Synthesis, characterization, and photophysical properties of paraben substituted cyclotriphosphazenes with hydrophilic side groups

Article abstract of DOI:10.1080/10426507.2020.1728759

In this study, five new paraben substituted cyclotriphosphazene compounds containing hydrophilic glycol groups were successfully synthesized. All synthesized cyclotriphosphazene compounds 1-10 were fully characterized via general spectroscopic techniques

Full text of DOI:10.1080/10426507.2020.1728759

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis, characterization, and photophysical
properties of paraben substituted
cyclotriphosphazenes with hydrophilic side groups
Elif Şenkuytu, Hande Eserci, Nagihan Bayık, Nadide Akbaş, Elif Okutan &
Gönül Yenilmez Çiftçi
To cite this article: Elif Şenkuytu, Hande Eserci, Nagihan Bayık, Nadide Akbaş, Elif Okutan &
Gönül Yenilmez Çiftçi (2020): Synthesis, characterization, and photophysical properties of paraben
substituted cyclotriphosphazenes with hydrophilic side groups, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2020.1728759
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1728759
Synthesis, characterization, and photophysical properties of paraben substituted
cyclotriphosphazenes with hydrophilic side groups
€ €
Elif S¸enkuytu , Hande Eserci, Nagihan Bayık, Nadide Akbas¸, Elif Okutan, and Gonul Yenilmez C¸iftc¸i
Department of Chemistry, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
ABSTRACT
ARTICLE HISTORY
Received 4 October 2019
Accepted 8 February 2020
In this study, five new paraben substituted cyclotriphosphazene compounds containing
hydrophilic glycol groups were successfully synthesized. All synthesized cyclotriphosphazene
compounds 1-10 were fully characterized via general spectroscopic techniques such as 1H, 31P
NMR and MALDI-TOF mass spectrometry. In addition, the investigations of the UV-vis absorption
and fluorescence emission properties of the 1-10 carried out via absorption and fluorescence
spectroscopies in different solvents. The absorbance bands of the all synthesized compounds 1-10
were observed at about 230–300nm in all solvents studied. Furthermore, the highest fluorescence
emission intensity of the compounds 1-10 was observed in tetrahydrofuran at about 312nm and
the lowest emission intensity was observed in chloroform. The synthesized molecules can be used
as custom designed molecules to investigate the DNA binding properties in automatic biosensor
device in our laboratories, since they carry hydrophilic glycol units for water solubility and paraben
derivatives for DNA effecting properties.
KEYWORDS
Paraben; cyclotriphospha-
zene; hydrophilic tails;
UV-vis absorption;
fluorescence
GRAPHICAL ABSTRACT
1. Introduction
constitute rationally designed cyclotriphosphazene systems
emerged to develop materials with useful chemical and
physical properties.[5] These properties of cyclotriphospha-
zene derivatives lead to a wide range of application areas of
these compounds as well as to differences in the application
at the same time. Examples of these applications include
such as biomedical materials, liquid crystals, flame retard-
ants, organic light-emitting diodes, photophysical materials,
Phosphazenes are an important class of inorganic chemistry.
Hexachlorocyclotriphosphazene, trimer, (N3P3Cl6), is
a
member of cyclophosphazene family. As a result of substitu-
tion reaction of cyclotriphosphazene with different nucleo-
philic reagents, cyclotriphosphazene derivatives having a
variety features, can be synthesized.[1,2] The versatile chemis-
try of cyclotriphosphazenes enable designing materials with
particular properties.[3,4] In this regard, diverse strategies to and fluorescence chemosensor.[6–13] In particular, the
CONTACT Elif S¸enkuytu
senkuytu@gtu.edu.tr
Department of Chemistry, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1728759.
ß 2020 Taylor & Francis Group, LLC

2
E. ŞENKUYTU ET AL.
Scheme 1. Synthesis of the cyclotriphosphazene derivatives 1-10.
biological applications of cyclotriphosphazenes have hydrophilic glycol units does provide interaction with water
attracted the attention of researchers in recent years and which is valuable for biocompatibility and in applications
studies in this area have increased. Especially, organocyclo- which needs to stimulate biological environment.[26–29] In
triphosphazenes were studied as a potential anti-cancer previous studies made by our group, paraben derivatives of
agent.[14–16] The side groups such as spermine, chalcone, cyclotriphosphazene and cyclotetraphosphazene were synthe-
sized and their DNA effects were investigated as potential
drug candidates.[20,24,25] In biological applications, workabil-
ity in water or in aqueous environments is an important fac-
tor. Therefore, it is very significant for biological and other
and parabens on the cyclotriphosphazene core were reported
to maintain cytotoxicity to these potential drug
candidates.[17–20]
Parabens are known antimicrobial agents, that have been
utilized in numerous daily use products thanks to their applications that synthesized compounds to be soluble in
broad antimicrobial spectrum.[21–23] Studies also concluded these solvents. To expedite hydrophilicity, in the current
the effect of parabens on DNA which empowered synthesis study paraben derivatives with different side groups and
of novel genotoxic compound.[20,24,25] Furthermore, tailor- glycol moieties were introduced in a single molecule
made decorated cyclotriphosphazene frameworks with (Scheme 1). The paraben cyclotriphosphazene compounds

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Table 1. 31P f Hg NMR parameters for compounds 1-10 in CDCl3.
1
d(31P NMR) [ppm]
2J(PP) [Hz]
Comp.
P (R1Cl)
P(R2)2
P(Cl)2
P(R1)(R2)
Spin system
2JAX
2JAB
MS (MALDI-TOF)
1
2
3
4
5
6
7
8
9
10
11.95
11.93
11.88
11.87
11.89
–
–
–
–
–
–
–
–
–
–
22.50
22.49
22.51
22.51
22.52
–
–
–
–
–
–
–
–
–
–
A2X
A2X
A2X
A2X
A2X
A2B
A2B
A2B
A2B
A2B
61.89
61.89
62.06
62.0
62.03
–
–
–
–
–
–
–
–
–
–
464.46 [M þ H]þ
478.81 [M þ H]þ
491.50 [M]þ
505.49 [M]þ
539.31 [M]þ
17.30
17.27
17.29
17.25
17.24
14.35
14.27
14.07
14.37
14.16
85.54
85.33
85.28
85.41
85.21
1102.46 [M]þ
1085.54 [M-C2H5]þ
1086.95 [M-C3H7]þ
1144.37 [M]þ
1085.58 [M-C7H9]þ
R1: paraben, R2: hydrophilic side groups.
with hydrophilic side groups were characterized by mass shown in Figure 1a,b, respectively. The signals include one
1
spectrometry (MALDI-TOF) and H and 31P NMR spectros-
triplet for the -PCl2 groups in the chemical shift range of
copy. In addition, UV-vis absorption and fluorescence emis-
d ¼ 11.87–11.65 ppm and a doublet for the –P(R1Cl) (R1 ¼
sion behaviors of the compounds 1-10 were investigated in
paraben) groups in the range of d ¼ 22.49–22.52 ppm (phos-
seven different solvent systems and the results obtained were
compared. The potential biological activity properties of the
parabens and the water solubility enhancement properties of
the hydrophilic groups are known. In the next phase of the
study, the DNA binding properties of the synthesized para-
ben-cyclotriphosphazene derivatives carrying hydrophilic
group will be investigated with automatic biosensor device
in our laboratories.
phorus-phosphorus coupling constants are average of about
2JPP ¼ 62 Hz, Table 1). The proton decoupled 31P NMR
spectrum of compounds 6-10 exhibited A2B spin systems, as
expected since the two different phosphorus nuclei of
the cyclotriphosphazene ring have close chemical shifts
(Table 1). For example for compound 8 the signals were seen
as one doublet of doublets for the -P(R2)2 (R2 ¼ hydrophilic
2
side groups) group (d ¼ 17.29 ppm, JPP ¼ 85.28 Hz) and one
doublet for the -P(R1)(R2) (R1 ¼ Paraben, R2 ¼ hydrophilic
2
side groups) group (d ¼ 14.07 ppm, JPP ¼ 85.28 Hz) in the
2. Result and discussion
spectrum, respectively (Figure 1b). Besides, when the proton
coupled 31P NMR spectrum of compound 8 was examined,
the d ¼ 17.29 ppm and d ¼ 14.07 ppm signals were seen as
split/broad multiplet peaks due to the -CH2 protons
(Figure 1c).
2.1. Synthesis and NMR characterization of parabene
substituted cyclotriphosphazenes
In the present work, paraben substituted cyclotriphospha-
zene compounds 1-5 and paraben functionalized cyclotri-
phosphazenes with hydrophilic side group 6-10 were
successfully synthesized and their synthesis strategies were
summarized in Scheme 1. Compounds 1 and 2 were synthe-
sized according to the literature where compounds 3-5 were
synthesized first time in this study by employing the
literature method. In these frameworks, firstly, reactions of
hexachlorocyclotriphosphazene with methylparaben, ethyl-
paraben, propylparaben, butylparaben and benzylparaben
were performed in the presence of THF/NaH to obtain com-
pounds 1-5, respectively. Then, the novel compounds 6-10,
containing hydrophilic side group cyclotriphosphazenes
were synthesized from the substitution reaction of mono
paraben substituted cyclotriphosphazene compounds 1-5
with triethylene glycol monomethyl ether (Scheme 1). Each
of the synthesized compounds 1-10 was characterized by
mass (MALDI-TOF), 1H and 31P NMR spectroscopy. The
In addition, the 1H NMR chemical shifts and coupling
constants of all protons in the experimental section con-
firmed the structures of synthesized compounds 1-10. While
the aromatic protons for the paraben substituted cyclotri-
phosphazene compounds 1-5 and paraben derivative cyclo-
triphosphazene compounds containing hydrophilic side
groups 6-10 were observed between 8.16–7.14 ppm, aliphatic
protons of paraben groups were observed between
5.39–0.81 ppm. In cyclotriphosphazene compounds contain-
ing hydrophilic side groups 6-10, in addition to these para-
ben aliphatic protons, the -OCH3 and -OCH2 protons were
observed as single peaks at approximately 3.35 ppm and as
multiple peaks in the range of 3.80-3.40 ppm, respectively
(e.g., Figure 2a for comp. 3 and 2b for comp. 8).
2.2. Ground state electronic absorption and
fluorescence properties
1
structure analysis data (mass, H and 31P NMR results) of
the compounds were presented in the experimental section.
Also, the 31P NMR chemical shifts and phosphorus–phos-
phorus coupling constants and mass spectrum values of syn-
thesized compounds 1-10 were summarized in Table 1. The
proton decoupled 31P NMR spectrum of compounds 1-5
were observed as A2X spin system due to the different envi-
ronments of the two different phosphorus nuclei on the
cyclotriphosphazene ring. As an example, the proton
The photophysical properties paraben substituted cyclotri-
phosphazene compounds 1-5 and paraben derivative cyclo-
triphosphazene compounds containing hydrophilic side
groups 6-10 were investigated using UV-vis and fluores-
cence spectroscopy. The ground state electronic absorption
and fluorescence emission behaviors of compounds were
evaluated in a variety of solvents such as tetrahydrofuran,
decoupled 31P NMR spectrum of compounds 3 and 8 were acetonitrile, dichloromethane, chloroform, dimethylsulfoxide,

4
E. ŞENKUYTU ET AL.
Figure 1. (a) The proton decoupled 31P NMR spectrum of 3, (b) the proton decoupled 31P NMR spectrum of 8; (c) the proton coupled 31P NMR spectrum of 8 in
CDCl3 solution.
Figure 2. (a) The 1H NMR spectrum of 3 and (b) the 1H NMR spectrum of 8 in CDCl3 solution.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
Figure 3. Absorbance spectra of (a) 3 and (b) 8 (100 mM) in different solvents.
Figure 4. Fluorescence spectra of (a) 3 and (b) 8 (100 mM) in different solvents (kexc.¼270 nm).
Figure 5. Excitation (dashed lines) and emission spectra (solid lines) of (a) for 3, (b) for 8 in tetrahydrofuran, kexc. ¼ 270 nm (C ¼ 100 mM).
methanol and ethanol (Figures 3–5 and Supporting Figures S26 and S27). In general, absorbance bands were
Information Figures S26–S33). When the absorbance of the observed in the range of 230–300 nm as broad bands for
compounds in different solvents was investigated, it was compounds 1-10 in all the studied solvents. These absorb-
found that the absorbance bands were not changed even if ance bands observed for compounds can be attributed to
the absorbance intensity of the compounds changed with p-p and n-p transitions.[30–33] In addition, the ground
the solvent effect (Figure 3 and Supporting Information state absorption spectra of the compounds in acetonitrile
ꢀ
ꢀ

6
E. ŞENKUYTU ET AL.
Table 2. Photophysical properties of cyclotriphosphazene derivatives (1–10).
Comp.
C (mM)
akab (nm)
kem (nm)
fi
a,b, 104 M–1.cm–1
cDStokes, max., min. (nm)
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
100
100
100
100
230, 268, 277
230, 270, 279
230, 271, 280
230, 267, 281
230, 271, 279
234, 269, 278
236, 270, 287
235, 268, 281
235, 271, 282
232, 272, 282
310(THF), 330(DMSO)
312(THF), 338(DMSO)
312(THF), 340(DMSO)
310(THF), 340(DMSO)
312(THF), 335(DMSO)
312(THF), 336(DMSO)
310(THF), 337(DMSO)
313(THF), 336(DMSO)
310(THF), 348(DMSO)
310(THF), 335(DMSO)
2.10
1.92
1.50
1.74
1.48
2.21
1.61
2.10
1.65
1.82
42, 25
43, 26
42, 27
42, 25
42, 27
40, 23
41, 26
41, 26
41, 24
43, 26
10
aAcetonitrile.
bMolar extinction coefficients.
cTetrahydrofuran.
were obtained at different concentrations. From these spec- 3.1.2. Synthesis of compound 3 (propyl 4-((2,4,4,6,6-penta-
chloro-1,3,5,2k5,4k5,6k5-triazatriphosphinin-2-
tra, the molar extinction coefficients of the compounds
yl)oxy)benzoate)
(1-10) were calculated according to Beer-Lambert law
(Supporting Information Figures S28 and S29). The solvent
effect in the fluorescence emission spectrum of compounds
(1-10) was also examined. According to fluorescence
emission spectra, the highest emission intensity of the com-
pounds (1-10) was observed at about 312 nm in tetrahydro-
furan. The lowest emission intensity for all compounds was
observed in chloroform. Also, there was no significant shift
in the fluorescence wavelength of the compounds (1-10) in
the other solutions except dimethylsulfoxide (Figure 4,
Supporting Information Figures S30 and S31). Depending
on the solvent effect, a red shift of approximately 25 nm
relative to the other solvents was observed at the fluores-
cence emission wavelength of all compounds (1-10) in
DMSO (Table 2). This shift can be due to non-covalent
intermolecular interactions between compounds and aro-
matic solvents. The emission and excitation spectrum of
compounds (1-10) in tetrahydrofuran are shown in Figure 5
and Supporting Information Figures S32 and S33.
Fluorescence emission maxima values of the compounds
were recorded in the range of 310-313 nm in THF (Table 2).
Stokes shift, which is known as the distance between max-
imum excitation and emission wavelength, is important for
fluorescence measurements. The Stokes Shift values of the
compounds (1-10) were observed in the range of approxi-
mately 23–43 nm measurements in tetrahydrofuran
(Table 2).
Hexachlorocyclotriphosphazene (1.0 g, 2.80 mmol) and NaH
(60% oil suspension, 0.056 g, 2.33 mmol) were dissolved in dry
THF (40 mL) under an argon atmosphere in a 250 mL three-
necked round-bottomed flask. The reaction mixture was
cooled in an ice bath and propyl 4-hydroxybenzoate (0.504 g,
2.8mmol) in dry THF (10 mL) was added to this stirred solu-
tion under an argon atmosphere. The reaction mixture was
stirred for 3 days at room temperature by control with TLC.
The reaction mixture was filtered to remove the formed
sodium chloride and the solvent was removed under reduced
pressure. Compound 3 (260 mg, 20%, white oil) was isolated
from the reaction mixture in silica gel (70-230 mesh) column,
using the n-hexane-DCM (1:1) system as the driving phase.
Spectral data of compound 3: MS (MALDI-TOF) (DIT) m/z
(%): Calcd. for (C10H11Cl5N3O3P3): 491.39; found 491.50
[M]þ. 31P NMR decoupled to (202 MHz, CDCl3, 298 K),
P(Cl)2 d ¼ 22.51 ppm (2P, 2JP-P ¼ 62.06 Hz); P(R1Cl)
2
d ¼ 11.88 ppm (1P, JP-P ¼ 62.06 Hz) Spin system: A2X
(Supporting Information Figure S5). 1H-NMR (500 MHz,
CDCl3, 298 K) d ppm, 8.13, d, 2H, Ha (3JHH ¼ 8.48 Hz); 7.36,
d, 2H, Hb (3JHH ¼ 8.48 Hz); 4.31, t, 2H, (-OCH2), (3JHH
6.70 Hz); 1.82, m, 2H (CH2); 1.06, t, 3H (-CH3), (3JHH
7.38 Hz) (Supporting Information Figure S6).
¼
¼
3.1.3. Synthesis of compound 4 (butyl 4-((2,4,4,6,6-penta-
chloro-1,3,5,2k5,4k5,6k5-triazatriphosphinin-2-yl)
oxy)benzoate)
Hexachlorocyclotriphosphazene (1.0 g, 2.80 mmol) and NaH
(60% oil suspension, 0.056 g, 2.33 mmol) were dissolved in
dry THF (40 mL) under an argon atmosphere in a 250 mL
three-necked round-bottomed flask. The reaction mixture
was cooled in an ice bath and butyl 4-hydroxybenzoate
(0.544 g, 2.8 mmol) in dry THF (10 mL) was added to this
stirred solution under an argon atmosphere. The reaction
mixture was stirred for 3 days at room temperature by con-
trol with TLC. The reaction mixture was filtered to remove
the formed sodium chloride and the solvent was removed
under reduced pressure. Compound 4 (283 mg, 20%, white
oil) was isolated from the reaction mixture in silica gel (70-
230 mesh) column, using the n-hexane-DCM (1:1) system as
the driving phase. Spectral data of compound 4: MS
3. Experimental
3.1. General material and methods
General material and methods were given in Supporting
Information.
3.1.1. Synthesis of compound 1 and 2
Compound 1 and 2 were synthesized according to the
literatures[34,35] and spectral data of all compounds (1-10)
were given in the supporting file (Supporting Information
Figures S1–S25).

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
(MALDI-TOF) (DHB) m/z (%): Calcd. for (C11H13Cl5N3O3P3): (DHB) m/z (%): Calc. for (C43H82N3O23P3): 1102.05; found
505.41; found 505.49 [M]þ. 31P NMR decoupled to (202 MHz, 1102.46 [M]þ. 31P NMR decoupled to (202 MHz, CDCl3,
2
2
CDCl3, 298 K), P(Cl)2 d ¼ 22.51 ppm (2P, JP-P ¼ 62.0 Hz); 298 K), P(R2)2 d ¼ 17.30 ppm (2 P, JP-P ¼ 85.54 Hz);
2
2
P(R1Cl) d ¼ 11.87 ppm (1P, JP-P ¼ 62.0 Hz) Spin system: A2X P(R1)(R2) d ¼ 14.35 ppm (1P, JP-P ¼ 85.54 Hz) Spin system:
(Supporting Information Figure S7). 1H-NMR (500 MHz, A2B (Supporting Information Figures S11 and S12).
CDCl3, 298 K) d ppm, 8.12, d, 2H, Ha (3JHH ¼ 8.33 Hz); 7.36, 1H-NMR (500 MHz, CDCl3, 298 K) d ppm, 8.06, d, 2H, Ha
d, 2 H, Hb (3JHH ¼ 8.33 Hz); 4.35, t, 2 H, (-OCH2), (3JHH
¼
(3JHH ¼ 7.50 Hz); 7.24, d, 2H, Hb (3JHH ¼ 7.50 Hz);
6.60 Hz); 1.78, m, 2H (CH2); 1.50, m, 2H (CH2); 1.00, t, 3H 3.76–3.50, m, 60 H (-OCH2); 3.33, s, 18 H, (-OCH3)
(-CH3), (3JHH ¼ 7.34 Hz) (Supporting Information Figure S8).
(Supporting Information Figure S13).
3.1.4. Synthesis of compound 5 (benzyl 4-((2,4,4,6,6-penta- 3.1.6. Synthesis of compound 7 (ethyl 4-((2,4,4,6,6-penta-
chloro-1,3,5,2k5,4k5,6k5-triazatriphosphinin-2-yl)oxy)
benzoate)
kis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ꢁ1,3,5,2k5,
4k5,6k5-triazatriphosphinin-2-yl)oxy)benzoate)
Hexachlorocyclotriphosphazene (1.0 g, 2.80 mmol) and NaH Triethylene glycol monomethyl ether (206 mg, 1.26 mmol) was
(60% oil suspension, 0.056 g, 2.33 mmol) were dissolved in dry dissolved in dry THF (50 mL) in a 250 mL round-bottomed
THF (40 mL) under an argon atmosphere in a 250 mL three- three-necked flask in an argon atmosphere. NaH (56 mg,
necked round-bottomed flask. The reaction mixture was cooled in 1.4 mmol (60%)) solid was added to the reaction medium and
an ice bath and benzyl-4-hydroxybenzoate (0.544 g, 2.8 mmol) in heated at reflux temperature of THF under reflux for 2 h. After
dry THF (10 mL) was added to this stirred solution under an cooling the reaction mixture to room temperature, the outdoor
argon atmosphere. The reaction mixture was stirred for 3 days at was cooled to about –10 ꢂC in an ice-salt bath. Compound 2
room temperature by control with TLC. The reaction mixture was (100 mg, 0.21 mmol) was slowly added to the reaction mixture
filtered to remove the formed sodium chloride and the solvent by dissolving in dry THF (100 mL). The reaction was allowed to
was removed under reduced pressure. Compound 5 (330 mg, warm to room temperature and stirred at room temperature for
22%, white oil) was isolated from the reaction mixture in silica gel 2 days by control with TLC. The reaction mixture was filtered
(70-230 mesh) column, using the n-hexane-DCM (1:1) system as through a sintered filter to remove the sodium chloride salt. The
the driving phase. Spectral data of compound 5: MS (MALDI- solvent of the filtrate was removed in vacuum using a rotary
TOF) (DIT) m/z (%): Calcd. for (C14H11Cl5N3O3P3): 539.43; evaporator. Compound 7 (110 mg, 47%, white oil) was isolated
found 539.31 [M]þ. 31P NMR decoupled to (202 MHz, CDCl3, from the reaction mixture in silica gel (70-230 mesh) column,
2
298 K), P(Cl)2 d ¼ 22.52 ppm (2P, JP-P ¼ 62.03 Hz); P(R1Cl) using the n-hexane-DCM (2: 3) system as the driving phase.
2
d ¼ 11.89 ppm (1P, JP-P ¼ 62.03 Hz) Spin system: A2X Spectral data of compound 7: MS (MALDI-TOF) (DIT) m/z
(Supporting Information Figure S9). 1H-NMR (500 MHz, CDCl3, (%): Calcd. for (C44H84N3O23P3): 1116.05; found 1085.54
298 K) d ppm, 8.16, d, 2H, Ha (3JHH ¼ 8.59 Hz); 7.47, d, 2H, Hc [M-C2H5]þ. 31P NMR decoupled to (202 MHz, CDCl3, 298K),
(3JHH ¼ 7.19 Hz); 7.42, t, 2H, Hd (3JHH ¼ 7.15 Hz); 7.38, d, 1H, P(R2)2 d ¼ 17.27 ppm (2P, 2JP-P ¼ 85.33 Hz); P(R1)(R2)
2
He; 7.36, d, 2H, Hb (3JHH ¼ 8.59 Hz); 5.39, s, 2 H (-OCH2) d ¼ 14.27 ppm (1P, JP-P ¼ 85.33 Hz) Spin system: A2B
(Supporting Information Figure S10).
(Supporting Information Figures S14 and S15). 1H-NMR
(500 MHz, CDCl3, 298 K) d ppm, 8.04, d, 2H, Ha (3JHH
¼
6.63 Hz); 7.21, d, 2H, Hb (3JHH ¼ 6.63 Hz); 3.75–3.45, m, 62 H
(-OCH2); 3.33, s, 15H, (-OCH3); 1.33–1.16, m, 3 H, (-CH3)
(Supporting Information Figure S16).
3.1.5. Synthesis of compound 6 (methyl 4-((2,4,4,6,6-pen-
takis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ꢁ1,3,5,2k5,
4k5,6k5-triazatriphosphinin-2-yl)oxy)benzoate)
Triethylene glycol monomethyl ether (190 mg, 1.17 mmol)
was dissolved in dry THF (50 mL) in a 250 mL round-bot- 3.1.7. Synthesis of compound 8 (propyl 4-((2,4,4,6,6-penta-
tomed three-necked flask in an argon atmosphere. NaH kis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ꢁ1,3,5,2k5,
(47 mg, 1.17 mmol (60%)) solid was added to the reaction 4k5,6k5-triazatriphosphinin-2-yl)oxy)benzoate)
medium and heated at reflux temperature of THF under Triethylene glycol monomethyl ether (541 mg, 3.3 mmol)
reflux for 2 h. After cooling the reaction mixture to room was dissolved in dry THF (50 mL) in a 250 mL round-bot-
temperature, the outdoor was cooled to about –10 ꢂC in an tomed three-necked flask in an argon atmosphere. NaH
ice-salt bath. Compound 1 (100 mg, 0.22 mmol) was slowly (40 mg, 2.75 mmol (60%)) solid was added to the reaction
added to the reaction mixture by dissolving in dry THF medium and heated at reflux temperature of THF under
(100 mL). The reaction was allowed to warm to room tem- reflux for 2 h. After cooling the reaction mixture to room
perature and stirred at room temperature for 2 days by con- temperature, the outdoor was cooled to about –10 ꢂC in an
trol with TLC. The reaction mixture was filtered through a ice-salt bath. Compound 3 (100 mg, 0.55 mmol) was slowly
sintered filter to remove the sodium chloride salt. The solv- added to the reaction mixture by dissolving in dry THF
ent of the filtrate was removed in vacuum using a rotary (100 mL). The reaction was allowed to warm to room tem-
evaporator. Compound 6 (120 mg, 50%, white oil) was iso- perature and stirred at room temperature for 2 days by con-
lated from the reaction mixture in silica gel (70-230 mesh) trol with TLC. The reaction mixture was filtered through a
column, using the n-hexane-DCM (2: 3) system as the driv- sintered filter to remove the sodium chloride salt. The solv-
ing phase. Spectral data of compound 6: MS (MALDI-TOF) ent of the filtrate was removed in vacuo using a rotary

8
E. ŞENKUYTU ET AL.
evaporator. Compound 8 (105 mg, 45%, white oil) was iso- added to the reaction mixture by dissolving in dry THF
lated from the reaction mixture in silica gel (70-230 mesh)
column, using the n-hexane-DCM (2: 3) system as the driv-
ing phase. Spectral data of compound 8: MS (MALDI-TOF)
(DHB) m/z (%): Calcd. for (C45H86N3O23P3): 1130.10; found
1086.95 [M-C3H7]þ. 31P NMR decoupled to (202 MHz,
(100 mL). The reaction was allowed to warm to room tem-
perature and stirred at room temperature for 2 days by con-
trol with TLC. The reaction mixture was filtered through a
sintered filter to remove the sodium chloride salt. The solv-
ent of the filtrate was removed in vacuo using a rotary evap-
orator. Compound 10 (95 mg, 43%, white oil) was isolated
from the reaction mixture in silica gel (70-230 mesh) col-
umn, using the hexane-DCM (2: 3) system as the driving
phase. Spectral data of compound 10: MS (MALDI-TOF)
(DHB) m/z (%): Calcd. for (C48H84N3O23P3): 1164.12; found
1085.58 [M-C7H9]þ. 31P NMR decoupled to (202 MHz,
2
CDCl3, 298 K), P(R2)2 d ¼ 17.29 ppm (2P, JP-P ¼ 85.28 Hz);
2
P(R1)(R2) d ¼ 14.07 ppm (1P, JP-P ¼ 85.28 Hz) Spin system:
1
A2B (Supporting Information Figures S17 and S18). H-NMR
(500 MHz, CDCl3, 298 K) d ppm, 8.00, d, 2H, Ha (3JHH
¼
6.72Hz); 7.14, d, 2H, Hb (3JHH ¼ 6.72 Hz); 3.70–3.40, m,
62H (-OCH2); 3.30, s, 15H, (-OCH3); 1.73–1.67, m, 2H,
(-CH2); 1.01–0.91, m, 3H, (-CH3) (Supporting Information
Figure S19).
2
CDCl3, 298 K), P(R2)2 d ¼ 17.24 ppm (2P, JP-P ¼ 85.21 Hz);
2
P(R1)(R2) d ¼ 14.16 ppm (1P, JP-P ¼ 85.21 Hz) Spin system:
A2B (Supporting Information Figures S23 and S24). 1H-
NMR (500 MHz, CDCl3, 298 K) d ppm, 8.03, d, 2H, Ha
(3JHH ¼ 7.21 Hz); 7.24, d, 2H, Hb (3JHH ¼ 7.21 Hz);
7.43–7.30, m, 5H, Hc/Hd/He; 3.76–3.49, m, 62 H (-OCH2);
3.36, s, 15 H, (-OCH3) (Supporting Information Figure S25).
3.1.8. Synthesis of compound 9 (buthyl 4-((2,4,4,6,6-penta-
kis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ꢁ1,3,5,2k5,
4k5,6k5-triazatriphosphinin-2-yl)oxy)benzoate)
Triethylene glycol monomethyl ether (420 mg, 2.5 mmol) was
dissolved in dry THF (50 mL) in a 250 mL round-bottomed
three-necked flask in an argon atmosphere. NaH (35 mg,
2.5 mmol (60%)) solid was added to the reaction medium and
heated at reflux temperature of THF under reflux for 2 h.
After cooling the reaction mixture to room temperature, the
outdoor was cooled to about –10 ꢂC in an ice-salt bath.
Compound 4 (100 mg, 0.51 mmol) was slowly added to the
reaction mixture by dissolving in dry THF (100 mL). The reac-
tion was allowed to warm to room temperature and stirred at
room temperature for 2 days by control with TLC. The reac-
tion mixture was filtered through a sintered filter to remove
the sodium chloride salt. The solvent of the filtrate was
removed in vacuo using a rotary evaporator. Compound 9
(90 mg, 40%, white oil) was isolated from the reaction mixture
in silica gel (70-230 mesh) column, using the n-hexane-DCM
(2: 3) system as the driving phase. Spectral data of compound
9: MS (MALDI-TOF) (DHB) m/z (%): Calcd. for
(C46H88N3O23P3): 1144.13; found 1144.37 [M]þ. 31P NMR
decoupled to (202 MHz, CDCl3, 298K), P(R2)2 d ¼ 17.25 ppm
4. Conclusion
In summary, in this study, five parabens substituted cyclotri-
phosphazene compounds 1-5 and five new paraben-deriva-
tive cyclotriphosphazenes containing hydrophilic side groups
6-10 were successfully synthesized. The structural properties
of all synthesized compounds were examined by MALDI-
TOF spectrometer, H, 31P NMR spectroscopy. The proton
1
decoupled 31P NMR spectrum of the compounds were
observed as A2X spin system for compounds 1-5, and as
A2B spin system for compounds 6-10. Additionally, the
photophysical properties (absorption and emission) of these
compounds 1-10 in different solvents were investigated
using UV-Vis and fluorescence spectroscopies. In general,
the absorbance bands of the compounds 1-10 were observed
at approximately 230–300 nm in all solvents studied. The
highest fluorescence emission intensity of compounds 1-10
was observed in tetrahydrofuran at about 312 nm, while the
lowest emission intensity was observed in chloroform. Due
to the potential biological activity properties of parabens, it
is thought that the synthesized new compounds may be bio-
logically active compounds. In the future application of this
study, the DNA binding properties of the synthesized para-
ben-cyclotriphosphazene derivatives carrying hydrophilic
groups will be investigated with automatic biosensor device
in our laboratories.
2
2
(2P, JP-P¼ 85.41 Hz); P(R1)(R2) d ¼ 14.37 ppm (1P, JP-P
¼
85.41 Hz) Spin system: A2B (Supporting Information Figures
1
S20 and S21). H-NMR (500 MHz, CDCl3, 298 K) d ppm, 8.05,
d, 2H, Ha (3JHH ¼ 7.17 Hz); 7.30, d, 2H, Hb (3JHH ¼ 7.17 Hz);
3.80–3.50, m, 62H (-OCH2); 3.38, s, 15H, (-OCH3); 2.10–2.02,
m, 2H, (-CH2); 1.66–1.59, m, 2H, (-CH2); 0.93–0.81, m, 3H,
(-CH3) (Supporting Information Figure S22).
3.1.9. Synthesis of compound 10 (benzyl 4-((2,4,4,6,6-pen-
takis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ꢁ1,3,5,2k5,
4k5,6k5-triazatriphosphinin-2-yl)oxy)benzoate)
Triethylene glycol monomethyl ether (360 mg, 2.2 mmol)
was dissolved in dry THF (50 mL) in a 250 mL round-bot-
tomed three-necked flask in an argon atmosphere. NaH
(30 mg, 2.2 mmol (60%)) solid was added to the reaction
medium and heated at reflux temperature of THF under
reflux for 2 h. After cooling the reaction mixture to room
temperature, the outdoor was cooled to about –10 ꢂC in an
Acknowledgments
This article is dedicated to Prof. Dr. Adem Kılıc¸ on the occasion of
his retirement.
ORCID
ice-salt bath. Compound 5 (100 mg, 0.43 mmol) was slowly Elif S¸enkuytu
http://orcid.org/0000-0002-3579-8062

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
9
X-Ray Crystal-Structure of Octapyrrolidinocyclotetraphosphazene.
N4P4(NC4H8)8. J. Mol. Struct. 1978, 49, 421–423. DOI: 10.1016/
0022-2860(78)87282-2.
References
[1] Ainscough, E. W.; Brodie, A. M.; Derwahl, A.; Kirk, S.; Otter,
C. A. Conformationally Rigid Chelate Rings in Metal
Complexes of Pyridyloxy-Substituted 2,2’-Dioxybiphenyl-
Cyclotetra- and Cyclotriphosphazene Platforms. Inorg. Chem.
2007, 46, 9841–9852. DOI: 10.1021/ic701241v.
[2] Allen, C. W. Regio-and Stereochemical Control in Substitution
Reactions of Cyclophosphazenes. Chem. Rev. 1991, 91, 119–135.
DOI: 10.1021/cr00002a002.
[3] Shaw, R. A.; Fitzsimmons, B. W.; Smith, B. C. The
Phosphazenes (Phosphonitrilic Compounds). Chem. Rev. 1962,
62, 247–281. DOI: 10.1021/cr60217a004.
[4] Elias, A. J.; Shreeve, J. M. Perfluorinated Cyclic Phosphazenes.
Adv. Inorg. Chem. 2001, 52, 335–358. DOI: 10.1016/S0898-
8838(05)52007-5.
[5] Breuer, O.; Sundararaj, U. Big Returns from Small Fibers: A
Review of Polymer/Carbon Nanotube Composites. Polym.
Compos. 2004, 25, 630–645. DOI: 10.1002/pc.20058.
[6] Jamain, Z.; Khairuddean, M.; Saidin, S. A. Synthesis and
Characterization of 1, 4-Phenylenediamine Derivatives
Containing Hydroxyl and Cyclotriphosphazene as Terminal
Group. J. Mol. Struct. 2019, 1186, 293–302. DOI: 10.1016/j.mol-
struc.2019.02.013.
[7] Brauge, L.; Veriot, G.; Franc, G.; Deloncle, R.; Caminade, A.-
M.; Majoral, J.-P. Synthesis of Phosphorus Dendrimers Bearing
Chromophoric End Groups: Toward Organic Blue Light-
Emitting Diodes. Tetrahedron 2006, 62, 11891–11899. DOI: 10.
1016/j.tet.2006.09.093.
[8] Bao, R.; Pan, M.; Qiu, J. J.; Liu, C. M. Synthesis and
Characterization of Six-Arm Star-Shaped Liquid Crystalline
Cyclotriphosphazenes. Chin. Chem. Lett. 2010, 21, 682–685.
DOI: 10.1016/j.cclet.2009.12.020.
[9] S¸enkuytu, E.; Ec¸ik, E. T. New Hexa-Bodipy Functionalized
Dendrimeric Cyclotriphosphazene Conjugates as Highly
Selective and Sensitive Fluorescent Chemosensor for Co2þ Ions.
Spectrochim. Acta A 2018, 198, 232–238. DOI: 10.1016/j.saa.
2018.03.002.
[10] Asmafiliz, N.; Berberoglu, I.; Ozgur, M.; Kilic, Z.; Kayalak, H.;
Acik, L.; Turk, M.; Hokelek, T. Phosphorus-Nitrogen
Compounds: Part 46. The Reactions of N3P3Cl6 with Bidentate
and Monodentate Ligands: The Syntheses, Structural
Characterizations, Antimicrobial and Cytotoxic Activities, and
DNA Interactions of (N/N)Spirocyclotriphosphazenes with 4-
Chlorobenzyl Pendant Arm. Inorg. Chim. Acta 2019, 495,
118949. DOI: 10.1016/j.ica.2019.05.048.
[17] Akbas, H.; Okumus, A.; Kilic, Z.; Hokelek, T.; Suzen, Y.; Koc,
L. Y.; Acik, L.; Celik, Z. B. Phosphorus-Nitrogen Compounds
Part 27. Syntheses, Structural Characterizations, Antimicrobial
and Cytotoxic Activities, and DNA Interactions of New
Phosphazenes Bearing Secondary Amino and Pendant (4-
Fluorobenzyl)Spiro Groups. Eur. J. Med. Chem. 2013, 70,
294–307. DOI: 10.1016/j.ejmech.2013.09.046.
[18] Sournies, F.; Labarre, J.-F.; Spreafico, F.; Filippeschi, S.; Quan
Jin, X. Attempts at the Production of More Selective
Antitumorals.
2.
The
Antineoplastic
Activity
of
Cyclophosphazenes Linked to Spermine. J. Mol. Struct. 1986,
147, 161–173. DOI: 10.1016/0022-2860(86)87067-3.
[19] Dueymes, M.; Fourniꢀe, G. J.; Mignon-Contꢀe, M.; In, S.; Contꢀe,
J. J. Prevention of Lupus Diseases in Mrl/I, Nzbxnzw, and Bxsb
Mice Treated with a Cyclophosphazene Derived Drug. Clin.
Immunol. Immunopathol. 1986, 41, 193–205. DOI: 10.1016/
0090-1229(86)90103-0.
[20] Ciftci, G. Y.; Senkuytu, E.; Incir, S. E.; Yuksel, F.; Olcer, Z.;
Yildirim, T.; Kilic, A.; Uludag, Y. First Paraben Substituted
Cyclotetraphosphazene Compounds and DNA Interaction
Analysis with a New Automated Biosensor. Biosens. Bioelectron.
2016, 80, 331–338. DOI: 10.1016/j.bios.2016.01.061.
[21] Pollock, T.; Weaver, R. E.; Ghasemi, R.; Decatanzaro, D. Butyl
Paraben and Propyl Paraben Modulate Bisphenol
a and
Estradiol Concentrations in Female and Male Mice. Toxicol.
Appl. Pharmacol. 2017, 325, 18–24. DOI: 10.1016/j.taap.2017.04.
001.
[22] Baytak, A. K.; Duzmen, S.; Teker, T.; Aslanoglu, M.
Voltammetric Determination of Methylparaben and Its DNA
Interaction Using
a Novel Platform Based on Carbon
Nanofibers and Cobalt-Nickel-Palladium Nanoparticles. Sens.
Actuators B Chem. 2017, 239, 330–337. DOI: 10.1016/j.snb.
2016.08.029.
[23] Amin, A.; Chauhan, S.; Dare, M.; Bansal, A. K. Degradation of
Parabens by Pseudomonas beteli and Burkholderia latens. Eur. J.
Pharm. Biopharm. 2010, 75, 206–212. DOI: 10.1016/j.ejpb.2010.
03.001.
[24] Ciftci, G. Y.; Senkuytu, E.; Incir, S. E.; Ecik, E. T.; Zorlu, Y.;
Olcer, Z.; Uludag, Y. Characterization of Paraben Substituted
Cyclotriphosphazenes, and a DNA Interaction Study with a
Real-Time Electrochemical Profiling Based Biosensor.
Microchim. Acta 2017, 184, 2307–2315. DOI: 10.1007/s00604-
017-2162-y.
€
[11] G€orgu€lu€, A. O.; Koran, K.; Ozen, F.; Tekin, S.; Sandal, S.
[25] Senkuytu, E.; Yildirim, T.; Olcer, Z.; Uludag, Y.; Ciftci, G. Y.
DNA Interaction Analysis of Fluorenylidene Double Bridged
Cyclotriphosphazene Derivatives. Inorg. Chim. Acta 2018, 477,
219–226. DOI: 10.1016/j.ica.2018.02.035.
Synthesis, Structural Characterization and Anti-Carcinogenic
Activity
Dioxybiphenyl and Chalcone Groups. J. Mol. Struct. 2015,
1087, 1–10. DOI: 10.1016/j.molstruc.2015.01.033.
of
New
Cyclotriphosphazenes
Containing
[26] Eserci, H.; S¸enkuytu, E.; Okutan, E. New Cyclotriphosphazene
Based Nanotweezers Bearing Perylene and Glycol Units and
Their Non-Covalent Interactions with Single Walled Carbon
Nanotubes. J. Mol. Struct. 2019, 1182, 1–8. DOI: 10.1016/j.mol-
struc.2019.01.023.
[27] Jadhav, V. B.; Toti, U. S.; Cui, J. X.; Jun, Y. J.; Sohn, Y. S.
Amphiphilic Cyclotriphosphazenes Grafted with Branched
Oligopeptides. Bull. Korean Chem. Soc. 2010, 31, 3735–3739.
DOI: 10.5012/bkcs.2010.31.12.3735.
[28] Toti, U. S.; Moon, S. H.; Kim, H. Y.; Jun, Y. J.; Kim, B. M.;
Park, Y. M.; Jeong, B.; Sohn, Y. S. Thermosensitive and
Biocompatible Cyclotriphosphazene Micelles. J. Control. Release
2007, 119, 34–40. DOI: 10.1016/j.jconrel.2007.01.003.
[29] Wang, N.; Ma, W. J.; Ren, Z. Q.; Du, Y. C.; Xu, P.; Han, X. J.
Prussian Blue Analogues Derived Porous Nitrogen-Doped
Carbon Microspheres as High-Performance Metal-Free
Peroxymonosulfate Activators for Non-Radical-Dominated
Degradation of Organic Pollutants. J. Mater. Chem. A 2018, 6,
884–895. DOI: 10.1039/C7TA08472B.
[12] Wang, D.; Feng, X. M.; Zhang, L. P.; Li, M.; Liu, M. M.; Tian,
A. L.; Fu, S. H. Cyclotriphosphazene-Bridged Periodic
Mesoporous Organosilica-Integrated Cellulose Nanofiber
Anisotropic Foam with Highly Flame-Retardant and Thermally
Insulating Properties. Chem. Eng. J. 2019, 375, 121933. DOI:
10.1016/j.cej.2019.121933.
[13] Okutan, E.; Eserci, H.; S¸enkuytu, E. New Perylenebisimide
Decorated Cyclotriphosphazene Heavy Atom Free Conjugate as
Singlet Oxygen Generator. Spectrochim. Acta A 2019, 222,
117232. DOI: 10.1016/j.saa.2019.117232.
[14] Yildirim, T.; Bilgin, K.; Ciftci, G. Y.; Ecik, E. T.; Senkuytu, E.;
Uludag, Y.; Tomak, L.; Kilic, A. Synthesis, Cytotoxicity and
Apoptosis of Cyclotriphosphazene Compounds as Anti-Cancer
Agents. Eur. J. Med. Chem. 2012, 52, 213–220. DOI: 10.1016/j.
ejmech.2012.03.018.
[15] Gleria, M.; Jaeger, R. D. Applicative Aspects of
Cyclophosphazenes; Nova Science Publishers: New York, 2004.
[16] Bovin, J. O.; Galy, J.; Labarre, J. F.; Sournies, F.
Cyclophosphazenes as Novel Potential Anti-Tumor Agents -

10
E. ŞENKUYTU ET AL.
[30] Wan, D.; Chen, Y.; Su, J.; Liu, L.; Zuo, Y. Ultraviolet
Absorption Redshift Induced Direct Photodegradation of
Halogenated Parabens under Simulated Sunlight. Water. Res.
2018, 142, 46–54. DOI: 10.1016/j.watres.2018.05.039.
[31] Wang, Q.; Zhang, Y.; Sun, H.; Chen, H.; Chen, X. Study
Ofinteractionofbutyl p-Hydroxybenzoatewithhumanserumalbumin
by Molecularmodelingandmulti-Spectroscopicmethod. J. Lumin.
2011, 131, 206–211. DOI: 10.1016/j.jlumin.2010.09.040.
Advanced Oxidation Processes. Chem. Eng. 2020, 379, 122334.
DOI: 10.1016/j.cej.2019.122334.
[34] Rolland, O.; Griffe, L.; Poupot, M.; Maraval, A.; Ouali, A.;
Coppel, Y.; Fournie, J. J.; Bacquet, G.; Turrin, C. O.; Caminade,
A. M.; et al. Tailored Control and Optimisation of the Number
of Phosphonic Acid Termini on Phosphorus-Containing
Dendrimers for the Ex-Vivo Activation of Human Monocytes.
Chem. Eur. J. 2008, 14, 4836–4850. DOI: 10.1002/chem.
200701063.
[32] Gmurek, M.; Miller, J. S.; Ledakowicz, S. Kinetics of the
Photosensitized Degradation of Benzyl 4-Hydroxybenzoate in
[35] Shimomoto, H.; Asano, H.; Itoh, T.; Ihara, E. Pd-Initiated
Homogeneous
Aqueous
Solution
under
Visible-Light
Controlled Polymerization of Diazoacetates with
a Bulky
Irradiation. Chem. Eng. 2012, 210, 417–424. DOI: 10.1016/j.cej.
Substituent: synthesis of Well-Defined Homopolymers and
Block Copolymers with Narrow Molecular Weight Distribution
from Cyclophosphazene-Containing Diazoacetates. Polym.
Chem. 2015, 6, 4709–4714. DOI: 10.1039/C5PY00532A.
2012.08.097.
ꢀ
ꢀ
ꢀ
[33] Alvarez, M. A.; Ruidıaz-Martınez, M.; Cruz-Quesada, G.;
Loꢀpez-Ramoꢀn, M. V.; Rivera-Utrilla, J.; Sꢀanchez-Polo, M.;
Mota, A. J. Removal of Parabens from Water by UV-Driven