A General Approach to Sequence-Controlled Polymers Using Macrocyclic Ring Opening Metathesis Polymerization

Article abstract of DOI:10.1021/jacs.5b04940

A new and general strategy for the synthesis of sequence-defined polymers is described that employs relay metathesis to promote the ring opening polymerization of unstrained macrocyclic structures. Central to this approach is the development of a small molecule "polymerization trigger" which when coupled with a diverse range of sequence-defined units allows for the controlled, directional synthesis of sequence controlled polymers.

Full text of DOI:10.1021/jacs.5b04940

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Communication
A General Approach to Sequence-Controlled
Polymers Using Macrocyclic ROMP
Will R. Gutekunst, and Craig J. Hawker
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2015
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A General Approach to Sequence-Controlled Polymers Using
Macrocyclic ROMP
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†
† ‡
,
Will R. Gutekunst* and Craig J. Hawker*
†
Materials Department, Materials Research Laboratory, University of California, Santa Barbara, California 93106, United
States
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡
Supporting Information Placeholder
ABSTRACT: A new and general strategy for the syn-
thesis of sequence-defined polymers is described
that employs relay metathesis to promote the ring
opening polymerization of unstrained macrocyclic
structures. Central to this approach is the develop-
ment of a small molecule “polymerization trigger”
which when coupled with a diverse range of se-
quence-defined units allows for the controlled, di-
rectional synthesis of sequence controlled polymers.
Biopolymers, such as proteins and DNA, clearly illus-
trate the power of defined polymer sequences, with
remarkable functions such as catalysis, molecular
recognition and data storage emerging. Inspired by
these natural, sequence-defined materials, strategies
to control the primary structure of synthetic poly-
mers has become an active area of research with the
aim to develop materials with next-generation per-
1
formance and functions. Synthetic methods for se-
quence-controlled polymerization fall into three
Scheme 1. Development of macrocyclic ROMP
general categories: iterative, step-growth and chain-
growth. Iterative strategies employ the classic Merri-
field approach in which each monomer is appended
7
ing metathesis polymerization (ROMP), and multi-
8
2
block copolymers. In order to combine the sequence
to the chain end sequentially. This leads to highly
precision of step-growth methods with the function-
al group tolerance and chain-growth characteristics
of ROMP, the living polymerization of sequence-
defined macrocycles is reported herein.
controlled microstructures, but is unable to produce
high molecular weights and is generally time inten-
sive. Step-growth approaches, such as click polymer-
3
4
ization or ADMET can generate elaborate periodic
polymers from preformed sequences, but lack con-
trol over polymer molecular weight and dispersity. In
contrast, chain-growth strategies have controlled
polymerization characteristics, but lack a high level
of sequence precision when compared to the previ-
ous methods. Recent advances in chain-growth
chemistry include the timed addition of kinetically
The challenge inherent to this approach is the lack of
ring strain for macrocycles when compared with tra-
ditional ROMP monomers (Scheme 1A). Inspiration
for this new strategy originates from Hoye’s seminal
9
work on relay-ring closing metathesis. A tandem
reaction was therefore desired that could “relay” a
ruthenium carbene to affect a kinetically driven, in-
tramolecular ring-opening of the macrocyclic olefin.
Further encouragement derives from
5
6
fast monomers, templated polymerizations, cy-
clooctene ring open-
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Scheme 3. Synthesis and x-ray crystal structure of
macrocyclic monomer 9
Scheme 2. Polymerization trigger synthesis
Choi’s polymerization of an unstrained cyclohexene
“sequence” was investigated. The macrocyclic mon-
10
using an alkyne unit as the relay (Scheme 1B).
omer 9 was prepared as shown in Scheme 3, involv-
ing EDC coupling, deprotection with TFA, and
HATU mediated macrocyclization. Significantly, the
macrocyclization gave the crystalline, 17-membered
monomer 9 in a very reasonable 79% yield.
While NHC-ligated Grubbs catalysts are highly reac-
11
tive towards terminal alkynes, the resulting vinyl
ruthenium carbenes are usually resistant to further
metathesis chemistry. As a result, the key to this pro-
cess is the close proximity of the cyclohexene olefin
to the alkyne, permitting fast intramolecular cycliza-
tion and rapid polymerization. Given this precedent,
it was reasoned that an unstrained macrocyclic
enyne should also be a competent monomer. With
this idea in mind, a small molecule “polymerization
trigger” was envisioned that contains the critical
enyne motif and also functional handles for incorpo-
ration of arbitrary macrocyclic sequences (Scheme
Initial attempts to polymerize macrocycle 9 with
rd
Grubbs 3 generation catalyst (G3) revealed solubili-
ty issues in THF, DCM and other traditional solvents.
While a DCM/methanol solvent system resulted in
homogeneous polymerization, rapid chain transfer
caused considerable broadening of the PDIs. Howev-
er, adding 3,5-dichloropyridine as
Table 1. Polymerization of macrocyclic monomer 9
1
C).
In order to test this concept, an efficient and scalable
synthesis of the polymerization trigger was devised
starting from readily available saccharin 1, a com-
mercial artificial sweetener. N-alkylation of saccha-
rin with propargyl bromide gives 2, which was then
subjected to a one-pot difunctionalization sequence
(Scheme 2). First, the saccharin heterocycle was re-
gioselectively ring-opened with veratryl alcohol 3, an
acid labile protecting group, to generate an interme-
diate sulfonamide anion. Addition of acetoxy allyl
bromide 4 to this anion in the same pot furnished
the desired enyne system 5 as a crystalline solid in 68
a
a
b
entry time (min) M/I
M
(g/mol)
Đ
conversion
38%
n
1
1
2
50
50
50
50
12.5
25
11,500
1.07
1.12
1.20
1.30
1.18
1.19
1.26
1.51
2
3
4
5
6
7
8
17,100
48%
5
22,100
24,900
8,500
79%
%
yield. Finally, the acetate was quantitavely cleaved
15
3
98%
with sodium methoxide to give the monoprotected
polymerization trigger 6. Notably, this short se-
quence employs inexpensive, readily available rea-
gents and does not require column chromatography,
as each intermediate is isolated via precipitation or
recrystallization.
90%
5
12,800
21,000
32,900
91%
10
15
50
75
89%
95%
a
Determined using DMF size exclusion chromatog-
b
In order to evaluate the competency of the polymeri-
zation trigger, a simple aliphatic amino acid
raphy calibrated with polystyrene standards. Deter-
mined by crude H-NMR.
1
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Table 2. Polymerization of sequenced macrocycles 10 and 11
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a
a
b
entry
monomer
time (min)
M/I
25
M (g/mol)
Đ
conversion
81%
n
1
10
10
11
11
11
11
5
10
3
10,800
19,300
9,400
1.18
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50
1.27
1.16
1.15
92%
12.5
25
77%
5
16,300
32,600
41,400
81%
10
15
50
1.26
1.39
92%
75
84%
a
b
Determined using DMF size exclusion chromatography calibrated with polystyrene standards. Determined by
1
crude H-NMR.
additional ligand resulted in controlled polymeriza-
ROMP. These monomers proved to polymerize slow-
er than 9 using the developed reaction conditions,
but reducing the amount of ligand to 20 mM led to
comparable reaction rates. Under these conditions,
both monomer 10 (entries 1 and 2) and monomer 11
(entries 3-6) produced sequence-defined polymers
with accurate control over molecular weight and low
polydispersity. For example, entry 4 gave P-11 with
tion of 9 to P-9 with excellent olefin stereoselectivity
1
2
(
9:1 E/Z), as shown in Table 1. When the polymeri-
zation was performed with a monomer to initiator
ratio (M/I) of 50:1 (entries 1–4), conversion of the
monomer increased with molecular weight over
time, with full conversion reached in 15 minutes at 0°
13
C. Further support for the chain growth and con-
trolled nature of this polymerization is the ability to
target different molecular weights by varying the
M/I, with high conversions being obtained in each
case (entries 5–8). This demonstrates the synthetic
utility of this novel macrocyclic ROMP as a variety of
polymers can be prepared with excellent control over
molecular weight and molecular weight distribution.
M of 32,600 and a PDI of 1.26, which corresponds to
n
a polymer chain consisting of ~250 perfectly se-
quenced units. This readily illustrates the precision
and wide range of chemical diversity that can be in-
corporated into these synthetic polymers with func-
tionality ranging from chiral esters to sulfonamides
to amides.
With this proof of concept established and general
conditions developed, more elaborate sequences
were developed following Meyer’s work on se-
A further unique aspect of this methodology com-
pared to traditional ROMP is the ability to control
functionality in the backbone of the polymer. Tradi-
tional ROMP polymers are not hydrolytically de-
gradable, a quality that limits their use in a number
14
quenced polyesters. The hybrid-polyester mono-
mers 10 and 11 were readily prepared using iterative
15
16
coupling methods (See SI for details), resulting in
0 and 23-membered macrocycles, respectively (Ta-
of applications. Since P-10 and P-11 are polyesters,
2
they can break down into their small molecule con-
stituents. To demonstrate this reactivity, P-11 was
degraded with triazabicyclodecene (TBD) using
ble 2). The monomers are comprised of the polymer-
ization trigger attached to a series of glycolate (Gly),
17
(
S)-lactate (Lact), (S)-phenyllactate (PhLact), and
conditions developed by Leibfarth and coworkers.
The reaction was readily followed by GPC analysis
β
beta-alanine ( Ala) units to give ABCD and/or E se-
quences that will be displayed in the backbone after
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Scheme 4. Degradation of P-11 with TBD
*hawker@mrl.ucsb.edu
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the MRSEC program of the National Science
Foundation (DMR 1121053, W.R.G. and C.J.H.) for fund-
ing. W.R.G thanks the NIH for a postdoctoral fellowship
(F32GM108323). We also thank Dr. Guang Wu (UCSB)
for X-ray analysis.
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REFERENCES
1
. (a) Lutz, J.-F., Polym. Chem. 2010, 1, 55-62; (b) Badi, N.; Lutz,
J.-F., Chem. Soc. Rev. 2009, 38, 3383.; (c) Lutz, J.-F.; Ouchi, M.;
Liu, D. R.; Sawamoto, M., Science 2013, 341.
2. (a) Merrifield, R. B., J. Am. Chem. Soc. 1963, 85, 2149; (b)
Espeel, P.; Carrette, L. L. G.; Bury, K.; Capenberghs, S.;
Martins, J. C.; Du Prez, F. E.; Madder, A., Angew. Chem. Int.
Ed. 2013, 52, 13261; (c) Pfeifer, S.; Zarafshani, Z.; Badi, N.; Lutz,
J.-F., J. Am. Chem. Soc. 2009, 131, 9195; (d) Rosales, A. M.;
Segalman, R. A.; Zuckermann, R. N., Soft Matter 2013, 9, 8400.
3
4
. Chen, Y.; Guan, Z., J. Am. Chem. Soc. 2010, 132, 4577.
. (a) Atallah, P.; Wagener, K. B.; Schulz, M. D., Macromolecules
013, 46, 4735; (b) Li, Z.-L.; Lv, A.; Du, F.-S.; Li, Z.-C.,
Macromolecules 2014, 47, 5942.
with a dramatic molecular weight reduction ob-
served after only 30 seconds and complete conver-
sion to small molecule methyl esters (12–15) after two
hours (Scheme 4). These degradation experiments
highlight the enabling nature of this macrocyclic
ROMP strategy for accessing sequence-defined pol-
ymers, as well as for introducing specific properties
into these materials.
2
5. (a) Pfeifer, S.; Lutz, J.-F., J. Am. Chem. Soc. 2007, 129, 9542; (b)
Schmidt, B. V. K. J.; Fechler, N.; Falkenhagen, J.; Lutz, J.-F.,
Nat. Chem. 2011, 3, 234; (c) Zamfir, M.; Lutz, J.-F., Nat.
Commun. 2012, 1138; (d) Moatsou, D.; Hansell, C. F.; O'Reilly,
R. K., Chem. Sci. 2014, 5, 2246.
6
. (a) Hibi, Y.; Ouchi, M.; Sawamoto, M., Angewandte Chemie
2011, 123, 7572; (b) Niu, J.; Hili, R.; Liu, D. R., Nat. Chem. 2013,
5, 282.
In summary, a small molecule polymerization trig-
ger 6 has been developed that allows for the facile
synthesis and polymerization of unstrained macro-
cyclic sequences. For the first time, polymers with
arbitrary functionality (ester, amide, sulfonamide,
aliphatic, aromatic, heterocyclic, etc.) within the
backbone can be produced while still providing con-
trol over molecular weight and molecular weight
distribution. Future work will examine the general
nature of this platform and its application to the
synthesis copolymers with traditional ROMP mon-
omers for the creation of new functional materials
with applications in fields ranging from catalysis to
self-assembly to drug delivery.
7. (a) Zhang, J.; Matta, M. E.; Hillmyer, M. A., ACS Macro Lett.
2012, 1, 1383; (b) Kobayashi, S.; Pitet, L. M.; Hillmyer, M. A., J.
Am. Chem. Soc. 2011, 133, 5794.
8
. (a) Gody, G.; Maschmeyer, T.; Zetterlund, P. B.; Perrier, S.,
Macromolecules 2014, 47, 3451; (b) Anastasaki, A.; Nikolaou,
V.; Pappas, G. S.; Zhang, Q.; Wan, C.; Wilson, P.; Davis, T. P.;
Whittaker, M. R.; Haddleton, D. M., Chem. Sci. 2014, 5, 3536.
9. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,
H., J. Am. Chem. Soc. 2004, 126, 10210.
10. (a) Park, H.; Choi, T.-L., J. Am. Chem. Soc. 2012, 134, 7270; (b)
Park, H.; Lee, H.-K.; Choi, T.-L., J. Am. Chem. Soc. 2013, 135,
10769.
11. Lee, O. S.; Kim, K. H.; Kim, J.; Kwon, K.; Ok, T.; Ihee, H.; Lee,
H.-Y.; Sohn, J.-H., J. Org. Chem. 2013, 78, 8242.
12. Kang, E.-H.; Yu, S. Y.; Lee, I. S.; Park, S. E.; Choi, T.-L., J. Am.
Chem. Soc. 2014, 136, 10508.
13. During polymerization a monomer isomerization process is
observed (15-20%); see SI for discussion.
ASSOCIATED CONTENT
14. (a) Li, J.; Rothstein, S. N.; Little, S. R.; Edenborn, H. M.;
Meyer, T. Y., J. Am. Chem. Soc. 2012, 134, 16352; (b) Li, J.;
Stayshich, R. M.; Meyer, T. Y., J. Am. Chem. Soc. 2011, 133,
Experimental procedures for preparation of all compounds
and characterization data for all compounds. This material
is available free of charge via the Internet at
http://pubs.acs.org.
6910.
1
5. (a) Takizawa, K.; Nulwala, H.; Hu, J.; Yoshinaga, K.; Hawker,
C. J., J. Poly. Sci., Part A: Polym. Chem. 2008, 46, 5977; (b)
Takizawa, K.; Tang, C.; Hawker, C. J., J. Am. Chem. Soc. 2008,
130, 1718.
AUTHOR INFORMATION
16. Fishman, J. M.; Kiessling, L. L., Angew. Chem. Int. Ed. 2013, 52,
5061.
Corresponding Author
*willgute@mrl.ucsb.edu
17. Leibfarth, F. A.; Moreno, N.; Hawker, A. P.; Shand, J. D., J.
Poly. Sci., Part A: Polym. Chem. 2012, 50, 4814.
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