Synthesis and conjugation of a triiodohydroxylamine for the preparation of highly X-ray opaque poly(ε-caprolactone) materials

Article abstract of DOI:10.1002/pola.28436

To address a need for highly X-ray opaque biodegradable materials, a series of poly(ε-caprolactone) derivatives were prepared using oxime post-polymerization modification to conjugate two different iodinated hydroxylamines. These materials were synthesized with up to 32 wt. % iodine content and demonstrated improved X-ray contrast relative to both the ketone precursors and previously reported monoiodinated materials.

Full text of DOI:10.1002/pola.28436

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Synthesis and Conjugation of a Triiodohydroxylamine for the Preparation
of Highly X-Ray Opaque Poly(e-Caprolactone) Materials
Brooke A. Van Horn,1 Lundy L. Davis,1 Samantha E. Nicolau,1 Emma E. Burry,1
Victoria O. Bailey,1 Fernanda D. Guerra,2 Frank Alexis,2,3 Daniel C. Whitehead4
1Department of Chemistry and Biochemistry, College of Charleston, 66 George Street, Charleston, South Carolina 29424
2Department of Bioengineering, Clemson University, 203 Rhodes Research Center Annex, Clemson, South Carolina 29634
3Department of Bioengineering, Institute of Biological Interfaces of Engineering, Clemson University, Clemson, South Carolina
29634-0905
4Department of Chemistry, Clemson University, 467 Hunter Laboratories, Clemson, South Carolina, 29634
Correspondence to: B. A. Van Horn (E-mail: vanhornba@cofc.edu)
Received 30 August 2016; accepted 1 November 2016; published online 00 Month 2016
DOI: 10.1002/pola.28436
ABSTRACT: To address a need for highly X-ray opaque biode-
gradable materials, a series of poly(e-caprolactone) derivatives
were prepared using oxime post-polymerization modification
to conjugate two different iodinated hydroxylamines. These
materials were synthesized with up to 32 wt. % iodine content
and demonstrated improved X-ray contrast relative to both the
ketone precursors and previously reported monoiodinated
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materials. 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A:
Polym. Chem. 2016, 00, 000–000
KEYWORDS: conjugation; iodine; oxime; polycaprolactone; X-ray
Moreover, the intended application of these materials in
medical imaging necessitates synthetic approaches that
result in biocompatible and potentially biodegradable prod-
ucts. For this reason, many groups including our own have
focused on polyester backbones,18–21 such as poly(e-capro-
lactone) (PCL), which have established biodegradability and
have been well-received in technology-transfer applications.
In this rapid communication, we report an expansion of our
recent work14,15 in the area of iodinated-PCL to include the
functionalization of poly(e-caprolactone-co-1,4-oxepan-1,5-
dione), P(CL-co-OPD), with a new synthetic O-(2,3,5-triiodo-
benyl)hydroxylamine to increase our material X-ray opacity.
In addition, we demonstrate that similar X-ray opacity to our
previously published monoiodo materials can be achieved
from the same P(CL-co-OPD) samples while keeping some of
the ketone handles free within the material for further func-
tionalization needs.
INTRODUCTION The design of new materials for cost-
effective and accessible medical imaging is an expanding
field that includes imaging modalities such as X-ray radiog-
raphy and computed tomography. Some of the strategies
which have emerged in contrast agent design take advan-
tage of the expanding synthetic capabilities offered and the
possibility for tailor-made polymers. The synthetic polymer
chemist’s toolbox is now equipped with a variety of func-
tional monomers and post-polymerization modification
reactions, including “Click”-type chemistries,1,2 to afford
these specialty functional materials. Within the scope of X-
ray opaque materials, a survey of recent literature features
synthetic polymers that exhibit X-ray contrast resulting
from the tunable iodine content of the materials prepared.
Some of the promising methods for the addition of iodine
to materials utilize covalently-bound iodine, such as (1)
polymerization of iodine-containing functional monomers
into polymers,3–11 and (2) post-polymerization modification
of prepared polymers with iodine12,13 or iodine-containing
small molecules.14–16 Our lab, alongside others in the field,
has focused on the second approach, and our strategy
hinges on the synthesis and post-functionalization of iodin-
ated hydroxylamines to ketone-containing polymers for the
preparation of novel X-ray opaque materials via oxime
chemistry.17
RESULTS AND DISCUSSION
To achieve the intended X-ray opacity in the functional PCL
materials, a triiodobenzyl hydroxylamine was prepared in
three synthetic steps from commercially available 2,3,5-triiodo-
benzyl alcohol as depicted in Scheme 1. An Appel reaction22 of
the alcohol with carbon tetrabromide and triphenylphosphine
Additional Supporting Information may be found in the online version of this article.
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SCHEME 1 Triiodohydroxylamine synthesis
in short reaction time (approximately 2 h) was employed to
afford 2,3,5-triiodobenzyl bromide, 1, in high yields consis-
tently > 85%. Subsequent reaction of the benzyl bromide with
N-hydroxyphthalimide in the presence of 18-crown-6 and
potassium carbonate allowed for the efficient conversion of
the bromide to the N-hydroxyphthalimido product, 2, after an
aqueous extraction and filtration over a silica plug to remove
the unreacted N-hydroxyphthalimide and 18-crown-6. The
phthalimido derivative was found to be stable for storage for
long times (>6 months) in a refrigerator and was used as an
intermediate. The desired O-(2,3,5-triiodobenzyl)hydroxyl-
amine, 3, was achieved by exposure of 2 to excess hydrazine
monohydrate in THF solution in less than 2 h as observed by
1H NMR spectroscopy and TLC. A quick purification of the
crude reaction using flash chromatography with 1% methanol
in dichloromethane afforded the pure product as a white solid
in >90% yield. All three small molecules were characterized
by 1H and 13C NMR spectroscopy, with appropriate shifts in
the benzylic hydrogen and carbon resonances in conversion of
AOH to ABr, ABr to AONPhth, and AONPhth to AONH2
being observed along with the appearance and disappearance
of the phthalimido group through the reactions.
benzylic hydrogens after conjugation [Fig. 1(a)] along with
the subtle but important shifts in the methylene protons of
the ester positions [Fig. 1(b)] and the carbonyl alpha-
hydrogens [Fig. 1(c)] in the OPD units before and after con-
jugation with the mono- and triiodohydroxylamines. Addi-
tional aromatic resonances in the 8.2–7.5 ppm region of the
proton spectra were also detected. Complete conversion of
the OPD units to mono- and triiodo oxime conjugates is clear
from these spectra. Moreover, exposure of the P(CL-co-OPD)
polymers to approximately 0.35 equivalents of O-(2,3,5-triio-
dobenzyl)hydroxylamine resulted in polymer conjugates with
measured conversions of OPD to oxime units of 38% and
41% for 7a and 7b, respectively. These conjugation conver-
sions were determined by integration of the ACH2AO(CO)A
ester protons in the OPD and oxime conjugated units as
depicted in Figure 1(c), and these are reasonable given the
potential experimental error for the masses measured and
the error of 1H NMR spectroscopy integrations. It is also
important to note that no unconjugated/free hydroxylamine
1
was detected at 4.69 ppm for the benzylic ACH2A in the H
NMR spectra (Supporting Information Fig. S1) to give artifi-
cially high X-ray contrast in our later X-ray imaging and
analysis.
With the pure triiodohydroxylamine in hand, acid-catalyzed
oxime conjugation reactions with previously synthesized
(PCL-co-OPD) polymers 5a and 5b were employed to pre-
pare the targeted highly iodinated PCLs, 8a and 8b, as
described in Scheme 2 and Table 1. These fully conjugated
materials were synthesized alongside equivalent mono-
iodinated polymers (using our previously reported O-(2-
iodobenzyl)hydroxylamine15)) 6a and 6b as well as partially
conjugated triiodo species 7a and 7b. The partial conjuga-
tion with the triiodohydroxylamine was performed to investi-
gate whether similar X-ray opacity to the monoiodo
materials could be achieved while keeping some of the
ketone units free for further conjugation reactions.
Further characterization of the materials by 13C NMR spec-
troscopy revealed new oxime A(C @ N) A resonances in the
156–157 ppm region of the spectra for conjugates 6a–8a
and 6b–8b with complete disappearances of the ketone car-
bonyl resonances for 6a, 8a, 6b, and 8b, from 205 to 206
ppm as visualized in Figure 2. Gel permeation chromatogra-
phy revealed very little change in the apparent molecular
weight of the polymers and their conjugates as noted by the
small shift in the Mn, Mw, and Mp before and after the conju-
gation steps, as shown in Figure 3 and Table 1 for samples
4a through 8a. In addition, the GPC results indicate no evi-
dence of unwanted or premature degradation of the polymer
backbone during the conjugation reactions, as the polydis-
persity of the samples was also relatively consistent between
conjugated samples from each P(CL-co-OPD) and the conju-
gated materials.
Each conjugate material was initially characterized by 1H
and 13C NMR spectroscopy as well as gel permeation chro-
matography. Figure 1 illustrates the appearance of the
2
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while its fully-monoidinated conjugate, 6a, gave a broad Tm
ranging from 35.7 to 44.2 8C. This depression in the melting
transition can be attributed to the disruption of the polymer
crystallinity by the attached large aromatic side chains, as
was reported and observed previously.14,15,23,24 The partially
and fully conjugated triiodo samples, 7a and 8a, respectively,
also displayed lower Tm values of 51.9 and 35.0 8C with the
partial conjugation 7a giving the intermediate Tm.
In addition, thermogravimetric analysis of the P(CL-co-OPD)
unconjugated samples and the iodinated conjugates followed
the expected trends as visualized in Supporting Information
Figure S3. Early decomposition of the OPD units (for 5b and
7b) between 200 and 300 8C was noted while the full conju-
gate (or conjugated portions) of the polymer 6b exhibited
decomposition between 275 and 350 8C with the triiodo con-
jugates including 8b showing continued rapid degradation to
less than 15% mass remaining by approximately 380 8C.
These results are consistent with previous observations of
lower thermal stability of the oxime conjugates of OPD poly-
mers in the literature.15
The X-ray contrast imaging properties of the functionalized
monoiodo and triiodo copolymers were then examined in
parallel. The iodine content of the final copolymers was cal-
culated to be 15.7, 16.4, and 32.4 weight percent iodine for
samples 6a, 7a, and 8a, respectively, for a fully conjugated
monoiodo sample, a partially conjugated triiodo sample, and
a fully conjugated triiodo sample. The percentages were cal-
culated with the assumption that each ketone reacts with
the monoiodo or triiodo hydroxylamine at the level sug-
gested by the proton NMR data. Figure 4(a) depicts the X-
ray contrast signal of disks with uniform size and weight of
the P(CL-co-OPD) unmodified polymer 5b alongside each of
the three conjugate polymers (6a, 7a, and 8a) with blank
wells between each sample. These images show the expected
trend of the unmodified sample having the lowest X-ray
opacity, the full monoiodo 6a and partial triiodo conjugates
7a being of intermediate contrast and the full triiodo conju-
gate 8a affording the highest contrast. Figure 4(b) graphical-
ly represents the observed numerical contrast X-ray intensity
for all six conjugated samples using ImageJ (NIH) and nor-
malized to the empty wells background signal. The numeri-
cal values for the X-ray intensities differ slightly from the
expected NMR calculated values but the trend among sam-
ples is as predicted, with the triiodo sample 8a being almost
doubly opaque as the monoiodo sample 6a.
SCHEME 2 Synthesis of iodinated PCL materials
CONCLUSIONS
In this rapid communication, we have illustrated the use of a
triiodohydroxylamine in the partial and full conjugation of
P(CL-co-OPD) polymers for the creation of highly X-ray opa-
que degradable polyester materials through post-
polymerization modification reactions and documented the
thorough characterization of these materials. The increased
X-ray contrast offered by the triiodo species and the remain-
ing ketone units within the partially-conjugated polymer
chains will now allow us to target multi-functional materials
Thermal characterization of the materials was conducted
using differential scanning calorimetry (DSC) to further con-
firm the anticipated effects of the conjugation of the iodinat-
ed small molecules to the polymers. The DSC results
(Supporting Information Fig. S2) confirmed that all of the
conjugates had lower and broader melting transition (Tm)
temperatures relative to the parent P(CL-co-OPD) polymers.
For example, sample 5a had an observed Tm peak of 60.9 8C
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TABLE 1 Monoiodinated and Triiodinated PCL Characterization Data
Weight
Iodine
Contentd
Conversion
to Oximeb
Mn
Mw
Mn (g mol21
)
1H NMRa
Sample Typea
(g mol21 c
)
(g mol21 c
)
Mw/Mn
c
Entry
4a
5a
6a
7a
8a
4b
5b
6b
7b
8b
P(CL78-co-TOSUO16
)
na
11,300
16,200
17,100
17,300
17,400
8300
22,300
23,400
24,100
24,400
24,700
13,800
15,200
16,300
16,800
16,700
1.98
1.44
1.41
1.41
1.42
1.72
1.35
1.33
1.31
1.32
11,800
11,100
13,000
14,000
18,800
10,100
9600
na
P(CL78-co-OPD16
P(CL78-co-(OPD-mod-Mono-I)16
P(CL78-co-OPD10-co-(OPD-mod-Tri-I)6)
P(CL78-co-(OPD-mod-Tri-I)16
P(CL71-co-TOSUO11
P(CL71-co-OPD11
P(CL71-co-(OPD-mod-Mono-I)11
P(CL71-co-OPD6.5-co-(OPD-mod-Tri-I)4.5
P(CL71-co-(OPD-mod-Tri-I)11
)
na
na
)
100%
38%
100%
na
15.7
16.4
32.4
na
)
)
)
na
11,200
12,300
12,900
12,700
na
)
100%
41%
100%
10,900
11,800
14,900
12.8
14.5
28.1
)
)
a
b
As determined by 1H NMR spectroscopy benzylic end group analysis
and CL to TOSUO mole ratio in the MeOH isolated polymers; Mono-
I 5 conjugation with O-(2-iodobenzyl)hydroxylamine; Tri-I 5 conjugation
with O-(2,3,5-triiodobenzyl)hydroxylamine, 3; P(CL-co-TOSUO) and
P(CL-co-OPD) syntheses previously reported in Reference #15 – DOI:
10.1002/pola.27706.
As calculated from 1H NMR spectroscopy integration of methylene
groups from OPD and oxime modified OPD units within the polymer
chain.
c
As determined by GPC using refractive index response of parallel sin-
gle runs against polystyrene standards for calibration.
d
Calculated from 1H NMR spectra using the percent conversion to
oxime assuming each oxime adds one or three iodine atoms.
from various hydroxylamines for specific biomedical applica-
tions and provide a route to achieve new versatile X-ray visi-
ble materials.
Fisher Scientific or VWR and used as received. Para-
toluenesulfonic acid monohydrate (TsOH, Sigma Aldrich) was
dissolved in THF to afford a 0.02 M solution.
EXPERIMENTAL
Characterization
Proton and carbon nuclear magnetic resonance (1H and 13C
NMR) spectroscopy experiments were conducted using a
400 MHz Bruker AVANCE III HD-NanoBay spectrometer.
Samples were acquired in deuterated chloroform for nt 5 64
or 256 for proton and nt 5 1024 or 4096 for carbon experi-
ments of small molecules and polymers, respectively. NMR
figures were generated using MNova 10.0 software. The
weight percent iodine were determined by integration of the
ACH2AO(CO)A ester protons in the OPD and oxime
Materials
2,3,5-triiodobenzyl alcohol, carbon tetrabromide, triphenyl-
phosphine, N-hydroxyphthalimide, potassium carbonate, 18-
crown-6, and hydrazine monohydrate were purchased from
Sigma Aldrich and used as received. Anhydrous sodium sul-
fate was purchased from Fisher Scientific and used as
received. All other solvents (hexanes, methanol (MeOH),
dichloromethane (CH2Cl2), acetone, deuterated chloroform
(CDCl3), and tetrahydrofuran (THF)) were purchased from
FIGURE 1 1H NMR spectral overlay of P(CL78-co-OPD16) 5a with iodinated PCL conjugates 6a, 7a, and 8a comparing the changes in
the (a) benzylic position, (b) ester methylene, and (c) alpha carbon to carbonyl regions before and after conjugation with mono-
and triiodo hydroxylamines.
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FIGURE 2 13C NMR spectral overlay of iodinated PCL conju-
gates 6b, 7b, and 8b in the ketone, ester, and oxime regions.
1
conjugated units from H NMR spectra assuming each oxime
adds one or three iodine atoms.
FIGURE 4 (a) X-ray images comparing unmodified P(CL78-co-
OPD16) 5a with a fully mono-iodinated conjugate 6a, a fully tri-
iodinated conjugate 8a, and a partially tri-iodinated conjugate
7a, and (b) graphical representation of the normalized X-ray
intensities for all X-ray samples.
GPC data were acquired on a Malvern GPCMax equipped at
35 8C using a Viscotek refractive index detector (VE3580)
with inhibited THF as an eluent. Samples were prepared at
1.0 mg/mL in THF and filtered through 0.2 lm PTFE syringe
filters (VWR International). Separation was achieved through
use of the following columns in series: Malvern (CLM3008-
Tguard) Organic Guard Column (10 mm 3 4.6 mm), Waters
Styragel HR 4ETHF, and Malvern (T6000M) General Mixed
Bed (300 mm 3 7.8mm) over a 30 min sample run with
molecular weights and polydispersity calculated from a
third-order calibration curve from twelve different polysty-
rene standards Mp ranging from 1050 to 3.8 3 106 Da.
180 8C at 5 8C per min. Thermogravimetric Analysis (TGA)
was performed on a TA Instruments Hi-Res TGA 2950 ther-
mogravimetric analyzer by running samples from 25 to 600
8C at 10 8C per min under nitrogen.
X-ray imaging was performed using a Tingle 325MVET X-ray
machine with 51 kVp, 300 mA and 5 ms exposure time. X-
ray samples were prepared from ꢀ10 mg disk each sample
including the synthesized P(CL-co-OPD) copolymer, 5a, and
its corresponding functionalized copolymers, 6a, 7a, and 8a.
All X-ray images were processed and image intensities quan-
tified using ImageJ (NIH) normalized to unmodified polymer.
Differential Scanning Calorimetry (DSC) experiments were
conducted on a Perkin Elmer DSC 7 over a range of 220 to
Synthesis of 2,3,5-Triiodobenzyl Bromide, 1
2,3,5-Triiodobenzyl alcohol (2.0 g, 4.1 mmol, 1.0 eq.) was
added to a 100 mL round bottom flask followed by 10 mL
of CH2Cl2 and allowed to stir for 10 min. Carbon tetrabro-
mide (1.77 g, 5.3 mmol, 1.3 eq.) was added to the reaction
flask to yield a white cloudy solution. Subsequently, triphe-
nylphosphine (1.61 g, 6.2 mmol, 1.5 eq.) was added to
afford a slightly yellow solution. The reaction completion
was monitored by TLC with CH2Cl2 eluent. No more starting
material alcohol was observed after approximately 2 h.
When complete, the reaction mixture was passed through a
silica gel plug on a frit, washed with additional 100 mL of
1:1 hexanes to CH2Cl2, and concentrated by rotary evapora-
tion to afford a white solid. Yield: 2.01 g (89% isolated). 1H
NMR (400 MHz, CDCl3, d): 8.12 (s, 1H, Ar H), 7.70 (s, 1H,
Ar H), 4.64 (s, 2H, benzyl ACH2A) ppm; 13C NMR (100
MHz, CDCl3, d): 146.9, 144.6, 137.8, 113.5, 112.4, 94.5, 41.3
ppm.
FIGURE 3 Overlay of GPC curves of copolymers 4a, 5a, 6a, 7a,
and 8a.
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Synthesis of 2,3,5-Triiodobenzyl-N-hydroxyphthalimide, 2
2,3,5-Triiodobenzyl bromide (1.0 g, 1.8 mmol, 1.0 eq.) was
added to a 250 mL RBF. Acetone (50 mL) was used as sol-
vent and the solution was allowed to stir approximately 5
min prior to adding 18-crown-6 (0.095 g, 0.36 mmol, 0.20
eq.), K2CO3 (0.43 g, 3.1 mmol, 1.7 eq.), and N-hydroxyphtha-
limide (0.45 g, 2.7 mmol, 1.5 eq.) to yield an orange color
change. The reaction was allowed to proceed overnight
where an additional color change from orange to purple was
observed. The reaction completion was monitored by TLC in
CH2Cl2 and verified by 1H NMR spectroscopy. Removal of
acetone solvent was achieved by rotary evaporation followed
by transfer to an Erlenmeyer flask using 100 mL CH2Cl2,
50 mL H2O, and 50 mL saturated NaHCO3 and stirring for
30 min. The quenched solution was separated into an orange
aqueous layer and a colorless organic phase. The aqueous
layer was further extracted with 3 3 50 mL CH2Cl2 and
combined with the original organic layer, washed 23 with
50 mL saturated NaHCO3, and then 50 mL of brine. The
crude product was further purified by filtration through sili-
ca plug on a frit to remove 18-crown 6, followed by a rinse
with 100 mL CH2Cl2 and drying of the eluent with anhy-
drous sodium sulfate. The filtrate was concentrated by rotary
evaporation and high vacuum to yield a white solid. Final
Yield: 1.09 g (95% isolated). 1H NMR (400 MHz, CDCl3, d):
8.21 (d, 1H, Ar H), 7.93 (d, 1H, Ar H), 7.86 (dd, 1H, phthali-
mido), 7.78 (dd, 1H, phthalimido), 5.28 (s, 2H, benzyl
ACH2A) ppm; 13C NMR (100 MHz, CDCl3, d): 163.2, 147.1,
141.5, 137.4, 134.4, 128.8, 123.7, 111.7, 111.3, 94.5, 85.0
ppm.
P(CL71-co-(OPD-mod-Tri-I)11)), 8b. P(CL71-co-OPD11) polymer
(0.60 g, 0.69 mmol ketone, 1.0 eq. of ketone) and THF
(9 mL) were added to a 20 dram scintillation vial and
allowed to stir. O-(2,3,5-triiodobenzyl)hydroxylamine (0.45 g,
0.90 mmol, 1.3 eq. per ketone) was added to the reaction
flask via pipette (as a solution in THF) followed by 2–3
drops of 0.02 M TsOH to catalyze the reaction. Reaction was
allowed to stir overnight and then precipitated in ice cold
methanol, collected over a course frit and dried further via
high vacuum. Final Yield: 0.766 g, 82% isolated as P(CL71
-
co-(OPD-mod-Tri-I)11)). 1H NMR (400 MHz, CDCl3, d): 8.15
(two s, 1H, Ar H oxime isomers), 7.51–7.49 (two d, 1 H, Ar
H oxime isomers) 7.4–7.35 (m, 5H, Ar H end group), 5.12 (s,
2H, benzylic H), 5.01–4.98 (two s, 2H, ACH2ONA oxime iso-
mers), 4.31–4.25 (overlapping t, 2H, ACH2OCOA oxime iso-
mers), 4.05 (t, 2H, ACH2OCOA CL), 3.65 (t, 2H, ACH2OH
end group), 2.75–2.50 (three t, 6H, OCOCH2CH2C(oxime)CH2-
CH2O- OPD oxime isomers), 2.31 (t, 2H, AOCOCH2A CL),
1.65 (m, 4H, AOCOCH2CH2CH2CH2CH2OA CL), 1.38 (m, 2H,
AOCOCH2CH2CH2CH2CH2OA CL) ppm. 13C NMR (100 MHz,
CDCl3, d): 173.5, 173.2, 172.6, 172.4, 157.7, 157.0, 146.0,
145.4, 136.5, 136.5, 111.8, 110.2, 94.5, 81.5, 81.4, 64.7, 64.4,
64.1, 60.8, 60.4, 53.4, 34.1, 34.0, 33.7, 30.2, 30.0, 29.8, 29.1,
28.4, 25.6, 24.6, 24.5 ppm; Tm, DSC 5 42.7 8C (range 36.3–
45.3 8C); TGA analysis: 25–270 8C, ꢀ0% mass loss; 270–325
8C, ꢀ25% mass loss; 320–380 8C, 85% mass loss; up to 600
8C, plateau to ꢀ92% mass loss.
ACKNOWLEDGMENTS
This work has been supported by multiple College of Charles-
ton sources to provide undergraduate researcher and faculty
stipends, supplies, and instrument time. The internal sources
include start-up funds, the Department of Chemistry and Bio-
chemistry, and the Undergraduate Research and Creative Activ-
ities office (SURF awards including SU2013-011 and SU2013-
035; RPGs including RP2013-007, RP2013-010, RP2014-010,
and RP2014-017). In addition, this research was supported by
a grant from the Howard Hughes Medical Institute to the Col-
lege of Charleston as part of their 2012 Undergraduate Science
Education Competition and by grants from the National Center
for Research Resources (5 P20 RR016461) and the National
Institute of General Medical Sciences (8 P20 GM103499) from
the National Institutes of Health. The National Science Founda-
tion MRI program (Grant No. 1429308) is also acknowledged
for the acquisition of the 400 MHz NMR instrument used in this
study. We would like to thank Kim Ivey for TGA and DSC
experiments.
Synthesis of O-(2,3,5-Triiodobenzyl)Hydroxylamine, 3
2,3,5-Triiodobenzyl hydroxyphthalimide (1.0 g, 1.6 mmol, 1.0
eq.) and THF (50 mL) were combined in a 200 mL RBF until
dissolved. Hydrazine monohydrate (0.50 mL, 10.0 mmol, 6.2
eq.) was added by syringe to the reaction and a light yellow
color change was observed. The reaction was allowed to pro-
ceed for 2 h at room temperature. A crude aliquot of reac-
1
tion mixture was analyzed by TLC and H NMR spectroscopy
to confirm the reaction was complete. The product was then
purified by flash column chromatography using 1% MeOH in
CH2Cl2 eluent. The product fractions were collected and con-
centrated in vacuum to afford a white solid. Yield: 0.72 g
1
(91% isolated). H NMR (400 MHz, CDCl3, d): 8.16 (d, 1H, Ar
H), 7.63 (d, 1H, Ar H), 5.60 (broad s, 2H, ANH2), 4.69 (s, 2H,
benzyl ACH2A) ppm; 13C NMR (100 MHz, CDCl3, d): 146.1,
145.0, 136.4, 111.9, 110.8, 94.5, 83.6 ppm.
General Polymer Synthesis
The syntheses of the P(CL-co-TOSUO) 4a and 4b, P(CL-co-
OPD) 5a and 5b, and P(CL-co-(OPD-mod-Mono-I)) 6a and 6b
materials were previously reported here in Polymer Chemis-
try.15 The materials 5a–8a and 5b–8b of this paper were
produced from the same the shelf-stable P(CL-co-TOSUO)
samples as that report.
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