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Ian Teasdale, Oliver Brüggemann, Helena Henke
Polyphosphazenes for Medical Applications
Also of Interest
Organophosphorus Chemistry.
Novel Developments
Keglevich (Ed.), 
ISBN ----, e-ISBN ----

Organocatalysis.
Stereoselective Reactions and Applications in Organic Synthesis
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Organoselenium Chemistry
Ranu, Banerjee (Eds.), 
ISBN ----, e-ISBN ----

Phosphorus Chemistry.
The Role of Phosphorus in Prebiotic Chemistry
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ISBN ----, e-ISBN ----

Solubility in Pharmaceutical Chemistry

Saal, Nair, 
ISBN ----, e-ISBN ----
Ian Teasdale, Oliver Brüggemann,
Helena Henke

Polyphosphazenes
for Medical
Applications
2 ED
Authors
Assoc. Prof. Dr. Ian Teasdale
Institute of Polymer Chemistry
Johannes Kepler University Linz
Altenbergerstrasse 69
4040 Linz
Austria
[email protected]

Prof. Dr. Oliver Brüggemann

Institute of Polymer Chemistry
Johannes Kepler University Linz
Altenbergerstrasse 69
4040 Linz
Austria
[email protected]

Dr. Helena Henke

Institute of Polymer Chemistry
Johannes Kepler University Linz
Altenbergerstrasse 69
4040 Linz
Austria
[email protected]

ISBN 978-3-11-065253-6
e-ISBN (PDF) 978-3-11-065418-9
e-ISBN (EPUB) 978-3-11-065291-8

Library of Congress Control Number: 2020935451

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie;
detailed bibliographic data are available on the Internet at http://dnb.dnb.de.

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Cover image: everythingpossible / iStock / Getty Images Plus
Typesetting: Integra Software Services Pvt. Ltd.
Printing and binding: CPI books GmbH, Leck

www.degruyter.com
Preface
Polyphosphazenes are a family of polymers based on the repeat unit structure of
phosphorus and nitrogen, connected by alternating double and single bonds. The
phosphorus atoms are thus pentavalent and the remaining two substituents (usually
organic) can be chosen from a vast selection to give poly(organo)phosphazenes with
a broad spectrum of properties and hence a wide range of applications. Indeed, poly-
phosphazenes with a vast array of properties and suggested applications have
been described in the scientific literature, predominantly pioneered by the group of
H.R. Allcock since the 1960s. Of the many poly(organo)phosphazenes reported, those
relevant for medical applications are particularly promising due to the unique and
tunable properties for highly demanding and evermore complex applications.
Synthetic polymer materials are now commonplace in medicine and can fulfill
a host of functions, from fixation devices to wound healing and from pharmaceuti-
cal formulations to polymer therapeutics. The objective of this volume is to bring
the reader up to date on the state of the art for poly(organo)phosphazenes designed
specifically for use in medical applications. In doing so, we review the progress
made in polyphosphazene preparation methods and review our present under-
standing of their essential properties. A further objective is in reviewing the latest
developments in this ever-expanding field to highlight the main areas of strength
and weakness and thus decipher the most hopeful future prospects for poly-
phosphazenes as biomedical materials.
The book is divided into four main chapters, each chapter containing a short
introduction to the topic, followed by the latest research highlights in that particu-
lar area. The aim of Chapter 1 is to bring the reader up to date with the current
synthetic procedures available for poly(organo)phosphazenes. The reader is in-
formed how structure–property relationships can be controlled to design novel
poly(organo)phosphazenes with specific properties for the desired application,
and how polymers with the required molecular weights and architectures can be
prepared. Chapter 2 looks into the degradability and bioerodability of poly(organo)-
phosphazenes. The rate of hydrolytic degradation of poly(organo)phosphazenes can
be tuned by the choice of organic substituent, such that the entire spectrum from long-
term biostable to rapidly eroding polymers can be prepared. Special attention is given
here to the degradation properties and how they can be controlled, since bioerosion
and degradability are essential properties for many medical applications, especially
those discussed in Chapters 3 and 4, namely nanomedicine and tissue engineering. In
these two chapters, the structural characteristics, preparation techniques and applica-
tion studies in medical fields are detailed, with a particular focus on the most recent
and most promising applications. This includes their use as immunoadjuvants and for
the stabilization and transport of proteins and DNA, as polymer therapeutics for
targeted drug delivery, and their development as injectable hydrogels for controlled
drug-release devices. Furthermore, a chapter is devoted to the use of poly(organo)

https://doi.org/10.1515/9783110654189-202
VI Preface

phosphazenes as degradable scaffolds for tissue regeneration. In Chapter 5, the most

important features are summarized and a critical assessment is given into the current
state of play and future prospects for polyphosphazenes in medicine.
This volume should not only provide a useful and critical summary for research-
ers already working in the field or looking to enter the field, but it is also hoped that
the content is of interest to those working in the biomedical fields in which these poly-
mers can be applied, to give a basic understanding of the materials available and high-
light the recent developments, possibilities and unanswered questions with regard to
their use in medical applications.
Contents
Preface V

Chapter 1
Synthetic procedures 1
1.1 Poly(dichloro)phosphazene 1
1.2 Macromolecular substitution 3
1.3 Ring-opening polymerization 4
1.4 Chain growth polycondensation 6
1.5 Macromolecular architecture 10
1.5.1 P=N backbone branching 10
1.5.2 Grafting 13
1.5.3 Block copolymers 16
1.5.4 Self-assembly 18
1.6 Conclusion 21
References 22

Chapter 2
Degradable poly(organo)phosphazenes 27
2.1 Bioerodible polymers for biomedicine 27
2.1.1 Bioerodible solid biomaterials and polymer matrices 28
2.1.2 Water-soluble, degradable polymers 30
2.2 Poly(organo)phosphazene degradation 31
2.2.1 Side-group influence on degradation kinetics 32
2.2.2 Amino acid ester-derived polyphosphazenes 35
2.2.3 The effect of pH 38
2.2.4 Stimuli-responsive degradation 39
2.3 Degradable molecular-level hybrids 41
2.4 Blends of poly(organo)phosphazenes 43
2.5 Bulk versus surface erosion 45
2.6 Degradation product cytotoxicity 46
2.7 Conclusion 46
References 47

Chapter 3
Nanomedicine 53
3.1 Polyphosphazenes in immunology 54
3.1.1 Vaccine adjuvants and delivery systems 54
3.1.2 Polyphosphazene electrolytes as immunological adjuvants 56
3.1.3 Structure–activity relationships 57
3.1.4 Safety considerations 60
VIII Contents

3.1.5 Immunological activity 61

3.1.6 Polyelectrolyte microsphere formulations 63
3.1.7 Alternative delivery routes 64
3.2 Protein delivery 66
3.3 Cationic polyphosphazenes and their polyplexes 67
3.3.1 Gene delivery 67
3.3.2 Gene silencing 70
3.3.3 Charged polyphosphazenes for enteral drug delivery 71
3.4 Controlled release from polyphosphazene matrices 72
3.4.1 Polyphosphazene-based drug depot devices 72
3.5 Polymer therapeutics 74
3.5.1 Macromolecular drug carriers 74
3.5.2 Polyphosphazene drug conjugates 75
3.5.3 Polyphosphazene carriers for photodynamic therapy 81
3.5.4 Colon-specific azo-based drug conjugates 82
3.6 Self-assembled micelles and polymersomes 84
3.7 Thermosensitive poly(organo)phosphazenes 87
3.7.1 Thermosensitive polymers 87
3.7.2 Thermosensitive polyphosphazene drug carriers 88
3.7.3 Injectable hydrogels 89
3.8 Theranostics 93
3.9 Conclusion 95
References 96

Chapter 4
Tissue engineering 107
4.1 Introduction to tissue engineering 107
4.2 Architecture of polyphosphazene scaffolds for tissue
engineering 107
4.2.1 Formats 109
4.2.1.1 Linear polyphosphazenes 109
4.2.1.2 Cross-linked polyphosphazenes 112
4.2.2 Properties 116
4.3 Applications of polyphosphazene scaffolds in tissue
engineering 120
4.3.1 Bone tissue engineering 121
4.3.2 Endothelial tissue engineering 126
4.3.3 Neural tissue engineering 128
4.4 Degradation of polyphosphazenes developed for tissue
engineering 129
4.5 Conclusion 135
References 135
 Contents IX

Chapter 5
Opportunities and challenges 139
5.1 From laboratory to clinic 139
5.2 Future prospects 140
References 141

Abbreviations 143

Index 147
Chapter 1
Synthetic procedures

The polyphosphazene structure is based on an inorganic backbone of alternating

phosphorus and nitrogen atoms (Figure 1.1). The inorganic backbone is responsible
for the many unique features of polyphosphazenes, including its high flexibility,
high thermal stability as well as hydrolytic degradability. The remaining substituents
of the pentavalent phosphorus atoms are most commonly of an organic nature, lead-
ing to poly(organo)phosphazenes. These side groups are decisive in determining the
resulting properties of the polymer. The properties can thus be systematically varied
through a combination of substituents, resulting in a large number of different poly-
phosphazenes with a wide range of properties and hence applications [1].

P N
n
R'

Inorganic–organic hybrid polymers

Figure 1.1: The inorganic polyphosphazene backbone can be substituted with a variety of organic
substituents to give polymers with a broad spectrum of chemical and physical properties and
access to advanced materials for a host of applications.

1.1 Poly(dichloro)phosphazene

The most commonly applied route to prepare poly(organo)phosphazenes remains

via the inorganic macromolecular precursor poly(dichloro)phosphazene, [NPCl2]n.
Poly(dichloro)phosphazene comprises two highly labile chlorine atoms per repeat
unit, which induces a synthetic flexibility by allowing the facile substitution of a
whole host of organic side groups and thus the preparation of a wide array of physical
and chemical properties. The [NPCl2]n backbone can be substituted by essentially any
given nucleophile (Figure 1.2), including H2O, which produces hydroxyphosphazenes
(with P–OH moieties), which cannot only lead to cross-linking via intermolecular
condensation but is also a degradation intermediate (see Chapter 2). Furthermore,
the by-product of this hydrolysis, HCl, would be expected to further accelerate
backbone degradation. Hydrolysis is exceptionally rapid, with extensive cross-
linking reported within days for solutions of [NPCl2]n stored in even extremely dry

https://doi.org/10.1515/9783110654189-001
2 Chapter 1 Synthetic procedures

Cl Cl
P N P N
OH Cl m m Crosslinking
Cl H2O O
P N P N
P N
Cl n –HCl Cl n –HCl
Cl n

Degradation

Figure 1.2: Hydrolysis pathway of poly(dichloro)phosphazene leading to degradation and cross-

linking.

solvents [2]. Hence, the hydrolytic sensitivity of the precursor becomes a primary
concern and indeed this conundrum has accompanied polyphosphazene synthe-
sis since its very beginnings [1].
Thus, the reproducible synthesis of this hydrolytically sensitive precursor, as
well as its characterization, stabilization and storage are major stepping stones in
the development of commercially viable materials. Synthetic reproducibility for any
application, not least for medical applications, where regulatory approval must be
met, is of critical importance. Furthermore, direct chromatographic analysis of this
hydrolytically unstable precursor is extremely difficult, with degradation and cross-
linking occurring in the column, meaning usually only indirect analysis of substi-
tuted derivatives can be applied.
To this end, Andrianov and coworkers have developed a stabilized route
using diglyme (Figure 1.3). The precise nature of the stabilization effect is un-
clear, although it is feasible that either diglyme coordination of water and/or the
stabilization of cationic degradation intermediates is responsible [2]. Using this
method it is possible to store [NPCl2]n for several years, without any detrimental
effects of hydrolysis and/or cross-linking being observed. Just as importantly,
this stabilization procedure has allowed the direct analysis of [NPCl2]n via size
exclusion chromatography [2], which may be important for procedure standardi-
zation. Indeed, good manufacturing practices have been developed for this pre-
cursor [3] and the method has been used for the preparation of polymers used in
clinical trials [4]. Furthermore, the storage in diglyme enables direct macromolecular
substitution without prior removal of the solvent.
 1.2 Macromolecular substitution 3

Diglyme : THF,
Vol/Vol

100 : 0 No Cross-Linking (4 years)

75 : 25 No Cross-Linking (4 years)

50 : 50 Cross-Linked

25 : 75 Cross-Linked

10 : 90 Cross-Linked

0 : 100 Cross-Linked

0 100 200 300 400 500

Cross-linking, hours

Figure 1.3: Stabilization of poly(dichloro)phosphazene in diglyme. THF, tetrahydrofuran. Reproduced

with permission from A.K. Andrianov, J. Chen and M.P. LeGolvan, Macromolecules, 2004, 37, 2, 414.
©2004, American Chemical Society [2].

1.2 Macromolecular substitution

Once prepared, the [NPCl2]n precursor is then substituted to give (more) hydrolyti-
cally stable polymers (Figure 1.4). This macromolecular substitution is a relatively
unique procedure and has a decisive influence on the properties of the polymers.
As previously mentioned, in this sense the (problematic) hydrolytic instability of
[NPCl2]n can be regarded as a double-edged sword, as it simultaneously facilitates
the macromolecular substitution of the polymer backbone and hence the variety of

Cl NHR
RNH2
P N P N
–HCl NHR n
Cl n

Cl OR
RONa
P N P N
NaCl OR n
Cl n

Figure 1.4: Most common routes for the macromolecular substitution of poly(dichloro)phosphazene.
4 Chapter 1 Synthetic procedures

poly(organo)phosphazenes that can be produced. The highly labile chlorine atoms

can be readily replaced by a host of nucleophiles, in particular, amines and alk-
oxides. In this manner, a wide variety of organic side groups can be coupled onto the
polyphosphazene backbone, and hundreds of poly(organo)phosphazenes have been
reported with wide-ranging properties (see [1] for a summary of many of those re-
ported up to 2003). This simple macrosubstitution would also lend itself in theory to
high-throughput synthesis, with the possibility of preparing a library of polymers
from a single [NPCl2]n chain [3].
Despite the high reactivity of the [NPCl2]n backbone, care must be taken to ensure
complete substitution, which consists of multiple parallel substitution reactions on a
single macromolecule. Incomplete chlorine replacement and thus residual P–Cl bonds
would not only lead to structural irregularities and inconsistent polymer functionality
but impact the degradation rates of the polymers and/or lead to cross-linking. The pres-
ence of residual chlorine atoms has been shown to considerably accelerate backbone
degradation rates [8]. As this process is inherently irregular, the composition and sta-
bility of the resulting poly(organo)phosphazene is unpredictable and thus must be
avoided. The use of “forcing conditions,” that is, an excess of the nucleophile, long
reaction times and appropriate reaction conditions ensure the complete removal of
chlorine atoms and thus reproducible polymers. Such reproducibility considerations
apply in particular when producing polymers for medical applications, as the effect
of this unpredictability could be highly detrimental.

1.3 Ring-opening polymerization

The traditional and most widely used route to prepare high-molecular-weight (Mw)
poly(dichloro)phosphazene is the thermally induced ring-opening polymerization
(ROP) of hexachlorophosphazene [5]. This is most commonly carried out in the mol-
ten state under vacuum, in a sealed tube at 250 °C (Figure 1.5). In this regard, a host
of variations have been attempted, with varying degrees of improvement over the
basic technique (for a comprehensive review of these see [1]). Importantly, the basic
procedure can also be scaled up to pilot plant or manufacturing level [1].
The preparation of [NPCl2]n in solution, with the added convenience that solution-
state synthesis offers, has also been achieved, for example, in 1,2,4-trichlorobenzene
(TCB) at 214 °C [6]. Furthermore, [NPCl2]n can also be synthesized via a convenient di-
rect solution state preparation from phosphorus pentachloride (PCl5) and ammonium
chloride (NH4Cl) in the presence of sulfamic acid and calcium sulfate dihydrate [7] in
refluxing TCB. Both the molten and solution-state synthetic routes provide high Mw
[NPCl2]n and for both routes catalysts such as OP(OPh)3/BCl3 or BCl3 [8] can be added
to achieve some Mw control. A convenient and widely applied route to control the Mw
of [NPCl2]n is the use of anhydrous aluminum chloride (2–10%) [9].
 1.3 Ring-opening polymerization 5

Cl Cl
Cl
P Δ
N N P N
Cl P P Cl Cl n
n N ROP
Cl Cl

Cl Cl Cl Cl Cl Cl
Cl Cl Cl Cl Cl Cl
P – P P P
N N Cl N N N N P P
N +
Cl P P+ Cl P P Cl Cl P P N N
N N Cl N Cl –
Cl Cl Cl Cl Cl

Figure 1.5: Commonly accepted mechanism for the ring-opening polymerization of

hexachlorophosphazene.

Generally, the ring-opening procedure requires a high purity of the hexachloro-

phosphazene [NPCl2]3 monomer for reproducible results. High temperatures are also re-
quired [10] although an ambient temperature approach in 1,2-dichlorobenzene with a
weakly coordinating anionic trialkylsilylium carborane [10] has also been carried out.
A further inherent drawback of ROP is the tendency to produce branching and subse-
quently crosslinked substances at higher conversions. This could be caused by traces
of moisture and thus the formation of hydroxyphosphazenes, but there is growing evi-
dence that this is a polymerization-based phenomenon (Figure 1.6), that is, cannot be
attributed purely to hydrolysis with the consequence that no amount of drying or puri-
fication will prevent this [2].

–
CI
+
CI P N
CI CI
N N P N
CI CI CI CI P
P P CI N
CI CI CI P N
N Δ N CI P
CI
CI CI N
P CI CI P+
CI CI
– CI
N P N N P
CI CI
P CI N P P CI N
CI P N CI CI
CI
CI

Figure 1.6: Proposed inherent cause of branching and (at higher conversions) cross-linking during
the synthesis of [NPCl2]n via ROP [2].
6 Chapter 1 Synthetic procedures

Furthermore, despite still being the route able to prepare the highest Mw, ROP in-
herently produces polymers with broad dispersities (Mu/Mn) >2 due to its initiation
mechanism, in which the formation of new chains can occur throughout. Although
high Ð values are perfectly tolerable for many medical applications, for example, as
inert biomaterials, the method is less suitable for some biomedical applications in
which precise molecular size is often an essential property. Furthermore, advanced
polymer architectures and macromolecular constructs cannot be readily attained via
this method, due to the absence of end-group control, and hence the development of
poly(dichloro)phosphazene with controlled Mw has been important in order to broaden
the spectrum of available applications.

1.4 Chain growth polycondensation

The development of a living polymerization route to poly(dichloro)phosphazenes is of

importance for many future medical applications of polyphosphazenes as it facilitates
the synthesis of [NPCl2]n with controlled Mw and opens the door to the preparation of
advanced macromolecular constructs. Thus the conception and development of living
cationic polymerization of phosphoranimines by Allcock and Manners [11, 12] can
be regarded as a major advancement in polyphosphazene science. As shown in
Figure 1.7, trichlorophosphoranimine (Cl3PNSi(CH3)3) is initiated with PCl5 and the ad-
dition of further monomer molecules proceeds via a living, chain growth polyconden-
sation, which itself is a relatively rarely observed polymerization mechanism [13],
with the elimination of trimethylchlorosilane ((CH3)3SiCl) until monomer conversion
is complete. The reaction can be carried out in solution (usually CH2Cl2) at ambient
temperatures, and the Mw can be controlled by the ratio of PCl5 to Cl3PNSi(CH3)3.
Analysis of macrosubstituted derivatives shows a linear increase in Mw with respect to
conversion, a clear indicator of a living polymerization [11] (Figure 1.8), and the Ð is
generally low (Mw/Mn = 1.01–1.4). Furthermore, in contrast to the ring-opening route,
branching of the [NPCl2]n is not generally observed, indeed the absence of reactions
between the phosphazene cations with internal P–Cl bonds has been ruled out in
small-molecule model studies [15]. Poly(dichloro)phosphazene obtained via a cationic
polymerization method is a living polymer with cationic chain ends that can be used,
for example, for controlled termination or reactions with another phosphoranimine
and because the chain ends remain active, block copolymers can be prepared via

Cl
2 eq. PCl5 Cl n Cl3P N Si(CH3)3 + –
+ – Cl3P N P N PCl3 PCl6
Cl3P N SiMe3 Cl P N PCl3 PCl6
–Me3SiCl –n Me3SiCl Cl n
Cl

Figure 1.7: Living cationic polymerization of Cl3PNSi(CH3)3 initiated by PCl5.

 1.4 Chain growth polycondensation 7

(a) (b)
Adjacent PCl2 Interior Monomer 1.0
groups to PCl3+ [Cl2P=N]n consumption

Remaining monomer
0.8

0.6
57
0.4
51

in)
0.2

on (m
44
0.0
37 0 10 20 30 40 50 60

ati
initi
30 Time after monomer addition (min)
(c) 1
24

after
0
17

Time

In (Mt/M0)
9 –1

Initiation 3 –2
with PCl5
Monomer
–3

0 –10 –20 –30 –40 –50 –60 –70 –4

0 10 20 30 40 50
δ (ppm) Time after monomer addition (min)

Figure 1.8: PCl5 initiated polymerization of Cl3PNSi(CH3)3 in CH2Cl2 monitored by 31P{1H} nuclear
magnetic resonance spectroscopy shows consumption of the monomer accompanied by linear
chain growth (a). The amount of remaining monomer can be plotted (b), showing its consumption
and a plot of ln(Mt/M0) over time (c) showing a linear relationship indicating the living nature of
the polymerization. Mt, monomer concentration at time t; M0, initial monomer concentration.
Reproduced with permission from Sandra Wilfert in “Novel and Functional Polyphosphazenes for
Biomedical Applications,” Johannes Kepler University, Linz, Austria, 2014 [PhD Thesis]. ©2014,
Johannes Kepler University [14].

sequential addition [16]. The living cationic polymerization pathway also allows ac-
cess to a variety of polymer architectures (see Section 2.5)
The precise mechanism is still a matter of investigation, although it would ap-
pear from both experimental observations of the monomer to initiator (M:I) ratios
to Mw attained [11], as well as from model studies [15], that two PCl5 molecules are
needed to form the initiating species with a PCl3+ cationic end group and PCl6− as the
counterion [17]. Other initiators and solvents have also been reported [11], but PCl5 in
CH2Cl2 appears to offer the best combination in terms of reaction kinetics and initiator
solubility. The PCl6− counterion, however, has also been reported to initiate chain
growth of Cl3PNSi(CH3)3 and thus could potentially cause competing chain growth
[15]. Furthermore, bidirectional chain growth has also been observed due to delocali-
zation of the charge on the propagating [Cl3PN–PCl3]+ species. As the two chain ends
may react at different rates, this could lead to broad dispersity [15] and, furthermore,
the precise control of molecular architecture is hindered. Trialkoxyphosphoranimines
can be used to ensure monodirectional growth, although the effectiveness appears
heavily dependent on the nature of the R groups [18] and more recently similar mono-
end-capped initiators of the type [R3P = N = PCl3][X] (X = Cl, PCl6) have been shown to
8 Chapter 1 Synthetic procedures

ensure monodirectional chain growth [19]. Similarly, the use of chlorinated phosphine
groups, R3PCl2, known to exist in their ionic form [R3PCl][Cl] in CH2Cl2 [20] can be used
to initiate the polymerization [21–23] (Figure 1.9) ensuring monodirectional growth and
thus can be used for the control of molecular architecture (see Section 1.5).
One limitation to this chain growth polycondensation method is the loss of con-
trol at higher M:I ratios (higher n). The origin of this could be competing initiating
species at lower concentrations of PCl5 and an upper limit has been experimentally
observed at approximately n = 100, above which it becomes difficult to precisely
control Mn and Ð [11, 24].
To achieve polymers with a much higher Mw, a solvent-free bulk polymeriza-
tion of Cl3PNSi(CH3)3 with either PCl5 [11, 12] or R3PCl2 [25] can yield polymers with
n = 400.
Another disadvantage is that the living cationic routes discussed are reliant on
the prior synthesis of the trichlorophosphoranimine monomer Cl3PNSi(CH3)3, and
thus the reliable preparation of this air and moisture-sensitive monomer is crucial
to the polymerization route. A relatively high-yielding monomer preparation can be
achieved (up to 80%) with good purity [26]. The complex preparation of this mono-
mer remains, however, the major bottleneck in terms of up-scaling of the prepara-
tion of polyphosphazenes via living cationic polymerization. The subsequent
polymerization is a facile ambient temperature procedure, but the repeated vacuum
distillations required to prepare Cl3PNSi(CH3)3 in sufficient purity are not conducive
to industrial manufacture.
In order to circumvent the tiresome preparation of Cl3PNSi(CH3)3, a one-pot
in situ synthesis of poly(dichloro)phosphazene directly from PCl3 has also been de-
veloped [27]. Although some loss in control of Ð is unavoidable, it is still superior to
that of a ring-opening procedure and may offer significant advantages in terms of
future scale-up of the preparation of [NPCl2]n via chain growth polycondensation.
An alternative route to [NPCl2]n via the thermal condensation polymerization of
Cl3P=(O)Cl2 is also possible, although this requires high temperatures and produ-
ces [NPCl2]n with relatively broad Ð [28]. Poly(organo)phosphazenes can also be
achieved directly, without the need for the [NPCl2]n precursor, via an anionic poly-
merization of N-silylphosphoranimines with fluoride ion initiators at 180 °C [29, 30],
although without quite achieving the control of the cationic route.
Alternatively, it has been shown that it is possible to prepare poly(alkyl/aryl)
phosphazenes, with a P–C bond connecting the organic component, directly from
N-silylphosphoranimines using (usually thermal) condensation methods [31]. Such
poly(alkyl/aryl)phosphazenes differ significantly in that they contain direct carbon
linkages on the phosphorus atom, not the oxygen or nitrogen atom most commonly
attained from the macrosubstitution of [NPCl2]n, and as such can be considered iso-
electronic analogues of silicones [32]. Although the R groups chosen here are some-
what limited compared with the macrosubstitution route, a large selection of poly
(alkyl/aryl)phosphazenes have been reported [32–34]. Furthermore, it has been shown
 1.4 Chain growth polycondensation 9

ROP
Cl Cl
P 250°C Cl
N N P N
Cl P P Cl ROP Mw/Mn = 2–7, n = 10,000
Cl n
Cl N Cl

Thermal condensation

R 180°C R
n RO P N SiMe3 P N Mw/Mn = 1.5–2.5, n = 200
R R n

Cl 250°C Cl
Mw/Mn = 1.5–2.5, n = 600
n Cl P N POCl2 P N
Cl Cl n

Anionic condenzation

R 125°C R Mw/Mn = 1.5–2.5, n = 200

n RO P N SiMe3 P N
R TBAF R n

Cationic polymerization

Cl
RT Mw/Mn = 1.01–1.4, n = 100
n Cl3P N SiMe3 P N
PCl5 Cl n

Cl
RT Mw/Mn = 1.01–1.4, n = 100
n Cl3P N SiMe3 P N
[R3PCl][Cl] Cl n

RT Cl
n Cl3P N SiMe3 P N Mw/Mn = 1.01–1.4, n = 100
[R3P=N=PCl3][PCl6] Cl n

R RT R
n Br P N SiMe3 P N Mw/Mn = 1.2–1.8, n = 100
R (MeO)3P R n

Figure 1.9: Summary of the major synthetic routes to polyphosphazenes, with approximate values for
the maximum chain lengths (n) normally prepared by this route and reported values for Ð (M /M ).
w n
RT, room temperature; TBAF, tetrabutylammonium fluoride.
10 Chapter 1 Synthetic procedures

that simple poly(alkyl/aryl)phosphazenes can undergo further macromolecular func-

tionalization, for example, electrophilic substitution of aromatic substituents [35] or
acidic methyl groups attached to the phosphorus can undergo deprotonation with n-
BuLi to give essentially macromolecular organolithium reagents which can undergo
organometallic additions to give a variety of functional groups [36]. Phosphine azides
have also been used but the explosive nature of some intermediates renders this a
less attractive route [37]. More recently, the ambient temperature polymerization
of P-bromo(alkyl/aryl)phosphoranimines, initiated by organic phosphites, has been
shown to be an effective route to poly(alkyl/aryl)phosphazenes, ensuring monodirec-
tional chain growth and relatively narrow Ð [38, 39].

1.5 Macromolecular architecture

1.5.1 P=N backbone branching

Organic-based dendrimers using hexachlorophosphazene as a multiplying linker

are relatively well known [40], exploiting the six functional groups of the phospha-
zene core to multiply functionality and reduce the steps required for high genera-
tion dendrimers. However, tailoring the polyphosphazene (P=N) backbone is an
altogether more difficult task and to the best of the author’s knowledge, no known
controlled branching of the P=N backbone has been achieved.
A phosphazene “dendrimer” has been prepared via living cationic polymeriza-
tion [41], although elegant, this chemistry is essentially reliant on the polyamido-
amine (PAMAM) core to provide the structural dendritic basis (Figure 1.10) and is
effectively a PAMAM-grafted-polyphosphazene. To achieve this, trialkoxyphosphoran-
imines are reacted with one equivalent of PCl5 to create the initiating species, which
upon the addition of Cl3PNSi(CH3)3 forms a polymer with a living chain end. This
chain end can be terminated with a previously prepared phosphoranimine-capped
polymer; in this case, a PAMAM dendrimer. This chemistry is also the basis for a num-
ber of organic–inorganic block copolymers (see Section 1.5.3). A triarmed star polymer
has also been prepared from a core functionalized with three phosphoranimines [42],
although this divergent approach appears to be less widely applicable [18] than the
quenching procedure performed for the synthesis of the dendrimers.
The development of the phosphine-mediated polymerization has opened the door
to star-shaped polymers, where polyphosphazene arms are grown from a central core
(Figure 1.11). To achieve three-arm stars, 1,1,1-tris(diphenylphosphino)methane is used
(Figure 1.11 (a)) [43], while the phosphazene trimer substituted with 3-(diphenyl-
phosphino)-1-propanamine yields a hexadiphenylphosphine subsequentially function-
ing as the core of a six-arm star [44]. These star-shaped polyphosphazenes substituted
with propargylamine are reacted with 1-thioglycerol in a thiol-yne photoreaction to fur-
ther increase the number of functional groups per repeat unit to 8 [44].
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