Poly(phosphorodiamidate)s by Olefin Metathesis Polymerization with Precise Degradation

Article abstract of DOI:10.1002/chem.201603990

Degradable polymers are a currently growing field of research for biomedical and materials science applications. The majority of such compounds are based on polyesters and polyamides. In contrast, their phosphorus-containing counterparts are much less studied, in spite of their potential precise degradation profile and biocompatibility. Herein, the first library of poly(phosphorodiamidate)s (PPDAs) with two P?N bonds forming the polymer backbone and a pendant P?OR group is prepared through acyclic diene metathesis polymerization. They are designed to vary in their hydrophilicity and are compared with the structural analogues poly(phosphoester)s (PPEs) with respect to their thermal properties and degradation profiles. The degradation of PPDAs can be controlled precisely by the pH: under acidic conditions the P?N linkages in the polymer backbone are cleaved, whereas under basic conditions the pendant ester is cleaved selectively and almost no backbone degradation occurs. The PPDAs exhibit distinctively higher thermal stability (from thermogravimetric analysis (TGA)) and higher glass transition and/or melting temperatures (from differential scanning calorimetry (DSC)) compared with analogous PPEs. This renders this exotic class of phosphorus-containing polymers as highly promising for the development of future drug carriers or tissue engineering scaffolds.

Full text of DOI:10.1002/chem.201603990

DOI: 10.1002/chem.201603990
Full Paper
&
Phosphorus-Containing Polymers
Poly(phosphorodiamidate)s by Olefin Metathesis Polymerization
with Precise Degradation
[
a]
Mark Steinmann, Manfred Wagner, and Frederik R. Wurm*
Abstract: Degradable polymers are a currently growing field
of research for biomedical and materials science applica-
tions. The majority of such compounds are based on polyes-
ters and polyamides. In contrast, their phosphorus-contain-
ing counterparts are much less studied, in spite of their po-
tential precise degradation profile and biocompatibility.
Herein, the first library of poly(phosphorodiamidate)s
thermal properties and degradation profiles. The degrada-
tion of PPDAs can be controlled precisely by the pH: under
acidic conditions the PÀN linkages in the polymer backbone
are cleaved, whereas under basic conditions the pendant
ester is cleaved selectively and almost no backbone degra-
dation occurs. The PPDAs exhibit distinctively higher thermal
stability (from thermogravimetric analysis (TGA)) and higher
glass transition and/or melting temperatures (from differen-
tial scanning calorimetry (DSC)) compared with analogous
PPEs. This renders this exotic class of phosphorus-containing
polymers as highly promising for the development of future
drug carriers or tissue engineering scaffolds.
(PPDAs) with two PÀN bonds forming the polymer backbone
and a pendant PÀOR group is prepared through acyclic
diene metathesis polymerization. They are designed to vary
in their hydrophilicity and are compared with the structural
analogues poly(phosphoester)s (PPEs) with respect to their
[5a,7]
Introduction
with a wide range of functional groups can be prepared.
Wooley and co-workers reported recently acid-labile poly(phos-
phoramidate)s (PPAs, 4): PPA and PPE share the same poly-
phosphodiester backbone (Scheme 1), but PPAs have an acid-
PÀN linkages in polymers have been only scarcely investigated
to date. The typical example of such compounds are poly(or-
ganophosphazene)s (POPs, 1), going back to pioneering works
[8]
labile phosphoramidate bond as a side group.
[
1]
from the 1960s. Their general structure (N=PR ) , with R as
2
n
a halogen, organic, or organometallic unit, is usually prepared
by the thermal ring-opening polymerization of hexachlorocy-
[
1]
clotriphosphazene. POPs with different properties such as hy-
drophilicity or crystallinity depending on the nature of the side
[
2–4]
group have been reported.
POPs have been discussed as
Scheme 1. General structures of poly(organophosphazene)s (POP, 1), poly-
phosphorodiamidate)s (PPDA, 2), poly(phosphoester)s (PPE, 3), and poly-
(phosphoramidates) (PPA, 4).
potential alternatives to conventional polymers and have
become probably one of the most famous “inorganic poly-
(
[
3a]
mers” to date.
However, the structural versatility of the main chain is limit-
ed with only P=N bonds forming the backbone. Herein, we
prepare the first poly(phosphorodiamidate)s (PPDAs, 2) with
two PÀN linkages and different alkyl chains in the backbone to
vary their hydrophilicity and crystallinity. In recent works, we
and other research groups have studied poly(phosphoester)s
One aspect that has been scarcely studied is polymers with
[9]
phosphoramidate linkages in the main chain, the so-called
main chain poly(phosphorodiamidate)s (PPDAs), which have
[10]
mostly been reported as aromatic flame-retardant oligomers.
Phosphorus-containing flame retardants show attractive prop-
erties compared with the previously used halogenated flame
retardants as they prevent toxic gases being released during
(
PPEs, 3) as a promising class of materials for applications from
[
5]
bio to materials science. Our group introduced the functional
group tolerant olefin metathesis polymerization to the prepa-
[11]
combustion and bioaccumulation or in general exhibit low
toxicity, which opens future possibilities for novel polymers
[
6]
ration kit of PPEs. Together with the chemical versatility of
the phosphotriester repeat units, linear or branched polymers
[12]
with PÀN linkages.
The acyclic diene metathesis polycondensation was used to
prepare a library of novel PPDAs with variable hydrophilicity.
These new compounds have been characterized and com-
pared with structurally analogous (also novel) PPEs with re-
spect to their thermal stability and hydrolysis. Monomers and
[
a] M. Steinmann, Dr. M. Wagner, Dr. F. R. Wurm
Max-Planck-Institut fꢀr Polymerforschung
Ackermannweg 10, 55128 Mainz (Germany)
E-mail: wurm@mpip-mainz.mpg.de
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201603990.
1
13
31
1
polymers were investigated by H NMR, C NMR, P NMR, H
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DOSY spectroscopy, and ESI-MS (only monomers). The thermal
properties reveal glass transition temperatures and/or melting
points depending on the microstructure. The degradation of
the water-soluble monomers and polymers was investigated
by variation of the pH. Under basic conditions, the pendant PÀ
O bond is cleaved selectively, whereas under acidic conditions
the backbone of PPDAs is degraded. In contrast, PPEs show
a statistical cleavage of the side or main chain under these
conditions.
These PPDAs broaden the scope of P-containing polymers
as future biodegradable materials with adjustable hydrophilici-
ty and precise degradation profile, and have additional poten-
tial for flame-retardant polymer additives.
Scheme 2. Synthetic strategy for phosphate and phosphorodiamidate
monomers for the ADMET polymerization: (i) a) alcohol, pyridine, b) water;
(
ii) a) amine, pyridine, b) water; (iii) alcohol, pyridine; (iv) amine, pyridine.
Results and Discussion
Monomer synthesis
For the comparison between PPEs and PPDAs, a library of dif-
ferent monomers was prepared (Scheme 2): the phosphate
monomers 5–10 carry either a PÀOH or a PÀOCH side group
3
with two unsaturated alkyl chains of different length attached
by PÀO bonds. Monomers 11–15 have analogous structures,
but instead of phosphoesters, two phosphoramidate linkages
attach the polymerizable groups.
The reasoning for choosing these monomer structures is
their expected stability profiles: it is well known that phospho-
diesters are resilient to hydrolysis, whereas phosphotriesters
can be cleaved hydrolytically. Such structures are compared
with our novel PDAs.
The monomers with PÀOH functionality are accessible by
esterification or amidation with 3-butene-1-amine, 3-butene-1-
ol, 7-octene-1-amine, 7-octene-1-ol, 10-undecene-1-amine, and
1
1
0-decene-1-ol, followed by careful hydrolysis (Scheme 2). The
phosphate monomers carrying a methyl ester side chain (8, 9,
0) can be prepared either by the direct coupling of methyl di-
Figure 1. H NMR (300 MHz, CDCl
(
3
, 298 K) spectra of 11 (top) and 13
3
1
bottom) (the inset shows the P{H} NMR spectrum (202 MHz)).
1
chlorophosphate with the respective unsaturated alcohol or by
Polymerization
treating POCl with two equivalents of the respective alcohol,
3
followed by hydrolysis. The intermediate monomer (i.e., with
the pendant hydroxyl group) is then reacted with trimethyl or-
The synthesis of PPEs and PPDAs was accomplished by acyclic
[5c,6a,14]
diene metathesis (Scheme 3).
For PPEs, typically Grubbs’
[
13]
thoacetate as previously reported.
first generation catalyst leads to polymers with high molecular
1
13
[5b]
H NMR and C{H} NMR spectroscopy, along with elemental
weights, but it produced only oligomers with phosphorodi-
analysis and ESI-MS confirmed the successful synthesis of the
monomers (see the Supporting Information). Monomer 5 is the
only water-soluble one of the phosphate-based monomers,
whereas for the phosphorodiamidates both “butenyl” mono-
mers (11 and 13) are water-soluble owing to the hydrophilic
phosphoramidate. Figure 1 shows the NMR spectra of mono-
amidates. Successful polymerization for PPDAs was observed
either in bulk (if the monomer is liquid) or in solution (50 wt%
in 1-chloronaphthalin) with 1 mol% of Hoveyda–Grubbs
second generation catalyst at room temperature to 608C at re-
duced pressure. The phosphate monomers are liquids with low
viscosity; during the polymerization, the viscosity increased
and the temperature was raised (to 508C) to ensure efficient
stirring for 8 to 16 h until the reaction mixture solidified.
Owing to the higher viscosity of the phosphorodiamidates,
their polymerization was conducted in solution and an addi-
tional 1 mol% catalyst was added to the mixture to promote
the polymerization after 2 h until the solution was too viscous
to allow efficient stirring (ca. 24 h). Catalyst deactivation oc-
1
mers 11 and 13. The H NMR spectrum of 13 exhibits the char-
acteristic doublet of a methoxy phosphoester at approximately
d=3.6 ppm (J=11.2 Hz), due to coupling with the NMR-active
31
phosphorus. The P{H} NMR spectra exhibit single resonances
at approximately d=8.7 ppm for 11 and d=17.0 ppm for 13,
31
which are consistent with the P NMR chemical shifts of other
[
8]
reported phosphorodiamidates.
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Scheme 3. ADMET polycondensation of unsaturated phosphates and phos-
phorodiamidates (i) Grubbs first generation catalyst, 508C, bulk; (ii) Grubbs–
Hoveyda second generation catalyst, RT, 1-chloronaphthalin; (iii) Pd/C, RT,
2 2
CH Cl .
curred during the reaction, which was visible as the color
changed during the polymerization in the case of Grubbs’ first
generation catalyst from purple to red and eventually to
brown; in case of the Hoveyda–Grubbs second generation cat-
alyst, the color changed from green to brown.
1
Figure 2. H DOSY NMR spectrum of monomer 14 (red) and the respective
polymer poly(14) (blue), proving the formation of internal double bonds at
5
PPEs can be obtained with higher molecular weights com-
pared with the PPDAs (Table 1). This is probably due to the
polymerization of the PDAs at room temperature and in solu-
tion. To generate higher molecular weight PPDAs, the solution
polymerization was conducted at 508C at a controlled reduced
pressure of 100 mbar (Method E in Table 1). Poly(8) and
poly(13), which is water soluble, exhibit lower molecular
weights probably owing to the negative neighboring effect de-
3
.4 ppm and the diffusion coefficient shift (500 MHz, 298 K, CDCl ).
surements were only successful for the PPEs with our setup
(see the Supporting Information); for PPDAs, GPC was not ap-
1
plicable. To estimate the molecular weights of the polymers, H
DOSY NMR spectroscopy calibrated with polystyrene (PS)
standards of different molecular weights was used instead. The
measurements revealed the diffusion coefficients of the poly-
mers, which can be calibrated to polymer standards (the cali-
bration curve is shown in the Supporting Information), allow-
ing the determination of an apparent Mw of unknown poly-
mers in solution without any column material (Table 1). This
method has been previously used to study polymerization ki-
[
6a]
scribed earlier. The successful polymerization can be detect-
1
ed easily from the H NMR spectra as the terminal double
bonds (at ca. d=5 ppm and 6 ppm in the monomers) are
transformed into internal double bonds during the polymeri-
zation, showing a broad resonance at approximately d=
1
5
.5 ppm (Figures 2 and 3). The overlay of the H DOSY spectra
of 14 and poly(14) proves the successful polymerization as the
diffusion coefficient is shifted to lower values after the reaction
[15]
netics and to determine polymer molecular weights.
(
Figure 2 and the Supporting Information for other mono-
mers).
In contrast to all monomers bearing a methoxy side chain,
which undergo successful ADMET (acyclic diene metathesis),
the monomers with OH side chains did not undergo efficient
homopolymerization under these conditions and only oligo-
mers were obtained. This is attributed to interactions of the PÀ
OH groups with the catalyst. However, it was possible to gen-
erate copolymers of the “OH series” with monomers carrying
methoxy side chains. PPEs and PPDAs in the range 1000–
À1
3
0000 gmol have been synthesized (Table 1 and the Sup-
porting Information for further details).
In addition to the unsaturated polymers that were obtained
directly after the metathesis, catalytic hydrogenation produces
the saturated analogues. The hydrogenation was carried out at
room temperature with palladium (10% Pd/C) at 25 bar (see
the Experimental Section for details). Figure 3 shows the com-
parison of poly(15) and the hydrogenated poly-H(15). After
hydrogenation, the double bond resonances at approximately
d=5 ppm disappear, indicating the saturated materials.
Molecular weight determination of phosphorus-containing
materials by gel permeation chromatography (GPC) is often
1
Figure 3. Comparison of the H NMR spectra (300 MHz, CDCl
poly(15) (top) and poly-H(15) (bottom).
3
, 298 K) of
[
5c,d]
difficult owing to possible column interactions.
GPC mea-
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Table 1. Molecular weight of polymers from the ADMET polycondensa-
Table 2. Thermal properties of polymers measured by DSC and TGA.
tion of phosphates and phosphorodiamidates.
[
a]
Polymer
T
[8C]
g
DC
[Jg
p
T
[8C]
m
DH
[Jg
m
À1
T
on
T
50%
[8C]
[
a]
[b]
wGPC
[c]
À1 À1
Polymer
Conditions
M
[
M
wNMR
ꢁ
K
]
]
[8C]
À1
À1
gmol
]
[gmol
]
Poly(8)
Poly-H(8)
Poly(9)
Poly-H(9)
Poly(10)
À65.4 0.438
À67.9 0.369
À49.6 0.439
–
–
–
13.8
17.2
57.7
–
–
–
22.4
50.4
77.3
10.0
9.9
21.1
–
–
–
–
212
211
287
259
282
288
142
185
194
231
267
217
247
278
287
107
220
364
272
314
314
300
314
368
343
393
373
441
395
279
292
296
482
449
Poly(8)
Poly-H(8)
Poly(13)
Poly-H(13)
Poly(9)
Poly-H(9)
Poly(14)
Poly-H(14)
Poly(10)
Poly-H(10)
Poly(15)
A
D
A
C
A
D
B
C
A
D
B
E
1400
1200
–
–
–
1.23
1.20
–
1100
1000
–
–
–
À37.22
À26.42
À61.79
–
–
–
À2.73
À23.94
À52.20
À25.40
À29.67
À39.00
–
–
–
À52.4 0.317
19700
21300
–
–
19900
16400
–
–
4.32
5.46
–
Poly-H(10) À45.0 0.389
Poly(13)
À22.3 0.521
–
2800
2400
Poly-H(13) À27.1 0.498
–
Poly(14)
37.2 0.0746
2.41
3.19
–
–
–
1.75
1.92
2.49
–
Poly-H(14)
Poly(15)
Poly-H(15)
Poly(5–10) À50.4 0.474
Poly(6–10) À46.9 0.316
Poly(7–10) À43.9 0.400
Poly(11–13) À33.4 0.531
Poly(12–15) À9.1 0.296
–
–
–
–
–
–
–
6500
12000
5800
–
Poly(15)
Poly-H(15)
Poly(5–10)
Poly(6–10)
Poly(7–10)
Poly(11–13)
Poly(12–15)
C
A
A
A
B
B
–
9500
13900
12000
–
–
–
–
–
1000
8000
[
a] Ton was monitored at a degradation degree of 5%.
–
—
[a] Conditions: A=bulk, 508C, 16 h; B=50 wt% solution of 1-chloronaph-
thalin, RT; C=CH Cl , RT, 16 h; D=toluene, RT, 16 h; E=50 wt% solution
2
2
After hydrogenation, higher melting points and higher melt-
of 1-chloronaphthaline, 508C. [b] Determined by GPC in THF measured
1
by refractive index detector. [c] Determined by H DOSY NMR spectrosco-
ing enthalpy values for both polymers are observed. The satu-
rated PPDA poly-H(15) exhibits the highest melting point of
the P-containing polymers prepared by ADMET to date: 77.38C
py.
À1
À1
(
DH =À52.20 Jg ) compared with 50.48C (DH =23.94 Jg )
m
m
for the unsaturated poly(15) owing to the disappearance of
the double bonds, which act as a defect during the crystalliza-
tion of the polymer (Table 2). The PPE equivalent poly-H(10)
Thermal properties
PPEs are used as flame retardant additives. In addition to the
phosphorus, PP(D)As have shown a synergistic effect of P and
shows a melting endotherm at approximately 57.78C (DH =
m
[
16]
À1
N to give high thermal stabilities. Furthermore, the charring
is relatively high compared with PPEs, which leads to the de-
61.79 Jg ).
The PPDAs exhibit strongly different thermal stabilities com-
pared with the PPEs as detected by TGA measurements
(Figure 4, Table 2). The starting degradation temperature of
PPDAs is lower than that of the PPEs; however, the tempera-
ture range in which the degradation occurs is much broader
with several degradation steps (Figure 4c, and Table 2 lists the
[
17]
crease of pyrolysis gases. The thermal properties of the poly-
mers were examined by thermogravimetric analysis (TGA) and
differential scanning calorimetry (DSC) under a nitrogen atmos-
phere. The PPEs exhibited glass transition temperatures of À30
to À708C. For unsaturated PPEs with six and fourteen methyl-
ene groups in the backbone, no melting was observed, where-
as poly(10) with 20 methylene groups exhibited a melting
point of approximately 178C.
onset of the mass loss (T ) and the 50% weight loss tempera-
on
ture (T50%)). The phosphorodiamidate unit degrades first at ap-
proximately 3758C and afterwards the carbon backbone de-
grades at approximately 4508C. Furthermore, the residue ob-
In comparison with PPEs, the thermal properties of PPDAs
differ strongly: all PPDAs exhibit higher glass transitions and/or
melting temperatures (Figure 4 and Table 2).
tained after TGA (under N ) up to 6008C remains approximate-
2
ly 30 wt%, rendering the PPDAs interesting for future flame-re-
tardant materials.
In Figure 4a and b, the DSC traces of PPDAs poly(13) and
poly(15) were compared with their phosphate analogues
poly(8) and poly(13). The main chain and the side chain of the
polymers are kept the same except that the two “ester oxygen
atoms” were exchanged by amidate linkages (NH instead of O).
For the amorphous materials poly(8) and poly(13), the glass
transition temperatures of the PPDA poly(13) are more than
Hydrolytic stability
In contrast to poly(phosphazene)s, only a few studies on the
hydrolytic stabilities of low-molecular-weight phosphorodiami-
[18]
[9]
[10]
dates, PPAs, or PPDAs have been conducted. Compared
with polyamides based on carboxylic acids and amines, the
phosphoramidate bond is relatively labile and can be hydro-
4
08C higher than for the PPE analogue poly(8) (Figure 4a).
Furthermore, the PPDA poly(15) (T =ca. 50.48C) shows an in-
m
[8]
crease in the melting point of more than 308C compared with
lyzed under mild acidic conditions, although they are rather
stable under basic conditions.
its PPE equivalent poly(10) (T =17.28C). The melting enthalpy
m
À1
is rather similar for both materials (DH (PPE)=26.42 Jg ;
The hydrolytic stabilities of PPDAs have been investigated at
different pH values. The kinetics of hydrolysis of the water-
soluble monomers 11 and 13 and their respective polymers
m
À1
DH (PPDA)=23.94 Jg ). For PPDA poly(15), the glass transi-
m
tion cannot be detected from the DSC curve.
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Figure 5. Monitoring the degradation of the PÀN bonds in 13 at pH 1.0 by
1
H NMR spectroscopy.
However, under basic conditions, the PÀOCH ester hydrolyzes
3
selectively and no further backbone degradation is observed
(
Figure 6 and Figure S16 in the Supporting Information). The
degradation for poly(13) was also compared with the degrada-
tion of the monomer 13: as expected, the degradation kinetics
are very similar (Figure 5 and the Supporting Information).
All other polymers were water insoluble. To study the degra-
dation of the hydrophobic polymers, poly(15) was converted
into polymer nanoparticles by a miniemulsion solvent evapora-
[20]
tion process.
A chloroform solution of poly(15) was dis-
persed by ultrasonication in an aqueous Lutensol solution with
subsequent evaporation of the organic solvent. A stable PPDA-
nanoparticle dispersion (diameter ca. 240 nm determined from
dynamic light scattering) was obtained. After the addition of
HCl (to pH 1.0), the degradation of the nanoparticles was stud-
ied. Owing to the hydrophobicity of the polymer, complete
backbone degradation was achieved after 7 days at room tem-
Figure 4. DSC thermograms of a) poly(8) versus poly(13), b) poly(10) versus
poly(15), and c) TGA of poly(10) versus poly(15).
31
perature. The P NMR spectra prove the polymer partly de-
graded after 3 days and completely degraded after 7 days (see
the Supporting Information).
1
were measured by H NMR spectroscopy. The hydrolysis of 11
These properties mean that the material is capable of specif-
ic cleavage of the side chain at basic conditions or the total
degradation of the polymer backbone at acidic conditions.
PPDAs would consequently present a new class of (bio)degrad-
able polymers for various applications, especially because of
the specific degradation of side or main chains. These results
indicate selective cleavage or control of the degradation pro-
file of PPDAs by adjusting of the pH value is possible.
and 13 was studied in aqueous buffer solutions at different pH
values (based on deuterium oxide, the conversion of pD=
[
19]
1
pH+0.4 was assumed ) and monitored by H NMR spectros-
copy. Two separate resonances can be used to analyze the
degradation. The signal of the methylene group next to the
amidate linkage (dꢀ3.0 ppm) is detected as a multiplet and
the pendant methoxy group shows up as a doublet owing to
coupling with phosphorus (d=3.65 ppm, J=11.2 Hz; the Sup-
porting Information shows the degradation in aqueous buffer
solutions at pH 1.0, 3.0, 5.0, 7.0, 8.0, and 13.0). Monomer 13
was degraded at a pH of 1.0 (Figure 5). The degradation was
Conclusions
A library of novel poly(phosphorodiamidate)s (PPDAs) and
structural analogues poly(phosphoester)s (PPEs) was prepared
by ADMET polycondensation. Polymers of variable hydrophilici-
ty were generated, carrying either a pendant methyl ester or
a free PÀOH group. Both unsaturated and saturated (after hy-
drogenation) polymers were realized. The monomers with the
methoxy side chains can be polymerized in all cases, whereas
the monomers carrying pendant PÀOH groups only undergo
1
monitored from the H NMR spectra by following the integral
values of the methoxy resonance.
In general, the cleavage of the PÀN bonds is strongly pH-de-
pendent and shows the highest degradation rate at pH 1.0,
reaching full completion after 10 h. The cleavage at pH 3.0 and
5
1
.0 is significantly slower than at pH 1.0. At pH 7.0, 8.0, and
3.0, the PPDA main chain remained stable for at least 70 days.
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high thermal stabilities and melting points, PPDAs might find
applications as novel biodegradable materials for tissue engi-
neering or drug delivery or also as flame-retardant materials.
Experimental Section
Monomer syntheses
8
-Azide-1-octene (1): 8-Azide-1-octene 1 was synthesized similarly
[21]
to the literature procedure by Li et al. NaN (3.4 g, 52.3 mmol,
3
2
.0 equiv) was added in one portion to a stirred solution of 8-
bromo-1-octene (5.00 g, 26.2 mmol, 1.0 equiv) in dry DMF (50 mL)
at 808C. After 16 h of stirring at 808C, the solution was poured
into H O (200 mL). The reaction mixture was extracted with ethyl
2
acetate (3ꢁ50 mL) and the combined organic phases were washed
with brine. The organic phase was dried over anhydrous MgSO4
and concentrated in vacuo. The crude 8-azide-1-octene 1 (3.8 g,
9
5%) was used in the next step without further purification.
1
1-Azide-1-decene (2): 11-Azide-1-decene 2 was prepared from 11-
[22]
bromo-1-decene as reported by Tsai et al. with modifications. 11-
Bromo-1-decene (5.00 g, 21.4 mmol, 1.0 equiv) was added in a solu-
tion of dry DMF (50 mL) and NaN (2.8 g, 42.9 mmol, 2.0 equiv) was
3
added in one portion at 808C. The reaction mixture was stirred for
1
6 h at 808C and filtered. The organic phase was extracted with n-
hexane (3ꢁ25 mL) separated and combined, dried over anhydrous
MgSO4, and concentrated in vacuo. The crude 11-azide-1-decene 2
(
3.9 g, 93%) was used in the next step without further purification.
-Octen-1-amine (3) and 10-decen-1-amine (4): 7-Octen-1-amine
and 10-decen-1-amine, 3 and 4, were synthesized by following the
7
[23]
reported procedure with modifications. A mixture of the azide 1
or 2 (26.2 mmol, 1.0 equiv) and Ph P (78.5 mmol, 3.0 equiv) in
3
a 10:1 solution of H O (8 mL) in THF (80 mL) was stirred at 608C
2
for 16 h. Subsequently, THF was removed under reduced pressure.
The aqueous residue was dissolved in acetonitrile (100 mL) with
HCl (10 mL, 10 wt%). After 1 h of stirring, the acetonitrile was re-
moved. H O (150 mL) was added to the mixture and the aqueous
2
phase was extracted once with CH Cl2 (1ꢁ25 mL). The aqueous
2
phase was freeze dried. Amine 3 (90%) or 4 (87%) was obtained
and used in the next step without further purification.
Representative procedure for synthesis of the “hydroxy-
and methylphosphate monomers”
Figure 6. Degradation of phosphoramidate bonds in monomers 11 (a),
1
1
3(b), and poly(13)(c) at different pH values monitored by H NMR spectros-
copy.
Bis-(but-3-en-1-yl)-methylphosphate (8): A mixture of 3-buten-1-
ol (11.1 g, 13.3 mL, 0.154 mol, 1.8 equiv) and Et N (15.6 g, 21.4 mL,
3
0
.154 mol, 1.8 equiv) in toluene (20 mL) was added to a stirred so-
lution of POCl3 (13.1 g, 8.0 mL, 0.0856 mol, 1.0 equiv) in toluene
50 mL) at room temperature. The resulting dispersion was stirred
copolymerization under certain conditions. Their molecular
1
weights were determined either by GPC or by H DOSY NMR
(
spectroscopy. The polymers of both series were compared
overnight at room temperature. Subsequently, Et N·HCl was re-
3
with respect to their thermal behavior (stability, T , T ) and hy-
moved by filtration. The filtrate was dried under reduced pressure
g
m
to remove solvents and excess POCl . Diethyl ether (40 mL) was
drolytic degradation. Glass transitions and melting points are
typically higher in the case of PPDAs compared with their
structurally analogous PPEs. The PÀN bonds in PPDAs can be
degraded by acidic hydrolysis, but are rather stable under
basic conditions. In contrast, the pendant PÀO bond in PPDAs
hydrolyses selectively under basic conditions without degrada-
tion of the backbone. Hydrophobic polymers were transformed
into aqueous nanoparticle dispersions by a miniemulsion pro-
tocol: they show slow hydrolysis under acidic conditions over
a period of several days. The specific degradation might be an
interesting feature for future applications. Combined with the
3
added to dissolve the dialkenyl chlorophosphate intermediate. The
solution was stirred vigorously with water (ca. 25 mL) for 48 h with,
exchanging the water phase several times.
The following purification was carried out with the water-soluble
monomer 5: The combined water phases were extracted with
ethyl acetate (3ꢁ50 mL), combined, and concentrated at reduced
pressure to yield pure di-(but-3-en-1-yl) phosphate 5 (Yield: 15.5 g,
0
.075 mol; 88%).
The following purification was carried out with water-insoluble
monomers 6 and 7: The diethyl ether phase was dried and the sol-
vent was removed at reduced pressure. The residue containing the
&
&
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6
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ÝÝ These are not the final page numbers!

Full Paper
dialkylene phosphates (6 or 7) was used without further purifica-
analysis calcd (%) for C H O P (332.21): C 61.42, H 10.01; found: C
17
33
4
tion.
61.68, H 10.17.
Compound 5 (7.0 g, 0.0340 mol, 1.0 equiv) was mixed and stirred
Bis-(undec-10-en-1-yl)-methylphosphate (10): Following the rep-
with trimethyl orthoacetate (8.2 g, 8.4 mL, 0.0679 mol, 2.0 equiv) at
resentative procedure described above (without purification by dis-
8
08C. After stirring overnight, water was added to deactivate the
tillation) using 10-undecen-1-ol, 10 was obtained as a yellowish oil
1
excess trimethyl orthoacetate. The water phase was extracted with
CH Cl (3ꢁ50 mL) and the extract was dried. After distillation at
(Yield: 86%). H NMR (500 MHz, 298 K, CDCl ): d=5.94–5.66 (ddt,
3
J=13.5, 10.1, 6.7 Hz, 2H), 5.11–4.80 (dd, J=30.3, 13.4 Hz, 4H),
4.14–3.93 (q, J=6.6 Hz, 4H), 3.86–3.64 (d, J=11.0 Hz, 3H), 2.17–
1.91 (q, J=6.8 Hz, 4H), 1.76–1.50 (m, 6H), 1.46–1.15 ppm (d, J=
2
2
À2
9
5
5
3
2
08C (5ꢁ10 mbar) pure 8 was obtained as a colorless oil (Yield:
.5 g, 0.0250 mmol; 74%). H NMR (500 MHz, 298 K, CDCl ): d=
1
3
13
.88–5.67 (ddt, J=17.0, 10.3, 6.7 Hz, 2H), 5.19–5.01 (m, 4H), 4.17–
.97 (q, J=6.9 Hz, 4H), 3.85–3.61 (d, J=11.1 Hz, 3H), 2.53–
43.3 Hz, 27H); C{H} NMR (126 MHz, 298 K, CDCl ): d=139.2, 114.2,
3
67.94, 67.89, 54.2, 54.1, 33.9, 30.40, 30.35, 29.54, 29.48, 29.21, 29.18,
13
31
.32 ppm (q, J=6.7 Hz, 4H); C{H} NMR (126 MHz, 298 K, CDCl ):
29.0, 25.5 ppm;
P{H} NMR (202 MHz, 298 K, CDCl ): d=
3
3
31
+
+
d=133.4, 117.8, 66.91, 66.86, 54.34, 54.27, 34.74, 34.69 ppm; P{H}
NMR (202 MHz, 298 K, CDCl ): d=0.03 ppm; ESI-MS: m/z 243.04
À1.51 ppm; ESI-MS: m/z 417.25 [M+H] , 439.23 [M+Na] , 833.51
+
+
[2M+H] 855.46 [2M+Na] ; elemental analysis calcd (%) for
3
,
+
[M+Na] ; elemental analysis calcd (%) for C H O P (220.09): C
C H O P (416.31): C 66.31, H 10.89; found: C 66.37, H 10.81.
9
17
4
23 45
4
4
9.09, H 7.78; found: C 49.23, H 7.61.
Bis-(but-3-en-1-yl)-phosphate (5): Following the representative
Representative procedure for synthesis of the phosphoro-
diamidate monomers
procedure described above, 5 was obtained as a yellowish oil
1
(
Yield: 15.5 g, 0.0750 mol; 88%). H NMR (500 MHz, 298 K, CDCl ):
3
d=11.84–11.30 (s, 1H), 5.96–5.67 (ddt, J=17.0, 10.3, 6.7 Hz, 2H),
.33–4.91 (m, 4H), 4.27–3.89 (q, J=7.0 Hz, 4H), 2.59–2.40 ppm (q,
N,N’-Bis-(but-3-en-1-yl)-phosphorodiamidate (11): A mixture of 3-
5
buten-1-amine (1.5 g, 1.9 mL, 0.0211 mol, 2.0 equiv) and Et N
3
1
3
J=6.7 Hz, 4H); C{H} NMR (126 MHz, 298 K, CDCl ): d=133.43,
(2.2 g, 3.1 mL, 0.0222 mol, 2.1 equiv) in toluene (20 mL) was added
3
1
3
33.39, 117.84, 117.78, 67.02, 66.97, 66.9, 66.8, 34.73, 34.68, 34.73,
to a stirred solution of POCl (1.6 g, 1.0 mL, 0.0106 mol, 1.0 equiv)
in toluene (50 mL) at room temperature. The resulting dispersion
was stirred overnight at room temperature and then filtered to
3
3
1
4.68 ppm; P{H} NMR (202 MHz, 298 K, CDCl ): d=0.20 ppm; ESI-
3
+
+
+
MS: m/z 657.08 [3M+K] , 863.11 [4M+K] , 1069.17 [5M+K] ; ele-
mental analysis calcd (%) for C H O P (206.07): C 46.60, H 7.33;
remove Et N·HCl. The solvent of the filtrate was removed under re-
8
15
4
3
found: C 46.45, H 7.27.
duced pressure. Ethyl acetate (50 mL) was added to dissolve the di-
alkenyl chlorophosphorodiamidate intermediate and 4-dimethyl-
aminopyridine (DMAP; 100 mg, 0.819 mmol) was added. The result-
ing mixture was stirred vigorously with water for 48 h, exchanging
the water several times. The ethyl acetate phases were combined
and washed with 10% HCl solution and brine. After removing the
solvent under reduced pressure, pure di-(but-3-en-1-yl) phosphoro-
Bis-(oct-7-en-1-yl)-phosphate (6): Following the representative
procedure described above until the synthesis steps of 5 using 7-
octen-1-ol, 6 was obtained as a yellowish oil (Yield: 54%). H NMR
1
(
300 MHz, 298 K, CDCl ): d=5.97–5.57 (m, 2H), 5.08–4.82 (m, 4H),
3
4
.52–4.15 (s, 5H), 4.13–3.89 (d, J=6.8 Hz, 4H), 2.22–1.89 (d, J=
13
6
.8 Hz, 4H), 1.82–1.49 (m, 4H), 1.52–0.97 ppm (m, 15H); C{H}
NMR (126 MHz, 298 K, CDCl ): d=137.1, 137.0, 112.4, 112.3, 75.4,
diamidate 11 was obtained as a yellowish oil (Yield: 0.86 g,
3
1
7
2
5.1, 74.9, 65.61, 65.56, 44.1, 31.8, 31.7, 28.3, 28.2, 26.9, 26.84,
0.00424 mmol; 73%). H NMR (300 MHz, 298 K, CDCl
3
): d=5.94–
31
6.81, 26.7, 23.4, 6.7 ppm; P{H} NMR (202 MHz, 298 K, CDCl ): d=
5.44 (td, J=17.1, 6.9 Hz, 2H), 5.28–4.90 (m, 4H), 3.19–2.81 (m, 4H),
3
+
+
13
À1.15 ppm; ESI-MS: m/z 319.17 [M+H] , 637.31 [2M+H] , 955.47
2.42–2.11 ppm (q, J=6.7 Hz, 4H); C{H} NMR (176 MHz, 298 K,
+
31
[
3M+H] ; elemental analysis calcd (%) for C H O P (318.20): C
CDCl
(202 MHz, 298 K, CDCl ): d=8.84 ppm; ESI-MS: m/z 391.21
3
): d=135.1, 117.4, 77.2, 77.1, 76.9, 40.3, 35.8 ppm; P{H} NMR
3
16
31
4
6
0.36, H 9.81; found: C 60.13, H 9.93.
+
+
[
(
2MÀH O+H] , 803.36 [3MÀ2H O+Na] ; elemental analysis calcd
2
2
Bis-(undec-10-en-1-yl)-phosphate (7): Following the representa-
tive procedure described above until the synthesis steps of 5 using
%) for C H N O P (204.10): C 47.05, H 8.39, N 13.72; found: C
8 17 2 2
4
7.14, H 8.39, N 13.58.
1
0-decen-1-ol, 7 was obtained as a yellowish oil (Yield: 60%).
1
H NMR (500 MHz, 298 K, CDCl ): d=8.89–8.70 (s, 2H), 5.93–5.68
N,N’-Bis-(oct-7-en-1-yl)-phosphorodiamidate (12): Following the
3
(
ddt, J=16.9, 10.2, 6.7 Hz, 2H), 5.09–4.82 (m, 4H), 4.17–3.78 (q, J=
representative procedure described above using 7-octen-1-amine
3, 12 was obtained as a yellowish oil (Yield: 62%). H NMR
(300 MHz, 298 K, D O): d=6.08–5.70 (ddt, J=17.0, 10.2, 6.7 Hz, 2H),
2
5.14–4.90 (m, 4H), 3.10–2.84 (t, J=7.5 Hz, 4H), 2.21–1.89 (q, J=
1
6
4
2
2
.7 Hz, 4H), 2.12–1.94 (q, J=6.9 Hz, 4H), 1.79–1.60 (p, J=6.7 Hz,
13
H), 1.49–1.14 ppm (d, J=44.5 Hz, 26H); C{H} NMR (126 MHz,
98 K, CDCl ): d=139.3, 114.3, 76.9, 67.91, 67.86, 34.0, 30.4, 30.3,
3
31
9.62, 29.58, 29.57, 29.30, 29.27, 29.1, 25.6 ppm; P{H} NMR
7.0 Hz, 3H), 1.78–1.51 (p, J=7.1 Hz, 4H), 1.51–1.19 ppm (m, 12H);
+
13
(
202 MHz, 298 K, CDCl ): d=1.18 ppm; ESI-MS: m/z 403.26 [M+H] ,
C{H} NMR (126 MHz, 298 K, CDCl ): d=142.6, 116.6, 42.0, 41.9,
3
3
+
+
8
05.48 [2M+H] , 1207.73 [3M+H] ; elemental analysis calcd (%)
35.4, 30.31, 30.18, 30.1, 29.2, 29.14, 29.09, 28.1, 27.9, 27.91, 27.90,
31
for C H O P (402.29): C 65.64, H 10.77; found: C 65.65, H 10.88.
27.88 ppm; P{H} NMR (202 MHz, 298 K, CDCl ): d=8.26 ppm; ESI-
3
2
2
43
4
+
+
MS: m/z 637.44 [2MÀH O+Na] , 915.55 [3MÀ2H O+H] , 1251.89
2
2
Bis-(oct-7-en-1-yl)-methylphosphate (9): Following the represen-
tative procedure described above (without purification by distilla-
tion) using 7-octen-1-ol, 9 was obtained as a yellowish oil (Yield:
+
[
4MÀ3H O+K] ; elemental analysis calcd (%) for C H N O P
2
16 33
2
2
(
316.23): C 60.73, H 10.51, N 8.85; found: C 60.59, H 10.56, N 8.81.
1
9
1
3
1
1
6
2
2%). H NMR (500 MHz, 298 K, CDCl ): d=5.91–5.67 (ddt, J=16.9,
3
0.2, 6.7 Hz, 2H), 5.12–4.83 (m, 4H), 4.11–3.96 (q, J=6.7 Hz, 4H),
.83–3.70 (dd, J=11.1, 6.4 Hz, 3H), 2.14–1.97 (q, J=7.8 Hz, 4H),
.80–1.60 (p, J=6.7 Hz, 4H), 1.52–1.28 ppm (dd, J=19.2, 7.2 Hz,
Representative procedure for synthesis of the methylphos-
phorodiamidate monomers
1
3
3H); C{H} NMR (126 MHz, 298 K, CDCl ): d=139.0, 114.44, 114.40,
N,N’-Bis-(but-3-en-1-yl)-methylphosphorodiamidate (13): A mix-
ture of 3-buten-1-amine (1.787 g, 2.300 mL, 25.12 mmol, 2.0 equiv),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 4.015 g, 3.944 mL,
26.38 mmol, 2.1 equiv), and DMAP (384 mg, 3.14 mmol, 0.25 equiv)
in CH Cl (10 mL) was added to a stirred solution of methyl dichlo-
3
7.93, 67.88, 67.8, 67.7, 54.2, 54.2, 33.7, 30.38, 30.36, 30.3, 28.84,
8.79, 28.74, 28.70, 28.68, 28.67, 28.65, 25.42, 25.39, 25.36 ppm;
3
1
P{H} NMR (202 MHz, 298 K, CDCl ): d=0.33ppm; ESI-MS: m/z
3
+
+
+
3
33.18 [M+H] , 355.15 [M+Na] , 687.32 [2M+Na] ; elemental
2
2
Chem. Eur. J. 2016, 22, 1 – 11
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7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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rophosphate (1.871 g, 1.260 mL, 12.56 mmol, 1.0 equiv) in CH Cl2
rated, dried over magnesium sulfate (MgSO ), filtered, and concen-
2
4
(
20 mL) at room temperature. The resulting solution was stirred
trated at reduced pressure (Yield: 920 mg, 4.18 mmol; 92%).
1
overnight at room temperature. The solvent of the filtrate was re-
moved under reduced pressure. The resulting residue was dis-
solved in diethyl ether. The diethyl ether phase was washed with
H NMR (500 MHz, 298 K, CDCl ): d=5.64–5.41 (m), 4.18–3.92 (m),
3
13
3.84–3.63 (m), 2.53–2.25 ppm (m); C{H} NMR (126 MHz, 298 K,
CDCl ): d=128.2, 127.3, 67.2, 67.14, 67.11, 67.09, 66.92, 66.88, 54.4,
3
31
1
0% HCl solution, NaHCO solution, and brine. After removing the
54.33, 54.31, 54.29, 33.70, 33.65, 28.70, 28.65 ppm; P{H} NMR
3
solvent under reduced pressure, pure 13 was obtained as a yellow-
ish oil (Yield: 1.92 g, 8.79 mmol; 70%). H NMR (500 MHz, 298 K,
(202 MHz, 298 K, CDCl ): d=0.08 ppm.
3
1
CDCl ): d=5.81–5.67 (ddt, J=17.1, 10.2, 6.9 Hz, 2H), 5.13–5.07 (m,
3
4
3
H), 3.67–3.63 (d, J=11.2 Hz, 3H), 3.02–2.94 (ddq, J=13.0, 6.5,
.1 Hz, 4H), 2.66 (s, 2H), 2.28–2.21 ppm (q, J=6.7 Hz, 4H); C{H}
[6a]
Representative procedure for catalytic hydrogenation
13
Polymer poly(8) (100 mg), CH Cl2 (5 mL), and 10% Pd/C catalyst
NMR (126 MHz, 298 K, CDCl ): d=135.4, 117.3, 51.8, 40.3, 36.2,
2
3
3
1
(5 mg) were charged into a reactor and flushed with argon. Hydro-
3
6.1 ppm; P{H} NMR (202 MHz, 298 K, CDCl ): d=16.67 ppm; ESI-
3
+
+
genation was then performed with vigorous stirring under a hydro-
gen pressure of 25 bar at room temperature for 16 h. The solution
was filtered over Celiteꢂ and polymer poly-H(8) was isolated after
solvent evaporation in a yield of 80%.
MS: m/z 219.11 [M+H] , 241.08 [M+Na] ; elemental analysis calcd
(
%) for C H N O P (218.12): C 49.33, H 8.78, N 12.84; found: C
9 19 2 2
4
9.11, H 8.70, N 12.96.
N,N’-Bis-(oct-7-en-1-yl)-methylphosphorodiamidate (14): Follow-
1
Poly-H(8): Hydrogenation of poly(8): yield: 82%. H NMR (300 MHz,
ing the representative procedure described above using 7-octen-1-
1
2
1
5
98 K, CDCl ): d=4.12–3.84 (m), 3.84–3.48 (m), 1.76–1.50 (m), 1.50–
amine 3, 14 was obtained as a yellowish oil (Yield: 84%). H NMR
3
13
.10 ppm (m); C{H} NMR (126 MHz, CDCl ): d=67.9, 67.6, 67.0,
(
500 MHz, 298 K, CDCl ): d=5.75–5.71 (td, J=16.9, 6.7 Hz, 2H),
3
3
31
4.2, 33.6, 33.5, 31.3, 30.2, 30.1, 25.0, 22.5, 14.0 ppm; P{H} NMR
4
2
.93–4.86 (m, 4H), 3.58–3.57 (d, J=11.2 Hz, 3H), 2.82 (m, 4H), 2.34–
.33 (d, J=6.8 Hz, 2H), 1.98–1.97 (q, J=6.8 Hz, 4H), 1.42–1.18 ppm
(
202 MHz, 298 K, CDCl ): d=0.38 ppm.
3
1
3
(
m, 23H); C{H} NMR (176 MHz, 298 K, CDCl ): d=138.9, 132.12,
Poly(9): The reaction was carried out following the general proce-
dure above with bis-(oct-7-en-1-yl)-methylphosphate 9 (150.0 mg,
3
1
3
2
32.06, 131.9, 128.53, 128.46, 114.3, 70.6, 51.7, 41.2, 41.1, 33.7, 32.0,
31
1
1.9, 29.7, 28.81, 28.75, 28.7, 26.6 ppm; P{H} NMR (202 MHz,
0.451 mmol) as the monomer for 16 h (yield: 85%). H NMR
+
98 K, CDCl ): d=16.87 ppm; ESI-MS: m/z 331.28 [M+H] , 683.47
(250 MHz, 298 K, CDCl ): d=5.42–5.14 (m), 4.11–3.82 (m), 3.78–3.59
3
3
+
+
13
[
2M+Na] , 1013.76 [3M+Na] ; elemental analysis calcd (%) for
(m), 2.07–1.78 (m), 1.74–1.45 (m), 1.45–1.07 ppm (m); C{H} NMR
C H N O P (330.24): C 61.79, H 10.68, N 8.48; found: C 61.67, H
(126 MHz, 298 K, CDCl ): d=138.87, 130.90, 130.25, 130.0, 129.8,
1
7
35
2
2
3
1
0.57, N 8.32.
114.3, 67.83, 67.78, 67.4, 67.3, 54.08, 54.08, 54.06, 33.6, 32.5, 32.4,
3
2
1.7, 30.3, 30.2, 29.6, 29.5, 28.7, 27.6, 27.1, 26.1, 25.3, 25.0,
N,N’-Bis-(undec-10-en-1-yl)-methylphosphorodiamidate (15): Fol-
lowing the representative procedure described above using 10-un-
31
4.8 ppm; P{H} NMR (202 MHz, 298 K, CDCl ): d=0.39 ppm.
3
1
decen-1-amine 4, 15 was obtained as a yellowish oil (Yield: 73%).
Poly-H(9): Hydrogenation of poly(9). Yield: 78%. H NMR
(300 MHz, 298 K, CDCl ): d=4.06–3.85 (m), 3.76–3.61 (m), 1.72–1.44
(m), 1.44–1.06 ppm (m); C NMR (126 MHz, CDCl ): d=67.9, 67.8,
1
H NMR (500 MHz, 298 K, CDCl ): d=5.88–5.65 (td, J=16.9, 6.7 Hz,
3
3
13
2
H), 5.05–4.83 (m, 4H), 3.79–3.43 (d, J=11.2 Hz, 3H), 2.97–2.74 (t,
3
J=7.9 Hz, 4H), 2.57–2.30 (d, J=8.0 Hz, 2H), 2.13–1.89 (m, 4H),
54.1, 54.0, 31.9, 30.32, 30.26, 29.63, 29.58, 29.5, 29.2, 27.6, 27.3,
26.6, 26.5, 26.4, 25.4, 24.7, 22.7, 22.6, 14.1 ppm; P NMR (202 MHz,
13
31
1
.53–1.38 (m, 4H), 1.38–1.09 ppm (d, J=46.7 Hz, 27H); C{H} NMR
(
176 MHz, 298 K, CDCl ): d=139.2, 132.11, 132.06, 131.9, 128.52,
298 K, CDCl ): d=0.37 ppm.
3
3
1
2
28.45, 114.1, 53.6, 51.69, 51.67, 41.6, 41.2, 39.8, 33.8, 32.02, 31.99,
9.52, 29.42, 29.36, 29.3, 29.2, 29.1, 28.9, 27.7, 26.7 ppm; P{H}
Poly(10): The reaction was carried out following the general proce-
dure above with bis-(undec-10-en-1-yl)-methylphosphate 10
31
NMR (202 MHz, 298 K, CDCl ): d=17.03 ppm; ESI-MS: m/z 415.37
3
(250.0 mg, 0.600 mmol) as the monomer for 8 h (yield: 78%).
+
+
+
+
[M+H] , 437.35 [M+Na] , 829.72 [2M+H] , 851.69 [3M+Na] ,
1
H NMR (700 MHz, 298 K, CDCl ): d=5.91–5.66 (m), 5.44–5.23 (m),
3
+
1
266.03 [3M+H] ; elemental analysis calcd (%) for C H N O P
23 47 2 2
5.04–4.85 (m), 4.07–3.94 (m), 3.79–3.67 (m), 2.08–1.87 (m), 1.76–
(
414.34): C 47.05, H 8.39, N 13.72; found: C 47.14, H 8.39, N 13.58.
13
1
1
2
.55 (m), 1.47–1.08 ppm (m); C{H} NMR (176 MHz, CDCl ): d=
3
30.4, 130.0, 69.0, 68.0, 54.20, 54.16, 32.7, 30.5, 30.4, 29.8, 29.62,
9.56, 29.3, 27.4, 25.6 ppm; P{H} NMR (284 MHz, 298 K, CDCl3):
31
Representative procedure for the ADMET polymerization of
the methylphosphate and methylphosphorodiamide mono-
mers
d=0.83 ppm.
1
Poly-H(10): Hydrogenation of poly(10). Yield: 84%. H NMR
(
(
500 MHz, 298 K, CDCl ): d=4.17–3.97 (m), 3.86–3.68 (m), 1.77–1.52
3
13
m), 1.47–1.08 ppm (m); C{H} NMR (126 MHz, CDCl ): d=67.9,
Poly(8): Bis-(but-3-en-1-yl)-methylphosphate 8 (1.0 g, 4.54 mmol)
and Grubbs catalyst (first generation: 37.4 mg, 0.0454 mmol,
1
3
6
2
2
7.8, 54.1, 54.0, 31.9, 30.33, 30.27, 29.72, 29.70, 29.67, 29.6, 29.53,
31
9.51, 29.3, 29.2, 25.4, 25.4, 22.7, 14.1 ppm; P{H} NMR (202 MHz,
98 K, CDCl ): d=0.38 ppm.
mol%; or Hoveyda–Grubbs second generation catalyst: 2 mol%
and 2 mol% after 2 h for PPDAs) were placed in a glass Schlenk
tube equipped with a magnetic stir bar under an argon atmos-
phere. The reaction was carried out under reduced pressure (to
remove the ethylene gas evolving during the metathesis reaction)
in bulk or solution at temperatures between RT and 508C for 16 h.
Poly(8) was obtained in bulk as a brownish viscous oil in quantita-
tive yield. Purification: tris-(hydroxymethyl) phosphine (ca. 50 equiv
with respect to the catalyst) was added to a solution of CH Cl and
3
Poly(13): The reaction was carried out following the general proce-
dure above with Hoveyda–Grubbs second generation catalyst
(11.4 mg, 0.00908 mmol, 2ꢁ2 mol%) and N,N’-bis-(but-3-en-1-yl)-
methylphosphorodiamidate 13 (100.0 mg, 0.458 mmol) as the
monomer in bulk for 16 h and in a 50 wt% 1-chloronaphthalin so-
1
lution for 20 h (yield: 75%). H NMR (300 MHz, 298 K, CDCl ): d=
3
5.62–5.53 (m), 5.15–5.07 (m), 3.62–3.59 (m), 3.53–3.32 (m), 2.91–
2
2
13
the polymer. After the addition of water, the emulsion was stirred
for several hours until the CH Cl phase was almost colorless. The
CH Cl phase was washed with aqueous 10% HCl and finally with
2.89 (m), 2.25–2.10 ppm (m); C{H} NMR (126 MHz, 298 K, CDCl3):
d=135.4, 131.2, 129.8, 128.7, 127.0, 117.32, 117.29, 117.25, 115.6,
2
2
31
51.9, 43.1, 43.0, 40.6, 40.2, 36.1, 34.9, 34.5, 17.6 ppm; P{H} NMR
2
2
brine to remove the catalyst residue. The CH Cl phase was sepa-
(202 MHz, 298 K, CDCl ): d=16.98 ppm.
2
2
3
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Poly(N,N’-hexan-1-yl methylphosphorodiamidate) (Poly-H(13)):
Hydrogenation of poly(13). Yield: 70%. H NMR (300 MHz, 298 K,
Copolymer of monomers 6 and 10 (Poly(6–10)): The reaction was
carried out following the general procedure above with bis-(oct-7-
en-1-yl)-phosphate 6 (51 mg, 0.160 mmol, 1 equiv) as hydroxyl
1
CDCl ): d=3.69–3.59 (m), 2.94–2.87 (m), 1.60–1.40 (m), 1.39–
3
1
3
1
1
4
2
.30 ppm (m); C{H} NMR (126 MHz, CDCl ): d=51.7, 45.5, 41.2,
0.9, 34.10, 34.05, 29.7, 19.9, 13.7 ppm; P{H} NMR (202 MHz,
monomer for 16 h. Yield: 86%. H NMR (300 MHz, 298 K, CDCl3):
3
31
d=5.49–5.23 (m), 4.15–3.90 (m), 3.84–3.68 (m), 2.15–1.86 (m), 1.82–
13
98 K, CDCl ): d=17.20–16.91 (m).
1.52 (m), 1.53–1.14 ppm (m); C{H} NMR (75 MHz, 298 K, CDCl3):
3
d=130.5, 130.3, 130.1, 129.8, 67.9, 67.8, 54.1, 54.0, 32.6, 32.5, 30.3,
Poly(14): The reaction was carried out following the general proce-
dure above with the Hoveyda–Grubbs second generation catalyst
31
3
2
0.2, 29.7, 29.5, 29.4, 29.2, 27.2, 25.4 ppm; P{H} NMR (121.5 MHz,
98 K, CDCl ): d=1.45–0.58, 0.57–0.20 ppm.
(
6.0 mg, 0.00964 mmol, 2ꢁ2 mol%) and N,N’-bis-(oct-7-en-1-yl)-
3
methylphosphorodiamidate 14 (100.0 mg, 0.241 mmol) as the
Copolymer of monomers 7 and 10 (Poly(7–10)): The reaction was
carried out following the general procedure above with bis-
(undec-10-en-1-yl)-phosphate 7 (51 mg, 0.160 mmol, 1 equiv) as
monomer in a 50 wt% 1-chloronaphthalin solution for 16 h (yield:
1
7
3%). H NMR (500 MHz, 298 K, CDCl ): d=5.55–5.24 (m), 5.11–4.85
3
1
(
(
m), 3.78–3.53 (m), 3.05–2.68 (m), 2.14–1.80 (m), 1.72–1.01 ppm
hydroxyl monomer for 16 h. Yield: 93%. H NMR (300 MHz, 298 K,
1
3
m); C{H} NMR (176 MHz, 298 K, CDCl ): d=130.5, 130.3, 130.1,
CDCl ): d=5.49–5.25 (m), 4.21–3.90 (m), 3.86–3.66 (m), 2.13–1.83
3
3
13
5
2
3.4, 53.1, 51.7, 41.2, 32.5, 32.0, 29.5, 29.3, 28.8, 27.1, 26.7,
(m), 1.81–1.49 (m), 1.49–1.14 ppm (m); C{H} NMR (75 MHz, 298 K,
3
1
6.3 ppm; P{H} NMR (121.5 MHz, 298 K, CDCl ): d=17.05 ppm
CDCl ): d=130.3, 129.8, 67.9, 67.8, 54.1, 54.0, 53.4, 32.6, 30.33,
3
3
31
(
m).
30.24, 29.7, 29.5, 29.2, 27.2, 25.4 ppm; P{H} NMR (121.5 MHz,
1
298 K, CDCl ): d=1.40–0.75, 0.39–0.19 ppm.
Poly-H(14): Hydrogenation of poly(14). Yield: 67%. H NMR
3
(
300 MHz, 298 K, CDCl ): d=3.70–3.59 (m), 2.97–2.83 (m), 1.50–1.35
Copolymer of monomers 11 and 13 (Poly(11–13)): The reaction
was carried out following the general procedure above with the
3
13
(
m), 1.36–1.23 ppm (m); C{H} NMR (75 MHz, CD Cl ): d=41.5,
2
2
3
1
3
2.5, 32.4, 32.2, 30.08, 30.0, 29.7, 27.2, 23.1, 14.3 ppm; P{H} NMR
Hoveyda–Grubbs
second
generation
catalyst
(14.4 mg,
(
202 MHz, 298 K, CDCl ): d=16.63 ppm (m).
0.0229 mmol, 2ꢁ2 mol%), N,N’-bis-(but-3-en-1-yl)-phosphorodiami-
date 11 (23.4 mg, 0.115 mmol, 1 equiv) as hydroxyl monomer and
N,N’-bis-(but-3-en-1-yl)-methylphosphorodiamidate 13 as methyl
3
Poly(15): The reaction was carried out following the general proce-
dure above with the Hoveyda–Grubbs second generation catalyst
(
yl)-methylphosphorodiamidate 15 (100.0 mg, 0.241 mmol) as the
monomer in a 50 wt% 1-chloronaphthalin solution for 16 h (yield:
7
(
1
5
2
2
monomer (100 mg, 0.458 mmol, 8 equiv) for 16 h. Yield: 88%.
6.0 mg, 0.00964 mmol, 2ꢁ2 mol%) and N,N’-bis-(undec-10-en-1-
1
H NMR (300 MHz, 298 K, CDCl ): d=5.62–5.14 (m), 3.71–3.50 (m),
.50–3.33 (m), 3.14–2.65 (m), 2.36–2.01 ppm (m); C{H} NMR
3
13
3
1
(75 MHz, 298 K, CD Cl ): d=136.2, 134.3, 131.5, 130.3, 129.2, 117.9,
1%). H NMR (500 MHz, 298 K, CDCl ): d=5.38–5.34 (m), 3.66–3.60
2
2
3
1
17.0, 43.3, 40.9, 40.7, 39.6, 36.5, 35.2, 34.8, 32.1, 23.0, 21.2, 18.3,
m), 2.89–2.85 (m), 2.50–2.26 (m), 1.97–1.93 (m), 1.47–1.43 (m),
31
1
3
17.8, 14.3 ppm; P{H} NMR (121.5 MHz, 298 K, CD Cl ): d=17.28,
2 2
.28–1.24 ppm (m); C{H} NMR (176 MHz, CDCl ): d=130.3, 129.9,
3
8
.68 ppm.
1.68, 51.66, 41.2, 32.59, 32.55, 32.04, 32.00, 29.8, 29.51, 29.46,
9.51, 29.46, 29.3, 29.2, 29.1, 27.2, 26.8 ppm; P{H} NMR (202 MHz,
3
1
Copolymer of monomers 12 and 15 (Poly(12–15)): The reaction
was carried out following the general procedure above with the
Hoveyda–Grubbs second generation catalyst (8.0 mg, 0.0128 mmol,
98 K, CDCl ): d=17.00 ppm (m).
3
1
Poly-H(15): Hydrogenation of poly(15). Yield: 81%. H NMR
2
ꢁ2 mol%),
N,N’-bis-(but-3-en-1-yl)-phosphorodiamidate 11
(
(
500 MHz, 298 K, CDCl ): d=3.67–3.56 (m), 2.97–2.78 (m), 2.53–2.41
3
1
3
(23.4 mg, 0.080 mmol, 1 equiv) as hydroxyl monomer and N,N’-bis-
m), 1.53–1.37 (m), 1.37–1.10 ppm (m); C{H} NMR (75 MHz,
31
(but-3-en-1-yl)-methylphosphorodiamidate 13 as methyl monomer
CD Cl ): d=41.5, 32.3, 30.1, 29.8, 27.2, 23.1, 14.3 ppm; P{H} NMR
(
2
2
1
(
100 mg, 0.241 mmol, 3 equiv) for 16 h. Yield: 82%. H NMR
202 MHz, 298 K, CDCl ): d=17.19 ppm.
3
(
300 MHz, 298 K, CDCl ): d=5.58–5.22 (m), 3.82–3.54 (m), 3.05–2.76
3
13
(m), 2.14–1.84 (m), 1.71–1.43 (m), 1.43–1.03 ppm (m); C{H} NMR
(
2
75 MHz, 298 K, CD Cl ): d=130.7, 41.5, 33.0, 32.4, 30.00, 29.99,
9.7, 29.5, 27.2, 18.1 ppm; P{H} NMR (121.5 MHz, 298 K, CD Cl ):
2 2
2
2
31
Representative procedure for the ADMET copolymerization
of methylphosphate monomers and methylphosphorodiami-
date monomers
d=17.88, 12.76, 9.44 ppm.
Procedure for hydrolytic degradation
Copolymer of monomer 5 and 10 (Poly(5–10)): Bis-(undec-10-en-
11, 13, or poly(13) (6.0 mg) were dissolved into deuterated buffer
1
3
-yl)-methylphosphate 10 (200 mg, 0.480 mmol, 3 equiv), bis-(but-
-en-1-yl)-phosphate 5 (33 mg, 0.160 mmol, 1 equiv), Grubbs first
solution (0.6 mL; pH 1.0: 0.136 mm hydrogen chloride/potassium
chloride solution, pH 3.0: 0.088 mm hydrogen chloride/potassium
hydrogen phthalate solution, pH 5.0: 0.100 mm sodium acetate/
acetic acid solution, pH 7.0: 0.01 mm phosphate buffered saline
generation catalyst (5.3 mg, 0.0064 mmol, 1 mol%; or Hoveyda–
Grubbs second generation catalyst: 2 mol% and 2 mol% after 2 h
for PPDAs) were placed in a glass Schlenk tube equipped with
a magnetic stirrer bar under an argon atmosphere. The reaction
was carried out at reduced pressure at a temperature of 508C for
(PBS) buffer solution, pH 8.0: 0.015 mm borax/hydrogen chloride
solution, pH 13: 0.145 mm sodium hydroxide/potassium chloride
solution). The mixtures were poured into NMR tubes and measured
during the degradation.
1
6 h for phosphate-based polymers and poly(11–13). For polymer
poly(12–15), the reaction was carried out in a 50 wt% 1-chloro-
naphthalin solution at reduced pressure at room temperature.
Poly(5–10) was obtained as an off-white viscous oil in quantitative
Preparation of PPDA nanoparticles
1
yield after 16 h. Purification: see above. Yield: 91%. H NMR
(
(
300 MHz, 298 K, CDCl ): d=5.64–5.21 (m), 4.15–3.89 (m), 3.82–3.61
Poly(15) (30 mg) was dissolved in chloroform (1 g, 846 mg) and
added to an aqueous solution of Lutensol AT50 (30 mg) in water
(5 g). The two-layer system was sonicated with a Brandon W450-D
sonifier with a 1/4 tip at 70% amplitude in a pulsed regime (30 s
sonication, 10 s pause) under ice cooling. The obtained miniemul-
3
m), 2.55–2.24 (m), 2.10–1.84 (m), 1.78–1.54 (m), 1.51–1.11 ppm (m);
1
3
C{H} NMR (75 MHz, 298 K, CDCl ): d=130.3, 129.8, 67.9, 54.1, 32.6,
3
31
3
(
0.3, 30.2, 29.7, 29.5, 29.4, 29.2, 27.2, 25.4 ppm; P{H} NMR
121.5 MHz, 298 K, CDCl ): d=1.38–0.50, 0.50–0.25 ppm.
3
Chem. Eur. J. 2016, 22, 1 – 11
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sion was stirred in the open at 408C for 16 h to evaporate the or-
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were divided into volumes of 500 mL and concentrated HCl (40 mL)
was added to each vial. Every other day one of those suspensions
was freeze dried, dissolved in deuterated chloroform, and mea-
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[
[
[
Keywords: acyclic diene metathesis
·
degradation
·
phosphorus · poly(phosphoester) · poly(phosphorodiamidate)
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Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 11
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ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Poly(phosphorodiamidate)s have been
prepared by ADMET (acyclic diene
metathesis) polycondensation. These
novel materials with adjustable hydro-
philicity represent an alternative to
poly(phosphazene)s or poly(phos-
phoester)s and exhibit a precise degra-
dation profile.
&
Phosphorus-Containing Polymers
M. Steinmann, M. Wagner, F. R. Wurm*
& – &&
&
Poly(phosphorodiamidate)s by Olefin
Metathesis Polymerization with
Precise Degradation
Chem. Eur. J. 2016, 22, 1 – 11
www.chemeurj.org
11
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ