Tunable pH- and CO2-Responsive Sulfonamide-Containing Polymers by RAFT Polymerization

Article abstract of DOI:10.1021/acs.macromol.5b01453

(Graph Presented). The controlled RAFT polymerization of a library of pH- and CO₂-responsive methacryloyl sulfonamides (MSAs) that possess pK_a values in the biologically relevant regime (pH = 4.5-7.4) is reported. Initial polymerizat

Full text of DOI:10.1021/acs.macromol.5b01453

Article
pubs.acs.org/Macromolecules
Tunable pH- and CO2‑Responsive Sulfonamide-Containing Polymers
by RAFT Polymerization
Brooks A. Abel,† Michael B. Sims,† 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
ABSTRACT: The controlled RAFT polymerization of a library of pH- and CO2-responsive methacryloyl sulfonamides (MSAs)
that possess pKa values in the biologically relevant regime (pH = 4.5−7.4) is reported. Initial polymerizations were conducted at
70 °C in DMF with 4-cyano-4-(ethylsulfanylthiocarbonylsulfanyl)pentanoic acid (CEP) or 4-cyanopentanoic acid dithiobenzoate
(CTP), resulting in polymers of broad molecular weight distributions (Mw/Mn > 1.20). As well, chain extension of a
poly(methacryloyl sulfacetamide) (pSAC) macro-CTA at 70 °C was unsuccessful, indicating a loss of “living” chain ends during
polymerization. However, by conducting the RAFT polymerization of MSAs at 30 °C with 2,2′-azobis(4-methoxy-2,4-
dimethylvaleronitrile), polymers with narrow molecular weight distributions (Mw/Mn < 1.15) and improved chain end retention
were obtained. Homopolymers of each MSA derivative were synthesized, and the influence of the sulfonamide R group on
monomer pKa and pH-dependent polymer solubility was determined during these studies. The facility by which these controlled
poly(MSAs) can be prepared via low-temperature RAFT without the need for functional group protection and the resulting pKa-
dependent pH- and CO2-responsive properties point to significant potential in areas including drug and gene delivery and
environmental remediation.
polymers derived from sulfa drugs was synthesized by classical
free radical or Michael-addition techniques.17 Variation of the
sulfonamide R group afforded facile, tunable control over
polymer pKa and subsequent pH-dependent solubility (Scheme
1). Recently, Bae and co-workers further demonstrated this
versatility in pKa selection for a variety of polymer-based
therapeutic applications.11,18−20 However, until now the
uncontrolled nature of the polymerization methods used to
prepare such polymers has limited the ability to attain well-
defined polymer architectures with the specific molecular
weights and narrow molecular weight distributions required for
responsive nanotherapeutics.
Reversible-deactivation radical polymerization (RDRP)
techniques such as nitroxide-mediated polymerization
(NMP), atom transfer radical polymerization (ATRP), and
reversible addition−fragmentation chain transfer (RAFT)
polymerization have made possible the synthesis of (co)-
INTRODUCTION
■
Recently, extensive research efforts have been directed toward
the synthesis of well-defined (co)polymers capable of rapid and
reversible changes in solubility and/or conformation in
response to external stimuli including pH,1−3 temperature,4,5
or ionic strength,6 among others.7−9 Of particular interest are
“smart” nanocarriers for drug and gene delivery that exploit
discrete changes in physiological pH to elicit the desired
therapeutic effect.10−14 Designing such polymeric systems
requires that the morphological transitions occur over a very
narrow designated pH range. Commonly, this specificity is
achieved by the selection of a monomer with a pKa at or near
the target transition pH; however, polymer design is
accordingly restricted by the limited choice in monomers and
their respective pKa values. Consequently, a facile method of
specifically tuning polymer pH-responsiveness while maintain-
ing a narrow transition range is needed.
A number of attempts have been made to systematically vary
the pH-responsiveness of polymers.15,16 One versatile approach
toward modification of polymer pKa was reported by Ringsdorf
in seminal work in which a library of sulfonamide-containing
Received: July 2, 2015
Revised: July 29, 2015
© XXXX American Chemical Society
A
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subsequently the pH-dependent solubility of the resulting
polymethacryloyl sulfonamides (pMSAs). During our study of
the weakly acidic/basic nature of the MSA derivatives chosen,
we found a remarkably facile and reversible CO2-induced
solubility transition in aqueous solutions. The demonstrated
control over RAFT polymerization of MSAs now allows new
routes for the synthesis of advanced polymer architectures with
tunable pH- and CO2-responsive properties for ultimate use in
biological and therapeutic applications.
Scheme 1. pH-Dependent Solubility of pMSAs
EXPERIMENTAL SECTION
■
Materials. 4-Cyanopentanoic acid dithiobenzoate25 (CTP) and 4-
cyano-4-(ethylsulfanylthiocarbonylsulfanyl)pentanoic acid12 (CEP)
were synthesized according to literature procedures. Methacryloyl
chloride (Aldrich, 97%) was distilled under vacuum and stored under
N2 at −10 °C prior to use. 4,4-Azobis(4-cyanovaleric acid) was
recrystallized from methanol and stored at −10 °C. N,N′-
Dimethylformamide (Acros, extra dry with sieves) was stirred under
vacuum at room temperature for 60 min prior to use in order to
remove traces of dimethylamine. 2,2′-Azobis(4-methoxy-2,4-dimethyl-
valeronitrile) (V-70) (Wako, 96%) sulfacetamide (Aldrich, >98%),
sulfamethazine (Aldrich, >99%), sulfamethizole (Aldrich, >99%),
sulfadimethoxine (Aldrich, >98.5%), sulfadoxine (Aldrich, >95%),
sulfabenzamide (TCI, >98%), trimesic acid, (Aldrich, 95%), 0.1 N
NaOH (Alfa Aesar, standardized), and 0.05 N HCl (Alfa Aesar,
standardized) were used as received.
polymers of a wide variety of architectures with predictable
molecular weights and narrow molecular weight distribu-
tions.21−23 In particular, RAFT has been used to directly
polymerize a variety of cationic, anionic, and other functional
monomers in organic or aqueous media without the necessity
of protecting group chemistries or postpolymerization mod-
ification.23,24 The facility of polymerization and excellent
functional group tolerance of RAFT polymerization have
driven our current objectives of synthesizing sulfonamide-
containing polymers in a controlled fashion.
In this article we report, to our knowledge, the first
controlled RAFT polymerization of a library of methacryloyl
sulfonamide (MSA) monomers possessing pKa values in the
biologically relevant regime (pH = 4.5−7.4). In this work we
show that temperature has a significant influence on the
polymerization of MSAs, with lower reaction temperatures
affording improved molecular weight control and functional
chain end retention. Varying the sulfonamide R group is shown
to be an effective means of adjusting monomer pKa and
Characterization. NMR spectra and monomer conversions were
obtained using a Varian INOVA 300 MHz NMR spectrometer in
DMSO-d6. Polymer molecular weights and molecular weight
distributions (Mw/Mn) were determined by size exclusion chromatog-
raphy (SEC) using 95:5 (v:v) DMF:CH3COOH 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
Table 1. Conversion, Molar Mass, and Molecular Weight Distribution Data for the RAFT Polymerization of MSAs in DMF at 70
a
°C
b
c
d
d
entry
monomer deriv
CTA
time (min)
conv (%)
[M]0 (mol/L)
1.0
Mntheory (g/mol)
Mnexp (g/mol)
Mw/Mn
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
mSAC
CTP
CTP
CTP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
120
360
600
120
360
600
120
360
600
120
360
600
120
420
600
120
360
600
120
420
600
7
10
12
22
67
81
13
48
66
16
51
69
35
79
85
12
47
73
15
62
67
3200
4500
4400
5800
1.19
1.18
1.27
1.27
1.41
1.44
1.27
1.24
1.26
1.22
1.27
1.29
1.55
1.78
1.81
1.23
1.20
1.28
1.10
1.45
1.47
mSAC
mSAC
5400
6200
mSAC
1.0
9400
14600
26400
29700
7400
mSAC
28500
34700
7000
mSAC
mSBZ
1.0
mSBZ
25000
34200
8800
22000
28100
13900
29800
35500
22000
34900
35200
15100
34600
44400
11100
25900
27100
mSBZ
mSMZ
mSMZ
mSMZ
mSMT
mSMT
mSMT
mSDMX
mSDMX
mSDMX
mSDOX
mSDOX
mSDOX
0.83
1.0
26800
36300
18000
40600
43300
6900
0.83
0.83
26800
41900
8800
35500
38500
a
b
Sulfonamide monomers were polymerized at 70 °C in DMF ([M]0:[CTA]0:[I]0 = 150:1.0:0.2) using V-501 as the initiator. 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 the sulfonamide monomer (5.84 ppm, 1H). Theoretical number-average molecular weights were calculated according to the
c
equation Mn = (ρMWmon[M]/[CTA]) + MWCTA, where ρ is the fractional monomer conversion, MWmon is the molecular weight of the monomer,
d
and MWCTA is the molecular weight of the CTA. As determined by SEC-MALLS (95:5 (v:v) DMF:CH3COOH 20 mM LiBr).
B
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Scheme 2. Synthetic Pathway for the CEP- or CTP-Mediated RAFT Polymerization of MSAs in DMF
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.
General Procedure for RAFT Polymerization of Methacryloyl
Sulfonamides. Briefly, MSA (5.0 × 10−3 mol, 150 equiv), CTA
(CTP or CEP) (3.3 × 10−5 mol, 1 equiv), initiator (V-70 or V-501)
1
(6.7 × 10−7 mol, 0.2 equiv), and trimesic acid (50 mg, H 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 =
1 M) or 6.0 mL (0.83 M) depending upon monomer solubility as
indicated in Table 1. The solution was then transferred to a 10 mL test
tube equipped with a magnetic stir bar and rubber septum followed by
purging with N2 for 40 min. 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 monomer vinyl proton (5.84 ppm, 1H). SEC-MALLS
(95% DMF/5% CH3COOH, 20 mM LiBr) was used to monitor the
progression of molecular weight and molecular weight distribution
(Mw/Mn) throughout each polymerization. Polymers isolated for
solubility studies were purified by precipitating the reaction mixture
into a 10-fold excess of MeOH followed by isolating the resulting
solids by ultracentrifugation. The isolated polymers were precipitated a
total of three times from DMF into MeOH before drying overnight in
vacuo.
Monomer Titrations. Monomer stock solutions (1 mM) were
prepared by weighing each MSA (0.1 mmol) into separate 100 mL
volumetric flasks, followed by the addition of 2.00 mL of 0.1 N NaOH
(0.2 mmol) to each flask. Once the monomers were completely
dissolved, DI H2O (18.2 MΩ resistance) was added to each volumetric
flask to achieve a final volume of 100 mL. 25 mL of each stock solution
was transferred to a 100 mL beaker containing a stir bar and titrated
against 0.05 N HCl in volume increments of 5 μL at 25 °C using a
Metrohm 848 Titrino Plus autotitrator. All titrations were performed
in triplicate.
pH-Dependent Polymer Solubility. Polymer solutions were first
prepared by dissolving each pMSA derivative (1 equiv of sulfonamide,
2.5 × 10−5 mol of sulfonamide functional groups) in 1.00 mL of 0.05
N NaOH (2 equiv, 5 × 10−5 mol) followed by dilution with DI H2O
(18.2 MΩ resistance) to a final volume of 2.50 mL ([SO2NH] = 10
mM). The polymer solution was transferred into a quartz cuvette, and
the solution pH adjusted incrementally by adding 1−10 μL of 0.2 N
HCl followed by measuring the % transmittance at λ = 500 nm using a
UV−vis spectrophotometer.
CO2-Dependent Polymer Solubility. In a 20 mL vial equipped
with magnetic stir bar and pierceable cap, pMSA (1 equiv sulfonamide,
2.0 × 10−5 mol sulfonamide functional groups) was dissolved in 400
μL of 0.05 N NaOH (1.25 equiv, 2.5 × 10−5 mol) and subsequently
diluted to a final volume of 3.00 mL ([SO2NH] = 6.7 mM) with DI
H2O (18.2 MΩ resistance). CO2-dependent polymer solubility was
examined between purge cycles by transferring the solutions to a
quartz cuvette and measuring the percent transmittance at 500 nm.
Purge cycles consisted of purging the solution with CO2 for 10 s or N2
for 25 min.
General Procedure for Methacryloyl Sulfonamide Synthesis.
Using a modified procedure,11 sulfa drug (40.0 mmol) was dissolved in
160 mL of a 1:1 (v:v) mixture of acetone and 0.5 N aqueous NaOH
and stirred while cooling in an ice bath. Methacryloyl chloride (4.10
mL, 42.0 mmol) was then added dropwise over 30 min followed by
removing the ice bath and stirring the reaction at room temperature
for an additional 60 min. The acetone was removed by rotary
evaporation, followed by adjusting the solution to pH = 2 with 6 N
HCl. The resulting solids were isolated using vacuum filtration and
washed with 100 mL of dilute HCl (0.01 N) prior to drying in vacuo
for 48 h, yielding the desired monomers as colorless to off-white solids.
The synthesis of methacryloyl sulfadoxine (mSDOX) required the use
of 240 mL of a 1:2 (v:v) mixture of acetone and 0.5 N aqueous NaOH.
Methacryloyl Sulfacetamide (mSAC). Yield: 10.29 g, 91%; mp
1
203−205 °C dec. H NMR (300 MHz, DMSO-d6): δ 11.99 (s, 1H),
10.20 (s, 1H), 8.11−7.65 (m, 4H), 5.84 (s, 1H), 5.58 (s, 1H), 1.93 (s,
3H), 1.89 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 168.69, 167.34,
143.72, 139.99, 133.13, 128.67, 121.03, 119.50, 23.22, 18.63.
Methacryloyl Sulfabenzamide (mSBZ). Yield: 12.89 g, 94%; mp
1
228−229 °C dec. H NMR (300 MHz, DMSO-d6): δ 12.46 (s, 1H),
10.22 (s, 1H), 8.02−7.87 (m, 4H), 7.83 (d, J = 7.2 Hz, 2H), 7.60 (t, J
= 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 5.84 (s, 1H), 5.58 (s, 1H), 1.93
(s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 167.36, 165.38, 143.79,
139.99, 133.24, 133.15, 131.54, 128.93, 128.61, 128.40, 121.03, 119.50,
18.62.
Methacryloyl Sulfadimethoxine (mSDMX). Yield: 14.72 g, 97%;
1
mp 216−218 °C dec. H NMR (300 MHz, DMSO-d6): δ 11.50 (s,
1H), 10.17 (s, 1H), 7.86 (m, 4H), 5.92 (s, 1H), 5.82 (s, 1H), 5.57 (s,
1H), 3.77 (s, 3H), 3.73 (s, 3H), 1.92 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): δ 171.67, 167.30, 164.26, 159.90, 143.41, 139.98, 133.68,
128.30, 120.96, 119.64, 84.57, 54.54, 53.81, 18.59.
Methacryloyl Sulfadoxine (mSDOX). Yield: 14.10 g, 93%; mp
198−199 °C. 1H NMR (300 MHz, DMSO-d6): δ 11.09 (s, 1H), 10.17
(s, 1H), 8.12 (s, 1H), 5.84 (s, 1H), 5.59 (s, 1H), 3.90 (s, 3H), 3.70 (s,
3H), 1.95 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 167.32, 161.63,
150.43, 143.14, 140.06, 134.61, 129.88, 128.61, 127.21, 120.92, 119.40,
60.28, 54.08, 18.64.
Methacryloyl Sulfamethazine (mSMZ). Yield: 13.39 g, 97%; mp
1
234−235 °C dec. H NMR (300 MHz, DMSO-d6): δ 11.47 (s, 1H),
10.10 (s, 1H), 7.86 (dd, J = 28.3, 8.6 Hz, 4H), 6.74 (s, 1H), 5.81 (s,
1H), 5.55 (s, 1H), 2.23 (s, 6H), 1.92 (s, 3H). 13C NMR (75 MHz,
DMSO): δ 167.61, 156.65, 143.19, 140.43, 135.08, 129.49, 121.24,
119.42, 113.97, 23.37, 19.04.
Methacryloyl Sulfamethizole (mSMT). Yield: 12.42 g, 91%; mp
1
215−217 °C dec. H NMR (300 MHz, DMSO-d6): δ 13.90 (s, 1H),
10.12 (s, 1H), 7.77 (dd, J = 37.4, 8.4 Hz, 4H), 5.82 (s, 1H), 5.56 (s,
1H), 2.44 (s, 3H), 1.92 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ
167.80, 167.20, 154.46, 142.65, 140.03, 136.05, 126.71, 120.83, 119.70,
18.65, 16.10.
RESULTS AND DISCUSSION
■
RAFT Polymerization of Methacryloyl Sulfonamides
(MSAs) at 70 °C. The MSA monomers (R groups shown in
C
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Scheme 2) were targeted for this work based upon their
respective pKa values (Table 3) that reside within the
biologically relevant pH range of 4.5−7.4. Utilizing a modified
literature procedure,11 high monomer yields (>90%) were
obtained from the reaction of methacryloyl chloride and the
appropriate sulfa drug precursor, as outlined in the Exper-
imental Section.
Achieving controlled RAFT polymerization of a given
monomer requires appropriate choice of CTA and polymer-
ization conditions. Previously, our group successfully utilized
the trithiocarbonate 4-cyano-4-(ethylsulfanylthiocarbonyl-
sulfanyl)pentanoic acid (CEP) and the dithioester 4-cyano-
pentanoic acid dithiobenzoate (CTP) to polymerize a wide
variety of (meth)acrylamide monomers in aqueous or organic
media in a controlled fashion.25,26 On the basis of that work, we
have investigated the RAFT polymerization of MSAs using
CEP and CTP as outlined in Scheme 2. It is worth noting that
although these monomers are water-soluble, polymerizations
were conducted in DMF in order to avoid CTA hydrolysis or
aminolysis.27
Mw/Mn > 1.20. The increased conversions achieved during the
CEP-mediated polymerization of mSAC prompted our use of
this CTA to polymerize each monomer derivative in order to
ascertain what influences the sulfonamide R group might have
on conversion, molar mass, and molecular weight distribution
(Table 1). As with the CEP-mediated polymerization of mSAC
at 70 °C, each substituted monomer derivative also yielded
moderately broad molecular weight distributions, typically
increasing with conversion, and indicative of limited polymer-
ization control.
Chain Extension of pSAC-CEP Macro-CTA at 70 °C.
The degree of “living” chain end retention was investigated by
synthesizing and isolating a macro-CTA (pSAC-CEP) (Mn =
7300 g/mol, Mw/Mn = 1.35), followed by chain extension with
mSAC to yield the corresponding chain extended polymer
(pSAC-b-pSAC-CEP). Figure 2 shows the SEC traces of both
Initially, CEP- and CTP-mediated RAFT polymerizations of
methacryloyl sulfacetamide (mSAC) were carried out at 70 °C
in DMF using V-501 as the initiator at molar ratios of [M]0:
[CTA]0:[I]0 = 150:1:0.2. As illustrated in Figure 1, a near-linear
Figure 2. SEC traces of pSAC macro-CTA (Mn = 7300 g/mol, Mw/Mn
= 1.35) and pSAC-b-pSAC after chain extension at 70 °C in DMF.
the initial monomodal pSAC-CEP macro-CTA and the
corresponding pSAC-b-pSAC-CEP polymer after chain exten-
sion with mSAC. The latter exhibits multimodality and broad
molecular weight distribution, indicating extensive loss of
“living” polymer chain ends during the initial polymerization of
the pSAC-CEP macro-CTA. Loss of “living” polymer chains is
most often attributed to irreversible radical termination,
undesirable chain transfer events, or degradation of the
thiocarbonylthio chain ends. During the CEP- and CTP-
mediated polymerizations of MSAs at 70 °C, we observed a loss
of the characteristic color of CEP (yellow) and CTP (pink)
after extended polymerization times, qualitatively indicating
degradation of the trithiocarbonate and dithioester moieties,
respectively. A quantitative study of the extent of this
degradation, as well as the precise mechanism by which it
occurs, is currently underway in our laboratories and is the
subject of a manuscript to be submitted.
RAFT Polymerization of Methacryloyl Sulfonamides
at 30 °C. Hypothesizing that a deleterious side reaction was
competing with chain extension during the CTA-mediated
polymerization, we lowered the reaction temperature. Such
approaches have been previously successful in RAFT polymer-
izations, yielding well-defined copolymers that maintained a
high degree of chain-end functionality.30−32 Figure 3 shows the
comparative SEC chromatograms of the CEP-mediated
polymerizations of mSAC at 70 and 30 °C under the
Figure 1. Kinetic plots for the CTP- and CEP-mediated RAFT
polymerization of mSAC at 70 °C in DMF ([M]0:[CTA]0:[I]0
150:1:0.2).
=
pseudo-first-order kinetic plot is observed for the polymer-
ization of mSAC with CEP at 70 °C. After an initialization
period of approximately 30 min, monomer conversion reached
81% after 600 min. The CTP-mediated polymerization of
mSAC at 70 °C under analogous conditions was significantly
slower, reaching only 12% monomer conversion after 600 min.
Retardation in rate of dithiobenzoate-mediated polymerizations
as compared to analogous reactions mediated by trithiocar-
bonates has been observed previously for styrenics, acrylates,
and acrylamides with some monomers failing to polymerize in
the presence of a dithiobenzoate RAFT agent.28,29
Despite near-ideal linear pseudo-first-order kinetic behavior,
the CEP-mediated polymerization of mSAC at 70 °C produced
polymers with Mw/Mn of 1.27 or higher (Table 1). Similarly,
the polymerization of mSAC with CTP yielded polymers with
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Figure 3. DMF SEC RI traces of pSAC-CEP polymerized at 30 and 70
°C using V-70 and V-501, respectively.
polymerization conditions outlined in Table 1. It should be
noted that the 30 °C reaction utilized the low decomposition
temperature initiator 2,2′-azobis(4-methoxy-2,4-dimethyl-
valeronitrile) (V-70). While both reactions produced polymers
with similar number-average molecular weights, the resulting
molecular weight distribution of the polymer synthesized at 30
°C (58% conversion, Mn = 29 700 g/mol, Mw/Mn = 1.05) was
substantially lower than the polymer prepared at 70 °C (67%
conversion, Mn = 26 400 g/mol, Mw/Mn = 1.41).
Figure 4a shows the kinetic plots for the respective CEP- and
CTP-mediated polymerizations of mSAC at 30 °C. The former
exhibited a longer pre-equilibrium (initialization) period (∼60
min) as compared to polymerization at 70 °C; however, linear
pseudo-first-order kinetic behavior was observed up to 600 min.
Deviation from linearity at longer times in this particular case is
possibly due to the reduced radical flux observed as the initiator
concentration decreases substantially at prolonged reaction
times, as we have previously reported.33 Figure 4b shows the
SEC chromatogram overlay at specified times during the 30 °C
polymerization of mSAC with CEP. The progression of the
polymer traces to lower elution volumes with corresponding
increases in RI intensity, without high molecular weight
shouldering, is indicative of controlled polymerization behavior
and thus maintenance of thiocarbonylthio functionality. This is
further indicated by the narrow molecular weight distributions
(Figure 4c) and linear progression of Mn vs monomer
conversion (Figure 4d) observed for the 30 °C polymerization
of mSAC. While Mn increases in a linear fashion during the
RAFT polymerization of mSAC at 30 °C, experimentally
determined molecular weights (Mnexp) are marginally higher
than those theoretically predicted (Mntheory) based upon
monomer conversion. The higher than expected molecular
weights determined by MALLS directly of aliquots taken from
the polymerization could be indicative of irreversible coupling
of CTA intermediate radicals during the initialization
stage.34−36
Table 2 summarizes the conversion, molar mass, and
molecular weight distribution data for the RAFT polymer-
ization of each MSA derivative in DMF at 30 °C using either
CTP or CEP as the RAFT agent and V-70 as the initiator.
Reducing the polymerization temperature to 30 °C results in
Figure 4. (a) Pseudo-first-order kinetic plots for the CTP- and CEP-
mediated RAFT polymerization of mSAC at 30 °C in DMF ([M]0:
[CTA]0:[I]0 = 150:1:0.2). (b) SEC overlay for CEP-mediated
polymerization of mSAC at 30 °C in DMF. (c) Mw/Mn versus
conversion. (d) Mn versus conversion.
E
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Table 2. Conversion, Molar Mass, and Molecular Weight Distribution Data for the RAFT Polymerization of MSAs in DMF at 30
a
°C
b
c
d
d
entry
monomer deriv
CTA
time (min)
conv (%)
[M]0 (mol/L)
1.0
Mntheory (g/mol)
Mnexp (g/mol)
Mw/Mn
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
mSAC
CTP
CTP
CTP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
CEP
350
710
1500
350
710
1500
350
710
1500
350
710
1500
240
360
780
240
360
780
240
360
780
19
34
53
26
58
81
10
30
69
11
35
61
8
8300
14700
22700
11300
24800
34600
5600
9500
16700
20500
16300
29700
37500
8100
1.02
1.01
1.03
1.08
1.05
1.03
1.19
1.12
1.02
1.12
1.06
1.06
1.16
1.06
1.05
1.11
1.05
1.04
1.10
1.06
1.07
mSAC
mSAC
mSAC
1.0
mSAC
mSAC
mSBZ
1.0
mSBZ
15900
36000
5700
14500
28600
10300
22100
35400
8100
mSBZ
mSMZ
mSMZ
mSMZ
mSMT
mSMT
mSMT
mSDMX
mSDMX
mSDMX
mSDOX
mSDOX
mSDOX
0.83
1.0
18200
32200
4200
14
54
7
7500
12200
33200
10800
16700
43800
8700
28200
6300
0.83
0.83
13
44
11
26
62
14800
35500
4200
7500
11800
25000
30100
a
b
Sulfonamide monomers were polymerized at 30 °C in DMF ([M]0:[CTA]0:[I]0 = 150:1.0:0.2) using V-70 as the initiator. 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)
c
to the vinyl proton of the sulfonamide monomer (5.84 ppm, 1H). Theoretical number-average molecular weights were calculated according to the
equation Mn = (ρMWmon[M]/[CTA]) + MWCTA, where ρ is the fractional monomer conversion, MWmon is the molecular weight of the monomer,
d
and MWCTA is the molecular weight of the CTA. As determined by SEC-MALLS (95:5 (v:v) DMF:CH3COOH 20 mM LiBr).
Mw/Mn values typically below 1.10 for all monomer derivatives.
Mn values determined by DMF SEC-MALLS are in reasonable
agreement with theoretical values calculated from monomer
conversion; however, Mnexp exceeds Mntheory in a similar manner
to that discussed earlier. Furthermore, all polymerizations
conducted at 30 °C maintained the characteristic color of the
parent CTA, indicating limited degradation as compared to that
at 70 °C.
The CTP-mediated polymerization of mSAC conducted at
30 °C resulted in 34% monomer conversion after 710 min and
narrow molecular weight distributions even after 1500 min of
polymerization (53% conversion, Mn = 20 500 g/mol, Mw/Mn
= 1.03) (Table 2) with the Mn values determined by DMF
SEC-MALLS agreeing well with the theoretical values. The
analogous reaction conducted at 70 °C yielded 12% monomer
conversion after 600 min and relatively broad molecular weight
distributions (Mn = 6200 g/mol, Mw/Mn = 1.27) (Table 1).
The strikingly higher rate of polymerization observed for the
CTP-mediated polymerization of mSAC performed at 30 °C as
compared to 70 °C is consistent with effectively minimizing
(though not completely eliminating) competing dithioester
degradation and limiting the accumulation of potentially rate-
retarding degradation byproducts.
Figure 5. SEC traces of pSAC-CEP macro-CTA (Mn= 25 100 g/mol,
Mw/Mn = 1.09) and pSAC-b-pSAC-CEP (Mn = 49 600 g/mol, Mw/Mn
= 1.07) after chain extension in DMF. Both polymerizations were
conducted at 30 °C.
Chain Extension of PSAC-CEP Macro-CTA at 30 °C. To
further demonstrate the controlled RAFT polymerization of
MSAs at low temperatures, a pSAC-CEP macro-CTA was
prepared at 30 °C using V-70 as the initiator and isolated before
chain extending with additional mSAC at 30 °C. Figure 5 shows
the SEC chromatogram of the pSAC-CEP macro-CTA (Mn =
25 100 g/mol, Mw/Mn = 1.09) and a distinct decrease in elution
volume of the chain-extended polymer (pSAC-b-pSAC-CEP)
(Mn = 49 600 g/mol, Mw/Mn = 1.07). The monomodal SEC
chromatogram and absence of low molecular weight tailing at
higher elution volumes of the chain extended polymer are
additional evidence of improved chain-end retention during the
polymerization of MSAs at 30 °C as compared to the analogous
chain extension conducted at 70 °C (Figure 2).
Methacryloyl Sulfonamide Monomer pKa Studies.
MSA monomer titrations were performed to determine the
pKa of each monomer derivative after converting the respective
sulfa drug precursors into the corresponding methacrylamides.
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The pKa of the sulfonamide (SO2NH) group of each monomer
derivative was determined by eq 1, where pHEP1/2 is the pH
corresponding to the half equivalence point (EP1/2) of the
titration curve. The volume of HCl titrant required to reach the
EP1/2 (VolEP ) was determined by eq 2, where VolEP is the
1/2
volume of HCl titrant required to reach the equivalence point
of the titration curve, [SO2NH] is the sulfonamide concen-
tration, [HCl] is the concentration of HCl titrant used, and
Volsol is the initial volume of the monomer solution being
titrated. Figure 6 shows the positions of the EP and EP1/2 on
the titration curve for mSAC.
pKa = pHEP
(1)
1/2
[SO NH]
[HCl]
1
2
2
VolEP = VolEP
+
Volsol
1/2
(2)
Figure 7. Substituent effects on pH-dependent solubility transitions of
sulfonamide-containing polymers. Percent transmittance was measured
using a UV−vis spectrophotometer (λ = 500 nm).
monomer. The changes in polymer solubility occur over a very
narrow range of typically 0.5 pH units. Table 3 summarizes the
pH-dependent solubility of each MSA derivative. The critical
onset of precipitation (pH*) is defined as the pH
corresponding to 90% light transmittance. For each of the
MSA derivatives, pH* of the polymer is greater than the pKa of
the corresponding monomer. The pH* of a particular pMSA is
dependent upon the monomer pKa and the relative hydro-
phobicity of the monomer derivative, both influenced by the
sulfonamide R group. The mutual influence of these two
parameters is readily apparent by comparing the pH* and pKa
values for pSAC and pSBZ (Table 3). While the pKa of mSBZ
(4.51) is lower than that of mSAC (4.88), the pH* for pSBZ
(5.3) is higher than that of pSAC (5.1) due to the greater
hydrophobicity of the benzoyl R group.
CO2-Dependent Solubility of Poly(methacryloyl sulfo-
namides). To date, CO2-responsive polymers rely almost
exclusively upon protonation of amine or amidine functional
groups by carbonic acid (produced upon dissolution of CO2 in
water) that alters polymer solubility and conformation in
solution.9,38 However, there are very few examples of CO2-
responsive polymers based upon acidic functional groups.39 In
order for acid-functional polymers to exhibit CO2-induced
changes in phase or conformation, the pKa of the acidic
functional group and more importantly the pH* of the
corresponding polymer must be greater than the pH of the
solution upon production of carbonic acid via dissolution of
CO2. Therefore, weakly acidic polyacids that exhibit pH-
responsive behaviors above pH = 4 (the pH of an aqueous
solution in equilibrium with 1 atm of CO2 at 25 °C) should also
exhibit similar changes in properties upon CO2-induced
solution acidification.
Figure 6. EP and EP1/2 locations on the titration curve of mSAC (1
mM) titrated against HCl (0.05 N) at 25 °C using a Metrohm 848
Titrino Plus autotitrator.
Table 3 contains the pKa values for each monomer calculated
using eq 1 along with the literature reported pKa values for the
Table 3. MSA Monomer and Polymer Titration Data
polymer Mnexp (g/mol) Mw/Mn sulfadrug pKa monomer pKa pH*
pSAC
31400
27500
32000
24400
43800
34400
1.04
1.03
1.05
1.03
1.04
1.08
5.38
4.57
5.29
6.16
6.70
7.49
4.88 0.01
4.51 0.01
5.19 0.03
5.44 0.01
5.75 0.01
7.33 0.02
5.3
5.7
6.3
6.7
7.5
7.9
pSBZ
pSMT
pSDOX
pSDMX
pSMZ
corresponding sulfa drug precursors. A general trend is
observed whereby the pKa of the MSA is lower than that of
the sulfa drug precursor which is consistent with the decrease in
pKa observed upon acetylation of the p-amino group of sulfa
drugs.37
pH-Dependent Solubility of Poly(methacryloyl sulfo-
namides). The titration curves (Figure 7) demonstrate the
facility by which the pH-dependent solubility of pMSAs can be
“tuned” by simply varying the sulfonamide R-group of the
The weakly acidic pMSA derivatives we report here exhibit
pH* values above pH = 5.0, making these ideal candidates as
CO2-responsive polymers. To demonstrate the reversible CO2-
responsiveness of pMSAs, polymethacryloyl sulfamethazine
(pSMZ) (Mn = 34 400 g/mol, Mw/Mn = 1.08) (1 equiv of
sulfonamide functional group) was dissolved in 0.05 N NaOH
(1.25 equiv) and diluted with DI H2O to yield a final [SO2NH]
= 6.7 mM and [NaOH] = 8.4 mM. The solution was purged
with CO2 (10 s) and then N2 (25 min) and the % transmittance
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DOI: 10.1021/acs.macromol.5b01453
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(λ = 500 nm) of the polymer solution measured before and
after each purge cycle using a UV−vis spectrophotometer.
Figure 8 shows % transmittance as a function of purge cycle
and illustrates the reversible CO2-triggered change in aqueous
solubility of pSMZ.
GR04355 and the National Science Foundation under Grant
IIA-1430364.
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■
A series of pMSA polymers with tunable, pH-dependent
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Corresponding Author
*E-mail: charles.mccormick@usm.edu (C.L.M.).
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Notes
The authors declare no competing financial interest.
This is paper number 157 in a series entitled “Water-Soluble
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