Supramolecular chemistry of phosphorus-containing (thia)calixarenes

Article abstract of DOI:10.1080/10426507.2010.525766

Molecular modeling, synthesis, and structural investigations of the phosphorus-containing (thia)calixarenes and their supramolecular complexes with biorelevant or ecologically hazardous molecules and ions are discussed within the context of cationic and m

Full text of DOI:10.1080/10426507.2010.525766

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Phosphorus, Sulfur, and Silicon and the
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Supramolecular Chemistry of
Phosphorus-Containing (Thia)Calixarenes
a
a
Sergiy O. Cherenok , Stanislav I. Miroshnichenko , Andriy B.
a
a
a
Drapailo , Olga I. Kalchenko , Roman V. Rodik , Vyacheslav
a
a
a
I. Boiko , Yury I. Matveev , Alexander V. Ruban & Vitaly I.
a
Kalchenko
a
Institute of Organic Chemistry , National Academy of Sciences of
Ukraine , Kyiv , Ukraine
Published online: 25 Apr 2011.
To cite this article: Sergiy O. Cherenok , Stanislav I. Miroshnichenko , Andriy B. Drapailo , Olga I.
Kalchenko , Roman V. Rodik , Vyacheslav I. Boiko , Yury I. Matveev , Alexander V. Ruban & Vitaly I.
Kalchenko (2011) Supramolecular Chemistry of Phosphorus-Containing (Thia)Calixarenes, Phosphorus,
Sulfur, and Silicon and the Related Elements, 186:4, 878-883, DOI: 10.1080/10426507.2010.525766
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Phosphorus, Sulfur, and Silicon, 186:878–883, 2011
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ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.525766
SUPRAMOLECULAR CHEMISTRY OF
PHOSPHORUS-CONTAINING (THIA)CALIXARENES
Sergiy O. Cherenok, Stanislav I. Miroshnichenko,
Andriy B. Drapailo, Olga I. Kalchenko, Roman V. Rodik,
Vyacheslav I. Boiko, Yury I. Matveev, Alexander V. Ruban,
and Vitaly I. Kalchenko
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Kyiv, Ukraine
Molecular modeling, synthesis, and structural investigations of the phosphorus-containing
(thia)calixarenes and their supramolecular complexes with biorelevant or ecologically haz-
ardous molecules and ions are discussed within the context of cationic and molecular recogni-
tion, extraction properties, and bioactivity.
Keywords Calixarenes; phosphonates; radionuclides; supramolecular complexes; thiacal-
ixarenes
INTRODUCTION
Calixarenes1,2 and their thia-analogues (thiacalixarenes) —synthetically available
macro(hetero)cyclic compounds—are employed as a platform for the introduction of a vari-
ety of functional groups at the phenol oxygen atoms (lower rim) and/or at the para-positions
3
(upper rim). The compounds due to multisite hydrogen bonding, specific stacking, electro-
static interactions, etc. demonstrate the unique abilities to recognize; bind in the host–guest
supramolecular complexes; and thereafter separate cations, anions, neutral molecules, and
4
biomolecules of appropriate sizes and architectures.
The phosphorus containing calixarenes functionalized with P(III) or P(V) functional
5
groups are of particular interest. Strong cation and hydrogen bond acceptor properties of the
6
phosphorus functionalities make them excellent binding sites for molecular recognition. In
this article, we report synthesis and supramolecular properties of the phosphorus-containing
calixarenes and thiacalixarenes, within the context of cationic and molecular recognition,
extraction properties, and bioactivity.
RESULTS and DISCUSSION
Synthesis of Phosphorylated Calixarenes
Calix[4]arenes 1 (Figure 1) containing phosphorus fragments at the upper rim of
the macrocycle have been synthesized by the Arbuzov–Tavs reaction of the appropriate
Received 29 July 2010; accepted 15 September 2010.
Address correspondence to V. I. Kalchenko, Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, 5, Murmanska str., 02660, Kyiv-94, Ukraine. E-mail: vik@ioch.kiev.ua
8
78

PHOSPHORUS-CONTAINING (THIA)CALIXARENES
879
tetrabromocalixarenes with alkyl esters of P(III) acids.7,8 High temperature (110–180 C),
excess of P(III) esters, and catalytic quantitives of anhydrous nickel bromide are needed to
achieve the satisfactory yields of compounds 1. Using the Arbuzov reaction of chloromethyl
derivatives of calix[4]arenes or thiacalix[4]arenes with alkyl esters of P(III) phospho-
rus acids, phosphorylated (thia)macrocycles 2, 3 (Figure 1) were synthesized with high
◦
9
,10
yields.
Calix[4]arenes 4 (Figure 1) in the cone conformation bearing OCH2P(O)Bu2 func-
tional groups at the narrow rim were synthesized by alkylation of the tetrahydroxycal-
ixarenes phenolic groups by tosylate of hydroxymethyldibutylphosphine oxide in the pres-
◦
11
ence of NaH (toluene, 95 C). The stereochemical outcome of the alkylation process is
highly controlled by metal cation. The reaction of the tetrahydroxycalix[4]arenes with the
R1 R2
R1
O
R2
R
R
R
R
1
R
PO OP
R1 R2
R
R2
PO
O
P
P
P
R
O
P
R
P
R
O
O
O
O
O
O
O O
R
O
O
Alk
Alk
R
Alk
Alk
R
R
1
2
1
R=OH,OAlk, Ph
R =H,OH,OAlk,Alk,Ph
2
R =OH,OAlk,Alk,Ph,NAlk2
R
R
R
R
O
R
R
R
R
R
R
P
R
P
P
R
O
P
O
O
O
O
S
O O
S
O
O
S
S
O
O
PBu2
Bu P O
O
O
2
H
H
H
O
PBu2 Bu P
O
H
2
3
4
R=H, t-Bu
R=OH,OAlk,Ph
O
O
O
P
O
O
(
RO)2
(RO)2
P
P(OR)2
(RO) P
P
P(OR)2
H
2
(OR)2
XH
HC
X
X
CH
HX
H
O O
O
O
OH
H
O
O HO
Y
H
Pr
Pr
Y
5
6
X=O,NH
R=H,Alk
X=H, CH(P(O)(OR)2)
2
Y=H, Pr
R=H, Alk
Figure 1 Chemical structures of phosphorylated calix[4]arenes 1–6.

8
80
S. O. CHERENOK ET AL.
O
P
O
O
P
H
EtO
EtO
EtO
EtO
HO
HO
N
NH2
NH2
NR
Y
P
*
*
*
R
X
X
X
X
H2
X
X
1. Me SiBr
X
X
(
EtO)
2
P(O)H
3
Y
Y
Y
Y
Y
Y
Y
Na
Pd(C)
2. MeOH
OEt
OEt
OEt
OH
OH
R
RHN
* P
O
P
H N * P
N
H N
2
OEt
2
H
O
O
7
a,b
8 a,b
9 a,b
5 a,b
*
a: (R, R)
b: (S, S)
a: R = CH(Ph)CH
*
(–)(S)
a: (R, R)
b: (S, S)
3
a: (SR, RS)
b: (RS, SR)
b: R = CH(Ph)CH (+)(R)
3
X = OH, Y= OPr
Figure 2 Stereoselective synthesis of calixarene bis-α-aminophosphonic acid 5.
tosylate of hydroxymethyldibutylphosphine oxide in the presence of cesium carbonate in re-
fluxing acetonitrile produces calixarene tetraphosphine oxides possessing the 1,3-alternate
conformation.
Calixarene bis-α-aminophosphonic acid 5 (X = NH) (Figure 2) as optically pure RR
or SS diastereomeric forms was synthesized by the Pudovik addition of dialkylphosphite
sodium salt to the C = N bond of chiral bis-iminocalixarenes 7, obtained by condensation of
12
bis-formylcalixarene with R or S phenylethylamine. Chiral phenylethyl auxiliary groups
in aminophosphonate 8 (Figure 2) were removed by hydrogenation on Pd/C catalyst, and
ethyl groups in compound 9 were removed by the reaction with trimethylbromosilane and
methanol.
Similar Pudovik phosphorylation of 5,17-diformylcalix[4]arene results in the forma-
1
3
tion of calixarene bis-α-hydroxyphosphonic acid 5 (X = O, R = H)) as a RS meso form.
Hydroxyphosphonates 5 (X = O, R = Alk) were converted quantitatively to calixarene
bis-methylenebisphosphonates 6 (X = H, Y = Pr) by reaction with a large excess of
14
(
RO)2P(O)Na in dialkylphosphite/dioxane solution. Tetrakis-methylenebisphosphonates
6
(X = CH[P(O)(OR)2]2, Y = H) were synthesized by a similar procedure starting with
tetraformylcalix[4]arene.
Supramolecular Properties of Phosphorylated Calixarenes
The extraction of americium and europium by (thia)calix[4]arenes 2–4 bearing a
9
,15–17
CH2P(O)R2 binding group at the upper or the lower rim has been investigated.
The
calix[4]arenes phosphine oxide groups show a considerable cooperative effect and extract
Am and Eu approximately 200 times better than the corresponding acyclic alkylphosphine
oxides (Figure 3). Distribution coefficients markedly depend on the size of the calixarene
skeleton, its conformation, and electronic features of the phosphorus atom substituents.
The micelle-mediated ultrafiltration method of purification of radioactive water from
the Chernobyl power station from uranium and transuranium elements is developed using
1
2
18
amphiphilic tetrapropoxycalix[4]arene tetraphosphine oxide 2 (R = R = R = Pr).
Coefficients of the detention of the radionuclides on the polysulfone membranes PS-100

PHOSPHORUS-CONTAINING (THIA)CALIXARENES
881
2
1
0
,5
2
,5
1
,5
0
1
2
3
4
5
6
7
8
O
O
Pr
O
O
Pr
Pr
O
Pr
Pr
P
P
O
O
Ph
Ph
O
Bu
Bu
P
Pr
P
P
O
P
O
O
4
5
6
O
O
O
O
O
O
Pr
Pr
Pr
Pr
4
4
6
P
P
O
P
Bu
P
Bu
P
Bu
O
O
O
Pr
Bu
Bu
Bu
0.01 M
Pr
Me
0
.04 M
0.01 M
0.01 M
0
.01 M
0.01 M
0.01 M
0.01 M
Figure 3 Am3 extraction by phosphine oxides. D—the metal distribution ratio between nitrobenzotrifluoride
+
◦
and HNO3 (0.1M) at 20 C.
with the pores diameters of 0.08 mkm, consist of 96.0–99.7% for the transuranium elements
and 94–97% for uranium.
The upper rim phosphorylated calixarenes form supramolecular complexes with
organic molecules and biomolecules. Stability constants of the host–guest complexes of
calixarene tetraphosphonate 1 (Alk = Pr, R = OPr-i) with benzene derivatives determined
−1
by the HPLC method in acetonitryle/water solution is in the range of 30–340 M depending
on substituents’ nature in the benzene guests (Figure 4).
The RS meso form of the calixarene bis-α-hydroxymethylphosphonic acids 5 (R =
H, X = O) was investigated as molecular receptor for L-amino acids and dipeptides using
13
isothermal titration calorimetry. The stability constants are in the range of 3000–17000
−1
−1
M
(25000–45000 M for dipeptides). Analysis of the effect of pH on the stability
constants confirms the presence of strong electrostatic interactions between the host and
guest.
The host–guest complexation of the calix[4]arene 1 (Alk = Pr, R = OPr-i) with uracil
derivatives in a methanol/acetonitrile/tetrahydrofuran/water (15:10:5:70 v/v) solution was
8
investigated by the reversed-phase HPLC method. The association constants (1200–6900
−1
M ) of the 1:1 complexes were determined.
Calixarene methylenebisphosphonic acids 6 (R = X = H, Y = Pr) displayed strong
14
inhibition of calf intestine alkaline phosphatase. The inhibition constant (Ki = 0.38 µM)
was found to be considerably lower than that of the simple methylenebisphosphonic acid
(
Ki = 67 µM). The action of the phosphorylated calix[4]arene 6 is concordant with partial
mixed-type inhibition.

8
82
S. O. CHERENOK ET AL.
Benzene
p-Xylene
N,N-Dimethylaniline
Chlorobenzene
Trifluoromethylbenzene
Toluene
3
3
2
2
1
1
50
00
50
00
50
00
m-Dinitribenzene
p-Bromotoluene
o-Bromotoluene
Aniline
5
0
0
Figure 4 Association constants of calix[4]arene tetraphosphonate 1 (Alk = Pr, R = OPr-i) complexes with
benzene derivatives (HPLC: Separon SGX C 18; MeCN:H2O, 86:14).
Optically pure RR and SS diastereomeres of calixarene α-aminophosphonic acids 5
(
X = NH, R = H) were investigated as inhibitors of porcine kidney alkaline phosphatase.
The Ki value characterizing the dissociation constant of the enzyme–inhibitor complex is
much smaller for calixarene aminophosphonic acids 5 (86 µM and 1.6 µM for RR and
SS diastereomeres, respectively) in comparison with Ki of the model S-4-hydroxybenzene
aminomethylphosphonic acid (590 µM). The inhibition constants significantly depend on
the absolute configuration of the aminophosphonyl fragments carbon atoms. The inhibition
stereoselectivity Кi(RR)/Ki(SS) = 50 (ꢀꢀG = 9.6 kJ/mol) is observed for the calixarene
bis-aminophosphonic acids 5.12
Calixarene tetrakis-methylenebisphosphonic acids 6 (X = CH[P(O)(OR)2]2, R =
Y = H) inhibit specifically 50% of fibrin polymerization in the fibrinogen+thrombin
reaction as well as monomeric fibrin desAABB polymerization in concentration up to
−
6
19
0
.5·10 M.
CONCLUSION
The combination of the phosphorus-containing receptor groups and macrocyclic
cavity supplies a significant potential for application of phosphorus-containing calixarenes
in supramolecular chemistry of material and life science. Promising application fields are
decontamination of radioactive wastes and chemosensor design. The design of artificial
water-soluble receptors, able to mimic enzymes (or influence them), is also an interesting
2
0,21
theme.
Biorelevant phosphoryl groups may play an important role in these processes.

PHOSPHORUS-CONTAINING (THIA)CALIXARENES
883
REFERENCES
1
. Gutsche, C. Calixarenes Revisited; The Royal Society of Chemistry: Cambridge, UK, 1998.
2
. Asfari, Z.; Boehmer, V.; Harowfield, J.; Vicens, J. Calixarenes 2001; Kluwer Academic Publish-
ers, Dordrecht, 2001.
3
4
. Iki, N.; Miyano, S. J. Incl. Phenom. Macrocycl. Chem. 2001, 41, 99–105.
. Vicens, J.; Harrowfield, J.; Baklouti, L. Calixarenes in the Nanoworld, 2007; Springer: Dordrecht,
2007, p. 395.
5
6
7
. Cherenok, S.; Kalchenko, V. Top. Heterocycl. Chem. 2009, 20, 229–273.
. Schrader, T. J. Incl. Phenom. Macrocycl. Chem. 1999, 34, 117–128.
. Kalchenko, V.; Atamas, L.; Pirozhenko, V.; Markovsky, L. Zh. Obshch. Khim. 1992, 62,
2
623–2624.
8. Kalchenko, O.; Marcinowicz, A., Poznanski, J., Cherenok, S.; Solovyov, A.; Zielenkiewicz, W.;
Kalchenko, V. J. Phys. Org. Chem. 2005, 18, 578–583.
9. Klimchuk, O.; Atamas, L.; Miroshnichenko, S.; Kalchenko, V.; Smirnov, I.; Babain, V.; Varnek,
A.; Wipff, G. J. Incl. Phenom. Macrocycl. Chem. 2004, 49, 47–52.
1
1
1
1
1
1
0. Kasyan, O.; Swierczynski, D.; Drapailo, A.; Suwinska, K.; Lipkowski, J.; Kalchenko, V. Tetra-
hedron Lett. 2003, 44, 7167–7170.
1. Kostin, G. A.; Us, T. V.; Korda, T. M.; Torgov, V. G.; Kuratieva, N. V.; Miroshnichenko, S. I.;
Kalchenko, V. I. J. Incl. Phenom. Macrocycl. Chem. 2010, 68, 131–137.
2. Cherenok, S.; Vovk, A.; Muravyova, I.; Shivanyuk, A.; Kukhar, V.; Lipkowski, J.; Kalchenko,
V. Org. Lett. 2006, 8, 549–552.
3. Zielenkiewicz, W.; Marcinowicz, A.; Cherenok, S.; Kalchenko, V.; Pozna n´ ski, J. Supramol.
Chem. 2006, 18, 167–176.
4. Vovk, A. I.; Kalchenko, V. I.; Cherenok, S. O.; Kukhar, V. P.; Muzychka, O. V.; Lozynsky, M.
O. Org. Biomol. Chem. 2004, 2, 3162–3166.
5. Atamas, L.; Klimchuk, O.; Rudzevich, V.; Pirozhenko, V.; Kalchenko, V., Smirnov, I., Babain,
V.; Efremova, T.; Varnek, A.; Wipff, G.; Arnaud-Neu, F.; Roch, M.; Saadioui, M.; Bohmer, V.
J. Supramol. Chem. 2002, 2, 421–427.
1
1
1
1
2
2
6. Arnaud-Neu, F.; Karavan, M.; Hubscher-Bruder, V.; Smirnov, I.; Kalchenko, V. J. Incl. Phenom.
Macrocycl. Chem. 2010, 66, 113–123.
7. Smirnov, I. V.; Karavan, M. D.; Efremova, T. I.; Babain, V. A.; Miroshnichenko, S. I.; Cherenok,
S. A.; Kalchenko, V. I. Radiochemistry (Russ.) 2007, 49, 482–492.
8. Rudenko, L. I.; Dzhuzha, O. V.; Khan, V. E.; Miroshnichenko, S. I.; Kalchenko, V. I. Dokl. Akad.
Nauk. Ukr. 2009, 164–167.
9. Gritsenko, P. G.; Lugovsky, E. V.; Koshel, T. A.; Cherenok, S. A.; Yushenko, A. A.; Chernishov,
V. I.; Kalchenko, V. I.; Komisarenko, S. V. Dokl. Akad. Nauk. Ukr. 2010, 175–179.
0. Shkrabak, O. A.; Kalchenko, O. I.; Rodik, R. V.; Veklich, T. O.; Kalchenko, V. I.; Kosterin, S.
O. Ukr. Biochem. J. 2008, 80, 90–100.
1. Vovk, A. I.; Kononets, L. A.; Tanchuk, V. Yu.; Cherenok, S. O.; Drapailo, A. B.; Kalchenko, V.
I.; Kukhar, V. P. Bioorg. Med. Chem. Lett. 2010, 20, 483–487.