Discrete and Stereospecific Oligomers Prepared by Sequential and Alternating Single Unit Monomer Insertion

Article abstract of DOI:10.1021/jacs.8b08386

Natural biopolymers, such as DNA and proteins, have uniform microstructures with defined molecular weight, precise monomer sequence, and stereoregularity along the polymer main chain that affords them unique biological functions. To reproduce such structurally perfect polymers and understand the mechanism of specific functions through chemical approaches, researchers have proposed using synthetic polymers as an alternative due to their broad chemical diversity and relatively simple manipulation. Herein, we report a new methodology to prepare sequence-controlled and stereospecific oligomers using alternating radical chain growth and sequential photoinduced RAFT single unit monomer insertion (photo-RAFT SUMI). Two families of cyclic monomers, the indenes and the N-substituted maleimides, can be alternatively inserted into RAFT agents, one unit at a time, allowing the monomer sequence to be controlled through sequential and alternating monomer addition. Importantly, the stereochemistry of cyclic monomer insertion into the RAFT agents is found to be trans-selective along the main chains due to steric hindrance from the repeating monomer units. All investigated cyclic monomers provide such trans-selectivity, but analogous acyclic monomers give a mixed cis- and trans-insertion.

Full text of DOI:10.1021/jacs.8b08386

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Article
Discrete and Stereospecific Oligomers Prepared by
Sequential and Alternating Single Unit Monomer Insertion
Zixuan Huang, Benjamin B. Noble, Nathaniel Corrigan, Yingying Chu, Kotaro Satoh, Donald S. Thomas,
Craig J. Hawker, Graeme Moad, Masami Kamigaito, Michelle L. Coote, Cyrille Boyer, and Jiangtao Xu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08386 • Publication Date (Web): 19 Sep 2018
Downloaded from http://pubs.acs.org on September 19, 2018
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Journal of the American Chemical Society
Discrete and Stereospecific Oligomers Prepared by Sequential and
Alternating Single Unit Monomer Insertion
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Zixuan Huang,a Benjamin B. Noble,b Nathaniel Corrigan,a Yingying Chu,a Kotaro Satoh,c Donald S.
Thomas,d Craig J. Hawker,e Graeme Moad,f Masami Kamigaito,c Michelle L. Coote,b* Cyrille Boyer,a* and
Jiangtao Xua*
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aCentre for Advanced Macromolecular Design and Australian Centre for NanoMedicine, School of
Chemical Engineering, UNSW Sydney, NSW 2052, Australia
bARC Centre of Excellence for Electromaterials Science, Research School of Chemistry, Australian National
University, Canberra, ACT 2601, Australia
cDepartment of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya
University, Furoꢀcho, Chikusaꢀku, Nagoya 464ꢀ8603, Japan
dNuclear Magnetic Resonance Facility, Mark Wainwright Analytical Centre, UNSW Sydney, NSW 2052,
Australia
eMaterials Research Laboratory and Departments of Materials, Chemistry and Biochemistry, University of
California, Santa Barbara, California 93106, United States
fCSIRO Manufacturing Bag 10, Clayton South, VIC 3169, Australia
ABSTRACT
Natural biopolymers, such as DNA and proteins, have uniform microstructures with defined molecular
weight, precise monomer sequence and stereoregularity along the polymer main chain that affords them
unique biological functions. To reproduce such structurally perfect polymers and understand the mechanism
of specific functions through chemical approaches, researchers have proposed using synthetic polymers as
an alternative due to their broad chemical diversity and relatively simple manipulation. Herein, we report a
new methodology to prepare sequenceꢀcontrolled and stereospecific oligomers using alternating radical
chain growth and sequential photoinduced RAFT single unit monomer insertion (PhotoꢀRAFT SUMI). Two
families of cyclic monomers, the indenes and the Nꢀsubstituted maleimides, can be alternatively inserted
into RAFT agents, one unit at a time, allowing monomer sequence to be controlled through sequential and
alternating monomer addition. Importantly, the stereochemistry of cyclic monomer insertion into the RAFT
agents is found to be transꢀ selective along the main chains due to steric hindrance from the repeating
monomer units. All investigated cyclic monomers provide such transꢀ selectivity, but analogous acyclic
monomers give a mixed cisꢀ and transꢀ insertion.
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INTRODUCTION
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Natural polymers, such as nucleic acids and proteins, are the basic structural components of life, which
participate in the construction of genes, cells, and tissues. These bioorganic macromolecules possess precise
monomer sequences and monomer chirality in their chemical structures which contributes to tuning interꢀ
and intracellular interaction, defining functional interfaces, and storing chemical or genetic information.1ꢀ4
The monomer sequence along these polymer chains defines the primary structure of macromolecules and the
position of specific functionalities, while the uniform chirality of monomer units is responsible for the
chemical configuration of molecular segments which will principally contribute to the helical formation and
spatial arrangement of macromolecular assemblies. For most naturallyꢀoccurring polymers, helical
structures are essential for exerting their sophisticated functions in nature.5ꢀ7
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Reproducing the chemical structures of these functional biomacromolecules and mimicking their natural
processes to understand the underlying mechanisms has been a great challenge for more than half a century.
There has been limited success, for instance, scientists have duplicated these structurally perfect polymers
from their natural monomers (nucleotides and amino acids) using chemical approaches, such as solidꢀphase
peptide synthesis and oligonucleotide synthesis, to create new macromolecules for a range of biomedical
and pharmacological applications.8ꢀ10 However, problems still remain in these systems with a limited
monomer and reaction setup scope restricting the large scale production and innovation of diverse polymer
structures. Additionally, such synthetically assembled polymers based on natural monomers have the issue
of in vitro and in vivo biostability, which limits the biomedical applicability due to adverse enzymatic
degradation.11 Taking these concerns into account, researchers have proposed using synthetic polymers
derived from nonꢀnatural monomers (e.g. vinyl monomers from petroleum industry) with defined monomer
sequence and chirality as an alternative, due to their broad chemical diversity, relatively simple manipulation,
and improved biostability.12 Most importantly, such polymers have the potential to open new opportunities
for the development of advanced materials for data storage,13ꢀ16 catalysis17ꢀ18 and drug delivery.19ꢀ21
Various strategies have been proposed for regulating monomer sequence and chain length of synthetic
polymers, including condensation chain polymerization,22 alternating radical polymerization,23ꢀ29 anionic
polymerization,30ꢀ31 ringꢀopening or cross metathesis polymerization,32ꢀ37 atom transfer radical addition
(ATRA),24ꢀ25, 38ꢀ40 iterative exponential growth,41ꢀ46 single unit monomer insertion (SUMI)12, 47ꢀ53 and various
organic coupling, condensation or “click” addition reactions.19, 54ꢀ68 Separation techniques, which include
automated flash chromatography69ꢀ71 and preparative recycling size exclusion chromatography,51, 72 have
also been developed to isolate discrete oligomers from synthetically derived oligomer mixtures. Recent
developments have been summarized in comprehensive review articles.73ꢀ76
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Compared to sequence control, stereoselectivity in the polymerization of nonꢀnatural monomers is far
more challenging and has received relatively little attention. Since the first discovery of synthetic isotactic
polypropylene in 1955,77 the development of polymerization techniques capable of controlling the
stereochemistry of vinyl polymers has generated considerable interest in polymer science, as the
stereoregularity significantly affects the physical and chemical properties of synthetic polymers.7, 78ꢀ80 To
mimic the natural precision inherent in most biopolymers, both sequenceꢀ and stereoꢀcontrol are vital, which
requires monodisperse or uniform synthetic polymers. In recent elegant reports by Johnson’s group,43ꢀ44, 81
exponential chain growth of chiral monomers (R and S configurations) can be incorporated into discrete
polymers with different block sequences using “click” chemistry. Hawker and Qiao’s work employed
column chromatography to separate discrete and monodisperse isotactic and syndiotactic poly(methyl
methacrylate) (PMMA) with defined monomer units, which were used to investigate the triple helix
formation of such polymers.71
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Recently, our group prepared discrete oligomers with monodisperse character and defined monomer
sequences by SUMI into thiocarbonylthio compounds in high yield (up to 95% isolated yield).49, 52, 82 The
synthesis of these discrete oligomers was based on the principle of selective photoactivation of SUMI
adducts, in which the increased CꢀS bond dissociation energy of the SUMI adduct was used to suppress
reactivation and multiple monomer insertions, which would reduce product purity and yield. As such, a
major challenge is the selection of appropriate monomer/chain transfer agents, and catalytic systems/light
wavelength combinations that meet these activation selectivity criteria. As a result, the monomer pool for
subsequent SUMI is reduced, which increases the difficulty in preparing longer oligomers with control over
the oligomer structures (Figure 1a).
In this article, these previous SUMI procedures have been significantly improved to allow for preparation
of discrete oligomers with multiple functionalities and theoretically “infinite” chain growth through a
sequential and alternating process (Figure 1b). This new protocol relies on alternating SUMI in which two
families of monomers, namely, indene (Ind) and maleimide, are able to be alternatively inserted into a
suitable RAFT agent and show little or no propensity for homopolymerization. The reaction kinetics for one
pair of alternating reactions are much easier to study in this process, while repetition of the alternating
process provides a facile method for increasing chain length and maintaining specificity. The selected
monomer families can be adapted to carry diverse functionality, in particular, a plethora of maleimide
monomers are available through substitution at the nitrogen position. There are a range of other monomer
families available that could expand the pool of potential monomers.83 As a result, the currently disclosed
strategy allows the monomer sequence and position of functionality to be tuned along the polymer chain.
Additionally, compared with other existing methods, our approach possesses the advantages of high
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conversion and isolated yield for each step, simple purification, and easy functionalization, while reserving
the merits of photoꢀRAFT such as the use of low energy sources, mild reaction conditions, functional group
tolerance, which allows the potential to easily access large scale production.
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Most significantly, these cyclic monomers insert in a stereospecific manner to form transꢀ linkages along
the polymer backbone (Figure 1b), even though the SUMI process is a radical chain growth mechanism,
which generally has less stereoselectivity. This is the first report of investigating stereochemistry of discrete
polymers prepared by SUMI processes. This SUMI method provides the opportunity to engineer
stereochemistry of every monomer through organic reactions during each cycle of insertion at a molecular
level. The discrete oligomers formed herein can be expanded to access a library of functional building
blocks with designed molecular chirality, enabling high order polymers to be prepared with
sequenceꢀspecific positioning of functionalities and chirality, and thus to rationally design interaction
capabilities by mimicking biological systems.
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Figure 1. (a) Discrete oligomers synthesized in our previous work and (b) discrete and stereospecific
oligomers synthesized in this work by photoꢀRAFT SUMI. X denotes functional substitution of the maleic
or maleimide monomer unit.
In this article, we investigate the mechanism of sequential and alternating photoꢀRAFT SUMI and
introduce the general criteria for screening monomers, RAFT agents and reaction conditions. Next, two
model pentamers with alternating Ind/maleimide monomers with diverse functionalities, were synthesized to
showcase the efficiency, versatility and robustness of this method. Interestingly, these cyclic monomers have
specific stereochemistry when inserted into the polymer chain, which gives only transꢀ configurations due to
steric hindrance, regardless of the reaction conditions, monomer families and functionalities. In the last part
of this article, we discuss the stereospecificity of the cyclic monomers inserted into various RAFT agents
with chiral and nonꢀchiral R (leaving) groups. 1D/2D NMR, XRD and modeling simulations are employed
to verify the stereoconfigurations with acyclic monomers being investigated for comparison.
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RESULTS AND DISCUSSION
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1. Photo-RAFT SUMI mechanism and monomer selection for discrete oligomer synthesis
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Scheme 1. Mechanism for photoꢀRAFT SUMI process and essential conditions for effective SUMI. kd:
decomposition rate constant of initial RAFT agent under light; kꢀd: recombination rate constant of initial
RAFT agent; kadd: addition rate constant of monomer to radical; kp: propagation rate constant of monomer to
its SUMI adduct radical; ktr: chain transfer rate constant of SUMI adduct radical to initial RAFT agent; kꢀtr:
chain transfer rate constant of R group radical (R·) from initial RAFT agent to SUMI adduct macroꢀRAFT
agent; ktr´: chain transfer rate constant of SUMI adduct radical to SUMI adduct macroꢀRAFT agent; kd´:
decomposition rate constant of SUMI adduct macroꢀRAFT agent under light; kꢀd´: recombination rate
constant of SUMI adduct macroꢀRAFT agent. For clarity, the PETꢀRAFT technique, which involves electron
transfer in the presence of a photoredox catalyst, was not depicted in the scheme.
The reaction mechanism for light activated RAFT SUMI is proposed in Scheme 1. It can be considered
as a development of the pioneering work of Zard and coworkers who described photoꢀRAFT SUMI of
lessꢀactivated vinyl monomers into xanthates.47, 84ꢀ85 RAFT SUMI has also been extensively explored by the
CSIRO group and used as a process for synthesizing functional RAFT agents.50, 53, 86ꢀ87 The initial RAFT
agent (ZCS2R) is activated under light to generate an R group radical (R·) and thiocarbonylthio anion or
radical (ZCS2·); this process can occur in the presence or absence of photocatalyst, depending on the
employed RAFT agents and the irradiation wavelength. The R· radical can react with monomer to form an
adduct radical, with the generation of the desired SUMI product occurring through coupling with
thiocarbonylthio anion or radical species, or alternatively, through an addition/fragmentation chain transfer
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process with dormant RAFT species. The latter pathway is accompanied by the generation of another
R· radical through fragmentation of the RAFT radical intermediate species.
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From the standpoint of the proposed mechanism, the monomer and RAFT agent selection plays a critical
role in determining the success of SUMI. The ideal monomers for achieving single unit monomer addition
are those which cannot undergo radical homopolymerization (propagation rate constant, kp ~ 0) but give
alternating copolymerization with other monomers under a range of conditions, and with high monomer
addition rate constants (kadd). Therefore, α,βꢀdisubstituted and conjugated vinyl monomers, such as
Nꢀsubstituted maleimide (Scheme 2a) and Ind (Scheme 2b), are ideal candidates due to their superior
capability for alternating copolymerization with high reaction rates. Moreover, most maleimide and Ind
monomers have also been reported to be nonꢀhomopolymerizable or low kp through radical processes, which
limits the formation of homopolymer side products.83 In addition, maleimide monomers are electron
accepting, while Ind monomers are electron donating, leading to formation of a charge transfer complex and
allowing for alternating copolymerization to occur with high reaction rates,88 although there has been debate
of the mechanism for on alternating copolymerization in the literatures.89ꢀ90 Maleic anhydride (MAn,
Scheme 2a) presents similar reaction behavior as maleimides, however, there is a high potential for
hydrolysis and thus ring opening during the reaction. Meanwhile, although maleate, fumarate and
transꢀβꢀmethylstyrene (TransꢀMeSt, Scheme 2b) have low kp (~ 0),83 their reaction yield for SUMI into
RAFT agents are very low (SI, see Section 2.3), suggesting addition rates of these monomers are not as high
as maleimides and Ind, and thus they are not ideal monomers for the SUMI process used in this study.
Another critical component in RAFT mediated SUMI reaction protocols is the selection of the chain
transfer agent. The high decomposition rate constant (kd) of RAFT agent (ZCS2R) was essential to ensure
rapid generation of the initiating radical; the kd value is directly related to the CꢀS bond dissociation energy
of RAFT agent. Employing the PETꢀRAFT (photoinduced electron/energy transfer ꢀ RAFT) technique91ꢀ92
and a great variety of photoredox catalysts, most RAFT agents can be activated under light with high kd. For
instance, trithiocarbonate can be easily activated to generate radicals with high efficiency in the presence of
zinc tetraphenylporphyrin (ZnTPP) under low energy red light.93 Direct evidence of high kd and kadd is the
rapid consumption of RAFT agents (ZCS2R) observed in these SUMI reactions.
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Scheme 2. Various α,βꢀdiꢀsubstituted vinyl monomers (electron acceptor (a) and electron donor monomers
(b)) investigated in this study. All monomers are employed for the investigation of stereochemistry of SUMI
adducts. Four monomers (PMI, HEMI, CEMI and Ind) are employed for the synthesis of discrete pentamers.
The reaction of the carbon centered R group radical from the starting RAFT agent with the disubstituted
monomers can also be manipulated through RAFT agent selection. For instance, nꢀbutyl benzyl
trithiocarbonate (BBTC, Scheme 3) with an electron donating benzyl group (R group) can react with
electron acceptor monomers such as malemides, maleates and fumarates, but not electron donor monomers
such as Ind and TransꢀMeSt. The trithiocarbonate (CPDTC, Scheme 3) with an electron accepting
cyanoꢀisopropyl group (R group) reacts in the reverse way. Meanwhile, high monomer/RAFT ratios (> 1/1)
may be necessary in specific cases to increase the rate of insertion. The excess monomer does not lead to the
formation of undesired higher oligomers (dimers, trimers, etc.) through multiple insertions as the monomer
will not homopolymerize (vide supra).
The other essential condition for effective SUMI processes is a high recombination rate constant (kꢀd´, kꢀd´
[ZCS2·] >> kp[Monomer] ~ 0), or high chain transfer rate constant (ktr > kꢀtr, ktr[ZCS2R] >> kp[Monomer] ~
0); this will ensure the effective formation of the SUMI adduct and prevent radical accumulation and
undesirable termination reactions. Other factors such as a low decomposition rate constant (kd’) for the
SUMI adduct are beneficial for the reaction efficiency and product purity but are not essential. Although it is
difficult to determine the rate constants for these SUMI processes experimentally, qualitative estimates are
helpful for understanding and optimizing such reactions.
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Scheme 3. Various RAFT agents with diverse R (leaving) groups investigated in this study. For the full
names of these compounds refer to Supporting Information. All RAFT agents are employed for the synthesis
of SUMI adducts shown in Scheme 5. Only BBTC is employed for the synthesis of discrete pentamers. The
asterisk (*) indicates the chiral carbon.
2. Sequence control of discrete oligomers using sequential and alternating SUMI
The initial RAFT agent for the synthesis of discrete oligomers was screened from the selection shown in
Scheme 3. Dithiobenzoates, CPDB and CPADB, are poor choices for sequential SUMI processes as their
monoꢀadducts cannot be reactivated (kd ~ 0) by common photocatalysts used for PETꢀRAFT technique.49 All
trithiocarbonates are suitable for SUMI reactions, but BBTC was selected as a model RAFT agent because it
has the simplest chemical structure (benzyl R group and nꢀbutylthiol Z group), which simplifies NMR
analysis compared to other RAFT agents. For example, the chiral R group in CDTPA leads to doubled
diastereomers in the final product and complicates NMR analysis. BBTC was synthesized using an
analogous procedure to BSTP, which has been reported in previous literature.91, 94 Following silica column
purification, nearly 60 g of BBTC RAFT agent was obtained; with the lower polarity of BBTC compared to
BSTP reducing the difficulty of the column purification process. Furthermore, while other trithiocarbonates
(CPDTC, CDTPA and DDMAT, Scheme 3) are commercially available, they are still relatively expensive.
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Scheme 4. Synthetic chemistry of two model discrete pentamers, BBTCꢀMꢀIꢀMꢀIꢀM and
BBTCꢀMꢀIꢀHMꢀIꢀCM.
Two model pentamers, BBTCꢀPMIꢀIndꢀPMIꢀIndꢀPMI (denoted as BBTCꢀMꢀIꢀMꢀIꢀM) with alternating
Nꢀphenylmaleimide
(PMI)
and
Ind,
and
BBTCꢀPMIꢀIndꢀHEMIꢀIndꢀCEMI
(denoted
as
BBTCꢀMꢀIꢀHMꢀIꢀCM) (Scheme 4) with diverse functionalities, were synthesized to evaluate the reaction
conditions and kinetic efficiency. There are two key SUMI steps which are repeated during the synthesis of
long oligomers: (1) the insertion of Ind to BBTCꢀM to generate BBTCꢀMꢀI, and (2) the insertion of
maleimide into BBTCꢀMꢀI to generate BBTCꢀMꢀIꢀM. The reaction kinetics of both steps were
comprehensively investigated using online monitoring techniques. The SUMI adducts were fully
characterized by NMR, GPC and ESIꢀMS. The structural verification of long oligomers (> 5 monomer units)
is challenging through NMR due to substantial signal overlap; as such, only GPC and ESIꢀMS were used for
characterization of the pentamers.
2.1 Synthesis of BBTC-M mono-adduct in Step A
We started the SUMI process by activating BBTC through the PETꢀRAFT technique in the presence of
PMI. Following the design principles outlined in Section 1, a suitable electron donorꢀacceptor pair between
the donating BBTC R group (benzyl) and maleimide acceptor was formed, leading to effective SUMI of
PMI into BBTC. The reaction was performed in the presence of ZnTPP as photocatalyst under red light,
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using the molar ratio of [PMI]:[BBTC]:[ZnTPP] =1/1/0.005. The kinetic profile of this reaction was
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determined by monitoring the conversion of BBTC against time using online H NMR spectroscopy using
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deuterated DMSO as reaction solvent (Figure 2a). The reaction proceeded quickly within the first 2 h and
slowed down to reach 65% after 10 h of irradiation. With the consumption of BBTC, the concentration of
BBTCꢀM increased and reached an equilibrium stage. The conversion of RAFT agent could not reach 100%
since the benzyl radical in BBTC is a poorer leaving group than the maleimidyl radical of the newly formed
SUMI adduct (BBTCꢀM). The light activation and addition/fragmentation process of BBTCꢀM competes
with that of BBTC, i.e., kd[BBTC] competes with kd’[BBTCꢀM], while ktr[BBTC] competes with
kꢀtr[BBTCꢀM]. The decomposition rate of BBTCꢀM is higher than that of BBTC (kd´ > kd) due to the lower
CꢀS bond dissociation energy of BBTCꢀM compared with BBTC. The chain transfer rate kꢀtr is higher than
ktr in this SUMI, which suggests fragmentation to produce SUMI product of BBTCꢀM (SI, Scheme S1) is
unfavorable.
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The stacked H NMR spectra (SI, Figure S3) at different time points (0, 1, and 9 h) clearly showed the
SUMI process proceeded smoothly without obvious side reactions, such as RAFT agent degradation by
irreversible termination and dimer formation (BBTCꢀMꢀM). The crude monoꢀadduct was purified by
column chromatography to give an isolated yield of 56%. Neat 1H and 13C NMR spectra (SI, Figures S4 and
S5) clearly confirmed the chemical structure and high purity of the monoꢀadduct. ESIꢀMS (Figure 3c and SI,
Figure S6) further confirmed the isolated product is BBTCꢀM. Surprisingly, a higher [PMI]/[BBTC] ratio
such as 5/1 could not improve the yield and adversely increased the risk of multiple PMI insertion (SI,
Figures S7 and S8).
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Figure 2. Kinetic study of sequential PETꢀRAFT SUMI processes from BBTC to BBTCꢀMꢀIꢀM monitored
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by online H NMR analysis (DMSOꢀd6, 400 MHz). Conversions of RAFT agents versus irradiation time:
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BBTC (a), BBTCꢀM (b) and BBTCꢀMꢀI (c); Stacked H NMR spectra indicated the SUMI processes:
BBTCꢀM to BBTCꢀMꢀI (d) and BBTCꢀMꢀI to BBTCꢀMꢀIꢀM (e). The scheme on the right depicts the
corresponding chemical structures of the growing SUMI products examined in this kinetic study.
2.2 Synthesis of BBTC-M-I dimer in Step B
The insertion of Ind to BBTCꢀM to prepare BBTCꢀMꢀI followed a similar process to Step A, with
identical reaction conditions employed, except for a higher monomer/RAFT ratio ([Ind]:[BBTCꢀM]:[ZnTPP]
= 5/1/0.005). An increased monomer/RAFT ratio was used due to the relatively low addition rate of Ind to
maleimidyl radicals, compared to that of PMI to benzyl radicals. In this step, the proposed reaction pathway
is similar with Step A (kd´ > kd and kꢀtr > ktr), as shown in the SI, Scheme S2. The slightly higher stability of
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Ind radicals compared to maleimidyl radicals causes kd´ > kd, and also leads to favorable fragmentation of
the intermediate to generate the Ind radical and not the SUMI product (BBTCꢀMꢀI). Therefore, the high
monomer/RAFT ratio improves the RAFT agent conversion and reaction yield by pushing the reaction
towards the desired SUMI product (BBTCꢀMꢀI), although it also increases the probability of dimer
formation.
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Figure 3. GPC traces and ESIꢀMS spectra for all SUMI adducts. GPC traces for the successive synthesized
oligomers, from BBTC to BBTCꢀMꢀIꢀMꢀIꢀM (a) and from BBTC to BBTCꢀMꢀIꢀHMꢀIꢀCM (b), and their
corresponding ESIꢀMS spectra (c) and (d). The full spectra for these SUMI adducts can be found in
Supporting Information.
The reaction kinetics showed the conversion of macroꢀRAFT agent, BBTCꢀM, reached 100% after 20 h
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of irradiation (Figure 2b). H NMR showed the reaction proceeded smoothly with the increased doublet
peak signals at δ 5.42 ppm and δ 6.05 ppm assigned to the two diastereomers of the terminal –CH– proton
(proton 3) in BBTCꢀMꢀI (Figure 2d). The peak signals at δ 5.28 ppm and δ 3.65 ppm assigned to the
protons 1 and 2 dropped to 10 % as the reaction time increased from 0 h to 12 h. After 20 h of irradiation, a
signal peak (m/z = 684.20) in ESIꢀMS was observed, which suggested the presence of double Ind insertion
(BBTCꢀMꢀIꢀI) ionized with Na+ (SI, Figure S9b). The double insertion is attributed to the low chain transfer
rate (kꢀtr > ktr), causing an increased probability of multiple monomer insertion after long irradiation times in
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the presence of excess monomer. Fortunately, a shorter reaction time (< 15 h) effectively suppressed the
formation of this Ind double insertion adduct (ESIꢀMS, SI, Figure S9a). As a result, the RAFT conversion in
Step B had to be limited to 85~95%. However, it is not necessary to push macroꢀRAFT conversion to 100%;
the unreacted BBTCꢀM will be unable to participate in the subsequent maleimide insertion reaction in Step
C, as the low maleimide homopolymerization rate (kp ~ 0) suppresses the formation of the dimeric
BBTCꢀMꢀM adduct. More importantly, this unreacted BBTCꢀM can be easily removed by column
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chromatography to afford pure BBTCꢀMꢀIꢀM trimer in Step C (vide infra). The H NMR spectrum for the
crude product after excess monomer (Ind) removal clearly demonstrated the presence of a mixture of
BBTCꢀMꢀI and BBTCꢀM (SI, Figure S10).
2.3 Synthesis of BBTC-M-I-M trimer in Step C
This step involves the highly efficient insertion of PMI into BBTCꢀMꢀI dimer to form the BBTCꢀMꢀIꢀM
trimer, which differentiates the insertion of PMI into BBTC in Step A due to a different R group (benzyl
radical versus Ind radical). Ind radicals are better leaving groups than both benzyl and maleimidyl radicals,
and thus the insertion of PMI into BBTCꢀMꢀI reached high conversions (95% isolated yield). The high chain
transfer rate (kꢀtr < ktr) made the intermediate species preferentially generate the trimer SUMI adduct rather
than the RAFT dimer and trimer adduct radical (SI, Scheme S3). The high decomposition rate (kd´ < kd) also
allowed for fast conversion of the RAFT agent (BBTCꢀMꢀI), which was reflected in the kinetic results
(Figure 2c). Nearly full conversion of the initial RAFT agent (BBTCꢀMꢀI) was observed after 15 h of
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irradiation, with a molar ratio of [PMI]/[BBTCꢀMꢀI] = 1/1. The H NMR spectra (Figure 2e) at different
time points of the reaction (0, 1, and 9 h) clearly indicated the gradual consumption of BBTCꢀMꢀI dimer by
the decrease of the peak signals at δ 5.42 and δ 6.05 ppm assigned to the proton 3 of terminal –CHꢀ in the
dimer BBTCꢀMꢀI, and generation of BBTCꢀMꢀIꢀM trimer by the increase of peak signals at δ 5.44, δ 5.38
and δ 5.0 ppm, assigned to the proton 4 of terminal –CH– in the trimer BBTCꢀMꢀIꢀM. As anticipated, the
unreacted BBTCꢀM monoꢀadduct (the peak signals for protons 1 and 2 in BBTCꢀM at 0 h) remained intact
during the reaction, which demonstrates that the presence of this species (from the previous insertion step)
does not affect the production of the target trimer. The unreacted BBTCꢀM can simply be removed by
conventional column chromatography. The Rf values in silica gel thin layer chromatography (TLC) for the
impurity, BBTCꢀM, and the product, BBTCꢀMꢀIꢀM, are very different (Rf = 0.7 for BBTCꢀM and 0.3 for
BBTCꢀMꢀIꢀM using 5/1 (v/v) hexane/ethyl acetate as the eluent), due to the increased polarity and
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molecular mass of BBTCꢀMꢀIꢀM. The H NMR spectra also indicated that other side reactions (multiple
maleimide insertion or RAFT agent degradation) were negligible.
After purification by column chromatography, the structure of the isolated BBTCꢀMꢀIꢀM trimer was
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verified by H and 13C NMR, HSQC, and HMBC (SI, Figure S11, S12, S13 and S14). The H NMR
spectrum is complicated due to the presence of several diastereomers for this compound. Furthermore, the
1H NMR spectrum measured in CDCl3 (SI, Figure S11) was different to that in DMSOꢀd6 (Figure 2e).
Particularly, the terminal –CH– proton shows different chemical shifts and profiles, which gives three peaks
from δ 4.9~5.5 ppm in DMSOꢀd6 and two peaks from δ 4.6~4.9 ppm in CDCl3. Moreover, the peaks from δ
4.6~4.9 ppm in CDCl3 are not all signals of terminal –CH– proton in these molecules, which was
demonstrated by the low integration values of the peaks. The other part of the signal for this proton is
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overlapped in the area from δ 3.95~4.15 ppm, which was demonstrated by the analysis of C NMR (SI,
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Figure S12), high resolution Hꢀ13C HSQC (SI, Figure S13), and Hꢀ13C HMBC (SI, Figure S14). HSQC
confirmed the rough assignment of every proton in the molecule and HMBC confirmed the peak location of
the terminal –CH– proton. To further confirm the structure of the synthetic compound, GPC and ESIꢀMS
analysis was performed. The GPC trace for this product showed a unimodal and symmetric peak, and a clear
shift in molecular weight compared to BBTCꢀM (Figure 3a). ESIꢀMS confirmed the molar mass of the
product to be 741.19, which matched well with the target compound ionized with Na+ (Figure 3c and SI,
Figure S15). A more detailed discussion for the structural verification of this compound can be found in
Supporting Information.
2.4 Synthesis of BBTC-M-I-M-I tetramer in Step D and BBTC-M-I-M-I-M pentamer in Step E
The tetramer and pentamer were successfully synthesized and isolated using the same procedures as those
for dimer and trimer synthesis under identical conditions in high yield (85% isolated yields for two reaction
steps). A conventional silica column was employed to remove excess monomer and trace amounts of
impurities, however, difficulties in purification arose due to reduced discrepancy in both molecular weights
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and polarity between two neighboring SUMI products. The final purified products were confirmed by H
NMR (SI, Figure S16 for BBTCꢀMꢀIꢀMꢀI tetramer and Figure S18 for BBTCꢀMꢀIꢀMꢀIꢀM pentamer), GPC
(Figure 3a) and ESIꢀMS (Figure 3c and SI, Figure S17 for BBTCꢀMꢀIꢀMꢀI tetramer and Figure S19 for
BBTCꢀMꢀIꢀMꢀIꢀM pentamer).
According to the reaction conditions and efficiency, the trithiocarbonate end group in each step can
always be activated easily in the coꢀmonomer system. The SUMI process described in this work can
therefore be repeated numerous times with the biggest challenge being separation of the product adducts
from the reaction mixture. However, the use of a support resin similar to those used in solidꢀphase peptide
synthesis could potentially increase the commercial viability of this SUMI process.
To demonstrate the endꢀgroup fidelity and the capability of the pentamer as a functional building block
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for constructing complex polymer architectures, the synthesized BBTCꢀMꢀIꢀMꢀIꢀM pentamer was employed
as macroꢀRAFT agent for the polymerization of methyl acrylate (MA) to prepare diblock copolymer
((BBTCꢀMꢀIꢀMꢀIꢀM)ꢀbꢀpoly(MA)) using the PETꢀRAFT technique with ZnTPP as the photocatalyst. The
ln([M]0/[M]t) derived from monomer conversion linearly increased with the exposure time to light (Figure
4a), indicating a constant radical concentration in the system. The kinetic plots of Mn versus monomer
conversion, ln([M]0/[M]t) versus exposure time and molecular weight distribution were investigated. The
linear increase of Mn,GPC versus monomer conversion (Figure 4b) demonstrated that this macroꢀRAFT agent
was able to mediate the controlled radical polymerization of MA. The experimental molecular weights at
different monomer conversions were slightly higher than the theoretical values calibrated by polystyrene
standards, which was attributed to the molecular weight of macroꢀRAFT agents. Regardless, the uniform
and symmetric molecular weight distributions showed no signs of tailing and the clear and complete shift in
molecular weight indicated the remarkable living character and endꢀgroup fidelity of macroꢀRAFT agents
(Figure 4c). Moreover, the dispersity (Mw/Mn in Figure 4b) was as low as 1.08 during polymerization,
illustrating that the pentamer is an excellent chain transfer agent. Additionally, “ON”/“OFF” experiments
revealed that the polymerization process can be started and stopped by switching the light “ON” and “OFF”
(Figure 4d); similar temporal control has been demonstrated previously in other PETꢀRAFT polymerization
systems.49, 93, 95
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Figure 4. Online Fourier transform nearꢀinfrared (FTNIR) measurement for kinetic study of PETꢀRAFT
polymerization of methyl acrylate (MA), using pentamer BBTCꢀMꢀIꢀMꢀIꢀM as macroꢀRAFT agent and
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ZnTPP as photocatalyst, with the molar ratio of [MA]:[macroꢀRAFT]:[ZnTPP] = 300:1:0.01 (~33 ppm
catalyst with respect to monomer concentration): (a) ln([M]0/[M]t) versus exposure time; (b) Mn and Mw/Mn
versus conversion; (c) molecular weight distributions at different time points, and (d) monomer conversion
versus time in the presence (ON) or in the absence (OFF) of light, red arrows represent the four sampling
time points for GPC analysis.
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2.5 BBTC-M-I-HM trimer and BBTC-M-I-HM-I-CM pentamer
A range of other functional trimers and pentamers were prepared by following the same synthetic
protocol as those for BBTCꢀMꢀIꢀM trimer and BBTCꢀMꢀIꢀMꢀIꢀM pentamer, except that the maleimide
monomers were changed to HEMI and CEMI (Scheme 2) for the third and fifth monomer insertion instead
of PMI (Scheme 4). The purification procedures were also similar, using conventional silica gel column and
gradient elution, except that the composition of solvents was a little different due to increased polarity of the
new SUMI compounds. The product for each step was fully characterized by 1H NMR (SI, Figure S20, S22
and S23) with GPC (Figure 3b) and ESIꢀMS (Figure 3d and SI, Figure S21 and S24) of the trimer and
pentamer providing solid evidence of successful production in high purity. Significantly, the isolated yields
were 95% and 86% for the trimer and pentamer, respectively.
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3. Stereospecificity of synthetic discrete oligomers
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The properties of natural and synthetic polymers are determined in large part by their geometrical and
stereochemical structure, i.e., degree of regularity of the substituents along macromolecular chain. In general,
high regularity imparts strength, high glass transition temperatures and hardness, together with restricted
solubility in solvents. Symmetry and regularity in macromolecular structures also enhance
microꢀcrystallinity, which is a key property for many applications of polymeric materials. Designing and
tuning microꢀcrystallinity of polymers at the molecular level is therefore a fundamental challenge for
synthetic chemists.
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Scheme 5. (a) PhotoꢀRAFT SUMI of cyclic monomers into various RAFT agents generating SUMI adducts
with allꢀtrans configuration; (b) PhotoꢀRAFT SUMI of acyclic monomers to RAFT agent (BBTC)
generating SUMI adducts with mixed cisꢀ and transꢀ configurations.
Having demonstrated the ability to control the sequence and chain length of synthetic oligomers, our
attention was turned to stereochemistry. As discussed previously in the characterization of synthetic
oligomers (Section 2), full structural determination of compounds with more than three monomer units is
difficult by NMR spectroscopy. Conveniently, it is not necessary to determine the stereoconfiguration for the
full length of final oligomer, as the oligomer is composed of repeating alternative monomer units of
Nꢀsubstituted maleimide and Ind; if we can determine the stereoregularity of one repeating unit, it will be
the same for all repeating units with increasing chain length. Initially, the stereochemistry of maleimide and
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Ind independently inserted into various RAFT agents with chiral and nonꢀchiral R groups was studied
(Scheme 5). Maleic anhydride and three acyclic monomers, DEM, DMF and TransꢀMeSt, were also
investigated for comparison.
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3.1 Stereochemistry of N-substituted maleimide unit in discrete oligomers
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In the chain growth polymerization of vinyl monomers, each propagation step results in the formation
of either one (αꢀsubstituted and α,αꢀdisubstituted monomers) or two (α,βꢀdisubstituted) stereogenic centers
with four different substituents for each. For α,βꢀdisubstituted monomers, both backbone atoms are
stereogenic with each possessing either R or S configuration. For the α,βꢀdisubstituted cyclic vinyl
monomers, four potential backbone configurations (R, R), (R, S), (S, R) and (S, S) exist; a pair of cisꢀ
enantiomers and a second pair of transꢀ enantiomers. With increasing degree of polymerization, the number
of possible diastereomers rises exponentially and higher order stereochemical classification (e.g. threo and
erytheo) becomes necessary.
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Figure 5. H NMR spectra (400 MHz, CDCl3) (δ 2.5~5.5 ppm) to demonstrate the transꢀ configuration of
maleimide unit in purified (a) BBTCꢀM and (b) CPDTCꢀIꢀM.
During the SUMI of PMI into trithiocarbonate of BBTC, the fragment radicals could theoretically add
to the maleimide double bond in both cisꢀ and transꢀ fashions. Therefore, the monoꢀadduct of BBTCꢀM
gives two diastereomers of cisꢀ and transꢀ configurations in fiveꢀmember ring units with their corresponding
enantiomers of mirrorꢀimage molecules (Scheme 5a). The cisꢀ and transꢀ diastereomers have different
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stereochemical structures and molecular environments for the corresponding protons. Therefore, H NMR
analysis, particularly the chemical shifts and coupling constants (J values) of specific protons, allows cisꢀ
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and transꢀ configurations to be distinguished. However, the H NMR spectrum (Figure 5a and SI, Figure
S4) of BBTCꢀM showed only one set of diastereotopic signals, implying formation of either a cisꢀ or transꢀ
configuration exclusively. The signal at δ 4.6 ppm was assigned to the proton of –CH– (5) giving a doublet,
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which is coupled with the proton of –CH– (6) and showed the same coupling constant of JH5,H6 = 7.2 Hz.
The other configuration (either cisꢀ or transꢀ) is supposed to show another doublet signal for the proton of –
CH– (5), but was not observed.
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The stereochemistry of Nꢀsubstituted maleimides has interested researchers since 1960s in attempting to
use homoꢀ and coꢀpolymerization to prepare polymers with helixꢀsense chirality.96ꢀ97 The anionic
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homopolymerization of maleimides provided allꢀtrans configuration at low (ꢀ78 C) to room temperature
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with anionic initiators.98 Radical homopolymerization of maleimides at elevated temperature (100 oC) with
the assistance of chiral solvent or catalyst also showed transꢀ stereoꢀconfiguration.99 The radical
copolymerization of maleimides and styrene or propylene provided a helical structure, with the maleimide
monomers most likely possessing an all transꢀ configuration.96 In contrast, the electronꢀdonorꢀacceptor
interaction of styrene and cyclic citraconic anhydride (a maleic derivative) resulted in a mixture of cisꢀ and
transꢀ configurations.100 Additionally, the single monomer radical addition of PMI to a xanthate gave a
transꢀ configuration due to the steric hindrance.47ꢀ48, 85 However, the chemical structure of the products was
not comprehensively confirmed. Due to the challenge of structural characterization of complex polymers,
the stereochemical outcome of maleimide polymerization is thus arguable. There are no effective tools for
polymers with large numbers of repeating monomer units, and as noted above previous experiments have
delivered conflicting results. In contrast, SUMI provides an excellent tool to synthesize discrete oligomers
with exact molecular weights, making it possible to confirm the stereoconfiguration and reaction mechanism,
using widely used analytical equipment (NMR and XRD, etc). Most importantly, this tool can be applied to
any monomers on the condition that they can be polymerized by iterative SUMI. In this study, the SUMI
adducts of α,βꢀdisubstituted vinyl monomers were synthesized and their stereochemistry was investigated
for the first time. Particularly, this approach is able to assess the stereospecific configuration of our synthetic
discrete oligomers in Section 2.
To elucidate the cisꢀ or transꢀ configuration of the product of SUMI of PMI into trithiocarbonates, we
performed single crystal Xꢀray diffraction (XRD) analysis and computational simulations. Single crystal
XRD is a powerful technique that provides accurate structural information on small organic compounds,
including the location of atoms, bond lengths, bond angles and stereoconfiguration. The sample for XRD
requires a crystalline compound, therefore, crystallization of monoꢀadduct compound, BSTPꢀM (Scheme 5a,
1H NMR shown in SI, Figure S25) was carefully performed; BSTPꢀM was selected rather than BBTCꢀM
due to the carboxylic acid moiety in BSTP, which facilitates more efficient crystallization. Fine needleꢀlike
crystals were obtained, suggesting that BSTPꢀM has good crystallinity and thus structural stereoregularity,
as crystallinity is often regarded as external manifestation of a regular arrangement at the molecular level.
XRD analysis of the obtained crystal perfectly matched with the expected molecular structure of BSTPꢀM
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and unambiguously demonstrates that PMI insertion results in a transꢀ configuration (Figure 6a).
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In agreement with the XRD results, computational modelling indicates that the transꢀBSTPꢀM
diastereomer is around 12.4 kJ/mol more stable than the corresponding cisꢀisomer (Figure 6b). This
GibbsꢀFree energy corresponds to a thermodynamic selectivity of over 99% for the transꢀ diastereomer (at
room temperature), indicating that the PMI insertion into BSTP is highly stereospecific.
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Figure 6. Single crystal XRD of BSTPꢀM (a) and modeling results showing the most stable conformations
of the transꢀ and cisꢀ BSTPꢀM diastereomers as well as their respective solutionꢀphase GibbsꢀFree Energies
(b).
To illustrate the broad applicability of this strategy, Nꢀsubstituted maleimide monomer, HM, and MAn
were also used to prepare the corresponding SUMI adducts BBTCꢀHM and BBTCꢀMAn (Scheme 5a). The
1H NMR spectroscopy (SI, Figure S30 and S31) revealed the same stereospecific preference for transꢀ
configurations of HM and MAn units in the adducts, suggesting cyclic maleimide and maleic monomers
have the same stereogenic preference regardless of their substitutions.
The RAFT agents of both BBTC and BSTP have nonꢀchiral R groups. To investigate RAFT agents
with chiral R groups, the insertion of PMI into CPDTCꢀI was performed and the resulting product analyzed
by NMR (Scheme 5a). Careful analysis of the NMR results can be used to elucidate the stereochemical
configuration of the PMI unit in the adduct (Figure 5b and SI, Figure S34), indicating the same transꢀ
configuration of the PMI unit in the adduct. There are two series (a and b) of proton signals which are
assigned to the two diastereomers of CPDTCꢀIꢀM, each containing a pair of enantiomers as verified by 2D
NMR analysis (SI, Figure S35-S37). If both transꢀ or cisꢀ configurations for PMI exist, there should be four
diastereomers which are attributed to each configuration (transꢀ or cisꢀ) with two different connection types
for the Ind R group (threo and erytheo). Thus, if all four diastereomers are generated, four series of proton
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signals would be anticipated. However, only two series signals were observed in the H NMR spectrum,
which are assigned to two diastereomers of the transꢀ configurations shown in Figure 5b.
It is worth noting that the two chemical shifts of the same protons in the adduct, such as –CH–S– (5),
were were highly sensitive to the adduct stereochemistry. The chemical shift for one diastereoisomer is δ 6.1
ppm and δ 5.2 ppm for the other, which is attributed to the aromatic ring current effect (SI, Scheme S4).
This proton has a very different chemical environment in each of the two transꢀ diastereomers; in one
isomer (threo) it is deshielded by the phenyl ring of the adjacent Ind unit and thus leads to higher chemical
shift.
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3.2 Stereochemistry of Ind unit in discrete oligomers
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Figure 7. H NMR spectra (400 MHz, CDCl3) (δ 2.5~6.4 ppm) to demonstrate the transꢀ configuration of
Ind in purified (a) CPDBꢀI and (b) CPADBꢀI.
As one of the alternating monomer units in these synthetic and discrete oligomers, Ind is different
from maleimide due to its asymmetrical structure. Interestingly, there are not many previous reports for its
polymerization stereochemistry.101ꢀ103 Five RAFT agents with electron accepting R groups (Scheme 3) were
therefore investigated for SUMI of Ind; three with nonꢀchiral R groups and two with chiral R groups.
The characterization of these SUMI adducts was carried out by 1D and 2D NMR. For instance, the 1H
NMR of purified CPDBꢀI (Figure 7a and full spectrum shown in SI, Figure S28) was obtained to confirm
the transꢀ configuration of the inserted cyclic Ind monomer with similar proton signals as that for BBTCꢀM
being observed (Figure 5a and SI, Figure S4). Computational modelling also indicated that the transꢀ
CPDBꢀI diastereomer is around 12.5 kJ/mol more stable than the corresponding cisꢀisomer (Figure S29).
Other SUMI adducts including CPDTCꢀI (SI, Figure S26) and DDMATꢀI (SI, Figure S27) had the same
stereospecific preference for transꢀ configurations as demonstrated by 1H NMR results. In the case of chiral
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R group such as CPADBꢀI, the H NMR spectrum (Figure 7b and full spectrum shown in SI, Figure S32)
showed a more complicated signal pattern than the nonꢀchiral R group of CPDBꢀI due to two diastereomers
derived from the chiral carbon of the R group, in which two sets of signals were very closely positioned. For
instance, the signal for proton 1 in Figure 7b (inset) at δ 6.02 ~ 6.15 ppm leads to two doublets centered at δ
6.06 ppm and 6.09 ppm, which belong to two different diastereomers. The CDTPAꢀI SUMI mono adduct
had the same 1H NMR profile (SI, Figure S33) as CPADBꢀI, attributed to the same chiral R group.
Computational modelling further confirmed the transꢀ configuration of Ind unit in the synthetic
oligomers with the potential energy surface (PES) for the insertion of PMI into CPDTCꢀI being examined.
In this reaction, the relative freeꢀenergy of four intermediate diastereomeric configurations (threoꢀcis,
erytheoꢀcis, threoꢀtrans and erytheoꢀtrans, SI, Figure S38) was compared to determine the most favorable
reaction pathways. The modelled conditions are identical to the experimental ones (solutionꢀphase in DMSO,
at 25 oC). The results clearly showed that both transꢀ insertion reactions are more kinetically favorable (> 10
kJ/mol) than either cisꢀ insertion pathway, suggesting that the Ind unit also prefers transꢀinsertion as for the
PMI unit.
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3.3 Stereochemistry of acyclic monomer unit in discrete oligomers
In the contrast to the behaviors observed for cyclic monomers, the SUMI of acyclic monomers
(Scheme 2) into RAFT agents did not show stereospecificity due to the lack of cyclic structure and a free
1
rotating single bond along the backbone. For instance, the H NMR spectrum of BBTCꢀDEM (SI, Figure
S41) showed two series of proton signals (a and b) which belong to two diastereomers, each of them with a
corresponding pair of enantiomers. The signals for the same protons in each diastereoisomer presented
different chemical shifts (0.12 ppm difference for the proton 5a and 5b of –CH–S–, 0.3 ppm for the proton
6a and 6b of –CH–CH–S–) and splitting patterns (doublet for the proton 7a and two quartets for proton 7b).
1
2D NMR (1Hꢀ1H COSY, Hꢀ13C HSQC and 1Hꢀ13C HMBC) was employed to confirm the structure and our
conclusion. It is interesting to note that the integrals for two proton signals are different, which suggested
that one of the diastereomers formed preferentially over the other during the SUMI process, presumably due
to a difference in steric hindrance.
To summarize the above results, the stereospecificity in the SUMI process relies on the monomer
structure; the cyclic monomer prefers transꢀ insertion regardless of the chirality of R groups, but the acyclic
monomer shows a mixture corresponding to both cisꢀ and transꢀ configurations. This can be attributed to
steric hindrance and the restricted rotation of cyclic monomers during radical addition (or recombination
step). In contrast, radical addition (or recombination) with acyclic monomers was not stereospecific due to
free rotation around the single bond of the CꢀC backbone.
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This stereochemical preference was independent of temperature and solvents. High temperature will
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not change the transꢀ opening of cyclic monomers (SI, Figure S39). Low polarity solvents, such as
cyclohexane, was also shown to have no effect on the stereospecific insertion of cyclic monomer into RAFT
agents (SI, Figure S40). Similarly, the photocatalysts investigated in this work do not induce
stereospecificity, because the transꢀ configuration is formed in both the presence and absence of
photocatalysts. The synthetic conditions used to synthesize the SUMI adducts varied depending on the
RAFT agents and monomers employed. For instance, BBTCꢀM and CPDTCꢀI were prepared through two
distinct photocatalytic processes. The synthesis of BBTCꢀM, described in the first section employed the
PETꢀRAFT technique to activate the RAFT agent BBTC to generate benzyl radical using a photocatalyst
ZnTPP under red LED light, followed by PMI monomer addition to form the desired adduct. CPDTCꢀI was
synthesized by direct photolysis of the RAFT agent CPDTC under blue LED light, and subsequent single
Ind addition. This protocol is similar to that used for single styrene insertion into a trithiocarbonate, which
was described in a previous report using the photoꢀRAFT SUMI approach.52
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CONCLUSION
In this contribution, we report a robust and highly efficient method of sequential and alternating single unit
monomer insertion for the preparation of discrete oligomers with sequence control and stereospecific
configuration (transꢀ) of inserted cyclic monomers. Two families of cyclic monomers, indene and
Nꢀsubstituted maleimide, were inserted into RAFT agents alternatively one unit at a time in high reaction
yields, which effectively controlled the monomer sequences. The structures were confirmed by an online
NMR kinetic study, GPC and ESIꢀMS. Moreover, for each investigated cyclic monomers, stereospecific
transꢀinsertion was observed due to steric hindrance from the growing oligomer chain. The stereochemistry
of these oligomer adducts was verified by 1D and 2D NMR and XRD and explained by quantumꢀchemical
modelling. This methodology provides a versatile approach to synthesize discrete polymers with precise
sequence and location of functionalities, while also illustrating a powerful synthetic pathway to model
oligomers for the investigation of absolute structure (e.g. stereochemistry) of synthetic polymers. The
research to expand the monomer pool (i.e. other nonꢀhomopolymerizable monomer families83 and functional
indenes104, 105) for this advanced method is currently under investigation.
ASSOCIATED CONTENT
Supporting information
Experimental details, NMR spectra and all raw computational data (Figures S1~S47, Tables S1, and
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Schemes S1~S5).This material is available free of charge via the Internet at http://pubs.acs.org.
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Notes
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The authors declare no competing financial interest.
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AUTHOR INFORMATION
Corresponding authors
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michelle.coote@anu.edu.au (M.C.)
cboyer@unsw.edu.au (C.B.)
j.xu@unsw.edu.au (J.X.)
ACKNOWLEDGEMENTS
J.X. and C.B. acknowledges Australian Research Council (ARC) for their Future Fellowships
(FT160100095 and FT120100096). J.X., K.S. and M.K. acknowledge Venture Business LaboratoryꢀNagoya
University for the financial support of visiting program. J.X. also acknowledges Dr. James Hook from Mark
Wainwright Analytical Centre at the UNSW Sydney and Prof. Junpo He from Fudan University for valuable
advice on NMR analysis. Single crystal Xꢀray data was acquired at Australian Synchrotron. The structure
determination and refinement was carried out by Ms. Ena Luis in School of Chemistry at UNSW Sydney
and Dr. Mohan Bhadbhade in Solid State and Elemental Analysis Unit, Mark Wainwright Analytical Centre
at UNSW Sydney. M.L.C gratefully acknowledges a Georgina Sweet ARC Laureate Fellowship and
generous allocations of supercomputing time on the National Facility of the Australian National
Computational Infrastructure. C.J.H. thanks the MRSEC program of the National Science Foundation
(DMRꢀ1720256).
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