Synthesis of ω-phosphonated poly(ethylene oxide)s through the combination of kabachnik-fields reaction and "click" chemistry

Article abstract of DOI:10.1002/pola.26399

The synthesis of new ω-phosphonic acid-terminated poly(ethylene oxide) (PEOs) monomethyl ethers was investigated by the combination of Atherton-Todd or Kabachnik-Fields reactions and the "click" copper-catalyzed 1,3-dipolar cycloaddition of azides and ter

Full text of DOI:10.1002/pola.26399

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Synthesis of x-Phosphonated Poly(ethylene oxide)s Through the
Combination of Kabachnik–Fields Reaction and ‘‘Click’’ Chemistry
1
1
Thi Thanh Thuy N’Guyen,1 Karima Oussadi,1,2 Veronique Montembault, Laurent Fontaine
ꢀ
1
ꢀ
ꢀ
ꢀ
ꢀ
LUNAM Universite, Institut des Molecules et Materiaux du Mans, Equipe Methodologie et Synthe`se des Polyme`res, UMR CNRS
ꢀ
6283, Universite du Maine, Avenue O. Messiaen, 72085 Le Mans Cedex 9, France
2
ꢀ
Universite des Sciences et de Technologie Mohamed Boudiaf, BP 1505, Oran El M’Naouar 31000, Algeria
Correspondence to: L. Fontaine (E-mail: laurent.fontaine@univ-lemans.fr)
Received 13 July 2012; accepted 27 September 2012; published online 19 October 2012
DOI: 10.1002/pola.26399
ABSTRACT: The synthesis of new x-phosphonic acid-terminated
poly(ethylene oxide) (PEOs) monomethyl ethers was investi-
gated by the combination of Atherton–Todd or Kabachnik–
Fields reactions and the ‘‘click’’ copper-catalyzed 1,3-dipolar
cycloaddition of azides and terminal alkynes. The Atherton–
Todd route fails to give the corresponding phosphonic acid-ter-
minated PEOs due to competitive cleavage of the PAN bond
during the dealkylation step. In contrast, the Kabachnik–Fields
route leads with very good yields to x-phosphonic acid-PEO
through ‘‘click’’ reaction of azido-PEO onto dimethyl aminopro-
pargyl phosphonate prepared by Kabachnik–Fields reaction
between propargylbenzylimine and dimethyl phosphonate,
followed by acidic hydrolysis. The reported methodology, pre-
cluding the use of anionic polymerization of ethylene oxide,
leads to novel well-defined phosphonic acid-terminated PEOs
from commercially available products in good yields. Moreover,
such a strategy can be adapted to anchor phosphonic acid func-
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tionality onto a wide range of polymers.
2012 Wiley Periodi-
cals, Inc. J Polym Sci Part A: Polym Chem 51: 415–423, 2013
KEYWORDS: aminophosphonates; Atherton–Todd reaction;
‘‘click’’ chemistry; functionalization of polymers; Kabachnik–
Fields reaction; MALDI; modification; poly(ethylene oxide); syn-
thesis; water-soluble polymers
INTRODUCTION Phosphorus-containing
polymers
have
the most widely used coatings for magnetic nanoparticles
because of its low cytotoxicity, hydrosolubility, and ability to
mask foreign substrates from the immune system.33 A num-
ber of PEO end-functionalized with various organophosphorus
groups have been investigated,34–39 especially in view of the
ability of organophosphates to bind to a wide range of metal
oxide surfaces.40–43 Nevertheless, only a few efficient synthe-
ses of phosphorylated end-functionalized PEOs have been
reported in the literature up to now. Besides esterification of
mPEG using POCl3 followed by partial hydrolysis,35–38 phos-
phorus end-functionalized PEOs were prepared via radical
addition reactions44,45 and Michael addition.46 Phosphonated
PEOs were prepared by Mosquet et al.47 and by Shephard
et al.36 through Moedritzer–Irani reaction.48 Phosphonated
PEOs have mainly found applications as steric stabilizers for
colloidal suspensions,47 and for coating metallic nanopar-
ticles.34–36,46 In this context, this report describes the combi-
nation of Atherton–Todd reaction6,8,12,13,16,49 and of Kabach-
nik–Fields reaction7,50–52 together with ‘‘click’’ chemistry53 for
the straightforward synthesis of mPEGs containing an x-phos-
phonyl functional group which are potential candidates for a
wide range of uses, including stabilization and dispersion of
metallic nanoparticles.34–42
attracted attention because of their broad application
areas.1–4 Polyphosphonates and polyphosphates are known
as fire-retardant additives,5 adhesion promoters and corro-
sion inhibitors,2 and chelating agents.6–8 Phosphorus-based
polymers can also be employed for various biomedical appli-
cations9,10 such as drug delivery,11–16 tissue engineering,17
and dental applications.18–20
Poly(ethylene oxide) (PEO)—also referred to as poly(ethylene
glycol) (PEG) for structures bearing hydroxyl end-groups—is
a neutral, non-toxic, hydrophilic synthetic polymer which has
found numerous applications.21 It has emerged as the poly-
mer of choice for use in pharmaceutical, biotechnical, and bio-
medical applications. Because of those interesting properties,
the range of PEO-based polymers has been expanded, includ-
ing complex structures of graft copolymers with PEO side
chains,22–24 and PEO oligomers with tailored functionalities at
the chain-ends.25 Some specific applications require heterobi-
functional PEOs with distinct reactive functional groups at the
ends of the polymer chain.26–32 One of the most commonly
used functionalized derivatives of PEO is methoxy-terminated
PEO (mPEG) which can serve as the building block for prepa-
ration of various heterobifunctional PEOs.25 PEO is also one of
Additional Supporting Information may be found in the online version of this article
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2012 Wiley Periodicals, Inc.
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SCHEME 1 Synthesis of propargyl phosphoramidates 1 and 2.
RESULTS AND DISCUSSION
Fig. S3(A)] to the proton of the triazole ring [e at 7.70 ppm,
Supporting Information Fig. S3(A)] that gave a 6:0.96 ratio.
The same conclusions could be drawn from the reaction
between 1 and PEOAN3 [Supporting Information Fig. S3(B)].
Moreover, the matrix-assisted laser desorption and ionization
time of flight (MALDI-TOF) mass spectra (Fig. 1) confirmed
the expected structures. As an example, the MALDI-TOF mass
spectrum of 4 [Fig. 1(A)] showed a single series of peaks
separated by m/z ¼ 44.04, the molecular weight of the PEO
repeat unit (calculated value ¼ 44.0262 g molꢀ1). The peak
at m/z ¼ 1900.15 corresponds to a polymer of 37 PEO units
ionized by a sodium atom, with a methyl group at one chain-
Atherton–Todd Route
Propargyl phosphoramidates bearing a dialkyl phosphonate
group, that is dimethyl prop-2-ynylphosphoramidate (1) and
diethyl prop-2-ynylphosphoramidate (2), were synthesized
via Atherthon–Todd reaction according to Scheme 1. The
reaction of diethyl phosphonate with N-propargylamine was
carried out according to a literature procedure,54 leading to
2 in 55% yield after distillation. The same procedure was
used to generate the new compound 1, which was obtained
in a modest 22% yield after recrystallization of the crude
solid product from hexane:dichloromethane. H, 13C, and 31P
NMR (see Supporting Information Figs. S1 and S2), as well
as high resolution mass spectrometry, confirmed the success-
ful synthesis of compounds 1 and 2.
1
end and
a
triazole diethylphosphoramidate group
ACH2ANHAP(O)(OEt)2 at the other chain-end (calculated
value ¼ 1900.06 g molꢀ1). The last step for obtaining phos-
phonic acid-terminated PEO monomethyl ether consists in
the deprotection of the phosphonates in a multi-step one-pot
procedure. The established methodology to remove the ester
protecting groups of phosphonates involving the use of tri-
methylsilyl bromide (TMSBr) has been used (Scheme 3).55
This transformation has been characterized by 31P NMR
(Supporting Information Fig. S4), with a shielding of the sig-
nal of the P(O) group from 10.86 ppm [Supporting Informa-
tion Fig. S4(A)] to 1.22 ppm [Supporting Information Fig.
S4(B)], which is consistent with values reported in the litera-
ture for aminophosphonic acids.56 1H NMR spectrum (Sup-
porting Information Fig. S5) also confirmed the total
disappearance of the signals due to the CH3 of the dimethyl-
phosphonate group and a shielding of the CH2 connecting
the phosphoramide group from 4.22 to 4.37 ppm. The
MALDI-TOF mass spectrum of the resulting product (Fig. 2)
shows a single series of peaks separated by m/z ¼ 44.10,
the molecular weight of the PEO repeat unit (calculated
value ¼ 44.0262 g molꢀ1). Nevertheless, the peak at m/z ¼
1956.08 corresponds to a polymer of 41 PEO units ionized
by a potassium atom, with a methyl group at one chain-end
and a triazole aminomethyl group at the other chain-end
(calculated value ¼ 1956.11 g molꢀ1). This means that the
PAN bond of 3 (and 4) is susceptible to TMSBr cleavage, as
The ‘‘click’’ coupling reactions were performed between 1 or
2
and azido-terminated PEO monomethyl ether 2000
(PEOAN3) as shown in Scheme 2. PEOAN3 was synthesized
by mesylation of hydroxyl-terminated PEO monomethyl
ether, followed by nucleophilic substitution using sodium az-
ide according to a literature procedure.23 The ‘‘click’’ reac-
tions were carried out in N,N-dimethylformamide (DMF) at
room temperature for 24 h using a stoichiometric ratio
between PEOAN3 and alkynyl groups in the presence of a
catalytic amount of Cu(I)Br with N,N,N0,N0,N"-pentamethyldie-
thylenetriamine (PMDETA) as the ligand. The phosphonate-
terminated PEO monomethyl ethers 3 and 4 (Scheme 2)
were purified by precipitation into diethyl ether.
1H NMR spectra of 2 and 4 clearly indicated the shift of the
alkyne proton at 2.25 ppm (e, Supporting Information Fig.
S2) to 7.70 ppm [e, Supporting Information Fig. S3(A)] as
well as the shift of the methylene group next to the alkyne
functionality at 3.68 ppm (d, Supporting Information Fig. S2)
to 4.22 ppm [d, Supporting Information Fig. S3(A)], which
correspond to the protons linked to the formed triazole ring.
Completion of the reaction was confirmed by the ratio of
integrations of peaks assigned to the CH3 protons of diethyl
phosphonate groups [a at 1.31 ppm, Supporting Information
SCHEME 2 Synthesis of phosphonate-terminated PEO monomethyl ethers 3 and 4.
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robust PAC bond between the phosphoryl moiety and the
PEO chain using the Kabachnik–Fields reaction.7,50–52
Kabachnik–Fields Route
Propargyl aminophosphonate 6 was synthesized through
Kabachnik–Fields reaction51,52 in
a two-step procedure
(Scheme 4) according to a literature protocol.57 In the first
step, N-benzylideneprop-2-yn-1-amine (5) was synthesized
from benzaldehyde and N-propargylamine in 77% yield.58 In
the second step, imine 5 was reacted with dimethyl phos-
phite undꢁer solvent-free and catalyst-free conditions for 8 h
at 60–80 C to afford dimethyl phenyl(prop-2-ynylamino)me-
thylphosphonate (6) in a very good 85% yield after silica gel
column chromatography. The structure of 6 was confirmed
1
by IR, H, 13C, 31P spectroscopy, and mass spectrometry. The
1H NMR spectrum of 6 [Supporting Information Fig. S7(A)]
showed the disappearance of the signal arising from the
CH¼¼N group of imine 5 at 8.56 ppm [Supporting Informa-
tion Fig. S6(A)] and concomitant appearance of a new peak
at 4.39 ppm ascribed to the CH(P) proton of 6. Moreover,
the 31P NMR spectrum of 6 [Supporting Information Fig.
S7(B)] showed a singlet at 25.06 ppm, in the region expected
for aminophosphonate derivatives.59–61
Typical ‘‘click’’ coupling reaction between PEOAN3 2000 and
5000 and 6 (Scheme 5) was then successfully performed in
DMF solvent at room temperature for 24 h under the condi-
tions reported above. The phosphonate-terminated PEO
monomethyl ethers 7a (from PEOAN3 2000) and 7b (from
PEOAN3 5000) were purified by precipitation into diethyl
ether.
Figure 3 shows the 1H NMR spectrum of dimethylphospho-
nate-terminated PEO 7a (see Supporting Information Fig. S8
for 7b). A set of new peaks was clearly observed at 7.61
ppm typical of the methine proton of the triazole ring, at
3.52–3.72 ppm typical of the protons for the ethylene oxide
units, at 3.38 ppm for the methoxy protons, at 4.52 ppm for
the A(triazole)ACH2CH2(OCH2CH2)44OCH3, and at 3.86 ppm
for the A(triazole)ACH2CH2(OCH2CH2)44OCH3 protons. Con-
comitant shielding of the CH linked to the phosphorus from
4.39 ppm [H5, Supporting Information Fig. S7(A)] to 4.12
ppm (H5, Fig. 3) also confirmed that the desired reaction
had taken place. Furthermore, integrations of the newly
FIGURE 1 MALDI-TOF mass spectra of (A) diethylphosphonate-
terminated PEO monomethyl ether (4) and (B) dimethylphosph-
onate-terminated PEO monomethyl ether (3); matrix: DCTB,
NaTFA.
evidenced by MALDI-TOF mass spectrometry, and as already
observed with phosphoramide esters generated from second-
ary amines.56 These results prompt us to use another
strategy to prepare x-phosphorylated PEO by introducing a
SCHEME 3 Reaction of phosphonate-terminated PEO with TMSBr.
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spectrum showed the appearance of a new broad absorbance
band at 3100 cmꢀ1, which confirmed the formation of phos-
phonic acid chain-end. To provide direct evidence for the
phosphonic acid-terminated PEO structure obtained, MALDI-
TOF analysis of 8a was carried out, as shown in Figure 5.
The MALDI-TOF mass spectrum of the resulting product
recorded in negative ion mode shows only one series of
peaks, which show a regular interval of 44.08 g molꢀ1 for
the molar mass that corresponds to the ethylene oxide unit.
In addition, the peak at m/z ¼ 2174.92 corresponds to a
deprotonated polymer of 43 PEO units, with a methyl group
at one chain-end and a phosphonic acid at the other chain-
end (calculated value ¼ 2174.21 g molꢀ1). Similar results
were obtained for 8b.
EXPERIMENTAL
Materials
Triethylamine (b.p.760 Torr ¼ 86 ꢁC) was distilled over CaH2
FIGURE 2 MALDI-TOF mass spectrum of the product resulting
from the attempted dealkylation reaction of 3 using TMSBr;
matrix: a-cyano-4-hydroxycinnamic acid, KTFA.
ꢁ
and was stored at ꢀ4 C after purification. Diethyl phosphite
(b.p.0.2
¼ 50 ꢁC) and dimethyl phosphite (b.p.0.2
¼
Torr
Torr
ꢁ
40 C) were distilled in vacuum before use. PEO monomethyl
ether (PEOAOH) 2000 (Mn NMR ¼ 2010 g molꢀ1) and PEO-
OH 5000 (Mn NMR ¼ 4600 g molꢀ1) were heated at 120 ꢁC
for 3 h under nitrogen atmosphere to remove excess water
before use. Azido-terminated PEO monomethyl ethers
(PEOAN3 2000 and 5000)23 and N-benzylideneprop-2-yn-1-
amine (5)58 were synthesized according to literature proce-
dures. All other chemicals were purchased from commercial
sources and used without further purification.
five-membered triazole ring proton (H9, Fig. 3) peak and the
methoxy-terminal PEO protons (H13, Fig. 3) peak gave a 3:1
ratio, indicating almost quantitative ‘‘click’’ transformation.
Moreover, the MALDI-TOF characterization of 7a sample
(Fig. 4) fully corroborates the results of 1H NMR analysis.
Only one population is observed with a peak-to-peak mass
increment of 44.04 g molꢀ1 corresponding to the molecular
weight of the PEO repeat unit (calculated value ¼ 44.0262 g
molꢀ1). Each signal of this series is assignable to the dime-
thylphosphonate-terminated PEO monomethyl ether 7a. For
instance, the peak at m/z ¼ 2066.19 is assigned to species
with a degree of polymerization of 42 ionized by a sodium
atom, with a methyl group at one end and a dimethylphos-
phonyl group at the other chain-end (calculated value ¼
2066.11 g molꢀ1).
General Characterization
NMR spectra were recorded on a Bruker Avance 400 spec-
trometer using deuterated chloroform or methanol as the
solvent and tetramethylsilane, 2,2-dimethyl-2-silapentane-5-
sulfonate (DSS) and H3PO4 as a reference for 1H, 13C, and
31P nuclei, respectively. Coupling constants and chemical
shifts are reported in hertz and in parts per million (ppm),
respectively. FTIR spectra were recorded using a Nicolet ava-
tar 370 DTGS spectrometer in transmittance mode. High re-
solution mass spectra (HR-MS) were recorded on a Waters-
The dimethylphosphonate-terminated PEO monomethyl
ethers 7a,b were then converted to their phosphonic acid
homologues 8a,b according to (i) the previous methodology
involving the use of TMSBr and (ii) using acidic hydrolysis
R
MicromassV GCT PremierTM (GC, CIþ, methane) using a HP
6890 GC apparatus equipped with a chromatographic col-
umn of 25 m, diameter 250 lm, thickness 0.25 lm. The sam-
ple was warmed at a temperature of 40 ꢁC for 5 min and
then further heated at a heating rate of 10 ꢁC minꢀ1 up to
220 ꢁC. HR-MS were recorded on Waters-Micromass GCT
Premier spectrometers. MALDI-TOF mass spectrometry
1
(Scheme 6). H NMR and 31P NMR spectroscopy (Supporting
Information Fig. S9) both confirmed a total conversion of the
ester groups into phosphonic acid by the disappearance of
the CH3 signal at 3.80 ppm and by a shift of the P signal
from 25.52 ppm to 13.29 ppm for 8a. Furthermore, the FTIR
SCHEME 4 Synthesis of propargylaminophosphonate 6.
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SCHEME 5 Synthesis of phosphonate-terminated PEO monomethyl ethers 7a (from PEOAN3 2000) and 7b (from PEOAN3 5000).
analysis was performed on a Bruker Biflex III MALDI-TOF
instrument equipped with nitrogen laser operating at 337
nm, a 2 GHz sampling rate digitizer, pulsed ion extraction
source and reflectron. The laser pulse width is 3 ns and
maximum power is 200 mJ. Spectra were recorded in the lin-
ear mode or negative mode with an acceleration voltage of
19 kV and delay of 200 ns. One hundred single shot acquisi-
tions were summed to give the spectra and the data were
analyzed using Bruker XTOF software. Samples were run in
a-cyano-4-hydroxycinnamic acid (HCCA) or 2-[(2E)-3-(4-tert-
butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB)
as the matrix doped with sodium trifluoroacetate (NaTFA),
potassium trifluoroacetate (KTFA), or sodium iodide as the
cationizing agent.
MHz), d (ppm): 81.27 (d, J ¼ 5.84 Hz, CACH), 71.20 (s,
CBCH), 53.08 (d, JPAC ¼ 5.29 Hz, CH3), 30.78 (s, NHACH2).
31P NMR (CDCl3, 161.96 MHz), d (ppm): 10.64. FTIR (cmꢀ1):
3221 (mNAH); 2955 and 2851 (mCAH); 2110 (mCBC); 1220
(mP¼¼O); 1182 (mPAOAC); 1103, 1033, and 990 (mPANAC). HR-
MS (CI). Calcd for C5H10NO3P þ Hþ: 164.0477. Found:
164.0480.
Diethyl Prop-2-ynylphosphoramidate 2
Purification by distillation under reduced pressure (b.p.0.3
¼ 75 ꢁC) afforded 2 (5.25 g; 55%) as a clear colorless
Torr
oil. 1H NMR (CDCl3, 400 MHz), d (ppm): 3.05 (s, 1H, NH),
4.08 (m, 4H, POCH2CH3), 3.68 (d, J ¼ 4.59 Hz, 2H, NHACH2),
2.25 (q, J ¼ 4.96 Hz, 1H, CBCH), 1.33 (t, J ¼ 4.03 Hz, 6H,
CH3). 13C NMR (CDCl3, 100.62 MHz), d (ppm): 81.50 (d, J ¼
5.29 Hz, CBCH), 70.70 (s, CBCH), 61.91 (d, JPAC ¼ 5.31 Hz,
POCH2), 30.28 (s, NHACH2), 15.77 (d, JPAC ¼ 7.37 Hz, CH3).
31P NMR (CDCl3, 161.96 MHz), d (ppm): 8.25. FTIR (cmꢀ1):
3226 (mNAH); 2994 and 2908 (mCAH); 2115 (mCBC); 1635
(mNAH); 1229 (mP¼O); 1166 (mPAOAC); 1116, 1029, and 970
(mPANAC). HR-MS (CI). Calcd for C7H14NO3P þ Hþ: 192.0790.
Found: 192.0790.
General Procedure for the Synthesis of
Propargylphosphoramidates via Atherton–Todd Reaction
A solution of di(m)ethyl phosphite (0.05 mol) in carbon tet-
rachloride (15 mL) was added dropwise to a mixture of N-
propargylamine (2.75 g, 0.05 mol), triethylamine (6.06 g,
0.06 mol), carbon tetrachloride (10 mL), and dichlorome-
thane (25 mL) under stirring. The mixture was stirred at
room temperature for 24 h, poured into dichloromethane
(50 mL) and then extracted with water (3 ꢂ 10 mL). The or-
ganic layer was dried over anhydrous magnesium sulfate
and filtered. The solvent was removed by evaporation.
Dimethyl Phenyl(prop-2-ynylamino)methylphosphonate 6
Imine 5 (7 mmol) and dimethyl phosphite (0.77 g; 7 mmol)
were placed in a 100-mL round-bottom flask equipped with
a magnetic stirrer, a reflux condenser, and a dropping funnel.
ꢁ
Dimethyl Prop-2-ynylphosphoramidate 1
The reaction mixture was heated for 8 h at 80 C. The a-ami-
The resulting solid was purified by recrystallization from
hexane:dichloromethane to afford 1 (1.8 g; 22%) as a beige
powder. 1H NMR (CDCl3, 400 MHz), d (ppm): 3.73 (s, 6H,
CH3), 3.66 (d, J ¼ 4.35 Hz, 2H, NHACH2), 3.33 (s, 1H, NH),
2.29 (t, J ¼ 2.46 Hz, 1H, CB CH). 13C NMR (CDCl3, 100.62
nophosphonate was purified by silica gel column chromatog-
raphy eluted with ethyl acetate:acetonitrile, 80:20, to give
pure 6 as a yellow oil. Yield: 85%. 1H NMR (CDCl3, 400
MHz), d (ppm): 7.48 (d, J ¼ 6.43 Hz, 2H, H1); 7.39–7.26 (m,
3H, H2 & H3); 4.39 (d, J ¼ 4.09 Hz, 1H, CHAP); 3.65 (m, 6H,
FIGURE 3 1H NMR spectrum of dimethylphosphonate-terminated PEO monomethyl ether 7a; solvent: CDCl3.
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terminated PEO monomethyl ethers were isolated by precipi-
tation into diethyl ether.
Dimethylphosphonate-Terminated PEO Monomethyl
Ether 3
1
White powder. Yield: 72%. H NMR (400 MHz, CDCl3), d (ppm):
7.70 (s, 1H, triazole), 4.53 (t,
J
¼
5.33 Hz, 2H,
NtriazoleACH2ACH2AO), 4.22 (d, J ¼ 4.82 Hz, 2H, NHACH2), 3.87
(t, J ¼ 5.53 Hz, 2H, NtriazoleACH2ACH2AO), 3.72 (s, 6H,
P(O)OACH3), 3.60–3.68 (m, 172H, CH2ACH2AO), 3.38 (s, 3H,
OACH3), 2.17 (s, 1H, NH). 13C NMR (100 MHz, CDCl3), d (ppm):
146.95 (C¼¼CANtriazole), 128.92 (C¼¼CANtriazole), 72.05
(CH2AOACH3), 70.69 (ACH2AO), 69.24 (NtriazoleACH2ACH2AO),
58.65 (CH3AO), 53.15 (d, JPAC ¼ 5.5 Hz, P(O)OACH3), 50.34
(NtriazoleACH2ACH2AO), 36.75 (NACH2). 31P NMR (CDCl3,
161.96 MHz), d (ppm): 10.86. FTIR (cmꢀ1): 2882 (mCAH); 1466
(mC¼¼C triazole); 1240 (mP¼O); 1146 (mPAOAC); 1101 (mPANAC).
FIGURE 4 MALDI-TOF mass spectrum of dimethylphospho-
nate-terminated PEO monomethyl ether 7a; matrix: DCTB,
KTFA.
Diethylphosphonate-Terminated PEO Monomethyl Ether 4
White powder. Yield: 70%. 1H NMR (400 MHz, CDCl3), d (ppm):
7.70 (s, 1H, triazole), 4.53 (t,
J
¼
5.77 Hz, 2H,
NtriazoleACH2ACH2AO), 4.22 (t, J ¼ 5.03 Hz, 2H, NHACH2),
4.06 (q, J ¼ 4.86 Hz, 4H, P(O)OCH2CH3), 3.87 (t, J ¼ 5.26 Hz,
2H, NtriazoleACH2ACH2AO), 3.52–3.73 (m, 172H, CH2ACH2AO),
3.38 (s, 3H, OACH3), 2.16 (s, 1H, NH), 1.31 (t, J ¼ 7.71 Hz, 6H,
P(O)OACH2CH3). 13C NMR (100 MHz, CDCl3), d (ppm): 146.83
(C¼¼CANtriazole), 122.75 (C¼¼CANtriazole), 71.56 (CH2AOACH3),
70.39 (ACH2AO), 69.25 (NtriazoleACH2ACH2AO), 61.96 (d,
JPAC ¼ 5.6 Hz, P(O)OACH2CH3), 58.95 (CH3AO), 50.35
(NtriazoleACH2ACH2AO), 36.72 (NACH2), 15.93 (d, JPAC ¼ 7.2
Hz, P(O)OACH2CH3). 31P NMR (CDCl3, 161.96 MHz), d (ppm):
8.31. FTIR (cmꢀ1): 2882 (mCAH); 1466 (mC¼C triazole); 1240
(mP¼¼O); 1146 (mPAOAC); 1103 (mPANAC).
CH3); 3.31 (m, 2H, CH2); 2.24 (s, NH); 2.29 (q, J ¼ 2.01 Hz,
1H, CBCH). 13C NMR (CDCl3, 100.62 MHz), d (ppm): 133.78
(d, J ¼ 6.25 Hz, C4); 128.37 (d, J ¼ 6.03 Hz, C3); 128.17 (d, J
¼ 2.59 Hz, C1); 127.83 (d, J ¼ 3.15 Hz, C2); 80.28 (CBCH);
71.93 (CBCH); 58.23 (d, J ¼ 5.63 Hz, CH3); 53.61 (t, J ¼
4.51 Hz, CHP); 35.87 (d, J ¼ 19.14 Hz, NACH2). 31P NMR
(CDCl3, 161.96 MHz), d (ppm): 25.06. IR (m, cmꢀ1): 3431
(mNAH); 2126 (mCBC); 1248 (mP¼O); 1146 (mPAOAC). HRMS
(CIAHþ). Calcd for C12H17NO3P þ Hþ: 255.0946. Found:
255.0817.
General Procedure for the Synthesis of
Phosphonate-Terminated PEO Monomethyl
Dimethylphosphonate-Terminated PEO Monomethyl
Ethers via ‘‘click’’ Coupling Reaction
Ether 7a (from PEOAN3 2000)
Yield: 70%. H NMR (400 MHz, CDCl3), d (ppm): 7.61 (s, 1H,
1
In a typical experiment, azido-terminated PEO monomethyl
ether (0.5 mmol), phosphonate derivative (0.5 mmol), and
N,N,N0,N0,N00-pentamethyldiethylenetriamine (PMDETA; 0.1 g,
0.6 mmol) were charged to a dry Schlenk tube along with
degassed DMF (5 mL). The tube was sealed with a rubber
septum and subjected to six freeze–pump–thaw cycles. This
solution was then cannulated under nitrogen into another
Schlenk tube, previously evacuated and filled with nitrogen,
containing Cu(I)Br (0.023 g, 0.16 mmol) and a stir bar. The
resulting solution was subsequently stirred at room tempera-
ture for 24 h. The reaction mixture was diluted with
dichloromethane (50 mL) and then washed with 3 ꢂ 100
mL of an aqueous ethylenediamine tetraacetate solution
(0.03 mol/L) to remove the catalyst. The organic layer was
dried over MgSO4 and filtered. The resulting phosphonate-
triazole); 7.46 (d, J ¼ 7.01 Hz, 2H, H1); 7.38–7.26 (m, 3H, H2
& H3); 4.52 (t, J ¼ 3.89 Hz, 2H, NtriazoleACH2ACH2AO); 4.12
(d, J ¼ 2.89 Hz, 1H, CHP); 3.94 (d, J ¼ 5.60 Hz, 2H,
NHACH2); 3.86 (t, J ¼ 4.86 Hz, 2H, NtriazoleACH2ACH2AO);
3.80 (s, 6H, P(O)OACH3); 3.52–3.72 (m, 172H, CH2ACH2AO);
3.38 (s, 3H, OACH3); 2.08 (s, 1H, NH). 13C NMR (100.62
MHz, CDCl3), d (ppm): 145.73 (C¼¼CANtriazole); 134.86 (C4);
128.94 (C3); 128.12 (C1); 127.98 (C2); 123.08
(C¼¼CANtriazole); 71.95 (CH2AOACH3); 70.95 (CH2AOACH2);
69.55 (NtriazoleACH2ACH2AO); 60.36 (CHP); 59.04 (OACH3);
53.58 (P(O)OACH3); 50.21 (NtriazoleACH2ACH2AO); 42.53
(NACH2). 31P NMR (CDCl3, 161.96 MHz), d (ppm): 25.52. IR
(m, cmꢀ1): 3436 (mNAH); 2883 (mCAH); 1466 (mC¼C triazole);
1242 (mP¼O); 1148 (mPAOAC).
SCHEME 6 Synthesis of phosphonic acid-terminated PEO monomethyl ethers 8a,b.
420
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reaction, the large excess of bromosilane and DCM were
removed by evaporation under low pressure. After the total
elimination of bromosilane, ethanol (50 mL) was added to the
flask and the stirring was continued for 24 h at room temper-
ature. Ethanol was removed under reduced pressure to obtain
the phosphonic acid-terminated PEO monomethyl ether.
General Procedure for Dimethylphosphonate-Terminated
PEO Monomethyl Ether Hydrolysis
In a 50-mL round-bottom flask equipped with a reflux con-
denser and a stir bar was placed the dimethylphosphonate-
terminated PEO monomethyl ether (0.05 mmol) in 5 mL of
ꢁ
HCl 20%. The solution was stirred and refluxed at 90 C for
6 h. Then the mixture was evaporated in vacuo to dryness.
The crude phosphonic acid-terminated PEO monomethyl
ether was dried at room temperature in vacuo for 24 h.
Phosphonic Acid-Terminated PEO Monomethyl Ether 8a
Brown powder. Yield: 90%. 1H NMR (400 MHz, CD3OD), d
(ppm): 8.13 (s, 1H, triazole); 7.60 (m, 2H, H1); 7.56–7.47 (m,
FIGURE 5 MALDI-TOF mass spectrum of phosphonic acid-ter-
minated PEO monomethyl ether 8a; matrix: DCTB, sodium
iodide.
3H, H2
NtriazoleACH2ACH2AO); 4.38 (m, 1H, CHP); 3.90 (t, J ¼ 5.21
Hz, 2H, NHACH2); 3.81 (t, 5.61 Hz, 2H,
&
H3); 4.63 (t,
J
¼
4.96 Hz, 2H,
Dimethylphosphonate-Terminated PEO Monomethyl
Ether 7b (from PEOAN3 5000)
J
¼
NtriazoleACH2ACH2AO); 3.70–3.52 (m, 172H, CH2ACH2AO);
3.36 (s, 3H, OACH3); 2.21 (s, 1H, NH). 13C NMR (100.62
MHz, CD3OD), d (ppm): 141.25 (C¼¼CANtriazole); 131.71 (C4);
130.83 (C3); 130.32 (C1); 129.57 (C2); 125.57
(C¼¼CANtriazole); 80.43 (CH2AOACH3); 73.65 (CH2AOACH2);
67.62 (NtriazoleACH2ACH2AO); 58.32 (CHP); 58.12 (OACH3);
54.76 (NtriazoleACH2ACH2AO); 37.07 (NACH2). 31P NMR
(CD3OD, 161.96 MHz), d (ppm): 13.29. IR (m, cmꢀ1): 3346
(mOH); 2884 (mCAH); 1466 (mC¼C, triazole); 1240 (mP¼O).
Brown powder. Yield: 75%. 1H NMR (400 MHz, CDCCl3), d
(ppm): 7.58 (s, 1H, triazole); 7.45 (s, 1H, H1); 7.40–7.33 (m,
3H, H2
&
H3); 4.52 (t,
J
¼
5.07 Hz, 2H,
NtriazoleACH2ACH2AO); 4.14 (m, 1H, CHP); 3.86 (m, 8H,
NtriazoleACH2ACH2AO, P(O)OCH3); 3.82–3.49 (m, 172H,
CH2ACH2AO); 3.46 (t, J ¼ 4.68 Hz, 2H, NHACH2); 3.38 (s,
3H, OACH3); 2.50 (s, 1H, NH). 13C NMR (100.62 MHz,
CD3OD),
d
(ppm): 145.69 (C¼¼CANtriazole); 135.10 (C4);
128.70 (C3); 128.12 (C1); 125.46 (C2); 123.04
(C¼¼CANtriazole); 71.92 (CH2AOACH3); 70.55 (CH2AOACH2);
69.50 (NtriazoleACH2ACH2AO); 60.31 (CHP); 59.01 (OACH3);
53.64 (P(O)OACH3); 45.56 (NtriazoleACH2ACH2AO); 42.49
(NACH2). 31P NMR (CD3OD, 161.96 MHz), d (ppm): 25.47.
Phosphonic Acid-Terminated PEO Monomethyl Ether 8b
Brown powder. Yield: 90%. 1H NMR (400 MHz, CDCCl3), d
(ppm): 8.15 (s, 1H, triazole); 7.60 (s, 1H, H1); 7.54–7.47 (m,
3H, H2
&
H3); 4.62 (t,
J
¼
4.82 Hz, 2H,
NtriazoleACH2ACH2AO); 4.40 (m, 1H, CHP); 3.90 (t, J ¼ 5.08
Hz, 2H, NtriazoleACH2ACH2AO); 3.80–3.48 (m, 172H,
CH2ACH2AO); 3.45 (t, J ¼ 4.68 Hz, 2H, NHACH2); 3.35 (s,
3H, OACH3); 2.88 (s, 1H, NH). 13C NMR (100.62 MHz,
Amino-Terminated PEO Monomethyl Ether from 3
1
Yellow oil. Yield: 69%. H NMR (400 MHz, CD3OD), d (ppm):
8.30 (s, 1H, triazole), 4.64 (t,
J
¼
5.5 Hz, 2H,
NtriazoleACH2ACH2AO), 4.37 (d, J ¼ 4.6 Hz; 2H, NHACH2),
3.90 (t, J ¼ 5.5 Hz, 2H, NtriazoleACH2ACH2AO), 3.74–3.56 (m,
172H, CH2ACH2AO), 3.38 (s, 3H, OACH3), 2.36 (s, 1H, NH).
13C NMR (100 MHz, CD3OD), d (ppm): 141.98 (C¼¼CANtriazole),
123.69 (C¼¼CANtriazole), 71.91 (CH2AOACH3), 70.55
(ACH2AO), 69.37 (NtriazoleACH2ACH2AO), 59.04 (CH3AO),
50.26 (NtriazoleACH2ACH2AO), 34.15 (NACH2).
CD3OD),
d
(ppm): 142.35 (C¼¼CANtriazole); 134.46 (C4);
132.54 (C3); 131.87 (C1); 130.39 (C2); 127.86
(C¼¼CANtriazole); 72.96 (CH2AOACH3); 71.56 (CH2AOACH2);
70.16 (NtriazoleACH2ACH2AO); 62.43 (CHP); 58.86 (OACH3);
44.73 (NtriazoleACH2ACH2AO); 41.96 (NACH2). 31P NMR
(CD3OD, 161.96 MHz), d (ppm): 13.29.
CONCLUSIONS
General Procedure for the Cleavage of
Dimethylphosphonate-Terminated PEO Monomethyl
Ethers Using TMSBr
The present study investigated the combination of Atherton–
Todd reaction, on the one hand, and the Kabachnik–Fields
reaction, on the other hand, together with ‘‘click’’ copper-cat-
alyzed 1,3-dipolar cycloaddition of azides and terminal
alkynes for introducing a phosphonic acid group at the
chain-end of PEO monomethyl ethers. Well-defined dialkyl-
phosphonate-terminated PEO monomethyl ethers were suc-
cessfully obtained from commercially available products in
good yields using the Atherton–Todd route. However, the
established methodology to remove the ester protecting
A solution of the dialkylphosphonate-terminated PEO mono-
methyl ether (0.05 mmol) in 5 mL of DCM was added to a
100-mL two-necked flask equipped with a stir bar, a nitrogen
inlet, and a dropping funnel. The solution was stirred at room
temperature under nitrogen and a solution of TMSBr (0.48 g,
3.2 mmol) in 5 mL of dichloromethane (DCM) was added
dropwise via the dropping funnel. The reaction mixture
was stirred for 24 h at room temperature. At the end of the
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18 Moszner, N.; Salz, U.; Zimmermann, J. Dent. Mater. 2005,
21, 895–910.
groups of phosphonates involving the use of TMSBr led to
PAN bond cleavage, as demonstrated by MALDI-TOF MS
analysis. In contrast, the Kabachnik–Fields route afforded x-
phosphonic acid-functionalized PEOs with good yields from
commercially available products. This work also conducted
structural analyses, including 1H, 13C, 31P NMR, and MALDI-
TOF MS, to confirm the structures of the so-obtained poly-
mers. The versatile strategy reported in this work can be
used to introduce a phosphonic acid group at the chain-end
of the wide range of polymers bearing an azido end-group
that are nowadays attainable. By varying the nature of the
aldehyde used in this strategy, virtually any functional group
can be inserted into the so-obtained x-phosphonic acid-func-
tionalized PEOs. The resulting end-functionalized polymers
could be used in a variety of applications, including biomedi-
cal applications for linking and coating for metal oxide
nanoparticles.
19 Catel, Y.; Degrange, M.; Le Pluart, L.; Madec, P. J.; Pham, T.
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