Synthesis of β-aminophosphonates and study of their acid-base properties and phase distribution in water-organic solvent systems

Article abstract of DOI:10.1007/s11178-005-0370-0

New and previously known β-aminoethylphosphonates were synthesized by addition of primary and secondary amines to vinylphosphonates, and their IR and NMR spectra were examined. Diethyl 2-diethyl-aminoethylphosphonate and diethyl 2-morpholinoethylphosphonate were found to be stronger bases than the corresponding aminomethylphosphonates, but all these are weaker bases than their precursors, nonphosphorylated amines. Distribution constants of β-aminophosphonates between water and some organic solvents were determined and compared with those of their α-amino homologs.

Full text of DOI:10.1007/s11178-005-0370-0

Russian Journal of Organic Chemistry, Vol. 41, No. 10, 2005, pp. 1481–1484. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 10, 2005,
pp. 1511–1515.
Original Russian Text Copyright © 2005 by Cherkasov, Galkin, Khusainova, Mostovaya, Garifzyanov, Nuriazdanova, Krasnova, Berdnikov.
Dedicated to Full Member of the Russian Academy of Sciences
N.S. Zefirov on His 70th Anniversary
Synthesis of ȕ-Aminophosphonates and Study
of Their Acid–Base Properties and Phase Distribution
in Water–Organic Solvent Systems
R. A. Cherkasov, V. I. Galkin, N. G. Khusainova, O. A. Mostovaya, A. R. Garifzyanov,
G. Kh. Nuriazdanova, N. S. Krasnova, and E. A. Berdnikov
Butlerov Chemical Institute, Kazan State University, ul. Kremlevskaya 18, Kazan, 420008 Tatarstan, Russia
e- mail: rafael.cherkasov@ksu.ru
Received April 12, 2005
Abstract—New and previously known ȕ-aminoethylphosphonates were synthesized by addition of primary
and secondary amines to vinylphosphonates, and their IR and NMR spectra were examined. Diethyl 2-diethyl-
aminoethylphosphonate and diethyl 2-morpholinoethylphosphonate were found to be stronger bases than
the corresponding aminomethylphosphonates, but all these are weaker bases than their precursors, nonphos-
phorylated amines. Distribution constants of ȕ-aminophosphonates between water and some organic solvents
were determined and compared with those of their Į-amino homologs.
In the series of our preceding publications we de-
scribed methods of synthesis and acid–base properties
of a large number of Į-aminophosphoryl compounds
[1] which can be regarded as phosphorus-containing
analogs of natural amino acids. In the recent years,
these compounds attract attention of researchers work-
ing in the fields of not only fine organic synthesis and
chemistry of biologically active substances but also
related sciences, such as biochemistry, pharmacology,
medicine, agricultural chemistry, etc. [2, 3]. Apart from
high efficiency as bioactive substances, Į-aminophos-
phoryl compounds were shown to be capable of form-
ing complexes with various species, including metal
ions, organic and inorganic acids, etc. [4, 5]. In partic-
ular, we studied Į-aminophosphonates as extractants
which ensured selective separation of noble metal ions
from concomitant elements [6]. Variation of substit-
uents at the phosphorus, Į-carbon, and nitrogen atoms
over a wide range showed that the most selective ex-
tractants were those aminophosphoryl reagents which
contained more than 20 carbon atoms; in this case, the
optimal hydrophilic–lipophilic balance was achieved.
It should be emphasized specially that the above
information was deduced by analysis of correlations
between the number of carbon atoms in the extractant
molecules and their distribution constants in water–
organic solvent systems [7]. Therefore, the latter pa-
rameter is necessary to elucidate the structure–property
relations with a view to effect subsequent purposeful
synthesis of extractants, bioactive, and other potential-
ly useful substances possessing an optimal combina-
tion of the desired characteristics.
The present article opens a series of publications
on the synthesis and study of extracting, membrane-
transfer, and ionophoric properties of a new class of
phosphorus-and-nitrogen-containing complexing
agents, ȕ-aminophosphoryl compounds. Here, we
report on the synthesis, acid–base properties, and
distribution constants in two-phase aqueous–organic
systems of a series of previously described and new
ȕ-aminophosphonates. When possible, the parameters
under study were compared with the data for their
analogs, Į-aminophosphonates, and precursors, the
corresponding amines. We believe that such analysis is
useful for estimation of factors responsible for physio-
logical and complexing properties of the compounds
under study.
Properties of ȕ-phosphorylated amines have been
studied to a considerably lesser extent, as compared to
their Į-homologs. However, even relatively poor in-
formation on their complexing power [8, 9] and other
practically important properties [10] suggests some
specificity of their extracting, membrane-transfer, and
1070-4280/05/4110-1481 © 2005 Pleiades Publishing, Inc.

CHERKASOV et al.
1482
ionophoric abilities, which are the subjects of our
studies.
protons of the neighboring methylene group (3JHH
=
6.3–8.3 Hz). Protons in the PCH2CH2N fragment con-
stitute AA' and BB' parts of an AA'BB'X spin system
where X is the phosphorus nucleus. The 1H NMR spec-
trum of diethyl 2-(N-butyl-N-octylamino)ethylphos-
phonate (III) is difficult to interpret: signals from
protons of the two methyl groups in the butyl and octyl
radicals on the nitrogen atom overlap in the region of
į 0.86 ppm, and methylene protons in the butyl and
octyl groups and methyl protons in the ethoxy groups
appeared at į 1.30–1.36 ppm.
The most accessible method of synthesis of
ȕ-aminoalkylphosphonates is based on the addition of
primary and secondary amines to unsaturated deriva-
tives of four-coordinate phosphorus acids [11]. We pre-
pared ȕ-aminoethylphosphonates by heating vinyl-
phosphonic acid esters with butylamine, diethylamine,
butyl(octyl)amine, and morpholine in the absence of
a catalyst (Scheme 1).
Scheme 1.
The acid–base properties of some of the synthe-
sized ȕ-aminophosphonates were estimated by measur-
ing pKBH+ values of the corresponding conjugate acids
according to the procedure described in [1]. The results
are collected in Table 1; for comparison, the data for
their Į-homologs and the corresponding amines in
water are given. Our results are consistent with the
relations between the structure and pKBH+ values,
which were obtained previously for Į-aminophospho-
nates. First of all, the examined Į- and ȕ-aminophos-
phoryl compounds are weaker bases than the corre-
sponding nonphosphorylated amines. ȕ-Aminophos-
phonates are stronger bases than their Į-analogs. As we
showed previously [1], introduction of a fairly strongly
electron-withdrawing phosphoryl group to the Į-car-
bon atom considerably reduces the basicity of amines,
on the average, by 4–5 log units. Naturally, the elec-
tron-withdrawing effect weakens as the phosphorus
center becomes more distant from the nitrogen atom.
The basicity of amines is higher by 2–3 log units than
that of their ȕ-phosphorylated derivatives. Unlike
fairly representative series of Į-aminophosphonates
[1], the series of available ȕ-aminophosphonates is
limited; therefore, it is difficult to draw any reliable
conclusions on the effect of their structure on the
basicity (a more detailed analysis will be performed
in our subsequent publications with a larger series of
ȕ-aminophosphoryl compounds). Here, we can note
only fairly sharp reduction (by almost 3 log units) in
the basicity upon replacement of diethylamino group
by electron-withdrawing morpholino group.
O
R1O
P
CH CH2
+
R2R3NH
R1O
O
R1O
P
CH2CH2NR2R3
R1O
I–VI
I, R1 = Et, R2 = H, R3 = Bu (I); II, R2 = R3 = Et; III, R2 = Bu,
R3 = C8H17O; IV, R2R3N = morpholino; V, R1 = i-Pr, R2 =
R3 = Et; VI, R1 = Bu, R2 = R3 = Et.
Compounds I and VI were reported previously
[12, 13]; however, their spectral parameters were not
given. Aminophosphonates I–VI are liquids which can
be distilled under reduced pressure and are soluble in
most organic solvents. Their IR spectra lack absorption
bands in the region 1640–1650 cm–1, which is typical
of stretching vibrations of double C=C bond; and no
N–H absorption (3200–3500 cm–1) was present in the
IR spectra of II–VI. A strong band at 1260 cm–1
belongs to the phosphoryl group. The IR spectrum of
aminophosphonate I contains NH absorption band at
3300 cm–1. Compounds I–VI showed in the 31P NMR
spectra only one signal at įP 29–32 ppm, indicating
formation of a single addition product. In the 1H NMR
spectra of I–VI we observed a multiplet at į 1.8–
1.9 ppm due to methylene protons in the Į-position
with respect to the phosphoryl group; this means that
the amino group is attached to the ȕ-carbon atom. The
Į-methyl-ene proton signal is split due to coupling
with the phosphorus nucleus (2JPH = 18.4–19.4 Hz) and
Table 1. Basicities of amines and the corresponding Į- and ȕ-aminophosphonates in water at 298±0.2 K
Amine
Et2NH
pKBH
+
Į-Aminophosphonate
pKBH+ (ǻpK)
ȕ-Aminophosphonate
pKBH+ (ǻpK)
10.93
Et2NCH2P(O)(OEt)2
6.61 (4.32)
Et2NCH2CH2P(O)(OEt)2
8.48 (2.45)
P(O)(OEt)2
N
NH
N
P(O)(OEt)2
08.36
3.89 (4.47)
5.67 (2.69)
O
O
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

SYNTHESIS OF ȕ-AMINOPHOSPHONATES
1483
Table 2. Distribution constants (logPo±0.05) of aminoethyl-
We also determined the distribution constants Po
of four Į- and ȕ-aminophosphonates in two-phase
systems water–organic solvent by two-phase acid–base
potentiometric titration. As organic solvents, we used
chloroform, carbon tetrachloride, xylene (a mixture of
isomers), toluene, and octanol. The logPo values were
calculated by linearization of the titration curve ac-
cording to Gran (by analogy to [7]). As follows from
the data in Table 2, the distribution constants of
ȕ-aminophosphonate II in all the examined two-phase
systems are lower than the corresponding values for di-
ethyl N,N-diethylaminomethylphosphonate (VII) con-
taining the same substituents at the phosphorus and
nitrogen atoms. It should be noted that within both
reaction series, Į- and ȕ-aminophosphonates, replace-
ment of less hydrophilic diethylamino group in com-
pounds II and VII by more hydrophilic morpholino
group (compounds IV and VIII) reduces the distribu-
tion constant. A linear correlation was found between
the distribution constants of Į- and ȕ-aminophospho-
nates having ethyl groups on the nitrogen: logPĮ =
0.34 + 1.00logPȕ; r = 0.997, s = 0.06, n = 5 (Table 2).
Obviously, the existence of such correlation suggests
a common mechanism of solvation of these compounds
in the examined solvents.
phosphonates in water–organic solvent systemsa
Solvent
Comp.
no.
CHCl3
CCl4
xylene toluene octanol
2.03
1.28
2.37
1.58
0.21
0.08
0.18
0.65
II
IV
0.65
0.41
0.48
0.95
VII
VIII
a
At 298±0.2 K.
in the electron density on the basic centers (nitrogen
and phosphoryl oxygen atoms), for their mutual accep-
tor effect becomes weaker. Clearly pronounced proton-
acceptor properties of aminophosphonates follow, e.g.,
from the results of our previous calorimetric studies on
reactions of Į-aminophosphonates with proton-donor
regents [15].
Unfortunately, the limited set of data for ȕ-amino-
phosphoryl compounds, as compared to much more
extensively studied Į-homologs, does not allow us to
draw more profound generalizations. We plan to per-
form a detailed study on the relations between the
structure of phosphorylated amines and their prac-
tically important properties using more representative
reaction series.
At first glance, decrease in the distribution con-
stants in going from diethyl N,N-diethylaminomethyl-
phosphonate (VII) to diethyl (2-diethylaminoethyl)-
phosphonate (II) (on the average, by 0.34 log unit;
Table 2) contradicts the relation found by us pre-
viously, according to which introduction of every
methylene group into the alkoxy substituents on the
phosphorus atom leads to increase in the distribution
constant, on the average, by 0.5 log unit [7]. We
believe that the observed distortion of the Leo–Hansch
additivity principle [14] may be rationalized as fol-
lows. Introduction of one or several methylene groups
into the ester fragments of Į-aminophosphonates
almost does not affect the electron density on the main
centers. As we found in [1], the basicity of Į-phosphor-
ylated amines within a wide homologous series re-
mains almost unchanged, for mutual effect of the
acceptor phosphoryl and amino groups does not
change. Therefore, the distribution constants of com-
pounds belonging to the above series is determined by
the number of carbon atoms in the molecule, i.e., by
hydrophilic–lipophilic balance. The situation changes
in going from Į- to ȕ-phosphorylated amines. In this
case, introduction of an additional methylene unit
between the phosphorus and nitrogen atoms increases
the hydrophilicity due to enhanced strength of H-com-
complexes with water molecules as a result of increase
EXPERIMENTAL
1
The H and 31P NMR spectra were recorded on
1
a Varian Unity-300 spectrometer at 300 MHz for H
and 121.42 MHz for 31P, using CDCl3 as solvent. The
1H chemical shifts were measured relative to the
residual solvent signal, and the 31P chemical shifts
were measured relative to 85% phosphoric acid as
external reference. The pKBH+ values were measured as
described in [1]. The procedure for determination of
distribution constants was reported in [7]. Į-Amino-
phosphonates VII and VIII were synthesized accord-
ing to the procedure described in [1].
Reaction of dialkyl vinylphosphonates with
primary and secondary amines. A mixture of
19 mmol of vinylphosphonate and 19 mmol of the cor-
responding amine was heated at 70–100°C until disap-
pearance from the IR spectrum of the absorption band
belonging to the double bond. ȕ-Aminoethylphospho-
nates I–VI were isolated by vacuum distillation.
Diethyl 2-(butylamino)ethylphosphonate (I).
Yield 4.12 g (73.3%), bp 85–86°C (0.8 mm), nD20
=
1.4420; published data [11]: bp 75–77°C (0.03 mm,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005

CHERKASOV et al.
1484
1
3
nD20 = 1.4400. H NMR spectrum, į, ppm: 0.87 t [3H,
3JHH = 7.3 Hz], 1.35 m [4H, CH3CH2(CH2)2O, JHH
=
=
=
3
3
7.3 Hz], 1.60 m (4H, CH3CH2CH2CH2O, JHH
CH3(CH2)3N, JHH = 7.1 Hz], 1.29 t (6H, CH3CH2O,
2
3
3JHH = 7.1 Hz), 1.31 m [2H, N(CH2)2CH2], 1.43 m
(2H, NCH2CH2C), 1.94 m (2H, PCH2CH2, 2JPH = 18.3,
3JHH = 7.4 Hz), 2.56 t (2H, NCH2, 3JHH = 7.1 Hz), 2.86 m
(2H, PCH2CH2, 3JHH = 7.4, 3JPH = 7.4 Hz), 4.06 m (4H,
CH3CH2O). 31P NMR spectrum: įP 31.3 ppm.
7.3 Hz), 1.86 m (2H, PCH2CH2, JPH = 19.2, JHH
8.2 Hz), 2.46 q (4H, CH2NCH2, 3JHH = 7.1 Hz), 2.76 m
3
3
(2H, PCH2CH2, JHH = 7.0, JHH = 8.2 Hz), 3.97 m
(4H, CH2CH2O). 31P NMR spectrum, įP 32.2 ppm.
Found, %: C 57.21; H 10.98; P 10.36. C14H32NO3P.
Calculated %: C 57.32; H 10.92; P 10.59
Diethyl 2-(diethylamino)ethylphosphonate (II).
Yield 3.6 g (80.4%), bp 71–72°C (0.8 mm), nD20
=
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 04-03-32906), by the Ministry of Education and
Science of the Russian Federation (program “Univer-
sities of Russia–Fundamental Research”) and by the
joint program of CRDF and the Ministry of Education
and Science of the Russian Federation (“Basic
Research and Higher Education,” no. REC-007).
1
1.4400. H NMR spectrum, į, ppm: 0.95 t (3H,
3
NCH2CH3, JHH = 7.1 Hz), 1.24 t (6H, CH3CH2O,
2
3JHH = 6.8 Hz), 1.82 m (2H, PCH2CH2, JPH = 19.4,
3JHH = 7.3 Hz), 2.42 q (4H, CH2NCH2, 3JHH = 7.1 Hz),
2.72 m (2H, PCH2CH2, 3JPH = 8.3, 3JHH = 7.3 Hz), 4.02 m
(4H, CH3CH2O). 31P NMR spectrum: įP 31.8 ppm.
Diethyl 2-(N-butyl-N-octylamino)ethylphos-
phonate (III). Yield 1.96 g (25%), bp 168–170°C
REFERENCES
1
(0.8 mm), n2D0 = 1.4504. H NMR spectrum, į, ppm:
2
3
1.87 m (2H, PCH2CH2, JPH = 19.2, JHH = 7.3 Hz),
1. Zakharov, S.V., Nuriazdanova, G.Kh., Garifzya-
nov, A.R., Galkin, V.I., and Cherkasov, R.A., Russ. J.
Gen. Chem., 2004, vol. 74, p. 873.
3
2.36 q (4H, CH2NCH2, JHH = 7.4 Hz), 2.73 m (2H,
3
3
PCH2CH2, JPH = 8.3, JHH = 7.1 Hz), 4.06 m (4H,
CH3CH2O). 31P NMR spectrum: įP 32.0 ppm. Found,
%: C 60.98; H 11.99. C17H40NO3P. Calculated, %:
C 60.53; H 11.86.
2. Cherkasov, R.A. and Galkin, V.I., Usp. Khim., 1998,
vol. 67, p. 940.
3. Aminophosphonic and Aminophosphinic Acids: Chem-
istry and Biological Activity, Kukhar, V.P. and Hud-
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4. Garifzyanov, A.R., Shirshova, N.V., and Cherka-
sov, R.A., Russ. J. Gen. Chem., 2005, vol. 75, p. 537.
5. Garifzyanov, A.R., Zakharov, S.V., and Cherka-
Diethyl 2-morpholinoethylphosphonate (IV).
Yield 4.69 g (80.5%), bp 97–98°C (0.8 mm), nD20
=
=
1.4640; published data [12]: bp 137°C (1 mm), nD20
1
1.4590. H NMR spectrum, į, ppm: 1.28 t (6H,
3
CH3CH2O, JHH = 7.1 Hz), 1.92 m (2H, PCH2CH2,
sov, R.A., Russ. J. Gen. Chem., 2005, vol. 75, p. 1057.
3
2JPH = 19.4, JHH = 8.2 Hz), 2.41 t (4H, CH2NCH2,
6. Garifzyanov, A.R., Zakharov, S.V., Kryukov, S.V.,
Galkin, V.I., and Cherkasov, R.A., Russ. J. Gen. Chem.,
2005, vol. 75, p. 1208.
3
3JHH = 4.7 Hz), 2.60 m (2H, PCH2CH2, JPH = 8.3,
3
3JHH = 8.2 Hz), 3.66 t (4H, NCH2CH2O, JHH
=
31
4.7 Hz), 4.06 m (4H, CH3CH2O). P NMR spectrum:
įP 29.8 ppm. Found, %: C 47.38; H 8.91; P 12.68.
C10H22NO4P. Calculated, %: C 47.81; H 8.76; P 12.35.
7. Garifzyanov, A.R., Nuriazdanova, G.Kh., and Cherka-
sov, R.A., Russ. J. Gen. Chem., 2004, vol. 74, p. 1885.
8. Gumienna-Kontecka, E., Galezowska, J., Drag, M.,
Lataika, R., Kafarski, P., and Kozlowski, H., Inorg.
Chim. Acta, 2004, vol. 357, p. 1632.
9. Rahman, M.S., Oliano, M., and Hii King Kuok,
Tetrahedron: Asymmetry, 2004, vol. 15, p. 1835.
10. Gubnitskaya, E.S., Peresypkina, L.G., and Samarai, L.I.,
Usp. Khim., 1990, vol. 59, p. 1386.
11. Pudovik, A.N. and Denisova, G.M., Zh. Obshch. Khim.,
1953, vol. 23, p. 263.
12. Gubnitskaya, E.S. and Peresypkina, L.G., Zh. Obshch.
Khim., 1989, vol. 59, p. 556.
Diisopropyl 2-(diethylamino)ethylphosphonate
(V). Yield 2.9 g (67%), bp 68–69°C (0.5 mm), nD20
=
1
1.4414. H NMR spectrum, į, ppm: 0.99 t (6H,
3
CH3CH2N, JHH = 7.2 Hz), 1.27 d [12H, (CH3)2CHO,
2
3JHH = 6.2 Hz], 1.82 m (2H, PCH2CH2, JPH = 19.3,
3JHH = 8.3 Hz), 2.46 q (4H, CH2NCH2, 3JHH = 7.1 Hz),
3
3
2.75 m (2H, PCH2CH2, JPH = 6.5, JHH = 8.3 Hz),
3
3
4.65 m [2H, (CH3)2CHO, JPH = 7.9, JHH = 6.2 Hz].
31P NMR spectrum: įP 29.6 ppm. Found, %: C 54.11;
H 10.69; P 11.70. C12H28NO3P. Calculated, %: C 54.34;
H 10.57; P 11.70.
13. Burger, A. and Sherlver, W.H., J. Med. Pharm. Chem.,
1961, vol. 4, p. 225.
Dibutyl 2-(diethylamino)ethylphosphonate (VI).
14. Leo, A., Hansch, C., and Elkins, D., Chem. Rev., 1971,
vol. 71, p. 525.
15. Sagadeev, E.V., Safina, Yu.G., and Cherkasov, R.A.,
Yield 1.95 g (56%), bp 91–92°C (0.7 mm), nD20
=
1
1.4456. H NMR spectrum, į, ppm: 0.98 t (6H,
3
CH3CH2N, JHH = 7.1 Hz), 1.33 t [6H, CH3(CH2)3O,
Russ. J. Org. Chem., 2004, vol. 40, p. 940.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 10 2005