Supported Ionic Liquid-Like Phases (SILLPs) as Immobilised Catalysts for the Multistep and Multicatalytic Continuous Flow Synthesis of Chiral Cyanohydrins

Article abstract of DOI:10.1002/cctc.201900086

Supported Ionic Liquid-Like Phases have been found to be efficient organocatalysts for the synthesis of cyanohydrin esters under solvent-free conditions by an “electrophile-nucleophile dual activation” based on hydrogen bond formation. The combination of

Full text of DOI:10.1002/cctc.201900086

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DOI: 10.1002/cctc.201900086
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Supported Ionic Liquid-Like Phases (SILLPs) as Immobilised
Catalysts for the Multistep and Multicatalytic Continuous
Flow Synthesis of Chiral Cyanohydrins
Edgar Peris,[a] Raúl Porcar,[a] María Isabel Burguete,[a] Eduardo García-Verdugo,*[a] and
Santiago V. Luis*[a]
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Supported Ionic Liquid-Like Phases have been found to be
efficient organocatalysts for the synthesis of cyanohydrin esters
under solvent-free conditions by an “electrophile-nucleophile
dual activation” based on hydrogen bond formation. The
combination of multiple and consecutive multicatalytic steps in
a single and integrated cascade process of organocatalytic
SILLPs with commercially available supported Candida antarcti-
ca lipase type B (CAL-B) has allowed developing an efficient
process for the multicatalytic synthesis of enantiopure cyanohy-
drins under flow conditions.
Introduction
use of solid phase chemistry, enabling not only flow
processes,[16–26] but the development of one-pot multicatalytic
multi-component transformations integrating several synthetic
reactions in a single process.[27,28] The inspiration for this
strategy is the biosynthetic machinery operating in nature,
where potentially incompatible chemical transformations are
separated by compartmentalisation, with reactive intermediates
being passed from one unit to the next one. Although past
decades have seen a significant progress in this direction, one-
pot multicatalytic reactions are still not of general application.[29]
The one-pot combination of catalytic and biocatalytic processes
is an even more challenging issue. Although different strategies
have been assayed to circumvent their mutual inactivation,[30,31]
the strong potential negative interferences between the
components of both systems (reagents, products and catalysts)
and the conditions needed for both processes have often
hampered the development of one-pot sequential telescoped
synthetic processes of this nature.
Here we report a methodology for the continuous flow
synthesis of cyanohydrins based on the combination of multiple
and consecutive multicatalytic steps in a single and integrated
cascade process, where organocatalysts based on so-called
Supported Ionic Liquid-Like Phases play a key role. The
combination of organocatalytic SILLPs with commercially avail-
able supported Candida antarctica lipase type B (CAL-B) has
allowed developing an efficient process for the multicatalytic
synthesis of enantiopure cyanohydrins under flow conditions.
Ionic Liquids (ILs) have emerged as exceptionally interesting
systems in many fields, including their use as reaction media for
catalytic processes.[1,2,3] In this context, a great effort has been
devoted to develop ILs with modified functionalities (Task-
Specific ILs-TSILs) in order to introduce groups providing
Brönsted and Lewis acidic o basic behaviour, organocatalytic or
organometallic properties, all of which can display a catalytic
activity.[4] In the search of practical applications of these
catalytically active TSILs, the full recovery of the catalytic system
needs to be always considered. Therefore, the use of supported
IL-phases has gained importance in this field.[5,6,7,8] For this
purpose, the covalent attachment of IL-phases to an organic
polymeric support has been demonstrated to transfer to the
surface of the polymer some of the main features of ILs at the
molecular level (stability, tuneable polarity, etc.) while avoiding
the possibility of leaching.[9,10,11] On the other hand, the
presence of the polymeric backbone offers an additional design
vector to optimise the macroscopic and process properties of
the overall catalytic system.[12,13] Indeed, these supported ionic-
liquid like phases (SILLPs) can be applied as “solid ionic solvents”
for catalytic processes in an analogous way to bulk ILs but
simplifying product isolation and recycling of the catalyst-IL-
phase. As for bulk ILs, structural changes/modifications in both
cation and anion result in widely varying properties of the
supported ILs, allowing their tuning for the specific needs of a
given catalytic process.[14,15] This approach combines the
advantages of ILs as catalyst supports and modifiers with the
Results and Discussion
[a] E. Peris, R. Porcar, M. I. Burguete, Dr. E. García-Verdugo, Prof. S. V. Luis
Department of Inorganic and Organic Chemistry, Supramolecular and
Sustainable Chemistry Group
Cyanohydrins have considerable synthetic potential as chiral
building blocks allowing their transformation into a large
number of chiral molecules, especially in the field of pharma-
ceuticals and agrochemicals.[32] Different methodologies have
been developed for their synthesis in both racemic and
enantiopure forms. A majority of methods reported for the
preparation of enantiopure cyanohydrins are based on the
Universitat Jaume I
Avda Sos Baynat s/n, 12071-Castellon (Spain)
E-mail: luiss@uji.es
cepeda@uji.es
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201900086
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Figure 1. Structure of drugs synthesisable through cyanosilylation of different aldehydes.
Scheme 1. Synthesis of chiral cyanohydrins by multiple catalytic cascade reactions.
asymmetric addition of a cyanide derivative, such as a silyl
cyanide, a cyanoformate, a cyanophosphate, or an acyl cyanide,
to a prochiral carbonyl compound by using a (chiral) Lewis acid
or a Lewis base catalyst or a combination of both types of
catalysts.[33,34] Alternatively, HCN biocatalytic addition has been
shown to provide high selectivity to a variety of prochiral
aldehydes. These two methods, however, present some limi-
tations. The first one requires the use of expensive chiral
organometallic systems, while for the biocatalytic approach,
albeit being more environmentally friendly,[35] the reversibility
of the reaction may cause deterioration of the enantiomeric
excess.[36,37] Thus, the design of simple and highly enantioselec-
tive processes with a low environmental footprint is still
needed.
the formation of the corresponding ester; 3) the enzymatic
kinetic resolution of the resulting cyanohydrin ester by trans-
esterification in presence of alcohol. In this way, at least three
different catalysts are required to develop a single-pot process.
It has been recently reported that Supported Ionic Liquid-
Like Phases (SILLPs) can efficiently catalyse the cyanosilylation
reaction of aldehydes and ketones (step-1).[39] Table 1 shows
that by using 6 (Figure 2) as a simple supported organocatalyst
the four aldehydes considered could be converted into the
corresponding cyanosilyl ethers (3a–d) with excellent yields.
Table 1. Batch multistep consecutive synthesis of cyanohydrins.
Substrate
R
Step-1[e]
Step-2[f]
Step-3[g]
In this study, four specific different aldehydes (1–4) for
which the corresponding cyanohydrins are key intermediates
for the total synthesis of different commercial drugs (Figure 1)
were selected as the starting materials.[38]
Scheme 1 depicts the general synthetic methodology
proposed to obtain the corresponding chiral cyanohydrins from
simple available aldehydes. The process requires three consec-
utive steps involving four catalytic reactions: 1) organocatalytic
cyanosilylation of the aldehydes; 2) transformation into the
corresponding methyl ester, which requires two consecutive
reactions, first the hydrolysis of the cyanosilyl ether and then
Entry
Yield
[%][a]
99
95
95
Yield
[%][b]
99
99
99
Yield
[%][c]
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ee
[%][d]
>99
>99
>99
>99
1
2
3
4
C6H5-
p-ClC6H4-
o-ClC6H4-
C4H3S-
95
99
52
[a] Conditions: 1 eq RCHO, 1.2 eq TMSCN; rt, 24 h, Cat: 25 mg per mmol of
RCHO. [b] Conditions: 1 eq substrate, 2 eq Ac2O, 40 C, 24 h, 50 mg of cat.
per mmol of substrate. [c] Conditions: 9.8 mL 2-Me-THF, 0.15 mL n-
propanol and 100 mg CAL-B (Novozym 435) per mmol of substrate, 60 C,
24 h, yield for 5a–d. [d] ee for 4a–d; ee>95% for 5a–d. [e] Catalysed by 6.
[f] Catalysed by 11. [g] Catalysed by Novozym 435.
°
°
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Figure 2. Catalysts assayed for the different steps of the overall process.
This methodology allows the first synthetic step to proceed
with excellent yield, 100% atom economy, no waste regarding
the side-products formation and unconverted reactants, use of
solvent-free conditions, excellent catalytic activity, and no
requirement for purification before performing the next step.
Step-2 involving the consecutive hydrolysis of the cyanosilyl
ether and the formation of the corresponding acetyl ester
requires a catalyst able to facilitate both reactions. Figure 2
illustrates the structure of the catalysts 7–14 evaluated for this
step under batch conditions. The screening was performed in
the absence and presence of acetic anhydride (Ac2O) to
evaluate the intrinsic activity of the catalyst for the silyl ether
hydrolysis (in the absence of Ac2O) and, alternatively, for the
two consecutive reactions (in the presence of 2 eq. of Ac2O).
The trimethylsilyl cyano ether (3a) derived from benzaldehyde
(step-1) was used as the model substrate for such screening
under solvent free conditions.[40]
The commercially available polymeric supported sulfonic
acids assayed (8 and 9) were able to promote the quantitative
hydrolysis of the silyl ether group, but not the acetylation of the
resulting cyanohydrin (<10%). The water absorbed on the
catalyst is likely to favour the hydrolysis of the silyl ether while
inhibiting ester formation (Table S1, entries 1 and 3). Indeed,
the opposite trend was observed when these catalysts (8 and 9)
were vacuum dried for 24 hours. The reaction performed in the
absence of Ac2O was inhibited (<15%), while in the presence
of Ac2O the consecutive catalysed desilylation and ester
formation took place (>90%, Table S1, entries 2 and 4). The
related silica-immobilised sulfonic catalyst (12) was also an
active catalyst displaying a good performance for the two
tested reactions (>90%, Table S1, entry 5).
However, the related Sc complex formed by reaction with Sc
(OTf)3 and the zwitterionic SILLP 10 led to moderate results for
the consecutive desilylation and acetylation reactions (Table S1,
entry 7). In the case of catalyst 13, prepared by treating SILLP
10 with acetic acid, initial results showed also a moderated
activity (Table S1, entry 9) for both coupled reactions. Interest-
ingly, while for catalyst 10 a significant loss of activity was
observed with reuse (Figure S1b), the reuse of catalyst 13 under
the same conditions showed an increase in its activity in such a
way that after four reuses yields >95% were obtained for the
synthesis of the corresponding cyano ester (Figure S1a). The
catalyst 14 was also active for synthesis of the cyano ester 4a
(Table S1, entry 11). Summarising, at least four supported
catalytic systems (11, 12, 13 and 14) were effective for the
consecutive desilylation and acetylation reactions required for
the step 2 of our proposed telescoping synthesis.
We also evaluate the direct preparation of cyanohydrin
acetal ester (4a) by the reaction of benzaldehyde with acetyl
cyanide under solvent free conditions and using different
catalysts (Table S3, SI). The catalysts tested were less efficient
providing lower yields than the two step reaction using TMSCN
and Ac2O as reagents and the catalysts based on SILLPs.
The final step can be achieved by the use of an enzymatic
catalyst.[46] Thus, the enantioselective hydrolysis of the racemic
mandelonitrile acetate ((�)-4a) in the presence of n-propanol
and using 2-methyl-tetrahydrofurane (2-Me-THF) as the solvent
was considered. The immobilised commercially available Lipase
B from Candida antarctica (Novozym 435) could be used to
transform the racemic cyanohydrin acetate into a mixture of (S)-
cyanohydrin and (R)-mandelonitrile acetate (>99.9% ee), with a
conversion slightly higher than 50% (Table 1, entry 1). The
effect of the concentration of the racemic mandelonitrile
acetate was then investigated (Table S2). Concentrated solu-
tions, up to 1 M, of rac-mandelonitrile acetate could be used
with good conversions (55%) and enantioselectivities (>99%
ee for 4a, Table S2, entry 2). The use of more concentrated
solutions of n-propanol (2 M in 2-Me-THF), however, produced a
decrease on the enantioselectivity of the kinetic resolution (KR)
(52% ee for 4a, Table S2, entry 3).
In the search of alternative catalytic systems, ILs and task
specific ILs have been used to catalyse both ester formation,[41,42]
and the desilylation reaction.[43] It has been also reported that
Sc(OTf)3/Ac2O mixtures can be efficient systems for the consec-
utive desilylation and acetylation of sugars and this mixture was
also very efficient in our case (entry 6 in Table S1).[44,45] In view
of these precedents, we prepared a series of task-specific SILLPs
(7, 10, 11, 13, 14 Figure 2) as potential catalysts for the second
step. Unfortunately, the initial screening of the catalyst 7
indicated that it was neither efficient for the hydrolysis nor for
the esterification in the presence of Ac2O (Table S1, entry 8).
Table 1 summarises the results obtained when the catalysts
6, 11 and Novozym 435 were applied for the synthesis, under
batch conditions, of the corresponding cyanohydrins from
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Figure 3. Evaluation of the catalyst stability for the two-step synthesis of racemic mandelonitrile acetate (4a) under continuous flow conditions. Black squares:
yield for step-1 after R-I; Red dots: yield for step-2 after R-II. a) step 1: RI: 1 g catalyst 6, 0.01 mLminÀ 1, r.t; step 2: R-II: 1 g catalyst 11, 0.019 mLminÀ 1. b) step 1:
R-I: 1 g catalyst 6, 0.01 mLminÀ 1, r.t.; step 2: R-II: 1 g catalyst 12, 0.02 mLminÀ 1 1a:TMSCN:Ac2O 1:1.1:1.2 (molar ratio).
aldehydes 1–4. The results demonstrate that it is possible to
obtain the corresponding cyanosilyl ethers (3a–d) and the
corresponding racemic cyanohydrin esters (4a–d) with excellent
yields (>90%) independently of the aldehyde used. Note-
worthy, the first and second steps were performed under
solvent-free conditions, where the single purification performed
before the subsequent step was the filtration of the correspond-
ing solid catalysts. The kinetic enzymatic resolution of the
cyanohydrin esters was able to selectively hydrolyse the
racemic esters to yield the (S)-enantiomer of the cyanohydrins
and leaving the corresponding (R)-cyanohydrin acetates (with
an enantiomeric excess >99.9%).
shields the catalytic centres from one another.[30,31,47,48] The use
of consecutive fix-bed reactors can provide the required
isolation of the catalysts by compartmentalisation and to favour
the simple and continuous production of the chiral target
without the need for isolation of any intermediates and without
requiring the separation of any catalysts, co-products, by-
products, and excess reagents.[16,27,28,49,50]
Thus, the use of a continuous flow process using benzalde-
hyde as the starting material to perform a telescopic synthesis
of the corresponding cyanohydrin was evaluated. Accordingly,
the continuous synthesis of the cyanohydrin esters using two
fixed-bed reactors coupled together in-line was initially eval-
uated. The first reactor (R-I) was packed with catalyst 6, and a
neat mixture of benzaldehyde and TMSCN (1:1.1 molar ratio)
was pumped at 0.01 mLminÀ 1. A second reactor (R-II) filled with
catalyst 11 was connected at the exit of R-I by means a T-piece,
which also allowed to mix the silyl ether coming out from R-I
with a stream containing acetic anhydride. The flow of this
steam was adjusted to a flow rate (0.009 mLminÀ 1) matching to
2 equivalents of Ac2O per each equivalent of the silyl ether
coming out from R-I. Although catalyst 11 was able to
simultaneously hydrolyse the silyl ether and to form the
corresponding ester yielding the desired rac-mandelonitrile
acetate, it did not show a long-term stability. A strong
deactivation of 11 was observed after 24 hours of continuous
use on stream (Figure 3a). After this time, the main product
collected at the outlet of the two reactors was the cyanosilyl
ether, indicating that though the second reactor was not stable
These results demonstrate that it is possible to perform the
synthesis of the enantiopure cyanohydrins by three consecutive
catalytic steps under batch conditions. However, when the
single-pot multicatalytic cascade reaction was evaluated, using
a combination of the different catalytic systems, the single
process fails. Indeed, even when different protocols were
assayed for the consecutive addition of the catalysts and/or
reagents, the global process proceeded with low conversion
and/or low enantioselection. Thus, the single-pot multicatalytic
process is not feasible under batch conditions due to the
incompatibility between the enzymatic catalyst and some of
the reagents and/or catalysts involved in the global synthetic
sequence.
A simple approach to enable cascade or concurrent chemo-
enzymatic reactions to occur without mutual inactivation is to
compartmentalise the different catalytic systems. This approach
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Figure 4. Evaluation of the catalyst stability for the two-step synthesis of racemic mandelonitrile acetate (4a) under continuous flow conditions. Black squares:
yield for step-1 after R-I; Red dots: yield for step-2 after R-II. a) step-1: R-I: 1 g catalyst 6, 0.01 mLminÀ 1, rt; step-2: R-II: 1 g catalyst 13, 0.019 mLminÀ 1
1a:TMSCN:Ac2O 1:1.1:2.
.
enough, R-I was still active. Indeed, this reactor (R-I) was stable
for at least 50 hours, with >95% yields, with the productivity
for this period being ca. 24 g of product / g of catalyst.
improvement of the yield from ca. 65% to ca. 90%, suggesting
SILLP 13 as a suitable catalyst for step-2.
The different stability of the catalysts can be rationalised
attending their differences at the molecular level. The catalyst
11 is a metallic salt with Lewis acid properties that in the
presence of an excess of acetic acid can lead to a significant
scandium leaching. Indeed, an increase in the amount of Ac2O
used in the reaction from 1.2 to 2 equivalents led to a faster
catalyst deactivation. Regarding the solid sulfonic acid catalyst
12, its partial deactivation can be associated to the lack of
efficient regeneration of the Brönsted acidity in the catalytic
cycle.
On the contrary, the bifunctional SILLP 13 can work as a
dual catalyst with a dramatic anion-cation cooperative effect
and a catalytically efficient combination of acidic and basic
sites. As detected by TGA SILLP 13 contains ca. 5% of water and
ca. 2% of acetic acid (see Figure S2). The acid sites, in the
presence of some water, can hydrolyse the cyanosilyl ether to
yield the corresponding alcohol.[51] On the other hand, the C-2
hydrogen at the imidazolium moiety can also contribute to the
electrophilic activation of the carbonyl group of Ac2O through
hydrogen bond formation. The efficient transformation of the
initially formed trimethyl silyl alcohol (TMSOH) into the
corresponding ether (TMS2O) is essential to regenerate the
catalytic water needed for the hydrolysis, which seems to be
facilitated by the presence of acetic acid molecules in 13. An
acetic acid molecule can also play a key role in the acylation
step by activating the Ac2O through hydrogen bonding.[52,53]
In order to confirm the deactivation suffered by the catalyst
11, a mixture of the cyanosilyl ether (3a) and Ac2O (1:1.2 eq.)
was pumped directly through R-II at 0.02 mLminÀ 1. The catalyst
was stable during the 3 first hours with yields >99%. However,
after an additional period of 24 hours on stream, the yield
dropped to <30%. These results highlight the importance of
assessing the long term stability of the catalyst for flow
processes. Even catalysts that are active for consecutive runs
under batch conditions might be not suitable for prolonged
used under continuous flow. In the light of the former results,
other active catalysts were evaluated for step-2 taking into
consideration the results previously discussed (according to
results in Table S1). Thus, an alternative R-II fix-bed reactor was
prepared with the commercially available silica-based sulfonic
acid catalyst 12 and the reaction mixture was pumped through
it at a flow rate of 0.02 mLminÀ 1. The catalyst was still active
after 20 hours of continuous use, although after 5 hours on
stream the activity dropped from >95% to 70% (Figure 3b).
Finally, catalyst 13 displayed a constant catalytic perform-
ance with a stable yield for 4a of ca. 65% for more than
40 hours of continuous use under flow conditions (Figure 4). At
the view of the stable performance of this catalyst, the
improvement in the obtained yield was assayed by adjusting
the experimental conditions. Indeed, an increase of the excess
of the Ac2O used from 1.2 to 2 equivalents rendered an
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Figure 5. Mechanistic model for the consecutive processes involved in the synthesis of cyanohydrin catalysed by SILLPs 6 and 13.
Therefore, the cation of the SILLP and the acetic acid activate
the electrophile, as hydrogen bond donors, while the anion
activates the nucleophile, as hydrogen bond acceptor. The
importance of the dual nature of catalyst 13 is demonstrated by
comparing its catalytic activity with the one for a mixture of 8
and 14, a SILLP containing acetate as the counteranion. The
mixed system is catalytically active but its activity decreases
with the reuse (Figure S3a) and the same is observed for 14
(Figure S3b).
A plausible reaction mechanism is presented in Figure 5
based on this dual activation effect. Here the SILLP is acting in a
similar fashion than related ILs in solution by an “electrophile–
nucleophile dual activation” through a cooperative hydrogen-
bonded network.[54,55,56,57] These results confirmed that sup-
ported ionic liquid phases are able to mimic the catalytic
behaviour found for bulk ILs with the additional advantages of
needing a smaller amount of IL, an easier isolation and recycling
and the possibility to work under continuous flow conditions.
The last step to complete the process is the continuous
kinetic resolution of the cyanohydrin ester obtained after the
second step. This process is a well stablished reaction under
batch conditions.[58] A bioreactor was prepared as a fix bed
reactor with Novozyme 435 (R-III) to evaluate the feasibility of
this approach. A solution of the racemic cyanohydrin ester 4a
in 2-Me-THF (0.1 M) and n-propanol as the transesterification
agent (2 equiv., 0.2 M) was pumped through the catalytic bed
demonstrated the feasibility of the KR of the racemic acetylated
mandelonitrile under continuous conditions. At the view of
these results, the telescoped synthesis of cyanohydrin was
assayed by using three consecutive fix bed reactors (R-I, R-II
and R-III) packed respectively with the organocatalytic SILLPs 6
and 13 and with Novozym 435 as the supported biocatalyst.
The results obtained for this set-up are summarized in Figure 6.
The reactors were coupled sequentially after each reactor
had reached the steady state without including any separation
step. Thus, the reactor R-II was connected to R-I after 1000 min,
when the first reaction was taking place with yields >90% to
afford the cyanosilyl ether 3a. In a similar way, R-III was
attached to the two previous ones after 3700 min, when the
corresponding acetate ((�)-4a) was obtained with >90%
conversion. In the last reactor, the racemic acetate was kineti-
cally resolved by the action of the enzyme, which selectively
hydrolysed the racemic esters to yield the (S)-enantiomer of the
cyanohydrin 5a and the corresponding (R)-cyanohydrin acetate
(4a) (with an enantiomeric excess >99% for a conversion to 5a
slightly higher than 50%).
Noteworthy, it was possible to achieve efficiently a coupled
process involving four consecutive reactions, which was not
feasible as a single-pot process under bath conditions. The
system was stable at least for two days (>3000 minutes) of
continuous use. Our results suggest that the combination of
continuous flow processes, SILLPs as organocatalytic phases
and biocatalysts can lead to an efficient process in terms of
catalytic efficiency but also regarding the process productivity
and sustainability. In this context, it should be mentioned that
step-1 and its combination with step-2 (step1+step-2) have
remarkably low E factors (0.1 and 0.93 respectively, Table S4),
which highlight the greenness of these two steps performed
°
(R-III) at 60 C and 40 bar. Thus, for a total flow rate of 0.35 mL/
min, an excellent and selective conversion of the cyanohydrin
ester to the corresponding alcohol (ca. 48% yield for the
alcohol) was found, with excellent enantiopurities for both the
(R)-acetylated mandelonitrile (95% ee) and the hydrolysed (S)-
mandelonitrile. (>99% ee, Figure S4). Thus, these results
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Figure 6. Evaluation of the catalyst stability for the multicatalytic synthesis of enantiopure mandelonitrile acetate ((R)-4a) under continuous flow conditions.
Black squares: yield for step-1 after R-I; red dots: yield for step-2 after R-II; green triangles: yield for step-3 after R-III; blue triangles: enantioselectivity for the
final product ((R)-4a) after R-III. Step-1: R-I: 1 g catalyst 6, 0.01 mLminÀ 1, rt; step-2: R-II: 1 g catalyst 13, 0.019 mLminÀ 1. 1a:TMSCN:Ac2O 1:1.1:2; step-3: RIII:
1 g Novozym 435 (CALB), 60 C, flow 0.35 mLminÀ 1, 0.1 M 4a in Me-THF:IPA (0.85:0.15).
°
under solvent free conditions. The use of an additional organic
solvent required in the KR step is reflected in the significant
increase of the E factor (21.8 without considering solvent
recovery). These values are however lower than those reported
for other catalytic and biocatalytic methods (see Tables S5 and
S6 in the SI) being inferior to the usual E values for a
pharmaceutical product ranging from 25 to 100.[59] Regarding
productivity, the obtained values for the individual steps range
from 100 to 200 mggÀ 1 hÀ 1, being the biocatalytic step the one
displaying the higher productivity. Overall, the space-time-yield
(STY) for the final step of the process, including the two chiral
products of interest formed, is 124 ggÀ 1 cat.hÀ 1 L, a value that
that observed in bulk ILs. Hence, SILLPs might be regarded as
“solid ionic solvents” or as nanostructured materials with
microenvironments displaying the same characteristics, at
molecular level, as their analogous ILs phases. Besides, their
insoluble nature enables their use under continuous flow,
allowing the possibility of combining organocatalytic and
biocatalytic successive reactions to facilitate complex synthetic
syntheses to occur in a single process, avoiding deactivation/
incompatibility issues found in the related single-pot batch
syntheses.
compares well for related biocatalytic processes described for Experimental Section
the synthesis of cyanohydrins using hydroxynitrile liases and
Experimental details are provided in the electronic supplementary
information
HCN, a more hazardous chemical reagent than TMSCN.[60,61]
Conclusions
Acknowledgements
In summary, the right combination of organocatalysts based on
Supported Ionic Liquid-Like Phases with a biocatalyst allows
successfully developing a valuable flow protocol for the multi-
catalytic, multistep, single-pot and metal-free synthesis of chiral
cyanohydrins with good yield and enantioselectivity. Our
studies also highlight the potential for catalytic applications of
This work was partially supported by G. V. (PROMETEO 2016-071)
and MINECO (CTQ2015-68429R). E. Peris thanks MICINN for the
financial support (FPU13/00685).
SILLPs designed with specific functionalities. An “electrophile– Conflict of Interest
nucleophile dual activation” through a complex network of
hydrogen bonding seems to be essential, in a similar way to
The authors declare no conflict of interest.
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E. Peris, R. Porcar, M. I. Burguete,
Dr. E. García-Verdugo*, Prof. S. V.
Luis*
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1 – 9
Supported Ionic Liquid-Like
9
Phases (SILLPs) as Immobilised
Catalysts for the Multistep and
Multicatalytic Continuous Flow
Synthesis of Chiral Cyanohydrins
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Step it up: An integrated cascade
multicatalytic multiple step flow
process based on the appropriated
combination of organocatalytic
supported ionic liquid-like phases
(SILLPs) together with commercially
available supported Candida antarcti-
ca lipase type B (CAL-B) is reported for
the efficient synthesis of enantiopure
cyanohydrins.