A Simple and Facile Approach to Aliphatic N-Substituted Functional Eight-Membered Cyclic Carbonates and Their Organocatalytic Polymerization

Article abstract of DOI:10.1021/jacs.5b06355

Aliphatic N-substituted functional eight-membered cyclic carbonates were synthesized from N-substituted diethanolamines by intramolecular cyclization. On the basis of the N-substituent, three major subclasses of carbonate monomers were synthesized (N-aryl

Full text of DOI:10.1021/jacs.5b06355

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Article
A Simple and Facile Approach to Aliphatic N-substituted Functional Eight-
Membered Cyclic Carbonates and Their Organo-catalytic Polymerization
Shrinivas Venkataraman, Victor W. L. Ng, Daniel J. Coady, Hans W. Horn, Gavin O Jones,
Tak Shun Fung, Haritz Sardón, Robert M. Waymouth, James L Hedrick, and Yi Yan Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b06355 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 13, 2015
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A Simple and Facile Approach to Aliphatic Nꢀsubstituted Functional EightꢀMembered
Cyclic Carbonates and Their Organoꢀcatalytic Polymerization
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Shrinivas Venkataraman,a Victor W. L. Ng,a Daniel J. Coady,b Hans W. Horn,b Gavin O. Jones,b
Tak Shun Fung,a Haritz Sardon,c Robert M. Waymouth,d James L. Hedrickb* and Yi Yan Yanga*
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a Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore
138669, Singapore
b IBM Almaden Research Center, 650 Harry Road, San Jose, CA 95120, USA
c POLYMAT, University of the Basque Country UPV/EHU Joxe Mari Korta Center, Avda.
Tolosa 72, 20018 DonostiaꢀSan Sebastián, Spain
d Department of Chemistry, Stanford University, Stanford, California 94305, United States
* Corresponding authors:
Tel: 1ꢀ408ꢀ927ꢀ1632; Fax: 1ꢀ408ꢀ927ꢀ3310; Eꢀmail: hedrick@almaden.ibm.com
Tel: 65ꢀ6824ꢀ7106; Fax: 65ꢀ6478ꢀ9084; Eꢀmail: yyyang@ibn.aꢀstar.edu.sg
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Abstract
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Aliphatic Nꢀsubstituted functional eightꢀmembered cyclic carbonates were synthesized from Nꢀ
substituted diethanolamines by intramolecular cyclization. Based on the Nꢀsubstituent, three
major subꢀclasses of carbonate monomers were synthesized (Nꢀaryl; Nꢀalkyl and Nꢀcarbamate).
Organoꢀcatalytic ring opening polymerization (ROP) of eightꢀmembered cyclic carbonates was
explored as a route to access narrowly dispersed polymers of predictable molecular weights.
Polymerization kinetics was highly dependent on the substituent on the nitrogen atom and the
catalyst used for the reaction. The use of triazabicyclodecene (TBD), instead of 1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) as the catalyst for the Nꢀalkyl substituted monomers
significantly enhanced the rate of polymerizations. Computational studies were performed to
rationalize the observed trends for TBD catalyzed polymerizations. With the optimal organoꢀ
catalyst all monomers could be polymerized generating wellꢀdefined polymers within a timespan
of ≤ 2 hours with relatively high monomer conversion ( ≥ 80%) and low molarꢀmass dispersity
(ÐM ≤ 1.3). Both the glass transition temperatures (Tg) and onset of degradation temperatures
(Tonset) of these polymers were found to be Nꢀsubstituent dependent and were in the range of
about – 45 to 35 °C and 230 to 333 °C, respectively. The copolymerization of the eight
membered monomers with 6ꢀmembered cyclic comonomers including commercially available Lꢀ
lactide and trimethylene carbonate, produced novel copolymers. The combination of inexpensive
starting materials, ease of ringꢀclosure and subsequent polymerization makes this an attractive
route to functional polycarbontes.
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Introduction
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The development of facile synthetic approaches to access wellꢀdefined degradable polymers with
diverse functional groups remains a challenge in contrast to wellꢀestablished synthetic techniques
for the formation of nondegradable synthetic polymers (e.g. acrylates) or natural polymers (e.g.
proteins). The ring opening polymerization (ROP) of functional cyclic precursors is a promising
strategy to synthesize wellꢀdefined degradable materials with excellent control over numerous
parameters,1 which could potentially suit various biomedical applications. Tremendous progress
has recently been made in the development of various classes of degradable and, in some cases,
functional polymers2 such as polyesters,3 polyphosphoesters,4 polycarbonates,5 and
polypeptides.6 In spite of these advances, many synthetic approaches suffer from challenges
arising from multiꢀstep routes for the synthesis of monomers or the postꢀfunctionalization of
reactive polymers, often requiring relatively expensive reagents or starting materials. Efficient
and straightforward access to degradable polymers from readily available and inexpensive
precursors will have implications for the synthesis of next generation biocompatible and ecoꢀ
friendly materials.
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Aliphatic cyclic carbonates are an important class of materials7 owing to their biodegradability,
low toxicity, biocompatibility and potential biomedical applications.8 Critically the successful
application of aliphatic polycarbonates in the biomedical field stems from unprecedented ease in
which many desired functionalities can be introduced.5,8 Significant effort has been devoted to
develop facile strategies to incorporate functionality at both the monomer level5,8–28 and postꢀ
polymerization16–23,26,29 by judicious combination of orthogonal coupling chemistries. Ease of
functional group installation coupled with functional group tolerant organoꢀcatalysts30 has
enabled the synthesis of wellꢀdefined polycarbonates that have impacted the medical field.
In our continued efforts towards the development of functional carbonate monomers, we have
explored the use of Nꢀsubstituted diethanolamines (DEAs) as inexpensive and readily available31
starting materials32 for the synthesis and subsequent polymerization of aliphatic Nꢀsubstituted
eightꢀmembered cyclic carbonate monomers. Functional 8ꢀmembered cyclic carbonates were
synthesized via intramolecular cyclization of the 1,5ꢀdiol of Nꢀsubstituted DEAs and
subsequently polymerized via organoꢀcatalytic ROP to access new functional aliphatic
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Nꢀsubstituted polycarbonates. The nucleophilic secondary amine of DEA can be used as a
reactive handle to chemoselectively introduce desired physicoꢀchemical functionalities without
selective protection and deprotection of the hydroxyl groups. More importantly, this approach
will offer a direct route to the synthesis of medium size functional cyclic carbonates, effectively
expanding the range of accessible polycarbonates.
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Results and Discussion
Monomer design and synthesis:
In general for ROP processes, the size of the monomer ring dictates ROP behavior and
importantly offers a unique opportunity to precisely engineer the presentation of functional
groups and their spacing. For example it has been demonstrated that the spacing of pendant
functional groups in peptides influenced numerous properties including their biodegradability.13
To date, functional aliphatic polycarbonates have been synthesized from fiveꢀ to sevenꢀ
membered cyclic carbonates.8 Except for a few reports, functional eightꢀmembered cyclic
carbonates are essentially unexplored.33–35 Feng and coꢀworkers reported that cyclizing Nꢀmethyl
diethanolamine to an 8ꢀmembered cyclic carbonate was not feasible, however they were able to
synthesize 16ꢀmembered cyclic carbonate monomer via thermal depolymerization of low
molecular weight oligomers. These large ring carbonates were shown to undergo enzymatic
polymerization.8,36 Yamada and coꢀworkers reported the synthesis of a number of Nꢀaryl
substituted eightꢀmembered cyclic carbonates in the 1980s;33,34 to the best of our knowledge, the
ROP of these substrates has not been explored. Recently, we reported the antimicrobial gels from
8ꢀmembered monoꢀ and diꢀcyclic carbonate monomers derived from Nꢀmethyl diethanolamine
and N,N,N′,N′ꢀtetrakisꢀ(2ꢀhydroxyethyl)ethylenediamine respectively.35 In order to access a wide
variety of eightꢀmembered cyclic carbonates, we envisioned a simple twoꢀstep approach starting
from DEA (Scheme 1). To demonstrate the feasibility of this approach, we chose a set of diols
(1) that are either commercially available (1a, b and f) or can be readily synthesized from DEA
via alkylation (1c with benzyl bromide), Michaelꢀaddition (1d and 1e with acrylates) or by
reactions with other readily commercially available reagents (1g and 1h). These diols were
successfully cyclized by reacting with either ethylchloroformate or triphosgene in the presence of
base to yield corresponding carbonate monomers (2aꢀh, Scheme 1, Figure S1ꢀS8) in overall
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isolated yields of ~21 – 53 %. As the formation of medium size rings is known to be
synthetically challenging,37 these yields are remarkable considering that no special conditions
such as high dilution were necessary. Collectively, these monomer examples demonstrate that
innumerable functional groups can be reliably introduced at the nitrogen site, including arylꢀ and
alkylꢀsubstituents as well as carbamates, providing access to novel classes of eightꢀmembered Nꢀ
heterocyclic aliphatic cyclic carbonates. It should be noted that latent reactive groups [such as
the protected carboxylic acid (2e), the protected secondary amine (2f) and the allyl group (2h)]
may serve as versatile handles for further chemical manipulation. The ability to access these
functional cyclic monomers with reasonable yield in a stepꢀefficient route from inexpensive and
commercially available precursors is a significant advance.
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Scheme 1. Schematic representation of twoꢀstep approach to access wellꢀdefined aliphatic
functional cyclic carbonate monomers by starting from inexpensive diethanolamine via (1)
chemoꢀselective derivatization of the secondary amine, followed by (2) intramolecular
cyclization to access 8ꢀmembered aliphatic Nꢀsubstituted cyclic carbonate monomers.
Kinetics of polymerization:
Since 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) has been demonstrated as an effective organoꢀ
catalyst (OC) for the ROP of different classes of cyclic monomers, we decided to explore DBU
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as a catalyst to polymerize these cyclic carbonates.30 The polymerization of selected monomers
2a, 2c and 2g with benzyl alcohol (BnꢀOH) as the initiator in the presence of DBU catalyst was
studied at room temperature in dichloromethane (DCM) solvent (1.0 mL) (([M]0 = 0.483 M
Ratio: [BnꢀOH]0 : [DBU] : [M]0 = 1.0 : 1.0 : 20). These monomers were chosen to represent
three major subꢀclasses of Nꢀsubstituents (Nꢀaryl; Nꢀalkyl and Nꢀcarbamate). The kinetics of
polymerization of these monomers was compared to that of trimethylene carbonate (TMC), a
commercially available 6ꢀmembered cyclic carbonate monomer. Dramatic difference in the rate
of polymerization between the monomers was observed (Figure 1AꢀB, closed symbols). Near
quantitative conversion of monomer 2a and 2g was observed in ~2 h, whereas only ~55%
conversion was observed for 2c even after 24 h and almost quantitative monomer conversion for
TMC in ~24 h. The semiꢀlogarithmic kinetic plot for all the monomers was found to be linear
(Figure 1CꢀD, closed symbols; Figure S9), indicating that the rate of polymerization was firstꢀ
order in monomer. Based on the kinetic plot, the following trend was observed for DBU: kobs
(DBU): 2g > 2a > TMC > 2c.
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As TBD has been known to dramatically improve the rates of ROP by serving as an efficient
catalyst,38 the influence of TBD on the polymerization of 2a, 2c and TMC was investigated
under conditions similar to those of DBU ([M]0 = 0.483 M; [BnꢀOH]0 : [TBD] : [M]0 = 1.0 : 1.0
: 20; DCM 1.0 mL). Faster polymerization rates were observed for all the monomers (Figure
1AꢀB, open symbols). Near quantitative conversion of monomer 2a and TMC was observed in <
10 min, whereas ~85 % conversion was observed for 2c after 2 h. The semiꢀlogarithmic kinetic
plot for all the monomers was found to be linear (Figure 1CꢀD, open symbols; Figure S9).
Based on the kinetic plot, the following trend was observed for TBD: kobs (TBD): TMC ~ 2a > 2c.
These results suggest that the OCꢀROP of these functional 8ꢀmembered cyclic carbonates occurs
in a controlled fashion, resulting in polymers with predictable molecular weights. In addition to
the observed dependence on the catalyst for the rates of these reactions (TBD > DBU), the rate
was also found to be highly dependent on the nature of the Nꢀsubstituent; carbonates with Nꢀaryl
substituents were observed to polymerize more rapidly than those from Nꢀalkyl carbonates.
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Figure 1. Kinetics of OCꢀROP of representative functional 8ꢀmembered cyclic carbonates 2a
(squares), 2c (circles) and 2g (triangles) compared to that of TMC (inverted triangles) for DBU
(closed symbols) or TBD (open symbols) as the catalyst: (A) monomer conversion versus time
plot with (B) zoom in showing the earlier time points; (C) semiꢀlogarithmic kinetic plot with (D)
zoom in showing the earlier time points. Conditions: [M]0 = 0.483 M; [BnꢀOH]0 : [M]0 :
[Catalyst] = 1.0 : 20 : 1.0; DCM = 1.0 mL.
Computational studies:
Computational studies were performed in order to understand the basis for the striking difference
in the polymerization kinetics using the computational protocol outlined in the accompanying
Supporting Information. The conformational space of the 8ꢀmembered cyclic monomer 2 (with
the nitrogen atom substituted with a CH3 group as a model for 2cꢀe) was surveyed first. Only
lowꢀlying conformers were considered in our nonꢀexhaustive search. One would expect that 8ꢀ
membered cyclic carbonates possess more conformations than corresponding 6ꢀmembered
carbonates. In addition, inversion of the nitrogen atom in the ring will increase the number of
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possible conformations, although these are expected to be limited by the presence of the rigid
carbonate groups. In all, six conformers were considered (see Figure S10, Supporting
Information). The twisted conformer 2’ (Figure 2) possesses the lowest free energy (by ꢁG ≥ 3.5
kcal/mol) and thus subsequent studies were limited to this conformer. The lowest conformer
found for 2a is also shown in Figure 2.
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2
2’
2a
Figure 2. Lowest energy conformers of the 8ꢀmembered cyclic amino carbonates 2’ and 2a, in
which R1 = CH3 present in 2’ represents a computational model for the functional R1 groups in
2c, 2d and 2e.
A complete computational study of possible ROP mechanisms would involve comparison of the
energies and structures for reactions used in experiments involving the various initiators,
monomers and catalysts. Such a study would be computationally costly and fall beyond the
scope of the present study and was consequently not done. Instead, based on insights from
previous studies on organoꢀcatalytic ringꢀopening polymerizations39–41 (which revealed the
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general reaction pathway shown in Figure 3), we restricted our attention to key stationary points
of the mechanism using CH3OH as a computational model for BnꢀOH, TBD as catalyst and 8ꢀ
membered carbonates 2 and 2’.
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Figure 3. Steps of the preferred ROP reaction pathway between a cyclic carbonate, an initiator
and the bifunctional organoꢀcatalyst TBD; for the ROP of Lꢀlactide, TS1 is the rateꢀlimiting
step39 while for other cyclic esters, both TS1 and TS2 possess comparable barrier heights.42
As illustrated in Figure 3, the ROP reaction starts with the formation of a reactant complex (RC)
in which the alcohol and carbonate are both activated by the TBD catalyst via bifunctional
activation. If the transition state for nucleophilic attack (TS1) is the rateꢀlimiting step of the
ROP, studying the RC might give insights into structural and electronic effects influencing the
observed reactivity trends.
The nitrogen atom present in the 8ꢀmembered carbonates is capable of forming a hydrogen bond
with the NꢀH of TBD, and may thereby disrupt binding of TBD with the alcohol and the
carbonyl group of the carbonate. Hydrogenꢀbonding should be especially pronounced when the
amine is aliphatic as in 2’ and related analogs. Through a nonꢀexhaustive conformational search
of complexes formed by TBD, 2’ and CH3OH we found several complexes that do not lie on the
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preferred pathway for ROP. One of these complexes include the lowꢀlying complex RCd which
is more stable than other predicted reactant complexes RCa, RCb, RCc (Figure 4; 3ꢀdimensional
structures are shown in Figure S10, Supporting Information). Although the differences in free
energy between these adducts are small (∆∆G ≤ 1.3 kcal/mol), to the extent that the TBD catalyst
speciates as intermediates RCb, RCc, and RCd, this would reduce the concentration of the active
TBD catalyst and thereby inhibit the rate of ROP of Nꢀalkyl substituted monomers (such as 2c).
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RCa
RCb
RCc
RCd
∆∆G
+0.5
+0.2
+1.3
0.0
Figure 4. Lowꢀlying complexes formed between TBD, 2’ and CH3OH (for 3ꢀdimensional
structures see Figure S11, Supporting Information). Free energies and relative free energies are
shown in kcal/mol.
In contrast to the Nꢀalkyl substituted 8ꢀmembered carbonates, the Nꢀaryl substituted 8ꢀmembered
carbonates such as 2a should be less capable of accepting Hꢀbonds from TBD since the lone
pairs on the nitrogen atoms are delocalized. The delocalization of the nitrogen lone pair can be
assessed from the outꢀofꢀplane (oop) dihedral angles formed by the three CꢀN bonds involving
the nitrogen atoms for 2a and 2’ relative to those for prototypical sp3 and sp2 hybridized nitrogen
atoms (Table 1). The rather small oop dihedral angle for 2a is due to resonance between the lone
pair on nitrogen and the directly attached aromatic substituent.
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Table 1. Outꢀofꢀplane dihedral angles (oop) formed by the CꢀN bonds involving the nitrogen
atom in the carbonate ring as an indicator of hydrogen bond acceptor strength (for the definition
of the oop angle see Figure S12).
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oop [º]
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sp3 (ideal tetrahedron)
(2’)
(2a)
sp2
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ꢀ12.5
19
0
If the rateꢀlimiting step of the ROP was the opening of the ring (TS2, Figure 3) as observed in
other systems,43 then the differences in the enthalpy of ringꢀopening may also manifest in the
activation energy for ringꢀopening and account for observed differences in reactivity between the
different 8ꢀmembered amino carbonates (e.g. 2’ (a surrogate for 2c) vs. 2a) and 6ꢀmembered
carbonates (e.g. TMC). To this end, we computed isodesmic measures for the enthalpies of ringꢀ
opening44,45 for (2’) and (2a)32,46 and compared them with that of TMC. An exhaustive conformer
search for the products of the isodesmic reactions (see Figures S13 and S14, Supporting
Information)46 was not attempted, instead structures were simply reoptimized.46 These
calculations reveal that the calculated enthalpy of ringꢀopening (ꢁHro) for the three cyclic
carbonates differ significantly (Table 1): ꢁHro = ꢀ6.6 kcal/mol (TMC), ꢀ10.0 kcal/mol (2’) and ꢀ
12.5 kcal/mol (2a). The comparatively more negative enthalpy of ringꢀopening for the Nꢀaryl
substituted carbonate 2a relative to Nꢀalkylated carbonate 2' is likely due to the relaxed
conformations of the ringꢀopened structure which allows the nitrogen to planarize and the N lone
pairs to delocalize into the aromatic ring (Figure S14c, see Supporting Information).47 Similar
trends in the enthalpy of ringꢀopening was observed for the Nꢀaryl and Nꢀalkyl morpholinones
obtained from diethanolamines.32 For the 8ꢀmembered ring DEA carbonates, the relative
magnitudes for the enthalpies of ringꢀopening of the carbonates 2a (ꢀ12.5 kcal/mol) > 2' (ꢀ10.0
kcal/mol) correlate with the faster rate of polymerization of Nꢀaryl 2a relative to Nꢀalkyl 2c.
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Exploration of polymerization conditions:
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The ROP behavior of these monomers was explored in a systematic fashion by using different
organoꢀcatalysts (Scheme 2, Table 2). A targeted degree of polymerization (DP) of ~ 20 was
chosen for the catalyst screening to compare different classes of monomers. These experiments
were carried out to assess the relative polymerizability of different subꢀclasses of monomers,
under comparable conditions. For monomer 2a, wellꢀdefined polymers of different DPn were
readily accessed in 2 h with 5.0 mol % of DBU as catalyst and benzyl alcohol as the initiator (in
relation to monomer; entries 1ꢀ3 in Table 2). By changing the catalyst from DBU to a
combination of DBU/TU or TBD, no major change in the polymerization behavior was
observed, except for an increase in the ÐM for the TBD catalyst (entries 2, 4 and 5). Considering
that TBD polymerizes 2a at a faster rate than both the DBU or DBU/TU catalysts, wellꢀdefined
polymers could be obtained in ~3 min (entry 6). Polymerization can also be initiated with both
small molecule initiators (BnꢀOH) and macroinitiators such as poly(ethylene glycol)
monomethyl ether (entries 2 and 7, respectively). In general, monomer 2a could be polymerized
in the presence of DBU catalyst, exhibiting moderately high to high monomer conversion (~86 –
99 %) within 2h; ÐM were typically below 1.3. Monomer 2b could also be polymerized under
similar conditions (entry 8). DBU polymerizes monomers 2cꢀe well, however the rate of
polymerization was significantly slower in comparison to 2a (entries 9, 10 and 14). TBD
catalyzes the ROP of these monomers more efficiently, and at a significantly faster rate (entries
11 ꢀ 13). For instance, monomer 2e could be polymerized with TBD achieving 71 % monomer
conversion at 2 h, while only 48% monomer conversion was observed for the reaction involving
DBU after 48 h with similar catalysts loading (entries 13 and 14). As for monomers 2fꢀh, the
polymerization proceeded well with DBU as the catalyst, with monomer conversion values
reaching 95 – 98 % after 2 h (entries 15 ꢀ 17); these results are consistent with the kinetics study.
Representative examples showcasing the polymerization of TMC with both DBU and TBD are
also listed for comparison (entries 18 – 21). These results demonstrate that with the optimal
catalyst and polymerization time, the organoꢀcatalyzed ROP of eightꢀmembered cyclic carbonate
occurs in a controlled fashion, yielding high conversion in ≤ 2 h, whilst maintaining relatively
low ÐM (< 1.3).
10
11
12
13
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15
16
17
18
19
20
21
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24
25
26
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52
53
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Preparative experiments targeting a range of molecular weights to generate materials for detailed
characterization are shown in Table 3 (Figure S15ꢀS36). Polymers with DP from 20 to 200 were
targeted, by using an initial monomer concentration of [M]0 = 0.483 M or [M]0 = 0.966 M,
benzyl alcohol as the initiator and 5 mol.% (relative to monomer) of DBU or TBD as the
catalyst. These conditions afforded monomer conversions ranging from 56 ꢀ 99% after two hours
at room temperature. The polycarbonates obtained from monomers 2a, 2b and 2f polymerized
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
with DBU at an initial monomer concentration of [M]0 = 0.966 M exhibited molecular weights of
SEC
Mn
= 10 – 13.5 kDa with ÐM = 1.17 ꢀ 1.25 (entries 4, 7 and 12, Table 3). For these samples,
1
the molecular weights calculated by H NMR endgroup analysis were comparable with that
SEC
predicted from the conversion and ratio of [M]0 / [I]0. However the Mn
values were lower
relative to those determined by endgroup analysis (MnNMR), which could be partly a consequence
of the different hydrodynamic volumes of the polycarbonates relative to the polystyrene
standards. The SEC for these polymers (entries 4, 7 and 12, Table 3, corresponding to Figure
S33, S35 and S36 respectively) exhibit bimodal traces. In contrast, the polycarbonates obtained
SEC
at lower [M]0 = 0.483 M exhibited molecular weights of Mn
= 4 – 5 kDa with ÐM = 1.13 ꢀ
1.23 (entries 2, 3, 13 and 14, Table 3). These molecular weight data are much lower than those
calculated by endgroup analysis (MnNMR) or those predicted from the conversion and ratio of
[M]0 / [I]0. The SEC traces for these polymers exhibit a unimodal peak (Figure S28, S30, S31
and S32). Collectively these data suggest that there are competitive pathways for enchainment
that become evident at [M]0 / [I]0 ratios ≥ 40 and this process is also dependent on the initial
monomer concentration, [M]0. Based on our previous studies, it is likely that at [M]0 / [I]0 ratios
≥ 40, when the concentration of the alcohol initiator [I]0 ≤ 0.01 M, the DBU catalyst can mediate
the ringꢀopening polymerization by two competitive mechanisms to afford a mixture of linear
and cyclic chains.48 DBU and other amidines have been shown to mediate the zwitterionic
polymerization of lactones in the absence of alcohol initiators to yield cyclic polymers.48–50.The
lower molecular weights observed by SEC (MnSEC) at lower monomer and initiator
concentrations are consistent with the formation of a mixture of linear and cyclic chains. In these
cases, the 1H NMR endgroup analysis overestimates the molecular weights (MnNMR) since only a
fraction of the chains are linear with benzyl alcohol endgroups.
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The results of Table 3 indicate that for the generation of higher molecular weight
polycarbonates, higher monomer concentrations are optimal. Nevertheless, for many biomedical
applications, higher molecular weigths are not always advantageous, as higher molecular weight
polymers are less readily cleared. For instance markedly reduced renal clearance was observed
for polymers of molecular weights higher than 20 kDa (for PEG),51 suggesting that the molecular
weights that can be accessed with the ROP of these aliphatic functional Nꢀsubstituted eightꢀ
membered cyclic carbonates could still be well utilized for nanomedicine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Degradable cationic polymers find applications as antimicrobials and also for therapeutics
delivery. Polymers derived from the protected secondary amine containing monomer (2f) would
serve as a platform to acess wellꢀdefined polycations. In order to explore the feasibility of
deprotecting the tBoc groups, a representative polymer (3f) was subjected to acidic conditions for
t
t
1h (~ 20 x molar excess per Boc group 90 vol. % solution in DCM) and over 95% of the Boc
1
groups were found to be deprotected (Figure S37). As per H NMR, no obvious degradation of
the polymer was observed and this might be due to the fact that the deprotection is carried out
under acidic conditions where the deprotected amines get immediately protonated, mitigating the
nucleophilicity of the amino residues. We have observed similar phenomenon with the
deprotection of pendant primary amine containing polycarbonates.9
O
O
O
R2 OH
O
O
O
O
OH
n-1
N
R2
N
R1
N
R1
R1
O
O
Catalyst, DCM, RT
2
3
Catalysts
CF3
N
N
S
N
N
N
H
CF3
N
N
H
H
DBU
TU
TBD
Scheme 2. Organoꢀcatalytic ROP of functional eightꢀmembered cyclic carbonate monomers
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Table 2. Exploration of reaction conditions for the organoꢀcatalyzed ROP of aliphatic functional Nꢀsubstituted eightꢀmembered cyclic
carbonates
6
7
8
9
SECd
Initiator
(I)
Monomer
Cat.
[I]0 : [M]0 :
%
Mn
d
Entrya
Time
ÐM
[C]b
Conv.c
(M)
(C)
(Da)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
BnꢀOH 2a (R1 = Ph)
DBU
DBU
DBU
1 : 10 : 0.5
1 : 20 : 1
1 : 40 : 2
2 h
2 h
2 h
2 h
2 h
3 min
2 h
2 h
2 h
24 h
2 h
2 h
2 h
48 h
2 h
2 h
2 h
2 h
8 h
2 h
86
97
99
95
99
95
92
82
5
57
87
69
71
48
96
98
97
19
65
96
94
2220
4220
7470
3930
2540
2830
10290
3970
700
2340
3310
1950
2840
2900
4790
4270
4330
640
1.07
1.09
1.12
1.10
1.83
1.24
1.14
1.15
1.08
1.21
1.21
1.19
1.33
1.21
1.14
1.13
1.12
1.23
1.19
2.09
1.19
BnꢀOH 2a (R1 = Ph)
BnꢀOH 2a (R1 = Ph)
BnꢀOH 2a (R1 = Ph)
BnꢀOH 2a (R1 = Ph)
BnꢀOH 2a (R1 = Ph)
emPEGꢀOH 2a (R1 = Ph)
BnꢀOH 2b (R1 = Tol)
BnꢀOH 2c (R1 = Bn)
BnꢀOH 2c (R1 = Bn)
BnꢀOH 2c (R1 = Bn)
BnꢀOH 2d (R1 = (CH2)2CO2Me)
DBU : TU 1 : 20 : 1 : 1
TBD
TBD
DBU
DBU
DBU
DBU
TBD
TBD
TBD
DBU
DBU
DBU
DBU
DBU
DBU
TBD
TBD
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
1 : 20 : 1
BnꢀOH 2e (R1 = (CH2)2CO2tBu)
t
BnꢀOH 2e (R1 = (CH2)2CO2 Bu)
BnꢀOH 2f (R1 = tBOC)
BnꢀOH 2g (R1 = EtOC)
BnꢀOH 2h (R1 = AllOC)
BnꢀOH
BnꢀOH
BnꢀOH
BnꢀOH
TMC
TMC
TMC
TMC
1950
2010
2830
2 min
a – All reactions were conducted in DCM (1.0 mL), corresponding to [M]0 = 0.483 M, except for entries 1 and 3 where [M]0 = 0.242
and 0.966 M respectively and the polymers were not purified for additional characterization; b – initiator to monomer ratio roundedꢀ
off to an integer; c – as determined by 1H NMR spectroscopy; d – based on crude sample, uncorrected polystyrene equivalent molar
mass (MnSEC) and molarꢀmass dispersity (ÐM) as determined by SEC with THF as eluent; e – Mn = 5.0 kDa
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Table 3. Sythesis and characterization of Nꢀsubstituted diethanolamineꢀbased aliphatic polycarbonates
5
6
7
8
Cat.
[M]0
conc.
(M)b
Monomer
(M)
Theo
NMR
SEC
[I]0 : [M]0
: [C]0
Conv. Mn
Mn
(Da)e
Mn
(Da)f
Tg
Tonset
Tmax
f
Entry
Polym.
ÐM
a
(C)
(%)c
(Da)d
(° C)g (° C)h (° C)h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
1
2
3
DBU 1: 40 : 2
DBU 1: 100 : 5
DBU 1: 200 : 10 0.483
0.483
0.483
88
95
94
7400
7320
19630
35520
6250 1.12 31.7
5350 1.13 30.8
4890 1.18 31.7
333
ꢀ
ꢀ
363
ꢀ
ꢀ
2a
2a
2a
2a
2b
2b
2b
2c
2d
2e
2f
3aꢀ1
3aꢀ2
3aꢀ3
3aꢀ4
3bꢀ1
3bꢀ2
3bꢀ3
3c
3d
3e
3fꢀ1
3fꢀ2
3g
19790
39070
20210
3560
6300
20900
6040
6620
5920
8430
4
DBU 1: 100 : 5
DBU 1: 20 : 1
DBU 1: 40 : 2
DBU 1: 100 : 5
TBD 1: 40 : 2
TBD 1: 40 : 2
TBD 1: 40 : 2
DBU 1: 40 : 2
DBU 1: 100 : 5
DBU 1: 100 : 5
DBU 1: 100 : 5
0.966
0.483
0.483
0.966
0.966
0.966
0.966
0.483
0.966
0.483
0.483
97
17870 10440 1.25 35.1
ꢀ
ꢀ
5
6
7
8
78
70
94
67
75
56
90
98
3580
5790
3700 1.09 23.0
5150 1.12 26.0
ꢀ
ꢀ
328
ꢀ
357
ꢀ
20090 11550 1.17
ꢀ
5880
6970
6020
8220
2740 1.28 ꢀ 30.4
2930 1.41 ꢀ 45.6
4320 1.41 ꢀ 37.2
7090 1.12 10.2
8.5
4360 1.16 ꢀ 8.6
5010 1.23 ꢀ.
278
230
260
232
ꢀ
308
258
275
245
ꢀ
9
10
11
12
13
14
22770
20220
21410
22650 13600 1.17
19720
19410
2f
2g
2h
> 99
> 99
262
249
285
275
3h
a – All reactions were conducted with benzyl alcohol as the initiator for 2 h and the initiator to monomer ratio roundedꢀoff to an
integer; b – all reactions conducted in DCM at the specified initial monomer concentration; c – as determined by 1H NMR
spectroscopy; d ꢀ MnTheo was calculated based on monomer conversion; e – determined by comparing the relative integral values of
intensities from the initiator (benzyl alcohol) and that of polymer by 1H NMR spectroscopy; f –uncorrected polystyrene equivalent
molar mass (MnSEC) and molarꢀmass dispersity (ÐM) as determined by SEC with THF as eluent; g – glass transition temperature as
determined by DSC based on second heating cycle; h ꢀ the initial temperature at which the polymer starts to degrade (Tonset) and the
temperature at maximum degradation rate (Tmax) were determined by TGA; ꢀ = not determined.
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Evaluation of thermal properties:
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Overlaid thermolytic profiles of diethanolamineꢀbased aliphatic Nꢀsubstituted
polycarbonates.
Differential scanning calorimetry (DSC) was conducted to evaluate the thermal properties of
these Nꢀsubstituted diethanolamineꢀbased aliphatic polycarbonates (Table 3, Figure S38ꢀS49).
The glass transition temperatures (Tg) of these polymers ranged from ~ ꢀ 46 to + 35 °C. The Nꢀ
aryl substituted polymers demonstrated relatively higher Tg compared to the Nꢀcarbamate and Nꢀ
alkyl class of polymers. Nꢀalkyl series demonstrated a relatively low Tg values (~ ꢀ 46 to ꢀ30 °C).
It is interesting to note that in spite of the monomers being structural isomers the Tg values of
polymers 3b and 3c are at least 50 °C apart, underscoring the ability to engineer the physicoꢀ
chemical properties of materials through the design of functional monomers. Thermoꢀ
gravimetric analysis (TGA) was conducted on representative samples to evaluate their thermal
stabilities by heating the polymeric sample from room temperature to 500 °C at 10 °C/min under
N2 atmosphere. The initial decomposition temperature or the temperature at which the material
started to degrade (Tonset) is an important measure of thermal stability of polymer. Tonset was
found to be in the range of 230 – 333 °C (Figure 5 and Table 3), depending on Nꢀsubstitution. A
trend similar to Tonset was observed for temperature at maximum degradation rate (Tmax, in the
range of ~ 245 – 363 °C) (Figure S50 and Table 3). Tonset data for most of the polymers are
comparable to that of reported PTMC values (~ 240 – 260 °C). It is noteworthy that the Nꢀaryl
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substituted class of polymers demonstrated significantly higher thermal stability (Tonset ~ 330
°C).22,52 Also, in comparison to poly(pentamethylene carbonate) (PPMC, Tonset = ~ 331 °C; Tmax
=
358 °C)53, an all carbon analogue of these Nꢀsubstituted diethanolamineꢀbased aliphatic
polycarbonates, most of the polymers demonstrate a relatively lower Tonset and Tmax values,
suggesting that the presence of nitrogen atom in the backbone could be contributing towards
lower thermal stabilities.
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11
12
13
14
15
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17
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19
20
21
22
23
24
25
26
27
28
29
30
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32
33
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Exploration of co-polymerization:
Copolymerization behaviors of selected monomers were also explored to demonstrate the
feasibility of integrating the new class of monomers with some of the existing classes of sixꢀ
membered cyclic esters and carbonates (Figure 6, Table 4). Monomer 2a was found to
copolymerize well with Lꢀlactide (LLA), MTCꢀOBn, and TMCꢀNHtBoc with relatively high and
almost comparable monomer conversion, whilst maintaining a low ÐM (entries 1, 3 and 4 in
Table 4). When the monomer conversion was monitored for the copolymerization of 2a and
LLA, it was evident that the LLA polymerized at a faster rate than 2a (conversion for LLA and
2a at 42 s = 70 and 8 % and at 1 h 7 min = 85 and 76% respectively). These data may indicate
that gradient polymers could be made, but further studies are necessary to characterize the
sequence distributions of these copolymers. The copolymerization of monomer 2a with TMC
(entry 2) and eightꢀmembered cyclic carbonates 2e (entry 5) proceeded with extremely different
polymerization kinetics, resulting in ~ 4 times higher incorporation of monomer 2a as compared
to the comonomer 2e.54 Collectively these copolymerization results highlight the possibilities of
not only accessing unique polymers with wellꢀdefined compositions and low molecular weight
distributions to tailor the physicoꢀchemical properties (such as melting point, glass transition
temperature, rate of degradation, etc.) but also engineering the polymer microꢀstructure (such as
pseudoꢀblock copolymer, gradient copolymer, 54 random copolymer, etc.).
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30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
Figure 6. Structure of selected cyclic monomers used for copolymerization with 2a.
Table 4. Copolymerization of selected cyclic monomers with 2a to access functional copolymers.
%
%
[I]0 : [M1]0 : [M2]0 : [C]b Time Conv. Conv.
(M1)c (M2)c
(SEC)
Initiator
(I)
Monomer
(M1)
Monomer
(M2)
Cat.
(C)
Mnd
Entrya
ÐM
d
1
2
3
4
5
BnꢀOH
BnꢀOH
BnꢀOH
BnꢀOH
BnꢀOH
2a (R1 = Ph)
2a (R1 = Ph)
2a (R1 = Ph)
2a (R1 = Ph)
2a (R1 = Ph)
DBU
DBU
DBU
DBU
DBU
1 : 10 : 10 : 1.0
1 : 10 : 10 : 1.0
1 : 10 : 10 : 1.0
1 : 10 : 10 : 1.0
1 : 10 : 10 : 1.0
2 h
2 h
2 h
2 h
2 h
95
> 99
95
97
81
82
14
96
3890
1.29
1.08
1.14
1.27
1.11
LꢀLactide
TMC
MTCꢀOBn
TMCꢀNHtBoc
2e
2800
4530
3650
2850
> 99
20
a –All reactions were conducted in DCM (1.0 mL), [M]0 = [M1]0 + [M2]0 = 0.483 M and the polymers were not purified for
additional characterization; b – initiator to monomer ratio rounded to integer; c – as determined by 1H NMR spectroscopy; d – based
on crude sample, uncorrected polystyrene equivalent molar mass (MnSEC) and molarꢀmass dispersity (ÐM).
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Conclusion
5
6
7
8
9
In summary, we have reported a straightforward route to acess functional eightꢀmembered
aliphatic cyclic carbonates by starting from DEAꢀbased precursors. Commercial availability of
numerous Nꢀsubstituted derivatives of DEA and straightforward chemoꢀselective derivatization
of DEA with readily available reagents including alkyl halide and acrylates, renders this
approach attractive for the facile development of novel functional monomers. Organoꢀcatalytic
ring opening polymerization of these carbonate monomers proceeded with excellent control,
paving access to wellꢀdefined functional polymers with predictable molecular weights and low
molarꢀmass dispersity. Depending upon the nature of Nꢀsubstitution, polymerization kinetics of
these monomers was found to vary from ~2 h to > 48 h. Through computation we rationalized
the reactivity trend for the organoꢀcatalytic ROP of the Nꢀsubstituted cyclic monomers with
TBD. ROP is promoted by the ability of TBD to form Hꢀbonding interactions with the alcohol
and the carbonyl group on the monomer. Aromatic substituents disrupt competing Hꢀbonding
interactions involving the amine in the ring, while aliphatic substituents do not. The glass
transition temperatures and thermolytic behavior of these polymers were found to be tunable
with the choice of Nꢀsubstituent. These monomers can also be copolymerized with other
monomers, including commercially available Lꢀlactide and trimethylene carbonates. Facile
synthesis and the degradable nature of these materials render them attractive for applications in
the biomedical field.
10
11
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13
14
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42
43
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50
51
52
53
54
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57
58
59
60
Acknowledgement
This work was funded by the Institute of Bioengineering and Nanotechnology (Biomedical
Research Council, Agency for Science, Technology and Research, Singapore), and IBM
Almaden Research Center, U.S.A. R. M. W. and J. L. H acknowledge the the National Science
Foundation (GOALI CHEꢀ1306730) for support. We thank Andy Tek (IBM) for the DSC
studies. Yugen Zhang (IBN) and Diane S. W. Lim (IBN) are gratefully acknowledged for the
scientific discussion.
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Supporting Information
5
6
7
8
1
Experimental details, computational details, FTIR, Hꢀ and 13CꢀNMR spectra of all monomers
and representative polymers, representative SEC chromatograms, processed TGA and DSC
curves.
9
10
11
12
13
14
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16
17
18
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