Norbornadienes: Robust and Scalable Building Blocks for Cascade "click" Coupling of High Molecular Weight Polymers

Article abstract of DOI:10.1021/jacs.9b06328

Herein, we report the development of a scalable and synthetically robust building block based on norbornadiene (NBD) that can be broadly incorporated into a variety of macromolecular architectures using traditional living polymerization techniques. By tak

Full text of DOI:10.1021/jacs.9b06328

Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Article
Norbornadienes: Robust and Scalable Building Blocks for
Cascade “Click” Coupling of High Molecular Weight Polymers
Andre H. St. Amant, Emre H. Discekici, Sophia J Bailey, Manuel S Zayas, Jung-Ah Song, Shelby L Shankel,
Shay N Nguyen, Morgan Whitney Bates, Athina Anastasaki, Craig J. Hawker, and Javier Read de Alaniz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06328 • Publication Date (Web): 07 Aug 2019
Downloaded from pubs.acs.org on August 7, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Norbornadienes: Robust and Scalable Building Blocks for Cascade
“Click” Coupling of High Molecular Weight Polymers
Andre H. St. Amant,†§ Emre H. Discekici,†‡§ Sophia J. Bailey,† Manuel S. Zayas,† Jung-Ah Song, ‡
Shelby L. Shankel,† Shay N. Nguyen, † Morgan W. Bates,‡ Athina Anastasaki,‡ Craig J. Hawker,*†‡⊥ and
Javier Read de Alaniz*†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
§AHS and EHD contributed equally
†Department of Chemistry and Biochemistry, ‡Materials Research Laboratory, and ⊥Materials Department, University of
California, Santa Barbara, California 93106, United States
Supporting Information Placeholder
SPAAC has been mostly limited to small-scale systems such as
dendritic12 or biological applications.13
ABSTRACT: Herein we report the development of a scalable and
synthetically robust building block based on norbornadiene (NBD)
that can be broadly incorporated into a variety of macromolecular
architectures using traditional living polymerization techniques. By
taking advantage of a selective and rapid deprotection with
tetrazine, highly reactive “masked” cyclopentadiene (Cp)
functionalities can be introduced into synthetic polymers as chain-
(a) Conventional Diels-Alder for polymer functionalization
O
O
O
N
R
slow conjugation
(2000x slower than Cp)
high temperatures
> 100 °C
end groups in
a quantitative and efficient manner. The
(b) Next generation NBD “click” for polymer functionalization
orthogonality of this platform further enables a cascade click
process where the “unmasked” Cp can rapidly react with
dienophiles, such as maleimides, through a conventional Diels–
Alder reaction. Coupling proceeds with quantitative conversions
allowing high molecular weight star and dendritic block
copolymers to be prepared in a single step under ambient
conditions.
O
N
N
N
N
Py
Py
O
O
N
R
N
R
C5H11
C5H11
O
one-pot, room temperature
Figure 1. (a) Current methods for maleimide-polymer conjugation
using anthracene or furan (b) Strategy reported herein introducing
masked Cp into polymers, highlighted by red bonds.
A more cost-effective and scalable metal-free “click” platform for
polymer synthesis is the Diels–Alder (DA) cycloaddition reaction.
DA systems have been utilized across numerous applications
ranging from polymer crosslinking,14,15 nanoparticle,16 surface
functionalization,17 and the preparation of antibody–drug
conjugates.18 Furan or anthracene-based dienes, in combination
with maleimide dienophiles, are arguably the most commonly
utilized building blocks for DA cycloaddition couplings in polymer
synthesis (Figure 1a).19 However, despite their orthogonality,
scalability, and wide spread availability, polymeric materials
prepared by DA cycloadditions are plagued with certain
fundamental limitations. For example, the propensity for furan-
maleimide DA adducts to undergo retro Diels-Alder (rDA)
reactions renders them unsuitable for applications requiring
elevated temperatures.20 Furthermore, the DA cycloaddition of
anthracene-maleimide suffers from the necessity for high
temperatures and long reaction times to achieve high coupling
efficiency.21
Introduction
The concept of “click” chemistry, first introduced by Sharpless and
coworkers in 2001, is based on the philosophy that chemical
reactions should be modular, simple, high yielding and orthogonal.1
These essential characteristics have had a profound impact across
the broader chemical sciences, transforming scientific disciplines
ranging from bioconjugation to functional polymer synthesis.2,3
A
range of post-polymerization modification strategies have emerged
from the concept of “click” chemistry, enabling the synthesis of
polymers with a diverse array of functionalities and architectures.4,5
Among these strategies, the copper catalyzed azide–alkyne click
(CuACC) represents one of the most highly utilized “click”
platforms in polymer synthesis, driven by the synthetic availability
of alkyne and azide building blocks.6 However, a longstanding
drawback for traditional CuAAC-based systems is the presence of
metal catalysts. This challenge was mitigated by the development
of copper-free or strain-promoted azide–alkyne click (SPACC)
chemistry; based on cyclooctyne derivatives,7 the inherent strain in
the cyclooctyne ring dramatically increases the rate of the
uncatalyzed reaction,8 enabling rapid room temperature coupling to
To overcome these challenges, an attractive alternative is to
significantly increase the reactivity of the diene or dienophile. Du
Prez and co-workers have reported the use of triazolinedione
(TAD) compounds as ‘spring-loaded’ dienophiles which react with
dienes at room temperature within minutes.22 The high reactivity of
TAD compounds offers an elegant method for functionalizing
polymers when less reactive dienes are required. In contrast, the
reactivity of the diene can be increased through the use of
azides.
However
the
long-term
instability
of
dibenzoazacyclooctyne systems (DIBAC) (storage at –20 °C),9 the
difficulties in scalability and prohibitively high cost10,11 renders
general use in functional polymer synthesis challenging. As such,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
cyclopentadiene (Cp) derivatives.23,24 Recognizing the potential of
O
i, ii
OH
C5H11
MeO
1
2
3
4
5
6
7
8
Cp as a polymer “click” platform, Barner-Kowollik and coworkers
have developed synthetic routes to access Cp-functionalized
polymers for conjugation with maleimides,25 electron-deficient
dithioesters,26-28 and carbon nanoparticles.29,30 For stable
backbones such as polystyrene or poly(ethylene glycol),
nucleophilic substitution using ionic cyclopentadienyl salts
(NaCp,26 LiCp,31 or Me2AlCp32) allows for the efficient synthesis
of Cp functionalized chain end derivatives. In the case of reactive
backbones, such as polyesters, an alternative substitution strategy
using nickelocene (NiCp2) has been developed.27,33,34 Despite the
success of these strategies, the ability to incorporate Cp has been
limited to chain-ends via post-polymerization strategies due to the
general instability24 of Cp and its high reactivity towards electron-
deficient vinyl monomers.35
+
C5H11
1
2
3
inexpensive
flavoring agent
commodity
chemical
36% (2 steps)
iii
iv
v, vi
O
O
O
Br
S
S
O
O
OH
OH
O
C12H25
NC
S
C5H11
C5H11
C5H11
4
5
6
9
Scheme 1. Synthesis of norbornadiene polymer building blocks. i)
neat, pressure vessel, 200 °C, 5 h, 50% ii) DIBAL, THF, 0 °C, 30
min, 71% iii) CDTPA, EDC·HCl, DMAP, DCM, rt, 16 h, 92% iv)
-Bromoisobutryl bromide, pyridine, THF, 0 °C, 2 h, 72% v) 2,2-
Bis(tert-butyldimethylsiloxymethyl)propionic acid, EDC·HCl,
DMAP, DCM, rt, 2 days, 86% vi) TBAF, THF, rt, 2 h, 73%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Identifying the limitations of general click strategies and the
associated promise of cyclopentadiene (Cp) derivatives as a highly
efficient coupling platform, we report the development of
norbornadiene (NBD) building block as a “masked” Cp unit that
can be used for the synthesis of high molecular weight tri-block and
star copolymers. Our interest is NBD derivatives is driven by their
scalability (derived from inexpensive starting materials such as
dicyclopentadiene) and compatibility with a wide variety of
Drawing inspiration from small molecule reports39,40 and the
pioneering development of additive-free polymer functionalization
based on norbornene-tetrazine coupling chemistry by Dove, Du
Prez, and O’Reilly,41 we identified norbornadiene (NBD), as a
“masked” Cp precursor. Together with the synthetic accessibility
demonstrated above, we envisaged that the high ring strain (32.2
kcal/mol)42-45 would allow for a cascade of selective cycloaddition
reactions when used in conjunction with tetrazine.43–45 This highly
efficient process proceeds through an initial inverse electron-
demand DA (IEDDA) reaction that releases N2, followed by a
retro-DA (rDA), to yield pyridazine46 and Cp as products.39,40 This
strategy therefore permits the facile incorporation of Cp into a
range of materials through the initial introduction of NBD units.
polymerization
techniques
such
as
reversible
addition−fragmentation chain-transfer (RAFT), atom transfer
radical polymerization (ATRP) and ring-opening polymerization
(ROP). A key insight in this study is the use of a cascade sequence
of DA reactions to quantitatively couple the NBD units with
dienophiles such as functional maleimides.36 This “unmasking” of
the NBD group is mediated by small molecule tetrazine derivatives
through an initial inverse-DA reaction leading to the in situ
generation of Cp functionalities that can then undergo efficient
conjugation with maleimide-functionalized materials (Figure 1b).
This novel cascade platform is metal-free, air tolerant, and
quantitative for even demanding systems such as the coupling of
high molecular weight, chain end functionalized linear polymers.
This allows well-defined block copolymers to be prepared on
multi-gram scale that are difficult to synthesize using traditional
polymerization strategies.
O
O
O
(a)
O
O
O
OH
n
O
OH
n
one-pot
R
N
O
O
C5H11
room temperature
C5H11
O
P1
P2
N
N
N
N
O
O
Py
Py
7
8
N
R
Py
Py
N
Py
Py
N
N
N
+
N
N
N
N
C5H11
C5H11
C5H11
Results and Discussion
Py
Py
P1a
P1b
Initial studies on the scalable synthesis of an NBD derivative
employed the commodity chemical dicyclopentadiene (1) and
methyl 2-octynoate (2), an inexpensive and innocuous flavoring
agent ($30 per kg). When 1 and 2 are heated neat in a pressure
vessel at 200 °C, the resulting methyl ester can be isolated via
distillation and subsequently reduced with DIBAL to furnish the
NBD alcohol 337 on a 50 g scale in a typical laboratory setting
(Scheme 1). The simplicity of this process coupled with the
availability of alkyne derivatives allows a range of other NBD
derivatives to be prepared. A notable example includes the reaction
of 1 with propargyl alcohol which affords the unsubstituted NBD
alcohol directly.38 Significantly it was observed that the NBD
derivatives were stable and could be stored at room temperature
under ambient conditions with no observable degradation or
2 H
(b)
(c)
P2
R =
(d)
9 H
Mn (SEC) = 42,000
Đ = 1.04
8.4
8.0
7.6
7.2
6.8
6.4
Chemical Shift (ppm)
Figure 2. (a) One-pot deprotection of NBD and conjugation with
maleimide. Note: quenched with norbornene after 4 h. (b) Pyrene
1
chain end functionality introduced to PLA. H NMR of (c) NBD-
instability over 6+ months. In addition,
a
variety of
functionalized PLA, P1 and (d) PyrM-functionalized PLA, P2 in
functionalization reactions can be performed on the NBD building
block to give functional initiator units for subsequent
polymerization reactions (Figure S23–S30). For example, the
alcohol 3 can be esterified to give the RAFT chain transfer agent,
4, the ATRP initiator, 5, or the difunctional bis(MPA) ROP
initiator, 6, in high yields.
dichloromethane-d2.
To demonstrate the versatility of 3 as a stable, “masked” Cp unit,
end-functionalized polylactide (PLA) P1 (Figure 2a) was prepared
using the base-catalyzed ROP of D,L-lactide and 3 as an initiator.
Significantly, the resulting polymer was determined to have a
degree of polymerization of ~500 (Mn = 42,000 g/mol and Đ =
1.04), which compares favorably with the theoretical DP of 440 and
illustrates the compatibility of the NBD unit under basic conditions.
Additionally, 1H NMR spectroscopy shows the unique signals for
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
the alkene present in the NBD units and confirms the efficient
introduction of NBD at the end of the high molecular weight PLA
chain.
by precipitation, P2 was obtained in quantitative yield with SEC
characterization before and after functionalization confirming no
change in molar mass distribution. Significantly, incorporation of
pyrene was determined to be >95% by both 1H NMR and UV-Vis
spectroscopy calibrating against known concentrations of PyrM
(Figure 2d, S31−34). Similar reactivity was observed for a range
of PLA molecular weights and for maleimides bearing more
complex biotin or azobenzene functionalities (Figure S35-36, S39-
40). The ability to employ a wide range of functional starting
materials and high (>40,000 kDa) molecular weight polymers
highlights the efficiency of NBD as a building block with this
“cascade click” strategy representing a viable alternative to both
CuAAC and SPAAC.47
1
2
3
4
5
6
7
8
The ability to liberate reactive Cp units was then demonstrated
through sequential “demasking” of the NBD group followed by
rapid, DA cycloaddition with readily available maleimide
dienophiles containing a range of functionality (e.g., dye,
biomolecule and photoswitch). From a practical point of view, one
advantage of this approach is that the maleimide group lies dormant
until the Cp group is revealed leading to a metal-free and room
temperature “cascade click” functionalization process.36 The
orthogonality of these cycloaddition processes combined with the
user-friendly nature of the reaction set-up addresses a number of
challenges that exist in the synthesis of complex macromolecular
architectures by coupling of polymeric building blocks. To validate
the efficient conjugation via a “cascade click” sequence, a solution
of P1 in CDCl3 was treated with the commercially available
tetrazine (DpTz, 2.4 equiv) and N-(1-pyrenyl)maleimide (PyrM,
1.2 equiv) at room temperature with no precaution to exclude water
or oxygen. As highlighted by Figure 2a, the cascade process
proceeds through an initial inverse electron-demand DA (IEDDA)
reaction with DpTz (7) at the unsubstituted olefin of NBD (P1 to
P1a). Upon release of N2 from P1a a subsequent retro-DA occurs
to yield an in situ generated terminal Cp unit (P1b) which
undergoes a DA reaction with the functionalized maleimide (8) to
give the desired pyrene-functionalized P2. Following purification
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The facile introduction of reactive Cp units to the chain ends of
polymeric systems now opens up the intriguing possibility of
coupling stable, end functionalized polymers to give high
molecular weight block copolymers and other complex
macromolecular architectures. To showcase the potential of this
new strategy, a PLA-b-PEO-b-[G-4 dendron] triblock copolymer
(P5) was prepared in a single step by coupling of a chain end
functionalized PLA-NBD ((P3), Mn = 21,800) derivative with a
maleimide-terminated PEO-b-[G-4 dendron] (P4). Significantly,
only a minor excess of P4 (1.5 equivalents) was required to drive
the reaction to completion with SEC showing the expected increase
in molecular weight for the desired triblock copolymer and no
detectable P3 (Figure S48).
(a)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
n
HO
DpTz (1.5 eq.)
CDCl3, rt, 16 h
HO
nO
O
O
O
O
N
O
N
O
m
N
N
N
N
O
O
m
O
+
O
O
C5H11
O
C5H11
O
N
N
O
O
O
O
O
O
O
O
O
O
P5
O
P4
O
O
O
P3
O
O
O
Mn(SEC) = 28,100
Đ = 1.04
O
O
Mn(SEC) = 21,800
Mn(SEC) = 6,300
Đ = 1.06
O
O
O
O
O
Đ = 1.08
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CDCl3
O
O
(b)
O
O
O
O
7.5
6.5
(c)
7.5
7.5
6.5
4.0
8.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
Figure 3. (a) Chemical schematic for synthesis of triblock copolymer, P5, using a sequential deprotection-conjugation strategy between
NBD-functionalized PLA (P3) and maleimide-terminated PEO-b-[G-4 dendron] (P4); 1H NMR of (b) NBD-functionalized PLA, P3 and (c)
triblock P5 in chloroform-d.
To further illustrate the power of this cascade click approach for
the synthesis of complex macromolecular architectures, we took
inspiration from dendrimer and star copolymer targets. The NBD-
containing diol 6 was subjected to standard lactide ROP conditions
to obtain a two-armed B2 precursor (P6, Figure 4a) where a
“masked” Cp unit is located at the mid-point of the PLA chain. This
allows access to high molar mass AB2 miktoarm star polymers
when coupled with linear maleimide-terminated polymers.
Maleimide-terminated poly(n-butyl methacrylate) (PnBMA) P748
synthesized using metal-free ATRP49 serves as the conjugation
partner (Mn(SEC) 9,600 g/mol, Đ = 1.26) with the corresponding
AB2 PnBMA-b-(PLA)2 miktoarm star copolymer P8 obtained after
room temperature reaction under ambient conditions (Figure 4a).
It is important to note that excess P7 was removed by simple
precipitation of the crude reaction mixture into a 1:1 v/v/
methanol:isopropanol solution. SEC-RI analysis confirmed the
efficient coupling and successful formation of a high molecular
weight AB2 miktoarm block copolymer (Figure 4b). 1H NMR
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
analysis of P8 corroborated a quantitative incorporation of PnBMA
P12) was prepared using polymer precursors of different molar
masses, targeting a fPLA ≈ 0.7 AB2 miktoarm (Figure S55–56).
Upon annealing, the miktoarm block copolymer also exhibited
microphase separation, forming hexagonally packed cylinders as
evidenced by SAXS (Figure S57). The ability to quickly and
efficiently link polymer precursors promotes a more facile avenue
to tune chemical composition and volume fraction of blocks
through this “mix and match” approach. We envision that this
strategy will enable easy access to a range of polymeric
architectures or potentially afford new opportunities in reactive
compatibilization of polymer blends.
1
2
3
4
5
6
7
8
and PLA blocks (Figure S53) based on the stoichiometric reaction
between chain-ends and the estimated molecular weight of each
precursor. Small-angle x-ray scattering (SAXS) provided
additional evidence for efficient conjugation and the absence of
unreacted homopolymer. After annealing P8 at 120 °C for 4 h,
multiple Bragg reflections corresponding to well-ordered lamellae
were observed with a characteristic length-scale (q* = 0.25 nm -1, d
= 25 nm) defined by the self-assembly of the neat and symmetric
AB2 block polymer (fPLA ≈ 0.5). As an additional demonstration of
the modularity of this platform, a second AB2 miktoarm star (S-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. (a) Chemical schematic for one-pot AB2 miktoarm star formation using a sequential deprotection-conjugation strategy between
two-arm NBD-functionalized PLA (P6) and maleimide-terminated PnBMA (P7) to yield P8. Note: quenched with norbornene after 5 h (b)
SEC-RI overlay of polymer precursors and purified AB2 miktoarm star (P8) (c) SAXS data confirming self-assembly of P8 to a well-ordered
lamellar structure.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: XX.
Conclusion
In conclusion, we have developed a cascade click strategy for the
Experimental details and characterization data, including Figures
facile preparation of high molecular weight macromolecular
S1−S38 (PDF)
architectures. Based on synthetically accessible and chemically
robust norbornadiene (NBD) building blocks, “masked” Cp units
AUTHOR INFORMATION
can be introduced into a range of polymeric systems. The general
compatibility of the NBD building block with common
polymerization techniques (i.e. RAFT, ATRP, ROP) is
demonstrated, highlighting the versatility and orthogonality of
NBD. Importantly, upon addition of DpTz, quantitative
deprotection of NBD to form Cp is observed via a rapid cascade of
DA reactions, and in the presence of a variety of functional
maleimide derivatives, in situ coupling then occurs via a traditional
DA cycloaddition. This metal-free process is highly efficient and
requires no heating or precaution for an air- or moisture-free
environment. Importantly, it is amenable across an array of
functional maleimides, making this strategy accessible to the
broader scientific community.
Corresponding Authors
* hawker@mrl.ucsb.edu
* javier@chem.ucsb.edu
ORCID
Andre H. St. Amant: 0000-0002-4842-1918
Emre H. Discekici: 0000-0001-7083-5714
Craig J. Hawker: 0000-0001-9951-851X
Javier Read de Alaniz: 0000-0003-2770-9477
Author Contributions
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
§AHS and EHD contributed equally.
8001.
(13)
(14)
(15)
(16)
Pickens, C. J.; Johnson, S. N.; Pressnall, M. M.; Leon, M. A.;
1
2
3
4
5
6
7
8
Berkland, C. J. Practical Considerations, Challenges, and
Limitations of Bioconjugation via Azide-Alkyne Cycloaddition.
Bioconjugate Chem. 2018, 29, 686–701.
Roos, K.; Dolci, E.; Carlotti, S.; Caillol, S. Activated Anionic
Ring-Opening Polymerization for the Synthesis of Reversibly
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Cross-Linkable
Poly(Propylene
Oxide)
Based
on
The research made use of shared facility of the UCSB MRSEC
(NSF DMR 1720256). AHS thanks the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
Furan/Maleimide Chemistry. Polym. Chem. 2016, 7, 1612–1622.
Hanlon, A. M.; Martin, I.; Bright, E. R.; Chouinard, J.; Rodriguez,
K. J.; Patenotte, G. E.; Berda, E. B. Exploring Structural Effects
in Single-Chain “Folding” Mediated by Intramolecular Thermal
Diels-Alder Chemistry. Polym. Chem. 2017, 8, 5120–5128.
Isakova, A.; Burton, C.; Nowakowski, D. J.; Topham, P. D. Diels-
Alder Cycloaddition and RAFT Chain End Functionality: An
Elegant Route to Fullerene End-Capped Polymers with Control
over Molecular Mass and Architecture. Polym. Chem. 2017, 8,
2796–2805.
Blinco, J. P.; Trouillet, V.; Bruns, M.; Gerstel, P.; Gliemann, H.;
Barner-Kowollik, C. Dynamic Covalent Chemistry on Surfaces
Employing Highly Reactive Cyclopentadienyl Moieties. Adv.
Mater. 2011, 23, 4435–4439.
St. Amant, A. H.; Huang, F.; Lin, J.; Rickert, K.; Oganesyan, V.;
Lemen, D.; Mao, S.; Harper, J.; Marelli, M.; Wu, H.; Gao, C.;
a
postgraduate scholarship (PGS-D). EHD thanks the NSF Graduate
Research Fellowship and the UCSB graduate division, Graduate
Research Mentorship Program (GRMP) fellowship for financial
support. SJB thanks the UCSB graduate division for a Chancellor’s
Fellowship. SLS and SNN thank the MARC Scholar Program
through the National Institute of Health (T34GM113848) for
support. AA is grateful to the European Union (EU) for a Marie
Curie Postdoctoral Fellowship and the California Nanosystems
Institute for an Elings Prize Fellowship in Experimental Science.
Small-angle X-ray scattering data were acquired at the DuPont-
Northwestern-Dow Collaborative Access Team (DND-CAT)
located at Sector 5 of the Advanced Photon Source (APS). DND-
CAT is supported by Northwestern University, E.I. DuPont de
Nemours & Co., and The Dow Chemical Company. Data was
collected using an instrument funded by the National Science
Foundation under Award Number 0960140. This research used
resources of the Advanced Photon Source, a U.S. Department of
Energy (DOE) Office of Science User Facility operated for the
DOE Office of Science by Argonne National Laboratory under
Contract No. DE-AC02-06CH11357.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17)
(18)
Read de Alaniz, J.; Christie, R. J.
A Diene–Containing
Noncanonical Amino Acid Enables Dual Functionality in
Proteins: Rapid Diels–Alder Reaction with Maleimide or
Proximity-Based Dimerization. Angew. Chem. Int. Ed. 2019, 58,
8489–8493.
Tasdelen, M. A. Diels-Alder “Click” Reactions: Recent
Applications in Polymer and Material Science. Polym. Chem.
2011, 2, 2133–2145.
Liu, Y. L.; Chuo, T. W. Self-Healing Polymers Based on
Thermally Reversible Diels-Alder Chemistry. Polym. Chem.
2013, 4, 2194–2205.
Rideout, D. C.; Breslow, R. Hydrophobic Acceleration of Diels-
Alder Reactions. J. Am. Chem. Soc. 1980, 102, 7816–7817.
Billiet, S.; De Bruycker, K.; Driessen, F.; Goossens, H.; Van
Speybroeck, V.; Winnie, J. M.; Du Prez, F. E. Triazolinediones
Enable Ultrafast and Reversible Click Chemistry for the Design
of Dynamic Polymer Systems. Nat. Chem. 2014, 6, 815–821.
Sauer, J.; Lang, D.; Mielert, A. The Order of Reactivity of Dienes
towards Maleic Anhydride in the Diels‐Alder Reaction. Angew.
Chem. Int. Ed. 1962, 1, 268–269.
(19)
(20)
(21)
(22)
REFERENCES
(1)
Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry:
Diverse Chemical Function from a Few Good Reactions. Angew.
Chem. Int., Ed. 2001, 40, 2004–2021.
Günay, K. A.; Theato, P.; Klok, H. A. Standing on the Shoulders
of Hermann Staudinger: Post-Polymerization Modification from
Past to Present. J. Polym. Sci. Part A Polym. Chem. 2013, 51, 1–
28.
Lunn, D. J.; Discekici, E. H.; Read de Alaniz, J.; Gutekunst, W.
R.; Hawker, C. J. Established and Emerging Strategies for
Polymer Chain-End Modification. J. Polym. Sci. Part A Polym.
Chem. 2017, 55, 2903–2914.
Blasco, E.; Sims, M. B.; Goldmann, A. S.; Sumerlin, B. S.;
Barner-Kowollik, C. 50th Anniversary Perspective: Polymer
Functionalization. Macromolecules 2017, 50, 5215–5252.
Brendel, J. C.; Martin, L.; Zhang, J.; Perrier, S. SuFEx-a
Selectively Triggered Chemistry for Fast, Efficient and
Equimolar Polymer-Polymer Coupling Reactions. Polym. Chem.
2017, 8, 7475–7485.
Leophairatana, P.; De Silva, C. C.; Koberstein, J. T. How Good
Is CuAAC “Click” Chemistry for Polymer Coupling Reactions?
J. Polym. Sci. Part A Polym. Chem. 2018, 56, 75–84.
Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. A Strain-Promoted
[3 + 2] Azide-Alkyne Cycloaddition for Covalent Modification
of Biomolecules in Living Systems. J. Am. Chem. Soc. 2004, 126,
15046–15047.
Tang, W.; Becker, M. L. “Click” Reactions: A Versatile Toolbox
for the Synthesis of Peptide-Conjugates. Chem. Soc. Rev. 2014,
43, 7013–7039.
(2)
(23)
(3)
(24)
(25)
Wilson, P. J.; Wells, J. H. The Chemistry and Utilization of
Cyclopentadiene. Chem. Rev. 1944, 34, 1–50.
Yameen, B.; Rodriguez-Emmenegger, C.; Preuss, C. M.; Pop-
Georgievski, O.; Verveniotis, E.; Trouillet, V.; Rezek, B.; Barner-
Kowollik, C. A Facile Avenue to Conductive Polymer Brushes
via Cyclopentadiene-Maleimide Diels-Alder Ligation. Chem.
Commun. 2013, 49, 8623–8625.
Inglis, A. J.; Sinnwell, S.; Stenzel, M. H.; Barner-Kowollik, C.
Ultrafast Click Conjugation of Macromolecular Building Blocks
at Ambien Temperature. Angew. Chem. Int. Ed. 2009, 48, 2411–
2414.
Yameen, B.; Zydziak, N.; Weidner, S. M.; Bruns, M.; Barner-
Kowollik, C. Conducting Polymer/SWCNTs Modular Hybrid
Materials via Diels-Alder Ligation. Macromolecules 2013, 46,
2606–2615.
Schenzel, A. M.; Moszner, N.; Barner-Kowollik, C. Self-
Reporting Dynamic Covalent Polycarbonate Networks. Polym.
Chem. 2017, 8, 414–420.
Nebhani, L.; Barner-Kowollik, C. Functionalization of Fullerenes
with Cyclopentadienyl and Anthracenyl Capped Polymeric
Building Blocks via Diels-Alder Chemistry. Macromol. Rapid
Commun. 2010, 31, 1298–1305.
Zydziak, N.; Hübner, C.; Bruns, M.; Barner-Kowollik, C. One-
Step Functionalization of Single-Walled Carbon Nanotubes
(SWCNTs) with Cyclopentadienyl-Capped Macromolecules via
Diels-Alder Chemistry. Macromolecules 2011, 44, 3374–3380.
Toncelli, C.; Bouwhuis, S.; Broekhuis, A. A.; Picchioni, F.
Cyclopentadiene-Functionalized Polyketone as Self-Cross-
Linking Thermo-Reversible Thermoset with Increased Softening
Temperature. J. Appl. Polym. Sci. 2015, 133, 42924.
Kennedy, J. P.; Castner, K. F. Synthesis of Substituted
(4)
(5)
(26)
(27)
(6)
(7)
(28)
(29)
(8)
(9)
Chadwick, R. C.; Van Gyzen, S.; Liogier, S.; Adronov, A.
Scalable Synthesis of Strained Cyclooctyne Derivatives.
Synthesis 2014, 46, 669–677.
(30)
(31)
(32)
(10)
(11)
Based on MilliporeSigma Price on June 10, 2019.
Dommerholt, J.; Rutjes, F. P. J. T.; van Delft, F. L. Strain-
Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and
Organic Azides. Top. Curr. Chem. 2016, 374, 16.
McNelles, S. A.; Adronov, A. Rapid Synthesis of Functionalized
High-Generation Polyester Dendrimers via Strain-Promoted
Alkyne-Azide Cycloaddition. Macromolecules 2017, 50, 7993–
(12)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Cyclopentadienes
and
Cyclopentadiene-Functionalized
Clicking for Polymer Functionalization and Coupling by
Polymers. Google Patents July 1980.
Tetrazine-Norbornene Chemistry. J. Am. Chem. Soc. 2011, 133,
13828–13831.
Khoury, P. R.; Goddard, J. D.; Tam, W. Ring Strain Energies:
1
2
3
4
5
6
7
8
(33)
(34)
(35)
Hughes, R. P.; Trujillo, H. A. Selective Solubility of
Organometallic Complexes in Saturated Fluorocarbons.
Synthesis of Cyclopentadienyl Ligands with Fluorinated
Ponytails. Organometallics 1996, 15, 286–294.
Inglis, A. J.; Paulöhrl, T.; Barner-Kowollik, C. Ambient
Temperature Synthesis of a Versatile Macromolecular Building
Block: Cyclopentadienyl-Capped Polymers. Macromolecules
2010, 43, 33–36.
Gonzalez, A.; Holt, S. L. Effect of Microemulsions on the Diels-
Alder Reaction: Endo/Exo Ratios in the Reaction of
Cyclopentadiene and Methyl Methacrylate. J. Org. Chem. 1982,
47, 3186–3188.
Pilgrim, B. S.; Roberts, D. A.; Lohr, T. G.; Ronson, T. K.;
Nitschke, J. R. Signal Transduction in a Covalent Post-Assembly
Modification Cascade. Nat. Chem. 2017, 9, 1276–1281.
Tuktarov, A. R.; Akhmetov, A. R.; Khuzin, A. A.; Dzhemilev, U.
M. Synthesis and Properties of Energy-Rich Methanofullerenes
Containing Norbornadiene and Quadricyclane Moieties. J. Org.
Chem. 2018, 83, 4160–4166.
Tanyeli, C.; Çelikel, G.; Akhmedov, I. M. Resolution of (±)-2-
Substituted Norbornadiene and Hexachloronorbornadiene
Derivatives Using CCL and PLE. Tetrahedron Asymmetry 2001,
12, 2305–2308.
Dalkiliç, E.; Güney, M.; Daştan, A.; Saracoglu, N.; Lucchi, O.
De; Fabris, F. Novel and Versatile Protocol for the Preparation of
Functionalized Benzocyclotrimers. Tetrahedron Lett. 2009, 50,
1989–1991.
Dalkiliç, E.; Daştan, A. Synthesis of Cyclopentadiene Derivatives
by Retro-Diels-Alder Reaction of Norbornadiene Derivatives.
Tetrahedron 2015, 71, 1966–1970.
Hansell, C. F.; Espeel, P.; Stamenović, M. M.; Barker, I. A.;
Dove, A. P.; Du Prez, F. E.; O'Reilly, R. K. Additive-Free
(42)
(43)
(44)
(45)
Substituted
Rings,
Norbornanes,
Norbornenes
and
Norbornadienes. Tetrahedron 2004, 60, 8103–8112.
Sauer, J.; Heinrichs, G. Kinetik Und Umsetzungen von 1.2.4.5-
Tetrazinen Mit Winkelgespannten Und Elektronenreichen
Doppelbindungen. Tetrahedron Lett. 1966, 7, 4979–4984.
Wilson, W. S.; Warrener, R. N. A Mild Retro-[ π 4 s + π 2 s ]
Cleavage Route to Furans and Fulvenes. J. Chem. Soc., Chem.
Commun. 1972, 4, 211–212.
Barlow, M. G.; Haszeldine, R. N.; Pickett, J. A. Heterocyclic
Polyfluoro-Compounds. Part 26. Synthesis of 3,6-Bis-
Trifluoromethyl-Pyridazines and -Dihydropyridazines. J. Chem.
Soc., Perkin Trans. 1 1978, 4, 378–380.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(36)
(37)
(46)
Oxtoby, N. S.; Blake, A. J.; Champness, N. R.; Wilson, C.
Structural Influence of Cis and Trans Coordination Modes of
Multi-Modal
Ligands
upon
Coordination
Polymer
Dimensionality. Dalton Trans. 2003, 20, 3838–3839.
(47)
(48)
Gao, H.; Matyjaszewski, K. Synthesis of Star Polymers by a
Combination of ATRP and the “Click” Coupling Method.
Macromolecules 2006, 39, 4960–4965.
Discekici, E. H.; St. Amant, A. H.; Nguyen, S. N.; Lee, I. H.;
Hawker, C. J.; Read de Alaniz, J. Endo and Exo Diels-Alder
Adducts: Temperature-Tunable Building Blocks for Selective
Chemical Functionalization. J. Am. Chem. Soc. 2018, 140, 5009–
5013.
(38)
(39)
(49)
Discekici, E. H.; Anastasaki, A.; Read de Alaniz, J.; Hawker, C.
J. Evolution and Future Directions of Metal-Free Atom Transfer
Radical Polymerization Macromolecules 2018, 51, 7421–7434.
(40)
(41)
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
Next generation norbornadiene “click” for polymer functionalization
4
5
6
7
O
N
N
N
N
Py
Py
O
O
N
R
N
R
C5H11
C5H11
O
one-pot, room temperature
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
ACS Paragon Plus Environment