Synthesis and hydrolysis behavior of side-chain functionalized norbornenes

Article abstract of DOI:10.1021/jo050556a

The stabilities of various functionalized norbornenes that are monomers for the ring-opening metathesis polymerization (ROMP) in aqueous solution were evaluated toward hydrolysis under a range of temperatures (37, 60, and 80 °C) and pH values (3-9). All monomers contain hydrolyzable linkages to pendant functional groups, and conclusions were drawn relating to how the chemical diversity of these pendant functional groups, in accordance with the pH and temperature variations, affect hydrolysis of the aforementioned linkages. The hydrolysis was monitored by reverse phase HPLC analysis, and/or NMR spectroscopy. As expected, monomers containing ester linkages were fairly labile at higher pH values, while acetal-based linkers were cleaved at lower pH values. β-Amino ester groups experienced a significant increase in hydrolysis rate, while carboxylic acid-containing monomers did not follow any clear trend. Saccharide-containing monomers exhibited unique behaviors for various pH values and temperature ranges.

Full text of DOI:10.1021/jo050556a

Synthesis and Hydrolysis Behavior of Side-Chain Functionalized
Norbornenes
Joseph R. Carlise,‡ Robert M. Kriegel,‡ William S. Rees, Jr.,†,‡ and Marcus Weck*,‡
School of Chemistry and Biochemistry and School of Materials Science and Engineering and
Molecular Design Institute, Georgia Institute of Technology, Atlanta, Georgia 30332-0400
marcus.weck@chemistry.gatech.edu
Received March 18, 2005
The stabilities of various functionalized norbornenes that are monomers for the ring-opening
metathesis polymerization (ROMP) in aqueous solution were evaluated toward hydrolysis under a
range of temperatures (37, 60, and 80 °C) and pH values (3-9). All monomers contain hydrolyzable
linkages to pendant functional groups, and conclusions were drawn relating to how the chemical
diversity of these pendant functional groups, in accordance with the pH and temperature variations,
affect hydrolysis of the aforementioned linkages. The hydrolysis was monitored by reverse phase
HPLC analysis, and/or NMR spectroscopy. As expected, monomers containing ester linkages were
fairly labile at higher pH values, while acetal-based linkers were cleaved at lower pH values.
â-Amino ester groups experienced a significant increase in hydrolysis rate, while carboxylic acid-
containing monomers did not follow any clear trend. Saccharide-containing monomers exhibited
unique behaviors for various pH values and temperature ranges.
Introduction
materials and devices,4 liquid crystalline5 and nonlinear
optical materials,6 and polymer-supported catalysis.7
ROMP is a highly efficient method of polymerization,
Norbornene has been used extensively as a monomer
for ring-opening metathesis polymerization (ROMP) across
a broad spectrum of applications,1 in fields as diverse as
drug delivery2 and biochemical applications,3 luminescent
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therein. (b) Tsai, M.-L.; Liu, C.-Y.; Wang, Y.-Y.; Chen, J.-Y.; Chou, T.-
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‡ School of Chemistry and Biochemistry.
† School of Materials Science and Engineering and Molecular Design
Institute.
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M.; Hopkins, B. T.; Koebberling, J. Chem. Rev. 2002, 102, 3301. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (d) Trimmer, M.
S. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
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J. E.; Young, T.; Kiessling, L. L. Org. Lett. 2002, 4, 2293. (c) Gestwicki,
J. E.; Strong, L. E.; Cairo, C. W.; Boehm, F. J.; Kiessling, L. L. Chem.
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10.1021/jo050556a CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/14/2005
5550
J. Org. Chem. 2005, 70, 5550-5560

Synthesis of Side-Chain Functionalized Norbornenes
both in organic and aqueous media, the latter being a
convenient route toward a number of biologically relevant
materials.3 For example, poly(norbornene) homo- and
copolymers substituted with oligopeptides have been used
to study competitive inhibition of fibroblast cell adhesion.3d
In another example, Kiessling and co-workers have used
ROMP for the synthesis of neoglycopolymers to study
cellular binding with L-selectin, a surface protein.3b
It is well-known that polymer degradation is the major
cause for change or loss of materials properties in many
poly(norbornene)-based materials.8 A primary mode of
degradation of poly(norbornene)s in biological applica-
tions might be the hydrolysis of water-labile moieties
within the polymer. In most norbornene monomer de-
signs a linkage between the polymerizable group and the
functional moiety is introduced.9 The choice of linker is
crucial since it will influence and partially determine the
conditions under which hydrolysis occurs. In the vast
majority of cases these linkages are carboxylic esters,
with other functionalities such as ethers, pure alkyl
chains, amides, etc. being the exception.1 Esters are
known to be sensitive to hydrolysis under both acidic and
basic conditions, and depending upon the structure can
hydrolyze in minutes (esters that give strong acids and
stable anions) or be stable for years (hydrophobic esters
of weak acids).10 Another important functional group in
biomaterials containing biological moieties such as sac-
charides is the acetal. In contrast to esters, acetals can
be cleaved rapidly in strongly acidic aqueous media and
are stable to basic conditions. Additionally, the structure
of a neighboring functional group greatly influences the
hydrolysis rate through steric and hydrophobic interac-
tions but also by the stability of the charged intermedi-
ates.11
FIGURE 1. Structures corresponding with combinations in
Table 1.
TABLE 1. Building Blocks 1 and 2, along with
Monomers 3-9, for Which the Hydrolysis Behavior Was
Investigated in This Studya
tether (R)
linkage (R′) functional group (R′′)
compd no. type
n
R′
type
R′′
type
m
R′′′
1
I
3
2
3
2
3
3
3
1
OH
Cl
2
I
3
I
OCH3
R′
4, 5
6
I
III
R′′
I
I
II
III
I
2
2
OCH3
OCH3
I
R′
I
R′′
R′′
R′′
R′′
7
I
R′
I
I
II
8
I
R′
9
II
R′
3
OCH3
a The compound number on the left corresponds with a specific
combination of tethers to norbornene, hydrolyzable linkages, and
functional groups, which are depicted in Figure 1.
A detailed study of the hydrolytic stability of function-
ally diverse norbornene monomers is of utmost impor-
tance to be able to predict and tailor important polymer
properties in aqueous solution and to relate polymer
performance to function. Despite the extensive use of
functionalized poly(norbornene)s in biomaterials, no
study has been carried out to gain a deeper understand-
ing of the hydrolysis behavior of these materials. This
report provides a study of the hydrolysis behavior of
various norbornene-based monomers, with a variety of
linker choices and pendant functional groups, each one
being subject to a range of pH values and temperatures.
Design Strategy
To gain a better understanding of the hydrolysis
behavior of norbornene monomers in aqueous media,
where hydrolysis may have the most significant influence
on polymer performance and properties, linkers and
functional moieties had to be chosen that were both water
soluble and hydrolyzable. All monomers studied herein
contain a norbornene as the polymerizable unit. Spacer
molecules, such as ethylene glycols and pure alkyl chains,
are attached to the norbornene via carboxylic ester
linkages. Finally, several functional groups are intro-
duced at the end of the spacer molecules. Figure 1 and
Table 1 outline the general monomer design and describe
the library of monomers that were studied. Two common
functionalities within the linkers were examined: esters
and acetals. The terminal functional groups that have
been employed in our design include saccharides, acids,
esters, and amines. Galactose was chosen as the saccha-
ride functional group because it has been shown by
Kiessling and co-workers that 7-oxonorbornene polymers
with pendant galactoses are very potent binding agents
to cellular recognition sites.12 The use of these oligo- or
polysaccharides to deliver drugs to specific sites at
cellular surfaces, or to the cellular interior via endosomal
transport is advantageous, provided that the drug can
(7) (a) Yang, L.; Mayr, M.; Wurst, K.; Buchmeiser, M. R. Chem. Eur.
J. 2004, 10, 5761. (b) Mayr, M.; Buchmeiser, M. R. Macromol. Rapid
Commun. 2004, 25, 231. (c) Krause, J. O.; Lubbad, S. H.; Nuyken, O.;
Buchmeiser, M. R. Macromol. Rapid Commun. 2003, 24, 875. (d)
Kroell, R. M.; Schuler, N.; Lubbad, S.; Buchmeiser, M. R. Chem.
Commun. 2003, 21, 2742. (e) Krause, J. O.; Lubbad, S.; Nuyken, O.;
Buchmeiser, M. R. Adv. Synth. Catal. 2003, 345, 996. (f) Schubert, U.
S.; Weidl, C. H.; Eschbaumer, C.; Kroell, R.; Buchmeiser, M. R. Polym.
Mater. Sci. Eng. 2001, 84, 514. (g) Arstad, E.; Barrett, A. G. M.;
Tedeschi, L. Tetrahedron Lett. 2003, 44, 2703. (h) Buchmeiser, M. R.;
Lubbad, S.; Mayr, M.; Wurst, K. Inorg. Chim. Acta 2003, 345, 145. (i)
Buchmeiser, M. R. Bioorg. Med. Chem. Lett. 2002, 12, 1837. (j) Skaff,
H.; Ilker, M. F.; Coughlin, E. B.; Emrick, T. J. Am. Chem. Soc. 2002,
124, 5729. (k) Pollino, J. M.; Weck, M. Org. Lett. 2002, 4, 753. (l) Yu,
K.; Sommer, W.; Richardson, J. M.; Weck, M.; Jones, C. W. Adv. Synth.
Catal. 2005, 347, 161.
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Wang, W.; Qu, B. J. Polym. Degrad. Stab. 2003, 81, 531. (c) Liu, C.;
Yu, J.; Sun, X.; Zhang, J.; He, J. Polym. Degrad. Stab. 2003, 81, 197.
(d) Wedlake, M. D.; Kohl, P. A. J. Mater. Res. 2002, 17, 632.
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heim, Germany, 2003; Vol. 3.
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5, 515. (b) Cordes, E. H.; Bull, H. G. Chem. Rev. 1974, 74, 581.
J. Org. Chem, Vol. 70, No. 14, 2005 5551

Carlise et al.
SCHEME 1. Synthesis of Norbornene Spacer
Molecules 1, 2, and 3a
SCHEME 2. Synthesis of PEG-Acetal Monomers 4
and 5a
a Reagents: (a) For 1: triethylene glycol (excess), THF, triethy-
lamine; For 2: chloroethoxyethanol, triethylamine, THF; For 3:
triethylene glycol monomethyl ether, triethylamine, THF.
be cleaved efficiently from the polymer backbone. Other
pendant functional groups employed in this study are
carboxylic acids, ethers, and tertiary amines. These side-
chain models represent a wide range of functional groups
and interactions and will allow for insights into the effect
of functional groups on the hydrolysis behavior of func-
tionalized norbornenes.
a Reagents: (a) oxalyl chloride, DMSO, triethylamine; (b)
glycerol, p-TsOH, toluene; (c) NaH, 2, THF.
SCHEME 3. Synthesis of Compounds 6 and 7a
Results and Discussion
A. Synthesis: Norbornene PEG Esters 1-3. Syn-
thesis of norbornene derivatives 1-3, norbornene trieth-
ylene glycol ester derivatives, was accomplished by
treatment of the norbornene acyl chloride 1013 with
triethylene glycol, 2-(2-chloroethyoxy)ethanol, and tri-
ethylene glycol methyl ether, respectively (Scheme 1),
giving yields in excess of 70%. The synthesis of com-
pounds 1-3 resulted in mixtures of endo/exo isomers in
approximately 4:1 ratios.
a Reagents: (a) DCC, DMAP, CH2Cl2; (b) pyridine, THF.
PEG-Based Norbornenes Containing Acetals in
Their Side-Chains: Monomers 4 and 5. Oxidation of
triethylene glycol monomethyl ether under Swern condi-
tions resulted in the formation of aldehyde 11 in 44%
yield.14 Treatment of 11 with glycerol and p-toluene-
sulfonic acid in toluene gave a 1:1 mixture of 12 and 13
in 89% yield. The formation of the five-membered-ring
adduct 12 is kinetically favored, while the six-membered-
ring adduct 13 is the thermodynamic product. Each of
the isomers exists as a diastereomeric pair and four sets
of triplets for the acetal proton are evident in the 1H NMR
spectrum of the mixture. Purification of the products,
either by distillation or column chromatography, did not
allow for isolation of the two compounds and in all cases
mixtures are obtained. Coupling of 12 and 13 to com-
pound 2 under basic conditions resulted in the formation
of acetals 4 and 5 in 64% yield as mixtures of five- and
six-membered adducts and endo/exo isomers (Scheme 2).
Norbornene Monomers Containing PEG-Ester
and Acid-Ester in Their Side-Chains: Monomers 6
and 7. The esterfication of 1 with 2-[2-(2-methoxyethoxy)-
ethoxy]acetic acid was carried out at ambient temper-
atures with DCC/DMAP in CH2Cl2 to give the PEG-ester
monomer 6 in 52% yield. Compound 7 was synthesized
by the reaction of 1 with glutaric anhydride in 82% yield
(Scheme 3).
Norbornene Linked to Galactose via Triethylene
Glycol Ester: Monomer 8. The synthesis of 8 started
with the oxidation of 1,2:3,4-di-O-isopropylidene galac-
topyranose, using Jones conditions to give 14 in 81%
yield.15 Coupling of 14 to 1 with use of DCC/DMAP gave
the acetal protected saccharide ester 15 in 60% yield.
Removal of the acetal protecting groups to give the free
tetra-ol 8 (Scheme 4) was achieved by treatment of 15
with 80% TFA (aq). Conversion after 1 h was 100% by
NMR analysis but isolation and purification of the
product resulted in lower yields (84%).
Synthesis of Monomer 9. Synthesis of 9 required the
triethylene glycol monomethyl ether monoacrylate 16,
which was synthesized from the condensation of trieth-
ylene glycol monomethyl ether and acryloyl chloride in
84% yield. Addition of 2 equiv of 16 to ethanolamine at
room temperature gave the bis-Michael addition product
17 in nearly quantitative yield (97%) after 24 h. Coupling
of 17 to 10 in THF with triethylamine at ambient
temperature gave product 9 in 64% yield after chroma-
tography (Scheme 5).
(12) (a) Smith, E. A.; Thomas, W. D.; Kiessling, L. L.; Corn, R. M.
J. Am. Chem. Soc. 2003, 125, 6140. (b) Gordon, E. J.; Sanders, W. J.;
Kiessling, L. L. Nature 1998, 392, 30. (c) Manning, D. D.; Strong, L.
E.; Hu, X.; Beck, P. J.; Kiessling, L. L. Tetrahedron 1997, 53, 11937.
(13) Jacobine, A. F.; Glaser, D. M.; Nakos, S. T. Polym. Mater. Sci.
Eng. 1989, 60, 211.
(14) Ros, T. D.; Prato, M.; Novello, F.; Maggini, M.; Banfi, E. J. Org.
Chem. 1996, 61, 9070.
(15) Godage, H. Y.; Fairbanks, A. J. Tetrahedron Lett. 2000, 41,
7589.
5552 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Side-Chain Functionalized Norbornenes
SCHEME 4. Synthesis of Compound 8
FIGURE 2. Pseudo-first-order hydrolysis kinetics for com-
pounds 4 and 5 at 37 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.6; 1,
pH 6.9; [, pH 7.4; +, pH 8.9.
SCHEME 5. Synthesis of Compound 9
FIGURE 3. Pseudo-first-order hydrolysis kinetics for com-
pounds 4 and 5 at 60 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.6; 1,
pH 6.9; [, pH 7.4; +, pH 8.9.
B. Hydrolysis. To investigate the effect of pH on the
hydrolysis of compounds 3-9, measurements were car-
ried out in the range of pH 3.1 to 8.9. A phosphate/citric
acid buffer was used for pH 3.1, acetate buffers were
employed for pH 4.6 and 5.6, phosphate buffers for pH
6.9 and 7.4, and borate buffer for pH 8.9. All buffers were
made to 0.1 M ionic strength, with the exception of pH
7.4, which was an isotonic phosphate buffered saline
solution. Solutions of 5 mM analyte were employed to
give conditions that would result in pseudo-first-order
kinetics. Temperatures of 80, 60, and 37 °C were inves-
tigated to study the influence of temperature on the
hydrolysis rate. The hydrolysis rates were measured by
HPLC analysis, using refractive index and/or UV detec-
tion and/or proton NMR.
Hydrolysis of 4 and 5. The hydrolyses of monomers
4 and 5 were achieved under the same conditions as
outlined above for 6 (Figures 2-4 and Table 2). However,
the formation of aldehyde was not detected, and the
expected aldehyde product was not retained under the
analysis conditions. Therefore, HPLC analyses were
carried out by measuring the consumption of starting
material. However, to verify this method and to quantify
the amount of aldehyde produced in the hydrolysis
reactions, a general method of aldehyde derivatization
was used: sample aliquots were treated with 2,4-dini-
trophenyl hydrazine to form the corresponding DNP
hydrazone, and the resulting sample was analyzed by UV
detection at 365 nm. At high pH, no detectable aldehyde
was produced, suggesting that the ester at the 2-position
of the norbornene unit is undergoing hydrolysis. The
amount of aldehyde produced at pH 3.1 does not correlate
with the extent of hydrolysis measured by the disappear-
ance of starting material, suggesting that an additional
decomposition product may be forming upon cleavage of
the acetal. Within the range of error, we are not able to
elucidate which hydrolysis mechanism is predominating
at low temperatures. At 37 °C, no significant hydrolysis
was detected from pH 4.6 to 7.4. Hydrolysis occurred at
the low and high pH values of 3.1 and 8.9. The calculated
half-life at pH 3.1 and 37 °C was 8.8 h, compared to 2.2
h at pH 8.9 and 37 °C.
The acetal moiety is well-known for its rapid hydrolysis
at low pH values, as well as its relative stability in
alkaline media. This common characteristic of acetals
matches well with our hydrolysis data for compounds 4
J. Org. Chem, Vol. 70, No. 14, 2005 5553

Carlise et al.
FIGURE 4. Pseudo-first-order hydrolysis kinetics for com-
pounds 4 and 5 at 80 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.6; 1,
pH 6.9; [, pH 7.4; +, pH 8.9.
FIGURE 5. Pseudo-first-order hydrolysis kinetics for com-
pound 3 at 80 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4; +, pH 8.9.
TABLE 2. Hydrolysis Data for a Mixture of Compounds
4 and 5
pH
k (h-1
)
R2
t1/2 (h)
compounds 4 and 5, 80 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.341
0.040
0.030
0.035
0.059
0.850
0.988
0.977
0.975
0.976
0.982
0.943
2.0
17
23
20
12
0.82
compounds 4 and 5, 60 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.215
0.022
0.012
0.012
0.043
0.513
0.991
0.995
0.992
0.996
0.996
0.996
3.2
32
58
58
16
1.4
compounds 4 and 5, 37 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.079
0.996
0.994
0.942
0.996
0.988
0.994
8.8
78
530
290
220
2.2
0.0089
0.0013
0.0024
0.0031
0.319
FIGURE 6. Pseudo-first-order hydrolysis kinetics for com-
pound 3 at 60 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4; +, pH 8.9.
TABLE 3. Hydrolysis Data for Compound 3
and 5, at all temperature ranges (Figures 2-4), where
at low pH, rapid acetal hydrolysis is observed. The
monomer was substantially more stable in both weakly
acidic and neutral aqueous solutions, but showed rapid
decomposition at pH 8.9. In terms of the acetal group,
this effect cannot be explained. To investigate if the
hydrolysis occurs at the ester linkage to the norbornene
instead of at the acetal for this set of circumstances, we
synthesized monomer 3, a monomer with a triethylene
glycol monomethyl ether directly linked to the nor-
bornene polymerizable unit via an ester. This monomer
models the ester linkage of 4 and 5 without any further
hydrolyzable moieties. The hydrolysis behavior of this
monomer at 60 and 80 °C correlated closely with the
unexpected hydrolysis data observed for 4 and 5 at pH
values of 8.9, giving a plausible explanation: cleavage
of the base-labile norbornene ester bond is occurring at
this slightly basic pH value. In 3 the pH value of 8.9 is
the only set of conditions where hydrolysis is achieved
pH
k (h-1
)
R2
t1/2 (h)
compound 3, 80 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.027
0.943
0.980
0.976
0.990
0.990
0.996
27
0.014
0.010
0.026
0.040
2.15
50
70
27
17
0.32
compound 3, 60 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.018
0.994
0.992
0.992
0.982
0.986
0.946
39
98
100
36
29
1.1
0.0071
0.0069
0.019
0.024
0.632
fairly rapidly, due to the base sensitivity of the ester
(Figures 5 and 6 and Table 3). This suggests that the
same hydrolytic cleavage of the ester may be occurring
for 4 and 5. At low pH, cleavage of the acetal is the
5554 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Side-Chain Functionalized Norbornenes
TABLE 4. Hydrolysis Data for Compound 6
pH
k (h-1
)
R2
t1/2 (h)
compound 6, 80 °C
4.6
5.7
6.9
7.4
0.044 ( 0.002
0.989
0.994
0.994
0.976
15.8
20.7
2.2
0.034 ( 0.001
0.311 ( 0.014
0.443 ( 0.048
1.6
compound 6, 60 °C
3.1
4.6
5.7
6.9
7.4
0.050 ( 0.004
0.032 ( 0.001
0.017 ( 0.001
0.099 ( 0.007
0.121 ( 0.011
0.940
0.995
0.964
0.950
0.970
13.7
21.9
41.9
6.9
5.7
compound 6, 37 °C
3.1
4.6
5.7
6.9
7.4
0.006 ( 0.004
0.002 ( 0.001
0.006 ( 0.003
0.017 ( 0.004
0.042 ( 0.006
≈100
450
≈100
40
0.933
0.951
0.895
17
dominant decomposition pathway, while at high pH, ester
hydrolysis predominates.
FIGURE 7. Pseudo-first-order hydrolysis kinetics for com-
pound 6 at 80 °C: b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4.
Hydrolysis of 6. The dependence of the hydrolysis of
6 on pH and temperature is shown in Figures 7-9 and
Table 4. At 80 °C, hydrolysis of 6 at pH 8.9 was rapid,
with a 45% to 50% loss in 2 h. Under acidic conditions,
the rate of hydrolysis is consistent with the expected
trend of the rate being inversely proportional to pH. At
near neutral or basic pH values, the rates of hydrolysis
are greatly enhanced when compared to data collected
at low pH conditions (Figure 7). Complete loss of 6 was
seen within 18 h near pH 7 and 80 °C. This does not
correlate with the accepted mechanisms of ester hydroly-
sis under either acidic or basic conditions, which depend
on an increase in electrophilicity of the carbonyl by
protonation under acidic conditions, or by the relatively
high nucleophilic character of hydroxide compared to
water, under basic conditions. The rate would be depend-
ent upon the nucleophilic character of water, which
should produce exceedingly slow reactions. The acceler-
ated rates near pH 7 suggest that the buffer identity
might play a significant role in the hydrolysis mechanism
at this pH. The same trends were observed for the
hydrolysis at 60 °C (Figure 8) and at 37 °C (Figure 9).
The pseudo-first-order half-lives range from 6 to 20 h.
Hydrolysis of 7. By investigating the hydrolysis
behavior of compound 7, we observed virtually no hy-
drolysis at 37 °C (half-lives of >200 h for all pH values)
(Figure 10), first-order kinetics at 60 °C (Figure 11), and
finally, great deviations from first-order kinetics at 80
°C (Figure 12), which are not accompanied by a substan-
tial rate increase. It is evident that this behavior does
not follow a clear hydrolysis trend.
expected acetal cleavage, but as pH increased, trends
began to mimic those of 3, suggesting that the ester was
hydrolyzing instead under that set of conditions. For 6,
we observed faster hydrolysis than that of 3 under all
conditions, suggesting that the ester farther removed
from the norbornenyl group was more labile under the
conditions used in the study. However, one of the initial
decomposition products observed for 6 showed subse-
quently further decomposition on a time scale identical
with that of 3, suggesting that this second hydrolysis step
matches the behavior of 3. These results thus confirm
the identities of the individual hydrolysis sites, recogniz-
able by their own unique characteristic hydrolysis be-
haviors. The observed rate decrease for the norbornenyl
ester is most likely due to the hydrophobic nature of the
norbornene, the steric bulk generated by this bridged
aliphatic group, or both. In compound 7, the ester that
is not directly attached to the norbornene is partially in
a highly hydrophobic environment, potentially shielding
While we are not able to unequivocally determine the
reason for this hydrolysis behavior, several possibilities
exist. During this study, we have observed that the ester
directly next to the norbornene hydrolyzes significantly
slower than other hydrolyzable sites that are further
removed from the norbornene (see the study of 3). This
has been evidenced by comparison of the hydrolysis data
for monomers 3-6. Hydrolysis data for 3 reflect only
hydrolysis at the ester adjacent to the norbornenyl group,
since this site is the only water labile site on the molecule.
Significant hydrolysis of 3 only occurs at basic pH values.
At lower pH values, monomers 4 and 5 exhibited the
FIGURE 8. Pseudo-first-order hydrolysis kinetics for com-
pound 6 at 60 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4.
J. Org. Chem, Vol. 70, No. 14, 2005 5555

Carlise et al.
FIGURE 11. Pseudo-first-order hydrolysis kinetics for com-
pound 7 at 60 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4; +, pH 8.9.
FIGURE 9. Pseudo-first-order hydrolysis kinetics for com-
pound 6 at 37 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4.
FIGURE 12. Hydrolysis kinetics for compound 7 at 80 °C:
9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4; +, pH
8.9.
FIGURE 10. Pseudo-first-order hydrolysis kinetics for com-
pound 7 at 37 °C: 9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9;
[, pH 7.4; +, pH 8.9.
While the half-lives are noticeably longer (approximately
20 min) at 60 °C, the rate of hydrolysis is still too fast to
quantitatively determine rate constants by HPLC analy-
sis. The increased rate of hydrolysis for this compound
may be due to several factors. It is hypothesized in the
literature that neighboring amine functionalities can act
as intramolecular nucleophilic catalysts in ester hydroly-
sis, thus contributing to higher degradation rates.16
Langer and Lynn also point out the possibility of a
potential retro-Michael addition occurring in molecules
synthesized via Michael addition reactions.17 In their
study, they employed a polymer containing esters and
tertiary amines along the polymer backbone to study the
cytotoxicity of the degradation products of their polymer
as a new transfection vector. They found that hydrolysis
it from easy access by water molecules. It is also a
common behavior of molecules bearing a hydrophobic end
on one side of the molecule, and an ionic charge on the
other, to form aggregates in solution, such is the case
with many common surfactants. In aqueous media, the
charged end of these molecules appears on the periphery
of any aggregates formed, further protecting any hydro-
phobic esters on the interior from hydrolysis. As the
temperature increases, noncovalent forces that aid in the
swelling of aggregates or the desolvation of molecules
may be overcome, causing the aggregates to collapse. This
behavior could potentially lead to a change in mechanism
at high temperature.
Hydrolysis of 9. The rate of hydrolysis of 9 at 80 and
60 °C at all pH values was too fast to be measured by
the methods employed in this study. It is estimated that
in buffered aqueous solution the half-lives of all mono-
mers are on the order of 5 to 10 min at all pH values.
(16) Lim, Y.-B.; Kim, C.-H.; Kim, K.; Kim, S. W.; Park, J.-S. J. Am.
Chem. Soc. 2000, 122, 6524.
(17) Lynn, D. M.; Langer, R. J. Am. Chem. Soc. 2000, 122, 10761.
5556 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Side-Chain Functionalized Norbornenes
TABLE 5. Hydrolysis Data for Compound 7
pH
k (h-1
)
R2
t1/2 (h)
compound 7, 80 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.011 ( 0.003
0.712
0.794
0.227
0.866
0.371
0.929
61.2
144
58.9
52.0
50.1
10.4
0.005 ( 0.001
0.012 ( 0.005
0.013 ( 0.002
0.014 ( 0.005
0.067 ( 0.007
compound 7, 60 °C
3.1
4.6
5.7
6.9
7.4
8.9
0.019 ( 0.004
0.015 ( 0.002
0.060 ( 0.002
0.015 ( 0.003
0.056( 0.007
0.043 ( 0.003
0.733
0.904
0.996
0.840
0.929
0.987
32.3
46.0
11.6
45.8
12.4
16.3
TABLE 6. Hydrolysis Data for Compound 9 at 37 °C
pH
k (h-1
)
R2
t1/2 (h)
4.6
5.7
6.9
7.4
8.9
0.027 ( 0.001
0.073 ( 0.002
0.095 ( 0.001
0.090 ( 0.002
0.149 ( 0.003
0.993
0.995
0.999
0.996
0.997
26.1
9.5
7.3
7.7
4.7
FIGURE 14. Hydrolysis kinetics for compound 8 at 37 °C:
9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4.
occurred faster at pH 7.4 than at 5.1. However, they
observed no retro-Michael addition products in their
systemsonly ester hydrolysis products, which suggests
that retro-Michael addition is not the primary degrada-
tion pathway for 9. Nucleophilic attack of the amine to
the ester carbonyl gives a positively charged quaternary
amide, which would be very active toward hydrolysis.
At 37 °C, the rates of hydrolysis are slow enough to
observe via HPLC analysis, and are described in Table
6 and Figure 13 below. The rate of hydrolysis increases
FIGURE 15. Hydrolysis kinetics for compound 8 at 60 °C:
9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4; +, pH
8.9.
again extremely rapid decomposition at pH 8.9, while pH
values of 3.1, 4.6, and 7.4 once again showed no observ-
able hydrolysis. However, pH 5.7 and 6.9 exhibited
pseudo-first-order kinetics. At 80 °C, decomposition at
pH 8.9 again was too fast to measure, while pH 3.1, 4.6,
and 5.7 gave fairly well-behaved pseudo-first-order kinet-
ics, displaying half-lives in the range of 5.1 h for pH 5.7
to 63 h for pH 3.1. As displayed in Figure 16, hydrolysis
of pH 6.9 was nonlinear. This result suggests the occur-
rence of side reactions or interactions of 8 with the buffer.
Hydrolysis kinetics measured for pH 7.4 did not follow
first order for any temperature range.
FIGURE 13. Pseudo-first-order hydrolysis kinetics for com-
pound 9 at 37 °C: b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4;
+, pH 8.9.
with pH, and was fastest at pH 8.9, consistent with the
findings of Langer and Lynn for their similar system.
Hydrolysis of 8. Compound 8 showed no significant
hydrolysis at 37 °C, with the exception of pH 8.9, which
appeared to decompose faster than the methods employed
in this study are able to measure. At 60 °C, there was
Conclusion
In conclusion, we have synthesized a library of chemi-
cally diverse norbornene compounds, an important class
of monomers for ROMP. Furthermore, we have investi-
gated their decomposition via hydrolysis in aqueous
J. Org. Chem, Vol. 70, No. 14, 2005 5557

Carlise et al.
in this study do not conclusively show which mechanisms
may be predominating. Third, the presence of a carboxylic
acid in the monomer structure results in the unpredict-
able hydrolysis of the monomer with non-first-order
kinetics. Fourth, saccharide-containing monomers hy-
drolyze rapidly in alkaline media while they are stable
under acidic conditions, an important finding for poly-
mers based on similar monomers has been suggested as
biomaterial. Furthermore, it is important to note that the
hydrolysis behavior of the monomers under some tem-
perature and pH conditions, in particular at neutral pH
values, does not follow the expected trends. We rational-
ize that these cases include either the participation of
neighboring groups and/or interactions of the monomers
with the buffer. Finally, we observed significant hydroly-
sis of the ester linkage directly bonded to the norbornene.
The use of ester linkages to support side-chains on poly-
(norbornene)s is also the most commonly employed
method for water-soluble polymers. Our results clearly
demonstrate that these esters are not stable under a wide
variety of temperatures and pH values, suggesting that
the stability of side-chain functionalized poly(norbornene)s
containing ester linkages is limited and this inherent
instability must be considered when designing function-
alized poly(norbornene)s.
FIGURE 16. Hydrolysis kinetics for compound 8 at 80 °C:
9, pH 3.1; b, pH 4.6; 2, pH 5.7; 1, pH 6.9; [, pH 7.4.
TABLE 7. Hydrolysis Data for Compound 8
pH
k (h-1
)
R2
t1/2 (h)
compound 8, 80 °C
3.1
4.6
5.7
6.9
7.4
0.011 ( 0.001
0.947
0.961
0.982
0.272
0.822
63
57.8
5.1
11.7
34.7
0.012 ( 0.001
0.136 ( 0.006
0.059 ( 0.021
0.020 ( 0.004
Experimental Section
Typical Esterfication Method 1: Bicyclo[2.2.1]hept-
5-ene-2-carboxlylic Acid 2-[2-(2-Hydroxyethoxy)ethoxy
Ethyl Ester, 1. To a solution of triethylene glycol (3.66 g, 24.4
mmol) and triethylamine (4.90 g, 48.8 mmol) in THF (200 mL)
was added compound 10 (3.63 g, 23.2 mmol) dropwise at 0 °C.
The mixture was warmed to ambient temperature and stirred
for 8 h. The mixture was diluted with diethyl ether and washed
with 5% NaOH (aq), 5% HCl (aq), sat. NaHCO3 (aq), and brine
and dried over Na2SO4. The solvent was removed under
reduced pressure and the residue distilled in vacuo to give
bicyclo[2.2.1]hepta-5-ene-2-carboxlylic acid 2-[2-(2-hydrox-
vethoxy)ethoxy]ethyl ester as a clear colorless liquid (5.21 g,
compound 8, 60 °C
3.1
4.6
5.7
6.9
7.4
0.001 ( 0.001
0.001 ( 0.001
0.034 ( 0.001
0.053 ( 0.008
0.004( 0.001
700
700
20.4
13.1
170
0.985
0.833
compound 8, 37 °C
3.1
4.6
5.7
6.9
7.4
0.005 ( 0.001
0.001 ( 0.002
0.002 ( 0.001
0.008 ( 0.004
0.003 ( 0.002
140
700
350
90
1
83%). H NMR (400 MHz, CDCl3): δ 6.15 (m, 1H), 6.10 (m, 2
H), 5.90 (m, 1H), 4.14-4.24 (m, 2H), 3.72-3.65 (m, 8H), 3.60
(t, J ) 8 Hz, 2H), 3.19 (br, 1H), 3.02 (br, 1H), 2.94 (m, 1H),
2.88 (br, 1 H), 2.22 (m, 1 H), 1.93-1.84 (m, 1H), 1.49-1.23
(m, 3H). 13C NMR (100 MHz, CDCl3): δ 176.1, 174.6, 137.9,
137.6, 135.6, 132.2, 72.4, 70.4, 70.2, 69.1, 63.2, 63.1, 61.6, 49.5,
46.5, 46.2, 45.6, 43.1, 42.9, 41.5, 30.2, 29.1. IR (neat): 3460
(br, -OH), 3060, 2940, 2870, 1730, 1630 (shoulder), 1450, 1190,
1110, 712 cm-1. MS(EI, 70 keV): m/z 139, 58 (100). Anal. Calcd
for C14H22O5: C, 62.20, H, 8.20. Found: C, 62.28, H, 8.29.
Bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid 2-(2-{2-[2-
(2-Methoxyethoxy)ethoxymethyl][1,3]dioxolan-4-ylmeth-
oxy}ethoxy)ethyl Ester and Bicyclo[2.21]hept-5-ene-2-
carboxylic Acid 2-(2-{2-[2-(2-Methoxyethoxy)ethoxy-
methyl][1,3]dioxan-5-yloxy}ethoxy)ethyl Ester, 4 and 5.
NaH (58.6 mg, 2.44 mmol) was added to a solution of a mixture
of 12 and 13 (0.53 g, 2.22 mmol) in THF (10 mL) under argon.
The mixture was stirred for 1 h at room temperature, 2 (0.56
g, 2.33 mmol) was added, and the resulting mixture was
refluxed for 24 h. KI (2 crystals) was added and reflux was
continued for an additional 24 h. The mixture was then cooled
to room temperature, the organic layer diluted with diethyl
ether (30 mL) and washed with water (20 mL), and the organic
layer concentrated under reduced pressure. The residue was
subjected to column chromatography (1:3 ethyl acetate:hexane,
silica) to yield a mixture of bicyclo[2.2.1]hept-5-ene-2-carboxylic
acid 2-(2-{2-[2-(2-methoxyethoxy)ethoxymethyl][1,3]dioxolan-
4-ylmethoxy}ethoxy)ethyl ester and bicyclo[2.2.1]hept-5-ene-
2-carboxylic acid 2-(2-{2-[2-(2-methoxyethoxy)ethoxymethyl]-
230
solution under a variety of pH and temperature ranges.
The investigated monomers contained either ester and/
or acetal linkages, as well as terminal functional groups
including esters, acids, ethers, and saccharides. During
the hydrolysis studies, the two extremes that we inves-
tigated were the amine/ester-based and the saccharide-
based monomers. The hydrolysis of tertiary amine/ester-
based monomers was very fast with half-lives of below
10 h for all temperatures and pH values investigated. In
contrast, the saccharide/ester-based monomer showed the
slowest hydrolysis at acidic conditions of any monomer
and condition studied.
A variety of important trends were observed during
these studies. First, the chemistry of the acetal functional
group allows for selective hydrolysis of the side-chain
either at the ester linkage of the norbornene at the
2-position (at high pH) or at the acetal group (at low pH).
Second, the presence of a â-amino functionality greatly
enhances the rate of hydrolysis and also changes the pH
dependence of the rate constants. This suggests a change
in the mechanism of hydrolysis by the involvement of
intramolecular assistance, but the experiments conducted
5558 J. Org. Chem., Vol. 70, No. 14, 2005

Synthesis of Side-Chain Functionalized Norbornenes
[1,3]dioxan-5-yloxy}ethoxy)ethyl ester as a clear colorless
(silica, 1:1 ethanol:ethyl acetate) to give galactopyranose-6-
uronic acid 2-{2-[2-(bicyclo[2.2.1]hept-5-ene-2-carbonyloxy)-
ethoxy]ethoxy}ethyl ester as a clear colorless viscous liquid.
Yield: 0.206 g (84%). 1H NMR (300 MHz, CDCl3): δ 6.12-
6.15 (m, 0.5H, vinyl endo), 6.04-6.08 (m, 1H, vinyl exo), 5.86-
5.89 (m, 0.5H, vinyl exo), 5.46 (s, br, 1H), 5.30 (s, br, 0.5H),
4.86 (m, 0.5H), 4.70 (m, 1H), 4.33 (m, 3H), 4.04 (m, 2H), 3.95
(m, 1H), 3.61 (m, 9H), 3.16 (s, br, 1H), 2.95 (m, 1H), 2.85 (s,
br, 1H), 2.62, (m, 1H), 2.19 (m, 1H), 1.88 (m, 1H), 1.63 (m,
1H), 1.36 (m, 2H), 1.21 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ 175.1, 138.2, 138.1, 136.2, 132.5, 81.4, 70.6, 70.5, 69.4, 69.3,
65.0, 64.9, 63.6, 49.9, 47.0, 46.0, 44.1, 43.5, 42.6, 40.1, 30.2.
IR (KBr): 3379 (br, -OH), 2947, 2877 (CH stretch), 1734 (Cd
O), 1452, 1340, 1205 (sp2 C-O), 1105, 1018 (sp3 C-O), 939,
808 cm-1. Anal. Calcd for C20H30O11: C, 53.81, H, 6.77.
Found: C, 53.74, H, 6.68.
[2-(2-Methoxyethoxy)ethoxy]acetaldehyde, 11. To a
solution of oxalyl chloride (3.59 g, 28.2 mmol) in dry CH2C12
(50 mL) at -78 °C under argon was added freshly distilled
DMSO (5 mL) slowly. The mixture was stirred for 30 min, and
then freshly distilled dry triethylene glycol monomethyl ether
(3.86 g, 23.6 mmol) was added via a syringe. The mixture was
stirred for an additional 30 min, triethylamine (20 mL) was
added over 10 min, and the mixture was stirred for 15 min
and then warmed to ambient temperature. Dilution with CH2-
Cl2 (50 mL), washing with water, and distillation of the organic
layer under reduced pressure yielded [2-(2-methoxyethoxy)-
ethoxy]acetaldehyde as a clear colorless liquid (2.10 g, 55%).
1H NMR (300 MHz, CDCl3): δ 9.62 (d, J ) 0.8 Hz, 1H), 4.06
(d, J ) 0.8 Hz, 2H), 3.59-3.67 (m, 4H), 3.54-3.57 (m, 2H),
3.43-3.47 (m, 2H), 3.28 (s, 3H). 13C NMR (100 MHz, CDC13):
δ 171.6, 76.7, 71.8, 70.9, 70.7, 59.0, 40.1. IR (neat): 2872, 1727,
1452, 1357, 1086 cm-1. MS(EI, 70 keV): m/z 87, 59 (100), 45,
31, 29, 15. Anal. Calcd for C7H14O4: C, 51.84, H, 8.70. Found:
C, 51.76, H, 8.66.
1
liquid (0.819 g, 83%). H NMR (400 MHz, CDC13): δ 6.13-
6.16 (m, 0.5H, vinyl endo), 6.08-6.10 (m, 0.5H, vinyl exo),
6.04-6.06 (m, 0.5H, vinyl exo), 5.86-5.88 (m, 0.5H, vinyl
endo), 5.13-5.17 (m, 0.5H), 5.02-5.05 (m, 0.5H), 4.20-4.35
(m, 1.5H), 3.89-4.13 (m, 4H), 3.74-3.79 (m, 0.5H), 3.49-3.68
(m, 12H), 3.33 (s, 3H), 2.87-3.16 (m, 3H), 2.19-2.23 (m, 0.5H),
1.82-1.89 (m, 1.5H), 1.22-1.47 (m, 3H). 13C NMR (100 MHz,
CDC13): δ 186.9, 186.8, 185.4, 185.3, 149.0, 148.8, 146.5, 143.1,
114.3, 114.0, 113.9, 88.3, 88.0, 87.7, 84.8, 83.0, 82.9, 82.8, 82.1,
81.4, 78.0, 75.2, 74.8, 69.9, 60.5, 57.6, 57.2, 56.6, 54.1, 53.9,
53.4, 52.5, 41.3, 40.1, 35.0. IR (neat): 3060.1, 2944.4, 2872.6,
1734.7, 1623.8, 1455.1, 1334.6, 1112.8, 717.4 cm-1. Anal. Calcd
for C22H36O9: C, 59.44, H, 8.16. Found: C, 59.43, H, 8.18.
Typical Esterfication Method 2: Bicyclo[2.2.l]hept-5-
ene-2-carboxylic Acid 2-[2-(2-{2-[2-(2-Methoxyethoxy)-
ethoxy]acetoxy}ethoxy)ethoxy]ethyl Ester, 6. A solution
of 2-(2-[2-methoxyethoxy]ethoxy)acetic acid (0.28 g, 1.55 mmol)
and 10 (0.42 g, 1.55 mmol) in CH2Cl2 (5 mL) was cooled to 0
°C. DMAP (0.19 g, 1.57 mmol) was slowly added and the
solution was stirred for 5 min. Then DCC (0.33 g, 1.58 mmol)
was added and the solution was allowed to warm to ambient
temperature over a period of 12 h, during which a white
precipitate was formed that was removed by filtration and
washed with additional CH2Cl2. The filtrate was washed with
aqueous NH4Cl (sat.), NaHCO3, and water and dried over Na2-
SO4, and the solvent was removed under reduced pressure.
The residue was subjected to column chromatography (1:2
ethyl acetate:hexane, silica) to afford bicyclo[2.2.1]hept-5-ene-
2-carboxylic acid 2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetoxy}-
ethoxy)ethoxy]ethyl ester as a clear colorless liquid (0.346 g,
52%). 1H NMR (400 MHz, CDCl3): δ 6.06-6.16 (m, 1.5H),
5.89-5.91 (m, 0.5H), 4.10-4.36 (m, 7H), 3.51-3.72 (m, 17H),
3.35 (s, 3H), 3.13 (s, br, 1H), 2.79-3.01 (m, 2H), 2.21-2.50
(m, 1.5H), 1.84-1.91 (m, 1.5H), 1.61-1.76 (m, 0.5H), 1.23-
1.50 (m, 3.5H). 13C NMR (100 MHz, CDCl3): δ 174.6, 170.3,
138.0, 137.6, 135.6, 132.2, 77.3, 77.0, 76.7, 71.8, 70.8, 70.5, 70.4,
69.2, 68.9, 68.4, 63.6, 63.1, 58.9, 49.5, 46.6, 46.2, 45.6, 43.1,
42.9, 42.4, 41.5, 36.9, 30.2, 29.1, 27.2. IR (neat): 2949.7, 2872.6,
1754.0, 1734.7, 1455.1, 1199.6, 1117.6, 847.6 cm-1. MS (CI,
isobutane): m/z 431 (M+ + H), 365, 293, 205 (100), 165, 133.
Anal. Calcd for C21H34O9: C, 58.59, H, 7.96. Found: C, 58.54,
H, 7.99.
{2-[2-(2-Methoxyethoxy)ethoxymethyl][1,3]dioxolan-4-
yl}methanol and 2-[2-(2-Methoxyethoxy)ethoxymethyl]-
[1,3]dioxan-5-ol, 12 and 13. A solution of freshly distilled
dry glycerol (0.49 g, 5.37 mmol), 11 (0.67 g, 4.13 mmol), and
p-TsOH (1 crystal) in PhCH3 was heated at reflux under argon
for 12 h with a Dean-Stark trap half filled with CaCl2. The
reaction mixture was concentrated under reduced pressure and
the residue purified by column chromatography (1:3 ethyl
acetate:hexane, silica) to give a mixture of {2-[2-(2-methoxy-
ethoxy)ethoxymethyl][1,3]dioxolan-4-yl}methanol and 2-[2-(2-
methoxyethoxy)ethoxymethyl][1,3]dioxan-5-ol as a clear color-
Pentanedioic Acid Mono(2-{2-[2-(bicyclo[2.2.1]hept-5-
ene-2-carbonyloxy)ethoxy]ethoxy}ethyl) Ester, 7. A solu-
tion of 1 (1.28 g, 4.75 mmol) and pyridine (3 mL) in THF (20
mL) was added to glutaric anhydride (0.57 g, 4.98 mmol) in
THF (10 mL) at ambient temperature and the mixture was
stirred for 12 h. The reaction mixture was diluted with diethyl
ether and washed with 10% HCl (aq), dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by column chromatography (1:1 ethyl acetate:hexane, silica)
to give pentanedioic acid mono(2-{2-[2-(bicyclo[2.2.1]hept-5-
ene-2-carbonyloxy)ethoxy]ethoxy}ethyl) ester as a clear color-
1
less liquid (0.81 g, 83%). H NMR (300 MHz, CDC13): δ 5.15
(t, J ) 4.0 Hz), 5.04 (t, J ) 2.7 Hz), 4.73 (t, J ) 4.4 Hz), 4.57
(t, J ) 4.5 Hz; total 1H), 4.24-4.12 (m, 1H), 4.08-3.49 (m, 14
H), 3.33 (s, 3H), 2.75 (br, 1H). 13C NMR (75 MHz, CDC13): δ
102.9, 102.8, 100.3, 99.5, 76.7, 76.4, 72.3, 72.1, 71.8, 71.7, 71.4,
71.2, 71.1, 71.1, 71.0, 70.5, 70.4, 66.8, 66.5, 64.1, 64.0, 63.5,
62.4, 61.1, 59.0. IR (neat): 3437 (br), 2883.2, 1108.9, 863.0
cm-1. MS (CI, isobutene): m/z 237 (M), 163, 121 (100), 117,
103. Anal. Calcd for C10H20O6: C, 50.84, H, 8.53. Found: C,
50.79, H, 8.52.
1
less liquid (1.49 g, 82%). H NMR (400 MHz, CDCl3): δ 6.16
(m, 1H), 5.91 (m, 1H), 4.23-4.14 (m, 4H), 3.82-3.73 (m, 8H),
3.19 (s, br, 1H), 2.98-2.87 (m, 2H), 2.43-2.36 (m, 4H), 2.02-
1.84 (m, 3H), 1.42-1.23 (m, 3H). 13C NMR (100 MHz, CDCl3):
δ 177.7, 174.7, 172.8, 138.0, 137.7, 135.6, 132.3, 72.4, 70.4, 70.3,
69.2, 63.5, 63.2, 61.6, 49.5, 46.6, 46.2, 45.6, 43.1, 43.0, 42.4,
41.5, 33.0, 32.8, 30.3, 29.2, 19.9, 19.7. IR (neat): 3296 (br,
-OH), 2963, 2880 (CH stretch), 1760, 1722 (CdO), 1447, 1139,
717 cm-1. MS(El, 70 keV): m/z 385 (M + H), 367, 301, 247,
205. 159. 120, 99 (100). 66. 55. HRMS: calcd for C19H28O8
384.1784, obsd 384.1779. Anal. Calcd for C19H28O8: C, 59.36,
H, 7.34. Found: C, 59.31, H, 7.45.
2:3,4:5-Diisopropylidine Galactopyranose-6-uronic
Acid, 14. A solution of 2:3,4:5-diisopropylidine galactopyranose
(2.61 g, 10.0 mmol) in acetone (10 mL) was slowly added to a
solution of CrO3 (1.49 g, 15.0 mmol) in acetone (30 mL) at 0
°C. The mixture was warmed to ambient temperature and
stirred for 5 h. Ethyl acetate was carefully added to the
mixture and the reaction was washed with water. The organic
layer was washed with brine and dried over Na2SO4, and the
solvent was removed under reduced pressure. The residue was
subjected to column chromatography (silica, 1:1 ethyl acetate:
hexanes) to give 2:3,4:5-diisopropylidine galactopyranose-6-
uronic acid as a clear, colorless, viscous liquid that crystallized
upon standing. Yield: 2.23 g (81%). 1H NMR (400 MHz,
DMSO-d6): δ 5.52 (d, J ) 5.02 Hz, 1H), 4.64 (dd, J ) 2.43,
7.73, 1H), 4.49 (dd, J ) 2.15, 7.73, 1H), 4.39 (dd, J ) 2.49,
5.02, 1H), 4.17 (d, J ) 2.14, 1H), 1.42 (s, 3H), 1.31 (s, 3H),
Galactopyranose-6-uronic Acid 2-{2-[2-(Bicyclo[2.2.1]-
hept-5-ene-2-carbonyloxy)ethoxy]ethoxy}ethyl Ester, 8.
Compound 15 (0.29 g, 0.55 mmol) was dissolved in 8 mL of a
solution of 80% TFA (aq) and stirred for 3 h at ambient
temperatures. The solvent was removed under reduced pres-
sure and the residue subjected to column chromatography
J. Org. Chem, Vol. 70, No. 14, 2005 5559

Carlise et al.
1.27 (s, 3H), 1.26 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ
168.9, 108.7, 108.3, 95.8, 71.5, 70.1, 69.6, 67.4, 25.8, 25.7, 24.7,
24.4. IR (KBr): 3491 (br, O-H) 2985, 2937 (sp3 CH stretch),
1722 (acid CdO), 1456, 1375, 1211, (sp2 C-O), 1164, 1118,
1070, 1022 (sp3 C-O), 904, 840, 790, 692, 511 cm-1. Anal.
Calcd for C12H18O7: C, 52.55, H, 6.62. Found: 52.41, H, 6.63.
N-(2-Hydroxyethyl)-4-azaheptanedicarboxylic Acid Di-
(2-[2-{2-methoxyethoxy}ethoxy]ethyl ester), 17. Ethanol-
amine (0.28 g, 4.6 mmol) was added dropwise to a stirred
sample of 16 (2.06 g, 9.45 mmol) at ambient temperature. The
flask was capped and the mixture stirred for 24 h. The mixture
was subjected to column chromatography (silica, 49:1 CH2Cl2:
MeOH) to give N-(2-hydroxyethyl)-4-azaheptanedicarboxylic
acid di(2-[2-{2-methoxyethoxy}ethoxy]ethyl ester) as a clear
colorless liquid. Yield: 2.10 g (97%). 1H NMR (300 MHz,
CDCl3): δ 4.20 (t, 4H, J ) 4.7 Hz), 3.69-3.50 (m, 22 H), 3.35
(s, 6H), 2.98 (br, 1H), 2.77 (t, 4H, J ) 6.9 Hz), 2.55 (t, 2H, J )
4.9 Hz), 2.46 (t, 4H, J ) 6.9 Hz). 13C NMR (75 MHz, CDCl3):
δ 172.4, 71.9, 70.6, 70.5, 70.5, 69.0, 63.7, 59.1, 59.1, 56.0, 49.1,
32.6. IR (neat): 3408.1 (br), 2878.4, 1735.2, 1456.1, 1253.6,
1181.2, 1108.9, 853.4. MS (CI, isobutene): m/z 498.4 (M + 1,
100) 466, 334, 292, 103. HRMS: calcd for C22H43NO11 497.2836,
obsd 497.28353. Anal. Calcd for C22H43NO11: C, 53.10, H, 8.71,
N, 2.81. Found: C, 53.18, H, 8.65, N, 2.79.
General Procedure for Hydrolysis. The hydrolysis of all
monomers was carried out with 5 mM solutions of analyte in
buffers of pH 3.1 (phosphate/citric acid), 4.6 (acetate), 5.7
(acetate), 6.9 (phosphate), 7.4 (phosphate-buffered saline), and
8.9 (borate). The samples were heated to 37, 60, and 80 °C
((0.1 °C) in a thermostatic oil bath and samples (50 µL) were
withdrawn and diluted to 1.00 mL in the appropriate mobile
phase prior to HPLC analysis. Samples were stored at -15
°C when not immediately analyzed.
Acknowledgment. Financial support has been pro-
vided by Halliburton Energy Services. M.W. gratefully
acknowledges a 3M Untenured Faculty Award, a Du-
Pont Young Professor Award, an Alfred P. Sloan Fel-
lowship, and a Blanchard Assistant Professorship.
Supporting Information Available: General experimen-
tal details, additional experimental procedures and charac-
terization, and instrumental setup for the HPLC analysis. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050556A
5560 J. Org. Chem., Vol. 70, No. 14, 2005