Perfluorophenyl phosphonate analogues of aromatic amino acids: Synthesis, X-ray and DFT studies

Article abstract of DOI:10.1016/j.tet.2018.01.019

Novel perfluorophenyl phosphonate analogues of phenylglycine and homophenylalanine were prepared in good to excellent yields, and subjected to solid state characterization by single-crystal X-ray diffraction analysis, and to investigations with the use of

Full text of DOI:10.1016/j.tet.2018.01.019

Accepted Manuscript
Perfluorophenyl phosphonate analogues of aromatic amino acids: Synthesis, X-ray
and DFT studies
Agata Pawłowska, Jean-Noël Volle, David Virieux, Jean-Luc Pirat, Agnieszka Janiak,
Mateusz Nowicki, Marcin Hoffmann, Donata Pluskota-Karwatka
PII:
S0040-4020(18)30041-3
10.1016/j.tet.2018.01.019
TET 29234
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 December 2017
Revised Date: 5 January 2018
Accepted Date: 9 January 2018
Please cite this article as: Pawłowska A, Volle Jean-Noë, Virieux D, Pirat J-L, Janiak A, Nowicki M,
Hoffmann M, Pluskota-Karwatka D, Perfluorophenyl phosphonate analogues of aromatic amino acids:
Synthesis, X-ray and DFT studies, Tetrahedron (2018), doi: 10.1016/j.tet.2018.01.019.
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Graphical abstract

ACCEPTED MANUSCRIPT
Perfluorophenyl phosphonate analogues of aromatic amino acids: synthesis,
X-ray and DFT studies
Agata Pawłowskaa,b, Jean-Noël Volle*b, David Virieuxb, Jean-Luc Piratb, Agnieszka Janiaka,
Mateusz Nowickia, Marcin Hoffmanna, Donata Pluskota-Karwatka*a
a Adam Mickiewicz University in Poznań, Faculty of Chemistry, Umultowska 89b,
61-614 Poznań, Poland, e-mail: donatap@amu.edu.pl
b AM2N, UMR 5253, ICGM, ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier
Cedex 5, France
Abstract
Novel perfluorophenyl phosphonate analogues of phenylglycine and homophenylalanine were
prepared in good to excellent yields, and subjected to solid state characterization by single-
crystal X-ray diffraction analysis, and to investigations with the use of DFT methods.
The α-aminophosphonates have a big potential for biological activity, and through SNAr
reactions may give an entrance to further structurally variable analogues of both amino acids.
Keywords: fluorinated aminophosphonates, phenylglycine, homophenylalanine, amino acids,
DFT calculations, X-ray analysis
1. Introduction
α-Aminophosphonic acids and their derivatives constitute a class of compounds that are
currently attracting interest due to their wide spectrum of biological activities and
pharmacological properties.1–3 Among the large family of α-aminophosphonates, various α-
amino-phosphonoesters of type 1 (Fig. 1) exhibited anticancer (1a),4,5 (Fig. 1) antioxidant,5
antibacterial,6 antimicrobial,7 anti-protozoal,8 and antiviral9 activities. The biological activity
of α-aminophosphonates can be explained by their structural similarity to the corresponding
amino-acid derivatives in which the planar carboxylic group is replaced by tetrahedral
phosphorus-containing moiety. The tetrahedral geometry of the phosphonate group can be
considered as a bioisostere of the high-energy transition state of ester10,11 or amide12,13 bond
hydrolyses. Therefore α-aminophosphonates can act as enzyme inhibitors.14,15 Moreover, they
are peptide mimetics.16 The importance of α-aminophosphonates is reflected in a variety of
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existing synthetic approaches. However, surprisingly limited attention was paid to the
synthesis of fluorine bearing phosphorus analogues of amino acids.17 Combination of fluorine
atoms with α-aminophosphonates offers opportunity to modulate physicochemical and
biological properties, and to greatly improve the metabolic stability of the resulting
molecules.18–20 Presence of fluorine atoms can enhance compound lipophilicity, and improve
the binding affinity to the target protein.21–23 The exploitation of fluorine containing
molecules has become an important strategy in protein biochemistry because it affords novel
mechanism for molecular recognition.24–27 Replacement of amino acids with their fluorinated
analogues is shown to have application in studying amino acid interactions within the protein
fold.28,29 These interactions can be tracked with 19F NMR spectroscopy also in living systems.
30
Among the procedures affording α-aminophosphonates, the three-component Kabachnik-
Fields reaction is an easily implemented synthetic approach. Consequently, it is the method of
choice.31–35 We initially used this procedure as well as its variations including syntheses under
microwave irradiation, under solvent-free conditions, and with application of different
catalysts however, none of the attempts resulted in the formation of desired fluorinated
products. Therefore we built our synthetic protocol on preparation of aldimine followed by a
hydrophosphonylation step to afford novel perfluorophenyl phosphonates of type 2 and
phospha homophenylalanine analogues of type 3 (Fig. 1).
Figure 1. α-Aminophosphonates of type 1, targeted perfluorinated phosphono-phenylglycine 2 and
homophenylalanine 3.
Structures of the obtained perfluorophenyl phosphonate analogues of phenylglycine and
homophenylalanine were studied in details by spectroscopic, crystallographic and
computational methods. Such an approach provided valuable information in regard to
preferable conformation, hydrogen bonds as well as other interactions present in the crystals
investigated.
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2. Results and discussion
2.1 Synthesis of α-aminophosphonates 2a-2j
Preparation of perfluorinated α-aminophosphonates 2 and 3 was planned by applying a one-
pot two step synthesis carried out under thermal conditions from commercially available
2,3,4,5,6-pentafluorobenzaldehyde
4
or
from
the
prepared
3-(2,3,4,5,6-
pentafluorophenyl)propanal 5 as starting materials.
At the outset, a modified strategy was investigated for the preparation of α-
aminophosphonates 2, by the use of sodium hydride with diethyl phosphite to form in situ the
phosphite anion. Nevertheless, preliminary reactions performed with aniline, toluidines and p-
chloroaniline led to the formation of the expected aminophosphonates 2a-e along with a
mixture of side-products 6a-e and 7 (Scheme 1).
Structures of the side-products 6a-e were proposed based on detailed analyses of MS, 19F
NMR and 31P{/1H} NMR spectra obtained for partially separated reaction mixtures. The
resulted data are presented in Table 1.
Table 1. Spectrometric and spectroscopic data obtained for 6a-e
Side-product
MS
19F NMR
31P{/1H} NMR
m/z
δ[ ppm]*
δ [ppm]*
[M+H]+ 392
-138.47 (s, 2F),
-142.86 – -142.98 (m, 2F)
18.94–18.88 (m)
6a
6b
6c
6d
6e
[M+H-(HP(O)(OEt)2)]+ 254
[M+H]+ 406
[M+H-(HP(O)(OEt)2)]+ 268
[M+H]+ 406
[M+H-(HP(O)(OEt)2)]+ 268
[M+H]+ 406
[M+H-(HP(O)(OEt)2)]+ 268
[M+H]+ 426
[M+H-(HP(O)(OEt)2)]+ 288
-133.11 – -133.20 (m, 2F), 19.05–18.99 (m)
-138.55 (s, 2F)
-132.01 – -132.12 (m, 2F), 19.09–19.03 (m)
-141.28 – -141.41 (m, 2F)
-131.81 – -131.94 (m, 2F),
18.98–18.92 (m)
-141.06 – -141.19 (m, 2F)
-138.24 (s, 2F),
18.59–18.54 (m)
-142.93 – -143.06 (m, 2F)
* Spectra performed in CDCl3 for partially separated reaction mixtures
The analyzed mas spectra besides the signals derived from protonated molecular ions of
compounds 6a-e, showed fragment ions signals corresponded to the loss of HP(O)(OEt)2 from
19
[M+H]+. In the F NMR spectra signals consistent with structures of para substituted in the
fluorophenyl rings derivatives were observed. Formation of tetrafluoro α-aminophosphonate
derivatives 6a-e was likely due to a nucleophilic aromatic substitution of fluorine atom in para
position of 2a-e by hydride ion derived from NaH used as a base in the upper branch of
reactions in Sheme 1, for deprotonation of diethyl phosphite but it acted also as nucleophile
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attacking fluorinated ring of the synthesized α-aminophosphonate. Similarly, phosphonate 7
was the result of the phosphite anion nucleophilic attack on the unreacted
pentafluorobenzaldehyde 4. To avoid these side-reactions, procedure without the base was
then applied. Aminophosphonates 2a-j were produced in good to excellent yields (14% to
98%). Lower yields were obtained only from N-alkylamines i.e. benzhydrylamine (14%) and
decylamine reagents (32%) (Scheme 1, Table 2).
Scheme 1. Products formed by reactions of 2,3,4,5,6-pentafluorobenzaldehyde 4 with anilines and diethyl
phosphite in the presence of NaH, and formation of perfluorophenyl phosphonate analogues of phenylglycine
2a-j.
Table 2. Isolated yields of 2a-2j
Product
2a
R
Yield [%]
Ph
57
98
90
81
54
55
80
95
14
32
p-MeC6H4
o-MeC6H4
m-MeC6H4
p-ClC6H4
p-NO2C6H4
p-MeOC6H4
PhCH2
2b
2c
2d
2e
2f
2g
2h
2i
Ph2CH
C10H23
2j
The free amine derivative 2k was obtained in almost quantitative yield (99%) by
hydrogenolysis of the N-benzyl derivative 2h, (Scheme 2). On the other hand, hydrogenolysis
of benzhydryl derivative 2i was less efficient, affording 2k in the yield of 30%. In parallel,
reaction of perfluorinated benzaldehyde with ammonium acetate resulted in the formation of
2k in only 6% yield, thus justifying the previous approach.
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Scheme 2. Preparation of perfluoro aminophosphonate 2k.
2.2 Synthesis of 3-(2,3,4,5,6-pentafluorophenyl)propanal 5
Synthesis of perfluorinated phospha-homophenylalanine derivatives 3 required the
preparation of perfluorophenylpropanal 5. Their formation was considered by two synthetic
pathways (Scheme 3). The first one (pathway A) was based on a two-step sequence from
pentafluorobenzaldehyde 4 and (triphenylphosphoranylidene)acetaldehyde 8 (Scheme 3). The
combination of these reagents in dichloromethane at
0
°C generated the
perfluorocinnamaldehyde 9 almost quantitatively. The reduction of this aldehyde was
performed in ethanol under a hydrogen atmosphere in the presence of palladium on charcoal.
Nevertheless, outcome of the reaction was unsatisfactory due to the formation of undesired
products and low yield (20%) in which the expected aldehyde 5 was obtained. The second
pathway B started from 2,3,4,5,6-pentafluorocinammic acid 10 (Scheme 3). Hydrogenation of
the alkene gave quantitatively 3-(2,3,4,5,6-pentafluorophenyl)propanoic acid 11. The
carboxylic acid was transformed into the aldehyde 5 through the formation of the alcohol
derivative 12 in 95% yield by treatment with BH3·THF and a controlled oxidation of this
alcohol with Dess-Martin periodinane reagent (DMP) in dichloromethane in 70% yield. This
is the first report on the aldehyde 5 synthesis through this sequence.
Scheme 3. Synthesis of 3-(2,3,4,5,6-pentafluorophenyl)propanal 5.
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2.3 Synthesis of α-aminophosphonates 3a-3i
α-Aminophosphonates 3 were synthesized using the protocol applied to preparation of
perfluorophenyl phosphonate analogues of phenylglycine 2a-j (Scheme 4). The reactions
proceeded in good yields for 3a-f with electron-rich anilines, whereas moderate yields were
observed for 3g-i when electron-poor anilines and alkylamines were employed (Table 3). The
whole of anilines and amines precursors, as well as isolated yields in which 3 were obtained,
are listed in Table 3.
Scheme 4. Formation of fluorinated phospha analogues 3a-i of homophenylalanine.
Table 3. Isolated yields of 3a-i
Yield
Product
R
[%]
64
61
55
54
49
48
11
18
16
Ph
3a
3b
3c
3d
3e
3f
p-MeOC6H4
p-MeC6H4
o-MeC6H4
m-MeC6H4
p-ClC6H4
p-NO2C6H4
PhCH2
3g
3h
3i
C10H23
2.4 Structural studies
For three phosphonate analogues of phenylglycine (2a, 2b, 2e) and for four analogues of
homophenylalanine (3b, 3c, 3d, 3e) crystal structures were determined by single-crystal X-ray
diffraction analyses.
The compounds 2a, 2b and 2e crystallize in the triclinic crystal system with the space group
P-1. Each compound has two molecules (mol1 and mol2) in the asymmetric part of unit cell
as shown in Fig. 2. The two symmetry independent molecules have a very similar
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3
3
conformation and the minor differences occur mainly within the aliphatic Csp -Csp -O-P
chains. These chains can adopt one of three conformations, either antiperiplanar (ap),
anticlinal (ac) or synclinal (sc). In 2a, the two aliphatic chains adopt an ac-ac conformation in
mol1 and an sc-ap conformation in mol2. The corresponding torsion angles are -100.2 and
120.8° in mol1 and -77.7 and -178.5° in mol2. In 2b, the combination of conformations of the
two aliphatic chains is ac-ap (-107.8 and 154.9°) in mol1 and sc-ac (64.2 and -97.8°) in mol2
3
3
while in 2e the Csp -Csp -O-P chains adopt an ap-ap (-173.2 and 176.4°) conformation in mol1
and an ac-ap (115.5 and -176.9°) conformation in mol2. In the molecules 2a, 2b and 2e, two
aromatic rings are oriented almost perpendicular to each other while the dihedral angles
between them are in the range 84.2 to 87.5°. X-ray data collection parameters are presented in
Table S1 in ESI.
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Figure 2. Asymmetric unit of 2a, 2b and 2e together with labelling scheme. Ellipsoids are drawn at the 30%
probability level, hydrogen atoms are represented by spheres of arbitrary radii.
Crystals of 3b, 3c, 3d and 3e suitable for X-ray analysis were obtained from toluene
by slow evaporation under ambient conditions. The asymmetric part of unit cell in the crystals
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studied consists of one molecule as is shown in Fig. 3. As is apparent from Fig. 3, molecules
3b, 3d and 3e have similar conformations within the aliphatic and the aromatic parts of the
molecules. In 3b and 3d, the aliphatic chains adopt an ac-ac conformation while in 3e, owing
to the presence of the disordered regions, this conformation is varied and a combination of ac-
ac, ac-ap or ap-ap can be observed. In 3b, 3d and 3e the two aromatic rings are far apart from
each other and the distances between their centers are 7.012 Å in 3b and 7.926 Å in 3d and
3e. These rings are mutually tilted to each other and the interplanar angle is ranging from 36.6
to 45.5°. The overall molecular conformation in 3b, 3d and 3e is extended. In contrast to this,
molecules 3c adopt a folded conformation in which two aromatic rings are relatively close to
each other and the distance between the ring centers is 3.551 Å. These rings are oriented
almost parallel to each other and the dihedral angle is only 2.6°. The folded conformation
present in crystal 3c is stabilized by intramolecular π...π interactions that occur between the
fluorinated and non-fluorinated aromatic rings; the ring offset is 1.52 Å. Both aliphatic chains
in 3c adopt an ap-ap conformation. X-ray data collection parameters for 3b, 3c, 3d and 3e are
presented in Table S2 in ESI.
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Figure 3. The asymmetric unit of 3b, 3c, 3d and 3e together with the labelling scheme. Ellipsoids are drawn at
the 30% probability level, hydrogen atoms are represented by spheres of arbitrary radii. Dashed lines indicate
intramolecular interactions in 3c and 3d. The disordered regions within themolecule3e have been omitted for
clarity.
The principal directional interactions in the crystal structures of both phenylglycine (2a, 2b
and 2e), and homophenylalanine (3b, 3c, 3d and 3e) analogues are the N-H...O hydrogen
bonds that hold two enantiomers of opposite stereochemistry together around a centre of
symmetry as it shown in Figure 4. This hydrogen bonding interactions generate a motif that
can be described by the graph set notation R2 (10).
2
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Figure 4. Dimeric motif of N-H..O(=P) hydrogen bonds present in all crystal investigated.
The geometric parameters describing the N-H...O hydrogen bonds in all crystal structures are
listed in Table 4.
Table 4. Geometrical parameters describing N-H..O hydrogen bonding in all crystals investigated.
D-H [Å]
H…A [Å]
D…A [Å]
D-H…A [°]
SYMM
2a
N1-H1…O1
N2-H2…O4
2b
0.83(3)
0.83(3)
2.18(2)
2.24(3)
2.981(3)
3.031(3)
162(3)
158(3)
-x, -y+2, -z+1
-x+1, -y+1, -z
N1-H1…O1
N2-H2…O4
2e
0.86(2)
0.85(2)
2.12(2)
2.16(2)
2.932(2)
2.974(2)
157(2)
160(2)
-x+1, -y+1, -z
-x, -y+2, -z+1
N1-H1…O1
N2-H2…O4
3b
0.81(2)
0.82(2)
2.16(2)
2.22(2)
2.952(2)
2.002(2)
167(2)
161(2)
-x, -y+1, -z+2
-x+1, -y+1, -z+1
N1-H1…O1
3c
N1-H1…O1
3d
N1-H1…O1
3e
N1-H1…O1
0.84(2)
0.82(3)
0.81(2)
0.84(3)
2.16(2)
2.13(4)
2.26(2)
2.06(3)
2.987(2)
2.935(4)
3.03(2)
170(2)
169(3)
160(2)
174(3)
-x+1, -y+1, -z+1
-x, -y+1, -z+1
-x+1, -y+1, -z+1
-x+½, -y+½, -z+1
2.898(4)
The different conformation of 3c comparing to conformations adopted by 3b, 3d and 3e
prompted us to study of 3c structure also by quantum-chemical methods. DFT calculations
indicated that for molecule 3c the conformation in which the aromatic rings are involved in π-
stacking is indeed energetically favored by ca 2.5 kcal/mol (M06-2X, wB97XD) or 0.5
11

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kcal/mol (B3LYP), (Table 5). Stacking parameters calculated in accordance to Glowka et al.
36
i.e. stacking distance h, shift r, tilt θ and twist φ also suggest preferable stacked geometry.
The stacking distance h calculated with M06-2X (3.1204 Å) and wB97XD (3.2358 Å) is
smaller than the proposed limit of 3.5 Å, and is close to it at B3LYP method (3.5555 Å). The
shift r ranges from 1.1969 Å to 2.1159 Å and is smaller than the 2.8 Å limit. As to the tilt
parameter θ the value of 50.61° obtained with B3LYP functional larger than 10° indicates the
absence of face to face π-stacking, while the values 2.05° and 0.23° calculated with M06-2X
and wB97XD permits the presence of face to face π-stacking. Stacking parameters calculated
with M062X and wB97XD are in very good agreement with those obtained from
experimental data (Table 5).
The single point energy difference between the stacked and the extended conformations were
also calculated at MP2/6-31G(d)//M06-2X/6-31G(d) level of theory and it occurred that the
stacked conformer is indeed energetically favored by 3.5 kcal/mol, which may indicate that
DFT functionals even those including dispersion corrections do not fully account for stacking
interactions.
It is of no surprise that B3LYP exchange-correlation functional seems to produce unreliable
results when dispersion forces need to be included 37, while the other two functionals M06-2X
and wB97XD appear to lead to much more plausible, similar outcome.
Table 5. Stacking parameters and energy difference between the extended and stacked conformers calculated for
molecule 3c and derived from X-ray analysis
Parameter
B3LYP
M062X
wB97XD
X-ray
analysis
ꢀE [kcal/mol]
h [Å]
0.49
2.53
2.48
3.5555
2.1159
3.1204
1.1969
3.2358
1.2152
3.210
1.52
r [Å]
l [Å]
Θ [°]
4.1375
50.61
3.3421
2.05
3.4565
0.23
3.552
2.6
φ [°]
59.61
22.17
21.82
20.2
The principal directional interactions in the studied crystal structures are the N-H...O hydrogen
38
bonds therefore row and counterpoise corrected interaction energies for 3c dimers formed
via a pair of NH···O=P hydrogen bonds were also calculated, (Table 6). The calculated
energies indicated the presence of strong favorable interactions. Again one should note that
B3LYP underestimates dispersion when compared to M06-2X and wB97XD functionals.
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Table 6. Interaction energies calculated for dimers of 3c formed via a pair of NH···O=P hydrogen bonds.
B3LYP M06-2X wB97XD
Interaction energy
(raw)# [kcal/mol]
-22.49
-32.82
-37.90
Interaction energy
(Counterpoise
-10.49
-21.91
-26.26
corrected) [kcal/mol]
# absolute energy base line in hartree: -3793.971040301581 (B3LYP), -3792.727314733594 (M06-2X),
-3793.077603041833 (wB97XD).
3. Conclusions
We synthesized a series of novel perfluorophenyl phosphonate analogues of phenylglycine
and homophenylalanine, and subjected these compounds to spectroscopic and spectrometric
studies as well as to investigations with the use of single-crystal X-ray diffraction analysis and
quantum chemical calculations. Such an approach provided important information with
respect to preferable conformation, hydrogen bonds as and other interactions present in the
crystals. No fluorinated phosphonic acid analogues of these amino acids were shown to be
agents acting toward phenylalanine ammonia lyase and aminopeptidases, respectively.39–41
Perfluorinated aromatic rings exhibit different electron density comparing to non fluorinated
ones. The reversed electron distribution may find reflection in biological activity of
compounds containing perfluorinated phenyl moieties because may influence their
interactions with phenyl rings of aromatic amino acids present in enzymes active centers.
Our synthetic protocol was built on a two step reaction consisting of preparation of aldimine
followed by a hydrophosphonylation. Such strategy occurred to be convenient and efficient
method for synthesis of perfluorophenyl phosphonate analogues of aromatic amino acids, the
compounds having a big potential for biological activity. It is worth to note that interaction
energy of dimer bond by a pair of N-H···O=P hydrogen bonds is as favorable as ca 25
kcal/mol. Moreover presence of heavily fluorinated aromatic rings makes these compounds
susceptible to SNAr reactions which may give an entrance to further structurally variable
analogues of both amino acids. Library of phenylglycine analogues may be especially
important as potential phenylalanine ammonia lyase inhibitors because it was shown, by
computational approach, that electron density of aromatic ring in phosphonic acid inhibitors
has a significant influence on their activity. Further studies aimed at evaluating biological
activity and synthetic potential of the obtained compounds are currently performed.
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4. Experimental section
4.1 General methods
Solvents were dried over 4Å molecular sieves. All moisture sensitive reactions were carried
out under nitrogen atmosphere with dry, freshly distilled reagents when possible. All
glassware was carefully dried under vacuum with a flameless heat gun. TLC was performed
on Merck Kieselgel 60-F254, and products were detected by UV light (254 nm) and with a
solution of potassium permanganate. Merck Kieselgel 60 (230-400 mesh) was used for
chromatography. All NMR spectra were acquired on a 400 MHz, 403 MHz or 600 MHz
spectrometers. Samples were dissolved in CDCl3 or in acetone-d6, and chemical shifts (δ) are
given in ppm. High resolution mass spectra were measured using electrospray ionization (ESI,
positive-ion mode).
4.2 Synthesis of 3-pentafluorophenylpropanal (5)
4.2.1 3-Pentafluorophenylpropanoic acid (11)
2,3,4,5,6-pentafluorocinnamic acid (10, 2.68 g, 11.3 mmol) was dissolved in ethyl acetate
(220 mL) and Pd/C (10%, 270 mg) was added under a hydrogen atmosphere. The reaction
mixture was stirred at room temperature for 22 h (TLC: hexane/AcOEt, 80:20, v/v). The
solution was filtered through a celite pad and the solvent was evaporated under reduced
pressure to afford a 3-pentafluorophenylpropanoic acid (11) as a white solid (2.60 g, 96%). 1H
NMR (400 MHz, CDCl3) δ = 2.97 (t, 2H, J = 7.5 Hz, -CH2CO2H), 2.64–2.60 (m, 2H, -CH2-
)
19
ppm. F NMR (377 MHz, CDCl
3
) δ = -143.45 to -143.53 (m, 2F), -156.42 (t, 1F, J = 20.9
) δ = 178.12 (s, COOH),
146.54–146.27 (m, C-F), 144.09–143.82 (m, C-F), 141.50–141.13 (m, C-F), 138.99–138.55
Hz), -162.16 to -162.30 (m, 2F) ppm.13C NMR (101 MHz, CDCl
3
(m, C-F), 136.48–136.09 (m, C-F), 113.16–112.75 (m, Car), 32.93 (s, -CH
2
-), 17.60 (s, -CH -)
2
ppm.
4.2.2 3-Pentafluorophenylpropane-1-ol (12)
3-pentafluorophenylpropanoic acid (11, 1.91 g, 7.95 mmol) was dissolved in dry THF (110
mL) and treated at room temperature with BH3-THF (13.23 mL) under N2 atmosphere. The
mixture was stirred at room temperature for 3.5 h. The excess of hydride was quenchedat 0 °C
with water (120 mL). The mixture was acidified with hydrochloric acid (3 M), and extracted
with diethyl ether (4 × 100 mL). The organic phases were combined and dried over MgSO4,
filtered and concentrated. The crude product was purified by chromatography (silica gel,
hexane/AcOEt, 80:20, v/v) to give 3-pentafluorophenylpropan-1-ol (12) as a colorless oil
1
(1.70 g, 95%). H NMR(400 MHz, CDCl3) δ = 3.72 (t, 2H, J = 6.2 Hz, -CH2OH), 2.87–2.82
(m, 2H, -CH2-), 1.92–1.85 (m, 2H, -CH2-), 1.46 (s, 1H, -OH) ppm. 19F NMR (377 MHz,
14

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CDCl3) δ = -144.29 (m, 2F), -157.73 (t, 1F, J = 20.8 Hz), -162.68 to -162.82 (m, 2F) ppm. 13C
NMR (101 MHz, CDCl3) δ = 146.42–146.15 (m, C-F), 143.99–143.68 (m, C-F), 140.98–
140.60 (m, C-F), 138.83–138.16 (m, C-F), 136.34–135.97 (m, C-F), 115.02–114.60 (m, Car),
61.60 (s, -CH2OH), 31.89 (s, -CH2-), 18.80 (s, -CH2-) ppm.
4.2.3 3-pentafluorophenylpropanal (5)
3-pentafluorophenylpropan-1-ol (12, 0.33 g, 1.46 mmol) was dissolved in dry
dichloromethane (5 mL), and Dess-Martin periodinane (0.74 g, 1.75 mmol) was added under
nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 h, and after
purification by chromatography (silica gel, cyclohexane/AcOEt, 80:20, v/v), 3-
1
pentafluorophenylpropanal 5 was obtained as white crystalline solid (0.23 g, 70%). H NMR
(400 MHz, CDCl3) δ = 9.74 (s, 1H, -CHO), 2.95 (t, 2H, J = 7.2 Hz, -CH2-), 2.73 (t, 2H, J =
19
7.4 Hz, -CH2-) ppm. F NMR (377 MHz, CDCl3) δ = -143.59 (m, 2F), -156.82 (t, 1F, J =
20.8 Hz), -162.28 to -162.42 (m, 2F) ppm. 13C NMR (101 MHz, CDCl3) δ = 199.49 (s, -
CHO), 146.40–146.18 (m, C-F), 144.02–143.71 (m, C-F), 141.40–141.12 (m, C-F), 138.90–
138.65 (m, C-F), 136.49–136.12 (m, C-F), 113.41–113.29 (m, Car), 42.54 (s, -CH2-), 15.13
(s, -CH2-) ppm.
4.3 General procedure for aminophosphonates (2a-j, 3a-i) synthesis
To the mixture of aldehyde 4 or 5 in dry toluene (10 mL), aniline or amine was added under a
N2 atmosphere. The reaction mixture was heated under reflux for 5 h, then HP(O)(OEt)2 was
added, and the mixture was heated under reflux for next 16 h. After cooling to room
temperature, the solvent was removed under reduced pressure, and the crude product was
purified by chromatography (silica gel, cyclohexane/ethyl acetate 1:1, v/v).
Diethyl ((perfluorophenyl)(phenylamino)methyl)phosphonate (2a): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.41 g, 2.04 mmol), aniline (0.19 g, 2.04 mmol), HP(O)(OEt)2
(0.53, 4.08 mmol), a pale green solid was obtained (0.48 g, 57%); mp = 104–106 °C. 1H NMR
(403 MHz, CDCl3) δ = 7.17–7.13 (m, 2H, Ph), 6.78–6.74 (m, 1H, Ph), 6.67–6.65 (m, 2H, Ph),
5.27 (dd, 1H, J = 26.5, 11.3 Hz, -CH-), 4.71 (dd, 1H, J = 11.3, 6.6 Hz, -NH-), 4.32–4.06 (m,
4H, 2 × -OCH2-), 1.34 (td, 3H, J = 7.1, 0.5 Hz, -OCH2CH3), 1.25 (td, 3H, J = 7.1, 0.5 Hz, -
19
OCH2CH3) ppm. F NMR (282 MHz, CDCl3) δ = -142.75 to -142.83 (m, 2F), -154.21 (td,
1F, J = 20.8, 4.3 Hz), -161.78 to -161.90 (m, 2F) ppm. 31P NMR (121 MHz, CDCl3) δ =
13
19.30–19.26 (m, 1P) ppm. C NMR (101 MHz, CDCl3) δ = 146.44 (s, C-F), 145.10 (d, J =
14.4 Hz, Car), 144.01 (s, C-F), 141.90 (s, C-F), 138.74–138.42 (m, C-F), 136.27–135.95 (m,
15

ACCEPTED MANUSCRIPT
C-F), 129.31 (s, CHar), 119.48 (s, CHar), 113.42 (s, CHar), 110.77–110.14 (m, Car), 64.00 (d,
J = 6.8 Hz, -OCH2-), 63.12 (d, J = 7.2 Hz, -OCH2-), 47.07 (d, J = 162.3 Hz, -CH-), 16.20,
16.14, 16.00, 15.94 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for C17H18F5NO3P [M+H]+:
410.0939, found: 410.0925.
Diethyl ((perfluorophenyl)(p-tolylamino)methyl)phosphonate (2b): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.52 g, 2.55 mmol), p-toluidine (0.27 g, 2.55 mmol), HP(O)(OEt)2
(0.66 mL, 5.10 mmol), a white solid was obtained (1.06 g, 98%); mp = 107–109 °C. 1H NMR
(403 MHz, CDCl3) δ = 6.98 (d, 2H, J = 8.0 Hz, Ph), 6.58–6.56 (m, 2H, Ph), 5.23 (dd, 1H, J =
26.2, 11.4 Hz, -CH-), 4.54–4.50 (m, 1H, -NH-), 4.31–4.05 (m, 4H, 2 × -OCH2-), 2.21 (s, 3H, -
19
PhCH3),1.35 (t, 3H, J = 7.1 Hz, -OCH2CH3), 1.26 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm. F
NMR (282 MHz, CDCl3) δ= -142.97 (d, 2F, J = 20.9 Hz), -154.25 (td, 1F, J = 20.9, 4.5 Hz), -
161.83 (t, 2F, J = 19.0 Hz) ppm. 31P NMR (121 MHz, CDCl3) δ = 19.43–19.39 (m, 1P) ppm.
13C NMR (101 MHz, CDCl3) δ = 144.22–143.86 (m, C-F), 142.78 (d, J = 15.0 Hz, Car),
142.10–141.73 (m, C-F), 139.56–139.25 (m, C-F), 138.84–138.50 (m, C-F), 136.33–136.03
(m, C-F), 129.94 (s, CHar), 129.05 (s, CarCH3), 113.74 (s, CHar), 110.87–110.58 (m, Car),
64.10 (d, J = 6.8 Hz, -OCH2-), 63.16 (d, J = 7.2 Hz, -OCH2-), 47.56 (d, J = 162.6 Hz, -CH-),
20.28 (s, -PhCH3), 16.36, 16.31, 16.16, 16.11 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for
C18H20F5NO3P [M+H]+: 424.1095, found: 424.1082.
Diethyl ((perfluorophenyl)(o-tolylamino)methyl)phosphonate (2c): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.50 g, 2.55 mmol), o-toluidine (0.27 g, 2.55 mmol), HP(O)(OEt)2
(0.66 mL, 5.10 mmol), a colorless oil was obtained (0.97 g, 90%).1H NMR (403 MHz,
CDCl3) δ = 7.08–7.04 (m, 2H, Ph), 6.73–6.71 (m, 1H, Ph), 6.51 (d, 1H, J = 7.9 Hz, Ph), 5.29
(dd, 1H, J = 25.7, 11.0 Hz, -CH-), 4.60 (dd, 1H, J = 11.0, 6.8 Hz, -NH-), 4.32–4.07 (m, 4H, 2
× -OCH2-), 2.23 (s, 1H, -PhCH3), 1.35 (td, 3H, J = 7.1, 0.5 Hz, -OCH2CH3), 1.27 (td, 3H, J =
7.1, 0.5 Hz, -OCH2CH3) ppm. 19F NMR (282 MHz, CDCl3) δ = -143.02 to -143.09 (m, 2F), -
154.16 to -154.32 (m, 1F), -161.74 to -161.86 (m, 2F) ppm. 31P NMR (121 MHz, CDCl3) δ =
13
19.49–19.37 (m, 1P) ppm. C NMR (101 MHz, CDCl3) δ = 144.15 (s, C-F), 143.11 (d, J =
13.8 Hz, Car), 142.20–141.85 (m, C-F), 139.68–139.29 (m, C-F), 138.89–138.60 (m, C-F),
136.40–136.11 (m, C-F), 130.67 (s, CHar), 127.12 (s, CHar), 123.54 (s, CarCH3), 119.04 (s,
CHar), 111.06–110.77 (m, Car), 109.95 (s, CHar), 64.06 (d, J = 6.8 Hz, -OCH2-), 63.25 (d, J
= 7.2 Hz, -OCH2-), 46.79 (d, J = 162.1 Hz, -CH-), 17.09 (s, -PhCH3), 16.35, 16.30, 16.18,
16.12 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for C18H20F5NO3P [M+H]+: 424.1095,
found: 424.1094.
16

ACCEPTED MANUSCRIPT
Diethyl ((perfluorophenyl)(m-tolylamino)methyl)phosphonate (2d): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.53 g, 2.55 mmol), m-toluidine (0.27 g, 2.55 mmol), HP(O)(OEt)2
(0.66 mL, 5.10 mmol), a pale yellow solid was obtained (0.88 g, 81%); mp = 108–110 °C. 1H
NMR (600 MHz, CDCl3) δ= 7.05 (t, 1H, J = 7.8 Hz, Ph), 6.61 (d, 1H, J = 7.5 Hz, Ph), 6.49 (s,
1H, Ph), 6.46–6.44 (m, 1H, Ph), 5.25 (dd, 1H, J = 26.2, 11.4 Hz, -CH-), 4.60–4.57 (m, 1H, -
NH-), 4.29–4.06 (m, 4H, 2 × -OCH2-), 2.25 (s, 3H, -PhCH3), 1.34 (t, 3H, J = 7.1 Hz, -
OCH2CH3), 1.25 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm. 19F NMR (282 MHz, CDCl3) δ = -
31
142.90 to -142.98 (m, 2F), -154.13 to -154.29 (m, 1F), -161.75 to -161.88 (m, 2F) ppm. P
13
NMR (121 MHz, CDCl3) δ = 19.39–19.27 (m, 1P) ppm. C NMR (151 MHz, CDCl3) δ =
146.20 (s, C-F), 145.24 (d, J = 14.3 Hz, Car),144.56 (s, C-F), 141.78–141.57 (m, C-F), 139.43
(s, CarCH3), 138.46–138.27 (m, C-F), 136.78–136.59 (m, C-F), 129.36 (s, CHar), 120.67 (s,
CHar), 114.67 (s, CHar), 110.95–110.75 (m, Car), 110.45 (s, CHar), 64.13 (d, J = 6.8 Hz, -
OCH2-), 63.24 (d, J = 7.2 Hz, -OCH2-), 47.27 (d, J = 162.4 Hz, -CH-), 21.48 (s, -PhCH3),
16.40, 16.37, 16.20, 16.17 (2
×
-OCH2CH3) ppm. HRMS (ESI+) calc. for C18H20F5NO3P
[M+H]+: 424.1095, found: 424.1093.
Diethyl (((4-chlorophenyl)amino)(perfluorophenyl)methyl)phosphonate (2e): From
2,3,4,5,6-pentafluorobenzaldehyde (0.49 g, 2.55 mmol), p-chloroaniline (0.33 g, 2.55 mmol),
HP(O)(OEt)2 (0.66 mL, 5.10 mmol), a pale yellow solid (0.61 g, 54%); mp = 101–103 °C. 1H
NMR (403 MHz, CDCl3) δ = 7.13–7.09 (m, 2H, Ph), 6.62–6.58 (m, 2H, Ph), 5.20 (dd, 1H, J =
26.1, 11.2 Hz, -CH-), 4.74 (dd, J= 11.1, 6.8 Hz ,1H, -NH-), 4.32–4.07 (m, 4H, 2 × -OCH2-),
1.35 (t, 3H, J = 7.1 Hz, -OCH2CH3), 1.26 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm. 19 F NMR (282
MHz, CDCl3) δ = -142.90 to -142.97 (m, 2F), -153.48 to -153.65 (m, 1F), -161.37 to -161.49
(m, 2F) ppm. 31P NMR (121 MHz, CDCl3) δ = 18.97–18.93 (m, 1P) ppm.13C NMR (101
MHz, CDCl3) δ = 146.68–146.17 (m, C-F), 143.80 (d, J = 14.5 Hz, Car), 142.15–141.86 (m,
C-F) 139.69–139.29 (m, C-F), 138.80–138.49 (m, C-F), 136.32–136.01 (m, C-F), 129.23 (s,
CHar), 124.27 (s, CarCl), 114.66 (s, CHar), 110.44–110.14 (m, Car), 64.05 (d, J = 6.8 Hz, -
OCH2-), 63.25 (d, J = 7.2 Hz, -OCH2-), 47.29 (d, J = 161.9 Hz, -CH-), 16.25, 16.20, 16.06,
16.00 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for C17H17ClF5NO3P [M+H]+: 444.0549,
found: 444.0543.
Diethyl (((4-nitrophenyl)amino)(perfluorophenyl)methyl)phosphonate (2f): From
2,3,4,5,6-pentafluorobenzaldehyde (0.35 g, 1.79 mmol), p-nitroaniline (0.25 g, 1.79 mmol),
HP(O)(OEt)2 (0.46 mL, 3.58 mmol), a yellow solid was obtained (0.38 g, 55%); mp = 120–
122 °C. 1H NMR (403 MHz, CDCl3) δ = 8.12–8.08 (m, 2H, Ph), 6.67–6.64 (m, 2H, Ph), 5.47–
5.42 (m, 1H, -NH-), 5.27 (dd, 1H, J = 25.5, 10.0 Hz, -CH-), 4.31–4.07 (m, 4H, 2 × -OCH2-),
17

ACCEPTED MANUSCRIPT
1.35 (td, 3H, J = 7.1, 0.5 Hz, -OCH2CH3), 1.28 (td, 3H, J = 7.1, 0.5 Hz, -OCH2CH3) ppm. 19F
NMR (282 MHz, CDCl3) δ = -142.42 to -142.49 (m, 2F), -152.50 to -152.66 (m, 1F), -160.78
31
(td, 2F, J = 21.2, 6.8 Hz) ppm. P NMR (121 MHz, CDCl3) δ = 17.95–17.83 (m, 1P) ppm.
13C NMR (101 MHz, CDCl3) δ = 150.64 (d, J = 12.5 Hz, Car), 146.62–146.26 (m, C-F)
144.12–143.81 (m, C-F), 142.64–142.25 (m, C-F), 140.05 (s, CarNO2), 139.06–138.72 (m, C-
F), 136.58–136.22 (m, C-F), 126.27 (s, CHar), 112.14 (s, CHar), 109.80–109.49 (m, Car),
64.33 (d, J = 6.9 Hz, -OCH2-), 63.78 (d, J = 7.2 Hz, -OCH2-), 46.50 (d, J = 160.9 Hz, -CH-),
16.42, 16.36, 16.23, 16.18 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for C17H17F5N2O5P
[M+H]+: 455.0790, found: 455.0788.
Diethyl (((4-methoxyphenyl)amino)(perfluorophenyl)methyl)phosphonate (2g): From
2,3,4,5,6-pentafluorobenzaldehyde (0.56 g, 2.86 mmol), p-methoxyaniline (0.35 g, 2.86
mmol), HP(O)(OEt)2 (0.74 mL, 5.72 mmol), a yellow solid was obtained (1.01 g, 80%); mp =
104–106 °C. 1H NMR (403 MHz, CDCl3) δ = 6.76–6.74 (m, 2H, Ph), 6.63–6.61 (m, 2H, Ph),
5.18 (dd, 1H, J = 26.2, 11.9 Hz, -CH-), 4.39 (dd, 1H, J = 11.8, 6.3 Hz, -NH-), 4.31–4.05 (m,
4H, 2 × -OCH2-), 3.71 (s, 3H, -OCH3), 1.37–1.33 (m, 3H, -OCH2CH3), 1.28–1.24 (m, 3H, -
19
OCH2CH3) ppm. F NMR (282 MHz, CDCl3) δ = -142.90 to -142.97 (m, 2F), -153.48 to -
31
153.65 (m, 1F), -161.37 to -161.49 (m, 2F) ppm. P NMR (121 MHz, CDCl3) δ = 19.43–
13
19.39 (m, 1P) ppm. C NMR (101 MHz, CDCl3) δ = 153.54 (s, Car),146.72–146.32 (m, C-
F), 144.28–143.85 (m, C-F), 142.18–141.75 (m, C-F), 139.6–138.52 (m, C-F),139.01 (d, J =
15.4 Hz, CarOCH3), 136.43–135.95 (m, C-F), 115.19 (s, CHar), 114.91 (s, CHar), 110.89–
110.59 (m, Car), 64.10 (d, J = 6.8 Hz, -OCH2-), 63.17 (d, J = 7.2 Hz, -OCH2-), 55.48 (s, -
OCH3), 48.42 (d, J = 162.5 Hz, -CH-), 16.38, 16.32, 16.18, 16.12 (2 × -OCH2CH3) ppm.
HRMS (ESI+) calc. forC18H20F5NO4P [M+H]+: 440.1045, found: 440.1038.
Diethyl ((benzylamino)(perfluorophenyl)methyl)phosphonate (2h): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.59 g, 3.10 mmol), benzylamine (0.33 g, 3.10 mmol),
1
HP(O)(OEt)2 (0.80 mL, 6.20 mmol), a colorless oil was obtained (1.23 g, 95%). H NMR
(600 MHz, CDCl3) δ = 7.30–7.22 (m, 5H, Ph) 4.45 (d, 1H, J = 24.6 Hz, -CH-), 4.26–4.03 (m,
4H, 2 × -OCH2-), 3.88 (d, 1H, J = 13.1 Hz, -CH2Ph), 3.71 (d, 1H, J = 13.1 Hz, -CH2Ph), 2.42
(br. s, 1H, -NH-), 1.33 (t, 3H, J = 7.1 Hz, -OCH2CH3), 1.23 (t, 3H, J = 7.1 Hz, -OCH2CH3)
19
ppm. F NMR (282 MHz, CDCl3) δ = -142.41 (s, 2F), -154.78 to -154.95 (m, 1F), -162.23
31
(td, 2F, J = 21.8, 7.8 Hz) ppm. P NMR (121 MHz, CDCl3) δ = 20.17–20.04 (m, 1P) ppm.
13C NMR (151 MHz, CDCl3) δ = 146.10 (s, C-F), 144.45 (s, C-F), 141.41–141.24 (m, C-F),
139.73–139.53 (m, C-F), 138.21 (s, Car), 136.60–136.42 (m, C-F), 128.30 (s, CHar), 128.19
(s, CHar), 127.36 (s, CHar), 110.96–110.76 (m, Car), 63.50 (d, J = 6.9 Hz, -OCH2-), 62.79 (d,
18

ACCEPTED MANUSCRIPT
J = 7.1 Hz, -OCH2-), 52.33 (d, J = 15.8 Hz, -CH2Ph), 50.87 (d, J = 163.1 Hz, -CH-), 16.22,
16.18, 16.06, 16.02 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc. for C18H20F5NO3P [M+H]+:
424.1095, found: 424.1087.
Diethyl ((benzhydrylamino)(perfluorophenyl)methyl)phosphonate (2i): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.58 g, 3.00 mmol), benzhydrylamine (0.55 g, 3.00 mmol),
HP(O)(OEt)2 (0.78 mL, 6.00 mmol), a white solid was obtained (0.21 g, 14%); mp = 131–133
°C. 1H NMR (403 MHz, CDCl3) δ = 7.38–7.18 (m, 10H, 2 × Ph), 4.77 (s, 1H, -CH(Ph)2), 4.42
(dd, 1H, J = 25.0, 12.4 Hz, -CH-), 4.32–4.22 (m, 2H, -OCH2-), 4.13–4.00 (m, 2H, -OCH2-),
2.74 (dd, 1H, J = 12.1, 4.4 Hz, -NH-), 1.39–1.35 (m, 3H, -OCH2CH3), 1.25–1.21 (m, 3H, -
OCH2CH3) ppm.19F NMR (282 MHz, CDCl3) δ = -142.90 to -142.98 (m, 2F), -154.13 to -
31
154.29 (m, 1F), -161.75 to -161.88 (m, 2F) ppm. P NMR (121 MHz, CDCl3) δ = 19.39–
19.27 (m, 1P) ppm.13C NMR (75 MHz, CDCl3) δ = 147.92–146.37 (m, C-F), 144.61–143.00
(m, C-F), 142.30 (br. d, 2 × Car), 142.49–142.14 (m, C-F), 139.43–138.76 (m, C-F), 136.22–
135.37 (m, C-F), 128.74–127.10 (m, 10 × CHar), 110.92–110.50 (m, Car), 65.66 (d, J = 14.6
Hz, -CH(Ph)2), 63.64 (d, J = 6.9 Hz, -OCH2-), 62.82 (d, J = 7.1 Hz, -OCH2-), 50.75 (d, J =
162.8 Hz, -CH-), 16.51, 16.43, 16.26, 16.18 (2 × -OCH2CH3) ppm. HRMS (ESI+) calc.
forC24H24F5NO3P [M+H]+: 500.1408, found: 500.1417.
Diethyl ((decylamino)(perfluorophenyl)methyl)phosphonate (2j): From 2,3,4,5,6-
pentafluorobenzaldehyde (0.5 g, 2.55 mmol), decylamine (0.40 g, 2.55 mmol), HP(O)(OEt)2
(0.66 mL, 5.10 mmol), a pale yellow oil was obtained (0.39 g, 32%).1H NMR (600 MHz,
CDCl3) δ = 4.47 (d, 1H, J = 24.6 Hz, -CH-), 4.28–4.06 (m, 4H, 2 × -OCH2-), 2.61–2.52 (m,
2H, -NHCH2-amine), 2.01 (br. s, 1H, -NH-), 1.52–1.25 (m, 22H, 2x -OCH2CH3, -(CH2)8-
amine), 0.88 (t, 3H, J = 6.8 Hz, -CH3-amine) ppm. 19F NMR (282 MHz, CDCl3) δ = -142.91
31
(s, 2F), -154.97 (t, 1F, J = 20.2 Hz), -162.16 to -162.28 (m, 2F) ppm. P NMR (121 MHz,
CDCl3) δ = 20.26–20.22 (m, 1P) ppm. 13C NMR (151 MHz, CDCl3) δ = 144.59 (s, C-F),
141.49–141.31 (m, C-F), 139.80–139.63 (m, C-F), 138.41–138.23 (m, C-F), 136.74–136.55
(m, C-F), 111.31–111.11 (m, Car), 63.58 (d, J = 6.7 Hz, -OCH2-), 62.84 (d, J = 7.1 Hz, -
OCH2-), 52.23 (d, J = 162.4 Hz, -CH-), 48.75 (d, J = 15.1 Hz, -NHCH2-amine), 31.84 (s, -
CH2-amine), 29.64–29.25 (m, -CH2-amine), 26.98 (s, -CH2-amine), 22.61 (s, -CH2-amine),
16.36, 16.32, 16.23, 16.19 (2 × -OCH2CH3), 14.01 (s, -CH3-amine) ppm. HRMS (ESI+) calc.
for C21H34F5NO3P [M+H]+: 474.2191, found: 474.2187.
Diethyl (3-(perfluorophenyl)-1-(phenylamino)propyl)phosphonate (3a): From 3-
(perfluorophenyl)propanal (0.10 g, 0.45 mmol), aniline (0.04 g, 0.45 mmol), HP(O)(OEt)2
(0.12 mL, 0.90 mmol), sodium hydride (0.02 g, 0.90 mmol), a white solid was obtained (0.13
19

ACCEPTED MANUSCRIPT
g, 64%); mp = 93–95 °C. 1H NMR (400 MHz, CDCl3) δ = 7.13–7.09 (m, 2H, Ph), 6.68 (t, 1H,
J = 7.3 Hz, Ph), 6.58 (d, 2H, J = 7.9 Hz, Ph), 4.07–3.89 (m, 4H, 2 × -OCH2-), 3.70 (br. s, 2H,
-NH- and -CH-), 2.92–2.87 (m, 1H, -CH2CH2CH-), 2.79–2.73 (m, 1H, -CH2CH2CH- ), 2.16–
2.12 (m, 1H, -CH2CH2CH-), 1.86–1.83 (m, 1H, -CH2CH2CH-), 1.21 (t, 3H, J = 7.1 Hz, -
OCH2CH3), 1.12 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm. 19F NMR (377 MHz, CDCl3) δ = -
144.07 (dd, 2F, J = 22.5, 8.4 Hz), -157.30 (t, 1F, J = 20.9 Hz), -162.46 to -162.59 (m, 2F)
31
13
ppm. P NMR (162 MHz, CDCl3) δ = 24.94 (s, 1P) ppm. C NMR (101 MHz, CDCl3) δ =
146.69 (d, J = 4.9 Hz, Car), 146.52–145.96 (m, C-F), 144.01–143.55 (m, C-F), 141.36–140.50
(m, C-F), 139.12–138.25 (m, C-F), 136.50–135.85 (m, C-F), 129.37 (s, CHar), 118.53 (s,
CHar), 114.47–113.98 (m, Car), 113.43 (s, CHar), 63.10 (d, J = 7.1 Hz, -OCH2-), 62.23 (d, J
= 7.4 Hz, -OCH2-), 50.66 (d, J = 155.7 Hz, -CH-), 30.29 (d, J = 4.7 Hz, -CH2CH2CH-), 19.33
(d, J = 14.0 Hz, -CH2CH2CH-), 16.49, 16.44, 16.42, 16.36 (2 × -OCH2CH3) ppm. HRMS
(ESI+) calc. for C19H22NO3F5P [M + H]: 438.1257, found: 438.1259.
Diethyl (1-((4-methoxyphenyl)amino)-3-(perfluorophenyl)propyl)phosphonate (3b):
From 3-(perfluorophenyl)propanal (0.07 g, 0.31 mmol), p-methoxyaniline (0.04 g, 0.31
mmol), HP(O)(OEt)2 (0.08 mL, 0.62 mmol), sodium hydride (0.02 g, 0.62 mmol), a pale
1
brown solid was obtained (0.1 g, 61%); mp = 85–87 °C. H NMR (400 MHz, CDCl3) δ =
6.72–6.68 (m, 2H, Ph), 6.56–6.52 (m, 2H, Ph), 4.08–3.89 (m, 4H, 2x -OCH2-), 3.68 (s, 3H,
PhOCH3), 3.62–3.54 (m, 1H, -CH-), 3.49 (br. s, 1H, -NH-), 2.95–2.88 (m, 1H, -CH2CH2CH-),
2.78–2.71 (m, 1H, -CH2CH2CH-), 2.14–2.08 (m, 1H, -CH2CH2CH-), 1.86–1.82 (m, 1H, -
CH2CH2CH-), 1.21 (t, 3H, J = 7.1 Hz, -OCH2CH3), 1.13 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm.
19F NMR (377 MHz, CDCl3) δ = -144.09 (dd, 2F, J = 22.5, 8.4 Hz), -157.47 (t, 1F, J = 20.9
Hz), -162.57 to -162.70 (m, 2F) ppm. 31P NMR (162 MHz, CDCl3) δ = 25.29 (s, 1P) ppm. 13C
NMR (101 MHz, CDCl3) δ = 151.76 (s, CarOCH3), 145.33–145.03 (m, C-F), 142.91–142.53
(m, C-F), 140.02–139.82 (m, C-F), 139.74 (d, J = 5.3 Hz, Car), 137.70–137.39 (m, C-F),
135.36–134.98 (m, C-F), 114.00 (s, CHar), 113.83 (s, CHar), 113.53–113.11 (m, Car), 61.96
(d, J = 7.0 Hz, -OCH2-), 61.12 (d, J = 7.4 Hz, -OCH2-), 54.71 (s, -OCH3), 50.90 (d, J = 154.4
Hz, -CH-), 29.25 (s, -CH2CH2CH-), 18.32 (d, J = 12.7 Hz, -CH2CH2CH-), 15.47, 15.42,
15.38, 15.32 (2x -OCH2CH3) ppm. HRMS (ESI+) calc. for C20H24NO4F5P [M+H]: 468.1363,
found: 468.1354.
Diethyl (3-(perfluorophenyl)-1-(p-tolylamino)propyl)phosphonate (3c): From 3-
(perfluorophenyl)propanal (0.09 g, 0.40 mmol), p-toluidine (0.05 g, 0.40 mmol), HP(O)(OEt)2
(0.11 mL, 0.80 mmol), sodium hydride (0.02 g, 0.80 mmol), a white solid was obtained (0.1
20

ACCEPTED MANUSCRIPT
g, 55%); mp 89–91 °C. 1H NMR (400 MHz, CDCl3) δ = 6.92 (d, 2H, J = 8.1 Hz, Ph), 6.49 (d,
2H, J = 8.4 Hz, Ph), 4.09–3.88 (m, 4H, 2 × -OCH2-), 3.69–3.57 (m, 2H, -NH- and -CH-),
2.93–2.86 (m, 1H, -CH2CH2CH-), 2.77–2.70 (m, 1H, -CH2CH2CH-), 2.17 (s, 3H, -PhCH3),
2.14–2.08 (m, 1H, -CH2CH2CH-), 1.86–1.79 (m, 1H, -CH2CH2CH-), 1.21 (t, 3H, J = 7.1 Hz, -
OCH2CH3), 1.13 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm. 19F NMR (377 MHz, CDCl3) δ = -
144.09 (dd, 2F, J = 22.5, 8.4 Hz), -157.44 (t, 1F, J = 20.9 Hz), -162.54 to -162.68 (m, 2F)
31
13
ppm. P NMR (162 MHz, CDCl3) δ = 25.13 (s, 1P) ppm. C NMR (101 MHz, CDCl3) δ =
146.32–146.08 (m, C-F), 144.39 (d, J = 5.5 Hz, Car), 143.84–143.73 (m, C-F), 143.68–140.47
(m, C-F), 138.84–138.38 (m, C-F), 136.36–136.01 (m, C-F), 129.83 (s, CHar), 127.79 (s,
CarCH3), 114.54–114.11 (m, Car), 113.59 (s, CHar), 63.10 (d, J = 7.0 Hz, -OCH2-), 62.18 (d,
J = 7.4 Hz, -OCH2-), 51.08 (d, J = 155.6 Hz, -CH-), 30.38 (d, J = 4.7 Hz, -CH2CH2CH-),
20.38 (s, -PhCH3), 19.35 (d, J = 13.7 Hz, -CH2CH2CH-), 16.51, 16.46, 16.42, 16.36 (2 × -
OCH2CH3) ppm. HRMS (ESI+) calc. for C20H24NO3PF5[M+H]: 452.1414, found: 452.1411.
Diethyl (3-(perfluorophenyl)-1-(o-tolylamino)propyl)phosphonate (3d): From 3-
(perfluorophenyl)propanal (0.07 g, 0.32 mmol), o-toluidine (0.03 g, 0.32 mmol), HP(O)(OEt)2
(0.08 mL, 0.64 mmol), sodium hydride (0.02 g, 0.64 mmol), a white solid was obtained (0.08
g, 54%); mp = 96–98 °C. 1H NMR (400 MHz, CDCl3) δ = 7.05–6.99 (m, 2H, Ph), 6.62 (t, 1H,
J = 7.3 Hz, Ph), 6.56 (d, 1H, J = 8.1 Hz, Ph), 4.09–3.88 (m, 4H, 2 × -OCH2-), 3.80–3.72 (m,
1H, -CH-), 3.60 (dd, 1H, J = 10.1, 4.4 Hz, -NH-), 2.94–2.87 (m, 1H, -CH2CH2CH-), 2.78–
2.71 (m, 1H, -CH2CH2CH-), 2.21–2.15 (m, 1H, -CH2CH2CH-), 2.13 (s, 3H, -PhCH3), 1.90–
1.83 (m, 1H, -CH2CH2CH-), 1.21 (t, 3H, J = 7.1 Hz, -OCH2CH3), 1.13 (t, 3H, J = 7.1 Hz, -
OCH2CH3) ppm. 19F NMR (377 MHz, CDCl3) δ = -144.15 (dd, 2F, J = 22.5, 8.4 Hz), -157.33
(t, 1F, J = 20.9 Hz), -162.46 to -162.60 (m, 2F) ppm. 31P NMR: (162 MHz, CDCl3) δ = 25.02
(s, 1P) ppm. 13C NMR (101 MHz, CDCl3) δ = 146.41–146.04 (m, C-F), 144.66 (d, J = 4.7 Hz,
Car), 143.95–143.62 (m, C-F), 141.08–140.88 (m, C-F), 138.83–138.46 (m, C-F), 130.53 (s,
CHar), 127.09 (s, CHar), 122.50 (s, CarCH3), 118.05 (s, CHar), 110.66 (s, CHar), 63.04 (d, J
= 7.1 Hz, -OCH2-), 62.28 (d, J = 7.3 Hz, -OCH2-), 50.68 (d, J = 155.7 Hz, -CH-), 30.57 (d, J
= 5.2 Hz, -CH2CH2CH-), 19.32 (d, J = 13.8 Hz, -CH2CH2CH-), 17.48 (s, -PhCH3), 16.47,
16.41, 16.35 (2 × -OCH2CH3) ppm. HRMS (ESI)+ calc. for C20H24NO3PF5 [M+H]: 452.1414,
found: 452.1412.
Diethyl (3-(perfluorophenyl)-1-(m-tolylamino)propyl)phosphonate (3e): From 3-
(perfluorophenyl)propanal (0.09 g, 0.40 mmol), m-toluidine (0.04 g, 0.40 mmol),
HP(O)(OEt)2 (0.10 mL, 0.80 mmol), sodium hydride (0.02 g, 0.80 mmol), a white solid was
1
obtained (0.09 g, 49%); mp = 91–93 °C. H NMR (400 MHz, CDCl3) δ = 7.01–6.97 (m, 1H,
21

ACCEPTED MANUSCRIPT
Ph), 6.50 (d, 1H, J = 7.4 Hz, Ph), 6.38–6.37 (m, 2H, Ph), 4.09–3.89 (m, 4H, 2x -OCH2-),
3.74–3.64 (m, 2H, -NH- and -CH-), 2.94–2.87 (m, 1H, -CH2CH2CH-), 2.78–2.71 (m, 1H, -
CH2CH2CH-), 2.20 (s, 3H, -PhCH3), 2.17–2.08 (m, 1H, -CH2CH2CH-), 1.88–1.79 (m, 1H, -
CH2CH2CH-), 1.22 (t, 3H,J = 7.1 Hz, -OCH2CH3), 1.13 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm.
19F NMR (377 MHz, CDCl3) δ = -144.05 (dd, 2F, J = 22.5, 8.4 Hz), -157.40 (t, 1F, J = 20.8
Hz), -162.52 to -162.66 (m, 2F) ppm. 31P NMR (162 MHz, CDCl3) δ = 25.01 (s, 1P) ppm. 13C
NMR (101 MHz, CDCl3) δ = 147.90–147.80 (m, C-F), 146.67 (d, J = 5.3 Hz, Car), 146.37–
146.08 (m, C-F), 143.93–143.56 (m, C-F), 139.19 (s, CarCH3), 138.86–138.38 (m, C-F),
136.33–136.03 (m, C-F), 129.21 (s, CHar), 119.44 (s, CHar), 114.20 (s, CHar), 110.54 (s,
CHar), 63.11 (d, J = 7.1 Hz, -OCH2-), 62.22 (d, J = 7.4 Hz, -OCH2-), 50.64 (d, J = 155.8 Hz, -
CH-), 30.33 (d, J = 4.9 Hz, -CH2CH2CH-), 21.57 (s, PhCH3), 19.36 (d, J = 13.7 Hz, -
CH2CH2CH-), 16.50, 16.44, 16.42, 16.36 (2 × -OCH2CH3) ppm. HRMS (ESI+): calc. for
C20H24NO3PF5 [M+H]: 452.1414, found: 452.1414.
Diethyl (1-((4-chlorophenyl)amino)-3-(perfluorophenyl)propyl)phosphonate (3f): From
3-(perfluorophenyl)propanal (0.10 g, 0.45 mmol), p-chloroaniline (0.06 g, 0.45 mmol),
HP(O)(OEt)2 (0.12 mL, 0.90 mmol), sodium hydride (0.02 g, 0.90 mmol), a white solid was
1
obtained (0.1 g, 48%); mp = 92–94 °C. H NMR (400 MHz, CDCl3) δ = 7.08–7.04 (m, 2H,
Ph), 6.53–6.49 (m, 2H, Ph), 4.08–3.89 (m, 4H, 2 × -OCH2-), 3.80 (dd, 1H, J = 10.4, 3.9 Hz, -
NH-), 3.66–3.59 (m, 1H, -CH-), 2.88–2.84 (m, 1H, -CH2CH2CH-), 2.78–2.71 (m, 1H, -
CH2CH2CH), 2.16–2.10 (m, 1H, -CH2CH2CH-), 1.87–1.81 (m, 1H, -CH2CH2CH-), 1.22 (t,
3H, J = 7.1 Hz, -OCH2CH3), 1.13 (t, 3H, J = 7.1 Hz, -OCH2CH3) ppm.19F NMR (377 MHz,
CDCl3) δ = -144.07 (dd, 2F, J = 22.5, 8.4 Hz), -157.07 (t, 1F, J = 20.9 Hz), -162.33 to -162.47
(m, 2F) ppm. 31P NMR (162 MHz, CDCl3) δ = 24.55 (s, 1P) ppm. 13C NMR (101 MHz,
CDCl3) δ = 146.35–146.11 (m, C-F), 145.37 (d, J = 4.5 Hz, Car), 143.87–143.67 (m, C-F),
141.13–140.86 (m, C-F), 138.87–138.49 (m, C-F), 136.38–136.05 (m, C-F), 129.17 (s, CHar),
122.98 (s, CarCl), 114.49 (s, CHar), 63.13 (d, J = 7.1 Hz, -OCH2-), 62.31 (d, J = 7.5 Hz, -
OCH2-), 50.82 (d, J = 156.3 Hz, -CH-), 30.11 (d, J = 4.5 Hz, -CH2CH2CH-), 19.27 (d, J =
13.3 Hz, -CH2CH2CH-), 16.51, 16.46, 16.43, 16.37 (2 × -OCH2CH3) ppm. HRMS (ESI+):
[M+H]+, calc. for C19H21NO3ClPF5 [M+H]: 472.0868, found: 472.0870.
Diethyl (1-((4-nitrophenyl)amino)-3-(perfluorophenyl)propyl)phosphonate (3g): From 3-
(perfluorophenyl)propanal (0.08 g, 0.36 mmol), p-nitroaniline (0.05 g, 0.36 mmol),
HP(O)(OEt)2 (0.10 mL, 0.72 mmol), sodium hydride (0.02 g, 0.72 mmol), a brown solid was
1
obtained (0.02 g, 11%); mp 95–97 °C. H NMR (400 MHz, CDCl3) δ = 8.06–8.02 (m, 2H,
Ph), 6.59–6.55 (m, 2H, Ph), 4.71–4.68 (m, 1H, -NH-), 4.12–3.90 (m, 4H, 2 × -OCH2-), 3.79–
22

ACCEPTED MANUSCRIPT
3.74 (m, 1H, -CH-), 2.87–2.76 (m, 2H, -CH2CH2CH-), 2.20–2.15 (m, 1H, -CH2CH2CH-),
1.94–1.88 (m, 1H, -CH2CH2CH-), 1.27–1.24 (m, 3H, -OCH2CH3), 1.12 (t, 3H, J = 7.1 Hz, -
OCH2CH3) ppm. 19F NMR (377 MHz, CDCl3) δ = -143.98 (dd, 2F, J = 22.4, 8.4 Hz), -156.34
(t, 1F, J = 20.9 Hz), -161.90 to -162.03 (m, 2F) ppm. 31P NMR: (162 MHz, CDCl3) δ = 23.16
(s, 1P) ppm. HRMS (ESI+) calc. for C19H21N2O5F5P [M+H]: 483.1108, found: 483.1107.
Diethyl (1-(benzylamino)-3-(perfluorophenyl)propyl)phosphonate (3h): From 3-
(perfluorophenyl)propanal (0.12 g, 0.54 mmol), benzylamine (0.06 g, 0.54 mmol),
HP(O)(OEt)2 (0.14 mL, 1.10 mmol), sodium hydride (0.03 g, 1.10 mmol), a dark yellow solid
was obtained (0.04 g, 18%); mp = 75–77 °C. 1H NMR (400 MHz, CDCl3) δ = 7.30–7.18 (m,
5H, Ph), 4.15–4.02 (m, 4H, 2 × -OCH2-), 3.94 (d, 1H, J = 12.9, 1H, -CH2Ph), 3.84–3.81 (m,
1H, -CH2Ph), 2.97–2.90 (m, 1H, -CH2CH2CH-), 2.84–2.80 (m, 1H, -CH-), 2.78–2.67 (m, 1H,
-CH2CH2CH), 2.00–1.91 (m, 1H, -CH2CH2CH), 1.79–1.67 (m, 2H, -NH- and -CH2CH2CH-),
1.30–1.26 (m, 6H, 2 × -OCH2CH3) ppm. 19F NMR (377 MHz, CDCl3) δ = -144.12 (dd, 2F, J
= 22.6, 8.4 Hz), -157.66 (t, 1F, J = 20.9 Hz), -162.64 to -162.78 (m, 2F) ppm. 31P NMR (162
MHz, CDCl3) δ = 27.51 (s, 1P) ppm. 13C NMR (101 MHz, CDCl3) δ = 138.71 (s, Car), 127.34
(d, J = 8.0 Hz, CHar), 126.19 (s, CHar), 61.14 (d, J = 6.8 Hz, -OCH2-), 61.07 (d, J = 6.8 Hz, -
OCH2-), 52.46 (d, J = 145.9 Hz,-CH-), 50.76 (d, J = 5.2 Hz, -CH2Ph), 28.68 (d, J = 2.6 Hz, -
CH2CH2CH-), 18.19 (d, J = 11.3 Hz, -CH2CH2CH-), 15.59, 15.57, 15.54, 15.51 (2 ×
-OCH2CH3) ppm. HRMS (ESI+): calc. for C20H24NO3PF5 [M+H]: 452.1414, found: 452.1415.
Diethyl (1-(decylamino)-3-(perfluorophenyl)propyl)phosphonate (3i): From 3-
(perfluorophenyl)propanal (0.12 g, 0.54 mmol), decylamine (0.08 g, 0.54 mmol),
HP(O)(OEt)2 (0.14 mL, 1.08 mmol), sodium hydride (0.03 g, 1.08 mmol), a white solid was
obtained (0.04 g, 16%); mp = 86–88 °C. 1H NMR (400 MHz, CDCl3) δ = 4.18–3.86 (m, 4H, 2
× -OCH2-), 2.97–2.53 (m, 5H, -CH2CH2CH- and -NHCH2-), 2.51–2.34 (m, 1H, -NH-), 2.02–
1.86 (m, 1H, -CH2CH2CH), 1.81–1.64 (m, 1H, -CH2CH2CH-), 1.43–1.19 (m, 22H, 2 × -
OCH2CH3, and -(CH2)8-amine), 0.81 (t, 3H,J = 6.7 Hz, -CH3-amine) ppm. 19F NMR (377
MHz, acetone-d6) δ = 31.74 (dd, 2F,J = 22.2, 8.2 Hz), 16.65 (t, 1F, J = 20.3 Hz), 12.13–12.00
(m, 2F) ppm. 31P NMR (162 MHz, acetone-d6) δ = 27.17 (s, 1P) ppm. HRMS (ESI+): calc. for
C23H38NO3PF5 [M+H]: 502.2509, found: 502.2511.
4.4 Procedure of 2k synthesis
4.4.1 Main pathway
Aminophosphonates: 2h (0.2g, 0.47 mmol) or 2i (0.2g, 0.40 mmol) was dissolved in ethyl
acetate (10 mL), and Pd/C (10%, 200 mg) was added under hydrogen atmosphere. The
23

ACCEPTED MANUSCRIPT
reaction mixture was stirred at room temperature for 3 days. The solution was filtered through
a celite pad, and the solvent was evaporated under reduced pressure. The product was purified
by chromatography (silica gel, hexane/AcOEt, 1:1, v/v) to give 2k in 99% yield from 2h, and
30% yield from 2i.
4.4.2 Alternate pathway
To the mixture of aldehyde 4 (0.3 g, 1.53 mmol)in dry toluene (10 mL), ammonium acetate
(0.12 g, 1.53 mmol) in dry ethanol (10 mL) was added dropwise under argon atmosphere. The
reaction mixture was heated under reflux for 5 h, then HP(O)(OEt)2 (0.39 mL, 3.06 mmol)
was added, and the mixture was heated under reflux for 16 h. After cooling to room
temperature, the solvent was removed under reduced pressure, and the crude product was
purified by chromatography (silica gel, hexane/ethyl acetate 1:1, v/v) to give 2k in 6% yield.
1
Diethyl (amino(perfluorophenyl)methyl)phosphonate (2k): pale yellow oil. H NMR (300
MHz, CDCl3) δ = 5.39 (d, 1H, J = 14.2 Hz, -CH-), 4.95 (br. s, 1H, -NH-), 4.28–4.12 (m, 4H,
2x -OCH2-), 1.34–1.29 (m, 6H, 2 × -OCH2CH3) ppm. 19F NMR (282 MHz, CDCl3) δ = -
31
140.92 to -141.00 (m, 2F), -154.23 to -154.40 (m, 1F), -162.28 to -162.45 (m, 2F) ppm. P
13
NMR (121 MHz, CDCl3) δ = 19.09–18.95 (m, 1P) ppm. C NMR (101 MHz, CDCl3) δ =
143.94 (s, C-F), 142.10–141.71 (m, C-F), 139.49–139.20 (m, C-F), 138.94–138.66 (m, C-F),
136.47–136.15 (m, C-F), 112.31 (t, J = 15.0 Hz, Car), 63.33, 63.26, 63.09, 63.01 (2 × -
OCH2), 45.82 (d, J = 154.2 Hz, -CH-), 16.37, 16.32, 16.27 (2 × -OCH2CH3) ppm. HRMS
(ESI+) calc. forC11H14F5NO3P [M+H]+: 334.0626, found: 334.0632.
4.5 X-ray diffraction
Reflection intensities for all crystals investigated (2a, 2b, 2e and 3b-3e) were measured on
Xcalibur diffractometer (Eos detector) equipped with a graphite monochromator and MoKα
radiation (λ=0.71073 Å). Data reduction and analysis were carried out with the CrysAlisPro
software. In all single-crystal experiments, except for 3e, the temperature of the crystals was
controlled with an Oxford Instruments Cryosystem cold nitrogen-gas blower. The crystals of
3c were found to be excessively twinned. The reflections of the two twin components were
separated using the CrysAlisPro. We found that the component 2 rotated about 3.88° around
[0.98 0.18 0.04] direct lattice direction. Subsequent refinement indicated that the twin fraction
of the second domain was 0.374(1).
24

ACCEPTED MANUSCRIPT
The structures were solved by direct methods using SHELXS42 and refined by the full-matrix
least-squares techniques with SHELXL42. All heavy atoms were refined anisotropically. The
hydrogen atoms bound to carbon atoms were placed at calculated positions and refined using
a riding model, and their isotropic displacement parameters were given a value 20% higher
than the isotropic equivalent for the atom to which the H atoms were attached (for methyl
hydrogen atoms this value has been increased to 50%). The positions of the amine H atoms
were located reliably on difference Fourier maps and their position and displacement
parameters were refined.
In 2b, the methyl group attached to aniline moieties in mol2 display dynamic disorder with
two alternative positions of methyl hydrogen atoms. In 3e, terminal carbon atoms of both
ethyl groups are split up into two positions. The occupancies for the two positions were
refined to 0.55 and 0.44 for C2 and C22, and 0.60 and 0.40 for C4 and C24, respectively. The
restraints for the 1,2- and 1,3-distances were applied.
Graphical images were produced in Mercury43 programs.
4.6 Computational methods
Quantum-chemical calculations were carried out within density functional theory framework
(DFT) with three different functionals namely B3LYP,44,45 M062X,46 and wB97XD47 with the
use of 6-31G(d) basis set,48,49 being the necessary compromise between the desired accuracy
and computer resources needed. Additionally MP2/6-31G(d)//M06-2X/6-31G(d) single point
energies were calculated.
Acknowledgements
This research was supported in part by PL-Grid Infrastructure
(http://www.plgrid.pl/en).
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ACCEPTED MANUSCRIPT
Notes
CCDC 1577624-1577630 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data%5Frequest/cif
27