Detailed studies of the interaction of 3-chloroaniline with O,O′-diphenylphosphorylisothiocyanate

Article abstract of DOI:10.1039/c5nj02588e

The reaction of neat 3-chloroaniline with neat SCN-P(O)(OPh)₂ leads to a new N-phosphorylated thiourea, 3-ClC₆H₄NHC(S)NHP(O)(OPh)₂ (1). The same reaction in non-dried CH₂Cl₂ or C₆H₆ leads to the salt-like compounds [3-ClC₆H₄NH₃]⁺[NCS]^- (2) and [3-ClC₆H₄NH₃]⁺[P(O)₂(OPh)₂]^-·0.5C₆H₆ (3·0.5C₆H₆), respectively, while using non-dried acetone yields 1-(3-chlorophenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione (4). Dissolution of 1 in non-dried CH₂Cl₂, C₆H₆ or Me₂CO leads to the direct formation of 2, 3·0.5C₆H₆ and 4, respectively. It was established that thione 4 is most likely formed through the thiourea 1-assisted aldol condensation of acetone leading to mesityl oxide. In turn the latter ketone interacts with 1 followed by its hydrolysis leading to 4. Compounds 1-4 have been characterized by NMR spectroscopy and elemental analysis and their molecular structures were elucidated by X-ray diffraction. Hirshfeld surface analysis showed that the structures of both 1 and 4 are mainly characterized by H?H, H?C, H?Cl and H?S contacts as well as by H?O in the structure of 1. The enrichment ratio, derived as the decomposition of the crystal contact surface between pairs of interacting chemical species, for 1 was found, as expected for the polar contacts, which are generally hydrogen bonds, to be significantly larger than unity for the contacts of the type H?O and H?S. A much larger than unity value was found for the enrichment ratio of the C?C contacts in the structure of 1, which is due to extensive π?π stacking in the crystal packing. The enrichment ratio for 4 was found to be larger than unity for the contacts of the type H?C and, but with a lesser degree, H?Cl and H?S.

Full text of DOI:10.1039/c5nj02588e

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Detailed studies of interaction of 3-chloroaniline with O,O'-
diphenylphosphorylisothiocyanate
Received 00th January 20xx,
Accepted 00th January 20xx
Maria G. Babashkina,* Koen Robeyns, Yaroslav Filinchuk and Damir A. Safin
DOI: 10.1039/x0xx00000x
2
The reaction of neat 3-chloroaniline with neat S=C=N–P(O)(OPh) leads to new N-phosphorylated thiourea, 3-
ClC
ClC
6
6
H
4
NHC(S)NHP(O)(OPh)
2
(1). The same reaction in non-dried CH
2
Cl
2
or C
), respectively, while using non-dried acetone
Cl , C
and 4, respectively. It was established that thione 4 is most likely
6 6
H leads to the salt-like compounds [3-
www.rsc.org/
+
–
+
–
H
4
NH
3
] [NCS] (2) and [3-ClC
6
H
4
NH
3
] [P(O)
2
(OPh)
2
] ∙0.5C
6
H
6
(3∙0.5C
6
H
6
yields 1-(3-chlorophenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione (4). Dissolution of 1 in non-dried CH
2
2
6 6
H
or Me C=O leads to the direct formation of 2, 3∙0.5C
2
6
H
6
formed through the thiourea 1-assisted aldol condensation of acetone leading to mesityl oxide. In turn the latter ketone
interacts with 1 followed by its hydrolysis leading to 4. Compounds 1–4 have been characterized by NMR spectroscopy and
elemental analysis and their molecular structures were elucidated by X-ray diffraction. Hirshfeld surface analysis showed
that the structures of both 1 and 4 are mainly characterized by H∙∙∙H, H∙∙∙C, H∙∙∙Cl and H∙∙∙S contacts as well as by H∙∙∙O in
the structure of 1. The enrichment ratio, derived as the decomposition of the crystal contact surface between pairs of
interacting chemical species, for 1 was found, as expected for the polar contacts, which are generally hydrogen bonds, to
be significantly larger than unity for the contacts of the type H∙∙∙O and H∙∙∙S. A much more larger than unity value was
found for the enrichment ratio of the C∙∙∙C contacts in the structure of 1, which is due to extensive π∙∙∙π stacking in the
crystal packing. The enrichment ratio for 4 was found to be larger than unity for the contacts of the type H∙∙∙C and, but
with a lesser degree, H∙∙∙Cl and H∙∙∙S.
Nothing similar was observed for OiPr-containing NTTUs.
On the other hand, multicomponent reactions are of ever
increasing interest and importance in chemistry for the
Introduction
We have extensively studied the synthesis, membrane
transport, extraction, separation and complexation properties
2
production of, e.g., organic and medicinal products of value.
1
of N-(thio)phosphorylated thioureas R R NC(S)NHP(X)(OR )
2
3
The main advantage of multicomponent reactions over
conventional ones is that three or more components act
together in a single reaction allowing to avoid possible time
consuming processes. This becomes even more crucial for drug
2
1
2
NTTUs) (R , R = H, alkyl, aryl; R = iPr, Ph; X = O, S), which are
3
(
readily obtained by reacting primary or secondary amines with
the corresponding N-(thio)phosphorylated isothiocyanate
3
1
1
2
Scheme 1). The crucial influence of the R R N function has
discovery. Moreover, the synthetic strategy based on
(
multicomponent reactions allows to vary and tune the
structure of the target product in a broad range. For example,
been established for the behavior of thioureas in solution as
well as their complexation properties. On the other hand, an
overwhelming majority of the reported NTTUs contains the
OiPr functions at the phosphoryl group, while only two
the Biginelli dihydropyrimidine synthesis, the so-called
4
Biginelli condensation”, is a one-pot three component
“
1
t,x
reaction, which is
a
powerful tool to produce
examples, RNHC(S)NHP(O)(OPh)
reported for the OPh-containing derivatives. Notably, it was
found that recrystallization of iPrNHC(S)NHP(O)(OPh) from
aqueous Me C=O leads to the formation of the salt-like
compound [iPrNH
2
(R
=
iPr, Ph),
were
5
dihydropyrimidine-2-thiones. This is a relatively novel class of
compounds, which is of great importance due to its
2
6
pharmacological activities such as antibacterial, antitumour,
7
2
8
antioxidative, analgesic and anti-inflammatory properties.
5,9
+
– 1t
3
2 2
] [P(O) (OPh) ] . This is most likely due to a
Furthermore, dihydropyrimidine-2-thiones were found to be
efficient antihypertensive agents as well as calcium channel
strong influence of the electron withdrawing OPh groups at
the P=O group leading to the weakening of the P–N bond.
1
0
blockers and neuropeptide Y antagonists.
Institute of Condensed Matter and Nanosciences, Université catholique de Louvain,
R3
R1
R3
H
N
Place
maria.babashkina@gmail.com
Electronic supplementary information (ESI) available: Crystallographic data
including CIF files), selected bond distances and angles, hydrogen bonds and π∙∙∙ π
L.
Pasteur
1,
1348
Louvain-la-Neuve,
Belgium.
E-mail:
R
1
O
N
O
3
2
3
NH
+
S
C
N
P
R
R
P
R
†
(
R2
O
O
X
S
X
stacking interactions. See DOI: 10.1039/x0xx00000x
1
2
3
1
Scheme 1. Synthesis of NTTUs (R , R = H, alkyl, aryl; R = iPr, Ph; X = O, S).
This journal is © The Royal Society of Chemistry 20xx
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In continuation of our comprehensive studies of the NTTU and 3∙0.5C
Journal Name
6
H
6
are shown as a broad singlet at about 8.15 ppm.
1
ligands, we have directed our attention to new N- The H NMR spectrum of
phosphorylated thiourea 3-ClC NHC(S)NHP(O)(OPh) ), 1.39 and 1.54 ppm, respectively, for the CH
containing OPh functions at the phosphoryl group as well as CH proton of the dihydropyrimidine ring was found as a
4
exhibits a singlet and a doublet at
6
H
4
2
(
1
3
protons, while the
functionalised arylamine fragment at the thiocarbonyl group. quartet at 5.00 ppm. Additionally, the spectrum of
Herein, we report the detailed studies on the solvent- contains a broad singlet at 7.90 ppm for the NH proton.
4 also
influenced interaction of 3-chloroaniline with N-
We have further used NMR spectroscopy to study
interaction of with CD Cl , C and acetone-d , each
containing few drops of D O. It was found that the P{ H}
NMR spectra of in the former two solvents contain a singlet
2
at about –11.4 ppm, characteristic for the [P(O) (OPh) ] anion.
phosphorylated isothiocyanate S=C=N–P(O)(OPh)
2
.
1
2
2
6
D
6
6
3
1
1
2
1
–
Results and discussion
2
This singlet appears after about 3 h and its intensity gradually
increases over the next 2–3 days accompanied by the decrease
Synthesis
The reaction of neat 3-chloroaniline with neat S=C=N–
31
1
of the P{ H} NMR signal of
process is also accompanied by the appearance of a broad
singlet at about 8.05 ppm, characteristic for the NH protons.
Thus, the thiourea exhibits the same decomposition pathway
both in CD Cl and C . However, the former solvent is
favorable for crystallization of the [NCS] anion-containing
derivative , while the latter solvent supports the formation of
the [P(O) (OPh)
1 till it completely disappears. This
P(O)(OPh)
2
leads to new N-phosphorylated thiourea
1
(Scheme
6 6
or C H
2). Surprisingly, the same reaction in non-dried CH
2
Cl
2
3
at ambient conditions leads to the salt-like compounds [3-
1
+
–
+
–
ClC
0.5C
acetone
6
H
4
NH
3
] [NCS]
3∙0.5C
yields
(
2)
6 4 3 2 2
and [3-ClC H NH ] [P(O) (OPh) ]
2
2
6 6
D
∙
6
H
6
(
6
H
6
), respectively, while using non-dried
1-(3-chlorophenyl)-4,4,6-trimethyl-3,4-
–
2
dihydropyrimidine-2(1H)-thione (
4
) (Scheme 2). It was also
, with an initial aim of
, C or Me C=O at ambient
–
2
2
] anion-containing compound 3, probably due
established that dissolution of
1
to efficient co-crystallization with the solvent molecules.
Much more complex results are observed upon dissolution
crystallization, in non-dried CH
2
Cl
2
6
H
6
2
1
conditions leads to the direct formation of
respectively (Scheme 2).
2,
3∙0.5C
6
H
6
and
4,
31
1
6
in acetone-d . Immediately after dissolution, the P{ H} NMR
spectrum contains a singlet corresponding to the starting
thiourea and a singlet at –7.9 ppm, most likely corresponding
to the thiourea species with the pronounced negative charge
formation on the phosphorylamide nitrogen atom. This is,
probably, due strong hydrogen bonding between the NHP
hydrogen atom and the oxygen atom of the solvent, which is
further supported by the relatively strong acidic nature of the
H
N
H
Et
2
O
Cl
N
O
O
P
S
1
O
11
NHP proton
arylNHC(S) and P(O)(OPh)
NMR spectrum of the completely deprotonated thiourea
induced by strong electron withdrawing
CH
2
Cl
2
CH
2
Cl
2
3
1
1
Cl
NH
2
[N
C
S]
2
groups. Furthermore, the P{ H}
Cl
Cl
NH
3
+
1,
2
which was obtained as its potassium salt K[3-
ClC H NHC(S)NP(O)(OPh) ] by reacting with KOH, contains a
C
6
H
6
C
H
6 6
6
4
2
O
O
O
O
O
S
C
N
P
NH
3
P
singlet at –6.8 ppm, also indicating a low-field shift of the
O
O
phosphorus signal upon deprotonation. After few hours a third
–
] anion, appears.
3
4
Me
singlet, characteristic for the [P(O)
2
(OPh)
2
Me
2
C
O
Me
Me
Me
2
C
O
The intensity of the thiourea signal gradually decreases, while
the intensity of the signal at –7.9 ppm increases and then
decreases with the constantly increasing signal of the
N
S
N
H
Cl
–
]
31
1
[
P(O)
2
(OPh)
2
anion. Finally, the P{ H} NMR spectrum
contains a unique singlet of the phosphate anion.
1
As it was mentioned above, the H NMR spectrum of freshly
Scheme 2. Synthesis of 1–4.
NMR spectroscopy
6
dissolved 1 in acetone-d exhibits four broad singlets at 10.97,
3
1
1
12.24, 13.72 and 13.91 ppm, with the former two peaks
corresponding to the NHP protons, while the latter two is due
to the arylNH protons. The signals at 10.97 and 13.72
correspond to the PNH and arylNH protons, respectively, of
the same major species, while the remaining two signals are
due to the corresponding NH protons of the other minor
species. This was supported by the ratio of their integral
intensities. It should be noted, that all signals of the NH
protons are significantly low field shifted due to strong
hydrogen bonding with the solvent molecules. After few hours
the NH signals, corresponding to the major species, decrease,
The P{ H} NMR signal of freshly dissolved
in acetone-d
respectively. The former signal is in the area characteristics for
1
and 3∙0.5C
6
H
6
6
appears as a singlet at –10.5 and –11.7 ppm,
1
t,x
1
2
the neutral RNHC(S)NHP(O)(OPh) (R = iPr, Ph). The H NMR
spectra of 1–4 in the same solvent each contain a multiplet
1
signal for the aryl protons at 6.90–7.81 ppm. The H NMR
spectrum of
3.72 and 13.91 ppm, with the former two peaks
corresponding to the NHP protons, while the latter two are
due to the arylNH protons. The NH protons in the spectra of
1 also contains four broad singlets at 10.97, 12.24,
1
3
2
2
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while the signals for the minor species increase and then chemical shift of the latter peak is characteristic for the NH
gradually decrease. Finally, all these singlets completely proton of
disappear and a new broad singlet at 7.96 appears. The
4.
O
O
H
N
O
H
N
H
N
H
N
H
N
H
N
H
N
H
N
2
Me C
O
- H
Cl
O
O
Cl
O
O
Cl
O
O
Cl
O
O
P
P
P
P
S
O
S
O
S
O
S
O
H
2
Me C O
H
O
2
H O
O
O
H
N
O
H
N
H
O
H
N
O
H
N
H
N
H
N
H
N
H
N
Cl
O
O
Cl
O
O
Cl
O
O
Cl
O
O
P
- H
2
O
P
P
P
S
O
S
O
S
O
S
O
O
H
N
Me
Me
N
Me
Me
OH /H O
Me
Me
2
Cl
N
H
O
O
Cl
N
N
H
O
P
P
- [P(O) (OPh) ]
2
2
N
O
S
O
S
O
H
S
Cl
Scheme 3. Probable mechanism of the reaction of 1 with acetone.
Thus, the signal for the NHP proton, being also acidic, formed between the corresponding aromatic rings of adjacent
exhibits a pronounced low field shift upon involving in molecules.
hydrogen bonding with acetone-d . We can tentatively
6
suggest, that acetone undergoes the aldol condensation,
which is catalyzed by the acidic NHP proton of
formation of mesityl oxide. The latter product further reacts
with yielding , accompanied by the hydrolysis of the starting
1, with the
1
4
thiourea within the N–P bond (Scheme 3). This hypothesis
requires additional in-depth studies, which are currently under
progress. However, it was also established that dissolution of
1
in mesityl oxide also leads to the formation of 4.
Fig. 1 View on the hydrogen bonded 1D chain in the structure of 1
(hydrogen atoms not involved in H-bonding and disordered phenyl rings are
omitted for clarity). Color code: C = black, H = light grey, Cl = green, N = blue,
O = red, P = violet, S = orange.
Crystal structures
According to X-ray data,
1 and 2, measured at 150(2) K, and
4, measured at 297(2) K, crystallize in the monoclinic P2 /c
1
space group, while 3∙0.5C H6, measured at 297(2) K, crystallize
6
in the triclinic P–1 space group, respectively. One of the phenyl
rings in the structure of
a 64% to 36% ratio.
1 is disordered over two positions with
The parameters of the C=S, C–N, P–N and P=O bonds
observed for are in the typical range for NTTUs (Table S1 in
the ESI†). The S=C–N–P=O backbone in the crystal phase have
a cis conformation (Fig. 1). The crystal structure of is
1
1
1
stabilized by intermolecular bifurcated hydrogen bonds of the
arylN–H∙∙∙O=P and PN–H∙∙∙O=P types (Fig. 1 and Table S5 in the
ESI†). As a result of these hydrogen bonds, 1D polymeric
Fig. 2 View on the hydrogen bonded 1D chain in the structure of 2
(hydrogen atoms not involved in H-bonding are omitted for clarity). Color
code: C = black, H = light grey, Cl = green, N = blue, S = orange.
chains are formed (Fig. 1). The structure of
1 is further
stabilized by intermolecular π∙∙∙π stacking interactions with an
interplanar separation of about 3.7 Å (Table S6 in the ESI†),
+
The structure of
2 comprises the [3-ClC H NH ] cations and
6 4 3
–
NCS] anions (Fig. 2). The thiocyanate anion is essentially
[
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planar with the S–C–N angle being about 179°, and the C=N in the ESI†). The crystal packing of
and C=S bond lengths close to double bonds (Table S2 in the centrosymmetric dimers connected by N–H∙∙∙S hydrogen
ESI†). Molecules of form 1D polymeric chains, which are bonds (Fig. 4, Table S5 in the ESI†).
constructed due to a net of intermolecular hydrogen bonds
between the hydrogen atoms of the NH group of the cation,
4 is characterized by
2
3
Hirshfeld surface analysis
and the N and S atoms, corresponding to three neighbouring
anions (Fig. 2 and Table S5 in the ESI†). As a result of H-bonds,
ten-membered heterocycles are formed (Fig. 2).
In order to examine the interactions in the crystal structures
1
2
of
fingerprint plots were obtained using CrystalExplorer 3.1.
According to the Hirshfeld surface analysis, for and 4 the
1 and 4, the Hirshfeld surface analysis and the 2D
1
3
14
1
intermolecular H∙∙∙H contacts, comprising 43.0 and 51.4% of
the total number of contacts respectively, are major
contributors to the crystal packing (Fig. 5, Table 1). The
shortest H∙∙∙H contacts are shown in the fingerprint plots of
and as characteristic spikes at d + d ≈ 1.7 and 2.6 Å,
respectively (Fig. 5). Furthermore, a subtle feature is evident in
the fingerprint plot of and it was also significantly less visible
in the corresponding plot of . In each of these cases there is a
splitting of the short H∙∙∙H fingerprint. This splitting occurs
hydrogen atoms not involved in H-bonding and benzene molecules are when the shortest contact is between three atoms, rather than
1
4
e
i
1
4
6 6
Fig. 3 View on the hydrogen bonded 1D chain in the structure of 3∙0.5(C H )
(
1
3
omitted for clarity). Color code: C = black, H = light grey, Cl = green, N = blue, for a direct two-atom contact.
O = red, P = violet, S = orange.
The crystal structure of 3∙0.5C
6 6
H was found to be a co-
+
–
crystallization product of [3-ClC
6
H
4
NH
benzene. The P–OPh and P O bond lengths in the structure of
∙0.5C indicate a single and intermediate between single
and double bonds, respectively (Table S3 in the ESI†).
Molecules of 3∙0.5C form 1D polymeric chains, which are
constructed due to a net of intermolecular hydrogen bonds
between the hydrogen atoms of the NH group of the cation
and the P O oxygen atoms, corresponding to three
3
] [P(O)
2
(OPh)
2
]
and
∙
∙∙
3
6 6
H
6 6
H
3
∙
∙∙
neighbouring anions (Fig. 3 and Table S5 in the ESI†). As a Fig. 5 2D fingerprint plots of observed contacts for 1 and 4.
result of H-bonds, eight- and twelve-membered heterocycles
6 6
are formed (Fig. 3). The structure of 3∙0.5C H is additionally
stabilized by intermolecular π∙∙∙π stacking interactions with an
The structures of 1 and 4 are also dominated by C∙∙∙H
interplanar separation of about 3.8 Å (Table S6 in the ESI†).
contacts, comprising 19.3 and 14.2%, respectively, of the total
Hirshfeld surface areas (Table 1). These contacts in both
fingerprint plots are shown in the form of clearly pronounced
“
wings” with the shortest d
recognized as characteristic of a C–H∙∙∙π interaction. It is
worth adding that the fingerprint plot of exhibits a significant
number of points at large d and d , shown as tails at the top
e i
+ d ≈ 2.7 Å (Fig. 5), which are
1
3
1
e
i
right of the plot (Fig. 5). These points, similar to those
13
Fig. 4 View on the hydrogen bonded dimer in the structure of 4 (hydrogen
atoms not involved in H-bonding are omitted for clarity). Color code: C =
black, H = light grey, Cl = green, N = blue, S = orange.
observed in the fingerprint plot of benzene and phenyl-
15
containing compounds,
correspond to regions on the
Hirshfeld surface without any close contacts to nuclei in
adjacent molecules.
The structure of
proportion of H∙∙∙Cl and H∙∙∙S contacts, comprising 16.3 and
4.8%, respectively, while a lower proportion (8.8 and 8.5%,
respectively) of the same contacts were found in the structure
of (Table 1). The structure of exhibits also a pronounced
4 is further characterized by a significant
The dihydropyrimidine ring of
4 is in an envelope
conformation and is essentially planar with maximum
deviation of 0.115 (4) Å for the carbon atom bearing two
methyl substituents (Fig. 4). The C=S bond length indicate a
double bond (Table S4 in the ESI†). The two six-membered
1
1
1
amount of H∙∙∙O contacts, comprising 11.6% of the total
Hirshfeld surface area (Table 1). The shortest H∙∙∙O and H∙∙∙S
rings in the structure of
4 are almost orthogonal that is
reflected in the corresponding torsion angles (Fig. 4, Table S4
contacts in the fingerprint plots of
1 and 4 are shown as a pair
4
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of sharp spikes at d
e
+ d
i
≈ 1.8 and 2.5 Å, respectively (Fig. 5). 3.8% (Table 1). They are shown on the fingerplot as the area of
= d ≈ 1.8–1.9 Å (Fig. 5).
in the ESI†) and N–H∙∙∙S (Fig. 4 and Table S5 in the ESI†) These contacts correspond to the presence of π∙∙∙π stacking
hydrogen bonds, respectively. The structure of is further interactions in the crystal structure of (Table S6 in the ESI†).
characterized by a proportion of C∙∙∙C contacts, comprising
These contacts correspond to the N–H∙∙∙O (Fig. 1 and Table S5 pale blue color on the diagonal at d
e
i
1
1
Table 1 Hirshfeld contact surfaces and derived “random contacts” and “enrichment ratios” for 1 and 4. Values in italics at the top of the table are the data
obtained from CrystalExplorer 3.1. The enrichment ratios were not computed when the “random contacts” were lower than 0.9%, as they are not
1
4
meaningful. The disordered part in the structure of 1 is omitted for clarity; however, its contribution is negligible.
1
4
H
C
N
Cl
O
P
S
H
C
N
Cl
S
Contacts (C, %)
H
43.0
19.3
0.2
–
–
–
–
–
–
51.4
14.2
1.0
16.3
/
–
–
–
–
C
3.8
0.1
1.9
0.4
0.0
0.0
–
–
–
–
–
0.0
0.0
0.0
/
–
–
–
N
0.0
1.2
0.0
0.0
0.0
–
–
–
–
0.0
0.0
/
–
–
Cl
8.8
0.0
0.7
0.0
0.4
–
–
–
0.2
/
–
O
11.6
0.0
0.1
0.0
0.0
–
–
/
P
0.0
0.0
–
/
/
/
/
/
S
8.5
0.0
14.8
0.0
0.0
2.2
0.0
Surface (S, %)
6
7.2
14.7
0.8
6.5
6.5
0.0.
4.3
74.6
7.1
0.5
9.5
8.5
Random contacts (R, %)
H
45.2
19.8
1.1
–
–
–
–
–
–
55.7
10.6
0.7
14.2
/
–
–
–
–
C
2.2
0.2
1.9
1.9
0.0
1.3
–
–
–
–
–
0.5
0.1
1.3
/
–
–
–
N
0.0
0.1
0.1
0.0
0.1
–
–
–
–
0.0
0.1
/
–
–
Cl
8.7
0.4
0.8
0.0
0.6
–
–
–
0.9
/
–
O
8.7
0.4
0.0
0.6
–
–
/
P
0.0
0.0
0.0
–
/
/
/
/
/
S
5.8
0.2
12.7
1.2
0.1
0.8
0.7
Enrichment (E)
H
C
0.95
0.97
0.18
1.01
1.33
/
–
–
–
/
/
/
/
/
–
–
–
/
–
–
–
–
/
–
–
–
–
–
/
–
–
–
–
–
–
/
0.92
1.34
/
–
–
–
/
/
/
/
/
–
–
–
–
–
/
1.73
/
/
–
N
Cl
O
P
/
–
1.0
0.21
/
1.15
/
0.0
/
0.2
/
/
/
/
/
/
/
/
S
1.47
0.0
/
/
/
1.17
0.0
/
/
Close inspection of other intermolecular contacts also
The H∙∙∙H contacts are favoured in the structures of both
since the enrichment ratios EHH are close to unity and
and
, respectively) of the interaction surface (Table 1). The ECH
ClH and ECCl values for the structure of are also very close to
are
two chemical species to be in contact. The enrichment ratio, even more pronounced (Table 1). The EClH and ECCl values is the
derived from the Hirshfeld surface analysis, is defined as the result of abundant S (67.2 and 74.6% for and
1
revealed a negligible proportion of C∙∙∙Cl, Cl∙∙∙N, Cl∙∙∙O, C∙∙∙O, and
4
Cl∙∙∙S, H∙∙∙N, C∙∙∙N and O∙∙∙O contacts in the structure of
Cl∙∙∙S, H∙∙∙N and Cl∙∙∙Cl contacts in the structure of (Table 1).
We have also determined the enrichment ratios (E) of the
intermolecular contacts for and
1; and generate an overwhelming majority (43.0 and 51.4% for 1
4
4
,
1
6
E
1
1
4
to study the propensity of unity, while the former two values for the structure of
4
H
1
4,
ratio between the proportion of actual contacts in the crystal respectively) proportion of hydrogen atoms on the molecular
and the theoretical proportion of random contacts. E is larger surface. The latter value, despite the contribution of C∙∙∙Cl
than unity for pair of elements with a higher propensity to contacts to the Hirshfeld surface area is negligible (CCCl = 1.9%),
form contacts, while pairs which tend to avoid contacts yield is explained by a minor proportion of chlorine atoms on the
and E value lower than unity.
molecular surface (SCl = 6.5%), decreasing the value RCCl (1.9%).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C5NJ02588E
ARTICLE
Journal Name
Abundant S
H
proportion of hydrogen atoms on the molecular Syntheses
surface also explains the higher propensity of the H∙∙∙S
contacts for both structures (ESH = 1.47 and 1.17 for and
respectively). Furthermore, the high S value for the structure
of is the reason that the H∙∙∙O contacts are enriched (EOH
.33). Interestingly, the C∙∙∙C contacts in the structure of
All syntheses were performed in non-dried solvents under
ambient conditions.
1
4,
H
Synthesis of 1. Neat 3-chloroaniline (0.127 g, 1 mmol) was
1
=
treated under vigorous stirring with neat (PhO)
g, 1.1 mmol). The formed dark yellow viscous oil was dissolved
in Et O (20 mL). The resulting solution was filtered and left
overnight. Colorless block-like crystals, suitable for X-ray
analysis, were filtered off, washed with Et O (3 10 mL) and
dried in vacuo. Yield: 0.394 g (94%). H NMR, : 6.96–7.81 (m,
2H, C + C ), 10.97 (br. s, 3.3H, PNH), 12.24 (br. s, 1H,
PNH), 13.72 (br. s, 3.5H, arylNH), 13.91 (br. s, 1.1H, arylNH)
2
P(O)NCS (0.321
1
1
are
the most enriched ones (ECC = 1.73), which is due to the
negligible value RCC (2.2%), though the contribution of C∙∙∙C
2
contacts to the Hirshfeld surface area in the structure of
1 is
2
×
also very negligible (CCC = 3.8%).
1
δ
Contacts of the type H∙∙∙N and C∙∙∙O, found in the structure
, and Cl∙∙∙Cl, appeared in the structure of , are very
6
6
H
5
6 4
H
of
1
4
impoverished (Table 1).
3
1
1
ppm. P{ H} NMR, δ: –7.9 (s, 1P), –10.5 (s, 3.6P) ppm. Anal.
calc. for C19 16ClN O PS (418.83): C, 54.49; H, 3.85; N, 6.69.
H
2 3
Found: C, 54.61; H, 3.91; N, 6.74.
Conclusions
Synthesis of 2–4 (Path A). A solution of 3-chloroaniline (0.127
In summary, we have demonstrated the synthesis of a new N-
phosphorylated thiourea, 3-ClNHC(S)NHP(O)(OPh) ), by the
addition of neat phosphorylisothiocyanate to neat 3-
6 6
chloroaniline. The same reaction in non-dried CH Cl or C H
g, 1 mmol) in CH
2
Cl
2
, C
6
H
6
or Me
2
C=O (10 mL) was treated
P(O)NCS (0.321
2
(1
under vigorous stirring with a solution of (PhO)
2
g, 1.1 mmol) in the same solvent (15 mL). The resulting
solution was stirred for 2 h, filtered and left for slow
evaporation at room temperature. Colorless plate-like crystals,
suitable for X-ray analysis, were obtained after two-three days.
2
2
–
+
leads to the salt-like compounds [3-ClC
6
H
4
NH
3∙0.5C
while using non-dried acetone yields 1-(3-chlorophenyl)-4,4,6-
trimethyl-3,4-dihydropyrimidine-2(1H)-thione ( ). Dissolution
of in non-dried CH Cl , C or Me C=O leads to the direct
formation of 3∙0.5C and , respectively. It was
established that thione is most likely formed through the
thiourea -assisted aldol condensation of acetone leading to
mesityl oxide. In turn the latter ketone interacts with
followed by its hydrolysis leading to . Thus, the thiourea
3
] [NCS] (
2) and
+
–
[
3-ClC
6
H
4
NH
3
] [P(O)
2
(OPh)
2
] ∙0.5C
6
H
6
(
6 6
H ), respectively,
2
Crystals were filtered off, washed with Et O (3 × 10 mL) and
dried in vacuo.
4
1
2
2
6
H
6
2
1
2
8
4
3
1
.
Yield: 0.162 g (87%). H NMR,
δ
: 7.21–7.38 (m, 4H, C
ClN S (186.66): C,
5.04; H, 3.78; N, 15.01. Found: C, 45.13; H, 3.72; N, 15.12.
6 4
H ),
2,
6
H
6
4
.18 (br. s, 3H, NH
3
) ppm. Anal. calc. for C
7
H
7
2
4
1
1
∙0.5(C
6
H
6
). Yield: 0.379 g (91%). H NMR,
+ C + C ), 8.13 (br. s, 3H, NH
: –11.7 ppm. Anal. calc. for C21
0.51; H, 4.84; N, 3.36. Found: C, 60.63; H, 4.77; N, 3.28.
δ: 6.90–7.45 (m,
1
1
31
1
7H, C
6
H
6
6
H
5
6
H
4
3
) ppm. P{ H}
4
H20ClNO P (416.82): C,
4
NMR,
δ
might be considered as a facile single source precursor for
Further research using other ketons and are under progress.
4.
6
1
4
.
Yield: 0.162 g (84%). H NMR,
δ
: 1.39 (s, 6H, C(CH
3
)
2
), 1.54
), 5.00 (q, JH,H = 1.1 Hz, 1H,
), 7.90 (br. s, 1H, NH) ppm.
2
15ClN S (266.79): C, 58.53; H, 5.67; N, 10.50.
Hirshfeld surface analysis showed that the structures of
both and are mainly characterized by H∙∙∙H, H∙∙∙C, H∙∙∙Cl and
H∙∙∙S contacts as well as by H∙∙∙O in the structure of . The
4
4
(
d, JH,H = 1.1 Hz, 3H, CH=CCH
CH=CCH ), 7.17–7.42 (m, 4H, C
Anal. calc. for C13
3
1
4
3
6 4
H
1
H
enrichment ratio, derived as the decomposition of the crystal
contact surface between pairs of interacting chemical species,
Found: C, 58.65; H, 5.61; N, 10.42.
Synthesis of 2–4 (Path B). Powdered sample of
1
(0.105 g, 0.25
for
1 was found, as expected for the polar contacts, which are
2 2 6 6 2
mmol) was dissolved in CH Cl , C H or Me C=O (15 mL). The
generally hydrogen bonds, to be significantly larger than unity
for the contacts of the type H∙∙∙O and H∙∙∙S. A much more
larger than unity value was found for the enrichment ratio of
resulting solution was stirred for 2 h and left overnight.
Colorless plate-like crystals, suitable for X-ray analysis, were
obtained after one-two days. Crystals were filtered off, washed
the C∙∙∙C contacts in the structure of
extensive π∙∙∙π stacking in the crystal packing. The enrichment
ratio for was found to be larger than unity for the contacts of
1, which is due to
with Et
2
O (3
Yield: 0.045 g (96%).
∙0.5(C ). Yield: 0.098 g (94%).
Yield: 0.060 g (90%).
× 10 mL) and dried in vacuo.
2
3
4
.
4
6 6
H
the type H∙∙∙C and, but with a lesser degree, H∙∙∙Cl and H∙∙∙S.
.
Experimental
Single crystal X-ray diffraction
The X-ray data of 1–4, obtained via Path A, were collected at
General procedures
1
50(2) (
6 6
1 and 2) and 297(2) 150(2) (3∙0.5(C H ) and 4) K on a
NMR spectra in acetone-d
00 MHz spectrometer at 25 °C. H and P{ H} NMR spectra Fox3D mirror). The data were integrated with the CrysAlisPro
6
were obtained on a Bruker Avance Mar345 image plate detector using Mo-K radiation (Xenocs
α
1
31
1
3
1
7
were recorded at 299.948, and 121.420 MHz, respectively. software. The implemented empirical absorption correction
Chemical shifts are reported with reference to SiMe ( H) and was applied. The structures were solved by SHELXS and
4
1
18
3
1
1
2
85% H
3 4
PO ( P{ H}). Elemental analyses were performed on a refined by full-matrix least squares on |F |, using
1
9
Thermoquest Flash EA 1112 Analyzer from CE Instruments.
SHELXL2014/7. Non-hydrogen atoms were anisotropically
refined and the hydrogen atoms were placed on calculated
6
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5NJ02588E
Journal Name
ARTICLE
positions in riding mode with temperature factors fixed at 1.2
M. G. Babashkina, M. Bolte and A. Klein, Heteroatom Chem.,
010, 21, 343; (j) M. G. Babashkina and D. A. Safin,
2
times Ueq of the parent atoms. Figures were generated using
2
the program Mercury.
0
Phosphorus Sulfur Silicon, 2010, 185, 1437; (k) M. G.
Babashkina, E. R. Shakirova, D. A. Safin, F. D. Sokolov, A.
Klein, Ł. Szyrwiel, M. Kubiak, H. Kozlowski and D. B.
Krivolapov, Z. Anorg, Allg. Chem., 2010, 636, 2626; (l) M. G.
Babashkina, D. A. Safin, A. Klein and M. Bolte, Eur. J. Inorg.
Chem., 2010, 4018; (m) D. A. Safin, M. G. Babashkina, M.
Bolte and M. Köckerling, Inorg. Chim. Acta, 2011, 370, 59; (n)
M. G. Babashkina, D. A. Safin, M. Srebro, P. Kubisiak, M. P.
−
1
Crystal data for 1.
C
19
H16ClN
2
O
3
PS, M
r
= 418.82 g mol ,
monoclinic, space group P2
c = 10.2468(2) Å, = 97.6257(19)°, V = 1975.30(6) Å , Z = 4, ρ =
1
/c, a = 17.7272(3), b = 10.9714(2),
3
β
−3
−1
1
.408 g cm , μ(Mo-Kα) = 0.402 mm , reflections: 11779
collected, 3630 unique, Rint = 0.024, R (all) = 0.0387, wR (all) =
.0951.
Crystal data for 2.
monoclinic, space group P2
.0694(12) Å, = 99.36(2)°, V = 846.6(3) Å , Z = 4, ρ = 1.464 g
1
2
0
Mitoraj, M. Bolte and Y. Garcia, CrystEngComm, 2011, 13
,
−
1
C
6
H
7
ClN, CNS; M
r
= 186.66 g mol ,
5321; (o) M. G. Babashkina, D. A. Safin, K. Robeyns, A.
Brzuszkiewicz, H. Kozlowski and Y. Garcia, CrystEngComm,
2012, 14, 1324; (p) M. G. Babashkina, D. A. Safin and Y.
Garcia, Polyhedron, 2012, 33, 114; (r) M. G. Babashkina, D. A.
1
/c, a = 15.742(4), b = 7.7102(9), c =
3
7
β
−3
−1
cm , μ(Mo-Kα) = 0.630 mm , reflections: 5161 collected,
523 unique, Rint = 0.076, R (all) = 0.0928, wR (all) = 0.2192.
Crystal data for 3∙0.5(C ). P, C ClN, 0.5(C ); M
416.80 g mol , triclinic, space group P–1, a = 6.7856(6), b =
1.797(5), c = 15.113(4) Å, α = 67.80(3) = 80.388(17),
Safin, K. Robeyns and Y. Garcia, Dalton Trans., 2012, 41
1
,
451; (s) D. A. Safin, M. G. Babashkina, A. P. Railliet, N. A.
1
1
2
6
H
6
C
12
H
10
O
4
6
H
7
6
H
6
r
Tumanov, K. Robeyns, E. Devlin, Y. Sanakis, Y. Filinchuk and
Y. Garcia, Dalton Trans., 2013, 42, 5532; (t) D. A. Safin, M. G.
Babashkina, K. Robeyns, M. P. Mitoraj, P. Kubisiak, M. Brela
and Y. Garcia, CrystEngComm, 2013, 15, 7845; (u) D. A. Safin,
M. G. Babashkina, M. Bolte and Y. Garcia, Polyhedron, 2013,
−1
=
1
7
0
0
,
β
γ =
3
−3
4.82(2)°, V = 1077.9(6) Å , Z = 2, ρ = 1.284 g cm , μ(Mo-Kα) =
−1
.277 mm , reflections: 12856 collected, 3723 unique, Rint
.035, R (all) = 0.0471, wR (all) = 0.1417.
S, M
/c, a = 8.4353(4), b = 14.9782(9), c
=
63, 133; (v) D. A. Safin, M. G. Babashkina, K. Robeyns, M.
1
2
Bolte and Y. Garcia, CrystEngComm, 2014, 16, 7053; (w) D. A.
Safin, M. G. Babashkina, P. Kubisiak, M. P. Mitoraj, C. S. Le
Duff, K. Robeyns and Y. Garcia, Eur. J. Inorg. Chem., 2014,
5522; (x) M. G. Babashkina, D. A. Safin, K. Robeyns and Y.
Garcia, Eur. J. Inorg. Chem., 2015, 1160.
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Brown and T. A. Keating, Acc. Chem. Res., 1996, 29, 123; (c)
−
1
Crystal data for 4.
C
13
H
15ClN
2
r
= 266.78 g mol ,
monoclinic, space group P2
1
3
=
1
11.5168(8) Å, β = 104.453(6)°, V = 1409.05(15) Å , Z = 4, ρ =
−
3
−1
.258 g cm , μ(Mo-Kα) = 0.400 mm , reflections: 9066
(all) = 0.0552, wR (all) =
2
3
collected, 2524 unique, Rint = 0.044, R
.1878.
CCDC 1423371 (
contain the supplementary crystallographic data. This data can
be obtained free of charge via
1
2
0
L. F. Tietze, and M. E. Lieb, Curr. Opin. Chem. Biol., 1998, 2,
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), 1423372 (2), 1423373 (3) and 1423374 (4)
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http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
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Acknowledgements
M. G. Babashkina and D. A. Safin thank WBI (Belgium) for the
post-doctoral positions. This work was partly supported by
FNRS (Belgium).
8
9
D. Sriram, P. Yogeeswari and R. V. Devakaram, Bioorg. Med.
Chem., 2006, 14, 3113.
A. C. L. Leite, R. S. Lima, D. R. M. Moreira, M. V. O. Cardoso,
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J. Name., 2013, 00, 1-3 | 7
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DOI: 10.1039/C5NJ02588E
ARTICLE
Journal Name
1
7 Rigaku Oxford Diffraction, CrysAlisPro Software system,
Version 1.171.37.31, Rigaku Corporation, Oxford, UK, 2014.
8 G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112.
9 G. M. Sheldrick, SHELXL2014/7, University of Göttingen,
Germany, 2014.
1
1
2
0 I. J. Bruno, J. C. Cole, P. R. Edgington, M. Kessler, C. F.
Macrae, P. McCabe, J. Pearson and R. Taylor, Acta
Crystallogr., 2002, B58, 389.
8
| J. Name., 2012, 00, 1-3
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New Journal of Chemistry
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DOI: 10.1039/C5NJ02588E
leads to 1. The same reaction in non-
The reaction of neat 3-chloroaniline with neat S=C=N–P(O)(OPh)
2
dried CH
Cl
2 2
6 6 2 6 6
or C H or Me C=O leads to 2, 3·0.5C H and 4, respectively.
Et O
2
3-ClC
6 4
H
NHC(S)NHP(O)(OPh)
2
(1)
Cl
NH
2
CH
2
Cl
2
2 2
CH Cl
+
[3-ClC
6
6
H
4
NH
3
]+[NCS]- (2)
C
6
H
6
C
H
6 6
[3-ClC
H
4
NH
3
]+[P(O) ]- (3)
(OPh)
2 2
Me
O
S
C
N
P
O
Me
2
C
O
Me
Me
Me
2
C
O
O
N
(4)
Cl
N
H
S