Synthesis of poly(2-oxazoline)s with side chain methyl ester functionalities: Detailed understanding of living copolymerization behavior of methyl ester containing monomers with 2-alkyl-2-oxazolines

Article abstract of DOI:10.1002/pola.27733

Poly(2-oxazoline)s with methyl ester functionalized side chains are interesting as they can undergo a direct amidation reaction or can be hydrolyzed to the carboxylic acid, making them versatile functional polymers for conjugation. In this work, detailed studies on the homo- and copolymerization kinetics of two methyl ester functionalized 2-oxazoline monomers with 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, and 2-n-propyl-2-oxazoline are reported. The homopolymerization of the methyl ester functionalized monomers is found to be faster compared to the alkyl monomers, while copolymerization unexpectedly reveals that the methyl ester containing monomers significantly accelerate the polymerization. A computational study confirms that methyl ester groups increase the electrophilicity of the living chain end, even if they are not directly attached to the terminal residue. Moreover, the electrophilicity of the living chain end is found to be more important than the nucleophilicity of the monomer in determining the rate of propagation. However, the monomer nucleophilicity can be correlated with the different rates of incorporation when two monomers compete for the same chain end, that is, in copolymerizations.

Full text of DOI:10.1002/pola.27733

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Synthesis of Poly(2-oxazoline)s with Side Chain Methyl Ester
Functionalities: Detailed Understanding of Living Copolymerization
Behavior of Methyl Ester Containing Monomers with 2-Alkyl-2-oxazolines
P. J. M. Bouten,1,2 Dietmar Hertsen,3 Maarten Vergaelen,1 Bryn D. Monnery,1 Saron Catak,3,4
Jan C. M. van Hest,2 Veronique Van Speybroeck,3 Richard Hoogenboom1
1Supramolecular Chemistry Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4,
9000 Ghent, Belgium
2Radboud University Nijmegen, Institute for Molecules and Materials (IMM), Heijendaalseweg 135, 6525 AJ Nijmegen,
The Netherlands
3Center for Molecular Modeling (CMM), Ghent University, Technologiepark 903, Zwijnaarde 9052, 9000 Ghent, Belgium (Member
of the QCMM Ghent–Brussels Alliance)
4Department of Chemistry, Bogazici University, Bebek, 34342 Istanbul, Turkey
Correspondence to: V. Van Speybroeck (E-mail: veronique.vanspeybroeck@ugent.be) or R. Hoogenboom (E-mail:
richard.hoogenboom@ugent.be)
Received 9 April 2015; accepted 3 June 2015; published online 29 June 2015
DOI: 10.1002/pola.27733
ABSTRACT: Poly(2-oxazoline)s with methyl ester functionalized
side chains are interesting as they can undergo a direct amida-
tion reaction or can be hydrolyzed to the carboxylic acid, mak-
ing them versatile functional polymers for conjugation. In this
work, detailed studies on the homo- and copolymerization
kinetics of two methyl ester functionalized 2-oxazoline mono-
mers with 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, and 2-n-
propyl-2-oxazoline are reported. The homopolymerization of
the methyl ester functionalized monomers is found to be faster
compared to the alkyl monomers, while copolymerization
unexpectedly reveals that the methyl ester containing mono-
mers significantly accelerate the polymerization. A computa-
tional study confirms that methyl ester groups increase the
electrophilicity of the living chain end, even if they are not
directly attached to the terminal residue. Moreover, the electro-
philicity of the living chain end is found to be more important
than the nucleophilicity of the monomer in determining the
rate of propagation. However, the monomer nucleophilicity
can be correlated with the different rates of incorporation
when two monomers compete for the same chain end, that is,
C
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in copolymerizations.
2015 Wiley Periodicals, Inc. J. Polym.
Sci., Part A: Polym. Chem. 2015, 53, 2649–2661
KEYWORDS: copolymers; density functional theory; molecular
dynamics; molecular modeling; polymerization kinetics; poly(2-
oxazoline)s
ter reversibility as compared to the gold standard poly(N-
isopropylacrylamide).14–16 The properties of PAOx can be
easily tuned by variation of the side chain substituent, also
enabling the incorporation of (protected) side chain
functionalities.17–30
INTRODUCTION The living cationic ring-opening polymeriza-
tion (CROP) of 2-oxazoline monomers (Scheme 1) was first
reported in the 1960s1–4 providing an easy access to a wide
variety of well-defined poly(2-alkyl/aryl-2-oxazoline)s
(PAOx) with controlled end-group functionality during initia-
tion and termination.5–9 PAOx are an interesting class of
polymers because of its highly tunable and diverse proper-
ties.6,10–12 Poly(2-methyl-2-oxazoline) (PMeOx) and poly(2-
ethyl-2-oxazoline) (PEtOx) are of special interest for biomed-
ical applications because of their biocompatibility and stealth
behavior that are similar to poly(ethylene glycol)
(PEG).6,10,11,13 PEtOx and poly(2-propyl-2-oxazoline) (PPro-
pOx) show lower critical solution (LCST) behavior with bet-
PAOx with methyl ester functionalized side chains are espe-
cially interesting as the methyl ester can be hydrolyzed to
the carboxylic acid, a versatile functionality for conjugation
of peptides and proteins. Furthermore, the methyl ester
group can undergo a direct noncatalyzed amidation reaction
to easily introduce a wide variety of side chain amide moi-
eties.31,32 Very recently, we reported an increased
Petra J. M. Bouten and Dietmar Hertsen contributed equally to this work.
Additional Supporting Information may be found in the online version of this article.
C
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nucleophilicities of the monomers and to assess the effect of
the methyl ester side chains in MestOx and C3MestOx on the
electrophilicity of the living cationic center. The computa-
tional approach consists of static density functional theory
(DFT) calculations on monomers, cationic chains and propa-
gation systems, as well as a semiempirical molecular dynam-
ics trajectory of a MestOx decamer, whereby the time
evolution of interactions is observed.
EXPERIMENTAL
Materials
2-Chloroethylamine hydrochloride, methyl p-toluenesulfonate
(MeOTs), and sodium carbonate were purchased from Acros
Organics. EtOx was kindly donated by Polymer Chemistry
Innovations. All other reagents were purchased from Sigma
Aldrich and used as received, except MeOx, EtOx, and MeOTs.
These were purified by distillation over barium oxide and
stored under argon. Dry solvents were obtained from a sol-
vent purification system from J. C. Meyer, with aluminum
oxide drying system and a nitrogen flow.
SCHEME 1 Cationic ring-opening polymerization of 2-
oxazolines with methyl p-toluenesulfonate as initiator and
piperidine as terminating agent.
propagation rate of the methyl ester containing monomer 2-
methoxycarbonylethyl-2-oxazoline (MestOx, 1) (Scheme 2)
during homopolymerization compared to 2-methyl-2-
oxazoline (MeOx, 3) or 2-ethyl-2-oxazoline (EtOx, 4), while
copolymerization surprisingly revealed slower incorporation
of MestOx.28 Previous computational modeling suggested
that the methyl ester group of the MestOx interacts with the
living chain end, causing a slight increase in electrophilicity
of the carbon atom C5, thereby enhancing the reactivity of
the oxazolinium ring. The nitrogen atom of the MeOx mono-
mer is more negative, and thus more nucleophilic and reactive
towards the chain end, than the nitrogen atom of the MestOx
monomer. This theory is indirectly supported by the work of
Saegusa and Ikeda.33 Nearby ester groups in the growing
polymer can also interact with the incoming MeOx monomer,
inducing higher nucleophilicity of the MeOx monomer.
Instrumentation
Nuclear magnetic resonance (NMR) spectra were recorded
on a Bruker DMC300 (300 MHz for 1H, 75 MHz for 13C) or
1
a Bruker DMX 500 (500 MHz for H, 125 MHz for 13C).
Electro spray ionization mass (ESI MS) spectra were
recorded on a Thermo Finnigan LCQ Advantage Max.
HR-MS was measured on an Agilent 1100 series HPLC
coupled to an Agilent 6220A TOF-MS equipped with ESI/
APCI multimode source.
Polymerization reaction mixtures were prepared in a VIGOR
Sci-Lab SG 1200/750 Glovebox system, with less than 1 ppm
of O2 and H2O.
Polymerizations were conducted in a Biotage Initiator Micro-
wave System with Robot Sixty utilizing capped reaction vials.
These vials were heated to 120 8C overnight, allowed to cool
to room temperature and filled with nitrogen prior to use.
All microwave polymerizations were performed with temper-
ature control (IR sensor).
In this contribution we describe the synthesis of a new
methyl ester containing monomer with a trimethylene (C3)
spacer between the oxazoline ring and the methyl ester
namely 2-methoxycarbonylpropyl-2-oxazoline (C3MestOx, 2).
Detailed studies on the homo- and copolymerization kinetics
of these two methyl ester functionalized 2-oxazoline mono-
mers, MestOx and C3MestOx, with MeOx, EtOx, and 2-n-
propyl-2-oxazoline (nPropOx, 5) are reported. To better
understand the observed copolymerization rate constants,
the Arrhenius parameters of MestOx, C3MestOx, and
MestOx–MeOx copolymerization were also determined by
studying the (co)polymerization at different temperatures.
Theoretical calculations were performed to compare the
Size exclusion chromatography (SEC) was performed on an
Agilent 1260—series HPLC system equipped with a 1260
ISO-pump, a 1260 automatic liquid sampler, a thermostatted
column compartment, a 1260 diode array detector (DAD),
and a 1260 refractive index detector (RID). Analyses were
performed on Mixed D columns and a guard column in
series at 50 8C. N,N-dimethylacetamide (DMA), containing
50 mM of LiCl, was used as an eluent, at a flow rate of
0.593 mL min21. The SEC eluograms were analyzed using
the Agilent Chemstation software with the GPC add on, cali-
brated against poly(methyl methacrylate) (PMMA) standards.
Gas chromatography (GC) was performed on a 7890A from
Agilent Technologies with an Agilent J&W Advanced Capillary
GC Column (30 m, 0.320 mm, and 0.25 lm). Injections were
SCHEME 2 Monomer structures of MestOx (1), C3MestOx (2),
MeOx (3), EtOx (4), and nPropOx (5). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
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performed with an Agilent Technologies 7693 auto sampler.
Detection was done with a Flame ionization detector (FID)
detector. Injector and detector temperatures were kept con-
stant at 250 and 280 8C, respectively. The column was ini-
tially set at 50 8C, followed by two heating stages: from 50
to 100 8C with a rate of 20 8C min21 and from 100 to 300
8C with a rate of 40 8C min21, and then held at this tempera-
ture for 0.5 min. Conversion was determined based on the
integration of monomer peaks using acetonitrile (CH3CN) as
an internal standard.
13C NMR (CDCl3, 75 MHz): d 5 172.9 (COOCH3), 169.2
(C(@N)O), 67.6 (CH2O), 54.3 (CH2N), 51.9 (OCH3), 30.2
(CH2COO), 23.2 (CH2N).
ESI MS: m/z: calculated 157.07, found 158.1 and 159.1
[M 1 H1].
HR-MS: m/z: theoretical 157.07389 Da, found 158.0811 Da
[M 1 H1]; D abundance 0.4 ppm.
Synthesis of Methyl 5-(2-chloroethylamino)-5-
oxopentanoate (2b, C3MestOx precursor)
Glutaric acid monomethyl ester chloride (2a, 50 g, 303.8
mmol, 41.98 mL) and 2-chloroethylamine hydrochloride
(35.24 g, 303.8 mmol) were suspended in dry dichlorome-
thane (375 mL) under an argon atmosphere. The reaction
mixture was cooled continuously to 0 8C while triethylamine
(66.09 g, 653 mmol, 90.8 mL) was added dropwise within
2 h. The reaction was allowed to warm to room temperature
overnight, after full addition of the TEA. The mixture was
washed with water (2 3 25 mL) and brine (1 3 25 mL).
The organic phase was dried over Na2SO4 and the solvent
was removed under reduced pressure. A yellow liquid (60 g,
289 mmol, 95%) was obtained.
Monomer Synthesis
Synthesis of Methyl 4-(2-chloroethyl)amino-4-
oxobutanoate (1b, MestOx-precursor)28
Methyl succinyl chloride (1a, 100 g, 664.2 mmol, 91.76 mL)
and 2-chloroethylamine hydrochloride (77.04 g, 664.2 mmol)
were suspended in dry dichloromethane (DCM, 750 mL)
under an argon atmosphere. The reaction mixture was
cooled continuously to 0 8C while triethylamine (TEA)
(144.50 g, 1428 mmol, 198.4 mL) was added dropwise
within 2 h. The reaction was allowed to warm to room tem-
perature overnight, after full addition of the TEA. The mix-
ture was washed with water (2 3 50 mL) and brine (1 3
50 mL). The organic phase was dried over Na2SO4 and the
solvent was removed under reduced pressure. The resulting
product was purified by filtration column chromatography
(neutral Al2O3, DCM:MeOH (methanol, 99:1) yielding product
1b as a yellow oil (107 g, 617.7 mmol, 83%).
1H NMR (CDCl3, 300 MHz): d 5 6.0 (br, 1H, NH), 3.67 (s, 3H,
OCH3), 3.61 (m, 4H, CH2Cl and CH2CH2Cl), 2.39 (t, 7.3 Hz,
2 H, NHC@OCH2), 2.27 (t, 7.3 Hz, 2H, CH2COOCH3), 1.97 (qt,
7.3 Hz, 2H, CH2CH2CH2).
13C NMR (CDCl3, 125 MHz): d 5 173.4 (C@ONH), 172.4
(C@OOCH3), 51.8 (OCH3), 44.2 (CH2Cl), 41.3 (NHCH2), 35.5
(NHC@OCH2), 33.1 (CH3C@OCH2), 20.9 (CH2CH2CH2).
1H NMR (CDCl3, 500 MHz): d 5 6.1 (br, 1H, NH), 3.68 (t, 2.1
Hz, 2H, CH2Cl), 3.61 (m, 5H, OCH3 and CH2CH2Cl), 2.68 (t,
7.0 Hz, 2 H, NCAOCH2), 2.52 (t, 7.0 Hz, 2H, CH2COOCH3).
ESI MS: m/z: calculated 207.07, found 208.0 and 210.0
[M 1 H1].
13C NMR (75 MHz, CDCl3): d 5 172.9 (C@ONH), 171.1
(C@OOCH3), 51.4 (OCH3), 43.5 (CH2CH2Cl), 40.8 (CH2Cl),
30.5 (CH3C5OCH2), 28.8 (CH3C5OCH2CH2).
Synthesis of 2-methoxycarbonylpropyl-2-oxazoline
(2, C3MestOx)
ESI MS: m/z: calculated 193.05, found 194.1 and 196.1
[M 1 H1], 216.1 and 218.1 [M 1 Na1].
The C3MestOx precursor (2b, 60 g, 289 mmol) and anhy-
drous sodium carbonate (27.6 g, 260 mmol) were mixed.
The reaction was performed overnight by mounting the flask
at the rotary evaporator (40 8C, 50 mbar) to allow good mix-
ing of the salt in the viscous mixture and providing a larger
surface area for evaporation of the released CO2. Subse-
quently, DCM was added, the reaction mixture was filtered
and the solvent was removed under reduced pressure. The
oil was distilled twice over barium oxide, under reduced
pressure, yielding a colorless liquid (24.8 g, 145 mmol,
50%).
Synthesis of 2-methoxycarbonylethyl-2-oxazoline
(1, MestOx)28
The MestOx precursor (1b, 107 g, 617.7 mmol) and anhy-
drous sodium carbonate (52.7 g, 497.3 mmol) were mixed.
The reaction was performed for 48 h by mounting the flask
at a rotary evaporator (40 8C, 50 mbar) to allow good mixing
of the salt in the viscous mixture, thereby providing a larger
surface area for evaporation of the released CO2. Subse-
quently DCM was added, the reaction mixture was filtered
and the solvent was removed under reduced pressure. The
oil was distilled twice over barium oxide, under reduced
pressure yielding a colorless liquid that crystallized in time
into a white solid (60 g, 381.8 mmol, 69%).
1H NMR (CDCl3, 500 MHz): d 5 4.3 (t, 2H, 9.5 Hz, CH2O), 3.8
(t, 9.5 Hz, 2H, CH2N@), 3.7 (s, 3H, COOCH3), 2.7 (t, 2H, 7.3
Hz, CH2COO), 2.6 (t, 2H, 7.3 Hz, CH2C(@N)O)), 1.97 (quint,
7.3 Hz, 2H, CH2CH2CH2)
1H NMR (CDCl3, 500 MHz,): d 5 4.3 (t, 2H, 9.4 Hz, CH2O), 3.8
(t, 9.4 Hz, 2H, CH2N@), 3.7 (s, 3H, COOCH3), 2.7 (t, 2H, 7.3
Hz, CH2COO), 2.6 (t, 2H, 7.3 Hz, CH2C(@N)O).
13C NMR (CDCl3, 75 MHz): d 5 173.6 (COOCH3), 167.8
(C(@N)O), 67.3 (CH2O), 54.5 (CH2N), 51.7 (OCH3), 32.9
(CH2COOCH3), 27.2 (CH2C(@N)O), 21.3 (CH2CH2CH2).
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TABLE 1 Overview of Different Reaction Times at Different Temperatures Used for Kinetic Studies
140 8C
120 8C
100 8C
80 8C
80 8C
All Monomers,
Homo- and
MestOx and
C3MestOx Homo,
MestOx and
C3MestOx Homo,
MeOx, EtOx, nPropOx,
MestOx, C3MestOx,
C3MestOx
MestOx
Sample
1
Copolymerization
1 s
MeOx–MestOx
1 s
MeOx–MestOx
7 min 30 s
Copolymerization
20 min
Copolymerization
35 min
2
3
4
5
6
7
2 min
4 min
6 min
8 min
10 min
12 min
7 min 30 s
15 min
15 min
30 min
45 min
1 h
40 min
60 min
80 min
100 min
120 min
70 min
105 min
140 min
175 min
210 min
245 min
22 min 30 s
30 min
37 min 30 s
45 min
1 h 15 min
1 h 30 min
ESI MS: m/z: calculated 171.09, found 172.1[M 1 H1].
Computational Methodology
A density functional theory (DFT) study was performed to
rationalize the polymerization kinetics of 2-oxazolines.28,35
The Gaussian 09 program package36 and the M06-2X/6-
311G(d,p) level of theory37 were used for all static calcula-
tions. The most stable conformations (minima) of the
2-oxazolines and their N-methyl oxazolinium cations were
found by means of conformational scans. Transition states
(first-order saddle points) were located for several propaga-
tion systems and connected with their prereactive and prod-
uct complexes by following the intrinsic reaction coordinate
(IRC).38–40 The nature of the minima and first-order saddle
points was verified by frequency calculations. Hirshfeld-I
(HI) charges were calculated for all systems,41,42 since this
charge scheme has proven useful for the analysis of the
CROP of 2-oxazolines28,35 and is relatively robust with
respect to conformational changes.42 In order to understand
the dynamic behavior of the interactions between the side
chains and the cationic centre, molecular dynamics simula-
tions were performed on a MestOx decamer with the CP2K
program43 within an NVT ensemble using the semiempirical
PM6 method.
HR-MS: m/z: theoretical 171.08954 Da, found 172.0976 Da
[M 1 H1]; D abundance 4.6 ppm.
Synthesis of 2-n-propyl-2-oxazoline (5, nPropOx)
nPropOx was synthesized according to literature.34 In brief,
butyronitrile (1 equiv.), amino ethanol (1.1 equiv.) and zinc
acetate dihydrate (catalyst, 0.02 equiv.) were refluxed at 130
8C overnight. The reaction mixture was cooled to room tem-
perature, and dichloromethane was added. The organic
phase was washed three times with water and once with
brine. After removing the dichloromethane under reduced
pressure, the monomer was purified by fractional distillation
over barium oxide.
Polymerization Kinetics
Stock solutions (7 mL) for polymerization kinetics were pre-
pared in the glovebox. The total monomer concentration
[Mtot] 5 [M1] 1 [M2] is 3 M, the monomer (M1 1 M2):initiator
ratio ½Mꢀ 5100, MeOTs was used as an initiator, acetonitrile
½Iꢀ
(CH3CN) was used as solvent. For copolymerizations the
molar ratio of both monomers was 50:50. The stock solution
was divided in 0.7 mL portions in separate 0.5–2 mL Biotage
reaction vials. The polymerization times used are listed in
Table 1. After the polymerization, 0.1 mL of polymerization
mixture was sampled and diluted with 0.9 mL of chloroform
for GC measurement. Conversion was determined based on
the integral of monomer peaks using CH3CN as an internal
standard. A second sample of 0.1 mL was diluted with
0.9 mL of DMA containing 50 mM of LiCl for SEC measure-
ment to determine Mn and Ð.
RESULTS AND DISCUSSION
Monomer Synthesis
The 2-(methyl ester functionalized) 2-oxazoline monomers,
MestOx, and C3MestOx, were prepared from commercially
available acid chlorides 1a (Scheme 3) and 2a through a
reaction with 2-chloroethylamine hydrochloride in the pres-
ence of triethylamine yielding intermediate compounds 1b
and 2b. The monomers (1 and 2) were obtained by ring clo-
sure of these intermediate compounds with a strong non-
S3
SCHEME 3 Synthesis of methyl ester containing 2-oxazolines.
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lower viscosity of the amide precursor 2b in comparison to
1b. As a result, the ring-closing reaction that involves release
of CO2 proceeded significantly faster.
Polymerization Kinetics
Homopolymerizations
All monomers (MestOx, C3MestOx, MeOx, EtOx, and nPro-
pOx) were polymerized with methyl p-toluenesulfonate
(MeOTs) as initiator,44 acetonitrile as solvent under micro-
wave irradiation at both 80 and 140 8C. Stock solutions were
prepared which contained solvent, monomers and initiator
at 3 M monomer concentration and a [M]/[I] ratio of 100.
The corresponding first order kinetic plots obtained at 140
8C reveal linear first-order kinetics for all monomers, indicat-
ing a constant concentration of propagating species in time
and, thus, the absence of termination reactions albeit chain
transfer can not be excluded [Fig. 1(A)]. Each data point rep-
resents a separate polymerization and, thus, the linearity of
these combined results proves the good reproducibility. The
livingness of the homopolymerizations was confirmed by a
linear increase of the number average molecular weight (Mn)
with conversion as well as the low dispersities of the result-
ing polymers (Ð < 1.17, 1B). Similar results were obtained at
80 8C, also revealing living polymerization of all monomers
(Supporting Information Figs. S1 and S2).
The polymerization rate constants (kp) were calculated from
the slope of the linear correlation between ln([M]0/[M]t) and
time in the first-order kinetic plots in Figure 1 and Support-
ing Information Figures S1 and are summarized in Table 2.
The rates obtained for MeOx and EtOx are in good agree-
ment with previously reported values,34 but the kp values of
nPropOx at 140 8C is slightly higher due to a small overshoot
in temperature to 150 8C during microwave heating of the
polymerization mixture.
FIGURE 1 (A) First-order kinetic plot for homopolymerization
of MeOx, EtOx, nPropOx, MestOx, and C3MestOx at 140 8C and
(B) number average molecular weight (Mn) and dispersity (Ð)
plotted against conversion. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Previous computational work revealed that the fast propaga-
tion of the MestOx monomer is due to an interaction of the
oxazolinium ring with the ester group in the side chain of the
MestOx, leading to higher electrophilicity of the 5 position and
thus enhancing the reactivity of the living chain end.28 A simi-
lar intramolecular activation was proposed between the amide
carbonyl of the last monomer before the oxazolinium chain
end, leading to a higher kp value compared to kp,1 value for the
first monomer addition during CROP.33
nucleophilic base (sodium carbonate) to avoid saponification
of the ester. This last reaction was performed on a rotary
evaporator under reduced pressure to allow good mixing of
the precursor oil and the salt and to ease the release of car-
bon dioxide.28 The monomers were obtained pure and dry
after distilling them twice over barium oxide. It should be
noted that the synthesis of C3MestOx was easier due to the
TABLE 2 Propagation Rate Constants for the Homopolymerizations
kp
kp
kp
kp
Monomer 1 T (8C) (1023 L mol21 s21
)
T (8C) (1023 L mol21 s21
)
T (8C) (1023 L mol21 s21
)
T (8C) (1023 L mol21 s21
)
MeOx
140
140
140a
140
140
133 6 4
99 6 3
80
80
80
80
80
4.13 6 0.15
2.99 6 0.05
3.86 6 0.27
6.91 6 0.29
5.29 6 0.38
EtOx
nPropOx
MestOx
C3MestOx
133 6 4
171 6 4
193 6 4
120
120
58.6 6 2.2
48.6 6 1.4
100
100
28.0 6 1.6
16.6 6 0.8
a
Value is slightly higher due to a small overshoot in temperature to 150 8C during microwave heating of the polymerization mixture.
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FIGURE 2 First-order kinetic plot for homopolymerization of
MestOx at different temperatures. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
At 140 8C C3MestOx is polymerizing faster than MestOx, while
at 80 8C the order is reversed, but both of them are still faster
than MeOx, EtOx, and nPropOx (Table 2). Similar results were
obtained for the intermediate temperatures 120 and 100 8C,
also revealing linear living polymerization kinetics (Fig. 2 and
Supporting Information Figures S3–S5). At these temperatures
MestOx also polymerizes faster than C3MestOx.
The logarithms of the kp values of MestOx and C3MestOx
show a linear relationship with the inverse temperature as
expected based on the Arrhenius equation (eq 1).
FIGURE 4 (A) First-order kinetic plot for copolymerization of
nPropOx and MestOx at 140 8C and (B) number average molec-
ular weight (Mn) and dispersity (Ð) plotted against conversion.
[Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]
2E
RT
A
kp5Ae
(1)
The Arrhenius plots for the MestOx and C3MestOx homopo-
lymerizations are shown in Figure 3. From these plots, the
activation energy (EA, MestOx 5 63.0 6 4.3 kJ mol21
A,C3MestOx 5 71.7 6 4.9 kJ mol21) and the frequency factor
(AMestOx 5 1.54 6 0.13
107 mol21 s21
C3MestOx 5 1.92 6 0.15 3 108 L mol21 s21) were calculated.
These activation energies are lower than for MeOx
,
E
3
L
,
A
(EA 5 75.4 6 0.5 kJ mol21 45
and EtOx (73.4 6 0.5 kJ
)
mol21),46 thereby indicating that the methyl ester groups
indeed lower the activation barrier for monomer addition.
Copolymerizations
To further examine the remarkable copolymerization behav-
ior of MestOx with MeOx and EtOx leading to reversed
monomer incorporation order compared to the homopolyme-
rization,28 the copolymerization of MestOx and C3MestOx
was studied with MeOx, EtOx, and nPropOx at both 80 and
140 8C with a monomer ratio of 50:50 using the same condi-
tions as for the homopolymerizations. The previously
reported copolymerizations of MestOx with MeOx or EtOx at
140 8C are also included to give a complete overview.28
FIGURE 3 Arrhenius plot of MestOx and C3MestOx. The data
from literature of MeOx45 and EtOx46 are included for compari-
son. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
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TABLE 3 Propagation Rate Constants and Apparent Reactivity Ratios for the Copolymerizations of MestOx and C3MestOx with
MeOx, EtOx, and nPropOx
kp,1 (1023 L mol21 s1)
kp,2 (1023 L mol21 s21
)
r1
(k1/k2)
r2
(k2/k1)
app
app
Monomer 1
Monomer 2
T (8C)
MeOx
EtOx
MestOx
140
140
140
140
140
140
120
100
80
244 6 6
89 6 3
2.74
1.67
1.86
1.98
1.26
1.44
2.71
3.29
3.79
1.68
1.90
2.36
1.41
1.40
0.37
0.60
0.54
0.50
0.79
0.70
0.37
0.30
0.26
0.60
0.53
0.42
0.71
0.72
MestOx
162 6 4
97 6 3
nPropOx
MeOx
EtOx
MestOx
212 6 6
114 6 3
C3MestOx
C3MestOx
C3MestOx
MestOx
184 6 12
144 6 4
93 6 8
113 6 3
nPropOx
MeOx
MeOx
MeOx
EtOx
157 6 7
109 6 6
73.3 6 6.3
29.2 6 1.4
5.09 6 0.13
4.50 6 0.26
4.65 6 0.13
7.91 6 0.62
5.80 6 0.26
7.37 6 0.38
27.1 6 1.8
8.90 6 0.44
1.34 6 0.07
2.68 6 0.20
2.45 6 0.16
3.36 6 0.03
4.10 6 0.14
5.27 6 0.24
MestOx
MestOx
MestOx
80
nPropOx
MeOx
EtOx
MestOx
80
C3MestOx
C3MestOx
C3MestOx
80
80
nPropOx
80
The first-order kinetic plots of nPropOx and MestOx copoly-
merization at 140 8C is shown in Figure 4(A) as representa-
tive example for all copolymerizations (Supporting
Information Figs. S6–S27). For all investigated copolymeriza-
tions, the 2-alkyl-2-oxazoline monomer was incorporated
faster than MestOx and C3MestOx in agreement with our
previous findings.28
the linearity proves the good reproducibility. The livingness
of the polymerization was confirmed by the linearly increas-
ing Mn with conversion as well as low dispersities (Ð) [Fig.
4(B)]. The discrepancy with the theoretical Mn values can be
addressed to the PMMA standards, that is, the different
hydrodynamic volume, used for the SEC calibration of the
experimental values as shown previously.28
Modeling showed that the monomers bearing alkyl and
methyl ester side chains compete for incorporation into the
same living chain, which is activated due to the interaction
between nearby MestOx and C3MestOx residues and the
chain end. Since the reacting nitrogen atom is more negative
and thus more nucleophilic in the monomers bearing alkyl
side chains, these monomers are incorporated faster into the
chain. The ester group in the growing polymer can also
interact with the incoming MeOx monomer, inducing higher
nucleophilicity of the MeOx monomer. The same interactions
are expected to occur during (co)polymerization of
C3MestOx.
The kp values were calculated from the slope of the kinetic
plots and are summarized in Table 3. Compared to the kp
values of the homopolymerization, the incorporation of 2-
alkyl-2-oxazoline monomers is accelerated while the incorpo-
ration of MestOx and C3MestOx is slowed down. This is due
to the activation of the alkyl monomer by the interaction of
the incoming alkyl monomer with the methyl ester side
chain of the growing polymer chain.
By dividing both kp values the apparent reactivity ratios
(rapp) for both monomers are calculated (Table 3).47 For
copolymerizations of MestOx and C3MestOx with EtOx and
nPropOx, changing the polymerization temperatures (140
and 80 8C) did not influence the rapp and, thus, the monomer
All first-order kinetic plots revealed a linear increase, indi-
cating a constant concentration of propagating species in
time and, thus, the absence of termination reactions. Each
data point represents a separate polymerization and, thus,
distribution of the resulting polymer is independent of the
app
temperature. In fact, for these copolymerizations r1
than 1.9 while r2
is less
app
is larger than 0.5, so there is only a
FIGURE 5 Monomer distribution of (A) MeOx (black, open) and MestOx (blue) after 80 8C copolymerization and (B) EtOx (red,
open) and C3MestOx (pink) after copolymerization at 140 8C along the polymer chain, calculated from the kinetics plots. [Color fig-
ure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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FIGURE 6 Gradient plots of the instantaneous copolymer composition along the polymer chains for (A) MestOx copolymers at
140 8C, (B) C3MestOx copolymers at 140 8C, (C) MestOx copolymers at 80 8C, and (D) C3MestOx copolymers at 80 8C. On the y axis
0 refers to no MestOx, 1 refers to fully MestOx and 0.5 to an equimolar mixture of both monomers. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
minor deviation from an ideal random monomer distribution.
The visualization of the monomer distributions in Figures
5(B) and 6 that are calculated based on the individual mono-
mers conversions in time confirms a near ideal random
structure for r1app < 1.9.
The copolymerizations of the more reactive MeOx with Mes-
app
tOx and C3MestOx have an r1
a r2
which is larger than 1.9 and
app
is smaller than 0.5, so the monomer distribution sig-
nificantly deviates from an ideal random distribution, for
example, a gradient copolymer is formed. The strength of the
gradient is determined by temperature and monomer. Lower
temperatures lead to stronger gradients while copolymers
with MestOx also have a stronger gradient than copolymers
with C3MestOx.
From the first-order kinetic plots the average distribution of
monomers along the polymer chain can be calculated. In Fig-
ure 5 two extremes are shown, in A the strongest gradient
obtained from MeOx and MestOx copolymerized at 80 8C and
in B the near random distribution of EtOx and C3MestOx
FIGURE 7 Temperature dependence of the apparent reactivity
ratios of MeOx–MestOx copolymerization. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.
com.]
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sus temperature in Figure 7, showing the temperature depend-
ence of the apparent reactivity ratios between 80 and 120 8C
while increasing further to 140 8C has no effect. The gradient
plots of MeOx–MestOx copolymerizations at different tempera-
tures are depicted in Figure 8, showing slightly stronger gradi-
ent formation at lower temperatures. Because the kp values
were determined at different temperatures, an Arrhenius plot
could be made (Fig. 9) and from this the activation energy
(EA, MeOx 5 76.16 5.8 kJ mol21
, EA,MestOx 5 83.4 6 5.6 kJ
mol21), and the frequency factor (AMeOx 5 1.04 6 0.09 3 107 L
mol21 s21, AMestOx 5 3.276 0.27 3 109 L mol21 s21) were cal-
culated. The activation energy of MeOx in the copolymerization
is a comparable to the activation energy of MeOx in homopoly-
merization (EA,MeOx 5 75.4 kJ mol21), while the activation of the
MestOx raised in comparison with homopolymerization (EA,
MestOx 5 63.0 6 4.3 kJ mol21).
FIGURE 8 Gradient plots of MeOx–MestOx copolymerization at
different temperatures. On the y axis 0 refers to no MestOx, 1
refers to fully MestOx, and 0.5 to an equimolar mixture of both
monomers. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Computational Rationalization
In order to rationalize the difference in polymerization
kinetics between 2-oxazolines bearing aliphatic (MeOx, EtOx,
nPropOx) and methyl ester side chains (MestOx, C3MestOx),
at first, a density functional theory (DFT) study was per-
formed.28,35 2-oxazolines and their N-methyl-2-oxazolinium
cations were studied as model systems for monomers and
living chain ends, respectively. Subsequently, a dimeric living
end was used to model the second propagation step for sev-
eral systems. As a final step, a molecular dynamics simula-
tion of a model polymer—MestOx decamer—was performed
to investigate the dynamic behavior of the polymer chain
and the time evolution of interactions within the living
chain.
copolymerized at 140 8C. For easier comparison the different
gradients are also plotted in Figure 6 clearly showing that the
first part of the polymers is slightly enriched in the comono-
mer and the final part of the copolymer is enriched in
(C3)MestOx.
As the MeOx–MestOx copolymerization showed the strongest
gradient formations as well as a temperature dependence of
the apparent reactivity ratios, the MeOx–MestOx kinetic studies
were also performed at two intermediate temperatures (100
and 120 8C). Both temperatures also revealed linear first-order
kinetics (Supporting Information Figs. S28 and S30), indicating
a constant concentration of propagating species in time and,
thus, absence of termination reactions. The livingness was con-
firmed by a linear increase of the Mn with conversion as well as
Ð values of the resulting polymer (Ð < 1.13, Supporting Infor-
mation Figs. S29 and S31). The kp values and rapp values are
listed in Table 3. The apparent reactivity ratios are plotted ver-
Various conformers were localized for the isolated oxazoline
monomers and their N-methyl oxazolinium cations corre-
sponding to different orientations of the side chain with
respect to the five-membered ring. The relative free energies
of these conformations are listed in Table 4, alongside
Hirshfeld-I charges of the N3 and C50 ring atoms. These
charges will be used as measures for the nucleophilicity of
the monomer and the electrophilicity of the living chain,
respectively. The Hirshfeld-I charge scheme has been suc-
cessfully used to rationalize kp’s for the CROP of 2-oxazoline
polymerizations28,35 and is robust with respect to conforma-
tional changes.42
The extended (ext) and interacting (int) conformations of
MestOx, C3MestOx (Fig. 10) and nPropOx systems stem from
the bond rotations in the side chain, since the five-membered
oxazoline and oxazolinium rings are relatively rigid. MestOx
and C3MestOx cations preferentially adopt a contracted or
interacting conformation in which the side chain interacts
with the oxazoline ring (DGint–ext(MestOx) 5 233.5 kJ mol21
,
DGint–ext (C3MestOx) 5 227.4 kJ mol21). This electrostatic cat-
ion–dipole interaction between the oxazolinium ion and the
carbonyl group of the MestOx side chain is an important fac-
tor in the kp increase of MestOx and C3MestOx and can be
found in prereactive complexes of propagations and molecular
dynamics simulations of longer living chains (see further).
FIGURE 9 Arrhenius plot for the MeOx–MestOx copolymeriza-
tion. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
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TABLE 4 Relative Gibbs-Free Energy and N3/C50 Hirshfeld-I Charges of the Most Stable Monomer and Cation Conformations
(ext 5 extended, int 5 interacting, M06-2X/6–311G(d,p), 413.15 K, 1 atm)
Monomer
Cation
DG (kJ mol21
)
N3 (e)
DG (kJ mol21
)
C50 (e)
MeOx
20.578
20.582
20.581
20.586
20.567
20.577
20.568
20.570
0.041
0.040
0.044
0.045
0.040
0.047
0.040
0.057
EtOx
NPropOx
ext
int
ext
int
ext
int
0.0
4.0
0.0
12.6
0.0
5.2
0.0
0.1
MestOx
0.0
233.5
0.0
C3MestOx
227.4
The opposite is true for the monomers: extended side chains
are favored over interacting conformations in these cases
(DGint–ext (MestOx) 5 12.6 kJ mol21, DGint–ext (C3MestOx) 5 5.2
kJ mol21, DGint–ext (nPropOx) 5 4.0 kJ mol21). The conformers
are equally stable in the case of nPropOx cations (DGint–ext
(nPropOx) 5 0.1 kJ mol21).
phatic monomers are more likely to react. The charge of
the oxazolinium carbon atom C50 is a measure for the elec-
trophilicity of the living homopolymer chain end. Cations
with aliphatic side chains are less electrophilic (MeOx
0.041, EtOx 0.040, nPropOx 0.044) than those with methyl
The charge of the 2-oxazoline nitrogen atom N3 is a mea-
sure for the nucleophilicity of the monomer. Therefore, 2-
oxazolines with aliphatic side chains (MeOx 20.578, EtOx
20.582, nPropOx 20.581) are more nucleophilic than those
with methyl ester side chains (MestOx 20.577, C3MestOx
20.570). The lower nucleophilicity of the methyl ester con-
taining monomers can be ascribed to a reduction of the
electron donating character of the aliphatic side chains
resulting from the electron withdrawing nature of the
methyl ester group. This leads to the observed incorpora-
tion rate in copolymerizations: if both types of monomers
compete for addition to the same living chain end, the ali-
FIGURE 11 Geometries of selected pre-reactive complexes and
˚
transition states (distances in A, interactions in green, mono-
FIGURE 10 Most stable conformation of the C3MestOx monomer
mers in red living chains in blue, M06-2X/6–311G(d,p), propa-
gation systems a–f in Table 5). [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
and
C3MestOx
and
MestOx
cation
(ext 5 extended,
int 5 interacting, M062X/6–311G(d,p)). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
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TABLE 5 N3/C50 Hirshfeld-I Charges of Selected Prereactive
Complexes (M06-2X/6–311G(d,p), 413.15 K, 1 atm)
role of the nearby side chains, four propagation reactions a–
d, in which a monomer is incorporated into a dimeric living
chain, were studied (Table 5 and Fig. 11) and a molecular
dynamics simulation was performed on a MestOx decameric
living chain (Fig. 12).
Monomer
Living Chain
N3 (e)
C50 (e)
A
b
MeOx
1MeOx–MeOx
20.635
20.623
20.631
20.610
0.065
0.070
0.074
0.071
MeOx
1MeOx–MestOx
1MeOx–C3MestOx
1MeOx–C3MestOx
The nearby MestOx and C3MestOx residues in the pre-
reactive complexes of propagation reactions b–d coordinate
toward the reactive center. The carbonyl oxygen atom of
their methyl ester side chain interacts with one of the hydro-
gen atoms attached to the electrophilic carbon atom C50 (b:
2.30 Å, c: 2.38 Å, d: 2.25 Å). This interaction withdraws elec-
tron density from the cationic ring, thereby increasing the
electrophilicity of the living chain end (Table 5, see further).
Since there is no methyl ester side chain present in the
MeOx homopolymerization (a), the corresponding living
chain end is less electrophilic.
C
D
MeOx
C3MestOx
ester side chains (MestOx 0.047, C3MestOx 0.057), given
the methyl ester interacts with the ring (MestOx: 0.047 vs.
0.040, C3MestOx: 0.057 vs. 0.040). The longer C3MestOx
side chain (trimethylene spacer) causes a larger electrophi-
licity increase than the shorter MestOx side chain (ethylene
spacer). This electrophilicity increase is almost absent in
nPropOx (nPropOx: 0.045 vs. 0.044). Due to steric/torsional
effects, the MestOx side chain is positioned closer to the
cationic center (2.61 Å, Fig. 11) than the C3MestOx side
chain (2.68 Å).
The carbonyl oxygen of the methyl esters interacts with the
chain end through one of the hydrogens atoms attached to
C50 and with one of the hydrogen atoms attached to the first
methyl(ene) group of the monomer side chain, both in the
transition states (SI) and the prereactive complexes of these
propagations (Fig. 11).
As a consequence, two opposing effects come into play during
the homopolymerization of 2-oxazolines bearing methyl ester
side chains: less nucleophilic monomers and more electrophilic
living chain ends. For 2-oxazolines bearing aliphatic side chains,
the situation is reversed: more nucleophilic monomers, but less
electrophilic living chain ends. Since the same order (C3Mes-
tOx > MestOx > nPropOx > MeOx > EtOx) was found for C50
charges (0.057 > 0.047 > 0.045 > 0.041 > 0.040) and homopoly-
merization rates (Table 2, kp(1023 L mol21 s) at 140 8C:
192.7 > 171.0, 133.2 > 132.7 > 98.7), the electrophilic effect is
seemingly more important for these 2-oxazolines. MestOx and
C3MestOx homopolymerizations are faster due to the interaction
between the methyl ester side chain and the 2-oxazolinium ring.
In the prereactive complexes of these larger systems [Fig. 11(a–
d), Hirshfeld-I charges in Table 5], the reactive nitrogen atom
N3 is more nucleophilic (20.635 ꢁ N3 ꢁ 20.610 in PRCs,
20.586 ꢁ N3 ꢁ 20.567 in isolated monomers) and the reactive
carbon atom more electrophilic (0.065 ꢁ C50 ꢁ 0.074 in PRCs,
0.040 ꢁ C50 ꢁ 0.057 in isolated cations) than in the isolated
monomers and cations, respectively. Complexation of the reac-
tants thus increases the reactivity, regardless of the nature of
the side chain. The higher nucleophilicity of the MeOx monomer
is confirmed (20.635 ꢁ N3 ꢁ 20.623 for MeOx, 20.610 for
C3MestOx). If nearby methyl esters are present in the living
dimer (b–d), the electrophilicity of the living chain is increased
relative to the MeOx homopolymerization a (0.065 for a,
0.070 ꢁ C50 ꢁ 0.074 for b–d). This electrophilicity increase is
larger for C3MestOx (0.074 for c) than for MestOx (0.070 for
The rate-enhancing effect of methyl ester side chains is not
limited to single-unit chains, such as the N-methyl oxazoli-
nium cations, since nearby MestOx and C3MestOx residues
can contribute to the electrophilicity and nucleophilicity
increase as well. In order to obtain a deeper insight into the
FIGURE 12 Snapshot of a MestOx homodecamer and selected distances during an MD simulation (selected interactions as green
and blue lines, PM6, NVT at 300 K). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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b), in accordance with the charges of N-methyl 2-oxazolinium
cations.
larger than that of MestOx and C3MestOx. The electrophilicity
increases were shown to be more important in determining
the rate of propagation than the inherent monomer nucleophi-
licity. This explains the faster homopolymerization of MestOx
and C3MestOx. In copolymerizations, however, multiple mono-
mers compete for the same living chain end and the most
nucleophilic one will be incorporated faster. This was con-
firmed by modeling the incorporation of a monomer into a
dimeric living chain for several polymerization systems.
The conformational space of the methyl ester groups and their
interactions with the oxazolinium chain end were investigated
by means of a semiempirical molecular dynamics (MD) simula-
tion of an elongated living chain (Fig. 12). A trajectory of about
100 ps was obtained for a cationic MestOx homodecamer.
Herein, two important interactions can be discerned: (a) one
between the oxazolinium ring and the side chain of the terminal
residue (green line) and (b) one between the side chain of the
antepenultimate residue (1MestOx–MestOx–MestOx–MestOx7)
and the ring (blue line). Remarkably, the side chain of the
penultimate residue (1MestOx–MestOx–MestOx–MestOx7) is
positioned further away from the ring (ꢂ5 Å) than that of the
antepenultimate residue (ꢂ3.5 Å). Irrespective of their position
in the living chain, methyl ester groups can cause intrachain sta-
bilization by coordinating toward the chain end when sterically
allowed. Similar behavior may also lead to interchain stabiliza-
tion when multiple living chains are in contact.
ACKNOWLEDGMENTS
The computational resources used in this work were provided
by Stevin Supercomputer Infrastructure Ghent University (Bel-
gium), the Hercules Foundation, and the Flemish Govern-
ment—Department EWI. V.V.S. and R.H. acknowledge the
Belgian Program on Interuniversity Attraction Poles initiated
by the Belgian State, the Prime Minister’s office (P7/05) and
the IWT for support via the Strategic Basic Research program
(SBO-120049). P.B and J.v.H. acknowledge the Polymer Innova-
tion Program (PIPM10006, General adhesive Tissue Tape). All
authors acknowledge the Special Research Fund of Ghent Uni-
versity; in particular PB for a joint PhD fellowship.
The calculations on isolated reactants and extended systems
are in good correlation. Interactions between the methyl
ester groups of the reactive or nearby residues and the chain
end withdraw electron density from the reactive carbon
atom and render the living chain more electrophilic. This
explains the higher homopolymerization rate of MestOx and
C3MestOx. Similar rate increases are found in the copolymer-
izations of MeOx/EtOx/nPropOx with MestOx/C3MestOx. In
these reactions, different monomers compete for the same
chain end and the nucleophilicity of each monomer controls
its rate of incorporation.
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methyl 2-oxazolinium cations, as well as in a molecular
dynamics simulation of a MestOx decameric living chain.
Both methyl ester groups attached to the terminal residue
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