Organometallics
Article
4
3JPC = 14.4 Hz, meta), 133.2 (d, JPC = 3.2 Hz, para). 31P NMR
(CDCl3, ppm): δ 22.3.
O-Alkyl S-Ethyl Phenylphosphonothioates (14−16). Com-
pounds 7, 9, and 10 were converted to the corresponding S-ethyl
phenylphosphonothioates by stirring 5.0 g (∼13 mmol) of the
dicyclohexylammonium salt in 100 mL of distilled toluene and 2.4 mL
(30 mmol) of iodoethane. The mixture was stirred for 3 days, and the
resulting suspension was filtered, washed with anhydrous hexanes, and
concentrated under reduced pressure. This oil was washed repeatedly
with anhydrous hexanes to remove the residual solid salt. The hexane
washes were concentrated down to the resulting oil (∼1.5 g, 6.3 mmol,
These phosphinates containing the P−H functionality were
converted to the dicyclohexylammonium salts of the corresponding
phosphonothioates (7−10) through a procedure described by Glazier
and co-workers for 8.6b This involved the addition of an equimolar
amount of sulfur to an ether (300 mL) solution of the phosphinate
(3−6) containing 1 equiv of dicyclohexylamine. The resulting solid
was collected by filtration, dried, and recrystallized with ethyl acetate.
A semi-microscale synthesis of the final phosphonothioates 11−16
was developed that began with the dicyclohexylammonium salt of the
phosphonothioate 8. The synthesis of O-ethyl S-methyl phenyl-
phosphonothioate (11) began with dissolving 0.50 g of 8 (1.3 mmol)
in 3.5 mL of methyl iodide (0.056 mol). This solution was stirred
constantly for 24 h, while being monitored by 31P NMR. Once the
formation of the final phosphonothioate (∼52 ppm) was confirmed,
the dicyclohexylammonium iodide salt was then filtered and purified
by several washes with HPLC-grade hexane. The hexane washes were
50% yield). Kugelrohr distillation was used if the hexane extractions
̈
did not remove impurities.
O-Methyl S-Ethyl Phenylphosphonothioate (14). 1H NMR
3
(CDCl3, ppm): δ 3.89 (d, JPH = 12.6 Hz, O−CH3, 3H), 2.77 (dq,
3
S−CH2−CH3, 2H), 1.28 (t, JHH = 7.1 Hz, S−CH2−CH3, 3H), 7.89
(t, ortho, 2H), 7.50 (m, meta, 2H), 7.58 (t, para, 1H). 13C NMR
(CDCl3, ppm): δ 53.2 (d, 2JPC3 = 7.1 Hz, O−CH3), 25.3 (d, 2JPC = 3.1
Hz, S−CH2−CH3), 15.4 (d, JPC = 5.7 Hz, S−CH2−CH3), 131.3 (d,
2JPC = 10.7 Hz, ortho), 129.4 (d. 3JPC = 14.9 Hz, meta), 134.1 (d, 4JPC
= 3.3 Hz, para), 132.3 (d, JPC = 150 Hz, ipso). 31P NMR (CDCl3,
ppm): δ 46.7. HRMS: calcd for C9H13O2SP 216.03739, found
216.03806.
concentrated using high-vacuum Kugelrohr distillation, giving a
̈
colorless oil (0.09 g, 0.42 mmol) with a 32% yield. Later syntheses
done without Kugelrohr distillation gave a 50% yield. 1H NMR
̈
O-Propyl S-Ethyl Phenylphosphonothioate (15). 1H NMR
(CDCl3, ppm): δ 4.16 (m, O−CH2−CH2CH3, 2H), 1.79 (m, O−
CH2−CH2−CH3, 2H), 1.01 (t, 3JHH = 8 Hz, O−CH2CH2−CH3, 3H),
(CDCl3, ppm): δ 4.31 (dq, O−CH2−CH3, 2H), 1.44 (t, O−CH2−
CH3, 3H), 2.20 (d, S−CH3, 3H), 7.89 (t, ortho, 2H), 7.52 (m, meta
2H), 7.59 (t, para 1H). 13C NMR (CDCl3, ppm): δ 62.61 (d, JPC
=
2
3
6.9 Hz, O−CH2−CH3), 12.38 (d, 3JPC = 3.3 Hz, O−CH2−CH3), 16.77
2.76 (m, S−CH2−CH3, 2H), 1.27 (t, JHH = 7.5 Hz, S−CH2−CH3,
3H), 7.89 (t, ortho, 2H), 7.49 (m, meta, 2H), 7.56 (t, para, 1H). 13C
(d, 2JPC = 6.9 Hz, S−CH3), 131.63 (d, 2JPC = 10.8 Hz, ortho), 128.8 (d,
2
3JPC = 14.5 Hz, meta), 133.0 (d, JPC = 3.2 Hz, para), 132.5 (d, JPC
=
4
NMR (CDCl3, ppm): δ 67.8 (d, JPC = 7.2 Hz, O−CH2−CH2CH3),
3
150.5 Hz, ipso). 31P NMR (CDCl3, ppm): δ 52.5. HRMS: calcd for
C9H13O2SP 216.03739, found 216.03835.
24.1 (d, JPC = 7.1 Hz, O−CH2−CH2−CH3), 10.5 (O−CH2CH2−
2
3
CH3), 131.5 (d, JPC = 10.9 Hz, ortho), 128.8 (d. JPC = 14.5 Hz,
meta), 132.7 (d, 4JPC = 3.1 Hz, para), 132.3 (d, JPC = 150 Hz, ipso). 31
P
O-Ethyl S-Propyl Phenylphosphonothioate (12). The dicyclo-
hexylammonium salt 8 (0.500 g, 1.3 mmol) was dissolved in 2 mL
(20.4 mmol) of 1-iodopropane and stirred for 1 day. An additional
0.25 mL (0.975 mmol) of 1-iodoproane was added to the solution
with continued stirring. The reaction was monitored with 31P NMR,
and once a single peak at around 52 ppm was obtained, the reaction
mixture could be purified. HPLC-grade hexane was added to the final
solution to precipitate out the dicyclohexylammonium iodide salt. The
clear hexane layer above was extracted, and further hexane washes
were done with the remaining dicyclohexylammonium iodide salt.
Combination of the hexane washes followed by drying in vacuo gave
NMR (CDCl3, ppm): δ 44.6. HRMS: calcd for C11H17O2SP
244.06869, found 244.06902.
O-Isopropyl S-Ethyl Phenylphosphonothioate (16). 1H NMR
(CDCl3, ppm): δ 4.93 (sept, O−CH−(CH3)2, 1H), 1.40 (d, O−CH−
(CH3)2, 6H), 2.75 (dq, S−CH2−CH3, 2H), 1.25 (t, S−CH2−CH3,
3H), 7.88 (t, ortho, 2H), 7.50 (m, meta, 2H), 7.54 (t, para, 1H). 13C
NMR (CDCl3, ppm): δ 71.9 (d, 2JPC = 7.0 Hz, O−CH−(CH3)2), 24.6
3
2
and 24.4 (dd, JHH = 6.3 Hz, O−CH−(CH3)2), 131.5 (d, JPC = 10.6
3
4
Hz, ortho), 128.8 (d. JPC = 14.9 Hz, meta), 132.6 (d, JPC = 3.1 Hz,
para), 132.3 (d, JPC = 150 Hz, ipso). 31P NMR (CDCl3, ppm): δ 43.3.
HRMS: calcd for C11H17O2SP 244.06869, found 244.06824.
Kinetics Experiment. The hydrolysis of phosphonothioates 1 and
11−16 with 2 was carried out in a pH 7 MOPS (300 mM in D2O)
buffer. The MOPS buffer was sparged with argon for 10 min. First, 30
mg (0.102 mmol) of 2 was transferred into an inlet reaction tube.
Outside the box, the degassed MOPS buffer (0.700 mL) was syringed
under argon flush into the reaction inlet tube containing 2. Compound
2 was allowed to dissolve in the D2O MOPS buffer for about 90−120
min to form a dark green solution. This solution was syringed into a
screw-cap NMR tube purged with argon for about 10 min. Finally, 2
μL (0.016 mmol) of the phenyl phosphonothioate was added using a
microliter syringe. This gave a 7:1 molar ratio of 2 to phenyl
phosphonothioate.
1
12 as a yellow oil (0.15 g, 0.64 mmol, 50% yield). H NMR (CDCl3,
ppm): δ 4.22 (dq, O−CH2−CH3, 2H), 1.41 (t, O−CH2−CH3, 3H),
2.72 (m, S−CH2−CH2−CH3, 4H), 0.93 (t, S−CH2−CH2−CH3, 3H),
7.89 (t, ortho, 2H), 7.51 (m, meta, 2H), 7.56 (t, para, 1H). 13C NMR
(CDCl3, ppm): δ 62.4 (d, 2JPC = 6.8 Hz, O−CH2−CH3), 16.7 (d, 3JPC
2
= 7.1 Hz, O−CH2−CH3), 32.7 (d, JPC = 3.0 Hz, S−CH2−CH2−
3
CH3), 24.4 (d, JPC =5.4 Hz, S−CH2−CH2−CH3), 14.5 (s, S−CH2−
CH2−CH3), 131.5 (d, 2JPC = 10.9 Hz, ortho), 128.8 (d, 3JPC = 14.6 Hz,
meta), 132.9 (d, 4JPC = 3.4 Hz, para). 31P NMR (CDCl3, ppm): δ 51.8.
HRMS: calcd for C11H17O2SP 244.06869, found 244.06822.
O-Ethyl S-isopropyl phenylphosphonothioate (13) was synthesized
in a similar manner with a slight variation. First 0.75 g of the 8 salt
(1.95 mmol) was stirred in 2 mL of 2-iodopropane (20.4 mmol). This
solution was stirred for approximately 2 days before an additional 1
mL of 2-iodopropane (10.2 mmol) was added. After the mixture was
stirred for another day, 31P NMR revealed the phosphonothioate
signal at ∼50 ppm; the dicyclohexylammonium salt was then gravity-
filtered and washed with HPLC-grade hexane followed by removal of
the solvent in vacuo. The iso-PEPP product 13 was formed (0.103 g,
0.422 mmol, 22%) as an orange oil. 1H (CDCl3, ppm): δ 4.22 (dq, O−
CH2−CH3, 2H), 1.39 (t, O−CH2−CH3, 3H), 3.38 (sep, S−CH−
(CH3)2, 1H), 1.28 and 1.41 (d, S−CH−(CH3)2, 6H), 7.9 (t, ortho,
2H), 7.50 (m, meta, 2H), 7.54 (t, para, 1H). 13C NMR (CDCl3, ppm):
NMR spectra were taken at 20 min time intervals over
approximately 13 h in order to examine the kinetics of the reaction.
31P NMR spectra were taken with 64 scans and a delay of 1 s between
each scan. The 31P NMR peaks of the starting phosphonothioate and
the product phosphonate were integrated for all spectra taken and
used to determine the rate of the reaction. It was found that rate
constants of the phosphonothioate hydrolysis reactions were
independent of the delay time (i.e., 5 s vs 15 s). Rate constants and
error bars shown in Figures 3−5 represent at least triplicate
independent runs.
2
3
δ 62.3 (d, JPC = 6.9 Hz, O−CH2−CH3), 16.7 (d, JPC = 7.0 Hz, O−
CH2−CH3), 37.8 (d, 2JPC = 2.5 Hz, S−CH−(CH3)2), 25.9 and 25.8 (d,
3JPC = 6.0 Hz, S−CH−(CH3)2), 131.4 (d, 2JPC = 11.8 Hz, ortho), 128.9
ASSOCIATED CONTENT
■
S
(d, JPC = 14.0 Hz, meta), 132.7 (d, JPC = 3.2 Hz, para). 31P NMR
(CDCl3, ppm): δ 50.7. HRMS: calcd for C11H17O2SP 244.06869,
found 244.06936.
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* Supporting Information
Figures giving details of the analyses. This material is available
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dx.doi.org/10.1021/om400382u | Organometallics 2013, 32, 4759−4765