Poly(α-methyleneglutarimide)s from radical polymerization of α-methyleneglutarimides

Article abstract of DOI:10.1002/pola.28977

α-Methyleneglutaric acid, a metabolite of niacin (nicotinic acid), can be easily converted to its cyclic anhydride. We report here the first conversion of α-methyleneglutaric anhydride to (a series of) α-methyleneglutarimides. These monomers can be radically polymerized to the title polymers. These have relatively high glass transition properties compared to the lower homologs derived from itaconimides (α-methylenesuccinimides).

Full text of DOI:10.1002/pola.28977

JOURNAL OF
POLYMER SCIENCE
WWW.POLYMERCHEMISTRY.ORG
ARTICLE
Poly(a-Methyleneglutarimide)s from Radical Polymerization of
a-Methyleneglutarimides
Yuanxian Wang , Shu Xu , Thomas R. Hoye
Department of Chemistry, 207 Pleasant St., SE, University of Minnesota, Minneapolis, Minnesota 55455
Correspondence to: T. R. Hoye (E-mail: hoye@umn.edu)
Received 6 January 2018; accepted 26 January 2018; published online 00 Month 2018
DOI: 10.1002/pola.28977
C
V
ABSTRACT: a-Methyleneglutaric acid, a metabolite of niacin (nic-
otinic acid), can be easily converted to its cyclic anhydride. We
report here the first conversion of a-methyleneglutaric anhydride
to (a series of) a-methyleneglutarimides. These monomers can
be radically polymerized to the title polymers. These have rela-
tively high glass transition properties compared to the lower
homologs derived from itaconimides (a-methylenesuccinimides).
2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym.
Chem. 2018, 00, 000–000
KEYWORDS: AIBN-initiated radical polymerization; reversible
addition-fragmentation chain-transfer (RAFT) polymerization;
depolymerization; potential biosourced monomer evaluation;
a-methyleneglutarate
INTRODUCTION A number of a-methylenelactones (cf. 11)
and -lactams (cf. 22) as well as itaconic anhydride (33) have
been reported to serve as monomers for free-radical (and
in some instances, anionic4) polymerization reactions (Figure
1). Radical polymerizations of a-methylenesuccinimides (4,
itaconimide derivatives) have been studied in somewhat
greater detail.4(c),5 However, we cannot locate any examples
of polymerization of a-methyleneglutaric anhydride (5).6
There are only three known a-methyleneglutarimides7 and
only the parent (6a) has been polymerized.4(d) Surprisingly,
none of these potential monomers has been made from a-
methyleneglutaric acid (9) or its anhydride 5.
CDCl3, or DMSO-d6 are referenced to either TMS (0.00 ppm)
of residual CHCl3 (7.26 ppm), or CHD2SOCD3 (2.50 ppm),
respectively. A non-first order multiplet is designated as
“nfom.” 13C NMR chemical shifts are referenced to chloro-
form CDCl3 (77.16 ppm) or DMSO-d6 (39.52 ppm). Proton
resonances are reported according to the following format:
chemical shift in ppm (multiplicity, coupling constants (J) in
Hz, integral value to the nearest whole proton, and assign-
ment). Infrared (IR) spectra were taken using neat solid or
liquid samples on either a Midac Prospect or Bruker Alpha
Platinum FT-IR spectrometer using attenuated total reflec-
tance (ATR) sampling. The wavenumbers of absorption
bands are given in cm21. Medium pressure liquid chroma-
tography (MPLC, 50–100 psi) was carried out on silica gel
(25–35 lm, 60 Å pore size) using hand-packed columns. A
Waters HPLC pump fitted with a Waters R401 differential
refractive index detector. Flash chromatography was per-
formed on silica gel columns (E. Merck, 40–63 lm). Mass
spectrometry data were collected on either (i) a Bruker Bio-
TOF II instrument using electrospray ionization and a PEG
internal calibrant for HRMS measurements or (ii) an Agilent
5973 GC-MS instrument with electron ionization (at 70 eV).
a-Methyleneglutarate (9) [Scheme 1(a)] is
a significant
metabolite of nicotinic acid.8 Given the potential for engi-
neering a synthetic biology approach for accessing 9 on a
large scale, we elected to study and report here its conver-
sion into various N-substituted a-methylene-glutarimide
derivatives 6 and the free-radical polymerization of each of
these monomers to a series of poly(a-methyleneglutari-
mide)s (PMGIs) [Scheme 1(b)].
EXPERIMENTAL
€
Melting points were determined on a Kofler hot stage and
are uncorrected. Size exclusion chromatography (SEC) meas-
urements were made on an Agilent 1100 series liquid chro-
matograph fitted with a Varian PLgel 5 mm guard column
and three Varian PLgel MIXED C columns (25 cm l 3
General Experimental Protocols
1H and 13C NMR spectra were recorded on a Bruker Avance
III 500 (500 MHz), Avance II 500 (500 MHz), or Avance III
400 (400 MHz) spectrometer. 1H NMR chemical shifts in
Y. Wang and S. Xu contributed equally to this article.
Additional Supporting Information may be found in the online version of this article.
C
V
2018 Wiley Periodicals, Inc.
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000
1

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
sealed culture tube. The tube was heated at 60 8C for 2 h.
After cooling and immersing in a 35–40 8C water bath, the
acetic anhydride and acetic acid were removed under vac-
uum. The resulting sample of anhydride 5 was obtained as a
pale-yellow oil and used without further purification.
3-Methylenepiperidine-2,6-Dione (6a)
FIGURE 1 (Potential) monomers of the a-methylene lactone,
The crude anhydride 5 (2.50 g, 20.0 mmol) in THF (20 mL)
was added slowly to 35% aqueous ammonia (10 mL) at 0 8C
for 5 min. The mixture was stirred and warmed to room
temperature over 30 min. The mixture was evaporated to
dryness on a rotary evaporator (ca 40 8C bath) and kept
under high vacuum for 2 h to give a pair of intermediate
amic acids (ca 7:1, 1H NMR, CD3OD) as a viscous, off-white
oil. From this oil, the NAH imide 6a (1.04 g, 8.4 mmol, 42%,
a white crystalline solid) was obtained by the procedure
used to prepare methylimide 6b. Purification was achieved
by flash chromatography on silica gel (methylene chloride
elution). NMR data were consistent with reported values.10
lactam, anhydride, and imide family.
7.5 mm d). Analyses were performed at 35 8C with either
chloroform or DMF as the mobile phase. A flow rate of 1
mL•min21 was used; effluent peaks were detected with a
differential refractive index detector (HP1047A). Molar masses
were determined against a 10-point calibration curve, estab-
lished using polystyrene standards. Thermogravimetric analy-
sis (TGA) was done on a TA Instruments Q-500 under a
nitrogen atmosphere and using a heating rate of 10 8C min21
.
Differential scanning calorimetry (DSC) was performed on a
TA Instruments Q-1000. The sample was hermetically sealed
in an aluminum pan, heated to 240 8C, equilibrated at that
temperature for 5 min, cooled to 220 8C, and ramped back to
240 8C at 10 8C min21. Data from this second heating cycle
were analyzed using Trios Software from TA Instruments.
1-Methyl-3-Methylenepiperidine-2,6-Dione (6b)
The crude anhydride 5 (2.53 g, 20.0 mmol) in THF (15 mL)
was added dropwise into methylamine (100 mmol, 33 wt %
ethanol solution, 10 mL) at 278 8C for 5 min. This homoge-
neous solution was warmed to room temperature over 30
min. After concentration under vacuum, a viscous pale yel-
low mixture was obtained, and 3M HCl (8 mL) was added.
The aqueous solution was extracted with ethyl acetate (three
3-Methylenedihydro-2H-Pyran-2,6(3H)-Dione (5)
Diacid 9 (6.0 g, 41.7 mmol, prepared by a reported method9)
was mixed with acetic anhydride (10.0 g, 100 mmol) in a
SCHEME 1 (a) Synthesis of a-methyleneglutarimides 6 from a-methyleneglutaric acid (9). (b) Polymerization of 6 to a family of
poly(a-methyleneglutarimides) (PMGIs) having different substituents on the imide nitrogen atom.
2
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000

JOURNAL OF
POLYMER SCIENCE
WWW.POLYMERCHEMISTRY.ORG
ARTICLE
times). The combined organic layers were washed with
brine, dried, and concentrated to give a pale-yellow oil (10b
and 10b0). The mixture of 10b and 10b0 was dissolved in
acetic anhydride (10 mL) and triethylamine (5.0 g, 50 mmol)
was added. This reaction solution was heated at 80 8C for
1 h. The mixture was allowed to cool to room temperature
and the solvents were evaporated under high vacuum. The
residue was diluted with EtOAc (20 mL). The organic layer
was washed with 3M HCl (20 mL) and brine and dried over
Na2SO4. After filtration and concentration, flash chromatogra-
phy (1:1 Hex:EtOAc elution) gave the N-methylimide 6b
(1.50 g, 10.8 mmol, 54%) as colorless oil. The NMR spectral
data were consistent with that reported for this com-
pound.7(b) 1H NMR (400 MHz, chloroform-d) d 6.32 (d,
J 5 1.4 Hz, 1H), 5.60 (d, J 5 1.4 Hz, 1H), 3.21 (s, 3H), and
2.76–2.65 (m, 4H). 13C NMR (100 MHz, chloroform-d) d
172.4, 166.3, 135.5, 124.8, 32.6, 26.9, and 25.8. IR (thin
film): 1722, 1672, 1635, 1364, 1303, 1114, 1049, and
950 cm21. LRMS (EI, 70 eV) m/z (diagnostic ion assignment,
rel int): 139 (M•1, 100%), 111 (M-CO•1, 25%), 110 (M–
NMe1, 30%), 82 (C5H6O•1, 30%), and 54 (C4H•61, 55%).
analogous three-step sequence as the one used to prepare n-
butylimide 6c from diacid 9. H NMR (400 MHz, chloroform-
1
d) d 6.31 (d, J 5 1.5 Hz, 1H), 5.58 (d, J 5 1.5 Hz, 1H), 3.78
(dd, J 5 13.0, 7.7 Hz, NCHaHb, 1H), 3.74 (dd, J 5 12.8, 7.2 Hz,
NCHaHb,1H), 2.74–2.64 (m, 4H), 1.76–1.65 (app septet,
J 5 6.5 Hz, CHEt, 1H), 1.36–1.15 (m, 8H), and 0.88 (t, J 5 7.2
Hz, 6H). 13C NMR (100 MHz, chloroform-d) d 172.4, 166.2,
135.8, 124.6, 43.6, 37.6, 32.9, 30.6, 28.6, 25.9, 24.0, 23.0,
14.1, and 10.6. IR (thin film): 2959, 2860, 1726, 1679, 1635,
1354, 1174, and 1121 cm21. LRMS (EI, 70 eV) m/z (diagnos-
tic ion assignment, rel int): 237 (M•1, 20%), 222 (M–Me1,
2%), 208 (M-Et1, 8%), 194 (M-Pr1, 2%), 180 (M-Bu1, 7%),
139 (M-heptene•1, 45%), 138 (M-heptyl1, 10%), and 126
(M-octenyl1, 100%).
3-Methylene-1-Phenylpiperidine-2,6-Dione (6e)
Aniline (2.42 g, 26.0 mmol) was added slowly to the crude
anhydride 5 (2.53 g, 20.0 mmol) in THF (20 mL) at 0 8C for
5 min. The mixture was stirred and warmed to room tem-
perature over 30 min. The mixture was recooled to 0 8C and
3M HCl (8 mL) was added. The aqueous solution was
extracted with ethyl acetate (33). The combined organic
layers were washed with brine, dried, and concentrated to
give a colorless oil. From this oil, the phenylimide 6e
(2.62 g, 13.0 mmol, 65%, a white crystalline solid) was
obtained by the procedure used to prepare methylimide 6b.
Purification was achieved by flash chromatography (methy-
lene chloride elution). m.p.: 107–109 8C. 1H NMR (400 MHz,
chloroform-d) d 7.47 (dd, J 5 7.5, 7.5 Hz, PhHm, 2H), 7.41 (t,
J 5 7.3 Hz, PhHp, 1H), 7.12 (br d, J 5 7.0 Hz, PhHo, 2H), 6.39
(d, J 5 1.5 Hz, 1H), 5.71 (d, J 5 1.5 Hz, 1H), and 2.92–2.81
(m, 4H). 13C NMR (100 MHz, chloroform-d) d 172.2, 166.1,
135.5, 135.4, 129.3, 128.7, 128.5, 125.9, 33.1, and 26.0. IR
1-Butyl-3-Methylenepiperidine-2,6-Dione (6c)
Butylamine (1.75 g, 24.0 mmol) was added slowly to the
anhydride 5 (2.53 g, 20.0 mmol) at 0 8C for 5 min. The
resulting, viscous, gel-like mixture was vigorously shaken (by
hand) and allowed to warm to room temperature over 30
min. The mixture was recooled to 0 8C and 3M HCl (8 mL)
was added. The aqueous solution was then extracted with
ethyl acetate (three times). The combined organic layers
were washed with brine, dried, and concentrated to give an
orange-colored oil. This material was not further purified,
but the 1H NMR spectrum suggested the presence of an ca.
1:4 mixture of isomeric amic acids 10c and 10c0: 1H NMR
(400 MHz, chloroform-d) d 6.29 (br s, HaHbC 5 CCO2H), 5.72
(br s, HbHaC 5 CCO2H), 5.58 (br s, HaHbC 5 CCONHBu), 5.35
(br s, HbHaC 5 CCONHBu), 3.32 (dt, J 5 6.9, 6.9 Hz,
C 5 CCONHCH2), 3.25 (dt, J 5 6.9, 6.9 Hz, CH2CONHCH2),
2.68–2.40 (overlapping triplets), 1.55–1.30 (m), and 0.92
(overlapping triplets). From this orange oil, the N-n-
butylimide 6c (3.08 g, 17.0 mmol, 85% from diacid 9, color-
less oil) was obtained by following the procedure used to
prepare N-methylimide 6b. The material was purified by
(thin film): 1728, 1680, 1365, 1290, 1183, and 940 cm21
.
HRMS (ESI-TOF): calculated C12H11NNaO12 224.0682, found
224.0678.
AIBN-Initiated Free-Radical Polymerization of 6a to
PMGIH
3-Methylenepiperidine-2,6-dione (6a, 0.040 g, 0.32 mmol),
(E)-2,20-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN,
0.3 mg, 2 mmol), and a magnetic stirring bar were added to
a culture tube. The tube was degassed through a series of
three freeze–pump–thaw cycles and then filled with N2. The
tube was capped and the reaction mixture was heated at
120 8C (external bath temperature) while being stirred for
0.5 h. After ca 10 min, stirring could no longer be main-
tained. The cooled, solidified reaction mixture was dissolved
in hot DMF (0.2 mL). This solution was allowed to cool to
ambient temperature, and the polymer was precipitated by
dropwise addition of the DMF solution to swirled methanol
held at 0 8C. The resulting slurry was cooled (220 8C) and
filtered. The solid was rendered free of solvent under vac-
uum overnight at 70 8C to provide 21 mg of PMGIH (53%
yield). IR (neat, selected peaks): 1687, 1407, 1258, 1182,
and 1107 cm21. DSC Tg 5 none observed prior to 140 8C, the
temperature of ca. 1% mass loss (TGA). SEC PS-GPC (CHCl3):
1
flash chromatography (3:1 Hex:EtOAc elution). H NMR (400
MHz, chloroform-d) d 6.30 (d, J 5 1.4 Hz, 1H), 5.58 (d, J 5 1.4
Hz, 1H), 3.80–3.76 (br t, J 5 7.6 Hz, 2H), 2.75–2.63 (m, 4H),
1.57–1.46 (nfom, 2H), 1.33 (sextet, J5 7.3 Hz, 2H), and 0.93 (t,
J5 7.3 Hz, 3H). 13C NMR (125 MHz, chloroform-d) d 171.9,
165.8, 135.7, 124.3, 39.8, 32.6, 30.0, 25.7, 20.1, and 13.6. IR
(thin film): 2959, 2872, 1719, 1672, 1350, 1183, and
1125 cm21. LRMS (EI, 70 eV) m/z (diagnostic ion assignment,
rel int): 181 (M•1, 60%), 166 (M–Me1, 10%), 152 (M-Et1,
30%), 139 (M-propene•1, 50%), 138 (M-propyl1, 30%), 126
(M-butenyl1, 100%), and 124 (M-Bu1, 35%).
1-(2-Ethylhexyl)-3-Methylenepiperidine-2,6-Dione (6d)
The imide 6d [2.10 g, 8.86 mmol, a colorless oil, 99% from
diacid 9 (1.29 g, 9.00 mmol)] was obtained by following an
Mn5 352,000 g mol21, Mw 5627,000 g mol21, D 5 1.8.
-
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000
3

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
AIBN-Initiated Free-Radical Polymerization of 6b to
PMGIMe
dissolved in hot DMF (0.5 mL). This solution was allowed to
cool to ambient temperature, and the polymer was precipi-
tated by addition to swirled methanol held at 0 8C. The result-
ing slurry was cooled (220 8C) and filtered. The solid was
rendered free of solvent under vacuum overnight at 70 8C to
1-Methyl-3-methylenepiperidine-2,6-dione (6b, 0.146 g, 1.05
mmol), (E)-2,20-(diazene-1,2-diyl)bis(2-methylpropanenitrile)
(AIBN, 1.2 mg, 7.3 mmol), and a magnetic stir bar were
added to a culture tube. The culture tube was degassed
through a series of three freeze–pump–thaw cycles and then
filled with N2. The reaction mixture was then heated at
90 8C (external bath temperature) for 48 h while the con-
tents were stirred. After a few hours, the mixture was suffi-
ciently viscous that stirring stopped. The cooled, solidified
reaction mixture was dissolved in hot DMF (0.5 mL), allowed
to cool to ambient temperature, and precipitated by addition
to swirled methanol held at 0 8C. The resulting slurry was
cooled (220 8C), filtered, and rendered free of solvent under
vacuum overnight at 70 8C to provide 98 mg of PMGIMe
(67% yield). 1H NMR (500 MHz, DMSO-d6): d 3.1–1.0 (over-
lapping multiplets, ca. 6H), and 3.0–2.7 (overlapping br sin-
glets, 3H). 13C NMR (125 MHz, DMSO-d6): d 176.8–176.1,
172.4–171.5, 46.2–44.6, 29.5–28.4, and 27.2–26.4. IR (neat,
1
provide 121 mg of PMGIEtHx (43% yield). H NMR (500 MHz,
CDCl3): d 3.97–3.24 (m, NCH2, 2H), 3.0–1.0 (overlapping mul-
tiplets, ca. 6H), 1.6–1.5 (m, NCH2CH, 1H), 1.4–1.0 (m, ca. 8H),
and 0.96–0.75 (m, 6H). 13C NMR (125 MHz, CDCl3): d 176.5–
175.3, 171.5–170.4, 46.5–42.5, 38.0–36.7, 30.9–30.1, 29.4–
27.6, 24.1–23.3, 23.3–22.7, 14.3–13.6, and 10.7–9.8. IR (neat,
selected peaks): 2958, 2928, 1724, 1666, 1456, 1347, 1175,
and 1122 cm21. DSC Tg 5 112 8C. SEC PS-GPC (CHCl3): Mn5
5,600 g•mol21, Mw 57,400 g•mol21, D 5 1.3.
-
AIBN-Initiated Free-Radical Polymerization of 6e to
PMGIPh
3-Methylene-1-phenylpiperidine-2,6-dione (6e, 0.440 g, 2.19
mmol) and (E)-2,20-(diazene-1,2-diyl)bis(2-methylpropaneni-
trile) (AIBN, 2.6 mg, 16 mmol) were dissolved in 2 mL of
benzene and added to a culture tube containing a magnetic
stirring bar. The culture tube was degassed through a series
of three freeze-pump-thaw cycles and then filled with N2.
The tube was capped and the reaction mixture was heated
at 90 8C (external bath temperature) and stirred for 48 h.
After a few hours, a precipitate was evident. The slurry was
cooled (220 8C) and filtered. The solid was rendered free of
solvent under vacuum overnight at 70 8C to provide 97 mg
of PMGIPh (22% yield). 1H NMR (500 MHz, DMSO-d6): d
7.8–6.4 (m, 5H, NC6H5), and 3.2–1.0 (overlapping multiplets,
6H). 13C NMR (125 MHz, DMSO-d6): d 178.0–176.0, 173.0–
171.2, 137.9–136.0, 131.0–127.5, 46.5–45.5, and 30.0–27.8.
IR (neat, selected peaks): 1729, 1674, 1358, 1181, 755, and
694 cm21. DSC Tg 5 none observed prior to 120 8C, the tem-
perature of ca. 1% mass loss (TGA). SEC PS-GPC (DMF):
selected peaks): 2948, 1719, 1660, 1291, and 1113 cm21
.
DSC Tg 5 none observed on second or subsequent heating
cycles. SEC PS-GPC (DMF): Mn5 406,000 g•mol21
,
Mw 5481,000 g•mol21, D 5 1.2.
-
AIBN-Initiated Free-Radical Polymerization of 6c to
PMGIBu
1-Butyl-3-methylenepiperidine-2,6-dione (6c, 0.470 g, 2.60
mmol) and (E)-2,20-(diazene-1,2-diyl)bis(2-methylpropaneni-
trile) (AIBN, 1.4 mg, 8.7 mmol) was added to a culture tube.
The culture tube was degassed through a series of three
freeze–pump–thaw cycles and then filled with N2. The reac-
tion mixture was heated at 90 8C for 48 h. The solidified
reaction mixture was then dissolved in hot DMF (0.5 mL),
allowed to cool to ambient temperature, and precipitated by
addition to swirled methanol held at 0 8C. The resulting
slurry was cooled (220 8C), filtered, and rendered free of
solvent under vacuum overnight at 70 8C to provide 343 mg
of PMGIBu (73% yield). 1H NMR (500 MHz, CDCl3): d 3.85–
3.35 (m, NCH2, 2H), 3.0–2.5 (m, CH2C@O, 2H), 3.0–1.0 (m,
ca. 4H), 1.4–1.2 (m, ca. 4H), and 0.96–0.84 (m, 3H). 13C NMR
(125 MHz, CDCl3): d 176.0–175.0, 171.0–170.1, 46.5–44.8,
41.0–39.7, 30.3–29.3, 29.3–27.5, 20.5–19.9, and 14.0–13.4. IR
Mn5 100,000 g mol21, Mw 5138,000 g mol21, D 5 1.4.
-
RAFT Polymerization of 6b to PMGIMe
AIBN (0.08 equiv, 0.08 mg, 0.5 lmol) was added as a stock
solution in DCM (1.4 mg mL21) to a 10 mL Schlenk flask.
The DCM was removed under reduced pressure and
2-{[(dodecylthio)carbonothioyl]thio}-2-methylpropanoic acid
(DDMAT, 1.0 equiv, 2.2 mg,
6 lmol) and 1-methyl-3-
(solid, ATR): 2959, 1721, 1663, 1348, 1184, and 1124 cm21
.
,
methylenepiperidine-2,6-dione (6b, 1080 equiv, 0.906 g, 6.52
mmol) were added to the Schlenk flask. The headspace was
degassed through several freeze–pump–thaw cycles, under
static vacuum, until bubbling no longer was observed during
thawing. Nitrogen was then admitted and the flask was
closed and heated in an oil bath held at 95 8C for 48 h while
the contents were stirred. The reaction mixture solidified
after ca 12 h and could no longer be stirred. The flask was
allowed to cool to ambient temperature, the residue was dis-
solved in hot DMF, and the polymer was precipitated by
addition to swirled methanol held at 0 8C. The resulting
slurry was cooled (220 8C) and filtered. The solid was ren-
dered free of solvent under vacuum overnight at 70 8C to
provide 0.71 g of PMGIMe (79% yield). IR (neat, selected
peaks): 1716, 1658, 1353, 1172, and 1111 cm21. DSC No
DSC Tg 5 153 8C. SEC PS-GPC (DMF): Mn 5 278,000 g mol21
Mw 5 336,000 g mol21, D 5 1.2.
-
AIBN-Initiated Free-Radical Polymerization of 6d to
PMGIEtHx
1-(2-Ethylhexyl)-3-methylenepiperidine-2,6-dione (6d, 0.282 g,
1.19 mmol), (E)-2,20-(diazene-1,2-diyl)bis(2-methylpropaneni-
trile) (AIBN, 1.8 mg, 11 mmol), and a magnetic stirring bar
were added to a culture tube. The culture tube was degassed
through a series of three freeze–pump–thaw cycles and then
filled with N2. The tube was capped and the reaction mixture
was heated at 90 8C (external bath temperature) while being
stirred for 48 h. After several hours, stirring could no longer
be maintained. The cooled, solidified reaction mixture was
4
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000

JOURNAL OF
POLYMER SCIENCE
WWW.POLYMERCHEMISTRY.ORG
ARTICLE
phase transition observed. SEC PS-GPC (DMF): Mn 5 307,000
solution. The headspace was degassed through several
freeze–pump–thaw cycles, under static vacuum, until bub-
bling no longer was observed during thawing. Nitrogen was
then admitted, and the flask was closed and heated in an oil
bath held at 95 8C for 48 h. After ca 12 h, a precipitate was
present. The resulting slurry was cooled (220 8C) and fil-
tered. The solid was rendered free of solvent under vacuum
overnight at 70 8C to provide 0.23 g of PMGIPh (25% yield).
IR (neat, selected peaks): 2963, 1729, 1673, 1356, 1258,
1179, 754, and 693 cm21. DSC Tg 5 none observed on sec-
ond or subsequent heating cycles. SEC PS-GPC (DMF):
g mol21, Mw 5 389,000 g mol21, D 5 1.3.
-
RAFT Polymerization of 6c to PMGIBu
AIBN (0.08 equiv, 0.08 mg, 0.5 lmol) was added as a stock
solution in DCM (1.4 mg mL21) to a 10 mL Schlenk flask. The
DCM was removed under reduced pressure and 2-{[(dode-
cylthio)carbonothioyl]thio}-2-methylpropanoic acid (DDMAT,
1.0 equiv, 2.2 mg, 6 lmol) and 1-butyl-3-methylenepiperidine-
2,6-dione (6c, 870 equiv, 0.941 g, 5.20 mmol) were added to
the Schlenk flask. The headspace was degassed through sev-
eral freeze–pump–thaw cycles, under static vacuum, until bub-
bling no longer was observed during thawing. Nitrogen was
then admitted and the flask was heated in an oil bath held at
95 8C. The reaction mixture solidified after ca 12 h. The flask
was allowed to cool to ambient temperature, the residue was
dissolved in hot DMF, and the polymer was precipitated by
addition to swirled methanol held at 0 8C. The resulting slurry
was cooled (220 8C) and filtered. The solid was rendered free
of solvent under vacuum overnight at 70 8C to provide 0.73 g
of PMGIBu (78% yield). IR (neat, selected peaks): 2958, 1721,
1660, 1346, 1183, and 1122 cm21. DSC Tg 5 161 8C. SEC PS-
Mn 5 100,000 g mol21, Mw 5 160,000 g mol21, D 5 1.6.
-
General Procedure for Thermal Degradation of PMGIs
Each of the PMGIs (ca 25 mg) was added to a culture tube,
and the tube was heated in a sand bath held at 300 8C for
5 h. The color of the mixture turned deep brown and color-
less liquid was observed in the cool part of the inner tube.
The residue was purified by MPLC (1:1 Hex:EtOAc elution) to
give monomers 6b–d, each as a colorless oil (40–60% yield).
RESULTS AND DISCUSSION
GPC (DMF): Mn 5 333,000 g•mol21, Mw 5 526,000 g•mol21
,
We synthesized the imides 6a–e as outlined in Scheme 1(a).
The glutarate derivative 9 was prepared by the known,11
phosphine-induced dimerization of ethyl acrylate (7) to the
bis-ethyl ester 8, followed by saponification. The known12
conversion of diacid 9 to anhydride 5 was readily effected
by treatment with hot acetic anhydride. The crude product
following distillative removal of acetic acid and excess acetic
anhydride was then directly treated with either aqueous
ammonium hydroxide or the appropriate amine. This gave
the mixture of amide-acids 10 (major) and 100 (minor), in
ratios in the range of ca 8:1 (see Experimental for details).
The temperature of these amine acylation reactions was var-
ied in view of the relative reactivity of the various amines
(see Experimental). Each 10/100 mixture was treated with
acetic anhydride and triethylamine at 80 8C for 2 h to effect
full conversion of the amide-acids to the imides 6a–e.
-
D 5 1.6.
RAFT Polymerization of 6d to PMGIEtHx
AIBN (0.08 equiv, 0.08 mg, 0.5 lmol) was added as a stock
solution in DCM (1.4 mg mL21) to a 10 mL Schlenk flask.
The DCM was removed under reduced pressure and 2-
{[(dodecylthio)carbonothioyl]thio}-2-methylpropanoic
acid
(DDMAT, 1.0 equiv, 2.2 mg, 6 lmol), 1-(2-ethylhexyl)-3-meth-
ylenepiperidine-2,6-dione (6d, 550 equiv, 0.782 g, 3.30
mmol), and a magnetic stirring bar were added to the
Schlenk flask. The headspace was degassed through several
freeze–pump–thaw cycles, under static vacuum, until bub-
bling no longer was observed during thawing. Nitrogen was
then admitted and the flask was sealed and heated in an oil
bath held at 95 8C for 48 h while the contents were stirred.
The reaction mixture solidified after ca 12 h. The flask was
allowed to cool to ambient temperature, the residue was dis-
solved in hot DMF, and the polymer was precipitated by
addition to swirled methanol held at 0 8C. The resulting
slurry was cooled (220 8C) and filtered. The solid was ren-
dered free of solvent under vacuum overnight at 70 8C to
provide 0.53 g of PMGIEtHx (68% yield). IR (neat, selected
peaks): 2956, 2926, 1722, 1664, 1455, 1347, 1175, and
1121 cm21. DSC Tg 5 118 8C. SEC PS-GPC (DMF): Mn 5 4,200
Each of the monomers 6a–e was polymerized to give the
corresponding PMGI under two sets of radical conditions
(Table 1): (i) uncontrolled free radical polymerization (FRP)
conditions, initiated by AIBN and (ii) reversible addition-
fragmentation chain-transfer polymerization (RAFT). For
each of 6a–d the polymerization was done in the bulk at a
temperature above the monomer melting point. For the high-
est melting monomer, the phenyl analog 6e (mp 107–
109 8C), better results were obtained for polymerization
done in (benzene) solution. Because of the relatively low sol-
ubility of the PMGIs, the reaction mixture never remained
homogeneous throughout the entire course of the reaction.
g mol21, Mw 5 6,100g mol21, D 5 1.5.
-
RAFT Polymerization of 6e to PMGIPh
AIBN (0.08 equiv, 0.08 mg, 0.5 lmol) was added as a stock
solution in DCM (1.4 mg mL21) to a 10 mL Schlenk flask.
The DCM was removed under reduced pressure and 2-
The essential details of the polymerization conditions are
shown in Table 1, as are the yields of isolated product (fol-
lowing precipitation) and the molecular weight characteris-
tics. DMF was the only reasonable solvent for all of the
PMGIs except PMGIEtHx (from 6d), and in that lone instance
the polymer was only sparingly soluble in DMF. PMGIEtHx
{[(dodecylthio)carbonothioyl]thio}-2-methylpropanoic
acid
(DDMAT, 1.0 equiv, 2.2 mg, 6 lmol) and 3-methylene-1-
phenylpiperidine-2,6-dione (6e, 760 equiv, 0.914 g, 4.55
mmol) were added to the Schlenk flask. The contents were
dissolved in 7 mL of benzene to give a homogeneous
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000
5

JOURNAL OF
POLYMER SCIENCE
ARTICLE
WWW.POLYMERCHEMISTRY.ORG
TABLE 1 Conditions for Bulka Polymerization of the a-Methyleneglutarimides 6 and Characteristics of the Resulting Poly(a-methyle-
neglutarimides) (PMGIs)
Target Mn
Mn,SEC
(gꢀmol21
Mw,SEC
(gꢀmol21
(gꢀmol21
)
Yieldd (%)
)
)
Tg (8C)
-
D
Monomer
Polymer
Method
T (8C)
Time (h)
c
g
g
6a
6b
6c
6d
6e
6b
6c
6d
6e
PMGIH
FRP
120
90
90
90
90
95
95
95
95
0.25
48
48
48
48
48
48
48
48
55
67
73
43
22
79
78
68
25
352,000e
406,000e
278,000e
5600f
100,000e
307,000e
333,000e
4200f
627,000
481,000
336,000
7400
1.8
1.2
1.2
1.3
1.4
1.3
1.6
1.5
1.6
c
c
c
c
PMGIMe
PMGIBu
PMGIEtHx
PMGIPh
PMGIMe
PMGIBu
PMGIEtHx
PMGIPh
FRP
FRP
153
FRP
112
g
FRP
138,000
389,000
526,000
6100
g
RAFTb
RAFTb
RAFTb
RAFT
150,000
150,000
130,000
150,000
161
118
g
100,000e
160,000
a
d
Monomers 6a–d were polymerized in the absence of solvent; polymer-
ization of monomer 6e was carried out in benzene solution
[6e]0 5 1.0 M.
Yield determined gravimetrically following precipitation.
DMF SEC calibrated with PS standards.
e
f
CHCl3 SEC calibrated with PS standards.
b
g
Monomer conversion was >90% as measured by 1H NMR analysis of
Glass transition not observed on second or any subsequent heating
a portion of the crude product mixture.
cycles. In some instances, there was a small endotherm seen on the
first heating cycle.
c
Monomer:AIBN (100:1).
did, however, readily dissolve in less polar organic solvents
such as chloroform, dichloromethane, tetrahydrofuran, and
acetone. Size exclusion chromatographic analysis (and com-
parisons) was challenging because of these solubility properties.
Notice the large variation in Mn and Mw values for PMGIEtHx
versus the other, DMF-soluble polymers, even though all were
synthesized under nominally the same conditions (Figure S5–
7). This presumably reflects the large uncertainty introduced
by analyzing these compounds against polystyrene (PS) stand-
ards and the considerably large, associated variation in hydro-
dynamic radii of these relatively highly polar polymers
compared with PS. In the case of N-phenyl polymer PMGIPh
prepared by RAFT polymerization (last entry), resonances were
sufficiently well resolved that it was possible to carry out NMR
end-group analysis, from which an Mn of 45 kg mol21 was
measured (Figure S9).
Finally, several simple polymer degradation experiments
were performed (Scheme 2). A precipitated sample of each
of the three N-alkylated polymers PMGIMe, PMGIBu, and
PMGIEtHx (ca 25 mg, each) was heated in a sealed vial for
5 h at 300 8C, a temperature guided by data from thermal
gravimetric analysis (Figures S3–4). A colorless liquid had
condensed into the cold zone of the vial. NMR analysis of the
liquid alone showed that it was primarily the corresponding
monomer, while analysis of the entire mixture indicated the
monomer 6b, 6c, or 6d as the principal component along
with what we judged to be a portion of remaining oligomeric
material (Figure S8). The entire mixture was chromato-
graphed to give 40–60% recovery of pure monomer.
The focused study we describe here is an example of an
approach that we sometimes follow when considering the
possible use of a monomer substrate that could, in principle,
be made available by optimization of a major metabolic path-
way. More specifically, following identification of such a
monomer candidate, we first synthesize it by more tradi-
tional chemical means, where the priority is on expediency
rather than economic, scalability, or biorenewability issues.
With that exploratory sample of monomer in hand, we then
study its polymerization to assess the chemical behavior
and/or material properties of the resulting polymer(s) to
inform a subsequent decision about investing in engineering
a feasible fermentation pathway to the monomer.
The glass transition temperatures (Tg) were examined for
each of these samples and are also shown in Table 1. The Tg
of PMGIBu is relatively high (161 8C (Figures S1–2)) com-
pared to that reported for the N-butyl 5-membered poly(a-
methylenesuccinimide) homolog (115 8C5(b) or 120 8C4(c))
.
The Tg of PMGIEtHx is 118 8C (Figures S1–2). No glass transi-
tions were observed for the other PMGIs at temperatures
below their onset of thermal decomposition (1% mass loss;
T
1% 5 140, 160, and 180 8C for PMGIPh PMGIH, and
,
PMGIMe, respectively) (Figures S1–2).
CONCLUSIONS
In conclusion, we have synthesized the series of a-methyl-
eneglutarimide derivatives 6a-e from a-methyleneglutaric
acid (9), a potentially bioresourcable entity. Each mono-
mer was radically polymerized under two sets of condi-
tions—FRP and RAFT. The resulting PMGIs are only
sparingly soluble in common organic solvents. Where
SCHEME 2 Thermal degradation of PMGIAlk
6
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000

JOURNAL OF
POLYMER SCIENCE
WWW.POLYMERCHEMISTRY.ORG
ARTICLE
3 (a) T. Okuda, K. Ishimoto, H. Ohara, S. Kobayashi, Macromole-
cules 2012, 45, 4166; (b) T. Otsu, J. Yang, Polym. Int. 1991, 8, 245.
observable, the polymers have relatively high Tg’s, which
suggests their possible utility in block copolymer applica-
tions. The PMGIs can be depolymerized thermally to
return the starting vinyl monomer. The overall approach is
an example of exploring, by wholly chemical means, the
potential utility of a new monomer/polymer pair that
could possibly be made available from an optimized or
engineered fermentation pathway, prior to investing in the
development of that protocol.
4 (a) a-Methylenebutyrolactone: M. K. Akkapeddi, Macromole-
cules 1979, 12, 546; J. T. Trotta, M. Jin, K. J. Stawiasz, Q.
Michaudel, W. Chen, B. P. Fors, J. Polym. Sci. A 2017, 55, 2730;
(b) N-Methyl a-methylenebutyrolactam: T. Ishizone, K.
Kitazawa, T. Suzuki, S. Kawauchi, Macromol. Symp. 2013, 323,
86; (c) N-Butyl itaconic imide: A. Matsumoto, S. Umehara, H.
Watanabe, T. Otsu, J. Polym. Sci. B, 1993, 31, 527; (d) K. Koch,
Alpha-methyleneglutarimide polymers and copolymers and
preparation thereof. U.S. Patent 3,706,716, December 19, 1972.
5 (a) T. Oishi, M. Momoi, M. Fujimoto, J. Polym. Sci. A 1983,
21, 1053; (b) T. Oishi, M. Momoi, M. Fujimoto, T. Kimura, J.
Polym. Sci. A 1983, 21, 1053.
ACKNOWLEDGMENTS
6 Y. Hirose, Y. Sakamoto, H. Tajima, S. Kawaguchi, K. Ito, J.
Phys. Chem. 1996, 100, 4612.
Support for this study was provided by grants to the Center for
Sustainable Polymers at the University of Minnesota from the
National Science Foundation [Center for Chemical Innovation
(CHE-1413862)] and the Minnesota Corn Growers Association.
Some of the NMR data were taken on an instrument purchased
with through the NIH Shared Instrumentation Grant program
(S10OD011952).
7 (a) M. J. Wanner, G. J. Koomen, Tetrahedron Lett. 1992, 33,
1513; (b) M. J. Wanner, G. J. Koomen, Tetrahedron Lett. 1989,
30, 2301.
8 (a) L. Tsai, I. Pastan, E. R. Stadtman, J. Biol. Chem. 1966, 241,
1807; (b) H. Kung, L. Tsai, T. C. Stadtman, J. Biol. Chem. 1971,
246, 6444; (c) T. A. Scott, Methods Enzymol. 1971, 18, 71.
9 J. Kagan, L. Tolentino, M. G. Ettlinger, J. Org. Chem. 1975,
40, 3085.
REFERENCES AND NOTES
10 M. J. Wanner, G. J. Koomen, Synthesis 1988, 1988, 325.
11 (a) H. Currier, M. M. Rauhut, Preparation of dialkyl 2-
methyleneglutarates. U.S. Patent 3,074,999, January 22, 1963;
(b) X. Hu, J. Zhang, X. Yang, Y. Xu, T. Loh, J. Am. Chem. Soc.
2015, 137, 3169.
1 (a) M. Ueda, M. Takahashi, Y. Imai, C. U. Pittman, Macromo-
lecules 1983, 16, 1300; (b) G. M. Miyake, Y. Zhang, E. Y. Chen,
Macromolecules 2010, 43, 4902.
2 (a) G. M. Iskander, T. R. Ovenell, T. P. Davis, Macromol.
Chem. Phys. 1996, 197, 3123; (b) I. M. Heyns, R. Pfukwa, B.
Klumperman, Biomacromolecules 2016, 17, 1795.
12 I. Suarez del Villar, A. Gradillas, J. Perez-Castells, Eur. J.
Org. Chem. 2010, 30, 5850.
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2018, 00, 000–000
7