Catalysis Communications 32 (2013) 81–85

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Short Communication

Modifier–substrate interactions of various types in the Orito reaction: Reversal of theenantioselection in the hydrogenation of ketopantolactone on Pt modified byβ-isocinchonine and O-phenylcinchonidine

György Szőllősi a,⁎, Katalin Balázsik a, Imre Bucsi b, Tibor Bartók c, Mihály Bartók a,b,⁎a Stereochemistry Research Group of the Hungarian Academy of Sciences, Dóm tér 8, H-6720 Szeged, Hungaryb Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungaryc Faculty of Engineering, University of Szeged, P.O. Box 433, H-6701 Szeged, Hungary

⁎ Corresponding author at: Stereochemistry Research Gof Sciences, Dóm tér 8, H-6720 Szeged, Hungary. Te62544200.

E-mail addresses: szollosi@chem.u-szeged.hu (G. Szőbartok@chem.u-szeged.hu (M. Bartók).

1566-7367/$ – see front matter © 2012 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.catcom.2012.12.009

a b s t r a c t

a r t i c l e i n f o

Article history:Received 24 September 2012Received in revised form 29 November 2012Accepted 11 December 2012Available online 20 December 2012

Keywords:Enantioselective hydrogenationPlatinumCinchona alkaloidKetopantolactoneReversal of enantioselectivityIntermediate complexes

The enantioselective hydrogenation of ketopantolactone (KPL) on Pt–alumina catalystmodified byβ-isocinchonine(β-ICN) andO-phenylcinchonidine (PhOCD) in toluene, acetic acid and theirmixtures under otherwise identical ex-perimental conditions was studied. Reversal of the enantioselection was obtained dependent on the concentrationof acetic acid (eemax=17% (S) on Pt–PhOCD and 50% (R) on Pt–β-ICN, respectively). The possible role inenantioselection of adducts forming in the reaction mixture and the stability of PhOCD under the conditions ofthe hydrogenation was investigated by ESI-MS. The results of the nonlinear phenomenon measurementson β-ICN+PhOCD mixtures suggest that the intermediate surface complexes β-ICN–KPL and PhOCD–KPLresponsible for the opposite enantioselection include different types of interactions and the enantioselection isdirected by the competition between these interactions.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

The latest research results on the Orito reaction [1] have been con-tinuously published in reviews (since 2005, [2–5]). It is clear fromthese reviews that further studies are needed to gain a better under-standing of the mechanism of this much-investigated heterogeneouscatalytic enantioselective hydrogenation, because, on the one hand, anumber of questions cannot be adequately answered without furtherexperimental data; on the other hand, a catalytic reaction consists ofseveral steps, each of which is dependent on numerous factors.

Hydrogenation of ketopantolactone (dihydro-4,4-dimethyl-2,3-furandione, KPL) is an outstandingly important model reaction ofstudies on the mechanism of the Orito reaction. Interpretation of the un-expected experimental data obtained in the course of studies in this fieldhas posed a difficult task for the scientists involved. Ever since thefirst re-port on the reaction using a cinchona-modified Pt–alumina catalyst inthe hydrogenation of KPL [6], many publications have presented resultson the stereochemistry of the Orito reaction. According to these reports,the presence of pseudo-enantiomer parent cinchonas (cinchonidine,

roup of theHungarian Academyl.: +36 62544279; fax: +36

llősi),

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CD; and cinchonine, CN) leads to the formation of products with the op-posite absolute configuration (see Scheme 1 and Fig. 1 for CD and CN)[1–5]. However, the behavior of certain derivatives of these chiral modi-fiers (PhOCD and β-ICN) proved to be quite unexpected as regards thestereochemistry of the hydrogenation. Namely, regarding the sense ofenantioselection, β-ICN worked similarly to CD and PhOCD similarly toCN. Results of these unexpected inversions using various methods andtheir interpretations have been described in a large number of reports(for examples see [7–10] on Pt–PhOCD and [11–15] on Pt–β-ICN chiralcatalysts).

Recognition of the unexpected inversion and its dependence on theAcOHconcentrationmade ambiguous the generality of theN\H\Oelec-trophilic mechanism already accepted until the beginning of 2000th. Itcould be returned to the earlier suggested so-called nucleophilic mecha-nism based on N\C intermediate complex (IC) (formed in the mixturevia the interaction between the carbonyl group of KPL and the chiralmodifierβ-ICN) [16], and to the suggestion that themechanismof a com-plex chemical reaction (such as the Orito reaction) cannot be interpretedby a single type of IC. Recalling the N\C type complex for the interpreta-tion of the unexpected inversion generated debate in the special litera-ture. The present work was inspired by the availability of two catalyticsystems (Pt–PhOCDand Pt–β-ICN),which separately both showed inver-sion and at the same time result in opposite sense of enantioselectivitycompared to each other. However, these catalytic systems under strictlyidentical reaction conditions (catalyst, substrate, reaction condition:

O O

O

+H2, Pt/Al2O3

CD: toluene, AcOH;PhOCD: AcOH;β-ICN*: toluene

O OH

O

OOH

O

+H2, Pt/Al2O3

CN: toluene, AcOH;PhOCD*: toluene;β-ICN: AcOH

* inversion of enantioselectivity

(R)-PL(S)-PLKPL

Scheme 1. Hydrogenation of ketopantolactone over Pt modified by cinchona alkaloids.

82 G. Szőllősi et al. / Catalysis Communications 32 (2013) 81–85

catalyst amount, pretreatment, solvent, substrate concentration, reac-tion temperature, hydrogen pressure, and stirring speed) were not yetexamined.

Since unexpected inversions were observed under different(non-identical) conditions, our aim was to study the behavior of thechiral catalysts (Pt–β-ICN and Pt–PhOCD) under completely identicalexperimental conditions. Conducting hydrogenations in the two mostcommonly used solvents of the Orito reaction, i.e. toluene and AcOHwas expected to be informative, because in the case of β-ICN reversal inthe enantioselection exhibited significant solvent dependence [11,13],which suggested a different mechanism at the origin of chiral induction.

It also appeared justified to study by ESI-MS, similarly to ethyl pyru-vate (EtPy), the role in enantioselection of the various adducts formedduring KPL hydrogenation. Moreover, it seemed quite important to in-vestigate the stabilities of chiral modifiers bringing about oppositeenantioselection (β-ICN and PhOCD). These investigations on the onehand confirmed that under identical conditions both the β-ICN andPhOCD modifiers are not transformed to CN and CD, however, adductswhich could have influence on the sense of the enantioselection mayform. On the other hand the studies on the nonlinear behavior of mix-tures of various compositions containing these modifiers provide directinformation on the different adsorption characteristics of these twoIC-s (β-ICN+KPL and PhOCD+KPL), determining the sense of theenantioselection.

2. Experimental

2.1. Materials

KPL (Aldrich) was subjected to azeotropic distillation with tolueneto remove water. Before use, the crystals were dried under vacuum inpresence of KOH pellets at 323 K for 24 h. CD and solvents (analyticalgrade, Fluka) were used as received. The preparation of β-ICN hasbeen described elsewhere [17]. PhOCD was prepared using literatureprocedure [7]. Engelhard E4759 5% Pt/Al2O3 catalyst was pretreatedat 673 K as previously described [18]. The catalyst was pretreated ina fixed-bed reactor by flushing with 30 mL min−1 He at 300–673 Kfor 30 min and 30 mL min−1 H2 at 673 K for 100 min. After coolingto room temperature in H2 the catalyst was flushed with He for30 min and stored until use.

N

NOH

HH

N

NO

HH

CD PhOCD

3

S R

2'

3'

8 9

5'

6'

7'

8'

1011 2

46

S R

Fig. 1. The structure of t

2.2. Spectroscopic methods

The ESI–MSD-ion-trap (AGILENT 1100 LC-MSD TRAP SL ion-trapMS)was operatedunder positive ion and autoMS–MSmodeusing the follow-ing parameters: ESI: capillary (needle) voltage=3.5 kV, capillary exitvoltage=136 V, drying gas (N2)=9 L/min, drying gas temperature=623 K, and nebulizer gas=40 psi; ion-trap: scan range=80–350 m/z,max. accumulation time=300 ms, fragmentation amplitude=1.5 V,and fragmentation time=40 ms. Solvent: methanol/0.1% AcOH; flowrate: 0.5 mL/min; concentration of sample: 0.1 μmol/L; injected volume1.5 μL.

2.3. Catalytic hydrogenation

Hydrogenations were performed in an atmospheric batch reactor.The catalytic system including catalyst (25 mg) and 5 mL of solvent(toluene or toluene and AcOH mixture) was loaded into the reactorand purged three times with H2. The catalyst was stirred and pre-hydrogenated for 30 min. The calculated amount of modifier wasinjected and after 0.5–1 min 1 mmol (128 mg) of KPL was addedand stirred in the presence of H2 for the required reaction time. Standardconditions were: 25 mg Pt/Al2O3, 5 mL solvent, [modifier] 0.1 mM/L,0.1 MPa H2 pressure, 294–297 K, ~900 rpm (diffusion control freereaction), and 1 mmol (128 mg) of KPL. The product identificationand the enantiomeric excess, ee%=|[R]− [S]|×100/([R]+[S]) weremonitored by gas chromatography (HP 6890 N GC-FID using 30 mlong Cyclodex-B capillary column, head pressure 21.65 psi He, and col-umn temperature 398 K. Retention times (min): 10.6 of (S)-PL, and 11.2of (R)-PL. The reproducibility was ±2%.

3. Results and discussion

3.1. Enantioselective hydrogenation of KPL using Pt–alumina catalystsmodified by β-ICN or PhOCD in toluene and in AcOH

There have been somewhat contradictory experimental observa-tions reported in the special literature regarding the stability of the chi-ral modifiers β-ICN and PhOCD in AcOH on Pt–alumina in the presenceof H2 at room temperature. Namely, the C\O bonds of β-ICN proved tobe stable in acetic acid [11,17], whereas PhOCD is unstable according to

N

N

HH

OHS R

N

N

HH

O

S R

CN -ICN

he chiral modifiers.

83G. Szőllősi et al. / Catalysis Communications 32 (2013) 81–85

ref. [8], while other experimental observations support the stability ofPhOCD in acetic acid too [10].

Fig. 2 shows conversion vs time curves obtained in the hydrogenationof KPL over modified catalysts Pt–β-ICN and Pt–PhOCD under identicalexperimental conditions. According to the experimental data outlinedin Fig. 2, KPL hydrogenation on Pt–β-ICN catalyst is faster in toluenethan in AcOH, whereas on Pt–PhOCD there is no difference. On both cat-alysts and in both solvents, there are significant differences not only inthe sense of enantioselection, but also in its magnitude. The above differ-ences exhibited by the two modified catalysts probably indicate differ-ences between the reaction mechanisms.

The earlier recognized reversal of the enantioselection in KPL hy-drogenation on the two modified catalysts (Pt–PhOCD and Pt–β-ICN)[7,13] was also confirmed by these experiments carried out underidentical experimental conditions. Namely, (i) when using β-ICN in tol-uene excess of (R)-PL was formed rather than (S)-PL expected on thebasis of the reaction with CN with identical absolute configuration(C8R,C9S), whereas (ii) the use of PhOCD resulted in formation of excess(S)-PL rather than the expected (R)-PL, which is formed in excess byusing CD having the same absolute configuration with PhOCD (C8S,C9R) (see Scheme 1).

3.2. Results of ESI-MS and MS–MS measurements

In the course of the enantioselective hydrogenation of EtPy, certainadducts were detected in the mixture by fast and easily carried outESI-MS analysis, based on which it was possible to draw conclusionson the mechanism of the chemical reaction [19,20]. Therefore it alsoappeared expedient to study the roles of alkali acetates (LiOH, NaOHand KOH introduced into the AcOH containing hydrogenationmixture).Naturally these are indirect conclusions, as the ESI-MS experiments giveinformation only on the solution phase and not on the chemistry occur-ring on the Pt surface. Unfortunately there is no other rapid method forsolid–liquid phase heterogeneous reactions at the present time thatcould verify the participation of different adducts, which form beforeand after hydrogenation. As to the absence of Pt in thesemeasurements,the short-lived formations developed on the catalyst surface in liquidphase reactions still cannot be detected easily.

ESI-MS and ESI-MS–MS spectra of KPL pre-hydrogenation mixtures,in both solvents, as well as those of the crude products of hydrogena-tions were recorded; the data of the spectra are shown in Table 1.From a large number of peaks, Table 1 mostly contains adducts identi-fied by MS–MS. The structures of adducts m/z 451 and 469 have been

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15

Con

vers

ion

(%)

Time (min)

ß-ICN / T, 50(R)

ß-ICN / A, 7(S)

PhOCD / T, 17(S)

PhOCD / A, 2(S)

ee (%)

Fig. 2. Enantioselective hydrogenation of KPL on β-ICN- and PhOCDmodified Pt/aluminacatalysts (standard conditions, see Subsection 2.3, T = toluene, A = acetic acid).

verified [19,20]. Adducts m/z 551 and 605 are hypothetical structures,and attempts to record their MS–MS spectra were unsuccessful. Themajority of adducts were identifiable among the products of hydroge-nations in both solvents, with the evident exception of m/z 195, 451and 469, which may only be formed in AcOH. Adducts having m/z 551and 605 were detectable only among the products of hydrogenationin toluene. Since the identification of a large number of peaks in theproducts was unsuccessful, ESI-MS studies of this type on the productsobtained in the presence of the chiral catalyst Pt–PhOCD were droppedfrom the research project.

Absence of the formation of the Na+ adducts of KPL, similar tothose observed in case of EtPy was surprising. It could be establishedunambiguously that the rigid structure of KPL does not allow the for-mation of adducts with as stable coordination as those formed in caseof EtPy [20]. Conversions and enantioselections were hardly affectedby the presence of alkali acetates: ee values were 50±2% of (R)-PL inthe presence of CD modifier.

The ESI-MS technique had also been proved to be suitable for study-ing the stability of cinchona alkaloids and their derivatives (CD, CN, andβ-ICN) under the conditions of the Orito reaction [12,19–21]. It wastherefore expedient to use ESI-MS to investigate the behavior of PhOCDunder the conditions of KPL hydrogenation. The results obtained aresummarized in Table 2. The most important conclusions drawn on thebasis ofm/z values are (taking into account the error limits of the abun-dance measurements): (i) there are minimal amounts of DHCD+H]+

and THCD+H]+ present in the reaction mixture (even during hydroge-nation in toluene for 65 min only 0.1–0.2%), consequently they donot in-fluence the sense of enantioselection significantly; (ii) m/z 373 and 375are formed from PhOCD, m/z 373 by hydrogenation of the vinyl groupandm/z 375 by partial hydrogenation of the quinoline skeleton. The ab-sence of the hydrogenation of the phenyl group is indicative of the tiltedtype adsorption of PhOCD. Accordingly, as a consequence of this type ofadsorption, the phenyl group is located far from the surface when themodifier is adsorbed on Pt, in agreement with the data in the literature[9].

3.3. Nonlinear phenomenon (NLP) measurements

In the course of previous studies on the individual elementarysteps of the complex mechanism of the Orito reaction, the nonlinearbehavior observed using mixtures of chiral modifiers was successfullyapplied [13,21–23]. As long as mixtures of different compositions oftwo modifiers (M1 and M2) show linear behavior, the two modifiersform the same type of M1+S and M2+S 1:1 complexes on the sur-face (where S is the substrate). If the hydrogenation results show

Table 1Adducts detected by positive ESI-MS and ESI-MS2 in solution resultedin hydrogenations of KPL.a

m/z Adducts

131 [PL+H]+

153 [PL+Na]+

183 [KPL+MeOH+Na]+

195 [PLacetate+Na]+

283 [2PL+Na]+

295 [β-ICN+H]+

297 [DHCD+H]+

299 [THCD+H]+

371 [PhOCD+H]+

373 [PhODHCD+H]+

375 [PhOTHCD+H]+

451 [O{Al(OAc)2}3+H]+

469 [451+H2O]+

551 [β-ICN+2KPL+H]+

605 [β-ICN+2KPL+MeOH+Na]+

a Abbreviations used: KPL (ketopantolactone), PL (pantolactone),β-ICN (β-isocinchonine), PhOCD (O-phenyl-cinchonidine), Ac (acetyl),DH (dihydro), TH (tetrahydro).

Table 2Hydrogenation of PhOCD in the absence and in the pressure of KPL on Pt/Al2O3 andproducts formed from the modifier detected by ESI-MS.a

Entry AcOH(vol.%)

Time(min)

Conv(%)b

Ee(%)b

Relative peak intensity of compoundswith the givenm/z values (%)c

297 299 371 373 375

1 0 0 – – b 0 100 0 02 0 10 – – b b 100 100 03 0 15 – – b b 40 100 04 0 25 – – b b 33 100 25 0 65 – – 0.1 0.2 6 100 36 0 11 100 18 1 1 0 100 257 0.1 12 100 15 1 1 0 100 228 1 10 100 10 b b 0 100 229 10 12 100 7 1 1 0 100 2010 100 15 100 2 b b 0 100 20

a Standard conditions (see Subsection 2.3), solvent: toluene.b Conversion of KPL when used and ee of PL (excess of S enantiomer).c m/z: 297=[DHCD+H]+, 299=[THCD+H]+, 371=[PhOCD+H]+, 373=

[PhODHCD+H]+, 375=[PhOTHCD+H]+.

84 G. Szőllősi et al. / Catalysis Communications 32 (2013) 81–85

nonlinear behavior, then the structure of the adsorbed complexes aredifferent. The bigger nonlinearity indicates more structural differ-ences. From the two complexes competing in the dynamic system,the one of which formation and transformation is more advantageouswill determine the sense of the enantioselection.

To estimate the dynamic competition of themodifiers on Pt–alumina,the enantioselective hydrogenation of KPL was carried out with so farunexamined mixtures of β-ICN and PhOCD. In order to obtain a largereffect, the experiments were carried out at 273 K, under otherwise stan-dard reaction conditions. Results obtained usingmixtures of the two cin-chona derivatives causing unexpected inversion (β-ICN and PhOCD)were compared with the already published data obtained usingCD+PhOCD and β-ICN+CN mixtures (Fig. 3).

As illustrated in Fig. 3, a strong NLP was observed in case ofβ-ICN+PhOCD mixtures. Only 4–5% β-ICN in the mixture was suffi-cient to produce the (R)-PL in excess. From the comparison of exper-imental data one can deduce the following adsorption strength onPt–alumina in the enantioselective hydrogenation of KPL in toluene:CD>β-ICN>CN>PhOCD. However, since the NLP depends not onlyon the chiralmodifier but also on the substrate to be hydrogenated [24],the NLP can presumably be interpreted on the basis of differences in the

Fig. 3. Nonlinear behavior of mixtures of chiral modifiers in the hydrogenation of KPL(standard conditions, see Subsection 2.3, 0.1 mM/L modifiers, 273 K).

structure of the substrate–modifier complexes formed. In accordancewith NLP studies to date, it can be concluded that the nonlinear be-havior shown in Fig. 3 is due to the different geometries of adsorbedmodifier–KPL complexes formed by dynamic competitive interac-tions, which are dependent on the modifier structure and the AcOHconcentration (and possibly on other reaction conditions).

3.4. Effect of the AcOH concentration on the ee

In previous studies different variants of the so-called nucleophilicmechanisms were suggested for the Orito reaction [11,16,25]. However,ref. [14] cautions against generalization: “It is understood that the resultsobtained in the KPL+β-ICN system only hold for this pair of compoundsand cannot be generalized for the entire Orito reaction.” In spite of this,other similar observations (unexpected inversions, dependence of eeon [H+]) did not exclude the possibility of a nucleophilic mechanism inthe case of other substrates either [4]. In recently published reports, how-ever, it is considered experimentally proven that the hydrogenation ofmethyl-benzoylformate and 2,2,2-trifluoroacetophenone over Pt–CD chi-ral catalyst occurs through N\H\O bond interaction in aprotic mediumas well [26,27]. These antecedents led us studying the enantioselectivehydrogenation of KPL – based on the already published results obtainedover the chiral catalyst Pt–β-ICN causing unexpected inversion [14,15] –on Pt–PhOCD, a chiral catalyst also causing unexpected inversion, underidentical experimental conditions. Experimental data as a functionof AcOH concentration, compared to those obtained on Pt–β-ICNare presented in Fig. 4.

The measurements with increasing AcOH concentration showeddecrease in the enantioselectivity in the presence of PhOCD modifieras well. Namely, the 17% (S) ee measured in toluene decreased to ~2%(S) when measured in AcOH. In EtPy and KPL hydrogenations carriedout under similar conditions on Pt–β-ICN, the dependence of ee onAcOH concentration allowed to conclude that the IC responsible forenantioselection is of N\C type [11,13]. This appeared all the moreplausible as the change in IC structure led to unexpected inversion onPt–PhOCD, too. Although the change in ee observed on Pt–PhOCD cata-lyst is smaller than that observed earlier on Pt–β-ICN, on the basis of thedata summarized in Fig. 4 the above explanation cannot be excluded, asthe concentration of complexes of nucleophilic character can be de-creased to zero by increasing the AcOH concentration. This also indicatesthat electrophilic and nucleophilic complexes probably are contenderspecies in the case of some modifier–substrate (M–S) pairs.

0

10

20

30

40

50

0.01 0.1 1 10 100

Ee

(%)

AcOH (vol %)

Pt-ß-ICN

Pt-PhOCD

(R)-PL

(S)-PL

Fig. 4. Reversal of ee in the enantioselective hydrogenations of KPL: effect of AcOH con-centration on ee (standard conditions, see Subsection 2.3).

85G. Szőllősi et al. / Catalysis Communications 32 (2013) 81–85

3.5. Interpretation of the results

Based on the experimental data presented in the manuscript – inparticular results from Subsections 3.3 and 3.4 – as well as the exper-imental observations and quantum chemical computations publishedin the literature, it seems justified to assume that enantioselection inthe Orito reaction cannot be interpreted via a single generalizable IC;it may rather be the simultaneous presence of different types of inter-actions dependent on a number of factors (modifier, substrate, andsolvent) that determines the sense of enantioselection. The followinginteractions may be supposed to operate on the surface of Pt:N\H—O_C, N\H—O, N–-H\O, O\H—O_C, C2\H—O, C8\H—O,C5′\H—O_C, C6′\H—O_C, C5′\H—O, C6′\H—O, N\H—F, andC\H—F.

The above conclusion regarding the nature of the M–S interactionsdetermining the structure of the IC responsible for enantioselection issupported by the following:

(i) in protic and aprotic conditions the N\H\O 1:1 IC was alreadyproposed in 1988 [28] which was later identified by direct spectro-scopic methods [26,29]; (ii) according to the “two-point H-bondingmodel”, the IC is also stabilized by aromatic C\H—O interactions, inaddition to the N\H\O interaction [30]; (iii) NMR measurementsin the absence of catalyst have experimentally confirmed the presenceof N\C type complexes and the existence of C\H—O_C interactionsbetween the cinchona alkaloid and KPL, consequently their role inenantioselection cannot be excluded in the case of some M–S pairs[14,15]; (iv) interaction of C2\H and C8\H of cinchona alkaloids withthe substrate carbonyl group, furthermore the existence of N\C andother interactions were verified by quantum chemical calculations[14,25,31]; (v) the conformation of the chiral modifier and/or ofthe ICs assumed in solution are altered by adsorption; as a conse-quence, not only the spatial position at the quinuclidine N, but alsothe type and the strength of the M–S interactions may be changed[32–34]; and (vi) very recently published STM/DFT studies in caseof 2,2,2-trifluoroacetophenone show that the chiral modifier inducesprochiral switching on the surface and different prochiral ratios pre-vail at different submolecular binding sites of the modifier [35].

3.6. Conclusions

Based on the above at the present stage of the research the role ofinteractions other than N\H\O in enantioselection cannot be ex-cluded. For example, in the enantioselective hydrogenations of KPLon Pt–PhOCD and Pt–β-ICN catalysts, processes accompanied by re-versal of the ee, the simultaneous presence and competition of inter-actions of different strengths may regulate enantioselection (variedmultiple bonding model). Results of not yet attempted ATR-IR mea-surements on the hydrogenation of KPL on Pt–PhOCD and Pt–β-ICNcatalysts are expected to contribute with significant new informationthat will promote a deeper understanding of the stereochemistry ofthe Orito reaction.

Acknowledgment

Financial support by the Hungarian National Science Foundation(OTKA Grant K 72065) is highly appreciated.

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