Synthesis, spectroscopic characterization, crystal structures, theoretical studies, and antibacterial evaluation of two novel N-phosphinyl ureas

Article abstract of DOI:10.1007/s00706-010-0436-8

Two novel N-phosphinyl ureas containing different substituents were synthesized and characterized by ¹H, ¹³C, and ³¹P NMR, IR, UV, mass spectroscopy, and elemental analysis. The crystal structures of these compounds were determined by X-ray crystallography. The structure of one compound exhibits the presence of two independent forms of the molecule with equal occupancy in the lattice and theoretical data reveal the same stabilization energies for these conformers. The title molecules have anti conformation with respect to the C=O and P=O bonds, whereas the other compound shows syn configuration. Quantum chemical calculations were applied to clarify this conformational behavior. Furthermore, the molecular geometry and vibrational frequencies of the new derivatives in the ground state were calculated by using the Hartree-Fock (HF) and density functional method (B3LYP) with 6-31+G* and 6-311+G* basis sets and compared with experimental values. The new derivatives were additionally tested in view of their antibacterial properties.

Full text of DOI:10.1007/s00706-010-0436-8

Monatsh Chem (2011) 142:183–192
DOI 10.1007/s00706-010-0436-8
ORIGINAL PAPER
Synthesis, spectroscopic characterization, crystal structures,
theoretical studies, and antibacterial evaluation of two novel
N-phosphinyl ureas
Khodayar Gholivand Nilufar Dorosti
•
Received: 3 August 2010 / Accepted: 3 December 2010 / Published online: 4 January 2011
Ó Springer-Verlag 2010
Abstract Two novel N-phosphinyl ureas containing dif-
ferent substituents were synthesized and characterized by
Introduction
1
13 31
H, C, and P NMR, IR, UV, mass spectroscopy, and
Substituted ureas are one of the most important classes of
chemical compounds due to their various biological
activities as anticancer [1], antibacterial [2], antiviral,
antifungal, and anti-HIV agents [3], agricultural pesticides,
herbicides, and plant growth regulators [4]. The stereo-
chemical and pharmacological properties of six-membered
phosphorus-containing heterocycles and their active role as
cyclophosphamide analogs have also attracted attention,
e.g., regarding their structural stability and conformational
behavior [5–8]. However, the combination of urea and
phosphoryl fragments can be interesting from different
points of view such as conformational and biological
properties and complexation.
elemental analysis. The crystal structures of these com-
pounds were determined by X-ray crystallography. The
structure of one compound exhibits the presence of two
independent forms of the molecule with equal occupancy
in the lattice and theoretical data reveal the same stabil-
ization energies for these conformers. The title molecules
have anti conformation with respect to the C=O and P=O
bonds, whereas the other compound shows syn configura-
tion. Quantum chemical calculations were applied to
clarify this conformational behavior. Furthermore, the
molecular geometry and vibrational frequencies of the new
derivatives in the ground state were calculated by using the
Hartree–Fock (HF) and density functional method
Although syntheses of molecules with the general for-
(
B3LYP) with 6-31?G** and 6-311?G** basis sets and
mula RNHC(O)NHP(O)R have been reported [9–12], little
2
compared with experimental values. The new derivatives
were additionally tested in view of their antibacterial
properties.
attention has been given to their biological properties [13]
and structural studies from either experimental or theoreti-
cal points of view [14] so far. Besides, in our previous
studies, the crystal structure of most of the compounds
containing a –C(O)NHP(O)– backbone showed that the
P=O and C=O bonds are in anti position with respect to
each other [15–19] and the syn configuration is rare in the
relevant studies [20, 21]. In this study, two new N-phos-
Keywords Vibrational assignment ꢀ
Conformational analysis ꢀ Antibacterial activity ꢀ
N-Phosphinyl urea
1
phinyl ureas were synthesized and characterized by IR, H,
3
1
31
C, and P NMR, UV, mass spectroscopy, and elemental
analysis. The molecular structure and conformational
properties in the solid state were determined by X-ray dif-
fraction analysis and vibrational spectroscopy. To further
investigate the conformation, quantum chemical calcula-
tions were applied. Furthermore, we calculated geometric
parameters of the title compounds in the ground state and
compared the observed IR spectra of these molecules with
calculated harmonic vibrations by Hartree–Fock (HF) and
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-010-0436-8) contains supplementary
material, which is available to authorized users.
K. Gholivand (&) ꢀ N. Dorosti
Department of Chemistry, Tarbiat Modares University,
P.O. Box 14115-175 Tehran, Iran
e-mail: gholi_kh@modares.ac.ir
123

1
84
K. Gholivand, N. Dorosti
3
1
methyl signals. The H NMR reveals large J
constants of about 24.5 Hz, which is related to an equa-
density functional theory (DFT) (B3LYP) methods. Finally,
the antibacterial activities of the compounds against
Staphylococcus aureus, Bacillus subtilis, Escherichia coli,
and Salmonella typhi were measured.
coupling
PNCH
torial proton with P–N–C–H torsion angle near 180°, as
obtained from X-ray crystallography. These values are
3
much larger than J
for acyclic phosphoramidates [17,
PNCH
3
1
8, 24]. Also, the C NMR indicates that J coupling
3
1
PC
2
constants are larger than J coupling constants.
Results and discussion
PC
The reaction of diamines with N-arylureidophoshoryl
dichlorides is a method for the formation of phosphorus-
containing heterocycles. As indicated in Scheme 1, we
synthesized two new heterocyclic compounds from the
reaction of N-phenylureidophosphoryl dichloride (2) and
N-(4-nitrophenyl)ureidophosphoryl dichloride (3) [22, 23]
with 2,2-dimethyl-1,3-diaminopropane in the presence of
an HCl scavenger (an excess amount of the corresponding
diamine).
Crystal structure analysis
Single crystals of 5,5-dimethyl-2-(N-phenylureido)-1,3,2-
diazaphosphorinane-2-oxide (4) and 5,5-dimethyl-2-[N-(4-
nitrophenyl)ureido]-1,3,2-diazaphosphorinane-2-oxide (5)
were grown from diffusion of diethyl ether into methanol
solution and ethanol/acetonitrile at room temperature.
Details of the crystallographic data collection and refine-
ment parameters are presented in Table 2. Molecular
structures are shown as Oak Ridge thermal ellipsoid plots
(ORTEP) in Figs. 1 and 2.
NMR study
Compound 4 exists as two crystallographically inde-
pendent molecules in the crystalline lattice (A and B) at a
1:1 ratio due to the different spatial orientations of the two
conformers relative to each other that cause different tor-
sion angles (Table 3). Each conformer is connected to four
molecules of the other conformer via P(O)ꢀꢀꢀH–N and
C(O)ꢀꢀꢀH–N hydrogen bonds. Linking of these hydrogen
bonds leads to form a two-dimensional polymeric chain in
Phosphorus–hydrogen and phosphorus–carbon coupling
3
1
constants and d ( P) data of compounds 4 and 5 are
summarized in Table 1. The P NMR spectra demonstrate
3
1
that substitution of a proton in 5 by a NO group results in a
2
shielded phosphorus atom. The CH groups on the diaza-
3
phosphorinane ring in these compounds are diastereotopic,
1 13
thus the H and C NMR spectra each show two separate
H
H O
N
N
H
H O
N
P
N
N
H
CH3
CH3
Cl
Cl
O
HN
C H NH
2
P
-
C H Cl, 2HCl
6
5
2
5
PCl + NH COOC H
2 5
Cl P(O)NCO
2
5
2
O
2)
(
1)
NH
NH
2
2
(4)
H C
3
(
3
2
H C
4
-NO
2 6 4 2
C H NH
H
H O
N
N
Cl
Cl
P
O
2
O N
(3)
NH
H C
3
2
3
2
NH
2
H C
H
H O
N
N
P
N
H
CH3
CH3
O
HN
O N
2
(
5)
Scheme 1
Table 1 Some spectroscopic data of compounds 4 and 5
3
1
3
J
2
J
2
J
2
J
3
Comp.
d ( P) (ppm)
PNCH (Hz)
PH-endocyclic (Hz)
PH-exocyclic (Hz)
PC-aliphatic (Hz)
JPC-aliphatic (Hz)
4
5
3.78
3.23
24.21
24.47
2.7
–
6.76
4.15
1.76
br
4.3
4.53
1
23

Two novel N-phosphinyl ureas
185
Table 2 Crystallographic data and structure refinement results for 4 and 5
4
5
Empirical formula
Formula weight
Temperature (K)
C
12
H
19
N
4 2
O P
C
12 18 5 4
H N O P
282.28
120(2)
327.28
120(2)
˚
Wavelength (A)
0.71073
0.71073
Crystal system, space group
Unit cell dimensions
Orthorhombic, P2
1
2
1
2
1
1
Monoclinic, P2 /c
˚
a (A)
5.7054(3)
17.4446(9)
27.8528(15)
90.0
17.124(4)
9.158(2)
9.769(2)
90.0
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
90.0
98.315(5)
90.0
90.0
3
˚
V (A )
2,772.1(3)
8
1,516.0(6)
4
Z
-3
)
Dcalc (g cm
1.353
1.434
-
1
)
Absorption coefficient (mm
0.203
0.208
F(000)
3
Crystal size (mm )
1,200
688
0.25 9 0.25 9 0.15
0.25 9 0.12 9 0.03
Range for data collection (°)
Index ranges
1.87–29.00
2.40–26.00
-7 B h B 7, -23 B k B 23, -37 B l B 37
30,853/7,364 [0.0315]
-21 B h B 21, -10 B k B 11, -12 B l B 11
8,561/2,969 [0.0570]
Reflections collected/unique [Rint
Completeness to h (%)
]
(29.00°) 99.9
Semiempirical from equivalents
(26.00°) 99.7
Semiempirical from equivalents
Absorption correction
Maximum and minimum transmission
Refinement method
0.972 and 0.956
0.986 and 0.964
2
2
Full-matrix least-squares on F
Full-matrix least-squares on F
Data/restraints/parameters
2
Goodness-of-fit on F
7,364/0/347
1.001
2,969/0/201
1.004
R indices (all data)
R1 = 0.0607,
wR2 = 0.1242
0.628 and -0.387
-0.06(10)
R1 = 0.0950,
wR2 = 0.1341
0.296 and -0.305
-
3
)
˚
Largest difference peak and hole (e A
Absolute structure parameter
Fig. 2 Molecular structure of 5 showing the atom-labeling scheme
and 50% probability level displacement ellipsoids
the crystalline lattice. Furthermore, there are intramolecu-
lar P=OꢀꢀꢀH–NPh hydrogen bonds in both conformers. The
crystal packing of 5 is dominated by the occurrence of
Fig. 1 Molecular structure of 4 showing the atom-labeling scheme
and 50% probability level displacement ellipsoids
123

1
86
K. Gholivand, N. Dorosti
Table 3 Optimized and experimental geometries of compound 4
Parameters
Experimental
B3LYP/6-311?G**
B3LYP/6-31?G**
HF/6-311?G**
HF/6-31?G**
˚
Bond lengths (A)
P(1)–N(1)
1.694(2)
1.630(2)
1.622(2)
1.691(2)
1.631(2)
1.632(19)
1.714
1.666
1.666
1.714
1.666
1.666
1.717
1.669
1.67
1.691
1.642
1.643
1.691
1.643
1.642
1.695
1.646
1.646
1.695
1.646
1.646
P(1)–N(3)
P(1)–N(4)
P(2)–N(5)
1.717
1.67
P(2)–N(7)
P(2)–N(8)
1.669
Bond angles (°)
O(1)–P(1)–N(1)
O(1)–P(1)–N(3)
O(1)–P(1)–N(4)
O(3)–P(2)–N(5)
O(3)–P(2)–N(7)
O(3)–P(2)–N(8)
Torsion angles (°)
O(1)–P(1)–N(3)–C(8)
O(1)–P(1)–N(4)–C(10)
N(1)–P(1)–N(3)–C(8)
N(1)–P(1)–N(4)–C(10)
O(3)–P(2)–N(7)–C(20)
O(3)–P(2)–N(8)–C(22)
N(5)–P(2)–N(7)–C(20)
N(5)–P(2)–N(8)–C(22)
108.17(10)
115.95(11)
113.50(10)
108.23(10)
113.47(10)
115.95(11)
107.76
117.48
114.13
107.76
114.12
117.49
107.91
117.38
114.09
107.91
114.11
117.36
108.44
117.81
114.07
108.44
114.07
117.81
108.58
117.94
113.96
108.58
113.96
117.94
-163.48(16)
167.49(17)
76.47(19)
162.1838
-157.4116
-75.7006
82.1347
163.5073
-159.0103
-74.1972
80.3999
164.2547
-158.9794
-73.2902
80.3072
164.8776
-159.4566
-72.4764
79.7560
-70.64(19)
-166.19(17)
162.56(17)
71.85(19)
-162.2147
157.4166
75.6619
-163.5070
159.0523
74.1992
-164.2207
158.9506
73.3282
-164.8379
159.4167
72.5171
-77.43(19)
-82.1354
-80.3484
-80.3417
-79.8012
˚
P=OꢀꢀꢀH–N and N–OꢀꢀꢀH–N hydrogen bonds, which lead to
a two-dimensional polymeric chain.
longer than the normal P=O bond length (1.45 A) [25]. It is
interesting to note that in conformers A and B the form
with the stronger P=O bond, i.e., B, has weaker P–(endo-
cyclic N) bonds.
The P–(endocyclic N) bond lengths in both compounds
4 and 5 are lower than the P–N bond of –C(O)N(H)P(O)–
moieties (Tables 3, 4). All of these bonds are in the range
The phosphorus atoms have slightly distorted tetrahedral
configuration with the angles in the range of 102.16(10)–
115.95(11)° (in A), 102.22(10)–115.95(11)° (in B), and
104.27(12)–114.34(12)° (in 5). Moreover, the P=O bond is
placed in an equatorial position. The equatorial preference
˚
.622(2)–1.694(2) A and thus are significantly shorter than
1
˚
a typical P–N single bond (1.77 A) [25]. The P=O bond
lengths found in the molecules A and B (1.483(18) and
1
˚ ˚
.480(18) A) and for compound 5 (1.47(2) A) are slightly
Table 4 Optimized and experimental geometries of compound 5
Parameters
Experimental
B3LYP/6-311?G**
B3LYP/6-31?G**
HF/6-311?G**
HF/6-31?G**
˚
Bond lengths (A)
P(1)–N(3)
1.661(2)
1.626(2)
1.637(2)
1.743
1.665
1.677
1.747
1.668
1.679
1.712
1.641
1.654
1.718
1.645
1.655
P(1)–N(4)
P(1)–N(5)
Bond angles (°)
O(4)–P(1)–N(3)
O(4)–P(1)–N(4)
Torsion angles (°)
O(4)–P(1)–N(4)–C(8)
O(4)–P(1)–N(5)–C(10)
N(3)–P(1)–N(4)–C(8)
N(3)–P(1)–N(5)–C(10)
112.34(12)
114.19(12)
113.73
116.14
113.67
116.21
113.50
115.83
113.54
116.03
-167.86(19)
169.08(18)
67.9(2)
-165.7335
163.2199
66.1622
-165.3793
162.5857
66.5685
-164.7100
162.9838
67.3757
-164.9590
162.6050
67.0283
-67.9(2)
-75.4521
-76.2161
-75.6917
-76.0729
1
23

Two novel N-phosphinyl ureas
187
for the P=O bond was previously observed by Bentrude
DFT (B3LYP) with 6-31?G** and 6-311?G** basis sets
are listed in Tables 3 and 4. Similar geometric parameters
are obtained by the two applied methods. Although the
biggest differences between calculated and experimental
[
26] and was attributed to the overlap of the endocyclic
nitrogen p orbital with the P–(exocyclic N) antibonding
orbital. The endocyclic nitrogen atoms in compounds 4 and
˚
values of bond lengths and angles are about 0.024 A and
5
are distorted from planarity. The sum of angles around
˚
these atoms in 4 are 352.78° and 351.86° for N(3) and N(4)
atoms, 352.35° and 350.41° for N(7) and N(8) atoms, and
in 5 are 344.9° and 346.38° for N(4) and N(5). The sum of
the surrounding angles for all the exocyclic nitrogen atoms
are almost 360°, therefore the environment of the N atoms
is practically planar.
0.048 A and 1.99° and 1.54° for HF and DFT methods,
respectively, the HF method at 6-311?G** for the bond
length and the DFT method at 6-31?G** for the bond
angles correlate slightly better than other levels for com-
pound 4.
For compound 5, the HF method with 6-311?G**
basis set correlates slightly better than the DFT method
for bond lengths and bond angles. The considerable dif-
ferences between the calculated and experimental data of
Mass spectroscopy
˚
the bond lengths are about 0.057 and 0.086 A for the HF
Mass spectra of two synthetic derivatives 4 and 5 with
and DFT method and those of angle values are 2.02 and
formula
(R = H
1.84° for the DFT and HF method, respectively. The
(
4), 4-NO (5)) reveal the presence of the molecular ions at
2
calculated energy for two conformers of compound 4 is
summarized in Table 5. The calculated data in Tables 3
and 5 indicate that the bond lengths and angles are
identical and the structural stability of conformer A is
equal to those of conformer B. Also, the data show that
the two conformers only have differences in their corre-
sponding torsion angles.
m/z = 282 and 327. In our previous studies, it was assumed
that the fragmentation pathway of compounds with the
´
general formula R–C H C(O)NHP(O)R involves P–N
6
4
2
cleavage and P–O formation. Subsequently, the rearranged
molecule is cleaved by using a pseudo-McLafferty mecha-
?
nism to generate R–PhCN and the related amidophosphoric
acid cations [17, 19, 27].
On the basis of the previously reported structures
[15–18, 28, 29] and the data obtained by theoretical
calculations [30, 31], orientation of the P=O and C=O
groups in –C(O)NHP(O)– skeleton is anti and the crystal
structure of 4 is in agreement with the data given in the
literature. In contrast, 5 is one of the few compounds that
is close to syn configuration with O(4)–P(1)–C(7)–O(3)
torsion angle of -52.73°, whereas calculations predict a
structure with anti conformation as the most stable form
for compound 5 (Table 6). This arrangement is attributed
to the packing effect that allows a hydrogen bond
between the phosphoryl oxygen atom and the two
hydrogens of the –NHC(O)NH– moiety (Fig. 3). Table 6
shows that the anti conformer has a larger total dipole
moment than the syn form, which is consistent with the
increased relative stability of the anti conformer. In fact,
some of the earlier studies on conformational analysis
have shown that a conformation with the larger dipole
moment becomes stabilized due to dipole–dipole inter-
action [32, 33].
In the present study, mass spectra of the title compounds
show that with insertion of NH between C=O and phenyl ring
the pseudo-McLafferty pathway is observed with very weak
intensity and the main pathway is C–N(1) bond cleavage
of the –N(1)HC(O)N(2)H– moiety. Then, the cleavage
pathway is the same as the constitution pathway of N-ary-
lureidophoshoryl dichlorides 2 and 3 (Scheme 1). The
fragmentation of synthesized products shows a peak at
m/z = 189, corresponding to the loss of aniline or nitroani-
line groups and formation of
.
Fragment ions at m/z = 93 and 138 are base peaks and
?
?
assigned to PhNH2 and 4-NO PhNH
.
2
2
UV–Vis study
The electronic spectra of compounds 4 and 5 were studied in
DMSO solution. The results revealed that a strong absor-
bance at 275 nm corresponds to the p–p* transition for 4.
This band shifts to 308 nm with higher intensity for 5. The
red-shifted band evidently arises from a resonance effect of
the 4-NO group. Besides, compound 5 has a weak absor-
2
Table 5 Calculated energy for conformers A and B of compound 4
by HF and DFT methods
bance at 370 nm which is consistent with the n–p* transition.
Level of theory
E (conformer A)
-
E (conformer B)
-1
(kJ mol )
1
)
Computational study
(kJ mol
B3LYP/6-311?G**
HF/6-311?G**
-3,099,849.311
-3,084,560.193
-3,099,849.311
-3,084,560.193
The experimental and optimized geometric parameters
(
bond lengths, bond angles, and dihedral angles) by HF and
123

1
88
K. Gholivand, N. Dorosti
Table 6 Calculated energy and the differences for conformer anti and syn of compound 5 by DFT method
Level of theory
E (anti conformer)
a.u.)
E (syn conformer)
(a.u.)
DEanti–syn
(kJ mol
Dipole moment
(anti) (D)
Dipole moment
(syn) (D)
-
1
(
)
B3LYP/6-311?G**
B3LYP/6-31?G**
-1,384.46274
-1,384.20232
-1,384.453334
-1,384.1939946
24.70
21.85
13.6298
13.3306
9.2367
9.4056
Tables 7 and 8. Since two conformers of compound 4 have
equal energy in the gas phase, only one molecular structure
was selected to obtain harmonic vibrational frequencies.
Calculated vibrational frequencies of 4 and 5 were
compared with the experimental data. Subsequently, a
tentative assignment of the observed bands in the infrared
spectra was carried out by comparison with theoretical
wavenumbers, as well as with the relevant data reported in
the literature for urea derivatives [34, 35] and related
phosphoramidates [15, 30, 31, 36]. To discuss the vibra-
tional assignments, we took the functional density (DFT)
and HF calculated wavenumbers corrected by a scale factor
of 0.960 and 0.902.
As can be seen from Table 7, the intense bands centered
-
1
at 3,205 and 2,935 cm
in the IR spectrum of 4 are
assigned to the N–H stretching vibration of amide and
amine groups. For 5 these modes were assigned to the
-
1
observed bands at 3,335, 3,090, and 2,920 cm (Table 8).
Fig. 3 Molecular structure of 5 showing hydrogen bond interactions
-
Well-defined absorptions at 1,677 and 1,699 cm corre-
1
Vibrational analysis
spond to C=O stretching mode for 4 and 5. Intense
-
1
absorptions observed at 1,184 and 1,200 cm
can be
We calculated the theoretical vibrational spectra of com-
pounds 4 and 5 and compared these calculations with their
experimental results. The most important absorptions
together with the computed vibrational data are listed in
assigned with confidence to the characteristic P=O
stretching mode for 4 and 5. It is interesting to note that
m(C=O) and m(P=O) modes for compound 5 appear at
higher frequencies than the corresponding modes of
Table 7 Comparison of the
experimental and calculated
vibrational frequencies ꢀm (cm
of 4
a
b
b
Experimental
B3LYP/6-311?G**
HF/6-311?G**
Assignment
-1
)
3
2
1
1
1
1
1
1
1
1
1
1
1
,205s
3,436(30)
3,274(367)
1,687(425)
1,588(259)
1,577(163)
1,537(331)
1,468(84)
1,419(33)
1,337(93)
1,291(287)
1,212(268)
1,060(226)
1,044(12)
969(49)
3,446(49)
3,390(253)
1,730(560)
629(346)
1,611(122)
1,572(308)
1,491(86)
1,438(71)
1,389(43)
1,284(698)
1,192(83)
1,080(155)
1,063(18)
971(12)
m(N–H)amide
m(N–H)amine
m(C=O)
,935m
,677vs
,593s
d(N–H)
,547s
d(Ring)
,487m
,448s
d(Ring? N–H), m(C–N)
d(Ring)
,381w
,336m
,256w
,184s
m(C–N), d(Ring)
d(N–H)
d(Ring), m(N–C–N)
m(P=O)
vs Very strong, s strong,
m medium, w weak,
m stretching, d deformation,
q rocking
,090m
,045m
m(C–N)
m(P–N)amine
Ring breathing, d(N–C–N)
m(P–N)amide
q(C–H)ring
1,019w
951m
a
Solid in KBr pellets
825(176)
815(6)
858(99)
b
Calculated band intensities in
-
858m
760(62)
1
kJ mol are given in
parentheses
7
46s
738(34)
699(70)
q(N–H)
1
23

Two novel N-phosphinyl ureas
189
Table 8 Comparison of the
experimental and calculated
vibrational frequencies ꢀm (cm
of 5
a
b
b
Experimental
B3LYP/6-311?G**
HF/6-311?G**
Assignment
-1
)
3
3
2
1
1
1
1
1
1
1
1
1
1
1
,335m
,090m
,920m
,699s
3,471(29)
3,438(42)
3,425(43)
1,688(192)
1,573(147)
1,519(252)
1,486(629)
1,386(488)
1,311(186)
1,225(106)
1,208(151)
1,128(446)
1,078(149)
1,044(186)
1,030(17)
864(27)
3,453(32)
3,442(45)
3,441(72)
1,743(293)
1,608(54)
1,590(239)
1,536(652)
1,457(130)
1,439(1317)
1,255(228)
1,235(215)
1,155(212)
1,110(91)
1,071(165)
1,058(30)
895(29)
m(N–H)amide
m(N–H)amine
m(N–H)amine
m(C=O)
,596m
,547m
,494s
d(Ring ? N–H)
m
2
as(NO ), d(N–H)
d(Ring ? N–H), m(C–N)
m(N–C-N), d(Ring)
,380w
,330s
m(C-NO
d(Ring)
m(P=O)
2
), d(Ring)
,299m
,200s
,105m
,075m
,042m
m(N–C–N)
vs Very strong, s strong,
m medium, w weak,
m stretching, d deformation,
q rocking
Ring breathing
m(C–N)
951w
922w
850s
m(P–N)amine
m(P–N)amide, d(N–C–N)
q(C–H)ring
a
Solid in KBr pellets
b
Calculated band intensities
839(40)
871(117)
-1
in kJ mol are given in
parentheses
6
47w
534(128)
560(169)
q(N–H)
compound 4 due to substitution of the electron-withdraw-
ing group on the phenyl ring in 5 that are in good
agreement with X-ray data. In molecule 5, the m (NO )
Antimicrobial activity
The compounds 4 and 5 were screened to evaluate their
antimicrobial activity against S. aureus (ATCC 6538P), B.
subtilis (ATCC 6633), E. coli (ATCC 35218), and S. typhi
(ATCC 19430) using the disk diffusion method and MIC
(minimum inhibitory concentration) experiments. The
results of the assays are presented in Table 9. The
screening data reveal that compound 5 exhibited higher
activity towards the tested microorganisms (MIC
as
2
-
1
mode is located at 1,547 cm
.
-
1
The observed bands at 1,256 and 1,380 cm
are
assigned to the N–C–N stretching vibration of compounds
and 5. The ring breathing normal mode was assigned to
4
the bands at 1,019 cm for 4 and 1,075 cm for 5. From
three medium absorptions centered at 1,090, 1,045, and
-
1
-1
-
51 cm for 4, the first can be assigned with confidence to
1
9
-
3
the C–N stretching mode, whereas the other two bands can
1.17–18.8 lg cm ) than compound 4 (MIC 385 to
-
3
be assigned to m(P–N)amine and m(P–N)amide. For derivative
[400 lg cm ). The MIC values of 4 and 5 against certain
bacterial strains indicate that S. aureus were more sensitive
to the toxicity of the synthesized compounds than other
microorganisms. The data show that compounds were
inactive against S. typhi. Furthermore, derivative 5 was the
more potent compound against B. subtilis; its activity was
higher than gentamycin. It may be concluded that the
structure of the tested compounds is the principal factor
-
1
, the bands located at 1,042, 951, and 922 cm were
5
attributed to the same modes. Moreover, the intense bands
-
1
observed at 1,593, 1,448, and 1,019 cm in the IR spec-
trum of 4 are assigned to modes associated with N–H, ring,
and N–C–N deformations (Table 7). Similar assignments
were provided for 5 to the observed very intense infrared
-
1
bands at 1,596, 1,494, and 922 cm (Table 8).
Table 9 Antimicrobial activity of compounds 4 and 5
Comp.
B. subtilis
E. coli
S. typhi
S. aureus
a
a
-3
)
-3
-3
-3
GIZ (mm) MIC (lg cm )
GIZ (mm) MIC (lg cm
GIZ (mm) MIC (lg cm
)
GIZ (mm) MIC (lg cm
)
4
5
11
14
[400
1.17
11
11
20
[400
18.8
11
10
21
[400
[400
3.12
12
11
20
385
4.69
3.12
Gentamycin 23
6.25
6.25
a
-3
The values indicate the diameters in mm for the zone of growth inhibition (GIZ) and minimal inhibitory concentration (MIC) in lg cm
observed after 24 h of incubation at 35 °C. Error values are within ± 1 mm. Moderately active (8–13); higher active ([14). Includes diameter of
disc (6.4 mm)
123

1
90
K. Gholivand, N. Dorosti
influencing the antimicrobial activity and changing the
substituents in the phenyl ring leads to compounds with
different antibacterial activity.
N-phenylureidophosphoryl dichloride (2) and N-(4-nitro-
phenyl)ureidophosphoryl dichloride (3).
General procedure for the synthesis
of N-phosphinylureas 4 and 5
Conclusion
A solution of 1.23 g 2,2-dimethyl-1,3-diaminopropane
Two new N-phosphinyl ureas were synthesized and char-
(12 mmol) was added dropwise to a suspension of 2 or 3
3
1
13
31
acterized by multinuclear ( H, C, and P) NMR, UV, IR
spectroscopy, elemental analysis, and mass spectrometry
techniques. X-ray crystallography confirmed the occur-
rence of two independent conformers for compound 4
with anti configuration around the dihedral angle of the
(6 mmol) in 30 cm dry diethyl ether and stirred at 0 °C.
After 5 h, the products were filtered off and washed with
H O.
2
5,5-Dimethyl-2-(N-phenylureido)-1,3,2-
diazaphosphorinane-2-oxide (4, C H N O P)
1
2 19 4 2
–
C(O)NHP(O)– skeleton. Quantum chemical calculations
1
Yield 85%; m.p.: 195–196 °C; H NMR (DMSO-d ):
6
predicted that the structural stability of these molecules is
equal. The crystal structure of compound 5 showed that the
P=O and C=O double bonds are in syn position with
respect to each other, whereas theoretical data showed that
anti conformation is stable. Furthermore, the harmonic
vibrations of the synthesized derivatives computed by the
RHF and DFT methods were in good agreement with the
experimental IR spectra values. The results of antimicro-
bial assays indicated that derivative 5 with an electron-
withdrawing group has higher activity against the tested
microorganisms.
d = 0.79 (s, 3H, CH ), 1.03 (s, 3H, CH ), 2.57 (ddd,
3
3
2
3
JHH = 11.92 Hz, JHH = 5.26 Hz, JPNCH = 24.21 Hz,
3
2
H), 2.98 (d, JHH = 11.93 Hz, 2H), 4.66 (d, JPNH =
2
2
2
1
7
3
.70 Hz, 2H, endocyclic NH), 6.95 (t, J = 7.22 Hz,
HH
3
H), 7.25 (t, JHH = 7.57 Hz, 2H), 7.36 (d, JHH
3
=
2
.99 Hz, 2H), 7.63 (d, J
= 6.76 Hz, 1H, NHP), 9.32
PNH
1
3
(
s, 1H, PhNH) ppm; C NMR (DMSO-d ): d = 23.29 (s,
6
3
CH ), 24.84 (s, CH ), 30.46 (d, J = 4.28 Hz), 52.35 (d,
3
3
PC
2
JPC = 1.76 Hz), 118.11 (s), 121.94 (s), 128.70 (s), 139.29
2
s), 153.33 (d, J = 2.33 Hz) ppm; P NMR (DMSO-
31
(
PC
d6): d = 3.78 (m) ppm; IR (KBr): ꢀm = 3,205 (s, N–H),
2,935 (m, N–H), 1,677 (vs, C=O), 1,593 (s), 1,547 (s),
1
,487 (m), 1,448 (s), 1,381 (w), 1,336 (m), 1,256 (w), 1,184
Experimental
(
s, P=O), 1,090 (m), 1,045 (m, P–N), 1,019 (w), 951 (m),
-
1
8
58 (m), 746 (s) cm ; UV–Vis (DMSO): k
= 275 nm;
max
Materials and methods
?
MS (70 eV): m/z = 282 (M ), 189 (M - C H NH ), 93
?
6
5
2
?
C H NH ).
(
6 5 2
All reactions were carried out under argon atmosphere.
All chemicals and solvents were purchased from Merck
1 13
and used without further purification. H, C, and
5,5-Dimethyl-2-[N-(4-nitrophenyl)ureido]-1,3,2-
diazaphosphorinane-2-oxide (5, C H N O P)
31
P
1
2 18 5 4
1
NMR spectra were recorded on a Bruker Avance DRS
Yield 70%; m.p.: 204–205 °C; H NMR (DMSO-d6):
d = 0.79 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.58 (ddd,
JHH = 11.86 Hz, JHH = 5.07 Hz, JPNCH = 24.47 Hz,
1
13
00 MHz spectrometer. H and C chemical shifts were
5
3
3
3
1
2
3
3
determined relative to TMS, P chemical shifts relative to
5% H PO as external standards. Infrared spectra were
2
8
2H), 3.01 (d, J = 11.80 Hz, 2H), 4.79 (s, 2H, endocy-
HH
3
4
3
clic NH), 7.62 (d, JHH = 9.05 Hz, 2H), 8.17 (d,
obtained by using KBr pellets on a Shimadzu IR-60
spectrometer. Elemental analysis was performed by using
a Heraeus CHN-O-RAPID apparatus. The experimental
data were in good agreement with the calculated values.
Melting points were determined on an electrothermal
apparatus. Mass spectra were obtained with MS model
3
2
JHH = 9.05 Hz, 2H), 7.92 (brd, JPNH = 4.15 Hz, 1H,
1
NHP), 10.06 (s, 1H, 4-NO -PhNH) ppm; C NMR
3
2
(DMSO-d ): d = 23.25 (s, CH ), 24.83 (s, CH ), 30.42
6
3
3
3
(d, J = 4.53 Hz), 52.34 (br), 117.51 (s), 125.10 (s),
PC
3
1
141.22 (s), 145.82 (s), 153.13 (s) ppm; P NMR (DMSO-
d6): d = 3.23 (m) ppm; IR(KBr): ꢀm =3,335 (m, N–H), 3,090
(m, N–H), 2,920 (m, N–H), 1,699 (s, C=O), 1,596
(m), 1,547 (m), 1,494 (s), 1,380 (w), 1,330 (s), 1,299
(m), 1,200 (s, P=O), 1,105 (m), 1,075 (m), 1,042 (m),
5
973 Network apparatus using 70 eV as ionization energy.
Electronic spectra were recorded on a Shimadzu UV-2100
spectrometer. Dichlorophosphinylureas 2 and 3 were pre-
pared by using a method reported by Kirsanov et al.
-
1
[
22, 23] (Scheme 1). First, dichloroisocyanatophosphine
951 (w), 922 (w, P–N), 850 (s), 647 (w) cm
;
oxide (1) was obtained from the reaction of phosphorus
pentachloride and ethyl carbamate in ethylene chloride,
then the treatment of aniline derivatives with 1 led to
UV–Vis (DMSO): k = 370, 308 nm; MS (70 eV):
max
?
m/z = 327 (M ), 189 (M -(4-NO C H NH ) ), 138
?
2
6
4
2
?
(4-NO C H NH ).
2
6
4
2
1
23

Two novel N-phosphinyl ureas
191
X-ray measurements
Acknowledgments The financial support of this work by the
Research Council of Tarbiat Modares University is gratefully
acknowledged.
X-ray data of compounds 4 and 5 were collected on a
Bruker SMART 1000 CCD single crystal diffractometer
with graphite monochromated Mo Ka radiation (k =
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