Scalable synthesis of hydroxymethyl alkylfuranoates as stable 2,5-furandicarboxylic acid precursors

Article abstract of DOI:10.1039/d0gc00770f

Hydroxymethyl furanoic acid and its derivatives have been synthesized in high yields and purity from gluconolactone. The reaction sequence allows the recovery of reagents and the use of bio-friendly chemicals and solvents, and can easily be scaled up. The reaction product on a >100 gram scale can be purified by a single purification method, such as distillation or precipitation. The overall yield is above 50%.

Full text of DOI:10.1039/d0gc00770f

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DOI: 10.1039/D0GC00770F
COMMUNICATION
Scalable Synthesis of Hydroxymethyl alkylfuranoates as Stable
,5-Furandicarboxylic acid Precursors
2
a
a
a
Martin Jæger Pedersen, Arminas Jurys and Christian Marcus Pedersen*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
1
8–
Hydroxymethyl furanoic acid and derivatives thereof have been oxidation to FDCA has to some extent reduced this problem.
synthesized in high yields and purity from gluconolactone. The
2
0
An alternative approach for the synthesis of FDCA precursors
reaction sequence allow recovery of reagents, use of bio-friendly and related furanoates, would use an already oxidized glucose
chemicals and solvents, and can easily be up-scaled. Reactions on derivative. Surprisingly, few have investigated this option. The
>100 gram scale can be purified by a single purification, such as a cheapest and simplest oxidation product of glucose is gluconic
destillation or precipitation. Overall yield is above 50%.
acid, where the aldehyde has been oxidised to the acid. This can
be done enzymatically or chemically and is already performed
2
1,22
on multiple ton scale, making it almost as cheap as glucose.
The corresponding lactone, gluconolactone, has therefore
Introduction
The conversion of abundant carbohydrates into platform
chemicals has received immense attention in the last two
decades.1–4 Glucose or related carbohydrates, such as fructose,
2
3
received some attention in valorising biomass. Baumann et
2
4
al.
have recently demonstrated that cyclopentanone
derivative can be synthesized from gluconolactone in flow. To
our knowledge, no examples of the direct synthesis of
furanoates from aldonolactones have been published. In this
communication, we describe a simple method for the
conversion of gluconolactone into alkylfuranoates, such as
hydroxymethyl methylfuranoate (HMMF, 2) and hydroxymethyl
furanoic acid (HMFA, 3). Furthermore, examples of derivative
synthesis are presented as well.
have been the main interest as these can be derived from
cellulose, which is the most abundant bio-polymer and by far
the cheapest source. Converting carbohydrates to chemicals, to
substitute fossil-based sources, involves dehydration reactions
as a central process. Simple acid mediated dehydration of
glucose and fructose has been known for more than a century
5
to produce short chain acids and furane compounds (Figure 1).
Where hydroxymethyl furfural (HMF) has received the most
6
–10
attention as a potential platform chemical.
One reason for
OH
O
OH
this is its conversion to furane dicarboxylic acid (FDCA, 1), when
HO
HO
HO
Enzymatically
or
Chemically
Acid treatment
oxidized.1
1–13
This can substitute phthalic acids in the industrial
O
OH
Special conditions
production of polymers. Countless methods have therefore
been published on HMF synthesis, notably many starting from
fructose as it is more reactive and easier to convert. However,
less relevant for an industrial production, where glucose or
OH OH
HO
Fructose
OH
Glucose
HO
O
-Unstable
-
O
Polymerized to humins
-Generates more waste
4
,8,14
sucrose, or even better, cellulose would be preferred.
H
Despite this the synthesis of HMF from fructose has been the
method of choice for several chemical companies developing
HMF
FDCA syntheses.15 Beside the more valuable fructose as Figure 1. Generalized outline for the conversion of glucose and fructose to HMF, an often
preferred starting material, HMF itself also cause extensive tedious and messy production.
problems in large-scale production. The presence of an
aldehyde and a hydroxyl group makes it particularly reactive
towards polymerisation. This leading to the formation of
Results and discussion
humins that remains problematic, both in preparation and To allow for selective functionalisation of gluconolactone, the
storage.1
6,17
Development of methods for direct one-pot first step in the synthesis is full acetylation. Aside from being a
protective group, the acetylation also serves for the activation
a. Universitetsparken 5, 2100 Copenhagen O, Denmark.
Footnotes relating to the title and/or authors should appear here.
†
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
of the 3-O, which is required for the subsequent elimination.
While acetylation of the 2-O lowers the pK
of 2-H. Besides HO
HO
HO
I2/H2SO4 cat.
AcO
View A
N
rt
a
ic
O
le
A
Online
c
O
O
DOI: 10.1039/D0GC00770F
a
AcO
AcO
Ac O (4.2 equiv)
2
being the simplest and cheapest dual function protective group,
the acetyl is an acetic acid derived group, which is a
non-hazardous and an unrestricted chemical. Acetylation of
carbohydrates is one of the most common reactions in
carbohydrate chemistry, and quantitative yields are normally
OH O
OAc O
Gluconolactone
AcO
O
HO
O
O
HCl, MeOH
AcO
O
57%
OMe
obtained, using standard conditions, i.e. excess Ac
pyridine. Keeping large-scale synthesis in mind, we optimized
the conditions in terms of reagent quantity, recovery, handling
2
O in
OAc
4
2, HMMF
3
: R=H (28 %)
5: R=Et (34%)
ROH, H+
HO
O
and yield. Acid catalysed esterification in neat Ac
most efficient method and advantageously avoiding amine
bases, such as pyridine. The amount of Ac O required could be
lowered to 4.2 equivalent before the yield was affected
2
O was the
O
6
: R=All (25%)
7
: R=nBu (37%)
8
: R=sBu (15%)
OR
2
(
Scheme 1). Several strong acid catalysts were screened, e.g. Scheme 1. Synthesis of HMMF and other ester-derivates directly from
gluconolactone in 3 steps, one-pot and one purification.
iodine could be used in very low amounts (0.15-0.087 mol%)
with full conversion. Iodine is however not compatible with
stainless steel equipment commonly used in industries and
hence exchanged for H
IR-120. This gave equally high yields and clean conversion.
In terms of price and handling H SO wasthe preferred acid. The
following β-elimination was directly performed by addition of
base to the reaction mixture. Several groups have previously
studied this reaction. A major issue is the double elimination,
when gluconolactone is acetylated using base catalysed
acetylation.2 Pedersen optimized the reaction conditions to
selectively give the mono-elimination of purified acetylated
With access to a variety furanoates, derived in a few simple
steps from gluconolactone, we studied some further
transformations demonstrating their versatility as potential
platform chemical. During the synthesis of HMMF applying HCl
or HBr as the acid catalysts, small amounts of the chloromethyl
methyl furanoate (CMMF) and bromomethyl methyl-furanoate
2 4
SO or a solid phase acid like Amberlite
2
4
(BMMF) were observed. As these compounds are potentially
valuable alkylating agents, their syntheses (Scheme 2) were
further investigated. Starting from HMMF, HCl (5 equiv., 37% in
water) or HBr (5 equiv., 47% in water) was used as the halide
source giving reasonable yields of CMMF 9 and BMMF 10 (62%
and 83% respectively).
5,26
2
7
gluconolactone applying triethylamine in CH
2
Cl
2
.
These
conditions were not suitable for our purpose and we therefore
aimed to find more industrially and environmentally friendly
conditions. After some investigation, NaOAc in stoichiometric
amounts or even in a catalytic amount dissolved in AcOH was
found to smoothly eliminate the 3-OAc in high yields. NaOAc is
a food additive, environmentally friendly and a very cheap base.
On prolonged reaction times the double elimination took place
as well. Besides generating acetic acid as the only by-product, a
further advantage was the ease of NaOAc recovery by filtration,
when used in stoichiometric amounts. The crude elimination
product 4 in MeOH was then treated with a catalytic amount of
acid, typically from adding AcCl, to acidify the solution (See
supporting information Table 1). When full conversion was
observed by TLC analysis the mixture could be directly purified
by fractional distillation, returning the MeOH and pure HMMF
in 56% overall yield from gluconolactone on a >100 g scale. The
methyl ester is particularly stable under these conditions and
could be stored for months without notably decomposition.
Similarly, other ester derivatives could be obtained just by
changing the alcohol used as solvent. In this way the ethyl 5,
allyl 6, n-butyl 7 and s-butyl 8 esters were synthesized, and
purified by chromatography. The corresponding carboxylic acid
HMFA 3 could easily be produced in one-pot, by addition of
As previously mentioned, HMMF and HMFA are observed
intermediates in the oxidation of HMF, readily undergoing
1
8,20
further oxidized to FCDA.
An old method is treating HMMF
with KMnO in basic water, oxidizing the hydroxymethyl to the
4
carboxylic acid and hydrolysed the methyl ester giving FDCA 1
in one step and 75% isolated yield as an off-white precipitate
after acidification. Several other oxidizing agents can be used
and have already been studied for the conversion of HMF into
1
8–20
FDCA,
where HMMF and HMFA have been observed as
2
8
intermediates. More modern methods include iron catalysed
2
9
aerobic oxidations. This protocol gave 23 % of a mixture
between the mono-methyl ester and FDCA, without
optimization. However, performing this oxidation on five gram
HMMF 2, we were able to isolate 42 % yield of a similar mixture.
KMnO , NaOH, H O
HO
O
4
2
O
O
O
75%
O
OMe
HO
OH
[Fe(NO ) , TEMPO, KCl]
3
3
O , DCE, 23-42%
2
2
, HMMF
1, FDCA
X
O
HX, H O
O
9, CMMF: X=Cl (62%)
0, BMMF: X=Br (83%)
2
1
either dilute HCl or H
2
SO
4
in water, followed by crystallization.
OMe
Generally, when other alcohols than methanol was used, we
observed a higher degree of side-product formation. In all
reaction the major side-product was a 2-H-pyranone derivative
like the double elimination product following β-elimination.
Scheme 2. HMMF is a versatile starting material that is easily oxidized to the
dicarboxylic acid or converted to its methyl halide.
2
| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
HMMF it most likely goes through several intermediates in
MeO
NH2
10, X=Br
View Article Online
H2N
X
O
O
OMe
equilibria. Based on the NMR-experime
DO
nt
I
t
:
he
10
.1
py
03
9ra/D
non
0
GC
e
00
s
7id70
e-
F
O
O
Na2CO3
O
N
O
N
O
product is enough to account for most of the loss of yield in the
conversion reactions of compound 4.
OMe
O
DMF
O
MeO
O
58%
OMe
NH2
H2N
11
2
, X=OH
Conclusions
MeOH
O
O
In conclusion a highly efficient and scalable method for
synthesizing hydroxymethyl furanoate derivatives from
cellulose-derived biomass has been developed. This can be
performed in a one-pot reaction allowing for good compliance
with a broad range of reaction vessels. Most importantly, this
method bypasses the unstable HMF as intermediate on the way
to the industrially interesting FDCA. The key intermediate,
HMMF or its acid HMFA, are both stable, storable and can be
HO
, X=OH
Et3N
HO
O
2
O
HN
N
NH2
NH
H
MeOH
6 % (2 steps)
1
2
2
O
OH
O
Scheme 3. Both BMMF and HMMF were converted into two potential
building blocks for polymerization reaction by simple transformations with
ethylenediamine.
We were able to synthesise a furane analogue of the widely prepared in high yield from gluconolactone. The reaction
used ethylenediaminetetraacetic acid (EDTA). Reacting BMMF sequence allow for recovery and recycling of reagents and
with ethylenediamine formed the tetramethyl ester 11 in 58 % solvents, and the final products are isolated by one single final
yield (Scheme 3).
purification.
One major downside to HMMF 2 and HMFA 3 is their dual
functionality, a well-known problem in polymerizations. To
circumvent this, most polymerization reactions use an A/B type
protocol with two components, each exposing one type of
functionality. Hence the interest into the dicarboxylic acid
Acknowledgements
The Villum Foundation is acknowledged for a block stipend for
MJP and EU for an Erasmus+ fellowship for AJ.
FDCA. However, reacting HMMF
2 sequentially with
ethylenediamine provided the diamide 12 in 26 % yield, which
fulfil the criteria exposing one type of functionality.
Conflicts of interest
MJP and CMP have filed a patent application containing part of
this publication PCT WO2019/170204 A1.
NMR studies
To gain insight into the transformation of gluconolactone into
HMMF, time-resolved NMR-spectroscopy was used to monitor Notes and references
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