A R T I C L E S
McWhirter et al.
methylphosphonate. The crude product was purified by a short silica
column to afford a viscous oil (2.65 g, 94%).
phenyl methylphosphonic acid as a viscous oil (1.60 g, 94%). This
was then was converted (quantitatively) to the sodium salt by
shaking in 1 equiv of sodium methoxide in methanol.
Bis(p-nitro-m-fluorophenyl) Methylphosphonate: Pale yellow
solid, 40% yield. 1H NMR (250 MHz, CDCl3) δ/ppm 8.11 (m,
2H, Ar-H), 7.15-7.25 (m, 4H, Ar-H), 1.97 (d, J ) 17.70 Hz,
3H, CH3). 31P NMR (101 MHz, CDCl3) δ/ppm 26.24. MS (EI+)
374 (M+). HRMS calcd for C13H9F2N2O7P, 374.0115; found,
374.0103.
p-Nitro-m-fluorophenyl Methylphosphonate: Pale yellow solid.
1H NMR (250 MHz, D2O) δ/ppm 8.17 (m, 1H, Ar-H), 7.10-7.20
(m, 2H, Ar-H), 1.46 (d, J ) 16.79 Hz, 3H, CH3). 31P NMR (101
MHz, D2O) δ/ppm 25.96. TOF MS (ES+) 280 (M + Na+). HRMS
calcd for C7H6FNO5Na2P (M + Na+), 279.9763; found, 279.9756.
p-Nitrophenyl Methylphosphonate: Pale yellow solid. 1H NMR
(250 MHz, D2O) δ/ppm 8.21 (d, J ) 9.16 Hz, 2H, Ar-H), 7.28
(m, J ) 9.16 Hz, 2H, Ar-H), 1.46 (d, J ) 16.79 Hz, 3H, CH3).
13C NMR (63 MHz, D2O) δ/ppm 157.54, 143.46, 125.89 (2C),
121.29 (2C), 12.37 (d, J ) 139.23 Hz, CH3). 31P NMR (101 MHz,
D2O) δ/ppm 25.59. TOF MS (ES+) 262 (M + Na+). HRMS calcd
for C7H7NO5Na2P (M + Na+), 261.9857; found, 261.9853.
m-Nitrophenyl Methylphosphonate: White solid. 1H NMR
(250 MHz, D2O) δ/ppm 7.97-8.03 (m, 2H, Ar-H), 7.50-7.59
(m, 2H, Ar-H), 1.44 (d, J ) 16.78 Hz, 3H, CH3). 13C NMR (63
MHz, D2O) δ/ppm 152.16, 148.57, 130.57, 128.01, 119.24, 116.20,
12.10 (d, J ) 138.29 Hz, CH3). 31P NMR (101 MHz, D2O) δ/ppm
25.87. TOF MS (ES+) 262 (M + Na+). HRMS calcd for
C7H7NO5Na2P (M + Na+), 261.9857; found, 261.9870.
Bis(p-nitrophenyl) Methylphosphonate: Pale yellow solid, 93%
1
yield. H NMR (250 MHz, CDCl3) δ/ppm 8.23 (d, J ) 9.16 Hz,
4H, Ar-H), 7.36 (dd, J ) 9.15 and 1.22 Hz, 4H, Ar-H), 1.95 (d,
J ) 18.01 Hz, 3H, CH3). 13C NMR (63 MHz, CDCl3) δ/ppm 154.60
(d, J ) 8.58 Hz, 2C), 145.11 (2C), 125.87 (4C), 121.06 (d, J )
4.77 Hz, 4C), 12.12 (d, J ) 145.91 Hz, CH3). 31P NMR (101 MHz,
CDCl3) δ/ppm 25.52. MS (EI+) 338 (M+, 100%). HRMS calcd
for C13H11N2O7P, 338.0303; found, 338.0290.
Bis(m-nitrophenyl) Methylphosphonate: Colorless oil, 85%
yield. 1H NMR (250 MHz, CDCl3) δ/ppm 7.97-8.04 (m, 4H,
Ar-H), 7.44-7.56 (m, 4H, Ar-H), 1.90 (d, J ) 17.70 Hz, 3H,
CH3). 13C NMR (63 MHz, CDCl3) δ/ppm 150.22 (d, J ) 8.59 Hz,
2C), 149.00 (2C), 130.72 (2C), 126.80 (d, J ) 3.81 Hz, 2C), 120.53
(2C), 116.06 (d, J ) 4.76 Hz, 2C), 11.97 (d, J ) 144.96 Hz, CH3).
31P NMR (101 MHz, CDCl3) δ/ppm 26.20. MS (EI+) 338 (M+,
100%). HRMS calcd for C13H11N2O7P, 338.0303; found, 338.0289.
Bis(p-chlorophenyl) Methylphosphonate: White solid, 97%
yield. 1H NMR (250 MHz, CDCl3) δ/ppm 7.29 (dd, J ) 2.14 and
8.85 Hz, 4H, Ar-H), 7.11 (dd, J ) 1.22 and 8.85 Hz, 4H, Ar-H),
1.80 (d, J ) 17.70 Hz, 3H, CH3). 13C NMR (63 MHz, CDCl3)
δ/ppm 148.63 (d, J ) 8.59 Hz, 2C), 130.79 (2C), 129.89 (4C),
121.83 (d, J ) 4.77 Hz, 4C), 11.59 (d, J ) 144.96 Hz, CH3). 31P
NMR (101 MHz, CDCl3) δ/ppm 24.97. MS (EI+) 316 (M+, 100%).
HRMS calcd for C13H11Cl2O3P, 315.9822; found, 315.9834.
Bis(m-chlorophenyl) Methylphosphonate: Colorless oil, 85%
yield. 1H NMR (250 MHz, CDCl3) δ/ppm 7.15-7.28 (m, 6H,
Ar-H), 7.06-7.12 (m, 2H, Ar-H), 1.81 (d, J ) 17.70 Hz, 3H,
CH3). 13C NMR (63 MHz, CDCl3) δ/ppm 150.51 (d, J ) 7.63 Hz,
2C), 135.12 (2C), 130.61 (2C), 125.75 (2C), 121.13 (d, J ) 4.77
Hz, 2C), 118.82 (d, J ) 3.82 Hz, 2C), 11.66 (d, J ) 144.96 Hz,
CH3). 31P NMR (101 MHz, CDCl3) δ/ppm 24.83. MS (EI+) 316
(M+, 100%). HRMS calcd for C13H11Cl2O3P, 315.9822; found,
315.9837.
p-Chlorophenyl Methylphosphonate: White solid. 1H NMR
(250 MHz, D2O) δ/ppm 7.35 (d, J ) 8.85 Hz, 2H, Ar-H), 7.09
(m, J ) 8.85 Hz, 2H, Ar-H), 1.38 (d, J ) 16.48 Hz, 3H, CH3).
13C NMR (63 MHz, D2O) δ/ppm 150.25, 129.60 (2C), 128.86,
122.56 (2C), 12.00 (d, J ) 138.28 Hz, CH3). 31P NMR (101 MHz,
D2O) δ/ppm 25.49. TOF MS (ES+) 251 (M + Na+). HRMS calcd
for C7H7ClO3Na2P (M + Na+), 250.9617; found, 250.9626.
1
m-Chlorophenyl Methylphosphonate: White solid. H NMR
(250 MHz, D2O) δ/ppm 7.32 (m, 1H, Ar-H), 7.17-7.20 (m, 2H,
Ar-H), 7.05-7.09 (m, 1H, Ar-H), 1.39 (d, J ) 16.48 Hz, 3H,
CH3). 13C NMR (63 MHz, D2O) δ/ppm 152.23, 134.13, 130.75,
124.41, 121.42, 119.62, 12.05 (d, J ) 138.28 Hz, CH3). 31P NMR
(101 MHz, D2O) δ/ppm 25.54. TOF MS (ES+) 251 (M + Na+).
HRMS calcd for C7H7O3Na2PCl (M + Na+), 250.9617; found,
250.9613.
1
p-Methylphenyl Methylphosphonate: White solid. H NMR
(250 MHz, D2O) δ/ppm 7.19 (d, J ) 8.24 Hz, 2H, Ar-H), 7.02
(m, J ) 8.24 Hz, 2H, Ar-H), 2.28 (s, 3H, PhCH3), 1.36 (d, J )
16.48 Hz, 3H, CH3). 13C NMR (63 MHz, D2O) δ/ppm 149.22,
134.34, 130.18 (2C), 120.94 (2C), 19.85, 11.94 (d, J ) 138.29 Hz,
CH3). 31P NMR (101 MHz, D2O) δ/ppm 25.34. TOF MS (ES+)
231 (M + Na+), 209 (M + H+). HRMS calcd for C8H10O3NaP
(M + H+), 209.0344; found, 209.0334.
Bis(p-methylphenyl) Methylphosphonate: White solid, 99%
1
yield. H NMR (250 MHz, CDCl3) δ/ppm 7.11 (d, J ) 8.85 Hz,
4H, Ar-H), 7.06 (d, J ) 8.85 Hz, 4H, Ar-H), 2.30 (s, 6H, PhCH3),
1.74 (d, J ) 17.71 Hz, 3H, CH3). 13C NMR (63 MHz, CDCl3)
δ/ppm 148.12 (d, J ) 8.58 Hz, 2C), 134.76 (2C), 130.26 (4C),
120.24 (d, J ) 3.81 Hz, 4C), 20.72 (2CH3), 11.32 (d, J ) 144.01
Hz, CH3). 31P NMR (101 MHz, CDCl3) δ/ppm 24.40. MS (EI+)
276 (M+, 100%). HRMS calcd for C15H17O3P, 276.0915; found,
276.0911.
Phenyl Methylphosphonate: White solid. 1H NMR (250 MHz,
D2O) δ/ppm 7.38 (m, 2H, Ar-H), 7.14-7.22 (m, 3H, Ar-H), 1.40
(d, J ) 16.48 Hz, 3H, CH3). 13C NMR (63 MHz, D2O) δ/ppm
151.64, 129.88 (2C), 124.43, 121.19, 121.13, 12.1 (d, J ) 138.29
Hz, CH3). 31P NMR (101 MHz, D2O) δ/ppm 25.35. TOF MS (ES+)
217 (M + Na+), 195 (M + H+). HRMS calcd for C7H8O3Na2P
(M + Na+), 217.0006; found, 217.0009.
1
Bisphenyl Methylphosphonate: Colorless oil, 94% yield. H
NMR (250 MHz, CDCl3) δ/ppm 7.29-7.35 (m, 4H, Ar-H),
7.13-7.21 (m, 6H, Ar-H), 1.78 (d, J ) 17.70 Hz, 3H, CH3). 13
C
NMR (63 MHz, CDCl3) δ/ppm 150.28 (d, J ) 7.63 Hz, 2C), 129.86
(4C), 125.25 (2C), 120.55 (d, J ) 3.82 Hz, 4C), 11.54 (d, J )
144.96 Hz, CH3). 31P NMR (101 MHz, CDCl3) δ/ppm 24.29. MS
(EI+) 248 (M+). HRMS calcd for C13H13O3P, 248.0602; found,
248.0594.
Kinetic Methods. For the hydrolysis of the methyl arylphos-
phonates, the reactions were monitored by initial rate measurements
using UV-vis spectroscopy to measure the appearance of phenolate
in 0.1 M NaOH. For 4NPMP, first-order behavior in both substrate
and hydroxide was confirmed at 25 °C. For the less reactive
substrates, data were gathered at several temperatures between 90
and 40 °C and extrapolated to 25 °C using an Arrhenius plot. The
pKa of each phenol was measured at 25 °C by monitoring the change
in absorbance due to the phenolate with changing pH. For the PP1γ-
catalyzed reactions, reactions were initiated by addition of enzyme
to an equilibrated mixture of substrate at 25 °C (I ) 0.45M, NaCl;
100 mM AMPD buffer; 1 mM MnCl2). For the reactions involving
phenols with a 4-nitro substituent, reactions could be monitored
by the appearance of the product phenolate using UV-vis
spectroscopy (410 nm). For the other leaving groups, reactions were
monitored either by quenching aliquots in strong base and monitor-
Synthesis of Aryl Methylphosphonate Sodium Salts
(Scheme 1). Aryl methylphosphonates were prepared by the
following procedure exemplified by preparation of phenyl meth-
ylphosphonate. A mixture of diphenyl methylphosphonate (2.46 g,
10 mmol) in 44 mL of NaOH (0.3 M) was heated to reflux until
the oil layer of diphenyl methylphosphonate was no longer visible
(about 30 min). The solution was rapidly cooled, neutralized to
pH 7 with HCl, and extracted with dichloromethane to remove the
phenol. The aqueous phase was then strongly acidified by adding
HCl and extracted with dichloromethane. The dichloromethane layer
was dried over Na2SO4. Removal of the solvent yielded the crude
9
13680 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008