Photocontrolled Radical Polymerization from Hydridic C-H Bonds

Article abstract of DOI:10.1021/jacs.0c00287

Given the ubiquity of carbon-hydrogen bonds in biomolecules and polymer backbones, the development of a photocontrolled polymerization selectively grafting from a C-H bond represents a powerful strategy for polymer conjugation. This approach would circumvent the need for complex synthetic pathways currently used to introduce functionality at a polymer chain end. On this basis, we developed a hydrogen-atom abstraction strategy that allows for a controlled polymerization selectively from a hydridic C-H bond using a benzophenone photocatalyst, a trithiocarbonate-derived disulfide, and visible light. We performed the polymerization from a variety of ethers, alkanes, unactivated C-H bonds, and alcohols. Our method lends itself to photocontrol which has important implications for building advanced macromolecular architectures. Finally, we demonstrate that we can graft polymer chains controllably from poly(ethylene glycol) showcasing the potential application of this method for controlled grafting from C-H bonds of commodity polymers.

Full text of DOI:10.1021/jacs.0c00287

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Communication
Photocontrolled radical polymerization from hydridic C–H bonds
Erin E Stache, Veronika Kottisch, and Brett P. Fors
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00287 • Publication Date (Web): 11 Feb 2020
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Photocontrolled radical polymerization from hydridic C–H bonds
Erin E. Stache, Veronika Kottisch†, and Brett P. Fors*
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Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
ABSTRACT: Given the ubiquity of carbon-hydrogen bonds in biomolecules and polymer backbones, the development of a photo-
controlled polymerization selectively grafting from a C–H bond would represent a powerful strategy for polymer conjugation. This
approach would circumvent the need for complex synthetic pathways currently used to introduce functionality at a polymer chain
end. On this basis, we have developed a hydrogen-atom abstraction strategy that allows for a controlled polymerization selectively
from a hydridic C–H bond using a benzophenone photocatalyst, a trithiocarbonate-derived disulfide, and visible light. We perform
the polymerization from a variety of ethers, alkanes, unactivated C–H bonds, and alcohols. Our method lends itself to photocontrol
which has important implications for building advanced macromolecular architectures. Finally, we demonstrate that we can graft
polymer chains controllably from poly(ethylene glycol) showcasing the potential application of this method for controlled grafting
from C–H bonds of commodity polymers.
Reversible-deactivation radical polymerizations (RDRPs)
represent one of the most versatile strategies for controlling
macromolecular architecture. Numerous synthetic methods
have been developed to obtain control over chain length and
dispersity. Reversible addition-fragmentation chain transfer
(RAFT) has emerged as a powerful tool for controlling radical
polymerizations.1-4 Additionally, photoinduced electron/energy
transfer (PET-RAFT) processes have been established as a
means to exact temporal and spatial control in these processes,5-
abstract a-oxy, a-amino, and hydrocarbon C–H bonds in con-
trast to a-acyl or more acidic C–H bonds. This selectivity will
also preclude unwanted C–H abstraction processes from the
growing polymer backbone of electron deficient monomers
used in controlled radical processes, which could lead to
undesirable cross-linking and branching.
Scheme 1. Design of HAT-RAFT polymerization
Ubiquity of C–H bonds in organic (macro)molecules
9
finding numerous applications for designing complex 3D
O
architectures.10 To employ these methods, however,
a
H
H3C
H
O
prefunctionalized initiator/chain transfer agent (CTA) must be
installed into a macromolecule, biomolecule, or small molecule
for a controlled polymerization. We envisioned a strategy that
eliminated the need for the preformation of a CTA and enabled
selective grafting of a polymer from hydridic C–H bonds would
be an opportunity to streamline macromolecular synthesis
(Scheme 1).11,12 The development of such a strategy would al-
low the direct formation of protein-polymer bioconjugates or
drug-polymer conjugates without prefunctionalization.13 Fur-
thermore, complex macromolecular architectures could be con-
trollably accessed via grafting from existing polymers in a sin-
gle step with spatial and temporal control.14
O
NH
CH3
n
n
H
O
H
H3C
CH3
small
molecules
polypeptides
proteins
polyethylene glycol polyethylene
(PEG) (PE)
• No existing method for in situ activation of a C–H bond
for a controlled radical polymerization
This work: Photocontrolled HAT-RAFT polymerization
R
S
S
n
SBu
HAT
H
S
R
S
SBu
Hydrogen-atom transfer (HAT) is a burgeoning synthetic
strategy to generate carbon centered radicals from C–H bonds.15
Benzophenone derivatives have been well demonstrated as
hydrogen-atom abstraction agents when excited with visible
light and the resultant ketyl radical acts as an electron donor.16,17
We hypothesized that radical polymerizations could be initiated
small molecules
biomolecules
polymers
BuS
S
S
bench stable
disulfide
• Photocontrolled radical polymerization from a C–H bond using
visible light
• Triplet sensitized ketone as photocatalyst and HAT agent
using this mechanism.18-20
Importantly,
benzophenone
derivatives, in the triplet excited state, can chemoselectively
abstract electron rich, hydridic C–H bonds, which would allow
the precise selection of grafting sites.21 The photogenerated
electrophilic oxygen-centered radical has been shown to
In an approach where we initiate polymerization with C–H
abstraction, we envisioned that control over the polymerization
could be imbued by a RAFT process via addition of a CTA.
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weights by changing the disulfide to monomer ratio (entries 2-
Page 2 of 6
However, the a-chain end of the final polymer would arise from
the chain end of the CTA, rather than the C–H bond initiator.
Therefore, to achieve efficient grafting we needed to develop a
method where the CTA was synthesized in situ from the radical
formed through C–H abstraction. We hypothesized that the use
of a precursor disulfide could effectively generate the CTA in
situ and provide the desired a-chain end (Scheme 1).
Additionally, this strategy should allow the employment of
multiple monomer classes with a single disulfide precursor,
without matching designed CTAs to a specific monomer, as a
macro-CTA would be generated in situ. After formation of the
CTA, further generation of radicals via HAT would grow
polymer chains controllably. The radical concentration could be
controlled by both the photocatalyst and the H-atom source
loading. This process could also lend itself to photocontrol, as
in the absence of light, radical chains would become dormant.
Upon generation of radical initiators via the light-gated HAT
process, a photocontrolled radical polymerization, initiated
from a ubiquitous C–H bond, would be obtained.
1
2
3
4
5
6
7
8
5). When CTA 1b was used in place of the disulfide and in the
absence of H-atom source, we observed no polymerization
(entry 6), suggesting that the excited state of the photocatalyst
cannot engage in PET-RAFT processes, nor is direct excitation
of the CTA responsible for polymerization under standard
conditions.22 Furthermore, when the polymerization was
conducted without photocatalyst, no conversion was observed,
precluding direct excitation of the disulfide to induce
polymerization (entry 7). With the optimized conditions, we
sought to explore the scope of the method to other monomer
classes. Benzyl acrylate (BnA) was efficiently polymerized
with good agreement between theoretical and experimental
molecular weight with excellent control over molecular weight
distribution (Table 1, entry 8). Methacrylates could be
polymerized under these reaction conditions, but similar results
were obtained in the absence of photocatalyst or HAT source
suggesting a competitive iniferter process.22,23
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When monitoring the reaction, we observed an induction
period prior to polymerization. After this initial period, it was
observed that Mn increased linearly with conversion, suggesting
a controlled radical process (Figure 1a). Unlike traditional
radical RAFT processes, we observed a small increase in
dispersity over time. We attribute this increase to continued
generation of alkyl radical and termination events. We also
hypothesized that the system may also be amenable to temporal
control, rather than just a photoinitiated process, if a traditional
radical RAFT mechanism is invoked. To test this hypothesis,
the polymerization was intermittently exposed to light while
monitoring conversion (Figure 1b). Gratifyingly, we observed
that conversion ceased upon removal from irradiation.
Moreover, polymerization continued upon additional
irradiation. This process was repeated, including a long “off”
period, in which polymerization was only observed in the
presence of the CFL.
Table 1. HAT-mediated polymerization of acrylates
SBu
S
1a, 2
O
O
n
S
dioxane, CFL
CO2R
RO
O
R = Me or Bn
theo
exp
Mn
(kg/mol)
Mn
(kg/mol)
entrya
[M]:[1a]:[2]
Đ
monomer
1
2
3
4
5
MA
MA
MA
MA
MA
MA
MA
BnA
100:1:0.5
50:1:0.5
5.3
2.4
8.9
4.6
1.12
1.26
1.15
1.17
1.13
n.d.
200:1:0.5
400:1:0.5
1000:1:0.5
100:1:0.5
100:1:0
10.2
17.8
54.3
0.0
13.8
21.8
51.5
n.d.
n.d.
19.0
O
6b
7
0.0
n.d.
8
100:1:0.5
16.0
1.23
To test the trithiocarbonate chain end fidelity of our
polymers, we isolated a sample of PMA synthesized under our
standard polymerization conditions. We then subjected the
macro-CTA to a solution of AIBN and BnA monomer in
benzene at 65 °C (Figure 1c). We observed efficient chain
extension under these conditions, obtaining a PMA-b-PBnA
copolymer with good matching of Mntheo and Mnexp and narrow
Đ. The GPC trace did indicate some remaining PMA macro-
CTA, and we attribute the incomplete conversion to reductive
termination events during the HAT-RAFT polymerization.
Based on GPC data of isolated homopolymer and copolymer,
we estimate 78% chain extension.
S
S
Me
S CO2H
S
SBu
BuS
S
BuS
S
F3CO
OMe
1a
1b
2
a Monomer (filtered through basic alumina), disulfide 1a, and
photocatalyst 2 dissolved in dioxane (0.04 M in 1a), degassed and
b
irradiated with a CFL. CTA 1b, used in place of 1a and 1,2-di-
chloroethane used as a solvent.
We began our studies employing disulfide 1a, photocatalyst
2,16 and dioxane as both the solvent and H-atom source. We
hypothesized that we could control the radical concentration of
this process by simply modifying the concentration of
photocatalyst while using the solvent as an H-atom source.
Methyl acrylate (MA) was efficiently polymerized in the
presence of a compact fluorescent lamp (CFL) with a narrow
dispersity (Đ) (Table 1, entry 1). The experimental molecular
weight (Mnexp) showed good agreement with theoretical
molecular weight (Mntheo), which was calculated such that one
disulfide gives one polymer chain. We were able to identify in-
initiation from dioxane as the major chain end by MALDI-TOF
(see supporting information for more details). In the absence of
disulfide, the polymerization is rapid and uncontrolled;
however, in the absence of light or H-atom source (1,2-
dichloroethane used as a solvent), no conversion of MA is
observed (see supporting information for more details).
Additionally, we could effectively target different molecular
Given these results, we propose the following mechanism
(Figure 1d). Upon excitation with visible light, photocatalyst 2
forms triplet excited state I. This diradical will abstract a
hydridic C–H bond to form alkyl radical II, which will
subsequently add to monomer to form a propagating polymer
chain. After homolysis with visible light, disulfide 1a can form
two trithiocarbonyl radicals (III), one of which can combine
with the electrophilic chain end to form macro-CTA (IV). Al-
ternatively, the electrophilic chain end can add to disulfide 1a
and generate III. The remaining radical (III) can be
subsequently reduced by the photocatalyst radical V to generate
the trithiocarbonic acid and turnover the catalyst. Upon
formation of IV, we propose that additional alkyl radicals are
generated from excitation of the photocatalyst to maintain a
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1.3
a)
b)
60
50
40
30
20
10
0
1.25
1.2
OFF
OFF
6
1.15
1.1
4
OFF
9
exp
Series1
Series2
Đ
Mn
OFF
2
1.05
1
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0
0
3
6
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15
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21
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27
0
20
40
60
80
100
Time (h)
Conversion (%)
c)
d)
S
O
BuS
SH
AIBN
S
SBu
O
n
Ar1
Ar2
CO2Bn
PhH, 65 °C
S
2
O MeO
O
SET
S
SBu
PT
O
O
S
m
SBu
b
S
n
O
III
S
OH
Ar2
O
O
O
O
Ar1
Ar2
Me
Bn
Ar1
I
Mnexp = 11.8 kg/mol
Đ = 1.11
PMA-b-PBnA
V
HAT
E1/2red = -2.05V
Mnexp = 28.3 kg/mol
Đ = 1.30
O
O
O
O
h!
S
SBu
H
2
1a
II
S
MA
III
S
Pn•
1a or III
Pn
BuS
S
S
S
SBu
IV
10
11
12
13
14
15
16
17
18
III
Retention time (min)
Figure 1. a) Linear growth of molecular weight vs. conversion. b) Temporal control of polymerization with intermittent light. c) Thermal
RAFT chain extension of PMA with BnA. d) Proposed mechanism; see Figure S47 for a full description of the proposed mechanism.
active RAFT process (see supporting information for a full
proposed mechanism). In the absence of light, termination
events generate an inactive polymerization state, but upon
generation of additional radical with irradiation, the RAFT
process can be restarted Termination events include reduction
of an active chain end to form an anion which will be rapidly
protonated, in addition to radical-radical coupling.24,25
served as C–H initiators, with N-methyl pyrrolidinone affording
similar results to THF, and even Cbz-(L)-proline methyl ester
afforded a well-
1a, 2
S
SBu
H
n
R
R
DCE, CFL
CO2Me
ethersa
S
(equiv)
MeO
O
acidic C-Ha
O
H
Me Me
H
O
H
To apply this method to various applications, such as grafting
from an existing polymer or biomolecule, we recognized that
using solvent quantities of C–H coupling partner may be
inefficient.16, 26-28 We therefore examined a number of C–H
initiators in reagent quantities relative to disulfide. In C–H
initiators with lower BDEs or more hydridic C–H bonds,29
radical initiation becomes more facile and when THF was used
as a solvent in a similar manner to Table 1, a completely
uncontrolled polymerization was observed. For THF, we found
that by reducing the C–H initiator concentration to 20
Me
O
(20)
Me
H
O
(256)
n.d.
n.d.
CH3
(20)
exp
9.8 kg/mol
1.33
7.2 kg/mol
7.1 kg/mol
1.05
3.5 kg/mol
Mn
Đ
theo
0.0 kg/mol
Mn
amidesa
alcoholsa
H
H
O
OH
H3C
OH
N
H
Me
(20)
(20)
(50)
8.0 kg/mol
1.08
4.3 kg/mol
12.3 kg/mol
1.18
7.8 kg/mol
12.1 kg/mol
1.21
8.5 kg/mol
equivalents, we were able to achieve
a
controlled
strong C–H bondsa
polymerization (Figure 2). When ethyl acetate was used as the
H-atom source, even in solvent quantities, no polymerization
was observed. Given the lack of hydridic C–H bonds in ethyl
acetate, this result is consistent with highly selective HAT
processes and suggests that unwanted abstraction from the
backbone of the polymer chain can be avoided.30 Amides also
H
H
CO2Me
Me
O
N
Cbz
H
O
OH
(20)
10.0 kg/mol
1.09
(116)
11.0 kg/mol
1.11
(50)
9.9 kg/mol
1.30
5.6 kg/mol
6.0 kg/mol
8.9 kg/mol
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Page 4 of 6
Figure 2. Examples of C–H initiators to mediate HAT-RAFT
use of a benzophenone derivative and visible light. We can
access a controlled polymerization by employing a RAFT
process, which can be accessed via an inexpensive and easily
modifiable disulfide. We have highlighted future applications
of this method in controlled polymerization from biomolecules
as well as commercial or commodity polymers.
polymerization, including controlled grafting from PEG. a MA (100
equiv, filtered through basic alumina), disulfide 1a (1 equiv), 2
(0.75-1.0 equiv) and C–H coupling partner (20-116 equiv)
dissolved in DCE (0.04 M in 1a), degassed and irradiated with a
CFL.
1
2
3
4
5
6
7
8
9
controlled polymerization, suggesting that biomolecules may serve
as C–H initiators in bioconjugation. Alcohols were also demon-
strated to function as initiators in this chemistry, with benzyl alco-
hol and ethanol affording well controlled polymerizations.31 Excit-
ingly, diethylene glycol monomethyl ether, a mimic for poly(eth-
ylene glycol) (PEG) afforded a well-controlled polymerization.
Furthermore, cyclohexane, with a C–H BDE of 100 kcal/mol af-
forded the desired PMA, albeit at higher C–H initiator loadings.
Cyclohexane is representative of a polyolefin, such as polyeth-
ylene, and provides future opportunities for grafting from commod-
ity polymers.14,32
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
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brief description (file type, i.e., PDF)
AUTHOR INFORMATION
Corresponding Author
PEG Graft
* bpf46@cornell.edu
Me
MA,
1a, 2
O
O
O
Me
Me
nO
OMe
Present Addresses
Me
nO
m
CFL
H
O
S
† Department of Chemistry, Massachusetts Institute of Technol-
ogy, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
x
S
SBu
13C NMR
Notes
PEG-2000
Any additional relevant notes should be placed here.
a) 300 equiv MA
b) 100 equiv MA
ACKNOWLEDGMENT
This work was supported by the NSF under the award number
CHE-1752140 (B.P.F). Additionally, this work made use of the
NMR Facility at Cornell University and is supported, in part, by the
NSF under the award number CHE-1531632. This work made use
of the Cornell Center for Materials Research Facilities supported
by the National Science Foundation under Award Number DMR-
1719875. B.P.F. thanks 3M for a Non-Tenured Faculty Award and
the Alfred P. Sloan Foundation for a Sloan Research Fellowship.
E.E.S acknowledges the Cornell Presidential Postdoctoral Fellow-
ship for financial support.
ꢀꢀ ꢅꢄꢀ
ꢅꢃꢀ
ꢅꢂꢀ
ꢅꢁꢀ
ꢅꢀꢀ
ꢆꢅꢇꢈꢉꢉꢊꢋ
ꢄꢀ
ꢃꢀ
ꢂꢀ
ꢁꢀ
ꢀ
a) Mnexp = 26.7 kg/mol
Đ = 1.16
b) Mnexp = 8.3 kg/mol
Đ = 1.12
REFERENCES
Figure 3. MA (100 or 300 equiv), poly(ethylene glycol) dimethyl
ether (3 equiv, MW = 2.0 kg/mol), 1a (1.0 equiv), 2 (1.0 equiv),
degassed and irradiated with a CFL.
(1) Keddie, D. J.; Moad, G.; Rizzardo, E.; Thang, S. H. RAFT agent
design and synthesis. Macromolecules 2012, 45, 5321-5342.
(2) Perrier, S. 50th Anniversary Perspective: RAFT–A user guide.
Macromolecules 2017, 50, 7433-7447.
Lastly, we demonstrated that a PEG polymer could also serve
as a C–H initiator (Figure 3). Under slightly modified
conditions, we employed 3 equivalents of a 2.0 kg/mol PEG-
dimethyl ether and obtained well controlled MA
polymerizations. With increasing amounts of C–H initiator
polymer, we observed increased conversion and molecular
weight (see SI for more details). We also observed that we could
achieve graft copolymers of designed molecular weight, 8.3
kg/mol to 26.7 kg/mol, by altering the equivalents of monomer.
Currently, there are no other examples of in situ controlled
grafting from a C–H bond of a PEG polymer.11,12 Excitingly, we
observe that even after precipitation, and removal of PEG
confirmed via GPC analysis, that a signal for PEG is observed
in the 13C NMR of the precipitated polymer.33 Furthermore, no
PEG degradation is observed via GPC analysis, highlighting the
advantage of our method for functionalizing PEG, where the
installation of thiocarbonyl compounds results in PEG decom-
position.
(3) a) McKenzie, T. G.; Fu, Q.; Uchiyama, M.; Satoh, K.; Xu, J.;
Boyer, C.; Kamigaito, M.; Qiao, G. G. Beyond traditional RAFT: Al-
ternative activation of thiocarbonylthio compounds for controlled
polymerization. Adv. Sci. 2016, 3, 1500394. b) Wu, C.; Corrigan, N.;
Lim, C.-H.; Jung, K.; Zhu, J.; Miyake, G.; Xu, J.; Boyer, C. Guiding
the design of organic photocatalyst for PET-RAFT polymerization:
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Gennaro, A.; Matyjaszewski, K. Toward electrochemically mediated
reversible addition–fragmentation chain-transfer (eRAFT) polymeriza-
tion: Can propagating radicals be efficiently electrogenerated from
RAFT agents? Macromoelcules 2019, 52, 1479-1488.
(5) Otsu, T.; Yoshida, M. ole of initiator‐transfer agent‐terminator
(iniferter) in radical polymerizations: Polymer design by organic disul-
fides as iniferters. Makromol. Chem., Rapid Commun. 1982, 3, 127-
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Polym. Sci. Part A: Polym. Chem. 2000, 38, 2121-2136.
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and versatile photoinduced living polymerization of conjugated and
We have demonstrated that ubiquitous C–H bonds can serve
as radical initiators for controlled radical polymerizations via
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unconjugated monomers and its oxygen tolerance. J. Am. Chem. Soc.
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loring the structure of polymer networks with iniferter-mediated photo-
growth. Polym. Chem. 2016, 76, 2955-2964. b) McKenzie, T. G.; Fu,
Q.; Wong, E. H. H.; Dunstan, D. E.; Qiao, G. G. Visible light mediated
controlled radical polymerization in the absence of exogenous radical
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(23) We observed a background reaction that gives similar results to
the HAT-RAFT process in the absence of dioxane (DCE used as a sol-
vent) or photocatalyst for MMA and BMA. This is likely due to direct
excitation of the disulfide and resultant CTA through an iniferter pro-
cess, see Ref. 5,6, 21.
1
2
3
4
5
6
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