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Reversal of Enantioselectivity in Aldol Reaction: New Dataon Proline/ c-Alumina Organic–Inorganic Hybrid Catalysts

Gyo ¨rgy Sz}oll}osi • Mónika Fekete •

András A. Gurka • Mihály Bartók

Received: 30 September 2013 / Accepted: 26 November 2013 / Published online: 12 December 2013

Springer Science+Business Media New York 2013

Abstract We report new results on the aldol reactions

between aldehydes of three different types (aromatic, ali-phatic and cycloaliphatic) and acetone/cycloalkanones as

reaction partners, driven by organic–inorganic hybrid cat-

alyst Pro/ c-Al2O3. In contrast to the homogeneous liquid-

phase reaction, over Pro/ c-Al2O3 reversal of the enantio-

selection in up to 20–40 % ee depending on the structure of

the aldehyde was observed in reactions of acetone.

Reversal of the ee in the presence of c-Al2O3 cannot be

generalized, as it has only been observed for acetone

among the ketones studied by us. It was proven using

methods of a great variety such as ultrasonic irradiation,

reuse measurements on used catalyst and the filtrate of

the first reaction, measurements on the L-Pro-L-Pro(OH)

dipeptide, studies using mixtures of L-Pro and D-Pro that

the organic–inorganic hybrid catalyst Pro/ c-Al2O3 formed

in situ is responsible for reversal of the ee. In the reactions

of cycloalkanones there is presumably competition

between the liquid-phase and the surface reaction over Pro/

c-Al2O3 with preference for the former. Based on these

results a surface reaction pathway was proposed. Although,

the ees obtained under heterogeneous catalytic conditions

are low, further studies may lead to application of this

unusual phenomenon for obtaining chiral heterogeneous

catalysts suitable for the preparation of the desired enan-

tiomer of a chiral compound using the same chiral source.

Keywords Asymmetric catalysis Aldol reaction

L-Pro/ c-Al2O3 catalyst Inversion of enantioselectivity

1 Introduction

Asymmetric heterogeneous catalysis has become widely

studied for the production of chiral compounds [1–6].

Easily available, optically active compounds of natural

origin (alkaloids, aminoacids, peptides, carbohydrates) are

advantageously used as chiral catalysts or catalyst modifi-

ers in these synthetic procedures. A widely used group of

chiral catalysts—especially in the aldol reaction studied in

this manuscript—is supported-proline and its synthetic

derivatives [7, 8]. In our studies on heterogeneous catalytic

asymmetric syntheses, in addition to enantioselective

hydrogenations [3], studies on organocatalytic reactions

[9–11], among which certain aldol reactions over poly-

styrene resin supported-proline catalysts were also initiated

[12]. In the meantime, considerable progress has been

made in the research of peptide-type immobilized organ-

ocatalysts [13–16].

In the course of investigating the mechanism of enan-

tioselective heterogeneous catalytic hydrogenations, an

unexpected inversion observed [17, 18] turned our atten-

tion to studying the role of this phenomenon, earlier rec-

ognized by Kagan et al. [19], in the origin of chiral

induction. As a first step, the pertinent literature was

reviewed [20], and it was found that at the present stage of

research it was not possible to draw general conclusions so

far. Among publications on heterogeneous chiral catalysts

causing unexpected inversion, our attention was also

attracted by the publication by Li and coworkers [21]

reporting the application of L-proline (and other L-amino

acids) as well as an organic–inorganic hybrid catalyst

G. Sz}oll}osi M. Bartók

MTA-SZTE Stereochemistry Research Group, Dóm tér 8,

Szeged 6720, Hungary

M. Fekete A. A. Gurka M. Bartók (&)

Department of Organic Chemistry, University of Szeged, Dóm

tér 8, Szeged 6720, Hungary

e-mail: [email protected]

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Catal Lett (2014) 144:478–486

DOI 10.1007/s10562-013-1177-1

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containing alumina in the aldol reaction. In the course of

their work these authors established that in the case of

amino acids adsorbed on c-alumina, ‘‘unexpected inver-

sion’’ occurred as compared to dissolved amino acids, i.e.

non-heterogenized catalysts. They demonstrated by UV-

Raman spectroscopy that adsorption on alumina brought

about the formation of a new type of catalyst designated

‘‘organic–inorganic hybrid catalyst’’.This manuscript present the results of our recent inves-

tigations aiming at the extension of the applicability of the

new heterogenized catalyst in the aldol reaction, the

accumulation of further data on the reaction mechanism,

increasing the optical yield, and collecting further infor-

mation regarding this practically important reaction.

2 Experimental

2.1 Materials

L-proline (L-Pro) and D-proline (D-Pro), and analytical

grade solvents were purchased from Sigma-Aldrich and

used as received. Aldehydes: 2-nitrobenzaldehyde (1), iso-

butyraldehyde (2), butyraldehyde (3), cyclohexanecarbox-

aldehyde (4) and ketones: acetone (5), cyclohexanone (6),

cyclopentanone (7) were purchased from Sigma-Aldrich

and purified either by crystallization or by distillation.

L-Pro-L-Pro(OH) was prepared according to known proce-

dure using L-Pro-OtBu and Fmoc-L-Pro-OH derivatives

purchased from Bachem GmbH and Sigma-Aldrich,

respectively [22]. Aluminum oxides were purchased from

Alfa Aesar (AA, 42576, c-Al2O3, 110 lm powder, BET

surface area 60 m2 g-1) and Sigma-Aldrich (SA, 544833,

nanopowder, c phase, particle size\50 nm, BET surface

area[40 m2 g-1) and were used as received, without any

pretreatment.

2.2 General Procedure for the Aldol Additions

The reactions were carried out in closed glass reactors. The

given amount of chiral amino acid catalyst (typically 0.075

or 0.15 mmol L-Pro or D-Pro) was suspended/dissolved in

2 mL acetone or the given amount of solvent followed by

addition of c-Al2O3, the corresponding aldehyde, ketone

(except reaction using acetone both as aldol donor and

solvent) and 5 lL n-tetradecane (as internal standard). The

reaction mixture was stirred magnetically at 25 C for the

given time. After the specified reaction time the catalyst

was removed either by washing with sat. NH4Cl and

extracting the products in ethyl acetate (reactions without

the use of c-Al2O3) or by centrifugation of the solid cata-

lyst (the Pro/ c-Al2O3) and washing the remaining solid

with ethyl acetate. The unified organic phases were

analysed by gas chromatography (GC). After some reac-

tions the Pro/ c-Al2O3 materials were dried and recycled

using identical reaction conditions (solvent, aldehyde,

ketone amounts) as in the first reaction. Reactions using

mixtures of L-Pro and D-Pro were carried by using the

appropriate amounts of the enantiomerically pure amino

acids. Reactions under sonication were carried out using

identical experimental setup, except instead of magneticagitation the reactors were immersed in a sonication bath

(Branson 1510, frequency 40 kHz) for 1 h.

2.3 Analysis Methods

Products were identified by their mass spectra using Agi-

lent Techn. 6890 N GC-5973 inert MSD and HP-1MS

60 m 9 0.25 mm i.d. capillary column. Quantitative ana-

lysis including enantiomeric separation was performed

using GC equipped with flame ionization detector (FID):

Agilent Techn. 6890N GC-FID and Cyclosil-B 30 m 9

0.25 mm i.d. chiral capillary column. Enantiomericexcesses (ee) were calculated using the formula ee [%] =

|conc R - conc S |/(conc R ? conc S ) 9 100, where conc R

and conc S are the concentrations of the aldol product

enantiomers. Chromatographic conditions and retention

times are shown in Table 1. The absolute configurations of

the aldol products were assigned by analogy with previ-

ously reported results using L-Pro as catalyst. The repro-

ducibility of the reactions was ±3 %.

IR spectra of the Pro/ c-Al2O3 materials recovered after

reactions were recorded on a Bio-Rad Digilab Division

FTS-65A/896 FT-IR spectrometer operated in diffuse

reflectance mode (DRIFT) between 4,000 and 400 cm-1 at

2 cm-1 resolution by averaging 256 scans.

3 Results and Discussion

In the present study several oxides were used as additives

in the aldol reaction of 1 with acetone, e.g. a-Al2O3, two c-

Al2O3-s, silica, mesoporous Al-silicates, zeolites, ThO2,

ZrO2, Y2O3 and ZnO. From these only c-Al2O3-s showed

inverted enantioselectivities, S enantiomer formed in

excess with L-Pro/ c-Al2O3 instead of R obtained with L-Pro

in the absence of oxide additive. Other oxide additives did

not exhibit any activity to invert the sense of enantiose-

lection in this reaction, i.e. using L-Pro an excess of

R product was formed in an ee close to 75 %, as if the

oxides were not present at all. According to these pre-

liminary experiments the two c-aluminas:c-Al2O3AA and

c-Al2O3AS were selected for further studies. Pro/ c-Al2O3catalysts were obtained under in situ conditions and char-

acterized by FT-IR spectrometry (Fig. 1). The spectra of

the used c-aluminas were compared with the spectra of the

Reversal of Enantioselectivity in Aldol Reaction on Proline/ c-Alumina 479

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as received materials and crystalline L-Pro, which con-

firmed the immobilization of L-Pro on the surface of the

c-Al2O3.

Characteristic experimental data obtained in aldol

reactions using several aldehydes and ketones of differenttypes are summarized in Tables 2, 3 and Figs. 2, 3. Table 2

presents results obtained in studies on aldol reactions

between acetone and an aromatic, an aliphatic or a cyclo-

aliphatic aldehyde. Namely, aldol reactions using 1 (R:2-

NO2C6H4), 2 (R:(CH3)2CH) or 4 (R:C6H11) as reaction

partners of acetone were studied. In addition to the cata-

lysts described in Ref. [21] (i.e. L-Pro/ c-Al2O3), their

variants containing D-Pro were also included in these

studies, mainly for the purpose of studying the dependence

of the product ee on the catalyst ee. As regards the actual

results, in the case of all three aldehydes the catalysts

containing D-Pro exhibited similar activities, but promotedthe formation of products of the opposite configuration as

compared to those containing L-Pro, just as expected. In the

reaction using D-Pro the S enantiomer formed in excess

(entries 2, 8, 12), in contrast with the R enantiomer

obtained in excess over D-Pro/ c-Al2O3 (entries 4, 10, 14).

The rate of the reactions conducted under identical

experimental conditions can be evaluated on the basis of

comparing conversions and reaction times. For example,

Fig. 2 represents changes in conversion and ee in the aldol

reaction of 1 with acetone catalyzed by L-Pro and L-Pro/

c-Al2O3AA catalysts. According to the relationship regard-

ing conversions of the three aldehydes we observed:

1 2[4. This relationship holds for both homogeneous

and heterogeneous phase reactions (i.e. in the presence of

c-Al2O3). Remarkably, there is no significant difference

between conversions in homogeneous and heterogeneous

phase reactions except at low reaction times.

The relationship regarding selectivities is different from

that regarding conversions, i.e.: 2[1[ 4. In the case of 4

the selectivity is especially low on heterogenized catalysts,

most probably due to secondary reactions occurring as a

consequence of the long reaction times needed. In accor-

dance with experimental data published earlier for

4-nitrobenzaldehyde [21], the change in configuration

brought about by heterogenization, i.e. the so-called

‘‘unexpected inversion’’ was observable in the reactions of

all three aldehydes. This reversal of the enantioselectivity

is usually only about 16–20 % in case of 1 (entries 3–6),

but can reach values up to 37–39 % in aldol reactions of 2

or 4 (entries 9, 10, 13, 14). In the course of the experiments

the dependence of conversion and ee on the amount of

Table 1 Chromatographic conditions used for analysing the aldol products over Cyclosil-B capillary column

Substrates Column temperature (C); hp (psi)a Retention times (min)

Aldehyde Ketone Aldehyde S or S ,S b R or R, Rb Other stereoisomers

1 5 115 C 10 min, 1 min-1 165 C 50 min; 22 34.5 94.6 96.5 –

2 5 40 C 5 min, 2 min-1 120 C 30 min; 20 2.5 36.6 36.1 –

4 5 55 C 5 min, 2 min-1 155 C 15 min; 20 21.5 55.3 55.8 –

2 6 40 C 5 min, 2 min-1 160 C 15 min; 20 2.5 53.8 54.4 55.5; 55.9

2 7 40 C 5 min, 2 min-1 160 C 15 min; 20 2.5 52.8 53.5 58.1; 58.3

3 6 40 C 5 min, 2 min-1 160 C 15 min; 20 3.0 57.3 58.4 58.8; 59.2

4 6 100 C 50 min, 1 min-1 115 C 125 min; 25 4.5 167.5 169.5 181.0; 183.3

a He head pressureb Absolute configurations of the corresponding aldol addition product enantiomers

Fig. 1 FT-IR spectra of crystalline L-Pro, c-aluminas and L-Pro/ c-

Al2O3 catalysts after use in aldol reaction of 2-nitrobenzaldehyde with

acetone, for reaction conditions see Table 1 entry 3

480 G. Sz}oll}osi et al.

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c-Al2O3 was also determined, as shown in Fig. 3 for 1. The

change in ee is especially conspicuous, which proves thesurface formation of a new enantioselective catalyst.

Although experimentally not determined, the amount of the

adsorbed L-Pro can be estimated from these results.

According to these results 0.15 mmol L-Pro is adsorbed on

150 mg c-Al2O3AA and about 200 mg c-Al2O3SA, as

further increase in the oxides amount didn’t result in

change in the ee, whereas lower oxide amounts gave

smaller or opposite ees. Accordingly, the coverage of the

oxides with L-Pro will be 60 mmol m-2 corresponding to

10 wt% L-Pro (AA) and 53 mmol m-2 corresponding to

8 wt% L-Pro (AS). The formation of a solid enantioselec-

tive catalyst is also suggested by the effect of sonication

[23, 24] on the reaction using L-Pro with added c-Al2O3(compare Table 2, entries 3–6), since in the reaction under

ultrasonication a 1 h reaction was sufficient for the

achievement of over 90 % conversion.

In Table 3 experimental data obtained in the aldol

reaction of 2, 3 or 4 with 6 and 7 under similar conditions

as in Table 2, were summarized. Due to the slower reaction

rates, longer reaction times (22–48 h) were needed to

achieve high conversions. The relationship describing the

order of conversions is 2 ? 7[ 2 ? 6 * 3 ? 6[4 ? 6.

The order of selectivities is: 2 ? 6[ 4 ? 6[ 2 ? 7 *

3 ? 6; as regards diastereoselectivities (anti / syn), in all

four reactions the formation of the anti diastereomer is

convincingly dominant. Unlike in the aldol reactions with

acetone (Table 2), enantioselectivities exceed 90 %, and

there is no characteristic difference between homogeneous

phase and heterogeneous phase reactions.

The most conspicuous new observation as compared to

the data summarized in Table 2, however, is the absence of

‘‘unexpected inversion’’: when using acetone, reversal of

enantioselectivity occurs, but when cycloalkanones are

used, it doesn’t. The probable reason for the absence of

reversal of the enantioselectivity lies in the inhibition of the

formation of the intermediate adduct (assumedly an

enamine) on the surface of c-alumina, as a consequence of

which the reaction proceeds in the solution rather than on

the surface. These experimental observations and espe-

cially the measurements on reuse (Table 4) allow con-

cluding that aldol reactions in these cases are indeed driven

by proline in the liquid phase. Reuse studies were carried

out for some of the reactions in order to substantiate this

assumption (Table 4).

Table 2 Aldol reaction between aldehydes and acetone catalyzed by L-Pro or D-Pro in the absence and presence of c-Al2O3

OO

R

OH

R

O

R

OOH

R

Ocatalyst

rt, stirring+ +

R: 2-NO2C6H4 (1) R: 2-NO2C6H4 (R -8) (S -8)

R: (CH3)2CH (2) R: (CH3)2CH (R -9) (S -9)

R: C6

H11

(4) R: C6

H11

(R -10) (S -10)

+R S

Entry Catalyst; (mmol) Aldehyde; (mmol) c-Al2O3; (mg) Time (h) Conversion (%) Selectivity (%)a ee (%); (conf.)a

1 L-Pro; 0.15 1; 0.5 – 5 90.5 80 74; ( R)

2 D-Pro; 0.15 1; 0.5 – 5 90 85 73; (S )

3 L-Pro; 0.15 1; 0.5 AA; 150 5 93 75 20; (S )

4 D-Pro; 0.15 1; 0.5 AA; 150 5 93 70 16; ( R)

5 L-Pro; 0.15 1; 0.5 AA; 150 1; )))b 91 75 18; (S )

6 D-Pro; 0.15 1; 0.5 AA; 150 1; )))b 94 79 17; ( R)

7 L-Pro; 0.15 2; 0.25 – 22 77 99 90; ( R)

8 D-Pro; 0.15 2; 0.25 – 22 70 99 89; (S )

9 L-Pro; 0.15 2; 0.25 SA; 250 22 65 99 39; (S )

10 D-Pro; 0.15 2; 0.25 SA; 250 22 52 98 34; ( R)

11 L-Pro; 0.15 4; 0.25 – 22 61 67 83; ( R)

12 D-Pro; 0.15 4; 0.25 – 22 51 75 82; (S )

13 L-Pro; 0.15 4; 0.25 SA; 250 22 76 19 37; (S )

14 D-Pro; 0.15 4; 0.25 SA; 250 22 80 16 37; ( R)

Reaction conditions: 2 mL acetonea Selectivity and ee of the aldol product, the absolute configuration of the excess enantiomer in bracketsb Reactions carried out by ultrasonication of the mixture


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The data listed in Table 4 clearly demonstrate that in

case of acetone reversed enantioselection is brought about

by the reaction taking place on the L-Pro/ c-Al2O3 catalyst

surface (entries 1–3). The aldol reaction of cyclohexanone,

however, is mainly driven by L-Pro in solution, thus a

homogeneous liquid phase reaction takes place (entries

12–17). Increase of the pretreatment temperature (c-Al2O3with L-Pro) did not have a favorable effect on the inter-

action between c-Al2O3 and L-Pro (see ees obtained in

entries 1–3 vs entries 9–11). On the in situ formed L

-Pro/ c-Al2O3 catalyst the ee was higher as compared to the pre-

viously prepared L-Pro/ c-Al2O3 obtained in DMSO before

addition of the reactants (entry 4 vs 1; entry 15 vs 12).

After both aldol reactions, the solid catalyst obtained fol-

lowing centrifugation of the reaction mixture produced

products in slightly higher ee upon reuse (entries 2, 7; 14,

17); however, addition of fresh reactants to the liquid phase

products (supernatant) resulted in no further reaction when

acetone is used (entry 5). By addition of 0.15 mmol L-Pro

Table 3 Aldol reaction between isobutyraldehyde, butyraldehyde, cyclohexanecarboxaldehyde and cyclohexanone or cyclopentanone

O

CH

2

O

R

OH

R

O

CH

2

R

O

CH

2

OH

R

O

CH

2

catalyst

rt, stirring+ +

( )n ( )n ( )n

R: (CH3)2CH (2

) n=1 (6

); R: (CH3)2CH, n=1 (S

,S

-11

) (R

,R

-11

)R: CH3CH2CH2 (3) n=0 (7); R: (CH3)2CH, n=0 (S ,S -12) (R ,R -12)

R: C6H11 (4) R: CH3CH2CH2, n=1 (S ,S -13) (R ,R -13)

6H11, n=1 (S ,S -14) (R ,R -14)

( )n

+S S

R

R

Entry Catalyst; (mmol) Aldehyde; (mmol) Ketone c-Al2O3; (mg) Time (h) Conversion (%) Selectivity (%)a Anti/syna ee (%); (conf.)a

1 L-Pro; 0.15 2; 0.5 6 – 44 75 97 98/2 85; (S ,S )

2 L-Pro; 0.15 2; 0.5 6 AA; 150 44 73 98 94/6 94; (S ,S )

3 L-Pro; 0.08 2; 0.25 6 SA; 125 44 80 97 97/3 96; (S ,S )

4 L-Pro; 0.08 2; 0.25 7 – 22 99 73 96/4 96; (S ,S )b

5 D-Pro; 0.08 2; 0.25 7 – 22 99 74 96/4 96; ( R, R)b

6 L-Pro; 0.08 2; 0.25 7 AA; 150 22 98 57 99/1 87; (S ,S )b

7 L-Pro; 0.08 2; 0.25 7 SA; 125 22 98 60 99/1 96; (S ,S )b

8 L-Pro; 0.08 3; 0.25 6 – 44 82 80 92/8 94; (S ,S )b

9 D-Pro; 0.08 3; 0.25 6 – 44 87 86 96/4 95; ( R, R)b

10 L-Pro; 0.08 3; 0.25 6 AA; 75 44 84 55 91/9 95; (S ,S )b

11 D-Pro; 0.08 3; 0.25 6 AA; 75 44 65 77 92/8 94; ( R, R)b

12 L-Pro; 0.08 3; 0.25 6 SA; 125 44 83 59 91/9 96; (S ,S )b

13 D-Pro; 0.08 3; 0.25 6 SA; 125 44 75 78 92/8 95; ( R, R)b

14 L-Pro; 0.15 4; 0.5 6 – 44 46 94 97/3 90; (S ,S )

15 L-Pro; 0.15 4; 0.5 6 AA; 150 44 28 89 92/8 94; (S ,S )

Reaction conditions: solvent 0.5 mL dimethyl sulfoxide (DMSO), 2 mmol ketonea Selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in bracketsb Assumed configuration based on similarity with known reactions

Fig. 2 Aldol reaction between 2-nitrobenzaldehyde and acetone:

effect of time on conversion (open symbols) and ee (closed symbols)

in absence (circles) and presence (triangles) of c-Al2O3AA; for

reaction condition see Table 2


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and fresh aldehyde to this solution the reaction continued,

however, the R enantiomer, characteristic to homoge-

neously catalyzed reaction formed in excess (entry 6). In

contrast in the reaction of cyclohexanone the reaction

continued by addition of fresh aldehyde to the liquid phase

mixture (supernatant) resulted over catalyst prepared in situ

L-Pro/ c-Al2O3 (see entries 15 and 16). Both c-Al2O3-s

performed similarly in the latter reaction; however inpresence of c-Al2O3SA the stereoselectivities obtained

were higher.

In addition to the above techniques, other methods were

also employed in order to investigate the origin of catalytic

centers responsible for the sense of the chiral induction. On

the one hand, the effect on enantioselection of the dipeptide

L-Pro-L-Pro(OH) potentially formed from L-Pro by Al2O3in the course of the aldol reaction was studied. On the other

hand, studies on the effect of the composition of L-Pro and

D-Pro catalyst mixtures, i.e. nonlinear effect studies, typi-

cally used in investigations of reaction mechanism [25–28]

were also carried out. The L-Pro-L-Pro(OH) dipeptide cat-alyst is known to catalyze the formation of the R product in

Fig. 3 Aldol reaction between 2-nitrobenzaldehyde and acetone:

effect of c-Al2O3 quantity on conversion (open symbols) and on

ee (closed symbols); c-Al2O3AA triangles, c-Al2O3SA diamonds,

a-Al2O3square. For reaction condition see Table 2

Table 4 Reuse of L-Pro/ c-Al2O3 catalysts in aldol reactions of 2-nitrobenzaldehyde (1) and isobutyraldehyde (2) with acetone (5) or cyclo-

hexanone (6) and others studies

Entry C atalyst; (mmol) Solvent; (mL ) Time ( h) Reuse nr . Conv ersion (%) Selectivity (%)a Anti/syna ee (%); (conf.)a

Reaction of 1 with 5b

1 L-Pro/ c-Al2O3AA; 0.15c DMSO; 0.5 5 – 82 86 – 3; (S )

2 L-Pro/ c-Al2O3; rcd – 5 1st 92 91 – 10; (S )

3 L-Pro/ c-Al2O3; rcd – 5 2nd 62 76 – 12; (S )

4 L-Pro/ c-Al2O3AA; 0.15, ise – 5 – 90 82 – 13; (S )

5 Liquid pro ductf – 5 – 45 82 – 12; (S )

6 Liquid pro ductf ? L-Pro; 0.15 – 5 – 80 91 – 40; ( R)

7 L-Pro/ c-Al2O3; rcd – 5 1st 70 82 – 15; (S )

8 L-Pro/ c-Al2O3; rcd – 5 2nd 34 69 – 14; (S )

9 L-Pro/ c-Al2O3AA; 0.15, 50Cc

DMSO; 0.5 5 – 91 92 – 7; (S )

10 L-Pro/ c-Al2O3; rcd – 5 1st 62 87 – 10; (S )

11 L-Pro/ c-Al2O3; rcd – 5 2nd 38 88 – 9; (S )

Reaction of 2 with 6g

12 L-Pro/ c-Al2O3AA; 0.075c DMSO; 0.5 44 – 91 87 83/17 76; (S ,S )

13 Liquid productf – 88 – 46 88 85/15 90; (S ,S )

14 L-Pro/ c-Al2O3; rcd DMSO; 0.5 88 1st 78 94 89/11 88; (S ,S )

15 L-Pro/ c-Al2O3AA; 0.075, ise DMSO; 0.5 44 – 92 91 92/8 85; (S ,S )



18 L-Pro/ c-Al2O3SA; 0.075, ise DMSO; 0.5 44 – 96 96 97/3 98; (S ,S )



a Selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in bracketsb Reaction conditions: reactions carried out in 2 mL acetone with 0.5 mmol 1 using 150 mg c-Al2O3AAc Catalyst prepared in solvent and used by addition of 1 and 5d Catalyst from previous entry recycled following centrifugatione Catalyst formed in situf Use of the separated liquid phase from the previous entryg Reaction conditions: 0.25 mmol 2, 2 mmol 6 using either 150 mg c-Al2O3AA or 125 mg c-Al2O3SA


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the aldol reaction of 4-nitrobenzaldehyde and acetone in

13 % ee [29]. Results of our experiments using this

dipeptide in the absence and presence of c-Al2O3 in

comparison with the amino acid L-Pro are summarized in

Table 5.

Three aldol reactions were used in this study, namely

those between 1 and 5, 2 and 5 or 6. Comparison of the data

regarding L-Pro and L-Pro-L-Pro(OH) allows the following

conclusions to be drawn: (i) Under the conditions of

homogeneous catalysis, catalysts L-Pro and L-Pro-L-

Pro(OH) catalyze the formation of products of opposite

configuration in all three reactions (entries 1 vs 3, 5 vs 7, 10

vs 12); (ii) Under the conditions of heterogeneous catalysis,

on catalyst L-Pro/ c-Al2O3 reversal of the enantioselection

takes place in the first two reactions (entries 1 vs 2, 5 vs 6),

whereas on catalyst L-Pro-L-Pro(OH)/ c-Al2O3 inversion is

observed only in the second one (entries 7 vs 9); (iii)

Accordingly, the reversal of the enantioselection recog-

nized by Li and coworkers [21] on L-Pro/ c-Al2O3 hybrid

catalysts is most probably not caused by the L-Pro-L-

Pro(OH) dipeptide formed in situ on the alumina surface

but, indeed, by the L-Pro/ c-Al2O3 catalyst of as yet

unknown surface structure.

Table 5 Comparison of the use of L-Pro and L-Pro-L-Pro(OH) catalysts in the absence and presence of c-Al2O3

Entry Catalyst; amount

(mmol)

Aldehyde;

(mmol)

Ketonea Solvent;

(mL)

c-Al2O3;

(mg)

Time

(h)

Conv.

(%)bSel.

(%)bAnti/

synbee (%);

(conf.)b

1 L-Pro; 0.15 1; 0.5 5 – – 5 91 80 – 74; ( R)

2 L-Pro; 0.15 1; 0.5 5 – AA; 150 5 93 75 – 20; (S )

3 L-Pro-L-Pro(OH)TFA;

0.15

c1; 0.5 5 – – 5 82 88 – 16; (S )


0.15c1; 0.5 5 – AA; 150 5 91 94 – 11; (S )

5 L-Pro; 0.075 2; 0.25 5 – – 22 77 99 – 90; ( R)

6 L-Pro; 0.075 2; 0.25 5 – SA; 250 22 65 99 – 39; (S )


0.075c2; 0.25 5 – – 22 64 90 – 23; (S )


0.075c2; 0.25 5 – AA; 150 22 79 70 – 0


0.075c2; 0.25 5 – SA; 250 22 77 85 – 6; ( R)

10 L-Pro; 0.075 2; 0.25 6 DMSO;

0.5

– 48 94 96 98/2 91; (S ,S )

11 L-Pro; 0.075 2; 0.25 6 DMSO;0.5

AA; 100 48 77 97 95/5 95; (S ,S )


0.075c2; 0.25 6 DMSO;

0.5

– 44 96 95 87/13 16; ( R, R)


0.075c2; 0.25 6 DMSO;

0.5

SA; 125 44 90 93 83/17 35; ( R, R)

a Reaction in 2 mL 5 or using 2 mmol 6b Conversion of the aldehyde, selectivity, diastereomer ratio and ee of the aldol products, the absolute configuration of the excess enantiomer in

bracketsc 1 equivalent triethylamine (as compared with the dipeptide salt) was added

Fig. 4 Effect of L-Pro- and D-Pro mixture composition on the ee

obtained in the aldol reaction of 2-nitrobenzaldehyde with acetone in

the absence (circles) and presence of c-Al2O3AA (triangles); closed

symbols 0.15 mmol, open symbols 0.075 mmol mixture of proline.

For reaction condition see Table 2


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In order to obtain new information on the mechanism of

the asymmetric aldol reaction taking place on the organic–

inorganic hybrid catalyst L-Pro/ c-Al2O3, experiments sim-

ilar to those described in Ref. [25] were also carried out.

Namely, we studied how the absolute configuration of the

product formed changed depending on the composition of

L-Pro and D-Pro mixtures as well as on in situ formed L-Pro/

c-Al2O3 and D-Pro/ c-Al2O3 catalysts mixtures under

identical experimental conditions. The data obtained in

these experiments on the linear or nonlinear behavior are

summarized in Fig. 4.

Reversed enantioselection catalyzed by L-Pro in thepresence of c-Al2O3 as compared to the reaction without

c-Al2O3 is again clearly shown in Fig. 4. Data shown in

this figure proved the assumption that, as suggested by Li

and coworkers [21], the reaction associated with reversal of

the ee observed in the presence of L-Pro/ c-Al2O3 catalyst is

driven by L-Pro chemisorbed on the surface of c-Al2O3. At

the same time, the linear effect obtained in presence of

c-Al2O3 confirms the validity of heterogeneous catalytic

nature of the reaction mechanism. In solution it is accepted

that the L-Pro catalyzed asymmetric aldol reaction proceeds

according to enamine mechanism as illustrated in

Scheme 1 [25]. Li and co-workers suggested the strong

chemisorption of L-Pro over the c-Al2O3, accordingly, the

proposed mechanism of the heterogeneous catalytic reac-

tion may be envisaged as shown in Scheme 2.

The unusual shape of the product ee versus catalyst ee

function in the absence of c-Al2O3 can be explained by the

results of Blackmond published in 2006 [26]. According to

these, at relatively low L-Pro concentrations, where L-Pro is

fully dissolved, a linear relationship can be observed in the

entire composition range of L-Pro ? D-Pro mixtures. Athigher proline concentrations, however, the catalyst is no

longer fully dissolved (the solution is visibly opaque), there

is ‘‘asymmetric amplification based on the equilibrium

solid–liquid phase behavior of amino acids in solution’’. In

this case the shape of the curve (see Fig. 1 in [ 26]) is

identical with that of the curve in Fig. 4 obtained by us in the

absence of alumina. The data in Fig. 4 also corroborate the

proposed mechanism of the aldol reaction involving an

enamine intermediate. At the same time, however, they also

NH

OH

O

O - H2ON

OH

O

+ RCHON

O

O

OH

R +

_

N

O

O

OH

R OH

H

+

_

- L-Pro

R

OH O

+

L-Pro + H2O

Scheme 1 Schematic enamine

mechanism of the L-Pro-

catalysed asymmetric aldol

reactions

O O

NH

AlO

AlO

O

O

O

H

Al

H

O

O

N

AlO

AlO

O

O

O

Al

H

H

H

O

+

-H2O

O

O

N

AlO

AlO

O

O

O

Al

HH

O OH

NH

AlO

AlO

O

O

O

H

Al

+

RO+

O

O

N

AlO

AlO

O

O

O

HH

OR

O O

N

AlO

AlO

O

O

OH

O

R

H

+

_

O

O

N

AlO

AlO

O

O

O

Al

H

H

HOH

RO

+H2O

+

Scheme 2 Suggested structure of the L-Pro/ c-Al2O3 catalyst and the mechanism of the asymmetric aldol reaction occurring on this catalyst

surface


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indicate that in one case the reaction is of the homogeneous

liquid phase type, whereas in the presence of Al2O3 the

reaction proceeds on the Pro/ c-Al2O3 catalyst formed on the

surface of c-Al2O3 rather than in the solution phase.

4 Conclusions

Li and coworkers [21] observed unexpected inversion in

the well-known, L-proline-catalyzed aldol reaction between

aromatic aldehydes and acetone in the presence of c-Al2O3additive. Namely, R product was formed instead of the

expected S product. The unexpected stereochemistry was

attributed to the effect of the organic–inorganic hybrid

catalyst L-Pro/ c-Al2O3 formed in the course of the reaction.

The present work reports the following, so far unpublished

experiments and their conclusions: (i) studies on aldol

reactions catalyzed by L-Pro and D-Pro between acetone,

cyclohexanone and cyclopentanone on the one hand and

2-nitrobenzaldehyde, isobutyraldehyde, butyraldehyde andcyclohexanecarboxaldehyde on the other hand; (ii) studies

on the effect of ultrasonic irradiation on the reaction rate

and on the enantioselection; (iii) experiments using L-Pro-

L-Pro(OH) dipeptide catalyst; (iv) the effect of the com-

position of L-Pro and D-Pro mixtures on the ee (linear/

nonlinear behavior); (v) reuse measurements on used cat-

alyst and its collected supernatant.

The experiments allowed the following new conclusions

to be drawn: (i) in the aldol reaction between 2-nitro-

benzaldehyde and acetone, in the presence of c-Al2O3,

under identical experimental conditions both L-Pro and

D-Pro produced unexpected inversion in ee of *20 %, as

opposed to the ee of *75 % of the reaction without

c-Al2O3; (ii) in the case of the aliphatic and cycloaliphatic

aldehydes, the ee of the reaction with c-Al2O3 was *40 %

and of that without Al2O3 was *90 %; (iii) reversal of the

ee cannot be generalized for aldol reactions in the presence

of c-Al2O3, because it has only been observed for acetone

among the ketones studied by us; (iv) our various experi-

ments supply further evidence to support the hypothesis of

Li et al., namely that the reaction takes place on the surface

of the L-Pro/ c-Al2O3 catalyst generated in the course of the

reaction; (v) in the case of cycloalkanones there is pre-

sumably competition between the liquid-phase and the

surface reaction with preference for the former, as a con-

sequence of which reversal of the ee fails to take place; (vi)

further research is needed to resolve the synthesis of chiral

organic–inorganic hybrid catalysts enabling higher ee val-

ues. Our current research is focused on using this hetero-

geneous catalytic system in a continuously operated high

pressure flow system to exploit the advantage of the het-

erogeneous nature of this hybrid catalyst. Other non-con-

ventional oxide supports will also be used for immobilizing

organocatalysts; in our preliminary experiments using

graphite oxide as inorganic support [30] for L-Pro we have

reached up to 50 % ee.

Acknowledgments Financial support by the Hungarian National

Science Foundation (OTKA Grant K 72065 and K 109278) is highly

appreciated. This research was realized in the frames of TÁMOP-

4.2.2.A-11/1/KONV-2012-0047 project.

References

1. De Vos DE, Vankelecom IFJ, Jacobs PA (eds) (2000) Chiral

catalyst immobilization and recycling. Wiley-VCH, Weinheim

2. Murzin DY, Maki-Arvela P, Toukoniitty E, Salmi T (2005) Catal

Rev Sci Eng 47:175

3. Bartók M (2006) Curr Org Chem 10:1533

4. Heitbaum M, Glorius F, Escher I (2006) Angew Chem Int Ed

45:4732

5. Mallat T, Orglmeister E, Baiker A (2007) Chem Rev 107:4863

6. Ding K, Uozumi Y (eds) (2008) Handbook of asymmetric het-

erogeneous catalysis. Wiley-VCH, Weinheim

7. Mukherjee S, Yang JW, Hoffmann S, List B (2007) Chem Rev

107:5471

8. Zlotin G, Kucherenko AS, Beletskaya IP (2009) Russ Chem Rev

78:737

9. Sz}oll}osi GY, Bartók M (2001) Chirality 13:614

10. Sz}oll}osi GY, Chatterjee A, Forgó P, Bartók M, Mizukami F

(2005) J Phys Chem A 109:860

11. London G, Sz}oll}osi GY, Bartók M (2007) J Mol Catal A 267:98

12. Sz}oll}osi GY, London G, Baláspiri L, Somlai CS, Bartók M

(2003) Chirality 15:S90

13. Benaglia M, Cinquini M, Cozzi F, Puglisi A, Celentano G (2002)

Adv Synth Catal 344:533

14. Andreae MRM, Davis AP (2005) Tetrahedron Asymmetry

16:2487

15. Revell JD, Gantenbein D, Krattiger P, Wennemers H (2006)

Biopolymers (Peptide Sci) 84:105

16. Gruttadauria M, Giacalone F, Marculescu AM, Meo PL, Riela S,

Noto R (2007) Eur J Org Chem 2007:4688

17. Bartók M, Sutyinszki M, Felföldi K, Sz}oll}osi GY (2002) Chem

Commun 1130

18. Bartók M, Balázsik K, Bucsi I, Sz}oll}osi GY (2006) J Catal 239:74

19. Kagan HB, Langlois N, Dang TP (1975) J Organomet Chem

90:353

20. Bartók M (2010) Chem Rev 110:1663

21. Zhong L, Xiao J, Li C (2006) J Catal 243:442

22. Howard PW, Jeffrey S, Burke P, Senter P (2011) PCT WO

2011/130613, Seatle Genetics Inc. and Spirogen Ltd

23. Török B, Felföldi K, Szakonyi G, Bartók M (1997) Ultrason

Sonochem 4:301

24. Török B, Balázsik K, Felföldi K, Bartók M (2001) Ultrason So-nochem 8:191

25. Sakthivel K, Notz W, Bui T, Barbas CF III (2001) J Am Chem

Soc 123:5260

26. Klussmann M, Iwamura H, Mathew SP, Wells DH Jr, Pandya U,

Armstrong A, Blackmond DG (2006) Nature 441:621

27. Klussmann M, Mathew SP, Iwamura H, Wells DH Jr, Armstrong

A, Blackmond DG (2006) Angew Chem Int Ed 45:7989

28. Blackmond DG (2000) Acc Chem Res 33:402

29. Shi LX, Sun Q, Ge ZM, Zhu YQ, Cheng TM, Li RT (2004)

Synlett 2004:2215

30. Sz}ori K, Puskás R, Sz}oll}osi GY, Bertóti I, Szépvölgyi J, Bartók M

(2013) Catal Lett 143:539


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