Triazine-Based Sequence-Defined Polymers with Side-Chain Diversity and Backbone-Backbone Interaction Motifs

Article abstract of DOI:10.1002/anie.201509864

Sequence control in polymers, well-known in nature, encodes structure and functionality. Here we introduce a new architecture, based on the nucleophilic aromatic substitution chemistry of cyanuric chloride, that creates a new class of sequence-defined polymers dubbed TZPs. Proof of concept is demonstrated with two synthesized hexamers, having neutral and ionizable side chains. Molecular dynamics simulations show backbone-backbone interactions, including H-bonding motifs and pi-pi interactions. This architecture is arguably biomimetic while differing from sequence-defined polymers having peptide bonds. The synthetic methodology supports the structural diversity of side chains known in peptides, as well as backbone-backbone hydrogen-bonding motifs, and will thus enable new macromolecules and materials with useful functions.

Full text of DOI:10.1002/anie.201509864

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International Edition: DOI: 10.1002/anie.201509864
German Edition: DOI: 10.1002/ange.201509864
Sequence-Defined Polymers
Hot Paper
Triazine-Based Sequence-Defined Polymers with Side-Chain Diversity
and Backbone–Backbone Interaction Motifs
Jay W. Grate,* Kai-For Mo, and Michael D. Daily
Abstract: Sequence control in polymers, well-known in nature,
encodes structure and functionality. Here we introduce a new
architecture, based on the nucleophilic aromatic substitution
chemistry of cyanuric chloride, that creates a new class of
sequence-defined polymers dubbed TZPs. Proof of concept is
demonstrated with two synthesized hexamers, having neutral
and ionizable side chains. Molecular dynamics simulations
show backbone–backbone interactions, including H-bonding
motifs and pi–pi interactions. This architecture is arguably
biomimetic while differing from sequence-defined polymers
having peptide bonds. The synthetic methodology supports the
structural diversity of side chains known in peptides, as well as
backbone–backbone hydrogen-bonding motifs, and will thus
enable new macromolecules and materials with useful func-
tions.
typically have monomers selected from natural and unnatural
alpha-amino acids, non-alpha-amino acids, and pseudo-amino
acids. Peptoids have amide bonds in the backbone where the
side chains are attached to a nitrogen atom instead of
a carbon atom, prepared by the solid-phase submonomer
synthesis approach without using amino acid monomers or
protecting groups.[3] Until recently, most synthetic sequence-
defined polymers have a similarity to polypeptides by virtue
of having amide bonds.
With resurgent interest in sequence-controlled and
sequence-defined polymers, additional bond-forming reac-
tions are being implemented to create new polymer archi-
tectures[1g–r] Lutz et al. described alternating cycloaddition
and amidation reactions in 2009 to create (AB)n sequence-
controlled polymer segments.[1h] This group employed the
same or similar strategies 2014 and 2105 to design sequence-
defined oligomers that encode digital information.[1i–l] The
sequencing could be decoded with tandem mass spectrome-
try.[1k,l] In 2013, Madder et al. described sequence-defined
trimers and tetramers where the polymer is extended by
a method that attaches a cyclic thiolactone, and a side chain is
added by nucleophilic aminolysis of the thiolactone.[1n] Han
et al. described sequence-controlled polymers prepared by
a radical initiated step-growth thiol-yne approach with func-
tional groups alternately arranged along the chain, which
could be further functionalized after polymerization.[1o] Han
asserted in this 2014 article that “all of the artificial SCPs
[sequence-controlled polymers] have no independent func-
tional groups suspended on backbone”, citing twenty five
references. In 2014, Solleder and Meier created a sequence-
defined tetramer using Passerini 3-component reactions and
thiol–ene chemistry, without protecting groups, where each
monomer unit contains a different amide-containing side
chain.[1p] Also in 2014, Porel and Alabi described two
sequence-defined 10-mers using allyl acrylamide building
S
equence control in synthetic polymers has gained renewed
interest,[1] because sequence leads to structure and function.
Sequence-controlled polymers have repeated sequence
motifs (e.g., (ABC)n) whereas sequence-defined polymers
have monomers in any predetermined order (e.g. ABCADC).
The latter polymers are epitomized by natural biopolymers
such as polypeptides and poly(nucleic acids), where pendant
side chains distinguish one monomer from another. In
polypeptides, the sequencing leads to diverse structures and
functions that are vital to life, including material architec-
tures, biocatalysis, molecular recognition, and transport
across membranes. Sequence in polymers was discussed in
a critical review by Lutz et al. in 2013, including discussions of
relevance to materials science.[1b] Some sequence-defined
oligomers and polymers fold into conformational structures
such as helices, and hence are called “foldamers”, which have
potential applications in materials science, catalysis, and
molecular recognition.[2]
Construction of synthetic poly(peptides) using biomolec-
ular machinery, solution synthesis, or solid-phase synthesis, is
well-established.[1b] Synthetic sequence-defined polymers
blocks and dithiols in
a
fluorous-assisted synthesis
approach.[1q] In this case, amide bond formation is not used
for chain extension reactions, but is present in the backbone.
A number of these recent approaches for sequence-defined
polymers were described by Lutz in 2015 in a review on
iterative approaches without protecting groups.[1m] Recently,
a unique photochemical strategy for defining sequence in
polymers, with a thermal deprotection step, was described and
[*] Dr. J. W. Grate, Dr. K.-F. Mo, Dr. M. D. Daily
Pacific Northwest National Laboratory
P.O. Box 999, Richland, WA 99352 (USA)
E-mail: jwgrate@pnnl.gov
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201509864.
demonstrated with symmetrical sequencing (BA)C(AB)n.[1r]
n
Gutekunst and Hawker described a relay metathesis method
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modifications or adaptations are made.
to polymerize sequence-defined macromonomers.[1s]
Here we introduce a new macromolecular architecture,
based on the nucleophilic aromatic substitution chemistry of
cyanuric chloride, that we call TZPs, for triazine-based
polymers. Selected examples shown in Scheme 1 illustrate
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Scheme 2. Submonomer solid-phase synthesis of a triazine-based
polymer.
Diverse side-chain functionalized molecular precursors
and monomers can be prepared taking advantage of the
stepwise reactivity in the nucleophilic aromatic substitution of
the three chlorine atoms of cyanuric chloride, a cheap
industrial chemical. Each substitution deactivates remaining
sites such that higher temperatures are required for each
substitution around the ring,[5] from À20 to 58C for first
reaction, rising from 188C to 358C for the next reaction, and
temperatures above 608C for the third. Degrees of substitu-
tion, and substitution with two or three different substituents,
are both readily controlled. Accordingly, we have synthesized
a variety of molecular precursors, including those indicated as
5a–f in Scheme 2, as well as additional precursors, monomers,
and protected monomers described in the Supporting Infor-
mation.
While a variety of polymer syntheses can follow from
these types of molecules, we were inspired by the submo-
nomer method for peptoids[3] to develop a submonomer
approach for sequence-defined TZPs, shown in Scheme 2.
This approach does not require any protecting groups in the
main chain assembly, and it takes advantage of the sequential
reactivity of triazine chlorine substituents to provide control.
The solid-phase method has the potential for automation. The
monosubstituted triazine ring submonomer 5 reacts at room
temperature or slightly elevated temperatures (358C), while
the linker section, using ethylene diamine in 20-fold excess,
reacts with the remaining chlorine-substituted site at elevated
temperatures, typically 808C. Use of the 358C temperature
for the addition of 5 enables shorter reaction times than at
room temperature. In this reaction, the submonomer begins
with two identical reaction sites, but the second of these
becomes different after the first is substituted. Rink amide
resin was selected for our synthetic scheme because the tether
chemistry is stable to the synthesis conditions. The release of
final product from the resin can be achieved using 50%
trifluoroacetic acid (TFA) in dichloromethane. (For detailed
methods and characterization of products, see the Supporting
Information.) For TZP 2, using monomer 5c, the crude
product was purified by reversed-phase HPLC on an ana-
lytical C-18 column to give, after evaporation of solvents
under reduced pressure, an amorphous white solid (35 mg,
43%, based on initial loading of the resin). The product was
characterized by HRMS, found m/z: 1776.3343, calcd for
[M+H]+/C72H75Cl6N31S6, 1776.3350.
Scheme 1. Triazine-based polymers.
a general architecture, 1, a homopolymer of defined length, 2,
and two sequence-defined heteropolymers, 3 and 4. There
have been a few reports describing triazine chemistry to make
pseudo-amino acids for incorporation into oligomeric pep-
tides.[4] In one case, the peptides were constructed entirely of
triazine-based pseudo-amino acids with different side chains
into small cyclic peptides containing up to four monomers.[4b]
Our architecture is distinct from peptides based on triazine-
containing pseudo-amino acids and amide bond chemistry.
We show that these new polymers meet three require-
ments for a new biomimetic sequence-defined architecture:
1) diverse side-chain-functionalized monomer units can be
prepared, 2) the units can be sequenced into chains, and
3) potential backbone–backbone interactions exist that could
influence conformational folding or intermolecular assembly.
The pendant Y-R groups in the general structure 1 are side
chains, while W-L-Z sections connecting triazine rings in the
backbone will be called linkers. The generalized atoms Y, W,
and Z are typically heteroatoms derived from reactive amines
or thiols.
A submonomer synthesis method, shown in Scheme 2,
provides a solid-phase iterative method to define sequence.
Linkers in Scheme 2 and the examples 2–4 are all ethylene
diamine, but need not be. The submonomer method for TZPs
supports sequence definition in both the Y-R side chains and
the W-L-Z backbone linker sections. Groups labeled Tand Te
are terminal groups, where T can be an amine arising from
cleavage from the Rink amide solid phase, and Te is typically
a hydrogen atom on an unreacted end of a linker. In another
variation, not shown, the terminal end may be another amine
group arising from final displacement of the last ring chloride
with ammonium hydroxide rather than adding a final linker.
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TZP 3 was prepared using triazine compounds 5a, 5b and
5c in a defined sequence. The crude product was purified by
reversed-phase HPLC (Figure 1) on a semipreparative C-18
column to give, after evaporation of solvents under reduced
pressure, 3 (48 mg, 75%, based on initial loading of the resin)
as an amorphous white solid. The high-resolution mass
spectrum of compound 3 (Figure 2) clearly shows the multiply
Figure 3. 1H NMR spectra (500 MHz) of TZPs 3 (upper) and 4
(bottom) in deuterated methanol.
Figure 1. HPLC chromatogram of crude and pure TZP 3.
Figure 2. High-resolution mass spectrum and isotopic pattern of TZP
3. The expanded spectrum shows the adduct [M+H]+.
charged adducts and we found that the observed m/z of the
parent [M+H]+ adduct (molecular formula C55H70ClN31S6) is
1392.4537 which agrees well with the calculated value. TZP 4
was prepared to demonstrate the ability to append side chains
with ionizable groups such as amines or carboxylic acids, as
would be desired for a truly biomimetic polymer architecture.
These were achieved using protected R groups, such as a tBu
ester-protected carboxylic acid in 5d, and the Boc-protected
(Boc = tert-butoxycarbonyl) amino group in 5e. Both of these
protecting groups remain on the functional group under the
conditions of polymer synthesis, while cleaving in one step
when the polymers are released from the Rink amide resin
with TFA. We obtained 4 (19 mg, 31%, based on initial
loading of the resin) as an amorphous white solid. After
purification, characterization by HRMS found m/z:
1348.5527, calcd [M+H]+ C49H74ClN35O4S3: 1348.5586.
Figure 4. Tandem MS spectra of the [M+H]+ adduct of TZPs 3 (upper)
and 4 (bottom). Fragments from breaking triazine rings(T) are
indicated by ring number and left(L) or right(R) fragments. See the
Supporting Information for details.
chain content of the synthesized structures. The relative peak
areas and assignments in Figure 3 show that the prepared
TZPs have the intended content. Tandem mass spectrome-
try[6] of TZPs 3 and 4, shown in Figure 4, confirm that the
monomers are in the intended order. Bond breaking of the
The presence of various side chains in the sequence-
defined TZPs 3 and 4 can be verified by NMR spectroscopy as
shown in Figure 3. The triazine groups have no protons and
the linkers have only methylene groups. Therefore, the NMR
spectra of TZPs with diverse side chains show peaks with
chemical shifts and integrated areas indicative of the side-
À
TZPs occurs between the aliphatic C N bonds in ethylene
diamine linkers, and by degradation of the triazine rings to
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Table 1: Calculated and observed masses of M and N fragment ions from
sequence-defined TZPs 3 and 4 obtained by tandem mass spectrometry.
TZP 3
TZP 4
calculated
198.0808
241.1230
491.1310
486.1965
683.2700
736.2045
933.2780
928.3435
1178.3515
1221.3837
1375.4251
observed
198.0797
241.1222
491.1325
486.1974
683.2698
736.2055
933.2786
928.3423
1178.3551
1221.3851
1375.4252
calculated
198.0808
268.1516
491.1310
463.2749
715.2332
660.3480
912.3067
884.4506
1107.4294
1177.5008
1331.5315
observed
198.0796
268.1515
491.1323
463.2753
715.2329
660.3484
912.3060
884.4386
1107.4299
not found
1331.5349
M1
N1
M2
N2
M3
N3
M4
N4
M5
N5
M6
give predictable fragments, the vast majority of which are
found. The mass spectra are shown in Figure 4, while the
expected and observed masses for the M and N fragments
(indicated by the arrows in Figure 4) are in Table 1. The
complementary fragments to the indicated M and N frag-
ments are typically much less intense but are found (see the
Supporting Information). Fragments from degradation and
cleavage at triazine rings, dubbed T, are observed from both
sides of the ring (indicate by L or R); more on these
T fragments is given in the Supporting Information. In
addition, some peaks are seen corresponding to the loss of
a side chain from the parent ion. The NMR and tandem MS
data for each sequence-defined TZP confirm that the
intended structures and sequences were actually synthesized.
The Supporting Information presents additional synthesis
examples and approaches, as well as detailed experimental
methods and characterization. This content includes a 12-mer
synthesis by the submomomer method, an alternative syn-
thesis approach using protected monomers as proof of
principle, and various additional conceptual synthetic
schemes for sequenced polymers from triazine-based molec-
ular precursors.
Figure 5. MD simulations of a) two tetramers and b) two trimers
interacting by hydrogen bonding and pi–pi interactions. Side chains
are S-ethyl, and nonpolar hydrogen atoms are not shown.
Given that the new TZP polymers are synthetically
accessible, we have performed molecular dynamics (MD)
simulations, revealing a variety of possible hydrogen-bonding
motifs as well as pi–pi interactions. Detailed methods and
additional examples are given in the Supporting Information.
Figure 5a shows the simulation of two interacting all-trans
tetramers, after two tetramers with S-ethyl side chains were
started in extended conformations in explicit solvent (see the
Supporting Information). Parameters for the triazine residues
and linkers were generated using the generalized amber force
field (GAFF) and the programs ACPYPE and Ante-cham-
ber,[7] and the simulation was carried out for 500 ns using
GROMACS4.6.4.[8] The found conformer, which represents
28.2% of population, shows 1) single hydrogen bonds
between ring nitrogen atoms and linker amino hydrogen
atoms that occur between the two chains (e.g. 2.3 Š), 2) single
hydrogen bonds connecting a ring nitrogen to the distal amino
group of an immediate linker section, stabilizing a turn (e.g.
2.2 Š), 3) pairs of hydrogen bonds between chains involving
ring nitrogen atoms and the adjacent amino group on one
Figure 6. Backbone–backbone hydrogen-bonding motifs found in
molecular dynamics simulations of triazine-based polymers. Paired
hydrogen bonds in DNA and peptide beta sheets are shown for
comparison.
chain interacting with the corresponding atoms of the other
chain in an antiparallel fashion (e.g. 2.0 and 2.2 Š, as well as
2.1 and 2.0 Š), and 4) interchain pi–pi interactions with ring–
ring distances of less than 4 Š. Turn and paired hydrogen
bonds are shown in Figure 6. The paired hydrogen bonds
indicate an intrinsic self-complementarity in this polymer
architecture, when the linker sections are derived from
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amino-based nucleophiles that leave an alpha-amino group
defined architecture and synthetic methodology will thus be
attached to the triazine ring.
enabling for new macromolecules and materials with useful
functions.
Simulation of two interacting all-cis trimers, shown in
Figure 5b, revealed a more extended pattern of cross-strand
paired hydrogen bonds (1.9–2.2 Š) and pi–pi interactions
(< 4 Š). The found conformer, which represents 100% of
population, is a nanorod with a repeating pattern of side
chains with a periodicity of 11–12 Š, where central rings on
each strand are stabilized by two pairs of hydrogen bonds and
a pi–pi interaction. In addition, as described in more detail in
the Supporting Information, this type of structure is inde-
pendently observed in folding of a related hexamer. When the
nanorod structure is extended to a dimer of pentamers, it
remains stable thereafter for 500 ns of explicit solvent
simulations.
Acknowledgements
This research was supported as part of the Materials Synthesis
and Simulation across Scales (MS3) initiative by the Labo-
ratory Directed Research and Development program at
Pacific Northwest National Laboratory (PNNL), a multi-
program national laboratory operated by Battelle for the U.S.
Department of Energy(DOE).
Keywords: biomimetics · macromolecules ·
The simulations show the possibilities for multiple back-
bone–backbone interactions, and hence potential conforma-
tional behavior of single macromolecules or self-assembly
between macromolecules. The paired hydrogen bonds are
reminiscent base-pair interactions in DNA, and also the pairs
of hydrogen bonds along interacting peptide strands in beta
sheets (Figure 6). The regularity and three-dimensional
ordering of side chains along the nanorod are reminiscent of
the side chains projecting from the outer surfaces of peptide
alpha-helix samples found in the literature on molecular
recognition and foldamers indicating that structures with
pyridine, pyrimidine or triazine architectures may be
expected to participate in hydrogen-bonding interactions,
create helical foldamers, or assemble into ribbons.[9] Paired
hydrogen bonds, consisting of complementary ring nitrogen
atoms and the protons on alpha-amino groups, as seen in our
simulations and shown in Figure 6, are present in examples of
triazine-containing self-complementary molecules and tria-
zine-containing oligomers that self-assemble into ribbons or
tapes.[9d,e] (Opportunities afforded by arrangements of multi-
ple hydrogen bonds in assembly processes and polymers have
been reviewed.[10]) Therefore, our simulations, in combination
with past experimental work on related structures, support
the idea that these new triazine-based sequence-defined
polymers have the potential for conformational structure or
self-assembly behavior because of backbone–backbone inter-
actions. We may anticipate that side-chain structures and
sequences may modulate the assembly processes.
This report describes the first general approach for
converting cyanuric chloride to side-chain functionalized
sequence-defined polymers, creating an architecture that is
distinctive from other sequence-defined polymer architec-
tures in nature or synthesis. The submonomer approach offers
tremendous opportunity for structural diversity, synthetically
varying and sequencing both the side chains and the linkers.
Heteroatoms can be selected that participate in hydrogen
bonding (NH), or those that do not (S), thus enabling or
limiting backbone/backbone interactions. As succinctly put
by Archer and Krische, “The capability of defining structure
carries with it the potential to engineer functionality”.[9d] The
simulations show that noncovalent interactions are available
that are similar to those in biopolymers, foldamers, and self-
assembled ribbons. The backbone has no readily hydrolyzed
structures such as esters or peptide bonds. This new sequence-
sequence-defined polymers · simulations · solid-phase synthesis
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Published online: February 10, 2016
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