Interaction of difluoromethylene phosphobetaine with heteroatom-centered electrophiles

Article abstract of DOI:10.1016/j.jfluchem.2019.02.008

A series of difluorinated phosphonium salts were obtained by reaction of difluoromethylene phosphobetaine with halogenating reagents, as well as arylsulfenyl and arylselenyl chlorides. The reaction proceeds via decarboxylation of the phosphobetaine followed by trapping of the difluorinated phosphorus ylide by heteroatom-centered electrophiles. The crystal structures of the phosphonium salts were studied by X-ray diffraction analysis. For the salt containing the CF₂I group and iodide counterion, the I?I interaction was identified in the solid state. The nature of this halogen bond was evaluated by quantum chemical calculations.

Full text of DOI:10.1016/j.jfluchem.2019.02.008

Accepted Manuscript
Title: Interaction of difluoromethylene phosphobetaine with
heteroatom-centered electrophiles
Authors: Alexey L. Trifonov, Liubov I. Panferova, Vitalij V.
Levin, Alexander D. Volodin, Alexander A. Korlyukov,
Alexander D. Dilman
PII:
S0022-1139(18)30517-7
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.02.008
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21 February 2019
Please cite this article as: Trifonov AL, Panferova LI, Levin VV, Volodin AD,
Korlyukov AA, Dilman AD, Interaction of difluoromethylene phosphobetaine
with heteroatom-centered electrophiles, Journal of Fluorine Chemistry (2019),
https://doi.org/10.1016/j.jfluchem.2019.02.008
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Interaction of difluoromethylene phosphobetaine with heteroatom-centered electrophiles
Alexey L. Trifonov,a,b Liubov I. Panferova,a Vitalij V. Levin,a Alexander D. Volodin,c Alexander
A. Korlyukov,c Alexander D. Dilman*,a
aN. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
bD. Mendeleev University of Chemical Technology of Russia, Higher Chemical College, 125047
Moscow, Miusskaya sq. 9, Russian Federation
cA. N. Nesmeyanov Institute of Organoelement Compounds, 119991 Moscow, Vavilov str. 28,
Russian Federation
adil25@mail.ru
Graphical Abstract
Synthesis of difluorinated phosphonium salts by interaction of the phosphobetaine reagent with
halogen and chalcogen electrophiles is described.
Highlights
 Reactions of difluoromethylene phosphobetaine
 Halogenation of fluorinated ylides
 Synthesis of fluorinated phosphonium salts

Abstract A series of difluorinated phosphonium salts were obtained by reaction of
difluoromethylene phosphobetaine with halogenating reagents, as well as arylsulfenyl and
arylselenyl chlorides. The reaction proceeds via decarboxylation of the phosphobetaine followed by
trapping of the difluorinated phosphorus ylide by heteroatom-centered electrophiles. The crystal
structures of the phosphonium salts were studied by X-ray diffraction analysis. For the salt
containing the CF2I group and iodide counterion, the I…I interaction was identified in the solid
state. The nature of this halogen bond was evaluated by quantum chemical calculations.
Keywords: phosphonium salts, phosphobetaine, phosphorus ylide, halogenation, halogen bonding
1. Introduction
Fluorinated organophosphorus compounds have emerged as valuable targets in medicinal
chemistry [1], as well as useful reagents for the synthesis of organofluorine compounds [2]. In
1964, difluorinated phosphorus ylide 1 was proposed as an intermediate generated from the
combination of triphenylphosphine and difluorocarbene [3], and since then it has been extensively
exploited for olefination of carbonyl compounds [4] (Scheme 1). Despite synthetic applications,
ylide 1 has not yet been spectroscopically characterized, presumably, due to its instability
associated with facile fragmentation into triphenylphosphine and difluorocarbene [5].
Correspondingly, this ylide must be generated in situ in the presence of a suitable electrophile,
which can attack at the ylide carbon. We have recently demonstrated that ylide 1 can react with
various -electrophiles such as Michael acceptors [6,7], azomethines [6], and carbonyl compounds
[6-8] affording difluorinated phosphonium salts. Salts of this type have numerous applications
associated with the cleavage of the carbon-phosphorus bond [9,10]. Herein we report that ylide 1,
generated from an inexpensive precursor, can be trapped by halogenating reagents, as well as
sulfur- and selenium-centered electrophiles.

Scheme 1. Chemistry of ylide 1.
2. Results and discussion
2.1. Synthetic studies.
Among various methods for the generation of ylide 1 [3-7,11,12], we were particularly interested
in application of difluoromethylene phosphobetaine 2 discovered by Xiao [12]. Reagent 2 can be
conveniently prepared on a hundred-gram scale from readily available chemicals – potassium
bromodifluoroacetate and triphenylphosphine. This compound is an air stable solid, which can be
shelf-stored at room temperature for a long time. However, upon mild heating, reagent 2 undergoes
decarboxylation with concomitant generation of ylide 1. Correspondingly, this reagent has found
numerous applications [5,6,12,13]. Thus, betaine 2 was combined with halogenating reagents, and
the mixture was heated in acetonitrile around 50 °C. The reactions were typically complete within
1.5 hours, as evidenced by cease of gas evolution, as well as dissolution of betaine 2. For
chlorination, N-chlorosuccinimide (NCS) was used, and then the mixture was treated with
iodomethane to scavenge succinimide counter-ion leading to iodide salt 3a. Bromination and
iodination reactions were carried out with elemental halogens affording salts 3b,c in good isolated
yields. Interaction of betaine 2 with arylsulfenyl and arylselenyl chlorides also worked well leading
to salts 3d,f in reasonable yields. Phenyl disulfide did not react with betaine 2 under standard
conditions. However, addition of iodomethane allowed smooth formation of expected salt 3e. The
role of iodomethane in this case is believed to methylate the disulfide reagent converting it to a
stronger sulfenylating species. Salts 3 are air sensitive solids, which should be stored under inert
atmosphere.

3. Structural studies
The structures of compounds 3a,c,f were studied by single crystal X-ray diffraction analysis
(Figure 1). For compound 3d, we have not been able to obtain crystals of satisfactory quality.
However, in attempt to perform counter ion exchange from chloride to iodide, we were fortunate to
identify a crystal containing the cationic fragment of salt 3d [14]. For salt 3b, the crystal structure
was reported in the literature [15]. Therefore, it is possible to compare structural parameters of all
types of phosphonium cations of salts 3. (Table 1).
Figure 1. General views of cation of 3a, salt 3c, cations of 3d and 3f (from left to right). Atoms are
presented as ellipsoids of anisotropic displacement (50% probability). Hydrogen atoms are omitted
for clarity.
The phosphonium cations have similar structural parameters. In particular, C-P bond distances
are close for the whole series irrespective of the nature of heteroatom group E. One of the most
noticeable features in salt 3c is a cation-anion interaction via I…I contact. The corresponding I…I
distance is 3.2674(9) Å that is 0.55 Å larger than I-I bond in solid iodine (2.7179(2) Å [16]). The
angle C-I…I of 172.06(18)° is close to linear and the angle P-C-I is 115(1)°, which is indicative of
halogen-halogen contact of type II [17]. The latter contacts are classified as true halogen bonds
[18].
The characteristics of halogen bond in 3c were studied using quantum chemical calculations.
Starting coordinates of cation and anion were taken from its X-ray structure. All calculations were

carried out with all-electron TZVPP basis set and PBE0 functional implemented into ORCA 3.0.3
program [19]. Relativistic effects were accounted using ZORA approximation. To save computation
time, RI (resolution of identity) approximation was utilized. Two models were calculated to find
structure that is most similar to that obtained from X-ray analysis. The first model is a simple
calculation of isolated cation-anion pair. In the second one, cation-anion pair was placed into
solvation continuum (COSMO model, dielectric constant 79). After optimization of atomic
coordinates, the resulted geometries were checked for the presence of negative eigenvalues of
hessian matrix. As a result, in the first model I…I distance was found to be 3.030 Å, while in the
second one this distance is 3.385 Å, with the latter being closer to the experimental value of
3.2674(9) Å. Correspondingly, the second model was used for further discussion.
Bond length and angles in optimized structure of the cation are in good agreement with
experimental values. For instance, C-I and F2C-P bonds are equal to 2.173 and 1.890 Å,
respectively, that reproduced experimental values within 0.02 Å.
According to analysis in terms of quantum theory of atoms in molecules (QTAIM) [20], bond
critical point (bcp) was found between the iodine atoms (Figure 2, (a)). In addition, the presence of
several C-H…F and C-H…I interactions was revealed. The value of electron density (r) in bcp of
I…I bond is rather small (0.02 a.u.), while its Laplacian is positive (0.042 a.u). This is indicative of
a closed-shell interaction. The energy of I…I bond was estimated by correlation formula proposed
by Espinosa [21] affording the value of 3.3 kcal/mol, which is on the same scale as weak hydrogen
bonds.

Figure 2. (a) Molecular graph of cation-anion pair 3c. Green points correspond to bond critical
points. (b) Isosurfaces of RDG function colorized according to the sign of 2.
Finally, the presence of halogen bond was illustrated by non-covalent interaction (NCI) analysis
[22]. This method utilizes dimensionless reduced density gradient (RDG). The sign of eigenvector
2 serves as a descriptor of the nature of non-covalent interactions (attractive or repulsive).
Isovalues of RDG colorized according to its value and sign of 2 were used in our study to reveal
the character of weak intermolecular bonds. The presence of separate isosurfaces in regions of small
values of electron density and its gradient is indicative for weak interatomic bonds and can be
described as an analog of bcp. Areas of negative values is indicative of attractive interactions
responsible for stabilization of particular atomic configuration in the crystal structure, and such an
area is clearly identified in the case of I…I bond in cation 3c. Indeed, small oblate disk-shaped
region is located between the iodine atoms (Figure 2, (b)). The similar attractive character of
intermolecular interactions is also demonstrated in the case of C-H…F and C-H…I interactions.

4. Conclusions
Difluorinated phosphonium salts bearing an additional halogen atom or a halcogen fragment can
be obtained from the readily accessible phosphobetaine reagent. The process involves the
interaction of transient difluorinated ylide with a source of electrophilic halogen, as well as sulfenyl
and selenyl based regents. Analysis of crystals of obtained salts suggested similar structural
parameters of cationic fluorinated phosphonium fragments. However, for the salt containing the
CF2I group and iodide counterion, the I…I interaction was observed, which was assigned to a
typical halogen bond with the estimated energy of 3.3 kcal/mol.
5. Experimental
5.1 General Experimental Procedures
All reactions were performed under an argon atmosphere. Dichloromethane was distilled from
CaH2 prior to use. Acetonitrile was distilled twice: from P2O5 and CaH2 successively and stored
over MS 3Å. High resolution mass spectra (HRMS) were measured using electrospray ionization
(ESI) and time-of-flight (TOF) mass analyzer. The measurements were done in a positive ion mode
(interface capillary voltage – 4500 V) or in a negative ion mode (3200 V); mass range from m/z 50
to m/z 3000. Phosphobetaine 2 was obtained according to a literature procedure [12]. NMR spectra
were recorded on a Bruker AM300 instrument in dry CDCl3 at 27 °C.
5.2. 4-Chlorophenylsulfenyl chloride [23].
A solution of 4-chlorobenzenethiol (30 mmol, 4.32 g) in thionyl chloride (75 mmol, 6.06 ml)
was heated with stirring in water bath at 70 °C until the formation of gas has stopped (about 1.5 h).
The resulting mixture was distilled under reduced pressure affording wine-red liquid. Bp 96-97 °C
(8 mbar). Yield 4.75 g (89%).
5.3. Phenylselenyl chloride [24].
A mixture of diphenyl diselenide (3000 mg, 9.62 mmol) and thionyl chloride (780 μL, 9.62
mmol) in carbon tetrachloride (5 mL) was stirred at room temperature for 30 min. The resulting

suspension was dissolved upon heating with a heat gun. Then, the mixture was cooled to –20 °C,
and kept for 2 h at this temperature without stirring. The solvent was decanted affording orange
crystals. Yield 2042 mg (94%). Mp 63-64 °C.
5.4. (Chlorodifluoromethyl)triphenylphosphonium iodide (3a).
A suspension of reagent 2 (1068 mg, 3.0 mmol), N-chlorosuccinimide (400 mg, 3.0 mmol) in
acetonitrile (2.0 mL) was heated with stirring in water bath at 50 °C for 1.25 h (until bubbling
stopped). The mixture was cooled to room temperature, methyl iodide (375 μL, 6.0 mmol) was
added, and the reaction mixture was stirred for 10 min at 40 °C. The solvent was evaporated under
vacuum to a half of its volume, and methyl tert-butyl ether (1.5 mL) was added. The mixture was
cooled to –20 °C, and kept for 16 h at this temperature without stirring. The solvent was decanted,
the residue was washed with methyl tert-butyl ether (3×1.5 mL), and the solid was recrystallized
from acetonitrile affording 1011 mg (yield 71%) of salt 3a as colorless crystals. Mp 156-157 °C
1
(dec.) H NMR (300 MHz, CDCl3), δ: 7.58-7.69 (m, 6H), 7.69-7.78 (m, 6H), 7.82-7.90 (m, 3H).
13C{1H} NMR (75 MHz, CDCl3), δ: 109.7 (d, J = 86.2 Hz), 124.2 (td, J = 324.0, 110.6 Hz), 131.0
(d, J = 13.3 Hz), 134.1 (d, J = 9.9 Hz), 137.2 (d, J = 2.2 Hz). 19F NMR (282 MHz, CDCl3), δ: –52.5
(d, J = 87.2 Hz). 31P{1H} NMR (121 MHz, CDCl3), δ: 33.9 (t, J = 87.2 Hz). HRMS (ESI): calcd for
C19H15ClF2P (M+) 347.0562, found 347.0564.
5.5. Synthesis of compounds 3b,c.
A mixture of reagent 2 (3.6 mmol, 1282 mg) and bromine (for 3b, 155 μL, 3.0 mmol) or iodine
(for 3с, 762 mg, 3.0 mmol) in acetonitrile (2.0 mL) was heated with stirring in water bath at 53 °C
for 1 h (until bubbling stopped). The mixture was cooled to room temperature, the solvent was
decanted, the residue was washed with acetonitrile (3×1.5 mL), and the resulting solid was dried
under vacuum with heating at 50 °C.
5.5.1. (Bromodifluoromethyl)triphenylphosphonium bromide (3b) [15].
Yield 1019 mg (72%). Pale-yellow crystals. Mp 169-170 °C (dec.). 1H NMR (300 MHz, CDCl3),
13
δ: 7.57-7.81 (m, 12H), 7.81-7.95 (m, 3H). C{1H} NMR (75 MHz, CDCl3), δ: 111.2 (d, J = 85.1

Hz), 116.3 (td, J = 333.9, 95.1 Hz), 131.2 (d, J = 14.4 Hz), 134.5 (d, J = 9.9 Hz), 137.4 (d, J = 3.3
Hz). 19F NMR (282 MHz, CDCl3), δ: –52.0, (d, J = 83.4 Hz). 31P{1H} NMR (121 MHz, CDCl3), δ:
32.4, (t, J = 83.4 Hz).
5.5.2. (Difluoroiodomethyl)triphenylphosphonium iodide (3c)
Yield 81% (1375 mg). Pale-brown crystals. Mp 172-173 °C (dec.). 1H NMR (300 MHz, CDCl3),
13
δ: 7.68-7.82 (m, 12H), 7.88-7.98 (m, 3H). C{1H} NMR (75 MHz, CDCl3), δ: 99.4 (td, J = 339.5,
50.9 Hz), 112.9 (d, J = 84.0 Hz), 130.8 (d, J = 12.1 Hz), 134.5 (d, J = 10.0 Hz), 136.6 (d, J = 3.3
Hz). 19F NMR (282 MHz, CDCl3), δ: –62.3 (d, J = 82.8 Hz). 31P{1H} NMR (121 MHz, CDCl3), δ:
25.2 (t, J = 82.8 Hz). HRMS (ESI): calcd for C19H15F2IP (M+) 438.9919, found 438.9921.
4.6. [Difluoro(4-chlorophenylthio)methyl]triphenylphosphonium chloride (3d).
A suspension of reagent 1 (5909 mg, 16.6 mmol) and 4-chlorophenylsulfenyl chloride (2980 mg,
16.6 mmol) in acetonitrile (10.0 mL) was heated with stirring in water bath at 50 °C for 1 h (until
bubbling stopped). The mixture was cooled to room temperature, the solvent was evaporated under
vacuum to a half of its volume, methyl tert-butyl ether (7 ml) was added. The mixture was cooled to
–20 °C, and kept for 16 h at this temperature without stirring. The solvent was decanted, the residue
was washed with methyl tert-butyl ether (3×5 mL), and the resulting solid was dried under vacuum
with heating at 50 °C. Yield 5542 mg (68%). Colorless crystals. Mp 74-75 °C. 1H NMR (300 MHz,
13
CDCl3), δ: 6.95 (d, 2H, J = 8.1 Hz), 7.15 (d, 2H, J = 8.1 Hz), 7.31-7.84 (m, 15H). C{1H} NMR
(75 MHz, CDCl3), δ: 110.6 (d, J = 84.0 Hz), 118.5, 125.5 (td, J = 309.6, 87.7 Hz), 129.3, 130.5 (d, J
19
= 13.3 Hz), 133.9 (d, J = 11.1 Hz), 136.7 (d, J = 3.3 Hz), 137.4, 137.5. F NMR (282 MHz,
31
CDCl3), δ: –70.3 (d, J = 91.1 Hz). P{1H} NMR (121 MHz, CDCl3), δ: 30.5, (t, J = 91.1 Hz).
HRMS (ESI): calcd for C25H19ClF2PS (M+) 455.0596, found 455.0609. In an attempt to effect
counter ion exchange, the reaction mixture obtained after heating of reagent 1 with 4-
chlorophenylsulfenyl chloride was cooled to room temperature. Then, methyl iodide (1.5 equiv)
19
was added and the mixture was stirred at 40 °C 10 min. The mixture was analyzed by F NMR
with 4-fluorotoluene as internal standard, which suggested the yield of 19% of cation of 3d. The

solvent was evaporated under vacuum to a half of its volume, the mixture was cooled to –20 °C,
and kept for 16 h at this temperature without stirring, and the resulting crystals were withdrawn and
studied by X-ray diffraction.
5.7. [Difluoro(phenylthio)methyl]triphenylphosphonium iodide (3e).
A suspension of reagent 2 (7.2 mmol, 2.563 g), phenyl disulfide (8.0 mmol, 1.744 g) and methyl
iodide (12 mmol, 744 μL) in acetonitrile (4.0 mL) was heated with stirring in water bath at 55 °C
for 2 h (until bubbling stopped). The mixture was cooled to room temperature, the solvent was
evaporated under vacuum to a half of its volume, and the mixture was cooled to –20 °C, and kept
for 16 h at this temperature without stirring. The solvent was decanted, the residue was washed with
methyl tert-butyl ether (3×2 mL), and the resulting solid was dried under vacuum at 50 °C affording
1
3.153 g (yield 72%) of salt 3e as pale-yellow crystals. Mp 194-195 °C (dec.). H NMR (300 MHz,
13
CDCl3), δ: 7.24-7.33 (m, 2H), 7.35-7.46 (m, 3H), 7.63-7.85 (m, 12H), 7.89-7.98 (m, 3H). C{1H}
NMR (75 MHz, CDCl3), δ: 111.4 (d, J = 84.3 Hz), 120.7 (m), 126.3 (td, J = 310.3, 90.2 Hz), 129.7,
19
131.1 (d, J = 13.2 Hz), 131.6, 134.6 (d, J = 10.5 Hz), 136.6, 137.2 (d, J = 3.0 Hz). F NMR (282
MHz, CDCl3), δ: –69.1 (d, J = 92.8 Hz). 31P{1H} NMR (121 MHz, CDCl3), δ: 29.8 (t, J = 92.8 Hz).
HRMS (ESI): calcd for C25H20F2PS (M+) 421.0986, found 455.0979.
5.8. [Difluoro(phenylselenyl)methyl]triphenylphosphonium iodide (3f).
A suspension of reagent 2 (3.240 g, 9.1 mmol), phenylselenyl chloride (1.744 g, 9.1 mmol) in
acetonitrile (4.0 mL) was heated with stirring in water bath at 50 °C for 1.5 h (until bubbling
stopped). The mixture was cooled to room temperature, and methyl iodide (850 μL, 13.65 mmol)
was added. The reaction mixture was stirred at 40 °C 10 min, then the solvent was evaporated under
vacuum to a half of its volume, methyl tert-butyl ether (3.0 ml) was added. The mixture was cooled
to –20 °C, and kept for 16 h at this temperature without stirring. The solvent was decanted, the
residue was washed with methyl tert-butyl ether (3×2 mL), and the resulting solid was dried under
vacuum with heating at 50 °C. Yield 3302 mg (61%). Pale-yellow crystals. Mp 153-154 °C (dec.).
1H NMR (300 MHz, CDCl3), δ: 6.96-7.04 (m, 2H), 7.09-7.17 (m, 1H), 7.18-7.23 (m, 2H), 7.44-7.63

13
(m, 12H), 7.68-7.89 (m, 3H). C{1H} NMR (75 MHz, CDCl3), δ: 110.7 (d, J = 84.0 Hz), 120.3
(m), 120.3 (td, J = 326.2, 78.5 Hz), 129.0, 130.1, 130.3 (d, J = 13.3 Hz), 133.7 (d, J = 9.9 Hz),
136.3, 136.4 (d, J = 2.2 Hz). 19F NMR (282 MHz, CDCl3), δ: –71.5 (d, J = 89.3 Hz). 31P{1H} NMR
(121 MHz, CDCl3), δ: 28.4 (t, J = 89.3 Hz). HRMS (ESI): calcd for C25H20F2PSe (M+) 469.0432,
found 469.0424.
6. X-ray analysis.
The structures were solved by direct method and refined in anisotropic approximation for non-
hydrogen atoms. Hydrogens atoms of methyl, methylene and aromatic fragments were calculated
according to those idealized geometry and refined with constraints applied to C-H and N-H bond
lengths and equivalent displacement parameters (Ueq(H) = 1.2Ueq(X), X - central atom of XH2
group; Ueq(H) = 1.5Ueq(Y), Y - central atom of YH3 group. All structures were solved with the
ShelXT1 program and refined with the ShelXL2 program. Molecular graphics was drawn using
OLEX23 program.
Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication [for 3a, CCDC 1887171; for 3c, CCDC
1887168; for 3d, CCDC 1887169; for 3f, CCDC 1887170]. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments
This work was supported by the Russian Foundation for Basic Research (project 18-33-00331).

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Table 1. Synthesis of phosphonium salts 3.
Electrophile
NCS; MeI
Product
Yield of 3, %a
71
3a
3b
3c
3d
Br2
72
81
68
I2
4-ClC6H4SCl
Ph2S2; MeI
72
61
3e
3f
PhSeCl; MeI
a Isolated yield.

Table 2. Selected structural parameters of cations Ph3P+CF2E, Å.
E
F2C-P
CPh-P
C-F
F2C-E
Cl
1.901(3)
1.883
1.785(3)
1.783
1.382(4)
1.347
1.695(4)
1.923
3a
3ba Br
I
1.870(7)
1.884(6)
1.878(2)
1.787(6)
1.783(6)
1.785(2)
1.362(7)
1.368(6)
1.360(2)
2.195(7)
1.786(6)
1.968(2)
3c
3d
3f
SAr
SePh
a Data from ref. [15].