A simple and efficient synthesis of functionalized cyclic carbonate monomers using a versatile pentafluorophenyl ester intermediate

Article abstract of DOI:10.1021/ja105332k

An improved two-step synthetic route to functionalized cyclic carbonate monomers that features a novel cyclic carbonate intermediate with an active pentafluorophenyl ester group (MTC-OPhF₅) has been developed. The versatile pentafluorophenyl ester intermediate can be synthesized on the gram to kilogram scale in one high-yielding step and is easy to store and handle on the benchtop. The active pentafluorophenyl ester of MTC-OPhF₅ is amenable to further substitution with suitable nucleophiles such as alcohols and amines to generate functionalized cyclic carbonates in high yields. The substitution reaction is tolerant of a wide variety of functionalities, including various hydrophobic and hydrophilic groups, reactive functionalities (via thiol-ene click chemistry or alkyl halides), and protected acids, alcohols, thiols, and amines. In view of the ever-increasing need for biodegradable and biocompatible polymers, this new methodology provides a simple and versatile platform for the synthesis of new and innovative materials.

Full text of DOI:10.1021/ja105332k

Published on Web 09/30/2010
A Simple and Efficient Synthesis of Functionalized Cyclic Carbonate
Monomers Using a Versatile Pentafluorophenyl Ester Intermediate
Daniel P. Sanders,*,† Kazuki Fukushima,† Daniel J. Coady,† Alshakim Nelson,† Masaki Fujiwara,‡
Manabu Yasumoto,‡ and James L. Hedrick*,†
IBM Almaden Research Center, 650 Harry Road, San Jose, California 95120, United States, and Central Glass
International, Inc., 650 Harry Road, San Jose, California 95120, United States
Received June 17, 2010; E-mail: dsand@us.ibm.com; hedrick@almaden.ibm.com
Scheme 1. Reported Synthetic Routes to Functionalized Cyclic
Carbonate Monomers
Abstract: An improved two-step synthetic route to functionalized
cyclic carbonate monomers that features a novel cyclic carbonate
intermediate with an active pentafluorophenyl ester group (MTC-
OPhF5) has been developed. The versatile pentafluorophenyl
ester intermediate can be synthesized on the gram to kilogram
scale in one high-yielding step and is easy to store and handle
on the benchtop. The active pentafluorophenyl ester of MTC-
OPhF5 is amenable to further substitution with suitable nucleo-
philes such as alcohols and amines to generate functionalized
cyclic carbonates in high yields. The substitution reaction is
tolerant of a wide variety of functionalities, including various
hydrophobic and hydrophilic groups, reactive functionalities (via
thiol-ene click chemistry or alkyl halides), and protected acids,
alcohols, thiols, and amines. In view of the ever-increasing need
for biodegradable and biocompatible polymers, this new meth-
odology provides a simple and versatile platform for the synthesis
of new and innovative materials.
alization step. Finally, the use of phosgene to install the cyclic
carbonate suffers from its toxicity and labor intensity (e.g., reactions
are performed at -78 °C with exhaustive workups). The use of
phosgene alternatives, such as various chloroformates, nitro-substituted
diphenylcarbonates, and carbonyl diimidazole,5-8 suffers from un-
wanted side reactions, low reactivity, or difficult workups.
The lack of a simple and efficient synthetic route to functionalized
cyclic carbonate monomers constitutes a significant barrier to the
widespread practical application of this cyclic monomer platform
in the production of tailored functional biodegradable polymers.
In particular, a versatile synthetic scheme based on a common
intermediate would be beneficial.
Aliphatic polycarbonates and polyesters have received consider-
able attention as biocompatible materials for drug delivery, polymer-
based therapeutics, and imaging contrast agents.1 Suitable polymers
can be prepared by ring-opening polymerization (ROP) of cyclic
carbonates or cyclic esters by cationic, anionic, coordination-
insertion, organocatalytic, and enzymatic methods.2 In order to
expand their versatility, access to cyclic monomers having a wide
variety of functional groups in a simple and cost-effective manner
is essential. While functionalized cyclic esters have been reported,
steric and ring-strain issues have limited the utility of this approach.3
Alternatively, many groups have focused on functionalized cyclic
carbonate monomers4 derived from 1,3-diols.
Scheme 2. General Synthetic Route to Functionalized Cyclic
Carbonate Monomers Using Pentafluorophenyl Ester Intermediate 1
A number of synthetic pathways for the preparation of func-
tionalized cyclic carbonates starting from 2,2-bis(hydroxymethyl)-
propionic acid (bis-MPA) have been reported (see Scheme 1). The
most direct synthetic route involves functionalization of the
carboxylic acid group under acidic or basic conditions prior to
installation of the cyclic carbonate (path A).5 Alternate pathways
B and C enable coupling of more sensitive functional groups via
more tedious and complicated protection/deprotection schemes. In
path B, the free carboxylic acid must be activated, typically by use
of dicyclohexylcarbodiimide or conversion to the acyl chloride, prior
to reaction with an alcohol or amine nucleophile.6 In path C, the
diols are protected (commonly as an acetonide) prior to function-
alization of the carboxylic acid.7 Unfortunately, these reported
schemes do not employ a common intermediate for the function-
Scheme 2 shows an improved two-step synthetic route to
functionalized cyclic carbonate monomers that features a novel
cyclic carbonate intermediate with an active pentafluorophenyl ester
group, MTC-OPhF5 (1). In contrast to an N-succinimidyl ester
variant reported by Zhou et al.,9 the versatile intermediate 1 and
† IBM Almaden Research Center.
‡ Central Glass International, Inc.
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14724 J. AM. CHEM. SOC. 2010, 132, 14724–14726
10.1021/ja105332k  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Ring-Opening Polymerization of Selected Monomers
To Form Functionalized Polycarbonates 3
its ethyl analogue ETC-OPhF5 (see the Supporting Information)
are easily synthesized on the gram to kilogram scale in one high-
yielding step. Reaction of bis-MPA with 2 equiv of commercially
available bis(pentafluorophenyl)carbonate (PFC) results in the one-
pot transformation of the carboxylic acid into a pentafluorophenyl
ester group and ring-closure of the 1,3-diol to generate a cyclic
carbonate (see the Supporting Information for individual model
reactions). Intermediate 1 is easy to store and handle on the
benchtop, and its active pentafluorophenyl ester group can be
reacted with suitable nucleophiles such as alcohols and amines to
generate functionalized cyclic carbonates in high yields.
Table 1. Polymerization of Functionalized Cyclic Carbonates
polymer
monomer
initiator
[M]/[I]
Mn (g/mol)
PDI
yield (%)
As opposed to phosgene, PFC is a crystalline solid that is easy
to handle and store. Ring closure of the 1,3-diol with PFC requires
a catalyst such as CsF to affect the ring closure without facilitating
concomitant polymerization. THF was found to be the most
effective solvent, likely because of the partial solubility of the CsF,
although acetonitrile was effective as well. During the initial stages
of the reaction, a significant amount of gas, presumably carbon
dioxide from formation of the pentafluorophenyl ester, was evolved
with a slight exotherm (∼5 °C). Upon completion (∼20 h), the
reaction mixture was concentrated and redissolved in methylene
chloride, where the much of the pentafluorophenol byproduct
precipitated and could be recovered. The product was then rinsed
with saturated aq. NaHCO3 then water, dried over MgSO4, and
concentrated. The crude product was recrystallized from an ethyl
acetate/hexane (1:1) mixture to afford 1 as a white crystalline
powder in 75% yield. The structure of MTC-OPhF5 was confirmed
by 13C, 1H, and 19F NMR spectroscopy as well as mass spectrometry.
A large number of functional carbonate monomers are easily
prepared by the direct reaction of the common intermediate 1 with
various nucleophiles. A series of alcohols and amines were surveyed
to generate monomers 2a-o (Figure 1) with a wide range of
functional groups, including various hydrophobic and hydrophilic
groups, reactive functionalities (via thiol-ene and triazole click
chemistry or alkyl halides), and protected acids, alcohols, thiols,
and amines. As before, the concern is accomplishing the function-
alization without opening the ring or effecting polymerization. Use
of weaker nucleophiles such as alcohols required a catalyst such
as CsF to facilitate the reaction. Selective reaction of amines with
the pentafluorophenyl ester group was accomplished without the
use of a catalyst by lowering the reaction temperature. This
transformation was accomplished in nearly quantitative conversions
with minimal, if any, carbonate ring opening.
3a
3b
3c
3d
3e
3f
2a
2b
2f
2g
2i
Bn-MPA
Bn-MPA
Bn-MPA
Bn-MPA
Bn-MPA
pyrenebutanol
108
54
102
101
99
17100
11500
4400
7300
6600
1.27
1.26
1.32
1.42
1.24
1.32
86
76
64
84
60
71
2o
63
10500
yl)phenyl)-3-cyclohexyl-2-thiourea(TU)and1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) to generate polymers 3a-f with predictable
molecular weights and narrow polydispersities (Scheme 3 and
Table 1).
In conclusion, we have reported a novel two-step synthesis that
enables a broad range of functionality to be incorporated into cyclic
carbonate monomers using a common and versatile pentafluorophe-
nyl ester intermediate. Subsequent polymerizations of the various
cyclic carbonates have demonstrated fidelity and control consistent
with previous reports6b and thus will permit higher-order architec-
tures (such as cross-linking, block copolymers, graft polymers, etc.)
to be constructed. In view of the ever-increasing need for
biodegradable and biocompatible polymers, along with new break-
throughs in self-assembly and nanotechnology, it is envisioned that
this improved route to functionalized cyclic carbonates will provide
a synthetically facile platform for the synthesis of new and
innovative materials, including a new class of polymeric activated
esters.9,10
Acknowledgment. The authors acknowledge Perstorp (Sweden)
for the generous supply of bis-MPA.
Supporting Information Available: Synthetic procedures and
characterization data for pentafluorophenyl ester 1, functionalized
cyclic carbonates 2, and functionalized polycarbonates 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Jerome, C.; Lecomte, P. AdV. Drug DeliVery ReV. 2008, 60, 1056. (b)
Andronova, N.; Albertsson, A. C. Biomacromolecules 2006, 7, 1489. (c)
Kricheldorf, H. R.; Rost, S. Macromolecules 2005, 38, 8220. (d) Albertsson,
A.-C.; Varma, I. K. Biomacromolecules 2003, 4, 1466. (e) Feng, J.; He,
F.; Zhuo, R. Macromolecules 2002, 35, 7175.
(2) For recent reviews, see: (a) Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.;
Waymouth, R. M. Macromolecules 2010, 43, 2093. (b) Kobayashi, S.
Macromol. Rapid Commun. 2009, 30, 237. (c) Dove, A. P. Chem. Commun.
2008, 6446. (d) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.;
Lohmeijer, B. G. G.; Hedrick, J. L. Chem. ReV. 2007, 107, 5813. (e)
Coulembier, O.; Degee, P.; Hedrick, J. L.; Dubois, P. Prog. Polym. Sci.
2006, 31, 723. (f) Matsumura, S. AdV. Polym. Sci. 2006, 194, 95. (g) Varma,
I. K.; Albertsson, A.-C.; Rajkhowa, R.; Srivastava, R. K. Prog. Polym.
Sci. 2005, 30, 949. (h) Stridsberg, K. M.; Ryner, M.; Albertsson, A.-C.
AdV. Polym. Sci. 2002, 157, 41. (i) Endo, T.; Shibasaki, Y.; Sanda, F. J.
Polym. Sci., Part A: Polym. Chem. 2002, 40, 2190. (j) Mecerreyes, D.;
Jerome, R.; Dubois, P. AdV. Polym. Sci. 1999, 147, 1.
(3) For recent reviews of functionalized cyclic esters for ROP, see: (a) Pounder,
R. J.; Dove, A. P. Polym. Chem. 2010, 1, 260. (b) Bourissou, D.; Moebs-
Sanchez, S.; Martin-Vaca, B. C. R. Chimie 2007, 10, 775. (c) Lou, X.;
Detrembleur, C.; Jerome, R. Macromol. Rapid Commun. 2003, 24, 161.
(4) Rokicki, G. Prog. Polym. Sci. 2000, 25, 259.
(5) (a) Weilandt, K. D.; Keul, H.; Hocker, H. Macromol. Chem. Phys. 1996,
197, 3851. (b) Al-Azemi, T. F.; Bisht, K. S. Macromolecules 1999, 32,
Figure 1. Functionalized cyclic carbonates 2 synthesized from 1.
Selected functionalized carbonate monomers were polymerized
using a catalyst system6b comprising 1-(3,5-bis(trifluorometh-
9
J. AM. CHEM. SOC. VOL. 132, NO. 42, 2010 14725

C O M M U N I C A T I O N S
6536. (c) Storey, R. F.; Mullen, B. D.; Melchert, K. M. J. Macromol.
Sci., Pure Appl. Chem. 2001, A38, 897. (d) Liu, Z.-L.; Zhou, Y.; Zhuo,
R.-X. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 4001. (e) Lu, C.;
Shi, Q.; Chen, X.; Lu, T.; Xie, Z.; Hu, X.; Ma, J.; Jing, X. J. Polym.
Sci., Part A: Polym. Chem. 2007, 45, 3204. (f) Hu, X.; Chen, X.; Xie, Z.;
Liu, S.; Jing, X. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 5518. (g)
Xie, Z.; Hu, X.; Chen, X.; Sun, J.; Shi, Q.; Jing, X. Biomacromolecules
2008, 9, 376.
F.; Tan, J. P. K.; Yang, Y. Y.; Waymouth, R. M.; Hedrick, J. L.
Biomacromolecules 2008, 9, 3051.
(7) (a) Al-Azemi, T. F.; Bisht, K. S. Polymer 2002, 43, 2161. (b) Mullen,
B. D.; Tang, C. N.; Storey, R. F. J. Polym. Sci., Part A: Polym. Chem.
2003, 41, 1978.
(8) Senet, J.-P. G. Sci. Synth. 2005, 18, 321.
(9) Zhou, Y.; Zhuo, R.-X.; Liu, Z.-L. Macromol. Rapid Commun. 2005, 26,
1309.
(6) (a) Goodwin, A. P.; Lam, S. S.; Fre´chet, J. M. J. J. Am. Chem. Soc. 2007,
129, 6694. (b) Pratt, R.; Nederberg, F.; Waymouth, R. M.; Hedrick, J. L.
Chem. Commun. 2008, 114. (c) Fukushima, K.; Pratt, R. C.; Nederberg,
(10) Theato, P. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 6677.
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