In 2004, the group of Hadjichristidis reported the primary amine-initiated
polymerization of NCAs under high vacuum conditions [45]. The strategy here
was to determine if a reduced level of impurities in the reaction mixture would
lead to fewer polymerization side reactions. Unlike the vinyl monomers usually
polymerized under high vacuum conditions, NCAs cannot be purified by distillation. Consequently, it is unclear if NCAs can be obtained in higher purity by high
vacuum recrystallization than by recrystallization under a rigorous inert atmosphere. However, the high vacuum method does allow for better purification of
polymerization solvents and the n-hexylamine initiator. It was found that polymerizations of γ-benzyl-L-glutamate NCA, Bn-Glu NCA, and Z-Lys NCA under high
vacuum in DMF solvent displayed all the characteristics of a living polymerization
system [45]. Polypeptides could be prepared with control over chain length; chain
length distributions were narrow and block copolypeptides were prepared. This
method has been used by Iatrou and coworkers to prepare a number of different
block copolypeptides, primarily PBLG segments connected to polymers of lysine,
leucine, tryosine, and the imino acid proline, and their microphase-separated
morphologies have been studied in the bulk state [46, 47].
For this method, the authors concluded that the side reactions normally observed
in amine-initiated NCA polymerizations are simply a consequence of impurities.
Because the main side reactions in NCA polymerizations do not involve reaction
with adventitious impurities such as water, but instead reactions with monomer,
solvent, or polymer (i.e., termination by reaction of the amine-end with an ester side
chain, attack of DMF by the amine-end, or chain transfer to monomer) [11], it
appears that removal of water or other reaction components is able to inhibit these
side reactions. A likely explanation for the polymerization control observed under
high vacuum is that CO 2 acts to promote side reactions of growing chains with
monomer, polymer, or solvent, and its removal from the reaction medium under
vacuum inhibits these reactions and promotes controlled polymerization. A number
of early and recent studies support this role of CO 2 as being detrimental to amineinitiated NCA polymerizations, where for some NCAs it is able to decrease chain
propagation rate by reversibly forming a carbamate with the amine endgroup and
may also catalyze side reactions [48, 49]. Thus, it is reasonable to speculate (vide
infra) that removal of CO 2 from NCA polymerizations under high vacuum is the
dominant factor in enabling controlled chain growth in these systems. Recently, in
polymerizations of O-benzyl-L-tyrosine NCA, Bn-Tyr NCA, in DMF, it was determined that although most side reactions are insignificant in the high-vacuum
polymerization, some termination of chains by reaction with DMF solvent does
occur [50].
Further insights into amine-initiated NCA polymerizations were also reported in
2004 by the group of Giani and coworkers [51]. This group studied the polymerization of ε-trifluoroacetyl-L-lysine NCA, TFA-Lys NCA, in DMF using
n-hexylamine initiator at different temperatures. In contrast to the high vacuum
work, the solvent and initiator were purified using conventional methods and the
polymerizations were conducted under a nitrogen atmosphere on a Schlenk line.
After complete consumption of NCA monomer, the crude polymerization mixtures
were analyzed by GPC and non-aqueous capillary electrophoresis (NACE).
12
T.J. Deming
polymerization of NCAs under high vacuum conditions [45]. The strategy here
was to determine if a reduced level of impurities in the reaction mixture would
lead to fewer polymerization side reactions. Unlike the vinyl monomers usually
polymerized under high vacuum conditions, NCAs cannot be purified by distillation. Consequently, it is unclear if NCAs can be obtained in higher purity by high
vacuum recrystallization than by recrystallization under a rigorous inert atmosphere. However, the high vacuum method does allow for better purification of
polymerization solvents and the n-hexylamine initiator. It was found that polymerizations of γ-benzyl-L-glutamate NCA, Bn-Glu NCA, and Z-Lys NCA under high
vacuum in DMF solvent displayed all the characteristics of a living polymerization
system [45]. Polypeptides could be prepared with control over chain length; chain
length distributions were narrow and block copolypeptides were prepared. This
method has been used by Iatrou and coworkers to prepare a number of different
block copolypeptides, primarily PBLG segments connected to polymers of lysine,
leucine, tryosine, and the imino acid proline, and their microphase-separated
morphologies have been studied in the bulk state [46, 47].
For this method, the authors concluded that the side reactions normally observed
in amine-initiated NCA polymerizations are simply a consequence of impurities.
Because the main side reactions in NCA polymerizations do not involve reaction
with adventitious impurities such as water, but instead reactions with monomer,
solvent, or polymer (i.e., termination by reaction of the amine-end with an ester side
chain, attack of DMF by the amine-end, or chain transfer to monomer) [11], it
appears that removal of water or other reaction components is able to inhibit these
side reactions. A likely explanation for the polymerization control observed under
high vacuum is that CO 2 acts to promote side reactions of growing chains with
monomer, polymer, or solvent, and its removal from the reaction medium under
vacuum inhibits these reactions and promotes controlled polymerization. A number
of early and recent studies support this role of CO 2 as being detrimental to amineinitiated NCA polymerizations, where for some NCAs it is able to decrease chain
propagation rate by reversibly forming a carbamate with the amine endgroup and
may also catalyze side reactions [48, 49]. Thus, it is reasonable to speculate (vide
infra) that removal of CO 2 from NCA polymerizations under high vacuum is the
dominant factor in enabling controlled chain growth in these systems. Recently, in
polymerizations of O-benzyl-L-tyrosine NCA, Bn-Tyr NCA, in DMF, it was determined that although most side reactions are insignificant in the high-vacuum
polymerization, some termination of chains by reaction with DMF solvent does
occur [50].
Further insights into amine-initiated NCA polymerizations were also reported in
2004 by the group of Giani and coworkers [51]. This group studied the polymerization of ε-trifluoroacetyl-L-lysine NCA, TFA-Lys NCA, in DMF using
n-hexylamine initiator at different temperatures. In contrast to the high vacuum
work, the solvent and initiator were purified using conventional methods and the
polymerizations were conducted under a nitrogen atmosphere on a Schlenk line.
After complete consumption of NCA monomer, the crude polymerization mixtures
were analyzed by GPC and non-aqueous capillary electrophoresis (NACE).
12
T.J. Deming