Synthesis, structural and toxicological investigations of quarternary phosphonium salts containing the P-bonded bioisosteric CH2F moiety

Article abstract of DOI:10.1039/d0nj02310h

Tertiary alkyl, aryl or amino phosphines PR3 (R = Me, nBu, C2H4CN, NEt2) and the bis[(2-diphenylphosphino)phenyl]ether (POP) were allowed to react with fluoroiodomethane to produce fluoromethyl phosphonium salts in yields between 60-99%. The compounds were characterized by vibrational and NMR spectroscopy and in most cases also by single crystal X-ray diffraction. Diphenyl(fluoromethyl) phosphine was synthesized as a mixed aryl-alkyl-phosphine and the TEP value (Tolman electronic parameter) was determined in order to explain its low reactivity. The molecular and crystal structures of the new fluoromethyl phosphonium salts [R3PCH2F]I with R = Me, C2H2CN and NEt2 as well as of the salt resulting from the fluoromethylation of POP provided additional information on the structural behavior of the bioisoster CH2F group bonded to phosphorus. Hydrogen bonding in the crystal is compared with that observed in the crystal structure of PPh3CH2FI. The toxicity of the sufficiently water soluble salt [Me3PCH2F]I was investigated and the toxicological effect of the CH2F group was compared to that of the bioisoster CH2OH group in THPS. This journal is

Full text of DOI:10.1039/d0nj02310h

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Synthesis, structural and toxicological
investigations of quarternary phosphonium salts
containing the P-bonded bioisosteric CH2F
moiety†
Cite this: New J. Chem., 2020,
44, 14306
Marco Reichel,
Cornelia Unger,
Sviatlana Dubovnik, Andreas Roidl,
Andreas Kornath
and Konstantin Karaghiosoff
*
Tertiary alkyl, aryl or amino phosphines PR3 (R = Me, nBu, C2H4CN, NEt2) and the bis[(2-diphenyl-
phosphino)phenyl]ether (POP) were allowed to react with fluoroiodomethane to produce fluoromethyl
phosphonium salts in yields between 60–99%. The compounds were characterized by vibrational and
NMR spectroscopy and in most cases also by single crystal X-ray diffraction. Diphenyl(fluoromethyl)
phosphine was synthesized as a mixed aryl–alkyl-phosphine and the TEP value (Tolman electronic
parameter) was determined in order to explain its low reactivity. The molecular and crystal structures of
the new fluoromethyl phosphonium salts [R3PCH2F]I with R = Me, C2H2CN and NEt2 as well as of the
salt resulting from the fluoromethylation of POP provided additional information on the structural
behavior of the bioisoster CH2F group bonded to phosphorus. Hydrogen bonding in the crystal is
compared with that observed in the crystal structure of PPh3CH2FI. The toxicity of the sufficiently water
soluble salt [Me3PCH2F]I was investigated and the toxicological effect of the CH2F group was compared
to that of the bioisoster CH2OH group in THPS.
Received 7th May 2020,
Accepted 2nd August 2020
DOI: 10.1039/d0nj02310h
rsc.li/njc
tetrakis(hydroxymethyl)phosphonium sulfate (THPS) is widely
used as biocide in oil pipelines and/or oil fields as well as in
Introduction
Phosphonium salts are a long known class of compounds and the paper producing industry against Gram negative bacteria.6
widely used by chemists, e.g. as starting materials for Wittig Considering the opposite charges of phosphonium cations and
reactions.1 Fluoromethyl phosphonium salts have been described Gram negative bacteria, it is not surprising that the mechanism
to serve as precursors for the synthesis of fluoroolefines,2 and of interaction is based on a strong electrostatic interaction. The
have also been employed to simple transfer the fluoromethyl mode of action can be described in such a way, that the
group to other substrates.3 This property of fluoromethyl phos- proteins of the membrane wall of the bacteria will react with
phonium salts is particularly interesting for the preparation of the CH2OH groups of THPS to form CH2NR2 with cleavage of
biological active compounds, due to the bioisosteric properties water. This event damages the structure of the bacteria and
of the CH2F group.3b,4 In the course of our recent systematic as consequence nonspecific increase of cell permeability or
investigations on fluoromethylating agents we experienced that abnormal morphology cause lysis (Fig. 1).7
very little is known on the structural properties of CH2F bonded to
It is already known from warfare agents of the G series
phosphorus.3a This prompted us to investigate some more phos- (sarin, cyclosarin, soman) that also strong element fluorine
phonium salts, containing the PCH2F structural motif. In addition bonds can be cleaved by organisms under formation of HF.8
to the fluoromethylating ability and the use for the synthesis of This prompted us to investigate, the toxicity of the most water
fluoroolefines the biological activity and in particular the toxicity soluble phosphonium salt, [Me3PCH2F]I, in particular regarding a
of fluoromethyl phosphonium salts is of interest.5 It is known possible cleavage of the C–F bond on hydrolysis under biological
that phosphonium salts containing the bioisosteric CH2OH conditions with formation of toxic HF.
group can have a biocidal effect on biofilms and in particular
¨
Department Chemie, Ludwig-Maximilian-Universitat, Butenandstr. 5-13 (D),
Results and discussion
¨
81377 Munchen, Germany. E-mail: Konstantin.Karaghiosoff@cup.uni-muenchen.de
† Electronic supplementary information (ESI) available: Copies of NMR spectra
and X-ray details. CCDC 1967513–1967517. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d0nj02310h
The new trifluoromethyl phosphonium salts 1–5 were prepared
by reaction of the respective phosphines with CH2FI (Scheme 1).
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Scheme 2 Synthesis of fluoromethyldipehnylphosphine 6a.
Fig. 1 Mechanism of interaction and mode of action of THPS with the cell
wall of Gram negative bacteria.
Fig. 2 TEP value of PPh2CH2F compared to the used and common
The phosphonium salts 1–5 are isolated as colorless crystalline phosphines.
air stable solids. Except for 1 they are quite poorly soluble in
water and readily soluble in polar aprotic solvents like MeCN,
DCM or THF.
corresponding methyl derivates.11 The same trend has been
reported for [Ph3PCH2F]BF4 as compared to [Ph3PCH3]BF4.12
While the 31P chemical shifts of the phosphonium salts 1–5
reflect also the influence of the other three substituents at
phosphorus the P-bonded CH2F group displays characteristic
1H, 13C and 19F chemical shifts and coupling constants (Table 1).
The 1H, 13C and 19F NMR signals of P–CH2F in 1–5 are
typically found in the quite narrow ranges of 5–6 ppm, 76–78 ppm
and ꢀ240 to ꢀ250 ppm, respectively. Also for the coupling
The challenge of phosphine fluoromethylation with CH2FI is
represented by the reaction rate, which is in part quite slow,
and by the choice of proper reaction conditions. In fact, already
small deviation from the selected reaction conditions lead to
the formation of byproducts, which are difficult to separate.
In general fluoromethylation with CH2FI is more difficult than
methylation with CH3I.9 Reaction time, necessary for complete
reaction, strongly depends on the substituents at phosphorus.
Fluoromethylation is fast (0.5 h/ꢀ78 1C) in the case of Me3P and
much slower in the case of nBu3P (32 h/35 1C) or bis(phosphine)
POP (24 h/110 1C). Thus the electron donor ability of the
phosphine seems to play an important role. Considering the
long reaction time needed for the fluoromethylation of triphenyl
phosphine the reaction of the new alkyl/aryl substituted fluoro-
methyldiphenylphosphine 6 with CH2FI was investigated.
Phosphine 6 is readily prepared starting from diphenylphosphine
by lithiation and subsequent fluoromethylation with CH2FI
(Scheme 2). Unfortunately, further reaction of 6 with CH2FI
under different conditions did not yield the corresponding
bis(fluoromethyl) phosphonium salt. Either no reaction or the
formation of several unidentified phosphorus containing products
at elevated temperatures was observed.
1
2
2
constants JCF (180–190 Hz), JPF (50–60 Hz) and JFH (44–46 Hz)
characteristic ranges are observed. The coupling of phosphorus to
the proton of CH2F is very small (o1 Hz), in contrast to 2JPH to the
protons of the other alkyl substituents at phosphorus in 3 and 4.
2
Only in the case of 1 a JPH coupling of 1.6 Hz to the CH2
protons of CH2F was clearly observed. This effect is obviously
due to the fluorine atom, as impressively shown by the 31P NMR
spectrum of 1 (Fig. 3, top). Coupling of phosphorus to the
2
methyl protons (15.0 Hz) is much larger than JPH to the
2
methylene protons (1.6 Hz); both are smaller than JPF of
45.3 Hz. These couplings cause splitting of the 31P NMR signal
of 1 to the well resolved multiplet shown in Fig. 3 (top). In the
19F NMR spectrum of 1 a doublet of triplets due to coupling of
19F with 31P and with 1H of the CH2F group is observed. Each of
the resulting six lines is further splitted by long range coupling
of 19F to 1H of the methyl groups over four bonds (Fig. 3
bottom). The NMR data of the CH2F group fit well to those
reported for [Ph3PCH2F]BF4.13
In order to characterize the phosphine 6 with respect to its
donor ability its Tolman electronic parameter (TEP) was deter-
mined (Fig. 2).10 In the series of phosphines the donor proper-
ties for 6 are similar to those for Ph2PMe and Ph3P, which
explains its low tendency to form the phosphonium salt.
The fluoromethyl phosphonium salts 1–5 have lower melting
points and lower decomposition temperatures as compared to the
Single crystals, suitable for X-ray diffraction studies were
obtained for compounds 1, 2, 4 and 5. Compound 1 crystallizes
Table 1 Chemical shifts and coupling constants for the CH2F group in the
fluoromethyl phosphonium salts 1–5
Chemical shift
Coupling constant
1H
13C
19F
1J(C,F)
2J(P,F)
2J(F,H)
1
2
3
4
5
6
5.44
5.77
5.92
5.85
6.28
5.28
77.1
78.2
76.1
76.8
—
ꢀ242
ꢀ241
ꢀ247
ꢀ249
ꢀ240
ꢀ230
183.8
182.6
190.4
188.3
—
60.3
59.9
51.6
56.8
62.2
114.0
45.3
45.9
45.9
44.8
46.0
49.0
Scheme 1 Synthesis of fluoromethylphosphonium iodides 1–5.
84.6
199.9
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Fig. 5 Hydrogen bonding in the crystal structure of compound 1. Only
one of the two positions of the CH2F group and only the relevant hydrogen
atoms are shown. DIAMOND representation,28 thermal ellipsoids are
shown at 50% probability level. Symmetry code: i: 1 ꢀ x, 1 ꢀ y, 1 ꢀ z;
ii: ꢀ0.5 + x, 0.5 ꢀ y, 0.5 ꢀ z.
Fig. 3 31P NMR spectrum (top) and 19F NMR spectrum (bottom) of 1 in
CDCl3.
Fig. 4 Molecular structure of compound 1 in the crystal; DIAMOND
representation,28 thermal ellipsoids are shown at 50% probability level.
The CH2F group is disordered over two positions; only one of the positions
is shown.
Fig. 6 Molecular structure of compound 2 in the crystal, DIAMOND
representation,28 thermal ellipsoids shown at 50% probability level.
in the orthorhombic space group Pnma with one formula unit
in the unit cell. The asymmetric unit is shown in Fig. 4. The
The phosphorus atom shows a distorted tetrahedral sur-
fluoromethyl group is disordered almost equally over two rounding, similar to that observed in the P(NEt2)3CH3+ cation.18
positions. The phosphorus displays a tetrahedral surrounding. The ethyl units are twisted with respect to each other. While the
The P,C distance to the CH2F group (1.792(2) Å) compares well C13–F1 (1.378(4) Å) and C26–F2 (1.393(4) Å) distances are in the
to that in the tetramethyl phosphonium cation (1.783(2) Å).14 expected range, the P1–C13 (1.824(3) Å) and P2–C26 (1.813(4) Å)
and seems to be somewhat shorter as compared to the corres- distances are elongated as compared to those in the
ponding distance in [Ph3PCH2F]I (1.810(4) Å)3a and to the P,C P(NEt2)3CH3 cation (1.783(3) Å)18 and in 1.
+
+
distance in P(CH2OH)4 (1.809(6) Å).15
Similar to 1, compound 2 also shows weak intermolecular
The C,F bond length (1.369(5) Å) is in the expected CHꢁ ꢁ ꢁF and CHꢁ ꢁ ꢁI interactions (Table 2), as already reported
range.3a,14a In the crystal weak interactions involving the iodide for [PPh3CH2F]I.3a,16 The CHꢁ ꢁ ꢁF interactions (Fig. 7) favour an
anion and the fluorine atom are observed (Fig. 5).
arrangement of the cations in the crystal to form chains, which
A weak hydrogen bond Fꢁ ꢁ ꢁH (2.489(4) Å)16 between the are interconnected by the iodide anions through CHꢁ ꢁ ꢁI
fluorine atom and one of the methyl hydrogen atoms of a hydrogen bonds.
second phosphonium cation leads to the formation of chains.
Compound 4 crystallizes in the monoclinic space group P21/c.
Similar interactions have been reported also for the crystal The asymmetric unit is shown in Fig. 8.
structure of Ph3PCH2FI.3a The iodide anions are located between
Atom distances and bond angles of phosphonium salt 4 are
the chains and display weak IꢁꢁꢁH interactions (3.14(2) Å)17 to as expected. The C1–F1 distance (1.384(2) Å) compares well to
hydrogen atoms of the CH2F group (Fig. 5).
those found for the fluoromethyl phosphonium salts 1 and
%
Compound 2 crystallizes in the triclinic space group P1 with 2 and seems to stay unaffected by the other substituents at
two formula units in the asymmetric unit (Fig. 6). phosphorus.
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Table 2 Structural parameters of the hydrogen bonds in the crystals of
compounds 1, 2, 4 and 5; bond lengths in Å, bond angles in 1
Compound Bond
d(D–H) d(Hꢁ ꢁ ꢁA) d(Dꢁ ꢁ ꢁA) +(D–Hꢁ ꢁ ꢁA)
1
2
C3B–H3Aꢁ ꢁ ꢁI1ii 0.99(2) 3.14(2) 4.026(3) 149.7(2)
C1–H1Aꢁ ꢁ ꢁI1
0.98(2) 3.02(2) 3.951(4) 159.7(3)
0.98(3) 2.48(4) 3.436(4) 162.6(2)
C3i–H3Aiꢁ ꢁ ꢁF1
C13–H13Aꢁ ꢁ ꢁI1 0.99(2) 2.92(2) 3.901(4) 178(2)
C13–H13Bꢁ ꢁ ꢁI1i 0.99(2) 3.13(2) 4.084(4) 164(1)
C25ii–H25iiꢁ ꢁ ꢁF1 0.98(2) 2.47(3) 3.324(6) 144.4(4)
4
5
C1–H1Aꢁ ꢁ ꢁI1ii
C9i–H9Aiꢁ ꢁ ꢁF1
C1–H1Bꢁ ꢁ ꢁF1i
C1–H1Aꢁ ꢁ ꢁI1
O2–H211ꢁ ꢁ ꢁI1
0.92(2) 3.13(9) 3.841(2) 91.6(7)
0.96(2) 2.46(1) 3.348(3) 153.4(8)
0.94(2) 2.68(2) 3.482(2) 143(1)
0.94(2) 2.95(2) 3.863(3) 165(1)
6b
0.88(2) 2.7(2)
3.45(2) 146(2)
C32i–H32iꢁ ꢁ ꢁF1 0.95(2) 2.60(2) 3.465(4) 152(2)
C44i–H44iꢁ ꢁ ꢁF1 0.96(3) 2.42(2) 3.181(3) 137(2)
Fig. 8 Molecular structure of compound 4 in the crystal; DIAMOND
representation,28 thermal ellipsoids drawn at 50% probability level.
C6–H6ꢁ ꢁ ꢁF1
0.97(3) 2.75(3) 3.250(3) 113(2)
Symmetry code: (1) i: 1 ꢀ x, 1 ꢀ y, 1 ꢀ z; ii: ꢀ0.5 + x, 0.5 ꢀ y, 0.5 ꢀ z; (2) i:
1 ꢀ x, 1 ꢀ y, ꢀz; ii: 1 ꢀ x, 1 ꢀ y, 1 ꢀ z; (4) i: 1 ꢀ x, ꢀ0.5 + y, 1.5 ꢀ z; ii:
1 ꢀ x, 1 ꢀ y, 1 ꢀ z; (5) i: ꢀx, 1 ꢀ y, 1 ꢀ z; (6b) i: ꢀx, 1 ꢀ y, 1 ꢀ z.
Fig. 9 Hydrogen bonding in the crystal structure of compound 4. Only
the relevant hydrogen atoms are shown. DIAMOND representation,28
thermal ellipsoids shown at 50% probability level. Symmetry code:
i: 1 ꢀ x, ꢀ0.5 + y, 1.5 ꢀ z; ii: 1 ꢀ x, 1 ꢀ y, 1 ꢀ z.
Fig. 7 Hydrogen bonding in the crystal structure of compound 2. Only
the relevant hydrogen atoms are shown. DIAMOND representation,28
thermal ellipsoids shown at 50% probability level. Symmetry code:
i: 1 ꢀ x, 1 ꢀ y, ꢀz; ii: 1 ꢀ x, 1 ꢀ y, 1 ꢀ z.
In the crystal the arrangement of cations and anions is governed
by weak OHꢁꢁꢁI, CHꢁꢁꢁI and CHꢁꢁꢁF hydrogen bonds (Fig. 11 and
In the crystal weak intermolecular CHꢁ ꢁ ꢁF interactions Table 2). Weak CHꢁꢁꢁF interactions favor the formation of dimers
between the CH2CN hydrogen atoms and fluorine as well as and involve one hydrogen atom of each CH2F group. The second
CHꢁ ꢁ ꢁI interactions between the CH2F hydrogen atoms and the hydrogen atom undergoes CHꢁꢁꢁI hydrogen bonding to one iodide
iodide anions are observed (Fig. 9). They result in a similar anion. The resulting aggregates are partially interconnected by
arrangement of cations and anions as found for phosphonium OHꢁꢁꢁI hydrogen bonds. In order to obtain a more precise analysis
salts 1 and 2.
of the intermolecular interactions in the crystal of the fluoro-
Phosphonium salt 5 crystallizes in the triclinic space group methyl phosphonium salts, fingerprint plots and Hirshfeld
%
P1. The asymmetric unit, shown in Fig. 10 contains one surfaces were created for compounds 2, 4 and 5. Phosphonium
molecule of water which position is occupied by a third. salt 1 has been omitted due to the disorder in the crystal. The red
The phosphorus atom P1 in the cation of 5 carrying the dots on the Hirshfeld surfaces indicate contacts between layers
CH2F group displays a distorted tetrahedral environment, while (Fig. 12).
the arrangement around P2 is pyramidal (sum of CPC angles
The sum di + de (di: distance from the Hirshfeld surface
304.31). As expected, CPC angles at P2 (100.6(2)–102.3(2)1) are to the nearest atom interior; de: distance from the Hirshfeld
smaller as compared to CPC angles at P1 (108.6(2)–111.4(2)). surface to the nearest atom exterior) indicates that all Hꢁ ꢁ ꢁI
The aryl substituents at both phosphorus atoms are rotated interactions in the structures of 2, 4 and 5 are weak. As can be
around the PC-axis to adopt a propeller-like arrangement. seen from the width of the flanks in plots (a)–(c) (Fig. 12) the
Atom distances and bond angles of the P–CH2F unit fit well number of hydrogen bonds to Iꢀ decrease in the order 4 4 2 4 5.
to those found for the fluoromethyl phosphonium salts 1, 2 and 4. The more pronounced spikes for HꢁꢁꢁF contacts in the case of 4
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Fig. 10 Molecular structure of compound 5 in the solid state DIAMOND
representation,28 thermal ellipsoids shown at 50% probability level. Water
position is only occupied by a third.
Fig. 12 Two dimensional fingerprint plot and the corresponding Hirshfeld
surface (bottom right in 2D plot) for 2 (a), 4 (b) and 5 (c). Color coding:
white, distance d equals vdW distance; blue, d exceeds VdW distance, red,
d, smaller than VdW distance). Population of close contacts of 2, 4 and 5 in
crystal is shown in plot d).
Fig. 11 Hydrogen bonding in the crystal structure of compound 5. Only
the relevant hydrogen atoms are shown. DIAMOND representation,28
thermal ellipsoids shown at 50% probability level. Symmetry code: i: ꢀx,
1 ꢀ y, 1 ꢀ z. The position of the water molecule displays a 30% occupancy.
Fig. 13 Molecular structure of (fluoromethyl)diphenyl phosphine oxide in
the crystal. DIAMOND representation,28 thermal ellipsoids shown at 50%
probability level.
(plot b), Fig. 12) indicate for this compound the greatest number
The phosphorus atom shows in all four molecules a dis-
of hydrogen bonds involving fluorine. The absence of such spikes torted tetrahedral arrangement of the substituents. The phenyl
in the case of 5 (plot c), Fig. 12) is representative for less HꢁꢁꢁF groups are slightly twisted against each other. The P–CH2F
interactions in the crystal, which is in accord with the formation distances (P1–C13: 1.815(2) Å; P2–C26: 1.817(2) Å; P3–C39:
of dimers. The sum of di + de also shows, that the HꢁꢁꢁF 1.813(2) Å; P4–C52 (1.817(2) Å) are slightly elongated as com-
interactions are weak.
pared to that in diphenylmethyl phosphine oxide (1.790(3) Å)19b
A single crystal of (fluoromethyl)diphenyl phosphine oxide and similar to that reported for diphenyl hydroxymethyl phos-
(6b),19a suitable for X-ray diffraction, was collected from an phine oxide (1.816(2) Å).20 The C–F bonds (C13–F1: 1.398(2) Å;
NMR tube originally containing the phosphine dissolved in C26–F2: 1.393(2) Å; C39–F3: 1.390(2) Å; C52–F4: 1.383(3) Å) fit
%
CDCl3. The compound crystallizes in the space group P1 with well to those observed for the phosphonium salts 1, 2 and 4 and
four crystallographically independent molecules in the asym- are obviously not influenced by phosphorus coordination.
metric unit (Fig. 13).
In the crystal one intramolecular and two weak intermolecular
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Fig. 14 Hydrogen bonding in the crystal structure of fluoromethyl diphenyl
phosphine oxide. For a better overview, H atoms were partially omitted.
DIAMOND representation,28 thermal ellipsoids shown at 50% probability
level. Symmetry code: i: ꢀx, 1 ꢀ y, 1 ꢀ z.
Hꢁ ꢁ ꢁF contacts to aromatic CH hydrogen atoms are observed
(Fig. 14 and Table 2).
However, the intermolecular Fꢁ ꢁ ꢁH interactions, which
according to a Hirshfeld analysis represent 12.4% of all inter-
molecular interactions in the crystal of 6b, are more numerous
than observed for 2, 4 or 5 (Fig. 12d).
In order to find out whether the phosphorus bonded CH2F
unit can react with the membrane proteins in analogy to the
bioisoteric P–CH2OH group (Fig. 1), it was first necessary to
choose a suitable phosphonium salt. Solubility tests showed
that only compound 1 is sufficiently soluble in water to per-
form such tests. Sodium iodide (EC50: 289.61) was measured
to rule out that a possible inhibition was caused by the iodide
anion. Tetramethyl phosphonium iodide was also included in
the investigations to determine whether the phosphonium
cation itself already has an inhibition effect on bacteria. The
inhibitory effect of water samples on the light emission of
Gram negative Vibrio fischeri bacteria,21 shows clear differ-
Fig. 16 E. coli bacteria colonies on a culture medium at four different
substrate concentrations; (a) control, (b) compound 1. (1): 24.7 mmol Lꢀ1
;
(2): 52.9 mmol Lꢀ1; (3): 105.9 mmol Lꢀ1; (4): 211.8 mmol Lꢀ1; (c) [PMe4]I. (1):
26.7 mmol Lꢀ1; (2): 57.3 mmol Lꢀ1; (3): 114.6 mmol Lꢀ1; (4): 229.3 mmol
L
ꢀ1; (d) [P(CH2OH)4]2SO4. (1): 1.35 mmol Lꢀ1; (2): 2.71 mmol Lꢀ1; (3):
5.42 mmol Lꢀ1; (4): 10.8 mmol Lꢀ1; (e) inhibited colony growth of contol,
NaI, 1, [PMe4]I and [P(CH2OH)4]2SO4.
ences for compound 1, [PMe4]I and THPS ([P(CH2OH)4]SO4) toxic.21,29 According to this, 1 and [PMe4]I (7) are considered
(Fig. 15). For classification of the toxicity the compounds with as non-toxic ([PMe4]I being at the limit of non-toxic), whereas
EC50 values lower than 0.10 g Lꢀ1 are categorized as very toxic THPS is considered as very toxic. Furthermore, the assessment
while compounds with EC50 values between 0.10 g Lꢀ1 and of bactericidal activity on E. coli was determined on the basis
1.00 g Lꢀ1 are rated as toxic and above 1.00 g Lꢀ1 as less of the number of colonies formed on a culture medium at four
different concentrations of the substrates.22 Due to the low
EC50 values for THPS, lower substrate concentrations during
the breeding of colonies on the plates were used. As already
indicated by the EC50 values, sodium iodide showed no effect
on the bacteria within this experiment. Compared with the
control sample (a), only [P(CH2OH)4]SO4 for the concentra-
tions 2, 3 and 4 shows lower colony numbers (Fig. 16). This
confirms the results obtained in Fig. 15, that only THPS is to
be classified as toxic. In Fig. 16 subsection e), the result of
additional growth inhibition studies is shown. The results
indicate that THPS also inhibits bacterial growth. All other
substances used do not inhibit bacterial growth. Based on
these investigations it can be concluded that the C–F bond in
1 remains stable despite the stronger enthalpy of HF for-
mation compared to H2O. This illustrates once more the high
metabolic stability of the CH2F group as compared to the
bioisosteric CH2OH group.3b
Fig. 15 EC50 values for [PMe3CH2F]I (1), [PMe4]I (7), and [P(CH2OH)4]SO4
(8) measured after 15 min (blue) and after 30 min (red).
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Conclusions
Synthesis and characterization
(Fluoromethyl)trimethylphosphonium iodide (1). Caution,
this reaction is very exothermic! Trimethylphosphine (7.06 g,
92.8 mmol) was condensed in a flask and cooled to ꢀ78 1C.
To this fluoroiodomethane (6.24 mL, 92.8 mmol) was carefuly
added. After 30 min the reaction mixture was allowed to warm
up to ambient temperature. The preticipate was dried in vacuo
and 1 was obtained as white powder (21.7 g, 0.09 mol, 99%).
In summary, we have reported an efficient and facile synthesis
method for a series of new fluoromethyl phosphonium salts in
high purity. Single crystal X-ray diffraction gives an insight in
the influence of the substituents at the phosphorus on the
structural parameters of the P–CH2F group. The C–F bond
length stays unaffected by substitution at phosphorus and
corresponds to a typical C–F single bond. The P–C bond length
fits well to that reported for bioisosteric P–CH2OH derivatives.
In all cases investigated weak intermolecular Hꢁ ꢁ ꢁI and Hꢁ ꢁ ꢁF
interactions are observed. They have been studied by Hirshfeld
analysis. In particular the Hꢁ ꢁ ꢁF interactions favor the for-
mation of hydrogen bonded chains in the crystal, which
represent the structural motif for the fluoromethyl phospho-
nium salts 1, 2 and 4. The Hꢁ ꢁ ꢁI contacts are characteristic for
the cation/anion interaction. Toxicological tests were carried
out on the most water soluble phosphonium salt 1. In contrast
to the toxic P–CH2OH structural motif the bioisosteric P–CH2F
group showed no toxicity in the case of the bacteria investi-
gated. This finding is anticipated to be useful for adjusting the
toxicity of P–CH2OH based biocides.
1
Phas. trans. 54 1C; 128 1C; Dec. p. 209 1C; H NMR (400 MHz,
D2O, 26 1C): d = 5.44 (d, 2JH,F = 45.3 Hz, 2H; CH2F), 2.05 (d, 2JH,P
=
15.0 Hz, 9H; CH3); 13C{1H} NMR (100.6 MHz, D2O, 26 1C): d = 77.1
(dd, 1JC,F = 183.8 Hz, 1JC,P = 64,6 Hz; CH2F), 4.9 (d, 1JC,P = 53.6 Hz;
2
CH3); 31P{1H} NMR (162 MHz, D2O, 26 1C): d = 27.2 (d, JP,F
=
60.3 Hz); 31P NMR (162 MHz, D2O, 26 1C): d = 27.2 (d of dezetts of
2
2
2
t, JP,F = 60.3 Hz, JP,H = 15.0 Hz to CH3, JP,H = 1.6 Hz to CH2F)
19F{1H} NMR (376 MHz, D2O, 26 1C): d = ꢀ242.8 (d, 2JF,P = 60.3 Hz);
19F NMR (376 MHz, D2O, 26 1C): d = ꢀ242.8 (dt, JF,P = 60.3 Hz,
2
2JF,H = 45.3 Hz); IR (ATR): n~ = 2993 (s), 2957 (m), 2919 (m),
2899 (m), 2886 (w), 1627 (w), 1567 (w), 1524 (w), 1440 (w), 1418 (w),
1397 (w), 1321 (w), 1304 (w), 1291 (m), 1224 (m), 1021 (s), 962 (s),
883 (s), 809 (m), 779 (m), 745 (w), 643 cmꢀ1 (m); Raman
(1000 mW): n~ = 2992 (s), 2958 (s), 2917 (s), 2900 (s), 2889 (s),
2791 (m), 1441 (w), 1418 (w), 1324 (w), 1290 (w), 1225 (w), 1025 (w),
972 (w), 940 (w), 885 (w), 783 (w), 746 (w), 646 (m), 379 (w), 272
(m), 250 cmꢀ1 (w); HRMS (FAB) (m/z): calcd for C4H10FP: 109.0582
[M+]; found, 109.0567; elemental analysis calcd (%) for C4H10FIP:
C 20.36 H 4.70; found C 20.40 H 4.66.
Experimental section
Materials and instruments
All compounds were handled using Schlenk techniques under
dry argon. The phosphines were obtained from BASF, Hoechst
AG and VWR. Fluoroiodomethane was distilled under inert
conditions before use. The samples for infrared spectroscopy
were placed under ambient conditions without further prepara-
tion onto an Smith DuraSamplIR II ATR device and measured
with a PerkinElmer BX II FR-IR System spectrometer. Raman
spectra was measured with a Bruker MultiRam FT Raman
spectrometer. Melting/decomposition points were determined
with a OZM DTA 552-Ex instrument. The samples for NMR
spectroscopy were prepared under inert atmosphere using Ar as
protective gas. The solvent used was dried using 3 Å mol sieve
and stored under Ar atmosphere. Spectra were recorded with a
Bruker Avance III spectrometer operating at 400.1 MHz (1H),
376.4 MHz (19F), 100.6 MHz (13C) and 162 MHz (31P). Chemical
shifts are referred to TMS (1H, 13C), CFCl3 (19F) and H3PO4 (31P).
All spectra were recorded at 299.15 K. Mass spectrometric data
were acquired with a Jeol MStation sectorfield instrument in
the FAB+ mode. Elemental burning analysis was performed
using an Elementar vario EL instrument. Single crystals, sui-
table for X-ray diffraction, were obtained by slow evaporation of
a solution in acetonitrile. Data collection was performed with
an Oxford Xcalibur 3 diffractometer equipped with a Spellman
generator (50 kV, 40 mA) and a Kappa CCD detector, operating
with Mo-Ka radiation (l = 0.71073 Å). Data collection and data
reduction were performed with the CrysAlisPro software.23
Absorption correction using the multiscan method23 was
applied. The structures were solved with SHELXS-97,24 refined
with SHELXL-9725 and finally checked using PLATON.26
Tris(diethylamino)(fluoromethyl)phosphonium iodide (2).
Tris(diethylamino)phosphine was synthesized as described in
literature.27 To a solution of fluoroiodomethane (0.676 mL,
10.0 mmol) in diethylether (90.0 mL) cooled to 0 1C, a solution
of tris(diethylamino)phosphine (2.73 mL, 10.0 mmol) in
diethylether (10 mL) was added slowly with stirring during
3 h. The solution was concentrated and cooled to ꢀ10 1C. The
precipitate was filtrated off and compound 2 was obtained as
colorless crystals (3.25 g, 0.008 mol, 80%). M.p. 70 1C; Dec. p.
1
2
130 1C; H NMR (400 MHz, CDCl3, 26 1C): d = 5.77 (d, JH,F
=
3
3
45.9 Hz, 2H; CH2F), 3.24 (dq, JH,P = 11.2 Hz, JH,H = 7.1 Hz,
3
12H; NCH2), 1.26 (t, JH,H = 7.1 Hz, 18H; CH3); 13C {1H} NMR
1
1
(100.6 MHz, CD3CN, 26 1C): d = 78.2 (dd, JC,F = 182.6, JC,P
=
2
130.3 Hz; CH2F), 40.1 (d, JC,P = 4.1 Hz, NCH2), 13.6 (s, CH3);
31P{1H} NMR (162 MHz, CDCl3, 26 1C): d = 48.1 (d, JP,F = 59.9
2
Hz); 19F{1H} NMR (376 MHz, CDCl3, 26 1C): d = ꢀ241.1 (d, 2JF,P
=
59.9 Hz); 19F NMR (376 MHz, CDCl3, 26 1C): d = ꢀ241.1 ppm
2
2
(dt, JF,P = 59.9 Hz, JF,H = 45.9 Hz); FT-IR (ATR): n~ = 2972 (m),
2925 (m), 2887 (m), 2840 (m), 1747 (w), 1643 (w), 1575 (w),
1465 (w), 1449 (w), 1385 (m), 1369 (m), 1292 (s), 1249 (s),
1209 (s), 1153 (s), 1112 (w), 1059 (w), 1016 (s), 971 (s), 928 (w),
801 (m), 764 (w), 704 (w), 625 cmꢀ1 (w); Raman (1000 mW):
n~ = 2974 (s), 2929 (s), 2896 (s), 2840 (s), 1451 (m), 1371 (w),
1371 (w), 1294 (w), 1207 (w), 1082 (w), 1023 (w), 981 (w), 953 (w),
928 (w), 795 (w), 625 (w), 412 (w), 316 cmꢀ1 (w); HRMS (FAB):
(m/z) calcd for C13H32FN3P: 280.2318 [M+], found, 280.2316;
elemental analysis calcd (%) for C13H32FIN3P: C 38.34 H 7.92 N
10.32; found C 37.06 H 8.13 N 10.01.
14312 | New J. Chem., 2020, 44, 14306--14315
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Tributyl(fluoromethyl)phosphonium iodide (3). To
NJC
1
a
Dec. p. 231 1C; H NMR (400 MHz, CDCl3, 26 1C): d = 7.95–7.89
solution of tributylphosphine (1.92, 9.50 mmol) in diethylether (m, 2H; ArH), 7.85–7.81 (m, 1H; ArH), 7.79–7.75 (m, 1H; ArH),
(15.0 mL), fluoroiodomethane (0.650 mL, 9.50 mmol) was 7.72–7.61 (m, 8H; ArH), 7.56–7.47 (m, 6H; ArH), 7.44–7.38 (m, 3H;
added in small portions over a period of 5 min. The solution ArH), 7.33–7.29 (m, 2H; ArH), 7.23–7.17 (m, 2H; ArH), 7.03–6.98
was heated to 35 1C for 32 h, the precipitate formed was (m, 2H; ArH), 6.82–6.79 (m, 1H; ArH), 6.28 ppm (dd, 2JH,F = 46.0,
filtrated off, washed with diethylether (2 ꢂ 15.0 mL) and dried 2JH,P = 12.8 Hz, 2H; CH2F); Due to the low solubility no 13C NMR
in vacuo. Compound 3 was obtained as white powder (2.34 g, spectrum of acceptable quality could be obtained. 31P{1H} NMR
1
6 mmol, 68%). M.p. 58 1C; H NMR (400 MHz, CDCl3, 26 1C): (162 MHz, CDCl3, 26 1C): d = 18.7 (d, 2JP,F = 62.2 Hz; 1P, PCH2F),
2
d = 5.92 (d, JH,F = 45.9 Hz, 2H; CH2F), 2.71–2.56 (m, 6H, CH2), 30.7 ppm (s; 1P, PPh2); 19F{1H} NMR (376 MHz, CDCl3, 26 1C):
3
2
1.70–1.45 (m, 12H, CH2), 1.00 (t, JH,H = 7.1 Hz, 9H; CH3); d = ꢀ240.3 ppm (d, JF,P = 62.2 Hz); 19F NMR (376 MHz, CDCl3,
13C NMR (100.6 MHz, CDCl3, 26 1C): d = 76.1 (dd, JC,F
190.4 Hz, JC,P = 58.1 Hz; CH2F), 24.1 (d, JC,P = 15.4 Hz; n~ = 3145 (w), 3048 (w), 2988 (w), 2887 (w), 1580 (mm), 1563 (m),
PCH2CH2), 23.8 (dd, 3JC,P = 4.6 Hz, 5JC,F = 0.7 Hz; PCH2CH2CH2), 1520 (m), 1475 (s), 1458 (s), 1435 (s), 1342 (w), 1314 (w), 1264 (m),
=
26 1C): d = ꢀ240.3 (dt, 2JF,P = 62.2 Hz, 2JF,H = 45.3 Hz); FT-IR (ATR):
1
1
2
1
4
18.1 (d, JC,P = 44.6 Hz; PCH2), 13.6 (d, JC,P = 0.8 Hz; CH3); 1233 (s), 1188 (m), 1157 (m), 1133 (w), 1110 (m), 1100 (m),
31P{1H} NMR (162 MHz, CDCl3, 26 1C): d = 32.8 (d, JP,F
=
1076 (w), 1029 (s), 996 (w), 907 (w), 886 (m), 793 (m), 754 (m),
2
51.6 Hz); 19F{1H} NMR (376 MHz, CDCl3, 26 1C): d = ꢀ247.9 744 (s), 721 (w), 702 (s), 688 (w), 620 (w), 542 (s), 505 cmꢀ1 (m);
(d, JF,P = 51.6 Hz); 19F NMR (376 MHz, CDCl3, 26 1C): Raman (1000 mW): n~ = 3143 (w), 3051 (s), 2884 (w), 2832 (w),
2
2
2
d = ꢀ247.9 (dt, JF,P = 51.6 Hz, JF,H = 45.9 Hz); FT-IR (ATR): 1584 (s), 1189 (w), 1164 (w), 1110 (w), 1098 (w), 1030 (m), 999 (s),
n~ = 2960 (s), 2934 (m), 2872 (w), 1572 (m), 1463 (m), 1379 (m), 794 (w), 692 (w), 671 (w), 615 (w), 584 (w), 306 (w), 262 (w), 225 (w),
1340 (m), 1313 (m), 1283 (m), 1231 (m), 1208 (m), 1099 (m), 177 cmꢀ1 (w); HRMS (EI): (m/z) calcd for C37H30FIOP2: 698.4964
1078 (m), 1011 (w), 968 (m), 916 (m), 866 (m), 801 (m), 746 (m), [M+], found, 571.1760; elemental analysis calcd (%) for
712 (m), 661 cmꢀ1 (w); Raman (1000 mW): n~ = 2965 (s), 2937 (s), C37H30FIOP2: C 63.62 H 4.33; found C 63.91 H 4.36.
2904 (s), 2874 (s), 2734 (w), 1447 (m), 1399 (w), 1315 (w), 1100 (w),
(Fluoromethyl)diphenylphosphine (6a). Diphenylphosphine
1052 (w), 890 (w), 661 (w), 245 cm-1 (w); HRMS (FAB): (m/z) calcd (0.499 mL, 2.87 mmol) was solved in THF (15.0 mL) and cooled
for C13H29FIP: 235.1985 [M+], found, 235.2005; elemental analysis to 0 1C. nButyllithium (2.43 mL, 1.30 M, 3.16 mmol) was added
calcd (%) for C13H29FIP: C 43.10 H 8.07; found C 42.97 H 8.05.
and the solution was stirred for 1 h. The deep red solution was
Tris(2-cyanoethyl)(fluoromethyl)phosphonium iodide (4). To cooled to ꢀ78 1C and fluoroiodomethane (0.194 mL, 2.87 mmol)
a solution of tris(2-cyanoethyl)phosphine (0.915 g, 4.74 mmol) in was added in portions over a period of 10 min. The reaction
acetonitrile (20.0 mL), fluoroiodomethane (0.350 mL, 4.74 mmol) mixture was allowed to warm up to ambient temperature
was added. The solution was stirred for 7 d and than concentrated overnight. Degassed water (0.50 mL) was added and THF was
in vacuo. The precipitate was filtrated off and dried in vacuo. removed in vacuo. The product was extracted with pentane
Crystalline colorless 4 was obtained (1.10 g, 3 mmol, 66%). M.p. (15.0 mL) and the solvent removed in vacuo. A colorless oil
1
2
138 1C; H NMR (400 MHz, CD3CN, 26 1C): d = 5.85 (d, JH,F
=
was obtained. (0.41 g, 2 mmol, 65%). M.p. ꢀ32 1C; Dec. p.
44.8 Hz, 2H; CH2F), 3.19–2.78 ppm (m, 12H, CH2); 13C NMR 235 1C; 1H NMR (400 MHz, CDCl3, 26 1C): d = 7.54–7.47 (m, 4H;
1
1
2
2
(100.6 MHz, CD3CN, 26 1C): d = 76.0 (dd, JC,F = 188.3, JC,P
=
ArH), 7.41–7.34 (m, 6H; ArH), 5.28 (dd, JH,F = 49.0 Hz, JH,P =
56.1 Hz; CH2F), 15.6 (d, 1JC,P = 46.0 Hz; PCH2), 11.9; 31P{1H} NMR 8.4 Hz, 6H; CH2F); 13C NMR (100.6 MHz, CDCl3, 26 1C): d =
(162 MHz, CDCl3, 26 1C): d = 35.3 (d, 2JP,F = 56.8 Hz); 19F{1H} NMR 133.5 (dd, 1JC,P = 17.7 Hz, 3JC,F = 0.8 Hz; C-i), 129.3, 128.7, 128.6,
(376 MHz, CDCl3, 26 1C): d = ꢀ249.5 (d, 2JF,P = 56.8 Hz); 19F NMR 84.6 (dd, JC,F = 199.9, JC,P = 21.3 Hz; CH2F); 31P{1H} NMR
1
1
(376 MHz, CDCl3, 26 1C): d = ꢀ249.5 ppm (dt, JF,P = 56.8, 2JF,H
=
(162 MHz, CDCl3, 26 1C): d = ꢀ11.9 (d, 2JP,F = 114.0 Hz; 19F{1H}
2
44.8 Hz); FT-IR (ATR): n~ = 3001 (w), 2958 (m), 2927 (s), 2899 (m), NMR (376 MHz, CDCl3, 26 1C): d = ꢀ230.4 (d, 2JP,F = 114.0 Hz);
2251 (s), 1571 (w), 1411 (s), 1362 (s), 1311 (m), 1243 (m), 1229 (m), 19F NMR (376 MHz, CDCl3, 26 1C): d = ꢀ230.4 (dt, 2JF,P = 114.0,
1191 (w), 1028 (s), 1005 (m), 978 (s), 940 (m), 880 (w), 804 (s), 781 2JF,H = 49.0 Hz); FT-IR (ATR): n~ = 3054 (m), 2918 (s), 1958 (m),
(s), 707 (m), 690 (m), 675 (m), 516 cmꢀ1 (m); Raman (1000 mW): 1889 (m), 1809 (m), 1586 (m), 1481 (m), 1433 (m), 1306 (m),
n~ = 2999 (w), 2960 (w), 2923 (s), 2901 (s), 2250 (s), 1411 (w), 1395 1236 (m), 1184 (m), 1123 (m), 1096 (m), 1069 (m), 977 (m),
(w), 1311 (w), 1246 (w), 1005 (w), 915 (w), 806 (w), 692 (w), 676 (w), 914 (w), 843 (m), 740 (w), 721 (m), 691 (m), 618 (m), 544 (m),
484 (w), 411 (w), 369 (w), 250 (w), 201 cmꢀ1 (w); HRMS (FAB): (m/z) 506 cmꢀ1 (m); Raman (1000 mW): n~ = 3142 (s), 3056 (m),
calcd for C10H14FIN3P: 226.2146 [M+], found, 226.0922; elemental 2958 (m), 2919 (m), 1587 (m), 1572 (w), 1435 (w), 1186 (w),
analysis calcd (%) for C10H14FIN3P: C 34.01 H 4.00 N 11.90; found 1159 (w), 1099 (w), 1029 (m), 1000 (s), 684 (w), 668 (w), 618 (w),
C 34.12 H 4.10 N 11.90.
377 (w), 262 (w), 204 cmꢀ1 (w); HRMS (EI): (m/z) calcd for
13H12FP: 218.2112 [M+], found 218.0653; elemental analysis
5-(Diphenylphosphino)-1-fluoromethyldiphenyl phosphonium
iodide (5). 1,10-(Oxydi-2,1-phenylene)bis(1,10-diphenylphosphine) calcd (%) C13H12FP: C 71.56 H 5.54; found C 71.74 H 5.78.
C
(0.30 g, 0.576 mmol) was dissolved in toluene (25.0 mL) and
Determination of TEP value. Ni(CO)4 (1.56 g, 9.17 mmol) was
fluoroiodomethane (0.100 mL, 1.5 mmol) was added. The solution condensed into a flask and pentane (25 mL) was added. The
was heated to 110 1C for 1 d and the resulting precipitate solution was cooled to ꢀ78 1C and a solution of (fluoromethyl)-
was filtrated off, washed with toluene (3 ꢂ 15.0 mL) and dried diphenylphosphine (0.20 g, 0.91 mmol) in pentane (10 mL)
in vacuo to yield colorless crystals of 5 (0.41 g, 0.58 mmol, 55%). was slowly added. The reaction mixture was warmed to room
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Paper
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temperature within 2 h, the solvent and the excess of Ni(CO)4
were removed in vacuo and a colorless solid was obtained.
FT-IR-TEP (ATR): n~ = 3060 (m), 2919 (m), 2068 (s), 1988 (m),
1943 (m), 1568 (m), 1488 (m), 1431 (m), 1334 (m), 1100 (m),
995 (m), 850 (m), 798 (m), 745 (m), 737 (m), 689 cmꢀ1 (m).
Reaction of fluoroiodomethane with (fluoromethyl)diphenyl
phosphine
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227–245; (b) A. Kanazawa, T. Ikeda and T. Endo, J. Appl.
Bacteriol., 1995, 78, 55–60.
Freshly prepared fluoromethyldiphenyl phosphine (0.41 g,
1.88 mmol) was dissolved in toluene (20.0 mL) and fluoroiodo-
methane (0.127 mL, 1.88 mmol) was added dropwise at
ambient temperature. The reaction mixture was stirred over
night. The 31P{1H} NMR spectrum showed no indication for the
formation of bis(fluoromethyl)diphenyl phosphonium iodide.
The reaction mixture was heated to reflux for 1 d. Again the
31P{1H} NMR spectrum showed no indication for the formation
of bis(fluoromethyl)diphenyl phosphonium iodide; instead in
addition to the starting phosphine 6 the formation of small
amounts of some unidentified phosphorus containing pro-
ducts (d31P = 45–22) was observed. Applying an analogous
procedure no reaction was observed also when using diethyl-
ether and acetonitrile as solvents.
8 M. Pohanka, Biomed. Pap., 2011, 155, 219–230.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
Financial support by Ludwig-Maximilian University is grateful
acknowledged. We are thankful to F-Select GmbH for a generous
donation of fluoroiodomethane. The authors thank Prof.
¨
Dr T. M. Klapotke, Ludwig-Maximilian University, for the generous
allocation of diffractometer time. Dr Peter Mayer is thanked, for the
help of solving the crystal structure of compound 1.
15 R.-X. Li, L. Zhou, P.-P. Shi, X. Zheng, J.-X. Gao, Q. Ye and
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14314 | New J. Chem., 2020, 44, 14306--14315
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NJC
25 G. M. Sheldrick, SHELXL-97: Program for the Refinement of 28 W. T. Pennington, J. Appl. Crystallogr., 1999, 32, 1028–
¨
Crystal Structures, University of Gottingen, Germany, 1997.
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