Single step preparation and conformational analysis of novel thiophosphorylated ligands based on calix[4]resorcinol matrix

Article abstract of DOI:10.1007/s10847-012-0190-0

We have synthesized novel calix[4]resorcinols with four 2-thioxo-1,3,2-dioxaphospholane groups introduced in aromatic substituents in the methylidene bridges of macromolecules by the condensation of new thiophosphorylated benzaldehyde with resorcinol and

Full text of DOI:10.1007/s10847-012-0190-0

J Incl Phenom Macrocycl Chem (2013) 76:231–235
DOI 10.1007/s10847-012-0190-0
SHORT COMMUNICATION
Single step preparation and conformational analysis of novel
thiophosphorylated ligands based on calix[4]resorcinol matrix
•
Irina R. Knyazeva Victoria I. Sokolova
•
•
Margit Gruner Wolf D. Habicher Julia K. Voronina
•
•
•
Alexander R. Burilov Michael A. Pudovik
Received: 24 February 2012 / Accepted: 30 May 2012 / Published online: 12 June 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract We have synthesized novel calix[4]resorcinols
with four 2-thioxo-1,3,2-dioxaphospholane groups intro-
duced in aromatic substituents in the methylidene bridges of
macromolecules by the condensation of new thiophosph-
orylated benzaldehyde with resorcinol and its derivatives in
acidic media with high yields. The formation of only one
rctt isomer with corresponding chair conformation is
observed, which was determined by 2D NMR-experiments.
derivatives with various aliphatic and aromatic aldehydes
[2–7] and can exist as four diastereomers. According to
¨
Hogberg [4], when all four substituents in the calixarene
matrix are cis-oriented, this compound is considered rccc
isomer. Three other isomers possess rcct, rctt and rtct
configurations of substituents (Fig. 1). The ratio of dia-
stereomers usually depends on the structure of the starting
aldehyde. The use of long-chain aliphatic aldehydes in the
condensation leads predominantly to the rccc isomer [2].
The condensation with aromatic aldehydes usually gives a
mixture of the rccc and rctt isomers [2, 5–7].
Keywords Thiophosphorylated calix[4]resorcinol ꢀ
Condensation ꢀ Resorcinol ꢀ Aldehyde ꢀ Conformation
Earlier we obtained novel calix[4]resorcinols bearing
phosphonate and phosphonium fragments on the lower rim
of the molecule by the condensation of phosphorylated
derivatives of benzaldehyde with resorcinol [7]. The sub-
stitution of oxygen atom of phosphoryl group for sulfur
atom is found to enhance remarkably the binding ability of
thiophosphate derivatives compared to the ‘‘soft’’ metal
ions like Ag?, Zn2?, Cd2?, Pb2?, Cu?, Pt2?, Pd2?, and so
on [8–10]. Assuming the macrocyclic effect, the binding
ability of the calixarene containing a few thiophosphoryl
groups can be anticipated to increase by several times with
respect to the linear thiophosphates.
Introduction
The great interest of many chemists to the calixarene
compounds, in particular, calix[4]resorcinols does not
weaken over the last decade. Special attention is devoted to
their synthesis, conformational behaviour, modification of
their upper and lower rims, and ability to form cavitands,
capsules, monolayers, and host–guest complexes [1].
Calix[4]resorcinols are known to be readily available
by acid-catalyzed condensation of resorcinol and its
Recently we have successfully synthesized novel calix[4]-
resorcinols with four diethylthiophosphate groups with the use
of 3- and 4-thiophosphorylated benzaldehydes as starting
materials in the condensation with resorcinol and its derivatives
[11]. Reaction proceeds strictly stereoselectively affording rctt
isomer in chair conformation with moderate yield (from 60 to
65 %). It should be noted that the introduction of thiophos-
phoryl groups in calixarene framework was so far labor-con-
suming process and involved predominantly the addition of
sulfur atom to trivalent phosphorus atoms, which were pri-
marily introduced on the upper rim of calix[4]resorcinols or
cavitands via O-phosphorylation [12, 13].
I. R. Knyazeva (&) ꢀ V. I. Sokolova ꢀ J. K. Voronina ꢀ
A. R. Burilov ꢀ M. A. Pudovik
State Budgetary-Funded Institution of Science, A. E. Arbuzov
Institute of Organic and Physical Chemistry of Kazan Scientific
Center, Russian Academy of Sciences, Arbuzov Str. 8,
420088 Kazan, Russian Federation
e-mail: ihazieva@mail.ru
M. Gruner ꢀ W. D. Habicher
TU Dresden, Institute of Organic Chemistry, Bergstr. 66,
01069 Dresden, Germany
123

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J Incl Phenom Macrocycl Chem (2013) 76:231–235
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
rccc
rcct
rctt
rtct
Fig. 1 Configurational isomers of calix[4]resorcinols
In this work, we demonstrated that new thiophosph-
orylated benzaldehyde 3 is a useful starting material for the
single-step stereoselective preparation of rctt isomers of
novel calix[4]resorcinols in chair conformation having four
2-thioxo-1,3,2-dioxaphospholane-containing aromatic sub-
stituents with high yields (up to 90 %).
˚
Fig. 2 View of 3 in the crystal. The selected bond lengths (A) and
angles (ꢁ) are: P2 O1 1.5667(16), P2 O3 1.5715(16), P2 O7
1.5908(16), P2 S6 1.8897(12), O1 P2 O3 99.37(9), O1 P2 O7
105.94(9), O3 P2 O7 100.64(9), O1 P2 S6 117.05(7), O3 P2 S6
117.34(8), O7 P2 S6 114.20(7)
1
The 31P, H, and 13C NMR data; ESI mass spectra; and
Results and discussion
elemental analysis are in a good agreement with the
structure proposed. The existence of only one signal in the
31P NMR spectrum at approx. 78–79 ppm for each com-
pound is a good evidence for the equivalence of four
phosphorus atoms in the molecule.
1H and 13C NMR spectra of 5a–c display a doubling of
their proton and carbon signals for the resorcinol fragments
as for analogous thiophosphorylated calix[4]resorcinols in
our previous publication [11]. This gives reason for the
exact elucidation of structures using 2D NMR-experi-
ments, namely, COSY, HSQC, HMBC and ROESY, and
the assignment of 1H and 13C signals according to the
designation of atoms (see Scheme 2).
Starting with HSQC correlations for C,H-3 and C,H-30
atoms, the NMR signals for calixarene rings and side chain
groups were determined step by step from the HSQC and
HMBC spectra. As was shown for compound 5a (Fig. 3), the
well-established HMBC correlations like Ci-4,40/H-3,30, as
well as Ci-4,40/5,50 and Ci-2,20/5,50, giving rise to the eluci-
dation of neighboring resorcinol C(H) and C-ipso atoms.
Further correlations between signals of H-1 bridge
protons with those of surrounding carbon atoms, namely,
Ci-2,20/H-1, C-3,30/H-1, as well as Ci-6,C-7/H-1, indicate
the symmetric arrangement of calixarene rings and their
neighboring side chain groups.
A new reactant 3 for calixarene design was obtained as
white solid in 58 % yield by the reaction of 2-chloro-2-
thioxo-1,3,2-dioxaphospholane with 4-hydroxybenzalde-
hyde and sodium hydride in anhydrous THF (Scheme 1).
The compound 3 crystallized from the acetone–water
mixture in the monoclinic crystal system and P21/c space
group. Four-coordinated phosphorus atom is a part of a
five-membered cycle, which has an envelope conformation
˚
with the deviation of C4 atom from plane at 0.396(2) A.
The selected bond lengths and angles around the phos-
phorus atom are in the range of the typical values for
thiophosphates and are given in the description of Fig. 2.
Molecules of 3 form chains along 0b axis by CH…O
interactions, benzene rings participate in the p…p interac-
tions; and, as a result, the layers are formed in b0c plane. The
layers are linked into a 3D structure by van der Waals forces.
The condensation of thiophosphorylated benzaldehyde 3
with resorcinol and its derivatives (2-methylresorcinol and
pyrogallol) 4a–c resulted in the formation of novel
calix[4]resorcinols 5a–c with four 2-thioxo-1,3,2-dioxa-
phospholane groups introduced in aromatic substituents of
the calixarene matrix (Scheme 2). It should be noted that
the reactions under study were accompanied by the side
processes, presumably decomposition of the starting alde-
hyde, under general conditions for this type of interaction
(mixture of protic polar solvents like alcohol and water and
mineral acid catalyst like concentrated hydrochloric acid)
[11]. High yields (up to 90 %) of desired products were
attained using chloroform as solvent and trifluoroacetic
acid as catalyst.
In order to gain an insight into the configuration of the
calixarene ring, in particular, for rcct or rctt, we checked the
ROESY spectrum of 5a (Fig. 4). Owing to the positive cross-
peak for calixarene ring protons H-3/H-30, the rctt isomer in
chair conformation is preferred. Finally, both different types
of resorcinol rings in the calixarene structure can be
Scheme 1 Synthetic procedure
for preparation of compound 3
S
S
O
O
O
NaH
THF
HO
CHO
+
P Cl
P O
CHO
O
1
2
3
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J Incl Phenom Macrocycl Chem (2013) 76:231–235
233
Scheme 2 Synthesis of
thiophosphorylated
calix[4]resorcinols 5a–c
R
R
5
4
HO
OH
S
HO
OH
O
O
CF3COOH
CHCl3
4
P O
CHO
+ 4
2
1
6
4
3
7
4 a-c
3
5 a-c
8
9
S
P
O
O
O
10
R = H (a), CH3 (b), OH (c)
10
distinguished by the means of different ROE intensities for
correlations between calixarene ring protons and side chain
protons like H-3/H-7 [ H-30/H-7 and H-3/H-1 [ H-30/H-1.
Consequently, the orientation of opposite resorcinol rings of
calixarene platform in solution is clearly evident—two ver-
tical (v) rings with C-1–C-40 and two horizontal (h) rings with
C-1–C-4 relative to the macrocycle plane.
spectrometer (166.93 MHz). NMR-experiments were car-
ried out in solutions (10 mmolꢀL–1) at 303 R. The IR
spectra of the compounds as emulsions in vaseline were
recorded on a Vector 22 FTIR Spectrometer (Bruker) in the
4,000–400 cm-1 range at a resolution of 1 cm-1. ESI
mass-spectra were recorded on an Esquire-LC 00084
instrument. Microelemental analyses data were obtained on
a CHN-3 analyzer and they were within 0.3 % of the
theoretical values for C, H, P, and S. The uncorrected
melting points were measured on a Boetius hot-stage
apparatus. Thin layer chromatography was performed on
Silufol-254 plates; visualization was carried out with UV
light. For column chromatography silica gel of 60 mesh
from Fluka was used. All solvents were dried according to
standard protocols.
Experimental
General procedures
1H and 13C NMR spectra as well as the 2D NMR spectra of
COSY, HSQC, HMBC, NOESY and ROESY type were
recorded on a Bruker AVANCE-600 spectrometer (600 and
150 MHz, respectively) in d6-DMSO or CDCl3; 31P NMR
spectra were recorded on a Bruker MSL-400 NMR-Fourier
X-ray crystallography
Suitable single crystals were obtained from a solution of 3
in mixture of acetone and water at ambient temperature.
The X-ray diffraction data for crystal of compound 3,
C9H9O4PS, was collected at 296 K on a Bruker AXS Smart
Apex II CCD diffractometer in the x and u-scan modes
˚
using graphite monochromated MoKa (k 0.71073A) radi-
ation. Crystallographic data for compound 3 are given in
Table 1. The structure was solved by direct method and
refined by the full matrix least-squares using SHELXTL
[14] and WinGX [15] programs. All non-hydrogen atoms
were refined anisotropically. The positions of hydrogen
atoms were located from the Fourier electron density
synthesis and were included in the refinement in the iso-
tropic riding model approximation. Figure was made using
PLATON [16].
Crystallographic data (excluding structure factors) for 3
have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication number CCDC
832280. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, [fax: ?44-(0)1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
Fig. 3 1H/13C-HMBC spectrum of 5a for the aromatic region
123

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J Incl Phenom Macrocycl Chem (2013) 76:231–235
Fig. 4 1H/13C-HMBC spectrum
of 5a for the aromatic region
5'
OH
1
HO
4'
2'
OH
5
2
4
3'
3
6
7
8
OH
9
O
S
P
O
O
10
10
2-(4-Formylphenoxy)-2-thioxo-1,3,2-dioxaphospholane
3
known procedure [17], in THF (80 mL) was added and
resulted suspension was stirred at heating (*45 ꢁC) in the
nitrogen atmosphere. The progress of the reaction was
monitored by TLC. After 2 h the precipitate was filtered,
washed with benzene. Then solvent from filtrate was evap-
orated and the crude product was purified by column chro-
matography using mixture dichloromethane/methanol
(20:0.5) as eluent. The pure compound 3 was obtained as
white solid (7.54 g, yield 58 %, Rf = 0.82). Mp 68–69 ꢁC.
31P NMR (166.93 MHz, CDCl3) d 76.8 ppm. 1H NMR
(600 MHz, CDCl3) d 4.51 (m, 4H, OCH2), 7.32 (d,
A solution of 4-hydroxybenzaldehyde 2 (6.50 g, 0.0532 mol)
in THF (80 mL) was added dropwise to the suspension of
NaH (1.28 g, 0.0532 mol) in THF (80 mL) at 10 ꢁC and
reaction mixture was stirred at room temperature for 60 min.
Then, the solution of 2-chloro-2-thioxo-1,3,2-dioxaphospho-
lane 1 (8.44 g, 0.0532 mol), synthesized according to a
3
3JHH = 8.69, 2H, CHar), 7.90 (d, JHH = 8.69, 2H, CHar),
Table 1 Crystallographic data for compound 3
9.97 (s, 1H, CHO) ppm. IR mmax: 824 cm-1 (P = S). ESI–
MS: m/z = 245 [M ? H]? (calcd. M = 244). Anal. calcd.
for C9H9O4PS: C, 44.26; H, 3.69; P, 12.70; S, 13.11. Found:
C, 44.17; H, 3.91; P, 12.76; S, 13.16.
Chemical formula
Formula mass
Temperature (K)
Crystal system
Space group
C9H9O4PS
244.19
296 (2)
Monoclinic
P21/c
Calix[4]resorcinol 5a
˚
a (A)
5.772(3)
22.147(11)
8.470(4)
97.500(6)
1073.4(10)
4
˚
b (A)
To the solution of resorcinol 4a (0.45 g, 4.10 mmol) in the
mixture of CHCl3 (5 mL) and CF3COOH (2 mL) the
solution of thiophosphorylated aldehyde 3 (1.00 g, 4.10
mmol) in CHCl3 (7 mL) was added dropwise. The reaction
mixture was stirred under argon atmosphere at 70 ꢁC for
5 h. The precipitate formed was filtered, washed with
diethyl ether and acetone. After drying in vacuo (40 ꢁC,
0.06 Torr) the product was obtained (1.20 g, yield 87 %)
as white powder. Mp [ 240 ꢁC (dec.). 31P NMR (166.93
MHz, DMSO-d6) d 78.8 ppm. 1H NMR (600 MHz, DMSO-
d6) d 4.51 (m, 16H, H10), 5.43 (s, 2H, H3h), 5.52 (s, 4H,
H1), 6.16 (s, 2H, H5v), 6.26 (s, 2H, H3v), 6.33 (s, 2H, H5h),
˚
c (A)
b (ꢁ)
3
˚
V (A )
Z
qcalc (g cm-3
l (cm-1
)
1.511
)
0.440
Reflections collected
Reflections observed (I [ 2r)
Reflections unique
R1, wR2 (2r data)
R1, wR2 (all data)
GooF on F2
8,049
1,078
2,108 (Rint = 0.0628)
0.0360, 0.0489
0.0852, 0.0489
0.822
3
3
6.62 (d, JHH = 8.52, 8H, H7), 6.72 (d, JHH = 8.52, 8H,
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J Incl Phenom Macrocycl Chem (2013) 76:231–235
235
H8), 8.60 (s, 4H, OHv), 8.70 (s, 4H, OHh) ppm. NMR 13C
(150 MHz, DMSO-d6) d 41.5 (s, C1), 67.6 (s, C10), 67.6
(s, C10), 101.8 (s, C5h), 101.9 (s, C5v), 119.3 (s, C8), 120.4
(s, C2h), 120.8 (s, C2v), 128.9 (s, C3v), 130.1 (s, C7), 131.4
(s, C3h), 141.7 (s, C6), 147.4 (s, C9), 152.7 (s, C4v), 152.9
(s, C4h). IR mmax: 831 (P = S); 924, 1028 (P-O-C); 3,100–
3,600 (OH) cm-1. ESI–MS: m/z = 1345 [M ? H]? (calcd.
M = 1344). Anal. calcd. for C60H52O20P4S4: C, 53.57; H,
3.87; P, 9.23; S, 9.52. Found: C, 53.59; H, 3.60; P, 8.98; S,
9.31.
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was obtained as light-pink powder by a method analogous
to that used to prepare 5a by the treatment of 2-methyl-
resorcinol 4b (0.57 g of 90 % purity, 4.10 mmol) with
aldehyde 3 (1.00 g, 4.10 mmol). Yield 1.42 g (89 %).
Mp [ 300 ꢁC (dec.). 31P NMR (166.93 MHz, DMSO-d6) d
1
78.9 ppm. H NMR (600 MHz, DMSO-d6) d 1.93 (s, 6H,
CHh3), 2.07 (s, 6H, CHv3), 4.54 (m, 16H, H10), 5.23 (s, 2H,
H3h), 5.65 (s, 4H, H1), 6.11 (s, 2H, H3v), 6.65 (d,
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(P = S); 960, 1025 (P-O-C); 3,200–3,600 (OH) cm-1
.
)
phosphate (UMPS2- or adenosine 50-O-thiomonophosphate
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calcd. for C64H60O20P4S4: C, 54.86; H, 4.29; P, 8.86; S,
9.14. Found: C, 54.73; H, 4.11; P, 8.61; S, 8.96.
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Calix[4]resorcinol 5c
was obtained as light-pink powder by a method analogous
to that used to prepare 5a by the treatment of pyrogallol 4c
(0.26 g, 2.06 mmol) with aldehyde 3 (0.5 g, 2.06 mmol).
Yield 0.58 g (80 %), Mp [ 196 ꢁC (dec.). 31P NMR
(166.93 MHz, DMSO-d6): d = 78.8 ppm. 1H NMR
(600 MHz, DMSO-d6) d 4.51 (m, 16H, H10), 5.07 (s, 2H,
H3h), 5.66 (s, 4H, H1), 5.93 (s, 2H, H3v), 6.62 (d,
3JHH = 8.4, 8H, H7), 6.73 (d, JHH = 8.4, 8H, H8), 7.61
3
(s, 6H, OHv), 7.71 (s, 6H, OHh) ppm. IR mmax: 831 (P = S);
924, 1026 (P-O-C); 3,100–3,600 (OH) cm-1. ESI–MS: m/
z = 1409 [M ? H]? (calcd. M = 1408). Anal. calcd. for
C60H52O24P4S4: C, 51.14; H, 3.69; P, 8.81; S, 9.09. Found:
C, 51.11; H, 3.30; P, 8.53; S, 8.98.
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123