Solid Lewis acids catalyze the carbon-carbon coupling between carbohydrates and formaldehyde

Article abstract of DOI:10.1021/cs5015964

The development of catalytic C-C bond formation schemes based on renewable substrates is important for defining sustainable paradigms for chemical manufacturing. With a few exceptions, aldol condensation reactions between biomass-derived platform chemicals have received little attention so far. Here the C-C coupling between 1,3-dihydroxyacetone (DHA) and formaldehyde into α-hydroxy-γ-butyrolactone (HBL) using Sn-Beta is demonstrated. Reactivity studies, coupled with spectroscopic and computational analyses, show that the formation of HBL proceeds by soft enolization of DHA followed by an aldol addition of formaldehyde to the Sn-enolate intermediate, generating erythrulose as an intermediate species. Isotopic labeling is used to reveal the position where formaldehyde is incorporated into HBL, providing further support for our proposed mechanism. Finally, combining the C-C coupling reaction with transfer hydrogenation of formaldehyde has allowed us to expand the substrate scope to include polyols glycerol and ethylene glycol.

Full text of DOI:10.1021/cs5015964

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Letter
Solid Lewis Acids Catalyze the Carbon-Carbon
Coupling between Carbohydrates and Formaldehyde
Stijn Van de Vyver, Caroline Odermatt, Kevin Romero, Teerawit Prasomsri, and Yuriy Roman-Leshkov
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 06 Jan 2015
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Page 1 of 10
ACS Catalysis
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Stijn Van de Vyver, Caroline Odermatt, Kevin Romero, Teerawit Prasomsri, and Yuriy Román-
Leshkov*
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United
States
ABSTRACT: The development of catalytic C–C bond formation schemes based on renewable substrates is important for defining
sustainable paradigms for chemical manufacturing. With a few exceptions, aldol condensation reactions between biomass-derived
platform chemicals have received little attention so far. Here the C–C coupling between 1,3-dihydroxyacetone (DHA) and formal-
dehyde into α-hydroxy-γ-butyrolactone (HBL) using Sn-Beta is demonstrated. Reactivity studies, coupled with spectroscopic and
computational analyses, show that the formation of HBL proceeds by soft enolization of DHA followed by an aldol addition of
formaldehyde to the Sn-enolate intermediate, generating erythrulose as an intermediate species. Isotopic labeling is used to reveal
the position where formaldehyde is incorporated into HBL, providing further support for our proposed mechanism. Finally, com-
bining the C–C coupling reaction with transfer hydrogenation of formaldehyde allows us to expand the substrate scope to include
polyols glycerol and ethylene glycol.
KEYWORDS: aldol condensation, biomass conversion, heterogeneous catalysis, isotope labeling studies, proton transfer, Sn-
Beta, soft enolization, solid Lewis acid
Metal centers with open coordination sites incorporated into
the framework of zeolites have attracted significant attention
as Lewis acid catalysts due to their ability to activate hydroxyl
and carbonyl functional groups. For example, Sn sites incor-
porated into a defect-free framework with the BEA topology
how the enolization and proton transfer steps are promoted by
the Sn centers. Also, there is a significant drive to develop
heterogeneous catalysts to avoid additional energy-intensive
separation and recovery steps, as well as irreversible deactiva-
1-3
2
4
tion upon interacting with water.
(
Sn-Beta) have shown remarkable activity for transformations
Table 1 shows results for C–C coupling reactions between
DHA and formaldehyde catalyzed by solid Lewis acids. Reac-
tivity studies were performed in batch reactors at 160 °C using
such as the Meerwein–Ponndorf–Verley (MPV) reduction of
aldehydes and ketones, the etherification of alcohols, and
the Baeyer–Villiger oxidation of ketones to lactones.
spite the prevalence of homogeneous acid and base catalysts
for aldol condensation reactions, the use of solid Lewis acids
remains largely unexplored. Few exceptions include the ob-
servation of Sn-catalyzed aldol condensation of glycolalde-
4
-7
4,8
9
,10
De-
1
,4-dioxane as solvent, paraformaldehyde as the formaldehyde
source, a metal:DHA ratio of 1:100 and a DHA:formaldehyde
ratio of 1:3. Sn-Beta showed the highest selectivity of all Beta
zeolites studied, generating an HBL yield of 60ꢀ% at 98% con-
1
1
2
5
version after 3 h (entry 1). Byproducts observed were lactic
acid (LA) and (1,3-dioxolan-4-yl)methanol (Supporting In-
formation, Figure S1), with the latter formed by acetalization
hyde
in
the
synthesis
of
methyl-4-methoxy-2-
12,13
hydroxybutanoate, methyl lactate or vinyl glycolate esters.
Sn-Beta and other Sn-containing silicates have also been used
for C–C bond formation reactions such as the intramolecular
cyclization of citronellal to isopulegol and the intermolecular
Prins reaction between β-pinene and paraformaldehyde for the
formation of nopol.
2
6
of formaldehyde with DHA. Previous studies have indicated
the promoting effect of water on the catalytic activity of
14
2
3
SnCl4. In our study, small amounts of water were found to
increase the solubility of paraformaldehyde as well as the
HBL yield (entry 2). The results given in Table 1 further indi-
cate that Sn is the optimal metal for the present reaction, as Zr-
, Hf-, Ti-, and Al-Beta showed drastically lower HBL yields
(entries 5–8). These catalysts, however, were found to pro-
mote side reactions originating from the high reactivity of
formaldehyde. Other Sn-containing catalysts, such as Sn in-
corporated into a mesoporous, amorphous framework (Sn-
MCM-41; entry 9) or stannosilicate zeolites with MFI topolo-
15-18
Here we show the first application of Sn-Beta for the cata-
lytic C–C coupling between triose sugars and formaldehyde to
form α-hydroxy-γ-butyrolactone (HBL), which is an important
chemical intermediate used for production of herbicides and
pharmaceutical agents.
19
2
0-22
Previously, HBL has been synthe-
sized by radical coupling between 1,3-dioxoranes, acrylates
and molecular oxygen, or by alkylation, hydrolysis and cy-
2
1
2
2
27
clization of hydroxy-4-methylthiobutyric acid. More recent-
ly, Yamaguchi et al. reported the direct catalytic transfor-
mation of 1,3-dihydroxyacetone (DHA) and formaldehyde
into HBL in the presence of tin(IV) chloride. For this reac-
tion, however, the mechanism remains unclear, particularly on
gy (Sn-MFI; entry 10) generated comparable HBL yields to
those obtained with Sn-Beta. From a mechanistic point of
view, it is important to note that extra-framework SnO nano-
2
2
3
particles impregnated on Si-Beta (SnO /Si-Beta) showed no
2
significant activity in generating HBL (entry 11). Finally, we
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Page 2 of 10
a
Table 1. Results for the Catalytic Conversion of DHA, Ethylene Glycol and Glycerol to HBL
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
c
Entry
Catalyst
Si/metal ratio
Substrate
Conv. [%]
Yield [%]
HBL
LA
1,3-DIOXO
derivatives
17
1
2
3
4
5
6
7
8
9
Sn-Beta
98
98
DHA
98
98
98
98
99
99
96
95
99
90
53
12
60
68
13
12
3
9
8
d
Sn-Beta
Sn-Beta
Sn-Beta
Zr-Beta
Hf-Beta
Ti-Beta
DHA
18
47
52
8
98
ethylene glycol
glycerol
DHA
1
98
10
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
111
112
140
13
DHA
7
3
12
3
DHA
6
3
Al-Beta
Sn-MCM-41
Sn-MFI
DHA
11
64
61
3
6
9
117
180
100
–
DHA
15
6
5
1
0
DHA
4
11
SnO /Si-Beta
DHA
<1
<1
<1
<1
2
1
a
2
None
DHA
<1
Reaction conditions: 2.4 mmol substrate, 7.2 mmol paraformaldehyde, 8 mL 1,4-dioxane, 0.024 mmol metal in added catalysts, 20
bar Ar at RT, 160 °C, 3 h. Determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Determined by
GC/FID and expressed relative to the initial molar amount of DHA. 1,3-DIOXO derivatives = (1,3-dioxolan-4-yl)methanol and
b
c
d
other substituted 1,3-dioxolane derivatives. Reaction performed in the presence of 2.4 mmol water.
Scheme 1. Proposed Mechanistic Pathway for the C–C Coupling between DHA and Formaldehyde Catalyzed by the Open
a
Site of Sn-Beta
a
13
H atoms involved in proton transfer and 1,2-hydride shift steps are marked in green and blue. C atoms are shown as red dots.
2
4
confirmed that the reaction does not occur in the absence of
DHA or formaldehyde, and that similar HBL yields can be
obtained when using glyceraldehyde as substrate.
(Step 3). Aldol addition of formaldehyde to the Sn-enolate
intermediate (Step 4), followed by proton transfer from the
silanol of the active site to the oxygen atom at the C4 position
Step 5), results in formation of erythrulose. The erythrulose
produced this way can then isomerize into erythrose through a
,2-hydride shift similar to that observed during glucose–
fructose isomerization with Sn-Beta (Step 6, intermediate
steps are not shown for simplicity). The presence of the car-
bonyl and β-hydroxyl group in erythrose makes it highly sus-
ceptible to dehydration via a retro-Michael reaction (Steps 7 to
(
The proposed reaction pathway for the C–C coupling be-
tween DHA and formaldehyde is depicted in Scheme 1. We
hypothesize that the critical aldol addition step is catalyzed by
Sn-Beta through a soft enolization process, wherein the Lew-
is acidic Sn site acts in concert with the weakly basic oxygen
atom in the framework Si–O–Sn ensemble to deprotonate
1
2
8
30
29
DHA. More specifically, in our proposed mechanism, the
1
3,31,32
8
).
We speculate that both the proton transfer step to
Lewis acidic framework Sn atom polarizes the carbonyl group
of DHA, resulting in a substantial increase in the acidity of the
α-proton (Step 1). This proton can consequently be removed
by the basic oxygen atom connected to Sn, generating a Sn-
enolate intermediate and a silanol group (Step 2). Coordina-
tion of the oxygen atom of formaldehyde to the Sn center in-
duces polarization in the molecule, further enhancing its reac-
tivity by increasing the electrophilicity of the aldehyde carbon
form the Sn-enolate intermediate and β-elimination of the hy-
droxyl group can be mediated by Sn-Beta. Alternatively,
erythrose dehydration may also proceed via classic Brønsted
acid catalysis. Subsequent cyclization of the retro-Michael
product involves an intramolecular hemiacetal reaction (Step
3
3
3
4
1
0). Lastly, a keto–enol tautomerization (Step 11) and a 1,2-
hydride shift (Step 12) generate the desired HBL product.
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The tentative mechanism is in agreement with previous ex-
perimental studies showing that Sn-Beta and SnCl catalyze
nuclear magnetic resonance (NMR). The mass spectrum of the
product mixture is identical to that obtained from the reaction
with unlabeled formaldehyde, but it is shifted by m/z=1 to
higher m/z ratios (Supporting Information, Figure S2). Specif-
ically, the main fragment ion at m/z 58, corresponding to the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
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5
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5
5
5
5
5
5
6
4
3
5,36
the following: (1) keto–enol tautomerization of DHA;
(2)
(3) isomerization of
erythrulose to erythrose; and (4) conversion of erythrose into
1
2,37
retro-aldol fragmentation of sugars;
3
8
3
2
13
+
40
HBL. Although enolization has not been observed during
resonantly stabilized species CH =CH–CH –OH, indicates
2
3
9
13
glucose-fructose isomerization with Sn-Beta, Dusselier et al.
postulated a Lewis acid catalyzed self-aldol addition of gly-
colaldehyde in the cascade synthesis of C4 α-hydroxy acids
that HBL contains the C label at the C4 position. This was
1
3
corroborated by the C NMR spectrum, which showed a main
resonance at δ=65.2 ppm corresponding to the C4 atom (Fig-
1
3
13
using homogeneous Sn halides. The mechanism shown in
Scheme 1 is new in that Steps 2 and 7 involve the transfer of a
proton from a C–H bond to the zeolite lattice. Recent compu-
tational studies on the catalytic activity of Sn-Beta support a
similar role for the weak basic oxygen atoms connected to Sn
in proton transfer reactions involved in the isomerization of
ure 1a). The highly selective incorporation of C atoms at the
C4 position of HBL can indeed be rationalized by considering
the proposed C–C bond formation mechanism (Scheme 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
DFT-calculated standard-state enthalpy (∆H° ) and Gibbs
rxn
free energy changes (∆G° ) for our mechanism (Scheme 1)
rxn
2
3
and the one proposed by Yamaguchi et al. are listed in Table
S1 in the Supporting Information. Formation of erythrulose
2
9
41
glucose to fructose. Another argument in favor of the hy-
pothesized pathway is the spectroscopic observation that Si–
O–M ensembles promote C–H activation, even in more chal-
lenging scenarios such as the initiation of ethylene polymeri-
is calculated to proceed exothermically with a ∆G° value of
rxn
−1
0
.4 kJ mol , which, although slightly positive, compares fa-
vorably to 16.8 kJ mol for the previously proposed aldol
addition of formaldehyde to pyruvic aldehyde to form 4-
−1
3
8
zation.
2
3
Formation of the aldol addition product erythrulose as a re-
action intermediate in the production of HBL was substantiat-
ed by using it as a reactant in place of DHA. A reaction of
erythrulose with Sn-Beta under identical conditions as those
used for DHA generated a 24% HBL yield, thus confirming
that erythrulose can undergo the suggested catalytic transfor-
mation. To further support the proposed mechanism, isotopi-
cally labeled formaldehyde was reacted with DHA in the pres-
hydroxy-2-oxobutanal. The estimated ∆G°rxn values of the
−1
ring closure and 1,2-hydride shift are -49.1 and -57.0 kJ mol ,
respectively, strengthening the feasibility of the reaction
mechanism shown in Scheme 1. Note that these values are
calculated for gas phase reactions as the solvation effect is
believed to be relatively small in the hydrophobic zeolite sys-
2
9,42
tem.
Future periodic density functional and other quantum
mechanical studies will be critical to accurately assess solva-
tion contributions and binding energies of the substrates with
the catalytic site.
1
3
ence of Sn-Beta and investigated using GC-MS and
C
a
To detect any possible carbohydrate products resulting from
the C–C coupling between DHA and formaldehyde, aliquots
taken from a standard reaction mixture at 3 h were derivatized
by trimethylsilylation (TMS) and analyzed by GC–MS. A
comparison of these mass spectra with those obtained from
TMS derivatives of a reaction mixture using isotopically la-
beled formaldehyde shows that under the temperature and
reaction times investigated, significant amounts of C5 sugars
are obtained (Figure 1b). We infer that these sugars are formed
by a second aldol addition of formaldehyde to the Sn-enolate
form of erythrose in an analogous way to Steps 4 and 5 in
Scheme 1. C4 and C5 aldose formation was tentatively con-
97
96
95
94
93
92
1
00
95
90
85
80
75
70
65
60
13
C chemical shift (ppm)
1
3
b
73
firmed by C NMR spectroscopy, which showed resonances
in the region between 90 and 100 ppm characteristic of the
1
1
00
8
6
4
2
0
0
0
0
0
4
3
103
147
anomeric C1 atom (inset in Figure 1a). Work is in progress
to identify these products by fractionation of the reaction mix-
ture and 2D NMR analysis. Importantly, negative control ex-
periments—omitting one of the key components (formalde-
hyde, DHA or catalyst)—gave no observable sugar formation.
261
129
203
73
00
To expand the substrate scope of this reaction, we investi-
gated the possibility of combining the C–C coupling with
transfer hydrogenation in a cascade reaction sequence. Our
previous studies showed that Lewis acid zeolites can catalyze
one-pot cascade processes in which the MPV reduction of
aldehydes occurs under the same reaction conditions as hy-
8
6
4
2
0
0
0
0
0
147
104
2
63
1
30
204
200
6
4
4
0
80
120
160
m/z
240
280
drolysis or etherification reactions. Here we demonstrate the
sequential Sn-Beta catalyzed Oppenauer (OPP) oxida-
tion/aldol condensation of ethylene glycol and glycerol, with
formaldehyde functioning both as hydrogen acceptor and con-
densation reagent. Under identical conditions to those used for
DHA, HBL could be formed with 12–13% yield at 98% con-
version (Table 1, entries 3–4). In view of the mechanism out-
13
Figure 1. (a) 400 MHz C NMR spectrum of the product
mixture obtained after reacting [ C]formaldehyde with DHA
13
in the presence of Sn-Beta. (b) Mass spectra of the TMS-sugar
derivatives obtained from reactions with unlabeled (top) and
isotopically labeled formaldehyde (bottom).
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lined in Scheme 1, we anticipated that the cascade reaction
Page 4 of 10
100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
could be initiated through hydrogen transfer between the alco-
hol and formaldehyde, resulting in the formation of DHA.
Interestingly, a similar process has been patented wherein Sn-
Beta catalyzes the oxidation of vanillyl alcohol in an aqueous
8
0
4
4
solution of formaldehyde. As a proof-of-concept experiment,
we performed a reaction of 2-hexanol with formaldehyde in
the presence of Sn-Beta. GC/MS analysis of the reaction mix-
ture showed formation of 1-hepten-3-one (Supporting Infor-
mation, Figure S3), which can only be explained by a tandem
OPP oxidation/aldol condensation of the formed 2-hexanone
with formaldehyde catalyzed by Sn-Beta. In addition, we iden-
tified methyl formate as one of the byproducts, indicating the
occurrence of a concomitant MPV reduction of formaldehyde
60
40
20
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
10
20
30
40
50
60
70
45
into methanol. The present reaction data, however, cannot
Time on stream (h)
exclude that dimerization of formaldehyde occurs through a
Lewis acid catalyzed Tishchenko reaction, thus requiring
further studies for confirmation.
4
6
Figure 2. Evolution of the DHA conversion (black diamonds)
and yields of HBL (blue triangles) and LA (red squares) as a
function of TOS. Reaction conditions: 2.6 wt% DHA in diox-
Table 2 shows the effect of the solvent and its dielectric
ane, 2.6 wt% formaldehyde solution (37 wt% in H O with 10-
4
7,48
2
constant (ε)
on the catalytic performance of Sn-Beta for the
1
3
5% methanol), 160 °C, 24 bar, weight hour space velocity of
5.6 h , flow rate of 3.7 mL h . Catalyst regeneration is indi-
reaction of DHA with formaldehyde. Aprotic polar solvents
such as tetrahydrofuran (THF) and γ-valerolactone (GVL)
generate comparable yields to those obtained with 1,4-dioxane
(Table 2, entries 2–3), while protic polar solvents such as eth-
anol lead to inferior HBL yields (1%; entry 4). GVL provides
a promising alternative for 1,4-dioxane because of its favora-
-1 -1
cated by the dashed line.
slightly at longer times. The resulting average productivity
was calculated to be approximately 18.1 g HBL per g catalyst
per h. Significantly higher LA yields were obtained compared
to the reactions performed under batch conditions, which can
be attributed to the presence of water in the reactant solution.
In contrast to the batch experiments, conversion levels were
kept at ca. 90% in the flow reactor in order to track deactiva-
tion more accurately. Consequently, we found a more complex
mixture of intermediates and oxygenated molecules than that
obtained in the batch reactors at the residence times shown in
Table 1. To study the potential reactivation of Sn-Beta and
infer its deactivation mechanism, regeneration of the catalyst
was attempted by flushing the catalyst bed with 1,4-dioxane
and in situ calcination in air at 550 °C for 5 h. After reactiva-
tion, we observed a deactivation profile similar to that of the
original sample, but with reduced HBL yields (≤ 25%). After
4
9
ble toxicological and physical properties. Although not yet
used industry-wide, it has recently attracted academic interest
as a renewable solvent in acid-catalyzed biomass conversion
5
0,51
reactions.
Note that the lack of selectivity in the case of
ethanol is likely due to its tendency to competitively adsorb on
Lewis acid centers, thereby hindering coordination of the reac-
4,24
tants with the active site.
Table 2. Effect of the Solvent on the Catalytic Performance
a
of Sn-Beta for the Reaction of DHA with Formaldehyde
b
entry
solvent
1,4-dioxane
THF
ε
conv. [%] HBL yield [%]
1
2
3
2.2
7.5
37
25
98
99
60
49
61
1
7
0 h of operation, the catalyst was recovered and characterized
by various techniques. Thermogravimetric analysis (TGA) of
this material revealed a 5% weight loss over a temperature
range of 150–600 °C (Supporting Information, Figure S5),
indicating the adsorption of carbonaceous components on the
GVL
>99
4
a
ethanol
89
b
Reaction conditions: see Table 1. Dielectric constants (ε)
were obtained from ref. 47 and 48.
zeolite. N physisorption measurements showed a decrease in
2
3 -1
micropore volume from 0.17 to 0.14 cm g (Supporting In-
formation, Figure S6), suggesting that catalyst deactivation
may, at least in part, be due to micropore collapse. However,
this structural damage did not result in significant changes to
the long-range topological order of the Beta zeolite as shown
by powder X-ray diffraction (PXRD; Supporting Information,
Figure S7).
The stability of Sn-Beta was investigated by simple recy-
cling experiments in which the catalyst was separated by fil-
tration, washed with acetone, dried and calcined in air at 550
°
C. Reusing Sn-Beta over three runs led to a decrease in HBL
yield of 20% while the DHA conversion remained almost con-
stant (Supporting Information, Figure S4). To investigate the
deactivation pathways in more detail, we also tested the cata-
lyst in a packed-bed flow reactor. In order to solubilize all
reactants flowing into the packed bed, an aqueous formalde-
hyde solution (37 wt%) was used instead of the dry polymeric
paraformaldehyde. Figure 2 shows a plot of the catalytic activ-
ity of Sn-Beta as a function of time on stream (TOS). Under
the conditions investigated, DHA conversion decreased from
In conclusion, we have demonstrated the C–C coupling be-
tween 1,3-dihydroxyacetone and formaldehyde using Sn-Beta
as solid Lewis acid catalyst. Remarkably, besides the main
product HBL, we were able to observe the formation of C5
sugars, indicating the occurrence of two consecutive aldol
addition reactions. Isotopic labeling studies corroborate a
mechanism involving soft enolization of DHA followed by an
aldol addition of formaldehyde to the Sn-enolate intermediate,
generating erythrulose as an intermediate species. Moreover,
combining the C–C coupling reaction with hydrogen transfer
9
5 to 87% over the course of 48 h. HBL yields stabilized be-
tween 34 and 36% after ca. 20 h on stream, then decreased
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ACS Catalysis
in a cascade sequence allowed us to extend this concept to
polyols such as glycerol and ethylene glycol, which could
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ultimately be exploited in cellulose conversion schemes. Our
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This work was sponsored by the Chemical Sciences, Geosciences
and Biosciences Division, Office of Basic Energy Sciences, Of-
fice of Science, U.S. Department of Energy, under Award No.
DE-FG0212ER16352. S.V.d.V. was partially supported by the
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