To obtain controlled polymerization, and not just single NCA addition reactions,
Schlaad’s group increased the reaction temperature (from 40
C to 80
C), which
was known from Knobler’s work to increase the equilibrium concentration of free
amine, as well as increase the exchange rate between amine and amine hydrochloride [57, 58]. Using primary amine hydrochloride end-capped polystyrene
macroinitiators to polymerize Z-Lys NCA in DMF, Schlaad’s group obtained
polypeptide hybrid copolymers in 70–80% yield after 3 days at elevated temperature. Although these polymerizations are slow compared to amine-initiated
polymerizations, the resulting polypeptide segments were well defined with very
narrow chain length distributions (M w /M n < 1.03). These distributions were much
narrower than those obtained using the free amine macroinitiator, which argues for
diminished side reactions in the polypeptide synthesis. The molecular weights of
the resulting polypeptide segments were found to be about 20–30% higher than
would be expected from the monomer to initiator ratios. This result was attributed
to termination of some fraction of initiator species by traces of impurities in the
NCA monomers, although the presence of unreacted polystyrene chains was not
reported. Recently, this methodology was extended to the preparation of new
hybrid copolymers of poly(Bn-Glu) from poly(2-isopropyl-2-oxazoline) [59] and
PEG-amine hydrochloride [60] macroinitiators.
The use of amine hydrochloride salts as initiators for controlled NCA polymerizations shows tremendous promise. The concept of fast, reversible deactivation of
a reactive species to obtain controlled polymerization is a proven concept in
polymer chemistry, and this system can be compared to the persistent radical effect
employed in all controlled radical polymerization strategies [61]. Like those
systems, success of this method requires a carefully controlled matching of the
polymer chain propagation rate constant, the amine/amine hydrochloride equilibrium constant, and the forward and reverse exchange rate constants between amine
and amine hydrochloride salt. This means that it is likely that reaction conditions
(e.g., temperature, halide counterion, solvent) will need to be optimized to obtain
controlled polymerization for each different NCA monomer, as is the case for most
vinyl monomers in controlled radical polymerizations. Within these constraints, it
is possible that controlled NCA homopolymerizations utilizing simple amine
hydrochloride initiators can be obtained; yet this method may not be advantageous
for preparation of block copolypeptides due to the need for monomer-specific
optimization.
Another interesting approach to obtaining controlled NCA polymerization using
silylated amines was reported in 2007 by Lu and Cheng. Hexamethyldisilazane
(HMDS) was used to initiate polymerizations of either Z-Lys NCA or Bn-Glu NCA
in DMF at ambient temperature and was found to give well-defined polypeptides of
controlled chain length and low polydispersity in high yield [62]. Addition of a
second batch of monomer to completed chains afforded block copolymers. Chain
growth in this system does not appear to show any of the common side reactions
found in amine-initiated NCA polymerization, which is attributed to the unique
properties of the N-trimethylsilyl (TMS) groups. The HMDS is proposed to transfer
a TMS group to the NCA, followed by addition of the silylamine to the resulting
Synthesis and Self-Assembly of Well-Defined Block Copolypeptides via. . .
15
Schlaad’s group increased the reaction temperature (from 40
C to 80
C), which
was known from Knobler’s work to increase the equilibrium concentration of free
amine, as well as increase the exchange rate between amine and amine hydrochloride [57, 58]. Using primary amine hydrochloride end-capped polystyrene
macroinitiators to polymerize Z-Lys NCA in DMF, Schlaad’s group obtained
polypeptide hybrid copolymers in 70–80% yield after 3 days at elevated temperature. Although these polymerizations are slow compared to amine-initiated
polymerizations, the resulting polypeptide segments were well defined with very
narrow chain length distributions (M w /M n < 1.03). These distributions were much
narrower than those obtained using the free amine macroinitiator, which argues for
diminished side reactions in the polypeptide synthesis. The molecular weights of
the resulting polypeptide segments were found to be about 20–30% higher than
would be expected from the monomer to initiator ratios. This result was attributed
to termination of some fraction of initiator species by traces of impurities in the
NCA monomers, although the presence of unreacted polystyrene chains was not
reported. Recently, this methodology was extended to the preparation of new
hybrid copolymers of poly(Bn-Glu) from poly(2-isopropyl-2-oxazoline) [59] and
PEG-amine hydrochloride [60] macroinitiators.
The use of amine hydrochloride salts as initiators for controlled NCA polymerizations shows tremendous promise. The concept of fast, reversible deactivation of
a reactive species to obtain controlled polymerization is a proven concept in
polymer chemistry, and this system can be compared to the persistent radical effect
employed in all controlled radical polymerization strategies [61]. Like those
systems, success of this method requires a carefully controlled matching of the
polymer chain propagation rate constant, the amine/amine hydrochloride equilibrium constant, and the forward and reverse exchange rate constants between amine
and amine hydrochloride salt. This means that it is likely that reaction conditions
(e.g., temperature, halide counterion, solvent) will need to be optimized to obtain
controlled polymerization for each different NCA monomer, as is the case for most
vinyl monomers in controlled radical polymerizations. Within these constraints, it
is possible that controlled NCA homopolymerizations utilizing simple amine
hydrochloride initiators can be obtained; yet this method may not be advantageous
for preparation of block copolypeptides due to the need for monomer-specific
optimization.
Another interesting approach to obtaining controlled NCA polymerization using
silylated amines was reported in 2007 by Lu and Cheng. Hexamethyldisilazane
(HMDS) was used to initiate polymerizations of either Z-Lys NCA or Bn-Glu NCA
in DMF at ambient temperature and was found to give well-defined polypeptides of
controlled chain length and low polydispersity in high yield [62]. Addition of a
second batch of monomer to completed chains afforded block copolymers. Chain
growth in this system does not appear to show any of the common side reactions
found in amine-initiated NCA polymerization, which is attributed to the unique
properties of the N-trimethylsilyl (TMS) groups. The HMDS is proposed to transfer
a TMS group to the NCA, followed by addition of the silylamine to the resulting
Synthesis and Self-Assembly of Well-Defined Block Copolypeptides via. . .
15