The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction

Article abstract of DOI:10.3762/bjoc.13.10

A family of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides was synthesized by the microwave-assisted solvent-free addition of dialkyl phosphites and diphenylphosphine oxide, respectively, to imines formed from benzaldehyde derivatives and primary amines. After optimization, the reactivity was mapped, and the fine mechanism was evaluated by DFT calculations. Two α-aminophosphonates were subjected to an X-ray study revealing a racemic dimer formation made through a N-H?O=P intermolecular hydrogen bridges pair.

Full text of DOI:10.3762/bjoc.13.10

The synthesis of α-aryl-α-aminophosphonates and
α-aryl-α-aminophosphine oxides by the
microwave-assisted Pudovik reaction
Erika Bálint*1, Ádám Tajti2, Anna Ádám2, István Csontos2, Konstantin Karaghiosoff3,
Mátyás Czugler2, Péter Ábrányi-Balogh4 and György Keglevich*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 76–86.
1MTΑ-BME Research Group for Organic Chemical Technology, 1521
Budapest, Hungary, 2Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics,
1521 Budapest, Hungary, 3Department Chemie,
doi:10.3762/bjoc.13.10
Received: 03 November 2016
Accepted: 15 December 2016
Published: 12 January 2017
Ludwig-Maximilians-Universität München, 81377 München, Germany
and 4Hungarian Academy of Sciences, Research Centre for Natural
Sciences, Institute of Organic Chemistry, 1519 Budapest, Hungary
Associate Editor: L. Vaccaro
Email:
© 2017 Bálint et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Erika Bálint* - ebalint@mail.bme.hu; György Keglevich* -
gkeglevich@mail.bme.hu
* Corresponding author
Keywords:
α-aryl-α-aminophosphine oxides; α-aryl-α-aminophosphonates;
microwave; Pudovik reaction
Abstract
A family of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides was synthesized by the microwave-assisted solvent-
free addition of dialkyl phosphites and diphenylphosphine oxide, respectively, to imines formed from benzaldehyde derivatives and
primary amines. After optimization, the reactivity was mapped, and the fine mechanism was evaluated by DFT calculations. Two
α-aminophosphonates were subjected to an X-ray study revealing a racemic dimer formation made through a N–H···O=P intermo-
lecular hydrogen bridges pair.
Introduction
α-Aminophosphonates and related derivatives, considered as the ponent condensation, where an amine, an aldehyde or ketone
structural analogues of α-amino acids, have significant impor- and a >P(O)H reagent, such as a dialkyl phosphite or a
tance, especially in medicinal [1-3] and agricultural chemistry secondary phosphine oxide react in a one-pot manner [6-10],
[4,5], due to their potential biological activity. The two major and the Pudovik (aza-Pudovik) reaction, in which a >P(O)H
synthetic routes towards α-aminophosphonate derivatives species is added on the double bond of imines [11-14]. In this
embrace the Kabachnik–Fields (phospha-Mannich) three-com- article, the latter pathway is utilized for the synthesis of α-aryl-
76

Beilstein J. Org. Chem. 2017, 13, 76–86.
α-aminophosphonates and α-aryl-α-aminophosphine oxides. In
most cases, the additions were carried out in the presence of a
catalyst and solvent. The use of many types of catalysts,
such as acids (HCOOH) [15] or bases (NaOH [16], 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) [17], tetramethylguanidine
(TMG) [18,19]), p-toluenesulfonyl chloride [20], metal salts
(MgSO4) [21], CdI2 [22]), metal complexes (BF3·EtO2 [23,24],
t-PcAlCl [15]), and phase-transfer catalysts [25] were reported.
The enantioselective hydrophosphonylation of imines was also
described, where chiral catalysts were applied in various sol-
vents [26-32]. There are a few examples, where the reactions
were performed in a solvent in the absence of any catalyst [33-
38], while in a few cases the catalysts, i.e., PTSA [39], Na [40],
Scheme 1: Synthesis of starting N-benzylideneamines 1.
TEA [21] or MoO2Cl2 [41], were used under solvent-free searching for the optimum temperature and reaction time
conditions. As for the microwave (MW)-assisted additions, only (Table 1). The products were α-aminophosphonates 2a–d and
two cases were reported, but the catalytic variations were α-aminophosphine oxide 2e.
carried out in kitchen MW ovens [32,42], and thus, do lack of
exact temperatures, these results cannot be reproduced. From a The addition of 1 equivalent of dimethyl phosphite (DMP) to
’green chemical’ point of view, the solvent-free and catalyst- imine 1a at 80 °C was almost complete after 30 min, and
free additions are of interest, however, in these reactions, rela- dimethyl ((butylamino)(phenyl)methyl)phosphonate (2a) could
tively long reaction times (1.5–10 h), and/or unreasonably large be isolated in a yield of 73% (Table 1, entry 1). Under similar
excesses (50–150 equiv) of the dialkyl phosphite were applied conditions, the comparative thermal experiment led to a lower
[43-52].
conversion of 79% (Table 1, entry 2). A full conversion could
be achieved by heating at 100 °C under MW for 30 min al-
The synthesis of α-aryl-α-aminophosphine oxides by the addi- though 1.2 equivalent of DMP were required. The formation of
tion of secondary phosphine oxides to imines is much less 6% of the N-methylated by-product 3 {δp (CDCl3) 25.4,
studied. Only a few publications were found and the reported [M + H]+found = 286.1582, C14H25NO3P requires 286.1567}
reactions were performed in solvent (in DEE, THF or toluene) was inevitable (Table 1, entries 3 and 4). Similar N-methyla-
[53-56], or in the presence of a chiral catalyst [57]. There is tions have been observed also in other cases [59,60]. At 80 °C,
only one solvent and catalyst-free example [58], but in this case diethyl phosphite (DEP) was less reactive than DMP, as after an
a long reaction time (9 h) was required. In the Pudovik synthe- irradiation time of 1 h, the conversion was only 76% (Table 1,
sis of α-aminophosphine oxides, the MW-assisted accomplish- entry 5). At 100 °C/30 min, the reaction proceeded better
ment has not been utilized at all. In the current paper, we (Table 1, entry 6), but a complete conversion was experienced
wished to develop a facile catalyst and solvent-free only when using 1.2 equivalents of DEP (Table 1, entry 7). In
MW-assisted method for the synthesis of α-aryl-α-aminophos- the latter case, aminophosphonate 2b was obtained in a yield
phonates and α-aryl-α-aminophosphine oxides by the addition of 85%. The comparative thermal experiment led again to a
of dialkyl phosphites or diphenylphosphine oxide to the double significantly lower conversion (Table 1, entry 8). Changing for
bond of imines, and aimed at the preparation of new derivatives. dibutyl phosphite (DBuP), and applying it in a 1.2-fold quantity
at 100 °C for 30 min, the addition was practically quantitative,
Results and Discussion
and aminophosphonate 2c was obtained in a yield of 90%
Synthesis of α-aryl-α-aminophosphonates
and α-aminophosphine oxides
At first, the imine starting materials 1 were prepared by the con-
densation of benzaldehyde and its chloro-substituted deriva-
tives with primary amines, such as butyl-, cyclohexylamine or
aniline at room temperature under solvent-free conditions
(Scheme 1).
(Table 1, entry 9). Under similar conditions, the reaction of
dibenzyl phosphite (DBnP) was also clear-cut and afforded
dibenzyl ((butylamino)(phenyl)methyl)phosphonate (2d) in
69% yield (Table 1, entry 10). Finally, diphenylphosphine oxide
(DPPO) was added to imine 1a. After 10 min irradiation at
100 °C, complete conversion was observed and aminophos-
phine oxide 2e was obtained in a yield of 89% (Table 1, entry
11).
Then, the reaction of N-benzylidene(butyl)amine (1a) with four
different dialkyl phosphites and diphenylphosphine oxide was Next N-benzylidene(cyclohexyl)amine (1b) was tried in the
investigated under MW-assisted solvent-free conditions aza-Pudovik reaction (Table 2).
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Beilstein J. Org. Chem. 2017, 13, 76–86.
Table 1: Addition of dialkyl phosphites and diphenylphosphine oxide to N-benzylidenebutylamine (1a).
Entry
Mode of
heating
>P(O)H
>P(O)H
(equiv)
T
(°C)
t
Composition (%)a
Yieldb
(%)
(min)
1a
2
1
2
MW
Δ
DMP
DMP
DMP
DMP
DEP
1
1
80
30
30
30
30
60
30
30
30
30
30
10
5
21
4
95 (2a)
79 (2a)
73
–
80
3
MW
MW
MW
MW
MW
Δ
1
100
100
80
90c (2a)
94c (2a)
76 (2b)
–
4
1.2
1
0
–
5
24
5
–
6
DEP
1
100
100
100
100
100
100
95 (2b)
–
7
DEP
1.2
1.2
1.2
1.2
1.2
0
100 (2b)
83 (2b)
85
–
8
DEP
17
1
9
MW
MW
MW
DBuP
DBnP
DPPO
99 (2c)
90
69
89
10
11e
0
100d (2d)
100d (2e)
0
aOn the basis of GC. bAfter column chromatography. cIn these experiments byproduct 3 was also formed in a proportion of 6% based on GC–MS:
dOn the basis of HPLC. eUnder N2 atmosphere.
Table 2: Addition of >P(O)H reagents to N-benzylidene(cyclohexyl)amine (1b).
Entry
Mode of
heating
>P(O)H
>P(O)H
(equiv)
T
(°C)
t
Composition (%)a
Yieldb
(%)
(min)
1b
4
1
2
MW
MW
MW
Δ
DMP
DMP
DMP
DMP
DEP
1.2
1.2
1.5
1.5
1.2
1.2
1.2
1.2
80
30
30
30
30
30
30
30
10
11
7
89 (4a)
93c (4a)
99 (4a)
–
100
100
100
100
100
100
100
–
3
1
87
–
4
9
91 (4a)
5
MW
MW
MW
MW
0
100 (4b)
96c (4c)
100d (4d)
100d (4e)
91
93
68
88
6
DBuP
DBnP
DPPO
4
7
0
8e
0
aOn the basis of GC. bAfter column chromatography. cThere was no change for further irradiation. dOn the basis of HPLC. eUnder N2 atmosphere.
78

Beilstein J. Org. Chem. 2017, 13, 76–86.
Its reaction with 1.2 equivalents of DMP at 80 °C for 30 min led were in the range of 92–97%, while the benzyl ester (5d)
to aminophosphonate 4a at a conversion of 89% (Table 2, entry was obtained in a yield of 70% (Table 3, entries 1–4). The
1). Even at 100 °C, no quantitative conversion could be aminophosphine oxide 5e was isolated in an 89% yield
achieved (Table 2, entry 2). There was need for 1.5 equivalents (Table 3, entry 5).
of DMP to attain a conversion of 99%. In this case, dimethyl
((cyclohexylamino)(phenyl)methyl)phosphonate (4a) was iso- Next, N-chlorobenzylidene(butyl)amines 1d–f were reacted
lated in a yield of 87% (Table 2, entry 3). The comparative ther- with dialkyl phosphites at 80–100 °C to obtain the
mal experiment led to a somewhat lower conversion (Table 2, corresponding α-aminophosphonates 6a–c, 7a–c and 8a–c.
entry 4). The addition of DEP and DBuP at 100 °C on the C=N The results are collected in Table 4. The dialkyl ((butyl-
moiety of imine 1b was quantitative or almost quantitative, re- amino)(chlorophenyl)methyl)phosphonates (6–8, a–c) were pre-
spectively. The corresponding aminophosphonates 4b and 4c pared in yields of 72–94% (Table 4, entries 1–9). There were no
could be prepared in yields of approximately 92% (Table 2, observable differences in the reactivities, as compared to the un-
entries 5 and 6). The reaction of N-benzylidene(cyclo- substituted model compound 1a.
hexyl)amine (1b) with DBnP at 100 °C afforded the target com-
pound 4d in a conversion of 100% that could be isolated in a All together 24 compounds including 21 α-aryl-α-aminophos-
yield of only 68% (Table 2, entry 7). The phosphinoylation of phonates and three α-aryl-α-aminophosphine oxides were ob-
imine 1b was carried out at 100 °C for 10 min. The yield of tained by column chromatography and characterized. Among
((cyclohexylamino)(phenyl)methyl)diphenylphosphine oxide the aminophosphonates, 16 are new, and five are known in the
(4e) was 88% (Table 2, entry 8). It can be noted that the literature, two out of the three aminophosphine oxides are new
reactivity of N-benzylidene(butyl)amine (1a) and N-benzyl- compounds.
idene(cyclohexyl)amine (1b) is comparable.
Study on the addition of diethyl phosphite to
N-benzylidene(butyl)amine by in situ FTIR
spectroscopy
N-Benzylideneaniline (1c) revealed a somewhat enhanced reac-
tivity in the reaction with the >P(O)H species (Table 3). The
electron-donating butyl and cyclohexyl groups decrease the
partial positive charge on the carbon atom of the >C=N- unit, as
compared to the phenyl substituent. Hence, complete additions
could be accomplished already at 80 °C within reaction
times of 10–30 min. The yields of aminophosphonates 5a–c
Then, we wished to follow the addition reaction of DEP to
N-benzylidene(butyl)amine (1a) at 80 °C in acetonitrile
(Scheme 2) by in situ Fourier transform IR spectroscopy.
Initially the IR spectra of the reaction components were re-
corded: imine 1a, DEP and diethyl ((butylamino)(phenyl)-
methyl)phosphonate (2b) (Table 5 and Figure 1). The spectrum
of imine 1a has a strong absorption band at 1648 cm−1 corre-
sponding to νC=N. At the same time, DEP may be identified by
the strong signals at 961, 1042 and 1251 cm−1 assigned to the
νP–O–C and the νP=O vibrations, respectively. The similar
νP–O–C and νP=O absorptions of the product α-aminophos-
phonate 2b were somewhat shifted to 1026, 1057 and
1242 cm−1, respectively.
Table 3: MW-assisted addition of >P(O)H reagents to N-benzylide-
neaniline (1c).
A segment of the time-dependent IR spectrum (3D diagram)
can be seen in Figure 2.
Entry >P(O)H
T
(°C)
t
Composition
(%)a
Yieldb
(%)
(min)
The obtained results from this study are shown in Figure 3 and
show the concentration profile of the starting components imine
1a and DEP and the product 2b. The diagram was constructed
by a so-called deconvolution on the basis of the decrease/
increase of the different absorptions on the reaction time scale.
This calculation (MCR-ALS, multivariate curve resolution –
alternating least squares) gives the concentration profiles of the
components and also the spectra of pure components. From
Figure 3, it can be seen that the addition reaction was complete
after 3.5 h.
1c
5
1
2
OMe
OEt
OBu
OBn
Ph
80
80
80
80
80
10
10
20
30
10
1
0
0
0
0
99 (5a)
100 (5b)
100 (5c)
100c (5d)
100c (5e)
92
93
97
70
89
3
4
5d
aOn the basis of GC. bAfter column chromatography. cOn the basis of
HPLC. dUnder N2 atmosphere.
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Beilstein J. Org. Chem. 2017, 13, 76–86.
Table 4: MW-assisted addition of dialkyl phosphites to N-chlorobenzylidene(butyl)amines 1d–f.
Entry
Imine
>P(O)H
>P(O)H
(equiv)
T
(°C)
t
Composition (%)a
Yieldb
(%)
(min)
1
Product
1
2
3
4
5
6
7
8
9
1d
1d
1d
1e
1e
1e
1f
DMP
DEP
1
80
100
100
80
30
20
30
30
20
30
30
20
30
1
0
99 (6a)
100(6b)
100 (6c)
88 (7a)
97 (7b)
93 (7c)
88 (8a)
100 (8b)
98 (8c)
91
72
74
80
94
73
75
80
81
1.2
1.2
1
DBuP
DMP
DEP
0
12
3
1.2
1.2
1
100
100
80
DBuP
DMP
DEP
7
12
0
1f
1.2
1.2
100
100
1f
DBuP
2
aOn the basis of GC. bAfter column chromatography.
low temperatures. There seems to be a slight disorder, which
becomes evident in the ellipsoids of the aniline ring and one of
the methyl carbon atoms (Figure 4).
The crystal structure of compound 5b was published almost
40 years ago [61], and a subsequent NMR and theoretical study
was also done for comparative purposes [62]. This latter work
claims SS and RR dimers, which is obviously wrong, as the
centrosymmetric dimers formed must be RS due to symmetry.
Scheme 2: Addition of diethyl phosphite to N-benzylidene(butyl)amine
in acetonitrile.
Finally, the characteristic IR absorptions were taken from the The crystal structure of 5b does not undergo a phase transition
calculated IR spectra and compared with those obtained in at −100 ºC, hence, it must be similar to the sample studied in the
acetonitrile solutions (Table 6). As can be seen, the agreement earlier work at room temperature [62]. Apart from the forma-
is rather good.
tion of the centrosymmetric dimer through a strong N–H···O=P
hydrogen bridge (cf. Table 7), there is a C–H…O short contact
to an ester oxygen atom of a next, translated and inverted 5b
molecule, as well. In this way, sheets of symmetry center
An X-ray crystallographic study on the
α-aminophosphonates 5b and 5d
Large crystals of 5b are composed of very thin plates and one of related dimers fused into endless sheets are formed in the
these plates was dissected and used for X-ray measurement at crystal (cf. Supporting Information File 1, Figure S1).
Table 5: Characteristic IR absorptions of the reaction components.
C6H5CH=NBu (1a)
(EtO)2P(O)H
961 cm−1
(EtO)2P(O)CH(Ph)NHBu (2b)
976 cm−1
νC=N
νC=N
νP–O–C
νP–O–C
νP=O
1026 cm−1
νP–O–C
νP–O–C
νP=O
1648 cm−1
1042 cm−1
1251 cm−1
1057 cm−1
1242 cm−1
80

Beilstein J. Org. Chem. 2017, 13, 76–86.
Figure 1: IR spectra of the reaction components in acetonitrile solution.
Figure 2: A segment of the time-dependent IR spectrum for the addition of diethyl phosphite to N-benzylidene(butyl)amine (1a) in acetonitrile under
formation of diethyl ((butylamino)(phenyl)methyl)phosphonate (2b).
Figure 3: Concentration profiles of the reaction components in the addition reaction at 80 °C in acetonitrile.
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Beilstein J. Org. Chem. 2017, 13, 76–86.
Table 6: IR absorptions measured and obtained from the 3D diagram after deconvolution (in cm−1).
C6H5CH=NBu (1a) (EtO)2P(O)H (EtO)2P(O)CH(Ph)NHBu (2b)
Measured
Obtained
Measured
Obtained
Measured
Obtained
1648
976
1648
976
1251
1073
1042
961
1262
1073
1046
980
1242
1057
1026
961
1246
1053
1026
961
Figure 4: Atomic numbering with anisotropic displacements plot of 5b
at −100 °C.
Figure 5: Atomic numbering with anisotropic displacements plot of 5d
at −100 °C.
In the crystal structure of 5d (Figure 5), the formation of
hydrogen-bonded dimers occurs through the same N–H···O=P
hydrogen bonds in the solid state (Table 7 and Supporting Infor-
mation File 1, Figure S2), too.
Table 7: Hydrogen bond dimensions (Å, Deg) for compounds 5b and
5d.a
5b
A short intramolecular H(1)···H(10) distance in 5b appears
to be nearly by −0.3 Å shorter than the sum of vdW radii
(2.11(2) << 2.40), and is somewhat similar to those observed in
other aminophosphonates [63]. No such short distance is seen in
compound 5d, where all H···H contacts appear around or longer
than the respective sums of van der Waals radii, and the only
short attractive contact is in the H-bridge promoted dimer.
D–H···A
N1–H1A···O1b 0.88(4)
C7–H7···O3c 0.94(3)
D–H (Å) H···A (Å) D···A (Å) D–H···A (°)
2.09(4) 2.957(3)
2.48(3) 3.367(3)
167(4)
159(1)
5d
N1–H1A···O1d 0.87(2)
2.20(2) 3.051(2)
166(2)
aD, donor; A, acceptor; bsymmetry related operator = 1−x,−y,−z;
csymmetry related operator = 1−x, 1−y,−z; dsymmetry related
operator = 1−x,−y,2−z.
Theoretical study on the addition of the
>P(O)H species to N-benzylideneamines
The calculations were carried out by the B3LYP/6-31G (d,p)
method. In the solvent-free reaction, the dielectric constant of pentavalent tetracoordinated form A was by 25–28 kJ mol−1
the P reagent was estimated as 78.3553. This value was taken more stable than the trivalent form B.
into account as an implicit solvent effect. First, the tautomeric
equilibria of dialkyl phosphites and diphenylphosphine oxide The calculations predicted the attack of the trivalent form B of
were studied (Table 8). It was not surprising to find that the the P reagent on the nitrogen atom of the C=N unit of the
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Beilstein J. Org. Chem. 2017, 13, 76–86.
Table 8: Relative enthalpies, free energies and entropies for the tautomeric forms in case of methoxy and phenyl substituents.
Y = MeO
ΔH
ΔG
ΔS
Y = Ph
ΔH
ΔG
ΔS
[kJ mol−1]
[kJ mol−1]
[J (mol K)−1]
[kJ mol−1]
[kJ mol−1]
[J (mol K)−1]
A
B
0
0
0
A
B
0
0
0
27.7
26.4
1.1
24.7
22.3
1.9
imine 1. Moreover, the P–C and the N–H bonds are formed in a Conclusion
single concerted step, via five-membered transition states TS 2, In conclusion, we have developed an efficient, solvent-free and
4, and 5 (Table 9) and the additions are in all cases exothermic. catalyst-free MW-assisted method for the Pudovik synthesis of
The reactions with dimethyl phosphite are more favorable than α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine
those with diphenylphosphine oxide. It can also be seen that the oxides. This method is a novel approach for the preparation of
additions to N-benzylideneaniline have the greatest driving the target compounds, and was optimized for each case.
force of ca. 31 kJ mol−1. The energy content of the TSs fall in Twenty-four derivatives were isolated and characterized. Except
the range of 77–89 kJ mol−1.
six compounds, these were new compounds. Furthermore, the
reactivity was mapped, and the mechanism was evaluated by
The energy diagrams for the reactions with dimethyl phosphite B3LYP/6-31G (d,p) calculations. The crystal structure of two
and diphenylphosphine oxide are shown in Figure 6 and α-aminophosphonates was studied by X-ray analysis suggesting
Figure 7, respectively.
centrosymmetric dimers.
Table 9: Relative enthalpies, free energies and entropies for the addition reaction of >P(O)H species to imines.
Y = MeO
ΔH0/ΔH#
[kJ mol−1]
ΔG0/ΔG#
[kJ mol−1]
ΔS0/ΔS#
[J (mol K)−1]
Y = Ph
ΔH0/ΔH#
[kJ mol−1]
ΔG0/ΔG#
[kJ mol−1]
ΔS0/ΔS#
[J (mol K)−1]
Z = Bu
B + 1a → 2a
TS 2a
Z = Bu
B + 1a → 2e
TS 2e
−21.1
−4.7
−13.1
−13.3
−10.9
3.5
−11.5
−9.3
83.9
100.5
80.8
92.4
Z = c-hex
B + 1b → 4a
TS 4a
Z = c-hex
B + 1b → 4e
TS 4e
−16.6
−5.6
−8.8
−6.0
−7.6
8.3
−12.8
−12.4
89.2
96.7
85.3
100.8
Z = Ph
B + 1c → 5a
TS 5a
Z = Ph
B + 1c → 5e
TS 5e
−31.3
−17.4
−11.2
−7.9
−30.9
−15.3
−12.5
−10.8
89.0
98.8
77.4
90.9
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Beilstein J. Org. Chem. 2017, 13, 76–86.
Figure 6: The energy diagram for the reaction with dimethyl phosphite.
Figure 7: The energy diagram for the reaction with diphenylphosphine oxide.
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Beilstein J. Org. Chem. 2017, 13, 76–86.
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Supporting Information
Supporting Information File 1
Experimental, X-ray crystallographic data, and NMR
spectra.
doi:10.1016/j.bmcl.2009.03.003
22.Kabachnik, M. M.; Ternovskaya, T. N.; Zobnina, E. V.; Beletskaya, I. P.
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doi:10.1023/A:1016578602100
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Acknowledgements
The above project was supported by the Hungarian Scientific
Research Fund (PD111895) and the Hungarian Research Devel-
opment and Innovation Fund (K119202).
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