Toward functional polyester building blocks from renewable glycolaldehyde with sn cascade catalysis

Article abstract of DOI:10.1021/cs400298n

Having been inspired by formose-based hypotheses surrounding the origin of life, we report on a novel catalytic route toward a series of recently discovered four-carbon α-hydroxy acids (AHA) and their esters from accessible and renewable glycolaldehyde (GA) in various solvents. The synthesis route follows a cascade type reaction network, and its mechanism with identification of the rate-determining step was investigated with in situ ¹³C NMR. The mechanistic understanding led to optimized reaction conditions with higher overall rates of AHA formation by balancing Bronsted and Lewis acid activity, both originating from the tin halide catalyst. An optimal H⁺/Sn ratio of 3 was identified, and this number was surprisingly irrespective of the Sn oxidation state. Further rate enhancement was accomplished by adding small amounts of water to the reaction mixture, boosting the rate by a factor of 4.5 compared with pure methanol solvent. The cascade reaction selectively yields near 60% methyl-4-methoxy-2- hydroxybutanoate (MMHB). In the optimized rate regime in methanol, an initial TOF of 7.4 mol_GA mol_Sn^-1 h^-1 was found. In sterically hindered alcohols (isopropyl alcohol), the rate of AHA formation was even higher, and the corresponding vinyl glycolate esters arose as the main product. Vinyl glycolic acid, 2,4-dihydroxybutanoic acid, and its lactone were formed significantly in nonprotic solvent. The corresponding AHAs have serious potential as building blocks in novel biobased polymers with tunable functionality. The incorporation of vinyl glycolic acid in polylactic acid-based polyesters is illustrated, and postmodification at the vinyl side groups indeed allows access to a range of properties, such as tunable hydrophilicity, which is otherwise difficult to attain for pure poly(l-lactic acid).

Full text of DOI:10.1021/cs400298n

Research Article
pubs.acs.org/acscatalysis
Toward Functional Polyester Building Blocks from Renewable
Glycolaldehyde with Sn Cascade Catalysis
Michiel Dusselier,*,† Pieter Van Wouwe,† Sanne De Smet,‡ Rik De Clercq,† Leander Verbelen,§
Peter Van Puyvelde,§ Filip E. Du Prez,‡ and Bert F. Sels*,†
†Center for Surface Chemistry and Catalysis, Katholieke Universiteit Leuven, Kasteelpark Arenberg 23, 3001 Leuven, Belgium
‡Department of Organic Chemistry, Polymer Chemistry Research Group, Ghent University, Krijgslaan 281, S4-bis, 9000 Ghent,
Belgium
§Department of Chemical Engineering, Katholieke Universiteit Leuven, Willem de Croylaan 46, 3001 Leuven, Belgium
S
* Supporting Information
ABSTRACT: Having been inspired by formose-based hypotheses
surrounding the origin of life, we report on a novel catalytic route
toward a series of recently discovered four-carbon α-hydroxy acids
(AHA) and their esters from accessible and renewable glycol-
aldehyde (GA) in various solvents. The synthesis route follows a
cascade type reaction network, and its mechanism with
identification of the rate-determining step was investigated with
in situ 13C NMR. The mechanistic understanding led to optimized
reaction conditions with higher overall rates of AHA formation by
balancing Brønsted and Lewis acid activity, both originating from
the tin halide catalyst. An optimal H+/Sn ratio of 3 was identified,
and this number was surprisingly irrespective of the Sn oxidation
state. Further rate enhancement was accomplished by adding small
amounts of water to the reaction mixture, boosting the rate by a factor of 4.5 compared with pure methanol solvent. The cascade
reaction selectively yields near 60% methyl-4-methoxy-2-hydroxybutanoate (MMHB). In the optimized rate regime in methanol,
an initial TOF of 7.4 molGA molSn−1 h−1 was found. In sterically hindered alcohols (isopropyl alcohol), the rate of AHA formation
was even higher, and the corresponding vinyl glycolate esters arose as the main product. Vinyl glycolic acid, 2,4-
dihydroxybutanoic acid, and its lactone were formed significantly in nonprotic solvent. The corresponding AHAs have serious
potential as building blocks in novel biobased polymers with tunable functionality. The incorporation of vinyl glycolic acid in
polylactic acid-based polyesters is illustrated, and postmodification at the vinyl side groups indeed allows access to a range of
properties, such as tunable hydrophilicity, which is otherwise difficult to attain for pure poly(L-lactic acid).
KEYWORDS: homogeneous catalysis, biomass, building blocks, glycolaldehyde, α-hydroxy acids, biodegradable polymers,
polylactic acid
and oceans.14,16−18 Traditional poly(L-lactic acid) (PLLA) has
INTRODUCTION
■
many good features, but also some limitations:8 it is a brittle
α-Hydroxy acids (AHAs) and their esters are of great appeal as
platform chemicals1−3 in the portfolio of renewable derived
polymer with poor elongation at break and lacks reactive side
solvents and as building blocks for polyesters.1,4,5 Lactic acid,1
for instance (a three-carbon AHA), is a rapidly growing
chain groups for chemical modification. Moreover, PLLA is
often considered too hydrophobic, causing inflammatory
responses when applied in vivo.12,19
commodity chemical; its ethyl ester (ethyl lactate6,7) is
becoming a renowned green solvent, and polylactic acid
(PLA) is currently one of the top volume bioplastics.8,9 Being
renewable10 and biodegradable,11−13 such polyesters not only
are useful to replace petroleum-derived plastics in certain
applications, but also have a promising future in biomedical and
in vivo applications because of their biocompatibility.14,15 Their
ever increasing popularity is due in part to rising concern over
the use of depleting fossil feedstock for the production of
classic polymers. Moreover, most of these polymers are
nondegradable and lie at the origin of a huge waste problem,
sadly exemplified by plastic scrap covering our remotest islands
Recently, intriguing four-carbon AHAs were discovered in
small amounts during the chemocatalytic conversion of hexoses
and hemicellulosic sugars to alkyl lactates with Sn-based
zeolites20,21 and with our Sn-containing silica/carbon compo-
site catalysts.5 The origin of these esters, namely, MVG (methyl
vinyl glycolate) and MMHB (methyl-4-methoxy-2-hydroxybu-
tanoate), was attributed to the presence of tetrose sugars,
Received: April 19, 2013
Revised: June 23, 2013
Published: June 25, 2013
© 2013 American Chemical Society
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formed by the retro-aldol splitting of glucose (Scheme 1).
Because of their structure, these AHAs could offer a solution to
ribose-sugar-based life under credible prebiotic conditions.37−40
The formose process entails several aldol reactions, eventually
leading to complex sugar mixtures and tars.41−43 Borates39,44
and silicates45 were found to stabilize (especially) pentoses
from these reaction mixtures, thereby possibly directing the
unselective formose reaction. In this way, for example, borate-
bound sugars are excluded to undergo further aldol
condensation.
Scheme 1. Overview of the Synthesis of Four-Carbon AHAs
from Tetroses22 and Glycolaldehyde (this work) and Some
of the Demonstrated Tunable (PLA-based) Copolymers
Inspired by this approach, and in the light of the future
availability of GA via biomass pyrolysis, we demonstrate here
the one-pot catalytic conversion of GA to four-carbon AHA
(esters) according to a complex cascade network. The
unselective aldol-based sugar synthesis is hereto combined
with the Sn-based homogeneous catalytic transformation of
tetroses to AHAs. In this way, the formation of unwanted larger
carbohydrates from tetroses and GA is circumvented. With the
help of in situ NMR, key insights into the reaction mechanism
and its catalytic needs are unravelled. Finally, the potential of
such derived AHA monomer building blocks is proved for the
first time by their copolymerization with lactic acid, leading to a
new range of tunable PLA based polymers with interesting
properties and easy access to functionalization, for instance, by
thiol/-ene chemistry (on polylactic acid-co-vinyl glycolate), as
visualized in Scheme 1.
METHODS
■
Catalytic Tests. Experiments were performed in 10 mL-
thick-walled glass vial reactors. In a typical experiment, 0.0025
mol of glycolaldehyde (0.150 g, dimeric form, Sigma-Aldrich)
was combined with 1.25 × 10−4 mol of Sn catalyst; for instance,
43.8 mg in the case of SnCl4·5H2O (Acros), in 2 mL of solvent
(methanol, ethanol, IPA, methanol/water). Naphthalene (50
mg) was used as the internal (or external) standard. A magnetic
stirring bar was then added, and the glass vials were closed by
crimp cap with a septum and placed into a multivial heating
block at 363 K. The mixture was allowed to react for certain
amounts of time ranging from 5 min to 26 h, depending on the
progress under continuous magnetic stirring. To quench
intrinsic HCl-derived Brønsted acidity (BA), precise amounts
of Dowex Monosphere 550A anion exchange resin based on a
quaternary amine in its OH− form were added to the catalytic
mixture. To add extrinsic HCl, a solution in methanol was
prepared and added. To determine the quenching capacity of
such a resin, it was fully exchanged under excess NaOH,
thoroughly washed, and titrated (anion exchange capacity of 1.5
mmol/g).
overcome certain of the PLA limitations by coincorporation:
MVG has a vinyl (and thus, easy access to functionalization)
instead of the methyl group in lactic acid, whereas MMHB
possesses a 4-methoxy substituent, a more polar tail group.
Moreover, the search for new catalytic routes toward such
molecules is interesting because they are very rare in nature, in
contrast to lactic acid. Recently, we delivered mechanistic
insight into the conversion of tetrose sugars to these novel
AHAs platform molecules with Sn halide catalysts.22 Especially,
MMHB was shown to be synthesized in high yield in methanol
under mild conditions from erythrulose and erythrose in one
step, involving many different types of reactions, as catalyzed by
Sn halides. Reported yields to MVG in this report were rather
low.
Although very useful for providing mechanistic evidence and
elucidating reaction pathways, the tetroses in previous study are
very expensive and not accessible on a large scale.22
Glycolaldehyde (GA),23 the “two-carbon” sugar, however, is
encountered in high yields when converting glucose via retro-
aldol splitting under subcritical hydrothermal conditions,24 and
more significantly, it is one of the major constituents of bio-oils
obtained via pyrolysis of biomass residue.25,26 Up to 10 wt %
yield of GA can be found in such oils obtained from the
pyrolysis of cellulose, nature’s most abundant renewable
biomass resource.27−34 These yields are relevant considering
the nonselective nature of the pyrolysis process and the
overwhelming availability of the feedstock. Moreover, successful
efforts have been made recently toward GA isolation from such
complex bio-oils.35
Analysis: Methyl-4-methoxy-2-hydroxybutanoate (MMHB),
methyl vinyl glycolate (MVG), and their alkyl analogues and
glycolaldehyde dimethyl acetal (GADMA) were analyzed by
gas chromatography on a 30 m Agilent HP-5 column and on a
chiral 25 m Agilent WCOT fused-silica CP-Chirasil-DEX CB
capillary column, both equipped with an FID detector and
ChemStation software. A chromatogram is illustrated in the
Supporting Information (Figure S6B) Product yields were
calculated via internal standards. Sensitivity factors were
obtained by calibration with commercial standards (MVG,
96%, TCI Europe; GADMA; 98% Alfa Aesar) or obtained by
ECN-based calculations,46 because of a lack of commercial
standard (for MMHB and alkyl analogues of MMHB and
MVG). Identification of the reaction products was carried out
In a totally different context, in search for the origin of life,
the formose-based synthesis of sugars starting from form-
aldehyde or GA (even found in outer space36,37) with the help
of mineral-derived alkali, borates, or amino acids is offering a
likely explanation for the rise of complex organic molecules and
1
by GC/MS analysis with electronic ionization, 13C NMR, H
NMR, and GC based on retention times of commercial
reference chemicals. A Hewlett-Packard 5989A mass spec-
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trometer using electronic ionization was used to further identify
the glycolaldehyde hemiacetal.
PLGPC50plus instrument, using a refractive index detector,
equipped with two Plgel 5 μm MIXED-D columns kept at 40
°C. Polystyrene standards were used for calibration, and THF,
as eluent at a flow rate of 1 mL/min. Samples were injected
using a PL AS RT autosampler. Static contact angle
measurements were performed with double deionized water
on polymer coated glass slides with a KSV NIMA CAM200
setup and its software. Hereto, the polymers were spin-coated
from a 5 wt % solution in CHCl3 or THF on a thin glass
preparation slide for 1 min at a rate of 1000 rpm attained in 2 s.
The slides were dried overnight at room temperature. Per slide,
3 drops were measured, and during measurement, 2 subdrops
were added. Thirty seconds after adding each subdrop, the
photographed droplet was fit according to the Young−Laplace
equation, and the static contact angle was calculated. At least 2
slides per polymer were prepared. Standard deviations were
calculated.
Thiol-ene Functionalization of Polymers. A typical
thiol-ene reaction was performed as follows: Functionalized
polymer PLLA-co-VG (12% vinyl) (100 mg; 0,19 mmol
alkene) was dissolved in dry THF (1.0 mL). Benzyl mercaptan
(99% Sigma-Aldrich, 0.38 mmol) and 2,2-dimethoxy-2-phenyl-
acetophenone (99% Sigma-Aldrich, 5.0 mg/mL) as photo-
initiator were added, and the solution was degassed for 30 min
with N2. In another case, 1-thioglycerol (>97%, Sigma-Aldrich)
was used. The reaction mixture was irradiated with UV-light
(365 nm) for 5 h at ambient conditions. The functionalized
polymer was collected by precipitation in cold methanol or
diethyl ether and dried prior to analysis.
In Situ Studies. Typically, 0.05 g of glycolaldehyde (dimeric
form, Sigma-Aldrich) was dissolved in either 0.6 mL of
CH3OH, CD3OD, isopropyl alcohol, acetonitrile, or dimethyl
sulfoxide (DMSO) or mixtures thereof with H2O or D2O, and a
13C NMR spectrum was recorded. Then this mixture was added
to a SnCl4·5H2O-containing vial. Different GA/Sn ratios were
used (2:1, 5:1, 10:1). As soon as the mixture was homogeneous,
it was transferred back to the 5 mm Norell tube and lowered
into a Bruker Avance II-plus 600 MHz spectrometer equipped
with a BBO probe or a Bruker Avance 400 MHz spectrometer
with a BBI probe. The sweep was put off in the case of
nondeuterated solvents. In this way, the first accumulation of
128 scans (6−7 min) (or 256 scans, depending on the signal-
to-noise ratio and the concentration) could be recorded ∼2.5
min after mixing. The number of desired acquisitions was put in
sequence and mostly run overnight. For temperatures other
than 298 K (usually 333 K), the spectrometer was allowed to
reach the temperature and equilibrate before the sample was
loaded. A Bruker Avance 300 MHz equipped with a BBO probe
was used for standard NMR measurements. Topspin 2.1
Software was used for controlling the spectrometers and
analyzing the results.
Polymerization via Polycondensation. MVG (97%, TCI
Europe) was filtered over activated basic aluminum oxide
(Sigma-Aldrich) to retain possible carboxylic acid impurities.
For the synthesis of polylactic acid-co-vinyl glycolate (7%), 0.7
g of MVG was dissolved in 20 mL of Millipore water, and 0.7 g
of Amberlyst 15, a strong acidic cation exchange resin, was
added as a hydrolysis catalyst (1 g). This mixture was
continuously stirred in an oil bath kept at 353 K. The mixture
was left to react until complete conversion of MVG, as analyzed
by GC. The resulting vinyl glycolate monomer (2-hydroxy-3-
butenoic acid) was ascertained by 1H and 13C NMR. Amberlyst
wet 15 (Sigma-Aldrich) was filtered off, and the excess of water
was slowly evaporated with a gentle nitrogen flow while
keeping the mixture at 333 K. The dried monomer (4.7 mmol,
0.48 g, oil) was mixed with 42.3 mmol of lactic acid (4.15 g of a
90 wt % aqueous solution, Sigma-Aldrich) to obtain a
monomer composition of vinyl glycolate/lactic acid of 1:10.
To this, p-xylene was added to obtain a 50 wt % monomer
mixture as well as 0.2 wt % (on monomer) of the SnCl2·2H2O
polycondensation catalyst, according to Kim et al.47 The
reaction vessel was equipped with a Dean−Stark trap (filled
before reaction with p-xylene) and left to reflux in an oil bath at
160 °C for 72 h. The resulting mixture was dissolved in CHCl3
and precipitated in excess cold CH3OH (nonsolvent). The
resulting polyester was filtered off and dried under vacuum.
Reference poly(L-lactic acid) was made in exactly the same
manner.
RESULTS
■
Occurrence of Glycolaldehyde in Reaction Condi-
tions. Commercial glycolaldehyde (GA) is found in its
crystalline dimeric form (1 in Scheme 2). This dimer is said
to decompose thermally into monomeric GA (2 in Scheme 2).
The free aldehyde group, however, is rarely encountered
because its main occurrence greatly depends on the solvent. In
water, for instance, its hydrate (2″) is the most encountered
form at standard conditions, and this form is easily detected in
Scheme 2. Occurrence of GA (2) and Its Basic Aldol
Reaction in Water (A) and Its Occurrence in Methanol (B)
1
1
1
Polymer Characterization. H-, H-COSY-, and H-/13C-
HSQC were recorded in CDCl3 on Bruker Avance 400 and 300
MHz spectrometers. In addition, 13C NMR and 13C-APT-NMR
were measured on a Bruker AM500 MHz spectrometer.
Thermal gravimetric analysis (TGA) was performed on the
polymer powders while heating them at a rate of 10 K/min
under N2 atmosphere using a TGA Q500 (TA Instruments)
equipped with an automatic sampler. Differential scanning
calorimetry (DSC) experiments were performed with a DSC
Q2000 (TA Instruments) by cycling between 283 and 483 K at
heating/cooling rates of 10 K/min under N2 atmosphere. Size
exclusion chromatography (SEC) was performed using a Varian
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13C NMR.48,49 In light of the origin of life, in length reviewed
by Benner et al. in a recent perspective,37 it was shown that GA,
when incubated in a borate buffer (pH 10.4) at 338 K for 1 h,
led to the formation of mainly threose and erythrose, two
tetrose sugars, in a yield of 86%.39 The aldol reaction arose
from the basicity of the medium (free OH−), and the
mechanism of this aldol reaction is generally known as the
enolate mechanism, involving the base-catalyzed enolization of
GA, transforming it into a nucleophile (seen as 2′ in Scheme
2), which attacks the aldehyde carbon of another GA molecule,
with the formation of a tetrose as the result (an aldose: threose
or erythrose). This reaction proves the ease of condensing GA
toward higher sugars in basic media, as illustrated in Scheme
2A, and it is the main mechanism behind the formose
reaction.42
In the same context, Kofoed et al. have studied GA
conversion in the absence of a base, catalyzed by a
ZnII(proline)2 Lewis acidic catalyst (proposed to be a likely
metalloenzyme precursor) under credible prebiotic condi-
tions.50 The aldol reactivity was postulated to be catalyzed by
the Lewis acidic ZnII center chelated with a glycolaldehyde
enolate. Burroughs et al. showed that esters of proteinogenic
amino acids (e.g., N-methyl leucine ethyl ester) were also able
to perform this reaction via the enamine aldol mechanism in
similar circumstances.51
The ultimate challenge for using GA as biomass feedstock for
the formation of four-carbon α-hydroxy acid esters (AHA) is
the cascade coupling of the aldol reaction of GA to tetroses
with the subsequent selective conversion to MMHB and MVG.
The established conversion of tetroses to AHA-containing
compounds with Sn halides salts is preferably carried out in
alcoholic media to avoid side product formation, side-reactions
with the formed carboxylic acid group and the formation of
tin(hydr)oxides.22
The occurrence of GA in methanol (Scheme 2B) plays a
crucial role in the conversion of GA to AHAs and was therefore
studied first with (in situ) 13C NMR. The spectral evidence is
presented in Figure 1. Part i of Figure 1 thus shows the
spectrum of the crystalline dimeric form 1, immediately after
dissolution in CH3OH at 298 K. When heating such a mixture
for only 5 min at 363 K, the cyclic dimer 1 undergoes a rapid
transformation to glycolaldehyde hemiacetal (GAHA, 3 in
Scheme 2), and its three signals98, 65, and 54 ppmare the
only ones found, as seen in Figure 1, part ii. During very long
incubation at 363 K, the diagnostic chemical shifts at 98 and 65
ppm gradually diminished in favor of two new signals at 105
and 62 ppm, whereas the signal at 54 ppm increased. This
change in 13C NMR signals corresponds to the formation of the
dimethyl acetal of GA (GADMA, 4 in Scheme 2), which has
overlapping methyl signals at 54 ppm, as seen in Figure 1, part
iii, and its chemical shifts were perfectly in agreement with a
commercial standard. This transformation (GAHA 3 into
GADMA 4) is, however, very slow in pure methanol at 363 K,
and it does not even seem to occur within 5 days of incubation
at 298 K. Thus, as seen in Scheme 2B, formation of GADMA
from GAHA requires sufficient time and heat or an appropriate
catalyst to accelerate the second acetalization. Such acetaliza-
tion reactions are reversible and typically catalyzed by Brønsted
(or Lewis) acids.52 This is evidenced by the rapid formation of
GADMA, within 30 min, when GA dimer was dissolved at 298
K in methanol containing HCl (in situ 13C NMR spectral
sequence for 10:1 GA/H+; see Supporting Information Figure
S1). The effect of Sn halide catalysts on the occurrence of GA
was therefore also studied with an identical GA solution in the
presence of SnCl4·5H2O in a 10:1 GA/Sn molar ratio in the
spectrometer at 298 K. The rapid transformation of GAHA to
GADMA could again clearly be witnessed by in situ NMR and
took about 90 min to completion; in fact, the last spectrum of
this sequence is shown in Figure 1, part iii. The same
experiment carried out at 333 K displayed nothing but
GADMA 4 after 2 min, proving the catalytic effect of
SnCl4·5H2O halides.
In conclusion, GA dimer 1 readily converts to the hemiacetal
GAHA 3, but it takes over 24 h to convert 3 further into
diacetal GADMA 4 without catalyst at 363 K in methanol. The
second acetalization is very fast in the presence of HCl or
SnCl4·5H2O catalysts, even at room temperature. In the latter
case, the acetalization activity likely originates from Brønsted
acidity by dissociation of chloride ligands with formation of
HCl. At 333 K, with such a catalyst, acetal 4 is formed
immediately from 1 in CH3OH.
Catalytic Cascade: Proof of Concept. To investigate the
ability of Sn halides and other soluble model catalysts to assist
the overall reaction of two GA molecules into four-carbon
AHAs (seen in Scheme 1) in alcoholic media, concentrated
solutions of GA dimer 1 were contacted with catalytic amounts
of Sn, Al, and Cr halides. These catalysts were recently
proposed in for the conversion of tetroses to AHAs.22 The
experiments were performed with 1.25 M GA in methanol at
363 K for ∼20 h. An intermediate sample was taken after 1 h of
reaction for a kinetic analysis. This reaction condition closely
matches the one used in our earlier study for the conversion of
tetrose sugars in CH3OH (0.625 M tetrose at 363 K).15 The
results of the screening are found in Table 1. Sn halides are,
indeed, able to perform the whole cascade reaction in CH3OH,
yielding between 50 and 60% of MMHB 9 (Scheme 3) from 1
after 20 h of reaction. As seen in entries 6 and 8, both SnII and
SnIV produce 9, whereas MVG is only a minor product. Starting
from a tetrose feedstock (erythrose) instead of 1, as seen in
entry 11, similar yields were obtained, albeit much faster.
The successful catalytic reactions prompted us to monitor
the reaction evolution in time in the presence of the tin
catalysts. One hour points are shown in entries 5 and 7, and the
kinetic plot is presented in Figure 2. The latter displays that
80% of the final yield (viz., 58% after 20 h) is already obtained
after 7 h of reaction. The primary product of the reaction
Figure 1. (i) GA dimer 1, 2 min after dissolution in CH3OH at 298 K.
(ii) Such mixture heated at 363 K for 5 min: formation of GAHA 3.
(iii) GA dimer 1 dissolved in CH3OH containing 10 mol % of
SnCl4·5H2O after 90 min at 298 K: GADMA 4.
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dimer 1 was noticed instantaneously upon contact with
SnCl4·5H2O in methanol at 333 K.
Table 1. Screening for the Conversion of Glycolaldehyde to
GADMA 4 and α-Hydroxy Acid Esters in CH3OH
a
Reaction with HCl, a model Brønsted acid catalyst, led to
neither MMHB 9 nor MVG formation, and the main product
was the acetal GADMA 4 (entries 2 and 3), in addition to other
acetalization products, such as 1,1,2-trimethoxyethane and
tetramethoxyethane. A reaction with catalytic amounts of base
(viz., NaOH) yielded no GC-detectable products. Other Lewis
acids (viz. AlIII and CrIII halides; entries 9 and 10) appeared
unable or very slow to convert 1 to AHAs and mainly 4.
Reaction with AlIII and CrIII halide catalysts is restricted to
acetalization, like HCl. Nevertheless, when contacting the two
metal halides with tetroses instead of dimeric GA 1, MMHB 9
was analyzed to be in the range of 12% yield after 1 h.22
In conclusion, Sn halides are unique in converting the
smallest sugar molecule glycolaldehyde into AHAs, preferably
to MMHB 9 in methanol, and Brønsted acids and other Lewis
acid catalysts mainly form diacetal GADMA 4.
entry
catalyst
HCl
t (h) GADMA (%) MMHB (%) MVG (%)
1
2
26
1
47
72
56
0
0
0
0
0
3
HCl
22
20
1
0
0
4
NaOH
0
0
5
SnIVCl4·5H2O
SnIVCl4·5H2O
SnIICl2·2H2O
SnIICl2·2H2O
AlIIICl3·6H2O
CrIIICl3·6H2O
SnIVCl4·5H2O
54
3
10
58
14
55
7
<1
3
6
20
1
7
51
1
<1
4
8
21
20
20
1
9
47
71
0
10
<1
50
0
b
11
2
a
Reactions at 363 K with 1.25 M GA (provided as dimer, 1) in
MeOH. GC-based yields; 5 mol % of catalyst (20 mol % for HCl, 10
mol % for NaOH). Reaction on 0.625 M of erythrose in CH3OH, 10
mol % of catalyst.
b
Proposal of the Reaction Pathway to MMHB.
Considering the above study on the occurrence of GA in
methanol and the earlier proposed reaction scheme for the
conversion of tetroses to four-carbon AHAs,22 a reaction
proved to be the acetal 4. This is in agreement with the 13C
NMR data mentioned above, where its formation from GA
Scheme 3. Proposed Cascade of Glycolaldehyde (dimeric form 1) to MMHB 9 in CH3OH in the Presence of Sn Halides
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Figure 2. Kinetic plot of the reaction with SnCl4·5H2O in the conditions of Table 1, footnote a.
pathway for the conversion of 1 to MMHB 9 with Sn halides is
postulated in Scheme 3. Acetalization in methanol rapidly
converts 1 quantitatively into 4 at elevated temperature and in
the presence of the Sn catalyst. To ascertain this, a reaction at
363 K with SnCl2·2H2O was quenched after 5 min in ice, and
dehydration may formally be written, as if catalyzed by the Sn
center. A similar reaction mechanism was proposed for the
dehydration of dihydroxyacetone to pyruvic aldehyde with Sn
halides.59 Even when incorporated in β-zeolites, Sn centers
were found capable of coordinating multiple oxygen groups of
sugars, and this proves, for instance, useful in the isomerization
of glucose to fructose60 via a hydride transfer mechanism61,62
and the epimerization of sugar borate complexes.63
1
both GC and H NMR pointed to formation of 4 in yields of
84 and 95% ( 5%), respectively. In fact, glycolaldehyde
dimethylacetal 4 may be regarded as the starting point under
the reaction conditions, which is fully in line with the first
points in the kinetic plot in Figure 2.
Scheme 3 suggests the formation of a reactive intermediate
vinyl glyoxal 6 as a result of the dehydration steps. This
unsaturated molecule is prone to be attacked by nucleophiles
on its conjugated vinyl group according to a 1,4-addition64,65
and on its terminal carbonyl via acetalization. Acetalization,
depicted as step 6, is fast in the reaction conditions and leads to
hemiacetal 7. Subsequent alcohol attack on the vinyl group,
presented as step 7 (in Scheme 3), follows a formal 1,4-
nucleophilic (Michael) addition on α,β-unsaturated carbonyls65
and leads to the formation of the hemiacetal of 4-methoxy-
ethylglyoxal (8, Scheme 3). This molecule has been
encountered in high amounts as an intermediate when reacting
tetrose sugars with tin halides.22 Earlier work on tetroses
showed that pure Brønsted acidic catalysts are also able to
accelerate the conversion of tetroses to the hemiacetal 8, but
then eventually lead to the formation of a dimethyl acetal of 8
(not shown). This further proves that the cascade of retro-
Michael dehydrations, hemiacetalization and 1,4-addition is also
catalyzed by Brønsted acids, but interestingly, not the final
further conversion of 8 to MMHB 9.22 This final step 8 is a
formal intramolecular Cannizzaro reaction, which shifts the
proton of the aldehyde (here in hemiacetal form) of 8 via
hydride transfer from the terminal carbon to the α-carbon, with
formation of α-hydroxy acid ester MMHB 9 as the final result.
This type of reaction occurs only with Sn Lewis acid sites under
mild conditions and is, for instance, also responsible for the
conversion of pyruvic aldehyde into lactates.1,5,66,67
To be able to perform a Sn halide-based aldol reaction step,
free GA 2 and its enol 2′ should be available. Therefore, step 1
in Scheme 3 considers the hydrolysis of 4 into the hemiacetal 3.
This step obviously requires the presence of water. Water can
be traced back to three different sources in the reaction: (i) Sn
halide is used in its hydrate form; (ii) water is also formed in
the reaction network, considering the two necessary retro-
Michael dehydrations of the tetrose en route to an AHA,22 and
(iii) when no special precautions are taken, methanol contains
1
small percentages of water, which is easily detected by H
NMR. Acetalization is reversible and usually catalyzed by acid
catalysts.53 Similar to the hydrolysis of 4 to 3 (step 1), the latter
is in equilibrium with free GA 2 and 2′, via the loss of another
methanol (step 2 in Scheme 3). Formally, this step can also be
written as a hydrolysis followed by dehydration. The enol
species 2′ is capable of attacking a free GA molecule 2 to form a
tetrose 5 via aldol addition. With Sn halides in alcoholic media,
the base-catalyzed aldol mechanism41,42,54 is excluded, since the
medium is neutral to acidic, depending on the level of
methanolysis/hydrolysis of the chloride ligands at the Sn Lewis
acidic center. Furthermore, the reported enamine aldol
mechanism51,55 is excluded due to lack of amines. This leaves
us with two possibilities: a Lewis acid Sn-catalyzed aldol, as in
the origin of life approach with ZnII by Kofoed et al.,55 or a
Brønsted acidic aldol addition. The latter may be tentatively
excluded because a reaction of 1 with HCl forms only 4, but
this will be discussed later.
As deduced from Table 1, the overall cascade transformation
of 1 into 9 in methanol is much slower than the reaction with
tetroses 5−9 (steps 4−8). This indicates that the rate-
determining step (rds) of the cascade occurs in steps 1−3.
Gaining insight into the rds of a cascade reaction is very
instructive to assess the foremost catalytic needs. Mechanistic
Following the formation of the tetrose 5, two retro-Michael
dehydration steps56 follow (step 4 and 5). Since Sn easily
coordinates to entities with multiple −OH or O bonds (such
as sugars) due to its strong Lewis acid character,57,58 such
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insight may suggest rate improvements by better balancing the
required multiple active sites.5,68,69 Two in situ NMR studies
were therefore performed to provide evidence for the proposed
reaction scheme, one for the conversion of a tetrose 5 and one
with glycolaldehyde as substrate.
turned in favor of 9 (Figure 3ii, signals 0″−5″) without visibly
passing through the hemiacetal of GA 3 or the hemiacetal of 4-
methoxyethylglyoxal 8. This suggests that the rate-determining
step of the cascade reaction is not the Lewis acid-catalyzed
Cannizzaro, but step 1, the hydrolysis of 4 to 3. Indeed, if, for
instance, step 2 were the slowest step, the hemiacetal 3 should
be clearly visible in the NMR spectra, which is not the case.
In conclusion, in contrast with the conversion of tetroses to
AHAs, the overall rate of MMHB formation from 1 is
determined by the Brønsted acid-catalyzed hydrolysis of acetal
4. This insight implies (1) an optimal balance between Lewis
and Brønsted acidity to obtain a maximum overall rate and (2)
a well-thought choice of the reaction solvent and the presence
of water as they determine the occurrence of GA. To
corroborate these hypotheses, several variations both at the
level of the catalyst (1), and of the solvent (2) are put forward
in a new series of experiments in the next paragraphs.
In Situ 13C NMR Study in CH3OH: GA vs Tetroses. The
rate-determining step in the conversion of tetroses (5 in
Scheme 3) to MMHB (9 in Scheme 3) can be deduced from
the in situ 13C NMR series shown in Figure 3, iii−v. The first
Mechanistic Implications at the Level of the Catalyst.
The interplay between the Lewis and Brønsted acidity derived
from the Sn halide salts in the reaction medium is thought to be
crucial to the overall rate of the cascade. On the basis of the
aforementioned results, it seems that step 1 in Scheme 3 (viz.,
the Brønsted acid catalyzed hydrolysis of acetal 4) determines
the overall rate. Reaction of 1 with 20 mol % HCl yields no 9,
but shows formation of only 4; the initially suggested Brønsted
acid-catalyzed enolate mechanism for the aldol addition is thus
not a major pathway here (entries 2, 3 in Table 1). The
observation proves that condensation of two GA molecules
requires the action of the Lewis acidic Sn (see step 3).
Although not rate-limiting, this Lewis acid-catalyzed addition is
crucial for the feasibility of the cascade, which leads to the
formation of 9. Although the main occurrence of GA in
methanol at room temperature is 3, when Brønsted acidity is
present, 4 dominates in a dynamic equilibrium. The same is
true in the presence of Sn halides, but the difference here is that
the slightest conversion of 4 to 3 and further to free GA 2 and
its enol 2′ allows aldol addition to a tetrose 5 under the action
of Lewis acidic Sn, with rapid subsequent conversion of 5 into
AHA esters. It is therefore very likely that a Lewis acid Sn-
catalyzed aldol reaction via the enolate mechanism is occurring,
as was postulated for ZnII by Kofoed et al. in their origin of life
approach. HCl, AlIII, and CrIII halides, for instance, appear
unable to efficiently catalyze the aldol coupling, and the
reaction its trapped in the production of acetal 4. Even though
these halides are able to fully convert tetrose feedstock in 1 h,22
their inefficient aldol traps the reaction with GA in acetal 4.
In conclusion, next to its role in the 1,2-hydride shift
(Cannizzaro, converting 8 to 9), Lewis acid tin is also essential
in catalyzing the aldol reaction of 2 to 5. However, because the
rate of the cascade is determined by the hydrolysis of acetal 4,
the balance between Brønsted and Lewis acidity is key to
understanding and directing the cascade reaction of 1 to 9
toward a high rate and selectivity and, thus, a high-volume
productivity.
Figure 3. In situ 13C NMR study with GA dimer 1 (i, ii) and
erythrulose (iii−v) in contact with SnIV·5H2O in CH3OH, at 333 K:
(i) 10 min, GADMA; (ii) 13 h later, presence of GADMA 4 and
MMHB 9; (iii) 10 min at 298 K, mainly tetrose; (iv) 10 min at 333 K,
formation of the hemiacetal of 4-methoxyethylglyoxal 8; (v) 100 min
at 333 K, formation of MMHB 9.
spectrum is obtained directly after mixing the tetrose 5 solution
with the Sn halide and shows mainly the four characteristic
peaks of erythrulose (Figure 3iii, signals 1−4). One can also
study the aldose erythrose, rendering the same catalytic
results,22 but its starting 13C NMR spectrum is less
straightforward.70 Quickly, after 10 min at 333 K, signals 0−4
vanished in favor of 6 new ones (Figure 3iv, signals 0′−5′),
which are indicative of the presence of the hemiacetal of 4-
methoxyethylglyoxal (8 in Scheme 3, earlier confirmed with
chemical ionization mass spectrometry22). After longer times,
namely, 100 min at 333 K, six new 13C NMR signals show the
presence of MMHB 9 (Figure 3v, signals 0″−5″). The in situ
time profile agrees with the intermediate accumulation of 8 and
hereby proves that the slowest step in the conversion of 5 to 9
is the final Cannizzaro (step 8 in Scheme 3).
A closer look at the properties of SnIVCl4·5H2O learns that in
water, hydrolysis to SnIV(OH)4 is complete and fast with
release of 4 HCl per Sn, lowering the pH of water. The same
was witnessed for SnIICl2·2H2O. When the chloride ligands of
SnIV are neutralized (for instance with NaOH), the SnIV centers
tend to condense, and precipitation is swift, pointing to the
formation of tin (hydr)oxides. In methanol, traces of water
could hydrolyze chloride ligands, but a methanolysis with
formation of HCl is possible, as well. Neutralization of the
However, when contacting 1 in the same reaction conditions,
the first spectra display the acetal GADMA 4 (Figure 3i, signals
1−3), and over prolonged reaction times, its signals slowly
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Figure 4. Initial rate of MMHB 9 formation in function of H+/Sn ratio. Variation of the ratios obtained for both SnII and SnIV by quenching Cl− with
an anion exchange resin (OH− form) or by adding extra HCl. The rate obtained by an equimolar mixture of SnCl2 and SnCl4 is presented with the
solid circle (•). Rates were measured in the linear part of reactions at 363 K with 1.25 M GA in the presence of 5 mol % of Sn in CH3OH (as
demonstrated in Figure 5).
generated acidity stoichiometrically in methanol with NaOH
also leads to cloudy suspensions, but no heavy precipitate, as in
water, was noticed. Under the nonneutralizing reaction
conditions in methanol, it is difficult to determine the exact
grade of methanolysis (and hydrolysis). Nevertheless, use of tin
chlorides in methanol delivers Brønsted acidity in the form of
HCl to the reaction medium, next to Lewis acid Sn centers. In
the envisioned cascade reaction in Scheme 3, where multiple
steps are catalyzed by either Brønsted acids, Lewis acids, or
both, the intrinsic balance between both types of acid sites is
crucially governed by the choice of halide and its ease of release.
Different kinetic experiments were undertaken with varying
Brønsted and Lewis acid contents to assess the influence of
different Brønsted vs Lewis acid ratios on the overall rate of
reaction. For probing higher ratios, external HCl is added,
whereas controlled assessment of lower ratios is obtained by
partial quenching of the HCl formed from the Sn halide by
methanolysis (and hydrolysis). Whereas the addition of HCl is
straightforward, quenching of HCl is carried out with a
quaternary ammonium anion exchange resin, exchanged in its
OH− form. This resin is added at the start of the reaction in
precise amounts (its capacity was measured by titration) so as
to capture the desired amount of Cl− and to quench H+ with
the released OH− equivalent. Test titration of such a resin with
HCl in methanol proved that the ion exchange process is rapid,
and the resin kept the medium free of acid until its point of
saturation was reached. Thus, depending on the amount of
resin or HCl added, different ratios of H+/Sn are attained for
both SnII and SnIV. Their influence on the rate of MMHB
formation is plotted in Figure 4.
network, a ratio of 3:1 H+/Sn indeed makes sense. A reaction
with only HCl (as in entry 2, Table 1) simulates an infinite H+/
Sn ratio (on the x-axis in Figure 4), for which 9 is not formed
because of a lack of aldolization (Sn) capacity. According to the
reaction scheme, this zero rate indeed derives from the fact that,
although the hydrolysis of 4 to 3 can be fast as a result of the
presence of Brønsted acidity, the slowest step is now found in
the aldol addition of 2 to 5, which does not pull GADMA 4
away from the equilibrium. Figure 4 thus shows the importance
of a balanced catalytic system with a preferred H+/Sn ratio of 3.
To further corroborate this “magic” number, a reaction was
performed with an equimolar mix of SnCl2 and SnCl4, which
should lead to the ideal H+/Sn ratio of 3. The result is plotted
in Figure 4 (solid circle). Under these conditions, it represents
the highest rate measured in methanol, proving once more that
subtle tuning of the H+/Sn ratio is a prerequisite to rapidly
convert 1 to 9. To witness a more efficient use of Sn, a reaction
with only 1 mol % of such SnII+IV mixture was performed, and
an initial rate of 3.4 molMMHB molSn h−1 was witnessed and
−1
yielded 50% of MMHB at full conversion. Note that these
mechanistic insights are very instructive for future development
of more sustainable heterogeneous Sn catalysts:58,67,71−74 not
only is the amount of Sn important, but also the presence of
some Brønsted acidity is required to form AHAs at a maximum
rate. A recent example, in which such subtle catalytic fine-
tuning (by, for instance, spatial compartmentalization of the
active sites) led to very high turnover frequencies (based on
Sn), was found in the carbon−silica composite catalyst design
described by de Clippel75 and Dusselier et al.5 for the formation
of lactate esters from trioses and hexoses.
Consequence of the Addition of Water on the Rate.
According to the enolate mechanism of the aldol addition, the
solvent and the occurrence of GA indisputably influence the
reaction rate and its selectivity. As seen above, the dominant
form of GA under reaction conditions in methanol is 4, whereas
the species of interest for aldol addition is free aldehyde 2 and
its enolate 2′. Indeed, although the equilibrium situation in the
upper part of Scheme 3 is in favor of 4, the reaction network is
dynamic as long as an appropriate Lewis acid catalyst is present.
The highest formation rate of 9 is clearly observed for a H+/
Sn ratio of 3, and this value is surprisingly irrespective of the
oxidation state of the Sn salt. In other words, the highest initial
rate is noticed either when SnCl2 is combined with 1 extra
equiv of HCl or by quenching 1 equiv of HCl with the resin,
when SnCl4 was used. It is noteworthy that the overall rate of
the cascade (at a certain temperature) can thus be maximized,
simply by adding 1 equiv of HCl per SnII site to the reaction.
Considering the rate-determining hydrolysis of 4 in the
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Figure 5. Kinetic plot for the conversion of 1.25 M GA in MMHB (9) catalyzed by 5 mol % of SnCl4·5H2O at 363 K in methanol (solid line) and in
a methanol/water mixture (7:1 volume ratio) (dashed line).
Moreover, considering the rate-determining hydrolysis step 1
(or in other words, as the equilibrium favors 4) in the overall
cascade, the addition of some aliquots of water should greatly
affect the overall reaction rate (or in other words, shift the
equilibrium). Figure 5 presents the kinetic plots of a reaction
carried out in either methanol or a mixture of 7:1 (v:v)
methanol to water. From these plots, the initial turnover
frequency (TOF) to convert GA dimer 1 to 9 was calculated,
and it appears that the rate is, indeed, more than 4.5 times
Table 2. Effect of Solvent Changes (other alcohols and
presence of water) on the Yield (obtained after 1h) to the
Corresponding AHAs
a
a
b
entry
solvent (v:v)
CH3OH
MMHB (%)
MVG (%)
ratio
1
2
3
10
34
35
<1
2
CH3OH/H2O 7:1
CH3OH/H2O 10:1
EtOH
17
17
2
c
c
c
4
26
5
5.7
0.7
d
d
d
5
IPA
15
22
−1
higher in the presence of water: namely, 3.7 vs 0.8 mol molSn
a
h−1. This value shows that Sn turns over GA at least 7.4 times
every hour, which corresponds to a high productivity of 34
gMMHB L−1 h−1 (first hour) in the concentrated solution. The
superior rate achieved as a result of adding small amounts of
water was seen as well with in situ 13C NMR (see Supporting
Information Figure S3). The spectral sequence demonstrates
the same profiles as in Figure 3i−ii, but in a much shorter time
frame: after 200 min at 333 K, all major signals encountered in
the NMR spectrum belong to 9.
MMHB yields, 1 h at 363 K using 1.25 M GA with 5 mol %
b
SnCl4·5H2O. Molar ratio of alkyl-4-alkoxy-2-hydroxy-butanoate/alkyl
vinyl glycolate. Reaction leads to ethyl-4-ethoxy-2-hydroxybutanoate
(EEHB) and ethyl vinyl glycolate (EVG). Reaction leads to
c
d
isopropyl-4-isopropoxy-2-hydroxybutanoate (IIHB) and isopropyl
vinyl glycolate (IVG). For identification, see Supporting Information
Figures S6 and S7.
pyrolysis oils.35 There is thus no need to perform expensive
drying to remove all the water from such GA solutions.
Methanol should simply be added to fairly concentrated
aqueous solutions of GA if MMHB is desired.
Other ratios of methanol to water were screened, as well, and
it was found that a ratio of 10:1 is sufficient to drastically
accelerate the reaction with respect to pure methanol (kinetic
plot, see Supporting Information Figure S4). The effect of
water is also apparent in the data of Table 2, which displays
MMHB yields after 1 h of reaction in different solvents.
Comparing entry 1 with entries 2 and 3 shows that, indeed, the
MMHB yield is more than tripled as a result of the addition of
water in the first hour. There is an optimum amount of water
required to speed up the reaction, since a rate decrease was
observed after adding too much water (a 1:1 volume ratio).
The latter is likely caused by the formation of insoluble Sn
(hydr)oxide species, as ascertained by precipitate formation
upon visual inspection. Since the reaction in water-containing
methanol is very fast, the temperature dependence of this
cascade reaction was assessed. At a volume ratio of methanol to
water of 7:1, the overall activation energy for formation of 9
from 1 corresponds to a value of 73 kJ·mol−1 (Arrhenius plot,
see Supporting Information Figure S5). The requirement of
water to speed up the overall reaction can be seen as an
advantage because GA is usually provided in aqueous solutions;
for instance, via its recently reported separation from biomass
Reaction in Other Solvent Media: Formation of Vinyl
Glycolate and Its Esters. Entries 4 and 5 in Table 2 show the
(nonoptimized) reactions carried out in ethanol and isopropyl
alcohol (IPA), respectively. In ethanol, the yield to the
corresponding ethyl vinyl glycolate (EVG) is noticeable
whereas the corresponding MVG formation in methanol barely
is; however, ethyl-4-ethoxy-2-hydroxybutanoate (EEHB) re-
mains the major product. The ratio of EEHB to EVG is around
6, whereas in methanol, the corresponding MMHB to MVG
ratio is usually above 15 (entries 1, 2 in Table 2 and 6, 8 in
Table 1). Use of IPA shows the reverse chemoselectivity with a
preference for vinyl glycolate ester (IVG) formation; the more
sterically demanding alcohol indeed led to ∼22% of isopropyl
vinyl glycolate (IVG) in 1 h of reaction time, in addition to 15%
of isopropyl-4-isopropoxy-2-hydroxybutanoate (IIHB). The
corresponding ratio of IIHB to IVG is thus clearly <1. Such
reverse selectivity pattern is in agreement with earlier reported
conversion of tetroses to AHAs.22
To understand the shift in product selectivity upon using
different solvents, the proposed reaction scheme is drawn in
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Scheme 4. Proposed Reaction of GA in IPA or Nonalcoholic Media with Sn Leading to Vinyl Glycolic Acid (VG) or Its
Isopropyl Ester (IVG), 2,4-Dihydroxybutanoic Acid (2,4-DHB) and α-Hydroxy-γ-butyrolactone (HBL)
more detail in the case of IVG formation in IPA (Scheme 4).
Comparison of this scheme with Scheme 3 reveals a major
difference at the level of the occurrence of GA. 13C NMR and
GC/MS witnessed no formation of the di-isopropyl acetal 4′,
which appears unfavorable for steric and electronic reasons.
Therefore, it is suggested that the reaction equilibrium in IPA is
more in favor of the hemiacetal 3′ and free GA (2 and 2′). A
kinetic experiment in IPA (see Supporting Information, Figure
S8) for the formation of AHA esters (the sum of IVG and
IIHB) attained a very fast initial rate of about 16 molAHA
different, and this difference is easily explained in the following
course of the cascade reaction, in accordance with Scheme 4.
Indeed, once the vinyl glyoxal 6 and its isopropyl hemiacetal
7′ is formed from the tetrose 5 as a result of two retro-Michael
dehydration steps, the unique selectivity pattern of IPA
becomes apparent: isopropyl alcohol, a more sterically hindered
and less nucleophilic alcohol, is less reactive toward the 1,4-
addition on the vinyl group than, for example, methanol,
whereas the rate of the intramolecular Cannizzaro, a 1,2-
hydride shift catalyzed by the Lewis acid Sn center, is not
greatly affected by variation of the alcoholate. Once the hydride
shift (step 6 in Scheme 4) proceeds, an α-hydroxy group is
formed on the second carbon, and the 1,4-addition on the vinyl
can thus no longer proceed because of a lack of conjugation.
IVG is thus the preferred product in isopropyl alcohol, and
MMHB is the dominant product in methanol. The 1,4-
nucleophilic addition is only slightly hindered in ethanol, when
compared with the intramolecular Cannizzaro, and significantly
more of the ethyl ether compound (EEHB) is formed (EEHB/
molSn h−1 in its very short linear part and reaches ∼40% of
−1
AHA esters already after 1.5 h of reaction. This reaction runs
very fast when compared with the aforementioned rates in
methanol because GA is less protected in (hemi)acetals, and
thus, more available for aldolization. Once the aldol reaction
has occurred with formation of tetrose 5, little difference is to
be expected between the reaction rates in isopropyl alcohol and
methanol. The product selectivity, though, is significantly
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EVG is 7:1). The rate in ethanol is also significantly higher than
after 700 min contains mainly VG (signals 1−4) next to some
2,4-DHB (signals 1″−4″).
in methanol, but lower than in isopropyl alcohol; its value
corresponds to 4 molAHA molSn h−1 (from Supporting
As seen in Scheme 4, dimer 1 is thus easily converted to free
GA 2 (and its enolate 2′ and some hydrates) in DMSO or
acetonitrile. Aldolization of GA under action of Sn produces
tetroses, which are prone to undergo two retro-Michael
dehydrations to form the reactive vinyl glyoxal 6. In DMSO,
the double bond of 6 is mostly preserved, and since traces of
water are the only nucleophile present, a hydrate of vinyl
glyoxal is formed, which transforms into VG as a consequence
of the tin-catalyzed internal Cannizzaro reaction. Water in
DMSO apparently does not favor attack on the vinyl because a
1,2-hydride shift of the hydrate is faster. To confirm VG as the
main product after reaction in DMSO (as seen, for instance, in
Figure 6iii), such a mixture was diluted in methanol and
allowed to react at 363 K. In this way, esterification of VG to
MVG in methanol with the assistance of the Sn-released HCl
could be monitored by GC/MS analysis; such MVG formation
may be interpreted as an indirect proof of VG formation in
DMSO.
−1
Information Figure S8). This is, of course, linked to the
occurrence of GA in ethanol, in which the formation of
glycolaldehyde diethyl acetal was noticed. Its formation was,
however, less pronounced than GADMA 4 in methanol,
implying a faster reaction in ethanol.
In addition to the mechanistic findings in alcohols, reactions
in nonalcoholic polar media were screened, as well (dimethyl
sulfoxide (DMSO) and acetonitrile). Interestingly, a selectivity
pattern similar to that in IPA was encountered in DMSO, with
vinyl glycol acid as the dominant product. The molar ratio of
2,4-dihydroxybutanoic acid (2,4-DHB) to VG is around 0.3,
according to NMR analysis on the crude mixture. Scheme 4
also summarizes the different reactions leading to VG and 2,4-
DHB in nonalcoholic solvents. VG formation follows the same
pathway as formation of IVG and MVG, with water as the
nucleophile, whereas we found that the formation of 2,4-DHB
surprisingly does not follow the analogue pathway of MMHB
synthesis in methanol (or IIHB in IPA, not shown). To unravel
what happens in such a solvent, a reaction at 333 K with 20 mol
% SnCl4·5H2O was followed in situ with 13C NMR in DMSO.
By comparing the AHA formation rate with that of a similar in
situ reaction in methanol (see the spectra in Figure 3), a very
fast formation of VG in DMSO was noticed: VG is already
formed after 1 h of reaction, whereas 12 h is required to form
MMHB in MeOH under comparable in situ circumstances.
This rate increase obviously originates from the high availability
of free GA because acetal formation in DMSO does not occur.
The evolving spectral sequence and time scale is shown in
Figure 6, as well as the final result of an in situ 13C NMR study
Although less pronounced, a competitive pathway was
encountered: after the first retro-Michael (step 3, Scheme 4),
an isomerization (step 4′, Scheme 4) can take place, forming 4-
hydroxyethylglyoxal 6′, which is easily hydrated to 7′′. This
compound, 7′′, was analyzed with in situ 13C NMR, as seen in
spectrum ii of Figure 6. Species 7′′ subsequently transforms
into AHA 2,4-DHB (as seen in Figure 6iii), according to the Sn
catalyzed intramolecular Cannizzaro reaction. A closer look at
2,4-DHB reveals that the molecule should be prone to
intramolecular esterification, especially in the presence of
some free HCl from the Sn halide, leading to a cyclic four-
carbon AHA ester: α-hydroxy-γ-butyrolactone (HBL). In fact,
HBL is the dominant product formed in acetonitrile, as
witnessed by the 13C NMR spectrum iv in Figure 6. Its
formation was also confirmed with GC/MS.
Incorporation of VG in Poly(L-lactic acid) (PLLA). After
successfully converting glycolaldehyde in various types of AHAs
(and their esters), such as MMHB, MVG, 2,4-DHB, and HBL,
we were interested in their ability as bioderived building blocks
for polymer chemistry. A conceptual proof of their value is
illustrated with the incorporation of VG into PLLA. Because
one of the shortfalls of traditional PLLA is its lack of reactive
side groups,8,19,76 the vinyl group of the VG monomer
potentially offers a creative solution to this problem by its
cocondensation with lactic acid. Such a copolymerization
approach has been proposed earlier for different monomers
by using functional lactide derivatives for ring-opening
polymerization.77−80 The incorporation of VG in PLLA has
not been reported, but it would offer a tremendous versatile
side group in PLLA, which could be further modified easily
with elegant organic chemistry, such as thiol-ene proto-
cols.81−83 For instance, if the vinyl is modified with a
hydrophilic moiety, another drawback of PLLA (namely, a
too-pronounced hydrophobicity) can be tackled at once.
To incorporate vinyl glycolic acid (VG) into PLLA, MVG
was hydrolyzed (see Supporting Information Figures S10, S11)
and mixed with L-lactic acid before polycondensation. The
copolymerization was performed via azeotropic distillation for
water removal, according to Kim et al.,47 in the presence of
SnCl2·2H2O catalyst in p-xylene. Not only are such tin halide
salts thus capable of producing the monomers from bioderived
GA (this work) and tetroses,15 they are also known catalysts for
the synthesis of PLA via polycondensation. After precipitation
Figure 6. (i−iii) In situ 13C NMR in DMSO: 1.25 M GA and 20 mol
% of SnCl4·5H2O evolving in time at 333 K (10, 110, and 700 min,
respectively, after mixing). (iv) Final spectrum of the in situ 13C NMR
study in acetonitrile (1.25 M GA, 2 h at 333 K, 50 mol % of
SnCl4·5H2O, acetonitrile/H2O = 7:1).
in acetonitrile. Spectrum i of Figure 6 shows the signals of the
products encountered in DMSO after 10 min at 333 K. Dimer
1 is likely completely converted to free GA and its enolate,48,49
and GA hydrates and possibly tetroses signals are also apparent
in the complex spectrum. The spectrum after 110 min, Figure
6ii, is easier to understand because it shows chemical shifts due
to VG (1 to 4) and the hydrate of 4-hydroxyethylglyoxal
(signals 1′−4′, structure 7′ in Scheme 4.) The product mixture
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of the polymer in cold MeOH, in which nonreacted monomers
1
remain soluble, H NMR (see Figure 7) and 13C-APT-NMR
1
Figure 7. H NMR of PLLA and PLLA-co-VG.
(see Supporting Information Figure S12) unambiguously
proved the incorporation of the vinyl monomer into PLLA.
The vinyl signals in Figure 7 (Hb, Hc, and Hd) as well as the
proton of the α-carbon (Ha), to which the vinyl is attached, are
found between 5.4 and 6.1 ppm. From the integration values of
these 1H NMR spectra, it was calculated that PLLA-co-VG with
7 and 12% of VG was successfully synthesized using different
ratios of monomer in the procedure. Table 3 presents the
Figure 8. Thermal properties of PLLA and PLLA-co-VG (7 or 12%):
(A) TGA (10 K/min, N2); (B) analysis via differential scanning
calorimetry (10 K/min, N2, first heating cycle).
Table 3. Different Polyesters and Some of Their Properties
measurements seemed to confirm this (Supporting Information
Figure S14). The thermograms in Figure 8B reveal that the
vinyl-containing polyesters are less (semi)crystalline than the
pure PLLA and melt at lower temperatures: the higher the vinyl
incorporation, the lower the melting point. The glass transition
for all three polymers was seen in the 323 to 333 K region. The
lower melting temperatures combined with their prolonged
thermal stability offers a broader window for thermal processing
when compared with the traditional PLLA (for Tg and Tm, see
Supporting Information Figure S14).
a
b
c
d
polymers
PLLA
Mn (g mol−1
)
Đ
Contact Angle (°)
17 100
14 500
12 600
1.9
1.7
1.6
76.3 0.4
77.3 2.5
PLLA-co-VG(7%)
PLLA-co-VG(12%)
Modified Polymers
e
f
Xvinyl (%)
PLLA-co-VG(12%)-BM
PLLA-co-VG(12%)-TG
>96
>98
76.3 2.4
66.7 1.9
a
Obtained via polycondensation. Value in brackets: mol % of VG units
b
in copolymer. Number averaged molecular weight via SEC, relative to
polystyrene. Dispersity. Water contact angle. Modified via radical
c
d
e
To prove the accessibility and reactivity of the vinyl moieties
in the novel PLLA-co-VG (12%), UV-initiated radical thiol-ene
derivatization experiments were performed with various thiols,
such as benzyl mercaptan (BM) under mild conditions. The
success and ease of this approach can be read from the vinyl
thiol-ene with benzyl mercaptan (BM) and thioglycerol (TG).
f
1
Conversion of the vinyl group upon modification, via H NMR.
molecular weight of benchmark PLLA (prepared in exactly the
same manner) and the novel PLLA-co-VG polymers; the values
are in the range of 12−17 000 g mol−1, and the dispersities, Đ,
range from 1.6 to 1.9 (SEC, see Supporting Information Figure
S13), with the novel polymers being a little more uniform in
chain length.
The thermal behavior of the novel polyesters was assessed,
and the data are summarized in Figure 8. It appears that when
more vinyl monomer is incorporated into PLLA, the polymer
remains stable for a longer time and, hence, degrades at a
higher temperature in the thermal gravimetric analysis (Figure
8A). For example, PLLA-co-VG (12%) was up to 75 K more
stable with respect to the genuine PLLA polymer. Possibly, the
high thermostability arises from temperature-induced cross-
linking. Several differential scanning calorimetry (DSC)
1
conversions in Table 3 and in the corresponding H NMR
spectra in Supporting Information Figure S15. BM successfully
reacted with the vinyl groups with an almost quantitative
conversion. More interestingly, because reference PLLA is often
considered too hydrophobic for certain applications, the ease of
functionalization was utilized as a tool to enhance its
hydrophilicity. Therefore, polar TG was chemically grafted
onto the double bond, and the vinyl conversion was complete.
Signals of the corresponding glycerol units were apparent in the
polymer after precipitation in cold diethyl ether (Supporting
Information Figure S15). In contrast to the reference PLA and
the other (thiol-functionalized) PLLA-co-VG polyesters in this
study, this TG-modified polymer did not precipitate in
methanol, in line with its enhanced polarity. Static water
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ACS Catalysis
Research Article
contact angle measurements on thin films, made via spin-
coating, corroborated this hypothesis: although neither the
incorporation of vinyl groups in PLLA nor the BM grafting
influenced the contact angle greatly with respect to that of
reference PLLA (76.3 0.4°, in agreement with literature84,85),
modification with the polar TG clearly caused a significant
decrease of 10° of the water contact angle (see Table 3). These
contact angles are visually presented in Figure 9 for PLLA and
the presence of the vinyl group allows easy modification of the
PLLA matrix to tune properties such as polarity; for instance, a
polar PLLA-co-VG was easily synthesized by reacting the
present vinyl groups with thioglycerol under UV irradiation
according to thiol-ene chemistry.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional in situ NMR studies (e.g., in methanol/water);
analysis of chemicals and raw reaction mixtures (NMR); kinetic
plots for reactions in IPA, ethanol, methanol, and methanol/
water; and an activation energy plot are provided. A full
characterization of the polymers (NMR, SEC, DSC (thermo-
grams featuring Tg and Tm)) is given, as well as some of the
representative static contact angle droplet photos. This
information is available free of charge via the Internet at
http://pubs.acs.org/.
AUTHOR INFORMATION
Figure 9. Structure of PLLA (left) and PLLA-co-VG(12%)-TG (right)
and a representative droplet photograph.
■
Corresponding Author
*E-mails: (B.F.S.) bert.sels@biw.kuleuven.be, (M.D.) michiel.
dusselier@biw.kuleuven.be.
PLLA-co-VG(12%)-TG (for more photos, see Supporting
Information Figure S16). This example nicely illustrates that
the novel four-carbon AHA monomers are easily incorporated
in PLLA and truly offer added value in light of a controlled
modification of the polymer functionality toward desired
properties.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.D. acknowledges “FWO Vlaanderen” (Grant 1.1.955.10N)
for financial support. The Research Council of the K.U. Leuven
(IDO-3E090504) is also acknowledged. We are grateful to
Karel Duerinckx for help with the in situ NMR. B.F.S. and
F.D.P. acknowledge the Belgian Program on Interuniversity
Attraction Poles initiated by the Belgian State, Prime Minister’s
office (Program P7/05) for financial support.
CONCLUSIONS
■
Glycolaldehyde, a main component of biomass-derived
pyrolysis oils, was converted in one step into various four-
carbon α-hydroxy acids and their esters. The choice of solvent
mainly determines the product selectivity of the GA-to-AHA
reaction. High yields of MMHB were, for instance, produced in
methanol, whereas VG and 2,4-DHB are the dominant
products in DMSO, and HBL is encountered in acetonitrile.
IVG is the dominant ester in isopropyl alcohol. The one-pot
reaction follows a complex cascade network in which both
Brønsted and Lewis acid centers are playing a crucial role.
Different intermediates and rate-determining steps were
identified by in situ 13C NMR. Sn halide salts are able to
foresee both types of acid activities, and an optimal ratio of
Brønsted to Lewis acid sites of ∼3 was determined in this work.
Surprisingly, this ratio was irrespective of the oxidation state of
the Sn ion. Lewis acid Sn is essential for the aldolization of GA
to tetroses and the intramolecular Cannizzaro of intermediate
glyoxals and their hemiacetals to the final AHAs (and their
esters), HCl is likely responsible for fast hydrolysis of acetals to
deprotect sufficient GA for aldolization and it is able to assist
the retro-Michael dehydrations of tetroses into glyoxals and
their 4-alkoxy ethers. Addition of some water to the reaction
mixture also greatly improved the rate of reaction in line with
the rate-determining GA (hemi)acetal hydrolysis in the overall
cascade. The elucidation of this cascade reaction and its
catalytic needs in terms of Lewis and Brønsted acidity should
be inspiring to develop adequate heterogeneous catalysts for
the title reaction.5,59,68,72−74
ABBREVIATIONS
■
MVG, EVG, and IVG: methyl, ethyl, and isopropyl vinyl
glycolate, respectively; MMHB or EEHB: (m)ethyl-4-(m)-
ethoxy-2-hydroxybutanoate; IIHB: isopropyl-4-isopropoxy-2-
hydroxybutanoate; GA: glycolaldehyde; GADMA: glycolalde-
hyde dimethyl acetal; GAHA: glycolaldehyde hemiacetal; VG:
vinyl glycolic acid; EtOH: ethanol; 2,4-DHB: 2,4-dihydrox-
ybutanoic acid; HBL: α-hydroxy-γ-butyrolactone; IPA: iso-
propyl alcohol; MeOH: methanol; DMSO: dimethyl sulfoxide;
PLLA: poly(L-lactic acid); PLLA-co-VG(x%): poly(L-lactic
acid)-co-(vinyl glycolic acid) with x% of VG units in the
copolymer; TG: thioglycerol; BM: benzyl mercaptan
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