Organocatalytic ring-opening polymerization of morpholinones: New strategies to functionalized polyesters

Article abstract of DOI:10.1021/ja503830c

The oxidative lactonization of N-substituted diethanolamines with the Pd catalyst [LPd(OAc)]₂²⁺[OTf^-]₂ generates N-substituted morpholin-2-ones. The organocatalytic ring-opening polymerization of N-acyl morpholin-2-ones occurs readily to generate functionalized poly(aminoesters) with N-acylated amines in the polyester backbone. The thermodynamics of the ring-opening polymerization depends sensitively on the hybridization of the nitrogen of the heterocyclic lactone. N-Acyl morpholin-2-ones polymerize readily to generate polymorpholinones, but the N-aryl or N-alkyl substituted morpholin-2-ones do not polymerize. Experimental and theoretical studies reveal that the thermodynamics of ring opening correlates to the degree of pyramidalization of the endocyclic N-atom. Deprotection of the poly(N-Boc-morpholin-2-one) yields a water-soluble, cationic polymorpholinone.

Full text of DOI:10.1021/ja503830c

Communication
pubs.acs.org/JACS
Organocatalytic Ring-Opening Polymerization of Morpholinones:
New Strategies to Functionalized Polyesters
Timothy R. Blake and Robert M. Waymouth*
Department of Chemistry, Stanford University, Stanford, California 94306, United States
S
* Supporting Information
growth synthesis;28,29,31 herein we report the oxidative
ABSTRACT: The oxidative lactonization of N-substi-
tuted diethanolamines with the Pd catalyst [LPd-
(OAc)]22+[OTf−]2 generates N-substituted morpholin-2-
ones. The organocatalytic ring-opening polymerization of
N-acyl morpholin-2-ones occurs readily to generate
functionalized poly(aminoesters) with N-acylated amines
in the polyester backbone. The thermodynamics of the
ring-opening polymerization depends sensitively on the
hybridization of the nitrogen of the heterocyclic lactone.
N-Acyl morpholin-2-ones polymerize readily to generate
polymorpholinones, but the N-aryl or N-alkyl substituted
morpholin-2-ones do not polymerize. Experimental and
theoretical studies reveal that the thermodynamics of ring
opening correlates to the degree of pyramidalization of the
endocyclic N-atom. Deprotection of the poly(N-Boc-
morpholin-2-one) yields a water-soluble, cationic poly-
morpholinone.
lactonization of substituted diethanolamines and the organo-
catalytic ring-opening polymerization of the resulting morpho-
lin-2-ones to generate a new class of functionalized poly-
(aminoesters).
Diethanolamines are a readily available class of industrial
chemicals.35 The catalytic oxidative lactonization of diethanol-
amines with the cationic Pd complex [(neocuproine)Pd-
(OAc)]2(OTf)2 120,36 affords the corresponding morpholin-2-
ones in isolated yields of 54%−76%. The oxidative cyclization
with 1 is tolerant of a variety of functionalized amines, and the
oxidative lactonization of the N-Boc diethanolamine was carried
out on a 2.0 g scale (Scheme 1).
Scheme 1. Synthesis and Oxidative Lactonization of
Substituted Diethanolamines
he synthesis of biodegradable synthetic polymers that
Tmimic the rich functional diversity of natural polymers is a
formidable challenge.1−3 Functionalized polyesters1−4 and
polycarbonates5,6 are an attractive class of artificial biopol-
ymers,7 biomedical materials,8,9 and functional materials that
can readily degrade in the environment.10,11 The ring-opening
polymerization of functional monomers is an attractive
synthetic strategy for the synthesis of these materials,1−4
despite the challenges1,2,12 encountered in developing expe-
dient synthetic methods6,13−16 to the requisite monomers.
We seek new catalytic strategies to generate functionalized
lactones17−23 or carbonates.24 The catalytic oxidative lactoniza-
tion of diethylene glycol is one of the major strategies for
generating dioxanone (1,4-dioxan-2-one, DX),17 an important
monomer for the generation of degradable poly(etheresters).25
The oxidative lactonization of substituted diethanolamines with
Ru,18,19,22 Pd,20 or Au21 catalysts provides an expedient
synthesis of N-substituted morpholin-2-ones, but little is
known regarding the ring-opening polymerization of these
lactones. The ring-opening polymerization of the related 2,5-
morpholinediones is known.26 The organocatalytic ring-open-
ing polymerization of N-substituted morpholin-2-ones would
provide a general strategy to prepare a family of functionalized
poly(aminoesters). Biodegradable poly(aminoesters) contain-
ing amines in the polymer backbone27−31 or as pendant
groups32 are an attractive class of biomedical materials,33
particularly for drug and gene delivery,28−30 or as antimicrobial
agents.34 Poly(aminoesters) are typically generated by step-
The organocatalytic ring-opening polymerization of four
morpholin-2-ones was investigated with 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD)37 and the 1,8-diazabicycloundec-7-
ene/thiourea (DBU/TU) catalyst systems38,39 (Scheme 1,
Table 1). Polymerizations were carried out at rt in toluene
solution with an alcohol initiator and catalyst loadings of 0.5−2
mol % (Table 1). Dichloromethane can also be used as a
solvent for the polymerization of MBoc, but in this solvent the
monomer conversions were lower. As previously observed,40
the DBU/TU system was less active than the guanidine TBD
for the ring-opening polymerization of MBoc, but yielded
narrower molecular weight distributions (Table 1, entries 1−4).
The organocatalytic ring-opening polymerization of morpholi-
nones MBoc and MODec in toluene proceeded to 84%−90%
conversion at rt, but the morpholinones MBn and MPh did not
Received: April 16, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja503830c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Organocatalytic Ring-Opening Polymerization of Morpholinones
b
c
entry
morpholinone
cat.
[M]:[I]:[C]
100:1:1
time/min
conv.
Mn
Mw/Mn
1
2
3
4
5
6
7
8
MBoc
DBU/TU
DBU/TU
TBD
360
360
5
87%
86%
86%
66%
90%
88%
0%
14.2
22.6
8.6
1.07
1.07
2.02
1.32
1.26
1.45
−
200:1:1
100:1:1
TBD
100:1:1 (CH2Cl2)
100:1:1
20
5.9
d
d
MODec
DBU/TU
TBD
1080
20
10.8
10.9
−
100:1:1
MBn
MPh
TBD
100:1:1
1080
1080
TBD
100:1:1
0%
−
−
a
b
c
d
Conditions: Monomer 1 M in toluene, 25 °C. [Monomer]:[ROH]:[catalyst]. Mn (kDa) determined in THF by PS calibrated GPC. Mn
determined in CHCl3 by PS calibrated GPC.
polymerize at all under similar conditions, even with the more
active TBD catalyst.
The ring-opening polymerization of the morpholinone MBoc
with DBU/TU in toluene exhibits the features of a living
polymerization: the molecular weight increases linearly with
conversion, the molecular weight distributions remain below
Mw/Mn ≤ 1.12 to high monomer conversion (≤87%), and the
decay in monomer concentration follows first-order kinetics.
Nevertheless, in toluene at rt, we observed no further monomer
conversion when the concentration of monomer approached
0.13 M (see Figures S7−S9, Supporting Information (SI)),
indicative of an approach to equilibrium.
Figure 1. Geometry at N for MBn (left) and MBoc (right).
degree of pyramidalization of the endocyclic N-atom, with the
energetics of ring opening. The enthalpies of ring opening were
calculated for a model ring-opening reaction with methyl
acetate (eq 1).44,45
The equilibrium monomer concentration for the polymer-
ization of MBoc was determined from both polymerization and
depolymerization experiments in the presence of TBD and
resulted in a final monomer concentration of [M]f = 0.13 M for
MBoc in toluene at 25 °C. When the same experiments were
carried out in dichloromethane, we measured [M]f = 0.35 M for
monomer MBoc, indicating that the nature of the solvent has a
significant influence on the thermodynamics of ring opening.41
The enthalpies of ring opening were determined for the ring-
opening polymerization of MBoc in C6D6. As the morpholin-2-
ones MBn and MPh do not polymerize, we investigated the ring
opening of MBn and MPh with CD3OD to yield the
corresponding methyl ester.42 Thus, while the relative ΔH°’s
of MBoc and MBn/MPh cannot be directly compared, these
experiments provide a means of comparing the relative
thermodynamic preferences of the morpholinones to undergo
ring opening in the presence of an alcohol.42
The results of these experiments (see Table S2, SI) reveal
that the enthalpy of polymerization for MBoc (ΔH°p= −4.8
0.3 kcal/mol) is larger than the enthalpies for the ring
opening of MPh (ΔH°ro(MPh) = −1.7 0.2 kcal/mol) and MBn
(ΔH°ro(MBn) = −1.1 0.1 kcal/mol) to give the methyl ester,
indicating that these latter two morpholinones are less
susceptible to ring opening. The low enthalpies of ring opening
for MBn and MPh are consistent with the low reactivity observed
for ring-opening polymerization.41
These calculations suggest that the enthalpies of ring opening
of morpholin-2-ones containing acylated N-atoms, MBoc
43
(ΔHcalc = −9.3 kcal/mol) and MOBut (ΔHcalc = −9.4 kcal/
mol), are more negative than those containing aryl MPh (ΔHcalc
= −8.7 kcal/mol) or alkyl-substituted MBn (ΔHcalc = −4.9 kcal/
mol) N-atoms.
Notably, while the experimental estimate for the enthalpy of
ring opening of the N-aryl morpholinone MPh with methanol to
generate the methyl ester is only ΔHro,MeOH = −1.7 kcal/mol,
the calculated enthalpy of ring opening of MPh (eq 1) is
intermediate to that of MBoc and MBn. This suggested to us that
MPh might be induced to copolymerize with the reactive MBoc
morpholinone. Copolymerization of MBoc and MPh results in
partial incorporation of MPh to yield a random polymer. In
contrast, the attempted copolymerization of MBoc and the N-
alkyl MBu showed no incorporation of the alkyl-substituted
morpholinone MBu (see Figures S1, S2, SI). This result is
consistent with the intermediate pyramidalization and ring-
opening enthalpy of MPh.
These findings provide important insights into the structural
factors that contribute not only to the thermodynamics of ring
opening polymerization reactions but also to lactonization and
other cyclization reactions.46 In particular, our experimental and
theoretical studies suggest that the ring-opening polymerization
of morpholin-2-ones is a general strategy to poly(aminoesters),
provided that the nitrogen is acylated.
DFT calculations (Gaussian 09, M06-2X DFT hybrid
functional, 6-311+G(d,p) basis set with the CPCM solvent
model in toluene) provided further insights. Geometry
43
optimizations of morpholinones MBoc, MOBut
,
MBn, and MPh
revealed significant differences in the conformations of the
lactone heterocycles. The N-atoms of N-alkyl or N-aryl MBn
and MPh are pyramidalized (Figure 1, left), whereas those of the
N-acyl MBoc and MOBu are typical of planar amides (Figure 1,
right).
A significant result of these calculations was a correlation
between the structure of the morpholin-2-ones, in particular the
The poly(morpholin-2-ones) generated from monomer MBoc
are soluble in organic solvents (THF, toluene, CH2Cl2, CHCl3)
and were isolated in yields 74%−77% as white solids after
dialysis in methanol to remove catalyst residues and the
monomer. The polymers generated from MODec were isolated
in yields of 77%−83% as white solids and are soluble in DCM
B
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Journal of the American Chemical Society
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The acid-catalyzed deprotection of the polymer derived from
MBoc (p(MBoc), (Mn = 10 800, Mn/Mw = 1.14, degree of
polymerization = 89) was carried out with trifluoroacetic acid
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remaining in solution for 48 h at rt (see Figure S6, SI).
In summary, we have shown that the oxidative lactonization
of diethanolamines and the organocatalytic ring-opening
polymerization of N-acyl substituted morpholin-2-ones provide
a general strategy to functionalized poly(aminoesters).
Experimental and theoretical studies reveal that the thermody-
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sensitively on the substituents of the endocyclic N-atom: N-
acyl morpholin-2-ones are readily polymerized, but those
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ASSOCIATED CONTENT
* Supporting Information
Synthetic details, characterization data, computational data, and
supplementary procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
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■
S
AUTHOR INFORMATION
Corresponding Author
waymouth@stanford.edu
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the Department of Energy
(DE-SC0005430) and the NSF (CHE-1306730). T.R.B. thanks
Dr. Antonio De Crisci for assistance with the DFT calculations.
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