Reaction of α-bromocarboxylic acids with hydrazine and dimethylhydrazine

Article abstract of DOI:10.1134/S1070427207120348

Nucleofilic reaction of a series of α-bromocarboxylic acids with hydrazine and dimethylhydrazine is studied. High reactivity of α-bromocarboxylic acids is revealed and a series of α- hydrazinoarboxylic acids and N-(1-carboxyalkyl)-N,N-dimethylhydrazinium

Full text of DOI:10.1134/S1070427207120348

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2007, Vol. 80, No. 12, pp. 2165−2168. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © S.A. Malin, B.M. Laskin, A.S. Malin, 2007, published in Khimicheskaya Promyshlennost’, 2007, Vol. 84, No. 7, pp. 335−339.
TECHNOLOGY OF ORGANIC
AND INORGANIC SUBSTANCES
Reaction of α-Bromocarboxylic Acids with Hydrazine
and Dimethylhydrazine
S. A. Malin, B. M. Laskin and A. S. Malin
Russian Scientific center “Applied Chemistry,” St. Petersburg, Russia
Received March 13, 2007
Abstract—Nucleofilic reaction of a series of α-bromocarboxylic acids with hydrazine and dimethylhydrazine is
studied. High reactivity of α-bromocarboxylic acids is revealed and a series of α-hydrazinoarboxylic acids and
N-(1-carboxyalkyl)-N,N-dimethylhydrazinium bromides are synthesized.
DOI: 10.1134/S1070427207120348
α-Bromocarboxylic acids are known as parent
compounds for the synthesis of potentially biologically
active compounds, α-hydrazino- and α-dimethyl-
hydrazinocarboxylic acids, the analogs of aminoacids.
These latter compounds show antiviral and antitumor
activity and can serve as a basis for producing antibiotics,
peptidomimetics and related substances [1−3].
Methods for the synthesis of α-hydrazinocarboxylic
acids have not been sufficiently studied and the known
data are mutually very contradicting in respect both
conditions of carrying out the process and product yields
[4−6]. Therefore we performed search of appropriate
methods for the synthesis of α-hydrazinocarboxylic acids
and study of main regularities of the process.
We studied influence of the reagents ratio, parameters
of duration and temperature and solvent (medium) nature
on the reaction proceeding and results. We found that
reaction of compounds Ia–d with hydrazine proceeds
smoothly enough at carrying out the process in the med-
ium of aqueous ethanol at the molar ratio I : hydrazine =
1: 4–6, temperature 70–80ºC and reaction dura-tion 6–8
h with high yield (50–70%) of compounds IIa–d.
Reaction conditions of IIa–d are listed in Table 1.
The most smooth process occurs with 40–60%
hydrazine hydrate which provides necessary solvation
of removing anion in the process of nucleophilic
substitution.
Isolation of α-hydrazinocarboxylic acids was carried
out by concentrating the reaction solution (by 40 –50%)
under vacuum followed by diluting with water and
filtrating the product. The crystals formed were filtered
off and recrystallized from 40% ethanol (α-hydrazino-
propanoic acid or hydrazoalanine), from isopropyl
alcohol (α-hydrazinobutyric acid), water (α-hydrazino-
isovaleric acid) or ethyl acetate (α-hydrazinophenyl-
acetic acid or hydrazinophenylalanine). The α-hy-
drazinocarboxylic acids obtained were characterized by
As the model targeted compounds we choose the
following α-bromocarboxylic acids: α-bromopropanoic
(Ia), α-bromobutyric (Ib), α-bromo-isovaleric (Ic) and
α-bromophenylacetic (Id). These α-bromoacids were
involved to the reaction of nucleophilic substitution with
hydrazine and dimethylhydrazine according to the
scheme:
1
means of elemental analysus, IR and H NMR
spectroscopy.
IR and NMR spectroscopy data (Table 2) and
elemental analyses (Table 3) confirmed structure and
composition of the obtained compounds.
The high reactivity of the bromine atom in α-bromo-
carboxylic acids in the reactions of nucleophilic sub-
where R is Me (a), Et (b), i-Pr (c) and Ph (d).
2165

MALIN et al.
Table 1. Reaction conditions for the synthesis of compoinds IIa–d
2166
α-Bromocarboxylic
Reaction
duration, h
Temperature,
ºC
No.
Mole ratio I : hydrazine
Yield, %
mp, ºC
acids
1
2
3
4
1 : 4
1 : 5
1 : 6
1 : 3
6
7
80
77
75
70
62
67
71
58
188–189
201–203
239–241
195–200
I a
I b
I c
I d
8
12
Table 2. Spectral characteristics of compounds IIa–d
No.
1
Compound
IR spectrum, cm–1
1H NMR spectrum, δ, ppm (DMSO-d6)
+
IIa
3120 (NH3 ); 1680 (C= O)
1.45 d (3H, CH3); 3.5 q (1H, CH); 6.22 s (4H, NH, NH2,OH)
1.1 t (3H, CH3); 1.7 m (2H, CH2); 3.28 q (1H, CH); 5.98 s (4H,
NH, NH2,OH)
+
2
3
4
IIb
IIc
IId
3115 (NH3 ); 1690 (C=O)
1.01 d (3H, CH3); 1.9 d (3H, CH3); 2.28 m (1H, CH); 3.1 d
(1H); 6.1 C(4H, NH, NH2, OH)
+
3130 NH3 ); 1685 (C=O)
+
3110 (NH3 ); 1700 (C=O)
4.48 s (1H, CH); 6.6 s (4H, NH, NH2,OH); 7.33–7.6 (5Harom
)
Table 3. Elemental analysis data for compounds IIa–d
Elemental analysis data
Compound
Formula
No.
found, %
H
calculated, %
C
N
C
H
N
C3H8 N2O2
C4H10N2O2
C5H12N2O2
C8H10N2O2
34.45
41.0
44.98
58.0
34.61
40.67
45.44
57.82
7.75
8.53
9.15
6.07
26.91
23.71
21.2
1
2
3
4
IIa
IIb
IIc
IId
7.8
27
8.7
22.8
21.7
16.4
9.22
6.11
16.86
Table 4. Reaction conditions for the synthesis of N-(1-carboxyalkyl)-N,N-hydrazinium bromides IIIa–c
No.
1
Compound
IIIa
Reaction duration, h
Temperature, ºC
Yield, %
62
mp, ºC
244
8
8.5
60
65
70
65
2
IIIb
65
239
3
IIIc
9
68
232
4
IIId
12–15
73
203
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 80 No. 12 2007

REACTION OF α-BROMOCARBOXYLIC ACIDS WITH HYDRAZINE
2167
stitution with hydrazine hydrate allowed us to expect that
dimethylhydrazine can also be involved in this process.
The latter compound is known possessing highr
enucleophilicity and basicity as compared with the
unsubstituted hydrazine, and this should promote
bromine substitution in the α-bromocarboxylic acids and
should lead to practically unstudied α-dimethylhy-
drazinocarboxylic acids. We studied reaction of dimethyl-
hydrazine with compounds Ia–d. As might be expected,
dimethylhydrazine reacts with compounds Ia–d in
absolute alcohol or acetonitrile medium smoothly. Small
excess of dimethylhydrazine (1.05 to 1.1 mol per 1 mol
of α-bromocarboxylic acid) was used and reaction was
carried out at 40–60ºC during 5–10 h leading to formation
of N-(1-carboxyalkyl)-N,N-hydrazinium bromides IIIa–
c in 60–70% yield according to equation:
It is noteworthy that the compounds obtained are
hygroscopic ones and require use of absolute solvents
both in the steps of synthesis and recrystallization.
Nature of the obtained compounds is confirmed by
the data of IR and 1H NMR spectroscopy (Table 5) and
the data of elemental analysis (Table 6). Presence in the
IR spectra of characteristic absorption bands in the region
of 3220–3240 cm–1characteristic adsorption attests
presence of protonated NH+3 group and points probably
to zwitter-ionic structure of α-dimethylhydrazinocarb-
oxylic acids. This also is confirmed by 1H NMR spectra
where occur signals (multiplet) in the range 3.1–3.5 ppm
depending on substituent R (500 MHz, DMSO-d6) of
α-methine fragment; presence of clearly defined signal
at 5.6 ppm (4H) and absence of signals of OH and NH2
groups points probably to zwitter-ionic structure of the
compounds.
Like with hydrazinocarboxylic acids, the
dimethylhydrazinium salts are characterized by signal
of methine group at 3.05–4.3 ppm (multiplet), by signal
of methyl groups at 3.5–3.6 ppm (singlet), while the
signal at 5.35–5.67 ppm (singlet) is probably in
correspondence with the existence of compounds IIIa–
d as internal salts.
EXPERIMENTAL
where R is Me (a), Et (b), i-Pr (c) and Ph (d).
1H NMR spectra are registered on a Bruker AM 500
spectrometer (internal reference TMS) in DMSO-d6. IR
spectra are obtained on a IKS-29 spectrmeter from the
pastes with Vaseline oil.
The data on the synthesis conditions of hydrazonium
salts IIIa–d are comprised in Table 4.
Isolation of the reaction products included concentrat-
ing the reaction solutions under vacuum, cooling from
–5 to –10ºC, filtrating the crystals formed and recrystal-
lizing them from 2:1 isopropyl alcohol–dioxane mixture.
General procedure for preparation of α-hy-
drazinocarboxylic acids IIa–Id. To a three-necks flask
equipped with mechanical stirrer, reflux condenser and
Table 5. Spectral characteristics of compounds IIIa–d
No.
1
Compound
IR spectrum, cm–1
1H NMR spectrum, δ, ppm (DMSO-d6)
1.55 d (3H, CH3); 3.15 q (1H, CH); 3.52 s (6H, 2CH3), 5.36 s
(3H, NH2, OH)
+
IIIa
3220 (NH3 ); 1610 (C= O)
0.94 t (3H, CH3); 2.2 m (2H, CH2); 3.05 q (1H, CH); 3.52 d
(6H, 2CH3), 5.4 s (3H, NH2, OH)
+
2
3
4
IIIb
IIIc
IIId
3250 (NH3 ); 1590 (C=O)
0.91 d (3H, CH3); 0.94 d (3H, CH3); 2.98 m (1H, CH); 3.6 d
(6H, 2CH3), 4.28 m (1H, CH); 5.66 s (3H, NH2, OH)
+
3300 NH3 ); 1595 (C=O)
3.58 d (6H, 2CH3), 4.12 C (1H, CH); 5.67 s (3H, NH2,OH);
+
3320 (NH3 ); 1620 (C=O)
7.64–8.03 (5Harom
)
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 80 No. 12 2007

MALIN et al.
2168
Table 6. Elemental analysis data for compounds IIa–d
Elemental analysis data
Compound
Formula
No.
found, %
calculated, %
N
C
H
N
Br*
38.0
C
H
Br
C5H13N2O2 Br
C6H15N2O2 Br
C7H17N2O2 Br
C10H15N2O2 Br
26.2
31.6
34.9
43.8
6.2
6.7
13.18
12.4
26.18
31.73
34.87
43.65
6.15
6.66
7.11
5.5
13.15
37.5
1
2
3
4
IIIa
IIIb
IIIc
IIId
35.22
33.07
29.1
12.34
35.18
33.14
29.04
7.13 11.59
5.7 10.21
11.62
10.18
Note: Content of bromine ion in compounds IIIa−d was analysed by the mercurymetric method.
thermometer was placed 20–30% solution of α-bromo-
carboxylic acid in 60–80% aqueous ethanol and
precalculated amount of 80% hydrzine hydrate
(bromocarboxylic acid to hydrazine hydrate mole ratio
is 1 : 4–5) was added dropwise. The reasction mixture
was heated to slow boiling, kept at this temperature for
4–8 h and then left for 12 h at 0–5ºC. The crystals formed
were filtered off and recrystallized from water or alcohol,
and dried. Yield of α-hydrazinocarboxylic acids 60–
70%.
and dried in a vacuum dessicator. Yield of hydrazonium
salts IIIa–d is 60–75%.
CONCLUSION
The α-hydrazino- and α-dimethylhydrazino-deriva-
tives of a series of carboxylic acids are synthesized, the
process of synthesis regularities are revealed, some of
physico-chemical properties of the compounds obtained
are measured and nature and assumed salt structure of
these compounds are established.
Procedure for preparation of N-(1-carboxyalkyl)-
N,N-hydrazinium bromides IIIa–c. To a three-necks
flask equipped with mechanical stirrer, reflux condenser
and thermometer was placed 20–30% solution of
α-bromocarboxylic acid in anhydrous acetonitrile. The
solution was cooled to 10–15ºC and to it was slowly
dozed precalculated amount of 40–50% solution of
dimethylhydrazine in acetonitrile (bromocarboxylic acid
to dimethylhydrazine mole ratio is 1 : 2–2.5) at the
temperature not below 20ºC. The reaction mixture was
then slowly heated to 40–50ºC, kept at this temperature
for 3–5 h monitoring continuously formation of mineral
bromine (mercurymetry). After completing the process,
the reaction mixture was cooled to 0–5ºC, the crystals
dropped were filtered off, washed with isopropyl alcohol
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