Para-Fluoro Postpolymerization Chemistry of Poly(pentafluorobenzyl methacrylate): Modification with Amines, Thiols, and Carbonylthiolates

Article abstract of DOI:10.1021/acs.macromol.7b01603

A methacrylic polymer undergoing highly efficient para-fluoro substitution reactions is presented. A series of well-defined poly(2,3,4,5,6-pentafluorobenzyl methacrylate) (pPFBMA) homopolymers with degrees of polymerization from 28 to 132 and ≤ 1.29 was p

Full text of DOI:10.1021/acs.macromol.7b01603

Article
pubs.acs.org/Macromolecules
Para-Fluoro Postpolymerization Chemistry of
Poly(pentafluorobenzyl methacrylate): Modification with Amines,
Thiols, and Carbonylthiolates
†
†
‡
†,‡,∥
‡
§
Janina-Miriam Noy, Ann-Katrin Friedrich, Kyle Batten, Mathamsanqa N. Bhebhe, Nicolas Busatto,
†
†
,†,‡,§
Rhiannon R. Batchelor, Ariella Kristanti, Yiwen Pei,
and Peter J. Roth*
†
Centre for Advanced Macromolecular Design (CAMD), University of New South Wales, Kensington, Sydney, NSW 2052, Australia
Nanochemistry Research Institute (NRI) and Department of Chemistry, Curtin University, Bentley, Perth, WA 6102, Australia
Department of Chemistry, University of Surrey - Guildford, Surrey GU2 7XH, United Kingdom
‡
§
∥Department of Chemistry, University College London, London WC1E 6BT, United Kingdom
*
S Supporting Information
ABSTRACT: A methacrylic polymer undergoing highly
efficient para-fluoro substitution reactions is presented. A
series of well-defined poly(2,3,4,5,6-pentafluorobenzyl meth-
acrylate) (pPFBMA) homopolymers with degrees of polymer-
ization from 28 to 132 and Đ ≤ 1.29 was prepared by the
RAFT process. pPFBMA samples were atactic (with triad
1
19
tacticity apparent in H and F NMR spectra) and soluble in
most organic solvents. pPFBMA reacted quantitatively through
para-fluoro substitution with a range of thiols (typically 1.1
equiv of thiol, base, RT, <1 h) in the absence of any observed
side reactions. Para-fluoro substitution with different (thio)-
carbonylthio reagents was possible and allowed for subsequent
one-pot cleavage of dithioester pendent groups with concurrent thia-Michael side group modification. Reactions with aliphatic
amines (typically 2.5 equiv of amine, 50−60 °C, overnight) resulted in complete substitution of the para-fluorides without any
observed ester cleavage reactions. However, for primary amines, H NR, double substitution reactions yielding tertiary
2
(
−C F ) NR amine bridges were observed, which were absent with secondary amine reagents. No reactions were found for
6
4 2
attempted modifications of pPFBMA with bromide, iodide, methanethiosulfonate, or thiourea, indicating a highly selective
reactivity toward nucleophiles. The versatility of this reactive platform is demonstrated through the synthesis of a pH-responsive
polymer and novel thermoresponsive polymers: an oligo(ethylene glycol)-functional species with an LCST in water and two
zwitterionic polymers with UCSTs in water and aqueous salt solution (NaCl concentration up to 178 mM).
INTRODUCTION
unsaturated groups such as dienes and alkynes which can
undergo cycloadditions and reactions with thiols.
A functional group that remains underexplored in the
polymer chemistry arena is the pentafluorobenzene (PFB)
motif, which undergoes selective nucleophilic aromatic
substitution reactions of the para-fluoride (which is the most
■
13,14
Postpolymerization modification (the introduction of chemical
functionality into a premade reactive precursor) is a versatile
synthetic pathway that provides unique access to functional
materials and enables the study of structure−property relation-
ships in series of functional daughter polymers with virtually
identical degrees of polymerization. While the concept is as old
activated having two ortho- and two meta-fluoride neigh-
15−17
bors).
Low molar mass PFB derivatives have been used for
1
and extensive as polymer science itself, much recent work is
based on vinyl systems and the architectural control offered by
18
the synthesis of monomers and for polymer end group
modification. Multifunctional PFB-functional building blocks
19
the suite of reversible deactivation radical polymerization
have been condensed for the preparation of metal-containing
2
−5
2
0
21
(
RDRP) methods.
For a reactive group to be suited for
linear polymers, hyperbranched polymers, and precision
22
postpolymerization modification, it must (i) be compatible with
polymerization conditions (or come with an easily removable
protecting group) and (ii) allow for selective and efficient
chemical modification, ideally under mild conditions. Com-
monly used chemical groups include the nucleophile-reactive
networks. PFB-functionalized end groups were exploited for
the functionalization of polythiophenes and the synthesis of
23
Received: July 26, 2017
Revised: August 25, 2017
6
,7
8−11
12
epoxide, azlactone,
and activated esters as well as
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.macromol.7b01603
Macromolecules XXXX, XXX, XXX−XXX

Macromolecules
Article
2
4
multiarm copolymers. With regards to postpolymerization
functionalization of side groups, however, the literature is, with
stored in a freezer. Anhydrous N,N-dimethylformamide (DMF) was
stored in a glovebox. Acetone was dried over molecular sieves (3 Å).
The triethylammonium salt of S-carboxypropyltrithiocarbonic acid was
2
1,25−28
very few exeptions,
limited to the modification of
4
7
29
prepared following a literature procedure.
2
,3,4,5,6-pentafluorostyrene-based (co)polymers with amines,
3
0
31−33
34
Pentafluorobenzyl Methacrylate (PFBMA). Potassium carbonate
(anhydrous, 17.22 g, 0.125 mol, 5 equiv) was suspended in anhydrous
acetone (160 mL). Methacrylic acid (3.22 g, 3.17 mL, 0.037 mol, 1.5
equiv), 2,3,4,5,6-pentafluorobenzyl bromide (6.5 g, 3.76 mL, 0.025
mol, 1 equiv), and butylated hydroxytoluene (BHT, three small
crystals) were added. The mixture was refluxed for 3 h, and complete
reaction was confirmed with TLC control (EtOAc−hexane 1:7). The
mixture was filtered to remove salts, and the solvent was removed
under reduced pressure. The residue was dissolved in diethyl ether
phosphite, and thiols
(including in water and on
The thiol−para-fluoro substitution reaction has
been combined with (and shown to be orthogonal to)
3
5−37
surfaces).
2
5,27
pentafluorophenyl-activated esters,
radical-mediated
2
4,38
thiol−ene additions,
and Cu-catalyzed azide−alkyne cyclo-
3
9
additions.
Herein, the reversible addition−fragmentation chain transfer
RAFT) synthesis and postpolymerization modification of
poly(2,3,4,5,6-pentafluorobenzyl methacrylate), pPFBMA, a
methacrylic system amenable to highly efficient para-fluoro
substitution reactions, is presented for the first time. A small
number of studies have described the synthesis of this polymer
4
0
(
(150 mL) and extracted with water (150 mL, pH 5), aqueous
NaHCO (3 × 150 mL, pH 9), and water (100 mL) again. The
3
organic phase was dried over magnesium sulfate and filtered through
basic aluminum oxide, and the solvent was removed under reduced
1
41
42
pressure. Three batches: yields 88%, 93%, and 95%. H NMR (400
through anionic polymerization, free-radical homo- and
MHz, CDCl ), δ/ppm = 6.11, 5.60 (2 × 1H, H C), 5.27 (2 H, t,
43
3
2
copolymerization with styrene, and the photoinitiator-free
4
13
J
= 1.4 Hz, OCH ), 1.93 (3 H, CH ). C NMR (101 MHz,
2 3
4
4
HF
photopolymerization but not its postmodification. Acyl
1
CDCl ), δ/ppm = 166.8 (CO), 147.2 and 144.7 (dm, J = 255 Hz,
3
CF
substitutions, key to the modification of Theato’s polymeric
1
2
1
× meta C−F), 143.2 and 140.7 (dm, J = 255 Hz, para C−F),
CF
45
1 2 3
pentafluorophenyl (PFP) esters, were not observed on PFB
esters. Instead, pPFBMA was found to react quantitatively
through para-fluoro substitution with thiols and amines, though
with a certain degree of double substitution when primary
amines were used. Additionally, reaction with several (thio)-
carbonylthio reagents enabled subsequent polymer analogous
modification. The high selectivity of the para-fluoro sub-
stitution was apparent by the lack of any observed reaction with
bromide, iodide, thiourea, and methanethiosulfonate nucleo-
philes. The versatility of this reactive scaffold is demonstrated
through the preparation of novel stimulus-responsive polymers.
39.0 and 136.5 (dtd, J = 255 Hz, J = 17 Hz, J = 4 Hz, 2 ×
CF
CF
CF
2
ortho C−F), 135.7 (C(CH )), 126.9 (H CC), 109.7 (td, J = 17
3
2
CF
3
19
Hz, JCF = 4 Hz, CH
MHz, CDCl
C
PFB), 53.8 (OCH
), 18.3 (CH ). F NMR (376
2
2
3
), δ/ppm = −141.9 (m, 2 F, ortho), −152.7 (t, 1 F, para),
3
−1
−
161.7 (m, 2 F, meta). FT-IR ν/cm = 2950, 2896 (w, C−H alkyl,
CCH stretch), 1722 (m−s, CO ester stretch), 1502 (s, CC
2
stretch), 1128 (s, C−O stretch), 1054 (s, C−F stretch). MS (ESI) m/z
+
13C
+
(
%) = 289.03 (100) [M + H] , 290.03 (10) [M + H] .
General Procedure for RAFT Polymerization. A mixture of PFBMA
varying equiv based on targeted DP), RAFT agent 2-cyano-2-propyl
(
benzodithioate (1 equiv), AIBN stock solution (containing 0.1 equiv
of AIBN in anisole), and anisole (total volume approximately 1.5-fold
volume of PFBMA) were mixed in a reaction vial. A stir bar was added,
and the vial was sealed with a septum and degassed for 30 min by
purging with nitrogen through a needle with a shorter needle fitted for
gas release. The vial was placed into a preheated oil bath (70 °C)
overnight (typically 15−16 h). After cooling in an ice−water bath, a
EXPERIMENTAL SECTION
Instrumentation. NMR spectroscopic measurements were
performed on 300, 400, or 500 MHz Bruker instruments in 5 mm
NMR tubes. Residual solvent signals of CHCl (δ = 7.26 ppm, δ =
■
3
H
C
sample (100 μL) was withdrawn, diluted with CDCl (500 μL), and
3
7
7.2 ppm), DMSO-d (δ = 2.51 ppm), and HDO (δ = 4.79 ppm)
1
19
5
H
H
19
analyzed by H and F NMR spectroscopy to determine monomer
conversion by comparison of the methylene group H signals and the
para- F NMR signals. The polymer was precipitated twice into an
were used as references. F NMR chemical shifts are given relative to
1
a CFCl standard.
3
19
Size exclusion chromatography (SEC) in dimethylacetamide
excess (approximately 20−30-fold in volume) of methanol, and the
(
DMAc) was performed on a Shimadzu system with four 300 × 7.8
2 5 4 3
product was collected as a pink solid by centrifugation followed by
mm linear phenogel columns (10 , 10 , 10 , and 500 Å) operating at
0 °C and a flow rate of 1 mL/min. Reported values are polystyrene
PS) equivalent molar masses based on a calibration with a series of
1
drying in a vacuum at 40 °C. H NMR (300 MHz, CDCl ), δ/ppm =
3
5
(
5
.07 and 5.03 (2 × bs, 2 H, OCH ), 2.05−1.65 (m, 2 H, backbone
2
CH ), 1.20−0.65 (m, 3 H, backbone CH including 1.14 (5%) mm,
2
3
narrow molar mass distribution PS standards with molar masses
ranging from 0.58 to 1820 kg/mol.
Fourier transform infrared spectroscopy (FT-IR) was performed on
a Bruker IFS 66/S instrument under attenuated total reflectance
1
9
0
.96 and 0.90 (35%) mr, and 0.79 and 0.75 (60%) rr triads). F NMR
(
282 MHz, CDCl ), δ/ppm = −141.8 (5%), −142.1 (35%), and
3
−
−
−
142.4 (60%) (3 m, 2 F, ortho), −152.0 (60%), −152.4 (35%), and
152.8 (5%) (3 m, 1 F, para), −161.5 and −161.7 (∼95%) and
(
ATR).
−1
162.1 (∼5%) (3 bs, 2 F, meta). FT-IR ν/cm = 2995, 2935 (w, C−
LCST and UCST cloud points were determined through temper-
H stretch), 1735 (m−s, CO ester stretch), 1504 (s, CC stretch),
ature-dependent optical turbidity measurements using an Avantium
Crystal16 system using heating/cooling rates of 1 °C/min. Cloud
points were determined at the onset of transmittance decrease during
heating (LCST type) or cooling (UCST type).
Microwave heating was done in a single-mode Anton Paar
Monowave 300 reactor using an infrared temperature sensor and
compressed air flow for simultaneous cooling.
1
132 (s, C−O, stretch), 1052 (s, C−F, stretch). T = 65 °C.
g
Postpolymerization Modification of PPFBMA with Thiols.
Generally, pPFBMA (40 mg) was dissolved in anhydrous DMF (1−
2
1
4
mL), and thiol (1.1−5 equiv) and base (triethylamine or DBU,
.05−5.1 equiv) were added. The mixture was stirred at RT−45 °C for
0 min−1 day, and the product was precipitated into methanol or
1
Differential scanning calorimetry (DSC) was done on a DSC
Q1000 by TA Instruments. The glass transition temperature, T , was
water. See main text for details. Thiophenol-modified: H NMR (300
MHz, CDCl
), δ/ppm = 7.29 (bs, 2 H), 7.19 (m, 3 H). Captopril-
modified: H NMR (300 MHz, DMSO-d ), δ/ppm = 4.00, 3.50, 2.70,
1.99−1.88, 1.07. n-Octanethiol-modified: H NMR (300 MHz,
CDCl ), δ/ppm = 2.97 (SCH ), 1.60 (SCH CH ), 1.40, 1.25
(CH ), 0.86 (CH ). n-Butanethiol-modified: H NMR (300 MHz,
CDCl ), δ/ppm = 2.98 (SCH ), 1.56 (SCH CH ), 1.45 (CH CH ),
g
3
1
determined from the second heating step of a heat−cool−heat cycle
6
1
(
rates 10 °C/min) from the intersection of extrapolated approximately
straight-line portions of the thermogram before and after the onset of
3
2
2
2
46
1
heat flow change.
2
3
Synthesis. General Remarks. All reagents were purchased from
Sigma-Aldrich and used without purification unless stated otherwise.
Azobis(isobutyronitrile) (AIBN) was recrystallized from methanol and
3
2
2
2
2
3
1
0.91 (CH ). 2-(Dimethylamino)ethanethiol-modified: H NMR (400
3
MHz, CDCl ), δ/ppm = 3.09 (bt, 2 H, SCH ), 2.55 (bt, 2 H, CH N)
3
2
2
B
DOI: 10.1021/acs.macromol.7b01603
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Macromolecules
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2
.25 (bs, 6 H, N(CH ) ). Backbone and COOCH methylene
diluting with CDCl3 (600 μL) and analyzing by 19F NMR
spectroscopy. Complete disappearance of starting material signals
was achieved in 10−144 h (see details in main text). In cases where the
ammonium hydrofluoride precipitated it was removed by filtration.
Products were isolated by precipitation into methanol or dialysis
3
2
2
resonances as above.
Quaternization of Poly[4-(2-(dimethylamino)ethylsulfanyl)-
,3,5,6-tetrafluorobenzyl methacrylate] with 1,3-Propane Sultone.
-(Dimethylamino)ethanethiol-modified pPFBMA (20 mg, 57 μmol
2
2
of repeat units, 1 equiv) was dissolved in 2,2,2-trifluoroethanol (400
μL). A separately prepared solution of 1,3-propane sultone (14.8 mg,
(regenerated cellulose, MWCO 3500 Da) against methanol or water−
1
ethanol 1:1. Butylamine-modified: H NMR (300 MHz, CDCl ), δ/
3
1
121 μmol, 2.1 equiv) in 2,2,2-trifluoroethanol was added, and the
ppm = 3.38, 1.57, 1.40, 0.93. Pentylamine-modified: H NMR (300
resulting homogeneous mixture was stirred for 5 days at 40 °C. The
MHz, CDCl ), δ/ppm = 3.37, 1.59, 1.48, 1.31, 0.89. Cyclohexylamine-
3
1
product was isolated by dialysis against ultrapure water and drying in a
modified: H NMR (300 MHz, CDCl ), δ/ppm = 3.50 (CHNH)
3
1
1
vacuum. H NMR (400 MHz, D O/NaBr), δ/ppm = 3.88
2.05−0.70 (CH ). 3-(Dimethylamino)propylamine-modified:
H
2
2
−
(
(
CH NCH ), 3.49 (N(CH ) ), 3.28 (SCH , CH SO ), 2.50
NMR (300 MHz, CDCl ), δ/ppm = 3.52 (NHCH ), 2.55 (CH N),
2
2
3
2
2
2
3
3
2
2
1
CH CH CH ).
2.32 (N(CH ) ), 1.83 (CH CH CH ). Piperidine-modified: H NMR
3 2 2 2 2
2
2
2
Quaternization of Poly[4-(2-(dimethylamino)ethylsulfanyl)-
,3,5,6-tetrafluorobenzyl methacrylate] with 1,4-Butane Sultone.
-(Dimethylamino)ethanethiol-modified pPFBMA (20 mg, 57 μmol
of repeat units, 1 equiv) was dissolved in 2,2,2-trifluoroethanol (400
μL). A separately prepared solution of 1,4-butane sultone (8.8 μL, 86
μmol, 1.5 equiv) in 2,2,2-trifluoroethanol was added, and the resulting
homogeneous mixture was filled into a 2 mL microwaveable
pressurized tube and heated to 120 °C for 15 h with stirring in a
microwave reactor, reaching a pressure of 7 bar. Complete conversion
was verified through 19F NMR analysis of a sample (50 μL) diluted
(300 MHz, CDCl ), δ/ppm = 3.21 (CH N(R)CH ), 1.64, 1.61
3
2
2
1
2
2
(CH CH CH ). 2EG/3EG/PEG350-modified: H NMR (CDCl −
2
2
2
3
CD OD 10:1, 400 MHz) δ/ppm = 3.55, 3.45 (OCH ), 3.29
3
2
1
(OCH ), 2.88 (NHCH ). 4-Benzylpiperidine-modified: H NMR
3 2
(400 MHz, CDCl ), δ/ppm = 7.24, 7.13 (Ph), 3.31, 3.02 (N(CH ) ),
3
2 2
2.54 (CH Ph), 1.73 (CH), 1.65, 1.36 (N(CH CH ) ). 1-(2-
2
2
2 2
1
Hydroxyethyl)piperazine-modified: H NMR (400 MHz, CDCl ), δ/
3
ppm = 3.67 (CH OH), 3.34 (Ar−NCH CH ), 2.64 (N(CH ) ).
2
2
2
2 3
Backbone and COOCH methylene resonances as above; for SEC and
2
19
F NMR data see the main text.
with D O (550 μL) containing NaBr (approximately 10 mg). Excess
2
1
,4-butane sultone phase separated from the NMR sample which did
RESULTS AND DISCUSSION
■
not influence the measurement. The product was isolated by dialysis
against ultrapure water (residual 1,4-butane sultone hydrolyzed and
dissolved slowly) and drying in vacuum. H NMR (400 MHz, D O/
NaBr), δ/ppm = 3.51 (CH NCH ), 3.22 (N(CH ) ), 3.02 (SCH ,
Synthesis of Monomers and Polymers. 2,3,4,5,6-
Pentafluorobenzyl acrylate (PFBA) and 2,3,4,5,6-penta-
fluorobenzyl methacrylate (PFBMA) were prepared in high
yields from (meth)acrylic acid and 2,3,4,5,6-pentafluorobenzyl
1
2
2
2
3
2
2
−
CH SO ), 1.98, 1.89 (CH CH CH CH ).
2
3
2
2
2
2
1
13
19
Postmodification of pPFBMA with Sodium Hydrogen Sulfide. A
solution of pPFBMA (10 mg, 37.6 μmol of repeat units, 1 equiv) in
anhydrous DMF (1.4 mL) was purged with nitrogen for 30 min, and
sodium hydrogen sulfide hydrate (4.2 mg, 75.2 μmol, 2 equiv) was
added under reverse nitrogen flow. The mixture turned light green,
green-blue, then dark blue, and green again upon stirring at RT for 30
bromide as confirmed by H, C, and F NMR spectroscopy,
ESI mass spectrometry, and FT-IR spectroscopy (see Scheme
A and Figures S1−S8 in the Supporting Information). While
1
Scheme 1. Synthesis of the Reactive Monomers 2,3,4,5,6-
Pentafluorobenzyl Acrylate and 2,3,4,5,6-Pentafluorobenzyl
Methacrylate (A) and RAFT Polymerization (B)
min. 19F NMR analysis of a sample (100 μL) diluted with CDCl (500
3
19
μL) confirmed complete reaction. F NMR (282 MHz, CDCl ), δ/
3
ppm = −139.3 (s, 2 F) and −139.6 (s, 2 F), no residual starting
material signals. Upon purification by dialysis against methanol, the
polymer cross-linked.
Triethylammonium p-Fluorodithiobenzoate. The (unstable) acid
derivative was prepared from 4-fluorophenylmagnesium bromide
solution (1 M in THF) and carbon disulfide according to a literature
48
procedure, followed by addition of triethylamine and drying in a
vacuum.
Postpolymerization Modification of PPFBMA with Dithioben-
zoate, Followed by Aminolysis and Thiol−Ene Modification.
pPFBMA (13.1 kg/mol, Đ = 1.20, 11.7 mg, 44 μmol of repeat units,
1
equiv) was dissolved in DMF (1.4 mL), and triethylammonium p-
fluorodithiobenzoate (20.8 mg, 76 μmol, 1.7 equiv) and triethylamine
17 μL, 122 μmol, 2.8 equiv) were added. The pink solution was
(
19
stirred at 65 °C for 24 h. F NMR analysis of a sample (250 μL)
diluted with CDCl (350 μL) confirmed absence of starting material
3
signals. The mixture was cooled to RT, and butyl acrylate (27 μL, 189
μmol, 4.3 equiv) and tert-butylamine (60 μL, 569 μmol, 12.9 equiv)
were added; the mixture stirred overnight at RT. The product was
precipitated into diethyl ether−hexane (4:1) and dried in a vacuum.
1
9
F NMR (282 MHz, DMSO-d ), δ/ppm = −134.0 (bs, 2 F), − 141.6
6
(
bs, 2 F), SEC 44.1 mg/mol, Đ = 1.56, bimodal.
Postpolymerization Modification of pPFBMA with Amines.
Generally, pPFBMA (40 mg, 0.15 mmol of repeat units, 1 equiv)
was dissolved in anhydrous DMF (1 mL), and butyl acrylate (to
the 19F NMR signals of the bromide starting material and the
(
meth)acrylate products did not differ strongly (Table 1), the
4
9
scavenge thiols release through RAFT end group aminolysis, 5 μL)
and amine (butylamine, pentylamine, cyclohexylamine, piperidine, 3-
dimethylamino)propylamine, aniline, 4-benzylpiperidine, 1-(2-
hydroxyethyl)piperazine, di(ethylene glycol) methyl ether amine
2EG), tri(ethylene glycol) methyl ether amine (3EG), PEG350 methyl
ether amine, 2.5 equiv) was added. The mixture was stirred at 50 or 60
C. Conversion was monitored by withdrawing samples (50 μL)
1
benzylic methylene group H NMR signal shifted from δ/ppm
4.49 (for the bromide) to δ/ppm = 5.27 and appeared as a
=
(
4
triplet with a J coupling constant of 1.4−1.5 Hz.
HF
After washing and filtration over basic aluminum oxide,
PFBMA was of sufficient purity for RAFT polymerization
without the need for chromatography or distillation. Six
(
°
C
DOI: 10.1021/acs.macromol.7b01603
Macromolecules XXXX, XXX, XXX−XXX

Macromolecules
Article
Table 1. Summary of Measured 19F NMR Chemical Shifts in CDCl of 2,3,4,5,6-Pentafluorobenzyl Derivatives (Sections 1 and
3
2
) and 2,3,5,6-Tetrafluorobenzyl Derivatives after Substitution of the Para-F with Sulfur- and Nitrogen-Based Nucleophiles
(
Section 3)
functional group
δF/ppm (ortho to benzylic) δF/ppm (meta to benzylic) δF/ppm (para to benzylic)
. small 2,3,4,5,6-pentafluorobenzyl-functional molecules, F C −CH −R, −R =
1
5
6
2
bromide (−Br)
hydrogen (−H)
−142.2
−143.3
−141.9
−141.9
−161.2
−152.8
−158.9
−152.7
−152.7
−163.6
−161.8
−161.7
acrylate (−OOC−CHCH )
2
methacrylate (−OOC−C(CH )CH )
3
2
2
. poly(2,3,4,5,6-pentafluorobenzyl methacrylate)
−142.4
a
pPFBMA
−161.6
−152.0
3
. para-substituted polymers, R−F C −CH O--, R− =
4 6 2
b
alkylthio (R′S−, 7 examples)
−141.6 to −142.7
−141.0 to −142.0
−141.7
−133.8 to −134.6
−133.9 to −134.3
−132.5
carbonylthio (R′C(=X)S−; thioacetate, dithioester, trithiocarbonate)
phenylthio (PhS)
sodium sulfido (NaS−)
−149.7
−139.4
alkylamino (R′HN−, 7 examples)
−145.6 to −146.5
−145.2
−160.6 to −161.8
−162.8
c
amino (H N−)
2
dialkylamino (R' N−, 10 examples)
−144.7 to −146.2
−151.1 to −152.3
2
a
Shift of major signal where tacticity splitting occurs. There is disagreement in the literature on the assignment of 19F NMR resonances of para
b
1
thiol-substituted 2,3,5,6-tetrafluorobenzyl derivatives. Assignments in this table are based on the measurement and interpretation of H-decoupled
1
19
and non- H-decoupled F NMR spectra of 2,3,4,5,6-pentafluorotoluene and after para-fluoro substitution with thiophenol. The ortho-fluorines of
c
these low molar mass species can be identified by their coupling to the toluic CH group; see Figure S9. Noy, J.-M.; Roth, P. J.; et al. Unpublished
3
work.
samples of poly(PFBMA), pPFBMA, with degrees of polymer-
ization ranging from 28 to 132, and narrow, monomodal molar
mass distributions were prepared using the RAFT process (see
Scheme 1B, Table 2, and Figure 1A). The PFB functional
methyl group resonances (Figure S10). Interestingly, all three
F NMR signals of pPFBMA showed a splitting with a similar
19
integral ratio (see Experimental Section and Figure S11),
suggesting that all fluorine atoms are affected by (and can be
analyzed to determine) tacticity. 19F NMR spectroscopy has
a
52−54
Table 2. List of Prepared pPFBMA Samples
been shown to be a powerful tool in determining tacticity.
target DP conv (%) DPNMR
b
b
SEC
Mn
(kg/mol) ĐSEC
Notably, however, for many reported cases the decisive fluorine
code
55−57
1
atoms were directly attached to the backbone.
The H
pPFBMA28
pPFBMA36
pPFBMA63
pPFBMA70
pPFBMA98
pPFBMA132
38
41
74
87
92
70
98
67
28
36
8.6
10.3
13.1
16.3
15.0
19.8
1.15
1.15
1.20
1.14
1.14
1.29
NMR signal of the methylene side group (COO−CH −PFB)
2
roughly reflected a similar splitting with the main peaks (δ/ppm
68
63
=
5.07, 5.03) showing an approximate 60:35 integration ratio
c
100
100
197
70
and the expected 5% component apparent as a shoulder around
δ = 5.16 ppm.
98
132
Polymer Modification: Thiols. With a series of well-
defined pPFBMA polymers in hand, their reactivity toward a
range of sulfur- and nitrogen-based nucleophiles was assessed.
Samples of pPFBMA were first reacted with thiophenol in the
presence of triethylamine and five different primary aliphatic
thiols, including hydrophilic and hydrophobic species and the
drug captopril, using 1,8-diazabicyclo[5.4.0]undec-7-ene
a
RAFT polymerizations were done using chain transfer agent 2-cyano-
2
-propyl benzodithioate, solvent anisole, and initiator AIBN at 70 °C
b
1
19
overnight. Determined by H and F NMR spectroscopy before
purification. Reaction time 8 h.
c
groups were stable during polymerization with no observed
evidence of decomposition or adverse effects on the polymer-
ization. A slight difference in F chemical shifts between
monomers and polymers enabled simple estimations of
monomer conversions using F NMR spectroscopy before
polymer isolation. All samples of pPFBMA were powdery solids
with a measured glass transition temperature of T = 65 °C,
higher than that of the non-fluorinated analogue poly(benzyl
25
1
9
(DBU) as base (see Scheme 2 and Table 3). Conversions
were monitored by withdrawing reaction samples, diluting with
1
9
1
9
CDCl , and measuring F NMR spectroscopy. Reactions were
3
19
continued until all F NMR signals associated with starting
material had disappeared (40 min−2 h). Isolated products were
g
1
19
characterized by H and F NMR spectroscopy, FT-IR
spectroscopy, and SEC.
50
methacrylate) (T = 54 °C) but lower than that of the
reactive styrenic counterpart poly(2,3,4,5,6-pentafluorostyrene)
g
In all cases, selective substitution of the para-fluoride was
found with no observed evidence of ester cleavage or
substitution of ortho- or meta-fluorides. 19F NMR spectra of
pPFBMA and after modification with thiophenol and a
representative aliphatic thiol are shown in Figure 2A−C.
Quantitative substitution was apparent by the disappearance of
5
1
(Tg = 95 °C). pPFBMA was found to be soluble in
chloroform, N,N-dimethylformamide, N,N-dimethylacetamide,
dimethyl sulfoxide, acetonitrile, anisole, acetone, tetrahydrofur-
an, diethyl ether, pyridine, and 2,2,2-trifluoroethanol but
insoluble in water, methanol, and hexane. As to be expected
from radical polymerization, pPFBMA samples were atactic
with a measured triad tacticity of 0.05 mm:0.35 mr:0.60 rr
19
the para- F signal and a downfield shift of approximately 28
ppm (cf. Table 1) of the meta-fluorides, the neighbors of the
functionalized position. Before purification, the replaced
1
determined by H NMR spectroscopic analysis of the backbone
D
DOI: 10.1021/acs.macromol.7b01603
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Macromolecules
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Scheme 2. para-Fluoro Postpolymerization Modification of
PPFBMA with Thiols
(
suggesting, as desired, the absence of acyl substitution
reactions), a red-shift of the CC aromatic vibrations from
−1
−1
ν(C F ) = 1504 cm to ν(C F SR) = 1472 cm was observed,
6
5
6 4
in agreement with the change in the aromatic substitution
pattern.
SEC of thiol-modified samples revealed molar mass
distributions and dispersities very similar to those of the
respective reactive starting materials (Table 3 and Figure
1
B,C), as to be expected for the postpolymerization
modification of side groups in the absence of side reactions.
Apparent molar masses, however, were found to decrease
slightly or increase (most significantly for the reaction with
captopril, Table 3, entry 2). It is stressed that SEC separates
polymers by hydrodynamic size (not molar mass). The
observed changes in measured PS-equivalent molar masses
thus indicated a compaction or expansion of the modified
polymer chains under the measurement conditions, in agree-
ment with their chemical modification.
Polymer Modification: Other Sulfur-Based Nucleo-
philes. Given the observed quantitative modification with
thiols under mild conditions, modification of pPFBMA with a
range of other sulfur-based nucleophiles was attempted
Figure 1. SEC traces of reactive pPFBMA species (A) and after
postpolymerization para-fluoro substitution with thiols (B, C) and
amines (C, D, E), and double modification with dithiobenzoate
followed by aminolysis and thiol−ene modification (F). x-Axes are PS-
equivalent molar masses in N,N-dimethylacetamide at 50 °C.
(
Scheme 3). A desired synthetic strategy was the introduction
of a nucleophile that would allow for subsequent release of a
tetrafluorophenylthiol (RC F → RC F −SR′ → RC F −SH)
6
5
6
4
6 4
to set the stage for a range of efficient thiol−X click
58
(
former para) fluoride appeared as broad signal between −120
chemistries for further modification. To this end, reaction
was first attempted using sodium methanethiosulfonate in a
synthetic route that was also envisaged to provide access to
functional nonsymmetrical disulfides (RC F → RC F −
1
9
and −165 ppm in F NMR spectra, usually with a lower than
expected integral. Addition of excess of DBU to NMR samples
(
in CDCl ) resulted in a sharp singlet at δ/ppm = −123.2
3
6
5
6 4
5
9
associated with the DBU hydrofluoride salt. After purification,
SSO R′ → RC F −SS−R″) (Scheme 3A) with potential for
2
6 4
1
9
60
F NMR signals associated with the replaced para-fluoride
drug-releasing applications. However, under all investigated
reaction conditions (solvents N,N-dimethylformamide, dimeth-
yl sulfoxide, pyridine; without base, with DBU, with triethyl-
amine; temperatures from RT to 80 °C), no reaction was
observed. When reactions were heated to 130 °C (or 90 °C in
the presence of DBU), 19F NMR analysis showed multiple
sharp signals suggesting the formation of small fluorinated
molecules through acyl substitution (pentafluorobenzyl alcohol
side product) or through nucleophilic substitution at the
benzylic position (polymeric carboxylate leaving group and
formation of substituted pentafluorobenzyl products).
1
disappeared. H NMR spectroscopy confirmed the quantitative
formation of functional thioether derivatives, including through
the appearance of a resonance associated with R−CH −SC F
2
6 4
methylene groups (for R = alkyl, δ/ppm (R−CH −SC F ) =
2
6 4
2
.98 (bt), compared to δ/ppm (R−CH −SH) = 2.54 (q) for
2
1
the respective thiol reagent). H NMR spectroscopic analysis
also indicated that excess reagent, base, and any other small
molecules had been removed during purification (Figure 3A−
C). FT-IR spectra of pPFBMA and after modification with 2-
(
dimethylamino)ethanethiol are shown in Figure 4. While the
−1
carbonyl CO stretching band (ν = 1735 cm ) was not
Reaction of pPFBMA with sodium hydrogen sulfide in the
1
9
significantly affected through the thiol−para-F substitution
absence of base was successful on one account (see F NMR in
E
DOI: 10.1021/acs.macromol.7b01603
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Macromolecules
Article
a
Table 3. Overview of Reaction Conditions and SEC Results for Postpolymerization Modifications of PPFBMA with Thiols
before modification
after modification
thiol
temp
(°C)
reaction time
(min)
MnSEC
(kg/mol)
MnSEC
(kg/mol)
b
b
ĐSEC
ĐSEC
entry
thiol
equiv
base, equiv
c
1
2
3
4
5
thiophenol
1.1
1.1
1.1
1.1
Et N, 1.05
45
25
25
25
25
60
40
40
40
90
10.5
10.5
8.6
1.15
1.15
1.15
1.15
1.14
10.3
39.3
10.3
8.5
1.16
1.15
1.18
1.16
n.d.
3
c
d
captopril
DBU, 2.1
c
butane-1-thiol
DBU, 1.05
DBU, 1.05
DBU, 5.1
c
octane-1-thiol
8.6
f
2-(dimethylamino)ethanethiol
hydrochloride
5.0
16.3
n.d.
e
g
f
6
1-thioglycerol
1.5
DBU, 1.4
25
120
16.3
1.14
n.d.
n.d.
a
19
b
In all cases, anhydrous N,N-dimethylformamide was used as solvent and quantitative conversions were confirmed by F NMR spectroscopy. With
c
d
regards to 1 equiv of PFBMA repeat units. The product was purified by precipitation into methanol. Additional base was used due to the carboxylic
acid group on captopril. In the presence of DBU the tertiary amine-functional polymer is isolated (as shown in Scheme 2); the product was purified
by precipitation into water. Incomplete reaction when lower amount was used. The product was purified by dialysis against methanol.
e
f
g
fluoro substitution after heating to 65 °C for 6 days. At a higher
temperature of 80 °C, cleavage of the methacrylic esters was
observed, and the reaction was deemed impractical for this
study. A dithioester-based nucleophile, however, enabled full
conversion to the tetrafluorophenyl benzenedithioate derivative
1
9
within 24 h at 65 °C (Scheme 3E) based on F NMR
spectroscopic analysis (see Table 1). Among several attempts,
optimal reaction conditions were an excess of dithioester (1.7
equiv) and of triethylamine (2.8 equiv) in anhydrous DMF. To
demonstrate the potential of this benzenedithioate-function-
alized species, a sample was aminolyzed (releasing thiolate
groups) in the presence of butyl acrylate, a thiol-reactive
Michael acceptor, giving the ester-functional thiol−ene product
1
in one step (Scheme 3F). H NMR spectroscopic analysis
confirmed successful modification. SEC analysis, however,
revealed a bimodal molar mass distribution (Figure 1F)
attributed to a small degree of cross-linking reactions, not
62
uncommon for thiol-functional polymers.
It is briefly mentioned that modification attempts of
pPFBMA with thiourea, tetrabutylammonium bromide, and
tetrabutylammonium iodide (DMF, 2.5 equiv, 80 °C, 2 days)
gave no reactions, demonstrating higher selectivity and stability
of pPFBMA toward nucleophiles compared to common
haloalkane substrates.
Polymer Modification: Amines. The arguably most
important class of nucleophiles for polymer modification
comprises amines. Modification of pPFBMA was investigated
with a selection of aromatic, primary, and secondary amines.
Amines were used in excess (2.5 equiv), and reactions were
19
Figure 2. 19F NMR spectra of pPFBMA (A, 500 MHz) and after para-
fluoro substitution reaction with thiols (B and C, 300 MHz), sodium
hydrogen sulfide (D, 300 MHz), primary amines (E, n-Bu = n-butyl,
stirred at 50 or 60 °C in DMF until F NMR spectroscopic
analysis of a withdrawn sample indicated complete disappear-
ance of signals associated with the starting material. Products
were isolated by precipitation or dialysis and characterized by
300 MHz; F, 3EG = tri(ethylene glycol) methyl ether amine, 400
1
19
MHz), and piperidine (F, 300 MHz).
H and F NMR spectroscopy, FT-IR spectroscopy, and SEC.
Reactions are summarized in Table 4 with structures of amines
shown in Scheme 4.
Figure 2D) but led to insoluble material in other attempts
For reactions with aniline (Table 4, entry 1), no para-fluoro
substitution occurred, and pristine pPFBMA starting material
was recovered. Being less nucleophilic than aliphatic amines,
aromatic amines typically show lower reactivity in nucleophilic
substitution reactions. In the case of pPFBMA, under the
investigated reaction conditions this reactivity difference was
sufficiently large to result in selective modification with
aliphatic amines only.
(
Scheme 3B).
Three carbonylthio reagents were used, with the aim of
49,61
enabling the wide range of “RAFT end group chemistries”
for polymer side group modification. Potassium thioacetate
showed reasonably high reactivity toward pPFBMA, but the
expected tetrafluorophenyl thioacetate product was too reactive
to be isolated with products containing about 30 mol % of
thiols (Scheme 3C). A trithiocarbonate-based nucleophile
(Scheme 3D), on the other hand, was less reactive (presumably
For all the employed aliphatic amines, reaction rates were
due to resonance stabilization of the anion) and gave 90% para-
lower than for thiols, with reactions requiring heating to 50−60
F
DOI: 10.1021/acs.macromol.7b01603
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Figure 3. 1H NMR spectra in CDCl3 of pPFBMA (A, 500 MHz) and after modification with butane-1-thiol (B, 300 MHz), 2-
dimethylamino)ethanethiol hydrochloride (in the presence of DBU) (C, 400 MHz), piperidine (D, 300 MHz), and 4-benzylpiperidine (E, 400
(
MHz) with relevant signals integrated and assigned.
hydroxyethyl)piperazine. As such, pPFPMA appeared to show
higher reactivity toward amines at 50 °C than poly(2,3,4,5,6-
pentafluorostyrene), which was shown not to react at this
27
temperature (24 h, 50 equiv of amines) and to require
microwave-assisted heating to 95 °C (20 min, 10 equiv of
29,63
amines).
Under our reaction conditions, no evidence of
acyl substitution or substitution of ortho- or meta-fluorides was
observed. SEC analysis of amine-modified products yielded
elugrams of similar shape and width as those of the respective
pPFBMA starting materials, with the exception of modification
with the oligo(ethylene glycol)-based amines, where shoulders
toward higher molar masses and slightly increased dispersities
were found (Figure 1C−E and Table 4). FT-IR analysis of the
oligo(ethylene glycol)methyl ether amine-modified samples
confirmed stronger absorbances of C−H and C−O bonds with
Figure 4. FT-IR spectra of pPFBMA (black) and after modification
with 2-(dimethylamino)ethanethiol (red) and piperidine (dotted) with
the shift of the aromatic CC stretching vibration inset.
an increasing length of the ethylene glycol-based side chains
19
(
Figure S12). For all primary amines, F NMR spectroscopy
confirmed complete modification through the disappearance of
the starting material signals and the appearance of resonances
characteristic of N-alkyl tetrafluoroaniline products (Table 1
°C overnight for reagents n-butylamine, n-pentylamine, cyclo-
19
hexylamine, 3-(dimethylamino)propylamine, piperidine, and 4-
benzylpiperidine and for 3−6 days for the sterically more
demanding oligo(ethylene glycol)-based amines and 1-(2-
and Figure 2E,F). Surprisingly, however, F NMR spectra also
contained signals associated with N,N-dialkyl tetrafluoroaniline
side groups. The amount of disubstituted aromatic rings ranged
G
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Scheme 3. Reaction of PPFBMA with the Sulfur-Based Nucleophiles Sodium Methanethiosulfonate (A), Sodium Hydrogen
Sulfide (B), Potassium Thioacetate (C), S-Carboxypropyl Trithiocarbonic Acid, Bis(triethylammonium) Salt (D), and
Triethylammonium 4-Fluorodithiobenzoate (E) Followed by Aminolysis and Thia-Michael Modification with Butyl Acrylate (F)
Table 4. Overview of Reaction Conditions, Molar Composition of Products, and SEC Results for Postpolymerization
a
Modifications of PPFBMA with Amines
before modification
after modification
b
MnSEC
(kg/mol)
MnSEC
(kg/mol)
T
(°C)
reaction
time (h)
disubstitution (Z)
(−C F ) NR (mol %)
entry
amine
ĐSEC
ĐSEC
comments
no reaction
6
4 2
1
2
3
4
5
aniline
60
50
60
60
60
10
15
10
10
10
8.6
8.6
8.6
8.6
8.6
1.15
1.15
1.15
1.15
1.15
n-butylamine
8
6
9
7
10.0
n.d.
n.d.
49.0
1.11
n.d.
n.d.
1.14
n-pentylamine
cyclohexylamine
3-(dimethylamino)-
propylamine
6
7
di(ethylene glycol) methyl
ether amine
50
50
69
69
28
28
16.3
16.3
1.14
1.14
19.4
18.1
1.27
1.21
water insoluble
water insoluble
LCST TCP 40 °C
tri(ethylene glycol) methyl
ether amine
c
8
9
PEG350 methyl ether amine
piperidine
50
50
50
50
144
15
26
0
16.3
8.6
1.14
1.15
1.14
1.14
23.7
7.9
1.25
1.15
n.d.
1
1
0
1
4-benzylpiperidine
24
0
16.3
16.3
n.d.
25.5
1-(2-hydroxyethyl)piperazine
64
0
1.13
pH-responsive
a
In all cases, 2.5 equiv of amine was used in anhydrous N,N-dimethylformamide as solvent. With the exception of aniline, complete disappearance of
PFBMA repeat units was confirmed by 19F NMR spectroscopy. See Scheme 4A. LCST-type cloud point (onset of transmittance decrease) of an
b
c
aqueous solution at a concentration of 5 g/L.
from 6 to 9 mol % for the set of smaller primary amines (Table
double substitutions occurred intramolecularly, possibly, as
shown in Scheme 4B, with the neighboring group. Double
substitutions have previously been described for reactions of
1
9
4, entries 2−5, representative F NMR spectrum in Figure 2E)
to 26−28 mol % found for the oligo(ethylene glycol) methyl
ether amine-modified samples (Table 4, entries 6−8,
representative 19F NMR spectrum in Figure 2F). Plausibly,
double substitutions occurred, in which N-alkyltetra-
fluoroaniline side groups (the secondary amines formed
through the intended substitution reaction) attacked another
PFB group forming N-alkyl-N,N-bis(tetrafluorophenyl) tertiary
amines (see Scheme 4B). With only small (or no) measured
increases in dispersity, it is assumed that the majority of such
64−67
low molar mass PFB derivatives with amines.
In fact,
64
Costa et al. recently described the reaction of a primary amine
with hexafluorobenzene, which produced only the doubly
substituted tertiary amine derivative and recovered unreacted
primary amine. The higher reactivity of the secondary amine
intermediate was attributed to a higher N−H acidity caused by
the fluorinated substituent. The proposed double substitution
1
on the polymeric substrate was in agreement with H NMR
H
DOI: 10.1021/acs.macromol.7b01603
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repeat unit, in excellent agreement with the 1H NMR
interpretation.
Scheme 4. Para-Fluoro Postpolymerization Modification of
PPFBMA with Amines: Formation of Copolymers
Comprising the Expected N-Functional Tetrafluoroaniline
Despite the unexpected side reactions, the modification of
pPFBMA with amines has potential in producing “smart”
polymers. The modification of pPFBMA with di- and
tri(ethylene glycol) methyl ether amine (Table 4, entries 6,
7) resulted in water-insoluble products. Addition of acid (until
pH ∼ 3) did not improve solubility, suggesting no significant
amount of protonation of the tetrafluoroaniline nitrogen atoms
and confirming their low basicity (the conjugate acid of the
Side Groups (X) as Well as N,N-Bis(tetrafluoroaniline) Side
a
Groups (Z) for the Reaction with Primary Amines (A);
Proposed Mechanism for Formation of Disubstituted
Species (B); and Modification of PPFBMA with Secondary
Amines in the Absence of Side Reactions (C)
+
comparable small molecule pentafluoroaniline (i.e., F C NH )
5
6
3
68
has a reported pK = −0.3). The modification of pPFBMA
with PEG3 methyl ether amine, however, yielded a product
a
50
with temperature-dependent aqueous solubility (below a critical
temperature) and measured LCST-type cloud points around
body temperature (Figures S14 and S15). As such, this
pPFBMA-derived species represents a new addition to the
PEG-based family of materials with similar stimulus-responsive
69,70
solution behavior.
Yet, copolymer formation and lack of compositional control
make the modification of pPFBMA with primary amines
unideal for the preparation of well-defined polymers. Gratify-
ingly, the modification of pPFBMA with the secondary amine
piperidine (Table 4, entry 9) was found to proceed without side
reactions with 19F NMR analysis showing only the expected
1
tertiary amine functionality (Figure 2G) and H NMR
measurements indicating the quantitative presence of the
expected cyclic substituent (Figure 3D). FT-IR analysis showed
−1
the absence of N−H stretching (around ν = 3500−3300 cm )
−1
and N−H bending (around ν = 1640−1550 cm , Figure 4)
vibrations and a red-shift of the CC aromatic vibrations from
−1
−1
ν(C F ) = 1504 cm to ν(C F NR ) = 1484 cm (Figure 4,
6
5
6
4
2
inset), confirming aromatic substitution. Based on these results,
two further secondary amines, including an N-functional
piperazine (Table 4, entries 10, 11; Scheme 4C), were tested
and found to react quantitatively in 24−64 h without observed
1
side reactions (see H NMR data in Figure 3E). By virtue of its
tertiary amine functionality, the 1-(2-hydroxyethyl)piperazine-
functional polymer was soluble in dilute aqueous HCl (pH 5−
6
) but precipitated above pH 7 when aqueous NaHCO was
3
added, demonstrating the preparation of a pH-responsive
polymer from the pPFPMA platform (Figures S16 and 17) .
Zwitterionic Temperature-Responsive Polymers. Fi-
nally, having shown selective quantitative postpolymerization
modification reactions of pPFBMA with sulfur- and nitrogen-
based nucleophiles, their potential in the development of novel
zwitterionic polymers with upper critical solution temperature
(
UCST) behavior in water is presented as a proof-of-concept.
This “smart” behavior involving solubility above a critical
7
1
temperature is known only for very few types of polymers,
including some zwitterionic sulfobetaines.
a
72,73
The molar composition (X, Z) can be estimated from the number of
Our group
1
R groups per repeat unit (= X + Z/2) obtained from H NMR
recently established that introduction of aromatic functionality
into sulfobetaine co- and terpolymers can be beneficial in
increasing UCST transition temperatures, realizing UCST
spectroscopy and the percentage of N,N-disubstituted tetrafluoroani-
line groups (= Z) from 19F NMR spectroscopy; see Table 4.
74,75
transitions at physiologically relevant NaCl concentration,
and in designing terpolymers with an LCST and UCST
results (Figure S13). For example, for the modification of
7
6
pPFBMA with di(ethylene glycol) methyl ether amine (DEG)
(miscibility gap). Exploiting the postpolymerization of
pPFBMA, zwitterionic and aromatic functionality could easily
be included into the same repeat unit.
1
(
Table 4, entry 6), H NMR analysis indicated an average
presence of 0.86 DEG side chains per repeat unit (Figure
1
9
S13B). To reiterate, F NMR spectroscopic analysis of this
sample indicated that 28% of aryl side groups formally
contributed half a functional group, equivalent to a substitution
efficiency of 0.86 (= 100% − 1/2 × 28%) DEG side chains per
Samples of 2-(dimethylamino)ethanethiol-modified
pPFBMA70 (Table 3, entry 5) were quaternized with 1,3-
propane sultone (5 days, 40 °C) and with 1,4-butane sultone
(15 h, 120 °C, microwave heating), followed by dialysis against
I
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water (Scheme 5). Microwave heating was necessary to push
the reaction with the commonly sluggish 1,4-butane sultone
to completion (Figure S18).
have much lower transition temperatures or to be fully soluble
75
in water within the observable temperature range of 0−100
75
°C, demonstrating the effect of the aromatic group on
decreasing solubility. The UCST transition temperature was
found, expectedly, to decrease with an increasing concentration
of added NaCl (Figure 6B), with approximately linear decreases
found for both species, though, surprisingly, with a larger slope
for the sulfobutylbetaine homopolymer. Fortuitously, the
sulfopropylbetaine derivative showed measurable cloud points
up to NaCl concentrations of 178 mM, above the physiological
concentration of approximately 154 mM. This data demon-
strates the potential in developing novel smart homopolymers
without the need for tuning through copolymerization as was
previously done to achieve UCST transitions at such high salt
concentrations.
Scheme 5. Successive Postpolymerization Modification of
Tertiary-Amine Functional PPFBMA70 Derivative with 1,3-
Propane Sultone (A) and 1,4-Butane Sultone (B) Giving the
Respective Sulfopropyl- and Sulfobutylbetaine-Functional
a
Species
CONCLUSION
■
A novel reactive polymer scaffold was introduced that benefits
from high-yielding, one-step monomer synthesis, well-con-
trolled methacrylate RAFT polymerization, polymer solubility
in a wide range of organic solvents, and efficient and selective
postpolymerizaton modification options. Poly(2,3,4,5,6-penta-
fluorobenzyl methacrylate) (pPFBMA) showed high reactivity
toward thiols, comparable to that of poly(2,3,4,5,6-pentafluoro-
styrene), reacting to completion within an hour at room
temperature. The resulting para-substituted aromatic structure
was exploited herein for the preparation of novel zwitterionic
homopolymers that showed aqueous UCST transition temper-
atures within a wide temperature and NaCl concentration
range. Reactions of pPFBMA with various amines did not result
in ester cleavage reactions common of the activated ester
pentafluorophenyl methacrylate analogues but proceeded with
selective and quantitative substitution of the para-fluorides. For
the use of primary amines, especially for sterically demanding
reagents, a disubstitution side reaction was observed which
resulted in a lower than expected presence of functional groups
a
Reactions were performed in 2,2,2-trifluoroethanol in which reagents
and products were soluble.
19F NMR spectroscopic analysis of the zwitterionic
homopolymers in D O/NaBr revealed essentially no change
2
19
of F chemical shifts compared to the tertiary amine precursor,
but peaks were broadened drastically which suggested poor
hydration of the hydrophobic fluorinated aromatic in the
aqueous solvent (Figure 5).
(
minimum observed degree of functionalization 86%) and
slightly increased molar mass dispersities (largest observed
increase Đ = 1.14 to Đ = 1.27). Nonetheless, modification of
pPFBMA with a PEG-based amine produced a novel species
with an aqueous LCST transition. Side reactions were not
observed for the reaction of pPFBMA with piperidine and
piperazine derivatives for which quantitative and selective side
group modification was found. For the first time, the
performance of other nucleophiles in para-fluoro postpolyme-
rization substitution was investigated, with pPFBMA proving to
be stable toward halides, thiosulfonate, and thiourea.
Modification with carbonylthio compounds, however, was
successful and allowed for subsequent one-pot aminolysis, in
situ release of tetrafluorophenylthiols, and their capture through
thia-Michael “click” modification, albeit accompanied by a
Figure 5. 19F NMR spectra of the tertiary amine-functional precursor
(
A) and after quaternization with 1,4-butane sultone showing peak
broadening (B) with solvents and peak assignments indicated.
1
9
broadening of the molar mass distribution. F NMR
spectroscopy served as an expedient tool throughout the
study, proving effective to determine tacticity and follow
modification reactions. A reference list of 19F NMR chemical
shifts was compiled. Given the synthetic importance of
postpolymerization modification, it is believed that this
selectively reactive methacrylic system will find widespread
applications in synthetic polymer science.
The two novel zwitterionic homopolymers showed the
desired UCST behavior in water with measured UCSTs of 56
°C (sulfopropylbetaine species) and 70 °C (sulfobutylbetaine
species); see Figure 6A for temperature−concentration phase
diagram and Figures S19−S21 for transmittance curves.
Analogous methacrylic sulfobetaines of a similar degree of
polymerization but lacking the aromatic ring can be expected to
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Figure 6. Temperature−concentration phase diagram indicating the temperatures above which the sulfopropylbetaine homopolymer (triangles) and
the sulfobutylbetaine homopolymer (squares) were found to be soluble in pure water (A) and transition temperatures of both species in dependence
of added NaCl (B).
(
2) Gauthier, M. A.; Gibson, M. I.; Klok, H.-A. Synthesis of
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.macro-
mol.7b01603.
■
Functional Polymers by Post-Polymerization Modification. Angew.
Chem., Int. Ed. 2009, 48 (1), 48−58.
(
Bound Polymers. In Controlled Radical Polymerization at and from Solid
Surfaces; Vana, P., Ed.; Springer International Publishing: Cham, 2016;
pp 163−192.
(4) Romulus, J.; Henssler, J. T.; Weck, M. Postpolymerization
Modification of Block Copolymers. Macromolecules 2014, 47 (16),
*
S
3) Jo, H.; Theato, P. Post-polymerization Modification of Surface-
1
13
Synthesis of 2,3,4,5,6-pentafluorobenzyl acrylate, H, C,
1
9
1
F NMR, and FT-IR spectra of monomers, H-coupled
1
and H-decoupled spectra of 2,3,4,5,6-pentafluorotoluene
5
(
437−5449.
1
13
and after modification with thiophenol, H− C HSQC
and 19F− F COSY NMR spectra of pPFBMA, FT-IR
spectra of oligo(ethylene glycol) methyl ether amine-
5) Roth, P. J. Composing Well-Defined Stimulus-Responsive
19
Materials Through Postpolymerization Modification Reactions. Macro-
mol. Chem. Phys. 2014, 215 (9), 825−838.
1
modified polymers, additional H NMR spectra of
(6) Edmondson, S.; Huck, W. T. S. Controlled growth and
subsequent chemical modification of poly(glycidyl methacrylate)
brushes on silicon wafers. J. Mater. Chem. 2004, 14 (4), 730−734.
amine-modified polymers, photographs of pH-responsive
1
polymer, H NMR spectra of zwitterionic polymer and
(
7) Zhang, Q.; Anastasaki, A.; Li, G.-Z.; Haddleton, A. J.; Wilson, P.;
its precursor, and turbidity curves and phase diagrams of
thermoresponsive polymers (PDF)
Haddleton, D. M. Multiblock sequence-controlled glycopolymers via
Cu(0)-LRP following efficient thiol-halogen, thiol-epoxy and CuAAC
reactions. Polym. Chem. 2014, 5 (12), 3876−3883.
AUTHOR INFORMATION
Corresponding Author
E-mail p.roth@surrey.ac.uk (P.J.R.).
■
*
(8) Buck, M. E.; Lynn, D. M. Azlactone-functionalized polymers as
reactive platforms for the design of advanced materials: Progress in the
last ten years. Polym. Chem. 2012, 3 (1), 66−80.
(
9) Carter, M. C. D.; Lynn, D. M. Covalently Crosslinked and
ORCID
Physically Stable Polymer Coatings with Chemically Labile and
Dynamic Surface Features Fabricated by Treatment of Azlactone-
Containing Multilayers with Alcohol-, Thiol-, and Hydrazine-Based
Nucleophiles. Chem. Mater. 2016, 28 (14), 5063−5072.
Peter J. Roth: 0000-0002-8910-9031
Notes
The authors declare no competing financial interest.
(
10) Ho, H. T.; Levere, M. E.; Fournier, D.; Montembault, V.;
Pascual, S.; Fontaine, L. Introducing the Azlactone Functionality into
Polymers through Controlled Radical Polymerization: Strategies and
Recent Developments. Aust. J. Chem. 2012, 65 (8), 970−977.
ACKNOWLEDGMENTS
■
Funding for J.-M.N. from the Faculty of Engineering at the
University of New South Wales is acknowledged. P.J.R.
acknowledges Ms. Georgia Khinsoe (All Saints’ College,
Perth) for performing turbidity measurements, Mr. Elden
Garrett (Curtin University) for assistance with microwave
heating experiments, Mrs. Violeta Doukova (University of
Surrey) for DSC measurements, and Prof. Andrew B. Lowe,
Prof. Mark Buntine, the Nanochemistry Research Institute
(
11) Zhu, Y.; Quek, J. Y.; Lowe, A. B.; Roth, P. J. Thermoresponsive
(Co)polymers through Postpolymerization Modification of Poly(2-
vinyl-4,4-dimethylazlactone). Macromolecules 2013, 46 (16), 6475−
6484.
(12) Das, A.; Theato, P. Activated Ester Containing Polymers:
Opportunities and Challenges for the Design of Functional Macro-
molecules. Chem. Rev. 2016, 116 (3), 1434−1495.
(13) Roth, P. J.; Theato, P. Polymer Analogous Reactions. In
(
NRI), and the Department of Chemistry at Curtin University
for support.
Reference Module in Materials Science and Materials Engineering;
Elsevier: 2016.
(
14) Durmaz, H.; Sanyal, A.; Hizal, G.; Tunca, U. Double click
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