Improved synthesis of 3-methoxy-4-hydroxymandelic acid by glyoxalic acid method

Article abstract of DOI:10.1016/j.tet.2013.07.031

The most important industrial process for the synthesis of vanillin is performed in two steps involving an condensation reaction of glyoxalic acid with guaiacol followed by an oxidative decarboxylation of the intermediary 3-methoxy-4-hydroxymandelic acid

Full text of DOI:10.1016/j.tet.2013.07.031

Tetrahedron 69 (2013) 8174e8177
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Improved synthesis of 3-methoxy-4-hydroxymandelic acid by
glyoxalic acid method
*
Dong-fang Niu, Hui-cheng Li, Xin-sheng Zhang
State Key Laboratory of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 May 2013
Received in revised form 4 July 2013
Accepted 11 July 2013
Available online 16 July 2013
The most important industrial process for the synthesis of vanillin is performed in two steps involving an
condensation reaction of glyoxalic acid with guaiacol followed by an oxidative decarboxylation of the
intermediary 3-methoxy-4-hydroxymandelic acid (MHPA) formed, thereby producing not only vanillin,
but also byproducts, which have to be eliminated. In the present study, we focused our efforts on the first
step of vanillin synthesis, namely, the condensation reaction governing the yield of vanillin. The factors
influencing the stability of glyoxalic acid were preliminarily evaluated to provide significant referential
value for suppressing the dismutation of glyoxalic acid in the condensation reaction, and the results
indicate that the stability of glyoxalic acid largely depends on the pH, temperature, and holding time of
the feed solution. Then the process of the condensation reaction was optimized under the factors af-
fecting the stability of glyoxalic acid, as well as the molar ratio of guaiacol to glyoxalic acid. Under the
optimized conditions, the maximum yield of the condensation reaction can reach to 88%.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Condensation reaction
Glyoxalic acid
Guaiacol
Vanillin
1. Introduction
The exceptionally wide application of vanillin in the food, cos-
metic, pharmaceutical, nutrition, and fine chemical industries makes
vanillin one of the most important aromatic compounds and justifies
the very large number of researches to improve its production pro-
cesses.1 Vanillin can be prepared by a few methods from different
starting materials, such as guaiacol,2 p-hydroxybenzaldehyde,3 cre-
sol,4 isoeugenol,5 or lignin,6 etc. Among those methods, the guaia-
coleglyoxalic acid route, which consists of two successive steps
involving a condensation reaction followed by an oxidation de-
carboxylation (Fig. 1), has become one of the most promising tech-
nology in vanillin synthesis due to its advantages in high efficiency,
short process, and simple equipments.
Currently, the primary drawback of the guaiacoleglyoxalic acid
route is the low yield of vanillin. This disadvantage has seriously
restricted the wider application of that method in industry. Due to
the lowyield of the condensation reaction compared with thatof the
following oxidation decarboxylation,7 how to improve the con-
densation reaction becomes a key for increasing the overall yield.
Generally, the condensation reaction between guaiacol and glyox-
alic acid according to reported procedures is carried out at room
temperature or even higher temperature, which not only contrib-
utes to the unsatisfied yield of MHPA (<80%, based on glyoxalic
Fig. 1. Synthesis of vanillin by the guaiacoleglyoxalic acid route.
acid), but also resulted in the poor product purity, as the product is
with dark color and requires further purification.8 It has been clear
that the condensation step also suffered from two side reactions.
One major issue is the tendency of glyoxalic acid to undergo Can-
nizzaro dismutation reaction, giving rise to glycolic acid and oxalic
acid (Fig. 2). Another problem encountered in the condensation
reaction is that the hydrogens on the ortho-position, or both the
ortho-position and para-position of guaiacol can be substituted by
glyoxalic acid to form 2-hydroxy-3-methoxylmandelic acid and 4-
hydroxyl-5-methoxyl-1,3-benzenediglycolic acid, respectively. Ob-
viously, there is still room and need to further optimize the first
condensation step in terms of yield and product purity.
Despite the numerous studies reported about this process, there
has been no systematic study undertaken concerning the conden-
sation reaction between guaiacol and glyoxalic acid. Attempting to
efficiently prevent the undesired reactions from occurring in the
* Corresponding author. Tel.: þ86 2164253528; fax: þ86 2164253528; e-mail
addresses: xszhang@ecust.edu.cn, xszhang2011@gmail.com (X.-sheng Zhang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.031

D.-fang Niu et al. / Tetrahedron 69 (2013) 8174e8177
8175
measured value of the glyoxalic acid concentration decreased sig-
nificantly when pH increased to 13, and that measured value was
18% lower than the corresponding theoretical value. From that
observation, a conclusion can be drawn: the stability of glyoxalic
acid strongly depends on the pH of the glyoxalic acid solution, and
the dismutation reaction of glyoxalic acid can readily take place in
the case of pH above 11.
1.00
Measured value
0.95
Theoretical value
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
Fig. 2. Possible pathways of the condensation reaction between guaiacol and glyoxalic
acid in alkaline solution.
2
4
6
8
10
12
14
pH
condensation reaction, we present here a systematic study of this
reaction from two aspects. First, the stability of glyoxalic acid in
alkaline solution was investigated with the aim at more effectively
avoiding the undesired dismutation reaction of glyoxalic acid;
second, the factors affecting the yield of MHPA were optimized one
by one in order to get a better understanding of how to control the
reaction selectivity.
Fig. 3. Loss of glyoxalic acid at different pH.
2.1.2. Effect of holding time on the stability of glyoxalic acid. The
glyoxalic acid solution prepared as described above was kept in
nitrogen atmosphere for different holding periods ranging from 1
to 24 h. All the study about holding time was conducted at room
temperature.
2. Results and discussion
As shown in Fig. 4, the glyoxalic acid concentration was kept
almost constant for the holding time of 24 h in the range of pH 3e9.
It can be observed that the glyoxalic acid concentration decreased
by 7% at pH 11 after 12 h, and then remained almost unchanged,
indicating that a small amount of glyoxalic acid had been converted
to glycolic acid and oxalic acid. Whereas the glyoxalic acid con-
centration declined by 14% at pH 12 after 24 h, and its descending
rate was two times as fast of that at pH 11. It should be pointed out
that almost 93% of glyoxalic acid initially presented in the solution
was consumed after 24 h at pH 13. The results show that the dis-
mutation reaction of glyoxalic acid can be effectively suppressed at
pHꢁ11 even if the holding time is up to 24 h. Otherwise, the
glyoxalic acid concentration will decrease sharply with increasing
the holding time at pH above 11.
2.1. Stability of glyoxalic acid
It may take several hours for the condensation reaction between
guaiacol and glyoxalic acid to complete. Thus, if either the pH, or
temperature of the reaction medium is not well controlled in the
process, the dismutation reaction of glyoxalic acid will be pro-
moted, which is not beneficial to improve the yield of MHPA.
Therefore, the stability of glyoxalic acid under different pH, tem-
perature, and holding time was studied to provide valuable guides
for better utilizing glyoxalic acid starting material in the conden-
sation reaction.
2.1.1. Effect of pH on the stability of glyoxalic acid. Industrial grade
glyoxalic acid of 20 g (37 wt %) was firstly diluted with water to the
concentration of 1.0 mol Lꢀ1 at room temperature, then 30% NaOH
was added in a dropwise fashion into the glyoxalic acid solution
under stirring to adjust the pH to 3, 5, 7, 9, 11, 13, respectively, the
volume of glyoxalic acid solution was recorded under the different
pH. In case that glyoxalic acid is too stable to undergo dismutation
reaction or other side reactions under different pH, the theoretical
values of the glyoxalic acid concentration can be calculated. Mean-
while, the corresponding measured values of the glyoxalic acid
concentration were determined by the sodium sulfite method.9
Fig. 3 showed that the measured value of the glyoxalic acid
concentration was nearly equal to its corresponding theoretical
value in the case of pH&5, indicating that the dismutation reaction
of glyoxalic acid did not happen in such conditions. It also indicated
that the measured concentration of glyoxalic acid was lower than
the corresponding theoretical value when the pH is higher than 5,
and the gap was getting bigger as the pH increased. When the pH of
the solution rose to 7 and 9, the measured value deviating from the
theoretical value was 4% and 7%, respectively. Furthermore, the
1.0
pH 3
pH 5
0.8
pH 7
pH 9
0.6
pH 11
pH 12
pH 13
0.4
0.2
0.0
0
5
10 15 20 25 30
t/(h)
Fig. 4. Concentration change of glyoxalic acid with holding time at different pH.

8176
D.-fang Niu et al. / Tetrahedron 69 (2013) 8174e8177
2.1.3. Effect of temperature on the stability of glyoxalic acid. Taking
into account that the condensation reaction between guaiacol and
glyoxalic acid was generally carried out at pH of 11e13, we selected
the solution with pH as 11 to study the temperature influence on
the stability of glyoxalic acid. The results were presented in Fig. 5.
13, respectively. The results here obtained show that the effect of
pH on the yield of MHPA is highly significant and that it is necessary
to maintain the pH at 11 so that the condensation reaction is op-
timized to obtain the maximum yield of MHPA.
90
80
70
60
50
40
30
20
10
o
0.80
10
25
40
50
C
o
C
C
C
0.75
0.70
0.65
0.60
0.55
0.50
o
o
9
10
11
12
13
0
5
10 15 20 25 30
pH
t/(h)
Fig. 6. The effect of pH on the yield of MHPA.
Fig. 5. Concentration change of glyoxalic acid with holding time at different temper-
atures at pH¼11.
2.2.2. Temperature. It should be remarked that the elevated tem-
perature will be undoubtedly helpful to speed up the condensation
reaction, but higher temperature will also accelerate the side re-
actions, decrease the utilization ratio of glyoxalic acid in the con-
densation reaction. The results obtained about the temperature
influence on the yield of MHPA were depicted in Fig. 7. The fol-
lowing condensation reaction was performed at the conditions of
pH 11 and 1.5 molar ratio of guaiacol to glyoxalic acid.
It can be observed that the glyoxalic acid concentration was
almost unaffected with the increasing holding time at 10 ꢂC. A 7%
decrease in the glyoxalic acid concentration was found at 25 ꢂC
after 24 h. When the temperature rose to 40 ꢂC, the glyoxalic acid
concentration decreased dramatically by 16% for the same period of
holding time. With the temperature further increasing to 50 ꢂC,
almost 34% of glyoxalic acid was consumed in the dismutation re-
action throughout the holding period. The results here obtained
suggest that temperature is shown to be a significant factor in the
undesired dismutation reaction of glyoxalic acid and that side re-
action can be effectively restrained in low temperature.
o
o
C
T = 5
C
89
88
87
86
85
84
83
T = 10
88
87
86
85
84
83
82
2.2. Condensation reaction
The results of previous experiments have proved that the sta-
bility of glyoxalic acid strongly depends on the pH of the feed so-
lution and the temperature. Additionally, it can be presumed that
reasonable control on the molar ratio of reactants is important to
restrain the undesired substitution reactions of guaiacol with
glyoxalic acid. Consequently, we focused our efforts on the impact
of pH, temperature, and molar ratio of the reactants to improve the
yield of the condensation reaction between guaiacol and glyoxalic
acid.
24 26 28 30 32 34 36
30
35
40
45
50
t/(h)
t/(h)
83
82
81
80
79
78
81
80
79
78
77
76
75
74
73
o
o
T = 20
C
T = 30
C
2.2.1. pH. It has been previously confirmed that pH of the feed
solution is imperative for restraining the dismutation reaction of
glyoxalic acid. Hence, the effect of pH on the yield of MHPA was
firstly studied at the conditions of the reaction temperature of
10 ꢂC, reaction time of 32 h, and molar ratio of guaiacol to glyoxalic
acid of 1.5. The results were shown in Fig. 6. It can be observed that
due to the negligible solubility of guaiacol in the reaction medium
at pH 9, the condensation reaction of guaiacol with glyoxalic acid
hardly occurred, leading to the MHPA yield of only 12%. Whereas
guaiacol could completely react with sodium hydroxide to generate
its water-soluble sodium salt at pH 11, obtaining a transparent so-
lution with light blue colour. The conversion of guaiacol to its
water-soluble sodium salt markedly promoted the condensation
reaction between guaiacol and glyoxalic acid, bringing the yield of
MHPA to the maximum value of 88%. Further increasing pH of the
reaction medium had little influence on the solubility of guaiacol,
but would accelerate the dismutation reaction of glyoxalic acid. As
a result, the yield of MHPA decreased to 83% and 51% at pH 12 and
20 21 22 23 24 25 26
12
14
16
18
20
t/(h)
t/(h)
o
77
76
75
74
73
72
71
T = 40
C
6
7
8
9
10
t/(h)
Fig. 7. The effect of temperature on the yield of MHPA.

D.-fang Niu et al. / Tetrahedron 69 (2013) 8174e8177
8177
It has been observed that when the temperature increased from 5
to 10 ꢂC, the completion time of the condensation reaction was
shortened by 11 h, but the yields of MHPA essentially remained the
same standing at 88% after the condensation reaction reached
equilibrium. That observation is in accordance with the previous
result that the dismutation reaction of glyoxalic acid can be effec-
tively inhibited at temperature below 10 ꢂC. Besides, it also showed
that when the temperature rose from 10 to 40 ꢂC, the completion
time of the condensation reaction was reduced from 32 to 8 h,
while the yield of the condensation reaction decreased from 88% to
77%. The lower yield at elevated temperature was attributed to the
aggravation of side reactions. The results indicate that the con-
densation reaction between guaiacol and glyoxalic acid is suitable
to perform at low temperature, even it means longer reaction time.
significant influence on the undesired dismutation reaction of
glyoxalic acid, and that side reaction can be effectively suppressed
within 24 h at the conditions of pHꢁ11 and temperature ꢁ25 ꢂC.
Based on the prevenient research, the condensation reaction be-
tween guaiacol and glyoxalic acid was performed under optimized
condition to afford MHPA with the maximum yield of 88%. This
study will bring valuable advantages to the industrial synthesis of
vanillin by the guaiacoleglyoxalic acid route.
4. Experimental section
4.1. General
The commercially available products were used without further
purification. The theoretical value of glyoxalic acid was calculated
without consideration of loss of glyoxalic acid at different pH. The
measured value of glyoxalic acid was determined by the sodium
sulfite method in consideration of loss of glyoxalic acid resulted
from dismutation reaction. The condensation reaction between
guaiacol and glyoxalic acid was carried out under atmospheric
pressure of nitrogen. Initially, guaiacol (0.15 mol) and water (230 g)
were added into a 500 ml four-neck bottom reactor, which was
fitted with an overhead stirrer. NaOH (30 wt %) was gradually added
under stirring to adjust the pH of the guaiacol solution to 11. The
reaction temperature was kept at 10 ꢂC by a water bath. The solu-
tion of sodium glyoxylate (0.1 mol) with pH 4e5 was subsequently
added dropwise into the guaiacol solution within 1 h under stirring.
The resulting mixture was stirred for another 1 h, and kept in
a resting state for 32 h to give MHPA in 88% yield. During the re-
action, samples were withdrawn and analyzed by HPLC at fixed
times. The unreacted guaiacol was recovered by extraction with
toluene after the pH of the condensation solution was adjusted to
4.5. 1H NMR spectral data of the product were compared to those of
authentic samples.
2.2.3. Molar ratio of guaiacol to glyoxalic acid. Attempting to re-
strain the undesired substitution reactions of guaiacol with glyox-
alic acid, we also studied the effect of the molar ratio of guaiacol to
glyoxalic acid on the yield of MHPA. Fig. 8 showed that the equi-
molar reaction of guaiacol with glyoxalic acid gave MHPA in 72%
yield. When the molar ratio of guaiacol to glyoxalic acid increased
to 1.2, the yield of MHPA rose rapidly to 80%. It was found that the
maximum yield of MHPA 88% could be achieved at a 1.5 molar ratio
of guaiacol and glyoxalic acid. With the molar ratio of guaiacol to
glyoxalic acid further increasing, it not only had no significant in-
fluence on the improvement of the product yield, but would also
increase the cost to recycle the unreacted guaiacol. The results re-
veal that guaiacol/glyoxalic acid molar ratio of 1.5 is adequate.
90
88
86
84
82
80
78
76
74
72
References and notes
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1.0 1.1 1.2 1.3 1.4 1.5 1.6
Molar ratio of guaiacol to glyoxalic acid
Fig. 8. The effect of molar ratio of guaiacol to glyoxalic acid on the yield of MHPA.
3. Conclusions
We reported for the first time a systematic study on the con-
densation reaction between guaiacol and glyoxalic acid from two
aspects. The study on the stability of glyoxalic acid reveals that the
three main parameters of pH, temperature, and holding time have
9. McFadden, B. A.; Howes, W. A. Anal. Biochem. 1960, 1, 240.