Influence of co-solvents in the highly efficient selective monohydrolysis of a symmetric diester

Article abstract of DOI:10.1016/j.tetlet.2007.09.152

The influence of the co-solvents in the selective monohydrolysis of a symmetric diester, in an aqueous NaOH medium at 0 °C, has been examined. The reactions were found to proceed through reaction media consisting of water with a small amount of a co-solvent and the starting symmetric diester. Slightly polar aprotic solvents that are slightly miscible with water, such as THF and acetonitrile, were found to be effective co-solvents.

Full text of DOI:10.1016/j.tetlet.2007.09.152

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Tetrahedron Letters 48 (2007) 8508–8510
Influence of co-solvents in the highly efficient selective
monohydrolysis of a symmetric diester
Satomi Niwayama,a,* Hezhen Wang,a Yoshikazu Hiragab and J. Cole Claytona
aDepartment of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
bDepartment of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
Received 14 September 2007; revised 24 September 2007; accepted 25 September 2007
Available online 29 September 2007
Abstract—The influence of the co-solvents in the selective monohydrolysis of a symmetric diester, in an aqueous NaOH medium at
0 ꢀC, has been examined. The reactions were found to proceed through reaction media consisting of water with a small amount of a
co-solvent and the starting symmetric diester. Slightly polar aprotic solvents that are slightly miscible with water, such as THF and
acetonitrile, were found to be effective co-solvents.
ꢁ 2007 Elsevier Ltd. All rights reserved.
Hydrolysis of an ester is one of the most commonly
applied reactions in organic chemistry. Historically,
one of the most widely used methods has been saponi-
fication with the use of base pellets such as NaOH or
KOH, and an alcohol, which is a water-miscible solvent.
This method has been generally useful for hydrolysis of
a single ester into a carboxylic acid on a large scale at
low cost.
CO R
2
co-solvent /
CO H
2
+
H O
3
aqueous NaOH
CO R
0 °C
2
CO R
2
R=Me or Et
Scheme 1. Selective monohydrolysis of symmetric diesters.
One of the most remarkable differences between this
monohydrolysis reaction and classical saponification is
the reaction media. The use of the aqueous NaOH or
KOH solution in the THF–water media at 0 ꢀC instead
of a solid base and an alcohol medium makes the
reaction mixture quite clean in all the cases we have tried
thus far, showing only spots of half-esters and dicarb-
oxylic acids, if they exist, on thin layer chromatography
plates after consumption of the starting diesters. There-
fore, we have studied the influence of solvents by chang-
ing the proportion of THF as well as the type of
co-solvent from THF to a variety of co-solvents. The
symmetric diester applied in this study is dimethyl
bicyclo[2.2.1]hept-2,5-diene-2,3-dicarboxylate, 1, which
afforded among the highest yields of the corresponding
half-ester (>99%), 2, with the highest selectivity as
reported earlier.2 Due to the high selectivity observed
for this diester, we reasoned that the role of the solvent
would become apparent.
By contrast, monohydrolysis of symmetric diesters with-
out the use of enzymes has been a more challenging task.
Limited examples have been reported for selective
saponification of symmetric diesters,1 but in most cases,
complex mixtures of the starting diesters, half-esters,
and diacids are formed even with the use of one equiva-
lent of the base, making separation and purification dif-
ficult. However, we previously reported highly efficient
selective monohydrolysis with the use of an aqueous
NaOH solution in the THF–water media at around
0 ꢀC (Scheme 1).2 This reaction enables selective
monohydrolysis of a series of symmetric diesters, yield-
ing the corresponding half-esters in high to quantitative
yields under these straightforward conditions. Because
half-esters are important building blocks, this reaction
is expected to have great synthetic versatility, and there-
fore we have been expanding the scope of this reaction
from various points of view.
*
Although some studies about effects of solvents in
hydrolysis of single esters have been reported,3 those
Corresponding author. Tel.: +1 806 742 3118; fax: +1 806 742
1289; e-mail: satomi.niwayama@ttu.edu
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.152

S. Niwayama et al. / Tetrahedron Letters 48 (2007) 8508–8510
8509
reporting such effects in hydrolysis of symmetric diesters
are limited to discussion of simple linear diesters4 or
symmetric diesters applying enzymes.5 Therefore it is
anticipated that our study will provide some practical
information about the role of the solvent and potentially
provide insight into the mechanisms of this selective
monohydrolysis.
optimal proportion of the THF as a co-solvent is
approximately the proportion reported previously.
Table 2 summarizes the results of changing a variety
of co-solvents under the same conditions of the 7% of
co-solvent and the reaction temperature.2 All the
co-solvents chosen here are easily volatile upon work-up.
Table 2. Effects of co-solvents in the monohydrolysis of 1
First, we changed the proportion of the THF as the
co-solvent, following the conditions we initially
reported.2,6 The total volume of the reaction mixture is
consistent with that in the previous study.2 The results
are summarized in Table 1. The yields are the best
isolated yields of half-ester 2 and recovered diester 1.
For the purpose of estimating the efficiency of the reac-
tions, the reaction rate constants were measured with
1) co-solvent (2 mL)-
water (20 mL)
2) 8 mL of 0.25 M
NaOH (1.7 eq)
0 °C, 1 h
3) H3O+
CO2CH3
CO2CH3
CO2H
CO2CH3
1
the reactions periodically monitored by H NMR.7
1 (1.2 mmol)
2
Co-solvent
Yielda (%)
Reaction rate constant
(L molÀ1 sÀ1
)
Table 1. Effect of volume of THF in the monohydrolysis of 1
THFb
>99 (0)
>99 (0)
90 (0.8)
86 (0)
88 (0.8)
9 (89)
4.70 0.02 · 10À2
4.85 0.40 · 10À2
3.73 0.50 · 10À2
3.48 0.06 · 10À2
3.29 0.02 · 10À2
8.60 0.27 · 10À4
4.59 0.07 · 10À2
1) THF-water
(total 22 mL)
CH3CN
Methanol
Ethanol
2-Propanol
CH2Cl2
None
2) 8 mL of 0.25 M
NaOH (1.7 eq)
0 °C
3) H3O+
CO2CH3
CO2CH3
CO2H
CO2CH3
>99 (0)
a Isolated yield of 2. Recovered 1 is shown in parenthesis.
b The same conditions reported in Ref. 2.
1 (1.2 mmol)
2
Volume (mL) Time
of THFa
Yieldb (%) Reaction rate constant
(L molÀ1 sÀ1
From these results, it is apparent that methylene
chloride showed a tremendous decrease in reaction rate,
but all other co-solvents or no co-solvent showed similar
reaction rates. More specifically, methylene chloride,
which has little miscibility with water, decreases the
reaction rate significantly due to the reduced exposure
of the carboalkoxy group to the aqueous NaOH. This
result is similar to the cases in which large percentages
of THF are applied as shown in Table 1. On the other
hand, other solvents that are water-miscible to a small
or large extent do not change the reaction rate
significantly. The isolated yields of half-ester 2 appear
to be the highest when THF, acetonitrile, or no
co-solvent is used, and slightly decrease when an alcohol
is used as a co-solvent. These results indicate that the
decreased yields may be due to the formation of the
small amount of the corresponding diacid, and/or to
the difficulty of extracting the product. Overall, THF
or acetonitrile appears to be the best co-solvent among
the solvents tested in this study for this selective
monohydrolysis reaction.
)
22 (73%)
18 (60%)
14 (47%)
10 (33%)
6 (20%)
2 (7%)c
1 (3%)
8 h
88 (0)
81 (1.2)
84 (0.4)
90 (1.6)
94 (1.2)
>99 (0)
>99 (0)
>99 (0)
3.26 0.02 · 10À3
6.06 0.12 · 10À3
1.10 0.02 · 10À2
2.06 0.23 · 10À2
2.56 0.06 · 10À2
4.70 0.02 · 10À2
4.81 0.10 · 10À2
4.59 0.07 · 10À2
6 h, 30 min
5 h, 20 min
3 h
70 min
70 min
70 min
70 min
0 (0%)
a Percentage of THF (v/v) is shown in parenthesis.
b Isolated yield of 2. Recovered 1 is shown in parenthesis.
c The same conditions reported in Ref. 2.
These results clearly indicate that decreasing the
proportion of THF to below 7% does not influence the
reaction rates significantly, but increasing the
proportion of THF diminishes the rates tremendously.
This tendency perhaps reflects the solubility of THF in
water under these conditions. The increased proportion
of THF is anticipated to decrease the exposure of the
carbomethoxy group to the aqueous NaOH. The yields
of the monohydrolysis reaction also decrease to some
extent as the proportion of THF increases, although
the yields remain extremely high even when no THF is
used. These reduced yields may be attributed to the
small amount of the corresponding diacid formed due
to the prolonged reaction time and remained in the
aqueous layer, or may be attributed to the difficulty of
extracting the half-ester. When the initial proportion
of THF is increased to 20% or greater, we often
observed formation of hydrates in the reaction mixture,
which constrained stirring and complicated the extrac-
tion of the product.8 Therefore, it appears that the
The small differences in the reaction rates observed in
the kinetic data may be explained by similar tendencies
reported earlier by the enhancement of hydrolysis with
the use of DMSO over ethanol, as DMSO is also an
aprotic solvent.3c Namely, DMSO effectively solvates
the transition state of hydrolysis of an ester and poorly
solvates the hydroxide ion, and hence activates the
hydroxide ion. As THF and acetonitrile are aprotic
solvents, the slightly enhanced reaction rates with these
solvents compared to those with water or alcohols,
protic solvents, may be attributed to such cumulative
effects.

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S. Niwayama et al. / Tetrahedron Letters 48 (2007) 8508–8510
24, 109–110; (c) Strube, R. E. Org. Synth. 1963, Col. Vol.
IV, 417–419; (d) Hutchinson, C. R.; Nakane, M.; Gollman,
H.; Knutson, P. L. Org. Synth. 1990, Col. Vol. VII, 323–
326; (e) Robertson, A.; Sandrock, W. F. J. Chem. Soc.
1933, 1617–1618; (f) Grakauskas, V.; Guest, A. M. J. Org.
Chem. 1978, 43, 3485–3488.
Therefore, we conclude that in the reaction mixture, the
small amount of THF or acetonitrile is dissolved in a
larger amount of water, making one aqueous phase,
and that the diester participates in the reaction as the
second phase, and the monohydrolysis occurs at the
interface between the aqueous phase and the diester.
The major role of THF or acetonitrile as a co-solvent
is likely that of dispersing the starting diesters more
smoothly to the reaction medium. This role is
particularly advantageous when the starting diester is a
solid as in many examples previously reported,2 while
the conditions free from an organic solvent are also
anticipated to offer another practical advantage as a
green reaction, especially on a large scale.
2. Niwayama, S. J. Org. Chem. 2000, 65, 5834–5836.
3. For example, (a) Balakrishnan, M.; Venkoba Rao, G.;
Venkatasubramanian, N. J. Chem. Soc., Perkin Trans. 2
1974, 10, 1093–1096; (b) Haberfield, P.; Friedman, J.;
Pinkston, M. F. J. Am. Chem. Soc. 1972, 94, 71–75; (c)
Roberts, D. D. J. Org. Chem. 1966, 31, 4037–4041; (d)
Frasson, C. M. L.; Brandao, T. A. S.; Zucco, C.; Nome, F.
J. Phys. Org. Chem. 2006, 19, 143–147.
4. For example, (a) Venkatasubramanian, N.; Venkoba Rao,
G. Tetrahedron Lett. 1967, 52, 5275–5280; (b) Watanabe,
K.; Takahashi, T.; Shinagawa, N. Nippon Kagaku Kaishi
1973, 10, 1831–1834; (c) Anantakrishnan, S. V.; Padha-
krishnamurti, P. S. Proc. Ind. Acad. Sci. 1962, 56, 249–
257.
5. For example, (a) Guanti, G.; Banfi, L.; Narisano, E.; Riva,
R.; Thea, S. Tetrahedron Lett. 1986, 27, 4639–4642; (b)
Terradas, F.; Teston-Henry, M.; Fitzpatrick, P. A.; Kilba-
nov, A. M. J. Am. Chem. Soc. 1993, 115, 390–396; (c)
Hirose, Y.; Kariya, K.; Sasaki, I.; Kurono, Y.; Ebiike, H.;
Achiwa, K. Tetrahedron Lett. 1992, 33, 7157–7160; (d)
Bjoerkling, F.; Boutelje, J.; Hjalmarsson, M.; Hult, K.;
Norin, T. J. Chem. Soc., Chem. Commun. 1987, 1041–
1042.
6. Standard conditions are as follows: The starting symmetric
diester (1.2 mmol) was dissolved in 2 mL of a co-solvent
and was diluted with 20 mL of water prior to the addition
of 8 mL of the aqueous NaOH (0.25 M) solution at 0 ꢀC.
The reaction mixture was acidified with 1 M HCl, saturated
with NaCl, extracted with ethyl acetate three or four times,
and dried with sodium sulfate.
7. The kinetic data were obtained from 12.5 mg (0.06 mmol)
of diester 1 delivered to each test tube, as well as water, a
co-solvent, and 0.25 M aqueous NaOH solution added
proportionally at 0 ꢀC in an ice-water bath in a cold
room. The reaction mixture was periodically quenched
with HCl and extracted with ethyl acetate, and the ethyl
acetate extract was concentrated under a vacuum for 1H
NMR analysis. The reaction rates were calculated from the
rate equation for second order kinetics, ln{b(a À x)/a/
(b À x)} = (a À b)kt, where a and b represent the initial
concentrations of the diester and NaOH, respectively,
and k, t, and x represent the reaction rate constant
(L molÀ1 sÀ1), time (s), and the concentration of the
consumed diester (M). All kinetic studies were repeated at
least twice and confirmed to be reproducible.
8. THF–water mixtures are known to form hydrates at a low
temperature. For example, (a) Iida, T.; Mori, H.;
Mochizuki, T.; Mori, Y. H. Chem. Eng. Sci. 2001, 56,
4747–4758; (b) Makino, T.; Sugahara, T.; Ohgaki, K. J.
Chem. Eng. Data 2005, 50, 2058–2060; (c) Dyadin, Y. A.;
Kuznetsov, P. N.; Yakovelev, I. I.; Pyrinova, A. V. Doklady
Akademii Nauk SSSR 1973, 208, 103–106; (d) Gao, S.;
Chapman, W. G.; House, W. Ind. Eng. Chem. Res. 2005,
44, 7373–7379.
From a technical point of view, alcohols are miscible in
water, and therefore extraction efficiency of the
half-ester is expected to decrease due to the hydrophilic
nature of the carboxyl group and the co-solvent. It
should also be noted that when these alcohols were used
as a co-solvent, turbidity was observed before the
addition of the aqueous NaOH solution, and the reac-
tion mixture thickened to some extent, but when THF
or acetonitrile was used, the diesters existed as separate
oil droplets, moving smoothly in the aqueous phase.
Upon acidifying, precipitation of the half-ester from
the reaction mixture was also most effective when
THF or acetonitrile instead of an alcohol was used,
perhaps due to the relatively non-polar aprotic nature
and reduced solubility of these solvents in water.
In summary, we found that this highly efficient selective
monohydrolysis of symmetric diesters is most effective
when a small amount of an aprotic solvent with a small
degree of miscibility with water was applied as a
co-solvent at a low temperature (ꢀ0 ꢀC). The reaction
appears to occur at the interface between the symmetric
diester and the aqueous phase that may contain the
co-solvent. Such solvent effects may play an important
role in the higher selectivity in our monohydrolysis
reaction over that of classical saponification.
Recently, water-mediated reactions have become
important as environmentally friendly reactions in green
chemistry. To our knowledge, the reaction described
here is among the first examples of water-mediated
reactions being applied to desymmetrization.9 We are
investigating further mechanistic studies such as steric
effects of the starting symmetric diester and other
physicochemical behavior of the reaction intermediates,
and the results will be reported in due course.
Acknowledgments
This work is supported by the National Science
Foundation-CAREER (CHE-0443265). We also thank
Texas Tech University for financial support.
9. Other examples of water-mediated desymmetrization can
be found in the following references: (a) Chong, J. M.;
Heuft, M. A.; Rabbat, P. J. Org. Chem. 2000, 65, 5837–
5838; (b) Rubinstein, I.; Kjaer, K.; Weissbuch, I.; Lahav,
M. Chem. Commun. 2005, 5432–5434; (c) Luo, Z.-B.; Hou,
X.-L.; Dai, L.-X. Tetrahedron: Asymmetry 2007, 18, 443–
446; (d) Ogawa, C.; Wang, N.; Boudou, M.; Azoulay, S.;
Manabe, K.; Kobayashi, S. Heterocycles 2007, 72, 589–
598.
References and notes
1. For example, (a) Corey, E. J. J. Am. Chem. Soc. 1952, 74,
5897–5905; (b) Vecchi, A.; Melone, G. J. Org. Chem. 1959,