Silica gel-immobilized multidisciplinary materials applicable in stereoselective organocatalysis and HPLC separation

Article abstract of DOI:10.1039/c7ra12658a

In this pilot study, we present novel bifunctional silica gel-immobilized materials applicable as heterogeneous organocatalysts and stationary phases in HPLC. The materials provided high stereoselectivity in both batch and continuous flow catalysis of a m

Full text of DOI:10.1039/c7ra12658a

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Silica gel-immobilized multidisciplinary materials
applicable in stereoselective organocatalysis and
HPLC separation†
Cite this: RSC Adv., 2018, 8, 1174
J. Tuma and M. Kohout
*
˚
In this pilot study, we present novel bifunctional silica gel-immobilized materials applicable as
heterogeneous organocatalysts and stationary phases in HPLC. The materials provided high
stereoselectivity in both batch and continuous flow catalysis of
a model Michael addition
(
cyclohexanone to (E)-b-nitrostyrene). In the batch reaction, the catalysts proved their sustainable
Received 21st November 2017
Accepted 20th December 2017
catalytic activity over five consecutive recycling experiments. Under continuous flow reaction conditions,
the catalytic activity was found to be superior to the batch reaction, and moreover, the same
immobilized materials were utilized as stationary phases in HPLC showing very good chemoselective
separation of model acidic analytes.
DOI: 10.1039/c7ra12658a
rsc.li/rsc-advances
organocatalysts covalently bound to the silica gel surface were
carried out, exploiting mostly L-proline, or Cinchona derivatives.
Introduction
Organocatalysis stands amongst the major areas of contempo- Such materials were (amongst others) employed in asymmetric
1
–6
47–51
52–56
rary stereoselective synthesis. Since its foundation on the aldol reactions,
Michael additions,
three-component
7,8
57,58
59–62
63
verge of the new millennia, stereoselective organocatalysis has reactions,
Diels–Alder reactions,
or alkylations. In
become widely exploited in countless organic reactions general, the utilized organocatalysts exhibited moderate to
9
–15
including Michael additions.
excellent conversions as well as stereoselectivity and good
46
In the past two decades, many organocatalysts have proven recyclability. Further studies were focused on non-covalently
to be very effective in Michael additions of C-nucleophiles immobilized organocatalysts bound to ion liquid-modied
16–24
64,65
(aldehydes, ketones, malonates) to nitroolens.
To ensure silica gel surface.
high stereoselectivity of the reaction, bifunctional organo-
The sole immobilization of the catalyst, however, is not
catalysts bearing secondary or tertiary amines together with sufficient enough to meet the high demands of a potential large
a second activating moiety, such as urea, or thiourea, have also scale application. If the immobilized catalyst is used in a batch
25–27
been developed.
reaction system, it still requires a separation step (usually
The bifunctional organocatalysts have demonstrated their ltration) to be properly regenerated. On the other hand, if the
high efficiency in both yield and stereoselectivity of the studied catalyst is incorporated into a ow reactor, the regeneration
reactions, however they suffer from a rather troublesome requirements are easily achievable by a simple washing step.
recovery, which usually leads to a partial loss of the catalyst. The Several recent publications have been focused on this topic
66
current approach to address this problem involves immobiliza- exploiting various types of solid supports, mostly poly-
2
8
67–70
71–73
tion of the catalyst to a solid support. Several types of solid styrene,
or silica gel.
Complementary to stereoselective synthesis, optically pure
organic frameworks, ion-modied resins for non-covalent compounds can be achieved by chiral separation of racemates
29–35
36,37
matrices, such as polystyrene,
metal nanoparticles,
metal–
38
39–41
42–45
74–77
binding,
or mesoporous silica
have been introduced as using chromatographic techniques.
In such a case, a proper
solid supports for various types of organocatalysts.
design of a suitable chiral stationary phase (CSP) bearing
Silica gel represents a well-dened and mechanically stable a chiral selector is essential in order to achieve good chro-
solid support for a large scale of organocatalytic species and matographic resolution.
ensures repeatable quantitative recycling of the heterogenized
In this work we present a study of four chiral functionalized
catalysts. Therefore, extensive studies of various chiral derivatives of carbonic acid (two carbamates, one urea, one
thiourea) terminated by an alkynyl, or alkenyl chain, which
46
enables efficient immobilization of the prepared compounds to
Department of Organic Chemistry, University of Chemistry and Technology Prague,
a modied silica gel (Scheme 1). The prepared compounds were
Technick a´ 5, Prague 6, 166 28, Czech Republic. E-mail: michal.kohout@vscht.cz
successfully employed as highly stereoselective homogeneous
organocatalysts in model Michael addition of cyclohexanone to
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra12658a
1
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homogeneous and heterogeneous catalysis (both batch and

ow setup) as well as in HPLC separation.
Results and discussion
First, the amino carbamate compound Ia was employed in
a model Michael addition of cyclohexanone with (E)-b-nitro-
styrene. The proposed reaction mechanisms towards all stereo-
isomers of the product is shown in Scheme 2. The reaction was
ꢀ
carried out at room temperature and 0 C in various solvents
(Table 1). Butyric, or acetic acid was used as a co-catalyst medi-
ating imine bond formation between the catalyst and cyclohexa-
none as well as supporting the hydrolysis of the corresponding
iminium salt formed aer the addition to nitrostyrene.
Scheme
1 The synthetic pathway towards the immobilized
compounds. For Experimental details see ESI.†
27
The amino carbamate compound Ia has proven to be
a potent catalyst for the studied reaction. A highly impactful
effect of the chosen solvent was observed. In general, the less
polar solvent was used, the higher yield and stereoselectivity
was achieved (Table 1, entries 1–4). The only exception was
a slightly lower yield obtained in hexane (Table 1, entry 1) than
in toluene (Table 1, entry 2) due to the lower solubility of the
catalyst in hexane.
(
E)-b-nitrostyrene (ee up to 95%, syn : anti up to 97 : 3). Aer
immobilization to the silica gel solid support, the materials
were exploited as heterogeneous catalysts in the same model
reaction (ee up to 90%, syn : anti up to 95 : 5). The immobilized
catalysts allowed for an easy regeneration with constant ster-
eoselective performance and only partial decrease in reaction
conversion. Moreover, the prepared materials were packed into
stainless steel columns and tested in a continuous ow
arrangement. Despite modest reaction conversions in this
setup, higher stereoselectivity to the batch reaction experiments
was obtained. The column-packed compounds were further
utilized as stationary phases for separation of model acidic
compounds (2-arylpropionic acids, N-protected 2-amino-
phosphonic acid mono-esters) using HPLC.
The best results, however, were found using neat cyclohex-
anone in the absence of solvent (Table 1, entries 5–6). At room
temperature, the reaction proceeded almost quantitatively with
9
1% ee and high syn-stereoselectivity (95 : 5). Lowering the
ꢀ
reaction temperature to 0 C led to a slight improvement in
stereoselectivity (ee ¼ 93%), while minor decrease in the reac-
tion conversion was observed (74%).
The other compounds from the series (Ib–d) were tested in
the same model Michael addition (Table 2) using the previously
obtained optimized conditions (Table 1, entry 5).
To our best knowledge, the presented materials are the rst
immobilized compounds applicable in highly stereoselective
Scheme 2 The proposed catalytic pathways towards the products of the studied Michael addition. For further details see ESI.†
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Table
catalyzed with Ia
1 Model Michael addition in homogeneous environment
a
b
Conversion
c
d
b
Entry
Catalyst
Solvent
(isol. yield ) [%]
ee [%]
syn : anti
Scheme 3 The decomposition of amino urea Ic.
1
2
3
4
5
6
Ia
Ia
Ia
Ia
Ia
Ia
Hexane
Toluene
DCM
73 (56)
86 (70)
61 (48)
30 (14)
94 (87)
74 (62)
84
81
75
51
91
93
92 : 8
94 : 6
92 : 8
82 : 18
95 : 5
95 : 5
The amino thiourea compound Id exhibited highly increased
catalytic activity in the model reaction. A full conversion was
obtained within only 5 h (Table 2, entry 4). Therefore, following
optimization regarding the amount of the catalyst was carried
out (Table 2, entries 5–7). 10 mol% of the catalyst Id provided
MeOH
e,f
Neat
e,f,g
Neat
a
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 250 ml, Ia
ꢀ
0
.05 mmol, butyric acid 0.0025 mmol, solvent 1 ml, t ¼ 25 C, reaction
b
1
c
time ¼ 48 h. Determined by
H
NMR. Puried by column quantitative conversion within acceptable time span (48 h) and
d
chromatography (hexane : ethyl acetate ¼ 5 : 1). Determined by
chiral HPLC (column YMC Amylose C, mobile phase heptane : IPA ¼
excellent stereoselectivity (Table 2, entry 5). Further decrease of
the catalyst amount led to protracted reaction time and
ꢁ
1
e
9
: 1, ow rate 0.7 ml min ). Additional 750 ml of cyclohexanone
f
was used instead of the solvent. 0.035 mmol of AcOH used instead a conversion drop without any signicant effect on the reaction
g
ꢀ
of butyric acid. Reaction carried out at t ¼ 0 C, reaction time ¼ 144 h.
stereoselectivity (Table 2, entries 6, 7).
The catalytic activity of the amino thiourea compound Id was
further studied in the same solvents as in the case of Ia
(
Table 3). Based on the previous experiments, only 10 mol% of
According to our expectations, the amino carbamate
compound Ib provided comparable results to its direct
analogue Ia (compare Table 2, entries 1 and 2). In the case of Ib,
the reaction time was deliberately prolonged in order to reach
quantitative conversion.
the catalyst was used in the reactions.
The obtained results have conrmed the previously observed
trend of solvent inuence. The less polar solvent is used, the
higher stereoselectivity is obtained (Table 3). While no product
was formed in methanol, the stereoselectivity found in hexane
Despite the fact that most of the current bifunctional orga-
nocatalysts employ a urea or thiourea moiety, in our case the
amino urea-type compound Ic provided only traces of the
desired product (Table 2, entry 3). The low to none activity of the
catalyst can be ascribed to its low stability. Surprisingly, in
contrast with its amino carbamate analogues Ia,b, it is prone to
spontaneous decomposition even at ambient temperature. This
decomposition is initiated by an intramolecular nucleophilic
attack of the secondary amino group of the catalyst to the urea
moiety followed by the detachment of corresponding aromatic
amine. This leads to the quick deactivation of the catalyst. We
have conrmed this undesired reaction mechanism by isolating
the decomposition products aer treatment of Ic with ethanol
at reux (Scheme 3; for experimental details see ESI†).
(
Table 3, entry 1) even equaled, if not exceeded, the original
experiment in neat cyclohexanone (compare to Table 2, entry 5).
The use of hexane, thus, overcomes the necessity of the neat
reaction conditions, which are rather inconvenient in terms of
a potential practical application.
The prepared compounds were further immobilized to
a modied silica gel. Either a radical-initiated addition of 3-
mercaptopropyl-modied silica gel to the terminal double bond
(Ib), or a click-reaction of 3-azidopropyl-modied silica gel to
the terminal triple bond (Ia,c,d) was used (Scheme 4).
The immobilized compound IIb was obtained in a total
ꢁ
1
loading of 80 mmol g , which corresponds to a 30% reaction
conversion. On the other hand, the materials IIa,c,d were yiel-
ded in the total coverage up to 249 mmol g , which corresponds
ꢁ
1
to an almost quantitative immobilization.
Table
2 Model Michael addition in homogeneous environment
a
catalyzed with Ia–Id under the optimized conditions
b
Table 3 Model Michael addition in homogeneous environment
catalyzed with Id
Reaction Conversion
time [h]
a
c
d
b
Entry Catalyst
(isol. yield ) [%] ee [%] syn : anti
b
Reaction Conversion
time [h]
1
2
3
4
5
6
7
Ia
Ib
Ic
Id
48
72
48
5
94 (87)
Quant. (91)
0
Quant. (79)
Quant. (85)
50 (42)
91
94
—
84
92
93
93
95 : 5
94 : 6
—
95 : 5
97 : 3
95 : 5
96 : 4
c
d
b
Entry Solvent
(isol. yield ) [%] ee [%] syn : anti
1
2
3
4
Hexane
Toluene 48
DCM
MeOH
72
61 (32)
Quant. (92)
77 (52)
0
95
89
80
—
94 : 6
91 : 9
90 : 10
—
Id (10 mol%) 48
Id (5 mol%) 120
Id (2 mol%) 120
72
72
7 (4)
a
a
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 250 ml,
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 1 ml,
ꢀ
ꢀ
Id 0.025 mmol, acetic acid 0.035 mmol, solvent 1 ml, t ¼ 25 C.
catalyst 0.05 mmol, acetic acid 0.035 mmol, solvent 1 ml, t ¼ 25 C.
b
1
c
b
1
c
Determined by H NMR. Puried by column chromatography
d
Determined by H NMR. Puried by column chromatography
d
(hexane : ethyl acetate ¼ 5 : 1). Determined by chiral HPLC (column
YMC Amylose C, mobile phase heptane : IPA ¼ 9 : 1, ow rate
(
hexane : ethyl acetate ¼ 5 : 1). Determined by chiral HPLC (column
YMC amylose C, mobile phase heptane : IPA ¼ 9 : 1, ow rate
ꢁ
1
ꢁ
1
0.7 ml min ).
0
.7 ml min ).
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analogues (Table 5). For both catalysts, a similar trend of the
solvent inuence to the experiments in homogeneous envi-
ronment was observed, i.e. the less polar solvent was used, the
higher stereoselectivity was obtained (ee up to 82%, syn : anti up
to 94 : 6).
In the case of the amino thiourea material IId, the reaction in
hexane notably surpassed the reaction conversion found in neat
cyclohexanone (compare Table 4, entry 4 and Table 5, entry 5).
Therefore, the reaction conditions in hexane were considered as
the optimized conditions, despite minor decrease of the reac-
tion stereoselectivity in comparison to the experiment in neat
cyclohexanone. As mentioned above, solvent conditions are
generally more convenient than the neat reaction conditions,
since they allow for cheaper potential practical applications.
The achieved results are comparable to values found for
a silica-supported pyrrolidine-triazole catalyst (ee up to 91%,
Scheme 4 Immobilization of the target compounds.
The obtained heterogeneous catalysts IIa–d were tested in
the same model Michael addition of cyclohexanone to (E)-b-
nitrostyrene under the optimized reaction conditions as for Ia–
d (Table 4).
Undoubtedly, in all cases the overall reaction conversion has
decreased in comparison to the experiments in homogeneous
environment. Surprisingly, the two amino carbamate catalysts
52
syn : anti up to 94 : 6) under neat conditions. The studied
organocatalysts slightly underperformed in comparison to an
imidazolium–pyrrolidine silica-supported catalyst, for which
very high values of enantio- and diastereoselectivity (ee up to
(IIa,b) yielded almost the same conversion (Table 4, entries 1, 2),
despite having signicantly different loading of the organo-
catalyst (see Scheme 4). On the other hand, the amino thiourea
catalyst IId, which was, based on the homogeneous experi-
ments, expected to be the most active, delivered only 25% of the
product (Table 4, entry 4). Based on these unexpected results, it
can be concluded that the kinetics of the reaction in heteroge-
neous environment is not driven by the chemical reaction itself.
The rate-limiting step is most probably denoted by the diffusion
of either the reagents into the silica gel pores (where the catalyst
molecules are bound), or the products from the pores into the
solvent. Nevertheless, it is worth pointing out that the prepared
immobilized compounds IIa,b,d have proven to be efficient
stereoselective heterogeneous catalysts of the studied reaction
9
9%, syn : anti up to 99 : 1) together with yields up to 96% were
53
reported. On the other hand, our results for the addition of
cyclohexanone to (E)-b-nitrostyrene are much better than those
achieved with a heterogeneous pyrrolidine-tetrazole organo-
catalyst (ee up to 55%, syn : anti up to 15 : 1), which was
however primarily developed for continuous ow Michael
72
addition of cyclohexanone to 4-nitrobenzaldehyde.
The performance of the immobilized heterogeneous cata-
lysts IIa and IId was subsequently studied in a series of recycling
experiments. Five consecutive reactions under the optimized
conditions (Table 4, entry 1 and Table 5, entry 5) with the same
batch of the catalyst were carried out. Aer each reaction, the
immobilized catalyst was ltered off the reaction mixture,
washed and used in the next cycle (Table 6).
Throughout the set of the experiments, both the immobi-
lized materials IIa and IId proved their permanent catalytic
activity. In the case of IIa, only a slight decrease of ee (7–9%)
(
ee ¼ 78–90%, syn : anti ¼ 90 : 10–95 : 5).
The amino urea compound IIc delivered a very poor yield of
the product with only moderate stereoselectivity (Table 4,
entry 3). It is highly probable that the immobilized catalyst
suffers from the same instability as its homogeneous precursor
Ic (see Scheme 3). Therefore its activity is limited accordingly.
The prepared heterogeneous catalysts IIa,d were further
tested in the same set of solvents as their homogeneous
Table
5 Model Michael addition in heterogeneous environment
a
catalyzed with IIa and IId
b
Conversion
c
d
b
Entry
Catalyst
Solvent
(isol. yield ) [%]
ee [%]
syn : anti
Table
catalyzed with IIa–d
4 Model Michael addition in heterogeneous environment
a
1
2
3
4
5
6
7
8
IIa
IIa
IIa
IIa
IId
IId
IId
IId
Hexane
Toluene
DCM
MeOH
Hexane
Toluene
DCM
44 (23)
51 (38)
39 (16)
16 (10)
37 (21)
23 (15)
17 (10)
7 (3)
82
78
70
46
80
78
74
53
92 : 8
94 : 6
92 : 8
82 : 18
94 : 6
94 : 6
92 : 8
86 : 14
b
Reaction Conversionc
d
b
Entry Catalyst time [h]
(isol. yield ) [%] ee [%] syn : anti
1
2
3
4
IIa
IIb
IIc
IId
72
72
72
72
51 (36)
49 (18)
10 (7)
78
90
58
86
95 : 5
90 : 10
83 : 17
94 : 6
MeOH
25 (10)
a
a
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 250 ml,
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 1 ml,
ꢀ
ꢀ
catalyst 0.05 mmol, acetic acid 0.035 mmol, solvent 1 ml, t ¼ 25 C,
catalyst 0.05 mmol, acetic acid 0.035 mmol, t ¼ 25 C, reaction time
b
1
c
b
1
c
reaction time ¼ 72 h. Determined by H NMR. Puried by column
¼
72 h.
Determined by
H
NMR.
Puried by column
d
d
chromatography (hexane : ethyl acetate ¼ 5 : 1). Determined by
chromatography (hexane : ethyl acetate ¼ 5 : 1). Determined by
chiral HPLC (column YMC Amylose C, mobile phase heptane : IPA ¼
chiral HPLC (column YMC Amylose C, mobile phase heptane : IPA ¼
ꢁ
1
ꢁ
1
9
: 1, ow rate 0.7 ml min ).
9
: 1, ow rate 0.7 ml min ).
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Table
6 Model Michael addition in heterogeneous environment Table 7 Model Michael addition: continuous flow reaction catalyzed
a
catalyzed with IIa and IId
with IIa and IId
b
c
Conversion
Conversion
c
d
b
d
e
c
Entry
Catalyst
Solvent
(isol. yield ) [%]
ee [%]
syn : anti
Entry
Catalyst
Solvent
(isol. yield ) [%]
ee [%]
syn : anti
e
af
1
2
3
4
5
6
7
8
9
IIa
IIa
IIa
IIa
IIa
IId
IId
IId
IId
IId
neat
51 (36)
34 (17)
37 (20)
32 (18)
35 (21)
37 (21)
21 (13)
20 (11)
22 (13)
19 (12)
78
72
70
69
69
80
80
89
81
79
95 : 5
94 : 6
96 : 4
96 : 4
93 : 7
94 : 6
95 : 5
92 : 8
94 : 6
93 : 7
1
IIa
IId
Neat
Hexane
32 (24)
7 (5)
86
80
93 : 7
94 : 6
e
bf
Neate
2
Neat
a
e
Reaction conditions: nitrostyrene 5.0 mmol, cyclohexanone 100 ml,
Neate
ꢁ1
ꢀ
acetic acid 50.0 mmol, ow 0.7 ml min , t ¼ 25 C, reaction time ¼
Neat
b
7
1
2 h. Reaction conditions: nitrostyrene 5.0 mmol, cyclohexanone
00 ml, acetic acid 50.0 mmol, ow 0.7 ml min , t ¼ 25 C, reaction
Hexane
Hexane
Hexane
Hexane
Hexane
ꢁ1
d
ꢀ
c
1
time ¼ 72 h. Determined by
H
NMR. Puried by column
e
chromatography (hexane : ethyl acetate ¼ 5 : 1). Determined by
chiral HPLC (column YMC Amylose C, mobile phase heptane : IPA ¼
ꢁ
1
f
1
0
9 : 1, ow rate 0.7 ml min ). Residence time ¼ 42 min.
a
Reaction conditions: nitrostyrene 0.25 mmol, cyclohexanone 250 ml,
ꢀ
catalyst 0.05 mmol, acetic acid 0.035 mmol, solvent 1 ml, t ¼ 25 C,
b
1
c
reaction time ¼ 72 h. Determined by H NMR. Puried by column
d
chromatography (hexane : ethyl acetate ¼ 5 : 1). Determined by the other hand, enantioselectivity has exceeded the original
chiral HPLC (column YMC Amylose C, mobile phase heptane : IPA ¼
batch experiments yielding ee ¼ 86%, while keeping the dia-
ꢁ1
e
9
: 1, ow rate 0.7 ml min ). Additional 750 ml of cyclohexanone
stereoselectivity at a very high ratio of syn : anti ¼ 93 : 7.
The compound IId yielded only 7% of the desired product.
However, equally high stereoselectivity as in the batch reactions
was obtained (ee ¼ 80%, syn : anti ¼ 94 : 6).
was used instead of the solvent.
aer the rst reaction cycle was observed (Table 6, entries 1–5),
The overall low yields of the studied continuous ow setup
whereas the catalyst IId yielded the same stereoselectivity could be explained by short residence time of the substrates
through the whole reaction span (Table 6, entries 6–10).
inside the catalytic columns, which leads to their limited
In the consequent reactions, a minor drop of conversion was interaction with the catalyst. This issue as well as other catalytic
found aer the rst cycle, however the average value remained properties can be addressed by an easy tunability of the catalytic
constant in further cycles (Table 6, entries 2–5 and 7–10). The system (varying the particle size and porosity of the solid
decrease in the reaction conversion might be a consequence of support, extending the spacer length of the catalyst, etc.).
a less effective re-activation of the catalyst by simple washing
aer each reaction cycle.
More efficient and already veried supports such as organic
29–35
36,37
polymers
or nanoparticles
have, however, not been
Furthermore, the compounds IIa and IId were packed in- considered in this study. The obvious reason is that we aimed
house into stainless steel columns (150 ꢂ 4 mm) and incorpo- for simultaneous use of the new materials as continuous ow
rated into a continuous ow system. As shown in Fig. 1, the organocatalysts and stationary phases for HPLC. Therefore, the
system contains only one reaction mixture reservoir that works silica gel solid support for the materials IIa–d was selected.
as both the inlet and outlet. Therefore, in terms of the reaction
The basic nature of the studied materials predetermines
kinetics, the system does not run a ow reaction, but rather them for efficient interaction with acidic analytes in the sense of
a batch reaction, which takes place inside the column. Never- ion-exchange process. Under weakly acidic mobile phase
theless, the main advantage of the continuous ow system – no conditions, the basic selector is protonated, while the analytes
need for the catalyst separation and simple regeneration by (organic acids) are fully or reversibly deprotonated. The elec-
washing – remains intact. The results are shown in Table 7. trostatic attraction between the charged functional groups is
Aer the reaction, the columns were washed with 1% solution primarily responsible for retention of analytes, while additional
of acetic acid in methanol to obtain the fully regenerated cata- interactions (p–p, hydrogen bonds, steric interactions) may
78,79
lyst for the next reaction cycle.
facilitate chiral recognition of enantiomers.
To test the properties of the prepared materials IIa–d as CSPs
In the case of IIa, the continuous ow reaction has delivered
an equal conversion as the batch reaction using the same for the separation of acidic analytes, two classes of compounds
catalyst aer the rst reaction cycle (Table 6, entries 2–5). On were chosen (Fig. 2). Analytes A1–A6 (2-arylpropionic acids)
belong among non-steroidal anti-inammatory drugs and thus
their purity (and enantiomeric purity) is oen the target of
quality control departments of pharmaceutical industries as
well as research laboratories. For analytes P1–P6 (N-protected 2-
aminophosphonic acid mono-esters), we have already reported
efficient enantioseparation on analytical scale using quinine-
80
and quinidine-based AX CSPs.
Although the studied immobilized compounds IIa–d did not
afford enantioseparation of the individual analytes, they
showed very good chemoselectivity allowing to separate
Fig. 1 The experimental setup for continuous flow reaction.
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Fig. 4 Separation of N-protected aminophosphonic acid mono-
esters P1–P6 in ion exchange mode under HPLC conditions using the
column-packed material IIa. Conditions: mobile phase, methanol/
acetic acid/ammonium acetate (99/1/0.5, v/v/w%); flow rate of 1
ꢁ
1
ꢀ
Fig. 2 The studied analytes: (a) 2-arylpropionic acids; (b) N-protected ml min ; temperature 20 C. The injection volume was 5 ml with the
ꢁ1
2-aminophosphonic acid mono-esters.
sample concentration of 1 mg ml . The detection wavelength was set
to 230 nm.
a mixture of analytes of each class. Selected examples are shown
in Fig. 3 and 4 (for other gures see ESI†). For the separation of aminophosphonic acid mono-ester derivatives. The lowest
various mixtures, reversed phase (RP) chromatography is retention was found for ibuprofen (A1) with a exible alkyl
commonly used. This technique takes the advantage of lipo- chain followed by naproxen (A2) (Fig. 3). On the other hand, the
philic stationary phases (usually silica modied with long alkyl second highest retention time was observed for bromo-
chains) operated in a polar mobile phase. Separation is based naproxen. It seems that the steric demand of the substituent
on hydrophobic interactions of analytes with the stationary connected to the central aromatic ring of the substance signif-
81
phase. RP chromatography has very broad application range,
icantly inuences its interaction with the selector.
however, highly polar and ionic analytes may be badly resolved
The importance of the size of substituents is well docu-
or not retained at all. Therefore the development of so-called mented by the separation of N-protected aminophosphonic acid
mixed-mode stationary phases that offer combination of mono-esters (Fig. 4). While mono-methyl esters P1–P3 based on
82
83,84
different interaction modes is of high interest nowadays.
The presented materials can be considered as RP-ion-exchange ycarbonyl protecting group showed only minor differences in
systems.
retention times, the introduction of bulkier ester group already
aliphatic aminophosphonic acids possessing a benzylox-
Overall, the arylpropionic acids were eluted slightly faster led to considerable shi in retention time. Additional elonga-
than N-protected aminophosphonic acid mono-esters, which tion of retention time was observed for phenylphosphonic
is in agreement with lower acidity (weaker electrostatic inter- mono-ester P5 and a dramatic shi towards higher retention
action) of arylpropionic acids in comparison with the was found in case of Fmoc-protected derivative P6. These results
indicate that the primary electrostatic interaction is further
supported by p–p interactions, which leads to higher retention.
This enhanced interaction is, however, not sufficient to facili-
tate chiral recognition of the analytes, thus, both enantiomers
still co-elute in one peak. This may be caused by the overall high

exibility of the immobilized compounds, which is important
for the catalytic function, but does not provide a pre-organized
binding site necessary for chiral recognition.
The only stationary phase that underperformed in the che-
moselective separation of the analytes was the amino carbamate
compound IIb. This material was prepared using a different
immobilization technique (see Scheme 4), which yielded only
ꢁ
1
low selector loading (80 mmol g ). Thus, the stationary phase is
not robust enough to effectively retain the analytes and there-
fore no separation is achieved (for chromatograms see ESI†).
Fig. 3 Separation of arylpropionic acids A1–A6 in ion exchange mode
under HPLC conditions using the column-packed material IIa.
Conditions: mobile phase, methanol/acetic acid/ammonium acetate
Conclusions
ꢁ1
ꢀ
In conclusion, a series of silica gel-based materials bearing
chiral bifunctional carbonic acid derivatives was designed and
synthesized. The prepared compounds were successfully
(
99/1/0.5, v/v/w%); flow rate of 1 ml min ; temperature 20 C. The
ꢁ1
injection volume was 5 ml with the sample concentration of 1 mg ml
.
The detection wavelength was set to 230 nm.
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