Ultrasonically-promoted synthesis of mandelic acid by phase transfer catalysis

in an ionic liquid
Qian Hua
a,
, Liu Dabin
a
, Lv Chunxu
b
a
Chemical Engineering School, Nanjing University of Science and Technology, Nanjing 210094, Peoples Republic of China
b
Jiangsu Pharmaceutical Intermediate Research Center, Nanjing 210094, Peoples Republic of China
a r t i c l e i n f o
Article history:
Received 21 July 2010
Received in revised form 13 October 2010
Accepted 23 December 2010
Available online 31 December 2010
Keywords:
Mandelic acid
Ultrasound
Phase transfer catalyst
Ionic liquid
Synthesis
a b s t r a c t
An efcient and facile process to synthesize mandelic acid through phase transfer catalysis (PTC; also
phase transfer catalyst) using ultrasound in an ionic liquid has been developed. Mandelic acid was syn-
thesized from benzaldehyde with chloroform in an 89.6% yield at 60 C for 2 h by using tetrabutyl ammo-
nium bromide (TBAB) as a phase transfer catalyst. Effects of different factors, such as frequency of
ultrasound, reaction temperature, kinds of PTC and solvents had been investigated to obtain the optimum
condition. It was observed that the ultrasonically promoted synthesis of mandelic acid by PTC in the ionic
liquid exhibited signicant enhancement in reaction yields under ambient conditions.
2010 Elsevier B.V. All rights reserved.
1. Introduction
Mandelic acid (MA) is an important starting material for the
resolution of (R)-mandelic acid and (S)-mandelic acid [13]. Their
derivatives have been widely employed for the manufacture of
semisynthetic penicillins or cephalosporins, and for the synthesis
of various other pharmaceuticals [4,5]. Many approaches for the
production of mandelic acid have been reported [69], and two
pathways have risen into prominence. One is based on the hydro-
cyanation of benzaldehyde in the presence of chloroform, which
gives rise to the corresponding cyanohydrin, followed by chemical
hydrolysis in the presence of strong acid (Scheme 1-A). This pro-
cess involves poisonous raw materials, generates copious quanti-
ties of salt and is not compatible with sensitive functional
groups, which is a serious drawback. The other pathway is feasible
by combining a chlorination of hypnone and a hydrolysis in alka-
line water (Scheme 1-B), but it also involves many disadvantages,
such as long reaction time, superuous solvent and low yield. Con-
sequently, the use of less toxic commercial reagents and new syn-
thetic methods are needed.
In recent years, ultrasound has been employed in various chem-
ical transformations with considerable enhancement in rate and
yield, and in several cases facilitates organic transformations at
ambient conditions which otherwise require drastic conditions of
temperature and pressure, or even unachievable reactions [10
14]. The driving energy is provided by cavitation, the formation
and collapse of bubbles, which liberates considerable energy in a
short period of time. The use of non-volatile solvents should pro-
vide a driving force to induce less volatile substrates to undergo
cavitational activation. The increasing use of non-aqueous room
temperature ionic liquids (IL) for synthetic purposes corresponds
to a new trend in organic chemistry. These liquids have no vapor
pressure, which should change considerably the characteristics of
cavitation in the bulk [1517]. For this reason, we have attempted
the combination of both ultrasound and IL to improve product
yields in a green chemical process.
To the best of our knowledge, the synthesis of mandelic acid by
the combination of phase transfer catalysis and ultrasonic irradia-
tion in IL has not yet been reported. A similar study combined PTC
and ultrasound without the presence of an IL, but, even with mod-
ulation of the ratio of the PTC, lowyields (81%) were produced [18].
In continuation of our research interest in the use of ultrasonic
irradiation, we present our studies toward the ultrasound-assisted
synthesis of mandelic acid catalyzed by a single phase transfer cat-
alyst in IL (Scheme 2).
2. Experiments
2.1. Chemicals and equipments
[BMIM]PF

6
, which was prepared by a reported method [19]
with a purity of more than 99.8% (tested by
1
H NMR), was directly
used in the ultrasonic nitration. Benzyltriethyl ammonium chloride
1350-4177/$ - see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.12.009

Corresponding author. Tel./fax: +86 025 84314929.

E-mail address: jyqianhua@yahoo.com.cn (Q. Hua).
Ultrasonics Sonochemistry 18 (2011) 10351037
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(BTEAC), tetramethyl ammonium chloride (TMAC), tetrabutyl
ammonium bromide (TBAB) and polyethylene glycol 500(PEG-
500) were of reagent grade and obtained from J&K Co. Ltd. All oth-
ers chemicals were also from commercial sources and of reagent
grade.
Melting points were uncorrected.
1
H NMR spectra was recorded
on Bruker DRX 300 instruments, using TMS as an internal standard
and CDCl
3
as the solvent. EI-MS was carried out with a Finnigan
TSQ Quantumm ultra AM GC/MS instrument. Sonication was per-
formed in a Hiton KGD-250B ultrasonic cleaner with a frequency
between 40 and 80 Hz with a rated input power of 120 W.
2.2. Synthesis of MA
10 ml (0.098 mol) benzaldehyde, 20 ml (0.249 mol) chloroform,
10 ml IL and 1 g PTC were placed in a three-neck 100 ml ask, and
stirred in a thermostated ultrasonic cleaning bath at 60 C under
nitrogen. Then 25 ml 50% aq. sodium hydroxide was added drop-
wise in 0.5 h under ultrasonic irradiation. After addition, the reac-
tion was continued at 60 C for 1.5 h under ultrasonic irradiation.
Then reaction mixture was quenched in 100 ml water, and the
aqueous layer and organic layer were separated. The IL was sepa-
rated from the organic layer by distillation under reduced pressure
and directly recycled for reuse. The aqueous layer was acidied to a
pH value of approximately one by using 50% aq. sulphuric acid, and
then extracted with the ethyl ether (20 ml 2). The combined ex-
tracts were distilled to remove ethyl ether under reduced pressure.
After recrystallization from toluene, pure crystalline MA was ob-
tained by ltration.
MA: m.p. 118119 C;
1
H NMR (300 MHz, CDCl
3
) d 9.02(1H, s),
7.327.64 (5H, m), 5.08 (1H, s), 2.39 (1H, s); EI-MS m/e151.9 (M
+
,
10).
3. Discussion
The effects of ultrasound, PTC, solvent and reaction temperature
were investigated as summarized in Table 1. The pronounced effect
of ultrasound can be easily demonstrated from the results shown
by the entries 23. In the absence of ultrasound, the reaction must
be performed for 8 h to produce a low yield of 42.4%. The addition
of ultrasound alone can effectively enhance the yield up to 72.9%
and reduce the reaction time to 2 h. One can observe that ultra-
sound with different frequencies leads to various results (entries
46). The yield increased at rst and then decreased with a varia-
tion of ultrasonic frequency from 40 to 80 kHz. The best yield
(89.6%) was obtained with sonication at 60 kHz.
The PTC is another important factor for the reaction. Without
PTC, the reaction time is long and the yield is only 26.3% (entry
1). When a PTC was added, ion exchange proceeded between the
PTC and sodium hydroxide in the aqueous phase and hydroxyl
was brought to organic phase, so that a series of reactions such
as <alpha> -elimination, carbonyl addition and hydrolysis were
carried out in the organic phase. This highly accelerates the reac-
tion rate and increases the yield. It can be seen from entry 4 and
1113 that the catalytic activity of TBAB is the best. The poor cat-
alytic results for PEG-500 are mainly due to its poor solubility in
oil.
As shown in entries 34, IL can effectively promote this reac-
tion. It has been observed that a solvent with a lower vapor pres-
sure in the bulk enhances the efciency of the use of ultrasound
in chemical reactivity [20]. Given that ionic liquids have low vapor
pressures, it is not surprising, then, that the use of ILs will facilitate
sonochemistry. From entries 4 and 910, it can be seen that there
was higher yield when a smaller amount of solvent was used. This
may be because of the fact that as the volume of the reaction mix-
ture increases, the power dissipated per unit volume i.e. power
density in the reaction mixture, decreases. This decreases the num-
ber of cavitational events per unit time per unit volume. From
these initial studies it was decided to use the minimum possible
amount of solvent (5 ml IL) for further reactions. Furthermore, IL
can be directly reused after simple partition. From entries 1213,
the yield is still above 80% even after the IL has been reused ve
times.
To improve the performance of the system further, the effect of
temperature on the yield of MA was studied. Here it can be ob-
served that there was much variation in the performance of the
system, as the yield of MA varied from 65.7% to 89.6%. Generally
speaking, higher temperatures accelerate the reaction rate and
produces higher yields. But in this reaction, chloroform is not only
CHO
OH
COOH
OH
CN
conc.HCl
reflux
HCN
CHCl
3
route A
route B
O
Cl
2
CHCl
2
NaOH
OH
COOH
=
O
CH
3
=
Scheme 1. Two approaches for the production of MA.
CHO
CHCl
3
50% aq. NaOH/
PTC (((
OH
COOH

Scheme 2. Process to synthesize MA through PTC using ultrasound in an IL.
Table 1
Ultrasonically-promoted synthesis of MA by phase transfer catalysis in an ionic liquid.
Entry PTC Frequency
(kHz)
Solvent Temperature
(C)
Yield
(%)
a
1 None None None 60 26.3
b
2 TBAB None None 60 42.4
b
3 TBAB 60 None 60 72.9
4 TBAB 60 5 ml IL 60 89.6
5 TBAB 40 5 ml IL 60 86.1
6 TBAB 80 5 ml IL 60 83.0
7 TBAB 60 5 ml IL 40 65.7
8 TBAB 60 10 ml
IL
80 72.4
9 TBAB 60 10 ml
IL
60 76.4
10 TBAB 60 20 ml
IL
60 61.8
11 BTEAC 60 5 ml IL 60 70.2
12 T MAC 60 5 ml IL 60 61.8
13 PEG-
500
60 5 ml IL 60 56.5
14 TBAB 60 5 ml IL 60 85.2
c
15 TBAB 60 5 ml IL 60 80.1
d
a
Yield is calculated from benzaldehyde.
b
The reaction is performed for 8 h.
c
IL is reused 2 times.
d
IL is reused 5 times.
1036 Q. Hua et al. / Ultrasonics Sonochemistry 18 (2011) 10351037
the reagent, but also the reux solvent. It is a volatile solvent with
a low boiling point and gradually decompose upon reaction with
oxygen. Under a higher temperature, its volatility and decomposi-
tion speed up, which reduces the product yield. Furthermore, benz-
aldehyde is also easily oxidized at high temperature. Because of
this, all the further experiments were carried out at 60 C.
4. Conclusion
A new process to synthesize MA in high yield by sonication in
the presence of a phase transfer catalyst under ambient condition
has been developed. This procedure not only enhances the yield
and shortens the reaction time, but also avoids the use of poison-
ous reagents, which is in accord with the demand of environmental
protection. Moreover, sonochemistry in IL as described in the pres-
ent work has opened up a new domain in the area of sonochemis-
try and liquid interface science, and can be conceptually envisaged
as a new tool in organic synthesis. Further work is in progress to
extrapolate these ndings to other organic transformations.
Acknowledgements
This work has been supported by National Basic Research Pro-
gram of China (6l3740l0l). We also would like to acknowledge
NUST Research Funding (No. 2010GJPY008, No. 2010ZYTS020) for
nancial assistance.
References
[1] P. Saravanan, V.K. Singh, Tetrahedron Lett. 39 (1998) 167.
[2] J.K. Whitesell, D. Reynolds, J. Org. Chem. 48 (1983) 3548.
[3] S.P. Zingg, E.M. Arnett, A.T. McPhail, A.A. Bothnerby, J. Am. Chem. Soc. 110
(1988) 1565.
[4] J. Mill, K.K. Schmiegel, W.N. Shaw, US Patent 4391826 (1983).
[5] Y. Yamazaki, H. Maeda, Agric. Biol. Chem. 50 (1986) 2621.
[6] G.M. Whitesides, M.A. Patterson, R.P. Szajewski, J. Org. Chem. 46 (1981) 4682.
[7] T. Mori, M. Furui, K. Nakamichi, E. Takahashi, US Patent 5441888 (1995).
[8] S.H. Lee, J.H. Choi, S.H. Park, J.I. Choi, S.Y. Lee, Enzyme Microb. Technol. 35
(2004) 429.
[9] H.R. Huang, J.H. Xu, Y. Xu, J. Pan, X. Liu, Tetrahedron 16 (2005) 2113.
[10] J.L. Luche, Ultrasonics 30 (3) (1992) 156.
[11] F. Ruo, Z. Yiyun, B. Ciguang, Ultrason. Sonochem. 4 (1997) 183.
[12] J.P. Mikkol, T. Salmi, Catal. Today 64 (2001) 271.
[13] G.V. Ambulgekar, B.M. Bhanage, S.D. Samant, Tetrahedron Lett. 46 (2005)
2483.
[14] A.K. Bose, B.K. Bamik, N. Lavlinsaia, M. Jayarman, M.S. Manhas, Chem. Tech. 27
(1997) 18.
[15] A.S. Larsen, J.D. Holbrey, F.S. Tham, C.A. Reed, J. Am. Chem. Soc. 122 (2000)
7264.
[16] E. Nicholas, Leadbeater, M.T. Hanna, J. Org. Chem. 67 (2002) 3145.
[17] P. Juliusz, C. Agnieszka, P. Ryszard, Ind. Eng. Chem. Res. 40 (2001) 2379.
[18] X. Hui, C. Yang, Ultrason. Sonochem. 15 (2008) 930.
[19] J. Fuller, R.T. Carlin, H. Long, D. Haworth, Chem. Commun. 12 (1994) 299.
[20] S.Z. Chen, Clean. Technol. 2 (2004) 7.
Q. Hua et al. / Ultrasonics Sonochemistry 18 (2011) 10351037 1037