Combined Role of the Asymmetric Counteranion-Directed Catalysis (ACDC) and Ionic Liquid Effect for the Enantioselective Biginelli Multicomponent Reaction

Article abstract of DOI:10.1021/acs.joc.8b02101

This work describes new chiral task-specific ionic liquids bearing chiral anions as the catalysts for the enantioselective multicomponent Biginelli reaction. For the first time, the combined role of asymmetric counteranion-directed catalysis (ACDC) and io

Full text of DOI:10.1021/acs.joc.8b02101

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Article
The Combined Role of Asymmetric Counteranion-
Directed Catalysis (ACDC) and Ionic Liquid Effect for
the Enantioselective Biginelli Multicomponent Reaction
Haline G. O. Alvim, Danielle Lobo Justo Pinheiro, Valter Henrique Carvalho-Silva, Mariana Fioramonte,
Fabio Cesar Gozzo, Wender Alves da Silva, Giovanni Wilson Amarante, and Brenno A. D. Neto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02101 • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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The Combined Role of Asymmetric Counteranion-Directed Catalysis (ACDC) and
Ionic Liquid Effect for the Enantioselective Biginelli Multicomponent Reaction
Haline G. O. Alvim,a Danielle L. J. Pinheiro,b Valter H. CarvalhoꢀSilva,c Mariana Fioramonte,d Fabio C.
Gozzo,d Wender A. da Silva,a Giovanni W. Amarante,b* and Brenno A. D. Neto,*a
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a
Laboratory of Medicinal and Technological Chemistry, University of Brasília, Chemistry Institute
(IQꢀUnB), Campus Universitário Darcy Ribeiro, CEP 70904ꢀ970 ꢀ P.O.Box 4478ꢀBrasília, DF, Brazil.
Phone: (+) 55 61 31073867. brenno.ipi@gmail.com
b
c
d
Chemistry Department, Federal University of Juiz de Fora Rua José Lourenço Kelmer, s/n, Campus
Universitário São Pedro, 36036ꢀ900, Juiz de Fora, MG (Brazil). giovanni.amarante@ufjf.edu.br
Grupo de Química Teórica e Estrutural de Anápolis, Unidade Universitária de Ciências Exatas e
Tecnológicas, Universidade Estadual de Goiás, P.O. Box 459, CEP 75001ꢀ970, Anápolis, GO, Brazil.
Institute of Chemistry, University of Campinas (Unicamp), Campinas, SP, Brazil.
Abstract. The current manuscript describes new chiral taskꢀspecific ionic liquids bearing chiral anions as
the catalysts for the enantioselective multicomponent Biginelli reaction. For the first time, the combined
role of asymmetric counteranionꢀdirected catalysis (ACDC) and ionic liquid effect (ILE) for the chiral
induction in the Biginelli multicomponent reaction is demonstrated. The chiral induction arises from a
supramolecular aggregate where the anion and the cation of the catalyst are alongside with a key cationic
intermediate of the reaction. Each component of the new catalyst had a vital role for the chiral induction
success. The mechanism of an asymmetric version of this multicomponent reaction is in addition
demonstrated for the first time using electrospray (tandem) mass spectrometry – ESIꢀMS(/MS). The
analyses indicated the reaction takes place preferentially and exclusively through the iminium
mechanism. Unprecedented supramolecular aggregates were detected by ESIꢀMS and characterized by
ESIꢀMS/MS. No intermediate of the other two possible reactions pathways could be detected. Theoretical
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calculations shed light on the transition state of the transformation during the key step of the chiral
induction and helped to elucidate the roles of the chiral anion (ACDC contribution) and of the
imidazoliumꢀcontaining nonꢀchiral cation derivative (ILE contribution) in the molecular reaction process.
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Key words. Catalysis, multicomponent reaction, ionic liquids, asymmetric counteranionꢀdirected
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catalysis (ACDC), ESIꢀMS, mechanism, chiral induction, Biginelli, DFT, theoretical calculations.
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Introduction
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Asymmetric synthetic methodologies are vital to the development of several natural and
nonꢀnatural bioactive compounds and have been used in several total syntheses.1 There
are however many achievements to be reached yet and several reactions still do not
show satisfactory chiral induction control. Several recently published reviews2ꢀ5 show
insights and new catalytic methodologies to overcome drawbacks such as poor
enantioselectivities. Among modern asymmetric catalytic approaches, asymmetric
counteranionꢀdirected catalysis (ACDC), is among the most promising strategies.6ꢀ9 B.
List defined ACDC as “asymmetric counteranion-directed catalysis refers to the
induction of enantioselectivity in a reaction proceeding through a cationic intermediate
by means of ion pairing with a chiral, enantiomerically pure anion provided by the
catalyst”.10 Since the first years of this century,10 attempts to make ACDC a feasible
methodology and a more general concept are observed. Success in several reactions
were reached by many groups using this relative new concept.11ꢀ17
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Just like ACDC, ionic liquids (ILs) are a class of ionic fluids that emerged at the
dawn of this century,18ꢀ20 although we know these materials for more than a century. ILs
are today also used in a plethora of industrial processes.21 Chiral ILs (CILs) were
reported22 for the first time in 1999 and a representative chiral induction through ionꢀ
pairing effects were later described by Wasserscheid and coworkers.23 CILs are
currently used for asymmetric induction in catalysis,24ꢀ26 but the ionic liquid effect
(ILE), that is, their ability of ionꢀpairing and larger supramolecular aggregates
formation,27 is poorly explored. Because of the positive ILE, many reactions with
charged intermediates had their yields and/or selectivities improved.28ꢀ33 ILs are indeed
capable of stabilizing reactive intermediates and transition states as argued by us34 and
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others.35 Ion pairs formation is indeed a key feature for the success of many reactions
conducted in the presence of ILꢀbased structures.36
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Multicomponent reactions (MCRs) are capable of addressing both diversity and
complexity in organic synthesis in a single high atom economy chemical step.37 MCRs
have been for instance employed as the key step in the synthesis of natural products.38
As reviewed,39ꢀ41 the chiral induction in MCRs may be a hard task42 and not always
satisfactory selectivities are achieved during the reaction. Approaches such as chiral
catalysts, asymmetric organocatalysis, chiral reagents and others are used to improve
both diastereoꢀ and enantioselectivities. Among MCRs, the Biginelli reaction43 allows
for the straight access of biologically active DHPM (3,4ꢀdihydropyrimidinꢀ2(1H)ꢀone or
ꢀthione) derivatives.44 For some, the Biginelli reaction is still considered the most
important MCR.45 In 2005, Zhu and coworkers46 used a new chiral ytterbium catalyst
for the first description of an enantioselective version of the Biginelli reaction.
Phosphoric acids derivatives were later used with relative success.47 Attempts to
improve yields, selectivities and to shorten reaction times were also described48ꢀ53 and
revised.54 Some major drawbacks are however still noted for this reaction. Low yields,
long reaction times (typically 7 days), low ee, catalysts’ synthesis with several synthetic
steps, and others are still drawbacks of the enantioselective Biginelli MCR.
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Based on our interest in the Biginelli reaction,55,56 we envisaged the synthesis of
a new CILs aiming at a combined effect of both ACDC and of ILE. The new catalysts
were therefore designed bearing in mind two specific components i.e. a chiral anion and
a Bronsted acid appended in the imidazolium cation. Herein, we wish to disclose our
results and show there is indeed a combined role of these two main effects for the
enantioselective version of the Biginelli MCR. The reaction mechanism was fully
investigated by ESI(+)ꢀMS(/MS) showing there is a preferable reaction pathway under
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the catalytic condition developed. The detection of unprecedented supramolecular
species allowed for DFT calculations to shed light on the possible transition states
during the chiral induction step.
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Results and Discussion
The designed chiral taskꢀspecific ILs were synthesized in quantitative yields by melting
ZMSI (a known zwitterionic compound obtained by treating sultone with 1ꢀ
methylimidazole) in the presence the respective chiral phosphoric acids (commercially
available) in a sealed Schlenk tube under inert atmosphere (Scheme 1).
Scheme 1. Synthesis of the chiral taskꢀspecific ionic liquids used in this work. *Aꢀ refers to the chiral
phosphate anion from the tested acids.
These catalysts were designed to have a Bronsted acid moiety appended to the
imidazolium cation while the anion would be from a chiral phosphoric acid derivative.
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Bronsted acid taskꢀspecific ILs acids display important physicochemical properties such
as strong acid character, as already reviewed.57 These salts are typically applied as
catalysts in Bronsted acid catalyzed reactions.58ꢀ60 Taskꢀspecific ILs are for long indeed
known as efficient catalysts.61 Enantiomerically pure phosphates and their derivatives
are currently used with success to induce chirality in many different reactions being
therefore a promising strategy toward chiral induction.62ꢀ69 To the best of our
knowledge, the combination of a chiral phosphates and taskꢀspecific ILs to afford new
CILs has not been explored yet. The promising combination has in principle the
advantage of a Bronsted acid catalysis in a chiral environment provided from the anion
of the catalyst.
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As will be discussed in due course, MSI.TRIP returned the best results in the
enantioselective MCR investigated and, therefore, additional characterizations by MS
analyses (positive and negative ion modes) were performed (Figure S1 in the
Supporting Information file). After treating the neutral ZMSI structure (blind to MS
analysis) with the chiral TRIP acid, it is noted the presence of an intense signal
attributed to the MSI cation of m/z 205, which could be isolated in the gas phase and
submitted to its structural MS/MS characterization. This feature pointed firmly to the
protonation of the ZMSI in the presence of TRIP. The analysis was repeated but in the
negative ion mode and a very intense signal of m/z 751 could be attributed to the chiral
anion from the TRIP acid. It also indicated an efficient H transfer from the chiral
phosphoric acid derivative to the ZMSI structure affording an intense anion signal.
After the proper characterizations, the three chiral catalysts were initially tested
in the model Biginelli reaction, that is, a reaction using urea, benzaldehyde and ethyl
acetoacetate as the reagents. All reactions were carried out under solventless conditions
using equimolar quantities of the reagents (0.2 mmol), at 30 °C and for 72 h. Initial
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attempts using 1 and 5 mol% of the CILs catalysts gave reasonable yields (62ꢀ86%)
except for MSI.VAPOL (99%). Switching the catalysts loadings to 10 mol% under
standard reaction conditions, the desired Biginelli adduct could be obtained in almost
quantitative yields (99%). MSI.VAPOL gave however unsuccessful enantiomeric
excess (ee 12%). Switching the catalyst backbone to MSI.H8Binol, a great
improvement in terms of enantioselectivity was observed (ee 70%). The extremely
bulky MSI.TRIP finally gave a nearly perfect enantioselectivity control (ee 99%). The
best reaction condition showed to be therefore 10 mol% of MSI.TRIP under solventless
conditions at 30 °C.
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In Table 1 it is summarized some chiral catalysts available in the literature, their
reactions conditions and results in comparison with our best catalytic system. Some
control experiments were also conducted using 10 mol% of a catalyst, 30 °C and 72 h of
reaction aiming at depicting whether there is a combined role of the Bronsted acid
cation of the catalyst and the chiral anion of MSI.TRIP. The reaction conducted with
ZMSI under these conditions returned the Biginelli adduct in only 47% (racemic) after
72 hours of reaction. Using TRIP itself as the catalyst, the product was obtained in 41%
of yield and 28% of ee. The sodium salt from TRIP was also tested and the DHPM was
isolated in only 17% of yield and a nearly zero ee was observed. The result with the
sodiated chiral catalyst is somehow expected since protonation (acidic medium) is
required to further the Biginelli reaction. In addition, with no protonated (cationic)
intermediate, the ion pair with the chiral anion will not constitute and, as a consequence,
no chiral induction is expected. These results already indicated the importance of all
components of the designed catalyst (MSI.TRIP) to the enantioselective Biginelli
reaction and their roles will be discussed in due course. We are aware, however, that
different chiral phosphoric acids may afford the desired DHPM with higher yields and
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ee but under completely different conditions50,52 (see Table 1). The use of TRIP as the
chiral inductor for Biginelli condensations, as described elsewhere,70 returned only
moderated yields and ee, as it is observed in this work.
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Table 1. Enantioselective model Biginelli reaction as carried out in the current work and as described by
others.
Mol%
Temp (°C) Solvent
Time (h)
Yield ee
1:2:3
Catalyst
Notes
Ref.
(%)
(%) (mmol)
The reaction required
10 mol% of HCl as
cocatalyst. Large
reagents excesses and
low yields.
10
0.20
0.60
0.60
CHCl3:
25
71
15
99
Dioxane
120
The reaction required
20 mol% of both
[Ph3CNH3 CF3CO2 ]
and F5C6CO2H.
10
0.73
0.73
1.46
+
ꢀ
THF:
25
51
72
50
60
93
94
98
94
85
Dioxane
96
pꢀMeOPhCHO
instead of PhCHO.
The reaction required
10 mol% of both
tBuNH2·TFA and
Cl3CCO2H
5
25
72
0.75
1.50
0.50
CH2Cl2
CH2Cl2
Iminium preꢀformed
and ethyl acetoacetate
was added after two
hours of reaction.
Large reagents
10
25
144
0.20
0.60
0.24
excesses.
Reaction under inert
atmosphere and large
reagents excesses.
pꢀO2NPhCHO
instead of PhCHO.
No reagent excess, no
5
50
72
0.10
0.30
0.12
52
Xylene
92
94
99
10
30
72
0.20
0.20
0.20
cocatalyst,
no
This
work
Solventless 99
solvent, no additive
and no addition order
are required.
MSI.TRIP
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A few other reports48,53,73ꢀ75 and some of Biginelliꢀlike76,77 reactions are also
found in the literature, but in general, these works have similar results and experimental
conditions as those cited in Table 1. The asymmetric version of the Biginelli reaction
was reviewed elsewhere.78 Depending on both the reaction condition and the nature of
the reagents, the asymmetric version may require up to 240 h to carry out.79
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Although all these works had brought great contributions to further the
asymmetric version of this MCR, it is important to highlight that all cited works do not
proceed experimentally as wished for MCRs. The aldehyde is mixed with urea
alongside with the catalyst at the beginning of the reaction. Only after two hours (on
average), the 1,3ꢀdicarbonyl compound is added to the reaction mixture. The Biginelli
reaction is known to be capable of taking place through at least three different
mechanisms, that is, the iminium or the enamine or the Knoevenagel pathways. These
three mechanism may be concurrent under typical Biginelli reaction conditions.55 By
mixing the aldehyde and urea in the absence of the third component, one may observe a
clear attempt of both to induce the iminium ion formation (from the iminium
mechanism – Scheme 2) and an attempt to avoid therefore the other two possible
mechanisms. These procedures proved to be important to the chiral induction step after
forming the iminium intermediate from the condensation of the aldehyde and the urea
(Scheme 2). Although it is not the preference for any MCR at all, where all reagents
should in principle be brought together (at the same time) in a oneꢀpot version.
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Scheme 2. Iminium mechanism of the Biginelli multicomponent reaction.
Using the catalyst developed in this work (MSI.TRIP), the idea of MCRs is
fully preserved and all reagents are brought together at once and no further additions
neither addition order are required. Solventless conditions are also a desirable feature,
although not essential.80 Beyond the chiral inductor, the enantioselective version of the
Biginelli reaction typically requires the addition of an acid cocatalyst (typically a strong
Bronsted acid) to befall (see Table 1). The dual function of MSI.TRIP i.e. the anion as
the chiral inductor and the Bronsted acid at the imidazolium derivative allows its direct
use in the reaction without requiring any cocatalyst.
Feng and coworkers74 demonstrated that the addition of organic salts has a
dramatic beneficial effect over the reaction displaying pronouncedly increased on the ee
values in the presence of such salts. As perused in Table 1, most of the available works
proceed through the addition of organic salts to improve the enantioselectivity of the
Biginelli MCR. MSI.TRIP has therefore a third function and acts as an organic salt, as
expected for ILs (organic salts in nature), thus merging in a single catalyst all features
required to succeed the enantioselective version of the Biginelli reaction.
The best condition developed for the use of MSI.TRIP was tested for other
substrates and results are summarized in Figure 1. The absolute stereochemistry could
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be confirmed by comparing the 4c [α]D = ꢀ 37.5 (c 0.16, MeOH) with the current
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available literature81 and only the (R) isomer is formed. The catalyst, beyond efficient,
could also be recovered and reused. Most of the Biginelli adducts are known to be
insoluble in ethanol and water. After the reaction, the catalyst could be recovered
(typically above 95% of catalyst recover) and reused (see details in the Experimental
Section). We also performed a reaction at 1 mmol scale of each reagent and similar
results were obtained for the model reaction.
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Figure 1. DHPMs from the enantioselective Biginelli reaction obtained using 0.20 mmol of the aldehyde,
0.20 mmol of the 1,3ꢀdicarbonyl compound, 0.20 mmol of urea (or thiourea) and 10 mol% of MSI.TRIP
at 30 °C for 72 h. Enantiomeric excess measured by enantiodiscriminating HPLC analyses.
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All proposed mechanisms of the enantioselective version of the Biginelli MCR
described so far are based on the iminium mechanism (Scheme 2) reexamined by
Kappe.82 It is known however that two other plausible mechanisms may concur and, to
avoid them, the iminium intermediate had to be preꢀformed in situ before the addition of
the third component of the MCR. Although this is the typical operating mechanism,
there are some works44,83ꢀ85 showing the iminium mechanism is not always the preferred
reaction pathway. The enantioselective mechanisms reported so far are in this context
basically an assumption the transformation is going through the iminium pathway.
Considering the iminium formation takes place in equilibrium, there is no warranty that
the other two mechanisms will not compete with the iminium. Without any real proof of
the preferred mechanism, the chiral step induction in the iminium intermediate is
therefore highly questionable, although plausible. We are aware however the transition
states associated with the chiral induction step are intimately dependent on the chiral
inductor used.
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Based on our experience in the investigation of MCRs mechanisms,86ꢀ89
including the Biginelli reaction,55,56 we decided to investigate the asymmetric version of
the Biginelli MCR using electrospray (tandem) mass spectrometry – ESIꢀMS(/MS).90ꢀ92
ESI proved to be an outstanding technique to an accurate investigation of several MCRs
mechanisms.93ꢀ97 We therefore prepared a solution of benzaldehyde, urea and ethyl
acetoacetate (50 ꢀM each) and mixed them in the presence of MSI.TRIP (5 ꢀM). The
solution was then injected and monitored online by MS and by its tandem MS/MS
version.
As a result, only intermediates from the iminium mechanism could be detected
(see Figure S2). These intermediates were previously characterized by us98 and by
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others.94 The most interesting results were however the detection and characterization of
unprecedent supramolecular aggregates of the iminium mechanism intermediates
alongside with the chiral anion (and some with the cation as well) of the catalyst (Figure
2 and Figures S3ꢀS4), which could be structurally characterized by ESI(+)ꢀMS/MS.
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Figure 2. (A) ESI(+)ꢀMS/MS of the iminium intermediate and the chiral moiety of the catalyst. (B)
ESI(+)ꢀMS/MS of the intermediate after 1,3ꢀdicarnonyl addition to the iminium ion alongside with the
chiral inductor. (C) ESI(+)ꢀMS/MS of the supramolecular aggregate bearing an intermediate from the
iminium mechanism, the chiral inductor and the imidazolium cation derivative. (D) ESI(+)ꢀMS/MS of a
supramolecular aggregate of the catalyst (type [C2A]+, C = cation and A = anion).
Figure 2A shows the iminium intermediate from the urea addition in the
aldehyde associated with the chiral anion of the MSI.TRIP catalyst. Figure 2B shows
the MS/MS characterization of the supramolecular aggregate bearing the reaction
intermediate after the addition of the 1,3ꢀdicarbonyl compound to the key iminium ion
in the presence of the chiral anion. The presence of the imidazolium derivative, the
chiral anion and one intermediate from the iminium mechanism in Figure 2C is, in fact,
an unprecedented supramolecular structure pointing firmly to a positive ILE and
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ACDC, that is, ionꢀpairing effects, formation of larger supramolecular ionic structures
and the possibility of chiral induction. Figure 2D shows the supramolecular structure
composed of two cations (MSI cation) associated with one chiral anion (TRIP anion
derivative) in a [C2A]+ type.99 No intermediate form the enamine neither from the
Knoevenagel mechanism were detected in the experiments.
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To ensure no intermediate of the Biginelli reaction mechanism neither those
supramolecular aggregates had escaped detection, we decided to monitor the reaction
using a chargeꢀtagged aldehyde derivative instead of benzaldehyde. This elegant
strategy of using chargeꢀtagged reagents100ꢀ102 was developed to facilitate the detection
and characterization of transient intermediates, intermediates with low abundance in the
ESIꢀMS spectrum, intermediates with fast kinetics of formation and/or consumption,
and for neutral intermediates (blind to MS), which detection would not be possible
without the charge tag appended in the reagent(s).
The experiments using the chargeꢀtagged aldehyde returned interesting results
(Figure 3 and Figures S5ꢀS6) and, once more, only intermediates from the iminium
mechanism could be detected. The lack of detection of intermediates from the
Knoevenagel neither from the enamine reaction pathways using a chargeꢀtagged reagent
is a strong evidence of the clear preference for the iminium mechanism under the
catalytic conditions developed herein. Aldehyde activation in the presence of
imidazoliumꢀbased ILs was proposed by Dupont, Eberlin and coꢀworkers.103 Later, we
observed this effect also for esters and carboxylic acids.104 This feature may be
contributing towards the iminium formation and favoring this reaction pathway.
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Figure 3. (A) ESI(+)ꢀMS/MS of the supramolecular structure bearing the bisureide intermediate
associated with the cation and anion of the catalyst. (B) ESI(+)ꢀMS/MS of the intermediate after 1,3ꢀ
dicarnonyl addition to the iminium ion and the chiral inductor. (C) ESI(+)ꢀMS/MS the supramolecular
aggregate of the key iminium intermediate associated with the chiral inductor and the imidazolium cation
derivative. (D) ESI(+)ꢀMS/MS of the Biginelli adduct associated with the chiral anion.
Supramolecular aggregates (C2A type ꢀ see Figure 3) detection and
characterization (MS/MS) bearing both the imidazolium derivative and the anion of the
catalyst plus the key intermediates of the iminium mechanism is a clear evidence of the
combined role of ILE (over the stabilization of the formed charged intermediates in the
reaction) and ACDC (due to the presence of the chiral anion).
Based on the evidences of the MS experiments described, DFT calculations were
performed to depict plausible transition states (TSs) to explain the chiral induction step
in the iminium intermediate upon 1,3ꢀdicarbonyl compound addition. We considered for
the calculations a supramolecular structure containing the iminium intermediate, the
chiral anion and the imidazolium derivative of the catalyst (as seen, for instance, in
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Figure 3C) to evaluate the possible TSs (Figure 4). The structure had its geometry fully
optimized.
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Figure 4. Plausible transition states for the enantioselective Biginelli reaction catalyzed by MSI.TRIP
calculated at HF/3ꢀ21G//wB97XDꢁ6ꢀ311G(d) level of theory. The addition to the iminium intermediate
was considered the key step of the chiral induction. (Top) Potential energies curves with specific
stationary points. (Bottom) Van der Waals representations of the transition states.
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In the TS showing the addition of the ethyl acetoacetate in the Re face (less
favored) it is noted the free approximation of both the iminium intermediate and of the
other reagent in an open arrangement. In the TS favoring the Si face however a cageꢀ
like arrangement is noted. In this case, the imidazolium derivative is capable of locking
the iminium intermediate alongside with the 1,3ꢀdicarbonyl compound one side while
the chiral anion locks the other side. As depicted from Figure 4, the chiral anion is
blocking the Re face of the C=O bond of the iminium intermediate and allowing for the
addition of the other reagent exclusively by the Si face. Although the energy difference
noted when comparing both possible TSs were not so large, the attack on the Si face
was clearly favored, as experimentally determined (99% ee). To better understand this
result and the energetic involved, TSs relative populations could also be predicted at
different temperatures from electronic energy differences (Figure 5) based on the
Boltzmann distribution analysis using the Boltzmann factor to estimate the ee (see the
experimental section for details).
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Figure 5. TS relative populations (Boltzmann distribution) from electronic energy differences using the
Boltzmann factor to estimate the ee.
The method returned a theoretical ee of 98.20% while the experimental result
had an ee of 99% therefore confirming the accuracy of the employed theoretical
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methodology to explain the plausible TS and the preferential Si face attack. Considering
the MS results revealed unprecedented larger supramolecular structures with at least
two chiral anions (Figures S3 and S6), it is expected a larger and more organized TS but
the size and complexity of these supramolecular structures considering more anions and
cations would not allow for such a high level of theory calculation.
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Based on the results described herein, a catalytic cycle could be proposed
(Scheme 3) to explain the enantioselective Biginelli MCR using MSI.TRIP.
Scheme 3. Catalytic cycle of the enantioselective Biginelli reaction catalyzed by MSI.TRIP. Note the
proposition is based on the iminium mechanism and the favored calculated TS is shown.
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In the proposed catalytic cycle, the aldehyde is protonated and the urea addition
takes place affording the key iminium intermediate. The chiral anion and the ZMSI
(imidazolium derivative) coordinates and the supramolecular chiral structure prone to
the 1,3ꢀdicarbonyl addition is formed likely the calculated cageꢀlike structure (Figure 4,
bottom and left). After, the Biginelli adduct is formed by cyclization and the acid
hydrogen is restored during the release of the ZMSI, the chiral anion and water.
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In summary, a new chiral Bronsted IL was successfully synthesized and applied
as the catalyst for the enantioselective version of the Biginelli reaction. The chiral IL
tested as the catalyst had three important roles acting as the acid hydrogen source, as the
chiral inductor and as an organic salt (like an additive). The mechanism analysis by
ESIꢀMS(/MS) allowed the detection and characterization of unprecedented chiral
supramolecular structures pointing to the presence of the chiral anion and the
imidazolium derivative in the structure. These results are strong evidences of the
combined role of ILE and ACDC. The iminium mechanism is highly favored in the
developed conditions and no intermediate of the other two mechanisms could be
detected. Theoretical calculations based on the detected unprecedent supramolecular
aggregated from MS results, shed light on the possible TS favoring the Si face attack by
the 1,3ꢀdicarbonyl reagent during the key step for the chiral induction in the model
reaction analyzed. DFT results also pointed to the importance of the chiral anion and of
the imidazolium derivative in the chiral induction step to proceed through a cageꢀlike
structure, thus once more pointing firmly to the combined role of ILE and ACDC. The
results described herein indeed open up a new avenue of opportunities for the
exploration of CILs allowing a unique combination of ILE and ACDC to be further
exploited.
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General. ESIꢀMS and ESIꢀMS/MS measurements were performed in the positive ion
mode (m/z 50ꢀ2000 range) on a HDMS instrument. This instrument has a hybrid
quadrupole/ion mobility/orthogonal acceleration timeꢀofꢀflight (oaꢀTOF) geometry and
was used in the TOF V+ mode. All samples were dissolved in methanol to form 50 ꢀM
solutions and were directly infused into the ESI source at a flow rate of 10 ꢀL/min after
5 minutes at 80 °C. ESI source conditions were as follows: capillary voltage 3.0 kV,
sample cone 20 V, extraction cone 3 V. NMR spectra were recorded on a 7.05 T
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1
instrument using a 5ꢀmm internal diameter probe operating at 600 MHz for H and at
150 MHz for 13C. Chemical shifts were expressed in parts per million (ppm) and
referenced by the signals of the residual hydrogen atoms of the deuterated solvent, as
indicated in the legends. Melting point were recorded using a sealed capillary tube.
Synthesis of the chiral catalysts. The new catalysts were prepared by treating the
zwitterionic MSI (1 mmol, 204 mg) with the respective phosphoric acids derivatives,
that is, (R)ꢀH8ꢀBinolꢀPA (1 mmol, 760 mg), or (R)ꢀVAPOL (1 mmol, 600 mg) or (R)ꢀ
TRIP (1 mmol, 752 mg). The mixtures were stirred for 6 h under inert atmosphere at 80
°C affording the respective catalysts in quantitative yields. MSI.H8Binol (965 mg),
MSI.VAPOL (805 mg) and MSI.TRIP (957 mg).
MSI.TRIP.
1ꢀmethylꢀ3ꢀ(3ꢀsulfopropyl)ꢀ1Hꢀimidazolꢀ3ꢀium
(R)ꢀ3,3′ꢀBis(2,4,6ꢀ
1
triisopropylphenyl)ꢀ1,1′ꢀbinaphthylꢀ2,2′ꢀdiyl phosphate. H NMR (600 MHz, CDCl3) δ
ppm 0.68 (d,
J
= 5.87 Hz, 7H), 0.89 (d,
J
= 6.60 Hz, 7H), 0.99 (dd, J = 15H), 1.22 (d,
= 6.60 Hz, 2H), 2.83 (qui,
J
= 6.97Hz, 15H), 2.52 ( qui,
J
= 6.60 Hz, 2H), 2.60 (qui,
J
J
=
6.97 Hz, 2H), 6.94 (d,
7.80 (s, 2H), 7.87 (d,
J
= 7.61 Hz, 5H), 7.31 (m, 5H), 7.49 (dt, J = 1.83, 6.24 Hz, 2H),
13
J
= 8.07Hz, 2H). C NMR (150 MHz, CDCl3) δ ppm 18.1, 22.7,
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23.3, 23.9, 24.1, 25.0, 26.3, 30.7, 30.9, 34.3, 120.2, 121.1, 122.08, 122.09, 125.6, 126.2,
127.4, 128.1, 131.0, 131.5, 132.2, 132.21, 132.5, 132.6, 145.8, 145.9, 147.5, 148.1,
148.4. HRMS (ESIꢀTOF) m/z: In the positive ion mode [M]+ Calcd for C7H13NO3S
205.0647; Found 205.0644. In the negative ion mode [M]ꢀ Calcd for C50H56O4P
751.3916; Found 751.3934.
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MSI.H8Binol. 1ꢀmethylꢀ3ꢀ(3ꢀsulfopropyl)ꢀ1Hꢀimidazolꢀ3ꢀium (R)ꢀ3,3'ꢀdiphenylꢀ1,1'ꢀ
1
H8ꢀbinaphthylꢀ2,2'ꢀdiyl phosphate. H NMR (500 MHz, CDCl3) δ ppm 0.92ꢀ0.89 (m,
10 H), 1.06ꢀ1.04 (m, 7 H), 1.10ꢀ1.09 (m, 7 H), 1.23ꢀ1.20 (m, 14 H), 1.89ꢀ1.81 (m, 8 H),
2.28ꢀ2.26 (m, 2 H), 2.32ꢀ2.29 (m, 2 H), 2.60ꢀ2.58 (m, 3 H), 2.67ꢀ2.64 (m, 3 H), 2.85ꢀ
13
2.78 (m, 10 H), 6.93ꢀ6.92 (m, 6 H), 6.97 (s, 3H). C NMR (125 MHz, CDCl3) 147.9,
147.8, 147.2, 144.0, 136.5, 133.9, 132.6, 131.8, 129.3, 126.8, 120.9, 120.0, 58.5, 34.2,
31.0, 30.6, 29.3, 27.8, 26.6, 24.9, 24.1, 23.9, 23.4, 23.9, 23.4, 22.9, 22.8, 18.3. HRMS
(ESIꢀTOF) m/z: In the positive ion mode [M]+ Calcd for C7H13NO3S 205.0647; Found
205.0648. In the negative ion mode [M]ꢀ Calcd for C50H64O4P 759.4542; Found
759.4547.
MSI.VAPOL. 1ꢀmethylꢀ3ꢀ(3ꢀsulfopropyl)ꢀ1Hꢀimidazolꢀ3ꢀium (R)ꢀ2,2ꢂꢀDiphenylꢀ3,3ꢂꢀ
biphenanthrylꢀ4,4ꢂꢀdiyl phosphate. 1H NMR (500 MHz, CDCl3) δ ppm 0.90ꢀ0.82 (m, 2
H), 1.25ꢀ1.19 (m, 2 H), 1.69ꢀ1.66 (m, 2H), 6.50 (d, 4 H, J = 7 Hz), 6.92 (t, 4 H, J = 7
Hz), 7.10ꢀ7.07 (m, 3 H), 7.48ꢀ7.47 (m, 5 H), 7.59ꢀ7.57 (m, 3 H), 7.68ꢀ7.67 (m, 3 H),
7.78ꢀ7.75 (m, 5 H). 13C NMR (125 MHz, CDCl3) 141.3, 139.8, 134.6, 133.3, 129.6,
129.1, 127.7, 127.1, 126.9, 126.7, 121.8, 47.0, 46.7, 39.7. HRMS (ESIꢀTOF) m/z: In the
positive ion mode [M]+ Calcd for C7H13NO3S 205.0647; Found 205.0645. In the
negative ion mode [M]ꢀ Calcd for C40H24O4P 599.1412; Found 599.1419.
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General procedure for the enantioselective Biginelli reaction and catalyst recover.
A Schlenk tube containing 0.2 mmol of aldehyde, 0.2 mmol of the 1,3ꢀdicarbonyl
compound, 0.2 mmol of urea (or thiourea), 10 mol% of the MSI.TRIP (9.5 mg) was
allowed to react at 30 °C for 72 h. All Biginelli adducts were purified by
chromatographic column using ethyl acetate and hexanes mixtures. Most of the
Biginelli adduct are not soluble in ethanol neither water. For these compounds (e.g. 4a),
ethanol was used to wash and recover the catalyst from the reaction mixture. The
procedure allows the catalyst to be recovered in up to 95% and reused without any
notable loss in yields and enantioselectivity. Biginelli adduct could also be crystallized
from hot ethanol, a known wellꢀstablished procedure used to purify these compounds.105
In this work, however, we purified them by chromatographic column because yields
were on average 15ꢀ25% lower when purified by the crystallization procedure.
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Computational procedures. The electronic structure calculation performed in this
work were carried within compound model chemistry HFꢁ3ꢀ21Gꢁꢁ
using Gaussian 09 program suite.106
wB97XDꢁ6ꢀ311G(d)
w
B97XD is a longꢀrange corrected hybrid density
functional with empirical dispersion correction with satisfactory accuracy for
thermochemistry, kinetics and noncovalent interactions.107 In spirit of the computational
protocol applied in the available literature,108,109 minimum energy reaction paths were
located using the relaxed scan procedure, since the conventional synchronous transitꢀ
guided quasiꢀNewton QST2 method was unable locating the transition state. To
elucidate the relative energy of the reaction, relaxed potential energy surface (PES)
scans were performed by driving the CꢀC bond (0.02 A over 10 steps) starting from
from 1.5A value up to 3.3A. The relaxed scan presented a loose and flat transition state
supporting the weakness of the conventional QST2 procedure.
Authors Information
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Giovanni W. Amarante (giovanni.amarante@ufjf.edu.br); ORCID 0000ꢀ0003ꢀ1004ꢀ
5395
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Brenno A. D. Neto (brenno.ipi@gmail.com; ORCID 0000ꢀ0003ꢀ3783ꢀ9283)
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Supporting Information
Catalyst analyses, ESIꢀMS/MS, chiral HPLC traces and NMR spectra related with this
manuscript. Energies and Cartesian coordinates for all calculated structures These
materials are available free of charge via the internet at http://pubs.acs.org.
Acknowledgments
This work has been supported by CAPES, CNPq, FINEPꢀMCT, FINATEC, FAPESP,
FAPEMIG, FAPDF, PrP/UEG, HighꢀPerformance Computing Center at the
Universidade Estadual de Goias (UEG) and DPPꢀUnB. BAD Neto also thanks INCTꢀ
Transcend group and LNLS.
References
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. The art and science of total synthesis at the dawn of the
twentyꢀfirst century. Angew. Chem., Int. Ed. 2000, 39, 44ꢀ122.
Honig, M.; Sondermann, P.; Turner, N. J.; Carreira, E. M. Enantioselective Chemoꢀ nd Biocatalysis: Partners in
Retrosynthesis. Angew. Chem., Int. Ed. 2017, 56, 8942ꢀ8973.
Long Nguyen, T. H.; Gigant, N.; Joseph, D. Advances in Direct MetalꢀCatalyzed Functionalization of Azobenzenes. ACS
Catal. 2018, 8, 1546ꢀ1579.
Filonenko, G. A.; van Putten, R.; Hensen, E. J. M.; Pidko, E. A. Catalytic (de)hydrogenation promoted by nonꢀprecious
metals ꢀ Co, Fe and Mn: recent advances in an emerging field. Chem. Soc. Rev. 2018, 47, 1459ꢀ1483.
Zou, Y.ꢀQ.; Hoermann, F. M.; Bach, T. Iminium and enamine catalysis in enantioselective photochemical reactions. Chem.
Soc. Rev. 2018, 47, 278ꢀ290.
Phipps, R. J.; Hamilton, G. L.; Toste, F. D. The progression of chiral anions from concepts to applications in asymmetric
catalysis. Nat. Chem. 2012, 4, 603ꢀ614.
Avila, E. P.; Amarante, G. W. Recent Advances in Asymmetric Counteranionꢀdirected Catalysis (ACDC). ChemCatChem
2012, 4, 1713ꢀ1721.
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. A powerful chiral counterion strategy for asymmetric transition metal
catalysis. Science 2007, 317, 496ꢀ499.
Milo, A.; Neel, A. J.; Toste, F. D.; Sigman, M. S. A dataꢀintensive approach to mechanistic elucidation applied to chiral
anion catalysis. Science 2015, 347, 737ꢀ743.
Mahlau, M.; List, B. Asymmetric CounteranionꢀDirected Catalysis: Concept, Definition, and Applications. Angew. Chem.,
Int. Ed. 2013, 52, 518ꢀ533.
Raynal, M.; Ballester, P.; VidalꢀFerran, A.; van Leeuwen, P. W. N. M. Supramolecular catalysis. Part 1: nonꢀcovalent
interactions as a tool for building and modifying homogeneous catalysts. Chem. Soc. Rev. 2014, 43, 1660ꢀ1733.
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(12)
(13)
(14)
(15)
(16)
(17)
James, T.; van Gemmeren, M.; List, B. Development and Applications of Disulfonimides in Enantioselective Review
Organocatalysis. Chem. Rev. 2015, 115, 9388ꢀ9409.
Jindal, G.; Kisan, H. K.; Sunoj, R. B. Mechanistic Insights on Cooperative Catalysis through Computational Quantum
Chemical Methods. ACS Catal. 2015, 5, 480ꢀ503.
Duarte, F.; Paton, R. S. Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphateꢀ
Mediated Desymmetrization. J. Am. Chem. Soc. 2017, 139, 8886ꢀ8896.
Seguin, T. J.; Wheeler, S. E. Stacking and Electrostatic Interactions Drive the Stereoselectivity of SilyliumꢀIon Asymmetric
CounteranionꢀDirected Catalysis. Angew. Chem., Int. Ed. 2016, 55, 15889ꢀ15893.
ClotꢀAlmenara, L.; RodriguezꢀEscrich, C.; OsorioꢀPlanes, L.; Pericas, M. A. PolystyreneꢀSupported TRIP: A Highly
Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes. ACS Catal. 2016, 6, 7647ꢀ7651.
Zhang, Z. P.; Bae, H. Y.; Guin, J.; Rabalakos, C.; van Gemmeren, M.; Leutzsch, M.; Klussmann, M.; List, B. Asymmetric
counteranionꢀdirected Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nat. Commun. 2016, 7,
12478.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18)
(19)
(20)
Hallett, J. P.; Welton, T. RoomꢀTemperature Ionic Liquids: Solvents for Synthesis and Catalysis. 2. Chem. Rev. 2011, 111,
3508ꢀ3576.
Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Ionic liquid (molten salt) phase organometallic catalysis. Chem. Rev. 2002,
102, 3667ꢀ3691.
van Rantwijk, F.; Lau, R. M.; Sheldon, R. A. Biocatalytic transformations in ionic liquids. Trends Biotechnol. 2003, 21,
131ꢀ138.
Plechkova, N. V.; Seddon, K. R. Applications of ionic liquids in the chemical industry. Chem. Soc. Rev. 2008, 37, 123ꢀ150.
Earle, M. J.; McCormac, P. B.; Seddon, K. R. DielsꢀAlder reactions in ionic liquids ꢀ A safe recyclable alternative to
lithium perchlorateꢀdiethyl ether mixtures. Green Chem. 1999, 1, 23ꢀ25.
Schulz, P. S.; Muller, N.; Bosmann, A.; Wasserscheid, P. Effective chirality transfer in ionic liquids through ionꢀpairing
effects. Angew. Chem., Int. Ed. 2007, 46, 1293ꢀ1295.
Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont, A. C.; Plaquevent, J. C. Ionic liquids and chirality:
opportunities and challenges. Tetrahedron-Asymmetry 2003, 14, 3081ꢀ3093.
Headley, A. D.; Ni, B. Chiral imidazolium ionic liquids: Their synthesis and influence on the outcome of organic reactions.
Aldrichim. Acta 2007, 40, 107ꢀ117.
(21)
(22)
(23)
(24)
(25)
(26)
Luo, S. Z.; Zhang, L.; Cheng, J. P. Functionalized Chiral Ionic Liquids: A New Type of Asymmetric Organocatalysts and
Nonclassical Chiral Ligands. Chem.-Asian J. 2009, 4, 1184ꢀ1195.
(27)
(28)
Dupont, J. From Molten Salts to Ionic Liquids: A "Nano" Journey. Acc. Chem. Res. 2011, 44, 1223ꢀ1231.
Gyton, M. R.; Cole, M. L.; Harper, J. B. Ionic liquid effects on MizorokiꢀHeck reactions: more than just carbene complex
formation. Chem. Commun. 2011, 47, 9200ꢀ9202.
Wang, Z.; Ji, P. J.; Li, X.; Cheng, J. P. DoubleꢀLine Hammett Relationship Revealed through Precise Acidity Measurement
of Benzenethiols in Neat Ionic Media: A Typical "Ionic Liquid Effect"? Org. Lett. 2014, 16, 5744ꢀ5747.
Qadir, M. I.; Scholten, J. D.; Dupont, J. Ionic liquid effect: selective aniline oxidative coupling to azoxybenzene by TiO2.
Catal. Sci. Technol. 2015, 5, 1459ꢀ1462.
Mao, C.; Wang, Z.; Wang, Z.; Ji, P.; Cheng, J.ꢀP. Weakly Polar Aprotic Ionic Liquids Acting as Strong Dissociating
Solvent: A Typical "Ionic Liquid Effect" Revealed by Accurate Measurement of Absolute pK(a) of Ylide Precursor Salts.
J. Am. Chem. Soc. 2016, 138, 5523ꢀ5526.
Tanner, E. E. L.; Hawker, R. R.; Yau, H. M.; Croft, A. K.; Harper, J. B. Probing the importance of ionic liquid structure: a
general ionic liquid effect on an SNAr process. Org. Biomol. Chem. 2013, 11, 7516ꢀ7521.
Goodrich, P.; Hardacre, C.; Paun, C.; Parvulescu, V. I.; Podolean, I. Ionic Liquid Effect on the Reversal of Configuration
for the Magnesium(II) and Copper(II) Bis(oxazoline)ꢀCatalysed Enantioselective DielsꢀAlder Reaction. Adv. Synth. Catal.
2008, 350, 2473ꢀ2476.
Rodrigues, T. S.; Silva, V. H. C.; Lalli, P. M.; de Oliveira, H. C. B.; da Silva, W. A.; Coelho, F.; Eberlin, M. N.; Neto, B.
A. D. MoritaꢀBaylisꢀHillman Reaction: ESIꢀMS(/MS) Investigation with Charge Tags and Ionic Liquid Effect Origin
Revealed by DFT Calculations. J. Org. Chem. 2014, 79, 5239ꢀ5248.
Lee, J. W.; Shin, J. Y.; Chun, Y. S.; Bin Jang, H.; Song, C. E.; Lee, S.ꢀG. Toward Understanding the Origin of Positive
Effects of Ionic Liquids on Catalysis: Formation of More Reactive Catalysts and Stabilization of Reactive Intermediates
and Transition States in Ionic Liquids. Acc. Chem. Res. 2010, 43, 985ꢀ994.
Stassen, H. K.; Ludwig, R.; Wulf, A.; Dupont, J. Imidazolium Salt Ion Pairs in Solution. Chem.-Eur. J. 2015, 21, 8324ꢀ
8335.
Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014,
114, 8323ꢀ8359.
Toure, B. B.; Hall, D. G. Natural Product Synthesis Using Multicomponent Reaction Strategies. Chem. Rev. 2009, 109,
4439ꢀ4486.
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(42)
Ramon, D. J.; Yus, M. Asymmetric multicomponent reactions (AMCRs): The new frontier. Angew. Chem., Int. Ed. 2005,
44, 1602ꢀ1634.
de Graaff, C.; Ruijter, E.; Orru, R. V. A. Recent developments in asymmetric multicomponent reactions. Chem. Soc. Rev.
2012, 41, 3969ꢀ4009.
Ahmadi, T.; Ziarani, G. M.; Gholamzadeh, P.; Mollabagher, H. Recent advances in asymmetric multicomponent reactions
(AMCRs). Tetrahedron-Asymmetry 2017, 28, 708ꢀ724.
Echemendia, R.; de La Torre, A. F.; Monteiro, J. L.; Pila, M.; Correa, A. G.; Westermann, B.; Rivera, D. G.; Paixao, M. W.
Highly Stereoselective Synthesis of NaturalꢀProductꢀLike Hybrids by an Organocatalytic/Multicomponent Reaction
Sequence. Angew. Chem., Int. Ed. 2015, 54, 7621ꢀ7625.
(43)
(44)
Tron, G. C.; Minassi, A.; Appendino, G. Pietro Biginelli: The Man Behind the Reaction. Eur. J. Org. Chem. 2011, 5541ꢀ
5550.
Lima, C. G. S.; Silva, S.; Goncalves, R. H.; Leite, E. R.; Schwab, R. S.; Correa, A. G.; Paixao, M. W. Highly Efficient and
Magnetically Recoverable Niobium Nanocatalyst for the Multicomponent Biginelli Reaction. ChemCatChem 2014, 6,
3455ꢀ3463.
De Oliveira, F. S.; De Oliveira, P. M.; Farias, L. M.; Brinkerhoff, R. C.; Sobrinho, R. C. M. A.; Treptow, T. M.; Montes
D'Oca, C. R.; Marinho, M. A. G.; Hort, M. A.; Horn, A. P.; Russowsky, D.; Montes D'Oca, M. G. Synthesis and
antitumoral activity of novel analogues monastrol–fatty acids against glioma cells. Med. Chem. Commun. 2018, 9, 1282ꢀ
1288.
(45)
24
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(46)
(47)
(48)
Huang, Y. J.; Yang, F. Y.; Zhu, C. J. Highly enantioseletive biginelli reaction using a new chiral ytterbium catalyst:
Asymmetric synthesis of dihydropyrimidines. J. Am. Chem. Soc. 2005, 127, 16386ꢀ16387.
Maji, R.; Mallojjala, S. C.; Wheeler, S. E. Chiral phosphoric acid catalysis: from numbers to insights. Chem. Soc. Rev.
2018, 47, 1142ꢀ1158.
Hang, Z. J.; Zhu, J.; Lian, X.; Xu, P.; Yu, H.; Han, S. A highly enantioselective Biginelli reaction using selfꢀassembled
methanoprolineꢀthiourea organocatalysts: asymmetric synthesis of 6ꢀisopropylꢀ3,4ꢀdihydropyrimidines. Chem. Commun.
2016, 52, 80ꢀ83.
Ding, D. R.; Zhao, C. G. Primary Amine Catalyzed Biginelli Reaction for the Enantioselective Synthesis of 3,4ꢀ
Dihydropyrimidinꢀ2(1H)ꢀones. Eur. J. Org. Chem. 2010, 3802ꢀ3805.
Chen, X. H.; Xu, X. Y.; Liu, H.; Cun, L. F.; Gong, L. Z. Highly enantioselective organocatalytic Biginelli reaction. J. Am.
Chem. Soc. 2006, 128, 14802ꢀ14803.
Saha, S.; Moorthy, J. N. Enantioselective Organocatalytic Biginelli Reaction: Dependence of the Catalyst on Sterics,
Hydrogen Bonding, and Reinforced Chirality. J. Org. Chem. 2011, 76, 396ꢀ402.
Xu, F. X.; Huang, D.; Lin, X. F.; Wang, Y. G. Highly enantioselective Biginelli reaction catalyzed by SPINOLꢀphosphoric
acids. Org. Biomol. Chem. 2012, 10, 4467ꢀ4470.
An, D.; Fan, Y. S.; Gao, Y.; Zhu, Z. Q.; Zheng, L. Y.; Zhang, S. Q. Highly enantioselective Biginelli reaction catalyzed by
double axially chiral bisphosphorylimides. Eur. J. Org. Chem. 2014, 2014, 301ꢀ306.
Gong, L. Z.; Chen, X. H.; Xu, X. Y. Asymmetric organocatalytic biginelli reactions: A new approach to quickly access
optically active 3,4ꢀDihydropyrimidinꢀ2ꢀ(1H)ꢀones. Chem.-Eur. J. 2007, 13, 8920ꢀ8926.
Alvim, H. G. O.; Lima, T. B.; de Oliveira, A. L.; de Oliveira, H. C. B.; Silva, F. M.; Gozzo, F. C.; Souza, R. Y.; da Silva,
W. A.; Neto, B. A. D. Facts, Presumptions, and Myths on the SolventꢀFree and CatalystꢀFree Biginelli Reaction. What is
Catalysis for? J. Org. Chem. 2014, 79, 3383ꢀ3397.
Silva, G. C. O.; Correa, J. R.; Rodrigues, M. O.; Alvim, H. G. O.; Guido, B. C.; Gatto, C. C.; Wanderley, K. A.;
Fioramonte, M.; Gozzo, F. C.; de Souza, R.; Neto, B. A. D. The Biginelli reaction under batch and continuous flow
conditions: catalysis, mechanism and antitumoral activity. RSC Adv. 2015, 5, 48506ꢀ48515.
Chiappe, C.; Rajamani, S. Structural Effects on the PhysicoꢀChemical and Catalytic Properties of Acidic Ionic Liquids: An
Overview. Eur. J. Org. Chem. 2011, 5517ꢀ5539.
Johnson, K. E.; Pagni, R. M.; Bartmess, J. Bronsted acids in ionic liquids: Fundamentals, organic reactions, and
comparisons. Monatsh. Chem. 2007, 138, 1077ꢀ1101.
Sebesta, R.; Kmentova, I.; Toma, S. Catalysts with ionic tag and their use in ionic liquids. Green Chem. 2008, 10, 484ꢀ496.
Lombardo, M.; Trombini, C. Ionic Tags in Catalyst Optimization: Beyond Catalyst Recycling. ChemCatChem 2010, 2,
135ꢀ145.
Lee, S. G. Functionalized imidazolium salts for taskꢀspecific ionic liquids and their applications. Chem. Commun. 2006,
1049ꢀ1063.
Avila, C. M.; Patel, J. S.; Reddi, Y.; Saito, M.; Nelson, H. M.; Shunatona, H. P.; Sigman, M. S.; Sunoj, R. B.; Toste, F. D.
Enantioselective HeckꢀMatsuda Arylations through Chiral Anion PhaseꢀTransfer of Aryl Diazonium Salts. Angew. Chem.,
Int. Ed. 2017, 56, 5806ꢀ5811.
Narute, S.; Parnes, R.; Toste, F. D.; Pappo, D. Enantioselective Oxidative Homocoupling and CrossꢀCoupling of 2ꢀ
Naphthols Catalyzed by Chiral Iron Phosphate Complexes. J. Am. Chem. Soc. 2016, 138, 16553ꢀ16560.
Nakamura, S.; Furukawa, T.; Hatanaka, T.; Funahashi, Y. Enantioselective azaꢀFriedelꢀCrafts reaction of cyclic ketimines
with indoles using chiral imidazolineꢀphosphoric acid catalysts. Chem. Commun. 2018, 54, 3811ꢀ3814.
Li, F.; Korenaga, T.; Nakanishi, T.; Kikuchi, J.; Terada, M. Chiral Phosphoric Acid Catalyzed Enantioselective Ring
Expansion Reaction of 1,3ꢀDithiane Derivatives: Case Study of the Nature of IonꢀPairing Interaction. J. Am. Chem. Soc.
2018, 140, 2629ꢀ2642.
Zhang, Z. P.; Xie, K. X.; Yang, C.; Li, M.; Li, X. Asymmetric Synthesis of Dihydrocoumarins through Chiral Phosphoric
AcidꢀCatalyzed Cycloannulation of paraꢀQuinone Methides and Azlactones. J. Org. Chem. 2018, 83, 364ꢀ373.
Yang, X.; Pang, S.; Cheng, F.; Zhang, Y.; Lin, Y. W.; Yuan, Q.; Zhang, F. L.; Huang, Y. Y. Enantioselective Synthesis of
1,3ꢀDisubstituted 1,3ꢀDihydroisobenzofurans via a Cascade Allylboration/OxoꢀMichael Reaction of oꢀFormyl Chalcones
Catalyzed by a Chiral Phosphoric Acid. J. Org. Chem. 2017, 82, 10388ꢀ10397.
(49)
(50)
(51)
(52)
(53)
(54)
(55)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(56)
(57)
(58)
(59)
(60)
(61)
(62)
(63)
(64)
(65)
(66)
(67)
(68)
(69)
(70)
Zhang, X.; Kormos, A.; Zhang, J. SelfꢀSupported BINOLꢀDerived Phosphoric Acid Based on a Chiral Carbazolic Porous
Framework. Org. Lett. 2017, 19, 6072ꢀ6075.
Reid, J. P.; Goodman, J. M. Selecting Chiral BINOLꢀDerived Phosphoric Acid Catalysts: General Model To Identify Steric
Features Essential for Enantioselectivity. Chem.-Eur. J. 2017, 23, 14248ꢀ14260.
Li, N.; Chen, X. H.; Song, J.; Luo, S. W.; Fan, W.; Gong, L. Z. Highly Enantioselective Organocatalytic Biginelli and
BiginelliꢀLike Condensations: Reversal of the Stereochemistry by Tuning the 3,3 'ꢀDisubstituents of Phosphoric Acids. J.
Am. Chem. Soc. 2009, 131, 15301ꢀ15310.
Xu, D.ꢀZ.; Li, H.; Wang, Y. Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst:
asymmetric synthesis of dihydropyrimidines. Tetrahedron 2012, 68, 7867ꢀ7872.
Wang, Y. Y.; Yang, H. T.; Yu, J. P.; Miao, Z. W.; Chen, R. Y. Highly Enantioselective Biginelli Reaction Promoted by
Chiral Bifunctional Primary AmineꢀThiourea Catalysts: Asymmetric Synthesis of Dihydropyrimidines. Adv. Synth. Catal.
2009, 351, 3057ꢀ3062.
Qu, H.; Li, X.; Mo, F.; Lin, X. Efficient synthesis of dihydropyrimidinones via a threeꢀcomponent Biginelliꢀtype reaction
of urea, alkylaldehyde and arylaldehyde. Beilstein J. Org. Chem. 2013, 9, 2846ꢀ2851.
Xin, J. G.; Chang, L.; Hou, Z. R.; Shang, D. J.; Liu, X. H.; Feng, X. M. An enantioselective Biginelli reaction catalyzed by
a simple chiral secondary amine and achiral Bronsted acid by a dualꢀactivation route. Chem.-Eur. J. 2008, 14, 3177ꢀ3181.
Yu, H.; Xu, P.; He, H. H.; Zhu, J.; Lin, H. L.; Han, S. Highly enantioselective enantioselective Biginelli reactions using
methanopyroline/thiourea ꢀ based dual organocatalyst systems: asymmetric synthesis of 4ꢀsubstituted unsaturated aryl
dihydropyrimidines. Tetrahedron-Asymmetry 2017, 28, 257ꢀ265.
(71)
(72)
(73)
(74)
(75)
(76)
(77)
(78)
(79)
Stucchi, M.; Lesma, G.; Meneghetti, F.; Rainoldi, G.; Sacchetti, A.; Silvani, A. Organocatalytic Asymmetric Biginelliꢀlike
Reaction Involving Isatin. J. Org. Chem. 2016, 81, 1877ꢀ1884.
Barbero, M.; Cadamuro, S.; Dughera, S. A Bronsted acid catalysed enantioselective Biginelli reaction. Green Chem. 2017,
19, 1529ꢀ1535.
Wan, J. P.; Lin, Y. F.; Liu, Y. Y. Catalytic Asymmetric Biginelli Reaction for the Enantioselective Synthesis of 3,4ꢀ
Dihydropyrimidinones (DHPMs). Curr. Org. Chem. 2014, 18, 687ꢀ699.
Guo, Y.; Gao, Z.; Meng, X.; Huang, G.; Zhong, H.; Yu, H.; Ding, X.; Tang, H.; Zou, C. Highly Enantioselective Biginelli
Reaction of Aliphatic Aldehydes Catalyzed by Chiral Phosphoric Acids. Synlett 2017, 28, 2041ꢀ2045.
25
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The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
7
8
(80)
(81)
(82)
(83)
Clark, J. H.; Macquarrie, D. J.; Sherwood, J. The combined role of catalysis and solvent effects on the biginelli reaction:
Improving efficiency and sustainability. Chem.-Eur. J. 2013, 19, 5174ꢀ5182.
GonzalezꢀOlvera, R.; Demare, P.; Regla, I.; Juaristi, E. Application of (1S,4S)ꢀ2,5ꢀdiazabicyclo 2.2.1 heptane derivatives in
asymmetric organocatalysis: the Biginelli reaction. Arkivoc 2008, 61ꢀ72.
Kappe, C. O. A reexamination of the mechanism of the Biginelli dihydropyrimidine synthesis. Support for an Nꢀ
acyliminium ion intermediate. J. Org. Chem. 1997, 62, 7201ꢀ7204.
Cepanec, I.; Litvic, M.; FilipanꢀLitvic, M.; Grungold, I. Antimony(III) chlorideꢀcatalysed Biginelli reaction: a versatile
method for the synthesis of dihydropyrimidinones through a different reaction mechanism. Tetrahedron 2007, 63, 11822ꢀ
11827.
9
(84)
Litvic, M.; Vecenaj, I.; Ladisic, Z. M.; Lovric, M.; Vinkovic, V.; FilipanꢀLitvic, M. First application of
hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, nonꢀhygroscopic acid catalyst in organic synthesis: a
simple and efficient protocol for the multigram scale synthesis of 3,4ꢀdihydropyrimidinones by Biginelli reaction.
Tetrahedron 2010, 66, 3463ꢀ3471.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(85)
(86)
Folkers, K.; Johnson, T. B. Researches on Pyrimidines. CXXXVI. The Mechanism of Formation of Tetrahydropyrimidines
by the Biginelli Reaction. J. Am. Chem. Soc. 1933, 55, 3784ꢀ3791.
Alvim, H. G. O.; Correa, J. R.; Assumpcao, J. A. F.; da Silva, W. A.; Rodrigues, M. O.; de Macedo, J. L.; Fioramonte, M.;
Gozzo, F. C.; Gatto, C. C.; Neto, B. A. D. HeteropolyacidꢀContaining Ionic LiquidꢀCatalyzed Multicomponent Synthesis of
Bridgehead Nitrogen Heterocycles: Mechanisms and Mitochondrial Staining. J. Org. Chem. 2018, 83, 4044ꢀ4053.
Medeiros, G. A.; da Silva, W. A.; Bataglion, G. A.; Ferreira, D. A. C.; de Oliveira, H. C. B.; Eberlin, M. N.; Neto, B. A. D.
Probing the Mechanism of the Ugi FourꢀComponent Reaction with ChargeꢀTagged Reagents by ESIꢀMS(/MS). Chem.
Commun. 2014, 50, 338ꢀ340.
Souza, R. Y.; Bataglion, G. A.; Ferreira, D. A. C.; Gatto, C. C.; Eberlin, M. N.; Neto, B. A. D. Insights on the Petasis
BoronoꢀMannich multicomponent reaction mechanism. RSC Adv. 2015, 5, 76337ꢀ76341.
Alvim, H. G. O.; Bataglion, G. A.; Ramos, L. M.; de Oliveira, A. L.; de Oliveira, H. C. B.; Eberlin, M. N.; de Macedo, J.
L.; da Silva, W. A.; Neto, B. A. D. TaskꢀSpecific Ionic Liquid Incorporating Anionic HeteropolyacidꢀCatalyzed Hantzsch
and Mannich Multicomponent Reactions. Ionic Liquid Effect Probed by ESIꢀMS(/MS). Tetrahedron 2014, 70, 3306ꢀ3313.
Coelho, F.; Eberlin, M. N. The Bridge Connecting GasꢀPhase and Solution Chemistries. Angew. Chem., Int. Ed. 2011, 50,
5261ꢀ5263.
(87)
(88)
(89)
(90)
(91)
(92)
(93)
Santos, L. S. What do We Know about Reaction Mechanism? The Electrospray Ionization Mass Spectrometry Approach. J.
Braz. Chem. Soc. 2011, 22, 1827ꢀ1840.
Ifa, D. R.; Wu, C. P.; Ouyang, Z.; Cooks, R. G. Desorption electrospray ionization and other ambient ionization methods:
current progress and preview. Analyst 2010, 135, 669ꢀ681.
Santos, V. G.; Godoi, M. N.; Regiani, T.; Gama, F. H. S.; Coelho, M. B.; de Souza, R. O. M. A.; Eberlin, M. N.; Garden, S.
J. The Multicomponent Hantzsch Reaction: Comprehensive Mass Spectrometry Monitoring Using ChargeꢀTagged
Reagents. Chem.-Eur. J. 2014, 20, 12808ꢀ12816.
De Souza, R.; da Penha, E. T.; Milagre, H. M. S.; Garden, S. J.; Esteves, P. M.; Eberlin, M. N.; Antunes, O. A. C. The
ThreeꢀComponent Biginelli Reaction: A Combined Experimental and Theoretical Mechanistic Investigation. Chem.-Eur. J.
2009, 15, 9799ꢀ9804.
Iacobucci, C.; Reale, S.; De Angelis, F. Elusive Reaction Intermediates in Solution Explored by ESIꢀMS: Reverse
Periscope for Mechanistic Investigations. Angew. Chem., Int. Ed. 2016, 55, 2980ꢀ2993.
Iacobucci, C.; Reale, S.; Gal, J.ꢀF.; De Angelis, F. Insight into the Mechanisms of the Multicomponent Ugi and Ugi–Smiles
Reactions by ESIꢀMS(/MS). Eur. J. Org. Chem. 2014, 2014, 7087ꢀ7090.
Bain, R. M.; Pulliam, C. J.; Cooks, R. G. Accelerated Hantzsch electrospray synthesis with temporal control of reaction
intermediates. Chem. Sci. 2015, 6, 397ꢀ401.
Ramos, L. M.; Guido, B. C.; Nobrega, C. C.; Corrêa, J. R.; Silva, R. G.; de Oliveira, H. C. B.; Gomes, A. F.; Gozzo, F. C.;
Neto, B. A. D. The Biginelli Reaction with an ImidazoliumꢀTagged Recyclable Iron Catalyst: Kinetics, Mechanism, and
Antitumoral Activity. Chem. -Eur. J. 2013, 19, 4156ꢀ4168.
Gozzo, F. C.; Santos, L. S.; Augusti, R.; Consorti, C. S.; Dupont, J.; Eberlin, M. N. Gaseous supramolecules of
imidazolium ionic liquids: "Magic" numbers and intrinsic strengths of hydrogen bonds. Chem.-Eur. J. 2004, 10, 6187ꢀ
6193.
(94)
(95)
(96)
(97)
(98)
(99)
(100) Chisholm, D. M.; McIndoe, J. S. Charged ligands for catalyst immobilisation and analysis. Dalton Trans. 2008, 3933ꢀ3945.
(101) Vikse, K. L.; Ahmadi, Z.; McIndoe, J. S. The application of electrospray ionization mass spectrometry to homogeneous
catalysis. Coord. Chem. Rev. 2014, 279, 96ꢀ114.
(102) Limberger, J.; Leal, B. C.; Monteiro, A. L.; Dupont, J. Chargeꢀtagged ligands: useful tools for immobilising complexes and
detecting reaction species during catalysis. Chem. Sci. 2015, 6, 77ꢀ94.
(103) Santos, L. S.; Neto, B. A. D.; Consorti, C. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Dupont, J.; Eberlin, M. N. The
role of ionic liquids in coꢀcatalysis of BaylisꢀHillman reaction: interception of supramolecular species via electrospray
ionization mass spectrometry. J. Phys. Org. Chem. 2006, 19, 731ꢀ736.
(104) de Oliveira, V. M.; de Jesus, R. S.; Gomes, A. F.; Gozzo, F. C.; Umpierre, A. P.; Suarez, P. A. Z.; Rubim, J. C.; Neto, B. A.
D. Catalytic Aminolysis (Amide Formation) from Esters and Carboxylic Acids: Mechanism, Enhanced Ionic Liquid Effect,
and its Origin. ChemCatChem 2011, 3, 1911ꢀ1920.
(105) Gore, S.; Baskaran, S.; Koenig, B. Efficient synthesis of 3,4ꢀdihydropyrimidinꢀ2ꢀones in low melting tartaric acidꢀurea
mixtures. Green Chem. 2011, 13, 1009ꢀ1013.
(106) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.: Gaussian 09, Revision A.02. Wallingford CT, 2009.
(107) Chai, J.ꢀD.; HeadꢀGordon, M. Longꢀrange corrected hybrid density functionals with damped atomꢀatom dispersion
corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615ꢀ6620.
(108) Klahn, M.; Garland, M. V. On the Mechanism of the Catalytic Binuclear Elimination Reaction in Hydroformylation
Systems. ACS Catal. 2015, 5, 2301ꢀ2316.
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(109) AbdelꢀAzeim, S.; Jedidi, A.; Eppinger, J.; Cavallo, L. Mechanistic insights into the reductive dehydroxylation pathway for
the biosynthesis of isoprenoids promoted by the IspH enzyme. Chem. Sci. 2015, 6, 5643ꢀ5651.
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