A Systematic Study of Metal Triflates in Catalytic Transformations of Glucose in Water and Methanol: Identifying the Interplay of Br?nsted and Lewis Acidity

Article abstract of DOI:10.1002/cssc.201900292

The specific type of acidity associated with the given metal trifloromethanesulfonates (Br?nsted or Lewis acidity) dramatically influences the course of reactions, and it is possible to select for disaccharides, fructose, methyl glucosides, or methyl levulinate. Glucose is transformed into a range of value-added molecules in water and methanol under the action of acidic metal triflates as catalysts, including their analogous Br?nsted acid-assisted or Br?nsted base-modified systems. A systematic study is presented of a range of metal triflates in methanol and water, pinning down the preferred conditions to select for each product.

Full text of DOI:10.1002/cssc.201900292

Accepted Article
Title: A systematic study of metal triflates in catalytic transformations
of glucose in water and methanol: identifying the interplay of
Brønsted and Lewis acidity
Authors: Iurii Bodachivskyi, Unnikrishnan Kuzhiumparambil, and D.
Bradley Glen Williams
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ChemSusChem
10.1002/cssc.201900292
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A systematic study of metal triflates in catalytic transformations
of glucose in water and methanol: identifying the interplay of
Brønsted and Lewis acidity
[
a]
[b]
[a]
Iurii Bodachivskyi, Unnikrishnan Kuzhiumparambil and D. Bradley G. Williams*
Abstract: The specific type of acidity associated with given metal
trifloromethanesulfonates (Brønsted- or Lewis acidity) dramatically
influences the course of reactions and it is possible to select for
disaccharides, fructose, methyl glucosides, or methyl levulinate.
Glucose is transformed into a range of value added molecules in
water and methanol under the action of acidic metal triflates as
catalysts, including their analogous Brønsted acid-assisted, or
Brønsted base-modified systems. We present a systematic study of a
range of metal triflates in methanol and water, pinning down the
preferred conditions to select for each product.
forcing reaction conditions.[6] While Brønsted acidity is achievable
by the addition of protic acids to the media, it is more difficult to
ensure Lewis acidity, due to deactivation of many Lewis acids in
aqueous solvents.[ The differing role of the acid catalysts at each
stage of the conversion of glucose, along with difficulties to
sustain Lewis acidity in water, requires the judicious selection of
robust catalysts that are capable of providing the requisite activity
to enable the substrate to be transformed into the desired product
in high yield and selectivity.
7]
The general understanding of the role of solid acid catalysts in
these processes has improved over the past few years, owing to
several elegant studies.[
8-10]
On the other hand, metal triflates are
water-tolerant homogeneous Lewis acid catalysts, which has
fostered their use in a number of chemical processes in aqueous
Introduction
and protic media, including the synthesis of platform
The production of bulk chemicals from naturally derived materials
is a foundation of sustainable chemical industrial development.
Among the various resources that are available, cellulose-derived
glucose in principle possesses the scale of manufacture and
overall availability to sustain a large chemical industry.[1] In the
presence of an acid catalyst, glucose may be converted into a
large portfolio of valuable organic building block chemicals
[7,11-14]
molecules.
Replacing the aqueous solvent with alcohols
permits the conversion of carbohydrates into desirable platform
molecules in enhanced yields and sometimes under milder
reaction conditions.[6,15-17] In the present work, we detail a
systematic study of a range of metal triflates and the responses
of the reactions in question to the prevailing conditions. In
particular, we probe the type of acidity (Brønsted or Lewis)
associated with metal triflates and their performance in
transformations of glucose into defined valuable molecules, in
aqueous media and methanol. This helps to build an improved
and more unified view of how to structure chemical processing of
glucose into platform chemicals. In particular, we probe the
conversion of glucose into disaccharides, into fructose and methyl
glucosides (MG), and into methyl levulinate (MLev). Along the
way, we consider HMF and 5-(methoxymethyl)furfural (MMF),
which are intermediates towards MLev.
(
platform molecules), all of which are realistic contenders to
substitute petrochemical products.[1-3] Despite this promise, the
acid-catalyzed valorization of glucose is challenging: complexities
arise because of the low selectivity of processes that are typically
performed in water and which require both Lewis and Brønsted
acid catalysts, as pictorially presented in Scheme S1 (Supporting
information).[1] It is considered that Lewis acids promote the
isomerization of glucose into fructose at moderate
temperatures,[
3,4]
and at elevated temperatures facilitate retro-
aldol reactions into low-molecular-weight sugars from which -
hydroxy acids are produced.[5] In turn, Brønsted acids usually
catalyze dehydration of fructose into 5-(hydroxymethyl)furfural
Results and Discussion
(
HMF) and rehydration thereof into levulinic acid under more
Metal triflates are efficient in the synthesis of some platform
molecules in both aqueous and alcohol media at elevated
[
[
a]
I. Bodachivskyi, Prof. Dr. D.B.G. Williams
University of Technology Sydney
School of Mathematical and Physical Sciences
Broadway NSW 2007, PO Box 123 Broadway NSW 2007 (Australia)
E-mail: Bradley.Williams@uts.edu.au
Dr. U. Kuzhiumparambil
University of Technology Sydney
Climate Change Cluster (C3)
Broadway NSW 2007, PO Box 123 Broadway NSW 2007 (Australia)
[14-16]
temperatures (180–240 °C).
Highly selective transformations
at lower temperatures are desirable and was an object of the
present study. To achieve this, the activity of a number of metal
triflates (Hf(OTf)
4
, Sn(OTf)
, or Y(OTf) ), Brønsted acids (TsOH and H
acid-assisted Brønsted acids (La(OTf)
/TsOH) was explored for the conversion of glucose at
2
, In(OTf)
3
, Al(OTf)
3
, AgOTf, LiOTf,
PO ) and
4
/H PO ,
b]
La(OTf)
Lewis
3
3
3
4
3
3
La(OTf)
3
lower temperatures, and in water or methanol under reflux at
atmosphere pressure. In water, fructose, an isomerization product
of glucose, is the desired and expected major product,[3,4] but the
Supporting information for this article is given via a link at the end of
the document.
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ChemSusChem
10.1002/cssc.201900292
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maximum yield of fructose was only 9 mol% (based on glucose,
Table S1). Metal triflates such as Sn(OTf) and Hf(OTf) promoted
2 4
of isomaltose over other glucose disaccharides under Brønsted
acid-catalyzed conditions, as observed experimentally.
the formation of dark-brown high molecular weight by-product
humins (insoluble condensation products of HMF with
saccharides[ – HMF is a dehydration product of fructose),
accounting for the substantial mass losses noted. In contrast,
AgOTf, or LiOTf showed no catalyst activity, potentially due to
weak complexation with the substrate. Interestingly, the dominant
reaction noted with Brønsted acids or Lewis acid-assisted
Brønsted acids was the catalyzed condensation of glucose into
isomaltose and oligosaccharides, as pictorially represented in
Scheme 1. While this condensation process has been known
since Emil Fischer’s day, most current research shows a distinct
focus on enzymatic methods, with little information relating to the
targeted chemical synthesis of disaccharides.[19-22] A selective
chemical method would therefore provide an exciting alternative
to enzymatic methods. As expected, the self-condensation of
glucose was more efficient in concentrated aqueous solutions (30
wt% glucose in water) and extended reaction times (12 h). The
highest conversion of glucose (43 wt%, of which 42 wt% is
accounted for immediately below, implying 98% selectivity to the
named products) into saccharide condensation products was
Aldose-ketose isomerization, required for the glucose-fructose
conversion, is more efficient in alcohols than water, affording alkyl
glycosides (glucoside (non-isomerization product) and fructoside
(isomerization product)) as major products.[3,8,17] Because the
yields of fructose were low in our first set of reactions, consistent
with dominant Brønsted acid activity, and to improve the outcome
towards fructose, we adopted a two-step one-pot process
conducting the isomerization in methanol (under reflux at
atmospheric pressure, 1 h), and then the hydrolysis of methyl
glycosides into fructose and glucose in water (under reflux at
atmospheric pressure, 1 h; Table 1 gives results after the secondstep).
18]
Table 1. Acid-catalyzed transformation of glucose in methanol and water[a]
Acid catalyst
Conv
[%]
Fructose MG
yield [%] yield [%] 0.01 M,
pH
pH
0.01 M,
MeOH
b]
[b]
H
2
O[
La(OTf)
3
/H
3
PO
4
12
41
8
0
9
9
7
0
5
9
9
5
1
0
2.04
2.05
2.08
2.21
2.39
2.61
3.12
3.60
3.66
5.16
0.72
0.50
0.59
2.74
1.07
0.53
1.09
1.75
2.66
6.10
Hf(OTf)
4
3
3 3 4
achieved by employing a combination of La(OTf) /H PO , and
TsOH
0
isomaltose was isolated as a main product (yield 17 wt% based
on glucose, Table S1) together with other water-soluble di-, tri-
and oligosaccharides (yield 5, 6 and 14wt%, respectively, Table
S2). For comparison, analogous enzymatic processes provide
isomaltose in 14wt% and oligosaccharides in 4wt% yield.[19] In our
hands, if water was allowed to distill slowly from the reaction
mixture to promote condensation reactions, trisaccharides and
oligomeric products predominated, along with water-insoluble
material the color of caramel. In this reaction, it is the Brønsted
acidity associated with the catalysts, including the metal
triflates,[12,13,23,24] that leads to the self-condensation of glucose.
H
3
PO
La(OTf)
Sn(OTf)
In(OTf)
4
0
0
3
/TsOH
7
0
2
29
29
42
64
0
4
3
15
24
47
0
Al(OTf)
Al(OTf)
AgOTf
3
/TBP[c]
3
4
.85[d]
4.04
[d]
LiOTf
4
3
5
0
0
5.33
6.31
6.90
La(OTf)
3
12
4.63
3.77
[d]
6
.05[d]
Y(OTf)
3
6
2
2
6.64
6
3.98
3.20
.02[d]
[d]
H-USY[e,17]
72
55
–
–
–
Scheme 1. Self-condensation of glucose into oligosaccharides.
[
a] Yields are specified in mol% based on glucose; ‘0’ or ‘99’ for the product
were identified on the basis of trace analysis by HPLC. OTf
trifluoromethanesulfonate; TsOH = p-toluenesulfonic acid; TBP = 2,6-di-
tert-butyl-4-methylpyridine. Reaction conditions: glucose (50 mg), methanol
=
A density-functional study at B3LYP/6-31+g(d) level of theory
considering the experimental reaction parameters (temperature,
pressure, solvation) found the transition state towards isomaltose
to be substantially more stable than those towards other
disaccharides (Scheme S2 shows the series of glucose dimers
considered; Scheme S3 shows a reaction mechanism with
intermediates). The finding implies a kinetic preference for
isomaltose (Figure S1). This observation, coupled with a stable
product (thermodynamically the second most favored product of
the entire series, Table S3), would account for the predominance
(2 mL), catalyst (20 mol% based on glucose), reflux at atmosphere
pressure, h, then solvent exchange with water (2 mL), reflux at
1
atmosphere pressure, 1 h. [b] pH readings were performed in triplicate in
water or aqueous methanol (98% alcohol) at 20 °C. [c] Reaction conditions:
glucose (50 mg), methanol (2 mL), Al(OTf) (20 mol% based on glucose),
3
TBP (60 mol% based on glucose), reflux at atmosphere pressure, 36 h,
then solvent exchange with water (2 mL), reflux at atmosphere pressure, 1
h. [d] pH values measured at 40 °C. [e] Reaction conditions:[ glucose (125
mg), methanol (4 g), H-USY zeolite (75 mg), 120 °C, 2 h, then addition of
water (2 g), 120 °C, 1 h.
17]
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This approach has been employed favorably in the presence of
zeolites.[8,17,25,26] Glucose, fructose and MG (as a 1:1 mixture of -
and -anomers of methyl glucopyranoside, as established by
quantitative NMR analysis of the product mixture after Step 2,
Figure S2) were obtained after two-step processing in methanol
after the one-step transformation in water (Table 1 and S1).
Methyl glucofuranosides and fructosides are readily converted
into glucose and fructose during the processing in water (i.e. the
second step, Figure S2). In turn, glucopyranosides were
somewhat stable to hydrolysis under the conditions we employed:
in all cases where Lewis acids were present, the amount of MG
after step 2 was identical to the amount of MG found after step 1
(formed in a 1:1 ratio, as determined by quantitative NMR
spectroscopy after each step).
pH determinations of solutions of various metal triflates in water
and methanol, respectively, revealed the strength of the Brønsted
acids formed in solution (Table 1). Metal triflates are typically
considered to be Lewis acids, but clearly possess Brønsted
acidity, sometimes comparable to strong protic Brønsted acids
3
and water; Al(OTf) was found to possess optimal Lewis acidity to
drive the isomerization reaction (24 mol% yield of fructose).Given
that a) conversion of glucose into fructose is favored by Lewis
acids and b) conversion of glucose or fructose into methyl
glycosides is favored by Brønsted acidity (similar to the self-
condensation of glucose, mentioned above), then it might be
possible to improve selectivity to fructose by minimizing the
Brønsted acid activity associated with the metal triflate catalysts.
2,6-Di-tert-butyl-4-methylpyridine (TBP) is known to discriminate
between Brønsted and Lewis acidity because it interacts
exclusively with hydrogen cations due to the extreme steric
hindrance exerted by the tert-butyl-groups, which prevents
3 4
(TsOH and H PO ). This phenomenon is caused by Lewis acid-
assisted Brønsted acidity through complexation of the metal
center with the protic solvent and release of hydrogen cation
[
27]
+
[28]
interactions at the N atom with any larger cations,
including
Al. Pleasingly, the addition of TBP as Brønsted base (3:1 based
on Al(OTf) ), reduced the amount of Brønsted acid-catalyzed
(typically present as H13
O
6
in dilute aqueous solutions) as was
[
24]
[23,24]
disclosed earlier for Al(OTf)
3
.
This effect is observed in both
and
. Certain mixed acids (Lewis + Brønsted), specifically the
/H PO pair, deliver the highest Brønsted acidity (Table
1), consistent with our previous studies.
3
media (water and methanol) and is prominent for Hf(OTf)
Sn(OTf)
La(OTf)
4
production of MG and simultaneously improved the selectivity to
and yield of fructose, albeit that the process required longer
reaction times (Table 1, Table S4). This outcome demonstrates
that catalyst systems which display both Lewis and Brønsted
acidity can be modulated towards Lewis acidity to develop
improved chemical selectivity (see below and Table 1 for a
discussion on the acidity of the metal triflates). It is worth noting
that the yield of the isomerization product fructose (47%),
produced under mild processing conditions, compares very
favorably with the industrially applied enzymatic method (42%).[1]
In rare instances, higher yields of fructose are achievable under
more forcing reaction conditions (Table 1).[17]
2
3
3
4
[
13]
TBP reduces the
Brønsted acidity of metal triflates but this effect was noted in
methanol only and rather little in the water, most likely due to the
poor solubility of TBP in water.
When considering the combined experimental data, the following
emerges:
a) the strongest Brønsted acids (where the acidity is due to a
protic acid or an assisted Brønsted acid), as determined by
pH measurements, provide the highest yields of
disaccharides in aqueous media and of MG in methanol;
b) Lewis acids catalyze the isomerization of glucose into
fructose, but those that induce the highest Brønsted acidity
also promote the formation of methyl glucopyranosides and
methyl glucofuranosides (in methanol) and humins;
c) TBP is capable of selectively neutralizing the Lewis acid-
assisted-Brønsted acidity while maintaining Lewis acidity in
methanol and therefore improves the selectivity of the
conversion of glucose into fructose.
Interrogation of the product after step 1, by NMR spectroscopy,
led to important observations. In particular, the first step delivers
high yields of a combination of methyl fructosides and methyl
glucofuranosides during the conversion in methanol, when the
Lewis acid Al(OTf)
3
is present, and only small amounts of
glucopyranosides (Figure 1). This is entirely consistent with
recent work with zeolite catalysts, in which methyl furanosides
were also identified as kinetic products.[8] In our work, in all
instances, diagnostic signals map perfectly onto those previously
determined for similar mixtures.[8] As anticipated, the addition of
With the view to converting glucose into other platform molecules,
which requires elevated temperatures, we conducted the two-step
processing in methanol for longer reaction times and at higher
3
TBP to Al(OTf) suppresses the Brønsted acidity associated with
Lewis acid catalyst and favors the formation of methyl fructosides
in preference to methyl glucosides (Figure 2). When only a
Brønsted acid is present (TsOH), or Lewis acid-assisted Brønsted
3
temperatures from 65 °C to 120 °C in the presence of Al(OTf) as
catalyst (Figure 4), followed by hydrolysis in water. We used a
sealed glass pressure-tube for temperatures above 65 °C. As is
evident from Figure 4a, extended reaction times do not influence
the yield of fructose (for solvent under reflux at ambient pressure)
but do improve the conversion of glucose into MG, HMF, MMF,
and MLev. Higher temperatures reduce the yield of fructose, due
to its conversion into furaldehydes and their ultimate rehydration
into MLev (Figures 4b-d). Arguably, methyl glucosides are also
converted into MLev at elevated temperatures after hydrolysis
into glucose. Furaldehydes appeared as their dimethyl acetals
after the processing in methanol and these readily hydrolyzed into
HMF and MMF after methanol-water solvent exchange (Figure S6).
3 3 4 4
acid (La(OTf) /H PO ), or hard Lewis acid (Hf(OTf) ), very high
yields of methyl glucosides are obtained (up to 94% as a mixture
of glucopyranosides and glucofuranosides, Figures 3, S3 and S4)
with no evidence for the formation of fructosides. The softer Lewis
acid (La(OTf) ) provides only little conversion into methyl
3
glucofuranosides under the applied conditions (Figure S5). These
observations also provide evidence that hard and soft Lewis acids
(
Hf(OTf)
4
3
and La(OTf) , respectively) mostly catalyze the
isomerization of glucose into fructose in water during the second
step; with these acids, the gains of fructose after the two-step
conversion in methanol and water are similar to those obtained
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Figure 1. 13C NMR spectrum and the ratio of carbohydrates obtained after Al(OTf)
-processing in methanol (step 1). Reaction conditions: glucose (50 mg), methanol
3


(
2.00 mL), Al(OTf)
3
(20 mol% based on glucose), reflux at atmosphere pressure, 1 h. Parameters of NMR analysis: 50 mg sample, D
2
O (0.60 mL), 25 °C. G , G ,
MG , MG , MGfur, MG , MF , MF , and MF

pyr
pyr
fur
fur
fur
pyr
mean -D-glucopyranose, -D-glucopyranose, methyl -D-glucopyranoside, methyl -D-glucopyranoside,
methyl -D-glucofuranoside, methyl -D-glucofuranoside, methyl -D-fructofuranoside, methyl -D-fructofuranoside, and methyl -D-fructopyranoside, respectively.
The anomeric C atoms (C-1) of the various compounds are labelled on the spectrum.
Figure 2. 13C NMR spectrum and the ratio of carbohydrates obtained after Al(OTf)
methanol (2.00 mL), Al(OTf) (20 mol% based on glucose), TBP (60 mol% based on glucose), reflux at atmosphere pressure, 36 h. Parameters of NMR analysis:
0 mg sample, D O (0.60 mL), 25 °C. G , G , MG , MG , MG , MF , MF , and MF mean -D-glucopyranose, -D-glucopyranose, methyl -D-
3
/TBP-processing in methanol (step 1). Reaction conditions: glucose (50 mg),
3


pyr
fur
fur
fur
fur
pyr
5
2
glucopyranoside, methyl -D-glucofuranoside, methyl -D-glucofuranoside, methyl -D-fructofuranoside, methyl -D-fructofuranoside, and methyl -D-
fructopyranoside, respectively. The anomeric C atoms (C-1) of the various compounds are labelled on the spectrum.
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Figure 3. 13C NMR spectrum and the ratio of carbohydrates obtained after TsOH-processing in methanol (step 1). Reaction conditions: glucose (50 mg), methanol


(
2.00 mL), TsOH (20 mol% based on glucose), reflux at atmosphere pressure, 1 h. Parameters of NMR analysis: 50 mg sample, D
2
O (0.60 mL), 25 °C. G , G ,

pyr
pyr
fur
fur
MG
,
MG
,
MG
, and MG
mean -D-glucopyranose, -D-glucopyranose, methyl -D-glucopyranoside, methyl -D-glucopyranoside, methyl -D-
glucofuranoside, and methyl -D-glucofuranoside, respectively. The anomeric C atoms (C-1) of the various compounds are labelled on the spectrum.
Figure 4. Al(OTf)
pressure. b), c), d) Temperature of the processing in methanol 80, 100, 120 °C, respectively. [a] Time of the processing in methanol. Reaction conditions: glucose
50 mg), methanol (2 mL), Al(OTf) (20 mol% based on glucose), then solvent exchange with water (2 mL), solvent under reflux at atmosphere pressure (1 h).
conversion of glucose, ● yield of fructose, × yield of MG, □ total yield of HMF and MMF, ▲ yield of MLev (identified immediately after the processing in methanol).
3
-catalyzed conversion of glucose via two-step process in methanol and water: a) Processing in methanol under solvent reflux at atmosphere
(
3
○
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to sufficient Brønsted acidity under more forcing reaction
conditions, but with insufficient Lewis or Brønsted acidity to
promote subsequent reactions, giving high selectivity. Catalysts
considered to be hard Lewis acids (e.g., Hf(OTf)
4 2
, Sn(OTf) and
In(OTf) , which also produce high Brønsted acidity) delivered
3
excellent outcomes towards MLev (Tables 1, 2). MLev is formed
by Lewis acid-catalyzed isomerization of glucose into fructose
followed by (Lewis acid-assisted) Brønsted acid-catalyzed
dehydration/rehydration processes. Sn(OTf)
2
offers superb
selectivity towards desirable products without significant
formation of by-product humins that were observed in aqueous
media at lower temperatures, affording MLev in 67% yield.
Table 2. Acid-catalyzed transformation of glucose in methanol and water[a]
Catalyst
Al(OTf)
Conv
Fructose MG
yield [%] yield [%] yield [%]
HMF and MMF MLev
yield[ [%]
b]
[
%]
Scheme 2. Acid-catalyzed transformation of glucose into platform molecules in
methanol and water, highlighting either Lewis acid- or Brønsted acid-catalysis
at each step.
3
99
0
0
0
0
0
0
10
71
14
93
13
89
0
0
0
0
0
0
59
7
La(OTf)
3
/
84
H
3
PO
4
Hf(OTf)
TsOH
4
90
93
13
39
0
MLev is the major product at elevated temperature, in an excellent
59% yield in a highly selective reaction (120 °C, 8 h, Figure 4d;
the yield remains unchanged at 12 h and 18 h). Model
transformations of fructose and HMF using TsOH as catalyst
H
3
PO
4
0
La(OTf)
TsOH
3
/
(
Table S5) highlight the notion that the dehydration/rehydration
89
0
processes are catalyzed by Brønsted acids. Scheme 2 provides
a summary of the conversion of glucose in methanol and water,
as discussed above, distinguishing between Lewis acid-promoted
reactions and Brønsted acid-catalyzed transformations.
Sn(OTf)
2
90
0
0
46
18
1
0
43
67
7[c]
[c]
[c]
[c]
[c]
9
In(OTf)
AgOTf
LiOTf
3
99
95
13
99
99
0
0
8
0
0
8
1
0
0
1
0
52
0
Various other metal triflates and Brønsted acids transform
glucose into derivative products MG and/or MLev in the two-step
transformation of glucose in methanol and water, to a greater or
lesser extent. Table 2 perfectly exemplifies the interplay between
Brønsted and Lewis acidity in these conversions of glucose to
product. Typical Brønsted acid catalysts or Lewis acid-assisted
Brønsted acids promoted the transformation of glucose into MG,
especially highlighted by TsOH (MG yield 93%, -anomer as
major product). In these reactions, the thermodynamic preference
for methyl glucopyranosides was evident with minimum formation
of the kinetic product methyl glucofuranosides (determined by
quantitative NMR analysis of the product mixture after Step 1,
Figures S7 and S8).[8] The anomalous apparent diminished
90
0
0
La(OTf)
3
89
72
9
Y(OTf)
3
9
[
a] Yields are specified in mol% based on glucose; ‘0’ or ‘99’ for the product
were identified on the basis of trace analysis by HPLC. Reaction conditions:
glucose (50 mg), methanol (2 mL), catalyst (20 mol% based on glucose),
120 °C, 8 h, then solvent exchange with water (2 mL), reflux at atmosphere
pressure, 1 h. [b] Yield of MLev was identified immediately after the
processing in methanol. [c] Reaction temperature = 140 °C, time = 4h.
3 3 4
Brønsted acid activity of La(OTf) /H PO , evidenced by only 77%
yield of MG compared to superior yields afforded by weaker
Brønsted acids, likely relates to precipitation of the catalyst at
elevated temperature, with a concomitant reduction of the
reaction rate, as is typical for heterogeneous systems.[29]
Conclusions
3 3
Surprisingly, Lewis acidic catalysts AgOTf, La(OTf) and Y(OTf) ,
with low Brønsted acidity at low temperature (Table 1), showed
high selectivity towards MG at elevated temperature, which relies
upon Brønsted acid activity. pH measurements of solutions of
these catalysts at 20 °C and 40 °C show the increased Brønsted
acidity in methanol and water (Table 1) associated with elevated
temperatures. This would be even higher at the elevated
temperatures under which the reactions are performed. This
suggests that the complexation of the catalyst and solvent leads
This systematic study of a range of metal triflates and some
associated (induced) Brønsted acid systems shows that the
selectivity is determined by the dominating Brønsted or Lewis
acidity. The nature of the dominant acidity can be manipulated by
varying the reaction conditions. Firstly, this includes the addition
of a protic acid to form Brønsted acidic combined acid complexes,
3 3 4
such as La(OTf) /H PO , which promote high conversion of
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ChemSusChem
10.1002/cssc.201900292
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glucose into disaccharides in aqueous solvent. Secondly, it
includes the addition of the Brønsted base TBP to inhibit Brønsted
acidity and thereby enhance the yield of fructose in two-step
processing in methanol and water. The activities of metal triflates
can be dramatically altered by raising the reaction temperature:
whereas some less active metal triflates show poor catalyst
activity at lower temperatures, their activity is enhanced at
elevated temperatures and is accompanied by very high
selectivity to product, being MG or MLev, with very little by-
product formation. It is noteworthy that Lewis acids which offer the
lowest Brønsted acidity at mild conditions, namely AgOTf,
hydrogen carbonate (40.0 mL, 0.05 M). An aliquot of the neutralized
aqueous system was centrifuged (20,000 × g for 10 min) and decanted,
and the recovered solutions were analyzed using the HPLC system to
provide the results detailed in the main text. A detailed method for
preparative separation of carbohydrates is presented in SI. NMR, IR, and
MS spectra for the isolated disaccharides were assigned by comparison
with literature data and spectra produced from an authentic commercial
sample of isomaltose.[31–34]
Isomaltose (reference sample).[31–34] 13C NMR (125 MHz, D
[D ]TMSP):  = 97.9, 96.0, 92.1, 75.9, 74.2, 74.0, 73.0, 71.7, 71.4, 71.3,
2
O, 25°C,
4
7
1
0.0, 69.5, 69.4, 69.3, 65.7, 65.6, 60.4; IR (neat): max = 3267, 2922, 1643,
421, 1348, 1263, 1149, 1102, 1007, 913, 842, 764, 501 cm–1; HRMS
La(OTf)
3
3
and Y(OTf) , promoted Brønsted acid-catalyzed
–
(ESI): m/z: calcd for C12
21
H O
11 [M–H] : 341.1089, found: 341.1096.
conversion of glucose into MG at higher temperature, and thus
become a source of hydrogen cation under such conditions, but
in highly selective processes. Alternatively, harder Lewis acids
Isolated disaccharides.[31–34] 13C NMR (125 MHz, D
O, 25°C, [D
2
4
]TMSP):

6
1
= 97.9, 96.0, 92.1, 75.9, 74.2, 74.0, 73.0, 72.4, 71.7, 71.4, 71.3, 70.0,
(
i.e. acids that preferentially interact with protic solvents) with
enhanced Brønsted acidity in water and methanol (e.g., Hf(OTf)
Sn(OTf) , In(OTf) and Al(OTf) ) can efficiently catalyze the
9.6, 69.5, 69.4, 69.3, 65.7, 65.6, 60.4; IR (neat): max = 3261, 2921, 1642,
567, 1421, 1353, 1149, 1099, 1011, 918, 842, 766, 495 cm–1; HRMS
4
,
–
2
3
3
21
(ESI): m/z: calcd for C12H O11 [M–H] : 341.1089, found: 341.1088.
transformation of glucose into MLev via an initial Lewis acid-
catalyzed isomerization step. These transformations of glucose
employing metal triflates affords a deeper insight of the overall
role of the acid catalyst in the production of target platform
molecules under specified reaction conditions. These insights
provide a springboard for future studies towards the selective
acid-catalyzed conversion of glucose, as well as other naturally
abundant carbohydrates, into a range of functional molecules.
Among the options of catalyst for the processing of native
biomass such as lignocellulose, metal triflates hold significant
promise towards sustainable industrial development.
Two-step acid-catalyzed conversion in methanol and water
Glucose (50 mg), methanol (2.00 mL) and acid catalyst (20 mol% based
on glucose), and in some instances base (2,6-di-tert-butyl-4-
methylpyridine, 60 mol% based on glucose), were introduced to a round-
bottom flask equipped with a condenser and magnetic follower. The
mixture was heated and stirred under reflux at atmosphere pressure for a
fixed period of time (step 1). Then methanol was evaporated under
reduced pressure (30 °C, 90 mbar) and water (2.00 mL) was added to the
reactor (solvent exchange). The resulting mixture was heated and stirred
under reflux at atmosphere pressure for 1 h (step 2). The reaction was
quenched by the addition of an aqueous solution of sodium hydrogen
carbonate (2.00 mL, 0.05 M) and the mixture was centrifuged (20,000 × g
for 10 min) and decanted. The recovered solutions were analyzed using
an HPLC system, as detailed in SI, to provide the results detailed in the
main text.
Experimental Section
Reagents and metal triflate catalysts (Hf(OTf)
Al(OTf) , AgOTf, LiOTf, La(OTf) or Y(OTf) ) and phosphoric acid (H
5 wt% aqueous solution) were used as supplied from commercial sources.
p-Toluenesulfonic acid monohydrate was dried under reduced pressure
60 °C, 1 mbar, 12 h) to generate anhydrous TsOH. HPLC grade solvents
4
,
Sn(OTf)
2
,
In(OTf)
3
,
Reactions at elevated temperatures of 80–120 °C in step 1 were
conducted in a sealed glass pressure tube. Glucose (50 mg), methanol
3
3
3
3 4
PO ,
8
(2.00 mL) and acid catalyst (20 mol% based on glucose) were introduced
to a glass pressure tube equipped with a magnetic follower and the reactor
was sealed. The mixture was heated and stirred at the predetermined
temperature for a fixed period of time (step 1). After cooling, the mixture
was transferred to a round-bottom flask and methanol was evaporated
under reduced pressure (30 °C, 90 mbar). Then water (2.00 mL) was
added to the reactor (solvent exchange) and the resulting mixture was
heated and stirred under reflux at atmosphere pressure for 1 h (step 2).
The reaction was quenched by the addition of an aqueous solution of
sodium hydrogen carbonate (2.00 mL, 0.05 M) and the mixture was
centrifuged (20,000 × g for 10 min) and decanted. The recovered solutions
were analyzed using an HPLC system to provide the results detailed in the
main text. Additional details of synthesis methods and preparative isolation
of products are presented in SI.
(
were employed for experiments. Methanol was dried over activated 3 Å
molecular sieves, accordingly to the established optimum method.[30] The
analytical data for synthesized products described in this manuscript have
been previously reported.[31–40] A details of analytical procedures and
theoretical methods are specified in SI.
Acid-catalyzed conversion of glucose in water
Glucose (50 mg), water (2.00 mL) and acid catalyst (20 mol% based on
glucose) were introduced to a round-bottom flask equipped with a
condenser and magnetic follower. The mixture was heated and stirred
under reflux at atmosphere pressure for 2 h. The reaction was quenched
by the addition of an aqueous solution of sodium hydrogen carbonate (2.0
mL, 0.05 M) to neutralize the catalyst. The neutralized aqueous systems
were centrifuged (20,000 × g for 10 min), and decanted, and recovered
solutions were analyzed using an HPLC system, as detailed in SI, to
provide the results detailed in the main text.
Methyl -D-glucopyranoside.[35–37] 1H NMR (500 MHz, D
2
O, 25 °C,
[
D
4
]TMSP):  = 4.82 (d, J = 3.5 Hz, 1H), 3.88 (dd, J = 12.5, 2.0 Hz, 1H),
.76 (dd, J = 12.5, 5.5 Hz, 1H), 3.69–3.63 (m, 2H), 3.56 (dd, J = 9.5, 3.8
O, 25°C,
]TMSP):  = 102.2, 102.1, 76.0, 74.4, 74.1, 72.4, 63.4, 57.9; IR (neat):
3
Hz, 1H), 3.43 (s, 3H), 3.41–3.38 (m, 1H); 13C NMR (125 MHz, D
2
[
D
4
For the targeted synthesis of disaccharides, glucose (500 mg), water (1.65
mL) and catalyst (20 mol% based on glucose) were charged to a round-
bottom flask equipped with a condenser, and magnetic follower and the
reaction mixture was heated and agitated under reflux at atmosphere
pressure for 12 h. The reaction mixture was diluted with aqueous sodium

1
max = 3542, 3232, 2912, 1460, 1430, 1372, 1340, 1302, 1226, 1185, 1103,
025, 991, 898, 842, 745, 666 cm–1; HRMS (ESI): m/z: calcd for C
H O
7 13 6
–
[M–H] : 193.0718, found: 193.0715.
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ChemSusChem
10.1002/cssc.201900292
FULL PAPER
HMF.[38] TLC: R
= 0.213 (1.5:1 hexane/EtOAc; UV, KMnO
); H NMR (500
1
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f
4
MHz, CDCl , 25 °C):  = 9.56 (d, J = 1.0 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H),
3
1
3
6
.50 (d, J = 3.5 Hz, 1H), 4.70 (s, 2H), 2.97 (br s, 1H, OH); C NMR (125
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MHz, CDCl , 25°C):  = 177.7, 160.7, 152.3, 123.0, 110.0, 57.5; IR (neat):
3

1
C
max = 3339, 3120, 2841, 1657, 1582, 1519, 1396, 1368, 1336, 1278, 1188,
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070, 1017, 986, 965, 806, 768, 511 cm–1; HRMS (ESI): m/z: calcd for
+
6 6
H O
3
H [M+H] : 127.0390, found: 127.0379.
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3
13
3

2
1
3
.5 Hz, 1H), 4.48 (s, 2H), 3.42 (s, 3H); C NMR (125 MHz, CDCl , 25°C):
= 177.7, 158.2, 152.6, 121.8, 111.1, 66.5, 58.7; IR (neat): max = 3119,
930, 2824, 1673, 1584, 1520, 1450, 1401, 1370, 1275, 1192, 1092, 1022,
001, 970, 944, 907, 810, 784, 756, 732, 509 cm–1; HRMS (ESI): m/z:
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calcd for C H O
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H [M+H] : 141.0546, found: 141.0536.
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MLev.[40] TLC: R
MHz, CDCl , 25 °C):  = 3.67 (s, 3H), 2.75 (t, J = 7.0 Hz, 2H), 2.57 (t, J =
.0 Hz, 2H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl
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438, 1362, 1315, 1213, 1162, 1068, 1029,1000, 970, 894, 812, 766, 574,
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Entry for the Table of Contents
FULL PAPER
The work discloses a systematic study
with fundamental insights relating to
Brønsted and Lewis acidity in metal
triflate-catalyzed transformations of
glucose in water and methanol. It
reveals the dominant type of acidity
and reaction conditions to obtain
isomaltose, fructose, methyl
glucosides, or methyl levulinate in
highly selective processes, and how to
optimize this acidity by manipulating
reaction conditions.
Iurii Bodachivskyi, Unnikrishnan
Kuzhiumparambil, D. Bradley G.
Williams*
Page No. – Page No.
A systematic study of metal triflates
in catalytic transformations of
glucose in water and methanol:
identifying the interplay of Brønsted
and Lewis acidity
This article is protected by copyright. All rights reserved.