Over the last years, in asymmetric organocatalysis, the use of alternative solvents
has increased, contributing to the reduction of waste formation, in many cases from
the use of volatile organic compounds as a reaction medium.[2 ] The development of greener chemistry is necessary and in this context, deep eutectic
solvents (DESs) emerged as a new generation of cheap and readily available solvents
which are simple to prepare.[3 ]
DESs are recyclable, reusable, stable, nonflammable, biodegradable, and nontoxic mixtures.
Some of its properties are similar to ionic liquids, however, these can be toxic and
are not biodegradable. These excellent properties give DESs the possibility of being
used as greener solvents as an alternative to those commonly used in synthesis. Currently,
DESs are already known as the solvents of the century.[4 ] Thanks to their low ecological footprint and attractive prices, plus the fact that
they are nontoxic and biodegradable, DESs have garnered significant interest and are
now considered as alternative ‘green’ solvents, with application in a wide range of
organic reactions.[5 ] DESs are built from hydrogen-bond donor and hydrogen-bond acceptor components and
gratifyingly can be easily adapted for specific applications. The most widely used
hydrogen-bond donor components, include: urea, thiourea, phenol, glucose, citric acid,
malonic acid, sorbitol, and glycerol. The most commonly used hydrogen bond acceptors
are: choline chloride, betaine, glycine, and proline.[6 ]
[7 ]
DESs have been applied in numerous chemical sectors, such as polymerizations, biotransformations,
such as solvents, in metal-catalyzed reactions, sample preparations, catalytic techniques,
and also in the design of new pharmaceutical formulations.[8 ]
DESs containing betaine and carbohydrates have been studied by Vicente et al.[9 ] Recently, Gutíerrez and coworkers modelled the interactions between DES constituents
using computational methods.[10 ]
A very peculiar and relevant aspect for asymmetric synthesis is the use of chiral
DESs that can be simultaneously used as a reaction medium and a source for asymmetric
induction, where the chirality of the solvent itself is very important.[11 ]
Recently, our group reported the first immobilization of cinchona organocatalysts
on porous glass beads and subsequent application in heterogeneous catalysis. We compared
their performance in both batch and flow systems.[12 ] In this paper we report our studies on immobilized cinchona-squaramide catalysts
in three different DESs, focusing on both catalytic activity and enantioselectivity
of the organocatalyst and its recyclability over several reaction cycles.
Considering the excellent enantioselective and catalytic properties that the cinchonidine-squaramide
catalyst[13 ] (Figure [1 ]) previously provided, a standard Michael reaction was tested, in order to evaluate
the enantioselectivity, yield, and number of catalytic cycles. This benchmark reaction
is easy to perform and provides an excellent measure of the efficiency of the system
under the parameters discussed above.[13 ]
[14 ]
Figure 1 Structure of the cinchonidine-squaramide catalyst
In the first part of this work, we selected a set of DESs, in which one of its components
is a chiral compound, and these compounds can be linear or cyclic (see the Supporting
Information, Tables I–III). All DESs presented in Tables I–III of the Supporting Information
were tested in the chosen Michael reaction. Figure [2 ] shows the chemical structures of the components of the DESs that were studied.
Figure 2 Chemical structure of hydrogen-bond acceptor (HBA) and hydrogen-bond donors (HBD)
In order to study the recyclability and performance of the catalyst, three different
quantities (5, 1, and 0.5 mol%) of the cinchonidine-squaramide organocatalyst were
tested in the Michael addition using the selected DESs, starting with the DES containing
d -sorbitol (DES A). The results obtained at a catalyst loading of 5 mol% are presented
in Table [1 ].
Table 1 Results of Michael Reactions (Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a ) Catalyzed by 5 mol% Cinchonidine-Squaramide Immobilized in DES A (Betaine:d -Sorbitol:Water)
Entry
DES A
Catalyst loading
Cycle
Yield (%)b
ee (%)c
1
betaine:
d -sorbitol: water
5 mol%
1
≥99
97
2
2
≥99
62
3
3
≥99
70
4
4
≥99
95
5
5
97
82
6
6
98
90
7
7
≥99
94
8
8
95
90
9
9
88
62
a Reaction conditions: 1 (0.275 mmol), 2 (0.25 mmol), DES A (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with a chiral stationary phase column.
After nine reaction cycles, there was a noticeable drop in both the yield and the
enantioselectivity (Table [1 ], entry 9), which suggested loss of catalytic activity. The yields were generally
consistent throughout, whilst there were some irregularities with the enantioselectivity
measurements, which may have been due to sampling errors (for instance, entry 2, 62%
ee, entry 3, 70% ee and then entry 4, 95% ee) or due to the chiral nature of the sorbitol
component that can potentially compete with the organocatalyst (see below for further
study of this effect). According to Alonso and co-workers, one of the factors that
influences the results is the partial solubility of DES or the catalyst in the extraction
solvents Hex:AcOEt (1:1) used to isolate the reaction product.[2 ] It is not easy to explain this observation, but it is a strong indication of a complex
dynamic system. This oscillation in enantioselectivity could be the result of dynamic
processes occurring in solution, i.e., the formation of several transient species
between the reagents, the DES constituents, and the organocatalyst. It is likely that
these transient species are chiral and influence the enantioselectivity of the reaction
(see below for further discussion). There were no indications of the structure of
these transient species, but they are probably formed through hydrogen bonds and other
noncovalent interactions, such as ion–dipole interactions and π–π interactions.
The reactions were run at 40 °C, as opposed to room temperature, for the purpose of
maintaining the DES in the liquid state (it tends to solidify at the latter temperature).
The use of 5 mol% of immobilized catalyst in the DESs containing d -sorbitol showed a high catalytic activity over nine cycles. Based on these excellent
results, we decided to decrease the catalytic loading to 1 mol%, and the results obtained
are shown in Table [2 ].
Table 2 Results of Michael Reactions (Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a ) Catalyzed by 1 mol% Cinchonidine-Squaramide Immobilized in DES (Betaine:d -Sorbitol:Water)
Entry
DES A
Catalyst loading
Cycle
Yield (%)b
ee (%)c
1
betaine:d -sorbitol:water
1 mol%
1
≥99
98
2
2
≥99
69
3
3
≥99
66
4
4
94
79
5
5
95
93
6
6
93
75
7
7
99
60
8
8
94
29
9
9
81
17
a Reaction conditions: 1 (0.275 mmol), 2 (0.25 mmol), DES B (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with a chiral stationary phase column.
Table [2 ] shows that 1 mol% of organocatalyst provided nine reaction cycles, the same number
of cycles achieved with 5 mol% of the same catalyst. From entry 1 to 9, Table [2 ], the yields were quantitative during the first three cycles and then decreased slightly
for the next 5 cycles, before bottoming out to 81% after the 9th cycle. Again, there
was an oscillatory trend with the enantioselectivities, which was probably due to
the dynamics of the chiral components (see below), but eventually bottomed out after
the 8th cycle falling to 29% ee and then 17% ee after the 9th cycle.
Since with only 1 mol% of catalyst we obtained nine reaction cycles, it was of interest
to decrease the loading to only 0.5 mol% catalyst (Table [3 ]). In this case the results were less encouraging, it was impossible to obtain quantitative
yields and although the yields remained consistent throughout the five cycles, the
enantioselectivity bottomed-out at 43% ee after the 5th cycle.
Table 3 Results of the Michael Reactions (Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a ) Catalyzed by 0.5 mol% Cinchonidine-Squaramide Immobilized on DES A (Betaine:d -Sorbitol:Water)
Entry
DES A
Catalyst loading
Cycle
Yield (%)b
ee (%)c
1
betaine:d -sorbitol:water
0.5 mol%
1
82
94
2
2
94
87
3
3
95
68
4
4
95
74
5
5
88
43
a Reaction conditions: 1 (0.275 mmol), 2 (0.25 mmol), DES A (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with a chiral stationary phase column.
From these studies we concluded that our organocatalyst performs best at 5 and 1 mol%
loading. Since these results were obtained using DES A, we also decided to study other
DESs containing d -sorbitol analogues: such as d -xylitol (DES B) and d -mannitol (DES C; Tables 4 and 5). On using DES B and C it was also possible to obtain
a high number of catalytic cycles with catalyst loadings of 1 and 0.5 mol%, respectively.
In a similar fashion to what happened upon using DES A these catalyst loads also presented
the most promising results. In the case of DES B (Table [4 ]), best results were obtained at 1 mol% catalyst loading; after 4 cycles both the
yield and enantioselectivity remained high (86% and 84% ee). However, in the case
of the system using 0.5 mol% catalyst, the enantioselectivity bottomed out at 10%
ee after the 4th cycle, although the yield was quantitative. This was a strong indication
of the competing or the antagonistic effects of the organocatalyst and the DES chiral
component (d -xylitol) (see below for DFT calculations).
Table 4 Results of Michael Reactions (Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a ) Catalyzed by 0.5 and 1 mol% Cinchonidine-Squaramide Immobilized on DES B (Betaine:d -Xylitol:Water)
Entry
DES B
Catalyst loading
Cycle
Yield (%)b
ee (%)c
1
betaine:d -xylitol:water
0.5 mol%
1
96
87
2
2
91
93
3
3
89
63
4
4
98
10
5
1 mol%
1
98
92
6
2
93
67
7
3
90
93
8
4
86
84
a Reaction conditions: 1 (0.275 mmol), 2 (0.250 mmol), DES B (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with a NOT A chiral stationary phase column.
Finally, Table [5 ] shows the results of the reactions catalyzed by 0.5 and 1 mol% of cinchonidine-squaramide
(catalyst A ) in the DES containing d -mannitol (DES C). The results shown in Table [5 ] correspond to loadings of 0.5 and 1 mol% of the catalyst. A 5th reaction cycle was
also performed with 0.5 mol% catalyst but unfortunately the DES solidified, a clear
indication of the increased density of the DES most likely due to increased hydrogen-bonding
network formation. The same also happened on the fourth reaction cycle using 1 mol%
catalyst. The yields obtained were good, albeit the enantioselectivities generally
lower that those obtained using DES A and B. It should be noted that DES C was partially
soluble in the solvent used in the extraction of the product.
Table 5 Results of Michael Reactions (Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a ) Catalyzed by 0.5 and 1 mol% Cinchonidine-Squaramide Immobilized in DES C (Betaine:d -Mannitol:Water)
Entry
DES C
Catalyst loading
Cycle
Yield (%)b
ee (%)c
1
betaine:d -mannitol:water
0.5 mol%
1
57
83
2
2
35
73
3
3
55
99
4
4
67
≥99
5
1 mol%
1
19
52
6
2
64
78
7
3
87
87
a Reaction conditions: 1 (0.275 mmol), 2 (0.25 mmol), DES C (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with a chiral stationary phase column.
The best enantioselectivities were obtained using both DES A and C, which are C6 sugars
(and epimers in the C-5 position; sorbitol C-(S )5 and mannitol C-(R )5), with the former giving the best results, probably due to the configuration of
the C-5 stereocenter. The C-5-sugar d -xylitol was the worst performer, probably due to the length of its backbone and its
influence on reactant solubility and transition-state stabilization.
Based on the best results that were obtained for DES A, to measure the scope of the
reaction, we decided to evaluate the reaction of cinchonidine-squaramide (1 mol%)
immobilized in DES A for the asymmetric Michael addition of methyl 2-oxocyclopentane-1-carboxylate
(4 ) and trans -β-nitrostyrene (2 ). Table [6 ] shows the results and gratifyingly shows that the catalytic system was active up
to ten cycles, maintaining the enantioselectivities, diastereoselectivities, and yields.
The diastereoselectivities increased significantly from the 1st to the 2nd cycles
and remained more or less constant until the 10th cycle, up to 97% de. Surprisingly,
the enantioselectivity of the major diastereomer (S ,R ) had very small variation over the 10 cycles, in the 1st cycle 94% ee and in the
last cycle 93% ee. The yields were almost quantitative during all the cycles, with
the exception of the 6th cycle, where the yield dropped to 56%, which may have been
a mixing issue.
Table 6 Results of the Michael Reactions with Methyl 2-Oxocyclopentane-1-carboxylate (4 ) and trans -β-Nitrostyrene (2 )a Catalyzed by 1 mol% Cinchonidine-Squaramide Immobilized on DES A
Entry
DES A
Catalyst (loading)
Cycle
Yield (%)b
de (%)c
ee (%)c
1
betaine:d -sorbitol:water
no
–
99
58
rac
2
1 mol%
1
99
73
94
3
2
99
92
86
4
3
99
93
84
5
4
99
92
92
6
5
99
94
88
7
6
56
94
96
8
7
98
94
93
9
8
97
97
94
10
9
98
97
95
11
10
97
97
93
a Reaction conditions: 4 (0.275 mmol), 2 (0.25 mmol), DES A (2 mL), 40 °C, 24 h.
b Determined by isolated mass.
c Determined by HPLC with a chiral stationary phase column.
As an interesting side study, to determine if the chiral DES had an impact on the
asymmetric induction, some reactions were carried out in the absence of catalyst.
Gratifyingly, the reaction showed for DES A a large enantioselectivity of 75% ee (Table
[7 ], entry 1), but interestingly when the reactions were performed using DES B and C
only an enantioselectivity of 3% ee was obtained and the yields were about 30% lower
(Table [7 ], entries 2 and 3).
Table 7 Results of Michael Reactions Carried Out in the Absence of Catalyst in DESs between
Acetylacetone (1 ) and trans -β-Nitrostyrene (2 )a
Entry
DES
Ratio
Yield (%)b
ee (%)c
1
betaine:d -sorbitol:water (DES A)
1:1:3
81
75
2
betaine:d -xylitol:water (DES B)
53
3
3
betaine:d -mannitol:water (DES C)
51
3
a Reaction conditions: 1 (0.275 mmol), 2 (0.25 mmol), DES (2 mL), 40 °C, 24 h.
b Determined by 1 H NMR spectroscopy using mesitylene as a standard.
c Determined by HPLC with chiral stationary phase column.
Figure 3 (A) Possible interactions between d -sorbitol and betaine. (B) Possible stabilization of the reaction transition state
(TS) by the key DES A components. The water molecules are not shown but they may act
as a bridge between the betaine and sorbitol components and perhaps also between the
DES components and the TS structure.
Figure 4 (A) Purported transition-state mechanism for the cinchona-squaramide catalyzed Michael
addition.[13 ]
[15 ] (B) Postulated role of the DES sorbitol component in stabilizing the transition
state (for clarity the betaine component is omitted).
It’s hard to understand the exact role of the chiral DES in these reactions. It appears
to have a specific role in establishing key hydrogen bonding networks with the reagents
and the catalyst. Some possible interactions are described in Figure [3 ]. In Figure [3 ]A, a possible interaction between d -sorbitol and betaine is shown, however, due to steric hindrance it is more likely
that the ratio between sorbitol and betaine would be 1:2 or 1:3 at most. In Figure
[3 ]B, the possible stabilization of the Michael addition transition state by sorbitol
and betaine is shown. For simplicity, water is not included, but for sure it must
also be a key component in stabilizing this transition state via specific H-bonding
interactions. Fluctuations in the enantioselectivities between cycles may be explained
via disruptions and changes in the H-bonding networks during the reaction cycles;
for example, the nitro groups of the various Michael addition intermediates shown
in the drawing in Figure [3 ]B may alternate between different hydroxyl groups of the sorbitol unit, which can
affect the bulk enantioselectivity. The oscillations in the enantioselectivities could
be due to dynamic matching and mismatching interactions. In the case of the catalyst’s
role, a purported mode of action is outlined in Figure [4 ]B[13 ]
[15 ] where it is suggested that the sorbitol component can form stable H-bonding interactions
with the two carbonyls of the squaramide unit, possibly lowering the energy of the
transition state. In fact, it’s very likely that the TS shown in Figure [4 ]B competes with that shown in Figure [4A ] and might explain these oscillations.
To gain deeper insights into the mechanism of this reaction in these systems we performed
DFT computational studies on a very simplistic model system at M06-2X/6-31G(d,p) level
using the Gaussian 16 software package.[16 ] Solvent effects were considered by the SMD continuum solvation model.[17 ] Four models were considered for the reaction between acetylacetone and trans -β-nitrostyrene environment (Figure [5 ]): (a) implicit water, (b) implicit water plus explicit water molecules, (c) implicit
water and sorbitol, (d) and implicit water and cinchona-squaramide catalyst.
Figure 5 Transition-state structures calculated (DFT) for the studied models displaying relevant
H-bonds with the TS structure
Transitions states for the different models shown in Figure [5 ] were found and the free energy profiles show an important reduction on the barrier
height (activation energy) when compared with the water models, not only for the cinchona-squaramide
case, but also on the sorbitol system. We found that it was the cinchona-squaramide
catalyst that gave the lowest TS energy (d, blue line Figure [6 ]) followed by the sorbitol system (c, red line Figure [6 ]) and, interestingly, it was the system composed of intrinsic and extrinsic water
that showed the highest energy barrier (grey line Figure [6 ]). This study shows clearly that the DES component sorbitol has a significant positive
effect on reaction transition state, probably at a catalytic level, supporting the
observed experimental results.
Figure 6 Free-energy profile for the different studied system. Free-energy profiles for the
different studied systems. Calculated energies relative to the energy of separated
reactants. Reactant adducts, transition states, and product adducts are represented
by R_add , TS and P_add , respectively.
Of all the DESs used in the standard reaction, DES A (betaine:d -sorbitol:water) was the one that gave the best results.[18 ]
[19 ]
[20 ]
[21 ] The use of low loads of catalyst, namely 5 and 1 mol%, provided the Michael adduct
with the best yields, ees, and greatest number of cycles, five and nine cycles, respectively,
in the case of acetylacetone and ten cycles in the case of methyl 2-oxocyclopentane-1-carboxylate.
The differences in the results with the various DESs may be accounted for by the different
sugar components used. The structure of d -mannitol is also very similar to that of d -sorbitol and the only aspect that distinguishes them is the orientation of one of
the hydroxyl groups. Some oscillations in the ees from one cycle to the next were
recorded, this can be due to various H-bonding modes between the DES components, the
reactants, and the catalyst (see above) but also the mixing may also have an influence,
poor mixing of the viscous DES may lead to a nonuniform or asymmetric distribution
of the components, including elements of the DES and the organocatalyst provoking
these oscillations in the enantioselectivity. DFT studies showed that sorbitol appears
to have a catalytic effect on the reaction through specific H-bonding effects. Furthermore
detailed experimental studies will be conducted in due course to understand more fully
the mechanistic nature of the reactions in these systems.
