Mechanistic Insights into Temperature-Dependent Trithiocarbonate Chain-End Degradation during the RAFT Polymerization of N-Arylmethacrylamides

Article abstract of DOI:10.1021/acs.macromol.5b02463

Mechanistic insights into trithiocarbonate degradation during the RAFT polymerization of N-arylmethacrylamides are reported. Previous work by our group showed significant RAFT agent degradation during the polymerization of N-arylmethacryloyl sulfonamides at 70 °C. Herein we report the influence of methacrylamide structure on trithiocarbonate degradation during the RAFT polymerizations of N-phenylmethacrylamide (PhMA) and N-benzylmethacrylamide (BnMA) in DMF at 70 and 30 °C. UV-vis spectroscopy revealed trithiocarbonate degradation occurs exclusively after covalent addition of monomer to the RAFT agent, with 60% trithiocarbonate degradation occurring after 12 h during the polymerization of PhMA at 70 °C compared to only 3% degradation measured during the polymerization of BnMA under identical conditions. Small molecule analogues of trithiocarbonate-functional poly(PhMA) and poly(BnMA) were synthesized by single monomer unit insertion and the kinetics and byproducts of degradation investigated by in situ ¹H NMR analysis at 70 °C. Trithiocarbonate degradation was ultimately shown to occur by N-phenyl-promoted, N-5 nucleophilic attack on the terminal thiocarbonyl by the ultimate methacrylamide unit.

Full text of DOI:10.1021/acs.macromol.5b02463

Article
pubs.acs.org/Macromolecules
Mechanistic Insights into Temperature-Dependent Trithiocarbonate
Chain-End Degradation during the RAFT Polymerization of
N‑Arylmethacrylamides
Brooks A. Abel† and Charles L. McCormick*,†,‡
‡
†Department of Polymer Science and Engineering and Department of Chemistry and Biochemistry, The University of Southern
Mississippi, Hattiesburg, Mississippi 39406-5050, United States
S
* Supporting Information
ABSTRACT: Mechanistic insights into trithiocarbonate deg-
radation during the RAFT polymerization of N-arylmethacryl-
amides are reported. Previous work by our group showed
significant RAFT agent degradation during the polymerization
of N-arylmethacryloyl sulfonamides at 70 °C. Herein we report
the influence of methacrylamide structure on trithiocarbonate
degradation during the RAFT polymerizations of N-phenyl-
methacrylamide (PhMA) and N-benzylmethacrylamide
(BnMA) in DMF at 70 and 30 °C. UV−vis spectroscopy
revealed trithiocarbonate degradation occurs exclusively after
covalent addition of monomer to the RAFT agent, with 60%
trithiocarbonate degradation occurring after 12 h during the polymerization of PhMA at 70 °C compared to only 3% degradation
measured during the polymerization of BnMA under identical conditions. Small molecule analogues of trithiocarbonate-
functional poly(PhMA) and poly(BnMA) were synthesized by single monomer unit insertion and the kinetics and byproducts of
degradation investigated by in situ 1H NMR analysis at 70 °C. Trithiocarbonate degradation was ultimately shown to occur by N-
phenyl-promoted, N-5 nucleophilic attack on the terminal thiocarbonyl by the ultimate methacrylamide unit.
successfully chain extend a poly(MSA) macro-chain-transfer
agent (macro-CTA). However, narrow molecular weight
distributions and controlled molecular weights were ultimately
achieved by conducting the polymerizations at 30 °C. The poor
polymerization control of MSAs at 70 °C surprisingly contrasts
numerous literature reports of successful RAFT polymer-
izations of (meth)acrylamides in organic and aqueous media at
temperatures greater than 60 °C,13,21−25 thus prompting our
current investigation.
INTRODUCTION
■
The acknowledged utility of reversible-deactivation radical
polymerization (RDRP) is the facile synthesis of polymers with
precise compositions, predetermined molecular weights, and
well-defined architectures while incorporating monomers
possessing a wide variety of functional groups.1−4 The success
of any RDRP technique depends greatly upon maintaining
“living” chain end fidelity. In particular, the reversible addition−
fragmentation chain transfer (RAFT) process must retain
thiocarbonylthio end groups in order to maintain the active/
dormant equilibrium necessary for polymerization control.
While thiocarbonylthio reactivity has often been exploited as a
facile means of postpolymerization end-group modification of
RAFT polymers,5−11 a number of deleterious side reactions
involving the thiocarbonylthio moiety can occur including
hydrolysis,12 aminolysis,12,13 thermolysis,14 oxidation,15,16 and
irreversible coupling of intermediate radicals.17−19 It is
therefore important to fully understand the nature of any
degradative reactions involving thiocarbonylthio end groups in
order to extend the current capabilities of RAFT polymer-
ization.
Since our initial report,20 we have conducted the RAFT
polymerization of N-phenylmethacrylamide (PhMA), an MSA
analogue lacking the sulfonamide functional group (vide infra).
Notably, the trithiocarbonate-mediated polymerization of
PhMA at 70 °C also results in relatively broad molecular
weight distributions (Mw/Mn = 1.30), indicating that the
sulfonamide functional group is not the primary cause for
chain-end degradation during polymerization of MSAs.
Previous reports regarding the atom transfer radical polymer-
ization (ATRP) of (meth)acrylamides attributed loss of “living”
chain ends to nucleophilic displacement of the terminal
bromine by the penultimate amide unit.26−28 Similarly,
oxazolone formation during peptide synthesis occurs by an
amide “backbiting” reaction.29 There is also literature precedent
Recently, we reported the RAFT polymerization of a library
of pH-responsive methacryloyl sulfonamide (MSA) monomers
derived from sulfa drugs.20 Loss of chain-end functionality was
observed during the polymerization of MSAs at the commonly
used temperature of 70 °C as evidenced, in part, by broad
molecular weight distributions (Mw/Mn > 1.3) and failure to
Received: November 12, 2015
Revised: December 16, 2015
Published: January 4, 2016
© 2016 American Chemical Society
465
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N-Benzylmethacrylamide (2). A synthetic procedure analogous to
that described for 1 was used to prepare N-benzylmethacrylamide. The
product was recrystallized from hot hexanes:THF (90:10) to yield 2
for the effects of N-aryl substitution on the cyclization of
(thio)carbamoyl derivatives formed during sequencing of
peptides by Edman’s degradation30 as well as the cyclization
of γ-bromobutyranilides.31 From these observations, we have
hypothesized that a similar reaction involving nucleophilic
attack on the ω-thiocarbonyl by the terminal methacrylamide
unit may be responsible for thiocarbonylthio degradation
during the RAFT polymerization of N-arylmethacrylamides.
In this contribution we report the influences of methacry-
lamide structure and reaction temperature on trithiocarbonate
degradation during the RAFT polymerization of N-substituted
methacrylamides. A detailed study of the trithiocarbonate-
mediated polymerizations of PhMA and N-benzylmethacryl-
amide (BnMA) using SEC-MALLS and UV−vis spectroscopy
has now provided a clear understanding of the influence of
methacrylamide structure on CTA degradation. Furthermore,
1
(17.88 g, 91%) as colorless needle-like crystals; mp 78−79 °C. H
NMR (300 MHz, CDCl3): δ 7.30 (m, 5H), 6.13 (s, 1H), 5.71 (s, 1H),
5.34 (s, 1H), 4.50 (d, 2H), 1.97 (s, 3H). 13C NMR (CDCl3): δ 168.43,
140.03, 138.41, 128.87, 127.97, 127.67, 119.89, 43.86, 18.89.
Sodium Dodecyl Trithiocarbonate (3). 1-Dodecanethiol (15.0 g,
74.1 mmol) was added dropwise over 30 min to a stirred suspension of
NaH (1.68 g, 70.0 mmol) in anhydrous diethyl ether (350 mL),
resulting in slow evolution of hydrogen gas. The reaction mixture was
vented and stirred overnight (12 h) at room temperature, after which
carbon disulfide (5.64 g, 74.1 mmol) was added dropwise over 10 min,
followed by stirring at room temperature for 60 min. The reaction
mixture was subsequently diluted with pentane (100 mL), and the
solids were isolated by vacuum filtration and further dried in vacuo to
yield 3 (18.55 g, 83%) as a yellow solid. 1H NMR (300 MHz, DMSO-
d6): δ 2.97 (t, 2H), 1.49 (m, 2H), 1.23 (b, 18H), 0.85 (t, 3H). 13C
NMR (DMSO-d6): δ 31.79, 29.55, 29.51, 29.27, 29.21, 29.14, 22.59,
14.45.
1
in situ H NMR analysis of RAFT polymer small molecule
analogues, prepared by single monomer unit insertion, affords
additional mechanistic insight into the specific degradation
pathway.
Bisdodecyl Trithiocarbonate (4). To a suspension of sodium
dodecyl trithiocarbonate (18.55 g, 61.7 mmol) in diethyl ether (200
mL) at room temperature was added solid I2 (8.62 g, 34.0 mmol) over
5 min. The reaction was stirred for 60 min at room temperature
followed by removal of the precipitated NaI salts by vacuum filtration.
The filtrate was transferred to a separatory funnel and washed with 5%
Na2S2O4 (1 × 150 mL), H2O (1 × 150 mL), and brine (1 × 150 mL)
before drying over MgSO4. The solvent was removed via rotary
evaporation to yield 4 (16.36 g, 96%) as a yellow oil that solidified
upon cooling to −10 °C. 1H NMR (300 MHz, CDCl3): δ 3.28 (t, 4H),
1.68 (m, 4H), 1.24 (b, 36H), 0.87 (t, 6H). 13C NMR (CDCl3): δ
221.74, 38.52, 32.13, 29.85, 29.77, 29.64, 29.57, 29.31, 29.16, 27.57,
22.91, 14.36.
EXPERIMENTAL SECTION
■
Materials. Methacryloyl chloride (Aldrich, 97%) was vacuum
distilled and stored under argon at −10 °C prior to use. Aniline
(Aldrich, 99%) and benzylamine (Aldrich, 98%) were vacuum distilled
immediately prior to use. 4,4-Azobis(4-cyanovaleric acid) (V501)
(Aldrich, 98%) and azobis(isobutyronitrile) (AIBN) (Aldrich, 98%)
were recrystallized from methanol and stored at −10 °C. N,N′-
Dimethylformamide (Acros, extra dry w/sieves) was stirred under
vacuum at room temperature for 60 min prior to use in order to
remove possible traces of dimethylamine. 2,2′-Azobis(4-methoxy-2,4-
dimethylvaleronitrile) (V-70) (Wako, 96%), 1-dodecanethiol (Aldrich,
98%), ethanethiol (Aldrich, 97%), carbon disulfide (Aldrich, 99.9%), 2-
bromoisobutyryl bromide (TCI, 98%), triethylamine (Aldrich, 99.5%),
NaH (Aldrich, 95%), and N,N′-dimethylformamide-d7 (Cambridge
Isotope, 99.5%) were used as received.
2-Cyano-2-propyldodecyl Trithiocarbonate (5). Bisdodecyl tri-
thiocarbonate (7.88 g, 14.2 mmol) and AIBN (2.33 g, 14.2 mmol)
were dissolved in EtOAc (250 mL), and the solution was purged with
N2 for 40 min before heating to 77 °C. After 12 h, a degassed solution
of AIBN (2.33 g, 14.2 mmol) in EtOAc (100 mL) was subsequently
added, and the reaction mixture was stirred for an additional 12 h at 77
°C. Purification by column chromatography (95:5 hexanes:EtOAc)
yielded 5 (7.36 g, 75%) as a yellow oil that solidified upon cooling to 0
Characterization. NMR spectra for structural analysis and
monomer conversions were obtained using a Varian INOVA 300
MHz NMR spectrometer. Polymer molecular weights and molecular
weight distributions (Mw/Mn) were determined by size exclusion
chromatography (SEC) using DMF 20 mM LiBr as the eluent at a
flow rate of 1.0 mL/min in combination with two Agilent PolarGel-M
columns heated to 50 °C and connected in series with a Wyatt Optilab
DSP interferometric refractometer and Wyatt DAWN EOS multiangle
laser light scattering (MALLS) detector (λ = 633 nm). Absolute
molecular weights and Mw/Mn were calculated using a Wyatt ASTRA
SEC/LS software package. The dn/dc values for each polymer
derivative in the above eluent at 35 °C were determined offline using a
Wyatt Optilab DSP interferometric refractometer and Wyatt ASTRA
dn/dc software.
N-Phenylmethacrylamide (1). Methacryloyl chloride (11.83 mL,
121 mmol) was added dropwise over 15 min to a stirred solution of
aniline (12.00 g, 121 mmol) and triethylamine (12.86 g, 127 mmol) in
CH2Cl2 (250 mL) that was previously cooled using an ice bath. Upon
complete addition of methacryloyl chloride, the reaction was stirred at
0 °C for 30 min followed by stirring at room temperature for an
additional 60 min. The reaction mixture was then transferred to a
separatory funnel and washed with 0.1 N HCl (1 × 200 mL), saturated
NaHCO3 (1 × 200 mL), and saturated NaCl (brine) (1 × 200 mL)
before drying over MgSO4. The solvent was removed via rotary
evaporation, and the isolated solids were recrystallized from hot
hexanes:THF (95:5) to yield 1 (17.52 g, 90%) as colorless needle-like
crystals; mp 80−81 °C. 1H NMR (300 MHz, CDCl3): δ 7.60 (s, 1H),
7.57 (d, 2H), 7.32 (t, 2H), 7.11 (t, 1H), 5.78 (s, 1H), 5.44 (s, 1H),
2.05 (s, 3H). 13C NMR (CDCl3): δ 166.87, 141.05, 137.95, 129.15,
124.57, 120.24, 120.04, 18.96.
1
°C. H NMR (300 MHz, CDCl3): δ 3.32 (t, 2H), 1.86 (s, 6H), 1.68
(m, 2H), 1.25 (b, 18H), 0.87 (t, 3H). 13C NMR (CDCl3): δ 217.96,
120.66, 42.54, 37.13, 32.11, 29.82, 29.74, 29.62, 29.54, 29.27, 29.12,
27.91, 27.25, 22.90, 14.35.
Sodium Ethyl Trithiocarbonate (6). A suspension of NaH (2.11 g,
83.5 mmol) in anhydrous diethyl ether (150 mL) was cooled to 0 °C
using an ice bath; ethanethiol (5.73 g, 92.3 mmol) was then added
dropwise over 15 min accompanied by vigorous evolution of hydrogen
gas. The reaction mixture was stirred for an additional 15 min at 0 °C
followed by dropwise addition of CS2 (7.03 g, 92.3 mmol) over 5 min,
and the reaction mixture was stirred for 60 min at room temperature
followed by dilution with pentane (100 mL). The resulting yellow
precipitate was isolated by vacuum filtration before drying in vacuo
yielding 6 (12.07 g, 90%) as a hygroscopic yellow solid. 1H NMR (300
MHz, D2O): δ 3.15 (q, 2H), 1.27 (t, 3H). 13C NMR (D2O): δ 35.36,
12.39.
2-Bromoisobutyranilide (7). 2-Bromoisobutyryl bromide (15.00
mL, 124 mmol) was added dropwise over 15 min to a stirred solution
of aniline (12.03 g, 124 mmol) and triethylamine (12.28 g, 124 mmol)
in CH2Cl2 (500 mL) that was previously cooled using an ice bath.
Upon complete addition of 2-bromoisobutyryl bromide, the reaction
was stirred at 0 °C for 30 min followed by stirring at room
temperature for an additional 60 min. The reaction mixture was then
transferred into a separatory funnel and washed with 0.1 N HCl (1 ×
400 mL), saturated NaHCO3 (1 × 400 mL), and brine (1 × 400 mL)
before drying over MgSO4 and removal of the solvent by rotary
evaporation. The isolated solids were recrystallized from hot hexanes
to yield 7 (29.13 g, 97%) as colorless needle-like crystals; mp 82−23
1
°C. H NMR (300 MHz, CDCl3): δ 8.45 (s, 1H), 7.55 (d, 2H), 7.35
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(t, 2H), 7.14 (t, 1H), 2.04 (s, 6H). 13C NMR (CDCl3): δ 170.12,
137.53, 129.24, 125.06, 120.11, 63.37, 32.75.
Trithiocarbonate Degradation Analysis by UV−Vis. Reactions
(final volume = 2500 μL) were performed using [CPDT]0 = 5 × 10−3
M and [M]0:[CPDT]0:[V501]0 = 10:1:0.2 in DMF. A typical
procedure was as follows: BnMA (250 μL of an 87.6 mg/mL stock
solution in DMF, 10 equiv), CPDT (250 μL of a 17.3 mg/mL stock
soln. in DMF, 1 equiv), V501 (25 μL of a 28.0 mg/mL stock solution
in DMF, 0.2 equiv), and DMF (1975 μL) were combined in a 4 mL
test tube equipped with magnetic stir bar and rubber septum. The
reaction was then degassed via four freeze−pump−thaw cycles and
backfilled under argon. An initial aliquot (50 μL) was taken using an
argon-purged gastight syringe and subsequently diluted into a quartz
cuvette containing 2500 μL of acetonitrile before measuring the
absorbance at λ = 320 nm using a Lambda 35 UV−vis spectrometer.
Subsequent aliquots (50 μL) were taken and analyzed in the same
manner.
N-Phenyl-2-(ethylsulfanylthiocarbonylsulfanyl)propanamide (8).
A solution of sodium ethyl trithiocarbonate (1.32 g, 8.3 mmol), 2-
bromoisobutyrylanilide (2.00 g, 8.3 mmol), and NaI (0.124 g, 0.83
mmol) in absolute EtOH (10 mL) was prepared and stirred at 22 °C
for 48 h. The reaction mixture was then precipitated twice into water
(100 mL), and the precipitate isolated by vacuum filtration and further
purified by recrystallization from absolute EtOH, resulting in large
needle-like crystals. The product, isolated by recrystallization, was
determined to be 5,5-dimethyl-3-phenyl-2-thioxothiazolidin-4-one
(9).32 Conducting the reaction at 60 °C for 12 h allowed for isolation
of 9 in higher yields for use in additional studies; mp 108−110 °C. 1H
NMR (300 MHz, CDCl3): δ 7.50 (m, 3H), 7.22 (d, 2H), 1.79 (s, 6H).
13C NMR (CDCl3): δ 199.80, 179.64, 135.43, 129.82, 129.70, 128.54,
55.59, 27.55.
1
In Situ H NMR Analysis. Samples of CPDT-PhMA and CPDT-
BnMA (2 × 10−2 M) in DMF-d7 were prepared immediately prior to
analysis by first adding DMF-d7 (0.60 mL) into an NMR tube
equipped with pierceable rubber septum, and the solvent was degassed
by two freeze−pump−thaw cycles to remove possible traces of
dimethylamine. The appropriate amount of CPDT-PhMA or CPDT-
BnMA was then added as a solid directly into the NMR tube
containing the previously degassed DMF-d7, and the resulting solution
was degassed by two additional freeze−pump−thaw cycles and
backfilled with argon. 1H NMR spectra were acquired at 70 °C
using a Bruker Ascend 600 MHz spectrometer.
CPDT-PhMA (10). A solution of 2-cyano-2-propyldodecyl trithiocar-
bonate (3.41 g, 9.9 mmol), PhMA (1.59 g, 9.9 mmol), and V-70
(0.609 g, 2.0 mmol) in DMF (35 mL) was prepared in a round-
bottomed flask equipped with magnetic stir bar, and the reaction
mixture was degassed via three freeze−pump−thaw cycles and
backfilled with argon. The reaction mixture was heated at 30 °C in
an oil bath for 48 h, followed by exposure to air and freezing in liquid
N2. The reaction mixture was then diluted with EtOAc (250 mL) and
transferred to a separatory funnel and washed with 75% brine (1 × 200
mL), H2O (1 × 200 mL), and brine (1 × 200 mL) and dried over
MgSO4. The crude product was then purified by column
chromatography (8:2 hexanes:EtOAc, Rf = 0.30), yielding 10 (0.511
RESULTS AND DISCUSSION
■
1
g, 10%) as a yellow solid. H NMR (300 MHz, CDCl3): δ 8.44 (s,
PhMA and BnMA Polymerization Kinetics. To our
knowledge, there are no reports detailing the effects of N-aryl
substitution on RAFT-mediated polymerization control of
(meth)acrylamides. To this end, we chose to compare the
RAFT polymerizations of N-phenylmethacrylamide (PhMA)
and N-benzylmethacrylamide (BnMA) under analogous
conditions (Scheme 1). BnMA was chosen based upon its
structural similarity to PhMA while lacking direct N-aryl
substitution.
1H), 7.45 (d, 2H), 7.32 (t, 2H), 7.12 (t, 1H), 3.26 (t, 2H), 2.55 (q,
2H), 2.02 (s, 3H), 1.64 (m, 2H), 1.47 (s, 3H), 1.46 (s, 3H), 1.23 (b,
18H), 0.87 (t, 3H). 13C NMR (CDCl3): δ 219.02, 169.43, 137.45,
129.02, 124.83, 120.51, 60.48, 45.13, 37.33, 31.91, 30.45, 29.62, 29.54,
29.42, 29.35, 29.10, 29.07, 28.90, 28.69, 27.62, 23.81, 22.70, 14.15.
CPDT-BnMA (11). A solution of 2-cyano-2-propyldodecyl trithio-
carbonate (2.00 g, 5.8 mmol), BnMA (1.01 g, 5.8 mmol), and AIBN
(0.190 g, 1.2 mmol) in DMF (20 mL) was prepared in a round-
bottomed flask equipped with magnetic stir bar, degassed via three
freeze−pump−thaw cycles, and backfilled with argon. The reaction
mixture was heated at 60 °C in an oil bath for 24 h, followed by
exposure to air and freezing in liquid N2. The reaction mixture was
then diluted with EtOAc (150 mL) and transferred to a separatory
funnel and washed with 75% brine (1 × 150 mL), H2O (1 × 150 mL),
and brine (1 × 150 mL) and dried over MgSO4. The crude product
was first purified by column chromatography (8:2 hexanes:EtOAc, Rf =
0.25) followed by recrystallization from MeOH:H2O (98:2) at −10 °C
Scheme 1. Synthetic Route for CPDT-Mediated
Polymerization of PhMA and BnMA in DMF at 70 or 30 °C
1
yielding 11 (0.475 g, 16%) as yellow crystals. H NMR (300 MHz,
CDCl3): δ 7.31 (m, 5H), 6.79 (t, 1H), 4.42 (q, 2H), 3.25 (t, 2H), 2.56
(q, 2H), 1.96 (s, 3H), 1.64 (m, 2H), 1.47 (s, 3H), 1.45 (s, 3H), 1.27
(b, 18H), 0.89 (t, 3H). 13C NMR (CDCl3): δ 219.32, 171.33, 137.62,
128.87, 128.38, 127.84, 125.04, 60.16, 45.04, 37.28, 32.12, 30.66,
29.84, 29.76, 29.64, 29.55, 29.47, 29.29, 29.14, 28.72, 27.87, 24.16,
22.90, 14.35.
Table 1 summarizes the conversion, molar mass, and
molecular weight distribution data for the polymerizations of
PhMA and BnMA in DMF at 70 and 30 °C, using the RAFT
agent 2-cyano-2-propyldodecyl trithiocarbonate (CPDT). The
effect of methacrylamide structure on polymerization control is
initially apparent by comparing the increase in molecular
weight distribution of poly(PhMA) (Mw/Mn = 1.30) relative to
that of poly(BnMA) (Mw/Mn = 1.15) synthesized under
identical reaction conditions. Limited molecular weight control
during polymerization of PhMA at 70 °C can also be seen in
the Mn vs conversion plot (Supporting Information, Figure S1)
which shows a decrease in Mn,exp relative to Mn,th at higher
conversions. By contrast, for the polymerization of BnMA at 70
°C, Mn,exp values mirror Mn,th values, indicating that the number
of active/dormant chain ends remain constant during polymer-
ization (Figure S2).
RAFT Polymerization of PhMA and BnMA. Briefly, monomer
(PhMA or BnMA) (10.0 mmol, 200 equiv), CPDT (5.0 × 10−5 mol, 1
equiv), initiator (V-70 or V501) (1.0 × 10−5 mol, 0.2 equiv), and
trimesic acid (50 mg, 1H NMR internal standard) were combined in a
10 mL graduated cylinder, and DMF was added to bring the final
solution volume to 5.0 mL ([M]0 = 2 M). The solution was then
transferred to a 10 mL test tube equipped with a magnetic stir bar and
rubber septum, degassed via three freeze−pump−thaw cycles, and
backfilled with argon. An initial aliquot (200 μL) was taken prior to
heating the reaction vessel at the indicated temperature with
subsequent aliquots taken at timed intervals and analyzed by 1H
NMR (DMSO-d6) to determine monomer conversion by comparing
the relative integral areas of the trimesic acid aromatic protons (8.64
ppm, 3H) to the vinyl proton of PhMA (5.86 ppm, 1H) or BnMA
(5.79 ppm, 1H). SEC-MALLS (DMF 20 mM LiBr) analysis of
aliquots was used to monitor molecular weight and molecular weight
distribution progression throughout each polymerization.
Figure 1 shows the kinetic plots for the 70 °C polymer-
izations of PhMA (black) and BnMA (red); each plot shows an
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the homopolymerizations of PhMA and BnMA at 70 °C show
similar minimal decreases in slope beyond 300 min despite
limited molecular weight control observed during the same
time period for the polymerization of PhMA. It might be
expected that RAFT agent degradation during polymerization
Table 1. Conversion, Molar Mass, and Molecular Weight
Distribution Data for the RAFT Polymerizations of PhMA
and BnMA in DMF at 70 and 30 °C
a
b
c
d
temp
time
conv
Mn,th
Mn,exp
d
entry monomer (°C) (min)
(%)
(g/mol) (g/mol) Mw/Mn
•
of PhMA would result in a decrease in the slope (kp[Pn ]) of
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
PhMA
PhMA
PhMA
PhMA
BnMA
BnMA
BnMA
BnMA
PhMA
PhMA
PhMA
PhMA
BnMA
BnMA
BnMA
BnMA
70
70
70
70
70
70
70
70
30
30
30
30
30
30
30
30
240
360
480
600
240
360
480
600
300
420
600
1380
300
420
600
1380
37
48
55
59
24
32
37
41
9
12400
16000
18200
19500
8900
14800
17300
18100
18900
11700
13400
15000
16100
6000
1.09
1.16
1.24
1.30
1.06
1.11
1.15
1.15
1.07
1.05
1.02
1.02
1.13
1.07
1.05
1.04
the pseudo-first-order kinetic plot due to chain transfer to thiol-
containing degradation byproducts. However, efficient chain
transfer can take place without influencing the rate of
polymerization if the rate of reinitiation by thiyl radicals is
greater than the rate of propagation (i.e., kiT > kp).34 The
decrease in Mn,exp relative to Mn,th throughout the 70 °C
polymerization of PhMA (Figure S1) is evidence of an
increasing number of polymer chains resulting from efficient
chain transfer.
Recently we demonstrated that improved chain end
retention and narrow molecular weight distributions can be
achieved during the RAFT polymerization of N-aryl MSAs by
reducing the reaction temperature.20 Likewise, as seen in Figure
2, the molecular weight distribution of poly(PhMA) synthe-
11500
13400
14600
3200
14
23
50
7
4900
7400
7800
10500
18800
3400
16600
2700
10
14
29
3700
4100
5100
5900
10400
11200
a
Polymerizations were conducted at 70 or 30 °C in DMF ([M]0:
[CTA]0:[I]0 = 200:1.0:0.2) using V501 or V-70 as the initiators,
b
respectively. Conversions were determined by 1H NMR (DMSO-d6)
by comparing the relative integral areas of trimesic acid (internal
standard) aromatic protons (8.64 ppm, 3H) to the vinyl proton of
c
PhMA (5.86 ppm, 1H) or BnMA (5.79 ppm, 1H). Theoretical Mn
values were calculated according to the equation Mn,th
=
(ρMWmon[M]0/[CTA]0) + MWCTA where ρ is the fractional
monomer conversion, MWmon is the molecular weight of the
monomer, and MWCTA is the molecular weight of the CTA.
d
Experimental Mn and Mw/Mn values were determined by SEC-
MALLS (DMF, 20 mM LiBr).
Figure 2. SEC RI chromatogram showing the effect of temperature on
molecular weight distribution for the CPDT-mediated RAFT
polymerization of PhMA in DMF at 70 and 30 °C.
sized at 30 °C (Mw/Mn = 1.02, Mn = 18 800) was markedly
narrower than that of poly(PhMA) synthesized under
analogous conditions at 70 °C (Mw/Mn = 1.30, Mn
=
18 900). Reduced polymerization temperature also afforded
improved molecular weight control during the polymerization
of PhMA as evidenced by the linear progression of Mn,exp with
conversion and good correlation between Mn,exp and Mn,th
values (Figure S3). As shown in Table 1, narrower molecular
weight distributions were also obtained during the polymer-
ization of BnMA at 30 °C (Mw/Mn < 1.10), but the additional
decrease was minimal due to already narrow Mw/Mn achieved
during polymerization at 70 °C.
The kinetic plots for the CPDT-mediated polymerizations of
PhMA and BnMA at 30 °C (Figure 3) exhibit initialization
times of 100 and 60 min, respectively, while demonstrating near
pseudo-first-order kinetic behavior up to at least 1380 min. The
increase in initialization time with decreasing temperature for
the RAFT polymerizations of PhMA and BnMA is consistent
with observations made by McLeary et al.33 The improved
linearity of the first-order kinetic plots is also consistent with
Figure 1. Kinetic plot for the CPDT-mediated polymerization of
PhMA and BnMA in DMF at 70 °C ([M]0 = 2.0 M, [M]0:[CTA]0:[I]0
= 200:1:0.2).
initialization period of approximately 30 min followed by
pseudo-first-order kinetic behavior up to 300 min with the
differences in slope of the curves indicative of the relative
propagation rate coefficients (kp) for each monomer derivative.
Similar initialization periods were observed previously for the
trithiocarbonate-mediated polymerizations of N-aryl MSAs and
are indicative of slow fragmentation/reinitiation by the RAFT
agent R-group.20,33 Interestingly, the first-order kinetic plots for
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Figure 3. Kinetic plot for the CPDT-mediated polymerization of
PhMA and BnMA in DMF at 30 °C ([M]0 = 2.0 M, [M]0:[CTA]0:[I]0
= 200:1:0.2).
previous low temperature RAFT polymerizations of (meth)-
acrylamides and is generally attributed to increased thiocarbo-
nylthio chain end retention.35,36
Trithiocarbonate Degradation during the CPDT-
Mediated Polymerizations of PhMA and BnMA. It is
evident from the molecular weight data summarized in Table 1
that chain end degradation is likely occurring during the 70 °C
polymerization of PhMA. Meanwhile, BnMA polymerization at
the same temperature affords narrower molecular weight
distributions with good correlation between Mn,th and Mn,exp
values. In order to ascertain the influences of each polymer-
ization component (i.e., solvent, monomer, and initiator) on
temperature-dependent trithiocarbonate degradation, reactions
were performed in DMF using combinations of CPDT,
monomer (PhMA or BnMA), and initiator (V501) at relative
concentrations of [CPDT]0:[M]0:[I]0 = 10:1.0:0.2 as illustrated
in Figure 4. The fractional change in total trithiocarbonate
(TTC) concentration ([TTC]/[TTC]0) was measured by
comparing the absorbance (λ = 320 nm) of diluted aliquots
taken at timed intervals to that of an initial aliquot at t = 0. It is
worth noting that only minimal change in the molar extinction
coefficient (ε) of CPDT at λ = 320 nm occurs after covalent
addition of PhMA or BnMA, allowing for accurate measure-
ment of the total [TTC] during polymerization. Figure S5
shows the Beer−Lambert plots and ε values at λ = 320 nm for
CPDT (ε320 = 9380 M−1 cm−1) and the corresponding single
monomer unit insertion adducts CPDT-PhMA (ε320 = 9560
M−1 cm−1) and CPDT-BnMA (ε320 = 10 300 M−1 cm−1).
Examination of Figure 4a reveals no measurable influences of
DMF (green ▼), PhMA (blue ▲), or V501 (red ●)
independently on [TTC]/[TTC]0 at 70 °C. However, a 60%
decrease in [TTC]/[TTC]0 is observed after 12 h when
CPDT, PhMA, and V501 are combined at 70 °C (black ■)
such that monomer addition to CPDT takes place. This result
supports terminal monomer unit-induced degradation in which
the ultimate methacrylamide unit is in a favored orientation for
O-5 or N-5 nucleophilic attack on the terminal thiocarbonyl
(Scheme 2). In this case “5” denotes the number of atoms
between the amide oxygen or nitrogen and the thiocarbonyl
carbon. By contrast, identical experiments performed with
BnMA showed minimal trithiocarbonate degradation during
Figure 4. Individual and combined influences of solvent, initiator, and
monomer on the time-dependent change in [TTC]/[TTC]0 as
measured by UV−vis spectroscopy ([M]0:[CTA]0:[I]0 = 10:1:0.2).
Trithiocarbonate degradation experiments were performed using (a)
PhMA or (b) BnMA as the monomer.
Scheme 2. Proposed Trithiocarbonate Degradation by O-5
or N-5 Nucleophilic Attack by the Terminal Methacrylamide
Unit
polymerization with only a 3% decrease in [TTC]/[TTC]0
observed after 12 h.
Previously, we attributed the substantially improved polymer-
ization control of MSAs and PhMA at 30 °C to increased chain
end retention.20 As seen in Figure 5, the effect of temperature
on trithiocarbonate degradation was confirmed by measuring
[TTC]/[TTC]0 during polymerization of PhMA at 30 °C
under analogous conditions used for experiments in Figure 4a.
At 30 °C, only 8% trithiocarbonate degradation was observed
after 720 min compared to 60% degradation for the same time
period at 70 °C.
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1
Figure 6. H NMR (300 MHz, CDCl3) spectrum of isolated N-5
cyclization/elimination product 9.
adduct of CPDT and PhMA (CPDT-PhMA) could be
marginally favored by stoichiometric control of monomer,
CTA, and initiator at 30 °C as outlined in Scheme 4. The
Figure 5. Trithiocarbonate degradation during the CPDT-mediated
polymerization of PhMA ([M]0:[CTA]0:[I]0 = 10:1:0.2) at 70 and 30
°C using V501 and V-70 as initiators, respectively.
Scheme 4. Synthesis of CPDT-PhMA and CPDT-BnMA by
Single Monomer Unit Insertion
Small Molecule Analogue Synthesis. In order to better
study the mechanism and byproducts of N-arylmethacrylamide-
promoted trithiocarbonate degradation, we attempted to
synthesize a small molecule analogue of trithiocarbonate-
terminated poly(PhMA). According to Scheme 3, the desired
Scheme 3. Synthetic Route for the Trithiocarbonate-
Terminated Poly(PhMA) Small Molecule Analogue 8
SMUI adduct of CPDT and BnMA (CPDT-BnMA) was
synthesized at 60 °C using AIBN as the initiator owing to the
lower nucleophilicity of the N-benzylamide at higher temper-
atures as previously demonstrated. The labeled 1H NMR
spectra of CPDT-PhMA (10) and CPDT-BnMA (11) are
shown in Figures 7a and 7b, respectively.
1
In Situ H NMR Analysis of CPDT-PhMA and CPDT-
1
BnMA Degradation at 70 °C. In situ H NMR analysis was
used to gain further insight into the mechanism and kinetics of
CPDT-PhMA and CPDT-BnMA degradation. The labeled H
1
product 8 should result from the SN1 reaction of sodium ethyl
trithiocarbonate and 2-bromoisobutyranilide. Despite the
reaction being performed at room temperature (22 °C),
isolation of 8 proved unsuccessful. Recrystallization of the
crude reaction mixture afforded 5,5-dimethyl-3-phenyl-2-
thioxothiazolidin-4-one (9), the N-5 cyclization product of 8
(Scheme 3). The structure of 9 was confirmed in part by
analysis of the 1H NMR spectrum (Figure 6) which is absent of
NMR spectra at select time points during the degradation
analysis of CPDT-PhMA at 70 °C in DMF-d7 are shown in
Figure 8. After 5 min, only the 1H resonances of CPDT-PhMA
are observed. Subsequently, new signals in the aromatic (7.4−
7.7 ppm) and aliphatic (1.5−2.7 ppm) regions corresponding
to degradation byproducts appear and increase in intensity with
time. Comparison of the 1H NMR chemical shifts of the
degradation byproducts (Figure 8) with those of 1-dodeca-
nethiol and 5,5-dimethyl-3-phenyl-2-thioxothiazolidin-4-one
(9) (Figures S6−S8) indicates that the byproducts of CPDT-
PhMA degradation are those formed exclusively by N-5
cyclization/elimination. Labeled resonances corresponding to
N-5 cyclization/elimination degradation byproducts are given
prime designation in the NMR spectrum (Figure 8) obtained at
491 min.
1
ethylsulfanyl −SCH2CH3 and amide −N−H H resonances.
1
The H and 13C chemical shifts of 9 match those reported
previously.32 1H NMR analysis of aliquots sampled during the
reaction (Scheme 3) showed rapid formation of 9, indicating
that under these conditions N-5 cyclization/elimination of the
transient species 8 occurs even at temperatures below 30 °C.
Small Molecule Analogue Synthesis via Single
Monomer Unit Insertion. Minimal degradation of CPDT
during the polymerization of PhMA at 30 °C indicates that
covalent adducts of PhMA and CPDT are stable at low
temperatures and can be formed by free radical processes.
Recently, single monomer unit insertion (SMUI)37,38 has
become a facile method for CTA synthesis, exploiting the
“initialization” phenomenon previously described by McLeary,
Klumperman, and co-workers.33 We found that the SMUI
Degradation of CPDT-BnMA at 70 °C (Figure 9) was also
1
monitored using in situ H NMR analysis. After 491 min,
minimal degradation was observed as shown in the expanded
regions of the 1H NMR spectrum in Figure 9 corresponding to
the 3-benzyl-2-thioxothiazolidin-4-one methylene (peak i′) and
the cyclized BnMA methyl (peak e′). Also visible is the
characteristic methylene of 1-dodecanethiol (peak d′) which is
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Figure 7. H NMR (300 MHz, CDCl3) spectra of (a) CPDT-PhMA and (b) CPDT-BnMA SMUI adducts.
1
Figure 8. H NMR (600 MHz, DMF-d7) overlay following the time-dependent degradation of CPDT-PhMA at 70 °C.
additional evidence of degradation by N-5 cyclization/
elimination.
attack results in loss of the N-phenylamide. The exclusive rate
of N-5 cyclization/elimination (pathway A) is equal to the rate
1
Kinetic analysis of CPDT-PhMA degradation also provides
additional evidence for exclusive N-5 cyclization/elimination.
As shown in Scheme 5, intramolecular N-5 nucleophilic attack
of the trithiocarbonate by adjacent methacrylamide can occur
by either cyclization/elimination (pathway A) or rearrangement
(pathway B) depending upon which C−S bond is cleaved. The
total rate of degradation of CPDT-PhMA by pathways A and B
is equal to the rate of change in area of the phenyl 1H
resonances (Figure 8, peaks i, j, and k) as N-5 nucleophilic
of change in area of the −CH2−S− H resonance (Figure 8,
peak d) as elimination of 1-dodecanethiol occurs. As shown in
Figure 10a, the fractional changes in area (At/A0) of peaks i
(7.70 ppm) and d (3.39 ppm) are essentially identical
throughout the 491 min experiment, indicating that pathway
A is the predominant contributor to the degradation of CPDT-
PhMA at 70 °C.
Kinetic analysis of CPDT-BnMA degradation (Figure 10b)
additionally supports the proposed degradation pathway of N-5
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Figure 9. H NMR (600 MHz, DMF-d7) overlay following the time-dependent degradation of CPDT-BnMA at 70 °C.
Scheme 5. Possible N-5 Nucleophilic Attack Degradation
Pathways
cyclization/elimination as shown by the comparable change in
At/A0 of peaks i (4.42 ppm) and d (3.37 ppm) (peak
assignments in Figure 9).
As seen in Figure 11, excellent agreement is observed
between the time-dependent fractional changes in [TTC]
measured during the CPDT-mediated polymerizations of
PhMA and BnMA by UV−vis spectroscopy (open data points)
and during CPDT-PhMA and CPDT-BnMA degradation
1
measured by in situ H NMR analysis (solid data points).
The half-lives (t1/2) of CPDT-PhMA and CPDT-BnMA at 70
°C in DMF were calculated to be t1/2 = 7.18 h and t1/2 = 78.5 h,
respectively, based upon the degradation rates measured using
1H NMR.
It is important to note that while we have determined that
significant trithiocarbonate degradation occurs by N-5 cycliza-
1
tion/elimination during the RAFT polymerization of PhMA at
70 °C, this work does not specifically address the influence of
N-phenyl substitution on increased amide nucleophilicity and
how this affects the observed reaction mechanism. We are
currently examining the influences of N-aryl substitution on
both reaction mechanism and rate of N-5 cyclization/
elimination and will report this in a future paper.
Figure 10. Time-dependent fractional change in the area of select H
chemical shifts during the degradation of (a) CPDT-PhMA and (b)
CPDT-BnMA in DMF-d7 at 70 °C.
Influence of 3-Phenyl-2-thioxothiazolidin-4-one
Chain Ends on RAFT Polymerization of PhMA. Typically,
RAFT agent degradation during polymerization results in the
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Figure 11. Time-dependent change in [TTC]/[TTC]0 at 70 °C in
DMF as measured by UV−vis spectroscopy during polymerization
1
(open circles) and as measured by in situ H NMR during SMUI
adduct degradation analysis (closed circles).
loss of active thiocarbonylthio chain ends affording “dead”
polymer chains that can no longer participate in the RAFT
process. However, we have shown that trithiocarbonate
degradation by N-5 cyclization/elimination during the polymer-
ization PhMA results in formation of a new cyclic
thiocarbonylthio end group. To date, there are few examples
of RAFT polymerizations mediated by cyclic thiocarbonylthio
compounds.39−41 However, Zhan and co-workers recently
reported the RAFT polymerization of vinyl acetate using 9 as
the RAFT agent, which resulted in incorporation of
thiocarbonylthio functionality into the polymer backbone.32
Similarly, it is plausible that the 3-phenyl-2-thioxothiazolidin-4-
one chain ends formed as a result of N-5 cyclization/
elimination could participate during the RAFT polymerization
of PhMA as shown in Scheme 6.
Figure 12. (a) Kinetic plot and (b) SEC RI chromatogram overlay for
the 9-mediated polymerization of PhMA in DMF at 70 °C ([PhMA]0
= 2.0 M, [PhMA]0:[9]0:[V501]0 = 200:1.0:0.2).
We investigated the possibility of 3-phenyl-2-thioxo-
thiazolidin-4-one chain ends participating in the RAFT process
by conducting the polymerization of PhMA at 70 °C in the
presence of 9, a small molecule analogue of N-5 cyclized
poly(PhMA) chain ends. Figure 12a shows the kinetic plot for
the 9-mediated polymerization of PhMA in DMF at 70 °C.
Linear pseudo-first-order kinetic behavior was observed up to
140 min with no initialization period. By contrast, the CPDT-
mediated polymerization of PhMA under identical conditions
exhibited a 30 min initialization period, consistent with similar
results first reported by Klumperman and co-workers.33 While
the linear pseudo-first-order kinetic behavior indicates a
Scheme 6. Proposed Mechanism for Radical Addition to 3-
Phenyl-2-thioxothiazolidin-4-one Chain Ends during RAFT
Polymerization of PhMA at 70 °C
•
constant kp[Pn ], the SEC RI overlay shown in Figure 12b
demonstrates that molecular weight control is not achieved
during the 9-mediated polymerization of PhMA at 70 °C. The
intensities of the SEC RI chromatograms shown in Figure 12b
increase with conversion, but the unchanging peak elution
volumes, which occur at the exclusion limit of the SEC system
(∼11.0 mL), are representative of uncontrolled polymerization
behavior where Mn does not scale linearly with monomer
conversion. While the polymers presented in Figure 12b were
too large to characterize by our SEC-MALLS system, it is worth
noting that a polyvinylpyridine standard of Mn = 475 000 g/mol
(Mw/Mn = 1.06) elutes at a volume of 11.5 mL. These results
suggest that 3-phenyl-2-thioxothiazolidin-4-one-terminated pol-
ymers do not participate in the normal CTA-mediated RAFT
polymerization of PhMA at 70 °C.
CONCLUSIONS
Methacrylamide-induced trithiocarbonate degradation during
RAFT polymerization has been investigated. N-Phenyl-
■
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors gratefully acknowledge the financial support
provided in part by the National Science Foundation Graduate
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