triphenylphosphine with salts III
and IIIa. a. A mixture of 0.1 g of salt III and 0.18 g
of triphenylphosphine in 5 ml of acetonitrile was
heated under reflux for 32 h. The reaction mixture was
filtered, and the acetonitrile filtrate was treated with
ether to isolate 0.1 g of a mixture of salts, containing,
1
according to the H NMR spectrum, 0.052 g (26.0%)
of product II and 0.048 g (25.0%) of product V. The
1
in a 4 : 1 : 4 ratio (1H NMR data). H NMR spectrum
31
1H and P spectra of salt II are consistent with those
of salt VII (DMSO-d6 + CCl4, 1:3), δ, ppm: 2.70–2.80
m (2H, CH2); 3.60 s (3H, Me); 3.90–4.00 m (2H,
P+CH2); 7.40–7.60 m (17H, Ph and Py). 31P NMR
spectrum: δP 29.90 ppm.
reported in [1]. 1H NMR spectrum of salt V (DMSO-d6 +
CCl4, 1:3), δ, ppm: 2.55–2.65 m (2H, CH2); 3.80–3.90
m (2H, P+CH2); 7.60–8.00 m (17H, Ph and Py). 31P
NMR spectrum: δP 30.18 ppm.
Reaction of salt I with triphenylphosphine in
aqueous hydrogen bromide. A mixture of 0.35 g of
salt I, 0.65 g of triphenylphosphine, and 0.45 ml of
46% HBr in 6 ml of water was heated at 75–80°C for
20 h. Extraction with chloroform and reprecipitation
with ether gave 10 g (11.23%) of compound II, mp
b. The reaction was performed similarly. From 0.52 g
of salt IIIa and 0.78 g of triphenylphosphine in 7 ml of
acetonitrile we obtained 0.5 g of a mixture of salts
comprising, according to the 1H NMR spectrum, 0.29 g
(27.2%) of product IIa and 0.21 g (23.0%) of product
1
Va. The H and 31P NMR spectra of the salts are
1
262°C. The H and 31P NMR spectra are consistent
similar to those obtained in the above experiment.
with those reported in [1].
Reaction of salt IV with triphenylphosphine. A
mixture of 0.20 g of salt IV and 0.67 g of triphenyl-
phosphine in 5 ml of acetonitrile was heated under
reflux for 34 h. The acetonitrile filtrate was poured into
ether, and the precipitate that formed was filtered off,
washed with ether, and dried in a vacuum to obtain
0.20 g of a mixture of products II, VI, and IV in a 16 :
Reaction of salt I with triphenylphosphine in
aqueous hydrogen bromide in the presence of
acetonitrile. A mixture of 0.35 g of salt I, 0.65 g of
triphenylphosphine, and 0.48 g of 42% aqueous HBr in
10 ml of acetonitrile was heated under reflux for 20 h.
The precipitate that formed was filtered off, washed
with acetonitrile, and dried in a vacuum to obtain
1
3 : 2 ratio (1H NMR data). The H and 31P NMR
1
0.176 g (44.0%) of acid VIII, mp > 270°C. H NMR
spectra of salt II are consistent with those reported in
[1]. H NMR spectrum of salt VI (DMSO-d6 + CCl4,
1 : 3), δ, ppm: 2.70 m (2H, CH2); 3.00 s (3H, Me);
3.90 m (2H, P+CH2); 7.60–8.00 m (15H, Ph); 8.15 d
(1H, J 7.5 Hz, Pim-H-picoline); 8.25 d.d (1H, J1 = J2
spectrum (DMSO-d6 + CCl4, 1:3), δ, ppm: 3.20 t (2H,
1
3J 7.1 Hz, CH2COOH); 5.00 t (2H, 3J 7.1 Hz, N+CH2);
3
3
8.20 d.d (2H, J1 7.5 Hz, J2 6.3, pyridine m-H); 8.70
d.d (1H, 3J1 = 3J2 7.5 Hz, pyridine p-H); 9.38 d (2H, 3J
6.3 Hz, pyridine о-H); 12.20–12.60 br (1H, CООH).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

FEATURES OF THE REACTION OF 2,3-DIHALOPROPANOIC ACIDS
1457
Found, %: C 51.28; H 5.40; Cl 18.85; N 7.51.
C8H10CINO2. Calculated, %: C 51.20; H 5.33; Cl
18.93; N 7.46.
products IV, X, and picoline hydrochloride in a 1 : 1 : 1
ratio (1H NMR data). The 1H spectra of salt IV are the
same as given above. H NMR spectrum of salt X
1
(DMSO-d6 + CCl4, 1:3), δ, ppm: 2.80 s (3H, Me); 5.95
and 6.45 s (2H, =CH2); 7.75 d.d (1H, J1 7.5, J2 6.3 Hz,
picoline p-H); 8.00 d (1H, J 7.5 Hz, picoline m-H);
8.20 d.d (1H, J1 7.5, J2 6.3 Hz, picoline m-H); 8.70 d
(1H, J 7.5 Hz, picoline o-H).
Reaction of salt I with triphenylphosphine in
aqueous hydrogen bromide in the presence of
benzaldehyde and acetonitrile. A mixture of 0.47 g
of salt I, 0.78 g of triphenylphosphine, 0.30 g of
benzaldehyde, and 0.57 g of 42% aqueous HBr in 7 ml
of acetonitrile was heated under reflux for 14–15 h.
Unreacted starting salt was filtered off and washed
with acetonitrile. The acetonitrile filtrate was poured
into ether, and the precipitate that formed was filtered
off, washed with acetonitrile, and dried in a vacuum to
obtain 0.41 g (22.0%) of compound II, mp >262°C.
The 1H and 31P NMR spectra are consistent with those
reported in [1].
The acetonitrile filtrate was poured into ether.
An oily precipitate formed and was filtered off,
thoroughly washed with ether, and dried in a vacuum
to obtain 0.40 g (6.43%) of product IX, mp 181–182°C.
The 1H NMR spectra are the same as given above.
Reaction of 2,3-dibromopropanoic acid with
picoline. A mixture of 4.35 g of 2,3-dibromopropanoic
acid and 1.74 g of picoline in 6–7 ml of acetonitrile
was heated under reflux for 6 h. The precipitate that
formed was filtered off, washed with acetonitrile, and
dried in a vacuum to obtain 2.20 g (50.0%) of salt XI,
mp 250–255°C. 1H NMR spectrum (DMSO-d6 + CCl4,
1 : 3), δ, ppm: 2.80 s (3H, Me); 6.80 d (1H, 3J 13.0,
=CHCOOH); 8.00–8.20 m (3H, N+–CH=, picoline m-H);
Reaction of salt Ia with pyridine. A mixture of
0.75 g of salt Ia and 0.32 g of pyridine in 10 ml of
acetonitrile was heated under reflux for 40 h. The
precipitate that formed was filtered off, washed with
acetonitrile, and dried in a vacuum to obtain 0.35 g
1
(38.0%) of product IX, mp 200–201°C. H NMR
3
3
spectrum (DMSO-d6 + CCl4, 1 : 3), δ, ppm: 7.10 d
(1H, =CH, J 14.0 Hz); 8.30 d.d (2H, H2, J1 7.8, J2
6.4 Hz); 8.55 d.d (1H, =CH, J 14.0 Hz); 8.80 t.t (1H,
H3, J1 7.8, J2 1.2 Hz); 9.42 d.d (2H, H1, J1 6.4, J2
1.1 Hz). Found, %: C 41.78; H 3.41; Br 34.81; N 6.14.
C8H8BrNO2. Calculated, %: C 41.73; H 3.47; Br
34.78; N 6.08.
8.60 d.d (1H, J1 = J2 7.5 Hz, picoline p-H); 9.18 d
(1H, 3J 6.3 Hz, picoline o-H); 13.50 br (1H, CООH).
The acetonitrile filtrate was poured into ether. A
precipitate formed and was filtered off, thoroughly
washed with ether, and dried in a vacuum to obtain
1.51 g (50.0%) of picoline hydrobromide, mp 45–50°C.
Reaction of 2,3-dibromopropanoic acid with
pyridine. a. Under reflux. A mixture of 1.16 g of 2,3-
dibromopropanoic acid and 0.395 g of pyridine in 5 ml
of acetonitrile was heated under reflux for 13 h. The
precipitate that formed was filtered off, washed with
acetonitrile, and dried in a vacuum to obtain 0.85 g of
a mixture of salts Ia and IX in a 15 : 2 ratio (1H NMR
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2. Von Doering, W. E. and Schreiber, K.C., J. Am. Chem.
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3. Johnson, A.W., Ylid Chemistry, London: Academic,
1966, p. 260.
4. Rodig, O.R., Pyridine and Its Derivatives, Abramo-
vitch, R.A., Ed., New York: Wiley, 1974, part 1, p. 353.
1
data). The H NMR spectra are the same as given
above.
b. At room temperature. The same reaction was
performed at room temperature. The reaction mixture
was treated as above to obtain 0.81 g of a mixture of
products Ia and IX in a 6 : 5 ratio (1H NMR data). The
1H NMR spectra are the same as given above.
5. Acheson, R.M., Adv. Heterocycl. Chem., 1963, vol. 1,
p. 143.
6. Krohnke, F. and Vogt, I., Ann., 1954, vol. 589, p. 26.
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1978.
Reaction of 2,3-dichloropropanoic acid with
picoline. A mixture of 5.72 g of 2,3-dichloropropanoic
acid and 3.72 g of picoline in 6 ml of acetonitrile was
heated under reflux for 60 h. The precipitate that
formed was filtered off, washed with acetonitrile, and
dried in a vacuum to obtain 0.70 g of a mixture of
8. Khachatryan, R.A., Kotikyan, S.Yu., Khachikyan, R.Dzh.,
Panosyan, G.A., Mirzakhanyan, R.A., and Indzhi-
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