Postpolymerization modification of hydroxyl-functionalized polymers with isocyanates

Article abstract of DOI:10.1021/ma2008018

The postpolymerization functionalization of hydroxyl-group terminated polymers (M_n in the range of 1000-6000 g mol^-1) such as poly(ethylene glycol) (PEG), poly(N-isopropylacrylamide) (PNIPAM), poly(N,N-dimethylacrylamide) (PDMAM), and poly(tert-butyl acrylate) (PtBA) with a wide range of functional isocyanate derivatives such as azobenzene, viologen, and anthracene has been investigated. It was shown by ¹H and ¹³C NMR, GPC, Fourier transform infrared spectroscopy (FTIR), and electrospray ionization mass spectrometry (ESI-MS) that a high degree of end-group conversion, typically >98%, with little or no formation of side products can be achieved at ambient temperature. PNIPAM, PDMAM, PtBA, and PHEAM polymers have been obtained by reversible addition-fragmentation chain transfer (RAFT) radical polymerization from a hydroxyl-group containing chain transfer agent (CTA). The formation of the carbamate has been shown to be compatible with the trithiocarbonate end-group of the RAFT polymers. Additionally, this approach allows for the direct functionalization of RAFT polymers without the need of additional steps such as deprotection or aminolysis of the CTA. This route was subsequently used for the preparation of a variety of side-chain functional polymers from poly(N-hydroxyethyl acrylamide) (PHEAM). Three different high yielding methods have been employed to prepare the isocyanates (R-NCO). Either amino or carboxylic acid precursors have been converted into the desired R-NCO or hydroxyl group moieties have been reacted with an excess of 1,6-hexamethylene diisocyanate (HDI) to statistically form the monofunctional product.

Full text of DOI:10.1021/ma2008018

ARTICLE
pubs.acs.org/Macromolecules
Postpolymerization Modification of Hydroxyl-Functionalized
Polymers with Isocyanates
Frank Biedermann,† Eric A. Appel,† Jesꢀus del Barrio,† Till Gruendling,‡ Christopher Barner-Kowollik,‡ and
Oren A. Scherman†,*
†Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW,
U.K.
‡Preparative Macromolecular Chemistry, Institut f€ur Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT),
Engesserstrasse 18, 76128 Karlsruhe, Germany
S Supporting Information
b
ABSTRACT: The postpolymerization functionalization of
hydroxyl-group terminated polymers (Mn in the range of 1000ꢀ
6000 g molꢀ1) such as poly(ethylene glycol) (PEG), poly(N-
isopropylacrylamide) (PNIPAM), poly(N,N-dimethylacrylamide)
(PDMAM), and poly(tert-butyl acrylate) (PtBA) with a wide range
of functional isocyanate derivatives such as azobenzene, viologen,
and anthracene has been investigated. It was shown by 1H and 13C
NMR, GPC, Fourier transform infrared spectroscopy (FTIR), and
electrospray ionization mass spectrometry (ESI-MS) that a high
degree of end-group conversion, typically >98%, with little or no
formation of side products can be achieved at ambient temperature.
PNIPAM, PDMAM, PtBA, and PHEAM polymers have been
obtained by reversible additionꢀfragmentation chain transfer (RAFT) radical polymerization from a hydroxyl-group containing chain
transfer agent (CTA). The formation of the carbamate has been shown to be compatible with the trithiocarbonate end-group of the RAFT
polymers. Additionally, this approach allows for the direct functionalization of RAFT polymers without the need of additional steps such as
deprotection or aminolysis of the CTA. This route was subsequently used for the preparation of a variety of side-chain functional polymers
from poly(N-hydroxyethyl acrylamide) (PHEAM). Three different high yielding methods have been employed to prepare the isocyanates
(RꢀNCO). Either amino or carboxylic acid precursors have been converted into the desired RꢀNCO or hydroxyl group moieties have
been reacted with an excess of 1,6-hexamethylene diisocyanate (HDI) to statistically form the monofunctional product.
’ INTRODUCTION
Chemical reactions that fulfill the aforementioned features have
been commonly termed “click” reactions in the literature but a
more precise definition stresses the importance of equimolarity in
polymer synthesis.13,14 Among those reactions that fulfill all of the
‘click’-criteria, one of the most widely utilized transformations is
based on the alkyneꢀazide cycloaddition and is very versatile in
postpolymerization modification of ATRP polymers.15ꢀ19 Re-
cently, nitroxides have been employed for postpolymerization
functionalization of ATRP polymers.20,21 On the other hand,
DielsꢀAlder cycloaddition reactions22ꢀ25 and thiolꢀene Michael
additions26ꢀ28 have received considerable interest for postpoly-
merization functionalization of RAFT polymers.29ꢀ31 However,
shortcomings in the orthogonality of azides and monomers32 as
well as instabilities of the RAFT end-groups33 and their side
reactions after aminolysis34 have also been discussed in the litera-
ture. Hydroxyl-functionalities both in monomer and initiator/CTA
The development of efficient synthetic protocols to decorate
polymers with functional units remains a key interest in macro-
molecular chemistry.1ꢀ4 The advent of controlled/living polym-
erization techniques has led to routinely accessible well-defined
macromolecular architectures and functional polymers. Most
notably, controlled radical polymerization (CRP) methods such
as reversible additionꢀfragmentation chain transfer (RAFT) and
atom transfer radical polymerization (ATRP) protocols as well as
ring-opening polymerizations (ROP) have been employed under
a wide range of conditions to introduce functional end-groups or
side-chains in polymers.5ꢀ12 Nevertheless, postpolymerization
functionalization methodologies are still needed if the desired fun-
ctionality is not compatible with the polymerization conditions.
Macromolecule modifications typically rely on efficient syn-
thetic protocols that guarantee a nearly quantitative conversion of
the polymer end-/side groups with little or no formation of side
products. Furthermore, mild reaction conditions are desirable to
avoid degradation of either the polymer or the functionality to be
introduced while the rate of conversion should be relatively high.
Received: April 6, 2011
Revised:
May 18, 2011
Published: May 26, 2011
r
2011 American Chemical Society
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Scheme 1. (a) Postpolymerization Functionalization of Hy-
droxyl End Groups and Side Chains of Polymers with Iso-
cyanates Achieved by Ambient Temperature Reaction under
Dibutyltin Dilaurate (TDL) Catalysis and (b) Polymer
Architectures Employed in the Current Study, where the
Carbamate Linker Is Omitted for Clarity
Scheme 2. Isocyanates Prepared from (a) Carboxylic Acids
via Acyl Azides through Thermal Curtius Rearrangements,
(b) from Amines Using Ambient Temperature Reaction with
Triphosgene and NEt3, and (c) from Statistical Mono-Func-
tionalization of HDI with Alcohols
Scheme 3. Wide Range of Functional End Groups Employed
To Show the Versatility of the Isocyanate-Based Post-
Polymerization Modification of Polymers
are compatible with CRP protocols with no need of (de)-
protection steps. Additionally, anionic ROP typically leads to a
hydroxyl end-group after quenching. Several approaches for the
transformation of hydroxyl-groups after polymerization have been
demonstrated. One example is the one-step conversion of the HO-
group into esters utilizing activated carboxylic acids that can, in
principle, lead to high end-group fidelity.35 Conversion of the
hydroxyl- to an amino end-group in a two step procedure
(typically a Mitsunobu reaction and subsequent hydrazinolysis)
has also been demonstrated36 which allows for the formation of
hydrolytically stable amide-bonds in a subsequent step. In addi-
tion, hydroxyl end-groups can also be converted into leaving
groups37 and subsequently displaced in a SN2 reaction by a
nucleophile. However, multistep postpolymerization reactions are
not only more time-consuming but also have a higher chance of
accumulation of nonreacted end-groups than a one-step procedure.
Isocyanates are well-known to react efficiently with thiols,
amines and alcohols; however, unprotected amino and thiol
groups cannot withstand certain CRP polymerization conditions.
Recently, the “thiolꢀisocyanate conjugation” has been utilized to
modify RAFT polymers after aminolysis to form thiocarbamates.38,39
The rapid reaction of alcohols and isocyanates under tin(II) or
tertiary amine catalysis to form carbamates is well documented.40
It has been largely employed for polyurethane synthesis;41ꢀ44
however, it has been utilized very infrequently for postpolymeriza-
tion modification.45 Herein, the postpolymerization functionaliza-
tion of hydroxyl-group terminated polymers such as poly(ethylene
glycol) (PEG), poly(N-isopropylacrylamide) (PNIPAM), poly-
(dimethylacrylamide) (PDMAM), and poly(tert-butyl acrylate)
(PtBA) with a wide variety of functional aromatic and aliphatic iso-
cyanates is reported (Scheme 1). The procedure was also applied
for thepreparation ofside-chain functional polymersfrom poly(N-
hydroxyethyl acrylamide) (PHEAM)).
Curtius rearrangement (see Scheme 2a). Following this proce-
dure, 2-naphthoic acid, biphenyl-4-carboxyl acid, and 9-anthra-
noic acid were transformed into the corresponding isocyanates
derivatives (see Scheme 3). The amino group of 2-fluorene
amine, 2-anthracene amine, 1-pyrene amine, 4-phenylazophenyl
amine, 2-amino-3-methoxydibenzo[b,d]furan, and 6-methyl-
2-(4-aminophenyl)benzothiazole was converted into an isocya-
nate functionality with the use of triphosgene47 (a solid phosgene
analogue) in an ambient temperature reaction with high yields
(see Scheme 2b). Furthermore, functional units containing a
hydroxyl group can be reacted with an excess of 1,6-hexamethy-
lene diisocyanate (HDI) to form the monofunctional addition
product carrying one remaining isocyanate group for subsequent
reaction as demonstrated for 1-(2-hydroxyethyl)- 10-methyl-
[4,40-bipyridine]-1,10-diium di(hexafluorophosphate) and um-
belliferone (Scheme 2c). In addition, some isocyanates such as
1-naphthyl isocyanate and 2-chloro-ethyl isocyanate are also com-
mercially available. The latter was transformed into 2-iodo-ethyl
’ RESULTS AND DISCUSSION
Isocyanate Preparation. First, the preparation of required
functional aliphatic and aromatic isocyante derivatives from either
carboxylic acids, amines or alcohols as depicted in Scheme 2 is
described. In the past, the laboratory synthesis of isocyanates from
carboxylic acids and amines required the use of the potentially
explosive sodium azide or highly toxic phosgene. Since the
(re)discovery of diphenylphosphoryl azide (DPPA)46 isocya-
nates can be safely prepared from carboxylic acids via thermal
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isocyanate by a Finkelstein reaction prior to reaction with PEG
(see Supporting Information for details of all aforementioned
compounds).
presence of most (in)organic bases impedes standard amide or
ester coupling schemes (see ref 55 and references therein).
Functionalization of Hydroxyl-Terminated Polymers.
With the isocyanate derivatives in hand, the postpolymerization
modification of hydroxyl-terminated polymers was pursued to
obtain end-terminated functional polymers. Typically, 3ꢀ5
equiv of the isocyanate component were employed to drive the
conversion of the hydroxyl end-group to completion. Dibutyltin-
dilaurate (TDL) was employed as a catalyst at ambient tempera-
ture (Scheme 1) in anhydrous dichloromethane (DCM) as a sol-
vent. Anhydrous acetonitrile was usedfor MVHex on account of its
poor solubility in DCM. The excess of isocyanate can be readily
removed by precipitation, washing steps or dialysis depending on
both the type of isocyanate and polymer used (see Supporting
Information).
The chemical structures for the functional units containing an
isocyanate group are shown in Scheme 3. The investigated func-
tional moieties include fluorophores (Pyr, BTP), photoactive chro-
mophores (AzoB), redox-active species/radical traps (such as
MVHex, 2Ant), base/oxidation sensitive species (F0) and chem-
ically modifiable units (such as IEt). Numerous reports have
described the use of azobenzenes and viologens (paraquat) for
light- and redox-switching48ꢀ50 applications, respectively as well
as their participation in hostꢀguest type interactions in supra-
molecular systems.51ꢀ54 Despite their usefulness, viologens are
difficult to conjugate with high efficiency to macromolecules.
The reaction of alkyl halides with 1-methyl-[4,40-bipyridin]-1-
ium in a SN2 fashion have been reported; however, they show
slow kinetics. Moreover, the decomposition of viologen in the
Initially, commercially available monohydroxyl functional poly-
(ethyleneglycol) monomethylether (HO-PEG-OMe) of different
molecular weight (1100, 2000, and 5000 g molꢀ1) was reacted
with variable isocyanate derivatives. Moreover, R,ω- and trifunc-
tional carbamate linked PEG derivatives were also prepared (see
Table 1 and Supporting Information, Tables S1, S2, and S3). The
incorporation of isocyanate derivatives into the polymer was con-
firmed by 1H and 13C NMR spectroscopy. Figure 1a and b depict
the 1H and 13C NMR spectra of fluorene terminated PEGꢀOMe
(2,000 g molꢀ1) as an example. The degree of functionalization
was determined from the 1H NMR spectrum by relative integration
of the well-separated methoxy-end-group (proton ω in Figure 1a)
Table 1. Fluorene (F0) End Group Functionalized Poly-
(ethylene glycol) (PEG) Polymers Prepared from Hydroxyl-
Terminated PEGs by Reaction with F0-NCO
polymer
Mn
(g molꢀ1
)
% functionalization
(1H NMR)a
% functionalization
(ESl-MS)b
architecture
R
2200
5200
2400
1800
>99
98
97.7
c
R
1
to the methylene group (proton c in Figure 1a) the H NMR
R,ω
>99
96.3
97.6
integrationadjacent to the carbamate linkage (signals at 3.39 and
4.47 ppm respectively, in CDCl3). For R,ω and trifunctionalized
PEGs, integration versus the backbone was performed. Table 1
collates the degree of functionalization for the fluorene PEGs
prepared in the current study (the degree of functionalization for
the rest of the materials is presented in Supporting Information,
Tables S1, S2, and S3). Near quantitative conversion is obtained
in all cases with no detectable side products (such as fluorenone).
tri
>99
a Measured by the integration of the methoxy-end group vs the met-
hylene group adjacent to the carbamate linkage for R functional PEG;
integration vs backbone for R,ω and trifunctional PEG (CDCl3).
b Measured by the relative integration of peak for [F0-PEG-OMeþNa]þ
vs [HO-PEG-OMeþNa]þ at same DP for R functional PEG; integra-
tion of [product þ Na]þ vs all [not fully reacted PEG speciesþNa]þ for
R,ω and trifunctional PEG. c not determined.
1
Figure 1. Characterization of F0-PEG-OMe (2000 g molꢀ1) by (a) H NMR, (b) 13C NMR, (c) high-resolution ESI-MS, and (d) GPC. These
methods confirm the high degree of end-group functionalization (>99%) as well as excellent purity of the material, most notably the absence of the
potential oxidation byproduct fluorenone.
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Scheme 4. Synthesis of CTAꢀOH and RAFT Functional
Polymers
Figure 2. 1H NMR (DMSO-d6, 500 MHz) spectra for (a) PNI-
PAMꢀOH and (b) PNIPAMꢀMV.
acrylate respectively in 1,4-dioxane at 70 °C with compound
CTAꢀOH as the RAFT agent and 4,40-azobis(4-cyanopentanoic
acid) (ACPA) as the radical initiator. The hydroxyl group con-
taining CTAꢀOH was synthesized in analogy to previously
reported one-pot procedures in high yield.56
After isolation, all the polymers were analyzed via a combina-
tion of 1H NMR and size exclusion chromatography (GPC). The
GPC traces indicated monomodal and narrow molecular weight
distributions for all the hydroxyl group-terminated polymers (see
Supporting Information) and gave evidence that free hydroxyl
1
groups did not affect radical polymerizations. The H NMR of
PNIPAMꢀOH is shown in Figure 2a as a representative example.
The signals at 4.43 ppm (protons g) clearly revealed the presence
of the benzyl alcohol moiety attached to the polymer chain. More-
over, the spectrum also displayed signals around 3.30 ppm cor-
responding to the resonance protons b of the ethylsulfanylthio-
carbonyl sulfanyl moiety and this verified that compound CTAꢀ
OH allowed for RAFT polymerizations. Having prepared the
hydroxyl group terminated RAFT polymers, the attachment of an
isocyanate-containing moiety was conducted in a similar manner
A calibration curve by standard addition of known amounts of
HOꢀPEGꢀOMe (2000 g molꢀ1) to DBF-PEGꢀOMe (2000 g
molꢀ1) shows a slope close of 1.08 and supports the accuracy of
1
to that described above for the PEG polymers. The H NMR
spectrum of PNIPAMꢀMV is shown in Figure 2b as a represen-
tative example. The incorporation of the MV moiety in the poly-
mer was evidenced by the appearance of signals at approximately
9.3 and 8.8 ppm (signals kꢀn) corresponding to the aromatic
protons of the viologen end-group. Moreover, the signal corre-
sponding to the methylene unit in R position with respect to the
hydroxyl group in PNIPAMꢀOH (signal g in Figure 2) shifted
from 4.50 to 5.00 ppm upon formation of the carbamate linkage.
Different isocyanate derivatives including MVHex, DBF, and
2Ant have been reacted with PNIPAM, PDMAM and (PtBA) as
depicted in Scheme 4 with high yields and end-group fidelity
(Table 2). Details for synthesis of these materials are shown in
the Supporting Information. As such, this approach enables the
direct functionalization of RAFT polymers using highly efficient
isocyanate conjugation chemistry without the need of additional
steps such as deprotection or aminolysis of the CTA. Therefore,
the strategy described above avoided the formation of bypro-
ducts such as disulfides from the aminolysis. Furthermore, as the
CTA was designed to carry the hydroxyl unit at the R-group,
it can be expected that every polymer chain carries the HO-
terminus after RAFT polymerization and is available for functio-
nalization with the isocyanate moiety in the subsequent step.57
1
the H NMR integration (see Figure S1 in the Supporting In-
formation for details). The signals at 154 and 65 ppm in the 13C
NMR spectra (Figure 1b) corresponding to the carbamate car-
bonyl and adjacent methylene group, respectively, gave further
evidence for the fluorene incorporation. Additionally, ESI-MS
experiments further validated the high degree of end-group
conversion and purity of the materials (Table 1 and Supporting
Information, Table S1). Finally, the reaction of (HO-PEG-OMe)
with an excess of 1,6-hexamethylene diisocyanate (HDI) and
subsequent hydrolysis of the isocyanate-end-group allows for a
surprisingly simple conversion into an amino-terminated poly-
(ethylene) glycol. Investigations into the use of the isocyanate-
terminated polymers for polymerꢀpolymer ligations are cur-
rently underway.
Expanding this postpolymerization modification procedure, a
range of hydroxyl-terminated RAFT polymers was functionalized
withrepresentative isocyanate derivatives (Scheme 4). Specifically,
hydroxyl-terminated poly(N,N-dimethylacrylamide) (PDMAM),
poly(N-iso-propyl-acrylamide) (PNIPAM) and poly(tert-butyl
acrylate (PtBA) were obtained via RAFT polymerization of N,
N-dimethylacrylamide, N-isopropylacrylamide and tert-butyl
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Finally, it should be also feasible to use the modified polymer as a
macroinitiator for subsequent polymerization as the CTA re-
mained intact.
Multivalent Side-Chain Functionalization. Further extend-
ing the postpolymerization functionalization protocol developed
above, side-chain functional polymers were synthesized using
RAFT polymerization (Scheme 5). Hydroxyl-functional acryla-
mide monomer, N-hydroxyethylacrylamide was used to prepare
poly(N-hydroxyethylacrylamide) (PHEAm) polymers bearing
hydroxyl groups pendant to the main chain. Using this simple,
commercially available monomer, polymers were obtained with a
high degree of functionality which was subsequently used for
isocyanate conjugation.
Table 2. End Group Functionalized Polymers Prepared from
Hydroxyl-Terminated RAFT Polymers by Reaction with
RꢀNCO
% functionalization
polymer
Mn (g molꢀ1
)
(1H NMR)a
PDIb
Initially a polymer of approximately 5700 g molꢀ1 (DP ∼50)
PHEAm was synthesized according to established procedures
(see Supporting Information). To demonstrate the efficacy of
this method for side-chain functionalization of the polymers,
three of the above-mentioned isocyanates were chosen: 1Np,
2Ant, and MVHex (see Scheme 3). The characterization of the
viologen pendant PHEAmꢀMV polymer is displayed in Figure 3.
Conversion was easily characterized to be a moderate 70% using
1H NMR integration of the appearing aromatic viologen peaks in
the region of 9.3ꢀ8.3 ppm (signals c,c0 and d,d0 in Figure 3b,
bottom). There were also corresponding decreases in the peaks
PNIPAMꢀDBF
PDMAMꢀDBF
PNIPAMꢀMV
PDMAMꢀMV
PtBuAꢀMV
3300
2900
3600
3400
4800
3400
4700
>95
>95
>95
>95
>95
85
1.45
1.52
1.40
1.51
1.32
1.42
1.37
PDMAMꢀ2Ant
PtBuAꢀ2Ant
92
a Measured by relative integration of methylene group adjacent to the
carbamate linkage vs backbone. b From GPC. See Supporting Informa-
tion for details.
Scheme 5. Reaction Scheme for the Preparation of Side-Chain Functional Polymers by Isocyanate Conjugation to a Hydroxy-
Pendant Polymer, Poly(N-hydroxyethylacrylamide) (PHEAm), Prepared by Reversible AdditionꢀFragmentation Chain Transfer
(RAFT) Polymerization
Figure 3. Characterization of P(HEAmꢀMV), shown in (a) by 1H NMR (b) and GPC (c). Comparison of the 1H NMR spectra of the starting polymer
PHEAm (top) and the MVHex conjugated polymer PHEAmꢀMV (bottom) confirms the degree of functionalization (70%). This is supported by the
overlay of GPC traces from the refractive index (RI), UV at 254 nm resulting from the MVHex functionality, and the UV at 312 nm resulting from the
trithiocarbonate end group on the polymer.
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from the methylene protons R and β to the hydroxyl-group
pendant from the chain of the starting material (apparent at
3.6 and 3.3 ppm, signals a and b in Figure 3b, top, respectively).
The aqueous GPC traces in Figure 3c also clearly demonstrated
the conjugation of the MVHex units as there is an overlay of the
refractive index trace with the UVꢀvisible absorbance traces cor-
responding to the remaining trithiocarbonate unit on the poly-
mer (312 nm) and the newly conjugated MVHex unit (254 nm).
It is interesting to note that in this case, although the retention
time of the material in the GPC did not change significantly, the
use of light scattering methods for molecular weight determina-
tion clearly displayed an increase in molecular weight from 5700
to 52 400 g molꢀ1, which is the expected increase for a conver-
sion of 70% as determined by 1H NMR data. An increase in the
polymer polydispersity index (PDI) from 1.17 to 1.55 was also
observed, further supporting the moderate conversion of the
side-chain units. The large increase in the molecular weight of a
monomeric unit bearing the MV functionality and the random
and incomplete distribution of these monomeric units along the
polymer chain leads to the observed increase in polydispersity.
The moderate conversion of the hydroxy-pendant functionality
by conjugation of the MVHex moiety was presumably on account
of the di-ionic nature of MVHex, which prevented high conversion
due to chargeꢀcharge repulsion.
the carbamate is fast and mild and has been shown to be com-
patible with the trithiocarbonate group of the RAFT polymers,
demonstrating compatibility with relatively labile functionality.
In conclusion, we have found that this synthetic route of conju-
gation can add value to the available repertoire of important post-
polymerization functionalization techniques.
’ EXPERIMENTAL SECTION
Materials. Representative Procedure for Route a. Synthesis
of 2-Naphthoyl Azide. 2-Naphthoyl azide was prepared in analogy to
literature procedures. To a stirred suspension of 2-naphthoic acid (3.4 g,
20 mmol) in 150 mL of dry toluene was added triethylamine (3.1 mL,
22 mmol) and DPPA (4.7 mL, 22 mmol). The solution was stirred at
room temperature for 48 h. The solvent was evaporated in vacuum and
the purple residue was purified by chromatography on silica with DCM
to yield the title compound (2.8 g, 16 mmol, 81%) as a white, waxy solid.
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1H), 7.92 (dd, 1H), 7.85
(d, 1H), 7.80ꢀ7.78 (m, 2H), 7.54ꢀ7.45 (m, 2H) ppm.
Synthesis of 2 Np-PEG-OMe (5000 g molꢀ1). A solution of
2-naphthoyl azide (1.2 g, 6.0 mmol) in 30 mL anhydrous o-dichlor-
obenzene was heated to 145 °C for 2 h under nitrogen atmosphere in a
100 mL two-neck RBF, equipped with a reflux condenser. After the
mixture was cooled down to room temperature, poly(ethylene glycol)
5000 monomethyl ether (3.0 g, 0.6 mmol) dissolved in 10 mL of anhy-
drous DCM and a drop of TDL was added at once and the mixture was
stirred for 48 h at room temperature. The product was obtained by pre-
cipitation from cold diethyl ether. The yellowish solid was redissolved in
ca. 30 mL DCM, filtered and reprecipitated in cold diethyl ether (2ꢁ).
Suction filtration yielded 2 Np-PEG-OMe (5000 g molꢀ1) (2.6 g,
0.5 mmol, 85%) as a white solid. 1H NMR (500 MHz, CDCl3: δ = 8.03
(s, 1H), 7.79ꢀ7.77 (m, 3H), 7.45ꢀ7.38 (m, 4H), 4.39 (t, 2H, 4.7 Hz),
(m, PEG backbone), 3.39 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3
δ = 153.4, 135.6, 133.9, 130.1, 128.7, 127.5, 127.4, 126.4, 124.5, 119.2,
114.7, 64.2, 59.0 ppm and PEG backbone signals. The purity was
confirmed by THFꢀGPC.
The conversion for both the 1Np and 2Ant moieties were
determined in an analogous way as similar shifts were observed in
the 1H NMR spectra. The conversion measured for the relatively
unhindered 1Np is very high at 98%, however, as 2Ant is signi-
ficantly more hindered, conversion decreases to a fairly moderate
65%. This would be expected for side-chain functionalization
with such a short linker to the polymer backbone. MVHex yielded
a higher conversion than 2Ant, despite being di-ionic, presumably
because the isocyanate functionality in MVHex is not as sterically
hindered as in the case of 2Ant. GPC analysis could not be directly
correlated before and after conjugation for both of these cases as
the starting PHEAm was characterized with water as the eluent,
while the PHEAmꢀ1Np and PHEAmꢀ2Ant polymers were no
longer water-soluble and were therefore characterized using THF
as the eluent. Although the molecular weights for these polymers
are likely inaccurate as they were determined using polystyrene
standards, the PDI data is informative as the PDI for the 2Ant is
significantly broadened to 1.57 on account of the moderate con-
version, while the PDI for the 1Np was only slightly broadened to
1.22 as the conversion was near quantitative. Similar to MVHex,
both cases displayed an overlay of the refractive index and UVꢀ
visible absorbance traces, verifying conjugation of the functionality
to the polymer backbone.
Representative Procedure for Route b. Synthesis of 2-fluorene-
isocyanate. To a stirred solution of 2-fluorene amine (3.0 g, 17 mmol)
and triethylamine (3.2 mL, 25 mmol) in 150 mL of anhydrous DCM,
kept in an ice-bath, was slowly added triphosgene (5.5 g, 19 mmol) in
several portions. The ice-bath was removed after 1 h and the mixture was
left for stirring at room temperature for 24 h. Purification was achieved
by flash chromatography on silica with DCM to yield the title compound
1
(3.0 g, 15 mmol, 85%) as an off-white solid. H NMR (400 MHz,
CDCl3): δ = 7.64 (d, 1H, 7.6 Hz), 7.60 (d, 1H, 8.1 Hz), 7.44 (d, 1H, 7.5
Hz), 7.31ꢀ7.27 (m, 1H), 7.24ꢀ7.20 (m, 1H), 7.17ꢀ7.16 (m, 1H), 7.01
(dd, 1H, 8.1 Hz, 2 Hz), 3.78 (s, 2H) ppm. 13C NMR (80 MHz, CDCl3):
δ = 145.1, 143.5, 141.2, 139.9, 132.1, 127.4, 127.3, 125.5, 125.0 123.9,
121.9, 121.0, 120.2, 37.2 ppm. FTIR: ν~ = 2250 cmꢀ1 (ꢀNCO).
Synthesis of F0-PEG-OMe (2000 g molꢀ1). To a solution of (0.5 g,
2.2 mmol) 2-fluorene isocyanate and poly(ethylene glycol) 2000
monomethyl ether (1.0 g, 0.5 mmol) in 10 mL of anhydrous DCM
was added a drop of TDL, and the mixture was stirred for 48 h at room
temperature. The product was obtained by precipitation from cold
diethyl ether. The solid was redissolved in ca. 30 mL DCM, filtered and
reprecipitated in cold diethyl ether. Suction filtration yielded F0-PEG-
OMe (2000 g molꢀ1) (0.8 g, 3.6 mmol, 72%) as a white solid. 1H NMR
(500 MHz, CDCl3): δ = 7.75 (s, 1H), 7.73ꢀ7.69 (m, 2H), 7.52 (d, 2H,
7.5 Hz), 7.30ꢀ7.22 (m), 4.38 (t, 2H, 4.6 Hz), 3.90 (s, 2H), 3.80ꢀ3.47
(m, PEG backbone), 3.39 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ = 153.6, 144.4, 143.0, 141.4, 137.2, 137.0, 126.7, 126.1, 124.9, 120.1,
119.4, 117.5, 115.5, 64.2, 59.0, 37.0 ppm and PEG backbone signals.
FTIR: ν~ = 1727 cmꢀ1 (ꢀNH(CO)Oꢀ). The purity was confirmed by
THFꢀGPC.
’ CONCLUSIONS
The postpolymerization functionalization of hydroxyl-func-
tional polymers (both end group and side chain) by hydrolysis-
stable carbamate formation with a wide range of functional
isocyanate derivatives yielding a high degree of conversion was
demonstrated. Three high yielding methods have been employed
to prepare the isocyanates, demonstrating that this method is
amenable for use with a wide variety of commercially available
starting materials. This approach enables the direct functionali-
zation of RAFT polymers without the need of additional steps
such as deprotection or aminolysis of the CTA, producing little
to no side products, which are easily removed using standard
polymer purification techniques. Additionally, the formation of
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Representative Procedure for Route c. Synthesis of MV-
Hex-NCO di(hexafluorophosphate). To a solution of 1-(2-hydro-
xyethyl)-10-methyl-[4,40-bipyridine]-1,10-diium di(hexafluorophosph-
ate) (0.5 g, 1.0 mmol) in 200 mL anhydrous acetonitrile was added excess
1,6-hexamethylene diisocyanate (2 mL) and a drop of TDL. The reaction
mixture was stirred for 24 h at room temperature. (The conversion can be
followed by infrared spectroscopy.) The solvent was evaporated under
reduced pressure to approximately 10 mL, and 200 mL of anhydrous diethyl
ether was added. A sticky, yellowish precipitate formed and the mixture was
stored in the freezer for 30 min. Then the solvent was decanted and the
residue redissolved in a minimum amount of anhydrous acetonitrile. The the
above-described steps were repeated (2ꢁ), and the yellowish, sticky solid
was dried under reduced pressure to yield the title compound (0.6 g, 87%).
1H NMR (500 MHz, DMSO-d6): δ = 9.31 (d, 2H, 6.7 Hz), 9.26 (d, 2H, 6.7
Hz), 8.77 (d, 2H, 6.7 Hz), 8.73 (d, 2H, 6.7 Hz), 7.22 (s, 1H), 4.93 (t, 2H, 4.7
Hz), 4.49 (t, 2H, 4.8 Hz), 4.41 (s, 3H), 3.28 (t, 2H, 6.2 Hz), 2.87 (q, 2H, 6.3
Hz), 1.46 (quin, 2H, 7.2 Hz), 1.35ꢀ1.12 (m, 6H) ppm; 13C NMR (80
MHz, DMSO-d6) δ = 155.3, 149.0, 148.0, 146.7, 146.4, 126.4, 126.1, 121.5,
62.1, 60.4, 48.1, 42.5, 30.4, 29.1, 25.6, 25.5 ppm. FTIR: ~ν = 2267 (-NCO),
1713 (ꢀNH(CO)Oꢀ) cmꢀ1. HRMS:m/zcalcd for [M ꢀ H]þ, 383.2072;
found, 383.2077; calcd for [M þ PF6]þ, 529.1792; found, 529.1797.
Synthesis of MV-Hex-PEG-OMe (5000 g molꢀ1). To a solution of
MVꢀHexꢀNCO di(hexafluorophosphate) (0.5 g, 0.7 mmol) in 20 mL
of anhydrous acetonitrile were added poly(ethylene glycol) 5000
monomethyl ether (1.0 g, 0.2 mmol) and a drop of TDL. The reaction
mixture was stirred for 24 h at room temperature. The solvent was
evaporated under reduced pressure, 100 mL of DCM was added, and the
resulting slurry was sonicated for 5 min. The remaining solid was filtered
off and washed with 100 mL of DCM. The solvent of the combined
organic phases was removed under reduced pressure to yield an off-
white solid. Counterion exchance and further purification can be
achieved by dialysis against 0.5 wt % aqueous sodium chloride solution
(2ꢁ, 12 h) followed by dialysis against deionized water (2ꢁ, 12 h).
Lyophilization yields the title compound as a fluffy, white solid (0.9 g,
0.16 mmol, 80%). 1H NMR (500 MHz, D2O): δ = 9.11 (d, 2H, 6.0 Hz),
9.03 (d, 2H, 6.0 Hz), 8.54 (d, 2H, 6.0 Hz), 8.85 (d, 2H, 6.0 Hz), 4.66 (s,
3H), 4.14 (mc, 2H), 3.79ꢀ3.50 (m, PEG backbone), 3.33 (s, 3H), 2.97
(m, 2H), 2.2ꢀ0.8 (m) ppm. FTIR: ν~ = 1714 cmꢀ1 (ꢀNH(CO)Oꢀ).
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’ ASSOCIATED CONTENT
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S
Supporting Information. Synthetic procedures and
b
characterization for the remaining materials. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Gruendling, T.; Oehlenschlaeger, K. K.; Frick, E.; Glassner, M.;
Schmid, C; Barner- Kowollik, C.; Macromol. Rapid Commun. 2011, 32.
(DOI: 10.1002/marc.201100159).
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: oas23@cam.ac.uk.
(26) Lowe, A. B. Polym. Chem. 2010, 1, 17–36.
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’ ACKNOWLEDGMENT
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F.B. thanks the German Academic Exchange Service (DAAD)
for financial support. C.B.-K. acknowledges continued support
from the Karlsruhe Institute of Technology (KIT) in the context
of the Excellence Initiative for leading German universities, the
German Research Council (DFG) and the ministry of Science
and Arts of the state of Baden-W€urttemberg. J.d.B is grateful for a
Marie Curie Intraeuropean Fellowship. OAS thanks the EPSRC,
the ERC and the Walters-Kundert Trust for financial support.
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