Utilization of catecholic functionality in natural safrole and eugenol to synthesize mussel-inspired polymers

Article abstract of DOI:10.1039/c9ra04719k

Naturally occurring safrole I upon epoxidation gave safrole oxide II, which underwent ring opening polymerization using a Lewis acid initiator/catalyst comprising of triphenylmethylphosphonium bromide/triisobutylaluminum to afford new polyether III in excellent yields. Epoxy monomer II and allyl glycidyl ether IV in various proportions have been randomly copolymerized to obtain copolymer V. A mechanism has been proposed for the polymerization reaction involving chain transfer to the monomers. A strategy has been developed for the deprotection of the methylene acetal of V using Pb(OAc)₄ whereby one of the methylene protons is replaced with a labile OAc group to give VI. The pendant allyl groups in VI have been elaborated via a thiol-ene reaction using cysteamine hydrochloride and thioglycolic acid to obtain cationic VII and anionic VIII polymers, both containing a mussel-inspired Dopa-based catechol moiety. During aqueous work up, the protecting group containing OAc was deprotected under mild conditions. Cationic VII and anionic VIII were also obtained via an alternate route using epoxide IX derived from 3,4-bis[tert-butyldimethylsilyloxy]allylbenzene. Monomer IX was homo- as well as copolymerized with IV using Lewis acid initiator/catalyst system to obtain homopolymer X and copolymer X1. Copolymer XI was then elaborated using a thiol-ene reaction followed by F^- catalysed silyl deprotection to obtain mussel inspired polymers VII and VIII, which by virtue of having charges of opposite algebraic signs were used to form their coacervate.

Full text of DOI:10.1039/c9ra04719k

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Utilization of catecholic functionality in natural
safrole and eugenol to synthesize mussel-inspired
Cite this: RSC Adv., 2019, 9, 21265
polymers†
a
Mouheddin T. Alhaffar,a Mohammad N. Akhtarb and Shaikh A. Ali
*
Naturally occurring safrole I upon epoxidation gave safrole oxide II, which underwent ring opening
polymerization using a Lewis acid initiator/catalyst comprising of triphenylmethylphosphonium bromide/
triisobutylaluminum to afford new polyether III in excellent yields. Epoxy monomer II and allyl glycidyl
ether IV in various proportions have been randomly copolymerized to obtain copolymer V. A mechanism
has been proposed for the polymerization reaction involving chain transfer to the monomers. A strategy
has been developed for the deprotection of the methylene acetal of V using Pb(OAc)4 whereby one of
the methylene protons is replaced with a labile OAc group to give VI. The pendant allyl groups in VI have
been elaborated via a thiol–ene reaction using cysteamine hydrochloride and thioglycolic acid to obtain
cationic VII and anionic VIII polymers, both containing a mussel-inspired Dopa-based catechol moiety.
During aqueous work up, the protecting group containing OAc was deprotected under mild conditions.
Cationic VII and anionic VIII were also obtained via an alternate route using epoxide IX derived from 3,4-
bis[tert-butyldimethylsilyloxy]allylbenzene. Monomer IX was homo- as well as copolymerized with IV
using Lewis acid initiator/catalyst system to obtain homopolymer X and copolymer X1. Copolymer XI
was then elaborated using a thiol–ene reaction followed by Fꢀ catalysed silyl deprotection to obtain
mussel inspired polymers VII and VIII, which by virtue of having charges of opposite algebraic signs were
used to form their coacervate.
Received 23rd June 2019
Accepted 1st July 2019
DOI: 10.1039/c9ra04719k
rsc.li/rsc-advances
covalently bonded into the interfaces may mitigate the delete-
rious effects of moisture, but it is a costly process.3 As such the
1 Introduction
situation demanded a closer look at the way mussel's adhesive
chemistry works. The byssus is a bundle of laments of DOPA
decorated proteins secreted by mussels that function to attach
the mussels to a solid surface whereby the catecholic func-
tionalities provide bidentate or covalent interfacial interactions.
The proteins themselves gain cohesiveness through metal
chelation, and covalent coupling.
The cohesive and adhesive roles played by the catechol
functionality of DOPA in byssal proteins and their effective
adhesive performance in turbulent wet environments have now
been rmly established. The biomimetic efforts have thus tar-
geted the attractive mussel byssal proteins. However, the
performance of biological adhesion, e.g., from mussels is much
superior to biomimetic adhesives. Recent advances demon-
strate that judicious biomimetic design incorporating key
elements in the natural adhesive system is essential to replicate
the wet adhesion of the marine organism.4,5 Several reviews deal
with the recent progress of mussel-inspired underwater adhe-
sives polymers having catechol-functional motifs for their
potential applications in anti-biofouling, biological adhesives,
and drug delivery.6,7 A review specically provides an overview of
the various applications of poly[2-(3,4-dihydroxyphenyl)ethyl-
amine] (i.e. polydopamine (PDA)) in tumor targeted drug
The performance of synthetic adhesive polymers in aquatic
environments is most oen frustrating because of the various
adverse effects of water or moisture in inducing hydrolysis,
swelling, interfacial wicking, etc.1,2 Rapid, strong and tough
moisture-resistant adhesion to solid surfaces in the sea by the
holdfast of marine mussels have lured many a researcher to
mimic the essential features of the adhesive chemistry practiced
by the mussels. Roughly 25–30 different adhesive proteins of
varying molar masses used by the mussels contained a consid-
erable proportion of randomly placed 3,4-dihydroxyphenyl-L-
alanine (L-DOPA) (z1–28 mol%) and 4-hydroxyarginine result-
ing from a post translational modication of amino acid tyro-
sine and arginine, respectively.1 To be an effective adhesive, it
must exert more favourable interaction with the wet polar
surfaces than a layer of water is able to offer. Polymers
aChemistry Department, King Fahd University of Petroleum & Minerals, Dhahran
31261, Saudi Arabia. E-mail: shaikh@kfupm.edu.sa; Fax: +966 13 860 4277; Tel:
+966 13 860 3830
bCenter for Rening and Petrochemicals, RI, King Fahd University of Petroleum &
Minerals, Dhahran 31261, Saudi Arabia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra04719k
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delivery systems and discusses the release behavior of the drug- functionality in DOPA for facile bidentate surface binding. Even
loaded PDA-based nanocarriers.8
in the more adverse pH of 8.2 of seawater, the mussels secret
The synthesis of mussel mimetic polymers include DOP- their proteins at a low pH of 5–6 in the conned space of
Apolypeptides9,10 and DOPA and lysine polypeptide copoly- a reducing environment where the redox balance is provided by
mers.11,12 Hydrogen bonding by phenolic hydroxyls of bidentate the thiol functionalities of a cysteine-rich protein.
DOPA leads to its bridging adhesion to the polysiloxane surface
It is our intention to synthesize mussel-inspired polymers
of mica.13 The mussel mimicking adhesives has also been using ring opening polymerization of epoxide (oxirane). Several
applied as complex coacervates,14,15 which are prepared using review articles summarize the developments in the ring opening
aqueous solutions of polyanions (e.g. DOPA-containing proteins polymerization of alkylene oxides via anionic, coordination and
having phosphoserine residues) and polycations (e.g. Dopa- cationic polymerization using a variety of catalysts including
containing proteins having 4-hydroxyarginine residues). With metal-free organocatalysts to synthesize linear homo- and
charge symmetry, the polymers of different algebraic signs amphiphilic block as well as branched, hyperbranched, and
undergo phase separation in a complex coacervation process, dendrimer like polyethers.31–33 Herein we report the use of
which is essential for wet adhesion. Synthesis of mussel readily available naturally occurring safrole (1) (Scheme 1) or
mimetic polymers have been achieved through polymerization eugenol (10) (Scheme 5) to synthesize epoxy functionalized
of catechol-based monomers.16,17 Dopamine methacrylamide monomers safrole oxide (2) (Scheme 1) and eugenol-derived 14
and 2-methoxyethyl acrylate or poly(ethylene glycol) methyl (Scheme 5) and their ring opening homo- and copolymerization
ether methacrylate has been copolymerized to give adhesive with allyl glycidyl ether (AGE) 7 (Scheme 2). The allyl pendants
polymers having divergent physical properties.18
of the mussel mimicking polymers decorated with catechol
A review article discusses the mussel-inspired chemistry in functionalities would then offer the latitude of transformation
the surface engineering of polymer membranes to improve their to ionic polymer backbones of both algebraic signs. The work
performance. Catecholamines, deposited on the membrane would thus pave the way to study these polymers from the
surface, serve as a surface component for membrane modi- perspective of coacervate adhesive.
cation or fabrication.19 Polydopamine capped graphene oxide
sheets are crosslinked by polyethylenimine leading to ultrahigh
modulus and high strength of macroscopic graphene oxide
papers, which broaden the potential applications of graphene.20
2 Experimental
2.1. Materials
The adhesive mechanism of mussel-inspired polymers has been
m-Chloroperbenzoic acid (MCPBA), LiCl, tert-butylammonium
investigated using the terpolymers of N-(3,4-dihydrox-
uoride (TBAF$3H2O), tert-butylammonium hydroxide (TBAH),
yphenethyl) methacrylamide (DMA), acrylic acid and butyl
4-dimethylaminopyridine (DMAP), iBu3Al solution (25% in
acrylate. The bulk adhesion was found to increase with a cor-
toluene),
eugenol,
2,2-dimethoxy-2-phenylacetophenone
responding increase in DMA content reaching a maximum at
around 40 mol%.21 Inspired by strong adhesion of mussel
(DMPA), t-butyldimethylsilyl chloride (TBDMSCl), thioglycolic
acid, cysteamine and safrole were purchased from Sigma
Aldrich. MePPh3Br and imidazole from Fluka, 1 M tert-buty-
lammonium uoride (TBAF) solution in THF from ChemCruz,
and diphenylsilane and B(C6F5)3 from Alfa Aesar were used as
received without any further purication. 4-Allylcatechol was
prepared by reacting eugenol with LiCl in dimethyl formamide
(DMF) as described.34 Allyl glycidyl ether (AGE) from Sigma
Aldrich was dried over CaH2 and distilled. Pb(AcO)4 was freshly
adhesive proteins,
a high-performance nanocomposite is
generated by assembling polydopamine-coated montmoril-
lonite with corn starch.22 Underwater-superoleophobic mate-
rials have been successfully developed by a two-step dip-coating
method with mussel-inspired coatings of polydopamine and
subsequent zwitterionic sulfobetaine methacrylate graing
onto stainless steel meshes and used in oil/water separation.23
Two functional catechols were incorporated into backbones of
polyacrylate and polyurethane, which showed excellent coat-
ability on various surfaces.24
Homo- and copolymers of catecholic monomer 3,4-dihy-
droxystyrene with styrene or styrene sulfonate has been re-
ported to give polymers having a wide range of physical
properties.18,25
A complex coacervate adhesive has been
synthesized from a mixture of catechol containing synthetic
polyanion and a synthetic polycation.14,26 Coating of poly-
ethylene glycol containing Dopa as an anchor has been
demonstrated to prevent bacterial adhesion and biolm
formation on a variety of surfaces.27,28 One of the serious
drawbacks of mussel proteins is the oxidation of DOPA at or
above neutral pH to DOPA quinone which has been shown to be
less sticky than DOPA. While the mussels have the talents29,30 to
control the deleterious oxidation, it remains a challenge to the
Scheme 1 Base catalyzed polymerization of safrole oxide 2 using
researchers to safeguard the integrity of the catecholic Bu4NF and Bu4NOH.
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d, J 7.9 Hz); dC (CDCl3): 28.39, 46.77, 52.53, 100.87, 108.26, 109.43,
121.85, 130.79, 146.28, 147.66 (CDCl3 middle carbon: 77.00).
2.4. Lewis acid catalyzed polymerization of safrole oxide 2
i
using Bu3Al38,39
As
described
in
entry
10
(Table
1),
methyl-
triphenylphosphonium bromide (11.9 mg, 0.0333 mmol) was
placed in an RB ask and closed with a rubber septum. Safrole
oxide 2 (445 mg, 2.5 mmol) and anhydrous toluene (1.6 mL)
were added under Ar by a syringe. The mixture was cooled to
ꢁC, then 1 M triisobutylaluminium solution (0.376 mL of
Scheme 2 Lewis acid catalyzed polymerization of safrole oxide 2, AGE
7 and activation of methylene group.
0
25 wt% in toluene, 0.403 mmol) was injected by a syringe under
Ar. The polymerization was quenched aer 2 h by adding 4 : 1
MeOH/H2O (v/v). Aer removal of the solvents, the residue was
dissolved in CH2Cl2 (50 mL) and ltered over Celite 545. The
ltrate was dried (over Na2SO4) and evaporated to obtain poly-
mer 6.
prepared.35 Membrane (Spectra/Por) with a MWCO of 6000–
8000 Daltons was purchased from Spectrum Laboratories, Inc.
2.2. Physical methods
For purication, polymer 6 (Scheme 2) was dissolved in
minimum amount of dichloromethane and then precipitated in
methanol; the polymer was then separated by centrifuge. This
process was repeated to remove the initiator and unreacted
monomer (found: C 67.0; H 5.6%. C10H10O3 requires C 67.41; H
5.66%); nmax (KBr) (Fig. S7†): 3444, 3066, 2899, 2772, 1608, 1475,
Elemental analyses were performed on a PerkinElmer (Series II
Model 2400). FTIR and NMR were recorded using a PerkinElmer
16F PC and a 500 MHz JEOL LA spectrometer, respectively.
Tetramethylsilane (TMS) in CDCl3 and residual H in D2O at
d 4.65 ppm were used as internal standards. The 13C chemical
shis in D2O were referenced against 13C peak of external
standard dioxane at d 67.4 ppm. Gel Permeation Chromato-
graphic analysis was performed at 30 ꢁC using a PL-GPC 220
manufactured by Agilent Technologies having two detectors (i.e.
Refractive Index & Light Scattering), equipped with two columns
(PL aquagel-OH 8 mm; 300 ꢂ 7.5 mm). Deionized water with
0.02 wt% NaN3 was used as solvent for water soluble polymer
samples. A sample solution of 5 mg/1.5 mL was prepared at
ambient temperature in water having 0.02 wt% NaN3. The
resulting solution (100 ml) was injected into the GPC columns
and chromatographic data was analyzed using GPC/SEC so-
ware by Agilent. In case of THF soluble polymer samples, GPC
was equipped with two columns (PLgel Olexis 300 ꢂ 7.5 mm).
The sample solution was prepared using tetrahydrofuran (THF)
containing 0.0125 wt% antioxidant, [2,6-di-tert-butyl-4-methyl
phenol (BHT)]. The equipment was calibrated using poly-
ethylene oxide (PEO) and polystyrene (PS) standards for water-
soluble and THF-soluble polymers, respectively.
1435, 1248, 1090, 1026, 742, and 693 cmꢀ1
.
2.5. Polymerization of AGE 7 (ref. 40 and 41)
solution of AGE (296 mg, 2.60 mmol), methyl-
A
7
triphenylphosphonium bromide (8.2 mg, 0.023 mmol) in
anhydrous toluene (1.6 mL) under Ar was cooled by ice bath,
then triisobutylaluminium (0.24 mL, 0.26 mmol of 25 wt% in
toluene) was added by a syringe under Ar. The polymerization
was stopped aer 2 h by adding 4 : 1 MeOH/H2O (10 mL). Aer
removing the solvents, the residue was dissolved in a CH2Cl2 (50
mL) and ltered over Celite 545. The ltrate was dried (Na2SO4)
and evaporated to obtain polymer 8.
2.6. Activation of methylene acetal of safrole 1 as a model
case42,43
Pb(OAc)4 (4.23 g, 9.5 mmol) was added under N2 to a solution of
ꢁ
safrole 1 (1.05 g, 6.48 mmol) in benzene (35 mL) at 75 C and
2.3. Synthesis of safrole oxide (2) from safrole (1)
stirred for 3 h. The reaction mixture was taken up in EtOAc (30
Safrole was converted to safrole oxide using a modied proce- mL) and washed with H2O (3 ꢂ 25 mL). The organic layer was
dure.36,37 Safrole 1 (32.4 g) was added to a solution of MCPBA (54 g, dried (Na2SO4) and concentrated. The residual liquid upon
0.22 mol, 70% purity) in chloroform (400 mL) and stirred at 25 ꢁC silica gel chromatography using EtOAc/hexane afforded 9 as
for 24 h. Aer adding additional MCPBA (20 g, 0.082 mol), the a faint yellow oil (1.08 g, 82%) (found: C 65.2; H 5.4%. C12H12O4
reaction mixture was stirred for a further 24 h and was washed with requires C 65.45; H 5.49%); dH (CDCl3): 2.09 (3H, s), 3.34 (2H, d,
10% sodium hydroxide solution (3 ꢂ 70 mL) and water (2 ꢂ 30 mL). J 6.7 Hz), 5.05–5.09 (2H, m), 5.89–5.96 (1H, m), 6.77 (1H, dd, J
The organic layer was dried (MgSO4) and concentrated. The residual 7.9 Hz, J 1.6 Hz), 6.83 (1H, d, J 1.6 Hz), 6.88 (1H, d, J 7.9 Hz), 7.66
liquid was puried by silica gel chromatography using hexane/ether (1H, s); dC (CDCl3): 20.92, 39.80, 108.85, 109.64, 112.64, 115.92,
as eluent to give safrole oxide (2) as a colorless oil (28.8 g, 67%). The 122.30, 134.88, 134.92, 137.16, 143.05, 144.83, 168.99, (CDCl3
oil was then distillated over calcium hydride to exclude any mois- middle carbon: 77.00); nmax (KBr) (Fig. S8†): 3079, 3005, 2979,
ture bp0.8 mbarHg 92 ꢁC. dH (CDCl3): 2.52 (1H, m), 2.83–3.73 (3H, m), 2914, 1838, 1768, 1639, 1495, 1445, 1376, 1255, 1216, 1181,
3.10 (1H, m), 5.91 (2H, s), 6.69 (1H, d, J 7.6 Hz), 6.74 (1H, s), 6.75 (1H, 1100, 1009, 963, and 760 cmꢀ1
.
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Table 1 Polymerizationa of Safrole Oxide (SO) (2) initiated with MePPh3Br (I) and catalyzed by iBu3Al (C)b
Yieldc (%)
Mn,Theor
Mn,Exp
PDI
d
e
Entry
I (mmol)
C (mmol)
[SO]/[I]
[C]/[I]
Time (h)
1
2
3
4
0.0256
0.0116
0.0458
0.0220
0
0.263
0.261
0.264
0.239
0.418
0.418
0.416
0.725
0.235
0.403
98
216
55
114
—
—
10.3
22.5
5.76
10.9
—
3
3
6
2
2
24
3
12
12
2
94
91
95
93
0
17 500
38 500
9800
14 450
7500
11 150
1.38
1.45
1.23
20 300
5
6f
7g
8
0
—
0
0.0331
0.0227
0.0222
0.0328
76
12.6
31.9
10.6
12.3
69
70
65
99
110
113
76
9
10
17 000
9970
1.32
a
Polymerization was carried out at 0 ꢁC using 2.5 mmol of monomer 2 with 1.8 mL of additional toluene except in entry 4 where no additional
b
i
c
toluene was added. 25 wt% solution in toluene (z1 M Bu3Al). NMR indicates complete conversion to polymer where isolated yields are over
d
e
90%. For entry 2: molar mass ¼ [molar mass of SO] ꢂ [SO]/[I] ¼ 178.19 ꢂ 216 ¼ 38 489 (assuming 100% conversion). GPC using light
scattering detector. f Carried out at 20 ꢁC. g 1 M Bu3Al solution in hexane.
i
2859, 1765, 1727, 1701, 1607, 1577, 1514, 1473, 1464, 1423,
2.7. Synthesis of [(4-allyl-1,2-phenylene)bis(oxy)]bis(tert-
butyldimethylsilane) (13) (Scheme 5)44
1292, 1256, 1224, 1159, 1127, 988, 907, 842, and 783 cmꢀ1
.
TBDMSCl (25.0 g, 166 mmol) and DMAP (2.11 g, 17 mmol) were
added under N2 to a mixture of allylcatechol 12 (10.86 g, 72.4
mmol) (Scheme 5) and imidazole (23.6 g, 347 mmol) in DMF
2.9. Lewis acid catalyzed polymerization of 14
ꢁ
ꢁ
As described in Table 2, methyltriphenylphosphonium bromide
was taken in an RB ask under Ar and closed with a rubber
septum. Epoxidized silyl derivative 14 and anhydrous toluene
were injected under Ar by a syringe. The mixture was cooled to
(130 mL) at 0 C. Aer stirring at 25 C for 16 h, the reaction
mixture was taken up in water (300 mL) and extracted with ether
(2 ꢂ 150 mL). Aer washing with water (4 ꢂ 200 mL), the ether
layer was dried (Na2SO4). The removal of the solvent followed by
distillation (bp0.2 mbarHg122 ꢁC) afforded 13 as a colorless oil
(20.5 g, 75%) (found: C 66.2; H 10.0%. C21H38O2Si2 requires C
66.60; H 10.11%); dH (CDCl3): 0.17 (12H, s), 0.97 (18H, s), 3.24
(2H, d, J 6.7 Hz), 4.99–5.03 (2H, m), 4.99–5.03 (1H, m), 6.59 (1H,
dd, J 1.8 Hz, J 8.3 Hz), 6.64 (1H, d, J 1.8 Hz), 6.72 (1H, d, J 8.3 Hz).
dC (CDCl3): ꢀ4.10, 18.44, 25.97, 39.45, 115.33, 120.83, 121.31,
121.47, 133.07, 137.83, 145.02, 146.59 (CDCl3 middle carbon:
77.01). IR KBr (Fig. S9†): 2957, 2930, 2896, 2859, 1640, 1606,
1577, 1510, 1473, 1463, 1421, 1294, 1254, 1228, 1155, 1125, 986,
ꢁ
0 C, then triisobutylaluminium solution (25 wt% in toluene)
was injected. Aer the specied time (Table 2), the reaction
mixture was quenched by adding 4 : 1 MeOH/H2O mixture (10
mL). Aer extracting with CH2Cl2 (2 ꢂ 25 mL), the organic layer
was dried (MgSO4), ltered over Celite 545 and concentrated to
obtain polymer 15a (Scheme 5). The polymer was puried by
dissolving in ether and precipitating in MeOH; the process was
repeated three times (found: C 63.6; H 9.8%. C21H38O3Si2
requires C 63.90; H 9.70%); nmax (KBr) (Fig. S11†): 2930, 2896,
2859, 1607, 1578, 1518, 1473, 1427, 1422, 1362, 1305, 1254,
912, 839, and 781 cmꢀ1
.
1224, 1160, 1128, 983, 852, 778, and 666 cmꢀ1
.
2.8. Synthesis of [(4-(oxiran-2-ylmethyl)-1,2-phenylene)
bis(oxy)]bis(tert-butyldimethylsilane) (14)45 (Scheme 5)
2.10. Random copolymerization of safrole oxide 2 and allyl
glycidyl ether 7
MCPBA (19.8 g, 80 mmol, 70% purity, 30% water) was dissolved All the experiments were performed under argon atmosphere.
in 150 mL CH2Cl2, and aqueous layer was removed. Silyl As described in (Table 3), methyltriphenylphosphonium
derivative 13 (16.3 g, 43 mmol) was added to the MCPBA/ bromide was placed in an RB ask under Ar and closed with
dichloromethane solution at 0 ꢁC and stirred at 25 ꢁC for a rubber septum. Safrole oxide 2, allyl glycidyl ether 7 and
24 h. The reaction mixture was washed with 10% NaOH solution anhydrous toluene were injected under Ar by a syringe. The
(3 ꢂ 20 mL) and water (2 ꢂ 25 mL). The CH2Cl2 layer was dried mixture was cooled to 0 ꢁC, and then triisobutylaluminium
(Na2SO4), concentrated and distilled (bp0.2 mbarHg127–130 ꢁC) to solution (25 wt% in toluene) was added under Ar in one portion
obtain 14 (10.7 g, 63%) as a colorless liquid (found: C 63.7; H by a syringe. The polymerization was stopped aer complete
1
9.6%. C21H38O3Si2 requires C 63.90; H 9.70%); dH (CDCl3): 0.17 polymerization (as indicated by H NMR spectrum) by adding
(6H, s), 0.18 (6H, s), 0.966 (9H, s), 0.971 (9H, s), 2.49 (1H, q), 2.66 4 : 1 MeOH/H2O mixture (10 mL); the mixture was extracted
(1H, dd, J 14.7 Hz, J 5.5 Hz), 2.74–2.68 (2H, m), 3.06–3.09 (1H, with CH2Cl2, dried (MgSO4), and ltered over Celite 545. The
m), 6.65 (1H, dd, J 8.3 Hz, J 2.2 Hz), 6.71 (1H, d, J 2.2 Hz), 6.74 ltrate upon evaporation afforded random copolymer 16
(1H, d, J 8.3 Hz). dC (CDCl3): (ꢀ) 4.11, 18.43, 25.94, 37.99, 46.72, (Scheme 6). The following IR data belong to a 1 : 1 copolymer of
52.57, 120.93, 121.82, 121.89, 130.14, 145.56, 146.65, (CDCl3 2 and 7. nmax (KBr) (Fig. S13†): 3076, 2869, 2773, 1646, 1608,
middle carbon: 77.02); nmax (KBr) (Fig. S10†): 3044, 2930, 2897, 1500, 1443, 1353, 1249, 1121, 928, 808, and 774 cmꢀ1 (found: C
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Table 2 Polymerizationa of silyl protected (SP) monomer 14 initiated with MePPh3Br (I) and catalysed by Bu3Al (C)b
RSC Advances
i
Yieldc (%)
Mn,Theor
Mn,Exp
PDI
d
e
Entry
I (mmol)
C (mmol)
[SP]/[I]
[C]/[I]
Time (h)
1
2
3
4
5
0.0213
0.0213
0.0495
0.0092
0.0370
0.24
0.70
0.53
0.53
0.53
117
117
50
272
68
11.3
32.9
10.7
57.6
14.3
1
2
20
40
18
0
—
—
60
90
75
85
27 700
17 700
80 200
22 800
16 300
12 900
11 500
10 300
1.8
1.5
1.6
1.8
a
Polymerization was carried out at 0 ꢁC for 6 h using 2.5 mmol of monomer 14 with 1.8 mL of additional toluene except in entry 4 where no
b
i
c
d
additional toluene was used. 25 wt% solution in toluene (z1 M Bu3Al). Isolated and NMR yields are similar within 2%. Mn for entry 2 ¼
[molar mass of SP] ꢂ [SP]/[I] ꢂ % conversion/100 ¼ 394.70 ꢂ 117 ꢂ 0.60 ¼ 27 708. e GPC using light scattering detector.
65.1; H 6.7%. Repeat units 2 and 7 in 1 : 1 requires C 65.74; H The polymer solution upon freeze-drying afforded the depro-
6.90%).
tected polymer 18 (394 mg, 86%). (15 mol% catechol units) nmax
(KBr) (Fig. S15†): 3469, 2960, 2923, 2857, 1624, 1494, 1384, 1259,
1105, 808, and 587 cmꢀ1 (found: C 45.6; H 7.9; N, 5.5; S, 12.1%.
Repeat units 2 (diol form) and 7 (aer thiolene reaction) in
15 : 85 requires C, 44.79; H, 7.75; N, 5.45; S, 12.47%).
2.11. Conversion of copolymer 16 to 17 (Scheme 6) using
lead tetraacetate
The procedure as described under Section 2.7 was followed.42,43
A solution of polymer 16 (containing 15 mol% safrole oxide 2
repeating unit) (1.1 g, 8.9 mmol of total repeating units and
2.13. Synthesis of 19 (Scheme 6) via thiol–ene reaction
1.33 mmol of safrole oxide units) in benzene (25 mL) was heated The copolymer 17 (prepared from entry 5, Table 3) (containing
to 75 ꢁC in a round bottom ask. Aer the addition of Pb(OAc)4 85 mol% repeating unit of allyl glycidyl ether 7) (240 mg,
(0.90 g, 2.0 mmol) under N2, the mixture was stirred at 75 ꢁC for 1.9 mmol, containing 1.6 mmol akene motifs) was dissolved in
4 h. Then, it was cooled, diluted with EtOAc (30 mL) and washed THF (3 mL). Thioglycolic acid (1.00, 11 mmol) and photo-
with H2O (3 ꢂ 25 mL). The organic layer was dried (Na2SO4) and initiator
2,2-dimethoxy-2-phenylacetophenone
concentrated to give 17. For a copolymer having 1 : 1 ratio of the (200 mg, 0.8 mmol) were added. Aer purging with N2 for
monomer units: nmax (KBr) (Fig. S14†): 3080, 3013, 2919, 2867, 10 min, the reaction mixture was irradiated with a 365 nm UV
(DMPA)
1763, 1645, 1496, 1446, 1352, 1215, 1105, 923, 786, 758 cmꢀ1
.
lamp until the completion of the reaction as revealed by 1H
The polymers having various compositions gave satisfactory NMR spectrum. The product dissolved in methanol was
elemental analysis.
precipitated in chloroform. The process was repeated to give 19
(292 mg, 81%). The polymer was found to be insoluble in water.
(15 mol% catechol units) nmax (KBr) (Fig. S16†): 3500 (br), 2916,
2869, 1734, 1601, 1520, 1471, 1111, 682, and 523 cmꢀ1 (found: C
48.1; H 6.5; S, 13.2%. Repeat units 2 (diol form) and 7 (aer
thiolene reaction) in 15 : 85 requires C, 48.88; H, 6.75; S,
13.61%).
2.12. Synthesis of 18 (Scheme 6) via thiol–ene reaction
The copolymer 17 (prepared from entry 5, Table 3) (containing
85 mol% repeating unit of allyl glycidyl ether 7) (274 mg,
2.2 mmol, containing 1.9 mmol of alkene motifs) was dissolved
in THF (2 mL) and methanol (1.5 mL). Cysteamine$HCl (1.4 g,
12
mmol)
and
photoinitiator
2,2-dimethoxy-2-
2.14. Copolymerization of silyl protected 14 and AGE 7
phenylacetophenone (DMPA) (227 mg, 0.9 mmol) were added.
The mixture was purged with N2 for 10 min, then irradiated with As described in (Table 4), silyl protected monomer 14, allyl
a 365 nm UV lamp until the completion of the reaction as glycidyl ether 7 and anhydrous toluene were added onto
revealed by 1H NMR spectrum. The reaction mixture was taken methyltriphenylphosphonium bromide contained in a RB ask
ꢁ
up in 1 : 1 MeOH/0.1 M HCl (5 mL) and dialyzed against water. under Ar. The mixture was cooled to 0 C and polymerization
Table 3 Random copolymerizationa of Safrole Oxide (SO) 2 and allyl glycidyl ether 7 initiated/catalyzed by MePPh3Br/iBu3Alb
Entry
SOc (mol%)
MePPh3Br (mmol)
Toluene (mL)
iBu3Al (mmol)
Temp. (ꢁC)
Time (h)
Yield (%)
1
2
50
50
50
50
15
0.063
0.065
0.025
0.042
0.040
2.5
2.0
1.0
3.0
2.5
0.835
0.860
0.484
0.513
0.534
20
20
0
0
0
20
24
2
18
20
91
93
89
92
93
3
4d
5e
a
b
i
c
Polymerization was carried out using a total of 5.0 mmol of monomer 2 and 7. 25 wt% solution in toluene (z1 M Bu3Al). Mol% of the
d
monomer in the mixture of the two monomers. This reaction was run using a total of 35 mmol of 2 and 7, however, calculations are shown
for the total of 5.0 mmol. e This reaction was run using a total of 50 mmol of 2 and 7, however, calculations are shown for the total of 5.0 mmol.
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Table 4 Random copolymerizationa of silyl protected oxide (SP) 14 and allyl glycidyl ether (AGE) 7 initiated with MePPh3Br (I) and catalyzed by
iBu3Al (C)b
SPc (mol%)
I (mmol)
[M]d/[I]
C (mmol)
[C]/[I]
Time (h)
Conv.e,f (%)
Mn,Theor
Mn,Exp
PDI
g
h
Entry
1
2
3
4
5
6
7i
8
50
50
25
10
10
10
10
5
0.045
0.053
0.045
0.045
0.092
0.012
0.032 in
0.045
111
94
111
111
54
417
156
111
0.76
0.76
0.50
0.50
0.50
0.50
0.50
0.50
17
14
11
11
5
42
16
11
3
5
12
12
3
15
17
12
88 (88)
95 (99)
99 (99)
96 (99)
84 (99)
78 (93)
99 (99)
98 (99)
23 900
20 500
15 800
14 300
12 700
6100
1.5
1.3
2.0
22 200
14 200
7900
5900
1.8
2.1
a
Polymerization was carried out at 0 ꢁC using a total of 5.0 mmol of monomer 14 and 7 with an additional amount toluene added (3.5 mL). b 25 wt%
solution in toluene (z1 M iBu3Al). c Mol% of the monomer the mixture of the two monomers. d Total monomers of silyl protected oxide 14 and allyl
glycidyl ether 7 is 5 mmol. e % conversion monomer 14 as determined by 1H NMR, the number in parentheses belongs to % conversion of AGE 7.
f
Isolated yield was in the range 85–95%. g Mn for entry 4 ¼ [molar mass of SP ꢂ 0.10 + molar mass of AGE ꢂ 0.90] ꢂ [M]/[I] ¼ 142.2 ꢂ 111 ¼ 15 784
h
i
(assuming 100% conversion). GPC with a light scattering detector. This reaction was run using a total of 30 mmol of 14 and 7; however,
calculation is based on a total of 5.0 mmol of monomers 14 and 7.
was started with the addition of triisobutylaluminium solution 25 ꢁC until the reaction is completed. The reaction mixture was
(25 wt% in toluene). The polymerization was stopped (aer its dialyzed against MeOH (to remove DMAP) for 30 min and then
1
completion as indicated by H NMR spectrum) by adding 4 : 1 against deionized water (1 h). The resultant polymer solution
MeOH/H2O mixture (10 mL) and extracted with CH2Cl2 (25 mL). was freeze-dried to obtain polymer 21 (1.11 g, 90%). For
The organic layer was dried (MgSO4), ltered over Celite 545, a sample of 21 derived from entry 2 (Table 4) (50% silyl): (found:
and concentrated to obtain 20 (Scheme 8). The polymer was C, 55.1; H, 8.9; N, 2.1; S, 4.8%. 21 in a 1 : 1 ratio of the repeating
dissolved in diethyl ether, precipitated in methanol and sepa- units requires C, 55.96; H, 9.07; N, 2.25; S, 5.15%); nmax (KBr)
rated by centrifuging. This process was repeated to obtain pure (Fig. S18†): 3430, 2962, 2927, 2857, 1637, 1511, 1467, 1422, 1385,
20. (25 mol% silyl protected, entry 3, Table 4): nmax (KBr) 1301, 1256, 1221, 1162, 1100, 981, 910, 840, 778, 664, and
(Fig. S17†): 3081, 3014, 2855, 1646, 1605, 1576, 1512, 1469, 1422, 614 cmꢀ1
.
1358, 1298, 1255, 1224, 1160, 984, 839, 782, 696, and 667 cmꢀ1
(found: C 62.3; H 9.0%. Repeat units 14 and 7 in 25 : 75 requires
2.17. Synthesis of 22 (Scheme 8) via thiol–ene reaction
C, 63.55; H, 9.30%).
(10 mol% catechol units)
The reaction was performed for polymer samples 20 having SP
14 and AGE 7 repeating units in mole ratios of 50 : 50 and
2.15. Silyl deprotection of polymer 15a
TBAF (1.0 M in THF) (1.26 mL, 1.26 mmol) was added to 10 : 90 to obtain polymer 22 using UV light in dark room.
a solution of polymer 15a (entry 4, Table 2) (227 mg, 0.575 Thioglycolic acid (1.88 g, 20.4 mmol) and photoinitiator
mmol) in THF (4 mL) under N2 at 0 ꢁC. Aer stirring at 0 ꢁC for DMPA (522 mg, 2.1 mmol) were added to a solution of copol-
1 h, a 1 : 1 mixture of H2O/acetic acid (2 mL) was added to the ymer 20 (entry 7, Table 4) (618 mg, 4.05 mmol akene motifs) in
reaction mixture. The work-up procedures included the evapo- THF (12 mL). Aer purging the mixture with N2 for 10 min, it
ꢁ
ration of the solvents, redissolving the residue in MeOH and was then irradiated with a 365 nm UV lamp at 25 C until the
precipitation in water. The process was repeated two times to reaction is completed. The THF-soluble product was precipi-
wash out remaining TBAF to obtain deprotected polymer 15b tated with the addition of ether to the reaction mixture. The
(Scheme 5), (yield: 72 mg, 75%). The uoride ion could chelate process of dissolving in THF followed by precipitation in ether
with catechol moiety according to literature.46,47 The polymer was repeated three times to obtain 22 (885 mg, 84%). For
was soluble in methanol but insoluble in H2O, Et2O and CH2Cl2 a sample of 22 derived from entry 2 (Table 4) (50% silyl): (found:
(found: C 64.7; H 5.8%. C9H10O3 requires C 65.05; H 6.07%); C, 57.2; H, 8.8; S, 5.1%. 22 in a 1 : 1 ratio of the repeating units
nmax (KBr) (Fig. S12†): 3445, 2921, 2870, 1608, 1521, 1446, 1363, requires C, 57.96; H, 8.72; S, 5.33%); IR for a 50 : 50 copolymer
1285, 1190, 1113, 1052, 958, 871, 811, 788, and 754 cmꢀ1
.
22 is given: (50% silyl) nmax (KBr) (Fig. S19†): 3458, 2931, 2858,
2511, 1727, 1632, 1511, 1467, 1421, 1385, 1301, 1255, 1223,
1122, 983, 910, 841, 790, 669, and 552 cmꢀ1
.
2.16. Synthesis of 21 (Scheme 8) via thiol–ene reaction
(10 mol% catechol units)48
2.18. Synthesis of 18 from 21 (catechol 10 mol%)
The copolymer 20 (entry 7, Table 4) (690 mg, containing
4.32 mmol of alkene motifs) was dissolved in THF (18 mL) and The copolymer 21 as obtained from 20 (1.0 mmol) (entry 7,
methanol (4.5 mL). Cysteamine$HCl (3.6 g, 33 mmol) and Table 4) using procedure described under Section 2.16, was
photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DMPA) dissolved in MeOH/0.5 M HCl (6 mL) and stirred under N2 at
(582 mg, 2.4 mmol) were added. Aer purging with N2 for 25 ꢁC for 18 h. The reaction mixture was dialyzed against water
10 min, the mixture was irradiated with a 365 nm UV lamp at and then freeze-dried to obtain polymer 18 in (90%) (found: C,
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43.0; H, 8.0; N, 5.5; S, 12.7%. 18 containing 10 mol% catechol a competing reaction between nucleophilic ring opening and
units requires C, 43.90; H, 7.82; N, 5.69; S, 13.02%). IR and NMR base catalysed elimination reaction via abstraction of labile
spectra of 18 (10 mol% catechol repeating unit) were found to benzylic protons as depicted in Scheme 1. The elimination
be like the one prepared earlier from safrole-oxide under process was very extensive with Fꢀ as conrmed by appearance
1
Section 2.14. Acid hydrolysis of silyl groups in 1 : 1 copolymer 21 of H signal at d 6.2, 6.5 and 4.1 ppm attributed to the –CH]
(i.e. containing 50 mol% catechol units) to get polymer 18 could CH–CH2–O motifs (Fig. S1b†). For the sake of comparison, the
not be achieved because of solubility problem.
1H NMR spectrum of cinnamyl alcohol is shown in Fig. S1c.†
The signals for the protons marked ‘a’, ‘b’ and ‘c’ are readily
identiable for comparison, thereby conrming the base cata-
lysed chain transfer to monomer 2 by abstraction of benzylic
protons leading to alkene motifs akin to the motifs of cinnamyl
alcohol. With TBAH, ring opening polymerization happened
accompanied by chain transfer via elimination process as
depicted by A (Scheme 1). The extensive chain transfer to
monomer led us to pursue this important polymerization using
other protocols with the objective of minimizing the chain
transfer, which puts a limit on the maximum molar mass
possible for the polymers.
In the precedent literature, considerable efforts have been
exerted to control the living character of the polymerization of
propylene oxide (PO). In most cases, alkali metal alkoxides and
hydroxides are widely used as anionic polymerization initia-
tors.49–51 The high basicity of propagating species (akin to an
alkoxide, ROꢀ) leads to the abstraction of proton from methyl
group of the PO, thereby constituting a chain transfer to the
monomer. This process also occurred in the current work
involving the base catalysed polymerization of safrole oxide (SO)
2, thereby resulting in the extensive formation of SO oligomers
possessing a terminal cinnamylic unsaturation (Scheme 1). One
signicant problem inherent in SO is the much higher acidity of
the benzylic protons than that of CH3 protons in PO; the labile
H in SO is, therefore, much more prone to base catalysed
abstraction than the methyl protons in PO.
2.19. Synthesis of 19 from 22 (catechol 10 mol%)
TBAF (1.0 M in THF) (0.25 mL, 0.25 mmol) was added to
a solution of polymer 22 (50 mg, 0.22 mmol) in THF (1.0 mL)
ꢁ
under N2 at 0 C and stirred for 12 h. Aer the elapsed time,
a 2 : 1 mixture of H2O/acetic acid (2 mL) was added. The crude
polymer was soluble in methanol but insoluble in H2O. There-
fore, it was puried by dissolving in methanol and precipitating
in water. The process was repeated two times to obtain polymer
19 (yield: 90%) (found: C, 47.5; H, 6.9; S, 13.9%. 19 containing
10 mol% catechol units requires C, 48.10; H, 6.78; S, 14.27%).
Removal of the acid hydrolysis of silyl groups in 1 : 1 copolymer
22 (i.e. containing 50 mol% catechol units) to get polymer 19
could not be achieved because of solubility problem. IR and
NMR spectra of 19 (10 mol% silyl) were found to be like the one
prepared earlier from safrole-oxide under Section 2.15.
2.20. Coacervate formation (10% catechol unit)
A sample of 19 (514 mg) was dissolved in MeOH and dialyzed
against NaHCO3 solution. Aer 1 h, the polymer became soluble
and the dialysis was continued against water for 24 h; the
polymer remained soluble. A solution of 18 (494 mg) in water
was added to the dialyzed solution; the resultant turbid mixture
was dialyzed against water for 24 h. The turbid solution was
freeze-dried to obtain the 23 (Scheme 8), the coacervate of 18
and 19 (1.00 g). nmax (KBr) (Fig. S20†): 3456, 2919, 2869, 1733 (w),
1620 (overlapping), 1578, 1461, 1384, 1280, 1226, 1110, 780, 900
Polymerization reaction of 2 using Lewis acid triisobutyla-
luminium as a catalyst and methyltriphenyphosphonium
bromide (I) as an initiator38,39,52 gave ring opened polymer 6 in
excellent yields (Scheme 2), (Table 1). The 1H NMR spectra
(Fig. 1c) revealed the formation of ring opened polymer without
any indication of chain transfer reaction via abstraction of
and 701 cmꢀ1
.
3 Results and discussion
Natural safrole 1 upon oxidation with MCPBA was converted to allylic proton.
its epoxide 2 (Scheme 1). Fig. 1a and 2a displays the 1H and 13
Experimental evidence suggests the requirement of [AlR3]/[I]
C
NMR spectra of 2. Numerous attempts were made to polymerize $ 1 for successful polymerization. Trialkylaluminum partici-
safrole oxide 2 using various basic catalyst (see ESI†). The pates in the formation of an aluminate complex as depicted by
results are given in (Table S1†). The ring opening polymeriza- ‘A’ (Scheme 3) which by itself is not reactive enough to effec-
tion monomer 2 as neat or in solvent THF was carried out under tively initiate and/or propagate the current SO polymerization.
argon using TBAF (1–6 mol%) or TBAH (2–5 mol%) or NaOtBu An excess of iBu3Al ensures a fast polymerization at 0 ꢁC owing
as initiators at 50–100 ꢁC for 2–72 h. Under the reaction to activating effect of the “free” triisobutylaluminum derivative
conditions, the monomer was recovered unreacted in the case as depicted by B. Note that the experimental molar masses of
of initiator NaOtBu (Table S1,† entry 14). TBA-initiated poly- poly(safrole oxide) (PSO) are not close to theoretical values
merization also failed to give any polymer (entries 1 and 2). In based on the formation of one polymer chain per Ph3MeP+Brꢀ
other cases, we were unable to obtain the expected polymer 5 (see Table 1). In the context of molar masses by GPC, it is worth
cleanly; extensive base catalysed elimination reaction occurred. mentioning that the chemical structures of the standards (PEO
Use of TBAH as the initiator led to the formation of polymer in or PS) and the polymers/copolymers are different. As such (for
ꢁ
high yields in the temperature range 70–100 C; however, the a note of caution), the investigated polymers/copolymers and
proton NMR analysis revealed the presence of alkene motifs standards may not have the same hydrodynamic radii for the
(z10 mol%) on the polymer terminal (Fig. S1b†). Here, the Fꢀ same molar mass. However, using the same standards, GPC has
or OHꢀ or the ring opened alkoxide ion (ROꢀ) is involved in been extensively used to determine the molar masses of
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Fig. 1 1H NMR spectra of (a) safrole oxide 2, (b) polymer 6, and (c) copolymer 16.
polymers/copolymers derived from epoxide containing a range charges on the ring-carbons involved in the ring opening
of substituents.38,39,53,54 The measured molar masses have then process, than on the benzyl hydrogens involved in the transfer
been compared with the theoretical values as described for the process to monomer (Scheme 1). Also, note that the basicity of
current polymers.
alkoxide species in alkoxy aluminate complexes B or C is greatly
Thus, the living-like polymerization of SO is jeopardized by reduced as compared to alkali metal alkoxide species, thereby
a signicant contribution of the chain transfer process to the inhibiting the proton abstraction reaction leading to chain
monomer. For the PO polymerization, it has been reported, transfer to the monomer.
however, that the number of PPO chains remains identical to
the number of Ph3MeP+Brꢀ molecules.38
It is reported that the initiation process involved the attack
by not only bromide but also by the isobutyl group and hydride
The polymerization mechanism may thus involve the elec- as shown in Scheme 3,39,52 thereby leading to three polymers
trophilic complex B which is inserted into the nucleophilic having bromide, isobutyl, and hydride end groups.52 iBu3Al can
species C (Scheme 3). The involvement of reactive complex B work both as a hydride as well as an isobutyl anion in the ring-
minimizes the transfer process to monomer SO, as observed in opening reaction.55,56
the cases involving alkali metal alkoxide initiators. The greater
Generally, propagation via nucleophilic attacks on the less
electron-withdrawing effect of R3Al in B imparts greater positive hindered methylene carbon of epoxides leads to regioregular
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Our research plan includes the synthesis of copolymers of
monomers safrole oxide 2 and allyl glycidyl ether 7 (Scheme 2).
In
this
context,
triisobutylaluminium-
bromide catalyst-initiator
methyltriphenyphosphonium
system was used to homopolymerize 7 to obtain polymer 8
(Scheme 2). The 1H and 13C NMR spectra of 7 and 8 are shown in
respective Fig. S2 and S3.† The spectral data is consistent with
the regioregular ring opening to give 8. As in the case of safrole
oxide polymer 6, the splitting of carbon marked ‘a’ in the 13C
NMR spectrum (Fig. S3b†) pointed toward the formation of an
atactic microstructure.
At this stage, we were apprehensive about the deprotection of
methylene acetal protecting group in PSO 6. Methylene acetal is
indeed a robust protective group which does not respond to acid
catalyzed deprotection. As a model case, safrole 1 was used for
examining the deprotection aspect using lead tetraacetate.42,61
To our relief, safrole 1 on treatment with the oxidizing agent
afforded 9 having labile acetoxy group (Scheme 2). In fact, the
similar acetoxy derivatives are usually removed during aqueous
work up leading to catechol motifs. The 1H and 13C NMR
spectra of 1 and 9 are shown in respective Fig. 3 and S4.† The
methylene protons of 1 marked ‘a’ (Fig. 3a) is shied downeld
in the spectrum of 9 (Fig. 3b) owing to the presence of electron
withdrawing AcO substituent. Similar downeld shi is
observed for the carbon marked ‘j’ in the 13C NMR spectrum
(Fig. S4b†).
Fig. 2 13C NMR spectra of (a) safrole oxide 2 and (b) polymer 6 in
CDCl3.
Unaware of the AcO group's ability in 9 (Scheme 2) to survive
during subsequent chemical transformation, we set out to
explore the related chemistry using silyl protecting group. In
this context, natural product eugenol 10 was demethylated and
protected by reacting with diphenylsilane in the presence of
catalyst tris-pentauorotriphenylborane to give 11 (Scheme 5).
To our dismay, silyl protected 11 was found to be extremely
moisture sensitive; it broke down during silica gel chromatog-
raphy to give allylcatechol 12 quantitatively. Thereaer, we
decided to prepare 12 via demethylation using LiCl. The ‘OH’
groups in 12 were then protected to give 13 by reacting with tert-
butyldimethylsilyl chloride in the presence of imidazole. Epox-
idation using m-chloroperbenzoic acid transformed 13 to 14
Scheme 3 Mechanism of Lewis acid catalyzed polymerization.
polymers.57,58 Optically pure (i.e. enantiopure) epoxides are thus
expected to provide an easy access to isotactic polymers since
the methine carbon retains its conguration (Scheme 4).
However, for a racemic epoxide, formation of an atactic polymer
is expected with equal percentages of mm, mr, rm and rr triads
(Scheme 4). 13C NMR MR spectrum revealed the regioregularity
and stereochemistry of monomer insertion. The observed
methine and methylene carbon signals ensure the exclusive
head-to-tail (HT) chain propagation.59 In the current work, while
the methine carbon marked ‘i’ appeared as single signal, the
methylene carbon marked ‘j’ resolved into triads and diads
(Fig. 2b). The 13C NMR spectrum thus showed the current
polymer 6 as atactic (Scheme 4).38,59,60
Scheme 4 Regioregular ring opening polymerization of enantiopure Fig. 3 1H NMR spectra of (a) safrole oxide 1 and (b) acetoxy safrole 9 in
and racemic epoxide.
CDCl3.
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Scheme 5 Lewis acid catalyzed polymerization of silylated epoxide 14.
which was then subjected to Lewis acid catalysed polymeriza-
tion to afford 15a. The results of the polymerization reaction are
given in (Table 2). The tert-butyldimethylsilyl groups in 15a were
then deprotected using tetrabutylammonium uoride to obtain
15b containing the catechol motifs.
Scheme 6 Lewis acid catalyzed copolymerization of epoxides 2/7 and
thiol–ene reaction.
Scheme 6. Numerous attempts to obtain block copolymers by
sequential addition of the monomers resulted in failures. At
every instance, the reaction resulted in the formation of
a mixture of homopolymers which were separated as explained
in the Experimental section. A plausible rationale is illustrated
in Scheme 7 where the hydride or butyl transfer to the second
monomer might be able to initiate new chain thereby resulting
in the formation of two homopolymers. We, therefore, shied
our attention to obtain the random copolymer from monomers
2 and 7 as shown in Scheme 6. Lewis acid catalysed polymeri-
zation of 2 and 7 afforded random copolymer 16 in excellent
yields. The results are given in (Table 3). The 1H spectra of
homopolymer 6 and the 1 : 1 2/7 random copolymer 16 are
displayed in Fig. 1b and c. The feed ratio of the monomers
matched with incorporated ratio of the corresponding repeating
units as determined by integration of several non-overlapping
proton signals Fig. 1c. The nding thus implies that the two
monomers have equal reactivity ratio.
The 1H and 13C NMR spectra of 14, 15a and 15b are shown in
respective Fig. 4 and S5.† The spectra conrmed the structures
of the monomer and polymers. The silyl protons and carbons
marked ‘a’, ‘b’ and ‘c’ in Fig. 4a, b, S5a and b† disappeared upon
deprotection of the silyl groups as indicated by the absence of
the corresponding signals in Fig. 4c and S5c.† However, it was
very difficult to remove the Fꢀ as it is known to bind strongly
with catechol motifs via H-bonding.46,47 In such a scenario, the
ammonium counterion remained with the polymer sample as
can be seen as minor peaks in the region around d 1 ppm
(Fig. 4c). Minor carbon signals are also observed in Fig. S5c.†
Next, we focussed our attention to Lewis acid catalysed
copolymerization reaction of SO (2) and AGE 7 as outlined in
The 1 : 1 random copolymer 16 was then subjected to lead
tetraacetate oxidation thereby giving copolymer 17 containing
acetoxy group (vide supra, Scheme 6). The 1H and spectra of 16
and 17 are displayed in Fig. 1c and 5a, respectively. The proton
marked ‘a’ (Fig. 1c) is shied downeld at ‘c’ (Fig. 5a) and the
new CH3CO protons marked ‘d0’ appeared at d 2 ppm as ex-
pected. The 13C NMR spectrum (Fig. S6†) also revealed the
formation of acetoxy derivative 17. The acetoxy carbons marked
‘r0’ and ‘q0’ appeared at d 20.5 and 170.3 ppm, respectively
(Fig. S6b†). Also note that carbon marked ‘a0’ in 17 is shied
downeld as compared to ‘a’ of 16 respectively (Fig. S6a†).
Fig. 4 1H NMR spectra of (a) 14 and (b) 15a in CDCl3; and (c) 15b in Scheme
7
A plausible hydride or isobutyl transfer to activated
CD3OD.
monomer 7.
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Scheme 8 Lewis acid catalyzed copolymerization of epoxides 14/7
and thiol–ene reaction.
d display the spectra for 21 and 22; the absence of alkene protons
in the range d 5–6 ppm clearly conrms the addition of the thio
group onto the double bonds.
Fig. 5 1H NMR spectra of 15 : 85 copolymer (a) 17 in CDCl3, (b) 18 and
(c) 19 in CD3OD.
The acetoxy derivative 17 was subjected to thiol–ene reaction
using photoinitiator 4-dimethylaminopyridine (DMAP) using UV
light (l ¼ 365 nm). The addition of cystemine$HCl (H3N+CH2-
CH2SH Clꢀ) and thioglycolic acid (HO2CCH2SH) to 17 with
a 15 : 85 ratio of SO 2/AGE 7 repeating units converted 17 to 18 and
19, respectively (Scheme 6). The 1H NMR spectra of 17, 18 and 19,
displayed in Fig. 5 conrms the successful transformation. The
acetoxy proton signal (marked ‘d’, Fig. 5a) disappeared in the
spectra of 18 and 19 (Fig. 5b and c) as a result of hydrolysis of the
functional motifs during aqueous workup under mild acidic
condition. This is further conrmed by the absence of the signal
(for proton marked ‘c’, Fig. 5a) in the spectra of 18 and 19 (Fig. 5b
and c). The spectra are consistent with the addition of the thiol
motifs into the alkene double bond as conrmed the absence of
alkene proton signals in Fig. 5b and c. The aromatic protons are
visible; chemical shis of some of the readily identiable protons
are assigned. The work presented in the previous paragraph are
repeated using silyl protected epoxide 14 which was copolymerized
with allyl glycidyl ether 7 (Scheme 8) to give copolymer 20 having
various proportions of the x/y units. The results of the polymeri-
zation are given in (Table 4). The silyl protected copolymer was
then elaborated using thiol–ene reaction as discussed before to
give 21 and 22, which on treatment with HCl and Bu4NF respec-
tively afforded 18 and 19 aer deprotection of the silyl groups. The
spectral analysis revealed the identical nature of the polymers to
the polymers derived via acetoxy protective groups (vide supra). The
1H NMR spectra of random copolymer 20 with SP/AGE ratio of 1 : 1
and 0.10 : 0.90 are shown in Fig. 6a and b, respectively. Fig. 6c and
Fig. 6 1H NMR spectra of (a) 50 : 50 copolymer 20 in CDCl3, (b)
10 : 90 copolymer 20 in CDCl3, (c) 10 : 90 copolymer 21 in CD3OD,
and (d) 10 : 90 copolymer 22 in CD3OD.
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Coacervate 23, obtained by treating aqueous solutions of HCl
salt 18 and Na-salt 19, was found to be insoluble in water
(Scheme 8). The strong interaction leading to the 23 is evinced
by inability of various concentration of NaCl to dislodge the
component polymers from the coacervate.
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4 Conclusions
The ring opening polymerization of safrole oxide 2, derived
from naturally occurring safrole 1, using basic catalyst led to the
9 H. Yamamoto, S. Yamauchi and S. Ohara, Biomimetics, 1992,
1, 219–238.
formation of intractable materials as a result of extensive chain 10 H. Tatehata, A. Mochizuki, T. Kawashima, S. Yamashita and
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338–341.
vate by electrostatic attraction. Such complex is expected to be 17 B. P. Lee, K. Huang, F. N. Nunalee, K. R. Shull and
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20 Y. Tian, Y. Cao, Y. Wang, W. Yang and J. Feng, Adv. Mater.,
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21 F. Zhang, S. Liu, Y. Zhang, Y. Wei and J. Xu, RSC Adv., 2012,
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Conflicts of interest
There are no conicts of interest to declare.
22 J. Li, M. Zhou, F. Cheng, Y. Lin and P. Zhu, Carbohydr.
Polym., 2019, 221, 113–119.
23 X. Chen, Y. Zhai, X. Han, H. Liu and Y. Hu, Appl. Surf. Sci.,
2019, 483, 399–408.
Acknowledgements
The authors would like to acknowledge the support provided by
King Abdulaziz City for Science and Technology (KACST) 24 J. Duan, W. Wu, Z. Wei, D. Zhu, H. Tu and A. Zhang, Green
through the Science & Technology Unit at King Fahd University Chem., 2018, 20, 912–920.
of Petroleum & Minerals (KFUPM) for funding this work 25 X.-D. Pan, Z. Qina, Y.-Y. Yana and P. Sadhukhana, Polymer,
through project no. 12-ADV2397 as part of the National Science,
2010, 51, 3453–3461.
Technology and Innovation Plan. The authors would like to 26 H. Shao, K. N. Bachus and R. J. Stewart, Macromol. Biosci.,
acknowledge the valuable guidance of Prof. Craig Hawker in
conducting this research work.
2009, 9, 464–471.
27 R. Ko, P. A. Cadieux, J. L. Dalsin, B. P. Lee, C. N. Elwood and
H. Razvi, J. Endourol., 2008, 22, 1153–1160.
28 B. P. Lee, J. L. Dalsin and P. B. Messersmith,
Biomacromolecules, 2002, 3, 1038–1047.
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