388
H.-Y. LIN ET AL.
of racemization and hydrolysis, where effects of ion-pair
formation between MTBD and water on the amine and
ion-pair concentrations were considered in deriving the
rate equations.
Chemical shifts in ppm from tetramethylsilane were as
follows: ꢂ1.61 (3H, t), 3.92 (3H, s), 3.95–4.00 (1H, q),
4.36–4.57 (2H, m), 7.12–7.17 (2H, q), 7.37–7.41 (1H, q),
7.67–7.73 (3H, m).
Racemization of (S)-naproxen 2,2,2-trifluoroethyl es-
ter. To 10 ml of anhydrous isooctane were added 1 mM
(S)-naproxen 2,2,2-trifluoroethyl ester and various bases
of different concentration with stirring at 45 ꢂC. Samples
were removed and injected into the above HPLC system
at different time intervals for analysis. From the time-
course variations of the enantiomeric excess for the ester
{i.e. eeS ¼ [(AS) ꢁ (AR)]/[(AS) þ (AR)] where (AS) and
(AR) are the concentrations of (S)- and (R)-naproxen
2,2,2-trifluoroethyl ester, respectively}, the first-order
interchange constant kint at each base concentration and
hence the second-order interchange constant kiꢀnt for the
base were estimated. Similar experiments with MTBD as
the base in anhydrous n-hexane and cyclohexane were
carried out.
EXPERIMENTAL
Materials. Optically pure (S)-naproxen [(S)-2-(6-methoxy-
2-naphthyl)propionic acid] was obtained from Sigma.
The strong neutral bases trioctylamine (TOA), 1,4-diaza-
bicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU), MTBD, tert-butyliminotris-
(dimethylamino)phosphorane (P1), tert-butyliminotris
(pyrrolidino)phosphorane (P1-tris) and 1-tert-butyl-4,
4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)pho-
sphoranylidenamino]-2ꢁ5,4ꢁ5-catenadi(phosphazene) (P4)
were purchased from Aldrich and Fluka. Other chemicals
of analytical grade were commercially available and
employed without further purification. Anhydrous isooc-
tane, cyclohexane and n-hexane were prepared by adding
molecular sieve (Type 3A, J. T. Baker) to the solvent for
more than 3 days.
Racemization and hydrolysis of (S)-naproxen 2,2,2-
trifluoroethyl ester. The racemization and hydrolysis of
1 mM (S)-naproxen 2,2,2-trifluoroethyl ester in isooctane,
n-hexane and cyclohexane containing different water
contents and MTBD were carried out. From the time-
course variations of (R)- and (S)-naproxen 2,2,2-trifluor-
oethyl ester concentrations and hence eeS, one could first
estimate the hydrolysis constant khy and kint, and then
the equilibrium constant Keq for the ion-pair formation
between MTBD and water and the kinetic constants for
hydrolysis.
Analysis. The racemization and hydrolysis of (S)-napro-
xen 2,2,2-trifluoroethyl ester in the organic solvent were
monitored by HPLC using a chiral column of (S,S)-
WHELK-01 from Regis capable of separating the internal
standard 2-nitrotoluene, (R)- and (S)-naproxen, (R)- and
(S)-ester with retention times of 4.5, 12.2, 21.5, 7.2 and
8.9 min, respectively. The mobile phase was a mixture of
n-hexane–propan-2-ol–acetic acid (80:20:0.5, v/v/v) at a
flow-rate of 1.0 ml minꢁ1. UV detection at 270 nm was
used for quantification at a column temperature of 25 ꢂC.
Synthesis of (S)-naproxen 2,2,2-trifluoroethyl ester.5 Fol-
lowing a standard procedure, the acid chloride of (S)-
naproxen was prepared by refluxing 20 ml of benzene
containing 3.45 g of the acid and 3.20 g of thionyl
chloride for 1.5 h. The resultant solution was evaporated
to dryness under vacuum, 30 ml of benzene containing
2.70 g of 2,2,2-trifluoroethanol and 1.19 g of pyridine
were added and the mixture was refluxed for 4 h. After
cooling the reaction solution, an aqueous solution (50 ml)
containing 6 mM sodium carbonate and deionized water
(100 ml) were successively employed four times and twice,
respectively, to extract the excess alcohol and remaining (S)-
naproxen. The organic layer was separated, dried over
magnesium sulfate, filtered and concentrated under vacuum.
After purification by silica gel chromatography with the
mobile phase n-hexane–ethyl acetate (2:1, v/v) and concen-
tration by vacuum, the desired (S )-naproxen 2,2,2-trifluor-
oethyl ester was obtained as a white powder and confirmed
by HPLC using authentic products from lipase-catalyzed
esterification of (R,S )-naproxen with 2,2,2-trifluoroethanol
in isooctane. 1H NMR spectra were also recorded at
400 MHz on a Bruker spectrometer in deuteriochloroform
solutions with tetramethylsilane as an internal standard.
RESULTS AND DISCUSSION
Racemization of (S)-naproxen ester in isooctane
The mechanism for the racemization of (S)-naproxen
2,2,2-trifluoroethyl ester involves ꢀ-proton abstraction
by the base to give a planar enolate. In most cases, the
ꢀ-proton abstraction is the rate-limiting step and the
mechanism can be expressed as follows:6
kint
(
kint
As
AR
ð1Þ
+
where AR and AS represent (R)- and (S)-naproxen 2,2,2-
trifluoroethyl ester, respectively. Therefore, the first-order
interconversion constant kint can be estimated from the
time-course data for eeS coupled with the theoretical
equation ln(eeS/eeS0) ¼ ꢁ 2tkint, where eeS0 and t are
the initial eeS and time, respectively.
Figure 1 demonstrates typical time-course variations of
ln(eeS/eeS0) at various DBU concentrations in isooctane
at 45 ꢂC, from which kint was determined and is presents
Copyright # 2004 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2004; 17: 387–392