High-Pressure-Mediated Thiourea-Organocatalyzed Asymmetric Michael Addition to (Hetero)aromatic Nitroolefins: Prediction of Reaction Parameters by PCP-SAFT Modelling

Article abstract of DOI:10.1002/cplu.202000364

Thiourea-organocatalyzed Michael additions of diethyl malonate to various heteroaromatic nitroolefins (13 examples) have been studied under high-pressure (up to 800 MPa) and ambient pressure conditions. High pressure was conducive to enhanced product yields by a factor of 2–12 at a given reaction time, high reaction rates (reaction times were decreased from 72–24 h down to 4–24 h) and high enantioselectivity. Elucidating the effects of solvents for maximizing reaction rates and yields has been carried out using the Perturbed-Chain Polar Statistical Associating Fluid Theory (PCP-SAFT), allowing for the first time a prediction of the kinetic profiles under high-hydrostatic-pressure conditions.

Full text of DOI:10.1002/cplu.202000364

A Multidisciplinary Journal Centering on Chemistry
Accepted Article
Title: High-Pressure-Mediated Thiourea-Organocatalyzed Asymmetric
Michael Addition to (Hetero)aromatic Nitroolefins: Prediction of
Reaction Parameters by PCP-SAFT Modelling
Authors: Thomas Weinbender, Michael Knierbein, Lukas Bittorf,
Christoph Held, Riko Siewert, Sergey P. Verevkin, Gabriele
Sadowski, and Oliver Reiser
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemPlusChem 10.1002/cplu.202000364
Link to VoR: https://doi.org/10.1002/cplu.202000364
01/2020

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High-Pressure-Mediated Thiourea-Organocatalyzed Asymmetric
Michael Addition to (Hetero)aromatic Nitroolefins: Prediction of
Reaction Parameters by PCP-SAFT Modelling
Thomas Weinbender[a]# & Michael Knierbein[b]#, Lukas Bittorf[b], Christoph Held[b], Riko Siewert[c],
Sergey P. Verevkin[c], Gabriele Sadowski*[b] and Oliver Reiser*[a]
[a]
[b]
[c]
Thomas Weinbender and Prof. Dr. Oliver Reiser
Institute of Organic Chemistry, University of Regensburg
Universitätsstr. 31, 93053 Regensburg, Germany
E-mail: oliver.reiser@chemie.uni-regensburg.de
Michael Knierbein, Lukas Bittorf, Dr. Christoph Held, Prof. Dr. Gabriele Sadowski
Laboratory of Thermodynamics, TU Dortmund University
Emil-Figge-Str. 70, 44227 Dortmund, Germany
E-mail: gabriele.sadowski@tu-dortmund.de
Riko Siewert and Prof. Dr. Sergey P. Verevkin
Department of Physical Chemistry, University of Rostock
Dr-Lorenz-Weg 1, 18059 Rostock, Germany
# Shared first authors
Supporting information for this article is given via a link at the end of the document.
reaction rates by Rothmund in 1896.[10] Since then, many groups
explored pressure effects for biochemical[11] and for chemical
reactions[12,13], whereas the pioneering study of Matsumoto and
Uchida[14] stands out as the first report of pressure effects on
asymmetric organocatalytic reactions. Apart from purely
academic interest, high-pressure applications have also gained
substantial industrial significance, e.g. in food processing.[15] High
pressure can improve reactions either indirectly by phase
transition (especially towards supercritical fluids) or directly by
volume effects. The latter typically occur in liquid-phase reactions
and are known to depend on solvent. Hence, we set out whether
the effects of solvent on reactions are altered at high pressure and
whether they can also be predicted by thermodynamic models.
Thus, in this study Perturbed-Chain Polar Statistical Associating
Fluid Theory (PCP-SAFT) was applied for the first time to an
organic reaction at very-high-pressure conditions of up to
800 MPa. PCP-SAFT was chosen for this purpose as it has been
successfully applied to compute the reacting agent’s interactions
in solution under ambient pressure and up to 2 MPa.[6]
Abstract: Thiourea-organocatalyzed Michael additions of diethyl
malonate to various heteroaromatic nitroolefins (13 examples) have
been studied under high-pressure (up to 800 MPa) and ambient
pressure conditions. High pressure was conducive to enhanced
product yields by a factor of 2-12 at a given reaction time, high
reaction rates (reaction times were decreased from 72-24 h down to
4-24 h) and high enantioselectivity. Elucidating the effects of solvents
for maximizing reaction rates and yields has been carried out using
the Perturbed-Chain Polar Statistical Associating Fluid Theory (PCP-
SAFT), allowing for the first time a prediction of the kinetic profiles
under high-hydrostatic-pressure conditions.
The efficiency of chemical reactions in terms of their rate, yield
and selectivity is influenced by several factors such as
temperature, pressure, concentration, and solvent. Therefore,
precise information and understanding of these factors are of
paramount importance for fine-tuning reaction conditions in order
to enhance rates and yields of the desired transformation.
Following the first report in 1862 of Berthelot et al.,[1] solvent
effects on chemical reactions were correlated with the solvent’s
polarity and were later explained by the solvation of the reacting
agents.[2] Several groups have studied the effects of solvent on
reaction rates and equilibria for chemical reactions[3] as well as for
biochemical reactions.[4] The solvent of a reaction has strong
effects on molecular interactions that can be quantified by
thermodynamic activities. Using thermodynamic models allows
for computing activities of the reacting agents in solvent and, thus,
predicting solvent effects on reaction. Different models have been
proven to correctly predict the influence of solvent on liquid-phase
reactions at atmospheric pressure.[5–7,8] However, the applicability
of these computational methods for very-high-pressure conditions
in liquid phases (100-800 MPa) has not been validated until today.
As a model system for this approach, we chose the Michael
addition of 1,3-dicarbonyl compounds to nitroolefins, being a well-
explored transformation, as the resulting nitroalkanes can easily
be transformed into different synthetically useful building blocks
harboring a wide variety of functional groups.[16] In 2003,
Takemoto and co-workers[17,18] developed an efficient method for
the highly enantio- and diastereoselective, conjugate addition of
1,3-dicarbonyl compounds to nitroolefins. In the presence of the
newly designed bifunctional thiourea catalyst 3, the trans-
formation proceeds at ambient pressure and room temperature,
however, prolonged reaction times and high catalyst loadings
(10 mol%, 12-72 h) are required.
The effects of high pressure in solution on the reaction equilibria
were first explored by Planck in 1887[9] and subsequently on
1
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access to thermodynamic activities and are therefore well-suited
tools that allow predicting solvent effects on reaction equilibria.[5,6]
Reaction kinetics are expressed in Equation (2) as change of the
product mole fraction with time.
ꢋꢌꢄꢅꢆꢇꢅꢈ
(2)
= ꢎꢏ ∙ ꢃꢆꢉꢊ ∙ ꢃꢄꢅꢈ − ꢎꢐꢏ ∙ ꢃꢄꢅꢆꢇꢅꢈ
ꢋꢍ
Here, ꢎꢏ and ꢎꢐꢏ denote the rate constants of the forth and back
reactions, respectively, that are directly linked to the
thermodynamic equilibrium constant according to Equation (3).
ꢎꢏ
Scheme 1: 1,4-conjugate addition of diethyl malonate (2) to N-, S- and O-
containing aromatic nitroolefins 1 catalyzed by thiourea derivative 3 at high
pressure.
ꢀ
ꢁꢂ
=
(3)
ꢎꢐꢏ
Owing to the activity-based expressions in Equation (1) and (2),
also the kinetic constants ꢎꢏ and ꢎꢐꢏ are independent of both,
concentrations and solvent. Based on these physical
relationships, thermodynamic models can be used to predict
solvent effects on reaction kinetics.[5,7]
Taking this precedent into account, we investigated whether a
rate acceleration can be achieved at high-pressure conditions
without erosion of enantioselectivity and moreover, if solvent
effects on reaction rate and yield at high pressure can be
predicted using Perturbed-Chain Polar Statistical Associating
Fluid Theory[19] (PCP-SAFT, Scheme 1). Michael-type reactions
belong to the class of bimolecular addition reactions, which are
known to be accelerated by high pressure due to a negative
volume of activation (in the range of −5 to −40 cm3 mol-1).[20,21] The
volume of activation is defined as the difference of the volume of
the transition state V‡ and the volume of the corresponding
The equilibrium constant ꢀ and the kinetic constants ꢎꢏ and ꢎꢐꢏ
ꢁꢂ
depend on pressure. These pressure effects on the reaction
equilibrium are quantified by the standard volume of reaction
∆ꢑꢒꢓ:
ꢕꢖꢗ ꢀ
−∆ꢑꢒꢓ
(
)
ꢁꢂ
=
ꢙ
ꢊ
ꢔ
(4)
ꢕꢘ
ꢚ ∙ ꢛ
reactants VA-B [13,20,22]
.
Applying transition-state theory allows quantifying pressure
effects on the reaction rate as a function of the volume of
activation:
Aiming to find the optimal solvent for the title reaction, we applied
PCP-SAFT to the Michael additions between diethyl malonate (2)
and trans-β-nitrostyrene (1a) (Scheme 2). The pure-component
thermodynamic data such as vapor pressure, density data, and
activity coefficients of the reacting agents were available in the
literature[23], except for Michael adduct 4a, which were therefore
determined experimentally. Based on these reaction-independent
data PCP-SAFT parameters were fitted (see Section 8 in
supporting information).
−∆ꢒ‡
( )
ꢕꢖꢗ ꢎ
=
ꢙ
ꢊ
ꢔ
(5)
ꢕꢘ
ꢚ ∙ ꢛ
In order to determine the equilibrium constant as well as the
kinetic constants, the reaction rate and the reaction-equilibrium
mole fractions for the addition of diethyl malonate (DEM, 2) to
trans-β-nitrostyrene (NST, 1a) were measured experimentally in
the solvent toluene at 0.1 MPa and at 440 MPa. Based on these
data, solvent effects on the reaction rate and equilibrium yield
were predicted via activity coefficients at 0.1 MPa as well as at
high-pressure conditions: First, the in-silico solvent screening was
performed at 0.1 MPa for solvents covering different solvent
classes.
Scheme 2: Model reaction of diethyl malonate (DEM, 2) and trans-β-
nitrostyrene (NST, 1a) in different solvents and at different pressures.
Thermodynamics limits the equilibrium-yield of chemical reactions,
depending on the reaction conditions. Further, reaction kinetics
depend on the solvent, which can be expressed via
thermodynamic activities of the reacting agents. These effect of
solvent and of pressure on yield and kinetics were investigated for
the reaction shown in Scheme 2. The equilibrium constant for this
reaction is given by Equation (1).
ꢃꢄꢅꢆꢇꢅꢈ
ꢀ
ꢁꢂ
=
(1)
ꢃꢆꢉꢊ ∙ ꢃꢄꢅꢈ
Equation (1) is based on thermodynamic activities of the reacting
agents 1a, 2 and 4a, which are defined as the product of the
equilibrium mole fractions and activity coefficients of the
respective component. ꢀ is a function of temperature and
pressure, however, it is independent of concentrations and of
solvents. Consequently, solvent effects on the reaction-
Figure 1: Mole fraction of the reaction product DENPEM plotted against
reaction time at 0.1 MPa and 25 °C in different solvents. Symbols: experimental
data (gray empty triangles: dichloromethane, blue triangles: toluene, red half-
filled triangles: n-hexane/toluene). Lines: PCP-SAFT predictions (gray:
dichloromethane, blue: toluene, solid red line: n-hexane/toluene, dashed red
line: n-hexane). Reaction conditions: Nitroolefin 1a (1.0 equiv), diethyl malonate
(DEM, 2) (2.0 equiv), catalyst 3 (1 mol%) in solvent (0.5 M, with respect to
nitroolefin 1a).
ꢁꢂ
equilibrium concentrations can be predicted for known ꢀ values
ꢁꢂ
based on the molecular interactions of the reacting agents with
the solvent. Thermodynamic models, e.g. PCP-SAFT, give
2
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The screening results showed that n-hexane had the strongest
beneficial effect on the reaction. That is, among the solvents
studied, PCP-SAFT predicted that n-hexane should lead to the
fastest reaction rate and also to the highest product yield at
reaction equilibrium. In contrast to that, it was predicted that
dichloromethane would have the most disadvantageous effect on
the reaction yield and kinetics (Figure 1, lines).
In order to validate the PCP-SAFT predictions, the kinetic profiles
were measured in different solvents (see Figure 1, triangles).
Dichloromethane, toluene and
a
solvent mixture of
n-hexane/toluene mixture (1:1, v/v) were chosen for this purpose.
The latter was necessary due to the insufficient solubility of the
reactants in pure n-hexane alone as solvent. The experimental
results were in excellent agreement with the PCP-SAFT
predictions, both with respect to kinetics but also reflected the
trend in yield at equilibrium for a given solvent. The data show that
PCP-SAFT is a meaningful tool for solvent screening using ther-
modynamic activities as proposed in equations (1) and (2).
Subsequently, the in-silico solvent screening was performed at
440 MPa to evaluate if PCP-SAFT can also be used to predict the
reactants and product activities in equations (1) and (2) at high
hydrostatic pressure (Figure 2).
Figure 3: Mole fraction of the reaction product DENPEM plotted against
reaction time at 25 °C in toluene. Symbols: experimental data at different
pressures (triangles: 0.1 MPa, diamonds: 440 MPa, squares: 800 MPa), lines:
PCP-SAFT predictions. Reaction conditions: Nitroolefin 1a (1.0 equiv), diethyl
malonate (DEM, 2) (2.0 equiv), catalyst 3 (1 mol%) in solvent (0.5 M, with
respect to nitroolefin 1a).
We next explored the scope of the Michael addition of diethyl
malonate (DEM, 2) and various heteroaromatic nitroolefins 1 at
440 MPa.[24] PCP-SAFT predicted DCM to be an inferior solvent,
which was consequently not chosen. Due to solubility reasons,
we had to compromise to run all reactions in toluene. The loading
of the catalyst 3 was reduced from the typically employed
10 mol%[17,18] to 1 mol%, and for comparison, ambient pressure
reactions under the same conditions were run in parallel. Under
these reaction conditions, the corresponding Michael adducts 4b-j
(Table 1, entries 1-9) were obtained at ambient pressure as well
as at high pressure in a clean reaction: lower yields obtained are
the results of an incomplete conversion of the reaction partners.
Gratifyingly, the high enantioselectivities obtained at ambient
pressures are mirrored at 440 MPa, indicating that pressure is not
inducing an uncatalyzed background reaction or altering the
catalyst-substrate arrangement necessary for asymmetric
induction. The benefit of the high-pressure conditions becomes
apparent when comparing yields at a given reaction time being
higher by a factor of 2-12, suggesting that the necessary, but
entropically disfavored ternary arrangement of nitroolefin 1, DEM
2 and catalyst 3 in the transition state has a negative volume of
activation.
Figure 2: Mole fraction of the reaction product DENPEM plotted against
reaction time at 440 MPa and 25 °C in different solvents. Symbols: experimental
data (gray empty diamonds: dichloromethane, blue diamonds: toluene, red half-
filled diamonds: n-hexane/toluene). Lines: PCP-SAFT predictions (gray:
dichloromethane, blue: toluene, solid red line: n-hexane/toluene, dashed red
line: n-hexane). Reaction conditions: Nitroolefin 1a (1.0 equiv), diethyl malonate
(DEM, 2) (2.0 equiv), catalyst 3 (1 mol%) in solvent (0.5 M, with respect to
nitroolefin 1a).
Table 1: Substrate scope of the Michael reaction of diethyl malonate (DEM, 2)
to different nitroolefins 1.
Also under high-pressure conditions, PCP-SAFT again predicts
the influence of solvent with respect to kinetics with high accuracy
(Figure 2, lines), being in strong agreement with the experimental
results (Figure 2, diamonds). Yet, PCP-SAFT slightly underesti-
mates the equilibrium endpoint in dichloromethane.
The approach followed in this study was finally evaluated at even
higher pressure (800 MPa), taken the reaction of 1a and 2 in
toluene as a representative example (Figure 3). PCP-SAFT
predicted a further rate acceleration but no significant change in
the equilibrium compared to performing the reaction at 440 MPa,
which was again verified by the experimental data obtained.
P
Entry
Ar
Time
Solvent
Yield[a]
4b, 50%
4b, 99%
4c, 20%
4c, 50%
4d, 28%
4d, 93%
4e, 18%
4e, 67%
ee[b]
(MPa)
94%
0.1
1
4 h
toluene
94%
440
0.1
[c]
2
3
4
24 h
24 h
24 h
toluene
toluene
toluene
[c]
440
0.1
92%
93%
86%
91%
440
0.1
440
3
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4f, 22%
4f, 79%
4g, 8%
4g, 80%
91%
91%
85%
85%
Acknowledgements
0.1
5
24 h
24 h
toluene
toluene
440
Financial support from the DFG Research Unit FOR 1979 (DFG-
SA700/23-1 and RE948/10-2) as well as from DFG in frame of the
priority program SPP 1708 “Material Synthesis Near Room
Temperature” (Project VE 265/14-1) and “Glycolysis:
thermodynamics and pathway predictions” (Project VE 265/12-1)
is gratefully acknowledged.
0.1
6
440
4h, 40%
4h, 83%
4i, 25%
4i, 32%
4j, 28%
4j, 67%
4k, 5%
4k, 62%
4l, 9%
91%
90%
88%
90%
87%
87%
60%
60%
70%
0.1
7
24 h
24 h
24 h
24 h
toluene
toluene
toluene
THF
440
0.1
8
440
Conflict of interest
0.1
9
440
The authors declare no conflict of interest.
0.1
10
440
Keywords: high-pressure chemistry • kinetics • Michael addition •
organocatalysis • thermodynamics
0.1
11
24 h
24 h
THF
THF
4l, 92%
4m, 10%
4m, 84%
70%
69%
69%
440
0.1
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10.1002/cplu.202000364
ChemPlusChem
COMMUNICATION
Entry for the Table of Contents
Hydrostatic
Pressure
Optimization of
reaction parameters
by PCP-SAFT
modelling
----- -- ----- --
-- -- ----- --- -
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12 examples @ 1 mol% catalyst,
up to 99% yield, up to 94% ee
PCP-SAFT modelling allows the prediction of optimal solvents at high hydrostatic pressure, as demonstrated for the asymmetric
addition of diethyl malonate to nitroolefins. Thus, reaction times (from 24-72 h down to 4-24 h) and catalyst loading (from 10 down to
1 mol%) could be considerably decreased without erosion of enantioselectivity. In addition, the application of high hydrostatic pressure
raised the product yield by a factor of 2-12.
Institute and/or researcher Twitter usernames: @reiser_group
6
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