A new selective route towards benzoic acid and derivatives from biomass-derived coumalic acid

Article abstract of DOI:10.1039/c7gc02041d

The selective production of aromatics from bio-based sources is an area of interest to expand the potential for greener alternatives to petroleum-derived chemicals. A scalable, efficient route to produce bio-based benzoates is demonstrated by carrying out heterogeneous catalytic reactions in non-toxic bio-based solvents at 180°C obtaining yields of up to 100 mol%. This approach extends the 2-pyrone (coumalic acid/methyl coumalate) Diels-Alder platform by utilizing a bioavailable co-reactant ethylene. A detailed investigation using a combination of kinetic experiments, DFT calculations, and multi-dimensional NMR was carried out to determine the detailed reaction network, and the corresponding activation energies for critical steps. Additionally, a series of experiments were conducted to maximize the yields by comparing different solvents, for both coumalic acid and methyl coumalate. Our results show that the choice of solvent was a significant factor when coumalic acid was the reactant (yields 71-92 mol%), while methyl coumalate was only minimally affected by the solvent (yields 95-100 mol%). Interestingly, the reaction network and kinetic analysis showed that the Diels-Alder reactions were not significantly different between coumalic acid and methyl coumalate, with the rate limiting step for both being decarboxylation with an activation barrier of 141 kJ mol^-1 compared to 77 kJ mol^-1 for the formation of the bicyclic adduct. Finally, the reaction cascade was found to be highly susceptible to by-product formation when as little as 5 vol% water was present in the solvent, which demonstrates that the absence of water is essential for high yielding benzoate production.

Full text of DOI:10.1039/c7gc02041d

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A new selective route towards benzoic acid and derivatives
from biomass-derived coumalic acid
eceived 00th January 20xx,
Accepted 00th January 20xx
Toni Pfennig,a,b Jack M. Carraher, a,b Ashwin Chemburkar, b,c Robert L. Johnson,a,b Austin
Anderson,a,b Jean-Philippe Tessonnier, a,b Matthew Neurockb,c and Brent H. Shanksa,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The selective production of aromatics from bio-based sources is an area of interest to expand the
potential for greener alternatives to petroleum-derived chemicals. A scalable, efficient route to
produce bio-based benzoates is demonstrated in up to 100 mol% yield by carrying out
heterogeneous catalytic reactions in non-toxic bio-based solvents at 180 °C. This approach extends
the 2-pyrone (coumalic acid/methyl coumalate) Diels-Alder platform by utilizing a bioavailable co-
reactant ethylene. A detailed investigation using a combination of kinetic experiments, DFT
calculations, and multi-dimensional NMR was carried out to determine the detailed reaction
network, and corresponding activation energies for critical steps. Additionally, a series of
experiments were conducted to maximize yields by comparing different solvents, for both coumalic
acid and methyl coumalate. Our results show that the choice of solvent was a significant factor when
coumalic acid was the reactant (yields 71-92 mol%), while methyl coumalate was only minimally
affected by the solvent (yields 95-100 mol%). Interestingly, the reaction network and kinetic analysis
showed that the Diels-Alder reactions were not significantly different between coumalic acid and
methyl coumalate, with the rate limiting step for both being decarboxylation with an activation
barrier of 141 kJ/mol compared to 77 kJ/mol for the formation of the bicyclic adduct. Lastly, the
reaction cascade was found to be highly susceptible to by-product formation when as little as 5 vol%
water was present in the solvent, which demonstrates that the absence of water is essential for high
yielding benzoate production.
products, so there is an incentive for the development of
selective processes to produce aromatics from bio-based
feedstocks.2, 6, 7
Introduction
The search for alternatives to fossil-based feedstocks has led
to rapid technological advances in the field of bio-renewable
chemicals creating many potential opportunities for materials
based on renewable carbon sources.1-6 Technologies to
produce aromatics from biomass-derived sources have
become targets of interest due to the expansion of shale gas
extraction, which has led to a relatively reduced availability of
Benzoic acid (BA) is a large scale commodity chemical with an
annual production of 638 kt8 currently produced by the partial
oxidation of toluene using a cobalt-manganese catalyst. BA is
used in a wide variety of applications including plasticizers,
preservatives, dyes/perfumes and as a feed to produce other
chemicals including phenol, caprolactam, and benzaldehyde.
Hence, a renewable pathway to produce BA would have broad
ranging impacts throughout the chemical value chain.
>C4 building blocks, including aromatics.2,
Aromatics are
6,
7
among the most important building blocks used by the
chemical industry for the production of a wide array of
One route to make bio-based BA is through a formic acid
mediated dehydration of quinic or shikimic acid produced via
fermentation. This process has several desirable features
including high yields for the chemical transformation of quinic
and shikimic acids into benzoic acid (up to 90%)2 and high
titers up to 60 g/L for quinic acid and 71 g/L shikimic acid
starting from the substrate glucose and using metabolically
engineered E. coli.9,10 Although, the primary drawback of this
approach is the intrinsically low maximum theoretical yield of
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the shikimic/quinic acid fermentation of 43 %, and to date the highest yields reported correspond to an
Journal Name
Scheme 1. The formation of benzoic acid starting from glucose fermentation to malic acid using acid catalysed dimerization to coumalic acid followed by a Diels-
Alder/decarboxylation/dehydrogenation reaction sequence to yield the desired aromatics
.
overall mol/mol yield of 23, and 27 %.10 This fermentation As part of the development of new biomass-derived and
bottleneck creates a significant problem for efficient utilization renewable processes, we report herein report on the synthesis
of the glucose feedstock. As a major fraction of the total cost of BA or MeBA from CMA or MeCMA, respectively, and
of the fermentation step is the glucose feedstock, its ethylene with very high yields of >91 mol-% utilizing a one-pot
inefficient utilization would have a significant negative impact sequential
Diels-Alder/decarboxylation/dehydrogenation
on the cost required to produce BA. reaction path. Considering the industrial importance of
An alternative pathway to bio-based BA and its methyl ester renewable BA, and the lack of available comprehensive
(MeBA) is through a furanic based platform utilizing a Diels- information about this alternative route in the literature, the
Alder reaction sequence of furan with methyl acrylate (or focus of this work is to provide detailed information of the
acrylic acid) showing moderate yields up to 51 mol%.7 reaction network, and intrinsic kinetics of individual reaction
Additionally Diels-Alder reactions of methyl furan with steps, which can be used to improve the overall process.
ethylene provides a viable pathway to produce bio-based
toluene, which could be utilized as a drop-in replacement for
Results and discussion
production of BA. Toluene selectivites, however, never
exceeded 46 mol% due to by-product formation.11
Improvement to this selectivity would require approaches to
improve the stability of the bio-based starting materials
thereby minimizing by-product formation.
The formation of benzoic acid from coumalic acid
Experiments were conducted to examine the BA and MeBA
yields obtained in several solvents using either CMA or
MeCMA, respectfully. The reaction between CMA and
ethylene in a nonpolar solvent, toluene, resulted in 71 mol%
yield of BA at 100 mol% CMA conversion (Table 1, Entry 1).
This outcome was similar to reported yields (76 %) for the
Another approach utilizing biological and chemical catalysis to
produce partially biomass-derived methyl benzoate (MeBA) is
based on the bio-based cyclic lactone methyl coumalate
(MeCMA). The formation of bio-based MeBA is accomplished
using a one-pot Diels-Alder/decarboxylation/dehydrogenation
reaction sequence between MeCMA and butyl vinyl ether with
excellent yields up to 89 mol%.12
Diels-Alder reaction of CMA with propylene in toluene,15,
16
which was thought to be due to CMA being sparingly soluble in
toluene leading to a substantial amount of CMA being
converted to unidentified by-products. Therefore, a solvent
was used to increase the solubility of CMA in order to improve
the overall reaction yield. We have previously shown that γ-
valerolactone (GVL) is a good polar aprotic solvent for this
reaction system due to structural similarities.16 The use of GVL
resulted in only a slightly higher BA yield of 76 mol% (Table 1,
Entry 2 and Figure S1). Still, a considerable amount (~24 mol%)
of the initial CMA was lost to by-product formation. Results
from previous studies suggested that CMA stability was limited
in GVL under reaction conditions due to the presence of
residual water in GVL.16 This hypothesis was tested by using
the polar aprotic solvents, 1,4-dioxane or acetone, resulting in
a significant improvement in the BA yield (Table 1, Entry 3 and
7). The reaction profile of the CMA consumption over time is
displayed in Figure S2. At 100 mol% CMA conversion the BA
selectivity was 91 mol% after a 4 hr reaction at 180 °C for both
solvents. From UPLC-PDA/QDa analysis, it was evident that
small amounts of (4) and (6) (see Scheme 2) were present.
Additionally, the formation of (4) was verified with NMR
analysis showing that roughly 6 mol% of (4) was formed (Table
1, Entry 3). At this reaction temperature, the dehydrogenation
reaction was extremely rapid as evident from the lack of an
Bio-based 2-pyrones can be produced by the fermentation of
14
glucose to form malic acid13,
followed by acid catalyzed
dimerization of malic acid to coumalic acid (Scheme 1).12 The
synthesis of 2-pyrone coumalic acid (CMA) via this route has
several attractive features. First, the atom efficiency of the
malic acid fermentation is highly favorable, with the capability
to even utilize
a CO2 fixating pathway allowing for a
theoretically yield of 2 moles of malate per mole of glucose
(Scheme 1).14 Second, efficient fermentation technology is
already developed for this route. For example, Novozymes
currently uses a metabolically engineered Aspergillus oryzae
capable of producing 1.38 mol malate per mol glucose at a
theoretical yield of 69 % and with high titers of 154 g/L, which
could be implemented on an industrial scale.13
An approach to improve the viability of the 2-pyrone
CMA/MeCMA platform is to utilize a less expensive dienophile
as the co-reactant. In theory ethylene should work in an
analogous fashion as butyl vinyl ether, but at a substantially
lower cost with nearly perfect atom efficiency. Additionally, as
the production of ethylene from bio-ethanol is commercially
demonstrated, a potential exists for 100 % bio-based process.3
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observable amount of the diene intermediate (3). This result shown that the dehydrogenation of
was consistent with previous studies16 in which we have
Table 1. Conversion of CMA/MeCMA with ethylene to BA/MeBA.
Conv.
(1) [mol%]
100
Selectivity
Entry
Reactant
CMA
Solvent
Toluene
GVL
(5) [mol%]
71
(3) [mol%]
[a]
(4) [mol%]
(6) [mol%]
[a]
1
2
3
4
5
6
7
[a]
[a]
CMA
100
76
[a]
[a]
CMA
1,4-Dioxane
Toluene
GVL
100
91±1.5
100±2
99±1
95±1
91
[a]
5.8 [d]
[b]
[a]
MeCMA
MeCMA
MeCMA
CMA
100
[b]
7±2 [c]
2±10 [c]
5±8 [c]
[a]
100
[b]
[b]
1,4-Dioxane
Acetone
100
2±7 [c]
[a]
2±3 [c]
[a]
100
Reaction conditions: Temperature: 180 °C; reaction time: 4 h, starting concentration: 10 mg ml-1 MeCMA/CMA (
500 psig ethylene, agitation: 400 rpm, Pd/C catalyst: 100 mg, [a] unable to quantify by-products with UPLC-PDA/QDa, [b] by-products not detected with GC-FID/MS,
[c] cyclohexadiene ( ) and cyclohexene ( ) intermediates were quantified based on methyl benzoate ( ) as reference due to the similar FID response factor. Double
Diels-Alder by-product was approximated using methyl benzoate as reference material, [d] quantified via
1H-NMR.
1) in 1,4-dioxane, reaction volume: 30 ml, pressure:
3
6
5
(
4)
(5)
the diene species proceeded significantly faster than the mol%). GC-MS analysis suggested that the remaining five
decarboxylation of the bicyclic intermediate, thereby percent was attributed to the unreacted methyl cyclohexa-1,5-
suggesting that the decarboxylation of the cycloadduct was diene carboxylate intermediate (3), the formation of methyl
the limiting step in the reaction network.16 Kinetic studies and cyclohex-1-ene carboxylate (6), and the double Diels-Alder
DFT calculations corroborate that decarboxylation is the rate (DDA) by-product (4), which was believed to be the outcome
limiting step, which will be discussed in the subsequent of a consecutive Diels-Alder reaction of (3) with ethylene
sections.
(Scheme 2). The concentration profile of (1), (2), (3), (4), (5)
Literature reports suggest that changing the functional group and (6) over time is displayed in Figure S17.The formation of
on the starting substrate could significantly influence the (2), (3), and (6) were validated via 2D-NMR COSY and HSQC
stability and reactivity towards Diels-Alder reactions.15,
17, 18
experiments (see Figure S1-S11) and will be explained in detail
This effect was demonstrated by Pacheco et al. using furanic in the following section.
dienes showing different product selectivities when various
oxidized versions of HMF were reacted with ethylene, which
Elucidating the reaction network
was purported to be the outcome of different functionalities
To elucidate where by-product formation was occurring,
of the oxygenated furans.17 Furthermore, Berard et al.
observed that the reaction of sorbic acid with ethylene
resulted in only low conversion (3 %), while using the ethyl
ester of sorbic acid instead, afforded a ~5 fold increase in
conversion (14 %).18 A similar phenomena was also observed
with 2-pyrones showing improved yields when reacting
MeCMA instead of CMA with propylene.15
experiments were performed to determine the reaction
network. Given the extensive work on Diels-Alder reactions of
2-pyrones12, 19-29 a reaction network was postulated, which is
depicted in (Scheme 2). The reaction of CMA/MeCMA with
ethylene follows a series of reactions that include Diels-Alder
adduct formation (2), decarboxylation of the adduct to yield
(3) and a Pd/C catalysed dehydrogenation reaction to form the
desired aromatics (5). In the presence of the Pd/C catalyst
additional minor products (4) and (6) were observed (Table 1,
Entry 6). The formation of (6) is likely the result of a Pd
catalysed hydrogenation of (3). The hydrogen needed for this
step was likely formed through dehydrogenation of (3) to (5).
Data shown in Figure S5 support the proposed reaction
network which is evident via the clear trend showing how the
conversion of (1) resulted in the formation of intermediates (2)
and (3) and small
Therefore, reactions were also run using MeCMA as the
reactant to determine if starting with the methyl ester of CMA
(MeCMA) would alter the reaction. Interestingly, the reaction
in toluene showed tremendous improvement in yield with 100
mol% selectivity after complete conversion (Table 1, Entry 4
and Figure S3). The higher selectivity with MeCMA was also
consistent with the hypothesis of the importance of the
solubility of the starting substrate in the 2-pyrone conversion.
Similarly, when the polar aprotic solvent GVL was used to
mediate the MeCMA and ethylene reaction, a conversion of
100 mol% with nearly 100 mol% MeBA selectivity (Table 1,
Entry 5 and Figure S4) was achieved. As the CMA conversion in
GVL only resulted in a selectivity of 76 mol% (Table 1, Entry 2
and Figure S1), the esterification of the carboxylate moiety
likely played a significant role in improving the selectivity.
Since CMA conversion to BA achieved the highest selectivity in
1,4-dioxane, we also performed the MeCMA conversion in 1,4-
dioxane. As shown in Table 1, Entry 6 reported only a slightly
better product selectivity (95 mol%) compared to CMA (91
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Journal Name
consumed. Based on these observations, it is evident that the
presence of water in the solvent has to be minimized to
maximize yields of the Diels-Alder reaction products.
(4)
Overall, GVL is an environmentally friendly renewable solvent
with many positive characteristics such as low toxicity and
biodegradability31-33 and, as such, is a desirable solvent for the
conversion of MeCMA to MeBA. However, when BA formation
was targeted, the effect of GVL on CMA stability was not as
high since 25 mol% of the starting material was lost most likely
through a concomitant degradation pathway (Table 1, Entry 2).
Moreover, the high boiling point of GVL would make the
product separation difficult. As such, a low boiling bio-based
acetone solvent could be utilized for increased BA selectivity of
91 mol% and would be an environmentally-advantaged
substitute.
O
OR
O
O
CO2
O
O
Pd/C
H2
(5)
O
O
OR
OR
(2)
O
OR
O
OR
(3)
(1)
R= H, CH3
(6)
O
OR
Scheme 2. Network for the reaction of CMA/MeCMA with ethylene.
amounts (<8 mol%) of (4) and (6) while (5) was formed.
Structural identification of the intermediates (2), (3) and by-
products (4) were determined by performing 1D and 2D NMR
experiments of the reaction products from the MeCMA
reaction with ethylene in the absence of catalyst to examine
the Diels-Alder/decarboxylation sequence (see Figure S6-S16
and Table S1-S3). These analyses confirmed the formation of
(2), (3) and (4).Without the catalyst, the by-product (6) was not
observed. Therefore, it appeared that the formation of (6) was
only realized when there was formation of hydrogen from
dehydrogenation of (4) to (5). Similar observations were made
when CMA was used as the starting substrate.
Table 2. Degradation of CMA and MeCMA in 1,4-dioxane.
CMA Conv.
Entry
Reactant
Solvent
(mol-%)
2516
10016
10
1
2
3
4
5
6
CMA
CMA
GVL
GVL + 5 vol% water
1,4-dioxane
CMA
MeCMA
CMA
1,4-dioxane
3
1,4-dioxane + 5 vol% water
1,4-dioxane + 5 vol% water
100
100
MeCMA
Reaction conditions: Temperature: 180 °C, reaction time:
concentration: 10 mg ml-1 MeCMA/CMA (
) in 1,4-dioxane, reaction volume: 30
ml, pressure: 500 psig N2, agitation: 400 rpm.
8 h, starting
1
Reaction kinetics of water mediated coumalic acid
breakdown
2-Pyrone degradation studies
Loss in selectivity due to MeCMA and CMA degradation was
examined. These reactions were performed in the absence of
ethylene or catalyst and the results are given in Table 2 and
Figures S17-S18. The results are consistent with a previous
study16 showing that CMA stability is compromised in GVL as
25 mol% of the starting material is degraded after 8 h at 180 °C
(Table 2, Entry 1). Identical tests in 1,4-dioxane showed that
both CMA and MeCMA were significantly more stable with
only 3 mol% of MeCMA and 10 mol% of CMA being converted
(Table 2, Entry 3 and 4). This observation demonstrated that
not only the solvent, but also the state of the starting
substrate (acid vs ester) impacts the stability of the 2-pyrone.
Given the observed selectivity loss (Table 1, Entry 2, 3 and 6) it
appears that CMA breakdown occurs concomitantly while
forming (2), thus, impacting the global yield of the desired
aromatic product.
The reaction kinetics and products from the water-mediated
breakdown of CMA were determined using NMR analysis with
deuterated dioxane-d8. Dioxane, an aprotic polar solvent, was
chosen as the ideal model system due to minimal by-product
formation and CMA/MeCMA degradation. Moreover, fully
deuterated dioxane-d8 was commercially available allowing
the kinetic studies to be performed in a closed system (high
pressure NMR tube from Wildmad-Labglass), which simplified
the product identification and quantification without further
sample workup.
Different D2O concentration (1-5 vol%) were added to the
reaction mixture to identify the CMA breakdown dependence
with respect to the water concentration. The main product
1
identified via H NMR after a 6.4 h reaction at 171 °C with 3
vol% D2O was 2-butenal yielding 14.5 mol% at 25.3 mol%
conversion (Figure S19). Minimal 2-butenal was observed with
1 vol% D2O and virtually none with 0 vol% D2O. The rate
constant for the CMA breakdown reaction, was obtained from
initial conversion data (no more than 20 mol% conversion). For
each D2O concentration experiment, a pseudo-first order
reaction in CMA was fit to the data. The changes with respect
to water in this regime were considered negligible as the
reactions were carried out in excess D2O (e.g. [D2O] was about
4 times [CMA]o at 1 vol% D2O). Fits of ln([CMA]t/[CMA]o) vs
time were linear and the observed rate constant (kobs) was
obtained from the slope. Interestingly, the plot of the pseudo-
first order rate constants kobs as a function of [D2O] revealed a
In a previous study, it was shown that the presence of small
amounts of water accelerated CMA degradation.16 A similar
water mediated breakdown was observed by Chia et al. when
the 2-pyrone, triacetic acid lactone (TAL), was exposed to
water and heat.30 They report that TAL undergoes ring-
opening in the presence of water but is stable in aprotic polar
solvents. To determine if the esterified 2-pyrone was more
resistant to breakdown due to water, MeCMA stability
experiments were also performed in 1,4-dioxane with 5 vol%
of water. (Table 2, Entry 6). These results show that
esterification did little to prevent breakdown in the presence
of water, since both CMA and MeCMA were entirely
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second order dependence on [D2O] with an independent
degradation pathway when no D2O was added (Figure 1).
Therefore, an overall rate law for CMA degradation was
expressed as:
O
O
O
H2
O
(1b)
(1)
(1a)
dGact = 74
dGrxn = 23
O
O
OH
OH
dGact = 126
dGrxn = 41
O
O
OH
O
OH
O
OH
ꢊ
ꢎ
ꢊ
ꢎꢒ
ꢀꢁꢂꢃ ꢄ ꢅꢆꢇꢈꢉ ꢋꢌꢍ ꢄ ꢅꢏꢆꢐ ꢑ ꢆꢒ ꢓꢒꢔ ꢕꢊꢋꢌꢍꢎ
(1)
O
O
dGact = 148
dGrxn = -70
+ H+
(1b)
(1c)
dGrxn = 41
- H+
OH
OH
O
The degradation of coumalic acid with and without the
presence of water can be captured by the paths shown in
Scheme 3. Further insights into the steps and mechanisms
responsible for the degradation of CMA to 2-butenal were
established by carrying out density functional theory
calculations (Scheme 4). The results suggest that water
initiated degradation of CMA proceeds via a nucleophilic
attack of water on the double bonds in CMA. The intermediate
formed (1a) subsequently undergoes ring-opening via keto-
O
O
O
O
OH
CO2
O
OH
O
dGact = 98
dGrxn = -71
O
(1c)
(1d)
dGrxn = 46
O
+ H+
- H+
O
O
OH
O
O
CO2
Scheme 4. CMA breakdown mechanism to 2-butenal in the presence of water
(Units in kJ/mol).
Diels-Alder reaction step (Table S4), it is evident that the CMA
degradation proceeds significantly slower (>100 times) than
the Diels-Alder addition step. Therefore, the observed loss in
product selectivity less likely originates from 2-pyrone
breakdown as opposed to by-product formation from
intermediates on the pathway to BA. This was further
supported by DFT calculations which predicted that the Gibbs
free energy of activation barrier for water addition (126
kJ/mol) was ~15 kJ/mol higher than ethylene addition (111
kJ/mol). The increase in the barrier is likely due to hydrogen
bonding stabilization of the reactant by water. Moreover, the
Gibbs free energy of reaction for ethylene addition (-79
kJ/mol) was calculated to be much more exothermic than that
for water addition (41 kJ/mol) suggesting that the Diels-Alder
adduct is thermodynamically favoured over CMA
decomposition. Therefore, it appears that the selectivity loss
of 24 mol% originates from intermediates (2) or (3) on the
pathway to BA when reacting CMA with ethylene in GVL (Table
1, Entry 2).
Figure 1. Plot of kobs as a function of [D2O]. Experimentally determined kobs are
represented as points and the line is a simulated fit to kobs = k1 + k2×[D2O]2 where
k1 = 1.03×10-4 min-1 and k2 = 1.51×10-4 M-2 min-1.
O
Products
k1
O
k2
Given that reactions performed in dry polar aprotic solvents
resulted in selectivities >90 mol% (with <10 mol% known by-
products (4) and (6)), it appears that residual water in GVL is
responsible for the selectivity loss likely from intermediate (2)
or (3). To test this hypothesis, reactions of (2) were performed
in situ (NMR tubes) in dioxane-d8 at 180 °C for 4 h in the
presence of 5 vol% D2O and without a catalyst. The results
from these experiments suggest that species in the 1H-NMR
spectra are primarily attributed to unidentified by-products
meaning that either (2) or (3) is further consumed to
unknowns in the presence of water. From this observation, it is
clearly critical to avoid water in the system to maximize
product yield by minimizing by-product formation from the
reactive intermediates.
H2O
+Products
O
HO
O
Scheme 3. General degradation of coumalic acid in the absence and presence of
water.
enol tautomerization to form a keto intermediate (1b). The
presence of water molecules facilitates this ring-opening by
providing a hydrogen bonding network to enable rapid proton
shuttling and a low energy paths for keto-enol tautomerization
and ring-opening. The intermediate (1b) has two carboxylic
groups, which can then undergo decarboxylation yielding 2-
butenal. This is very similar to
a previously reported
mechanism for water catalysed ring-opening and
decarboxylation of triacetic acid lactone.29
To further validate whether CMA breakdown is solely
responsible for the observed selectivity loss (Table 1, Entry 2, 3
and 6) or is a result of by-product formation on the pathway to
BA, the rate constants of CMA breakdown and CMA Diels-
Alder addition with ethylene were compared. Based on the
rate constants provided in Figure 1 and calculated from the
Reaction kinetics in the absence of catalyst
Kinetic measurements were performed in 1,4-dioxane which is
an excellent model solvent for detailed kinetic analyses as it
has
a low boiling point, results in minimal by-product
formation during reaction and is readily available commercially
in the fully deuterated dioxane-d8 form to perform
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complementary in situ NMR analysis. Choosing a solvent with a the Diels-Alder reaction of CMA (or MeCMA) (depicted in
low boiling point (compared to GVL) was critical for isolation, Figure 3A) was calculated based on the slope of the Arrhenius
identification and quantification (via NMR) of the temperature plot shown in Figure 3B and Figure S21. The reaction of CMA
sensitive reactant CMA (1) and intermediates (2) and (3) for and MeCMA with ethylene, resulted in a similar activation
both the Diels-Alder and decarboxylation reactions. Fully barrier of 77 kJ/mol. The experimental values were compared
resolved spectra of the formation of (2) and (3) are depicted in to the DFT-calculated barriers, which showed excellent
Figure 2 showing that the peak assignments and the method of agreement as the calculated enthalpic activation barriers were
quantification via NMR was unambiguous with carbon 67 and 68 kJ/mol, respectively. Therefore, the functionality
balances of >96 mol%.
Diels-Alder reaction step
The activation barrier associated with the formation of the
Diels-Alder (DA) adduct (2) was investigated by comparing the
rate of consumption of CMA at temperatures ranging from 90-
120 °C. Under these conditions, the cycloadduct was formed in
high yields without breakdown of CMA simplifying the
examination of the kinetics of this single step. The net rate of
cycloadduct formation can be written as the forward rate of
cycloaddition formation via Diels Alder reaction between CMA
and ethylene minus the rate of the back reaction involving the
retro Diels-Alder (rDA) of the cycloadduct. Assuming both of
these reactions are elementary, the net rate can be written as
that in equation 2.This equation can be simplified (Equation 3)
based on the experimental conditions since ethylene was in
~10x excess, which was validated by plots of
ln([CMA]t/[CMA]0) versus time all giving linear relationships Figure 2. NMR trace of the Diels-Alder and decarboxylation reaction.
(Figure S20 and S21( MeCMA)). The experimental results and
(acid or ester) had negligible influence on the 2-pyrone
reactivity (Table S4). Literature reports for the cycloaddition of
CMA derivatives and dienophiles with donating or withdrawing
substituents report activation barriers that range from 2834 to
11821 kJ/mol when using butyl vinyl ether or methyl acrylate,
respectively. Given the nature of an inverse electron demand
Diels-Alder cycloaddition, dienophiles with higher electron
density from donating substituents should react more readily
than dienophiles with electron withdrawing substituents.34, 35
With an activation barrier of 77 kJ/mol, the reaction of CMA
(MeCMA) and ethylene showed that the unactivated
dienophile resulted in intermediate Diels-Alder reactivity.
spectra (Figure 2) suggested that the rDA reaction had only a
minimal contribution as (2) can be obtained with yields of 98
mol%, which further showed that k1,DA >>k1,rDA and justified
the simplification of equation (3) into (4). DFT calculations also
fully support this since ethylene addition is predicted to be
highly exothermic (-127 kJ/mol).
ꢊ
ꢎꢊ
ꢎ
ꢊ
ꢎ
ꢅꢀꢁꢂꢃ ꢄ ꢆꢐ,ꢖꢃ ꢋꢌꢍ ꢗꢘꢙꢚꢛꢜꢝꢜ ꢅ ꢆꢐ,ꢞꢖꢃ ꢓꢍꢟ
(2)
(3)
ꢠ
ꢊ
ꢎ
ꢊ
ꢎ
ꢅꢀꢁꢂꢃ ꢄ ꢆꢐ,ꢖꢃ ꢋꢌꢍ ꢅ ꢆꢐ,ꢞꢖꢃ ꢓꢍꢟ
ꢅꢀꢁꢂꢃ ꢄ ꢆꢐꢠ ,ꢖꢃꢊꢋꢌꢍꢎ
(4)
The observed rate constants at temperatures in the range of
90-120 °C are given in Table S4. The activation energy (EA) for
6 | J. Name., 2012, 00, 1-3
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ARTICLE
Figure 3. Network kinetic analysis of coumalic acid reaction with ethylene. (A) Diels-Alder reaction followed by thermal CO2 extrusion. (B) Measured activation energy
of the Diels-Alder reaction of CMA and ethylene in 1,4-dioxane at temperatures between 90-120 °C. (C) DFT-calculated reaction energy profile diagram for the CMA
reaction with ethylene to the Diels-Alder adduct followed by decarboxylation to cyclohexa-1,5-diene carboxylic acid intermediate and CO2. (D) Measured activation
energy
of
the
thermal
decarboxylation
reaction
of
CMA-DAP
in
1,4-dioxane
at
temperatures
between
140-150
°C.
Figure 4. Bicyclic lactone decarboxylation. (A) Bond length (Å) of the cycloadduct of CMA and ethylene. (B) The asynchronic thermal decarboxylation mechanism of
the CMA/ethylene Diels-Alder adduct to cyclohexa-1,5-diene carboxylic acid. (
cyclohexa-1,5-diene carboxylic acid with a more advanced C-O bond cleavage.
C
) Bond length (Å) of the transition state of the cycloadduct CO2 extrusion towards the
Decarboxylation reaction step
The rate law for the decarboxylation step was assumed to
Examination of the bicyclic lactone (DAP) intermediate follow unimolecular first order kinetics (Equation 5).
decarboxylation was carried out at temperatures ranging from
140-160 °C. The reactant, intermediate (2), was prepared using
a 16 h reaction at 110 °C in 1,4-dioxane, which yielded almost
ꢅꢀꢖꢃꢡ ꢄ ꢆꢒ,ꢞꢖꢃꢊꢓꢍꢟꢎ
(5)
pure DAP (2) with only trace amounts of intermediate (3) and During the decarboxylation reactions, no accumulation of CMA
unreacted (1). Decarboxylation reactions were performed (or MeCMA) was observed at any of the temperatures tested,
using high pressure Wilmad-Labglass NMR tubes. The which provided additional support that k1,DA>>k1,rDA and helped
synthesized DAP (2) was dissolved in dioxane-d8 within the to validate the assumption that the equilibrium between CMA
tubes and the decarboxylation reactions as a function of time (or MeCMA) and DAP (2) was strongly shifted towards DAP
was measured via NMR (Figure 2).
formation. Plots of ln([DAP]t/[DAP]0) vs time resulted in linear
trends for all temperatures tested (Figure S22-23).
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The activation barriers for the decarboxylation of Diels-Alder reaction, giving evidence that the extrusion of CO2
CMA/MeCMA-derived (2) (142/133 kJ/mol) were calculated is the rate limiting step, which is in agreement with DFT
based on the slope of the Arrhenius plots (Figure 3D and results. The high activation barrier of the CO2 extrusion
Figure S22) using the observed rate constants (Table S5). DFT afforded the successful isolation of (2), granting access to
calculations predicted an enthalpic activation barrier of 148 bicyclic molecules in high yield and selectivity that could be
kJ/mol for both bicyclic lactones (CMA-DAP and MeCMA-DAP) utilized as synthetic starting substrates to synthesize a broad
as shown in Figure 3C. The DFT barriers agree well with those array of new compounds. For instance, we have shown that
from experiment. Abdullahi et al. reported that the diene intermediates (3) from bicyclic lactones (2) can be
decarboxylation of the bicyclic lactone formed from ethyl excessed through controlled thermal extrusion of CO2,
coumalate and butyl vinyl ether also result in a high activation providing access to novel molecules with dual-functionality.
barrier of 111 kJ/mol which is also in close agreement with the These insights can be leveraged to produce a plethora of
DFT results that give a CO2 extrusion barrier of 120 kJ/mol.36 products based on the coumalate conversion platform.
By comparing these results with our experimental activation
energy, it is evident that the decarboxylation step is
Experimental
significantly influenced by the degree of functionalization of
the bicyclic lactone intermediate. DFT energy mapping
calculations (Figure 4) further suggested a mechanism where
the CO2-bridge leaves in an asynchronous fashion with a
significantly elongated C-O bond in the transition state. As
such, the C-O bond cleavage occurs prior to C-C bond cleavage,
which is in agreement with observations from the literature.36
From this analysis we conclude that the rate-limiting step in
this reaction network is the decarboxylation reaction of (2).
We observed that all reactions run with catalyst led to only
minimal accumulation of (3), suggesting that the rate of (3)
dehydrogenation is much more rapid than the rate of (3)
formation. These results provide critical insight for what
should be targeted to further enhance the overall process.
Clearly, finding a catalyst to reduce the activation barrier of
the rate-limiting decarboxylation would allow for this reaction
to be carried out under milder reaction conditions, which
would improve overall yields by reducing the extent to which
by-products were formed.
Reagents and Materials
Coumalic acid (>97 %), γ-valerolactone (98 %), and 10 wt% Pd
on activated carbon were obtained from Sigma Aldrich.
Toluene (99.9 %), methanol (MS grade), water (MS grade),
acetic acid (MS grade) were obtained from Fischer Scientific.
Methyl coumalate (Acros Organics, 98 %), ethylene (99.5 %).
The deuterated solvents benzene-d6 (99.5 %), dioxane-d8
(99.5 %) were obtained from Cambridge Isotope Laboratories
Inc. All chemicals were used without further purification.
Apparatus and general procedure
Reaction kinetic measurements for the overall reaction of CMA
(or MeCMA) and ethylene were performed using a 50 ml micro
reactor system from Parr (4590 Series). Catalytic reactions
were carried out using a 10 wt% Pd/C catalyst, which was
added to the CMA (or MeCMA) containing solution before the
reactor was sealed and purged five times with nitrogen to
remove residual air. The reactor was then charged with
ethylene for approximately 30 min until saturation of ethylene
in the solvent was achieved. Subsequently, the system
Conclusions
In this work, we have shown that the Diels-Alder chemistry temperature was increased to the desired reaction condition
between CMA (or MeCMA) and ethylene can yield high with a heating rate of 10 K min-1. Samples were periodically
conversion and selectivity towards BA (or MeBA), which withdrawn from the reactor through a high pressure sampling
provides
a renewable alternative to current benzoate tip tube to follow the reaction progress over time. Samples
production. We were able to effectively elucidate the reaction were withdrawn once the reactor reached the desired reaction
network and revealed kinetic information such as activation temperature as the starting point reference. After the liquid
energies for the Diels-Alder and the decarboxylation step. phase reaction products were collected, the samples were
Although CMA stability studies revealed two independent filtered through a 0.2 micron syringe filter and analysed via
break down pathways as a function of water concentration NMR, UPLC-PDA/QDa and GC-FID/MS.
resulting in 2-butenal as the main by-product, the CMA The Diels-Alder reaction evaluation of CMA or MeCMA with
decomposition rate was significantly slower than the Diels- ethylene were performed at a temperature range between 90-
o
Alder cycloaddition indicating that CMA stability is not a 120 C without the presence of catalyst following the reaction
contributing factor. Instead, we have shown that the procedure described above. The solvent 1,4-dioxane was used
selectivity loss is a result of the formation of (4) and (6) and due to its superior solubility of both CMA and MeCMA.
that in the presence of water intermediates on the pathway to The decarboxylation reaction studies of the Diels-Alder
BA led to by-product generation. Thus, the avoidance of water product (DAP) decarboxylation were performed at
a
is critical to improve overall selectivity. Utilizing MeCMA gave temperature range between 140-160 oC, using high pressure
diminished by-product formation, consequently improving NMR tubes from Wilmad-Labglass. The reactant (2) for this
benzoate selectivity.
study was synthesized via Diels-Alder reaction of CMA (or
o
Kinetic studies revealed that the activation barrier of the MeCMA) and ethylene in 1,4-dioxane at 110 C for 16 h giving
decarboxylation reaction was considerably higher than for the high yield (>98 %). Through evaporation (using a stream of dry
8 | J. Name., 2012, 00, 1-3
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air) of the solvent, the reaction product (2) was obtained and ester version of (1), (3), (4), (5), and (6) were verified with NIST
subsequently dissolved in dioxane-d8. The solution was then MS spectral library.
transferred into the high-pressure NMR tubes. Before the tube
was sealed, 2.5 μl of an internal standard (dimethyl formamid, Computational
DMF) was added to perform quantitative analysis.
All of the calculations reported herein were performed using
38
density functional theory with the M062X37,
hybrid
Subsequently, the tubes were placed into a heated oil bath to
functional as implemented in Gaussian 0939. Optimizations
were performed with a 6-311G+(d,p)40 basis set on an ultrafine
grid and tight convergence criterion for force. Solvation was
modeled implicitly using the SMD model.41 Thermal
corrections and partition functions were calculated within
Gaussian at 298.15 K and subsequently used to calculate
enthalpy and Gibbs free energies of all species. A factor of RT
ln(24.46) was added to the free energies of all species to
account for change of reference state from 1 atm to 1 M in
solution. For degradation in water, additional corrections were
applied corresponding to 55.56 M concentration of the bulk
solvent.
initiate the decarboxylation reaction. The tubes were
periodically taken out of the oil bath cooled to room
1
temperature and the reaction products were analysed via H-
NMR. Running the reaction in a deuterated solvent allowed for
direct NMR sample analysis of the reaction products without
further sample workup.
Reaction kinetics measurements of water mediated CMA
breakdown was performed using different amounts of D2O
added to the solution comprising the deuterated solvent
dioxane-d8 and the reactant CMA. This reaction was
conducted using high pressure NMR tubes from Wilmad-
LabGlass that were loaded with the reaction solution, sealed
and heated without exposing the reaction solution to the
gaseous reactant ethylene to exclusively investigate the
stability of CMA under reaction conditions. Here, a 0.15 M
stock solution of coumalic acid and 0.025 M solution of DMSO2
(internal standard) was prepared in deuterated dioxane-d8. A
total volume of 300 μL of stock solution were added to the
high pressure NMR tubes (Wilmad-Labglass) and H2O or D2O
were added to yield 0-5 vol%. NMR tubes were sealed and
heated to 171 ˚C. Samples were removed and allowed to cool
to room temperature prior to collection of 1H NMR spectra.
To elucidate the reaction network of the MeCMA reaction with
ethylene, 2D-NMR structural assignments were carried out
Acknowledgements
We gratefully acknowledge funding from the National Science
Foundation under Award EEC-0813570, the Iowa State
University Chemical Instrument Facility staff members, and the
Minnesota Supercomputing Institute (MSI) at the University of
Minnesota. Furthermore, we would like to acknowledge all co-
workers at CBiRC for their support.
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