Investigation of the dynamic nature of 1,2-oxazines derived from peralkylcyclopentadiene and nitrosocarbonyl species

Article abstract of DOI:10.1039/c6ob00400h

We have investigated the reversible hetero-Diels-Alder reaction of 1,2-oxazines derived from a peralkylcyclopentadiene and a series of nitrosocarbonyl dienophiles. The nature of the dienophile was found to impart broad tunability to the dynamic character of the oxazine adducts. The reversibility was also observed in polymeric systems. The fidelity of the reaction and tunable sensitivity toward elevated temperature and water signify potential applications in the development of dynamic covalent materials or delivery systems for small molecule payloads.

Full text of DOI:10.1039/c6ob00400h

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Investigation of the dynamic nature of 1,2-
oxazines derived from peralkylcyclopentadiene
and nitrosocarbonyl species†
Cite this: Org. Biomol. Chem., 2016,
14, 5617
Received 20th February 2016,
Accepted 26th April 2016
Victoria K. Kensy,a Gregory I. Peterson,‡a Derek C. Church,a Neal A. Yakelisb and
Andrew J. Boydston*a
DOI: 10.1039/c6ob00400h
www.rsc.org/obc
We have investigated the reversible hetero-Diels–Alder reaction of
1,2-oxazines derived from a peralkylcyclopentadiene and a series
of nitrosocarbonyl dienophiles. The nature of the dienophile was
found to impart broad tunability to the dynamic character of the
oxazine adducts. The reversibility was also observed in polymeric
systems. The fidelity of the reaction and tunable sensitivity toward
elevated temperature and water signify potential applications in
the development of dynamic covalent materials or delivery
systems for small molecule payloads.
Fig. 1 Generalized depiction of the reversible HDA reaction of
nitrosocarbonyls.
architectures and functional materials. A key example from
Read de Alaniz and coworkers demonstrated application of
nitrosocarbonyl HDA reactions to prepare block copolymers
via highly efficient polymer chain end coupling.15 In their
report, reactive nitrosocarbonyl dienophiles were generated
in situ at polymer chain ends either by oxidation of hydroxamic
acids or cycloreversion of 9,10-dimethylanthracene-based
adducts. In the presence of a complementary cyclopentadiene-
terminated polymer, efficient chain end coupling was
accomplished.
Inspired by this movement toward applications in the
polymer field, we considered integration of polymer chain end
coupling and nitrosocarbonyl hydrolysis to enable controlled
deconstruction of block copolymers.16 For this purpose, the
1,2-oxazine moiety was employed as a thermally labile trigger.
Upon thermolysis, subsequent hydrolysis of the nitrosocarbo-
Introduction
For decades, the hetero-Diels–Alder (HDA) reaction of nitroso-
carbonyl species has been utilized as a versatile synthetic
transformation for production of 1,2-oxazines (Fig. 1).1–7
Attractive aspects include the potential for regio- and stereo-
controlled introduction of nitrogen and oxygen into carbon
frameworks, and ample opportunities for downstream
manipulation of the N-substituted oxazine. In a subset of
examples of 1,2-oxazine applications, the ready reversibility of
the HDA reaction was targeted as a means to control in situ
generation of highly reactive nitrosocarbonyl moieties. For
example, King, Miyata, and Toscano have highlighted the
potential to use this cycloreversion for generation of HNO, a
purported therapeutic, presumably following hydrolysis of the
nitrosocarbonyl intermediate.8–14
nyl intermediate initiated
a controlled depolymerization
sequence leading to deconstruction of a self-immolative
polymer block. Clearly, the “click-like” nature of the HDA reac-
tion, tunable cycloreversion of oxazines, diverse reactivity of
nitrosocarbonyl species, and overall structural modularity
provide a powerful combination for advances in polymer and
materials designs.
More recently, the dynamic HDA reaction of nitrosocarb-
onyls has been applied in the design of advanced polymeric
We became interested in the potential applications of poly-
mers and network materials bearing high densities of oxazine
moieties. One may envision, for example, taking advantage of
robust dynamic covalency to access covalent adaptable net-
works as has been demonstrated for Diels–Alder and HDA
adducts.17–21 Such systems display broad tunability with
regard to stimuli-responsiveness and overall materials pro-
perties, stemming largely from the modularity of the diene
and dienophile building blocks. On the other hand, controlled
aDepartment of Chemistry, University of Washington, Seattle, Washington 98195,
USA. E-mail: ajb1515@uw.edu
bDepartment of Chemistry, Pacific Lutheran University, Tacoma, Washington 98447,
USA
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, extended plots for 8, and characterization of all new compounds.
CCDC 1454902 and 1454903. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c6ob00400h
‡Current address: Department of Polymer Science, University of Akron, Akron,
Ohio, 44325, USA.
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breakdown of oxazine-rich materials could enable controlled mediate was then used to prepare a series of oxazines via HDA
release of HNO. HNO generation has received a lot of attention reaction with nitrosocarbonyl species generated in situ.1,28–30
in recent years due to its purported use as a treatment of
We initially evaluated the use of CuCl/pyridine to catalyze
cardiovascular diseases and as an anticancer agent.22–26 the nitrosocarbonyl formation. Although good yields of 11
Notably, the breadth of potential applications place disparate were achieved via oxidation of 7 in the presence of 3, ana-
demands on the reactivity of the oxazine and constituent nitroso- logous reactions with coupling partners 4–6 were met with
carbonyl species (high fidelity cycloaddition/cycloreversion limited success. Turning instead to tetrabutylammonium peri-
versus hydrolytic instability) while maintaining a need for odate (TBAP) as a stoichiometric oxidant remedied the situ-
retro-HDA reactions to take place at moderate temperatures. ation, providing the corresponding oxazines 8–10 in good to
To further explore the chemical space and potential appli- excellent yields. Notably, each oxazine was isolated as a
cations of oxazine-based systems, we have investigated the mixture of what appeared to be a roughly 3 : 1 ratio of two dia-
reversibility and robustness of a series of oxazines relevant to stereomers (each racemic).
polymer-oriented applications. Herein, we describe our investi-
Separation of the isomers by standard chromatographic
gations of the reactivity of oxazines derived from a series of techniques was unsuccessful. However, we found that slow
nitrosocarbonyl dienophiles and a peralkylcyclopentadiene. vapour diffusion of diethyl ether into solutions of 10 in
Particular focus is placed upon comparative analysis of the CH2Cl2 produced single crystals suitable for X-ray analysis. We
reversibility of the HDA reaction as a function of nitrosocarb- were able to separate crystals that were ultimately found to be
onyl structure, and overall fidelity of the cycloaddition/cyclo- individual diastereomers 10a and 10b (Fig. 3), which can be
reversion equilibrium versus deleterious side reactions.
viewed as anti and syn isomers, respectively. With small quan-
tities of each diastereomer of 10 at hand, we were able to
obtain a discrete H NMR spectrum for each. From these, we
1
identified 10a as the major diastereomer produced in the
initial mixture of products. The CH3 groups indicated in Fig. 3
proved to be useful diagnostic handles for 1H NMR analyses
and tracking of anti and syn isomers for oxazines 8, 9, and 11
by analogy to 10.
Results and discussion
Motivated by potential downstream applications in the devel-
opment of functional polymeric materials, we targeted
oxazines that were based upon readily polymerizable norbor-
nene frameworks.27 Additionally, we centered upon cyclopenta-
diene-based oxazines to provide an attractive starting point
for balance between stability and reversibility of the HDA
adducts. Toward this end, coupling of carboxylic acid 1 and
alcohol 2 in the presence of carbonyldiimidazole (CDI) pro-
vided ester 3 in 70% isolated yield (Fig. 2). This pivotal inter-
We next turned toward probing the dynamic nature of each
oxazine. Specifically, each set of isomers was heated in DMSO-
1
d6 (15 mM) and monitored by H NMR spectroscopy. In each
case, the initial mixture contained a roughly 3 : 1 ratio of dia-
stereomers, which equilibrated to a roughly 1 : 1 ratio over
time. At ambient temperature, no observable isomerization
took place for any of the oxazines over the course of several
hours. When heated at 37 °C (Fig. 4, top), we observed gradual
equilibration of the diastereomers with strong dependence
upon the nature of the nitrosocarbonyl component. For
example, oxazine 8 did not appear to reach equilibrium even
Fig. 3 Molecular structures obtained via single crystal X-ray analysis of
(left) 10a, and (right) 10b. Ellipsoids drawn at the 50% probability level,
protons removed for clarity.
Fig. 2 Synthesis of norbornene-tethered oxazine isomers. In each case,
reactions proceeded to 100% conversion as judged by TLC.
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ible isomerization over the course of several days, whereas
changes in the diastereomeric ratios for 10 and 11 appeared to
have ceased after a few hours. Further increase in the tempera-
ture to 80 °C (Fig. 4, bottom) resulted in full equilibration
within minutes for 10 and 11 (50 and 25 min, respectively),
whereas the composition of 8 continued to show gradual
change over the course of several hours (see ESI† for extended
plots).
As stated previously, the oxazine retro-HDA reaction
releases nitrosocarbonyl species, which have the potential to
undergo hydrolysis, dimerization, or ene reactions.32 These
deleterious reactions were not observed to any appreciable
extent in the experiments represented in Fig. 4 despite pro-
longed reaction times and no special precautions being taken
to dry the DMSO solvent. To explore the oxazine reactivity in
aqueous environment, we examined each of the oxazines at
60 °C in a 30% D2O/DMSO-d6 mixture, which was the
maximum D2O content at which each of the oxazines
remained soluble at room temperature. Each oxazine mixture
1
was monitored by H NMR spectroscopy for 156 h. Oxazines 8
and 9 showed no loss of oxazine content and isomerization
rates similar to those observed in DMSO-d6. In contrast, exam-
ination of oxazine 10 revealed a small amount of cyclopenta-
diene 3 (4.5%) developing over the course of the experiment
(Fig. 5, top). Presumably, the formation of 3 can be ascribed to
Fig. 4 Equilibration of oxazines in DMSO-d6. Solid line = isomer A,
dashed line = isomer B. Black = 8, red = 9, blue = 10, green = 11. Data
points are an average of three runs, errors bars = one standard deviation,
lines are for visual aid only.31 Percent composition refers to the ratio of
isomers A and B.
within 12 d at 37 °C, indicating much slower isomerization
than oxazines bearing more electron donating substituents
(cf. 9–11). Oxazine 9 appeared to isomerize more rapidly than
8, but also continued to show gradual change in the ratio of
isomers up to 12 d. The hydroxyurea-derived systems (10 and
11) were found to approach equilibrium at the highest relative
rates. The facile isomerization, particularly of 10 and 11, at
37 °C suggests to us that these platforms may be suitable for
incorporation into dynamic covalent networks or related
materials that become active under biological conditions.
The general trend in isomerization rate (8 < 9 < 10 < 11) was
preserved at the higher temperatures as well (Fig. 4). At 60 °C
Fig. 5 Equilibration and hydrolysis of oxazines in D2O/DMSO-d6 at
60 °C.31 Solid line = isomer A, dashed line = isomer B. (top) Oxazine 10
in blue, cyclopentadiene 3 in orange. (bottom) Oxazine 11 in green,
cyclopentadiene 3 in orange. Data points are an average of two runs,
lines are for visual aid only. Percent composition refers to the fraction of
(Fig. 4, middle), the least reactive oxazine (8) displayed discern- each species relative to the total sum of isomer A, isomer B, and 3.
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hydrolysis of the intermediate nitrosocarbonyl species. When
oxazine 11 was examined under the aqueous reaction con-
ditions, we found nearly complete loss of both oxazine
isomers and concomitant formation of 3 (Fig. 5, bottom).
Collectively, these results confirm that the oxazine moiety can
be structurally tuned toward either robust dynamic behaviour
or controlled degradation.
Encouraged by the results from the small molecule oxazine
studies, we next explored whether the dynamic nature would
remain consistent within related polymeric systems. Toward
this end, we synthesized poly(11) via ring-opening metathesis
polymerization (ROMP) using a third-generation Grubbs cata-
lyst (Fig. 6).33 Specifically, monomer 11 was reacted with the
Ru-based initiator (35 : 1 initial monomer to initiator ratio) in
CH2Cl2 at 0 °C for 3 h, at which point full consumption of
monomer was confirmed by 1H NMR analysis. Following ter-
mination of the polymerization with ethyl vinyl ether, filtration
through alumina/Celite, and isolation by precipitation of the
polymer into methanol, we obtained poly(11) in 57% isolated
yield. Analysis of poly(11) by 1H NMR spectroscopy and gel-per-
meation chromatography (GPC) indicated intact oxazines (3 : 1
ratio of isomers), a weight-average molecular weight (Mw) of
30.0 kDa, and a molecular weight dispersity (Đ) of 1.05.
With poly(11) at hand, we then monitored the isomeriza-
tion of the oxazine units using a solution of the polymer in
DMSO-d6 at 60 °C and variable-temperature 1H NMR spec-
troscopy (VT-NMR). The alkene proton resonances within the
polymer backbone were compared with the diagnostic methyl
signals of the oxazine isomers over the course of the experi-
ment. Under these conditions, poly(11) showed no signs of
degradation of the oxazine units and complete isomerization
within 5 h, consistent with the equilibration time of monomer
11 (Fig. 7).
Fig. 7 Equilibration of oxazine 11 (green) and poly(11) (purple) in
DMSO-d6 at 60 °C. Solid line = anti isomer, dashed line = syn isomer.
Percent composition refers to the ratio of anti and syn isomers.
To investigate the potential for dynamic nitrosocarbonyl
exchange from the polymeric system, poly(11) was heated at
60 °C in the presence of either oxazine 9 or 10, each in a 2 : 1
ratio relative to oxazine repeat units in poly(11) (Fig. 8). After
heating each mixture, the solution was added dropwise into an
excess of cold methanol, causing selective precipitation of
the polymeric species. In each case, 1H NMR analysis of the
final polymers revealed signals consistent with successful
conversion of oxazine units, giving rise to poly(9-co-11) and
poly(10-co-11) from the corresponding small molecule
Fig. 8 Dynamic oxazine crossover between poly(11) and small mole-
cule oxazines 9 and 10. Oxazines are a mixture of anti and syn isomers;
single isomer shown for simplicity.
oxazines. Each copolymer was found to have a ca. 2 : 1 ratio of
oxazine units consistent with the initial feed ratios. These
experiments confirm the ability to successfully crossover
oxazine functionality with a polymeric system, and may
provide opportunities for post-polymerization modifications
and reversible crosslinking strategies.
Conclusions
We have investigated a series of N-carbonyl-substituted ox-
azines that display readily reversible HDA reactivity. Coinciden-
tal production of a diastereomeric mixture of each oxazine
Fig. 6 ROMP of 11 to produce poly(11). Oxazines are a mixture of anti
and syn isomers; single isomer shown for simplicity.
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We gratefully acknowledge financial support from the National
Science Foundation (DMR-1452726) and the University of
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