Decarboxylation of Δ9-tetrahydrocannabinol: Kinetics and molecular modeling

Article abstract of DOI:10.1016/j.molstruc.2010.11.061

Efficient tetrahydrocannabinol (Δ⁹-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ⁹-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ⁹- THC-acid naturally present in the plant into the psychoactive Δ⁹-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol^-1 and a pre-exponential factor of 3.7 × 10⁸ s^-1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ⁹- THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ⁹-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ⁹-THC from the plant.

Full text of DOI:10.1016/j.molstruc.2010.11.061

Journal of Molecular Structure 987 (2011) 67–73
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Decarboxylation of
D
9-tetrahydrocannabinol: Kinetics and molecular modeling
a
a
b
a,c
Helene Perrotin-Brunel a, , Wim Buijs , Jaap van Spronsen , Maaike J.E. van Roosmalen , Cor J. Peters
,
⇑
Rob Verpoorte d, Geert-Jan Witkamp a
a Laboratory for Process Equipment, Delft University of Technology, Leeghwaterstraat 44, 2628 CA Delft, The Netherlands
b FeyeCon D&I B.V., Rijnkade 17a, 1382 GS Weesp, The Netherlands
c The Petroleum Institute, P.O. Box 2533, Abu Dhabi, United Arab Emirates
d Division of Pharmacognosy, Section Metabolomics, Institute of Biology, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Efficient tetrahydrocannabinol (D
9-THC) production from cannabis is important for its medical applica-
Article history:
Received 22 July 2010
Received in revised form 19 November 2010
Accepted 19 November 2010
Available online 28 November 2010
tion and as basis for the development of production routes of other drugs from plants. This work presents
one of the steps of
9-THC production from cannabis plant material, the decarboxylation reaction,
transforming the
9-THC-acid naturally present in the plant into the psychoactive 9-THC. Results of
D
D
D
experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ molꢀ1 and
a pre-exponential factor of 3.7 ꢁ 108 sꢀ1
.
Keywords:
Using molecular modeling, two options were identified for an acid catalyzed b-keto acid type mecha-
Decarboxylation
Tetrahydrocannabinol
Cannabis
Kinetics
Molecular modeling
nism for the decarboxylation of
D
9-THC-acid. Each of these mechanisms might play a role, depending on
the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction.
Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill,
and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol
mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier
and the pre-exponential factor of the decarboxylation of
D
9-THC-acid. Evidence for this was found by
performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carbox-
ylic acids supporting this hypothesis. The presented approach is important for the development of a sus-
tainable production of
D
9-THC from the plant.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
waste; principally organic solvents such as heptane and isopropyl
ether. To improve this production process, reducing the number
of process steps, energy consumption, water consumption and
waste production, is crucially important. In a recent patent [4],
At present there is a growing interest in cannabis and its medic-
inal uses [1,2]. Cannabis contains more than 400 different ingredi-
ents, including at least 60 cannabinoids. The major active
both
D D
9-THCA and 9-THC are extracted into an organic solvent
component, called (ꢀ)-
D
9-tetrahydrocannabinol (
D
9-THC), does
followed by decarboxylation with aqueous base in the same sol-
vent. Despite the obvious improvement presented, many process
not occur at significant concentrations in the plant, but is formed
by decarboxylation of its corresponding acid upon heating.
steps are still needed to obtain pure
process would start from a solid plant source with the highest level
of
9-THCA, which then is extracted, decarboxylated, and purified
D
9-THC. In our view, the ideal
As described in a patent [3],
D D
9-THC acid ( 9-THCA) is obtained
from plant material by extraction into an aqueous solvent under
basic pH conditions. After acidification of aqueous fraction, the
aqueous fraction was extracted using a non-polar solvent, yielding
D
in the minimum number of steps, avoiding water, inorganic salts,
and organic solvents.
the acid in high purity in organic solvent.
D
9-THCA is then con-
As most cannabinoids in the plant, including D
9-THC, are pres-
verted to
D
9-THC which is further purified and combined with a
ent as their acid precursor, decarboxylation in the solid phase (i.e.
in the plant material) followed by extraction into a neutral solvent,
might be considered a viable option. Previous work on the decar-
boxylation of cannabinoids in the solid phase has been performed
in closed reactors [5,6], open reactors and on a glass surface [7].
However, little research has been performed to understand the
kinetics and the mechanism of solid state reaction in cannabis,
despite the fact that these are crucial for scale-up.
carrier for pharmaceutical use. The total process includes seven
different steps and four purification steps and requires a lot of
energy, while producing a lot of inorganic/organic contaminated
water. The contaminations are mainly inorganic salts and organic
⇑
Corresponding author. Tel.: +31 15 278 55 61; fax: +31 15 278 69 75.
E-mail address: h.perrotin-brunel@tudelft.nl (H. Perrotin-Brunel).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.11.061

68
H. Perrotin-Brunel et al. / Journal of Molecular Structure 987 (2011) 67–73
The first section of this paper presents experimental work to
on Total Energies, corrected for Zero Point Energy contributions
(ZPE-contributions).
determine the best reaction conditions (i.e. temperature and time)
for decarboxylation and its kinetics. Molecular modeling is then
used to support or justify proposed mechanism and kinetics
parameters for this solid state reaction in accordance with avail-
able literature and experimental data herein.
3. Results and discussion
3.1. Experimental results
Decarboxylation is a rather common chemical reaction in which
a carboxyl group splits off from a compound as carbon dioxide. The
2. Experimental
reaction for
by light or heat during e.g. storage or smoking. This reaction trans-
forms the acidic cannabinoids to their psychoactive forms
9-THC.
D
9-THCA shown schematically in Fig. 1, can be induced
2.1. Materials
D
Methanol was HPLC grade and was purchased from J.T. Baker
(Deventer, The Netherlands). Medical grade cannabis plant mate-
rial (female flower-tops) was obtained from Bureau Medicinale
Cannabis (The Hague, The Netherlands). It had a
of about 18%, and virtually no free
9-THC. The water content was
ꢂ3.6%. The standards of
9-THC (4.2 mg mLꢀ1 in methanol – ref
number 130-151205x) and
9-THCA (1.0 mg mLꢀ1 – ref number
In this article, only thermal decarboxylation will be considered. As
described above, the decarboxylation reaction has been studied in
the range of 90–140 °C. Under the experimental conditions, the
D
9-THCA content
highest yield to
D
9-THC was obtained at 110 °C and 110 min. Anal-
D
ysis of the data leads to the conclusion that this solid state reaction
surprisingly obeys a first order rate law. Raw kinetic data are pre-
sented in Fig. 2. Related k values are reported in Table 1. The cor-
responding ln k versus 1/T plots are shown in Fig. 3. This is a
straight line, described by the formula:
D
D
380-250407), with purity higher than 98%, were kindly donated
by PRISNA B.V.
E
ln k ¼ ln k0 ꢀ
RT
2.2. Method
from which E and k0 are determined to be 84.8 kJ molꢀ1 and
A sample of around 400 mg cannabis was blended in a mixer,
and heated at different temperatures in vacuum conditions for a
certain time. The temperature range studied was from 90 to
140 °C. To follow the reaction rate, a sample was taken every
5 min for the first hour and then every half an hour until the con-
3.7 ꢁ 108 sꢀ1 respectively.
3.2. Literature results
version of
D D
9-THCA to 9-THC was complete. Each solid sample
In the literature, only a few liquid phase thermal decarboxyl-
ation reactions of carboxylic acids, both aromatic as well as non-
aromatic, can be found [10–13]. Li and Brill reported experimental
activation energies for the first order decarboxylation of a series of
OH substituted benzoic acids under acidic conditions, ranging from
82 to 97 kJ molꢀ1 for 2,4,6-trihydroxybenzoic acid and 2,3-dihy-
droxybenzoic acid. Their k0-values range from 3.61 ꢁ 1010 sꢀ1 to
3.58 ꢁ 108 sꢀ1, the latter being similar to the one observed by us
[13].
was extracted with 50 mL methanol and sonicated for 15 min be-
fore being analysed with HPLC. In a series of extraction experi-
ments it was determined that the extraction process was
essentially complete. Calibration lines were determined for both
D
9-THCA and 9-THC. By this method the solid samples were
D
inherently corrected for weight loss (up to ꢂ30% at 140 °C) during
thermal treatment. Balances during the experiments, based on the
molalities of
D D
9-THCA and 9-THC, are >95%, indicating that the
In addition, by applying computational chemistry techniques
(B3LYP/6-31Gꢃ), Li and Brill found that intra-molecular decarbox-
ylation of the acids via a four membered ring transition state
yielded a very high activation barrier, thus suggesting that a real
first order process is very unlikely. The calculated activation barri-
ers for four-membered transition state for a series of caboxylic
acids ranged from 213 kJ molꢀ1 for 2,4-dihydroxybenzoic acid, to
225 kJ molꢀ1 for 2-hydroxybenzoic acid, and with a constant value
of 260 kJ molꢀ1 for 3-hydroxybenzoic acid, 3,5-dihydroxybenzoic
acid, and benzoic acid itself.
Li and Brill also found that the addition of one molecule of water
in the mechanism transformed the preferred transition state from
a four membered ring to a six membered ring with concomitant
reduction in the activation barrier to 130 kJ molꢀl, a value much
closer to the experimental values. However, these values are still
far too high, especially if it is realized that these barriers are based
on the ꢂ28 kJ molꢀl energetically unfavorable anti-conformer of
the acid [10–13] which acts as a highly reactive intermediate.
Recently, Chuchev and BelBruno [14] published a study on the
mechanism of the decarboxylation of ortho-substituted benzoic
acids, wherein they supported the work of Li and Brill that a single
water molecule is a potential model for an aqueous environment.
In addition, they concluded that the presence of a water molecule
forces the reaction through a keto-intermediate in the case of 2-
hydroxybenzoic-acid. The keto-intermediate then intramolecularly
decarboxylates to yield phenol and CO2. The overall process is illus-
trated in Fig. 4. However, their calculated activation barrier for the
decarboxylation of salicylic acid is ꢂ150 kJ molꢀ1, which is still
decarboxylation process itself proceeds with ꢂ100% selectivity.
Some skeletal rearrangements however cannot be excluded.
2.3. HPLC analyses
The HPLC profiles were acquired on a Chromapack HPLC system
consisting of an Isos pump, an injection valve and a UV–VIS detec-
tor (model 340 – Varian). The system is controlled by Galaxie
Chromatography software. The profiles were recorded at 228 nm,
as absorption by the solute is at its maximum at this wavelength.
The analytical column was a Vydac (Hesperia, CA) C18, type
218MS54 (4.6 ꢁ 250 mm2, 5
lm). The mobile phase consisted of
a mixture of methanol–water in a concentration gradient contain-
ing 25 mM of formic acid (pH 3). The methanol/water concentra-
tion ratio was linearly increased from 65% to 100% over 25 min,
and then kept constant for 3 min. Then the column was re-equili-
brated under initial conditions for 4 min, so the total running time
was 32 min. The flow rate was 1.5 mL minꢀ1 [8].
2.4. Molecular modeling
The Spartan ’06 package [9] was used for all calculations. All
structures were optimized using DFT B3LYP, level (6- 31Gꢃꢃ), start-
ing from PM3 optimized geometries. Transition states were identi-
fied and characterised using its unique imaginary vibrational
frequency or Internal Reaction Coordinate. Thermodynamical cor-
rections were applied; however activation energies were based

H. Perrotin-Brunel et al. / Journal of Molecular Structure 987 (2011) 67–73
69
Fig. 1. Model of the decarboxylation reaction of
D
9-THCA.
H
6
5
4
3
2
1
0
OH
O
O
413 K
403 K
393 K
383 K
373 K
O
OH
O
OH
H
CO2
+
Fig. 4. Decarboxylation of 2-hydroxybenzoic acid via the b-keto acid pathway.
and a low amount of water (3.6 w% = 2.0 mol kgꢀ1). The low value
for k0 might be explained by the fact that it is a solid state reaction,
or a catalytic process, leading to a pseudo-first order process. A
molecular modeling study has been performed to test this
hypothesis.
3.3. Molecular modeling results
D
9-THCA is a large molecule and therefore computationally
intensive with respect to memory and time. 2-Hydroxybenzoic
acid has been used as a suitable, simplest model for
9-THCA. Fur-
thermore both experimental and computational studies have been
performed with 2-hydroxybenzoic acid. To allow a meaningful
0
10
20
30
40
50
60
70
D
Time (min)
Fig. 2. Plot of ln[
temperatures.
D
9-THCA]0/[ 9-THCA] as
D a function of time at different
comparison between our work on
D
9-THCA, and the existing liter-
ature on 2-hydroxybenzoic acid, the different options were inves-
tigated for 2-hydroxybenzoic acid first.
Table 1
As a starting point we initially confirmed the computational
work of Li and Brill [13], and Chuchev and BelBruno [14] with
respect to the geometries of the transition states both for the direct
uncatalyzed and one water molecule catalyzed pathways. The
geometries look very similar, and important bond lengths are sim-
ilar within 0.01 Å.
Next, a mechanism was developed in which an organic acid was
used as a catalyst to assist in the decarboxylation reaction. This
allows the adaptation of the actual acid strength of the catalyst
or implicitly the pH of the environment, while avoiding computa-
tionally intensive calculations. A disadvantage might be that ther-
modynamic corrections become meaningless in most cases, except
for the ZPE. However, this is already the case, particularly for the
entropy contributions, as experiments were carried out in solid
phase, but not in the gas phase.
Values of the constant rate
temperatures.
k and of the regression coefficient at different
T (K)
103 k (sꢀ1
)
R2
413
403
393
383
373
6.7
3.8
2.1
1.1
0.5
0.9949
0.998
0.9958
0.982
0.9426
To obtain a good computational model catalyst for the decar-
boxylation reaction, several acids were investigated and compared
in Table 2, for the case of 2-hydroxybenzoic acid. For the decarbox-
ylation of
D
9-THCA catalysis the work was limited to formic acid
and trifluoroacetic acid. As can be seen in Table 2, the differences
in activation energies for 2-hydroxybenzoic acid in both pathways
with acetic acid, formic acid and trifluoroacetic acid are within
5 kJ molꢀ1. Thus the acid strength of the catalyst does not seem
to be a large discriminator in the calculations. Using formic acid
as a model catalyst, two different transition states, shown in
Fig. 5, could be located, both leading to the previously mentioned
keto-intermediate.
Fig. 3. ln k as a function of 1/T – Arrhenius’ law.
significantly too high. Hence, it should be noted that the observed
first order reaction can only be understood in terms of a pseudo-
first order reaction on a molecular level.
The structure of the transition state with a value of 93 kJ molꢀ1
resembles the geometry of the transition state proposed by
Chuchev and BelBruno and illustrated in Fig. 6 [14], with the
hydrogen of the acid of the substrate in anti-position. Churchev
For
phase with a large amount of
D
9-THCA in Cannabis Flos, the reaction takes place in a solid
D
9-THCA (18 w% = 0.57 mol kgꢀ1
)

70
H. Perrotin-Brunel et al. / Journal of Molecular Structure 987 (2011) 67–73
Table 2
et al. reaction pathway presented in [14], shows in fact a three pro-
ton transfer process, starting with protonation of the -C next to
Calculated activation energies of salicylic acid and
catalyst.
D
9-THCA with different acids as
a
the COOH-group, followed by the transfer of the proton in anti-po-
sition of the substrate COOH-group to the catalyst, and finally pro-
ton transfer of the phenol group to the carboxylate group of the
substrate. This mechanism will be referred to as indirect keto-enol
pathway.
Acid catalyst
Ea 2-hydroxybenzoic Ea 2-hydroxybenzoic
acid (kJ molꢀ1 acid (kJ molꢀ1
E
a D9-THCA
(kJ molꢀ1
)
)
)
Direct keto-enol
Indirect keto-enol
Direct keto-
enol
Acetic acid
Formic acid
Trifluoroacetic 100
acid
105
104
89
Not
The pathway with an activation barrier of 104 kJ molꢀ1 resem-
bles a direct keto-enol pathway. Fig. 7 shows the IRC-plots of the
formation of the keto-isomer of 2-hydroxybenzoic acid with formic
and trifluoroacetic acid as catalyst via the keto-enol pathway. The
determined
81, 58indirect
71
93
88
ν = i764 cm-1
C-H = 1.266 Å
ν = i1280 cm-1
C-H = 1.306 Å
CO-HO = 1.334 Å
ArO-H = 1.254 Å
OH-O=C = 1.163 Å
Ea = 104 kJ mol-1
Ea = 93 kJ mol-1
Fig. 5. The two transition states for formic acid catalyzed decarboxylation of 2-hydroxybenzoic acid.
Fig. 6. Indirect keto-enol pathway according to Churchev and BelBruno [14]; structural details of the keto-enol transition state are listed below.

H. Perrotin-Brunel et al. / Journal of Molecular Structure 987 (2011) 67–73
71
distance between the phenolic O–H atoms was taken as a measure
for the reaction coordinate. The reaction starts from the phenol and
ends with the keto-isomer. The geometries of the transition states
change only slightly.
For
for the catalyzed direct keto-enol route with formic acid
in catechol (weak acid), and 92 kJ molꢀ1 as an average of two dis-
tinct values: 91.4 kJ molꢀ1 in an HCl-solution of pH = 1.3, and
92.7 kJ molꢀ1 in an HCl-solution of pH = 2.7, thus showing a
marked influence of both solvent and pH. A similar observation
can be made for 2,6-dihydroxybenzoic acid. Here three values are
reported: 111.1 kJ molꢀ1 in catechol, 92.7 kJ molꢀ1 at pH = 1.4
and 100.7 kJ molꢀ1 at pH = 2.0. Again, the dependence of the exper-
imental activation energy on solvent type and pH is remarkable.
As can be seen from Table 3, the lowest value for the activation
energy of 2-hydroxybenzoic acid, obtained experimentally in a
strongly acidic environment, corresponds computationally with
the indirect keto-enol pathway yielding an activation barrier of
92 kJ molꢀ1. The latter requires the presence of a proton (in anti-
position) of the substrate acid function. Under strongly acidic con-
ditions this requirement is fulfilled. Under less acidic conditions
this is not the case, and then the direct keto-enol pathway comes
D
9-THCA decarboxylation, the computed activation barrier
(81 kJ molꢀ1
) compared well with the experimental value
(85 kJ molꢀ1). However, the computed activation barriers for tri-
fluoroacetic acid (71 kJ molꢀ1) and the indirect keto-enol pathway
(58 kJ molꢀ1) are much lower than the experimental values. Fig. 8
shows the IRC and the transition state of the first step of the for-
mic acid catalyzed decarboxylation of
D
9-THCA. Fig. 9 shows the
overall reaction energy profile of the entire reaction, including
the second step, the intra-molecular proton transfer of the acid
to the keto-function.
into play, resulting in an activation barrier of 104 kJ molꢀ1
.
3.4. Discussion
The case of 2,6-dihydroxybenzoic acid is more complicated. It is
a significantly stronger acid than 2-hydroxybenzoic acid, so the
requirements for the indirect keto-enol pathway are no longer ful-
filled in an HCl-solution of pH = 1.4. The direct keto-enol pathway
leads to an activation barrier of 92 kJ molꢀ1, close to the experi-
mental value. The next experimental value of 101 kJ molꢀ1 at
pH = 2.0, can be understood as a loss of coordination of one of
the phenolic groups to the adjacent acid group due to the higher
pH. Calculations for these systems lead to an activation barrier of
102 kJ molꢀ1. With respect of the experimental work in catechol,
computations with either formic acid or catechol itself as an acid
catalyst, the indirect keto-enol pathway leads to an activation bar-
rier of 114 kJ molꢀ1 close to the experimental value. The indirect
pathway here is rationalized by the fact that 2,6-dihydroxybenzoic
acid in catechol will not dissociate. Furthermore, it shows that for-
mic acid can even act as a reasonable model for catechol.
Aliphatic and aromatic acids are usually present [15] as plant
constituents in cannabis. Inspired by the results of molecular mod-
eling, the presence of acids other than
D
9-THCA was verified exper-
imentally. A sample of around 400 mg of cannabis was blended in a
mixer, and extracted with distilled water after sonication for
10 min. The pH of the resulting aqueous solution was 6.1. A sample
of 1600 mg of cannabis, yielded an aqueous solution with pH = 5.5.
Under these conditions,
D
9-THCA does not dissolve into water but
short chain carboxylic acids do. Thus, acetic acid or formic acid not
only can be used as a model for acid catalysis, but might be a real-
istic case from an experimental point of view as well. Furthermore,
it offers a plausible explanation for the low value of k0, as the
experimental acidity is low.
To get a better overall understanding of the two different mech-
anistic options in acid catalyzed decarboxylation, Table 3 shows
the comparison of experimental values with computational results
obtained for a series of 2-hydroxybenzoic acids with formic acid as
catalyst. Experimental data are scarce but, fortunately, well docu-
mented [13,14]. For the decarboxylation of 2-hydroxybenzoic acid
two experimental activation energies are reported: 97.4 kJ molꢀ1
From the computational results obtained it would be tempting
to speculate what the activation barrier would become if strongly
acidic conditions were applied in the case of
D
9-THCA. However,
the application of strong acids, containing halogens or sulfur would
not contribute to the sustainability of the overall process.
Fig. 7. IRC’s of the formation of the keto-isomer of 2-hydroxybenzoic acid decarboxylation catalyzed by trifluoroacetic acid and formic acid via the direct keto-enol pathway.

72
H. Perrotin-Brunel et al. / Journal of Molecular Structure 987 (2011) 67–73
Fig. 8. IRC of
D
9-THCA decarboxylation catalyzed by formic acid via the direct keto-enol pathway.
Fig. 9. Energy profile of formic acid catalyzed decarboxylation of
D
9-THCA.
Table 3
catalysis by an acid, put forward by Li and Brill, and Churchev
and Belbruno was extended, and a new direct keto-enol route
was found. This route offers the best explanation for the experi-
Activation energies of substituted 2-hydroxybenzoic acids with formic acid as
catalyst.
Compound
Ea-exp (kJ molꢀ1
)
Ea-comp (kJ molꢀ1
)
mental results obtained with
D
9-THCA, both with respect to the
2-Hydroxybenzoic acid
97 [10], 92 [13]
111 [10], 101, 92 [13]
85
104a, 92b
114b, 102c, 92a,
81a
activation barrier and the pre-exponential factor. However both
routes can play a role, depending on the exact experimental condi-
tions, as an analysis of available experimental and computational
results shows.
2,6-Dihydroxybenzoic acid
D
9-THCA
a
b
c
Direct keto-enol pathway.
Indirect keto-enol pathway.
Direct keto-enol pathway with one phenolic OH group not forming an hydrogen
bridge with the acid function.
Acknowledgment
Financial support by STW (Project No. LFA 7426) is gratefully
acknowledged. The authors would also like to thank Pablo Cabeza
Perez for his experimental contribution to this work.
4. Conclusions
Decarboxylation of
D
9-THCA can be described as a pseudo-first
order reaction catalyzed by formic acid, as a model for short chain
organic acids present in the flowers of the cannabis plant. The pres-
ence of such acids was verified in a series of extraction experi-
ments. Also, the computational idea of catalysis by water to
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