Exploiting Chitin as a Source of Biologically Fixed Nitrogen: Formation and Full Characterization of Small-Molecule Hetero- And Carbocyclic Pyrolysis Products

Article abstract of DOI:10.1021/acs.joc.9b03438

Pyrolysis of variously pretreated or untreated samples of chitin (1) and certain congeners at 150-350 °C afforded a range of platform molecules, as exemplified by compounds 4, 5, 6, 8, 12 and 13. All of these products have been fully characterized, including by single-crystal X-ray analysis. Pathways for the formation of them are proposed and theoretical studies of certain aspects of these described.

Full text of DOI:10.1021/acs.joc.9b03438

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Featured Article
Exploiting Chitin as a Source of Biologically Fixed
Nitrogen: Formation and Full Characterization of Small
Molecule Hetero- and Carbo-Cyclic Pyrolysis Products
Maryam Nikahd, Jiri Mikusek, Li-Juan Yu, Michelle L. Coote,
Martin G Banwell, Chenxi Ma, and Michael G Gardiner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03438 • Publication Date (Web): 05 Feb 2020
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Exploiting Chitin as a Source of Biologically Fixed Nitrogen:
Formation and Full Characterization of Small Molecule
Hetero- and Carbo-Cyclic Pyrolysis Products
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†
†
†,§
†,§
Maryam Nikahd, Jiri Mikusek, Li-Juan Yu, Michelle L. Coote,
Martin G. Banwell,*,†, ‡ Chenxi Ma and Michael G. Gardiner
†
†
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†
Research School of Chemistry, Institute of Advanced Studies
The Australian National University, Canberra, ACT 2601, Australia
§ ARC Centre of Excellence for Electromaterials Science, Research School of
Chemistry,
The Australian National University, Canberra, ACT 2601, Australia
‡
Institute for Advanced and Applied Chemical Synthesis,
Jinan University, Guangzhou 510632, China
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Abstract: Pyrolysis of variously pre-treated or untreated samples of chitin (1) and certain
congeners at 150-350 °C afforded a range of platform molecules, as exemplified by
compounds 4, 5, 6, 8, 12 and 13. All of these products have been fully characterized,
including by single-crystal X-ray analysis. Pathways for the formation of them are
proposed and theoretical studies of certain aspects of these described.
INTRODUCTION
Chitin (1, Figure 1), which is comprised of linearly-linked repeating units of N-
acetylglucosamine (NAG, 2), is an abundant biopolymer that is found in the exoskeleta of
crustaceans, the cuticles of insects, plankton and the cell walls of fungi. It has been
estimated that such organisms produce ca. 100 billon tons annually.1 Unlike its even more
common counterpart cellulose (3), chitin is a source of biologically-fixed nitrogen and
has thus attracted interest as a potential precursor, through thermally-promoted
depolymerization processes, to small organic molecules that contain this heteroatom.
Such compounds, that are otherwise known as biomass-derived platform molecules,2
could serve, for example, as sustainably-produced building blocks for chemical synthesis.
Such possibilities have attracted some attention, particularly in more recent times, and a
range of such depolymerization products has been observed,3 one of which was employed
in chemical syntheses.4
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Figure 1: The structures of chitin (1), NAG (2) and cellulose (3)
Our ongoing interest5 in exploiting the small molecule products arising from the pyrolytic
depolymerization of acid-treated cellulose,6 most particularly levoglucosenone and its
hydrogenation product Cyrene™ (now marketed as a replacement for the industrial
solvent NMP),7 have prompted us to examine the outcomes of applying similar conditions
to chitin. The results of such studies are reported here and reveal that a plethora of small
molecule, nitrogen-containing reaction products (Figure 2), including previously
unreported ones, can be obtained by pyrolysis. The distribution of such products appears
to be influenced significantly by the way in which chitin is treated prior to pyrolysis.
Reaction pathways for the formation of these products are advanced and theoretical
support for some of these are also presented.
Figure 2: Structures of the products, 4-15, arising from pyrolysis of pre-treated and
untreated chitin (1), chitosan and/or NAG (2).
RESULTS AND DISCUSSION
Initial chitin pyrolysis experiments (Entry 1, Table 1) were conducted by external heating
of untreated and commercially supplied chitin placed in a glass vessel under reduced
pressure (5 mbar) at 300-350 °C for 1.0 h (see Experimental Section and Supporting
Information – SI – for full details).8 The condensate collected at liquid nitrogen
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temperatures was combined with the methanolic washings of the residue remaining in the
pyrolysis zone and this mixture then subjected to chromatographic fractionation. By such
means small amounts of compounds 4, 5 and 6 were obtained with each being fully
characterized by spectroscopic methods including, in the case of the first and third of
these, single-crystal X-ray analysis (see SI for details). Under such conditions, and in
every other instance as well, significant quantities (normally > 50%) of acetamide (7)
were also observed and the structure of this confirmed by both single-crystal X-ray
analysis and spectroscopic comparisons with an authentic sample. Conventional
spectroscopic analysis of the methanol-washed and dried residue (comprising up to 50%
of the original mass of chitin) suggested it was a complex mixture of oligomeric materials
that we have not investigated further at this stage.
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Table 1: Products observed from pyrolysis of pre-treated and untreated chitin (1),
chitosan (N-deacyl-2) and NAG (2).
Entry Substrate Pre-treatment
Pyrolysis
conditions
Productsa
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4
chitin
chitin
chitin
chitin
none
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4, 5, 6, 7
4, 5, 6, 7, 8, 9
6, 7, 8, 9, 12, 13
levoglucosenone, 7
3% aq. H3PO4 200-350 °C/1.5 to 6 h
glacial AcOH
40% aq.
glyoxal
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150-300 °C/1.5 h
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7, 10
none
Na2HPO4
7, 10, 15
a The quantities of the products obtained from the various pyrolysis experiments involved are given in
the Experimental Section. Acetamide (7) was always the dominant product and could be obtained
in up to 90% yield.
Pyrolysis of chitin under the same conditions as detailed above but that had now been
pre-treated with 3% aqueous phosphoric acid at ambient temperatures for various periods
of time (5 min to 72 h) before being dried (to a free flowing powder) provided (Entry 2,
Table 1) not only the previously observed products (viz. 4-7) in similar yields but, in
addition, the 2H-pyran-2-one 8 and oxazole 9. The structures of these last two compounds
were also confirmed by single-crystal X-ray analysis. Interestingly, when chitin was pre-
treated with glacial acetic acid rather than phosphoric acid (and the ensuing mixture then
dried prior to pyrolysis), new, small-molecule breakdown products were observed (Entry
3, Table 1). In particular, 2H-pyran-2-one 12 and benzo[d]oxazole 13 were now obtained
(and the structures of these also confirmed by single-crystal X-ray analysis) along with
the previously observed products 6-9. Chitin was also treated with 40% aqueous glyoxal
solution and the resulting mixture then dried prior to pyrolysis. Under the usual pyrolytic
conditions (Entry 4, Table 1) such pre-treated material once again afforded acetamide (7)
as the major product with the only other isolable and fully characterizable small-molecule
product now being levoglucosenone.
The polymer chitosan (N-deacetylchitin) is derived from chitin through treatment with
alkali, a process purported to remove the associated acetyl groups and so producing a
linear polymer of glucosamine. However, subjecting commercially acquired chitosan to
essentially the same pyrolytic conditions (Entry 5, Table 1) as employed before gave
small amounts of the previously observed N-acetyl-containing compounds 6 and 7 as well
as furan 10 and 4H-pyran-4-one 11. Once again, the structures of these last two
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compounds were confirmed by single-crystal X-ray analysis. Another product of this
process was 3-hydroxypyridine (14) that could only be characterized by single-crystal X-
ray analysis of its trifluoracetate salt (formed as a result of using trifluoroacetic acid as a
solvent in part of an HPLC purification process). Presumably the N-acylated products
arise through pyrolysis of the residual chitin contained within the sample of chitosan
employed.
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Pyrolysis of untreated NAG (Entry 6, Table 1) gave just two isolable products, namely
acetamide (7) and the previously observed furan 10. Pre-treatment of NAG with
Na2HPO4 prior to its pyrolysis also gave compounds 7 and 10 but these were now
accompanied by the deacylated counterpart of the latter, namely compound 15 and the
structure of which was also established by single-crystal X-ray analysis.
Only one member of the suite of cyclic products obtained from the above-mentioned
pyrolyses has been isolated and fully characterized previously. Thus, the disubstituted
furan 10 has been reported3a-c as a major pyrolysis product and exploited as a starting
material in chemical syntheses.4 Intriguingly, compound 10 has also been isolated from
the whole bodies of Polyphaga plancyi Bolivar,9 an insect widely distributed in China. In
1984 Franich and co-workers suggested,10 based on mass spectrometric analyses, that
compounds 8 and 11 are formed by pyrolysis of NAG. More recently, Wu’s group has
suggested3e that furan 15 is obtained from the “fast” pyrolysis of chitin but only appear to
base this claim on GC/MS data. Interestingly, using the same analytical technique,
Stankiewicz et al have suggested11 that compounds 8, 11 and 15 are formed through the
biodegradation of the chitin-protein complex contained within in crustacean cuticle.
Certain of the other cyclic products obtained here, namely 6,12 12,13 1314 and 14,15 have
also been obtained by chemical synthesis but the remaining ones, viz. 4, 5 and 9, have not
been described in the literature. Further, while pyrazines have been reported3e as
significant products from the high temperature (600 °C) pyrolysis of chitin no obvious
formation of such compounds was observed in the present study, an outcome we attribute
to the milder conditions involved.
From a mechanistic point-of-view, the formation of platform molecules 4-6 and 8-15
from chitin (1) almost certainly commences with cleavage of the associated glycosidic
bond so as to form the oxonium ion 16 (Scheme 1), a species also likely to be obtained
from NAG (3) and stabilized through participation of the adjacent (neighboring)
acetamido group via formation of isomer 17.
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Scheme 1: Possible intermediates arising from the pyrolysis of chitin (1) or NAG (2) and
their conversion into products 10 and 12.
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In keeping with earlier proposals,3b we suggest cation 16 would be readily converted into
NAG (2) and that the open-chain form of this (18) cyclizes to give the corresponding
furanose 19, three-fold dehydration of which would afford the observed and disubstituted
furan 10. Given the structural relationship between this product and its mono-substituted
and co-produced counterpart 15, we believe this is formed by C2-deacylation rather than
through a retro-Diels-Alder reaction as proposed by Wu.3e In an alternative reaction
pathway, selective oxidation of NAG could give the lactone-aldehyde 20 that might be
expected to lose the elements formic acid and water (no order implied) and thereby
forming the observed 2H-pyran-2-one 12.
A possible but distinct pathway for the formation of the related 2H-pyran-2-one 8 is
shown in Scheme 2 and would involve the conversion of cation 17 into the oxazolidin-2-
ol 21 that itself fragments with an accompanying 1,4-hydride shift16 (see red arrow)
across the -face of the pyranose framework and loss of water to afford the C6-
deoxygenated lactone 22 that itself undergoes two-fold dehydration to give the observed
product 8.
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Scheme 2: A possible pathway from cation 17 to pyrolysis product 8.
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A related pathway for the formation of the isomeric furanolactones 4 and 5 is shown in
Scheme 3. Specifically, conversion of compound 21 into isomer 23 followed by a 1,4-
hydride shift (see red arrow) within the latter species (cf 21  22 in Scheme 2) could
deliver the dihydroxylated furanone 24 that upon two-fold dehydration would afford
compounds 4 and 5. A high-level ab initio molecular orbital theory study of the 1,4-
hydride shifts proposed in the Schemes 2 and 3 revealed the energetically feasibile nature
of these processes and suggests each proceeds in a stepwise manner and involves the
intermediacy of a bridging water molecule (see the SI for details).
Scheme 3: A possible pathway from compound 21 to pyrolysis products 4 and 5.
The elimination/intramolecular aldol/1,3-hydride shift sequence shown in Scheme 4
could account for the formation of cyclopentenone 6 from the cation 16. Thus, an E1
elimination process within the latter species would deliver a product, 25, primed for an
intramolecular aldol reaction and so affording cyclopentane 26 that could isomerize to the
oxazolidin-2-ol 27. A 1,3-hydride shift17 (see red arrow) and accompanying loss of the
elements of water within this last compound would deliver the keto-aldehyde 28 and
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subsequent hydration, retro-aldol and dehydration processes could then provide
compound 6.
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Scheme 4: A possible pathway from cation 16 to cyclopentenone 6.
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The formation of the 4H-pyran-4-one 11 could arise, as shown in Scheme 5, through a
two-fold 1,2-hydride shift sequence and accompanying dehydration18 that would deliver
compound 29. Tautomerization of this last species would generate the enol 30, the E-form
of which could cyclize in a 6-exo-trig process to lactol 31 that upon the loss of the
elements of water could provide the observed product 11.
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Scheme 5: A pathway from compound 18 to 4H-pyran-4-one 11
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Given that each embodies an oxazole ring, the pathways leading to the formation of
compounds 9 and 13 are likely to be related (connected) and one such possibility is
shown in Scheme 6. Thus, deprotonation of cation 17 followed by acid-catalyzed
isomerization of the resulting dihydro-oxazole 32 would afford compound 33 that could
undergo a 1,2-hydride shift with accompanying dehydration and so affording the methyl
ketone 34. The necessary loss of the two remaining hydroxyl groups within this last
compound presents an interesting conundrum and we speculate that one of various
possible -dicarbonyl compounds that are often observed during the decomposition of
monosacharides (and represented in the general form RCOCOR)19 could react with the
diol residue associated with compound 34 so as to form the bis-lactol 35 that could itself
undergo the illustrated fragmentation reaction (with accompanying loss of two molecules
of RCO2H)20,21 and thereby producing the observed -arylated ,-unsaturated ketone 9.
This product could then rearrange to isomer 36, a system presumed to be capable of
engaging in a thermally-induced 6-electrocyclic ring closure, the product of which could
be expected to oxidize and so form the benzannulated oxazole 13.
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Scheme 6: A possible pathway for the formation of oxazoles 9 and 13 from cation 17
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Scheme 7 depicts a possible pathway for the formation of the final heterocyclic pyrolysis
product, namely 3-hydroxypyridine (14). Specifically, tautomerisation of the E1 product
25 to the corresponding aldehyde followed by an intramolecular Schiff base condensation
reaction might be expected to provide the N-acylimminium ion 38, a species capable of
engaging in a formyl group migration reaction that leads to isomer 39 (this conversion
may proceed via the corresponding azomethine ylides). Dehydration of diol 39 and
accompanying aromatization would then provide the pyridium ion 40 that upon
hydrolysis would afford 3-hydroxypyridine (14) and malonic semialdehyde (3-
oxopropanoic acid – not detected). The HPLC purification process (involving
trifluoroacetic acid as a component of the mobile phase) used to isolate product 14
resulted in the formation of its trifluoroacetate salt that proved amenable to single-crystal
X-ray analysis (see the SI for details).
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Scheme 7: Possible pathway for the conversion of the E1 product 25 into
3-hydroxypyridine (14).
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The foregoing mechanistic proposals clearly suggest that in almost every instance the
acetamido group of chitin and NAG is intimately involved in some way in the formation
of the observed pyrolysis products.
CONCLUSION
The present work highlights the diversity of reaction pathways available in the pyrolysis
of chitin and the corresponding monomer NAG. Some control over these can be achieved
by the manner in which these substrates are treated prior to pyrolysis and the
temperatures at which the depolymerization process is conducted. The mechanistic
proposals advanced here, and that will be the subject of a range of experiments to be
carried out in our laboratories,li should help inform how further control can be exerted
and so that higher yields of products 4-6 and 8-15 might be realized. As such these
biomass-derived platform molecules could assume considerable significance. Compounds
4, 5, 8, 11 and 12, for example, are dehydro--amino acid derivatives and could thus
serve as potentially abundant precursors to a range of biologically useful materials.22
EXPERIMENTAL
General Experimental Protocols
Unless otherwise specified, proton (1H) and proton-decoupled carbon [13C{1H}] NMR
spectra were recorded at room temperature in base-filtered CDCl3 on a Varian
1
spectrometer operating at 400 MHz for proton and 100 MHz for carbon nuclei. For H
NMR spectra, signals arising from the residual protio-forms of the solvent were used as
1
the internal standards. H NMR data are recorded as follows: chemical shift (δ)
[multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is defined
as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the
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above. The signal due to residual CHCl3 appearing at δH 7.26 and the central resonance of
1
13
the CDCl3 “triplet” appearing at δC 77.16 were used to reference H and C{1H} NMR
spectra, respectively. Infrared spectra (max) were recorded on a Perkin–Elmer 1800
Series FTIR Spectrometer. Samples were analyzed as thin films. Low-resolution ESI
mass spectra were recorded on a single quadrupole liquid chromatograph-mass
spectrometer, while high-resolution measurements were conducted on a time-of-flight
instrument. Low- and high-resolution EI mass spectra were recorded on a magnetic-sector
machine. Melting points were measured on a Reichert melting point microscope and are
uncorrected. Analytical thin layer chromatography (TLC) was performed on aluminum-
backed 0.2 mm thick silica gel 60 F254 plates as supplied by Merck. Eluted plates were
visualized using a 254 nm UV lamp and/or by treatment with a suitable dip followed by
heating. These dips included phosphomolybdic acid : ceric sulfate : sulfuric acid (conc.) :
water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium permanganate : potassium carbonate
: 5% sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL : 300 mL). Flash
chromatographic separations were carried out following protocols defined by Still et al.23
with silica gel 60 (40–63 m) as the stationary phase and using the AR- or HPLC-grade
solvents indicated. Reverse-phase HPLC purifications were carried out using an Alltima
C18 250 × 22 mm column using, as the eluting solvent 3:7 v/v water/acetonitrile at a flow
rate of 10 ml/min. and ambient temp. Compounds 4 and 5 were purified using YMC-Pack
ODS-AQ, 250 x 20 mm (P/N 81105) column. Starting materials and reagents were
generally available from the Sigma–Aldrich, Merck, TCI, Strem or Lancaster Chemical
Companies and were used as supplied. Drying agents and other inorganic salts were
purchased from the AJAX, BDH or Unilab Chemical Companies. Tetrahydrofuran
(THF), methanol and dichloromethane were dried using a Glass Contour solvent
purification system that is based upon a technology originally described by Grubbs et
al.24 Petroleum ether refers to the fraction boiling between 40 and 60 °C. Where
necessary, reactions were performed under a nitrogen atmosphere.
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Specific Chemical Transformations
Treated or untreated chitin (10.0 g, ex. Aldrich Chemical Co.), either on its own or
intimately mixed with acid-washed and chromatography-grade sand (20 g), was loaded
into the main chamber of the (Type 1) pyrolysis apparatus shown in Figures S1 and S2.
Once the traps had been charged with liquid nitrogen, the pressure in the system was
reduced to 5 mm Hg using a standard vacuum pump that was connected via a Schlenk
line (vacuum/gas manifold). The exterior surface of the main chamber was then wrapped
with electrical heating tape and a current applied via a rheostat such that an external
temperature of ca. 150-350 °C was obtained (see Figure S3). Heating was continued for
the specified period then the power supply disconnected and once the tape was cool to the
touch this was removed and the apparatus opened to the atmosphere. The residue in the
pyrolysis chamber (see Figure S4) was washed with methanol, as was the sintered glass
frit and glass line leading into the round-bottomed flask that had been sitting in the liquid
nitrogen or dry ice and acetone trap. These washings were added into the flask and the
resulting mixture concentrated under reduced pressure. The brown oil thus obtained was
subjected to flash chromatography (silica gel) under the specified conditions and the
relevant fractions subjected, as required, to further purification including, in some
instances, using reverse-phase HPLC techniques. In every instance a significant
proportion (up 90% yield) of the brown oil was comprised of acetamide (7) as determined
by NMR and IR spectroscopic as well as mass spectrometric analyses and comparisons
with an authentic sample.
In another mode (Type 2) of pyrolysis (Figure S5), a round-bottomed flask containing
chitin (10 g) (Figure S6) was fitted with a short-path distillation tube that was itself
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connected to a receiver flask sitting in a liquid nitrogen or dry-ice/acetone bath. The
receiver flask was, in turn, connected to a liquid nitrogen trap and, through this, to a
Schlenk line by which means the whole apparatus could be evacuated using a vacuum
pump. Heat was applied to the reaction flask/chamber by means of an aluminum heating
block. To facilitate heat transfer to the contents of the reaction flask either metal ball
bearings, canola oil or sand could be mixed with the chitin (see Figure S7). The reaction
temperature was held at 150-350 °C for the specified time after which heating was
stopped then the cooled apparatus disassembled. The residue in the pyrolysis flask (see
Figure S8) was washed with methanol as was the distillation tube leading into the
receiver flask. These washings were added into the receiver flask and the resulting
mixture concentrated under reduced pressure. The brown oil thus obtained was subjected
to flash chromatography (silica gel) under the specified conditions and the relevant
fractions subjected, as required, to further purification including, in some instances, using
reverse-phase HPLC techniques. In every instance a significant proportion (up 90% yield)
of the brown oil was comprised of acetamide (7) as determined by NMR and IR
spectroscopic as well as mass spectrometric analyses and comparisons with an authentic
sample.
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(a)
Pyrolysis of Untreated Chitin.
Chitin (10.0 g) with or without intimately mixed acid-washed and chromatography-grade
sand (20 g), was loaded into the pyrolysis apparatus shown in Figure S1 and with the cold
traps in place the pressure in the system was reduced to 5 mm Hg and then heating
commenced.
Run #1: No sand, 300 °C, 1 h. The weight of the residue obtained after washing with
methanol and drying was 4.0 g. Subjection of this residue (a brown oil) to flash
chromatography (silica gel, 4:6  3:7  1:1  0:10 v/v petroleum ether /ethyl acetate
gradient elution) afforded two fractions, A and B.
Concentration of fraction A (Rf = 0.5 in 3:7 v/v ethyl acetate/petroleum ether)
afforded a 3:1 mixture of compounds 4 and 5 (7.4 mg) as a white, crystalline solid, m.p. =
113-128 °C. A solution of this material in methanol was allowed to stand at ambient
temperatures for one week and during which time crystals formed. Subjection of one of
these to single-crystal X-ray analysis revealed this to be comprised of compound 5.
Concentration of fraction B (Rf = 0.2 in 3:7 v/v ethyl acetate/petroleum ether)
gave compound 6 (135.3 mg) as a white, crystalline solid, m.p. = 100-113 °C (ex.
methanol).
Run #2: Sand, 350 °C, 1 h. The weight of residue obtained after washing with methanol
and drying was 1.4 g. Subjection of this residue to flash chromatography (silica gel, 3:7
v/v petroleum ether /ethyl acetate elution) led to the isolation of compound 6 (131.3 mg).
This material was identical to that obtained from Run #1.
(b)
Pyrolyses of H3PO4-treated Chitin.
Chitin (10.0 g) was treated with 3% H3PO4 (200 ml) and the resulting slurry mixed under
the conditions specified below then filtered and the solids thus retained dried under the
indicated conditions. The dried solid was subjected to pyrolysis in the apparatus described
at Figure S5 (unless otherwise specified) above or by suspending the treated chitin in
canola oil (60 mL) or using ball bearings (or without either of these). Heating of the
substrate was then carried out at the indicated temperature under reduced pressure (5 mm
Hg).
Run #1: Treatment of chitin with 3% aq. H3PO4 for 5 minutes then filtration and
overnight air drying, heating at 200 °C for 3 h without ball bearings or canola oil. The
weight of residue obtained after washing with methanol and drying was 171.1 mg.
Subjection of the residue to reverse-phase HPLC (3:7 v/v water/acetonitrile elution)
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afforded, after concentration of appropriate fractions, a 3:1 mixture of compounds 4 and 5
(4.4 mg). This material was identical to that obtained previously.
Run #2: Treatment of chitin with 3% aq. H3PO4 for 5 minutes then filtration and
overnight air drying, heating at 200 °C in canola oil (60 ml) for 2 h. The weight of residue
after obtained after washing with methanol and drying was 342.1 mg. Subjection of this
residue to reverse-phase HPLC (3:7 v/v water/acetonitrile elution) afforded a 3:1 mixture
of compounds 4 and 5 (54.8 mg). This material was identical to that obtained previously.
Run #3: Treatment of chitin with 3% aq. H3PO4 for 48 h then filtration and overnight
drying in a desiccator. The resulting material was divided into three equal parts with each
being heated at 300 °C for 6 h in the presence of ball bearings. The combined weight of
the residues obtained after washing with methanol and drying was 456.6 mg. Subjection
of this residue to flash column chromatography (silica gel, 1.5:8.5 then 1:4 v/v ethyl
acetate/hexane elution) afforded three fractions, A, B and C.
Concentration of fraction A (Rf = 0. 5 in 3:7 v/v ethyl acetate/petroleum ether)
gave a 3:1 mixture of compounds 4 and 5 (17.9 mg). This material was identical to that
obtained previously.
Concentration of fraction B (Rf = 0.3 in 3:7 v/v ethyl acetate/petroleum ether)
gave compound 9 (5.1 mg,) as a white, crystalline solid, m.p. = 64-74 °C (ex. methanol).
Concentration of fraction C (Rf = 0.2 in 3:7 v/v ethyl acetate/petroleum ether)
gave compound 8 (5.7 mg) as a white, crystalline solid, m.p. = 114-124 °C (ex.
methanol).
Run #4: Treatment of chitin with 3% aq. H3PO4 for 24 h then filtration and overnight
drying in a desiccator. Resulting material intimately mixed with acid washed and
chromatography grade sand then heating at 350 °C in the apparatus shown in Figure S1
for 1.5 h. The weight of residue obtained after washing with methanol and drying was
660 mg. Subjection of this residue to flash column chromatography (silica gel, 3:7 to 4:6
v/v ethyl acetate/petroleum ether gradient elution) afforded, after concentration of the
appropriate fractions, a 3:1 mixture of compounds 4 and 5 (28.5 mg). This material was
identical to that obtained previously.
Run #5: Chitin (10.0 g) was intimately mixed with H3PO4 (1.0 g of solid material) then
heated at 350 °C for 1.5 h using the apparatus described in Figure S1. The weight of the
residue obtained after washing with methanol and drying was 2.97 g. Subjection of this
residue to flash column chromatography (silica gel, 2:3 v/v petroleum ether/ethyl acetate
elution) afforded, after concentration of the appropriate fractions (Rf = 0.2 in 3:7 v/v ethyl
acetate/petroleum ether), compound 6 (87.6 mg) as a white, crystalline solid. This
material was identical to that obtained earlier.
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(c)
Pyrolyses of AcOH-treated Chitin.
Chitin (10.0 g) was treated with glacial acetic acid (150 mL) and the resulting slurry
heated under as detailed below then the cooled mixture was filtered and the solids thus
retained dried under the indicated conditions. The dried solid was subjected to pyrolysis
in the apparatus shown in Figure S1 and with or without acid-washed and
chromatography grade sand (20 g) present. The resulting mixture was heated at 350 °C
for 2 h.
Run #1: Chitin was heated in refluxing glacial AcOH for 3 days then the cooled
and filtered material was dried under a stream of air for 2 days. The resulting material
was heated at 350 °C for 2 h. The weight of the residue obtained after washing with
methanol and drying was 4.88 g. Subjection of this residue to flash chromatography
(silica gel, 1:1  6:4 v/v ethyl acetate/petroleum ether  elution) and then, in some
instances (as indicated by the citation of a Rt value), subjected to reverse-phase HPLC
(3:7 v/v water/acetonitrile elution) gave fractions A-E.
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Concentration fraction A (Rf = 0.3 in 3:7 v/v ethyl acetate/petroleum ether and Rt
= 17.063 min) gave compound 9 (4.9 mg), as a white, crystalline solid that was identical
in all respects with the sample obtained earlier.
Concentration of fraction B [Rf = 0.2(5) in 3:7 v/v ethyl acetate/petroleum ether]
gave compound 6 (67.6 mg) as a white, crystalline solid that was identical in all respects
with the material obtained earlier.
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Concentration of fraction C [Rf = 0.2(0) in 3:7 v/v ethyl acetate/petroleum ether
and Rt = 15.5 min] gave compound 8 (6.8 mg) as a white, crystalline solid that was
identical in all respects with the material obtained earlier.
Concentration of fraction D (Rf = 0.7 in 0.5:9.5 v/v methanol/chloroform and Rt =
13.5 min) gave compound 12 (4.6 mg) as a white, crystalline solid, m.p. = 124-133 °C
(ex. methanol)
Concentration of fraction E (Rf = 0.3 in 0.5:9.5 v/v methanol/chloroform and Rt =
17.0 min) gave compound 13 (9.5 mg) as a white, crystalline solid, m.p. = 74-88 °C (ex.
methanol).
Run #2: Chitin was stirred overnight in glacial acetic acid then filtered and air-dried
before being heated at 350 °C in for 1.5 h The weight of residue (a brown oil) obtained
after washing with methanol and drying was 3.57 g. This oil was to subjected to flash
chromatography (silica gel, 2:3 v/v ethyl acetate/petroleum ether elution) and
concentration of the relevant fractions (Rf = 0.2 in 3:7 v/v ethyl acetate/petroleum ether)
gave compound 6 (33.9 mg) as a white, crystalline solid that was identical in all respects
with the material obtained earlier.
(d)
Pyrolysis of Glyoxal-treated Chitin.
Chitin (10.0 g) was treated with glyoxal (20 mL of a 40% aqueous solution) and water
(30 mL). The resulting suspension was stirred for 12 h at ambient temperatures then the
supernatant liquid decanted and resulting wet solid filtered under reduced pressure
(Buchner funnel) and the solid thus retained dried in a desiccator. The dried and free-
flowing solid was mixed with sand (20 g) and this mixture subjected to pyrolysis for 2 h
at 250 °C in the apparatus shown at Figure S1. After cooling and washing the relevant
parts of the apparatus with methanol, 500 mg of a brown oil was obtained. Subjection of
this material to flash column chromatography (silica gel, 3:7 v/v ethyl acetate/petroleum
ether elution) afforded, after concentration of the appropriate fractions (Rf = 0.8 in 1:1 v/v
ethyl acetate/petroleum ether), levoglucosenone (9 mg). This was identical, in all respects
with an authentic sample.
(e)
Pyrolysis of Untreated Chitosan.
In a single run, chitosan (10.0 g) was subjected to pyrolysis, at 350 °C for 1.5 h, in the
apparatus shown at Figure S1. The weight of oily residue obtained after cooling and
washing the relevant parts of the apparatus with methanol and then concentrating of the
ensuing solution under reduced pressure was 2.07 g. Subjection of this material to flash
chromatography (silica gel, 2:8  10:0 v/v ethyl acetate/petroleum ether then 1:9 v/v
methanol/ethyl acetate gradient elution) afforded two fractions, A and B.
Concentration of fraction A (Rf = 0.2 in 3:7 v/v petroleum ether/ethyl acetate)
afforded compound 6 (16 mg), as a white, crystalline solid that was identical in all
respects with the sample obtained earlier.
Subjection of fraction B (Rf = 0.4 in 1:9 v/v methanol/chloroform) to reverse-
phase HPLC (3:7 v/v water/acetonitrile elution) gave three new fractions, C-E.
Concentration of fraction C (Rf = 0.3 in 0.5:9.5 v/v methanol/chloroform and Rt =
7.992 min) gave compound 14 (7.6 mg) as a white, crystalline solid, m.p. = 59-73 °C (ex.
methanol).
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Concentration of fraction D (Rf = 0.4 in 0.5:9.5 v/v methanol/chloroform and Rt =
14.139 min) gave compound 11 (1 mg) as a white crystalline solid, m.p. = 116-127 °C
(ex. methanol).
Concentration of fraction E (Rf = 0.2 in 0.5:9.5 v/v methanol/chloroform and Rt =
14.362 min) gave compound 10 (1.5 mg) as a white, crystalline solid, m.p. = 124-133 °C
(ex. methanol).
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(f)
Pyrolysis of Untreated and Treated NAG
Run #1: NAG (10.0 g) was subjected to pyrolysis at 350 °C for 1.5 h in the apparatus
described at Figure S1. The weight of residue after washing with methanol and drying
was 1.157 g. Subjection of this residue (a brown oil) to flash column chromatography
(silica gel, 3:7 v/v petroleum ether/ethyl acetate elution) afforded, after concentration of
the relevant fractions (Rf = 0. 2 in 0.5:9.5 v/v methanol/chloroform), compound 10 (20.2
mg) as a white, crystalline solid that was identical, in all respects, with the sample
obtained earlier.
Run #2: An intimate mixture of NAG (4.4 g, 0.02 mole) and Na2HPO4 (2.8 g, 0.02 mole)
was subjected to pyrolysis in the apparatus described at Figure S5 with stepwise heating
in 50 °C increments every 0.5 h from 150 to 300 °C (total heating time 2.5 h). The weight
of residue obtained after cooling and washing with methanol then drying was 562.2 mg.
Subjection of this residue (a brown oil) to flash column chromatography (silica gel, 3:7
v/v petroleum ether/ethyl acetate elution elution) then reverse-phase HPLC (3:7 v/v
water/ acetonitrile) afforded two fractions, A and B.
Concentration of fraction A (Rf = 0.2 in 0.5:9.5 v/v methanol/chloroform and Rt =
13.036 min) afforded compound 10 (6.4 mg) as a white, crystalline solid that was
identical in all respects with the sample obtained earlier.
Concentration of fraction B (Rf = 0.2 in 0.5:9.5 v/v methanol/chloroform and Rt =
13.445 min) gave compound 15 (6.9 mg) as a white, crystalline solid, m.p. = 122-136 °C
(ex. methanol).
Compound Characterization
(E)- and (Z)-3-Acetamido-5-ethylidenefuran-2(5H)-one (4 and 5, respectively)
O
O
NH
O
1H NMR (400 MHz, CD3OD) δ (major isomer) 7.51 (s, 1H), 5.34 (q, J = 7.4 Hz, 1H),
2.14 (s, 3H), 1.91 (d, J = 7.4 Hz, 3H) (resonance due to NH group proton not observed); δ
(minor isomer) 7.79 (s, 1H), 5.67 (q, J = 7.7 Hz, 1H), 2.16 (s, 3H), 1.89 (d, J = 7.6 Hz,
3H) (resonance due to NH group proton not observed); 13C{1H} NMR (100 MHz, CDCl3)
δ (both isomers) 169.2, 169.0, 166.9, 149.0, 148.7, 126.2, 125.6, 120.2, 116.0, 110.9,
110.5, 106.3, 23.8, 11.9 (two resonances obscured or overlapping); IR (ATR) νmax 3330,
1752, 1696, 1628, 1550, 1328, 1244, 1104, 771 cm–1. MS (EI, 70 eV) m/z 167 (M+•,
23%), 125 (100), 69 (23); HRMS (EI) m/z: (M+•) calcd for C8H9NO3 167.0582; Found
167.0585.
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2-Acetamidocyclopent-2-en-1-one (6)12
5
6
7
8
9
O
O
HN
10
11
12
13
14
15
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1H NMR (400 MHz, CD3OD) δ 7.83 (broad s, 1H), 2.61-2.67 (complex m, 2H), 2.33-2.39
(complex m, 2H), 2.10 (s, 3H) (resonance due to NH group proton not observed);
13C{1H} NMR (100 MHz, CD3OD) δ 205.3, 171.9, 143.1, 138.5, 33.1, 25.8, 23.2; IR
(ATR) νmax 3329, 1682, 1622, 1532, 1418, 1313, 786 cm–1; MS (EI, 70 eV) m/z 139 (M+•,
100%); HRMS (EI) m/z: (M+•) calcd for C7H9NO2 139.0633; Found 139.0634.
3-Acetamido-6-methyl-2H-pyran-2-one (8)10,11
O
O
HN
O
1H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 7.3 Hz, 1H), 7.80 (broad s, 1H), 6.16 (d, J =
13
7.3 Hz, 1H), 2.24 (s, 3H), 2.15 (s, 3H); C NMR (100 MHz, CD3OD) δ 172.5, 161.4,
157.4, 128.1, 113.9, 104.7, 79.5, 23.8, 19.1. IR (ATR) νmax 3337, 2925, 1713, 1681,
1643, 1420, 1338, 1110, 832, 770, 547 cm–1; MS (EI, 70 eV) m/z 167 (M+•, 38%), 149
(21), 125 (100), 97 (75), 96 (58); HRMS (EI) m/z: (M+•) calcd for C8H9NO3 167.0582;
Found 167.0584.
(E)-4-(2-Methyloxazol-4-yl)but-3-en-2-one (9)
O
O
N
1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.47 (d, J = 16.0 Hz, 1H), 6.77 (d, J = 16.0
13
Hz, 1H), 2.48 (s, 3H), 2.34 (s, 3H); C{1H} NMR (100 MHz, CD3OD) δ 200.8, 164.7,
142.3, 138.4, 133.1, 128.7, 27.3, 13.5; IR (ATR) νmax 1670, 1638, 1362, 1266, 1239,
1104, 971, 808 cm-1; MS (EI, 70 eV) m/z (%) 151 (M+•, 45%), 136 (100), 109 (28), 107
(25), 80 (30); HRMS (EI) m/z: (M+•) calcd for C8H9NO2 151.0633; Found 151.0635.
N-(5-Acetylfuran-3-yl)acetamide (10)3a-c,9
O
O
HN
O
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1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.20 (s, 1H), 2.45 (s, 3H), 2.11 (s, 3H)
13
(resonance due to NH group proton not observed); C{1H} NMR (100 MHz, CD3OD) δ
188.9, 170.9, 151.9, 137.5, 128.4, 111.8, 25.8, 22.7; IR (ATR) νmax 3283, 1651, 1572,
1500, 1367, 1329, 1195, 927, 768, 601 cm–1; MS (EI) m/z 167 (M+•, 68%), 125 (92), 110
(100); HRMS (EI) m/z: (M+•) calcd for C8H9NO3 167.0582; Found 167.0583.
5-Acetamido-2-methyl-4H-pyran-4-one (11)10,11
10
11
12
13
14
15
16
17
18
19
20
21
22
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O
O
HN
O
1H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 6.33 (s, 1H), 2.34 (s, 3H), 2.17 (s, 3H)
(resonance due to NH group proton not observed); C{1H} NMR (100 MHz, CD3OD) δ
13
174.8, 171.9, 168.8, 158.9, 147.0, 112.8, 23.3, 19.7; IR (ATR) νmax 3293, 1645 1616,
1548, 1412, 1207 cm–1; MS (ESI, +ve) m/z 190 [(M + Na)+, 79%], 161 (65), 159 (100),
126 (64), 96 (64); HRMS (ESI) m/z: [M + Na]+ calcd for C8H9NO3Na 190.0475; Found
190.0470.
3-Acetamido-2H-pyran-2-one (12)13
O
O
HN
O
1H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 6.39
(dd, J = 7.2 and 5.1 Hz, 1H), 2.17 (s, 3H) (resonance due to NH group proton not
observed); 13C{1H} NMR (100 MHz, CD3OD) δ 172.7, 160.8, 146.7, 127.1, 126.0, 107.9,
23.9; IR (ATR) νmax 3336, 1715, 1672, 1631, 1530, 1342, 1129, 772 cm–1; MS (ESI, +ve)
m/z 176 [(M+Na)+, 99%], 162 (60), 130 (100), 112 (73), 102 (73); HRMS (ESI) m/z: [M
+ Na]+ calcd for C7H7NO3Na 176.0318; Found 176.0313.
2-Methylbenzo[d]oxazol-6-ol (13)14
OH
O
N
1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 8.5 Hz, 1H), 6.94 (s, 1H), 6.80 (d, J = 8.5 Hz,
1H), 2.56 (s, 3H) (resonance due to OH group proton not observed); 13C{1H} NMR (100
MHz, CD3OD) δ 157.1, 126.1, 119.7, 113.9, 112.6, 110.6, 98.1, 14.0; IR (ATR) νmax
3236, 1621, 1486, 1451, 1299, 1137, 1110 cm–1; MS (ESI, +ve) m/z 150 [(M + H)+,
100%], 130 (48), 102 (40), 91 (44), 74 (39); HRMS (ESI) m/z: [M + H]+ calcd for
C8H8NO2 150.0544; Found 150.0550.
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Pyridin-3-ol (14)15
5
6
7
8
9
10
11
12
13
14
15
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This compound could only be characterized by single-crystal X-ray analysis (details
presented below).
N-(Furan-3-yl)acetamide (15)11
O
HN
O
1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.36 (broad s, 1H), 6.37 (broad s, 1H), 2.08
(s, 3H) (resonance due to NH group proton not observed); 13C{1H} NMR (100 MHz,
CD3OD) δ 170.6, 142.7, 133.4, 126.1, 105.6, 22.7; IR (ATR) νmax 3278, 1657, 1563,
1378, 1289, 1166, 870, 765 cm–1; MS (EI, 70 eV) m/z 125 (M+•, 88%), 83 (100), 69 (29);
HRMS (EI) m/z: (M+•) calcd for C6H7NO2 125.0477; Found 125.0479.
Crystallographic Studies.
Crystallographic Data.
Compound 5. C H NO , M = 167.16, T = 150 K, triclinic, space group P , Z = 2, a =
1
8
9
3
4.6446(8) Å, b = 8.456(2) Å, c = 10.7100(16) Å;  = 89.422(18)°,  = 86.974(13)°,  =
80.489 (18)°; V = 414.27(14) Å3, Dx = 1.340 Mg m–3, 1635 unique data (2max = 147°), R
= 0.087 [for 1222 reflections with I > 2.0(I)]; Rw = 0.266 (all data), S = 1.06.
Compound 6. C7H9NO2, M = 139.15, T = 150 K, monoclinic, space group, C2/c, Z = 8, a
= 18.5157(10) Å, b = 9.4421(5) Å, c = 7.9012(4) Å;  = 90°,  = 101.918(5)°,  = 90°; V
= 1351.57(13) Å3, Dx = 1.368 Mg m–3, 1519 unique data (2max = 58.446°), R = 0.0572
[for 1263 reflections with I > 2.0(I)]; Rw = 0.1168 (all data), S = 1.061.
Compound 8. C H NO , M = 167.16, T = 150 K, triclinic, space group P , Z = 2, a =
1
8
9
3
6.9199(4) Å, b = 7.5328(5) Å, c = 7.9552(5) Å;  = 96.283(6)°,  = 97.670(5)°,  =
109.017(6)°; V = 383.32(2) Å3, Dx = 1.448 Mg m–3, 1538 unique data (2max = 147.4°), R
= 0.054 [for 1469 reflections with I > 2.0(I)]; Rw = 0.152 (all data), S = 1.00.
Compound 9. C8H13NO4, M = 187.19, T = 150 K, monoclinic, space group I2/m, Z = 4, a
= 5.6345(4) Å, b = 6.4841(5) Å, c = 25.9775(17) Å;  = 90°,  = 95.661(7)°,  = 90°; V =
944.44(12) Å3, Dx = 1.317 Mg m–3, 1159 unique data (2max = 57.714°), R = 0.0167 [for
1034 reflections with I > 2.0(I)]; Rw = 0.1044 (all data), S = 1.060.
Compound 10. C8H11NO4, M = 185.18, T = 150 K, monoclinic, space group P21/c, Z = 4,
a = 6.160(4) Å, b = 11.4782(5) Å, c = 11.3108(5) Å;  = 90°,  = 102.768(5)°,  = 90°; V
= 863.02 (8) Å3, Dx = 1.425 Mg m–3, 2066 unique data (2max = 58.316°), R = 0.0604 [for
1389 reflections with I > 2.0(I)]; Rw = 0.1480 (all data), S = 1.080.
Compound 11. C8H9NO3, M = 167.16, T = 150 K, triclinic, space group P-1, Z = 2, a =
3.8928(10) Å, b = 9.3628(16) Å, c = 10.7006(14) Å;  = 81.053(12)°,  = 83.731(16)°, 
= 79.026°; V = 376.94 (13) Å3, Dx = 1.473 Mg m–3, 1486 unique data (2max = 147.304°),
R = 0.0649 [for 1141 reflections with I > 2.0(I)]; Rw = 0.1760 (all data), S = 1.029.
Compound 12. C7H7NO3, M = 153.14, T = 150 K, triclinic, space group P-1, Z = 2, a =
3.7878(3) Å, b = 9.6277(8) Å, c = 10.3407(8) Å;  = 63.995(8)°,  = 84.352(7)°,  =
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80.203(7)°; V = 333.86(5) Å3, Dx = 1.523 Mg m–3, 1337 unique data (2max = 146.992°),
R = 0.0362 [for 1192 reflections with I > 2.0(I)]; Rw = 0.0985 (all data), S = 1.051.
Compound 13. C8H7NO2, M = 149.15, T = 150 K, triclinic, space group P-1, Z = 2, a =
6.5474(7) Å, b = 7.2418(7) Å, c = 7.6043(7) Å;  = 77.401(8)°,  = 85.073(8)°,  =
78.699(9)°; V = 344.70 (6) Å3, Dx = 1.437 Mg m–3, 1378 unique data (2max = 147.654°),
R = 0.0450 [for 1124 reflections with I > 2.0(I)]; Rw = 0.1211 (all data), S = 1.051.
Compound 14. C7H6F3NO3, M = 209.13, T = 150 K, triclinic, space group P-1, Z = 2, a =
6.2250(14) Å, b = 7.862(3) Å, c = 8.7433(18) Å;  = 103.85(2)°,  = 94.753(18)°,  =
95.55(2)°; V = 4.11.04 (19) Å3, Dx = 1.690 Mg m–3, 1393 unique data (2max = 133.192°),
R = 0.0856 [for 788 reflections with I > 2.0(I)]; Rw = 0.2456 (all data), S = 1.024.
Compound 15. C6H7NO2, M = 125.13, T = 150 K, orthorhombic, space group Pbca, Z =
8, a = 9.6520(4) Å, b = 9.3307(5) Å, c = 13.2182(6) Å; V = 1190.43(10) Å3, Dx = 1.396
Mg m–3, 1199 unique data (2max = 147.496°), R = 0.0464 [for 1073 reflections with I >
2.0(I)]; Rw = 0.1330 (all data), S = 1.082.
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Structure Determinations.
Data for compound 5, 6, 8, 9 and 11-15 were measured on a Rigaku SuperNova
diffractometer using CuKα, graphite monochromator (λ = 1.54184 Å) while data for
compound 10 were measured on the same machine using a MoKα, graphite
monochromator (λ = 0.71073 Å). Data collection, cell refinement and data reduction
employed the CrysAlis PRO program25 while SHELXT26 and SHELXL27 were used for
structure solution and refinement. Atomic coordinates, bond lengths and angles, and
displacement parameters have been deposited at the Cambridge Crystallographic Data
Centre (CCDC nos. 1935464-1935469). These data can be obtained free-of-charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Accession Codes
CCDC depositions 1943032-1943041 contain the supplementary crystallographic data for
this
paper.
These
data
can
be
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
THEORETICAL STUDIES
Methodologies
Geometries were optimized at the M06-2X/6-31+G(d) level of theory28 and frequencies
were also calculated at this level. Geometries were verified either as local minima or
transition states. Entropies, thermal corrections, and zero-point vibrational energies were
scaled using the recommended scaling factors.29 Single-point energies were calculated
using the high-level composite ab initio method G3(MP2,CC) to improve accuracy.30 For
all species investigated, conformational searching was performed with the energy-
directed tree search (EDTS) algorithm31 to identify conformations with the lowest Gibbs
free-energy. All standard ab initio molecular orbital theory and density functional theory
(DFT) calculations were carried out using the Gaussian 0932 and Molpro 201533 software
packages.
Outcomes
The mechanisms for the conversion of compound 21 into 22 (Scheme S1) and 23 into 24
(Scheme S2) were studied using high-level ab initio molecular orbital theory calculations.
A variety of reaction pathways was considered and the most energetically feasible ones
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are shown. In both transformations, deprotonation of the tertiary OH associated with the
oxazolidine ring triggers ring opening, affording the first intermediate (INT 1) that upon
re-protonation provides a species (INT 2) that can itself undergo a hydride shift
accompanied by a concerted C–O bond cleavage. The resulting intermediate (INT 3) can
then lose water to afford compound 22. An analogous pathway appears to operate in the
case of the conversion 23  24 In both cases the rate determining hydride shift is highly
exergonic (G = –403.1 kJ mol–1 and –331.5 kJ mol–1), and proceeds with experimentally
accessible barriers of 84.3 kJ mol–1 and 111.1 kJ mol–1 for the processes leading to
products 22 and 24, respectively.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free-of-charge on the ACS Publications website
at DOI: 10.1021/acs.joc.XXXXXX.
Experimental procedures, spectroscopic data, copies of the NMR spectra of
compounds 4-13 and 15, X-ray data and derived ORTEPs for pyrolysis products
5-15, theoretical studies of key aspects of the mechanisms shown in Schemes 2
and 3 together with full details of the calculations and raw computational data.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Martin.Banwell@anu.edu.au
ORCID
Martin G. Banwell: 0000-0002-0582-475X
Michelle Coote: 0000-0003-0828-7053
Jiri Mikusek: 0000-0001-5425-0193
Author Contributions
The manuscript was written through contributions from all of the authors. All of the
authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the Australian Government and Circa Pty Ltd for the provision of an
Innovations Connections grant. Funding from the Australian Research Council is
gratefully acknowledged (including through grants FL170100041 and CE140100012) as
is support (to MN) from the Islamic Government of Iran. Dr Hideki Onagi (RSC) and Mr
Daniel Barktus (RSC) are thanked for outstanding technical assistance.
REFERENCES
1.
Yan, N.; Chen, X. Don’t Waste Seafood Waste, Nature, 2015, 524, 155-158 and
references cited therein.
2.
Lie, Y.; Ortiz, P.; Vendamme, R.; Vanbroekhoven, K.; Farmer, T. J.
BioLogicTool: A Simple Visual Tool for Assisting in the Logical Selection of
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7
8
9
Pathways from Biomass to Products. Ind. Eng. Chem. Res. 2019, 58, 15945-
15957.
3.
For some representative reports, see: (a) Chen, J.; Wang, M.; Ho, C.-T. Volatile
Compounds Generated from Thermal Degradation of N-Acetylglucosamine. J.
Agric. Food Chem. 1998, 46, 3207-3209; (b) Drover, M. W.; Omari, K. W.;
Murphy, J, N.; Kerton, F. M. Formation of a Renewable Amide, 3-Acetamido-5-
acetylfuran, via Direct Conversion of N-Acetyl-D-glucosamine. RSC Advances,
2012, 2, 4642-4644; (c) Chen, X.; Gao, Y.; Wang, L.; Chen, H.; Yan, N. Effect of
Treatment Methods on Chitin Structure and its Transformation into Nitrogen-
Containing Chemicals. ChemPlusChem 2015, 80, 1565-1572; (d) Gao, X.; Chen,
X.; Zhang, J.; Guo, W.; Jin, F.; Yan, N. Transformation of Chitin and Waste
Shrimp Shells into Acetic Acid and Pyrrole. ACS Sustainable Chem. Eng. 2016, 4,
3912-3920; (e) Liu, C.; Zhang, H.; Xiao, R.; Wu, S. Value-Added Organonitrogen
Chemicals Evolution from Pyrolysis of Chitin and Chitosan. Carbohydrate
Polymers, 2017, 156, 118-124; (f) Hülsey, M. J.; Yang, H.; Yan, N. Sustainable
Routes for the Synthesis of Renewable Heteroatom-Containing Chemicals. ACS
Sustainable Chem. Eng. 2018, 6, 5694-5707; (g) Zhang, P.; Hu, H.; Tang, H.;
Yang, Y.; Liu, H.; Lu, Q.; Li, X.; Worasuwannarak, N.; Yao, H. In-depth
Experimental Study of Pyrolysis Characteristics of Raw and Cooking Treated
Shrimp Shell Samples. Renewable Energy, 2019, 139, 730-738.
See, for example: (a)Liu, Y.; Stähler, C.; Murphy, J. N.; Furling, B. J.; Kerton, F.
M. Formation of a Renewable Amine and an Alcohol via Transformations of 3-
Acetamido-5-acetylfuran. ACS Sustainable Chem. Eng. 2017, 5, 4916-4922; (b)
Pham, T. T.; Chen, X.; Yan, N.; Sperry, J. A Novel Dihydrodifuropyridine
Scaffold Derived from Ketones and the Chitin-derived Heterocycle 3-Acetamido-
5-acetylfuran. Monatsh Chem. 2018, 149, 857-861; (c) Sadiq, A. D.; Chen, X.;
Yan, N.; Sperry, J. Towards the Shell Biorefinery: Sustainable Synthesis of the
Anticancer Alkaloid Proximicin A from Chitin. ChemSusChem 2018, 11, 532-
535; (d) Pham, T. T.; Gözaydin, G.; Söhnel, T.; Yan, N.; Sperry, J. Oxidative
Ring-Expansion of a Chitin-Derived Platform Enables to Unexplored 2-Amino
Sugar Chemical Space. Eur. J. Org. Chem. 2019, 1355-1360.
(a) Ma, X., Anderson, N., White, L. V., Bae, S., Raverty, W., Willis, A. C. and
Banwell, M. G. The Conversion of Levoglucosenone into Isolevoglucosenone.
Aust. J. Chem. 2015, 68, 593-599; (b) Ma, X., Liu, X., Yates, P., Rafferty, W.,
Banwell, M. G., Ma, C., Willis, A. C., Carr, P. D. Manipulating the Enone Moiety
of Levoglucosenone: 1,3-Transposition Reactions Including Ones Leading to
Isolevolglucosenone. Tetrahedron 2018, 74, 5000-5011.
(a) Wang, Z.; Lu, Q.; Zhu, X.-F.; Zhang, Y. Catalytic Fast Pyrolysis of Cellulose
to Prepare Levoglucosenone Using Sulfated Zirconia. ChemSusChem, 2011, 4,
79-84; (b) Kudo, S.; Goto, N.; Sperry, J.; Norinaga, K.; Hayashi, J-i. Production
of Levoglucosenone and Dihydrolevoglucosenone by Catalytic Reforming of
Volatiles from Cellulose Pyrolysis Using Supported Ionic Liquid Phase. ACS
Sustainable Chem. Eng. 2017, 5, 1132-1140 and references cited therein.
(a) Camp, J. E. Bio-available Solvent Cyrene: Synthesis, Derivatization and
Applications. ChemSusChem. 2018, 11, 3048-3055. (b) https://cen.acs.org/busin-
ess/biobased-chemicals/New-solvent-Cyrene-takes-NMP/97/i22 (accessed 07/05/
2019).
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.
5.
6.
7.
8.
A range of experiments was undertaken in an effort to promote heat transfer to the
substrate (viz. to the chitin, chitosan or NAG). These included placing ball
bearings inside the vessel and stirring the contents magnetically, using mixtures of
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the substrate with acid washed sand and suspensions of the substrate in canola oil.
Details are provided in the SI.
9.
Zhu, H.-J.; Yan, Y.-M.; Tu, Z.-C.; Luo, J.-F.; Liang, R.; Yang, T.-H.; Cheng, Y.-
X.; Wang, S.-M. Compounds from Polyphaga plancyi and their Inhibitory
Activities Against JAK3 and DDR1 Kinases. Fitoterapia, 2016, 114, 163-167.
Franich, R. A.; Goodin, S. J.; Wilkins, A. L. Acetamidofurans,
Acetamidopyrones, and Acetamidoacetaldehyde from Pyrolysis of Chitin and N-
Acetylglucosamine, J. Anal. Appl. Pyrolysis, 1984, 7, 91-100.
Staniewicz, B. A.; Mastalerz, M.; Hof, C. H. J.; Bierstedt, A.; Flannery, M. G.;
Briggs, D. E. G.; Evershed, R. P. Biodegradation of the Chitin-Protein Complex in
Crustacean Cuticle. Org. Geochem. 1998, 28, 67-76.
Effenberger, F.; Beisswenger, T.; Az, R. Decomposition of 2-Azido Ketones to 2-
(Acetylamino)-2-alken-1-ones by Perrhenate Catalysis. Chem. Ber. 1985, 118,
4869-4876.
Nin, A.P.; de Lederkremer, R. M.; Varela, O. Synthesis of (2S, 4R, 5R)-4,5,6-
Trihydroxynorleucine and 5-Hydroxynorvaline from Precursors Obtained by an
Unusual Rearrangement in a 5,6-Dihydro-2-pyrone. Tetrahedron, 1996, 52,
12911-12918.
Schreiner, E. P.; Wolff, B.; Winiski, A. P.; Billich, A. 6-(2-Adamantan-2-ylidene-
hydroxybenzoxazole)-O-sulfamate. A Potent Non-steroidal Irreversible Inhibitor
of Human Steroid Sulfatase. Bioorg. Med. Chem. Lett. 2003, 13, 4313-4316.
Caprio, V. 7.03 - Pyridines and their Benzo Derivatives: Reactivity of
Substituents. Comprehensive Heterocyclic Chemistry III. 2008, 7, 101-169.
Denmark, S. E.; Jaunet, A. Catalytic, Enantioselective, Intramolecular
Carbosulfenylation of Olefins. Preparative and Stereochemical Aspects. J. Org.
Chem. 2014, 79, 140-171 and references cited there-in.
For useful commentaries on such processes, see: (a) Boelma, E.; Wieringa, J. H.;
Wynberg, H.; Starting, J. An Intramolecular 1,3-Hydride Shift in the Adamantane
Series. Tetrahedron Lett. 1973, 2377-2380; (b) Faraldos, J. A.; Wu, S.; Chappll,
J.; Coates, R. M. Doubly Labeled Patchouli Alcohol from Singly Labeled [2-
2H1]Farnesyl Diphosphate Catalyzed by Recombinant Patchouli Synthase. J. Am.
Chem. Soc. 2010, 132, 2998-3008; (c) Assary, R. S.; Curtiss, L. A. Comparison of
Sugar Molecule Decomposition through Glucose and Fructose. A High-Level
Quantum Chemical Study. Energy & Fuels, 2012, 26, 1344-1352; (d) Rinkel, J.;
Rabe, P.; Garbeva, P.; Dickschat, J. S. Lessons from 1,3-Hydride Shifts in
Sesquiterpene Cyclizations. Angew. Chem. Int. Ed. 2016, 55, 13593-13596.
These dehydration processes could also involve direct elimination of the elements
of water across two conjoined carbons or a cyclodehydration process leading to an
intermediate epoxide that rearranges to the corresponding aldehyde or ketone.
Novotny, O.; Cejpek, K.; Velisek, J. Formation of -Hydroxy and -Dicarbonyl
Compounds during Degradation of Monosaccharides. Czech J. Food Sci. 2007,
25, 119-130.
10.
11.
12.
13.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14.
15.
16.
17.
18.
19.
20.
21.
22.
Clearly the pre-treatment of chitin with glyoxal failed to enhance the production
of compound 9 (see Entry 4, Table 1).
This possible mode of deoxygenation of vicinal diols is one we are currently
exploring, especially through pyrolysis of the derived Ley acetals.
Bogart, J. W.; Bowers, A. A. Dehydroamino acids: Chemical Multi-tools for Late-
stage Diversification. Org. Biomol. Chem. 2019, 17, 3653-3669 and references
cited therein.
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2
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5
6
7
8
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23.
24.
Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for
Preparative Separations with Moderate Resolution. J. Org. Chem., 1978, 43,
2923–2925.
Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Safe and Convenient Procedure for Solvent Purification. Organometallics, 1996,
15, 1518–1520.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25.
26.
27.
28.
CrysAlis PRO Version 1.171.37.35h (release 09-02-2015 CrysAlis171.NET)
(compiled Feb 9 2015,16:26:32) Agilent Technologies: Oxfordshire, UK.
Sheldrick, G. M. SHELXT – Integrated Space-Group and Crystal-Structure
Determination. Acta Cryst. 2015, A71, 3-8.
Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Cryst. 2015,
C71, 3-8.
Zhao, Y.; Truhlar, D. G., The M06 suite of density functionals for main group
thermochemistry, thermochemical kinetics, noncovalent interactions, excited
states, and transition elements: two new functionals and systematic testing of four
M06-class functionals and 12 other functionals. Theoretical Chemistry Accounts
2008, 120, 215-241.
Alecu, I.; Zheng, J.; Zhao, Y.; Truhlar, D. G., Computational thermochemistry:
scale factor databases and scale factors for vibrational frequencies obtained from
electronic model chemistries. Journal of chemical theory and computation 2010,
6, 2872-2887.
29.
30.
31.
32.
33.
Curtiss, L. A.; Raghavachari, K.; Redfern, P. C.; Baboul, A. G.; Pople, J. A.,
Gaussian-3 theory using coupled cluster energies. Chemical Physics Letters 1999,
314, 101-107.
Izgorodina, E. I.; Lin, C. Y.; Coote, M. L., Energy-directed tree search: an
efficient systematic algorithm for finding the lowest energy conformation of
molecules. Physical Chemistry Chemical Physics 2007, 9, 2507-2516.
Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.; Cheeseman, J.;
Scalmani, G.; Barone, V.; Petersson, G.; Nakatsuji, H.; et al., Gaussian 09.
Revision E. 01. Gaussian Inc., Wallingford, CT, USA. 2009.
Werner, H.; Knowles, P.; Knizia, G.; Manby, F.; Schütz, M.; Celani, P.; Györffy,
W.; Kats, D.; Korona, T.; Lindh, R.; et al., MOLPRO, Version 2015.1, a Package
of ab initio Programs. 2015.
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