Selective radical addition with a designed heterobifunctional halide: A primary study toward sequence-controlled polymerization upon template effect

Article abstract of DOI:10.1021/ja9031314

(Chemical Equation Presented) A ruthenium(II)-catalyzed, highly selective, quantitative radical addition of an alkene, methacrylic acid (MAA), has been achieved by using a template halide (2) containing a built-in amine group as a recognition site for the

Full text of DOI:10.1021/ja9031314

Published on Web 07/15/2009
Selective Radical Addition with a Designed Heterobifunctional Halide:
A Primary Study toward Sequence-Controlled Polymerization
upon Template Effect
Shohei Ida, Takaya Terashima, Makoto Ouchi,* and Mitsuo Sawamoto*
Department of Polymer Chemistry, Graduate School of Engineering, Kyoto UniVersity, Katsura, Nishikyo-ku,
Kyoto 615-8510, Japan
Received April 20, 2009; E-mail: ouchi@living.polym.kyoto-u.ac.jp; sawamoto@star.polym.kyoto-u.ac.jp
Scheme 2. Radical Addition of MAA with the Template Halide
In recent years, template-assisted synthesis has been directed
toward perfecting structural control of molecules, as inspired by
biological macromolecules (typically, DNA and proteins) that are
finely defined in terms of not only molecular weight but also
“sequence” of repeat units or functionality along the backbone.1
For such systems, one needs to achieve at least two targets: a
controlled synthetic reaction having perfect chemo- and regiose-
lectivity and a method (or a reaction field) where a particular
substrate (monomer) is specifically recognized, allowing structural
input to be transcribed and expressed. For the latter, a promising
approach is a template-assisted system in which target substrates
are efficiently recognized via such interactions as hydrogen bonding,
coordination, or ionic or hydrophobic interactions for sequence
expression.
Like the transcription and expression of sequence information
in natural polymers, the introduction of a template into a polym-
erization field would provide clues about sequence control in
artificial polymer synthesis. For this purpose, we designed template
initiators (2) in which a template unit is built into a relatively rigid
framework, allowing a particular monomer to be recognized and
thereby specifically incorporated into the growing chain via living
radical propagation (Scheme 1). To construct such a model system,
we employed a new heterobifunctional halide (1) derived from
o-hydroxymethylphenol in which two different initiating sites
(C-Cl bonds) are placed ortho to each other. The haloether part is
for living cationic polymerization to generate an oligomeric template
component, whereas the haloester part is for a subsequent living
radical polymerization to be regulated by the neighboring template
segment placed in the hairpin-shaped rigid framework. In the
template segment, we introduced an oligomeric unit of pendant
aminoethyl group(s) that would selectively recognize acid-bearing
monomers (Scheme 2).
For the former target, we have pioneered two precision poly-
merizations, Lewis acid-catalyzed living cationic2 and metal-
mediated living radical3 polymerizations, both of which allow
syntheses of well-defined polymers with controlled molecular
weights and narrow molecular weight distributions. Notably, the
radical system is important in terms of the wide variety of appli-
cable monomers and tolerance of functional groups. Nevertheless,
the sequence of constitutional repeat units along the polymer
backbone is far more challenging and to date has not been controlled
even in these living processes, except for rather simple AB- and
ABC-alternating copolymerizations.4 Previous attempts at so-called
template polymerizations are abundant but, to our knowledge,
without remarkable sequence control.5
Scheme 1. Template Initiators from a Heterobifunctional Halide for
Template-Assisted Living Radical Polymerization
For the template introduction, we first performed living cationic
polymerization from the precursor 1 using di-tert-butyl {N-
[2(vinyloxy)ethyl]imido}dicarboxylate (BocVE), a vinyl ether with
a protected pendant amino function. The reaction was catalyzed
with SnCl4 in conjunction with (n-Bu)4NCl as an additive.7 Rather
unexpectedly, some specific conditions turned out to allow a
selective single monomer addition to the cationic site generated
from the haloether in 1: [BocVE]0 ) 50 mM; [1]0 ) 10 mM;
[SnCl4]0 ) 10 mM; [(n-Bu)4NCl]0 ) 5.0 mM in CH2Cl2 at -78
°C [Scheme 2; see the Supporting Information (SI)]. Quenching of
the cationic intermediate with LiBH4, followed by deprotection of
the Boc site with excess HCl to afford the corresponding amine,
gave the target template initiator 2, as verified by 1H NMR analysis
(see the SI). Importantly, the haloester moiety in 1 remained intact
during these addition and workup steps.
This communication reports our initial approach toward sequence
control in our living radical polymerization via template-bearing
initiators coupled with metal catalysts; the synthesis of the
“template” initiator is based on our living cationic polymerization
(Scheme 1). Prior to sequence control in polymerization, we
examined the template-effect for metal-catalyzed radical addition
(Kharash reaction),6 a model for our living radical polymerization
(Scheme 2). Though conventional radical reactions are performed
with excess halide relative to alkene substrate in order to prevent
oligomerization, we herein deliberately performed a radical addition
under equimolar conditions ([halide]0 ) [alkene substrate]0) to
demonstrate the adequacy and potential of this template model.
With the template-bearing halide 2, radical addition of meth-
acrylic acid (MAA) was initiated in toluene at 80 °C (1:1 2/MAA
molar ratio) with the ruthenium complex catalyst RuCl(Ind)-
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10.1021/ja9031314 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
(PPh3)2 (Ind ) η-C9H7), one of the most useful catalysts for metal-
catalyzed living radical polymerization8 and radical addition.9
Through its acid function, MAA is expected to be “recognized”
by the amine template located in the vicinity of the initiating site.
MAA was consumed at almost the same rate as the halide, as
1
monitored by H NMR spectroscopy, suggesting the predominant
formation of a 1:1 adduct rather than oligomeric products (Figure
1a). On average, the isolated product contained 1.22 units of MAA
per haloester moiety in 2 (see the SI). Furthermore, the molecular
mass determined by electrospray ionization mass spectrometry (ESI-
MS) was 522.0, close to 522.2 for [M + H]+ of the adduct.
Figure 2. (a) Time-conversion curves using template 2 and (b) comparison
of the reaction selectivities determined by kinetic analysis using 2 and ECPA
for competitive radical addition between MAA and MMA in toluene at 80
°C: [MAA]0 ) [MMA]0 ) [2 or ECPA]0) 50 mM; [RuCl(Ind)(PPh3)2]0 )
4.0 mM; [n-BuNH2]0 ) 0 or 50 mM (for ECPA).
addition, where oligomerization might also occur. In fact, additional
experiments indicated that less-polar solvents (e.g., toluene) and
lower concentrations (<50 mM) facilitate the specific monoaddition.
In conclusion, we have demonstrated a quantitative and highly
selective radical addition using a template initiator (2) containing
a built-in amine group as the recognition site for the carboxyl group
of the substrate in the close vicinity of the radical-forming site.
Obviously, the designed placement of the recognition site is
important, and it should also be noted that both the radical formation
and the subsequent addition are finely controlled by the ruthenium
complex, are free from undesirable side-reactions, and maximize
the expression of template recognition. Another contributing factor
is that the template initiator can be cleanly and conveniently
synthesized by living cationic addition/polymerization reactions.
These results for the model addition reactions are now being
extended to “template-assisted” polymerizations, by which further
control over the repeat-unit sequence will be examined and possibly
demonstrated.
Figure 1. Time-conversion curves in radical additions of halides (C-Cl
compounds) to MAA in toluene at 80 °C, based on consumption of (2) the
C-Cl bond in the halide [(a) 2; (b) ECPA] and (b) the CdC bond in MAA.
Conditions: [halide]0 ) [MAA]0 )100 mM; [RuCl(Ind)(PPh3)2]0 ) 4.0 mM;
[n-BuNH2]0 ) (a) 0 and (b) 100 mM.
In sharp contrast, in a control radical addition with a haloester
without a built-in template amino group [ethyl 2-chloro-2-pheny-
lacetate (ECPA)] in the presence of an externally added amine (n-
BuNH2), MAA was consumed much faster than the initiating site,
resulting in oligomers rather than a 1:1 adduct (Figure 1b). Actually,
ESI-MS analysis detected only a minor amount of the adduct.
From these results, the preferential formation of the 1:1 addition
is most likely triggered by the specific interaction (recognition) of
the template amine with the acid in MAA, which brings the
monomer into the close vicinity of the radical site in 2. Separate
1H NMR experiments also confirmed the specific acid-base
interaction between MAA and the amine in 2 (see the SI).
To further prove the template effect, we examined the competi-
tive radical addition to 2 of MAA and methyl methacrylate (MMA)
in toluene at 80 °C [1:1:1 MAA/MMA/2 molar ratio, RuCl(Ind)-
(PPh3)2 catalyst]. As shown in Figure 2a, the acid monomer reacted
much faster than the ester counterpart. More quantitatively, the
initial first-order rate constant (k′) was ∼40 times greater for the
Acknowledgment. This research was partially supported by the
Ministry of Education, Science, Sports and Culture through a Grant-
in-Aid for Creative Science Research (18GS0209).
Supporting Information Available: Experimental details, 1H NMR
spectra, and kinetic analysis data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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