View Article Online

Polymer
View Journal

Chemistry
Accepted Manuscript

This article can be cited before page numbers have been issued, to do this please use: P. Nanjan and M.
Porel, Polym. Chem., 2019, DOI: 10.1039/C9PY00886A.
Volume 8
This is an Accepted Manuscript, which has been through the
Polymer
Number 25
21 September 2017
Pages 5255-5446
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemistry Accepted Manuscripts are published online shortly after acceptance,
rsc.li/polymers

before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.

You can find more information about Accepted Manuscripts in the

Information for Authors.

Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
ISSN 1759-9962 Terms & Conditions and the Ethical guidelines still apply. In no event
PAPER
Huiyuan Wang, Yongzhuo Huang et al.
A mannosylated PEI–CPP hybrid for TRAIL gene targeting
shall the Royal Society of Chemistry be held responsible for any errors
delivery for colorectal cancer therapy

or omissions in this Accepted Manuscript or any consequences arising

from the use of any information it contains.

rsc.li/polymers
 Page 1 of 22 PleasePolymer
do not Chemistry
adjust margins

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

Sequence-defined Non-natural Polymers: Synthesis and

Polymer Chemistry Accepted Manuscript

Applications
Received 00th January 20xx,
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Accepted 00th January 20xx Pandurangan Nanjan and Mintu Porel*

DOI: 10.1039/x0xx00000x
Precise control over the monomer sequence on a polymer backbone, resulting a sequence-defined polymer
(SDP), is a crucial parameter for tuning their structures, properties, and functions. The examples of natural
SDPs are the proteins and nucleic acids that possess the structural and functional complexity to live a life. A
highly sophisticated machinery has evolved in the living organisms for the de-novo synthesis of natural SDPs.
However, absolute control on the monomer sequence in a non-natural polymer is still challenging. In
comparison to biopolymers, non-natural SDP has an even wider scope of unlimited functional side-chains as
well as backbone diversity. Hence, SDP is a perfect platform for generating extensive structural complexity
such as self-assembly into nanostructures, folding, the formation of stimuli-responsive sites, catalytic sites,
etc. In this review, we have penned down the current status of the SDPs that holds tremendous potential for
future research and development. This review seeks to draw attention to the development of non-natural
SDPs via innovative synthetic routes established in the recent past. Followed by the synthesis and
characterization, the next obvious step to move the field forward is to explore SDP for potential applications.
Hence this review is divided into two parts: (i) diversified synthetic strategy of SDP (ii) applications of SDPs in
the material and biomedical sciences. This field is progressing rapidly; there are immense possibilities for
exploring different chemical reactions to develop novel classes of SDP, and many potential application
opportunities are there via pre-determined sequence in synthetic polymer.

1. INTRODUCTION properties. The structural properties determine the bulk

properties of a material such as elasticity, solubility,
Sequence control in the synthetic polymers is important for
conductivity, biocompatibility, etc7. Hence, understanding and
modulating their structure, properties and functions and
mastering the principle that rules the properties of the
hence has added renewed interest in the recent past 1,2. The
materials is crucial for the future generation of materials. The
inspiration for developing synthetic sequence-defined
secondary and tertiary structure of the biopolymers develops
polymers (SDP) comes from the nature as the major part of a
from the non-covalent interaction between backbones and
living system is made of sequence-defined biopolymers such as
side chain residues. Hence functional groups of both the
proteins and nucleic acids. Monomeric sequence is the prime
backbone and side chain are important to tune the structure of
factor leading to the structural complexity and self-assembly
a macromolecule. Thus, development of novel
property of biopolymers, and eventually rewarding them with
macromolecular backbone with sequence-specific side-chain
diverse functional aspects such as biocatalysis3, information
arrangement is instrumental for developing materials with
storage/transport4, molecular recognition5 etc. For example,
tuneable properties.
~20,000 genes have been identified in the human physiology
(through Human Genome Project)6 with the option of four
nucleotide-monomers (guanine, adenine, thymine/uracil and
cytosine) and one kind of backbone. An efficient human
system can generate more than one million different proteins
utilizing those genes. Compared to the natural SDP, non-
natural synthetic SDP has even broader scope for backbone
and pendant functionality to manipulate its structure and Figure 1. Differences between the peptide and peptoid backbones8,9.

The seminal discovery in this field is sequence-defined peptoid

(Fig. 1) which is a peptidomimetic polymer with

Discipline of Chemistry, Indian Institute of Technology Palakkad, Kerala-

678557, India.

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 2 of 22

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Figure 2. Syntheses of different SDP through solid-supported methodologies.

Scheme 1. Synthesis of oligothiophenes by Stille coupling reaction19.

N-substituted amide backbone whereas natural peptide has C- enzymatic stability9-15. Considering this example, it is obvious
substituted amide backbone8,9. This small change in the that in addition to diverse functionality at the pendant group,
backbone has been proven to have a high impact in backbone diversity in a macromolecule is also essential to tune
overcoming many challenges posed by peptides such as their properties and functions. Non-natural SDP has unique

Please do not adjust margins

 Page 3 of 22 PleasePolymer
do not Chemistry
adjust margins
Journal Name
advantages such as access to unlimited functionalities, better
environmental and biological stability, flexible chemical and
physical properties via modular functional groups and
economical synthetic route. However, it is indeed a synthetic
challenge to precisely control the sequence of monomer in a
growing polymer chain. Several research groups are trying to
overcome this challenge by developing new classes of SDP
through their potential synthetic strategies. Here we would
like to draw readers’ attention towards two terminologies in
this field: sequence-controlled polymer (SCP) and sequence-
defined polymer (SDP) which will be employed frequently in
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.
this review16. In SDP, the sequence of monomer is controlled
to some degree and this control can be absolute but not
necessarily. SDP is a subclass of SCP. In SDP, the sequence of
monomer is absolutely defined with an exact chain length.
We have attempted to cover three main categories of
synthetic strategy: i) solid-supported synthesis, ii) soluble-
supported synthesis and iii) support-free synthesis. In addition
to the diverse pendant functional groups, this account pays
attention to the different backbones of SDP generated by
different methods. The functional group of SDP-backbone is
dependent on the reaction performed to assemble the
building blocks. Hence diversity of backbones is coupled with
the diversity of synthetic methods. As the inspiration of non-
natural SDP comes from the natural SDP such as a peptide,
until recently, most of the synthetic SDP have a peptide-type
backbone by virtue of having amide bonds. Realizing the
importance of different backbone of a polymer for tuning its
properties, additional bond-forming reactions are being
investigated to create new polymer architectures. All these
different classes of SDP-backbones, their synthesis, physical
properties, and applications have been detailed here. The
advantages, as well as limitations of each synthetic method
and the important features of the backbones and their
applications, have been mentioned in each section. The last
part of this review highlights the recent applications of SDPs in
wide fields from material to biomedical sciences including
coding and decoding systems, anti-bacterial, anti-
inflammatory, gene-delivering system, anti-proteases
applications, etc. We have detailed here how the structure and
properties of a specific class of SDP contribute for a specific
application and the effect of monomer sequence to improve
the activity for each case.
2. SDP-BACKBONE DIVERSITY COUPLED WITH
SYNTHETIC STRATEGY
This section covers three major synthetic strategies for SDP: (i)
solid-supported synthesis, (ii) soluble-supported synthesis and
(iii) support-free synthesis.
2.1. SDP by solid-supported synthesis
Solid-supported synthesis is a conventional and powerful
technique for polymer syntheses17. The pioneer contribution
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ARTICLE
View Article Online
of Merrifield for polypeptide synthesis DOI:brought
10.1039/C9PY00886A
a major
paradigm shift in the area of polymer methodology18. Solid-
supported synthesis has advantages to remove excess starting
materials, reagents and undesired intermediates in the
synthesis by washing. In this section, we have covered
different solid-supported methodologies for the preparation of
SDP. Fig. 2 represents an overall picture of different backbones
developed through solid-supported methodologies.
2.1.1. Sequence-defined oligothiophenes
Polymer Chemistry Accepted Manuscript
Solid-supported synthesis of sequence-defined asymmetric
oligothiophenes19 was first reported by Frechet et al.
Oligothiophenes are one of the important class of compounds
which was found to have different optical and electronic
properties20. Additionally, it is also environmentally stable
both in normal and oxidized states. Sequence-defined
oligothiophene backbone was achieved by utilizing a Stille
coupling reaction (Scheme 1). Thiophene scaffolds were
prepared using brominated thiophene and a trimethyl stannyl
compound in presence of palladium catalyst. Bromination was
performed at each step so that self-polymerization can be
avoided. Thus, monodisperse oligothiophenes were
synthesized successfully through Stille coupling and
bromination reaction sequences. By utilizing this method, up
to 5-mer has been synthesized efficiently with good purity.
These rigid oligothiophenes show better solubility and optical
properties19. In this method, the solid support was prepared by
the nucleophilic displacement reaction of 2,2-bithiophene-5-
carboxylic acid and macroporous Merrifield-type
chloromethylated resin.
2.1.2. Multifunctional polyamidoamines
Polyamidoamine (PAA), peptidomimetic polymers, show
inherent immunogenicity and reduced cyto- and hemo-toxicity
in vivo21. Additionally, these compounds are often utilized for
aggregation purposes due to their structural diversity. Hence,
PAA can be used as nano carriers. PAAs were synthesized at
multigram scale by the sequential addition-reaction of succinic
acid and diamines on a solid-support (Scheme 2)22. The fully
automated peptide synthesizer was used for this methodology
and upto 10-mer PAA was synthesized without any side
reaction. The synthesis of PAA is designed in such a way that
the backbone can be readily tuned with the wide range of
available diamine derivatives.
2.1.3. Sequence-defined Polymers with Polypeptoid Block
Copolymer
A unique class of sequence-defined block copolymer has been
synthesized via azide-alkyne “Click reaction” between azide
functionalized polybutyl acrylate and alkyne functionalized
polypeptoids with 2-methoxyethyl side chains (Scheme 3)23.
Copolymerization resulted in lowering the aggregation and
hence order-disorder properties of the polymer were also
reduced. Due to this advantage, polymers comprised of 18 to
48 monomers were efficiently prepared without much
J. Name ., 2013, 00, 1 -3 | 3
 PleasePolymer
do not Chemistry
adjust margins Page 4 of 22

ARTICLE Journal Name

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 2. Synthesis of polyamidoamines through aminolysis and coupling strategies22.

Scheme 3. Sequence-defined polymers on polypeptoid block copolymer by Click chemistry23.

difficulty. Further, chiral functionalities have been
incorporated in the polypeptoid backbone to assess if it has
any effect on secondary structures. Results suggested that
chirality does influence the secondary structure for the specific
type of interactions.
2.1.4. SDP with amide-thioether backbone
Espeel et al., developed a two-step iterative strategy
(aminolysis followed by Michael addition) for the synthesis of
amide-thioether based polymer by utilizing thiolactone
building blocks on a solid-support (2-chlorotrityl resin)
(Scheme 4)24,25. The first step involves the aminolysis of cyclic
thioether via releasing a thiol for subsequent Michael addition
reactions24,25. Triphenylphosphine catalyst played a dual role:
i) reduced the disulfide bond formation and ii) improved the
Michael addition reaction. Though it works perfectly fine up to
3-4 monomers, but in the case of higher degree polymers the
reaction became slower. This difficulty was further overcome
by carrying out the reaction under microwave conditions 24,25.
2.1.5. SDP with triazine based scaffold
Grate et al., have established a solid-supported triazine-based
SDP scaffold to mimic backbone-backbone interaction of

4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 5 of 22 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 4. Chemo-selective synthesis of oligomer with amide-thioether backbone24,25.

Scheme 5. Synthesis of sequence-defined oligotriazine polymers26.

biopolymers26. This method provides a macromolecule based
on aromatic nucleophilic substitution of cyanuric chloride.
Triazine moiety has unique structural properties which can be
used to control the substitution reactions. For example, the
first substitution was performed in <5 oC (Scheme 5)26. After
the first substitution, the system is deactivated and the next
substitution cannot be performed at the same temperature.
The second substitution was performed at room temperature.
Similarly, the third substitution was only possible at a higher
temperature (>80oC). The novelty of this backbone is that it
has the ability to form backbone-backbone interaction like
biopolymers, but stable under a harsh condition which is not
possible with the normal biopolymers.
2.1.6. Sequence-defined oligoazidopeptides from natural and
synthetic building blocks
sequence-defined oligoazidopeptides27 have been synthesized
by using natural (i.e. amino-acids) and synthetic building
blocks. An azido-amino acid was synthesized by reacting a
resin supported amino acid with an azido-acid via spacer chain
such as acetyl, hexyl, isobutyl and methyl propionyl
derivatives27 (Scheme 6). Thereafter, copper-assisted Click
reaction was performed with the supported azide group and
amine terminal alkyne. The azido-peptides were prepared via
repetition of amide formation followed by Click reactions
(Scheme 6). The azido-peptides provide not only flexibility to
the polymer, but also it is used to generate spacing between
controlled insertions of amino-acids residues.

This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00, 1 -3 | 5

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 6 of 22

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 6. Synthesis of sequence-defined oligoazidopeptides27.

Figure 3. Soluble-supported synthesis.

Please do not adjust margins

 Page 7 of 22 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

View Article Online

2.2. SDP-backbone via soluble-supported polymer
synthesis
The soluble support has unique advantages such as complete
miscibility of supported substrate with the reactants which
improves the reaction rate and ease of stepwise monitoring
the reactions by analytical tools. The SDP-backbones which are
developed through soluble-supported reactions are compiled
in Fig. 3.
DOI: 10.1039/C9PY00886A
methods focus on diverse pendant group and having less
access on modulating the backbone, this method allows
generating SDP with a wide variety of backbone diversity.
2.2.2. Sequence-defined oligo(phosphodiester)s
Sequence-defined oligo(phosphodiester)s was prepared
through the iterative phosphorylation on styrene-based
soluble-support. This strategy was developed based on a
three-step cycle: (i) coupling of the hydroxyl with a

Polymer Chemistry Accepted Manuscript

2.2.1. Sequence-defined oligo azido-amides by soluble- phosphoramidite monomer, (ii) oxidation of the phosphite into
support a phosphate, (iii) deprotection of a resin-bound hydroxyl group
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Lutz group has reported a soluble-supported synthesis for
sequence-defined oligoazidoamides by utilizing chemo-
selective reactions28. The method involves two chemo-
selective reactions (azide-alkyne Click reaction and amide
formation) on styrene based soluble-support. This method was
developed by a strategic design of two monomers: (i) alkyne
terminal acid and (ii) azide terminal amine (Scheme 7). This
class of SDP was synthesized via consequence reaction of
soluble-supported azide with an acid terminal alkyne.
Thereafter the acid group was amidified with the amine group
of azide terminal amine monomer28. While other synthetic
(Scheme 8)29. The products can be generated even at minute
time scale with high yield by utilizing this methodology. As a
result, sequence-defined polynucleotides containing >100
residues have been synthesized. This methodology employs
two reactive phosphoramidite monomers: (i) 2-cyanoethyl (3-
dimethoxytrityloxy-propyl) diisopropylphosphoramidite, and ii)
2-cyanoethyl (3-dimethoxytrityloxy-2,2-dimethyl-propyl)
diisopropylphosphoramidite.

Scheme 7. Synthesis of oligoazidoamides28.

This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00, 1 -3 | 7

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 8 of 22

ARTICLE Journal Name

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 8. Synthesis of sequence-defined oligo(phosphodiester)s29.

Scheme 9. Synthesis of oligoetheramides through orthogonal reactions30.

8 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 9 of 22 PleasePolymer
do not Chemistry
adjust margins

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

2.2.3. Sequence-defined oligothioetharamides by soluble hydroxyproline which was synthesized by coupling of the
fluorous support fluorous-Cbz-NHS ester with hydroxyproline (Scheme 10)34.
Porel et al., reported a unique soluble-supported strategy to The next substituted hydroxyproline was attached in SDP by

Polymer Chemistry Accepted Manuscript

achieve the polymerization reaction in a controlled way via amidation in the presence of carbonyldiimidazole. Monomer
utilizing orthogonal organic reactions 30-33. The two important coupling condition was optimized for complete conversion by
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

aspects of this strategy (Scheme 9) are: (i) soluble fluorous the addition of excess monomer at each step (Scheme 10).

Scheme 10. Oligohydroxy-proline polymers by amidation and coupling strategies34.

support was introduced for the first time for SDP synthesis and
(ii) a unique monomer was designed and synthesized namely
allyl-acrylamide monomer. Rationale behind the design of
allyl-acrylamide monomer is while the allyl group performs the
photoinduced thiol-ene reaction with a thiol, the acryloyl
group undergoes Michael addition with a thiol and both the
reactions are rapid and quantitative (quantitative yield in 1.5
min and 5 min for thiol-ene and Michael addition respectively).
As both the reaction requires thiol, a dithiol was chosen as a
co-monomer for this strategy. Fluorous support was efficient
to maintain fast solution kinetics and purification was also
rapid by the virtue off fluorous solid phase extraction. After
repeating the desired cycle of the abovementioned two
reactions, the final oligoetharamide was cleaved from the
fluorous support via acid cleavage of the perfluorocarbon alkyl
chain.
2.2.4. Sequence-defined oligomers with proline-based
backbone by fluorous support
Anderson et al., have developed a class of SDP with proline
moiety utilizing fluorous support from hydroxyproline building
blocks. Synthesis began with fluorous-benzyl-protected
2.2.5. Sequence-defined multifunctional polyethers via liquid
phase synthesis
Sequence-defined polyethers have received significant
attraction due to its properties like water solubility,
biocompatibility and stealth effect 35,36. Livingston et al., has
reported a novel soluble phase synthetic strategy coupled with
molecular sieving to synthesize sequence-defined
multifunctional polyethers (Scheme 11)37. This strategy has the
advantage for real-time monitoring to ensure the completion
of each step and quick purification via size-exclusion molecular
sieving to yield pure sequence-defined polyethers. The authors
have shown an efficient approach for site-selective post-
synthetic modification that makes this method versatile to
tune its structure and function. This method has been
developed based on two synthetic aspects i.e. firstly it involves
the utilizing protection-deprotection chemistry37 for the
generation of growing monomer with terminal functional
groups. Second step involves Williamson ether synthesis with
hydroxyl end. The stepwise reactions are outlined in Scheme
11.
2.2.6. Synthesis of sequence-defined vinyl polymers

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 10 of 22

ARTICLE Journal Name

In this report, the authors have established a new class of
sequence-defined vinyl polymers38. The method involves
iterative atom transfer radical addition (ATRA) of an allylic
alcohol on vinyl polymer. The synthetic process starts with the
activation of C-Br of the chain via ATRA. Then, the oxidation of
alcohol performed to achieve carboxylic acid followed by
esterification leading to the reactive synthon which can be
reactivated via ATRA reaction. The sequence-defined vinylic
View Article Online
DOI:same
polymer was synthesized by repeating the 10.1039/C9PY00886A
sequence of
orthogonality reactions (Scheme 12). Additionally, the
synthesized polymer can be easily purified due to their large
polarity differences between the product and impurities.
Poly(methyl-acrylate) (PMA) was used as a soluble-support38.

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 11. Synthesis of multi-functional PEG-based sequence-defined polymers37.

10 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 11 of 22 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 12. Synthesis of sequence-defined vinyl polymer38.

Scheme 13. Synthesis of sequence-defined peptoid39.

2.3 SDP backbone by support-free polymer synthesis
Support-free methodologies were developed without solid or
soluble support; hence they are free from any limitation
arising from support. The backbones developed based on the
support-free methods are mentioned below (Fig. 4).
2.3.1. Synthesis of peptoids, peptidomimetic SDP, through
iterative Ugi reactions.
Peptoids were synthesized via de nova design and iterative Ugi
four-component reactions (Scheme 13)39. The pre-designed
peptoids were synthesized from amino acid- a dual synthon
i.e. amine and acid which sequentially react with an aldehyde
and an isocyanide. This synthetic strategy is soluble-supported,
scalable and versatile to different functional groups.
Additionally, the coupling strategy was introduced in Ugi
reaction to achieve structural diversity of peptoids. Further, it
has also been extended for the incorporation of DNA with
sequence-defined peptoid39 which can potentially be applied
to the area of drug delivery. This could be a unique strategy
which can provide structural versatility on both the backbone
and pendant groups. Peptoids have been able to solve several
limitations for therapeutical applications of peptide.
2.3.2. SDP with a multifunctional backbone (ester and
thioether)
Oligothioether-ester backbone has been introduced by
Solleder et al., in SDP via Passerini three-component reaction
(P-3CR)40 in combination with thiol-ene reactions41,42. Reaction
of a long chain acid (e.g., stearic acid or acid functionalized
polyethylene glycol) with an aldehyde and desired functional
group substituted cyanide was used for synthesizing sequence-
defined oligothioether-ester (Scheme 14). Thereafter, an acid
terminal thiol reacts with the alkene of the first step product
via thiol-ene reaction. Each step was purified by precipitation
via polyethylene glycol group or the starting long chain. This is
a protection group-free strategy and multiple side chains have
been shown to get attached on this class of SDP.
2.3.3. Photoinitiated reactions for multifunctional SDP

This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1 -3 | 11

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 12 of 22

ARTICLE Journal Name

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Figure 4. Backbones developed through support-free strategies.

Scheme 14. Synthesis of sequence-defined oligomer by Passerini/thiol-ene reactions41.

You et al., designed a one-pot reaction for sequence-ordered
copolymers involving three-component reactions such as
photoinitiated thiol-ene, acryloyl-thiol Michael addition, and
ring opening of thiolactone by an amine43. The strategy
employs three types of monomers: ethylene dimethacrylate
(A), amine substituted thiol (B), and thiolactone (C). Michael
addition of aminothiols was carried out with acrylate and
methacrylate. Methacrylate does not react with amines
without a catalyst, but reacts with thiols quantitatively, even
under catalyst-free conditions. Taking advantage of these
selective reactions and susceptibility of amine for aminolysis of
thiolactones, an ABC-sequenced oligomer was synthesized
efficiently (Scheme 15). Then photoinduced reaction of the
free thiol with the alkene moved to the next step of
polymerization (Scheme 15). By this support-free one-pot
synthetic strategy, SDP has been synthesized with backbones
including ester, thioether and amide moieties. The amines are
more susceptible for aminolysis of thiolactones (C) and affords
CBABC polymer with thio-end at each side. When a dibromo-
maleimide (D) was added to CBABC sequence, it underwent
highly selective substitution reaction by the thiols yielding a
DCBABCD sequence with a thio-maleimide functional group at
each-end (Scheme 15). Finally, DCBABCD-sequenced

12 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 13 of 22 PleasePolymer
do not Chemistry
adjust margins

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Scheme 15. Photo-initiated multi-functional SDP43.

Scheme 16. Photo-initiated orthogonal reactions for sequence-defined phthalimide-based SDP44.

Scheme 17. Xanthate-based polymers via RAFT-mediated reaction46.

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 14 of 22

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

copolymer was prepared by the nucleophilic addition of of concept has been demonstrated via the isolation of
amines on thiomaleimide. Utilizing this strategy, ABC-, intermediate products. Based on this approach, it is possible to
CBABCD-, and DCBABCD sequence ordered copolymers were develop SDP through photoligation reactions 44.

Polymer Chemistry Accepted Manuscript

prepared43. 2.3.5. Sequence-defined functional polymers with xanthate
2.3.4. Sequence-defined phthalimide-based polymers backbone via RAFT-mediated reactions
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

A unique class of SDP was synthesized by a new photo-ligation
reaction strategy through bifunctional orthogonal reactions
(Scheme 16)44,45. The monomers were designed based on the
selective photochemical reaction by utilizing complementary
dienophile/diene molecules. The reaction starts with
photoactive bifunctional monomers, i.e. a photoenol or a
phenacylsulfide respectively, and a diene or dienophilic unit.
An open chain diene is reacted with a photoenol, whereas a
dienophile releasing phenacylsulfide is reacted with a
dienophile (furan protected maleimide function) (Scheme 16).
The synthetic key making this concept feasible is the
orthogonality i.e. the non-reactivity of the diene and the
activated dienophile not undergoing a ligation process and are
distinctly addressable via photochemical methods. The proof
A catalyst-free strategy for single unit monomer insertion
(SUMI) into reversible addition-fragmentation chain transfer
(RAFT) agents has been developed through photo-initiated
reaction at low-intensity visible light 46,47. The reported study
demonstrates that catalyst-free photo-SUMI is a versatile
method for a wide range of monomer varieties with high
efficiency. By this strategy, an oligomer consisting of five
different monomers in the defined sequence was successfully
synthesized. The oligomers comprising five defined vinyl
monomers repeat units were produced by an iterative method
through three consecutive SUMI reactions, two intermediate
esterification (coupling reaction) and three thiol-ene additions
(Scheme 17). The scope of this strategy has been expanded to
a wide variety of different substituted monomers including
acrylate, acrylamide and styrenic derivatives.

Scheme 18. Ring-opening metathesis for SDP48.

Scheme 19. Synthesis of SDP via Flow-IEG method49.

Please do not adjust margins

 Page 15 of 22 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

2.3.6. SDPs with multifunctional backbone via ring opening
metathesis of macrocycles
Gutekunst et al., developed a directional iterative strategy to
synthesize SDP by triggering polymer metathesis reactions.
This class of polymers has a unique backbone with multi-
functionality (such as amide, sulfonamide, ester, aliphatic,
aromatic, heterocyclic etc.). The concept was originally
established through regioselective cleavage of functionalized
saccharin48. The key step of this strategy is that the saccharin
was cleaved regio-selectively in the presence of veratrole
2.3.7. Scalable synthesis of SDP through flow-iterative
View Article Online
exponential growth method DOI: 10.1039/C9PY00886A
The effective semi-automated flow technique was developed
by Johnson group for the synthesis of SDP at a multi-gram
scale49,50. A Flow-iterative exponential growth (Flow-IEG)
system was developed allowing “plug and play” monomer
selection which ultimately resulted in the architecturally new
defined polymer in an efficient way. The Click reaction was
utilized for Flow-IEG systems due to its efficiency, chemo-
selectivity, and easy preparation of coupling partners (Scheme

Polymer Chemistry Accepted Manuscript

alcohol and an acid labile protecting group. During this step, 19). Due to the aforementioned advantages of this
sulfonamide anion was generated that was further reacted methodology, it makes the process suitable for large scale
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

with acetoxy-allyl bromide in the same pot to give the desired productions in polymer industries. So far, Flow-IEG is the only
enyne (Scheme 18). Further, the acetate was removed method available for the scalable synthesis of monodispersed
efficiently with sodium methoxide yielding a monoprotected macromolecules that is able to control both sequence and
polymerization trigger. The key advantages of this strategy are architecture individually.
cost-effective, readily accessible reagents and without
requiring column chromatography, the intermediate at each
step was isolated via precipitation or recrystallization.

Scheme 20. Synthesis of sequence-defined oligoether51.

Scheme 21. Synthesis of sequence-defined vinyl polymer52.

This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1 -3 | 15

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 16 of 22

View Article Online

DOI: 10.1039/C9PY00886A

REVIEW

2.3.8. Sequence-defined oligo ether synthesis 2.3.9. Sequence-defined vinyl copolymers by regioselective
A new class of sequence-defined oligo ether was prepared ring-opening strategy
through iterative strategy by utilizing hydroxy-aromatic The ring-opening metathesis was applied for efficient synthesis

Polymer Chemistry Accepted Manuscript

aldehydes and ketones as monomers. This strategy involves of SDPs from multi-substituted cyclooctenes using different
two-step reaction of Mitsunobu coupling and carbonyl Grubbs catalysts52. By introducing substituents region-
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

reduction to provide a protecting-group-free path with high
yield51. Mitsunobu reaction was useful for ether bond
formation since it provides a good activation for primary and
secondary aliphatic alcohols (act as nucleophiles) which was
utilized for the coupling reaction for ethers with different
nucleophiles such as phenols (Scheme 20). The assembly
process was started with Mitsunobu coupling of benzyl alcohol
and the hydroxy-aromatic aldehyde or ketone as a nucleophile
since carbonyl group would not be able to interfere ether bond
formation. After coupling, the carbonyl group was reduced to a
benzylic alcohol functionality for the next cycle of ether bond
formation. Synthesized oligomers were screened for protease
activity and found to inhibit trypsin, chymotrypsin, and
subtilisin in micromolar ranges.
specifically at 3-position of cyclooctenes resulted in the
efficient ring-opening and thus producing highly regio- and
stereo-regular polyalkenamers in Head-to-tail and E-selective
manner (Scheme 21). Further, sequence-defined vinyl
copolymers were synthesized upon selective hydrogenation
using p-toluenesulfonyl hydrazide at higher temperature. The
method also suggested that the stereo-control could be
achieved by the selective incorporation of pre-designed
stereoisomers.
2.3.10. Iterative exponential growth strategy for stereo-
controlled SDPs
The Johnson group have developed a unique iterative
exponential growth strategy (IEG+) to synthesize a new class of

Scheme 22. Iterative strategy for stereo-controlled SDP53.

Scheme 23. Preparation of sequence-defined polylactic acid derivatives54.

Please do not adjust margins

 Page 17 of 22 PleasePolymer
do not Chemistry
adjust margins
Journal Name
stereo-controlled/defined (Scheme 22) SDPs (up to 6 kDa) via
enantiopure epoxides53. The reported method has includes the
following steps: i) a unique chiral monomer (TMS stereo-
controlled/defined (Scheme 22) SDPs (up to 6 kDa) via
enantiopure epoxides53. The reported method has includes the
protected epoxide 1R alkyne), utilized for chemo-selective
substitution by sodium azide reaction to yield azido-1R-alcohol
ii) the synthesized latent functional group-alcohol efficiently
converted into acetate by the reaction of acetic anhydride, iii)
a reactive partner i.e. 1S alkyne was used for the next iterative
step with the product of step i. iv) Coupling reaction of azido-
1R-alcohol and 1S alkyne produced the first generation dimer
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.
with a desired side-chain reactive functionality. Further the
reaction sequence was repeated with steps i to iv constitute an
IEG+ cycle which introduces a new side-chain group (Scheme
22). Additionally, the selective deprotection of acetate enables
the polyhydroxy functionality which is ultimately soluble in
water enhancing the scope of biomedical applications.
2.3.11. Sequence-defined polylactic acid derivatives
A series of sequence-defined polylactic acids have been
synthesized via ester formation by hydroxy and acid groups in
presence of 1,3-diisopropylcarbodiimide (DIC) and 4-
(dimethylamino)pyridinium p-toluene sulfonate (DPTS) and
sequential protection and deprotection chemistry (Scheme
23). Further, it was analyzed for anti-inflammatory activity 54
which was detailed in the application section.
3. APPLICATIONS OF SYNTHETIC SDP
In this section, we aim to highlight the recent applications of
non-natural SDP. These examples will pave the path for the
next generation of polymer science.
3.1 SDP as information storage via coding system
Genetic information is stored in DNA via sequence of four
nucleic acids (four codes) and similarly, a computer binary
language utilizing two different codes. Inspired by nature, Lutz
group has developed information storage in the SDP which
was designed and synthesized to encode a message. They have
developed a new class with wide range of SDP consisting of a
binary codes 0 and 1 bit that can potentially be implemented
in a synthetic macromolecule-SDP via two strategic building
blocks; one with hanging -H and the other one with -CH3 group
for 0 and 1 bit respectively (Fig. 5A)28,55,56. According to this
concept each monomer is inserted at a desired sequence in
the right position. These digitally important SDP are aimed to
be employed for long term data storage and product
characterization. For example, Lutz group has developed 2D
molecular barcode by a three-component and a four-
component library to encode a 2-bytes model binary
sequence. These coded libraries were efficiently incorporated
with various plastics through a solvent casting method.
Resulted materials were selectively identified by mass
spectrometric technique (LCMS/MS) even with the micro-
quantities. This system opens up many exciting opportunities
including anti-counterfeiting and traceability applications 57.
This work unlocks a new avenue for sequence-coded synthetic
polymers which is beyond the scope of homopolymers or co-
polymers.
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ARTICLE
3.2. Anti-microbial SDP View Article Online
DOI: 10.1039/C9PY00886A
Anti-biotic resistance is one of the alarming issues around the
globe. The reported studies suggested that peptidomietics
with structurally modified peptides backbones such as α-, β-
and γ-AApeptides, and peptoids have already shown their
resistance through proteolysis pathway58. Further,
conventional organic polymers i.e. Nylon-359 and others i.e.
poly(methacrylates)60, poly(acrylamides)61 have shown less
efficacy on different broad spectrum bacterial strains tested 62.
This situation strongly suggests that development and
Polymer Chemistry Accepted Manuscript
approval of new antibacterial drugs is the need of the hour.
Keeping this in view, Porel et al., from Alabi group have
developed a new class of antibacterial SDP named as
oligothioetheramides which were synthesized by orthogonal
reactions of allylacrylamide and dithiol building blocks through
orthogonal chemistry62-66. Oligothioetheramides showed
potential antibacterial activity against Gram Positive bacteria
including pathogenic-methycillin resistant Staphylococcus
aureus (MRSA) and vanomycin resistant Entrococcus as well as
non-pathogenic Bacillus subtilis and Staphylococcus
epidermidis. Most importantly the activity was shown to be
improved by modulating overall hydrophobicity of
oligothioetheramides via tuning the backbone functionality. As
the bacterial cell membrane is enriched with negatively
charged phosphate groups and hydrophobic lipids, a potential
antibacterial agent needs to possess cationic charge and
hydrophobic moiety. The balance between cationic charge and
hydrophobicity is the key factor to enhance agent the
selectivity of the antibiotics towards bacterial cell membrane
over the mammalian cell membrane66. Porel et al., developed
a library of antibacterial oligothioetheramides 62 keeping six
cationic moieties fix through pendant functional groups and
varied by modulating the backbone functionality through
different dithiols (Fig. 5B). Studies indicated that the
oligothioetharamides work against different bacterial cells via
membrane permeabilization and hydrophobicity structural
conformation was playing a key role to regulate this activity.
Additionally, some candidates exhibited a high degree of
activity (minimum inhibitory concentration∼ 0.5-5 μM) against
clinically relevant pathogens in serum, with minimum or no
toxicity against RBCs and HEK293 cells.
3.3. SDP as gene delivery agents
Gene therapy is one of the powerful tools in oncology in recent
years21. Polyamido amines (PAAs) play a major role in drug
delivery and gene therapy due to their intrinsic properties such
as i) PAAs has capability of changing basicity with the tailored
molecules through their amine functionality (pH dependent)
which influences the lysosomotropic and intracytoplasmic
delivery67, ii) PAAs can enter from endosomal/lysosome to
cytoplasm and form strong interaction through polycations of
PAA with negatively charged DNA or RNA thus protecting the
DNA by nuclease attack and then delivering the drug to the
target68. Due to their specific gene delivering properties, PAAs
envisage designing of novel sequence-defined (SD)-PAA with
tailored endosolytic properties for plasmid DNA delivery. The
SD-PAAs involve the effective incorporation of bio-reversible
cystine residues in their scaffold along with polycations which
J. Name ., 2013, 00 , 1 -3 | 17
 PleasePolymer
do not Chemistry
adjust margins Page 18 of 22

ARTICLE Journal Name

View Article Online

DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Figure 5. Applications of different sequence-defined polymer systems.

is reflected in the efficient binding with DNA69. Later, the same
group have developed different variety of SD-PAAs for their
gene delivery applications70. In gene therapy, sodium iodide
symporter (NIS) occupies major role based on its well-known
functions such as non-invasive imaging of vector bio-
distribution and their specific expressions in tumours cells.
With the aim of improvement in the present gene therapy,
Sarah et al., developed novel SDPs comprising of polyethylene
glycol (PEG) and cationic (ethanoamino) amide cores coupled
with a mesenchymal- epithelial transition factor (c-Met)-
binding peptide 2 (cMBP2) and they have shown potential
activity towards targeting receptor in human hepta-cellular
cancer (HuH7) mouse model (Fig. 5C). These polymers were
coupled with NIS-DNA for transduction, specificity and
therapeutic efficacy and they showed improved efficiency with
reduced toxicity in tumours cells71.
3.4 Sequence-defined oligoethers possess protease inhibitory
activity
Sequence-defined oligoethers (Fig. 5D) were efficiently
synthesized by Olivier et al. A library of this class of SDPs was
screened for protease inhibitory activity51. The proteases have
channel-like binding pockets and can interact with different
residues on each side of the peptide bond of their peptide
substrates. Based on the protein model, oligoethers were
screened for protease inhibitory activities 51. Results suggest
that among different length of oligoethers, the tetramer and
pentamer (Fig. 5D) show maximum activity at a micromolar
concentration. None of the other compounds such as
monomers, dimers, trimers show activity indicating that
tetramers and pentamers effectively bind in the protein
pockets which resulted in the inhibitory activities.
3.5 Anti-inflammatory responsive SDP
Meyer group has shown the importance of backbone in a SDP
for its anti-inflammatory responsive activity54,72,73. Control on
the backbone structure in sequence-defined poly (lactic-co-
glycolic acid)s (PLGAs) (Fig. 5E) has shown significant influence
on the production and release of micro particles as acidic
products on matrices. This backbone-dependent tuning
property reflected on neutralization and anti-inflammatory
responses. The backbone was comprised of lactic acid and
glycolic acid and was efficiently prepared through sequence-
defined strategy to modify the microstructure of PLGA. The in
vivo and in vitro studies of SDP were effectively monitored by
using non-invasive-radiometric two-photon microscopy (TPM)
method72,73. The study was conducted to analyse how
effectively the polymer can control the changes in the pH as
well as its particle nature. Through this macromolecular
design, accumulation and percolation of acidic by-products,
degradation rate, foreign body response and microparticle
morphology were efficiently controlled.

18 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 19 of 22 PleasePolymer
do not Chemistry
adjust margins
Journal Name
4. CONCLUSIONS
An impressive effort has been made during the last few
decades for understanding and controlling of polymer
sequences. Among these above-mentioned synthetic
categories, solid and soluble-supported strategies have
become popular as reliable source to produce different classes
of SDPs. Support-free approach is also gaining interest and
progressing rapidly in SDP field. With the help of well-
established synthetic protocols as well as upcoming new
techniques, there are immense possibilities for developing
novel macromolecules with pre-determined sequences for
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.
potential applications in material and biomedical sciences.
Only a handful of reactions have been explored including
amination, Click reaction, Michael addition, thiol-ene,
esterification, etherification, radical reactions etc. Still there
are huge possibilities for the improvement of reactions to
move the field forward. The goal is to make the synthetic
strategy towards high yielding at shorter time and mild
reaction condition, developing SDPs with diverse structural
features.
New strategies are needed to address the current challenges of
SDP field. For example, present methodologies allow for the
synthesis of short to medium oligomers/ polymers with the range of
1000 to 10,000 Da. Polymers with higher molecular weight with
precisely controlled monomer sequences is definitely one of the
exciting challenges to overcome. Although, efficiency of the
synthetic strategies has progressed quite fast in SDP field, still it
encounters several limitations such as lowering of reactivity when
the chain growth increases, using high equivalent of reagents,
difficulty of regeneration of support, limited accuracy for controlling
sequences for support-free systems etc. There is a pressing need to
develop new synthetic methods to overcome these limitations and
bring more and more diversity in backbone and pendant
functionalities with innovative properties. Different classes of SDPs
have shown promising application in a wide range of fields starting
from nanotechnology to biomedical sciences. As SDP has
opportunity to tune its properties by changing the monomer
sequences and functionality, this is a great platform to develop
innovative materials to address any specific application. In
summary, this review presents an in-depth understanding of SDP
field which can bring more and more diversity in materials in terms
of structure, properties and applications in near future.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the Indian Institute of Technology
Palakkad and the Ramanujan Fellowship, Science and
Engineering Research Board, Department of Science and
Technology for the financial support.
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins
ARTICLE
References View Article Online
DOI: 10.1039/C9PY00886A
1. N. Badi and J. F. Lutz, Chem. Soc. Rev., 2009, 38, 3383-3390.
2. D. Chan-Seng and J. F. Lutz, Solid-Phase Synthesis as a Tool
for the Preparation of Sequence-Defined Oligomers Based on
Natural Amino Acids and Synthetic Building Blocks.
Sequence-Controlled Polymers: Synthesis, Self-Assembly,
and Properties. 2014, Chapter 7, pp103-116.
3. V. K. Nair, M. K. More, J. J. Sawant, V. P. Thikekar, P. A. Philip,
M. D. Ojha and V. S. Gomase, Int. J. Chem. Res., 2009, 1, 1-7.
4. J. Bornholt, L. Ceze, R. Lopez, G. Seelig, D. M. Carmean, K. A.
Strauss, DNA-Based Archival Storage System. 2013; ASPLOS
’16 April 2–6, 2016, Atlanta, GA, USA.
Polymer Chemistry Accepted Manuscript
5. R. Kaiser and T. L. Hood, Nature, 1991, 350, 656-657.
6. C. DeLisi and F. Santa, Nature, 2008, 455, 876-877.
7. J. F. Lutz, M. Ouchi, D. R. Liu and M. Sawamoto, Science,
2013, 341, 1238149-1238156.
8. A. S. Knight, E. Y. Zhou, M. B. Francis and R. N. Zuckermann,
Adv. Mater., 2015, 27, 5665-5691.
9. R. N. Zuckermann, J. M. Kerr, B. H. K. Stephen and W. H.
Moos, J. Am. Chem. Soc., 1992, 114, 10646-10647.
10. R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D. Huebner, D.
A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg and C. K.
Marlowe, J. Am. Chem. Soc. 1992, 89, 9367-9371.
11. J. Sun and R. N. Zuckermann, ACS Nano., 2013, 7, 4715-4732.
12. S. A. Fowler and H. E. Blackwell, Org. Biomol. Chem., 2009, 7,
1508-1524.
13. J. S. Laursen, J. Engel-Andreasen and C. A. Olsen, Acc. Chem.
Res., 2015, 48, 2696-2704.
14. C. Jainfang, J. Chai, G. Liu, K. Chaicharoen and C.
Wesdemiotis, Macromolecules, 2008, 41, 8980-8985.
15. G. Liu and L. Jia, Angew. Chem. Int. Ed., 2006, 45, 129-131.
16. J. F. Lutz, Macromol. Rapid. Comm., 2017, 38, 1700582-
1700594.
17. J. W. Labadie, Curr. Opin. Chem. Biol., 1998, 2, 346-352.
18. M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003, 103,
3401-3430.
19. P. R. L. Malenfant and J. M. J. Frechet, Chem. Commun.,
1998, 2657-2658.
20. J. Roncali, Chem. Rev., 1997, 97, 173-206.
21. P. Y. Vuillaume, M. Brunelle, M. R. Van Calsteren, S. Laurent-
Lewandowski, A. Begin, R. Lewandowski, B. G. Talbot and Y.
Elazhary, Biomacromolecules, 2005, 6, 1769-1781.
22. P. Kos, U. Lachelt, D. He, Y. Nie, Z. Gu and E. Wagner, J.
Pharm. Sci., 2015, 104, 464-475.
23. E. C. Davidson, A. M. Rosales, A. L. Patterson, B. Russ, B. Yu,
R. N. Zuckermann, and R. A. Segalman, Macromolecules,
2018, 51, 2089-2098.
24. P. Espeel, L. L. G. Carrette, K. Bury, S. Capenberghs, J. C.
Martins, F. E. Du prez and A. Madder, Angew. Chem. Int. Ed.,
2013, 52, 13261-13264.
25. T. T. Trinh, C. Laure and J. F. Lutz, Macromol. Chem. Phys.,
2015, 216, 1498-1506.
26. J. W. Grate, K. F. Mo and M. D. Daily, Angew. Chem. Int. Ed.,
2016, 55, 3925-3930.
27. D. Chan-Seng and J. F. Lutz, ACS Macro Lett., 2014, 3, 291-
294.
28. T. T. Trinh, L. Oswald, D. Chan-Seng and J. F. Lutz, Macromol.
Rapid Commun. 2014, 35, 141-145.
29. N. F. Konig, S. Telitel, S. Poyer, L. Charles and J. F. Lutz,
Macromol. Rapid Commun., 2017, 38, 1700651-1700656.
30. M. Porel and C. A. Alabi, J. Am. Chem. Soc., 2014, 136, 13162-
13165.
31. M. Porel, J. S. Brown and C. A. Alabi, Synlett., 2015, 26, 565-
571.
32. M. Porel, D. N. Thornlow, N. N. Phan and C. A. Alabi, Nat.
Chem., 2016, 8, 590-596.
J. Name ., 2013, 00 , 1 -3 | 19
 PleasePolymer
do not Chemistry
adjust margins Page 20 of 22

ARTICLE Journal Name

33. J. S. Brown, Y. M. Acevedo, G. D. He, J. H. Freed, P. Clancy 65. J. S. Brown, Z. J. Mohamed, C. M. Artim, D. N. Thornlow, J. F.
View Article Online
and C. A. Alabi, Macromolecules, 2017, 50, 8731-8738. Hassler, V. P. Rigoglioso, S. Daniel andDOI:
C. A. Alabi, Commun.
10.1039/C9PY00886A
34. R. L. Kanasty, A. J. Vegas, L. M. Ceo, M. Maier, K. Charisse, J. Biol., 2018, 220, 1-9.
K. Nair, R. Langer and D. G. Anderson, Angew. Chem. Int. Ed., 66. C. Pitsalidis, A. Pappa, M. Porel, C. M. Artim, G. C. Faria, D. D.
2016, 55, 9529-9533. Duong, C. A. Alabi, S. Daniel, A. Salleo and R. M. Owens, Adv.
35. K. Knop, R. Hoogenboom, D. Fischer and U. S. Schubert, Mater., 2018, 180, 1-8.
Angew. Chem. Int. Ed., 2010, 49, 6288-6308. 67. L. Hartmann, Macromol. Chem. Phys., 2011, 212, 8-13.
36. H. V. Nguyen, D. C. Ehrlich, S. J. Huh, B. Vangamudi, K. D. 68. S. Richardson, P. Ferruti and R. Duncan, J. Drug. Targeting,
Economides, A. M. Neenan, J. C. Ackley, J. Baddour, S. 1999, 6, 391-404.
Paramasivan, S. W. Brady, E. J. Held, L. A. Reiter, P. W. 69. D. Schaffert, C. Troiber and E. Wagner, Bioconjugate Chem.,
Kopesky, D. E. Chickering, P. Blume-Jensen and J. A. Johnson, 2012, 23, 1157-1165.
Nat. Biomed. Eng., 2018, 2, 822-830. 70. T. Lehto and E. Wagner, Nanomedicine, 2014, 9, 2843-2859.

Polymer Chemistry Accepted Manuscript

37. R. Dong, R. Liu, P. R. J. Gaffney, M. Schaepertoens, P. 71. S. Urnauer, S. Morys, A. K. Levacic, A. M. Muller, C. Schug, K.
Marchetti, C. M. Williams, R. Chen and A. G. Livingston, Nat. A. Schmohl, N. Schwenk, C. Zach, J. Carlsen, P. Bartenstein, E.
Chem., 2019, 11, 136-145. Wagner and C. Spitzweg, Mol. Ther., 2016, 24, 1395-1404.
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

38. X. Tong, B. H. Guo and Y. Huang, Chem. Commun., 2011, 47, 72. M. A. Washington, D. J. Swiner, K. R. Bell, M. V. Fedorchak, R.
1455-1457. Little and T. Y. Meyer, Biomater. Sci., 2019, 7, 490-505.
39. S. Wang, Y. Tao, J. Wang, Y. Tao and X. Wang, Chem. Sci., 73. R. M. Weiss, J. Li, H. H. Liu, M. A. Washington, J. A. Giesen, S.
2019, 10, 1531-1538. M. Grayson and T. Y. Meyer, Macromolecules, 2017, 50, 550-
40. M. G. Passerini, Gazz. Cheim. Ital., 1921, 51, 126-129. 560.
41. S. C. Solleder and M. A. R. Meier, Angew. Chem. Int. Ed.,
2014, 53, 711-714.
42. O. Kreye, T. Tommy and M. A. R. Meier, J. Am. Chem. Soc.,
2011, 133, 1790-1792.
43. J. J. Yan, D. Wang, D. C. Wu and Y. Z. You, Chem. Commun.,
2013, 49, 6057-6059.
44. N. Zydziak, F. Feist, B. Huber, J. O. Mueller and C. Barner-
Kowollik, Chem. Commun., 2015, 51, 1799-1802.
45. N. Zydziak, W. Konrad, F. Feist, S. Afonin, S. Weidner and C.
Barner-Kowollik, Nat. Commun., 2016, 7, 1-10.
46 C. Fu, Z. Huang, C. J. Hawker, G. Moad, J. Xu and C. Boyer,
Polym. Chem., 2017, 8, 4637-4643.
47. J. J. Haven, J. Vandenbergh, V. Kurita, J. Gruber and T.
Junkers, Polym. Chem., 2015, 6, 5752-5765.
48. W. R. Gutekunst and C. J. Hawker, J. Am. Chem. Soc., 2015,
137, 8038-8041.
49. F. A. Leibfarth, J. A. Johnson and T. F. Jamison, Proc. Natl.
Acad. Sci. U. S. A., 2015, 112, 10617-10622.
50. J. K. Szymanski, Y. M. Abul-Haija and L. Cronin, Acc. Chem.
Res., 2018, 51, 649-658.
51. O. Renaudet and J. L. Reymond, Org. Lett., 2004, 6, 397-400.
52. J. Zhang, M. E. Matta, and M. A. Hillmyer, ACS Macro Lett.,
2012, 1, 1383−1387.
53. J. C. Barnes, D. J. C. Ehrlich, A. X. Gao, F. A. Leibfarth, Y. Jiang,
E. Zhou, T. F. Jamison and J. A. Johnson, Nat. Chem., 2015, 7,
810-815.
54. M. A. Washington, S. C. Balmert, M. V. Fedorchak, S. R. Little,
S. C. Watkins and T. Y. Meyer, Acta Biomater., 2018, 65, 259-
271.
55. N. Zydziak, W. Konrad, F. Feist, S. Afonin, S. Weidner and C.
Barner-Kowollik, Nat. Commun., 2016, 7, 1-10.
56. J. F. Lutz, Macromolecules, 2015, 48, 4759-4767.
57. D. Karamessini, S. Poyer, L. Charles and J. F. Lutz, Macromol.
Rapid Commun., 2017, 38, 1700426-1700430.
58. C. D. Fjell, J. A. Hiss, R. E. Hancock and G. Schneider, Nat.
Rev. Drug Discov., 2011, 11, 37-51.
59. B. P. Mowery, A. H. Lindner, B. Weisblum, S. S. Stahl and S. H.
Gellman, J. Am. Chem. Soc., 2009, 131, 9735−9745.
60. K. Kuroda and W. F. DeGrado, J. Am. Chem. Soc., 2005, 127,
4128−4129.
61. H. Tang, R. J. Doerksen, T. V. Jones, M. L. Klein and G. N. Tew,
Chem. Biol., 2006, 13, 427−435.
62. M. Porel, D. N. Thornlow, C. M. Artim and C. A. Alabi, ACS
Chem. Biol., 2017, 12, 715-723.
63. C. M. Artim, N. N. Phan, C. A. Alabi and R. F. Smith, ACS Infect
Dis., 2018, 4, 1257-1263.
64. E. A. Hoff, C. M. Artim, J. S. Brown and C. A. Alabi, Macromol.
Biosci., 2018, 18, 1800241-1800247.

20 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

 Page 21 of 22 PleasePolymer
do not Chemistry
adjust margins

Journal Name ARTICLE

View Article Online

Biographies DOI: 10.1039/C9PY00886A

Polymer Chemistry Accepted Manuscript

Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Pandurangan Nanjan obtained his M.Sc. in Chemistry from Periyar University, Tamilnadu, India in 2006.
Thereafter he worked in Merchem Limited from 2006 to 2009 and then joined Professor Asoke Banerji’s group
at Amrita University, Kerala, India in 2009 as Senior Research Fellow under the Department of Biotechnology
(DBT) project. He registered for his PhD under the guidance of Prof. Banerji in 2012. His Ph.D. work was
focuses on isolation, characterization, synthesis and biological activities of natural products. In 2018, he joined
Dr. Mintu Porel’s group in Indian Institute of Technology Palakkad, India as a post-doctoral researcher under.
His present interest is to develop sequence-defined macromolecules for different structure and functions.

Mintu Porel is currently an assistant professor (and Ramanujan Fellow) in the discipline of chemistry at
Indian Institute of Technology Palakkad, India. Her current research work is focused on the design and
synthesis of novel classes of sequence-defined macromolecules and their application in material and
biomedical sciences. She received her Ph.D. in supramolecular photochemistry from University of Miami,
Miami, USA under the supervision of Professor V. Ramamurthy in 2013. Before joining University of
Miami, she completed her B.Sc. in Chemistry from Calcutta University, India in 2005 and M.Sc. from
Indian Institute of Technology Delhi, India in 2007. She did her first postdoctoral work in Professor
Jingyue Ju’s group at Columbia University, New York, USA. Thereafter she moved to Cornell University,
New York, USA as a postdoctoral researcher in Professor Alabi’s laboratory and worked on designing new
sequence-defined polymers and their applications as antibacterial agents.

This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1 -3 | 21

Please do not adjust margins

 PleasePolymer
do not Chemistry
adjust margins Page 22 of 22

ARTICLE Journal Name

View Article Online

TOC DOI: 10.1039/C9PY00886A

To do……

Many promising
opportunities in terms of
synthesis and applications

Polymer Chemistry Accepted Manuscript

Synthesis
Published on 09 September 2019. Downloaded by Northwestern University on 9/9/2019 5:57:57 AM.

Sequence-defined
polymer

22 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins