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Journal ArticleDOI

Primary ammonium/tertiary amine-mediated controlled ring opening polymerisation of amino acid N-carboxyanhydrides.

15 Oct 2015-Chemical Communications (Royal Society of Chemistry)-Vol. 51, Iss: 86, pp 15645-15648

TL;DR: Stable commercial primary ammonium chlorides were combined with tertiary amines to initiate the controlled ring opening polymerisation of amino acid N-carboxyanhydrides to yield polypeptides with defined end group structure, predetermined molar mass and narrow molarmass distribution.

AbstractStable commercial primary ammonium chlorides were combined with tertiary amines to initiate the controlled ring opening polymerisation of amino acid N-carboxyanhydrides to yield polypeptides with defined end group structure, predetermined molar mass and narrow molar mass distribution.

Topics: Tertiary amine (62%), Molar mass distribution (54%), Molar mass (53%)

Summary (1 min read)

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Summary

  • Stable commercial primary ammonium chlorides were combined with tertiary amines to initiate the controlled ring opening polymerisation of amino acid N-carboxyanhydrides to yield polypeptides with defined end group structure, predetermined molar mass and narrow molar mass distribution.
  • Achieving good control over polymerisation reactions is essential for the synthesis of well-defined polymers.
  • Typically, anionic, cationic, controlled radical and ring opening polymerisation (ROP) techniques are applied to synthesise polymers with predetermined composition, functionality, molar mass, and low dispersity.
  • These properties are essential in the fields of selfassembly and biomimicry.
  • Self-assembled and biomimetic supramolecular assemblies, such as micelles, vesicles, hydrogels and hierarchical scaffolds, are often developed for biomedical or materials science applications. [2] [3] [4] [5] [6] [7].
  • Polypeptides are very interesting polymers, not only because they can be designed to be biocompatible and biodegradable, but also because they can be synthesised in a controlled manner by ROP of amino acid N-carboxyanhydrides (NCAs).
  • 8, 9 The non-metal catalysed ROP of NCAs is known to proceed via two distinct pathways, namely the normal amine mechanism (NAM) and the activated monomer mechanism (AMM) (Scheme 1a and b).
  • 10 The NAM is favoured by the use of nucleophilic initiators such as primary amines and yields welldefined polypeptides.
  • The AMM is favoured by bases, such as tertiary amines, and yields polypeptides with high molar mass and dispersity.
  • It is challenging to completely suppress the AMM.
  • Over the past two decades, considerable advances in controlled NCA polymerisation have been realised.

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Mathematisch-Naturwissenschaftliche Fakultät
Charlotte D. Vacogne | Helmut Schlaad
Primary ammonium/tertiary amine-
mediated controlled ring opening
polymerisation of amino acid
N-carboxyanhydrides
Postprint archived at the Institutional Repository of the Potsdam University in:
Postprints der Universität Potsdam
Mathematisch-Naturwissenschaftliche Reihe ; 307
ISSN 1866-8372
http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-102718
Suggested citation referring to the original publication:
Chem. Commun. 51 (2015), pp. 15645–15648
DOI http://dx.doi.org/10.1039/C5CC06905J


This journal is
©
The Royal Society of Chemistry 2015 Chem. Commun., 2015, 51, 15645--15648 | 15645
Cite this: Chem. Commun., 2015,
51,15645
Primary ammonium/tertiary amine-mediated
controlled ring opening polymerisation of amino
acid N-carboxyanhydrides
Charlotte D. Vacogne
a
and Helmut Schlaad*
b
Stable commercial primary ammonium chlorides were combined
with tertiary amines to initiate the controlled ring opening poly-
merisation of amino acid N-carboxyanhydrides to yield polypep-
tides with defined end group structure, predetermined molar mass
and narrow molar mass distribution.
Achieving good control over polymerisation reactions is essential
for the synthesis of well-defined polymers. Typically, anionic,
cationic, controlled radical and ring opening polymerisation
(ROP) techniques are applied to synthesise polymers with pre-
determined composition, functionality, molar mass, and low
dispersity.
1
These properties are essential in the fields of self-
assembly and biomimicry. Self-assembled and biomimetic
supramolecular assemblies, such as micelles, vesicles, hydrogels
and hierarchical scaffolds, are often developed for biomedical or
materials science applications.
2–7
In this context, polypeptides
are very interesting polymers, not only because they can be
designed to be biocompatible and biodegradable, but also
because they can be synthesised in a controlled manner by
ROP of amino acid N-carboxyanhydrides (NCAs).
8,9
The non-metal catalysed ROP of NCAs is known to proceed
via two distinct pathways, namely the normal amine mecha-
nism (NAM) and the activated monomer mechanism (AMM)
(Scheme 1a and b).
10
The NAM is favoured by the use of
nucleophilic initiators such as primary amines and yields well-
defined polypeptides. The AMM is favoured by bases, such as
tertiary amines, and yields polypeptides with high molar mass
and dispersity. Although the choice of initiator can influence the
NCA polymerisation pathway, it is challenging to completely
suppress the AMM. Over the past two decades, considerable
advances in controlled NCA polymerisation have been realised.
The effort was mostly aimed at the elimination of side reactions,
notably the AMM, by using transition metal catalysts,
11
silazane
12
and ammonium salts
13
as initiators, by lowering the reaction
temperature
14
and by applying high vacuum techniques.
15
Also
primary/tertiary amine organocatalytic systems have been intro-
duced promoting an accelerated amine mechanism through
monomer activation (AAMMA).
16
Ammonium salts are attractive alternatives to amines as
initiators for ROP of NCAs as they are more stable, easier to
handle and to purify. Schlaad et al.
13
postulated that the
ammonium-mediated ROP mechanism may involve an equili-
brium between dormant (ammonium) and active (amine) o-chain
ends (Scheme 1c), leading to a controlled propagation like in
living cationic polymerisation or nitroxide-mediated radical
polymerisation. It was suggested that the protons introduced
via the ammonium salts would protonate NCA anions and
thereby suppress the AMM.
13,17,18
However, this technique
proved ineffective for hydrophobic NCAs, possibly as a result
of this equilibrium being too far shifted to the ammonium side
due to a more apolar reaction medium.
19,20
For instance, g-benzyl-
L-glutamate (BLG) NCA could only be polymerised by a mixture of
the ammonium salt and its corresponding primary amine,
17
thus
somehow defeating the initial purpose of using the sole ammo-
nium salt as an initiator. Being able to establish an alternative
ammonium-mediated ROP without the need for the corresponding
amine would be extremely beneficial because aside from the
aforementioned advantages ammonium salts, especially the
chlorides, are easier to synthesise and more readily available for
purchase than their amine counterparts.
Since the use of a primary amine in combination with its
corresponding ammonium salt for the polymerisation of
B
LG–NCAs seems to only serve the purpose of shifting the
dormant–active equilibrium to allow the polymerisation to pro-
ceed (Scheme 1c), we questioned whether a catalyst could serve
the same purpose. In an effort to establish a more versatile
variant of the ammonium-mediated polymerisation, we decided
to investigate catalysts that could be universally used in combi-
nation with any ammonium salt initiator. Since tertiary amines
a
Max Planck Institute of Colloids and Interfaces, Department of Colloid Chemistry,
Research Campus Golm, 14424 Potsdam, Germany
b
University of Potsdam, Institute of Chemistry, Karl-Liebknecht-Straße 24-25,
14476 Potsdam, Germany. E-mail: schlaad @uni-potsdam.de
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5cc06905j
Received 17th August 2015,
Accepted 7th Sept ember 2015
DOI: 10.1039/c5cc06905j
www.rsc.org/chemcomm
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are less good nucleophiles than they are basic,
21
we set out to
investigate mixtures of primary ammonium salts and tertiary
amines (Scheme 1d). As mentioned earlier, tertiary amines like
triethylamine (TEA) are used as catalysts to promote an uncon-
trolled polymerisation of NCAs via the AMM to obtain long
polypeptides within very short timeframes; but as a drawback,
such polypeptides also exhibit high dispersity, typically greater
than 2, and no defined end groups.
8,22
To our surprise, we
obtained well-defined polymers with narrow molar mass dis-
tributions and predefined end groups. We, therefore, sought to
establish the robustness of this new controlled ROP of NCAs.
1,2,3-Tris(aminomethyl)benzene (TAB) is an amine that can
be used as a trifunctional initiator for ROP of NCAs but is only
available for purchase in the form of its trihydrochloride salt
(TAB3HCl).
23
It was, therefore, chosen as a candidate to test
our primary ammonium/tertiary amine-mediated ROP of NCAs.
We initially studied the efficacy of TAB 3HCl as an initiator for
the polymerisation of B
LG–NCA. We followed monomer con-
version and dispersity by SEC and molar mass by
1
H-NMR
(ESI). We found that the polymerisation was very slow with
only 13% conversion after seven days at room temperature (r.t.)
(Fig. 1a), and 48% conversion after seven days at 50 1C (Fig. 1b).
We then used a 1 : 0.5 mixture of TAB3HCl and TEA for the
polymerisation of B
LG–NCA (Fig. 1c). The resulting polypeptide
had a low dispersity (1.08) and 67% conversion was achieved
after five days at room temperature. The reaction was stopped
after seven days and the polymers were worked up and analysed
by
1
H-NMR. End group analysis showed that the number-
average molar mass (M
n
) closely matched the targeted molar
mass (ESI). In order to assess whether TEA was solely respon-
sible for this faster and controlled ROP, we followed a ‘control’
polymerisation by SEC (Fig. 1d) and
1
H-NMR. For this control
reaction, we used a solution of TEA to initiate the poly-
merisation of B
LG–NCA. The SEC traces and
1
H-NMR spectra
showed that the polymerisation was clearly uncontrolled
(M
n
4 77 kDa, dispersity 4 2) and concluded that the AMM
was the dominant mechanism (Scheme 1b). These results
confirmed that TAB3HCl and TEA, when used as an initiator
mixture, have a kind of synergistic effect on the polymerisation
of B
LG–NCA in that it proceeds in a controllable fashion. It
appears that the NAM was most likely the dominant mecha-
nism of the primary ammonium/tertiary amine-mediated ROP
of NCAs, however, as suggested by Scheme 1d, not excluding
the occurrence of the AMM (vide infra).
In order to study the robustness and limits of the process, a
series of polymerisations of B
LG–NCA were initiated with mixtures
of 1-pyrenemethylamine hydrochloride (PyAHCl) (1 equiv.) and
TEA (0 to 1.5 equiv.) at different ratios. The results, shown
in Table 1, reveal that the rate of polymerisation increases with
increasing amount of TEA, as expected. For all PyAHCl/TEA ratios,
except 1 : 1.5, the polypeptides exhibited very low dispersities
(o1.1) suggesting that the primary ammonium/tertiary amine-
mediated polymerisations proceeded in a controlled manner. More-
over, SEC analysis with (RI and) UV at l = 340 nm (Fig. 2) allowed to
conclude–onaqualitativebasis–thatallpolypeptidefractions
carried a pyrene unit (the only species absorbing at this wavelength),
Scheme 1 (a) Normal amine mechanism (NAM), (b) activated monomer mechanism (AMM), (c) proposed mechanism for the ammonium-mediated ring
opening polymerisation
13
and (d) primary/tertiary amine–ammonium equilibrium.
Fig. 1 SEC traces of PBLGs obtained during the polymerisations of
B
LG–NCA (150 equiv.) in DMF initiated by (a) TAB3HCl (1 equiv.), r.t.; (b)
TAB3HCl (1 equiv.), 50 1C; (c) TAB3HCl/TEA (1 : 0.5 equiv.), r.t.; and (d) TEA
(0.5 equiv.), r.t.; the peak (*) is a high molar mass polystyrene (PS2M; 2 MDa)
used as internal standard for calculating the monomer conversion (ESI).
Table 1 Results of the polymerisations of BLG–NCA at room temperature
initiated by PyAHCl/TEA (molar ratio 1 : x, x = 0 to 1.5)
PyAHCl/TEA 1 : 0 1 : 0.2 1 : 0.5 1 : 0.7 1 : 0.9 1 : 1.1 1 : 1.5
24 h
Conversion 37% 50% 70% 80% 88% 94%
Dispersity 1.12 1.07 1.07 1.07 1.07 1.90
120 h
Conversion 25% 77% 86% 95% 96% 99% 100%
Dispersity 1.06 1.10 1.08 1.07 1.08 1.08 1.90
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which is supportive of the NAM. In the case of the uncontrolled
polymerisation, i.e. PyAHCl/TEA = 1 : 1.5, the polypeptide chains,
but not all, were labelled with pyrene (Fig. 2b).
Interestingly, for all PyAHCl/TEA initiator mixtures ranging
from 1 : 0 to 1 : 1.1, a secondary UV
340nm
(+RI) absorption peak
was generally observed at high elution volumes ( 420 mL) and
disappeared with time, as the polymerisation proceeded
(Fig. 2a). This observation could be explained by the coexistence
of both NAM and AMM, as a consequence of the equilibrium
shown in Scheme 1d, where the AMM plays a determining role in
the early stages of the polymerisation and the NAM would
progressively take over, provided that the initial TEA/PyAHCl
ratio is under a certain limit (o1.5). More precisely, the tertiary
amine would initially generate N-acylated NCA oligomers
through the ‘fast’ AMM (Scheme 1b) but the primary ammonium
chlorides, present in greater quantities (Scheme 1d), would
regulate the propagation by (i) imposing the NAM, causing the
N-acylated NCA oligomers to be progressively incorporated at
the o-end of other growing chains (hence the disappearance of
secondary RI peak), and (ii) providing protons to prevent the
AMM from dominating throughout the propagation (hence the
final monomodal and narrow molar mass distribution), thereby
ensuring rapid incorporation of any unreacted primary amine
either via ‘normal’ initiation or via the reaction with a-ends of
N-acylated NCA oligomers (hence the disappearance of the
secondary UV
340nm
peak over time).
The underlying primary ammonium/tertiary amine equili-
brium (Scheme 1d) suggests that the ratio of total amines (both
primary and tertiary) to HCl (amine/HCl) should affect the
polymerisation rate. The larger the amine/HCl ratio, the higher
the concentration of active amine chain ends and with it the
polymerisation rate. However, at a too large amine/HCl ratio the
controlled nature of the reaction will be lost. Likewise, the lower
the amine/HCl ratio, the higher the concentration of dormant
ammonium chain ends, ultimately leading to an inhibition of
the polymerisation.
In order to validate this dormant–active species model, we
repeated the PyAHCl/TEA (1 : 0.5) initiated polymerisation of
B
LG–NCA, and added HCl (1 equiv. with respect to TEA) 24 h
following the initiation. At that stage, the amine/HCl ratio was
hence adjusted to 1, thereby shifting the equilibrium to the
dormant side. At 81 h, we added TEA (1 equiv. with respect to
previously added HCl), and let the reaction run for another
87 h. SEC analysis showed that the polymerisation was ‘paused’
following the addition of HCl at 24 h as neither the monomer
conversion (Fig. 3a) nor the molar mass of the polymer (Fig. 3b)
had increased between 24 h and 81 h. After 81 h, both molar
mass and conversion started to increase again, indicating that
the polymerisation resumed following the addition of TEA.
These results not only support the dormant–active mechanism
for the ammonium-mediated ROP of NCAs, but also suggest
that the correlation observed between polymerisation rates and
TEA/PyAHCl ratios (Table 1) may in fact result from the
aforementioned cause-effect relationship between amine/HCl
ratios and polymerisation rates.
Although the results support a dormant–active species equi-
librium mechanism, the complete mechanism is likely to be
more complex. As suggested by the secondary UV
340nm
peak in
the SEC results (Fig. 2) and the uncontrolled polymerisation
initiated by PyAHCl/TEA 1 : 1.5, the chain growth may be the
result of both NAM and AMM. In addition, the predominance
of one mechanism over the other may not only vary with the
primary to tertiary amine and amine/HCl ratios, but may also
vary throughout the chain growth process. It should also be
noted that the amine–ammonium equilibrium depends greatly
on solution pH, solvent polarity and total concentration, making
a prediction of the reaction kinetics difficult (work in progress).
In order to demonstrate the general applicability and versa-
tility of this new technique, we tested it with another bulky
tertiary amine, i.e. diisopropylethylamine (DIPEA, Hu
¨
nig’s base),
and two other hydrophobic NCAs, i.e.
L-leucine (LLeu) and
L-phenylalanine (LPhe) NCAs (see ESI and Fig. 4). As a represen-
tative example, the time-conversion plot for the polymerisation of
LLeu–NCA (and BLG–NCA, for comparison, Fig. 4a) initiated by
benzylamine (BnA), benzylamine hydrochloride (BnAHCl), BnA
HCl/TEA, and TEA is shown in Fig. 4b. Most importantly, the
Fig. 2 SEC traces (RI in black, UV
340nm
in purple) of polymerisations of
B
LG–NCA (150 equiv.) in DMF initiated by (a) PyAHCl/TEA (1 : 1.1) at (top to
bottom) 2 h, 6 h, 10 h, 24 h; (b) PyAHCl/TEA (1 : 1.5) at (top to bottom) 2 h,
6 h, 8 h, 24 h; the peak (*) is a high molar mass polystyrene (PS2M, 2 MDa)
used as internal standard for calculating the monomer conversion (ESI).
Fig. 3 Polymerisation of BLG–NCA (150 equiv.) in DMF initiated by PyA
HCl/TEA (1 : 0.5 equiv.), paused at 24 h by adding HCl and resumed at 81 h
by adding TEA. (a) time-conversion plot, (b) numbe r-average molar mass
and dispersities (at 24 h, 81 h, 120 h, and 168 h) determined by SEC.
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