Mild and versatile potassium fluoride/tetrabutylammonium fluoride protocol for ester hydrolysis

Article abstract of DOI:10.14233/ajchem.2018.20937

A mild and versatile protocol of potassium fluoride/tetrabutylammonium fluoride (KF/TBAF) in aqueous tetrahydrofuran for ester hydrolysis has been developed. The method is applied on variety of aliphatic and aromatic ester moieties bearing acid or base sensitive functional groups. The conditions have been also applied on acetates to yield alcohols. The chirality of optically pure esters remained intact with the conditions of the reaction.

Full text of DOI:10.14233/ajchem.2018.20937

Asian Journal of Chemistry; Vol. 30, No. 2 (2018), 309-311
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2018.20937
Mild and Versatile Potassium Fluoride/Tetrabutylammonium
Fluoride Protocol for Ester Hydrolysis
*
D. VIJAYALAKSHMI, K. BALAKRISHNA and SHAIK MUSTAFA
Department of Chemistry, GITAM Deemed to be University, Hyderabad Campus, Rudaram, Sangareddy-502 329, India
*
Corresponding author: E-mail: mustaff_02@yahoo.co.in
Received: 22 July 2017; Accepted: 31 October 2017;
Published online: 31 December 2017;
AJC-18697
A mild and versatile protocol of potassium fluoride/tetrabutylammonium fluoride (KF/TBAF) in aqueous tetrahydrofuran for ester hydrolysis
has been developed. The method is applied on variety of aliphatic and aromatic ester moieties bearing acid or base sensitive functional
groups. The conditions have been also applied on acetates to yield alcohols. The chirality of optically pure esters remained intact with the
conditions of the reaction.
Keywords: Carboxylic acids, Esters, Hydrolysis, Potassium fluoride, Tetrabutylammonium bromide.
INTRODUCTION
EXPERIMENTAL
The functional group transformations play an important
Benzothiazolinone was purchased from Sigma-Aldrich.
The solvents used in the synthesis were distilled before use.
All other chemicals were of AR grade and were used without
further purification. All melting points were obtained on Elico
instrument, India (model MP96) and are uncorrected. NMR
spectra were recorded on Bruker Top Spin Instrument. IR
spectra were recorded using BrukerAlpha T OPUS instrument
Synthetic procedure for compound 4: To a solution of
compound 3 (227 mg, 1 mmol) in DMF (5 mL) was added
role to change the properties of the organic compounds and to
utilize them for various applications from medical to material
world. In the way, the success of the transformation is achieved
when the other sensitive functional groups present in the subs-
trates are unaffected. The hydrolysis of ester is an important
conversion, which leads to variety of carboxylic acid derivatives.
The carboxylic acid functional groups are found in many
bioactive natural and synthetic organic compounds.Generally
this conversion is being accomplished either by acidic [1] or
alkaline [2] reagents and the reaction mechanism is well studied
theoretically [3,4]. The drawback of these reaction conditions
are seen when the substrates are holding other sensitive func-
tional groups. In this view, various methods were developed
for the ester hydrolysis viz., solid acids (e.g. zirconium phos-
phate), acidic ion-exchange resins (e.g. amberlite and zeolite)
and even lipid-coated lipases [5]. Ishihara et al. [6] reported
micelle-type N,N-diarylammonium pyrosulfate catalyst for the
hydrolysis of various esters. But the reagents used by them
are not easily available and expensive chemicals are needed
for the preparation of the same.
2 3
K CO (276 mg, 2.0 mmol) followed by ethyl bromo acetate
(167 mg, 1.1 mmol) and the resultant suspension was stirred
at room temperature for 16 h. The reaction mixture was diluted
with ethyl acetate (40 mL) and washed with water (3 × 30
2 4
mL). The organic layer was dried over Na SO and evaporated
under reduced pressure to afford a crude product which was
triturated with hexane to give a off white coloured solid (300
1
mg, 0.96 mmol); m.p. 49-53 °C; H NMR (CDCl
3
, 300 MHz):
δ (ppm) 7.29 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1
Hz, 1H), 4.66 (s, 2H), 4.24 (q, J = 7.2, 2H), 3.52 (t, J = 6.3,
1H), 3.39 (t, J = 6.3, 1H), 2.81 (t, J = 7.2 Hz, 2H), 2.22-2.01
13
3
(m, 2H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (CDCl , 75 MHz):
The hydrolysis conditions reported in this communication
are mild, high yielding and performed under neutral conditions
with commercially available reagents. Further, the chiral centres
of the optically pure esters are unaffected under the reaction
conditions.
δ (ppm): 167.1, 162.9, 136.5, 135.1, 126.9, 122.8, 122.6, 110.3,
62.2, 44.0, 43.6, 34.2, 32.3, 14.2; ESI-Ms (M+1) = 314.
General procedure for ester and acetate hydrolysis:
To a solution of ester or acetate (1 mmol) in THF (5 mL) was
added alkali metal fluoride (2 mmol) followed by quaternary

310 Vijayalakshmi et al.
Asian J. Chem.
ammonium salt (1 M in THF, 2 mL) and the resultant solution
was stirred for 7 h. The reaction mixture was diluted with ethyl
acetate (30 mL) and washed with water (2 × 20 mL) followed
by brine solution (20 mL). The organic layer was dried over
TABLE-1
HYDROLYSIS OF ESTERS AND ACETATES
USING KF/TBAF IN aq. THF
O
O
KF / TBAF
R1
OR2
THF, 70 o
R1
OH
R OH
2
C
MgSO
4
and concentrated under reduced pressure to get a crude
7
8
7
h
compound, which was triturated with hexane to get the corres-
ponding product in 60-95 % yield.
Yield
(%)
Entry
Ester
Carboxylic acid
1
Compound 6: Off white solid, m.p. 166-169 °C; H NMR
a
p-NO -PhCO Me
2
p-NO -PhCO H
2
93
95
2
2
(
CD
3
OD, 300 MHz): δ (ppm) 7.42 (s, 1H), 7.22 (d, J = 7.8 Hz,
H), 6.83 (d, J = 7.8 Hz, 1H), 4.69 (s, 2H), 3.54 (t, J = 6.3, 1H),
b
p-OMe-PhCO Me
2
p-OMe-PhCO H
2
1
2
7
1
S
O
N
S
O
N
13
3
.81 (t, J = 7.2 Hz, 2H), 2.12-2.02 (m, 2H); C NMR (CD OD,
c
81
84
5 MHz): δ (ppm): 172.2, 162.7, 136.6, 135.3, 126.5, 122.8,
22.3, 110.2, 45.9, 43.6, 32.1, 31.7; ESI-Ms (M+1) = 286.
O
O
EtO
HO
O
O
N
O
O
N
RESULTS AND DISCUSSION
d
The initial aim was to synthesize the fluoro compound 5
O
O
(
Scheme-I) and to utilize the further modified derivatives for
EtO
HO
PET studies [6]. The chloro compound 3 was synthesized using
a known procedure [7]. The same compound 3 was N-alkylated
with ethyl bromo acetate to form compound 4 which was confir-
e
f
PhCH
2
CO Me
2
PhCH CO
2
2
H
90
81
COOCH3
COOH
1
med by its H NMR spectrum which showed the corresponding
g
h
i
PhOCOMe
2-Naphthyl-OCOMe
(S)-PhCH(OH)COOMe
L-
PhOH
71
73
72
N–CH
corresponding ester peaks at δ 4.25 as a quartet for –CH
at δ 1.27 as a triplet for –CH protons. When the fluorination
2
peak at δ 4.6 ppm as a singlet for two protons and the
2-Naphthyl-OH
(S)-PhCH (OH)COOH
L-
2
and
3
j
70
PhCH(NHBOC)COOMe PhCH(NHBOC)COOH
reaction was performed on 4 using KF/TBAF in THF under
refluxing conditions a more polar spot was observed on TLC.
After completion of the reaction the compound was isolated
trans-2-Octenoic
trans-2-Octenoic acid
methylester
k
l
90
86
p-NO -PhCO Bn
2
p-NO -PhCO H
2 2
2
1
and H NMR spectrum of the same showed the absence of
O
O
ethyl signals for the ester group. The CH
ppm were not disappeared in the spectrum, which indicated
the presence of CH Cl functionality as such under the reaction
2
Cl peaks of 3 at 3.5
m
O
OH
88
76
O
O
2
EtO
O
HO
O
conditions. When the same reaction was performed for 15 h, a
mixture of chloro and fluoro acid compounds with 3 to 2 of
respective ratio was observed.
14
N
H
N
H
Ph = Phenyl, Reaction conditions: All the reactions were performed on
.5 mmol scale with 2 eq. potassium fluoride, 2 eq. of tetrabutyl-
ammonium fluoride, 2 eq. of H O in 0.2 M THF
0
The same conditions including 2 eq. of water were applied
on various aliphatic and aromatic ester moieties (Table-1) and
to the surprise the hydrolysis was observed in all the reactions
and the carboxylic acids were formed about 70-95 % yield.
Then the conditions were applied to de protect acetate group
of phenol and 2-naphthol. The reaction was yielded free
phenol and 2-naphthol in 62 and 64 % yield, respectively.
Further the conditions were applied on optically pure methyl-
2
shown optical rotation of [α]
of N-(tert-butoxycarbonyl)-L-phenylalanine was shown [α]
25°, (c = 2.0 in methanol). The esters (7a, 7b, 7e, 7f, 7g, 7h,
D
+140°,(c = 2.0 in water) and that
D
+
7
i, 7j, 7k and 7l) and the carboxylic acids (8a, 8b, 8e, 8f, 8g,
h, 8i, 8j, 8k and 8l) mentioned in the Table-1 are commercially
8
known compounds and are confirmed by matching with the
authentic compounds. The esters 7c, 7d, 7m, 7n, 7o and the
carboxylic acids 8c, 8d, 8m, 8n, 8o are reported in the literature
(
S)-mandelate of optical rotation [α]
and on N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester
of optical rotation [α] -4°,(c = 2 in methanol). The two optically
D
+144°,(c = 1 in methanol)
D
[8-16] and are confirmed by matching the analytical data with
the authentic compounds.
active esters afforded the corresponding carboxylic acids with
the chirality unaffected. The isolated (S)-mandelic acid was
S
N
O
Expected
O
S
F
S
Br
O
O
OEt
KF / TBAF
o
THF, 70 C
(5)
N
O
N
H
Cl
Cl
EtO
K CO / DMF
2
(3)
3
(4)
O
7
h
S
N
Formed
EtO
O
Cl
(
6)
O
HO
Scheme-I: Unexpected hydrolysis of ester derivative

Vol. 30, No. 2 (2018)
Mild and Versatile Potassium Fluoride/Tetrabutylammonium Fluoride Protocol for Ester Hydrolysis 311
Further the reaction was tried on p-nitromethyl benzoate
7a) in different solvents (Table-2) and the solvent THF was
found the best in terms of time and yield of the reaction. The
the reactivity and yields are found to be in the order of LiF >
NaF > KF > CsF and KF > CsF > NaF > LiF, respectively. The
mechanistic studies and the ester hydrolysis reactions with
alkaline earth metal halides and transition metal salts are in progress.
(
hydrolysis reaction was performed on p-nitromethyl benzoate
(7a) using other potassium halides under standardized conditions
Conclusion
(Table-3).After 7 h the reaction with KCl/TBAF and KBr/TBAF
A mild and versatile method for ester hydrolysis is
disclosed. Under the optimized conditions, diverse esters have
undergone the hydrolysis reactions to yield the corresponding
carboxylic acids. The KF/TBAF combination is found as a
best combination for ester hydrolysis reaction in terms of time,
mildness and yield of the reaction. LiF and NaF were compara-
tively more reactive but the yield of the product was less
compared to potassium fluoride. CsF needed prolonged times
for ester hydrolysis. The acetate functionalities have also been
undergone hydrolysis reaction to yield corresponding phenols.
Under the reaction conditions, the chirality of the optically
pure esters remain intact. The trial reactions with alkaline earth
metal fluorides and transition metal fluorides are ongoing.
was shown only 15-20 % conversion. The prolonged reaction
times upto 24 h did not increase more than a 5 % further
conversion. The reaction with KI/TBAF was still slow and showed
only 8-10 % conversion after 7 h. The reaction was performed
with TBAB, TBAI quaternary ammonium salts using potassium
fluoride as alkali metal salt in aq. THF. But the reactions showed
no formation of trace of corresponding carboxylic acids.
TABLE-2
HYDROLYSIS REACTION IN DIFFERENT SOLVENTS
CO Me
2
2
CO H
KF/TBAF
o
aq. Solvent, temp ( C)
7 h
NO2
NO2
ACKNOWLEDGEMENTS
Solvent
Benzene
MeCN
DCM
Temperature (°C)
Yield (%)
10
The authors are thankful to the financial assistances from
DST with project No.SB/FT/CS-034/2012 (SERB, New Delhi,
India) and UGC with project F.No.42-306/2013 (SR) (New
Delhi, India).
Reflux
80
25
40
20
DMF
100
100
70
Trace
Trace
No reaction
93
DMSO
EtOH
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