Some new compounds with P(E)NHC(O) (E = lone pair, O, S) linkage: Synthesis, spectroscopic, crystal structures, theoretical studies, and antimicrobial evaluation

Article abstract of DOI:10.1007/s00706-013-0960-4

New phosphinoamides, chalcogenides, and amidophosphates were synthesized and characterized by ¹H, ¹³C, ³¹P NMR, IR spectroscopy, and elemental analysis. The ¹³C NMR spectra of two phosphinoamides exhibit obvious differences between their ¹ J(P,C) coupling constants (128.3 Hz in one compound vs. 439.2 Hz in another compound). Natural bond orbital analysis was performed to clarify the electronic behavior of the title molecules. The crystal structures of three derivatives were determined by X-ray crystallography. The structure of N-(Diphenylphosphino)-2- pyrazinecarboxamide contains two symmetry-independent forms of the molecule with equal occupancy in the lattice. Density functional theory calculations indicate that two conformers of this compound are identical from an energy point of view. Strong intermolecular N-H···O(P) hydrogen bonds lead to a centrosymmetric dimer in Diphenyl N-(2-pyrazinylcarbonyl)phosphoramidate, whereas N-H···(O)C and N-H···N hydrogen bonds in N-(Diphenylphosphino)-2-pyrazinecarboxamide and N-(Diphenylphosphinothioyl)-2-pyrazinecarboxamide sulfide, respectively, form a one-dimensional polymeric chain in their structures. The in vitro antimicrobial activity of the amidophosphates was evaluated against various microbial strains of Gram positive and Gram negative bacteria and fungi.

Full text of DOI:10.1007/s00706-013-0960-4

Monatsh Chem (2013) 144:1417–1425
DOI 10.1007/s00706-013-0960-4
ORIGINAL PAPER
Some new compounds with P(E)NHC(O) (E 5 lone pair, O, S)
linkage: synthesis, spectroscopic, crystal structures, theoretical
studies, and antimicrobial evaluation
•
Khodayar Gholivand Niloufar Dorosti
Received: 8 June 2012 / Accepted: 5 March 2013 / Published online: 4 April 2013
Ó Springer-Verlag Wien 2013
Abstract New phosphinoamides, chalcogenides, and
amidophosphates were synthesized and characterized by 1H,
13C, 31P NMR, IR spectroscopy, and elemental analysis. The
13C NMR spectra of two phosphinoamides exhibit obvious
differences between their 1J(P,C) coupling constants
(128.3 Hz in one compound vs. 439.2 Hz in another com-
pound). Natural bondorbitalanalysiswasperformed toclarify
the electronic behavior of the title molecules. The crystal
structures of three derivatives were determined by X-ray
crystallography. The structure of N-(Diphenylphosphino)-
2-pyrazinecarboxamide contains two symmetry-independent
forms of the molecule with equal occupancy in the lattice.
Density functional theory calculations indicate that two
conformers of this compound are identical from an energy
point of view. Strong intermolecular N–HꢀꢀꢀO(P) hydrogen
bonds lead to a centrosymmetric dimer in Diphenyl N-(2-
pyrazinylcarbonyl)phosphoramidate, whereas N–Hꢀꢀꢀ(O)C
and N–HꢀꢀꢀN hydrogen bonds in N-(Diphenylphosphino)-
2-pyrazinecarboxamide and N-(Diphenylphosphinothioyl)-
2-pyrazinecarboxamide sulfide, respectively, form a one-
dimensional polymeric chain in their structures. The in vitro
antimicrobial activity of the amidophosphates was evaluated
against various microbial strains of Gram positive and Gram
negative bacteria and fungi.
Keywords Synthesis ꢀ NBO ꢀ X-ray crystallography ꢀ
Antimicrobial
Introduction
The study on phosphorus(III) and (V) derivatives is
important owing to their crucial role in various areas of
science including synthesis, coordination, biomedicine, and
theoretical matters [1–4]. On the other hand, carboxamide
compounds such as nicotinamide, isonicotinamide, pyraz-
ineamide (PZA), and urea are materials with a wide range
of chemical and biological applications [5–14]. The pres-
ence of these amides together with the phosphorus atom
has led to extensive structural and functional diversity
of these compounds. Synthesis [15–20], coordination
chemistry [21–24], and biological activities [25–27] of
derivatives containing the corresponding amides (except
PZA) with a C(O)NHP(E) (E = lone pair, O, S, Se) skel-
eton have been reported in the literature. To further study
this area, six new derivatives (1–3 and 5–7) were synthe-
sized and characterized. The known compounds 4 and 8
[28, 29] were also prepared to investigate the effect of the
phosphorus substituent on structural and biological prop-
erties. Molecules 2, 3, and 5 reported in this work are the
first examples of phosphorus compounds bearing a PZA
moiety. The crystal structures of these compounds were
determined by X-ray crystallography. Additionally, natural
bonding orbital (NBO) analysis was used to get a more
detailed insight into orbital interactions in molecules 1 and
2. Compounds 5–8 were also screened for antimicrobial
activity against Bacillus subtilis, Staphylococcus aureus,
Escherichia coli, Pseudomonas aeruginosa, S. epidermidis,
Aspergillus niger and Candida albicans.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-0960-4) contains supplementary
material, which is available to authorized users.
K. Gholivand (&)
Department of Chemistry, Tarbiat Modares University, P.O. Box
14115-175, Tehran, Iran
e-mail: gholi_kh@modares.ac.ir
N. Dorosti
Department of Chemistry, Payame Noor University, P.O. Box
19395-3697, Tehran, Iran
123

1418
K. Gholivand, N. Dorosti
Scheme 1
H
H
N
N
P
O
1
O
(C6H5)2PCl
-Et3NHCl
+ DMAP + Et3N
R
NH2
O
P
N
N
H
2
N
S
O
S
P
N
N
H
N
3
Results and discussion
Scheme 2
RC(O)NHNa + H2 R = C6H5NH, C4H3N2, C5H4N
RC(O)NH2 + NaH
Phosphinoamides 1 and 2 containing a –PNHC(O)– moiety
were obtained by the condensation of chlorodiphenyl-
phosphine with N-phenylurea and pyrazineamide,
respectively, in the presence of excess triethylamine and a
catalytic amount of 4-(dimethylamino)pyridine (DMAP)
(Scheme 1). The presence of a P(III) atom provides an
opportunity for a variety of oxidation products to be syn-
thesized. Two chalcogenides with different functional
groups [P(S)NHC(O) (3) and P(O)NHC(O) (4)] were pre-
pared. Compound 3 was synthesized by reaction of 2 with
elemental sulfur in toluene, whereas 4 was obtained by
reaction of C6H5NHC(O)Na with diphenylphosphinic
chloride (Schemes 1 and 2). Syntheses of amidophosphates
5–8 were also performed in a similar manner by treat-
ment of the corresponding amide salts RC(O)NHNa
[R = C4H3N2 (5), C5H4N (nicotin (6) and isonicotin
(7)), and C6H5NH (8)] with diphenylchlorophosphate
(Scheme 2).
O
H
N
H
N
(C6H5)2P(O)Cl
R = C6H5NH
P
RC(O)NHNa
O
4
(C6H5O)2P(O)Cl
O
O
P
O
R = C4H3N2
N
N
H
O
N
5
O
O
P
O
H
H
N
O
N
O
N
P
H
O
O
O
N
6
8
Some spectroscopic data of compounds 1–8 are listed in
Table 1. The 31P{1H} NMR spectra show a single reso-
nance at d(P) = 22.46 and 51.54 ppm for compounds 2
and 3, respectively. Results show that the presence of a
sulfur atom in 3 leads to the deshielding of the phosphorus
atom in this derivative relative to 2. The phosphorus
chemical shift of compounds 5–8 is about -12.06 ppm
O
O
P
O
N
H
O
N
7
123

Some new compounds with P(E)NHC(O) (E = lone pair, O, S) linkage
Table 1 Some spectroscopic data of compounds 1–8
1419
Compound
d(31P)/ppm
2JPH/Hz
1JPC/Hz
d(NH)/ppm
2JPC/Hz
3JPC/Hz
1
2
3
4
5
6
7
8
16.75
22.42
10.06
128.92
8.46
9.36
9.84
8.50
9.08
8.60
9.08
6.87
10.19
2.64
11.80
10.15
6.92
–
12.95
–
439.19
13.59, 5.63
13.57
51.54
–
103.85
15.61
–
132.49
12.43
-12.04
-12.04
-12.08
-12.08
12.65
–
–
–
–
10.49, 4.70
5.09
–
–
–
6.94
6.77
4.83
4.88
˚
which demonstrates the large shift to higher field for these
1
compounds relative to those of 1–4. The H NMR spectra
d(O(2)ꢀꢀꢀO(4)) = 3.014 A] in the crystalline network. The
phosphoryl and carbonyl groups show an anti configuration
(Fig. 3). The phosphorus atoms have a slightly distorted
tetrahedral configuration with the angles in the range of
100.69(11)–102.32(11)° (in A), 102.06(10)–102.23(11)°
(in B), 101.38(7)–15.57(5)° (in 3), and 101.77(8)–
116.86(8)° (in 5).
exhibit the presence of an amide proton in the range of
6.87–9.84 ppm with 2J(P,H) = 10.06, 12.65 Hz in 1 and 5.
1
Moreover, the 13C NMR reveals a J(P,C) coupling con-
stant of 439.19 Hz for compound 2 that is much larger than
1J(P,C) for molecule 1 (128.92 Hz).
˚
The P–N distances in the derivative 2 (1.728(2) A in
˚
A and 1.718(2) A in B) are slightly longer than those in the
Crystal structure analysis
˚
compounds 3 and 5 (1.703(13) A and 1.653(17) A,
˚
Single crystals of compounds 2, 3, and 5 were obtained
after slow evaporation of solutions (see ‘‘Experimental’’) at
room temperature. The crystal data and the details of the
X-ray analysis are given in Table 2. Selected bond lengths
and angles are summarized in Tables 3 and S1 (supple-
mentary material). Hydrogen bonding data are collected
in the Supplementary Material (Table S2). Molecular
structures of these compounds are presented in Figs. 1, 2,
and 3.
respectively) and thus are significantly shorter than a
˚
typical P–N single bond (1.77 A) [32]. The sum of the
surrounding angles for all of the amidic nitrogen atoms is
almost 360° and therefore the environment of the N atoms
is practically planar.
The crystal data of molecules 2 and 3 show that the P–C
bond lengths do not differ significantly from one another.
The phosphorus to sulfur bond length in phosphine sulfide
˚
3 (1.923 A) is shorter than the typical bond in Ph3PS (P=S:
˚
1.951(2)–1.954(2) A) [33, 34].
Compounds 2 and 3 crystallize in orthorhombic and
monoclinic systems with Z = 8 and 4, respectively.
Derivative 2 exists as two crystallographically independent
molecules in the crystalline lattice (A and B) owing to the
different torsion angles (Table S1). This phenomenon was
observed for some of our previously reported structures
[30, 31]. Each conformer is connected to two molecules of
the other conformer via C(O)ꢀꢀꢀH–N hydrogen bonds
leading to two infinite zigzag polymeric chains in the lat-
tice (Fig. 1). The other molecule contains one conformer
with the P=S and C=O groups in a syn configuration. The
intermolecular N(1)–H(N1)ꢀꢀꢀN(3) hydrogen bonding pro-
duces a one-dimensional polymeric chain (Fig. 2). There is
also pꢀꢀꢀp stacking interaction with the centroid-to-centroid
Computational studies
Similar to some of our previously reported structures,
compound 2 exists as two crystallographically independent
molecules in a 1:1 ratio in the crystalline lattice [35, 36].
Hence quantum chemical calculations were used to further
clarify the conformation of 2. The experimental and opti-
mized geometric parameters (bond lengths, bond angles,
and dihedral angles) by Hartree–Fock (HF) and density
functional theory (DFT) (B3LYP) with 6-31?G** basis
sets are listed in the Supplementary Material.
The calculated energy for two conformers of 2 is sum-
marized in Tables 4 and S1. These calculated data indicate
that the bond lengths and angles are identical and the
structural stability of conformer A is equal to that of con-
former B (DE = 0). Also, the data show that the two
conformers only have differences in their corresponding
torsion angles.
˚
distance of 3.56 A between phenyl and pyrazine rings.
Derivative 5 crystallizes in monoclinic system with
Z = 8. The structure contains one amidic hydrogen atom
and forms a centrosymmetric dimer via intermolecular
–P=OꢀꢀꢀH–N– hydrogen bonds. Further, there is intramo-
lecular P1(O4)ꢀꢀꢀ(O2)C1 electrostatic interaction [with
123

1420
K. Gholivand, N. Dorosti
Table 2 Crystal data collection and structure refinement parameters for compounds 2, 3, and 5
2
3
5
Empirical formula
Formula weight
Temperature/K
C17H14N3OP
307.28
C17H14N3OPS
339.34
C17H14N3O4P
355.28
120(2)
100(2)
120(2)
˚
Wavelength/A
0.71073
0.71073
0.71073
Crystal system, space group
Unit cell dimensions
Orthorhombic, P212121
Monoclinic, P21/n
Monoclinic, C2/c
˚
a/A
9.1136(4)
17.9701(8)
18.0500(8)
90.0
6.6766(3)
26.3223(12)
8.9120(4)
90.0
22.3843(12)
9.4659(5)
16.0564(8)
90.0
˚
b/A
˚
c/A
a/°
b/°
c/°
90.0
90.4280(10)
90.0
106.6680(10)
90.0
90.0
3
˚
V/A
2,956.1(2)
8
1,566.18(12)
4
3,259.2(3)
8
Z
D
calc/Mg m-3
1.381
1.439
1.448
Absorption coefficient/mm-1
0.191
0.316
0.197
F(000)
1,280
704
1,472
Crystal size/mm3
Range for data collection/°
Index ranges
0.40 9 0.20 9 0.20
1.60–29.00
0.55 9 0.50 9 0.30
1.55–28.00
0.37 9 0.26 9 0.14
1.90–27.10
-12 B h B 12, -24 B k B 23, -8 B h B 8, -34 B k B 34,
-28 B h B 28, -12 B k B 12,
-20 B l B 20
-24 B l B 24
32,932/7,874 (0.0439)
(29.00°) 99.9
-11 B l B 11
17,075/3,762 (0.0194)
(28.00°) 99.5
Reflections collected/unique (Rint
Completeness to h/%
)
15,166/3,561 (0.0410)
(27.10°) 98.6
Absorption correction
Semiempirical from equivalents Semiempirical from equivalents Semiempirical from equivalents
0.967 and 0.9522 0.911 and 0.845 0.9749 and 0.9316
Full-matrix least-squares on F2 Full-matrix least-squares on F2 Full-matrix least-squares on F2
Maximum and minimum transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
7,874/0/405
3,762/0/212
3,561/0/226
1.011
1.006
1.001
R indices (all data)
R1 = 0.0609, wR2 = 0.1014
0.452 and -0.246
-0.05(8)
R1 = 0.0364, wR2 = 0.0928
0.686 and -0.732
R1 = 0.0633, wR2 = 0.1017
0.353 and -0.500
-3
˚
Largest difference peak and hole/e A
Absolute structure parameter
NBO analysis
the carbonyl and phenyl ring in the structure C6H5NHC
(O)NHP(C6H5)2 (1), assuming that the Lp(Namide) in
compound 1 tends to contribute more in Lp(N) ? r*(P–C)
when the Lp(Naniline) participates in resonance interaction
with the p*(C=O) p-antibonding orbital. The NBO calcu-
lations were performed at HF/6-31?G** level for the
structures 1 and 2. The results of NBO calculations
are summarized in Table 5. A stabilization energy of
318.36 kJ/mol was obtained for the Lp(Naniline) ? p*
(C=O) delocalization effect that causes a decrease in the
stabilization energy of the Lp(Namide) ? p*(C=O) inter-
action from 379.68 kJ/mol in 2 to 257.46 kJ/mol in 1. Also,
this effect attenuates the Lp(Namide) ? r*(P–C) interac-
tion and decreases the strength of the P–N bond in the latter
compound. These results explain the 13C NMR spectra in
which a large value for 1J(P,C) was observed for the
The electronic delocalizations Lp(N) ? r*(P–X) and
Lp(N) ? p*(C=O), where Lp(N) is a lone pair on a
nitrogen atom and X = Cl, have been well known and
reported previously for compounds I and II with an RC(O)
NHP(O)Cl2 (R = CF3 (I), CCl3 (II)) skeleton [37, 38]
(Table 5). To further study this system, we investigated
two other molecules (III and IV) with R = C6H5 and
C6H5NH. As shown in Table 5, such electronic effects are
influenced by the electronic nature of substituent R. The
aim of the present work is to investigate the factors that
affect the intensity of the Lp(N) ? p*(C=O) and
Lp(N) ? r*(P–C) interactions in compounds 1 and 2. The
electronic delocalization Lp(N) ? r*(P–C) is expected to
become more intense on insertion of an NH group between
123

Some new compounds with P(E)NHC(O) (E = lone pair, O, S) linkage
1421
˚
Table 3 Selected bond lengths/A and angles/° for compounds 3 and
5
3
5
˚
Bond lengths/A
P(1)–N(1)
1.7026(13) P(1)–N(1)
1.6529(17)
1.4612(15)
1.5690(15)
1.5793(14)
P(1)–S(1)
1.9232(6)
P(1)–O(1)
P(1)–C(14)
1.7976(15) P(1)–O(3)
1.8080(15) P(1)–O(4)
P(1)–C(8)
Bond angles/°
N(1)–P(1)–C(14)
N(1)–P(1)–C(8)
C(14)–P(1)–C(8)
N(1)–P(1)–S(1)
C(14)–P(1)–S(1)
C(8)–P(1)–S(1)
C(1)–N(1)–P(1)
105.56(7)
101.38(7)
107.29(7)
115.57(5)
115.28(5)
110.57(5)
O(1)–P(1)–O(3)
116.86(8)
115.12(8)
101.77(8)
111.56(9)
102.63(8)
107.64(8)
125.68(14)
O(1)–P(1)–O(4)
O(3)–P(1)–O(4)
O(1)–P(1)–N(1)
O(3)–P(1)–N(1)
O(4)–P(1)–N(1)
Fig. 2 A one-dimensional polymeric chain and pꢀꢀꢀp stacking
interaction in compound 3
122.50(11) C(1)–N(1)–P(1)
C(1)–N(1)–H(1N1) 116.3(15)
P(1)–N(1)–H(1N1) 121.1(15)
C(1)–N(1)–H(1A) 117.2
P(1)–N(1)–H(1A) 117.2
Fig. 3 Centrosymmetric dimer of compound 5, produced by hydro-
gen bonds
clotrimazole were used for comparison. The results are
presented in Table 6. The screening data reveal that
derivative 5 exhibited effective activity against all the
bacterial species, probably owing to antimycobacterial
properties of the PZA group [39]. Additionally, the MIC
values of new compounds against certain microbial strains
indicate that 8 was the most potent compound against S.
aureus at 165 lg/cm3. All the molecules were less active
than gentamicin. The antifungal activity of the compounds
was also studied against two pathogenic fungi. Derivative
5 inhibited the growth of C. albicans at 510 lg/cm3.
Generally, it may be concluded that the structure of the
tested derivatives is the principal factor influencing the
antimicrobial activity, and changing the substituents on
–P(O)(OPh)2 leads to compounds with different antimi-
crobial activity.
Fig. 1 Two independent polymeric chains in compound 2
coupling of the ipso carbon atom of the phenyl ring with
the phosphorus atom in compound 2 (Table 1).
Antimicrobial activity
Molecules 5–8 were screened for in vitro antimicrobial
activities against two Gram negative bacteria (E. coli and
P. aeruginosa), three Gram positive bacteria (B. subtilis,
S. aureus, and S. epidermidis), and two fungi (A. niger
and C. albicans) by using cup-plate agar and microdilu-
tion methods. Known antibiotics like gentamicin and
123

1422
K. Gholivand, N. Dorosti
Table 4 Calculated energy for conformers A and B of compound 2 by HF and DFT methods
Level of theory
Energy/a.u.
Dipole moment/D
Conformer A
Conformer B
Conformer A
Conformer B
B3LYP/6-31?G**
HF/6-31?G**
-1,237.141077
-1,230.921633
-1,237.141077
-1,230.921633
4.9555
5.2450
4.9535
5.2448
Table 5 Delocalization effects and stabilization energies of compounds I–IV, 1, and 2
Compound
Formula
Stabilization energies (kJ/mol)
Lp(Namide) ? p*(C=O)
Lp(Namide) ? r*(P–X)c
Lp(Naniline) ? p*(C=O)
I
CF3C(O)NHP(O)Cl2a,b
217.14
221.76
120.12
133.56
257.46
379.68
42.42
42.42
50.82
55.86
39.48
38.22
–
II
III
IV
1
CCl3C(O)NHP(O)Cl2a,b
C6H5C(O)NHP(O)Cl2
C6H5NHC(O)NHP(O)Cl2
C6H5NHC(O)NHP(C6H5)2
C4N2H3C(O)NHP(C6H5)2
–
–
332.22
318.36
–
2
a
For these compounds, see Refs. [34, 35]
b
c
The values are related to the B3LYP/6-31?G** level
X = Cl (I–IV), C (1, 2)
Experimental
Center as supplementary publication nos. CCDC 742002
(C17H14N3OP), CCDC 786390 (C17H14N3OPS), and
CCDC 742000 (C17H14N3O4P). Copies of the data may be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: ?44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.
ac.uk).
Chlorodiphenylphosphine, diphenyl chlorophosphate, diph-
enylphosphinic chloride, 2-pyrazinecarboxamide, 3-pyridin-
ecarboxamide, 4-pyridinecarboxamide, and N-phenylurea
were used as supplied. All reactions were carried out under
argon atmosphere. 1H, 13C, and 31P NMR spectra were
recorded on a Bruker Avance DRS 500 MHz spectrometer.
1H and 13C chemical shifts were determined relative to TMS,
and 31P chemical shifts relative to 85 % H3PO4 as external
standards. Infrared spectra were obtained byusing KBr pellets
on a Shimadzu IR-60 spectrophotometer. Elemental analysis
wasperformedbyusinga HeraeusCHN-O-RAPIDapparatus.
Melting points were determined on an Electrothermal
apparatus.
Computational methods
All quantum chemical calculations were performed with
the Gaussian 98 [42] system of programs, implemented on
a Pentium 4 computer. The calculations were performed for
molecules in the gaseous phase. The molecular geometries
were optimized by using B3LYP and HF methods with
6-31?G** basis sets. The electronic delocalization was
rationalized by a natural bond orbital (NBO) analysis [43],
using the HF/6-31?G** method of approximation.
X-ray crystal structure analysis
X-ray data were collected on a Bruker SMART 1000 CCD
for compounds 2 and 5 and a Bruker APEX II CCD single-
crystal diffractometer for compound 3 with graphite
Biological evaluation
˚
monochromated Mo Ka radiation (k = 0.71073 A). The
The cup-plate agar method [44] was used to determine the
antibacterial activity of compounds 5–8 against three Gram
positive bacteria, namely Bacillus subtilis (ATCC 6633),
Staphylococcus aureus (ATCC 6538P), and S. epidermidis
(ATCC 12229); two Gram negative bacteria, namely
Escherichia coli (ATCC 35218) and Pseudomonas aeru-
ginosa (ATCC 9027); and two fungi, namely Aspergillus
niger (ATCC 16404) and Candida albicans (ATCC
10218). Base plates were prepared by pouring of
structures were refined with SHELXL-97 [40] by full-
matrix least-squares on F2. The positions of hydrogen
atoms were obtained from the difference Fourier map.
Routine Lorentz and polarization corrections were applied
and an absorption correction was performed for compounds
using the SADABS program [41].
Crystallographic data for the structures 2, 3, and 5 have
been deposited with the Cambridge Crystallographic Data
123

Some new compounds with P(E)NHC(O) (E = lone pair, O, S) linkage
Table 6 Antimicrobial activity of compounds 5–8
1423
Compound
B. subtilis
E. coli
S. aureus
S. epidermidis
GIZa
MICa
GIZ
MIC
GIZ
MIC
GIZ
MIC
5
18
10
11
10
23
–
510
–
–
23
14
12
10
20
–
510
18
11
11
12
20
–
510
4,500
4,500
[5,000
6
6
4,500
4,500
4,400
6.25
–
11
11
12
20
–
4,500
[5,000
[5,000
6.25
–
[5000
[5000
165
7
8
Gentamicin
Clotrimazole
3.12
–
–
Compound
P. aeruginosa
C. albicans
A. niger
GIZ
GIZ
MIC
GIZ
MIC
MIC
5
–
–
11
–
510
–
–
–
6
12
11
13
20
–
4,500
4,500
[5,000
1.5
–
–
7
–
–
–
–
8
11
–
4,400
–
–
–
Gentamicin
Clotrimazole
–
–
–
20
0.3
22
2.4
Error values are within 1 mm; moderately active (8–13), higher active ([14), – not active
a
The values indicate the diameters in mm for the zone of growth inhibition (GIZ) and minimal inhibitory concentration (MIC) in lg/cm3
observed after 24 h of incubation at 35 °C
autoclaved Mueller–Hinton (MH) agar (for bacteria) and
Sabouraud Dextrose agar (for fungi) into sterile petri dishes
and allowing them to settle. The compounds dissolved in
using DMSO were performed. All microdilution experi-
ments were performed in duplicate and repeated three
times.
dimethyl sulfoxide (DMSO) at
a concentration of
7,000 lg/cm3 were used. Then, the solutions of the com-
pound tested were placed on the well of the media
inoculated with the microorganisms. The plates were
incubated at 35 °C and 24 h for the microorganism cul-
tures. After incubation, the growth inhibition zones around
the discs were measured by diameters of inhibition zones
and are shown in Table 6. Gentamicin and clotrimazole
were used as reference antibacterial and antifungal drugs,
respectively. DMSO was used as a solvent control.
Synthesis of derivatives 1 and 2
Derivatives 1 and 2 were prepared according to the liter-
ature procedures [46] (Scheme 1). Then, 0.6 cm3
chlorodiphenylphosphine (3.3 mmol) was added to a
solution of 0.45 g N-phenylurea (3.3 mmol) for 1 and
0.41 g pyrazinamide (3.3 mmol) for 2, 0.35 g triethyl-
amine (3.5 mmol), and 0.04 g 4-dimethylaminopyridine
(DMAP, 0.33 mmol) in 30 cm3 THF and refluxed over-
night. The reaction mixture was filtered to remove a white
solid (Et3NꢀHCl). The solvent was removed in vacuo
leaving white and pale yellow solids, respectively. Com-
pound 2 was crystallized from a mixture of ethanol/heptane
at room temperature.
Also, the minimal inhibitory concentration (MIC) values
for compounds 5–8 defined as the lowest concentration of
the compound preventing the visible growth were deter-
mined by using the microdilution broth method [45]. The
test compounds dissolved in DMSO were first diluted to the
highest concentration (7,000 lg/cm3) to be tested. Then
serial twofold dilutions were prepared in concentration
ranges from 50 to 7,000 lg/cm3 in 10 cm3 sterile tubes. A
prepared suspension of the standard microorganisms was
added to each dilution in a 1:1 ratio. The microorganism
growth (or lack of it) was determined visually after incu-
bation for 24 h at 35 °C. MIC values were studied for the
same microbial strains and are given in Table 6. Genta-
micin and clotrimazole were used as reference antibacterial
and antifungal drugs, respectively. Control experiments
N-Diphenylphosphino-N0-phenylurea (1, C19H17N2OP)
Yield 20 %; m.p.: 225–226 °C; 1H NMR (DMSO-d6):
3
3
d = 6.98 (t, JHH = 7.23 Hz, 1H), 7.24 (t, JHH
7.71 Hz, 2H), 7.33 (d, JHH = 7.99 Hz, 2H), 7.53
=
3
3
(t, JHH = 7.34 Hz, 4H), 7.58 (t, JHH = 7.13 Hz, 2H),
3
3
7.80 (dd, JHH = 7.45 Hz, JPH = 12.34 Hz, 4H), 8.48
3
2
(d, JPH = 10.06 Hz, 1H, NHP), 8.89 (s, 1H, PhNH)
ppm; 13C NMR (DMSO-d6): d = 118.26 (s), 122.57
(s), 128.60 (d, JPC = 12.95 Hz), 128.79 (s), 131.10
3
123

1424
K. Gholivand, N. Dorosti
2
(d, JPC = 10.19 Hz), 131.92 (d, JPC = 2.64 Hz), 132.00
4
(4.8 mmol) was added dropwise to a suspension of the
amide salt in 10 cm3 THF. After 24 h, the precipitate of
NaCl was filtered, and the solvent was removed in vacuum.
Colorless crystals of compound 5 were obtained by slow
evaporation of a dichloromethane/heptane solution.
(d, JPC = 128.92 Hz), 138.68 (s), 152.44 (s) ppm; 31P
1
3
NMR (DMSO-d6): d = 16.75 (d, JPH = 11.11 Hz) ppm;
IR (KBr): m = 3,315 (NH), 3,055, 2,860, 1,685 (C=O),
1,594, 1,543, 1,463, 1,434 (P–Ph), 1,313, 1,179, 1,122,
1,100, 1,077, 1,042, 1,021, 990, 910, 802, 773, 741, 718,
N-(Diphenylphosphinyl)-N0-phenylurea
(4, C19H17N2O2P)
690, 590, 520, 475, 425 cm-1
.
N-(Diphenylphosphino)-2-pyrazinecarboxamide
Yield 30 %; m.p.: 201–202 °C (Ref. [28] 205–206 °C).
(2, C17H14N3OP)
Yield 20 %; m.p.: 132–133 °C; 1H NMR (DMSO-d6):
Diphenyl N-(2-pyrazinylcarbonyl)phosphoramidate
(5, C17H14N3O4P)
3
d = 7.52 (m, JHH = 7.55 Hz,
4
Ar–H), 7.61 (t,
Yield 40 %; m.p.: 110–111 °C; 1H NMR (DMSO-d6):
3JHH = 7.45 Hz, 2 Ar–H), 7.94 (dd, JPH = 13.25 Hz,
3JHH = 7.8 Hz, 4 Ar–H), 8.57 (s, 1 Py–H), 8.83 (d,
3JHH = 2.25 Hz, 1 Py–H), 9.07 (s, 1H, NHP), 9.46 (s, 1
Py–H) ppm;13C NMR (DMSO-d6): d = 128.7 (d,
3JPC = 13.59 Hz), 129.8 (s), 129.9 (s), 130.9 (s), 131.6
3
d = 7.26 (m, 6 Ar–H), 7.42 (m, 4 Ar–H), 8.55 (m, 1 Py–
3
H), 8.83 (d, JHH = 2.4 Hz,
1
Py–H), 9.08 (d,
3
2JPH = 12.65 Hz, 1H, NHP), 9.46 (d, JHH) = 1.3 Hz, 1
Py–H) ppm; 13C NMR (DMSO-d6): d = 119.9 (d,
3JPC = 4.70 Hz), 125.2 (s), 129.3 (s), 141.8 (d,
3JPC = 10.49 Hz), 142.2 (s), 144.4 (s), 148.1 (s), 149.5
(d, 2JPC = 6.92 Hz), 162.9 (s) ppm; 31P NMR (DMSO-d6):
d = -12.04 (b) ppm; IR (KBr): m = 3,230 (N–H), 1,712
(C=O), 1,585, 1,481, 1,448, 1,387, 1,284, 1,210, 1,188
(P=O), 1,154, 1,103, 1,062, 1,019, 989, 877, 768, 687, 583,
2
(s), 131.7 (s), 131.8 (s), 132.8 (d, JPC = 2.64 Hz), 142.7
3
(s), 142.9 (d, JPC = 5.63 Hz), 144.9 (d, JPC
1
=
439.19 Hz), 144.1 (s), 144.8 (s), 147.6 (s), 166.6 (s) ppm;
31P NMR (DMSO-d6): d = 22.46 (b) ppm; IR (KBr):
m = 3,300 (NH), 1,665 (C=O), 1,469, 1,447 (P–Ph), 1,386,
1,167, 1,128, 1,094, 1,016, 864, 805, 742, 692, 630, 506,
502, 431 cm-1
.
428 cm-1
.
Diphenyl N-(3-pyridinylcarbonyl)phosphoramidate
(6, C18H15N2O4P)
N-(Diphenylphosphinothioyl)-2-pyrazinecarboxamide
(3, C17H14N3OPS)
Yield 40 %; m.p.: 100–101 °C; 1H NMR (DMSO-d6):
3
3
Sulfur (1.5 mmol, 0.05 g) was added to a solution of 0.46 g
diphenylphosphino-2-pyrazinecarboxamide (1.5 mmol) in
20 cm3 toluene and refluxed overnight. The solvent was
removed in vacuo leaving a solid. This solid was crystal-
lized from a hot toluene solution. Yield 15 %; m.p.:
149–150 °C; 1H NMR (DMSO-d6): d = 7.54 (td,
d = 7.16 (t, JHH = 7.8 Hz, 4H), 7.35 (t, JHH = 8.0 Hz,
2H), 7.90 (s, 1H), 8.11 (d, 3JHH = 5.6 Hz, 4H), 8.60 (s, 1H,
NHP), 8.90 (d, JHH = 6.2 Hz, 3H) ppm; 13C NMR
3
3
(DMSO-d6): d = 112.5 (s), 119.6 (d, JPC = 5.09 Hz),
123.4 (s), 124.3 (s), 129.6 (s), 145.5 (s), 145.9 (s), 164.8 (s)
ppm; 31P NMR (DMSO-d6): d = -12.04 (s) ppm; IR
(KBr): m = 3,245 (N–H), 3,110, 1,711 (C=O), 1,688,
1,591, 1,487, 1,257, 1,206, 1,168 (P=O), 1,095, 991, 903,
4
3
3JHH = 7.55 Hz, JPH = 3.5 Hz, 4 Ar–H), 7.61 (t, JHH
=
7.15 Hz,
2
Ar–H), 7.94 (dd, 3JPH = 14.30 Hz,
3JHH = 7.5 Hz, 4 Ar–H), 8.80 (d, JHH = 2.1 Hz, 1 Py–
3
770, 532 cm-1
.
3
H), 8.95 (d, JHH = 2.3 Hz, 1 Py–H), 9.16 (s, 1 Py–H),
9.84 (s, 1H, NHP) ppm; 13C NMR (DMSO-d6): d = 128.5
(d, JPC = 13.57 Hz), 131.1 (d, JPC = 11.80 Hz), 131.7
Diphenyl N-(4-pyridinylcarbonyl)phosphoramidate
(7, C18H15N2O4P)
3
2
Yield 30 %; m.p.: 104–106 °C; 1H NMR (DMSO-d6):
1
(d, JPC = 103.85 Hz), 132.0 (s), 143.5 (s), 143.8 (s),
d = 7.17 (d, 3JHH = 8.35 Hz,
4
Ar–H), 7.35
148.5 (s), 165.2 (s) ppm; 31P NMR (DMSO-d6): d = 51.54
(b) ppm; IR (KBr): m = 3,435 (NH), 3,195, 1,689 (C=O),
1,463, 1,431 (P–Ph), 1,376, 1,221, 1,100, 1,044, 1,018,
3
(t,3JHH = 7.75 Hz, 4 Ar–H), 7.58 (t, JHH = 2.7 Hz, 2
3
Ar–H), 8.31 (d, JHH = 7.6 Hz, 2 Py–H), 8.80 (d,
3JHH = 4.6 Hz, 2 Py–H), 9.08 (s, 1H, NHP) ppm; 13C
825, 746, 720, 680, 637, 498, 405 cm-1
.
3
NMR (DMSO-d6): d = 119.9 (d, JPC = 4.83 Hz), 124.2
(s), 126.8 (s), 129.6 (s), 137.5 (s), 149.7 (s), 151.2 (d,
2JPC = 6.94 Hz), 152.7 (s), 160.9 (s) ppm; 31P NMR
(DMSO-d6): d = -12.08 (s) ppm; IR (KBr): m = 3,155
(N–H), 1,719 (C=O), 1,599, 1,526, 1,486, 1,407, 1,287,
General procedure for the synthesis of derivatives 4–8
Compounds 4–8 were prepared by two processes
(Scheme 2). For the first step, 0.27 g NaH (7.2 mmol) was
added to a suspension of the amide (4.8 mmol) in 25 cm3
toluene . The mixture was refluxed for 4 h. The amide salt
was filtered and dried. Afterward, diphenylphosphinic
1,213, 1,179 (P=O), 1,020, 907, 771, 665, 531 cm-1
.
Diphenyl N-(phenylaminocarbonyl)phosphoramidate
(8, C19H17N2O4P)
Yield 20 %; m.p.: 155–156 °C (Ref. [29] 155–156 °C).
chloride for
4 or diphenylchlorophosphate for 5–8
123

Some new compounds with P(E)NHC(O) (E = lone pair, O, S) linkage
1425
Acknowledgments The financial support of this work by the
Research Council of Tarbiat Modares University is gratefully
acknowledged.
24. Victor AT, Katerina EG, Vladimir MA, Jolanta SK, Konstantin
VD (2005) Polyhedron 24:1007
25. Xu K, Angell C (2000) Inorg Chim Acta 298:16
26. Amirkhanov VM, Trush VA (1995) Zh Obshch Khim 65:1120
27. Makarov MV, Leonova ES, Rybalkina EY, Tongwa P, Khrusta-
lev VN, Timofeeva TV, Odinets IL (2010) Eur J Med Chem
45:992
References
28. Baulina TV, Goryunova IB, Petrovskii PV, Matrosov EI, Go-
ryunov EI, Nifant’ev EE (2006) Dokl Chem 409:129
29. Kirsanov AV, Zhmurova IN (1957) Zh Obshch Khim 27:1002
30. Gholivand K, Shariatinia Z, Pourayoubi M (2006) Polyhedron
25:711
31. Gholivand K, Shariatinia Z, Mashhadi SM, Daeepour F, Far-
shidnasab N, Mahzouni HR, Taheri N, Amiri Sh, Ansar Sh (2009)
Polyhedron 28:307
32. Cogridge DEC (1995) Phosphorus, an outline of its chemistry,
biochemistry, and technology, 5th edn. Elsevier, Amsterdam
33. Ziemer B, Rabis A, Steinberger HU (2000) Acta Crystallogr Sect
C 56:58
34. Chekhlov AN (2002) J Struct Chem 43:364
35. Gholivand K, Dorosti N (2011) Monatsh Chem 142:183
36. Gholivand K, Shariatinia Z, Afshar F, Faramarzpour H, Ya-
ghmaian F (2007) Main Group Chem 6:231
1. Milton HL, Wheatly MV, Slawin AMZ, Woollins JD (2004)
Polyhedron 23:2575
2. Gholivand K, Dorosti N, Shariatinia Z, Ghaziany F, Sarikhani S,
Mirshahi M (2011) Med Chem Res 20:1287
3. Gholivand K, Madani Alizadehgan A, Mojahed F, Dehghan G,
Mohammadirad A, Abdollahi M (2008) Z Naturforsch 63C:241
4. Gholivand K, Mostaanzadeh H, Koval T, Dusek M, Erben MF,
Stoeckli-Evansd H, Della Vedova CO (2010) Acta Crystallogr
Sect 66:441
5. Mazzini S, Monderelli R, Ragg E, Scaglioni L (1995) J Chem Soc
Perkins Trans 2:285
6. Olsen RA, Liu L, Ghaderi N, Johns A, Hatcher ME, Mueller LJ
(2003) J Am Chem Soc 125:10125
7. Kang S-K, Lee J-H, Lee Y-C, Kim C-H (2006) Biochim Biophys
Acta 1760:724
8. Velcheva EA, Daskalova LI (2005) J Mol Struct 741:85
9. Deady LW, Rogers ML, Zhuang L, Baguleyb BC, Denny WA
(2005) Bioorg Med Chem 13:1341
10. Akyuz S, Andreeva L, Minceva-Sukarova B, Basar G (2007) J
Mol Struct 399:834
´
11. Miotti RD, Maia AS, Paulino IS, Schuchardt U, Oliverira W
(2002) J Alloys Compd 344:92
12. Remko M (2009) J Mol Struct (Theochem) 897:73
13. Dimitrova Y, Daskalova LI (2009) Spectrochim Acta A 71:1720
14. Kim YJ, Ryu JH, Cheon YJ, Lim HJ, Jeon R (2007) Bioorg Med
Chem Lett 17:3317
´
37. Iriarte AG, Erben MF, Gholivand K, Jios JL, Ulic SE, Vedova
COD (2008) J Mol Struct 886:66
38. Iriarte AG, Cutin EH, Erben MF, Ulic SE, Jios JL, Vedova COD
(2008) Vib Spectrosc 46:107
39. Kushner S, Dalalian H, Sanjurjo JL, Bach FL, Safir SR, Smith
VK, Williams JH (1952) J Am Chem Soc 74:3617
40. Sheldrick GM (1998) SHELXTL V.5.10, structure determination
software suite. Bruker AXS, Madison, WI
41. Sheldrick GM (1998) SADABS V.2.01, Bruker/Siemens area
detector absorption correction program. Bruker AXS, Madison,
WI
´
´
´
´
´
15. Garcıa-Bueno R, Santana MD, Sanchez G, Garcıa J, Garcıa G,
42. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Zakrzewsky VG, Montgomery JA Jr, Stratman
RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN,
Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R,
Menucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Pet-
ersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck
AD, Raghavachari K, Foresman JB, Cioslovski J, Ortiz JV, Ba-
boul AG, Stefanov BB, Liu G, Liashenko A, Piskorz P,
Komaromi I, Gomperts R, Martin RI, Fox DJ, Keith T, Al-Laham
MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW,
Johnson B, Chen W, Wong MW, Andres JL, Gonzales C, Head-
Gordon M, Replogle ES, Pople JA (1998) Gaussian revision A.6.
Gaussian, Pittsburgh
´
´
Perez J, Garcıa L (2009) J Organomet Chem 694:316
16. Safin DA, Babashkina MG, Bolte M, Klein A (2010) Inorg Chim
Acta 363:1791
17. Gholivand K, Oroujzadeh N, Afshar F (2010) J Organomet Chem
695:1383
18. Gholivand K, Afshar F, Shariatinia Z, Zare K (2010) Struct Chem
21:629
19. Sokolov FD, Safin DA, Zabirov NG, Brusko VV, Khairudinov
BI, Krivolapov DB, Litvinov IA (2006) Eur J Inorg Chem
10:2027
20. Breuer E, Schlossman A, Safadi M, Gibson D, Chorev M, Leader
H (1990) J Chem Soc Perkin Trans 1:3263
21. Miton HL, Wheatly MV, Slawin AMZ, Woollins JD (2004)
Polyhedron 23:2575
43. Reed AE, Curtiss LA, Weinhold F (1988) Chem Rev 88:899
44. Barry AL (1977) Bio Abstr 64:25183
22. Ly TQ, Slawin AMZ, Woollins JD (1999) Polyhedron 18:1761
23. Bhattacharyya P, Ly TQ, Slawin AMZ, Woollins JD (2001)
Polyhedron 20:1803
45. Vincent JG, Vincent HW (1994) Proc Soc Exp Biol Med 55:162
46. Ly TQ, Woollins JD (1998) Coord Chem Rev 176:451
123